IP Library › Patent Application 11832265

Patent Application

App. No. 11/832,265

COMPOSITIONS AND METHODS FOR TREATING, CONTROLLING, REDUCING, OR AMELIORATING INFECTIONS AND SEQUELAE THEREOF

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App. No.: 11/832,265

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Abstract

A composition for treating, controlling, reducing, ameliorating, or alleviating infections and their inflammatory sequelae comprises a dissociated glucocorticoid receptor agonist (“DIGRA”) and an anti-infective agent, such as an antibacterial, antiviral, antifungal, antiprotozoal agent, or a combination thereof. The composition can be formulated for topical application, injection, or implantation.

Claims (214)

1 . A composition comprising: (a) a dissociated glucocorticoid receptor agonist (“DIGRA”), a prodrug thereof, or a pharmaceutically acceptable salt thereof; and (b) an anti-infective agent.

2 . The composition of claim 1 , further comprising a physiologically acceptable carrier.

3 . The composition of claim 2 , wherein (a) the DIGRA, the prodrugs thereof, or the pharmaceutically acceptable salts thereof; and (b) the anti-infective agent are present in the composition in amounts sufficient to be effective for treating, controlling, reducing, ameliorating, or alleviating an infection and inflammatory sequelae thereof.

4 . The composition of claim 3 , wherein said infection is selected from the group consisting of blepharitis, conjunctivitis, keratitis, trachoma, and combinations thereof.

5 . The composition of claim 3 , wherein said infection is selected from the group consisting of anterior blepharitis, posterior blepharitis, herpes simplex keratitis, herpes zoster keratitis, bacterial keratitis, fungal keratitis, fusarium keratitis, acanthamoeba keratitis, cytomegalovirus retinitis, toxoplasma retinitis, herpes zoster conjunctivitis, bacterial conjunctivitis, bacterial infection of aqueous and vitreous humours, endophthalmitis, panophthalmitis, trachoma, and combinations thereof.

6 . The composition of claim 3 , wherein the DIGRA comprises a compound having Formula I

wherein A and Q are independently selected from the group consisting of unsubstituted and substituted aryl and heteroaryl groups, unsubstituted and substituted cycloalkyl and heterocycloalkyl groups, unsubstituted and substituted cycloalkenyl and heterocycloalkenyl groups, unsubstituted and substituted cycloalkynyl and heterocycloalkynyl groups, and unsubstituted and substituted heterocyclic groups; R 1 and R 2 are independently selected from the group consisting of hydrogen, unsubstituted C 1 -C 15 linear or branched alkyl groups, substituted C 1 -C 15 linear or branched alkyl groups, unsubstituted C 3 -C 15 cycloalkyl groups, and substituted C 3 -C 15 cycloalkyl groups; R 3 is selected from the group consisting of hydrogen, unsubstituted C 1 -C 15 linear or branched alkyl groups, substituted C 1 -C 15 linear or branched alkyl groups, unsubstituted C 3 -C 15 cycloalkyl and heterocycloalkyl groups, substituted C 3 -C 15 cycloalkyl and heterocycloalkyl groups, aryl groups, heteroaryl groups, and heterocyclylic groups; B comprises a carbonyl, amino, divalent hydrocarbon, or heterohydrocarbon group; E is hydroxy or amino group; and D is absent or comprises a carbonyl group, —NH—, or —NR′—, wherein R′ comprises an unsubstituted or substituted C 1 -C 15 linear or branched alkyl group; and wherein R 1 and R 2 together may form an unsubstituted or substituted C 3 -C 15 cycloalkyl group.

7 . The composition of claim 6 , wherein the composition causes a lower level of at least an adverse side effect in a subject than another composition comprising at least a glucocorticoid used to treat, control, reduce, or ameliorate the same condition.

8 . The composition of claim 7 , wherein said level of said at least an adverse side effect is determined by in vitro testing.

9 . The composition of claim 7 , wherein said level of said at least an adverse side effect is determined in vivo.

10 . The composition of claim 7 , wherein said at least a glucocorticoid is selected from the group consisting of dexamethasone, prednisone, prednisolone, methylprednisolone, medrysone, triamcinolone, triamcinolone acetonide, loteprednol etabonate, physiologically acceptable salts thereof, combinations thereof, and mixtures thereof.

11 . The composition of claim 7 , wherein said at least an adverse side effect is selected from the group consisting of glaucoma, cataract, hypertension, hyperglycemia, hyperlipidemia, and hypercholesterolemia.

12 . The composition of claim 7 , wherein the level of said at least an adverse side effect is determined at a time selected from the group consisting of about 14 days, about 30 days, about 2 months, about, 3 months, about 4 months, about 5 months, and about 6 months, after the composition is first administered to, and is present in, a subject.

13 . The composition of claim 12 , wherein the DIGRA has Formula I

Wherein A and Q are independently selected from the group consisting of aryl and heteroaryl groups substituted with at least a halogen atom, cyano group, hydroxy group, or C 1 -C 10 alkoxy group; R 1 , R 2 , and R 3 are independently selected from the group consisting of unsubstituted and substituted C 1 -C 5 alkyl groups; B is a C 1 -C 5 alkylene group; D is the —NH— or —NR′-group, wherein R′ is a C 1 -C 5 alkyl group; and E is the hydroxy group.

14 . The composition of claim 13 , wherein the anti-infective agent is selected from the group consisting of bacitracin zinc, chloramphenicol, ciprofloxacin hydrochloride, erythromycin, gatifloxacin, gentamycin sulfate, levofloxacin, moxifloxacin, ofloxacin, sulfacetamide sodium, polymyxin B, tobramycin sulfate, trifluridine, vidarabine, acyclovir, valacyclovir, famcyclovir, foscarnet, ganciclovir, formivirsen, cidofovir, amphotericin B, natamycin, fluconazole, itraconazole, ketoconazole, miconazole, polymyxin B sulfate, neomycin sulfate, clotrimazole, propamidine isethionate, polyhexamethylene biguanide, chlorhexidine, pyrimethamine, sulfadiazine, folinic acid (leucovorin), clindamycin, trimethoprim-sulfamethoxazole, and combinations thereof.

15 . The composition of claim 7 , wherein the DIGRA has Formula I

wherein A comprises a dihydrobenzofuranyl group substituted with a halogen atom; Q comprises a quinolinyl or isoquinolinyl group substituted with a C 1 -C 10 alkyl group; R 1 and R 2 are independently selected from the group consisting of unsubstituted and substituted C 1 -C 5 alkyl groups; B is a C 1 -C 3 alkylene group; D is the —NH— group; E is the hydroxy group; and R 3 comprises a completely halogenated C 1 -C 10 alkyl group.

16 . The composition of claim 7 , wherein the DIGRA has Formula I

wherein A comprises a dihydrobenzofuranyl group substituted with a fluorine atom; Q comprises a quinolinyl or isoquinolinyl group substituted with a methyl group; R 1 and R 2 are independently selected from the group consisting of unsubstituted and substituted C 1 -C 5 alkyl groups; B is a C 1 -C 3 alkylene group; D is the —NH— group; E is the hydroxy group; and R 3 comprises a trifluoromethyl group.

17 . The composition of claim 7 , wherein the DIGRA has Formula II

wherein R 4 and R 5 are independently selected from the group consisting of hydrogen, halogen, cyano, hydroxy, C 1 -C 10 alkoxy groups, unsubstituted C 1 -C 10 linear or branched alkyl groups, substituted C 1 -C 10 linear or branched alkyl groups, unsubstituted C 3 -C 10 cyclic alkyl groups, and substituted C 3 -C 10 cyclic alkyl groups.

18 . The composition of claim 7 , wherein the DIGRA has Formula III

19 . The composition of claim 7 , wherein the DIGRA has Formula IV

20 . The composition of claim 1 , further comprising an additional anti-inflammatory agent selected from the group consisting of non-steroidal anti-inflammatory drugs (“NSAIDs”), peroxisome proliferator-activated receptor (“PPAR”) ligands, combinations thereof, and mixtures thereof.

21 . The composition of claim 7 , wherein the DIGRA has Formula I, wherein

(a) A is an aryl group optionally independently substituted with one to three substituent groups, which are independently selected from the group consisting of C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 1 -C 3 alkanoyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1 -C 5 alkoxy, C 2 -C 5 alkenyloxy, C 2 -C 5 alkynyloxy, aryloxy, acyl, C 1 -C 5 alkoxycarbonyl, aroyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C 1 -C 5 alkylaminocarbonyloxy, C 1 -C 5 dialkylaminocarbonyloxy, C 1 -C 5 alkanoylamino, C 1 -C 5 alkoxycarbonylamino, C 1 -C 5 alkylsulfonylamino, aminosulfonyl, C 1 -C 5 alkylaminosulfonyl, C 1 -C 5 dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C 1 -C 5 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C 1 -C 5 alkyl, C 1 -C 5 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone;

(b) R 1 and R 2 are each independently hydrogen or C 1 -C 5 alkyl;

(d) B is C 1 -C 5 alkyl, C 2 -C 5 alkenyl, or C 2 -C 5 alkynyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of B is independently C 1 -C 3 alkyl, hydroxy, halogen, amino, or oxo;

(e) D is absent;

(f) E is the hydroxy group; and

(g) Q is an azaindolyl group optionally independently substituted with one to three substituent groups, wherein each substituent group of Q is independently C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1 -C 5 alkoxy, C 2 -C 5 alkenyloxy, C 2 -C 5 alkynyloxy, aryloxy, acyl, C 1 -C 5 alkoxycarbonyl, C 1 -C 5 alkanoyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C 1 -C 5 alkylaminocarbonyloxy, C 1 -C 5 dialkylaminocarbonyloxy, C 1 -C 5 alkanoylamino, C 1 -C 5 alkoxycarbonylamino, C 1 -C 5 alkylsulfonylamino, aminosulfonyl, C 1 -C 5 alkylaminosulfonyl, C 1 -C 5 dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, or amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C 1 -C 5 alkyl, ureido wherein either nitrogen atom is optionally independently substituted with C 1 -C 5 alkyl, C 1 -C 5 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of Q is optionally independently substituted with one to three substituent groups selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogen, hydroxy, oxo, cyano, amino, and trifluoromethyl.

22 . The composition of claim 7 , wherein the DIGRA has Formula I, wherein

(a) A is an aryl or heteroaryl group, each optionally independently substituted with one to three substituent groups, which are independently selected from the group consisting of C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 1 -C 3 alkanoyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1 -C 5 alkoxy, C 2 -C 5 alkenyloxy, C 2 -C 5 alkynyloxy, aryloxy, acyl, C 1 -C 5 alkoxycarbonyl, aroyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C 1 -C 5 alkylaminocarbonyloxy, C 1 -C 5 dialkylaminocarbonyloxy, C 1 -C 5 alkanoylamino, C 1 -C 5 alkoxycarbonylamino, C 1 -C 5 alkylsulfonylamino, aminosulfonyl, C 1 -C 5 alkylaminosulfonyl, C 1 -C 5 dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C 1 -C 5 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C 1 -C 5 alkyl, C 1 -C 5 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone;

(b) R 1 and R 2 are each independently hydrogen or C 1 -C 5 alkyl, or R 1 and R 2 together with the carbon atom they are commonly attached to form a C 3 -C 8 spiro cycloalkyl ring;

(d) R 3 is a carbocycle, heterocyclyl, aryl, heteroaryl, carbocycle-C 1 -C 8 alkyl, aryl-C 1 -C 8 alkyl, aryl-C 1 -C 8 haloalkyl, heterocyclyl-C 1 -C 8 alkyl, heteroaryl-C 1 -C 8 alkyl, carbocycle-C 2 -C 8 alkenyl, aryl-C 2 -C 8 alkenyl, heterocyclyl-C 2 -C 8 alkenyl, or heteroaryl-C 2 -C 8 alkenyl, each optionally independently substituted with one to three substituent groups;

(e) D is the —NH— group;

(f) E is the hydroxy group; and

(g) Q comprises a methylated benzoxazinone.

23 . The composition of claim 7 , wherein the DIGRA has Formula I, wherein

(b) R 1 and R 2 are each independently hydrogen or C 1 -C 5 alkyl, or R 1 and R 2 together with the carbon atom they are commonly attached to form a C 3 -C 8 spiro cycloalkyl ring;

(e) D is absent;

(f) E is the hydroxy group; and

(g) Q is an aryl or heteroaryl group one to three substituent groups, which are independently selected from the group consisting of C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 1 -C 3 alkanoyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1 -C 5 alkoxy, C 2 -C 5 alkenyloxy, C 2 -C 5 alkynyloxy, aryloxy, acyl, C 1 -C 5 alkoxycarbonyl, aroyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C 1 -C 5 alkylaminocarbonyloxy, C 1 -C 5 dialkylaminocarbonyloxy, C 1 -C 5 alkanoylamino, C 1 -C 5 alkoxycarbonylamino, C 1 -C 5 alkylsulfonylamino, aminosulfonyl, C 1 -C 5 alkylaminosulfonyl, C 1 -C 5 dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C 1 -C 5 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C 1 -C 5 alkyl, C 1 -C 5 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of Q is optionally independently substituted with one to three substituent groups selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 alkoxy, acyl, C 1 -C 3 silanyloxy, C 1 -C 5 alkoxycarbonyl, carboxy, halogen, hydroxy, oxo, cyano, heteroaryl, heterocyclyl, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C 1 -C 5 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C 1 -C 5 alkyl, and trifluoromethyl.

24 . The composition of claim 7 , wherein the DIGRA has Formula I, wherein

(a) A is an aryl, heteroaryl, or C 5 -C 15 cycloalkyl group, each optionally independently substituted with one to three substituent groups, which are independently selected from the group consisting of C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 1 -C 3 alkanoyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1 -C 5 alkoxy, C 2 -C 5 alkenyloxy, C 2 -C 5 alkynyloxy, aryloxy, acyl, C 1 -C 5 alkoxycarbonyl, aroyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C 1 -C 5 alkylaminocarbonyloxy, C 1 -C 5 dialkylaminocarbonyloxy, C 1 -C 5 alkanoylamino, C 1 -C 5 alkoxycarbonylamino, C 1 -C 5 alkylsulfonylamino, aminosulfonyl, C 1 -C 5 alkylaminosulfonyl, C 1 -C 5 dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C 1 -C 5 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C 1 -C 5 alkyl, C 1 -C 5 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone;

(b) R 1 and R 2 are each independently hydrogen, C 1 -C 5 alkyl, C 5 -C 15 arylalkyl, or R 1 and R 2 together with the carbon atom they are commonly attached to form a C 3 -C 8 spiro cycloalkyl ring;

(d) B is the carbonyl group or methylene group, which is optionally independently substituted with one or two substituent groups selected from C 1 -C 5 alkyl, hydroxy, and halogen;

(e) D is absent;

(f) E is the hydroxy group or amino group wherein the nitrogen atom is optionally independently mono- or di-substituted by C 1 -C 5 alkyl; and

(g) Q comprises a pyrrolidine, morpholine, thiomorpholine, piperazine, piperidine, 1H-pyridin-4-one, 1H-pyridin-2-one, 1H-pyridin-4-ylideneamine, 1H-quinolin-4-ylideneamine, pyran, tetrahydropyran, 1,4-diazepane, 2,5-diazabicyclo[2.2.1]heptane, 2,3,4,5-tetrahydrobenzo[b][1,4]diazepine, dihydroquinoline, tetrahydroquinoline, 5,6,7,8-tetrahydro-1H-quinolin-4-one, tetrahydroisoquinoline, decahydroisoquinoline, 2,3-dihydro-1H-isoindole, 2,3-dihydro-1H-indole, chroman, 1,2,3,4-tetrahydroquinoxaline, 1,2-dihydroindazol-3-one, 3,4-dihydro-2H-benzo[1,4]oxazine, 4H-benzo[1,4]thiazine, 3,4-dihydro-2H-benzo[1,4]thiazine, 1,2-dihydrobenzo[d][1,3]oxazin-4-one, 3,4-dihydrobenzo[1,4]oxazin-4-one, 3H-quinazolin-4-one, 3,4-dihydro-1H-quinoxalin-2-one, 1H-quinnolin-4-one, 1H-quinazolin-4-one, 1H-[1,5]naphthyridin-4-one, 5,6,7,8-tetrahydro-1H-[1,-5]naphthyridin-4-one, 2,3-dihydro-1H-[1,5]naphthyridin-4-one, 1,2-dihydropyrido[3,2-d][1,3]oxazin-4-one, pyrrolo[3,4-c]pyridine-1,3-dione, 1,2-dihydropyrrolo[3,4-c]pyridin-3-one, or tetrahydro[b][1,4]diazepinone group, each optionally independently substituted with one to three substituent groups, wherein each substituent group of Q is independently C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1 -C 5 alkoxy, C 2 -C 5 alkenyloxy, C 2 -C 5 alkynyloxy, aryloxy, acyl, C 1 -C 5 alkoxycarbonyl, C 1 -C 5 alkanoyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C 1 -C 5 alkylaminocarbonyloxy, C 1 -C 5 dialkylaminocarbonyloxy, C 1 -C 5 alkanoylamino, C 1 -C 5 alkoxycarbonylamino, C 1 -C 5 alkylsulfonylamino, C 1 -C 5 alkylaminosulfonyl, C 1 -C 5 dialkylaminosulfonyl, halogen, hydroxy, carboxy, oxo, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C 1 -C 5 alkyl, ureido wherein either nitrogen atom is optionally independently substituted with C 1 -C 5 alkyl, or C 1 -C 5 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of Q is optionally independently substituted with one to three substituent groups selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxycarbonyl, acyl, aryl, benzyl, heteroaryl, heterocyclyl, halogen, hydroxy, oxo, cyano, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C 1 -C 5 alkyl, or ureido wherein either nitrogen atom is optionally independently substituted with C 1 -C 5 alkyl.

25 . The composition of claim 7 , wherein the DIGRA has Formula I, wherein

(b) R 1 and R 2 are each independently hydrogen, C 1 -C 5 alkyl, C 5 -C 15 arylalkyl, or R 1 and R 2 together with the carbon atom they are commonly attached to form a C 3 -C 8 spiro cycloalkyl ring;

(c) R 3 is hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, carbocycle, heterocyclyl, aryl, heteroaryl, carbocycle-C 1 -C 8 alkyl, carboxy, alkoxycarbonyl, aryl-C 1 -C 8 alkyl, aryl-C 1 -C 8 haloalkyl, heterocyclyl-C 1 -C 8 alkyl, heteroaryl-C 1 -C 8 alkyl, carbocycle-C 2 -C 8 alkenyl, aryl-C 2 -C 8 alkenyl, heterocyclyl-C 2 -C 8 alkenyl, or heteroaryl-C 2 -C 8 alkenyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R 3 is independently C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 8 cycloalkyl, phenyl, C 1 -C 5 alkoxy, phenoxy, C 1 -C 5 alkanoyl, aroyl, C 1 -C 5 alkoxycarbonyl, C 1 -C 5 alkanoyloxy, aminocarbonyloxy, C 1 -C 5 alkylaminocarbonyloxy, C 1 -C 5 dialkylaminocarbonyloxy, aminocarbonyl, C 1 -C 5 alkylaminocarbonyl, C 1 -C 5 dialkylaminocarbonyl, C 1 -C 5 alkanoylamino, C 1 -C 5 alkoxycarbonylamino, C 1 -C 5 alkylsulfonylamino, C 1 -C 5 alkylaminosulfonyl, C 1 -C 5 dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, oxo, trifluoromethyl, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C 1 -C 5 alkyl, ureido wherein either nitrogen atom is optionally independently substituted with C 1 -C 5 alkyl, C 1 -C 5 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein R 3 cannot be trifluoromethyl;

(d) B is the carbonyl group or methylene group, which is optionally independently substituted with one or two substituent groups selected from C 1 -C 5 alkyl, hydroxy, and halogen;

(e) D is absent;

(f) E is the hydroxy group or amino group wherein the nitrogen atom is optionally independently mono- or di-substituted by C 1 -C 5 alkyl; and

26 . The composition of claim 7 , wherein the DIGRA has Formula I, wherein

(b) R 1 and R 2 are each independently hydrogen or C 1 -C 5 alkyl, or R 1 and R 2 together with the carbon atom they are commonly attached to form a C 3 -C 8 spiro cycloalkyl ring;

(d) B is the carbonyl group;

(e) D is the —NH— group;

(f) E is the hydroxy group; and

(g) Q comprises an optionally substituted phenyl group having the formula

wherein X 1 , X 2 , X 3 and X 4 are each independently selected from the group consisting of hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 1 -C 5 alkoxy, C 1 -C 5 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, C 1 -C 5 alkanoyl, C 1 -C 5 alkoxycarbonyl, C 1 -C 5 acyloxy, C 1 -C 5 alkanoylamino, C 1 -C 5 carbamoyloxy, urea, aryl, and amino wherein the nitrogen atom may be independently mono- or di-substituted by C 1 -C 5 alkyl, and wherein said aryl group is optionally substituted by one or more hydroxy or C 1 -C 5 alkoxy groups, and wherein either nitrogen atom of the urea group may be independently substituted by C 1 -C 5 alkyl; or Q is an aromatic 5- to 7-membered monocyclic ring having from one to four heteroatoms in the ring independently selected from nitrogen, oxygen, and sulfur, optionally independently substituted with one to three substituent groups selected from the group consisting of hydrogen, halogen, hydroxy, trifluoromethyl, trifluoromethoxy, C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 1 -C 5 alkoxy, C 1 -C 5 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, C 1 -C 5 alkanoyl, C 1 -C 5 alkoxycarbonyl, C 1 -C 5 acyloxy, C 1 -C 5 alkanoylamino, C 1 -C 5 carbamoyloxy, urea, aryl optionally substituted by one or more hydroxy or C 1 -C 5 alkoxy groups, and amino wherein the nitrogen atom may be independently mono- or di-substituted by C 1 -C 5 alkyl, and wherein either nitrogen atom of the urea group may be independently substituted by C 1 -C 5 alkyl.

27 . The composition of claim 7 , wherein the DIGRA has Formula I, wherein

(b) R 1 and R 2 are each independently hydrogen or C 1 -C 5 alkyl;

(c) R 3 is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, carbocycle, heterocyclyl, aryl, heteroaryl, carbocycle-C 1 -C 8 alkyl, aryl-C 1 -C 8 alkyl, aryl-C 1 -C 8 haloalkyl, heterocyclyl-C 1 -C 8 alkyl, heteroaryl-C 1 -C 8 alkyl, carbocycle-C 2 -C 8 alkenyl, aryl-C 2 -C 8 alkenyl, heterocyclyl-C 2 -C 8 alkenyl, or heteroaryl-C 2 -C 8 alkenyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R 3 is independently C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 8 cycloalkyl, phenyl, C 1 -C 5 alkoxy, phenoxy, C 1 -C 5 alkanoyl, aroyl, C 1 -C 5 alkoxycarbonyl, C 1 -C 5 alkanoyloxy, aminocarbonyloxy, C 1 -C 5 alkylaminocarbonyloxy, C 1 -C 5 dialkylaminocarbonyloxy, aminocarbonyl, C 1 -C 5 alkylaminocarbonyl, C 1 -C 5 dialkylaminocarbonyl, C 1 -C 5 alkanoylamino, C 1 -C 5 alkoxycarbonylamino, C 1 -C 5 alkylsulfonylamino, C 1 -C 5 alkylaminosulfonyl, C 1 -C 5 dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, oxo, trifluoromethyl, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C 1 -C 5 alkyl, ureido wherein either nitrogen atom is optionally independently substituted with C 1 -C 5 alkyl, or C 1 -C 5 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein R 3 cannot be trifluoromethyl;

(d) B is C 1 -C 5 alkylene, C 2 -C 5 alkenylene, or C 2 -C 5 alkynylene, each optionally independently substituted with one to three substituent groups, wherein each substituent group of B is independently C 1 -C 3 alkyl, hydroxy, halogen, amino, or oxo;

(e) D is absent;

(f) E is the hydroxy group; and

(g) Q comprises an azaindolyl group optionally independently substituted with one to three substituent groups, wherein each substituent group of Q is independently C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1 -C 5 alkoxy, C 2 -C 5 alkenyloxy, C 2 -C 5 alkynyloxy, aryloxy, acyl, C 1 -C 5 alkoxycarbonyl, C 1 -C 5 alkanoyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C 1 -C 5 alkylaminocarbonyloxy, C 1 -C 5 dialkylaminocarbonyloxy, C 1 -C 5 alkanoylamino, C 1 -C 5 alkoxycarbonylamino, C 1 -C 5 alkylsulfonylamino, aminosulfonyl, C 1 -C 5 alkylaminosulfonyl, C 1 -C 5 dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C 1 -C 5 alkyl, ureido wherein either nitrogen atom is optionally independently substituted with C 1 -C 5 alkyl, or C 1 -C 5 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of Q is optionally independently substituted with one to three substituent groups selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogen, hydroxy, oxo, cyano, amino, or trifluoromethyl.

28 . The composition of claim 7 , wherein the DIGRA has Formula I, wherein

(a) A is an aryl or heteroaryl group, each optionally independently substituted with one to three substituent groups, which are independently selected from the group consisting of C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 1 -C 3 alkanoyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1 -C 5 alkoxy, C 2 -C 5 alkenyloxy, C 2 -C 5 alkynyloxy, aryloxy, acyl, C 1 -C 5 alkoxycarbonyl, aroyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C 1 -C 5 alkylaminocarbonyloxy, C 1 -C 5 dialkylaminocarbonyloxy, C 1 -C 5 alkanoylamino, C 1 -C 5 alkoxycarbonylamino, C 1 -C 5 alkylsulfonylamino, aminosulfonyl, C 1 -C 5 alkylaminosulfonyl, C 1 -C 5 dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C 1 -C 8 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C 1 -C 5 alkyl, C 1 -C 5 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone;

(b) R 1 and R 2 are each independently hydrogen or C 1 -C 5 alkyl, or R 1 and R 2 together with the carbon atom they are commonly attached to form a C 3 -C 8 spiro cycloalkyl ring;

(e) D is absent;

(f) E is the hydroxy group; and

(g) Q comprises a heteroaryl group optionally independently substituted with one to three substituent groups, which are independently selected from the group consisting of C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 1 -C 3 alkanoyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1 -C 5 alkoxy, C 2 -C 5 alkenyloxy, C 2 -C 5 alkynyloxy, aryloxy, acyl, C 1 -C 5 alkoxycarbonyl, aroyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C 1 -C 5 alkylaminocarbonyloxy, C 1 -C 5 dialkylaminocarbonyloxy, C 1 -C 5 alkanoylamino, C 1 -C 5 alkoxycarbonylamino, C 1 -C 5 alkylsulfonylamino, aminosulfonyl, C 1 -C 5 alkylaminosulfonyl, C 1 -C 5 dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C 1 -C 5 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C 1 -C 5 alkyl, C 1 -C 5 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of Q is optionally independently substituted with one to three substituent groups selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 alkoxy, acyl, C 1 -C 3 silanyloxy, C 1 -C 5 alkoxycarbonyl, carboxy, halogen, hydroxy, oxo, cyano, heteroaryl, heterocyclyl, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C 1 -C 5 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C 1 -C 5 alkyl, or trifluoromethyl.

29 . The composition of claim 7 , wherein the DIGRA has Formula I, wherein

(b) R 1 and R 2 are each independently hydrogen or C 1 -C 5 alkyl;

(e) D is absent;

(f) E is the hydroxy group; and

30 . The composition of claim 7 , wherein the DIGRA has Formula I, wherein

(b) R 1 and R 2 are each independently C 1 -C 5 alkyl, wherein one or both are independently substituted with hydroxy, C 1 -C 5 alkoxy, C 1 -C 5 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C1-C5 alkyl or aryl;

(e) D is absent;

(f) E is the hydroxy group; and

31 . The composition of claim 7 , wherein the DIGRA has Formula I, wherein

(a) A is an aryl, heteroaryl, heterocyclyl, or C 3 -C 8 cycloalkyl group, each optionally independently substituted with one to three substituent groups, which are independently selected from the group consisting of C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 1 -C 3 alkanoyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1 -C 5 alkoxy, C 2 -C 5 alkenyloxy, C 2 -C 5 alkynyloxy, aryloxy, acyl, C 1 -C 5 alkoxycarbonyl, aroyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C 1 -C 5 alkylaminocarbonyloxy, C 1 -C 5 dialkylaminocarbonyloxy, C 1 -C 5 alkanoylamino, C 1 -C 5 alkoxycarbonylamino, C 1 -C 5 alkylsulfonylamino, aminosulfonyl, C 1 -C 5 alkylaminosulfonyl, C 1 -C 5 dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C 1 -C 5 alkyl or aryl, ureido wherein either nitrogen atom is optionally independently substituted with C 1 -C 5 alkyl, C 1 -C 5 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone;

(b) R 1 and R 2 are each independently hydrogen, C 1 -C 5 alkyl, C 5 -C 15 arylalkyl, or R 1 and R 2 together with the carbon atom they are commonly attached to form a C 3 -C 8 spiro cycloalkyl ring;

(c) B is the carbonyl group or methylene group, which is optionally independently substituted with one or two substituent groups selected from the group consisting of C 1 -C 3 alkyl, hydroxy, and halogen;

(d) R 3 is the trifluoromethyl group;

(e) D is absent;

(f) E is hydroxy group or amino group wherein the nitrogen atom is optionally independently mono- or di-substituted by C 1 -C 5 alkyl; and

(g) Q comprises a 5- to 7-membered heterocyclyl ring fused to a 5- to 7-membered heteroaryl or heterocyclyl ring, each optionally independently substituted with one to three substituent groups, wherein each substituent group of Q is independently C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1 -C 5 alkoxy, C 2 -C 5 alkenyloxy, C 2 -C 5 alkynyloxy, aryloxy, acyl, C 1 -C 5 alkoxycarbonyl, C 1 -C 5 alkanoyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C 1 -C 5 alkylaminocarbonyloxy, C 1 -C 5 dialkylaminocarbonyloxy, C 1 -C 5 alkanoylamino, C 1 -C 5 alkoxycarbonylamino, C 1 -C 5 alkylsulfonylamino, C 1 -C 5 alkylaminosulfonyl, C 1 -C 5 dialkylaminosulfonyl, halogen, hydroxy, carboxy, oxo, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C 1 -C 5 alkyl, ureido wherein either nitrogen atom is optionally independently substituted with C 1 -C 5 alkyl, or C 1 -C 5 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of Q is optionally independently substituted with one to three substituent groups selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkoxycarbonyl, acyl, aryl, benzyl, heteroaryl, heterocyclyl, halogen, hydroxy, oxo, cyano, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C 1 -C 5 alkyl, and ureido wherein either nitrogen atom is optionally independently substituted with C 1 -C 5 alkyl or trifluoromethyl, wherein Q cannot be 1H-[1,5]naphthyridin-4-one.

32 . The composition of claim 7 , wherein the DIGRA has Formula I, wherein

(b) R 1 and R 2 are each independently hydrogen, C 1 -C 5 alkyl, C 5 -C 15 arylalkyl, or R 1 and R 2 together with the carbon atom they are commonly attached to form a C 3 -C 8 spiro cycloalkyl ring;

(d) R 3 is hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, carbocycle, heterocyclyl, aryl, heteroaryl, carbocycle-C 1 -C 8 alkyl, carboxy, alkoxycarbonyl, aryl-C 1 -C 8 alkyl, aryl-C 1 -C 8 haloalkyl, heterocyclyl-C 1 -C 8 alkyl, heteroaryl-C 1 -C 8 alkyl, carbocycle-C 2 -C 8 alkenyl, aryl-C 2 -C 8 alkenyl, heterocyclyl-C 2 -C 8 alkenyl, or heteroaryl-C 2 -C 8 alkenyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R 3 is independently C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 8 cycloalkyl, phenyl, C 1 -C 5 alkoxy, phenoxy, C 1 -C 5 alkanoyl, aroyl, C 1 -C 5 alkoxycarbonyl, C 1 -C 5 alkanoyloxy, aminocarbonyloxy, C 1 -C 5 alkylaminocarbonyloxy, C 1 -C 5 dialkylaminocarbonyloxy, aminocarbonyl, C 1 -C 5 alkylaminocarbonyl, C 1 -C 5 dialkylaminocarbonyl, C 1 -C 5 alkanoylamino, C 1 -C 5 alkoxycarbonylamino, C 1 -C 5 alkylsulfonylamino, C 1 -C 5 alkylaminosulfonyl, C 1 -C 5 dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, oxo, trifluoromethyl, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C 1 -C 5 alkyl, ureido wherein either nitrogen atom is optionally independently substituted with C 1 -C 5 alkyl, C 1 -C 5 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein R 3 cannot be trifluoromethyl;

(e) D is absent;

(f) E is hydroxy group or amino group wherein the nitrogen atom is optionally independently mono- or di-substituted by C 1 -C 5 alkyl; and

33 . The composition of claim 7 , wherein the DIGRA has Formula I, wherein

(b) R 1 and R 2 are each independently hydrogen or C 1 -C 5 alkyl;

(e) D is absent;

(f) E is the hydroxy group; and

(g) Q comprises an indolyl group optionally substituted with one to three substituent groups, wherein each substituent group of Q is independently C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1 -C 5 alkoxy, C 2 -C 5 alkenyloxy, C 2 -C 5 alkynyloxy, aryloxy, acyl, C 1 -C 5 alkoxycarbonyl, C 1 -C 5 alkanoyloxy, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonyloxy, C 1 -C 5 alkylaminocarbonyloxy, C 1 -C 5 dialkylaminocarbonyloxy, C 1 -C 5 alkanoylamino, C 1 -C 5 alkoxycarbonylamino, C 1 -C 5 alkylsulfonylamino, aminosulfonyl, C 1 -C 5 alkylaminosulfonyl, C 1 -C 5 dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C 1 -C 5 alkyl, ureido wherein either nitrogen atom is optionally independently substituted with C 1 -C 5 alkyl, or C 1 -C 5 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of Q is optionally independently substituted with one to three substituent groups selected from the group consisting of C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogen, hydroxy, oxo, cyano, amino, and trifluoromethyl.

34 . The composition of claim 7 , wherein the DIGRA has Formula I, wherein

(b) R 1 and R 2 are each independently hydrogen or C 1 -C 5 alkyl, or R 1 and R 2 together with the carbon atom they are commonly attached to form a C 3 -C 8 spiro cycloalkyl ring;

(c) R 3 is carbocycle, heterocyclyl, aryl, heteroaryl, carbocycle-C 1 -C 8 alkyl, carboxy, alkoxycarbonyl, aryl-C 1 -C 8 alkyl, aryl-C 1 -C 8 haloalkyl, heterocyclyl-C 1 -C 8 alkyl, heteroaryl-C 1 -C 8 alkyl, carbocycle-C 2 -C 8 alkenyl, aryl-C 2 -C 8 alkenyl, heterocyclyl-C 2 -C 8 alkenyl, or heteroaryl-C 2 -C 8 alkenyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R 3 is independently C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 8 cycloalkyl, phenyl, C 1 -C 5 alkoxy, phenoxy, C 1 -C 5 alkanoyl, aroyl, C 1 -C 5 alkoxycarbonyl, C 1 -C 5 alkanoyloxy, aminocarbonyloxy, C 1 -C 5 alkylaminocarbonyloxy, C 1 -C 5 dialkylaminocarbonyloxy, aminocarbonyl, C 1 -C 5 alkylaminocarbonyl, C 1 -C 5 dialkylaminocarbonyl, C 1 -C 5 alkanoylamino, C 1 -C 5 alkoxycarbonylamino, C 1 -C 5 alkylsulfonylamino, C 1 -C 5 alkylaminosulfonyl, C 1 -C 5 dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, oxo, trifluoromethyl, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C 1 -C 5 alkyl, ureido wherein either nitrogen atom is optionally independently substituted with C 1 -C 5 alkyl, C 1 -C 5 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone;

(d) B is the methylene or carbonyl group;

(e) D is the —NH— group;

(f) E is the hydroxy group; and

(g) Q comprises the group

35 . The composition of claim 7 , wherein the DIGRA has Formula I, wherein

(b) R 1 and R 2 are each independently hydrogen or C 1 -C 5 alkyl, or R 1 and R 2 together with the carbon atom they are commonly attached to form a C 3 -C 8 spiro cycloalkyl ring;

(e) D is absent;

(f) E is —NR 6 R 7 , wherein R 6 and R 7 are each independently hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 alkoxy, C 2 -C 8 alkenyloxy, C 2 -C 8 alkynyloxy, hydroxy, carbocyclyl, heterocyclyl, aryl, aryloxy, acyl, heteroaryl, carbocycle-C 1 -C 8 alkyl, aryl-C 1 -C 8 alkyl, aryl-C 1 -C 8 haloalkyl, heterocyclyl-C 1 -C 8 alkyl, heteroaryl-C 1 -C 8 alkyl, carbocycle-C 2 -C 8 alkenyl, aryl-C 2 -C 8 alkenyl, heterocyclyl-C 2 -C 8 alkenyl, heteroaryl-C 2 -C 8 alkenyl, or C 1 -C 5 alkylthio wherein the sulfur atom is oxidized to a sulfoxide or sulfone, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R 6 and R 7 are independently C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 8 cycloalkyl, phenyl, C 1 -C 5 alkoxy, phenoxy, C 1 -C 5 alkanoyl, aroyl, C 1 -C 5 alkoxycarbonyl, C 1 -C 5 alkanoyloxy, aminocarbonyl, C 1 -C 5 alkylaminocarbonyl, C 1 -C 5 dialkylaminocarbonyl, aminocarbonyloxy, C 1 -C 5 alkylaminocarbonyloxy, C 1 -C 5 dialkylaminocarbonyloxy, C 1 -C 5 alkanoylamino, C 1 -C 5 alkoxycarbonylamino, C 1 -C 5 alkylsulfonylamino, aminosulfonyl, C 1 -C 5 alkylaminosulfonyl, C 1 -C 5 dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, oxo, trifluoromethyl, trifluoromethoxy, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C 1 -C 5 alkyl, ureido wherein either nitrogen atom is optionally independently substituted with C 1 -C 5 alkyl, or C 1 -C 5 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone; and

(g) Q comprises a heteroaryl group optionally independently substituted with one to three substituent groups, wherein each substituent group of Q is independently C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 1 -C 5 alkoxy, C 2 -C 5 alkenyloxy, C 2 -C 5 alkynyloxy, aryloxy, acyl, C 1 -C 5 alkoxycarbonyl, C 1 -C 5 alkanoyloxy, aminocarbonyl, C 1 -C 5 alkylaminocarbonyl, C 1 -C 5 dialkylaminocarbonyl, aminocarbonyloxy, C 1 -C 5 alkylaminocarbonyloxy, C 1 -C 5 dialkylaminocarbonyloxy, C 1 -C 5 alkanoylamino, C 1 -C 5 alkoxycarbonylamino, C 1 -C 5 alkylsulfonylamino, aminosulfonyl, C 1 -C 5 alkylaminosulfonyl, C 1 -C 5 dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, trifluoromethyl, trifluoromethoxy, trifluoromethylthio, nitro, or amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C 1 -C 5 alkyl; or ureido wherein either nitrogen atom is optionally independently substituted with C 1 -C 5 alkyl; or C 1 -C 5 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein each substituent group of Q is optionally independently substituted with one to three substituent groups selected from C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halogen, hydroxy, oxo, cyano, amino, or trifluoromethyl.

36 . The composition of claim 7 , wherein the DIGRA has Formula I, wherein

(b) R 1 and R 2 are each independently hydrogen or C 1 -C 5 alkyl, or R 1 and R 2 together with the carbon atom they are commonly attached to form a C 3 -C 8 spiro cycloalkyl ring;

(c) R 3 is C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, carbocycle, heterocyclyl, aryl, heteroaryl, carbocycle-C 1 -C 8 alkyl, carboxy, alkoxycarbonyl, aryl-C 1 -C 8 alkyl, aryl-C 1 -C 8 haloalkyl, heterocyclyl-C 1 -C 8 alkyl, heteroaryl-C 1 -C 8 alkyl, carbocycle-C 2 -C 8 alkenyl, aryl-C 2 -C 8 alkenyl, heterocyclyl-C 2 -C 8 alkenyl, or heteroaryl-C 2 -C 8 alkenyl, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R 3 is independently C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 8 cycloalkyl, phenyl, C 1 -C 5 alkoxy, phenoxy, C 1 -C 5 alkanoyl, aroyl, C 1 -C 5 alkoxycarbonyl, C 1 -C 5 alkanoyloxy, aminocarbonyloxy, C 1 -C 5 alkylaminocarbonyloxy, C 1 -C 5 dialkylaminocarbonyloxy, aminocarbonyl, C 1 -C 5 alkylaminocarbonyl, C 1 -C 5 dialkylaminocarbonyl, C 1 -C 5 alkanoylamino, C 1 -C 5 alkoxycarbonylamino, C 1 -C 5 alkylsulfonylamino, C 1 -C 5 alkylaminosulfonyl, C 1 -C 5 dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, oxo, trifluoromethyl, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C 1 -C 5 alkyl, ureido wherein either nitrogen atom is optionally independently substituted with C 1 -C 5 alkyl, C 1 -C 5 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone, wherein R 3 cannot be trifluoromethyl;

(e) D is absent;

(f) E is —NR 6 R 7 , wherein R 6 and R 7 are each independently hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, C 1 -C 8 alkoxy, C 2 -C 8 alkenyloxy, C 2 -C 8 alkynyloxy, hydroxy, carbocyclyl, heterocyclyl, aryl, aryloxy, acyl, heteroaryl, carbocycle-C 1 -C 8 alkyl, aryl-C 1 -C 8 alkyl, aryl-C 1 -C 8 haloalkyl, heterocyclyl-C 1 -C 8 alkyl, heteroaryl-C 1 -C 8 alkyl, carbocycle-C 2 -C 8 alkenyl, aryl-C 2 -C 8 alkenyl, heterocyclyl-C 2 -C 8 alkenyl, heteroaryl-C 2 -C 5 alkenyl, or C 1 -C 5 alkylthio wherein the sulfur atom is oxidized to a sulfoxide or sulfone, each optionally independently substituted with one to three substituent groups, wherein each substituent group of R 6 and R 7 are independently C 1 -C 5 alkyl, C 2 -C 5 alkenyl, C 2 -C 5 alkynyl, C 3 -C 8 cycloalkyl, phenyl, C 1 -C 5 alkoxy, phenoxy, C 1 -C 5 alkanoyl, aroyl, C 1 -C 5 alkoxycarbonyl, C 1 -C 5 alkanoyloxy, aminocarbonyl, C 1 -C 5 alkylaminocarbonyl, C 1 -C 5 dialkylaminocarbonyl, aminocarbonyloxy, C 1 -C 5 alkylaminocarbonyloxy, C 1 -C 5 dialkylaminocarbonyloxy, C 1 -C 5 alkanoylamino, C 1 -C 5 alkoxycarbonylamino, C 1 -C 5 alkylsulfonylamino, aminosulfonyl, C 1 -C 5 alkylaminosulfonyl, C 1 -C 5 dialkylaminosulfonyl, halogen, hydroxy, carboxy, cyano, oxo, trifluoromethyl, trifluoromethoxy, nitro, amino wherein the nitrogen atom is optionally independently mono- or di-substituted by C 1 -C 5 alkyl, ureido wherein either nitrogen atom is optionally independently substituted with C 1 -C 5 alkyl, or C 1 -C 5 alkylthio wherein the sulfur atom is optionally oxidized to a sulfoxide or sulfone; and

37 . The composition of claim 7 , further comprising an additional anti-inflammatory agent selected from the group consisting of NSAIDs, PPAR ligands, combinations thereof, and mixtures thereof.

38 . The composition of claim 10 , further comprising an additional anti-inflammatory agent selected from the group consisting of NSAIDs, PPAR ligands, combinations thereof, and mixtures thereof.

39 . The composition of claim 38 , wherein said additional anti-inflammatory agent comprises a PPAR ligand.

40 . The composition of claim 16 , further comprising an additional anti-inflammatory agent selected from the group consisting of NSAIDs, PPAR ligands, combinations thereof, and mixtures thereof.

41 . The composition of claim 17 , further comprising an additional anti-inflammatory agent selected from the group consisting of NSAIDs, PPAR ligands, combinations thereof, and mixtures thereof.

42 . The composition of claim 19 , further comprising an additional anti-inflammatory agent selected from the group consisting of NSAIDs, PPAR ligands, combinations thereof, and mixtures thereof.

43 . The composition of claim 41 , wherein said additional anti-inflammatory agent comprises a PPAR ligand.

44 . The composition of claim 42 , wherein said additional anti-inflammatory agent comprises a PPAR ligand.

45 . A method for treating, controlling, reducing, ameliorating, or alleviating an infection and sequelae thereof, the method comprising: (a) providing a composition comprising: (i) a DIGRA, a prodrug thereof, or a pharmaceutically acceptable salt thereof; and (ii) an anti-infective agent; and (b) administering to a subject an amount of the composition at a frequency sufficient to treat, control, reduce, ameliorate, or alleviate the condition or disorder in the subject.

46 . The method of claim 45 , wherein the DIGRA has Formula I

47 . The method of claim 46 , wherein the composition further comprises an additional anti-inflammatory agent.

48 . The method of claim 47 , wherein said additional anti-inflammatory agent is selected from the group consisting of NSAIDs, PPAR ligands, combinations thereof, and mixtures thereof.

49 . The method of claim 46 , wherein the composition comprises a composition of claim 6 .

50 . The method of claim 46 , wherein the composition comprises a composition of claim 7 .

51 . The method of claim 46 , wherein the composition comprises a composition of claim 10 .

52 . The method of claim 46 , wherein the composition comprises a composition of claim 11 .

53 . The method of claim 46 , wherein the composition comprises a composition of claim 12 .

54 . The method of claim 46 , wherein the composition comprises a composition of claim 13 .

55 . The method of claim 46 , wherein the composition comprises a composition of claim 14 .

56 . The method of claim 46 , wherein the composition comprises a composition of claim 15 .

57 . The method of claim 46 , wherein the composition comprises a composition of claim 16 .

58 . The method of claim 46 , wherein the composition comprises a composition of claim 17 .

59 . The method of claim 46 , wherein the composition comprises a composition of claim 18 .

60 . The method of claim 46 , wherein the composition comprises a composition of claim 19 .

61 . The method of claim 46 , wherein the composition comprises a composition of claim 20 .

62 . The method of claim 46 , wherein the composition comprises a composition of claim 21 .

63 . The method of claim 46 , wherein the composition comprises a composition of claim 22 .

64 . The method of claim 46 , wherein the composition comprises a composition of claim 23 .

65 . The method of claim 46 , wherein the composition comprises a composition of claim 24 .

66 . The method of claim 46 , wherein the composition comprises a composition of claim 25 .

67 . The method of claim 46 , wherein the composition comprises a composition of claim 26 .

68 . The method of claim 46 , wherein the composition comprises a composition of claim 27 .

69 . The method of claim 46 , wherein the composition comprises a composition of claim 28 .

70 . The method of claim 46 , wherein the composition comprises a composition of claim 29 .

71 . The method of claim 46 , wherein the composition comprises a composition of claim 30 .

72 . The method of claim 46 , wherein the composition comprises a composition of claim 31 .

73 . The method of claim 46 , wherein the composition comprises a composition of claim 32 .

74 . The method of claim 46 , wherein the composition comprises a composition of claim 33 .

75 . The method of claim 46 , wherein the composition comprises a composition of claim 34 .

76 . The method of claim 46 , wherein the composition comprises a composition of claim 35 .

77 . The method of claim 46 , wherein the composition comprises a composition of claim 36 .

78 . Use of a DIGRA, a prodrug thereof, or a pharmaceutically acceptable salt thereof and an anti-infective agent to produce a composition for treating an infection and inflammatory sequelae thereof.

79 . The use of claim 78 , further including the use of an additional anti-inflammatory agent other than a DIGRA, prodrugs thereof, and pharmaceutically acceptable salts thereof.

80 . A method for manufacturing a composition for treating an infection and inflammatory sequelae thereof, the method comprising:

(a) providing a DIGRA, a prodrug thereof, or a pharmaceutically acceptable salt thereof;

(b) providing an anti-infective agent; and

(c) combining (i) said DIGRA, prodrug thereof, or pharmaceutically acceptable salt thereof; and (ii) said anti-infective agent with a pharmaceutically acceptable carrier.

81 . The method of claim 80 , wherein the DIGRA has Formula I

82 . The method of claim 80 , wherein the DIGRA has Formula I

wherein A and Q are independently selected from the group consisting of aryl and heteroaryl groups substituted with at least a halogen atom, cyano group, hydroxy group, or C 1 -C 10 alkoxy group; R 1 , R 2 , and R 3 are independently selected from the group consisting of unsubstituted and substituted C 1 -C 5 alkyl groups; B is a C 1 -C 5 alkylene group; D is the —NH— or —NR′-group, wherein R′ is a C 1 -C 5 alkyl group; and E is the hydroxy group.

83 . The method of claim 80 , wherein the DIGRA has Formula I

84 . The method of claim 80 , wherein the DIGRA has Formula II

85 . The method of claim 80 , wherein the DIGRA has Formula III

86 . The method of claim 80 , wherein the DIGRA has Formula IV

Assignments (8)

RELEASE OF SECURITY INTEREST Recorded Apr 8, 2025

From: BARCLAYS BANK PLC, AS COLLATERAL AGENT

To: SOLTA MEDICAL, INC.; PRECISION DERMATOLOGY, INC.; BAUSCH HEALTH IRELAND LIMITED (F/K/A/ VALEANT PHARMACEUTICALS IRELAND LIMITED); SALIX PHARMACEUTICALS, INC.; SALIX PHARMACEUTICALS, LTD; SANTARUS, INC.; MEDICIS PHARMACEUTICAL CORPORATION; HUMAX PHARMACEUTICAL S.A.; SOLTA MEDICAL IRELAND LIMITED; BAUSCH & LOMB MEXICO, S.A. DE C.V.; BAUSCH+LOMB OPS B.V.; BAUSCH HEALTH AMERICAS, INC.; BAUSCH HEALTH COMPANIES INC.; BAUSCH HEALTH HOLDCO LIMITED; BAUSCH HEALTH MAGYARORSZAG KFT (A/K/A BAUSCH HEALTH HUNGARY LLC); BAUSCH HEALTH POLAND SPOLKA Z OGRANICZONA ODPOWIEDZIALNOSCIA (F/K/A VALEANT PHARMA POLAND SPOLKA Z OGRANICZONA ODPOWIEDZIALNOSCIA); BAUSCH HEALTH US, LLC; BAUSCH HEALTH, CANADA INC. / SANTE BAUSCH, CANADA INC.; ICN POLFA RZESZOW SPOLKA AKCYJNA (A/K/A ICN POLFA RZESZOW S.A.); ORAPHARMA, INC.; PRZEDSIEBIORSTWO FARMACEUTYCZNE JELFA SPOLKA AKCYJNA (A/K/A PRZEDSIEBIORSTWO FARMACEUTYCZNE JELFA S.A.); SOLTA MEDICAL DUTCH HOLDINGS B.V.; V-BAC HOLDING CORP.; VRX HOLDCO LLC; 1261229 B.C. LTD.; 1530065 B.C. LTD.

Reel/Frame 070778/0199 →

NOTICE OF SUCCESSION OF AGENCY Recorded Jan 9, 2015

From: GOLDMAN SACHS LENDING PARTNERS, LLC

To: BARCLAYS BANK PLC, AS SUCCESSOR AGENT

Reel/Frame 034749/0689 →

SECURITY AGREEMENT Recorded Sep 4, 2013

From: BAUSCH & LOMB INCORPORATED

To: GOLDMAN SACHS LENDING PARTNERS LLC, AS COLLATERAL AGENT

Reel/Frame 031156/0508 →

RELEASE OF SECURITY INTEREST Recorded Aug 13, 2013

From: CITIBANK N.A., AS ADMINISTRATIVE AGENT

To: WP PRISM INC. (N/K/A BAUSCH & LOMB HOLDINGS INC.); BAUSCH & LOMB INCORPORATED; ISTA PHARMACEUTICALS

Reel/Frame 030995/0444 →

SECURITY AGREEMENT Recorded Aug 6, 2012

From: BAUSCH & LOMB INCORPORATED; EYEONICS, INC.

To: CITIBANK N.A., AS ADMINISTRATIVE AGENT

Reel/Frame 028728/0645 →

RELEASE OF SECURITY INTEREST Recorded Aug 5, 2012

From: CREDIT SUISSE AG, CAYMAN ISLANDS BRANCH

To: BAUSCH & LOMB INCORPORATED

Reel/Frame 028726/0142 →

SECURITY AGREEMENT Recorded Nov 16, 2007

From: BAUSCH & LOMB INCORPORATED; B&L CRL INC.; B&L CRL PARTNERS L.P.; B & L DOMESTIC HOLDINGS CORP.; B&L FINANCIAL HOLDINGS CORP.; B&L SPAF INC.; B&L VPLEX HOLDINGS, INC.; BAUSCH & LOMB CHINA, INC.; BAUSCH & LOMB INTERNATIONAL INC.; BAUSCH & LOMB TECHNOLOGY CORPORATION; BAUSCH & LOMB REALTY CORPORATION; BAUSCH & LOMB SOUTH ASIA, INC.; SIGHT SAVERS, INC.; WILMINGTON MANAGEMENT CORP.; WILMINGTON PARTNERS L.P.; B&L MINORITY DUTCH HOLDINGS LLC; IOLAB CORPORATION; RHC HOLDINGS, INC.; WP PRISM, INC.

To: CREDIT SUISSE

Reel/Frame 020122/0722 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 1, 2007

From: WARD, KEITH W.; HU, ZHENZE; PHILLIPS, GARY; KERPPOLA, RAILI

To: BAUSCH & LOMB INCORPORATED

Reel/Frame 019630/0399 →