# US 11,306,084 B2 · Integrin antagonists

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- Number: US 11,306,084 B2
- Document ID: US11306084B2
- Status: Granted
- Kind: B2
- Application number: 16/474,505
- Filed: 2017-12-28
- Published: 2019-11-14
- Granted: 2022-04-19
- Earliest claimed: 2016-12-29
- Assignees: Saint Louis University; Indalo Therapeutics, Inc.
- Applicants: Saint Louis University; Indalo Therapeutics, Inc.
- Inventors: Peter G. Ruminski; David W. Griggs; Scott Seiwert
- Web page: https://patentgrep.com/patent/US11306084B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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

The present disclosure provides pharmaceutical agents, including those of the formula: (I) wherein the variables are defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such pharmaceutical agents. Methods of using the pharmaceutical agents are also provided. The compounds may be used for the inhibition or antagonism of integrins ανβι and/or α5βι. In some embodiments, the compounds provided herein exhibit reduced inhibitory or antagonistic activity of integrins ανβ3, ανβ5, ανβ6, ανβ8, and/or αIIbβ3.

## Claims

### Claim 1

A compound of the formula:
or a pharmaceutically acceptable salt or tautomer thereof,
wherein:
R1 is hydrogen, unsubstituted C1-8alkyl, substituted C1-8alkyl;
R2 is hydrogen, unsubstituted C1-8alkyl, or substituted C1-8alkyl;
X is hydrogen, halo, cyano, unsubstituted C1-12alkyl, substituted C1-12alkyl, unsubstituted C1-12alkoxy, substituted C1-12alkoxy, unsubstituted 3-10 membered heterocycloalkyl, substituted 3-10 membered heterocycloalkyl, unsubstituted C2-12acyloxy, substituted C2-12acyloxy, or
where R4 and R5 are each independently unsubstituted C1-8alkyl or substituted C1-8alkyl, and
R6 is hydrogen, —OH, —CN, —NH2, —CF3, —CF2H, —CH2F, —CO2H, —CO2—C1-8alkyl, —C(═O)NH2, —CH2OH, —CH2O—C1-8alkyl, or C1-8alkoxy, or
X is
where A′ is —CF2—, —O—, C1-6alkanediyl, C1-8alkoxydiyl, or a covalent bond, thereby forming a cyclopropane ring, and
R7 is —OH, —CN, —NH2, —CO2H, —CO2—C1-8alkyl, —C(═O)NH2, —CF3, —CF2H, —CH2F, —CH2OH, —CH2O—C1-8alkyl, C1-8alkyl or C1-8alkoxy;
Y is t-butyl, or
where R8 and R9 are each independently unsubstituted C1-8alkyl or substituted C1-8alkyl,
and R10 is hydrogen, —OH, —CN, —NH2, —CF3, —CF2H, —CFH2, —CO2H, —CO2—C1-8alkyl, —C(═O)NH2, —CH2OH, CH2O—C1-8alkyl, or C1-8alkoxy, or
Y is
where A″ is —CF2—, —O—, C1-6alkanediyl, C1-8alkoxydiyl, or a covalent bond, thereby forming a cyclopropane ring; and R11 is —OH, —CN, —NH2, —CO2H, —CO2—C1-8alkyl, —C(═O)NH2, —CF3, —CF2H, —CH2F, —CH2OH, —CH2O—C1-8alkyl, C1-8alkyl or C1-8alkoxy.

### Claim 2 (depends on 1)

The compound of claim 1 further defined as:
or a pharmaceutically acceptable salt or tautomer thereof.

### Claim 3 (depends on 1)

The compound of claim 1 further defined as:
or a pharmaceutically acceptable salt or tautomer thereof,
wherein:
R1 is unsubstituted C1-8alkyl, substituted C1-8alkyl;
R2 is hydrogen, unsubstituted C1-6alkyl, or substituted C1-6alkyl;
X is halo, cyano, unsubstituted C1-12alkyl, substituted C1-12alkyl, unsubstituted C1-12alkoxy, substituted C1-12alkoxy, unsubstituted 3-10 membered heterocycloalkyl, substituted 3-10 membered heterocycloalkyl, unsubstituted C2-12acyloxy, substituted C2-12acyloxy, or
or
X is
where A′ is —CF2—, —O—, C1-6alkanediyl, C1-8alkoxydiyl, or a covalent bond, thereby forming a cyclopropane ring;
R8 and R9 are each independently are each independently unsubstituted C1-6alkyl or substituted C1-6alkyl; and
and R10 is hydrogen, —OH, —CN, —NH2, —CF3, —CF2H, —CFH2, —CO2H, —CO2—C1-6alkyl, —C(═O)NH2, —CH2OH, CH2O—C1-6alkyl, or C1-6alkoxy.

### Claim 4 (depends on 1)

The compound of claim 1 further defined as:
or a pharmaceutically acceptable salt or tautomer thereof.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein R2 is hydrogen and R1 is selected from the group consisting of unsubstituted C1-8alkyl and methyl.

### Claim 6 (depends on 1)

The compound according to claim 1, wherein X is hydrogen, halo, cyano, unsubstituted C1-12alkyl, substituted C1-12alkyl, unsubstituted C1-12alkoxy, substituted C1-12alkoxy, unsubstituted 3-10 membered heterocycloalkyl, substituted 3-10 membered heterocycloalkyl, unsubstituted C2-12acyloxy, or substituted C2-12acyloxy or

### Claim 7 (depends on 1)

The compound of claim 1, wherein X is bromo, fluoro, or chloro.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein X is selected from the group consisting of —CF3, —OH, cyano, unsubstituted C1-8alkyl, unsubstituted C3-6alkyl, t-butyl, unsubstituted C1-8alkoxy, methoxy, and isopropoxy.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein Y is t-butyl or

### Claim 10 (depends on 1)

The compound of claim 1, wherein R8 and R9 are each independently unsubstituted C1-8alkyl.

### Claim 11 (depends on 1)

The compound according to claim 1, wherein R10 is hydrogen, —CH3, —CF3, —CF2H, or —CFH2.

### Claim 12 (depends on 1)

The compound according to claim 1 wherein Y is

### Claim 13 (depends on 8)

The compound of claim 8, wherein A″ is C1-3alkanediyl, C1-4alkoxydiyl, or a covalent bond, thereby forming a cyclopropane ring.

### Claim 14 (depends on 8)

The compound according to claim 8, wherein R11 is —CF3, —CF2H, —CH2F, methoxy, —CH2O—CH3, —CH2O—C1-6alkyl, C1-6alkyl or C1-8alkoxy.

### Claim 15 (depends on 1)

The compound according to claim 1, wherein the carbon atom 21 is in the S configuration.

### Claim 16 (depends on 1)

The compound according to claim 1, wherein X is in the 3 position.

### Claim 17 (depends on 1)

The compound according to claim 1, wherein Y is in the 4 or 5 position.

### Claim 18 (depends on 1)

The compound according to claim 1, wherein the compound is an integrin antagonist.

### Claim 19 (depends on 18)

The compound of claim 18, wherein the integrin is an α5β1 integrin or ανβ1 integrin.

### Claim 20 (depends on 9)

The compound of claim 9, wherein the compound exhibits an IC50 value for the α5β1 integrin of less than 50 nM, 40 nM, 30 nM, 20 nM, 15 nm or 1 nM, or a range defined by any of the preceding as measured by a solid phase receptor assay for α5β1 integrin function.

### Claim 21 (depends on 1)

The compound according to claim 1, wherein the compound exhibits an IC50 value for the ανβ1 integrin of less than 15 nM as measured by a solid phase receptor assay for ανβ1 integrin function.

### Claim 22 (depends on 1)

The compound according to claim 1 wherein the compound exhibits an IC50 value for an ανβ3 integrin of less than 10 nM as measured by a solid phase receptor assay for ανβ3 integrin function.

### Claim 23 (depends on 1)

The compound according to claim 1, wherein the compound exhibits an IC50 value for an ανβ5 integrin of less than 10 nM as measured by a solid phase receptor assay for ανβ5 integrin function.

### Claim 24 (depends on 1)

The compound according to claim 1, wherein the compound exhibits an IC50 value for the ανβ1, ανβ3, and ανβ5 integrins of less than 10 nM as measured by a solid phase receptor assays for ανβ1, ανβ3, and ανβ5 integrin function.

### Claim 25 (depends on 1)

The compound according to claim 1, wherein the compound exhibits an IC50 value for the ανβ6 and ανβ8 integrins of greater than 10 nM as measured by solid phase receptor assays for ανβ6 and ανβ8 integrin function.

### Claim 26 (depends on 1)

The compound of claim 1, wherein the compound is further defined as:
or a pharmaceutically acceptable salt thereof.

### Claim 27 (depends on 1)

The compound of claim 1 further defined as:
or a pharmaceutically acceptable salt thereof.

### Claim 28 (depends on 1)

A pharmaceutical composition comprising:
a) the compound according to claim 1; and
b) an excipient.

### Claim 29 (depends on 13)

The pharmaceutical composition of claim 13, wherein the pharmaceutical composition is formulated for administration: orally, intraadiposally, intraarterially, intraarticularly, intracranially, intradermally, intralesionally, intramuscularly, intranasally, intraocularly, intrapericardially, intraperitoneally, intrapleurally, intraprostatically, intrarectally, intrathecally, intratracheally, intratumorally, intraumbilically, intravaginally, intravenously, intravesicularlly, intravitreally, liposomally, locally, mucosally, parenterally, rectally, subconjunctival, subcutaneously, sublingually, topically, transbuccally, transdermally, vaginally, in crémes, in lipid compositions, via a catheter, via a lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, or via localized perfusion.