# US 11,299,487 B2 · Compounds and compositions as modulators of TLR signaling

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- Number: US 11,299,487 B2
- Document ID: US11299487B2
- Status: Granted
- Kind: B2
- Application number: 16/830,110
- Filed: 2020-03-25
- Published: 2020-10-01
- Granted: 2022-04-12
- Earliest claimed: 2019-03-26
- Assignees: Neuropore Therapies, Inc.
- Applicants: Neuropore Therapies, Inc.
- Inventors: Srinivasa Reddy Natala; Wolfgang J. Wrasidlo; Emily M. Stocking
- Web page: https://patentgrep.com/patent/US11299487B2

## CPC

- C07D 417/10: linked by a carbon chain containing aromatic rings
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- C07C 235/56: having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
- C07D 207/06: with radicals, containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D 211/10: with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 233/24: Radicals substituted by nitrogen atoms not forming part of a nitro radical
- C07D 249/06: with aryl radicals directly attached to ring atoms
- C07D 249/08: 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D 261/08: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 263/32: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 265/30: not condensed with other rings
- C07D 265/36: condensed with one six-membered ring
- C07D 271/06: 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
- C07D 275/02: not condensed with other rings
- C07D 277/28: Radicals substituted by nitrogen atoms
- C07D 295/033: with the ring nitrogen atoms directly attached to carbocyclic rings
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 401/10: linked by a carbon chain containing aromatic rings
- C07D 403/04: directly linked by a ring-member-to-ring-member bond
- C07D 403/10: linked by a carbon chain containing aromatic rings
- C07D 403/14: containing three or more hetero rings
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/14: containing three or more hetero rings
- C07D 409/10: linked by a carbon chain containing aromatic rings
- C07D 413/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 413/10: linked by a carbon chain containing aromatic rings
- C07D 413/14: containing three or more hetero rings
- C07D 417/04: directly linked by a ring-member-to-ring-member bond
- C07D 471/08: Bridged systems
- C07D 487/08: Bridged systems
- C07D 491/052: the oxygen-containing ring being six-membered
- C07D 498/02: in which the condensed system contains two hetero rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

The present disclosure relates to substituted aryl and heteroaryl compounds, pharmaceutical compositions comprising such compounds, and use of such compounds in methods of treatment or in medicaments for treatment of inflammatory diseases and certain neurological disorders that are related to inflammatory signaling processes, including but not limited to misfolded proteins.

## Claims

### Claim 1

A compound of Formula (A):
or a tautomer, or a pharmaceutically acceptable salt of any of the foregoing,
wherein
R1 is —OH;
R2 is —C(O)H;
R3 is C1-C6alkoxy or halogen;
G1 and G2 are each CH;
indicates that the ring is aromatic;
Y1 is C or N;
Y2 is CH, N, NH, S, or O;
Y3 is C or N;
Y4 is CH, N, NH, S, or O;
Y5 is CR7, N, NH, S, or O;
wherein no more than one of Y1, Y2, Y3, Y4, and Y5 is S or O and no more than four of Y1, Y2, Y3, Y4, and Y5 are N or NH;
R7 is H or C1-C6alkyl;
n is 0, 1, 2, or 3;
R4 is
indicates that the ring is saturated, partially unsaturated, or fully unsaturated;
G3 is CH(X1—R6a), C(X1—R6a), N, N(X1—R6a), S, or O;
G4 is CH(X2—R6b), C(X2—R6b), N, N(X2—R6b), S, or O;
G5 is CH(X3—R6c), C(X3—R6c), N, N(X3—R6c), S, or O;
G6 is CH(X4—R6d), C(X4—R6d), N, N(X4—R6d), S, or O; and
G7 is N, C, or CH;
X1, X2, X3, and X4 are each independently absent,
m is 1-6;
R6a, R6b, R6c, and R6d are each independently hydrogen, C1-C6alkyl, C1-C6alkoxy, halo, —OH, —NRpRq, aryl, heterocyclyl, heteroaryl, —C1-C6alkyl-heterocyclyl, —OC(O)-heterocyclyl, —C(O)Rh, —S(O)2NRw1Rw2, —S(O)2Ry, or —NRz1S(O)2Rz2, wherein the C1-C6alkyl and C1-C6alkoxy of R6a, R6b, R6c, and R6d are each independently unsubstituted or substituted with one or more groups selected from the group consisting of cycloalkyl and halogen; the aryl and heteroaryl of R6a, R6b, R6c, and R6d are each independently unsubstituted or substituted with one or more groups selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, C3-C8cycloalkyl, —OH, and C1-C6alkyl-OH; and the heterocyclyl, —C1-C6alkyl-heterocyclyl, and —OC(O)-heterocyclyl of R6a, R6b, R6c, and R6d are each independently unsubstituted or substituted with one or more groups selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, halo, —OH, C1-C6alkyl-OH, ═O, and ═S;
each Rh is independently selected from the group consisting of H, C1-C6alkyl, C1-C6alkoxy, and C3-C8cycloalkyl, and —NRrRs;
each Rp is independently H or C1-C6alkyl;
each Rq is independently C2-C3alkyl, —C(O)Rt, —C(O)ORu, or —C(O)NRv;
each Rr, Rs, Rw1, and Rz1 is independently selected from H and C1-C6alkyl; and
each Rt, Ru, Rv, Rw2, Ry, and Rz2 is independently selected from H, C1-C6alkyl, unsubstituted or substituted C3-C8cycloalkyl, and unsubstituted or substituted heterocyclyl;
or
G5 is CH(X3—R6c) or C(X3—R6c), G6 is CH(X4—R6d) or C(X4—R6d), and R6c and R6d are taken together with the carbon atoms to which they are attached to form a 6-membered aryl, a 6-membered heterocyclyl, or a 6-membered heteroaryl ring; wherein the 6-membered aryl, 6-membered heterocyclyl, and 6-membered heteroaryl rings are each independently unsubstituted or substituted.

### Claim 2 (depends on 1)

The compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R3 is selected from the group consisting of —OCH3, Cl, and F.

### Claim 3 (depends on 1)

The compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein
is selected from the group consisting of

### Claim 4 (depends on 1)

The compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein n is 0.

### Claim 5 (depends on 1)

The compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein
G3 is C(X1—R6a); X1 is absent,
m is 1-6; R6a is hydrogen, C1-C6alkyl, C1-C6haloalkyl, halo, C6-C12 aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl;
G4 is C(X2—R6b) or N; X2 is absent,
m is 1-6; and R6b is hydrogen, C1-C6alkyl, C1-C6haloalkyl, halo, C6-C12 aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl;
G5 is C(X3—R6c); X3 is absent,
m is 1-6; and R6c is hydrogen, C1-C6alkyl, C1-C6haloalkyl, halo, C6-C12 aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl;
G6 is C(X4—R d); X4 is absent,
m is 1-6; and R6d is hydrogen, C1-C6alkyl, C1-C6haloalkyl, halo, C6-C12 aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; and
G7 is C.

### Claim 6 (depends on 1)

The compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein one or more of R6, R6b, R6c, and R6d are independently selected from the group consisting of C1-C6alkyl, C1-C6alkoxy, halo, —OH, —NRpRq, aryl, heterocyclyl, heteroaryl, —C1-C6alkyl-heterocyclyl, —OC(O)-heterocyclyl, —C(O)Rh, —S(O)2NRw1Rw2, —S(O)2Ry, and —NRz1S(O)2Rz2.

### Claim 7 (depends on 1)

The compound of claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein the compound is

### Claim 8 (depends on 1)

A pharmaceutical composition comprising at least one compound according to claim 1, or a tautomer thereof, or a pharmaceutically acceptable salt of any of the foregoing, optionally further comprising a pharmaceutically acceptable excipient.