Inhibitors of Hexokinase and Methods of Use Thereof Related Applications This application claims the benefit of priority to U.S. Provisional Patent Application No.62/358,371, filed July 5, 2016, which application is hereby incorporated by reference in its entirety. Background The Warburg Effect is a biochemical phenotype of certain types of malignant tumors. The effect, observed by Otto Warburg in the 1920s, describes the tendency of such tumors to metabolize glucose to lactic acid even when oxygen is present. Over expression of hexokinase II (HKII) is a general feature of tumors that exhibit the Warburg Effect, and is believed to play an important role in how these tumors survive and spread aggressively to surrounding tissue.

Inhibition of HKII provides a promising avenue for targeting such tumors by killing the cancer cells or by interrupting the pathway by which the cells metabolize glucose to obtain ATP. By interrupting the cells’ metabolism, HKII inhibition either blocks tumor growth, kills the cells, or may render the cells more susceptible to other attacks, such as natural attacks (e.g., natural human immune responses against the tumor) or treatment- based attacks (e.g., radiation therapy, administration of chemotherapeutic agents, etc.). At least one small-molecule HKII inhibitor has shown promise as an antitumor agent: In preclinical studies, 3-bromopyruvate, a small-molecule HKII inhibitor, has shown some efficacy at targeting and destroying certain tumor cells. Therefore, inhibition of HKII may serve as a promising means of treating certain types of aggressive cancers in humans or other mammals.

There is therefore a continuing need to discover and develop new chemical entities that inhibit HKII and that may be useful as antitumor agents for administration to humans or other mammals. Summary of Invention In certain embodiments, the invention relates to compounds having the structure of Formula (I): (I),

and pharmaceutically acceptable salts thereof, wherein R ¹ -R ⁶ , R ^8a , R ^8b , R ^9a , R ^9b , Z, X ¹ , and R ^a are as defined in the specification.

In some embodiments, the invention relates to pharmaceutical compositions of a compound of Formula (I), and a pharmaceutically acceptable carrier.

The invention also relates to methods of treating cancer, comprising administering to a subject a compound of the invention.

The invention further relates to methods of inhibiting proliferation of a cancer cell comprising contacting a cancer cell with a compound of the invention.

The invention also provides methods of inhibiting hexokinase activity in a cell, comprising contacting a cell with a compound of the invention. Brief Description of the Drawings Figure 1 is a graft showing the effect of a hexokinase inhibitor of the invention in an A549 lung xenograft in a mouse model. Detailed Description of the Invention In certain aspects, the invention provides substituted heterocycles and

pharmaceutical compositions thereof, which can be used as antitumor agents, antifungal agents, or as anti-angiogenesis inhibitors. In particular, such substituted compounds are useful as HKII inhibitors. I. COMPOUNDS

In certain embodiments, the invention relates to compounds having the structure of Formula (I), or a pharmaceutically acceptable salt thereof: wherein:

R ¹ represents -G ¹ -OH, -G ¹ -O-R ¹³ , -G ¹ -NH ₂ , -G ¹ -NH-R ¹³ , or -G ¹ -NR ¹³ R ¹⁴ , alkyl, - (alkylene)-OH, -(alkylene)-O-R ¹¹ , -(alkylene)-SH, -(alkylene)-S-R ¹¹ , -(alkylene)- S(O)R ¹¹ , -(alkylene)-SO2-R ¹¹ , -(alkylene)-NH2, -(alkylene)-NH-R ¹¹ , -(alkylene)- NR ¹¹ R ¹² , -C(O)-R ¹¹ , -(alkylene)-C(O)-R ¹¹ , -CO ₂ H, -(alkylene)-CO ₂ H, -C(O)-O- R ¹¹ , -(alkylene)-C(O)-O-R ¹¹ , -(alkylene)-O-C(O)-R ¹¹ , -C(O)-NH2, -(alkylene)- C(O)-NH2, -C(O)-NH-R ¹¹ , -(alkylene)-C(O)-NH-R ¹¹ , -C(O)-NR ¹¹ R ¹² , - (alkylene)NR ¹¹ R ¹² , -(alkylene)-NH-C(O)-R ¹¹ , -(alkylene)-N(R ¹² )-C(O)-R ¹¹ , - (alkylene)-NH-C(O)-NH2, -(alkylene)-NH-C(O)-NHR ¹¹ , -(alkylene)-NH-C(O)- NR ¹¹ R ¹² , -(alkylene)-N(R ¹² )-C(O)-NH2, -(alkylene)-N(R ¹² )-C(O)-NHR ¹¹ , - (alkylene)-N(R ¹² )-C(O)-NR ¹¹ R ¹² , -(alkylene)-SO ₂ -NH ₂ , -(alkylene)-SO ₂ -NH-R ¹¹ , - (alkylene)-SO ₂ -NR ¹¹ R ¹² , -(alkylene)-NH-SO ₂ -R ¹¹ , or -(alkylene)-N(R ¹² )-SO ₂ -R ¹¹ , where the alkyl, and alkylene groups are optionally substituted;

R ² represents -OH, -O-R ²¹ , -NH2, -NH-R ²¹ , -NR ²¹ R ²² , -O-C(O)-R ²¹ , -NH-C(O)-R ²¹ , - N(R ²² )-C(O)-R ²¹ , -NH-C(O)-O-R ²¹ , -N(R ²² )-C(O)-O-R ²¹ , -NH-C(O)-NH ₂ , -NH- C(O)-NHR ²¹ , -NH-C(O)-NR ²¹ R ²² , -N(R ²² )-C(O)-NH2, -N(R ²² )-C(O)-NHR ²¹ , - N(R ²² )-C(O)-NR ²¹ R ²² , -NH-SO2-R ²¹ , or -N(R ²² )-SO2-R ²¹ ;

or R ¹ and R ² , together with the intervening atoms, form an optionally substituted cycloalkyl or heterocycloalkyl ring;

R ³ represents -OH or -O-R ³¹ ;

R ⁴ represents -OH or -O-R ⁴¹ ;

R ⁵ represents -G ⁵ -OH, -G ⁵ -O-R ⁵¹ , -G ⁵ -NH ₂ , -G ⁵ -NH-R ⁵¹ , or -G ⁵ -NR ⁵¹ R ⁵² ;

G ¹ and G ⁵ each independently represent -CR ^b R ^c -,-C(O)-, or a bond;

Z represents O, C(O), or C(R ^Z1 )(R ^Z2 );

X ¹ represents N or C-R ⁷ ;

R ⁶ represents hydrogen or optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl,

(cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, (cycloalkyl)alkoxy, heterocyclylalkoxy, (heterocyclyl)alkoxy, aryloxy, arylalkoxy, heteroaryloxy, or heteroarylalkoxy;

R ⁷ represents hydrogen or lower alkyl;

R ^8a and R ^8b independently are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,

(cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R ⁸¹ , -SH, -S-R ⁸¹ , -S(O)R ⁸¹ , -SO ₂ -R ⁸¹ , -NH ₂ , -NH-R ⁸¹ , - NR ⁸¹ R ⁸² , -C(O)-R ⁸¹ , -CO2H, -C(O)-O-R ⁸¹ , -O-C(O)-R ⁸¹ , -O-(alkylene)-C(O)-R ⁸¹ , - O-(alkylene)-C(O)-OR ⁸¹ , -C(O)-NH2, -C(O)-NH-R ⁸¹ , -C(O)-NR ⁸¹ R ⁸² , -NH-C(O)- R ⁸¹ , -N(R ⁸² )-C(O)-R ⁸¹ , -NH-C(O)-NH ₂ , -NH-C(O)-NHR ⁸¹ , -NH-C(O)-NR ⁸¹ R ⁸² , - N(R ⁸² )-C(O)-NH2, -N(R ⁸² )-C(O)-NHR ⁸¹ , -N(R ⁸² )-C(O)-NR ⁸¹ R ⁸² , -O-C(O)-NR ⁸¹ R ⁸² , -O-C(O)-NH-R ⁸¹ , -O-C(O)-NH2, -NH-C(O)-OR ⁸¹ , -N(R ⁸² )-C(O)-OR ⁸¹ , -NH- (alkylene)-C(O)-R ⁸¹ , -N(R ⁸² )-(alkylene)-C(O)-R ⁸¹ , -NH-(alkylene)-C(O)-NH ₂ , -NH- (alkylene)-C(O)-NHR ⁸¹ , -NH-(alkylene)-C(O)-NR ⁸¹ R ⁸² , -N(R ⁸² )-(alkylene)-C(O)- NH2, -N(R ⁸² )-(alkylene)-C(O)-NHR ⁸¹ , -N(R ⁸² )-(alkylene)-C(O)-NR ⁸¹ R ⁸² , -O- (alkylene)-C(O)-NR ⁸¹ R ⁸² , -O-(alkylene)-C(O)-NH-R ⁸¹ , -O-(alkylene)-C(O)-NH ₂ , - NH-(alkylene)-C(O)-OR ⁸¹ , -N(R ⁸² )-(alkylene)-C(O)-OR ⁸¹ , -SO ₂ -NH ₂ , -SO ₂ -NH- R ⁸¹ , -SO2-NR ⁸¹ R ⁸² , -NH-SO2-R ⁸¹ , -N(R ⁸² )-SO2-R ⁸¹ , -C(S)-NH2, -C(S)-NH-R ⁸¹ , - C(S)-NR ⁸¹ R ⁸² , -NH-C(S)-R ⁸¹ , -N(R ⁸² )-C(S)-R ⁸¹ , -NH-C(S)-NH2, -NH-C(S)-NHR ⁸¹ , -NH-C(S)-NR ⁸¹ R ⁸² , -N(R ⁸² )-C(S)-NH ₂ , -N(R ⁸² )-C(S)-NHR ⁸¹ , -N(R ⁸² )-C(S)- NR ⁸¹ R ⁸² , halogen, -NO2, or cyano, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted;

R ^9a and R ^9b independently are hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl,

(cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R ⁹¹ , -SH, -S-R ⁹¹ , -S(O)R ⁹¹ , -SO ₂ -R ⁹¹ , -NH ₂ , -NH-R ⁹¹ , - NR ⁹¹ R ⁹² , -C(O)-R ⁹¹ , -CO ₂ H, -C(O)-O-R ⁹¹ , -O-C(O)-R ⁹¹ , -O-(alkylene)-C(O)-R ⁹¹ , - O-(alkylene)-C(O)-OR ⁹¹ , -C(O)-NH2, -C(O)-NH-R ⁹¹ , -C(O)-NR ⁹¹ R ⁹² , -NH-C(O)- R ⁹¹ , -N(R ⁹² )-C(O)-R ⁹¹ , -NH-C(O)-NH2, -NH-C(O)-NHR ⁹¹ , -NH-C(O)-NR ⁹¹ R ⁹² , - N(R ⁹² )-C(O)-NH ₂ , -N(R ⁹² )-C(O)-NHR ⁹¹ , -N(R ⁹² )-C(O)-NR ⁹¹ R ⁹² , -O-C(O)-NR ⁹¹ R ⁹² , -O-C(O)-NH-R ⁹¹ , -O-C(O)-NH2, -NH-C(O)-OR ⁹¹ , -N(R ⁹² )-C(O)-OR ⁹¹ , -NH- (alkylene)-C(O)-R ⁹¹ , -N(R ⁹² )-(alkylene)-C(O)-R ⁹¹ , -NH-(alkylene)-C(O)-NH2, -NH- (alkylene)-C(O)-NHR ⁹¹ , -NH-(alkylene)-C(O)-NR ⁹¹ R ⁹² , -N(R ⁹² )-(alkylene)-C(O)- NH2, -N(R ⁹² )-(alkylene)-C(O)-NHR ⁹¹ , -N(R ⁹² )-(alkylene)-C(O)-NR ⁹¹ R ⁹² , -O- (alkylene)-C(O)-NR ⁹¹ R ⁹² , -O-(alkylene)-C(O)-NH-R ⁹¹ , -O-(alkylene)-C(O)-NH2, - NH-(alkylene)-C(O)-OR ⁹¹ , -N(R ⁹² )-(alkylene)-C(O)-OR ⁹¹ , -SO ₂ -NH ₂ , -SO ₂ -NH- R ⁹¹ , -SO ₂ -NR ⁹¹ R ⁹² , -NH-SO ₂ -R ⁹¹ , -N(R ⁹² )-SO ₂ -R ⁹¹ , -C(S)-NH ₂ , -C(S)-NH-R ⁹¹ , - C(S)-NR ⁹¹ R ⁹² , -NH-C(S)-R ⁹¹ , -N(R ⁹² )-C(S)-R ⁹¹ , -NH-C(S)-NH2, -NH-C(S)-NHR ⁹¹ , -NH-C(S)-NR ⁹¹ R ⁹² , -N(R ⁹² )-C(S)-NH ₂ , -N(R ⁹² )-C(S)-NHR ⁹¹ , -N(R ⁹² )-C(S)- NR ⁹¹ R ⁹² , halogen, -NO ₂ , or cyano, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted;

R ¹¹ , R ¹² , R ²¹ , R ²² , R ⁸¹ , R ⁸² , R ⁹¹ , and R ⁹² are each independently selected from substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl;

or any of R ¹¹ and R ¹² , R ²¹ and R ²² , R ⁸¹ and R ⁸² , or R ⁹¹ and R ⁹² , together with the nitrogen atom to which they are attached when attached to the same nitrogen atom, are optionally taken together to form an optionally substituted heterocyclic ring;

R ¹³ , R ¹⁴ , R ³¹ , R ³² , R ⁴¹ , R ⁴² , R ⁵¹ , and R ⁵² are each independently selected from alkyl,

alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, -C(O)-R ¹⁰³ , -C(O)-OH, -C(O)-O-R ¹⁰³ , -C(O)-NH2, -C(O)-N(H)-R ¹⁰³ , -C(O)-NR ¹⁰³ R ¹⁰⁴ , and -SO2-R ¹⁰³ , where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, and aralkyl groups are optionally substituted; and

R ¹⁰³ and R ¹⁰⁴ independently for each occurrence represent substituted or unsubstituted

alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl;

or R ¹⁰³ and R ¹⁰⁴ , together with the nitrogen atom to which they are attached when attached to the same nitrogen atom, are optionally taken together to form an optionally substituted heterocyclic ring;

R ^a represents hydrogen, alkyl, alkoxyalkyl, acyloxyalkyl, -C(O)-O-R ¹⁰⁵ , or -C(O)-R ¹⁰⁵ ; R ¹⁰⁵ represents substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,

aralkyl, heteroaryl, or heteroaralkyl;

R ^b and R ^c are each independently for each occurrence selected from H, alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, heteroaralkyl, alkenyl, and alkynyl;

or R ^b and R ^c , together with the carbon atom to which they are attached, optionally form a C ₃ -C ₆ cycloalkyl; and R ^Z1 and R ^Z2 each independently represent hydrogen, hydroxyl, alkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, hydroxyalkyl, haloalkyl, alkoxy, or haloalkoxy. In certain embodiments, X ¹ represents N or CH. In certain preferred such embodiments, X ¹ represents CH, while in alternative embodiments, X ¹ represents N. In yet other embodiments, X ¹ represents CR ⁷ , wherein R ⁷ represents hydrogen or lower alkyl, such as C ₁ -C ₆ alkyl.

In certain embodiments, X ¹ is CR ⁷ , wherein R ⁷ represents lower alkyl, e.g., methyl, ethyl, or isopropyl.

Substituent R ^a may represent a masking moiety, e.g., in prodrug embodiments of the compound of Formula (I) or (Ia). In certain embodiments, R ^a represents H or alkyl. In certain such embodiments, R ^a represents H, while in alternative embodiments, R ^a represents hydrogen, alkyl, alkoxyalkyl, acyloxyalkyl, -C(O)-O-R ¹⁰⁵ , or -C(O)-R ¹⁰⁵ , wherein:

R ¹⁰⁵ represents substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,

aralkyl, heteroaryl, or heteroaralkyl.

In certain embodiments, R ^a represents methyl, ethyl, isopropyl, propyl, or butyl. Alternatively, R ^a may be hydrogen.

In certain embodiments, Z represents O.

In certain embodiments, R ¹ represents alkyl, for example, methyl or ethyl. In certain embodiments, R ¹ represents substituted alkyl, such as haloalkyl or hydroxyalkyl. For example, R ¹ may represent hydroxymethyl, fluoromethyl, difluoromethyl, or trifluoromethyl.

In certain embodiments, R ¹ represents -G ¹ -OH, -G ¹ -O-R ¹³ , -G ¹ -NH ₂ , -G ¹ -NH-R ¹³ , - G ¹ -NR ¹³ R ¹⁴ , -(alkylene)-OH, -(alkylene)-O-R ¹¹ , -(alkylene)-NH ₂ , -(alkylene)-NH-R ¹¹ , - (alkylene)-NR ¹¹ R ¹² , -CO2H, -(alkylene)-CO2H, -C(O)-O-R ¹¹ , -(alkylene)-C(O)-O-R ¹¹ , - (alkylene)-O-C(O)-R ¹¹ , -C(O)-NH ₂ , -(alkylene)-C(O)-NH ₂ , -C(O)-NH-R ¹¹ , -(alkylene)- C(O)-NH-R ¹¹ , -C(O)-NR ¹¹ R ¹² , -(alkylene)NR ¹¹ R ¹² , -(alkylene)-NH-C(O)-R ¹¹ , or - (alkylene)-N(R ¹² )-C(O)-R ¹¹ . In certain such embodiments, R ¹ represents -G ¹ -OH, -G ¹ -O- R ¹³ , -G ¹ -NH2, -G ¹ -NH-R ¹³ , -G ¹ -NR ¹³ R ¹⁴ , -(alkylene)-CO2H, -(alkylene)-C(O)-O-R ¹¹ , or - (alkylene)-C(O)-NH ₂ , such as -G ¹ -OH, -G ¹ -O-R ¹³ , -G ¹ -NH ₂ , -G ¹ -NH-R ¹³ , or -G ¹ -NR ¹³ R ¹⁴ , e.g., -G ¹ -OH or -G ¹ -O-R ¹³ .

In certain of the foregoing embodiments, G ¹ represents -CH2-. In certain embodiments, R ¹ represents -(alkylene)-OH, or -(alkylene)-O-R ¹¹ . In certain such embodiments, the alkylene group is substituted one or more times with a substituent independently selected from fluoro and chloro. In other certain such embodiments, R ¹¹ is C _1-6 alkyl optionally substituted with one or more substituents independently selected from fluoro and chloro. In certain preferred embodiments, R ¹ represents -CH ₂ OH.

In certain embodiments of R ¹ as described above, the alkylene group is -CH ₂ - or– In certain embodiments, at least one of R ⁶ , R ^8a , R ^8b , R ^9a , and R ^9b is not hydrogen. In certain embodiments, R ³ represents -OH or -O-R ³¹ . In certain preferred embodiments, R ³ represents -OH.

In certain embodiments, R ³ represents -O-R ³¹ , wherein R ³¹ is C1-6 alkyl optionally substituted one or more times with substituents independently selected from halogen, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino ethylamino, dimethylamino, trifluoromethyl, and trifluoromethoxy.

In alternative embodiments, R ³ represents -O-R ³¹ , wherein R ³¹ is selected from - C(O)-R ¹⁰³ , -C(O)-O-R ¹⁰³ , -C(O)-N(H)-R ¹⁰³ , -C(O)-NR ¹⁰³ R ¹⁰⁴ , and -SO ₂ -R ¹⁰³ . In certain preferred embodiments, R ³¹ is -C(O)-R ¹⁰³ . In certain such embodiments, R ¹⁰³ is preferably substituted or unsubstituted alkyl, e.g., methyl, ethyl, or isopropyl.

In certain embodiments, R ⁴ represents -OH or -O-R ⁴¹ .

In certain embodiments, R ⁴ represents -O-R ⁴¹ , wherein R ⁴¹ is C1-6 alkyl optionally substituted one or more times with substituents selected independently from halogen, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino ethylamino, dimethylamino, trifluoromethyl, and trifluoromethoxy.

In certain embodiments, R ⁴ represents -O-R ⁴¹ , wherein R ⁴¹ is selected from -C(O)- R ¹⁰³ , -C(O)-O-R ¹⁰³ , -C(O)-N(H)-R ¹⁰³ , -C(O)-NR ¹⁰³ R ¹⁰⁴ , and -SO ₂ -R ¹⁰³ , preferably -C(O)- R ¹⁰³ . R ¹⁰³ is preferably substituted or unsubstituted alkyl, e.g., methyl, ethyl, or isopropyl.

In certain preferred embodiments R ⁴ represents -OH.

In certain preferred embodiments, R ³ represents -O-R ³¹ and R ⁴ represents -O-R ⁴¹ , and R ³¹ and R ⁴¹ are both -C(O)-R ¹⁰³ . Alternatively, R ³ and R ⁴ may both be -OH.

In certain embodiments of the compound of Formula (I) or (Ia), R ⁵ represents -G ⁵ - OH or -G ⁵ -O-R ⁵¹ . In certain alternative embodiments, R ⁵ represents -G ⁵ -NH2, -G ⁵ -NH-R ⁵¹ , or -G ⁵ -NR ⁵¹ R ⁵² . In certain embodiments, optionally in combination with the embodiments described above, G ⁵ represents -CR ^b R ^c -. R ^b and R ^c are each independently selected from H or a carbon-based substituent such as alkyl, cycloalkyl, (cycloalkyl)alkyl, aralkyl, heteroaralkyl, alkenyl, or alkynyl. Alternatively, R ^b and R ^c , together with the carbon atom to which they are attached, optionally form a C3-C6 cycloalkyl. In exemplary embodiments, G ⁵ can be - C(alkyl) ₂ - or -CH(alkyl).

In certain preferred embodiments, G ⁵ is -CH ₂ -. In alternative embodiments, G ⁵ represents -C(O)-.

In certain preferred embodiments, R ⁵ represents -CH2OH. Alternatively, R ⁵ may represent -CH ₂ -O-R ⁵¹ , wherein R ⁵¹ is alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, or aralkyl, optionally substituted at any position with one or more substituents independently selected from halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, alkyl, haloalkyl, or haloalkoxy. For example, R ⁵¹ can be alkyl, cycloalkyl,

(cycloalkyl)alkyl, aryl, or aralkyl, optionally substituted at any position with one or more substituents independently selected from halogen, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino, ethylamino, dimethylamino, trifluoromethyl, trifluoromethoxy. In certain preferred embodiments, R ⁵¹ is methyl, ethyl, or isopropyl.

In certain embodiments, R ⁵ represents -CH2-O-R ⁵¹ , wherein R ⁵¹ is selected from - C(O)-R ¹⁰³ , -C(O)-O-R ¹⁰³ , -C(O)-N(H)-R ¹⁰³ , -C(O)-NR ¹⁰³ R ¹⁰⁴ , and -SO2-R ¹⁰³ , preferably - C(O)-R ¹⁰³ . R ¹⁰³ is preferably substituted or unsubstituted alkyl, e.g., methyl, ethyl, or isopropyl.

In certain embodiments, R ⁵ represents -CH2-NH2.

In certain embodiments, R ⁵ represents -CH ₂ NH-R ⁵¹ , and R ⁵¹ is alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, or aralkyl, optionally substituted at any position with one or more substituents independently selected from halogen, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino, ethylamino, dimethylamino, trifluoromethyl, and trifluoromethoxy. In certain preferred embodiments, R ⁵¹ is methyl, ethyl, or isopropyl.

In certain embodiments, R ⁵ represents -CH2NH-R ⁵¹ , and R ⁵¹ is C1-6 alkyl optionally substituted one or more times with substituents selected independently from the group consisting of halogen, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino ethylamino, dimethylamino, trifluoromethyl, and trifluoromethoxy.

In certain embodiments, R ⁵ represents -CH2NH-R ⁵¹ or -CH2NR ⁵¹ R ⁵² . In certain such embodiments, R ⁵¹ and R ⁵² are selected from alkyl, -C(O)-R ¹⁰³ , -C(O)-O-R ¹⁰³ , -C(O)- N(H)-R ¹⁰³ , -C(O)-NR ¹⁰³ R ¹⁰⁴ , and -SO2-R ¹⁰³ . In certain preferred embodiments, R ⁵ represents -CH2NH-R ⁵¹ , wherein R ⁵¹ is -C(O)-R ¹⁰³ or -SO2-R ¹⁰³ .

In certain such embodiments, R ¹⁰³ is optionally substituted alkyl, aryl, aralkyl, or heteroaryl, such as substituted or unsubstituted alkyl, e.g., methyl, ethyl, propyl, or isopropyl. Alternatively, R ¹⁰³ may represent alkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl, optionally substituted at any position with one or more substituents selected from halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, alkyl, haloalkyl, or haloalkoxy.

In certain exemplary embodiments, R ¹⁰³ represents isoxazolyl (e.g., isoxazol-5-yl), phenyl, imidazolyl (e.g., imidazol-4-yl), oxazolyl (e.g., 2-oxazolyl), or benzyl, optionally substituted at any position with one or more substituents selected from halogen, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino, ethylamino, dimethylamino, trifluoromethyl, and trifluoromethoxy, such as isoxazol-5-yl, optionally substituted with methyl, or phenyl, optionally substituted with one or more halogens, or imidazol-4-yl optionally substituted with methyl, or oxazole-5-yl optionally substituted with methyl.

In certain exemplary embodiments, R ¹⁰³ represents benzyl.

In certain embodiments, R ⁶ is not hydrogen. In other embodiments, R ⁶ represents H. In certain embodiments, R ⁶ represents optionally substituted alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, (cycloalkyl)alkoxy, heterocyclylalkoxy, (heterocyclyl)alkoxy, aryloxy, arylalkoxy, heteroaryloxy, or heteroarylalkoxy.

In certain embodiments, R ⁶ represents substituted or unsubstituted -CH2-(1- naphthyl), -CH2-(2-naphthyl), or -CH2-(phenyl), such as unsubstituted -CH2-(1-naphthyl), - CH ₂ -(2-naphthyl), or -CH ₂ -(phenyl).

In certain embodiments, R ⁶ represents -CH ₂ -(1-naphthyl), -CH ₂ -(2-naphthyl), or - CH2-(phenyl), substituted at at any position with one or more substituents R ⁶⁵ ,

wherein:

R ⁶⁵ , independently for each occurrence, is selected from substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R ¹⁰¹ , -SH, -S-R ¹⁰¹ , -S(O)R ¹⁰¹ , -SO2- R ¹⁰¹ , -NH ₂ , -NH-R ¹⁰¹ , -NR ¹⁰¹ R ¹⁰² , -C(O)-R ¹⁰¹ , -CO ₂ H, -C(O)-O-R ¹⁰¹ , -O-C(O)-R ¹⁰¹ , O-C(O)-OR ¹⁰¹ , -C(O)-NH2, -C(O)-NH-R ¹⁰¹ , -C(O)-NR ¹⁰¹ R ¹⁰² , -NH-C(O)-R ¹⁰¹ , - N(R ¹⁰² )-C(O)-R ¹⁰¹ , -NH-C(O)-NH2, -NH-C(O)-NHR ¹⁰¹ , -NH-C(O)-NR ¹⁰¹ R ¹⁰² , - N(R ¹⁰² )-C(O)-NH ₂ , -N(R ¹⁰² )-C(O)-NHR ¹⁰¹ , -N(R ¹⁰² )-C(O)-NR ¹⁰¹ R ¹⁰² , -O-C(O)- NR ¹⁰¹ R ¹⁰² , -O-C(O)-NH-R ¹⁰¹ , -O-C(O)-NH2, -NH-C(O)-OR ¹⁰¹ , -N(R ¹⁰² )-C(O)- OR ¹⁰¹ , -SO2-NH2, -SO2-NH-R ¹⁰¹ , -SO2-NR ¹⁰¹ R ¹⁰² , -NH-SO2-R ¹⁰¹ , -N(R ¹⁰² )-SO2- R ¹⁰¹ , halogen, -NO ₂ , and cyano; and

R ¹⁰¹ and R ¹⁰² independently for each occurrence represent substituted or unsubstituted

alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.

In certain such embodiments, R ⁶⁵ is selected from halo, hydroxyl, alkyl, alkoxy, haloalkyl, and haloalkoxy.

Alternatively, R ¹⁰¹ and R ¹⁰² may be alkyl, optionally substituted by an amide, carboxylic acid, ester, or ketone.

In certain embodiments, R ⁶ represents alkyl, alkenyl, alkynyl, cycloalkyl,

(cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or

heteroaralkyl, such as (cycloalkyl)alkyl, (heterocyclyl)alkyl, aralkyl, or heteroaralkyl, optionally substituted at any position with one or more substituents R ⁶⁵ , wherein R ⁶⁵ is defined above.

In certain embodiments, R ⁶ represents -CH ₂ -(1-naphthyl), -CH ₂ -(2-naphthyl), or - CH ₂ -(phenyl), e.g., substituted at any position with one or more substituents R ⁶⁵ , wherein R ⁶⁵ is defined above, or wherein each occurrence of R ⁶⁵ is independently selected from halo, hydroxyl, alkyl, alkoxy, haloalkyl, and haloalkoxy.

In certain exemplary embodiments described above, R ⁶⁵ represents halo, hydroxyl, -CO2H, cyano, or optionally substituted alkyl, alkoxy, haloalkyl, haloalkoxy, - SO2-(alkyl), -C(O)-O-(alkyl), -S(alkyl), -S(haloalkyl), heteroaryl, or aryl.

In certain embodiments, R ⁶ is C _1-6 alkyl, e.g., isobutyl.

In certain embodiments, R ⁶ is (cycloalkyl)alkyl, e.g., -C _1-6 alkylene-C _3-10 cycloalkyl, where the alkylene and cycloalkyl groups are optionally substituted with one or more with substituents independently selected from fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.

In certain embodiments, R ⁶ is -CH2-C3-10 cycloalkyl, where the cycloalkyl group is optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy. In certain such embodiments, R ⁶ is cyclohexylmethyl. In certain embodiments, R ⁶ is (heterocyclyl)alkyl, (e.g., -C1-6 alkylene-heterocyclyl), optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.

In certain embodiments, R ⁶ is -CH ₂ -heterocyclyl, where the heterocyclyl group is optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy. In certain such embodiments, R ⁶ is tetrahydropyran-4-ylmethyl.

In certain embodiments, R ⁶ is heteroaralkyl (e.g., -C1-6 alkylene-heteroaryl), optionally substituted with one or more substituents selected independently from fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.

In certain embodiments, R ⁶ is -CH2-heteroaryl, where the heteroaryl group is optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy.

In certain embodiments, R ⁶ is -CH ₂ -pyridyl, where the pyridyl group is optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy. In certain such embodiments, the pyridyl group is optionally substituted with one or two chloro groups, e.g., R ⁶ is 2-chloro-pyridin-5- ylmethyl.

In certain embodiments, R ⁶ is–CH2-benzothiazol-2-yl, optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, methyl, trifluoromethyl, and trifluoromethoxy.

In certain embodiments, R ⁶ is–CH2-benzofuran-2-yl, optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, methyl, trifluoromethyl, and trifluoromethoxy.

In certain embodiments, R ⁶ is–CH2-benzothiphene-2-yl, optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, methyl, trifluoromethyl, and trifluoromethoxy.

In certain embodiments, R ⁶ is–CH2-quinoxalin-2-yl, optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, methyl, trifluoromethyl, and trifluoromethoxy.

In certain embodiments, R ⁶ is–CH2-benzimidazol-2-yl, optionally substituted with one or more substituents independently selected from fluoro, chloro, hydroxy, methyl, trifluoromethyl, and trifluoromethoxy. In certain embodiments, R ⁶ is substituted or unsubstituted aralkyl (e.g., -C1-6 alkylene-aryl). For example, aralkyl may be substituted by one or more occurrences of R ⁶⁵ , as defined above.

In certain embodiments, R ⁶ is -CH(CH ₃ )-aryl, optionally substituted by one or more occurrences of R ⁶⁵ , as defined above.

In certain embodiments, R ⁶ is -CH(CH ₃ )-phenyl, where the phenyl group is optionally substituted one or more times with substituents independently selected from fluoro, chloro, methyl, hydroxy, trifluoromethyl, and trifluoromethoxy.

In certain embodiments, R ⁶ is -CH(CH3)-phenyl.

In certain embodiments, R ⁶ is -CH ₂ -aryl (e.g., -CH ₂ -naphthyl), optionally substituted by one or more occurrences of R ⁶⁵ , as defined above.

In certain embodiments, R ⁶ is -CH2-(2-naphthyl), -CH2-(1-naphthyl), or -CH(CH3)2- naphthyl, where the naphthyl group is optionally substituted one or more times with substituents independently selected from fluoro, chloro, hydroxy, trifluoromethyl, and trifluoromethoxy. In certain such embodiments, R ⁶ is -CH2-(2-naphthyl), while in other embodiments, R ⁶ is -CH ₂ -(1-naphthyl).

In certain embodiments, R ⁶ is -CH ₂ -phenyl, where the phenyl group is optionally substituted one or more times with substituents selected independently from R ⁶⁵ . For example R ⁶ can be -CH2-phenyl, where the phenyl group is optionally substituted one or two times with substituents selected independently from the group consisting of fluoro, chloro, bromo, methyl, methoxy, -SO2-CH3, -CO2CH3, -CO2H, trifluoromethyl,

trifluoromethoxy, -SCF3, 3-methyl-1,2,4-oxadiazol-5-yl, 1,2,4-triazol-1-yl, morpholin-4-yl- sulfonyl, pyrazol-1-yl, -CN, phenyl, -O-C _2-5 alkyl, and -C _2-5 alkyl.

In exemplary embodiments, R ⁶ is 3,4-dichlorobenzyl or 2,4-dichlorobenzyl.

In exemplary embodiments, R ⁶ is 4-(methanesulfonyl)benzyl or 4- (trifluoromethyl)benzyl.

In exemplary embodiments, R ⁶ is 2-chloro-4-fluorobenzyl or 4-fluorobenzyl.

In exemplary embodiments, R ⁶ is 3-chloro-4-methoxy-benzyl or 4-isopropyl-benzyl. In exemplary embodiments, R ⁶ is 2,4-difluorobenzyl, 4-fluorobenzyl, 3- (methoxy)benzyl, 4-(3-methyl-1,2,4-oxadiazol-5-yl)benzyl, 2-chloro-4-methoxybenzyl, 4-(trifluoromethoxy)benzyl, 4-(1,2,4-triazol-1-yl)benzyl, 2,4-dimethylbenzyl, 4- (methoxycarbonyl)-benzyl, 4-(trifluoromethylsulfanyl)-benzyl, 4-(morpholin-4-ylsulfonyl)- benzyl, 2-methoxybenzyl, 4-(pyrazol-1-yl)benzyl, 2,6-dichlorobenzyl, 4-(methoxy)benzyl, benzyl, 4-cyanobenzyl, 2-(methanesulfonyl)-4-chlorobenzyl, 2,4-di(trifluoromethyl)- benzyl, 3,5-dichlorobenzyl, 3-chloro-4-fluorobenzyl, 2,5-dichlorobenzyl, 3-chloro-5- fluorobenzyl, 4-bromobenzyl or 3-phenyl-benzyl.

In certain preferred embodiments, R ² represents -OH or -O-R ²¹ . In certain such embodiments, R ² represents -O-R ²¹ , but in more preferred embodiments, R ² represents - OH.

In certain embodiments, R ²¹ represents optionally substituted alkyl, alkenyl, or alkynyl. For example, R ²¹ may be C1-12 alkyl, C2-12 alkenyl, or C2-12 alkynyl, wherein each is optionally substituted one or more times with substituents selected independently from the group consisting of halogen, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino, ethylamino, dimethylamino, trifluoromethyl, and trifluoromethoxy.

In certain embodiments, R ²¹ represents methyl, ethyl, isopropyl, -CH2-CH=CH2, or –CH ₂ -C≡C-CH ₃ , e.g., methyl or ethyl.

In other exemplary embodiments, R ²¹ represents 3,3-dimethyl-butyl, 2,2-dimethyl- propyl, 1,1-dimethyl-prop-2-ynyl, 1,1-dimethyl-but-2-ynyl, or 1,1-diethyl-prop-2-ynyl.

In certain embodiments, R ²¹ represents C _3-10 cycloalkyl optionally substituted one or more times with substituents selected independently from halogen, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino, ethylamino, dimethylamino, trifluoromethyl, and trifluoromethoxy. For example, R ²¹ may be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

In other embodiments, R ² is -OH or -NH2, -NH-R ²¹ , or -NR ²¹ R ²² , e.g., -OH or -NH- R ²¹ . Alternatively, R ² may be -OH or -N(C1-6 alkyl)-R ²¹ , such as -OH or -N(CH3)-R ²¹ .

In certain such embodiments, R ²¹ may represent optionally substituted C _1-10 alkyl, such as C _1-10 alkyl optionally substituted with halogen.

In other such embodiments, R ²¹ is C1-6 alkyl optionally substituted one or more times with substituents independently selected from halogen, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino, ethylamino, dimethylamino, trifluoromethyl, and trifluoromethoxy. For example, R ²¹ may be methyl, ethyl, or isopropyl, preferably methyl.

In certain embodiments, R ² represents is -OH or -NH-C(O)-R ²¹ .

In certain embodiments, R ² represents -OH or -N(C _1-6 alkyl)-C(O)-R ²¹ . For example, R ² may be -N(CH3)-C(O)-R ²¹ .

In certain embodiments, R ² represents–OH, -NH-C(O)-NH2, -NH-C(O)-NHR ²¹ , - NH-C(O)-NR ²¹ R ²² , -N(R ²² )-C(O)-NH ₂ , -N(R ²² )-C(O)-NHR ²¹ , or -N(R ²² )-C(O)-NR ²¹ R ²² . In certain embodiments, R ² is–OH, -NH-C(O)-O-R ²¹ or -N(R ²² )-C(O)-O-R ²¹ . In certain embodiments, R ² is -NH-C(O)-O-R ²¹ . In certain such embodiments, R ²¹ and R ²² independently are C _1-12 alkyl, C _2-12 alkenyl, C _2-12 alkynyl, phenyl, benzyl, wherein each is optionally substituted one or more times with substituents independently selected from halogen, methyl, ethyl, isopropyl, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino, ethylamino, dimethylamino, trifluoromethyl, and trifluoromethoxy.

In certain embodiments, R ² is -OH or -NR ²¹ R ²² , wherein R ²¹ and R ²² combine to form a ring selected from pyrrolidino, piperidino, piperazino, morpholino, and

thiomorpholino, where each said ring is optionally substituted by one or more substituents independently selected from halogen, methyl, ethyl, isopropyl, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino, ethylamino, dimethylamino, and oxo. Alternatively, R ²¹ and R ²² combine to form a pyrrolidino or a piperidinyl ring, where each said ring is optionally substituted by one or more substituents independently selected from halogen, methyl, ethyl, isopropyl, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino, ethylamino, and dimethylamino.

In certain embodimennts, R ¹ and R ² , together with the intervening atoms, form an optionally substituted cycloalkyl or heterocycloalkyl ring. For example, R ¹ and R ² may together form a tetrahydrofuran ring that is fused to the remainder of the molecule.

In certain embodiments of the invention, R ^8a and R ^8b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, -OH, -OR ⁸¹ , halogen, and cyano. In more particular embodiments of the invention, one or both of R ^8a or R ^8b may be -OR ⁸¹ , halogen, or cyano. In certain embodiments, R ^8a and R ^8b are each hydrogen.

In certain embodiments, R ^8a is hydrogen. In other embodiments, R ^8a is not hydrogen, e.g., -OH, -O-R ⁸¹ , cyano, or halogen.

In certain embodiments, R ^8a is -O-R ⁸¹ or -O-C(O)R ⁸¹ . In certain such embodiments, R ⁸¹ is selected from substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl. In certain exemplary embodiments, R ⁸¹ is alkyl, e.g., methyl or ethyl.

In certain embodiments, R ^8b is hydrogen. In other embodiments, R ^8b is not hydrogen, e.g., -OH, -O-R ⁸¹ , cyano, or halogen.

In certain embodiments, R ^8b is -O-R ⁸¹ or -O-C(O)R ⁸¹ . In certain such embodiments, R ⁸¹ is selected from substituted or unsubstituted alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl. In certain exemplary embodiments, R ⁸¹ is alkyl, e.g., methyl or ethyl. In other exemplary

embodiments, R ^8b is -O-benzyl.

In certain embodiments, R ^8a , R ^8b , and R ^9a are each hydrogen.

In certain embodiments, R ^9a and R ^9b are each independently selected from hydrogen, alkyl, alkenyl, alkynyl, -OH, -OR ⁹¹ , halogen, and cyano, preferably such that at least one of R ^9a and R ^9b represents -OR ⁹¹ . In certain such embodiments, R ⁹¹ represents alkyl. In more particular embodiments of the invention, one or both of R ^9a or R ^9b may be - OR ⁹¹ , halogen, or cyano.

In certain preferred embodiments, R ^9b represents -OR ⁹¹ . In certain such

embodiments, R ⁹¹ represents alkyl.

In certain embodiments, R ^9a and R ^9b each independently represent alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl, optionally substituted at any position by one or more substituents R ⁹⁵ , wherein:

R ⁹⁵ , independently for each occurrence, is selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R ¹⁰¹ , -SH, -S-R ¹⁰¹ , -S(O)R ¹⁰¹ , -SO ₂ -R ¹⁰¹ , -NH ₂ , -NH-R ¹⁰¹ , - NR ¹⁰¹ R ¹⁰² , -C(O)-R ¹⁰¹ , -CO2H, -C(O)-O-R ¹⁰¹ , -O-C(O)-R ¹⁰¹ , O-C(O)-OR ¹⁰¹ , -C(O)- NH2, -C(O)-NH-R ¹⁰¹ , -C(O)-NR ¹⁰¹ R ¹⁰² , -NH-C(O)-R ¹⁰¹ , -N(R ¹⁰² )-C(O)-R ¹⁰¹ , -NH- C(O)-NH ₂ , -NH-C(O)-NHR ¹⁰¹ , -NH-C(O)-NR ¹⁰¹ R ¹⁰² , -N(R ¹⁰² )-C(O)-NH ₂ , - N(R ¹⁰² )-C(O)-NHR ²¹ , -N(R ¹⁰² )-C(O)-NR ¹⁰¹ R ¹⁰² , -O-C(O)-NR ¹⁰¹ R ¹⁰² , -O-C(O)-NH- R ¹⁰¹ , -O-C(O)-NH2, -NH-C(O)-OR ¹⁰¹ , -N(R ¹⁰² )-C(O)-OR ¹⁰¹ , -SO2-NH2, -SO2-NH- R ¹⁰¹ , -SO ₂ -NR ¹⁰¹ R ¹⁰² , -NH-SO ₂ -R ¹⁰¹ , -N(R ¹⁰² )-SO ₂ -R ¹⁰¹ , halogen, -NO ₂ , and cyano, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted; and

R ¹⁰¹ and R ¹⁰² independently for each occurrence represent substituted or unsubstituted

alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.

In certain embodiments, R ^9a is hydrogen. In other embodiments, R ^9a is not hydrogen, e.g., -OH or -O-R ⁹¹ . In certain embodiments, R ^9a is -O-R ⁹¹ . In certain such embodiments, R ⁹¹ is C1-4 alkyl, e.g., methyl.

In certain embodiments, R ^9a is halogen, e.g., bromo or chloro. In certain embodiments, R ^9a is C1-6 alkyl, e.g., methyl, ethyl, or isopropyl.

In certain embodiments, R ^9a is C2-6 alkenyl, e.g., vinyl.

In certain embodiments, R ^9a is -C(O)-R ⁹¹ , -C(O)-NHR ⁹¹ , -S(O) ₂ -R ⁹¹ ,–C(O)-O-R ⁹¹ , or–CO ₂ H, wherein R ⁹¹ is -C _1-6 alkyl, optionally substituted with halogen, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino, ethylamino, dimethylamino, trifluoromethyl, and trifluoromethoxy. For example, R ⁹¹ can be methyl, ethyl, or isopropyl.

In certain embodiments, R ^9a is C _3-10 cycloalkyl, e.g., cyclopentyl or cyclopenten-1- yl.

In certain embodiments, R ^9a is phenyl, optionally substituted with one or more substituents R ⁹⁵ wherein:

R ⁹⁵ , independently for each occurrence, is selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R ¹⁰¹ , -SH, -S-R ¹⁰¹ , -S(O)R ¹⁰¹ , -SO ₂ -R ¹⁰¹ , -NH ₂ , -NH-R ¹⁰¹ , - NR ¹⁰¹ R ¹⁰² , -C(O)-R ¹⁰¹ , -CO ₂ H, -C(O)-O-R ¹⁰¹ , -O-C(O)-R ¹⁰¹ , O-C(O)-OR ¹⁰¹ , -C(O)- NH2, -C(O)-NH-R ¹⁰¹ , -C(O)-NR ¹⁰¹ R ¹⁰² , -NH-C(O)-R ¹⁰¹ , -N(R ¹⁰² )-C(O)-R ¹⁰¹ , -NH- C(O)-NH ₂ , -NH-C(O)-NHR ¹⁰¹ , -NH-C(O)-NR ¹⁰¹ R ¹⁰² , -N(R ¹⁰² )-C(O)-NH ₂ , - N(R ¹⁰² )-C(O)-NHR ²¹ , -N(R ¹⁰² )-C(O)-NR ¹⁰¹ R ¹⁰² , -O-C(O)-NR ¹⁰¹ R ¹⁰² , -O-C(O)-NH- R ¹⁰¹ , -O-C(O)-NH2, -NH-C(O)-OR ¹⁰¹ , -N(R ¹⁰² )-C(O)-OR ¹⁰¹ , -SO2-NH2, -SO2-NH- R ¹⁰¹ , -SO2-NR ¹⁰¹ R ¹⁰² , -NH-SO2-R ¹⁰¹ , -N(R ¹⁰² )-SO2-R ¹⁰¹ , halogen, -NO2, and cyano, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted; and

R ¹⁰¹ and R ¹⁰² independently for each occurrence represent substituted or unsubstituted

alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.

In certain embodiments, R ^9a is phenyl, optionally substituted with one or more substituents R ⁹⁵ , wherein each occurrence of R ⁹⁵ is independently selected from chloro, fluoro, C1-6 alkyl, -O-R ⁹¹ , -CO2H, -CO2-R ⁹¹ , -S(O)2-R ⁹¹ , and hydroxyl, and R ⁹¹ is C1-C6 alkyl or C1-C6 haloalkyl.

In certain embodiments, R ^9a is selected from furan-3-yl, pyrazol-4-yl, thiazol-5-yl, thiazol-4-yl, thiazol-2-yl, oxazol-2-yl, imidazol-2-yl, isoxazol-4-yl, [1,2,4]oxadiazol-5-yl, [1,3,4]thiadiazol-5-yl, optionally substituted with one or more occurrences of R ⁹⁵ as described above. In certain such embodiments, R ⁹⁵ is methyl. In certain embodiments, R ^9b is hydrogen. In other embodiments, R ^9b is not hydrogen, e.g., -OH or -O-R ⁹¹ , such as -O-R ⁹¹ . In certain such embodiments, R ⁹¹ is C1-4 alkyl, e.g., methyl, ethyl, isopropyl, or n-propyl. In other such embodiments, R ⁹¹ is - (CH ₂ ) ₂ -OCH ₃ . In certain embodiments, R ⁹¹ is C _3-10 cycloalkyl, e.g., cyclohexyl.

In certain embodiments, R ^9b is halogen, e.g., bromo or chloro.

In certain embodiments R ^9b is C _1-6 alkyl (e.g., methyl, ethyl, or isopropyl).

In certain embodiments, R ^9b is C _2-6 alkenyl, e.g., vinyl.

In certain embodiments R ^9b is -C(O)-R ⁹¹ , -C(O)-NHR ⁹¹ , -S(O)2-R ⁹¹ ,–C(O)-O-R ⁹¹ , and–CO2H. In certain such embodiments, R ⁹¹ is -C1-6 alkyl, optionally substituted with halogen, hydroxy, methoxy, ethoxy, isopropoxy, amino, methylamino, ethylamino, dimethylamino, trifluoromethyl, and trifluoromethoxy. For example, R ⁹¹ can be methyl, ethyl, or isopropyl.

In certain embodiments, R ^9b is C _3-10 cycloalkyl, e.g., cyclopentyl or cyclopenten-1- yl.

In certain embodiments, R ^9b is phenyl, optionally substituted with one or more substituents R ⁹⁵ wherein:

R ⁹⁵ , independently for each occurrence, is selected from alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, -OH, -O-R ¹⁰¹ , -SH, -S-R ¹⁰¹ , -S(O)R ¹⁰¹ , -SO2-R ¹⁰¹ , -NH2, -NH-R ¹⁰¹ , - NR ¹⁰¹ R ¹⁰² , -C(O)-R ¹⁰¹ , -CO ₂ H, -C(O)-O-R ¹⁰¹ , -O-C(O)-R ¹⁰¹ , O-C(O)-OR ¹⁰¹ , -C(O)- NH2, -C(O)-NH-R ¹⁰¹ , -C(O)-NR ¹⁰¹ R ¹⁰² , -NH-C(O)-R ¹⁰¹ , -N(R ¹⁰² )-C(O)-R ¹⁰¹ , -NH- C(O)-NH2, -NH-C(O)-NHR ¹⁰¹ , -NH-C(O)-NR ¹⁰¹ R ¹⁰² , -N(R ¹⁰² )-C(O)-NH2, - N(R ¹⁰² )-C(O)-NHR ²¹ , -N(R ¹⁰² )-C(O)-NR ¹⁰¹ R ¹⁰² , -O-C(O)-NR ¹⁰¹ R ¹⁰² , -O-C(O)-NH- R ¹⁰¹ , -O-C(O)-NH ₂ , -NH-C(O)-OR ¹⁰¹ , -N(R ¹⁰² )-C(O)-OR ¹⁰¹ , -SO ₂ -NH ₂ , -SO ₂ -NH- R ¹⁰¹ , -SO2-NR ¹⁰¹ R ¹⁰² , -NH-SO2-R ¹⁰¹ , -N(R ¹⁰² )-SO2-R ¹⁰¹ , halogen, -NO2, and cyano, where the alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, and heteroaralkyl groups are optionally substituted; and

R ¹⁰¹ and R ¹⁰² independently for each occurrence represent substituted or unsubstituted

alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclyl, (heterocyclyl)alkyl, aryl, aralkyl, heteroaryl, or heteroaralkyl.

In certain embodiments, R ^9b is phenyl, optionally substituted with one or more substituents R ⁹⁵ , wherein each occurrence of R ⁹⁵ is independently selected from chloro, fluoro, C1-6 alkyl, -O-R ⁹¹ , -CO2H, -CO2-R ⁹¹ , -S(O)2-R ⁹¹ , and hydroxyl, and R ⁹¹ is C1-C6 alkyl C1-C6 haloalkyl.

In certain embodiments, R ^9b is 4-fluorophenyl, 4-chlorophenyl, 4- (methanesulfonyl)-phenyl, 2-methoxyphenyl, cyano, or -NO ₂ .

In certain embodiments, R ^9b is heteroaryl, optionally substituted by one or more occurrences of R ⁹⁵ as described above.

In certain embodiments, R ^9b is furan-3-yl, pyrazol-4-yl, thiazol-5-yl, thiazol-4-yl, thiazol-2-yl, oxazol-2-yl, imidazol-2-yl, isoxazol-4-yl, [1,2,4]oxadiazol-5-yl,

[1,3,4]thiadiazol-5-yl, optionally substituted with one or more occurrences of R ⁹⁵ as described above. In certain such embodiments, R ⁹⁵ is methyl.

In certain embodiments, R ^9b is pyridyl (e.g., 3-pyridyl or pyridyl-4-yl), optionally substituted with one or two substituents selected independently from the group consisting of methyl and methoxy.

In certain embodiments, R ^9b is 3-pyridyl, 6-methylpyridin-3-yl, 2-methoxypyridin- 3-yl, 2,3-dimethylpyridin-4-yl, 1H-tetrazol-5-yl, 4-methylthiazol-2-yl, 1,3,5-trimethyl-1H- pyrazol-4-yl, 3,5-dimethylisoxazol-4-yl, pyrimidin-5-yl, or -C(S)-NH ₂ .

In certain embodiments, at least one of R ⁶ , R ^8a , R ^8b , R ^9a , and R ^9b is not H.

In certain embodiments, compounds of the invention may be prodrugs of the compounds of Formula (I) or (Ia), e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester. In certain such embodiments, the prodrug is metabolized to the active parent compound in vivo (e.g., the ester is hydrolyzed to the corresponding hydroxyl, or carboxylic acid).

In certain embodiments, compounds of the invention may be racemic. In certain embodiments, compounds of the invention may be enriched in one enantiomer. For example, a compound of the invention may have greater than 30% ee, 40% ee, 50% ee, 60% ee, 70% ee, 80% ee, 90% ee, or even 95% or greater ee. The compounds of the invention have more than one stereocenter. Consequently, compounds of the invention may be enriched in one or more diastereomer. For example, a compound of the invention may have greater than 30% de, 40% de, 50% de, 60% de, 70% de, 80% de, 90% de, or even 95% or greater de.

In certain embodiments, wedged and dashed lines indicate relative stereochemistry in the compounds of Formula (I) or (Ia). In other embodiments, wedged and dashed lines indicate absolute stereochemistry in the compounds of Formula (I) or (Ia). Where no stereochemistry is indicated, the compound may be either stereoisomer or a mix of stereoisomers at the indicated position.

In certain embodiments, as as will be described in detail below, the present invention relates to methods of treating or preventing cancer with a compound of Formula (I) or (Ia) or a pharmaceutically acceptable salt thereof. In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one enantiomer of a compound (e.g., of Formula I). An enantiomerically enriched mixture may comprise, for example, at least 60 mol percent of one enantiomer, or more preferably at least 75, 90, 95, or even 99 mol percent. In certain embodiments, the compound enriched in one enantiomer is substantially free of the other enantiomer, wherein substantially free means that the substance in question makes up less than 10%, or less than 5%, or less than 4%, or less than 3%, or less than 2%, or less than 1% as compared to the amount of the other enantiomer, e.g., in the composition or compound mixture. For example, if a composition or compound mixture contains 98 grams of a first enantiomer and 2 grams of a second enantiomer, it would be said to contain 98 mol percent of the first enantiomer and only 2% of the second enantiomer.

In certain embodiments, the therapeutic preparation may be enriched to provide predominantly one diastereomer of a compound (e.g., of Formula I). A diastereomerically enriched mixture may comprise, for example, at least 60 mol percent of one diastereomer, or more preferably at least 75, 90, 95, or even 99 mol percent.

In certain embodiments, the present invention provides a pharmaceutical preparation suitable for use in a human patient in the treatment of cancer, comprising an effective amount of any compound of Formula (I) or (Ia), and one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical preparations may be for use in treating or preventing a condition or disease as described herein. In certain embodiments, the pharmaceutical preparations have a low enough pyrogen activity to be suitable for use in a human patient.

Compounds of any of the above structures may be used in the manufacture of medicaments for the treatment of any diseases or conditions disclosed herein.

Exemplary compounds of Formula I are depicted in the Examples. The compounds in the Examples may be depicted as the free base or the conjugate acid. Compounds may be isolated in either the free base form, as a salt (e.g., a hydrochloride salt) or in both forms. In the chemical structures shown below, standard chemical abbreviations are sometimes used.

Compounds of the invention inhibit HK2 enzyme activity. Compounds that inhibit HK2 enzyme activity are potentially useful in treating diseases, disorders, or conditions where inhibition of HK2 is beneficial, such as fungal infections or various cancers (e.g., tumors of the pancreas, ovary, or liver).

The compounds of Formula (I) or (Ia) and/or pharmaceutically acceptable salts thereof may therefore be useful in the treatment of one or more of these diseases. II. USES OF HEXOKINASE II INHIBITORS

In certain aspects, the invention provides methods of treating cancer, comprising administering to a subject a compound of Formula (I) or (Ia), e.g., in a therapeutically effective amount.

In certain embodiments, the cancer may be one or a variant of Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Adrenocortical Carcinoma, AIDS- Related Cancers (Kaposi Sarcoma and Lymphoma), Anal Cancer, Appendix Cancer, Atypical Teratoid/Rhabdoid Tumor, Basal Cell Carcinoma, Bile Duct Cancer (including Extrahepatic), Bladder Cancer, Bone Cancer (including Osteosarcoma and Malignant Fibrous Histiocytoma), Brain Tumor (such as Astrocytomas, Brain and Spinal Cord Tumors, Brain Stem Glioma, Central Nervous System Atypical Teratoid/Rhabdoid Tumor, Central Nervous System Embryonal Tumors, Craniopharyngioma, Ependymoblastoma, Ependymoma, Medulloblastoma, Medulloepithelioma, Pineal Parenchymal Tumors of Intermediate Differentiation, Supratentorial Primitive Neuroectodermal Tumors and Pineoblastoma), Breast Cancer, Bronchial Tumors, Burkitt Lymphoma, Basal Cell Carcinoma, Bile Duct Cancer (including Extrahepatic), Bladder Cancer, Bone Cancer (including Osteosarcoma and Malignant Fibrous Histiocytoma), Carcinoid Tumor, Carcinoma of Unknown Primary, Central Nervous System (such as Atypical

Teratoid/Rhabdoid Tumor, Embryonal Tumors and Lymphoma), Cervical Cancer, Childhood Cancers, Chordoma, Chronic Lymphocytic Leukemia (CLL), Chronic

Myelogenous Leukemia (CML), Chronic Myeloproliferative Disorders, Colon Cancer, Colorectal Cancer, Craniopharyngioma, Cutaneous T-Cell Lymphoma (Mycosis Fungoides and Sézary Syndrome), Duct, Bile (Extrahepatic), Ductal Carcinoma In Situ (DCIS), Embryonal Tumors (Central Nervous System), Endometrial Cancer, Ependymoblastoma, Ependymoma, Esophageal Cancer, Esthesioneuroblastoma, Ewing Sarcoma Family of Tumors, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Eye Cancer (like Intraocular Melanoma, Retinoblastoma), Fibrous

Histiocytoma of Bone (including Malignant and Osteosarcoma) Gallbladder Cancer, Gastric (Stomach) Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumors (GIST), Germ Cell Tumor (Extracranial, Extragonadal, Ovarian), Gestational Trophoblastic Tumor, Glioblastoma, Glioma, Hairy Cell Leukemia, Head and Neck Cancer, Heart Cancer, Hepatocellular (Liver) Cancer, Histiocytosis, Langerhans Cell, Hodgkin Lymphoma, Hypopharyngeal Cancer, Intraocular Melanoma, Islet Cell Tumors (Endocrine, Pancreas), Kaposi Sarcoma, Kidney (including Renal Cell), Langerhans Cell Histiocytosis, Laryngeal Cancer, Leukemia (including Acute Lymphoblastic (ALL), Acute Myeloid (AML), Chronic Lymphocytic (CLL), Chronic Myelogenous (CML), Hairy Cell), Lip and Oral Cavity Cancer, Liver Cancer (Primary), Lobular Carcinoma In Situ (LCIS), Lung Cancer (Non-Small Cell and Small Cell), Lymphoma (AIDS-Related, Burkitt, Cutaneous T-Cell (Mycosis Fungoides and Sézary Syndrome), Hodgkin, Non-Hodgkin, Primary Central Nervous System (CNS), Male Breast Cancer, Malignant Fibrous Histiocytoma of Bone and Osteosarcoma, Medulloblastoma, Medulloepithelioma, Melanoma (including Intraocular (Eye)), Merkel Cell Carcinoma, Mesothelioma (Malignant), Metastatic

Squamous Neck Cancer with Occult Primary, Midline Tract Carcinoma Involving NUT Gene, Mouth Cancer, Multiple Endocrine Neoplasia Syndromes, Multiple Myeloma/Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndromes,

Myelodysplastic/Myeloproliferative Neoplasms, Chronic Myeloid Leukemia (CML), Acute Myelogenous Leukemia (AML), Myeloma and Multiple Myeloma, Myeloproliferative Disorders (Chronic), Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Oral Cavity Cancer, Lip and Oropharyngeal Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma of Bone, Ovarian Cancer (such as Epithelial, Germ Cell Tumor, and Low Malignant Potential Tumor), Pancreatic Cancer (including Islet Cell Tumors),

Papillomatosis, Paraganglioma, Paranasal Sinus and Nasal Cavity Cancer, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pheochromocytoma, Pineal Parenchymal Tumors of Intermediate Differentiation, Pineoblastoma and Supratentorial Primitive Neuroectodermal Tumors, Pituitary Tumor, Plasma Cell Neoplasm/Multiple Myeloma, Pleuropulmonary Blastoma, Pregnancy and Breast Cancer, Primary Central Nervous System (CNS) Lymphoma, Prostate Cancer, Rectal Cancer, Renal Cell (Kidney) Cancer, Renal Pelvis and Ureter, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoma (such as Ewing Sarcoma Family of Tumors, Kaposi, Soft Tissue, Uterine), Sézary Syndrome, Skin Cancer (such as Melanoma, Merkel Cell Carcinoma, Nonmelanoma), Small Cell Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinoma, Squamous Neck Cancer with Occult Primary, Metastatic Stomach (Gastric) Cancer, Supratentorial Primitive Neuroectodermal Tumors, T-Cell Lymphoma (Cutaneous, Mycosis Fungoides and Sézary Syndrome), Testicular Cancer, Throat Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Trophoblastic Tumor (Gestational), Unknown Primary, Unusual Cancers of

Childhood, Ureter and Renal Pelvis, Transitional Cell Cancer, Urethral Cancer, Uterine Cancer, Endometrial, Uterine Sarcoma, Waldenström Macroglobulinemia and Wilms Tumor.

In certain embodiments, the cancer is a solid tumor. The subject is generally one who has been diagnosed as having a cancerous tumor or one who has been previously treated for a cancerous tumor (e.g., where the tumor has been previously removed by surgery). The cancerous tumor may be a primary tumor and/or a secondary (e.g., metastatic) tumor.

In certain embodiments, the solid tumor is a highly glycolytic tumor.

In certain embodiments, the subject is a mammal, e.g., a human.

The methods of the invention may not be limited to treating any particular type of cancer or cancerous tumor. In some embodiments, the cancerous tumor comprises cancer cells of a highly glycolytic phenotype. Such tumors are referred to herein as highly glycolytic tumors. Highly glycolytic tumors can be located in a wide range of tissue types, including brain, colon, urogenital, lung, renal, prostate, pancreas, liver, esophagus, stomach, hematopoietic, breast, thymus, testis, ovarian, skin, bone marrow, or uterine tissues. Highly glycolytic tumors are known to those of skill in the art. In general, highly glycolytic tumors are tumors that exhibit a high rate of glucose metabolism to synthesize high levels of ATP. In contrast, normal cells obtain most of their ATP from oxidative phosphorylation, with only about 10% of their ATP being generated by glycolysis. Procedures that may be suitably used to identify whether cancer cells are of a highly glycolytic phenotype may be found in U.S. Patent Application Publication No.2010/0203110, incorporated herein by reference. In some embodiments, highly glycolytic tumors comprise cells that obtain at least 40% or at least 50% of their ATP from glycolysis under aerobic conditions. In some embodiments, highly glycolytic tumors comprise cells that, when contacted with an HKII inhibitor at a concentration of about 1-10 nM, or about 10-100 nM, or 100-1000 nM, or 1- 10 µM, shows a substantial decrease in its rate of ATP generation, e.g., at least a 10% decrease in its rate of ATP generation, or at least a 20% decrease in its rate of ATP generation, or at least a 25% decrease in its rate of ATP generation, or at least a 30% decrease in its rate of ATP generation, or at least a 40% decrease in its rate of ATP generation, or at least a 50% decrease in its rate of ATP generation, or at least a 60% decrease in its rate of ATP generation, or at least a 75% decrease in its rate of ATP generation. In some embodiments, highly glycolytic tumors comprise cells that exhibit an increased uptake of fluorine-labeled deoxyglucose (FDG) in comparison to normal cells, when such uptake is measured by positron emission tomography (PET). In such embodiments, standard solutions of FDG may be used in conducting standard procedures of conducting PET imaging of a tumor. In some such embodiments, the uptake of FDG in cells of the highly glycolytic tumor is at least 2-3 times that of the uptake of FDG in normal cells, or at least 3-4 times that of the uptake of FDG in normal cells, or at least 4-5 times that of the uptake of FDG in normal cells, or at least 5-6 times that of the uptake of FDG in normal cells, or at least 6-7 times that of the uptake of FDG in normal cells.

In certain embodiments, the cancer is associated with tissue of the bladder, bone marrow, breast, colon, kidney, liver, lung, ovary, pancreas, prostate, skin or thyroid.

In certain embodiments, the method of treating cancer further comprises conjointly administering radiation therapy.

In some embodiments, the invention provides for the use of a compound of the invention in combination with radiation therapy. An optimized dose of radiation therapy may be given to a subject as a daily dose. Optimized daily doses of radiation therapy may be from 0.25 to 0.5 Gy, 0.5 to 1.0 Gy, 1.0 to 1.5 Gy, 1.5 to 2.0 Gy, 2.0 to 2.5 Gy, and 2.5 to 3.0 Gy. In some embodiments, the daily dose of radiation is from 2.0 to 3.0 Gy. A higher dose of radiation may be administered if a tumor is resistant to lower doses of radiation. High doses of radiation may reach 4 Gy. Further, the total dose of radiation administered over the course of treatment may range from 50 to 200 Gy. In some embodiments, the total dose of radiation administered over the course of treatment ranges from 50 to 80 Gy. In some embodiments, a dose of radiation is given over a time interval of 1, 2, 3, 4, or 5 minutes, wherein the amount of time is dependent on the dose rate of the radiation source. In some embodiments, a daily dose of optimized radiation may be administered 4 or 5 days a week, for approximately 4 to 8 weeks. In other embodiments, a daily dose of optimized radiation may be administered daily seven days a week, for approximately 4 to 8 weeks. In some embodiments, a daily dose of radiation may be given a single dose. In some other embodiments, a daily dose of radiation may given as two or more doses. In a further embodiment, the optimized dose of radiation may be a higher dose of radiation than can be tolerated by the subject on a daily base. As such, high doses of radiation may be administered to a subject, but in less frequent dosing regimen.

The invention is not limited to any particular type of radiation. The types of radiation that may be used in cancer treatment are well known in the art and include electron beams, high-energy photons from a linear accelerator or from radioactive sources such as cobalt or cesium, protons, and neutrons. For example, ionizing radiation may be x- ray radiation.

Further, the invention is not limited to any particular method of administering the radiation. Methods to administer radiation are well known in the art. Such methods include, but are not limited to, external beam radiation, internal beam radiation, and radiopharmaceuticals. In external beam radiation, a linear accelerator is used to deliver high-energy x-rays to the area of the body affected by cancer. Because the source of radiation originates from outside of the body, external beam radiation may be used to treat large areas of the body with a uniform dose of radiation. Internal radiation therapy, also known as brachytherapy, involves delivery of a high dose of radiation to a specific site in the body. Two main types of internal radiation therapy include interstitial radiation, where a source of radiation is placed in the effected tissue, and intracavity radiation, where the source of radiation is placed in an internal body cavity a short distance from the affected area. Radioactive material may also be delivered to tumor cells by attachment to tumor- specific antibodies. The radioactive material used in internal radiation therapy is typically contained in a small capsule, pellet, wire, tube, or implant. On the other hand,

radiopharmaceuticals are unsealed sources of radiation that may be given orally, intravenously or directly into a body cavity.

Radiation therapy may also include stereotactic surgery or stereotactic radiation therapy, wherein a precise amount of radiation is delivered to a small tumor area using a linear accelerator or gamma knife and three-dimensional conformal radiation therapy (3DCRT), which is a computer assisted therapy to map the location of the tumor prior to radiation treatment.

In some embodiments, the method of treating cancer further comprises conjointly administering one or more additional chemotherapeutic agents.

Chemotherapeutic agents that may be conjointly administered with compounds of the invention include: ABT-263, aminoglutethimide, amsacrine, anastrozole, asparaginase, AZD5363, Bacillus Calmette–Guérin vaccine (bcg), bicalutamide, bleomycin, bortezomib, buserelin, busulfan, campothecin, capecitabine, carboplatin, carfilzomib, carmustine, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, cobimetinib, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin, dexamethasone, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil and 5-fluorouracil, fluoxymesterone, flutamide, gemcitabine, genistein, goserelin, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, lenalidomide, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, miltefosine, mitomycin, mitotane, mitoxantrone, MK2206, nilutamide, nocodazole, octreotide, oxaliplatin, paclitaxel, pamidronate, pentostatin, pazopanib, perifosine, PF-04691502, plicamycin, pomalidomide, porfimer, procarbazine, raltitrexed, rituximab, romidepsin, selumetinib, sorafenib, streptozocin, sunitinib, suramin, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, topotecan, trametinib, trastuzumab, tretinoin, vinblastine, vincristine, vindesine, vinorelbine, and vorinostat (SAHA). For example, chemotherapeutic agents that may be conjointly administered with compounds of the invention include: aminoglutethimide, amsacrine, anastrozole, asparaginase, bcg, bicalutamide, bleomycin, bortezomib, buserelin, busulfan, campothecin, capecitabine, carboplatin, carfilzomib, carmustine, chlorambucil,

chloroquine, cisplatin, cladribine, clodronate, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin, dichloroacetate, dienestrol, diethylstilbestrol, docetaxel, doxorubicin, epirubicin, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gemcitabine, genistein, goserelin, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, lenalidomide, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, mechlorethamine, medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, nocodazole, octreotide, oxaliplatin, paclitaxel, pamidronate, pentostatin, perifosine, plicamycin, pomalidomide, porfimer, procarbazine, raltitrexed, rituximab, sorafenib, streptozocin, sunitinib, suramin, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, topotecan, trastuzumab, tretinoin, vinblastine, vincristine, vindesine, and vinorelbine. In other embodiments, chemotherapeutic agents that may be conjointly administered with compounds of the invention include: ABT-263, dexamethasone, 5- fluorouracil, PF-04691502, romidepsin, and vorinostat (SAHA). In certain embodiments of the methods of the invention described herein, the chemotherapeutic agent conjointly administered with compounds of the invention is a taxane chemotherapeutic agent, such as paclitaxel or docetaxel. In certain embodiments of the methods of the invention described herein, the chemotherapeutic agent conjointly administered with compounds of the invention is doxorubicin. In certain embodiments of the methods of the invention described herein, a compound of the invention is administered conjointly with a taxane

chemotherapeutic agent (e.g., paclitaxel) and doxorubicin.

In certain embodiments, the chemotherapeutic agent is selected from

aminoglutethimide, amsacrine, anastrozole, asparaginase, bcg, bicalutamide,

bisphosphonate, bleomycin, bortezomib, buserelin, busulfan, campothecin, capecitabine, carboplatin, carfilzomib, carmustine, chlorambucil, chloroquine, cisplatin, cladribine, clodronate, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, demethoxyviridin, dichloroacetate, dienestrol,

diethylstilbestrol, docetaxel, doxorubicin, epirubicin, eribulin, estradiol, estramustine, etoposide, everolimus, exemestane, filgrastim, fludarabine, fludrocortisone, fluorouracil, fluoxymesterone, flutamide, gemcitabine, genistein, goserelin, hydroxyurea, idarubicin, ifosfamide, imatinib, interferon, irinotecan, ixabepilone, lenalidomaide, letrozole, leucovorin, leuprolide, levamisole, lomustine, lonidamine, mechlorethamine,

medroxyprogesterone, megestrol, melphalan, mercaptopurine, mesna, metformin, methotrexate, mitomycin, mitotane, mitoxantrone, mutamycin, nilutamide, nocodazole, octreotide, oxaliplatin, paclitaxel, pamidronate, pentostatin, perifosine, plicamycin, pomalidomide, porfimer, procarbazine, raltitrexed, rituximab, sorafenib, streptozocin, sunitinib, suramin, tamoxifen, temozolomide, temsirolimus, teniposide, testosterone, thalidomide, thioguanine, thiotepa, titanocene dichloride, topotecan, trastuzumab, tretinoin, vinblastine, vincristine, vindesine, and vinorelbine.

In certain embodiments, the methods include conjoint administration with a chemotherapeutic agent selected from afatinib dimaleate, bevacizumab, carboplatin, ceritinib, cisplatin, crizotinib, docetaxel, doxorubicin hydrochloride; erlotinib

hydrochloride, etoposide, gefitinib, gemcitabine hydrochloride, mechlorethamine hydrochloride, methotrexate, paclitaxel, pemetrexed disodium, ramucirumab, topotecan hydrochloride, and vinorelbine tartrate.

Many combination therapies have been developed for the treatment of cancer. In certain embodiments, compounds of the invention may be conjointly administered with a combination therapy. Examples of combination therapies with which compounds of the invention may be conjointly administered are included in Table 1.

Table 1: Exemplary combinatorial therapies for the treatment of cancer.

n cer a n em o men s, e con o n y a m n s ere c emo erapeu c agen s selected from inhibitors of metabolic enzymes, such as inhibitors of glucose transporters, hexokinase, pyruvate kinase M2, lactate dehydrogenase A, pyruvate dehydrogenase kinase, fatty acid synthase and/or glutaminase.

In some embodiments, the conjointly administered chemotherapeutic agent is an immuno-oncology therapeutic, such as an inhibitor of arginase, CTLA-4, indoleamine 2,3- dioxygenase, and/or PD-1/PD-L1. In certain exemplary embodiments, the immuno- oncology agent is abagovomab, adecatumumab, afutuzumab, alemtuzumab, anatumomab mafenatox, apolizumab, blinatumomab, BMS-936559, catumaxomab, durvalumab, epacadostat, epratuzumab, indoximod, inotuzumab ozogamicin, intelumumab, ipilimumab, isatuximab, lambrolizumab, MED14736, MPDL3280A, nivolumab, obinutuzumab, ocaratuzumab, ofatumumab, olatatumab, pembrolizumab, pidilizumab, rituximab, ticilimumab, samalizumab, or tremelimumab. In some embodiments, the invention provides for the use of a compound of the invention in combination with an AMPK agonist for simultaneous, subsequent, or sequential administration. AMPK agonists include, but are not limited to, the following: biguanides (e.g., metformin, phenformin, buformin, or proguanil); resveratrol; AICA- riboside (5-aminoimidazole-4-carboxamide riboside); AICA base (5-aminoimidazole-4- carboxamide); SAICAR (5-amino-4-imidazole-N-succinocarboxamide riboside); ZMP (5- aminoimidazole-4-carboxamide-1-beta-D-ribofuranosyl-5’-mon ophosphate); 6-MPR (6- mercaptopurine riboside); or a pharmaceutically acceptable salt of any of the foregoing.

In some embodiments, the invention provides for the use of a compound of the invention in combination with another antitumor agent for simultaneous, subsequent, or sequential administration. Said“antitumor agents” include, but are not limited to, the following: platinum-based agents, such as carboplatin and cisplatin; nitrogen mustard alkylating agents; nitrosourea alkylating agents, such as carmustine (BCNU) and other alkylating agents; antimetabolites, such as methotrexate; purine analog antimetabolites; pyrimidine analog antimetabolites, such as fluorouracil (5-FU), gemcitabine, and capecitabine; hormonal antineoplastics, such as goserelin, leuprolide, and tamoxifen;

natural antineoplastics, such as taxanes (e.g., docetaxel and paclitaxel), aldesleukin, interleukin-2, etoposide (VP-16), interferon alfa, and tretinoin (ATRA); antibiotic natural antineoplastics, such as bleomycin, dactinomycin, daunorubicin, doxorubicin, and mitomycin; and vinca alkaloid natural antineoplastics, such as vinblastine and vincristine.

In some further embodiments, the invention provides for the use of a compound of the invention in combination with another agent for simultaneous, subsequent, or sequential administration, where the other agent need not be considered as an antitumor agent. Such other agents include the following: dactinomycin; daunorubicin HCl; docetaxel;

doxorubicin HCl; epoetin alfa; etoposide (VP-16); ganciclovir sodium; gentamicin sulfate; interferon alfa; leuprolide acetate; meperidine HCl; methadone HCl; ranitidine HCl;

vinblastin sulfate; and zidovudine (AZT). For example, fluorouracil may be formulated with epinephrine and bovine collagen to form a combination, which may be used along with a compound of any one of embodiments 1 to 215. Still further, the following listing of amino acids, peptides, polypeptides, proteins, polysaccharides, and other large molecules may also be administered in addition to a compound of any one of embodiments 1 to 215: interleukins 1 through 18, including mutants and analogues; interferons or cytokines, such as interferons-alpha, -beta, and -gamma; hormones, such as luteinizing hormone releasing hormone (LHRH) and analogues and, gonadotropin releasing hormone (GnRH); growth factors, such as transforming growth factor-beta (TGF-beta), fibroblast growth factor (FGF), nerve growth factor (NGF), growth hormone releasing factor (GHRF), epidermal growth factor (EGF), fibroblast growth factor homologous factor (FGFHF), hepatocyte growth factor (HGF), and insulin growth factor (IGF); tumor necrosis factor-alpha and - beta (TNF-alpha and -beta); invasion inhibiting factor-2 (IIF-2); bone morphogenetic proteins 1-7 (BMP 1-7); somatostatin; thymosin-alpha-1; gamma-globulin; superoxide dismutase (SOD); complement factors; anti-angiogenesis factors; and antigenic materials.

In some embodiments, the invention provides for the use of a compound of the invention in combination with an additional chemotherapeutic agent for simultaneous, subsequent, or sequential administration. Such additional chemotherapeutic agents include, but are not limited to, the following: altretamine, asparaginase, BCG, bleomycin sulfate, busulfan, carboplatin, carmustine (bis-chloroethylnitrosourea), chlorambucil, cisplatin, claladribine, 2-chloro-deoxyadenosine, cyclophosphamide, cytarabine, dacarbazine imidazole carboxamide, dactinomycin, daunorubicin-daunomycin, dexamethasone, doxorubicin, etoposide, floxuridine, fluorouracil, fluoxymesterone, flutamide, fludarabine, goserelin, hydroxyurea, idarubicin HCL, ifosfamide, interferon alfa, interferon alfa 2a, interferon alfa 2b, interferon alfa n3, irinotecan, leucovorin calcium, leuprolide, levamisole, lomustine, megestrol, melphalan, L-sarcosylin, melphalan hydrochloride, MESNA, mechlorethamine, methotrexate, mitomycin, mitoxantrone, mercaptopurine, paclitaxel, plicamycin, prednisone, procarbazine, streptozocin, tamoxifen, 6-thioguanine, thiotepa, vinblastine, vincristine, and vinorelbine tartrate.

In some embodiments, the invention provides for the use of a compound of the invention in combination with an autophagy inhibitor agent for simultaneous, subsequent, or sequential administration. Such autophagy inhibitor agents include, but are not limited to, chloroquine, hydroxychloroquine, and Spautin-1.

In some embodiments, the invention provides for the use of a compound of the invention in combination with another active substance for simultaneous, subsequent, or sequential administration. Such other biological substances include, but are not limited to, the following: other chemotherapeutic agents, scavenger compounds, antibiotics, antivirals, anti-fungals, anti-inflammatories, vasoconstrictors and anticoagulants, and antigens useful for cancer vaccine applications. Scavenger compounds include, but are not limited to the following: thiol-containing compounds such as glutathione, thiourea, and cysteine; alcohols such as mannitol, substituted phenols; quinones, substituted phenols, aryl amines; and nitro compounds.

In certain embodiments, conjoint administration of the hexokinase II inhibitor(s) of Formula (I) or (Ia) with one or more additional therapeutic agent(s) (e.g., one or more additional chemotherapeutic agent(s)) provides improved efficacy relative to each individual administration of the hexokinase II inhibitor (e.g., a compound of Formula I or (Ia)) or the one or more additional therapeutic agent(s). In certain such embodiments, the conjoint administration provides an additive effect, wherein an additive effect refers to the sum of each of the effects of individual administration of the hexokinase II inhibitor and the one or more additional therapeutic agent(s). In certain embodiments, coadministration produces a synergistic effect.

In certain embodiments, the hexokinase II inhibitor and the one or more additional chemotherapeutic agents are administered simultaneously. In alternative embodiments, the one or more additional chemotherapeutic agents are administered within about 5 minutes to within about 168 hours prior to or after administration of the hexokinase II inhibitor.

In another aspect, the invention may provide for the use of a compound of any one of embodiments 1 to 215 for the treatment of a parasitic infection that relies heavily on glycolysis for the generation of ATP. Such parasites may include Trypanosoma brucei and Trypanosoma cruzi. Other such parasites may include Plasmodium falciparum and Brugia malayi.

In another aspect, the invention may provide for the use of a compound of Formula (I) or (Ia) to induce tumor-specific oxidative stress cell death. In an embodiment, the method comprises increasing the production of reactive oxygen species (such as free radical compounds) in tumor cells relative to normal cells. In another embodiment, the method comprises inhibition of glycolysis and NADPH synthesis, whereby the level of ROS is increase in a tumor cell relative to a normal cell.

In certain embodiments, the invention provides methods of inhibiting proliferation of a cancerous cell comprising contacting a cancerous cell with an effective amount of a compound of Formula (I) or (Ia).

The invention also provides methods of inhibiting hexokinase activity in a cell, comprising contacting a cell with a compound of of Formula (I) or (Ia). In certain embodiments, the cell is a cancer cell. Such methods may be performed in vivo or in vitro. III. KITS

In certain embodiments, the present invention provides a kit comprising: a) one or more single dosage forms of a hexokinase inhibitor described herein; b) one or more single dosage forms of a chemotherapeutic agent as mentioned above; and c) instructions for the administration of the compound of the invention and the chemotherapeutic agent for the treatment of cancer.

The present invention provides a kit comprising:

a) a pharmaceutical formulation (e.g., one or more single dosage forms) comprising a compound of the invention; and

b) instructions for the administration of the pharmaceutical formulation, e.g., for

treating or preventing cancer.

In certain embodiments, the kit further comprises instructions for the administration of the pharmaceutical formulation comprising a compound of the invention conjointly with a chemotherapeutic agent as mentioned above. In certain embodiments, the kit further comprises a second pharmaceutical formulation (e.g., as one or more single dosage forms) comprising a chemotherapeutic agent as mentioned above.

The disclosure also provides kits for detecting whether a subject having a cancer is likely to be responsive to hexokinase inhibitors. The kit may include one or more agents for detecting the amount of expression of a protein of the invention [e.g., the amount of the protein, and/or the amount of a nucleic acid (e.g., an mRNA) encoding the protein]. The agents in the kit can encompass, for example, antibodies specific for the proteins, or probes specific for the mRNA that can be used to hybridize to the RNA (or to a cDNA generated from it) or to perform RT-PCR. The kit may also include additional agents suitable for detecting, measuring and/or quantitating the amount of protein or nucleic acid. Among other uses, kits of the invention can be used in experimental applications. A skilled worker will recognize components of kits suitable for carrying out a method of the invention.

Optionally, a kit of the invention may comprise instructions for performing the method. Optional elements of a kit of the invention include suitable buffers, containers, or packaging materials. The reagents of the kit may be in containers in which the reagents are stable, e.g., in lyophilized form or stabilized liquids. The reagents may also be in single use form, e.g., for the performance of an assay for a single subject. IV. PHARMACEUTICAL COMPOSITIONS

In certain embodiments, the present invention provides pharmaceutical

compositions comprising a compound of any preceding claim and a pharmaceutically acceptable carrier.

The compositions and methods of the present invention may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the compound is preferably administered as a pharmaceutical composition comprising, for example, a compound of the invention and a pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration (i.e., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier), the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule (including sprinkle capsule and gelatin capsule), granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop.

A pharmaceutically acceptable carrier can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a compound of the invention. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable carrier, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a selfemulsifying drug delivery system or a selfmicroemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention.

Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The phrase "pharmaceutically acceptable carrier" as used herein means a

pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be

"acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as

pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and

suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; (21) modified and unmodified cyclodextrins, and (22) other non-toxic compatible substances employed in pharmaceutical formulations.

A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally (for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules

(including sprinkle capsules and gelatin capsules), boluses, powders, granules, pastes for application to the tongue); absorption through the oral mucosa (e.g., sublingually); anally, rectally or vaginally (for example, as a pessary, cream or foam); parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension); nasally; intraperitoneally; subcutaneously; transdermally (for example as a patch applied to the skin); and topically (for example, as a cream, ointment or spray applied to the skin, or as an eye drop). The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water. Details of appropriate routes of administration and compositions suitable for same can be found in, for example, U.S. Pat. Nos.6,110,973, 5,731,000, 5,541,231, 5,427,798, 5,358,970 and 4,172,896, as well as in patents cited therein.

The formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. The amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 1 percent to about ninety-nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.

Methods of preparing these formulations or compositions include bringing into association an active compound, such as a compound of the invention, with the carrier and, optionally, one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.

Formulations of the invention suitable for oral administration may be in the form of capsules (including sprinkle capsules and gelatin capsules), cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), lyophile, powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil- in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient. Compositions or compounds may also be administered as a bolus, electuary or paste.

In some embodiments, where the compound is delivered orally in a unit dosage form, the amount of a compound of the invention in the unit dosage form ranges from 50 to 1000 mg, or from 100 to 500 mg. In some embodiments, the amount of compound in the unit dosage form is 100 mg, or 150 mg, or 200 mg, or 250 mg, or 300 mg, or 350 mg, or 400 mg, or 450 mg, or 500 mg. The amount of drug administered at any single

administration may vary according to various factors. In some embodiments, the amount of drug administered at any single administration ranges from 100 mg/m ² to 2000 mg/m ² , or from 250 mg/m ² to 1500 mg/m ² , or from 500 mg/m ² to 1500 mg/m ² , where the m ² unit refers to the body surface area of the subject. In some embodiments, the amount of drug administered at any single administration is 500 mg/m ² , or 750 mg/m ² , or 1000 mg/m ² , or 1250 mg/m ² , or 1500 mg/m ² . In general, for oral delivery, a compound of the invention may be administered one or more times a day, such as once a day, twice a day, or three times a day. Such dosing may occur for a set period of time or a series of set periods of time. For example, a compound of the invention may be administered to a subject one or more times a day for a period of 1-4 weeks, such as one week, two weeks, or three weeks, or four weeks. Such a period may be followed by a rest period of 1-4 weeks (or one week, two weeks, three weeks, or four weeks), which may then be followed by another administration period of 1-4 weeks (or one week, two weeks, three weeks, or four weeks).

To prepare solid dosage forms for oral administration (capsules (including sprinkle capsules and gelatin capsules), tablets, pills, dragees, powders, granules and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; (10) complexing agents, such as, modified and unmodified cyclodextrins; and (11) coloring agents. In the case of capsules (including sprinkle capsules and gelatin capsules), tablets and pills, the pharmaceutical compositions may also comprise buffering agents. 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 sugars, as well as high molecular weight polyethylene glycols and the like.

A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative,

disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceutical compositions, such as dragees, capsules (including sprinkle capsules and gelatin capsules), pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the

gastrointestinal tract, optionally, in a delayed manner. Examples of embedding

compositions that can be used include polymeric substances and waxes. The active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.

Liquid dosage forms useful for oral administration include pharmaceutically acceptable emulsions, lyophiles for reconstitution, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, cyclodextrins and derivatives thereof, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.

Formulations of the pharmaceutical compositions for rectal, vaginal, or urethral administration may be presented as a suppository, which may be prepared by mixing one or more active compounds with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.

Formulations of the pharmaceutical compositions for administration to the mouth may be presented as a mouthwash, or an oral spray, or an oral ointment.

Alternatively or additionally, compositions can be formulated for delivery via a catheter, stent, wire, or other intraluminal device. Delivery via such devices may be especially useful for delivery to the bladder, urethra, ureter, rectum, or intestine.

Formulations which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.

Dosage forms for the topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants that may be required.

The ointments, pastes, creams and gels may contain, in addition to an active compound, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to an active compound, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.

Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body. Such dosage forms can be made by dissolving or dispersing the active compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like, are also contemplated as being within the scope of this invention. Exemplary ophthalmic formulations are described in U.S. Publication Nos.2005/0080056, 2005/0059744, 2005/0031697 and 2005/004074 and U.S. Patent No.6,583,124, the contents of which are incorporated herein by reference. If desired, liquid ophthalmic formulations have properties similar to that of lacrimal fluids, aqueous humor or vitreous humor or are compatable with such fluids. A preferred route of administration is local administration (e.g., topical administration, such as eye drops, or administration via an implant).

The phrases "parenteral administration" and "administered parenterally" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,

transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.

Pharmaceutical compositions suitable for parenteral administration comprise one or more active compounds in combination with one or more pharmaceutically acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.

In some embodiments, the concentration of a compound of of the invention in a liquid pharmaceutical composition ranges from 1 to 100 mg/mL, or from 5 to 70 mg/mL, or from 10 to 50 mg/mL. In some embodiments, the intravenous delivery or intra-arterial delivery of the liquid pharmaceutical composition comprising an a compound of the invention comprises continuous intravenous infusion or intra-arterial infusion of the liquid pharmaceutical composition for a time period of from 15 minutes to 3 hours, or from 15 minutes to 2 hours, or from 15 minutes to 1 hour. For each such period of infusion, the dose of a compound of the invention delivered to the subject can, in some embodiments, range from 50 mg/m ² to 2000 mg/m ² , or from 75 mg/m ² to 1500 mg/m ² , or from 100 mg/m ² to 1000 mg/m ² , where the m ² unit refers to the surface area of the subject to whom the drug is administered. A treatment regimen may involve a series of such periods of intravenous infusion or intra-arterial infusion. For example, in some embodiments, such periods of intravenous infusion or intra-arterial infusion may occur about a week apart from each other, and may, in some embodiments, occur within a cycle that includes weeks where no infusion of the drug occurs. For example, in some embodiments, the treatment may involve a 21-day cycle, where periods of continuous intravenous infusion or intra-arterial infusion occur on Day 1 and Day 8, or, alternatively, the treatment may involve a 28-day cycle, where periods of continuous intravenous infusion or intra-arterial infusion occur on Day 1, Day 8, and Day 15. Doses of a compound of the invention may be adjusted up or down to account for various factors, such as patient health, side effects, effectiveness of the course of treatment, etc.

Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of

microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of a drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form.

Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

Injectable depot forms are made by forming microencapsulated matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide.

Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissue.

For use in the methods of this invention, active compounds can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient in combination with a pharmaceutically acceptable carrier.

Methods of introduction may also be provided by rechargeable or biodegradable devices. Various slow release polymeric devices have been developed and tested in vivo in recent years for the controlled delivery of drugs, including proteinacious

biopharmaceuticals. A variety of biocompatible polymers (including hydrogels), including both biodegradable and non-degradable polymers, can be used to form an implant for the sustained release of a compound at a particular target site.

Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factors including the activity of the particular compound or combination of compounds employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound(s) being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound(s) employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readily determine and prescribe the therapeutically effective amount of the pharmaceutical composition required. For example, the physician or veterinarian could start doses of the pharmaceutical composition or compound at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. By “therapeutically effective amount” is meant the concentration of a compound that is sufficient to elicit the desired therapeutic effect. It is generally understood that the effective amount of the compound will vary according to the weight, sex, age, and medical history of the subject. Other factors which influence the effective amount may include, but are not limited to, the severity of the patient's condition, the disorder being treated, the stability of the compound, and, if desired, another type of therapeutic agent being administered with the compound of the invention. A larger total dose can be delivered by multiple

administrations of the agent. Methods to determine efficacy and dosage are known to those skilled in the art (Isselbacher et al. (1996) Harrison’s Principles of Internal Medicine 13 ed., 1814-1882, herein incorporated by reference).

In general, a suitable daily dose of an active compound used in the compositions and methods of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

If desired, the effective daily dose of the active compound may be administered as one, two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In certain embodiments of the present invention, the active compound may be administered two or three times daily. In preferred embodiments, the active compound will be administered once daily.

The patient receiving this treatment is any animal in need, including primates, in particular humans, and other mammals such as equines, cattle, swine and sheep; and poultry and pets in general.

In certain embodiments, compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent. As used herein, the phrase “conjoint administration” refers to any form of administration of two or more different therapeutic compounds such that the second compound is administered while the previously administered therapeutic compound is still effective in the body (e.g., the two compounds are simultaneously effective in the patient, which may include synergistic effects of the two compounds). For example, the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either concomitantly or sequentially. In certain embodiments, the different therapeutic compounds can be administered within one hour, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, or a week of one another. Thus, an individual who receives such treatment can benefit from a combined effect of different therapeutic compounds.

In certain embodiments, conjoint administration of compounds of the invention with one or more additional therapeutic agent(s) (e.g., one or more additional chemotherapeutic agent(s)) provides improved efficacy relative to each individual administration of the compound of the invention (e.g., compound of formula I) or the one or more additional therapeutic agent(s). In certain such embodiments, the conjoint administration provides an additive effect, wherein an additive effect refers to the sum of each of the effects of individual administration of the compound of the invention and the one or more additional therapeutic agent(s).

This invention includes the use of pharmaceutically acceptable salts of compounds of the invention in the compositions and methods of the present invention. The term “pharmaceutically acceptable salt” as used herein includes salts derived from inorganic or organic acids including, for example, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, phosphoric, formic, acetic, lactic, maleic, fumaric, succinic, tartaric, glycolic, salicylic, citric, methanesulfonic, benzenesulfonic, benzoic, malonic, trifluoroacetic, trichloroacetic, naphthalene-2-sulfonic, and other acids. Pharmaceutically acceptable salt forms can include forms wherein the ratio of molecules comprising the salt is not 1:1. For example, the salt may comprise more than one inorganic or organic acid molecule per molecule of base, such as two hydrochloric acid molecules per molecule of compound of Formula (I) or (Ia). As another example, the salt may comprise less than one inorganic or organic acid molecule per molecule of base, such as two molecules of compound of Formula (I) or (Ia) per molecule of tartaric acid.

In further embodiments, contemplated salts of the invention include, but are not limited to, alkyl, dialkyl, trialkyl or tetra-alkyl ammonium salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, L-arginine,

benenthamine, benzathine, betaine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)ethanol, ethanolamine, ethylenediamine, N- methylglucamine, hydrabamine, 1H-imidazole, lithium, L-lysine, magnesium, 4-(2- hydroxyethyl)morpholine, piperazine, potassium, 1-(2-hydroxyethyl)pyrrolidine, sodium, triethanolamine, tromethamine, and zinc salts. In certain embodiments, contemplated salts of the invention include, but are not limited to, Na, Ca, K, Mg, Zn or other metal salts.

The pharmaceutically acceptable acid addition salts can also exist as various solvates, such as with water, methanol, ethanol, dimethylformamide, and the like. Mixtures of such solvates can also be prepared. The source of such solvate can be from the solvent of crystallization, inherent in the solvent of preparation or crystallization, or adventitious to such solvent.

Wetting agents, emulsifiers and lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal-chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like. Additional Uses

In other aspects, the invention may provide methods of inhibiting proliferation of a cancerous cell comprising contacting the cancerous cell with a compound of the invention. As used herein,“inhibiting proliferation” refers to slowing the rate of cell division of one or more cells, which includes causing the cell death of one or more cells. In some such embodiments, the cancerous cell is a cancerous cell of a highly glycolytic phenotype, as described above. The contacting can occur in vitro (e.g., on a cancerous cell that has been biopsied from a tumor, or purchased from commercial sources, etc.) or in vivo (e.g., within a subject, whether the tumor has grown within the subject or has been grafted in). In some embodiments, the contacting occurs in an in vitro environment. In some other

embodiments, the contacting occurs in an in vivo environment. In another aspect, the invention may provide methods of suppressing anaerobic glucose metabolism in a cancerous cell. In some embodiments, the method includes administering a compound of the invention to a subject. In some embodiments, the method includes contacting the cancerous cell with a compound of the invention.

In another embodiment, the invention may provide a method of inhibiting the activity of the HK2 enzyme in a cancerous cell. In some embodiments, the method includes administering a compound of the invention to a subject. In some embodiments, the method includes contacting the cancerous cell with a compound of the invention.

In another aspect, the invention may provide methods of interrupting the glycolytic pathway in a cancerous cell. In some embodiments, the method includes administering a compound of the invention to a subject. In some embodiments, the method includes contacting the cancerous cell with a compound of the invention.

The present invention may also provide methods of treating disorders and diseases associated with excessive and/or abnormal angiogenesis. Inappropriate and ectopic expression of angiogenesis can be deleterious to an organism. A number of pathological conditions are associated with the growth of extraneous blood vessels. These include, e.g., diabetic retinopathy, ischemic retinal-vein occlusion, and retinopathy of prematurity, age- related macular degeneration, neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma, inflammation, rheumatoid arthritis (RA), restenosis, in-stent restenosis, vascular graft restenosis, etc. In addition, the increased blood supply associated with cancerous and neoplastic tissue, encourages growth, leading to rapid tumor enlargement and metastasis. Moreover, the growth of new blood and lymph vessels in a tumor provides an escape route for renegade cells, encouraging metastasis and the consequence spread of the cancer. Thus, compounds of the present invention may be utilized to treat and/or delay onset of any of the aforementioned angiogenesis disorders, e.g., by inhibiting and/or reducing blood vessel formation; by inhibiting, blocking, reducing, decreasing, etc.

endothelial cell proliferation or other types involved in angiogenesis, as well as causing cell death or apoptosis of such cell types.

In each of the methods or uses described above, a compound of the invention may be administered to a subject as part of a pharmaceutically composition, as described above.

Examples of compounds of Formula (I) or pharmaceutically acceptable salts thereof having potentially useful biological activity are depicted in the Examples and in Table 3. The ability of compounds Formula (I) or pharmaceutically acceptable salts thereof to inhibit HK2 was established with the representative compounds of Formula (I) listed in Table 2 using the assay described below. V. DEFINITIONS

The term“acyl” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)-, preferably alkylC(O)-.

The term“acylamino” is art-recognized and refers to an amino group substituted with an acyl group and may be represented, for example, by the formula

hydrocarbylC(O)NH-.

The term“acyloxy” is art-recognized and refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

The term“alkoxy” refers to an alkyl group, preferably a lower alkyl group, having an oxygen attached thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy and the like.

The term“alkoxyalkyl” refers to an alkyl group substituted with an alkoxy group and may be represented by the general formula alkyl-O-alkyl.

The term“alkenyl”, as used herein, refers to an aliphatic group containing at least one double bond and is intended to include both "unsubstituted alkenyls" and "substituted alkenyls", the latter of which refers to alkenyl moieties having substituents replacing a hydrogen on one or more carbons of the alkenyl group. Such substituents may occur on one or more carbons that are included or not included in one or more double bonds.

Moreover, such substituents include all those contemplated for alkyl groups, as discussed below, except where stability is prohibitive. For example, substitution of alkenyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

An“alkyl” group or“alkane” is a straight chained or branched non-aromatic hydrocarbon which is completely saturated. Typically, a straight chained or branched alkyl group has from 1 to about 20 carbon atoms, preferably from 1 to about 10 unless otherwise defined. Examples of straight chained and branched alkyl groups include methyl, ethyl, n- propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl. A C1-C6 straight chained or branched alkyl group is also referred to as a "lower alkyl" group.

Moreover, the term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyls" and "substituted alkyls", the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents, if not otherwise specified, can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkyl may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF ₃ , -CN and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF3, -CN, and the like.

An“alkylene” group is a straight chained or branched non-aromatic hydrocarbon diradical which is completely saturated. Typically, a straight chained or branched alkylene group has from 1 to about 20 carbon atoms, preferably from 1 to about 10 unless otherwise defined. Examples of straight chained and branched alkylene groups include methylene, ethylene, 1,3-n-propylene, 1,1-iso-propylene, 2,2-n-butylene, and the like. A C ₁ -C ₆ straight chained or branched alkylene group is also referred to as a "lower alkylene" group.

Moreover, the term "alkylene" (or "lower alkylene") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkylenes" and "substituted alkylenes", the latter of which refers to alkylene moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Such substituents, if not otherwise specified, can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For instance, the substituents of a substituted alkylene may include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl and sulfonate), and silyl groups, as well as ethers, alkylthios, carbonyls (including ketones, aldehydes, carboxylates, and esters), -CF ₃ , -CN and the like. Exemplary substituted alkylenes are described below.

The term“C _x-y ” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkylene, alkenyl, alkynyl, or alkoxy is meant to include groups that contain from x to y carbons in the chain. For example, the term“Cx-yalkyl” refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched- chain alkyl groups that contain from x to y carbons in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl, etc. C0 alkyl indicates a hydrogen where the group is in a terminal position, a bond if internal. The terms“C2-yalkenyl” and“C2- _y alkynyl” refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

The term“alkylamino”, as used herein, refers to an amino group substituted with at least one alkyl group.

The term“alkylthio”, as used herein, refers to a thiol group substituted with an alkyl group and may be represented by the general formula alkylS-.

The term“alkynyl”, as used herein, refers to an aliphatic group containing at least one triple bond and is intended to include both "unsubstituted alkynyls" and "substituted alkynyls", the latter of which refers to alkynyl moieties having substituents replacing a hydrogen on one or more carbons of the alkynyl group. Such substituents may occur on one or more carbons that are included or not included in one or more triple bonds.

Moreover, such substituents include all those contemplated for alkyl groups, as discussed above, except where stability is prohibitive. For example, substitution of alkynyl groups by one or more alkyl, carbocyclyl, aryl, heterocyclyl, or heteroaryl groups is contemplated.

The term“amide”, as used herein, refers to a group

wherein each R ¹⁰ independently represent a hydrogen or hydrocarbyl group, or two R ¹⁰ are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.

The terms“amine” and“amino” are art-recognized and refer to both unsubstituted and substituted amines and salts thereof, e.g., a moiety that can be represented by

wherein each R ¹⁰ independently represents a hydrogen or a hydrocarbyl group, or two R ¹⁰ are taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure.

The term“aminoalkyl”, as used herein, refers to an alkyl group substituted with an amino group.

The term“aralkyl”, as used herein, refers to an alkyl group substituted with an aryl group.

The term“aryl” as used herein include substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon. Preferably the ring is a 5- to 7- membered ring, more preferably a 6-membered ring. The term“aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like.

The term“carbamate” is art-recognized and refers to a group

wherein R ⁹ and R ¹⁰ independently represent hydrogen or a hydrocarbyl group, such as an alkyl group, or R ⁹ and R ¹⁰ taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.

The terms“carbocycle”, and“carbocyclic”, as used herein, refers to a saturated or unsaturated ring in which each atom of the ring is carbon. The term carbocycle includes both aromatic carbocycles and non-aromatic carbocycles. Non-aromatic carbocycles include both cycloalkane rings, in which all carbon atoms are saturated, and cycloalkene rings, which contain at least one double bond.“Carbocycle” includes 5-7 membered monocyclic and 8-12 membered bicyclic rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated and aromatic rings. Carbocycle includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. The term“fused carbocycle” refers to a bicyclic carbocycle in which each of the rings shares two adjacent atoms with the other ring. Each ring of a fused carbocycle may be selected from saturated, unsaturated and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. Any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits, is included in the definition of carbocyclic. Exemplary “carbocycles” include cyclopentane, cyclohexane, bicyclo[2.2.1]heptane, 1,5- cyclooctadiene, 1,2,3,4-tetrahydronaphthalene, bicyclo[4.2.0]oct-3-ene, naphthalene and adamantane. Exemplary fused carbocycles include decalin, naphthalene, 1,2,3,4- tetrahydronaphthalene, bicyclo[4.2.0]octane, 4,5,6,7-tetrahydro-1H-indene and

bicyclo[4.1.0]hept-3-ene.“Carbocycles” may be susbstituted at any one or more positions capable of bearing a hydrogen atom.

A“cycloalkyl” group is a cyclic hydrocarbon which is completely saturated.

“Cycloalkyl” includes monocyclic and bicyclic rings. Typically, a monocyclic cycloalkyl group has from 3 to about 10 carbon atoms, more typically 3 to 8 carbon atoms unless otherwise defined. The second ring of a bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. Cycloalkyl includes bicyclic molecules in which one, two or three or more atoms are shared between the two rings. Bicyclic cycloalkyl groups may include fused bicyclic cycloalkyl groups in which each of the rings shares two adjacent atoms with the other ring. The second ring of such a fused bicyclic cycloalkyl may be selected from saturated, unsaturated and aromatic rings. An exemplary fused bicyclic cycloalkyl group is tetralinyl. A“cycloalkenyl” group is a cyclic hydrocarbon containing one or more double bonds.

The term“carbocyclylalkyl”, as used herein, refers to an alkyl group substituted with a carbocycle group.

The term“carbonate” is art-recognized and refers to a group -OCO ₂ -R ¹⁰ , wherein R ¹⁰ represents a hydrocarbyl group.

The term“carboxy”, as used herein, refers to a group represented by the

formula -CO ₂ H. The term“ester”, as used herein, refers to a group -C(O)OR ¹⁰ wherein R ¹⁰ represents a hydrocarbyl group.

The term“ether”, as used herein, refers to a hydrocarbyl group linked through an oxygen to another hydrocarbyl group. Accordingly, an ether substituent of a hydrocarbyl group may be hydrocarbyl-O-. Ethers may be either symmetrical or unsymmetrical.

Examples of ethers include, but are not limited to, heterocycle-O-heterocycle and aryl-O- heterocycle. Ethers include“alkoxyalkyl” groups, which may be represented by the general formula alkyl-O-alkyl.

The terms“halo” and“halogen” as used herein means halogen and includes chloro, fluoro, bromo, and iodo.

The terms“hetaralkyl” and“heteroaralkyl”, as used herein, refers to an alkyl group substituted with a hetaryl group.

The term "heteroalkyl", as used herein, refers to a saturated or unsaturated chain of carbon atoms and at least one heteroatom, wherein no two heteroatoms are adjacent.

The terms“heteroaryl” and“hetaryl” include substituted or unsubstituted aromatic single ring structures, preferably 5- to 7-membered rings, more preferably 5- to 6- membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms“heteroaryl” and “hetaryl” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine, and the like.

The term“heteroatom” as used herein means an atom of any element other than carbon or hydrogen. Preferred heteroatoms are nitrogen, oxygen, and sulfur.

The terms“heterocyclyl”,“heterocycle”, and“heterocyclic” refer to substituted or unsubstituted non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures include at least one heteroatom, preferably one to four heteroatoms, more preferably one or two heteroatoms. The terms “heterocyclyl” and“heterocyclic” also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is heterocyclic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, and the like. Heterocyclyl groups can also be substituted by oxo groups. For example, “heterocyclyl” encompasses both pyrrolidine and pyrrolidinone.

The term“heterocyclylalkyl”, as used herein, refers to an alkyl group substituted with a heterocycle group.

The term“hydrocarbyl”, as used herein, refers to a group that is bonded through a carbon atom that does not have a =O or =S substituent, and typically has at least one carbon-hydrogen bond and a primarily carbon backbone, but may optionally include heteroatoms. Thus, groups like methyl, ethoxyethyl, 2-pyridyl, and trifluoromethyl are considered to be hydrocarbyl for the purposes of this application, but substituents such as acetyl (which has a =O substituent on the linking carbon) and ethoxy (which is linked through oxygen, not carbon) are not. Hydrocarbyl groups include, but are not limited to aryl, heteroaryl, carbocycle, heterocyclyl, alkyl, alkenyl, alkynyl, and combinations thereof.

The term“hydroxyalkyl”, as used herein, refers to an alkyl group substituted with a hydroxy group.

The term“lower” when used in conjunction with a chemical moiety, such as, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy is meant to include groups where there are ten or fewer non-hydrogen atoms in the substituent, preferably six or fewer. A“lower alkyl”, for example, refers to an alkyl group that contains ten or fewer carbon atoms, preferably six or fewer. In certain embodiments, acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy

substituents defined herein are respectively lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they appear alone or in combination with other substituents, such as in the recitations hydroxyalkyl and aralkyl (in which case, for example, the atoms within the aryl group are not counted when counting the carbon atoms in the alkyl substituent).

As used herein, the term“oxo” refers to a carbonyl group. When an oxo substituent occurs on an otherwise saturated group, such as with an oxo-substituted cycloalkyl group (e.g., 3-oxo-cyclobutyl), the substituted group is still intended to be a saturated group. When a group is referred to as being substituted by an“oxo” group, this can mean that a carbonyl moiety (i.e., -C(=O)-) replaces a methylene unit (i.e., -CH2-).

The terms“polycyclyl”,“polycycle”, and“polycyclic” refer to two or more rings (e.g., cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls) in which two or more atoms are common to two adjoining rings, e.g., the rings are“fused rings”. Each of the rings of the polycycle can be substituted or unsubstituted. In certain embodiments, each ring of the polycycle contains from 3 to 10 atoms in the ring, preferably from 5 to 7.

The term“silyl” refers to a silicon moiety with three hydrocarbyl moieties attached thereto.

The term“substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that“substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as“unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to an“aryl” group or moiety implicitly includes both substituted and unsubstituted variants.

The term“sulfate” is art-recognized and refers to the group -OSO3H, or a pharmaceutically acceptable salt thereof. The term“sulfonamide” is art-recognized and refers to the group represented by the general formulae

wherein R ⁹ and R ¹⁰ independently represents hydrogen or hydrocarbyl, such as alkyl, or R ⁹ and R ¹⁰ taken together with the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.

The term“sulfoxide” is art-recognized and refers to the group -S(O)-R ¹⁰ , wherein R ¹⁰ represents a hydrocarbyl.

The term“sulfonate” is art-recognized and refers to the group SO3H, or a pharmaceutically acceptable salt thereof.

The term“sulfone” is art-recognized and refers to the group -S(O)2-R ¹⁰ , wherein R ¹⁰ represents a hydrocarbyl.

The term“thioalkyl”, as used herein, refers to an alkyl group substituted with a thiol group.

The term“thioester”, as used herein, refers to a group -C(O)SR ¹⁰ or -SC(O)R ¹⁰ wherein R ¹⁰ represents a hydrocarbyl.

The term“thioether”, as used herein, is equivalent to an ether, wherein the oxygen is replaced with a sulfur.

The term“urea” is art-recognized and may be represented by the general formula

wherein R ⁹ and R ¹⁰ independently represent hydrogen or a hydrocarbyl, such as alkyl, or either occurrence of R ⁹ taken together with R ¹⁰ and the intervening atom(s) complete a heterocycle having from 4 to 8 atoms in the ring structure.

“Protecting group” refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3 ^rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols.1-8, 1971-1996, John Wiley & Sons, NY. Representative nitrogen protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”), tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”), 2-trimethylsilyl-ethanesulfonyl (“TES”), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”), nitro-veratryloxycarbonyl (“NVOC”) and the like. Representative hydroxylprotecting groups include, but are not limited to, those where the hydroxyl group is either acylated (esterified) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers,

tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPS groups), glycol ethers, such as ethylene glycol and propylene glycol derivatives and allyl ethers.

As used herein, a therapeutic that“prevents” a disorder or condition refers to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

The term“treating” includes prophylactic and/or therapeutic treatments. The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

The term“prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into the therapeutically active agents of the present invention (e.g., a compound of formula I). A common method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids) are preferred prodrugs of the present invention. In certain

embodiments, some or all of the compounds of formula (I) or (Ia) in a formulation represented above can be replaced with the corresponding suitable prodrug, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate or carboxylic acid present in the parent compound is presented as an ester. Examples

Examples of compounds of Formula (I) or pharmaceutically acceptable salts thereof having useful biological activity are shown below (Table 1).

Table 1

23 5-bromo-1-(2-naphthylmethyl)- N-[(3R,4R,5S,6R)-2,4,5- trihydroxy-3,6- bis(hydroxymethyl)tetrahydropy ran-3-yl]indole-3-carboxamide

24 5,6-difluoro-1-(2- naphthylmethyl)-N- [(3R,4R,5S,6R)-2,4,5- trihydroxy-3,6- bis(hydroxymethyl)tetrahydropy ran-3-yl]indole-3-carboxamide

25 1-[(2-cyanophenyl)methyl]-6- methoxy-N-[(3R,4R,5S,6R)- 2,4,5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropy ran-3-yl]indole-3-carboxamide

26 1-[(3-cyanophenyl)methyl]-6- methoxy-N-[(3R,4R,5S,6R)- 2,4,5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropy ran-3-yl]indole-3-carboxamide

27 1-[(4-cyanophenyl)methyl]-6- methoxy-N-[(3R,4R,5S,6R)- 2,4,5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropy ran-3-yl]indole-3-carboxamide 33 6-[2-(methylamino)-2-oxo- ethoxy]-1-(2-naphthylmethyl)- N-[(3R,4R,5S,6R)-2,4,5- trihydroxy-3,6- bis(hydroxymethyl)tetrahydropy ran-3-yl]indole-3-carboxamide 34 1-(benzothiophen-2-ylmethyl)-6- methoxy-N-[(3R,4R,5S,6R)- 2,4,5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropy ran-3-yl]indole-3-carboxamide

35 5-fluoro-6-methoxy-1-(2- naphthylmethyl)-N- [(3R,4R,5S,6R)-2,4,5- trihydroxy-6-(hydroxymethyl)-3- methyl-tetrahydropyran-3- yl]indole-3-carboxamide

36 4-fluoro-1-(2-naphthylmethyl)- N-[(3R,4R,5S,6R)-2,4,5- trihydroxy-3,6- bis(hydroxymethyl)tetrahydropy ran-3-yl]indole-3-carboxamide

37 6-(2-methylpropanoyl)-1-(2- naphthylmethyl)-N- [(3R,4R,5S,6R)-2,4,5- trihydroxy-3,6- bis(hydroxymethyl)tetrahydropy ran-3-yl]indole-3-carboxamide

The ability of compounds Formula (I) or pharmaceutically acceptable salts thereof to inhibit HK2 and inhibit proliferation of cancer cells was established with the representative compounds of Formula (I) listed in Tables 2-5 using the assays described below. A. Chemical Syntheses

The general procedures used in the methods to prepare the compounds of the present invention are described below. General Experimental Section

LC-MS data are obtained using gradient elution on a parallel MUX system, running four Waters 1525 binary HPLC pumps, equipped with a MUX-UV 2488 multichannel UV- Vis detector (recording at 215 and 254 nM) and a Leap Technologies HTS PAL

autosampler using a Sepax GP-C18, 4.6 x 50 mm; 5 micron particle-size column. In general, a three minute gradient is run from 25% B (97.5%acetonitrile, 2.5% water, 0.05% TFA) and 75% A (97.5% water, 2.5% acetonitrile, 0.05% TFA) to 100% B. The system is interfaced with a Waters Micromass ZQ mass spectrometer using electrospray ionization. MassLynx software is employed. All MS data were obtained in the positive mode unless otherwise noted. The reported m/z data are generally accurate within about ±1 for the M+ ion.

1H NMR data were obtained on a Varian Mercury 400 MHz spectrometer and chemical shifts were referenced using either the residual solvent proton signal (e.g., residual CHCl ₃ in CDCl ₃ ) or the TMS signal as an internal reference. Microwave heating procedures were used in some experiments and, in these cases, a DISCOVER microwave synthesis system (CEM, Matthews, NC, USA) was used which included the use of pressurized glass reaction vessels at elevated temperatures. Medium pressure liquid chromatography (MPLC) was performed using Teledyne Isco CombiFlash Companion and CombiFlash Rf instruments, monitoring elution by UV absorption at 215 and 254 nM.

All reagents and solvents including anhydrous solvents were commercially available and were used as received unless described otherwise. Any solutions of Grignard reagents and organolithium reagents were commercially available and were used as received and at the concentrations listed on their labels. Reactions are stirred using a magnetic stirring apparatus and magnetic stir bar in most cases. All reactions using air-sensitive reagents were run under inert gas. For reactions not heated using a microwave-generating apparatus, the reaction temperatures reported in the experimental section refer to the temperatures of an oil bath or cooling bath placed around a reaction vessel. For reactions performed using a microwave-generating apparatus, the temperatures refer to the temperatures reported by the microwave apparatus. Abbreviations

Below are definitions of some common abbreviations that are used in the specification. The specification may also employ other abbreviations whose meanings are well known in the relevant art. Cbz = benzyloxycarbonyl

DCM = dichloromethane

DIC = N,N’-diisopropylcarbodiimide

DIEA, DIPEA = diisopropylethylamine

DME = 1,2-dimethoxyethane

DMF = N,N'-dimethylformamide

DMSO = dimethylsulfoxide

Et2O, ether = diethyl ether

EtOAc = ethyl acetate

EtOH = ethanol

h or hr = hours(s)

1H NMR = proton NMR analysis

HATU = N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmeth ylene]-N- methylmethanaminium hexafluorophosphate N-oxide

HBTU = 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate HCl = hydrochloric acid

HMDS = hexamethyldisilazane

LC/MS, LCMS = liquid chromatography- mass spectrometry analysis

MeOH = methanol

min = minute(s)

NMP = N-methylpyrrolidinone

rt = room temperature

SiO ₂ = silica gel

TEA = triethylamine

THF = tetrahydrofuran

TMSCl = chlorotrimethylsilane

TLC = thin layer chromatography

M = molar concentration

N = normal concentration General Procedure A : Alkylation of 1H-Indole/Indazole Carboxylic Acid To a solution of a 1H-indole/indazole carboxylic acid (20 mmol) in dry THF or DMF or DMSO (100 mL) is added slowly sodium hydride (60% dispersion in mineral oil, 60 mmol). To this mixture is added an alkyl bromide or chloride, or an aryl alkyl bromide or chloride (60 mmol), and the reaction mixture is heated to 50-60 ^C for 3 hr. The mixture is then cooled to rt and poured onto crushed ice and acidified with 2 N aqueous HCl to pH 4. The precipitate is collected, washed with water and dried. Alternatively, the reaction workup mixture is extracted with ethyl acetate. The organic layer is washed with water and brine, and is then dried over sodium sulfate and concentrated in vacuo to give an N- alkylated indole/indazole carboxylic acid. General Procedure B: Preparation of Indole Carboxylic Acids

Step 1: An indole derivative (20 mmol) is dissolved in DCM (15 mL) and pyridine (40 mmol) was added. The solution is cooled to ~ 0 ^C, and a solution of trichloroacetyl chloride (20 mmol) in DCM (5 mL) is added over the course of about 30 min. The cooling bath is removed and the reaction mixture is stirred at rt overnight. All the volatiles are removed under reduced pressure. The mixture is then stirred with ethanol-water (1:1, 15 mL) for 10 min, and the product is filtered off, dried and used without further purification. Alternatively, the reaction mixture is partitioned between water and ethyl acetate. The organic phase is washed with water, 1.0 N HCl, and brine. The organic layer is dried over Na2SO4 and concentrated under reduced pressure to give a trichloroacetyl indole derivative. Step 2: To the trichloroacetyl indole derivative (0.096 mmol) in NMP (0.20 mL) is added K ₂ CO ₃ (0.144 mmol) and alkyl chloride or bromide (0.125 mmol), and the reaction mixture is stirred overnight at rt. To the reaction mixture is added aqueous NaOH (0.10 mL, 4 N) and the reaction mixture is stirred overnight and then neutralized with 1.0 N HCl (pH = 7- 7.5). The reaction mixture is then partitioned between water and ethyl acetate. The organic layer is washed with water and brine, and is then dried over Na2SO4 and concentrated under reduced pressure to give an indole carboxylic acid. General Procedure C: HBTU Coupling

To a stirring solution of an amine or amine hydrochloride (1 mmol), a carboxylic acid (1 mmol), and HBTU (1 mmol) in dry DMF (2 mL), is added DIEA (2-3 mmol). The reaction mixture is heated at 90 ^C for 1 hour. The reaction progress is monitored by TLC and/or LCMS. The mixture is then concentrated in vacuo and the residue is purified by silica gel flash chromatography using a gradient of 2-10 % MeOH in DCM to give an amide. Intermediate Syntheses Intermediate 1; 6-Methoxy-1-(2-naphthylmethyl) indole-3-carboxylic acid

To a stirred solution of 6-methoxy-1H-indole-3-carboxylic acid (100 g, 520 mmol.) in DMF (4.0 L) at 0 ^o C was added NaH (60.0 g, 60% dispersion in mineral oil). After 2.5h.2- (bromomethyl)naphthalene (114 g, 520 mmol) followed by THF (1.0 L) were added and the mixture was stirred overnight at rt. To mixture was added ice followed by ice-water (6.0 L) containing HCl (200 ml, 37% aqueous). The mixture was stirred for 2h. The precipitate was collected by filtration, washed with H ₂ O (2.0 L), hexane/EtOAc (2.0 L, 4:1) and dried to give 163 g of 6-methoxy-1-(2-naphthylmethyl)indole-3-carboxylic acid, Intermediate 1. LCMS m/z 331.9. ¹ H NMR (400 MHz, DMSO-d6): δ 11.97 (s, 1H), 8.09 (s, 1H), 7.90-7.80 (m, 5H), 7.52-7.45 (m, 2H), 7.40 (dd, 1H), 7.12 (d, 1H), 6.81 (dd, 1H), 5.60 (s, 2H), 3.72 (s, 3H) ppm. Intermediate 2; (4aR,6S,8S,8aR)-6,8-Dibenzyloxy-2-phenyl-4,4a,8,8a- tetrahydropyrano[3,2-d][1,3]dioxin-7-one

(2S,3S,4S,5S,6R)-2-Benzyloxy-6-(hydroxymethyl)tetrahydropyra n-3,4,5-triol

Step 1; To a suspension of D-mannose (250 g, 555 mmol) in benzyl alcohol (1.0 L) was added acetyl chloride (40 mL). The mixture was stirred at 50 ^o C for 2 h. Benzyl alcohol was removed under high vacuum at 75 ^o C. The residue was then triturated with ethyl acetate to form a white solid. It was filtered and washed with ethyl acetate to give (2S,3S,4S,5S,6R)- 2-benzyloxy-6-(hydroxymethyl)tetrahydropyran-3,4,5-triol

(~250 g). ¹ H NMR (400 MHz, CD ₃ OD): δ 7.23-7.42 (m, 5H), 4.83 (s, 1H), 4.75 (d, 1H), 4.51 (d, 1H), 3.80-3.90 (m, 2H), 3.68-3.79 (m, 2H), 3.55-3.67 (m, 2H) ppm (protons on OH were not visible).

(4aR,6S,7S,8R,8aS)-6-Benzyloxy-2-phenyl-4,4a,6,7,8,8a-hex ahydropyrano[3,2- d][1,3]dioxine-7,8-diol

Step 2; To a solution of (2S,3S,4S,5S,6R)-2-benzyloxy-6-(hydroxymethyl)tetrahydropyra n- 3,4,5-triol (107.2 g, 397 mmol) in dry DMF (400 mL) was added PTSA (7.6 g, 39.7 mmol) and benzaldehyde dimethylacetal (59.5 mL, 397 mmol). The reaction mixture was stirred for 2 h at 60 ^o C under reduced pressure (200 mbar) using a rotary evaporator. The solvent was then evaporated, and the residue dissolved in ethyl acetate. The organic phase was washed with saturated NaHCO3, and the water phase was washed with ethyl acetate. The combined organic phase was washed again with water, dried, and concentrated. The crude product was purified by column chromatography (DCM to DCM/MeOH 20:1) to give (4aR,6S,7S,8R,8aS)-6-benzyloxy-2-phenyl-4,4a,6,7,8,8a-hexahy dropyrano[3,2- d][1,3]dioxine-7,8-diol (70 g). ¹ H NMR (400 MHz, CD3OD): δ 7.26-7.54 (m, 10H), 5.60 (s, 1H), 4.86 (s, 1H), 4.72 (d, 1H), 4.55 (d, 1H), 4.12-4.20 (m, 1H), 3.88-4.00 (m, 3H), 3.72- 3.86 (m, 2H) ppm (protons on OH were not visible). (4aR,6S,7S,8R,8aS)-6-Benzyloxy-8-methyl-2-phenyl-4,4a,6,7,8, 8a-hexahydropyrano[3,2- d][1,3]dioxin-7-ol

Step 3; To a suspension of (4aR,6S,7S,8R,8aS)-6-benzyloxy-2-phenyl-4,4a,6,7,8,8a- hexahydropyrano[3,2-d][1,3]dioxine-7,8-diol (114.3 g, 319 mmol) in dry toluene (1000 mL) was added Bu ₂ SnO (81 g, 325 mmol). The reaction mixture was stirred for 3 h at 120 ^o C. It was then allowed to cool to ambient temperature. Bu4NBr (109 g, 338 mmol), cesium fluoride (49.4 g, 325 mmol), and benzyl bromide (39.8 mL, 335 mmol) were added. The reaction mixture was stirred for 3 h at 120 ^o C, then allowed to cool to ambient temperature and diluted with ethyl acetate. The organic phase was washed with saturated NaHCO ₃ , and then filtered over Celite. The water phase was extracted with ethyl acetate. The combined organic phase was washed again with water, dried, and concentrated. The crude product was purified by column chromatography (hexanes to hexanes/ethyl acetate 1:1) to give (4aR,6S,7S,8R,8aS)-6-benzyloxy-8-methyl-2-phenyl-4,4a,6,7,8, 8a-hexahydropyrano[3,2- d][1,3]dioxin-7-ol (115 g). ¹ H NMR (400 MHz, CD3OD): δ 7.18-7.54 (m, 15H), 5.59 (s, 1H), 4.86 (s, 1H), 4.58-4.70 (m, 3H), 4.49 (d, 1H), 4.02-4.20 (m, 3H), 3.74-3.90 (m, 3H) ppm (protons on NH and OH were not visible).

(4aR,6S,8S,8aR)-6,8-Dibenzyloxy-2-phenyl-4,4a,8,8a-tetrah ydropyrano[3,2-d][1,3]dioxin- 7-one

Step 4; To a solution of oxalyl choride (50.3 mL, 594 mmol) in dry DCM (1000 mL) at -78 ^o C was slowly added DMSO (82 mL, 1.15 mol). The reaction was allow to stir 10 min, and a solution of (4aR,6S,7S,8R,8aS)-6-benzyloxy-8-methyl-2-phenyl-4,4a,6,7,8, 8a- hexahydropyrano[3,2-d][1,3]dioxin-7-ol (115 g, 256 mmol) in dry DCM (500 mL) was added at -78 ^o C. The reaction was stirred another 1 h at -78 ^o C. Triethylamine (317 mL, 2.27 mol) was added, and the reaction mixture was stirred for 1 h at 0 ^o C. It was then allowed to warm to ambient temperature. Water was added and the phases were separated. The water phase was extracted with ethyl acetate. The combined organic phase was dried and concentrated. The crude material was dissolved in DCM and diluted with hexanes. The resulting precipitate was collected by filtration and rinsed (10% ether in hexanes) to give (4aR,6S,8S,8aR)-6,8-dibenzyloxy-2-phenyl-4,4a,8,8a-tetrahydr opyrano[3,2-d][1,3]dioxin- 7-one (84 g). ¹ H NMR (400 MHz, CDCl3): δ 7.26-7.54 (m, 15H), 5.56 (s, 1H), 4.95 (s, 1H), 4.92 (d, 1H), 4.74 (dd, 2H), 4.60 (dd, 2H), 4.20-4.36 (m, 2H), 3.89 (t, 1H), 3.80 (t, 1H) ppm. Intermediate 3; (4aR,6R,8S,8aR)-6,8-Dibenzyloxy-2-phenyl-4,4a,8,8a-tetrahydr opyrano [3,2-d][1,3]dioxin-7-one

Step 1; To a solution of D-mannose (54 g, 300 mmol) in a 1L round-bottom flask was added Bu ₂ SnO (7.5 g, 30 mmol), TBAB (29.1 g, 90 mmol), DIEA (131 mL, 750 mmol) and BnBr (125 mL, 1050 mmol). The reaction was stirred at 70ºC for 2.5h. It turned into a pale-brown-yellow syrup, which was cooled to rt, dissolved in DCM and filtration-column through ~1.5 kg silica-gel flash chromatography eluting with hexanes, then ethyl acetate in hexanes (10% ethyl acetate– hexane gradient to 100% ethyl acetate) to give the title product as colorless sticky solid, 58.3 g. LCMS m/z 361.9. ¹ H NMR (400 MHz, CDCl3): δ 7.37-7.26 (m, 10H), 5.09 (dd, 1H), 5.02 (d, 1H), 4.84 (d, 1H), 4.69 (d, 1H), 4.64 (d, 1H), 4.54 (d, 1H), 4.11 (m, 1H), 3.71 (m, 1H), 3.69 (m, 1H), 3.56(t, 1H), 3.36(m, 1H) ppm (protons on OH were not visible). (4aR,6R,7S,8R,8aR)-6,8-Dibenzyloxy-2-phenyl-4,4a,6,7,8,8a-he xahydropyrano[3,2- d][1,3]dioxin-7-ol

Step 2; To a solution of above (2R,3S,4S,5R,6R)-2,4-dibenzyloxy-6- (hydroxymethyl)tetrahydropyran-3,5-diol (58 g, 161 mmol) in DMF (600 mL) in a 1L round-bottom flask was added benzaldehyde dimethyl acetal (58 mL) and p-TSA monohydrate (2 g). The reaction mixture was stirred at 50 ^o C overnight. After cooling to rt, the reaction was poured into ice and sodium bicarbonate. The mixture was stirred and white solid crashed out. It was collected, re-crystallized in MeOH, dried under vacuum to give the title compound as a white solid, 40 g. LCMS m/z 449.7. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.49 (m, 2H), 7.33(m, 13H), 5.58(s, 1H), 4.96 (d, 1H), 4.92 (d, 1H), 4.81 (d, 1H), 4.64 (d, 1H), 4.49 (d, 1H), 4.37 (dd, 1H), 3.82 (t, 1H), 3.72 (m, 1H), 3.63 (m, 2H), 3.45 (m, 1H) ppm (protons on OH were not visible). (4aR,6R,8S,8aR)-6,8-Dibenzyloxy-2-phenyl-4,4a,8,8a-tetrahydr opyrano[3,2-d][1,3]dioxin- 7-one

Step 3; To a solution of (4aR,6R,7S,8R,8aR)-6,8-dibenzyloxy-2-phenyl-4,4a,6,7,8,8a- hexahydropyrano[3,2-d][1,3]dioxin-7-ol (37 g) in DMSO (150 mL) in a 1L round-bottom flask was added Ac2O (250 mL). The reaction was stirred under nitrogen at 50 ^o C overnight. After cooling to rt, the reaction was poured into ice and sodium bicarbonate. The mixture was stirred and white solid crashed out. It was collected, re-crystallized in MeOH, dried under vacuum to give the title compound as a white solid, 28 g. LCMS m/z 447.9. ¹ H NMR (400 MHz, CDCl ₃ ): δ 7.60-7.20 (m, 15H), 5.58 (s, 1H), 4.97 (d, 1H), 4.92 (d, 1H), 4.85 (s, 1H), 4.75 (d, 1H), 4.71 (d, 1H), 4.47 (dd, 1H), 4.21 (d, 1H), 3.98 (t, 1H), 3.87 (t, 1H), 3.66(m, 1H) ppm. Intermediate 4; (3R,4R,5S,6R)-3-Amino-3,6-bis(hydroxymethyl)tetrahydropyran- 2,4,5- triol Hydrochloride

Step 1; To a solution of (4aR,6R,8S,8aR)-6,8-dibenzyloxy-2-phenyl-4,4a,8,8a- tetrahydropyrano[3,2-d][1,3]dioxin-7-one (Intermediate 3, 0.45g, 1 mmol) in anhydrous THF (5 ml) was added anhydrous chloroform (0.4 mL, 3eq). The mixture was stirred under nitrogen at -78 ^o C. A 1 M solution of LiHMDS (lithium hexamethyldisilazide) in THF (3 mL) was added dropwise. The reaction was stirred at -78 ^o C for 2h, and then poured into an ice-cold water, the mixture was extracted with DCM and washed with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4 and condensed. The residue was purified by silica gel flash chromatography eluting with hexanes/ethyl acetate

(v/v=10:1) to give (4aR,6R,7S,8S,8aR)-6,8-dibenzyloxy-2-phenyl-7-(trichlorometh yl)- 4a,6,8,8a-tetrahydro-4H-pyrano[3,2-d][1,3]dioxin-7-ol (0.52g ). LCMS m/z 565.8 ¹ H NMR (400 MHz, CDCl3): δ 7.40-7.18 (m, 15H), 5.54 (s, 1H), 5.20 (s, 1H), 4.89 (d, 1H), 4.82 (d, 1H), 4.73 (d, 1H), 4.65 (d, 1H), 4.48 (t, 1H), 4.27 (dd, 1H), 4.21 (d, 1H), 3.82 (m, 1H), 3.65 (t, 1H) ppm. Step 2; To a solution of (4aR,6R,7S,8S,8aR)-6,8-dibenzyloxy-2-phenyl-7- (trichloromethyl)-4a,6,8,8a-tetrahydro-4H-pyrano[3,2-d][1,3] dioxin-7-ol (0.52 g, 0.92 mmol) in anhydrous methanol (5 mL) was added sodium azide (0.5 g) and 18-crown-6 (10 mg). The mixture was stirred under nitrogen at rt for 10 min.. A solution of DBU (0.67 ml, 5 eq) in THF (3 ml) was added dropwise. The reaction was stirred at 50 ^o C for 1h. After cooling to rt, the reaction mixture was evaporated to dryness. The residue was taken by ethyl acetate with brine _. The organic layer was dried over MgSO ₄ and condensed. The residue was purified by silica gel flash chromatography eluting with hexanes/ethyl acetate (v/v=5:1 to 3:1) to give methyl (4aR,6R,7R,8R,8aS)-7-azido-6,8-dibenzyloxy-2-phenyl- 4a,6,8,8a-tetrahydro-4H-pyrano[3,2-d][1,3]dioxine-7-carboxyl ate (0.166 g). LCMS m/z 532.9 ¹ H NMR (400 MHz, CDCl3): δ 7.45-7.25 (m, 15H), 5.62 (s, 1H), 4.92 (d, 1H), 4.82(d, 1H), 4.81 (d, 1H), 4.67 (d, 1H), 4.59 (s, 1H), 4.40(m, 2H), 3.95 (t, 1H), 3.88 (s, 3H), 3.67(d, 1H), 3.40 (m, 1H) ppm. Step 3; To a suspension of LiAlH4 (40mg) in anhydrous diethyl ether was added a solution of methyl (4aR,6R,7R,8R,8aS)-7-azido-6,8-dibenzyloxy-2-phenyl-4a,6,8,8 a-tetrahydro- 4H-pyrano[3,2-d][1,3]dioxine-7-carboxylate (0.1g) in anhydrous diethyl ether (2 mL) dropwise at 0 ^o C. The reaction was stirred at 0 ^o C for 30 min then further stirred at rt for 30 min. The reaction was quenched with a saturated aqueous solution of Na2SO4 (1ml) and was followed by addition of a 10% aqueous solution of NaOH (1 mL). The mixture was extracted with DCM (2x50 mL). The organic layer was dried over MgSO ₄ and condensed. The residue was purified by silica gel flash chromatography eluting with DCM/ethyl acetate (v/v=5:1 to 5:2) to give [(4aR,6R,7R,8R,8aS)-7-amino-6,8-dibenzyloxy-2-phenyl- 4a,6,8,8a-tetrahydro-4H-pyrano[3,2-d][1,3]dioxin-7-yl]methan ol (0.039 g). LCMS m/z 478.9. ¹ H NMR (400 MHz, CDCl3): δ 7.42-7.18 (m, 15H), 5.54 (s, 1H), 4.94 (d, 1H), 4.81 (d, 1H), 4.58(d, 1H), 4.50 (d, 1H), 4.47(s, 1H), 4.31 (dd, 1H), 3.97 (d, 1H), 3.80(m, 3H), 3.64 (d, 1H), 3.45(m, 1H) ppm. Step 4; [(4aR,6R,7R,8R,8aS)-7-Amino-6,8-dibenzyloxy-2-phenyl-4a,6,8, 8a-tetrahydro- 4H-pyrano[3,2-d][1,3]dioxin-7-yl]methanol (0.18g) was placed in a 250-mL hydrogenation bottle and dissolved by addition of methanol (10 mL), THF (10 mL) and a solution of 4M HCl in 1,4-dioxane (0.2 mL). Pd-C (10% wet, 0.15 g) was added, the bottle was flushed several times with hydrogen. With the initial reading on the pressure gauge about 45 p.s.i., the bottle was stirred at rt for overnight. The catalyst was removed by filtration and washed with methanol. The filtrate was evaporated to dryness to give (3R,4R,5S,6R)-3-amino-3,6- bis(hydroxymethyl)tetrahydropyran-2,4,5-triol, Intermediate 4 (0.07 g). LCMS m/z 210.3. ¹ H NMR (400 MHz, CD3OD): δ 5.23 (s, 1H), 3.88 (d, 1H), 3.79 (d, 1H), 3.75 (d, 1H), 3.65 (m, 3H), 3.34(t, 1H) ppm (protons on NH and OH were not visible). Intermediate 5; (3R,4R,5S,6R)-3-Amino-6-(hydroxymethyl)-3-methyl-tetrahydrop yran- 2,4,5-triol Hydrochloride

Step 1; To a stirred solution of Intermediate 2 (45 g, 100.9 mmol) in THF (1 L) was added Ti(OEt)4 ( 27.6 g, 121.08 mmol) and (R)-(+)-2-methyl-2-propanesulfinamide (17.12 g, 141.26 mmol). The solution was stirred for 14 h at 50 ^o C, allowed to cool to room temperature and diluted with H ₂ O. The resulting suspension was filtered through Celite with an EtOAc rinse and the filtrate was extracted with EtOAc. The combined organics were dried over MgSO4, filtered and concentrated. (Note: N-sulfinyl ketimines are known to hydrolyze so this material was used immediately after solvent removal.) To a stirred solution of this residue in THF (1 L) and at -78 ^O C was added MeMgBr (158 mL, 1.4 M in THF:toluene (1:3)). The solution was allowed to warm to room temperature, stirred 14 h and then quenched with saturated aqueous NH ₄ Cl. The mixture was extracted with Et ₂ O. The organics were dried over MgSO ₄ , filtered, concentrated and purified by flash chromatography (SiO2, 10% to 40% acetone gradient in hexanes) to give 40 g of N- [(4aR,6S,7R,8R,8aS)-6,8-dibenzyloxy-7-methyl-2-phenyl-4a,6,8 ,8a-tetrahydro-4H- pyrano[3,2-d][1,3]dioxin-7-yl]-2-methyl-propane-2-sulfinamid e. LCMS m/z 566.2. ¹ H NMR (400 MHz, CDCl3): δ 7.41-7.23 (m, 15H), 5.57 (s, 1H), 4.42 (s, 1H), 4.83 (d, 1H), 4.68-4.60 (m, 3H), 4.32 (s, 1H), 4.24 (dd, 1H), 4.02-3.96 (m, 1H), 3.82 (dt, 2H), 3.70 (d, 1H), 1.63 (s, 3H), 1.20 (s, 9H) ppm. Step 2; To a stirred solution of N-[(4aR,6S,7R,8R,8aS)-6,8-dibenzyloxy-7-methyl-2- phenyl-4a,6,8,8a-tetrahydro-4H-pyrano[3,2-d][1,3]dioxin-7-yl ]-2-methyl-propane-2- sulfinamide (40 g, 70.8 mmol) in dioxane (400 mL) was added HCl (37 mL, 4M dioxane solution). After 30 min. the solution was concentrated and diluted with Et ₂ O. The resulting precipitate was collected by filtration, washed (10% Et2O in Hexanes) and allowed to dry. To a stirred solution of the resulting white powder in DCM (300 mL) and sat. aqueous NaHCO ₃ (300 mL) was added Di-tert-butyl dicarbonate (34 g, 155.7 mmol). The biphasic mixture was stirred for 18 h, extracted with DCM and the combined organics were concentrated. The resulting residue was purified by flash chromatography (SiO2, 10% to 60% EtOAc gradient in hexanes) to give 27 g of tert-butyl N-[(4aR,6S,7R,8R,8aS)-6,8- dibenzyloxy-7-methyl-2-phenyl-4a,6,8,8a-tetrahydro-4H-pyrano [3,2-d][1,3]dioxin-7- yl]carbamate. LCMS m/z 562.2. ¹ H NMR (400 MHz, CDCl3): δ 7.47-7.25 (m, 15H), 5.58 (s, 1H), 5.44 (s, 1H), 5.00 (d, 1H), 4.76 (s, 1H), 4.66 (t, 2H), 4.52 (d, 1H), 4.21 (dd, 1H), 3.95-3.83 (m, 3H), 3.78 (t, 1H), 1.52 (s, 3H), 1.38 (s, 9H) ppm. Step 3; To a stirred solution of tert-butyl N-[(4aR,6S,7R,8R,8aS)-6,8-dibenzyloxy-7- methyl-2-phenyl-4a,6,8,8a-tetrahydro-4H-pyrano[3,2-d][1,3]di oxin-7-yl]carbamate (14 g, 25 mmol) in THF/MeOH (260 mL, 1:1) was added palladium on carbon (5.2 g, 10% (dry basis), wet Degussa type) and HCl (15 mL, 4M dioxane solution). The mixture was stirred under 45 psi of H2 for 14 h, filtered through Celite with a MeOH rinse and concentrated to give (3R,4R,5S,6R)-3-amino-6-(hydroxymethyl)-3-methyl-tetrahydrop yran-2,4,5-triol hydrochloride (Intermediate 5) as a solid (7 g). ¹ H NMR (400 MHz, CD3OD): δ 5.61 and 5.02 (s, 1H), 4.20-3.55 (m, 5H), 1.46 and 1.32 (s, 3H) ppm (protons on NH and OH were not visible). Intermediate 6; 5-Fluoro-6-methox -1- 2-na hth lmeth l indole-3-carboxylic acid

Step 1: To a suspension of 4-fluoro-3-methoxy-aniline (37.5 g, 266 mmol) in dry DCM (500 mL) was added K ₂ CO ₃ (38.6 g, 279 mmol). The reaction mixture was cooled to -15 ^C, and a solution of bromine (13.63 mL, 266 mmol) in DCM (100 mL) was slowly added. It was stirred at -15 ^C for 1 h. The mixture was then allowed to warm to rt, and water was added. The reaction workup mixture was extracted with DCM. The organic layer was dried over sodium sulfate and concentrated in vacuo. The solid was dissolved in DCM and hexanes was added. The precipitate was filtered, washed with hexanes, and dried to give 2- bromo-4-fluoro-5-methoxy-aniline (53.5 g). Step 2: 2-Bromo-4-fluoro-5-methoxy-aniline (107 g, 0.486 mol) was dissolved in MeOH (400 mL) and methyl propiolate (130 mL, 1.46 mol) was added. The reaction mixture was stirred at reflux for 72 h. All the volatiles are removed under reduced pressure. The material was then triturated with hexanes three times, and the product was filtered off, dried and used without further purification, giving methyl 3-(2-bromo-4-fluoro-5-methoxy- anilino)prop-2-enoate (121.4 g). Step 3: To a solution of methyl 3-(2-bromo-4-fluoro-5-methoxy-anilino)prop-2-enoate (121.4 g, 0.399 mol) in anhydrous DMF (375 mL) was added tributylamine (190 mL, 0.799 mol) and tri(o-tolyl)phosphine (60.7 g, 0.20 mol). The reaction mixture was degassed twice then back filled with nitrogen. Palladium(II) acetate (8.96 g, 39.9 mmol) was added, and the reaction mixture was again degassed and back filled with nitrogen. It was stirred at 110 ^o C overnight, then allow to cool to rt. The reaction mixture was then partitioned between water and ethyl acetate. The organic layer was washed twice with 0.5 N HCl, and then dried over Na2SO4 and concentrated under reduced pressure. The material was then triturated three times with ethyl acetate, and the product was filtered off, dried and used without further purification, giving methyl 5-fluoro-6-methoxy-1H-indole-3-carboxylate (38.3 g). Step 4: To methyl 5-fluoro-6-methoxy-1H-indole-3-carboxylate (38.3 g, 171.6 mmol) in dry DMF (80 mL) was added K2CO3 (35.6 g, 257.4 mmol). To this mixture was added 2- (bromomethyl)naphthalene (45.5 g, 205.9 mmol), and the reaction mixture was stirred at rt overnight. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with water, dried over Na2SO4, and concentrated under reduced pressure. This material was dissolved in DCM/MeOH, and hexanes was added. The solid product was filtered off, washed with hexanes, dried and used without further purification, giving methyl 5-fluoro-6-methoxy-1-(2-naphthylmethyl)indole-3-carboxylate (55.6 g). Step 5: To 5-fluoro-6-methoxy-1-(2-naphthylmethyl)indole-3-carboxylate (55.6 g, 153 mmol) in THF/MeOH (150 mL, 2:1) was added aqueous NaOH (50 mL, 612 mmol) and the reaction mixture was stirred at 50 ^o C overnight. The reaction was concentrated and water was added. It was then acidified with 1.0 N HCl (pH = 3). The precipitate was filtered, washed with water, and then dried under vacuum. This material was triturated with ethyl acetate and dried under vacuum to give 5-fluoro-6-methoxy-1-(2-naphthylmethyl)indole-3- carboxylic acid (49 g). LCMS m/z 351.1. ¹ H NMR (400 MHz, DMSO-d6): δ 12.11 (s, 1H), 8.14 (s, 1H), 7.94-7.85 (m, 4H), 7.66 (d, 1H), 7.54-7.46 (m, 2H), 7.43 (t, 2H), 5.64 (s, 2H), 3.82 (s, 3H) ppm.

Example 1

6-Methoxy-1-(2-naphthylmethyl)-N-[(2R,3R,4R,5S,6R)-2,4,5- trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a solution of (2R,3R,4R,5S,6R)-3-amino-3,6- bis(hydroxymethyl)tetrahydropyran-2,4,5-triol (Intermediate 4) (25 mg) in DMF (0.8 mL) was added 6-methoxy-1-(2-naphthylmethyl)indole-3-carboxylic acid (Intermediate 1) (47 mg) and DIEA (0.1 mL). The mixture was stirred at rt for 5 min. HBTU (45 mg) was added. The reaction was stirred at 63 ^o C for 4h. After cooling to rt, the mixture was diluted with DCM (20 mL). The organic layer was washed with saturated aqueous solution of NaHCO3, dried over MgSO4 and condensed. The residue was purified by silica gel flash chromatography eluting with DCM/ methanol (v/v=100:10) to give 6-methoxy-1-(2- naphthylmethyl)-N-[(2R,3R,4R,5S,6R)-2,4,5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide (2.7 mg). LCMS m/z 523.8. ¹ H NMR (400 MHz, CD3OD): δ 7.95-7.55 (m, 2H), 7.84-7.78 (m, 2H), 7.78-7.72 (m, 1H), 7.65 (s, 1H), 7.48-7.42 (m, 2H), 7.31 (dd, 1H), 6.75 (d, 1H), 6.86 (dd, 1H), 5.56-5.50 (m, 3H), 4.58-4.00 (m, 3H), 3.95-3.40 (m, 4H), 3.73 (s, 3H) ppm (protons on NH and OH were not visible). Example 2

6-Methoxy-1-(1-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-tri hydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a solution of 6-methoxy-1-(1-naphthylmethyl)indole-3-carboxylic acid (prepared from 6-methoxyindole-3-carboxylic acid and 1-bromomethylnaphthalene following General Procedure A) (378 mg, 1.14 mmol) in anhydrous DMF (3 mL) was added Intermediate 4 (200 mg, 0.814 mmol), DIEA (0.426 mL, 2.44 mmol), and HBTU (370 mg, 0.977 mmol). The reaction was stirred at 55 ^o C for 6 h, then at rt overnight. Solvent was evaporated, and the mixture was purified by silica gel flash chromatography eluting with 0-10% methanol in DCM to give 6-methoxy-1-(1-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihyd roxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide (47 mg). LCMS m/z 523.8. ¹ H NMR (400 MHz, CD3OD): δ 8.01 (s, 1H), 7.95-7.77 (m, 3H), 7.53 (s, 2H), 7.39 (t, 1H), 7.10-6.95 (m, 2H), 6.90 (d, 1H), 5.86 (s, 2H), 5.53 (s, 1H), 4.56-3.92 (m, 3H), 3.90-3.42 (m, 8H) ppm (protons on NH and OH were not visible). Example 3

1-[(2,4-Dichlorophenyl)methyl]-6-methoxy-N-[(3R,4R,5S,6R) -2,4,5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a solution of 1-[(2,4-dichlorophenyl)methyl]-6-methoxy-indole-3-carboxylic acid (prepared from 6-methoxyindole-3-carboxylic acid and 2,4-dichlorobenzyl bromide following General Procedure A) (399 mg, 1.14 mmol) in anhydrous DMF (3 mL) was added Intermediate 4 (200 mg, 0.814 mmol), DIEA (0.426 mL, 2.44 mmol), and HBTU (370 mg, 0.977 mmol). The reaction was stirred at 55 ^o C for 6 h, then at rt overnight. Solvent was evaporated, and the mixture was purified by silica gel flash chromatography eluting with 0-10% methanol in DCM to give 1-[(2,4-dichlorophenyl)methyl]-6-methoxy- N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-3,6-bis(hydroxymethyl)tetr ahydropyran-3-yl]indole-3- carboxamide (76 mg). LCMS m/z 541.8. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.97-7.89 (m, 1H), 7.88-7.95 (m, 1H), 7.55 (s, 1H), 7.23 (d, 1H), 6.87 (s, 2H), 6.79 (s, 1H), 5.56 (s, 1H), 5.48 (s, 2H), 4.60-3.87 (m, 3H), 3.85-3.44 (m, 7H) ppm (protons on NH and OH were not visible). Example 4

6-Bromo-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihy droxy-3,6- bis h drox meth l tetrah dro ran-3- l indole-3-carboxamide

To a stirred solution of 6-bromo-1-(2-naphthylmethyl)-indole-3-carboxylic acid (prepared from 6-bromoindole-3-carboxylic acid and 2-bromomethylnaphthalene following General Procedure A) (254 mg, 0.68 mmol) and HBTU (283 mg, 0.75 mmol) in DMF (5 mL) was added DIPEA (0.3 mL, 1.7 mmol). After 20 min (3R,4R,5S,6R)-3-amino-3,6- bis(hydroxymethyl)tetrahydropyran-2,4,5-triol (200 mg, 0.82 mmol) was added and the solution was stirred for 14 h at 50 ^o C. The solution was concentrated, dispersed onto SiO2 and purified by flash chromatography (SiO ₂ , 0% to 10% MeOH gradient in DCM/acetone (1:1) to give 92 mg of 6-bromo-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihydro xy- 3,6-bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxam ide. LCMS m/z 572.0. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.95-7.85 (m, 2H), 7.84-7.70 (m, 3H), 7.65 (s, 1H), 7.48-7.40 (m, 2H), 7.31 (d, 1H), 6.96 (s, 1H), 6.85 (d, 1H), 5.55 (s, 3H), 4.58-4.00 (m, 3H), 3.95-3.40 (m, 4H), 3.73 (s, 3H) ppm (protons on NH and OH were not visible). Example 5

1-[(2,4-Dichlorophenyl)methyl]-5-methoxy-N-[(3R,4R,5S,6R) -2,4,5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a solution of 1-[(2,4-dichlorophenyl)methyl]-5-methoxy-indole-3-carboxylic acid (prepared from 5-methoxyindole-3-carboxylic acid and 2,4-dichlorobenzyl bromide following General Procedure A) (399 mg, 1.14 mmol) in anhydrous DMF (3 mL) was added Intermediate 4 (200 mg, 0.814 mmol), DIEA (0.426 mL, 2.44 mmol), and HBTU (370 mg, 0.977 mmol). The reaction was stirred at 55 ^o C for 6 h, then at rt overnight.

Solvent was evaporated, and the mixture was purified by silica gel flash chromatography eluting with 0-10% methanol in DCM to give 1-[(2,4-dichlorophenyl)methyl]-5-methoxy- N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-3,6-bis(hydroxymethyl)tetr ahydropyran-3-yl]indole-3- carboxamide (81 mg). LCMS m/z 541.7. ¹ H NMR (400 MHz, CD3OD): δ 7.99 (s, 1H), 7.56 (s, 1H), 7.43 (d, 1H), 7.32 (s, 1H), 7.26 (d, 1H), 7.07 (d, 1H), 6.85 (d, 1H), 5.58 (s, 1H), 5.40 (s, 2H), 4.60-4.00 (m, 3H), 3.95-3.37 (m, 7H) ppm (protons on NH and OH were not visible). Example 6

1-[(2,5-Dichlorophenyl)methyl]-6-methoxy-N-[(3R,4R,5S,6R) -2,4,5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a solution of 1-[(2,5-dichlorophenyl)methyl]-6-methoxy-indole-3-carboxylic acid (prepared from 6-methoxyindole-3-carboxylic acid and 2,5-dichlorobenzyl bromide following General Procedure A) (399 mg, 1.14 mmol) in anhydrous DMF (3 mL) was added (3R,4R,5S,6R)-3-amino-3,6-bis(hydroxymethyl)tetrahydropyran- 2,4,5-triol hydrochloride (200 mg, 0.814 mmol), DIEA (0.426 mL, 2.44 mmol), and HBTU (370 mg, 0.977 mmol). The reaction was stirred at 55 ^o C for 6 h, then at rt overnight. Solvent was evaporated, and the mixture was purified by silica gel flash chromatography eluting with 0- 10% methanol in DCM to give 1-[(2,5-dichlorophenyl)methyl]-6-methoxy-N- [(3R,4R,5S,6R)-2,4,5-trihydroxy-3,6-bis(hydroxymethyl)tetrah ydropyran-3-yl]indole-3- carboxamide (67 mg). LCMS m/z 541.8. ¹ H NMR (400 MHz, CD3OD): δ 7.98-7.90 (m, 1H), 7.89-7.80 (m, 1H), 7.48 (d, 1H), 7.40-7.28 (m, 1H), 6.90 (s, 2H), 6.77 (s, 1H), 5.57 (s, 1H), 5.48 (s, 2H), 4.60-4.00 (m, 3H), 3.96-3.58 (m, 7H) ppm (protons on NH and OH were not visible). Example 7

1-(1,3-Benzothiazol-2-ylmethyl)-6-methoxy-N-[(3R,4R,5S,6R )-2,4,5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a stirred solution of 1-(1,3-benzothiazol-2-ylmethyl)-6-methoxy-indole-3-carboxyli c acid (prepared from 6-methoxyindole-3-carboxylic acid and 2-bromomethylbenzothiazole following General Procedure A) (230 mg, 0.68 mmol) and HBTU (283 mg, 0.75 mmol) in DMF (5 mL) was added DIPEA (0.3 mL, 1.7 mmol). After 20 min Intermediate 4 (200 mg, 0.82 mmol) was added and the solution was stirred for 14 h at 50 ^o C. The solution was concentrated, dispersed onto SiO ₂ and purified by flash chromatography (SiO ₂ , 0% to 10% MeOH gradient in DCM/acetone (1:1) to give 80 mg of 1-(1,3-benzothiazol-2-ylmethyl)-6- methoxy-N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-3,6-bis(hydroxymet hyl)tetrahydropyran-3- yl]indole-3-carboxamide. LCMS m/z 530.3. ¹ H NMR (400 MHz, CD3OD): δ 8.02-7.95 (m, 2H), 7.94-7.84 (m, 2H), 7.49 (t, 1H), 7.39 (t, 1H), 7.04 (s, 1H), 6.87 (dd, 1H), 5.84 (s, 2H), 5.58 (s, 1H), 4.68-4.02 (m, 3H), 3.95-3.40 (m, 4H), 3.77 (s, 3H) ppm (protons on NH and OH were not visible). Example 8

1-(2-Naphthylmethyl)-6-thiazol-2-yl-N-[(3R,4R,5S,6R)-2,4, 5-trihydroxy-3,6- bis h drox meth l tetrah dro ran-3- l indole-3-carboxamide

6-Bromo-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid was synthesized from 6- bromoindole and 2-bromomethylnaphtlalene following General Procedure A.

6-Bromo-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid was taken into methanol. To this solution was added 2 M trimethylsilyldiazomethane in hexane (excess, 1.2-1.5 equiv). The mixture was stirred for 30 min and was concentrated to dryness. The residue was purified by silica gel column chromatography (hexane-EtOAc) to give 6-bromo-1- naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid methyl ester.

6-Bromo-1-naphthalen-2-ylmethyl-1H-indole-3-carboxylic acid methyl ester (5.9 g) and 2- tributylstannanyl-thiazole (7.1 g) were dissolved in DMF (30 mL) and the mixture was purged with nitrogen for 10 min. To this reaction mixture was added

dichlorobis(triphenylphosphine) palladium (II) (0.89 g) and the mixture was purged with nitrogen for another 10 min. The reaction mixture was stirred at 80 ^o C for 3.0 h, cooled to rt, and EtOAc (25 mL) and saturated KF solution (20 mL) were added. The reaction mixture was stirred at rt for 30 min and filtered through celite. The organic layer was separated, washed with water , brine, dried over Na ₂ SO ₄ . The solvent was evaporated and the residue was purified by silica gel flash chromatgraphy using a gradient of 10-20 % EtOAc in hexanes to give 1-naphthalen-2-ylmethyl-6-thiazol-2-yl-1H-indole-3-carboxyli c acid methyl ester.

The above ester was dissolved in 1:1 THF: methanol (20 mL) and was added 2.0 N lithium hydroxide (5.0 mL). The mixture was heated at 90 ^C overnight, cooled to rt, 1.0 N HCl (10 ml) was added and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give 1-(2-naphthylmethyl)-6- thiazol-2-yl-indole-3-carboxylic acid (5.0 g).

To a stirred solution of 1-(2-naphthylmethyl)-6-thiazol-2-yl-indole-3-carboxylic acid (261 mg, 0.68 mmol) and HBTU (283 mg, 0.75 mmol) in DMF (5 mL) was added DIPEA (0.3 mL, 1.7 mmol). After 20 min Intermediate 4 (200 mg, 0.82 mmol) was added and the solution was stirred for 14 h at 50 ^o C. The solution was concentrated, dispersed onto SiO ₂ and purified by flash chromatography (SiO2, 0% to 10% MeOH gradient in DCM/acetone (1:1) to give 80 mg of 1-(2-naphthylmethyl)-6-thiazol-2-yl-N-[(3R,4R,5S,6R)-2,4,5- trihydroxy-3,6-bis(hydroxymethyl)tetrahydropyran-3-yl]indole -3-carboxamide. LCMS m/z 573.3 ¹ H NMR (400 MHz, CD3OD): δ 8.20-8.02 (m, 3H), 7.90-7.65 (m, 5H), 7.80-7.20 (m, 5H), 5.70-5.55 (m, 3H) 4.60-4.05 (m, 3H), 3.99-3.40 (m, 4H) ppm (protons on NH and OH were not visible). Example 9

1-(Cyclohexylmethyl)-6-methoxy-N-[(3R,4R,5S,6R)-2,4,5-tri hydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a solution of 1-(cyclohexylmethyl)-6-methoxy-indole-3-carboxylic acid (prepared from 6-methoxyindole-3-carboxylic acid and cyclohexylmethyl bromide following General Procedure A) (328 mg, 1.14 mmol) in anhydrous DMF (3 mL) was added Intermediate 4 (200 mg, 0.814 mmol), DIEA (0.426 mL, 2.44 mmol), and HBTU (370 mg, 0.977 mmol). The reaction was stirred at 55 ^o C for 6 h, then at rt overnight. Solvent was evaporated, and the mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1) to give 1-(cyclohexylmethyl)-6-methoxy-N- [(3R,4R,5S,6R)-2,4,5-trihydroxy-3,6-bis(hydroxymethyl)tetrah ydropyran-3-yl]indole-3- carboxamide (90 mg). LCMS m/z 479.3. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.02-7.92 (m, 1H), 7.79-7.67 (m, 1H), 6.95 (s, 1H), 6.86 (d, 1H), 5.65-5.42 (m, 1H), 4.60-4.04 (m, 3H), 3.82-3.40 (m, 9H), 1.80-0.90 (m, 11H) ppm (protons on NH and OH were not visible). Example 10

1-[(3,4-Dichlorophenyl)methyl]-6-methoxy-N-[(3R,4R,5S,6R) -2,4,5-trihydroxy-3,6- bis h drox meth l tetrah dro ran-3- l indazole-3-carboxamide

To a solution of 1-[(3,4-dichlorophenyl)methyl]-6-methoxy-indazole-3-carboxyl ic acid (prepared from 6-methoxyindazole-3-carboxylic acid and 3,4-dichlorobenzyl bromide following General Procedure A) (400 mg, 1.14 mmol) in anhydrous DMF (3 mL) was added Intermediate 4 (200 mg, 0.814 mmol), DIEA (0.426 mL, 2.44 mmol), and HBTU (370 mg, 0.977 mmol). The reaction was stirred at 55 ^o C for 6 h, then at rt overnight.

Solvent was evaporated, and the mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1) to give 1-[(3,4- dichlorophenyl)methyl]-6-methoxy-N-[(3R,4R,5S,6R)-2,4,5-trih ydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indazole-3-carboxamid e (105 mg). LCMS m/z 542.2. ¹ H NMR (400 MHz, CD3OD): δ 8.12-8.01 (m, 1H), 7.45 (d, 1H), 7.40 (s, 1H), 7.17- 7.09 (m, 1H), 6.98 (s, 1H), 6.91 (d, 1H), 5.68-5.45 (m, 3H), 4.68-4.00 (m, 3H), 3.98-3.40 (m, 7H) ppm (protons on NH and OH were not visible). Example 11

1-(2-Naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-3, 6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a stirred solution of 1-(2-naphthylmethyl)-indole-3-carboxylic acid (prepared from indole-3-carboxylic acid and 2-bromomethylnaphthalene following General Procedure A) (204 mg, 0.68 mmol) and HBTU (283 mg, 0.75 mmol) in DMF (5 mL) was added DIPEA (0.3 mL, 1.7 mmol). After 20 min Intermediate 4 (200 mg, 0.82 mmol) was added and the solution was stirred for 14 h at 50 ^o C. The solution was concentrated, dispersed onto SiO2 and purified by flash chromatography (SiO2, 0% to 10% MeOH gradient in DCM/acetone (1:1) to give 55 mg of 1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide. LCMS m/z 494.4 ¹ H NMR (400 MHz, CD3OD): δ 8.10-7.92 (m, 2H), 7.78-7.60 (m, 3H), 7.51 (s, 1H), 7.45-7.25 (m, 3H), 7.24-7.15 (m, 3H), 5.64 and 5.58 (s, 1H), 5.36 (s, 2H) 4.60-4.05 (m, 3H), 3.99-3.40 (m, 4H) ppm (protons on NH and OH were not visible). Example 12

1-[(3,4-Dichlorophenyl)methyl]-6-methoxy-N-[(3R,4R,5S,6R) -2,4,5-trihydroxy-3,6- bis h drox meth l tetrah dro ran-3- l indole-3-carboxamide

To a solution of 1-[(3,4-dichlorophenyl)methyl]-6-methoxy-indole-3-carboxylic acid (prepared from 6-methoxyindole-3-carboxylic acid and 3,4-dichlorobenzyl bromide following General Procedure A) (399 mg, 1.14 mmol) in anhydrous DMF (3 mL) was added Intermediate 4 (200 mg, 0.814 mmol), DIEA (0.426 mL, 2.44 mmol), and HBTU (370 mg, 0.977 mmol). The reaction was stirred at 55 ^o C for 6 h, then at rt overnight.

Solvent was evaporated, and the mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1) to give 1-[(3,4- dichlorophenyl)methyl]-6-methoxy-N-[(3R,4R,5S,6R)-2,4,5-trih ydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide (52 mg). LCMS m/z 541.2. ¹ H NMR (400 MHz, CD3OD): δ 7.96-7.80 (m, 2H), 7.44 (d, 1H), 7.34 (s, 1H), 7.07 (d, 1H), 6.95-6.80 (m, 2H), 5.65-5.34 (m, 3H), 4.64-4.00 (m, 3H), 3.96-3.36 (m, 7H) ppm (protons on NH and OH were not visible). Example 13

1-[(3,4-Dichlorophenyl)methyl]-5-methoxy-N-[(3R,4R,5S,6R) -2,4,5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a solution of 1-[(3,4-dichlorophenyl)methyl]-5-methoxy-indole-3-carboxylic acid (prepared from 5-methoxyindole-3-carboxylic acid and 3,4-dichlorobenzyl bromide following General Procedure A) (299 mg, 0.855 mmol) in anhydrous DMF (3 mL) was added Intermediate 4 (150 mg, 0.611 mmol), DIEA (0.319 mL, 1.833 mmol), and HBTU (278 mg, 0.733 mmol). The reaction was stirred at 55 ^o C for 6 h, and the solvent was evaporated. The mixture was purified by silica gel flash chromatography eluting with 0- 10% methanol gradient in DCM/acetone (1:1) to give 1-[(3,4-dichlorophenyl)methyl]-5- methoxy-N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-3,6-bis(hydroxymet hyl)tetrahydropyran-3- yl]indole-3-carboxamide (153 mg). LCMS m/z 541.2. ¹ H NMR (400 MHz, CD3OD): δ 8.02-7.90 (m, 1H), 7.62-7.54 (m, 1H), 7.43 (d, 1H), 7.36-7.30 (m, 1H), 7.26 (d, 1H), 7.07 (d, 1H), 6.87 (d, 1H), 5.64-5.33 (m, 3H), 4.60-4.00 (m, 3H), 3.98-3.45 (m, 7H) ppm

(protons on NH and OH were not visible). Example 14

6-(2-Morpholinoethoxy)-1-(2-naphthylmethyl)-N-[(3R,4R,5S, 6R)-2,4,5-trihydroxy-3,6- bis h drox meth l tetrah dro ran-3- l indole-3-carboxamide

To a stirred solution of 1H-indol-6-ol (500mg, 3.76 mmol) at 0 ^o C in DMF (10 mL) was added NaH (200 mg, 60% dispersion in mineral oil). After 1 h 4-(2-chloroethyl)morpholine (1.0 g, 5.6 mmol) was added and the solution was stirred for 14 h at rt. The mixture diluted with H ₂ O, extracted with EtOAc, dried (Na ₂ SO ₄ ), concentrated and purified by flash chromatography (SiO2, 0% to 10% MeOH gradient in DCM) to give 650 mg of 4-[2-(1H- indol-6-yloxy)ethyl]morpholine.

To a stirred solution of 4-[2-(1H-indol-6-yloxy)ethyl]morpholine (1.0 g, 4.0 mmol) in DMF was added TFAA (0.67 mL, 4.9 mmol). The solution stirred for 14 h at rt, diluted with H2O, extracted with EtOAc, dried (Na2SO4) and concentrated. The residue was mixed into 10% aqueous NaOH, refluxed for 4h, cooled, washed with DCM, and acidified to pH 2.0 with HCl. The resulting solids were filtered, washed with H2O, and air dried. To a stirred solution of the dry solids (290 mg) in DMF (3 mL) at 0 ^o C was added NaH (9 mg, 60% dispersion in mineral oil). After 1h 2-(bromomethyl)naphthalene (227 mg, 1.0 mmol) was added and the mixture was stirred for 14 h at rt. The mixture was diluted with H ₂ O, acidified to pH 6.0 using 1.0 M HCl, extracted with EtOAc, dried (Na2SO4), concentrated and purified by flash chromatography (SiO ₂ , 0% to 10% MeOH gradient in DCM) to give 100 mg of 6-(2-morpholinoethoxy)-1-(2-naphthylmethyl)indole-3-carboxyl ic acid.

To a stirred solution of 6-(2-morpholinoethoxy)-1-(2-naphthylmethyl)indole-3-carboxyl ic acid (100 mg, 0.23 mmol) and HBTU (95 mg, 0.25 mmol) in DMF (3 mL) was added DIPEA (0.12 mL, 0.7 mmol). After 20 min Intermediate 4 (70 mg, 0.3 mmol) was added and the solution was stirred for 14 h at 65 ^o C. The solution was concentrated, dispersed onto SiO2 and purified by flash chromatography (SiO2, 0% to 10% MeOH gradient in

DCM/acetone (1:1) to give 30 mg of 6-(2-morpholinoethoxy)-1-(2-naphthylmethyl)-N- [(3R,4R,5S,6R)-2,4,5-trihydroxy-3,6-bis(hydroxymethyl)tetrah ydropyran-3-yl]indole-3- carboxamide. LCMS m/z 623.0 ¹ H NMR (400 MHz, CD3OD): δ 8.03-7.92 (m, 2H), 7.86- 7.72 (m, 3H), 7.64 (s, 1H), 7.52-7.41 (m, 2H), 7.39-7.25 (m, 1H), 7.69 (s, 1H), 6.90 (d, 1H), 5.57 (s, 3H), 4.60-4.00 (m, 5H), 3.95-3.40 (m, 8H), 3.0-2.90 (m, 2H), 2.82-2.70 (m, 4H) ppm (protons on NH and OH were not visible). Example 15

5-Fluoro-1-(1-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trih ydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a stirred solution of 5-fluoro-1-(1-naphthylmethyl)-indole-3-carboxylic acid (prepared from 5-fluoroindole-3-carboxylic acid and 1-bromomethylnaphthalene following General Procedure A) (160 mg, 0.5 mmol) and HBTU (212 mg, 0.56 mmol) in DMF (4 mL) was added DIPEA (0.26 mL, 1.5 mmol). After 20 min Intermediate 4 (150 mg, 0.6 mmol) was added and the solution was stirred for 14 h at 65 ^o C. The solution was concentrated, dispersed onto SiO2 and purified by flash chromatography (SiO2, 0% to 10% MeOH gradient in DCM/acetone (1:1) to give 15 mg of 5-fluoro-1-(1-naphthylmethyl)-N- [(3R,4R,5S,6R)-2,4,5-trihydroxy-3,6-bis(hydroxymethyl)tetrah ydropyran-3-yl]indole-3- carboxamide. LCMS m/z 511.9. ¹ H NMR (400 MHz, CD3OD): δ 8.08-7.95 (m, 1H), 7.95- 7.84 (m, 3H), 7.82-7.73 (m, 1H), 7.60-7.45 (m, 3H), 7.38 (t, 1H), 7.09-6.98 (m, 2H), 5.91 (s, 2H), 5.55 and 5.48 (s, 1H), 4.55-4.00 (m, 3H), 3.90-3.50 (m, 4H) ppm (protons on NH and OH were not visible). Example 16

5-Fluoro-6-methoxy-1-(1-naphthylmethyl)-N-[(3R,4R,5S,6R)- 2,4,5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a stirred solution of 5-fluoro-6-methoxy-1-(1-naphthylmethyl)-indole-3-carboxylic acid (prepared in analogous fashion to Intermediate 6 with use of 1-bromomethylnaphthalene in place of 2-bromomethylnaphthalene) (175 mg, 0.5 mmol) and HBTU (212 mg, 0.56 mmol) in DMF (4 mL) was added DIPEA (0.26 mL, 1.5 mmol) After 20 min Intermediate 4 (150 mg, 0.6 mmol) was added and the solution was stirred for 14 h at 65 ^o C. The solution was concentrated, dispersed onto SiO2 and purified by flash chromatography (SiO2, 0% to 10% MeOH gradient in DCM/acetone (1:1)) to give 20 mg of 5-fluoro-6-methoxy-1-(1- naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide. LCMS m/z 541.9. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.08-7.95 (m, 1H), 7.94-7.88 (m, 1H), 7.85 (d, 1H), 7.76-7.70 (m, 2H), 7.56-7.48 (m, 2H), 7.37 (t, 1H), 7.10 (t, 1H), 7.03 (t, 1H), 5.83 (s, 2H), 5.55 and 5.53 (s, 1H), 4.55-4.00 (m, 3H), 3.90-3.50 (m, 4H) 3.78 (s, 3H) ppm (protons on NH and OH were not visible). Example 17

5-Fluoro-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trih ydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a solution of 5-fluoro-1-(2-naphthylmethyl)indole-3-carboxylic acid (prepared from 6- fluoroindole-3-carboxylic acid and 2-bromomethylnaphthalene following General

Procedure A) (191 mg, 0.598 mmol) in anhydrous DMF (3 mL) was added Intermediate 4 (105 mg, 0.427 mmol), DIEA (0.224 mL, 1.28 mmol), and HBTU (195 mg, 0.513 mmol). The reaction was stirred at 55 ^o C for 6 h, then at rt overnight. Solvent was evaporated, and the mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1) to give 5-fluoro-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)- 2,4,5-trihydroxy-3,6-bis(hydroxymethyl)tetrahydropyran-3-yl] indole-3-carboxamide (73 mg). LCMS m/z 511.2. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.07-7.96 (m, 1H), 7.78-7.60 (m, 4H), 7.57 (s, 1H), 7.42-7.27 (m, 3H), 7.21 (d, 1H), 6.87 (t, 1H), 5.58-5.40 (m, 3H), 4.50- 3.89 (m, 3H), 3.85-3.30 (m, 4H) ppm. (protons on NH and OH were not visible). Example 18

5-Fluoro-6-methoxy-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)- 2,4,5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a solution of Intermediate 6 (209 mg, 0.598 mmol) in anhydrous DMF (3 mL) was added Intermediate 4 (105 mg, 0.427 mmol), DIEA (0.224 mL, 1.28 mmol), and HBTU (195 mg, 0.513 mmol). The reaction was stirred at 55 ^o C for 6 h, then at rt overnight.

Solvent was evaporated, and the mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1) to give 5-fluoro-6-methoxy-1- (2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide (135 mg). LCMS m/z 541.2. ¹ H NMR (400 MHz, CD3OD): δ 7.92-7.80 (m, 1H), 7.78-7.60 (m, 4H), 7.57 (s, 1H), 7.42-7.30 (m, 2H), 7.22 (d, 1H), 7.01 (d, 1H), 5.57-5.41 (m, 3H), 4.50-3.86 (m, 3H), 3.84- 3.32 (m, 7H) ppm (protons on NH and OH were not visible). Example 19

6-Methoxy-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-tri hydroxy-6-(hydroxymethyl)- 3-methyl-tetrahydropyran-3-yl]indole-3-carboxamide

To a stirred solution of [(4aR,6R,7S,8S,8aS)-7-amino-6-benzyloxy-8-(phenoxymethyl)-2- phenyl-4a,6,8,8a-tetrahydro-4H-pyrano[3,2-d][1,3]dioxin-7-yl ]methanol

(275 mg, 0.57 mmol) in THF (5 mL) was added TEA (0.15 mL) and di-tert-butyl dicarbonate (150 mg, 0.69 mmol). The solution was stirred for 14 h at rt and concentrated. The residue was dissolved in EtOAc, washed with H ₂ O, dried (Na ₂ SO ₄ ) and concentrated to give 330 mg of tert-butyl N-[(4aR,6R,7S,8S,8aS)-6-benzyloxy-7-(hydroxymethyl)-8- (phenoxymethyl)-2-phenyl-4a,6,8,8a-tetrahydro-4H-pyrano[3,2- d][1,3]dioxin-7- yl]carbamate. To a stirred solution of tert-butyl N-[(4aR,6R,7R,8R,8aS)-6,8-dibenzyloxy-7- (hydroxymethyl)-2-phenyl-4a,6,8,8a-tetrahydro-4H-pyrano[3,2- d][1,3]dioxin-7- yl]carbamate (329 mg, 0.57 mmol) in DCM (10 mL) was added pentafluorophenyl chlorothionoformate (0.097 mL, 0.57 mmol) and pyridine (0.055 mL, 0.68 mmol). The solution was stirred for 14 h at rt. The solution was washed with H2O, dried (Na2SO4), concentrated and purified by flash chromatography (SiO ₂ , 0% to 30% EtOAc gradient in hexanes) to give 130 mg of tert-butyl N-[(4aR,6R,7R,8R,8aS)-6,8-dibenzyloxy-7- [(2,3,4,5,6-pentafluorophenoxy)carbothioyloxymethyl]-2-pheny l-4a,6,8,8a-tetrahydro-4H- pyrano[3,2-d][1,3]dioxin-7-yl]carbamate.

To a stirred solution of tert-butyl N-[(4aR,6R,7R,8R,8aS)-6,8-dibenzyloxy-7-[(2,3,4,5,6- pentafluorophenoxy)carbothioyloxymethyl]-2-phenyl-4a,6,8,8a- tetrahydro-4H-pyrano[3,2- d][1,3]dioxin-7-yl]carbamate (120 mg, 0.15 mmol) in tris(trimethylsilyl)silane (0.35 mL) was added azobisisobutyronitrile (10 mg, 0.06 mmol).The mixture was heated for 1.5 h at 90 ^o C and a second portion of azobisisobutyronitrile (10 mg, 0.06 mmol) was added. The stirred solution was heated for 45 min. at 115 ^o C. The cooled mixture was purified by flash chromatography (SiO ₂ , 0% to 20% EtOAc gradient in hexanes) to give 75 mg of tert-butyl N-[(4aR,6R,7R,8R,8aS)-6,8-dibenzyloxy-7-methyl-2-phenyl-4a,6 ,8,8a-tetrahydro-4H- pyrano[3,2-d][1,3]dioxin-7-yl]carbamate. To a stirred solution of tert-butyl N-[(4aR,6R,7R,8R,8aS)-6,8-dibenzyloxy-7-methyl-2- phenyl-4a,6,8,8a-tetrahydro-4H-pyrano[3,2-d][1,3]dioxin-7-yl ]carbamate (75 mg, 0.13 mmol) in THF/MeOH (6 mL, 1:1) was added palladium on carbon (30 mg, 10% (dry basis), wet Degussa type) and HCl (0.15 mL, 4M Dioxane solution). The mixture was stirred under 45 psi of H ₂ for 14 h, filtered through Celite with a MeOH rinse and concentrated to give a solidified foam (42 mg) that was used directly in the next reaction.

To a stirred solution of 6-methoxy-1-(2-naphthylmethyl)-indole-3-carboxylic acid (65 mg, 0.2 mmol) and HBTU (75 mg, 0.22 mmol) in DMF (2 mL) was added DIPEA (0.1 mL, 0.6 mmol) After 15 min. the product from the previous step (42 mg, 0.2 mmol) was added and the solution was stirred for 14 h at 60 ^o C. The solution was concentrated, dispersed onto SiO2 and purified by flash chromatography (SiO2, 0% to 10% MeOH gradient in

DCM/acetone (1:1) to give 8 mg of 6-methoxy-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)- 2,4,5-trihydroxy-6-(hydroxymethyl)-3-methyl-tetrahydropyran- 3-yl]indole-3-carboxamide. LCMS m/z 508.0. ¹ H NMR (400 MHz, CD3OD): δ 7.94-7.71 (m, 5H), 7.65 (s, 1H), 7.47- 7.42 (m, 2H), 7.32 (dt, 1H), 6.95 (d, 1H), 6.85 (s, 1H), 5.61 and 5.30 (s, 1H), 5.55 (s, 2H), 4.20 and 3.98 (d, 1H), 3.82-3.39 (m, 4H), 3.74 (s, 3H), 1.54 and 1.32 (s, 3H) ppm (protons on NH and OH were not visible). Example 20

6-Acetyl-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trih ydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a solution of 6-acetyl-1-(2-naphthylmethyl)indole-3-carboxylic acid (prepared from 6- acetylindole-3-carboxylic acid and 2-bromomethylnaphthalene following General Procedure A) (252 mg, 0.733 mmol) in anhydrous DMF (3 mL) was added Intermediate 4 (150 mg, 0.611 mmol), DIEA (0.320 mL, 1.83 mmol), and HBTU (278 mg, 0.733 mmol). The reaction was stirred at 55 ^o C for 5 h, then at rt overnight. Solvent was evaporated, and the mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1) to give 6-acetyl-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)- 2,4,5-trihydroxy-3,6-bis(hydroxymethyl)tetrahydropyran-3-yl] indole-3-carboxamide (74 mg). LCMS m/z 535.3. ¹ H NMR (400 MHz, CD3OD): δ 8.32-8.22 (m, 1H), 8.20-8.10 (m, 2H), 7.90-7.74 (m, 4H), 7.71 (s, 1H), 7.50-7.40 (m, 2H), 7.34 (d, 1H), 5.69 (s, 2H), 5.64- 5.56 (m, 1H), 4.65-3.98 (m, 3H), 3.96-3.45 (m, 4H), 2.59 (s, 3H) ppm (protons on NH and OH were not visible). Example 21

tert-Butyl 2-[1-(2-naphthylmethyl)-3-[[(3R,4R,5S,6R)-2,4,5-trihydroxy-3 ,6- bis(hydroxymethyl)tetrahydropyran-3-yl]carbamoyl]indol-6-yl] oxyacetate

To a stirred solution of 1H-indol-6-ol (2.8mg, 21 mmol) at 0 ^o C in DMF (50 mL) was added NaH (1.0 g, 60% dispersion in mineral oil). After 1 h tert-butyl 2-bromoacetate (4.1 g, 21 mmol) was added and the solution was stirred for 14 h at rt. The mixture diluted with H ₂ O, extracted with EtOAc, dried (Na ₂ SO ₄ ), concentrated and purified by flash

chromatography (SiO2, 0% to 10% MeOH gradient in DCM) to give 2.9 g of tert-butyl 2- (1H-indol-6-yloxy)acetate.

To a stirred solution of tert-butyl 2-(1H-indol-6-yloxy)acetate in DCM (25 mL) and pyridine (1.38 g, 17.5 mmol) at 0 ^C was added and a solution of trichloroacetyl chloride (3.2 g, 17.5 mmol) in DCM (5 mL). The mixture was stirred for 14 h at rt, and

concentrated. The residue was dissolved in EtOAc, washed with water, 1.0 N HCl, and brine. The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure to give 5.2 g of tert-butyl 2-[[3-(2,2,2-trichloroacetyl)-1H-indol-6-yl]oxy]acetate.

To a stirred mixture of tert-butyl 2-[[3-(2,2,2-trichloroacetyl)-1H-indol-6-yl]oxy]acetate (5.2 g, 13.26 mmol) and K ₂ CO ₃ (2.75 g, 20 mmol) in NMP (75 mL) was added 2- (bromomethyl)naphthalene (4.2 g, 20 mmol). The mixture was stirred for 14 h, diluted with H2O, extracted with EtOAc, dried (Na2SO4), concentrated and purified by flash

chromatography (SiO2, 0% to 30% EtOAc gradient in hexanes) to give 4.3 g of tert-butyl 2- [1-(2-naphthylmethyl)-3-(2,2,2-trichloroacetyl)indol-6-yl]ox yacetate.

To a stirred solution of tert-butyl 2-[1-(2-naphthylmethyl)-3-(2,2,2-trichloroacetyl)indol-6- yl]oxyacetate (4.2 g, 7.9 mmol) in THF/MeOH/H2O (60 mL, 1:1:1) was added LiOH (280 mg, 40 mmol). The mixture was stirred for 14 h, acidified to pH 6.0 using 1.0 M HCl, extracted with EtOAc, dried (Na ₂ SO ₄ ), concentrated and purified by flash chromatography (SiO2, 0% to 70% EtOAc gradient in hexanes) to give 1.5 g of 6-(2-tert-butoxy-2-oxo- ethoxy)-1-(2-naphthylmethyl)indole-3-carboxylic acid and 1.2 g of 2-[3-methoxycarbonyl- 1-(2-naphthylmethyl)indol-6-yl]oxyacetic acid. To a stirred solution of 6-(2-tert-butoxy-2-oxo-ethoxy)-1-(2-naphthylmethyl)indole-3- carboxylic acid (81 mg, 0.27 mmol) and HBTU (0.165 mL, 0.29 mmol) in DMF (4 mL) was added DIPEA (0.26 mL, 0.8 mmol). After 20 min Intermediate 4 (81 mg, 0.33 mmol) was added and the solution was stirred for 14 h at 55 ^o C. The solution was concentrated, dispersed onto SiO2 and purified by flash chromatography (SiO2, 0% to 10% MeOH gradient in DCM/acetone (1:1) to give 35 mg of 1-[(4-tert-butylphenyl)methyl]-6-methoxy- N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-3,6-bis(hydroxymethyl)tetr ahydropyran-3-yl]indole-3- carboxamide. LCMS m/z 624.1 ¹ H NMR (400 MHz, CD3OD): δ 8.03-7.92 (m, 2H), 7.86- 7.72 (m, 2H), 7.60 (s, 1H), 7.52-7.41 (m, 2H), 7.39-7.22 (m, 1H), 7.19-7.09 (m, 1H), 7.00- 6.85 (m, 2H), 5.64-5.48 (m, 3H), 4.60-3.40 (m, 7H), 4.53 (s, 2H), 1.30 (s, 9H) ppm (protons on NH and OH were not visible). Example 22

6-Methylsulfonyl-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2, 4,5-trihydroxy-3,6- bis h drox meth l tetrah dro ran-3- l indole-3-carboxamide

To a solution of 6-methylsulfonyl-1-(2-naphthylmethyl)indole-3-carboxylic acid (prepared from 6-methylsulfonylindole-3-carboxylic acid and 2-bromomethylnaphthalene following General Procedure A) (193 mg, 0.488 mmol) in anhydrous DMF (3 mL) was added Intermediate 4 (100 mg, 0.407 mmol), DIEA (0.213 mL, 1.22 mmol), and HBTU (185 mg, 0.488 mmol). The reaction was stirred at 55 ^o C for 5 h, then at rt overnight. Solvent was evaporated, and the mixture was purified by silica gel flash chromatography eluting with 0- 10% methanol gradient in DCM/acetone (1:1) to give 6-methylsulfonyl-1-(2- naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide (35 mg). LCMS m/z 571.2. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.42-8.28 (m, 1H), 8.16 (s, 1H), 7.92-7.79 (m, 4H), 7.78- 7.68 (m, 2H), 7.52-7.40 (m, 2H), 7.36 (d, 1H), 5.80-5.55 (m, 3H), 4.65-3.98 (m, 3H), 3.95- 3.40 (m, 4H) ), 3.08 (s, 3H) ppm (protons on NH and OH were not visible). Example 23

5-Bromo-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihy droxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a stirred solution of 5-bromo-1-(2-naphthylmethyl)-indole-3-carboxylic acid (prepared from 5-bromoindole-3-carboxylic acid and 2-bromomethylnaphthalene following General Procedure A) (190 mg, 0.5 mmol) and HBTU (212 mg, 0.56 mmol) in DMF (4 mL) was added DIPEA (0.26 mL, 1.5 mmol). After 20 min Intermediate 4 (150 mg, 0.6 mmol) was added and the solution was stirred for 14 h at 65 ^o C. The solution was concentrated, dispersed onto SiO2 and purified by flash chromatography (SiO2, 0% to 10% MeOH gradient in DCM/acetone (1:1) to give 70 mg of 5-bromo-1-(2-naphthylmethyl)-N- [(3R,4R,5S,6R)-2,4,5-trihydroxy-3,6-bis(hydroxymethyl)tetrah ydropyran-3-yl]indole-3- carboxamide. ¹ H NMR (400 MHz, CD3OD): δ 8.24(m, 1H), 8.02 (m, 1H), 7.83-7.64 (m, 3H), 7.52 (s, 1H), 7.32-7.42 (m, 2H), 7.25-7.11 (m, 3H), 5.68-5.58 (m, 1H), 5.37 (s, 2H), 4.58-4.02 (m, 3H), 3.80-3.40 (m, 4H) ppm (protons on NH and OH were not visible).

Example 24

5,6-Difluoro-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5- trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

5,6-Difluoro-1H-indole (1.17 g, 7.6 mmol) was dissolved in DCM (20 mL) and pyridine (1.85 mL, 22.9 mmol) was added. The solution was cooled to ~ 0 ^C, and a solution of trichloroacetyl chloride (1.28 mL, 11.4 mmol) in DCM (5 mL) was added over the course of about 30 min. The cooling bath was removed and the reaction mixture was stirred at rt overnight. All the volatiles are removed under reduced pressure. The mixture was then stirred with ethanol-water (1:1, 15 mL) for 10 min, and the product was filtered off and dried. Further purification by silica gel flash chromatography eluting with 0-100% ethyl acetate gradient in hexanes to give 2,2,2-trichloro-1-(5,6-difluoro-1H-indol-3-yl)ethanone (1.0 g).

To 2,2,2-trichloro-1-(5,6-difluoro-1H-indol-3-yl)ethanone (1.0 g, 3.35 mmol) in NMP (20 mL) was added K ₂ CO ₃ (695 mg, 5.03 mmol) and 2-(bromomethyl)naphthalene (1.11 g, 5.03 mmol), and the reaction mixture was stirred overnight at rt. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with water, dried over Na ₂ SO ₄ , and concentrated under reduced pressure. This material was purified by silica gel flash chromatography eluting with 0-100% ethyl acetate gradient in hexanes to give 2,2,2-trichloro-1-[5,6-difluoro-1-(2-naphthylmethyl)indol-3- yl]ethanone.

To 2,2,2-trichloro-1-[5,6-difluoro-1-(2-naphthylmethyl)indol-3- yl]ethanone solution in THF/MeOH (6 mL, 1:1) was added aqueous NaOH (3 mL, 2.5 N) and the reaction mixture was stirred overnight and then neutralized with 1.0 N HCl (pH = 6). The precipitate was filtered, washed with water, and then dried under vacuum to give 5,6-difluoro-1-(2- naphthylmethyl)indole-3-carboxylic acid (175 mg).

To a solution of 5,6-difluoro-1-(2-naphthylmethyl)indole-3-carboxylic acid (88 mg, 0.26 mmol) in anhydrous DMF (3 mL) was added Intermediate 4 (64 mg, 0.26 mmol), DIEA (0.136 mL0.78 mmol), and HBTU (118 mg, 0.31 mmol). The reaction was stirred at 55 ^o C for 5 h, and the solvent was evaporated. The mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1) to give 5,6- difluoro-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihydr oxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide (22 mg). LCMS m/z 530.0. ¹ H NMR (400 MHz, CD3OD): δ 8.18-8.06 (m, 1H), 8.00-7.88 (m, 1H), 7.86-7.76 (m, 4H), 7.69 (s, 1H), 7.56-7.36 (m, 2H), 7.32 (d, 1H), 5.68-5.52 (m, 3H), 4.60-4.02 (m, 3H), 3.98- 3.36 (m, 4H) ppm (protons on NH and OH were not visible). Example 25

1-[(2-Cyanophenyl)methyl]-6-methoxy-N-[(3R,4R,5S,6R)-2,4, 5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a stirred mixture of 6-methoxy-1H-indole-3-carboxylic acid (220 mg, 1.15 mmol) and K ₂ CO ₃ (477 mg, 3.45 mmol) in NMP (16 mL) was added 2-(bromomethyl)benzonitrile (563 mg, 2.88 mmol). The mixture was stirred for 14 h.2 N NaOH (2.8 mL) was added and the stirred mixture was heated to 50 ^o C for 12 h. The cooled solution was poured into H2O and acidified to pH 2.0 using 1.0 M HCl. The resulting precipitate was collected by filtration, washed with H ₂ O and air dried to give 280 mg of 1-[(2-cyanophenyl)methyl]-6- methoxy-indole-3-carboxylic acid.

To a stirred solution of 1-[(2-cyanophenyl)methyl]-6-methoxy-indole-3-carboxylic acid (82 mg, 0.27 mmol) and HBTU (112 mg, 0.29 mmol) in DMF (4 mL) was added DIPEA (0.26 mL, 0.8 mmol). After 20 min Intermediate 4 (81 mg, 0.33 mmol) was added and the solution was stirred for 14 h at 55 ^o C. The solution was concentrated, dispersed onto SiO2 and purified by flash chromatography (SiO ₂ , 0% to 10% MeOH gradient in DCM/acetone (1:1) to give 40 mg of 1-[(2-cyanophenyl)methyl]-6-methoxy-N-[(3R,4R,5S,6R)-2,4,5- trihydroxy-3,6-bis(hydroxymethyl)tetrahydropyran-3-yl]indole -3-carboxamide. LCMS m/z 499.0. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.95-7.85 (m, 2H), 7.75 (d, 1H), 7.55-7.37 (m, 2H), 7.05 (d, 1H), 6.90-6.80 (m, 2H), 5.65-5.50 (m, 3H), 4.60-3.98 (m, 3H), 3.95-3.40 (m, 4H), 3.76 (s, 3H) ppm (protons on NH and OH were not visible). Example 26

1-[(3-Cyanophenyl)methyl]-6-methoxy-N-[(3R,4R,5S,6R)-2,4, 5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a stirred mixture of 6-methoxy-1H-indole-3-carboxylic acid (220 mg, 1.15 mmol) and K ₂ CO ₃ (477 mg, 3.45 mmol) in NMP (16 mL) was added 3-(bromomethyl)benzonitrile (563 mg, 2.88 mmol). The mixture was stirred for 14 h.2 N NaOH (2.8 mL) was added and the stirred mixture was heated to 50 ^o C for 12 h. The cooled solution was poured into H2O and acidified to pH 2.0 using 1.0 M HCl. The resulting precipitate was collected by filtration, washed with H2O and air dried to give 205 mg of 1-[(3-cyanophenyl)methyl]-6- methoxy-indole-3-carboxylic acid.

To a stirred solution of 1-[(3-cyanophenyl)methyl]-6-methoxy-indole-3-carboxylic acid (82 mg, 0.27 mmol) and HBTU (112 mg, 0.29 mmol) in DMF (4 mL) was added DIPEA (0.26 mL, 0.8 mmol). After 20 min Intermediate 4 (81 mg, 0.33 mmol) was added and the solution was stirred for 14 h at 55 ^o C. The solution was concentrated, dispersed onto SiO2 and purified by flash chromatography (SiO ₂ , 0% to 10% MeOH gradient in DCM/acetone (1:1) to give 37 mg of 1-[(3-cyanophenyl)methyl]-6-methoxy-N-[(3R,4R,5S,6R)-2,4,5- trihydroxy-3,6-bis(hydroxymethyl)tetrahydropyran-3-yl]indole -3-carboxamide. LCMS m/z 499.0. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.95-7.85 (m, 2H), 7.65-7.35 (m, 4H), 6.90-6.80 (m, 2H), 5.59-5.45 (m, 3H), 4.60-3.98 (m, 3H), 3.95-3.40 (m, 4H), 3.76 (s, 3H) ppm (protons on NH and OH were not visible). Example 27

1-[(4-Cyanophenyl)methyl]-6-methoxy-N-[(3R,4R,5S,6R)-2,4, 5-trihydroxy-3,6- bis h drox meth l tetrah dro ran-3- l indole-3-carboxamide

To a stirred mixture of 6-methoxy-1H-indole-3-carboxylic acid (220 mg, 1.15 mmol) and K2CO3 (477 mg, 3.45 mmol) in NMP (16 mL) was added 4-(bromomethyl)benzonitrile (563 mg, 2.88 mmol). The mixture was stirred for 14 h.2 N NaOH (2.8 mL) was added and the stirred mixture was heated to 50 ^o C for 12 h. The cooled solution was poured into H2O and acidified to pH 2.0 using 1.0 M HCl. The resulting precipitate was collected by filtration, washed with H ₂ O and air dried to give 460 mg of 1-[(4-cyanophenyl)methyl]-6- methoxy-indole-3-carboxylic acid.

To a stirred solution of 1-[(4-cyanophenyl)methyl]-6-methoxy-indole-3-carboxylic acid (82 mg, 0.27 mmol) and HBTU (112 mg, 0.29 mmol) in DMF (4 mL) was added DIPEA (0.26 mL, 0.8 mmol). After 20 min Intermediate 4 (81 mg, 0.33 mmol) was added and the solution was stirred for 14 h at 55 ^o C. The solution was concentrated, dispersed onto SiO2 and purified by flash chromatography (SiO2, 0% to 10% MeOH gradient in DCM/acetone (1:1) to give 41 mg of 1-[(4-cyanophenyl)methyl]-6-methoxy-N-[(3R,4R,5S,6R)-2,4,5- trihydroxy-3,6-bis(hydroxymethyl)tetrahydropyran-3-yl]indole -3-carboxamide. LCMS m/z 499.0. ¹ H NMR (400 MHz, CD3OD): δ 7.95-7.85 (m, 2H), 7.65 (d, 2H), 7.30 (d, 2H), 6.90- 6.80 (m, 2H), 5.59-5.45 (m, 3H), 4.60-3.98 (m, 3H), 3.95-3.40 (m, 4H), 3.75 (s, 3H) ppm (protons on NH and OH were not visible). Example 28

1-[(4-Chlorophenyl)methyl]-6-methoxy-N-[(3R,4R,5S,6R)-2,4 ,5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a stirred mixture of 6-methoxy-1H-indole-3-carboxylic acid (220 mg, 1.15 mmol) and K ₂ CO ₃ (477 mg, 3.45 mmol) in NMP (16 mL) was added 1-(bromomethyl)-4-chloro- benzene (589 mg, 2.88 mmol). The mixture was stirred for 14 h.2 N NaOH (2.8 mL) was added and the stirred mixture was heated to 50 ^o C for 12 h. The cooled solution was poured into H2O and acidified to pH 2.0 using 1.0 M HCl. The resulting precipitate was collected by filtration, washed with H2O and air dried to give 380 mg of 1-[(4-chlorophenyl)methyl]- 6-methoxy-indole-3-carboxylic acid.

To a stirred solution of 1-[(4-chlorophenyl)methyl]-6-methoxy-indole-3-carboxylic acid (82 mg, 0.26 mmol) and HBTU (112 mg, 0.29 mmol) in DMF (4 mL) was added DIPEA (0.26 mL, 0.8 mmol). After 20 min Intermediate 4 (81 mg, 0.33 mmol) was added and the solution was stirred for 14 h at 55 ^o C. The solution was concentrated, dispersed onto SiO ₂ and purified by flash chromatography (SiO ₂ , 0% to 10% MeOH gradient in DCM/acetone (1:1) to give 44 mg of 1-[(4-chlorophenyl)methyl]-6-methoxy-N-[(3R,4R,5S,6R)-2,4,5- trihydroxy-3,6-bis(hydroxymethyl)tetrahydropyran-3-yl]indole -3-carboxamide. LCMS m/z 508.0. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.90-7.69 (m, 2H), 7.35-7.21 (m, 2H), 7.18-7.09 (m, 2H), 6.90-6.80 (m, 2H), 5.59 (s, 1H), 5.33 (s, 2H), 4.60-3.98 (m, 3H), 3.95-3.40 (m, 4H), 3.75 (s, 3H) ppm (protons on NH and OH were not visible).

Example 29

1-[(3,4-Difluorophenyl)methyl]-6-methoxy-N-[(3R,4R,5S,6R) -2,4,5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a stirred mixture of 6-methoxy-1H-indole-3-carboxylic acid (220 mg, 1.15 mmol) and K ₂ CO ₃ (477 mg, 3.45 mmol) in NMP (16 mL) was added 1-(bromomethyl)-3,4-difluoro- benzene (589 mg, 2.88 mmol). The mixture was stirred for 14 h.2 N NaOH (2.8 mL) was added and the stirred mixture was heated to 50 ^o C for 12 h. The cooled solution was poured into H ₂ O and acidified to pH 2.0 using 1.0 M HCl. The resulting precipitate was collected by filtration, washed with H2O and air dried to give 400 mg of 1-[(2,3- difluorophenyl)methyl]-6-methoxy-indole-3-carboxylic acid.

To a stirred solution of 1-[(3,4-difluorophenyl)methyl]-6-methoxy-indole-3-carboxylic acid (82 mg, 0.26 mmol) and HBTU (112 mg, 0.29 mmol) in DMF (4 mL) was added DIPEA (0.26 mL, 0.8 mmol). After 20 min Intermediate 4 (81 mg, 0.33 mmol) was added and the solution was stirred for 14 h at 55 ^o C. The solution was concentrated, dispersed onto SiO ₂ and purified by flash chromatography (SiO ₂ , 0% to 10% MeOH gradient in

DCM/acetone (1:1)) to give 37 mg of 1-[(3,4-difluorophenyl)methyl]-6-methoxy-N- [(3R,4R,5S,6R)-2,4,5-trihydroxy-3,6-bis(hydroxymethyl)tetrah ydropyran-3-yl]indole-3- carboxamide. LCMS m/z 510.0. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.92-7.81 (m, 2H), 7.25- 7.05 (m, 3H), 6.90-6.80 (m, 2H), 5.63-5.55 (m, 1H), 5.38 (s, 2H), 4.60-3.98 (m, 3H), 3.95- 3.40 (m, 4H), 3.78 (s, 3H) ppm (protons on NH and OH were not visible). Example 30

1-[(3-tert-Butylphenyl)methyl]-6-methoxy-N-[(3R,4R,5S,6R) -2,4,5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a stirred solution of 1-[(3-tert-butylphenyl)methyl]-6-methoxy-indole-3-carboxylic acid (prepared from 6-methoxyindole-3-carboxylic acid and 3-tert-butylbenzyl bromide following General Procedure A) (82 mg, 0.24 mmol) and HBTU (112 mg, 0.29 mmol) in DMF (4 mL) was added DIPEA (0.26 mL, 0.8 mmol). After 20 min Intermediate 4 (81 mg, 0.33 mmol) was added and the solution was stirred for 14 h at 55 ^o C. The solution was concentrated, dispersed onto SiO ₂ and purified by flash chromatography (SiO ₂ , 0% to 10% MeOH gradient in DCM/acetone (1:1) to give 48 mg of 1-[(3-tert-butylphenyl)methyl]-6- methoxy-N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-3,6-bis(hydroxymet hyl)tetrahydropyran-3- yl]indole-3-carboxamide. LCMS m/z 530.1. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.92-7.75 (m, 2H), 7.40-7.10 (m, 3H), 6.95-6.80 (m, 3H), 5.63-5.55 (m, 1H), 5.34 (s, 2H), 4.60-3.98 (m, 3H), 3.95-3.40 (m, 4H), 3.74 (s, 3H), 1.25 (s, 9H) ppm (protons on NH and OH were not visible). Example 31

1-[(4-tert-Butylphenyl)methyl]-6-methoxy-N-[(3R,4R,5S,6R) -2,4,5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a stirred solution of 1-[(4-tert-butylphenyl)methyl]-6-methoxy-indole-3-carboxylic acid (prepared from 6-methoxyindole-3-carboxylic acid and 4-tert-butylbenzyl bromide following General Procedure A) (82 mg, 0.24 mmol) and HBTU (112 mg, 0.29 mmol) in DMF (4 mL) was added DIPEA (0.26 mL, 0.8 mmol). After 20 min Intermediate 4 (81 mg, 0.33 mmol) was added and the solution was stirred for 14 h at 55 ^o C. The solution was concentrated, dispersed onto SiO ₂ and purified by flash chromatography (SiO ₂ , 0% to 10% MeOH gradient in DCM/acetone (1:1)) to give 43 mg of 1-[(4-tert-butylphenyl)methyl]-6- methoxy-N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-3,6-bis(hydroxymet hyl)tetrahydropyran-3- yl]indole-3-carboxamide. LCMS m/z 530.1. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.90-7.69 (m, 2H), 7.40-7.23 (m, 2H), 7.20-7.08 (m, 2H), 6.95-6.80 (m, 2H), 5.63-5.22 (m, 3H), 4.60-3.98 (m, 3H), 3.95-3.40 (m, 4H), 3.75 (s, 3H), 1.25 (s, 9H) ppm (protons on NH and OH were not visible). Example 32

6-Methoxy-1-(2-quinolylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-tri hydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a solution of 6-methoxy-1H-indole-3-carboxylic acid (717 mg, 3.75 mmol) in dry DMF (30 mL) was added slowly sodium hydride (60% dispersion in mineral oil, 180 mg, 4.5 mmol). To this mixture was added 2-(bromomethyl)quinoline (1.0 g, 4.5 mmol), and the reaction mixture was stirred overnight at rt. The mixture was then acidified with 1 N aqueous HCl, and water was added. The reaction workup mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and was then dried over sodium sulfate and concentrated in vacuo to give 6-methoxy-1-(2-quinolylmethyl)indole-3- carboxylic acid. LCMS m/z 333.9.

To a solution of 6-methoxy-1-(2-quinolylmethyl)indole-3-carboxylic acid (149 mg, 0.448 mmol) in anhydrous DMF (3 mL) was added Intermediate 4 (100 mg, 0.407 mmol), DIEA (0.213 mL, 1.22 mmol), and HBTU (185 mg, 0.488 mmol). The reaction was stirred at 55 ^o C for 16 h. Solvent was evaporated, and the mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1). The residue was dissolved in ethyl acetate, washed with water, dried, and concentrated to give 6- methoxy-1-(2-quinolylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihydro xy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide (14 mg). LCMS m/z 525.0. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.16 (d, 1H), 8.05 (d, 1H), 8.00 (s, 1H), 7.94-7.82 (m, 2H), 7.77 (t, 1H), 7.57 (t, 1H), 7.07 (d, 1H), 6.94 (s, 1H), 6.83 (d, 1H), 5.56-5.72 (m, 3H), 4.65- 3.99 (m, 3H), 3.97-3.45 (m, 7H) ppm (protons on NH and OH were not visible). Example 33

6-[2-(Methylamino)-2-oxo-ethoxy]-1-(2-naphthylmethyl)-N-[ (3R,4R,5S,6R)-2,4,5- trihydroxy-3,6-bis(hydroxymethyl)tetrahydropyran-3-yl]indole -3-carboxamide

To a stirred solution of 6-(2-tert-butoxy-2-oxo-ethoxy)-1-(2-naphthylmethyl)indole-3- carboxylic acid (81 mg, 0.27 mmol) and HBTU (0.165 mL, 0.29 mmol) in DMF (4 mL) was added DIPEA (0.26 mL, 0.8 mmol). After 20 min methylamine (0.165 mL, 2.0 M THF solution) was added and the solution was stirred for 14 h at 55 ^o C. The solution was diluted with H2O, extracted with EtOAc, dried (Na2SO4), concentrated. The residue was stirred at rt in 1:1:1 THF:MeOH:H2O and was treated with NaOH (24 mg). After 2 h the mixture was concentrated in vacuo and the residue was purified by flash chromatography (SiO ₂ , 0% to 10% MeOH gradient in DCM) to give 70 mg of 6-[2-(methylaminooxy)-2- oxo-ethoxy]-1-(2-naphthylmethyl)indole-3-carboxylic acid.

To a stirred solution of 6-[2-(methylaminooxy)-2-oxo-ethoxy]-1-(2-naphthylmethyl)indo le- 3-carboxylic acid (70 mg, 0.18 mmol) and HBTU (75 mg, 0.2 mmol) in DMF (4 mL) was added DIPEA (0.1 mL, 0.54 mmol). After 20 min Intermediate 4 (53 mg, 0.22 mmol) was added and the solution was stirred for 14 h at 55 ^o C. The solution was concentrated, dispersed onto SiO2 and purified by flash chromatography (SiO2, 0% to 10% MeOH gradient in DCM/acetone (1:1) to give 18 mg of 6-[2-(methylamino)-2-oxo-ethoxy]-1-(2- naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide. LCMS m/z 581.0 ¹ H NMR (400 MHz, CD ₃ OD): δ 8.75-7.90 (m, 2H), 7.86-7.72 (m, 3H), 7.63 (s, 1H), 7.55-7.41 (m, 2H), 7.39-7.22 (m, 1H), 7.00-6.88 (m, 2H), 5.64-5.48 (m, 3H), 4.60-4.02 (m, 3H), 4.44 (s, 2H), 3.80-3.40 (m, 4H), 2.65 (s, 3H) ppm (protons on NH and OH were not visible). Example 34

1-(Benzothiophen-2-ylmethyl)-6-methoxy-N-[(3R,4R,5S,6R)-2 ,4,5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a stirred solution of 1-(benzothiophen-2-ylmethyl)-6-methoxy-indole-3-carboxylic acid (prepared from 6-methoxyindole-3-carboxylic acid and 2-bromomethylbenzothiophene following General Procedure A) (115 mg, 0.34 mmol) and HBTU (142 mg, 0.4 mmol) in DMF (4 mL) was added DIPEA (0.2 mL, 1.1 mmol). After 20 min Intermediate 4 (100 mg, 0.22 mmol) was added and the solution was stirred for 14 h at 55 ^o C. The solution was concentrated, dispersed onto SiO ₂ and purified by flash chromatography (SiO ₂ , 0% to 10% MeOH gradient in DCM/acetone (1:1) to give 40 mg of 1-(benzothiophen-2-ylmethyl)-6- methoxy-N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-3,6-bis(hydroxymet hyl)tetrahydropyran-3- yl]indole-3-carboxamide. LCMS m/z 530.0. ¹ H NMR (400 MHz, CD3OD): δ 8.00-7.83 (m, 2H), 7.79-7.65 (m, 2H), 7.38-7.22 (m, 3H), 7.06 (s, 1H), 6.87 (dd, 1H), 5,65 (s, 2H), 5.57- 5.56. (m, 1H), 4.68-4.02 (m, 3H), 3.95-3.40 (m, 4H), 3.80 (s, 3H) ppm (protons on NH and OH were not visible). Example 35

5-Fluoro-6-methoxy-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)- 2,4,5-trihydroxy-6- (hydroxymethyl)-3-methyl-tetrahydropyran-3-yl]indole-3-carbo xamide

To a stirred solution of Intermediate 6 (11.2 g, 33.0 mmol) and HATU (13.2 g, 34.6 mmol) in DMF (300 mL) was added DIPEA (17.2 mL, 99 mmol). After 30 min Intermediate 5 (7 g, 30.5 mmol) was added and the solution was stirred for 14 h at 50 ^o C. The solution was concentrated, dissolved in EtOAc and washed with H ₂ O followed by brine. The organics were dried over NaSO ₄ , filtered, concentrated and purified by flash chromatography (SiO ₂ , 0% to 10% MeOH gradient in DCM/acetone (1:1)) to give 2.4 g of 5-fluoro-6-methoxy-1- (2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydr oxymethyl)-3-methyl- tetrahydropyran-3-yl]indole-3-carboxamide. LCMS m/z 525.2. ¹ H NMR (400 MHz, CD3OD): δ 7.94 (d, 1H), 7.83-7.71 (m, 4H), 7.66 (s, 1H), 7.47-7.44 (m, 2H), 7.32 (dt, 1H), 7.09 (d, 1H), 5.61 and 5.36 (s, 1H), 5.57 (s, 2H), 4.25 and 3.98 (d, 1H), 3.90-3.36 (m, 4H), 3.79 (s, 3H), 1.53 and 1.31 (s, 3H) ppm (protons on NH and OH were not visible). Example 36

4-Fluoro-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trih ydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

4-Fluoro-1H-indole (1.0 g, 7.4 mmol) was dissolved in DCM (20 mL) and pyridine (1.8 mL, 22.2 mmol) was added. The solution was cooled to ~ 0 ^C, and a solution of trichloroacetyl chloride (1.24 mL, 11.1 mmol) in DCM (3 mL) was added over the course of about 30 min. The cooling bath was removed and the reaction mixture was stirred at rt overnight. All the volatiles are removed under reduced pressure. The mixture was then stirred with ethanol-water (1:1, 15 mL) for 10 min, and the product was filtered off and dried. Further purification by silica gel flash chromatography eluting with 0-100% ethyl acetate gradient in hexanes to give 2,2,2-trichloro-1-(4-fluoro-1H-indol-3-yl)ethanone (785 mg).

To 2,2,2-trichloro-1-(4-fluoro-1H-indol-3-yl)ethanone (785 mg, 2.8 mmol) in NMP (20 mL) was added K2CO3 (580 mg, 4.2 mmol) and 2-(bromomethyl)naphthalene (929 mg, 4.2 mmol), and the reaction mixture was stirred overnight at rt. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with water, dried over Na2SO4, and concentrated under reduced pressure. This material was purified by silica gel flash chromatography eluting with 0-100% ethyl acetate gradient in hexanes to give 2,2,2-trichloro-1-[4-fluoro-1-(2-naphthylmethyl)indol-3-yl]e thanone (568 mg).

To 2,2,2-trichloro-1-[4-fluoro-1-(2-naphthylmethyl)indol-3-yl]e thanone (568 mg, 1.35 mmol) solution in THF/MeOH (6 mL, 1:1) was added aqueous NaOH (3 mL, 2.5 N) and the reaction mixture was stirred overnight and then neutralized with 1.0 N HCl (pH = 6). The precipitate was filtered, washed with water, and then dried under vacuum to give 4- fluoro-1-(2-naphthylmethyl)indole-3-carboxylic acid (302 mg).

To a solution of 4-fluoro-1-(2-naphthylmethyl)indole-3-carboxylic acid (118 mg, 0.37 mmol) in anhydrous DMF (2 mL) was added Intermediate 4 (100 mg, 0.407 mmol), DIEA (0.213 mL, 1.22 mmol), and HBTU (168 mg, 0.444 mmol). The reaction was stirred at 55 ^o C for 5 h, then at rt overnight. Solvent was evaporated. The mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1) to give 4-fluoro-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihydr oxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide (53 mg). LCMS m/z 512.0. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.22-8.07 (m, 1H), 7.92 (d, 1H), 7.86-7.73 (m, 2H), 7.67 (s, 1H), 7.53-7.44 (m, 2H), 7.40-7.29 (m, 2H), 7.25-7.12 (m, 1H), 7.04-6.88 (m, 1H), 5.70- 5.54 (m, 3H), 4.60-3.98 (m, 3H), 3.96-3.38 (m, 4H) ppm (protons on NH and OH were not visible). Example 37

6-(2-Methylpropanoyl)-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6 R)-2,4,5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a stirred solution of 6-bromo-1-(2-naphthylmethyl)indole-3-carboxylic acid (2.0 g, 5.26 mmol) in DMF (30 mL) was added potassium carbonate (1.09 g, 7.89 mmol) and iodomethane (0.49 mL, 7.89 mmol). The mixture was stirred for 1.5 h at 70 ^o C, diluted with H ₂ O and extracted with EtOAc followed by DCM. The combined organics were dried (Na2SO4), filtered, concentrated and purified by flash chromatography (SiO2, 0% to 100% EtOAc gradient in hexanes) to give 1.4 g of methyl 6-bromo-1-(2-naphthylmethyl)indole-3- carboxylate. ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 8.34 (s, 1H), 7.98-7.78 (m, 6H), 7.52-7.45 (m, 2H), 7.40-7.33 (m, 2H), 5.68 (s, 2H), 3.81 (s, 3H) ppm.

A stirred solution of methyl 6-bromo-1-(2-naphthylmethyl)indole-3-carboxylate

(1.36 g, 3.46 mmol), tributyl(1-ethoxyvinyl)tin (1.75 mL, 5.19 mmol) and

bis(triphenylphosphine)palladium(II) dichloride (243 mg, 0.35 mmol) in degassed DMF (25 mL) was heated overnight at 90 ^o C. To the cooled solution was added 3.0 N HCl (60 mL). After stirring for 2 h the solution was extracted with EtOAc. The combined organics were dried (Na ₂ SO ₄ ), filtered, concentrated and purified by flash chromatography (SiO ₂ , DCM) to give 495 mg of methyl 6-acetyl-1-(2-naphthylmethyl)indole-3-carboxylate. ¹ H NMR (400 MHz, DMSO-d6): δ 8.58 (s, 1H), 8.28 (s, 1H), 8.10 (d, 1H), 7.93-7.80 (m, 5H), 7,55- 7.40 (m, 3H), 5.81 (s, 2H), 3.83 (s, 3H), 2.60 (s, 3H) ppm.

To a solution of methyl 6-acetyl-1-(2-naphthylmethyl)indole-3-carboxylate (200 mg, 0.56 mmol) in dry THF (5 mL) was added iodomethane (0.697 mL, 11.2 mmol). The reaction mixture was cooled to -78 ^C, and LiHMDS (1 M, 2.25 mL, 2.25 mmol) was slowly added. It was stirred at -78 ^C for 20 min then allowed to return to rt and stirred overnight. The reaction mixture was again cooled to -78 ^C, and LiHMDS (1 M, 2.25 mL, 2.25 mmol) was added. It was allowed to stir at rt for 24 h. Saturated ammonium chloride solution was then added. The reaction workup mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and was then dried over sodium sulfate and concentrated in vacuo. This material was purified by silica gel flash chromatography eluting with 0- 100% ethyl acetate gradient in hexanes to give methyl 6-(2-methylpropanoyl)-1-(2- naphthylmethyl)indole-3-carboxylate (76 mg).

To methyl 6-(2-methylpropanoyl)-1-(2-naphthylmethyl)indole-3-carboxyla te (76 mg, 0.197 mmol) solution in THF/MeOH (2 mL, 1:1) was added aqueous NaOH (1 mL, 2.5 N) and the reaction mixture was stirred overnight and then neutralized with 1.0 N HCl (pH = 6). The precipitate was filtered, washed with water, and then dried under vacuum to give 6-(2- methylpropanoyl)-1-(2-naphthylmethyl)indole-3-carboxylic (54 mg).

To a solution of 6-(2-methylpropanoyl)-1-(2-naphthylmethyl)indole-3-carboxyli c acid (54 mg, 0.145 mmol) in anhydrous DMF (2 mL) was added Intermediate 4 (39 mg, 0.16 mmol), DIEA (0.84 mL, 0.479 mmol), and HBTU (66 mg, 0.174 mmol). The reaction was stirred at 55 ^o C for 16 h. Solvent was evaporated, and the mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1) to give 6-(2- methylpropanoyl)-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5 -trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide (14 mg). LCMS m/z 564.0. ¹ H NMR (400 MHz, CD3OD): δ 8.35-8.22 (m, 1H), 8.19-8.05 (m, 1H), 7.91-7.70 (m, 6H), 7.53-7.40 (m, 2H), 7.38-7.21 (m, 1H), 5.76-5.57 (m, 3H), 4.70-4.00 (m, 3H), 3.98-3.37 (m, 5H), 1.08 (d, 6H) ppm (protons on NH and OH were not visible). Example 38

6-Chloro-5-fluoro-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2 ,4,5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

6-Chloro-5-fluoro-1H-indole (1.29 g, 7.4 mmol) was dissolved in DCM (20 mL) and pyridine (1.8 mL, 22.2 mmol) was added. The solution was cooled to ~ 0 ^C, and a solution of trichloroacetyl chloride (1.24 mL, 11.1 mmol) in DCM (3 mL) was added over the course of about 30 min. The cooling bath was removed and the reaction mixture was stirred at rt overnight. All the volatiles are removed under reduced pressure. The mixture was then stirred with ethanol-water (1:1, 15 mL) for 10 min, and the product was filtered off and dried. Further purification by silica gel flash chromatography eluting with 0-100% ethyl acetate gradient in hexanes to give 2,2,2-trichloro-1-(6-chloro-5-fluoro-1H-indol-3- yl)ethanone (1.86 g).

To 2,2,2-trichloro-1-(6-chloro-5-fluoro-1H-indol-3-yl)ethanone (1.86 g, 5.9 mmol) in NMP (20 mL) was added K2CO3 (1.22 g, 8.86 mmol) and 2-(bromomethyl)naphthalene (1.96 mg, 8.86 mmol), and the reaction mixture was stirred overnight at rt. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with water, dried over Na2SO4, and concentrated under reduced pressure. This material was purified by silica gel flash chromatography eluting with 0-100% ethyl acetate gradient in hexanes to give 2,2,2-trichloro-1-[6-chloro-5-fluoro-1-(2-naphthylmethyl)ind ol-3- yl]ethanone (300 mg).

To 2,2,2-trichloro-1-[6-chloro-5-fluoro-1-(2-naphthylmethyl)ind ol-3-yl]ethanone (300 mg, 0.66 mmol) solution in THF/MeOH (4 mL, 1:1) was added aqueous NaOH (2 mL, 2.5 N) and the reaction mixture was stirred overnight and then neutralized with 1.0 N HCl (pH = 6). The precipitate was filtered, washed with water, and then dried under vacuum to give 6- chloro-5-fluoro-1-(2-naphthylmethyl)indole-3-carboxylic acid (118 mg).

To a solution of 6-chloro-5-fluoro-1-(2-naphthylmethyl)indole-3-carboxylic acid (100 mg, 0.283 mmol) in anhydrous DMF (2 mL) was added Intermediate 4 (77 mg, 0.311 mmol), DIEA (0.163 mL, 0.934 mmol), and HBTU (140 mg, 0.368 mmol). The reaction was stirred at 55 ^o C for 5 h, then at rt overnight. Solvent was evaporated. The mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1) to give 6-chloro-5-fluoro-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4, 5-trihydroxy- 3,6-bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxam ide (24 mg). LCMS m/z 545.9. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.20-8.08 (m, 1H), 7.91 (d, 1H), 7.87-7.76 (m, 3H), 7.70 (s, 1H), 7.62 (d, 1H), 7.52-7.38 (m, 2H), 7.32 (d, 1H), 5.67-5.54 (m, 3H), 4.61-3.96 (m, 3H), 3.94-3.40 (m, 4H) ppm (protons on NH and OH were not visible). Example 39

6-Acetyl-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trih ydroxy-6-(hydroxymethyl)-3- methyl-tetrahydropyran-3-yl]indole-3-carboxamide

To a stirred solution of 6-acetyl-1-(2-naphthylmethyl)-6-methoxy-indole-3-carboxylic acid (prepared as in Example 20) (100 mg, 0.3 mmol) and HATU (142 mg, 0.32 mmol) in DMF (4 mL) was added DIPEA (0.15 mL, 0.9 mmol). After 20 min Intermediate 5 (100 mg, 0.22 mmol) was added and the solution was stirred for 14 h at 55 ^o C. The solution was concentrated, dispersed onto SiO2 and purified by flash chromatography (SiO2, 0% to 10% MeOH gradient in DCM/acetone (1:1) to give 16 mg of 6-acetyl-1-(2-naphthylmethyl)-N- [(3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)-3-methyl-t etrahydropyran-3- yl]indole-3-carboxamide. LCMS m/z 520.3. ¹ H NMR (400 MHz, CD3OD): δ 8.72-8.10 (m, 4H), 7.90-7.75 (m, 3H), 7.70 (s, 1H), 7.49-7.18 (m, 3H), 5.72-5.45 (m, 3H), 4.40-3.40 (m, 5H), 2.58 (s, 3H), 1.55 and 1.32 (s, 3H) ppm (protons on NH and OH were not visible). Example 40

6-Methoxy-1-(6-quinolylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-tri hydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a solution of 6-methoxy-1H-indole-3-carboxylic acid (526 mg, 2.75 mmol) in dry DMF (20 mL) was added slowly sodium hydride (60% dispersion in mineral oil, 550 mg, 13.75 mmol). To this mixture was added 6-(bromomethyl)quinoline hydrobromide (1.0 g, 3.3 mmol), and the reaction mixture was heated to 50-60 ^C for 1 hr. The mixture was then cooled to rt and poured onto crushed ice and acidified with 2 N aqueous HCl to pH 6. The precipitate was collected, washed with water and dried to give 6-methoxy-1-(6- quinolylmethyl)indole-3-carboxylic acid (496 mg). LCMS m/z 333.9. To a solution of 6-methoxy-1-(6-quinolylmethyl)indole-3-carboxylic acid (123 mg, 0.37 mmol) in anhydrous DMF (2 mL) was added Intermediate 4 (100 mg, 0.407 mmol), DIEA (0.213 mL, 1.22 mmol), and HBTU (168 mg, 0.444 mmol). The reaction was stirred at 55 ^o C for 5 h, then at rt overnight. Solvent was evaporated, and the mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1). The residue was dissolved in ethyl acetate, washed with water, dried, and

concentrated to give 6-methoxy-1-(6-quinolylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihyd roxy- 3,6-bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxam ide (24 mg). LCMS m/z 524.9. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.81 (d, 1H), 8.24 (d, 1H), 8.05-7.96 (m, 1H), 7.95- 7.89 (m, 1H), 7.70-7.60 (m, 2H), 7.55-7.40 (m, 2H), 6.94 (s, 1H), 6.86 (d, 1H), 5.69-5.55 (m, 3H), 4.60-4.02 (m, 3H), 3.96-3.40 (m, 7H) ppm (protons on NH and OH were not visible). Example 41

4-Chloro-6-methoxy-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)- 2,4,5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

4-Chloro-6-methoxy-1H-indole (250 mg, 1.38 mmol) was dissolved in DCM (5 mL) and pyridine (0.334 mL, 4.13 mmol) was added. The solution was cooled to ~ 0 ^C, and a solution of trichloroacetyl chloride (0.231 mL, 2.07 mmol) in DCM (1 mL) was added over the course of about 30 min. The cooling bath was removed and the reaction mixture was stirred at rt overnight. All the volatiles are removed under reduced pressure. The mixture was then stirred with ethanol-water (1:1, 15 mL) for 10 min, and the product was filtered off and dried. Further purification by silica gel flash chromatography eluting with 0-100% ethyl acetate gradient in hexanes to give 2,2,2-trichloro-1-(4-chloro-6-methoxy-1H-indol-3- yl)ethanone (320 mg).

To 2,2,2-trichloro-1-(4-chloro-6-methoxy-1H-indol-3-yl)ethanone (641 mg, 1.96 mmol) in NMP (10 mL) was added K2CO3 (406 mg, 2.94 mmol) and 2-(bromomethyl)naphthalene (650 mg, 2.94 mmol), and the reaction mixture was stirred overnight at rt. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with water, dried over Na2SO4, and concentrated under reduced pressure. This material was purified by silica gel flash chromatography eluting with 0-100% ethyl acetate gradient in hexanes to give 2,2,2-trichloro-1-[4-chloro-6-methoxy-1-(2-naphthylmethyl)in dol-3- yl]ethanone.

To 2,2,2-trichloro-1-[4-chloro-6-methoxy-1-(2-naphthylmethyl)in dol-3-yl]ethanone solution in THF/MeOH (4 mL, 3:1) was added aqueous NaOH (1 mL, 2.5 N) and the reaction mixture was stirred overnight and then neutralized with 1.0 N HCl (pH = 6). The precipitate was filtered, washed with water, and then dried under vacuum to give 4-chloro- 6-methoxy-1-(2-naphthylmethyl)indole-3-carboxylic acid (125 mg). To a solution of 4-chloro-6-methoxy-1-(2-naphthylmethyl)indole-3-carboxylic acid (125 mg, 0.342 mmol) in anhydrous DMF (3 mL) was added Intermediate 4 (92 mg, 0.376 mmol), DIEA (0.197 mL, 1.13 mmol), and HBTU (156 mg, 0.41 mmol). The reaction was stirred at 55 ^o C for 6 h, then at rt overnight. Solvent was evaporated. The mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1) to give 4-chloro-6-methoxy-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)- 2,4,5-trihydroxy-3,6-bis(hydroxymethyl)tetrahydropyran-3-yl] indole-3-carboxamide (27 mg). LCMS m/z 557.8. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.88-7.73 (m, 4H), 7.68-7.58 (m, 1H), 7.51-7.40 (m, 2H), 7.31 (d, 1H), 6.91 (s, 1H), 6.84 (s, 1H), 5.64-5.46 (m, 3H), 4.58- 4.02 (m, 3H), 3.96-3.36 (m, 7H) ppm (protons on NH and OH were not visible). Example 42

1-(7-Isoquinolylmethyl)-6-methoxy-N-[(3R,4R,5S,6R)-2,4,5- trihydroxy-3,6- bis h drox meth l tetrah dro ran-3- l indole-3-carboxamide

To a solution of a 6-methoxy-1H-indole-3-carboxylic acid (191 mg, 1.0 mmol) in NMP (15 mL) was added K2CO3 (553 mg, 4.0 mmol). To this mixture was added 7- (bromomethyl)isoquinoline hydrobromide (909 mg, 3.0 mmol), and the reaction mixture was stirred overnight at rt. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with water, dried over Na2SO4, and concentrated under reduced pressure. This material was purified by silica gel flash chromatography eluting with 0-100% ethyl acetate gradient in hexanes to give 1-(7-isoquinolylmethyl)-6- methoxy-indole-3-carboxylic acid (120 mg). LCMS m/z 333.8. To a solution of 1-(7-isoquinolylmethyl)-6-methoxy-indole-3-carboxylic acid (106 mg, 0.319 mmol) in anhydrous DMF (2.5 mL) was added Intermediate 4 (71 mg, 0.29 mmol), DIEA (0.152 mL, 0.87 mmol), and HATU (132 mg, 0.348 mmol). The reaction was stirred at 55 ^o C overnight. Solvent was evaporated, and the mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1). The residue was dissolved in ethyl acetate, washed with water, dried, and concentrated to give 1-(7- isoquinolylmethyl)-6-methoxy-N-[(3R,4R,5S,6R)-2,4,5-trihydro xy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide (12 mg). LCMS m/z 524.9. ¹ H NMR (400 MHz, CD3OD): δ 9.12 (s, 1H), 8.39 (d, 1H), 7.89 (s, 1H), 7.96-7.82 (m, 3H), 7.77 (d, 1H), 7.61 (d, 1H), 6.94 (s, 1H), 6.85 (d, 1H), 5.71-5.55 (m, 3H), 4.65-4.00 (m, 3H), 3.98-3.40 (m, 7H) ppm (protons on NH and OH were not visible). Example 43

4,6-Difluoro-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5- trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

4,6-Difluoro-1H-indole (1.17 g, 7.6 mmol) was dissolved in DCM (20 mL) and pyridine (1.85 mL, 22.9 mmol) was added. The solution was cooled to ~ 0 ^C, and a solution of trichloroacetyl chloride (1.28 mL, 11.4 mmol) in DCM (5 mL) was added over the course of about 30 min. The cooling bath was removed and the reaction mixture was stirred at rt overnight. All the volatiles are removed under reduced pressure. The mixture was then stirred with ethanol-water (1:1, 15 mL) for 10 min, and the product was filtered off and dried. Further purification by silica gel flash chromatography eluting with 0-100% ethyl acetate gradient in hexanes to give 2,2,2-trichloro-1-(4,6-difluoro-1H-indol-3-yl)ethanone (1.37 g).

To 2,2,2-trichloro-1-(4,6-difluoro-1H-indol-3-yl)ethanone (1.37 g, 4.59 mmol) in NMP (20 mL) was added K ₂ CO ₃ (951 mg, 6.88 mmol) and 2-(bromomethyl)naphthalene (1.52 g, 6.88 mmol), and the reaction mixture was stirred overnight at rt. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with water, dried over Na ₂ SO ₄ , and concentrated under reduced pressure. This material was purified by silica gel flash chromatography eluting with 0-100% ethyl acetate gradient in hexanes to give 2,2,2-trichloro-1-[4,6-difluoro-1-(2-naphthylmethyl)indol-3- yl]ethanone (375 mg). To 2,2,2-trichloro-1-[4,6-difluoro-1-(2-naphthylmethyl)indol-3- yl]ethanone (375 mg) solution in THF/MeOH (4 mL, 1:1) was added aqueous NaOH (2 mL, 2.5 N) and the reaction mixture was stirred overnight and then acidified with 1.0 N HCl (pH = 2). The precipitate was filtered, washed with water, and then dried under vacuum to give 4,6- difluoro-1-(2-naphthylmethyl)indole-3-carboxylic acid (175 mg).

To a solution of 4,6-difluoro-1-(2-naphthylmethyl)indole-3-carboxylic acid (150 mg, 0.445 mmol) in anhydrous DMF (3 mL) was added Intermediate 4 (99 mg, 0.404 mmol), DIEA (0.212 mL, 1.21 mmol), and HATU (184 mg, 0.485 mmol). The reaction was stirred at 50 ^o C overnight. Solvent was evaporated. The mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1) to give 4,6- difluoro-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihydr oxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide (108 mg). LCMS m/z 530.2. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.18-8.04 (m, 1H), 7.90-7.76 (m, 3H), 7.69 (s, 1H), 7.54-7.42 (m, 2H), 7.33 (d, 1H), 7.17 (d, 1H), 6.86 (t, 1H), 5.64-5.54 (m, 3H), 4.60-3.98 (m, 3H), 3.96-3.44 (m, 4H) ppm (protons on NH and OH were not visible). Example 44

1-(6-Isoquinolylmethyl)-6-methoxy-N-[(3R,4R,5S,6R)-2,4,5- trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a solution of 6-methoxy-1H-indole-3-carboxylic acid (191 mg, 1.0 mmol) in NMP (15 mL) was added K ₂ CO ₃ (553 mg, 4.0 mmol). To this mixture was added 6- (bromomethyl)isoquinoline hydrobromide (909 mg, 3.0 mmol), and the reaction mixture was stirred overnight at rt. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with water, dried over Na ₂ SO ₄ , and concentrated under reduced pressure. This material was purified by silica gel flash chromatography eluting with 0-100% ethyl acetate gradient in hexanes to give 1-(6-isoquinolylmethyl)-6- methoxy-indole-3-carboxylic acid (218 mg). LCMS m/z 333.8.

To a solution of 1-(6-isoquinolylmethyl)-6-methoxy-indole-3-carboxylic acid (200 mg, 0.602 mmol) in anhydrous DMF (3 mL) was added Intermediate 4 (134 mg, 0.547 mmol), DIEA (0.286 mL, 1.64 mmol), and HATU (250 mg, 0.656 mmol). The reaction was stirred at 50 ^o C for 24 h. Solvent was evaporated, and the mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1). The residue was dissolved in ethyl acetate, washed with water, dried, and concentrated to give 1-(6- isoquinolylmethyl)-6-methoxy-N-[(3R,4R,5S,6R)-2,4,5-trihydro xy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide (24 mg). LCMS m/z 524.9. ¹ H NMR (400 MHz, CD3OD): δ 9.17 (s, 1H), 8.37 (d, 1H), 8.02 (d, 1H), 7.96 (s, 1H), 7.94- 7.87 (m, 1H), 7.69 (d, 1H), 7.62 (s, 1H), 7.51 (d, 1H), 6.91 (s, 1H), 6.86 (d, 1H), 5.71-5.55 (m, 3H), 4.63-4.00 (m, 3H), 3.96-3.37 (m, 7H) ppm (protons on NH and OH were not visible). Example 45

5-Chloro-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trih ydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a stirred solution of 5-chloro-1-(2-naphthylmethyl)indole-3-carboxylic acid (prepared from 5-chloroindole-3-carboxylic acid and 2-bromomethylnaphthalene following General Procedure A) (167 mg, 0.5 mmol) and HATU (208 mg, 0.55 mmol) in DMF (4 mL) was added DIPEA (0.26 mL, 1.5 mmol). After 20 min Intermediate 4 (150 mg, 0.6 mmol) was added and the solution was stirred for 14 h at 55 ^o C. The solution was concentrated, dispersed onto SiO ₂ and purified by flash chromatography (SiO ₂ , 0% to 10% MeOH gradient in DCM/acetone (1:1) to give 70 mg of 5-chloro-1-(2-naphthylmethyl)-N- [(3R,4R,5S,6R)-2,4,5-trihydroxy-3,6-bis(hydroxymethyl)tetrah ydropyran-3-yl]indole-3- carboxamide. LCMS m/z 527.9. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.18-8.04 (m, 2H), 7.86- 7.74 (m, 3H), 7.66 (s, 1H), 7.49-7.40 (m, 3H), 7.36-7.28 (m, 1H), 7.20-7.12 (m, 1H), 5.64- 5.52 (m, 3H), 4.58-4.02 (m, 3H), 3.80-3.40 (m, 4H) ppm (protons on NH and OH were not visible). Example 46

5-Methoxy-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-tri hydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a stirred solution of 5-methoxy-1-(2-naphthylmethyl)-indole-3-carboxylic acid

(prepared from 5-methoxyindole-3-carboxylic acid and 2-bromomethylnaphthalene following General Procedure A) (167 mg, 0.5 mmol) and HATU (208 mg, 0.55 mmol) in DMF (4 mL) was added DIPEA (0.26 mL, 1.5 mmol). After 20 min Intermediate 4 (150 mg, 0.6 mmol) was added and the solution was stirred for 14 h at 55 ^o C. The solution was concentrated, dispersed onto SiO2 and purified by flash chromatography (SiO2, 0% to 10% MeOH gradient in DCM/acetone (1:1) to give 78 mg of 5-methoxy-1-(2-naphthylmethyl)- N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-3,6-bis(hydroxymethyl)tetr ahydropyran-3-yl]indole-3- carboxamide. LCMS m/z 523.9. ¹ H NMR (400 MHz, CD3OD): δ 8.02-7.98 (m, 1H), 7.86- 7.72 (m, 3H), 7.66 (s, 1H), 7.64-7.55 (m, 1H), 7.49-7.40 (m, 2H), 7.38-7.12 (m, 2H), 6.88- 6.79 (m, 1H), 5.64-5.48 (m, 3H), 4.58-4.02 (m, 3H), 3.80-3.40 (m, 4H), 3.82 (s, 3H) ppm (protons on NH and OH were not visible). Example 47

7-Fluoro-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trih ydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

7-Fluoro-1H-indole (890 mg, 7.6 mmol) was dissolved in DCM (20 mL) and pyridine (1.6 mL, 19.8 mmol) was added. The solution was cooled to ~ 0 ^C, and a solution of trichloroacetyl chloride (1.1 mL, 9.9 mmol) in DCM (5 mL) was added over the course of about 30 min. The cooling bath was removed and the reaction mixture was stirred at rt overnight. All the volatiles are removed under reduced pressure. The mixture was then stirred with ethanol-water (1:1, 15 mL) for 10 min, and the product was filtered off and dried. Further purification by silica gel flash chromatography eluting with 0-100% ethyl acetate gradient in hexanes to give 2,2,2-trichloro-1-(7-fluoro-1H-indol-3-yl)ethanone (1.22 g).

To 2,2,2-trichloro-1-(7-fluoro-1H-indol-3-yl)ethanone (1.22 g, 4.35 mmol) in NMP (20 mL) was added K ₂ CO ₃ (902 mg, 6.52 mmol) and 2-(bromomethyl)naphthalene (1.44 g, 6.52 mmol), and the reaction mixture was stirred overnight at rt. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with water, dried over Na ₂ SO ₄ , and concentrated under reduced pressure. This material was purified by silica gel flash chromatography eluting with 0-100% ethyl acetate gradient in hexanes to give 2,2,2-trichloro-1-[7-fluoro-1-(2-naphthylmethyl)indol-3-yl]e thanone (900 mg).

To 2,2,2-trichloro-1-[7-fluoro-1-(2-naphthylmethyl)indol-3-yl]e thanone (900 mg, 2.06 mmol) solution in THF/MeOH (7 mL, 5:2) was added aqueous NaOH (2 mL, 2.5 N) and the reaction mixture was stirred overnight and then neutralized with 1.0 N HCl (pH = 6). The precipitate was filtered, washed with water, and then dried under vacuum to give 7- fluoro-1-(2-naphthylmethyl)indole-3-carboxylic acid (579 mg).

To a solution of 7-fluoro-1-(2-naphthylmethyl)indole-3-carboxylic acid (143 mg, 0.448 mmol) in anhydrous DMF (3 mL) was added Intermediate 4 (100 mg, 0.407 mmol), DIEA (0.213 mL, 1.22 mmol), and HATU (186 mg, 0.488 mmol). The reaction was stirred at 50 ^o C for 5 h, then overnight at rt. Solvent was evaporated. The mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1) to give 7-fluoro-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihydr oxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide (75 mg). LCMS m/z 512.1. ¹ H NMR (400 MHz, CD3OD): δ 8.12-8.01 (m, 1H), 7.88 (d, 1H), 7.84-7.80 (m, 2H), 7.77- 7.70 (m, 1H), 7.58 (s, 1H), 7.49-7.40 (m, 2H), 7.37-7.28 (m, 1H), 7.18-7.06 (m, 1H), 7.00- 6.88 (m, 1H), 5.80-5.55 (m, 3H), 4.65-3.98 (m, 3H), 3.95-3.37 (m, 4H) ppm (protons on NH and OH were not visible). Example 48

4-Methyl-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trih ydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

4-Methyl-1H-indole (1.0 g, 7.6 mmol) was dissolved in DCM (20 mL) and pyridine (1.85 mL, 22.9 mmol) was added. The solution was cooled to ~ 0 ^C, and a solution of trichloroacetyl chloride (1.28 mL, 11.4 mmol) in DCM (5 mL) was added over the course of about 30 min. The cooling bath was removed and the reaction mixture was stirred at rt overnight. All the volatiles are removed under reduced pressure. The mixture was then stirred with ethanol-water (1:1, 15 mL) for 10 min, and the product was filtered off and dried. Further purification by silica gel flash chromatography eluting with 0-100% ethyl acetate gradient in hexanes to give 2,2,2-trichloro-1-(4-methyl-1H-indol-3-yl)ethanone (1.89 g).

To 2,2,2-trichloro-1-(4-methyl-1H-indol-3-yl)ethanone (1.89 g, 6.87 mmol) in NMP (40 mL) was added K2CO3 (1.42 g, 10.3 mmol) and 2-(bromomethyl)naphthalene (2.28 g, 10.3 mmol), and the reaction mixture was stirred overnight at rt. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with water, dried over Na2SO4, and concentrated under reduced pressure. This material was purified by silica gel flash chromatography eluting with 0-100% ethyl acetate gradient in hexanes to give 2,2,2-trichloro-1-[4-methyl-1-(2-naphthylmethyl)indol-3-yl]e thanone (1.0 g).

To 2,2,2-trichloro-1-[4-methyl-1-(2-naphthylmethyl)indol-3-yl]e thanone (1.0 g, 2.4 mmol) solution in THF/MeOH (3 mL, 2:1) was added aqueous NaOH (1 mL, 2.5 N) and the reaction mixture was stirred overnight and then neutralized with 1.0 N HCl (pH = 6). The precipitate was filtered, washed with water, and then dried under vacuum to give 4-methyl- 1-(2-naphthylmethyl)indole-3-carboxylic acid (930 mg).

To a solution of 4-methyl-1-(2-naphthylmethyl)indole-3-carboxylic acid (141 mg, 0.448 mmol) in anhydrous DMF (3 mL) was added Intermediate 4 (100 mg, 0.407 mmol), DIEA (0.213 mL, 1.22 mmol), and HATU (186 mg, 0.488 mmol). The reaction was stirred at 50 ^o C for 5 h, then overnight at rt. Solvent was evaporated. The mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1) to give 4-methyl-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihydr oxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide (13 mg). LCMS m/z 507.8. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.90-7.70 (m, 3H), 7.61 (s, 1H), 7.54-7.38 (m, 3H), 7.30 (d, 1H), 7.24 (d, 1H), 7.07 (t, 1H), 6.92 (d, 1H), 5.69-5.43 (m, 3H), 4.70-4.02 (m, 3H), 3.96-3.38 (m, 4H), 2.67 (s, 3H) ppm (protons on NH and OH were not visible).

Example 49

7-Methyl-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trih ydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

7-Methyl-1H-indole (1.0 g, 7.6 mmol) was dissolved in DCM (20 mL) and pyridine (1.85 mL, 22.9 mmol) was added. The solution was cooled to ~ 0 ^C, and a solution of trichloroacetyl chloride (1.28 mL, 11.4 mmol) in DCM (5 mL) was added over the course of about 30 min. The cooling bath was removed and the reaction mixture was stirred at rt overnight. All the volatiles are removed under reduced pressure. The mixture was then stirred with ethanol-water (1:1, 15 mL) for 10 min, and the product was filtered off and dried. Further purification by silica gel flash chromatography eluting with 0-100% ethyl acetate gradient in hexanes to give 2,2,2-trichloro-1-(7-methyl-1H-indol-3-yl)ethanone (1.05 g).

To 2,2,2-trichloro-1-(7-methyl-1H-indol-3-yl)ethanone (1.05 g, 3.8 mmol) in NMP (15 mL) was added K ₂ CO ₃ (787 mg, 5.7 mmol) and 2-(bromomethyl)naphthalene (1.26 g, 5.7 mmol), and the reaction mixture was stirred overnight at rt. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with water, dried over Na ₂ SO ₄ , and concentrated under reduced pressure. This material was purified by silica gel flash chromatography eluting with 0-100% ethyl acetate gradient in hexanes to give 2,2,2-trichloro-1-[7-methyl-1-(2-naphthylmethyl)indol-3-yl]e thanone (1.3 g).

To 2,2,2-trichloro-1-[7-methyl-1-(2-naphthylmethyl)indol-3-yl]e thanone (1.3 g, 3.12 mmol) solution in THF/isopropanol (10 mL, 1:1) was added aqueous NaOH (5 mL, 2.5 N) and the reaction mixture was stirred overnight and then acidified with 1.0 N HCl (pH = 2). The precipitate was filtered, washed with water, and then dried under vacuum to give 7-methyl- 1-(2-naphthylmethyl)indole-3-carboxylic acid (875 mg).

To a solution of 7-methyl-1-(2-naphthylmethyl)indole-3-carboxylic acid (141 mg, 0.448 mmol) in anhydrous DMF (3 mL) was added Intermediate 4 (100 mg, 0.407 mmol), DIEA (0.213 mL, 1.22 mmol), and HATU (186 mg, 0.488 mmol). The reaction was stirred at 50 ^o C for 5 h, then overnight at rt. Solvent was evaporated. The mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1) to give 7-methyl-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihydr oxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide (33 mg). LCMS m/z 508.0. ¹ H NMR (400 MHz, CD3OD): δ 8.02-7.90 (m, 2H), 7.80 (d, 2H), 7.60 (d, 1H), 7.52-7.34 (m, 2H), 7.21 (s, 1H), 7.16 (d, 1H), 7.10 (t, 1H), 6.90 (d, 1H), 5.80-5.40 (m, 3H), 4.65-4.02 (m, 3H), 4.00-3.44 (m, 4H), 2.47 (s, 3H) ppm (protons on NH and OH were not visible). Example 50

4-Methoxy-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-tri hydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a solution of 4-methoxy-1-(2-naphthylmethyl)indole-3-carboxylic acid (prepared from 4-methoxyindole-3-carboxylic acid and 2-bromomethylnaphthalene following General Procedure A) (148 mg, 0.448 mmol) in anhydrous DMF (3 mL) was added Intermediate 4 (100 mg, 0.407 mmol), DIEA (0.213 mL, 1.22 mmol), and HATU (186 mg, 0.488 mmol). The reaction was stirred at 40 ^o C overnight. Solvent was evaporated. The mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1) to give 4-methoxy-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5- trihydroxy-3,6-bis(hydroxymethyl)tetrahydropyran-3-yl]indole -3-carboxamide (43 mg). LCMS m/z 523.7. ¹ H NMR (400 MHz, CD3OD): δ 8.02-7.88 (m, 1H), 7.84-7.68 (m, 3H), 7.62 (d, 1H), 7.55-7.35 (m, 3H), 7.27 (d, 1H), 7.20-7.05 (m, 1H), 6.73 (d, 1H), 5.80 (s, 2H), 5.62-5.41 (m, 1H), 4.60-3.98 (m, 3H), 3.96-3.38 (m, 7H) ppm (protons on NH and OH were not visible). Example 51

1-(2-Naphthylmethyl)-5-(trifluoromethoxy)-N-[(3R,4R,5S,6R )-2,4,5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a stirred solution of 1-(2-naphthylmethyl)-5-(trifluoromethoxy)-indole-3-carboxyli c acid (prepared from 5-trifluoromethoxyindole-3-carboxylic acid and 2-bromomethylnaphthalene following General Procedure A) (210 mg, 0.54 mmol) and HATU (208 mg, 0.55 mmol) in DMF (4 mL) was added DIPEA (0.26 mL, 1.5 mmol). After 20 min Intermediate 4 (150 mg, 0.6 mmol) was added and the solution was stirred for 14 h at 55 ^o C. The solution was concentrated, dispersed onto SiO ₂ and purified by flash chromatography (SiO ₂ , 0% to 10% MeOH gradient in DCM/acetone (1:1) to give 110 mg of 1-(2-naphthylmethyl)-5- (trifluoromethoxy)-N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide. LCMS m/z 577.8. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.25-8.10 (m, 1H), 8.03 (s, 1H), 7.87-7.75 (m, 2H), 7.68 (s, 1H), 7.52 (d, 1H), 7.49-7.40 (m, 2H), 7.38-7.15 (m, 2H), 7.14-7.05 (m, 1H), 5.68-5.55 (m, 3H), 4.58-4.02 (m, 3H), 3.80-3.40 (m, 4H) ppm (protons on NH and OH were not visible). Example 52

5-Cyano-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihy droxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a stirred solution of 5-cyano-1-(2-naphthylmethyl indole-3-carboxylic acid (prepared from 5-cyanoindole-3-carboxylic acid and 2-bromomethylnaphthalene following General Procedure A) (160 mg, 0.5 mmol) and HATU (208 mg, 0.55 mmol) in DMF (4 mL) was added DIPEA (0.26 mL, 1.5 mmol). After 20 min Intermediate 4 (150 mg, 0.6 mmol) was added and the solution was stirred for 14 h at 55 ^o C. The solution was concentrated, dispersed onto SiO2 and purified by flash chromatography (SiO2, 0% to 10% MeOH gradient in DCM/acetone (1:1) to give 90 mg of 5-cyano-1-(2-naphthylmethyl)-N- [(3R,4R,5S,6R)-2,4,5-trihydroxy-3,6-bis(hydroxymethyl)tetrah ydropyran-3-yl]indole-3- carboxamide. LCMS m/z 518.9. ¹ H NMR (400 MHz, CD3OD): δ 8.51 (s, 1H), 8.30-8.20 (m, 1H), 7.87-7.75 (m, 2H), 7.69 (s, 1H), 7.68-7.60 (m, 1H), 7.54-7.40 (m, 3H), 7.38-7.28 (m, 2H), 5.68-5.48 (m, 3H), 4.58-4.02 (m, 3H), 3.85-3.40 (m, 4H) ppm (protons on NH and OH were not visible). Example 53

N-[(3R,4R,5S,6R)-3-Ethyl-2,4,5-trihydroxy-6-(hydroxymethy l)tetrahydropyran-3-yl]-5- fluoro-6-methoxy-1-(2-naphthylmethyl)indole-3-carboxamide

To a stirred solution of Intermediate 2 (1.5 g, 3.36 mmol) in THF (20 mL) was added Ti(OEt)4 ( 1.53 g, 6.7 mmol) and (R)-(+)-2-methyl-2-propanesulfinamide (468 mg, 3.86 mmol). The solution was stirred for 14 h at 50 ^o C, allowed to cool to rt and diluted with H ₂ O. The resulting suspension was filtered through Celite with an EtOAc rinse and the filtrate was extracted with EtOAc. The combined organics were dried over MgSO4, filtered and concentrated. To a stirred solution of this residue in THF (50 mL) and at -78 ^o C was added EtMgBr (8.4 mL, 1.0M in THF). The solution was allowed to warm to rt, stirred 14 h and then quenched with saturated aqueous NH4Cl. The mixture was extracted with Et2O. The organics were dried over MgSO4, filtered, concentrated and purified by flash chromatography (SiO ₂ , 10% to 40% acetone gradient in hexanes) to give 1.6 g of N- [(4aR,6S,7R,8R,8aS)-6,8-dibenzyloxy-7-ethyl-2-phenyl-4a,6,8, 8a-tetrahydro-4H- pyrano[3,2-d][1,3]dioxin-7-yl]-2-methyl-propane-2-sulfinamid e. LCMS m/z 580.9.

To a stirred solution of N-[(4aR,6S,7R,8R,8aS)-6,8-dibenzyloxy-7-ethyl-2-phenyl- 4a,6,8,8a-tetrahydro-4H-pyrano[3,2-d][1,3]dioxin-7-yl]-2-met hyl-propane-2-sulfinamide (1.6 g, 2.8 mmol) in dioxane (30 mL) was added HCl (1.5 mL, 4M dioxane solution). After 30 min. the solution was concentrated and diluted with Et ₂ O. The resulting precipitate was collected by filtration, washed (10% Et ₂ O in Hexanes) and allowed to dry. To a stirred solution of the resulting white powder in DCM (30 mL) and sat. aqueous NaHCO3 (30 mL) was added Di-tert-butyl dicarbonate (1.3 g, 6.15 mmol). The biphasic mixture was stirred for 18 h, extracted with DCM and the combined organics were concentrated. The resulting residue was purified by flash chromatography (SiO2, 10% to 60% EtOAc gradient in hexanes) to give 1.3 g of tert-butyl N-[(4aR,6S,7R,8R,8aS)-6,8-dibenzyloxy-7-ethyl-2- phenyl-4a,6,8,8a-tetrahydro-4H-pyrano[3,2-d][1,3]dioxin-7-yl ]carbamate. LCMS m/z 577.0. To a stirred solution of tert-butyl N-[(4aR,6S,7R,8R,8aS)-6,8-dibenzyloxy-7-ethyl-2- phenyl-4a,6,8,8a-tetrahydro-4H-pyrano[3,2-d][1,3]dioxin-7-yl ]carbamate (1.3 g, 2.25 mmol) in THF/MeOH (20 mL, 1:1) was added palladium on carbon (1.2 g, 10% (dry basis), wet Degussa type) and HCl (1.2 mL, 4 M Dioxane solution). The mixture was stirred under 45 psi of H2 for 14 h, filtered through Celite with a MeOH rinse and concentrated to give a yellow solidified foam (207 mg) that was used directly in the next reaction.

To a stirred solution of Intermediate 6 (406 mg, 1.2 mmol) and HATU (456 mg, 1.2 mmol) in DMF (8 mL) was added DIPEA (0.55 mL, 3.0 mmol) After 30 min. the product of the previous step (207 mg) was added and the solution was stirred for 14 h at 50 ^o C. The solution was concentrated, dissolved in EtOAc and washed with H ₂ O followed by brine. The organics were dried over NaSO4, filtered, concentrated and purified by flash chromatography (SiO2, 0% to 10% MeOH gradient in DCM/acetone (1:1) to give 30 mg of 5-fluoro-6-methoxy-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4 ,5-trihydroxy-6- (hydroxymethyl)-3-ethyl-tetrahydropyran-3-yl]indole-3-carbox amide. LCMS m/z 539.9. ¹ H NMR (400 MHz, CD3OD): δ 7.99-7.64 (m, 6H), 7.48-7.42 (m, 2H), 7.36-7.29 (m, 1H), 7.14-7.08 (m, 1H), 5.58 (s, 2H), 5.41 and 5.36 (s, 1H), 4.25-4.00 (m, 1H), 3.89-3.45 (m, 4H), 3.79 (s, 3H), 2.69-2.40 (m, 1H), 1.90-1.72 (m, 1H), 1.13-0.89 (m, 3H) ppm (protons on NH and OH were not visible). Example 54

5-Chloro-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trih ydroxy-6-(hydroxymethyl)-3- methyl-tetrahydropyran-3-yl]indole-3-carboxamide

To a stirred solution of 5-chloro-1-(2-naphthylmethyl indole-3-carboxylic acid (prepared as in Example 45) (167 mg, 0.5 mmol) and HATU (208 mg, 0.55 mmol) in DMF (4 mL) was added DIPEA (0.26 mL, 1.5 mmol). After 20 min Intermediate 5 (150 mg, 0.6 mmol) was added and the solution was stirred for 14 h at 55 ^o C. The solution was concentrated, dispersed onto SiO ₂ and purified by flash chromatography (SiO ₂ , 0% to 10% MeOH gradient in DCM/acetone (1:1) to give 72 mg of 5-chloro-1-(2-naphthylmethyl)-N- [(3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)-3-methyl-t etrahydropyran-3- yl]indole-3-carboxamide. LCMS m/z 511.7. ¹ H NMR (400 MHz, CD3OD): δ 8.14-8.02 (m, 2H), 7.86-7.74 (m, 3H), 7.66 (s, 1H), 7.49-7.40 (m, 3H), 7.31 (m, 1H), 7.15 (dt, 1H), 5.64 and 5.42 (s, 1H), 5.57 (s, 2H), 4.32 and 3.99 (d, 1H), 3.89-3.39 (m, 4H), 1.54 and 1.32 (s, 3H) ppm (protons on NH and OH were not visible). Example 55

5-Bromo-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihy droxy-6-(hydroxymethyl)-3- methyl-tetrahydropyran-3-yl]indole-3-carboxamide

To a solution of 5-bromo-1-(2-naphthylmethyl)indole-3-carboxylic acid (prepared as in Example 23) (456 mg, 1.2 mmol) in anhydrous DMF (2 mL) was added Intermediate 5 (250 mg, 1.09 mmol), DIEA (0.571 mL, 3.27 mmol), and HATU (497 mg, 1.31 mmol). The reaction was stirred at 40 ^o C overnight. Solvent was evaporated. The mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1). Silica gel flash chromatography was repeated eluting with 0-5% methanol in DCM to give 5-bromo-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihydro xy-6- (hydroxymethyl)-3-methyl-tetrahydropyran-3-yl]indole-3-carbo xamide (42 mg). LCMS m/z 556.3. ¹ H NMR (400 MHz, CD3OD): δ 8.27 (d, 1H), 8.06 (d, 1H), 7.86-7.71 (m, 3H), 7.64 (s, 1H), 7.52-7.40 (m, 2H), 7.36 (d, 1H), 7.33-7.24 (m, 2H), 5.65 and 5.43 (s, 1H), 5.56 (s, 2H), 4.32 and 3.99 (d, 1H), 3.94-3.35 (m, 4H), 1.54 and 1.32 (s, 3H) ppm (protons on NH and OH were not visible). Example 56

4-Methoxy-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-tri hydroxy-6-(hydroxymethyl)- 3-methyl-tetrahydropyran-3-yl]indole-3-carboxamide

To a solution of 4-methoxy-1-(2-naphthylmethyl)indole-3-carboxylic acid (prepared as in Example 50) (398 mg, 1.2 mmol) in anhydrous DMF (2 mL) was added Intermediate 5 (250 mg, 1.09 mmol), DIEA (0.571 mL, 3.27 mmol), and HATU (497 mg, 1.31 mmol). The reaction was stirred at 40 ^o C overnight. Solvent was evaporated. The mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1). Silica gel flash chromatography was repeated eluting with 0-5% methanol in DCM to give 4-methoxy-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihyd roxy-6- (hydroxymethyl)-3-methyl-tetrahydropyran-3-yl]indole-3-carbo xamide (24 mg). LCMS m/z 508.4. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.90 (d, 1H), 7.81-7.74 (m, 2H), 7.73-7.67 (m, 1H), 7.61 (t, 1H), 7.48 (s, 1H), 7.46-7.37 (m, 2H), 7.34-7.22 (m, 1H), 7.17-7.00 (m, 1H), 6.71 (d, 1H), 5.79 (s, 2H), 5.63-5.25 (m, 1H), 4.20 and 3.99 (d, 1H), 3.91-3.33 (m, 7H), 1.55 and 1.34 (s, 3H) ppm (protons on NH and OH were not visible). Example 57

1-(Benzothiophen-2-ylmethyl)-6-methoxy-N-[(3R,4R,5S,6R)-2 ,4,5-trihydroxy-6- (hydroxymethyl)-3-methyl-tetrahydropyran-3-yl]indole-3-carbo xamide

To a solution of 1-(benzothiophen-2-ylmethyl)-6-methoxy-indole-3-carboxylic acid (prepared as in Example 34) (405 mg, 1.2 mmol) in anhydrous DMF (2 mL) was added Intermediate 5 (250 mg, 1.09 mmol), DIEA (0.571 mL, 3.27 mmol), and HATU (497 mg, 1.31 mmol). The reaction was stirred at 40 ^o C overnight. Solvent was evaporated. The mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1). Silica gel flash chromatography was repeated eluting with 0-5% methanol in DCM to give 1-(benzothiophen-2-ylmethyl)-6-methoxy-N- [(3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxymethyl)-3-methyl-t etrahydropyran-3- yl]indole-3-carboxamide (75 mg). LCMS m/z 514.3. ¹ H NMR (400 MHz, CD3OD): δ 7.95- 7.82 (m, 2H), 7.78-7.65 (m, 2H), 7.36-7.22 (m, 3H), 7.10-6.98 (m, 1H), 6.86 (d, 1H), 5.72- 5.25 (m, 3H), 4.20 and 3.99 (d, 1H), 3.92-3.34 (m, 7H), 1.54 and 1.33 (s, 3H) ppm (protons on NH and OH were not visible). Example 58

7-Methoxy-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-tri hydroxy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a solution of 7-methoxy-1H-indole-3-carboxylic acid (1.0 g, 5.23 mmol) in dry DMF (10 mL) was added slowly sodium hydride (60% dispersion in mineral oil, 628 mg, 15.69 mmol). To this mixture was added 2-(bromomethyl)naphthalene (1.27 g, 5.75 mmol), and the reaction mixture was heated to 50-60 ^C for 1 hr. The mixture was then cooled to rt and poured onto crushed ice and acidified with 2 N aqueous HCl to pH 6. The precipitate was collected, washed with water and dried to give 7-methoxy-1-(2-naphthylmethyl)indole-3- carboxylic acid (1.66 g).

To a solution of 7-methoxy-1-(2-naphthylmethyl)indole-3-carboxylic acid (148 mg, 0.448 mmol) in anhydrous DMF (3 mL) was added Intermediate 4 (100 mg, 0.407 mmol), DIEA (0.213 mL, 1.22 mmol), and HATU (186 mg, 0.488 mmol). The reaction was stirred at 40 ^o C overnight. Solvent was evaporated. The mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1). Silica gel flash chromatography was repeated eluting with 0-5% methanol in DCM to give 7- methoxy-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihydro xy-3,6- bis(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide (15 mg). LCMS m/z 523.8. ¹ H NMR (400 MHz, CD ₃ OD): δ 8.08-8.00 (m, 1H), 7.86-7.72 (m, 3H), 7.62 (d, 1H), 7.50- 7.41 (m, 3H), 7.30 (d, 1H), 7.23-7.07 (m, 1H), 6.77 (d, 1H), 5.66-5.47 (m, 3H), 4.50-4.02 (m, 6H), 3.98-3.40 (m, 4H) ppm (protons on NH and OH were not visible). Example 59

5-Fluoro-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trih ydroxy-6-(hydroxymethyl)-3- methyl-tetrahydropyran-3-yl]indole-3-carboxamide

To a solution of 5-fluoro-1-(2-naphthylmethyl)indole-3-carboxylic acid (prepared as in Example 17) (383 mg, 1.2 mmol) in anhydrous DMF (2 mL) was added Intermediate 5 (250 mg, 1.09 mmol), DIEA (0.571 mL, 3.27 mmol), and HATU (497 mg, 1.31 mmol). The reaction was stirred at 40 ^o C overnight. Solvent was evaporated. The mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1). Silica gel flash chromatography was repeated eluting with 0-5% methanol in DCM to give 5-fluoro-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihydr oxy-6- (hydroxymethyl)-3-methyl-tetrahydropyran-3-yl]indole-3-carbo xamide (69 mg). LCMS m/z 496.3. ¹ H NMR (400 MHz, CD3OD): δ 8.08 (d, 1H), 7.86-7.70 (m, 4H), 7.66 (s, 1H), 7.51- 7.37 (m, 3H), 7.30 (m, 1H), 6.95 (dt, 1H), 5.64 and 5.39 (s, 1H), 5.58 (s, 2H), 4.29 and 4.00 (d, 1H), 3.92-3.33 (m, 4H), 1.54 and 1.33 (s, 3H) ppm (protons on NH and OH were not visible). Example 60

1-(2-Naphthylmethyl)-5-thiazol-2-yl-N-[(3R,4R,5S,6R)-2,4, 5-trihydroxy-6- (hydroxymethyl)-3-methyl-tetrahydropyran-3-yl]indole-3-carbo xamide

1-(2-Naphthylmethyl)-5-thiazol-2-yl-indole-3-carboxylic acid was prepared analogously to the method described for 1-(2-naphthylmethyl)-6-thiazol-2-yl-indole-3-carboxylic acid, an intermediate for Example 8. To a solution of 1-(2-naphthylmethyl)-5-thiazol-2-yl-indole-3-carboxylic acid (461 mg, 1.2 mmol) in anhydrous DMF (2 mL) was added Intermediate 5 (250 mg, 1.09 mmol), DIEA (0.571 mL, 3.27 mmol), and HATU (497 mg, 1.31 mmol). The reaction was stirred at 40 ^o C overnight. Solvent was evaporated. The mixture was purified by silica gel flash

chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1). Silica gel flash chromatography was repeated eluting with 0-5% methanol in DCM to give 1-(2- naphthylmethyl)-5-thiazol-2-yl-N-[(3R,4R,5S,6R)-2,4,5-trihyd roxy-6-(hydroxymethyl)-3- methyl-tetrahydropyran-3-yl]indole-3-carboxamide (84 mg). LCMS m/z 561.3. ¹ H NMR (400 MHz, CD3OD): δ 8.68 (d, 1H), 8.10 (d, 1H), 7.90-7.73 (m, 5H), 7.68 (s, 1H), 7.61- 7.50 (m, 2H), 7.49-7.40 (m, 2H), 7.33 (dt, 1H), 5.68 and 5.46 (s, 1H), 5.60 (d, 2H), 4.36 and 4.03 (d, 1H), 3.94-3.38 (m, 4H), 1.60 and 1.35 (s, 3H) ppm (protons on NH and OH were not visible). Example 61

5-Cyano-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihy droxy-6-(hydroxymethyl)-3- methyl-tetrahydropyran-3-yl]indole-3-carboxamide

To a solution of 3-formyl-1H-indole-5-carbonitrile (2.0 g, 11.8 mmol) in dry DMF (20 mL) was added K ₂ CO ₃ (2.44 g, 17.7 mmol) and 2-(bromomethyl)naphthalene (3.12 g, 14.2 mmol), and the reaction mixture was stirred overnight at 80 ^C. The mixture was then cooled to rt and poured into water, then extracted with ethyl acetate. The organic layer was washed with water and brine, and was then dried over sodium sulfate and concentrated in vacuo to give 3-formyl-1-(2-naphthylmethyl)indole-5-carbonitrile (2.9 g).

To 3-formyl-1-(2-naphthylmethyl)indole-5-carbonitrile (2.9 g, 9.34 mmol) in acetone (250 mL) was added a solution of KMnO4 (3.8 g, 24.0 mmol) in water (50 mL), and the reaction mixture was stirred for 2 h at rt. Hydrogen peroxide (10 mL) was carefully added dropwise, and the reaction was allow to stir an additional 15 min. The mixture was filtered through Celite, then extracted with ethyl acetate. The organic layer was washed with 0.5 N HCl, water, and brine, and was then dried over sodium sulfate and concentrated in vacuo to give 5-cyano-1-(2-naphthylmethyl)indole-3-carboxylic acid.

To a solution of 5-cyano-1-(2-naphthylmethyl)indole-3-carboxylic acid (392 mg, 1.2 mmol) in anhydrous DMF (2 mL) was added Intermediate 5 (250 mg, 1.09 mmol), DIEA (0.571 mL, 3.27 mmol), and HATU (497 mg, 1.31 mmol). The reaction was stirred at 40 ^o C overnight. Solvent was evaporated. The mixture was purified by silica gel flash

chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1). Silica gel flash chromatography was repeated eluting with 0-5% methanol in DCM to give 5-cyano-1- (2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydr oxymethyl)-3-methyl- tetrahydropyran-3-yl]indole-3-carboxamide (42 mg). LCMS m/z 503.3. ¹ H NMR (400 MHz, CD3OD): δ 8.51 (d, 1H), 8.23 (d, 1H), 7.88-7.74 (m, 3H), 7.69 (s, 1H), 7.63 (d, 1H), 7.52-7.42 (m, 3H), 7.37-7.27 (m, 1H), 5.69 and 5.53 (s, 1H), 5.64 (d, 2H), 4.42 and 3.99 (d, 1H), 3.93-3.38 (m, 4H), 1.55 and 1.31 (s, 3H) ppm (protons on NH and OH were not visible). Example 62

5-Methoxy-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-tri hydroxy-6-(hydroxymethyl)- 3-methyl-tetrahydropyran-3-yl]indole-3-carboxamide

To a solution of 5-methoxy-1-(2-naphthylmethyl)indole-3-carboxylic acid (prepared as for Example 46) (398 mg, 1.2 mmol) in anhydrous DMF (2 mL) was added Intermediate 5 (250 mg, 1.09 mmol), DIEA (0.571 mL, 3.27 mmol), and HATU (497 mg, 1.31 mmol). The reaction was stirred at 40 ^o C overnight. Solvent was evaporated. The mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1). Silica gel flash chromatography was repeated eluting with 0-5% methanol in DCM to give 5-methoxy-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihyd roxy-6- (hydroxymethyl)-3-methyl-tetrahydropyran-3-yl]indole-3-carbo xamide (51 mg). LCMS m/z 508.3. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.97 (d, 1H), 7.86-7.72 (m, 3H), 7.64 (s, 1H), 7.57 (dd, 1H), 7.50-7.42 (m, 2H), 7.38-7.27 (m, 2H), 6.83 (d, 1H), 5.62 and 5.30 (s, 1H), 5.55 (s, 2H), 4.20 and 4.00 (d, 1H), 3.93-3.37 (m, 7H), 1.56 and 1.35 (s, 3H) ppm (protons on NH and OH were not visible). Example 63

7-Methoxy-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-tri hydroxy-6-(hydroxymethyl)- 3-methyl-tetrahydropyran-3-yl]indole-3-carboxamide

To a solution of 7-methoxy-1-(2-naphthylmethyl)indole-3-carboxylic acid (prepared as for Example 58) (398 mg, 1.2 mmol) in anhydrous DMF (2 mL) was added Intermediate 5 (250 mg, 1.09 mmol), DIEA (0.571 mL, 3.27 mmol), and HATU (497 mg, 1.31 mmol). The reaction was stirred at 40 ^o C overnight. Solvent was evaporated. The mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1). Silica gel flash chromatography was repeated eluting with 0-5% methanol in DCM to give 7-methoxy-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihyd roxy-6- (hydroxymethyl)-3-methyl-tetrahydropyran-3-yl]indole-3-carbo xamide (23 mg). LCMS m/z 508.3. ¹ H NMR (400 MHz, CD3OD): δ 8.04-7.94 (m, 1H), 7.86 (d, 1H), 7.83-7.78 (m, 1H), 7.76-7.70 (m, 1H), 7.61 (s, 1H), 7.56-7.39 (m, 3H), 7.28 (d, 1H), 7.21-7.06 (m, 1H), 6.80- 6.72 (m, 1H), 5.59 and 5.26 (s, 1H), 5.54 (s, 2H), 4.42-3.98 (m, 4H), 3.96-3.38 (m, 4H), 1.55 and 1.36 (s, 3H) ppm (protons on NH and OH were not visible). Example 64

4-Chloro-6-methoxy-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)- 2,4,5-trihydroxy-6- (hydroxymethyl)-3-methyl-tetrahydropyran-3-yl]indole-3-carbo xamide

To a solution of 4-chloro-6-methoxy-1-(2-naphthylmethyl)indole-3-carboxylic acid (prepared from 4-chloro-6-methoxyindole-3-carboxylic acid and 2- bromomethylnaphthalene following General Procedure A) (439 mg, 1.2 mmol) in anhydrous DMF (2 mL) was added Intermediate 5 (250 mg, 1.09 mmol), DIEA (0.571 mL, 3.27 mmol), and HATU (497 mg, 1.31 mmol). The reaction was stirred at 40 ^o C overnight. Solvent was evaporated. The mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1). Silica gel flash

chromatography was repeated eluting with 0-5% methanol in DCM to give 4-chloro-6- methoxy-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihydro xy-6-(hydroxymethyl)-3- methyl-tetrahydropyran-3-yl]indole-3-carboxamide (16 mg). LCMS m/z 542.3. ¹ H NMR (400 MHz, CD3OD): δ 7.88-7.71 (m, 4H), 7.65 (s, 1H), 7.51-7.40 (m, 2H), 7.36-7.27 (m, 1H), 6.90 (s, 1H), 6.83 (s, 1H), 5.63 and 5.35 (s, 1H), 5.52 (s, 2H), 4.27 and 3.93 (d, 1H), 3.91-3.35 (m, 7H), 1.55 and 1.32 (s, 3H) ppm (protons on NH and OH were not visible). Example 65

6-Ethoxy-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trih ydroxy-6-(hydroxymethyl)-3- methyl-tetrahydropyran-3-yl]indole-3-carboxamide

To a solution of 1H-indol-6-ol (1.0 g, 7.51 mmol) in acetone (15 mL) was added cesium carbonate (3.67 g, 11.27 mmol). To this mixture was added bromoethane (0.616 mL, 8.26 mmol), and the reaction mixture was stirred overnight at rt. The reaction mixture was filtered, and the solvent was evaporated. The mixture was purified by silica gel flash chromatography eluting with 0-100% ethyl acetate gradient in hexanes to give 6-ethoxy- 1H-indole (812 mg).

6-Ethoxy-1H-indole (2.34 g, 14.5 mmol) was dissolved in DCM (15 mL) and pyridine (3.52 mL, 43.55 mmol) was added. The solution was cooled to ~ 0 ^C, and a solution of trichloroacetyl chloride (1.28 mL, 11.4 mmol) in DCM (10 mL) was added over the course of about 30 min. The cooling bath was removed and the reaction mixture was stirred at rt overnight. All the volatiles are removed under reduced pressure. The mixture was then stirred with ethanol-water (1:1, 15 mL) for 10 min, and the product was filtered off and dried. Further purification by silica gel flash chromatography eluting with 0-100% ethyl acetate gradient in hexanes to give 2,2,2-trichloro-1-(6-ethoxy-1H-indol-3-yl)ethanone (2.41 g).

To 2,2,2-trichloro-1-(6-ethoxy-1H-indol-3-yl)ethanone (2.41 g, 7.86 mmol) in DMF (20 mL) was added K ₂ CO ₃ (1.63 g, 11.8 mmol) and 2-(bromomethyl)naphthalene (2.09 g, 9.43 mmol), and the reaction mixture was stirred overnight at rt. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with water, dried over Na ₂ SO ₄ , and concentrated under reduced pressure. This material was purified by silica gel flash chromatography eluting with 0-100% ethyl acetate gradient in hexanes to give 2,2,2-trichloro-1-[6-ethoxy-1-(2-naphthylmethyl)indol-3-yl]e thanone (1.5 g).

To 2,2,2-trichloro-1-[6-ethoxy-1-(2-naphthylmethyl)indol-3-yl]e thanone (1.5 g, 3.36 mmol) solution in THF/isopropanol (15 mL, 2:1) was added aqueous NaOH (5 mL, 2.5 N) and the reaction mixture was stirred overnight and then neutralized with 1.0 N HCl (pH = 6). The precipitate was filtered, washed with water, and then dried under vacuum to give 6-ethoxy- 1-(2-naphthylmethyl)indole-3-carboxylic acid (1.2 g).

To a solution of 6-ethoxy-1-(2-naphthylmethyl)indole-3-carboxylic acid (414 mg, 1.2 mmol) in anhydrous DMF (2 mL) was added Intermediate 5 (250 mg, 1.09 mmol), DIEA (0.571 mL, 3.27 mmol), and HATU (497 mg, 1.31 mmol). The reaction was stirred at 40 ^o C overnight. Solvent was evaporated. The mixture was purified by silica gel flash

chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1). Silica gel flash chromatography was repeated eluting with 0-5% methanol in DCM to give 6-ethoxy- 1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hy droxymethyl)-3-methyl- tetrahydropyran-3-yl]indole-3-carboxamide (25 mg). LCMS m/z 522.4. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.95-7.86 (m, 2H), 7.85-7.71 (m, 3H), 7.64 (s, 1H), 7.50-7.40 (m, 2H), 7.30 (dt, 1H), 6.92 (d, 1H), 6.83 (d, 1H), 5.61 and 5.29 (s, 1H), 5.52 (s, 2H), 4.22 and 4.00 (d, 1H), 3.96 (q, 2H), 3.90-3.36 (m, 4H), 1.54 and 1.33 (s, 3H), 1.31 (t, 3H) ppm (protons on NH and OH were not visible). Example 66

4-Fluoro-6-methoxy-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)- 2,4,5-trihydroxy-6- (hydroxymethyl)-3-methyl-tetrahydropyran-3-yl]indole-3-carbo xamide

4-Fluoro-6-methoxy-1H-indole (250 mg, 1.51 mmol) was dissolved in DCM (5 mL) and pyridine (0.367 mL, 4.54 mmol) was added. The solution was cooled to ~ 0 ^C, and a solution of trichloroacetyl chloride (0.253 mL, 2.27 mmol) in DCM (2 mL) was added over the course of about 30 min. The cooling bath was removed and the reaction mixture was stirred at rt overnight. All the volatiles are removed under reduced pressure. The mixture was then stirred with ethanol-water (1:1, 15 mL) for 10 min, and the product was filtered off and dried. Further purification by silica gel flash chromatography eluting with 0-100% ethyl acetate gradient in hexanes to give 2,2,2-trichloro-1-(4-fluoro-6-methoxy-1H-indol-3- yl)ethanone (283 mg).

To 2,2,2-trichloro-1-(4-fluoro-6-methoxy-1H-indol-3-yl)ethanone (283 mg, 0.911 mmol) in DMF (3 mL) was added K ₂ CO ₃ (189 mg, 1.37 mmol) and 2-(bromomethyl)naphthalene (242 mg, 1.09 mmol), and the reaction mixture was stirred overnight at rt. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with water, dried over Na ₂ SO ₄ , and concentrated under reduced pressure. This material was purified by silica gel flash chromatography eluting with 0-100% ethyl acetate gradient in hexanes to give 2,2,2-trichloro-1-[4-fluoro-6-methoxy-1-(2-naphthylmethyl)in dol-3- yl]ethanone (215 mg).

To 2,2,2-trichloro-1-[4-fluoro-6-methoxy-1-(2-naphthylmethyl)in dol-3-yl]ethanone (215 mg, 0.477 mmol) solution in THF/isopropanol (4.5 mL, 2:1) was added aqueous NaOH (1.5 mL, 2.5 N) and the reaction mixture was stirred at 50 ^o C overnight and then neutralized with 1.0 N HCl (pH = 6). The precipitate was filtered, washed with water, and then dried under vacuum to give 4-fluoro-6-methoxy-1-(2-naphthylmethyl)indole-3-carboxylic acid (154 mg).

To a solution of 4-fluoro-6-methoxy-1-(2-naphthylmethyl)indole-3-carboxylic acid (154 mg, 0.441 mmol) in anhydrous DMF (2 mL) was added Intermediate 5 (92 mg, 0.401 mmol), DIEA (0.210 mL, 1.2 mmol), and HATU (183 mg, 0.481 mmol). The reaction was stirred at 40 ^o C overnight. Solvent was evaporated. The mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1). Silica gel flash chromatography was repeated eluting with 0-5% methanol in DCM to give 4- fluoro-6-methoxy-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5 -trihydroxy-6- (hydroxymethyl)-3-methyl-tetrahydropyran-3-yl]indole-3-carbo xamide (48 mg). LCMS m/z 526.4. ¹ H NMR (400 MHz, CD3OD): δ 7.92 (d, 1H), 7.84-7.74 (m, 3H), 7.66 (s, 1H), 7.51- 7.42 (m, 2H), 7.32 (dd, 1H), 6.87-6.80 (m, 1H), 6.63 (ddd, 1H), 5.58 and 5.28 (s, 1H), 5.55 (s, 2H), 4.20 and 3.99 (d, 1H), 3.92-3.35 (m, 7H), 1.54 and 1.34 (s, 3H) ppm (protons on NH and OH were not visible). Example 67

6-Methoxy-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-tri hydroxy-6-(hydroxymethyl)- 3-(methoxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

To a stirred solution of [(4aR,6R,7R,8R,8aS)-7-amino-6,8-dibenzyloxy-2-phenyl-4a,6,8, 8a- tetrahydro-4H-pyrano[3,2-d][1,3]dioxin-7-yl]methanol (432 mg, 0.9 mmol) in DMF (8 mL) at 0 ^o C was added NaH (40 mg, 60% dispersion in mineral oil). After 30 min. the mixture was cooled to -78 ^o C and MeI (127 mg, 0.9 mmol) in DMF (0.5 mL) was added dropwise. After 2 h the mixture was diluted with saturated aqueous NH4Cl and EtOAc. The organics were washed with H2O, brine, dried (Na2SO4), concentrated and purified by flash chromatography (SiO ₂ , 10% to 50% EtOAc gradient in hexanes) to give 200 mg of

(4aR,6R,7R,8R,8aS)-6,8-dibenzyloxy-7-(methoxymethyl)-2-ph enyl-4a,6,8,8a-tetrahydro- 4H-pyrano[3,2-d][1,3]dioxin-7-amine.

To a stirred solution of (4aR,6R,7R,8R,8aS)-6,8-dibenzyloxy-7-(methoxymethyl)-2-pheny l- 4a,6,8,8a-tetrahydro-4H-pyrano[3,2-d][1,3]dioxin-7-amine (200 mg, 0.4 mmol) in

THF/MeOH (12 mL, 1:1) was added palladium on carbon (80 mg, 10% (dry basis), wet Degussa type) and HCl (0.15 mL, 4M Dioxane solution). The mixture was stirred under 45 psi of H ₂ for 14 h, filtered through Celite with a MeOH rinse and concentrated to give a solidified foam (120 mg) that was used directly in the next reaction. To a stirred solution of Intermediate 1 (385 mg, 1.16 mmol) and HBTU (426 mg, 1.13 mmol) in DMF (8 mL) was added DIPEA (0.6 mL, 3.6 mmol) After 15 min. the product from the previous step (200 mg, 0.9 mmol) was added and the solution was stirred for 14 h at 65 ^o C. The solution was concentrated, dispersed onto SiO ₂ and purified by flash chromatography (SiO2, 0% to 10% MeOH gradient in DCM/acetone (1:1)) to give 50 mg of 6-methoxy-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihyd roxy-6-(hydroxymethyl)- 3-(methoxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide. LCMS m/z 537.3 ¹ H NMR (400 MHz, CD3OD): δ 7.95-7.70 (m, 5H), 7.65 (s, 1H), 7.50-7.41 (m, 2H), 7.31 (d, 1H), 6.95 (d, 1H), 6.86 (dd, 1H), 5.55 (s, 2H), 5.54-5.42 (m, 1H), 4.50-4.10 (m, 2H), 4.00-3.50 (m, 5H), 3.74(s, 3H), 3.42 and 3.36 (s, 3H) ppm (protons on NH and OH were not visible). Example 68

6-Methoxy-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-tri hydroxy-3-(2-hydroxyethyl)- 6-(hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide

Example 69

N-[(3aR,4R,5S,6R,7aR)-4,5-Dihydroxy-6-(hydroxymethyl)-2,3 ,4,5,6,7a- hexahydrofuro[2,3-b]pyran-3a-yl]-6-methoxy-1-(2-naphthylmeth yl)indole-3-carboxamide

To a suspension of (4aR,6R,8S,8aR)-6,8-dibenzyloxy-2-phenyl-4,4a,8,8a- tetrahydropyrano[3,2-d][1,3]dioxin-7-one (Intermediate 3) (3.0 g, 6.72 mmol) in anhydrous toluene (30 ml) was added methyl (triphenylphosphoranylidene) acetate (3.5 g, 10.08 mmol). The mixture was heated at reflux for 16 hr (water removed by Dean-Stark condensing). It was then condensed under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 0-100% ethyl acetate gradient in hexanes to give methyl 2-[(4aR,6R,8R,8aS)-6,8-dibenzyloxy-2-phenyl-4,4a,8,8a-tetrah ydropyrano[3,2- d][1,3]dioxin-7-ylidene]acetate (2.5 g ).

Methyl 2-[(4aR,6R,8R,8aS)-6,8-dibenzyloxy-2-phenyl-4,4a,8,8a-tetrah ydropyrano[3,2- d][1,3]dioxin-7-ylidene]acetate was taken up in 7 N NH3/MeOH and heated in a sealed tube at 70 °C for 72 h. The reaction mixture was then condensed under reduced pressure, and the residue was purified by silica gel flash chromatography eluting with 5% methanol in DCM to give methyl 2-[(4aR,6R,7R,8R,8aS)-7-amino-6,8-dibenzyloxy-2-phenyl-4a,6, 8,8a- tetrahydro-4H-pyrano[3,2-d][1,3]dioxin-7-yl]acetate (1.1 g). LCMS m/z 521.0.

To a suspension of LiAlH ₄ (27 mg, 0.722 mmol) in anhydrous THF was added a solution of methyl 2-[(4aR,6R,7R,8R,8aS)-7-amino-6,8-dibenzyloxy-2-phenyl-4a,6, 8,8a-tetrahydro- 4H-pyrano[3,2-d][1,3]dioxin-7-yl]acetate (75 mg, 0.144 mmol) in anhydrous THF (3 mL) dropwise at 0 ^o C. The reaction was stirred at 0 ^o C for 1 h, then further stirred overnight at rt. The reaction was quenched with a saturated aqueous solution of Na ₂ SO ₄ (1ml) and was followed by addition of a 10% aqueous solution of NaOH (1 mL). The mixture was diluted with ethyl acetate (50 mL) and filtered. The organic layer was dried over sodium sulfate and condensed to give 2-[(4aR,6R,7R,8R,8aS)-7-amino-6,8-dibenzyloxy-2-phenyl-4a,6, 8,8a- tetrahydro-4H-pyrano[3,2-d][1,3]dioxin-7-yl]ethanol, which was used in the next step without further purification.. LCMS m/z 493.0.

To a solution of 2-[(4aR,6R,7R,8R,8aS)-7-amino-6,8-dibenzyloxy-2-phenyl-4a,6, 8,8a- tetrahydro-4H-pyrano[3,2-d][1,3]dioxin-7-yl]ethanol in methanol-THF (1:1, 5 mL) was added 4M HCl in 1,4-dioxane (0.1 mL). Pd-C (10% wet, 0.1 g) was added, and the reaction mixture was stirred overnight under a hydrogen atmosphere at 45 p.s.i. The catalyst was removed by filtration and washed with methanol. The filtrate was evaporated to dryness to give the crude product (3R,4R,5S,6R)-3-amino-3-(2-hydroxyethyl)-6- (hydroxymethyl)tetrahydropyran-2,4,5-triol hydrochloride, which was used in the next step without further purification.

HMDS (0.65 mL, 3.12 mmol) and TMSCl (0.396 mL, 3.12 mmol) were added to a solution of (3R,4R,5S,6R)-3-amino-3-(2-hydroxyethyl)-6-(hydroxymethyl)te trahydropyran-2,4,5- triol hydrochloride (135 mg, 0.52 mmol) in pyridine (4 mL). The reaction mixture was heated overnight at 100 °C. The mixture was allowed to cool, poured into water, and was extracted with hexanes. The organic layer was washed with water, dried over sodium sulfate, and the solvent was removed to give the crude product (200 mg).

To a suspension of 6-methoxy-1-(2-naphthylmethyl)indole-3-carboxylic acid (181 mg, 0.546 mmol) in anhydrous DCE (3 mL) was added DIEA (0.111 mL, 0.637 mmol), and HBTU (207 mg, 0.546 mmol), and the reaction mixture was stirred at rt for 10 min. The crude amine (200 mg) from the previous step was then added. The reaction was stirred overnight at rt, and the solvent was evaporated. The mixture was purified by silica gel flash chromatography eluting with 0-10% methanol gradient in DCM/acetone (1:1) to give 6- methoxy-1-(2-naphthylmethyl)-N-[(3R,4R,5S,6R)-2,4,5-trihydro xy-3-(2-hydroxyethyl)-6- (hydroxymethyl)tetrahydropyran-3-yl]indole-3-carboxamide (Example 68) (27 mg). LCMS m/z 537.3. ¹ H NMR (400 MHz, CD ₃ OD): δ 7.98-7.88 (m, 2H), 7.86-7.72 (m, 3H), 7.68 (s, 1H), 7.51-7.42 (m, 2H), 7.33 (d, 1H), 7.02-6.90 (m, 1H), 6.87 (t, 1H), 5.72-5.42 (m, 3H), 3.93-3.43 (m, 10H), 2.51-2.20 (m, 2H) ppm (protons on NH and OH were not visible). N-[(3aR,4R,5S,6R)-4,5-dihydroxy-6-(hydroxymethyl)-2,3,4,5,6, 7a-hexahydrofuro[2,3- b]pyran-3a-yl]-6-methoxy-1-(2-naphthylmethyl)indole-3-carbox amide (Example 69) (9 mg) was isolated in the above purification procedure as a minor component found in the less polar fractions. LCMS m/z 519.2. ¹ H NMR (400 MHz, CD3OD): δ 7.99 (d, 1H), 7.94 (s, 1H), 7.87-7.72 (m, 3H), 7.66 (s, 1H), 7.53-7.41 (m, 2H), 7.32 (dd, 1H), 6.96 (d, 1H), 6.85 (dd, 1H), 5.75 (s, 1H), 5.46 (s, 2H), 4.59 (d, 1H), 4.22-4.01 (m, 3H), 3.95-3.85 (m, 1H), 3.80-3.72 (m, 4H), 3.69-3.60 (m, 1H), 2.71-2.52 (m, 1H), 2.31-2.19 (m, 1H) ppm (protons on NH and OH were not visible). Examples of compounds of Formula (I) or pharmaceutically acceptable salts thereof having potentially useful biological activity are shown in Tables 2-5, below. The ability of compounds Formula (I) or pharmaceutically acceptable salts thereof to inhibit HK2 was established with the representative compounds of Formula (I) or pharmaceutically acceptable salts listed in Tables 2 and 4 using the assays described below. BIOLOGICAL ASSAYS

The following assay methods may be used to identify and evaluate compounds of Formula (I) that are effective in inhibiting the HK2 enzyme. Hexokinase 2 (HK2) Enzyme Assay

Human hexokinase assay utilized ATP and glucose as substrates and detection of ADP product using the ADP-Glo detection system (Promega). Assays were performed in black 384-well flat-bottom plates (Greiner). Recombinant human hexokinase 2 enzyme was purchased from US Biologicals. Compounds were diluted in DMSO prior to addition in the assay. Typically, assays were performed by incubating enzyme (0.2– 10 nM) with or without inhibitor (0.00001-100 µM), 0.001-1.0 mM ATP, 0.1-100 mM MgCl2, 0.1-100 mM KCl, 1-10 mM DTT, and 0.01-10 mM glucose together for the time range of 5-120 minutes at room temperature in a final assay volume of 10 µL. The buffer used to bring the final assay volume up to 10 ^L was 25 mM HEPES, pH 7.4, containing 1-5% DMSO and 0.1 % BSA. Reactions were terminated by addition of 10 µL ADP-Glo and plates were incubated at room temperature for 40 minutes. Then 20 µL Kinase Detect buffer was added and plates were incubated 1 hour at room temperature with shaking. Then, the plate was read for Luminiscence using and Envision instrument (Perkin Elmer).

Measurement of ADP was accomplished by generating an ADP standard curve according to the manufacturer’s protocol. RFUs were converted to ADP concentration (µM) from the ADP standard curve. Total RFUs (C ⁺ ) and background control RFUs (C-) wells contained DMSO instead of compound. A plot of ADP concentration (µM) against log compound was generated, and IC50 values were determined from plots using GraphPad PRISM according to the 4 parameter logistic equation Y=Bottom+(Top- Bottom)/1+10^((Log(IC50)-X)*HillSlope)) where X is the logarithm of compound concentration and Y is ADP concentration in µM. Table 2, below, shows the results for various compounds tested in the HK2 Enzyme Assay, described above. Results are reported as the concentration at which the IC50 was observed on the response curve.

In Vitro Cell Proliferation Assay

Compounds may be tested for their ability to inhibit cell proliferation and viability. Dual Hoechst 33342 dye/ propidium iodide staining may be used to measure cell number and cell viability.

The antiproliferative activity of compounds may be studied using a panel of human tumor cells obtained from ATCC: SKOV-3 (human ovarian carcinoma cell line). These adherent cells (1,000– 20,000) may be plated in complete media (RPMI-1640, DMEM, F12K, or McCoy’s 5A) containing 10% dialyzed fetal bovine serum (Gibco) and glucose (1- 25 mM) in tissue-culture-treated Optilux 96-well black plates (Becton Dickinson) and placed in a humidified incubator at 37 ºC, 95% O2, 5% CO2 for 18-24 hours. Media may be removed and replaced with 90 ^L fresh media. A compound (0.00001-100 µM) may be diluted in media containing 3% DMSO and added to cells. Untreated cells or cells containing compound may be incubated for 24-96 hours. During the last 30 minutes of the incubation period, 10 µL of a propidium iodide (10 µg/mL)/Hoescht 33342 dye reagent (32 µM) in PBS may be added to each well and incubated in a humidified incubator at 37 ºC, 95% O ₂ , 5% CO ₂ .

Propidium iodide/ Hoechst 33342 fluorescent staining of cells may be measured using an IN Cell 2000 analyzer instrument with 10X objective. The instrument setting for the Hoechst channel may be excitation at 350 nm and emission at 455 nm. The setting for the propidium iodide channel may be excitation at 550 nm and emission at 605 nm. The nuclei may be counted in the Hoechst 33342 channel; the dead cells may be counted in the propidium iodide channel. Compound IC50 values may be determined from the cell number (Hoechst nuclear dye) versus compound concentration curve plots using GraphPad PRISM according to the 4 parameter logistic equation Y=Bottom+(Top-Bottom)/1+10^((Log(IC50)- X)*Hill Slope)). For cell death analysis, compound IC ₅₀ values may be determined from percentage of cells positive for PI dye versus compound concentration curve plots using GraphPad PRISM according to the 4 parameter logistic equation Y=Bottom+(Top- Bottom)/1+10^((Log(IC ₅₀ )-X)*Hill Slope)). Exemplary compounds of the invention were analyzed via the In Vitro Cell Proliferation Assay above. Results are shown in Table 3 below. Table 3

Recombinant Human Hexokinase 2 Enzyme Assay

Recombinant human hexokinase 2 was purchased from R and D Systems (product #8179- HK-020) and assayed using the Universal Kinase Activity Kit from R and D Systems (product #EA004) according to the manufacturer’s instruction. The assay couples to production of ADP by hexokinase to the generation of phosphate by the coupling phosphatase CD39L2/ENTPD6. Phosphate is then reacted with malachite green and the colored product is measured by absorbance at 620 nm. All reactions were carried out in duplicate wells of a 96-well plate in a final volume of 50 µL and contained either 1 mM or 5 mM glucose, 0.2 mM ATP, 1.5 ng/µL recombinant human hexokinase 2 (14.7 nM), 2 ng/µL coupling phosphatase, and 0– 10 µM inhibitor (1% final DMSO concentration) in a buffer containing 25 mM Hepes, 150 mM NaCl, 10 mM MgCl2 and 10 mM CaCl2, pH 7.0. Reactions were initiated by addition of hexokinase and were allowed to proceed at room temperature for 30 minutes prior to being quenched. Product formation was quantified using a phosphate standard curve. Following subtraction of background absorbance values from wells lacking hexokinase, data were normalized to DMSO control wells and fitted to a four parameter dose-response equation using GraphPad Prism software. Exemplary compounds of the invention were analyzed via the Recombinant Human Hexokinase 2 Enzyme Assay above. Results are shown in Table 4 below. Table 4

Cell Titer-Glo Anti-Proliferation Assays

H838 cells were obtained from the American Type Culture Collection (ATCC) and cultured in 5% CO ₂ at 37 ^C. Cells were seeded at 5,000 cells/well in RPMI 1640 media

supplemented with 10% FBS, 2 mM glutamine and antibiotics in triplicate wells of a 96- well tissue culture plate and allowed to adhere overnight. The following day, media was changed to RPMI 1640 media containing 5 mM glucose, 2 mM glutamine, 10% FBS, antibiotics and 0– 50 µM inhibitor (0.5% final DMSO). After 72 hours, cellular ATP content was measured using Cell Titer-Glo reagent (Promega product #G7572) according to the manufacturer’s instruction. Data were normalized to DMSO control wells and fitted with a four parameter equation using GraphPad Prism Software. Exemplary compounds of the invention were analyzed via the Cell Titer-Glo Anti- Proliferation Assay, above. Results are shown in Table 5 below. Table 5

Xenograft Study

Female scid/beige mice (n=20) age 6-8 weeks were implanted subcutaneously with 1 x 10 ⁷ A549 lung adenocarcinoma cells per mouse suspended in PBS. When tumors reached ~280mm ³ , mice were randomized into the following two groups of n=10 mice/group: 1) Vehicle control (40% sulfobutyl ether-β-cyclodextrin) and 2) HKII inhibitor dosed at intraperitoneally at 50 mg/kg (formulated at 5 mg/mL in 40% SBECD). For both groups, dosing was initiated on Day 14 and continued twice daily intraperitoneally until study end. Tumors were measured with calipers three times per week and tumor volume calculated using the formula tumor volume (mm ³ ) = (a x b ² /2) where‘b’ is the smallest diameter and‘a’ is the largest perpendicular diameter. ***P-value < 0.001 (Two- sided T-test).

The hexokinase II inhibitor used in the xenograft study was the compound of Example 35. Incorporation by Reference All publications and patents mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. Equivalents While specific embodiments of the subject invention have been discussed, the above specification is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims below. The full scope of the invention should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations.