# US 9,751,830 B2 · Inhibitors of the tumor necrosis factor receptor complex

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- Number: US 9,751,830 B2
- Document ID: US9751830B2
- Status: Granted
- Kind: B2
- Application number: 13/634,368
- Filed: 2011-03-07
- Published: 2015-12-24
- Granted: 2017-09-05
- Earliest claimed: 2010-03-15
- Assignees: The Trustees of the University of Pennsylvania
- Applicants: Ramachandran Murali; Mark I. Greene
- Inventors: Ramachandran Murali; Mark I. Greene
- Web page: https://patentgrep.com/patent/US9751830B2

## CPC

- C07C 233/25: having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
- A61K 31/075: Ethers or acetals
- C07C 217/18: the six-membered aromatic ring or condensed ring system containing that ring being further substituted
- C07C 217/20: by halogen atoms, by trihalomethyl, nitro or nitroso groups, or by singly-bound oxygen atoms
- C07C 217/32: the six-membered aromatic ring or condensed ring system containing that ring being further substituted
- C07C 233/18: having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- 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)

## Abstract

The present invention relates to compounds of formula (I) that are inhibitors of tumor necrosis factor receptor I, compositions comprising such compounds, and methods of using such compounds and compositions thereof in the treatment of TNF-α mediated conditions: Formula (I)

## Claims

### Claim 1

A compound having the structure of formula I:
wherein,
A1-A5 and B1-B4 are independently H, halo, hydroxyl, nitro, cyano, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted acyl, —(CH2)m—S(O)qR2, —N(R1)2, —(CH2)m—X4—C(X5)—R2, —(CH2)m—C(X5)—X4—R2, —O—(CH2)m—X4—C(X5)—R2, —O—(CH2)m—C(X5)—X4—R2, —SO3H, or —S(O)q—R1, or one or more pairs of A1-A2 or A2-A3 or A3-A4, or A4-A5 or B1-B2 or B3-B4, together with the respective carbons to which they are attached, form a C4-8 alkyl, heteroalkyl, aryl, or heteroaryl ring, provided that at least one of A1-A5 moieties comprises—(CH2)m—X4—C(X5)—R2;
X1, X2, and X5 are O;
X4 is independently O or NH;
X3 is NR1;
m, n, and p and are each independently 0 or 1; q is 0, 1, or 2;
R1 is independently in each case H, or optionally substituted aryl, heteroaryl, alkyl, or acyl;
R2 is optionally substituted alkyl, aryl, or heteroaryl;
R3 is independently in each case H, R1, —OR1, or when taken together with another R3 attached to the same carbon is ═O;
and provided that the compound does not have the structure of formula II:

### Claim 2 (depends on 1)

The compound of claim 1 wherein said compound is capable of binding in a cavity of a tumor necrosis factor receptor (TNF-R), said cavity bounded by Cys-76, Arg-77, Asp-93, Cys-96, Arg-104, Asn-110, Phe-112, and Lys-132 of SEQ ID No. 0001.

### Claim 3 (depends on 1)

The compound of claim 1 wherein A5 is —(CH2)m—X4—C(X5)—R2.

### Claim 4 (depends on 1)

The compound of claim 1 wherein X3 is NH.

### Claim 5 (depends on 3)

The compound of claim 3 wherein A1, A2, A3, and A4 are H.

### Claim 6 (depends on 1)

The compound of claim 1 wherein A4 is —(CH2)m—X4—C(X5)—R2 and wherein A1, A2, A3, and A5 are H.

### Claim 7 (depends on 1)

The compound of claim 1 wherein A3 is —(CH2)m—X4—C(X5)—R2 and wherein A1, A2, A4, and A5 are H.

### Claim 8 (depends on 4)

The compound of claim 4 wherein m=0 or 1, X5 is O, and R2 is C1-3 linear alkyl.

### Claim 9 (depends on 8)

The compound of claim 8 wherein —(CH2)m—X4—C(O)—R2 is —(CH2)—X4—C(O)CH3.

### Claim 10 (depends on 8)

The compound of claim 8 wherein —(CH2)m—X4—C(O)—R2 is —X4—C(O)CH3.

### Claim 11 (depends on 1)

The compound of claim 1 wherein n=0.

### Claim 12 (depends on 3)

The compound of claim 3 wherein n=0.

### Claim 13 (depends on 1)

The compound of claim 1 wherein p=0.

### Claim 14 (depends on 3)

The compound of claim 3 wherein p=0.

### Claim 15 (depends on 1, 3)

The compound of claim 1 or 3, wherein n=p=0.

### Claim 16 (depends on 1)

The compound of claim 1 wherein R1 is linear or branched C1-3 alkyl or branched C1-3 carboxyalkyl and R2 is linear or branched C1-3 alkyl or linear.

### Claim 17 (depends on 16)

The compound of claim 16 wherein R1 and R2 are each independently fluorinated or perfluorinated.

### Claim 18 (depends on 1)

The compound of claim 1 having the structure:
wherein R1 is each independently H, linear or branched C1-3 alkyl, or linear or branched C1-3 carboxyalkyl and R2 is linear or branched C1-3 alkyl.

### Claim 19 (depends on 18)

The compound of claim 18 having the structure:

### Claim 20 (depends on 18)

The compound of claim 18 having the structure:

### Claim 21 (depends on 18)

The compound of claim 18 having the structure:

### Claim 22 (depends on 18)

The compound of claim 18 having the structure:

### Claim 23 (depends on 1)

A compound of claim 1 that inhibits at least 40% of TNFα induced cytolysis at a concentration of 50 micromolar.

### Claim 24 (depends on 1)

A compound of claim 1 that inhibits at least 60% of TNFα induced cytolysis at a concentration of 90 micromolar.

### Claim 25 (depends on 1)

A compound of claim 1 that inhibits at least 40% of luciferase activity within 4 hours of incubation with 20 ng/ml TNFα for 4 hours, at a concentration of 75 micromolar of the compound.

### Claim 26 (depends on 1)

A compound of claim 1 that inhibits at least 60% of luciferase activity within 4 hours of incubation with 20 ng/ml TNFα for 4 hours, at a concentration of 100 micromolar of the compound.

### Claim 27 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1 or a compound having the structure of formula II
and a pharmaceutically acceptable excipient.

### Claim 28 (depends on 27)

A pharmaceutical composition of claim 27, wherein said compound is present in an amount effective to inhibit the activity of a tumor necrosis factor alpha (TNF-α) protein.

### Claim 29 (depends on 1)

A method of treating a patient having an inflammatory disease condition mediated by tumor necrosis factor alpha (TNFα) activity, the method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 1 or a compound having the structure of formula II
or a pharmaceutically acceptable salt thereof.

### Claim 30 (depends on 29)

The method of claim 29 wherein the compound causes an allosteric change in the conformation of TNF-R.

### Claim 31 (depends on 29)

The method of claim 29, wherein the inflammatory disease condition is arthritis.

### Claim 32 (depends on 29)

The method of claim 29, wherein the inflammatory disease condition is Crohn's Disease.

### Claim 33 (depends on 29)

The method of claim 29, wherein the inflammatory disease condition is inflammatory neuropathy, Lou Gehrig's disease, or Alzheimer's disease.

### Claim 34 (depends on 27)

The pharmaceutical composition of claim 27, comprising a compound having the structure of formula II
and a pharmaceutically acceptable excipient.

### Claim 35 (depends on 1, 27)

The pharmaceutical composition of claim 27, wherein the compound of claim 1 is:
wherein R1 is each independently H, linear or branched C1-3 alkyl, or linear or branched C1-3 carboxyalkyl and R2 is linear or branched C1-3 alkyl.

### Claim 36 (depends on 1, 27)

The pharmaceutical composition of claim 27, wherein the compound of claim 1 is:

### Claim 37 (depends on 29)

The method of claim 29, wherein the compound has the structure of formula II

### Claim 38 (depends on 1, 29)

The method of claim 29, wherein the compound of claim 1 is
wherein R1 is each independently H, linear or branched C1-3 alkyl, or linear or branched C1-3 carboxyalkyl and R2 is linear or branched C1-3 alkyl.

### Claim 39 (depends on 1, 29)

The method of claim 29, wherein the compound of claim 1 is

### Claim 40 (depends on 38)

The method of claim 38, wherein the inflammatory disease condition is arthritis, Crohn's Disease, inflammatory neuropathy, Lou Gehrig's disease, or Alzheimer's disease.

### Claim 41 (depends on 39)

The method of claim 39, wherein the inflammatory disease condition is arthritis, Crohn's Disease, inflammatory neuropathy, Lou Gehrig's disease, or Alzheimer's disease.