# US 2023/0053860 A1 · Modulators of mas-related g-protein receptor x4 and related products and methods

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- Number: US 2023/0053860 A1
- Document ID: US20230053860A1
- Status: Published application
- Kind: A1
- Application number: 17/531,660
- Filed: 2021-11-19
- Published: 2023-02-23
- Earliest claimed: 2019-03-28
- Assignees: Escient Pharmaceuticals, Inc.
- Applicants: Escient Pharmaceuticals, Inc.
- Inventors: Adam Yeager; Brandon Selfridge; Marcos Sainz; Esther Martinborough; Marcus Boehm; Liming Huang
- Web page: https://patentgrep.com/patent/US20230053860A1

## CPC

- A61K 31/192: having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid {(cannabinoids A61K31/658)}
- A61P 17/04: Antipruritics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 37/02: Immunomodulators
- C07C 43/23: containing hydroxy or O-metal groups
- C07C 49/753: containing ether groups, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] groups
- C07C 65/24: polycyclic
- C07C 65/28: having unsaturation outside the aromatic rings
- C07C 69/76: Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C 69/78: Benzoic acid esters
- C07C 69/92: with etherified hydroxyl groups
- C07C 217/48: the carbon skeleton being unsaturated and containing rings
- C07C 217/76: having amino groups bound to carbon atoms of six-membered aromatic rings and etherified hydroxy groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
- C07C 235/42: having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
- C07C 237/22: having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated (peptides C07K)
- C07C 255/29: containing cyano groups and acylated amino groups bound to the carbon skeleton
- C07C 255/41: the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
- C07C 255/54: containing cyano groups and etherified hydroxy groups bound to the carbon skeleton
- C07C 255/57: containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
- C07C 259/10: having carbon atoms of hydroxamic groups bound to carbon atoms of six-membered aromatic rings
- C07C 309/15: the nitrogen atom of at least one of the amino groups being part of any of the groups [IMAGE cpc-sch-C07C-0975.gif], X being a hetero atom, Y being any atom
- C07C 309/42: having the sulfo groups bound to carbon atoms of non-condensed six-membered aromatic rings
- C07C 311/21: having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
- C07C 311/51: Y being a hydrogen or a carbon atom
- C07C 311/58: having nitrogen atoms of the sulfonylurea groups bound to hydrogen atoms or to acyclic carbon atoms
- C07D 205/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 207/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 207/325: with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
- C07D 207/36: Oxygen or sulfur atoms
- C07D 209/20: substituted additionally by nitrogen atoms, e.g. tryptophane
- C07D 211/42: attached in position 3 or 5
- C07D 211/46: having a hydrogen atom as the second substituent in position 4
- C07D 213/65: attached in position 3 or 5
- C07D 213/79: Acids; Esters
- C07D 213/84: Nitriles
- C07D 217/02: with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D 217/24: Oxygen atoms
- C07D 233/64: with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
- C07D 241/24: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 249/08: 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D 257/04: Five-membered rings
- C07D 261/18: Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
- C07D 263/04: having no double bonds between ring members or between ring members and non-ring members
- 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 271/06: 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
- C07D 271/07: with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
- C07D 277/34: Oxygen atoms
- C07D 277/64: with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
- C07D 285/08: 1,2,4-Thiadiazoles; Hydrogenated 1,2,4-thiadiazoles
- C07D 307/60: Two oxygen atoms, e.g. succinic anhydride
- C07D 307/68: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 307/79: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D 307/83: Oxygen atoms
- C07D 317/46: condensed with one six-membered ring
- C07D 333/38: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 333/54: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 491/107: with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07C 2601/04: with a four-membered ring
- C07C 2601/08: the ring being saturated
- C07C 2601/14: The ring being saturated
- C07C 2602/08: the other ring being five-membered, e.g. indane
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Methods are provided for modulating MRGPR X4 generally, or for treating a MRGPR X4 dependent condition more specifically, by contacting the MRGPR X4 or administering to a subject in need thereof, respectively, an effective amount of a compound having the structure of Formula (I): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein n, x, A, Q1, Q2, Z, R, R1, R2, R3, R4 and R5 are as defined herein. Pharmaceutical compositions containing such compounds, as well as to compounds themselves, are also provided.

## Claims

### Claim 1

A compound having one of the following structures, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof:
Cpd No.
Structure
1-55
1-78
5-1
4-10
1-65
4-11
1-58
1-56
9-1
1-82
1-85
1-29
1-101
2-3
1-103
1-112
4-7
11-1

### Claim 2 (depends on 1)

The compound of claim 1, wherein the compound is Cpd. No. 1-55.

### Claim 3 (depends on 1)

The compound of claim 1, wherein the compound is Cpd. No. 1-78.

### Claim 4 (depends on 1)

The compound of claim 1, wherein the compound is Cpd. No. 5-1.

### Claim 5 (depends on 1)

The compound of claim 1, wherein the compound is Cpd. No. 4-10.

### Claim 6 (depends on 1)

The compound of claim 1, wherein the compound is Cpd. No. 1-65.

### Claim 7 (depends on 1)

The compound of claim 1, wherein the compound is Cpd. No. 4-11.

### Claim 8 (depends on 1)

The compound of claim 1, wherein the compound is Cpd. No. 1-58.

### Claim 9 (depends on 1)

The compound of claim 1, wherein the compound is Cpd. No. 1-56.

### Claim 10 (depends on 1)

The compound of claim 1, wherein the compound is Cpd. No. 9-1.

### Claim 11 (depends on 1)

The compound of claim 1, wherein the compound is Cpd. No. 1-82.

### Claim 12 (depends on 1)

The compound of claim 1, wherein the compound is Cpd. No. 1-85.

### Claim 13 (depends on 1)

The compound of claim 1, wherein the compound is Cpd. No. 1-29.

### Claim 14 (depends on 1)

The compound of claim 1, wherein the compound is Cpd. No. 1-101.

### Claim 15 (depends on 1)

The compound of claim 1, wherein the compound is Cpd. No. 2-3.

### Claim 16 (depends on 1)

The compound of claim 1, wherein the compound is Cpd. No. 1-103.

### Claim 17 (depends on 1)

The compound of claim 1, wherein the compound is Cpd. No. 1-112.

### Claim 18 (depends on 1)

The compound of claim 1, wherein the compound is Cpd. No. 4-7.

### Claim 19 (depends on 1)

The compound of claim 1, wherein the compound is Cpd. No. 11-1.

### Claim 20 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)

A pharmaceutical composition comprising a compound of any one of claims 1-19 and a pharmaceutically acceptable excipient.

### Claim 21 (depends on 20)

The pharmaceutical composition of claim 20, further comprising a second therapeutic agent.

### Claim 22 (depends on 21)

The pharmaceutical composition of claim 21, wherein the second therapeutic agent is ursodeoxycholic acid (UDCA), norUrsodeoxycholic acid, cholestyramine, stanozolol, naltrexone, rifampicin, Alisol B 23-acetate (AB23A), curcumin, dihydroartemisinin, fenofibrate, bezafibrate, metronidazole, methotrexate, colchicine, metformin, betaine, glucagon, naltrexone, a farnesoid X-receptor (FXR) agonist, a peroxisome proliferator-activated receptor (PPAR) agonist, a thyroid hormone receptor beta (TRβ) agonist, or any combination thereof.

### Claim 23 (depends on 22)

The pharmaceutical composition of claim 22 wherein:
(a) the FXR agonist is obeticholic acid, Turofexorate isopropyl (WAY-362450), 3-(2,6-dichlorophenyl)-4-(3′-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole (GW4064), PX20606 (PX-102), PX-101, INT-767, INT-787, TERN-101, altenusin, tropifexor (LJN452), nidufexor, turofexorate isopropyl, fexaramine, silymarin, silybin, hedragonic acid, cafestol, Cilofexor (GS-9674 or Px-104), EDP-305, BAR704, BAR502, EYP-001, RDX-023, AGN-242266, HPG-1860, MET-409, AGN-242256, EP-024297, IOT-022, M-480, INV-33, RDX023-02, or any combination thereof,
(b) the PPAR agonist is a PPAR-alpha agonist, a PPAR-gamma agonist, a PPAR-delta agonist, a PPAR-alpha/gamma dual agonist, a PPAR alpha/delta dual agonist, a PPAR gamma/delta dual agonist, or PPAR alpha/gamma/delta pan agonist, optionally wherein:
the PPAR alpha agonist is fenofibrate, ciprofibrate, pemafibrate, gemfibrozil, clofibrate, binifibrate, clinofibrate, clofibric acid, nicofibrate, pirifibrate, plafibride, ronifibrate, theofibrate, tocofibrate, or SRI 0171;
the PPAR gamma agonist is rosiglitazone, pioglitazone, deuterium-stabilized R-pioglitazone, efatutazone, ATx08-001, OMS-405, CHS-131, THR-0921, SER-150-DN, KDT-501, GED-0507-34-Levo, CLC-3001, or ALL-4;
the PPAR delta agonist is GW501516 (endurabol or ({4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)sulfanyl]-2-methylphenoxy} acetic acid)), MBX8025 (seladelpar or {2-methyl-4-[5-methyl-2-(4-trifluoromethyl-phenyl)-2H-[1,2,3]triazol-4-ylmethylsylfanyl]-phenoxy}-acetic acid), GW0742 ([4-[[[2-[3-fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]-thio]-2-methyl phenoxy] acetic acid), L165041, HPP-593, or NCP-1046;
the PPAR alpha/gamma agonist is saroglitazar, aleglitazar, muraglitazar, tesaglitazar, or DSP-8658;
the PPAR alpha/delta agonist is elafibranor or T913659;
the PPAR gamma/delta agonist is a conjugated linoleic acid (CLA) or T3D-959; and
the PPAR alpha/gamma/delta agonist is IVA337 (lanifibranor), TTA (tetradecylthioacetic acid), bavachinin, GW4148, GW9135, bezafibrate, lobeglitazone, 2-(4-(5,6-methylenedioxybenzo[d]-thiazol-2-yl)-2-methylphenoxy)-2-methylpropanoic acid (MHY2013), or CS038; or
(c) the TRβ agonist is sobetirome, eprotirome, GC-24, MGL-3196, MGL-3745, VK-2809, KB141 [3,5-dichloro-4-(4-hydroxy-3-isopropylphenoxy) phenylacetic acid], MB07811 (2R,4S)-4-(3-chlorophenyl)-2-[(3,5-dimethyl-4-(4′-hydroxy-3′-isopropylbenzyl)phenoxy)-methyl]-2-oxido-[1,3,2]-dioxaphosphonane), or any combination thereof.