NZ711932B2 - Mannose derivatives for treating bacterial infections - Google Patents

Abstract

The present invention relates to compounds useful for the treatment or prevention of bacteria infections. These compounds have formula (I) The invention also provides processes for making the compounds described herein. Furthermore, the present invention provides a composition comprising the compounds described herein, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The present invention also provides methods of treating or preventing bacteria infection in a subject, comprising administering to the subject an effective amount of the compound or the composition described herein. ds described herein, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The present invention also provides methods of treating or preventing bacteria infection in a subject, comprising administering to the subject an effective amount of the compound or the composition described herein.

Description

MANNOSE DERIVATIVES FOR TREATING BACTERIAL INFECTIONS CROSS REFERENCE TO RELATED APPLICATIONS This present invention claims the benefit, under 35 U.S.C. §ll9, of United States Provisional ation No. 61/777,398, filed March 12, 2013; the entire contents of which are incorporated herein by reference.

BACKGROUND OF THE INVENTION lnflammatory bowel disease (lBD‘) is a complex chronic inflammatory er, with the tt ,0 more common forms being ulcerative colitis (UC‘) and Crohn’s disease (CD). lBD is a actorial disease that results from a combination of predisposing genetic factors, envirornnental rs, dyshiosis of the gastrointestinal rnicrobiota and an opriate matory response (Man et al., 2011, Nat Rev Gastroenterol Hepatol, Mar, 8(3): 152—68).

Several studies on fecal and inucosa~associated bacterial communities have shown that the iota ofpatients with Crohn’s e (CD) difter tron} those of healthy controls, as well as those of patients with ulcerative colitis (UC), Although the reported changes are not always tent, numbers of Escherichia coir" are generally increased, whereas Firmz’cures are searcer in CD patients (Peterson et al., 2008, Cell Host Microbe, 3: 17-27; Frank et al., 2007, Proc. Natl. Acad. Sci., 104:13780—13785). Whether these changes are causative factors or consequences of mation, it s controversial. To date, several pathogens have been proposed as causative agents, in particular, adherent-invasive E. coil C) has been reported to be more prevalent in CD patients than in controls in several countries (United Kingdom, France and the USA) (Darfeuille-Michaud er al., 2004, enterology, 127:412-421; Martinez-Medina et al., 2009, Inflamm Bowel Dis., 15:872- 882). AIEC strains have been isolated from ileal lesions in ~350/Ei of CD patients compared to 69/6, of healthy subjects. One of the leatures ol’AlEC is their ability to adhere and invade epithelial cells. it is known from various models that the binding of adhesins e "pressed on the bacterial cell surface to defined glycosylated receptors on the host tissue surface is considered to he an initial and critical step in pathogenesis, then opening a new avenue for therapy such as blocking the ction be ween type l pill and CEACAMé, a known host receptor for Finill (Barnich et al., 2007, J. Clin. Invest., 117: 1566—1574; Carvalho et al., 2009, JEM, vol. 206, no. 10, 189). Therefore, inhibition of adhesion, and consequently intracellular replication of AIEC in epithelial cells, may prevent establishment of a sub-n'iucosal infection leading to mucosal inflammation and epithelial barrier disruption It has also been demonstrated recently that FimH antagonists are potentially effective in treating urinary tract infections (J. Med. Chem. 2010, 53, 8627-8641).

SUMMARY OF THE ION The present invention provides compounds useful for the treatment or prevention of bacteria infections, such as urinary tract infection (UTI) and inflammatory bowel diseases (IBD).

The compounds of the present invention are represented by the following structure of Formula Ia, or a pharmaceutically able salt thereof: wherein M, M2, Ring A, Ring A2, Z, JA, JB, m, r, t, and u are described herein.

In a particular aspect of the invention, there is provided a compound of Formula I I or a pharmaceutically acceptable salt thereof, n each M and M2 is independently or , wherein: Y1 is -O-, -O(C1-C4 aliphatic)-, oC1-C4 aliphatic)-, -S-, -S(C1-C4 aliphatic)-, -S(O)p-, -S(O)p(C1-C4 aliphatic)-, or -(C1-C6)aliphatic; Y2 is -O(C1-C4 aliphatic)-, oC1-C4 aliphatic)-, -S(C1-C4 tic)-, -SO2(C1-C4 aliphatic)-, or -(C1-C6) aliphatic; X1 is methyl or -U1-V1; X1 is ally substituted with 1-4 occurrences of halo; U1 is -(CH2)q- or -C(O)-; (followed by page 2a) V1 is a C1-C10 aliphatic wherein up to four methylene units can be optionally replaced with -O-, -NR2-, -S-, -C(O)-, -S(O)-, -S(O)2-, or P(O); X2 is H, C1-C10 aliphatic, -U2-V2, or -Q; U2 is -(CH2)q- or -C(O)-; V2 is a C1-C10 tic wherein up to four methylene units can be optionally replaced with -O-, -NR2-, -S-, -C(O)-, -S(O)-, -S(O)2-, or P(O); Q is a 3-8 membered saturated, partially unsaturated, or aromatic ring having 0-4 heteratoms selected from oxygen, nitrogen, or sulfur; wherein X2 is ally substituted with 1-4 ences of halo, CN, NO2, or C1-C10 aliphatic n up to three methylene units of the C1-C10 aliphatic can be optionally replaced with -NR-, -O-, -S-, -C(O)-, or -S(O)-, or –S(O)2-; each X3, X4, X5, and X6 is independently H or C1-3alkyl; provided that only one of X2, X3, X4, X5, and X6 is not H; Ring A is C3-C10 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, or 5-14 membered aryl; wherein the cyclyl or heteroaryl independently has 1-6 heteroatoms selected from oxygen, nitrogen, or sulfur; Ring A2 is optionally absent, C3-C10 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, or -14 membered aryl; Z is –CH=CH-, -C C-, or Ring B substituted by (JB)n; Ring B is C3-C10 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, or 5-14 membered heteroaryl; wherein said heterocyclyl or heteroaryl independently has 1-6 heteroatoms ed from oxygen, nitrogen, or sulfur; each JA, JA2 , and JB is independently halogen, CN, NO2, oxo, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, (C6-10 aryl)-(C1-C6alkyl)-, (5-10 membered heteroaryl)-(C1-C6alkyl)-, (C3-8 cycloalkyl)-(C1-C6alkyl)-, (3-8 membered heterocyclyl)-(C 1-C6alkyl)-, or a C1-C12 aliphatic; wherein up to four methylene units of the C1-C12 aliphatic or up to three methylene units of the lkyl can be optionally replaced with -NR, -O, -S-, -C(O)-, -S(O)-, -S(O)2-, or P(O); each JA, JA2 , and JB is independently and optionally substituted with 1-5 occurrences of halo, CN, NO2, or C1- C10 aliphatic wherein up to three methylene units of the C1-C10 aliphatic can be optionally replaced with -NR-, -O-, -S-, -C(O)-, or -S(O)-, or –S(O)2-; R and R2 are each independently H, C1-C6 aliphatic, or C3-6cycloalkyl; each m, n, and u is ndently 0, 1, 2, 3, or 4; each t and r is ndently 0 or 1; and (followed by page 2b) each p and q is independently 1 or 2.

The compounds of the invention have modified mannose moieties which have an cted increase in stability compared to compounds with unmodified mannose moieties.

The present invention also provides ses for making the compounds described herein. Furthermore, the present invention provides a composition comprising the compounds described herein, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The present ion also es methods of treating or preventing bacteria infection in a subject, comprising administering to the subject an effective amount of the compound or the composition bed herein.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds useful for the treatment or prevention of bacteria ions, such as urinary tract infection (UTI) and inflammatory bowel diseases (IBD).

In one embodiment, the nds of the present invention are represented by the following structure of Formula I: or a pharmaceutically acceptable salt thereof, n [FOLLOWED BY PAGE 3] each M and M2 is independently X4 OH X3 Y1\‘er Yif or M together with Ring A form a spiro—fused tricyclic ring as shown below: H OH wherein: Y1 is -O-, -O(C1-C4 aliphatic)-, -O(haloC1-C4 aliphatic)-, -S-, -S(C1-C4 aliphatic)-, -, —S(O)p(C1—C4 aliphatic)-, or -(C1-C6)aliphatic; Y2 is -O(C1-C4 aliphatic)-, -S(C1-C4 aliphatic)-, -SOZ(C1-C4 aliphatic)-, or 6) aliphatic; Y3 is -O-, -O(C1-C4 aliphatic)-, -O(haloC1-C4 aliphatic)-, -S-, -S(C1-C4 tic)-, -S(O)p-, —S(O)p(C1—C4 aliphatic)-, or -(C1-C6)aliphatic; each ZZ, Z3, Z4, and Z6 is independently OH or F; ed that at least one of ZZ, Z3, Z4, and Z6 is F; X1 is —U1—V1; X1 is optionally substituted with 1—4 occurrences of halo; U1 is -(CH2)q- or —C(O)—; V1 is a C1_C10 aliphatic wherein up to four ene units can be optionally replaced with —O—, —NR2—, —S—, —C(O)—, —S(O)—, —S(O)2—, or P(O); x2 is H, 01.010 aliphatic, —U2—V2, or —Q; U2 is q— or —C(O)—; V2 is a C1_C10 aliphatic wherein up to four methylene units can be optionally replaced with —O—, —NR2—, —S—, —C(O)—, —S(O)—, —S(O)2—, or P(O); Q is a 3—8 membered saturated, lly unsaturated, or aromatic ring having 0-4 heteratoms selected from oxygen, nitrogen, or sulfur; wherein X2 is optionally substituted with 1—4 occurrences of halo, CN, N02, or C1-C10aliphatic wherein up to three methylene units of the C1-C10aliphatic can be optionally replaced with —NR—, —O—, —S—, —C(O)—, or —S(O)—, or —; each X3, X4, X5, and X6 is independently H or kyl; ed that only one of X2, X3, X4, X5, and X6 is not H; Ring A is C3_C10 lkyl, 3—12 membered cyclyl, C640 aryl, or 5—14 membered heteroaryl; wherein the heterocyclyl or heteroaryl independently has 1-6 heteroatoms selected from oxygen, nitrogen, or sulfur; Ring A2 is optionally absent, C3_C10 cycloalkyl, 3—12 membered heterocyclyl, C640 aryl, or — l4 membered heteroaryl; Z is —CH=CH-, -CEC-, or Ring B; Ring B is C3_C10 cycloalkyl, 3—12 membered heterocyclyl, C640 aryl, or 5—14 membered heteroaryl; wherein said heterocyclyl or heterocyclyl independently has 1-6 heteroatoms selected from oxygen, nitrogen, or sulfur; each JA, JAZ, and JB is independently halogen, CN, N02, oxo, C3_g cycloalkyl, 3—8 membered heterocyclyl, C640 aryl, 5—10 ed heteroaryl, (€6-10 aryl)—(C1—C6alkyl)—, (5—10 membered heteroaryl)—(C1—C6alkyl)—, (C3_g cycloalkyl)—(C1—C6alkyl)—, (3—8 membered heterocyclyl)-(C1-C6alkyl)-, or a C1_C12 aliphatic; n up to four methylene units of the C1_C12 aliphatic or up to three methylene units of the C1-C6alkyl can be optionally replaced with —NR, —0, —S—, —C(O)—, —S(O)—, —S(O)2—, or P(O); each JA, JAZ, and JB is independently and optionally substituted with 1—5 occurrences of halo, CN, N02, or C1— Cloaliphatic wherein up to three methylene units of the C1-C10aliphatic can be optionally replaced with —NR—, —O—, —S—, —C(O)—, or —S(O)—, or —; R and R2 are each ndently H, C1-C6 aliphatic, or C3_6cycloalkyl; each m, n, and u is independently 0, l, 2, 3, or 4; each t and r is independently 0 or 1; and each p and q is independently l or 2.

In one embodiment, the compounds of the present invention are represented by the following ure of Formula Ia, or a pharmaceutically acceptable salt thereof: (JA)m (JB)n or a pharmaceutically acceptable salt thereof, wherein M is X4 OH r Y2 X3 H Yix \rr" or M and one occurrence of JA, together with Ring A, form a spiro—fused tricyclic ring optionally bonded to Ring B as shown in a D: Formula D Y1 is —O—, —O(C1—C4alkyl)—, —S—, —S(C1—C4alkyl)—, —S(O)p—, —S(O)p(C1—C4alkyl)—, or —(C1—C6)alkyl; Y2 is —O(C1—C4alkyl)—, —S(C1-C4alkyl)-, -SOZ(C1-C4alkyl)-, or -(C1-C6)alkyl; Y3 is —O—, —O(C1—C4alkyl)—, —S—, —S(C1—C4alkyl)—, —S(O)p—, —S(O)p(C1—C4alkyl)—, or —(C1—C6)alkyl; wherein the alkyl groups in Y1, Y2, and Y3 are each optionally and independently substituted with 1-4 halo; each ZZ, Z3, Z4, and Z6 is independently OH or F; provided that at least one of ZZ, Z3, Z4, and Z6 is F; each X3, X4, and X6 is H or C1_3alkyl; X1 is —U1—V1; X1 is optionally substituted with 1—4 occurrences of halo; U1 is —(CH2)q— or —C(O)—; V1 is a C1_C10 aliphatic wherein up to four methylene units can be ally replaced with —O—, —NR2—, —S—, —C(O)—, —S(O)—, —S(O)2—, or P(O); X2 is H or —U2—V2; X2 is optionally substituted with 1—4 occurrences of halo; U2 is —(CH2)q— or —C(O)—; V2 is a C1_C10 aliphatic wherein up to four methylene units can be ally replaced with —O—, —NR2—, —S—, —C(O)—, —S(O)—, —S(O)2—, or P(O); X5 is H or C1_3alkyl; provided that at least one of X2, X3, X4, X5, and X6 is not H; and when X2 is other than H, then X3, X4, and X6 are all H; Ring A is C3_Cg cycloalkyl, 3-8 membered heterocyclyl, C640 aryl, or 5—10 membered heteroaryl; Ring A is optionally bonded to Ring B; Ring B is absent or is C3_Cg cycloalkyl, 3-8 membered heterocyclyl, C6_10 aryl, (C640 aryl)— (C1—C6alkyl)—, or 5—10 membered heteroaryl; each JA and JB is independently halogen, CN, N02, C3_g cycloalkyl, 3—8 membered heterocyclyl, C640 aryl, 5—10 membered heteroaryl, (€6-10 aryl)—(C1—C6alkyl)—, (5—10 membered heteroaryl)—(C1-C6alkyl)-, or a C1_C12 tic wherein up to four methylene units of the C1_C12 aliphatic can be optionally replaced with —NR, —0, —S—, —C(O)—, —S(O)—, -SOz-, or 13(0); each JA and IE is ndently and optionally tuted with 1—5 occurrences of halo, CN, or N02; R and R2 are each independently H, C1-C6 aliphatic, or C3_6cycloalkyl; R1 is H or C1_3alkyl; each m, n, and q is independently 0, l, 2, 3, or 4; and each p and q is ndently l or 2.

It shall be understood that when a ring or a bond is drawn with a dotted line, this means that the ring or bond is optionally t. It shall also be understood that rings described as C3_C10 cycloalkyl, 3—12 membered heterocyclyl, C640 aryl, or 5—14 membered heteroaryl include monocyclic, bicyclic, and tricyclic rings. For example, a C3_C10 cycloalkyl includes ted or lly unsaturated monocyclic C3_gcycloalkyl and ted or partially unsaturated €8.12 cycloalkyl bicyclic rings. A 3—12 membered heterocyclyl includes monocyclic saturated or partially unsaturated 3-8 membered heterocyclyl rings haVing 1-4 heteroatoms selected from oxygen, en, or sulfur; bicyclic saturated or partially unsaturated 8-12 membered heterocyclyl rings having 1-6 heteroatoms selected from oxygen, nitrogen, or sulfur; and tricyclic saturated or partially unsaturated 10-14 membered heterocyclyl rings having 1-6 atoms selected from oxygen, nitrogen, or sulfur. A C640 aryl includes phenyl and naphthyl. A 5—14 membered heteroaryl includes a monocyclic 5—6 membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur; a bicyclic 8—10 membered heteroaryl having 1—6 heteroatoms selected from oxygen, nitrogen, or ; and a tricyclic 10-14 membered heteroaryl having 1-6 heteroatoms selected from oxygen, nitrogen, or sulfur. A yclic ring is considered aryl or heteroaryl if at least one ring is aromatic.

In some embodiments, Ring A2 is ; r and q are 0; t is l; and Z is Ring B as shown in Formula Ia: (JA)m (JB)n In some embodiments, the compound is not one of the following: In some embodiments, Ring A is €6.10 aryl or 5—10 membered heteroaryl. In some embodiments, Ring A is phenyl or naphthyl. In some ments, Ring A is phenyl. In some embodiments, Ring A is bonded to Ring B; and Ring B is C640 aryl or 5-10 membered heteroaryl. In some ments, Ring B is .

In some embodiments, Ring A is bonded to Ring B as represented in Formula II: M \ / \ ‘ / (JA)m (JB)n Formula II; wherein Ring M, JA, JB, m, and n are as defined herein.

In some embodiments, IA is halo, haloC1_4aliphatic, C1_4aliphatic, -O(C1_4aliphatic), and IE is N02, R)2, C(O)OR, or CONH—(CH2)2—O—(CH2)2—O—(CH2)2—NH2.

In some embodiments, Y1, Y2, and Y3 are -O-. In some embodiments, Y1, Y2, or Y3 is C1_6aliphatic, wherein the aliphatic groups in Y1, Y2, and Y3 are each optionally and independently substituted with 1-4 halo. In some embodiments, the In other embodiments, M is . In yet other embodiments, Y2 is O. In some embodiments, X1 is C1_3alkyl. In certain embodiments, X1 is methyl.

Another embodiment provides a compound of formula A: X40H x6 OH (mm (31% Formula A wherein Y1 is —O—, C4alkyl)—, —S—, —S(C1—C4alkyl)—, —S(O)p—, —SOp (C1—C4alkyl)—, or 6)aliphatic; X2 is H, 01.010 aliphatic, —U2—V2, or —U2—V2—Q; U2 is —(CH2)q— or —C(O)—; V2 is a C1_C10 aliphatic wherein up to four methylene units can be optionally replaced with —O—, —NR2—, —S—, —C(O)—, —S(O)—, —S(O)2—, or P(O); Q is a 3—8 membered saturated, partially unsaturated, or aromatic ring haVing 0-4 toms selected from oxygen, nitrogen, or sulfur; n X2 is optionally substituted with 1—4 ences of halo, CN, N02, or C1-C10aliphatic wherein up to three ene units of the C1-C10aliphatic can be optionally replaced with —NR—, —O—, —S—, —C(O)—, or —S(O)—, or —S(O)2—; R2 is H, C1-C6 aliphatic, or C3_6cycloalkyl; each X3, X4, and X6 is independently H or C1_3alkyl; X5 is H; provided that only one of X2, X3, X4, X5, and X6 is not H; Ring A is C3_C10 cycloalkyl, 3—12 membered heterocyclyl, C6_10 aryl, or 5—14 membered heteroaryl; wherein the heterocyclyl or heteroaryl independently has 1-6 heteroatoms selected from oxygen, nitrogen, or sulfur; Ring A is optionally bonded to Ring B; Ring B is absent, C3_C10 cycloalkyl, 3-12 membered heterocyclyl, C640 aryl, or 5-14 membered aryl; wherein said heterocyclyl or heterocyclyl independently has 1—6 heteroatoms selected from , nitrogen, or sulfur; each JA and JB is independently halogen, CN, N02, C3_g cycloalkyl, 3—8 membered heterocyclyl, C640 aryl, 5—10 membered heteroaryl, (€6-10 aryl)—(C1—C6alkyl)—, (5—10 membered heteroaryl)—(C1-C6alkyl)-, or a C1_C12 aliphatic wherein up to four methylene units of the C1_C10 tic can be optionally replaced with —NR, —O—, —S—, , —S(O)—, —soz—, or 13(0); each JA and IE is independently and optionally substituted with 1—5 occurrences of halo, CN, or N02; R is H, C1-C6 aliphatic, C3_6cycloalkyl, C(O)OH, C(O)O(C1_4alkyl), or C(O)(C1_4alkyl); each m and n is independently 0, l, 2, 3, or 4; and each p and q is independently l or 2.

In some embodiments, Y1 is —O—, —O(C1—C4alkyl)—, —S—, —S(C1—C4alkyl)—, —S(O)p—, —S(O)p(C1—C4alkyl)—, or 6)alkyl; X2 is H or —U2—V2; X2 is optionally tuted with 1—4 occurrences of halo; U2 is —(CH2)q— or —C(O)—; V2 is a C1_C10 aliphatic wherein up to four methylene units can be optionally replaced with —O—, —NR2—, —S—, —C(O)—, —S(O)—, —S(O)2—, or P(O); R2 is H, C1-C6 tic, or C3_6cycloalkyl; each X3, X4, and X6 is independently H or C1_3alkyl; X5 is H; ed that at least one of X2, X3, X4, X5, and X6 is not H; and when X2 is other than H, then X3, X4, and X6 are all H; Ring A is C3_Cg cycloalkyl, 3-8 membered heterocyclyl, C640 aryl, or 5—10 ed heteroaryl; wherein the heterocyclyl or heteroaryl independently has 1-6 heteroatoms selected from oxygen, nitrogen, or sulfur; Ring A is optionally bonded to Ring B; Ring B is C3_Cg cycloalkyl, 3-8 membered heterocyclyl, C640 aryl, (C6_10 aryl)-(C1-C6alkyl)-, or 5— 10 membered heteroaryl; wherein said heterocyclyl or heterocyclyl ndently has 1-6 heteroatoms selected from oxygen, en, or sulfur; each IA and IE is ndently halogen, CN, N02, C3_g cycloalkyl, 3—8 membered heterocyclyl, C640 aryl, 5—10 membered heteroaryl, (€6-10 aryl)—(C1—C6alkyl)—, (5—10 membered heteroaryl)—(C1-C6alkyl)-, or a C1_C12 aliphatic wherein up to four methylene units of the C1_C10 aliphatic can be optionally replaced with —NR, —O—, —S—, —C(O)—, —S(O)—, —soz—, or 13(0), each JA and IE is independently and optionally substituted with 1—5 occurrences of halo, CN, or N02; R is H, C1-C6 aliphatic, C3_6cycloalkyl, C(O)OH, C(O)O(C1_4alkyl), or C(O)(C1_4alkyl); each m, n, and q is independently 0, l, 2, 3, or 4; each p and q is independently l or 2.

According to another embodiment, X2 is H, cpc10 aliphatic, —U2—V2, or —U2—V2—Q; U2 is —(CH2)q— or —C(O)—; V2 is a C1_C10 aliphatic wherein up to four methylene units can be optionally replaced with —O—, —NR2—, —S—, —C(O)—, —S(O)—, —S(O)2—, or P(O); Q is a 3-8 membered saturated, partially unsaturated, or aromatic ring haVing 0-4 heteratoms selected from oxygen, nitrogen, or sulfur; wherein X2 is optionally substituted with 1—4 occurrences of halo, CN, N02, or C1-C10aliphatic wherein up to three methylene units of the C1-C10aliphatic can be ally replaced with —NR—, —O—, —S—, , or , or —S(O)2—; wherein each R3 and R5 is independently H, kyl, or -(C1_3alkyl)-(phenyl).

In some embodiments, Y2 is —O—.

In some ments, X2 is H; C1_6alkyl; or -U1-V1; wherein U2 is —(CH2)q— and v2 is —OR3—; —OC(O)N(R2)2—, —N(R2)2, —N(R2)C(O)R3, — OR5, —NHC(O)NHR2, —NHSOZR3, NHRZ, —C(O)OR3, C(O)N(R2)2, —SOZR3, -S(O)R3, —SOZNHR3, -SR3, —P(O)(OR3)2, —OP(O)(OR3)2; or U2 is C(0) and V2 is —OR3 or N(R2)2; wherein each R3 and R5 is independently H, C1_3alkyl, or -( C1_3alkyl)-(phenyl).

In some embodiments, U1 is —(CH2)q—. In other ments, U2 is —(CH2)q—. In some embodiments q is 1. In other embodiments, X2 is H, C1_6alkyl or -(CH2)qOR3. In yet other embodiments, X2 is , CH20H, CH2N3, CHzNHz, CH20CH2CH20CH2Ph, N/\>—/OH CHZOCHZCHZOH, or CHZOCHzPh. In yet other , CH2NHC(O)CH3, embodiments, X2 is methyl, CHzOH, or CHZOCHzPh. In some embodiments, X2 is C1_4alkyl.

In other embodiments, X2 is methyl.

In some embodiments, X6 is C1_6alkyl. In other ments, X6 is methyl, ethyl, or isopropyl. In some embodiments, X3 is methyl. In some embodiments, one of X2, X3, X4, X5, and X6 is -U1-V1 and the other five of of X2, X3, X4, X5, and X6 are H.

In some embodiments, IA and JB are each independently halo, CN, liphatic, C(O)(C3_6cycloalkyl), or C(O)(3—8 membered heterocyclyl having 1—2 atoms selected from O, NH, N(C1_4alkyl), or S); wherein up to three methylene units of the C1_10aliphatic group are optionally replaced with O, NH, N(C1_4alkyl), S, C(O), 8(0), or S(O)2; each IA and IE is independently and optionally tuted with 1—3 occurrences of halo.

In some embodiments, IA is chloro, fluoro, CN, CH3, CH2CH3, CH(CH3)2, OCH3, or OCF3. In other embodiments, J3 is halo, CN, OCH3, C(O)NH(CH3), C(O)N(CH3)2, N02, C(O)OH, C(O)OCH3, C(O)NH(CH2)ZO(CH2)ZO(CH2)2NH2, C(O)NH(CH2)ZOCH3, C(O)NH(cyclopropyl), C(O)NH(CH2)2(4—methylpiperazinyl), C(O)NHCH(CHZOH)CH(OH)CH3, C(O)NHC(CHZOH)3, C(O)NHC(CHZOH)2CH3, C(O)NHCH(CHzOH)2, C(O)NH(CH2)2(morpholinyl), C(O)NHCH2(tetrahydropyranyl), (tetrahydropyranyl), C(O)NHCH2(4-BOCpiperidinyl), C(O)NH(CH2)2N(CH3)2, -methylpiperazinyl), C(O)NHCH(CHZOH)COOH, C(O)pyrrolidinyl, N(CH2CHZOH)C(CHZOH)3, C(O)NHCH(CHZOH)CH(OH)CH3, S(O)2NH2, S(O)2NC(CH3)3, O(tetrahydropyranyl),wherein said tetrahydropyranyl is optionally substituted with C1_4alkyl, fluoro, OH, or CHzOH. In some embodiments, the tetrahydropyranyl is a sugar le, such as a glycosyl or mannosyl group.

Another embodiment provides a compound of formula B: HO —0 HO x1 _____ I: B ; (JA)m (JB)n FormulaB wherein Y2 is C4alkyl)—, —S(C1—C4alkyl)—, —S(O)—, —SOZ(C1—C4alkyl)—, or —(C1—C6)alkyl; X1 is —U1—V1; X1 is optionally substituted with 1—4 ences of halo; U1 is —(CH2)q— or —C(O)—; V1 is a C1_C10 aliphatic wherein up to four methylene units can be optionally replaced with —O—, —NR2—, —S—, —C(O)—, —S(O)—, —S(O)2—, or P(O); Ring A is C3_C10 cycloalkyl, 3—12 membered heterocyclyl, C6_10 aryl, or 5—14 membered heteroaryl; wherein the heterocyclyl or aryl independently has 1-6 heteroatoms ed from oxygen, nitrogen, or sulfur; Ring A is optionally bonded to Ring B; Ring B is absent, C3_C10 cycloalkyl, 3-12 membered heterocyclyl, C640 aryl, or 5-14 membered heteroaryl; wherein said heterocyclyl or heterocyclyl ndently has 1—6 heteroatoms ed from , nitrogen, or sulfur; each JA and JB is independently halogen, CN, N02, C3_g cycloalkyl, 3—8 membered heterocyclyl, C640 aryl, 5—10 membered heteroaryl, (€6-10 aryl)—(C1—C6alkyl)—, (5—10 membered heteroaryl)—(C1-C6alkyl)-, or a C1_C12 aliphatic wherein up to four methylene units of the C1_C10 aliphatic can be optionally replaced with —NR, —O—, —S—, —C(O)—, —S(O)—, —soz—, or 13(0); each JA and IE is independently and optionally substituted with 1—5 occurrences of halo, CN, or N02; R is H, C1-C6 aliphatic, C3_6cycloalkyl, C(O)OH, C(O)O(C1_4alkyl), or C(O)(C1_4alkyl); each m and n is independently 0, l, 2, 3, or 4; each q is independently l or 2.

In some embodiments, Y2 is —O(C1—C4alkyl)—, —S(C1—C4alkyl)—, —S(O)—, —SOZ(C1—C4alkyl)—, or —(C1—C6)alkyl; X1 is —U1—V1; X1 is ally substituted with 1—4 occurrences of halo; U1 is q— or —C(O)—; V1 is a C1_C10 aliphatic wherein up to four methylene units can be optionally replaced with —O—, —NR2—, —S—, —C(O)—, —S(O)—, —S(O)2—, or P(O); Ring A is C3_Cg cycloalkyl, 3-8 membered heterocyclyl, C640 aryl, or 5—10 membered heteroaryl; Ring A is optionally bonded to Ring B; Ring B is C3_Cg cycloalkyl, 3-8 membered heterocyclyl, C640 aryl, (C6_10 aryl)-(C1-C6alkyl)-, or 5— 10 ed heteroaryl; each JA and JB is ndently halogen, CN, N02, C3_g cycloalkyl, 3—8 membered cyclyl, C640 aryl, 5—10 membered heteroaryl, (€6-10 aryl)—(C1—C6alkyl)—, (5—10 membered heteroaryl)—(C1-C6alkyl)-, or a C1_C12 aliphatic wherein up to four methylene units of the C1_C10 aliphatic can be optionally replaced With —NR, —O—, —S—, —C(O)—, —S(O)—, —soz—, or 13(0); each JA and IE is independently and optionally substituted with 1—5 occurrences of halo, CN, or N02; R is H, C1-C6 aliphatic, C3_6cycloalkyl, C(O)OH, C(O)O(C1_4alkyl), or C(O)(C1_4alkyl); each m and n is independently 0, l, 2, 3, or 4.

In some embodiments, X1 is C1_6alkyl; or —U1-V1; wherein U2 is —(CH2)q— and v2 is —OR3—; —OC(O)N(R2)2—, —N(R2)2, —N(R2)C(O)R3, —NHC(O)OR5, —NHC(O)NHR2, —NHSOZR3, —NHSOZNHR2, —C(O)OR3, C(O)N(R2)2, , -S(O)R3, —SOzNHR3, -SR3, —P(O)(OR3)2, —OP(O)(OR3)2; or U2 is C(0) and v2 is —OR3 or N(R2)2; R is H, C1-C6 aliphatic, C3_6cycloalkyl, C(O)OH, C(O)O(C1_4alkyl), or C(O)(C1_4alkyl); R2 is H, C1-C6 aliphatic, or C3_6cycloalkyl; and R3 is H, C1_3alkyl, or —( C1_3alkyl)—(phenyl).

In other embodiments, X1 is C1_6alkyl; or —U1-V1; wherein U2 is —(CH2)q— and v2 is —OR3—; —OC(O)N(R2)2—, —N(R2)2, C(O)R3, —NHC(O)OR5, —NHC(O)NHR2, —NHSOZR3, —NHSOZNHR2, —C(O)OR3, C(O)N(R2)2, —SOzR3, -S(O)R3, R3, -SR3, —P(O)(OR3)2, —OP(O)(OR3)2; or U2 is C(0) and v2 is —OR3 or N(R2)2; R is H, C1-C6 aliphatic, C3_6cycloalkyl, C(O)OH, C(O)O(C1_4alkyl), or C(O)(C1_4alkyl); R2 is H, C1-C6 tic, or C3_6cycloalkyl; and R3 is H, C1_3alkyl, or —( kyl)—(phenyl).

In some ments, X1 is kyl. In some embodiments, X1 is methyl. In yet other embodiments, Y2 is —O(C1—C4alkyl)—. IN other embodiments, Y2 is —O(haloC1—C4 alkyl)—.

In some ments, Y2 is -O(C1-C4alkyl)-, Ring A is phenyl, Ring B is absent, and IA is C(O)NH(C1_4alkyl).

Another embodiment provides a compound of a C: Formula C wherein each Zl, ZZ, Z3, and Z4 is independently H or F; provided that at least one of Z, ZZ, Z3, and Z4 is F; Y3 is —O—, —O(C1—C4alkyl)—, —S—, —S(C1—C4alkyl)—, —S(O)p —, —SOp(C1—C4alkyl)—, or —(C1—C6)alkyl; Ring A is C3_C10 cycloalkyl, 3—12 membered cyclyl, C6_10 aryl, or 5—14 membered aryl; wherein the heterocyclyl or heteroaryl independently has 1-6 heteroatoms selected from , nitrogen, or sulfur; Ring A is optionally bonded to Ring B; Ring B is absent, C3_C10 cycloalkyl, 3-12 membered heterocyclyl, C640 aryl, or 5-14 membered heteroaryl; wherein said heterocyclyl or cyclyl independently has 1—6 heteroatoms selected from oxygen, nitrogen, or sulfur; each JA and JB is independently halogen, CN, N02, C3_g cycloalkyl, 3—8 membered heterocyclyl, C640 aryl, 5—10 membered heteroaryl, (€6-10 aryl)—(C1—C6alkyl)—, (5—10 membered heteroaryl)—(C1-C6alkyl)-, or a C1_C12 aliphatic wherein up to four methylene units of the C1_C10 aliphatic can be optionally replaced with —NR—, —O—, —S—, —C(O)—, —S(O)—, —soz— or 13(0); each JA and IE is independently and optionally substituted with 1—5 occurrences of halo, CN, or N02; R is H, C1-C6 aliphatic, C3_6cycloalkyl, C(O)OH, C1_4alkyl), or C(O)(C1_4alkyl); each m and n is independently 0, l, 2, 3, or 4; p is l or 2.

In another embodiment, each Zl, ZZ, Z3, and Z4 is ndently H or F; provided that at least one of Z, ZZ, Z3, and Z4 is F; Y3 is —O—, —O(C1—C4alkyl)—, —S—, —S(C1—C4alkyl)—, —S(O)p —, —SOp(C1—C4alkyl)—, or —(C1—C6)alkyl; Ring A is C3_Cg cycloalkyl, 3-8 ed heterocyclyl, C640 aryl, or 5—10 ed aryl; Ring A is optionally bonded to Ring B; Ring B is C3_Cg cycloalkyl, 3-8 membered heterocyclyl, C640 aryl, (C6_10 aryl)-(C1-C6alkyl)-, or 5— 10 ed heteroaryl; each JA and JB is independently halogen, CN, N02, C3_g cycloalkyl, 3—8 membered heterocyclyl, C640 aryl, 5—10 membered heteroaryl, (€6-10 aryl)—(C1—C6alkyl)—, (5—10 membered heteroaryl)—(C1-C6alkyl)-, or a C1_C12 aliphatic wherein up to four methylene units of the C1_C10 aliphatic can be optionally replaced with —NR, —O—, —S—, —C(O)—, —S(O)—, 2014/024411 —soz— or 13(0); each JA and IE is independently and ally substituted with 1—5 occurrences of halo, CN, or N02; R is H, C1-C6 aliphatic, C3_6cycloalkyl, C(O)OH, C(O)O(C1_4alkyl), or C(O)(C1_4alkyl); each m and n is independently 0, l, 2, 3, or 4.

In some embodiments, only one of Z1, Z2, Z3, and Z4 is F and the other three are H. In some embodiments, Z1 is F. In some embodiments, Z2 is F. In some ments, Z3 is F. In some embodiments, Z4 is F.

In some embodiments, Y3 is —O—.

According to another embodiment, Ring A is phenyl. In some embodiments, IA is halo, C1_4aliphatic, or -O(C1_4aliphatic); wherein said C1_4aliphatic, or -O(C1_4aliphatic) is optionally tuted with 1-4 halo. ing to another embodiment, Ring B is a 5-10 membered heteroaryl.

Another embodiment provides a compound of formula D: Formula D wherein Ring B is absent, C3_C10 cycloalkyl, 3-12 membered heterocyclyl, C640 aryl, or 5-14 membered heteroaryl, wherein said heterocyclyl or heterocyclyl independently has 1—6 heteroatoms selected from oxygen, nitrogen, or sulfur; each JA and IE is independently halogen, CN, N02, C3_g cycloalkyl, 3—8 ed heterocyclyl, C640 aryl, 5—10 membered heteroaryl, (€6-10 aryl)—(C1—C6alkyl)—, (5—10 membered heteroaryl)—(C1-C6alkyl)-, or a C1_C12 aliphatic wherein up to four methylene units of the C1_C10 aliphatic can be optionally replaced with —NR, —O—, —S—, , —S(O)—, —soz—, or 13(0); each JA and IE is independently and optionally substituted with 1—5 occurrences of halo, CN, or N02; R is H, C1-C6 aliphatic, C3_6cycloalkyl, C(O)OH, C(O)O(C1_4alkyl), or C(O)(C1_4alkyl); each m and n is independently 0, l, 2, 3, or 4.

According to another embodiment, 2014/024411 Ring B is C3_Cg cycloalkyl, 3-8 membered heterocyclyl, C640 aryl, (C6_10 aryl)-(C1-C6alkyl)-, or 5—10 membered heteroaryl; each IA and IE is independently halogen, CN, N02, C3_g cycloalkyl, 3—8 membered heterocyclyl, C640 aryl, 5—10 membered heteroaryl, (€6-10 aryl)—(C1-C6alkyl)—, (5—10 membered heteroaryl)-(C1-C6alkyl)-, or a C1_C12 aliphatic wherein up to four ene units of the C1_C10 aliphatic can be optionally ed With —NR, —O—, —S—, —C(O)—, —S(O)— or 13(0); each JA and IE is independently and ally tuted with 1—5 , —soz—, occurrences of halo, CN, or N02; R is H, C1-C6 aliphatic, C3_6cycloalkyl, C(O)OH, C(O)O(C1_4alkyl), or C(O)(C1_4alkyl); each m and n is independently 0, l, 2, 3, or 4.

In some embodiments, Ring B is phenyl and IE is C(O)NHCH3, OCH3, or N02.

Another embodiment provides a compound as represented by formula III: M a t (JA)m (JA2)q In some embodiments, M and M2 are the same. In other embodiments, M and M2 are different.

In some embodiments, M is In other embodiments, M2 is In yet other embodiments, M2 together with Ring A2 form In some embodiments, Y1 is O and X2 is methyl. In other embodiments, t is l and Z is phenyl or pyridyl. In yet other embodiments, t is 0.

Another ment provides a compound as represented by formula E: (Wu X2 H H OH HO H HO Formula E.

In some embodiments, Ring A and Ring A2 are phenyl. In other embodiments, X2 is C1_4alkyl. In some embodiments, X2 is methyl.

In some embodiments, IA and JA2 are each independently CN, halo, C1_6alkyl, wherein up to one ene unit of said kyl is optionally replaced with O, S, NH, N(C1_6alkyl), C(O), 8(0), or S(O)2 substituted with 1—3 occurrences of halo. In other embodiments, JA and JA2 are each independently CN, methyl, ethyl, pyl, fluoro, chloro, OCH3, or OCF3.

Another embodiment provides a compound as represented by formula F: Formula F.

In some embodiments, Ring A and Ring A2 are phenyl. In some embodiments, Ring B is cloalkyl, phenyl, or l. In some embodiments, JA and JA2 are each independently CN, halo, C1_6alkyl, n up to one methylene unit of said C1_6alkyl is optionally replaced with O, S, NH, N(C1_6alkyl), C(O), 8(0), or S(O)2 substituted With 1—3 occurrences of halo. In other embodiments, IA and JA2 are each independently methyl; m is l; and u is 1. In yet other embodiments, IE is phenyl optionally substituted with methyl and H0 ye OH E—OIm-QOH0 OH Another embodiment provides a compound as represented by formula G: H OH Formula G.

In some embodiments, X2 is methyl, Ring A and Ring A2 are phenyl; JA and J3 are each independently methyl; m is l; and n is 1.

Another embodiment provides a compound as represented by formula H: Formula H.

In some embodiments, t is l and Z is phenyl or pyridyl. In other embodiments, t is 0.

In yet another ment, Ring A and Ring A2 are phenyl. r embodiment provides a compound is selected from one or more of the following tables: Tablel O ""06 O ...\\O O O grog HO HO HO HO". N02 HOW F Br F HOW F Br OH OH 0H 1 2 3 CF3 OMe Ho" HOW F N/ F N/ H0" F Br H OH OH OH 4 5 6 WO 65107 0 *‘O O HO 0 O ""0 O HO O Ho" F 0/ Ho" F N/ OH O ‘1’ O O O "‘"O O HONFW OOH O F O o N Ho‘" OH O N/ H H OH OH 11 12 TableZ o ,0 HO ‘ O OH ..... , / 13 15 WO 65107 Table4 O "‘0 HO 33 Hill HofioHo""' 0 OHOH O O HO OH Ho""' OH 36 37 WO 65107 Table 5 WO 65107 WO 65107 WO 65107 WO 65107 WO 65107 WO 65107 WO 65107 WO 65107 2014/024411 The present invention also provides processes for making the compounds described herein. These processes are described generally in the Schemes below.

The present invention also es a composition sing the compound described herein, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

The present invention also provides a method of treating or preventing bacteria infection in a subject, comprising administering to the subject an effective amount of the compound or the composition described herein.

In an embodiment of the method, the bacteria infection is y tract infection or inflammatory bowel disease.

Another embodiment provides a method of ng or ting a bacteria infection in a subject, comprising administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a composition comprising said compound. In some ments, the bacteria infection is urinary tract infection or inflammatory bowel disease. In some embodiments, the bacteria ion is ulcerative colitis.

In other embodiments, the bacteria infection is s disease. In some embodiments, bacteria infection is the cause of Crohn’s Disease or tive colitis. In some embodiments, the bacteria infections are caused by AIEC (adherent—invasive e. coli) s.

Another embodiment provides a method of treating or preventing inflammatory bowel disease in a subject, comprising administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or a composition comprising said nd. In some embodiments, the subject is a patient. In other embodiments, the subject is a human. In some embodiments, the inflammatory bowel disease is Crohn’s Disease. In other embodiments, the inflammatory bowel disease is ulcerative colitis.

Another embodiment provides a method of inhibiting FimH in bacteria from an e. coli ial strain isolated from patients with inflammatory bowel disease, comprising contacting the bacteria with an effective amount of a compound described herein, or a ceutically acceptable salt thereof, or a composition sing said compound. In some embodiments, the bacterial strain is LF—82.

Another embodiment provides a method of inhibiting FimH in a subject, comprising stering to the subject an effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a composition comprising said compound.

Another ment provides a method of inhibiting adhesion of e. 6012' in a subject, comprising stering to the subject an effective amount of a compound described herein, or a pharmaceutically able salt thereof, or a composition comprising said compound. In some embodiments, the inhibition of on results in the prevention of the establishment of a sub—musosal infection.

Another embodiment provides a method of blocking the interaction between type 1 pili and CEACAM6 in a subject, comprising administering to the subject an ive amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a composition comprising said compound.

As described herein, a specified number range of atoms includes any integer therein.

For example, a group having from 1-4 atoms could have 1, 2, 3, or 4 atoms.

The term "stable", as used herein, refers to compounds that are not substantially d when ted to conditions to allow for their production, detection, recovery, storage, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible nd is one that is not substantially altered when kept at a temperature of 40°C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

The term "aliphatic" or "aliphatic group", as used herein, means a straight-chain (i.e., unbranched), or branched, hydrocarbon chain that is completely ted or that contains one or more units of unsaturation but is omatic.

Unless ise specified, tic groups contain 1-20 tic carbon atoms. In some embodiments, aliphatic groups n 1-10 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments aliphatic groups contain 1-4 aliphatic carbon atoms. Aliphatic groups may be linear or branched, substituted or unsubstituted alkyl, alkenyl, or alkynyl groups. Specific examples include, but are not limited to, methyl, ethyl, isopropyl, n-propyl, sec-butyl, vinyl, n-butenyl, ethynyl, and utyl.

The term "alkyl" as used herein means a saturated straight or branched chain hydrocarbon. The term "alkenyl" as used herein means a ht or branched chain hydrocarbon comprising one or more double bonds. The term "alkynyl" as used herein means a straight or branched chain hydrocarbon comprising one or more triple bonds.

The term "cycloaliphatic" (or "carbocycle" or "carbocyclyl" or "carbocyclic") refers to a non-aromatic monocyclic carbon containing ring which can be saturated or contain one or more units of unsaturation, having three to fourteen ring carbon atoms. In some embodiments, the ring has three to ten ring carbon atoms; in other embodiments, the ring has three to six carbon atoms. The term includes polycyclic fused, spiro or bridged carbocyclic ring systems. The term also includes polycyclic ring systems in which the carbocyclic ring can be fused to one or more non—aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combination thereof, wherein the radical or point of attachment is on the carbocyclic ring. Fused bicyclic ring systems comprise two rings which share two adjoining ring atoms, bridged bicyclic group comprise two rings which share three or four nt ring atoms, spiro ic ring systems share one ring atom. Examples of liphatic groups include, but are not limited to, cycloalkyl and cycloalkenyl groups. Specific examples include, but are not limited to, exyl, cyclopropenyl, and cyclobutyl.

The term "heterocycle" (or "heterocyclyl", or "heterocyclic") as used herein means refers to a non-aromatic monocyclic ring which can be ted or contain one or more units of unsaturation, haVing three to en ring atoms in which one or more ring carbons is replaced by a heteroatom such as, N, S, or O. In some embodiments, the ring has three to ten ring atoms; in other embodiments, the ring has three to six ring atoms. In yet other embodiments, the ring has five to six ring atoms. The term includes clic fused, spiro or bridged heterocyclic ring systems. The term also includes polycyclic ring systems in which the heterocyclic ring can be fused to one or more non—aromatic carbocyclic or heterocyclic rings or one or more aromatic rings or combination thereof, wherein the radical or point of attachment is on the heterocyclic ring.

Examples of heterocycles include, but are not limited to, dinyl, piperizinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, azepanyl, diazepanyl, triazepanyl, azocanyl, diazocanyl, triazocanyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, oxazocanyl, oxazepanyl, thiazepanyl, thiazocanyl, benzimidazolonyl, ydrofuranyl, tetrahydropyranyl, ydrothiophenyl, for example, 3-morpholino, , morpholino, including, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino, morpholino, l-pyrrolidinyl, 2- idinyl, 3-pyrrolidinyl, l-tetrahydropiperazinyl, 2-tetrahydropiperazinyl, 3- tetrahydropiperazinyl, l-piperidinyl, 2-piperidinyl, 3-piperidinyl, l-pyrazolinyl, 3- pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl, l-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4- piperidinyl, 2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, l-imidazolidinyl, 2- imidazolidinyl, azolidinyl, 5-imidazolidinyl, indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, thienothienyl, thienothiazolyl, benzothiolanyl, benzodithianyl, 3-(1- alkyl)-benzimidazol-2—onyl, and l,3-dihydro-imidazol-2—onyl.

Cyclic groups, (e.g. cycloaliphatic and heterocycles), can be linearly fused, bridged, or spirocyclic.

The term oatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon ding, any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the nized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring, for example N (as in 3,4-dihydro-2H—pyrrolyl), NH (as in idinyl) or NR+ (as in N- substituted pyrrolidinyl)).

The term "unsaturated", as used herein, means that a moiety has one or more units of ration. As would be known by one of skill in the art, unsaturated groups can be partially unsaturated or fully unsaturated. Examples of partially unsaturated groups include, but are not limited to, butene, exene, and tetrahydropyridine. Fully unsaturated groups can be aromatic, anti-aromatic, or non-aromatic. Examples of fully unsaturated groups include, but are not limited to, phenyl, cyclooctatetraene, pyridyl, thienyl, and l- methylpyridin-2(lH)-one.

The term "alkoxy", or "thioalkyl", as used , refers to an alkyl group, as previously defined, attached to the molecule through an oxygen ("alkoxy" e. g., yl) or sulfur ("thioalkyl" e.g., -S-alkyl) atom.

The terms "haloalkyl", "haloalkenyl", liphatic", and "haloalkoxy" mean alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. This term includes perfluorinated alkyl groups, such as —CF3 and —CF2CF3.

The terms "halogen", "halo", and "hal" mean F, Cl, Br, or I.

The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to carbocyclic aromatic ring systems. The term "aryl" may be used hangeably with the term "aryl ring".

Carbocyclic aromatic ring groups have only carbon ring atoms (typically six to fourteen) and include monocyclic aromatic rings such as phenyl and fused polycyclic aromatic ring systems in which two or more carbocyclic aromatic rings are fused to one another. Examples include l-naphthyl, thyl, l-anthracyl and 2—anthracyl. Also included within the scope of the term "carbocyclic aromatic ring", as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings (carbocyclic or heterocyclic), such as in an indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, where the radical or point of attachment is on the aromatic ring.

The term "heteroaryl", "heteroaromatic", "heteroaryl ring", "heteroaryl group" and "heteroaromatic group", used alone or as part of a larger moiety as in "heteroaralkyl" or "heteroarylalkoxy", refers to heteroaromatic ring groups haVing five to en members, including monocyclic aromatic rings and polycyclic aromatic rings in which a monocyclic aromatic ring is fused to one or more other aromatic ring. Heteroaryl groups have one or more ring heteroatoms. Also included within the scope of the term "heteroaryl", as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings (carbocyclic or heterocyclic), where the l or point of attachment is on the aromatic ring. Bicyclic 6,5 heteroaromatic ring, as used herein, for example, is a six ed heteroaromatic ring fused to a second five membered ring, wherein the radical or point of attachment is on the six membered ring.

It shall be understood that a 5—10 membered heteroaryl includes both monocyclic and bicyclic rings. For example, it could include 5-6 membered monocyclic rings having 1—4 heteroatoms selected from oxygen, nitrogen, or sulfur and 8-10 membered bicyclic rings having 1—6 heteroatoms selected from oxygen, nitrogen, or sulfur. es of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, zinyl, imidazolyl, pyrrolyl, pyrazolyl, lyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl or thiadiazolyl including, for example, 2-furanyl, 3-furanyl, N- imidazolyl, 2—imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-pyrazolyl, 4- pyrazolyl, l-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2—pyrimidinyl, 4- pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, zolyl, 4-thiazolyl, 5-thiazolyl, 2-triazolyl, 5- triazolyl, olyl, nyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, benzotriazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, nyl, benzisoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl, oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, purinyl, nyl, l,3,5-triazinyl, quinolinyl (e.g., 2-quinolinyl, 3- quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., uinolinyl, uinolinyl, or 4- isoquinolinyl).

The term "protecting group" and "protective group" as used herein, are interchangeable and refer to an agent used to temporarily block one or more desired functional groups in a compound with multiple reactive sites. In certain embodiments, a protecting group has one or more, or ably all, of the following characteristics: a) is added selectively to a functional group in good yield to give a protected substrate that is b) stable to reactions occurring at one or more of the other ve sites; and c) is selectively removable in good yield by reagents that do not attack the regenerated, deprotected functional group. As would be understood by one d in the art, in some cases, the reagents do not attack other reactive groups in the compound. In other cases, the reagents may also react with other reactive groups in the compound. Examples of protecting groups are detailed in Greene, T.W., Wuts, P. G in "Protective Groups in Organic Synthesis", Third n, John Wiley & Sons, New York: 1999 (and other editions of the book), the entire contents of which are hereby incorporated by reference. The term gen protecting group", as used herein, refers to an agent used to temporarily block one or more desired nitrogen reactive sites in a multifunctional compound. Preferred nitrogen ting groups also possess the characteristics exemplified for a protecting group above, and certain exemplary nitrogen protecting groups are also detailed in r 7 in Greene, T.W., Wuts, P. G in ctive Groups in Organic Synthesis", Third Edition, John Wiley & Sons, New York: 1999, the entire contents of which are hereby incorporated by reference.

In some embodiments, where indicated, a methylene unit of an aliphatic chain is optionally replaced with another atom or group. Examples of such atoms or groups include, but are not limited to, —NR—, —O—, —C(O)—, —C(=N—CN)—, —C(=NR)—, —C(=NOR)—, —S—, —S(O)—, and —S(O)2—. These atoms or groups can be combined to form larger groups. Examples of such larger groups include, but are not limited to, —OC(O)—, O—, —COz—, —C(O)NR— , CN), —NRC(O)—, —NRC(O)O—, —S(O)2NR—, —NRSOz—, —NRC(O)NR—, —OC(O)NR—, and -NRSOZNR-, wherein R is for example, H or C1_6aliphatic, or is ise d herein.

It should be tood that these groups can be bonded to the methylene units of the aliphatic chain via single, double, or triple bonds. An example of an al replacement (nitrogen atom in this case) that is bonded to the aliphatic chain via a double bond would be —CH2CH=N—CH3. In some cases, especially on the terminal end, an optional replacement can be bonded to the aliphatic group via a triple bond. One example of this would be CHZCHZCHZCEN. It should be understood that in this situation, the terminal nitrogen is not bonded to another atom.

It should also be understood that, the term "methylene unit" can also refer to branched or substituted methylene units. For example, in an isopropyl moiety [-CH(CH3)2], a en atom (e.g. NR) replacing the first recited "methylene unit" would result in dimethylamine [-N(CH3)2]. In ces such as these, one of skill in the art would understand that the nitrogen atom will not have any additional atoms bonded to it, and the "R" from "NR" would be absent in this case.

The terms "carbon units" and "methylene units" are interchangeable. It shall be understood that these terms refer to carbon units of an aliphatic group of varying bond orders, such as the four dual "methylene units" shown in the hydrocarbon below: HC=CH—CH2CECH.

Only those replacement and combinations of groups that result in a stable structure are contemplated. Optional replacements can occur both within the chain and/or at either end of the chain; i.e. both at the point of attachment and/or also at the terminal end. Two optional replacements can also be adjacent to each other within a chain so long as it s in a chemically stable compound. The optional replacements can also completely replace all of the carbon atoms in a chain. For example, a C3 aliphatic can be optionally replaced by -NR- and —NR— to form —NRC(O)NR— (a urea).

, —C(O)—, Unless otherwise indicated, if the replacement occurs at the terminal end, the replacement atom is bound to an H on the terminal end. For example, if -CH2CH2CH3 were optionally replaced with —O—, the resulting compound could be H3, —CH20CH3, or ZOH. It should be understood that if the terminal atom does not contain any free valence electrons, then a hydrogen atom is not required at the terminal end (e.g., —CH2CH2CH=O or 2CEN).

Unless otherwise indicated, structures depicted herein are also meant to include all isomeric (e. g., enantiomeric, diastereomeric, geometric, conformational, and rotational) forms of the structure. For example, the R and S configurations for each asymmetric , (Z) and (E) double bond s, and (Z) and (E) conformational isomers are included in this invention. As would be understood to one skilled in the art, a substituent can freely rotate around any rotatable bonds. For example, a substituent drawn as also represents Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, geometric, mational, and rotational mixtures of the present compounds are within the scope of the ion.

Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention.

In the compounds of this invention any atom not specifically designated as a particular e is meant to represent any stable isotope of that atom. Unless otherwise stated, when a on is designated specifically as "H" or "hydrogen", the position is understood to have hydrogen at its natural abundance isotopic composition. Also unless otherwise stated, when a position is designated cally as "D" or "deuterium", the position is understood to have ium at an abundance that is at least 3340 times greater than the natural abundance of deuterium, which is 0.015% (i.e., at least 50.1% incorporation of deuterium).

"D" and "d" both refer to deuterium.

Additionally, unless otherwise indicated, structures depicted herein are also meant to include nds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of a carbon by a 13C— or riched carbon are within the scope of this invention. Such compounds are useful, for e, as analytical tools or probes in biological assays.

As described herein, where indicated compounds of the invention may optionally be substituted with one or more substituents, such as are rated generally herein, or as exemplified by particular classes, subclasses, and species of the invention. It will be appreciated that the phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted." In general, the term "substituted", whether preceded by the term "optionally" or not, refers to the replacement of hydrogen radicals in a given ure with the radical of a specified substituent. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable on of the group, and when more than one position in any given ure may be substituted with more than one substituent selected from a specified group, the tuent may be either the same or different at every on.

Only those choices and combinations of substituents that result in a stable structure are contemplated. Such choices and combinations will be apparent to those of ordinary skill in the art and may be determined without undue experimentation.

The term "ring atom" is an atom such as C, N, O or S that is in the ring of an aromatic group, cycloalkyl group or non-aromatic heterocyclic ring.

A "substitutable ring atom" in an aromatic group is a ring carbon or en atom bonded to a hydrogen atom. The hydrogen can be optionally ed with a suitable substituent group. Thus, the term "substitutable ring atom" does not include ring nitrogen or carbon atoms which are shared when two rings are fused. In addition, "substitutable ring atom" does not e ring carbon or nitrogen atoms when the structure depicts that they are already attached to a moiety other than hydrogen.

An aryl group as defined herein may contain one or more substitutable ring atoms, which may be bonded to a suitable substituent. Examples of suitable substituents on a substitutable ring carbon atom of an aryl group include R’. R’ is -Ra, -Br, -Cl, -1, -F, -ORa, - SRa, —O—CORa, —CORa, —CSRa, —CN, —N02, —NCS, —SO3H, —N(RaRb), — COORa, —NRcNRcCORa, —NRcNRcCOzRa, —CHO, —CON(RaRb), — OC(O)N(RaRb), —CSN(RaRb), —NRcCORa, —NRcCOORa, —NRcCSRa, —NRcCON(RaRb), — NRcNRcC(O)N(RaRb), —NRcCSN(RaRb), c)—N(RaRb), N(RaRb), —NRd— C(=NRc)—N(RaRb), —NRcNRaRb, —S(O)pNRaRb, zN(RaRb), —NRcS(O)pRa, — S(O)pRa, —OS(O)pNRaRb or —OS(O)pRa; n p is l or 2.

Ra—Rd are each independently —H, an aliphatic group, aromatic group, non-aromatic carbocyclic or heterocyclic group or -N(RaRb), taken together, form a non-aromatic heterocyclic group. The aliphatic, aromatic and non-aromatic heterocyclic group represented by Ra—Rd and the non-aromatic heterocyclic group represented by —N(RaRb) are each optionally and independently substituted with one or more groups represented by R#.

Preferably Ra—Rd are unsubstituted.

R# is halogen, Rt —OR+, -SR+, —NOz, -CN, —N(R+)2, —COR+, —COOR+, —NHCOZR+, — NHC(O)R+, —NHNHC(O)R+, —NHC(O)N(R+)2, —NHNHC(O)N(R+)2, —NHNHCOZR+, — C(O)N(R+)2, —OC(O)R+, -OC(O)N(R+)2, -S(O)2R+, —sozN(R+)2, -S(O)R+, —NHsozN(R+)2, — NHsoth, —C(=S)N(R+)2, or —C(=NH)—N(R+)2.

R+ is —H, a C1-C4 alkyl group, a monocyclic aryl group, a non-aromatic carbocyclic or heterocyclic group each optionally substituted with alkyl, haloalkyl, alkoxy, haloalkoxy, halo, -CN, -NOZ, amine, alkylamine or dialkylamine. ably R+ is tituted.

An aliphatic or a omatic heterocyclic or carbocyclic group as used herein may contain one or more substituents. Examples of suitable substituents for an aliphatic group or a ring carbon of a non-aromatic heterocyclic group is R’ ’. R’ ’ include those substituents listed above for R’ and =0, =S, =NNHR**, =NN(R**)2, =NNHC(O)R**, =NNHCO2 (alkyl), Z (alkyl), =NR**, spiro cycloalkyl group or fused cycloalkyl group. Each R** is independently ed from hydrogen, an unsubstituted alkyl group or a substituted alkyl group. Examples of tuents on the alkyl group ented by R** include amino, alkylamino, dialkylamino, arbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, laminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.

When a heterocyclyl, aryl, or heteroaralkyl group contains a nitrogen atom, it may be substituted or unsubstituted. When a nitrogen atom in the aromatic ring of a heteroaryl group has a substituent the nitrogen may be a quaternary nitrogen.

A preferred position for substitution of a omatic nitrogen-containing heterocyclic group is the nitrogen ring atom. Suitable substituents on the nitrogen of a non- aromatic heterocyclic group or heteroaryl group e —R’\, —N(R/\)2, \, COZRA, — C(O)C(O)R/\, —SOzR/\, SOz N(R/\)2, C(=S)N(RA)2, C(=NH)—N(RA)2, and —NRASOZRA; wherein R" is hydrogen, an aliphatic group, a substituted aliphatic group, aryl, substituted aryl, heterocyclic or carbocyclic ring or a substituted heterocyclic or carbocyclic ring.

Examples of substituents on the group represented by RA include alkyl, haloalkoxy, haloalkyl, alkoxyalkyl, sulfonyl, alkylsulfonyl, halogen, nitro, cyano, hydroxy, aryl, carbocyclic or heterocyclic ring, oxo, amino, alkylamino, lamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyloxy, alkoxy, carboxy, carbonyl, or alkylcarbonyl. Preferably RA is not substituted.

Non-aromatic nitrogen containing cyclic rings that are substituted on a ring nitrogen and attached to the remainder of the molecule at a ring carbon atom are said to be N substituted. For example, an N alkyl piperidinyl group is attached to the remainder of the molecule at the two, three or four position of the piperidinyl ring and substituted at the ring nitrogen with an alkyl group. Non-aromatic nitrogen containing heterocyclic rings such as pyrazinyl that are substituted on a ring nitrogen and attached to the remainder of the molecule at a second ring nitrogen atom are said to be N’ substituted—N—heterocycles. For example, an N’ acyl N—pyrazinyl group is attached to the remainder of the molecule at one ring en atom and substituted at the second ring nitrogen atom with an acyl group.

As used herein an optionally substituted aralkyl can be substituted on both the alkyl and the aryl n. Unless otherwise ted as used herein optionally substituted aralkyl is optionally substituted on the aryl portion.

The terms "a bond" and "absent" are used interchangeably to indicate that a group is The compounds of the ion are defined herein by their chemical structures and/or chemical names. Where a compound is referred to by both a chemical structure and a chemical name, and the al structure and chemical name conflict, the chemical structure is inative of the compound’s identity.

The compounds of this invention can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable salt.

Pharmaceutically Acceptable Salts As used herein, the term "pharmaceutically acceptable salt" refers to salts of a compound which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower s without undue side effects, such as, toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. For example, S. M.

Berge et al., describe pharmaceutically able salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1—19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. These salts can be prepared in sita during the final isolation and purification of the compounds. Acid addition salts can be prepared by l) reacting the purified compound in its free-based form with a suitable organic or inorganic acid and 2) isolating the salt thus formed.

Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other s used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, onate, dodecylsulfate, ethanesulfonate, formate, te, glucoheptonate, glycerophosphate, glycolate, gluconate, ate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, odide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, , oxalate, palmitate, te, pectinate, persulfate, 3-phenylpropionate, phosphate, e, pivalate, propionate, salicylate, te, succinate, e, tartrate, thiocyanate, p-toluenesulfonate, noate, valerate salts, and the like.

Base addition salts can be prepared by l) reacting the purified compound in its acid form with a le c or inorganic base and 2) isolating the salt thus formed. Salts derived from appropriate bases include alkali metal (e. g., sodium, lithium, and potassium), alkaline earth metal (e. g., magnesium and calcium), ammonium and N+(C1_4alkyl)4 salts.

This invention also envisions the quaternization of any basic nitrogen-containing groups of WO 65107 the compounds disclosed herein. Water or luble or dispersible products may be obtained by such quatemization.

Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary um, and amine cations formed using rions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, loweralkyl ate and aryl sulfonate. Other acids and bases, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid or base addition salts.

It should be understood that this invention includes mixtures/combinations of different pharmaceutically acceptable salts and also mixtures/combinations of compounds in free form and pharmaceutically acceptable salts.

In addition to the compounds of this invention, pharmaceutically acceptable derivatives or prodrugs of the compounds of this invention may also be employed in compositions to treat or prevent the herein identified disorders.

As used herein and unless otherwise indicated, the term "prodrug" means a tive of a compound that can hydrolyze, oxidize, or otherwise react under biological conditions (in vitro or in vivo) to e a compound of this invention. Prodrugs may become active upon such reaction under biological conditions, or they may have activity in their ted forms.

Examples of prodrugs contemplated in this invention include, but are not d to, analogs or derivatives of compounds of the invention that comprise biohydrolyzable moieties such as biohydrolyzable amides, biohydrolyzable esters, biohydrolyzable carbamates, biohydrolyzable carbonates, biohydrolyzable ureides, and biohydrolyzable phosphate analogues. Other examples of prodrugs include derivatives of compounds of the ion that comprise —NO, —NOz, —ONO, or —ONOz moieties. Prodrugs can typically be prepared using well—known methods, such as those described by BURGER'S MEDICINAL CHEMISTRY AND DRUG DISCOVERY (1995) 172—178, 949—982 ed E. Wolff ed., 5th ed).

A "pharmaceutically acceptable derivative" is an adduct or derivative which, upon administration to a patient in need, is capable of providing, ly or ctly, a compound as otherwise described herein, or a metabolite or residue thereof. Examples of pharmaceutically acceptable derivatives e, but are not limited to, esters and salts of such .

A "pharmaceutically acceptable derivative or prodrug" includes any pharmaceutically acceptable ester, salt of an ester or other derivative or salt thereof of a compound, of this invention which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. Particularly favoured tives or gs are those that increase the ilability of the compounds of this invention when such nds are administered to a t (e.g., by allowing an orally administered compound to be more y absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment (e.g., the brain or tic system) relative to the parent species.

Pharmaceutically acceptable prodrugs of the compounds of this invention include, without limitation, esters, amino acid esters, phosphate esters, metal salts and sulfonate esters.

As used herein, the phrase "side effects" encompasses unwanted and adverse effects of a therapy (e.g., a prophylactic or therapeutic agent). Side effects are always unwanted, but unwanted effects are not necessarily adverse. An adverse effect from a therapy (e. g., prophylactic or therapeutic agent) might be harmful or uncomfortable or risky. Side effects include, but are not d to fever, chills, lethargy, intestinal toxicities (including gastric and intestinal ulcerations and erosions), , vomiting, neurotoxicities, nephrotoxicities, renal toxicities (including such conditions as papillary necrosis and chronic interstitial nephritis), hepatic toxicities (including elevated serum liver enzyme levels), myelotoxicities (including leukopenia, myelosuppression, thrombocytopenia and anemia), dry mouth, ic taste, prolongation of gestation, weakness, somnolence, pain (including muscle pain, bone pain and headache), hair loss, asthenia, dizziness, extra-pyramidal symptoms, akathisia, cardiovascular disturbances and sexual dysfunction.

In one embodiment the t invention is a ceutical composition comprising a compound of the present ion and a pharmaceutically acceptable carrier, diluent, nt or vehicle. In one embodiment the present invention is a pharmaceutical composition comprising an effective amount of compound of the present invention and a pharmaceutically able carrier, t, adjuvant or vehicle. Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients or carriers suitably selected with respect to the intended form of administration, and consistent with conventional pharmaceutical practices.

A pharmaceutically acceptable carrier may contain inert ingredients which do not unduly inhibit the biological activity of the compounds. The pharmaceutically acceptable carriers should be biocompatible, e. g., xic, non—inflammatory, non—immunogenic or devoid of other undesired reactions or side—effects upon the administration to a subject.

Standard pharmaceutical formulation techniques can be employed.

The pharmaceutically acceptable carrier, adjuvant, or vehicle, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the ation thereof Except insofar as any conventional r medium is incompatible with the compounds of the invention, such as by producing any undesirable biological effect or otherwise interacting in a rious manner with any other component(s) of the pharmaceutically able composition, its use is contemplated to be within the scope of this invention.

Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, e, sorbic acid, or potassium sorbate, l glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, ium trisilicate, nyl idone, polyacrylates, waxes, hylene—polyoxypropylene—block polymers, wool fat, sugars such as lactose, e and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered anth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, seed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene ; esters such as ethyl oleate and ethyl laurate; agar; ing agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's on; ethyl alcohol, and phosphate buffer solutions, as well as other non- toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the ition, according to the judgment of the formulator.

The compounds of t invention or pharmaceutical salts thereof may be formulated into pharmaceutical compositions for administration to a subject as defined herein. These pharmaceutical compositions, which se an amount of the nds effective to treat or prevent a bacteria infection, such as IBD, and a pharmaceutically acceptable carrier, are another embodiment of the present ion.

In one embodiment the present invention is a method of treating or preventing a bacteria infection, such as IBD, in a subject in need thereof, comprising administering to the subject an effective amount of a compound or composition of the present invention.

As used herein, the terms "subject", "patient" and "mammal" are used interchangeably. The terms "subject" and "patient" refer to an animal (e. g., a bird such as a chicken, quail or turkey, or a mammal), ably a mammal including a non-primate (e.g., a cow, pig, horse, sheep, , guinea pig, rat, cat, dog, and mouse) and a primate (e. g., a monkey, chimpanzee and a human), and more preferably a human. In one embodiment, the subject is a man animal such as a farm animal (e. g., a horse, cow, pig or sheep), or a pet (e. g., a dog, cat, guinea pig or rabbit). In a preferred embodiment, the subject is a human.

As used herein, an "effective amount" refers to an amount ient to elicit the desired biological response. In the t invention the d biological response is to reduce or ameliorate the severity, duration, progression, or onset of a bateria infection, prevent the advancement of a bateria infection, cause the regression of a bateria infection, prevent the recurrence, development, onset or progression of a symptom associated with a bateria infection, or enhance or improve the lactic or therapeutic effect(s) of another therapy. The precise amount of compound administered to a t will depend on the mode of administration, the type and severity of the e or condition and on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. It will also depend on the degree, severity and type of bateria infection, and the mode of administration. The skilled artisan will be able to determine appropriate s depending on these and other s. When co-administered with other agents, e.g., when co— administered with a bateria infection agent, an "effective amount" of the second agent will depend on the type of drug used. Suitable dosages are known for approved agents and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition(s) being treated and the amount of a compound of the ion being used. In cases where no amount is expressly noted, an effective amount should be assumed.

As used , the terms "treat", "treatment" and "treating" refer to the reduction or amelioration of the progression, severity and/or duration of a a infection, or the amelioration of one or more symptoms (preferably, one or more discernible symptoms) of a bateria infection resulting from the administration of one or more therapies (e.g., one or more therapeutic agents such as a compound of the invention). In specific embodiments, the terms "treat", "treatment" and "treating" refer to the amelioration of at least one measurable physical parameter of a bacteria infection. In other embodiments the terms "treat", "treatment" and "treating" refer to the inhibition of the progression of a a infection, either physically by, e. g., stabilization of a discernible symptom, physiologically by, e. g., stabilization of a physical parameter, or both. In other embodiments the terms "treat", "treatment" and "treating" refer to the reduction or ization of a bateria infection.

As used herein, the terms "prevent", "prevention" and "preventing" refer to the reduction in the risk of acquiring or developing a given bateria infection, or the reduction or inhibition of the recurrence or a bateria infection. In one embodiment, a compound of the invention is administered as a tative measure to a patient, preferably a human, having a c predisposition to any of the conditions, diseases or disorders described herein.

The pharmaceutically acceptable compositions of this ion can be administered to humans and other animals orally, rectally, parenterally, intracistemally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), y, as an oral or nasal spray, or the like, depending on the severity of the infection being treated.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable ons, microemulsions, solutions, suspensions, syrups and elixirs. In on to the active compounds, the liquid dosage forms may n inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3—butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and es f Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

Inj ectable preparations, for example, sterile inj ectable aqueous or oleaginous sions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile inj e preparation may also be a e injectable on, suspension or emulsion in a ic erally acceptable diluent or solvent, for example, as a solution in l,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, e, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono— or erides. In addition, fatty acids such as oleic acid are used in the preparation of inj ectables.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating izing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile able medium prior to use.

In order to g the effect of a compound of the present invention, it is often ble to slow the absorption of the compound from subcutaneous or uscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of tion of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the nd in biodegradable polymers such as polylactide—polyglycolide. Depending upon the ratio of nd to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable rs include poly(orthoesters) and poly(anhydrides). Depot inj ectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are ible with body tissues.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a itory wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, e, sucrose, e, mannitol, and c acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar--agar, calcium carbonate, potato or tapioca starch, c acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering .

Solid compositions of a similar type may also be employed as s in soft and hard- fllled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric gs and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they e the active ingredient(s) only, or preferentially, in a certain part of the inal tract, optionally, in a delayed manner. Examples of ing compositions that can be used include ric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

The active compounds can also be in ncapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, s, es, pills, and granules can be prepared with coatings and shells such as enteric coatings, release lling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active nd may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e. g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a n part of the inal tract, optionally, in a delayed manner.

Examples of embedding compositions that can be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is d under sterile conditions with a pharmaceutically acceptable carrier and any needed vatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present invention contemplates the use of ermal patches, which have the added advantage of providing controlled delivery of a nd to the body. Such dosage forms can be made by dissolving or sing the compound in the proper medium. tion enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by sing the compound in a polymer matrix or gel.

The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted oir. The term "parenteral" as used herein es, but is not limited to, aneous, intravenous, uscular, intra—articular, intra-synovial, intrastemal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally or intravenously.

Sterile injectable forms of the itions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using le dispersing or wetting agents and suspending agents. The sterile able preparation may also be a sterile inj ectable solution or suspension in a non-toxic parenterallyacceptable diluent or solvent, for example as a solution in l,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In on, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be ed including synthetic mono— or di—glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of inj ectables, as are natural pharmaceutically- acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.

These oil solutions or suspensions may also contain a long-chain alcohol t or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are ly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form ing, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include, but are not limited to, lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents 2014/024411 include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, n sweetening, flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene s.

The pharmaceutical compositions of this ion may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical ations are readily prepared for each of these areas or organs.

Topical application for the lower intestinal tract can be effected in a rectal suppository ation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more rs. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, fying wax and water. Alternatively, the ceutical compositions can be ated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically able carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2 octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, ably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative such as benzylalkonium de. Alternatively, for ophthalmic uses, the pharmaceutical itions may be formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in , employing 2014/024411 benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents.

The dosage regimen utilizing the compounds of present invention can be selected in accordance with a y of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the renal and hepatic function of the subject; and the particular compound or salt thereof ed, the duration of the treatment; drugs used in combination or coincidental with the specific compound employed, and like factors well known in the l arts. The skilled artisan can readily determine and prescribe the effective amount of the compound of present invention required to treat, for example, to prevent, inhibit (fully or partially) or arrest the progress of the disease.

Dosages of the compounds of present invention can range from n about 0.01 to about 100 mg/kg body weight/day, about 0.01 to about 50 mg/kg body weight/day, about 0.1 to about 50 mg/kg body weight/day, or about 1 to about 25 mg/kg body weight/day. It is understood that the total amount per day can be administered in a single dose or can be administered in multiple dosings such as twice, three or four times per day.

The compounds for use in the method of the invention can be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosage for subjects undergoing treatment, with each unit containing a predetermined quantity of active al calculated to e the d therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form can be for a single daily dose or one of multiple daily doses (e.g., about 1 to 4 or more times per day). When multiple daily doses are used, the unit dosage form can be the same or different for each dose.

An effective amount can be achieved in the method or pharmaceutical composition of the ion employing a compound of present invention or a pharmaceutically acceptable salt thereof alone or in ation with an additional suitable therapeutic agent, for example, a -therapeutic agent. When combination therapy is employed, an effective amount can be achieved using a first amount of a compound of present invention or a ceutically acceptable salt f and a second amount of an additional suitable therapeutic agent.

In one embodiment, the compound of present ion and the additional therapeutic agent, are each administered in an effective amount (i.e., each in an amount which would be WO 65107 eutically effective if administered alone). In another embodiment, the compound of present invention and the additional therapeutic agent, are each administered in an amount which alone does not provide a therapeutic effect (a erapeutic dose). In yet another ment, the compound of present ion can be administered in an effective , while the additional therapeutic agent is administered in a sub-therapeutic dose. In still r embodiment, the compound of present invention can be administered in a sub— therapeutic dose, while the additional eutic agent, for example, a suitable cancertherapeutic agent is administered in an effective amount.

As used herein, the terms "in combination" or "coadministration" can be used interchangeably to refer to the use of more than one therapies (e. g., one or more lactic and/or therapeutic agents). The use of the terms does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a subject.

Coadministration encompasses stration of the first and second amounts of the compounds of the coadministration in an essentially simultaneous manner, such as in a single pharmaceutical composition, for example, capsule or tablet having a fixed ratio of first and second amounts, or in multiple, separate capsules or tablets for each. In addition, such coadministration also encompasses use of each compound in a sequential manner in either order.

When coadministration involves the separate administration of the first amount of a compound of present invention and a second amount of an additional therapeutic agent, the compounds are administered sufficiently close in time to have the desired therapeutic effect.

For example, the period of time between each administration which can result in the desired therapeutic effect, can range from minutes to hours and can be determined taking into account the properties of each nd such as potency, lity, bioavailability, plasma half-life and kinetic profile. For example, a compound of present invention and the second eutic agent can be administered in any order within about 24 hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about 1 hour of each other or within about 30 minutes of each other.

More, specifically, a first therapy (e.g., a prophylactic or therapeutic agent such as a compound of the invention) can be administered prior to (e. g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e. g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy (e.g., a prophylactic or therapeutic agent such as an anti- cancer agent) to a subject.

It is understood that the method of coadministration of a first amount of a nd of present ion and a second amount of an additional therapeutic agent can result in an enhanced or synergistic therapeutic , wherein the combined effect is r than the additive effect that would result from separate administration of the first amount of the compound of present ion and the second amount of the additional therapeutic agent.

As used herein, the term "synergistic" refers to a combination of a compound of the invention and another therapy (e.g., a prophylactic or therapeutic agent), which is more ive than the additive effects of the therapies. A synergistic effect of a ation of therapies (e.g., a combination of prophylactic or eutic agents) permits the use of lower s of one or more of the therapies and/or less frequent administration of said therapies to a subject. The ability to utilize lower dosages of a therapy (e. g., a prophylactic or therapeutic agent) and/or to administer said therapy less frequently reduces the toxicity associated with the administration of said therapy to a subject without reducing the efficacy of said therapy in the prevention, management or treatment of a disorder. In addition, a synergistic effect can result in improved efficacy of agents in the prevention, ment or treatment of a disorder. Finally, a synergistic effect of a combination of therapies (e. g., a ation of prophylactic or therapeutic ) may avoid or reduce adverse or unwanted side effects associated with the use of either therapy alone.

The presence of a synergistic effect can be determined using suitable methods for assessing drug interaction. le methods include, for example, the Sigmoid-Emax equation (Holford, N.H.G. and Scheiner, L.B., Clin. Pharmacokinet. 6: 429-453 ), the equation of Loewe additivity (Loewe, S. and Muischnek, H., Arch. Exp. Pathol Pharmacol. 114: 313-326 (1926)) and the median-effect equation (Chou, TC. and Talalay, P., Adv.

Enzyme Regul. 22: 27—55 (1984)). Each equation referred to above can be applied with experimental data to generate a corresponding graph to aid in assessing the effects of the drug ation. The corresponding graphs associated with the equations referred to above are the concentration—effect curve, isobologram curve and combination index curve, respectively.

The activity of the compounds as inhibitors of bacteria infection may be assayed in vitro or in vivo. In vitro assays include assays that determine inhibition of the FimH activity.

Alternate in vitro assays quantitate the ability of the inhibitor to bind to the FimH and may be measured either by radiolabelling the inhibitor prior to g, isolating the inhibitor complex and determining the amount of radiolabel bound, or by running a competition experiment where new inhibitors are incubated with the FimH bound to known radioligands. ed conditions for assaying a compound utilized in this ion are set forth in the Examples below.

EXPERIMENTAL DETAILS The following abbreviations are used in the examples below: AcOH acetic acid AczO acetic ide aq aqueous BF3.OEt2 loxonio—trifluoro—boron CH3CN acetonitrile CCl3CN trichloroacetonitrile CDCl3 chloroform-D conc concentrate CV column volume CszCO3 cesium carbonate Cu(OAc)2 diacetoxycopper CHzClz methylene chloride or dichloromethane DMAP 4-dimethylaminopyridine DMF dimethylformamide DMSO dimethylsulfoxide Eq. equivalent EtOAc ethyl acetate h hour Hex hexanes LiOH.HZO lithium ide monohydrate M molar MeOH methanol NaOMe sodium methoxide Min minute MS 4A molecular sieves 4 angstrom MTBE methyl tert—butyl ether WO 65107 NazSO4 sodium sulfate NMO N—methylmorpholine-N—oxide OsO4 osmium tetroxide PdClz palladium (II)chloride Pd(OAc)2 palladium (II)acetate PdC12(dppf). CHzClz (l,l'-Bis-(diphenylphosphino)—ferrocene)palladium (II) dichloride Pd(OH)2 dihydroxy palladium Pd(PPh3)4 tetrakis(triphenylphosphine) ium Pyr pyridine RT room temperature Siliacat DPP-Pd Silica ted diphenylphosphine palladium TBABr tetrabutyl ammonium bromide TEA triethylamine THF tetrahydrofuran TLC thin layer chromatography TMSOTf trimethylsilyl trifluoromethanesulfonate The compounds of this invention may be prepared in light of the specification using steps generally known to those of ordinary skill in the art. Those compounds may be analyzed by known methods, including but not limited to LC—MS (liquid chromatography mass spectrometry), HPLC (high performance liquid chromatography) and NMR ar magnetic resonance). It should be understood that the specific conditions shown below are only examples, and are not meant to limit the scope of the conditions that can be used for making compounds of this invention. Instead, this ion also es conditions that would be apparent to those skilled in that art in light of this specification for making the compounds of this invention. Unless otherwise indicated, all variables in the following schemes are as defined herein.

Mass spec. samples are analyzed on a Waters UPLC y mass spectrometer operated in single MS mode with ospray ionization. Samples are introduced into the mass spectrometer using chromatography. Mobile phase for the mass spec. analyses consisted of 0.1% formic acid and itrile-water mixture. Column gradient conditions are 5%—85% acetonitrile-water over 6 minutes run time Acquity HSS T3 1.8um 2.1 mm ID x5 0 mm. Flow rate is 1.0 mL/min. As used herein, the term "Rt(min)" refers to the LC—MS retention time, in minutes, associated with the compound. Unless ise indicated, the LC—MS method utilized to obtain the reported retention time is as detailed above.

Purification by e phase HPLC is carried out under rd conditions using either Phenomenex Gemini 21.2 mm ID x 250 mm column (5pm), Gemini 21.2 mm ID x 75 mm column, (5 um),1 10A or in most cases a Waters XSELECT CSH Prep C18 (5 pm) ODB 19x100mm column. Elution is performed using a linear gradient CH3CN—H20 (with or without 0.01%TFA buffer or 0.1% HCOH) as mobile phase. Solvent system is ed according to the polarity of the compound, Flow rate, 20 mL/min. Compounds are collected either by UV or Waters 3100 Mass Detector, ESI Positive Mode. Fractions containing the desired compound are ed, concentrated (rotary evaporator) to remove excess CH3CN and the resulting aqueous solution is lyophilized to afford the desired material in most cases as a white foam.

HPLC analytical method is performed on Phenomenex Gemini C18 3um 110A 4.6 mm ID x 250 mm, Phenomenex Gemini C18 3um 110 A 4.6 mm ID x 50 mm, using different combinations of H20 (0.01%TFA as buffer) as mobile phase, Flow rate, 1 mL/min, PDA 210 nm. Method A: Phenomenex Gemini C18 3um 110A 4.6 mm ID x 250mm; (10- 50% acetonitrile-water for 40 min, 0.01% TFA). Method B: Phenomenex Gemini C18 3um 110A 4.6 mm ID x 250mm; (50-90% acetonitrile-water for 40 min, 0.01% TFA). Method C: Phenomenex Gemini C18 3um 110A 4.6mm ID x 50mm; (20-60% acetonitrile-water for 10 min, 0.01% TFA). Method D: Phenomenex Gemini C18 3um 110A 4.6mm ID x 50mm; (10- 50% acetonitrile-water for 10 min, 0.01% TFA).

General s of Synthesis: EXAMPLEs bed n are prepared according to the following general METHODs METHOD 1: Preparation of biaryl INTERMEDIATEs of type III Biaryl intermediates of type III are prepared (Scheme 1) by palladium catalyzed cross— coupling between arylboronic acid or aryl-pinacol boronate of type I (commercially available of prepared from the corresponding halide) and aryl-halides of type 11. Alternatively, the coupling partners are the arylboronic acid or inacol boronate of Type IV rcially available of prepared from the corresponding halide) and aryl-halides of type V.

Scheme 1 (JB)n T HO J (JB)n (JA)m (~J B)n J Pd catalyst METHOD 2: sis of EXAMPLES of Formula A and C Compounds of Formula A and C can be prepared in a two steps synthetic sequence (Scheme 2). Glycosylation of biaryls of type 111 can be achieved by three distinct synthetic routes (Scheme 2). Firstly, activation of the anomeric yl derivative of type VI by Lewis acid (BF3OEt2) in presence of the biaryl of type 111 gives the protected (PG is Ac) ide of type VII. Alternatively, glycosylation of biaryls of type 111 can be achieved by activation of the trichloroimidate of type VIII with trimethylsilyl triflate. Lastly, activation of the ic fluoride of type IX with mercuric bromide in presence of biaryls type 111 can afford the fully protected mannosides of type VII. Finally, protective group removal (saponification for acetate and enolysis for benzyl ether) on VII will generate the desired mannosides of type X.

Scheme 2 BF30Et2 PG: protecting group (e.g. Ac, Bn) TMSOTf \O x3 Y1 B VII \f‘ (mm (JB)n Deprotection HgBr2 METHOD 3: Synthesis of ES of Formula A and C Alternatively, mannosides of a A and C can be prepared in a three steps synthetic sequence (Scheme 3). Glycosylation of II in conditions previously described in Method 2 can generate intermediates of type XI which can be submitted to a palladium catalyzed cross coupling with I to generate fully protected mannosides of type VII. Deprotection in ion previously described generates the desired mannoside of type X.

WO 65107 BF30Et2 (JA)m PG: protecting group (e.g. Ac, Bn) TMSOTf (JA)m x (JA)m (J B )n HgBr2 + H—Y1 X or (mm 0/3 X = Br, I, OTf (JB)n Deprotection VII *3 Y1 0 x (A) Q (me (JB)n (JA)m (JB)n METHOD 4: Synthesis of EXAMPLES of Formula A and C Alternatively, mannosides of type XI can be converted to their corresponding pinacol boronate XII followed by a palladium zed cross coupling with aryl bromides of type V to generate previously described mannosides VII (Scheme 4).

Scheme 4 Pd st X = Br, I, OTf Deprotection (JA)m (JB)n (mm (JB)n METHOD 5: Synthesis of EXAMPLES of Formula D Mannosides of Formula D can be prepared in a two steps sequence (Scheme 5). Lewis acid (e. g. BF3OEt2) promoted addition of phenols of type XIII on (E)-2—((3S,4S,5R,6R)- 3,4,5-tris(benzyloxy)((benzyloxy)methyl)tetrahydro-2H-pyranylidene)ethyl acetate affords the spiro—mannoside XIV( see Tetrahedron, 2010, 66, 5229—5234). Finally, enolysis of the benzyl protective groups generates the desired mannosides of type XV. 2014/024411 XIII XIV 'fl‘X’ METHOD 6: Synthesis of EXAMPLES of Formula B Mannosides of Formula B can be prepared in a two steps synthetic sequence (Scheme 6).

Trimethylsilyl triflate ed addition of alcohols of type XVII onto mannosides of type XVI generates the a-O-mannosides of type XVIII. Hydrogenolysis of the latter generates the desire mannosides XIX.

Scheme6 H OBn OB /O H n OBn BnO BnO XVIII _ | BnO TMSOTf H BnO x1 H +H Y2 _ ..... I‘ B —> H I ,' Y2 H H OH H l (JA)m (JB)n Deprotection ~ "'\ XVII METHOD 7: sis of EXAMPLES of Formula E Bis-mannosides of Formula E can be prepared in three parallel synthetic route involving two steps each. First, palladium catalyzed coupling between the pinacole boronate X11 and the halogenated aryl XX provides the fully protected bis-mannoside XXI. Removal of protective groups of XXI generates the desired bis—mannoside XXII. Alternatively, halogenated aryl XI and XX can be coupled directly under palladium catalysis (see J. Org.

Chem. 2003, 68, 393 8—3942 when X=Br and J. Org. Chem. 2012, 77, 2971-2977 when X=I).

Finally, double idation of bis-phenol of type XXIII by activation of the anomeric O- acetyl derivative of type VI by a Lewis acid (e. g. BF3OEt2) can also provide the desired fully protected bis—mannoside XXI. 2014/024411 Scheme 7 Pd catalyst TBABr / Pd(OAc)2 X=Br / \ N N XX"(E) (JA) ‘— (Wu X2 H H OH HO H METHOD 8: Synthesis of EXAMPLES of Formula F Bis-mannosides of Formula F can be prepared in two steps Via a double palladium catalyzed cross coupling between the pinacol boronate X11 and a bis—halogenated aryl or heteroaryl. The resulting nnoside XXIV can subsequently be deprotected under standard conditions to afford the desire bis—mannoside XXV.

WO 65107 Scheme 8 X is halo and PG is a suitable hydroxyl protecting group.

METHOD 9: Synthesis of EXAMPLEs of Formula G Mannosides of Formula G can be prepared in one step Via a double ium / copper catalyzed Sonogashira coupling between the aryl bromide XXVI, obtained from removal of protective groups on XI, and TMS-acetylene.

Scheme 9 Pd catalyst Cul/DBU METHOD 10: Synthesis of EXAMPLES of Formula H Compounds of Formula H can be prepared in two steps. Firstly, palladium catalyzed cross coupling between the aryl bromide XXIX and the pinacol boronate XXVIII can generate the desired biaryl XXX. Removal of the protective group would afford the desired bis-spiro-mannoside XXXI. Intermediates XXIX and XXVIII can be generated from coupling described in Method 5 using appropriately tuted phenols.

Scheme 10 Pd st XXXI (H) Carbohydrate EDIATEs M1 to M22 depicted in Figure l are used in the preparation of EXAMPLEs described therein.

WO 65107 Figure 1 Ace" OAc F OBn (M1) (M2) (M3) ation of INTERMEDIATE M1 (2R,3 R,6R)(acetoxymethyl)-3 -fluorotetrahydro-2H-pyran-2,4,5-triyl triacetate 0 .\\OAc Am" F The title compound is prepared according to the procedure describe in Angew. Chem. Int.

Ed. 2010, 49, 8724—8728 Preparation of INTERMEDIATE M2 :4aR,6R,7S,8S8,aR)—7—(benzyloxy)fluorophenyl(phenylthio)hexahydropyrano[3,2-][1,3]dioxine The title nd is prepared according to the procedure describe in JOC, 2007, 72, 1681-1690.

Preparation of INTERMEDIATE M3 o "to and" OBn OBn Step I: (2R,3R,4S,5S,6R)(acetoxymethyl)(4-iodophenoxy)tetrahydro-2H-pyran-3,4,5- triyl triacetate O "‘0 Aco"' OAc To a solution of commercially available [(2R,3R,4S,5S,6R)—3,4,5,6— tetraacetoxytetrahydropyranyl]methyl acetate (3.814 g, 9.771 mmol) and 4-iodophenol (2.650 g, 12.05 mmol) in 1,2-dichloroethane (35 mL) at 0°C was added BF3.OEt2 (1.810 mL, 14.66 mmol) dropwise. The reaction mixture is warmed to RT and d at 40°C for 12h.

The reaction mixture is cooled to RT, poured in a saturated aqueous NaHCO3 and diluted with CHzClz. The organic layer is separated and the aqueous layer is back washed With CHzClz. The combined organic fractions are dried over NazSO4, filtered and concentrated.

The desired compound is purified on a Silica gel column (100g) using Hexane / EtOAc (20 to 60% EA) as the eluant on a BiotageTM system to afford the title compound , 75% yield).

Step II: (2R,3S,4S,5S,6R)—2—(((tert—butyldiphenylsilyl)oxy)methyl)—6—(4— iodophenoxy)tetrahydro-2H-pyran-3,4,5-triol Ho"' OH To a solution of R,4S,5S,6R)-3,4,5-triacetoxy(4-iodophenoxy)tetrahydropyran- ethyl acetate from Step I (4.014 g, 7.29 mmol) in MeOH (100 mL) is added NaOMe (1.58 mL of 25 %w/V, 7.29 mmol). The reaction mixture is stirred overnight at RT. The reaction mixture is quenched with acetic acid (420 uL, 7.386 mmol) and concentrated. The e is suspended in 500mL of T01 and the mixture is concentrated in vacuo. The residue is partially dissolved in DMF (100 mL), cooled 0°C and tert—butyl-chloro-diphenyl-silane (4.00 mL, 15.38 mmol) then 4H-imidazole (2.023 g, 29.72 mmol) are added. The reaction mixture is stirred 3h at 0°C then allowed to warm to RT and stirred over two days. The resulting mixture is poured in HZO/EtZO (l/ l). The organic layer is separated, washed with water (2x), brine, dried over MgSO4, filtered and trated. The residue is purified over a large pad of silica gel eluting with 10, 20, 50 and 100% EtOAc in Hex to afford the desired material (3.725 g, 82% yield) Step III: tert—butyldiphenyl(((2R,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)(4-iodophenoxy) tetrahydro-2H-pyranyl)methoxy)silane To a solution of tert—butyldiphenyl(((2R,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)—6-(4- iodophenoxy) ydro-2H-pyranyl)methoxy)silane from Step 11 (3.725 g, 6.003 mmol) and benzyl bromide (2.90 mL, 24.4 mmol) in DMF (30 mL) at 0°C is added portion wise NaH (801 mg, 20.0 mmol). The reaction mixture was allowed to warm to RT and was d for 12hrs. The reaction mixture is poured in a saturated aqueous on on NH4Cl and extracted with EtZO. The organic layer was washed with water (twice), brine, dried over MgSO4, filtered and concentrated. The resulting crude mixture is purified on a pad of silica gel using Hexane / EtOAc (0, 2, 4% EA) as the eluent to afford the title compound (4.002 g, 73% yield) as a colorless oil.

Step IV: ((2R,3R,4S,5S,6R)—3,4,5-tris(benzyloxy)(4-iodophenoxy)tetrahydro-2H-pyran yl)methanol o 0 Bno‘" OBn OBn To a solution of tert—butyldiphenyl(((2R,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)—6-(4- iodophenoxy) tetrahydro-2H-pyranyl)methoxy)silane from Step III (4.002 g, 4.402 mmol) in THF (75 mL) is added acetic acid (100 "L, 1.76 mmol) then tetrabutylammonium fluoride (10.6 mL of 1 M, 10.6 mmol). The reaction mixture is stirred overnight at RT. The ing mixture is concentrated in vacuo and he residue is purified on a Silica gel column (100g) using Hexane / EtOAc ( 10 to 30% EA) as the eluant on a BiotageTM system to afford the title compound (2.583 g, 85% yield) as a colorless oil.

Step V: INTERMEDIATE M3 To a solution of ((2R,3R,4S,5S,6R)-3,4,5-tris(benzyloxy)(4-iodophenoxy)tetrahydro- 2H-pyranyl)methanol from Step IV (444 mg, 0.646 mmol) in CHzClz (5.02 mL) at 0°C is added 6,7,8,9,10—octahydropyrimido[1,2—a]azepine (193 uL, 1.293 mmol) then XtalFluor-E (163 mg, 0.711 mmol) . The reaction mixture is d at 0°C for 2h the poured in a saturated aqueous solution on NaHCO3 and diluted with CHzClz. The organic layer is separated, dried over NazSO4, filtered and concentrated. The resulting crude mixture is ed on a Silica gel column (25g) using Hexane / EtOAc (0 to 20% EA) as the eluant on a eTM system to afford the title compound (52mg, 12% yield).

Preparation of INTERMEDIATE M4 (3 S,4S,5R,6R)(acetoxymethyl)methyltetrahydro-2H-pyran-2,3,4,5-tetrayl tetraacetate 0 OAc W OAc AcO 1,, Step I: (3aS,6R,6aS)((R)-2,2-dimethyl-1,3-dioxolanyl)—3a-(hydroxymethyl)-2,2- dimethyltetrahydrofuro[3 ,4-d][1,3]dioxol—4—ol O oOH To a suspension of (3aS,4S,6R,6aS)—6—((R)—2,2—dimethyl—1,3—dioxolan—4-yl)—2,2— dimethyltetrahydrofuro[3,4-d][1,3]dioxolol (commercially available) (25.00 g, 96.1 mmol) and K2C03 (19.92 g, 144.1 mmol) in MeOH (250.0 mL) is added formic acid (37% in water,178.7 mL, 2.401 mmol). The reaction mixture is stirred 64 hrs at 95°C, cooled to 0°C, neutralized (pH 7) with aqueous H2804 (10%). The mixture is stirred 15 min at 0°C, at which point the resulting precipitate is ed off and the mother liquor is concentrated in vacuo to provide a colorless oil. The crude oil is dissolved in CHzClz and the organic phase is washed with water and brine. The solution is dried over NaZSO4, filtered, concentrated in vacuo and finally purified by flash column chromatography(220g of silica) using 40-100% EtOAc /Hexane over 15 CV to afford the title compound (19.3 g, 66.5 mmol, 69%).

Step II: (3 aS,6R,6aS)((R)-2,2-dimethyl-1,3-dioxolanyl)—3 roxymethyl)-2,2- yldihydrofuro[3 ,4-d][1,3]dioxol—4(3 aH)—one "if0 0 OOH In a 3 neck round bottom flask of (3 L), equipped with ical stirring and thermocouple is added (3 aS,6R,6aS)—6—((R)—2,2—dimethyl—1,3—dioxolanyl)—3a— (hydroxymethyl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol—4—ol from Step I (38 g, 130.9 mmol), CszCO3 (23.58 g, 235.6 mmol) and water (1.33 L). The ing mixture is cooled down to 3°C using ice/water bath, then Brz (31.37 g, 10.11 mL, 196.3 mmol) is added over 5 min. The reaction mixture is d to reach RT gradually and stir 16 h. The reaction mixture is flushed with N2 (bubbling in solution) for 30 min, treated with 300 ml of aqueous saturated NaZSZO3 for 15 min and extracted with (3x200ml) CHzClz. The combined organic phases are washed with water, dry over NazSO4, filtered, concentrated and purified by flash column chromatography(220g of silica ) using 0-75% EtOAc e over 10 CV to afford the tittle compound (29.0 g, 101 mmol, 77%).

Step III: (3 aS,6R,6aS)—6-((R)—2,2-dimethyl-1,3-dioxolanyl)-3a-(iodomethyl)-2,2- dimethyldihydrofuro[3 ,4-d][1,3]dioxol—4(3 aH)—one O o | In a 2L round bottom flask, equipped with mechanical stirring and a condenser is loaded (3 6aS)((R)-2,2-dimethyl-1,3 -dioxolanyl)-3 a-(hydroxymethyl)-2,2- yldihydrofuro[3,4—d][1,3]dioxol—4(3aH)—one (30.5 g, 106 mmol), imidazole (25.93 g, 380.9 mmol) and triphenylphosphane (72.15 g, 275.1 mmol), toluene (915.0 mL) followed by 12 (69.82 g, 275.1 mmol). The reaction mixture is stirred at 85°C for 90 min, cooled to RT and filtered. The solid is washed with 200 ml of toluene and to the combined filtrates is added 150 ml of aqueous saturated Na2S203 and 25 ml NaCl. The resulting solution is stirred for 15 min. The organic layer is separated, washed with saturated NaHC03 and 25 ml of brine. The organic phase is dried over NazSO4, filtered, concentrated and purified using 320g of silica and 100% Hexane 4 CV and 0—80% over 7 CV to afford the tittle compound (39.0 g, 97.9 mmol, 92.6%) as a white solid.

Step IV: (3 6aS)—6—((R)—2,2—dimethyl— 1 ,3 —dioxolan—4—yl)—2,2,3a— hyldihydrofuro[3 ,4-d][1,3]dioxol—4(3 aH)—one (3 aS,6R,6aS)((R)-2,2-dimethyl- 1,3 -dioxolanyl)-3 omethyl)-2,2- yldihydrofuro[3,4-d][1,3]dioxol-4(3 aH)-one from Step III (39 g, 97.94 mmol) is dissolve in EtOH (195 mL). To the resulting solution is added Et3N (16.4 mL, 118 mmol) and Pd/C 10 % wet (1.04 g, 9.79 mmol). The reaction mixture was stirred under H2 atmosphere (40 psi) for 72 h. The resulting reaction mixture is filtered on celite, the latter washed with 600ml of EtOH. The combined solutions are diluted with 1.6 L of CHzClz and 800ml of saturated aqueous Na2S203 is added. This mixture is d for 15 min. The organic phase is separated, washed with 800ml of saturated aqueous Na2S203. After separation, the organic phase is dried over NazSO4, filtered and concentrated. This crude materiel is recrystallized in 40 mL of EtOH and 25 mL of heptane at 830 C. Upon cooling the resulting lline material is collected by filtration to afford the title nd (24.3 g, 89.3 mmol, 91%) as a white solid.

Step V: (3 aS,6R,6aS)—6—((R)—2,2-dimethyl- 1 ,3 -dioxolanyl)-2,2,3 a- trimethyltetrahydrofuro[3 ,4-d][1,3]dioxol—4—ol "'Me XO DIBAL (24.2 mL of 1.5 M, 36.4 mmol) in toluene is added dropwise over 10 min to a cold (—78°C ) solution of (3 aS,6R,6aS)—6—((R)—2,2-dimethyl—1,3-dioxolan—4—yl)—2,2,3a— trimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one from Step IV (9.00 g, 33.1 mmol) in CHzClz (90 mL). The reaction e is stirred at -78°C for 2h. Upon completion, the cold reaction mixture is quenched with 4 ml of MeOH added dropwise over 2 min and then allowed to warm to RT over 30 min. 500 ml of saturated s sodium tartrate is added and the resulting slurry is stirred vigorously for 1h at room temp. The organic phase is separated, washed with water, brine, dried over NaZSO4, ed and trated to afford the title compound (22.1 g, 80.7 mmol, 98%).

Step VI: (3 S,4S,5S,6R)—6—(hydroxymethyl)—3-methyltetrahydro-2H-pyran-2,3,4,5-tetraol HOARI-—, OHHO 0 OH To a solution of (3 aS,6R,6aS)((R)-2,2-dimethyl-1,3-dioxolanyl)-2,2,3a- trimethyltetrahydrofuro[3,4-d][1,3]dioxolol from Step V (9.00 g, 32.8 mmol) in H20 (45 mL) and dioxane (45 mL) is added Dowex 50WX4 resin (4.5 g). The reaction mixture is stirred at 60°C for 16 h, cooled to RT, filtered and concentrated to afford the tittle compound (6.25 g, 32.19 mmol, 98%).

Step VII: INTERMEDIATE M4 To a solution of (3 S,6R)—6—(hydroxymethyl)—3—methyltetrahydro—2H—pyran—2,3,4,5— tetraol from Step VI (7.40 g, 38.11 mmol) in pyridine (148 mL) is added DMAP (931 mg, 7.62 mmol) and ACZO (71.9 mL, 762 mmol). The reaction mixture is stirred at 60°C for 16 h, cooled down to RT, diluted with CHzClz (300 mL) and water (300 mL) is added over 10 min and the final mixture stirred for 15 min. The organic phase is ted, washed twice with 250 ml of HCl 1N followed by brine, dried over NazSO4, filtered, and trated. cation on BiotageTM SNAP silica cartridge (220 g) using EtOAc (40% to 80% in 10 CV) / Hex as eluent afforded the title compound (11.1 g, 72%) as a one to one mixture of 0t and [3 diastereoisomers at the anomeric carbon. 1H NMR (400 MHz, CDCl3) a mixture of OL/B (ca. 1:1) 5 6.86 (s, 1H, Hm), 5.62 (s, 1H, H13), 5.42—5.05 (m, 4H), 4.30—4.05 (m, 4H), 4.04—3.82 (m, 2H), 2.20—2.03 (m, 30H, 10 OAc), 1.62 (s, 3H, CH3 0t or [3), 1.48 (s, 3H, CH3 0L or [3).

Preparation of INTERMEDIATE M5 (3 S,4S,5R,6R)—6—((S)acetoxyethyl)tetrahydro-2H-pyran-2,3 ,4,5 -tetrayl tetraacetate : 0 OAc AcO‘" 0A0 Step I: (2R,3R,4S,5S,6S)—3,4,5,6-tetrabenzyloxytetrahydropyranyl]methanol O "\OBn Bno"' OBn The title compound is prepared using the procedure described in: Daragics, K.; Fiigedi, P.

Tet. Lett., 2009, 50, 2914—2916.

Step II: (1 S)—1—[(2R,3 S,4S,5 S,6S)-3 ,4,5,6-tetrabenzyloxytetrahydropyranyl]ethanol : O MOB" Bno‘" OBn To a solution of (2R,3R,4S,5S,6S)-3,4,5,6-tetrabenzyloxytetrahydropyranyl]methanol from Step I (856 mg, 1.58 mmol) in DMSO (4.66 mL), and Et3N (1.103 mL, 7.915 mmol) in CHzClz (4.7 mL) at 0°C is added SO3.pyridine complex (1.260 g, 7.915 mmol) in 3 portions.

The reaction is stirred for 1h. Upon completion, the reaction mixture is diluted with EtOAc, and washed successively with water, 10% aqueous potassium bisulfate, saturated aqueous NaHCO3 and brine. The c phase is dried over MgSO4, filtered and concentrated in vacuo. The e is co—evaporated twice with benzene to give crude aldehyde which is used without further purification in the next step. MeMgBr (1.90 mL of 3 M, 5.68 mmol) is added to a solution of (2S,3S,4S,SS,6S)-3,4,5,6-tetrabenzyloxytetrahydropyrancarbaldehyde (1.531 g, 2.842 mmol) in THF (14 mL) at 0°C. The reaction mixture is stirred for 15min then stirred for 90 minutes at RT. Upon tion, a saturated aqueous solution of NH4Cl is added to the mixture and the product is extracted from the aqueous phase with CHzClz (3 times). The combined organic layers are dried over NaZSO4, filtered and concentrated in vacuo. The residue is purified twice by flash chromatography using first a gradient of 0-60% EtOAc: Hex, then 10—20% EtOAc: Hex for the second time, to provide the title nd (989.7mg, 63% yield).

LC—MS: m/z = 577.5 (M+Na+).

The 1H NMR corresponds to the one reported in the literature in: Doores, K.J.; Fulton, Z.; Hong, V.; Patel, M.K.; Scanlan, C.N., Wormald, M.R.; Finn, M.G.; , D.R.; , I.A.; Davis, B.G. PNAS, 2010, 107, 17107—17112.

Step III: INTERMEDIATE M5 The title compound is ed from (18)—l—[(2R,3S,4S,SS,6S)—3,4,5,6— tetrabenzyloxytetrahydropyranyl]ethanol using the procedure described in: Doores, K.J.; Fulton, Z.; Hong, V.; Patel, M.K.; Scanlan, C.N., Wormald, M.R.; Finn, M.G.; Burton, D.R.; , I.A.; Davis, B.G. PNAS, 2010, 107, 17107—17112.

Preparation of INTERMEDIATE M6 (3 S,4S,5R,6R)((R)- l -acetoxyethyl)tetrahydro-2H-pyran-2,3 ,4,5 -tetrayl tetraacetate AcO‘" OAc Step 1: [(1R)— l—[(2R,3 S,4S,5 S,6S)-3 ,4,5,6-tetrabenzyloxytetrahydropyranyl] ethyl] 4- nitrobenzoate 0 Me @O H ? O "\OBn OZN Bno‘" OBn WO 65107 A solution of (1S)—1-[(2R,3S,4S,5S,6S)-3,4,5,6-tetrabenzyloxytetrahydropyran yl]ethanol from INTERMEDIATE M5 Step II (990 mg, 1.78 mmol), triphenylphosphine (749 mg, 2.85 mmol), isopropyl —isopropoxycarbonyliminocarbamate in toluene 40 %w/v (1.44 mL, 2.85 mmol) and THF (17.8 mL) is cooled to 0°C and 4—nitrobenzoic acid (477 mg, 2.85 mmol) is added. The reaction mixture is allowed to warm up to RT over 4 hours. Upon completion, the reaction is concentrated in vacuo and the crude mixture is purified by flash chromatography using a gradient of 0—100% EtOAc: Hex to e the title compound (1.03g, 82% yield). 1H NMR (400 MHz, CDCl3) 5 8.25 — 8.13 (m, 4H), 7.43 — 7.13 (m, 20H), 5.52 (qd, J= 6.6, 1.9 Hz, 1H), 5.05 — 4.95 (m, 2H), 4.77 — 4.61 (m, 6H), 4.44 (d, J: 11.8 Hz, 1H), 4.06 — 3.88 (m, 3H), 3.83 (dd, J= 3.0, 2.0 Hz, 1H), 1.36 (d, J= 6.6 Hz, 3H).

Step II: (1 R)— 1 — [(2R,3 S,4S,5 S,6S)-3 ,4,5 ,6-tetrabenzyloxytetrahydropyranyl] ethanol ; o AOBn Bno‘" OBn [(1R)—1—[(2R,3 S,4S,5 S,6S)-3 ,4,5,6-tetrabenzyloxytetrahydropyranyl]ethyl] 4- nitrobenzoate from Step I (1.03 g, 1.46 mmol) is ved in EtOH (6 mL), THF (6 mL) and water (2.6 mL). NaOH (293 mg, 7.32 mmol) is added to the mixture and the resulting solution is allowed to stir at RT for 2 hours. Upon completion, the solution is concentrated in vacuo and the crude residue is partitioned between water and CHzClz 3 times. The c layers are combined, dried over , filtered and concentrated in vacuo. The crude residue is purified by flash chromatography using a gradient 10-40% EtOAc/Hex to provide the title compound slightly contaminated (661mg, 81% yield). LC—MS: m/z = 577.7 (M+Na+) Step III: (2 S,3 S,4S,5S,6R)—6-[(1R)—1-hydroxyethyl]tetrahydropyran-2,3,4,5-tetrol =.o‘.o\H Ho"' OH OH Nitrogen is bubbled through a solution of (1R)—1—[(2R,3S,4S,5S,6S)—3,4,5,6— tetrabenzyloxytetrahydropyranyl]ethanol from Step II (661 mg, 1.192 mmol) in MeOH (12 mL). To the resulting solution is added Pd/C, wet, Degussa (126.9 mg, 0.1192 mmol). The reaction is allowed to stir at RT for 4 days under an atmosphere of hydrogen gas (1 atm). At that point, the reaction does not progress any r. The crude mixture is filtered over Celite and rinsed with MeOH and CHzClz. The filtrate is concentrate in vacuo to provide a crude mixture of several products. ium hydroxide (83.7 mg, 0.119 mmol) is charged in a degassed solution of the above mentioned mixture and acetic acid (68.0 uL, 1.19 mmol) in MeOH (10 mL). The reaction mixture is allowed to stir for 2 days under 1 atm of hydrogen gas. The solution is filtered over Celite and the filtrate is concentrated in vacuo to provide again a mixture of several products. Finally, palladium ide (280 mg, 0.399 mmol) is charged in a degassed solution of the above ned mixture and acetic acid (57.0 uL, 0.996 mmol) in MeOH (7 mL). The reaction mixture is allowed to stir for 2 days under 1 atm of H2. Upon tion of the reaction, the solution is filtered over Celite and rinsed with MeOH. The liquor is concentrated in vacuo and the crude product is co—evaporated 3 times with benzene to remove any remaining AcOH. The crude product is used directly in the next step. LC—MS: m/z = 217.2 (M+Na+) Step IV: INTERMEDIATE M6 Crude (2S,3 S,4S,5 S,6R)—6—[(1R)—l—hydroxyethyl]tetrahydropyran-2,3,4,5-tetrol from Step 111 (193.4 mg, 0.996 mmol) is stirred in ACZO (5.0 mL, 53 mmol) and pyridine (10 mL) at RT for 18 hours. Upon completion, the reaction mixture is concentrated in vacuo and co— evaporated With benzene. The residue is purified by flash chromatography using first a gradient of 20-50% EtOAc: Hex, and then a second chromatography is performed using 20- 40% EtOAc: Hex to provide de title compound (290mg, 72% yield over 2 last steps).

LC—MS: m/z = 427.3 (M+Na)+.

Preparation of INTERMEDIATE M7 [(2R,3 S,4S,5 S)—3 ,4,5,6-tetraacetoxymethyl-tetrahydropyranyl]methyl acetate ; 0 OAc Aco"' OAc OAc The ttle nd is prepared using the ure described in: Doores, K.J.; Fulton, Z.; Hong, V.; Patel, M.K.; Scanlan, C.N., Wormald, M.R.; Finn, M.G.; , D.R.; Wilson, I.A.; Davis, B.G. PNAS, 2010, 107, 17107—17112.

Preparation of INTERMEDIATE M8 (3 S,4S,5R,6R)—6—(acetoxymethyl)((benzyloxy)methyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl tetraacetate Step I: (3 aS,6R,6aS)—3 a-((benzyloxy)methyl)((R)-2,2-dimethyl-1,3 -dioxolanyl)—2,2- dimethyldihydrofuro[3 ,4-d][1,3]dioxol—4(3 aH)—one KL?O 0 o OBn To a cold (0°C) solution of (3aS,6R,6aS)—6—((R)—2,2—dimethyl—1,3-dioxolan—4—yl)—3a— (hydroxymethyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one from INTERMEDIATE M4 Step II (1.500 g, 5.203 mmol) in DMF (23 mL) is added NaH (250 mg, 6.24 mmol). The reaction mixture is stirred for 15 min, then, benzyl bromide (743 "L, 6.24 mmol) is added and the final reaction mixture is d at RT for 2h. The reaction mixture is partitioned between EtOAc and water. The organic layer is dried over NazSO4, concentrated and purified by flash chromatography (0-50% Hexane) to afford the tittle compound (1200 mg, 3.171 mmol, 61%). 1H NMR (400 MHz, CDCl3) 5 7.48 — 7.08 (m, 5H), 4.75 (d, J: 3.2 Hz, 1H), 4.60 (d, J: 12.1 Hz, 1H), 4.53 (d, J: 12.0 Hz, 1H), 4.50 — 4.32 (m, 2H), 4.18 — 4.09 (m, 1H), 4.08 (dd, J: 9.1, 3.9 Hz, 1H), 3.94 (d, J: 9.1 Hz, 1H), 3.72 (d, J: 9.1 Hz, 1H), 1.47 (s, 6H), 1.39 (s, 6H).

Step II: (3 aS,6R,6aS)—3a-((benzyloxy)methyl)—6-((R)-2,2-dimethyl-1,3-dioxolanyl)-2,2- dimethyltetrahydrofuro[3 ,4-d][1,3]dioxol—4—ol M140 0 o OBn The title compound is ed according to the procedure described in INTERMEDIATE M4 Step V but using (3aS,6R,6aS)-3a-((benzyloxy)methyl)((R)-2,2- yl-1,3 -dioxolanyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one from Step 1. LC—MS: m/z = 403.4 (M+Na)+.

Step III: (3 S,4S,5 S,6R)—3 —((benzyloxy)methyl)(hydroxymethyl)tetrahydro-2H-pyran- 2,3 ,4,5-tetraol To a solution of (3 aS,6R,6aS)—3a-((benzyloxy)methyl)((R)-2,2-dimethyl-1,3-dioxolan- 4-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxolol from Step II (1000 mg, 2.63 mmol) in dioxane (17 mL) and water (8.5 mL) is added TFA (2.05 mL, 26.6 mmol). The reaction mixture is stirred at RT for 16h. The resulting mixture is concentrated in vacuo, co— ated with toluene to afford the title compound (780 mg, 2.60 mmol, 98.80%) which is used in the next step without any further purification.

Step IV: INTERMEDIATE M8 To a cold (0°C ) solution of (3 S,4S,5S,6R)—3 —((benzyloxy)methyl)—6— (hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol from Step III (750 mg, 2.50 mmol) in ne (5.1 mL) is added DMAP (61 mg, 0.499 mmol) then, ACZO (2.36 mL, 24.9 mmol) was added. The reaction mixture was stirred for 16 h at RT. The reaction mixture is partitioned between EtOAc and water. The organic layer is separated, dried over NazSO4, filtered and concentrated. The residue is purified on BiotageTM SNAP silica dge (10 g) using EtOAc (0% to 50% in 10 CV) / Hex as eluent to afford the title compound (300 mg, 24%) as a ess oil. 1H NMR (400 MHz, CDC13) a mixture of oc/B (ca. 1:2) 5 7.37—7.20 (m, 10H), 6.81 (s, 1H, Hm), 6.06 (s, 1H, H13), 5.63 (d, J= 8.1 Hz, 1H), 5.60 (d, J= 8.1 Hz, 1H), 5.38 (t, J= 9.9 Hz, 1H), 5.25 (t, J= 9.8 Hz, 1H), 4.56—3.77 (m, 14H), 2.15—1.90 (m, 30H). LC—MS: m/z = 533.8 +.

Preparation of INTERMEDIATE M9 [(2E)—2— [(3 S,4S,5R,6R)—3 ,4,5-tribenzyloxy(benzyloxymethyl)tetrahydropyran ylidene]ethyl] acetate O OAc BnO / BnO‘" OBn Step I: methyl 2-(tributylphosphoranylidene)acetate To a cold (0°C) solution of tributylphosphane (5.00 mL, 20.0 mmol) in toluene (20 mL) under N2 atmosphere is added methyl 2-bromoacetate (1.90 mL, 20.1 mmol). The ing slurry is warmed to RT and stirred ght under N2 atmosphere. The resulting mixture is concentrated in vacuo, redissolved in CH2Cl2 (50 mL), washed sequentially with aqueous 1N NaOH (2 x 20 mL), H20 (20 mL), dried over MgSO4, filtered and concentrated to provide the title compound (5.35 g, 97% yield) as a colorless oil Step II: methyl (2E)[(3S,4S,5R,6R)-3,4,5-tribenzyloxy (benzyloxymethyl)tetrahydropyranylidene]acetate o OMe BnO / v 0 BnO‘ OBn OBn To a solution of methyl 2-(tributylphosphoranylidene)acetate from Step I (2.01 g, 7.31 mmol) in toluene (9.0 mL) placed in a pressure tube is added (3 S,4S,5R,6R)—3,4,5— tribenzyloxy(benzyloxymethyl)tetrahydropyranone (prepared according to reference Org Lett, 2011, , 3628—3631 (2.00 g, 3.71 mmol). The pressure tube is capped and stirred at 80°C for 20 h. After cooling down to RT, the on mixture is purified by flash chromatography on a BiotageTM SNAP silica cartridge (100 g) using a nt of EtOAc (0 to 20%) in Hex, affording the title compound (2.01 g, 91% yield) as a colorless oil.

Step III: (2E)[(3S,4S,5R,6R)-3,4,5-tribenzyloxy(benzyloxymethyl)tetrahydropyran ylidene]ethanol o OH BnO / BnO". OBn To a cold (—78 °C) solution of methyl (2E)—2—[(3S,4S,5R,6R)—3,4,5—tribenzyloxy—6— (benzyloxymethyl)tetrahydropyranylidene]acetate from Step 8 g, 3.30 mmol) in toluene (20 mL) under N2 atmosphere is added DIBAL solution in toluene (5.60 mL of 1.5 M, 8.40 mmol) over lh via syringe-pump. The reaction e is stirred for r 2 h, then 40 mL of saturated Rochelle salt solution followed by 40 mL EtOAc is added and the mixture is stirred at RT for 3h. The layers are separated; the aqueous layer is back extracted with EtOAc (2 x 40 mL). The combined organic extracts are washed with brine (40 mL), dried over Na2SO4, filtered and concentrated. The crude product is purified by flash chromatography on a BiotageTM SNAP silica cartridge (50 g) using a gradient of EtOAc (0 to %) in CHzClz, affording the title compound (1.28 g, 68% yield) as a colorless oil which fies to a white solid.

Step IV: INTERMEDIATE M9 To a solution of (2E)[(3 S,4S,5R,6R)-3,4,5-tribenzyloxy (benzyloxymethyl)tetrahydropyranylidene]ethanol from Step 111 (1.28 g, 2.26 mmol) in CHzClz (15 mL) is added pyridine (550 uL, 6.80 mmol), DMAP (28 mg, 0.23 mmol) followed by AczO (530 "L, 5.62 mmol). After stirring for 3h, the reaction mixture is ed with H20 and aqueous 1N HCl solution (10 mL each). The layers are separated, the aqueous layer is back extracted with CHzClz (2x 10 mL). The combined organic extracts are concentrated and co—evaporated with heptane ) to provide title nd (1.36 g, 99% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) 5 7.43 — 7.23 (m, 18H), 7.22 — 7.13 (m, 2H), 5.51 (t, J = 8.2 Hz, 1H), 4.94 (d, J = 10.8 Hz, 1H), 4.75 — 4.61 (m, 4H), 4.60 — 4.49 (m, 3H), 4.45 — 4.31 (m, 2H), 4.28 — 4.13 (m, 2H), 3.86 — 3.72 (m, 2H), 3.66 — 3.52 (m, 2H), 2.00 (s, 3H). ation of INTERMEDIATE M10 (2R,3 S,4S,5R,6R)(acetoxymethyl)(4-bromomethylphenoxy)methyltetrahydro-2H- pyran-3 riyl triacetate AcO ‘\\04©*Br OAc To a solution of INTERMEDIATE M4 (2.06 g, 5.094 mmol) in CH2C12 (10 mL) is added 4-bromomethyl—phenol (1.9 g, 10.16 mmol) followed by BF3.OEt2 (3.87 mL, 30.5 mmol).

The resulting mixture is stirred at 40°C for 6 h, cooled to RT, poured slowly into a saturated NaHCO3 aqueous solution (50 mL) while stirring vigorously. The mixture is diluted with CHzClz (10 mL), the organic layer is separated and the aqueous layer is back extracted with CHzClz (2x 5mL). The combined organic layers are concentrated and the residue purified on BiotageTM SNAP silica cartridge (50 g) eluting with Hex / EtOAc (0% to 50%) to afford the title compound (1.82 g, 67.2%) as a white crystalline solid. 1H NMR (400 MHz, CDCl3) 5 7.30 (d, J = 2.0 Hz, 1H), 7.28 = 8.7 Hz, 1H), 6.24 (s, 1H), 5.57 (d, J — 7.22 (m, 1H), 7.04 (d, J = 9.7 Hz, 1H), 5.39 (t, J = 9.9 Hz, 1H), 4.17 (dd, J = 12.2, 5.4 Hz, 1H), 4.10 (dd, J =12.2, 2.4 WO 65107 Hz, 1H), 4.00 (ddd, J = 10.2, 5.4, 2.3 Hz, 1H), 2.26 (s, 3H), 2.15 (s, 3H), 2.14 (s, 3H), 2.04 (s, 6H), 1.63 (s, 3H).

Preparation of INTERMEDIATE M11 (2R,3 S,4S,5 2—(4-bromochlorophenoxy)(hydroxymethyl)-3 -methyltetrahydro-2H- pyran-3,4,5-triol HO _.\04©*Br Ho‘" OH Step I: (2R,3S,4S,5R,6R)(acetoxymethyl)(4-bromochlorophenoxy)—3- methyltetrahydro-2H-pyran-3,4,5-triyl triacetate AcO‘" OAC OAc The title compound is prepared according to the procedure described for INTERMEDIATE M10 but using ochloro-phenol as reagent. The title compound is purified on BiotageTM SNAP silica cartridge (50 g) eluting With Hex / EtOAc (0% to 35%) and isolated as a White solid (40%).

Step II: INTERMEDIATE M11 To a solution of [(2R,3R,4S,5S,6R)—3,4,5-triacetoxy(4-bromochloro-phenoxy)- -methyl-tetrahydropyranyl]methyl acetate from Step I (1.317 g, 2.387 mmol) in MeOH is added NaOMe in MeOH (4.77 mL of 0.5 M, 2.39 mmol). The reaction is stirred at RT for 18h. The reaction is neutralized with acidic Amberlyst resin, filtered and concentrated to give the title compound (888 mg, 86.1%) as a White solid. 1H NMR (400 MHz, CD3OD) 5 7.54 (s, 1H), 7.38 (d, J = 8.9 Hz, 1H), 7.32 (d, J = 8.9 Hz, 1H), 5.22 (s, 1H), 3.78 — 3.61 (m, 4H), 3.56 (dd, J = 8.7, 4.4 Hz, 1H), 1.39 (s, 3H). LCMS (M+H)+ 384.78 Preparation of INTERMEDIATE M12 (2R,3 S,4S,5R,6R)—6-(acetoxymethyl)(3 -bromochlorophenoxy)methyltetrahydro-2H- 3 ,4,5-triyl triacetate Cl Br 0 "OTC; Aco‘" OAC To a mixture of INTERMEDIATE M4 (200 mg, 0.495 mmol) and 3-bromo—2—chloro— phenol (154 mg, 0.742 mmol) in roethane (2.60 mL) is added BF3.OEt2 (190 uL, 1.50 mmol). The mixture is stirred at 60 OC overnight in a sealed tube. The resulting mixture is cooled down to RT, 2 mL of saturated aqueous NaHCO3 solution is added carefully, ed by 2 mL CHzClz. The organic layers is separated (phase separator) and the aqueous layer is back extracted with CHzClz (2 x 2 mL). The combined organic extracts are concentrated and the residue purified on eTM SNAP silica cartridge (10 g) eluting with is Hex / EtOAc in, (0—50%, 12CV, 50% 5CV) to afford the title compound (93 mg, 34%) as a white solid. LCMS (M+Na)+ 575.18 Preparation of INTERMEDIATE M13 (2R,3 S,4S,5R,6R)—6-(acetoxymethyl)(5-bromochlorophenoxy)-3 -methyltetrahydro-2H- 3 riyl triacetate [AC/$15342"0 "CGBr The title compound is prepared according to the procedure described for INTERMEDIATE M12 but using 5-bromochloro-phenol as reagent. The reaction is stirred for 48h and the title compound is isolated as a white solid (34%). LCMS (M+Na)+ 573.19 Preparation of INTERMEDIATE M14 (3 S,4S,5R,6R)—6—(acetoxymethyl)-3 -(azidomethyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl tetraacetate 0 OAc mo" '2, 0A0 To a solution of (3 S,4S,5 S,6R)—3-(azidomethyl)(hydroxymethyl)tetrahydropyran- 2,3,4,5—tetrol (prepared according to the ure describe in Tetrahedron: Asymmetry 18 (2007) 1502—1510) (650 mg, 2.76 mmol) in pyridine (13 mL) is added DMAP (68 mg, 0.55 2014/024411 mmol) and A020 (5.2 mL, 55.3 mmol). The reaction mixture is stirred at 60°C for 16 h, cooled down to RT, diluted with CHzClz (13 mL) and water (13 mL) is added over 2 min and the final mixture stirred for 5 min. The organic phase is separated, washed twice with 25 ml of HCl 1N followed by brine, dried over Na2S04, filtered, and concentrated. Purification on BiotageTM SNAP silica cartridge (40 g) using EtOAc (0% to 80% in 10 CV) in Hex as eluent afforded the title nd (850 mg, 69%) as a two to one mixture of CC and [3 diastereoisomers at the anomeric carbon. 1H NMR (400 MHz, CDCl3) a mixture of oc/B (ca. 2:1) 5 6.72 (s, 1H, Hm), 5.91 (s, 1H, H13), 5.33 (d, J: 9.7 Hz, 1 H10), 5.4l(d, J: 9.3 Hz, 1 H13), 5.38 (t, J: 10.0 Hz, 1 H10), 5.38 (t, J=10.0 Hz, 1 Hm), 5.24 (t, J: 9.4 Hz, Hus), 4.33 — 3.80 (m, 5H), 2.22—2.17 (m, 6H), 2.12—2.07 (m, 6H), 2.05 (s, 3H).

Preparation of INTERMEDIATE M15 (3 S,4S,5R,6R)—6—(acetoxymethyl)((2-(benzyloxy)ethoxy)methyl)tetrahydro-2H-pyran- 2,3 ,4,5-tetrayl tetraacetate 0 OAc Aco‘" '3 GAO O\\/OBn Step I: (3 aS,6R,6aS)—3 a-((2-(benzyloxy)ethoxy)methyl)((R)-2,2-dimethyl- 1,3 -dioxolan yl)—2,2-dimethyldihydrofuro[3 ,4-d] [ l ,3 ]dioxol—4(3 e O ""\ )VO 0 \\‘OBn To a cold (0°C) solution of (3aS,6R,6aS)—6—((R)—2,2—dimethyl—l,3-dioxolan—4—yl)—3a— (hydroxymethyl)-2,2-dimethyldihydrofuro[3,4-d] [ l ,3 ]dioxol-4(3 aH)-one from INTERMEDIATE M4 step II (800 mg, 2.78 mmol) in DMF (12.0 mL) is added sodium;hydride (144 mg, 3.6 mmol). The reaction mixture is stirred for 15 min and 2- bromoethoxymethylbenzene (571 "L, 3.61 mmol) is added. The reaction mixture is stirred at 60°C for 16 h, ioned between EtOAc and water, the c phase is dried over Na2S04, concentrated and purified by flash chromatography on silica (0-50% EtOAC/Hexane) to afford the tittle compound (452 mg, 39%) as a ess oil. 1H NMR (400 MHz, Chloroform—d) 5 7.41 — 7.21 (m, 5H), 4.80 (d, J: 2.8 Hz, 1H), 4.53 (s, 2H), 4.46 — 4.36 (m, 2H), 4.13 (dd, J: 9.1, 5.4 Hz, 1H), 4.09 — 4.01 (m, 1H), 3.99 (d, J: 9.2 Hz,lH), 3.82 (d, J: WO 65107 9.2 Hz, 1H), 3.77 — 3.64 (m, 2H), 3.58 (td, J: 4.6, 1.5 Hz, 2H), 1.46 (s, 3H), 1.45 (s, 3H), 1.40 (s, 3H), 1.39 (s, 3H).

Step II: (3 aS,6R,6aS)-3a-((2-(benzyloxy)ethoxy)methyl)—6-((R)-2,2-dimethyl-1,3 -dioxolan yl)—2,2-dimethyltetrahydrofuro [3 ,4-d][1,3]dioxol—4—ol o"I? O ""\ )TO o ‘\‘OBn DIBAL (1.13 mL of 1.5 M, 1.7 mmol) in toluene is added dropwise to a cold (—78°C) solution of (3aS,6R,6aS)-3a-((2-(benzyloxy)ethoxy)methyl)((R)-2,2-dimethyl-1,3- dioxolanyl)-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3 aH)-one (650 mg, 1.5 mmol) in CHzClz (6.5 mL). The reaction mixture is stirred at -78°C for 2h. Upon completion, the cold reaction e is quenched with 0.3 ml of MeOH added dropwise over 2 min and then is d to warm to RT over 30 min. 50 ml of saturated aqueous sodium tartrate is added and the resulting slurry is stirred vigorously for 1h at room temp. The organic phase is separated, washed with water, brine, dried over NaZSO4, filtered and concentrated to afford the title compound (625 mg, 96%) Step III: (3 S,4S,5S,6R)—3—((2-(benzyloxy)ethoxy)methyl)—6-(hydroxymethyl)tetrahydro-2H- pyran-2,3,4,5-tetraol 0 OH Ho‘" '- OH OH \Owoan To a solution of (3 aS,6R,6aS)—3a—((2—(benzyloxy)ethoxy)methyl)—6—((R)—2,2—dimethyl— 1,3-dioxolanyl)—2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxolol (650 mg, 1.53 mmol) in H20 (3.3 mL) and dioxane (3.3 mL) is added Dowex 50WX4 resin (300 mg). The on mixture is stirred at 60°C for 16 h, cooled to RT, filtered and concentrated to afford the tittle compound (450 mg, 85%).

Step 1V: EDIATE M15 To a solution of (3 S,4S,5S,6R)—3—((2—(benzyloxy)ethoxy)methyl)—6— (hydroxymethyl)tetrahydro-2H-pyran-2,3,4,5-tetraol (450 mg, 1.31 mmol) in pyridine (9.0 mL) is added DMAP (32 mg, 0.26 mmol) and ACZO (2.5 mL, 26.1 mmol). The reaction mixture is d at 60°C for 16 h, cooled down to RT, diluted with CH2Clz (18 mL) and water (18 mL) is added over 2 min and the final mixture stirred for 15 min. The organic phase is separated, washed twice with 10 ml of HCl 1N followed by brine, dried over NaZSO4, filtered, and trated. Purification on BiotageTM SNAP silica cartridge (80 g) using EtOAc (20% to 80% in 10 CV) in Hex as eluent ed the title compound (450m g, 62%) as a 45/55 mixture of 0L and [3 diastereoisomers at the anomeric carbon. 1H NMR (400 MHz, CDC13) a mixture of oc/B (ca. 4555) 5 7.43 — 7.29 (m, 5H), 6.77 (s, 1H, Hm), 6.03 (s, 1H, H13), 5.58 (dd, J= 16.5, 9.7 Hz, 1H, Hm), 5.38 (t, J: 10.0 Hz, 1H, Hus), 5.24 (s, 1H), 4.51(m, 2H), 4.32 — 3.97 (m, 4H), 3.82 (m, 1H), 3.68 — 3.39 (m, 4H), 2.19 — 1.92 (m, 15H).

INTERMEDIATE M16 to M22 are prepared ing to the procedure described for INTERMEDIATE M10 using the appropriately substituted phenol.

INTERMEDIATE Name 1H NMR (2R,3S,4S,5R,6R)—6— (400 MHz, CDCl3) 5 7.00 (m, 1H), 6.98 (acetoxymethyl)(4- (d, J = 1.3 Hz, 2H), 6.12 (s, 1H), 5.55 (d, 2-methoxyphenoxy)— J = 9.7 Hz, 1H), 5.34 (t, J = 9.9 Hz, 1H), 3-methyltetrahydro-2H- 4.29 — 4.19 (m, 1H), 4.20 — 4.05 (m, 2H), pyran-3,4,5-triyl triacetate 3.82 (s, 3H), 2.13 (s, 3H), 2.09 (s, 3H), 2.05 (s,3H), 2.01 (s,3H), 1.65 (s, 3H). (2R,3S,4S,5R,6R)—6— (400 MHz, CDCl3) 5 7.29 (dt, J = 2.5, 0.6 (acetoxymethyl)(4- Hz, 1H), 7.23 (dd, J = 8.8, 2.6 Hz, 1H), bromoethylphenoxy) 7.04 (d, J = 8.7 Hz, 1H), 6.24 (s, 1H), methyltetrahydro-2H-pyran- 5.55 (d, J = 9.7 Hz, 1H), 5.37 (t, J = 9.9 3,4,5-triyl triacetate Hz, 1H), 4.15 (dd, J = 12.2, 5.3 Hz, 1H), 4.07 (dd, J = 12.3, 2.4 Hz, 1H), 4.00 — 3.89 (m, 1H), 2.63 (q, I = 7.5 Hz, 2H), 2.13 (s, 3H), 2.12 (s, 3H), 2.03 (s, 3H), 2.02 (s, 3H), 1.61 (s, 3H), 1.22 (t, J = 7.5 Hz, 3H). (2R,3S,4S,5R,6R)—6— (400 MHz, CDCl3) 5 7.72 (d, J: 2.4 Hz, (acetoxymethyl)(4- 1H), 7.65 (dd, J = 9.0, 2.5 Hz, 1H), 7.24 bromocyanophenoxy)—3— (d, J = 9.0 Hz, 1H), 6.33 (s, 1H), 5.59 (d, M18 methyltetrahydro-2H-pyran- J = 9.7 Hz, 1H), 5.46 — 5.33 (m, 1H), 3,4,5-triyl triacetate 4.25 — 4.04 (m, 3H), 2.16 (s, 3H), 2.13 (s, 3H), 2.05 (s, 3H), 2.05 (s, 3H), 1.70 (s, 3H . ,4S,5R,6R)—6— (400 MHz, CDC13) 5 7.43 (dd, J = 9.8, (acetoxymethyl)(4-i0d0- 2.1 Hz, 1H), 7.36 (dt, J = 8.7, 1.7 Hz, 2—flu0r0phen0xy)—3— 1H), 6.97 (t, J = 8.5 Hz, 1H), 6.16 (s, M19 methyltetrahydro-2H-pyran- 1H), 5.51 (d, J = 9.7 Hz, 1H), 5.35 (t, J = 3,4,5-triy1 triacetate 9.6 Hz, 1H), 4.20 — 4.04 (m, 3H), 2.11 (s, 3H), 2.10 (s, 3H), 2.02 (s, 3H), 2.01 (s, 3H 1.62 , s, 3H. (2R,3S,4S,5R,6R)—6— (400 MHz, CDC13) 5 7.34 (d, J = 1.8 Hz, (acetoxymethy1)(5- 1H), 7.08 (dd, J = 8.0, 1.8 Hz, 1H), 7.01 br0m0methy1phen0xy) (dd, J = 8.0, 0.5 Hz, 1H), 6.21 (s, 1H), methyltetrahydro-2H-pyran- 5.54 (d, J = 9.7 Hz, 1H), 5.33 (t, J = 9.9 3,4,5-triy1 triacetate Hz, 1H), 4.17 (dd, J = 12.1, 6.3 Hz, 1H), 4.12 — 3.96 (m, 2H), 2.20 (s, 3H), 2.13 (s, 3H), 2.12 (s, 3H), 2.06 (s, 3H), 2.02 (s, 3H 1.61 , s, 3H. (2R,3S,4S,5R,6R)—6— (400 MHz, CDC13) 5 7.42 (dq, J= 2.4, (acetoxymethy1)—2—(4— 1.2 Hz, 1H), 7.36 (dd, J= 8.8, 2.4 Hz, br0m0—2— 1H), 7.18 (d, J= 8.9 Hz, 1H), 6.24 (s, M21 isopropylphenoxy)—3— 1H), 5.54 (d, J= 9.7 Hz, 1H), 5.37 (t, J= tetrahydro-2H-pyran- 9.9 Hz, 1H), 4.19 — 4.04 (m, 2H), 4.03 — 3,4,5-triy1 triacetate 3.95 (m, 1H), 2.13 (s, 3H), 2.11 (s, 3H), 2.03 s, 3H ,2.02 s, 3H 1.60 , s, 3H. (2R,3S,4S,5R,6R)—6— (acetoxymethy1)—2—(4— br0m0—2— (trifluoromethoxy)phen0xy)- 3-methy1tetrahydrO-2H- o ran-3,4,5-tri 1triacetate Biaryls INTERMEDIATES A1 to A12 depicted in Figure 2 are used in the ation Of EXAMPLES described therein OH OH OH OH OH OH OH Me 0 F Cl Me Me O ""6 O O O O 0 (A1) (A2) (A3) (A4) (A5) (A6) (A7) (A8) 0 o D 0 O 0 O 0 0 0 O o O O 0 HN.Me HN‘Me HN‘Me HN‘Me HN‘Me OMe OH OH OH OH OH OH O O O F O (A9) (A10) 0' 0 A11) 0 O ( (A12) Me (A13) F30 (A14) 0 D o O 0 O O O 0 O O N02 O OMe OMe HN. HN\ Me Me HN‘Me HN‘Me Preparation of INTERMEDIATE A1 3-(4-hydroxyphenyl)-N-methyl-benzamide A mixture of [3-(methylcarbamoyl)phenyl]boronic acid (3.41 g, 19.1 mmol), 4- bromophenol (3.00 g, 17.3 mmol), K2CO3 (3.60 g, 26.01 mmol) and SiliaCat DPP—Pd (667 mg, 0.173 mmol) are combined in a re vessel. MeOH (30 mL) is added and the reaction e is stirred 2h at 80°C. The reaction mixture is cooled to RT, filtered on Celite and the precipitate is washed with portions of MeOH. The ed tes are concentrated. The residue is partitioned between aqueous 1N HCl solution and EtOAc (50 mL each). The layers are separated and the aqueous layer is back extracted with EtOAc (2 x mL). The combined organic extracts are washed with brine (25 mL), dried over NaZSO4, filtered and concentrated to provide crude product which is purified by flash chromatography on a eTM SNAP silica cartridge (100 g) using a EtOAc (50%) in CHzClz as eluent. The solids that crystallized upon concentration of the mixed fractions is collected by filtration providing a first crop of the title compound (814 mg, 21% yield) as a white solid.

Concentration of the pure fractions from the chromatography s a second crop of the title compound (1.66 g, 42% yield) as a white solid. 1H NMR (400 MHz, CDCl3) 5 7.96 — 7.87 (m, 2H), 7.68 — 7.58 (m, 2H), 7.50 — 7.39 (m, 3H), 6.97 — 6.85 (m, 2H), 6.37 (bs, 1H), 3.02 (d, J= 4.8 Hz, 3H).

Preparation of INTERMEDIATE A2 3-(4-hydroxymethyl-phenyl)-N-methyl-benzamide The title compound is prepared following the same procedure described for INTERMEDIATE A1, using 4-bromomethyl-phenol (6.67 g, 35.7 mmol) as starting material. The crude product is passed through a silica plug using EtOAc, concentrated then recrystallized using a mixture of THF (80 mL) and CHzClz (25 mL), providing the title nd (2.63 g, 31% yield) as an off—white solid. tration of the mother liquors followed by purification by flash chromatography on a BiotageTM SNAP silica cartridge (100 g) using a gradient of EtOAc (0 to 50%) in CHzClz afforded a second crop of the title compound (2.53 g, 29% yield) as an off—white solid. 1H NMR (400 MHz, DMSO—D6) 5 9.48 (s, 1H), 8.50 (d, J = 4.6 Hz, 1H), 8.00 (t, J= 1.6 Hz, 1H), 7.75 — 7.63 (m, 2H), 7.52 — 7.40 (m, 2H), 7.35 (dd, J = 8.3, 2.3 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 2.79 (d, J= 4.5 Hz, 3H), 2.19 (s, 3H).

General preparation of INTERMEDIATES A3 to A14 (Table A) OH HOcB,OH X O + _.

Br 0 A ave vial is charged with the appropriate substituted 4-bromophenol and phenyl boronic acid (1 eq.), K2CO3 (1.5 eq.) and SiliaCat DPP—Pd (0.1 eq.) in MeOH. The vial is capped and submitted to ave irradiation for 15 s at 120 OC. The reaction mixture is partitioned between aqueous 1N HCl solution and CHzClz. The layers are separated and the aqueous layer is back extracted twice with CH2C12. The combined organic extracts are dried over NaZSO4, concentrated and purified by flash chromatography on a eTM SNAP silica gel cartridge using a gradient of EtOAc in CHzClz to afford the title compound.

Table A: INTERMEDIATE 1H NMR (400 MHz, DMSO—D6) 5 9.47 (s, 1H), 8.50 (d, J: 4.5 Hz, 1H), 7.99 (t, 3'-ethyl-4'- .1 = 1.6 Hz, 1H), 7.75 — 7.62 (m, 2H), hydroxy-N—methyl- 7.46 (t, J = 7.7 Hz, 1H), 7.42 (d, J = 2.2 [1,1'—biphenyl]—3— Hz, 1H), 7.35 (dd, J = 8.3, 2.4 Hz, 1H), carboxamide 6.86 (dd, J = 8.3, 2.1 Hz, 1H), 2.79 (d, J = 4.5 Hz, 3H), 2.60 (q, J: 7.5 Hz, 2H), H NMR (400 MHz, 6) 5 9.16 4'—hydroxy—3'— (s, 1H), 8.51 (d, J = 4.6 Hz, 1H), 8.01 (t, y-N— J= 1.6 Hz, 1H), 7.78 — 7.65 (m, 2H), A4 methyl—[1,1'— 7.48 (t, J = 7.7 Hz, 1H), 7.23 (d, J = 2.1 bipheny1] Hz, 1H), 7.13 (dd, J = 8.2, 2.1 Hz, 1H), carboxamide 6.86 (d, J = 8.2 Hz, 1H), 3.86 (s, 3H), 2.80 d, J 4.5 Hz, 3H. 1H NMR (400 MHz, DMSO—Dd) 5 10.04 (s, 1H), 8.53 (d, J = 4.4 Hz, 1H), 8.03 (t, J = 1.6 Hz, 1H), 7.76 (d, J = 1.8 Hz, 1H), 3,_fluor0_4,_ 7.74 (d, J = 1.7 Hz, 1H), 7.55 (dd, J = hydroxy_N_methy1_ A5 12.8, 2.2 Hz, 1H), 7.49 (t, J = 7.7 Hz, [1 1,_bipheny1]_3_ ca}boxamide 1H), 7.41 — 7.35 (m, 1H), 699 (m, 1H), 2.80 (d, J = 4.5 Hz, 3H). F NMR (376 MHz, dmso) 5 9 (dd, J = 1H NMR (400 MHz, DMSO—D6) 5 10.37 3 -Ch101‘0—4 -, , (s, 1H), 8.54 (d, J — 4.5 Hz, 1H), 8.03_ (t, hydroxy_N_methy1_ A6 J = 1.6 Hz, 1H), 7.78 — 7.71 (m, 3H), [1 1,_bipheny1]_3_ ca’moxamide 7.55 — 7.45 (m, 2H), 7.06 (d, J: 8.5 Hz, 1H), 2.80 (d, J = 4.5 Hz, 3H). 1H NMR (400 MHz, CDC13) 5 8.40 (t, J = 2.0 Hz, 1H), 8.14 (ddd, J = 8.2, 2.2, 1.0 Hz, 1H), 7.86 (ddd, J = 7.8, 1.7, 1.0 A7 8131;111:1141—f3ldenol Hz, 1H), 7.57 (t, J = 8.0 Hz, 1H), 7.41 (d, J = 2.0 Hz, 1H), 7.36 (dd, J = 8.2, 2.3 Hz, 1H), 6.89 (d, J = 8.2 Hz, 1H), 4.86 s, 1H 2.34 , s, 3H.

Prepared by 6sterificdtion (1V160H/ HCI? methyl 4'—hydroxy— 0f c0mmerc1a11y avallable 4 -hydroxy-3 - 3 —methy1—[1,1, , A8 methyl-[1 1'-bipheny1]—3-carb0xylic acid bipheny1] ’ carboxylate LCMS: m/z = 243.47 M+H + 1H NMR (400 MHz, CDC13) 5 8.61 (t, J =1.6 Hz, 1H), 8.41 (d, J: 1.6 Hz, 2H), hydroxi-[ldimeth 1 4,_ 7.61 — 7.51 (m, 2H), 6.98 — 6.92 (m, 2H), A9 4.96 (s, 1H), 3.97 (s, 6H). bipheny1]_375_ dicarboxylate H NMR (400 MHz, DMDO) 5 10.08 (s, , , 1H), 8.49 (d, J=4.4 Hz, 1H), 7.91 (d, J: fi—guorofil: 1.3 Hz, 1H), 7.82 — 7.70 (m, 1H), 7.65 — y my methV1_ A10 7.56 (m, 1H), 7.50 (t, J: 7.7 Hz, 1H), [1,1'-bipheny1]—3— 7.38 (dd, J = 9.4, 8.6 Hz, 1H), 6.72 (dd, J carboxamide = 8.4, 2.3 Hz, 1H), 6.68 (dd, J = 12.8, 2.3 Hz, 1H), 2.78 (d, J = 4.5 Hz, 3H).

H NMR (400 MHz, DMSO ) 5 10.04 (s, , , 1H), 8.48 (d, J = 4.5 Hz, 1H), 7.89 — 7.65 fi'ghlor0'4 ' (m, 2H), 7.60 — 7.40 (m, 2H), 7.26 (d, J = y {OXY'N'met yh 1' A11 8.4 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H), [1’1 'blph‘?ny1]'3' 6.83 (dd, J = 8.4, 2.4 Hz, 1H), 2.77 (d, J = carboxamide 4.5 Hz, 3H). 1H NMR (400 MHz, DMSO) 5 9.61 (s, , , 1H), 8.42 (d, J = 4.5 Hz, 1H), 7.83 (t, J = fi'fifgihfixNXfiéth 1.6 Hz, 1H), 7.73 — 7.64 (m, 1H), 7.60 — A12 [1y 1,_biyhen 11—3?1_ 7.49 (m, 1H), 7.41 (t, J = 7.7 Hz, 1H), ca}boxfmid1: 7.12 (d, J = 8.2 Hz, 1H), 6.51 (d, J = 2.2 Hz, 1H), 6.45 (dd, J = 8.2, 2.2 Hz, 1H), 3.70 (s, 3H), 2.77 (d, J = 4.5 Hz, 3H). 1H NMR (400 MHz, dmso) 5 9.40 (s, , , 1H), 8.45 (d, J = 4.4 Hz, 1H), 7.85 — 7.65 fi'fifihfizem (m, 2H), 7.56 — 7.28 (m, 2H), 7.03 (d, J = A13 — 6.57 (m, 2H), 2.77 (d, [ .yh 8.2 Hz, 1H), 6.75 1p W]1 3? 7 J = 4.5 Hz, 3H), 2.14 (s, 3H). carboxamide H NMR (400 MHz, DMSO) 5 10.23 (s, 4'—hydroxy—N— 1H), 8.47 (d, J = 4.5 Hz, 1H), 7.86 — 7.81 methyl—2'— (m, 1H), 7.73 (s, 1H), 7.48 (t, J = 7.7 Hz, A14 (trifluoromethy1)- 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.23 (d, J = [1,1'-bipheny1]—3- 8.4 Hz, 1H), 7.16 (d, J = 2.5 Hz, 1H), carboxamide 7.08 (dd, J = 8.4, 2.4 Hz, 1H), 2.76 (d, J = 4.5 Hz, 3H).

Preparation of EXAMPLE 1: (2R,3 S,4S,5 S,6R)—6—(4—bromomethy1—phenoxy)—5 -fluoro (hydroxymethy1)tetrahydropyran-3 ,4-diol 0 _\\OO Ho"' F Br Step I:[[(2,R3R,48,SS,6R)—3,4-diacetoxy(4-bromomethy1—phenoxy)fluoro- tetrahydropyrany1]methyl acetate .390 In a pressure vessel, a suspension of [(2R,3R,4S,5S)—3,4,6—triacetoxy—5—fluoro— tetrahydropyran-2—y1]methy1 acetate (prepared ing to the ure described in Angew. Chem. Int. Ed. 2010, 49, 8724—8728) (199 mg, 0.568 mmol) and 4—bromo—2— methylphenol (217 mg, 1.160 mmol) in CHzClz (6.0 mL) is d with BF3.OEt2 (215 uL, 1.697 mmol) added dropwise. The reaction mixture is stirred for 5 min at RT, capped and stirred at 40°C for 16 h. After cooling down to RT, 5 mL saturated aqueous NaHCO3 is added. The layers are separated and the aqueous layer is r extracted with CHzClz (2x2 mL). The ed organic extracts are concentrated and the crude product is purified by flash chromatography on a BiotageTM SNAP silica cartridge (10 g) using a gradient of EtOAc (0 to 30%) in Hex. ation of the pure fractions ed the title compound as a white solid (179 mg, 66% yield). 1H NMR (400 MHz, CDCl3) 5 7.31 (d, J: 2.4 Hz, 1H), 7.29 - 7.24 (m, 1H), 7.02 (d, J= 8.7 Hz, 1H), 5.64 (dd, J= 6.4, 2.0 Hz, 1H), 5.50 - 5.36 (m, 2H), 4.98 (dt, J= 49.5, 2.1 Hz, 1H), 4.26 (dd, J= 12.4, 5.1 Hz, 1H), 4.09 (dd, J: 12.4, 2.3 Hz, 1H), 4.06 - 3.99 (m, 1H), 2.24 (s, 3H), 2.14 (s, 3H), 2.06 (s, 3H), 2.05 (s, 3H). 19F NMR (376 MHz, CDCl3) 5 —204.49 (ddd, J= 49.4, 29.4, 6.4 Hz). ESI—MS m/z calc. 476.05, found 499.30 + Step II: EXAMPLE 1 To a solution of [(2R,3R,4S,5S,6R)-3,4-diacetoxy(4-bromomethyl-phenoxy) fluoro-tetrahydropyranyl]methyl acetate from Step I (98 mg, 0.205 mmol) in MeOH (4.0 mL) is added NaOMe in MeOH (205 "L of 0.5 M, 0.103 mmol). After stirring overnight, the reaction mixture is treated with prewashed Dowex 50WX4-400 resin filtered and rinsed with MeOH (3 x 1 mL). Combined filtrates are concentrated to provide the title compound (70 mg, 89%) as a White solid. 1H NMR (400 MHz, CD3OD) 5 7.31 (d, J= 1.9 Hz, 1H), 7.27 (dd, J= 8.6, 2.1 Hz, 1H), 7.16 (d, J= 8.7 Hz, 1H), 5.70 (dd, J= 6.7, 1.7 Hz, 1H), 4.91 — 4.72 (m, 1H), 3.96 (ddd, J= 30.8, 9.7, 2.6 Hz, 1H), 3.78 (dd, J= 12.1, 2.5 Hz, 1H), 3.75 — 3.66 (m, 2H), 3.62 — 3.53 (m, 1H), 2.21 (s, 3H). "P NMR (376 MHz, CD30D) 5 -206.88 (ddd, J: 49.4, 30.9, 6.9 Hz). ESI—MS m/z calc. 351.17, found 373.20 (M+Na)+ Preparation of EXAMPLE 2: (2R,3 S,4S,5 S,6R)—5—fluoro(hydroxymethyl)((3-methyl-3'-nitro-[1,1'-biphenyl]—4- yl)oxy)tetrahydro-2H-pyran-3,4-diol 0 no 0 Ho‘" F 0N02 OH In a microwave vial is charged (2R,3S,4S,5S,6R)(4-bromomethyl-phenoxy) fluoro(hydroxymethyl)tetrahydropyran-3,4-diol (EXAMPLE 1) (32 mg, 0.0911 mmol), (3- henyl)boronic acid (18 mg, 0.107 mmol), CszCO3 (89 mg, 0.273 mmol), SiliaCat DPP- Pd (35 mg, 0.00911 mmol) and 2mL CH3CN. The vial is degassed, capped and submitted to microwave for 10 min at 100°C. The reaction mixture is diluted with MeOH and CHzClz (1 mL each) and passed thru a 500 mg isolute silica cartridge, rinsed with CHzClz/MeOH mixture (1:1, 4 x 1 mL). ed filtrates are concentrated and the crude product is purified by reverse-phase flash chromatography on a BiotageTM SNAP C18 cartridge (12 g), using a gradient of MeCN (10 to 90%) in H20. The pure fractions are combined and concentrated to e the title compound (18 mg, 50% yield) as a pale yellow solid. 1H NMR (400 MHz, CD3OD) 5 8.41 (t, J= 1.9 Hz, 1H), 8.17 (dd, J= 8.2, 1.4 Hz, 1H), 7.99 (d, J= 8.3 Hz, 1H), 7.66 (t, J= 8.0 Hz, 1H), 7.57 — 7.47 (m, 2H), 7.37 (d, J= 8.4 Hz, 1H), 5.81 (dd, J= 6.7, 1.7 Hz, 1H), 4.88 (dt, J: 49.4, 2.2 Hz, 1H), 4.02 (ddd, J= 30.8, 9.6, 2.6 Hz, 1H), 3.86 — 3.77 (m, 2H), 3.73 (dd, .1: 12.1, 5.3 Hz, 1H), 3.63 (ddd, J: 7.6, 4.9, 2.1 Hz, 1H), 2.33 (s, 3H). 191: NMR (376 MHz, CD3OD) 5 —206.84 (ddd, J= 49.3, 30.8, 6.7 Hz). ESI—MS m/z calc. 393.12238, found 394.34 (M+1)+ Preparation of EXAMPLE 3: (2R,3 S,4S,5 S,6R)—6- [4-bromo(trifluoromethyl)phenoxy] fluoro (hydroxymethyl)tetrahydropyran-3 ,4-diol 0 ..\OO Ho‘" F Br Step 2R3R,4S,5S,6,R)diacetoxy[4-bromo(trifluoromethyl)phenoxy]fluoro- tetrahydropyranyl]methyl acetate Ami) The title compound is prepared from [(2R,3R,4S,5S)—3,4,6—triacetoxy—5—fluoro— tetrahydropyranyl]methyl acetate (106 mg, 0.303 mmol) and 4—bromo—2— (trifluoromethyl)phenol (151 mg, 0.627 mmol) according to the procedure described in EXAMPLE 1 step 1. Purification by flash chromatography on a eTM SNAP silica cartridge (10 g) using a gradient of EtOAc (0 to 30%) in Hex afforded the title compound (41 mg, 26% yield) is obtained as a white foamy solid. 1H NMR (400 MHz, CDCl3) 5 7.75 (d, J = 2.4 Hz, 1H), 7.64 (dd, .1: 8.9, 2.4 Hz, 1H), 7.22 (d, J: 9.0 Hz, 1H), 5.72 (dd, J: 6.3, 2.0 Hz, 1H), 5.50 — 5.34 (m, 2H), 5.00 (dt, .1: 49.2, 2.2 Hz, 1H), 4.27 (dd, .1: 12.4, 4.8 Hz, 1H), 4.09 (dd, J: 12.4, 2.3 Hz, 1H), 4.03 (ddd, J: 9.0, 4.7, 2.3 Hz, 1H), 2.13 (s, 3H), 2.06 (s, 6H). 19F NMR (376 MHz, CDC13) 5 -62.52 (s), -205.28 (ddd, J= 49.2, 29.4, 6.3 Hz). ESI— MS m/z calc. 531.25, found 553.27 (M+Na)+ Step II: EXAMPLE 3 Removal of the acetate protecting groups of [(2R,3R,4S,5S,6R)—3,4—diacetoxy—6—[4— bromo(trifluoromethyl)phenoxy]fluoro-tetrahydropyranyl]methyl acetate from Step I (39 mg, 0.0734 mmol) using the ol described for EXAMPLE 1 Step 11 provided the title nd (29 mg, 93% yield) as a White solid. 1H NMR (400 MHz, CD3OD) 5 7.77 — 7.70 (m, 2H), 7.46 (d, J= 8.5 Hz, 1H), 5.86 (dd, J= 6.5, 1.8 Hz, 1H), 4.80 (dt, J= 49.1, 2.3 Hz, 1H), 3.93 (ddd, J= 30.7, 9.6, 2.6 Hz, 1H), 3.80 (dd, J= 12.1, 2.3 Hz, 1H), 3.77 — 3.65 (m, 2H), 3.61 — 3.52 (m, 1H).19F NMR (376 MHz, CD3OD) 5 -63.91 (s, 3F), —207.57 (ddd, J= 49.2, 30.8, 6.7 Hz, 1F). ESI—MS m/z calc. 403.98825, found 403.37 (M+1)+ Preparation of EXAMPLE 4 3 —[4— [(2R,3 S,4S,5 S,6R)—3 —fluoro—4,5-dihydroxy(hydroxymethyl)tetrahydropyranyl] oxy(trifluoromethyl)phenyl]-N-methyl-benzamide O "‘0 O HO 0 Ho‘" F N"Vle OH The title compound is prepared according to the procedure described for EXAMPLE 2 but using (2R,3 S,4S,5S,6R)—6—[4-bromo(trifluoromethyl)phenoxy]fluoro (hydroxymethyl)tetrahydropyran-3,4-diol (EXAMPLE 3) (21.4 mg, 0.0501 mmol) and [3- (methylcarbamoyl)phenyl]boronic acid (13 mg, 3 mmol). Purification by reverse phase HPLC and freeze-drying the combined ons containing the desired material provided the title compound (12 mg, 51% yield) as a fluffy white solid. 1H NMR (400 MHz, CD3OD) 5 8.06 (t, J= 1.7 Hz, 1H), 7.95 — 7.87 (m, 2H), 7.84 — 7.75 (m, 2H), 7.63 (d, J= 8.5 Hz, 1H), 7.56 (t, J= 7.8 Hz, 1H), 5.92 (dd, J= 6.5, 1.8 Hz, 1H), 4.93 — 4.75 (m, 1H), 3.99 (ddd, J= .7, 9.6, 2.6 Hz, 1H), 3.82 (dd, J= 12.2, 2.3 Hz, 1H), 3.78 — 3.69 (m, 2H), 3.67 — 3.58 (m, 1H), 2.95 (s, 3H). "P NMR (376 MHz, CD30D) 5 —63.47 (s, 3F), —207.47 (ddd, J: 49.4, .7, 6.6 Hz, 1F). ESI—MS m/z calc. 459.1305, found 460.38 (M+1)+ ation of EXAMPLE 5 (2R,3 S,4S,5 S,6R)—6—(4—bromo—2-methoxy-phenoxy)fluoro (hydroxymethyl)tetrahydropyran-3 ,4-diol o Om Ho‘" F Br Step I:[([2R,3R,4S,5S6,R)—3,4—diacetoxy—6—(4—bromo—2—methoxy—phenoxy)—5—fluoro— tetrahydropyranyl]methyl acetate .3910 The title compound is prepared according to the procedure described for EXAMPLE 1 Step I using [(2R,3R,4S,5S)—3,4,6-triacetoxyfluoro-tetrahydropyranyl]methyl acetate (102 mg, 0.291 mmol) and 4-bromomethoxy-phenol (116 mg, 0.571 mmol). Purification by flash chromatography on a BiotageTM SNAP silica dge (10 g) using a gradient of EtOAc (0 to 40%) in Hex afforded the title compound (71 mg, 49% yield) as a colorless gum. 1H NMR (400 MHz, CDCl3) 5 7.07 — 6.88 (m, 3H), 5.58 (dd, J= 6.9, 1.6 Hz, 1H), 5.49 (ddd, J= 28.0, 10.1, 2.4 Hz, 1H), 5.40 (t, J= 9.3 Hz, 1H), 5.03 (dt, J: 49.4, 2.1 Hz, 1H), 4.26 (dd, J: 14.0, 4.8 Hz, 2H), 4.16 — 4.06 (m, 1H), 3.84 (s, 3H), 2.13 (s, 3H), 2.07 (s, 3H), 2.04 (s, 3H). "P NMR (376 MHz, CDC13) 5 —204.14 (ddd, J: 49.5, 28.2, 6.9 Hz). ESI—MS m/Z calc. 493.27, found 493.28 (M+1)+ Step II: EXAMPLE 5 Removal of the acetate protecting groups of [(2R,3R,4S,5S,6R)—3,4—diacetoxy—6—(4— bromomethoxy-phenoxy)fluoro-tetrahydropyranyl]methyl acetate from Step I (67 mg, 0.136 mmol) using the protocol bed for EXAMPLE 1 Step 11 ed the title compound (50 mg, 98% yield) as a colorless solid. 1H NMR (400 MHz, CD3OD) 5 7.18 — 7.09 (m, 2H), 7.03 (dd, J= 8.6, 2.3 Hz, 1H), 5.56 (dd, J= 7.1, 1.9 Hz, 1H), 4.94 — 4.72 (m, 1H), 3.96 (ddd, J= 31.0, 9.3, 2.6 Hz, 1H), 3.84 (s, 3H), 3.82 — 3.67 (m, 4H). 19F NMR (376 MHz, CD3OD) 5 —206.72 (ddd, J= 49.8, 30.9, 7.2 Hz). ESI—MS m/z calc. 366.01144, found 367.28 (M+1)+ ation of EXAMPLE 6 - [4[—([2R,3S,4S,5S,6R)—3—fluoro—4,5—dihydroxy— 6-(hydroxymethyl)tetrahydropyranyl]oxymethyl-phenyl]--Nmethyl-benzamide Step I:[[(2,R3R,4S,5S,6R)—3,4—diacetoxyfluoro[2-methyl[3- lcarbamoMyl)phenyl]phenoxy]tetrahydropyranyl]methyl acetate A microwave vial is charged [(2R,3R,4S,5S,6R)-3,4-diacetoxy(4-bromomethyl- phenoxy)fluoro-tetrahydropyranyl]methyl acetate from EXAMPLE 1 Step I (75 mg, 0.157 mmol), N—methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide (49 mg, 0.188 mmol), CszCO3 (178 mg, 0.546 mmol), Si1iaCat DPP-Pd (67 mg, 0.01742 mmol) and 2mL CH3CN. The vial is degassed, capped and ted to microwave for 10 min at 100°C.

The reaction mixture is diluted with EtOAc, filtered on Celite and washed with portions of EtOAc. The combined filtrates are concentrated and the crude product is purified by flash tography on a BiotageTM SNAP silica cartridge (10 g) using a gradient of EtOAc (50 to 80%) in Hex to provide the title compound as a white foamy solid (55 mg, 66% yield).

ESI—MS m/z calc. 531.19, found 532.62 (M+1)+ Step II: EXAMPLE 6 Removal of the acetate protecting groups of R,4S,5S,6R)—3,4—diacetoxy—5—fluoro—6— [2-methyl[3 -(methylcarbamoyl)phenyl]phenoxy]tetrahydropyranyl]methyl acetate from Step I (45 mg, 0.0847 mmol) using the protocol described for EXAMPLE 1 Step 11 provided the title compound (34 mg, 98% yield) as a white fluffy solid. 1H NMR (400 MHz, CD3OD) 8.02 (t, J= 1.6 Hz, 1H), 7.78 — 7.71 (m, 2H), 7.54 — 7.44 (m, 3H), 7.34 (d, J= 8.5 Hz, 1H), 5.78 (dd, J= 6.8, 1.9 Hz, 1H), 4.87 (dt, J= 49.4, 4.9 Hz, 1H), 4.02 (ddd, J= 30.9, 9.6, 2.6 Hz, 1H), 3.84 — 3.69 (m, 3H), 3.67 — 3.60 (m, 1H), 2.94 (s, 3H), 2.32 (s, 3H). 19F NMR (376 MHz, CD3OD) 5 —206.77 (ddd, J= 49.6, 31.0, 6.8 Hz). ESI—MS m/z calc. 405.15875, found 406.52 (M+1)+ Preparation of EXAMPLE 7 — [4—[([2R,3S,4S,5S,,6R)—3—fluorodihydroxy(hydroxymethyl)tetrahydropyran yl] nyl]]--Nmethyl-benzamide «(flow Step I:[([2,R3R,4S,5S,6R)—3,4—diacetoxy—5—fluoro—6—[4—[3— (methylcarbamoyl)phenyl]phenoxy]tetrahydropyranyl]methyl acetate Ac:C/O\\E‘J\F\0\O‘inifle In a pressure vessel, a solution of INTERMEDIATE M1 (124 mg, 0.354 mmol) and INTERMEDIATE A1 (161 mg, 0.708 mmol) in CHzClz (3.7 mL) is treated with 20 (135 "L, 1.06 mmol) added se, the mixture is stirred at RT for 5 min, then warmed up to 40 OC and stirred overnight then more BF3.OEt2 is added ((135 "L, 1.06 mmol)), and the reaction mixture is stirred at 40 OC overnight. After cooling down to RT, 3 mL saturated aqueous NaHC03 solution, and 1 mL CHCl3-iPrOH mixture (4: 1) are added. The layers are separated and the aqueous layer is extracted with CHCl3-iPrOH e (4: 1, 3x2 mL). The combined organic extracts are concentrated, and the resulting crude product is purified by flash chromatography on a BiotageTM SNAP silica cartridge (25 g), using a gradient of MeOH (0 to 5%) in CHzClz. Fractions containing product are trated and purified again on flash chromatography on a eTM SNAP silica cartridge (10 g), using a gradient of EtOAc (50—100%) in Hex. The pure fractions are concentrated to dryness, affording title compound as a white foamy solid (18 mg, 10% yield). 1H NMR (400 MHz, CDCl3) 5 7.96 (s, 1H), 7.67 (dd, J: 8.1, 4.3 Hz, 2H), 7.57 (d, J: 8.7 Hz, 2H), 7.48 (t, J: 7.7 Hz, 1H), 7.18 (d, J: 8.7 Hz, 2H), 6.21 (s, 1H), 5.75 (dd, J: 6.6, 1.5 Hz, 1H), 5.59 — 5.34 (m, 2H), 4.99 (d, J: 49.5 Hz, 1H), 4.29 (dd, J: 12.6, 5.1 Hz, 1H), 4.16 — 4.00 (m, 2H), 3.04 (d, J: 4.8 Hz, 3H), 2.15 (s, 3H), 2.06 (s, 3H), 2.04 (s, 3H).

Step II: E 7 Removal of the acetate protecting groups of [(2R,3R,4S,5S,6R)—3,4—diacetoxy—5— fluoro[4-[3 -(methylcarbamoyl)phenyl]phenoxy]tetrahydropyranyl]methyl acetate from Step I (18 mg, 0.034 mmol) using the protocol described for EXAMPLE 1 Step II provided the title compound (12 mg, 86% yield) as a white fluffy solid. 1H NMR (400 MHz, CD3OD) 8.03 (t, J: 1.7 Hz, 1H), 7.80 — 7.72 (m, 2H), 7.67 — 7.58 (m, 2H), 7.52 (t, J: 7.8 Hz, 1H), 7.29 — 7.19 (m, 2H), 5.76 (dd, J: 6.9, 1.7 Hz, 1H), 4.91 — 4.75 (m, 1H), 3.98 (ddd, J: 30.9, 9.5, 2.6 Hz, 1H), 3.80 (dd, J: 12.0, 2.4 Hz, 1H), 3.77 — 3.70 (m, 2H), 3.69 — 3.61 (m, 1H), 2.94 (s, 3H).

ESI—MS m/z calc. 391.14313, found 392.31 (M+H)+ Preparation of EXAMPLE 8 3 —[4— [(2R,3 S,4S,5 S,6R)—3 —fluoro—4,5-dihydroxy(hydroxymethyl)tetrahydropyranyl] oxymethoxy-phenyl]-N-methyl-benzamide O -"O O HO 0 Ho‘" F N"Vle The title compound is ed according to the procedure described for EXAMPLE 2 but using (2R,3 S,4S,5 S,6R)—6—(4—bromomethoxy-phenoxy)—5-f1uoro(hydroxymethyl) tetrahydropyran-3,4-diol (EXAMPLE 5) (40 mg, 0.106 mmol) and [3-(methylcarbamoyl) phenyl]boronic acid (28 mg, 0.156 mmol). Purification by reverse phase HPLC and freezedrying the combined fractions containing the desired material provided the title compound (18 mg, 40% yield) as a fluffy white solid. 1H NMR (400 MHz, CD30D) 5 8.05 (t, J = 1.7 Hz, 1H), 7.82 — 7.70 (m, 2H), 7.52 (t, J= 7.8 Hz, 1H), 7.36 — 7.27 (m, 2H), 7.21 (dd, J= 8.3, 2.1 Hz, 1H), 5.64 (dd, J: 7.1, 1.8 Hz, 1H), 4.89 (dt, J= 49.6, 2.3 Hz, 1H), 4.02 (ddd, J= 31.0, 9.5, 2.5 Hz, 1H), 3.94 (s, 3H), 3.88 — 3.70 (m, 4H), 2.95 (s, 3H). 191: NMR (376 MHz, CD30D) 5 —206.65 (ddd, J= 49.6, 30.8, 7.1 Hz). ESI—MS m/z calc. 421.1537, found 422.41 (M+1)+ Preparation of EXAMPLE 9 Dimethyl 5— [4— [(2R,3 S,4S,5 S,6R)—3 —fluoro—4,5 —dihydroxy—6— xymethyl)tetrahydropyranyl]oxyphenyl]benzene- 1,3 -dicarboxylate 0 "‘0 O HO 0 Ho‘" F OH D OMe O OMe Step I: yl (2R,3S,4S,5R,6R)-4,5-diacetoxy(acetoxymethyl)—3—fluoro— tetrahydropyranyl]oxyphenyl]benzene-1,3 -dicarboxylate 0 "‘0 O A00 0 Am" F O OMe OAc o OMe The title compound is prepared ing to the procedure described for EXAMPLE 7 but using INTERMEDIATE M1 (207 mg, 0.591 mmol) and INTERMEDIATE A9 (3 64 mg, 1.18 mmol). After purification by flash tography on a BiotageTM SNAP silica dge (10 g) using a gradient of EtOAc (0 to 50%) in Hex, the title compound (204 mg, 60% yield) is obtained as a White solid which was used directly in the next step.

Step II: EXAMPLE 9 Removal of the acetate protecting groups of dimethyl 5-[4-[(2R,3S,4S,5R,6R)-4,5- diacetoxy(acetoxymethyl)—3 -fluoro-tetrahydropyranyl]oxyphenyl]benzene- 1,3 - dicarboxylate from Step I (204 mg, 0.354 mmol) using the protocol described for EXAMPLE 1 Step II and purification by e phase flash chromatography on BiotageTM SNAP C18 cartridge (30 g) using a gradient of MeCN (10—70%) in H2O provided the title compound (64 mg, 39% yield) as a White solid. 1H NMR (400 MHz, CD3OD) 5 8.57 (t, J = 1.6 Hz, 1H), 8.44 (d, J=1.6 Hz, 2H), 7.72 — 7.56 (m, 2H), 7.39 — 7.20 (m, 2H), 5.79 (dd, J: 6.9, 1.8 Hz, 1H), 4.92 — 4.76 (m, 1H), 3.99 (ddd, J: 30.9, 9.6, 2.7 Hz, 1H), 3.81 (dd, J: 12.0, 2.4 Hz, 1H), 3.77 — 3.70 (m, 2H), 3.69 — 3.62 (m, 1H). ESI—MS m/z calc. 450.1326, found 451.24 (M+1)+ Preparation of EXAMPLE 10 7—[(2R,3 S,4S,5 S,6R)—3 —fluoro—4,5 —dihydroxy(hydroxymethyl)tetrahydropyranyl]oxy methyl-chromenone o "‘0 o 0 Ho‘" / OH Me Step I:[[(,2R3R,4S,5S,6,R)—34—diacetoxy-5—fluoro—6—(4—methyl—2—oxo-chromen—7—yl)oxy— tetrahydropyranyol]methyl acetate The title compound is prepared according to the procedure described for EXAMPLE 7 but using INTERMEDIATE M1 (201 mg, 0.574 mmol) and 4-methylumbelliferone (201 mg, 1.14 mmol). Purification by flash chromatography on a BiotageTM SNAP silica cartridge (10 g) using a gradient of EtOAc (0 to 20%) in CHzClz afforded the title compound (26 mg, 10% yield) as a white foamy solid which is used directly in the next step.

Step II: EXAMPLE 10 Removal of the acetate protecting groups [(2R,3R,4S,5S,6R)—3,4—diacetoxy—5—fluoro—6—(4— methyloxo-chromenyl)oxy-tetrahydropyranyl]methyl e (25 mg, 0.054 mmol) using the ol bed for EXAMPLE 1 Step II and purification by flash chromatography on a BiotageTM SNAP silica cartridge (12 g), using a gradient of MeOH (0 to 10%) in CHzClz provided the title compound (13 mg, 68% yield) as a white solid. 1H NMR (400 MHz, CD30D) 5 7.73 (d, J= 8.8 Hz, 1H), 7.19 (d, J= 2.4 Hz, 1H), 7.15 (dd, J= 8.8, 2.5 Hz, 1H), 6.22 (d, J: 1.2 Hz, 1H), 5.87 (dd, J= 6.9, 1.9 Hz, 1H), 4.92 — 4.76 (m, 1H), 3.96 (ddd, J= 30.8, 9.6, 2.7 Hz, 1H), 3.84 — 3.65 (m, 3H), 3.62 — 3.52 (m, 1H), 2.46 (d, J: 1.2 Hz, 3H). 19F NMR (376 MHz, CD3OD) 5 -207.48 (ddd, J: 49.2, 30.8, 6.8 Hz). ESI—MS m/Z calc. 340.09583, found 341.27 (M+1)+ Preparation of EXAMPLE 11 4'—(((2R,3R,4S,5R,6R)fluoro-3,5-dihydroxy(hydroxymethyl)tetrahydro-2H-pyran yl)oxy)O-N-methyl-[[1, 1b-iphenyl]]--3carboxamide"0 HO" OH0 F Step I: (4aR,7R, 8S,8aR)—7—(benzyloxy)—8—fluoro—6—(4—iodophenoxy)—2— phenylhexahydropyrano[[3 ,2-d][1,3]dioxine smog. :0 To a cold (-40°C) solution of INTERMEDIATE M2 (140 mg, 0.3094 mmol) and 4- iodophenol (109 mg, 0.495 mmol) in CH2C12 (4.5 mL) is added pyrrolidine—2,5—dione (111 mg, 0.495 mmol) and trifluoromethanesulfonic acid (4 11L, 0.0460 mmol). The reaction e is stirred 1h at -40°C and 16h at RT. The resulting mixture is partitioned between saturated NaHCO3 (4 ml) and CHzClz (8 ml). The organic extract is dried (NazSO4), filtered, evaporated to dryness and purified on BiotageTM SNAP silica cartridge (10 g) using EtOAc (0% to 20% in 10 CV) in Hex as eluent to afford the titled compound (100 mg, 0.178 mmol, 57%). LC—MS: m/z = 563.39 (M+H)+.

Step II: 4'-(((4aR,6R7R,8S,8aR)(benzyloxy)—8-fluorophenylhexahydropyrano[3,2- ][1,3]dioxinyl)oxy)-N—methyl- [1, 1-biphenyl]carboxamide $695.41 To a solution of N—methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)benzamide (56mg, 0.215 mmol) and (4aR,7R,8S,8aR)—7—(benzyloxy)—8—fluoro—6—(4—iodophenoxy)—2— phenylhexahydropyrano[3,2-d][1,3]dioxine (110 mg, 0.1960 mmol) from Step I in MeOH (1.65 mL) is added CszCO3 (194 mg, 0.598 0mmol) and SiliaCat DPP—Pd (78mg, 0.020 mmol). The reaction mixture is d 10 min at 100°C in the microwave. The resulting mixture is filtered through celite, the latter is washed with MeOH and the combined filtrate is concentrated. This material is partitioned n Water (4 ml) and EtOAc (8 ml). The organic extracts are dried over NazSO4, filtered, ated to dryness and purified on BiotageTM SNAP silica cartridge (12 g) using EtOAc (0% to 100% in 10 CV) in Hex as eluent to afford the titled compound (45 mg, 0.079 mmol, 40%). LC—MS: m/z = 570.53 (M+H)+.

Step III: EXAMPLE 11 A mixture of 4'-(((4aR,7R,8S,8aR)(benzyloxy)—8—fluoro—2— phenylhexahydropyrano [3 ,2-d][1,3]dioxinyl)oxy)-N-methyl-[1,1'-biphenyl]-3 - carboxamide from Step II (45 mg, 0.079 mmol) and 20 wt% Pd(OH)2 on carbon (32 mg, 0.0082 mmol) in dry MeOH (675 11L) is stirred for 24 hours under H2 atmosphere at 80 PS1.

The ing mixture is filtered through celite, the catalyst washed with MeOH, the ed filtrates are concentrated and purified by reverse phase HPLC to afford the title compound (8.5 mg, 0.021 mmol, 27%). 1H NMR (400 MHz, CD3OD) 5 8.01 (t, J: 1.8 Hz, 1H), 7.81 — 7.67 (m, 2H), 7.65 — 7.54 (m, 2H), 7.49 (t, J= 7.8 Hz, 1H), 7.33 — 7.16 (m, 2H), .57 (dd, J= 4.6, 2.0 Hz, 1H), 4.77 (ddd, J= 49.5, 9.3, 3.4 Hz, 1H), 4.26 (ddd, J= 6.5, 3.5, 2.0 Hz, 1H), 4.03 (dt, J= 12.9, 9.6 Hz, 1H), 3.84 — 3.66 (m, 2H), 3.61 (ddd, J= 10.0, 5.0, 2.7 Hz, 1H), 2.92 (s, 3H). LC—MS: m/z = 392.34 (M+H)+.

Preparation of EXAMPLE 12 4'—(((2R,3S,4S,5S,6S)—6—(fluoromethyl)-3,4,5-trihydroxytetrahydro-2H-pyranyl)oxy)-N- methyl-[[1, 1b-iphenyl]]—3 -carboxamide Step I: N—methyl—4'—(((2R,3S,4S,5S,6S)-3,4,5-tris(benzyloxy)—6-(fluoromethyl)tetrahydro-2H- pyran---2yl)oxy)-[[1, 1b-iphenyl]]--3carboxamide To a solution of EDIATE M3 (83 mg, 0.1243 mmol) and [3- (methylcarbamoyl)phenyl]boronic acid (35 mg, 0.1956 mmol) in t—butanol (4 mL) is added NazCO3 (300 11L of 2 M, 0.6000 mmol) t hen PdClz(PPh3)2 (6 mg, 0.03384 mmol) . The reaction mixture is degased three time (house vacuum then nitrogen) then stirred 5hrs at 80 0 C. The resulting dark brown mixture is cooled to RT, diluted with 15mL EtOAc and filtered on a pad of silica gel. The latter is washed with two portions of 15ml of EtOAc. The combined fractions are concentrated and the residue ed on a Silica gel column (Snap 10g) using Hexane / EtOAc ( 20 to 80% on 20CV ) as the eluent on a BiotageTM system to afford the title compound (61mg, 90% pure, 67% yield).

Step II: EXAMPLE 12 To a solution of N—methyl-4'-(((2R,3S,4S,5S,6S)—3,4,5—tris(benzyloxy)—6— (fluoromethyl)tetrahydro-2H-pyranyl)oxy)-[1,1'-biphenyl]carboxamide from Step I (61 mg, 0.083 mmol) in MeOH (8 mL) is added 2 (19 mg, 0.1353 mmol). The reaction e is d overnight under 100psi of H2. The resulting mixture is filtered on a Isolut Celite 545 cartridge, the latter washed with MeOH (2x4mL) and concentrated. The resulting mixture (29mg) is dissolved in MeOH and purified by HPLC. Fractions (4x6mL) containing the desired material are combined, concentrated and finally lyophilized to afford the title compound as a fluffy white solid (20mg, 60% yield). 1H NMR (400 MHz, DMSO—d6) 5 8.55 (d, J = 4.5 Hz, 1H), 8.07 (s, 1H), 7.80 — 7.72 (m, 2H), 7.68 (d, J = 8.8 Hz, 2H), 7.52 (t, J = 7.7 Hz,1H), 7.18 (d, J = 8.8 Hz, 2H), 5.51 (d, J = 1.6 Hz, 1H), 4.65 = — 4.38 (m, 2H), 3.88 (dd, J 31,19 Hz,1H), 3.74 (dd, J = 8.7, 3.2 Hz, 1H), 3.67 = 4.5 Hz, 3H). — 3.52 (m, 2H), 2.81 (d, J 19F NMR (376 MHz, DMSO—dg) 5 —0.75 (td, J = 47.9, 25.9 Hz). LC—MS: m/z = 392.31(M+H)+ Preparation of EXAMPLE 13 N,3'-dimethyl-4'-(((2R,3 S,4S,5S,6R)—3,4,5-trihydroxy(hydroxymethyl) tetrahydro-2H-pyranyl)oxy)-[1, 1'-biphenyl] -3 -carboxamide Step I: (2R,3 S,4S,5R,6R)(acetoxymethyl)-3 -methyl((3 -methyl-3 '-(methylcarbamoyl)- [1, 1'-biphenyl]yl)oxy)tetrahydro-2H-pyran-3 ,4,5-triyl triacetate To a sion of INTERMEDIATE M4 (10.80 g, 26.71 mmol) and INTERMEDIATE A2 (10.31 g, 42.74 mmol) in 1,2-dichloroethane (162.0 mL) at 0°C is added BF3.Et20 (10.15 mL, 80.13 mmol) se. The resulting mixture is d at 40°C for 48 h, cooled down to 3°C and quenched with 30 ml of saturated aqueous NaHCO3 while stirring. The resulting suspension is filtered and the organic phase is separated, dried over NaZSO4, filtered, and concentrated. Purification on 220 g of silica with 40-100% EtOAc/Hexane over 15 CV on a BiotageTM system to afford the title compound (7.8 g, 12.70 mmol, 48%) as a white solid. 1H NMR (400 MHz, CD3OD) 5 8.02 (t, J= 1.8 Hz, 1H), 7.74 (ddt, J= 7.8, 4.7, 1.3 Hz, 2H), 7.58 — 7.34 (m, 3H), 7.21 (d, J= 8.5 Hz, 1H), 6.33 (s, 1H), 5.63 (d, J= 9.7 Hz, 1H), 5.40 (t, J= 9.9 Hz, 1H), 4.20 (dd, J= 12.3, 5.0 Hz, 1H), 4.14 — 3.94 (m, 2H), 2.93 (s, 3H), 2.36 (s, 3H), 2.13 (s, 3H), 2.12 (s, 3H), 2.02 (s, 3H), 1.98 (s, 3H), 1.64 (s, 3H).

Step II: EXAMPLE 13 To a stirred solution of [(2R,3R,4S,5S,6R)-3,4,5-triacetoxymethyl[2-methyl [3-(methylcarbamoyl)phenyl]phenoxy]tetrahydropyranyl]methyl acetate from Step I (3.70 g, 6.32 mmol) in dry MeOH (93 mL) at RT is added NaOMe (704 uL of 25 %w/w, 3.16 mmol). The resulting mixture is stirred 2h, followed by addition of te IR—120 resin until the reaction mixture pH reaches 4. The ing mixture is filtered, and concentrated to dryness to afford the tittle compound (2.600 g, 6.141 mmol, 97%) as a white solid. 1H NMR (400 MHz, CD3OD) 5 8.00 (t, J = 1.8 Hz, 1H), 7.72 (ddt, J = 8.0, 5.2, 1.2 Hz, 2H), 7.52 — 7.38 (m, 3H), 7.31 (d, J = 8.5 Hz, 1H), 5.27 (s, 1H), 3.82 — 3.62 (m, 4H), 3.58 (m, 1H), 2.92 (s, 3H), 2.31 (s, 3H), 1.40 (s, 3H). LC—MS: m/z = 418.2 (M+H)+.

Preparation of EXAMPLE 14 N—methyl-3 -[4- [(2R,3 S,4S,5 S,6R)—3 rihydroxy(hydroxymethyl)-3 -methyl- tetrahydropyranyl]oxyphenyl]benzamide O "‘0 O HO o HO". "OWL/lie N,Me The title compound is prepared according to the procedure described in EXAMPLE 13 but using INTERMEDIATE Al in Step I. In Step II, the on is ed by treating the on e through a prewashed lg SCX-2 cartridge, washing with portions of MeOH.

The combined filtrates are concentrated and purified by reverse phase HPLC to afford the desired compound (41% yield over two steps). 1H NMR (400 MHz, CD3OD) 5 8.03 (t, J = 1.7 Hz, 1H), 7.80 — 7.69 (m, 2H), 7.67 — 7.57 (m, 2H), 7.51 (t, J = 7.8 Hz, 1H), 7.28 — 7.15 (m, 2H), 5.24 (s, 1H), 3.78 — 3.62 (m, 6H), 2.94 (s, 3H), 1.39 (s, 3H). ESI—MS m/z calc. 403.43, found 404.14 (M+l)+ Preparation of EXAMPLE 15 3 —[3—chloro—4—[(2R,3 S,4S,5S,6R)-3,4,5-trihydroxy(hydroxymethyl)—3-methyl- tetrahydropyranyl]oxy-phenyl]-N-methyl-benzamide \\' 'IIMeO OH H OH O The title compound is prepared according to the procedure described in EXAMPLE 13 but using INTERMEDIATE A6 in Step I. In Step II, the reaction is quenched by treating the reaction mixture through a prewashed lg SCX-2 cartridge, washing with ns of MeOH.

The combined filtrates are concentrated and purified by reverse phase HPLC to afford the desired compound (6.5% yield over two steps). 1H NMR (400 MHz, CD3OD) 5 8.04 (t, J = 1.7 Hz, 1H), 7.83 = 8.6, 2.3 Hz, 1H), 7.54 (d, J= 7.8 Hz, 1H), — 7.70 (m, 3H), 7.59 (dd, J 7.50 (d, J= 8.7 Hz, 1H), 5.32 (s, 1H), 3.85 — 3.59 (m, 5H), 2.95 (s, 3H), 1.45 (s, 3H). ESI— MS m/z calc. , found 438.09 (M+l)+ Preparation of EXAMPLE 16 3—[3—fluoro—4—[(2R,3S,4S,5S,6R)-3,4,5-trihydroxy(hydroxymethyl)methyl- tetrahydropyranyl] oxy-phenyl] -N-methyl-benzamide Ho/fixo O 0 \v "Me O ,Me OH H The title compound is prepared according to the procedure described in EXAMPLE 13 but using INTERMEDIATE A5 in Step I. In Step II, the on is quenched by treating the reaction mixture through a prewashed 1 g SCX-2 cartridge, g with portions of MeOH.

The combined tes are concentrated and purified by reverse phase HPLC to afford the desired nd (27% yield over two steps). 1H NMR (400 MHz, CD3OD) 5 8.04 (t, J = 1.7 Hz, 1H), 7.82 — 7.73 (m, 2H), 7.57 — 7.40 (m, 4H), 5.23 (s, 1H), 3.86 — 3.64 (m, 5H), 2.95 (s, 3H), 1.43 (s, 3H). 191: NMR (376 MHz, CD30D) 5 -134.69 (dd, .1 = 12.1, 7.7 Hz). ESI— MS m/z calc. 421.42, found 422.37 (M+1)+ Preparation of EXAMPLE 17 3 —[3 xy—4— [(2R,3 S,4S,5 S,6R)-3 ,4,5-trihydroxy(hydroxymethyl)-3 -methyl- tetrahydropyranyl] oxy-phenyl]-N-methyl-benzamide O "‘0 O HO o v Me HO‘ , Me OH H The title compound is prepared according to the procedure described in EXAMPLE 13 but using INTERMEDIATE A4 in Step I. In Step II, the reaction is quenched by treating the reaction mixture through a prewashed 1 g SCX-2 cartridge, washing with portions of MeOH.

The ed filtrates are concentrated and purified by reverse phase HPLC to afford the desired compound (21% yield over two steps). 1H NMR (400 MHz, CD3OD) 5 8.05 (t, J = 1.7 Hz, 1H), 7.81 — 7.71 (m, 2H), 7.52 (t, J = 7.8 Hz, 1H), 7.34 — 7.25 (m, 2H), 7.20 (dd, J = 8.3, 2.2 Hz, 1H), 5.17 (s, 1H), 3.92 (s, 3H), 3.89 — 3.82 (m, 1H), 3.81 — 3.66 (m, 4H), 2.95 (s, 3H), 1.45 (s, 3H). ESI—MS m/z calc. 433.45, found 434.17 (M+1)+ Preparation of E 18 (2R,3 S,4S,5 S,6R)—6-(hydroxymethyl)-3 -methyl[2-methyl(3 - nitrophenyl)phenoxy]tetrahydropyran-3 ,4,5 -triol Homo 0(v 'IIMe N02 The title compound is prepared according to the procedure bed in EXAMPLE 13 but using INTERMEDIATE A7 in Step I. In Step II, the reaction is quenched by treating the reaction mixture through a prewashed 1g SCX-2 cartridge, washing with portions of MeOH. The combined filtrates are concentrated and ed by reverse phase HPLC to afford the desired compound (46% yield over two steps). 1H NMR (400 MHz, CD3OD) 5 8.42 (t, J = 2.0 Hz, 1H), 8.16 (ddd, J = 8.2, 2.2, 0.8 Hz, 1H), 8.00 (ddd, J = 7.8, 1.6, 0.9 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.55 = 8.4 Hz, 1H), 5.31 — 7.44 (m, 2H), 7.37 (d, J (s, 1H), 3.81 — 3.67 (m, 4H), 3.64 — 3.52 (m, 1H), 2.34 (s, 3H), 1.42 (s, 3H). ESI—MS m/z calc. 405.40, found 428.18 (M+Na) I Preparation of EXAMPLE 19 (2R,3 S,4S,5 S,6R)—2-(2-chloro(5 -nitroindolinyl)phenoxy)(hydroxymethyl)-3 - methyltetrahydro-2H-pyran-3 ,4,5-triol Agni)NW Step II: (2R,3 S,4S,5R,6R)(acetoxymethyl)(2-chloro(5 -nitroindolinyl)phenoxy)-3 - tetrahydro-2H-pyran-3,4,5-triyl triacetate ACOAC pmz A microwave vial is charged with (2R,3S,4S,5R,6R)(acetoxymethyl)(4-bromo chlorophenoxy)methyltetrahydro-2H-pyran-3,4,5-triyl triacetate from INTERMEDIATE M11 Step I (60 mg, 0.109 mmol) 5—nitroindoline (26.8 mg, 0.163 mmol) , , CszCO3 (110 mg, 0.337 mmol) X—Phos (5.2 mg, 0.011 mmol), Pd2(dba)3 (1.5 mg, 0.0016 mmol) and toluene (880 uL). The e is then heated to 100°C for 15 minutes in the microwave, ed on Celite, concentrated to dryness and the residue purified by flash column chromatography on silica gel (10 to 80 % EtOAc in Hex) to give the title compound (32 mg, 47% yield).

Step II: EXAMPLE 19 The title nd is prepared according to the procedure described in EXAMPLE 13 in Step II. The reaction is quenched by treating the reaction mixture through a prewashed lg SCX-2 cartridge, washing with portions of MeOH. The combined filtrates are concentrated and purified by reverse phase HPLC to afford the desired nd. 1H NMR (400 MHz, CD3OD) 5 8.00 (m, 2H), 7.45 (d, J = 8.9 Hz, 1H), 7.38 (d, J = 2.7 Hz, 1H), 7.26 (dd, J = 8.9, 2.7 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 5.22 (s, 1H), 4.09 (t, J = 9.0 Hz, 2H), 3.72 (m, 5H), 3.21 (t, J = 9.0 Hz, 2H), 1.43 (s, 3H). LCMS m/z (M+H)+ = 467.23 Preparation of EXAMPLE 20 3 —[3 —ethyl—4— [(2R,3 S,4S,5 S,6R)-3 ,4,5-trihydroxy(hydroxymethyl)-3 l- tetrahydropyranyl] oxy-phenyl]-N-methyl-benzamide 0 -"O O Ho 0 "'Me Ho"' N/ The title compound is prepared according to the procedure described in EXAMPLE 13 but using INTERMEDIATE A3 in Step I. In Step II, the reaction is quenched by ng the on mixture through a prewashed lg SCX-2 cartridge, washing with portions of MeOH.

The combined filtrates are concentrated and purified by reverse phase HPLC to afford the desired compound (37% yield over two steps). 1H NMR (400 MHz, CD3OD) 5 8.03 (t, J = 1.7 Hz, 1H), 7.80 — 7.64 (m, 2H), 7.54 — 7.42 (m, 3H), 7.35 (d, J= 8.4 Hz, 1H), 5.31 (s, 1H), 3.80 — 3.68 (m, 4H), 3.66 — 3.52 (m, 1H), 2.95 (s, 3H), 2.83 — 2.67 (m, 2H), 1.42 (s, 3H), 1.27 (t, J = 7.5 Hz, 3H).ESI—MS m/z calc. 431.1944, found 432.24 (M+l)+ Preparation of EXAMPLE 21 3 —[3—methyl[(2R,3 S,4S,5 S,6R)—3 ,4,5-trihydroxy(hydroxymethyl)-3 -methyl- ydropyranyl]oxyphenyl]benzoic acid OH Me 0 _..o .nMe HO‘ OH OH OH O Step 1: Methyl 3-[3-methyl[(2R,3S,4S,5R,6R)-3,4,5-triacetoxy(acetoxymethyl)—3- methyltetrahydropyranyl]oxy-phenyl]benzoate OAc Me 0 MO Aco‘ OAc OAc O OMe The title compound is prepared according to the ure described in EXAMPLE 13 but using INTERMEDIATE A8 in Step 1. Purification on BiotageTM SNAP silica cartridge afforded the title compound (21% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) 5 8.23 (s, 1H), 7.99 (d, J= 7.6 Hz, 1H), 7.74 (d, J= 7.6 Hz, 1H), 7.53 — 7.38 (m, 3H), 7.28 (d, J = 6.3 Hz, 1H), 5.51 — 5.35 (m, 3H), 4.31 (dd, J= 12.5, 5.2 Hz, 1H), 4.14 — 4.06 (m, 2H), 3.96 (s, 3H), 2.38 (s, 3H), 2.26 (s, 3H), 2.16 (s, 3H), 2.05 (d, J= 2.3 Hz, 6H), 1.39 (s, 3H). LC— MS: m/z = 609.31 (M+Na)+.

Step II: hyl-4'-(((2R,3 S,4S,5R,6R)-3,4,5-triacetoxy(acetoxymethyl) methyltetrahydro-2H-pyranyl)oxy)-[1,1'-biphenyl]—3 xylic acid To a solution of methyl 3-[3-methyl[(2R,3 R,6R)-3,4,5-triacetoxy (acetoxymethyl)methyl-tetrahydropyranyl]oxy-phenyl]benzoate from Step I (237 mg, 0.404 mmol) in MeOH (4 mL) was added aqueous NaOH 2M (807 uL of 2 M, 1.61 mmol) and the reaction was stirred for 3h. The reaction mixture is quenched with aqueous HCl 4M (101 uL of 4 M, 0.404 mmol) until pH reaches 2 and the resulting mixture was lyophilized overnight. The residue is dissolved in pyridine and to the solution is added AczO (305 uL, 3.23 mmol) and DMAP (2.5 mg, 0.020 mmol). The reaction is stirred at RT for 18h, poured in HCl 1N, diluted with EtOAc and stirred 15min. The organic phase is separated, washed with water, brine, dried over NazSO4, filtered, concentrated in vacuo. The residue is purified on eTM SNAP silica cartridge (10 g) to give title compound (168 mg, 73% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) 5 8.28 (t, J: 1.6 Hz, 1H), 8.08 — 8.03 (m, 1H), 7.82 — 7.76 (m, 1H), 7.53 (t, J: 7.8 Hz, 1H), 7.48 — 7.40 (m, 2H), 7.27 (s, 1H), 5.52 — 5.35 (m, 3H), 4.31 (dd, J: 12.7, 5.4 Hz, 1H), 4.13 — 4.06 (m, 2H), 2.37 (s, 3H), 2.16 (s, 3H), 2.13 (s, 3H), 2.05 (d, J = 1.0 Hz, 6H), 1.38 (s, 3H).LC—MS: m/z = 595.62 (M+Na)+.

Step III: EXAMPLE 21 To a solution of 3'-methyl-4'-(((2R,3S,4S,5R,6R)-3,4,5-triacetoxy(acetoxymethyl)—3- methyltetrahydro-2H-pyranyl)oxy)-[1,1'-biphenyl]—3 -carboxylic acid from Step II (20 mg, 0.035 mmol) in MeOH (300 uL) was added NaOMe in MeOH (35 uL of 0.5 M, 0.018 mmol) until pH = 9 is reached. The reaction is stirred at RT for 18h. The reaction is neutralized with acidic Amberlyst resin, filtered and concentrated to give title compound (12 mg, 75%) as a white solid. 1H NMR (400 MHz, CD3OD) 5 8.19 (s, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.49 (t, J = 7.7 Hz, 1H), 7.42 (d, J = 9.3 Hz, 2H), 7.31 (d, J = 8.3 Hz, 1H), 5.27 (s, 1H), 3.78 — 3.67 (m, 4H), 3.64 — 3.55 (m, 1H), 2.31 (s, 3H), 1.40 (s, 3H). LC—MS: m/z = 405.18 (M+H)+.

Preparation of EXAMPLE 22 N-[2-[2-(2-aminoethoxy)ethoxy]ethyl]—3-[3-methyl[(2R,3S,4S,5S,6R)-3,4,5-trihydroxy—6— (hydroxymethyl)methyl-tetrahydropyranyl]oxy-phenyl]benzamide :1:Wm H2N\/\O/\/O Step I: tert—butyl N—[2—[2—[2—[[3—[3—methyl—4—[(2R,3 S,4S,5S,6R)—3,4,5—trihydroxy—6— (hydroxymethyl)methyl-tetrahydropyranyl]oxy-phenyl]benzoyl]amino]ethoxy] ethoxy] ethyl]]carbamate BocHN\/\O/\/0 To a solution of 3'-methyl-4'-(((2R,3S,4S,5R,6R)-3,4,5-triacetoxy(acetoxymethyl)—3- methyltetrahydro-2H-pyranyl)oxy)-[1,1'-biphenyl]—3-carboxylic acid from EXAMPLE 21 Step II (148 mg, 0.259 mmol) in DMF (5.2 mL) is added tert—butyl N—[2—[2—(2— thoxy)ethoxy]ethyl]carbamate (70.6 mg, 0.284 mmol). The solution is cooled at 0°C, HATU (118 mg, 0.310 mmol) and DIPEA (59 uL, 0.34 mmol) are added. The ing mixture is warmed to RT and stirred for 3h. The reaction is diluted with EtOAc and washed 3 times with saturated s NH4Cl. The combined aqueous phases are ted 5 times with EtOAc. The combined organic phases are dried over MgSO4 and concentrated in vacuo.

The residue is purified on BiotageTM SNAP silica cartridge (10 g). The combined fractions containing the desired t are combined, concentrated and dissolved in MeOH (5 mL).

To this was added NaOMe in MeOH (517 uL of 0.5 M, 0.259 mmol) until pH = 9 is reached.

The resulting mixture is d overnight. The reaction was neutralized with Amberlyst acidic resin and concentrated to give title compound (81 mg, 45%) as a white solid. 1H NMR (400 MHz, CD3OD) 5 8.02 (s, 1H), 7.73 (ddd, J = 7.8, 3.3, 1.5 Hz, 2H), 7.51 — 7.42 (m, 3H), 7.30 (d, J = 8.5 Hz, 1H), 5.27 (s, 1H), 3.75 — 3.56 (m, 11H), 3.48 (t, J = 5.6 Hz, 2H), 3.31 — 3.27 (m, 4H), 3.17 (t, J = 5.6 Hz, 2H), 2.30 (s, 3H), 1.39 (2s, 12H). LC—MS: m/z = 635.43 (M+H)+ Step II: EXAMPLE 22 To tert—butyl N—[2—[2—[2—[[3—[3 —methyl—4—[(2R,3S,4S,5S,6R)—3,4,5—trihydroxy—6— (hydroxymethyl)methyl-tetrahydropyranyl]oxy-phenyl]benzoyl]amino]ethoxy] ethoxy]ethyl]carbamate from Step I (70.6 mg, 0.102 mmol) is added TFA in CHZClz 1:1 (7mL) and the mixture is stirred for 5 min. The reaction is concentrated in vacuo to give title compound as a TFA salt (65 mg, 91%) as a white solid. 1H NMR (400 MHz, CD30D) 5 8.02 (s, 1H), 7.77 = 18.4, 10.9 Hz, 3H), 7.31 (d, J = 8.0 Hz, 1H), 5.27 — 7.70 (m, 2H), 7.48 (dd, J (s, 1H), 3.78 = 5.6 Hz, 4H), 3.04 (s, 2H), 2.31 — 3.63 (m, 12H), 3.61 (d, J (s, 3H), 1.40 (s, 3H).

LC—MS: m/z = 535.75 (M+H)+ Preparation of EXAMPLE 23 4'—(((2R,3 S,4S,5 S,6R)-3 zyloxy)methyl)—3 rihydroxy(hydroxymethyl)tetrahydro- 2H-pyranyl)oxy)-N,3'-dimethyl-[1,1'-biphenyl]—3 xamide HOm") O O ....... ||\ "I".

OH O [Me H The title compound is prepared according to the procedure described in EXAMPLE 13 but using INTERMEDIATE M8 in Step 1. 1H NMR (400 MHz, CD3OD) 5 8.03 (t, J = 1.8 Hz, 1H), 7.73 (ddt, J = 9.3, 7.9, 1.3 Hz, 2H), 7.55 — 7.37 (m, 3H), 7.35 — 7.22 (m, 1H), 7.20 — 7.04 (m, 5H), 5.64 (s, 1H), 4.61 (d, J = 12.2 Hz,1H), 4.36 (d, J = 12.1 Hz, 1H), 3.88 — 3.67 (m, 5H), 3.67 — 3.40 (m, 2H), 2.93 (s, 3H), 2.13 (s, 3H). LC-MS: m/z = 524.3 (M+H)+ Preparation of EXAMPLE 24 N,3'—dimethyl—4'—(((2R,3S,4S,5S,6R)-3,4,5-trihydroxy-3,6-bis(hydroxymethyl)tetrahydro-2H- pyranyl)oxy)-[1,1'-biphenyl]—3 -carboxamide Step I: (2R,3 S,4S,5R,6R)(acetoxymethyl)—3 -(hydroxymethyl)((3 -methyl-3 '- (methylcarbamoyl)-[1, 1'-biphenyl] yl)oxy)tetrahydro-2H-pyran-3 ,4,5 -triyl triacetate 0 Me Me NH Aco""" 1| OAc OAcOH To a solution of [(2R,3R,4S,5S,6R)-3,4,5-triacetoxy(benzyloxymethyl)[2-methyl [3-(methylcarbamoyl)phenyl]phenoxy]tetrahydropyranyl]methyl acetate from E 23 Step 1 (100 mg, 0.145 mmol) in EtOH (3.3 mL) and AcOH (33 "L, 0.5784 mmol) is added Pd(OH)2 20% (41 mg, 0.058 mmol). The reaction mixture is stirred under 1 atm of H2 for 16h. The resulting mixture is filtered over celite, the latter is rinsed with MeOH and the combined MeOH ons are concentrated in vacuo. The residue is purified on BiotageTM SNAP silica dge (10 g) using EtOAc (0-75%, 10CV) in Hex as eluent to afford the title compound (65 mg, 75%) as a solid. LC—MS: m/z = 602.6 (M+H)+.

Step II: EXAMPLE 24 To a stirred solution of (2R,3 S,4S,5R,6R)(acetoxymethyl)(hydroxymethyl)((3- methyl-3'-(methylcarbamoyl)—[ 1, 1 '-biphenyl]yl)oxy)tetrahydro-2H-pyran-3 ,4,5-triyl triacetate from Step I (20 mg, 0.033 mmol) in dry MeOH (1.2 mL) at RT is added NaOMe (66uL of 0.5 M, 0.039 mmol). The resulting mixture is stirred 16 hour, neutralized with Dowex 50 WX4-400 ion-exhange resin (H+). The mixture is was filtered, trated in vacuo and purified by reverse phase HPLC to afford the title compound (6.0 mg, 41%) as a white solid. 1H NMR (400 MHz, CD30D) 5 8.00 (t, J= 1.8 Hz, 1H), 7.71 (ddt, J= 7.7, 4.9, 1.2 Hz, 2H), 7.55 — 7.40 (m, 3H), 7.33 (d, J= 8.5 Hz, 1H), 5.56 (s, 1H), 3.95 (d, J= 11.5 Hz, 1H), 3.87 (d, J= 11.4 Hz, 1H), 3.82 — 3.65 (m, 4H), 3.58 (dt, J= 6.8, 3.3 Hz, 1H), 2.92 (s, 3H), 2.28 (s, 3H).

Preparation of EXAMPLE 25 N—methyl-3 -[3 -methyl[(2R,3 S,4S,5R,6R)-3,4,5-trihydroxy(hydroxymethyl)methyl- tetrahydropyranyl]oxy-phenyl]benzamide 0 0 HO O o v .M6 HO‘ OH N HO Me Step 1: (2R,4aR,6S,7S,8R,8aR)(benzyloxy)((tert-butyldimethylsilyl)oxy) phenylhexahydropyrano [3 ,2-d] [1 ,3]dioxin—7—ol 0‘" OH OTBDMS To a solution of commercially available (4aR,6S,7S,8R,8aS)benzyloxyphenyl- 4,4a,6,7,8,8a-hexahydropyrano[5,6-d][1,3]dioxine—7,8-diol (8.00 g, 22.3 mmol) and 4H- imidazole (2.181 g, 32.03 mmol) in DMF (72 mL) is added utyl-chloro-dimethyl-silane (4.189 g, 5.17 mL, 27.79 mmol). The reaction mixture is stirred for 120 s, and then partitioned between EtOAc and water. The organic extracts are dried over NaZSO4, filtered, evaporated to dryness and purified on silica gel using 0—20% EtOAc: Hex as eluent to afford the title compound (9.83 g, 88 % yield). 1H NMR (400 MHz, DMSO—D6) 5 7.54 — 7.26 (m, 10H), 5.68 (s, 1H), 5.10 (dd, J: 11.8, 4.6 Hz, 1H), 4.83 (d, J: 1.3 Hz,1H), 4.74 (d, J: 12.2 Hz, 1H), 4.55 (d, J: 12.2 Hz, 1H), 4.16 (dt, J: 12.2, 6.1 Hz, 1H), 4.03 — 3.92 (m, 2H), 3.87 — 3.76 (m, 1H), 3.75 — 3.57 (m, 1H), 0.87 (s, 9H), 0.07 (s, 3H), 0.02 (s, 3H).

Step 2: S,7S,8R,8aR)—6—(benzyloxy)—8—((tert—butyldimethylsilyl)oxy)—2— phenylhexahydro-pyrano[3 ,2-d] [1 ,3]dioxin—7—ol @%OTBDMS To a solution of (2R,4aR,6S,7S,8R,8aR)—6-(benzyloxy)((tert-butyldimethylsilyl)oxy)- 2-phenylhexahydropyrano[3,2-d][1,3]dioxinol from Step I (600 mg, 1.269 mmol) in DMF (6.0 mL) at 0°C is added NaH (55mg, 1.40 mmol). The reaction mixture is stirred for 15 minutes, then BnBr (181uL, 1.52 mmol) is added. The reaction mixture is d 2h at RT.

Upon completion, the reaction mixture is partitioned between water and EtOAc. The organic extracts are dried over NaZSO4, filtered, and evaporated to s. The crude product is purified on silica gel using 0-10% EtOAc: Hex as eluent to afford the title compound (530 mg, 71% yield). 1H NMR (400 MHz, DMSO—d6) 5 7.55 — 7.22 (m, 15H), 5.75 (s, 1H), 5.03 (d, J = 1.1 Hz, 1H), 4.73 (m, 3H), 4.56 (d, J = 12.1 Hz, 1H), 4.21 — 3.88 (m, 3H), 3.82—3.52 (m, 3H), 0.82 (s, 9H), 0.05 (s, 3H), 0.01 (s, 3H).

Step III: (4aR,6S,7S,8S,8aS)—6,7—bis(benzyloxy)—2-phenylhexahydropyrano[3,2- d][l,3]dioxin—8—ol 0019000o .053O OH To a solution of (4aR,6S,7S,8R,8aR)—6—(benzyloxy)—8—((tert—butyldimethylsilyl)oxy)—2- phenylhexahydropyrano[3,2-d][1,3]dioxinol from Step II (7.80 g, 13.86 mmol) in THF (78 mL), in a closed reaction vessel, is added AcOH (1.18 mL, 20.8 mmol) and tetrabutylammonium fluoride (41.6 mL of l M, 41.6 mmol). The reaction mixture is stirred at 60°C for 1h and cooled down to RT. The reaction mixture is then partitioned between water and EtOAc, and the aqueous phase is extracted with EtOAc 3 times. The ed organic extracts are dried over NaZSO4, filtered and evaporated to dryness. The crude product is purified on silica gel using 0—25% EtOAc: Hex as eluent to afford the title nd (4.90 g, 79%). 1H NMR (400 MHz, DMSO—D6) 5 7.47 — 7.11 (m, 15H), 5.69 — 5.53 (m, 1H), 5.30 — .16 (m, 1H), 4.97 (t, J = 9.3 Hz, 1H), 4.77 — 4.56 (m, 3H), 4.54 — 4.36 (m, 1H), 4.17 — 4.05 (m, 1H), 3.94 — 3.78 (m, 2H), 3.78 — 3.47 (m, 3H).

Step IV: (4aR,6S,7R,8aR)-6,7-dibenzyloxyphenyl-4a,6,7,8a-tetrahydro-4H-pyrano[3,2- d][l,3]dioxin—8—one o .053 To a solution of (4aR,6S,7S,8S,8aS)-6,7—bis(benzyloxy)—2—phenylhexahydropyrano[3,2— d][l,3]dioxinol from Step III (500 mg, 1.115 mmol) in CHzClz (5.0 mL) is added a solution of Dess—Martin periodinane (709 mg, 1.672 mmol) in CHzClz (5.0 mL) drop Wise over 5 minutes. The mixture is d for 3 hours. The reaction mixture is partitioned between s saturated solution ofNaHCO3 and CHzClz. The aqueous phase is extracted 3 times using CHzClz The combined c extracts are dried over NaZSO4, filtered and evaporated to s. The crude product is purified on silica gel using 0—25% EtOAc: Hex as eluent to afford the title compound (320 mg, 64% yield). 1H NMR (400 MHz, DMSO—D6) 5 7.44 — 7.21 (m, 15H), 5.79 (s, 1H), 5.32 (d, J: 1.2 Hz, 1H), 5.00 (d, J: 9.5 Hz, 1H), 4.70 (d, .1: 11.7 Hz, 1H), 4.59 — 4.46 (m, 3H), 4.25 (dd, J: 9.6, 4.4 Hz, 1H), 4.05 — 3.83 (m, 3H).

Step V: (4aR,6S,7S,8aS)—6,7—dibenzyloxy—8—methylene—2—phenyl—4a,6,7,8a—tetrahydro—4H— pyrano[3,2-d][1,3]dioxine cnmoo To a solution of methyl(triphenyl)phosphonium bromide (2.080 g, 5.823 mmol) in THF (22.40 mL) at 0°C is added potassium utoxide (5.38 mL of 1 M, 5.38 mmol). The e is stirred at 0°C for 30 minutes. To this e is added via syringe a solution of (4aR,6S,7R,8aR)-6,7-dibenzyloxyphenyl-4a,6,7,8a-tetrahydro-4H-pyrano[3,2- d][1,3]dioxinone from Step IV (2 g, 4.479 mmol) in THF (22.40 mL). The resulting mixture is allowed to warm up to RT and stir overnight. Upon completion, a saturated solution of aqueous NH4Cl is added and the reaction mixture is extracted with EtOAc 3 times. The combined organic extracts are dried over , filtered and concentrated in vacuo. The crude product is purified by flash chromatography using a gradient of 5-20% EtOAc: Hex to afford the title compound (1.31 g, 66% yield). 1H NMR (400 MHz, CDCl3) 5 7.62 — 7.50 (m, 2H), 7.46 — 7.23 (m, 13H), 5.68 (s, 1H), 5.46 (dt, J = 2.0, 1.2 Hz, 1H), 5.18 (d, J = 1.9 Hz, 1H), 4.96 (d, J =1.2 Hz, 1H), 4.74 (d, J = 12.0 Hz, 1H), 4.67 (d, J = 12.1 Hz, 1H), 4.59 — 4.49 (m, 1H), 4.41 (dd, J = 15.1, 10.3 Hz, 2H), 4.22 (dd, J = 5.6, 2.6 Hz, 1H), 3.98 (s, 1H), 3.95 — 3.83 (m, 2H). LCMS: m/z = 467.4 (M+Na)+.

Step VI: (4aR,6S,7S,8S,8aR)—6,7—dibenzyloxyphenyl-spiro[4a,6,7,8a-tetrahydro-4H- pyrano [3 ,2-d][1,3]dioxine-8,2'-oxirane] H VG ceo mo (4aR,6S,7S,8aS)—6,7—dibenzyloxymethylenephenyl-4a,6,7,8a-tetrahydro-4H- pyrano[3,2—d][1,3]dioxine from Step V (1.23 g, 2.767 mmol) is dissolved in CHzClz (28 mL) and m-CPBA (1.116 g, 4.981 mmol) is added. The mixture is stirred at RT for 3 hours.

Another load of m-CPBA (1.116 g, 4.981 mmol) is added and the ing solution is stired for 3 days. Then m-CPBA (272mg) is added again and the solution is stirred overnight. Upon completion, the mixture is d over Celite and a saturated solution ofNaHCO3 is added.

The resulting mixture is extracted 3 times with CHzClz. The combined organic extracts are dried over , filtered and concentrated in vacuo. The crude residue obtained is purified by flash chromatography using a gradient of 5-20% EtOAc: Hex. The desired ons are combined and the concentrated in vacuo. Then a second purif1cation is performed using 5— % EtOAc: Hex to afford the title nd (396mg, 31% yield). 1H NMR (400 MHz, CDCl3) 5 7.58 — 7.19 (m, 15H), 5.60 (s, 1H), 5.01 — 4.88 (m, 2H), 4.75 (d, J = 12.1 Hz, 1H), 4.68 (d, J = 12.1 Hz, 1H), 4.52 (d, J = 12.0 Hz, 1H), 4.44 (d, J = 9.4 Hz, 1H), 4.27 (dd, J = .0, 4.5 Hz, 1H), 4.04 (td, J = 9.8, 4.5 Hz, 1H), 3.97 — 3.86 (m, 1H), 3.40 — 3.34 (m, 1H), 3.21 (d, J = 5.1 Hz, 1H), 2.74 (d, J = 5.1 Hz, 1H). LCMS: m/z = 483.1 (M+Na)+.

Step VII: (4aR,6S,7S,8S,8aR)—6,7—dibenzyloxy—8—(iodomethyl)—2—phenyl-4a,6,7,8a— tetrahydro-4H-pyrano[3 ,2-d] [1 ,3]dioxin-8—ol 12 (393 mg, 1.55 mmol) is added to a solution of PPh3 (404 mg, 1.55 mmol) in CHzCLz (5.9 mL) and the mixture is stirred at RT for 5 minutes, at which point a solution of (4aR,6S,7S,8S,8aR)—6,7—dibenzyloxyphenyl-spiro[4a,6,7,8a-tetrahydro-4H-pyrano[3,2- d][1,3]dioxine—8,2'—oxirane] from Step VI (396 mg, 0.8599 mmol) in CHzClz (4.887 mL) is added. The resulting on is stirred for 5hours. Upon completion, the reaction is quenched with a 10% aqueous on ofNaHSO3 and the mixture is vigorously stirred for 5 minutes.

The resulting mixture is diluted with ether and the layers are separated. The organic phase is washed successively with water and brine, dried over NazSO4, filtered and concentrated in vacuo. The crude product is purified by flash chromatography using 0—20% EtOAc: Hex as eluent to afford the title compound (204mg, 40% . 1H NMR (400 MHz, CDCl3) 5 7.53 = 1.4 Hz, 1H), 4.75 (d, J = 12.3 Hz, 1H), 4.72 — 7.28 (m, 15H), 5.54 (s, 1H), 4.94 (d, J — 4.62 (m, 2H), 4.54 (d, J = 12.3 Hz, 1H), 4.27 — 4.17 (m, 1H), 4.05 — 3.90 (m, 3H), 3.88 — 3.68 (m, 3H), 3.07 (d, J = 2.3 Hz, 1H).

Step VIII: (4aR,6S,7S,8S,8aR)-6,7-dibenzyloxymethylphenyl-4a,6,7,8a-tetrahydro-4H- pyrano[3,2-d] [1,3]dioxin-8—ol :0 Mo o 93 @OHE o/\©Ho" To a solution of (4aR,6S,7S,8S,8aR)—6,7—dibenzyloxy—8-(iodomethyl)—2—phenyl—4a,6,7,8a— tetrahydro-4H-pyrano[3,2-d][1,3]dioxinol from Step VII (204 mg, 0.3467 mmol) in toluene (6.932 mL) is added yltin hydride (15 mg, 140 "L, 0.520 mmol) and AIBN (3.4 mg, 0.021 mmol). The resulting solution is stirred at 90°C for 12 hours. Upon completion, the reaction mixture is concentrated in vacuo. The residue is purified by flash chromatography using 0—30% EtOAc: Hex to afford the title compound (121mg, 75% yield). 1H NMR (400 MHz, CDCl3) 5 7.54 — 7.45 (m, 2H), 7.43 — 7.28 (m, 13H), 5.56 (s, 1H), 5.02 — 4.95 (m, 1H), 4.80 — 4.55 (m, 3H), 4.49 (d, J = 12.1 Hz, 1H), 4.28 — 4.17 (m, 1H), 3.90 — 3.71 (m, 3H), 3.53 — 3.44 (m, 1H), 2.93 (s, 1H), 1.51 (s, 3H). LCMS: m/z = 463.4 (M+H)+ Step IX: [(2R,3R,4S,5S)-3,4,5,6-tetraacetoxymethyl-tetrahydropyranyl]methyl acetate 0 OAc moi/i?" 0A0 (4aR,6S,7S,8S,8aR)—6,7—dibenzyloxymethylphenyl-4a,6,7,8a-tetrahydro-4H- pyrano[3,2—d][1,3]dioxinol from Step VIII (151 mg, 0.3265 mmol) is dissolved in MeOH (3.265 mL) and the mixture is degassed with nitrogen. Pd/C, wet, Degussa (139 mg, 0.131 mmol) is added to the mixture, which is then stirred at RT under 1 atm of H2 for 6 days. The on mixture is filtered over Celite and rinsed with MeOH and . The solution is concentrated in vacuo.

The e of crude products (mixture of the fully deprotected and mono—benzylated compounds) is then stirred in pyridine (5 mL) with acetic anhydride (2.5 mL, 26.50 mmol) at RT for 18 hours. (7.9 mg, 0.065 mmol) DMAP is added and the reaction mixture is stirred 2 hours, then pyridine (1 mL), and acetic anhydride (0.5 mL, 5.30 mmol) and (7.9 mg, 0.065 mmol) DMAP are added and the on is stirred overnight. Upon completion, the reaction mixture is concentrated in vacuo and porated with benzene 3 times. The crude product is purified by flash chromatography using a gradient of 0—50% EtOAc: Hex. A second ation is necessary, this time using 10—30% EtOAc: Hex.

The product obtained is dissolved in MeOH (1.658 mL) and the mixture is degassed with nitrogen for several minutes, at which point Pd/C, wet, Degussa (52.93 mg, 0.04974 mmol) is added and the mixture is stirred over weekend under 1 atm of H2. The mixture is filtered over Celite and rinsed with MeOH and CHzClz. The filtrate is trated in vacuo and the product is dissolved in pyridine (5 mL) and AczO (2.5 mL, 26.50 mmol) is added. The mixture is stirred at RT for 12 hours. Upon completion, the on mixture is trated in vacuo and co—evaporated with benzene. The crude product is purified by flash chromatography using 0- 50% EtOAc: Hex as gradient to afford the title nd (37mg, 13% overall yield). LCMS: m/z = 427.3 +.

Step X: [(2R,3R,4S,5S,6R)-3,4,5-triacetoxymethyl[2-methyl[3- (methylcarbamoyl)phenyl]phenoxy]tetrahydropyranyl]methyl acetate 0 "‘0 O A00 0 mo" ., OAc 0 "’Me AcO lVIe To a solution of [(2R,3R,4S,5S)-3,4,5,6-tetraacetoxymethyl-tetrahydropyran yl]methyl acetate from Step IX (37.0 mg, 0.0915 mmol) and INTERMEDIATE A2 (44.2 mg, 0.1830 mmol) in l,2-dichloroethane (523.2 uL) at 0°C in a microwave vial is added BF3.OEt2 (34.8 uL, 0.275 mmol) dropwise. The mixture is allowed to warm up to RT and then is warmed up to 40 OC and stirred overnight. Upon completion, the reaction mixture is cooled to RT and the reaction mixture is purified ly by flash chromatography using a gradient of 40—90% EtOAc: Hex to afford the title compound (27mg, 50% yield). LCMS: m/z = 586.4 (M+H)+ Step XI: EXAMPLE 25 To a stirred solution of [(2R,3R,4S,5S,6R)-3,4,5-triacetoxymethyl[2-methyl[3- (methylcarbamoyl)phenyl]phenoxy]tetrahydropyranyl]methyl acetate from Step X (27 mg, 0.0461 mmol) in dry methanol (461 uL) at RT is added a solution ofNaOMe 25 %w/v in MeOH (9.964 uL, 0.04611 mmol). The resulting mixture is stirred 2 hours. LCMS indicated that the reaction is completed. Upon completion the mixture is loaded onto a SPE, SXC cartridge (lg). The column is rinsed with MeOH for the lent of 4 CV. The filtrate is concentrated in vacuo to e the crude desired product. Finally, the product is submitted for reverse phase purification to afford the title compound (19 mg, 66% yield). 1H NMR (400 MHz, CD3OD) 5 8.02 (d, J = 1.9 Hz, 1H), 7.74 (ddd, J = 8.0, 5.0, 1.6 Hz, 2H), 7.54 — 7.42 (m, 3H), 7.31 (d, J = 8.4 Hz, 1H), 5.55 (d, J =1.8 Hz, 1H), 3.86 — 3.63 (m, 5H), 2.94 (s, 3H), 2.32 (s, 4H), 1.50 (s, 3H). LCMS: m/z = 418.31 (M+H)+ Preparation of EXAMPLE 26 N—methyl[3-methyl[(2S,3S4S,5S,6R)-3,4,5-trihydroxy(hydroxymethyl)methyl- tetrahydropyranyl] oxy--phenyl]]benzamide Step I:[[(2,R3S,4S,5S,6,S)—34,5-triacetoxymethyl[2-methyl[3- (methylcarbamo":1)phenyl]phenoxy]tetrahydropyranyl]methyl acetate A00 ' A00"- OAC To a solution of INTERMEDIATE M7 (123 mg, 0.304 mmol) and INTERMEDIATE A2 (147 mg, 0.608 mmol) in 1,2-dichloroethane (1.73 mL) at 0°C is added BF3.OEt2 (116 "L, 0.913 mmol) dropwise. The mixture is allowed to warm up to RT and then is heated up to 40°C and stirred overnight. Upon tion, the reaction mixture is cooled down to RT and loaded ly on a flash chromatography column. The purification is performed using a gradient of 20-80% EtOAc: Hex. The mixed fractions are collected and purified again by flash chromatography using a gradient of 30—70% EtOAc: Hex. The pure t collected from the first and second purifications are ed to provide the desired title compound (150 mg, 84% yield). 1H NMR (400 MHz, CD3OD) 5 8.02 (t, J= 1.8 Hz, 1H), 7.77 — 7.68 (m, 2H), 7.55 — 7.40 (m, 3H), 7.19 (d, J= 8.5 Hz, 1H), 5.71 (d, J= 2.8 Hz, 1H), 5.70 (s, 1H), .68 — 5.66 (m, 1H),5.51 (dd, J= 2.8, 2.1 Hz, 1H), 4.05 — 3.94 (m, 2H), 2.94 (s, 3H), 2.32 (s, 3H), 2.20 (s, 3H), 2.11 (s, 3H), 2.08 (s, 3H), 2.04 (s, 3H), 1.31 (s, 3H). LC—MS: m/z = 586.7 (M+H)+ Step II: E 26 To a stirred solution of [(2R,3S,4S,5S,6S)-3,4,5—triacetoxymethyl—6—[2—methyl—4—[3- (methylcarbamoyl)phenyl]phenoxy]tetrahydropyranyl]methyl acetate (150 mg, 0.2561 mmol) in dry methanol (2.561 mL) at RT is added a solution of sodium methoxide in methanol 25 %w/V (55.34 "L, 0.2561 mmol). The resulting mixture is stirred 2 hours. Upon completion, the mixture is diluted with minimum MeOH and loaded onto a SPE, SXC cartridge (1g). The column is rinsed with MeOH for the equivalent of 4 CV. The filtrate is concentrated in vacuo to provide the title compound (89 mg, 71% yield). 1H NMR (400 MHz, CD3OD) 5 8.00 (t, J: 1.8 Hz, 1H), 7.76 — 7.67 (m, 2H), 7.52 — 7.41 (m, 3H), 7.27 (d, J = 8.4 Hz,1H), 5.58 (d, J: 1.8 Hz, 1H), 4.16 (dd, J: 10.1, 3.2 Hz, 1H), 4.12 — 4.02 (m, 2H), 3.52 (d, J: 11.5 Hz, 1H), 3.43 (d, J: 11.6 Hz, 1H), 2.92 (s, 3H), 2.27 (s, 3H), 1.09 (s, 3H).

LC—MS: m/z = 418.3 (M+H)+ Preparation of EXAMPLE 27 N—methyl—3—[3—methyl—4—[(2R,3S,4S,5S,6,R)—34,5—trihydroxy—6—[(1S)—1— hydroxyethyl]tetrahydropyranyl]oxy--phenyl]benzamide Met. ' ‘0‘ HO" OH0 Step ,R3R,4S,5S,6,R)—35-diacetoxy[(1S)acetoxyethyl][2-methyl[3- lcarbamohil)phenyl]phenoxy]tetrahydropyranyl] acetate -e_o \0 A00‘ To a on of INTERMEDIATE M5 (96.0 mg, 0.237 mmol) and INTERMEDIATE A2 (115 mg, 0.475 mmol) in 1,2-dichloroethane (1.4 mL) at 0°C is added BF3.OEt2 (90.3 "L, 0.712 mmol) drop wise. The mixture is allowed to warm up to RT and then is heated up to 40 °C. The resulting solution is stirred ght. Upon completion, the reaction mixture is cooled to RT and loaded directly on a flash chromatography column. The purification is performed using a gradient of 30-100% EtOAc: Hex. A second flash chromatography is performed, this time using a 30—70% EtOAc: Hex to afford the title compound (66 mg, 47% yield). LC—MS: m/z = 586.6 (M+H)+ Step II: EXAMPLE 27 To a stirred solution of [(2R,3R,4S,5S,6R)-3,5-diacetoxy[(1S)acetoxyethyl][2- methyl[3 -(methylcarbamoyl)phenyl]phenoxy]tetrahydropyranyl] acetate from Step I (66 mg, 0.113 mmol) in dry methanol (1.2 mL) at RT is added a solution ofNaOMe in MeOH 25 %W/v (24.35 "L, 0.1127 mmol). The ing mixture is stirred 1 hour. Upon completion the mixture is concentrated and loaded onto a SPE, SXC cartridge (1g). The column is rinsed with MeOH for the equivalent of 4 CV. The filtrate is concentrated in vacuo to provide the product which is lyophilized in a mixture of MeOH and water (41mg, 82% yield). 1H NMR (400 MHz, CD3OD) 5 8.52 (s, 1H), 8.01 (t, J = 1.8 Hz, 1H), 7.72 (ddt, J = 7.9, 5.0, 1.3 Hz, 2H), 7.47 (td, J = 8.5, 8.1, 6.1 Hz, 3H), 7.24 (d, J = 8.5 Hz, 1H), 5.61 (d, J = 1.8 Hz, 1H), 4.12 — 4.01 (m, 2H), 4.00 — 3.82 (m, 2H), 2.98 — 2.86 (m, 3H), 2.29 (s, 3H), 1.08 (d, J = 6.6 Hz, 3H).LC—MS: m/z = 418.5 (M+H)+ Preparation of EXAMPLE 28 (2R,3S,4S,5S,6R)[2-chloro(5-nitroindolin- 1-yl)phenoxy]-6(-[1-S) 1 -hydroxyethyl ]t-etrahydropyran3 ,4,5 -triol @109 Step I: [(2R,3R,4S,5 3,5—diacetoxy—2—[(1S)—1—acetoxyethyl]—6—(4—bromo—2—chloro— phenoxy)tetrahydropyranyl] acetate H :\CI : O _\\O Aco‘" 0A0 0A0 To a solution of INTERMEDIATE M5 (100 mg, 0.250 mmol) and 4-bromochloro- phenol (101 mg, 0.490 mmol) in CH2C12 (1.5 mL) at 0°C is added BF3.OEt2 (97 11L, 0.76 mmol) dropwise. The mixture is allowed to warm up to RT and then is heated up to 40 °C.

The resulting solution is d overnight. Upon completion, the reaction mixture is cooled to RT and loaded directly on a flash chromatography column. The cation is med using a gradient of 0-40% EtOAc/Hex to afford the title product (95 mg, 0.17 mmol, 69.60%). LC—MS: m/z = 575.43 (M+Na)+ Step 11: Me CI E 0 so<1 Aco‘" OAc N A microwave vial is charged with R,4S,5S,6R)-3,5-diacetoxy[(1S)—1— acetoxyethyl](4-bromochloro-phenoxy)tetrahydropyranyl] acetate from Step I (82.0 mg, 0.150 mmol), 5—nitroindoline (12.0 mg, 0.072 mmol), CszCO3 (48.0 mg, 0.15 mmol), X— Phos (2.0 mg, 0.0042 mmol) and Pd2(DBA)3 (0.55 mg, 0.00060 mmol). Toluene (1.2 mL) is added, and the vial is degassed (house—vacuum then N2), capped and submitted to microwave for 15 min at 100 °C. The reaction mixture is diluted with EtOAc passed on a 500 mg silica cartridge and eluted with EtOAc. The residual mixture is concentrated under reduced pressure and is used as is for the next step without further purification.

Step III: EXAMPLE 28 To a stirred solution of [(2R,3R,4S,5S,6R)-3,5-diacetoxy[(1S)acetoxyethyl][2- chloro(5-nitroindolinyl)phenoxy]tetrahydropyranyl] e from Step II (0.15 mmol) in dry MeOH (2 mL) at RT is added NaOMe (150 uL of 0.5 M, 0.0740 mmol). The resulting mixture is d for 4 hour at RT. Upon completion the mixture is concentrated and loaded onto a cation-exchange resin (SXC, cartridge, 1g). The column is rinsed with methanol for the equivalent of 4 CV. The mixture is purified using reverse phase HPLC. The combined fractions containing the desired material are lyophilized to afford the title nd (47mg, 82% yield). 1H NMR (400 MHz, CD3OD) 5 8.53 (s, 1H), 8.11 — 7.94 (m, 1H), 7.49 = 8.7 Hz, 1H), 5.60 (s, 1H), 4.18 — 7.18 (m, 3H), 6.84 (d, J — 4.01 (m, 2H), 3.92 (dd, J = 205,113 Hz, 2H), 3.41 = 6.6 Hz, 3H). — 3.33 (m, 1H), 3.25 — 3.16 (m, 1H), 1.07 (d, J LC—MS: m/z = 467.35 (M+H)+ Preparation of EXAMPLE 29 N—methyl[3-methyl[(2R,3S,4S,5S,6,R)-34,5-trihydroxy[(1R)hydroxyethyl] tetrahydropyran-e2-yl] henyl]]benzamide Step 1: (2R,3R,4S,5S,6,R)diacetoxy[(1R)acetoxyethyl][2-methyl[3- (methylcarbamoyl)phenyl]phenoxy]tetrahydropyranyl] acetate 2 '21 : o ‘0 To a solution of INTERMEDIATE M6 (145 mg, 0.359 mmol) and INTERMEDIATE A2 (173 mg, 0.717 mmol) in 1,2-dichloroethane (2.050 mL) at 0°C in a microwave vial is added BF3.OEt2 136 "L, 1.08 mmol) dropwise . The mixture is allowed to warm up to RT, and then stirred overnight at 40°C and. Upon completion, the reaction mixture is cooled down to RT and loaded directly onto a flash chromatography column. The purification is performed using a gradient of 30-100% EtOAc: Hex. The mixed fractions are collected and purified again by flash chromatography using a nt of 50—85% EtOAc: Hex. The pure product ted from the first and second purifications are ed to provide the desired compound (210mg, 67% yield). LC-MS: m/z = 586.7 (M+H)+ Step II: EXAMPLE 29 To a stirred solution of [(2R,3R,4S,5S,6R)-3,5-diacetoxy[(1R)acetoxyethyl][2- methyl[3 -(methylcarbamoyl)phenyl]phenoxy]tetrahydropyranyl] acetate from Step I (141 mg, 0.241 mmol) in dry MeOH (2.5 mL) at RT is added a solution ofNaOMe in MeOH 25 %w/v (52 "L, 0.24 mmol). The resulting mixture is stirred 1 hour at RT. Upon completion, the mixture is trated and the crude product is loaded in minimum methanol onto a SPE, SXC cartridge (1g). The column is rinsed with MeOH for the equivalent of 4 CV. The filtrate is concentrated in vacuo to provide the crude product which is submitted for reverse phase HPLC. The pure fractions are combined and lyophilized directly to provide the title nd (38.9 mg, 36% yield). 1H NMR (400 MHz, CD3OD) 5 8.00 (t, J = 1.8 Hz, 1H), 7.72 (ddt, J = 7.9, 5.1, 1.3 Hz, 2H), 7.51 = — 7.42 (m, 3H), 7.28 (d, J 8.5 Hz, 1H), 5.52 (d, J = 1.8 Hz, 1H), 4.05 (dd, J = 3.4, 1.8 Hz, 1H), 4.00 (qd, J =6.5, 4.6 Hz, 1H), 3.94 (dd, J = 9.3, 3.4 Hz, 1H), 3.76 (t, J = 9.6 Hz, 1H), 3.49 (dd, J = 9.8, 4.5 Hz, 1H), 2.92 (s, 3H), 2.30 (s, 3H), 1.18 (d, J = 6.4 Hz, 3H). LC—MS: m/z = 418.2 (M+H)+ Preparation of EXAMPLE 30 N—methyl-3 -[3 -methyl[(2R,3 S,4S,5S,6R)-3,4,5-trihydroxy[(1S)—1-hydroxymethylpropyl ]tetrahydropyranyl]oxy-phenyl]benzamide Step I: (1 ethyl[(2R,3 S,4S,5 S,6S)-3,4,5,6-tetrabenzyloxytetrahydropyran yl]propan01 To a on of (2R,3R,4S,5S,6S)—3,4,5,6-tetrabenzyloxytetrahydropyranyl]methanol (Daragics, K.; Fugedi, P. Tet. Lett., 2009, 50, 2914—2916) (1.500 g, 2.774 mmol), DMSO (8.159 mL), and NEt3 (1.93 mL, 13.9 mmol) in CH2C12 (8.2 mL) at 0°C is added SO3.pyridine complex (2.208 g, 13.87 mmol) in 3 portions. The reaction is stirred for 1hour.

Upon completion, the on e is diluted with EtOAc, and washed with water, 10% aqueous potassium bisulfate, saturated aqueous NaHCO3 and brine. The c layer is dried over MgSO4 and concentrated in vacuo. The residue is co—evaporated twice with benzene to give crude aldehyde which is used without further purification.

Bromo—isopropyl-magnesium (957 "L of 2.9 M, 2.77 mmol) is added to a solution of (2S,3 S,4S,5S,6S)—3,4,5,6—tetrabenzyloxytetrahydropyrancarbaldehyde (747 mg, 1.39 mmol) in THF (7.0 mL) at 0°C. The on is stirred for 15 min and the ice bath is removed and the mixture is stirred over 15min at RT. Upon completion, the e is quenched with a saturated aqueous NH4Cl. The aqueous layer is back extracted 3 times with EtOAc. The combined organic layers are dried over NaZSO4, filtered and concentrated in vacuo. The crude product is purified by flash chromatography using a gradient of 0-50% EtOAc: Hex to afford the title compound (407mg, 50% yield over 2 steps). 1H NMR (400 MHz, CD3Cl) 5 7.26 (s, 20H), 5.00 — 4.87 (m, 2H), 4.79 — 4.59 (m, 6H), 4.42 (d, J = 12.0 Hz, 1H), 4.26 — 4.14 (m, 1H), 3.97 (dd, J = 9.5, 3.1 Hz, 1H), 3.89 — 3.75 (m, 2H), 3.43 (dd, J = 10.7, 8.8 Hz, 1H), 1.98 (d, J = 10.8 Hz, 1H), 1.92 (dt, J = 8.9, 6.7 Hz, 1H), 1.07 (d, J = 6.7 Hz, 3H), 0.91 (d, J = 6.7 Hz, 3H). LC—MS: m/z = 605.0 (M+Na)+.

Step II: (3 S,4S,5 S,6R)—6—[(1S)—1-hydroxymethyl-propyl]tetrahydropyran-2,3 ,4,5-tetrol (1 S)—2-methyl[(2R,3 S,4S,5 S,6S)-3 ,4,5 ,6-tetrabenzyloxytetrahydropyranyl]propan- 1—01 from step I (407 mg, 0.698 mmol) is dissolved in MeOH (7.2 mL) and the mixture is degassed with nitrogen. Pd/ C, wet, Degussa (446 mg, 0.419 mmol) is added to the mixture, which is then stirred at RT under 1 atm of H2 ght. The next day, the H2 is refilled and AcOH (159 uL, 2.794 mmol) is added. The reaction is stirred over the weekend. The reaction mixture is filtered over Celite, rinsed with MeOH and CH2C12 and the filtrate is concentrated in vacuo. The residue is dissolved in EtOH (6.983 mL) and AcOH (159 uL, 2.79 mmol) and the mixture is ed with nitrogen. Pd(OH)2 (294 mg, 0.419 mmol) is added to the mixture, which is then stirred at RT for 2 days under 1 atm of H2. The reaction mixture is filtered over , rinsed with MeOH and CHzClz. The filtrate is concentrated in vacuo to afford the title compound which is used as such in the next step. LC—MS: m/z = 245.2 (M+Na)+.

Step III: [(3 S,4S,5R,6R)-2,3 ,5 -triacetoxy[(1S)—1-acetoxymethyl- ]tetrahydropyranyl] acetate (3 S,4S,5 S,6R)—6—[(1S)—1-hydroxymethyl-propyl]tetrahydropyran-2,3 ,4,5 -tetrol from Step 11 (155 mg, 0.698 mmol) is dissolved in pyridine (10 mL) and ACZO (5.0 mL, 53 mmol) is added. The mixture is stirred at RT for 12 hours. The reaction mixture is concentrated in vacuo and co—evaporated with benzene 3 times. Purification of the crude product is performed by flash chromatography using a gradient of 0-50% EtOAc: Hex to afford the title nd (35.7mg, 11% yield). LC—MS: m/z = 455.3 +.

Step 1V: [(2R,3R,4S,5 S,6R)—3,5—diacetoxy[(1S)acetoxymethyl-propyl][2-methyl- 4-[3-(methylcarbamoyl)phenyl]phenoxy]tetrahydropyranyl] acetate To a on of [(3S,4S,5R,6R)—2,3,5—triacetoxy-6—[(1S)acetoxy—2—methyl— propyl]tetrahydropyranyl] acetate from Step III (35.7 mg, 0.0826 mmol) and INTERMEDIATE A2 (39.8 mg, 0.165 mmol) in 1,2—dichloroethane (505 uL) at 0°C is added BF3.OEt2 (31.4 uL, 0.248 mmol) dropwise. The mixture is allowed to warm up to RT and then is warmed up to 40 OC and stirred overnight. Upon completion, the on mixture is cooled down to RT and purified directly by flash chromatography using a gradient of 40- 100% EtOAc: Hex to afford the title compound (29.3mg, 58% yield). LC—MS: m/z = 614.4 (M+H)+ 2014/024411 Step V: EXAMPLE 30 To a stirred solution of [(2R,3R,4S,5S,6R)—3,5—diacetoxy—2—[(1S)—1—acetoxymethyl- propyl]—6-[2-methyl[3-(methylcarbamoyl)phenyl]phenoxy]tetrahydropyranyl] acetate from Step IV (29.3 mg, 0.04775 mmol) in dry MeOH (500.2 uL) at RT is added a solution of NaOMe in MeOH 25 %W/v (10.3 "L, 0.0478 mmol). The resulting mixture is stirred 2 hours at RT. Upon completion the mixture is diluted in minimum MeOH and loaded onto a SPE, SXC cartridge (1g). The column is rinsed with MeOH for the equivalent of 4 CV. The filtrate is concentrated in vacuo to provide the crude product which is purified by reverse phase HPLC to afford the title compound (10.8 mg, 51% . 1H NMR (400 MHz, CD30D) 5 8.00 (t, J = 1.8 Hz, 1H), 7.72 (ddt, J = 7.1, 4.0, 1.2 Hz, 2H), 7.56 — 7.37 (m, 3H), 7.20 (d, J = 8.5 Hz, 1H), 5.66 (d, J = 1.8 Hz, 1H), 4.10 — 4.01 (m, 1H), 3.96 (dd, J = 5.4, 2.1 Hz, 2H), 3.58 (dt, J = 7.3, 1.4 Hz, 1H), 3.38 — 3.30 (m, 1H), 2.92 (s, 3H), 2.29 (s, 3H), 1.84 — 1.64 (m, 1H), 0.92 (d, J = 6.7 Hz, 3H), 0.38 (d, J = 6.7 Hz, 3H). LC—MS: m/z = 446.0 (M+H)+.

Preparation of EXAMPLE 3 1 N—methyl-3 -[3 -methyl[(2R,3 S,4S,5 S,6R)-3,4,5-trihydroxy[(1S)—1-hydroxypropyl] tetrahydropyranyl]oxy-phenyl]benzamide ? O .\‘O O HO 0 Ho‘" OH "’Me Step I: ((2R,3 S,4S,5 S,6S)—3 ,4,5 ,6-tetrakis(benzyloxy)tetrahydro-2H-pyranyl)propan- 1-ol To a on of (2R,3R,4S,5S,6S)—3,4,5,6-tetrabenzyloxytetrahydropyranyl]methanol (Daragics, K.; Fiigedi, P. Tet. Lett., 2009, 50, 2914—2916) (1.500 g, 2.774 mmol), DMSO (8.159 mL), and NEt3 (1.93 mL, 13.9 mmol) in CHzClz (8.15 mL) at 0°C is added SO3.pyridine complex (2.208 g, 13.87 mmol) in 3 portions. The reaction is stirred for 1hour.

Upon completion, the reaction mixture is diluted with EtOAc, and washed with water, 10% aqueous ium bisulfate, saturated aqueous NaHCO3 and brine. The organic is dried over MgSO4 and concentrated in vacuo. The residue is co—evaporated twice with benzene to give crude aldehyde which is used t further purification.

EtMgBr (924.7 "L of 3M in Et20, 2.774 mmol) is added to a solution of (2S,3S,4S,SS,6S)— 3,4,5,6-tetrabenzyloxytetrahydropyrancarbaldehyde (747 mg, 1.39 mmol) in THF (6.9 mL) at 0°C. The reaction mixture is allowed to stir for 15 minutes at that temperature and then the ice bath is removed. The mixture is allowed to stir at RT for another 15 minutes.

Upon completion, the mixture is quenched with saturated aqueous NH4Cl. The aqueous layer is back extracted 3 times with EtOAc. The combined organic layers are dried over NaZSO4, filtered and concentrated in vacuo. The crude product is purified by flash chromatography using a gradient of 0-50% EtOAc: Hex to provide the title compound. , 80% yield over 2 steps). LC—MS: m/z = 591.5 (M+Na)+.

Step H:(3 S,4S,5 S,6R)—6—[(1S)hydroxypropyl]tetrahydropyran-2,3 ,4,5 -tetrol (1 S)—1—[(2R,3 S,4S,5 S,6S)-3 ,4,5,6-tetrabenzyloxytetrahydropyranyl]propanol (63 3 mg, 1.113 mmol) is dissolved in MeOH (11.13 mL) and the mixture is degassed with nitrogen. Pd on C, 10% w/w, wet, Degussa (710.7 mg, 0.6678 mmol) is then added to the mixture. The reaction mixture is allowed to stir at RT under 1 atm of H2. After 1 day, the H2 is d, AcOH (253 uL, 4.45 mmol) is added and the reaction is stirred over the weekend.

The mixture is filtered over Celite, rinsed with MeOH and CH2C12 and the e is trated in vacuo. This crude mixture is the dissolved in EtOH (11 mL) and AcOH (253 "L, 4.45 mmol) and the mixture is degassed with nitrogen. Palladium hydroxide 10% w/w (313 mg, 0.445 mmol) is added to the mixture. The solution is then stirred at RT under 1 atm of H2 for 2 days. At that point, the reaction mixture is filtered over Celite, rinsed with MeOH and CHzClz and the e is trated in vacuo. The crude product is used as such in the next step. LC—MS: m/z = 231.2 (M+Na)+.

Step III: [(3 S,4S,5R,6R)-2,3 ,5 -triacetoxy[(1S)acetoxypropyl]tetrahydropyranyl] acetate (3 S,4S,5S,6R)—6—[(1S)—1—hydroxypropyl]tetrahydropyran-2,3,4,5-tetrol from Step II (231 mg, 1.11 mmol) is dissolved in pyridine (10 mL) and AczO (5.0 mL, 53.0 mmol) is added. The mixture is stirred at RT for 12 hours. The reaction e is then trated in vacuo and co—evaporated with benzene. Purification using flash chromatography is performed using a gradient of 0— 50% EtOAc: Hex. The title compound is obtained and is used as such in the next step. LC-MS: m/z = 441.2 (M+Na)+.

Step IV: [(2R,3R,4S,5 S,6R)—3 ,5 —diacetoxy[(1S)—1-acetoxypropyl][2-methyl[3 - (methylcarbamoyl)phenyl]phenoxy]tetrahydropyranyl] acetate To a solution of [(3S,4S,5R,6R)—2,3,5—triacetoxy—6-[(1S)—1— acetoxypropyl]tetrahydropyranyl] acetate from Step III (51.4 mg, 0.123 mmol) and INTERMEDIATE A2 (59.31mg, 0.246 mmol) in 1,2-dichloroethane (730 uL) at 0°C is added BF3.OEt2 (46.7 uL, 0.369 mmol) dropwise. The mixture is allowed to warm up to RT and is then heated up to 40°C and stirred overnight. Upon completion, the reaction mixture is cooled down to RT and purified ly by flash chromatography using a nt of 40- 100% EtOAc: Hex. The title compound is obtained and can be used as such in the next step.

LC—MS: m/z = 622.4 (M+Na)+.

Step V: EXAMPLE 31 To a stirred solution of [(2R,3R,4S,5S,6R)-3,5-diacetoxy[(1S)acetoxypropyl][2- methyl[3 -(methylcarbamoyl)phenyl]phenoxy]tetrahydropyranyl] acetate from Step N (47.7 mg, 0.07955 mmol) in dry MeOH (814 uL) at RT is added a solution ofNaOMe in MeOH 25 %w/v (17.19 uL, 0.07955 mmol). The resulting e is stirred for 2 hours.

Upon completion, the reaction mixture is diluted in minimum MeOH and loaded onto a SPE, SXC dge (1g). The column is rinsed with MeOH for the equivalent of 4 CV. The filtrate is concentrated in vacuo to e the crude product which is purified by reverse phase HPLC to provide the title compound (15.5mg, 3% yield over 4 steps). 1H NMR (400 MHz, CD30D) 5 8.02 (t, J = 1.8 Hz, 1H), 7.81 = 8.5 — 7.68 (m, 2H), 7.56 — 7.41 (m, 3H), 7.23 (d, J Hz, 1H), 5.65 (d, J = 1.8 Hz, 1H), 4.09 = 5.4, — 4.03 (m, 1H), 3.97 (dd, J 1.8 Hz, 2H), 3.77 — 3.69 (m, 1H), 3.44 — 3.38 (m, 1H), 2.94 (s, 3H), 2.31 (s, 3H), 1.56 (dt, J = 13.5, 7.5 Hz, 1H), 1.35 (tq, J = 14.5, 7.3 Hz, 1H), 0.66 (t, J = 7.4 Hz, 3H).

LC—MS: m/z = 432.1 (M+H)+.

Preparation of EXAMPLE 32 (2R,3'S,4'S,5'S,6'R)—6'—(hydroxymethyl)methoxy-spiro[chromane-2,2'-tetrahydropyran]- 3',4',5'—triol ( HO". OH OH Step I: S,4'S,5'R,6'R)-3',4',5'-tribenzyloxy-6'-(benzyloxymethyl)methoxy- spiro[chromane—2,2'-tetrahydropyran] BnO .0 BnO‘fl OBn To a cold (0°C) solution of INTERMEDIATE M9 (87 mg, 0.143 mmol) and 4- methoxyphenol (53.0 mg, 0.430 mmol) in CH2Cl2 (2 mL) is added BF3.OEt2 (18.0 11L, 0.142 mmol). After stirring for 30 min at 0°C, the reaction mixture is diluted with H20 and CH2Cl2 (3 mL each). The layers are separated and the aqueous layer is back extracted with CH2Cl2 (1 mL). The combined c extracts are concentrated and purified by flash chromatography on a BiotageTM SNAP silica dge (10 g) using a gradient of EtOAc (0 to 20%) in Hex, affording the title compound (43 mg, 45% yield) as a white foamy solid.

Step II: EXAMPLE 32 Pd(OH)2 (16.5 mg, 0.0024 mmol) is charged in a pressure vessel flushed with N2. MeOH is added (1 mL), followed by a solution of (2R,3'S,4'S,5'R,6'R)—3',4',5'—tribenzyloxy—6'— (benzyloxymethyl)methoxy-spiro[chromane-2,2'-tetrahydropyran] from Step I (43 mg, 0.064 mmol) in MeOH (2 mL) and EtOAc (2 mL). AcOH (15.0 11L, 0.264 mmol) is added, the pressure vessel is purged with H2 (3x), and then stirred overnight under 45 psi H2. The reaction mixture is filtered on Celite, and the catalyst is rinsed with portions of MeOH. The combined es are concentrated and co—evaporated with benzene to e crude product, which is purified by flash chromatography on a eTM SNAP silica cartridge (10 g) using a nt of MeOH (0 to 20%) in CH2C12 affording the title compound (12 mg, 57% yield) as a white solid. 1H NMR (400 MHz, CD3OD) 5 6.74 — 6.60 (m, 3H), 4.06 (dd, J = 9.5, 3.4 Hz, 1H), 3.79 = 9.9, 4.5, 2.7 Hz, 1H), 3.00 (ddd, J = 16.6, 12.9, — 3.60 (m, 7H), 3.52 (ddd, J 6.2 Hz, 1H), 2.63 (ddd, J = 16.4, 5.8, 2.2 Hz, 1H), 2.35 (ddd, J = 13.6, 6.2, 2.4 Hz, 1H), 1.71 (td, J = 13.2, 6.0 Hz, 1H). ESI—MS m/z calc. 312.32, found 335.29 (M+Na)+ Preparation of EXAMPLE 33 N—methyl—3—[(2R,3'S,4'S,5'S,6'R)-3',4',5'-trihydroxy-6'-(hydroxymethyl)spiro[chromane-2,2'- tetrahydropyran]yl]benzamide Step I: yl—3—[(2R,3'S,4'S,5'R,6'R)—3',4',5'—tribenzyloxy—6'— (benzyloxymethyl)spiro[chromane-2,2'-tetrahydropyran]yl]benzamide The title compound is prepared according to the procedure described in EXAMPLE 32 using INTERMEDIATE M9 (116 mg, 0.19 mmol) and INTERMEDIATE A1 (138 mg, 0.610 mmol) in THE (2.7 mL). After 1h at 0 OC, another equivalent of BF3.OEt2 is added and stirring is pursued for 15h at 0°C and 25h at RT. Purification by flash chromatography on a BiotageTM SNAP silica cartridge (10 g) using a gradient of EtOAc (0 to 20%) in CHzClz provided the title (18 mg, 12% yield) as a colorless gum.

Step II: EXAMPLE 33 Using N-methyl[(2R,3'S,4'S,5'R,6'R)—3',4',5'-tribenzyloxy-6'- (benzyloxymethyl)spiro[chromane-2,2'-tetrahydropyran]yl]benzamide from Step I (23 mg, 0.030 mmol). Purification of the crude product by preparative thin layer chromatography on silica gel (10x20 cm, 1 mm thickness) using 20% MeOH in CHzClz as . Final material is dissolved in HZO/MeCN mixture (20% MeCN), ted and lyophilized to afford the title compound (8.9 mg, 69% yield) as a White fluffy solid. 1H NMR (400 MHz, CD3OD) 5 8.01 (t, J = 1.7 Hz, 1H), 7.78 — 7.67 (m, 2H), 7.49 (t, J = 7.8 Hz, 1H), 7.45 — 7.35 (m, 2H), 6.96 — 6.83 (m, 1H), 4.11 (dd, J = 9.5, 3.4 Hz, 1H), 3.81 (d, J = 3.4 Hz, 1H), 3.74 (t, J = 9.7 Hz, 1H), 3.70 — 3.66 (m, 1H), 3.58 (ddd, J = 9.9, 4.2, 3.1 Hz, 1H), 3.18 = — 3.05 (m, 1H), 2.76 (ddd, J .8, 5.6, 2.2 Hz, 1H), 2.43 (ddd, J = 13.5, 6.0, 2.4 Hz, 1H), 1.79 (td, J = 13.3, 5.9 Hz, 1H).

ESI-MS m/z calc. , found 416.39 (M+1)+ Preparation of EXAMPLE 34 (2R,3'S,4'S,5'S,6'R)—6'-(hydroxymethyl)(3 -nitrophenyl)spiro[chromane—2,2'- tetrahydropyran]-3',4',5'-triol Step I: S,4'S,5'R,6'R)—3',4',5'-tribenzyloxy-6'-(benzyloxymethyl)(3- nitrophenyl)spiro[chromane-2,2'-tetrahydropyran] The title compound is prepared according to the procedure described in EXAMPLE 32 using INTERMEDIATE M9 (307 mg, 0.50 mmol) and 4-(3 -nitrophenyl)phenol (326 mg, 1.52 mmol) as starting materials and 45 minutes reaction time. Purification by flash chromatography on a BiotageTM SNAP silica cartridge (25 g) using a gradient of EtOAc (0 to %) in Hex then a second purification on a BiotageTM SNAP silica cartridge (10 g) using a gradient of EtOAc (0 to 10%) in CHzClz provided the title compound (87 mg, 23% yield) as an off-white foamy solid.

Step II: EXAMPLE 34 To a cold (—78 °C) stirred solution (2R,3'S,4'S,5'R,6'R)—3',4',5'—tribenzyloxy—6'— (benzyloxymethyl)—6-(3-nitrophenyl)spiro[chromane-2,2'-tetrahydropyran] from Step I (85 mg, 0.11 mmol) and 1,2,3,4,5-pentamethylbenzene (166 mg, 1.12 mmol) in CHzClz (6.8 mL) is added a solution of BCl3 in CHzClz (1.10 mL of 1.0 M, 1.11 mmol). After stirring for 2h at —78 0C, the reaction e is quenched with MeOH (6.8 mL), warmed to RT, concentrated and purified on a BiotageTM SNAP silica cartridge (10 g) using a nt of MeOH (0 to %) in CHzClz to afford the title compound (32 mg, 69 % yield) as a pale yellow solid. 1H NMR (400 MHz, CD3OD+DMSO—D6) 5 8.42 (t, J = 2.0 Hz, 1H), 8.17 (ddd, J = 8.2, 2.2, 0.9 2014/024411 Hz, 1H), 8.01 (ddd, J = 7.8, 1.6, 1.0 Hz, 1H), 7.67 (t, J = 8.0 Hz, 1H), 7.53 — 7.40 (m, 2H), 6.96 (d, J = 9.1 Hz, 1H), 4.10 (dd, J = 9.5, 3.4 Hz, 1H), 3.81 (d, J = 3.4 Hz, 1H), 3.77 — 3.66 (m, 3H), 3.57 (dt, J = 9.9, 3.7 Hz, 1H), 3.20 — 3.05 (m, 1H), 2.79 (ddd, J = 16.3, 5.7, 2.3 Hz, 1H), 2.44 (ddd, J = 13.7, 6.2, 2.6 Hz, 1H), 1.80 (td, J = 13.1, 5.8 Hz, 1H). ESI—MS m/z calc. 403.1267, found 404.23 (M+H)+ ation of EXAMPLE 35 N—methyl(2-(((2S,3S,4S,5S,6R)—3,4,5-trihydroxy(hydroxymethyl)methyltetrahydro- anyl)oxy)ethyl)benzamide 0 0 Ho"' OH ‘Me OH 0 Step I: N—methyl—4-(2-(((2S,3 S,4S,5R,6R)-3,4,5-tris(benzyloxy)((benzyloxy)methyl)—2- methyltetrahydro-2H-pyranyl)oxy)ethyl)benzamide 0 o and" OBn ‘Me OBn 0 To a stirred solution of (2S,3S,4S,5R,6R)—3,4,5-tris(benzyloxy)—6—((benzyloxy)methyl)—2— methyltetrahydro—2H—pyran—2—ol (prepared according to the procedure described in Tetrahedron 2001, 57,4297—4309) (309 mg, 0.558 mmol) and 4-(2-hydroxyethyl)—N—methyl- benzamide (100 mg, 0.558 mmol) in CHzClz (4.6 mL) is added trimethylsilyl trifiuoromethanesulfonate (20.0 11L, 0.112 mmol). The reaction mixture is stirred at RT for 16 h. The resulting mixture is quenched with NEt3 (39.0 11L, 0.279 mmol), stirred for 20 min, concentrated and purified on BiotageTM SNAP silica cartridge (10 g) eluting with EtOAc (0% to 100%, in 10 CV) in Hex to afford the title compound (190 mg, 0.2521 mmol, 45%) as a gum. LC—MS: m/z = 716.66 (M+H)+.

Step II: EXAMPLE 35 To a stirred solution of N—methyl(2-(((2S,3 S,4S,5R,6R)-3,4,5-tris(benzyloxy) ((benzyloxy)methyl)methyltetrahydro-2H-pyranyl)oxy)ethyl)benzamide from Step I (190 mg, 0.265 mmol) in MeOH (1.9 mL) and EtOAC (1.9 mL) is added Pd/C 20% wet (40.0 mg, 0.376 mmol). The on mixture is stirred 16h under an atmosphere of H2 (latm). The catalyst is filtered off and washed with MeOH/CHzClz. The combined es are concentrated and purified by flash chromatography (0- 20 % MeOH/CH2C12) to afford the title compound (60 mg, 60% yield). 1H NMR (400 MHz, CD3OD) 5 7.70 (d, J = 8.2 Hz, 2H), 7.31 (d, J = 8.2 Hz, 2H), 3.77 (dd, J = 9.5, 3.4 Hz, 1H), 3.75 — 3.66 (m, 3H), 3.57 (dd, J = 11.7, 5.9 Hz, 1H), 3.53 (d, J = 3.4 Hz, 1H), 3.46 (t, J = 9.7 Hz, 1H), 3.08 (ddd, J = 10.0, 6.0, 2.4 Hz, 1H), 2.92 — 2.83 (m, 5H), 1.32 (s, 3H). LC-MS: m/z = 356.0 (M+H)+.

Preparation of EXAMPLE 36 The title compound is prepared according to the procedure described for EXEMPLE 35 but using 2-phenylethanol in Step I. 1H NMR (400 MHz, CD30D) 5 7.32 — 7.07 (m, 5H), 3.87 — 3.54 (m, 5H), 3.54 (d, J = 3.3 Hz, 1H), 3.47 (d, J = 9.7 Hz, 1H), 3.19 (dddd, J = 9.8, 6.0, 2.4, 0.9 Hz, 1H), 2.82 (t, J = 6.9 Hz, 2H), 1.32 (s, 3H). LC—MS: m/z = 299.3 (M+H)+. ation of EXAMPLE 37 (2S,3 S,4S,5 S,6R)—2—(benzyloxy)(hydroxymethyl)-3 -methyltetrahydro-2H-pyran-3 ,4,5-triol HO/m‘OVO\\- "IMe OH Step I: (3 S,4S,5R,6R)—6—(acetoxymethyl)hydroxymethyltetrahydro-2H-pyran-3,4,5-triyl triacetate O OH ‘0 "Me To a cold (0°C) on of INTERMEDIATE M4 (505 mg, 1.25 mmol) in THF (7 mL) is added a solution ofNH3 in MeOH (3.60 mL of 7 M, 25.2 mmol). The resulting mixture is stirred for 2h at 0°C, concentrated and purified by flash chromatography on a eTM SNAP silica cartridge (25 g) using a gradient of EtOAc (0 to 60%) in Hex to afford the title compound (273 mg, 60% yield) as a White foamy solid. 1H NMR (400 MHz, CDCl3) 5 5.98 (d, J = 4.5 Hz, 1H), 5.44 (d, J = 9.7 Hz, 1H), 5.33 (d, J = 9.8 Hz, 1H), 4.23 (dt, J = 9.9, 3.7 Hz, 1H), 4.15 (d, J = 3.7 Hz, 2H), 3.12 (d, J = 4.5 Hz, 1H), 2.10 (s, 6H), 2.09 (s, 3H), 2.04 (s, 3H), 1.54 (s, 3H).

Step II: (2R,3 S,4S,5R,6R)(acetoxymethyl)—3 l(2,2,2-trichloro iminoethoxy)tetrahydro-2H-pyran-3 ,4,5-triyl triacetate 1 3 2 HNYCCI3 meno .0 \\- -"Me To a cold (0°C) solution of (3 S,4S,5R,6R)—6—(acetoxymethyl)hydroxy—3— methyltetrahydro-2H-pyran-3,4,5-triyl triacetate from step I (273 mg, 0.754 mmol) in CHzClz (11 mL) is added 2,2,2—trichloroacetonitrile (765 uL, 7.54 mmol) followed by DBU (12.0 "L, 0.0754 mmol) dropwise. The reaction mixture is stirred for 1h at 0°C then 2h at RT. The resulting mixture is concentrated and d on a eTM SNAP silica cartridge (25 g) using a gradient of EtOAc (0 to 50%) in Hex to provide the title compound (278 mg, 73% yield) as a colorless gum. 1H NMR (400 MHz, CDCl3) 5 8.82 (s, 1H), 7.04 (s, 1H), .43 (d, J = 3.7 Hz, 1H), 4.27 — 4.04 (m, 4H), 2.14 (s, 3H), 2.12 (s, 3H), 2.06 (s, 3H), 2.05 (s, 3H), 1.59 (s, 3H).

Step III: (2 S,3 S,4S,5R,6R)(acetoxymethyl)(benzyloxy)-3 -methyltetrahydro-2H-pyran- 3 ,4,5-triyl triacetate AGO/\Q‘OQ(p -'IMe To a cold (—20°C) stirred solution of (2R,3S,4S,5R,6R)—6—(acetoxymethyl)—3—methyl—2—(2,2,2— trichloroiminoethoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate from Step II (111 mg, 0.219 mmol) in CHzClz (2.0 mL) are added powdered moleculear sieve 4A (110 mg) and phenylmethanol (23.7 mg, 0.219 mmol) under N2 atmosphere and the mixture is stirred for 10 min. TMSOTf (9.0 "L, 0.23 eq.) is then added and the resulting e is stirred for 30 min.

The reaction mixture is quenched with ted aqueous NaHCO3, the c phase is washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified on BiotageTM SNAP silica cartridge (10 g) using EtOAc (10% to 50%) in Hex as eluent to give title compound (45.0 mg, 50%) as a colorless oil Step 1V: EXAMPLE 37 To a cold (0°C) solution of (2S,3S,4S,5R,6R)—6—(acetoxymethyl)—2—(benzyloxy)—3— methyltetrahydro-2H-pyran-3,4,5-triyl triacetate from Step II (45.0 mg, 0.110 mmol) in MeOH (1 mL) is added, NaOMe (110 mL, 0.5 M, 0.055 mmol). The reaction e is warmed to RT and stirred ght. The reaction mixture is quenched with DOWEX 50WX4-400 resin until pH reaches 4—5, filtered, and concentrated. The residue is purified by BiotageTM SNAP C18 cartridge (10 g) eluting with CH3CN (20-30%) in water to afford the title compound (25 mg, 76% yield) as a White solid. 1H NMR (400 MHz, CD30D) 5 7.39 — 7.22 (m, 5H), 4.72 (d, J = 11.9 Hz, 1H), 4.52 (s, 1H), 4.48 (d, J = 11.9 Hz, 1H), 3.81 (dd, J = 11.7, 2.2 Hz, 1H), 3.72 (dd, J =11.7, 5.4 Hz, 1H), 3.65 = 9.2 Hz, — 3.59 (m, 1H), 3.56 (t, J 1H), 3.48 (d, J = 8.7 Hz, 1H), 1.22 (s, 3H).

Preparation of EXAMPLE 3 8 3 —[4— [(2R,3 S,4S,5 3 —(azidomethyl)—3 ,4,5 droxy—6— (hydroxymethyl)tetrahydropyranyl] oxy-3 -methyl-phenyl] -N-methyl-benzamide HOAqI‘xO O O --------|\ W" [Me OH N3 H Step I: (2R,3 S,4S,5R,6R)(acetoxymethyl)—3-(azidomethyl)((3-methyl-3'- (methylcarbamoyl)-[1, 1'-biphenyl] yl)oxy)tetrahydro-2H-pyran-3 ,4,5 -triyl triacetate ,M .

OAoNS 0 To a suspension of INTERMEDIATE M14 (850 mg, 1.90 mmol) and EDIATE A2 (737 mg, 3.10 mmol) in 1,2-dichloroethane (13.0 mL) at 0°C is added BF3.Et20 (725 uL, .70 mmol) dropwise. The resulting mixture is d at 40°C for 16h, cooled down to 3°C and quenched with 2 ml of saturated aqueous NaHCO3 while stirring. The resulting suspension is filtered and the organic phase is separated, dried over NazSO4, filtered, and concentrated. Purif1cation on Isco CombiFlash® silica gel cartridge (40 g) eluting with EtOAc (40-100%) in Hex (15 CV) ed the title compound (192 mg, 16%) as a white solid. LC-MS: m/z = 627.5 (M+H)+.

Step II: EXAMPLE 38 To a stirred solution of (2R,3S,4S,5R,6R)(acetoxymethyl)—3-(azidomethyl)—2-((3- methyl-3'-(methylcarbamoyl)—[ 1, 1 '-biphenyl]yl)oxy)tetrahydro-2H-pyran-3 ,4,5-triyl triacetate from Step I (200 mg, 0.32 mmol) in dry MeOH (5.0 mL) at RT is added a solution ofNaOMe in MeOH (36 11L of 0.50 M, 0.16 mmol). The resulting mixture is stirred for 2 h, neutralized by the addition of Ambilite IR-120 resin until the reaction mixture pH d 4.

The resulting e is filtered, trated and purified on Isco CombiFlash® silica gel cartridge (12 g) eluting with MeOH (0-10%) in CHzClz/ (15 CV) to afford the title compound (105 mg, 68%) as a white solid. 1H NMR (400 MHz, CD3OD) 5 8.01 (t, J: 1.8 Hz, 1H), 7.72 (ddt, J= 7.7, 6.0, 1.3 Hz, 2H), 7.53 — 7.40 (m, 3H), 7.34 (d, J= 8.4 Hz, 1H), 5.52 (s, 1H), 3.83 (d, J= 12.8 Hz, 1H), 3.78—3.70 (m, 4H), 3.62—3.65 (m, 1H), 3.51 (d, J= 12.8 Hz, 1H), 2.92 (s, 3H), 2.30 (s, 3H). LC—MS: m/z = 459.3 (M+H)+. ation of EXAMPLE 39 to 43 EXAMPLES 39 to 43 are ed according to the following general procedure using lNTERMEDIATEs M4 and A10 to A14 respectively. Vials are charged with the appropriate phenols (1.2 eq. ). A solution of INTERMEDIATE M4 (100 mg, 0.247 mmol) in 1,2—dichloroethane (1.5 mL) is added followed by (100 uL, 0.789) is added to each vial. The vial is capped and the final mixture is stirred at 60°C overnight. The resulting crude mixture is cooled down to RT, quenched by careful addition of 2 mL saturated aqueous NaHCO3 solution and d with CHzClz (2 mL). The organic layer is separated and the aqueous layer is back extracted with CHzClz (2x2 mL). The combined organic extracts are concentrated. The resulting crude residue is dissolved in MeOH (2 mL) and treated with NaOMe in MeOH (500 uL of 0.5 M). The mixture is stirred for 2h at RT, passed through a prewashed lg SCX-2 cartridge. The latter is washed MeOH (3 x 1 mL) and the combined fractions are concentrated. The residue is finally purified by reverse phase HPLC to afford the title compounds.

LCMS Name 1H—NMR m/z (M+H)+ 3—[2—fluoro—4— (400 MHz, CD3OD) 5 7.95 (d, J = [(2R,3S,4S,5S,6R)—3,4,5— 1.3 Hz, 1H), 7.83 — 7.72 (m, 1H), trihydroxy 7.68 (dd, J = 7.8, 1.2 Hz, 1H), (hydroxymethyl)—3—methyl— 7.58 — 7.41 (m, 2H), 7.10 — 6.95 tetrahydropyranyl]oxy- (m, 2H), 5.25 (s, 1H), 3.88 — 3.56 phenyl]-N—methyl- (m, 5H), 2.94 (s, 3H), 1.38 (s, benzamide 3H). 3-[2-chloro (400 MHz, CD30D) 5 7.84 (t, J = [(2R,3S,4S,5S,6R)—3,4,5— 1.5 Hz, 1H), 7.83 — 7.77 (m, 1H), trihydroxy 7.58 (dt, J = 7.7, 1.4 Hz, 1H), (hydroxymethyl)methyl- 7.52 (t, J = 7.6 Hz, 1H), 7.34 (d, J tetrahydropyranyl]oxy- = 8.5 Hz, 1H), 7.31 (d, J = 2.5 phenyl]-N—methyl- Hz, 1H), 7.18 (dd, J = 8.5, 2.5 Hz, benzamide 1H), 5.25 (s, 1H), 3.85 — 3.57 (m, 5H), 2.93 (s, 3H), 1.38 (s, 3H). 3 —[2-methoxy (400 MHz, CD30D) 5 7.90 (t, J = [(2R,3 S,4S,5S,6R)—3,4,5— 1.6 Hz, 1H), 7.77 - 7.67 (m, 1H), trihydroxy—6— 7.66 - 7.58 (m, 1H), 7.44 (t, J = (hydroxymethyl)methyl- 7.7 Hz, 1H), 7.26 (d, J = 8.4 Hz, tetrahydropyranyl]oxy- 1H), 6.86 (d, J = 2.2 Hz, 1H), ]-N-methyl- 6.82 (dd, J = 8.4, 2.3 Hz, 1H), benzamide 5.23 (s, 1H), 3.80 (s, 3H), 3.79 - 3.66 (m, 5H), 2.93 (s, 3H), 1.40 (s, 3H). yl-3 -[2-methyl (400 MHz, CD30D) 5 7.77 (dt, J [(2R,3 S,4S,5S,6R)—3,4,5— = 7.5, 1.5 Hz, 1H), 7.75 - 7.70 trihydroxy—6— (m, 1H), 7.50 (t, J = 7.5 Hz, 1H), (hydroxymethyl)methyl- 7.46 (dt, J = 7.6, 1.5 Hz, 1H), ydropyranyl]oxy- 7.16 (d, J = 8.3 Hz, 1H), 7.06 (d, phenyl]benzamide J = 2.4 Hz, 1H), 7.02 (dd, J = 8.3, 2.5 Hz, 1H), 5.21 (s, 1H), 3.82 - 3.61 (m, 5H), 2.93 (s, 3H), 2.23 (s, 3H), 1.38 (s, 3H).

N—methyl[2- (400 MHz, CD30D) 5 7.84 (dt, J (trifluoromethyl) = 7.5, 1.6 Hz, 1H), 7.76 (s, 1H), [(2R,3 S,4S,5S,6R)—3,4,5— 7.56 - 7.41 (m, 4H), 7.34 (d, J = 43 trihydroxy—6— 8.5 Hz, 1H), 5.31 (s, 1H), 3.82 — 472.67 (hydroxymethyl)-3 -methyl- 3.57 (m, 5H), 2.92 (s, 3H), 1.40 tetrahydropyranyl]oxy- (s, 3H). phenyl]benzamide Preparation of EXAMPLE 44 to 47 EXAMPLES 44 and 45 are prepared using INTERMEDIATE M13, EXAMPLES 46 and 47 using INTERMEDIATE M12 according to the following general procedure. Microwave vials are loaded with the appropriate phenyl boronic acid (1.5 eq.), CszCO3 (3.0 eq.), and at DPP—Pd (0.1 eq.). INTERMEDIATE M12 or M13 (45 mg, 1.0 eq.) are ved in MeCN (2 mL) and added to each vial. The vials are capped and microwaved, 15 min at 100°C. The resulting e is diluted with CH2C12:EtOAc (1: 1) and passed through a 500 mg bondelut silica gel cartridge, eluting with CHZClz-EtOAc (1:1) (ca 5 mL total). The resulting fractions are combined and concentrated. The residue is dissolved in MeOH (1 mL) and NaOMe in MeOH is added and the final mixture is stirred for 2h at RT. The resulting mixture is passed through a prewashed 1g SCX-2 cartridge, washed with MeOH (3 x 1 mL). 2014/024411 The combined filtrates are concentrated and the residue is d by reverse phase HPLC to afford to desired material.

EXAMPLE Name 1H—NMR 3'[4'Ch10r0'3' (400 MHz, CD30D) 5 8.07 (t, J = S,4S,5S,6R)—3,4,5— 1.7 Hz, 1H), 7.86 — 7.77 (m, 2H), trihydroxy 7.72 (d, J = 2.0 Hz, 1H), 7.54 (t, J (hydroxymethy1)methy1— = 7.8 Hz, 1H), 7.48 (d, J = 8.3 tetrahydropyrany1]oxy— HZ, 1H), 7-33 (dd: J = 8-37 2-0 HZ, pheny1]_N_methy1_ 1H), 5.36 (s, 1H), 3.91 — 3.60 (m, benzamide 5H), 2.95 (s, 3H), 1.47 (s, 3H). 4'[4'Ch10r0'3' (400 MHz, CD30D) 5 7.89 (d, J = [(2R,3S,4S,5S,6R)—3,4,5- 8.4 Hz, 2H), 7.74 (d, J = 8.4 Hz, trihydrOXy 2H), 7.71 (d, J = 2.0 Hz, 1H), (hydroxymethy1)methy1— 7.48 (d, J = 8.3 Hz, 1H), 7.32 (dd, tetrahydropyrany1]oxy- J = 8.3, 2.0 Hz, 1H), 5.34 (s, 1H), pheny1]-N-methy1- 3-91 ' 3-60 (m, 5H), 2-94 (S: 3H), 1.47 (s, 3H). benzamide 3'[2'Ch10r0'3' (400 MHz, CD30D) 5 7.88 — 7.80 S,4S,5S,6R)—3,4,5— (m, 2H), 7.61 — 7.49 (m, 2H), 7.44 trihydroxy (dd, J = 8.4, 1.4 Hz, 1H), 7.34 (t, (hydroxymethy1)methy1— J = 8.0 Hz, 1H), 7.05 (dd, J = 7.6, tetrahydropyrany1]oxy_ 1.4 Hz, 1H), 5.32 (s, 1H), 3.86 — pheny1]-N-methy1- 3-61 (m, 5H), 2-93 (S: 3H), 1-44 benzamide (s, 3H). 4—[2-ch10r0 (400 MHz, CD30D) 5 7.93 — 7.81 [(2R,3S,4S,SS,6R)—3,4,5— (m, 2H), 7.55 — 7.48 (m, 2H), 7.44 trihydroxy (dd, J = 8.4, 1.4 Hz, 1H), 7.37 — 47 (hydroxymethy1)methy1— 7.28 (m, 1H), 7.03 (dd, J = 7.6, 438.54 tetrahydropyrany1]oxy— 1.4 Hz, 1H), 5.32 (s, 1H), 3.86 - pheny1]—N—methy1— 3.60 (m, 5H), 2.95 (s, 3H), 1.44 benzamide (5’ 3H)‘ Preparation of EXAMPLE 48 3—[4—[(2R,3S,4S,5S,6R)(aminomethy1)-3,4,5-trihydroxy (hydroxymethy1)tetrahydropyrany1]oxymethy1—pheny1]-N-methy1—benzamide O »""‘O O HO o ...... I|\ w, [Me OHNH2 fl To a stirred solution of EXAMPLE 38 (35 mg, 0.076 mmol) in EtOH (700 uL) and water (700 uL) is added 10% Pd /C (4 mg, 0.033 mmol). The resulting mixture is stirred for 16 hours under an H2 atmosphere, ed on celite, concentrated and purified on Isco CombiFlash® C18 cartridge (12 g) eluting with CH3CN (5 to 50%) in water to afford the title compound (8 mg, 23%) as a White solid. 1H NMR (400 MHz, CD3OD) 5 8.00 (t, J = 1.7 Hz, 1H), 7.72 (ddt, J = 7.2, 4.1, 1.2 Hz, 2H), 7.43—7.51 (m, 3H), 7.34 (d, J = 8.5 Hz, 1H), 5.47 (s, 1H), 3.86 (d, J = 9.1 Hz, 1H), 3.80 — 3.69 (m, 3H), 3.59 — 3.49 (m, 1H), 3.22 (d, J = 13.5 Hz, 1H), 2.98 d, (J = 13.5 Hz, 1H), 2.92 (s, 3H), 2.32 (s, 3H). LC—MS: m/z = 433.15 (M+H)+. ation of EXAMPLE 49 3 —[4— [(2R,3 S,4S,5 S,6R)-3 -(2-benzyloxyethoxymethyl)-3 ,4,5 -trihydroxy xymethyl)tetrahydropyranyl] oxy-3 -methyl-phenyl] -N-methyl-benzamide Step I: (2R,3 S,4S,5R,6R)—6-(acetoxymethyl)-3 -((2-(benzyloxy)ethoxy)methyl)—2-((3 -methyl- 3'-(methylcarbamoyl)—[1,1'-biphenyl]yl)oxy)tetrahydro-2H-pyran-3 ,4,5-triyl triacetate To a mixture of INTERMEDIATE M15 (450 mg, 0.820 mmol) and INTERMEDIATE A2 (392 mg, 1.62 mmol) in dichloroethane (6.3 mL) is added BF3.OEt2 (309 "L, 2.43 mmol).

The mixture is d at 40°C overnight. The resulting mixture is cooled down to RT; quenched by addition of 2 mL of saturated aqueous NaHCO3. The resulting suspension is filtered and the c phase is separated, dried over NaZSO4, filtered, and concentrated.

The e is purified on Isco CombiFlash® silica gel cartridge (40 g) eluting with EtOAc (0—100%) in Hex (15 CV) to afford the title compound (165 mg, 28%) as a White solid. LC— MS: m/z = 758.2 (M+Na)+.

Step II: EXAMPLE 49 To a stirred on of (2R,3S,4S,5R,6R)(acetoxymethyl)-3 -((2- (benzyloxy)ethoxy)methyl)((3 -methyl-3'-(methylcarbamoyl)-[1,1'-biphenyl]—4- yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate from Step I (20 mg, 0.027 mmol) in dry MeOH (1.0 mL) at RT is added a solution of MeONa in MeOH (3 uL of 25 %w/w, 0.014 mmol). The resulting mixture is d for 2 hours, neutralized by the addition of Ambilite IR-120 resin until the reaction mixture pH d 4. The resulting mixture is filtered and concentrated to afford the tittle compound (14 mg, 86%) as a white solid. 1H NMR (400 MHz, CD3OD) 5 7.98 (t, J = 1.8 Hz, 1H), 7.73 — 7.64 (m, 2H), 7.52 — 7.40 (m, 2H), 7.38 (dd, J = 8.6, 2.4 Hz, 1H), 7.31 (d, J = 8.6 Hz, 1H), 7.25 — 7.05 (m,5H), 5.57 (s, 1H), 4.37 (s, 2H), 3.91 (d, J = 9.9 Hz, 1H), 3.84 (d, J = 9.9 Hz, 1H), 3.80 — 3.65 (m, 5H), 3.64 — 3.49 (m, 4H), 2.93 (s, 3H), 2.31 (s, 3H). LC—MS: m/z = 658.11 (M+1)+.

Preparation of EXAMPLE 50 N—methyl-3 -[3 l [(2R,3 S,4S,5 3 ,4,5-trihydroxy-3 -(2-hydroxyethoxymethyl) (hydroxymethyl)tetrahydropyranyl]oxy-phenyl]benzamide Step I: (2R,3 R,6R)—6-(acetoxymethyl)-3 -((2-hydroxyethoxy)methyl)((3 -methyl-3 '- (methylcarbamoyl)-[1, 1'-biphenyl] yl)oxy)tetrahydro-2H-pyran-3 ,4,5 -triyl triacetate To a stirred solution of (2R,3S,4S,5R,6R)(acetoxymethyl)-3 -((2- (benzyloxy)ethoxy)methyl)((3 -methyl-3'-(methylcarbamoyl)-[1,1'-biphenyl]—4- yl)oxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate from EXAMPLE 49 Step I (150 mg, 0.200 mmol) in dry EtOH (3.8 mL) and AcOH (47 uL, 0.82 mmol) is added Pd(OH)2 (20% wet, 57 mg, 0.082 mmol). The resulting mixture is stirred for 16 hours under an H2 atmosphere, filtered on celite and concentrated to afford the tittle compound (125 mg, 95%) as a white solid. 1H NMR (400 MHz, CDCl3) 5 7.96 (t, J: 1.8 Hz, 1H), 7.66 (dd, J: 7.9, 1.8 Hz, 2H), 7.54 — 7.42 (m, 2H), 7.42 — 7.33 (m, 1H), 7.23 (d, J: 8.5 Hz, 1H), 6.21 (s, 1H), 5.86 (d, J: 9.7 Hz, 1H), 5.43 (t, J: 10.0 Hz, 1H), 4.29 — 4.16 (m, 2H), 4.16 — 4.04 (m, 2H), 3.99 (d, J: .0 Hz, 1H), 3.71 (m, 1H), 3.65 — 3.55 (m, 1H), 3.56 — 3.39 (m, 2H), 3.05 (d, J: 4.8 Hz, 3H), 2.36 (s, 3H), 2.21 (s, 3H), 2.12 (s, 3H), 2.06 (s, 3H), 2.04 (s, 3H). 2014/024411 Step II: EXAMPLE 50 To a stirred solution of (2R,3S,4S,5R,6R)(acetoxymethyl)—3-((2-hydroxyethoxy)— methyl)((3 -methyl-3'-(methylcarbamoyl)-[1, 1'-biphenyl] yl)oxy)tetrahydro-2H-pyran- 3,4,5-triyl triacetate from Step I (30 mg, 0.046 mmol) in dry MeOH (1.5 mL) at RT is added a solution ofNaOMe in MeOH (5 "L of 25 %w/w, 0.023mmol). The resulting mixture is stirred for 2 hours, neutralized by the addition of Ambilite IR-120 resin until the reaction mixture pH reached 4. The resulting mixture is filtered and concentrated to afford the tittle nd (19 mg, 82%) as a White solid. 1H NMR (400 MHz, CD3OD) 5 7.92 (t, J = 1.8 Hz, 1H), 7.64 (ddt, J = 8.1, 5.3, 1.3 Hz, 2H), 7.45 = 8.4 Hz, 1H), 5.48 (s, — 7.30 (m, 4H), 7.25 (d, J 1H), 3.85 — 3.73 (m, 2H), 3.73 — 3.58 (m, 4H), 3.58 — 3.33 (m, 5H), 2.84 (s, 3H), 2.24 (s, 3H).

LC—MS: m/z = 478.3 (M+H)+.

Preparation of EXAMPLE 5 1 N—methyl-3 thyl[(2R,3 S,6R)-3,4,5-trihydroxy(hydroxymethyl)[[4- (hydroxymethyl)triazol- 1 thyl]tetrahydropyranyl] oxy-phenyl]benzamide To a d solution of EXAMPLE 38 (25 mg, 0.054 mmol), sodium ascorbate (29 mg, 0.16 mmol), propyn—1—ol (174 uL, 0.055 mmol) in NMP (235 uL) is added CuOAc (1.0 mg, 0.010 mmol). The resulting mixture is stirred for 48 hours at room temperature, filtered and purified by reverse phase HPLC to afford the title compound (15 mg, 54%) as a white solid.

LC—MS: m/z=515.16 (M+1).

Preparation of EXAMPLE 52 3 —[4—[(2R,3 S,4S,5S,6R)(acetamidomethyl)-3 ,4,5-trihydroxy (hydroxymethyl)tetrahydropyranyl] oxy-3 -methyl-phenyl] -N-methyl-benzamide To a d solution of EXAMPLE 48 (70 mg, 0.16 mmol) in THE (1.6 mL) is added NaOAc (1.6 mL of 50 %W/V, 9.8 mmol) and acetyl chloride (10.0 uL, 0.16 mmol). The resulting mixture is stirred for 16 hours at RT, filtered, concentrated and purified using reverse phase HPLC to afford the tittle compound (8 mg, 10%). LC—MS: m/z = 475.76 (M+1). ation of EXAMPLE 53 3 —[3 —chloro—4— [(2R,3 S,4S,5 S,6R)-3 ,4,5-trihydroxy(hydroxymethyl)—3 -methyl- tetrahydropyranyl]oxy-phenyl]-N-(2-methoxyethyl)benzamide To a degased (N2) mixture of INTERMEDIATE M11 (40 mg, 0.09261 mmol), t- Bu3PH+.BF4' (5.0 mg, 0.017 mmol) and Pd2(dba)3 (17.0 mg, 0.0186 mmol) in THF (300 uL)/water (300 uL) is added a solution of [3-(2-methoxyethylcarbamoyl)phenyl]boronic acid (21.0 mg, 0.0942 mmol) in NMP (200 uL). K3PO4 (39 mg, 0.1837 mmol) is then added and the reaction mixture is d at 75°C for 18 hours. The resulting mixture is filtered, and the filtrate is purified by reverse phase HPLC to afford the title compounds (8.5 mg, 18%) as a white solid. 1H NMR (400 MHz, CD3OD) 5 8.03 (d, J = 1.5 Hz, 1H), 7.81 — 7.69 (m, 3H), 7.54 (ddd, J = 25.0, 12.9, 5.4 Hz, 3H), 5.30 (s, 1H), 3.80 — 3.61 (m, 6H), 3.57 (s, 4H), 3.38 (s, 3H), 1.44 (s, 3H). LC—MS: m/z = 482.25 (M+H)+.

Preparation of EXAMPLE 54 2—chloro [3 -chloro [(2R,3 S,4S,5 S,6R)—3 rihydroxy(hydroxymethyl)—3 -methyl- tetrahydropyranyl] oxy-phenyl]-N-cyclopropyl-benzamide To a mixture of INTERMEDIATE M11 (40.0 mg, 0.104 mmol), Pd(OAc)2 (5.0 mg, 0.022 mmol) and dicyclohexylphosphanylphenyl)-2,4-dimethoxy- phenyl]sulfonyloxysodium (23.0 mg, 0.0449 mmol) in 500 uL of MeTHF is added [3—chloro— 4-(cyclopropylcarbamoyl)phenyl]boronic acid (200 uL of 0.5 M, 0.100 mmol) and K2CO3 aq. (100 uL of 4.5 M, 0.450 mmol). The reaction mixture is stirred at 65°C for 18 hours. The resulting mixture is filtered, and the filtrate is purified by reverse phase HPLC to afford the title compounds (3.0 mg, 5%) as a White solid. 1H NMR (400 MHz, CD3OD) 5 7.62 — 7.57 (m, 2H), 7.47 (dd, J = 15.7, 5.1 Hz, 2H), 7.39 (t, J = 8.3 Hz, 2H), 5.22 (s, 1H), 3.70 — 3.57 (m, 3H), 3.57 — 3.50 (m, 2H), 2.78 (ddd, J =11.1, 7.5, 4.0 Hz, 1H), 1.34 (s, 3H), 0.77 — 0.68 (m, 2H), 0.58 = 499.15 (M+H)+. — 0.50 (m, 2H). LC—MS: m/z ation of EXAMPLE 55 —[3 —chloro—4—[(2R,3 S,4S,5 S,6R)-3 ,4,5-trihydroxy(hydroxymethyl)-3 l- tetrahydropyranyl]oxy-phenyl]fiuoro-N—methyl-benzamide 0 ".10 HO o """'Me HOW» ,Me OH H OH O EXAMPLE 55 is prepared according to the procedure described for EXAMPLE 54 using 4-fiuoro(methylcarbamoyl)phenyl]boronic acid as starting al. The on mixture is stirred 2h at 80°C. The title compound is purified by e phase HPLC and isolated as a white solid (2.4 mg, 6%). LC—MS: m/z = 456.22 (M+H)+.

Preparation of EXAMPLE 56 3 —[3 —chloro—4—[(2R,3 S,4S,5 S,6R)-3 ,4,5-trihydroxy(hydroxymethyl)-3 -methyl- tetrahydropyranyl]oxy-phenyl]fiuoro-N—methyl-benzamide EO O w """MeO ,Me OH H EXAMPLE 56 is prepared according to the procedure described for EXAMPLE 54 using o(methylcarbamoyl)phenyl]boronic acid as starting material. The reaction mixture is stirred 2h at 80°C. The title compound is purified by reverse phase HPLC and isolated as a white solid (0.96 mg, 2%). LC—MS: m/z = 455.11 (M+H)+.

Preparation of EXAMPLE 57 Methyl 3 - [3 -methyl [(2R,3 S,4S,5 S,6R)—3 ,4,5 -trihydroxy(hydroxymethyl)-3 -methyl- tetrahydropyranyl] oxy-phenyl]benzoate O -""O O HO o Ho"‘ unIIMOHe To a suspension of Methyl 3-[3-methyl[(2R,3S,4S,5R,6R)-3,4,5-triacetoxy (acetoxymethyl)methyltetrahydropyranyl]oxy-phenyl]benzoate from EXAMPLE 21, Step I (1.62 g, 2.762 mmol) in MeOH (6 mL) is added NaOMe in MeOH (5.94 mL of 0.5 M, 2.97 mmol). The reaction mixture is stirred at RT. After 30min a white precipitate formed and an additional amount of MeOH (6 mL) is added. The mixture is stirred for 2h, quenched with DOWEX acid resin until pH 4, stirred for 5 min. The resin is filtered off, washed with MeOH (30 mL). The combined filtrates are trated to afford the title compound (1.12 g, 67%) as a White solid. 1H NMR (400 MHz, CD3OD) 5 8.18 (t, J = 1.6 Hz, 1H), 7.96 — 7.88 (m, 1H), 7.83 = 7.8 Hz, 1H), 7.46 = 8.3 — 7.74 (m, 1H), 7.50 (t, J — 7.39 (m, 2H), 7.31 (d, J Hz, 1H), 5.27 (s, 1H), 3.92 (s, 4H), 3.77 — 3.65 (m, 3H), 3.63 — 3.53 (m, 1H), 2.31 (s, 2H), 1.40 (s, 3H).

Preparation of EXAMPLE 5 8 N—[2-(4-methylpiperazinyl)ethyl][3 -methyl[(2R,3 S,6R)-3,4,5-trihydroxy—6— (hydroxymethyl)-3 -methyl-tetrahydropyranyl]oxy-phenyl]benzamide 0 _"..\o HO o (\N,Me How me E N/\/N\) E 58 is prepared according to the procedure described for E 22 Step I using EXAMPLE 21 and 2-(4-methylpiperazinyl)ethanamine as ng material. The reaction mixture is stirred 2h at RT. The resulting crude mixture is purified directly by reverse phase HPLC to afford the title compound as a White solid (67% yield). 1H NMR (400 MHz, CD3OD) 5 8.02 (brs, 1H), 7.73 (brd, J = 7.7 Hz, 2H), 7.51 = — 7.42 (m, 3H), 7.31 (d, J 8.5 Hz, 1H), 5.27 (s, 1H), 3.77 — 3.67 (m, 4H), 3.62 — 3.51 (m, 3H), 2.71 — 2.39 (m, 10H), 2.31 (s, 3H), 2.28 (s, 3H), 1.40 (s, 3H). LC—MS: m/z = 530.52 (M+H)+.

Preparation of EXAMPLEs 59 to 72 EXAMPLEs 59 to 72 are prepared according to the procedure described for E 58 using the appropriate commercially available amine.

EXAMPLE Name 1H—NMR N— [(1 8,2 S)—2—hydroxy— 1 — (400 MHz, CD3OD) 5 8.06 (brs, (hydroxymethy1)propyl]-3 - J: 1.6 Hz, 1H), 7.80 — 7.71 (m, [3 —methy1—4— 2H), 7.53 — 7.43 (m, 3H), 7.31 [(2R,3 S,4S,5 S,6R)—3,4,5— (d, J = 8.5 Hz, 1H), 5.27 (s, trihydroxy—6— 1H), 4.15 — 4.04 (m, 2H), 3.81 — (hydroxymethy1)-3 - 3.65 (m, 6H), 3.63 — 3.54 (m, methyl-tetrahydropyran-Z- 1H), 2.31 (s, 3H), 1.40 (s, 3H), 1] 0x - ohen l]benzamide 1.21 d, J 6.3 Hz, 3H.

N—[2—hydroxy- 1 1 - , (400 MHz, CD3OD) 5 8.00 (t, J bis(hydroxymethy1)ethyl]- =17 Hz, 1H), 7.72 (td, J = 8.5, 3 —[3 1—4— 1.7 Hz, 2H), 7.52 — 7.41 (m, [(2R,3 S,4S,5 S,6R)—3,4,5— 3H), 7.30 (d, J = 8.5 Hz, 1H), trihydroxy—6— 5.27 (s, 1H), 3.87 (s, 6H), 3.76 — (hydroxymethy1)-3 - 3.67 (m, 4H), 3.63 — 3.53 (m, methyl-tetrahydropyran-Z- 1H), 2.31 (s, 3H), 1.40 (s, 3H). yl] eny1]benzamide N—[2—hydroxy- 1- (400 MHz, CD3OD) 5 7.97 (s, (hydroxymethy1) 1H), 7.76 — 7.65 (m, 2H), 7.53 — methyl-ethyl]—3 -[3 -methyl- 7.41 (m, 3H), 7.30 (d, J = 8.4 ,3 S,4S,SS,6R)— Hz, 1H), 5.27 (s, 1H), 3.88 — 3 ,4,5 -trihydroxy—6- 3.66 (m, 8H), 3.65 — 3.53 (m, (hydroxymethy1)-3 - 1H), 2.31 (s, 3H), 1.40 (s, 3H), methyl-tetrahydropyran-Z- 1.38 (s, 3H). [1] yl] 0xy-pheny1]benzamide N—[2—hydroxy- 1- (400 MHz, CD3OD) 8 8.06 (t, J (hydroxymethyl)ethyl]-3 - =17 Hz, 1H), 7.79 — 7.68 (m, [3 —methy1—4— 2H), 7.52 — 7.43 (m, 3H), 7.30 [(2R,3 S,4S,5 S,6R)—3,4,5— (d, J = 8.5 Hz, 1H), 5.27 (s, trihydroxy—6— 1H), 4.24 — 4.12 (m, 1H), 3.80 — (hydroxymethy1)-3 - 3.67 (m, 8H), 3.63 — 3.53 (m, methyl-tetrahydropyran-Z- 1H), 2.31 (s, 3H), 1.40 (s, 3H). 1] 0x - ohen l]benzamide 3 —[3 —methy1—4— (400 MHz, CD30D) 5 8.02 (t, J [(2R,3 S,4S,5 S,6R)—3,4,5— = 1.7 Hz, 1H), 7.73 (dd, J = 7.8, trihydroxy—6— 1.5 Hz, 2H), 7.53 — 7.42 (m, (hydroxymethy1)-3 - 3H), 7.31 (d, J = 8.5 Hz, 1H), methyl-tetrahydropyran-Z- 5.27 (s, 1H), 3.76 — 3.66 (m, yl] 0xy-pheny1]—N—(2- 8H), 3.62 — 3.53 (m, 3H), 2.62 morpholinoethy1)benzamid (t, J = 6.7 Hz, 2H), 2.58 — 2.50 e (m, 4H), 2.31 (s, 3H), 1.40 (s, 3 —[3 —methy1—4— (400 MHz, CD3OD) 5 8.05 — [(2R,3 S,4S,5 S,6R)—3 ,4,5 — 8.00 (m, 1H), 7.77 — 7.69 (m, trihydroxy—6— 2H), 7.51 — 7.42 (m, 3H), 7.31 (hydroxymethy1)-3 - (d, J = 8.5 Hz, 1H), 5.27 (s, methyl-tetrahydropyran-Z- 1H), 4.48 (d, J = 7.8 Hz, 1H), yl] 0xy-pheny1]—N— 3.99 — 3.33 (m, 9H), 3.22 — 3.08 [[(2R,3 S,4S,5R)—3 ,4,5,6— (m, 2H), 2.31 (s, 3H), 1.40 (s, ydroxytetrahydropyr 3H). an-2—y1]methyl]benzamide 3 —[3 —methy1—4— (400 MHz, CD30D) 5 8.13 — [(2R,3 S,4S,5 S,6R)—3 ,4,5 — 8.08 (m, 1H), 7.79 (d, J = 7.7 trihydroxy—6— Hz, 1H), 7.76 — 7.69 (m, 1H), (hydroxymethy1)-3 - 7.53 = — 7.43 (m, 3H), 7.30 (d, J methyl-tetrahydropyran-Z- 8.5 Hz, 1H), 5.27 (s, 1H), 4.60 yl] 0xy-pheny1]—N— (d, J = 7.7 Hz, 1H), 4.06 (t, J = [(3R,4S,SS,6R)—2,3,5— 10.1 Hz, 1H), 3.94 — 3.33 (m, trihydroxy—6— 10H), 2.31 (s, 3H), 1.40 (s, 3H). (hydroxymethy1)tetrahydr0 pyrany1]benzamide tert—butyl 4-[[[3-[3-methy1— (400 MHz, CD3OD) 8 8.00 (brs, 4—[(2R,3 S,4S,SS,6R)— 1H), 7.72 (d, J = 7.8 Hz, 2H), 3 ,4,5-trihydr0xy—6- 7.51 = — 7.42 (m, 3H), 7.31 (d, J (hydroxymethy1) 8.5 Hz, 1H), 5.27 (s, 1H), 4.12 — methyl-tetrahydropyran-Z- 4.02 (m, 2H), 3.75 — 3.68 (m, yl]0xy— 4H), 3.63 — 3.54 (m, 1H), 2.84 — ]benzoyl]amin0]met 2.66 (m, 2H), 2.31 (s, 3H), 1.89 hyl]piperidine — 1.69 (m, 3H), 1.43 (s, 9H), carboxylate 1.40 (s, 3H), 1.23 — 1.06 (m, 2H .

N—[2— (400 MHz, CD3OD) 5 8.46 (s, (dimethylamin0)ethyl] -3 - 1H), 8.07 (t, J = 1.7 Hz, 1H), [3 —methy1—4— 7.79 — 7.72 (m, 2H), 7.53 — 7.41 [(2R,3 S,4S,5 S,6R)—3,4,5— (m, 3H), 7.31 (d, J = 8.5 Hz, trihydroxy—6— 1H), 5.27 (s, 1H), 3.76 — 3.66 (hydroxymethy1)-3 - (m, 6H), 3.62 — 3.54 (m, 1H), methyl-tetrahydropyran-Z- 3.19 — 3.12 (m, 2H), 2.79 (s, 1] 0x - ohen l]benzamide 6H 2.31 1.40 , s, 3H , s, 3H. (4-methy1piperaziny1)- (400 MHz, CD30D) 5 8.29 (brs, [3 — [3 1—4— 1H), 7.70 — 7.66 (m, 1H), 7.60 [(2R,3 S,4S,5 S,6R)—3,4,5— (t, J = 1.6 Hz, 1H), 7.49 (t, J = roxy—6— 7.7 Hz, 1H), 7.44 — 7.38 (m, (hydroxymethy1)-3 - 2H), 7.35 — 7.26 (m, 2H), 5.26 methyl-tetrahydropyran-Z- (s, 1H), 3.94 — 3.44 (m, 9H), 2.74 — 2.48 (m, 4H), 2.41 (s, ohen l]methan0ne (2S)—3 —hydr0xy—2—[[3 —[3— (400 MHz, CD30D) 5 8.09 (s, methyl 1H), 7.83 — 7.72 (m, 2H), 7.55 — [(2R,3 S,4S,5 S,6R)—3,4,5— 7.43 (m, 3H), 7.31 (d, J= 8.4 trihydroxy—6— Hz, 1H), 5.27 (s, 1H), 4.73 (t, J (hydroxymethy1) = 4.4 Hz, 1H), 4.06 — 3.93 (m, methyl-tetrahydropyran 2H), 3.79 — 3.67 (m, 4H), 3.62 — yl]0xy— 3.54 (m, 1H), 2.31 (s, 3H), 1.40 phenyl]benzoy1]amin0]pr0 (s, 3H). panoic acid [3 — [3 —methy1—4— [(2R,3 S,4S,5 S,6R)—3,4,5— trihydroxy—6— (hydroxymethy1)-3 - methyl-tetrahydropyran yl] 0xy-pheny1]pheny1]— o rrolidin anone ydr0xy- 1 , 1 - (400 MHz, CD3OD) 8 8.27 (d, J bis(hydr0xymethy1)ethyl] - = 18.5 Hz, 1H), 8.02 (t, J = 8.7 N—(2-hydr0xyethyl)—3 —[3 — Hz, 1H), 7.85 (d, J = 7.5 Hz, methyl 1H), 7.53 (q, J = 7.4 Hz, 1H), [(2R,3 S,4S,5 S,6R)—3 ,4,5 — 7.44 (d, J = 9.2 Hz, 2H), 7.32 roxy—6— (d, J = 8.3 Hz, 1H), 5.27 (s, (hydroxymethy1)-3 - 1H), 4.59 (dd, J = 15.5, 8.3 Hz, methyl-tetrahydropyran 3H), 3.86 — 3.78 (m, 4H), 3.73 yl] 0xy-pheny1]benzamide (dd, J = 11.7, 7.3 Hz, 6H), 3.63 — 3.55 (m, 2H), 2.31 (s, 3H), N—[( 1 S,2R)—2—hydr0xy— 1 — (hydroxymethyl)pr0py1]—3 - [3—methy1—4— [(2R,3 S,4S,5 S,6R)—3,4,5— trihydroxy—6— (hydroxymethy1) methyl-tetrahydropyran 1]0x - ohen l]benzamide Preparation of EXAMPLE 73 3 —flu0r0—N—methy1—5 -[3 -methy1—4- [(2R,3 S,4S,5 S,6R)—3 ,4,5-trihydr0xy(hydr0xymethy1)-3 - methyl-tetrahydropyrany1]0xy-pheny1]benzamide To a mixture of EDIATE M10 (30.0 mg, 0.0565 mmol), Pd(OAc)2 (4.0 mg, 0.018 mmol) and [3-(2-dicyclohexylphosphanylphenyl)-2,4-dimeth0xy- phenyl]sulfonyloxysodium (14.0 mg, 0.0273 mmol) is added a degased NMP solution of [3— fluoro—5—(methylcarbamoyl)phenyl]boronic acid (200 uL of 0.50 M, 0.100 mmol) followed by a d aqueous solution of K2CO3 (100 uL of 2.5 M, 0.250 mmol). The final mixture is stirred at 65°C for 18h. To the resulting on mixture is cooled to RT and NaOMe (50 uL of 25 %W/V, 0.231 mmol in MeOH) is added. The resulting mixture is stirred 4h at RT and finally neutralized with AcOH (50uL). The resulting mixture is filtered (CHROMSPEC Syringe Filters 4mm PTFE, 0.45pm), the volatile are concentrated and the residual NMP solution is purified by reverse phase HPLC to afford the title compound as a white solid. LC- MS: m/z = 436.28 (M+H)+.

Preparation of EXAMPLEs 74 to 104.

EXAMPLEs 74 to 104 are prepared according to the procedure described for compound 73 using the appropriate boronic acid.

EXAMPLE (2R,3 S,4S,5 S,6R) [4-(4-fluorophenyl)methyl- phenoxy](hydroxymethyl)—3 -methyl-tetrahydropyran- 3 ,4,5-triol (2R,3 S,4S,5 S,6R) [4-(2,4-difluorophenyl)—2-methyl- phenoxy](hydroxymethyl)—3 l-tetrahydropyran- 3 ,4,5-triol (2R,3 S,4S,5 S,6R)—2— [4-(3 luorophenyl)methyl- phenoxy](hydroxymethyl)—3 -methyl-tetrahydropyran- 3 ,4,5-triol (2R,3 S,4S,SS,6R)—2—[4-(5 -chlorofluoro-phenyl) methyl-phenoxy](hydroxymethyl)-3 l- tetrah dro. ran-3,4,5-triol (2R,3 S,4S,SS,6R)—2—[4—(3 ofluoro-phenyl) methyl-phenoxy](hydroxymethyl)-3 l- tetrahydropyran-3 ,4,5 -triol 4—methoxy—3—[3—methyl—4—[(2R,3 S,4S,SS,6R)—3,4,5— trihydroxy(hydroxymethyl)-3 -methyl-tetrahydropyran yl]oxy-phenyl]benzonitrile (2R,3 S,4S,SS,6R)—2—[4-(3 o-5 -methoxy-phenyl) methyl-phenoxy](hydroxymethyl)-3 -methyl- tetrah dro. ran-3,4,5-triol (2R,3 S,4S,5 S,6R) [4-(4-chloromethoxy-phenyl) -phenoxy](hydroxymethyl)-3 -methyl- tetrah dro. ran-3,4,5-triol (2R,3 S,4S,5 S,6R) [4-(3 ,4-dichlorophenyl)methyl- 82 phenoxy]-6—(hydroxymethyl)-3 -methyl-tetrahydropyran- 429.29 3 ,4,5-triol N,N—dimethy1—3 —[3 —methy1—4—[(2R,3 S,6R)—3 ,4,5— trihydroxy(hydroxymethy1)-3 -methy1—tetrahydropyran 1]0x - ohen amide 3 —[3—methy1—4—[(2R,3 S,4S,SS,6R)—3 rihydr0xy—6— (hydroxymethy1)-3 l-tetrahydropyran-Z-y1] oxy- ohen l]benzenesulf0namide [2—flu0r0—5—[3—methy1—4—[(2R,3 S,4S,5 S,6R)—3 ,4,5— trihydroxy(hydroxymethy1)-3 -methy1—tetrahydropyran yl]0xy-pheny1]phenyl]errolidiny1—methan0ne N—tert—buty1—3 —[3 —methy1—4—[(2R,3 S,4S,SS,6R)—3,4,5— trihydroxy(hydroxymethy1)-3 -methy1—tetrahydropyran yl]oxy-phenyl]benzenesulfonamide (2R,3 S,4S,5S,6R)[4-(4-flu0r0-3 -methy1-phenyl) methyl-phenoxy](hydr0xymethy1)-3 -methy1- tetrah dro. ran-3,4,5-tri01 (2R,3 S,4S,5 S,6R)-2— [4-(3 ,4-difluorophenyl)-2—methy1- y](hydr0xymethy1)—3 -methy1-tetrahydr0pyran- 3 ,4,5-tri01 (2R,3 S,4S,5 S,6R)—6—(hydr0xymethy1)—2—[4—(1H—ind01—6—y1)— 2-meth 1- ohenox ]—3 -meth l-tetrah dro o ran-3,4,5-tri01 (2R,3 S,4S,5 S,6R)—2—[4-(3-flu0r0meth0xy-pheny1) methyl-phenoxy](hydr0xymethy1)-3 -methy1- tetrahydropyran-3 ,4,5 -tri01 (2R,3 S,4S,5 S,6R)-2— flu0r0meth0xy-pheny1) methyl-phenoxy](hydr0xymethy1)-3 -methy1- tetrahydrogyran-3 ,4,5-tri01 (2R,3 S,4S,SS,6R)—2—[4-(3 -ch10r0flu0r0-pheny1)-2— methyl-phenoxy](hydr0xymethy1)-3 -methy1- tetrah dro. ran-3,4,5-tri01 (2R,3 S,4S,SS,6R)—2—[4-(3 -ch10r0flu0r0-pheny1)-2— methyl-phenoxy](hydr0xymethy1)-3 -methy1- tetrah dro. ran-3,4,5-tri01 (2R,3 S,4S,5 2— [4-(3 ,5-dimethoxyphenyl)methy1— phenoxy](hydr0xymethy1)—3 -methy1-tetrahydr0pyran- 3 ,4,5-tri01 (2R,3 S,4S,5 S,6R)-2— [4-(2,5-dimeth0xypheny1)methy1— phenoxy](hydr0xymethy1)—3 1-tetrahydr0pyran- 3 ,4,5-tri01 (2R,3 S,4S,SS,6R)[4-(3 -ch10r0meth0xy-pheny1) methyl-phenoxy](hydr0xymethy1)-3 -methy1- tetrah dro. ran-3,4,5-tri01 (2R,3 S,4S,SS,6R)[4-(5 -ch10r0meth0xy-pheny1) methyl-phenoxy](hydr0xymethy1)-3 -methy1- tetrah dro. ran-3,4,5-tri01 (2R,3 S,4S,5 S,6R)—2— [4-(3 ,5-diflu0r0meth0xy-pheny1) 98 methyl-phenoxy](hydr0xymethy1)-3 -methy1- 427.04 tetrahydropyran-3 ,4,5 -tri01 (2R,3 S,4S,5S,6R)—2—[4-(3 ,5-difluoromethoxy-phenyl) methyl-phenoxy](hydroxymethyl)-3 -methyl- tetrah dro. ran-3,4,5-triol (2R,3 S,4S,5 2— [4-(4,5-dichloromethoxy-phenyl)-2— methyl-phenoxy](hydroxymethyl)-3 -methyl- tetrah dro. ran-3,4,5-triol 4—methyl—3—[3—methyl—4—[(2R,3 S,4S,5S,6R)—3,4,5— trihydroxy(hydroxymethyl)—3 -methyl-tetrahydropyran yl]oxy-phenyl]benzonitrile [2—fluoro—5—[3—methyl—4—[(2R,3 S,4S,5 S,6R)—3 ,4,5— trihydroxy(hydroxymethyl)—3 -methyl-tetrahydropyran yl]oxy-phenyl]phenyl]-morpholino-methanone [3—fluoro—5—[3—methyl—4—[(2R,3 S,4S,5 S,6R)—3 ,4,5— roxy(hydroxymethyl)—3 -methyl-tetrahydropyran l]ox - ohen l] ohen l]—mo o-methanone (2R,3 S,4S,5 S,6R)—6-(hydroxymethyl)[4-(4-hydroxy-3 - methyl-phenyl)-2—methyl-phenoxy] -3 -methyl- tetrah dro. ran-3,4,5-triol Preparation of E 105 (Route A) (2R,3 S,4S,5 S,6R)—6-(hydroxymethyl)-3 -methyl-2— [2—methyl[3 -methyl [(2R,3 S,4S,5 S,6R)-3 ,4,5 -trihydroxy(hydroxymethyl)—3 -methyl-tetrahydropyranyl] oxy- phenyl]phenoxy]tetrahydropyran-3,4,5-triol Step I: (2R,3 S,4S,5R,6R)(acetoxymethyl)—3-methyl(2-methyl(4,4,5,5-tetramethyl- 1,3 ,2-dioxaborolanyl)phenoxy)tetrahydro-2H-pyran-3 riyl triacetate 0 ~~""O ACO‘" me" c time0 Me To a degased (N2) solution of INTERMEDIATE M10 (11.00 g, 20.70 mmol), KOAc (1.06 g, 41.1 mmol) and Bis(pinacolato)diboron (7.885 g, 31.1 mmol) in DMF (110 mL) is added PdClz(dppf)—DCM (845 mg, 1.04 mmol). The reaction mixture is degased (3x) and d at 80°C for 16 h. The reaction is cooled to RT, quenched with EtOAc and aqueous saturated NH4C1 and filtered on celite. The organic phase is separated, dried over NaZSO4, filtered, concentrated and purified on Isco CombiFlash® silica gel cartridge (220 g) eluting with EtOAc ) in Hex (13 CV) to afford the title compound (10.6 g, 89%) as a White solid. 1H NMR (400 MHz, CDCl3) 5 7.64 — 7.54 (m, 2H), 7.13 (d, J= 8.1 Hz, 1H), 6.31 (s, 1H), 5.59 (d, J= 9.7 Hz, 1H), 5.38 (t, J= 9.9 Hz, 1H), 4.17 (dd, J: 12.2, 5.2 Hz, 1H), 4.07 — 3.93 (m, 2H), 2.27 (s, 3H), 2.13 (s, 3H), 2.12 (s, 3H), 2.02 (s, 6H), 1.61 (s, 3H), 1.32 (s, 12H).

Step II: [(2R,3R,4S,5S,6R)—3 ,4,5-triacetoxy[2-methyl[3 -methyl[(2R,3 S,4S,5R,6R)- 3 ,4,5-triacetoxy(acetoxymethyl)—3-methyl-tetrahydropyranyl]oxy-phenyl]phenoxy]—5- methyl-tetrahydropyranyl]methyl acetate To a degased mixture of INTERMEDIATE M10 (10.0 g, 18.8 mmol), (2R,3 S,4S,5R,6R)— 6-(acetoxymethyl)-3 -methyl(2-methyl(4,4,5,5-tetramethyl- 1,3 xaborolan yl)phenoxy)tetrahydro-2H-pyran-3,4,5-triyl triacetate from Step I (10.9 g, 18.8 mmol) and K2CO3 (13.03 g, 94.3 mmol) in 2-MeTHF (217 mL) is added water (43.4 mL), Pd(OAc)2 (623 mg, 2.78 mmol) and [3 -(2-dicyclohexylphosphanylphenyl)-2,4-dimethoxyphenyl ]sulfonyloxysodium (2.89 g, 5.64 mmol). The reaction e is degased (3 times) and heated at 65°C for 80 min. The reaction e is cooled down with an ice bath, the aqueous phase is separated, extracted with 200 ml EtOAc. The combined organic phase is washed with 300 ml of aqueous saturated NH4Cl, brine, dried over Na2SO4, filtered on celite and concentrated. The residue is purified on Isco CombiFlash® silica gel cartridge (330 g) eluting with Acetone (0-3 5%) in Hex (22 CV) to afford the title compound (14.7 g, 86%) as a white solid. 1H NMR (400 MHz, CDCl3) 5 7.33 (dd, J= 2.4, 0.9 Hz, 2H), 7.28 (ddd, J= 8.5, 2.4, 0.7 Hz, 2H), 7.19 (d, J= 8.5 Hz, 2H), 6.29 (s, 2H), 5.60 (d, J= 9.7 Hz, 2H), 5.40 (t, J= 9.8 Hz, 2H), 4.18 (dd, J: 12.2, 5.2 Hz, 2H), 4.14 — 4.00 (m, 4H), , 6H), 2.14 (s, 6H), 2.13 (s, 6H), 2.03 (s, 6H), 2.02 (s 1.64 (s, 6H). , 6H), Step III: EXAMPLE 105 To a suspension of [(2R,3R,4S,5S,6R)—3,4,5—triacetoxy—6—[2—methyl-4—[3—methyl—4— [(2R,3 R,6R)—3 riacetoxy(acetoxymethyl)-3 -methyl-tetrahydropyranyl] oxy- phenyl]phenoxy]methyl-tetrahydropyranyl]methyl acetate (16.0 g, 17.7 mmol) in MeOH (910 mL) is added NaOMe (1.97 mL of 25 %w/w, 8.86 mmol). The reaction mixture is stirred 90 min and neutralized by passing through 133 g of Dowex 50W4 H+ resin and 250 ml of methanol is used to wash the column after neutralization. The filtrate is concentrated until a white solid precipitated and the suspension is stirred for 45 min at 0°C, filtered and washed with 10 ml of cold MeOH. The solid is dried at 40°C under vacuum for 16 h to afford the title compound (8.50 g, 85%). 1H NMR (400 MHz, CD3OD) 5 7.38 — 7.30 (m, 4H), 7.26 (d, J = 8.4 Hz, 2H), 5.25 (s, 2H), 3.79 — 3.69 (m, 8H), 3.66 — 3.55 (m, 2H), 2.30 (s, 6H), 1.41 (s, 6H). LC—MS: m/z = 567.59 (M+H)+.

Alternative preparation of EXAMPLE 105 (Route B) Step I: (2R,3 S,4S,5R,6R)(acetoxymethyl)(4-iodomethylphenoxy) methyltetrahydro-2H-pyran-3 ,4,5-triyl tate OAc Me Aco‘" 3 OAc I OA'i/zle To a solution of INTERMEDIATES M4 (5.00 g, 12.4 mmol) in CHzClz (25 mL) is added 4-iodomethyl-phenol (5.79 g, 24.7 mmol) and BF3.OEt2 (9.5 mL, 74.9 mmol). The on mixture is stirred at 40°C for 90 min, cooled down to RT and poured slowly into a saturated aqueous NaHCO3 (100 mL) while stirring vigorously. The organic layer is separated and the aqueous layer is back ted with CHzClz (2x 25mL). The combined organic layers are concentrated and purified on BiotageTM SNAP silica cartridge (100 g) eluting with EtOAc (0—50%) in Hex (14CV) to afford the title compound (3.56 g, 50%) as a light yellow solid. 1H NMR (400 MHz, CDCl3) 5 7.47 (dd, J: 2.2, 0.9 Hz, 1H), 7.41 (ddd, J = 8.6, 2.3, 0.7 Hz, 1H), 6.91 (d, J: 8.6 Hz, 1H), 6.22 (s, 1H), 5.54 (d, J: 9.7 Hz, 1H), 5.37 (t, J: 9.9 Hz, 1H), 4.20 — 4.02 (m, 2H), 4.00 — 3.94 (m, 1H), 2.22 (d, J: 0.7 Hz, 3H), 2.13 (s, 3H), 2.12 (s, 3H), 2.02 (s, 6H), 1.60 (s, 3H).

Step II: [(2R,3R,4S,5S,6R)—3,4,5-triacetoxy-5 -methyl[2-methyl[3-methyl [(2R,3 S,4S,5R,6R)—3 ,4,5-triacetoxy(acetoxymethyl)-3 l-tetrahydropyranyl] oxy- phenyl]phenoxy]tetrahydropyranyl]methyl acetate OAcO E: 'u‘sOAC 0"" OAC To a mixture of ,4S,5R,6R)(acetoxymethyl)(4-iodomethylphenoxy) methyltetrahydro-2H-pyran-3,4,5-triyl triacetate from Step I (1.00 g, 1.73 mmol), TBABr (557 mg, 1.73 mmol) and Pd(OAc)2 (19 mg, 0.086 mmol) in DMF (15 mL) is added triethylamine (602 "L, 4.32 mmol). The reaction mixture is stirred at 110°C for 15 h, cooled down to RT and d with EtOAc (50 mL). The organic layer is washed with water (2x 25mL), brine, dried over NazSO4, filtered and concentrated. The residue is purified on BiotageTM SNAP silica cartridge (100 g) eluting with EtOAc (10-60%) in Hex gradient (13CV) to afford the title compound (303 mg, 39%) as a yellow solid.

Step III: EXAMPLE 105 l of the acetate tive group to afford EXAMPLE 105 is performed as previously described in Route A Step 111.

Alternative ation of EXAMPLE 105 (Route C) Step I: [(2R,3R,4S,5S,6R)-3,4,5-triacetoxymethyl[2-methyl[3 -methyl [(2R,3 S,4S,5R,6R)—3 ,4,5-triacetoxy(acetoxymethyl)-3 -methyl-tetrahydropyranyl] oxy- phenyl]phenoxy]tetrahydropyranyl]methyl acetate To a solution of INTERMEDIATE M10 (50.0 mg, 0.0940 mmol) in DMF (1.25 mL) is added PdClz.(CH3CN)2 (1.8 mg, 0.0047 mmol) and N1,N1,N1',N1',N2,N2,N2',N2'— octamethylethene-l,1,2,2-tetramine (44 "L, 0.19 mmol). The reaction mixture is heated at 50°C for 16 h, cooled to RT, diluted with water and extracted with EtOAc (3 x 15 mL). The combined organic layers are dried over NazSO4, filtered, concentrated and purified on BiotageTM SNAP silica cartridge (10 g) eluting with EtOAc (10% to 75%) in Hex to afford the title compound (12 mg, 28%).

Step II: EXAMPLE 105 Removal of the acetate tive group to afford EXAMPLE 105 is performed as previously described in Route A Step 111.

Alternative preparation of EXAMPLE 105 (Route D) Step I: [(2R,3R,4S,5S,6R)-3,4,5-triacetoxymethyl[2-methyl[3 -methyl [(2R,3 S,4S,5R,6R)—3 ,4,5-triacetoxy(acetoxymethyl)-3 -methyl-tetrahydropyranyl] oxy- phenyl]phenoxy]tetrahydropyranyl]methyl acetate To a solution of INTERMEDIATES M4 (100 mg, 0.25 mmol) in CHzClz (500 uL) is added 4-(4-hydroxymethyl-phenyl)methyl-phenol (26 mg, 0.12 mmol) and BF3.OEt2 (188 "L, 1.48 mmol). The reaction mixture is heated at 40°C for 4.5 h, cooled to RT and poured slowly into saturated aqueous NaHCO3 (2 mL) while stirring vigorously. The organic phase is separated and the he aqueous phase is back extracted with . The combined organic layers are dried over NazSO4, filtered, concentrated and purified on BiotageTM SNAP silica cartridge (12 g) eluting with EtOAc (20% to 55%) in Hex to afford title compound (25 mg, 22%).

Step II: EXAMPLE 105 Removal of the acetate protective group to afford EXAMPLE 105 is performed as previously described in Route A Step III.

Preparation of E 106 (2R,3 S,4S,5 6—(hydroxymethyl)—3 —methyl—2— [4— [4— [(2R,3 S,4S,5 S,6R)—3 ,4,5 —trihydroxy— 6-(hydroxymethyl)-3 -methyl-tetrahydropyranyl] nyl]phenoxy]tetrahydropyran- 3 riol.

EXAMPLE 106 is prepared in two steps according to the procedure described for EXAMPLE 105 Route D but using [1,1'-biphenyl]—4,4'-diol as reagent. In the first step (glycosidation), the on mixture is stirred 3 days at 40°C. In the second step (deprotection), the reaction mixture is stirred overnight and the resulting mixture is purified eTM SNAP C18 cartridge (12 g) eluting using CH3CN (10% to 25%) in water as eluent to afford the title compound. 1H NMR (400 MHz, CD30D) 5 7.52—7.46 (m, 2H), 7. 18—7. 11 (m, 2H), 5.18 (s, 1H), 3.78—3.59 (m, 5H), 1.36 (s, 3H).

Preparation of EXAMPLE 107 (2R,3 S,4S,5 S,6R)—2- [2-chloro [3 -chloro [(2R,3 S,4S,5 S,6R)—3 rihydroxy (hydroxymethyl)-3 -methyl-tetrahydropyranyl] oxy-phenyl]phenoxy] (hydroxymethyl)-3 - methyl-tetrahydropyran-3 ,4,5-triol EXAMPLE 107 is prepared in two steps according to the procedure bed for EXAMPLE 105 Route C but using EDIATE M11. 1H NMR (400 MHz, CD3OD) 5 7.60 (m, 2H), 7.51 - 7.34 (m, 4H), 5.27 (s, 2H), 3.81 - 3.53 (m, 10H), 1.42 (s, 6H). LC-MS: m/z = 608.43 (M+H)+.

Preparation of EXAMPLE 108 (2R,3 S,4S,5 6—(hydroxymethyl)—3 —methyl—2— [ [7—[(2R,3 S,4S,5 S,6R)—3 ,4,5—trihydroxy—6— (hydroxymethyl)-3 -methyl-tetrahydropyranyl]oxynaphthyl] oxy]tetrahydropyran-3 ,4,5 - triol EXAMPLE 108 is prepared in two steps ing to the procedure described for EXAMPLE 105 Route D but using naphthalene-2,7-diol as reagent. In the first step (glycosidation), the reaction mixture is stirred overnight at 40°C. In the second step the title compound is purified by reverse phase HPLC. 1H NMR (400 MHz, CD3OD) 5 7.70 (d, J = 8.9 Hz, 1H), 7.54 (dd, J = 49.6, 2.9 Hz, 1H), 7.25 — 6.95 (m, 1H), 5.29 (s, 1H), 3.83 — 3.54 (m, 5H), 1.37 (d, J = 10.4 Hz, 3H).

Preparation of EXAMPLEs 109 to 115 EXAMPLEs 109 to 115 are prepared according to the procedure described for EXAMPLE 105 Route C but using the INTERMEDIATEs M16 to M22 tively in the first step. All EXAMPLEs are purified by reverse phase HPLC following final deprotection (NaOMe/MeOH).

LCMS EXAMPLE Name 1H—NMR m/z (M+H)+ ,4S,5S,6R)—6— (400 MHz, CD3OD) 5 7.23 (hydroxymethy1)[2-meth0xy- (d, J = 8.4 Hz, 2H), 7.16 4-[3-meth0xy (d, J = 2.1 Hz, 2H), 7.09 [(2R,3 S,4S,5S,6R)—3,4,5— (dd, J = 8.3, 2.1 Hz, 2H), 109 trihydroxy—6—(hydroxymethy1)—3— 5.12 (s, 2H), 3.88 (s, 6H), 599.6 methyl-tetrahydropyran 3.84 (dt, J = 7.3, 2.6 Hz, y1]0xy-pheny1]phen0xy]—3- 2H), 3.80 — 3.64 (m, 8H), methyl-tetrahydropyran-3,4,5- 1.42 (s, 6H). triol ,4S,5S,6R)—2—[2—ethy1—4— (400 MHz, CD3OD) 5 7.35 [3—ethy1—4—[(2R,3S,4S,5S,6R)— — 7.30 (m, 4H), 7.29 — 7.24 3,4,5—trihydr0xy—6— (m, 2H), 5.25 (s, 2H), 3.77 110 (hydroxymethy1)—3—methy1— — 3.66 (m, 8H), 3.62 — 3.51 595 2 tetrahydropyrany1]oxy- (m, 2H), 2.70 (qd, J = 7.3, ' pheny1]phen0xy] 2.2 Hz, 4H), 1.39 (s, 6H), (hydroxymethy1)methy1— 1.23 (t, J = 7.5 Hz, 6H). tetrah dro. ran-3,4,5-tri01 —[3—cyan0—4—[(2R,3S,4S,5S,6R)— (400 MHz, CD3OD) 5 7.92 3,4,5-trihydr0xy (d, J = 2.3 Hz, 2H), 7.86 (hydroxymethy1)methy1— (dd, J = 8.9, 2.4 Hz, 2H), tetrahydropyrany1]oxy- 7.57 (d, J = 8.9 Hz, 2H), 111 pheny1]—2-[(2R,3S,4S,5S,6R)— 5.37 (s, 2H), 3.81 — 3.64 589.6 3,4,5—trihydr0xy—6— (m, 8H), 3.59 (ddd, J = 8.9, (hydroxymethy1)methy1— 5.5, 2.4 Hz, 2H), 1.44 (s, tetrahydropyrany1]oxy- 6H). benzonitrile (2R,3S,4S,5S,6R)—2—[2—flu0r0—4— (400 MHz, CD3OD) 5 7.48 [3—flu0r0—4—[(2R,3 S,4S,5S,6R)— — 7.25 (m, 6H), 5.18 (s, trihydr0xy—6— 2H), 3.83 — 3.63 (m, 10H), 112 (hydroxymethy1)methy1— 1.40 (s, 6H). 575.42 tetrahydropyrany1]oxy- phenyl]phen0xy]—6— (hydroxymethy1)-3 -methy1— tetrah dro. ran-3,4,5-tri01 (2R,3S,4S,5S,6R)—6— (400 MHz, CD3OD) 5 7.43 (hydroxymethy1)methy1—2-[2- (s, 2H), 7.22 — 7.09 (m, methyl[4-methy1—3- 4H), 5.27 (s, 2H), 3.84 — [(2R,3 S,4S,5S,6R)—3,4,5— 3.59 (m, 10H), 2.25 (s, 113 trihydroxy—6—(hydroxymethy1)—3— 6H), 1.40 (s, 6H). 567.55 -tetrahydropyran yIJOXy- phenyl]phenoxy]tetrahydr0pyran- 3 ,4, 5 -tri01 (2R,3S,4S,5S,6R)—6— (400 MHz, CD3OD) 5 (hydroxymethyl)—3-methyl[2- 7.55—7.52 (m, 4H), 7.48— (trifluoromethoxy)—4-[3- 7.46 (m, 2H), 5.26 (s, 2H), (trifluoromethoxy)—4- 3.81 — 3.64 (m, 8H), 3.61 114 [(2R,3 S,4S,5S,6R)—3,4,5— (m, 2H), 1.38 (s, 6H). trihydroxy(hydroxymethyl)-3 - methyl-tetrahydropyran yl]oxy— phenyl]phenoxy]tetrahydropyran- triol (2R,3S,4S,5S,6R)—6— (400 MHz, CD3OD) 5 7.36 (hydroxymethyl)—2-[2-isopropyl- (d, J = 1.9 Hz,2H), 7.33 — 4-[3-isopropyl 7.26 (m, 4H), 5.27 (s, 2H), [(2R,3S,4S,5S,6R)—3,4,5— 3.80 — 3.63 (m, 8H), 3.61 — 115 trihydroxy—6—(hydroxymethyl)—3— 3.52 (m, 2H), 3.43 — 3.31 623.6 methyl-tetrahydropyran (m, 2H), 1.40 (s, 6H), 1.27 yl]oxy-phenyl]phenoxy]—3- (dd, J = 6.9, 4.6 Hz, 12H). methyl-tetrahydropyran-3,4,5— triol Preparation of EXAMPLE 1 16 (2R,3 S,4S,5 S,6R)—6-(hydroxymethyl)-3 -methyl [2-methyl[4- [3 -methyl [(2R,3 S,4S,5 S,6R)-3 ,4,5 -trihydroxy(hydroxymethyl)—3 -methyl-tetrahydropyranyl] oxy- phenyl]phenyl]phenoxy]tetrahydropyran-3 ,4,5-triol no""5HO 25 OH OH O To a degased mixture of 4,4,5,5-tetramethyl[4-(4,4,5,5-tetramethyl-1,3,2- orolanyl)phenyl]-l,3,2-dioxaborolane (30.0 mg, 0.0909 mmol) INTERMEDIATE M10 (96.6 mg, 0.182 mmol) and 3-(2-dicyclohexylphosphanylphenyl)-2,4-dimethoxy- esulfonic acid (Sodium Ion (1)) (18.67 mg, 0.0364 mmol) in 2—Me THF (600.0 uL) and Water (120.0 uL) is added sequentially K2CO3 (62.8 mg, 0.455 mmol) and Pd(OAc)2 (4.1 mg, 0.018 mmol). The ing mixture is stirred at 60°C for 16 h, cooled to RT, diluted with water and extracted with EtOAc (3 x 8 mL). The combined organic extracts are passed through a phase separator and concentrated to afford a crude mixture Which was dissolved in MeOH (400 mL). To the resulting solution is added NaOMe in MeOH (400 uL of 0.5 M, 0.200 mmol) and the mixture is d for 18 h. The reaction is quenched with DOWEX 50WX4 hydrogen form resin until pH 4-5, diluted with ol (25 mL), filtered and concentrated. The residue is dissolved in ~0.75 mL of DMSO and the solution is purified on a BiotageTM SNAP C18 (30 g) eluting with CH3CN (10% to 63%, 11 CV) in water to afford the title compound (10.8 mg, 18%) as a White solid. 1H NMR (400 MHz, CD3OD) 5 7.59 (s, 4H), 7.46 — 7.39 (m, 4H), 7.29 (d, J = 8.4 Hz, 2H), 5.26 (s, 2H), 3.78 — 3.69 (m, 8H), 3.65 — 3.55 (m, 2H), 2.30 (s, 6H), 1.40 (s, 6H).

Preparation of E 1 17 (2R,3 S,4S,5 S,6R)—6-(hydroxymethyl)-3 -methyl [2-methyl[2- [3 -methyl [(2R,3 S,4S,5 S,6R)-3 ,4,5 -trihydroxy(hydroxymethyl)—3 -methyl-tetrahydropyranyl] oxy- phenyl] ethynyl]phenoxy]tetrahydropyran-3 ,4,5 -triol Step I: (2R,3 S,4S,5 S,6R)(4-bromomethylphenoxy)(hydroxymethyl)-3 - methyltetrahydro-2H-pyran-3 riol To a solution of INTERMEDIATE M10 (320 mg, 0.602 mmol) in MeOH (4.8 mL) is added NaOMe (600 11L of 0.5 M, 0.300 mmol). The mixture is d at RT for 3h, ed through a prewashed 1g SCX-2 cartridge. The latter is wash three times with MeOH. The combined MeOH fractions are concentrated to dryness to afford the title compound (215 mg, 92%). 1H NMR (400 MHz, CD3OD) 5 7.29 (d, J = 2.0 Hz, 1H), 7.25 (dd, J = 8.7, 2.4 Hz, 1H), 7.16 (d, J = 8.8 Hz, 1H), 5.20 (s, 1H), 3.79 — 3.64 (m, 4H), 3.62 — 3.45 (m, 1H), 2.23 (s, 3H), 1.38 (s, 3H). LCMS m/z (M+Na)+ = 387.53 Step II: EXAMPLE 117 A mixture of (2R,3S,4S,5S,6R)(4-bromomethyl-phenoxy)(hydroxymethyl) methyl-tetrahydropyran-3,4,5-triol from Step I (108 mg, 0.297 mmol), PdC12(PPh3)2 (12.5 mg, 0.0178 mmol) and copper iodide (5.6 mg, 0.030 mmol) in CH3CN (1.5 mL) is placed in a microwave Vial (10 mL). DBU (267 11L, 1.78 mmol) and Water (10 11L, 0.55 mmol) are added and the mixture is degased before TMS—acetylene (21 11L, 0.15 mmol) is added. The tube is sealed and stirred vigorously at 80°C for 20 h. The mixture is cooled to RT, concentrated and the residue is dissolved in DMSO (0.5 mL). The resulting on is purified on BiotageTM SNAP C18 (30 g) eluting with CH3CN (0% to 50%, 15 CV) in water.

The fractions containing the desired material are combined and concentrated. The residue is further purified by reverse phase HPLC to afford the title nd (12.4 mg, 14%) as a white solid. 1H NMR (400 MHz, CD3OD) 6 7.28 = 9.2 Hz, 2H), - 7.24 (m, 4H), 7.20 (d, J .24 (s, 2H), 3.76 — 3.64 (m, 8H), 3.59 — 3.49 (m, 2H), 2.22 (s, 6H), 1.37 (s, 6H). LCMS m/z (M+H)+ = 591.47 Preparation of EXAMPLE 1 18 (2R,3 S,4S,5 S,6R)—2—[4—[3 ,5—bis [3 —methyl—4—[(2R,3 S,4S,5 S,6R)—3,4,5—trihydroxy—6— (hydroxymethyl)-3 -methyl-tetrahydropyranyl] oxy-phenyl]phenyl] methyl-phenoxy] (hydroxymethyl)-3 -methyl-tetrahydropyran-3 ,4,5-triol Step I: (2R,3 R,6R)(acetoxymethyl)—3-methyl(2-methyl(4,4,5,5-tetramethyl- 1,3 xaborolanyl)phenoxy)tetrahydro-2H-pyran-3 ,4,5-triyl triacetate To a degased mixture of EDLATES M10 (1.00 g, 1.88 mmol), KOAc (3 69 mg, 3.76 mmol) and Bis(pinacolato)diboron (717 mg, 2.82 mmol) in DMF (10.0 mL) is added PdClz(dppf)—DCM (77 mg, 0.094 mmol). The reaction is d at 80°C for 21 h, cooled to RT and partitioned between EtOAc and saturated aqueous NH4C1. The organic layer is separated, filtered on celite, dried over NaZSO4, filtered, concentrated and the residue is purified on BiotageTM SNAP Ultra silica cartridge (25 g) eluting with EtOAc (10-60%) in 8 Hex as gradient to afford the title compound (971 mg, 89%) as a White solid. 1H NMR (400 MHz, CDC13) 5 7.65 — 7.56 (m, 2H), 7.13 (d, J: 8.2 Hz, 1H), 6.31 (s, 1H), 5.59 (d, J: 9.7 Hz, 1H), 5.38 (t, J: 9.9 Hz, 1H), 4.17 (dd, J=12.2, 5.2 Hz, 1H), 4.08 — 3.94 (m, 2H), 2.27 (s, 3H), 2.13 (s, 3H), 2.12 (s, 3H), 2.02 (s, 6H), 1.61 (s, 3H), 1.32 (s, 12H).

Step II: Per-acetylated EXAMPLE 118 To a degased solution of (2R,3S,4S,5R,6R)—6—(acetoxymethyl)—3 —methyl—2—(2—methyl—4— (4,4,5 ,5-tetramethyl- 1,3 xaborolanyl)phenoxy)tetrahydro-2H-pyran-3 ,4,5 -triyl triacetate from Step I (100 mg, 0.17 mmol), 1,3,5-triiodobenzene (24 mg, 0.052 mmol) in 2- Me THF (3.75 mL) and Water (750 uL) is added K2CO3 (36 mg, 0.26 mmol), Pd(OAc)2 (1.0 mg, 0.0052 mmol) and 3-(2-dicyclohexylphosphanylphenyl)—2,4-dimethoxy-benzenesulfonic acid (Sodium Ion (1)) (5 mg, 0.010 mmol). The reaction mixture is degassed, stirred at 70°C for 2h, cooled down to RT and partitioned n EtOAc and water. The organic layer is separated, filtered on celite, dried over NazSO4, flltered, concentrated and purified on BiotageTM SNAP Ultra silica cartridge (12 g) eluting with EtOAc (20-80%) in Hex as gradient to afford the per-acetylated EXAMPLE 118 (50 mg, 61 %) as a white solid. 1H NMR (400 MHz, CD3OD) 5 7.68 (d, J: 1.4 Hz, 3H), 7.58 (d, J: 2.4 Hz, 3H), 7.54 (dd, J: 8.6, 2.3 Hz, 3H), 7.23 (d, J: 8.6 Hz, 3H), 6.35 (s, 3H), 5.64 (d, J: 9.7 Hz, 3H), 5.41 (t, J: 9.9 Hz, 3H), 4.21 (dd, J: 12.2, 4.9 Hz, 3H), 4.12 — 3.97 (m, 6H), 2.37 (s, 9H), 2.14 (s, 9H), 2.12 (s, 9H), 2.02 (s, 9H), 1.99 (s, 9H), 1.64 (s, 9H).

Step III: EXAMPLE 118 To a solution of the etylated EXAMPLE 118 from Step II (50 mg, 0.035 mmol) in MeOH (1.0 mL) is added NaOMe (4.0 uL of 25 %W/W, 0.018 mmol). The resulting suspension is stirred 2h at RT followed by on of Ambilite IR—120 resin until the reaction mixture pH reaches 4. The suspension is diluted with MeOH (10 mL), filtered and concentrated to afford the tittle nd (30 mg, 88%). 1H NMR (400 MHz, CD30D) 5 7.63 (s, 3H), 7.54 — 7.42 (m, 6H), 7.32 (d, J = 8.4 Hz, 3H), 5.28 (s, 3H), 3.82 — 3.66 (m, 12H), 3.61 (dt, J = 6.9, 3.6 Hz, 3H), 2.33 (s, 9H), 1.41 (s, 9H). LCMS m/z (M+H)+ = 925.81 Preparation of EXAMPLE 1 19 (2R,3 S,4S,5 S,6R)—6-(hydroxymethyl)-3 -methyl hyl[5- [3 -methyl [(2R,3 S,4S,5 S,6R)-3 ,4,5 -trihydroxy(hydroxymethyl)—3 -methyl-tetrahydropyranyl] oxy- ] -3 -pyridyl]phenoxy]tetrahydropyran-3 ,4,5-triol To a degased on (2R,3S,4S,5R,6R)—6—(acetoxymethyl)—3—methyl—2-(2—methyl-4— (4,4,5 ramethyl- 1,3 ,2-dioxaborolanyl)phenoxy)tetrahydro-2H-pyran-3 ,4,5 -triyl triacetate from EXAMPLE 118 Step I (204 mg, 0.35 mmol), 3—bromo—5—iodo—pyridine (50.0 mg, 0.180 mmol) in 2—MeTHF (1.9 mL) and Water (375 uL) is added K2CO3 (74.0 mg, 0.530 mmol), Pd(OAc)2 (2.0 mg, 0.011 mmol) and 3-(2-dicyclohexylphosphanylphenyl)-2,4- dimethoxy-benzenesulfonic acid (Sodium Jon (1)) (11 mg, 0.021 mmol). The reaction is degassed again, stirred at 70°C for 16h and then cooled to RT. The organic layer is separated, dried over NaZSO4, filtered on celite, diluted with MeOH (1 mL) and 2—Me THF (2 mL) and treated with NaOMe (352 "L of 0.5 M, 0.18 mmol) for 2 h at room temperature.

The reaction mixture is neutralized with AcOH (20 "L, 0.35 mmol), concentrated and purified by e phase HPLC to afford the title compound (8 mg, 14%). 1H NMR (400 MHz, CD3OD) 5 8.66 (s, 2H), 8.16 (d, J = 1.8 Hz, 1H), 7.62 = 8.5 — 7.42 (m, 4H), 7.36 (d, J Hz, 2H), 5.29 (s, 2H), 3.81 = 6.8, 3.5 Hz, 2H), 2.33 — 3.63 (m, 8H), 3.58 (dt, J (s, 6H), 1.40 (s, 6H). LCMS m/z (M+H)+ = 644.38 Preparation of EXAMPLEs 120, 121 and 122 EXAMPLEs 120 to 122 are prepared according to the procedure described for EXAMPLE 119 using the appropriately substituted commercially available bis-halogenated phenyl or pyridine. 2014/024411 LCMS EXAMPLE 1H— MR m/z (M+H)+ (2R,3 S,4S,5S,6R)—6— (400 MHz, CD3OD) 5 7.70 xymethy1)-3 -methy1—2- [2- (t, J = 1.8 Hz, 1H), 7.51 — methy1[3-[3 -methy1—4- 7.37 (m, 7H), 7.30 (d, J = 120 [(2R,3 S,4S,5 S,6R)—3 ,4,5— 8.3 Hz, 2H), 5.27 (s, 2H), 644.3 trlhydroxy(hydroxymethyl)—3—. 3.79 — 3.66 (m, 8H), 3.60 methyl-tetrahydropyrany1]oxy- (dp, J = 6.8, 3.2 Hz, 2H), pheny1]pheny1]phen0xy]tetrahydr 2.31 (s, 6H), 1.40 (s, 6H). ogyran-3,4,5-triol (2R,3S,4S,5S,6R)—6— (400 MHz, CD3OD) 5 7.95 — (hydroxymethy1)methy1—2-[2— 7.86 (m, 4H), 7.80 (d, J = methyl[6-[3 -methy1—4- 7.8 Hz,1H), 7.66 (d, J = 7.8 [(2R,3 S,4S,5S,6R)—3,4,5— Hz, 2H), 7.34 (d, J = 8.4 Hz, 121 trihydroxy—6—(hydroxymethy1)—3— 2H), 5.31 (s, 2H), 3.78 — 644.3 methyl-tetrahydropyrany1]oxy— 3.67 (m, 8H), 3.59 (dt, J = pheny1] 6.9, 3.5 Hz, 2H), 2.34 (s, pyridy1]phen0xy]tetrahydropyran- 6H), 1.41 (s, 6H). 3,4,5-triol (2R,3S,4S,5S,6R)—6— (400 MHz, CD3OD) 5 8.58 — (hydroxymethy1)methy1—2-[2- 8.46 (m, 1H), 7.96 (dd, J = methyl—4—[2—[3—methy1—4— 1.8, 0.8 Hz, 1H), 7.81 — 7.76 [(2R,3 S,4S,5S,6R)—3,4,5— (m, 2H), 7.67 — 7.60 (m, trihydroxy(hydroxymethy1)-3— 2H), 7.54 (dd, J = 5.4, 1.7 122 methyl—tetrahydropyran—2—y1]oxy— Hz, 1H), 7.36 (dd, J = 8.5, 645.2 pheny1] 6.5 Hz, 2H), 5.31 (s, 2H), pyridy1]phen0xy]tetrahydropyran- 3.88 — 3.62 (m, 8H), 3.58 3 ,4, 5 -triol (ddd, J = 8.3, 6.8, 3.6 Hz, 2H), 2.34 (s, 6H), 1.40 (d, J = 1.0 Hz, 6H).

Preparation of EXAMPLE 123 (2R,3 S,4S,5 S,6R)—6-(hydroxymethy1)-3 -methy1—2-[2-methy1—4-[2-[3-methy1—4- [(2R,3 S,4S,5 3 ,4,5 -trihydroxy(hydroxymethy1)—3 -methyl-tetrahydropyrany1] oxy- phenyl]cyclopropy1]phen0xy]tetrahydropyran-3 ,4,5-triol CO AOOéaolee Step I: (2R,3 S,4S,5R,6R)(acet0xymethy1)-3 1—2-(2-methy1((E)(6-methy1—4,8- diox0-1,3 ,6,2-dioxazaborocany1)Viny1)phen0xy)tetrahydro-2H-pyran-3 ,4,5-triy1 triacetate To a Vial containing, 2-[(E)bromovinyl]methyl-1,3,6,2-dioxazaborocane—4,8—dione (95.1 mg, 0.363 mmol), [(2R,3R,4S,5S,6R)-3,4,5-triacetoxymethyl[2-methyl (4,4,5 ,5 -tetramethyl-1,3 ,2-dioxaborolanyl)phenoxy]tetrahydropyranyl]methyl acetate from E 118 Step I (175 mg, 0.303 mmol) are added under a nitrogen atmosphere PdClz(dppf). CHzClz (22.1 mg, 0.0303 mmol) and K3PO4 (192.7 mg, 0.908 mmol) in CH3CN (1.2 mL). The Vial is sealed and allowed to stir at RT for 3 days. The mixture is filtered on a pad of silica gel and the filtrate is concentrated. The residue is purified on a BiotageTM SNAP silica dge eluting with EtOAc in Hex as gradient to afford title compound (107.6 mg, 56%).

Step II: [(2R,3R,4S,5 S,6R)—3 ,4,5-triacetoxy-5 -methyl [2-methyl[(E) [3 -methyl [(2R,3 S,4S,5R,6R)-3 ,4,5-triacetoxy(acetoxymethyl)-3 -methyl-tetrahydropyranyl] oxyphenyl ]Vinyl]phenoxy]tetrahydropyranyl]methyl acetate OM0OAc "Me AC0 ‘3, g OAc ACO OAC OAC To a Vial containing INTERMEDIATE M10 (144.4 mg, 0.272 mmol) and (2R,3 S,4S,5R,6R)(acetoxymethyl)-3 -methyl(2-methyl((E)(6-methyl-4,8-dioxo- 1,3 ,6,2-dioxazaborocanyl)Vinyl)phenoxy)tetrahydro-2H-pyran-3 ,4,5-triyl tate ( 107.6 mg, 0.170 mmol) is added under a nitrogen atmosphere PdClz(dppf). CHzClz (12.4 mg, 0.0170 mmol) and K3PO4 (108.2 mg, 0.510 mmol) in CH3CN (1.4 mL). The Vial is sealed and allowed to stir at 60°C overnight. The mixture is d on a pad of silica gel and the filtrate is concentrated. The residue is purified on a BiotageTM SNAP silica dge eluting with EtOAc in Hex to afford title compound (40 mg, 25%).

Step III: [(2R,3R,4S,5S,6R)—3,4,5-triacetoxymethyl[2-methyl[2-[3-methyl [(2R,3 S,4S,5R,6R)-3 ,4,5-triacetoxy(acetoxymethyl)-3 -methyl-tetrahydropyranyl] oxy- phenyl]cyclopropyl]phenoxy]tetrahydropyranyl]methyl acetate A O 0’" OAc O O nge rQOAC Meo OAC .,,l AcO Me 2., Acos OAc OAc OAC To a solution of [(2R,3R,4S,5S,6R)-3,4,5-triacetoxymethyl[2-methyl[(E)—2-[3- methyl[(2R,3S,4S,5R,6R)-3,4,5-triacetoxy(acetoxymethyl)methyl-tetrahydropyran- 2-yl]oxy-phenyl]vinyl]phenoxy]tetrahydropyranyl]methyl acetate from Step II (40 mg, 0.043 mmol) and Pd(OAc)2 (4.8 mg, 0.022 mmol) in CHzCLz (1.0 mL) at 0°C is added dropwise a solution of ethane (5.4 mL of 0.8 M, 4.3 mmol) and the solution is stirred until complete conversion to desired material (monitored by LCMS). The resulting mixture is filtered over celite and the filtrate is concentrated under d re to afford a crude mixture (40.6 mg) of the title compound. The latter is used in the next step without further purification.

Step 1V: E 123 A crude mixture of [(2R,3R,4S,5S,6R)-3,4,5-triacetoxymethyl[2-methyl[2-[3- methyl[(2R,3S,4S,5R,6R)-3,4,5-triacetoxy(acetoxymethyl)methyl-tetrahydropyran- 2-yl]oxy-phenyl]cyclopropyl]phenoxy]tetrahydropyranyl]methyl acetate from Step III (40.6 mg) is dissolved in MeOH (323 uL) and NaOMe (86 uL of 0.5 M, 0.043 mmol) is added. The resulting mixture is allowed to stir overnight at RT. AcOH (0.9 "L, 0.015 mmol) is added and the mixture is concentrated. The residue is purified by reverse phase HPLC to afford the Title compound (4.1 mg) as a white solid. 1H NMR (400 MHz, CD30D) 5 7.10 (d, J = 8.2 Hz, 3H), 6.96 = 9.8 Hz, 5H), 5.14 (d, J = 6.5 Hz, 2H), 3.76 = — 6.85 (m, J — 3.66 (m, J .2, 4.1 Hz, 9H), 3.65 = 4.7 Hz, 3H), 2.19 (s, 6H), 1.96 (t, 2H), 1.37 (s, 6H), — 3.55 (m, J 1.27 (t, J = 7.1 Hz, 2H). LCMS m/z (M+H)+ = 607.7 Preparation of EXAMPLE 124 (2R,3'S,4'S,5'S,6'R)—6'-(hydroxymethyl)spiro[chromane-2,2'-tetrahydropyran]-3',4',5',6-tetrol (VRT—1178998) HOH- ’0 OH HO OH Step I: (2R,3'S,4'S,5'R,6'R)—3',4',5',6-tetrabenzyloxy-6'-(benzyloxymethyl)spiro[chromane- 2,2'-tetrahydropyran] Bnow ::‘ ab} >—0Bn BnO OBn To a cold (0°C) solution of INTERMEDIATE M9 (1.99 g, 3.27 mmol) and 4— oxyphenol (1.97 g, 9.84 mmol) in CHzClz (48 mL) is added BF3.OEt2 (420 11L, 3.31 mmol). After stirring for 45 min at 0°C, the reaction e is quenched with H20 (25 mL), stirred for 15 min and the layers are separated. The s layer is back extracted with CHzClz (2 x 25 mL) and the combined organic extracts are concentrated to about 25 mL. The precipitated unreacted phenol is removed by filtration. The filtrate is purified on a BiotageTM SNAP silica cartridge (100g) eluting with EtOAc (0 to 20%) in Hex as nt to afford the title compound (1.56 g, 64% yield) as a colorless gum. 1H NMR (400 MHz, CDCl3) 5 7.47 — 7.05 (m, 25H), 6.81 — 6.55 (m, 3H), 5.04 (d, J = 11.6 Hz, 1H), 4.96 (s, 2H), 4.90 (d, J = 10.6 Hz, 1H), 4.84 (s, 2H), 4.72 (d, J =11.6 Hz, 1H), 4.59 (d, J =10.6 Hz, 1H), 4.54 (d, J = 11.7 Hz, 1H), 4.41 — 4.30 (m, 2H), 4.11 (t, J = 9.7 Hz, 1H), 3.85 (d, J = 2.8 Hz, 1H), 3.82 (ddd, J = .0, 4.6, 1.6 Hz, 1H), 3.74 (dd, J =11.6, 4.7 Hz, 1H), 3.64 (dd, J = 11.5, 1.6 Hz, 1H), 2.95 (ddd, J = 16.3, 13.2, 6.4 Hz, 1H), 2.59 — 2.48 (m, 1H), 2.42 (ddd, J = 12.8, 5.9, 1.6 Hz, 1H), 1.50 (dt, J = 13.0, 5.8 Hz,1H).

Step II: EXAMPLE 124 A pressure vessel is d with (2R,3'S,4'S,5'R,6'R)—3',4',5',6—tetrabenzyloxy-6'— (benzyloxymethyl)spiro[chromane-2,2'-tetrahydropyran] from Step I (646 mg, 0.863 mmol) in EtOAc (5 mL) and MeOH (10 mL). Pd(OH)2 (31 mg, 0.044 mmol) (slurry in MeOH) is added, followed by acetic acid (245 11L, 4.31 mmol). The reaction mixture is further diluted with MeOH (10 mL) and EtOAc (15 mL). The pressure vessel is filled with H2 and vented (3X), then stirred overnight under 45 psi H2 on a Parr shaker. The reaction e is vented under N2, filtered on Celite, and the catalyst is carefully rinsed with portions of MeOH. The combined filtrates are concentrated and coevaporated with heptane. Analysis by NMR showed the reaction is lete so the crude mixture is resubmitted to the exact reaction conditions and work-up to provide after co-evaporation with 1,4-dioxane (2x) the title compound (251 mg, 89% yield) as an off—white solid. 1H NMR (400 MHz, CD3OD) 5 6.62 (d, J = 8.4 Hz, 1H), 6.56 — 6.47 (m, 2H), 4.06 (dd, J = 9.5, 3.4 Hz, 1H), 3.76 — 3.62 (m, 4H), 3.52 (ddd, J = 9.9, 4.5, 2.8 Hz, 1H), 2.96 (ddd, J = 16.7, 12.9, 6.2 Hz, 1H), 2.57 (ddd, J = 16.4, 6.0, 2.3 Hz, 1H), 2.32 (ddd, J = 13.4, 6.1, 2.4 Hz, 1H), 1.69 (td, J = 13.1, 6.0 Hz, 1H).

LCMS m/z (M+Na)+ = 321.29 Preparation of EXAMPLE 125 (2R,3 'S,4'S,5'S,6'R)—6'—(hydroxymethy1)—6—[3—methy1—4—[(2R,3 S,4S,5 S,6R)—3,4,5—trihydroxy— 6-(hydroxymethyl)methyl-tetrahydropyranyl]oxy-phenyl]spiro[chromane-2,2'- tetrahydropyran]—3 ',4',5'-triol HO Me, OH 0 ' Ho--- ., : o b O O 0‘ HO OH Step I: [(2R,3'S,4'S,5'S,6'R)—3',4',5'-trihydroxy-6'-(hydroxymethyl)spiro[chromane—2,2'- tetrahydropyran]yl] trifluoromethanesulfonate Ho--- H0 or? To a solution of EXAMPLE 124 (730 mg, 2.24 mmol) and 1,1,1-trifluoro-N—phenyl-N— (trifluoromethylsulfonyl)methanesulfonamide (962 mg, 2.69 mmol) in DMF (10 mL) is added TEA (625 "L, 4.48 mmol) and the reaction mixture is d for 24h, then concentrated to dryness. The crude product is purified on a BiotageTM SNAP silica cartridge (50g) eluting with a gradient of MeOH (0-20%) in CHzClz to afford the title compound (842 mg, 87% yield) as a ess solid contaminated with TEA. 1H NMR (400 MHz, CD3OD) 5 7.14 — 7.02 (m, 2H), 6.93 (d, J = 8.8 Hz, 1H), 4.06 (dd, J = 9.5, 3.4 Hz, 1H), 3.79 (d, J = 3.4 Hz, 1H), 3.74 — 3.60 (m, 3H), 3.52 (ddd, J = 9.9, 4.6, 3.1 Hz, 1H), 3.15 — 2.99 (m, 1H), 2.72 (ddd, J = 16.6, 5.6, 2.2 Hz, 1H), 2.42 (ddd, J = 13.7, 6.1, 2.3 Hz, 1H), 1.74 (td, J = 13.3, 5.8 Hz, 1H). LCMS m/z (M+H)+ = .

Step II: [(2R,2'R,3'R,4'S,5'S)-3',4',5'-triacetoxy—6— (trifluoromethylsulfonyloxy)spiro[chromane-2,6'-tetrahydropyran]-2'-yl]methyl acetate AcOI . - ’o OTf AcO OAc To a Vial containing [(2R,3'S,4'S,5'S,6'R)—3',4',5'-trihydroxy—6'— (hydroxymethyl)spiro[chromane-2,2'-tetrahydropyran]yl] trifluoromethanesulfonate from Step I (840 mg, 1.95 mmol) and DMAP (49 mg, 0.401 mmol) is added pyridine (2.8 mL, 34.6 mmol) followed by AczO (3.32 mL, 35.1 mmol). After stirring for 25h, the reaction mixture is diluted with CHzClz (30 mL) and ed with H20 and 1N HCl (15 mL each). The layers are separated and the aqueous layer is back extracted with CHzClz (2 x 15 mL). The combined organic extracts are concentrated and coevaporated with CHZClz/heptane (3x). The crude e is d by flash chromatography on a BiotageTM SNAP silica cartridge (50g) eluting with a gradient of EtOAc ) in Hex to afford the title compound (907 mg, 78% yield) as a white crystalline solid. 1H NMR (400 MHz, CDCl3) 5 7.07 (dd, J = 8.9, 2.9 Hz, 1H), 7.02 (d, J = 2.8 Hz, 1H), 6.99 (d, J = 8.9 Hz, 1H), 5.65 (dd, J = 10.1, 3.5 Hz, 1H), .43 (d, J = 3.5 Hz, 1H), 5.32 (t, J = 10.2 Hz, 1H), 4.23 (dd, J = 12.3, 5.8 Hz, 1H), 4.02 — 3.92 (m, 2H), 2.98 (ddd, J = 16.7, 13.1, 6.4 Hz, 1H), 2.69 (ddd, J = 6.5, 5.2, 0.8 Hz, 1H), 2.22 (s, 3H), 2.18 (ddd, J = 13.5, 6.3, 1.9 Hz, 1H), 2.06 (s, 3H), 2.01 (s, 3H), 1.90 (s, 3H), 1.70 (td, J = 13.4, 6.1 Hz, 1H). "P NMR (376 MHz, CDC13) 5 -72.88 (s). LCMS m/z (M+H)+ = 599.34 Step III: [(2R,3R,4S,5S,6R)—3,4,5-triacetoxymethyl[2-methyl[(2R,3'S,4'S,5'R,6'R)- 3',4',5'-triacetoxy-6'-(acetoxymethyl)spiro[chromane-2,2'-tetrahydropyran] yl]phenoxy]tetrahydropyranyl]methyl acetate AcO pAc AcO Me, OAc 0 ' AcOII' O ._ ‘. b O O O AcO OAc A pressure tube is charged with [(2R,3R,4S,5S,6R)—3,4,5-triacetoxy—5—methyl—6—[2- methyl(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolanyl)phenoxy]tetrahydropyranyl]methyl acetate from EXAMPLE 118 Step I (71.0 mg, 0.123 mmol), [(2R,2'R,3'R,4'S,5'S)—3',4',5'— triacetoxy(trifluoromethylsulfonyloxy)spiro[chromane-2,6'-tetrahydropyran]-2'-yl]methyl acetate from Step 11 (50.0 mg, 0.0835 mmol), K2C03 (58.0 mg, 0.420 mmol), Pd(OAc)2 (4.9 mg, 0.022 mmol) and [3-(2-dicyclohexylphosphanylphenyl)-2,4-dimethoxy- phenyl]sulfonyloxysodium (V—Phos) (13.6 mg, 0.0265 mmol). The tube is capped and degassed (vaccuum then N2, 3x) and 2-methyltetrahydrofuran (1.0 mL) and H20 (200 uL) are added. The tube is ed again and transferred to a ted (65°C) oil bath. After stirring for 2 h, the reaction e is cooled down to RT, passed through a small plug of Celite, rinsing with EtOAc (5 mL) and saturated aqueous NH4Cl solution (3 mL). The layer is separated and the aqueous layer is back extracted with EtOAc (2 x 3 mL). The combined organic extracts are dried over NazSO4, filtered and concentrated. The crude residue is purified by flash chromatography on a on a BiotageTM SNAP silica cartridge (10g) eluting with a nt of EtOAc (20-80%) in Hex to afford the title compound (73 mg) as a colorless solid contaminated with pinacol. 1H NMR (400 MHz, CDCl3) 5 7.36 — 7.33 (m, 1H), 7.31 (dd, J = 5.0, 2.2 Hz, 1H), 7.28 (d, J = 2.3 Hz, 1H), 7.24 (d, J = 1.9 Hz, 1H), 7.20 (d, J = 8.5 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 6.31 (s, 1H), 5.71 (dd, J = 10.1, 3.5 Hz, 1H), 5.62 (d, J = 9.7 Hz, 1H), 5.44 (d, J = 3.3 Hz, 1H), 5.40 (d, J = 9.8 Hz, 1H), 5.35 (t, J = 10.1 Hz, 1H), 4.26 (dd, J = 12.0, 5.1 Hz, 1H), 4.20 (dd, J = 12.2, 5.2 Hz, 1H), 4.16 — 3.95 (m, 4H), 3.00 (ddd, J = 16.4, 13.2, 6.1 Hz, 1H), 2.76 — 2.64 (m, 1H), 2.34 (s, 3H), 2.25 — 2.11 (m, 10H), 2.06 (s, 3H), 2.05 (s, 6H), 2.02 (s, 3H), 1.91 (s, 3H), 1.74 (td, J = 13.2, 6.0 Hz, 1H), 1.66 (s, 3H). LCMS m/z (M+Na)+ = 923.71 Step IV: EXAMPLE 125 To a suspension of [(2R,3R,4S,5S,6R)—3,4,5—triacetoxy—5—methyl—6—[2-methyl—4— [(2R,3'S,4'S,5'R,6'R)-3',4',5'-triacetoxy-6'-(acetoxymethyl)spiro[chromane-2,2'- tetrahydropyran]yl]phenoxy]tetrahydropyranyl]methyl acetate from Step III (66.5 mg, 0.0738 mmol) in MeOH (1.3 mL) is added NaOMe in MeOH (300 11L of 0.5 M, 0.150 mmol.

After ng for 3h, the reaction mixture is diluted with MeOH (2 mL), d with prewashed Dowex 50WX4—400 resin, ed and washed with portions of MeOH. The combined filtrates are concentrated and purified on a BiotageTM SNAP C18 cartridge (12 g) eluting with a gradient of CH3CN (10-90%) in H20. The fractions ning the desired material are combined, concentrated, redissolved in H20/ CH3CN (20%) mixture and freeze— dried to provide the title compound (26.7 mg, 59% yield) as a fluffy white solid. 1H NMR (400 MHz, CD3OD) 5 7.38 = 9.1 Hz, 1H), 5.25 (s, 1H), 4.10 (dd, J — 7.21 (m, 5H), 6.84 (d, J = 9.5, 3.4 Hz, 1H), 3.80 (d, J = 3.4 Hz, 1H), 3.77 — 3.66 (m, 7H), 3.65 — 3.52 (m, 2H), 3.08 (ddd, J = 16.4, 13.0, 6.2 Hz, 1H), 2.72 (ddd, J = 7.3, 5.2, 1.7 Hz, 1H), 2.41 (ddd, J = 13.2, 5.8, 2.2 Hz, 1H), 2.29 (s, 3H), 1.77 (td, J = 13.2, 5.9 Hz, 1H), 1.41 (s, 3H). LCMS m/z (M+H)+ = 565.49 Preparation of EXAMPLE 126 (2R,3'S,4'S,5'S,6'R)—6'—(hydroxymethyl)—6—[(2R,3'S,4'S,5'S,6'R)—3',4',5'—trihydroxy—6'— (hydroxymethyl)spiro[chromane-2,2'-tetrahydropyran]yl]spiro[chromane-2,2'- tetrahydropyran]—3',4',5'-triol Step I: [(2R,2'R,3'R,4'S,5'S)-3',4',5'-triacetoxy(4,4,5,5-tetramethyl-1,3,2-dioxaborolan yl)spiro[chromane-2,6'-tetrahydropyran]-2'-yl]methyl acetate A00I . ' o B\ Aco OAc [or0 A pressure tube is charged with [(2R,2'R,3'R,4'S,5'S)—3',4',5'—triacetoxy (trifluoromethylsulfonyloxy)spiro[chromane-2,6'-tetrahydropyran]-2'-yl]methyl acetate from Step 11 (501 mg, 0.837 mmol), KOAc (170 mg, 1.73 mmol), Bis(pinacolato)diboron (321 mg, 1.26 mmol) and PdClz(dppf).CH2Clz (35 mg, 0.0429 mmol), capped and degassed (vacuum then N2 3x). DMF (5.0 mL) is added, the reaction mixture is degassed again, then heated at 80°C for 4h. The reaction e is diluted with saturated aqueous NH4Cl solution and EtOAc (15 mL each). The layers are separated and the organic layer is washed with saturated s NH4Cl solution (15 mL), dried over NazSO4, filtered and concentrated. The crude e is purified on a BiotageTM SNAP silica cartridge (50g) eluting with a gradient of EtOAc (0-60%) in Hex to afford the title compound (457 mg, 95% yield) as a White solid. 1H NMR (400 MHz, CDCl3) 5 7.61 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H), 6.95 (d, J = 8.1 Hz, 1H), .68 (dd, J = 10.1, 3.4 Hz, 1H), 5.42 (d, J = 3.4 Hz, 1H), 5.34 (t, J = 10.1 Hz, 1H), 4.24 (dd, J = 12.1, 4.9 Hz, 1H), 4.01 (ddd, J = 9.8, 4.9, 2.3 Hz, 1H), 3.94 (dd, J = 12.2, 2.4 Hz, 1H), 3.03 — 2.86 (m, 1H), 2.75 — 2.53 (m, 1H), 2.21 (s, 3H), 2.16 (ddd, J = 13.2, 5.8, 1.8 Hz, 1H), 2.05 (s, 4H), 2.00 (s, 3H), 1.93 (s, 3H), 1.69 (td, J = 13.3, 5.8 Hz, 1H), 1.33 (s, 12H). LCMS m/z + = 599.48 Step II: [(2R,2'R,3'R,4'S,5'S)—3',4',5'—triacetoxy—6—[(2R,3'S,4'S,5'R,6'R)—3',4',5'—triacetoxy—6'— (acetoxymethyl)spiro[chromane—2,2'-tetrahydropyran]yl]spiro[chromane-2,6'- tetrahydropyran]-2'-yl]methyl acetate The title compound is prepared according to the procedure described for EXAMPLE 125 Step 111 using [(2R,2'R,3'R,4'S,5'S)-3',4',5'-triacetoxy(4,4,5,5-tetramethyl-1,3,2- dioxaborolanyl)spiro[chromane-2,6'-tetrahydropyran]-2'-yl]methyl e from Step I and [(2R,2'R,3'R,4'S,5'S)-3',4',5'-triacetoxy(trifluoromethylsulfonyloxy)spiro[chromane-2,6'- tetrahydropyran]-2'-yl]methyl acetate from EXAMPLE 125 Step I. The title compound (79% yield) is obtained as a white solid. 1H NMR (400 MHz, CDCl3) 5 7.32 (dd, J = 8.2, 2.1 Hz, 2H), 7.24 (broad s, 2H), 6.98 (d, J = 8.4 Hz, 2H), 5.70 (dd, J = 10.1, 3.3 Hz, 2H), 5.44 (d, J = 3.3 Hz, 2H), 5.35 (t, J =10.1Hz, 2H), 4.26 (dd, J = 11.9, 4.9 Hz, 2H), 4.10 — 3.91 (m, 4H), 3.07 — 2.89 (m, 2H), 2.70 (dd, J = 16.9, 5.4 Hz, 2H), 2.27 — 2.13 (m, 8H), 2.06 (s, 6H), 2.02 (s, 6H), 1.92 (s, 6H), 1.74 (td, J = 13.0, 5.7 Hz, 2H). LCMS m/z (M+Na)+ = 899.72 Step III EXAMPLE 126 The title compound is prepared according to the ure described for EXAMPLE 125 Step 1V starting with [(2R,2'R,3'R,4'S,5'S)-3',4',5'-triacetoxy[(2R,3'S,4'S,5'R,6'R)—3',4',5'— triacetoxy-6'-(acetoxymethy1)spiro[chromane-2,2'-tetrahydropyran]y1]spiro[chromane- 2,6'-tetrahydropyran]-2'-y1]methy1 acetate from Step 11. 1H NMR (400 MHz CD30D) 5 7.33 = 9.5, 3.4 Hz, 2H), 3.79 (d, J = 3.4 Hz, 2H), — 7.22 (m, 4H), 6.89 — 6.78 (m, 2H), 4.10 (dd, J 3.74 (t, J = 9.7 Hz, 2H), 3.71 = 9.9, 4.2, 3.1 Hz, 2H), 3.07 (ddd, J — 3.65 (m, 4H), 3.57 (ddd, J = 17.5, 13.0, 6.1 Hz, 2H), 2.77 = 13.3, 5.8, 2.2 Hz, 2H), 1.76 (td, — 2.67 (m, 2H), 2.40 (ddd, J J = 13.2, 5.9 Hz, 2H). LCMS m/z (M+H)+ = 563.49 Preparation of EXAMPLE 127 (2R,3'S,4'S,5'S,6'R)—6'—(hydroxymethy1)—6—[4—[(2R,3'S,4'S,5'S,6'R)—3',4',5'—trihydroxy—6'— (hydroxymethy1)spiro[chromane-2,2'-tetrahydropyran]y1]pheny1]spiro[chromane-2,2'- tetrahydropyran]—3',4',5'-triol Step I: [(2R,2'R,3'R,4'S,5'S)—3',4',5'—triacetoxy—6—[4—[(2R,3'S,4'S,5'R,6'R)—3',4',5'—triacetoxy— 6'-(acetoxymethy1)spiro[chromane-2,2'-tetrahydropyran]y1]pheny1]spiro[chromane-2,6'- tetrahydropyran]-2'-y1]methy1 acetate A pressure tube is charged with [(2R,2'R,3'R,4'S,5'S)—3',4',5'—triacetoxy—6—(4,4,5,5— tetramethyl- 1,3 ,2-dioxaborolany1)spiro[chromane-2,6'-tetrahydropyran] -2'-y1]methy1 acetate from EXAMPLE 126 Step I (105 mg, 0.182 mmol), 1,4-dibromobenzene (20 mg, 0.0845 mmol), K2CO3 (64 mg, 0.463 mmol), )2 (2.6 mg, 0.0116 mmol) and [3-(2- dicyclohexylphosphanylpheny1)-2,4-dimethoxy-phenyl]sulfonyloxysodium s) (9 mg, 0.0176 mmol). The tube is capped and degassed (vacuum then N2, 3x) and 2— methyltetrahydrofuran (400 uL) and H20 (80 uL) are added, the tube is degassed again and transferred to a preheated (65°C) oil bath. After stirring for 2 h, the reaction mixture is cooled down to RT, diluted With CH2C12 (3 mL) and H20 (2 mL). The layers are separated and the aqueous layer is back extracted with CHzClz (2 x 1 mL). The combined organic extracts are concentrated. The crude residue is purified on a eTM SNAP silica cartridge (10g) eluting with a gradient of EtOAc (50-100%) in Hex to afford the title compound (71 mg) as a white solid contaminated with pinacol. 1H NMR (400 MHz, CDCl3) 5 7.59 (s, 4H), 7.43 (dd, J = 8.4, 2.2 Hz, 2H), 7.35 (d, J = 2.1 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 5.72 (dd, J = .1, 3.5 Hz, 2H), 5.46 (d, J = 3.5 Hz, 2H), 5.35 (t, J = 10.1 Hz, 2H), 4.27 (dd, J = 12.1, 5.1 Hz, 2H), 4.05 (ddd, J = 10.1, 5.2, 2.5 Hz, 2H), 4.00 (dd, J = 12.0, 2.5 Hz, 2H), 3.03 (ddd, J = .9, 12.9, 5.8 Hz, 2H), 2.79 — 2.65 (m, 2H), 2.29 — 2.14 (m, 8H), 2.07 (s, 6H), 2.02 (s, 6H), 1.92 (s, 6H), 1.76 (dt, J = 13.2, 5.9 Hz, 2H). LCMS m/z (M+H)+ = 975.72.

Step II: EXAMPLE 127 The title compound is prepared ing to the procedure described for EXAMPLE 125 Step 1V starting with 'R,3'R,4'S,5'S)—3',4',5'—triacetoxy—6—[4—[(2R,3'S,4'S,5'R,6'R)— 3',4',5'-triacetoxy-6'-(acetoxymethyl)spiro[chromane-2,2'-tetrahydropyran] yl]phenyl]spiro[chromane-2,6'-tetrahydropyran]-2'-yl]methyl acetate from Step I. 1H NMR (400 MHz, CD3OD) 5 7.60 (s, 4H), 7.44 = — 7.34 (m, 4H), 6.93 — 6.85 (m, 2H), 4.11 (dd, J 9.5, 3.4 Hz, 2H), 3.81 (d, J = 3.4 Hz, 2H), 3.79 = 9.9, 3.7 Hz, 2H), — 3.67 (m, 6H), 3.59 (dt, J 3.11 (ddd, J = 16.7, 12.9, 6.0 Hz, 2H), 2.75 (ddd, J = 16.2, 5.5, 2.0 Hz, 2H), 2.43 (ddd, J = 13.4, 6.0, 2.4 Hz, 2H), 1.79 (td, J = 13.3, 5.8 Hz, 2H). LCMS m/z (M+H)+ = 639.49 Preparation of EXAMPLE 128 (2R,3'S,4'S,5'S,6'R)—6'—(hydroxymethyl)—6—[3—[(2R,3'S,4'S,5'S,6'R)—3',4',5'—trihydroxy—6'— (hydroxymethyl)spiro[chromane-2,2'-tetrahydropyran]yl]phenyl]spiro[chromane-2,2'- tetrahydropyran]—3',4',5'-triol The title compound is prepared in two steps ing to the procedure described for EXAMPLE 127 but using 1,3-dibromobenzene in the first Step. 1H NMR (400 MHz, CD3OD+DMSO—D6) 5 7.80 — 7.65 (m, 1H), 7.57 — 7.37 (m, 7H), 6.97 — 6.88 (m, 2H), 4.10 (dd, J = 9.5, 3.4 Hz, 2H), 3.82 (d, J = 3.4 Hz, 2H), 3.78 = 9.9, 3.7 — 3.67 (m, 6H), 3.58 (dt, J Hz, 2H), 3.11 (ddd, J = 16.4, 12.9, 6.1 Hz, 2H), 2.79 (ddd, J = 7.8, 5.3, 2.1 Hz, 2H), 2.43 (ddd, J = 13.4, 5.9, 2.4 Hz, 2H), 1.80 (td, J = 13.2, 5.8 Hz, 2H). LCMS m/z (M+H)+ = 639.49 Preparation of EXAMPLE 129 S,4'S,5'S,6'R)—6'—(hydroxymethyl)—6—[5—[(2R,3'S,4'S,5'S,6'R)—3',4',5'—trihydroxy—6'— (hydroxymethyl)spiro[chromane-2,2'-tetrahydropyran]yl]—3-pyridyl]spiro[chromane-2,2'- tetrahydropyran]—3',4',5'-triol The title compound is prepared in two steps according to the procedure described for EXAMPLE 127 but using 3,5-dibromopyridine in the first Step. 1H NMR (400 MHz, CD30D) 5 8.63 (broad s, 2H), 8.13 (s, 1H), 7.51 - 7.36 (m, 4H), 7.01 - 6.86 (m, 2H), 4.09 (dd, J = 9.5, 3.4 Hz, 2H), 3.80 (d, J = 3.4 Hz, 2H), 3.76 - 3.63 (m, 6H), 3.56 (ddd, J = 9.9, 4.2, 3.2 Hz, 2H), 3.18 = 16.5, 5.5, 2.1 Hz, 2H), 2.42 (ddd, J = 13.4, - 2.97 (m, 2H), 2.76 (ddd, J .9, 2.3 Hz, 2H), 1.77 (td, J = 13.3, 5.8 Hz, 2H). LCMS m/z (M+H)+ = 640.47 Thermal shift Assay The carbohydrate ition domain of the protein FimH (Ml-T179) with an uncleavable C-terminus 6-His tag is cloned in a pET21b plasmid and expressed in E. coli and purified to neity. The thermal stabilization of the protein upon ligand binding is measured in a 96-well format on a ViiATM 7 (Life Technologies, Carlsbad, CA) RT-PCR ment. The assay is conducted in duplicate in 20 mM Tris pH 7.4 and 150 mM NaCl at a final concentration of 5.6uM and 5611M for protein and ligand, respectively. An environmentally-sensitive dye (Applied Biosystems Protein Thermal ShiftTM Dye (P/N 4461141)) is added to each well to a final ratio of 1:1000. Plates are spun at 1000 x g for 1 minute and incubated at room ature for 10 minutes. Thermal stability of protein with and without ligand is measured from 45°C to 85°C at a scan rate of /sec. The resulting data is analyzed using Protein Thermal ShiftTM Software (version 1.1) with DMSO control used as reference. Table 2 below provides the delta thermal melt for compounds 1—129 in the thermal shift assay.

Table 2 ND # *Delta Thermal melt (0C) l—l 3(1) 2 6.01 (1) 3 3.2 (1) 4 5.6 (1) "4.39 :0 11 (2). : 0.105(2) ll 2.6 (1) l2 0.06 0.11 (2) 13 10.71 0(2) —25 7.9 :: 0 (4) —26 5.405 :: 0.005 (2) —27 3 7 -: 0.041 (4) ——28 ——29 32 8 0.058 (4) 33 8.9 0.115 (4) 5.6 0(1) *Delta Thermal melt :: rd error of the mean (number of repeats) Bacterial Binding Assay The purpose of the Bacterial Binding Assay (BBA) is to determine the inhibition activity of selective FimH antagonists on the ial strain LP 82 binding to the glycoprotein BSA- (Mannose)3.

Below is a list of the Materials used to run the BBA are described below. h—t LB broth: Supplier: Gibco, #10855 9909.09er." D—PBS: Supplier: Wisent, #311CL LB agar plates 96—well black plate (high binding): Supplier: Costar, #3 925 TopSealTM-A adhesive sealing films; Supplier PerkinElmer, #6005185 Carbonate-bicarbonate buffer pH 9.6 tablets, Supplier: Medicago, #09—8922—24 Water, Supplier: Gibco, —162 Bovine serum n (BSA): Supplier: Sigma, 8 (Man)3-BSA (a1-3, (XI-6 Mannotriose-BSA, 1mg), V—Labs, #NGP1336, lot# HGDX37—169—1 . Tween 20: Supplier: Sigma, #P9416 11. Bright—Glo Luciferase Assay System: Supplier: Promega, #E2610 12. LF82/Luciferase strain: Invasive ability of an Escherichia coli strain isolated from the ileal mucosa of a patient with Crohn's e. Boudeau J, Glasser AL, Masseret E, Joly B, ille-Michaud A, Infect Immun. 1999, 67(9), 4499—509 Solutions and buffers used to run the BBA are bed below. 1. 0.04M carbonate—bicarbonate buffer (coating buffer) pPOSQMer’N L BSA-(Man)3: Dissolve 1mg of (Man)3-BSA in 25 mL of water. 4000ug/mL BSA 40ug/mL BSA lug/mL BSA-(Man)3: 150 uL of 40ug/mL BSA-(Man)3 + 5.85 mL of 40ug/mL BSA 0.5ug/mL BSA-(Man)3 in 0.02M carbonate-bicarbonate buffer. 20ug/mL BSA in 0.02M carbonate-bicarbonate buffer Blocking buffer (2% BSA/DPBS): lg of BSA in 50 mL D-PBS 2X binding buffer (0.2% BSA/D-PBS): 5 mL of blocking buffer + 45 mL D-PBS.

H,_i t—‘O . Washing buffer /0.01% Tween 20): 10 uL of Tween 20 in 100 mL D-PBS.. 1X Bright-Glo rase substrate: Dilute 1:1 the Bright-Glo Luciferase Assay System with D—PBS The experimental protocol to run the BBA is described below.

Overnight culture of LF82/Luciferase strain: Into two Falcon 50 mL tubes, add 20 mL of LB + 20uL of 50 mg/mL Kanamycin and inoculate with a loop from glycerol stock of the LF82/Luciferase strain. Incubate overnight at 37°C with no shaking.

Glycoprotein coating of 96—well plates: Add 100 uL/well of 0.5—2 ug/mL BSA- (Man)3. L BSA is used as the control background. Seal plate using an adhesive sealing film and incubate overnight at room temperature. Wash the l plate three times with 150 uL/well of D-PBS, add 170 l of blocking on and incubate 45 min (minimum) at room temperature.

Preparation of ial suspension: Mix the two cultures tubes (40 mL) and perform a 1:10 dilution in LB (900 pl LB + 100 pl culture. Measure optical density (OD) of the bacterial cultures. ODl ~5x108 cells/mL. Centrifuge LF82 culture for 20 min at 3500 rpm at room temperature. Re-suspend bacterial pellet in D-PBS and centrifuge again for 20 min at 3500 rpm. Re—suspend bacterial pellet in D—PBS to obtain a bacterial concentration of 2 x 109 bacteria / mL. Dilute 1/10 in D-PBS to obtain a final bacterial concentration of 2 X 108 bacteria/ mL (= 107 bacteria/ 50 uL). Perform 1/ 10 serial dilutions in LB of each bacterial suspension, plate 10uL of dilutions on LB agar plates (final dilutions of 107) and incubate ght at 37°C and count CFUs to determine the actual bacteria density in the assay.

Bacterial binding assay: Add 147 "L 2X binding buffer to compound plate (containing 3 "L of compound). After blocking step is performed (at least 45 min), wash plates three times with 200 uL/well of D-PBS. With a 100 uL multichannel manual pipettor, add 50uL/well of nd diluted in 2X binding buffer. With a 100 "L multichannel manual pipettor, add ell of bacterial suspension. e at slow speed for 1 min and incubate 40-75 min at room temperature. Wash 5 times with 150 uL/well of washing buffer and then once with D-PBS. Add 100uL/well of IX Bright-Glo Luciferase substrate. Read luminescence by using the Analyst HT plate reader or the Trilux 1450 eta plate reader.

Table 3 below provides IC50 data for compounds 1—129 in the bacterial binding assay.

Table 3 Compound BaCterlféilglnilg/lg Assay 8 5.4 :: 0.2 (2) 1 \I/A 2 1.15:: 0.35 (2) -0(2) 3 /A 0.132 :: 0.044 (4) : 0.141 (4) 0.013 :: 0.002(4) 7 8.62 :: 1.298 (5) 16 0.067 :: 0.018(4) 2014/024411 17 49 0.28 -- 0 02 (2) 18 50 0.83 -- 0 17 (2) 19 5 1 7.15 :: 0.05 (2) 0.02 0(2) 52 0.048 -- 0 01 (2) 21 5 3 0.024 0 006 (3) 22 54 : 0.004(6) 0.042 0.007 (2) 23 55 : 0.025 (2) 0.02 :: 0.0005 (2) 24 56 : 0.003 (7) 0.024 0.0005 (2) 57 : 0.018 (4) 0.017 :: 0.004 (2) 26 5 8 : 0.544 (6) 0.013 :: 0.001 (6) 27 5 9 0.02 0 004 (6) 28 1.3 :: 0 (2) 29 >10 0(2) 6 1 0.022 0.006 (2) >10 0(2) 62 0.009 0.003 (2) 31 >10 0(2) 63 0.012 0.003 (2) 32 0.333 0.1 (3) 64 0.02 :: 0.0005 (2) 33 0.027 0.008 (3) 65 0.02 :: 0.008 (2) 34 0.079 0.031 (2) 66 0.011 :: 0.003 (2) 1.8 0.3 (2) 67 0.015 :: 0.006 (2) 36 WA 68 0.026 :: 0.004 (2) 37 >10 0(2) 69 0.03 :: 0.012 (3) 38 0 39 71 0 008 _- 0 002(2) 40 72 0.036 0.009 (2) 41 73 0.016 .005 (2) 42 74 : 0.255 (2) 0.18 :: 0.04 (2) 43 75 : 0.474 (4) 0.038 :: 0.018(2) 44 76 : 0.012 (4) 0.024 0.003 (2) 45 77 : 0.034 (2) 0.15::0(2) 46 78 : 0.038 (4) 0.094 :: 0.006 (2) 47 7 : 0.029 (4) 0.02 :: 0.005 (2) 48 0.605 :: 0.215(2) 80 0.055 0 015(2) 86 0.026 0.008 (2) 111 0.006 0.002 (4) 87 0.087 0.033 (2) 112 0.068 0.011 (2) 88 2.95 0.15 (2) 113 0.015 0.011 (3) 89 0.455 0.095 (2) 114 0.001 0.001 (4) 90 0.083 0.003 (2) 1 15 0.004 0.0006 (2) 91 1 16 0.03 :_0013 (3). 92 1 94 1 19 0.0006 __ 0.0002 (3)- 95 1 20 0 003. 0 002 (2) 96 0.02 0.009 (2) 1 21 0.006 : 0.0008 (2) 97 0.11 0.02 (2) 122 0.0006 0.0003 (2) 98 0.016 0.007 (3) 123 0.001 0.0005 (2) 99 0.038 0.008 (2) 124 0.65 0.55 (2) 100 0.155 0.025 (2) 125 0.011 0.011 (4) 101 1.185 :0.215(2) 126 0.008 0 (2) N/A = not ble Competitive Binding Assay The first 177 amino acids of the FimH protein can be sed as a fusion protein with thrombin in a pET21b plasmid in bacteria. This FimH protein sequence contains the carbohydrate recognition domain (CRD) and shall be termed FimH-CRD. Following bacterial sion of the protein, the FimH-CRD protein is purified to homogeneity and the thrombin tag removed by protease cleavage. A competitive binding assay by fluorescence WO 65107 polarization is performed using 5 nM of the Alexa 647 mannoside probe and 60 nM of the FimH-CRD. The samples are assayed in a low volume 384 well microtiter plate in a final volume of 20 ul. The final assay buffer conditions are the following, 50 mM Tris-Cl, ph 7.0, 100 mM NaCl, 1 mM EDTA, 5 mM B-mercaptoethanol, 0.05 % BSA and 2.5% DMSO. Two assays are performed for FimH, termed assay 1 or assay 2. The assay ions are the same for both assays except the ing: assay 1 has compounds prepared by manual dilution in a serial dilution factor with 12—point dose response while assay 2 has nds ed by a robotics system also through a serial dilution factor (12 point dose response) and initially prepared in duplicate in 384 well-Corning opylene round bottom plates. The assay 2 plates have compound which is then frozen and must be thawed prior to use. Initially the Alexa 647 probe and the FimH-CRD are added to the assay buffer and then 0.5 ul of test compound (assay 1 or 2) between 0.4 nM to 75 uM final concentration are added (12 point titration with 3-fold serial dilution). Control wells for the Alexa 647 probe are prepared with the same conditions except for the addition of the RD protein. Plates are then incubated for 5 hrs at room temperature in the dark and under humid conditions to prevent drying. Plates are read using the SpectraMax Paradigm multi-mode plate reader and the appropriate fluorescent polarization detection dge (Alexa-647).

Alexa 647 mannoside probe is prepared using the similar procedure reported for FAM mannoside (Han, Z. et. al., 2010, J. Med. Chem., 53, 4779) and is described in the scheme below.

Alexa647 mannoside To a blue colored stirred solution of (2S,3S,4S,5S,6R)—2—(4-aminobutoxy)—6— (hydroxymethyl)tetrahydropyran-3,4,5-triol (2.21 mg, 0.009 mmol) and the (2E)[(2E,4E)- —[3 ,3 -dimethylsulfonato(3 -sulfonatopropyl)indoliumyl]penta-2,4-dienylidene]-3 - [6-(2,5-dioxopyrrolidinyl)oxyoxo-hexyl]—3 -methyl(3 -sulfonatopropyl)indoline-5 - sulfonate (Potassium Ion (3)) (4.9 mg, 0.0044 mmol) in DMF (44 uL) is added Et3N (5.4 mg, 7.0 "L, 0.053 mmol) at RT. The solution is stirred at room temperature over night, concentrated, dissolved in water and purified on 12 g C-18 silica gel cartridge on Isolera system using acetonitrile in water (0 to 40%, 10 CV) and followed by lization to afford Alexa 647 mannoside probe (3.3 mg, 34%) as deep blue solid.

The Kd values of the compounds are determined from dose response curves using twelve trations per compound in duplicate. Curves are fitted to data points using Fluorescence Polarization competitive displacement analysis, and de are interpolated from the resulting curves using GraphPad Prism software, version 50.4 (GraphPad software Inc., San Diego, CA, USA).

Mouse Feces Stability Assay The mouse feces ity assay can be used to measure the stability of FimH antagonists in an environment that mimics the gut. Fresh mouse feces samples from a number of animals (at least 4) are homogenized with 10 volumes (w/v) of 100 mM potassium phosphate buffer (pH 6.5) using a her device. The feces mixture is then centrifuged 5 min at 2000g and the supernatant is ted for incubation. Compounds to be tested are spiked at 100 uM in the feces supernatant and incubated at 370 C up to 6 hours. The enzymatic reaction is stopped by adding 9 volumes of itrile containing 0.1% formic acid and an internal standard. The mixture is centrifuged and the supematants are analyzed by HPLC-MS/MS to assess percentage of parent remaining relative to a control sample. The compounds of the present invention are unexpectedly and surprisingly stable compared to similar compounds where the mannose moiety is not ed (& Compound A).

In vitro mice feces Compound ure stability - % Parent remaining at 6h Human Feces Stability Assay The human feces stability assay ca be used to measure the stability of FimH antagonists in an environment that mimics the gut. Fresh human feces samples from 3 donors are homogenized with 10 volumes (W/v) of 100 mM ium phosphate buffer (pH 6.5) using a Stomacher device. The feces mixture is then centrifuged 5 min at 2000g and supernatant is collected for incubations. nds to be tested are spiked at 100 uM in feces supernatant and incubated at 370 C up to 24 hours. The enzymatic reaction is stopped by adding 9 volumes of acetonitrile ning 0.1% formic acid and internal standard. The mixture is fuged and the supernatants are analysed by HPLC—MS/MS to assess percentage of parent remaining ve to a control sample. The compounds of the present invention are unexpectedly and surprisingly stable compared to similar compounds Where the mannose moiety is not modified (see Compound A). 2014/024411 In vitro human feces compound Structure stability - % Parent remainin - at 24h Mouse Excretion Study Following FimH Antagonist Oral Dosing Mice are dosed 10 mg/kg orally (10 mL/kg; 0.5% methocel) with FimH antagonists and urine and feces are collected on ice up to 72h in excretion cages. ollection, feces samples are diluted with 10 volumes of water and homogenized using a Stomacher device.

Feces mixture and urine samples are then quenched with itrile containing an internal standard, centrifuged, and the supernatants are then diluted with 1 volume of water prior to analysis by HPLC-MS/MS in SRM mode. The compounds of the present ion are unexpectedly and surprisingly stable compared to similar compounds where the mannose moiety is not modified (see Compound A).

% Oral dose % Oral dose Compound Structure red recovered Number intact in mice intact in mice feces urine While we have described a number of embodiments of this invention, it is apparent that our basic examples may be altered to provide other embodiments that utilize the compounds, methods, and processes of this ion. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments that have been represented by way of example herein.

Claims (32)

1. A compound of Formula I 5 or a pharmaceutically acceptable salt thereof, wherein each M and M2 is independently or , wherein: Y1 is -O-, -O(C1-C4 aliphatic)-, -O(haloC1-C4 aliphatic)-, -S-, -S(C1-C4 aliphatic)-, -S(O)p-, 10 (C1-C4 aliphatic)-, or -(C1-C6)aliphatic; Y2 is -O(C1-C4 aliphatic)-, oC1-C4 aliphatic)-, -S(C1-C4 aliphatic)-, -SO2(C1-C4 aliphatic)-, or -(C1-C6) aliphatic; X1 is methyl or -U1-V1; X1 is optionally substituted with 1-4 occurrences of halo; U1 is -(CH2)q- or ; 15 V1 is a C1-C10 aliphatic wherein up to four methylene units can be optionally replaced with -O-, -NR2-, -S-, -C(O)-, -S(O)-, -S(O)2-, or P(O); X2 is H, C1-C10 aliphatic, -U2-V2, or -U2-V2-Q; U2 is -(CH2)q- or -C(O)-; V2 is a C1-C10 aliphatic wherein up to four methylene units can be optionally ed 20 with -O-, -NR2-, -S-, -C(O)-, -S(O)-, -, or P(O); Q is a 3-8 ed saturated, partially unsaturated, or ic ring having 0-4 heteratoms selected from oxygen, nitrogen, or sulfur; wherein X2 is optionally substituted with 1-4 occurrences of halo, CN, NO2, or C1-C10aliphatic wherein up to three methylene units of the C1-C10aliphatic can be 25 optionally ed with -NR-, -O-, -S-, -C(O)-, or -S(O)-, or –S(O)2-; each X3, X4, X5, and X6 is independently H or C1-3alkyl; ed that only one of X2, X3, X4, X5, and X6 is not H; Ring A is C3-C10 cycloalkyl, 3-12 membered cyclyl, C6-10 aryl, or 5-14 ed heteroaryl; wherein the heterocyclyl or heteroaryl independently has 1-6 heteroatoms selected from oxygen, nitrogen, or sulfur; 5 Ring A2 is optionally absent, C3-C10 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, or 5-14 membered heteroaryl; Z is –CH=CH-, -C C-, or Ring B substituted by (JB)n; Ring B is C3-C10 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, or 5-14 membered heteroaryl; wherein said heterocyclyl or heteroaryl independently has 1-6 heteroatoms 10 ed from oxygen, en, or sulfur; each JA, JA2, and JB is independently halogen, CN, NO2, oxo, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, (C6-10 (C1-C6alkyl)-, (5-10 membered heteroaryl)-(C1-C6alkyl)-, (C3-8 cycloalkyl)-(C1-C6alkyl)-, (3-8 membered cyclyl)-(C1-C6alkyl)-, or a C1-C12 aliphatic; wherein up to four methylene units of 15 the C1-C12 aliphatic or up to three methylene units of the C1-C6alkyl can be optionally replaced with -NR, -O, -S-, -C(O)-, -S(O)-, -, or P(O); each JA, JA2, and JB is independently and optionally substituted with 1-5 occurrences of halo, CN, NO2, or C1- C10aliphatic wherein up to three methylene units of the C1-C10aliphatic can be optionally replaced with -NR-, -O-, -S-, -C(O)-, or -S(O)-, or –S(O)2-; 20 R and R2 are each independently H, C1-C6 aliphatic, or C3-6cycloalkyl; each m, n, and u is independently 0, 1, 2, 3, or 4; each t and r is independently 0 or 1; and each p and q is independently 1 or 2.

2. The compound of claim 1, wherein Ring A2 is absent; r is 0; t is 1; and Z is Ring B as 25 shown in Formula Ia:

3. The compound of claim 2, as represented in Formula II: Formula II.

4. The compound of claim 3, wherein JA is halo, haloC1-4aliphatic, C1-4aliphatic, -O(C1-4aliphatic); and JB is NO2, C(O)N(R)2, C(O)OR, or CH2)2-O-(CH2)2-O-(CH2)2-NH2.

5. The compound of claim 1, wherein M is and Y2 is -O-.

6. The compound of claim 1, n X1 is methyl.

7. The compound of any one of claims 1-4, as represented by formula A: 10 Formula A wherein Y1 is -O-, -O(C1-C4alkyl)-, -S-, -S(C1-C4alkyl)-, -S(O)p-, -SO p (C1-C4alkyl)-, or -(C1-C6)aliphatic; X2 is H, C1-C10 aliphatic, -U2-V2, or -U2-V2-Q; 15 U2 is -(CH2)q- or -C(O)-; V2 is a C1-C10 aliphatic n up to four methylene units can be optionally replaced with -O-, -NR2-, -S-, -C(O)-, -S(O)-, -S(O)2-, or P(O); Q is a 3-8 membered saturated, lly unsaturated, or aromatic ring having 0-4 heteratoms selected from , en, or sulfur; 20 wherein X2 is optionally substituted with 1-4 occurrences of halo, CN, NO2, or C1-C10aliphatic wherein up to three methylene units of the C1-C10aliphatic can be optionally replaced with -NR-, -O-, -S-, -C(O)-, or -S(O)-, or –S(O)2-; R2 is H, C1-C6 aliphatic, or C3-6cycloalkyl; each X3, X4, and X6 is independently H or C1-3alkyl; X5 is H; provided that only one of X2, X3, X4, and X6 is not H; Ring A is C3-C10 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, or 5-14 membered heteroaryl; wherein the heterocyclyl or aryl independently has 1-6 heteroatoms 5 selected from oxygen, nitrogen, or sulfur; Ring A is optionally bonded to Ring B; Ring B is absent, C3-C10 cycloalkyl, 3-12 membered cyclyl, C6-10 aryl, or 5-14 membered heteroaryl; wherein said heterocyclyl or heteroaryl ndently has 1-6 heteroatoms selected from oxygen, nitrogen, or sulfur; each JA and JB is independently n, CN, NO2, C3-8 cycloalkyl, 3-8 membered 10 heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, (C6-10 aryl)-(C1-C6alkyl)-, (5-10 membered heteroaryl)-(C1-C6alkyl)-, or a C1-C12 aliphatic wherein up to four methylene units of the C1-C12 aliphatic can be optionally replaced with –NR, -O-, -S-, , -S(O)-, -SO2-, or P(O); each JA and JB is independently and optionally substituted with 1-5 occurrences of halo, CN, or NO2; 15 R is H, C1-C6 aliphatic, C3-6cycloalkyl; each m and n is independently 0, 1, 2, 3, or 4; each p and q is ndently 1 or 2.

8. The compound of any one of claims 1-4, as represented by formula B: 20 Formula B wherein Y2 is -O(C1-C4alkyl)-, -S(C1-C4alkyl)-, -S(O)-, -SO2(C1-C4alkyl)-, or 6)alkyl; X1 is methyl or -U1-V1; X1 is optionally substituted with 1-4 occurrences of halo; U1 is -(CH2)q- or -C(O)-; 25 V1 is a C1-C10 aliphatic wherein up to four methylene units can be optionally replaced with -O-, -NR2-, -S-, -C(O)-, -S(O)-, -S(O)2-, or P(O); R2 is H, C1-C6 aliphatic, or C3-6cycloalkyl; Ring A is C3-C10 lkyl, 3-12 membered heterocyclyl, C6-10 aryl, or 5-14 ed heteroaryl; wherein the heterocyclyl or heteroaryl independently has 1-6 heteroatoms selected from oxygen, nitrogen, or sulfur; Ring A is optionally bonded to Ring B; Ring B is absent, C3-C10 cycloalkyl, 3-12 membered heterocyclyl, C6-10 aryl, or 5-14 5 membered aryl; wherein said heterocyclyl or heteroaryl independently has 1-6 heteroatoms ed from oxygen, nitrogen, or sulfur; each JA and JB is independently halogen, CN, NO2, C3-8 cycloalkyl, 3-8 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, (C6-10 aryl)-(C1-C6alkyl)-, (5-10 membered heteroaryl)-(C1-C6alkyl)-, or a C1-C12 tic wherein up to four ene 10 units of the C1-C10 aliphatic can be optionally replaced with -NR, -O-, -S-, -C(O)-, -S(O)-, -SO2-, or P(O); each JA and JB is independently and optionally substituted with 1-5 occurrences of halo, CN, or NO2; R is H, C1-C6 aliphatic or C3-6cycloalkyl; each m and n is independently 0, 1, 2, 3, or 4; 15 each p and q is independently 1 or 2.

9. The compound of claim 1, as represented by formula III: Formula III. 20

10. The compound of claim 1, wherein M is and M2 is

11. The nd of claim 10, wherein Y1 is O and X2 is methyl.

12. The compound of any one of claims 9-11, wherein t is 1 and Z is phenyl or pyridyl.

13. The compound of any one of claims 9-11, n t is 0. 5

14. The compound of any one of claims 9-11, wherein Ring A and Ring A2 are phenyl.

15. The nd of claim 1, as represented by formula E: Formula E.

16. The compound of claim 15, wherein Ring A and Ring A2 are phenyl. 10

17. The compound of claim 15 or 16 wherein X2 is methyl.

18. The compound of any one of claims 15-17, wherein JA and JA2 are each independently CN, methyl, ethyl, isopropyl, fluoro, chloro, OCH3, or OCF3.

19. The compound of claim 1, as represented by formula F: Formula F.

20. The compound of claim 19, wherein Ring A and Ring A2 are phenyl.

21. The compound of claim 0, wherein Ring B is C3-6cycloalkyl, phenyl, or pyridyl. 5

22. The compound of any one of claims 19 to 21, wherein JA and JA2 are each independently CN, halo, C1-6alkyl, wherein up to one methylene unit of said C1-6alkyl is optionally replaced with O, S, NH, N(C1-6alkyl), C(O), S(O), or S(O)2 tuted with 1-3 occurrences of halo.

23. The compound of claim 22, wherein JA and JA2 are each independently methyl; m is 1; 10 and u is 1.

24. The compound of claim 1, as represented by formula G: H OH OH HO H H X2 (JA)m X2 H (JA2)u H H OH HO H Formula G.

25. The compound of claim 24, wherein X2 is methyl; Ring A and Ring A2 are phenyl; JA and JB are each independently methyl; m is 1; and u is 1.

26. The compound of claim 1, wherein the compound is selected from one of the 5 ing: Compound No. Structure O O 25 HO O HO OH N HO Me H O O HO O 49 OH Me HO N OH O O O 87 Me Me O O 96 Me Cl

27. A composition comprising the compound of any one of claims 1-26 or a ceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

28. Use of an effective amount of the compound of any one of claims 1-26 or a 5 pharmaceutically acceptable salt thereof, or the composition of claim 27 in the cture of a medicament for treating or preventing a bacteria infection in a subject.

29. The use of claim 28, wherein the bacteria infection is urinary tract ion or inflammatory bowel disease.

30. The use of claim 29, wherein the bacteria infection is colitis. 10

31. The use of claim 29, wherein the bacteria infection is Crohn’s disease.

32. The compound of claim 1, substantially as herein bed with reference to any one of the Examples thereof.