# US 10,479,775 B1 · PPAR agonists, compounds, pharmaceutical compositions, and methods of use thereof

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- Number: US 10,479,775 B1
- Document ID: US10479775B1
- Status: Granted
- Kind: B1
- Application number: 16/510,976
- Filed: 2019-07-15
- Published: 2019-11-07
- Granted: 2019-11-19
- Earliest claimed: 2015-10-07
- Assignees: Mitobridge, Inc.; The Salk Institute for Biological Studies
- Applicants: Mitobridge, Inc.; The Salk Institute for Biological Studies
- Inventors: Michael Downes; Ronald M. Evans; Arthur Kluge; Bharat Lagu; Masanori Miura; Sunil Kumar Panigrahi; Michael Patane; Susanta Samajdar; Ramesh Senaiar; Taisuke Takahashi
- Web page: https://patentgrep.com/patent/US10479775B1

## CPC

- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- C07D 233/64: with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
- C07D 405/10: linked by a carbon chain containing aromatic rings
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided herein are compounds and compositions useful in increasing PPARδ activity. The compounds and compositions provided herein are useful for the treatment of PPARδ related diseases (e.g., muscular diseases, vascular disease, demyelinating disease, and metabolic diseases).

## Claims

### Claim 1

A compound having the structure of Formula (Ibb):
or a pharmaceutically acceptable salt thereof, wherein:
R1 is hydrogen, halogen, —C1-C4-alkyl, —C1-C4-haloalkyl, —CN, —C1-C4-alkoxy, —C1-C4-haloalkoxy, or —C3-C6-cycloalkyl;
R2 is hydrogen, halogen, —CN, —C1-C4-alkyl, —C1-C4-haloalkyl, —C3-C6-cycloalkyl, —C1-C4-alkoxy, —C1-C4-haloalkoxy, —S(C1-C4-alkyl), —SO2(C1-C4-alkyl), 5- or 6-membered heterocyclyl, aryl, 5-membered heteroaryl, —≡—R2A, —O(CH2)mR2B, —NH(C1-C4-alkyl), —N(C1-C4-alkyl)2, or —C(O)(C1-C4-alkyl), wherein aryl and heteroaryl are optionally substituted with halogen, —OH, —CN, C1-C4-alkyl, formyl, acetyl, acetoxy, or carboxy, and wherein m is an integer having value of 1, 2, or 3;
R2A and R2B are each independently —C1-C4-alkyl, —C1-C4-haloalkyl, or —C3-C6-cycloalkyl;
each R20 is independently hydrogen, halogen, —C1-C4-alkyl, —CN, or —C1-C4-alkoxy; and
x is an integer having a value of 1 or 2.

### Claim 2 (depends on 1)

The compound of claim 1, wherein R2 is halogen, —C1-C4-alkyl, —C1-C4-haloalkyl, —C1-C4-haloalkoxy, —S(C1-C4-alkyl), or furanyl, wherein the furanyl can be optionally substituted with —C1-C4-alkyl, or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound of claim 1, wherein R2 is halogen, —CH3, —C1-haloalkyl, —C1-haloalkoxy, —SCH3, or furanyl, wherein the furanyl can be optionally substituted with —CH3, or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 3)

The compound of claim 3, wherein R1 is hydrogen or halogen, or a pharmaceutically acceptable salt thereof.

### Claim 5 (depends on 4)

The compound of claim 4, wherein each R20 is independently hydrogen or halogen, or a pharmaceutically acceptable salt thereof.

### Claim 6 (depends on 5)

The compound of claim 5, wherein R2 is chloro, unsubstituted furanyl, —CH3, —CF3, —OCF3, —OCHF2, or —SCH3, or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 5)

The compound of claim 5, wherein R2 is —CF3 or —OCF3, or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 5)

The compound of claim 5, wherein R2 is —CF3, or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 8)

The compound of claim 8, wherein R1 is hydrogen or fluoro, or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 9)

The compound of claim 9, wherein R20 is hydrogen or fluoro, or a pharmaceutically acceptable salt thereof.

### Claim 11

(R)-3-methyl-6-(2-((5-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoic acid, or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

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

### Claim 13 (depends on 1)

A method of treating a PPARδ related disease or condition in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 13)

The method of claim 13, wherein the PPARδ related disease is a muscle structure disorder, a neuronal activation disorder, a muscle fatigue disorder, a muscle mass disorder, a mitochondrial disease, a beta oxidation disease, a metabolic disease, a cancer, a vascular disease, an ocular vascular disease, a muscular eye disease, or a renal disease.

### Claim 15 (depends on 14)

The method of claim 14, wherein:
the muscle structure disorder is selected from Bethlem myopathy, central core disease, congenital fiber type disproportion, distal muscular dystrophy (MD), Duchenne & Becker MD, Emery-Dreifuss MD, facioscapulohumeral MD, hyaline body myopathy, limb-girdle MD, a muscle sodium channel disorders, myotonic chondrodystrophy, myotonic dystrophy, myotubular myopathy, nemaline body disease, oculopharyngeal MD, or stress urinary incontinence;
the neuronal activation disorder is selected from amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, Guillain-Barre syndrome, Lambert-Eaton syndrome, multiple sclerosis, myasthenia gravis, nerve lesion, peripheral neuropathy, spinal muscular atrophy, tardy ulnar nerve palsy, or toxic myoneural disorder;
the muscle fatigue disorder is selected from chronic fatigue syndrome, diabetes (type I or II), glycogen storage disease, fibromyalgia, Friedreich's ataxia, intermittent claudication, lipid storage myopathy, MELAS, mucopolysaccharidosis, Pompe disease, or thyrotoxic myopathy;
the muscle mass disorder is cachexia, cartilage degeneration, cerebral palsy, compartment syndrome, critical illness myopathy, inclusion body myositis, muscular atrophy (disuse), sarcopenia, steroid myopathy, or systemic lupus erythematosus;
the mitochondrial disease is selected from Alpers's Disease, CPEO-Chronic progressive external ophthalmoplegia, Kearns-Sayra Syndrome (KSS), Leber Hereditary Optic Neuropathy (LHON), MELAS-Mitochondrial myopathy, encephalomyopathy, lactic acidosis, and stroke-like episodes, MERRF-Myoclonic epilepsy and ragged-red fiber disease, NARP-neurogenic muscle weakness, ataxia, and retinitis pigmentosa, or Pearson Syndrome;
the beta oxidation disease is selected from systemic carnitine transporter, carnitine palmitoyltransferase (CPT) II deficiency, very long-chain acyl-CoA dehydrogenase (LCHAD or VLCAD) deficiency, trifunctional enzyme deficiency, medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, short-chain acyl-CoA dehydrogenase (SCAD) deficiency or riboflavin-responsive disorders of β-oxidation (RR-MADD);
the metabolic disease is selected from hyperlipidemia, dyslipidemia, hyperchlolesterolemia, hypertriglyceridemia, HDL hypocholesterolemia, LDL hypercholesterolemia and/or HLD non-cholesterolemia, VLDL hyperproteinemia, dyslipoproteinemia, apolipoprotein A-I hypoproteinemia, atherosclerosis, disease of arterial sclerosis, disease of cardiovascular systems, cerebrovascular disease, peripheral circulatory disease, metabolic syndrome, syndrome X, obesity, diabetes (type I or II), hyperglycemia, insulin resistance, impaired glucose tolerance, hyperinsulinism, diabetic complication, cardiac insufficiency, cardiac infarction, cardiomyopathy, hypertension, Non-alcoholic fatty liver disease (NAFLD), Nonalcoholic steatohepatitis (NASH), thrombus, Alzheimer disease, neurodegenerative disease, demyelinating disease, multiple sclerosis, adrenal leukodystrophy, dermatitis, psoriasis, acne, skin aging, trichosis, inflammation, arthritis, asthma, hypersensitive intestine syndrome, ulcerative colitis, Crohn's disease, or pancreatitis;
the cancer is a cancer of the colon, large intestine, skin, breast, prostate, ovary, or lung;
the vascular disease is selected from peripheral vascular insufficiency, peripheral vascular disease, intermittent claudication, peripheral vascular disease (PVD), peripheral artery disease (PAD), peripheral artery occlusive disease (PAOD), or peripheral obliterative arteriopathy;
the ocular vascular disease is selected from age-related macular degeneration (AMD), stargardt disease, hypertensive retinopathy, diabetic retinopathy, retinopathy, macular degeneration, retinal haemorrhage, or glaucoma;
the muscular eye disease is selected from strabismus, progressive external ophthalmoplegia, esotropia, exotropia, a disorder of refraction and accommodation, hypermetropia, myopia, astigmatism, anisometropia, presbyopia, a disorders of accommodation, or internal ophthalmoplegia; and
the renal disease is selected from glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, acute nephritis, recurrent hematuria, persistent hematuria, chronic nephritis, rapidly progressive nephritis, acute kidney injury, chronic renal failure, diabetic nephropathy, or Bartter's syndrome.

### Claim 16 (depends on 11)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier or excipient and the compound of claim 11 or pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 15)

The method of claim 15, comprising administering to the subject in need thereof a therapeutically effective amount of (R)-3-methyl-6-(2-((5-methyl-2-(6-(trifluoromethyl)pyridin-3-yl)-1H-imidazol-1-yl)methyl)phenoxy)hexanoic acid, or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 17)

The method of claim 17, wherein the PPARδ related disease is a renal disease.

### Claim 19 (depends on 18)

The method of claim 18, wherein the renal disease is acute kidney injury.

### Claim 20 (depends on 15)

The method of claim 15, wherein the renal disease is acute kidney injury.