# US 12,758,564 B2 · Methods and materials for inhibiting CB1 activity

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- Number: US 12,758,564 B2
- Document ID: US12758564B2
- Status: Granted
- Kind: B2
- Application number: 18/022,654
- Filed: 2021-11-19
- Published: 2024-01-04
- Granted: 2026-10-13
- Earliest claimed: 2020-11-20
- Assignees: University of Pittsburgh—Of the Commonwealth System of Higher Education
- Applicants: University of Pittsburgh—Of the Commonwealth System of Higher Education
- Inventors: Beibei Chen; Toren Finkel; Yuan Liu
- Web page: https://patentgrep.com/patent/US12758564B2

## CPC

- A61K 31/635: having a heterocyclic ring, e.g. sulfadiazine
- 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

This document provides compounds that can inhibit CB1 activity within a mammal (e.g., a human), as well as the methods of using such compounds for treating diseases, disorders, and conditions such as obesity, fear, metabolic-related disorders, diabetes, dyslipidaemia, and atherosclerosis.

## Claims

### Claim 1

A method of inhibiting CB-1 activity within a mammal, wherein said method comprises administering, to said mammal, an effective amount of a compound of Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
X1 is selected from O;
X2 is NR4;
X3 is C(═O),
n is 0 or 1;
R2 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein each of C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
each R3 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
each R4 is each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1; wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
R5 is H or halo,
R6 is halo or C1-C6 alkyl,
R7 a group of formula (i):
and R8 is H;
or R8 is a group of formula (i):
and R7 is H;
R11 is selected from C1-3 alkyl and ring A, wherein C1-3 alkyl is optionally substituted with C6 aryl;
RN is selected from H, or
R11 and RN, together with the N atom to which they are attached, for a 5-6 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R9;
each R9 is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1,
ring A is selected from C6-10 aryl, C3-10 cycloalkyl, each of which is substituted with 1-10 substituents independently selected from RA;
each RA is independently selected from halo, CN, ORa1, and C(O)Rb1,
each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl.

### Claim 2 (depends on 1)

The method of claim 1, wherein:
each R3 is independently selected from H and C1-6 alkyl;
R2 is selected from H and C1-6 alkyl; or
each R4 is independently selected from H, C1-6 alkyl, and C1-6 haloalkyl, wherein said C1-6 alkyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
R5 is H or halo;
R6 is halo;
RN is selected from H; or
RN and R11, together with the N atom to which they are attached, form a ring selected from morpholinyl, piperidinyl, and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
each RA is independently selected from halo, CN, and
each Ra1, Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, and C1-4 haloalkyl.

### Claim 3 (depends on 1)

The method of claim 1, wherein the compound of Formula (I) has formula (Ib):
or a pharmaceutically acceptable salt thereof, wherein Hal is halogen.

### Claim 4 (depends on 3)

The method of claim 3:
R2 is selected from H and C1-6 alkyl;
R4, R5, and R8 are each H;
RN is H; or
RN and R11, together with the N atom to which they are attached, form a ring selected from pyrrolidinyl, morpholinyl, and piperazinyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from R9;
ring A is selected from C6-10 aryl and C3-10 cycloalkyl, each of which is optionally substituted with 1-10 substituents independently selected from RA, and
each RA is independently selected from halo, CN, ORa1, and C(O)Rb1.

### Claim 5 (depends on 1)

The method of claim 1, wherein said inhibiting CB-1 activity comprises treating a disease or condition selected from obesity, fear, metabolic-related disorder, diabetes, dyslipidaemia, atherosclerosis, and liver disorder.

### Claim 6 (depends on 5)

The method of claim 5, wherein said liver disorder is fatty liver disease, nonalcoholic steatohepatitis (NASH), cirrhosis, or liver cancer.

### Claim 7

A method of inhibiting CB-1 activity within a mammal, wherein said method comprises administering, to said mammal, an effective amount of a compound selected from:
or a pharmaceutically acceptable salt thereof, wherein
R2 is selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein each of C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl is optionally substituted with 1, 2, or 3 substituents independently selected from R9:
each R3 is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
each R4 is each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, S(O)2Rb1, and S(O)2NRc1Rd1, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are each optionally substituted with 1, 2, or 3 substituents independently selected from R9;
R5 is H or halo,
R6 is halo or C1-C6 alkyl
R7 is a group of formula (i):
and R8 is H;
or R8 is a group of formula (i):
and R7 is H;
R11 is selected from C1-3 alkyl and ring A, wherein C1-3 alkyl is optionally substituted with C6 aryl;
RN is selected from H, or
R11 and RN, together with the N atom to which they are attached, for a 5-6 membered heterocycloalkyl, optionally substituted with 1, 2, or 3 substituents independently selected from R9;
each R9 is independently selected from H, halo, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, CN, NO2, ORa1, C(O)Rb1, C(O)NRc1Rd1, C(O)ORa1, NRc1Rd1, NRc1C(O)Rb1, NRc1C(O)ORa1, NRc1S(O)2Rb1, S(O)2Rb1, and S(O)2NRc1Rd1;
ring A is selected from C6-10 aryl, C3-10 cycloalkyl, each of which is substituted with 1-10 substituents independently selected from RA;
each RA is independently selected from halo, CN, ORa1, C(O)Rb1 and each Ra1 and Rb1, Rc1, and Rd1 is independently selected from H, C1-6 alkyl, C1-4 haloalkyl.

### Claim 8

A method of inhibiting CB-1 activity within a mammal, wherein said method comprises administering, to said mammal, an effective amount of a compound selected from any one of the following compounds:
or a pharmaceutically acceptable salt thereof.