# US 8,541,581 B2 · Inhibitors of fatty acid amide hydrolase

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- Number: US 8,541,581 B2
- Document ID: US8541581B2
- Status: Granted
- Kind: B2
- Application number: 13/263,324
- Filed: 2010-04-07
- Published: 2012-04-12
- Granted: 2013-09-24
- Earliest claimed: 2009-04-07
- Assignees: Infinity Pharmaceuticals, Inc.
- Applicants: Alfredo C. Castro; Catherine A. Evans; Louis Grenier; Michael J. Grogan
- Inventors: Alfredo C. Castro; Catherine A. Evans; Louis Grenier; Michael J. Grogan
- Web page: https://patentgrep.com/patent/US8541581B2

## CPC

- C07F 5/025: {Boronic and borinic acid compounds}
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/06: Antimigraine agents
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/20: Hypnotics; Sedatives
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided herein are compounds of formula (I): or pharmaceutically acceptable salts, solvates or prodrugs thereof or mixtures thereof, wherein Z1, Z2, X1, X2, X3, R1, R2, R3, R4, m and n are defined herein. Also provided are pharmaceutically acceptable compositions that include a compound of formula I and a pharmaceutically acceptable excipient. Also provided are methods for treating an FAAH-mediated disorder comprising administering to a subject in need thereof a therapeutically effective amount of a compound or composition of the present invention.

## Claims

### Claim 1

A compound of formula III:
or a pharmaceutically acceptable salt, solvate or prodrug thereof, or mixture thereof, wherein:
is selected from a single bond and a double bond;
m is 1 when is a single bond;
m is 0 when is a double bond;
Z1 is —OR14;
Z2 is —OR15;
R1, R2, R3, R4, R6, R7, R12 and R13 each independently is selected from H, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 perhaloalkyl, —CN, —OR16, NR17R18, —C(O)R19, C3-10 carbocyclyl, C6-10 aryl, C7-12 aralkyl, 3-10 membered cycloheteroalkyl, and 5-10 membered heteroaryl;
R8 is selected from C2-6 alkenyl, C2-6 alkynyl, —C(O)R20, —C(O)NR22R23, S(O)2R24, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered cycloheteroalkyl, 5-10 membered heteroaryl, and —(CH2)p—R25;
R14 and R15, at each occurrence, each independently is selected from H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
R16, at each occurrence, each independently is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, C7-12 aralkyl, 3-10 membered cycloheteroalkyl, and 5-10 membered heteroaryl;
R17 and R18, at each occurrence, each independently is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —C(O)R26, —C(O)OR27, C3-10 carbocyclyl, C6-10 aryl, C7-12 aralkyl, 3-10 membered cycloheteroalkyl, and 5-10 membered heteroaryl;
R19, at each occurrence, each independently is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, C7-12 aralkyl, 3-10 membered cycloheteroalkyl, and 5-10 membered heteroaryl;
R20 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered cycloheteroalkyl, 5-10 membered heteroaryl, and —(CH2)q—R28;
R22 and R23 each independently is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered cycloheteroalkyl, 5-10 membered heteroaryl, and —(CH2)r—R29;
R24 is selected from C1-6 alkyl, C2-6 alkenyl, alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered cycloheteroalkyl, 5-10 membered heteroaryl, and —(CH2)t—R30;
R25 is selected from C3-10 carbocyclyl, C6-10 aryl, 3-10 membered cycloheteroalkyl, and 5-10 membered heteroaryl;
R26 and R27 each independently is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, C7-12 aralkyl, 3-10 membered cycloheteroalkyl, and 5-10 membered heteroaryl;
R28, R29, and R30, at each occurrence, each independently is selected from —OR31, —NR32R33, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered cycloheteroalkyl, and 5-10 membered heteroaryl;
R31, R32 and R33, at each occurrence, each independently is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, C7-12 aralkyl, 3-10 membered cycloheteroalkyl, and 5-10 membered heteroaryl; and
p, q, r, and t, at each occurrence, each independently is selected from 1, 2, 3, 4, 5 and 6.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R8 is selected from —C(O)R20, —C(O)NR22R23, S(O)2R24, and —(CH2)p—R25.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R8 is —C(O)R20, and R20 is selected from C1-6 alkyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered cycloheteroalkyl, 5-10 membered heteroaryl, and —(CH2)q—R28.

### Claim 4 (depends on 3)

The compound of claim 3, wherein R20 is —(CH2)q—R28, and R28 is selected from C3-10 carbocyclyl, C6-10 aryl, 3-10 membered cycloheteroalkyl, and 5-10 membered heteroaryl.

### Claim 5 (depends on 3)

The compound of claim 3, wherein R20 is —(CH2)q—R28, and R28 is —NR32R33.

### Claim 6 (depends on 5)

The compound of claim 5, wherein R32 and R13 each independently is selected from H, C1-6 alkyl, and C7-12 aralkyl.

### Claim 7 (depends on 1)

The compound of claim 1, wherein R8 is —C(O)NR22R23.

### Claim 8 (depends on 7)

The compound of claim 7, wherein R22 and R23 each independently is selected from H, C1-6 alkyl, and —(CH2)r—R29.

### Claim 9 (depends on 8)

The compound of claim 8 wherein R29 is selected from C6-10 aryl and 5-10 membered heteroaryl.

### Claim 10 (depends on 1)

The compound of claim 1, wherein R8 is —S(O)2R24.

### Claim 11 (depends on 10)

The compound of claim 10, wherein R24 is selected from C1-6 alkyl, C6-10 aryl, 5-10 membered heteroaryl, and —(CH2)t—R30.

### Claim 12 (depends on 1)

The compound of claim 1, wherein R8 is —(CH2)p—R25.

### Claim 13 (depends on 12)

The compound of claim 12, wherein R25 is selected from C6-10 aryl and 5-10 membered heteroaryl.

### Claim 14 (depends on 1)

The compound of claim 1, wherein R12 is H and R13 is H.

### Claim 15 (depends on 1)

The compound of claim 1, wherein R6 is H and R7 is H.

### Claim 16 (depends on 1)

The compound of claim 1, wherein is a double bond and m is 0.

### Claim 17 (depends on 1)

The compound of claim 1, wherein is a single bond and m is 1.

### Claim 18 (depends on 17)

The compound of claim 17, wherein R2 is H.

### Claim 19 (depends on 1)

The compound of claim 1, wherein R1 is H.

### Claim 20 (depends on 1)

The compound of claim 1, wherein R3 is H and R4 is H.

### Claim 21 (depends on 1)

The compound of claim 1, wherein R14 is H and R15 is H.

### Claim 22 (depends on 1)

The compound of claim 1, wherein the compound is selected from:
or a pharmaceutically acceptable salt, solvate or prodrug thereof, or mixture thereof.

### Claim 23 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt, solvate or prodrug thereof, or mixture thereof and a pharmaceutically acceptable excipient.

### Claim 24 (depends on 1)

The compound of claim 1, wherein the compound is of the formula IIIa:
or a pharmaceutically acceptable salt, solvate or prodrug thereof, or mixture thereof.

### Claim 25 (depends on 1)

The compound of claim 1, wherein the compound is of the formula IIIb:
or a pharmaceutically acceptable salt, solvate or prodrug thereof, or mixture thereof.