INHIBITORS OF UNDECAPRENYL PYROPHOSPHATE SYNTHASE

RELATED APPLICATIONS

This application claims priority from U.S. Provisional patent application 60/820,367, filed July 26, 2006, which application is hereby expressly incorporated herein in its entirety, including formulae and exemplification. This application is related to U.S. Provisional Application 60/820,368, filed on July 26, 2006, which is hereby expressly incorporated by reference herein in its entirety, including formulae and exemplification.

BACKGROUND OF THE INVENTION

Prenyltransferases are enzymes important in lipid, peptidoglycan, and glycoprotein biosynthesis. These enzymes act on molecules having a five-carbon isoprenoid substrate. Prenyltransferases are classified into two major subgroups according to whether they catalyze the cis- or trarø-prenylation of products in the prenyl chain elongation. E-type prenyltransferases catalyze /rαra-prenylation and z- type prenyltransferases catalyze cw-prenylation. Bacterial undecaprenyl pyrophosphate synthase (UPPS), also known as undecaprenyl diphosphate synthase, is a z-type prenyltransferase that catalyzes the sequential condensation of eight molecules of isoprenyl pyrophosphate (IPP) with trans, trans -famesyl pyrophosphate (FPP) to produce the 55-carbon molecule termed undecaprenyl pyrophosphate. Undecaprenyl pyrophosphate is released from the synthase and dephosphorylated to form undecaprenyl phosphate that serves as the essential carbohydrate and lipid carrier in bacterial cell wall and lipopolysaccharide biosynthesis.

Emerging resistance to currently used antibacterial agents has generated an urgent need for antibiotics acting by different mechanisms. Undecaprenyl pyrophosphate synthase exists ubiquitously in bacteria and plays an essential and critical roll in the cell wall biosynthesis pathway. Thus, undecaprenyl pyrophosphate synthase is essential for cell viability and provides a valid and unexploited molecular target for

SUMMARY OF THE INVENTION

The present invention relates to compounds which inhibit the activity of UPPS, the use of these compounds for treating bacterial disease, pharmaceutical compositions comprising these compounds, as well as methods of identifying these compounds.

In another aspect, the invention pertains, at least in part, to a compound of Formula (X)

wherein represents a single or a double bond; n is an integer from 0-3;

X is selected from the group consisting of NR _x CR _x R _x and O; each R _x is independently selected from the group consisting of H, -Mi, -Mi-M ₂ , -Z-M ₂ , and -Mj-Z-M ₂ ; Mi and M ₂ are independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, halogen, NO ₂ , CN, OR _W , NR _W R _W , CO ₂ R _W , -C(O)R _W , -COR _W , NR _w C(O)Rw, NR _w C(0)NR _w Rw, NR _W R _W C(O)O, C(O)NR _W R _W , which may be optionally substituted, wherein each R _w is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group;

Z is selected from the group consisting of-O-, -NH-, -CR _Z R _Z -, -S-, -S(O)-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O-,-S(O) ₂ -, -CH(OH)-, -CH(OR ₂ ), - C(O)CH OH)CH ₂ -, -

CH(OR ₂ )CH ₂ -, and any combination thereof, wherein each R _z is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy;

Ai, Bi, Ci, and Dj are independently selected from the group consisting of CH ₂ , CRi, CR ₂ R ₃ , N, and NR ₄ (e.g., wherein one or two of Ai, Bi ₅ Ci, and Di is N or NR ₄ ); each Ri, R ₂ , R ₃ , and R ₄ are independently selected from the group consisting of H, an aliphatic group (e.g., alkyl, alkenyl, alkynyl etc.), a carbocyclic group (e.g., saturated or unsaturated), a heterocyclic group (e.g., saturated or unsaturated), an acyl group, halogen, NO ₂ , CN, OR ₃ , NR ₃ R ₃ , CO ₂ R ₃ , -C(O)R ₃ , -COR ₃ , NR ₃ C(O)R ₃ , NR ₃ C(O)NR ₃ R ₃ , NR ₃ R ₃ C(O)O-, C(O)NR ₃ R ₃ , which may be optionally substituted, wherein each R _a is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group; R ₅ is selected from the group consisting of -Gi, -Gi-G ₂ , -Y-G ₂ , and -Gj-Y-G ₂ ;

Gi and G ₂ are independently selected from H, an aliphatic group, a carbocyclic group, and a heterocyclic group, which may be optionally substituted with one or more of substituents; and

Y is selected from the group consisting of-O-, -NH-, -CR _y R _y -, -S-, -S(O)-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O-,-S(O) ₂ -, -CH(OH)-, -CH(0R _y ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(ORy)-, -CH(OH)CH ₂ -, - CH(OR _y )CH ₂ -, and any combination thereof, wherein each R _y is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy; R ₆ is selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group (e.g. , H, phenyl, benzyl, isobutyl, cyclohexyl, cyclohexylmethyl, m-methoxy phenyl, alkyl, aryl, and heterocycle); and

R ₇ and Rg are absent or independently selected from the group consisting of H, halogen (e.g., F), OH, an alkoxy group, an aliphatic group, and a carbocyclic group, which may be optionally substituted (e.g., by hydroxy or alkoxy).

It will be noted that the structure of some of the compounds of this invention includes asymmetric carbon atoms. It is to be understood accordingly that the isomers arising f eomers) are included within th Such isomers can be

obtained in substantially pure form by classical separation techniques and by stereochemical^ controlled synthesis. That is, unless otherwise stipulated, any chiral carbon center may be of either (R)- or (S)-stereochemistry. Furthermore, alkenes can include either the E- or Z-geometry, where appropriate. Additionally, one skilled in the art will appreciate that the chemical structures as drawn may represent a number of possible tautomers, and the present invention also includes those tautomers.

Accordingly, another embodiment of the invention is a substantially pure single stereoisomer or a mixture of stereoisomers, e.g., pre-determined to be within specific amounts. Moreover, it should be understood that the compounds of the present invention, comprise compounds that satisfy valency requirements known to the ordinarily skilled artisan. Additionally, compounds of the present invention comprise stable compounds as well as though compounds that may be modified, e.g., chemically or through appropriate formulation, to become stable. In certain embodiments, such stability is guided by time periods that are sufficient to allow administration to and/or treatment of a subject.

In addition, compounds of the invention further include derivatives of the compounds depicted below modified to adjust at least one chemical or physical property of a depicted compound. In certain embodiments, the modification comprises substitution of a carbon atom with a heteroatom or addition of a heteroatom-containing substituent (e.g., substituted by a substituent selected from the group consisting of hydroxy, alkoxy, heterocycle and an acyl group), such that one or more of the chemical or physical properties of the depicted compound have been enhanced, e.g., with respect to potency or selectivity. For example, particular embodiments of substituted alkyl moieties may be -CH ₂ OH or -CH ₂ OCH ₃ .

In an additional embodiment, the substituents may comprise those substituents known in the art to be useful for fluoro-quinolones (e.g., based on known chemistry, chemical or physical properties imparted by such substitution, or improved biological activity), as described further herein. In an additional aspect, the invention is a compound of Formula XI:

wherein

: represents a single or a double bond; m and n are independently selected from 0, 1, or 2;

X is selected from the group consisting of NR _x CR _x R _x and O; each R _x is independently selected from the group consisting of H, -M], -Mi -M ₂ , -Z-M ₂ , and -M ₁ -Z-M ₂ ;

M] and M ₂ are independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, halogen, NO ₂ , CN, OR _W , NR _W R _W , CO ₂ R _w , -C(O)R _W , -COR _W , NR _W C(O)R _W , NR _W C(O)NR _W R _W , NR _W R _W C(O)O, C(O)NR _W R _W , which may be optionally substituted, wherein each R _w is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group; Z is selected from the group consisting of-O-, -NH-, -CR _Z R _Z -, -S-, -S(O)-, -

C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ Ch-S(O) ₂ -, -CH(OH)-, -CH(OR ₂ ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(OR,)-, -CH(OH)CH ₂ -, - CH(OR _z )CH ₂ -, and any combination thereof, wherein each R _z is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy;

R], R] _a , R ₂ , R ₃ , Rt, R _4a are independently selected from the group consisting of H, an aliphatic group (e.g., alkyl, alkenyl, alkynyl etc.), a carbocyclic group (e.g., saturated or unsaturated), a heterocyclic group (e.g., saturated or unsaturated), an acyl group, halogen, NO ₂ , CN, OR ₃ , NR ₃ R ₃ , CO ₂ R ₃ , -C(O)R ₃ , -COR ₃ , NR ₃ C(O)R ₃ , NR ₃ C(O)NR ₃ R ₃ , NR ₃ R ₃ C(O)O-, C(O)NR ₃ R ₃ , which may be optionally substituted, wherein each R ₃ is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group;

R _2a and R ₃₃ are absent or independently selected from the group consisting of H, an aliphatic group (e.g., alkyl, alkenyl, alkynyl etc.), a carbocyclic group (e.g., saturated or unsaturated), a heterocyclic group (e.g., saturated or unsaturated), an acyl group, halogen, NO ₂ , CN, OR _a , NR ₃ R ₃ , CO ₂ R ₃ , -C(O)R ₃ , -COR ₃ , NR ₃ C(O)R ₃ , NR ₃ C(O)NR ₃ R ₃ , NR ₃ R ₃ C(O)O-, C(O)NR ₃ R ₂ , which may be optionally substituted, wherein each R ₃ is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group;

R ₅ is selected from the group consisting of -Gi, -G ₁ -G ₂ , -Y-G ₂ , and -Gj-Y-G ₂ ;

Gi and G ₂ are independently selected from H, an aliphatic group, a carbocyclic group, and a heterocyclic group, which may be optionally substituted with one or more of substituents; and

Y is selected from the group consisting of -O-, -NH-, -CR _y R _y -, -S-, -S(O)-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ CK-S(O) ₂ -, -CH(OH)-, -CH(0R _y ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(0R _y )-, -CH(OH)CH ₂ -, - CH(ORy)CH ₂ -, and any combination thereof, wherein each R _y is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy;

R _<5 is selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group; R ₇ and Rs are absent or independently selected from the group consisting of H, halogen (e.g., F), OH, an alkoxy group, an aliphatic group, and a carbocyclic group, which may be optionally substituted (e.g., by hydroxy or alkoxy);

E] and F ₁ are independently selected from CHR ₉ and NR ₉ ; and each R9 is independently selected from the group consisting of H, alkoxy, hydroxyl, halogen, an aliphatic group, a heterocyclic group, a carbocyclic group, an acyl group, amino, and cyano.

Another aspect of the invention relates to a compound of Formula XII:

(XII)

wherein n is 0 or 1 ; represents a single or a double bond; X is selected from the group consisting ofNR _x CR _x R _x and O; each R _x is independently selected from the group consisting of H, -M ₁ , -Mi-M ₂ , -Z-M ₂ , and -M]-Z-M ₂ ;

Mi and M ₂ are independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, halogen, NO ₂ , CN, OR _W , NR _W R _W , CO ₂ Rw, -C(O)R _W , -COR _W , NR _W C(O)R _W , NR _W C(O)NR _W R _W , NR _w R _w C(0)0, C(O)NR _W R _W , which may be optionally substituted, wherein each R _w is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group;

Z is selected from the group consisting of -O-, -NH-, -CR _Z R _Z -, -S-, -S(O)-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ CK-S(O) ₂ -, -CH(OH)-, -CH(0R _z ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(OR _Z )-, -CH(OH)CH ₂ -, - CH(OR _z )CH ₂ -, and any combination thereof, wherein each R _z is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy; Ai, Bi, C], and Di are independently selected from the group consisting of

CRi and N (e.g., wherein one or two of Ai, Bi, C ₁ , and Di is N); each Ri is independently selected from the group consisting of H, an aliphatic group (e.g., alkyl, alkenyl, alkynyl etc.), a carbocyclic group (e.g., saturated or unsaturated), a heterocyclic group (e.g., saturated or unsaturated), an acyl group, halogen, NO ₂ , CN, 0R _a , NR _a R _a , CO ₂ R ₃ , -C(O)R ₃ , -COR ₃ , NR ₃ C(O)R ₃ ,

NR ₈ C(O)NR ₃ R ₈ , NR ₈ R ₈ C(O)O-, C(O)NR ₃ R ₈ , which may be optionally substituted, wherein each R _a is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group;

R ₅ is selected from the group consisting of -Gi, -Gi-G ₂ , -Y-G ₂ , and -Gi-Y-G ₂ ; Gi and G ₂ are independently selected from H, an aliphatic group, a carbocyclic group, and a heterocyclic group, which may be optionally substituted with one or more of substituents; and

Y CR _y R _y -, -S-, -S(O)-, - C(O)-, -N OH)-, -CH(0R _y ), -

C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(OR _y )-, -CH(OH)CH ₂ -, - CH(ORy)CH ₂ -, and any combination thereof, wherein each R _y is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy;

R _έ is selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group; and

R _? and R ₈ are absent or independently selected from the group consisting of H, halogen (e.g., F), OH, an alkoxy group, an aliphatic group, and a carbocyclic group, which may be optionally substituted (e.g., by hydroxy or alkoxy).

Another aspect of the invention pertains to a compound of Formula XIII:

wherein Ri, R ₃ , R ₄ , and R _x are independently selected from the group consisting of H, benzyl, pyridinyl, tetrahydro-pyranyl, methyl- lH-imidazolyl, cyclohexylmethyl, phenethyl, p-chlorobenzyl, carboxylic acid benzyl ester, propionic acid tert-butyl ester, tert-butyl ester, ethanone, hydroxy, methoxy, ethoxy, propoxy, butoxy, t- butoxy, phenyl, isobutyl, methyl, ethyl, propyl, butyl, cyclohexyl, cyclohexylmethyl, m-methoxy phenyl, carboxylic acid 2-methoxy-ethyl ester, 3,3-dimethyl-butan-l-one, 2,2-dimethyl-propan-l-one, carboxylic acid methyl ester, alkyl, halogen, NO ₂ , CN, OR ₃ , NR ₃ R ₃ , CO ₂ R ₃ , -C(O)R ₃ , -COR ₃ , NR ₃ C(O)R ₃ , NR ₃ C(O)NR ₃ R ₃ , NR ₃ R _a C(O)O-, C(O)NR ₃ Ra, aryl, and heterocycle, which may be optionally substituted with methoxy or 2-methoxy-ethoxy, wherein each R ₃ is independently selected from the group consisting of H, alkyl, aryl, and heterocycle;

R ₂ is selected from the group consisting of H, benzyl, tert-butyl ester, ethanone th l eth l b li id 2 th thyl ester, 3,3-dimethyl-butan-l-

one, 2,2-dimethyl-propan-l-one, and carboxylic acid methyl ester; or R ₂ and R7 taken together may form a 5-7 membered heterocyclic ring;

R ₅ is selected from the group consisting of -Gi, -Gj-G ₂ , -Y-G ₂ , and -Gj-Y-G ₂ ;

G] and G ₂ are independently selected from the group consisting of phenyl, cyclopentyl, cycloheptyl, piperidinyl, cyclohexyl, lH-[l,2,4]triazolyl, isopropyl- [l,3,4]thiadiazolyl, benzothiazolyl, 3 -methyl-butyl, which may be optionally substituted with one or more of substituent moieties selected from the group consisting of -C(O)NH ₂ , phenyl, p-methoxy phenyl, -0(CH ₂ ) _S CH ₃ , and carboxylic acid methyl ester; Y is selected from the group consisting of-O-, -NH-, -CR _y R _y -, -S-, -S(O)-, -

C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O- -S(O) ₂ -, -CH(OH)-, -CH(0R _y ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(0R _y )-, -CH(OH)CH ₂ -, - CH(OR _y )CH ₂ -, and any combination thereof, wherein each R _y is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy;

R^ is selected from the group consisting of H, alkyl, aryl, and heterocycle; and

R ₇ and R^ are absent or independently selected from the group consisting of H, aryl and, alkyl; or R ₂ and R7 taken together may form a 5-7 membered heterocyclic ring. Another aspect of the invention pertains to a compound of Formula XIV:

wherein Ri, R ₂ , R ₄ , and R _x are independently selected from the group consisting of H, benzyl, pyridinyl, tetrahydro-pyranyl, methyl- lH-imidazo IyI, cyclohexylmethyl, phenethy onic acid tert-butyl

ester, tert-butyl ester, ethanone, hydroxy, methoxy, ethoxy, propoxy, butoxy, t- butoxy, phenyl, isobutyl, methyl, ethyl, propyl, butyl, cyclohexyl, cyclohexylmethyl, m-methoxy phenyl, carboxylic acid 2-methoxy-ethyl ester, 3,3-dimethyl-butan-l-one, 2,2-dimethyl-propan-l-one, carboxylic acid methyl ester, alkyl, halogen, NO ₂ , CN, OR ₃ , NR ₃ R ₃ , CO ₂ R ₃ , -C(O)R ₃ , -COR ₃ , NR ₃ C(O)R ₃ , NR ₃ C(O)NR ₃ R ₃ , NR ₃ R ₃ C(O)O-, C(O)NR ₃ R ₃ , aryl, and heterocycle, which may be optionally substituted with methoxy or 2-methoxy-ethoxy, wherein each R ₃ is independently selected from the group consisting of H, alkyl, aryl, and heterocycle;

R ₃ is selected from the group consisting of H, benzyl, tert-butyl ester, ethanone, methyl, ethyl, carboxylic acid 2-methoxy-ethyl ester, 3,3-dimethyl-butan-l- one, 2,2-dimethyl-propan-l-one, and carboxylic acid methyl ester; or R3 and R ₇ taken together may form a 5-7 membered heterocyclic ring;

R ₅ is selected from the group consisting Of -G ₁ , -Gj-G ₂ , -Y-G ₂ , and -G ₁ -Y-G ₂ ; G ₁ and G ₂ are independently selected from the group consisting of phenyl, cyclopentyl, cycloheptyl, piperidinyl, cyclohexyl, lH-[l ,2,4]triazolyl, isopropyl- [l ,3,4]thiadiazolyl, benzothiazolyl, 3-methyl-butyl, which may be optionally substituted with one or more of substituent moieties selected from the group consisting of -C(O)NH ₂ , phenyl, p-methoxy phenyl, -O(CH ₂ )5CH ₃ , and carboxylic acid methyl ester; Y is selected from the group consisting of-0-, -NH-, -CR _y R _y -, -S-, -S(O)-, -

C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O- -S(O) ₂ -, -CH(OH)-, -CH(OR _x ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(0R _y )-, -CH(OH)CH ₂ -, - CH(OR _y )CH ₂ -, and any combination thereof, wherein each R _y is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy;

Re is selected from the group consisting of H, alkyl, aryl, and heterocycle; and R ₇ and Rs are absent or independently selected from the group consisting of H, aryl and, alkyl; or R ₃ and R ₇ taken together may form a 5-7 membered heterocyclic ring. In yet an additional aspect, the present invention relates to a method for treating bacterial disease comprising administering to a subject a compound of the following formula

wherein

R is a functionalizing moiety;

Q ₂ is a multicyclic hydroxydicarbonyl moiety; and

T is a tail moiety, such that a bacterial disease is treated in the subject. Exemplary compounds, include, but are not limited to compounds of Formulae I-XV.

In another aspect, the present invention is a method for treating bacterial disease comprising administering a potent and selective undecaprenyl pyrophosphate synthase (UPPS) inhibitor to a subject, such that a bacterial disease is treated in the subject.

Another aspect of the invention pertains to a method for treating bacterial disease comprising administering a selective UPPS inhibitor to a subject, such that a bacterial disease is treated in the subject.

In yet another aspect of the invention pertains to a method for treating bacterial disease comprising administering a potent UPPS inhibitor to a subject, such that a bacterial disease is treated in the subject.

Another aspect of the invention is a method for inhibiting undecaprenyl pyrophosphate synthase (UPPS) comprising administering to a bacterium compromised subject an activity-enhanced UPPS inhibitor, such that UPPS is inhibited in the subject.

An additional aspect of the invention relates to a method for selectively inhibiting undecaprenyl pyrophosphate synthase (UPPS) comprising the step of administering to a bacterium compromised subject an activity-enhanced UPPS inhibitor wherein the UPPS/FPPS specificity ratio is less than or equal to about 0.02, e.g., less than or equal to about 0.01, e.g., less than or equal to about 0.002, e.g., less than or equal to about 0.001, e.g., less than or equal to about 0.0002, e.g., less than or equal to about 0.0001, such that UPPS is selectively inhibited in the subject.

In another aspect, the invention is directed to a method for treating a bacterium compromised subject comprising the step of administering to a bacterium compromised subject an activity-enhanced UPPS inhibitor effective to treat a disease or disorder associated with a UPPS enabled bacterium, such that the bacterium compromised subject is treated.

An additional aspect of the invention is directed to a method for inhibiting undecaprenyl pyrophosphate synthase (UPPS) comprising the step of contacting UPPS with an activity-enhanced UPPS inhibitor, such that UPPS is inhibited.

In another aspect, the invention pertains to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, and a pharmaceutically acceptable carrier.

In yet another aspect, the invention is directed to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the invention, e.g., a potent and/or selective UPPS inhibitor; and instructions for using the compound to treat a bacterial disease.

Another aspect of the invention pertains to a method for identifying an activity-enhanced UPPS inhibitor comprising screening drug candidates for threshold activity; confirming that the molecular structure of a selected drug candidate contains a hydroxydicarbonyl moiety; analyzing said selected drug candidate to ensure enhanced selectivity or potency; determining that said selected drug candidate possesses a UPPS/FPPS specificity ratio is less than or equal to about 0.02, e.g., less than or equal to about 0.01 , e.g. , less than or equal to about 0.002, e.g. , less than or equal to about 0.001 , e.g., less than or equal to about 0.0002, e.g., less than or equal to about 0.0001 , or the selected IC ₅₀ of the drug candidate against UPPS is less than or equal to about 2.0 μM, e.g., less than or equal to about 1.0 μM, e.g., less than or equal to about 0.5 μM, e.g., less than or equal to about 0.1 μM, e.g., less than or equal to about 0.05 μM, e.g., less than or equal to about 0.01 μM, e.g., less than or equal to about 0.005 μM; and identifying said selected drug candidate as an activity-enhanced UPPS inhibitor.

DETAILED DESCRIPTION OF THE INVENTION

The compounds provided by the present invention are inhibitors of UPPS. In particular embodiments, the compounds of the invention are selective and/or potent inhibitor f UPPS I ddi i h i i l id harmaceutical

compositions comprising these compounds and methods of using these compounds for treating bacterial disease, such as bacterial infection.

Definitions For convenience, the definitions of several terms that will be used throughout the specification have been assembled below:

The term "aliphatic group" includes organic moieties characterized by straight or branched-chains, typically having between 1 and 22 carbon atoms, e.g., between 1 and 8 carbon atoms, e.g., between 1 and 6 carbon atoms. In complex structures, the chains may be branched, bridged, or cross-linked. Aliphatic groups include alkyl groups, alkenyl groups, alkynyl groups, and any combination thereof.

As used herein, "alkyl" groups include saturated hydrocarbons having one or more carbon atoms, e.g., between 1 and 22 carbon atoms, e.g., between 1 and 8 carbon atoms, e.g., between 1 and 6 carbon atoms, including straight-chain alkyl groups {e.g., methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc.), cyclic alkyl groups (or "cycloalkyl" or "alicyclic") (e.g., cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.), branched-chain alkyl groups (isopropyl, tert-butyl, sec-butyl, isobutyl, etc.), and alkyl-substituted alkyl groups (e.g., alkyl-substituted cycloalkyl groups and cycloalkyl-substituted alkyl groups). In certain embodiments, a straight-chain or branched-chain alkyl group may have 30 or fewer carbon atoms in its backbone, e.g., C]-C _3O for straight-chain or C ₃ -C ₃₀ for branched-chain. In certain embodiments, a straight-chain or branched-chain alkyl group may have 20 or fewer carbon atoms in its backbone, e.g., C1-C ₂ 0 for straight-chain or C3-C ₂ 0 for branched-chain, and in more particular embodiments 18 or fewer. Likewise, in certain embodiments cycloalkyl groups have from 3-10 carbon atoms in their ring structure, and in more particular embodiments have 3-7 carbon atoms in the ring structure. The term "lower alkyl" refers to alkyl groups having from 1 to 6 carbons in the chain, and to cycloalkyl groups having from 3 to 6 carbons in the ring structure. In certain embodiments, the alkyl group (e.g., straight, branched, cyclic, and lower alkyl group) is substituted. In particular embodiments, the alkyl group is substituted with one or more halogens, e.g., F. In a specific embodiment, the alkyl group is in combination with halogen moiety. Accordingly,

and for convenience herein, reference to an alkyl moiety may also incorporate haloalkyl moieties, regardless of whether specific embodiments recited herein are differentiated by explicitly making reference to haloalkly moieties.

Unless the number of carbons is otherwise specified, "lower" as in "lower aliphatic," "lower alkyl," "lower alkenyl," etc. as used herein means that the moiety has at least one and less than about 8 carbon atoms. In certain embodiments, a straight-chain or branched-chain lower alkyl group has 6 or fewer carbon atoms in its backbone (e.g., Ci-C ₆ for straight-chain, C ₃ -C ₆ for branched-chain), and in particular embodiments, 4 or fewer. Likewise, in certain embodiments cycloalkyl groups have from 3-8 carbon atoms in their ring structure, and in more particular embodiments have 5 or 6 carbons in the ring structure. The term "Ci-C ₆ " as in "Ci-C ₆ alkyl" means alkyl groups containing 1 to 6 carbon atoms.

Moreover, unless otherwise specified the term alkyl includes both "unsubstituted alkyls" and "substituted alkyls," the latter of which refers to alkyl groups having substituents replacing one or more hydrogens on one or more carbons of the hydrocarbon backbone. Such substituents may include, for example, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino

(including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide nitro, trifluoromethyl, cyano, azido, heterocyclic, alkylaryl, or aromatic (including heteroaromatic) groups.

An "arylalkyl" group is an alkyl group substituted with an aryl group (e.g., phenylmethyl (i.e., benzyl)). An "alkylaryl" moiety is an aryl group substituted with an alkyl group (e.g. , />-methylphenyl (i.e.,p-to\y\)). The term "«-alkyl" means a straight-chain (i.e., unbranched) unsubstituted alkyl group. An "alkylene" group is a divalent analog of the corresponding alkyl group. Examples of alkylene groups include ethylene (-CH ₂ CH ₂ -), propylene (-CH ₂ CH ₂ CH ₂ -), butylene (- CH ₂ CH ₂ CH ₂ CH ₂ -) and 1-methyethylene (-CH(CH ₃ )CH ₂ -). The terms "alkenyl", "alkynyl ps analogous to alkyls, but whic bond respectively.

Examples of alkenylene groups include ethenylene (-CH=CH-), propenylene (- CH=CHCH ₂ -), 2-butenylene (-CH ₂ CH=CHCH ₂ -) and 1-methyethenylene (- C(CHs)CH-). Suitable alkenyl and alkynyl groups include groups having 2 to about 12 carbon atoms, preferably from 2 to about 6 carbon atoms. The term "haloalkyl" describes alkyl moieties that contain one or more of the same or different halogen substituents, e.g., F or Cl. In particular, the term "haloalkyl" includes alkyl moieties comprising one halogen group, alkyl moieties that are perfluorinated, as well as any level of halogenation in between the two extremes. Exemplary haloalkyl moieties include, but are not limited to -CF ₃ , -CH ₂ F, -CHF ₂ , - CF ₂ CF ₃ , -CF ₂ CF ₃ , -CHFCF ₃ , -CF ₂ CF ₃ , -CF ₂ CF ₂ H, and -CF ₂ CHF ₂ . In addition, haloalkyl groups may be straight chain or branched and may be optionally substituted with additional substituents (i.e., other than the halogen substituents). In-particular embodiments, the haloalkyl is -CF ₃ .

The term "aromatic or aromatic group" and "aryl or aryl group" includes unsaturated and aromatic cyclic hydrocarbons (e.g., benzyl or phenyl) as well as unsaturated and aromatic heterocycles containing one or more rings. Aryl groups may also be fused or bridged with a bond (e.g., biphenyl), alicyclic or heterocyclic rings that are not aromatic so as to form a polycycle (e.g., tetralin). An "arylene" group is a divalent analog of an aryl group. The term "carbocycle or carbocyclic group" includes any possible saturated or unsaturated closed ring alkyl groups (or "cycloalkyl" or "alicyclic" or "carbocyclic" groups) (e.g., cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.), any possible C ₃ -Cj ₂ saturated or unsaturated halogenated closed ring alkyl groups, and substituted or unsubstituted aromatic groups, e.g., phenyl. In certain embodiments, the carbocyclic group is a substituted or unsubstituted C ₃ -Cj _O carbocyclic ring.

The term "heterocyclic group" includes closed ring structures analogous to carbocyclic groups in which one or more of the carbon atoms in the ring is an element other than carbon, for example, nitrogen, sulfur, or oxygen (e.g. cyclic ethers, lactones, lactams, azitidines). Heterocyclic groups may be saturated or unsaturated. Heterocyclic groups may be halogenated. Additionally, heterocyclic groups (such as pyrrolyl, pyridyl, isoquinolyl, quinolyl, purinyl, and furyl) may have aromatic character, in which case they may be referred to as "heteroaryl" or "heteroaromatic" groups. ubstituted or unsubsti

Unless otherwise stipulated, carbocyclic and heterocyclic (including heteroaryl) groups may also be substituted at one or more constituent atoms.

Examples of heteroaromatic and heteroalicyclic groups may have 1 to 3 separate or fused rings with 3 to about 8 members per ring and one or more N, O, or S heteroatoms. In general, the term "heteroatom" includes atoms of any element other than carbon or hydrogen, preferred examples of which include nitrogen, oxygen, sulfur, and phosphorus. Heterocyclic groups may be saturated or unsaturated or aromatic.

Examples of heterocycles include, but are not limited to, acridinyl; azocinyl; benzimidazolyl; benzofuranyl; benzothiofuranyl; benzothiophenyl; benzoxazolyl; benzthiazolyl; benztriazolyl; benztetrazolyl; benzisoxazolyl; benzisothiazolyl; benzimidazolinyl; carbazolyl; 4aH-carbazolyl; carbolinyl; chromanyl; chromenyl; cinnolinyl; decahydroquinolinyl; 2H,6H-l,5,2-dithiazinyl; dihydrofuro[2,3-b]tetrahydrofuran; furanyl; furazanyl; imidazolidinyl; imidazolinyl; imidazolyl; lH-indazolyl; indolenyl; indolinyl; indolizinyl; indolyl; 3H-indolyl; isobenzofuranyl; isochromanyl; isoindazolyl; isoindolinyl; isoindolyl; isoquinolinyl; isothiazolyl; isoxazolyl; methylenedioxyphenyl; moφholinyl; naphthyridinyl; octahydroisoquinolinyl; oxadiazolyl; 1,2,3-oxadiazolyl; 1,2,4-oxadiazolyl;

1,2,5-oxadiazolyl; 1,3,4-oxadiazolyl; oxazolidinyl; oxazolyl; oxazolidinyl; pyrimidinyl; phenanthridinyl; phenanthrolinyl; phenazinyl; phenothiazinyl; phenoxathiinyl; phenoxazinyl; phthalazinyl; piperazinyl; piperidinyl; piperidonyl;

4-piperidonyl; piperonyl; pteridinyl; purinyl; pyranyl; pyrazinyl; pyrazolidinyl; pyrazolinyl; pyrazolyl; pyridazinyl; pyridooxazole; pyridoimidazole; pyridothiazole; pyridinyl; pyridyl; pyrimidinyl; pyrrolidinyl; pyrrolinyl; 2H-pyrrolyl; pyrrolyl; quinazolinyl; quinolinyl; 4H-quinolizinyl; quinoxalinyl; quinuclidinyl; tetrahydro furanyl; tetrahydroisoquinolinyl; tetrahydroquinolinyl; tetrazolyl;

6H-l,2,5-thiadiazinyl; 1,2,3-thiadiazolyl; 1,2,4-thiadiazolyl; 1,2,5-thiadiazolyl;

1,3,4-thiadiazolyl; thianthrenyl; thiazolyl; thienyl; thienothiazolyl; thienooxazolyl; thienoimidazolyl; thiophenyl; triazinyl; 1,2,3-triazolyl; 1,2,4-triazolyl; 1,2,5-triazolyl; 1,3,4-triazolyl; and xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl; furanyl; thienyl; pyrrolyl; pyrazolyl; pyrrolidinyl; imidazolyl; indolyl; benzimidazolyl; lH-indazolyl; oxazolidinyl; benzotriazolyl; benzisoxazolyl; oxindoly ed are fused ring and spiro co cles.

A common hydrocarbon aryl group is a phenyl group having one ring. Two- ring hydrocarbon aryl groups include naphthyl, indenyl, benzocyclooctenyl, benzocycloheptenyl, pentalenyl, and azulenyl groups, as well as the partially hydrogenated analogs thereof such as indanyl and tetrahydronaphthyl. Exemplary three-ring hydrocarbon aryl groups include acephthylenyl, fluorenyl, phenalenyl, phenanthrenyl, and anthracenyl groups.

Aryl groups also include heteromonocyclic aryl groups, i.e., single-ring heteroaryl groups, such as thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyridazinyl groups; and oxidized analogs thereof such as pyridonyl, oxazolonyl, pyrazolonyl, isoxazolonyl, and thiazolonyl groups. The corresponding hydrogenated (i.e., non-aromatic) heteromonocylic groups include pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl and piperidino, piperazinyl, and morpholino and morpholinyl groups. Aryl groups also include fused two-ring heteroaryls such as indolyl, isoindolyl, indolizinyl, indazolyl, quinolinyl, isoquinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromenyl, isochromenyl, benzothienyl, benzimidazolyl, benzothiazolyl, purinyl, quinolizinyl, isoquinolonyl, quinolonyl, naphthyridinyl, and pteridinyl groups, as well as the partially hydrogenated analogs such as chromanyl, isochromanyl, indolinyl, isoindolinyl, and tetrahydroindolyl groups. Aryl groups also include fused three-ring groups such as phenoxathiinyl, carbazolyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxazinyl, and dibenzofuranyl groups.

Some typical aryl groups include substituted or unsubstituted 5- and 6- membered single-ring groups. In another aspect, each Ar group may be selected from the group consisting of substituted or unsubstituted phenyl, pyrrolyl, furyl, thienyl, thiazolyl, isothiaozolyl, imidazolyl, triazolyl, tetrazolyl, pyrazolyl, oxazolyl, isooxazolyl, pyridinyl, pyrazinyl, pyridazinyl, and pyrimidinyl groups. Further examples include substituted or unsubstituted phenyl, 1 -naphthyl, 2-naρhthyl, biphenyl, 1 -pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5- isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridy enzothiazolyl, purinyl,

2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5- quinoxalinyl, 3-quinolyl, and 6-quinolyl groups.

The term "amine" or "amino," as used herein, refers to an unsubstituted or substituted moiety of the formula -NR ^a R ^b , in which each R ^a and R ^b are each independently hydrogen, alkyl, aryl, or heterocyclyl, or each R ^a and R , taken together with the nitrogen atom to which they are attached, form a cyclic moiety having from 3 to 8 atoms in the ring. Thus, the term amino includes cyclic amino moieties such as piperidinyl or pyrrolidinyl groups, unless otherwise stated. Thus, the term "alkylamino" as used herein means an alkyl group having an amino group attached thereto. Suitable alkylamino groups include groups having 1 to about 12 carbon atoms, e.g., from 1 to about 6 carbon atoms. The term amino includes compounds or moieties in which a nitrogen atom is covalently bonded to at least one carbon or heteroatom. The term "dialkylamino" includes groups wherein the nitrogen atom is bound to at least two alkyl groups. The term "arylamino" and "diarylamino" include groups wherein the nitrogen is bound to at least one or two aryl groups, respectively. The term "alkylarylamino" refers to an amino group which is bound to at least one alkyl group and at least one aryl group. The term "alkaminoalkyl" refers to an alkyl, alkenyl, or alkynyl group substituted with an alkylamino group. The term "amide" or "aminocarbonyl" includes compounds or moieties which contain a nitrogen atom which is bound to the carbon of a carbonyl or a thiocarbonyl group. The term "azaalkyl" refers to an alkyl group in which one or more -CH ₂ - units have been replaced by an -N(R)- group, where R is hydrogen or Ci-Q-alkyl. If an azaalkyl group includes two or more N(R) groups, any two N(R) groups are separated by one or more carbon atoms. The terms "alkylthio" or "thiaalkoxy" refers to an alkyl group, having a sulfhydryl group attached thereto. Suitable alkylthio groups include groups having 1 to about 12 carbon atoms, e.g., from 1 to about 6 carbon atoms. The term "thiaalkyl" refers to an alkyl group in which one or more -CH ₂ - units have been replaced by a sulfur atom. If a thiaalkyl group includes two or more sulfur atoms, any two sulfur atoms are separated by one or more carbon atoms.

The term "alkylcarboxyl" as used herein means an alkyl group having a carboxyl group attached thereto.

T p having an oxygen atom att groups having 1 to

about 12 carbon atoms, e.g., between 1 and 8 carbon atoms, e.g., between 1 and 6 carbon atoms, e.g., methoxy, ethoxy, propoxy, ter/-butoxy and the like. Examples of alkoxy groups include methoxy, ethoxy, isopropyloxy, propoxy, butoxy, and pentoxy groups. The alkoxy groups can be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alky laryl amino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an ^ aromatic or heteroaromatic moieties. Examples of halogen substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, trichloromethoxy, etc., as well as perhalogenated alkyloxy groups. The term "oxaalkyl" refers to an alkyl group in which one or more - CH ₂ - units have been replaced by an oxygen atom. If an oxaalkyl group includes two or more oxygen atoms, any two oxygen atoms are separated by one or more carbon atoms. The term "acylamino" includes moieties wherein an amino moiety is bonded to an acyl group. For example, the acylamino group includes alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido groups.

The terms "alkoxyalkyl", "alkylaminoalkyl" and "thioalkoxyalkyl" include alkyl groups, as described above, which further include oxygen, nitrogen or sulfur atoms replacing one or more carbons of the hydrocarbon backbone.

The term "carbonyl" or "carboxy" includes compounds and moieties which contain a carbon connected with a double bond to an oxygen atom. Examples of moieties which contain a carbonyl include aldehydes, ketones, carboxylic acids, amides, esters, anhydrides, etc. The term "ether" or "ethereal" includes compounds or moieties which contain an oxygen atom bonded to two carbon atoms. For example, an ether or ethereal group includes "alkoxyalkyl" which refers to an alkyl, alkenyl, or alkynyl group substituted with an

The term "nitro" means -NO ₂ ; the term "halogen" or "halogen" or "halo" designates -F, -Cl, -Br or -I; the term "thiol," "thio," or "mercapto" means SH; and the term "hydroxyl" or "hydroxy" means -OH.

The term "acyl" refers to a carbonyl group that is attached through its carbon atom to a hydrogen (i.e., a formyl), an aliphatic group (e.g., acetyl), an aromatic group (e.g., benzoyl), and the like. The term "substituted acyl" includes acyl groups where one or more of the hydrogen atoms on one or more carbon atoms are replaced by, for example, an alkyl group, alkynyl group, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, cyano, amino (including alkyl amino, dialkylamino, arylamino, diarylamino, and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamide, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

Unless otherwise specified, the chemical moieties of the compounds of the invention, including those groups discussed above, may be "substituted or unsubstituted." In some embodiments, the term "substituted" means that the moiety has substituents placed on the moiety other than hydrogen (i.e., in most cases, replacing a hydrogen), which allow the molecule to perform its intended function. In certain embodiments, examples of substituents include moieties selected from substituted or unsubstituted aliphatic moieties. In particular embodiments, the exemplary substituents include, but are not limited to , straight or branched alkyl (e.g., Ci-C ₅ ), cycloalkyl (e.g., C ₃ -C ₈ ), alkoxy (e.g., C ₁ -C ₆ ), thioalkyl (e.g., Cj-C ₆ ), alkenyl (e.g., C ₂ -C ₆ ), alkynyl (e.g., C ₂ -C ₆ ), heterocyclic, carbocyclic, aryl (e.g., phenyl), aryloxy (e.g., phenoxy), arylkyl (e.g., benzyl), aryloxyalkyl (e.g., phenyloxyalkyl), arylacetamidoyl, alkylaryl, heteroaralkyl, alkylcarbonyl and arylcarbonyl or other such acyl group, heteroarylcarbonyl, and heteroaryl groups, as well as (CR'R") o-

₃ NR'R" (e.g., -NH ₂ ), (CR'R") ₀ - ₃ CN (e.g., -CN), -NO ₂ , halogen (e.g., -F, -Cl, -Br, or -I), (CR'R")o. ₃ C(halogen) ₃ (e.g., -CF ₃ ), (CR'R") _0-3 CH(halogen) ₂ , (CR'R") NH)NR'R", (CR'R") R")o. ₃ H,

(CR'R")o _-3 S(0)o-3R' (e.g., -SO ₃ H), (CR'R")o- ₃ 0(CR'R")o-3H (e.g., -CH ₂ OCH ₃ and -OCH ₃ ), (CR'R")o- ₃ S(CR'R")o- ₃ H (e.g., -SH and -SCH ₃ ), (CR'R") ₀ - ₃ θH (e.g., -OH), (CR'R")o _-3 COR', (CR'R")o- ₃ (substituted or unsubstituted phenyl), (CR ⁵ R ⁵⁵ V ₃ (C ₃ -C ₈ cycloalkyl), (CR'R") _0-3 CO ₂ R' (e.g., -CO ₂ H), and (CR'R")o- ₃ θR' groups, wherein R' and R" are each independently hydrogen, a C]-Cs alkyl, C ₂ -C ₅ alkenyl, C ₂ -C ₅ alkynyl, or aryl group; or the side chain of any naturally occurring amino acid.

In another embodiment, a substituent may be selected from straight or branched alkyl (e.g., C]-C ₅ ), cycloalkyl (e.g., C ₃ -C ₈ ), alkoxy (e.g., C]-C ₆ ), thioalkyl (e.g., CpC ₆ ), alkenyl (e.g., C ₂ -C ₆ ), alkynyl (e.g., C ₂ -C ₆ ), heterocyclic, carbocyclic, aryl (e.g., phenyl), aryloxy (e.g., phenoxy), aralkyl (e.g., benzyl), aryloxyalkyl (e.g., phenyloxyalkyl), arylacetamidoyl, alkylaryl, heteroaralkyl, alkylcarbonyl and arylcarbonyl or other such acyl group, heteroarylcarbonyl, or heteroaryl group, (CR'R")o _-lo NR'R" (e.g., -NH ₂ ), (CR'R")o-ioCN (e.g., -CN), NO ₂ , halogen (e.g., F, Cl, Br, or I), (CR'R")o-ioC(halogen) ₃ (e.g., -CF ₃ ), (CR'R")o _-10 CH(halogen) ₂ , (CR'R")o.ioCH ₂ (halogen), (CR ⁵ R ⁵⁵ V ₁₀ CONR ⁵ R ⁵⁵ , (CR'R")o-io(CNH)NR'R", (CR'R") _0- ,oS(0) _1-2 NR'R", (CR ⁵ RO _O - _IO CHO ₅ (CR ⁵ RO _{O-1 O} O(CR ⁵ RO _O - _{I O} H, (CR'R") _0- i 0S(O) _0-3 R' (e.g., -SO ₃ H), (CR ⁵ R ⁵⁵ V ₁ OO(CR ⁵ R ⁵⁵ V ₁₀ H (e.g., -CH ₂ OCH ₃ and -OCH ₃ ), (CR ⁵ R")o _-lo S(CR ⁵ R") _o-3 H (e.g., -SH and -SCH ₃ ), (CR ⁵ R ⁵⁵ ) _0-10 OH (e.g., -OH), (CR ⁵ R ⁵⁵ V ₁₀ COR', (CR'R") _0-10 (substituted or unsubstituted phenyl), (CR ⁵ R ⁵⁵ Vi _O (C ₃ -C ₈ cycloalkyl), (CR ⁵ R ⁵⁵ V ₁₀ CO ₂ R ⁵ (e.g., -CO ₂ H), or (CR ⁵ R") _0-10 OR ⁵ group, or the side chain of any naturally occurring amino acid; wherein R ⁵ and R ⁵⁵ are each independently hydrogen, a C ₁ -Cs alkyl, C ₂ -C ₅ alkenyl, C ₂ -Cs alkynyl, or aryl group, or R ⁵ and R ⁵⁵ taken together are a benzylidene group or a -(CH ₂ ^O(CHa) ₂ - group. It will be understood that "substitution ⁵⁵ or "substituted with ⁵⁵ includes the implicit proviso that such substitution is in accordance with the 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 ⁵⁵ is meant 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 nonaromatic substituents of organic c or more. It should further b ay be attached to the

moiety that is substituted in any orientation (regardless of whether such attachment orientation is indicated herein by the manner of description, e.g., by a dash)

In some embodiments, a "substituent" may be selected from the group consisting of, for example, CF ₃ , OCF ₃ , iodo, chloro, bromo, -C(O)NH ₂ , - O(CH ₂ ) ₅ CH ₃ , carboxylic acid methyl ester, phenyl, p-methoxy phenyl, -NHC(O)NH ₂ , -C(O)O(CH ₂ ^N(CH ₂ CHs) ₂ , t-butyl, fluoro, methoxy, hydroxy, isopropyl, cyano, isopropenyl tetrahydropyran, benzyl, amino, -C(O)OH, -C(O)CH ₃ , -CH ₂ CO ₂ H, methyl, -(CH ₂ ^-OH, methoxy, 2-methoxy-ethoxy, pyrrolidinyl, 4-methylpiperazinyl, piperazinyl, H, alkyl, halogen, NO ₂ , CN, 0R _b , NR _t R ₁ ,, C0 ₂ R _b , -C(O)R _b , -COR _b , NR _b C(0)R _b , NR _t C(O)NR _b R _b , NR _b R _b C(O)O-, C(0)NR _b R _b , aryl, and heterocycle, which may be optionally substituted with methoxy or 2-methoxy-ethoxy, wherein each R _b is independently selected from the group consisting of H, alkyl, aryl, and heterocycle, tert-butyl ester, ethanone, methyl, ethyl, carboxylic acid 2-methoxy-ethyl ester, 3,3-dimethyl-butan-l-one, 2,2-dimethyl-propan-l-one, hydroxy, methoxy, ethoxy, propoxy, butoxy, and t-butoxy.

In certain embodiments, the substituent may be selected from the group consisting of H, an aliphatic group {e.g., alkyl, alkenyl, alkynyl etc.), a carbocyclic group (e.g., saturated or unsaturated), a heterocyclic group (e.g., saturated or unsaturated), halogen, NO ₂ , CN, 0R _a , NR _a R _a , CO ₂ R ₃ , -C(O)R ₃ , -COR ₃ , NR ₃ C(O)R ₃ , NR ₃ C(O)NR ₃ R ₃ , NR ₃ R ₃ C(O)O-, C(O)NR ₈ R ₃ , which may be optionally substituted, wherein each R _a is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group.

In an additional embodiment, the substituents may comprise those substituents known in the art to be useful for fluoroquinolones (e.g., based on known chemistry, chemical or physical properties imparted by such substitution, or improved biological activity). Accordingly, substituents for the compounds of the invention also include those substituents described for fluoro-quinolones known in the art, for example, in U.S. Patent Applications Nos. 7,019,143; 6,964,966; 6,329,391 ; 6,900,224; 2006 0052359; 6,573,260; 5,563,155; 6,387,928; 5,519,016; 6,184,388; 5,457,014; 6,034,100; and 5,364,861. In particular, substituents may include substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted morpholine, substituted or unsubstituted thiomorpholino

substituted or unsubstituted aziridine, substituted or unsubstituted azetidine, substituted or unsubstituted pyrrolidine, substituted or unsubstituted dihydro isoindolyl, octahydro pyrolo [3, 4, -b] pyridiyl, substituted or unsubstituted Cμs alkyl substituted or unsubstituted C _3-6 cycloalkyl, substituted or unsubstituted aryl, OCF ₃ - OCH ₃ , -OCHF ₂ , ethyl, t-butyl, or 4 fluorophenyl.

Compounds of the Invention

The compounds of the invention, e g., Formulae I-XV, particular compounds thereof (and substituted derivatives as described herein) are intended to be within the scope of the invention, i.e., regardless of their activity. Accordingly, the compounds of the invention include, but are not limited to compounds of the following formula:

R-Q-T

wherein R is a functionalizing moiety; Q is a hydroxydicarbonyl moiety; and T is a tail moiety.

The language "hydroxydicarbonyl moiety" describes a core moiety of certain compounds of the invention, i.e., Q, which comprise the following moiety:

The skilled artisan would understand that such moieties may comprise a substructure of a ring system by cyclization of the left side of the depicted structure, for example, including but are not limited to monocyclic rings mutli-cyclic, e.g., bicyclic (such as fused bicyclic), rings containing this hydroxydicarbonyl moiety. In particular embodiments, the hydroxydicarbonyl moiety is five or six membered monocyclic ring containing this hydroxydicarbonyl moiety. In another particular embodiment, the hydroxy d bicyclic ring

containing this hydroxydicarbonyl moiety. It should be understood that, in certain embodiments of the invention, the hydroxydicarbonyl moiety is useful as a phosphate mimic.

The language "functionalizing moiety" describes a moiety of certain compounds of the invention that may be used to functionalize the hydroxydicarbonyl moiety, i.e., the Q moiety, which comprises a substituent (e.g., including spiro type substituents) that allows the compound of the invention to perform its intended function. For example, in certain embodiments of the invention, the functionalizing moiety is -Mi, -M1-M2, -Z-M ₂ , and -Mj-Z-M ₂ , wherein Mi and M ₂ are independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, which may be optionally substituted; and Z is a linking moiety.

In certain embodiments, the functionalizing moiety may be selected from the group consisting of H, an aliphatic group (e.g., alkyl, alkenyl, alkynyl etc.), a carbocyclic group (e.g., saturated or unsaturated), a heterocyclic group (e.g., saturated or unsaturated), halogen, NO ₂ , CN, OR ₃ , NR ₃ R ₃ , CO ₂ R ₃ , -C(O)R ₃ , -COR ₃ ,

NR ₃ C(O)R ₃ , NR ₃ C(O)NR ₃ R ₃ , NR ₃ R ₃ C(O)O-, C(O)NR ₃ R ₃ , which may be optionally substituted, wherein each R ₃ is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group.

The language "tail moiety" describes a moiety of certain compounds of the invention that is linked to the hydroxydicarbonyl moiety and may be used to occupy the hydrophobic cleft of the UPP synthase enzyme, and include moieties that allow the compound of the invention to perform its intended function. Exemplary Tail Moieties include, but are not limited to moieties such as -Gi, -G]-G ₂ , -Y-G ₂ , and -Gi- Y-G ₂ , wherein Gi and G ₂ are independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group, which may be optionally substituted with one or more of substituents; and Y is a linking moiety.

It should be noted that the functionalizing moiety and the tail moiety may be modified to adjust at least one chemical or physical property of the compounds of the invention. In certain embodiments, the modification comprises substitution of a carbon atom with a heteroatom or addition of a heteroatom-containing substituent (e.g., substituted by a substituent selected from the group consisting of hydroxy, alkoxy, heterocycle and an acyl group), such that one or more of the chemical or physical nced, e.g., with respect to poten cation is made to adjust

one or more of the following attributes: acidity, lypohilicity, solubility. Moreover, such adjustment may result from the substitution itself, i.e., a direct effect, or the adjustment may indirectly result from the affect on the compound as a whole, e.g., by conformation changes. In certain embodiments, the modification comprises substitution of a carbon atom with a heteroatom or addition of a heteroatom- containing substituent, such that one or more of the chemical or physical properties of R-Q ₂ -T have been enhanced. In particular embodiments, R or T is substituted by a substituent selected from the group consisting of hydroxy, alkoxy, heterocycle and an acyl group. The "linking moiety," may contain 1-8 atoms or may be a bond, and serves as the connection point through which tail moiety or functionalizing moiety is linked to the hydroxydicarbonyl moiety of the compounds of the invention, wherein 3 atoms directly connect the tail moiety to the hydroxydicarbonyl moiety. In certain embodiments, the linking moiety may comprise, but is not limited to, substituted or unsubstituted alkyl (e.g., methylene chains), amide groups, acyl groups, heteroatoms, or a combination thereof. In specific embodiments, the linking moiety may be of -O-, -NH-, -CRyRy-, -S-, -S(O)-, -C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O- -S(O) ₂ -, -CH(OH)-, -CH(ORy), -C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(ORy)-, - CH(OH)CH ₂ -, - CH(OR _y )CH ₂ -, and any combination thereof, wherein each R _y is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy.

In another embodiment, a compound of the invention is represented by Formula:

R-Q ₂ -T

wherein R is a functionalizing moiety; Q ₂ is a multi-cyclic, e.g., bicyclic, hydroxydicarbonyl moiety; and T is a tail moiety. In specific embodiments, the multi-cyclic hydroxydicarbonyl moiety is a fused multicyclic ring. In particular embodiments, T is selected from the group consisting of -Gi, -G]-G ₂ , -Y-G2, and -Gi- Y-G ₂ , and wherein G] and G ₂ are independently selected from the group consisting of substituted or unsubstituted saturated or unsaturated heterocyclic or carbocyclic rings; and Y is

I of Formulae

R _m -Q ₂ -T; R-Q ₂ -T ₁₁₁ ; R _m -Q ₂ -T _rn ;

wherein R _m is a functionalizing moiety modified to adjust at least one chemical or physical property of R-Q ₂ -T; T _m is a tail moiety modified to adjust at least one chemical or physical property Of R-Q ₂ -T; and Q ₂ are defined as noted hereinabove. In certain embodiments, the modification comprises substitution of a carbon atom with a heteroatom or addition of a heteroatom-containing substituent, e.g., wherein R or T is substituted by a substituent selected from the group consisting of hydroxy, alkoxy, heterocycle and an acyl group, such that one or more of the chemical or physical properties of R-Q ₂ -T have been enhanced.

A. Compounds of Formula I

In embodiment aspect, the invention is directed to a compound of Formula I:

wherein

: represents a single or a double bond;

X is selected from the group consisting OfNR _x CR _x R _x and O;

R and R _2a are absent or independently selected from the group consisting of H, an aliphatic group (e.g., alkyl, alkenyl, alkynyl etc.), a carbocyclic group (e.g., saturated or unsaturated), a heterocyclic group (e.g., saturated or unsaturated), halogen, NO ₂ , CN, OR _a , NR _a R _a , CO ₂ R ₃ , -C(O)R ₃ , -COR ₃ , NR ₃ C(O)R ₃ , NR ₂ C(O)NR ₃ R ₃ , NR ₃ R ₃ C(O)O-, C(O)NR ₃ R ₃ , which may be optionally substituted, wherein i i d d l l f h sisting of H, an aliphatic group, a R ₁ , taken together,

may form a substituted or unsubstituted spiro heterocyclic or carbocyclic ring, which may optionally be substituted (e.g., by an aliphatic group, a carbocyclic group, or a heterocyclic group); or R ₂ and R _2a , taken together, may form a substituted or unsubstituted spiro heterocyclic or carbocyclic ring, which may optionally be substituted (e.g., by an aliphatic group, a carbocyclic group, or a heterocyclic group);

Ri and R ₂ are independently selected from the group consisting of H, -M ₁ , -Mj-M ₂ , -Z-M ₂ , and -M ₁ -Z-M ₂ ; or R and R ₁ , taken together, may form a substituted or unsubstituted spiro heterocyclic or carbocyclic ring, which may optionally be substituted; or R ₂ and R _2a , taken together, may form a substituted or unsubstituted spiro heterocyclic or carbocyclic ring, which may optionally be substituted; or Ri and R ₂ , taken together, may form a substituted or unsubstituted saturated or unsaturated heterocyclic or carbocyclic monocyclic or bicyclic ring; M ₁ and M ₂ are independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, halogen, NO ₂ , CN, OR _W , NR _W R _W , CO ₂ R _W , -C(O)R _W , -COR _W , NR _W C(O)R _W , NR _W C(O)NR _W R _W , NR _w R _w C(0)0, C(O)NR _W R _W , which may be optionally substituted, wherein each R _w is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group;

Z is selected from the group consisting of -O-, -NH-, -CR _y R _y -, -S-, -S(O)-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O- -S(O) ₂ -, -CH(OH)-, -CH(0R _y ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(ORy)-, -CH(OH)CH ₂ -, - CH(OR _y )CH ₂ -, and any combination thereof, wherein each R _y is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy; R ₃ is selected from the group consisting Of-G ₁ , -G ₁ -G ₂ , -Y-G ₂ , and -Gi-Y-G ₂ ;

G ₁ and G ₂ are independently selected from H, an aliphatic group, a carbocyclic group, and a heterocyclic group, which may be optionally substituted with one or more of substituents;

Y is selected from the group consisting of-0-, -NH-, -CR _y R _y -, -S-, -S(O)-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O-,-S(O) ₂ -, -CH(OH)-, -CH(0R _y ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(0R _y )-, -CH(OH)CH ₂ -, - CH(ORy)CH ₂ -, and any combination thereof, wherein each R _y is independently selected carbocyclic group, a heterocy

R ₃ is selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group (e.g. , selected from the group consisting of phenyl, benzyl, isobutyl, cyclohexyl, cyclohexylmethyl, m-methoxy phenyl, alkyl, aryl, and heterocycle).

B. Compounds of Formula II

Another embodiment of the invention pertains to a compound of Formula II:

wherein

X is selected from the group consisting of NR _x CR _x R _x and O;

R is selected from the group consisting of H, an aliphatic group (e.g., alkyl, alkenyl, alkynyl etc.), a carbocyclic group (e.g., saturated or unsaturated), a heterocyclic group (e.g., saturated or unsaturated), halogen, NO ₂ , CN, OR _a , NR _a R _a , CO ₂ R ₃ , -C(O)R ₃ , -CORa, NR ₃ C(O)R ₃ , NR ₃ C(O)NR ₃ R ₃ , NR ₃ R ₃ C(O)O-, C(O)NR ₃ R ₃ , which may be optionally substituted, wherein each R _a is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group; or R and R], taken together, may form a substituted or unsubstituted spiro heterocyclic or carbocyclic ring, which may optionally be substituted (e.g., by an aliphatic group, a carbocyclic group, or a heterocyclic group);

R] and R _x are independently selected from the group consisting of H, -M], -M]-M ₂ , -Z-M ₂ , and -M]-Z-M ₂ ; or R and Rj, taken together, may form a substituted or unsubstituted spiro heterocyclic or carbocyclic ring, which may optionally be substituted; or R] and R _x , taken together, may form a substituted or unsubstituted saturated or unsaturated heterocyclic monocyclic or multi-cyclic ring;

M] and M ₂ are independently selected from the group consisting of H, an aliphatic ogen, NO ₂ , CN, OR _W ,

NR _W R _W , CO ₂ R _W , -C(O)R _W , -COR _W , NR _W C(O)R _W , NR _W C(O)NR _W R _W , NR _W R _W C(O)O, C(O)NR _W R _W , which may be optionally substituted, wherein each R _w is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group; Z is selected from the group consisting of-O-, -NH-, -CR _y R _y -, -S-, -S(O)-, -

C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ CK-S(O) ₂ -, -CH(OH)-, -CH(0R _y ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(ORy)-, -CH(OH)CH ₂ -, - CH(ORy)CH ₂ -, and any combination thereof, wherein each R _y is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy;

R ₂ is selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group (e.g., selected from the group consisting of phenyl, benzyl, isobutyl, cyclohexyl, cyclohexylmethyl, m-methoxy phenyl, alkyl, aryl, and heterocycle); R ₃ is selected from the group consisting of -Gi, -Gi-G ₂ , -Y-G ₂ , and -Gi-Y-G ₂ ;

Gi and G ₂ are independently selected from H, an aliphatic group, a carbocyclic group, and a heterocyclic group, which may be optionally substituted with one or more of substituents; and

Y is selected from the group consisting of-O-, -NH-, -CR _y R _y -, -S-, -S(O)-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O-,-S(O) ₂ -, -CH(OH)-, -CH(0R _y ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(OR _y )-, -CH(OH)CH ₂ -, - CH(OR _y )CH ₂ -, and any combination thereof, wherein each R _y is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy.

C. Compounds of Formula III

In another embodiment, the compound of the invention is represented by Formula III:

wherein

: represents a single or a double bond; X is selected from the group consisting OfNR _x CR _x R _x and O;

R and R _2a are absent or independently selected from the group consisting of H, benzyl, pyridinyl, tetrahydro-pyranyl, methyl- lH-imidazo IyI, cyclohexylmethyl, phenethyl, p-chlorobenzyl, carboxylic acid benzyl ester, propionic acid tert-butyl ester, tert-butyl ester, ethanone, hydroxy, methoxy, ethoxy, propoxy, butoxy, t- butoxy, phenyl, isobutyl, methyl, ethyl, propyl, butyl, cyclohexyl, cyclohexylmethyl, m-methoxy phenyl, carboxylic acid 2-methoxy-ethyl ester, 3,3-dimethyl-butan-l-one, 2,2-dimethyl-propan- 1 -one, carboxylic acid methyl ester, alkyl, halogen, NO ₂ , CN, OR _a , NR ₃ Ra, CO ₂ R ₃ , -C(O)R ₃ , -CORa, NRaC(O)R ₃ , NR _a C(O)NR _a R _a , NR _a R _a C(0)0-, C(O)NR ₃ R ₃ , aryl, and heterocycle, which may be optionally substituted with methoxy or 2-methoxy-ethoxy, wherein each R ₃ is independently selected from the group consisting of H, alkyl, aryl, and heterocycle;

R] and R ₂ are independently selected from the group consisting of H, benzyl, pyridinyl, tetrahydro-pyranyl, methyl- lH-imidazolyl, cyclohexylmethyl, phenethyl, p- chlorobenzyl, carboxylic acid benzyl ester, propionic acid tert-butyl ester, tert-butyl ester, ethanone, hydroxy, methoxy, ethoxy, propoxy, butoxy, t-butoxy, phenyl, isobutyl, methyl, ethyl, propyl, butyl, cyclohexyl, cyclohexylmethyl, m-methoxy phenyl, carboxylic acid 2-methoxy-ethyl ester, 3,3-dimethyl-butan-l -one, 2,2- dimethyl-propan- 1 -one, carboxylic acid methyl ester, alkyl, halogen, NO ₂ , CN, OR _b , NR _b R _b , CO ₂ R _b , -C(O)Rb, -COR _b , NR _b C(0)R _b , NRbC(O)NR _b Rb, NRbRbC(O)O-, C(O)NRbRb, aryl, and heterocycle, which may be optionally substituted with methoxy or 2-methoxy-ethoxy, wherein each R _b is independently selected from the group consisting of H, alkyl, aryl, and heterocycle; or Ri and R ₂ , taken together, may form a substituted or unsubstituted saturated or unsaturated heterocyclic or carbocyclic monocyc

each R _x is independently selected from the group consisting of H, benzyl, pyridinyl, tetrahydro-pyranyl, methyl- lH-imidazolyl, cyclohexylmethyl, phenethyl, p- chlorobenzyl, carboxylic acid benzyl ester, propionic acid tert-butyl ester, tert-butyl ester, ethanone, hydroxy, methoxy, ethoxy, propoxy, butoxy, t-butoxy, phenyl, isobutyl, methyl, ethyl, propyl, butyl, cyclohexyl, cyclohexylmethyl, m-methoxy phenyl, carboxylic acid 2-methoxy-ethyl ester, 3,3-dimethyl-butan-l-one, 2,2- dimethyl-propan-1-one, carboxylic acid methyl ester, alkyl, halogen, NO ₂ , CN, OR _c , NRcRc, CO ₂ Rc, -C(O)Rc, -CORc, NRcC(O)Rc, NRcC(O)NRcRc, NRcRcC(O)O-, C(O)NR ₀ Rc, aryl, and heterocycle, which may be optionally substituted with methoxy or 2-methoxy-ethoxy, wherein each R _c is independently selected from the group consisting of H, alkyl, aryl, and heterocycle;

R ₃ is selected from the group consisting of -Gi, -Gj-G ₂ , -Y-G ₂ , and -Gj-Y-G ₂ ; Gj and G ₂ are independently selected from the group consisting of phenyl, cyclohexyl, cyclopentyl, 4-indanyl, pyrimidinyl, N-morpholino, furanyl, thiophenyl, pyrrolyl, N-lH-pyridin-2-onyl, bicyclo[4.2.0]octa-l,3,5-trien-3-yl, 1-indanyl, naphthalenyl, tetrahydro-naphthalenyl, pyrazine, [l,2,3]thiadiazolyl, 3-isoxazolyl, 5- indolyl, 2,3-dihydro-indol-6-yl, indazol-5-yl, benzo[2,l,3]thiadiazol-5-yl, cycloheptyl, isopropyl-[l,3,4]thiadiazolyl, benzothiazolyl, 3 -methyl-butyl, 1 H-pyrazolyl, oxazolyl, piperidinyl, lH-imidazolyl, pyrrolidinyl, piperazinyl, lH-[l,2,4]triazolyl, and pyridinyl, which may be optionally substituted with one or more of substituent moieties selected from the group consisting Of CF ₃ , OCF ₃ , iodo, chloro, bromo, - C(O)NH ₂ , -O(CH ₂ ) ₅ CH ₃ , carboxylic acid methyl ester, phenyl, p-methoxy phenyl, - NHC(O)NH ₂ , -C(O)O(CH ₂ ) ₂ N(CH ₂ CH ₃ ) ₂ , t-butyl, fluoro, methoxy, hydroxy, isopropyl, cyano, isopropenyl tetrahydropyran, benzyl, amino, -NHC(O)OC(CH ₃ ) _S , - C(O)OH, -C(O)CH ₃ , -CH ₂ CO ₂ H, methyl, and -(CH ₂ ) ₂ -OH; and

Y is selected from the group consisting of-O-, -NH-, -CR _y R _y -, -S-, -S(O)-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O- -S(O) ₂ -, and any combination thereof, wherein each R _y is independently selected from the group consisting of H, alkyl, aryl, heterocycle, hydroxy, or alkoxy; and R ₄ is selected from the group consisting of H, phenyl, benzyl, isobutyl, cyclohexyl, cyclohexylmethyl, m-methoxy phenyl, alkyl, aryl, and heterocycle.

In particular embodiments, Rj and R ₂ , taken together, form a substituted or unsubsti mbered monocyclic ring comprisi eroatom is substituted

with a moiety selected from the group consisting of H, benzyl, tert-butyl ester, ethanone, methyl, ethyl, carboxylic acid 2-methoxy-ethyl ester, 3 ,3 -dimethyl -butan-1- one, 2,2-dimethyl-propan- 1 -one, hydroxy, methoxy, ethoxy, propoxy, butoxy, t- butoxy, and carboxylic acid methyl ester. In other particular embodiments, X is NR _x , e.g., wherein R _x is H.

For example, taken together, Rj and R ₂ of Formula III may form

wherein represents a single or a double bond; positioned perpendicular to a bond indicates a point of connection to the remainder of the compound; and W, Z, Rl , and R2 may be defined as noted herein below for Formula XI. In a specific embodiment, taken together, R ₁ and R ₂ of Formula III may form

R1

R2^L W {

wherein represents a single or a double bond; and positioned perpendicular to a bond indicates a point of connection to the remainder of the compound In a more specific embodiment, taken together, Rj and R ₂ of Formula III may form

wherein represents a single or a double bond, and positioned perpendicular to a bond indicates a point of connection to the remainder of the compound. In a more specific embodiment, taken together, Rj and R ₂ of Formula III may form

R1 R1 RcN W

^

RcN.

wherein represents a single or a double bond, and Rc may be defined as noted herein below for Formula XI . In a more specific embodiment, taken together, Ri and R ₂ of Formula III may form

R1 _{R 1}

RcN ^^

wherein represents a single or a double bond; and positioned perpendicular to a bond indicates a point of connection to the remainder of the compound. In a more specific embodiment, taken together, Rj and R ₂ of Formula III may form

RcN ^'

RcN _^ ^

In one embodiment, the compound may be represented by the following formulae:

e.g., where X = NH or O.

In another embodiment, the compound may be represented by the following formula:

wherein, one of R ₅ and R^ is H and the other is selected from the group of pyrrolidin- 1 - yl, piperazine-1-yl, 4-methylpiperazine-l-yl, 3-methyl piperazine-1-yl, 3,5-dimethyl- piperazin-1-yl, 3-amino-pyrrolidin-l-yl, octahydro-pyrrolo[3,4-b]pyridine-6-yl, and 6- amino-3-aza-bicyclo[3.1.0]hex-3-yl. In particular embodiments, X is NH or O.

In another embodiment, the compound may be represented by the following formulae:

wherein,

A ₂ , B ₂ are independently selected from the group consisting of CR ₅ and N; C ₂ is selected from the group consisting of S, O, and NR ₅ ; R ₅ is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, an acyl group, halogen, -NO ₂ , trifluoromethyl, difluoromethyoxy, trifluoromethyoxy, azido, -CN, -OR ₃ , -NR ₃ R ₃ , - CO ₂ R ₃ , -C(O)R ₃ , -NR ₃ C(O)R ₃ , -NR ₃ C(O)NR ₃ R ₃ , -C(O)NR ₃ R ₃ , NR ₃ SO ₂ R ₃ , - SO ₂ NR ₃ R ₃ , -C(O)OR ₃ , - OC(O) R ₃ , - NR ₃ C(O)OR ₃ , C(O)NR ₃ R ₃ , and -SO ₂ R ₃ .

R ₃ is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group; X is selected from the group consisting of NR _x CR _x R _x and O; each R _x is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group; in the case where X is CR _x R _x , R _x may additionally be selected from nitro, cyano, OR _W , NR _W R _W , CO ₂ R _W , -C(O)R _W , NR _W C(O)R _W , NR _W C(O)NR _W R _W , C(O)NR _W R _W , which may be optionally substituted, wherein each R _w is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group.

R ₃ is selected from the group consisting of -Gi, -Gi-G ₂ , -Y-G ₂ , and -Gj-Y-G ₂ ; Gi and G ₂ are independently selected from H, an aliphatic group, a carbocyclic group, and a heterocyclic group, which may be optionally substituted with one or more of substituents;

Y is selected from the group consisting of-O-, -NH-, -CR _y R _y -, -S-, -S(O)-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O- -S(O) ₂ -, -CH(OH)-, -CH(OR ₅ ,), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(OR _y )-, -CH(OH)CH ₂ -, - CH(OR _y )CH ₂ -, and any combination thereof, wherein each R _y is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy; and

R ₄ is selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group. In a particular embodiment, the compound may be represented by the following formulae: _#

In specific embodiments, C ₂ is S or O. In another specific embodiment, R ₅ is an aliphatic group, a carbocyclic group or a heterocyclic group.

D. Compounds of Formula IV

In an additional embodiment, the compound of the invention is represented by Formula IV:

wherein

X is selected from the group consisting of NR _x CR _x R _x and O;

R is selected from the group consisting of H, benzyl, pyridinyl, tetrahydro- pyranyl, methyl- lH-imidazolyl, cyclohexylmethyl, phenethyl, p-chlorobenzyl, carboxyl t-butyl ester, ethanone,

hydroxy, methoxy, ethoxy, propoxy, butoxy, t-butoxy, phenyl, isobutyl, methyl, ethyl, propyl, butyl, cyclohexyl, cyclohexylmethyl, m-methoxy phenyl, carboxylic acid 2- methoxy-ethyl ester, 3,3-dimethyl-butan-l-one, 2,2-dimethyl-propan-l-one, carboxylic acid methyl ester, alkyl, halogen, NO ₂ , CN, OR ₃ , NR ₃ R ₃ , CO ₂ R ₃ , -C(O)R ₃ , -COR ₃ , NR ₃ C(O)R ₃ , NR ₃ C(O)NR ₃ Ra, NR ₃ RaC(O)O-, C(O)NR ₃ R ₃ , aryl, and heterocycle, which may be optionally substituted with methoxy or 2-methoxy-ethoxy, wherein each R ₃ is independently selected from the group consisting of H, alkyl, aryl, and heterocycle; or R and Ri, taken together, may form a substituted or unsubstituted spiro heterocyclic or carbocyclic ring, which may optionally be substituted with a benzyl group;

Ri and R _x are independently selected from the group consisting of H, benzyl, pyridinyl, tetrahydro-pyranyl, methyl- lH-imidazo IyI, cyclohexylmethyl, phenethyl, p- chlorobenzyl, carboxylic acid benzyl ester, propionic acid tert-butyl ester, tert-butyl ester, ethanone, hydroxy, methoxy, ethoxy, propoxy, butoxy, t-butoxy, phenyl, isobutyl, methyl, ethyl, propyl, butyl, cyclohexyl, cyclohexylmethyl, m-methoxy phenyl, carboxylic acid 2-methoxy-ethyl ester, 3,3-dimethyl-butan-l-one, 2,2- dimethyl-propan-l-one, carboxylic acid methyl ester, alkyl, halogen, NO ₂ , CN, OR _b , NR _b Rb, CO ₂ Rb, -C(0)R _b , -C0R _b , NR _b C(O)R _b , NR _b C(O)NR _b R _b , NR _b R _b C(O)O-, C(O)NR _b R _b , aryl, and heterocycle, which may be optionally substituted with methoxy or 2-methoxy-ethoxy, wherein each R _b is independently selected from the group consisting of H, alkyl, aryl, and heterocycle; or Ri and R _x , taken together, may form a substituted or unsubstituted saturated or unsaturated heterocyclic monocyclic or multi-cyclic ring; or R and Rj, taken together, may form a substituted or unsubstituted spiro heterocyclic or carbocyclic ring, which may optionally be substituted with a benzyl group;

R ₂ is selected from the group consisting of H, phenyl, benzyl, isobutyl, cyclohexyl, cyclohexylmethyl, m-methoxy phenyl, alkyl, aryl, and heterocycle;

R ₃ is selected from the group consisting of -Gj, -Gj-G ₂ , -Y-G ₂ , and -Gi-Y-G ₂ ; G] and G ₂ are independently selected from the group consisting of phenyl, cyclohexyl, cyclopentyl, 4-indanyl, pyrimidinyl, N-morpholino, furanyl, thiophenyl, pyrrolyl, N-l H-pyridin-2-onyl, bicyclo[4.2.0]octa-l,3,5-trien-3-yl, 1-indanyl, naphthalenyl, tetrahydro-naphthalenyl, pyrazine, [l ,2,3]thiadiazolyl, 3-isoxazolyl, 5- indolyl, 2 i i diazol-5-yl, cycloheptyl, isopropy 1 H-pyrazolyl, oxazolyl,

piperidinyl, 1 H-imidazolyl, pyrrolidinyl, piperazinyl, lH-[l,2,4]triazolyl, and pyridinyl, which may be optionally substituted with one or more of substituent moieties selected from the group consisting Of CF ₃ , OCF ₃ , iodo, chloro, bromo, - C(O)NH ₂ , -0(CH ₂ ) _S CH ₃ , carboxylic acid methyl ester, phenyl, p-methoxy phenyl, - NHC(O)NH ₂ , -C(O)O(CH ₂ ) ₂ N(CH ₂ CH ₃ )2, t-butyl, fluoro, methoxy, hydroxy, isopropyl, cyano, isopropenyl tetrahydropyran, benzyl, amino, -NHC(O)OC(CH ₃ ) ₃ , - C(O)OH, -C(O)CH ₃ , -CH ₂ CO ₂ H, methyl, and -(CH ₂ ) ₂ -OH; and

Y is selected from the group consisting of-0-, -NH-, -CR _y R _y -, -S-, -S(O)-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O-,-S(O) ₂ -, and any combination thereof, wherein each R _y is independently selected from the group consisting of H, alkyl, aryl, heterocycle, hydroxy, or alkoxy. In certain embodiments, Ri and R _x , taken together, form a substituted or unsubstituted saturated or unsaturated Sve-, six-, or seven- membered monocyclic ring comprising 1-2 heteroatoms. In certain embodiments, Ri and R _x , taken together, form a substituted or unsubstituted saturated or unsaturated nine- or ten-membered bicyclic ring comprising 1-2 heteroatoms.

E. Compounds of Formula V and VA

In another embodiment, the invention pertains, at least in part, to a compound of Formula (V)

wherein represents a single or a double bond; n is an integer from 0-3;

X is selected from the group consisting OfNR _x CR _x R _x and O; each R _x is independently selected from the group consisting of H, -Mi, -M

Mi and M ₂ are independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, halogen, NO ₂ , CN, OR _W , NR _W R _W , CO ₂ R _w , -C(O)R _W , -COR _W , NR _W C(O)R _W , NR _W C(O)NR _W R _W , NR _W R _W C(O)O, C(O)NR _W R _W , which may be optionally substituted, wherein each R _w is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group;

Z is selected from the group consisting of-O-, -NH-, -CR _Z R _Z -, -S-, -S(O)-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O- -S(O) ₂ -, -CH(OH)-, -CH(OR ₂ ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(OR _Z )-, -CH(OH)CH ₂ -, - CH(OR _z )CH ₂ -, and any combination thereof, wherein each R _z is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy;

Ai, Bi, Ci, and Dj are independently selected from the group consisting of CH ₂ , CRi, CR ₂ R ₃ , N, and NR ₄ (e.g., wherein one or two of Ai, Bi, Ci, and Di is N or NR ₄ ); each R], R ₂ , R ₃ , and R ₄ are independently selected from the group consisting of H, an aliphatic group (e.g., alkyl, alkenyl, alkynyl etc.), a carbocyclic group (e.g., saturated or unsaturated), a heterocyclic group (e.g., saturated or unsaturated), an acyl group, halogen, ox, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, - NR ₃ SO ₂ R ₃ , -SO ₂ NR ₃ R ₃ , -OC(O) R ₃ , -NR ₃ C(O)OR ₃ , -SO ₂ R ₃ , NO ₂ , CN, OR ₃ , NR ₃ R ₃ , CO ₂ R ₃ , -C(O)R ₃ , -COR ₃ , NR ₃ C(O)R ₃ , NR ₃ C(O)NR ₃ R ₃ , NR ₃ R ₃ C(O)O-, C(O)NR ₃ R ₃ , which may be optionally substituted, wherein each R ₃ is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group; or any two of Ri , R ₂ , R ₃ , or R ₄ , taken together, may form a substituted or unsubstituted saturated or unsaturated heterocyclic or carbocyclic 3-8 membered ring, which is optionally substituted with one to three groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifloromethyoxy, - NR ⁵ SO ₂ R", -SO ₂ NR ⁵ R", - C(O)R ⁵ , -C(O)OR', - OC(O)R', - NR'C(0)0R", - NR ⁵ C(O)R", C(O)NR ⁵ R", -SO ₂ R ⁵ , NR ⁵ R", -NR'C(0)NR"R"\ -OR', aryl, heteroaryl, and arylalkyl, wherein R ⁵ , R" and R ⁵ " independently are selected from the group consisting of hydrogen, alkyl, alkenyl, and aryl;

R ₅ is selected from the group consisting of -Gi, -G]-G ₂ , -Y-G ₂ , and -Gi-Y-G ₂ ;

Gi and G ₂ are independently selected from H, an aliphatic group, a carbocyclic group, and a heterocyclic group, which may be optionally substituted with one or more of substituents; and

Y is selected from the group consisting of-O-, -NH-, -CR _y R _y -, -S-, -S(O)-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O-,-S(O) ₂ -, -CH(OH)-, -CH(OR _y ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(OR _y >, -CH(OH)CH ₂ -, - CH(OR _y )CH ₂ -, and any combination thereof, wherein each R _y is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy; R« is selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group (e.g., H, phenyl, benzyl, isobutyl, cyclohexyl, cyclohexylmethyl, m-methoxy phenyl, alkyl, aryl, and heterocycle); and

R ₇ and R« are absent or independently selected from the group consisting of H, halogen (e.g., F), OH, an alkoxy group, an aliphatic group, and a carbocyclic group, which may be optionally substituted (e.g., by hydroxy or alkoxy). In certain embodiments of the invention, R ₇ is not H, e.g., R ₇ is lower alkyl or halogen. In certain embodiments, where X is NR _x or O and Bi and/or Ci is/are CRi, Ri is selected from the group consisting of heterocycles and bulky amines (e.g., Ri is not small N, or small N-acyl, NO ₂ ) In certain embodiments, each R ₂ and R ₃ are independently selected from the group consisting of hydrogen, halogen, -CN, -NO ₂ , an aliphatic group, a carbocyclic group, a heterocyclic group, OR ₃ , NR ₃ R ₃ , CO ₂ R ₃ , -C(O)R ₃ , NR ₃ C(O)R ₃ , NR ₃ C(O)NR ₃ R ₃ , C(O)NR ₃ R ₃ , which may be optionally substituted, wherein each R ₃ is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group; or R ₂ and R ₃ may be taken together with the atom to which they are attached may form a 3 to 10 membered carbocyclic, heteroaryl or heterocyclic ring.

In certain embodiments, each R ₄ is selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, a arylalkyl group, a heteroarylalkyl group, -C(O)OR ₃ , C(O)R ₃ , C(O)NR ₃ R ₃ , and -SO ₂ R ₃ .

In certain embodiments of Formula V, Gi is a mono or bicyclic aromatic or heteroaromatic group which may be optionally substituted with one or more substitue tic group, a carbocyclic group, a halogen, -NO ₂ ,

trifluoromethyl, difluoromethyoxy, trifluoromethyoxy, azido, -CN, -OR _g , -SR _g - NR _g R _g , -CO ₂ R _g , -C(O)R _g , -NR _g C(O)R _g , -NR _g C(O)NR _g R _g , -C(O)NR ₈ R ₈ , NR _g SO ₂ R ₈ , - SO ₂ NR _g R ₈ , -C(O)OR ₈ , - OC(O) R ₈ , - NR _g C(O)OR _g , C(0)NR _g R _g , -SO ₂ R _g , -(CH ₂ ) ₂ - OR _g and -CH ₂ NR _g R _g , wherein R _g is selected from H, aliphatic, carbocyclic, heterocyclic and heteroaromatic groups.

In certain embodiments of Formula V, G ₂ is an aliphatic group, or a mono or bicyclic carbocyclic or heterocyclic group (e.g. , aromatic or heteroaromatic group) which may be optionally substituted with one or more substituents selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, an acyl group, halogen, -NO ₂ , trifluoromethyl, difluoromethyoxy, trifluoromethyoxy, azido, -CN, -OR ₈ , -SR ₈ -NR ₈ R ₈ , -CO ₂ R ₈ , -C(O)R ₈ , -NR ₈ C(O)R ₈ , -NR ₈ C(O)NR ₈ R ₈ , - C(O)NR _g R ₈ , NR _g SO ₂ R ₈ , -SO ₂ NR _g R _g , -C(O)OR ₈ , - OC(O) R _g , - NR _g C(O)OR _g , C(O)NR _g R _g , -SO ₂ R _g , -(CH ₂ ) ₂ -OR _g and -CH ₂ NR _g R _g , wherein R _g is selected from H, aliphatic, carbocyclic, heterocyclic and heteroaromatic groups. It will be noted that the structure of some of the compounds of this invention includes asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry (e.g. , all enantiomers and diastereomers) are included within the scope of this invention unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemical^ controlled synthesis. That is, unless otherwise stipulated, any chiral carbon center may be of either (R)- or (5)-stereochemistry. Furthermore, alkenes can include either the E- or Z-geometry, where appropriate. Additionally, one skilled in the art will appreciate that the chemical structures as drawn may represent a number of possible tautomers, and the present invention also includes those tautomers. Accordingly, another embodiment of the invention is a substantially pure single stereoisomer or a mixture of stereoisomers, e.g., pre-determined to be within specific amounts.

Moreover, it should be understood that the compounds of the present invention, comprise compounds that satisfy valency requirements known to the ordinarily skilled artisan. Additionally, compounds of the present invention comprise stable compounds (i.e., based upon empirical data or on the skilled artisan's understanding of stable bond formation) as well as though compounds that may be modified h i ll h h ri f l i to become stable. In

certain embodiments, such stability is guided by time periods that are sufficient to allow administration to and/or treatment of a subject.

In addition, compounds of the invention further include derivatives of the compounds depicted below modified to adjust at least one chemical or physical property of depicted compound. In certain embodiments, the modification comprises substitution of a carbon atom with a heteroatom or addition of a heteroatom- containing substituent (e.g., substituted by a substituent selected from the group consisting of hydroxy, alkoxy, heterocycle and an acyl group), such that one or more of the chemical or physical properties of the depicted compound have been enhanced, e.g., with respect to potency or selectivity. For example, particular embodiments of substituted alkyl moieties may be -CH ₂ OH or -CH ₂ OCH ₃ .

In yet another embodiment, the invention is directed to a compound of Formula VA:

wherein represents a single or a double bond;

X is selected from the group consisting OfNR _x CR _x R _x and O; each R _x is independently selected from the group consisting of H, benzyl, pyridinyl, tetrahydro-pyranyl, methyl- 1 H-imidazo IyI, cyclohexylmethyl, phenethyl, p- chlorobenzyl, carboxylic acid benzyl ester, propionic acid tert-butyl ester, tert-butyl ester, ethanone, hydroxy, methoxy, ethoxy, propoxy, butoxy, t-butoxy, phenyl, isobutyl, methyl, ethyl, propyl, butyl, cyclohexyl, cyclohexylmethyl, m-methoxy phenyl, carboxylic acid 2-methoxy-ethyl ester, 3,3-dimethyl-butan-l-one, 2,2- dimethyl-propan-1-one, carboxylic acid methyl ester, alkyl, halogen, NO ₂ , CN, OR _a , NR _a R _a , CO ₂ R ₃ , -C(O)R ₃ , -CORa, NR ₃ C(O)Ra, NR ₃ C(O)NR ₃ Ra, NR ₃ RaC(O)O-, C(O)NR ubstituted with methoxy

or 2-methoxy-ethoxy, wherein each R _a is independently selected from the group consisting of H, alkyl, aryl, and heterocycle;

Ai, Bi, Ci, and Dj are independently selected from the group consisting of CH ₂ , CRi, CR ₂ R ₃ , N, and NR ₄ ; Ri- R ₃ are independently selected from the group consisting of pyrrolidinyl, 4- methylpiperazinyl, piperazinyl, H, alkyl, halogen, NO ₂ , CN, OR _b , NR _b R _b , CO ₂ R _b , - C(0)R _b , -CORb, NRbC(O)Rb, NR _b C(0)NR _b R _b , NR _b R _b C(O)O-, C(0)NR _b R _b , aryl, and heterocycle, which may be optionally substituted with methoxy or 2-methoxy-ethoxy, wherein each R _b is independently selected from the group consisting of H, alkyl, aryl, and heterocycle; or R ₂ and R ₃ , taken together, may form a substituted or unsubstituted spiro heterocyclic or carbocyclic ring, which may optionally be substituted with a benzyl group;

R ₄ is selected from the group consisting of H, benzyl, tert-butyl ester, ethanone, methyl, ethyl, carboxylic acid 2-methoxy-ethyl ester, 3,3-dimethyl-butan-l- one, 2,2-dimethyl-propan-l -one, and carboxylic acid methyl ester;

R ₅ is selected from the group consisting of -Gi, -Gj-G ₂ , -Y-G ₂ , and -Gj-Y-G ₂ ; Gi and G ₂ are independently selected from the group consisting of phenyl, cyclohexyl, cyclopentyl, 4-indanyl, pyrimidinyl, N-morpholino, furanyl, thiophenyl, pyrrolyl, N-lH-pyridin-2-onyl, bicyclo[4.2.0]octa-l,3,5-trien-3-yl, 1 -indanyl, naphthalenyl, tetrahydro-naphthalenyl, pyrazine, [1 ,2,3]thiadiazolyl, 3-isoxazolyl, 5- indolyl, 2,3-dihydro-indol-6-yl, indazol-5-yl, benzo[2,l ,3]thiadiazol-5-yl, cycloheptyl, isopropyl-[l ,3,4]thiadiazolyl, benzothiazolyl, 3 -methyl-butyl, lH-pyrazolyl, oxazolyl, piperidinyl, lH-imidazolyl, pyrrolidinyl, piperazinyl, lH-[l,2,4]triazolyl, and pyridinyl, which may be optionally substituted with one or more of substituent moieties selected from the group consisting of CF ₃ , OCF ₃ , iodo, chloro, bromo, -

C(O)NH ₂ , -O(CH ₂ ) ₅ CH ₃ , carboxylic acid methyl ester, phenyl, p-methoxy phenyl, - NHC(O)NH ₂ , -C(O)O(CH ₂ ) ₂ N(CH ₂ CH ₃ ) ₂ , t-butyl, fluoro, methoxy, hydroxy, isopropyl, cyano, isopropenyl tetrahydropyran, benzyl, amino, -NHC(O)OC(CH ₃ ) ₃ , - C(O)OH, -C(O)CH ₃ , -CH ₂ CO ₂ H, methyl, and -(CH ₂ ) ₂ -OH; and Y is selected from the group consisting of-O-, -NH-, -CR _y R _y -, -S-, -S(O)-, -

C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O-,-S(O) ₂ -, -CH(OH)-, -CH(0R _y ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(0R _y )-, -CH(OH)CH ₂ -, - CH(ORy)C d i h is independently

selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy;

R^ is selected from the group consisting of H, phenyl, benzyl, isobutyl, cyclohexyl, cyclohexylmethyl, m-methoxy phenyl, alkyl, aryl, and heterocycle; and R.7 and Rs are absent or independently selected from the group consisting of H, aryl and, alkyl. In certain embodiments of the invention, R ₇ is not H, e.g., R ₇ is lower alkyl or halogen. In certain embodiments, one of Ai, Bi, Ci, or Di is N, or NR ₄ . In certain embodiments, two of Ai, Bi, Ci, or Di is N, or NR ₄ .

In certain embodiments of the compounds of Formula VA, Gi is selected from the group consisting of phenyl, 4-indanyl, pyrimidinyl, cyclohexyl, cyclopentyl, cycloheptyl, isopropyl-[l,3,4]thiadiazolyl, benzothiazolyl, 3-methyl-butyl, IH- Pyrazolyl, and lH-[l,2,4]triazolyl, pyridinyl, which may be optionally substituted with one or more of substituent moieties selected from the group consisting of CF ₃ , OCF ₃ , iodo, -C(O)NH ₂ , -O(CH ₂ ) ₅ CH ₃ , carboxylic acid methyl ester, phenyl, p- methoxy phenyl, -NHC(O)NH ₂ , -C(O)O(CH ₂ ) ₂ N(CH ₂ CH ₃ ) ₂ ,t-butyl, methyl-dimethyl- amine, cyano, ethyl, benzyl, methyl, fluoro, chloro, -SCH ₃ , -S(O) ₂ CH ₃ , methoxy, and -(CHz) ₂ -OH.

In certain additional embodiments of the compounds of Formula VA, G ₂ is selected from the group consisting of phenyl, N-morpholino, furanyl, thiophenyl, pyrrolyl, N-lH-pyridin-2-onyl, and benzothiazolyl, cyclohexyl, oxazolyl, piperidinyl, lH-pyrazolyl, lH-imidazolyl, pyrrolidinyl, and piperazinyl, which may be optionally substituted with one or more of substituent moieties selected from the group consisting of methyl, ethyl, benzyl, cyano, CF ₃ , carboxylic acid methyl ester, methyl- dimethyl-amine, -SCH ₃ , -C(O)NH ₂ , -(CH ₂ ) ₂ -OH, -S(O) ₂ CH ₃ , chloro and bromo. In certain embodiments of the compounds of the Formula VA, where X is NR _x or O and Bj and/or Ci is/are CRi, Ri is selected from the group consisting of heterocycles and bulky amines (e.g., Ri is not small N, or small N-acyl, NO ₂ )

G. Compounds of Formula VI and VIA

In an additional embodiment, the invention is a compound of Formula VI:

wherein

: represents a single or a double bond;

X is selected from the group consisting OfNR _x CR _x R _x and O; each R _x is independently selected from the group consisting of H,

-Mi, -Mi-M ₂ , -Z-M ₂ , and -MpZ-M ₂ ;

Mi and M ₂ are independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, halogen, NO ₂ , CN, OR _W , NR _W R _W , CO ₂ Rw, -C(O)R _W , -COR _W , NR _W C(O)R _W , NR _W C(O)NR _W R _W , NR _w R _w C(0)0, C(O)NR _W R _W , which may be optionally substituted, wherein each R _w is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group;

Z is selected from the group consisting of -O-, -NH-, -CR _Z R _Z -, -S-, -S(O)-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O- -S(O) ₂ -, -CH(OH)-, -CH(OR ₂ ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(OR ₂ )-, -CH(OH)CH ₂ -, -

CH(OR _z )CH ₂ -, and any combination thereof, wherein each R _z is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy;

Ri, Ri _a , R ₂ , R ₃ , R ₄ , R( _a are independently selected from the group consisting of H, an aliphatic group (e.g., alkyl, alkenyl, alkynyl etc.), a carbocyclic group (e.g., saturated or unsaturated), a heterocyclic group (e.g., saturated or unsaturated), an acyl group, halogen, NO ₂ , CN, 0R _a , NR _a R _a , CO ₂ R ₃ , -C(O)R ₃ , -COR ₃ , NR ₃ C(O)R ₃ , NR ₃ C(O)NR ₃ R ₃ , NR ₃ R ₃ C(O)O-, C(O)NR ₃ R ₃ , which may be optionally substituted, wherein each R _a is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group;

R ₂₃ and R ₃₃ are absent or independently selected from the group consisting of H, an aliphatic group (e g alkyl alkenyl alkynyl etc ) a carbocyclic group (e.g., saturated or unsaturated), an acyl

group, halogen, NO ₂ , CN, OR _a , NR ₃ R ₃ , CO ₂ R ₃ , -C(O)R ₃ , -COR ₃ , NR ₃ C(O)R ₃ , NR ₃ C(O)NR ₃ R ₃ , NR ₃ R ₃ C(O)O-, C(O)NR ₃ R ₃ , which may be optionally substituted, wherein each R ₃ is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group; R5 is selected from the group consisting of -Gi, -Gi-G ₂ , -Y-G ₂ , and -G ₁ -Y-G ₂ ;

Gi and G ₂ are independently selected from H, an aliphatic group, a carbocyclic group, and a heterocyclic group, which may be optionally substituted with one or more of substituents; and

Y is selected from the group consisting of-0-, -NH-, -CR _y R _y -, -S-, -S(O)-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O- -S(O) ₂ -, -CH(OH)-, -CH(OR _y ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(OR _y )-, -CH(OH)CH ₂ -, - CH(ORy)CH ₂ -, and any combination thereof, wherein each R _y is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy; R6 is selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group; and

R7 and Rg are absent or independently selected from the group consisting of H, halogen (e.g., F), OH, an alkoxy group, an aliphatic group, and a carbocyclic group, which may be optionally substituted (e.g. , by hydroxy or alkoxy). In certain embodiments of the invention, R ₇ is not H, e.g., R ₇ is lower alkyl or halogen.

In an additional embodiment, the invention is a compound of Formula VIA:

wherein represents a single or a double bond;

X is selected from the group consisting of NR _x CR _x R _x and O; each R is independently selected from the group consisting of H, benzyl, pyridiny xylmethyl, phenethyl, p-

chlorobenzyl, carboxylic acid benzyl ester, propionic acid tert-butyl ester, tert-butyl ester, ethanone, hydroxy, methoxy, ethoxy, propoxy, butoxy, t-butoxy, phenyl, isobutyl, methyl, ethyl, propyl, butyl, cyclohexyl, cyclohexylmethyl, m-methoxy phenyl, carboxylic acid 2-methoxy-ethyl ester, 3,3-dimethyl-butan-l -one, 2,2- dimethyl-propan-1-one, carboxylic acid methyl ester, alkyl, halogen, NO ₂ , CN, OR ₃ , NR _a R _a , CO ₂ R ₃ , -C(O)R ₃ , -COR ₃ , NR ₃ C(O)R ₃ , NR ₃ C(O)NR ₃ R ₃ , NR ₃ R ₃ C(O)O-, C(O)NR ₃ R ₃ , aryl, and heterocycle, which may be optionally substituted with methoxy or 2-methoxy-ethoxy, wherein each R ₃ is independently selected from the group consisting of H, alkyl, aryl, and heterocycle; R ₁ , Ri _a , R ₂ , R ₃ , R ₄ , R _4a are independently selected from the group consisting of pyrrolidinyl, 4-methylpiperazinyl, piperazinyl, H, alkyl, halogen, NO ₂ , CN, OR _b , NR _b Rb, C0 ₂ R _b , -C(O)Rb, -C0R _b , NR _b C(0)R _b , NR _b C(O)NRbRb, NRbRbC(O)O-, C(O)NR _b Rt,, aryl, and heterocycle, which may be optionally substituted with methoxy or 2-methoxy-ethoxy, wherein each R _b is independently selected from the group consisting of H, alkyl, aryl, and heterocycle; or Ri and R ₄ , taken together, may form a substituted or unsubstituted spiro heterocyclic or carbocyclic ring;

R _2a and R ₃₃ are absent or independently selected from the group consisting of pyrrolidinyl, 4-methylpiperazinyl, piperazinyl, H, alkyl, halogen, NO ₂ , CN, OR _c , NR _e R _c , CO ₂ R _c , -C(O)R _e , -COR _e , NR _c C(O)R _e , NR _c C(O)NR _e R _c , NR _e R _c C(O)O-, C(O)NR _c R _c , aryl, and heterocycle, which may be optionally substituted with methoxy or 2-methoxy-ethoxy, wherein each R ₀ is independently selected from the group consisting of H, alkyl, aryl, and heterocycle;

R ₅ is selected from the group consisting of -Gi, -Gj-G ₂ , and -Gi-Y-G ₂ ; Gi and G ₂ are independently selected from the group consisting of phenyl, cyclohexyl, lH-pyrazolyl, oxazolyl, piperidinyl, 1 H-imidazolyl, pyrrolidinyl, piperazinyl, lH-[l ,2,4]triazolyl, and pyridinyl, which may be optionally substituted with one or more of substituent moieties selected from the group consisting of CF ₃ , OCF ₃ , 1, phenyl, p-methoxy phenyl, t-butyl, fluoro, methoxy, and -(CH ₂ ) ₂ -OH;

Y is selected from the group consisting of-0-, -NH-, -CR _y R _y -, -S-, -S(O)-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O-,-S(O) ₂ -, -CH(OH)-, -CH(0R _y ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(0R _y )-, -CH(OH)CH ₂ -, - CH(OR _y )CH ₂ -, and any combination thereof, wherein each R _y is independently selected f i i i arbocyclic group, a heterocy

R^ is selected from the group consisting of H, alkyl, aryl, and heterocycle; and R. ₇ and R« are absent or independently selected from the group consisting of H, aryl and, alkyl. In certain embodiments of the invention, R ₇ is not H, e.g., Rj is lower alkyl or halogen. In certain embodiments, G] is selected from the group consisting of phenyl, cyclohexyl, 1 H-pyrazolyl, and lH-[l,2,4]triazolyl, pyridinyl, which may be optionally substituted with one or more of substituent moieties selected from the group consisting Of CF ₃ , OCF ₃ , 1, phenyl, p-methoxy phenyl, t-butyl, fluoro, methoxy, and -(CFb) ₂ -OH. In certain embodiments, G ₂ is selected from the group consisting of phenyl, cyclohexyl, oxazolyl, piperidinyl, 1 H-pyrazolyl, 1 H-imidazolyl, pyrrolidinyl, and piperazinyl.

H. Compounds of Formula VII and VIIA

Another embodiment of the invention relates to a compound of Formula VII:

wherein represents a single or a double bond;

X is selected from the group consisting OfNR _x CR _x R _x and O; each R _x is independently selected from the group consisting of H, -M], -Mj-M ₂ , -Z-M ₂ , and -M]-Z-M ₂ ;

M] and M ₂ are independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, halogen, NO ₂ , CN, OR _W , NRwRw, CO ₂ R _W , -C(O)R _W , -COR _W , NR _W C(O)R _W , NR _W C(O)NR _W R _W , NR _w R _w C(0)0, C(O)NR _W R _W , which may be optionally substituted, wherein each R _w is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group;

Z is selected from the group consisting of-O-, -NH-, -CR _Z R _Z -, -S-, -S(O)-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O- -S(O) ₂ -, -CH(OH)-, -CH(OR ₂ ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(OR ₂ )-, -CH(OH)CH ₂ -, - CH(OR _z )CH ₂ -, and any combination thereof, wherein each R _z is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy;

R], R ₂ , R ₃ , and R ₄ are selected from the group consisting of H, an aliphatic group, a heterocyclic group, a carbocyclic group, alkoxy, hydroxyl, amino, nitro, cyano, carbonyl, and thiocarbonyl, which may be optionally substituted; R ₅ is selected from the group consisting of -Gi, -Gj-G ₂ , -Y-G ₂ , and -Gi-Y-G ₂ ;

Gi and G ₂ are independently selected from H, an aliphatic group, a carbocyclic group, and a heterocyclic group, which may be optionally substituted with one or more of substituents; and

Y is selected from the group consisting of-O-, -NH-, -CR _y R _y -, -S-, -S(O)-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O-,-S(O) ₂ -, -CH(OH)-, -CH(0R _y ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(0R _y )-, -CH(OH)CH ₂ -, - CH(ORy)CH ₂ -, and any combination thereof, wherein each R _y is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy; Re is selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group; and

R ₇ and Rg are absent or independently selected from the group consisting of H, halogen (e.g., F), OH, an alkoxy group, an aliphatic group, and a carbocyclic group, which may be optionally substituted (e.g., by hydroxy or alkoxy). In certain embodiments, where X is NR _x or O, R ₂ and R ₃ are selected from the group consisting of heterocycles and bulky amines (i.e., R ₂ and R ₃ are not small N, small N-acyl, or NO ₂ ). In particular embodiments, R ₂ and R ₃ are selected from the group consisting of substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted morpholine, substituted or unsubstituted thiomorpholino substituted or unsubstituted aziridine, substituted or unsubstituted azetidine, substituted or unsubstituted pyrrolidine, substituted or unsubstituted dihydro isoindolyl, octahydro pyrolo [3, 4, -b] pyridiyl, substituted or unsubstit d C lk l b i d b i d C loalkyl, substituted or unsubstit 4 fluorophenyl.

The term "bulky amine" is art-recognized and is used to describe substituted amines that comprise substituents that create steric bulk, either alone or in combination. In contrast, the term "small" as used herein in the language "small N" or "small N-acyl" describe substituted amine groups or N-acyl groups comprising subtituents with low steric bulk.

Another embodiment of the invention relates to a compound of Formula VIIA:

wherein represents a single or a double bond; X is selected from the group consisting OfNR _x , CR _x R _x and O; each R _x is independently selected from the group consisting of H, benzyl, pyridinyl, tetrahydro-pyranyl, methyl- 1 H-imidazolyl, cyclohexylmethyl, phenethyl, p- chlorobenzyl, carboxylic acid benzyl ester, propionic acid tert-butyl ester, tert-butyl ester, ethanone, hydroxy, methoxy, ethoxy, propoxy, butoxy, t-butoxy, phenyl, isobutyl, methyl, ethyl, propyl, butyl, cyclohexyl, cyclohexylmethyl, m-methoxy phenyl, carboxylic acid 2-methoxy-ethyl ester, 3,3-dimethyl-butan-l-one, 2,2- dimethyl-propan-1-one, carboxylic acid methyl ester, alkyl, halogen, NO ₂ , CN, OR ₃ , NR _a R _a , CO ₂ R ₃ , -C(O)R ₃ , -COR ₃ , NR ₃ C(O)R ₃ , NR ₃ C(O)NR ₃ R ₃ , NR ₃ R ₃ C(O)O-, C(O)NR ₃ R ₃ , aryl, and heterocycle, which may be optionally substituted with methoxy or 2-methoxy-ethoxy, wherein each R ₃ is independently selected from the group consisting of H, alkyl, aryl, and heterocycle;

Ri, R ₂ , R ₃ , and R ₄ are selected from the group consisting of chloro, bromo, pyrrolidinyl, 4-methylpiperazinyl, piperazinyl

R ₅ is selected from the group consisting of -Gj, -G]-G ₂ , -Y-G ₂ , and -G]-Y-G ₂ ; G] and G ₂ are independently selected from the group consisting of phenyl, cyclohexyl, lH-[l,2,4]triazolyl, pyridinyl, piperidinyl, oxazolyl, which may be optionally substituted with one or more of substituent moieties selected from the

group consisting of methoxy, phenyl, p-methoxy phenyl, chloro, bromo, CF ₃ , OCF ₃ , - O(CH ₂ ) ₅ CH ₃ , -NHC(O)NH ₂ , -C(O)NH ₂ , and -C(O)O(CH ₂ )2N(CH ₂ CH ₃ ) ₂ ;

Y is selected from the group consisting of-O-, -NH-, -CR _y R _y -, -S-, -S(O)-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O-,-S(O) ₂ -, -CH(OH)-, -CH(0R _y ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(0R _y )-, -CH(OH)CH ₂ -, -

CH(ORy)CH ₂ -, and any combination thereof, wherein each R _y is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy; and

R _ό is selected from the group consisting of H, alkyl, aryl, and heterocycle. In certain embodiments, G] is selected from the group consisting of phenyl, cyclohexyl, lH-[l,2,4]triazolyl, pyridinyl, which may be optionally substituted with one or more of substituent moieties selected from the group consisting of methoxy, phenyl, p-methoxy phenyl, CF ₃ , OCF ₃ , -O(CH ₂ ) ₅ CH ₃ , - NHC(O)NH ₂ , -C(O)NH ₂ , and -C(O)O(CH ₂ ) ₂ N(CH ₂ CH3)2. In certain embodiments, wherein G ₂ is selected from the group consisting of phenyl, cyclohexyl, piperidinyl, oxazolyl, which may be optionally substituted with one or more of substituent moieties selected from the group consisting of chloro, and bromo.

In certain embodiments of the compounds of Formula VIIA, where X is NR _x or O, R ₂ and R ₃ are selected from the group consisting of heterocycles and bulky amines (i.e., R ₂ and R ₃ are not small N, small N-acyl, or NO ₂ ). In particular embodiments, R ₂ and R ₃ are selected from the group consisting of substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted morpholine, substituted or unsubstituted thiomorpholino substituted or unsubstituted aziridine, substituted or unsubstituted azetidine, substituted or unsubstituted pyrrolidine, substituted or unsubstituted dihydro isoindolyl, octahydro pyrolo [3, 4, -b] pyridiyl, substituted or unsubstituted C ₁ . ₅ alkyl, substituted or unsubstituted C ₃ . ₆ cycloalkyl, substituted or unsubstituted aryl, OCF ₃ -OCH ₃ , - OCHF ₂ , ethyl, t-butyl, and 4 fluorophenyl.

L Compounds of Formula VIII and VIIIA

In yet another embodiment, the invention is directed to a compound of Formula

wherein represents a single or a double bond; X is selected from the group consisting OfNR _x CR _x R _x and O; each R _x is independently selected from the group consisting of H, -Mi, -M1-M2, -Z-M ₂ , and -M ₁ -Z-M ₂ ;

M ₁ and M ₂ are independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, halogen, NO ₂ , CN, OR _W , NRwRw, CO ₂ Rw, -C(O)Rw, -COR _W , NR _W C(O)R _W , NR _W C(O)NR _W R _W , NR _w R _w C(0)0, C(O)NR _W R _W , which may be optionally substituted, wherein each R _w is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group;

Z is selected from the group consisting of -O-, -NH-, -CR _Z R _Z -, -S-, -S(O)-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ CK-S(O) ₂ -, -CH(OH)-, -CH(OR ₂ ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(OR ₂ )-, -CH(OH)CH ₂ -, - CH(OR _z )CH ₂ -, and any combination thereof, wherein each R _z is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy; E ₁ and F ₁ are independently selected from CHR ₁ and NRj; each R ₁ is independently selected from the group consisting of H, alkoxy, hydroxyl, halogen, an aliphatic group, a heterocyclic group, a carbocyclic group, an acyl group, amino, and cyano;

R ₅ is selected from the group consisting Of -G ₁ , -G ₁ -G ₂ , -Y-G ₂ , and -GpY-G ₂ ; Gi and G ₂ are independently selected from H, an aliphatic group, a carbocyclic group, and a heterocyclic group, which may be optionally substituted with one or more of b tit d

Y is selected from the group consisting of-O-, -NH-, -CR _y R _y -, -S-, -S(O)-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O- -S(O) ₂ -, -CH(OH)-, -CH(OR _y ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(OR _y )-, -CH(OH)CH ₂ -, - CH(OR _y )CH ₂ -, and any combination thereof, wherein each R _y is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy;

R^ is selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group; and

R ₇ and Re are absent or independently selected from the group consisting of H, an aliphatic group, and a carbocyclic group, which may be optionally substituted (e.g., by hydroxy or alkoxy). In certain embodiments of the invention, R ₇ is not H, e.g., R ₇ is lower alkyl or halogen.

In yet another embodiment, the invention is directed to a compound of Formula VIIIA:

(VIIIA) wherein represents a single or a double bond;

X is selected from the group consisting of NR _x CR _x R _x and O; each R _x is independently selected from the group consisting of H, benzyl, pyridinyl, tetrahydro-pyranyl, methyl- lH-imidazolyl, cyclohexylmethyl, phenethyl, p- chlorobenzyl, carboxylic acid benzyl ester, propionic acid tert-butyl ester, tert-butyl ester, ethanone, hydroxy, methoxy, ethoxy, propoxy, butoxy, t-butoxy, phenyl, isobutyl, methyl, ethyl, propyl, butyl, cyclohexyl, cyclohexylmethyl, m-methoxy phenyl, carboxylic acid 2-methoxy-ethyl ester, 3,3-dimethyl-butan-l-one, 2,2- dimethyl-propan-1-one, carboxylic acid methyl ester, alkyl, halogen, NO ₂ , CN, OR ₃ , NR ₃ R ₃ , CO ₂ R ₃ , -C(O)R ₃ , -COR ₃ , NRaC(O)R ₃ , NR ₃ C(O)NR ₃ Ra, NR ₃ RaC(O)O-, C(O)NR ₃ R _a , aryl, and heterocycle, which may be optionally substituted with methoxy

or 2-methoxy-ethoxy, wherein each R _a is independently selected from the group consisting of H, alkyl, aryl, and heterocycle;

Ei and Fi are independently selected from CHRi and NRi; each Ri is independently selected from the group consisting of H, benzyl, tert- butyl ester, ethanone, methyl, ethyl, carboxylic acid 2-methoxy-ethyl ester, 3,3- dimethyl-butan- 1 -one, 2,2-dimethyl-propan-l-one, and carboxylic acid methyl ester; R ₅ is selected from the group consisting of -Gi, -G ₁ -G ₂ , -Y-G ₂ , and -Gi-Y-G ₂ ; Gi and G ₂ are independently selected from the group consisting of phenyl, cyclopentyl, cycloheptyl, piperidinyl, cyclohexyl, lH-[l,2,4]triazolyl, isopropyl- [1 ,3,4]thiadiazolyl, benzothiazolyl, 3 -methyl-butyl, which may be optionally substituted with one or more of substituent moieties selected from the group consisting Of -C(O)NH ₂ , phenyl, p-methoxy phenyl, -O(CH ₂ ) ₅ CH ₃ , and carboxylic acid methyl ester;

Y is selected from the group consisting of -O-, -NH-, -CR _y R _y -, -S-, -S(O)-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O- -S(O) ₂ -, -CH(OH)-, -CH(0R _y ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(0R _y )-, -CH(OH)CH ₂ -, - CH(OR _y )CH ₂ -, and any combination thereof, wherein each R _y is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy; Rn is selected from the group consisting of H, alkyl, aryl, and heterocycle; and

R ₇ and Rs are absent or independently selected from the group consisting of H, aryl and, alkyl. In certain embodiments of the invention, R7 is not H, e.g., R ₇ is lower alkyl or halogen. In certain embodiments, Gi is selected from the group consisting of phenyl, cyclopentyl, cycloheptyl, lH-[l,2,4]triazolyl, isopropyl-[l ,3,4]thiadiazolyl, benzothiazolyl, 3-methyl-butyl, which may be optionally substituted with one or more of substituent moieties selected from the group consisting Of-C(O)NH ₂ , phenyl, p- methoxy phenyl, -0(CH ₂ ) _S CH ₃ , CF ₃ , and carboxylic acid methyl ester. In certain embodiments, G ₂ is selected from the group consisting of piperidinyl, cyclohexyl, pyrrolidinyl, piperazinyl, lH-imidazolyl, and phenyl, which may be optionally substituted with one or more of substituent moieties selected from the group consisting of -(CH ₂ ) ₂ -OH.

J. C

A mpound of Formula IX:

wherein

Ri, R ₃ , R ₄ , and R _x are independently selected from the group consisting of H, benzyl, pyridinyl, tetrahydro-pyranyl, methyl- 1 H-imidazolyl, cyclohexylmethyl, phenethyl, p-chlorobenzyl, carboxylic acid benzyl ester, propionic acid tert-butyl ester, tert-butyl ester, ethanone, hydroxy, methoxy, ethoxy, propoxy, butoxy, t- butoxy, phenyl, isobutyl, methyl, ethyl, propyl, butyl, cyclohexyl, cyclohexylmethyl, m-methoxy phenyl, carboxylic acid 2-methoxy-ethyl ester, 3,3-dimethyl-butan-l-one, 2,2-dimethyl-propan-l-one, carboxylic acid methyl ester, alkyl, halogen, NO ₂ , CN, OR _a , NR _a R _a , CO ₂ R ₃ , -C(O)R ₃ , -COR ₃ , NR ₃ C(O)R ₃ , NR _a C(O)NR _a R _a , NR ₃ R ₃ C(O)O-, C(0)NR _a R _a , arylj and heterocycle, which may be optionally substituted with methoxy or 2-methoxy-ethoxy, wherein each R ₃ is independently selected from the group consisting of H, alkyl, aryl, and heterocycle; R ₂ is selected from the group consisting of H, benzyl, tert-butyl ester, ethanone, methyl, ethyl, carboxylic acid 2-methoxy-ethyl ester, 3,3-dimethyl-butan-l- one, 2,2-dimethyl-propan-l-one, and carboxylic acid methyl ester; or R ₂ and R ₇ taken together may form a 5-7 membered heterocyclic ring;

R ₅ is selected from the group consisting of -Gj, -Gj-G ₂ , -Y-G ₂ , and -Gj-Y-G ₂ ; Gj and G ₂ are independently selected from the group consisting of phenyl, cyclopentyl, cycloheptyl, piperidinyl, cyclohexyl, lH-[l ,2,4]triazolyl, isopropyl- [l,3,4]thiadiazolyl, benzothiazolyl, 3-methyl-butyl, which may be optionally substituted with one or more of substituent moieties selected from the group consisting of -C(O)NH ₂ , phenyl, p-methoxy phenyl, -0(CH ₂ ) _S CH ₃ , and carboxylic acid methyl ester;

Y is selected from the group consisting of -O-, -NH-, -CR _y R _y -, -S-, -S(O)-, - C(O)-, -NHC(O) C(O)NH NHC(O)CH CK S(O) CH(OH)-, -CH(OR _x ), - C(O)CH OH)CH ₂ -, -

CH(ORy)CH ₂ -, and any combination thereof, wherein each R _y is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy;

Rn is selected from the group consisting of H, alkyl, aryl, and heterocycle; and R ₇ and R ₈ are absent or independently selected from the group consisting of H, aryl and, alkyl; or R ₂ and R ₇ taken together may form a 5-7 membered heterocyclic ring. In certain embodiments of the invention, R ₇ is not H, e.g., R ₇ is lower alkyl or halogen.

K. Compounds of Formula X

In another embodiment, the invention pertains, at least in part, to a compound of Formula (X)

wherein represents a single or a double bond; n is an integer from 0-3; X is selected from the group consisting OfNR _x CR _x R _x and O; each R _x is independently selected from the group consisting of H, -M), -M]-M ₂ , -Z-M ₂ , and -M)-Z-M ₂ ;

M] and M ₂ are independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, halogen, NO ₂ , CN, OR _W , NR _W R _W , CO ₂ Rw, -C(O)R _w , -COR _W , NR _W C(O)R _W , NR _W C(O)NR _W R _W , NR _W R _W C(O)O, C(O)NR _W R _W , which may be optionally substituted, wherein each R _w is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocy

Z is selected from the group consisting of -O, -NH-, -CR _Z R _Z -, -S-, -S(O)-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ Ov-S(O) ₂ -, -CH(OH)-, -CH(OR ₂ ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(OR _Z )-, -CH(OH)CH ₂ -, - CH(OR _z )CH ₂ -, and any combination thereof, wherein each R _z is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy;

A], Bi, Ci, and Di are independently selected from the group consisting of CH ₂ , CRi, CR ₂ R ₃ , N, and NR ₄ (e.g., wherein one or two of Ai, Bj, Ci, and Di is N or NR ₄ ); E] is N or CR ₇ ; each Ri, R ₂ , R ₃ , and R ₄ are independently selected from the group consisting of H, an aliphatic group (e.g., alkyl, alkenyl, alkynyl etc.), a carbocyclic group (e.g., saturated or unsaturated), a heterocyclic group (e.g., saturated or unsaturated), an acyl group, halogen, NO ₂ , CN, OR ₃ , NR ₃ R ₃ , CO ₂ R ₃ , -C(O)R ₃ , -COR ₃ , NR ₃ C(O)R ₃ , NR ₃ C(O)NR ₃ R ₃ , NR ₃ R ₃ C(O)O-, C(O)NR ₃ R ₃ , which may be optionally substituted, wherein each R ₃ is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group;

R ₅ is selected from the group consisting of -Gi, -Gj-G ₂ , -Y-G ₂ , and -Gj-Y-G ₂ ;

Gi and G ₂ are independently selected from H, an aliphatic group, a carbocyclic group, and a heterocyclic group, which may be optionally substituted with one or more of substituents; and

Y is selected from the group consisting of -O- , -NH-, -CR _y R _r , -S-, -S(O)-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ Ov-S(O) ₂ -, -CH(OH)-, -CH(ORy), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(0R _y )-, -CH(OH)CH ₂ -, - CH(OR _y )CH ₂ -, and any combination thereof, wherein each R _y is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy;

Rn is selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group (e.g., H, phenyl, benzyl, isobutyl, cyclohexyl, cyclohexylmethyl, m-methoxy phenyl, alkyl, aryl, and heterocycle); and

R ₇ and R ₈ are absent or independently selected from the group consisting of H, halogen (e.g., F), OH, an alkoxy group, an aliphatic group, and a carbocyclic group, which m xy). In certain embodim kyl or halogen. In

certain embodiments, R ₄ is not halogen, NO ₂ , CN, NR ₃ R ₃ , NR ₃ C(O)R ₃ , NR ₃ C(O)NR ₃ R ₃ , Or NR ₃ R ₃ C(O)O-.

In certain embodiments of the compounds of Formula X, each R _x is independently selected from the group consisting of H, benzyl, pyridinyl, tetrahydro- pyranyl, methyl- lH-imidazolyl, cyclohexylmethyl, phenethyl, p-chlorobenzyl, carboxylic acid benzyl ester, propionic acid tert-butyl ester, tert-butyl ester, ethanone, hydroxy, methoxy, ethoxy, propoxy, butoxy, t-butoxy, phenyl, isobutyl, methyl, ethyl, propyl, butyl, cyclohexyl, cyclohexylmethyl, m-methoxy phenyl, carboxylic acid 2- methoxy-ethyl ester, 3,3-dimethyl-butan-l-one, 2,2-dimethyl-propan-l-one, carboxylic acid methyl ester, alkyl, halogen, NO ₂ , CN, OR ₃ , NR ₃ R ₃ , CO ₂ R ₃ , -C(O)R ₃ , -COR ₃ , NR ₃ C(O)R ₃ , NR ₃ C(O)NR ₃ R ₃ , NR ₃ R ₃ C(O)O-, C(O)NR ₃ R ₃ , aryl, and heterocycle, which may be optionally substituted with methoxy or 2-methoxy-ethoxy, wherein each R ₈ is independently selected from the group consisting of H, alkyl, aryl, and heterocycle. In particular embodiments, Gi and G ₂ are independently selected from the group consisting of phenyl, cyclohexyl, cyclopentyl, 4-indanyl, pyrimidinyl, N-morpholino, furanyl, thiophenyl, pyrrolyl, N-lH-pyridin-2-onyl, bicyclo[4.2.0]octa-l ,3,5-trien-3-yl, 1-indanyl, naphthalenyl, tetrahydro-naphthalenyl, pyrazine, [l,2,3]thiadiazolyl, 3-isoxazolyl, 5-indolyl, 2,3-dihydro-indol-6-yl, indazol- 5-yl, benzo[2,l,3]thiadiazol-5-yl, cycloheptyl, isopropyl-[l ,3,4]thiadiazolyl, benzothiazolyl, 3 -methyl -butyl, lH-pyrazolyl, oxazolyl, piperidinyl, lH-imidazolyl, pyrrolidinyl, piperazinyl, lH-[l,2,4]triazolyl, and pyridinyl, which may be optionally substituted with one or more of substituent moieties selected from the group consisting of CF ₃ , OCF3, iodo, chloro, bromo, -C(O)NH ₂ , -O(CH ₂ )sCH ₃ , carboxylic acid methyl ester, phenyl, p-methoxy phenyl, -NHC(O)NH ₂ , - C(O)O(CH ₂ ) ₂ N(CH ₂ CH ₃ ) ₂ , t-butyl, fluoro, methoxy, hydroxy, isopropyl, cyano, isopropenyl tetrahydropyran, benzyl, amino, -NHC(O)OC(CH ₃ ) ₃ , -C(O)OH, - C(O)CH ₃ , -CH ₂ CO ₂ H, methyl, and -(CH ₂ ) ₂ -OH. In certain embodiments, one of Ai, B ₁ , Ci, or Di is N, Or NR ₄ . In certain embodiments, two of Ai, Bi, Ci, or Di is N, or NR ₄ . In certain embodiments of the compounds of Formula X, Gi is selected from the group consisting of phenyl, 4-indanyl, pyrimidinyl, cyclohexyl, cyclopentyl, cycloheptyl, isopropyl-[l,3,4]thiadiazolyl, benzothiazolyl, 3 -methyl -butyl, IH- Pyrazoly ptionally substituted with one up consisting Of CF ₃ ,

OCF ₃ , iodo, -C(O)NH ₂ , -O(CH ₂ ) ₅ CH ₃ , carboxylic acid methyl ester, phenyl, p- methoxy phenyl, -NHC(O)NH ₂ , -C(O)O(CH ₂ ) ₂ N(CH ₂ CH ₃ ) ₂ ,t-butyl, methyl-dimethyl- amine, cyano, ethyl, benzyl, methyl, fluoro, chloro, -SCH ₃ , -S(O) ₂ CH ₃ , methoxy, and -(CH ₂ ) ₂ -OH.

In certain embodiments of the compounds of Formula X, , G ₂ is selected from the group consisting of phenyl, N-morpholino, furanyl, thiophenyl, pyrrolyl, N-IH- pyridin-2-onyl, and benzothiazolyl, cyclohexyl, oxazolyl, piperidinyl, lH-pyrazolyl, 1 H-imidazolyl, pyrrolidinyl, and piperazinyl, which may be optionally substituted with one or more of substituent moieties selected from the group consisting of methyl, ethyl, benzyl, cyano, CF ₃ , carboxylic acid methyl ester, methyl-dimethyl-amine, - SCH ₃ , -C(O)NH ₂ , -(CH ₂ ) ₂ -OH, -S(O) ₂ CH ₃ , chloro and bromo.

L. Compounds of Formula XI In an additional embodiment, the invention is a compound of Formula XI:

wherein

: represents a single or a double bond; m and n are independently selected from 0, 1, or 2;

X is selected from the group consisting OfNR _x CR _x R _x and O; each R _x is independently selected from the group consisting of H, -Mi, -Mj-M ₂ , -Z-M ₂ , and -Mj-Z-M ₂ ;

Mi and M ₂ are independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, halogen, NO ₂ , CN, OR _W , NR _W R _W , CO ₂ R _w , -C(O)Rw, -COR _W , NR _W C(O)R _W , NR _W C(O)NR _W R _W , NR _W R _W C(O)O, C(O)NR ch R _w is independently

selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group;

Z is selected from the group consisting of-O-, -NH-, -CR _Z R _Z -, -S-, -S(O)-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O- -S(O) ₂ -, -CH(OH)-, -CH(OR _z ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(OR _Z )-, -CH(OH)CH ₂ -, -

CH(OR ₂ )CH ₂ -, and any combination thereof, wherein each R _z is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy;

R5 is selected from the group consisting of -Gi, -G]-G ₂ , -Y-G ₂ , and -G]-Y-G ₂ ; G] and G ₂ are independently selected from H, an aliphatic group, a carbocyclic group, and a heterocyclic group, which may be optionally substituted with one or more of substituents; and

Y is selected from the group consisting of-O-, -NH-, -CR _y R _y -, -S-, -S(O)-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O- -S(O) ₂ -, -CH(OH)-, -CH(0R _y ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(0R _y )-, -CH(OH)CH ₂ -, -

CH(ORy)CH ₂ -, and any combination thereof, wherein each R _y is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy;

Ru is selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group;

R ₇ and R« are absent or independently selected from the group consisting of H, halogen (e.g., F), OH, an alkoxy group, an aliphatic group, and a carbocyclic group, which may be optionally substituted (e.g., by hydroxy or alkoxy);

E] and F] are independently selected from CHR ₉ and NR ₉ ; and each R ₉ is independently selected from the group consisting of H, alkoxy, hydroxyl, halogen, an aliphatic group, a heterocyclic group, a carbocyclic group, an acyl group, amino, and cyano. In certain embodiments of the invention, R7 is not H, e.g., Rη is lower alkyl or halogen.

In certain embodiments of the compounds of Formula XI, each R _x is independently selected from the group consisting of H, benzyl, pyridinyl, tetrahydro- pyranyl, methyl- lH-imidazolyl, cyclohexylmethyl, phenethyl, p-chlorobenzyl, carboxylic acid benzyl ester, propionic acid tert-butyl ester, tert-butyl ester, ethanone, hydroxy isobutyl, methyl, ethyl, propyl, b yl, carboxylic acid 2-

methoxy-ethyl ester, 3,3-dimethyl-butan-l -one, 2,2-dimethyl-propan-l-one, carboxylic acid methyl ester, alkyl, halogen, NO ₂ , CN, OR _a , NR ₃ R ₃ , CO ₂ R ₃ , -C(O)R ₃ , -COR ₃ , NR ₃ C(O)R ₃ , NR ₃ C(O)NR ₃ R ₃ , NR ₃ R ₃ C(O)O-, C(O)NR ₃ R ₃ , aryl, and heterocycle, which may be optionally substituted with methoxy or 2-methoxy-ethoxy, wherein each R _a is independently selected from the group consisting of H, alkyl, aryl, and heterocycle.

In certain embodiments of the compounds of Formula XI, Gi and G ₂ are independently selected from the group consisting of phenyl, cyclohexyl, IH- pyrazolyl, oxazolyl, piperidinyl, lH-imidazolyl, pyrrolidinyl, piperazinyl, IH- [l,2,4]triazolyl, and pyridinyl, which may be optionally substituted with one or more of substituent moieties selected from the group consisting of CF ₃ , OCF ₃ , 1, phenyl, p- methoxy phenyl, t-butyl, fluoro, methoxy, and -(CH ₂ ) ₂ -OH. In particular embodiments of the compounds of Formula VII, Gj is selected from the group consisting of phenyl, cyclohexyl, lH-pyrazolyl, and lH-[l,2,4]triazolyl, pyridinyl, which may be optionally substituted with one or more of substituent moieties selected from the group consisting OfCF ₃ , OCF ₃ , 1, phenyl, p-methoxy phenyl, t-butyl, fluoro, methoxy, and -(CHi) ₂ -OH. In particular embodiments of the compounds of Formula VII, G ₂ is selected from the group consisting of phenyl, cyclohexyl, oxazolyl, piperidinyl, 1 H-pyrazolyl, lH-imidazolyl, pyrrolidinyl, and piperazinyl.

M. Compounds of Formula XII

Another embodiment of the invention relates to a compound of Formula XII:

wherein n is O or 1 ;

X is selected from the group consisting OfNR _x CR _x R _x and O; each R _x is independently selected from the group consisting of H, -Mi, -M1-M2, -Z-M ₂ , and -MpZ-M ₂ ;

Mi and M ₂ are independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, halogen, NO ₂ , CN, OR _W , NR _W R _W , CO ₂ R _W , -C(O)R _W , -COR _W , NR _W C(O)R _W , NR _W C(O)NR _W R _W , NR _w R _w C(0)0, C(O)NR _W R _W , which may be optionally substituted, wherein each R _w is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group; Z is selected from the group consisting of-O-, -NH-, -CR _Z R _Z -, -S-, -S(O)-, -

C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O-,-S(O) ₂ -, -CH(OH)-, -CH(OR ₂ ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(OR,)-, -CH(OH)CH ₂ -, - CH(ORz)CH ₂ -, and any combination thereof, wherein each R _z is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy;

Ai, Bi, Ci, and Dj are independently selected from the group consisting of CRi and N (e.g., wherein one or two of Ai, Bi, Ci, and Di is N); each Ri is independently selected from the group consisting of H, an aliphatic group (e.g., alkyl, alkenyl, alkynyl etc.), a carbocyclic group (e.g., saturated or unsaturated), a heterocyclic group (e.g., saturated or unsaturated), an acyl group, halogen, NO ₂ , CN, 0R _a , NR ₃ R ₃ , CO ₂ R ₃ , -C(O)R ₃ , -COR ₃ , NR ₃ C(O)R ₃ , NR ₃ C(O)NR ₃ R ₃ , NR ₃ R ₃ C(O)O-, C(O)NR ₃ R ₃ , which may be optionally substituted, wherein each R _a is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group; R ₅ is selected from the group consisting of -Gj, -Gi-G ₂ , -Y-G ₂ , and -Gj-Y-G ₂ ;

Gi and G ₂ are independently selected from H, an aliphatic group, a carbocyclic group, and a heterocyclic group, which may be optionally substituted with one or more of substituents; and

Y is selected from the group consisting of-O-, -NH-, -CR _y R _y -, -S-, -S(O)-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O-,-S(O) ₂ -, -CH(OH)-, -CH(0R _y ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(OR _y )-, -CH(OH)CH ₂ -, - CH(ORy)CH ₂ -, and any combination thereof, wherein each R _y is independently selected carbocyclic group, a heterocy

R^ is selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group; and

Ry and R ₈ are absent or independently selected from the group consisting of H, halogen (e.g., F), OH, an alkoxy group, an aliphatic group, and a carbocyclic group, which may be optionally substituted (e.g., by hydroxy or alkoxy). In certain embodiments, each R ₁ is selected from the group consisting of chloro, bromo, pyrrolidinyl, 4-methylpiperazinyl, piperazinyl

In certain embodiments of Formula XII, where X is NR _x or O and B ₁ and/or C ₁ is/are CRi, Ri is selected from the group consisting of heterocycles and bulky amines (e.g., Ri is not small N, or small N-acyl, NO ₂ ).

In certain embodiments of compounds of Formula XII, each R _x is independently selected from the group consisting of H, benzyl, pyridinyl, tetrahydro- pyranyl, methyl- lH-imidazo IyI, cyclohexylmethyl, phenethyl, p-chlorobenzyl, carboxylic acid benzyl ester, propionic acid tert-butyl ester, tert-butyl ester, ethanone, hydroxy, methoxy, ethoxy, propoxy, butoxy, t-butoxy, phenyl, isobutyl, methyl, ethyl, propyl, butyl, cyclohexyl, cyclohexylmethyl, m-methoxy phenyl, carboxylic acid 2- methoxy-ethyl ester, 3,3-dimethyl-butan-l-one, 2,2-dimethyl-propan-l-one, carboxylic acid methyl ester, alkyl, halogen, NO ₂ , CN, OR ₃ , NR ₂ R ₃ , CO ₂ R ₃ , -C(O)R ₃ , -COR ₃ , NR ₃ C(O)R ₃ , NR ₃ C(O)NR ₃ R ₃ , NR ₃ R ₃ C(O)O-, C(O)NR ₃ R ₃ , aryl, and heterocycle, which may be optionally substituted with methoxy or 2-methoxy-ethoxy, wherein each R ₃ is independently selected from the group consisting of H, alkyl, aryl, and heterocycle;

In certain embodiments of compounds of Formula XII, Gi and G ₂ are independently selected from the group consisting of phenyl, cyclohexyl, IH- [l,2,4]triazolyl, pyridinyl, piperidinyl, oxazolyl, which may be optionally substituted with one or more of substituent moieties selected from the group consisting of methoxy, phenyl, p-methoxy phenyl, chloro, bromo, CF ₃ , OCF ₃ , -O(CH ₂ )sCH ₃ , - NHC(O)NH ₂ , -C(O)NH ₂ , and -C(O)O(CH ₂ ) ₂ N(CH ₂ CH ₃ ) ₂ . In particular embodiment embodiments, G] is selected from the group consisting of phenyl, cyclohexyl, IH- [l,2,4]triazolyl, pyridinyl, which may be optionally substituted with one or more of substituent moieties selected from the group consisting of methoxy, phenyl, p- methoxy phenyl, CF ₃ , OCF ₃ , -O(CH ₂ ) ₅ CH ₃ , -NHC(O)NH ₂ , -C(O)NH ₂ , and - C(O)O(C selected from the group consistin may be optionally

substituted with one or more of substituent moieties selected from the group consisting of chloro, and bromo.

N. Compounds of Formula XIII and XIV

Another embodiment of the invention pertains to a compound of Formula

XIII:

wherein

Ri, R ₃ , R ₄ , and R _x are independently selected from the group consisting of H, benzyl, pyridinyl, tetrahydro-pyranyl, methyl- lH-imidazolyl, cyclohexylmethyl, phenethyl, p-chlorobenzyl, carboxylic acid benzyl ester, propionic acid tert-butyl ester, tert-butyl ester, ethanone, hydroxy, methoxy, ethoxy, propoxy, butoxy, t- butoxy, phenyl, isobutyl, methyl, ethyl, propyl, butyl, cyclohexyl, cyclohexylmethyl, m-methoxy phenyl, carboxylic acid 2-methoxy-ethyl ester, 3,3-dimethyl-butan-l-one, 2,2-dimethyl-propan-l-one, carboxylic acid methyl ester, alkyl, halogen, NO ₂ , CN, OR ₃ , NR _a R _a , CO ₂ R ₃ , -C(O)R ₃ , -COR _a , NR ₃ C(O)R ₃ , NR ₃ C(O)NR ₃ R ₃ , NR ₃ R ₃ C(O)O-, C(O)NR ₃ R ₃ , aryl, and heterocycle, which may be optionally substituted with methoxy or 2-methoxy-ethoxy, wherein each R _a is independently selected from the group consisting of H, alkyl, aryl, and heterocycle;

R ₂ is selected from the group consisting of H, benzyl, tert-butyl ester, ethanone, methyl, ethyl, carboxylic acid 2-methoxy-ethyl ester, 3,3-dimethyl-butan-l- one, 2,2-dimethyl-propan-l-one, and carboxylic acid methyl ester; or R ₂ and R ₇ taken together may form a 5-7 membered heterocyclic ring;

R i l t d f th i ti f G G G ₂ , -Y-G ₂ , and -Gi-Y-G ₂ ;

Gi and G ₂ are independently selected from the group consisting of phenyl, cyclopentyl, cycloheptyl, piperidinyl, cyclohexyl, lH-[l,2,4]triazolyl, isopropyl- [l,3,4]thiadiazolyl, benzothiazolyl, 3 -methyl-butyl, which may be optionally substituted with one or more of substituent moieties selected from the group consisting Of -C(O)NH ₂ , phenyl, p-methoxy phenyl, -O(CH ₂ ) ₅ CH ₃ , and carboxylic acid methyl ester;

Y is selected from the group consisting of-O-, -NH-, -CR _y R _y -, -S-, -S(O)-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ CK-S(O) ₂ -, -CH(OH)-, -CH(OR _y ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(OR _y )-, -CH(OH)CH ₂ -, - CH(ORy)CH ₂ -, and any combination thereof, wherein each R _y is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy;

Re is selected from the group consisting of H, alkyl, aryl, and heterocycle; and

R ₇ and Rg are absent or independently selected from the group consisting of H, aryl and, alkyl; or R ₂ and R ₇ taken together may form a 5-7 membered heterocyclic ring. In certain embodiments of the invention, R ₇ is not H, e.g., Kη is lower alkyl or halogen.

Another embodiment of the invention pertains to a compound of Formula XIV:

wherein

Ri, R ₂ , R ₄ , and R _x are independently selected from the group consisting of H, benzyl, pyridinyl, tetrahydro-pyranyl, methyl- lH-imidazolyl, cyclohexylmethyl, phenethyl, p-chlorobenzyl, carboxylic acid benzyl ester, propionic acid tert-butyl ester, ter opoxy, butoxy, t-

butoxy, phenyl, isobutyl, methyl, ethyl, propyl, butyl, cyclohexyl, cyclohexylmethyl, m-methoxy phenyl, carboxylic acid 2-methoxy-ethyl ester, 3,3-dimethyl-butan-l-one, 2,2-dimethyl-propan-l-one, carboxylic acid methyl ester, alkyl, halogen, NO ₂ , CN, OR ₃ , NR ₃ R ₃ , CO ₂ R ₃ , -C(O)R ₃ , -COR ₃ , NR ₃ C(O)R ₃ , NR ₃ C(O)NR ₃ R ₃ , NR ₃ R ₃ C(O)O-, C(0)NR _a R _a , aryl, and heterocycle, which may be optionally substituted with methoxy or 2-methoxy-ethoxy, wherein each R ₃ is independently selected from the group consisting of H, alkyl, aryl, and heterocycle;

R ₃ is selected from the group consisting of H, benzyl, tert-butyl ester, ethanone, methyl, ethyl, carboxylic acid 2-methoxy-ethyl ester, 3,3-dimethyl-butan-l- one, 2,2-dimethyl-propan-l-one, and carboxylic acid methyl ester; or R ₃ and R7 taken together may form a 5-7 membered heterocyclic ring;

R ₅ is selected from the group consisting of -Gi, -G]-G ₂ , -Y-G ₂ , and -G]-Y-G ₂ ; G] and G ₂ are independently selected from the group consisting of phenyl, cyclopentyl, cycloheptyl, piperidinyl, cyclohexyl, lH-[l,2,4]triazolyl, isopropyl- [1 ,3,4]thiadiazolyl, benzothiazolyl, 3 -methyl -butyl, which may be optionally substituted with one or more of substituent moieties selected from the group consisting Of -C(O)NH ₂ , phenyl, p-methoxy phenyl, -0(CH ₂ ) _S CH ₃ , and carboxylic acid methyl ester;

Y is selected from the group consisting of-0-, -NH-, -CR _y R _y -, -S-, -S(O)-, - C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O-,-S(O) ₂ -, -CH(OH)-, -CH(0R _y ), - C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, -CH ₂ CH(0R _y )-, -CH(OH)CH ₂ -, - CH(0R _y )CH ₂ -, and any combination thereof, wherein each R _y is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, hydroxy, and alkoxy; R^ is selected from the group consisting of H, alkyl, aryl, and heterocycle; and

R ₇ and Rs are absent or independently selected from the group consisting of H, aryl and, alkyl; or R ₃ and R ₇ taken together may form a 5-7 membered heterocyclic ring. In certain embodiments of the invention, R ₇ is not H, e.g., R ₇ is lower alkyl or halogen.

O. Compounds of Formula XV

I re directed to compou

wherein

represents a single or a double bond, with the provision that R ₃ and R ₄ are absent if is a double bond.

X is selected from the group consisting of NR _x CR _z R _z and O;

R _x is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group; each R _z is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, NO ₂ , CN, OR _W , NR _W R _W , CO ₂ R _W , - C(O)Rw, NR _W C(O)R _W , NRwC(O)NRwRw, and C(O)NR _W R _W , which may be optionally substituted, wherein each R _w is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group;

is a annelated 5-, 6- or 7- membered unsubstituted or substituted carbocyclic or heterocyclic saturated or partly saturated ring system, with the provision that the ring system is not a 6-membered carbocyclic ring system when is a double bond

R3 and R4 are absent or independently selected from the group consisting of H, F, OH, an alkyl group, a carbocyclic group, and an alkoxy group which may be optionally substituted;

R5 is selected from the group consisting of -Gi, -Gi-G ₂ , -Y-G ₂ , and -Gi-Y-G ₂ ;

Gi and G ₂ are independently selected from H, an aliphatic group, a carbocyclic group, and a heterocyclic group, which may be optionally substituted with one or more of substituents;

Y is selected from the group consisting of -O-, -NH-, -CR _y R _y -, -S-, -S(O), C(O)-, -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O- -S(O) ₂ -, -CH(0R _y ), -C(O)CH ₂ -, - CH ₂ C(O)-, - -CH ₂ CH(ORy)-, - CH(ORy)CH ₂ -, and any combination thereof, wherein each Ry is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group or a heterocyclic group; and

R^ is selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group.

In certain embodiments of the compounds of Formula XV

is selected from the following group of substituted ring systems:

wherein represents a single or a double bond; positioned perpendicular to a bond indicates a point of connection to the remainder of Formula XV;

W, Z are selected independently from the group consisting of CRbRb, NR ₀ or O, with the provision that W and Z are not CR _b R _b in the case of the 6-membered ring systems if is a double bond in Formula XV;

R _b is independently selected from the group consisting of hydrogen, halogen, -CN, -NO ₂ , an aliphatic group, a carbocyclic group, a heterocyclic group, OR _W ,

NR _W R _W , CO ₂ R _W , -C(O)R _W , NR _W C(O)R _W , NR _W C(O)NR _W R _W , C(O)NR _W R _W , which may be optionally substituted, wherein each R _w is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group; or the two R _b moieties taken together with the atom to which they are attached may form a 3 to 10 membered carbocyclic, heteroaryl or heterocyclic ring;

R _c is selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, a arylalkyl group, a heteroarylalkyl group, -C(O)OR ₃ , C(O)R ₃ , C(O)NR ₃ R ₃ , and -SO ₂ R ₃ ;

Rl and R2 are independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, an acyl group, oxo, halogen, -NO ₂ , trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,-CN, -OH, -OR ₃ , NH ₂ , -NR _a R _a , -C(O)R ₃ , -NR ₃ C(O)R ₃ , -NR ₃ C(O)NR ₃ R ₃ , -C(O)NR ₃ R ₃ , NR ₃ SO ₂ R ₃ , -SO ₂ NR ₃ R ₃ , -C(O)OR ₃ , - OC(O) R ₃ , - NR ₃ C(O)OR ₃ , C(O)NR ₃ R ₃ , -SO ₂ R ₃ which may be optionally substituted; or Rl and R2taken together, may form a substituted or unsubstituted saturated or unsaturated heterocyclic or carbocyclic 3-8 membered ring; and each R _a is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group; or in the case where two R ₃ are attached to a single atom, the two R _a together with the atom to which they are attached may form a 3 to 10 member carbocyclic, heteroaryl or heterocyclic ring, each of which is optionally substituted with one to three groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifloromethyoxy, - NR ⁵ SO ₂ R", -S0 ₂ NR'R", - C(O)R', -C(O)OR', - OC(O)R', - NR ³ C(O)OR", - NR ³ C(O)R", C(O)NR ³ R", -SO ₂ R ³ , NR ³ R", -NR ³ C(O)NR ³³ R ³ ", -OR ³ , aryl, heteroaryl, and arylalkyl, wherein R", R" and R ³ " independently are selected from the group consisting of hydrogen, alkyl, alkenyl, and aryl.

In certain embodiments of the compounds of Formula XV:

is selected from the following group of ring systems:

and R^ is selected from the group consisting of H and an aliphatic group (the remainder the substituents are defined as above).

In certain embodiments of the compounds of Formula XV:

is selected from the following group of ring systems:

R1

R2^

W '

and X is selected from the group consisting OfNR _x and O; and

R _x is selected from the group consisting of H, an aliphatic group, a carbocyclic group and a heterocyclic group; and

R^ is selected from the group consisting of H or an aliphatic group (the remainder the substituents are defined as above). In certain embodiments of the compounds of Formula XV :

is selected from the following group of ring systems:

R1 RcN ^J>C ^ ^R1 _r c-

RcN^

^R1 o ^R1 *^

RON 1

with the provision that in Formula XV is a single bond if the ring system is a 6-membered carbocyclic ring system;

Rl is selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, an acyl group, oxo, halogen, -NO ₂ , trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,-CN, -OH, -OR ₃ , NH ₂ , - NR ₃ Ra, -C(O)R ₃ , -NR ₃ C(O)R ₃ , -NR ₃ C(O)NR ₃ R ₃ , -C(O)NR ₃ R ₃ , NR ₃ SO ₂ R ₃ , - SO ₂ NR ₃ R ₃ , -C(O)OR ₃ , - OC(O) R ₃ , - NR ₃ C(O)OR ₃ , C(O)NR ₃ R ₃ , and -SO ₂ R ₃ which may be optionally substituted; X is selected from the group consisting OfNR _x and O;

R _x is selected from the group consisting of H, an aliphatic group, a carbocyclic group and a heterocyclic group; and

R ₆ is selected from the group consisting of H and an aliphatic group (the remainder the substituents are defined as above). In certain embodiments of the compounds of Formula XV:

s selected from the following group of ring systems:

in Formula XV is a single bond

Rl i l t d f th i ti f H li hatic group, a carbocyc alogen, -NO ₂ ,

trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,-CN, -OH, -OR _a , NH ₂ , - NR ₃ Ra, -C(O)R ₃ , -NR ₃ C(O)R ₃ , -NR ₃ C(O)NRaR ₃ , -C(0)NR _a R _a , NR ₃ SO ₂ R ₃ , - SO ₂ NR ₃ R ₃ , -C(O)OR ₃ , - OC(O) R ₃ , - NR ₃ C(O)OR ₃ , C(O)NR ₃ R ₃ , and -SO ₂ R ₃ which may be optionally substituted; X is NH; and

Re is selected from H or an aliphatic group (the remainder the substituents are defined as above).

In certain embodiments of the compounds of Formula XV:

is selected from the following group of ring systems:

R1 _R1

RcN^- ^R |<\

L /- RcN . / ^^ ^ in Formula XV is a single bond;

Rl is selected from the group consisting of H, an aliphatic group, a carbocyclic group, a heterocyclic group, an acyl group, oxo, halogen, -NO ₂ , trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido,-CN, -OH, -OR ₃ , NH ₂ , - NR ₈ R ₃ , -C(O)R ₃ , -NR ₃ C(O)R ₃ , -NR ₃ C(O)NR ₃ R ₃ , -C(O)NR ₃ R ₃ , NR ₃ SO ₂ R ₃ , -

SO ₂ NR ₃ R ₃ , -C(O)OR ₃ , - OC(O) R ₃ , - NR ₃ C(O)OR ₃ , C(O)NR ₃ R ₃ , and -SO ₂ R ₃ which may be optionally substituted;

X is NH;

R ₃ , R ₄ are independently selected from the group consisting of H and an alkyl group;

Y is selected from the group consisting of-0-, -NH-, -CH2-, -S-, -S(O), C(O)- , -NHC(O)-, -C(O)NH-, -NHC(O)CH ₂ O- -S(O) ₂ -, -CH(OH)-, -C(O)CH ₂ -, -CH ₂ C(O)-, -CH ₂ CH(OH)-, and -CH(OH)CH ₂ -; and

R^ is H (the remainder the substituents are defined as above). In certain embodiments of the compounds of Formula XV:

is selected from the following group of ring systems:

RcN " ^"" ^

RcN

R _a is independently selected from the group consisting of H, an aliphatic group, a carbocyclic group, and a heterocyclic group; or in the case where two R ₃ are attached to a single atom, the two R ₃ together with the atom to which they are attached may form a 3 to 10 member carbocyclic or heterocyclic ring; X is NH;

R ₃ is selected from the group consisting of H and an alkyl group;

R ₄ Is H;

Y is selected from the group consisting of -O, -NH-, -CH2-, and C(O)-; and

Rn is H (the remainder the substituents are defined as above). In certain embodiments of the compounds of Formula XI, G] is a mono or bicyclic aromatic or heteroaromatic group which may be optionally substituted with one or more substituents from the group consisting of H, an aliphatic group, halogen, -NO ₂ , trifluoromethyl, difluoromethyoxy, trifluoromethyoxy, azido, -CN, -OR ₃ , -SR _a -

NRaR ₃ , -CO ₂ R ₃ , -C(O)R ₃ , -NR ₃ C(O)Ra, -NRaC(O)NR ₃ Ra, -C(O)NR ₃ Ra, NR ₃ SO ₂ Ra, - SO ₂ NR _a R ₃ , -C(O)OR _a , - OC(O) R ₃ , - NR ₃ C(O)OR ₃ , C(O)NR ₃ R ₃ , -SO ₂ R ₃ , -(CH ₂ ) ₂ -OR ₃ and -CH ₂ NR ₃ R ₃ , wherein each R _a is selected from H, aliphatic, carbocyclic, heterocyclic and heteroaromatic groups.

In certain embodiments of the compounds of Formula XV, Gi is a mono or bicyclic aromatic or heteroaromatic group which may be optionally substituted with one or more substituents from the group consisting of H, an aliphatic group, halogen, -NO ₂ , trifluoromethyl, difluoromethyoxy, trifluoromethyoxy, azido, -CN, -OR ₃ , -SR ₃ - NR ₃ R ₃ , -CO ₂ R ₃ , -C(O)R ₃ , -NR ₃ C(O)R ₃ , -NR ₃ C(O)NR ₃ R ₃ , -C(O)NR ₃ R ₃ , NR ₃ SO ₂ R ₃ , - SO ₂ NR ₈ R ₃ , -C(O)OR ₃ , - OC(O) R ₃ , - NR ₃ C(O)OR ₃ , C(O)NR ₃ R ₃ , -SO ₂ R ₃ , -(CH ₂ ) ₂ -OR ₃ and -CH ₂ NR ₃ Ra; and G ₂ is selected from the group consisting of an aliphatic group, a carbocyclic group, and a heterocyclic group which is optionally substituted with one or more substituents from the group consisting of H, an aliphatic group, halogen, - NO ₂ , trifluoromethyl, difluoromethyoxy, trifluoromethyoxy, azido, -CN, -OR ₃ , -SR ₃ - NR ₃ R ₃ , -CO ₂ R ₃ , -C(O)R ₃ , -NR ₃ C(O)R ₃ , -NR ₃ C(O)NR ₃ R ₃ , -C(O)NR ₃ R ₃ , NR ₃ SO ₂ R ₃ , - SO ₂ NR ₃ R ₃ , -C(O)OR ₃ , - OC(O) R ₃ , - NR ₃ C(O)OR ₈ , C(O)NR ₃ R ₃ , -SO ₂ R ₃ , -(CH ₂ ) ₂ -OR ₃ and — CH ₂ NR _a R _a , wherein each R _a is selected from H, aliphatic, carbocyclic, heterocyclic and heteroaromatic groups.

In certain embodiments of the invention, compounds or substituents that are not mod hich would otherwise be understo t included within the

genus structures of the invention, i.e., Formulae I-XV. In one particular embodiment, such substituents may include substituents, or R groups, that are attached to the alpha carbon in the ring of the genus structures (alpha to the heteroatom, X, in the ring), where X is NR _x ; wherein such substituents include the following general types of substituents: halogen, NO ₂ , CN, NRR (e.g. , NR _a R _a ), NRC(O)R, NRC(O)NRR, and NRRC(O)O-. In another particular embodiment, such substituents may include substituents, or R groups, bonded to the nitrogen atoms of NR type moieties of the formulae described herein (e.g. , present in the genus structure as an NR type substituent or present in a markush group or markush group series that combine to result in an NR type substituent, e.g., R _x OfNR _x may be defined as -Mi-M ₂ , which in turn may be defined as a substituent that may be otherwise understood as unstable by the ordinarily skilled artisan); wherein such substituents include the following general types of substituents: halogen, NO ₂ , CN, NRR (e.g., NR _a R _a ), NRC(O)R, NRC(O)NRR, and NRRC(O)O-. For clarity, these embodiments comprise compounds of Formulae I-XV where the substituents listed above for the R groups, or those that would combine to from the R groups, are removed from the definitions/substituents indicated for the respective formulae (and where all other substituents/definitions are identical).

Moreover, it should be understood that the compounds of the present invention, comprise compounds that satisfy valency requirements known to the ordinarily skilled artisan. Additionally, compounds of the present invention comprise stable compounds as well as those compounds that may be modified, e.g., chemically or through appropriate formulation, to become stable. In certain embodiments, such stability is guided by time periods that are sufficient to allow administration to and/or treatment of a subject.

Particular compounds of the invention include, but are not limited to, those set forth below in Tables 1 and 2 and salts thereof. Moreover, it should be understood that each of the compounds listed in Tables 1 are separate embodiments of the invention, and are presented in tabular form only as a convenience, i.e., compounds 1- 229 should be considered as separately listed and each compound could be the subject of a separate claim in this invention.

In addition, specific compounds of the invention further include derivatives of the comp chemical or physical property modification comprises

substitution of a carbon atom with a heteroatom or addition of a heteroatom- containing substituent (e.g., substituted by a substituent selected from the group consisting of hydroxy, alkoxy, heterocycle and an acyl group), such that one or more of the chemical or physical properties of the depicted compound have been enhanced, e.g., with respect to potency or selectivity. In certain embodiments, the modification is made to adjust one or more of the following attributes: acidity, lypohilicity, solubility. Moreover, such adjustment may result from the substitution itself, i.e., a direct effect, or the adjustment may indirectly result from the affect on the compound as a whole, e.g. , by conformation changes.

Table 1

In another embodiment, the invention includes any novel compound or pharmaceutical compositions containing compounds of the invention described herein. For example, compounds and pharmaceutical compositions containing compounds set forth herein (e.g., Tables 1 and 2) are part of this invention, including salts thereof, e.g., a pharmaceutically acceptable salt.

In particular embodiments, the compounds in Tables 1 and 2 can be administered using all of the methods described herein, such as combining the compound with a carrier material suitable for oral, nasal, topical, transdermal, buccal, sublingual, rectal, vaginal and/or parenteral administration. For example, formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets and lozenges.

The invention also relates to salts of the compounds of the invention and, in particular, to pharmaceutically acceptable salts. A "pharmaceutically acceptable salt" includes parent compound and

does not impart any undesired toxicological effects. The salts can be, for example, salts with a suitable acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and the like; acetic acid, oxalic acid, tartaric acid, succinic acid, malic acid, benzoic acid, pamoic acid, alginic acid, methanesulfonic acid, naphthalenesulfonic acid, and the like. Also included are salts of cations such as ammonium, sodium, potassium, lithium, zinc, copper, barium, bismuth, calcium, and the like; or organic cations such as tetralkylammonium and trialkylammonium cations. Combinations of the above salts are also useful. Salts of other acids and/or cations are also included, such as salts with trifluoroacetic acid, chloroacetic acid, and trichloroacetic acid.

It will be noted that the structure of some of the compounds of this invention includes asymmetric carbon atoms. It is to be understood accordingly that the isomers arising from such asymmetry (e.g., all enantiomers and diastereomers) are included within the scope of this invention unless indicated otherwise. Such isomers can be obtained in substantially pure form by classical separation techniques and by stereochemically controlled synthesis. That is, unless otherwise stipulated, any chiral carbon center may be of either (R)- or (S^-stereochemistry. Furthermore, alkenes can include either the E- or Z-geometry, where appropriate. Additionally, one skilled in the art will appreciate that the chemical structures as drawn may represent a number of possible tautomers, and the present invention also includes those tautomers.

Accordingly, another embodiment of the invention is a substantially pure single stereoisomer or mixtures of stereoisomers, e.g., pre-determined to be within specific amounts.

It will further be noted that, depending upon, e.g., the methods for isolating and purifying the compounds of the present invention, there may exist a number of polymorphs of each individual compound. As used herein, the term "polymorph" refers to a solid crystalline phase of a compound of the invention, resulting from the possibility of at least two different arrangements of the molecules of the compound in the solid state. Crystalline forms of a particular compound of the invention, e.g. , a compound of Table 1 , are of particular importance because they may be formulated in various oral unit dosage forms as for example as tablets or capsules for the treatment of bacterial disease in patients. Variations in crystal structure of a pharmac nufacturability and stability id oral dosage form

formulation. Therefore it may be preferred to produce a compound of the invention in a pure form consisting of a single, thermodynamically stable crystal structure. It has been determined, for example, that the crystal structure of known compounds produced in accordance with commonly utilized synthesis may not be the most thermodynamically stable polymorphic form. Furthermore, it has been demonstrated that a polymorphic form may undergo conversion to a different polymorphic form when subjected to conventional manufacturing processes, such as grinding and milling. As such, certain polymorphic forms, which may not be the most thermodynamically stable form of the compound, could undergo polymorph conversion over time.

Polymorphs of a given compound will be different in crystal structure but identical in liquid or vapor states. Moreover, solubility, melting point, density, hardness, crystal shape, optical and electrical properties, vapor pressure, stability, etc., may all vary with the polymorphic form. Remington's Pharmaceutical Sciences, 18th Edition, Mack Publishing Co. (1990), Chapter 75, pages 1439-1443. Such polymorphs are also meant to be included in the scope of this invention. Varying polymorphs may be created, for example, by applying kinetic energy, e.g., by grinding, milling, or stirring, preferably at low temperature or by applying heat and subsequently cooling in a controlled manner. The compounds of the present invention may exist as a single polymorphic form or as a mixture of multiple polymorphic forms.

Furthermore, the compounds of the present invention may be suitable for silicon switching as described, e.g., in Drug Discovery Today 8(12): 551-6 (2003) "Chemistry challenges in lead optimization: silicon isoteres in drug discovery." Briefly, it has recently been discovered that certain carbon atoms in organic compounds, such as the compounds of the present invention, may be replaced by silicon atoms without noticeable loss in activity. Accordingly, in one embodiment, the present invention is directed to a compound of the invention as described herein, e.g., Table 1 , wherein one or more of the carbons in the molecule has been replaced by a silicon. The skilled artisan can readily determine which compounds are eligible for silicon switching, which carbons of such compounds may be replaced, and how to effect the switch using no more than routine experimentation found, e.g., in Drug Discover n lead optimization: silicon is

In certain embodiments, the compounds of the present invention are characterized by a unique structure which imparts surprisingly improved properties to these compounds as compared to the prior art compounds, e.g., for use in inhibiting UPPS or treating bacterial disease. Specifically, the compounds of the present invention are characterized by the presence of a hydroxydicarbonyl moiety. This moiety, in combination with a functionalizing moiety and tail moiety, e.g., R-Q-T, within the core of the structure, enhances the selectivity of the compounds described herein for UPP synthase versus other synthases, such as FPPS. In fact, many of the compounds of the present invention are further characterized by their potent and/or selective binding to UPP S .

Methods of Using the Compounds of the Invention

The compounds of the invention have been determined to useful at least in the treatment of bacterial disease, e.g., bacterial infection. Accordingly, in one embodiment, the invention relates to a method for treating bacterial disease comprising administering to a subject a compound of the invention, e.g., a compound of Formula

R-Q-T wherein R is a functionalizing moiety; Q is a hydroxydicarbonyl moiety, e.g., a bicyclic hydroxydicarbonyl moiety; and T is a tail moiety, such that a bacterial disease is treated in the subject.

The language "bacterial disease" describes disease states that are the result of the actions of one or more bacterium. For example, bacterial disease includes, but is not limited to bacterial infection or the symptomology and disease state in a subject associated with a bacterium, e.g., the actions of a bacterium. In certain embodiments, the symptomology and disease state associated with the bacterium is selected from the group consisting of inflammation, fever, and bacterial infection related pain. In certain embodiments, the bacterial disease is a bacterial infection, e.g., an acute bacterial infection or a chronic bacterial infection.

The language "bacterial infection" is art-recognized, and describes disease states resulting from the infection or attack of a host or subject by one or more bacterium ociated with, for example m, e.g., .hospital gram

positive infection; a bacterium selected from the group consisting of S. aureus, Group

A Streptococcus, E.faecalis, and Coagulase-negative Staphylococcus; with E. coli.,

S. aureus, E.faecalis, or S. pneumoniae.

In certain embodiments, the bacterial infection is an outpatient skin infection or a skin structure infection, e.g. , wherein the bacterial infection is associated with a bacterium selected from the group consisting of S. aureus and Group A

Streptococcus.

In certain embodiments, the bacterial infection is community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA), e.g., wherein the bacterial infection is associated with methicillin-resistant Staphylococcus aureus (MRSA). In yet other embodiments, the bacterial infection is an antibiotic-associated colitis infection, e.g., wherein the bacterial infection is associated with C. difficile. In still yet another embodiment, the bacterial infection is nosocomial pneumonia, e.g., wherein the bacterial infection is associated with S.aureus or wherein the bacterial infection is associated with gram negative bacterium, e.g., P. aeruginosa, Klebsiella,

Enterobacter, E. coli, or Acinetobacter.

In particular embodiments, the bacterial infection is selected from the group consisting of Actinomycosis; Anthrax; Aspergillosis; Bacteremia; Bacterial Infections and Mycoses; Bacterial Meningitis; Bartonella Infections; Botulism; Brucellosis; Bubonic plague; Burkholderia Infections; Campylobacter Infections; Candidiasis;

Cat-Scratch Disease; Chlamydia Infections; Cholera; Clostridium Infections;

Coccidioidomycosis; Cross Infection; Cryptococcosis; Dermatomy coses; Diphtheria;

Ehrlichiosis; Epidemic Typhus; Escherichia coli Infections; Fasciitis, Necrotizing;

Fuso bacterium Infections; Gas Gangrene; Gonorrhea; Gram-Negative Bacterial Infections; Gram-Positive Bacterial Infections; Hansen's Disease; Histoplasmosis;

Impetigo; Klebsiella Infections; Legionellosis; Leprosy; Leptospirosis; Listeria

Infections; Lyme Disease; Maduromycosis; Melioidosis; MRSA infection;

Mycobacterium Infections; Mycoplasma Infections; Nocardia Infections;

Onychomycosis; Pertussis; Plague; Pneumococcal Infections; Pseudomonas Infections; Psittacosis; Q Fever; Rat-Bite Fever; Relapsing Fever; Rheumatic Fever;

Rickettsia Infections; Rocky Mountain Spotted Fever; Salmonella Infections; Scarlet

Fever; Scrub Typhus; Sepsis; Sexually Transmitted Diseases, Bacterial; Shigellosis;

Shock, S ions; Streptococcal

Infection Tuberculosis;

Tularemia; Typhoid Fever; Typhus, Epidemic Louse-Borne; Whooping Cough; Vibrio Infections; Yaws; Yersinia Infections; Zoonoses; and Zygomycosis.

In another embodiment, the bacterial infection is a respiratory tract infection, e.g., wherein the bacterial infection is associated with S. pneumonia, H. influenza, Moraxella, L. pneumonia, Chlamydia, or mycoplasma.

In yet another embodiment, the bacterial infection is a sexually transmitted disease, e.g., wherein the bacterial infection is Chlamydia trachomatis or Neisseria gonorrheae.

In certain embodiments, the compounds of the invention are useful in treating bacterial infection wherein said bacterial infection is resistant to other antibiotics.

The term "subject," includes living organisms in which a bacterial disease can occur, or which are susceptible bacterial disease. Examples include animals such as mammals, including, but not limited to, primates {e.g., humans), cows, sheep, goats, horses, pigs, dogs, cats, rabbits, guinea pigs, rats, mice or other bovine, ovine, equine, canine, feline, rodent, murine species, or transgenic species thereof. In particular embodiments, the subject is human, e.g., the compound of the invention is preselected for its use in treating bacterial disease in humans.

In certain embodiments of the invention, the subject is in need of treatment by the methods of the invention, e.g., by a UPPS inhibitor selected for its UPPS inhibition, and is selected for treatment based on this need. A subject in need of treatment is art-recognized, and includes subjects that have been identified as having a disease or disorder associated with UPPS or having a bacterial disease, having a symptom of such a disease or disorder, or at risk of such a disease or disorder, and would be expected, based on diagnosis, e.g. , medical diagnosis, to benefit from treatment {e.g., curing, healing, preventing, alleviating, relieving, altering, remedying, ameliorating, improving, or affecting the disease or disorder, the symptom of the disease or disorder, or the risk of the disease or disorder). For example, the subject may be a "bacterium compromised subject," wherein such subject is identified as being infected by at least one bacterium. In particular embodiment, the subject is in need of treatment by the compounds of the invention, and is selected for treatment based on this need. In another particular embodiment, the subject is in need of treatment by the compounds of the inv selected for treatment based on

As used herein, the term "administering" to a subject includes dispensing, delivering or applying a compound of the invention in a pharmaceutical formulation (as described herein), to a subject by any suitable route for delivery of the compound to the desired location in the subject, including delivery by either the parenteral or oral route, intramuscular injection, subcutaneous/intradermal injection, intravenous injection, buccal administration, topical delivery, transdermal delivery and administration by the rectal, colonic, vaginal, intranasal or respiratory tract route. In certain embodiments, the route for delivery of the compound is oral.

In certain embodiments, the compound of any of the formulae described herein, e g., R-Q-T (and particular embodiments thereof, e g , Table 1 ) is an inhibitor of UPPS.

The terms "inhibitor" or "UPPS inhibitor," as used herein, include compounds, e g , compounds described herein, which bind to and/or inhibit the UPPS enzyme. In certain embodiments of the invention, the inhibitors described herein are activity enhanced with respect to known compounds which interact with UPPS. The language "activity enhanced" describes inhibitors of the invention that are at least one of either potent or selective. In particular embodiments, the compounds of the invention are pre-selected for their UPPS inhibition

In one embodiment, the compound of the invention is "potent," or possesses enhanced potency, against UPPS. A compound is "potent" against UPP synthase if the IC ₅₀ value for binding to UPPS is less than or equal to about 2.0 μM, e g , less than or equal to about 1 0 μM, e g , less than or equal to about 0.5 μM, e.g , less than or equal to about 0 1 μM, e g , less than or equal to about 0.05 μM, e g , less than or equal to about O.OlμM, e g , less than or equal to about 0.005 μM It should be understood that embodiments of the invention include compounds that fall within Formulae I-XV, having IC50 value for binding to UPPS, for example, of less than or equal to about 2.0 μM, e g , less than or equal to about 1.0 μM, e g , less than or equal to about 0.5 μM, e g , less than or equal to about 0.1 μM, e g , less than or equal to about 0.05 μM, e g , less than or equal to about O.OlμM, e g , less than or equal to about 0.005 μM. Furthermore, it should be understood that all values and ranges encompassed by these ranges, are meant to be encompassed within the scope of the present invention. Moreover, all values that fall within these ranges, as well as the upper or ed by the present

application. For example, the range "less than or equal to about 1.0 μM" includes values such as, 0.75 μM, 0.69 μM, and 0.50-0.35 μM.

In another embodiments, the compound of the invention is "selective," or possesses enhanced selectivity, for UPPS. For example, the present invention includes compounds that are selective, or possess enhanced selectivity, for UPPS relative to FPPS. A compound is "selective" for the UPP synthase relative to a second synthase, if the IC ₅₀ of the compound for the second enzyme is at least 50- fold, e.g., at least 100-fold, e.g., at least 1 , 000-fold, e.g., at least 10,000-fold greater than the IC ₅₀ for UPPS. Moreover, the IC ₅₀ of a compound is determined as described in Example 15. It should be understood that embodiments of the invention include compounds that fall within Formulae I-XV, having a selectivity of at least 50-fold, e.g., at least 100-fold, e.g., at least 1, 000-fold, e.g., at least 10,000-fold greater than the IC ₅₀ for UPPS over a second enzyme. Furthermore, it should be understood that all values and ranges encompassed by these ranges, are meant to be encompassed within the scope of the present invention. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application. For example, the range "at least 50-fold" includes values such as, 65 fold, 85 fold, and 100-200 fold.

Additionally, the selectivity may be quantified by means of a specificity ratio defined as

UPPS IC ₅₀ / FPPS IC ₅₀ .

In certain embodiments, the specificity ratio of a compound of the invention with enhanced selectivity is less than or equal to about 0.02, e.g., less than or equal to about 0.01 , e.g., less than or equal to about 0.002, e.g., less than or equal to about 0.001 , e.g. , less than or equal to about 0.0002, e.g. , less than or equal to about 0.0001. Furthermore, all values and ranges encompassed by these ranges are meant to be encompassed within the scope of the present invention. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application. For example, the range "less than or equal to about 0.002" includes values such as, 0.002, 0.001 , and 0.001-0.0001.

In another embodiment, the present invention is a method for treating bacterial disease comprising administering a potent and selective undecaprenyl pyrophosphate synthase sease is treated in the subject.

In yet another embodiment of the invention pertains to a method for treating bacterial disease comprising administering a potent UPPS inhibitor to a subject, such that a bacterial disease is treated in the subject.

Another embodiment of the invention pertains to a method for treating bacterial disease comprising administering a selective UPPS inhibitor to a subject, such that a bacterial disease is treated in the subject.

An additional embodiment of the invention is directed to a method for inhibiting undecaprenyl pyrophosphate synthase (UPPS) comprising the step of contacting UPPS with an activity-enhanced UPPS inhibitor, such that UPPS is inhibited. In certain embodiments, the activity-enhanced UPPS inhibitor possesses enhanced selectivity for UPPS, e.g., enhanced selectivity for UPPS over farnesyl pyrophosphate synthetase (FPPS). In certain embodiments, the activity-enhanced UPPS inhibitor possesses enhanced potency in inhibiting UPPS. In particular embodiments, the activity-enhanced UPPS inhibitor is used as an antibacterial. In other particular embodiments, the activity-enhanced UPPS inhibitor is used as an antibiotic. As used herein, the term "antibacterial" is distinct from "antibiotic," in that antibacterial is intended to describe an agent that is used directly on the bacteria, e.g., on a surface, while antibiotic is intended to describe an agent that is administered to a subject infected with the bacteria to inhibit/treat the bacteria. Another embodiment of the invention is a method for inhibiting undecaprenyl pyrophosphate synthase (UPPS) comprising administering to a bacterium compromised subject an activity-enhanced UPPS inhibitor, such that UPPS is inhibited in the subject.

An additional embodiment of the invention relates to a method for selectively inhibiting undecaprenyl pyrophosphate synthase (UPPS) comprising the step of administering to a bacterium compromised subject an activity-enhanced UPPS inhibitor wherein the UPPS/FPPS specificity ratio is less than or equal to about 0.02, e.g., less than or equal to about 0.01, e.g., less than or equal to about 0.002, e.g., less than or equal to about 0.001, e.g., less than or equal to about 0.0002, e.g., less than or equal to about 0.0001 , such that UPPS is selectively inhibited in the subject.

In another embodiment, the invention is directed to a method for treating a bacterium compromised subject comprising the step of administering to a bacterium comprom ective to treat a disease

or disorder associated with a UPPS enabled bacterium, such that the bacterium compromised subject is treated.

An additional embodiment of the invention pertains to a method for treating a subject suffering from a bacterial disorder, comprising administering to a subject a compound, such that the subject is treated for a bacterial disorder by a compound of the invention, e.g., compounds of Table 1.

Another embodiment of the invention pertains to a method for identifying an activity-enhanced UPPS inhibitor comprising screening drug candidates for threshold activity; confirming that the molecular structure of a selected drug candidate contains a hydroxydicarbonyl moiety; analyzing said selected drug candidate to ensure enhanced selectivity or potency; determining that said selected drug candidate possesses a UPPS/FPPS specificity ratio is less than or equal to about 0.02, e.g., less than or equal to about 0.01 , e.g., less than or equal to about 0.002, e.g., less than or equal to about 0.001 , e.g. , less than or equal to about 0.0002, e.g., less than or equal to about 0.0001 , or the selected IC ₅₀ of the drug candidate against UPPS is less than or equal to about 2.0 μM, e.g., less than or equal to about 1.0 μM, e.g., less than or equal to about 0.5 μM, e.g., less than or equal to about 0.1 μM, e.g., less than or equal to about 0.05 μM, e.g., less than or equal to about 0.0 lμM, e.g., less than or equal to about 0.005 μM; and identifying said selected drug candidate as an activity-enhanced UPPS inhibitor.

As used herein, the term "effective amount" includes an amount effective, at dosages and for periods of time necessary, to achieve the desired result, e.g., sufficient to treat the condition, i.e., bacterial disease, in a subject. An effective amount of a compound of the invention, as defined herein, may vary according to factors such as the disease state, age, and weight of the subject, and the ability of the compound to elicit a desired response in the subject. Dosage regimens may be adjusted to provide the optimum therapeutic response. An effective amount is also one in which any toxic or detrimental effects (e.g., side effects) of the compound are outweighed by the therapeutically beneficial effects.

A he invention (i.e., an effective dy weight, for example,

about 0.01 to 25 mg/kg body weight, for example, about 0.1 to 20 mg/kg body weight. The skilled artisan will appreciate that certain factors may influence the dosage required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of a compound of the invention can include a single treatment or, for example, can include a series of treatments. It will also be appreciated that the effective dosage of the compound used for treatment may increase or decrease over the course of a particular treatment. The methods of the invention further include administering to a subject a therapeutically effective amount of a compound of the invention in combination with another pharmaceutically active compound known to treat the disease or condition, e.g., an antibiotic. Pharmaceutically active compounds that may be used depend upon the condition to be treated, but include as examples Penicillin, Cephalosporin, Griseofulvin, Bacitracin, Polymyxin B, Amphotericin B, Erythromycin, Neomycin, Streptomycin, Tetracycline, Vancomycin, Gentamicin, and Rifamycin. The compound of the invention and the additional pharmaceutically active compound may be administered to the subject in the same pharmaceutical composition or in different pharmaceutical compositions (at the same time or at different times).

Pharmaceutical Compositions of the Compounds of the Invention The present invention also provides pharmaceutically acceptable formulations and compositions comprising one or more compounds of the invention. In certain embodiments, the compound of the invention is present in the formulation in a therapeutically effective amount, e.g., an amount effective to inhibit UPPS or treat a bacterial disease. Accordingly, in one embodiment, the invention pertains to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the invention, and a pharmaceutically acceptable carrier.

I ackaged pharmaceutical composi effective amount of a

compound of the invention, e.g., a potent and/or selective UPPS inhibitor; and instructions for using the compound to treat a bacterial disease.

The term "container' ^" includes any receptacle for holding the pharmaceutical composition. For example, in one embodiment, the container is the packaging that contains the pharmaceutical composition. In other embodiments, the container is not the packaging that contains the pharmaceutical composition, i.e. , the container is a receptacle, such as a box or vial that contains the packaged pharmaceutical composition or unpackaged pharmaceutical composition and the instructions for use of the pharmaceutical composition. Moreover, packaging techniques are well known in the art. It should be understood that the instructions for use of the pharmaceutical composition may be contained on the packaging containing the pharmaceutical composition, and as such the instructions form an increased functional relationship to the packaged product. However, it should be understood that the instructions can contain information pertaining to the compound's ability to perform its intended function, e.g. , treating, preventing, or reducing a UPPS associated disorder in a subject.

Another embodiment of the invention relates to a packaged pharmaceutical composition comprising a container holding a therapeutically effective amount of a compound of the invention, and instructions for using the compound to selectively treat a bacterial disease in a subject.

Such pharmaceutically acceptable formulations typically include one or more compounds of the invention as well as one or more pharmaceutically acceptable carriers and/or excipients. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the compounds of the invention, use thereof in the pharmaceutical compositions is contemplated. Supplementary pharmaceutically active compounds known to treat bacterial disease, i.e., antibiotic agents, as described above, can also be incorporated into the compositions of the invention. Suitable pharmaceutically active compounds that may be used a i d

A ulated to be compatible

with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral {e.g., inhalation), transdermal (topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

Formulations for Administration

The compounds for use in the invention can be formulated for administration by any suitable route, such as for oral or parenteral, for example, transdermal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g., trans- and perivaginally), (intra)nasal and (trans)rectal), intravesical, intrapulmonary, intraduodenal, intrathecal, subcutaneous, intramuscular, intradermal, intra-arterial, intravenous, intrabronchial, inhalation, and topical administration.

Suitable compositions and dosage forms include, for example, tablets, capsules, caplets, pills, gel caps, troches, dispersions, suspensions, solutions, syrups, granules, beads, transdermal patches, gels, powders, pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs, suppositories, liquid sprays for nasal or oral administration, dry powder or aerosolized formulations for inhalation, compositions and formulations for intravesical administration and the like. It should be understood that the formulations and compositions that would be useful in the present invention are not limited to the particular formulations and compositions that are described herein.

Oral Administration

For example, for oral administration the compounds can be in the form of tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., polyvinylpyrrolidone, hydroxypropylcellulose or hydroxypropylmethylcellulose); fillers (e.g., cornstarch, lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrates (e.g., sodium starch glycollate); or wetting agents (e.g., sodium lauryl sulphate). If desired, the tablets can be coated using suitable methods and coating materials such as OP ADR Y™ film coating systems available from Colorcon, West Point, Pa. (e.g., OP ADR Y™ OY Type, OY-C Type, Organic Enteric OY-P Type, Aqueous Enteric OY-A Type, OY-PM Type and OP ADR Y™ White, 32Kl 8400). Liquid preparation for oral administration can be in the form of solutions, syrups or suspensions. The liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agent (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxy benzoates or sorbic acid).

Tablets may be manufactured using standard tablet processing procedures and equipment. One method for forming tablets is by direct compression of a powdered, crystalline or granular composition containing the active agent(s), alone or in combination with one or more carriers, additives, or the like. As an alternative to direct compression, tablets can be prepared using wet-granulation or dry-granulation processes. Tablets may also be molded rather than compressed, starting with a moist or otherwise tractable material; however, compression and granulation techniques are preferred. The dosage form may also be a capsule, in which case the active agent- containing composition may be encapsulated in the form of a liquid or solid (including particulates such as granules, beads, powders or pellets). Suitable capsules can be hard or soft, and are generally made of gelatin, starch, or a cellulosic material, with gelatin capsules preferred. Two-piece hard gelatin capsules are preferably sealed, such as with gelatin bands or the like. (See, for e.g., Remington: The Science and Practice of Pharmacy, supra), which describes materials and methods for preparing encapsulated pharmaceuticals. If the active agent-containing composition is present w e used to dissolve the

active agent(s). The carrier should be compatible with the capsule material and all components of the pharmaceutical composition, and should be suitable for ingestion.

Parenteral Administration

For parenteral administration, the compounds for use in the method of the invention can be formulated for injection or infusion, for example, intravenous, intramuscular or subcutaneous injection or infusion, or for administration in a bolus dose and/or continuous infusion. Suspensions, solutions or emulsions in an oily or aqueous vehicle, optionally containing other formulatory agents such as suspending, stabilizing and/or dispersing agents can be used. Transmucosal Administration

Transmucosal administration is carried out using any type of formulation or dosage unit suitable for application to mucosal tissue. For example, the selected active agent can be administered to the buccal mucosa in an adhesive tablet or patch, sublingually administered by placing a solid dosage form under the tongue, lingually administered by placing a solid dosage form on the tongue, administered nasally as droplets or a nasal spray, administered by inhalation of an aerosol formulation, a non- aerosol liquid formulation, or a dry powder, placed within or near the rectum ("transrectal" formulations), or administered to the urethra as a suppository, ointment, or the like. Preferred buccal dosage forms will typically comprise a therapeutically effective amount of an active agent and a bioerodible (hydrolyzable) polymeric carrier that may also serve to adhere the dosage form to the buccal mucosa. The buccal dosage unit can be fabricated so as to erode over a predetermined time period, wherein drug delivery is provided essentially throughout. The time period is typically in the range of from about 1 hour to about 72 hours. Preferred buccal delivery preferably occurs over a time period of from about 2 hours to about 24 hours. Buccal drug delivery for short term use should preferably occur over a time period of from about 2 hours to about 8 hours, more preferably over a time period of from about 3 hours to about 4 hours. As needed buccal drug delivery preferably will occur over a time period of from about 1 hour to about 12 hours, more preferably from about 2 hours to about 8 hours, most preferably from about 3 hours to about 6 hours. Sustained buccal drug delivery will preferably occur over a time period of from about 6 hours t rs to about 48 hours,

most preferably from about 24 hours to about 48 hours. Buccal drug delivery, as will be appreciated by those skilled in the art, avoids the disadvantages encountered with oral drug administration, e.g., slow absorption, degradation of the active agent by fluids present in the gastrointestinal tract and/or first-pass inactivation in the liver. The amount of the active agent in the buccal dosage unit will of course depend on the potency of the agent and the intended dosage, which, in turn, is dependent on the particular individual undergoing treatment, the specific indication, and the like. The buccal dosage unit will generally contain from about 1.0 wt. % to about 60 wt. % active agent, preferably on the order of from about 1 wt. % to about 30 wt. % active agent. With regard to the bioerodible (hydrolyzable) polymeric carrier, it will be appreciated that virtually any such carrier can be used, so long as the desired drug release profile is not compromised, and the carrier is compatible with the active agents to be administered and any other components of the buccal dosage unit. Generally, the polymeric carrier comprises a hydrophilic (water-soluble and water- swellable) polymer that adheres to the wet surface of the buccal mucosa. Examples of polymeric carriers useful herein include acrylic acid polymers and co, e.g., those known as "carbomers" (Carbopol , which may be obtained from B. F. Goodrich, is one such polymer). Other suitable polymers include, but are not limited to: hydrolyzed polyvinyl alcohol; polyethylene oxides (e.g., Sentry Polyox™ water soluble resins, available from Union Carbide); polyacrylates (e.g., Gantrez™, which may be obtained from GAF); vinyl polymers and copolymers; polyvinylpyrrolidone; dextran; guar gum; pectins; starches; and cellulosic polymers such as hydroxypropyl methylcellulose, (e.g. , Methocel , which may be obtained from the Dow Chemical Company), hydroxypropyl cellulose (e.g. , Klucel , which may also be obtained from Dow), hydroxypropyl cellulose ethers (see, e.g., U.S. Pat. No. 4,704,285 to

Alderman), hydroxyethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate phthalate, cellulose acetate butyrate, and the like.

Other components can also be incorporated into the buccal dosage forms described herein. The additional components include, but are not limited to, disintegrants, diluents, binders, lubricants, flavoring, colorants, preservatives, and the like. Examples of disintegrants that may be used include, but are not limited to, cross- linked po yplasdone™ XL, which may be o elluloses, such as

croscarmelose (e.g., Ac-di-sol , which may be obtained from FMC), alginic acid, and sodium carboxymethyl starches (e.g., Explotab™, which can be obtained from Edward Medell Co., Inc.), methylcellulose, agar bentonite and alginic acid. Suitable diluents include those which are generally useful in pharmaceutical formulations prepared using compression techniques, e.g., dicalcium phosphate dihydrate (e.g., Di- Tab™, which may be obtained from Stauffer), sugars that have been processed by cocrystallization with dextrin (e.g., co-crystallized sucrose and dextrin such as Di- Pak™, which may be obtained from Amstar), calcium phosphate, cellulose, kaolin, mannitol, sodium chloride, dry starch, powdered sugar and the like. Binders, if used, include those that enhance adhesion. Examples of such binders include, but are not limited to, starch, gelatin and sugars such as sucrose, dextrose, molasses, and lactose. Particularly preferred lubricants are stearates and stearic acid, and an optimal lubricant is magnesium stearate.

Sublingual and lingual dosage forms include tablets, creams, ointments, lozenges, pastes, and any other suitable dosage form where the active ingredient is admixed into a disintegrable matrix. The tablet, cream, ointment or paste for sublingual or lingual delivery comprises a therapeutically effective amount of the selected active agent and one or more conventional nontoxic carriers suitable for sublingual or lingual drug administration. The sublingual and lingual dosage forms of the present invention can be manufactured using conventional processes. The sublingual and lingual dosage units can be fabricated to disintegrate rapidly. The time period for complete disintegration of the dosage unit is typically in the range of from about 10 seconds to about 30 minutes, and optimally is less than 5 minutes.

Other components can also be incorporated into the sublingual and lingual dosage forms described herein. The additional components include, but are not limited to binders, disintegrants, wetting agents, lubricants, and the like. Examples of binders that can be used include water, ethanol, polyvinylpyrrolidone; starch solution gelatin solution, and the like. Suitable disintegrants include dry starch, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic monoglyceride, lactose, and the like. Wetting agents, if used, include glycerin, starches, and the like. Particularly preferred lubricants are stearates and polyethylene glycol. Additional components that may be incorporated into sublingual and lingual dosage f k ill b h kill d in this art (See, e.g., Remingt

Transurethal Administration

With regard to transurethal administration, the formulation can comprise a urethral dosage form containing the active agent and one or more selected carriers or excipients, such as water, silicone, waxes, petroleum jelly, polyethylene glycol ("PEG"), propylene glycol ("PG"), liposomes, sugars such as mannitol and lactose, and/or a variety of other materials, with polyethylene glycol and derivatives thereof particularly preferred. A transurethral permeation enhancer can be included in the dosage from. Examples of suitable permeation enhancers include dimethylsulfoxide ("DMSO"), dimethyl formamide ("DMF"), N,N-dimethylacetamide ("DMA"), decylmethylsulfoxide ("ClO MSO"), polyethylene glycol monolaurate ("PEGML"), glycerol monolaurate, lecithin, the 1 -substituted azacycloheptan-2-ones, particularly 1 -n-dodecylcyclazacycloheptan-2-one (available under the trademark Azone™ from Nelson Research & Development Co., Irvine, Calif.), SEP A™ (available from Macrochem Co., Lexington, Mass.), surfactants as discussed above, including, for example, Tergitol™, Nonoxynol-9™ and TWEEN-80™, and lower alkanols such as ethanol.

Transurethral drug administration, as explained in U.S. Pat. Nos. 5,242,391, 5,474,535, 5,686,093 and 5,773,020, can be carried out in a number of different ways using a variety of urethral dosage forms. For example, the drug can be introduced into the urethra from a flexible tube, squeeze bottle, pump or aerosol spray. The drug can also be contained in coatings, pellets or suppositories that are absorbed, melted or bioeroded in the urethra. In certain embodiments, the drug is included in a coating on the exterior surface of a penile insert. It is preferred, although not essential, that the drug be delivered from at least about 3 cm into the urethra, and preferably from at least about 7 cm into the urethra. Generally, delivery from at least about 3 cm to about 8 cm into the urethra will provide effective results in conjunction with the present method.

Urethral suppository formulations containing PEG or a PEG derivative can be conveniently formulated using conventional techniques, e.g., compression molding, heat molding or the like, as will be appreciated by those skilled in the art and as described in the pertinent literature and pharmaceutical texts. (See, e.g., Remington: The Scie s typical methods of

preparing pharmaceutical compositions in the form of urethral suppositories. The PEG or PEG derivative preferably has a molecular weight in the range of from about 200 to about 2,500 g/mol, more preferably in the range of from about 1,000 to about 2,000 g/mol. Suitable polyethylene glycol derivatives include polyethylene glycol fatty acid esters, for example, polyethylene glycol monostearate, polyethylene glycol sorbitan esters, e.g., polysorbates, and the like. Depending on the particular active agent, urethral suppositories may contain one or more solubilizing agents effective to increase the solubility of the active agent in the PEG or other transurethral vehicle. It may be desirable to deliver the active agent in a urethral dosage form that provides for controlled or sustained release of the agent. In such a case, the dosage form can comprise a biocompatible, biodegradable material, typically a biodegradable polymer. Examples of such polymers include polyesters, polyalkylcyanoacrylates, polyorthoesters, polyanhydrides, albumin, gelatin and starch. As explained, for example, in PCT Publication No. WO 96/40054, these and other polymers can be used to provide biodegradable microparticles that enable controlled and sustained drug release, in turn minimizing the required dosing frequency.

The urethral dosage form will preferably comprise a suppository that is from about 2 to about 20 mm in length, preferably from about 5 to about 10 mm in length, and less than about 5 mm in width, preferably less than about 2 mm in width. The weight of the suppository will typically be in the range of from about 1 mg to about 100 mg, preferably in the range of from about 1 mg to about 50 mg. However, it will be appreciated by those skilled in the art that the size of the suppository can and will vary, depending on the potency of the drug, the nature of the formulation, and other factors. Transurethral drug delivery may involve an "active" delivery mechanism such as iontophoresis, electroporation or phonophoresis. Devices and methods for delivering drugs in this way are well known in the art. Iontophoretically assisted drug delivery is, for example, described in PCT Publication No. WO 96/40054, cited above. Briefly, the active agent is driven through the urethral wall by means of an electric current passed from an external electrode to a second electrode contained within or affixed to a urethral probe.

Transrectal Administration

Preferred transrectal dosage forms can include rectal suppositories, creams, ointments, and liquid formulations (enemas). The suppository, cream, ointment or liquid formulation for transrectal delivery comprises a therapeutically effective amount of the selected active agent and one or more conventional nontoxic carriers suitable for transrectal drug administration. The transrectal dosage forms of the present invention can be manufactured using conventional processes. The transrectal dosage unit can be fabricated to disintegrate rapidly or over a period of several hours. The time period for complete disintegration is preferably in the range of from about 10 minutes to about 6 hours, and optimally is less than about 3 hours. Other components can also be incorporated into the transrectal dosage forms described herein. The additional components include, but are not limited to, stiffening agents, antioxidants, preservatives, and the like. Examples of stiffening agents that may be used include, for example, paraffin, white wax and yellow wax. Preferred antioxidants, if used, include sodium bisulfite and sodium metabisulfite. Vaginal or Perivaginal Administration

Preferred vaginal or perivaginal dosage forms include vaginal suppositories, creams, ointments, liquid formulations, pessaries, tampons, gels, pastes, foams or sprays. The suppository, cream, ointment, liquid formulation, pessary, tampon, gel, paste, foam or spray for vaginal or perivaginal delivery comprises a therapeutically effective amount of the selected active agent and one or more conventional nontoxic carriers suitable for vaginal or perivaginal drug administration. The vaginal or perivaginal forms of the present invention can be manufactured using conventional processes as disclosed in Remington: The Science and Practice of Pharmacy, supra (see also drug formulations as adapted in U.S. Pat. Nos. 6,515,198; 6,500,822; 6,417, 186; 6,416,779; 6,376,500; 6,355,641; 6,258,819; 6,172,062; and 6,086,909). The vaginal or perivaginal dosage unit can be fabricated to disintegrate rapidly or over a period of several hours. The time period for complete disintegration is preferably in the range of from about 10 minutes to about 6 hours, and optimally is less than about 3 hours. Other components can also be incorporated into the vaginal or perivaginal dosage forms described herein. The additional components include, but are not limited to, stiffening agents, antioxidants, preservatives, and the like. Examples of stiffenin fin, white wax and

yellow wax. Preferred antioxidants, if used, include sodium bisulfite and sodium metabisulfite.

Intranasal or Inhalation Administration The active agents can also be administered intranasally or by inhalation.

Compositions for intranasal administration are generally liquid formulations for administration as a spray or in the form of drops, although powder formulations for intranasal administration, e.g., insufflations, nasal gels, creams, pastes or ointments or other suitable formulators can be used. For liquid formulations, the active agent can be formulated into a solution, e.g. , water or isotonic saline, buffered or unbuffered, or as a suspension. Preferably, such solutions or suspensions are isotonic relative to nasal secretions and of about the same pH, ranging e.g., from about pH 4.0 to about pH 7.4 or, from about pH 6.0 to about pH 7.0. Buffers should be physiologically compatible and include, for example, phosphate buffers. Furthermore, various devices are available in the art for the generation of drops, droplets and sprays, including droppers, squeeze bottles, and manually and electrically powered intranasal pump dispensers. Active agent containing intranasal carriers can also include nasal gels, creams, pastes or ointments with a viscosity of, e.g., from about 10 to about 6500 cps, or greater, depending on the desired sustained contact with the nasal mucosal surfaces. Such carrier viscous formulations can be based upon, for example, alkylcelluloses and/or other biocompatible carriers of high viscosity well known to the art (see e.g., Remington: The Science and Practice of Pharmacy, supra). Other ingredients, such as preservatives, colorants, lubricating or viscous mineral or vegetable oils, perfumes, natural or synthetic plant extracts such as aromatic oils, and humectants and viscosity enhancers such as, e.g., glycerol, can also be included to provide additional viscosity, moisture retention and a pleasant texture and odor for the formulation. Formulations for inhalation may be prepared as an aerosol, either a solution aerosol in which the active agent is solubilized in a carrier (e.g., propellant) or a dispersion aerosol in which the active agent is suspended or dispersed throughout a carrier and an optional solvent. Non-aerosol formulations for inhalation can take the form of a liquid, typically an aqueous suspension, although aqueous solutions may be used as well In such a case the carrier is typically a sodium chloride solution having a concen o normal body fluid. In

addition to the carrier, the liquid formulations can contain water and/or excipients including an antimicrobial preservative (e.g., benzalkonium chloride, benzethonium chloride, chlorobutanol, phenylethyl alcohol, thimerosal and combinations thereof), a buffering agent (e.g., citric acid, potassium metaphosphate, potassium phosphate, sodium acetate, sodium citrate, and combinations thereof), a surfactant (e.g., polysorbate 80, sodium lauryl sulfate, sorbitan monopalmitate and combinations thereof), and/or a suspending agent (e.g., agar, bentonite, microcrystalline cellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, tragacanth, veegum and combinations thereof). Non-aerosol formulations for inhalation can also comprise dry powder formulations, particularly insufflations in which the powder has an average particle size of from about 0.1 μm to about 50 μm, preferably from about 1 μm to about 25 μm.

Topical Formulations

Topical formulations can be in any form suitable for application to the body surface, and may comprise, for example, an ointment, cream, gel, lotion, solution, paste or the like, and/or may be prepared so as to contain liposomes, micelles, and/or microspheres. Preferred topical formulations herein are ointments, creams and gels.

Ointments, as is well known in the art of pharmaceutical formulation, are semisolid preparations that are typically based on petrolatum or other petroleum derivatives. The specific ointment base to be used, preferably provides for optimum drug delivery, and, preferably, will provides for other desired characteristics as well, e.g., emolliency or the like. The ointment base is preferably inert, stable, nonirritating and nonsensitizing. As explained in Remington: The Science and Practice of Pharmacy, supra, ointment bases can be grouped in four classes: oleaginous bases; emulsifiable bases; emulsion bases; and water-soluble bases. Oleaginous ointment bases include, for example, vegetable oils, fats obtained from animals, and semisolid hydrocarbons obtained from petroleum. Emulsifiable ointment bases, also known as absorbent ointment bases, contain little or no water and include, for example, hydroxystearin sulfate, anhydrous lanolin and hydrophilic petrolatum. Emulsion ointment bases are either water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, and include, for example, cetyl alcohol, glyceryl monostearate, lanolin and stearic acid. Preferred water-soluble ointment bases are prepared from polyethylene glycols o e Science and Practice

of Pharmacy, supra).

Creams, as also well known in the art, are viscous liquids or semisolid emulsions, either oil-in-water or water-in-oil. Cream bases are water-washable, and contain an oil phase, an emulsifier and an aqueous phase. The oil phase, also called the "internal" phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant. The emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant. As will be appreciated by those working in the field of pharmaceutical formulation, gels-are semisolid, suspension-type systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout the carrier liquid, which is typically aqueous, but also, preferably, contain an alcohol and, optionally, an oil. Preferred "organic macromolecules," i.e., gelling agents, are crosslinked acrylic acid polymers such as the "carbomer" family of polymers, e.g., carboxypolyalkylenes that may be obtained commercially under the Carbopol trademark. Also preferred are hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers and polyvinylalcohol; cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums such as tragacanth and xanthan gum; sodium alginate; and gelatin. In order to prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be dispersed by trituration, mechanical mixing, and/or stirring.

Various additives, known to those skilled in the art, may be included in the topical formulations. For example, solubilizers may be used to solubilize certain active agents. For those drugs having an unusually low rate of permeation through the skin or mucosal tissue, it may be desirable to include a permeation enhancer in the formulation; suitable enhancers are as described elsewhere herein.

Transdermal Administration

The compounds of the invention may also be administered through the skin or mucosal tissue using conventional transdermal drug delivery systems, wherein the agent is contained within a laminated structure (typically referred to as a transdermal "patch") that serves as a drug delivery device to be affixed to the skin. Transdermal drug del tated using

electrotransport, e.g., iontophoresis. In a typical transdermal "patch," the drug composition is contained in a layer, or "reservoir," underlying an upper backing layer. The laminated structure may contain a single reservoir, or it may contain multiple reservoirs. In one type of patch, referred to as a "monolithic" system, the reservoir is comprised of a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery. Examples of suitable skin contact adhesive materials include, but are not limited to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and the like. Alternatively, the drug-containing reservoir and skin contact adhesive are separate and distinct layers, with the adhesive underlying the reservoir which, in this case, may be either a polymeric matrix as described above, or it may be a liquid or hydrogel reservoir, or may take some other form.

The backing layer in these laminates, which serves as the upper surface of the device, functions as the primary structural element of the laminated structure and provides the device with much of its flexibility. The material selected for the backing material should be selected so that it is substantially impermeable to the active agent and any other materials that are present, the backing is preferably made of a sheet or film of a flexible elastomeric material. Examples of polymers that are suitable for the backing layer include polyethylene, polypropylene, polyesters, and the like. During storage and prior to use, the laminated structure includes a release liner. Immediately prior to use, this layer is removed from the device to expose the basal surface thereof, either the drug reservoir or a separate contact adhesive layer, so that the system may be affixed to the skin. The release liner should be made from a drug/vehicle impermeable material. Transdermal drug delivery systems may in addition contain a skin permeation enhancer. That is, because the inherent permeability of the skin to some drugs may be too low to allow therapeutic levels of the drug to pass through a reasonably sized area of unbroken skin, it is necessary to coadminister a skin permeation enhancer with such drugs. Suitable enhancers are well known in the art and include, for example, those enhancers listed above in transmucosal compositions.

Intrathecal Administration

One common system utilized for intrathecal administration is the APT Intrathec PT Intrathecal uses a

small pump that is surgically placed under the skin of the abdomen to deliver medication directly into the intrathecal space. The medication is delivered through a small tube called a catheter that is also surgically placed. The medication can then be administered directly to cells in the spinal cord involved in conveying sensory and motor signals associated with lower urinary tract disorders.

Another system available from Medtronic that is commonly utilized for intrathecal administration is the fully implantable, programmable SynchroMed™ Infusion System. The SynchroMed™ Infusion System has two parts that are both placed in the body during a surgical procedure: the catheter and the pump. The catheter is a small, soft tube. One end is connected to the catheter port of the pump, and the other end is placed in the intrathecal space. The pump is a round metal device about one inch (2.5 cm) thick, three inches (8.5 cm) in diameter, and weighs about six ounces (205 g) that stores and releases prescribed amounts of medication directly into the intrathecal space. It can be made of titanium, a lightweight, medical-grade metal. The reservoir is the space inside the pump that holds the medication. The fill port is a raised center portion of the pump through which the pump is refilled. The doctor or a nurse inserts a needle through the patient's skin and through the fill port to fill the pump. Some pumps have a side catheter access port that allows the doctor to inject other medications or sterile solutions directly into the catheter, bypassing the pump. The SynchroMed™ pump automatically delivers a controlled amount of medication through the catheter to the intrathecal space around the spinal cord, where it is most effective. The exact dosage, rate and timing prescribed by the doctor are entered in the pump using a programmer, an external computer-like device that controls the pump's memory. Information about the patient's prescription can be stored in the pump's memory. The doctor can easily review this information by using the programmer. The programmer communicates with the pump by radio signals that allow the doctor to tell how the pump is operating at any given time. The doctor also can use the programmer to change your medication dosage.

Methods of intrathecal administration can include those described above available from Medtronic, as well as other methods that are known to one of skill in the art.

Intravesical Administration

The term intravesical administration is used herein in its conventional sense to mean delivery of a drug directly into the bladder. Suitable methods for intravesical administration can be found in U.S. Pat. Nos. 6,207,180 and 6,039,967, for example.

Additional Administration Forms Additional dosage forms of this invention include dosage forms as described in U.S. Pat. No. 6,340,475, U.S. Pat. No. 6,488,962, U.S. Pat. No. 6,451,808, U.S. Pat. No. 5,972,389, U.S. Pat. No. 5,582,837, and U.S. Pat. No. 5,007,790. Additional dosage forms of this invention also include dosage forms as described in U.S. patent application Ser. No. 20030147952, U.S. patent application Ser. No. 20030104062, U.S. patent application Ser. No. 20030104053, U.S. patent application Ser. No. 20030044466, U.S. patent Application Ser. No. 20030039688, and U.S. patent application Ser. No. 20020051820. Additional dosage forms of this invention also include dosage forms as described in PCT Patent Application WO 03/35041, PCT Patent Application WO 03/35040, PCT Patent Application WO 03/35029, PCT Patent Application WO 03/35177, PCT Patent Application WO 03/35039, PCT Patent Application WO 02/96404, PCT Patent Application WO 02/32416, PCT Patent Application WO 01/97783, PCT Patent Application WO 01/56544, PCT Patent Application WO 01/32217, PCT Patent Application WO 98/55107, PCT Patent Application WO 98/11879, PCT Patent Application WO 97/47285, PCT Patent Application WO 93/18755, and PCT Patent Application WO 90/1 1757.

For intrabronchial or intrapulmonary administration, conventional formulations can be employed.

Further, the compounds for use in the method of the invention can be formulated in a sustained release preparation, further described herein. For example, the compounds can be formulated with a suitable polymer or hydrophobic material which provides sustained and/or controlled release properties to the active agent compound. As such, the compounds for use the method of the invention can be administered in the form of microparticles for example, by injection or in the form of wafers or discs by implantation. In one embodiment, the dosage forms of the present invention include pharmaceutical tablets for oral administration as described in U.S. patent application Ser. No. 20030104053. For example, suitable dosage forms of the present invention can com modes of drug delivery.

The dosage forms of this invention include dosage forms in which the same drug is used in both the immediate-release and the prolonged-release portions as well as those in which one drug is formulated for immediate release and another drug, different from the first, is formulated for prolonged release. This invention encompasses dosage forms in which the immediate-release drug is at most sparingly soluble in water, i.e., either sparingly soluble or insoluble in water, while the prolonged-release drug can be of any level of solubility.

EXAMPLES

This invention is further illustrated by the following examples, which should not be construed as limiting.

Example 1

Preparation of Thia-aza-indene Compounds

The general synthetic preparation of thia-aza-indene compounds of the invention are described below.

SCHEME 1

A1 A2

A2a. R = cyclopropylmethyl A2b. R = 4-phenoxy-phenyl A2c. R = 4-phenoxy-benzyl A2d. R = 2-(2,6-dichloro-phenylsulfanyl)-ethyl A2e. R

A2f. R = 4-tert-butyl-cyclohexyl

A2g. R = 2-morpholin-4-yl-ethyl

A2h. R = 4-( 1 , 1 -dioxo-thiomorpholin-4-ylmethyl)-phenyl

A2i. R = l,5-bis-(4-methoxy-phenyl)-lH-[l ,2,4]triazol-3-yl

/. Preparation of Al

7-Hydroxy-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carboxylic acid methyl ester was prepared according to literature procedure (J. Chem. Res., Synopses (1989), (7), 196-7). ¹ H-NMR (400 MHz, CHCl ₃ -*/): δ ppm 3.80 (s, 3 H), 6.84 (s, 1 H), 8.25

(d, ./=3.54 Hz, 1 H), 11.08 (s, 1 H), 12.76 (s, 1 H). MS : m/z, (ES+) = 226, (ES-) =

224.

//. Preparation of A2a (Step 1)

7-hydroxy-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carboxylic acid cyclopropyl-methyl-amide, Al, (25mg, 0.22 mmol) and cyclopropylmethylamine (80 uL, 1.1 mmol) were dissolved in 8: 1 tetrahydrofuran/dimethylformamide (4.5 mL). The resulting solution was heated in a sealed tube using microwave irradiation at 125° for 10 min. The crude reaction mixture was concentrated under reduced pressure to give a solid. The crude solid was washed with methanol, filtered and dried to provide A2a (12mg). ¹ H-NMR (400 MHz, CHCl ₃ -^: δ ppm - 0.26 (m, 2 H), 0.49 (m, 2 H), 1.06 (bs, 1 H), 3.26 (t, 2 H) 6.98 (s, 1 H), 8.27 (s, 1 H), 10.29 (s, 1 H), 11.36 (s, 1 H). MS: m/z, (ES+) =265, (ES-) = 263

///. Additional Compounds

T f i th yields ranging from 10-50%

A. A2b.

7-Hydroxy-5-oxo-4,5-dihydro2-thia-4-aza-indene-6-carboxylic acid (4- phenoxy-phenyl)-amide. ¹ H NMR (400 MHz, DMSO-J ₆ ) δ ppm 7.02-7.07 (m, 5 H), 7.14 (m, IH), 7.40 (m, 2 H), 7.65 (d, J=9.09 Hz, 2 H), 8.40 (d, J=2.53 Hz, IH), 11.65 (s, IH), 12.52 (s, IH).

B. A2c.

7-Hydroxy-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carboxy lic acid 4- phenoxy-benzylamide. MS: m/z, (ES-) = 391.

C. A2d.

7-Hydroxy-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carboxy lic acid [2-(2,6- dichloro-phenylsulfanyl)-ethyl]-amide. MS: m/z, (ES+) = 429, (ES-) = 427.

D. A2e.

7-Hydroxy-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carboxy lic acid (4- cyclohexyl-phenyl)-amide. MS: m/z, (ES+) = 369, (ES-) = 367.

E. A2f .

7-Hydroxy-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carboxy lic acid (4-tert- butyl-cyclohexyl)-amide. MS: m/z, (ES+) = 349, (ES-) = 347.

F. A2g.

7-Hydroxy-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-caτbox ylic acid (2- morpholin-4-yl-ethyl)-amide. MS: m/z, (ES+) = 324, (ES-) = 322.

G. A2h.

7-Hydroxy-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carboxy lic acid [4-(l ,1- dioxo-thiomorpholin-4-ylmethyl)-phenyl]-amide. MS: m/z, (ES-) = 432.

H

7-Hydroxy-5-oxo-4H,5H-2-thia-4-aza-indene-6-carboxylic acid [1 ,5-bis-(4- methoxy-phenyl)-lH-[l,2,4]triazol-3-yl]-amide. MS: m/z, (ES+) = 490, (ES-) = 488.

Example 2 Preparation ofBicyclic Hydroxydicarbonyl Compounds

The general synthetic preparation of additional bicyclic hydroxydicarbonyl compounds of the invention are described below.

SCHEME 2

To a solution of C-I (12.26 g, 72 mmol) in Diethyl ether (150 mL) at -30C in a three neck round bottom flask, were added a chilled premixed solution of dichloro malonate (3.38 g) and triflic acid (4.0 g, 26.4 mmol) dropwise. The mixture was stirred at -20C for 2 hrs. Then it was warmed to -5 C in 2 hrs and quenched with water. The crude was concentrated under reduced pressure and purified using silica- gel column chromatography to give the desired compounds C-2. Recrystallized to a light yel

To a solution of C-2 (610 mg, 3.7 mmol) in Toluene (40 mL) at 5OC in a three neck round bottom flask, was added methyl chloroformate (700mg, 7.4 mmol). The mixture was heated at reflux over night. More methyl chloroformate (350 mg, 3.7 mmol) added and stirred at reflux for over night. The crude was concentrated under reduced pressure and purified using silica-gel column chromatography to give the desired compounds C-3.

A mixture of C-3 (70 mg, 0.31mmol) and 4-piperidinylaniline (140 mg, 0.7 mmol) in toluene (15 mL) was heated at reflux over night. The crude was concentrated under reduced pressure and purified using silica-gel column chromatography to give the desired compounds C-4. Yield: 80 mg (50-80%).

Example 3 Preparation ofBicyclic Hydroxydicarbonyl Compounds

The general synthetic preparation of additional bicyclic hydroxydicarbonyl compounds of the invention are described below.

SCHEME 3

C2 C3

C3a. R = biphenyl-4-yl C3b. R = 4-cyclohexyl-phenyl C3c. R = 4-phenoxy-phenyl

C3d. R = 4-trifluoromethyl-phenyl

C3e. R = 4-hexyloxy-phenyl

C3f. R = l,5-bis-(4-methoxy-phenyl)-lH-[l,2,4]triazol-3-yl

/. Preparation of Cl (Step 1)

To a solution of 2-amino-5 -phenyl -thiophene-3-carboxylic acid ethyl ester (3.7 g, 15 mmol) and triethylamine (7.6 mL, 45 mmol) in dichloromethane (150 niL) was added methyl malonyl chloride (3.2 mL, 30 mmol) slowly at 0°C. Then the reaction l ti ti d t t t i ht, washed with saturated NaHCO rated to provide 2-(2-

methoxycarbonyl-acetylamino)-5-phenyl-thiophene-3-carboxylic acid ethyl ester, Cl (3.1 g, 59%), as a yellow solid. ¹ H-NMR (400 MHz, CHCl ₃ -J): δ ppm 1.41 (t, J=7.07 Hz, 3 H), 3.62(s, 2 H), 3.85 (s, 3 H), 4.42 (q, J=7.07 Hz, 2 H), 7.27 (m, 1 H) 7.37 (t, J=7.58 Hz, 12 H), 7.44 (s, 1 H), 7.59 (d, J=7.07 Hz, 2H), 12.04 (s, 1 H); MS: m/z = (ES+) = 348, (ES-) = 346.

//. Preparation ofC2 (Step 2)

To a solution of Cl (0.35 g, 1.0 mmol) in anhydrous dimethylformamide (7 niL), was added sodium hydride (102 mg, 4.0 mmol) in portions under argon. The resulting mixture was stirred at room temperature for 2 h, then heated at 80°C overnight. After cooling to room temperature, the reaction mixture was poured into ice water and stirred for 1 h. The precipitate was collected and washed sequentially with dimethylformamide, ethyl acetate and methanol to provide 4-hydroxy-6-oxo-2- phenyl-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid methyl ester, C2 (0.12 g,

40%) as a brownish solid. MS: m/z = (ES+) = 302, (ES-) = 300.

///. Preparation of C 3 (Step 3)

General Procedure: A mixture of C2 (30 mg, 0.10 mmol) and the appropriate amine (0.15 mmol) in tetrahydrofuran (2-5 mL) was heated using microwave irradiation at 150-160°C for 15 min. The precipitated solids were collected and washed with dimethylformamide, tetrahydrofuran, ethyl acetate and methanol depending on the properties of products, giving solid products C3 in 20-60% yields.

A. C3a.

4-Hydroxy-6-oxo-2-phenyl-6,7-dihydro-thieno[2,3-b]pyridine-5 -carboxylic acid biphenyl-4-ylamide. ¹ H-NMR (400 MHz, DMSO-J ₆ ): δ ppm 7.36 (t, J=7.33 Hz, 2 H), 7.46 (q, J=7.33 Hz, 4 H), 7.72 (m, 8 H), 12.59 (s, 1 H), 13.06 (s, 1 H), 16.25 (s, 1 H); M

B. C3b.

4-Hydroxy-6-oxo-2-phenyl-6,7-dihydro-thieno[2,3-b]pyridin e-5-carboxylic acid (4-cyclohexyl-phenyl)-amide. MS: m/z (ES+) = 445, (ES-) = 443

C. C3c.

4-Hydroxy-6-oxo-2-phenyl-6,7-dihydro-thieno[2,3-b]pyridin e-5-carboxylic acid (4-phenoxy-phenyl)-amide. MS: m/z (ES+) = 455, (ES-) = 453

D. C3d.

4-Hydroxy-6-oxo-2-phenyl-6,7-dihydro-thieno[2,3-b]pyridin e-5-carboxylic acid (4-trifluoromethyl-phenyl)-amide. MS: m/z (ES+) = 431, (ES-) = 429

E. C3e.

4-Hydroxy-6-oxo-2-phenyl-6,7-dihydro-thieno[2,3-b]pyridine-5 -carboxylic acid (4-hexyloxy-phenyl)-amide. MS: m/z (ES+) = 463, (ES-) = 461

F. C3f.

4-Hydroxy-6-oxo-2-phenyl-6,7-dihydro-thieno[2,3-b]pyridin e-5-carboxylic acid [l ,5-bis-(4-methoxy-phenyl)-lH-[l,2,4]triazol3-yl]-amide. MS: m/z (ES+) = 566, (ES-) = 564

Example 4 Preparation ofBicyclic Hydroxydicarbonyl Compounds

The general synthetic preparation of additional bicyclic hydroxydicarbonyl compounds of the invention are described below. Compounds D-I, E-I, F-I and G-I were synthesized according to the following Steps 1 and 2, starting with reaction of methyl malonyl chloride and methyl 2-amino-5-bromobenzoate, methyl anthranilate, methyl 2-amino-6-methoxybenzoate and methyl N-methylanthranilate, respectively.

/. Step 1

SCHEME 4

Dl Rl = H, R2 = Br, R3 = H

El Rl = H, R2 = H, R3 = H

Fl Rl = OMe, R2 = H, R3 = H

Gl Rl

D2a-g Rl = H, R2 = Br, R3 = H

D2a R4 = 4-phenoxy-phenyl

D2b R4 = biphenyl-4-yl D2c R4 = 2-phenoxy-phenyl

D2d R4 = 4-cyclohexyl-phenyl

D2e R4 = 4-hexyloxy-phenyl

D2f R4 = 4-trifluoromethoxy-phenyl

D2g R4 = 6-trifluoromethyl-pyridin-3-yl

E2a-v Rl = H, R2 = H, R3 = H

E2a R4 = 4-hexyloxy-phenyl

E2b R4 = 4-cyclohexyl-phenyl

E2c R4 = 2-carbamoyl-phenyl E2d R4 = 4-methoxy-phenyl

E2e R4 = 4-phenoxy-phenyl

E2f R4 = biphenyl-4-yl

E2g R4 = 2-amino-4-cyclohexyl-phenyl

E2h R4 = morpholin-4-yl E2i R4 = 2-piperazin-l-yl-nicotinonitrile

E2j R4 = (4-chloro-phenyl)-piperidin-4-yl-methanone

E2k R4 = cyclopropylmethyl

E21 R4 = 4-ter/-butyl-cyclohexyl

E2m R4 = 4-oxazol-5-yl-phenyl E2n R4 = 3-phenoxy-phenyl

E2o R4 = 2-morpholin-4-yl-ethyl

E2p R4 = 4-(2-morpholin-4-yl-ethyl)-piperazine

E2q R4 = 6-trifluoromethyl-pyridin-3-yl

E2r R4 = 4-morpholin-4-yl-phenyl E2s R4 = 2-phenoxy-phenyl

E2t R4 = 4-pentyl-phenyl

E2u R4 = 4-pentyloxy-phenyl

E2v R4

F2a-c Rl = OMe, R2 = H, R3 = H F2a R4 = 4-cyclohexyl-phenyl F2b R4 = 4-phenoxy-phenyl F2c R4 = 2-carbamoyl-phenyl

G2a-c Rl = H, R2 = H, R3 = Me G2a R4 = 4-phenoxy-phenyl

G2b R4 = l,5-bis-(4-methoxy-phenyl)-lH-[l,2,4]triazol-3-yl G2c R4 = 4-trifluoromethoxy-phenyl

A. Dl.

6-Bromo-4-hydroxy-2-oxo- 1 ,2-dihydro-quinoline-3-carboxylic acid methyl ester. ¹ H-NMR (400 MHz, DMSOd ₆ ): δ ppm 3.85 (s, 3 H), 7.23 (d, J=9.09 Hz, 1 H), 7.77 (dd, J=8.59, 2.02 Hz, 1 H), 8.03 (d, J=2.02 Hz, 1 H), 1 1.68 (s, 1 H) 13.07 (s, 1 H).

B. El.

4-Hydroxy-2-oxo-l,2-dihydro-quinoline-3-carboxylic acid methyl ester. IH NMR (400 MHz, DMSO-D6) δ ppm 3.87 (s, 3 H), 7.21 (t, J=7.58 Hz, 1 H), 7.27 (d, J=8.08 Hz, 1 H), 7.63 (t, J=7.58 Hz, 1 H), 7.94 (d, J=8.08 Hz, 1 H), 1 1.53 (s, 1 H), 13.34 (s, 1 H). MS : m/z = (m+l) = 220, (m-1) = 218.

C. Fl.

4-Hydroxy-5-methoxy-2-oxo- 1 ,2-dihydro-quinoline-3-carboxylic acid methyl ester. ¹ H-NMR (400 MHz, DMSOd ₆ ): δ ppm 3.79 (s, 3 H), 3.95 (s, 3 H), 6.79 (d, J=8.08 Hz, 1 H), 6.90 (d, J=8.08 Hz, 1 H), 7.51 (m, IH), 1 1.46 (s, 1 H), 1 1.57 (s, 1 H).

D. Gl.

4-Hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydro-quinoline-3-carboxylic acid methyl ester. ¹ H-NMR (400 MHz, DMSO-J ₆ ): δ ppm 3.55 (s, 3H), 3.85 (s, 3H), 7.32 (tr, IH,

J= 8 Hz ), 7.53 (d, IH, J= 8 Hz), 7.75 (tr, IH ₅ J= 8 Hz), 8.06 (d, IH, J = 8 Hz). MS : m/z = (ES+) = 234, (ES-) = 232.

E. D2a. 6-Bromo-4-hydroxy-2-oxo-l ,2-dihydro-quinoline-3-carboxylic acid (4- phenoxy-phenyl)-amide

Methyl ester Dl (284 mg, 0.95 mmol) and />-phenoxy aniline (550 mg, 2.8 mmol) were dissolved in tetrahydrofiiran (8 mL) in a microwave vessel. The vessel was sealed and the resulting solution was heated in the microwave (170 ⁰ C, 20 min). Completion of the reaction was indicated by LCMS. Upon standing at RT, a precipitate was seen to form. The solid was isolated by filtration and washed with hexane and dried to yield the final product. A second crop of product was obtained from the mother liquor to provide D2a (280mg, 65%). ¹ H-NMR (400 MHz, DMSO- d ₆ ): 6 ppm 7.05 (m, 4 H), 7.15 (m, 1 H), 7.39 (m, 3 H), 7.66 (m, 2 H) 7.87 (m, 1 H), 8.08 (s, 1 H), 12.20 (s, 1 H), 12.50 (s, 1 H). ). MS : m/z, (ES+) = 453, (ES-) = 451. The following compounds were prepared by the methods noted above.

i. D2b 6-Bromo-4-hydroxy-2-oxo-l,2-dihydro-quinoline-3-carboxylic acid biphenyl-

4-ylamide. MS : m/z, (ES+) = 437, (ES-) = 435.

U. D2c 6-Bromo-4-hydroxy-2-oxo-l,2-dihydro-quinoline-3-carboxylic acid (2- phenoxy-phenyl)-amide. MS : m/z, (ES+) = 453, (ES-) = 451.

iii. D2d

6-Bromo-4-hydroxy-2-oxo-l,2-dihydro-quinoline-3-carboxyli c acid (4- cyclohexyl-phenyl)-amide. MS : m/z, (ES+) = 443, (ES-) = 441.

iv. D2e

6-Bromo-4-hydroxy-2-oxo-l,2-dihydro-quinoline-3-carboxyli c acid (4- hexyloxy-phenyl)-amide. MS : m/z, (ES+) = 461, (ES-) = 459.

v. D2f

6-Bromo-4-hydroxy-2-oxo-l ,2-dihydro-quinoline-3-carboxylic acid (4- trifluoromethoxy-phenyl)-amide. MS : m/z, (ES+) = 445, (ES-) = 443

vi. D2g

6-Bromo-4-hydroxy-2-oxo- 1 ^-dihydro-quinoline-S-carboxylic acid (6- trifluoromethyl-pyridin-3-yl)-amide. ¹ H-NMR (400 MHz, DMS(W ₆ ): δ ppm 7.37 (d, J=8.59 Hz, 1 H), 7.88 (dd, J=8.84, 2.27 Hz, 1 H), 7.93 (d, J=8.59 Hz, 1 H), 8.07 (s, 1 H), 8.41 (d, J=8.59 Hz, 1 H), 8.97 (s, 1 H), 12.29 (s, 1 H), 12.88 (s, 1 H), 15.79 (s, 1 H). MS : m/z, (ES+) =428, (ES-) = 430.

vii. E2a 4-Hydroxy-2-oxo-l,2-dihydro-quinoline-3-carboxylic acid (4-hexyloxy- phenyl)-amide. MS : m/z, (ES+) = 381, (ES-) = 379.

viii. E2b

4-Hydroxy-2-oxo- 1 ,2-dihydro-quinoline-3-carboxylic acid (4-cyclohexyl- phenyl)-amide. MS : m/z, (ES+) = 363, (ES-) = 361.

ix. E2c

4-Hydroxy-2-oxo-l,2-dihydro-quinoline-3-carboxylic acid (2-carbamoyl- phenyl)-amide. MS : m/z, (ES+) = 324, (ES-) = 322.

x. E2d

4-Hydroxy-2-oxo-l ,2-dihydro-quinoline-3-carboxylic acid (4-methoxy- phenyl)-amide. MS: m/z, (ES+) = 311, (ES-) = 309.

xi. E2e

4-Hydroxy-2-oxo-l ,2-dihydro-quinoline-3-carboxylic acid (4-phenoxy- phenyO-amide. MS: m/z, (ES+) = 373, (ES-) = 371.

xii. E2f

4-Hydroxy-2-oxo-l ,2-dihydro-quinoline-3-carboxylic acid biphenyl-4-yl amide. MS: m/z, (ES+) = 357, (ES-) = 355.

xϋ. E2g

4-Hydroxy-2-oxo-l ,2-dihydro-quinoline-3-carboxylic acid (2-amino-4- cyclohexyl-phenyl)-amide. MS: m/z, (ES+) = 379, (ES-) = 377.

xiii. E2h

4-Hydroxy-3-(morpholine-4-carbonyl)-lH-qυinolin-2-one. MS : m/z, (ES+) = 275, (ES-) = 273.

xiv. E2i

2-[4-(4-Hydroxy-2-oxo-l,2-dihydro-qυinoline-3-carbonyl)- piperazin-l-yl]- nicotino-nitrile. MS: m/z = (ES+) = 376, (ES-) = 374.

xv. E2j 3-[4-(4-Chloro-benzoyl)-piperidine-l-carbonyl]-4-hydroxy-lH- qυinolin-2- one. MS: m/z = (ES+) = 411, (ES-) = 409.

xvi. E2k 4-Hydroxy-2-oxo-l,2-dihydro-quinoline-3-carboxylic acid cyclopropylmethyl-amide. MS: m/z, (ES+) = 259, (ES-) = 257.

xvii. E21

4-Hydroxy-2-oxo-l ^-dihydro-quinoline-S-carboxylic acid (4-tert-butyl- cyclohexyl)-amide. MS : m/z, (ES+) = 343, (ES-) = 341.

xviii. E2m

4-Hydroxy-2-oxo-l ,2-dihydro-quinoline-3-carboxylic acid (4-oxazol-5-yl- phenyl)-amide. MS: m/z, (ES+) = 311, (ES-) = 309.

xix. E2n

4-Hydroxy-2-oxo-l ,2-dihydro-quinoline-3-carboxylic acid (3-phenoxy- phenyl)-amide. MS: m/z = (ES+) = 373, (ES-) = 371.

xx. E2o

4-Hydroxy-2-oxo-l ,2-dihydro-quinoline-3-carboxylic acid (2-morpholin-4-yl- ethyl)-amide. MS : m/z, (ES+) = 318, (ES-) = 316.

xxi. E2p

4-Hydroxy-3-[4-(2-morpholin-4-yl-ethyl)-piperazine-l-carb onyl]-lH- quinolin-2-one. MS: m/z = (ES+) = 387, (ES-) = 385.

xxii. E2q

4-Hydroxy-2-oxo- 1 ,2-dihydro-quinoline-3-carboxylic acid (6-trifluoromethyl- pyridin-3-yl)-amide. MS: m/z, (ES+) = 350, (ES-) = 348.

xxiii. E2r

4-Hydroxy-2-oxo-l ,2-dihydro-quinoline-3-carboxylic acid (4-morpholin-4-yl- phenyl)-amide. MS: m/z, (ES+) = 366, (ES-) = 364.

xxiv. E2s

4-Hydroxy-2-oxo- 1 ,2-dihydro-quinoline-3-carboxylic acid (2-phenoxy- phenyl)-amide. MS: m/z, (ES+) = 348, (ES-) = 346.

xxv. E2t

4-Hydroxy-2-oxo-l 2-dihydro-quinoline-3-carboxylic acid (4-pentyl-phenyl)- amide.

xxvi. E2u

4-Hydroxy-2-oxo-l,2-dihydro-quinoline-3-carboxylic acid (4-pentyloxy- phenyO-amide. MS: m/z, (ES+) = 35, (ES-) = 349.

xxvii. E2v 4-Hydroxy-2-oxo-l,2-dihydro-quinoline-3-carboxylic acid (3-benzyloxy- phenyl)-amide. MS: m/z, (ES+) = 387(ES-) = 385.

xxviii. F2a

4-Hydroxy-5-methoxy-2 -oxo-1 ,2-dihydro-quinoline-3-carboxylic acid (4- cyclohexyl-phenyl)-amide. MS: m/z, (ES+) = 393, (ES-) = 391.

xxix. F2b

4-Hydroxy-5-methoxy-2-oxo-l ,2-dihydro-quinoline-3-carboxylic acid (4- phenoxy

xxx. F2c

4-Hydroxy-5-methoxy-2-oxo-l,2-dihydro-quinoline-3-carboxy lic acid (2- carbamoyl-phenyl)-amide. MS: m/z, (ES+) = 354, (ES-) = 352.

xxxi. G2a

4-Hydroxy-l-methyl-2-oxo-l,2-dihydro-quinoline-3-carboxyl ic acid (4- phenoxy-phenyl)-amide. MS: m/z, (ES+) = 387, (ES-) = 385.

xxxii. G2b

4-Hydroxy-l-methyl-2-oxo-l ,2-dihydro-quinoline-3-carboxylic acid [1,5-bis- (4-methoxy-phenyl)-lH-[l,2,4]triazol-3-yl]-amide. ¹ H-NMR (400 MHz, DMSO-J ₆ ): δ ppm 3.71 (s, 3 H), 3.78 (s, 3 H), 3.83 (s, 3 H), 6.97 (d, J=8.59 Hz, 2 H), 7.07 (d,

J=8.59 Hz, 2 H), 7.41 (m, 5 H), 7.70 (d, J=8.59 Hz, 1 H), 7.86 (m, 1 H), 8.16 (d,

J=8.08 Hz, 1 H) 12.99 (s, 1 H), 16.28 (s, 1 H). MS : m/z, (ES+) = 498, (ES-) = 496.

xxxiii. G2c

4-Hydroxy- 1 -methyl-2-oxo- 1 ,2-dihydro-quinoline-3 -carboxylic acid (4- trifluoro-methoxy-phenyl)amide. MS : m/z, (ES+) = 379, (ES-) = 377.

Steps 2-4

SCHEME 5

Step 2:

A. D3

4-Hydroxy-2-oxo-3-(4-phenoxy-phenylcarbamoyl)-l ,2-dihydro-quinoline-6- carboxylic acid.

B mg, 0.22 mmol), DMAP (150 mg uct (20mg, 7% mol/mol)

were combined in a microwave tube. To the mixture was added 1 : 1 dioxane/ethanol (10 niL) followed by DIEA (220 uL, 1.24 mmol). The sealed reaction vessel was purged with a stream of nitrogen for 2 min. The reaction was heated in the microwave at 180 ⁰ C for 10 min. LCMS shows multiple peaks. The crude methyl ester was purified by multiple injections by reverse phase prep LC. The combined fractions were hydrolyzed with dioxane-water-LiOH at 40 ⁰ C. The crude was concentrated under reduced pressure and acidified with AcOH. A fluffy precipitate which formed was isolated by filtration to yield carboxylic acid D3 (26mg). ¹ H-NMR (400 MHz, DMSO-J ₆ ): δ ppm 7.05 (m, 4 H), 7.15 (t, 1 H, J= 7.6 Hz), 7.41 (m, 2 H), 7.48 (d, 1 H, J= 8.6 Hz), 7.68 (d, 2 H, J= 8.6 Hz), 8.19 (d, 1 H, J= 8.6 Hz), 8.57 (s, 1 H), 12.35 (s, 1 H), 12.42 (s, 1 H), 13.10 (s, 1 H). MS: m/z, (ES+) = 417, (ES-) = 415

Step3:

B. D4 4-Hydroxy-6-(morpholine-4-carbony l)-2-oxo- 1 ,2-dihydro-quinoline-3 - carboxylic acid (4-phenoxy-phenyl)-amide.

Carboxylic acid D3 (25 mg, 0.06 mmol), HATU (75 mg, 0.2 mmol), morpholine (25 uL, 0.25 mmol) were dissolved in anhydrous dimethylformamide (2 niL). The resulting mixture was stirred overnight at room temperature during which time a precipitate formed. Solvent was removed under reduced pressure and the resulting solid purified by reverse phase preparative LC to provide amide D4 (5mg). MS : m/z, (ES+) = 486, (ES-) = 484.

Step 4:

C. D5

6- Allyl-4-hydroxy-2-oxo- 1 ,2-dihydro-quinoline-3 -carboxylic acid (4- hexyloxy-phenyl)-amide.

2-Allyl-4,4,5,5-tetramethyl-l ,3,2-dioxa-borolane (30 mg, 0.18 mmol), amide D2e (75 mg, 0.16 mmol) and potassium carbonate (50 mg, 0.34 mmol) were slurried in 3: 1 toluene/water (4 mL). The reaction mixture was purged by slow bubbling of nitrogen through it. Tetrakis(triphenylphosphine)palladium (20 mg, 10% mol/mol) was added and the reaction was heated to reflux. After six hours, the reaction was cooled and acetic acid was added slowly followed by an aqueous workup. Product was isolated by column chromatography and recrystallization. H-NMR (400 MHz, DMSCM ₆ ): δ ppm 0.88 (m, 3 H), 1.31 (m, H), 1.42 (m, 2 H) 1.72 (m, 2 H), 3.27 (s, 2 H), 3.47 (d, J=6.57 Hz, 1 H), 3.96 (t, J=6.32 Hz, 1 H) 5.1 (m, 1 H), 6.0 (m, IH), 6.96 (d, J=8.59 Hz, 1 H), 7.35 (d, IH, J= 8.6 Hz), 7.57 (m, 3H), 7.81 (s, IH), 12.0 (s, IH), 12.5 (s, IH). MS : m/z, (ES+) = 421, (ES-) = 419.

Example 5 Preparation of A dditional Bicyclic Hydroxydicarbonyl Compounds

The general synthetic preparation of additional bicyclic hydroxydicarbonyl compounds of the invention are described below.

SCHEME 6

28 29 30

a1 : R = cyclohexyl a2: R = phenyl a3: R = phenoxyl a4: R = imιdazol-1-yl- a5: R = tπfluoromethyl a6: R = piperidιn-1-yl a7- R = tπfluoromethoxy

31 a1-a7

Reagents: (a) TEA, DCM, methyl malonyl chloride; (b) 0.5 M NaOMe in MeOH, THF, reflux, 2h; (c) aniline, THF 120 ⁰ C, 8 min, microwave synthesizer.

/. Synthesis of intermediates

A. Methyl (2i?)-4-[(3-methoxy-3-oxopropanoyl)amino]-2-inethyl-5- oxo-2,5-dihydrofuran-3-carboxylate (29)

To a stirred solution of methyl (2R)-4-amino-2-methyl-5-oxo-2,5- dihydrofuran-3-carboxylate (28, 0.6 g, 3.5 mmol) in dichloromethane (15 mL) was added triethylamine (0.49 mL, 3.5 mmol), followed by addition of methyl malonyl chloride (0.75 mL, 7.0 mmol) portionwise at 0 ⁰ C under N ₂ atmosphere. The reaction mixture was stirred for further 16 h, then diluted with 50 mL dichloromethane. The organic solution was washed with water and brinea and dried over Na ₂ SO ₄ . The crude material was purified by flash chromatography, eluting with 20-100% EtOAc/ hexane. Fractions containing the desired product were combined and concentrated to afford the title compound as an off-white solid (1.0 g, 95%). MS (ES+): m/z = 272 (M+l) IH NMR (400 MHz, CHLOROFORM-D) δ = 3.50 (s, 2H) 3.68 - 3.76 (m, 1 H) 3.80 (s, 3 H) 3.86 (s, 3 H) 5.28 (b, I H)

B. Methyl (5/?)-4-hydroxy-5-methyl-2,7-dioxo-l,2,5,7- tetrahydrofuro[3,4-Z>]pyridine-3-carboxylate (30, U-5796-027-P1)

To a stirred solution of 29 (0.9 g, 3.0 mmol) in anhydrous THF (30 mL) was added 0.5 M sodium methoxide in MeOH (6.0 mL, 3.0 mmol) portionwise under N ₂ atmosphere, and the resulting mixture was refluxed for 2h. The mixture was cooled and the insoluble salt was filtered and dissolved in 15 mL water. The aqueous solution was washed with DCM and adjusted to pH 1 with 1 N HCl followed by extraction with DCM (3x). The organic phase was combined, dried over Na ₂ SC^, and concentrated to afford the title compound as an off white solid (0.45 g, 60%). MS (ES+): m/z = 240 (M+l ) IH NMR (400 MHz, DMSO-D6) δ = 1.53 (d, J=6.57 Hz, 3H) 3.77 (s, 3 H) 5.55 (q, J=6.57 Hz, 1 H) 12.43 (s, 1 H).

//. Synthesis of examples

A. General procedure for the formation of amides 31 with ester 30:

To a solution of ester 30 (0.21 mmol, 1 eq) in DMF (1.5 mL) was added aniline (0.21 mmol, leq) and the resulting mixture was heated in a microwave synthesizer at 150 ⁰ C for 10 min. A precipitate was generated. The suspension was filtered and the solid was rinsed with cold methanol to afford amides 31.

B. (5R)-7V-(4-cyclohexylphenyl)-4-hydroxy-5-methyl-2,7-dioxo-l, 2,5,7- tetrahydrofuro [3,4-b]pyridine-3-carboxamide (31a3)

To a solution of 30 (50 mg, 0.21 mmol) in DMF (1.5 mL) was added 4- phenoylaniline (39 mg, 0.21 mmol) and the resulting mixture was heated in a microwave synthesizer at 150 ⁰ C for 10 min. A large amount of precipitate was generated. The suspension was filtered and the solid was rinsed with cold methanol to afford the title compound as a white solid (50 mg, 61 %). MS (ES+): m/z = 393 (M+l ) Hz, 3 H) 5.64 (d, J=6.57

Hz, 1 H) 7.05 (dd, ./=16.17, 8.59 Hz, 4 H) 7.13 - 7.18 (m, 1 H) 7.40 (t, J=7.83 Hz, 2 H) 7.66 (d, J=9.09 Hz, 2 H) 12.52 (s, 1 H) 13.21 (s, 1 H) 16.15 (s, IH)

According to the general protocol described above, the following compounds were synthesized:

Compound Structure Name MS:

# m/z

31al (5R)-N-(4-cyclohexylphenyl) 383

-4-hydroxy-5-methyl-2,7- dioxo-l,2,5,7-tetrahydrofuro

[3,4-b]pyridine-3- carboxamide

31a2 (5R)-N-biphenyl-4-yl-4- 377 hydroxy-5-methyl-2,7-dioxo- l,2,5,7-tetrahydrofuro[3,4- b]pyridine-3-carboxamide

31a4 (5R)-4-hydroxy-N-[4-(lH- 367 imidazol- 1 -yl)phenyl] -5- methyl-2,7-dioxo- 1 ,2,5,7- tetrahydrofuro [3 ,4- b]pyridine-3-carboxamide

31a5 (5R)-4-hydroxy-5-methyl- 369

2,7-dioxo-N-[4-

(trifluoromethyl)phenyl] - l,2,5,7-tetrahydrofuro[3,4- b]pyridine-3-carboxamide

31a6 (5i?)-4-hydroxy-5 -methyl- 384

2,7-dioxo-N-(4-piperidin-l- ylphenyl)-l,2,5,7- tetrahydrofuro [3 ,4- δ]pyridine-3-carboxamide

31a7 (5i?)-4-hydroxy-5-methyl- 385

2,7-dioxo-N-[4- (trifluoromethoxy)pheny 1] -

1 ,2,5,7-tetrahydrofuro[3,4- b] pyridine-3 -carboxamide

Example 6 Preparation of Additional Bicydic Hydroxydicarbonyl Compounds

The general synthetic preparation of additional bicyclic hydroxydicarbonyl compou

SCHEME 7

Y = CH ₂ (Me) Y = BocNH (Et)

38 a1 X= BocNH, Y = CH ₂ 37 a1 X= BocNH, Y = CH ₂ (Me) 36 a1 X= BocNH, Y = CH ₂ (Me) 38 a2 X= CH ₂ , Y = BocNH 37 a2 X= CH ₂ , Y = BocNH (Et) 36 a2 X= CH ₂ , Y = BocNH (Et)

39 a1b1-a1b7 X= BocNH, Y = CH ₂ 39 a1b1-a1b7 X= NH ₂ , Y = CH ₂ 39 a2b1-a2b7 X= CH ₂ , Y = BocNH 39a2b1-a2b7 X= CH ₂ , Y = NH ₂

a1 b1 (trans), a2b1 : R = cyclohexyl a1b2, a2b2 R = phenyl a1b3, a2b3 R = phenoxyl a1b4, a2b4 R = 1H-imidazole a1b5, a2b5 R = 2-pιperazin-1-yl-ethanol a1b6 (trans), a2bδ- R = 1 H-piperidine a1b7, a2b7 R = 1 H-pyrιdιn-2-one a1b8, a2b8: R = trifluoromethyl a1b9, a1 b9: R = pyrrolidin-1-yl

Reagents: (a) Boc ₂ O, Na ₂ CO ₃ aq., THF, 0 ⁰ C to rt; (b) Boc ₂ O, Pd-C, H ₂ , EtOH; (c) NH ₃ in EtOH, MeOH, reflux; (d) NaBH(OAc) ₃ , HOAc, MeCN, O ⁰ C, (e) ClCOCH ₂ COOMe, TEA, DCM; (f) 0.5M NaOMe in MeOH, THF, reflux, 2h; (g) aniline, THF 120 ⁰ C, 8 min, microwave synthesizer; (h) 4M HCl in dioxane, iPrOH, 8O ⁰ C.

/. Synthesis of intermediates

A. 1-tert-Butyl 3-methyl 4-oxopiperidine-13-dicarboxylate (34al)

Methyl 4-oxo-3-piperidine-carboylate hydrochloride (5 g, 30.2 mmol) was suspended in 60 niL THF and charged with Boc anhydride (6.6 g, 30.2 mmol) and sodium bicarbonate 2N aqueous solution (60 mL, 4.0 mmol) at 0 ⁰ C. The reaction mixture was allowed to stir at room temperature for 16 h. The reaction mixture was washed with water (2 x 30 mL) and brine (40 mL), dried over Na ₂ SO ₄ and concentrated in vacuo to afford the title compound as colorless oil (9 g, 93%). MS (ES-): m/z = 256 (M-I) IH NMR (400 MHz, CHLOROFORM-D) δ = 1.48 (s, 9 H) 2.37 (t, J=5.81 Hz, 2 H) 2.60-2.63 (m, I H) 3.56 (t, J=5.81 Hz, 2 H) 3.78 (s, 3 H) 4.05 (s, 2 H)

B. 1-tert-Butyl 3-methyl 4-amino-5,6-dihydropyridine-l,3(2H)- dicarboxylate (35al)

To a solution of 34al (3 g, 10.5 mmol) in methanol (43 mL), was added ammonium in MeOH (7.5 mL, 52 mmol, 7M). The resulting mixture was heated under reflux for 8 hours. The reaction mixture was cooled to room temperature, and the solvent was evaporated off under reduced pressure. The obtained crude product was dissolved in DCM (40 mL) and the organic layer was washed with water (2 X 50 mL) and brine (2 x 50 mL), dried over sodium sulfate and concentrated to afford a yellow oil. The crude product was purified by flash chromatography eluting with 40% EtOAc in hexane. Fractions containing the desired product were combined and concent d (2.8 g, 99%). MS

(ES+): m/z = 257 (M+l) IH NMR (400 MHz, CHLOROFORM-D) δ = 1.46 (s, 9 H) 2.29 (t, J=S. Sl Hz, 2 H) 3.52 (t, J=5.81 Hz, 2 H) 3.70 (s, 3 H) 4.06 (s, 2 H)

C. l-tert-Butyl-3-methyl 4-aminopiperidine-l,3-dicarboxylate (36al)

To a solution of 35al (2.5 g, 9.3 mmol) in acetonitrile (43 mL), was added triacetoxyborohydride (5 g, 23.6 mmol) and acetic acid (30 mL) at 0 ⁰ C. The resulting mixture was stirred at 0 ⁰ C for 2 hours. The reaction mixture was concentrated in vacuo and diluted with water. The aqueous phase was adjusted to pH 8 and washed with DCM (3 x 50 mL). The organic phases were combined and dried over Na ₂ SCU and afforded the title compound as a white solid (1.8g, 68%). MS

(ES+): m/z = 259 (M+l) IH NMR (400 MHz, CHLOROFORM-D) δ = 1.45 (s, 9 H) 1.65 - 1.75 (m, 1 H) 1.76 - 1.87 (m, 1 H) 2.25 (s, 3 H) 2.67 (ddd, J=7.96, 3.92, 3.79 Hz, 1 H) 3.34 - 3.43 (m, 1 H) 3.48 - 3.58 (m, 1 H) 3.63 (s, 1 H) 3.69 - 3.79 (m, 3H)

D. Methyl l-(tert-butoxycarbonyl)-4-[(3-methoxy-3- oxopropanoyl)amino]piperidine-3-carboxylate (37al)

To a stirred solution of 36al (1 g, 3.9 mmol) and triethylamine (546 μL, 3.9 mmol) in dichloromethane (20 mL) was added methyl malonyl chloride (460 μL, 4.3 mmol) portionwise at 0 ⁰ C under N ₂ atmosphere. The reaction mixture was stirred for further 16 h, then diluted with 30 mL dichloromethane. The organic solution was washed with water and brine and dried over Na ₂ SO ₄ . The solvent was then removed to give the title compound as a white solid (1.2 g, 78%). The material was used without = 357 (M-I) IH NMR

(400 MHz, CHLOROFORM-D) δ = 1.44 (s, 9 H) 1.60 (s,l H) 1.65 - 1.75 (m, 1 H) 1.93 - 2.04 (m, 1 H) 2.81 (d, J=3.54 Hz, 1 H) 2.97 (t, J=I 1.62 Hz, 1 H) 3.15 (dd, J=13.89, 3.28 Hz, 1 H) 3.29 - 3.31 (m, 2 H) 3.72 (s, 3H) 3.75 (s, 3 H) 4.26 - 4.34 (m, 1 H) 4.37 (dd, J=I 3.89, 2.27 Hz, 1 H) 7.74 (d, J=8.O8 Hz, 1 H)

E. Methyl 6-(tert-butoxycarbonyl)-4-hydroxy-2-oxo-l,2,4a,5,6,7,8,8a- octahydro-l,6-naphthyridine-3-carboxylate (38al)

To a stirred solution of 37al (2.4 g, 6.7 mmol) in anhydrous THF (30 rnL) was added sodium methoxide in MeOH (13 mL, 6.5 mmol, 0.5 M) portionwise under N ₂ atmosphere. The resulting mixture was refluxed for 2h, then concentrated in vacuo. The resulting residue was dissolved in 20 mL water and washed with DCM (30 mL). The aqueous phase was adjusted to pH 1 and washed with DCM (3 x 70 mL). The combined organic phases were dried over Na ₂ SO ₄ and concentrated under the reduced pressure to afford the title compound as a off-white solid (1.2 g, 52%). MS (ES+): m/z = 327 (M+l) IH NMR (500 MHz, DMSO-D6) δ = 1.35 - 1.42 (m, 9 H) 1.51- 1.75 (m, IH) 1.96 (d, J=13.24 Hz, 0.5 H) 2.14 (s, 0.5 H) 2.39-2.35 (m, 0.5H) 2.62 (s, 0.5 H) 3.05 (s, 0.5 H) 3.10 - 3.19 (m, 0.5 H) 3.56 (s, 1 H) 3.58 - 3.67 (m, 1 H) 3.70 (d, J=3.78 Hz, 3 H) 3.75-3.84 (m, 0.5 H) 3.94 - 4.04 (m, 1 H) 4.29 (s, 0.5 H)

F. 3-Oxo-piperidine-l,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (34a2)

To ethyl -N-benzyl - 3-oxo-4-piperidinecarboxylate hydrochloride (25 g, 95.7 mmmol 05.2 mmol),

triethylamine (16 mL, 114.8 mmol) and Pd(0H) ₂ (1.34g). The reaction mixture was hydrogenated under 60 psi hydrogen for 10 hours. The reaction mixture was filtered and concentrated under reduced pressure, then diluted with EtOAc and washed with water, brine and sodium sulfate to provide a yellow oil (19g, 72% ) MS (ES-): m/z = 270 (M-I) IH NMR (400 MHz, CHLOROFORM-D) δ = 1.26 (t, J=7.14Hz, 3 H) 1.41 (s, 9 H) 2.23 - 2.32 (m, 2 H) 3.06 (d, J=7.33 Hz, 2 H) 3.44 (t, J=5.75 Hz, 2 H) 3.98 (s, 1 H) 4.19 (q, J=7.07 Hz, 2 H)

G. 5-Amino-3,6-dihydro-2H-pyridine-l,4-dicarboxylic acid 1-tert- butyl ester 4-ethy] ester (35a2)

To a solution of 34a2 (24 g, 88.5 mmol) was added ammonium in EtOH (88 mL, 180 mmol, 2M). The reaction mixture was heated to 6OC for 3 h. The solvent was evaporated under reduced pressure to afford a yellow solid ( 23 g, 91.5% ). MS (ES+): m/z = 271 (M+l)

H. 3-Amino-piperidine-l,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (36a2)

To a mixture of 35a2 (3.O g, 11.1 mmol) in acetonitrile (3OmL) and acetic acid (30 mL was added NaBH(OAc) ₃ (6.19 g, 27.7 mmol) at O ⁰ C for 3 hours. The reaction mixture was concentrated under vacuo. The residue was diluted with DCM, washed with Na ₂ S0zt, brine, dried over MgSO ₄ and concentrated in vacuo to yield the product (2.0 g, 66.2%) without further purification. MS (ES+): m/z = 273 (M+l)

I. 3-(2-Methoxycarbonyl-acetylamino)-piperidine-l,4-dicarboxyli c acid 1-tert-butyl ester 4-ethyl ester (37a2)

To a stirred solution of 36a2 (2.18 g, 7.6 mmol) and triethylamine (1.32 mL,

9.43mmol) in dichloromethane (25 mL) was added methyl malonyl chloride (977 μL, 9.125 mmol) portionwise at 0 ⁰ C under N ₂ atmosphere. The reaction mixture was stirred for further 16 h, then diluted with 30 mL dichloromethane. The organic solution was washed with water and brine and dried over Na ₂ SO ₄ . The solvent was then removed to give the title compound as a white solid (2.15 g, 76.7%). The material was used without further purification in the next step. MS (ES-): m/z = 371 (M-I)

4-Hydroxy-2-oxo-2,4a,5,6,8,8a-hexahydro-lH-[l,7]naphthyri dine-3,7- dicarboxylic acid 7-tert-butyl ester 3-methyl ester (38a2)

To solution of 37a2 (2.48 g, 6.65 mmol) in MeOH was added sodium methoxide in MeOH (27 mL, 14 mmol, 0.5 M) portionwise under N ₂ atmosphere. The resulting mixture was refluxed for 2h, then concentrated in vacuo. The resulting residue was dissolved in 20 mL water and washed with DCM (30 mL). The aqueous phase was adjusted to pH 1 and extracted with DCM (3 x 70 mL). The combined organic phases were dried over Na ₂ SO ₄ and concentrated under the reduced pressure to afford crude product. The crude product was purified by flash column chromatography (50% EtOAc in hexane, then 100% EtOAc, then 2% MeOH in DCM as eluen 1.0 g, 46%). The

compounds exists as a ~ 1 :1 mixture of cis and trans isomers. HRMS : meas. 327.1554 (M+l) calc. 327.1556

This compound class (compounds 38, 39 and 40) exists as two tautomers in DMSO-d6.

//. Synthesis of examples

A. General Procedure for the formation of amides 39 from esters 38 with anilines: To a solution of 38 (0.28-3.8 mmol, 1 eq) in THF (2-15 mL) was added aniline

(0.28-3.8 mmol, 1 eq). The resulting mixture was heated in a microwave synthesizer at 120 ⁰ C for 10 min, then concentrated in vacuo. The crude compound was triturated with MeOH (and in some cases with additional hexane) to afford amides 39. In order to obtain a single diastereomer compound, the crude material was diluted in DCM (40 mL) and washed with water and brine. The organic phase was dried over sodium sulfate and concentrated and the mixture was purified by flash chromatography on silica gel eluting with 40% EtOAc and hexane to afford both cis and trans amides.

B. Trans-tert-butyl 4-hydroxy-3-[(7V-(4- piperidin-1-yl- phenyl)amino)carbonyl]-2-oxo-l,4a,5,7,8,8a-hexahydro-l,6-nap hthyridine-6(2H)- carboxylate (39alb6-trans)

To a solution of 38a 1 (1.3 g, 3.8 mmol) in THF (15 mL) was added 4- piperidinoaniline (667 mg, 3.8 mmol). The resulting mixture was heated in a microwave synthesizer at 120 ⁰ C for 10 min, then concentrated in vacuo and diluted with DCM (40 mL). The organic solution was washed with water (2 x 30 mL) and brine (2 30 L) Th i h dri d di ulfate and concentrated to afford y flash chromatography

eluting with 40% EtOAc and hexane. Both cis and trans diastereomers were collected. The title compound was isolated as a white solid (500 mg, 27%). MS (ES+): m/z = 471 (M+l) IH NMR (600 MHz, DMSO-D6) δ = 1.41 (s, 9 H) 1.52 (d, J=5.29 Hz, 2 H) 1.58 - 1.63 (m, 4 H) 1.95-2.01 (m, 1 H) 2.35 (t, J=12.00 Hz, 1 H) 2.61-2.67 (m, 1 H) 3.07 - 3.12 (m, 4 H) 3.39-3.44 (m, IH) 4.05 (S, IH) 4.38 (s, 1 H) 6.91 (t, J=8.59 Hz, 3 H) 7.31 - 7.36 (m, 3 H) 8.98 (s, 1 H) 11.68 (s, 1 H)

C. 4-Hydroxy-2-oxo-3-(4-piperidin-l-yl-phenylcarbamoyl)- 2,4a,5,6,8,8a-hexahydro-lH-[l,7]naphthyridine-7-carboxyIic acid tert-butyl ester (41a2b6)

To a solution of 38a2 (400 mg, 1.23 mmol) in THF (5 mL) was added 4- piperidinoaniline (238 mg, 1.35 mmol) and the resulting mixture was heated in a microwave synthesizer at 100 ⁰ C for 5 min. From the reaction mixtures THF was evaporated, triturated with 0.5 ml MeOH and 0.5 ml hexane and then filtered to collected a light brown solid (432 mg 74.7% ) MS (ES+): m/z 471 (M+l) IH NMR (600 MHz, DMSO-D6) δ = 1.40 (s, 9 H) 1.52 (d, J=5.10 Hz, 2 H) 1.61 (m, 4 H) 2.06 (d, j=13.97 Hz, 1 H) 2.43 (m, 1 H) 3.10 (q, J=5.10 Hz, 4 H) 3.19 (m, 1 H) 3.31 (q, J=4.90 Hz, 4 H) 4.06 (s, 1 H) 4.30 (s, 1 H) 6.91 (m, 2 H) 7.33 (m, 2 H) The following compounds were prepared as described above:

Compound Structure Name MS:

# m/z (M+l)

39 albl p. tert-Butyl 4-hydroxy-3-[(N- 470 f S f _i ^^ cyclohexylphenyl)amino)carbo " ^" OC X ^a nyl]-2-oxo-l,4a,5,6,7,8,8a-

B ° hexahydro-l,6-naphthyridine-

6(2H)-carboxylate

39 alb3 tert-Butyl 4-hydroxy-3-[(N-(4- 480 carbony

hexahydro- 1 ,6-naphthyridine-

6(2H)-carboxylate alb4 tert-Butyl 4-hydroxy-3-[(N-(4- 454

(lH-imidazol-1- yl)phenyl)amino)carbonyl]-2- oxo-l,4a,5,7,8,8a-hexahydro-

1 ,6-naphthyridine-6(2H)- carboxylate

alb5 tert-Butyl 4-hydroxy-3-{[N-(4- 516 (4-(2-hydroxy-ethyl)-

-COO piperazin-1-yl)- phenyl)amino]carbonyl} -2- oxo-1 ,4a,5, 7,8, 8a-hexahydro- 1 ,6-naphthyridine-6(2H)- carboxylate alb6-cis Cis-tert- Butyl 4-hydroxy-3- 471 [(N-(4- piperidin-1-yl- phenyl)amino) carbonyl]-2-oxo-l,4a,5,7,8,8a- hexahydro- 1 ,6-naphthyridine- 6(2H)-carboxylate alb7 tert-Butyl 4-hydroxy-3-[(N-(6- 404 oxocyclohexa-2,4-dien- 1 - yl)amino)carbonyl] -2-oxo- 1 ,4a,5,7,8,8a-hexahydro- 1 ,6- naphthyridine-6(2H)- carboxylate

a2b9 457

1 yl phenyl) amide7carboxylic

39a2b6 4-Hydroxy-2-oxo- 1,2,5,6,7,8- 471 hexahydro-[l,7]naphthyridine- 3-carboxylic acid (4-piperidin- 1 -yl-phenyl)-amide7carboxylic acid tert-butyl ester

D. General Procedure for the removal of the Boc-protecting group from compounds 39 to form compounds 40:

To a solution of 39 (0.1-1 mmol, 1 eq) in isopropanol (1-10 mL) was added HCl in dioxane (0.6-6 mmol, 4M, 6 eq) at 0 ⁰ C. The reaction mixture was heated to 80 ⁰ C and refluxed for 2 h. Solid precipitated out. The suspension was filtered and the solid was rinsed with cold isopropanol to afford amides 40 as hydrochloride salts.

E. trans-4-Hydroxy-2-oxo-λ ^r -(4-piperidin-l-yl-phenyI)-

1 ,2,4a,5,6,7,8,8a-octahydro-l ,6-naphthyridine-3-carboxamide (40al b6-trans)

To a solution of 39alb6-trans (500 mg, 1 mmol) in isopropanol (10 mL) was added HCl in dioxane (1.5 mL, 6.0 mmol, 4M) at 0 ⁰ C. The reaction mixture was heated at 80 ⁰ C and refluxed for 2 h until solid precipitated out. The suspension was filtered and the solid was rinsed with cold isopropanol to afford the title compound as a white solid (330 mg, 80%). MS (ES+): m/z = 371 (M+l) IH NMR (500 MHz, DMSO-D6) δ = 1.50-2.0 (m, 5 H) 2.15 (d, J=I 1.98 Hz, 2 H) 2.83 - 2.93 (m, 3 H) 3.37 (d, J=I 1.98 Hz, 3 H) 3.44 (s, 3 H) 3.56 - 3.66 (m, 2 H) 7.65 (s, 2H) 9.55-9.40 (m, 2H)

The compounds in the following table were prepared as described above in the general protocol:

Compound Structure Name MS:

# m/z

4OaIbI N-Cyclohexylphenyl-4-yl-4- 370 hydroxy-2-oxo-

^■ oX- 1 ,2,4a,5,6,7,8,8a-octahydro-

1 ,6-naphthyridine-3- carboxamide

4OaIbI- Trans-N-Cyclohexylphenyl- 370 trans 4-y 1-4 -hydroxy-2 -oxo- 1 ,2,4a,5,6,7,8,8a-octahydro-

1 ,6-naphthyridine-3- carboxamide

40al b2 N-Biphenyl-4-yl-4-hydroxy- 364

2-oxo-l, 2,4a,5,6,7,8,8a-

O# octahydro-1 ,6-naphthyridine-

3-carboxamide

40al b3 4-Hydroxy-2-oxo-N-(4- 380

CCv phenoxyphenyl)-

1 ,2,4a,5,6,7,8,8a-octahydro-

1 ,6-naphthyridine-3- carboxamide

40al b4 4-Hydroxy-N-[4-(lH- 354 imidazol- 1 -yl)phenyl]-2-oxo-

1 ,2,4a,5,6,7,8,8a-octahydro-

1 ,6-naphthyridine-3- carboxamide

40al b5 4-Hydroxy-N-{4-[4-(2- 416 hydroxy-ethyl)- piperazin- 1 -yl]-phenyl } -2- oxo-1 , 2,4a,5,6,7,8,8a- octahydro- 1 ,6-naphthyridine-

3-carboxamide

40alb6 .0 4-Hydroxy-2-oxo-N-(4- 371 piperidin- 1 -yl-phenyl)-

ΌX ^>' l,2,4a,5, 6,7,8, 8a-octahydro-

1 ,6-naphthyridine-3- carboxamide

40alb6-cis Cis-4-Hydroxy-2-oxo-N-(4- 371 piperidin- 1 -yl-phenyl)-

1 ,2,4a,5,6,7,8,8a-octahydro-

1 ,6-naphthyridine-3- carboxamide

40al b8 4-Hydroxy-N-(4- 356 trifluoromethylphenyl)-2- oxo-l,2,4a,5,6,7,8,8a- octahydro- 1 ,6-naphthyridine-

3-carboxamide

40al b9 O 4-Hydroxy-2-oxo-N-(4- 357 pyrrolidin- 1 -ylphenyl)-

"sλA " 1 ,2,4a,5,6,7,8,8a-octahydro-

40alb7 4-hydroxy-2-oxo-N-(6- 304 o56 ^' oxocyclohexa-2,4-dien- 1 -yl)-

1 ,2,4a,5,6,7,8,8a-octahydro-

1 ,6-naphthyridine-3- carboxamide

40a2bl 370 -

40a2b8 356 -

40a2b6 371 - e

40a2b9 357

dine-3 carboxylicacid(4-pyrro lidin- 1 -yl-phenyl)-amide

Example 7 Preparation of Additional Bicy die Hydroxy dicarbonyl Compounds

The general synthetic preparation of additional bicyclic hydroxydicarbonyl compounds of the invention are described below.

SCHEME 8

35a1 X= BocN, Y = CH ₂ (Me) 41 a1 X= BocN Y = CH ₂ (Me) 42 a1 X= BocN, Y = CH ₂ 35a2 X= CH ₂ , Y = BocN (Et) 41 a2 X= CH ₂ , Y = BocN (Et) 42a2 X= CH ₂ , Y = BocN

44 a1b1 - albX X= NH, Y = CH ₂ 43 a1b1- a2bXX= BocN, Y= CH ₂ 44 a2b1 - a2bX X= CH, Y=NH 43 a2b1- a2bx X= CH ₂ , Y = BocN

a1b1 (trans), a2b1 R = cyclohexyl a1b2, a2b2 R = phenyl

Reagents: (a) ClCOCH ₂ COOMe, TEA, DCM; (b) 0.5M NaOMe in MeOH, THF, reflux, 2h; (c) aniline, THF 120 ⁰ C, 8 min, microwave; (d) 4M HCl in dioxane, iPrOH, 8O ⁰ C

/. Synthesis of intermediates

A. Methyl l-/er/-butyl 3-methyl 4-[(3-methoxy-3- oxopropanoyl)amino]-5,6-dihydropyridine-l,3(2H)-dicarboxylat e (41a)

To a stirred solution of 1 -tert-butγ\ 3-methyl 4-amino-5,6-dihydropyridine- l,3(2H)-dicarboxylate (35a, synthesis see Scheme 7, 1 g, 3.9 mmol) in dichloromethane (20 mL) was added triethylamine (0.55 mL, 3.9 mmol) followed by methyl malonyl chloride (0.46 mL, 4.3 mmol) portionwise at 0 ⁰ C under N ₂ atmosph Th ti i t ti d f f th 16 h then diluted with 250 mL dich water and brine, dried

over Na ₂ SO ₄ . The solvent was then removed to give the title compound as a yellow solid (1.2 g, 78%). The material was used without further purification in the next step. MS (ES-): m/z = 355 (M-I)

B. Methyl 6-tert-butyl 3-methyl 4-hydroxy-2-oxo-6-phenyl-l,2,5,6- tetrahydropyridine-3-carboxylate (42a, U-5796-067-P1)

To a stirred solution of 41al (1.2g, 3.4 mmol) in anhydrous THF (15 mL) was added sodium methoxide (6.7 mL, 3.4 mmol, 0.5 M in MeOH) portionwise under N ₂ atmosphere, and the resulting mixture was refluxed for 2h. The mixture was cooled and the insoluble salt was filtered and dissolved in 10 mL water. The aqueous solution was adjusted to pH 2 with 1 N HCl and extracted with EtOAc (3x). The organic phase was combined, dried over Na ₂ SO ₄ , and concentrated. The crude material was Recry stall ized from EtOAc/hexane (2:1) to afford the title compound as an off white solid (400 mg, 35%). MS (ES+): m/z = 325 (M+l) IH NMR (600 MHz, DMSO-D6) δ = 1.39 - 1.45 (m, 9 H) 2.54 (t, J=5.19 Hz, 2 H) 3.51 - 3.58 (m, 2 H) 3.82 (s, 3 H) 4.15 (s, 2 H) 11.49 (s, 1 H) 13.34 (s, 1 H)

C. 5-(2-Methoxycarbonyl-acetylamino)-3,6-dihydro-2H-pyridine-l, 4- dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (41a2)

To a stirred solution of 5-amino-3,6-dihydro-2H-pyridine-l,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (35a2), synthesis see Scheme 7, (2.56 g, 9 mmol) in dichloromethane (25 mL) was added triethylamine (1.39 mL, 9.93 mmol), followed by meth ise at 0 ⁰ C under N ₂

atmosphere. The reaction mixture was stirred for further 12 h at it, then diluted with 250 mL dichloromethane. The organic solution was washed with water and brine, dried over Na ₂ SO ₄ . The solvent was then removed to give the title compound as a yellow solid (2.33 g, 66%). The material was used without further purification in the next step. MS (ES-): m/z = 369 (M-I)

D. 4-Hydroxy-2-oxo-2,5,6,8-tetrahydro-lH-[l,7]naphthyridine-3,7 - dicarboxylic acid 7-tert-butyl ester 3-methyl ester (42a2)

To a stirred solution of 41a2 (2.33 g, 6 mmol) in anhydrous MeOH (10 mL) was added sodium methoxide (61 mL, 30 mmol, 0.5 M in MeOH) portionwise under N ₂ atmosphere, and the resulting mixture was refluxed for 3h. The mixture was cooled and the insoluble salt was filtered and dissolved in 10 mL water. The aqueous solution was adjusted to pH 2 with 1 N HCl and extracted with EtOAc. The organic phase was combined, dried over Na ₂ SO ₄ , and concentrated. The crude material was recrystallized from isopropanol to afford the title compound as an off white solid (825 mg, 40.3%). MS (ES+): m/z = 325 (M+l) IH NMR (400 MHz, DMSO-D6) δ = 1.41 (s, 9 H) 2.38 (t, J=5.56 Hz, 2 H) 3.52 (t, J=5.56 Hz, 2 H) 3.81 (s, 3 H) 4.26 (s, 2 H)

//. Synthesis of examples

A. General procedure for the formation of amides 43 from esters 42:

To a solution of ester 42 (0.22 mmol, 1 eq) in DMF (1.5 mL) was added aniline (0.22 mmol, 1 eq). The resulting mixture was heated in a microwave synthesizer at 150 ⁰ C for 10 min. Precipitate was generated. The suspension was filtered and the solid was rinsed with cold methanol to afford amides 43.

B. tert-Butyl 3-[(7V-(4-cyclohexylpheπyl)amino)carbonyl]-4-hydroxy- 2-oxo-l,5 7 8 t t h d l 6 hth idi 6(2H) b late (43albl)

To a solution of 42al (75 mg, 0.22 mmol) in DMF (1.5 mL) was added 4- cyclohexylaniline (38.5 mg, 0.22 mmol) and the resulting mixture was heated in a microwave synthesizer at 150 ⁰ C for 10 min. The suspension was filtered and the solid was rinsed with cold methanol to afford the title compound as a white solid (70 mg, 65%). MS (ES+): m/z = 468 (M+l) IH NMR (600 MHz, DMSO-D6) δ = 1.24 (m, 1 H) 1.34 (m, 2 H) 1.38 (m, 2 H) 1.43 (s, 9 H) 1.70 (d, J=12.00 Hz, 1 H) 1.78 (d, J=6.00 Hz , 4 H) 2.62 (s, 2 H) 3.58 (s, 2 H) 4.20 (s, 2 H) 7.23 (d, J=7.37 Hz, 2 H) 7.51 (d, J=7.55 Hz, 2 H) 1 1.99 (s, 1 H) 12.45 (s, 1 H) 15.71 (s, 1 H)

C. tert-Butyl -3-[(iV-(4-cyclohexylphenyl)amino)carbonyl]-4-hydroxy- 2-oxo-l,5,7,8-tetrahydro-l,6-naphthyridine-6(2H)-carboxylate (43a2bl)

To a solution of 42a2 (144.7 mg, 0.44 mmol) in TηF (2 mL) was added 4- cyclohexyl aniline (85.4 mg , 0.48 mmol). The reaction mixture was heated at 100 ⁰ C in a microwave synthesizer for 5 minutes. The suspension was filtered and the solid was rinsed with cold isopropanol to afford the title compound as a white solid (60 mg, 29 %). MS (ES+): m/z = 468 (M+l) 1η NMR (600 MHz, DMSO-D6) δ = 1.22 (d, J=I 1.62 Hz, 2 H) 1.33-1.43 (m, 13H) 1.70 (d, J=I 1.62 Hz, 2H) 1.78 (d, J=9.09 Hz, 4H) 3.56 (d, J=12.09 Hz, 2 H) 3.68 (s, 1 H) 3.94 (s, IH) 7.21 (s, 2 H), 7.75 (s, 2 H) The compound below was prepared in a analogous manner:

Compo MS:

# m/z

43alb2 469

.0 tert-Butyl 4-hydroxy-3 [(N- (4-piperidin- 1 -yl-phenyl)- amino)carbony 1] -2 -OXO- l,5,7,8-tetrahydro-l,6- naphthyridine-6(2H)- carboxylate

D. General procedure for Boc deprotection of amides 43 to form compounds 44:

To a solution of 43 (0.1 nimol, 1 eq) in isopropanol (2 mL) was added 4 M HCl in dioxane (0.64 mmol, 0.64 eq) at 0 ⁰ C. The reaction mixture was heated at 80 ⁰ C and refluxed for 2 h until large amounts of solid precipitated out. The suspension was filtered and the solid was rinsed with cold isopropanol to afford amides 44 as hydrochloride salts.

E. iV-Cyclohexylphenyl-4-yl-4-hydroxy-2-oxo-l,2,5,6,7,8-hexahyd ro- l,6-naphthyridine-3-carboxamide (44albl)

To a solution of 43albl (50 mg, 0.1 mmol) in isopropanol (2 mL) was added 4 M HCl in dioxane (160 μL, 0.64 mmol) at 0 ⁰ C. The reaction mixture was heated at 80 ⁰ C and refluxed for 2 h. The suspension was filtered and the solid was rinsed with cold isopropanol to afford the title compound as a white solid (40 mg, 94%). MS (ES+): m/z 368 (M+l) 1 η NMR (600 MHz, DMSO-D6) δ = 1.04 (d, J=6.04 Hz, 1 H) 1.43 (b, 2 H) 1.89 (b, 4H) 2.90 (t, J=5.67 Hz, 2 H) 3.37 (s, 3 H) 3.56 (d, J=12.09 Hz, 2 H) 3.68 (s, 1 H) 3.94 (s, 2 H) 7.75 (s, 2 H) 9.72 (s, 2 H) 12.29 (s, 1 H) 12.52 (s, 1 H) 15.57 (s, 1 H)

F. 4-Hydroxy-2-oxo-1^2,5,6,7,8-hexahydro-[l,7]naphthyridine-3- carboxyli id (4 l h l h l) id (44 2bl)

To a solution of 43albl (15 mg, 0.032 mmol) in isopropanol (0.5 mL) was added 4 M HCl in dioxane (59 μL, 0.24 mmol) at 0 °C. The reaction mixture was heated at 70 ⁰ C and refluxed for 2 h. The suspension was filtered and the solid was rinsed with cold isopropanol to afford the title compound as a white solid (12.7 mg, 75 %). MS (ES+): m/z 368 (M+l) IH NMR (400 MHz, DMSO-D6) d = 1.23 (d, J=I 1.12 Hz, 1 H) 1.38 (m, 4 H) 1.70 (d, J=12.13 Hz, 1 H) 1.79 (d, J=9.60 Hz, 4 H) 2.64 (t, J=5.56 Hz, 2 H) 4.10 (s, 3 H) 7.24 (d, J=7.58 Hz, 2 H) 7.52 (d, J=8.08 Hz, 2 H) 9.51 (s, 2 H) 12.12 (s, 1 H) 12.37 (s, 1 H)

The compounds in the following table were prepared as described above:

Compound Structure Name MS:

# m/z

44alb2 .0 4-Hydroxy-2-oxo-N-(4- 369 piperidin- 1 -yl-phenyl)- l,2,5,6,7,8-hexahydro-l,6- naphthyridine-3- carboxamide

44a2b2 4-Hydroxy-2-oxo- 369 1,2,5,6,7,8-hexahydro-

[ 1 ,7]naphthyridine-3 - carboxylic acid (4-piperidin- 1 -yl-phenyl)-amide

Example 8 Preparation of Additional Bicyclic Hydroxydicarbonyl Compounds

The general synthetic preparation of additional bicyclic hydroxydicarbonyl compou

SCHEME 9

45 a1 X = CH ₂ (CiS) 46 a1 X = CH ₂ (CiS) 47a1 X = CH ₂ (CiS) 45 a2 X = NBoc (trans) 46 a2 X = NBoc (trans) 47 a2 X = NBoc (trans)

48 a1b1-a1b7 X = CH ₂ (cιs) 49 a2b1-a2b6 and a2b8 (trans)

48 a2b1-a2b6 and a2b8 X = BocNH (trans)

a1b1 , a2b R ¹ 4-cyclohexylphenyl a1b2, a2b2 R' 4-bιphenyl a1b3, a2b3 R ¹ 4-phenoxyl a1 b4, a2b4 R ¹ 4-ιmιdazol-1-yl-phenyl a1b5, a2b5 R' 4-tπfluoromethylphenyl a1 b6, a2b6 R ¹ 4-pιpeπdιn-1 -yl-phenyl a1b7 R ^{1 :} 4-(trιfluoromethoxy)phenyl a2b8 R' ^: 3-(6-trιfluoromethyl)pyπdιnyl

Reagents: (a) TEA, DCM; (b) 0.5 M NaOMe in MeOH, THF, reflux, 2h, (c) aniline, THF 120 ⁰ C, 8 min, microwave, (d) 4 M HCl in dioxane, isopropanol, reflux, 2h

/. Synthesis of intermediates

A. Trans-1-tert-butyl 3-methyl 4-[(3-methoxy-3- oxopropanoyl)amino]pyrrolidine-13-dicarboxylate (46a2)

To a stirred solution of trørø ^am no l V Boc S pyrolidinecarboxylic acid ethyl es mmol) in

dichloromethane (40 mL) was added methyl malonyl chloride (830 μL, 7.74 mmol) portionwise at 0 ⁰ C under N ₂ atmosphere. The reaction mixture was stirred for further 16 h, then diluted with 60 mL dichloromethane. The organic solution was washed with water and brine, dried over Na ₂ SC^. The solvent was then removed to give the title compound as a light yellow solid (2.5 g, 59%). The material was used without further purification in the next step. MS (ES+): m/z = 359 (M+ 1)

B. Trans-6-tert-butyl-4-hydroxy-3-methyl-2-oxo-l ,2,4a,5,7,7a- hexahydro-6H-pyrrolo [3,4-b] pyridine-3,6-dicarboxylate (47a2)

To a stirred solution of 46a2 (2.4 g, 4.7 mmol) in anhydrous THF (10 mL) was added 0.5 M sodium methoxide in methanol (9.4 mL, 4.7 mmol) portionwise under N ₂ atmosphere. The resulting mixture was refluxed for 2h, then concentrated in vacuo. The resulting residue was suspended in 50 mL ether and filtered, then the collected solid was dissolved in 50 mL water. The aqueous solution was adjusted to pH 1 with 1 N HCl and extracted with DCM (3 X 40 mL). The organic phase was combined, dried over Na ₂ Sθ ₄ , and concentrated under the reduced pressure to afford the title compound as a off-white solid (1 g, 77%). MS (ES+): m/z = 313 (M+l) IH NMR (400 MHz, CHLOROFORM-D) δ = 1.40 (s, 9 H) 3.14 - 3.24 (m, 1 H) 3.64 (dd, J=I 1.87, 5.31 Hz, 2 H) 3.73 (ddd, J=9.85, 5.31, 5.05 Hz, 2 H) 3.83 (d, J=9.09 Hz, 1 H) 3.93 (s, 3 H) 4.11 - 4.17 (m, 1 H) 5.28 (b, 1 H) 14.22 (s, 1 H)

//. Synthesis of examples

A. General procedure for the formation of amides 48 from esters 47 with anilines:

To a solution of ester 47 (0.19-0.67 mmol, 1 eq) in THF (2-3 mL) was added aniline (0.19-0.67 mmol, 1 eq). The resulting mixture was heated in a microwave synthes The crude product was

purified by silica gel flash chromatography, eluting with 20% EtOAc in hexane. Fractions containing the desired product were concentrated to afford amides 48.

B. Trans-butyl - 3 [(N-(4- cyclohexyl-phenyl)-amino)carbonyl]-4- hydroxy— 2-oxo-2,4a,5,6,7,7a-hexahydro-lH-pyrrolo[3,4-b]pyridine-3- carboxamide (48a2bl)

To a solution of 47a2 (150 mg, 0.46 mmol) in THF (2 mL) was added 4- cyclohexyl aniline (80 mg, 0.46 mmol) and the resulting mixture was heated in a microwave synthesizer at 100 ⁰ C for 10 min, then concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with 20% EtOAc in hexane. Fractions containing the desired product were concentrated to afford the title compound as a white solid (100 mg, 46%) MS (ES+): m/∑ 456 (M+l) IH NMR (400 MHz, DMSO-D6) δ = 1.18 - 1.27 (m, 2H) 1.30 - 1.39 (m, 3 H) 1.40 (s, 9 H) 1.70 (d, J=12.13 Hz, 2 H) 1.78 (d, J=9.60 Hz, 5 H) 3.08-3.13 (m, 1 H) 3.45-3.73 (m, 3 H) 4.12-4.26 (m, IH) 7.19 - 7.24 (m, 2 H) 7.39 - 7.45 (m, 2 H)

As described above and in Scheme 21, the following compounds were prepared as examples:

Compound Structure Name MS: m/z

48albl C/5--N-(4-cyclohexyl 355 phenyl)-4-hydroxy-2-oxo- aY ^< 2,4a,5,6,7,7a-hexahydro-lH- cyclopenta[b]pyridine-3 - carboxamide

48alb2 Cis -τV-biphenyl-4-yl-4- 349 hydroxy-2-oxo-2,4a,5,6,7,7a- ne-3 -

carboxamide

48alb3 Cw-4-hydroxy-2-oxo-N-(4- 365 phenoxyphenyl)-2,4a,5,6,7,7a- hexahydro- 1 H- cyclopenta[b]pyridine-3- carboxamide

48alb4 Cw-4-hydroxy-N-[4-(lH- 339 imidazol-1 -yl)phenyl]-2-oxo-

2,4a,5,6,7,7a-hexahydro-lH- cyclopenta[b]pyridine-3- carboxamide

48alb5 Cw-4-hydroxy-2-oxo- N-[4-( 341 cόό trifluoromethyl)phenyl] -

2,4a,5,6,7,7a-hexahydro-lH- cyclopenta[b]pyridine-3- carboxamide

48alb6 .o Cw-4-hydroxy-2-oxo- N-(4- 356 piperidin-1-yl-phenyl) -

COO ^' 2,4a,5,6,7,7a-hexahydro-lH- cyclopenta[b]pyridine-3 - carboxamide

48alb7 Cw-4-hydroxy-2-oxo-N-[4- 356

(trifluoromethoxy)phenyl] - 2,4a,5,6,7,7a-hexahydro-lH- cyclopenta[b]pyridine-3- carboxamide

C. General Procedure for the Boc deprotection to form compounds

49:

To a solution of 48 (0.17 mmol, 1 eq) in isopropanol (2 mL) was added 4 M HCl in dioxane (1.0 mmol, 5.9 eq) at 0 ⁰ C. The reaction mixture was heated at 80 ⁰ C and refluxed for 2 h. Solid precipitated out. The suspension was filtered and the solid was rinsed with cold isopropanol to afford amides 49 as hydrochloride salts.

D. Trans-ν-(4- cyclohexyl-phenyl)-4-hydroxy~2-oxo-2,4a,5,6,7,7a- hexahydro-lH-pyrrolo[3,4-A]pyridine-3-carboxamide (49a2bl)

To a solution of 48a2bl (80 mg, 0.17 mmol) in isopropanol (2 mL) added 4 M HCl in dioxane (0.25 mL, 1.0 mmol) at 0 ⁰ C. The reaction mixture was heated at 80 ⁰ C and reflux ed for 2 h until a large amount of solid precipitated out. The suspension was filtered and the solid was rinsed with cold isopropanol to afford the title compound as a white solid (50 mg, 84%). MS (ES+): m/z =356 (M+l) IH NMR (400 MHz, DMSO-D6) δ = 1.16 - 1.27 (m, 1 H) 1.30 - 1.42 (m, 4 H) 1.69 (d, J=12.13 Hz, 1 H) 1.77 (d, J=9.09 Hz, 4 H) 2.42-2.47 (m, IH) 3.25 (d, J=7.07 Hz, 2 H) 3.42 (d, J=5.05 Hz, 1 H) 3.47 - 3.65 (m, 2 H) 4.32 (s, 1 H) 7.21 (d, J=8.O8 Hz, 2 H) 7.39 (d, J=8.O8 Hz, 2 H) 9.05 (s, 1 H) 9.35 (s, 2 H) 11.87 (s, 1 H) 12.07 (s, IH)

According to the general procedure described above, the following examples were prepared:

Compound Structure Name MS:

# m/z

49a2b2 7rø>«-N-biphenyl-4-yl-4- 350 hydroxy-2-oxo-2,4a,5,6,7,7a- hexahydro-1 H-pyrrolo[3,4- b]pyridine-3 -carboxamide

49a2b4 7>αrø--4-hydroxy-N-[4-(lH- 340 imidazol- 1 -yl)phenyl]-2-oxo- 2,4a,5,6,7,7a-hexahydro-lH- pyrrolo [3 ,4-6]pyridine-3 - carboxamide

49a2b5 7ra«s-4-hydroxy-2-oxo-N-[4- 342 (trifluoromethyl)phenyl] - 2,4a,5,6,7,7a-hexahydro-lH- pyrrolo [3 ,4-ό]pyridine-3 - carboxamide

49a2b8 7ra7M-4-hydroxy-2-oxo-iV-[6- 343 oiό (trifluoromethyl)pyridin-3-yl]- 2,4a,5,6,7,7a-hexahydro-lH- pyrrolo[3,4-&]pyridine-3- carboxamide

Example 9 Preparation of Additional Bicyclic Hydroxy dicarbonyl Compounds

The general synthetic preparation of additional bicyclic hydroxydicarbonyl compounds of the invention are described below.

SCHEME 10

= CH ₂ X= CH ₂ CH ₂

51 a1 R= cydohexyl X = CH ₂ R'= benzyl

51 a2 R= cydohexyl X = CH ₂ R- ethyl

51 a3 R= 1-pipendiπyl, X= CH ₂ CH ₂ , R'= ethyl

52 a1-a3 a1 R = methyl a2 R= 2-methoxy-ethyl a3 R= 2-propynyl

40a2b6 53a1-a2 a1 R = methyl a2 R = 2-methoxy-ethyl

A. Trans-6-acetyl-4-hydroxy-7V-(4-piperidin-l-yl-phenyl)-2-oxo- l,2,4a,5,6,7,8,8a-octahydro-l,6-naphthyridine-3-carboxamide (50a2)

To a solution of 40alb6 (40 mg, 0.1 mmol) in THF (1.5 mL) was added acetyl chloride (6.77 μL, 0.1 mmol) and triethylamine (27 36 μL 0 20 mmol) at 0 ⁰ C. The suspens action mixture was

quenched with water at 0 ⁰ C and diluted with DCM (20 mL). The organic solution was washed with water and brine, dried over Na ₂ SO ₄ and concentrated under the reduced pressure. The crude compound was triturated with methanol to afford the title compound as a white solid (25 mg, 62%) MS (ES+): m/z = 413 (M+ 1) IH NMR (500 MHz, DMSO-D6) δ = 1.30-1.40 (m, IH) 1.50-1.55 (m, 3 H) 1.59-1.64 (m, 4 H) 1.93 - 2.06 (m, 4 H) 2.24 - 2.35 (m, 1 H) 2.45-2.55 (m, IH) 2.83 - 2.93 (m, 0.5 H) 3.06 - 3.00 (m, 0.5 H) 3.10 (d, J=5.04 Hz, 4 H) 3.43 - 3.52 (m, 1 H) 3.90 (d, J=15.00 Hz, 0.5 H) 4.11 - 4.18 (m, 0.5 H) 4.51 (d, J=10.00 Hz, 0.5 H) 4.88 - 4.82 (m, 0.5H) 6.91 (d, J=8.20 Hz, 2 H) 7.30 - 7.37 (m, 2 H) 8.99 (d, J=13.87 Hz, 1 H) 11.69 (s, 1 H)

B. Trans-6-ethyl-4-hydroxy- 2-oxo- 7V-(4-piperidin-l-yl-phenyl)- l^^ajS^^jSjβa-octahydro-ljό-naphthyridine-S-carboxamide (51a3)

To a solution of 40alb6 (36 mg, 0.09 mmol) in 1, 2-DCE (1 mL) was added acetaldehyde (6 μL, 0.1 mmol), triethylamine (11.1 μL, 0.08 mmol) and triacetoxyborohydride (49 mg, 0.22 mmol). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water at 0 ⁰ C and diluted with DCM (20 mL). The organic solution was washed with water and brine, dried over Na ₂ SO ₄ and concentrated under the reduced pressure. The crude compound was triturated with methanol to afford the title compound as a white solid (10 mg, 28%) MS (ES+): m/z = 399 (M+l) IH NMR (400 MHz, MeOH-d4) δ = 1.27 (t, J=7.33 Hz, 3 H) 1.54 - 1.62 (m, 2 H) 1.68 - 1.75 (m, 4 H) 1.76-1.87 (m, 1 H) 2.21- 2.16 (m, 1 H) 2.44 (s, 1 H) 2.57 (s, I H) 2.71 (t, J= 12.00 Hz, 1 H) 2.90 (s, 2 H) 3.1 1 (t, J=5.00 Hz , 3 H) 3.34 - 3.48 (m, 2 H) 3.72 (d, J=12.00 Hz ,1 H) 6.97 (d, J=9.09 Hz, 2 H) 7.39 (t, J=8.08 Hz, 2 H).

C. Trans-methyl-3-(anilinocarbonyl)-4-hydroxy-2-oxo- N-(4- piperidin-l-yl-phenyl)-l,4a,5,7,8,8a-hexahydro-l,6-naphthyri dine-6(2H)- carboxylate (52al)

To a solution of 40alb6 (40 mg, 0.09 mmol) in DCM (1 niL) was added methyl chloro formate (7.2 μL, 0.1 mmol), and triethylamine (26 μL, 0.19 mmol) at 0 ⁰ C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water at 0 ⁰ C and diluted with DCM (20 mL). The organic solution was washed with water and brine, dried over Na ₂ SO ₄ and concentrated under the reduced pressure. The crude compound was triturated with methanol to afford the title compound as a white solid (17 mg, 42%) MS (ES+): m/z = 429 (M+l) IH NMR (500 MHz, DMSO-D6) δ = 1.40 - 1.49 (m, 1 H) 1.52 (d, J=AAX Hz, 2 H) 1.60-1.65 (m, 4 H) 1.91-2.00 (m, 1 H) 2.38-2.45 (m, 1 H) 2.61-2.70 (m, IH) 2.79 (s, 1 H) 304-3.14 (m, 4 H) 3.40-3.43 (m, 1 H) 3.61 (d, J=5.00 Hz, 3 H) 4.07 (s, 1 H) 4.41 (s, 1 H) 6.91 (d, J=8.00 Hz, 2 H) 7.31 -7.66 (m, 2 H) 8.99 (s, 1 H) 11.68 (s, 1 H)

D. 4-Hydroxy-2-oxo-3-(4-piperidin-l-yl-phenylcarbamoyl)- 2,4a,5,6,8,8a-hexahydro-lH-[l,7]naphthyridine-7-carboxylic acid methyl ester (53al)

To a solution of 40a2b6 (20 mg, 0.05 mmol) in DCM (1 mL) was added methyl c (8.3 μL, 0.06 mmol) at

0 ⁰ C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water at 0 ⁰ C and diluted with DCM (20 mL). The organic solution was washed with water and brine, dried over Na ₂ SO ₄ and concentrated under the reduced pressure. The crude compound was triturated with methanol to afford the title compound as a white solid (6.4 mg, 27.7 %) MS (ES+): m/z = 429 (M+ 1) IH NMR (400 MHz, CHLOROFORM-D) δ = 1.35 (s, 1 H) 1.50 (dq, J=5.81, 5.64 Hz, 4 H) 1.63 (dt, J=I 1.12, 5.56 Hz, 8 H) 1.79 (s, 1 H) 1.93 (d, J=10.11 Hz, 1 H) 2.60 (t, J=10.61 Hz, 2 H) 3.02 - 3.09 (m, 7 H) 3.15 (d, J=10.11 Hz,

1 H) 3.19 - 3.25 (m, 1 H) 3.61 - 3.69 (m, 5 H) 3.82 - 3.94 (m, 1 H) 6.83 (d, J=9.09 Hz, 3 H) 7.32 (d, J=7.07 Hz, 3 H)

The following compounds were also prepared as those noted above:

Compound Structure Name MS:

# m/z

50al P ₁ Trans-6-acetyl- N-(4- 398

« i « i _j cyclohexylphenyl)-4-hydroxy

-(XX ^" " -2-oxo-2,4a,5,6,7,7a- hexahydro- 1 H-pyrrolo[3,4- 6]pyridine-3-carboxamide

5 IaI (Q Trans-6-benzyl- N-(4- 446

X( λXXXj cyclohexylphenyl)-4-hydroxy-

^" 4A ^"" 2-oxo-2,4a,5,6,7,7a- hexahydro- 1 H-pyrrolo [3 ,4- έ]pyridine-3 -carboxamide

51a2 Trans- N-{A- 384 cyclohexylphenyl)-6-ethyl-4- hydroxy-2-oxo- 2,4a,5,6,7,7a- hexahydro-1 H-pyrrolo [3,4- £>]pyridine-3 -carboxamide

52a2 O 2-Methoxyethyl-/rarø-3- 473

. _^^ l-^-VS-^ (anilinocarbonyl)-4-hydroxy-

" ^! ' 2-oxo- N-(4-piperidin-l-yl- phenyl)-l,4a,5,7,8,8a- hexahydro-1 ,6-naphthyridine- 6(2H)-carboxylate

52a3 Prop-2-yn-l-yl-trans-3- 453 (anilinocarbonyl)-4-hydroxy- 2-oxo- N-(4-piperidin-l-yl- phenyl)-l,4a,5,7,8,8a- hexahydro-1 ,6-naphthyridine- 6(2H)-carboxylate

53a2 4-Hydroxy-2-oxo-3-(4- 473 pipendin-l-yl-phenylcarbam- phenylcarbamoyl)- 2,4a,5,6,8,8a-hexahydro-lH -[1 ,7]naphthyridine-7- carboxylic acid 2-methoxy- ethyl ester

Example 10 Preparation of Additional Bicyclic Hydroxydicarbonyl Compounds

5

The general synthetic preparation of additional bicyclic hydroxydicarbonyl compounds of the invention are described below.

SCHEME 11

12 a X = CH ₂ (CiS) 13 a X = CH ₂ (cis) 14 a X = CH ₂ (cis)

12 b X = NBoc (trans) 13 b X = NBoc (trans) 14 b X = NBoc (trans)

R2

15 a X = CH ₂ (cis) J Q 15 b X = NBoc (trans)

Reagents: (a) TEA, DCM; (b) 0.5 M NaOMe in MeOH, THF, reflux, 2h; (c) aniline, THF 120 ⁰ C, 8 min, microwave 15

Example 11 Preparation of Additional Bicyclic Hydroxydicarbonyl Compounds

20 Th l h i i f ddi i l bi lic hydroxydicarbonyl compou

SCHEME 12

19 a1 X= BocNH, Y = CH ₂ 19 a2 X= CH ₂ , Y = BocNH

17

22 a1 X= BocNH, Y = CH ₂ 21 a1 X= BocNH, Y = CH ₂ 20 a1 X= BocNH, Y = CH ₂ 22 a2 X= CH ₂ , Y = BocNH 21 a2 X= CH ₂ , Y = BocNH 20 a2 X= CH ₂ , Y = = BocNH

23 a1 X= BocNH, Y = CH ₂ 24 a1 X= NH ₂ , Y = CH ₂ 23 a2 X= CH ₂ , Y = BocNH 24 a2 X= CH ₂ , Y = NH ₂

Reagents: (a) BoC ₂ O, Na ₂ CO ₃ aq., THF, 0 ⁰ C to rt; (b) BoC ₂ O, Pd-C, H ₂ , EtOH; (c) NH ₃ in EtOH, MeOH, reflux; (d) NaBH(OAc) ₃ , HOAc, MeCN, O ⁰ C, (e) ClCOCH ₂ COOMe, TEA, DCM; (f) 0.5M NaOMe in MeOH, THF, reflux, 2h; (g) aniline, THF 120 ⁰ C, 8 min, microwave; (h) 4M HCl in dioxane, iPrOH, 80 ⁰ C

/. Synthesis of examples

According to the general procedure the following boc-protected examples 23 were prepared:

Compound Structure Name

#

23 alb3 tert-butyl 4-hydroxy-3-[(N-(4- phenoxyphenyl)amino)carbony

•NλλO l]-2-oxo-l ,4a,5,7,8,8a- hexahydro- 1 ,6-naphthyridine-

6(2H)-carboxylate

23 alb4 tert-butyl 4-hydroxy-3-[(N-(4-

(lH-imidazol-1-

^~ -c&/ yl)phenyl)amino)carbonyl]-2- oxo-1 ,4a,5,7,8, 8a-hexahydro-

1 ,6-naphthyridine-6(2H)- carboxylate

23 alb5 tert-butyl 4-hydroxy-3-{[N-(4-

(4-(2-hydroxy-ethyl)- piperazin-1 -yl)- phenyl)amino]carbonyl}-2- oxo-1 ,4a,5, 7,8, 8a-hexahydro-

1 ,6-naphthyridine-6(2H)- carboxylate

23 albό .0 tert-butyl 4-hydroxy-3-[(N-(4- piperidin- 1 -yl-phenyl)amino)

-α#- carbonyl]-2-oxo-l ,4a,5,7,8,8a- hexahydro-1 ,6-naphthyridine-

6(2H)-carboxylate

23 alb9 tert-butyl 4-hydroxy-3-[(N-(6-

-oft-- oxocyclohexa-2,4-dien-l - yl)amino)carbonyl] -2-oxo-

1 ,4a,5,7,8,8a-hexahydro-l ,6- naphthyridine-6(2H)- carboxylate

According to the general procedure the following examples 24 were prepared as hydrochloride salts:

Compound Structure Name

#

24alb2 N-biphenyl-4-yl-4-hydroxy-

2-oxo-l,2,4a,5,6,7,8,8a- oiό octahydro- 1 ,6-naphthyridine-

3-carboxamide

24alb3 4-hydroxy-2-oxo-N-(4-

L T phenoxyphenyl)- 1 ,2,4a,5,6,7,8,8a-octahydro-

1 ,6-naphthyridine-3- carboxamide

24a Ib4 r 4-hydroxy-N-[4-(lH- imidazol- 1 -yl)phenyl] -2-oxo-

OCX " 1 ,2,4a,5,6,7,8,8a-octahydro-

1 ,6-naphthyridine-3- carboxamide

24alb5 4-hydroxy-N-{4-[4-(2- hydroxy-ethyl)- piperazin-l-yl]-phenyl}-2- oxo-1 , 2,4a,5,6,7,8,8a- octahydro- 1 ,6-naphthyridine-

3-carboxamide

24alb6 -O 4-hydroxy-τV-(4-piperidin- 1 - yl-phenyl)-2-oxo-

1 ,2,4a,5,6,7,8,8a-octahydro- 1 ,6-naphthyridine-3- carboxamide

24a Ib7 4-hydroxy-N-(4-

UX ^1' trifluoromethylphenyl)-2- oxo-l,2,4a,5,6,7,8,8a- octahydro- 1 ,6-naphthyridine-

3-carboxamide

24alb8 4-hydroxy-2-oxo-N-(4- pyrrolidin- 1 -ylphenyl)-

1 ,2,4a,5,6,7,8,8a-octahydro- 1 ,6-naphthyridine-3- carboxamide

24alb9 4-hydroxy-2-oxo-N-(6-

CCX ^1' oxocyclohexa-2,4-dien-l-yl)-

1 ,2,4a,5,6,7,8,8a-octahydro-

1 ,6-naphthyridine-3- carboxamide

Example 12 Preparation of Additional Bicyclic Hydroxydicarbonyl Compounds

The general synthetic preparation of additional bicyclic hydroxydicarbonyl compounds of the invention are described below.

SCHEME 13

19 a X= BocN, Y = CH ₂ 25 a X= BocN, Y = CH ₂ 26 a X= BocN, Y = CH ₂

19 b X= CH ₂ , Y= BocN 25 b X= CH ₂ , Y = BocN 26 b X= CH ₂ , Y = BocN

28 a X= NH, Y = CH ₂ 27 a X= BocN, Y = CH ₂

28 b X= CH ₂ , Y = NH 27 b X= CH ₂ , Y = BocN

Reagents: (a) ClCOCH ₂ COOMe, TEA, DCM; (b) 0.5M NaOMe in MeOH, THF, reflux, 2h; (c) aniline, THF 120 ⁰ C, 8 min, microwave; (d) 4M HCl in dioxane, iPrOH, 8O ⁰ C

/. Synthesis of intermediates

A. Methyl 1-tert-butyl 3-methyI 4-[(3-methoxy-3- oxopropanoyI)amino]-5,6-dihydropyridine-l,3(2H)-dicarboxyIat e (25a)

To a stirred solution of l-ter/-butyl 3-methyl 4-amino-5,6-dihydropyridine- l,3(2H)-dicarboxylate (19a, synthesis see above, 1 g, 3.9 mmol) in dichloromethane (20 mL) was charged with triethylamine (0.55 mL, 3.9 mmol) and followed by adding methyl malonyl chloride (0.46 mL, 4.3 mmol) portionwise at 0 °C under N ₂ atmosphere. The reaction mixture was stirred for further 16 h, then diluted with 250 mL dichloromethane. The organic solution was washed with water and brine, dried over Na ₂ SO ₄ . The solvent was then removed to give the title compound as a yellow solid (1.2 g, 78%). The material was used without further purification in the next step.

B. Methyl 6-tert-buty\ 3-methyl 4-hydroxy-2-oxo-6-phenyl-l,2,5,6- tetrahydropyridme-3-carboxylate (26a)

To a stirred solution of 25a 1 (1.2g, 3.4 mmol) in anhydrous THF (15 mL) was added sodium methoxide (6.7 mL, 3.4 mmol, 0.5 M in MeOH) portion wise under N ₂ atmosphere, and the resulting mixture was refluxed for 2h. The mixture was cooled and the insoluble salt was filtered and dissolved in 10 mL water. The aqueous solution was adjusted to pH 2 with 1 N HCl and extracted with EtOAc (3X). The organic phase was combined, dried over Na ₂ SO ₄ , and concentrated. The crude material was recrystalized in EtOAc/hexane (2: 1) mixed solution to afford the title compound as an off white solid (400 mg, 35%).

II. Synthesis of examples

According to the general procedure several boc-protected examples 263 were prepared. According to the general procedure the several examples of compounds related to 27 were prepared as hydrochloride salts:

Example 13 Preparation of Additional Bicyclic and Multicyclic Hydroxydicarbonyl Compounds

The general synthetic preparation of additional bicyclic and multicyclic hydroxydicarbonyl compounds of the invention are described below.

SCHEME 14

Step 2 Et B-4X, 4Y, 4Z Me = Me

of B-6Ya

B-7 1) Cis isomer I B-72) Cisisomer Il B-7 3) trans isomer I B-74 ) trans isomer Il

/. Step 1

A. B-3X

B-I (95%, 2.00 g, 9.63 mmol), THF (30 mL) and Et ₃ N (2.03 g, 20.1 mmol) were mixed and stirred at O ⁰ C. To the mixture was added ethyl malonate chloride (90%, 1.61 g, 9.62 mmol) slowly. The resulting mixture was stirred at room temperature overnight. Volatiles were removed under reduced pressure. The residue was added saturated NaHCO ₃ , extracted with EtOAc, dried with Na ₂ Sθ ₄ and purified with silica-gel chromatography to give the desired product B-3X. Yield 72%.

B. B-3Y and B-3Z

Similar procedures were used except methyl manonlate chloride was used. Yield 67-73%.

//. Step 2 A. B-4X

B-3X (2.12 g, 7.43 mmol), NaOEt (21% in EtOH, 9.63 g, 29.3 mmol) were mixed in MeOH (30 mL) and the resulting mixture was heated at 80 ⁰ C for 20 h. Volatiles were removed under reduced pressure and the residue was added 3N HC1/H ₂ O until acidic pH. The aqueous solution was extracted with EtOAc and CH ₂ Cl ₂ . The organic solutions were combined, dried over Na ₂ Sθ ₄ , filtered, concentrated and purified with silica-gel chromatography to give the desired product B-4X which is a mixture of diastereomers: Yield 84%.

B. B-4Y Similar procedure was used except that 6 equivalent of NaOEt was used and reaction was stirred at 80 ⁰ C overnight. Yield 76%.

C. B-4Z

Similar procedure was used except that reaction was stirred at rt for 5 d. Yield 51%.

///. Step 3

A. B-6Xa (from B-4X and B-5a)

B-4X(76 mg, 0.31 mmol), THF (2 mL) and B-Sa (67 mg, 0.38 mmol) were mixed and microwaved at 120 ⁰ C for 10 min. The mixture was concentrated and MeOH was added to the solution. Solid can be seen precipitated from the solution, filtration followed by washing with MeOH gave the desired product. Yield 48%. B-6Xb, B-6Xc, B-Xd, B-6Ya, B-6Yb, B-6Yc, B-6Za were prepared using similar procedure. Yield: 4 - 73%. Stereochemistry of B-6Za is endo- endo, confirmed by NMR. The rest of B-6 are diastereomers mixtures.

IV. Step 4

Compound B-6Ya was separated with IA chiral column, 40% CH ₃ CN, 60% EtOH, to give four isomers: B-7.1(cis isomer I, positive optical rotation, Rt = 11.98 min.); B-7.2 (cis isomer II, negative optical rotation, Rt = 13.68 min.); B-7.3 (trans isomer I, negative optical rotation, Rt = 22.75 min.); B-7.4 (trans isomer II, positive optical rotation, Rt = 29.96 min.). Sterochemistry confirmed by NMR.

B-6Xa MS m/z (C ₂ ]H ₂₇ N ₃ O ₃ , Calcd. 369) found 370 (ES ⁺ ) 368 (ES ^" ); ¹ H NMR (400 MHz, CDCl ₃ ) i ppm 1 1.50, 1 1.95 (ws, ws, IH), 7.37 (wm, 2H), 6.89 (wm, 2H), 5.04, 5.17, 5.20, 5.28 (s, s, s,s, IH, ), 3.67 - 3.68, 3.08 - 3.20 (wm, wm, 5H), 1.18 - 2.47 (m, 15H).

B-6Xb MS m/z (C ₂₂ H ₂₈ N ₂ O ₃ , Calcd. 355) found 369 (ES ⁺ ) 367 (ES ^" ); ¹ H NMR (400 MHz, CDCl ₃ ) 5 ppm 1 1.58, 11.98 (s, s, IH), 7.33 - 7.39 (m, 2H), 7.11 (d, J= 8.0 Hz, 2H), 5.09, 5.22, 5.30 (s, s, s, IH, ), 3.67 - 3.68, 3.14 - 3.21 (m, m, IH), 1.16 - 2.42 (m, 20H).

B-6Xc MS m/z (C ₂₀ H ₂₅ N ₃ O ₃ , Calcd. 355) found 356 (ES ⁺ ) 354 (ES ^" ); ¹ H NMR (400 MHz, CDCl ₃ ) 5 ppm 11.35, 11.90 (s, s, IH), 7.25 - 7.46 (m, 2H), 6.46 (d, J= 8.0 Hz, 2H), 4.99, 5.12, 5.20 (s, s, s, IH, ), 3.67 - 3.68, 3.13 - 3.23 (m, m, 5H), 1.32 - 2.40 (m, 13H).

B-6Xd MS m/z (C ₇ H ₁₇ F ₃ N ₂ O ₃ , Calcd. 354) found 355 (ES ⁺ ) 353 (ES ^' ); ¹ H NMR (400 MHz, CDCl ₃ ) 5 ppm 11.92 - 12.18 (m, IH), 7.59 - 7.64 (m, 2H), 7.51 - 7.53 (m, 2H), 5.13, 5.26, 5.35 (s, s, s, IH, ), 3.69 - 3.70, 3.15 - 3.20(m, m, IH), 1.25 - 2.52 (m, 9H).

B-6Ya MS m/z (C _2I H ₂₅ N ₃ O ₃ , Calcd. 353) found 368 (ES ⁺ ) 366 (ES ^" ); ¹ H NMR (400 MHz, CDCl ₃ ) s ppm 11.50, 1 1.95 (s, s, IH, ), 7.29 - 7.36 (m, 2H), 6.85 (ws, 2H), 5.69 - 5.73 (m, IH), 5.58 - 5.61 (m, IH), 5.22, 5.32 (s, s, IH, ), 3.46 - 3.57 (m, IH), 3.07 (ws, 4H), 2.09 - 2.72 (m, 5H), 1.49 - 1.64 (m, 6H).

B-6Yb MS m/z (C ₂₂ H ₂₆ N ₂ O ₃ , Calcd. 366) found 367 (ES ⁺ ) 365 (ES-); ¹ HNMR (400 MHz, CDCl ₃ ) 3 ppm 11.50, 11.60, 11.88, 12.00 (s, s,s, s, IH, ), 7.33 - 7.40 (m, 2H), 7.11 (d, J= 8.0 Hz, 2H), 5.70 - 5.73 (m, IH), 5.58 - 5.62 (m, IH), 5.15, 5.27, 5.45 (s, s, s, IH, ), 3.46 - 3.54 (m, I H), 2.00 - 2.75 (m, 5H), 1.20 - 1.80 (m, HH).

B-6Yc MS m/z (C ₂₀ H ₂₃ N ₃ O ₃ , Calcd. 353) found 354 (ES ⁺ ) 352 (ES ^" ); ¹ H NMR (400 MHz, CDCl ₃ ) 5 ppm 1 1.20, 1 1.25, 11.65, 11.78 (s, s,s, s, 1 H, ), 7.1 1 - 7.32 (m, 2H), 6.31 - 6.35 (m, 2H), 5.58 - 5.62 (m, IH), 5.41 - 5.57 (m, I H), 5.17, 5.08, 4.95 (s, s, s, IH, ), 3.32 - 3.70 (m, IH), 3.06 - 3.09 (m, 4H), 1.70 - 2.59 (m, 9H).

B-6Za MS m/z (C _{2 I} H ₂₅ N ₃ O ₃ , Calcd. 367) found 368 (ES ⁺ ) 366 (ES ^" ); ¹ H NMR (400 MHz, CDCl ₃ ) 5 ppm 1 1.50, 12.00 (s, s, IH), 7.18 (d, J= 8.0 Hz, 2H), 6.68 (d, J= 8.0 Hz, 2H), 6.00 - 6.02 (m, 2H), 5.11, 5.32 (s, s, IH, ), 3.85 (m, IH), 2.92 - 3.01 (m, 2H), 2.89 - 2.91 (m, 4H), 1.12 - 1.50 (m, 8H).

B-7.1 MS m/z (C ₂ ,H ₂₅ N ₃ O ₃ , Calcd. 367) found 368 (ES ⁺ ) 366 (ES ^" ); ¹ H NMR (400 MHz, CDCl ₃ ) i ppm 11.41 , 11.80 (s, s, IH, ), 7.27 - 7.45 (m, 2H), 6.82 - 6.93 (m, 2H), 5.58 - 5.75 (m, IH), 5.51 - 5.55 (m, I H), 5.07, 5.30 (s, s, IH, ), 3.72 - 3.84 (m, IH), 3.04 - 3.07 (m, 4H), 2.68 - 2.71 (m, IH), 2.03 - 2.58 (m, 4H), 1.48 - 1.81 (m, 6H).

B-7.2 MS m/z (C ₂ ,H ₂₅ N ₃ O ₃ , Calcd. 367) found 368 (ES ⁺ ) 366 (ES ^" ); ¹ H NMR (400 MHz, C 2H), 6.82 - 6.93 (m, 2H), 5.5 , IH, ), 3.70 - 3.84 (m,

IH), 3.04 - 3.07 (m, 4H), 2.68 - 2.71 (m, IH), 2.03 - 2.58 (m, 4H), 1.48 - 1.81 (m, 6H).

B-7.3 MS m/z (C ₂₁ H ₂ 5N3O ₃ , Calcd. 367) found 368 (ES ⁺ ) 366 (ES ^" ); ¹ H NMR (400 MHz, CDCl ₃ ) 5 ppm 11.94, 11.49 (s, s, IH, ), 7.27 - 7.44 (m, 2H), 6.82 - 6.92 (m, 2H), 5.69 - 5.72 (m, IH), 5.54 - 5.61 (m, IH), 5.22, 5.32 (s, s, IH, ), 3.45 - 3.72 (m, IH), 3.04 - 3.07 (m, 4H), 2.48 - 2.72 (m, 2H), 2.02 - 2.37 (m, 3H), 1.40- 1.65 (m, 6H).

B-7.4 MS m/z (C ₂₁ H ₂ 5N ₃ O ₃ , Calcd. 367) found 368 (ES ⁺ ) 366 (ES ^" ); ¹ H NMR (400 MHz, CDCl ₃ ) - ppm 11.94, 11.49 (s, s, IH, ), 7.27 - 7.45 (m, 2H), 6.82 - 6.93 (m, 2H), 5.69 - 5.75 (m, IH), 5.55 - 5.62 (m, IH), 5.22, 5.31 (s, s, IH, ), 3.45 - 3.72 (m, IH), 3.04 - 3.07 (m, 4H), 2.48 - 2.72 (m, 2H), 2.02 - 2.37 (m, 3H), 1.40- 1.65 (m, 6H).

Example 14

The general synthetic preparation of additional bicyclic hydroxydicarbonyl compounds of the invention are described below.

SCHEME 15

B-3 (CiS) B-4 (trans)

Me Et Me Et

/. Step 3 B-2

A mixture of B-I (7.0 g, 27.2 mmol) [Bioorg. Med. Chem. 2003, 11, 581- 590.], potassium carbonate (7.5 g, 54.5 mmol), and iodomethane (3.4 mL, 54.5 mmol) in dry acetone was heated under reflux (70 ⁰ C bath) overnight. After completion, the reaction mixture was cooled to ambient temperature. The reaction mixture was filtered through 30 mL/30 M fritted filter to remove salt. The filtrate was concentrated under reduced pressure to yield a brown oil. The crude was purified

using silica gel column chromatography to give B-2 as a colorless oil. Yield: 5.53 g (75%)

//. Step 4 B-3 and B-4

A 250 mL of round-bottomed flask equipped with dean-stark condenser was charged with B-2 (3.88 g, 14.2 mmol) and toluene (70 mL). Then to the solution were added benzylamine (1.7 mL, 15.6 mmol) and p-toluenesulfonic acid monohydrate (50 mg, catalytic amount). The resulting mixture was heated under reflux (bath 140 ⁰ C) for 5 h. The reaction mixture was concentrated under reduced pressure to yield a yellow solid.

The crude solid was dissolved in acetonitrile (35 mL) in a 250 mL of round- bottomed flask. At 0 ⁰ C, to the solution were added acetic acid (23 mL, 398 mmol) and sodium triacetoxyborohydride (7.94 g, 35.6 mmol) portionwise. The resulting mixture was stirred at 0 ⁰ C for 30 min and at room temperature for 1.5 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved with dichloromethane (100 mL) and added with saturated sodium carbonate slowly. Gases released vigorously. The organic layer was separated, washed with brine, dried over sodium sulfate, filtered, and concentrated. The two diastereomers were separated using silica gel column chromatography. The upper isomer was identified as cis (B-3) and the lower isomer was assigned as trans (B-4) after 2D- and NOE NMR study.

///. Step 5 B-5

To a 100 mL round-bottomed flask were charged B-3 (1.0 g, 2.76 mmol), palladium on carbon (10%, 290 mg, 0.276 mmol), and methanol (50 mL). After degassed, the mixture was hydrogenated for 1 h at ambient temperature. The reaction mixture was filtered to remove the catalyst, and then concentrated to give a yellow oil (B-5). The crude was used next step without further purification.

IV. Step 6 B-7

To a 100 mL round-bottomed flask were charged B-5 (791 mg), dichloromethane (12 mL), and triethylamine (0.46 mL) at 0 ⁰ C. To the resulting solution was added methyl 3-chloro-3-oxopropionate dropwise at 0 ⁰ C. The reaction mixture was warmed to room temperature and then stirred for 2 h. The reaction mixture was diluted with dichloromethane and washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated to yield an orange solid (B-

7).

V. Step 7 B-9

To a solution of B-7 (1.45 g, 2.80 mmol) in dry tetrahydrofuran (14 mL) was added potassium te/t-butoxide (1 M, 8.4 mL, 8.40 mmol). The resulting mixture was heated under reflux for 2.5 h. The reaction mixture was concentrated and dissolved with water (75 mL) and adjusted to pH = 1 with 1 N-hydrochloric acid. The crude was extracted with dichloromethane (3 x 100 mL), dried over sodium sulfate, filtered, and concentrated to give an orange solid (B-9). Yield: 1.03 g

VI. Step 8 B-Il

B-9 (110 mg) and N-(4-aminophenyl)piperidine (57 mg) were dissolved in N,N-dimethylforrnamide (1 mL). To the resulting solution was heated (120-200 ⁰ C) using microwave for 5-20 mins. The crude was concentrated under reduced pressure and purified using silica gel column chromatography to give the desired compound (B-I l).

VIL Step 9 B-13 To a solution of B-11 (0.70 g) in 1,4-dioxane (1 mL) was added 4 N-HCl in

1,4-dioxane (6 mL) at 0 ⁰ C. The resulting mixture was heated under reflux for 2 h. After cooling to room temperature, the precipitate was filtered and washed with ethyl acetate. lumn chromatography to provi

VIIL Step 10 B-15a To a solution of B-13 (60 mg, 0.154 mmol) in methanol (1.5 niL) were added 35% formaldehyde (0.030 mL, 0.308 mmol) and sodium cyanoborohydride (7 mg, 0.169 mmol) at room temperature. The resulting mixture was stirred at the same temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified using silica gel column chromatography to provide B- 15a.

B-Il

¹ H-NMR (400 Mz, DMSOd ₆ ): δ 1.08 (s, 2 H), 1.18 (s, 1 H), 1.39 (m, 9 H), 1.55 (m, 7 H), 1.75 (m, 1 H), 2.88 (d, J = 12.63 Hz, 0.67 H), 3.12 (m, 5 H), 3.31 (broad, 1 H), 3.49 (m, 1.7 H), 3.94 (d, J = 12.63 Hz, 1 H), 6.91 (m, 2 H), 7.33 (t, Jl = 9.09 Hz, J2 = 9.60 Hz, 2 H), 7.93 (s, 0.35 H), 8.87 (s, 0.64 H), 1 1.89 (s, 0.58 H), 12.0 (s, 0.36 H); MS calcd for C ₂₆ H ₃₆ N ₄ O ₅ , 484, found ES ⁺ = 485, ES ^" = 483.

B-12 η-NMR(400 MHz, CDCl ₃ ): δ 1.1 1 (s, 1.2 H), 1.19 (s, 1.8 H), 1.48 (s, 9 H), 1.58 (m, 4 H), 1.71 (m, 4 H), 2.72 (m, 2 H), 3.14 (m, 4 H), 3.47 (m, 1 H), 4.38 (m, 2 H), 5.03 (broad, 0.6 H), 5.41 (broad, 0.4 H), 6.91 (d, J = 4.00 Hz, 2 H), 7.38 (t, J = 8.00 Hz, 2 H), 1 1.50 (broad, 0.6 H), 1 1.84 (broad, 0.4 H); MS calcd for C ₂₆ H ₃₆ N ₄ O ₅ 484, found ES ⁺ = 485, ES ^" = 483.

B-13

¹ H-NMR (400 Mz, DMSO-d ₆ ): δ 1.09 (s, 3 H) 1.52 (m, 3 H), 1.62 (m, 5 H), 2.23 (d, J = 13.14, 1 H), 2.84 (m, 1 H), 3.10 (t, Jl = 5.56 Hz, J2 = 5.31 Hz, 4 H), 3.12 (broad, 2 H), 3.30 (broad, 1 H), 4.08 (m, 0.6 H), 6.91 (d, J = 9.09 Hz, 2 H), 7.35 (d, J = 9.09 Hz, 2 H), 12.0 (s , 1 H); MS calcd for C _2I H ₂₈ N ₄ O ₃ , 384, found ES ⁺ = 385, ES ^" = 383.

B-14

η-NM ), 1.59 (m, 5 H), 2.43 (m, 2 H H), 6.84 (d, J = 9.20 Hz,

2 H), 7.32 (d, J = 8.18 Hz, 2 H), 11.84 (s, 1 H); MS calcd for C ₂₁ H ₂₈ N ₄ O ₃ 384, found ES ⁺ = 385, ES ^" = 383.

B-15a ¹ H-NMR (400 Mz, DMSOd ₆ ): δ 1.06 (s, 1.83 H), 1.18 (s, 1.27 H), 1.53 (m, 2 H), 1.60 (m, 4 H), 1.70 (broad, 2 H), 1.86 (broad, 0.5 H), 1.99 (broad, 1 H), 2.12 (d, J = 10.86 Hz, 3 H), 2.56 (m, 1 H), 3.10 (t, Jl = 5.31 Hz, J2 = 4.80 Hz, 5 H), 3.18 (broad,

1 H), 3.28 (s, 0.64 H), 6.92 (m, 2 H), 7.35 (d, J = 8.84 Hz, 2 H), 7.88 (s, 0.27 H), 8.81 (s, 0.48 H), 11.97 (s, 0.56 H), 12.04 (s, 0.34 H); MS calcd for C ₂₂ H ₃₀ N ₄ O ₃ , 398, found ES ⁺ = 399, ES ^" = 397.

B-16a

η-NMR(400 MHZ, CDCl ₃ ): δ 1.25 (s, 1.4 H), 1.35 (s, 1.6 H), 1.57 (m, 4 H), 1.69 (m, 4 H), 1.93 (m, 3 H), 2.29 (s, 3 H), 2.91 (d, J = 9.34 Hz, 1 H), 3.01 (t, J = 10.78 Hz, 1 H), 3.12 (m, 4 H), 3.28 (m, 1 H), 5.30 (s, 0.6 H) 5.41 (s, 0.4 H), 6.89 (d, J = 8.99 Hz,

2 H), 7.37 (m, 2 H), 11.53 (s, 0.6 H), 11.91 (s, 0.4 H); MS calcd for C ₂₂ H ₃₀ N ₄ O ₃ 398, found ES ⁺ = 399, ES ^" = 397.

B-16b ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 1.19 (s, 3 H), 1.24 (t, J = 7.07 Hz, 4 H), 1.58

(broad, 3 H), 1.73 (broad, 5 H), 1.87 (m, 1 H), 2.05 (d, J = 12.38 Hz, 1 H), 2.92 (m, 1 H), 3.02 (m, 2 H), 3.61 (m, 4 H), 7.25 (broad, 2 H), 7.49 (broad, 2 H), 8.96 (broad, 1 H), 9.31 (broad, 1 H), 11.61 (broad, 1 H); MS calcd for C ₂₃ H ₃₂ N ₄ O ₃ 412, found ES ⁺ = 413, ES ^" = 411.

Example 15

The general synthetic preparation of additional bicyclic hydroxydicarbonyl compounds of the invention are described below.

SCHEME 16

/. Step U C-2

To a B-I (6.0 g, 23.3 mmol) in anhydrous methanol (95 mL) was added 7.0 M ammonia in methanol (16.6 mL, 1 17 mmol), and then the mixture was refluxed for 8 h. The reaction mixture was cooled to room temperature and removed methanol under reduced pressure to yield a brown oil. The crude was purified using silica gel column chromatography to yield a white solid (C-2). Yield: 3.1 g.

//. Step 12 C-3

C-3 was prepared as in Step 6, as described above.

///. Step 13 C-4

To a solution of C-3 (2.35 g, 5.60 mmol) in dry tetrahydrofuran (22 mL) was added 25% Sodium methoxide in methanol (1.21 mL, 5.60 mmol). The resulting mixture was heated under reflux for 2 h. The reaction mixture was concentrated and dissolved with water (60 mL) and adjusted to pH = 1 with 1 N-hydrochloric acid. The crude was extracted with dichloromethane (2 x 100 mL), dried over sodium sulfate, filtered, and concentrated to give an yellow solid. The crude was suspended with ethyl acetate (30 mL)/hexane (15 mL) solution and then filtered to yield a white solid (C-4). Yield: 818 mg

TV Step 14 C-5

C- 5 was prepared as in Step 8 procedure, as described above.

V. Step 15 C-6

C-6 was prepared as in Step 9 procedure, as described above.

VL Step 16 C-I C-7 was prepared as in Step 10 procedure, as described above.

C-7a

¹ H-NMR (400 MHz, DMSOd ₆ ): δ 1.52 (m, 2 H), 1.61 (m, 4 H), 2.35 (s, 3 H), 2.61 (m, 4 H), 3.10 (m, 4 H), 3.19 (s, 2 H), 6.92 (d, J = 9.09 Hz, 2 H), 7.43 (d, J = 8.84 Hz, 2 H), 1 1.86 (broad, 1 H), 12.34 (broad, 1 H), 15.78 (s, 1 H); MS calculated from C ₂₁ H ₂₆ N ₄ O ₃ 382, found ES ⁺ = 383, ES ^" = 381.

C-7b

¹ H-NMR (400 MHz, DMSOd ₆ ): δ 1.51 (m, 2 H), 1.61 (m, 4 H), 2.63 (m, 2 H), 3.10

(m, 4 H H), 7.43 (d, J = 9.09 Hz,

2 H), 11.95 (s, 1 H), 12.28 (s, 1 H), 15.98 (s, 1 H); MS calcd from C ₂₂ H ₂₆ N ₄ O ₅ 426, found ES ⁺ = 427, ES ^" = 425.

C-7c ¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 1.22 (broad, 1 H), 1.52 (broad, 2 H), 1.60 (b, 4 H),

2.08 (broad, 3 H), 2.71 (m, 2 H), 3.10 (m, 4 H), 3.67 (m, 2.3 H), 4.29 (m, 2 H), 6.92 (d, J = 8.84 Hz, 2 H), 7.43 (d, J = 9.09 Hz, 2 H), 11.95 (broad, 0.5 H), 12.29 (broad, 0.5 H), 15.87 (broad, 0.6 H), 15.96 (broad, 0.4 H); MS calcd from C ₂₂ H ₂₆ N ₄ O ₄ 410, found ES ⁺ = 411, ES- = 409.

C-7d

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 0.97 (s, 4 H), 1.00 (s, 5 H), 1.52 (m, 2 H), 1.61 (m, 4 H), 2.31 (s, 2 H), 2.57 (broad, 1 H), 2.67 (broad, 1 H), 3.10 (t, J = 5.56 Hz, 4 H), 3.72 (m, 2 H), 4.30 (s, 1 H), 4.34 (s, 1 H), 6.92 (d, J = 9.09 Hz, 2 H), 7.43 (d, J = 9.09 Hz, 2 H), 1 1.94 (d, J = 11.62, 1 H), 12.29 (d, J = 7.58 Hz, 1 H), 15.87 (s, 0.4 H), 15.98 (s, 0.6 H); MS calcd from C ₂₆ H ₃₄ N ₄ O ₄ 466, found ES ⁺ = 467, ES ^" = 465.

C-7e

¹ H-NMR (400 MHz, DMSO-d ₆ ): δ 1.28 (s, 9 H), 1.59 (broad, 2 H), 1.67 (broad, 4 H), 2.70 (broad, 2 H), 3.17 (broad 2 H), 3.85 (broad, 2 H), 4.43 (broad, 2 H), 6.99 (d, J =

9.09 Hz, 2 H), 7.50 (d, J = 9.10 Hz, 2 H), 12.02 (broad, 1 H), 12.35 (broad, 1 H), 16.00 (broad, 1 H); MS calcd for C ₂₅ H ₃₂ N ₄ O ₄ 452, found ES ⁺ = 453, ES ^" = 451.

Example 16

Determination of Binding to UPPS

The ability of several of the compounds described herein to bind to UPPS was also tested as follows.

Streptococcus pneumonia UPPS was cloned into pET-15b, expressed and purified as an N-terminal His-tag fusion using affinity chromatography. The working stock of UPPS was prepared by mixing the purified enzyme with liposome made from E. coli total lipids extract (Avanti Polar Lipis, Inc., Alabaster, AL). The substrates FPP and from Sigma. Biomol

Green reagent was from Biomol International (Plymouth Meeting, PA). All other chemicals were from Sigma at the highest grade.

For testing a compound, UPPS was first incubated with the compound at desired concentrations for 20 minutes in the UPPS reaction buffer that contained 100 mM Tris-HCl, pH 7.3, 50 mM KCl, 1 mM MgCl ₂ , 0.01% Triton X-100, and 20 μg/mL BSA. The reaction was then initiated by the addition of a mixture of FPP, IPP, and E. coli inorganic phosphatase made in the same UPPS reaction buffer. The final concentrations for FPP and IPP were 3 μM and 16 μM, respectively. The inorganic phosphate generated in the reactions was then quantified with Biomol Green reagent, which was then used to determine the rate of the reaction and the inhibitory activity of the compound.

For example, the results of the binding assay for several compounds are shown the table below:

Table 2: 1C so Values for Binding to UPPS

Key IC ₅₀ limited enzyme interaction (IC ₅₀ > 50 μM) some enzyme interaction (50 μM > IC ₅₀ > 10 μM) good enzyme interaction (10 μM > IC ₅₀ > 0.01 μM)

Many of the compounds in Tables 1, have also been tested to determine their minimum inhibitory concentration (MIC) for a variety of bacteria. The MIC values ranged from 0.5 μg/mL to greater than about 128 μg/mL. In particular embodiments, the MIC value was less than 64 μg/mL, e.g., less than 32 μg/mL.

Equivalents Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures, embodiments, claims, and examples described herein. Such equivalents were considered to be within the scope of this invention and covered by the claims appended hereto. For example, it should be understood, that modifications in reaction conditions, including reaction times, reaction size/volume, and experimental reagents, such as solvents, catalysts, pressures, atmospheric conditions, e.g., nitrogen atmosphere, and reducing/oxidizing agents, etc., with art-recognized alternatives and using no more than routine experimentation, are within the scope of the present application.

It is to be understood that wherever values and ranges are provided herein, e.g., in ages of subject populations, dosages, blood levels, IC ₅₀ , and specificity ratios, all values and ranges encompassed by these values and ranges, are meant to be encompassed within the scope of the present invention. Moreover, all values that fall within these ranges, as well as the upper or lower limits of a range of values, are also contemplated by the present application.

Incorporation by Reference

The contents of all references, issued patents, and published patent applications cited throughout this application are hereby expressly incorporated herein in their entireties by reference.