# US 10,245,259 B2 · Methods of treating RBP4 related diseases with triazolopyridines

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- Number: US 10,245,259 B2
- Document ID: US10245259B2
- Status: Granted
- Kind: B2
- Application number: 16/008,838
- Filed: 2018-06-14
- Published: 2018-12-20
- Granted: 2019-04-02
- Earliest claimed: 2018-06-14
- Assignees: Belite Bio, Inc
- Applicants: Belite Bio, Inc
- Inventors: Yu-Hsin Tom Lin; Cheng-Chi Irene Wang
- Web page: https://patentgrep.com/patent/US10245259B2

## CPC

- A61K 31/4545: containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 31/4985: Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 31/5365: ortho- or peri-condensed with heterocyclic ring systems
- A61K 31/5383: ortho- or peri-condensed with heterocyclic ring systems
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- 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

## Abstract

Provided herein are heterocyclic derivative compounds and pharmaceutical compositions comprising said compounds that are useful for the treatment of retinal binding protein (RBP4) related diseases, such as obesity and the like.

## Claims

### Claim 1

A method of treating a metabolic disease or disorder in a subject in need thereof, the method comprising administering to the subject a composition comprising a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof
wherein:
each R1 is independently halogen, haloalkyl, or alkyl;
R2 is —H, —OH, or halogen;
p is 0, 1, 2, 3, 4, or 5; and
A has the structure:
wherein:
α, β, χ, and δ are each independently absent or present, and when present each is a bond;
X is N;
Z1 is S, O, or N;
Z2 is S, O, N, or NR3;
R3 is H, C1-C4 alkyl, or oxetane; and
B is a substituted or unsubstituted fused 5-, 6-, or 7-membered ring structure; and
wherein the metabolic disease or disorder is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

### Claim 2 (depends on 1)

The method of claim 1, wherein:
when α is present, then Z1 and Z2 are N, X is N, β is present, and χ and δ are absent.

### Claim 3 (depends on 1)

The method of claim 1, wherein A has the structure
wherein
n is 0, 1, or 2;
α, β, χ, δ, ε, and ϕ are each independently absent or present, and when present each is a bond;
Z1 is S, O, or N;
Z2 is S, O, N or NR3,
wherein R3 is H, C1-C4 alkyl, or oxetane;
X is N;
Y1, Y2, Y3 and each occurrence of Y4 are each independently CR4, C(R5)2, NR6, O, N, SO2, or —(C═O)—, wherein:
each R4 is independently H, halogen, C1-C10 alkyl, C1-C10 cycloalkyl, —O(C1-C10 alkyl), —C(O)OH, —C(O)O(C1-C10 alkyl), —C(O)NH2, —C(O)NH (C1-C4 alkyl), —C(O)N(C1-C4 alkyl)2, —NHC(O)NH(C1-C10 alkyl), —NHC(O)N(C1-C4 alkyl)2, —SO2NH(C1-C10 alkyl), —SO2N(C1-C10 alkyl)2, —CN, or —CF3;
each R5 is independently H or C1-C10 alkyl; and
each R6 is independently H, C1-C10 alkyl, C3-C6 cycloalkyl, —(C1-C10 alkyl)CF3, —(C1-C10 alkyl)OCH3, —(C1-C10 alkyl)-halogen, —SO2(C1-C10 alkyl), —SO2(C1-C10 alkyl)-CF3, —SO2(C1-C10 alkyl)OCH3, —SO2(C1-C10 alkyl)-halogen, —C(O)(C1-C10 alkyl), —C(O)(C1-C10 alkyl)CF3, —C(O)(C1-C10 alkyl)OCH3, —C(O)(C1-C10 alkyl)-halogen, —C(O)NH(C1-C10 alkyl), —C(O)N(C1-C10 alkyl)2, —(C1-C10 alkyl)C(O)OH, —C(O)NH2, or oxetane.

### Claim 4 (depends on 1)

The method of claim 1, wherein:
when α is present, then Z1 and Z2 are N, X is N, β is present, and χ and δ are absent;
when ε and ϕ are each present, then n=1, and each of Y1, Y2, Y3, and Y4, are independently —CR4— or N; or
when ε and ϕ are each absent, then n=0, 1 or 2, each of Y1, Y2, Y3, and each occurrence of Y4 are independently C(R5)2, NR6, O, or SO2.

### Claim 5 (depends on 1)

The method of claim 1, wherein:
α, β, ε, and ϕ are present;
χ and δ are absent;
Z1 is N;
Z2 is N; and
X is N.

### Claim 6 (depends on 1)

The method of claim 1, wherein A has the structure:
wherein:
Y1, Y2, Y3 and Y4 are each independently CR4 or N; and
each R4 is independently H, halogen, C1-C10 alkyl, C1-C10 cycloalkyl, —O(C1-C10 alkyl), —C(O)OH, —C(O)O(C1-C10 alkyl), —C(O)NH2, —C(O)NH (C1-C4 alkyl), —C(O)N(C1-C4 alkyl)2, —NHC(O)NH(C1-C10 alkyl), —NHC(O)N(C1-C4 alkyl)2, —SO2NH(C1-C10 alkyl), —SO2N(C1-C10 alkyl)2, —CN, or —CF3.

### Claim 7 (depends on 1)

The method of claim 1, wherein A has the structure
wherein:
each R4 is independently H, halogen, C1-C4 alkyl, C3-C6 cycloalkyl, —O(C1-C4 alkyl), —CN, —CF3, —C(O)OH, —C(O)NH2, —C(O)N(CH3)2, —C(O)NHCH3, or —NHC(O)N(CH3)2.

### Claim 8 (depends on 1)

The method of claim 1, wherein each R1 is independently F, Br, Cl, C1-6 haloalkyl, or C1-6 alkyl.

### Claim 9 (depends on 1)

The method of claim 1, wherein each R1 is independently F or CF3.

### Claim 10

A method of treating a metabolic disease or disorder in a subject in need thereof, the method comprising administering to the subject a composition comprising a therapeutically effective amount of a compound having the structure:
or a pharmaceutically acceptable salt thereof; and
wherein the metabolic disease or disorder is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

### Claim 11

A method of treating a metabolic disease or disorder in a subject in need thereof, the method comprising administering to the subject a composition comprising a therapeutically effective amount of a compound having the structure:
or a pharmaceutically acceptable salt thereof; and
wherein the metabolic disease or disorder is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

### Claim 12 (depends on 1)

The method of claim 1, wherein the metabolic disease or disorder is non-alcoholic fatty liver disease (NAFLD).

### Claim 13 (depends on 1)

The method of claim 1, wherein the therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof is up to 25 mg per day, up to 50 mg per day, up to 75 mg per day, up to 100 mg per day, up to 150 mg per day, up to 200 mg per day, up to 400 mg per day, up to 600 mg per day, up to 800 mg per day, or up to 1000 mg per day.

### Claim 14 (depends on 1)

The method of claim 1, wherein 24 hours after administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, the serum or plasma levels of RBP4 are reduced by at least 50% from baseline.

### Claim 15 (depends on 1)

The method of claim 1, wherein 24 hours after administration of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, the serum or plasma levels of RBP4 are reduced by at least 1 mg/dL.

### Claim 16 (depends on 1)

The method of claim 1, wherein the disease or disorder is non-alcoholic steatohepatitis (NASH).

### Claim 17 (depends on 1)

The method of claim 1, wherein the compound is administered to the subject orally or intravenously.

### Claim 18 (depends on 1)

The method of claim 1, wherein the administration is to treat an existing disease or disorder.