# US 10,307,423 B2 · FBXO3 inhibitors

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- Number: US 10,307,423 B2
- Document ID: US10307423B2
- Status: Granted
- Kind: B2
- Application number: 15/138,120
- Filed: 2016-04-25
- Published: 2016-08-18
- Granted: 2019-06-04
- Earliest claimed: 2012-06-08
- Assignees: University of Pittsburgh—Of the Commonwealth System of Higher Education; The United States Government as represented by the Department of Veterans Affairs
- Applicants: University of Pittsburgh—Of the Commonwealth System of Higher Education; The United States Government as represented by the Department of Veterans Affairs
- Inventors: Beibei Chen; Rama K. Mallampalli
- Web page: https://patentgrep.com/patent/US10307423B2

## CPC

- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/137: Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine {or methadone}
- A61K 31/341: not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
- A61K 31/381: having five-membered rings
- A61K 31/402: 1-aryl substituted, e.g. piretanide
- A61K 31/4155: non condensed and containing further heterocyclic rings
- A61K 31/4178: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/435: having six-membered rings with one nitrogen as the only ring hetero atom
- A61K 31/4418: having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61K 31/5375: 1,4-Oxazines, e.g. morpholine
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 11/06: Antiasthmatics
- A61P 19/00: Drugs for skeletal disorders
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 35/00: Antineoplastic agents
- C07C 211/01: having amino groups bound to acyclic carbon atoms
- C07C 211/53: having the nitrogen atom of at least one of the amino groups further bound to a hydrocarbon radical substituted by amino groups
- C07C 229/38: having amino groups bound to acyclic carbon atoms and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
- C07D 207/06: with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D 211/14: with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
- C07D 213/06: containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
- C07D 213/36: Radicals substituted by singly-bound nitrogen atoms (nitro radicals C07D213/26)
- C07D 213/38: having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 233/61: with hydrocarbon radicals, substituted by nitrogen atoms not forming part of a nitro radical, attached to ring nitrogen atoms
- C07D 233/64: with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
- C07D 239/26: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 265/30: not condensed with other rings
- C07D 277/28: Radicals substituted by nitrogen atoms
- C07D 295/135: with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

A compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of: wherein X is a divalent linking moiety; and R1-R10 are each individually H, optionally-substituted alkyl, optionally-substituted alkoxy, optionally-substituted aryl, optionally-substituted cycloalkyl, optionally-substituted heterocyclic, halogen, amino, or hydroxy, provided that at least one of R3 or R8 is an optionally-substituted alkyl, a substituted alkoxy, optionally-substituted aryl, optionally-substituted cycloalkyl, optionally-substituted heterocyclic, or halogen.

## Claims

### Claim 1

A method for inhibiting pro-inflammatory cytokine release in a subject in need thereof, comprising administering to the subject an FBXO3 inhibitor, wherein the FBXO3 inhibitor is an N-heterocyclic-substituted benzathine wherein the N-heterocyclic substituent is selected from pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, isoxazolyl, furazanyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, thiadiazolyl, dithiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or triazinyl.

### Claim 2

A method for treating an inflammatory disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an FBXO3 inhibitor, wherein the FBXO3 inhibitor is an N-heterocyclic-substituted benzathine wherein the N-heterocyclic substituent is selected from pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, isoxazolyl, furazanyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, thiadiazolyl, dithiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or triazinyl, and wherein the inflammatory disorder is asthma, chronic obstructive lung disease, pulmonary fibrosis, pneumonitis, pneumonia, cystic fibrosis, psoriasis, arthritis/rheumatoid arthritis, rhinitis, pharyngitis, cystitis, prostatitis, dermatitis, allergy, nephritis, conjunctivitis, encephalitis, meningitis, opthalmitis, uveitis, pleuritis, pericarditis, myocarditis, atherosclerosis, human immunodeficiency virus related inflammation, diabetes, osteoarthritis, psoriatic arthritis, inflammatory bowel disease, colitis, sepsis, vasculitis, bursitis, connective tissue disease, autoimmune disease, viral or influenza-induced inflammation, or edema.

### Claim 3 (depends on 2)

The method of claim 2, wherein the N-heterocyclic-substituted benzathine compound comprises a divalent diamine core moiety, a first aryl-containing moiety at a first terminal end of the divalent diamine core moiety, and a second aryl-containing moiety at a second terminal end of the divalent diamine core moiety, and at least one of the first aryl-containing moiety or the second aryl-containing moiety is substituted with the N-heterocyclic substituent.

### Claim 4 (depends on 2)

The method of claim 2, wherein the N-heterocyclic-substituted benzathine compound, or a pharmaceutically acceptable salt or ester thereof, has a structure of formula I:
wherein X is a divalent or tetravalent linking moiety; and
R1-R10 are each individually H, optionally-substituted alkyl, optionally-substituted alkoxy, optionally-substituted aryl, optionally-substituted cycloalkyl, optionally-substituted heterocycle, halogen, amino, or hydroxy, provided at least one of R3 or R8 is an N-heterocyclic selected from pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, isoxazolyl, furazanyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, thiadiazolyl, dithiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or triazinyl.

### Claim 5 (depends on 4)

The method of claim 4, wherein R3 is an N-heterocyclic and R8 is an N-heterocyclic.

### Claim 6 (depends on 4)

The method of claim 4, wherein R3 and R8 are each a 6-membered N-heterocyclic.

### Claim 7 (depends on 6)

The method of claim 6, wherein the 6-membered N-heterocyclic is selected from pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or triazinyl.

### Claim 8 (depends on 4)

The method of claim 4, wherein X is optionally-substituted alkanediyl.

### Claim 9 (depends on 6)

The method of claim 6, wherein X is an alkanediyl having a structure of —CnH2n— wherein n is 2 to 5.

### Claim 10 (depends on 4)

The method of claim 4, wherein X is —CH2—CH2—.

### Claim 11 (depends on 4)

The method of claim 4, wherein the compound has a structure of:

### Claim 12 (depends on 9)

The method of claim 9, wherein the 6-membered N-heterocyclic is pyrimidinyl.

### Claim 13 (depends on 5)

The method of claim 5, wherein R1, R2, R4, R5, R6, R7, R9 and R10 are each individually H or halogen.

### Claim 14 (depends on 2)

The method of claim 2, wherein the FBXO3 inhibitor occupies an ApaG domain cavity of the FBXO3 protein.

### Claim 15 (depends on 2)

The method of claim 2, wherein the inflammatory disorder is sepsis.

### Claim 16 (depends on 2)

The method of claim 2, wherein the inflammatory disorder is pneumonia.

### Claim 17 (depends on 2)

The method of claim 2, wherein the inflammatory disorder is induced by infection with Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus pneumoniae, Haemophilus influenza, or Escherichia coli.

### Claim 18 (depends on 2)

The method of claim 2, wherein the inflammatory disorder is chronic obstructive lung disease.

### Claim 19

A method for treating an FBXO3-mediated disorder or injury in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of an FBXO3 inhibitor, wherein the FBXO3-mediated disorder or injury is selected from malaria, toxic lung exposure, cancer, Alzheimer's, or a burn-related injury, wherein the cancer is selected from leukemia, lymphoma, bronchogenic carcinoma, adenocarcinoma of the breast, colon, ovary, thyroid, pancreas, stomach, or prostate, squamous cell cancer, small cell cancer, melanoma, sarcoma, or metastatic cancer, and wherein the FBXO3 inhibitor is an N-heterocyclic-substituted benzathine wherein the N-heterocyclic substituent is selected from pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, isoxazolyl, furazanyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, thiadiazolyl, dithiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or triazinyl.

### Claim 20

A method for inhibiting FBXO3-induced ubiquitination and degradation of FBXL2 in a subject in need thereof, comprising contacting FBXO3-containing tissue or cells with an N-heterocyclic-substituted benzathine wherein the N-heterocyclic substituent is selected from pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, isoxazolyl, furazanyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, thiadiazolyl, dithiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or triazinyl.

### Claim 21

A method for inhibiting bacterial growth in a subject in need thereof or on a surface of an object, comprising administering to the subject or the surface of the object an effective amount of an FBXO3 inhibitor.

### Claim 22

A method for inhibiting a bioactivity of FBXO3 protein in a subject in need thereof, comprising contacting FBXO3 with a compound that interacts with amino acid residues Y308, N335, E341, T368 and 5370 that are present in an ApaG domain cavity of the FBXO3 protein.

### Claim 23 (depends on 1)

The method of claim 1, wherein the FBXO3 inhibitor, or a pharmaceutically acceptable salt or ester thereof, has a structure of formula I:
wherein X is a divalent or tetravalent linking moiety; and
R1-R10 are each individually H, optionally-substituted alkyl, optionally-substituted alkoxy, optionally-substituted aryl, optionally-substituted cycloalkyl, optionally-substituted heterocycle, halogen, amino, or hydroxy, provided at least one of R3 or R8 is an N-heterocyclic selected from pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, isoxazolyl, furazanyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, thiadiazolyl, dithiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or triazinyl.

### Claim 24 (depends on 23)

The method of claim 23, wherein the cytokine is at least one of TNFα, IL-β, or IL-6.

### Claim 25 (depends on 24)

The method of claim 24, wherein R3 and R8 are each a 6-membered N-heterocyclic.

### Claim 26 (depends on 24)

The method of claim 24, wherein X is —CH2—CH2—.

### Claim 27 (depends on 25)

The method of claim 25, wherein X is —CH2—CH2—.

### Claim 28 (depends on 1)

The method of claim 1, wherein the FBXO3 inhibitor has a structure of:

### Claim 29

A method for diminishing supraphysiological levels of at least one of TNFα, IL-β, or IL-6 in a subject in need thereof, comprising administering to the subject, an effective amount of a compound, or a pharmaceutically acceptable salt or ester thereof, having a structure of formula I:
wherein X is an alkanediyl having a structure of —CnH2n— wherein n is 2 to 5;
R1, R2, R4-R7, R9 and R10 are each individually H, optionally-substituted alkyl, optionally-substituted alkoxy, optionally-substituted aryl, optionally-substituted cycloalkyl, optionally-substituted heterocycle, halogen, amino, or hydroxy;
R3 is an N-heterocyclic selected from pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, isoxazolyl, furazanyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, thiadiazolyl, dithiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or triazinyl; and
R8 is an N-heterocyclic selected from pyrrolyl, H-pyrrolyl, pyrrolinyl, pyrrolidinyl, oxazolyl, oxadiazolyl, isoxazolyl, furazanyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, triazolyl, tetrazolyl, thiadiazolyl, dithiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, or triazinyl.

### Claim 30 (depends on 29)

The method of claim 29, wherein R3 and R8 are each pyrimidinyl.

### Claim 31 (depends on 30)

The method of claim 30, wherein X is —CH2—CH2—.

### Claim 32 (depends on 4)

The method of claim 4, wherein the inflammatory disorder is inflammatory bowel disease.

### Claim 33 (depends on 4)

The method of claim 4, wherein the inflammatory disorder is Crohn's disease.

### Claim 34 (depends on 4)

The method of claim 4, wherein the inflammatory disorder is colitis.

### Claim 35 (depends on 11)

The method of claim 11, wherein the inflammatory disorder is inflammatory bowel disease.

### Claim 36 (depends on 11)

The method of claim 11, wherein the inflammatory disorder is Crohn's disease.

### Claim 37 (depends on 11)

The method of claim 11, wherein the inflammatory disorder is colitis.