# US 10,118,914 B2 · Beta-arrestin-biased cannabinoid CB1 receptor agonists and methods for making and using them

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- Number: US 10,118,914 B2
- Document ID: US10118914B2
- Status: Granted
- Kind: B2
- Application number: 15/383,922
- Filed: 2016-12-19
- Published: 2017-06-15
- Granted: 2018-11-06
- Earliest claimed: 2014-06-20
- Assignees: The University of North Carolina at Greensboro
- Applicants: The University of North Carolina at Greensboro
- Inventors: Patricia H. Reggio; Derek M. Shore; Dow P. Hurst
- Web page: https://patentgrep.com/patent/US10118914B2

## CPC

- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 209/42: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 405/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention provides compounds having a CB1 receptor-binding moiety and a directing moiety. In related aspects, the invention provides pharmaceutical compositions containing compounds of the invention, methods for inhibiting a pathway modulated in part by the CB1 receptor activity, and methods for treating a condition or disorder mediated in part by CB1 receptor activity. In certain embodiments, the compounds are compounds of Formula I. Methods of preparing compounds of Formula I are also described. In another aspect, the invention provides methods of identifying a selective agonist of the beta-arrestin pathway over the G-protein pathway.

## Claims

### Claim 1

A compound having the Formula I:
or a pharmaceutically acceptable salt thereof;
wherein
R1 is selected from the group consisting of halo, cyano, nitro, and acetyl;
R2 is selected from the group consisting of C1-12 alkyl, C0-4 alkyl-C3-8 cycloalkyl, and C0-4 alkyl-C6-10 aryl,
R3 is selected from the group consisting of C3-C8 cycloalkyl and 4- to 8-membered heterocyclyl;
W is selected from the group consisting of N and CR1a, wherein R1a is selected from the group consisting of H and R1;
X is selected from the group consisting of O, C═O, and NR4, wherein R4 is selected from the group consisting of H and C1-6 alkyl;
Y1, Y2, and Y3 are independently selected from the group consisting of N and CH;
Z is selected from the group consisting of O, CH2, and NR4, wherein R4 is selected from the group consisting of H and C1-6 alkyl;
subscript t is 0 when W is CR1a and R1a is R1;
subscript t is 1 when W is N or when W is CR1a and R1a is H; and
L is selected from the group consisting of
wherein
R5, R6, R7, and R8 are independently selected from the group consisting of H and OH, provided that at least one of R5 and R6 is H and at least one of R7 and R8 is H, or
one of R5 and R6 is taken together with one of R7 and R8 to form a 5- to 6-membered saturated carbocyclic or heterocyclic group, or
R5 and R7 are absent and R6 and R8 are taken together to form a 5- to 6-membered unsaturated carbocyclic or heterocyclic group, and
R9 and R10 are independently selected from the group consisting of H and OH, provided that at least of R9 and R10 is H.

### Claim 2 (depends on 1)

The compound of claim 1, according to the formula
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 2)

The compound of claim 2, according to the formula
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 3)

The compound of claim 3, having a formula selected from the group consisting of
or a pharmaceutically acceptable salt thereof, wherein
R1 is selected from the group consisting of Cl and F.

### Claim 5 (depends on 4)

The compound of claim 4, which is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.

### Claim 6 (depends on 5)

The compound of claim 5, which is:
5-chloro-N-(2-cyclopropyl-4-(piperidin-1-yl)phenethyl)-3-ethyl-1H-indole-2-carboxamide;
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1 and one or more pharmaceutically acceptable excipients.

### Claim 8 (depends on 1)

A method of treating a condition or disorder mediated in part by CB1 receptor activity in a patient having the condition or disorder, the method comprising administering to the patient an effective amount of a compound of claim 1.

### Claim 9 (depends on 8)

The method of claim 8, wherein the condition is selected from the group consisting of glaucoma, pain, nausea, neurodegeneration, and appetite loss.

### Claim 10 (depends on 7)

A kit comprising a composition of claim 7, and instructions for use.

### Claim 11 (depends on 2)

A method of preparing a compound of claim 2 comprising forming a reaction mixture containing:
a compound of formula III
and a compound of formula IV
under conditions sufficient to form a compound of formula II

### Claim 12 (depends on 11)

The method of claim 11, wherein the compound of formula IV is a compound of formula (IVe), which is prepared by a process comprising:
contacting an aldehyde IVa
wherein LG1 and LG2 are independently leaving groups, with a cyclic amine under conditions sufficient to form a compound of formula IVb
converting the compound of formula IVb to a compound of formula IVc
contacting the compound of formula IVc with diazomethane under conditions sufficient to form a compound of formula IVd
and
reducing the compound of formula IVd to form the compound of formula IVe

### Claim 13 (depends on 11)

The method of claim 11, wherein the compound of formula IV is a compound of formula IVm, which is prepared by a process comprising:
forming a reaction mixture containing a metal-salen catalyst, a protected amine, and a compound of formula IVf
wherein LG3 is a leaving group, under conditions sufficient to form a compound of formula IVg
wherein PG is a protecting group
contacting the compound of formula IVg with a cyclic amine under conditions sufficient to form a compound of formula IVh
and
deprotecting the compound of formula IVh to form the compound of formula IVm

### Claim 14 (depends on 11)

The method of claim 11, wherein the compound of formula IV is a compound of formula Ivl, which is prepared by a process comprising:
reducing a compound of formula IVi
under conditions sufficient to form a compound of formula IVj
wherein X is a halogen and U is S or O; and
coupling the compound of formula IVj with a compound of formula IVk
wherein each R is independently selected from the group consisting of H, and C1-6 alkyl, under conditions sufficient to form the compound of formula IVl