# US 10,246,454 B2 · Substituted 3,4-dihydro-2H-pyrido[1,2-a]pyrazine-1,6-diones as gamma secretase modulators

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- Number: US 10,246,454 B2
- Document ID: US10246454B2
- Status: Granted
- Kind: B2
- Application number: 14/761,801
- Filed: 2014-01-16
- Published: 2015-12-10
- Granted: 2019-04-02
- Earliest claimed: 2013-01-17
- Assignees: Janssen Pharmaceutica NV
- Applicants: Janssen Pharmaceutica NV
- Inventors: François Paul Bischoff; Adriana Ingrid Velter; Frederik Jan Rita Rombouts; Michel Anna Jozef De Cleyn; Sven Franciscus Anna Van Brandt; Henricus Jacobus Maria Gijsen; Chiara Zavattaro; Frans Alfons Maria Van den Keybus
- Web page: https://patentgrep.com/patent/US10246454B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/16: Anti-Parkinson drugs
- 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 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention is concerned with novel substituted pyrido-piperazinone derivatives of Formula (I) wherein R1, R2, R3, R4, R5, L, Z and X have the meaning defined in the claims. The compounds according to the present invention are useful as gamma secretase modulators. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.

## Claims

### Claim 1

A compound of Formula (I):
or a pharmaceutically acceptable addition salt, stereoisomer or tautomer thereof,
wherein:
X is CR6 or N;
L is a covalent bond, —C(═O)—C1-6alkanediyl-, —C1-6alkanediyl-, or C1-6alkanediyl, wherein two germinal hydrogen atoms are replaced by C2-6alkanediyl;
R0 is a ring system selected from the group consisting of piperidinyl optionally substituted with one or more substituents each independently selected from the group consisting of halo and C1-4alkyl optionally substituted with one or more halo substituents;
R1 is Ar1 or Ar2;
R2 is hydrogen or C1-4alkyl;
R3 is hydrogen;
R4 is hydrogen, halo or C1-4alkyl;
R5 is hydrogen or C1-4alkyl;
R6 is hydrogen or C1-4alkyl;
R9 is hydrogen, C3-7cycloalkyl or phenyl;
Ar1 is a ring system selected from the group consisting of thienyl, thiazolyl, pyrrolidinyl, piperidinyl, pyrazolyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, 1,2-benzisoxazolyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, 1,2,4-triazolo[4,3-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, 3,4-dihydro-1-benzopyranyl, 1,2-benzisothiazolyl, indazolyl, and 1,2,3,4-tetrahydroisoquinolinyl, wherein said ring system is optionally substituted with one or more substituents each independently selected from the group consisting of halo, oxo, Ar3, R0, and C1-4alkyl optionally substituted with one or more substituents each independently selected from the group consisting of halo and C1-4alkyloxy;
Ar2 is phenyl substituted with one substituent selected from the group consisting of OR9 and 3-azabicyclo[3.1.0]hexanyl, and further optionally substituted with one, two or three C1-4alkyloxy optionally substituted with one or more halo substituents;
Ar3 is phenyl optionally substituted with one or more CF3 substituents; and
Z is methylene.

### Claim 2 (depends on 1)

The compound according to claim 1, wherein:
R1 is Ar1; and
Ar1 is a ring system selected from the group consisting of thienyl, thiazolyl, pyrrolidinyl, piperidinyl, pyrazolyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-dihydroisobenzofuranyl, 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridinyl, 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, 1,2,4-triazolo[4,3-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, 3,4-dihydro-1-benzopyranyl, indazolyl, and 1,2,3,4-tetrahydroisoquinolinyl.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein R1 is Ar2.

### Claim 4 (depends on 3)

The compound according to claim 3, wherein R2 is C1-4alkyl.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein L is —C1-6alkanediyl-.

### Claim 6 (depends on 5)

The compound according to claim 5, wherein the carbon atom substituted with R2 has the R configuration.

### Claim 7 (depends on 6)

The compound according to claim 6, wherein the compound is represented by formula (I-x)

### Claim 8 (depends on 1)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and, as active ingredient, a therapeutically effective amount of a compound according to claim 1.

### Claim 9 (depends on 1)

A method for modulating γ-secretase activity in a subject having a disease or condition selected from the group consisting of Alzheimer's disease, traumatic brain injury, mild cognitive impairment, senility, dementia, dementia with Lewy bodies, cerebral amyloid angiopathy, multi-infarct dementia, dementia pugilistica, Down's syndrome, dementia associated with Parkinson's disease and dementia associated with beta-amyloid, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound according to claim 1.

### Claim 10 (depends on 9)

The method according to claim 9, wherein the subject has Alzheimer's disease.

### Claim 11 (depends on 1, 8)

A method for modulating γ-secretase activity in a subject having a disease or condition selected from the group consisting of neurocognitive disorder due to Alzheimer's disease, neurocognitive disorder due to traumatic brain injury, neurocognitive disorder due to Lewy body disease, neurocognitive disorder due to Parkinson's disease and vascular neurocognitive disorder, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound according to claim 1 or a pharmaceutical composition according to claim 8.