# US 2019/0169187 A1 · S1pr2 antagonists and uses therefor

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- Number: US 2019/0169187 A1
- Document ID: US20190169187A1
- Status: Published application
- Kind: A1
- Application number: 16/269,339
- Filed: 2019-02-06
- Published: 2019-06-06
- Earliest claimed: 2015-06-01
- Assignees: Dalhousie University
- Applicants: Dalhousie University
- Inventors: Christopher McMaster; Gordon Simms
- Web page: https://patentgrep.com/patent/US20190169187A1

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 31/444: containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- 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 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 19/10: for osteoporosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/02: Ophthalmic agents
- C07C 229/24: having more than one carboxyl group bound to the carbon skeleton, e.g. aspartic acid
- C07C 317/48: the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07F 9/3808: {Acyclic saturated acids which can have further substituents on alkyl}
- C07J 31/006: {not covered by C07J31/003}
- C07F 9/091: {with hydroxyalkyl compounds with further substituents on alkyl}
- C07F 9/65583: {each of the hetero rings containing nitrogen as ring hetero atom}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- C07J: STEROIDS (seco-steroids C07C)

## Abstract

Methods and compositions are provided for the treatment of familial exudative vitreoretinopathy (FEVR) through the administration of a therapeutically effective amount of a sphingosine-1-phosphate receptor type 2 (S1PR2) antagonist. Also provided herein are (Z)-3-((2,6-dichloropyridin-4-yl)amino)-3-(((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)amino)acrylonitrile and analogs thereof, and their use in treating retinopathies and diseases characterized by insufficient angiogenesis.

## Claims

### Claim 1

A compound of formula (XI):
or a pharmaceutically-acceptable salt thereof,
wherein:
G is CR10 or NR11, wherein R10 and R11 are each independently selected from the group consisting of H, C1-C4 alkyl, and benzyl;
Rx and Ry are independently selected from the group consisting of H, C1-C4 alkyl, and benzyl; or Rx and Ry are joined to form a 5- or 6-membered heterocycloalkyl ring; and,
the cyano group is in the (Z) or (E) configuration.

### Claim 2 (depends on 1)

The compound of claim 1, wherein:
G is CR10 and R10 is H; and,
Ry is H.

### Claim 3 (depends on 2)

The compound of claim 2, selected from the group consisting of:
(E)-3-((2,6-dichloropyridin-4-yl)amino)-3-(((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)(methyl)amino)acrylonitrile;
(E)-3-((2,6-dichloropyridin-4-yl)amino)-3-(ethyl((4-isopropyl-1,3-dimethyl-1 H-pyrazolo[3,4-b]pyridin-6-yl)methyl)amino)acrylonitrile;
(E)-3-((2,6-dichloropyridin-4-yl)amino)-3-(((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)(propyl)amino)acrylonitrile;
(E)-3-(butyl((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)amino)-3-((2,6-dichloropyridin-4-yl)amino)acrylonitrile;
(E)-3-((2,6-dichloropyridin-4-yl)amino)-3-(isopropyl((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)amino)acrylonitrile;
(E)-3-(benzyl((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)amino)-3-((2,6-dichloropyridin-4-yl)amino)acrylonitrile; and,
a structural enantiomer of the foregoing, wherein the cyano group is in the (Z) form.

### Claim 4 (depends on 1)

The compound of claim 1, wherein:
G is CR10 and R10 is H; and,
Rx is H.

### Claim 5 (depends on 4)

The compound of claim 4, selected from the group consisting of:
(Z)-3-((2,6-dichloropyridin-4-yl)(methyl)amino)-3-(((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)amino)acrylonitrile;
(Z)-3-((2,6-dichloropyridin-4-yl)(ethyl)amino)-3-(((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)amino)acrylonitrile;
(Z)-3-((2,6-dichloropyridin-4-yl)(propyl)amino)-3-(((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)amino)acrylonitrile;
(Z)-3-(butyl(2,6-dichloropyridin-4-yl)amino)-3-(((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)amino)acrylonitrile;
(Z)-3-((2,6-dichloropyridin-4-yl)(isopropyl)amino)-3-(((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)amino)acrylonitrile;
(Z)-3-(benzyl(2,6-dichloropyridin-4-yl)amino)-3-(((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)amino)acrylonitrile; and,
a structural enantiomer of the foregoing, wherein the cyano group is in the (E) form.

### Claim 6 (depends on 1)

The compound of claim 1, wherein:
G is CR10; and,
Rx and Ry are each H.

### Claim 7 (depends on 6)

The compound of claim 6, selected from the group consisting of:
(Z)-3-((2,6-dichloropyridin-4-yl)amino)-3-((1-(4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)ethyl)amino)acrylonitrile;
(Z)-3-((2,6-dichloropyridin-4-yl)amino)-3-((1-(4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)propyl)amino)acrylonitrile;
(Z)-3-((2,6-dichloropyridin-4-yl)amino)-3-((1-(4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-methylpropyl)amino)acrylonitrile;
(Z)-3-((2,6-dichloropyridin-4-yl)amino)-3-((1-(4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-phenylethyl)amino)acrylonitrile; and,
a structural enantiomer of the foregoing, wherein the cyano group is in the (E) form.

### Claim 8 (depends on 1)

The compound of claim 1, wherein:
G is NR11; and,
Rx and Ry are each H.

### Claim 9 (depends on 8)

The compound of claim 8, selected from the group consisting of:
(E)-3-((2,6-dichloropyridin-4-yl)amino)-3-(2-(4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)hydrazinyl)acrylonitrile;
(E)-3-((2,6-dichloropyridin-4-yl)amino)-3-(2-(4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-methylhydrazinyl)acrylonitrile;
(E)-3-((2,6-dichloropyridin-4-yl)amino)-3-(2-ethyl-2-(4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)hydrazinyl)acrylonitrile;
(E)-3-((2,6-dichloropyridin-4-yl)amino)-3-(2-(4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)-2-propylhydrazinyl)acrylonitrile;
(E)-3-(2-butyl-2-(4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)hydrazinyl)-3-((2,6-dichloropyridin-4-yl)amino)acrylonitrile;
(E)-3-((2,6-dichloropyridin-4-yl)amino)-3-(2-isopropyl-2-(4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)hydrazinyl)acrylonitrile;
(E)-3-(2-benzyl-2-(4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)hydrazinyl)-3-((2,6-dichloropyridin-4-yl)amino)acrylonitrile; and,
a structural enantiomer of the foregoing, wherein the cyano group is in the (Z) form.

### Claim 10 (depends on 1)

The compound of claim 1, wherein:
G is CR10 and R10 is H.

### Claim 11 (depends on 10)

The compound of claim 10, selected from the group consisting of:
(Z)-3-((2,6-dichloropyridin-4-yl)(methyl)amino)-3-(((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)(methyl)amino)acrylonitrile;
(Z)-3-((2,6-dichloropyridin-4-yl)(methyl)amino)-3-(isopropyl((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)amino)acrylonitrile;
(Z)-3-((2,6-dichloropyridin-4-yl)(isopropyl)amino)-3-(((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)(methyl)amino)acrylonitrile;
(Z)-3-(benzyl((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)amino)-3-((2,6-dichloropyridin-4-yl)(methyl)amino)acrylonitrile;
(Z)-3-(benzyl(2,6-dichloropyridin-4-yl)amino)-3-(((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)(methyl)amino)acrylonitrile; and,
a structural enantiomer of the foregoing, wherein the cyano group is in the (E) form.

### Claim 12 (depends on 1)

The compound of claim 1, wherein:
G is C10 and C10 is H; and,
Rx and Ry are joined to form a 5- or 6-membered heterocycloalkyl ring.

### Claim 13 (depends on 12)

The compound of claim 12, selected from the group consisting of:
(Z)-2-(1-(2,6-dichloropyridin-4-yl)-3-((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)tetrahydropyrimidin-2(1H)-ylidene)acetonitrile;
(Z)-2-(1-(2,6-dichloropyridin-4-yl)-3-((4-isopropyl-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridin-6-yl)methyl)imidazolidin-2-ylidene)acetonitrile; and,
a structural enantiomer of the foregoing, wherein the cyano group is in the (E) form.

### Claim 14 (depends on 1)

A method of treating an eye condition in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of the compound of claim 1, or a pharmaceutically-acceptable salt thereof.

### Claim 15 (depends on 14)

The method of claim 14, wherein the eye condition is caused by a primary defect in retinal vascularization followed by secondary aberrant neovascularization that can result in retina detachment.

### Claim 16 (depends on 14)

The method of claim 14, wherein the eye condition is a retinopathy.

### Claim 17 (depends on 16)

The method of claim 16, wherein the retinopathy is selected from the group consisting of diabetic retinopathy, macular degeneration, hypertensive retinopathy, radiation retinopathy, solar retinopathy, retinopathy of prematurity (ROP), Norrie disease (ND), familial exudative vitreoretinopathy (FEVR), Coats' disease, sickle cell retinopathy, and retinitis pigmentosa.

### Claim 18 (depends on 17)

The method of claim 17, wherein the retinopathy is FEVR.

### Claim 19 (depends on 1)

A method of treating a disease characterized by insufficient angiogenesis in a subject in need thereof, comprising administering to the subject a pharmaceutically effective amount of the compound of claim 1, or a pharmaceutically-acceptable salt thereof.

### Claim 20 (depends on 19)

The method of claim 19, wherein the disease is selected from the group consisting of atherosclerosis, hypertension, diabetes, restenosis, pre-eclampsia, menorrhagia, neonatal respiratory distress, pulmonary fibrosis, nephropathy, osteoporosis, amyotrophic lateral sclerosis, stroke, and Alzheimer's disease.