# US 12,006,321 B2 · Substituted pyrazolo[1,5-a]pyrimidines as apelin receptor agonists

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- Number: US 12,006,321 B2
- Document ID: US12006321B2
- Status: Granted
- Kind: B2
- Application number: 17/742,977
- Filed: 2022-05-12
- Published: 2023-02-02
- Granted: 2024-06-11
- Earliest claimed: 2017-08-09
- Assignees: Sanford Burnham Prebys Medical Discovery Institute
- Applicants: Sanford Burnham Prebys Medical Discovery Institute
- Inventors: Layton H. Smith; Anthony B. Pinkerton; Paul Hershberger; Patrick Maloney; Danielle McAnally
- Web page: https://patentgrep.com/patent/US12006321B2

## CPC

- C07D 487/04: Ortho-condensed systems
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/02: Ophthalmic agents
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided herein are agonists of the apelin receptor of Formula (I): for the treatment of disease. The compounds disclosed herein are useful for the treatment of a range of cardiovascular, renal and metabolic conditions.

## Claims

### Claim 1

A compound of Formula (I):
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,
wherein:
R1 is H, halogen, CN, alkyl, C(O)N(R7)2, C(O)OH, C(O)OR6, NH2, O(alkyl), O(phenyl), or aryl, wherein the alkyl is optionally substituted with one or more substituents independently selected from the group consisting of OH and O(alkyl);
R2 is H, halogen, CN, alkyl, C(O)N(R7)2, C(O)OH, C(O)OR6, NH2, O(alkyl), O(phenyl), or aryl, wherein the alkyl is optionally substituted with one or more substituents independently selected from the group consisting of OH and O(alkyl);
R3 is alkyl;
R4 is alkyl, haloalkyl, or cycloalkyl;
R5 is C(O)N(R9)2, C(O)OH, or C(O)OR8;
each R6 is independently H, alkyl, haloalkyl, NH2, O(alkyl), O(haloalkyl), cycloalkyl, heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl;
each R7 is independently H, alkyl, haloalkyl, NH2, O(alkyl), O(haloalkyl), cycloalkyl, heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl;
R8 is H, alkyl, haloalkyl, NH2, O(alkyl), O(haloalkyl), cycloalkyl, heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl; and
each R9 is independently H, alkyl, haloalkyl, NH2, O(alkyl), O(haloalkyl), cycloalkyl, heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl.

### Claim 2 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:
R1 is H or alkyl; and
R2 is H or alkyl.

### Claim 3 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R4 is alkyl.

### Claim 4 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:
R5 is C(O)N(R9)2; and
each R9 is independently H or alkyl.

### Claim 5 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein R5 is C(O)OH.

### Claim 6 (depends on 1)

The compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof, wherein:
R5 is C(O)OR8; and
R8 is alkyl.

### Claim 7 (depends on 1)

A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of claim 1, or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.

### Claim 8 (depends on 7)

A method for inhibiting apelin receptor activity in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 7.

### Claim 9 (depends on 8)

The method of claim 8, wherein the subject has a disease or disorder selected from the group consisting of cardiac autonomic neuropathy, diabetes mellitus, a diabetic late complication, a diabetic macrovasculopathy, a diabetic microvasculopathy, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, insulin resistance, a metabolic disease, and a metabolic disorder.

### Claim 10 (depends on 9)

The method of claim 9, wherein the metabolic disease or metabolic disorder is metabolic syndrome.

### Claim 11 (depends on 8)

The method of claim 8, wherein the subject has a disease or disorder selected from the group consisting of cardiac hypertrophy, cardiomyopathy, a cardiovascular disease, a cardiovascular disorder, coronary heart disease, heart failure, left ventricular dysfunction, myocardial infarction, myocardial remodeling, stroke, and valvular heart disease.

### Claim 12 (depends on 11)

The method of claim 11, wherein the heart failure is selected from the group consisting of diabetic heart failure, diastolic heart failure, heart failure with a preserved ejection fraction, and systolic heart failure.

### Claim 13 (depends on 11)

The method of claim 11, wherein the left ventricular dysfunction is left ventricular dysfunction after myocardial infarction.

### Claim 14 (depends on 11)

The method of claim 11, wherein the myocardial remodeling is myocardial remodeling after cardiac surgery or myocardial remodeling after infarction.

### Claim 15 (depends on 8)

The method of claim 8, wherein the subject has a disease or disorder selected from the group consisting of atherosclerosis, ischemia damage, nonfunctional blood vessels, peripheral arterial occlusive disease, a vascular disease, and a vascular disorder.

### Claim 16 (depends on 15)

The method of claim 15, wherein the ischemia damage is selected from the group consisting of ischemia damage of the heart, ischemia damage of the kidney, and ischemia damage of the retina, or a combination thereof.

### Claim 17 (depends on 15)

The method of claim 15, wherein the vascular disease or vascular disorder is selected from the group consisting of vascular hypertrophy, a vascular permeability disorder, vascular remodeling, and vascular stiffness.

### Claim 18 (depends on 17)

The method of claim 17, wherein the vascular permeability disorder is vascular permeability.

### Claim 19 (depends on 8)

The method of claim 8, wherein the subject has a disease or disorder selected from the group consisting of acute renal failure, a central nervous system-dependent disturbed fluid homeostasis, a central nervous system-independent disturbed fluid homeostasis, chronic renal failure, and hypertension.

### Claim 20 (depends on 19)

The method of claim 19, wherein the hypertension is selected from the group consisting of portal hypertension, pulmonary hypertension, and systolic hypertension.

### Claim 21 (depends on 8)

The method of claim 8, wherein the subject has an infectious disease.