# US 10,245,254 B2 · Glutaminase inhibitors

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- Number: US 10,245,254 B2
- Document ID: US10245254B2
- Status: Granted
- Kind: B2
- Application number: 15/516,002
- Filed: 2015-10-01
- Published: 2017-10-12
- Granted: 2019-04-02
- Earliest claimed: 2014-10-03
- Assignees: University of Pittsburgh—Of the Commonwealth System of Higher Education; Cornell University
- Applicants: University of Pittsburgh—Of the Commonwealth System of Higher Education; Cornell University
- Inventors: Lee A. McDermott; Prema C. Iyer; Richard A. Cerione; William P. Katt
- Web page: https://patentgrep.com/patent/US10245254B2

## CPC

- A61K 31/433: Thidiazoles
- A61K 31/4535: containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
- A61P 35/00: Antineoplastic agents
- C07D 285/135: Nitrogen atoms
- C07D 401/14: containing three or more hetero rings
- C07D 417/12: linked by a chain containing hetero atoms as chain links
- C07D 417/14: containing three or more hetero rings
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

A compound, or a pharmaceutically acceptable salt thereof, having a structure of: wherein A is a ring; Y1 and Y2 are each independently N or C with the proper valency; X1 and X2 are each independently —NH—, —O—, —CH2—O—, —NH—CH2—, or —N(CH3)—CH2—, provided that when at least one of X1 and X2 is —CH2—O—, —NH—CH2—, or —N(CH3)—CH2— then the —CH2— is directly connected to A; a and b are each independently 0 or 1; c and d are each independently 0 or 1; Z1 and Z2 are each independently a heterocyclic; and R1 and R2 are each independently optionally substituted alkyl, optionally substituted aralkyl, optionally substituted cycloalkyl, amino, optionally substituted heteroaralkyl, optionally substituted alkylalkoxy, optionally substituted alkylaryloxy, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl; provided that if Y1 and Y2 are each C, then a is 1 and b is 1; provided that if Y1 and Y2 are each N, then a is 0 and b is 0; provided that if Y1 is N and Y2 is C, then a=0 and b=1; provided that if Y1 is C and Y2 is N, then a=1 and b=0; provided that if c=0 and d=0, then R1 and R2 are both amino; provided that if c is 1 and d is 1, then both R1 and R2 are not amino; provided that if c is 0 and d is 1, then R1 is amino and R2 is optionally substituted alkyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaralkyl, optionally substituted alkylalkoxy, optionally substituted alkylaryloxy, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl; and provided that if c is 1 and d is 0, then R2 is amino and R1 is optionally substituted alkyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaralkyl, optionally substituted alkylalkoxy, optionally substituted alkylaryloxy, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl.

## Claims

### Claim 1

A compound, or a pharmaceutically acceptable salt thereof, of structure:
wherein A is a piperidinyl;
Y1 and Y2 are each independently N or C with the proper valency;
X1 and X2 are each independently —NH—, —O—, —CH2—O—, provided that when at least one of X1 and X2 is —CH2—O—, then the —CH2— is directly connected to A;
a and b are each independently 0 or 1;
c and d are each independently 0 or 1;
Z1 and Z2 are each independently selected from thiadiazole, pyridazine, or pyridine; and
R1 and R2 are each independently optionally substituted alkyl, optionally substituted aralkyl, optionally substituted cycloalkyl, amino, optionally substituted heteroaralkyl, optionally substituted alkylalkoxy, optionally substituted alkylaryloxy, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl;
provided that if Y1 is N and Y2 is C, then a=0 and b=1;
provided that if Y1 is C and Y2 is N, then a=1 and b=0;
provided that if c=0 and d=0, then R1 and R2 are both amino;
provided that if c is 1 and d is 1, then both R1 and R2 are not amino;
provided that if c is 0 and d is 1, then R1 is amino and R2 is optionally substituted alkyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaralkyl, optionally substituted alkylalkoxy, optionally substituted alkylaryloxy, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl; and
provided that if c is 1 and d is 0, then R2 is amino and R1 is optionally substituted alkyl, optionally substituted aralkyl, optionally substituted cycloalkyl, optionally substituted heteroaralkyl, optionally substituted alkylalkoxy, optionally substituted alkylaryloxy, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocycloalkyl.

### Claim 2 (depends on 1)

The compound of claim 1, wherein A is selected from:

### Claim 3 (depends on 1)

The compound of claim 1, wherein at least one of a orb is 1.

### Claim 4 (depends on 1)

The compound of claim 1, wherein at least one of X1 or X2 is —NH—, —O—, or —CH2—O—.

### Claim 5 (depends on 1)

The compound of claim 1, wherein a is 1, b is 0, and X1 is —NH—, —O—, or —CH2—O—.

### Claim 6 (depends on 1)

The compound of claim 1, wherein a is 0, b is 1, and X2 is —NH—, —O—, or —CH2—O—.

### Claim 7 (depends on 1)

The compound of claim 1, wherein Z1 and Z2 are each the same.

### Claim 8 (depends on 1)

The compound of claim 1, wherein Z1 and Z2 are each independently selected from:

### Claim 9 (depends on 1)

The compound of claim 1, wherein c and d are each 1.

### Claim 10 (depends on 1)

The compound of claim 1, wherein at least one of R1 and R2 is benzyl or optionally-substituted benzyl, methyl, pyridinylmethyl, or cyclopropylmethyl.

### Claim 11 (depends on 1)

The compound of claim 1, wherein c and d are each 0, and R1 and R2 are each —NH2.

### Claim 12 (depends on 1)

The compound of claim 1, wherein c is 1, R1 is optionally-substituted benzyl, methyl, pyridinylmethyl, or cyclopropylmethyl, d is 0, and R2 is —NH2.

### Claim 13 (depends on 1)

The compound of claim 1, wherein c is 0, R1 is —NH2, d is 1, and R2 is optionally-substituted benzyl, methyl, pyridinylmethyl, or cyclopropylmethyl.

### Claim 14 (depends on 1)

The compound of claim 1, wherein Z1 and Z2 groups are each
c and d are each 1; and at least one of R1 and R2 is benzyl or substituted benzyl.

### Claim 15 (depends on 1)

The compound of claim 1, wherein the compound is selected from 2-Phenyl-N-{5-[1-(5-phenylacetylamino-[1,3,4]thiadiazol-2-yl)-piperidin-4-yloxy]-[1,3,4]thiadiazol-2-yl}-acetamide;
N-{5-[1-(5-Acetylamino-[1,3,4]thiadiazol-2-yl)-piperidin-4-yloxy]-[1,3,4]thiadiazol-2-yl}-acetamide;
N-{5-[1-(5-Amino-[1,3,4]thiadiazol-2-yl)-piperidin-4-yloxy]-[1,3,4]thiadiazol-2-yl}-2-phenyl-acetamide;
2-(Pyridin-3-yl)-N-(5-(4-((5-(2-(pyridin-3-yl)acetamido)-1,3,4-thiadiazol-2-yl)oxy)piperidin-1-yl)-1,3,4-thiadiazol-2-yl)acetamido;
2-Cyclopropyl-N-(5-(4-((5-(2-cyclopropylacetamido)-1,3,4-thiadiazol-2-yl)oxy)piperidin-1-yl)-1,3,4-thiadiazol-2-yl)acetamido;
2-Phenyl-N-{6-[1-(6-phenylacetylamino-pyridazin-3-yl)-piperidin-4-yloxy]-pyridazin-3-yl}-acetamide;
2-Phenyl-N-(5-(4-((5-(2-phenylacetamido)-1,3,4-thiadiazol-2-yl)amino)piperidin-1-yl)-1,3,4-thiadiazol-2-yl)acetamido;
2-Phenyl-N-{6-[1-(5-phenylacetylamino-[1,3,4]thiadiazol-2-yl)-piperidin-4-yloxy]-pyridazin-3-yl}-acetamide;
N-(6-[1-{5-(2-Pyridin-2-yl-acetylamino)-[1,3,4]thiadiazol-2-yl]-piperidin-4-yloxy}-pyridazin-3-yl)-2-(3-trifluoromethoxy-phenyl)-acetamide;
2-Phenyl-N-[5-{1-(5-phenylacetylamino-[1,3,4]thiadiazol-2-yl)-piperidin-4-ylmethoxy]-[1,3,4]thiadiazol-2-yl}-acetamide;
2-(Pyridin-2-yl)-N-{5-[(1-{5-[2-(pyridin-2-yl)acetamido]-1,3,4-thiadiazol-2-yl}piperidin-4-yl)amino]-1,3,4-thiadiazol-2-yl}acetamido;
2-(Pyridin-3-yl)-N-{5-[(1-{5-[2-(pyridin-3-yl)acetamido]-1,3,4-thiadiazol-2-yl}piperidin-4-yl)amino]-1,3,4-thiadiazol-2-yl}acetamido;
2-(Pyridin-2-yl)-N-{5-[(1-{5-[2-(pyridin-2-yl)acetamido]-1,3,4-thiadiazol-2-yl}piperidin-4-yl)oxy]-1,3,4-thiadiazol-2-yl}acetamido;
2-(Pyridin-4-yl)-N-{5-[(1-{5-[2-(pyridin-4-yl)acetamido]-1,3,4-thiadiazol-2-yl}piperidin-4-yl)amino]-1,3,4-thiadiazol-2-yl}acetamido; or
2-Cyclopropyl-N-[5-(4-{[5-(2-phenylacetamido)-1,3,4-thiadiazol-2-yl]amino}piperidin-1-yl)-1,3,4-thiadiazol-2-yl]acetamido.

### Claim 16 (depends on 1)

The compound of claim 1, wherein the compound is selected from

### Claim 17 (depends on 1)

A pharmaceutical composition comprising at least one compound of claim 1, and a pharmaceutically acceptable additive.