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NZ775640B2 - New heterocyclic compounds - Google Patents
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NZ775640B2 - New heterocyclic compounds - Google Patents

New heterocyclic compounds Download PDF

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Publication number
NZ775640B2
NZ775640B2 NZ775640A NZ77564019A NZ775640B2 NZ 775640 B2 NZ775640 B2 NZ 775640B2 NZ 775640 A NZ775640 A NZ 775640A NZ 77564019 A NZ77564019 A NZ 77564019A NZ 775640 B2 NZ775640 B2 NZ 775640B2
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NZ
New Zealand
Prior art keywords
pyrido
oxazin
hexahydro
alkyl
formula
Prior art date
Application number
NZ775640A
Other versions
NZ775640A (en
Inventor
Uwe Grether
Zbinden Katrin Groebke
Benoit Hornsperger
Carsten Kroll
Bernd Kuhn
Marius Daniel Rinaldo Lutz
Hara Fionn O
Hans Richter
Didier Rombach
Original Assignee
F Hoffmann La Roche Ag
Filing date
Publication date
Application filed by F Hoffmann La Roche Ag filed Critical F Hoffmann La Roche Ag
Priority claimed from PCT/EP2019/081870 external-priority patent/WO2020104494A1/en
Publication of NZ775640A publication Critical patent/NZ775640A/en
Publication of NZ775640B2 publication Critical patent/NZ775640B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

The invention provides new heterocyclic compounds having the general formula (I) wherein A, B, L, X, R1, R2, R3 and R4 are as described herein, compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds.

Claims (51)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein: 5 (i) X is C-R ; L is a covalent bond, –(CH ) -N(C -alkyl)–, –(CH ) -NH–, –N(C -alkyl)- 2 n 1-6 2 n 1-6 (CH ) –, –NH-(CH ) –, –(CH ) -O–, –O-(CH ) –, –SO -N(C -alkyl)–, –SO - 2 p 2 p 2 n 2 p 2 1-6 2 NH–, –N(C -alkyl)-SO –, –NH-SO –, carbonyl, –(CH ) –, –CHR –, –CF - 1-6 2 2 2 n 2 (CH2)n–, –(CH2)p-CF2–, –(CH2)n-S–, –S-(CH2)p–, –SO2–, –C(O)-NH–, –C(O)- 10 N(C -alkyl)–, –NH-C(O)– or –N(C -alkyl)-C(O)–; and 1-6 1-6 A is: 7 8 9 (i) C -aryl substituted with R , R and R ; or 10 11 12 (ii) 5-14 membered heteroaryl substituted with R , R and R ; or (ii) X is N; 15 L is a covalent bond, –(CH ) –, –CHR –, –SO –, carbonyl, –N(C -alkyl)- 2 n 2 1-6 (CH ) –, –NH-(CH ) –, –O-(CH ) –, –CF -CH –, –N(C -alkyl)-SO –, –NH- 2 p 2 p 2 p 2 2 1-6 2 SO –, –NH-C(O)– or –N(C -alkyl)-C(O)–; and 2 1-6 A is: 7 8 9 (i) C6aryl substituted with R , R and R ; or 10 11 12 20 (ii) 5-14 membered heteroaryl substituted with R , R and R ; or (iii) X is N; L is C -alkoxycarbonyl, C -aryloxycarbonyl or 5-14 membered 1-6 6-14 heteroaryloxycarbonyl; and A is absent; 25 B is a bicyclic spirocycle; 1 2 3 4 5 R , R , R , R and R are independently hydrogen, halogen, hydroxy, C -alkyl or halo-C 1-6 1- -alkyl; R is C -aryl or 5-14 membered heteroaryl; 7 8 9 10 11 12 R , R , R , R , R and R are each at each occurrence independently hydrogen, hydroxy, C -alkyl, halo-C -alkyl, halogen, C -alkoxy, halo-C -alkoxy, SF , C - 1-6 1-6 1-6 1-6 5 1-6 alkylsulfonyl, cyano or a group ; C is 5-14 membered heteroaryl, 3-14 membered heterocyclyl or C -cycloalkyl; C1 C2 C3 5 R , R and R are each independently hydrogen, C -alkyl, halo-C -alkyl, oxo, 1-6 1-6 halogen, hydroxy, C -alkoxy or halo-C -alkoxy; 1-6 1-6 each occurrence of n is independently 0, 1, 2 or 3; each occurrence of p is independently 1, 2 or 3; and q is 0, 1 or 2. 10
2. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: (i) X is C-R ; L is –(CH ) -N(C -alkyl)–, –(CH ) -NH–, –N(C -alkyl)-(CH ) –, –NH- 2 n 1-6 2 n 1-6 2 p 15 (CH ) –, –(CH ) -O–, –O-(CH ) –, –SO -N(C -alkyl)–, –SO -NH–, –N(C - 2 p 2 n 2 p 2 1-6 2 1-6 alkyl)-SO –, –NH-SO –, carbonyl, –(CH ) –, –CHR –, –CF -(CH ) –, – 2 2 2 n 2 2 n (CH ) -CF –, –(CH ) -S–, –S-(CH ) –, –SO –, –C(O)-NH–, –C(O)-N(C - 2 p 2 2 n 2 p 2 1-6 alkyl)–, –NH-C(O)– or –N(C -alkyl)-C(O)–; and A is: 7 8 9 20 (i) C -aryl substituted with R , R and R ; or 10 11 12 (ii) 5-14 membered heteroaryl substituted with R , R and R ; or (ii) X is N; L is –(CH ) –, –CHR –, –SO –, carbonyl, –N(C -alkyl)-(CH ) –, –NH-(CH ) –, 2 n 2 1-6 2 p 2 p –O-(CH ) –, –CF -CH –, –N(C -alkyl)-SO –, –NH-SO –, –NH-C(O)– or – 2 p 2 2 1-6 2 2 25 N(C -alkyl)-C(O)–; and A is: 7 8 9 (i) C -aryl substituted with R , R and R ; or 10 11 12 (ii) 5-14 membered heteroaryl substituted with R , R and R ; or (iii) X is N; L is C -alkoxycarbonyl, C -aryloxycarbonyl or 5-14 membered 1-6 6-14 5 heteroaryloxycarbonyl; and A is absent; B is a bicyclic spirocycle; R is hydrogen or C -alkyl; R is hydrogen or C -alkyl; 10 R is hydrogen, C -alkyl, halo-C -alkyl, halogen or hydroxy; 1-6 1-6 R is hydrogen, C -alkyl, halo-C -alkyl, halogen or hydroxy; 1-6 1-6 R is hydrogen, C -alkyl, halo-C -alkyl, halogen or hydroxy; 1-6 1-6 R is C6aryl or 5-14 membered heteroaryl; 7 8 9 10 11 12 R , R , R , R , R and R are each at each occurrence independently hydrogen, C - 15 alkyl, halo-C -alkyl, halogen, C -alkoxy, halo-C -alkoxy, SF , SO CH , cyano, a 1-6 1-6 1-6 5 2 3 group , a group or a group ; R is hydrogen, C -alkyl, halo-C -alkyl, halogen, hydroxy or C -alkoxy; and 1-6 1-6 1-6 R is hydrogen, C -alkyl, halo-C -alkyl, halogen, hydroxy, C -alkoxy; or 1-6 1-6 1-6 13 14 R and R , taken together with the carbon atom to which they are attached, form a 4 20 membered ring containing 0, 1 or 2 heteroatoms selected from oxygen and NR ; R is hydrogen, C -alkyl or halo-C -alkyl; R is hydrogen, hydroxy, C -alkyl, halo-C -alkyl or cyano; 1-6 1-6 R is hydrogen, hydroxy, halo-C -alkyl, C -alkyl or cyano; 1-6 1-6 R is hydrogen or C -alkyl; 25 each occurrence of n is independently 0, 1, 2 or 3; each occurrence of p is independently 1, 2 or 3; and q is 0, 1 or 2.
3. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.
4. The compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.
5. The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen. 5
6. The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.
7. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or halo-C -alkyl.
8. The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically 10 acceptable salt thereof, wherein R is hydrogen.
9. The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein R is C -aryl.
10. The compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen, hydroxy, C -alkyl, halo-C -alkyl, 1-6 1-6 15 halogen, C -alkoxy, halo-C -alkoxy, SF or a group ; wherein 1-6 1-6 5 C is 5-14 membered heteroaryl or 3-14 membered heterocyclyl; R is C -alkyl, halo- C -alkyl or oxo; and 1-6 1-6 C2 C3 R and R are both hydrogen.
11. The compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically 20 acceptable salt thereof, wherein R is hydrogen, C -alkyl, halo-C -alkyl, halogen, C - 1-6 1-6 1-6 alkoxy, halo-C -alkoxy or SF . 1-6 5
12. The compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen, fluoro, chloro, CF , methyl, methoxy, trifluoromethoxy or SF .
13. The compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen, C -alkoxy, halo-C - 1-6 1-6 alkyl or halogen.
14. The compound of formula (I) according to any one of claims 1 to 12, or a 5 pharmaceutically acceptable salt thereof, wherein R is hydrogen, halo-C -alkyl or halogen.
15. The compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen, CF , chloro or fluoro.
16. The compound of formula (I) according to any one of claims 1 to 15, or a 10 pharmaceutically acceptable salt thereof, wherein R is hydrogen.
17. The compound of formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R is halogen or halo-C -alkyl.
18. The compound of formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R is halo-C -alkyl. 15
19. The compound of formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R is CF .
20. The compound of formula (I) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or halo-C -alkyl.
21. The compound of formula (I) according to any one of claims 1 to 19, or a 20 pharmaceutically acceptable salt thereof, wherein R is hydrogen or CF .
22. The compound of formula (I) according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R is hydrogen.
23. The compound of formula (I) according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein A is phenyl or pyridyl. 25
24. The compound of formula (I) according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein: X is C-R ; L is a covalent bond, –(CH ) -N(C -alkyl)–, –(CH ) -NH–, –(CH ) -O–, –OCH –, – 2 n 1-6 2 n 2 n 2 CH –, –SO –, –SO -N(C -alkyl)– or –SO -NH–; 2 2 2 1-6 2 n is 0 or 1; and R is as defined herein. 5
25. The compound of formula (I) according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein: X is C-R ; L is a covalent bond, –CH O–, –O–, –OCH –, –CH – or –SO -N(C -alkyl)–; and 2 2 2 2 1-6 R is as defined herein. 10
26. The compound of formula (I) according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein: X is C-R ; L is a covalent bond, –CH O–, –O–, –OCH –, –CH – or –SO -N(methyl)–; and 2 2 2 2 R is as defined herein. 15
27. The compound of formula (I) according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein: X is N; L is a covalent bond, –CH –, –CHR – or –SO –; and R is as defined herein. 20
28. The compound of formula (I) according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein: X is N; and L is –CH – or –SO –.
29. The compound of formula (I) according to any one of claims 1 to 28, or a 25 pharmaceutically acceptable salt thereof, wherein B is a bicyclic spirocycle having formula (II): wherein: X is as defined herein; 1 2 3 4 Y , Y , Y and Y are each independently –(CH ) –, –(CH ) O–, –O(CH ) –, – 2 m 2 m 2 m (CH ) NH– or –NH(CH ) –; 2 m 2 m 5 each occurrence of m is independently 1, 2 or 3; the wavy line indicates the point of attachment of bicyclic spirocycle B to L in formula (I); the asterisk indicates the point of attachment of bicyclic spirocycle B to the remainder of formula (I). 10
30. The compound of formula (I) according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein B is a bicyclic spirocycle having formula (II): wherein: 15 X is as defined herein; Y is –(CH ) – or –(CH ) O–, wherein m is 1 or 2; 2 m 2 m Y is –CH – or –CH O–; Y and Y are each independently –(CH ) –, wherein m is 1 or 2; the wavy line indicates the point of attachment of bicyclic spirocycle B to L in formula (I); 20 and the asterisk indicates the point of attachment of bicyclic spirocycle B to the remainder of formula (I).
31. The compound of formula (I) according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein B is a bicyclic spirocycle having formula 25 (II): wherein: X is as defined herein; Y is –CH –; Y is –CH – or –CH O–; 5 Y and Y are each independently –(CH ) –, wherein m is 1 or 2; the wavy line indicates the point of attachment of bicyclic spirocycle B to L in formula (I); the asterisk indicates the point of attachment of bicyclic spirocycle B to the remainder of formula (I). 10
32. The compound of formula (I) according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein B is a bicyclic spirocycle selected from the group consisting of: ; ; ; ; ; ; ; and wherein: 15 (i) a wavy line indicates the point of attachment of bicyclic spirocycle B to L in formula (I); and an asterisk indicates the point of attachment of bicyclic spirocycle B to the remainder of formula (I); or (ii) a wavy line indicates the point of attachment of bicyclic spirocycle B to the 20 remainder of formula (I); and an asterisk indicates the point of attachment of bicyclic spirocycle B to L in formula
33. The compound of formula (I) according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein B is a bicyclic spirocycle selected from 25 the group consisting of: * * * ; ; ; ; and ; wherein a wavy line indicates the point of attachment of bicyclic spirocycle B to L in formula (I); 5 an asterisk indicates the point of attachment of bicyclic spirocycle B to the remainder of formula (I).
34. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: (i) X is C-R ; 10 L is a covalent bond, –CH -N(C -alkyl)–, –CH -NH–, –O–, –CH O–, –OCH –, 2 1-6 2 2 2 –CH –, –SO –, –SO -N(C -alkyl)– or –SO -NH–; and 2 2 2 1-6 2 A is: 7 8 9 (i) C -aryl substituted with R , R and R ; or 10 11 12 (ii) 5-14 membered heteroaryl substituted with R , R and R ; or 15 (ii) X is N; L is a covalent bond, –CH –, –CHR – or –SO –; and 7 8 9 A is C -aryl substituted with R , R and R ; or (iii) X is N; L is C -alkoxycarbonyl; and 20 A is absent; B is a bicyclic spirocycle having formula (II): wherein: Y is –(CH ) – or –(CH ) O–, wherein m is 1 or 2; 2 m 2 m Y is –CH – or –CH O–; Y and Y are each independently –(CH ) –, wherein m is 1 or 2; the wavy line indicates the point of attachment of bicyclic spirocycle B to L in formula (I); and 5 the asterisk indicates the point of attachment of bicyclic spirocycle B to the remainder of formula (I); 1 2 3 4 9 12 each of R , R , R , R , R and R is hydrogen; R is hydrogen or C -alkyl; R is C -aryl; 10 R is hydrogen, hydroxy, C -alkyl, halo-C -alkyl, halogen, C -alkoxy or halo-C - 1-6 1-6 1-6 1-6 alkoxy, SF or a group ; R is hydrogen, C -alkoxy, halo-C -alkyl or halogen; 1-6 1-6 R is halogen or halo-C -alkyl; R is hydrogen or halo-C -alkyl; 15 R is C -alkyl, halo- C -alkyl or oxo; 1-6 1-6 C2 C3 R and R are both hydrogen; and C is 5-14 membered heteroaryl or 3-14 membered heterocyclyl.
35. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: 20 (i) X is C-R ; L is –CH O–, –OCH –, –O–, –CH – or –SO -N(C -alkyl)–; and 2 2 2 2 1-6 A is: 7 8 9 (i) C -aryl substituted with R , R and R ; or 10 11 12 (ii) 5-14 membered heteroaryl substituted with R , R and R ; or 25 (ii) X is N; L is –CH – or –SO –; and 7 8 9 A is C -aryl substituted with R , R and R ; or B is a bicyclic spirocycle having formula (II): wherein: Y is –CH –; Y is –CH – or –CH O–; 5 Y and Y are each independently –(CH ) –, wherein m is 1 or 2; the wavy line indicates the point of attachment of bicyclic spirocycle B to L in formula (I); and the asterisk indicates the point of attachment of bicyclic spirocycle B to the remainder of formula (I); 1 2 3 4 5 9 12 10 each of R , R , R , R , R , R , and R is hydrogen; R is hydrogen, C -alkyl, halo-C -alkyl, halogen, C -alkoxy, halo-C -alkoxy or 1-6 1-6 1-6 1-6 R is hydrogen, halo-C -alkyl or halogen; R is halo-C -alkyl; and 15 R is hydrogen or halo-C -alkyl.
36. The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: (i) X is C-R ; L is –CH2O–, –OCH2–, –O–, –CH2– or –SO2-N(methyl)–; and 20 A is: 7 8 9 (i) phenyl substituted with R , R and R ; or 10 11 12 (ii) pyridyl substituted with R , R and R ; or (ii) X is N; L is –CH – or –SO –; and 7 8 9 25 A is phenyl substituted with R , R and R ; or B is a bicyclic spirocycle selected from the group consisting of: ; and wherein the wavy line indicates the point of attachment of bicyclic spirocycle B to L in formula (I); and the asterisk indicates the point of attachment of bicyclic spirocycle B to the remainder of formula (I); 1 2 3 4 5 9 12 5 each of R , R , R , R , R , R , and R is hydrogen; R is hydrogen, fluoro, chloro, CF , methyl, methoxy, trifluoromethoxy or SF ; R is hydrogen, CF , chloro or fluoro; R is CF ; and R is hydrogen or CF . 10
37. The compound of formula (I) according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from the group consisting of: (4aR,8aS)(6-(2-Chloro(trifluoromethoxy)phenoxy)azaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 15 (4aR,8aS)(2-(2-Fluoro(trifluoromethyl)phenoxy)azaspiro[3.5]nonane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(2-Fluoro(trifluoromethyl)phenoxy)azaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(2-Methoxy(trifluoromethyl)phenoxy)azaspiro[3.3]heptane 20 carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(2-Fluoro(trifluoromethoxy)phenoxy)azaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(2-Chlorofluorophenoxy)azaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 25 (4aR,8aS)(6-(4-(Trifluoromethyl)phenoxy)azaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(4-Chloro(trifluoromethyl)phenoxy)azaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(2,4-Difluorophenoxy)azaspiro[3.3]heptanecarbonyl)hexahydro-2H- 30 pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(3-Fluoro(trifluoromethyl)phenoxy)azaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(2-Fluoro(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(2-Chlorofluorobenzyl)-2,6-diazaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 5 (4aR,8aS)(2-(2-Fluoro(trifluoromethyl)benzyl)-2,7-diazaspiro[3.5]nonane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-((2-Chlorofluorophenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(7-(2-Fluoro(trifluoromethyl)benzyl)-2,7-diazaspiro[4.4]nonane 10 carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-((2-Fluoro(trifluoromethyl)phenyl)sulfonyl)-2,6- diazaspiro[3.3]heptanecarbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(2-(2-Fluoro(trifluoromethyl)benzyl)-2,6-diazaspiro[3.4]octane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 15 rac-(4aR,8aS)-N-((R)(3-Oxooctahydro-2H-pyrido[4,3-b][1,4]oxazinecarbonyl) oxaazaspiro[4.5]decanyl)benzenesulfonamide; rac-(4aR,8aS)-N-((S)(3-Oxooctahydro-2H-pyrido[4,3-b][1,4]oxazinecarbonyl) oxaazaspiro[4.5]decanyl)benzenesulfonamide; rac-(4aR,8aS)(2-Benzhydryl-2,6-diazaspiro[3.4]octanecarbonyl)hexahydro-2H- 20 pyrido[4,3-b][1,4]oxazin-3(4H)-one; rac-(4aR,8aS)(4-((4-Fluorophenyl)sulfonyl)oxa-4,9-diazaspiro[5.5]undecane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-((4,5-bis(trifluoromethyl)pyridinyl)oxy)azaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 25 (4aR,8aS)(6-((5,6-Bis(trifluoromethyl)pyridinyl)oxy)azaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 2-Chlorofluoro-N-methyl-N-((R)((4aR,8aS)oxooctahydro-2H-pyrido[4,3- b][1,4]oxazinecarbonyl)oxaazaspiro[4.5]decanyl)benzenesulfonamide; (4aR,8aS)(6-((5-(Trifluoromethyl)pyridinyl)oxy)azaspiro[3.3]heptane 30 carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-((4-Methyl(trifluoromethyl)benzyl)oxy)azaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(2-((2-Chlorofluorophenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-((2-Fluoro(trifluoromethyl)benzyl)oxy)azaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 5 N-((S)((4aR,8aS)Oxooctahydro-2H-pyrido[4,3-b][1,4]oxazinecarbonyl)oxa azaspiro[4.5]decanyl)(trifluoromethyl)benzenesulfonamide; N-Methyl-N-((R)((4aR,8aS)oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine carbonyl)oxaazaspiro[4.5]decanyl)benzenesulfonamide; 2-Chlorofluoro-N-((S)((4aR,8aS)oxooctahydro-2H-pyrido[4,3-b][1,4]oxazine 10 carbonyl)oxaazaspiro[4.5]decanyl)benzenesulfonamide; N-((S)((4aR,8aS)Oxooctahydro-2H-pyrido[4,3-b][1,4]oxazinecarbonyl)oxa azaspiro[4.5]decanyl)(trifluoromethyl)benzenesulfonamide; (4aR,8aS)(3-((2-Chlorofluorobenzyl)(methyl)amino)oxaazaspiro[4.5]decane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 15 (4aR,8aS)(3-((2-Chlorofluorobenzyl)(methyl)amino)oxaazaspiro[4.5]decane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(3-((2-Chlorofluorobenzyl)amino)oxaazaspiro[4.5]decane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(3-((2-Chlorofluorobenzyl)amino)oxaazaspiro[4.5]decane 20 carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(2-((4-(Trifluoromethyl)phenyl)sulfonyl)-2,7-diazaspiro[3.5]nonane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; rac-(4aR,8aS)(3-((2-Chlorofluorobenzyl)amino)oxaazaspiro[4.5]decane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 25 (4aR,8aS)(2-(Phenylsulfonyl)-2,7-diazaspiro[3.5]nonanecarbonyl)hexahydro-2H- pyrido[4,3-b][1,4]oxazin-3(4H)-one; rac-tert-butyl 6-((4aR,8aS)oxooctahydro-2H-pyrido[4,3-b][1,4]oxazinecarbonyl)- 2,6-diazaspiro[3.4]octanecarboxylate; (4aR,8aS)(6-(4-(1-methyl-1H-pyrazolyl)phenyl)azaspiro[3.3]heptane 30 carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(2-fluorohydroxybenzyl)azaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(2-hydroxybenzyl)azaspiro[3.3]heptanecarbonyl)hexahydro-2H- pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(2-(4-(2-oxopyrrolidinyl)phenyl)-2,6-diazaspiro[3.4]octane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 5 (4aR,8aS)(6-(2-fluoromethoxybenzyl)azaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(4-(pentafluoro-l6-sulfaneyl)phenyl)azaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(2-fluoro(trifluoromethyl)benzyl)azaspiro[3.3]heptane 10 carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(2,4-difluorobenzyl)azaspiro[3.3]heptanecarbonyl)hexahydro-2H- pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(2-methoxy(trifluoromethyl)benzyl)azaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 15 (4aR,8aS)(6-((2-chlorofluorophenoxy)methyl)azaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-((2-fluoro(trifluoromethyl)benzyl)oxy)(trifluoromethyl) azaspiro[3.3]heptanecarbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(2-fluoro(trifluoromethyl)phenyl)azaspiro[3.3]heptane 20 carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(4-(2-(trifluoromethyl)pyrrolidinyl)phenyl)azaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(2-chlorofluorobenzyl)azaspiro[3.3]heptanecarbonyl)hexahydro- 2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 25 (4aR,8aS)(6-(2-fluoro(trifluoromethyl)benzyl)azaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(4-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(3-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.3]heptane 30 carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(2-(4-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.4]octane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(2-(3-(trifluoromethyl)phenyl)-2,6-diazaspiro[3.4]octane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(2-(4-isopropoxyphenyl)-2,6-diazaspiro[3.4]octanecarbonyl)hexahydro- 2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 5 (4aR,8aS)(6-(4-isopropoxyphenyl)-2,6-diazaspiro[3.3]heptanecarbonyl)hexahydro- 2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(2-(4-methoxymethylphenyl)-2,6-diazaspiro[3.4]octane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(2-(4-chloro(trifluoromethyl)phenyl)-2,6-diazaspiro[3.4]octane 10 carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(2-(2-fluoropyridinyl)-2,6-diazaspiro[3.4]octanecarbonyl)hexahydro- 2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(2,5-bis(trifluoromethyl)phenyl)-2,6-diazaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 15 (4aR,8aS)(6-((4-fluoro(trifluoromethyl)phenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane- 2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-((2-chlorofluorophenyl)sulfonyl)azaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-((3-chloro(trifluoromethyl)phenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane- 20 2-carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-((2,4-bis(trifluoromethyl)phenyl)sulfonyl)-2,6-diazaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(2,6-difluorobenzyl)azaspiro[3.3]heptanecarbonyl)hexahydro-2H- pyrido[4,3-b][1,4]oxazin-3(4H)-one; and 25 (4aR,8aS)(6-(2-methoxybenzyl)azaspiro[3.3]heptanecarbonyl)hexahydro-2H- pyrido[4,3-b][1,4]oxazin-3(4H)-one.
38. A compound of formula (I) according to any one of claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein said compound of formula (I) is selected from the group consisting of: 30 (4aR,8aS)(6-(2-Chloro(trifluoromethoxy)phenoxy)azaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(2-(2-Fluoro(trifluoromethyl)phenoxy)azaspiro[3.5]nonane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(2-Fluoro(trifluoromethyl)phenoxy)azaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 5 (4aR,8aS)(6-(2-Methoxy(trifluoromethyl)phenoxy)azaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(2-Fluoro(trifluoromethoxy)phenoxy)azaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(2-Chlorofluorophenoxy)azaspiro[3.3]heptane 10 carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(4-(Trifluoromethyl)phenoxy)azaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(4-Chloro(trifluoromethyl)phenoxy)azaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 15 (4aR,8aS)(6-(2,4-Difluorophenoxy)azaspiro[3.3]heptanecarbonyl)hexahydro-2H- pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(2-Fluoro(trifluoromethyl)benzyl)-2,6-diazaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-((4,5-bis(trifluoromethyl)pyridinyl)oxy)azaspiro[3.3]heptane 20 carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(4-(pentafluoro-l6-sulfaneyl)phenyl)azaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(2-fluoro(trifluoromethyl)benzyl)azaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; 25 (4aR,8aS)(6-(2,4-difluorobenzyl)azaspiro[3.3]heptanecarbonyl)hexahydro-2H- pyrido[4,3-b][1,4]oxazin-3(4H)-one; (4aR,8aS)(6-(2-methoxy(trifluoromethyl)benzyl)azaspiro[3.3]heptane carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one; and (4aR,8aS)(6-((2-chlorofluorophenoxy)methyl)azaspiro[3.3]heptane 30 carbonyl)hexahydro-2H-pyrido[4,3-b][1,4]oxazin-3(4H)-one.
39. A process of manufacturing the compounds of formula (I) according to any one of claims 1 to 38, or pharmaceutically acceptable salts thereof, comprising: (a) reacting a first amine of formula 1, wherein R and R are as described in any one of claims 1 to 38, with a second amine 2, wherein A, B, L, X, R and R are as described in any one of 5 claims 1 to 38 XN B H in the presence of a base and a urea forming reagent, to form said compound of formula (I); and optionally (b) transforming said compound of formula (I) to a pharmaceutically acceptable salts 10 thereof.
40. A compound of formula (I) according to any one of claims 1 to 38, when manufactured according to the process of claim 39.
41. The compound of formula (I) according to any one of claims 1 to 38 and 40, wherein said compound of formula (I) has an IC for monoacylglycerol lipase below 10 µM. 15
42. A compound of formula (I) according to any one of claims 1 to 38, 40 and 41 for use as therapeutically active substance.
43. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 38, 40 and 41 and a therapeutically inert carrier.
44. A compound of formula (I) according to any one of claims 1 to 38, 40 and 41 or of a 20 pharmaceutical composition according to claim 43 for use in the treatment or prophylaxis of neuroinflammation, neurodegenerative diseases, pain, cancer and/or mental disorders in a mammal.
45. A compound of formula (I) according to any one of claims 1 to 38, 40 and 41 or of a pharmaceutical composition according to claim 43 for use in the treatment or prophylaxis of multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy induced neuropathy, acute pain, chronic pain and/or spasticity 5 associated with pain in a mammal.
46. The use of a compound of formula (I) according to any one of claims 1 to 38, 40 and 41 for the preparation of a medicament for the treatment or prophylaxis of neuroinflammation, neurodegenerative diseases, pain, cancer and/or mental disorders in a human. 10
47. The use of a compound of formula (I) according to any one of claims 1 to 38, 40 and 41 for the preparation of a medicament for the treatment or prophylaxis of multiple sclerosis, Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, traumatic brain injury, neurotoxicity, stroke, epilepsy, anxiety, migraine, depression, hepatocellular carcinoma, colon carcinogenesis, ovarian cancer, neuropathic pain, chemotherapy induced 15 neuropathy, acute pain, chronic pain and/or spasticity associated with pain in a human.
48. The compound according to any one of claims 1 to 38, 40 to 42, 44 and 45, substantially as herein described with reference to any example thereof.
49. The process according to claim 39, substantially as herein described with reference to any example thereof. 20
50. The pharmaceutical composition according to claim 43, substantially as herein described with reference to any example thereof.
51. The use according to claim 46 or 47, substantially as herein described with reference to any example thereof.
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