# US 8,785,436 B2 · 1,3-oxazines as BACE 1 and/or BACE2 inhibitors

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 8,785,436 B2
- Document ID: US8785436B2
- Status: Granted
- Kind: B2
- Application number: 13/467,085
- Filed: 2012-05-09
- Published: 2012-11-22
- Granted: 2014-07-22
- Earliest claimed: 2011-05-16
- Assignees: Hoffmann-La Roche Inc.
- Applicants: Hans Hilpert; Robert Narquizian; Emmanuel Pinard; Alessandra Polara; Mark Rogers-Evans; Thomas Woltering; Wolfgang Wostl
- Inventors: Hans Hilpert; Robert Narquizian; Emmanuel Pinard; Alessandra Polara; Mark Rogers-Evans; Thomas Woltering; Wolfgang Wostl
- Web page: https://patentgrep.com/patent/US8785436B2

## CPC

- C07D 413/10: linked by a carbon chain containing aromatic rings
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- 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 5/16: for decreasing, blocking or antagonising the activity of the thyroid hormones
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- 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 17/00: Drugs for dermatological disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 21/02: Muscle relaxants, e.g. for tetanus or cramps
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- 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 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 265/08: having one double bond between ring members or between a ring member and a non-ring member
- C07D 413/12: linked by a chain containing hetero atoms as chain links
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention provides compounds of formula I having BACE1 and/or BACE2 inhibitory activity, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances. The active compounds of the present invention are useful in the therapeutic and/or prophylactic treatment of e.g. Alzheimer's disease and type 2 diabetes.

## Claims

### Claim 1

A compound of formula I,
wherein
X is selected from the group consisting of
aryl,
aryl substituted by 1-2 substituents individually selected from R1,
heteroaryl,
heteroaryl substituted by 1-2 substituents individually selected from R1 and halogen-aryl,
C3-6-cycloalkyl, and
C3-6-cycloalkyl substituted by 1-2 substituents individually selected from R1;
Y is selected from the group consisting of
—C═O—NH—,
—CH2—,
—NH—
—NH—CHR7—,
—O—CH2—, and
absent;
Z is selected from the group consisting of
aryl,
aryl substituted by 1-2 substituents individually selected from R8,
heteroaryl,
heteroaryl substituted by 1-2 substituents individually selected from R8,
C3-6-cycloalkyl,
C3-6-cycloalkyl substituted by 1-2 substituents individually selected from R8,
heterocyclyl,
heterocyclyl substituted by 1-2 substituents individually selected from R8,
C2-6-alkynyl,
C1-6-alkyl, and
C1-6-alkyl substituted by 1-3 substituents individually selected from R9;
R1 is selected from the group consisting of
hydrogen,
halogen, and
C1-6-alkyl;
R2 is selected from the group consisting of
hydrogen,
C1-6-alkyl, and
halogen-C1-3-alkyl;
R3 is selected from the group consisting of
hydrogen,
halogen, and
C1-6-alkyl;
R4 is selected from the group consisting of
hydrogen
halogen, and
C1-6-alkyl;
R5 is selected from the group consisting of
hydrogen and
C1-6-alkyl;
R6 is selected from the group consisting of
hydrogen and
C1-6-alkyl;
R7 is selected from the group consisting of
hydrogen and
C1-6-alkyl;
R8 is selected from the group consisting of
halogen,
cyano,
C1-6-alkyl,
halogen-C1-6-alkyl,
C1-6-alkoxy,
halogen-C1-6-alkoxy,
aryl,
halogen-aryl, and
C3-6-cycloalkyl; and
R9 is selected from the group consisting of
halogen,
cyano,
C1-6-alkoxy, and
halogen-C1-6-alkoxy;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound according to claim 1
wherein
X is selected from the group consisting of
aryl,
aryl substituted by 1-2 substituents individually selected from R1,
heteroaryl, and
heteroaryl substituted by 1-2 substituents individually selected from R1;
Y is selected from the group consisting of
—C═O—NH—,
—CH2—,
—NH—
—NH—CHR7—,
—O—CH2—, and
absent;
Z is selected from the group consisting of
aryl,
aryl substituted by 1-2 substituents individually selected from R8,
heteroaryl,
heteroaryl substituted by 1-2 substituents individually selected from R8,
C3-6-cycloalkyl,
C3-6-cycloalkyl substituted by 1-2 substituents individually selected from R8,
heterocyclyl,
heterocyclyl substituted by 1-2 substituents individually selected from R8, and
C2-6-alkynyl;
R1 is selected from the group consisting of
hydrogen,
halogen, and
C1-6-alkyl;
R2 is selected from the group consisting of
hydrogen,
C1-6-alkyl, and
halogen-C1-3-alkyl;
R3 is selected from the group consisting of
hydrogen,
halogen, and
C1-6-alkyl;
R4 is selected from the group consisting of
hydrogen
halogen, and
C1-6-alkyl;
R5 is selected from the group consisting of
hydrogen and
C1-6-alkyl;
R6 is selected from the group consisting of
hydrogen and
C1-6-alkyl;
R7 is selected from the group consisting of
hydrogen and
C1-6-alkyl; and
R8 is selected from the group consisting of
halogen,
cyano,
C1-6-alkyl,
halogen-C1-6-alkyl,
C1-6-alkoxy,
halogen-C1-6-alkoxy,
aryl,
halogen-aryl, and
C3-6-cycloalkyl;
or a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The compound according to claim 1, wherein R2 is C1-6-alkyl.

### Claim 4 (depends on 3)

The compound according to claim 3, wherein R2 is methyl.

### Claim 5 (depends on 1)

The compound according to claim 1, wherein R3 is halogen.

### Claim 6 (depends on 5)

The compound according to claim 5, wherein R3 is F.

### Claim 7 (depends on 1)

The compound according to claim 1, wherein R4 is H, methyl or F.

### Claim 8 (depends on 1)

The compound according to claim 1, wherein R5 is H.

### Claim 9 (depends on 1)

The compound according to claim 1, wherein R6 is H.

### Claim 10 (depends on 1)

The compound according to claim 1, wherein X is aryl substituted by halogen.

### Claim 11 (depends on 9)

The compound according to claim 9, wherein X is phenyl substituted by F.

### Claim 12 (depends on 1)

The compound according to claim 1, wherein Y is —NHCH2—, —NH— or absent.

### Claim 13 (depends on 1)

The compound according to claim 1, wherein Z is heteroaryl substituted by 1-2 substituents individually selected from R8 and C3-6-cycloalkyl.

### Claim 14 (depends on 1)

The compound according to claims 1, wherein R8 is selected from the group consisting of
halogen,
cyano,
C1-6-alkyl, and
halogen-C1-6-alkyl.

### Claim 15 (depends on 1)

The compound according to claim 1, selected from the group consisting of
(S)-4-{5-[(4-Chloro-1-difluoromethyl-1H-pyrazol-3-ylmethyl)-amino]-2-fluoro-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(4R,5R)-5-Fluoro-4-[2-fluoro-5-(2-methoxy-phenylamino)-phenyl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(4R,5R)-4-[5-(2-Difluoromethoxy-phenylamino)-2-fluoro-phenyl]-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(4R,5R)-5-Fluoro-4-{2-fluoro-5-[(thiophen-2-ylmethyl)-amino]-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(4R,5R)-5-Fluoro-4-{2-fluoro-5-[(thiophen-3-ylmethyl)-amino]-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(4R,5R)-5-Fluoro-4-[2-fluoro-5-(2-fluoro-benzylamino)-phenyl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(4R,5R)-4-[5-(Cyclopropylmethyl-amino)-2-fluoro-phenyl]-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(4R,5R)-5-Fluoro-4-{2-fluoro-5-[1-(4-fluoro-phenyl)-1H-pyrazol-4-yl]-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(4R,5R)-5-Fluoro-4-[2-fluoro-5-(4-methyl-pyrazol-1-yl)-phenyl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(4R,5R)-4-{5-[(4-Chloro-1-difluoromethyl-1H-pyrazol-3-ylmethyl)-amino]-2-fluoro-phenyl}-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine, and
(4R,5R)-4-{5-[(4-Chloro-1-methyl-1H-pyrazol-3-ylmethyl)-amino]-2-fluoro-phenyl}-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
or a pharmaceutical acceptable salt thereof.

### Claim 16 (depends on 1)

The compound according to claim 1, selected from the group consisting of
(4R,5R)-5-Fluoro-4-{2-fluoro-5-[1-(2-methyl-5-trifluoromethyl-oxazol-4-yl)-ethylamino]-phenyl}-4,5-dimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-4-{5-[(4-Chloro-1-difluoromethyl-1H-pyrazol-3-ylmethyl)-amino]-2-fluoro-phenyl}-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-4-{5-[1-(4-Chloro-1-methyl-1H-pyrazol-3-yl)-ethylamino]-2-fluoro-phenyl}-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-4-{5-[1-(5-Cyclopropyl-isoxazol-3-yl)-ethylamino]-2-fluoro-phenyl}-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
4-[5-(5-Chloro-pyridin-3-yl)-2-fluoro-phenyl]-4-difluoromethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-4-[5-(5-Chloro-pyridin-3-yl)-2-fluoro-phenyl]-4-difluoromethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(S)-4-[5-(5-Chloro-pyridin-3-yl)-2-fluoro-phenyl]-4-difluoromethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-5,5-Difluoro-4-methyl-4-[3-(3,3,3-trifluoro-propoxy)-phenyl]-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
2-[3-((R)-2-Amino-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenylamino]-benzonitrile,
(R)-5,5-Difluoro-4-(2-fluoro-5-o-tolylamino-phenyl)-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine, and
(R)-4-(5-Cyclopentylamino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
or a pharmaceutical acceptable salt thereof.

### Claim 17 (depends on 1)

The compound according to claim 1, selected from the group consisting of
(R)-4-(3′,5′-Dichloro-4-fluoro-biphenyl-3-yl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
3′-((R)-2-Amino-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-6-chloro-4′-fluoro-biphenyl-3-carbonitrile,
(R)-4-[5-(1,1-Dioxo-2,3-dihydro-1H-1λ6-benzo[b]thiophen-3-ylamino)-2-fluoro-phenyl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
5-[3-((4R,5R)-2-Amino-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-nicotinonitrile,
7-[3-((R)-2-Amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenylamino]-6,7-dihydro-5H-[1]pyrindine-3-carbonitrile,
[3-((R)-2-Amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-(3-chloro-6,7-dihydro-5H-[1]pyrindin-7-yl)-amine,
8-[3-((R)-2-Amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenylamino]-5,6,7,8-tetrahydro-quinoline-3-carbonitrile,
4-[3-((R)-2-Amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-phenoxymethyl]-benzonitrile,
3-((R)-2-Amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-N-prop-2-ynyl-benzamide,
3-[4-((R)-2-Amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-pyrazol-1-yl]-benzonitrile, and
(1R,2R)-((R)-2-Amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-cyclopropanecarboxylic acid(3-chloro-quinolin-8-yl)-amide,
or a pharmaceutical acceptable salt thereof.

### Claim 18 (depends on 1)

The compound according to claim 1, selected from the group consisting of
(1S,2S)-((R)-2-Amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-cyclopropanecarboxylic acid(3-chloro-quinolin-8-yl)-amide,
(1R,2R)-2-((R)-2-Amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-cyclopropanecarboxylic acid(6-cyano-thieno[3,2-b]pyridin-3-yl)-amide,
(R)-4-(5-{1-[4-Chloro-1-(2,2-difluoro-ethyl)-1H-pyrazol-3-yl]-ethylamino}-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(4R,5R)-4-[5-(3,5-Difluoro-benzylamino)-2-fluoro-phenyl]-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-4-[3-(5-Chloro-pyridin-2-yl)-7-fluoro-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-4-[5-(6-Chloro-benzooxazol-2-yl)-2,4-difluoro-phenyl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-5,5-Difluoro-4-{2-fluoro-5-[1-(5-methyl-2H-pyrazol-3-yl)-ethylamino]-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-5,5-Difluoro-4-{2-fluoro-5-[1-(2-methyl-5-trifluoromethyl-oxazol-4-yl)-ethylamino]-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-5,5-Difluoro-4-{2-fluoro-5-[(3-methyl-oxetan-3-ylmethyl)-amino]-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-4-[5-(Cyclopropylmethyl-amino)-2-fluoro-phenyl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine, and
(R)-5,5-Difluoro-4-[2-fluoro-5-(tetrahydro-furan-3-ylamino)-phenyl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
or a pharmaceutical acceptable salt thereof.

### Claim 19 (depends on 1)

The compound according to claim 1, selected from the group consisting of
(R)-5,5-Difluoro-4-[2-fluoro-5-(oxetan-3-ylamino)-phenyl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-5,5-Difluoro-4-{2-fluoro-5-[(tetrahydro-furan-3-ylmethyl)-amino]-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-5,5-Difluoro-4-{2-fluoro-5-[1-(4-fluoro-phenyl)-1H-pyrazol-4-yl]-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-4-[5-(5-Chloro-pyridin-3-yl)-2,4-difluoro-phenyl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-5,5-Difluoro-4-methyl-4-[3-(4-trifluoromethyl-benzyloxy)-phenyl]-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-5,5-Difluoro-4-methyl-4-[2-(4-methyl-benzyl)-3H-benzoimidazol-5-yl]-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-5,5-Difluoro-4-[5-fluoro-2-(4-methoxy-benzyl)-1H-indol-6-yl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-5,5-Difluoro-4-[5-fluoro-2-(4-methyl-benzyl)-3H-indol-6-yl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-5,5-Difluoro-4-[2-fluoro-5-(2-methoxy-phenylamino)-phenyl]-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-5,5-Difluoro-4-[2-fluoro-5-(2-trifluoromethyl-phenylamino)-phenyl]-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-5,5-Difluoro-4-[2-fluoro-5-(6-trifluoromethyl-pyridin-2-ylamino)-phenyl]-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine, and
(R)-5,5-Difluoro-4-[2-fluoro-5-(3-phenyl-cyclopentylamino)-phenyl]-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
or a pharmaceutical acceptable salt thereof.

### Claim 20 (depends on 1)

The compound according to claim 1, selected from the group consisting of
(R)-4-[5-(5-Chloro-pyridin-3-yl)-2-fluoro-phenyl]-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-4-[2-(4-Ethyl-benzyl)-3H-benzoimidazol-5-yl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-4-[5-((RS)-2,2-Difluoro-cyclopropylmethoxy)-phenyl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-4-[1-(3-Ethynyl-phenyl)-1H-pyrazol-4-yl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-4-(2,4-Difluoro-5-pyrimidin-5-yl-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-4-[5-(2-Chloro-phenylamino)-2-fluoro-phenyl]-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(S)-4-(5-Cyclopentylamino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-4-[3-(4-Chloro-benzyloxy)-phenyl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-4-(3-Cyclopropylmethoxy-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine, and
(1S,2S)-rel-2-((R)-2-Amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-cyclopropanecarboxylic acid(3-chloro-quinolin-8-yl)-amide;
or a pharmaceutical acceptable salt thereof.

### Claim 21 (depends on 1)

The compound according to claim 1, selected from the group consisting of
(S)-4-{5-[(4-Chloro-1-difluoromethyl-1H-pyrazol-3-ylmethyl)-amino]-2-fluoro-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(4R,5R)-4-[5-(2-Difluoromethoxy-phenylamino)-2-fluoro-phenyl]-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(4R,5R)-4-[5-(Cyclopropylmethyl-amino)-2-fluoro-phenyl]-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(4R,5R)-4-{5-[(4-Chloro-1-difluoromethyl-1H-pyrazol-3-ylmethyl)-amino]-2-fluoro-phenyl}-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(4R,5R)-4-{5-[(4-Chloro-1-methyl-1H-pyrazol-3-ylmethyl)-amino]-2-fluoro-phenyl}-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(4R,5R)-5-Fluoro-4-[2-fluoro-5-(2-fluoro-benzylamino)-phenyl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(4R,5R)-5-Fluoro-4-[2-fluoro-5-(2-methoxy-phenylamino)-phenyl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(4R,5R)-5-Fluoro-4-[2-fluoro-5-(4-methyl-pyrazol-1-yl)-phenyl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(4R,5R)-5-Fluoro-4-{2-fluoro-5-[(thiophen-2-ylmethyl)-amino]-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(4R,5R)-5-Fluoro-4-{2-fluoro-5-[(thiophen-3-ylmethyl)-amino]-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine, and
(4R,5R)-5-Fluoro-4-{2-fluoro-5-[1-(2-methyl-5-trifluoromethyl-oxazol-4-yl)-ethylamino]-phenyl}-4,5-dimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
or a pharmaceutical acceptable salt thereof.

### Claim 22 (depends on 1)

The compound according to claim 1, selected from the group consisting of
(4R,5R)-5-Fluoro-4-{2-fluoro-5-[1-(4-fluoro-phenyl)-1H-pyrazol-4-yl]-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-4-(2,4-Difluoro-5-pyrimidin-5-yl-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-4-(3′,5′-Dichloro-4-fluoro-biphenyl-3-yl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-4-(5-{1-[4-Chloro-1-(2,2-difluoro-ethyl)-1H-pyrazol-3-yl]-ethylamino}-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-4-(5-Cyclopentylamino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-4-[3-(4-Chloro-benzyloxy)-phenyl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-4-[3-(5-Chloro-pyridin-2-yl)-7-fluoro-3,4-dihydro-2H-benzo[1,4]oxazin-6-yl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-4-[5-(1,1-Dioxo-2,3-dihydro-1H-1λ6-benzo[b]thiophen-3-ylamino)-2-fluoro-phenyl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-4-[5-(2-Chloro-phenylamino)-2-fluoro-phenyl]-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-4-[5-(5-Chloro-pyridin-3-yl)-2,4-difluoro-phenyl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine, and
(R)-4-[5-(5-Chloro-pyridin-3-yl)-2-fluoro-phenyl]-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
or a pharmaceutical acceptable salt thereof.

### Claim 23 (depends on 1)

The compound according to claim 1, selected from the group consisting of
(R)-4-[5-(6-Chloro-benzooxazol-2-yl)-2,4-difluoro-phenyl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-4-[5-(Cyclopropylmethyl-amino)-2-fluoro-phenyl]-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-4-{5-[(4-Chloro-1-difluoromethyl-1H-pyrazol-3-ylmethyl)-amino]-2-fluoro-phenyl}-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-4-{5-[1-(4-Chloro-1-methyl-1H-pyrazol-3-yl)-ethylamino]-2-fluoro-phenyl}-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-4-{5-[1-(5-Cyclopropyl-isoxazol-3-yl)-ethylamino]-2-fluoro-phenyl}-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-5,5-Difluoro-4-(2-fluoro-5-o-tolylamino-phenyl)-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-5,5-Difluoro-4-[2-fluoro-5-(2-methoxy-phenylamino)-phenyl]-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-5,5-Difluoro-4-[2-fluoro-5-(2-trifluoromethyl-phenylamino)-phenyl]-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-5,5-Difluoro-4-[2-fluoro-5-(3-phenyl-cyclopentylamino)-phenyl]-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-5,5-Difluoro-4-[2-fluoro-5-(6-trifluoromethyl-pyridin-2-ylamino)-phenyl]-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine, and
(R)-5,5-Difluoro-4-[2-fluoro-5-(oxetan-3-ylamino)-phenyl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
or a pharmaceutical acceptable salt thereof.

### Claim 24 (depends on 1)

The compound according to claim 1, selected from the group consisting of
(R)-5,5-Difluoro-4-[2-fluoro-5-(tetrahydro-furan-3-ylamino)-phenyl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-5,5-Difluoro-4-[5-fluoro-2-(4-methoxy-benzyl)-1H-indol-6-yl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-5,5-Difluoro-4-[5-fluoro-2-(4-methyl-benzyl)-3H-indol-6-yl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-5,5-Difluoro-4-{2-fluoro-5-[(3-methyl-oxetan-3-ylmethyl)-amino]-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-5,5-Difluoro-4-{2-fluoro-5-[(tetrahydro-furan-3-ylmethyl)-amino]-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-5,5-Difluoro-4-{2-fluoro-5-[1-(2-methyl-5-trifluoromethyl-oxazol-4-yl)-ethylamino]-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-5,5-Difluoro-4-{2-fluoro-5-[1-(4-fluoro-phenyl)-1H-pyrazol-4-yl]-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-5,5-Difluoro-4-{2-fluoro-5-[1-(5-methyl-2H-pyrazol-3-yl)-ethylamino]-phenyl}-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-5,5-Difluoro-4-methyl-4-[2-(4-methyl-benzyl)-3H-benzoimidazol-5-yl]-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(R)-5,5-Difluoro-4-methyl-4-[3-(4-trifluoromethyl-benzyloxy)-phenyl]-5,6-dihydro-4H-[1,3]oxazin-2-ylamine, and
(S)-4-(5-Cyclopentylamino-2-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
or a pharmaceutical acceptable salt thereof.

### Claim 25 (depends on 1)

The compound according to claim 1, selected from the group consisting of
[3-((R)-2-Amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-(3-chloro-6,7-dihydro-5H-[1]pyrindin-7-yl)-amine,
2-[3-((R)-2-Amino-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenylamino]-benzonitrile,
3′-((R)-2-Amino-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-6-chloro-4′-fluoro-biphenyl-3-carbonitrile,
3-((R)-2-Amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-N-prop-2-ynyl-benzamide,
4-[3-((R)-2-Amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-phenoxymethyl]-benzonitrile,
5-[3-((4R,5R)-2-Amino-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-nicotinonitrile,
7-[3-((R)-2-Amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenylamino]-6,7-dihydro-5H-[1]pyrindine-3-carbonitrile, and
8-[3-((R)-2-Amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenylamino]-5,6,7,8-tetrahydro-quinoline-3-carbonitrile,
or a pharmaceutical acceptable salt thereof.

### Claim 26 (depends on 1)

The compound according to claim 1, selected from the group consisting of
(4R,5R)-4-[5-(Cyclopropylmethyl-amino)-2-fluoro-phenyl]-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(4R,5R)-4-{5-[(4-Chloro-1-difluoromethyl-1H-pyrazol-3-ylmethyl)-amino]-2-fluoro-phenyl}-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
(4R,5R)-4-{5-[(4-Chloro-1-methyl-1H-pyrazol-3-ylmethyl)-amino]-2-fluoro-phenyl}-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine,
[3-((R)-2-Amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-(3-chloro-6,7-dihydro-5H-[1]pyrindin-7-yl)-amine,
5-[3-((4R,5R)-2-Amino-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenyl]-nicotinonitrile, and
7-[3-((R)-2-Amino-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-4-yl)-4-fluoro-phenylamino]-6,7-dihydro-5H-[1]pyrindine-3-carbonitrile.

### Claim 27

A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I
wherein
X is selected from the group consisting of
aryl,
aryl substituted by 1-2 substituents individually selected from R1,
heteroaryl,
heteroaryl substituted by 1-2 substituents individually selected from R1 and halogen-aryl,
C3-6-cycloalkyl, and
C3-6-cycloalkyl substituted by 1-2 substituents individually selected from R1;
Y is selected from the group consisting of
—C═O—NH—,
—CH2—,
—NH—
—NH—CHR7—,
—O—CH2—, and
absent;
Z is selected from the group consisting of
aryl,
aryl substituted by 1-2 substituents individually selected from R8,
heteroaryl,
heteroaryl substituted by 1-2 substituents individually selected from R8,
C3-6-cycloalkyl,
C3-6-cycloalkyl substituted by 1-2 substituents individually selected from R8,
heterocyclyl,
heterocyclyl substituted by 1-2 substituents individually selected from R8,
C2-6-alkynyl,
C1-6-alkyl, and
C1-6-alkyl substituted by 1-3 substituents individually selected from R9;
R1 is selected from the group consisting of
hydrogen,
halogen, and
C1-6-alkyl;
R2 is selected from the group consisting of
hydrogen,
C1-6-alkyl, and
halogen-C1-3-alkyl;
R3 is selected from the group consisting of
hydrogen,
halogen, and
C1-6-alkyl;
R4 is selected from the group consisting of
hydrogen
halogen, and
C1-6-alkyl;
R5 is selected from the group consisting of
hydrogen and
C1-6-alkyl;
R6 is selected from the group consisting of
hydrogen and
C1-6-alkyl;
R7 is selected from the group consisting of
hydrogen and
C1-6-alkyl;
R8 is selected from the group consisting of
halogen,
cyano,
C1-6-alkyl,
halogen-C1-6-alkyl,
C1-6-alkoxy,
halogen-C1-6-alkoxy,
aryl,
halogen-aryl, and
C3-6-cycloalkyl; and
R9 is selected from the group consisting of
halogen,
cyano,
C1-6-alkoxy, and
halogen-C1-6-alkoxy;
or a pharmaceutically acceptable salt thereof
and a pharmaceutically acceptable carrier.