# US 2015/0307533 A1 · Spirocyclic sulfones as gamma secretase inhibitors

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- Number: US 2015/0307533 A1
- Document ID: US20150307533A1
- Status: Published application
- Kind: A1
- Application number: 14/647,769
- Filed: 2013-11-22
- Published: 2015-10-29
- Earliest claimed: 2012-11-29
- Assignees: Merck Sharp & Dohme Corp.
- Applicants: Merck Sharp & Dohme Corp.
- Inventors: DMITRI PISSARNITSKI; ZHIQIANG ZHAO
- Web page: https://patentgrep.com/patent/US20150307533A1

## CPC

- C07F 9/6561: containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
- A61K 31/27: of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/353: 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
- A61K 31/355: Tocopherols, e.g. vitamin E
- A61K 31/357: having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
- A61K 31/382: having six-membered rings, e.g. thioxanthenes (thiothixene A61K31/496)
- A61K 31/403: condensed with carbocyclic rings, e.g. carbazole
- A61K 31/473: ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
- A61K 31/665: having oxygen as a ring hetero atom, e.g. fosfomycin
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- C07D 311/80: Dibenzopyrans; Hydrogenated dibenzopyrans
- C07D 491/107: with only one oxygen atom as ring hetero atom in the oxygen-containing ring
- C07D 493/10: Spiro-condensed systems
- C07D 495/10: Spiro-condensed systems
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)
- 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)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

Disclosed herein are compounds of Formula (I), wherein each of the substituents is given the definition as set forth in the specification and claims. Also disclosed are pharmaceutical compositions containing the compound of Formula (I) and use of the compound in the treatment of neurodegenerative diseases or conditions such as Alzheimer's disease.

## Claims

### Claim 1

A compound of the Formula (I):
wherein:
A is a 4 to 7 membered spirocyclic ring comprising at least one heteroatom selected from the group consisting of N, O, S, S(O)2, P(O)R1, and N—S(O)2—R1, wherein the spirocyclic ring is optionally substituted with 1 to 3 substituents selected from the group consisting of C1-3alkyl and ═O;
R1 is C1-6alkyl optionally substituted with halo;
Each L1 is independently selected from the group consisting of 1) C1-3alkyl optionally substituted with halo, and 2) halo;
Each L2 is independently selected from the group consisting of 1) C1-3alkyl optionally substituted with halo, and 2) halo; and
n is 0 to 3.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein L1 and L2 are halo.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein L1 is fluoro and L2 is chloro.

### Claim 4 (depends on 1)

The compound according to claim 1, wherein the compound is of Formula (Ia)

### Claim 5 (depends on 1)

The compound according to claim 1, wherein the compound is of Formula (II)

### Claim 6 (depends on 5)

The compound according to claim 5, wherein A is a 4 to 7 membered spirocyclic ring comprising at least one O heteroatom.

### Claim 7 (depends on 5)

The compound according to claim 5, wherein A is a 4 to 7 membered spirocyclic ring comprising one N heteroatom.

### Claim 8 (depends on 5)

The compound according to claim 5, wherein A is a 4-7 membered spirocyclic ring comprising one S heteroatom.

### Claim 9 (depends on 5)

The compound according to claim 5, wherein A is a 4-7 membered spirocyclic ring comprising one S(O)2 heteroatom.

### Claim 10 (depends on 5)

The compound according to claim 5, wherein A is a 6-7 membered spirocyclic ring comprising two O heteroatoms and the heteroatom P(O)R1.

### Claim 11 (depends on 10)

The compound according to claim 10, wherein R1 is methyl.

### Claim 12 (depends on 5)

The compound according to claim 5, wherein L1 and L2 are halo.

### Claim 13 (depends on 12)

The compound according to claim 12, wherein L1 is fluoro and L2 is chloro.

### Claim 14

A compound which is selected from the group consisting of:

### Claim 15 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

### Claim 16 (depends on 14)

A pharmaceutical composition comprising the compound according to claim 14 and a pharmaceutically acceptable carrier.

### Claim 17 (depends on 1)

A method for treating Alzheimer's disease, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1.

### Claim 18 (depends on 1)

A method of treating Alzheimer's disease comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound of claim 1 and a therapeutically effective amount of at least one drug selected from the group consisting of: BACE inhibitors; muscarinic antagonists; cholinesterase inhibitors; gamma secretase inhibitors; gamma secretase modulators; HMG-CoA reductase inhibitors; non-steroidal anti-inflammatory agents; N-methyl-D-aspartate receptor antagonists; anti-amyloid antibodies; vitamin E; nicotinic acetylcholine receptor agonists; CB1 receptor inverse agonists or CB1 receptor antagonists; an antibiotic; growth hormone secretagogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors; GABAA inverse agonists; inhibitors of amyloid aggregation; glycogen synthase kinase beta inhibitors; promoters of alpha secretase activity; PDE-10 inhibitors; Exelon (rivastigmine); Cognex (tacrine); Tau kinase inhibitor; anti-Abeta vaccine; APP ligands; agents that upregulate insulin cholesterol lowering agents; cholesterol absorption inhibitors; fibrates; LXR agonists; LRP mimics; nicotinic receptor agonists; H3 receptor antagonists; histone deacetylase inhibitors; hsp90 inhibitors; m1 muscarinic receptor agonists; 5-HT6 receptor antagonists; mGluR1; mGluR5; positive allosteric modulators or agonists; mGluR2/3 antagonists; anti-inflammatory agents that can reduce neuroinflammation; Prostaglandin EP2 receptor antagonists; PAI-1 inhibitors; and agents that can induce Abeta efflux.

### Claim 19 (depends on 1)

A method of treating a neurodegenerative disease or condition selected from the group consisting of: Down's Syndrome, mild cognitive impairment, glaucoma, cerebral amyloid angiopathy, stroke, dementia, microgliosis, brain inflammation, traumatic brain injury and olfactory function loss, the method comprising administering to a patient in need thereof a therapeutically effective amount of at least one compound of claim 1.