# US 11,998,537 B2 · Substituted indole dimer compounds

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- Number: US 11,998,537 B2
- Document ID: US11998537B2
- Status: Granted
- Kind: B2
- Application number: 17/287,735
- Filed: 2019-10-22
- Published: 2021-12-23
- Granted: 2024-06-04
- Earliest claimed: 2018-10-24
- Assignees: Bristol-Myers Squibb Company
- Applicants: Bristol-Myers Squibb Company
- Inventors: Alaric J. Dyckman; Brian K. Whiteley; John L. Gilmore
- Web page: https://patentgrep.com/patent/US11998537B2

## CPC

- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- A61K 47/54: the modifying agent being an organic compound
- A61K 47/55: the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
- A61P 37/00: Drugs for immunological or allergic disorders
- 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)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Disclosed are compounds of Formula (I) Formula (I) N-oxides, or salts thereof, wherein G1, G2, L, R1a, R1b, R4, R5, n, m, x, and y are defined herein. Also disclosed are methods of using such compounds as inhibitors of signaling through Toll-like receptor 7, or 8, or 9, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating inflammatory and autoimmune diseases.

## Claims

### Claim 1

A compound of Formula (I)
or N-oxide or a salt thereof, wherein:
L is —(CH2)q— or -L1-NRxC(O)—(CH2)t—C(O)NRx-L2-;
L1 and L2 are independently —(CH2)1-3—;
q is an integer in the range of 10 to 30;
t is an integer in the range of 2 to 24;
G1 and G2 are independently:
(iv) a 9-membered heterocyclic ring selected from:
or
(v) 10-membered heterocyclic ring selected from:
R1a and R1b are independently H, Cl, —CN, C1-4 alkyl, C1-3 fluoroalkyl, C1-3 hydroxyalkyl, hydroxy-fluoroalkyl, C3-6 cycloalkyl, —CH2(C3-6 cycloalkyl), —C(O)O(C1-3 alkyl), or tetrahydropyranyl;
each R2 is independently halo, —CN, —OH, —NO2, C1-4 alkyl, C1-2 fluoroalkyl, C1-2 cyanoalkyl, C1-3 hydroxyalkyl, C1-3 aminoalkyl, —O(CH2)1-2OH, —(CH2)0-4O(C1-4 alkyl), C1-3 fluoroalkoxy, —(CH2)1-4O(C1-3 alkyl), —O(CH2)1-2OC(O)(C1-3 alkyl), —O(CH2)1-2NRxRx, —C(O)O(C1-3 alkyl), —(CH2)0-2C(O)NRyRy, —C(O)NR4C1-5 hydroxyalkyl), —C(O)NRx(C2-6 alkoxyalkyl), —C(O)NRx(C3-6 cycloalkyl), —NRyRy, —NRy(C1-3 fluoroalkyl), —NRy(C1-4 hydroxyalkyl), —NRxH2(phenyl), —NRxS(O)2(C3-6 cycloalkyl), —NRx(O)(C1-3 alkyl), —NRxH2(C3-6 cycloalkyl), —(CH2)0-2S(O)2(C1-3 alkyl), —(CH2)0-2(C3-6 cycloalkyl), —(CH2)0-2(phenyl), morpholinyl, dioxothiomorpholinyl, dimethyl pyrazolyl, methylpiperidinyl, methylpiperazinyl, amino-oxadiazolyl, imidazolyl, triazolyl, or —C(O)(thiazolyl);
R2a is C1-6 alkyl, C1-3 fluoroalkyl, C1-6 hydroxyalkyl, C1-3 aminoalkyl, —(CH2)0-4O(C1-3 alkyl), C3-6 cycloalkyl, —(CH2)1-3C(O)NRxRx, —CH2(C3-6 cycloalkyl), —CH2(phenyl), tetrahydrofuranyl, tetrahydropyranyl, or phenyl;
each R2b is independently H, halo, —CN, —NRxRx, C1-6 alkyl, C1-3 fluoroalkyl, C1-3 hydroxyalkyl, C1-3 fluoroalkoxy, —(CH2)0-2O(C1-3 alkyl), —(CH2)0-3C(O)NRxRx, —(CH2)1-3(C3-6 cycloalkyl), —C(O)O(C1-3 alkyl), —C(O)NR4C1-3 alkyl), —CRx═CRxRx, or —CRx═CH(C3-6 cycloalkyl);
R2c is R2a or R2b;
R2d is R2a or R2b; provided that one of R2c and R2d is R2a, and the other of R2c and R2 is R2b;
each R4 is independently F, —OH, C1-2 alkyl, or —OCH3; or two R4 attached to the same carbon atom form ═O; or wherein when m or n is at least 2, two R4, each attached to a different carbon atom adjacent to the nitrogen atom in a piperidinyl ring, can form a —CH2CH2— bridge;
each R5 is independently F, Cl, —CN, C1-3 alkyl, C1-2 fluoroalkyl, or —OCH3;
each Rx is independently H or —CH3;
each Ry is independently H or C1-6 alkyl;
m is zero, 1, 2, 3, or 4;
n is zero, 1, 2, 3, or 4;
each p is independently zero, 1, 2, 3, or 4;
x is zero, 1, or 2; and
y is zero, 1, or 2.

### Claim 2 (depends on 1)

The compound according to claim 1, or N-oxide or a salt thereof, wherein:
each of G1 and G2 is independently:

### Claim 3 (depends on 1)

The compound according to claim 1, or N-oxide or a salt thereof, wherein:
q is an integer in the range of 12 to 24; and
t is an integer in the range of 2 to 20.

### Claim 4 (depends on 1)

The compound according to claim 1, or N-oxide or a salt thereof, wherein:
R1a and R1b are independently H, Cl, —CN, C1-4 alkyl, C1-2 fluoroalkyl, C1-2 hydroxyalkyl, or —C(O)O(C1-2 alkyl);
each R2 is independently F, Cl, —CN, —OH, C1-4 alkyl, C1-2 fluoroalkyl, C1-2 cyanoalkyl, C1-3 hydroxyalkyl, C1-3 aminoalkyl, C1-4 alkoxy, —NRyRy, —C(O)NRyRy, —C(O)NRx(C1-4 hydroxyalkyl), —C(O)NRx(C2-4 alkoxyalkyl), —C(O)NRx(C3-6 cycloalkyl), —S(O)2(C1-3 alkyl), C3-6 cycloalkyl, morpholinyl, phenyl, or dimethyl pyrazolyl;
each R4 is independently F, —CH3, or —OCH3;
each R5 is independently F, Cl, —CN, C1-2 alkyl, or —OCH3;
m is zero, 1, or 2;
n is zero, 1, or 2;
p is zero, 1, or 2;
x is zero, or 1; and
y is zero, or 1.

### Claim 5 (depends on 1)

The compound according to claim 1, or N-oxide or a salt thereof, wherein:
R1a and R1b are independently —CH2CH3 or —CH(CH3)2;
each R2 is independently —CH3 or —OCH3;
each R2a is —CH3;
each R2b is independently H, Cl, or —CH3;
each R4 is independently F, —CH3, or —OCH3; and
each R5 is independently F, Cl, —CN, —CH3, —CF3, or —OCH3.

### Claim 6 (depends on 1)

The compound according to claim 1 or a salt thereof, wherein:
G1 and G2 are each
R1a and R1b are each —CH(CH3)2;
each R2 is —OCH3;
L is —(CH2)18— or -L1-NRx(O)—(CH2)t—C(O)NRx-L2-;
L1 and L2 are each —(CH2)2—;
t is an integer in the range of 2 to 12;
m is zero;
n is zero;
each p is 1;
x is zero; and
y is zero.

### Claim 7 (depends on 1)

The compound according to claim 1 or a salt thereof, wherein said compound is:
N1,N13-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)tridecanediamide (1);
N1,N14-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)tetradecanediamine (2);
N1,N12-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)dodecanediamide (3);
N1,N11-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)undecanediamide (4);
N1,N9-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)nonanediamide (5);
N1,N8-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)octanediamide (6);
N1,N10-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)decanediamide (7);
N1,N7-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)heptanediamide (8);
N1,N6-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)adipamide (9);
N1,N12-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)dodecanediamide (10);
N1,N4-bis(2-(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)ethyl)succinamide (11); or
1,18-bis(4-(3-isopropyl-2-(8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-6-yl)-1H-indol-5-yl)piperidin-1-yl)octadecane (12).

### Claim 8 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically-acceptable salt thereof; and a pharmaceutically acceptable carrier.