HPDL inhibitors to treat non-malignant diseases

Abstract

Various methods of treating a disease or condition, such as cancer, autoimmune disease, or any disease involving cellular proliferation are presented herein comprising administering to the subject an effective amount of an HPDL inhibitor compound or pharmaceutical composition as described herein.

Description

Attorney Docket No: 243735.000456 HPDL INHIBITORS TO TREAT NON-MALIGNANT DISEASES CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application SerialNo.63 / 691,917, filed September 6, 2024, which is hereby incorporated by reference in its entirety. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support under R35GM147119 awarded by the National Institutes of Health. The government has certain rights in the invention. FIELD OF THE INVENTION

[0003] The invention provides methods of treating a disease or condition byadministering an effective amount of a 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) inhibitor. Treatable diseases and conditions include, but are not limited to, non- malignant diseases, benign tumors; growth of tumor cells or proliferating immune cells; inappropriate growth and proliferation of cells in benign but debilitating diseases; scarring; scar formation; excessive scarring; keloid; fibrosis and superficial fibrosing disorder; ankylosing spondylitis; Adhesive capsulitis; RASopathies; chronic kidney disease; heterotopic ossification; tuberous sclerosis (TSC); adhesions following surgery; and stiffening of tissues with aging. BACKGROUND

[0004] Coenzyme Q (CoQ), or ubiquinone, is a ubiquitous cofactor found in alleukaryotes and in most bacteria. Coenzyme Q consists of a 1,4 benzoquinone headgroup that can be reversibly oxidized or reduced, attached to an isoprenoid tail of varying lengths (1). In humans, this tail contains 10 isoprene units. For this reason, human Coenzyme Q is called Coenzyme Q10 (CoQ10). In mammalian cells, CoQ10 is found in most biological membranes, where it is thought to function as an antioxidant (2). In the mitochondrion, CoQ10 accepts electrons from respiratory complexes I and II and 1 318985012Attorney Docket No: 243735.000456 transfers them to complex III. CoQ10 is critical for the electron transport chain and for mitochondrial function because it is the only lipid-soluble, endogenously synthesized single-electron carrier in the cell, which allows it to transfer electrons to and from the iron-sulfur clusters in the enzymes of the electron transport chain (3).

[0005] Cells require CoQ10 for mitochondrial function and must maintain an adequatesupply of this coenzyme for growth and survival. It has long been known that CoQ10 can be absorbed in limited quantities from the diet and that it likely is synthesized at multiple sites in the cell (4-6). The CoQ10 tail synthesis pathway, which is a branch of the mevalonate pathway, has been studied for decades (7). Because both cholesterol and the CoQ10 tail are derived from mevalonate, CoQ10 supplementation is recommended for management of statin-induced muscle symptoms (SAMS), but the results of CoQ10 supplementation trials for treatment of SAMS are equivocal (8), in part due to an incomplete understanding of CoQ10 absorption and pharmacokinetics. In contrast to the CoQ10 tail synthesis reactions, the biosynthetic reactions of the CoQ10 headgroup are not fully characterized in humans (9). It is known that tyrosine is the precursor for the CoQ10 quinone headgroup, and that tyrosine is catabolized to 4-hydroxyphenylpyruvate (4-HPPA), which is in turn converted by a series of unknown reactions to 4- hydroxybenzoate (4-HB).4-HB is conjugated by the COQ2 enzyme to the polyprenyl tail that anchors CoQ10 in the membrane (10) (FIG.1A). There has been recent progress in identifying some of the CoQ10 headgroup synthesis genes in yeast (11), but the enzymes of CoQ10 headgroup synthesis in humans remain unknown. The discovery of new human CoQ10 biosynthesis genes and intermediates is important because loss of known CoQ10 synthesis genes results in childhood neurodegenerative diseases that often present with encephalopathy and seizures (12-15). In addition, CoQ10 is important for mitochondrial electron transport chain (ETC) activity, which is necessary for cell growth (14,15). Revealing the mechanisms that proliferating cells use to maintain CoQ10 biosynthesis and ETC activity will improve our understanding of the metabolic requirements supporting deranged cell proliferation in cancer and autoimmune diseases and enable the development of CoQ10 synthesis inhibitors to control these diseases.

[0006] It was discovered that 4-hydroxymandelate (4-HMA) is a novel intermediate inthe human CoQ10 headgroup biosynthesis pathway, and 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) (FIG.1A) is identified as the enzyme that makes it (16). HPDL is a previously unannotated mitochondrial iron-dependent dioxygenase that 2 318985012Attorney Docket No: 243735.000456 catalyzes the oxidative decarboxylation of 4-HPPA to 4-HMA, which is the first irreversible step in the human CoQ10 headgroup synthesis pathway. It was found that HPDL deletion decreases the incorporation of labeled tyrosine into CoQ10 and reduces the formation of orthotopically implanted pancreatic ductal adenocarcinoma (PDAC) tumors. This defect is restored by addback of wild-type HPDL. In contrast, addback of catalytically inactive HPDL fails to restore the growth of HPDL-null tumors. Multiple missense and nonsense HPDL mutations were shown to segregate with a childhood neurodegenerative disorder presenting with spasticity and encephalopathy, and an inherited form of cerebral palsy (17-20). In addition, HPDL overexpression accelerates the growth of PDAC cells (21) and breast cancers. These studies did not elucidate the reaction catalyzed by HPDL or the mechanisms for these phenotypes. The work showing that HPDL catalyzes a critical step in CoQ10 headgroup synthesis explains these phenotypes and suggests that HPDL inhibition could decrease the growth of cells in benign and malignant conditions.

[0007] As such, there is an unmet need for novel therapeutics based on HPDLinhibition for treatment of various diseases and conditions, including HPDL-dependent tumors, cancers (e.g., pancreatic and breast cancers), autoimmune diseases, and any diseases involving unnecessary or uncontrolled cellular proliferation or mitochondrial activation. SUMMARY OF THE INVENTION

[0008] The present invention addresses the unmet need specified in the BackgroundSection, above, and other needs by providing HPDL inhibitors for use in such treatment.

[0009] In one aspect, provided herein is a method of treating a disease or condition in asubject in need thereof. This method comprises administering to the subject a therapeutically effective amount of a compound selected from the group consisting of: a. ibuprofen or an ibuprofen derivative having the structure of Formula (I):or awherein: 3 318985012Attorney Docket No: 243735.000456 R1 is selected from C1-12 alkyl, C4-12 alkylcycloalkyl, -NH2, -C(O)heteroaryl, - C(O)heterocyclyl, and phenyl, wherein C1-12alkyl, C4-12alkylcycloalkyl, and phenyl can be optionally substituted by one or more of halogen, -OH, =O, and combinations thereof; R2 is selected from C1-6 alkylene, phenylene, heteroarylene, and heterocyclene, wherein C1-6 alkylene, phenylene, heteroarylene, and heterocyclene, can be optionally substituted by one or more R´ groups; R3 and R4 are independently selected from hydrogen, C1-6 alkyl, -NH2, - C(O)OH, -C(O)NH2, and phenyl, wherein C1-6alkyl and phenyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof; or R5 is hydrogen or C1-12 alkyl; R5and R4combine with the carbon atom to which they are attached to form C3-12 cycloalkyl; R´ is independently selected at each occurrence from C1-6alkyl, halogen, and - OH, and combinations thereof; or R3and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl; b. dopamine or a dopamine derivative having the structure of Formula (II):,R6 and R7 are independently selected from -OH and -C(O)OH; R8 and R9 are independently selected from hydrogen and -NH2; R10is selected from hydrogen and -C(O)OH; and R11 is selected from hydrogen and C1-6 alkyl; c. flurbiprofen, ellagic acid, methyldopa, disulfiram, idelalisib, eltrombopagolamine, crystal violet, verteporfin, pioglitazone HCl, rosiglitazone HCl, enoxolone, triamcinolone, tideglusib, tolcapone, thimerosal, zinc pyrithione, 4 318985012Attorney Docket No: 243735.000456 montelukast sodium, nitroxoline, carbenoxolone sodium, sildenafil mesylate, saxagliptin hydrate, fenoldopam mesylate, gallic acid, clofoctol, hexachlorophene, cetylpyridinium chloride, povidone iodine, bithionol, bronopol, bardoxolone methyl, oltipraz, troglitazone, cangrelor tetrasodium, bismuth subcitrate potassium, puromycin, ledipasvir, obeticholic acid, erlotinib, tenofovir alafenamide, entrectinib. venetoclaxthe, 5-benzyl-1H-tetrazole, aspirin, 2-[4-(7-chloro-2-quinoxalinyloxy) phenoxy]propionic acid (XK469), or combinations thereof; d. a compound of formula or, whereinfrom the group consisting of a non-malignant disease; benign tumors; growth of tumor cells or proliferating immune cells; inappropriate growth and proliferation of cells in benign but debilitating diseases; scarring; scar formation; excessive scarring; keloid; fibrosis and superficial fibrosing disorder; Adhesive capsulitis; RASopathies; chronic kidney disease; heterotopic ossification; tuberous sclerosis (TSC); adhesions following surgery; heterotopic ossification; and stiffening of tissues with aging.

[0010] In another aspect, provided herein is a method of treating a disease or conditionin a subject in need thereof. This method comprises administering to the subject a therapeutically effective amount of a compound selected from the group consisting of: a. ibuprofen or an ibuprofen derivative having the structure of Formula (I):or awherein: 5 318985012Attorney Docket No: 243735.000456 R1 is selected from C1-12 alkyl, C4-12 alkylcycloalkyl, -NH2, -C(O)heteroaryl, - C(O)heterocyclyl, and phenyl, wherein C1-12alkyl, C4-12alkylcycloalkyl, and phenyl can be optionally substituted by one or more of halogen, -OH, =O, and combinations thereof; R2 is selected from C1-6 alkylene, phenylene, heteroarylene, and heterocyclene, wherein C1-6 alkylene, phenylene, heteroarylene, and heterocyclene, can be optionally substituted by one or more R´ groups; R3 and R4 are independently selected from hydrogen, C1-6 alkyl, -NH2, - C(O)OH, -C(O)NH2, and phenyl, wherein C1-6alkyl and phenyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof; or R5 is hydrogen or C1-12 alkyl; R5and R4combine with the carbon atom to which they are attached to form C3-12 cycloalkyl; R´ is independently selected at each occurrence from C1-6alkyl, halogen, and - OH, and combinations thereof; or R3and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl; b. dopamine or a dopamine derivative having the structure of Formula (II):,R6 and R7 are independently selected from -OH and -C(O)OH; R8 and R9 are independently selected from hydrogen and -NH2; R10is selected from hydrogen and -C(O)OH; and R11 is selected from hydrogen and C1-6 alkyl; and c. flurbiprofen, ellagic acid, methyldopa, disulfiram, idelalisib, eltrombopagolamine, crystal violet, verteporfin, pioglitazone HCl, rosiglitazone HCl, enoxolone, triamcinolone, tideglusib, tolcapone, thimerosal, zinc pyrithione, 6 318985012Attorney Docket No: 243735.000456 montelukast sodium, nitroxoline, carbenoxolone sodium, sildenafil mesylate, saxagliptin hydrate, fenoldopam mesylate, gallic acid, clofoctol, hexachlorophene, cetylpyridinium chloride, povidone iodine, bithionol, bronopol, bardoxolone methyl, oltipraz, troglitazone, cangrelor tetrasodium, bismuth subcitrate potassium, puromycin, ledipasvir, obeticholic acid, erlotinib, tenofovir alafenamide, entrectinib. venetoclaxthe, 5-benzyl-1H-tetrazole, aspirin, 2-[4-(7-chloro-2-quinoxalinyloxy) phenoxy]propionic acid (XK469), or combinations thereof, wherein the disease or condition is selected from the group consisting of a non-malignant disease; benign tumors; growth of tumor cells or proliferating immune cells; inappropriate growth and proliferation of cells in benign but debilitating diseases; scarring; scar formation; excessive scarring; keloid; fibrosis and superficial fibrosing disorder; Adhesive capsulitis; RASopathies; chronic kidney disease; heterotopic ossification; tuberous sclerosis (TSC); adhesions following surgery; heterotopic ossification; and stiffening of tissues with aging.

[0011] In an additional aspect, provided herein is a method of decreasingCoQ10biosynthesis in a subject in need thereof. This method comprises administering to the subject a therapeutically effective amount of an ibuprofen derivative having the structure of Formula (IA), 5-benzyl-1H-tetrazole, aspirin, or 2-[4-(7-chloro-2-quinoxalinyloxy) phenoxy]propionic acid (XK469),salt thereof, wherein: R1is selected from C1-12alkyl, C4-12alkylcycloalkyl, -C(O)heteroaryl, and - C(O)heterocyclyl, wherein C1-12 alkyl and C4-12 alkylcycloalkyl can be optionally substituted by one or more of =O; R2 is selected from phenylene, heteroarylene, and heterocyclene, wherein phenylene, heteroarylene, and heterocyclene can be optionally substituted by one or more R´ groups; 7 318985012Attorney Docket No: 243735.000456 R3 and R4 are independently selected from hydrogen, C1-6 alkyl, -C(O)OH, and - C(O)NH2, wherein C1-6alkyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof; R5 is hydrogen or C1-12 alkyl; or R4 and R5 combine with the carbon atom to which they are attached to form C3-12 cycloalkyl; R´ is independently selected at each occurrence from C1-6 alkyl, halogen, and -OH, and combinations thereof; or R3and R´ combine with the carbon atoms to which they are attached to form C3-12cycloalkyl, with the proviso that if R5is hydrogen, R1is unsubstituted C1-12alkyl, and R2is phenylene, then i) R3 is -C(O)NH2 or ii) R3and R´ combine with the carbon atoms to which they are attached to form C3-12cycloalkyl.

[0012] In an additional aspect, provided herein is a method of treating cancer,autoimmune disease, or any disease involving cellular proliferation in a subject in need thereof, comprising the following steps: a. determining expression level of 4-hydroxyphenylpyruvate dioxygenase-like(HPDL) in a sample obtained from the subject; b. comparing the HPDL expression level determined in step (a) with a control level ofHPDL expression; and c. administering an effective amount of an HPDL inhibitor to the subject exhibiting ahigher level of HPDL expression as compared to the control level, wherein the HPDL inhibitor is a compound that is an ibuprofen derivative having the structure of Formula (IA), 5-benzyl-1H-tetrazole, aspirin, or 2-[4-(7-chloro-2- quinoxalinyloxy) phenoxy]propionic acid (XK469),salt thereof, wherein: R1 is selected from C1-12 alkyl, C4-12 alkylcycloalkyl, -C(O)heteroaryl, and - C(O)heterocyclyl, wherein C1-12alkyl and C4-12alkylcycloalkyl can be optionally substituted by one or more of =O; 8 318985012Attorney Docket No: 243735.000456 R2 is selected from phenylene, heteroarylene, and heterocyclene, wherein phenylene, heteroarylene, and heterocyclene can be optionally substituted by one or more R´ groups; R3 and R4 are independently selected from hydrogen, C1-6 alkyl, -C(O)OH, and -C(O)NH2, wherein C1-6 alkyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof; R5 is hydrogen or C1-12 alkyl; or R4 and R5 combine with the carbon atom to which they are attached to form C3-12cycloalkyl; R´ is independently selected at each occurrence from C1-6 alkyl, halogen, and -OH, and combinations thereof; or R3 and R´ combine with the carbon atoms to which they are attached to form C3-12cycloalkyl, with the proviso that if R5 is hydrogen, R1 is unsubstituted C1-12 alkyl, and R2is phenylene, then i) R3is -C(O)NH2or ii) R3and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl.

[0013] In an additional aspect, provided herein is a method of determiningeffectiveness of a treatment for cancer, autoimmune disease, or any disease involving cellular proliferation in a subject, comprising the following steps: a. determining expression level of 4-hydroxyphenylpyruvate dioxygenase-like(HPDL) in a first sample obtained from the subject before the subject receives a treatment for cancer comprising administering a therapeutically effective amount of a compound that is an ibuprofen derivative having the structure of Formula (IA), 5-benzyl-1H-tetrazole, aspirin, or 2-[4-(7-chloro-2- quinoxalinyloxy) phenoxy]propionic acid (XK469),salt thereof, wherein: R1 is selected from C1-12 alkyl, C4-12 alkylcycloalkyl, -C(O)heteroaryl, and - C(O)heterocyclyl, wherein C1-12alkyl and C4-12alkylcycloalkyl can be optionally substituted by one or more of =O; 9 318985012Attorney Docket No: 243735.000456 R2 is selected from phenylene, heteroarylene, and heterocyclene, wherein phenylene, heteroarylene, and heterocyclene can be optionally substituted by one or more R´ groups; R3 and R4 are independently selected from hydrogen, C1-6 alkyl, -C(O)OH, and -C(O)NH2, wherein C1-6 alkyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof; R5 is hydrogen or C1-12 alkyl; or R4 and R5 combine with the carbon atom to which they are attached to form C3-12cycloalkyl; R´ is independently selected at each occurrence from C1-6 alkyl, halogen, and -OH, and combinations thereof; or R3 and R´ combine with the carbon atoms to which they are attached to form C3-12cycloalkyl, with the proviso that if R5 is hydrogen, R1 is unsubstituted C1-12 alkyl, and R2is phenylene, then i) R3is -C(O)NH2or ii) R3and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl; b. determining expression level of HPDL in a second sample obtained from thesubject after the subject has received the treatment for cancer, autoimmune disease, or any disease involving cellular proliferation; c. comparing the HPDL expression levels determined in the first sample and thesecond sample; and d. determining that (i) the treatment is effective if the HPDL expression level inthe second sample is lower than HPDL expression level in the first sample, or (ii) the treatment is not effective if the HPDL expression level in the second sample is not lower than the HPDL expression level in the first sample.

[0014] In an additional aspect, provided herein is a method of predicting prognosis ofcancer in a subject having cancer, autoimmune disease, or any disease involving cellular proliferation, comprising the following steps: a. determining expression level of 4-hydroxyphenylpyruvate dioxygenase-like(HPDL) protein in a sample obtained from the subject; b. comparing the HPDL expression level determined in step (a) with a control level ofHPDL expression; and 10 318985012Attorney Docket No: 243735.000456 c. determining the subject (i) as having poor prognosis if the HPDL expression levelis higher than the control level, or (ii) as having good prognosis if the HPDL expression level is lower than or equal to the control level, wherein if the subject is determined to have poor prognosis, the method further comprising administering to the subject a single-agent chemotherapy, supportive care, and / or a compound that is an ibuprofen derivative having the structure of Formula (IA), 5-benzyl-1H-tetrazole, aspirin, or 2-[4-(7-chloro-2-quinoxalinyloxy) phenoxy]propionic acid (XK469), salt thereof, wherein:12 C4-12 alkylcycloalkyl, -C(O)heteroaryl, and -C(O)heterocyclyl, wherein C1-12alkyl and C4-12alkylcycloalkyl can be optionally substituted by one or more of =O; R2is selected from phenylene, heteroarylene, and heterocyclene, wherein phenylene, heteroarylene, and heterocyclene can be optionally substituted by one or more R´ groups; R3 and R4 are independently selected from hydrogen, C1-6 alkyl, -C(O)OH, and -C(O)NH2, wherein C1-6 alkyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof; R5 is hydrogen or C1-12 alkyl; or R4 and R5 combine with the carbon atom to which they are attached to form C3-12 cycloalkyl; R´ is independently selected at each occurrence from C1-6alkyl, halogen, and -OH, and combinations thereof; or R3and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl, with the proviso that if R5is hydrogen, R1is unsubstituted C1-12alkyl, and R2 is phenylene, then i) R3 is -C(O)NH2 or ii) R3and R´ combine with the carbon atoms to which they are attached to form C3-12cycloalkyl. 11 318985012Attorney Docket No: 243735.000456

[0015] In an additional aspect, provided herein is a method of inhibiting an immuneresponse in a subject in need thereof. This method comprises administering to the subject a therapeutically effective amount of an ibuprofen derivative having the structure of Formula (IA), 5-benzyl-1H-tetrazole, aspirin, or 2-[4-(7-chloro-2-quinoxalinyloxy) phenoxy]propionic acid (XK469), salt thereof, wherein:12 alkyl, C4-12 alkylcycloalkyl, -C(O)heteroaryl, and - C(O)heterocyclyl, wherein C1-12 alkyl and C4-12 alkylcycloalkyl can be optionally substituted by one or more of =O; R2 is selected from phenylene, heteroarylene, and heterocyclene, wherein phenylene, heteroarylene, and heterocyclene can be optionally substituted by one or more R´ groups; R3and R4are independently selected from hydrogen, C1-6alkyl, -C(O)OH, and - C(O)NH2, wherein C1-6 alkyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof; R5 is hydrogen or C1-12 alkyl; or R4 and R5 combine with the carbon atom to which they are attached to form C3-12 cycloalkyl; R´ is independently selected at each occurrence from C1-6 alkyl, halogen, and -OH, and combinations thereof; or R3 and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl, with the proviso that if R5 is hydrogen, R1 is unsubstituted C1-12 alkyl, and R2 is phenylene, then i) R3is -C(O)NH2or ii) R3and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl.

[0016] In an additional aspect, provided herein is a method of reducing an immuneresponse to a vaccine in a subject in need thereof. This method comprises administering to the subject a therapeutically effective amount of an ibuprofen derivative having the 12 318985012Attorney Docket No: 243735.000456 structure of Formula (IA), 5-benzyl-1H-tetrazole, aspirin, or 2-[4-(7-chloro-2- quinoxalinyloxy) phenoxy]propionic acid (XK469), salt thereof, wherein:12alkyl, C4-12alkylcycloalkyl, -C(O)heteroaryl, and - C(O)heterocyclyl, wherein C1-12 alkyl and C4-12 alkylcycloalkyl can be optionally substituted by one or more of =O; R2 is selected from phenylene, heteroarylene, and heterocyclene, wherein phenylene, heteroarylene, and heterocyclene can be optionally substituted by one or more R´ groups; R3 and R4 are independently selected from hydrogen, C1-6 alkyl, -C(O)OH, and - C(O)NH2, wherein C1-6alkyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof; R5is hydrogen or C1-12alkyl; or R4 and R5 combine with the carbon atom to which they are attached to form C3-12 cycloalkyl; R´ is independently selected at each occurrence from C1-6 alkyl, halogen, and -OH, and combinations thereof; or R3 and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl, with the proviso that if R5 is hydrogen, R1 is unsubstituted C1-12 alkyl, and R2 is phenylene, then i) R3 is -C(O)NH2 or ii) R3and R´ combine with the carbon atoms to which they are attached to form C3-12cycloalkyl.

[0017] In an additional aspect, provided herein is a method of reducing antibodyproduction in a subject in need thereof. This method comprises administering to the subject a therapeutically effective amount of an ibuprofen derivative having the structure of Formula (IA), 5-benzyl-1H-tetrazole, aspirin, or 2-[4-(7-chloro-2-quinoxalinyloxy) phenoxy]propionic acid (XK469), 13 318985012Attorney Docket No: 243735.000456 salt thereof, wherein:alkyl, C4-12alkylcycloalkyl, -C(O)heteroaryl, and - C(O)heterocyclyl, wherein C1-12 alkyl and C4-12 alkylcycloalkyl can be optionally substituted by one or more of =O; R2 is selected from phenylene, heteroarylene, and heterocyclene, wherein phenylene, heteroarylene, and heterocyclene can be optionally substituted by one or more R´ groups; R3 and R4 are independently selected from hydrogen, C1-6 alkyl, -C(O)OH, and - C(O)NH2, wherein C1-6 alkyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof; R5is hydrogen or C1-12alkyl; or R4 and R5 combine with the carbon atom to which they are attached to form C3-12 cycloalkyl; R´ is independently selected at each occurrence from C1-6 alkyl, halogen, and -OH, and combinations thereof; or R3 and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl, with the proviso that if R5 is hydrogen, R1 is unsubstituted C1-12 alkyl, and R2 is phenylene, then i) R3 is -C(O)NH2 or ii) R3and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl.

[0018] In an additional aspect, provided herein is a method of inhibiting growth of atumor in a subject in need thereof. This method comprises administering to the subject a therapeutically effective amount of an ibuprofen derivative having the structure of Formula (IA), 5-benzyl-1H-tetrazole, aspirin, or 2-[4-(7-chloro-2-quinoxalinyloxy) phenoxy]propionic acid (XK469),14 318985012Attorney Docket No: 243735.000456 or a pharmaceutically acceptable salt thereof, wherein: R1is selected from C1-12alkyl, C4-12alkylcycloalkyl, -C(O)heteroaryl, and - C(O)heterocyclyl, wherein C1-12 alkyl and C4-12 alkylcycloalkyl can be optionally substituted by one or more of =O; R2 is selected from phenylene, heteroarylene, and heterocyclene, wherein phenylene, heteroarylene, and heterocyclene can be optionally substituted by one or more R´ groups; R3 and R4 are independently selected from hydrogen, C1-6 alkyl, -C(O)OH, and - C(O)NH2, wherein C1-6alkyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof; R5is hydrogen or C1-12alkyl; or R4 and R5 combine with the carbon atom to which they are attached to form C3-12 cycloalkyl; R´ is independently selected at each occurrence from C1-6 alkyl, halogen, and -OH, and combinations thereof; or R3 and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl, with the proviso that if R5 is hydrogen, R1 is unsubstituted C1-12 alkyl, and R2 is phenylene, then i) R3 is -C(O)NH2 or ii) R3and R´ combine with the carbon atoms to which they are attached to form C3-12cycloalkyl.

[0019] In an additional aspect, provided herein is a method of treating a subject havingan activating variant in the HPDL gene, any other gene in the CoQ headgroup synthesis pathway, or any gene controlling the CoQ headgroup synthesis pathway. This method comprises administering to the subject a therapeutically effective amount of an ibuprofen derivative having the structure of Formula (IA), 5-benzyl-1H-tetrazole, aspirin, or 2-[4- (7-chloro-2-quinoxalinyloxy) phenoxy]propionic acid (XK469),salt thereof, wherein: 15 318985012Attorney Docket No: 243735.000456 R1 is selected from C1-12 alkyl, C4-12 alkylcycloalkyl, -C(O)heteroaryl, and - C(O)heterocyclyl, wherein C1-12alkyl and C4-12alkylcycloalkyl can be optionally substituted by one or more of =O; R2 is selected from phenylene, heteroarylene, and heterocyclene, wherein phenylene, heteroarylene, and heterocyclene can be optionally substituted by one or more R´ groups; R3 and R4 are independently selected from hydrogen, C1-6 alkyl, -C(O)OH, and - C(O)NH2, wherein C1-6 alkyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof; R5 is hydrogen or C1-12 alkyl; or R4and R5combine with the carbon atom to which they are attached to form C3-12cycloalkyl; R´ is independently selected at each occurrence from C1-6alkyl, halogen, and -OH, and combinations thereof; or R3and R´ combine with the carbon atoms to which they are attached to form C3-12cycloalkyl, with the proviso that if R5is hydrogen, R1is unsubstituted C1-12alkyl, and R2is phenylene, then i) R3 is -C(O)NH2 or ii) R3and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] FIG. 1A shows incorporation of tyrosine into the CoQ10 headgroup via HPDL.4-HMA.4-hydroxyphenylpyruvate (4-HPPA) is a canonical catabolite of tyrosine. It is discovered that the enzyme hydroxy-phenylpyruate dioxygenase-like (HPDL) converts 4- HPPA to 4-hydroxymandelate (4-HMA), which is converted to 4-hydroxybenzoate (4- HB), the immediate precursor of the CoQ10 headgroup.

[0021] FIG. 1B shows fractions from HPDL purification run on a Coomassie stainedgel of high purity after Talon metal affinity and cation exchange. It is demonstrated that His-tagged HPDL can be produced and purify using expiSF9 expression system.

[0022] FIGS. 2A-2C show GC-MS tracking of 4HMA allows to follow HPDL activityafter purification. FIG.2A is a schematic representation of HPDL catalytic reaction, FIG.2B shows GC-MS detection of 4HMA produced following enzymatic assay on 16 318985012Attorney Docket No: 243735.000456 purified enzyme. FIG.2C demonstrates GC-MC kinetic characterization of HPDL activity.

[0023] FIG. 3 shows conditions for the enzyme essay.

[0024] FIGS. 4A-4B shows results of the screening of compounds 2-9 for pocketwhere carboxylate binds.

[0025] FIGS. 5A-5E show results of the screening of compounds 10-13 and 15-19 forchannel region.

[0026] FIGS. 6A-6C show results of the thermal shift assay for ibuprofen (FIG. 6A),flurbiprofen (FIG.6B), and aspirin (FIG.6C).

[0027] FIG. 7 shows conditions for crystallization screening.DETAILED DESCRIPTION OF THE INVENTION

[0028] The HPDL enzyme catalyzes the production of 4-hydroxymandelic acid (4-HMA), the first committed step in mammalian coenzyme Q10 (CoQ10) headgroup synthesis. Inhibitors of HPDL have the potential to attenuate the growth of tumor cells and of proliferating immune cells, and could be useful in the treatment of cancer. In addition, inhibitors of HPDL could attenuate the inappropriate growth and proliferation of cells in benign but debilitating diseases. These diseases include excessive scarring such as keloids, diseases involving fibrosis such as nephrogenic systemic fibrosis, idiopathic pulmonary fibrosis, chronic kidney disease, radiation-induced fibrosis including radiation-induced pulmonary fibrosis, hepatic fibrosis, Dupuytren's contracture, Peyronie's disease, Scleroderma, Adhesive capsulitis, Post-MI myocardial fibrosis, and adhesions following surgery; heterotopic ossification, RASopathies, TSC, and benign tumors such as meningiomas and vestibular schwannomas. Autoimmune diseases also require cellular proliferation and activation, and could be treated by HPDL inhibition. HPDL inhibitors could also be used to reduce scar formation after surgery, and reduce stiffening of tissues (e.g. arteries) with aging.

[0029] Some aspects of the present application are based on the discovery that HPDLcatalyzes a critical step in the synthesis of the headgroup of Coenzyme Q10 (CoQ10). HPDL makes R-4-hydroxymandelate ((R)-4-HMA), which is a long sought intermediate in the synthesis of the CoQ10 headgroup. R-4-HMA is converted to 4-hydroxybenzoic acid (4-HB).4-HMA is chiral, with both (R) and (S)-enantiomers theoretically possible, 17 318985012Attorney Docket No: 243735.000456 and HPDL appears to produce exclusively the R-enantiomer of this molecule. The data here also show that 4-HMA is readily taken up by cells and incorporated into CoQ10.

[0030] Because the pharmacokinetics of CoQ10 are not well understood and it is notclear how much orally ingested CoQ10 is actually absorbed, and because 4-HMA is soluble, the natural product of HPDL, and is taken up by cells, supplementation with 4- HMA, 4-HB, or other intermediates (e.g., 4-hydroxybenzoylformate (4-HBF), 4- hydroxybenzaldehyde (4-HBz)) should treat patients with CP or neurodevelopmental disease induced by HPDL mutations. If CoQ10 were readily absorbed and entered the brain, it could treat this disease as well.

[0031] To facilitate an understanding of the principles and features of the variousembodiments of the invention, various illustrative embodiments are explained below. Although exemplary embodiments of the invention are explained in detail, it is to be understood that other embodiments are contemplated. Accordingly, it is not intended that the invention is limited in its scope to the details of construction and arrangement of components set forth in the following description or examples. The invention is capable of other embodiments and of being practiced or carried out in various ways. Also, in describing the exemplary embodiments, specific terminology will be resorted to for the sake of clarity.

[0032] As used herein, the terms “about” or “approximately” for any numerical valuesor ranges indicate a suitable dimensional tolerance that allows the part or collection of components to function for its intended purpose as described herein. More specifically, “about” or “approximately” may refer to the range of values ±20% of the recited value, e.g. “about 90%” may refer to the range of values from 71% to 99%.

[0033] As used herein, the term “alkane” refers to aliphatic hydrocarbons of formulaCnH2n+2, which may be straight or branched having about 1 to about 40 (e.g., 1–2, 1–3, 1– 4, 1–5, 1–6, 1–7, 1–8) carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkyl chain. Exemplary alkanes include methane, ethane, n-propane, i-propane, n-butane, t-butane, n- pentane, and 3-pentane. The term “alkylene” refers to a divalent group formed from an alkane by removal of two hydrogen atoms. Exemplary alkylene groups include, but are not limited to, divalent groups derived from the alkanes described above.

[0034] As used herein, the term “alkyl” is given its ordinary meaning in the art and caninclude saturated aliphatic groups, including straight-chain alkyl groups, branched-chain 18 318985012Attorney Docket No: 243735.000456 alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In certain embodiments, a straight chain or branched chain alkyl has about 1–20 carbon atoms in its backbone (e.g., C1-20 for straight chain, C2-20 for branched chain), and alternatively, about 1–10 carbon atoms, or about 1 to 6 carbon atoms. In some embodiments, a cycloalkyl ring has from about 3–10 carbon atoms in their ring structure where such rings are monocyclic or bicyclic, and alternatively about 5, 6 or 7 carbons in the ring structure. In some embodiments, a cycloalkyl group is a cyclopropyl, a cyclobutyl, a cyclopentyl, or a cyclohexyl group. In some embodiments, an alkyl group can be a lower alkyl group, wherein a lower alkyl group comprises 1–4 carbon atoms (e.g., C1-4 for straight chain lower alkyls). When used in the context of a divalent alkyl group, it is to be understood that “alkyl” refers to an alkylene group.

[0035] As used herein, the term “cycloalkyl” refers to a non-aromatic saturated orunsaturated mono- or polycyclic ring system which may contain 3 to 8 (3, 4, 5, 6, 7, 8, 3– 4, 3–5, 3–6, 3–7, 4–5, 4–6, 4–7, 4–8, 5–6, 5–7, 5–8, 6–7, 6–8, 7–8) carbon atoms, and which may include at least one double bond. Exemplary cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, anti-bicyclopropane, or syn-bicyclopropane.

[0036] The term “alkylcycloalkyl” refers to a moiety of the formula –RaRb or RaRb–where Rais an alkyl as defined above and Rbis a cycloalkyl as defined above.

[0037] As used herein, the term “alkenyl” refers to an alkyl group, as defined herein,including straight-chain alkenyl groups, branched-chain alkenyl groups, and cycloalkenyl groups having one or more double bonds. In certain embodiments, a straight chain or branched chain alkenyl has about 1–20 carbon atoms in its backbone (e.g., C2-20 for straight chain, C3-20for branched chain), and alternatively, about 2–10 carbon atoms, or about 2 to 6 carbon atoms. In some embodiments, an alkenyl group has 1, 2, 3, 4, 5, or 6 double bonds. In some embodiments, a cycloalkenyl ring has from about 3–10 carbon atoms in the ring structure where such rings are monocyclic or bicyclic, and alternatively about 5, 6 or 7 carbons in the ring structure, and 1, 2, or 3 double bonds. In some embodiments, a cycloalkenyl group is a cyclopropenyl, a cyclobutenyl, a cyclobutadienyl, a cyclopentenyl, a cyclopentadienyl, a cyclohexenyl, or a cyclohexadienyl group. In some embodiments, an alkenyl group can be a lower alkenyl group, wherein a lower alkenyl group comprises 2–4 carbon atoms (e.g., C2-4 for straight 19 318985012Attorney Docket No: 243735.000456 chain lower alkenyls). In one embodiment, a cycloalkenyl group has six carbon atoms and one double bond.

[0038] As used herein, the term “alkynyl” refers to an alkyl group, as defined herein,including straight-chain alkynyl groups, branched-chain alkynyl groups, and cycloalkynyl groups having one or more triple bonds. In certain embodiments, a straight chain or branched chain alkynyl has about 2–20 carbon atoms in its backbone (e.g., C2-20 for straight chain, C3-20 for branched chain), and alternatively, about 2–10 carbon atoms, or about 2 to 6 carbon atoms. In some embodiments, an alkynyl group has 1, 2, 3, 4, 5, or 6 triple bonds. In some embodiments, a cycloalkynyl ring has from about 6–12 carbon atoms in the ring structure where such rings are monocyclic or bicyclic, and alternatively about 8, 9, or 10 carbons in the ring structure, and 1, 2, or 3 triple bonds. In some embodiments, an alkynyl group can be a lower alkynyl group, wherein a lower alkynyl group comprises 2–4 carbon atoms (e.g., C2-4for straight chain lower alkynyls).

[0039] The term “heteroalkyl” is given its ordinary meaning in the art and refers toalkyl groups as described herein in which one or more carbon atoms is replaced with a heteroatom (e.g., oxygen, nitrogen, sulfur, and the like). In some embodiments, a heteroalkyl group can have one or more of methylene groups replaced with -O-, -S-, or - NH-, in which the hydrogen of -NH- is optionally substituted. Examples of heteroalkyl groups include, but are not limited to, alkoxy, poly(ethylene glycol)-, alkyl-substituted amino, tetrahydrofuranyl, piperidinyl, morpholinyl, etc.

[0040] The term “haloalkyl” is given its ordinary meaning in the art and refers to alkylgroups as described herein in which one or more hydrogen atoms is replaced by a halogen atom, i.e., F, Cl, Br, or I. In some embodiments a haloalkyl group can be a perfluoroalkyl group, i.e., a group where all hydrogen atoms are replaced with fluoride atoms. In some embodiments a haloalkyl group can be a halomethyl group, i.e., a C1 group with 1, 2, or 3 halogen atoms, e.g., -CF3, -CF2H, -CH2F, -CH2Cl, -CH2Br; -CH2I. In some embodiments a haloalkyl group can be, e.g., -CF3, -CF2H, -CH2F, -CH2Cl, -CH2Br; -CH2I, -CH2CF3, CH2CH2F, -CH2CH2Br, -CH2CH2Cl, -CH2CH2I, etc.

[0041] The term “haloalkoxy” is given its ordinary meaning in the art and refers toalkoxy groups as described herein, i.e. alkyl groups bonded to an oxygen atom, in which one or more hydrogen atoms is replaced by a halogen atom, i.e., F, Cl, Br, or I. In some embodiments a haloalkoxy group can be a perfluoroalkoxy group, i.e., a group where all hydrogen atoms are replaced with fluoride atoms. In some embodiments a haloalkoxy 20 318985012Attorney Docket No: 243735.000456 group can be, e.g., -OCF3, -OCF2H, -OCH2F, -OCH2Cl, -OCH2Br; -OCH2I, -OCH2CF3, - OCH2CH2F, -OCH2CH2Br, -OCH2CH2Cl, -OCH2CH2I, etc.

[0042] The term “aryl” used alone or as part of a larger moiety as in “aralkyl,”“aralkoxy,” “aryloxy” or “aryloxyalkyl,” refers to monocyclic or bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring members. The term “aryl” can be used interchangeably with the term “aryl ring.” In certain embodiments of the present disclosure, “aryl” refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, binaphthyl, anthracyl and the like, which can bear one or more substituents. Also included within the scope of the term “aryl,” as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0043] The term “arylene” means a group obtained by removal of a hydrogen atomfrom an aryl group. Non-limiting examples of arylene include phenylene and naphthylene.

[0044] The term “aralkyl” refers to alkyl groups as described herein in which one ormore hydrogen atoms is substituted by aryl groups, where the radical or point of attachment is on the alkyl group. The alkyl part of an aralkyl group is optionally substituted as described in the term “alkyl” above. The aryl part of the aralkyl group is optionally substituted as described in ther term “alkyl” above.

[0045] The term “alkylaryl” refers to aryl groups as described herein in which one ormore hydrogen atoms is substituted by alkyl groups, where the radical or point of attachment is on the aryl group. The aryl part of the alkylaryl group is optionally substituted as described in the term “aryl” above. The alkyl part of an alkylaryl group is optionally substituted as described in the term “alkyl” above.

[0046] The terms “heteroaryl” and “heteroar-,” used alone of as part of a larger moiety,e.g., “heteroaralkyl,” or “heteroaralkoxy,” refer to groups having 5 to 10 ring atoms (i.e., monocyclic or bicyclic), in some embodiments 5, 6, 9, or 10 ring atoms. In some embodiments, such rings have 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term “heteroatom” refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quatemized form of a basic nitrogen. Heteroaryl groups 21 318985012Attorney Docket No: 243735.000456 include, without limitation, pyridine, quinoline, isoquinoline, quinolizine, pyrido[1,2- a]pyrazine, 1,8-naphthyridine, purine, chromene, indole, phenanthrene, benzo[H]quinoline, anthraquinone, and phenanthrol[1,2-b]furan groups. In some embodiments, a heteroaryl is a heterobiaryl group, such as bipyridyl and the like. The terms “heteroaryl” and “heteroar-,” as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H—quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. A heteroaryl group can be monocyclic, bicyclic, tricyclic, tetracyclic, and / or otherwise polycyclic. The term “heteroaryl” can be used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” any of which terms include rings that are optionally substituted. The term “heteroaralkyl” refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0047] The term “heteroarylene” means a group obtained by removal of a hydrogenatom from an heteroaryl group.

[0048] As used herein, the terms “heterocycle,” “heterocyclyl,” “heterocyclic radical,”and “heterocyclic ring” are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7–10-membered bicyclic heterocyclic moiety that is saturated, partially unsaturated, or aromatic, and having, in addition to carbon atoms, one or more, e.g., one to four, heteroatoms, as defined above. As used herein, the term “heterocycle” encompasses heteroaryl groups, as defined above. In one embodiment, a heterocycle can be a saturated, partially unsaturated, or aromatic, 5-7 membered monocyclic moiety comprising from 1 to 3 nitrogen atoms, e.g., a pyrrole, an imidazole, a pyrazole, a pyrazole, a triazole, a piperidine, a piperazine, a pyridazine, a pyridine, 2H-pyridine, a pyridone, a pyrimidine, or a pyrazine, including monovalent or divalent radicals thereof. When used in reference to a ring atom of a heterocycle, the term “nitrogen” includes a substituted nitrogen. In one embodiment, a heterocycle can be a saturated, partially unsaturated, or aromatic, 5-7 membered monocyclic moiety comprising from 1 to 3 oxygen atoms, e.g., a tetrahydrofuran (i.e., oxolane), a furan, a dihydrofuran, a dioxolane, 22 318985012Attorney Docket No: 243735.000456 a tetrahydropyran (i.e., oxane), a pyran, a dihydropyran, a dioxane, a dioxine, a trioxane, an oxepane, or an oxepine, including monovalent or divalent radicals thereof. In one embodiment, a heterocycle can be thiophene, oxazole, thiazole, or morpholine, including monovalent or divalent radicals thereof.

[0049] A heterocyclic ring can be attached, e.g., to its pendant group, at any heteroatomor carbon atom that results in a stable structure. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms “heterocycle,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical,” are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as phenyl, indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl. A heterocyclyl group can be monocyclic, bicyclic, tricyclic, tetracyclic, and / or otherwise polycyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted by a heterocyclyl.

[0050] The term “heteroatom” means one or more of oxygen, sulfur, nitrogen,phosphorus, or silicon, including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen. In some embodiments, a heteroatom can be a substitutable nitrogen of a heterocyclic ring.

[0051] The term “heterocyclene” means a group obtained by removal of a hydrogenatom from a heterocyclyl group.

[0052] The term “unsaturated,” as used herein, means that a moiety has one or moreunits of unsaturation.

[0053] The term “halogen” means F, Cl, Br, or I atom, and / or its radical or substituent,namely -F, -Cl, -Br, or -I.

[0054] As described herein, in certain embodiments, certain compounds of thedisclosure can be indicated to comprise “optionally substituted” moieties. When indicated, in general, the term “substituted,” whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group can have a suitable substituent at each substitutable position of the group, and when more 23 318985012Attorney Docket No: 243735.000456 than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable,” as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0055] As used herein, a substituent, e.g., -B, can be represented as a , wheredenotes a point of attachment.

[0056] Unless otherwise stated, structures depicted herein are also meant to include allisomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the disclosure.

[0057] The present application also includes pharmaceutically acceptable salts of thecompounds described herein. The “pharmaceutically acceptable salts” include a subset of the “salts” described above which are conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418 and Berge, SM et al, Journal of Pharmaceutical Science, 1977, 66, 1, 1-19. By way of an example, in an embodiment of the disclosure pharmaceutically acceptable salts can comprise a suitable anion selected from F−, Cl−, Br−, I−, OH−,−BF4, CF3SO3−, monobasic sulfate, dibasic sulfate, monobasic phosphate, dibasic phosphate, or tribasic phosphate, NO3−, PF6−, NO2−, carboxylate, CeFfSO3−, (where e=2-10 and f=2e+1), acetate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bitartrate, camsylate, carbonate, citrate, decanoate, edetate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolate, glycollyalarsanilate, hexanoate, hydrabamine, hydroxynaphthoate, isthionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, mucate, napsylate, octanoate, oleate, 24 318985012Attorney Docket No: 243735.000456 oxalate, palmitate, pamoate, pantothenate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, tartrate, teoclate, tosylate, or triethiiodide. By way of another example, in an embodiment of the disclosure pharmaceutically acceptable salts can comprise a suitable cation selected from aluminum, arginine, benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, lithium, meglumine, potassium, procaine, sodium, triethylamince, or zinc. The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0058] The term “prodrug” as used herein includes a chemical which may betransformed in vivo to a pharmacologically active drug. The term “metabolite” as used herein includes a chemical that a given agent is transformed into in vivo.

[0059] The enantiomeric excess, or “ee,” for a given pair of enantiomers is thepercentage of the major enantiomer less the percentage of the minor enantiomer. A “racemate” or “racemic mixture” is an equal mixture of two enantiomers and therefore has 0% ee.

[0060] The term “enantiomerically enriched” or “enantioenriched” as used hereinincludes compounds that are mixtures with one enantiomer's being present in excess over the other (ee >0% and <100%). For example, a sample of 40% ee consists of 70% of the major enantiomer and 30% of the minor enantiomer.

[0061] The term “enantiomerically pure” or “enantiopure” as used herein includescompounds where the quantification of the minor enantiomer becomes difficult, e.g., with an ee of 99% or greater. Ideally, enantiopure compounds consist of a single enantiomer only.

[0062] The term “sample” as used herein includes any biological specimen obtainedfrom a subject or patient. Samples that can be used in the methods of the present disclosure include, without limitation, tumor sample, whole blood, plasma, serum, red blood cells, white blood cells (e.g., peripheral blood mononuclear cells (PBMC), polymorphonuclear (PMN) cells), ductal lavage fluid, nipple aspirate, lymph (e.g., disseminated tumor cells of the lymph node), bone marrow aspirate, saliva, urine, stool (i.e., feces), sputum, bronchial lavage fluid, tears, fine needle aspirate (e.g., harvested by 25 318985012Attorney Docket No: 243735.000456 random periareolar fine needle aspiration), any other bodily fluid, a tissue sample such as a biopsy (e.g., needle biopsy), and cellular extracts thereof. In some embodiments, when the subject is a pregnant female, the sample may be a fetal DNA sample (e.g., cell-free fetal DNA (cffDNA)).

[0063] As used herein, the term “subject” or “patient” refers to mammals and includes,without limitation, human and veterinary animals. In a preferred embodiment, the subject is human. In another preferred embodiment, the subject is a human or an infant.

[0064] The terms “treat” or “treatment” of a state, disorder or condition include: (1)preventing or delaying the appearance of at least one clinical or sub-clinical symptom of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; or (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or sub-clinical symptom thereof; or (3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or sub-clinical symptoms. The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.

[0065] An “effective amount” of a compound described herein refers to an amountsufficient to elicit the desired biological response, i.e., treating the state, disorder or condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. An effective amount encompasses therapeutic and prophylactic treatment.

[0066] A “therapeutically effective amount” of a compound described herein is anamount sufficient to provide a therapeutic benefit in the treatment of a state, disorder or condition or to delay or minimize one or more symptoms associated with the state, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or 26 318985012Attorney Docket No: 243735.000456 avoids symptoms or causes of the condition, and / or enhances the therapeutic efficacy of another therapeutic agent.

[0067] It must also be noted that, as used in the specification and the appended claims,the singular forms “a,” “an” and “the” include plural references unless the context clearly dictates otherwise. For example, reference to a component is intended also to include composition of a plurality of components. References to a composition containing “a” constituent is intended to include other constituents in addition to the one named. In other words, the terms “a,” “an,” and “the” do not denote a limitation of quantity, but rather denote the presence of “at least one” of the referenced item.

[0068] Also, in describing the exemplary embodiments, terminology will be resorted tofor the sake of clarity. It is intended that each term contemplates its broadest meaning as understood by those skilled in the art and includes all technical equivalents which operate in a similar manner to accomplish a similar purpose.

[0069] It is also to be understood that the mention of one or more method steps doesnot preclude the presence of additional method steps or intervening method steps between those steps expressly identified. Similarly, it is also to be understood that the mention of one or more components in a composition does not preclude the presence of additional components than those expressly identified.

[0070] The materials described hereinafter as making up the various elements of thepresent invention are intended to be illustrative and not restrictive. Many suitable materials that would perform the same or a similar function as the materials described herein are intended to be embraced within the scope of the invention. Such other materials not described herein can include, but are not limited to, materials that are developed after the time of the development of the invention, for example. Any dimensions listed in the various drawings are for illustrative purposes only and are not intended to be limiting. Other dimensions and proportions are contemplated and intended to be included within the scope of the invention. Compounds of the Disclosure

[0071] In a specific aspect of the present invention, the compound is ibuprofen or anibuprofen derivative having the structure of Formula (I): 27 318985012Attorney Docket No: 243735.000456 or a pharmaceutically R1is selected-NH2, -C(O)heteroaryl, - C(O)heterocyclyl, and phenyl, wherein C1-12 alkyl, C4-12 alkylcycloalkyl, and phenyl can be optionally substituted by one or more of halogen, -OH, =O, and combinations thereof; R2is selected from C1-6alkylene, phenylene, heteroarylene, and heterocyclene, wherein C1-6 alkylene, phenylene, heteroarylene, and heterocyclene, can be optionally substituted by one or more R´ groups; R3and R4are independently selected from hydrogen, C1-6alkyl, -NH2, - C(O)OH, -C(O)NH2, and phenyl, wherein C1-6 alkyl and phenyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof; or R5is hydrogen or C1-12alkyl; R5 and R4 combine with the carbon atom to which they are attached to form C3- 12cycloalkyl; R´ is independently selected at each occurrence from C1-6 alkyl, halogen, and - OH, and combinations thereof; or R3 and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl.

[0072] In some embodiments, R1 is C1-12 alkyl.

[0073] In some embodiments, R2 is phenylene.

[0074] In some embodiments, R3 is C1-6 alkyl.

[0075] In some embodiments, R4 is -C(O)OH or -C(O)NH2.

[0076] In some embodiments, R5 is hydrogen. In other embodiments, R5 is C1-12 alkyl.

[0077] In some embodiments, the compound has the structure of Formula (IA), 5-benzyl-1H-tetrazole, aspirin, or 2-[4-(7-chloro-2-quinoxalinyloxy) phenoxy]propionic acid (XK469), 28 318985012Attorney Docket No: 243735.000456 ,C4-12alkylcycloalkyl, -C(O)heteroaryl, and - C(O)heterocyclyl, wherein C1-12 alkyl and C4-12 alkylcycloalkyl can be optionally substituted by one or more of =O; R2 is selected from phenylene, heteroarylene, and heterocyclene, wherein phenylene, heteroarylene, and heterocyclene can be optionally substituted by one or more R´ groups; R3 and R4 are independently selected from hydrogen, C1-6 alkyl, -C(O)OH, and - C(O)NH2, wherein C1-6 alkyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof; R5is hydrogen or C1-12alkyl; or R5 and R4 combine with the carbon atom to which they are attached to form C3-12 cycloalkyl; R´ is independently selected at each occurrence from C1-6 alkyl, halogen, and -OH, and combinations thereof; or R3 and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl, or a pharmaceutically acceptable salt thereof.

[0078] In some embodiments, the compound has the structure of Formula (IA), 5-benzyl-1H-tetrazole, aspirin, or 2-[4-(7-chloro-2-quinoxalinyloxy) phenoxy]propionic acid (XK469), ,R1 is selected from C1-12 alkyl, C4-12 alkylcycloalkyl, -C(O)heteroaryl, and - C(O)heterocyclyl, wherein C1-12alkyl and C4-12alkylcycloalkyl can be optionally substituted by one or more of =O; 29 318985012Attorney Docket No: 243735.000456 R2 is selected from phenylene, heteroarylene, and heterocyclene, wherein phenylene, heteroarylene, and heterocyclene can be optionally substituted by one or more R´ groups; R3 and R4 are independently selected from hydrogen, C1-6 alkyl, -C(O)OH, and - C(O)NH2, wherein C1-6 alkyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof; R5 is hydrogen or C1-12 alkyl; or R5 and R4 combine with the carbon atom to which they are attached to form C3-12 cycloalkyl; R´ is independently selected at each occurrence from C1-6 alkyl, halogen, and -OH, and combinations thereof; or R3 and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl, with the proviso that if R5 is hydrogen, R1 is unsubstituted C1-12 alkyl, and R2 is phenylene, then i) R3is -C(O)NH2or ii) R3and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl; or a pharmaceutically acceptable salt thereof.

[0079] In some embodiments, the compound of Formula (IA) is selected from thegroup consisting of ,30 318985012Attorney Docket No: 243735.000456 ,31 318985012Attorney Docket No: 243735.000456R1 is selected from C1-12 alkyl, -NH2, and phenyl, wherein C1-12 alkyl and phenyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof; R2is selected from C1-6alkylene and phenylene, wherein C1-6alkylene and phenylene can be optionally substituted by one or more of halogen, -OH, and combinations thereof; and 32 318985012Attorney Docket No: 243735.000456 R3 and R4 are independently selected from hydrogen, C1-6 alkyl, -NH2, -CO2H, and phenyl, wherein C1-6alkyl and phenyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof, or a pharmaceutically acceptable salt thereof.

[0082] In some embodiments, the compound has the structure of Formula (IB’)::havingthe structure of Formula (IB) is selected from the group consisting of:

[0085] In some embodiments, the compound having the structure of Formula (IB) is:a

[0086] In some embodiments, the compound having the structure of Formula (IB) is:a pharmaceutically acceptable salt thereof.of the present invention, the compound is dopamineor a dopamine derivative having the structure of Formula (II): 33 318985012Attorney Docket No: 243735.000456 ,- -C(O)OH; R8 and R9 are independently selected from hydrogen and -NH2; R10 is selected from hydrogen and -C(O)OH; and R11is selected from hydrogen and C1-6alkyl.

[0088] In some embodiments, the compound having the structure of Formula (II) isselected from the group consisting of: , anda pharmaceutically acceptable salt thereof.compound having the structure of Formula (II) isselected from the group consisting of: a

[0090] In another specific aspect of the present invention the compound is selectedfrom the group consisting of flurbiprofen, ellagic acid, methyldopa, disulfiram, idelalisib, eltrombopag olamine, crystal violet, verteporfin, pioglitazone HCl, rosiglitazone HCl, 34 318985012Attorney Docket No: 243735.000456 enoxolone, triamcinolone, tideglusib, tolcapone, thimerosal, zinc pyrithione, montelukast sodium, nitroxoline, carbenoxolone sodium, sildenafil mesylate, saxagliptin hydrate, fenoldopam mesylate, gallic acid, clofoctol, hexachlorophene, cetylpyridinium chloride, povidone iodine, bithionol, bronopol, bardoxolone methyl, oltipraz, troglitazone, cangrelor tetrasodium, bismuth subcitrate potassium, puromycin, ledipasvir, obeticholic acid, erlotinib, tenofovir alafenamide, entrectinib. venetoclaxthe, 5-benzyl-1H-tetrazole, aspirin, 2-[4-(7-chloro-2-quinoxalinyloxy) phenoxy]propionic acid (XK469), and combinations thereof.

[0091] In some embodiments, the compound is flurbiprofen, ellagic acid,methyldopa, disulfiram, idelalisib, eltrombopag olamine, crystal violet, verteporfin, pioglitazone HCl, rosiglitazone HCl, enoxolone, triamcinolone, tideglusib, tolcapone, thimerosal, zinc pyrithione, montelukast sodium, nitroxoline, carbenoxolone sodium, sildenafil mesylate, saxagliptin hydrate, fenoldopam mesylate, gallic acid, clofoctol, hexachlorophene, cetylpyridinium chloride, povidone iodine, bithionol, bronopol, bardoxolone methyl, oltipraz, troglitazone, cangrelor tetrasodium, bismuth subcitrate potassium, puromycin, ledipasvir, obeticholic acid, erlotinib, tenofovir alafenamide, entrectinib. venetoclaxthe, or combinations, or a pharmaceutically acceptable salt thereof.

[0092] In another specific aspect of the present invention the compound isa

[0093] In another embodiment, the compound of the present disclosure (e.g., acompound of Formula (I)-(II)) is provided as an enantioenriched mixture of the R- enantiomer. In one embodiment, the compound of the present disclosure (e.g., a compound of Formula (I)-(II)) is present with an enantiomeric excess (ee) of about 20% or greater, or about 30% or greater, or about 40% or greater, or about 50% or greater, or about 60% or greater, or about 70% or greater, or about 80% or greater, or about 85% or greater, or about 90% or greater, or about 95% or greater, or about 96% or greater, or about 97% or greater, or about 98% or greater, or about 99% or greater, or about 99.5% or greater, or about 99.9% or greater. 35 318985012Attorney Docket No: 243735.000456

[0094] In one embodiment, the compound of the present disclosure (e.g., a compoundof Formula (I)-(II)) is present with an enantiomeric excess (ee) of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 99%.

[0095] In another embodiment, the compound of the present disclosure (e.g., acompound of Formula (I)-(II)) is provided as the enantiopure R-enantiomer.

[0096] In another embodiment, the compound of the present disclosure (e.g., acompound of Formula (I)-(II)) is provided as an enantioenriched mixture of the S- enantiomer. In one embodiment, the compound of the present disclosure (e.g., a compound of Formula (I)-(II)) is present with an enantiomeric excess (ee) of about 20% or greater, or about 30% or greater, or about 40% or greater, or about 50% or greater, or about 60% or greater, or about 70% or greater, or about 80% or greater, or about 85% or greater, or about 90% or greater, or about 95% or greater, or about 96% or greater, or about 97% or greater, or about 98% or greater, or about 99% or greater, or about 99.5% or greater, or about 99.9% or greater.

[0097] In one embodiment, the compound of the present disclosure (e.g., a compoundof Formula (I)-(II)) is present with an enantiomeric excess (ee) of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 99%.

[0098] In another embodiment, the compound of the present disclosure (e.g., acompound of Formula (I)-(II)) is provided as the enantiopure S-enantiomer.

[0099] An effective amount of a compound may vary from about 0.001 mg / kg to about1000 mg / kg in one or more dose administrations for one or several days (depending on the mode of administration). In certain embodiments, the effective amount per dose varies from about 0.001 mg / kg to about 1000 mg / kg, from about 0.01 mg / kg to about 750 mg / kg, from about 0.1 mg / kg to about 500 mg / kg, from about 1.0 mg / kg to about 250 mg / kg, and from about 10.0 mg / kg to about 150 mg / kg.

[0100] Compounds of the present disclosure as well as their pharmaceuticallyacceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, or prodrugs thereof can be administered alone or in a form of a pharmaceutical composition. 36 318985012Attorney Docket No: 243735.000456

[0101] Pharmaceutical compositions can be prepared by any method known in the artof pharmacology. In general, such preparatory methods include the steps of bringing the compound(s) described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit.

[0102] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, asa single unit dose, and / or as a plurality of single unit doses. As used herein, a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.

[0103] Relative amounts of the active ingredient, the pharmaceutically acceptableexcipient, and / or any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w / w) active ingredient.

[0104] Pharmaceutically acceptable excipients used in the manufacture of providedpharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.

[0105] Exemplary diluents include calcium carbonate, sodium carbonate, calciumphosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

[0106] Exemplary granulating and / or dispersing agents include potato starch, cornstarch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) 37 318985012Attorney Docket No: 243735.000456 (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0107] Exemplary surface active agents and / or emulsifiers include natural emulsifiers(e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, propylene glycol monostearate, and polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), sorbitan tristearate (Span 65), glyceryl monooleate, sorbitan monooleate (Span 80)), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor™), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68, Poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0108] Exemplary binding agents include starch (e.g., cornstarch and starch paste),gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, 38 318985012Attorney Docket No: 243735.000456 methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl- pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0109] Exemplary preservatives include antioxidants, chelating agents, antimicrobialpreservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0110] Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0111] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA)and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0112] Exemplary antifungal preservatives include butyl paraben, methyl paraben,ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0113] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol,phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol. 39 318985012Attorney Docket No: 243735.000456

[0114] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0115] Other preservatives include tocopherol, tocopherol acetate, deteroximemesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.

[0116] Exemplary buffering agents include citrate buffer solutions, acetate buffersolutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D- gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and mixtures thereof.

[0117] Exemplary lubricating agents include magnesium stearate, calcium stearate,stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0118] Exemplary natural oils include almond, apricot kernel, avocado, babassu,bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, 40 318985012Attorney Docket No: 243735.000456 silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0119] Liquid dosage forms for oral and parenteral administration includepharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates of the invention are mixed with solubilizing agents such as Cremophor™, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0120] Injectable preparations, for example, sterile injectable aqueous or oleaginoussuspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0121] The injectable formulations can be sterilized, for example, by filtration througha bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. 41 318985012Attorney Docket No: 243735.000456

[0122] In order to prolong the effect of a drug, it is often desirable to slow theabsorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.

[0123] Compositions for rectal or vaginal administration are typically suppositorieswhich can be prepared by mixing the conjugates of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

[0124] Solid dosage forms for oral administration include capsules, tablets, pills,powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (I) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

[0125] Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, 42 318985012Attorney Docket No: 243735.000456 optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0126] The active ingredient can be in a micro-encapsulated form with one or moreexcipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes.

[0127] Dosage forms for topical and / or transdermal administration of a compound ofthis invention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and / or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and / or any needed preservatives and / or buffers as can be required. Additionally, the present invention contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and / or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and / or by dispersing the active ingredient in a polymer matrix and / or gel.

[0128] Suitable devices for use in delivering intradermal pharmaceutical compositionsdescribed herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid 43 318985012Attorney Docket No: 243735.000456 vaccines to the dermis via a liquid jet injector and / or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder / particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.

[0129] Formulations suitable for topical administration include, but are not limited to,liquid and / or semi-liquid preparations such as liniments, lotions, oil-in-water and / or water-in-oil emulsions such as creams, ointments, and / or pastes, and / or solutions and / or suspensions. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w / w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

[0130] A pharmaceutical composition can be prepared, packaged, and / or sold in aformulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and / or using a self-propelling solvent / powder dispensing container such as a device comprising the active ingredient dissolved and / or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0131] Low boiling propellants generally include liquid propellants having a boilingpoint of below 65° F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w / w) of the composition, and the active ingredient may constitute 0.1 to 20% (w / w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and / or solid anionic surfactant and / or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient). 44 318985012Attorney Docket No: 243735.000456

[0132] Pharmaceutical compositions formulated for pulmonary delivery may providethe active ingredient in the form of droplets of a solution and / or suspension. Such formulations can be prepared, packaged, and / or sold as aqueous and / or dilute alcoholic solutions and / or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and / or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and / or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.

[0133] Formulations described herein as being useful for pulmonary delivery are usefulfor intranasal delivery of a pharmaceutical composition of the invention. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

[0134] Formulations for nasal administration may, for example, comprise from about aslittle as 0.1% (w / w) to as much as 100% (w / w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition of the invention can be prepared, packaged, and / or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and / or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w / w) active ingredient, the balance comprising an orally dissolvable and / or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and / or an aerosolized and / or atomized solution and / or suspension comprising the active ingredient. Such powdered, aerosolized, and / or aerosolized formulations, when dispersed, may have an average particle and / or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

[0135] A pharmaceutical composition can be prepared, packaged, and / or sold in aformulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1 / 1.0% (w / w) solution and / or suspension of 45 318985012Attorney Docket No: 243735.000456 the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and / or one or more other of the additional ingredients described herein. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and / or in a liposomal preparation. Ear drops and / or eye drops are contemplated as being within the scope of this invention.

[0136] Although the descriptions of pharmaceutical compositions provided herein areprincipally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation.

[0137] Compounds provided herein are typically formulated in dosage unit form forease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0138] The compounds and compositions provided herein can be administered by anyroute, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., 46 318985012Attorney Docket No: 243735.000456 systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).

[0139] The exact amount of a compound required to achieve an effective amount willvary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. The desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

[0140] The effective amount of the compound in the composition that may be used inaccordance with the present disclosure may vary from about 0.0001 mg / kg to about 1000 mg / kg in one or more dose administrations for one or several days (depending on the mode of administration). In certain embodiments, the effective amount per dose varies from about 0.0001 mg / kg to about 1000 mg / kg, from about 0.001 mg / kg to about 1000 mg / kg, from about 0.01 mg / kg to about 750 mg / kg, from about 0.1 mg / kg to about 500 mg / kg, from about 1.0 mg / kg to about 250 mg / kg, and from about 10.0 mg / kg to about 150 mg / kg.

[0141] The compounds and compositions provided herein can be administered to asubject once a day, twice a day, three times a day, or four or more times a day. Alternatively, the compounds and compositions provided herein can be administered to a subject once a week, twice a week, three times a week, or four or more times a week. The compounds and compositions provided herein can also be administered to a subject once every two weeks, once every three weeks, once a month, once every two month, once every three month, once every four month, once every five month, once every six month, once every seven month, once every eight month, once every nine month, once every ten month, once every eleven month, once a year, or once every two years.

[0142] The compounds and compositions provided herein can be administered to asubject for about a week, about two weeks, about three weeks, about four weeks, about a 47 318985012Attorney Docket No: 243735.000456 month, about two months, about three months, about four months, about five months, about six months, about seven months, about eight months, about nine months, about ten months, about eleven months, about one year, about two years, about three years, about four years, about five years, about six or more years, about ten or more years, or about twenty or more years.

[0143] The compounds and compositions provided herein can be administered to asubject until the subject reaches the age of about 1 month, about 2 months, about 3 months, about 4 months, about 5 months, about 6 months, about 7 months, about 8 months, about 9 months, about 10 months, about 11 months, about 1 year, about 2 years, about 3 years, about 5 years, about 6 years, about 10 years, about 12 years, about 16 years, about 18 years, about 21 years, about 25 years, or about 30 years.

[0144] In certain embodiments, an effective amount of a compound for administrationone or more times a day to a 70 kg adult human may comprise about 0.0001 mg to about 10000 mg, about 0.0001 mg to about 9000 mg, about 0.0001 mg to about 8000 mg, about 0.0001 mg to about 7000 mg, about 0.0001 mg to about 6000 mg, about 0.0001 mg to about 5000 mg, about 0.0001 mg to about 4000 mg, about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 10000 mg, about 0.1 mg to about 5000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 100 mg, about 1 mg to about 10000 mg, about 1 mg to about 90000 mg, about 1 mg to about 8000 mg, about 1 mg to about 7000 mg, about 1 mg to about 6000 mg, about 1 mg to about 5000 mg, about 1 mg to about 4000 mg, about 1 mg to about 3000 mg, about 1 mg to about 2000 mg, about 1 mg to about 1000 mg, about 10 mg to about 90000 mg, about 10 mg to about 8000 mg, about 10 mg to about 7000 mg, about 10 mg to about 6000 mg, about 10 mg to about 5000 mg, about 10 mg to about 4000 mg, about 10 mg to about 3000 mg, about 10 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 90000 mg, about 100 mg to about 8000 mg, about 100 mg to about 7000 mg, about 100 mg to about 6000 mg, about 100 mg to about 5000 mg, about 100 mg to about 4000 mg, about 100 mg to about 3000 mg, about 100 mg to about 2000 mg, about 100 mg to about 1000 mg, about 1000 mg to about 90000 mg, about 1000 mg to about 8000 mg, about 1000 mg to about 7000 mg, about 1000 mg to about 6000 mg, about 1000 mg to about 5000 mg, about 1000 mg to about 4000 mg, about 1000 mg to about 3000 mg, or about 1000 mg to about 2000 mg or of a compound per unit dosage form. 48 318985012Attorney Docket No: 243735.000456

[0145] In certain embodiments, an effective amount of a compound for administrationone or more times a day to a 30 kg child may comprise about 0.0001 mg to about 10000 mg, about 0.0001 mg to about 9000 mg, about 0.0001 mg to about 8000 mg, about 0.0001 mg to about 7000 mg, about 0.0001 mg to about 6000 mg, about 0.0001 mg to about 5000 mg, about 0.0001 mg to about 4000 mg, about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 10000 mg, about 0.1 mg to about 5000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 100 mg, about 1 mg to about 10000 mg, about 1 mg to about 90000 mg, about 1 mg to about 8000 mg, about 1 mg to about 7000 mg, about 1 mg to about 6000 mg, about 1 mg to about 5000 mg, about 1 mg to about 4000 mg, about 1 mg to about 3000 mg, about 1 mg to about 2000 mg, about 1 mg to about 1000 mg, about 10 mg to about 90000 mg, about 10 mg to about 8000 mg, about 10 mg to about 7000 mg, about 10 mg to about 6000 mg, about 10 mg to about 5000 mg, about 10 mg to about 4000 mg, about 10 mg to about 3000 mg, about 10 mg to about 2000 mg, about 10 mg to about 1000 mg, about 100 mg to about 90000 mg, about 100 mg to about 8000 mg, about 100 mg to about 7000 mg, about 100 mg to about 6000 mg, about 100 mg to about 5000 mg, about 100 mg to about 4000 mg, about 100 mg to about 3000 mg, about 100 mg to about 2000 mg, about 100 mg to about 1000 mg, about 1000 mg to about 90000 mg, about 1000 mg to about 8000 mg, about 1000 mg to about 7000 mg, about 1000 mg to about 6000 mg, about 1000 mg to about 5000 mg, about 1000 mg to about 4000 mg, about 1000 mg to about 3000 mg, or about 1000 mg to about 2000 mg or of a compound per unit dosage form.

[0146] In certain embodiments, the compounds described herein may be at dosagelevels sufficient to deliver from about 0.001 mg / kg to about 100 mg / kg, from about 0.01 mg / kg to about 50 mg / kg, preferably from about 0.1 mg / kg to about 40 mg / kg, preferably from about 0.5 mg / kg to about 30 mg / kg, from about 0.01 mg / kg to about 10 mg / kg, from about 0.1 mg / kg to about 10 mg / kg, and more preferably from about 1 mg / kg to about 25 mg / kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic and / or prophylactic effect.

[0147] It will be appreciated that dose ranges as described herein provide guidance forthe administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical 49 318985012Attorney Docket No: 243735.000456 practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0148] It will be also appreciated that a compound or composition, as described herein,can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents).

[0149] The compound or composition can be administered concurrently with, prior to,or subsequent to, one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Each additional pharmaceutical agent may be administered at a dose and / or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and / or with the compound or composition described herein in a single dose or administered separately in different doses. The particular combination to employ in a regimen will take into account compatibility of the inventive compound with the additional pharmaceutical agent(s) and / or the desired therapeutic and / or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually. Methods of Treatment and Uses

[0150] The present invention also provides methods of using the compound(s) orpharmaceutical compositions comprising the compound(s) described herein, such as of a compound selected from the group consisting of: a. ibuprofen or an ibuprofen derivative having the structure of Formula (I);b. dopamine or a dopamine derivative having the structure of Formula (II);c. flurbiprofen, ellagic acid, methyldopa, disulfiram, idelalisib, eltrombopagolamine,crystal violet, verteporfin, pioglitazone HCl, rosiglitazone HCl, enoxolone, triamcinolone, tideglusib, tolcapone, thimerosal, zinc pyrithione, montelukast sodium, nitroxoline, carbenoxolone sodium, sildenafil mesylate, saxagliptin hydrate, fenoldopam mesylate, gallic acid, clofoctol, hexachlorophene, cetylpyridinium chloride, povidone iodine, bithionol, bronopol, bardoxolone methyl, oltipraz, troglitazone, cangrelor tetrasodium, bismuth subcitrate 50 318985012Attorney Docket No: 243735.000456 potassium, puromycin, ledipasvir, obeticholic acid, erlotinib, tenofovir alafenamide, entrectinib. venetoclaxthe, 5-benzyl-1H-tetrazole, aspirin, 2-[4-(7- chloro-2-quinoxalinyloxy) phenoxy]propionic acid (XK469), or combinations thereof; and d. a compound of or.provides methods of using the compound(s) orpharmaceutical compositions comprising the compound(s) described herein, such as of a compound selected from the group consisting of: a. ibuprofen or an ibuprofen derivative having the structure of Formula (I);b. dopamine or a dopamine derivative having the structure of Formula (II); andc. flurbiprofen, ellagic acid, methyldopa, disulfiram, idelalisib, eltrombopagolamine,crystal violet, verteporfin, pioglitazone HCl, rosiglitazone HCl, enoxolone, triamcinolone, tideglusib, tolcapone, thimerosal, zinc pyrithione, montelukast sodium, nitroxoline, carbenoxolone sodium, sildenafil mesylate, saxagliptin hydrate, fenoldopam mesylate, gallic acid, clofoctol, hexachlorophene, cetylpyridinium chloride, povidone iodine, bithionol, bronopol, bardoxolone methyl, oltipraz, troglitazone, cangrelor tetrasodium, bismuth subcitrate potassium, puromycin, ledipasvir, obeticholic acid, erlotinib, tenofovir alafenamide, entrectinib. venetoclaxthe, 5-benzyl-1H-tetrazole, aspirin, 2-[4-(7- chloro-2-quinoxalinyloxy) phenoxy]propionic acid (XK469), or combinations thereof.

[0152] In some embodiments, the compound(s) or pharmaceutical compositions of thepresent disclosure may be useful for treating a disease or condition selected from the group consisting of a non-malignant disease; benign tumors; growth of tumor cells or proliferating immune cells; inappropriate growth and proliferation of cells in benign but debilitating diseases; scar formation; scarring; excessive scarring; keloid; fibrosis and 51 318985012Attorney Docket No: 243735.000456 superficial fibrosing disorder; Adhesive capsulitis; RASopathies; chronic kidney disease; heterotopic ossification; tuberous sclerosis (TSC); adhesions following surgery; heterotopic ossification; and stiffening of tissues with aging.

[0153] In some embodiments, the disease or condition is fibrosis and superficialfibrosing disorder selected from the group consisting of nephrogenic systemic fibrosis, idiopathic pulmonary fibrosis, chronic fibrosis due to chronic kidney disease, radiation- induced fibrosis, hepatic fibrosis, Dupuytren's contracture, Peyronie's disease, Scleroderma, and Post-MI myocardial fibrosis. In some embodiments, the radiation- induced fibrosis is radiation-induced pulmonary fibrosis.

[0154] In some embodiments, the scar formation is scar formation after surgery orinjury, including keloid.

[0155] In some embodiments, the benign tumors are selected from meningiomas andvestibular schwannomas.

[0156] In some embodiments, the reducing stiffening of tissues is reducing stiffening ofarteries.

[0157] In some embodiments, the compound(s) or pharmaceutical compositions of thepresent disclosure can be administered in combination with a therapeutically effective amount of an inbibitor of HPDL.

[0158] In some embodiments, the compound(s) or pharmaceutical compositions of thepresent disclosure may be useful in inhibiting an immune response in a subject in need thereof.

[0159] In some embodiments, the subject being treated has cancer.

[0160] In some embodiments, the subject has leukemia, breast cancer, prostate cancer,lung cancers, ovarian cancer, pancreatic cancer, hepatocellular cancer, sarcoma, vascular endothelial cancer, central nervous system cancers (e.g., astrocytoma, gliosarcoma, neuroblastoma, oligodendroglioma, and glioblastoma), bronchus cancer, larynx cancer, esophagus cancer, colon cancer, colorectal cancer, gastro-intestinal cancer, melanoma, endometrial cancer, renal scancer, bladder cancer, liver cancer, or endocrine cancer (e.g., thyroid cancer). In some embodiments, the subject has pancreatic cancer.

[0161] In some embodiments, the subject is receiving immune checkpoint blockade orother immuno-oncology agents. In some embodiments, the subject is receiving cell-based therapies. 52 318985012Attorney Docket No: 243735.000456

[0162] In some embodiments, the subject has an infection and the activated oraugmented immune response is against said infection. The subject can have a viral infection, a bacterial infection, a fungal infection, and a parasitic infection. In some embodiments, the subject has a chronic bacterial, fungal, viral, or parasitic infection. In some embodiments, the subject has sepsis.

[0163] Examplary viral infections include herpes simplex virus (HSV), varicella-zostervirus (VZV), human papillomavirus, influenza, cytomegalovirus (CMV), varicella-zoster virus, hepatitis B, hepatitis C, human immunodeficiency virus (HIV), COVID-19, ebola, or flu.

[0164] Examplary bacterial infections include infections caused by gram positive cocci(MRSA, MSSA, or Streptococci), gram negative bacili (E. coli, P. mirabilis, Klebsiella, Pseudomonas, ESCAPPM), gram-negative cocci (N. gonorrhoeae or N. meningitidis), anaerobes, or atypicals (Mycoplasma).

[0165] Examplary fungal infections include fungal nail infections, ringworm, vaginalcandidiasis, candida infections of the mouth, throat, and esophagus, blastomycosis, valley fever (coccidioidomycosis), C. gattii infection, histoplasmosis, paracoccidioidomycosis, aspergillosis, candida auris, C. neoformans infection, invasive candidiasis, mucormycosis, pneumocystis pneumonia, talaromycosis (penicilliosis), fungal eye infections, mycetoma, sporotrichosis, fungal meningitis (including healthcare-associated fungal meningitis).

[0166] Examplary parasitic infections include infections caused by various protozoa(malaria, babesiosis, toxoplasmosis, infections caused by amoebas, including granulomatous amebic encephalitis (GAE) and amebiasis, chagas disease (american trypanosomiasis), sleeping sickness (african trypanosomiasis), leishmaniasis, trichomoniasis, and giardia), helminths (enterobiasis, soil-transmitted helminths (STH), schistosomiasis, echinococcosis, and strongyloides), and ectoparasites (lice, scabies, fleas, or mites).

[0167] In some embodiments, the compound(s) or pharmaceutical compositions of thepresent disclosure may be useful in reducing an immune response to a vaccine in a subject in need thereof.

[0168] The compound or composition can be administered concurrently with, prior to,or subsequent to, administration of a vaccine. The compound or composition can be administered together with the vaccine. The compound or composition and the vaccine 53 318985012Attorney Docket No: 243735.000456 can be administered simultaneously in the same composition. The compound or composition and the vaccine can be administered simultaneously in different compositions. Alternatively, the compound or composition can be administered before, during, or after the administration of the vaccine.

[0169] In some embodiments, the compound(s) or pharmaceutical compositions of thepresent disclosure may be useful in reducing an antibody production in a subject.

[0170] In some embodiments, the administration of the compound(s) or pharmaceuticalcompositions of the present disclosure may result in reducing monoclonal antibody production.

[0171] In some embodiments, the compound(s) or pharmaceutical compositions of thepresent disclosure may be useful in inhibiting growth of a tumor in a subject.

[0172] In some embodiments, the compound(s) or pharmaceutical compositions of thepresent disclosure may be administered to a subject a prophylactic. In some embodiment, the compound(s) or pharmaceutical compositions of the present disclosure may be administered to a subject above a particular age (e.g., above 60, or 65, or 70, or 75 years of age), or who have presented to their physicians or to the hospital with multiple infections.

[0173] In some embodiments, the compound(s) or pharmaceutical compositions of thepresent disclosure may be used to treat autoimmune diseases. In some embodiments, autoimmune diseases are the ones mediated by immune complex formation. In some embodiments, the autoimmune disease is selected from a group consisting of vasculitis, rheumatoid arthritis, scleroderma, Sjogren’s syndrome, and systemic lupus erythematosus.

[0174] In various embodiments of the methods described above, the subject is amammal. In some embodiments, the subject is a human.

[0175] In some embodiments, the subject is a pediatric subject 0 to 18 years of age. Insome embodiments, the subject is a child, including an unborn fetus, a newborn, an infant, or a toddler. In some embodiments, treating an unborn fetus using methods described herein may involve treating a pregnant female carrying the unborn fetus.

[0176] In some embodiments, the subject is an adult. In some embodiments, the subjectis an elderly adult. In some embodiments, the subject is 65 year old adult or older. 54 318985012Attorney Docket No: 243735.000456

[0177] In some embodiments, when the subject being treated is a child, the child maybe treated with the compound(s) or pharmaceutical compositions comprising the compound(s) described herein.

[0178] In some embodiments, the method may involve treating a newborn or infant byadministering the compound(s) or pharmaceutical compositions comprising the compound(s) described herein to the newborn or infant.

[0179] In some embodiments, the method may involve treating an unborn fetus byadministering the compound(s) or pharmaceutical compositions comprising the compound(s) described herein to the pregnant female.

[0180] In some embodiments, the control level of HPDL expression is determined innormal tissue from the same subject, a sample from a normal subject, or is a predetermined value.

[0181] In some embodiments, the expression level of HPDL is determined bydetermining the level of 4-HMA in the sample.

[0182] In various embodiments of the methods described above, the methodcomprising not administering an HPDL inhibitor to the subject exhibiting a lower or equivalent level of HPDL expression as compared to the control level.

[0183] In various embodiments of the methods described above, the method furthercomprising administering one or more additional treatments to the subject, wherein said additional treatments are selected from a chemotherapy, a chemoradiotherapy, a neoadjuvant chemoradiotherapy, a radiotherapy, a surgery, and any combination thereof.

[0184] In some embodiments, the additional treatment is a platinum-basedchemotherapy and the method further comprises administering an electron transport chain (ETC) inhibitor.

[0185] In some embodiments, the electron transport chain (ETC) inhibitor ismetformin, phenformin, BAY84-2243, carboxyamidotriazole, ME344, Fenofibrate, mIBG (meta-iodobenzylguanidine), Alpha-TOS, Lonidamine, Atovaquone, Arsenic trioxide, Nitric Oxide, or Hydrocortisone, or a combination thereof.

[0186] In some embodiments, the compound(s) or pharmaceutical compositions of thepresent disclosure may be useful in treating a disease or disorder selected from the group consisting of heart disease, neurodegenerative disease, migraine headache, neurodevelopmental disease, infertility, pulmonary disease, muscle disease, liver disease, pancreatic disease, oral disease, ophthalmic disease, hearing disease, diseases of 55 318985012Attorney Docket No: 243735.000456 pregnancy, diseases of prematurity, aging disorders, movement disorders, infectious disease, and any disease in which Coenzyme Q declines, in a subject in need thereof.

[0187] In some embodiments, the heart disease is selected from the group consisting ofheart failure, high blood pressure, recovery post cardiac surgery, and statin-induced myopathy.

[0188] In some embodiments, the method comprises one or more of reducing LDLcholesterol, improving insulin sensitivity, and decreasing diabetic or other neuropathy.

[0189] In some embodiments, the neurodegenerative disease is selected from the groupconsisting of Parkinson’s disease, Alzheimer’s disease, Amyotrophic lateral sclerosis (ALS), and demyelinating and white matter disease.

[0190] In some embodiments, the neurodevelopmental disease is cerebral palsy.

[0191] In some embodiments, the method comprises augmenting egg or sperm quality.

[0192] In some embodiments, the pulmonary disease is chronic obstructive pulmonarydisease (COPD) or asthma.

[0193] In some embodiments, the muscle disease is muscular dystrophy.

[0194] In some embodiments, the liver disease is characterized by toxicity due tostatins or liver injury.

[0195] In some embodiments, the pancreatic disease is selected from the groupconsisting of type 1 diabetes, type 2 diabetes, and exocrine insufficiency.

[0196] In some embodiments, the oral disease is selected from the group consisting oftooth decay, periodontitis, and gum decay.

[0197] In some embodiments, the ophthalmic disease is selected from the groupconsisting of macular degeneration, cataract formation, retinal detachment, and retinitis pigmentosa.

[0198] In some embodiments, the hearing disease is hearing loss.

[0199] In some embodiments, the disease of pregnancy is placental insufficiency orpre-eclampsia.

[0200] In some embodiments, the disease of prematurity is selected from the groupconsisting of prematurity, retinopathy of prematurity, and cerebral palsy.

[0201] In some embodiments, the compound(s) or pharmaceutical compositions of thepresent disclosure may be useful in treating a subject having an activating variant in the HPDL gene, any other gene in the CoQ headgroup synthesis pathway, or any gene controlling the CoQ headgroup synthesis pathway. 56 318985012Attorney Docket No: 243735.000456

[0202] In a specific aspect, the treatment for cancer is selected from one or more HPDLinhibitors, a chemotherapy, a chemoradiotherapy, a neoadjuvant chemoradiotherapy, a radiotherapy, a surgery, and any combination thereof.

[0203] In some embodiments, the compound(s) or pharmaceutical compositions of thepresent disclosure may be useful in treating cancer, autoimmune disease, or any disease involving cellular proliferation in a subject in need thereof, comprising the following steps: a. determining expression level of 4-hydroxyphenylpyruvate dioxygenase-like(HPDL) in a sample obtained from the subject; b. comparing the HPDL expression level determined in step (a) with a controllevel of HPDL expression; and c. administering an effective amount of the compound(s) or pharmaceuticalcompositions of the present disclosure to the subject exhibiting a higher level of HPDL expression as compared to the control level.

[0204] In various embodiments of the methods described above, the sample comprisescirculating tumor cells.

[0205] In various embodiments of the methods described above, the methodcomprising not administering an HPDL inhibitor to the subject exhibiting a lower or equivalent level of HPDL expression as compared to the control level.

[0206] In various embodiments of the methods described above, the method furthercomprising administering one or more additional treatments to the subject, wherein said additional treatments are selected from a chemotherapy, a chemoradiotherapy, a neoadjuvant chemoradiotherapy, a radiotherapy, a surgery, and any combination thereof.

[0207] In some embodiments, the additional treatment is a platinum-basedchemotherapy and the method further comprises administering an electron transport chain (ETC) inhibitor.

[0208] In some embodiments, the electron transport chain (ETC) inhibitor ismetformin, phenformin, BAY84-2243, carboxyamidotriazole, ME344, Fenofibrate, mIBG (meta-iodobenzylguanidine), Alpha-TOS, Lonidamine, Atovaquone, Arsenic trioxide, Nitric Oxide, or Hydrocortisone, or a combination thereof.

[0209] In some embodiments, the compound(s) or pharmaceutical compositions of thepresent disclosure may be useful in determining effectiveness of a treatment for cancer, 57 318985012Attorney Docket No: 243735.000456 autoimmune disease, or any disease involving cellular proliferation in a subject, comprising the following steps: a. determining expression level of 4-hydroxyphenylpyruvate dioxygenase-like(HPDL) in a first sample obtained from the subject before the subject receives a treatment for cancer comprising administering a therapeutically effective amount of a compound(s) or pharmaceutical compositions of the present disclosure; b. determining expression level of HPDL in a second sample obtained from the subjectafter the subject has received the treatment for cancer, autoimmune disease, or any disease involving cellular proliferation; c. comparing the HPDL expression levels determined in the first sample and thesecond sample; and d. determining that (i) the treatment is effective if the HPDL expression level in thesecond sample is lower than HPDL expression level in the first sample, or (ii) the treatment is not effective if the HPDL expression level in the second sample is not lower than the HPDL expression level in the first sample.

[0210] In a specific aspect, the treatment for cancer is selected from one or more HPDLinhibitors, a chemotherapy, a chemoradiotherapy, a neoadjuvant chemoradiotherapy, a radiotherapy, a surgery, and any combination thereof.

[0211] In some embodiments, the compound(s) or pharmaceutical compositions of thepresent disclosure may be useful in predicting prognosis of cancer in a subject having cancer, autoimmune disease, or any disease involving cellular proliferation, comprising the following steps: a. determining expression level of 4-hydroxyphenylpyruvate dioxygenase-like(HPDL) protein in a sample obtained from the subject; b. comparing the HPDL expression level determined in step (a) with a control level ofHPDL expression; and c. determining the subject (i) as having poor prognosis if the HPDL expression levelis higher than the control level, or (ii) as having good prognosis if the HPDL expression level is lower than or equal to the control level, wherein if the subject is determined to have poor prognosis, the method further comprising administering to the subject a single-agent chemotherapy, supportive care, and / or a compound(s) or pharmaceutical compositions of the present disclosure. 58 318985012Attorney Docket No: 243735.000456

[0212] In various embodiments of the methods described above, the method furthercomprises administering an additional compound having the structure of Formula (I’): , salt thereof, wherein:Q is selected from ; R’1, R’2, and R’3 from hydrogen, C1-12 alkyl, C1-12 alkenyl,C6-12aryl, C1-12aralkyl, C1-4haloalkyl, or a combination thereof, each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S; -OH, =O, - CO2H, -NO2, -NH2, -NHR*, -NR*2, -N-OH, -HSO3, -H2PO3, -OR*, -(C=O)-R*, - CO2R*, -CO-NH2, -CO-NHR*, -SO2-NHR*, or adjacent two moieties combine to form a fused ring which may optionally contain 1-3 heteroatoms selected from halogen, O, N, and S and which may be further substituted by one or more R*; R’4 and R’5 are independently selected from -OH and -CO2H; R’6and R’7are independently selected from hydrogen, C1-12alkyl, C1-12alkenyl, C6-12aryl, C1-12 aralkyl, C1-4 haloalkyl, or a combination thereof, each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S; -OH, =O, -CO2H, -NO2, -NH2, -NHR*, -NR*2, -N-OH, -HSO3, -H2PO3, -OR*, -(C=O)-R*, -CO2R*, -CO-NH2, -CO-NHR*, -SO2-NHR*, or R6and R7combine to form a fused ring, and R* is independently selected at each occurrence from hydrogen or C1-C12 hydrocarbons each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S and combinations thereof.

[0213] In some embodiments, Q is , at least one of R’1, R’2, and R’3 is not H.

[0214] In some embodiments, the additional compound has the structure of Formula(I’A): 59 318985012Attorney Docket No: 243735.000456 , salt thereof.the additional compound has the structure of Formula(I’B): , salt thereof.some the additional compound has the structure of Formula(I’C): ,salt thereof.

[0217] In some embodiments, the additional compound has the structure of Formula(I’D): ,salt thereof, wherein Q is -O- or -NH-.

[0218] In some embodiments, the additional compound has the structure of Formula(I’E): 60 318985012Attorney Docket No: 243735.000456 , salt thereof.the additional compound having the structure of Formula(I’) is selected from the group consisting of: ,

[0220] In various embodiments of the methods described above, the method furthercomprising administering an additional compound having the structure of Formula (II’): ,wherein: R’’1is selected from -NO2, -Cl, and a C1-12alkyl which may be optionally substituted with one or more of -OH, =O, -CO2H, -NO2, -NH2, -NHR*, -NR*2, -N-OH, -HSO3, -H2PO3, - OR*, -(C=O)-R*, -CO2R*, -CO-NH2, -CO-NHR*, and -SO2-NHR*; R’’2, R’’3, R’’4, R’’5, R’’6 and R’’7 are independently selected from hydrogen, C1-12 alkyl, C1-12alkenyl, C6-12aryl, C1-12aralkyl, C1-4haloalkyl, or a combination thereof, each of 61 318985012Attorney Docket No: 243735.000456 which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S; -OH, =O, -CO2H, -NO2, -NH2, -NHR*, -NR*2, -N-OH, -HSO3, -H2PO3, -OR*, -(C=O)-R*, -CO2R*, -CO-NH2, -CO-NHR*, -SO2R*, -SO2-NHR*, or adjacent two moieties combine to form a fused ring which may optionally contain 1-3 heteroatoms selected from halogen, O, N, and S and which may be further substituted by one or more R*, and R* is independently selected at each occurrence from hydrogen or C1-C12 hydrocarbons each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S and combinations thereof.

[0221] In some embodiments, the additional compound does not have the structureselected (sulcotrione).

[0222] Inof Formul(II’A):a,

[0223] In some embodiments, the additional compound has the structure of Formula(II’B): ,

[0224] In some embodiments, R’’1 is a C1-12 alkyl substituted with one or more of -OH,=O, -CO2H, -NO2, -NH2, -NHR*, -NR*2, -N-OH, -HSO3, -H2PO3, -OR*, -(C=O)-R*, - CO2R*, -CO-NH2, -CO-NHR*, and -SO2-NHR*.

[0225] In some embodiments, the additional compound having the structure of Formula(II’) is selected from the group consisting of: 62 318985012Attorney Docket No: 243735.000456 , asome(II’) is selected from the group consisting of: ,

[0227] In various embodiments of the methods described above, the method furthercomprising administering N-[5-[[4-[5-[acetyl(hydroxy)amino]pentylamino]-4- oxobutanoyl]-hydroxyamino]pentyl]-N'-(5-aminopentyl)-N'-hydroxybutanediamide (Deferoxamine; DFO).

[0228] In some embodiments, the control level of HPDL expression is determined innormal tissue from the same subject, a sample from a normal subject, or is a predetermined value.

[0229] In various embodiments of the methods described above, the subject hasunresectable or borderline resectable pancreatic cancer. 63 318985012Attorney Docket No: 243735.000456

[0230] In some embodiments of the methods of predicting prognosis of cancer,autoimmune disease, or any disease involving cellular proliferation in a subject having cancer as described above, the method comprising the single-agent chemotherapy is platinum-based chemotherapy. In some embodiments, the method further comprises administering an electron transport chain (ETC) inhibitor in combination with the single- agent chemotherapy. In some embodiments, the electron transport chain (ETC) inhibitor is metformin, phenformin, BAY84-2243, carboxyamidotriazole, ME344, Fenofibrate, mIBG (meta-iodobenzylguanidine), Alpha-TOS, Lonidamine, Atovaquone, Arsenic trioxide, Nitric Oxide, or Hydrocortisone, or a combination thereof.

[0231] In some embodiments of the methods of predicting prognosis of cancer,autoimmune disease, or any disease involving cellular proliferation in a subject having cancer as described above, the method further comprising administering to the subject a multiagent chemotherapy, chemoradiotherapy, and / or neoadjuvant chemoradiotherapy if the subject is determined to have good prognosis. In some embodiments, the multiagent chemotherapy is FOLFIRINOX (Leucovorin calcium / Folinic acid, 5-fluorouracil, Irinotecan, Oxaliplatin).

[0232] In various embodiments of the methods described above, the HPDL expressionlevel is determined at mRNA level via RNA-seq, reverse transcription polymerase chain reaction (rt-PCR), or fluorescence in situ hybridization (FISH).

[0233] In various embodiments of the methods described above, the HPDL expressionlevel is determined at protein level via immunohistochemistry (IHC) staining or immunofluorescence. In some embodiment, the HPDL protein expression level is determined via chromogenic IHC staining using an anti-HPDL antibody as the primary antibody and an HRP-linked secondary antibody followed by DAB staining.

[0234] In various embodiments of the methods described above, the cancer fortreatment is pancreatic cancer.

[0235] In various embodiments of the methods described above, the pancreatic cancerfor treatment is pancreatic ductal adenocarcinoma (PDAC) or neuroendocrine pancreatic cancer.

[0236] In various embodiments of the methods described above, the compoundsdisclosed above are used to treat tumors, cancers (e.g., pancreatic and breast cancers), neurodegenerative disorders (e.g., childhood neurodegenerative disorders with spasticity 64 318985012Attorney Docket No: 243735.000456 and encephalopathy, and the inherited form of cerebral palsy), autoimmune diseases, and any diseases involving cellular proliferation.

[0237] In some embodiments, the compounds disclosed above are used to treat cancers,autoimmune diseases, and any diseases involving cellular proliferation.

[0238] In some embodiment, the cancers, autoimmune diseases, and any diseasesinvolving cellular proliferation are HPDL-dependent.

[0239] In some embodiment, the compounds disclosed above are used to treat HPDL-dependent tumor.

[0240] In some embodiment, the compounds disclosed above are used to treat HPDL-dependent cell proliferation.

[0241] In various embodiments of the methods described above, the compoundsdisclosed above block the synthesis of CoQ10.

[0242] In various embodiments of the methods described above, the compoundsdisclosed above attenuate the growth of HPDL-dependent tumors.

[0243] In various embodiments of the methods described above, the compoundsdisclosed above prevent the proliferation of benign or malignant cells involved in disease processes.

[0244] As described above, there is an unmet need for novel therapeutics based onHPDL inhibition for treatment of various diseases and conditions, including HPDL- dependent tumors, cancers (e.g., pancreatic and breast cancers), autoimmune diseases, and any diseases involving unnecessary or uncontrolled cellular proliferation or mitochondrial activation.

[0245] Unexpectedly, the present invention found that ibuprofen, dopamine, and relatedcompounds inhibit the dioxygenase HPDL and attenuate the proliferation of HPDL- dependent cells in vitro and in vivo. These results demonstrate that ibuprofen and dopamine, and their derivatives, can block the synthesis of CoQ10. These results also demonstrate that HPDL can be targeted with and inhibited by ibuprofen and dopamine, and their derivatives.

[0246] Advantageously, ibuprofen and dopamine, and their derivatives, as HPDLinhibitors, attenuate the growth of HPDL-dependent tumors or cell proliferation. They are of potent and specific HPDL inhibitors that can be of therapeutic value in preventing the proliferation of benign or malignant HPDL-dependent cells involved in disease processes, such cancer, autoimmune disease, or any disease involving cellular proliferation. The 65 318985012Attorney Docket No: 243735.000456 diseases also include HPDL-dependent tumors, cancers (e.g., pancreatic and breast cancers), and neurodegenerative disorders (e.g., childhood neurodegenerative disorders with spasticity and encephalopathy, and the inherited form of cerebral palsy). EXAMPLES

[0247] The following examples are provided to further describe some of theembodiments disclosed herein. The examples are intended to illustrate, not to limit, the disclosed embodiments. Example 1. Expression and Purification of a Recombinant Version of HPDL Using Insect Cells Expression System

[0248] This experiment demonstrates the expression and purification of arecombinant version of HPDL using insect cells expression system. A culture of expiSF9 cells (5×106 viable cells / mL and ≥ 90% viability) were infected with high-titer virus (human His-tagged HPDL). The infected cells were cultured at 27°C and then harvest 3 days after infection. Pellets were resuspended in lysis buffer (20 mM Tris, pH 7.5, 200 mM NaCl, 10% glycerol and 5 mM imidazole) and sonicated, and cell debris were pelleted by centrifugation (20,000 × g, 30 min). The supernatant was collected and purified using Talon affinity resin (Takara), followed by cation exchange on Akta purifier using a SP HP column (GE Healthcare). Protein purity was assessed via SDS / PAGE and Coomassie staining and pure protein was store at -80°C at high concentration (>3 mg / ml) in a buffer containing 20 mM Tris, pH 7.5, 200 mM NaCl and 1mM TCEP.

[0249] Fractions from HPDL purification run on a Coomassie stained gel (FIG. 1B)show high purity after Talon metal affinity and cation exchange. It is demonstrated that His-tagged HPDL can be produced and purify using expiSF9 expression system. Example 2. Recombinant HPDL Produced in the Laboratory

[0250] This experiment demonstrates that recombinant HPDL produced in thelaboratory was catalytically active. His-tagged HPDL (12 ng / μL) was incubated with 400 µM of HPPA in assay buffer (20 mM HEPES pH 7.4, 20 µM FeSO4, 0.5 mM sodium ascorbate, and 1 mM β-mercaptoethanol) for 1 h at 37 °C. At the end of the assay, 10 µl of mixture was retrieved and prepared for analysis by gas chromatography–mass spectrometry. 66 318985012Attorney Docket No: 243735.000456

[0251] GC-MS detection of 4HMA produced following enzymatic assay on purifiedenzyme (FIG.2A) as shown in FIG.2B indicates the high catalytical activity of HPDL. FIG.2C demonstrates GC-MC kinetic characterization of HPDL activity. Example 3. Evaluation of Small Molecules

[0252] This experiment evaluates small molecules in order to identify binders ofHPDL. Enzyme assay conditions are shown in FIG.3. Data for screening for pocket where carboxylate binds are shown in Table 1 and FIGS.4A-4B. Data for screening forchannel region are shown in Table 2 and FIGS. 5A-5E.Table 1. Screening SAR Catalog for Pocket where Carboxylate Binds Docking N b MW D IC50 It67 318985012Attorney Docket No: 243735.000456 Table 2. Screening SAR Catalog for Channel Region Docking score Number MW (Da) IC50 Iteme esu s o e e a s assay o upoe , u poe , a asp aeshown in FIGS.6A-6C.

[0254] FIG.7 shows conditions for crystallization screening.

[0255] Additional HPDL Inhibitors are shown in Table 3.Table 3. Additional Candidate HPDL Inhibitors Structure IC5068 318985012Attorney Docket No: 243735.000456 References 1. Morton RA. Ubiquinone. Nature. Nature Publishing Group; 1958 Dec 27;182(4652):1764–7. 2. Quiles JL, Ochoa JJ, Ramirez-Tortosa MC, Linde J, Bompadre S, Battino M, et al. Coenzyme Q concentration and total antioxidant capacity of human milk at different stages of lactation in mothers of preterm and full-term infants. Free Radic Res.2006 Feb;40(2):199–206. 3. Gutman M. Electron flux through the mitochondrial ubiquinone. Biochim Biophys Acta.1980 Dec 22;594(1):53–84. 4. Bentinger M, Dallner G, Chojnacki T, Swiezewska E. Distribution and breakdown of labeled coenzyme Q10 in rat. Free Radic Biol Med.2003 Mar 1;34(5):563–75. 5. Bentinger M, Tekle M, Brismar K, Chojnacki T, Swiezewska E, Dallner G. Stimulation of coenzyme Q synthesis. Biofactors.2008;32(1-4):99–111. 6. Tekle M, Bentinger M, Nordman T, Appelkvist E-L, Chojnacki T, Olsson JM. Ubiquinone biosynthesis in rat liver peroxisomes. Biochem Biophys Res Commun. 2002 Mar 15;291(5):1128–33. 7. Faust JR, Goldstein JL, Brown MS. Synthesis of ubiquinone and cholesterol in human fibroblasts: regulation of a branched pathway. Arch Biochem Biophys [Internet].1979 Jan;192(1):86–99. Retrieved from: https: / / linkinghub.elsevier.com / retrieve / pii / 0003986179900742 8. Taylor BA. Does Coenzyme Q10 Supplementation Mitigate Statin-Associated Muscle Symptoms? Pharmacological and Methodological Considerations. Am J Cardiovasc Drugs. Springer International Publishing; 2018 Apr;18(2):75–82. 9. Stefely JA, Pagliarini DJ. Biochemistry of Mitochondrial Coenzyme Q Biosynthesis. Trends Biochem Sci.2017 Oct;42(10):824–43. PMCID: PMC5731490 10. Forsgren M, Attersand A, Lake S, Grünler J, Swiezewska E, Dallner G, et al. Isolation and functional expression of human COQ2, a gene encoding a polyprenyl transferase involved in the synthesis of CoQ. Biochem J.2004 Sep 1;382(Pt 2):519–26. PMCID: PMC1133808 11. Payet L-A, Leroux M, Willison JC, Kihara A, Pelosi L, Pierrel F. Mechanistic Details of Early Steps in Coenzyme Q Biosynthesis Pathway in Yeast. Cell Chem Biol.2016 Oct 20;23(10):1241–50. 69 318985012Attorney Docket No: 243735.000456 12. Acosta MJ, Vazquez Fonseca L, Desbats MA, Cerqua C, Zordan R, Trevisson E, et al. Coenzyme Q biosynthesis in health and disease. Biochim Biophys Acta.2016 Aug;1857(8):1079–85. 13. Hirano M, Garone C, Quinzii CM. CoQ(10) deficiencies and MNGIE: two treatable mitochondrial disorders. Biochim Biophys Acta.2012 May;1820(5):625– 31. PMCID: PMC3319470 14. Birsoy K, Wang T, Chen WW, Freinkman E, Abu-Remaileh M, Sabatini DM. An Essential Role of the Mitochondrial Electron Transport Chain in Cell Proliferation Is to Enable Aspartate Synthesis. Cell [Internet].2015 Jul 30;162(3):540–51. Retrieved from: http: / / dx.doi.org / 10.1016 / j.cell.2015.07.016 15. Sullivan LB, Gui DY, Hosios AM, Bush LN, Freinkman E, Vander Heiden MG. Supporting Aspartate Biosynthesis Is an Essential Function of Respiration in Proliferating Cells. Cell. Elsevier; 2015 Jul 30;162(3):552–63. PMCID: PMC4522278 16. Banh RS, Kim ES, Spillier Q, Biancur DE, Yamamoto K, Sohn ASW, et al. The polar oxy-metabolome reveals the 4-hydroxymandelate CoQ10 synthesis pathway. Nature.2021 Sep;597(7876):420–5. 17. Husain RA, Grimmel M, Wagner M, Hennings JC, Marx C, Feichtinger RG, et al. Bi-allelic HPDL Variants Cause a Neurodegenerative Disease Ranging from Neonatal Encephalopathy to Adolescent-Onset Spastic Paraplegia. Am J Hum Genet.2020 Aug 6;107(2):364–73. PMCID: PMC7413886 18. Ghosh SG, Lee S, Fabunan R, Chai G, Zaki MS, Abdel-Salam G, et al. Biallelic variants in HPDL, encoding 4-hydroxyphenylpyruvate dioxygenase-like protein, lead to an infantile neurodegenerative condition. Genet Med.2021 Mar;23(3):524– 33. 19. Morgan NV, Yngvadottir B, O'Driscoll M, Clark GR, Walsh D, Martin E, et al. Evidence that autosomal recessive spastic cerebral palsy-1 (CPSQ1) is caused by a missense variant in HPDL. Brain Commun.2021;3(1):fcab002. PMCID: PMC7892364 20. Wiessner M, Maroofian R, Ni M-Y, Pedroni A, Müller JS, Stucka R, et al. Biallelic variants in HPDL cause pure and complicated hereditary spastic paraplegia. Brain [Internet].2021 Jun 22;144(5):1422–34. Retrieved from: 70 318985012Attorney Docket No: 243735.000456 http: / / eutils.ncbi.nlm.nih.gov / entrez / eutils / elink.fcgi?dbfrom=pubmed&id=339702 00&retmode=ref&cmd=prlinks. PMCID: PMC8219359 21. Ye X, Wei X, Liao J, Chen P, Li X, Chen Y, et al.4-Hydroxyphenylpyruvate Dioxygenase-Like Protein Promotes Pancreatic Cancer Cell Progression and Is Associated With Glutamine-Mediated Redox Balance. Front Oncol. 2020;10:617190. PMCID: PMC7848781 * * *

[0256] The present invention is not to be limited in scope by the specific embodimentsdescribed herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

[0257] All patents, applications, publications, test methods, literature, and othermaterials cited herein are hereby incorporated by reference in their entirety as if physically present in this specification. 71 318985012

Claims

Attorney Docket No: 243735.000456 Claims What is claimed is:

1. A method of treating a disease or condition in a subject in need thereof, the methodcomprising administering to the subject a therapeutically effective amount of a compound selected from the group consisting of: a. ibuprofen or an ibuprofen derivative having the structure of Formula (I):or a wherein:12C4-12alkylcycloalkyl, -NH2, -C(O)heteroaryl, - C(O)heterocyclyl, and phenyl, wherein C1-12 alkyl, C4-12 alkylcycloalkyl, and phenyl can be optionally substituted by one or more of halogen, -OH, =O, and combinations thereof; R2 is selected from C1-6 alkylene, phenylene, heteroarylene, and heterocyclene, wherein C1-6alkylene, phenylene, heteroarylene, and heterocyclene, can be optionally substituted by one or more R´ groups; R3and R4are independently selected from hydrogen, C1-6alkyl, -NH2, - C(O)OH, -C(O)NH2, and phenyl, wherein C1-6 alkyl and phenyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof; or R5is hydrogen or C1-12alkyl; R5and R4combine with the carbon atom to which they are attached to form C3-12cycloalkyl; R´ is independently selected at each occurrence from C1-6alkyl, halogen, and - OH, and combinations thereof; or R3and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl; b. dopamine or a dopamine derivative having the structure of Formula (II):72 318985012Attorney Docket No: 243735.000456 ,- -C(O)OH; R8and R9are independently selected from hydrogen and -NH2; R10 is selected from hydrogen and -C(O)OH; and R11is selected from hydrogen and C1-6alkyl; c. flurbiprofen, ellagic acid, methyldopa, disulfiram, idelalisib, eltrombopagolamine, crystal violet, verteporfin, pioglitazone HCl, rosiglitazone HCl, enoxolone, triamcinolone, tideglusib, tolcapone, thimerosal, zinc pyrithione, montelukast sodium, nitroxoline, carbenoxolone sodium, sildenafil mesylate, saxagliptin hydrate, fenoldopam mesylate, gallic acid, clofoctol, hexachlorophene, cetylpyridinium chloride, povidone iodine, bithionol, bronopol, bardoxolone methyl, oltipraz, troglitazone, cangrelor tetrasodium, bismuth subcitrate potassium, puromycin, ledipasvir, obeticholic acid, erlotinib, tenofovir alafenamide, entrectinib. venetoclaxthe, 5-benzyl-1H-tetrazole, aspirin, 2-[4-(7-chloro-2-quinoxalinyloxy) phenoxy]propionic acid (XK469), or combinations thereof; and d. a compound of formula or,is selected from the group consisting of a non- malignant disease; benign tumors; growth of tumor cells or proliferating immune cells; inappropriate growth and proliferation of cells in benign but debilitating diseases; scarring; scar formation; excessive scarring; keloid; fibrosis and superficial fibrosing disorder; 73 318985012Attorney Docket No: 243735.000456 Adhesive capsulitis; RASopathies; chronic kidney disease; heterotopic ossification; tuberous sclerosis (TSC); adhesions following surgery; heterotopic ossification; and stiffening of tissues with aging.

2. A method of treating a disease or condition in a subject in need thereof, the methodcomprising administering to the subject a therapeutically effective amount of a compound selected from the group consisting of: a. ibuprofen or an ibuprofen derivative having the structure of Formula (I):or a wherein:12 C4-12 alkylcycloalkyl, -NH2, -C(O)heteroaryl, - C(O)heterocyclyl, and phenyl, wherein C1-12alkyl, C4-12alkylcycloalkyl, and phenyl can be optionally substituted by one or more of halogen, -OH, =O, and combinations thereof; R2 is selected from C1-6 alkylene, phenylene, heteroarylene, and heterocyclene, wherein C1-6alkylene, phenylene, heteroarylene, and heterocyclene, can be optionally substituted by one or more R´ groups; R3 and R4 are independently selected from hydrogen, C1-6 alkyl, -NH2, - C(O)OH, -C(O)NH2, and phenyl, wherein C1-6 alkyl and phenyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof; or R5 is hydrogen or C1-12 alkyl; R5and R4combine with the carbon atom to which they are attached to form C3-12 cycloalkyl; R´ is independently selected at each occurrence from C1-6alkyl, halogen, and - OH, and combinations thereof; or R3and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl; b. dopamine or a dopamine derivative having the structure of Formula (II):74 318985012Attorney Docket No: 243735.000456 ,- -C(O)OH; R8and R9are independently selected from hydrogen and -NH2; R10 is selected from hydrogen and -C(O)OH; and R11is selected from hydrogen and C1-6alkyl; and c. flurbiprofen, ellagic acid, methyldopa, disulfiram, idelalisib, eltrombopagolamine, crystal violet, verteporfin, pioglitazone HCl, rosiglitazone HCl, enoxolone, triamcinolone, tideglusib, tolcapone, thimerosal, zinc pyrithione, montelukast sodium, nitroxoline, carbenoxolone sodium, sildenafil mesylate, saxagliptin hydrate, fenoldopam mesylate, gallic acid, clofoctol, hexachlorophene, cetylpyridinium chloride, povidone iodine, bithionol, bronopol, bardoxolone methyl, oltipraz, troglitazone, cangrelor tetrasodium, bismuth subcitrate potassium, puromycin, ledipasvir, obeticholic acid, erlotinib, tenofovir alafenamide, entrectinib. venetoclaxthe, 5-benzyl-1H-tetrazole, aspirin, 2-[4-(7-chloro-2-quinoxalinyloxy) phenoxy]propionic acid (XK469), or combinations thereof, wherein the disease or condition is selected from the group consisting of a non- malignant disease; benign tumors; growth of tumor cells or proliferating immune cells; inappropriate growth and proliferation of cells in benign but debilitating diseases; scarring; scar formation; excessive scarring; keloid; fibrosis and superficial fibrosing disorder; Adhesive capsulitis; RASopathies; chronic kidney disease; heterotopic ossification; tuberous sclerosis (TSC); adhesions following surgery; heterotopic ossification; and stiffening of tissues with aging.

3. The method of claim 1 or claim 2, wherein the disease or condition is fibrosis andsuperficial fibrosing disorder selected from the group consisting of nephrogenic systemic fibrosis, idiopathic pulmonary fibrosis, chronic fibrosis due to chronic kidney disease, 75 318985012Attorney Docket No: 243735.000456 radiation-induced fibrosis, hepatic fibrosis, Dupuytren's contracture, Peyronie's disease, Scleroderma, and Post-MI myocardial fibrosis.

4. The method of claim 3, wherein the radiation-induced fibrosis is radiation-inducedpulmonary fibrosis.

5. The method of claim 1 or claim 2, wherein the scar formation is scar formation aftersurgery or injury, including keloid.

6. The method of claim 1 or claim 2, wherein the benign tumors are selected frommeningiomas and vestibular schwannomas.

7. The method of claim 1 or claim 2, wherein the reducing stiffening of tissues isreducing stiffening of arteries.

8. The method of any one of claims 1-7, wherein the compound is an ibuprofenderivative having the structure of Formula (IA), 5-benzyl-1H-tetrazole, aspirin, or 2-[4-(7- chloro-2-quinoxalinyloxy) phenoxy]propionic acid (XK469), ,R1 is selected from C1-12 alkyl, C4-12 alkylcycloalkyl, -C(O)heteroaryl, and - C(O)heterocyclyl, wherein C1-12alkyl and C4-12alkylcycloalkyl can be optionally substituted by one or more of =O; R2is selected from phenylene, heteroarylene, and heterocyclene, wherein phenylene, heteroarylene, and heterocyclene can be optionally substituted by one or more R´ groups; R3 and R4 are independently selected from hydrogen, C1-6 alkyl, -C(O)OH, and -C(O)NH2, wherein C1-6alkyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof; R5is hydrogen or C1-12alkyl; or 76 318985012Attorney Docket No: 243735.000456 R5 and R4 combine with the carbon atom to which they are attached to form C3- 12cycloalkyl; R´ is independently selected at each occurrence from C1-6 alkyl, halogen, and - OH, and combinations thereof; or R3 and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl, with the proviso that if R5 is hydrogen, R1 is unsubstituted C1-12 alkyl, and R2 is phenylene, then i) R3 is -C(O)NH2 or ii) R3and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl; or a pharmaceutically acceptable salt thereof.

9. The method of any one of claims 1-7, wherein the compound is ibuprofen or anibuprofen derivative having the structure of Formula (IB): (IB) wherein R1 is selected from C1-12 alkyl, -NH2, and phenyl, wherein C1-12 alkyl and phenyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof; R2is selected from C1-6alkylene and phenylene, wherein C1-6alkylene and phenylene can be optionally substituted by one or more of halogen, -OH, and combinations thereof; and R3 and R4 are independently selected from hydrogen, C1-6 alkyl, -NH2, -CO2H, and phenyl, wherein C1-6alkyl and phenyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof, or a pharmaceutically acceptable salt thereof.

10. The method of claim 9, wherein the compound has the structure of Formula (IB’):(IB’), or a pharmaceutically acceptable salt thereof. 77 318985012Attorney Docket No: 243735.000456 11. The method of claim 9, wherein the compound has the structure of Formula (IB”):(IB”), or a pharmaceutically acceptable salt thereof.9, where the compound having the structure of Formula (IB)is selected from the group consisting of: , a13. The method of claims 9, where the compound having the structure of Formula (IB)is: ,salt thereof.

14. The method of any one of claims 1-7, wherein the compound is dopamine or adopamine derivative having the structure of Formula (II).

15. The method of any one of claims 1-7 and 14, where the compound having thestructure of Formula (II) is selected from the group consisting of: 78 318985012Attorney Docket No: 243735.000456 , anda pharmaceutically acceptable salt thereof.claims 1-7 and 15-16, where the compound having thestructure of Formula (II) is selected from the group consisting of: , or a17. The method of any one of claims 1-7, wherein the compound is flurbiprofen, ellagicacid, methyldopa, disulfiram, idelalisib, eltrombopag olamine, crystal violet, verteporfin, pioglitazone HCl, rosiglitazone HCl, enoxolone, triamcinolone, tideglusib, tolcapone, thimerosal, zinc pyrithione, montelukast sodium, nitroxoline, carbenoxolone sodium, sildenafil mesylate, saxagliptin hydrate, fenoldopam mesylate, gallic acid, clofoctol, hexachlorophene, cetylpyridinium chloride, povidone iodine, bithionol, bronopol, bardoxolone methyl, oltipraz, troglitazone, cangrelor tetrasodium, bismuth subcitrate potassium, puromycin, ledipasvir, obeticholic acid, erlotinib, tenofovir alafenamide, entrectinib. venetoclaxthe, or combinations thereof, or a pharmaceutically acceptable salt thereof. 79 318985012Attorney Docket No: 243735.000456 18. The method of any one of claims 1-7, wherein the compound is.thereof,comprising administering to the subject a therapeutically effective amount of an ibuprofen derivative having the structure of Formula (IA), 5-benzyl-1H-tetrazole, aspirin, or 2-[4-(7- chloro-2-quinoxalinyloxy) phenoxy]propionic acid (XK469), salt thereof, wherein:R1 is selected from C1-12 alkyl, C4-12 alkylcycloalkyl, -C(O)heteroaryl, and - C(O)heterocyclyl, wherein C1-12alkyl and C4-12alkylcycloalkyl can be optionally substituted by one or more of =O; R2is selected from phenylene, heteroarylene, and heterocyclene, wherein phenylene, heteroarylene, and heterocyclene can be optionally substituted by one or more R´ groups; R3 and R4 are independently selected from hydrogen, C1-6 alkyl, -C(O)OH, and - C(O)NH2, wherein C1-6alkyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof; R5is hydrogen or C1-12alkyl; or R4 and R5 combine with the carbon atom to which they are attached to form C3-12 cycloalkyl; R´ is independently selected at each occurrence from C1-6 alkyl, halogen, and -OH, and combinations thereof; or R3 and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl, with the proviso that if R5is hydrogen, R1is unsubstituted C1-12alkyl, and R2is phenylene, then i) R3 is -C(O)NH2 or ii) R3and R´ combine with the carbon atoms to which they are attached to form C3-12cycloalkyl. 80 318985012Attorney Docket No: 243735.000456 20. The method of claim 19, further comprising administering to the subject atherapeutically effective amount of an inhibitor of HPDL.

21. A method of treating cancer, autoimmune disease, or any disease involving cellularproliferation in a subject in need thereof, comprising the following steps: a. determining expression level of 4-hydroxyphenylpyruvate dioxygenase-like(HPDL) in a sample obtained from the subject; b. comparing the HPDL expression level determined in step (a) with a controllevel of HPDL expression; and c. administering an effective amount of an HPDL inhibitor to the subjectexhibiting a higher level of HPDL expression as compared to the control level, wherein the HPDL inhibitor is a compound that is an ibuprofen derivative having the structure of Formula (IA), 5-benzyl-1H-tetrazole, aspirin, or 2-[4- (7-chloro-2-quinoxalinyloxy) phenoxy]propionic acid (XK469),salt thereof, wherein: R1 is selected from C1-12 alkyl, C4-12 alkylcycloalkyl, -C(O)heteroaryl, and - C(O)heterocyclyl, wherein C1-12 alkyl and C4-12 alkylcycloalkyl can be optionally substituted by one or more of =O; R2 is selected from phenylene, heteroarylene, and heterocyclene, wherein phenylene, heteroarylene, and heterocyclene can be optionally substituted by one or more R´ groups; R3 and R4 are independently selected from hydrogen, C1-6 alkyl, -C(O)OH, and -C(O)NH2, wherein C1-6alkyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof; R5is hydrogen or C1-12alkyl; or R4 and R5 combine with the carbon atom to which they are attached to form C3-12cycloalkyl; 81 318985012Attorney Docket No: 243735.000456 R´ is independently selected at each occurrence from C1-6 alkyl, halogen, and -OH, and combinations thereof; or R3 and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl, with the proviso that if R5 is hydrogen, R1 is unsubstituted C1-12 alkyl, and R2 is phenylene, then i) R3 is -C(O)NH2 or ii) R3and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl.

22. The method of claim 21, wherein the sample comprises circulating tumor cells.

23. The method of any one of claims 21-22, wherein the control level of HPDLexpression is determined in normal tissue from the same subject, a sample from a normal subject, or is a predetermined value.

24. The method of any one of claims 21-23, wherein the expression level of HPDL isdetermined by determining the level of 4-HMA in the sample.

25. A method of determining effectiveness of a treatment for cancer, autoimmunedisease, or any disease involving cellular proliferation in a subject, comprising the following steps: a. determining expression level of 4-hydroxyphenylpyruvate dioxygenase-like(HPDL) in a first sample obtained from the subject before the subject receives a treatment for cancer comprising administering a therapeutically effective amount of a compound that is an ibuprofen derivative having the structure of Formula (IA), 5-benzyl-1H-tetrazole, aspirin, or 2-[4-(7-chloro-2- quinoxalinyloxy) phenoxy]propionic acid (XK469),salt thereof, wherein: 82 318985012Attorney Docket No: 243735.000456 R1 is selected from C1-12 alkyl, C4-12 alkylcycloalkyl, -C(O)heteroaryl, and - C(O)heterocyclyl, wherein C1-12alkyl and C4-12alkylcycloalkyl can be optionally substituted by one or more of =O; R2 is selected from phenylene, heteroarylene, and heterocyclene, wherein phenylene, heteroarylene, and heterocyclene can be optionally substituted by one or more R´ groups; R3 and R4 are independently selected from hydrogen, C1-6 alkyl, -C(O)OH, and -C(O)NH2, wherein C1-6 alkyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof; R5 is hydrogen or C1-12 alkyl; or R4and R5combine with the carbon atom to which they are attached to form C3-12 cycloalkyl; R´ is independently selected at each occurrence from C1-6alkyl, halogen, and -OH, and combinations thereof; or R3and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl, with the proviso that if R5is hydrogen, R1is unsubstituted C1-12alkyl, and R2 is phenylene, then i) R3 is -C(O)NH2 or ii) R3and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl; b. determining expression level of HPDL in a second sample obtained from thesubject after the subject has received the treatment for cancer, autoimmune disease, or any disease involving cellular proliferation; c. comparing the HPDL expression levels determined in the first sample and thesecond sample; and d. determining that (i) the treatment is effective if the HPDL expression level inthe second sample is lower than HPDL expression level in the first sample, or (ii) the treatment is not effective if the HPDL expression level in the second sample is not lower than the HPDL expression level in the first sample.

26. The method claim 25, wherein the treatment for cancer is selected from one or moreHPDL inhibitors, a chemotherapy, a chemoradiotherapy, a neoadjuvant chemoradiotherapy, a radiotherapy, a surgery, and any combination thereof. 83 318985012Attorney Docket No: 243735.000456 27. A method of predicting prognosis of cancer in a subject having cancer, autoimmunedisease, or any disease involving cellular proliferation, comprising the following steps: a. determining expression level of 4-hydroxyphenylpyruvate dioxygenase-like(HPDL) protein in a sample obtained from the subject; b. comparing the HPDL expression level determined in step (a) with a controllevel of HPDL expression; and c. determining the subject (i) as having poor prognosis if the HPDL expressionlevel is higher than the control level, or (ii) as having good prognosis if the HPDL expression level is lower than or equal to the control level, wherein if the subject is determined to have poor prognosis, the method further comprising administering to the subject a single-agent chemotherapy, supportive care, and / or a compound that is an ibuprofen derivative having the structure of Formula (IA), 5-benzyl-1H-tetrazole, aspirin, or 2-[4-(7-chloro-2- quinoxalinyloxy) phenoxy]propionic acid (XK469),salt thereof, wherein: R1 is selected from C1-12 alkyl, C4-12 alkylcycloalkyl, -C(O)heteroaryl, and -C(O)heterocyclyl, wherein C1-12 alkyl and C4-12 alkylcycloalkyl can be optionally substituted by one or more of =O; R2 is selected from phenylene, heteroarylene, and heterocyclene, wherein phenylene, heteroarylene, and heterocyclene can be optionally substituted by one or more R´ groups; R3and R4are independently selected from hydrogen, C1-6alkyl, -C(O)OH, and -C(O)NH2, wherein C1-6 alkyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof; R5 is hydrogen or C1-12 alkyl; or R4and R5combine with the carbon atom to which they are attached to form C3-12 cycloalkyl; R´ is independently selected at each occurrence from C1-6alkyl, halogen, and -OH, and combinations thereof; or 84 318985012Attorney Docket No: 243735.000456 R3 and R´ combine with the carbon atoms to which they are attached to form C3-12cycloalkyl, with the proviso that if R5 is hydrogen, R1 is unsubstituted C1-12 alkyl, and R2 is phenylene, then i) R3 is -C(O)NH2 or ii) R3and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl.

28. The method of claim 27, wherein the control level of HPDL expression isdetermined in normal tissue from the same subject, a sample from a normal subject, or is a predetermined value.

29. The method of claim 27 or 28, wherein the subject has unresectable or borderlineresectable pancreatic cancer.

30. The method of any one of claims 21-24 and 27-29, further comprisingadministering an additional compound having the structure of Formula (I’): ,salt thereof, wherein: Q is selected from ; R’1, R’2, andselected from hydrogen, C1-12 alkyl, C1-12 alkenyl, C6-12aryl, C1-12aralkyl, C1-4haloalkyl, or a combination thereof, each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S; -OH, =O, - CO2H, -NO2, -NH2, -NHR*, -NR*2, -N-OH, -HSO3, -H2PO3, -OR*, -(C=O)-R*, - CO2R*, -CO-NH2, -CO-NHR*, -SO2-NHR*, or adjacent two moieties combine to form a fused ring which may optionally contain 1-3 heteroatoms selected from halogen, O, N, and S and which may be further substituted by one or more R*; R’4 and R’5 are independently selected from -OH and -CO2H; R’6and R’7are independently selected from hydrogen, C1-12alkyl, C1-12alkenyl, C6-12aryl, C1-12 aralkyl, C1-4 haloalkyl, or a combination thereof, each of which optionally 85 318985012Attorney Docket No: 243735.000456 contains 1-8 heteroatoms selected from halogen, O, N, and S; -OH, =O, -CO2H, -NO2, -NH2, -NHR*, -NR*2, -N-OH, -HSO3, -H2PO3, -OR*, -(C=O)-R*, -CO2R*, -CO-NH2, -CO-NHR*, -SO2-NHR*, or R6 and R7 combine to form a fused ring, and R* is independently selected at each occurrence from hydrogen or C1-C12 hydrocarbons each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S and combinations thereof.

31. The method of claim 30, wherein when Q , at least one of R’1, R’2,is not H.

32. The method of claim 30, wherein the additional compound has the structure ofFormula (I’A): ,salt thereof.

33. The method of claim 30, wherein the additional compound has the structure ofFormula (I’B): ,salt thereof.

34. The method of claim 30, wherein the additional compound has the structure ofFormula (I’C): 86 318985012Attorney Docket No: 243735.000456 , salt thereof.

35. The method of claim 30, wherein the additional compound has the structure ofFormula (I’D): , salt thereof, wherein Q is -O- or -NH-.

36. The method of claim 30, wherein the additional compound has the structure ofFormula (I’E): ,salt thereof.

37. The method of claim 30, wherein the additional compound having thestructure of Formula (I’) is selected from the group consisting of: 87 318985012Attorney Docket No: 243735.000456 ,, or a pharmaceutically acceptable salt38. The method of any one of claims 21 and 27, further comprising administering anadditional compound having the structure of Formula (II’): ,wherein: R’’1 is selected from -NO2, -Cl, and a C1-12 alkyl which may be optionally substituted with one or more of -OH, =O, -CO2H, -NO2, -NH2, -NHR*, -NR*2, -N-OH, -HSO3, - H2PO3, -OR*, -(C=O)-R*, -CO2R*, -CO-NH2, -CO-NHR*, and -SO2-NHR*; R’’2, R’’3, R’’4, R’’5, R’’6and R’’7are independently selected from hydrogen, C1-12alkyl, C1-12alkenyl, C6-12aryl, C1-12aralkyl, C1-4haloalkyl, or a combination thereof, each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S; -OH, =O, -CO2H, -NO2, -NH2, -NHR*, -NR*2, -N-OH, -HSO3, -H2PO3, -OR*, -(C=O)- R*, -CO2R*, -CO-NH2, -CO-NHR*, -SO2R*, -SO2-NHR*, or adjacent two moieties combine to form a fused ring which may optionally contain 1-3 heteroatoms selected from halogen, O, N, and S and which may be further substituted by one or more R*, and 88 318985012Attorney Docket No: 243735.000456 R* is independently selected at each occurrence from hydrogen or C1-C12 hydrocarbons each of which optionally contains 1-8 heteroatoms selected from halogen, O, N, and S and combinations thereof.

39. The method of claim 38, wherein the additional compound does not have thestructure selected from (nitisinone) (sulcotrione).

40. The method of claim 38, wherein the additional compound has the structure ofFormula (II’A): ,41. The method of claim 38, wherein the additional compound has the structure ofFormula (II’B): ,42. The method of claim 38, wherein R’’1 is a C1-12 alkyl substituted with one or moreof -OH, =O, -CO2H, -NO2, -NH2, -NHR*, -NR*2, -N-OH, -HSO3, -H2PO3, -OR*, - (C=O)-R*, -CO2R*, -CO-NH2, -CO-NHR*, and -SO2-NHR*. 89 318985012Attorney Docket No: 243735.000456 43. The method of claim 38, wherein the additional compound having the structure ofFormula (II’) is selected from the group consisting of: ,a pharmaceutically acceptable salt thereof.

44. The method of claim 38, wherein the additional compound having the structure ofFormula (II’) is selected from the group consisting of: ,90 318985012Attorney Docket No: 243735.000456 45. The method of any one of claims 21 and 27, further comprising administering N-[5-[[4-[5-[acetyl(hydroxy)amino]pentylamino]-4-oxobutanoyl]-hydroxyamino]pentyl]- N'-(5-aminopentyl)-N'-hydroxybutanediamide (Deferoxamine; DFO).

46. The method of any one of claims 21-24, wherein the method comprises notadministering an HPDL inhibitor to the subject exhibiting a lower or equivalent level of HPDL expression as compared to the control level.

47. The method of any one of claims 21-24, further comprising administering one ormore additional treatments to the subject, wherein said additional treatments are selected from a chemotherapy, a chemoradiotherapy, a neoadjuvant chemoradiotherapy, a radiotherapy, a surgery, and any combination thereof.

48. The method of claim 47, wherein the additional treatment is a platinum-basedchemotherapyand the method further comprises administering an electron transport chain (ETC) inhibitor.

49. The method of claim 27, wherein the method further comprises administering anelectron transport chain (ETC) inhibitor in combination with the single-agent chemotherapy.

50. The method of claims 48 or 49, wherein the electron transport chain (ETC) inhibitoris metformin, phenformin, BAY84-2243, carboxyamidotriazole, ME344, Fenofibrate, mIBG (meta-iodobenzylguanidine), Alpha-TOS, Lonidamine, Atovaquone, Arsenic trioxide, Nitric Oxide, or Hydrocortisone, or a combination thereof.

51. A method of inhibiting an immune response in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of an ibuprofen derivative having the structure of Formula (IA), 5-benzyl-1H-tetrazole, aspirin, or 2-[4-(7-chloro-2- quinoxalinyloxy) phenoxy]propionic acid (XK469),91Attorney Docket No: 243735.000456 or a pharmaceutically acceptable salt thereof, wherein: R1is selected from C1-12alkyl, C4-12alkylcycloalkyl, -C(O)heteroaryl, and - C(O)heterocyclyl, wherein C1-12 alkyl and C4-12 alkylcycloalkyl can be optionally substituted by one or more of =O; R2 is selected from phenylene, heteroarylene, and heterocyclene, wherein phenylene, heteroarylene, and heterocyclene can be optionally substituted by one or more R´ groups; R3 and R4 are independently selected from hydrogen, C1-6 alkyl, -C(O)OH, and - C(O)NH2, wherein C1-6alkyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof; R5is hydrogen or C1-12alkyl; or R4 and R5 combine with the carbon atom to which they are attached to form C3-12 cycloalkyl; R´ is independently selected at each occurrence from C1-6 alkyl, halogen, and -OH, and combinations thereof; or R3 and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl, with the proviso that if R5 is hydrogen, R1 is unsubstituted C1-12 alkyl, and R2 is phenylene, then i) R3 is -C(O)NH2 or ii) R3and R´ combine with the carbon atoms to which they are attached to form C3-12cycloalkyl.

52. A method of reducing an immune response to a vaccine in a subject in need thereof,comprising administering to the subject a therapeutically effective amount of an ibuprofen derivative having the structure of Formula (IA), 5-benzyl-1H-tetrazole, aspirin, or 2-[4-(7- chloro-2-quinoxalinyloxy) phenoxy]propionic acid (XK469),salt thereof, wherein: R1is selected from C1-12alkyl, C4-12alkylcycloalkyl, -C(O)heteroaryl, and - C(O)heterocyclyl, wherein C1-12 alkyl and C4-12 alkylcycloalkyl can be optionally substituted by one or more of =O; 92 318985012Attorney Docket No: 243735.000456 R2 is selected from phenylene, heteroarylene, and heterocyclene, wherein phenylene, heteroarylene, and heterocyclene can be optionally substituted by one or more R´ groups; R3 and R4 are independently selected from hydrogen, C1-6 alkyl, -C(O)OH, and - C(O)NH2, wherein C1-6 alkyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof; R5 is hydrogen or C1-12 alkyl; or R4 and R5 combine with the carbon atom to which they are attached to form C3-12 cycloalkyl; R´ is independently selected at each occurrence from C1-6 alkyl, halogen, and -OH, and combinations thereof; or R3 and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl, with the proviso that if R5 is hydrogen, R1 is unsubstituted C1-12 alkyl, and R2 is phenylene, then i) R3is -C(O)NH2or ii) R3and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl.

53. A method of reducing an antibody production in a subject in need thereof,comprising administering to the subject a therapeutically effective amount of an ibuprofen derivative having the structure of Formula (IA), 5-benzyl-1H-tetrazole, aspirin, or 2-[4-(7- chloro-2-quinoxalinyloxy) phenoxy]propionic acid (XK469),salt thereof, wherein: R1is selected from C1-12alkyl, C4-12alkylcycloalkyl, -C(O)heteroaryl, and - C(O)heterocyclyl, wherein C1-12 alkyl and C4-12 alkylcycloalkyl can be optionally substituted by one or more of =O; R2 is selected from phenylene, heteroarylene, and heterocyclene, wherein phenylene, heteroarylene, and heterocyclene can be optionally substituted by one or more R´ groups; 93 318985012Attorney Docket No: 243735.000456 R3 and R4 are independently selected from hydrogen, C1-6 alkyl, -C(O)OH, and - C(O)NH2, wherein C1-6alkyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof; R5 is hydrogen or C1-12 alkyl; or R4 and R5 combine with the carbon atom to which they are attached to form C3-12 cycloalkyl; R´ is independently selected at each occurrence from C1-6 alkyl, halogen, and -OH, and combinations thereof; or R3and R´ combine with the carbon atoms to which they are attached to form C3-12cycloalkyl, with the proviso that if R5is hydrogen, R1is unsubstituted C1-12alkyl, and R2is phenylene, then i) R3 is -C(O)NH2 or ii) R3and R´ combine with the carbon atoms to which they are attached to form C3-12cycloalkyl.

54. A method of inhibiting growth of a tumor in a subject in need thereof, comprisingadministering to the subject a therapeutically effective amount of an ibuprofen derivative having the structure of Formula (IA), 5-benzyl-1H-tetrazole, aspirin, or 2-[4-(7-chloro-2- quinoxalinyloxy) phenoxy]propionic acid (XK469),salt thereof, wherein: R1 is selected from C1-12 alkyl, C4-12 alkylcycloalkyl, -C(O)heteroaryl, and - C(O)heterocyclyl, wherein C1-12alkyl and C4-12alkylcycloalkyl can be optionally substituted by one or more of =O; R2is selected from phenylene, heteroarylene, and heterocyclene, wherein phenylene, heteroarylene, and heterocyclene can be optionally substituted by one or more R´ groups; R3 and R4 are independently selected from hydrogen, C1-6 alkyl, -C(O)OH, and - C(O)NH2, wherein C1-6alkyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof; R5is hydrogen or C1-12alkyl; or 94 318985012Attorney Docket No: 243735.000456 R4 and R5 combine with the carbon atom to which they are attached to form C3-12 cycloalkyl; R´ is independently selected at each occurrence from C1-6 alkyl, halogen, and -OH, and combinations thereof; or R3 and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl, with the proviso that if R5 is hydrogen, R1 is unsubstituted C1-12 alkyl, and R2 is phenylene, then i) R3 is -C(O)NH2 or ii) R3and R´ combine with the carbon atoms to which they are attached to form C3-12cycloalkyl.

55. A method of treating a subject having an activating variant in the HPDL gene, anyother gene in the CoQ headgroup synthesis pathway, or any gene controlling the CoQ headgroup synthesis pathway, comprising administering to the subject a therapeutically effective amount of an ibuprofen derivative having the structure of Formula (IA), 5-benzyl- 1H-tetrazole, aspirin, or 2-[4-(7-chloro-2-quinoxalinyloxy) phenoxy]propionic acid (XK469),salt thereof, wherein: R1 is selected from C1-12 alkyl, C4-12 alkylcycloalkyl, -C(O)heteroaryl, and - C(O)heterocyclyl, wherein C1-12 alkyl and C4-12 alkylcycloalkyl can be optionally substituted by one or more of =O; R2is selected from phenylene, heteroarylene, and heterocyclene, wherein phenylene, heteroarylene, and heterocyclene can be optionally substituted by one or more R´ groups; R3 and R4 are independently selected from hydrogen, C1-6 alkyl, -C(O)OH, and - C(O)NH2, wherein C1-6alkyl can be optionally substituted by one or more of halogen, -OH, and combinations thereof; R5is hydrogen or C1-12alkyl; or R4 and R5 combine with the carbon atom to which they are attached to form C3-12 cycloalkyl; 95 318985012Attorney Docket No: 243735.000456 R´ is independently selected at each occurrence from C1-6 alkyl, halogen, and -OH, and combinations thereof; or R3 and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl, with the proviso that if R5 is hydrogen, R1 is unsubstituted C1-12 alkyl, and R2 is phenylene, then i) R3 is -C(O)NH2 or ii) R3and R´ combine with the carbon atoms to which they are attached to form C3-12 cycloalkyl.

56. The method of any one of claims 1-55, wherein the subject is a mammal.

57. The method of claim 56, wherein the subject is a human.

58. The method of claim 56 or 57, wherein the subject is a child.

59. The method of claim 56 or 57, wherein the subject is an adult.

60. The method of any one of claims 1-8 and 19-59, wherein R1 is C1-12 alkyl.

61. The method of any one of claims 1-8 and 19-60, wherein R2 is phenylene.

62. The method of any one of claims 1-8 and 19-61, wherein R3 is C1-6 alkyl.

63. The method of any one of claims 1-8 and 19-62, wherein R4 is -C(O)OH or -C(O)NH2.

64. The method of any one of claims 1-8 and 19-63, wherein R5 is hydrogen.

65. The method of any one of claims 1-8 and 19-63, wherein R5 is C1-12 alkyl.

66. The method of any one of claims 1-8 and 19-59, wherein the compound of Formula(IA) is selected from the group consisting of 96 318985012Attorney Docket No: 243735.000456 , , ,318985012Attorney Docket No: 243735.000456 ,any onefrom the group consisting of .98 318985012

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