# US 12,109,263 B2 · Integrin agonists or activating compounds and methods for making and using same

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- Number: US 12,109,263 B2
- Document ID: US12109263B2
- Status: Granted
- Kind: B2
- Application number: 17/471,922
- Filed: 2021-09-10
- Published: 2022-04-21
- Granted: 2024-10-08
- Earliest claimed: 2020-09-10
- Applicants: 7 Hills Pharma LLC
- Inventors: Robert W Strozier
- Web page: https://patentgrep.com/patent/US12109263B2

## CPC

- A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants
- A61K 31/16: Amides, e.g. hydroxamic acids
- A61K 31/381: having five-membered rings
- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/4436: containing a heterocyclic ring having sulfur as a ring hetero atom
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 39/0011: {Cancer antigens}
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61P 35/00: Antineoplastic agents
- A61P 37/04: Immunostimulants
- A61K 2039/55511: {Organic adjuvants}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Small molecule integrin agonists or integrin activating compounds including at least one di-alkylaryl amine end group and at least one alkyl or alkenoxy linking group including at least one protonatable moiety, wherein the compounds enhance vaccine efficacies, enhance adoptive cell therapy efficacies, enhance immunotherapy efficacies, enhance therapeutic antibody therapy efficacies, enhance checkpoint inhibitor therapy efficacies, enhance effector cell therapy efficacies, and enhanced cell based transplant efficacies and wherein at protonatable moiety either protonate at biological pHs or bears a charge with associated pharmaceutically acceptable counterion making the compound water soluble to improve bioavailability and methods for making and using same.

## Claims

### Claim 1

A composition comprising:
one or more antigens, and
one or more integrin activating or agonist compounds of the general Formulas:
wherein:
the R1 and R2 groups are independently a —(CH2)-aryl group, or a —(CH2)-heterocyclylaryl group, or the R1 and R2 groups combine to form a fused heterocyclylaryl group including at least one nitrogen-containing aryl group, and
n independently is an integer having a value between 1 and 6;
wherein:
the R1 and R2 groups are independently a —(CH2)-aryl group, or a —(CH2)-heterocyclylaryl group, or the R1 and R2 groups combine to form a fused heterocyclylaryl group including at least one nitrogen-containing aryl group, and
n independently is an integer having a value between 1 and 6;
wherein:
the R1 and R2 groups are independently a —(CH2)-aryl group, or a —(CH2)-heterocyclylaryl group, or the R1 and R2 groups combine to form a fused heterocyclylaryl group including at least one nitrogen-containing aryl group, and
n independently is an integer having a value between 1 and 6;
wherein:
the R1 and R2 groups are independently a —(CH2)-aryl group, or a —(CH2)-heterocyclylaryl group, or the R1 and R2 groups combine to form a fused heterocyclylaryl group including at least one nitrogen-containing aryl group, and
n independently is an integer having a value between 1 and 6;
wherein:
the R1 and R2 groups are independently a —(CH2)-aryl group, or a —(CH2)-heterocyclylaryl group, or the R1 and R2 groups combine to form a fused heterocyclylaryl group including at least one nitrogen-containing aryl group, and
n independently is an integer having a value between 1 and 6;
wherein:
the R1 and R2 groups are independently a —(CH2)-aryl group, or a —(CH2)-heterocyclylaryl group, or the R1 and R2 groups combine to form a fused heterocyclylaryl group including at least one nitrogen-containing aryl group, and
n independently is an integer having a value between 1 and 6;
wherein:
the R1 and R2 groups are independently a —(CH2)-aryl group, or a —(CH2)-heterocyclylaryl group, or the R1 and R2 groups combine to form a fused heterocyclylaryl group including at least one nitrogen-containing aryl group, and
n independently is an integer having a value between 1 and 6; and
wherein:
the R1 and R2 groups are independently a —(CH2)-aryl group, or a —(CH2)-heterocyclylaryl group, or the R1 and R2 groups combine to form a fused heterocyclylaryl group including at least one nitrogen-containing aryl group, and
n independently is an integer having a value between 1 and 6,
wherein:
the one or more integrin activating or agonist compounds may be administered before, during, and/or after the administration of the one or more antigens, and
the one or more integrin activating or agonist compounds activate one or more integrins.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the integrins are selected from the group consisting of α4β1, α4β7, α5β1, αLβ2, and combinations thereof.

### Claim 3 (depends on 1)

The composition of claim 1, wherein the one or more antigens comprise one or more anti-cancer antigens.

### Claim 4 (depends on 1)

The composition of claim 1, further comprising:
a pharmaceutically acceptable carrier.

### Claim 5 (depends on 1)

The composition of claim 1, wherein the one or more integrin activating or agonist compounds are present in an agonist molar amount between about 1 femtomolar (fM) and about 300 micromolar (μM).

### Claim 6 (depends on 1)

The composition of claim 1, wherein the one or more integrin activating or agonist compounds of Formula (IIIb) are selected from the group consisting of: (a) 2-[bis(thenyl)aminocarbonyloxyethoxy],6-[bis(thenyl)aminocarbonyl oxyethoxy]pyridine, (b) 2-[bis(thenyl)aminocarbonyloxyethoxyethoxy],6-[bis(thenyl) aminocarbonyloxyethoxyethoxy]pyridine, (c) 2-[bis(3-methoxybenzyl)aminocarbonyl oxyethoxy],6-[bis(3-methoxybenzyl) aminocarbonyloxy ethoxy]pyridine, (d) 2-[bis(3-methoxybenzyl)aminocarbonyloxyethoxyethoxy],6-[bis(3-methoxy benzyl)aminocarbonyloxyethoxyethoxy]pyridine, (e) 2-[(3-methoxybenzyl)(4-dimethylaminobenzyl) aminocarbonyloxyethoxy],6-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyl oxyethoxy]pyridine, (f) 2-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy ethoxyethoxy], 6-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy ethoxy]pyridine, (g) 2-[bis(4-methoxybenzyl)aminocarbonyloxyethoxy],6-[bis(4-methoxy benzyl)aminocarbonyloxyethoxy]pyridine, (h) 2-[bis(4-methoxybenzyl)amino carbonyloxyethoxyethoxy],6-[bis(4-methoxybenzyl)aminocarbonyloxyethoxyethoxy]pyridine, (i) 2-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy], 6-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy]pyridine, (j) 2-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy], 6-[(4-methoxybenzyl)(4-dimethyl aminobenzyl)aminocarbonyloxyethoxyethoxy]pyridine, (k) 2-{6-[2-(9H-carbazol-9-yl-carbonyloxy)ethoxy]-2-pyridyloxy} ethyl-9H-carbazole-9-carboxylate, (1) 2-[2-(6-{2-[2-(9-carbazolylcarbonyloxy)ethoxy]ethoxy}-2-pyridyloxy)ethoxy]ethyl 9-carbazolecarboxylate, (m) 2-{6-[2-(3,6-dimethoxy-9H-carbazol-9-yl carbonyloxy)ethoxy]-2-pyridyloxy}ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, (n) 2-[2-(6-{2-[2-(3,6-dimethoxy-9-carbazolylcarbonyloxy)ethoxy]ethoxy}-2-pyridyloxy)ethoxy]ethyl 3,6-dimethoxy-9-carbazolecarboxylate, and (o) combinations thereof.

### Claim 7 (depends on 1)

The composition of claim 1, wherein the one or more integrin activating or agonist compounds of Formula (IVb) are selected from the group consisting of: (a) 2-[({bis[(2-thienyl)methyl]aminocarbonyloxy} ethoxy)methyl]-6-[({bis [(2-thienyl)methyl]amino carbonyloxy} ethoxy)methyl]pyridine, (b) 2-[({bis[(2-thienyl)methyl]aminocarbonyloxy} ethoxyethoxy)methyl]-6-[({bis[(2-thienyl) methyl]aminocarbonyloxy} ethoxyethoxy)methyl]pyridine, (c) 2-[({bis(3-methoxybenzyl)aminocarbonyloxy} ethoxy)methyl]-6-[({bis(3-methoxybenzyl)amino carbonyloxy} ethoxy)methyl]pyridine, (d) 2-[({bis(3-methoxybenzyl)aminocarbonyloxy} ethoxyethoxy)methyl]-6-[({bis(3-methoxybenzyl)aminocarbonyloxy} ethoxyethoxy) methyl]pyridine, (e) 2-[({(3-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyl oxy} ethoxy)methyl]-6-[({(3-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyl oxy}ethoxy)methyl]pyridine, (f) 2-[({(3-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyloxy} ethoxyethoxy)methyl]-6-[({(3-methoxybenzyl,4-dimethylamino benzyl)aminocarbonyloxy} ethoxyethoxy)methyl]pyridine, (g) 2-[({bis(4-methoxybenzyl)aminocarbonyloxy} ethoxy)methyl]-6-[({bis(4-methoxybenzyl) aminocarbonyloxy} ethoxy)methyl]pyridine, (h) 2-[({{bis(4-methoxybenzyl)aminocarbonyloxy} ethoxyethoxy)methyl]-6-[({{bis(4-methoxybenzyl)aminocarbonyloxy} ethoxyethoxy)methyl] pyridine, (i) 2-[({(4-methoxybenzyl,4-dimethylaminobenzyl) aminocarbonyloxy} ethoxy)methyl]-6-[({(4-methoxybenzyl,4-dimethylaminobenzyl)amino carbonyloxy}ethoxy)methyl]pyridine, (j) 2-[({(4-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyloxy} ethoxyethoxy)methyl]-6-[({(4-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyloxy}ethoxyethoxy)methyl] pyridine, (k) 2-[(6-{[2-(9H-carbazol-9-ylcarbonyloxy)ethoxy]methyl}-2-pyridyl)methoxy]ethyl 9H-carbazole-9-carboxylate, (1) 2-(2-{[6-({2-[2-(9H-carbazolylcarbonyloxy)ethoxy]ethoxy} methyl)-2-pyridyl]methoxy} ethoxy)ethyl 9-carbazolecarboxylate, (m) 2-[(6-{[2-(3,6-dimethoxy-9H-carbazol-9-ylcarbonyloxy)ethoxy]methyl}-2-pyridyl)methoxy]ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, (n) 2-(2-{[6-({2-[2-(3,6-dimethoxy-9H-carbazolylcarbonyloxy) ethoxy]ethoxy} methyl)-2-pyridyl]methoxy} ethoxy)ethyl 3,6-dimethoxy-9-carbazolecarboxylate, and (o) combinations thereof.

### Claim 8 (depends on 1)

The composition of claim 1, wherein the one or more integrin activating or agonist compounds of Formula (IVb) are selected from the group consisting of: (a) 3-[bis(thenyl)aminocarbonyloxyethoxy],5-[bis(thenyl)aminocarbonyloxy ethoxy]pyridine, (b) 3-[bis(thenyl)aminocarbonyloxyethyoxyethoxy],5-[bis(thenyl) aminocarbonyloxyethyoxy ethoxy]pyridine, (c) 3-[bis(3-methoxybenzyl)aminocarbonyloxyethoxy], 5-[bis(3-methoxybenzyl)aminocarbonyloxyethoxy]pyridine, (d) 3-[bis(3-methoxybenzyl)amino carbonyloxyethoxyethoxy],5-[bis(3-methoxybenzyl)aminocarbonyloxy ethoxyethoxy]pyridine, (e) 3-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy],5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy]pyridine, (f) 3-[(3-methoxybenzyl)(4-dimethyl aminobenzyl)aminocarbonyloxyethoxy],5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)amino carbonyloxyethoxy]pyridine, (g) 3-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy ethoxyethoxy],5-[(4-methoxybenzyl)(4-dimethylaminobenzyl) aminocarbonyloxy ethoxyethoxy]pyridine, (h) 3-[bis(4-methoxybenzyl)aminocarbonyloxyethoxy],5-[bis(4-methoxybenzyl)amino carbonyloxyethoxy]pyridine, (i) 3-[bis(3-methoxybenzyl)aminocarbonyloxy ethoxyethoxy],5-[bis(3-methoxybenzyl)aminocarbonyloxyethoxyethoxy]pyridine, (j) 3-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy],5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy]pyridine, (k) 3-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy], 5-[(4-methoxybenzyl)(4-dimethylaminobenzyl) aminocarbonyloxyethoxyethoxy]pyridine, (1) 2-{5-[2-(9H-carbazol-9-ylcarbonyloxy)ethoxy]-3-pyridyloxy} ethyl 9H-carbazole-9-carboxylate, (m) 2-[2-(5-{2-[2-(9-carbazolylcarbonyloxy)ethoxy]ethoxy}-3-pyridyloxy)ethoxy]ethyl 9-carbazolecarboxylate, (n) 2-{5-[2-(3,6-dimethoxy-9H-carbazol-9-ylcarbonyloxy)ethoxy]-3-pyridyloxy} ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, (0) 2-[2-(5-{2-[2-(3,6-dimethoxy-9H-carbazolylcarbonyloxy) ethoxy]ethoxy}-3-pyridyloxy)ethoxy]ethyl 3,6-dimethoxy-9-carbazolecarboxylate, and (p) combinations thereof.

### Claim 9 (depends on 1)

The composition of claim 1, wherein the one or more integrin activating or agonist compounds of Formula (IVb) are selected from the group consisting of: (a) 3-{bis[(2-thienyl)methyl]aminocarbonyloxy}ethoxy)methyl]-5-{bis[(2-thienyl)methyl]aminocarbonyloxy} ethoxy)methyl]pyridine, (b) 3-{bis[(2-thienyl) methyl]aminocarbonyloxy}ethoxymethoxy)methyl]-5-{bis[(2-thienyl)methyl]aminocarbonyloxy} ethoxyethoxy)methyl]pyridine, (c) 3-{bis(3-methoxybenzyl)aminocarbonyloxy} ethoxy)methyl]-5-{bis(3-methoxybenzyl)amino carbonyloxy} ethoxy)methyl]pyridine, (d) 3-{bis(3-methoxybenzyl)aminocarbonyloxy} ethoxy ethoxy)methyl]-5-{bis(3-methoxy benzyl)aminocarbonyloxy} ethoxyethoxy)methyl]pyridine, (e) 3-(3-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyloxy} ethoxy)methyl]-5-(3-methoxy benzyl,4-dimethylaminobenzyl)aminocarbonyloxy} ethoxy)methyl]pyridine, (f) 3-(3-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyloxy} ethoxymethoxy)methyl]-5-(3-methoxybenzyl,4-dimethylaminobenzyl)aminocarbonyloxy} ethoxyethoxy)methyl]pyridine, (g) 3-{bis(4-methoxybenzyl)aminocarbonyloxy} ethoxy)methyl]-5-{bis(4-methoxybenzyl)amino carbonyloxy} ethoxy)methyl]pyridine, (h) 3-{bis(4-methoxybenzyl) amino carbonyloxy} ethoxyethoxy)methyl]-5-{bis(4-methoxybenzyl)aminocarbonyloxy} ethoxyethoxy)methyl]pyridine, (i) 3-(4-methoxybenzyl,4-dimethylaminobenzyl) aminocarbonyloxy}ethoxy)methyl]-5-(4-methoxybenzyl,4-dimethylaminobenzyl)amino carbonyloxy} ethoxy)methyl]pyridine, (j) 3-(4-methoxybenzyl,4-dimethylaminobenzyl)amino carbonyloxy} ethoxyethoxy)methyl]-5-(4-methoxybenzyl,4-dimethylaminobenzyl)amino carbonyloxy} ethoxyethoxy)methyl]pyridine, (k) 2-[(5-{[2-(9H-carbazol-9-ylcarbonyloxy)ethoxy]methyl}-3-pyridyl)methoxy]ethyl 9H-carbazole-9-carboxylate, (1) 2-(2-{[5-({2-[2-(9-carbazolylcarbonyloxy)ethoxy]ethoxy} methyl)-3-pyridyl]methoxy} ethoxy)ethyl 9-carbazolecarboxylate, (m) 2-[(5-{[2-(3,6-dimethoxy-9H-carbazol-9-ylcarbonyloxy)ethoxy]methyl}-3-pyridyl)methoxy]ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, (n) 2-(2-{[5-({2-[2-(3,6-dimethoxy-9-carbazolylcarbonyloxy) ethoxy]ethoxy} methyl)-3-pyridyl]methoxy} ethoxy)ethyl 3,6-dimethoxy-9-carbazolecarboxylate, and (o) combinations thereof.

### Claim 10 (depends on 1)

The composition of claim 1, wherein the one or more integrin activating or agonist compounds of Formula (IVb) are selected from the group consisting of: (a) 3-[bis(thenyl)aminocarbonyloxyethoxy],5-[bis(thenyl)aminocarbonyloxyethoxy]dimethylamino benzene, (b) 3-[bis(thenyl)aminocarbonyloxy ethoxyethoxy],5-[bis(thenyl)amino carbonyloxyethoxyethoxy]dimethylaminobenzene, (c) 3-[bis(3-methoxybenzyl)aminocarbonyloxy ethoxy],5-[bis(3-methoxybenzyl)aminocarbonyloxyethoxy]dimethylaminobenzene, (d) 3-[bis(3-methoxybenzyl)aminocarbonyl oxyethoxyethoxy],5-[bis(3-methoxybenzyl)aminocarbonyloxyethoxy ethoxy]dimethylaminobenzene, (e) 3-[(3-methoxybenzyl)(4-dimethylaminobenzyl)amino carbonyloxyethoxy],5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy] dimethylaminobenzene, (f) 3-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy ethoxyethoxy],5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy] dimethylaminobenzene, (g) 3-[bis(4-methoxybenzyl)aminocarbonyloxyethoxy],5-[bis(4-methoxy benzyl)aminocarbonyloxyethoxy]dimethylaminobenzene, (h) 3-[bis(4-methoxybenzyl)amino carbonyloxyethoxyethoxy], 5-[bis(4-methoxybenzyl) aminocarbonyloxyethoxyethoxy] dimethylaminobenzene, (i) 3-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy ethoxy],5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy]dimethylamino benzene, (j) 3-[(4-methoxy benzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy],5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy]dimethylaminobenzene, (k) 2-{3-[2-(9H-carbazol-9-ylcarbonyloxy)ethoxy]-5-(dimethylamino)phenoxy} ethyl 9H-carbazole-9-carboxylate, (1) 2-[2-(3-{2-[2-(9-carbazolylcarbonyloxy) ethoxy]ethoxy}-5-(dimethylamino)phenoxy)ethoxy]ethyl 9-carbazolecarboxylate, (m) 2-{3-[2-(3,6-dimethoxy-9H-carbazol-9-ylcarbonyloxy)ethoxy]-5-(dimethylamino)phenoxy} ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, (n) 2-[2-(3-{2-[2-(3,6-dimethoxy-9-carbazolylcarbonyloxy)ethoxy] ethoxy}-5-(dimethylamino) phenoxy)ethoxy]ethyl 3,6-dimethoxy-9-carbazolecarboxylate, and (o) combinations thereof.

### Claim 11 (depends on 1)

The composition of claim 1, wherein the one or more integrin activating or agonist compounds of Formula (IVb) are selected from the group consisting of: (a) 3-[bis(thenyl)aminocarbonyloxyethoxy],5-[bis(thenyl)aminocarbonyloxyethoxy]dimethyl benzylamine, (b) 3-[bis(thenyl)aminocarbonyloxyethoxyethoxy],5-[bis(thenyl)aminocarbonyloxyethoxyethoxy] dimethylbenzylamine, (c) 3-[bis(3-methoxybenzyl)aminocarbonyloxyethoxy],5-[bis(3-methoxy benzyl)aminocarbonyloxyethoxy]dimethylbenzylamine, (d) 3-[bis(3-methoxybenzyl)amino carbonyloxyethoxyethoxy],5-[bis(3-methoxybenzyl)aminocarbonyloxyethoxyethoxy] dimethylbenzyl amine, (e) 3-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy],5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)amino carbonyloxyethoxy]dimethylbenzylamine, (f) 3-[(3-methoxybenzyl)(4-dimethylaminobenzyl) aminocarbonyloxyethoxyethoxy],5-[(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxyethoxy], dimethylbenzylamine, (g) 3-[bis(4-methoxybenzyl)aminocarbonyloxyethoxy],5-[bis(4-methoxybenzyl)aminocarbonyloxyethoxy] dimethylbenzylamine, (h) 3-[bis(4-methoxybenzyl)aminocarbonyloxyethoxyethoxy],5-[bis(4-methoxybenzyl) aminocarbonyloxy ethoxyethoxy]dimethylbenzylamine, (i) 3-[(4-methoxybenzyl)(4-dimethyl aminobenzyl)aminocarbonyloxyethoxy],5-[(4-methoxybenzyl)(4-dimethylaminobenzyl) aminocarbonyloxyethoxy]dimethylbenzylamine, (j) 3-[(4-methoxybenzyl)(4-dimethylamino benzyl)aminocarbonyloxyethoxyethoxy],5-[(4-methoxybenzyl)(4-dimethylaminobenzyl)amino carbonyloxyethoxyethoxy]dimethylbenzylamine, (k) 2-{3-[2-(9H-carbazol-9-yl-carbonyloxy) ethoxy]-5-[(dimethylamino)methyl]phenoxy} ethyl 9H-carbazole-9-carboxylate, (1) 2-[2-(3-{2-[2-(9-carbazolyl carbonyloxy)ethoxy]ethoxy}-5-[(dimethylamino)methyl]phenoxy) ethoxy]ethyl 9-carbazole carboxylate, (m) 2-{3-[2-(3,6-dimethoxy-9H-carbazol-9-yl-carbonyloxy)ethoxy]-5-[(dimethyl amino)methyl]phenoxy} ethyl 3,6-dimethoxy-9H-carbazole-9-carboxylate, (n) 2-[2-(3-{2-[2-(3,6-dimethoxy-9-carbazolyl carbonyloxy)ethoxy]ethoxy}-5-[(dimethylamino)methyl]phenoxy) ethoxy]ethyl 3,6-dimethoxy-9-carbazolecarboxylate, and (o) combinations thereof.

### Claim 12 (depends on 1)

The composition of claim 1, wherein the one or more integrin activating or agonist compounds of Formula (IVb) are selected from the group consisting of: (a) bis(2-{bis(2-thienyl methyl) aminocarbonyloxy} ethyl)2,6-pyridinedicarboxylate, (b) bis(2-{bis(2-thienylmethyl) aminocarbonyloxyethoxy} ethyl)2,6-pyridinedicarboxylate, (c) bis(2-{bis[3-methoxybenzyl]aminocarbonyloxy} ethyl)2,6-pyridinedicarboxylate, (d) bis(2-{bis[3-methoxybenzyl]aminocarbonyloxyethoxy}ethyl)2,6-pyridinedicarboxylate, (e) bis(2-{(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy}ethyl) 2,6-pyridine dicarboxylate, (f) bis(2-{(4-methoxybenzyl)(4-dimethylaminobenzyl)amino carbonyloxyethoxy} ethyl)2,6-pyridinedicarboxylate, (g) bis(2-{bis[4-methoxybenzyl]amino carbonyloxy} ethyl)2,6-pyridinedicarboxylate, (h) bis(2-{bis[4-methoxybenzyl]amino carbonyloxyethoxy} ethyl)2,6-pyridinedicarboxylate, (i) bis(2-{(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy} ethyl)2,6-pyridinedicarboxylate, (j) bis(2-{(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy} ethyl) 2,6-pyridinedicarboxylate, and (k) combinations thereof.

### Claim 13 (depends on 1)

The composition of claim 1, wherein the one or more integrin activating or agonist compounds of Formula (IVb) are selected from the group consisting of: (a) bis(2-{bis(2-thienylmethyl]aminocarbonyloxy} ethyl)3,5-pyridinedicarboxylate, (b) bis(2-{bis(2-thienylmethyl]aminocarbonyloxyethoxy} ethyl) 3,5-pyridinedicarboxylate, (c) bis(2-{bis(3-methoxybenzyl)aminocarbonyloxy} ethyl)3,5-pyridinedicarboxylate, (d) bis(2-{bis[3-methoxybenzyl]aminocarbonyloxyethoxy} ethyl)2,6-pyridinedicarboxylate, (e) bis(2-{(3-methoxybenzyl)(4-methylaminobenzyl)aminocarbonyloxy} ethyl)3,5-pyridine dicarboxylate, (f) bis(2-{(3-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxy ethoxy} ethyl)2,6-pyridinedicarboxylate, (g) bis(2-{bis(4-methoxybenzyl)aminocarbonyloxy} ethyl)3,5-pyridinedicarboxylate, (h) bis(2-{bis[4-methoxybenzyl]aminocarbonyloxyethoxy} ethyl)3,5-pyridinedicarboxylate, (i) bis(2-{bis(4-methoxybenzyl)(4-methylaminobenzyl)amino carbonyloxy} ethyl)3,5-pyridinedicarboxylate, (j) bis(2-{(4-methoxybenzyl)(4-dimethylaminobenzyl)aminocarbonyloxyethoxy} ethyl) 2,6-pyridinedicarboxylate, and (k) combinations thereof.