# US 10,766,858 B2 · Substituted benzamides and methods of use thereof

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- Number: US 10,766,858 B2
- Document ID: US10766858B2
- Status: Granted
- Kind: B2
- Application number: 16/088,417
- Filed: 2017-03-28
- Published: 2019-04-18
- Granted: 2020-09-08
- Earliest claimed: 2016-03-30
- Assignees: Genentech, Inc.; Xenon Pharmaceuticals Inc.
- Applicants: Genentech, Inc.; Xenon Pharmaceuticals Inc.
- Inventors: Sultan Chowdhury; Christoph Martin Dehnhardt; Thilo Focken; Michael Edward Grimwood; Ivan William Hemeon; Steven McKerrall; Daniel Sutherlin
- Web page: https://patentgrep.com/patent/US10766858B2

## CPC

- C07C 381/10: Compounds containing sulfur atoms doubly-bound to nitrogen atoms
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- C07D 205/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 211/22: by oxygen atoms
- C07D 211/42: attached in position 3 or 5
- C07D 213/69: Two or more oxygen atoms
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The invention provides compounds having the general formula I: (i) and pharmaceutically acceptable salts thereof, wherein the variables RA, RAA, subscript n, ring A, X2, L, subscript m, X1, ring B, R1, and RN have the meaning as described herein, and compositions containing such compounds and methods for using such compounds and compositions.

## Claims

### Claim 1

A compound of formula I:
or a salt thereof wherein:
R1 is C1-8 alkyl, C2-8 alkenyl, C1-8 haloalkyl, C1-8 alkoxy, 3-20 membered carbocycle, C-linked 3-20 membered heterocycle, or —NR1AR1B, herein R1A and R1B are each independently selected from the group consisting of hydrogen, C1-8 alkyl, C1-8 alkoxy, and wherein R1A and R1B are optionally combined to form a 3-20 membered heterocycle; and wherein R1 is optionally substituted with from 1 to 5 substituents selected from the group consisting of C1-4 alkyl, C3-4 haloalkyl, F, Cl, Br, I, —OH, —CN, —NO2, —NRR1aRR1b, —ORR1a, —SRR1a, —Si(RR1a)3 and C3-6 carbocycle; wherein RR1a and RR1b are independently selected from the group consisting of hydrogen, C1-8 alkyl, and C1-8 haloalkyl;
RN is hydrogen, C1-4 alkyl or C1-4 haloalkyl;
L is a linker selected from the group consisting of C1-4 alkylene, C2-4 alkenylene and C2-4 alkynylene, wherein L is optionally substituted with from 1 to 3 substituents selected from the group consisting of ═O, C1-4 alkyl, halo, and C1-4 haloalkyl;
the subscript m is 0 or 1;
X1 and X2 are each independently selected from the group consisting of absent, —O—, —S(O)—, —S(O)2— and —N(RX)— wherein Rx is H, C1-8 alkyl, C1-8 alkanoyl, or —S(O)2(C1-8 alkyl), and wherein if the subscript m is 0 then one of X1 or X2 is absent;
the subscript n is 0, 1, 2, 3, 4, or 5;
the ring A is a 3-20 membered carbocyclyl, a 6-20 membered aryl, a 5-20 membered heteroaryl, or a 3-20 membered heterocyclyl;
each RAA is independently selected from the group consisting of C1-6 alkyl, C1-6 haloalkyl, C1-6 heteroalkyl, CN, F, Cl, Br and I; and
RA is selected from the group consisting of absent, CN, F, Cl, Br, I, RA1O—(XRB)—, (3-20 membered aryl)-(XRA)—, (3-20 membered heteroaryl)-(XRA)—, (3-20 membered carbocycle)-(XRA)—, (3-20 membered heterocycle)-(XRA)—, —RA2, and —S(O)2—RA2, wherein said 3-20 membered aryl, 3-20 membered heteroaryl, 3-20 membered carbocycle and 3-20 membered heterocycle of RA is optionally substituted with from 1 to 5 substitutents selected from, F, Cl, Br, I, —NH2, —OH, —CN, —NO2, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4(halo)alkoxy, C1-4 alkylamino, C1-4 dialkylamino, C1-4 alkanoyl, C1-4 akyl-OC(═O)—, C1-4 alkyl-S(O)2—, C3-6 carbocycle, and phenyl that is optionally substituted with one or more substituents selected from fluoro, chloro, and bromo; RA1 is selected from the group consisting of hydrogen, C1-8 alkyl, C2-8 alkenyl, C1-8 haloalkyl, C3-8 cycloalkyl, phenyl and benzyl; RA2 is a C1-8 alkyl that is optionally substituted with one or more substituents selected from oxo (═O), fluoro, amino, C1-4 alkylamino and C1-4 dialkylamino; XRA is selected from the group consisting of absent, —O—, —S—, —N(H)—, —N(C1-4 alkyl)-, —S(O)—, —S(O)2—, —C(═O)—, C1-4 alkylene, C1-4 heteroalkylene, C2-4 alkenylene and C2-4 alkynylene; XRB is selected from the group consisting of absent, C1-4 alkylene, C1-4 heteroalkylene, C2-4 alkenylene and C2-4 alkynylene; wherein any C1-4 alkylene, C1-4 heteroalkylene, C2-4 alkenylene and C2-4 alkynylene of XRA or XRB is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-4 alkyl, C1-4 haloalkyl, C1-4 heteroalkyl, oxo (═O), hydroxy, and phenyl that is optionally substituted with 1 to 5 substitutents selected from, F, Cl, Br, I, —NH2, —OH, —CN, —NO2, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4(halo)alkoxy, C1-4 alkylamino and C1-4 dialkylamino; or wherein XRA or XRB is optionally substituted with 2 substituents that combine to form a 3-5 membered carbocycle or a 3-5 membered heterocycle;
the ring B is selected from:
D1 is N or C(RD1);
D3 is N or C(RD3);
RD1, RD2, RD3 and RD4 are each independently selected from the group consisting of H, F, Cl, Br, I, —CN, C1-8 alkyl, C1-8 haloalkyl, C1-8 alkoxy, 3-12 membered cycloalkyl, 3-12 membered heterocycle, phenyl and 5-6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O and S, wherein said 5-6 membered heteroaryl is further optionally substituted with from 1 to 3 substituents selected from F, Cl, Br, I, —CN, C1-4 alkyl, C1-4 haloalkyl and C1-4 alkoxy;
R22 and R23 are each independently selected from the group consisting of H, F, Cl, Br, I, —CN, C1-8 alkyl, C1-8 haloalkyl and C1-8 alkoxy;
R24 is selected from the group consisting of H, F, CL, Br, I, —CN, C1-8 alkyl, C1-8 haloalkyl, C1-8 alkoxy, 3-12 membered carbocycle, 3-12 membered heterocycle, phenyl and 5-6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O and S, wherein said 5-6 membered heteroaryl is further optionally substituted with from 1 to 3 R5 substituents selected from F, Cl, Br, I, —CN, C1-4 alkyl, C1-4 haloalkyl and C1-4 alkoxy;
R32 and R33 are each independently selected from the group consisting of H, F, Cl, Br, I, —CN, C1-8 alkyl, C1-8 haloalkyl and C1-8 alkoxy;
R34 is selected from the group consisting of H, F, Cl, Br, 1, —CN, C1-8 alkyl, C2-8 alkenyl, C1-8 haloalkyl, C1-8 alkoxy, 3-12 membered carbocycle, 3-12 membered heterocycle, phenyl and 5-6 membered heteroaryl comprising 1 to 3 heteroatoms selected from N, O and S, wherein said 5-6 membered heteroaryl is further optionally substituted with from 1 to 3 substituents selected from F, Cl, Br, I, —CN, C1-4 alkyl, C1-4 haloalkyl and C1-4 alkoxy;
R42 is selected from the group consisting of H, F, Cl, Br, I, —CN, C1-8 alkyl, C1-8 haloalkyl and C1-8 alkoxy;
R43 is selected from the group consisting of H, F, Cl, Br, I, —CN, C1-8 alkyl, C1-8 haloalkyl and C1-8 alkoxy;
R44 is selected from the group consisting of H, F, Cl, Br, I, —CN, C1-8 alkyl, C1-8 haloalkyl and C1-8 alkoxy; and
R45 is selected from the group consisting of H, C1-8 alkyl, C1-8 haloalkyl, C1-8 alkoxy, and 3-12 membered cycloalkyl, wherein said C1-8 alkoxy, and 3-12 membered cycloalkyl are optionally substituted with 1-3 substituents selected from F, Cl, Br and I.

### Claim 2 (depends on 1)

The compound of claim 1 wherein R1 is methyl, cyclopropyl, cyclopropylmethyl, 1-azetidinyl, 1-methylcycloprop-1-yl, difluoromethyl, N-methylamino, ethyl, 2-methoxyeth-1-yl, 2-trimethylsilyleth-1-yl, propyl, 1,1,1-trifluoroprop-3-yl, butyl, morpholino, pyrrolidino, or 3-fluoroazetidin-1-yl.

### Claim 3 (depends on 1)

The compound of claim 1, wherein X1 is —O— or —N(H)—; X2 is absent; the subscript m is 1; and -(L)- is selected from the group consisting of —CH2—, —C(═O)—, —C(H)(CH3)—, —CH2—CH2—, —CH2—C(H)(CH3)—, —C(H)(CH3)—C(H2)—, —CH2CH2CH2—, —CH2—C(H)(CH13)—CH2— or —CH2CH2CH2CH2—.

### Claim 4 (depends on 1)

The compound of claim 1, wherein X1 is absent; X2 is —O— or —N(H)—; the subscript m is 1; and -(L)- is selected from the group consisting of —CH2—, —C(═O)—, —C(H)(CH3)—, —CH2—CH2—, —CH2—C(H)(CH3)—, —C(H)(CH3)—C(H2)—, —CH2CH2CH2—, —CH2—C(H)(CH3)—CH2—, and —CH2CH2CH2CH2—.

### Claim 5 (depends on 1)

The compound of claim 1, wherein the ring A is a 3-15 membered carbocyclyl, a 6-12 membered aryl, a 5-12 membered heteroaryl, or a 3-15 membered heterocyclyl.

### Claim 6 (depends on 1)

The compound of claim 1, wherein A is optionally substituted and is selected from azetidine, pyrrolidine, piperidine, morpholine, homopiperazine, and piperazine.

### Claim 7 (depends on 1)

The compound of claim 1, wherein the ring B is:
RD1 is selected from the group consisting of F, Cl, cyclopropyl, and 2-methoxy-3-pyridyl;
RD2 is H;
RD3 is selected from the group consisting of F, Cl, and Br, and
RD4 is H.

### Claim 8 (depends on 1)

The compound of claim 1, wherein:
is selected from the group consisting of:

### Claim 9 (depends on 1)

The compound of claim 1, wherein:
is selected from the group consisting of:

### Claim 10 (depends on 1)

The compound of claim 1, wherein RAA is selected from the group consisting of methyl, trifluoromethyl, ethyl, F, Cl, Br, and 1.

### Claim 11 (depends on 1)

The compound of claim 1, wherein RA is selected from the group consisting of

### Claim 12 (depends on 1)

The compound of claim 1, wherein the compound has the formula Ia:

### Claim 13 (depends on 1)

The compound of claim 1, which is a compound of formula Ib:

### Claim 14 (depends on 1)

The compound of claim 1, wherein the compound has the formula Id:

### Claim 15 (depends on 1)

The compound of claim 1, wherein:
has the formula:

### Claim 16 (depends on 1)

The compound of claim 1, wherein:
is selected from the group consisting of:

### Claim 17 (depends on 1)

The compound of claim 1, wherein the group:
is selected from the group consisting of:

### Claim 18 (depends on 1)

A pharmaceutical composition comprising a compound of formula I as described in claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

### Claim 19 (depends on 1)

The compound of claim 1 which is selected from:
and salts thereof.