NZ616817B2 - Spiro-[1,3]-oxazines and spiro-[1,4]-oxazepines as bace1 and/or bace2 inhibitors - Google Patents
Spiro-[1,3]-oxazines and spiro-[1,4]-oxazepines as bace1 and/or bace2 inhibitors Download PDFInfo
- Publication number
- NZ616817B2 NZ616817B2 NZ616817A NZ61681712A NZ616817B2 NZ 616817 B2 NZ616817 B2 NZ 616817B2 NZ 616817 A NZ616817 A NZ 616817A NZ 61681712 A NZ61681712 A NZ 61681712A NZ 616817 B2 NZ616817 B2 NZ 616817B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- difluoro
- amino
- oxazine
- chroman
- amine
- Prior art date
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- 238000002156 mixing Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000006011 modification reaction Methods 0.000 description 1
- QDHHCQZDFGDHMP-UHFFFAOYSA-N monochloramine Chemical compound ClN QDHHCQZDFGDHMP-UHFFFAOYSA-N 0.000 description 1
- 102000005614 monoclonal antibodies Human genes 0.000 description 1
- 108010045030 monoclonal antibodies Proteins 0.000 description 1
- 125000002950 monocyclic group Chemical group 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 210000002569 neurons Anatomy 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 230000003000 nontoxic Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N o-xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003204 osmotic Effects 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 125000005961 oxazepanyl group Chemical group 0.000 description 1
- YRKXMHZOKUGRML-UHFFFAOYSA-N oxazepin-3-amine Chemical class NC1=NOC=CC=C1 YRKXMHZOKUGRML-UHFFFAOYSA-N 0.000 description 1
- 125000000160 oxazolidinyl group Chemical group 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- BSCHIACBONPEOB-UHFFFAOYSA-N oxolane;hydrate Chemical compound O.C1CCOC1 BSCHIACBONPEOB-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial Effects 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 239000000546 pharmaceutic aid Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000010773 plant oil Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- OZAIFHULBGXAKX-UHFFFAOYSA-N precursor Substances N#CC(C)(C)N=NC(C)(C)C#N OZAIFHULBGXAKX-UHFFFAOYSA-N 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000002335 preservative Effects 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000000750 progressive Effects 0.000 description 1
- 230000001737 promoting Effects 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000002633 protecting Effects 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 230000017854 proteolysis Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000005412 pyrazyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000000168 pyrrolyl group Chemical group 0.000 description 1
- LCTONWCANYUPML-UHFFFAOYSA-M pyruvate Chemical compound CC(=O)C([O-])=O LCTONWCANYUPML-UHFFFAOYSA-M 0.000 description 1
- 125000002943 quinolinyl group Chemical group N1=C(C=CC2=CC=CC=C12)* 0.000 description 1
- 125000004621 quinuclidinyl group Chemical group N12C(CC(CC1)CC2)* 0.000 description 1
- 239000002287 radioligand Substances 0.000 description 1
- 230000001105 regulatory Effects 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 230000000276 sedentary Effects 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000001117 sulphuric acid Substances 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000000946 synaptic Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- 230000002123 temporal effect Effects 0.000 description 1
- 125000004853 tetrahydropyridinyl group Chemical group N1(CCCC=C1)* 0.000 description 1
- 125000005958 tetrahydrothienyl group Chemical group 0.000 description 1
- 125000004632 tetrahydrothiopyranyl group Chemical group S1C(CCCC1)* 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000005297 thienyloxy group Chemical group S1C(=CC=C1)O* 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- RTAQQCXQSZGOHL-UHFFFAOYSA-N titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 description 1
- 230000002588 toxic Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 239000003656 tris buffered saline Substances 0.000 description 1
- PTIBVSAWRDGWAE-UHFFFAOYSA-K trisodium;phosphate;heptahydrate Chemical compound O.O.O.O.O.O.O.[Na+].[Na+].[Na+].[O-]P([O-])([O-])=O PTIBVSAWRDGWAE-UHFFFAOYSA-K 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 238000002424 x-ray crystallography Methods 0.000 description 1
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Classifications
-
- 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
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
- C07D265/12—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems
- C07D265/14—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring
- C07D265/18—1,3-Oxazines; Hydrogenated 1,3-oxazines condensed with carbocyclic rings or ring systems condensed with one six-membered ring with hetero atoms directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- C07D498/10—Spiro-condensed systems
-
- 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
- C07D498/12—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 three hetero rings
- C07D498/20—Spiro-condensed systems
Abstract
The disclosure relates to spiro-[1,3]-oxazines and spiro-[1,4]-oxazepines of formula (I) with 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 Alzheimer's disease and type 2 diabetes. Example compounds include: (R)-N-(2'-amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]-6-yl)-5-cyanopicolinamide, (R)-6-(5-chloropyridin-3-yl)-5',5'-difluoro-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-amine, (R)-N-(2'-amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]-6-yl)-5-chloropicolinamide, and (R)-N-(2'-amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]-6-yl)-5-fluoropicolinamide. seful in the therapeutic and/or prophylactic treatment of Alzheimer's disease and type 2 diabetes. Example compounds include: (R)-N-(2'-amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]-6-yl)-5-cyanopicolinamide, (R)-6-(5-chloropyridin-3-yl)-5',5'-difluoro-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-amine, (R)-N-(2'-amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]-6-yl)-5-chloropicolinamide, and (R)-N-(2'-amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]-6-yl)-5-fluoropicolinamide.
Description
Case 27426
Case 27426
Spiro-[1,3]-oxazines and spiro-[1,4]-oxazepines as BACE1 and/or BACE2 inhibitors
Background Art
Alzheimer’s disease (AD) is a neurodegenerative disorder of the central nervous system
and the leading cause of a progressive dementia in the elderly population. Its clinical symptoms
are impairment of memory, cognition, temporal and local orientation, judgment and reasoning
but also severe emotional disturbances. There are currently no treatments available which can
prevent the disease or its progression or stably reverse its clinical symptoms. AD has become a
major health problem in all societies with high life expectancies and also a significant economic
burden for their health systems.
AD is characterized by 2 major pathologies in the central nervous system (CNS), the
occurrence of amyloid plaques and neurofibrillar tangles (Hardy et al., The amyloid hypothesis
of Alzheimer's disease: progress and problems on the road to therapeutics, Science. 2002 Jul
19;297(5580):353-6, Selkoe, Cell biology of the amyloid beta-protein precursor and the
mechanism of Alzheimer's disease, Annu Rev Cell Biol. 1994;10:373-403). Both pathologies are
also commonly observed in patients with Down’s syndrome (trisomy 21), which also develop
AD-like symptoms in early life. Neurofibrillar tangles are intracellular aggregates of the
microtubule-associated protein tau (MAPT). Amyloid plaques occur in the extracellular space;
their principal components are Aβ-peptides. The latter are a group of proteolytic fragments
derived from the β-amyloid precursor protein (APP) by a series of proteolytic cleavage steps.
Several forms of APP have been identified of which the most abundant are proteins of 695, 751
and 770 amino acids length. They all arise from a single gene through differential splicing. The
Aβ-peptides are derived from the same domain of the APP but differ at their N- and C-termini,
the main species are of 40 and 42 amino-acid length. There are several lines of evidence which
strongly suggest that aggregated Aβ-peptides are the essential molecules in the pathogenesis of
AD: 1) amyloid plaques formed of Aβ-peptides are invariably part of the AD pathology; 2) Aβ-
peptides are toxic for neurons; 3) in Familial Alzheimer’s Disease (FAD) the mutations in the
disease genes APP, PSN1, PSN2 lead to increased levels of Aβ-peptides and early brain
amyloidosis; 4) transgenic mice which express such FAD genes develop a pathology which bears
many resemblances to the human disease. Aβ-peptides are produced from APP through the
sequential action of 2 proteolytic enzymes termed β- and γ-secretase. β-Secretase cleaves first in
the extracellular domain of APP approximately 28 amino acids outside of the trans-membrane
domain (TM) to produce a C-terminal fragment of APP containing the TM- and the
cytoplasmatic domain (CTFβ). CTFβ is the substrate for γ-secretase which cleaves at several
adjacent positions within the TM to produce the Aβ peptides and the cytoplasmic fragment. The
SMU / 07.03.2012
γ-secretase is a complex of at least 4 different proteins, its catalytic subunit is very likely a
presenilin protein (PSEN1, PSEN2). The β-secretase (BACE1, Asp2; BACE stands for β-site
APP-cleaving enzyme) is an aspartyl protease which is anchored into the membrane by a
transmembrane domain (Vassar et al., Beta-secretase cleavage of Alzheimer's amyloid precursor
protein by the transmembrane aspartic protease BACE, Science. 1999 Oct 22;286(5440):735). It
is expressed in many tissues of the human organism but its level is especially high in the CNS.
Genetic ablation of the BACE1 gene in mice has clearly shown that its activity is essential for
the processing of APP which leads to the generation of Aβ-peptides, in the absence of BACE1
no Aβ-peptides are produced (Luo et al., Mice deficient in BACE1, the Alzheimer's beta-
secretase, have normal phenotype and abolished beta-amyloid generation, Nat Neurosci. 2001
Mar;4(3):231-2, Roberds et al., BACE knockout mice are healthy despite lacking the primary
beta-secretase activity in brain: implications for Alzheimer's disease therapeutics, Hum Mol
Genet. 2001 Jun 1;10(12):1317-24). Mice which have been genetically engineered to express the
human APP gene and which form extensive amyloid plaques and Alzheimer’s disease like
pathologies during aging fail to do so when β-secretase activity is reduced by genetic ablation of
one of the BACE1 alleles (McConlogue et al., Partial reduction of BACE1 has dramatic effects
on Alzheimer plaque and synaptic pathology in APP Transgenic Mice. J Biol Chem. 2007 Sep
7;282(36):26326). It is thus presumed that inhibitors of BACE1 activity can be useful agents for
therapeutic intervention in Alzheimer’s disease (AD).
Type 2 diabetes (T2D) is caused by insulin resistance and inadequate insulin secretion from
pancreatic β-cells leading to poor blood-glucose control and hyperglycemia (M Prentki & CJ
Nolan, “Islet beta-cell failure in type 2 diabetes.” J. Clin. Investig. 2006, 116(7), 1802-1812).
Patients with T2D have an increased risk of microvascular and macrovascular disease and a
range of related complications including diabetic nephropathy, retinopathy and cardiovascular
disease. In 2000, an estimated 171 million people had the condition with the expectation that this
figure will double by 2030 (S Wild, G Roglic, A Green, R.Sicree & H King, “Global prevalence
of diabetes”, Diabetes Care 2004, 27(5), 1047-1053), making the disease a major healthcare
problem. The rise in prevalence of T2D is associated with an increasingly sedentary lifestyle and
high-energy food intake of the world’s population (P Zimmet, KGMM Alberti & J Shaw,
“Global and societal implications of the diabetes epidemic” Nature 2001, 414, 782-787).
β-Cell failure and consequent dramatic decline in insulin secretion and hyperglycemia
marks the onset of T2D. Most current treatments do not prevent the loss of β-cell mass
characterizing overt T2D. However, recent developments with GLP-1 analogues, gastrin and
other agents show that preservation and proliferation of β-cells is possible to achieve, leading to
an improved glucose tolerance and slower progression to overt T2D (LL Baggio & DJ Drucker,
“Therapeutic approaches to preserve islet mass in type 2 diabetes”, Annu. Rev. Med. 2006, 57,
265-281).
Tmem27 has been identified as a protein promoting beta-cell proliferation (P Akpinar, S
Kuwajima, J Krützfeldt, M Stoffel, “Tmem27: A cleaved and shed plasma membrane protein
that stimulates pancreatic β cell proliferation”, Cell Metab. 2005, 2, 385-397) and insulin
secretion (K Fukui, Q Yang, Y Cao, N Takahashi et al., “The HNF-1 target Collectrin controls
insulin exocytosis by SNARE complex formation”, Cell Metab. 2005, 2, 373-384). Tmem27 is a
42 kDa membrane glycoprotein which is constitutively shed from the surface of β-cells, resulting
from a degradation of the full-length cellular Tmem27. Overexpression of Tmem27 in a
transgenic mouse increases β-cell mass and improves glucose tolerance in a diet-induced obesity
DIO model of diabetes. Furthermore, siRNA knockout of Tmem27 in a rodent β-cell
proliferation assay (e.g. using INS1e cells) reduces the proliferation rate, indicating a role for
Tmem27 in control of β-cell mass.
In the same proliferation assay, BACE2 inhibitors also increase proliferation. However,
BACE2 inhibition combined with Tmem27 siRNA knockdown results in low proliferation rates.
Therefore, it is concluded that BACE2 is the protease responsible for the degradation of
Tmem27. Furthermore, in vitro, BACE2 cleaves a peptide based on the sequence of Tmem27.
The closely related protease BACE1 does not cleave this peptide and selective inhibition of
BACE1 alone does not enhance proliferation of β-cells.
The close homolog BACE2 is a membrane-bound aspartyl protease and is co-localized
with Tmem27 in human pancreatic β -cells (G Finzi, F Franzi, C Placidi, F Acquati et al.,
“BACE2 is stored in secretory granules of mouse and rat pancreatic beta cells”, Ultrastruct
Pathol. 2008, 32(6), 246-251). It is also known to be capable of degrading APP (I Hussain, D
Powell, D Howlett, G Chapman et al., “ASP1 (BACE2) cleaves the amyloid precursor protein at
the β-secretase site” Mol Cell Neurosci. 2000, 16, 609-619), IL-1R2 (P Kuhn, E Marjaux, A
Imhof, B De Strooper et al., “Regulated intramembrane proteolysis of the interleukin-1 receptor
II by alpha-, beta-, and gamma-secretase” J. Biol. Chem. 2007, 282(16), 11982-11995) and
ACE2. The capability to degrade ACE2 indicates a possible role of BACE2 in the control of
hypertension.
Inhibition of BACE2 is therefore proposed as a treatment for T2D with the potential to
preserve and restore β-cell mass and stimulate insulin secretion in pre-diabetic and diabetic
patients. It is therefore an object of the present invention to provide selective BACE2 inhibitors,
or at least to provide the public with a useful alternative. Such compounds are useful as
therapeutically active substances, particularly in the treatment and/or prevention of diseases
which are associated with the inhibition of BACE2.
Furthermore, the formation, or formation and deposition, of β-amyloid peptides in, on or
around neurological tissue (e.g., the brain) are inhibited by the present compounds, i.e. inhibition
of the Aβ-production from APP or an APP fragment.
The present invention provides novel compounds of formula I, their manufacture,
medicaments based on a compound in accordance with the invention and their production as well
as the use of compounds of formula I for the manufacture of medicaments for the control or
prevention of illnesses such as Alzheimer’s disease and type 2 diabetes. The novel compounds of
formula I have improved pharmacological properties.
Field of the Invention
The present invention provides spiro-[1,3]-oxazines and spiro-[1,4]-oxazepines having
BACE1 and/or BACE2 inhibitory properties, their manufacture, pharmaceutical compositions
containing them and their use as therapeutically active substances.
Summary of the Invention
The present invention provides a compounds of formula I,
wherein the substituents and variables are as described below and in the claims, or a
pharmaceutically acceptable salt thereof.
The present compounds have Asp2 (β-secretase, BACE1 or Memapsin-2) inhibitory
activity and can therefore be used in the therapeutic and/or prophylactic treatment of diseases
and disorders characterized by elevated β-amyloid levels and/or β-amyloid oligomers and/or
β-amyloid plaques and further deposits, particularly Alzheimer's disease. And/or the present
compounds have BACE2 inhibitory activity and can therefore be used in the therapeutic and/or
prophylactic treatment of diseases and disorders such as type 2 diabetes and other metabolic
disorders.
Detailed Description of the Invention
The present invention provides a compound of formula I and their pharmaceutically
acceptable salts thereof, the preparation of the above mentioned compounds, medicaments
containing them and their manufacture as well as the use of the above mentioned compounds in
the therapeutic and/or prophylactic treatment of diseases and disorders which are associated with
inhibition of BACE1 and/or BACE2 activity, such as Alzheimer’s disease and type 2 diabetes.
Furthermore, the formation, or formation and deposition, of β-amyloid plaques in, on or around
neurological tissue (e.g., the brain) are inhibited by the present compounds by inhibiting the Aβ
production from APP or an APP fragment.
The following definitions of the general terms used in the present description apply
irrespectively of whether the terms in question appear alone or in combination with other groups.
Unless otherwise stated, the following terms used have the definitions given below. It must
be noted that, as used in the specification and the appended claims, the singular forms “a”, “an,”
and “the” include plural referents unless the context clearly dictates otherwise.
The term "C -alkyl", alone or in combination with other groups, stands for a hydrocarbon
radical which can be linear or branched, with single or multiple branching, wherein the alkyl
group in general contains 1 to 6 carbon atoms, for example, methyl (Me), ethyl (Et), propyl,
isopropyl (i-propyl), n-butyl, i-butyl (isobutyl), 2-butyl (sec-butyl), t-butyl (tert-butyl), isopentyl,
2-ethyl-propyl, 1,2-dimethyl-propyl and the like. The term "C -alkyl", alone or in combination
with other groups, stands for a hydrocarbon radical which can be linear or branched, wherein the
alkyl group comprises 1 to 3 carbon atoms. Particular examples are “C -alkyl” are "C -alkyl".
1-6 1-3
Specific examples are methyl and ethyl. Most specific group is methyl.
The term “cyano-C -alkyl”, alone or in combination with other groups, refers to C -
1-6 1-6
alkyl as defined herein, which is substituted by one or multiple cyano, particularly 1-5 cyano,
more particularly 1 cyano. Examples are cyano-methyl and the like.
The term “halogen-C -alkyl”, alone or in combination with other groups, refers to C -
1-6 1-6
alkyl as defined herein, which is substituted by one or multiple halogen, particularly 1-5 halogen,
more particularly 1-3 halogen, most particularly 1 halogen or 3 halogen. The term “halogen-C -
alkyl”, alone or in combination with other groups, refers to C -alkyl as defined herein, which is
substituted by one or multiple halogen, particularly 1-5 halogen, more particularly 1-3 halogen,
most particularly 1 halogen or 3 halogen. Particular halogen is fluoro. Particular “halogen-C -
alkyl” is fluoro-C -alkyl and particular “halogen-C -alkyl” is fluoro-C -alkyl. Examples are
1-6 1-3 1-3
difluoromethyl, chloromethyl, fluoromethyl and the like. A specific example is trifluoromethyl.
The term “C -alkoxy-C -alkyl”, alone or in combination with other groups, refers to C
1-6 1-6 1-
-alkyl, which is substituted by one or multiple C -alkoxy as defined herein. Examples are
6 1-6
MeO-Me, 1MeO-Et, 2MeO-Et, 1MeO-2EtO-propyl and the like.
The term “cyano”, alone or in combination with other groups, refers to N≡C-(CN).
The term "halogen", alone or in combination with other groups, denotes chloro (Cl), iodo
(I), fluoro (F) and bromo (Br). Particular “halogen” are Cl and F. Specific “halogen” is F.
The term "heteroaryl", alone or in combination with other groups, refers to an aromatic
carbocyclic group of having a single 4 to 8 membered ring or multiple condensed rings
containing 6 to 14, in particular 6 to 10 ring atoms and containing 1, 2 or 3 heteroatoms
individually selected from N, O and S, in particular N and O, in which group at least one
heterocyclic ring is aromatic. Examples of "heteroaryl" include benzofuryl, benzoimidazolyl,
1H-benzoimidazolyl, benzooxazinyl, benzoxazolyl, benzothiazinyl, benzothiazolyl, benzothienyl,
benzotriazolyl, furyl, imidazolyl, indazolyl, 1H-indazolyl, indolyl, isoquinolinyl, isothiazolyl,
isoxazolyl, oxazolyl, pyrazinyl, pyrazolyl (pyrazyl), 1H-pyrazolyl, pyrazolo[1,5-a]pyridinyl,
pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, quinolinyl, tetrazolyl, thiazolyl, thienyl, triazolyl,
6,7-dihydro-5H-[1]pyrindinyl and the like. Particular "heteroaryl" are pyridinyl, pyrimidinyl and
1H-pyrazolyl. Specific groups are pyridinyl, pyridinyl, pyridinyl, pyrimidinyl and
1H-pyrazolyl.
The term “aryl” denotes a monovalent aromatic carbocyclic mono- or bicyclic ring system
comprising 6 to 10 carbon ring atoms. Examples of aryl moieties include phenyl and naphthyl.
Particular “aryl” is phenyl.
The term “heterocyclyl”, alone or in combination with other groups, denotes a monovalent
saturated or partly unsaturated mono- or bicyclic ring system of 4 to 9 ring atoms, containing 1,
2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon.
Bicyclic means consisting of two cycles having two ring atoms in common, i.e. the bridge
separating the two rings is either a single bond or a chain of one or two ring atoms. Examples for
monocyclic saturated heterocyclyl are azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-
thienyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, piperidinyl,
tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-
thiomorpholinyl, azepanyl, diazepanyl, homopiperazinyl, or oxazepanyl. Examples for
bicyclic saturated heterocyclyl are 8-aza-bicyclo[3.2.1]octyl, quinuclidinyl, 8-oxaaza-
bicyclo[3.2.1]octyl, 9-aza-bicyclo[3.3.1]nonyl, 3-oxaaza-bicyclo[3.3.1]nonyl, or 3-thiaaza-
bicyclo[3.3.1]nonyl. Examples for partly unsaturated heterocyclyl are dihydrofuryl, imidazolinyl,
dihydro-oxazolyl, tetrahydro-pyridinyl, or dihydropyranyl. Particular “heterocyclyl” is
tetrahydrofuranyl.
The term "C -alkoxy", alone or in combination with other groups, stands for an
-O-C -alkyl radical which can be linear or branched, with single or multiple branching, wherein
the alkyl group in general comprises 1 to 6 carbon atoms, for example, methoxy (OMe, MeO),
ethoxy (OEt), propoxy, isopropoxy (i-propoxy), n-butoxy, i-butoxy (iso-butoxy),
2-butoxy (sec-butoxy), t-butoxy (tert-butoxy), isopentyloxy (i-pentyloxy) and the like. Particular
“C -alkoxy” are groups with 1 to 4 carbon atoms. Specific examples are methoxy and ethoxy.
The term “halogen-C -alkoxy”, alone or in combination with other groups, refers to C -
1-6 1-6
alkoxy as defined herein, which is substituted by one or multiple halogens, in particular fluoro.
Particular “halogen-C -alkoxy” are fluoro-C -alkoxy. Specific groups are difluoromethoxy
1-6 1-6
and trifluoromethoxy.
The term “C -alkynyl”, alone or in combination with other groups, denotes a monovalent
linear or branched saturated hydrocarbon group of 2 to 6 carbon atoms, in particular from 2 to 4
carbon atoms, and comprising one, two or three triple bonds. Examples of C -alkynyl include
ethynyl, propynyl and n-butynyl. Specific examples are ethynyl and propynyl.
The term "pharmaceutically acceptable salts" refers to salts that are suitable for use in
contact with the tissues of humans and animals. Examples of suitable salts with inorganic and
organic acids are, but are not limited to acetic acid, citric acid, formic acid, fumaric acid,
hydrochloric acid, lactic acid, maleic acid, malic acid, methane-sulfonic acid, nitric acid,
phosphoric acid, p-toluenesulphonic acid, succinic acid, sulfuric acid, sulphuric acid, tartaric
acid, trifluoroacetic acid and the like. Specific examples are formic acid, trifluoroacetic acid and
hydrochloric acid. Particular are hydrochloric acid, trifluoroacetic acid and fumaric acid.
The terms “pharmaceutically acceptable carrier” and “pharmaceutically acceptable
auxiliary substance” refer to carriers and auxiliary substances such as diluents or excipients that
are compatible with the other ingredients of the formulation.
The term "pharmaceutical composition" encompasses a product comprising specified
ingredients in pre-determined amounts or proportions, as well as any product that results, directly
or indirectly, from combining specified ingredients in specified amounts. Particularly it
encompasses a product comprising one or more active ingredients, and an optional carrier
comprising inert ingredients, as well as any product that results, directly or indirectly, from
combination, complexation or aggregation of any two or more of the ingredients, or from
dissociation of one or more of the ingredients, or from other types of reactions or interactions of
one or more of the ingredients.
The term “inhibitor” denotes a compound which competes with, reduces or prevents the
binding of a particular ligand to particular receptor or which reduces or prevents the inhibition of
the function of a particular protein.
The term “half maximal inhibitory concentration” (IC ) denotes the concentration of a
particular compound required for obtaining 50% inhibition of a biological process in vitro. IC
values can be converted logarithmically to pIC values (-log IC ), in which higher values
50 50
indicate exponentially greater potency. The IC value is not an absolute value but depends on
experimental conditions e.g. concentrations employed. The IC value can be converted to an
absolute inhibition constant (Ki) using the Cheng-Prusoff equation (Biochem. Pharmacol. (1973)
22:3099). The term “inhibition constant” (Ki) denotes the absolute binding affinity of a
particular inhibitor to a receptor. It is measured using competition binding assays and is equal to
the concentration where the particular inhibitor would occupy 50% of the receptors if no
competing ligand (e.g. a radioligand) was present. Ki values can be converted logarithmically to
pKi values (-log Ki), in which higher values indicate exponentially greater potency.
“Therapeutically effective amount” means an amount of a compound that, when
administered to a subject for treating a disease state, is sufficient to effect such treatment for the
disease state. The “therapeutically effective amount” will vary depending on the compound,
disease state being treated, the severity or the disease treated, the age and relative health of the
subject, the route and form of administration, the judgment of the attending medical or veterinary
practitioner, and other factors.
The term “as defined herein” and “as described herein” when referring to a variable
incorporates by reference the broad definition of the variable as well as preferred, more preferred
and most preferred definitions, if any.
The terms “treating”, “contacting” and “reacting” when referring to a chemical reaction
means adding or mixing two or more reagents under appropriate conditions to produce the
indicated and/or the desired product. It should be appreciated that the reaction which produces
the indicated and/or the desired product may not necessarily result directly from the combination
of two reagents which were initially added, i.e., there can be one or more intermediates which
are produced in the mixture which ultimately leads to the formation of the indicated and/or the
desired product.
The term “protecting group” denotes the group which selectively blocks a reactive site in a
multifunctional compound such that a chemical reaction can be carried out selectively at another
unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry.
Protecting groups can be removed at the appropriate point. Exemplary protecting groups are
amino-protecting groups, carboxy-protecting groups or hydroxy-protecting groups. The term
“amino-protecting group” denotes groups intended to protect an amino group and includes
benzyl, benzyloxycarbonyl (carbobenzyloxy, CBZ), 9-Fluorenylmethyloxycarbonyl (FMOC), p-
methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert-butoxycarbonyl (BOC),
triphenylmethyl (Tr), 4-monomethoxytrityl (MMTr), 4,4-dimethoxy-trityl (DMTr), 4,4',4"-
trimethoxytrityl and trifluoroacetyl. Further examples of these groups are found in T. W. Greene
and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, 2nd ed., John Wiley & Sons, Inc.,
New York, NY, 1991, chapter 7; E. Haslam, “Protective Groups in Organic Chemistry”, J. G. W.
McOmie, Ed., Plenum Press, New York, NY, 1973, Chapter 5, and T.W. Greene, “Protective
Groups in Organic Synthesis”, John Wiley and Sons, New York, NY, 1981. The term “protected
amino group” refers to an amino group substituted by an amino-protecting groups. Particular
amino-protecting groups are tert-butoxycarbonyl group and dimethoxytrityl.
The term “leaving group” denotes the group with the meaning conventionally associated
with it in synthetic organic chemistry, i.e., an atom or group displaceable under substitution
reaction conditions. Examples of leaving groups include halogen, in particular bromo, alkane- or
arylenesulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl,
benzenesulfonyloxy, tosyloxy, and thienyloxy, dihalophosphinoyloxy, optionally substituted
benzyloxy, isopropyloxy, and acyloxy.
The term “aromatic” denotes the conventional idea of aromaticity as defined in the
literature, in particular in IUPAC - Compendium of Chemical Terminology, 2nd, A. D.
McNaught & A. Wilkinson (Eds). Blackwell Scientific Publications, Oxford (1997).
The term “pharmaceutically acceptable excipient” denotes any ingredient having no
therapeutic activity and being non-toxic such as disintegrators, binders, fillers, solvents, buffers,
tonicity agents, stabilizers, antioxidants, surfactants or lubricants used in formulating
pharmaceutical products.
Whenever a chiral carbon is present in a chemical structure, it is intended that all
stereoisomers associated with that chiral carbon are encompassed by the structure.
The invention also provides pharmaceutical compositions, methods of using, and methods
of preparing the aforementioned compounds.
All separate embodiments can be combined.
One embodiment of the invention is a compound of formula I,
wherein
7a 7b
V is -CR R -;
2a 2b
W is -CR R -;
1a 1b
X is -CR R -, -O-, -S- or -SO -;
Y -NH-C=O-;
Z is selected from the group consisting of
i) heteroaryl,
ii) heteroaryl substituted by 1-4 substituents individually selected from R ,
iii) aryl, and
iv) aryl substituted by 1-4 substituents individually selected from R ,
R is selected from the group consisting of
i) hydrogen,
ii) halogen, and
iii) C -alkyl;
R is selected from the group consisting of
i) hydrogen,
ii) halogen, and
iii) C -alkyl;
R is selected from the group consisting of
i) hydrogen, and
ii) C -alkyl;
R is selected from the group consisting of
i) hydrogen,
ii) aryl, and
iii) C -alkyl;
2a 2b
or R and R together with the C they are attached form a heterocyclyl;
R is selected from the group consisting of
i) hydrogen, and
ii) halogen,
R is selected from the group consisting of
i) hydrogen, and
ii) halogen,
R is selected from the group consisting of
i) hydrogen, and
ii) C -alkyl,
R is selected from the group consisting of
i) hydrogen, and
ii) C -alkyl,
R is selected from the group consisting of
i) hydrogen, and
ii) C -alkyl;
R is selected from the group consisting of
i) hydrogen, and
ii) C -alkyl;
R is selected from the group consisting of
i) cyano,
ii) cyano-C -alkyl,
iii) halogen,
iv) halogen-C -alkoxy,
40 v) halogen-C -alkyl,
vi) C -alkoxy,
vii) C -alkoxy-C -alkyl,
1-6 1-6
viii) C -alkynyl, and
ix) C -alkyl;
n is 0 or 1;
m is 0 or 1;
p is 0 or 1;
or pharmaceutically acceptable salts thereof.
A certain embodiment is a compound as described herein, wherein
7a 7b
V is -CR R -;
2a 2b
W is -CR R -;
1a 1b
X is -CR R -, -O-, -S- or -SO -;
Y -NH-C=O-;
Z is selected from the group consisting of
i) heteroaryl,
ii) heteroaryl substituted by 1-2 substituents individually selected from R , and
iii) aryl substituted by 1-2 substituents individually selected from R ,
R is selected from the group consisting of
i) hydrogen,
ii) halogen, and
iii) C -alkyl;
R is selected from the group consisting of
i) hydrogen,
ii) halogen, and
iii) C -alkyl;
R is selected from the group consisting of
i) hydrogen, and
ii) C -alkyl;
R is selected from the group consisting of
i) hydrogen,
ii) phenyl, and
iii) C -alkyl;
2a 2b
or R and R together with the C they are attached form tetrahydropyranyl;
R is halogen;
R is halogen;
R is hydrogen;
R is hydrogen;
R is hydrogen;
R is hydrogen;
R is selected from the group consisting of
i) cyano,
ii) halogen,
iii) halogen-C -alkyl, and
iv) C -alkoxy,
n is 0 or 1;
m is 0 or 1;
p is 0 or 1;
or pharmaceutically acceptable salts thereof.
A certain embodiment is a compound as described herein, wherein
7a 7b
V is -CR R -;
2a 2b
W is -CR R -;
1a 1b
X is -CR R -;
Y -NH-C=O-;
Z is selected from the group consisting of
i) heteroaryl,
ii) heteroaryl substituted by 1-2 substituents individually selected from R , and
iii) aryl substituted by 1-2 substituents individually selected from R ,
R is selected from the group consisting of
i) hydrogen,
ii) halogen, and
iii) C -alkyl;
R is selected from the group consisting of
i) hydrogen,
ii) halogen, and
iii) C -alkyl;
R is selected from the group consisting of
i) hydrogen, and
ii) C -alkyl;
R is selected from the group consisting of
i) hydrogen,
ii) phenyl, and
iii) C -alkyl;
R is halogen;
R is halogen;
R is hydrogen;
R is hydrogen;
R is hydrogen;
R is hydrogen;
R is selected from the group consisting of
i) cyano,
ii) halogen, and
iii) halogen-C -alkyl;
n is 0 or 1;
m is 0 or 1;
p is 0 or 1;
or pharmaceutically acceptable salts thereof.
A certain embodiment is a compound as described herein, wherein
1a 1b
X is -CR R -;
Y -NH-C=O-;
Z is heteroaryl substituted by R ,
R is hydrogen;
R is hydrogen;
R is halogen;
R is halogen;
R is hydrogen;
R is hydrogen;
R is hydrogen;
R is hydrogen;
R is selected from the group consisting of
i) cyano, and
ii) halogen, and
n is 0;
m is 1;
p is 0;
or pharmaceutically acceptable salts thereof.
A certain embodiment is a compound as described herein, wherein n is 0.
A certain embodiment is a compound as described herein, wherein n is 1.
A certain embodiment is a compound as described herein, wherein m is 0.
A certain embodiment is a compound as described herein, wherein m is 1.
A certain embodiment is a compound as described herein, wherein p is 0.
A certain embodiment is a compound as described herein, wherein p is 1.
1a 1b 1a
A certain embodiment is a compound as described herein, wherein X is -CR R - and R
and R are both hydrogen.
1a 1b
A certain embodiment is a compound as described herein, wherein X is -CR R -.
A certain embodiment is a compound as described herein, wherein R is hydrogen.
A certain embodiment is a compound as described herein, wherein R is halogen.
A certain embodiment is a compound as described herein, wherein R is F.
A certain embodiment is a compound as described herein, wherein R is C -alkyl.
A certain embodiment is a compound as described herein, wherein R is methyl.
A certain embodiment is a compound as described herein, wherein R is hydrogen.
A certain embodiment is a compound as described herein, wherein R is halogen.
A certain embodiment is a compound as described herein, wherein R is F.
A certain embodiment is a compound as described herein, wherein R is C -alkyl.
A certain embodiment is a compound as described herein, wherein R is methyl.
A certain embodiment is a compound as described herein, wherein R is C -alkyl.
A certain embodiment is a compound as described herein, wherein R is methyl.
A certain embodiment is a compound as described herein, wherein R is hydrogen.
A certain embodiment is a compound as described herein, wherein R is C -alkyl.
A certain embodiment is a compound as described herein, wherein R is methyl.
A certain embodiment is a compound as described herein, wherein R is hydrogen.
A certain embodiment is a compound as described herein, wherein R is aryl.
A certain embodiment is a compound as described herein, wherein R is phenyl.
2a 2b
A certain embodiment is a compound as described herein, wherein R and R form
together with the C to which they are attached form heterocyclyl.
2a 2b
A certain embodiment is a compound as described herein, wherein R and R form
together with the C to which they are attached tetrahydropyranyl.
A certain embodiment is a compound as described herein, wherein X is -O-.
A certain embodiment is a compound as described herein, wherein X is -S-.
A certain embodiment is a compound as described herein, wherein X is –SO -.
2a 2b
A certain embodiment is a compound as described herein, wherein p is 1, W is -CR R -
2a 2b
and R and R are both hydrogen.
7a 7b 7a
A certain embodiment is a compound as described herein, wherein V is –CR R - and R
and R are both hydrogen.
7a 7b
A certain embodiment is a compound as described herein, wherein V is –CR R -.
A certain embodiment is a compound as described herein, wherein R is hydrogen.
A certain embodiment is a compound as described herein, wherein R is hydrogen.
2a 2b
A certain embodiment is a compound as described herein, wherein W is –CR R -.
A certain embodiment is a compound as described herein, wherein R is halogen.
A certain embodiment is a compound as described herein, wherein R is F.
A certain embodiment is a compound as described herein, wherein R is halogen.
A certain embodiment is a compound as described herein, wherein R is F.
A certain embodiment is a compound as described herein, wherein R is hydrogen.
A certain embodiment is a compound as described herein, wherein R is hydrogen.
A certain embodiment is a compound as described herein, wherein Y is -NH-C=O-.
A certain embodiment is a compound as described herein, wherein Z is heteroaryl
substituted by halogen or cyano.
A certain embodiment is a compound as described herein, wherein Z is 2-chloropyridinyl,
3,5-dichlorophenyl, 3,5-dichloropyridinyl, 3-cyano-phenyl, 4-chloro-1H-pyrazoleyl, 5-
chloropyridinyl, 5-chloropyridinyl, 5-cyanopyridinyl, 5-cyanopyridinyl, 5-fluoropyridinyl, 5-
fluoropyridinyl, 5-methoxypyridinyl, 5-trifluoromethylpyridinyl or pyrimidinyl.
A certain embodiment is a compound as described herein, wherein Z is 2-chloropyridin
yl, 3,5-dichlorophenyl, 3,5-dichloropyridinyl, 3-cyano-phenyl, 4-chloro-1H-pyrazoleyl, 5-
chloropyridinyl, 5-chloropyridinyl, 5-cyanopyridinyl, 5-cyanopyridinyl, 5-
fluoropyridinyl, 5-fluoropyridinyl, 5-methoxypyridinyl, 5-trifluoromethylpyridinyl or
pyrimidinyl.
A certain embodiment is a compound as described herein, wherein Z is 5-cyanopyridin
yl, 5-chloropyridinyl, 5-chloropyridinyl or 5-fluoropyridinyl.
A certain embodiment is a compound as described herein, wherein Z is heteroaryl.
A certain embodiment is a compound as described herein, wherein Z is pyrimidinyl.
A certain embodiment is a compound as described herein, wherein Z is heteroaryl
substituted by 1-2 substituents individually selected from R .
A certain embodiment is a compound as described herein, wherein Z is 1H-pyrazolyl,
pyridinyl or pyrimidinyl.
A certain embodiment is a compound as described herein, wherein Z is 1H-pyrazolyl,
pyridinyl, pyridinyl, pyridinyl or pyrimidinyl.
A certain embodiment is a compound as described herein, wherein Z is aryl.
A certain embodiment is a compound as described herein, wherein Z is aryl substituted by
1-4 substituents individually selected from R .
A certain embodiment is a compound as described herein, wherein Z is phenyl substituted
by 1-2 substituents individually selected from chloro and cyano.
A certain embodiment is a compound as described herein, wherein R is cyano.
A certain embodiment is a compound as described herein, wherein R is halogen.
A certain embodiment is a compound as described herein, wherein R is chloro.
A certain embodiment is a compound as described herein, wherein R is fluoro.
A certain embodiment is a compound as described herein, wherein R is halogen-C -alkyl.
A certain embodiment is a compound as described herein, wherein R is trifluoromethyl.
A certain embodiment is a compound as described herein, wherein R is C -alkoxy.
A certain embodiment is a compound as described herein, wherein R is methoxy.
A certain embodiment is a compound as described herein, selected from the group
consisting of
(R)(5-chloropyridinyl)-5',5'-difluoro-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'-
[1,3]oxazin]-2'-amine,
(2'R,4R)-6'-(5-chloropyridinyl)-5,5-difluoro-5,5'',6,6''-tetrahydro-4''H-dispiro[1,3-oxazine-
4,4'-chromene-2',3''-pyran]amine formate,
(2RS,4R)-5',5'-difluorophenyl(pyrimidinyl)-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazin]-2'-amine,
(2RS,4R)(3,5-dichlorophenyl)-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazin]-2'-amine,
(2RS,4R)(3,5-dichlorophenyl)-6',6'-difluorophenyl-6',7'-dihydro-2'H-spiro[chroman-4,5'-
[1,4]oxazepin]-3'-amine,
(2RS,4R)(5-chloropyridinyl)-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazin]-2'-amine,
(2RS,4R)(5-chloropyridinyl)-6',6'-difluorophenyl-6',7'-dihydro-2'H-spiro[chroman-4,5'-
[1,4]oxazepin]-3'-amine,
(2RS,4R)-6',6'-difluorophenyl(pyrimidinyl)-6',7'-dihydro-2'H-spiro[chroman-4,5'-
[1,4]oxazepin]-3'-amine,
(2'S,4R)-6'-(5-chloropyridinyl)-5,5-difluoro-5,5'',6,6''-tetrahydro-4''H-dispiro[1,3-oxazine-
4,4'-chromene-2',3''-pyran]amine formate,
(R)(2'-Amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]
yl)benzonitrile,
(R)-4,4,5',5'-tetrafluoro(5-fluoropyridinyl)-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'-
[1,3]oxazin]-2'-amine,
(R)(2'-amino-4,4,5',5'-tetrafluoro-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'-
[1,3]oxazine]yl)nicotinonitrile,
(R)(2'-amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]
yl)nicotinonitrile,
(R)(2'-amino-5',5'-difluoro-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'-[1,3]oxazine]
yl)nicotinonitrile,
(R)-5',5'-difluoro(5-methoxypyridinyl)-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-
amine,
(R)-5',5'-difluoro(pyrimidinyl)-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazin]-2'-amine,
(R)-5',5'-difluoro(pyrimidinyl)-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-amine,
(R)(2-chloropyridinyl)-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazin]-2'-
amine,
(R)(3,5-dichlorophenyl)-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazin]-2'-
amine,
(R)(3,5-dichlorophenyl)-5',5'-difluoro-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-amine,
(R)(3,5-dichlorophenyl)-6',6'-difluoro-6',7'-dihydro-2'H-spiro[chroman-4,5'-[1,4]oxazepin]-3'-
amine,
(R)(5-chloropyridinyl)-5',5'-difluoro-2,2-dimethyl-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazin]-2'-amine,
(R)(5-chloropyridinyl)-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazin]-2'-
amine,
(R)-6'-(5-chloropyridinyl)-5,5-difluoro-5,6-dihydrospiro[[1,3]oxazine-4,4'-thiochroman]
amine,
(R)(5-chloropyridinyl)-5',5'-difluoro-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-amine,
(R)(5-chloropyridinyl)-6',6'-difluoro-6',7'-dihydro-2'H-spiro[chroman-4,5'-[1,4]oxazepin]-
3'-amine,
(R)(5-chloropyridinyl)-4,4,5',5'-tetrafluoro-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'-
[1,3]oxazin]-2'-amine,
(R)-N-(2'-amino-5',5'-difluoro-2,2-dimethyl-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazine]yl)-
5-chloropicolinamide,
(R)-N-(2'-amino-5',5'-difluoro-2,2-dimethyl-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazine]yl)-
-cyanopicolinamide,
(R)-N-(2'-amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]yl)
cyanopicolinamide,
(R)-N-(2'-amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]yl)
chloropicolinamide,
(R)-N-(2'-amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]yl)
fluoropicolinamide,
(R)-N-(2'-amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]yl)
(trifluoromethyl)picolinamide,
(R)-N-(2'-amino-5',5'-difluoro-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'-[1,3]oxazine]
yl)chloropicolinamide,
(R)-N-(2'-amino-5',5'-difluoro-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'-[1,3]oxazine]
yl)cyanopicolinamide,
(R)-N-(2'-amino-5',5'-difluoro-4,4-dimethyl-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'-
[1,3]oxazine]yl)cyanopicolinamide,
(R)-N-(2-amino-5,5-difluoro-5,6-dihydrospiro[[1,3]oxazine-4,4'-thiochroman]-6'-yl)
chloropicolinamide,
(R)-N-(2-amino-5,5-difluoro-5,6-dihydrospiro[[1,3]oxazine-4,4'-thiochroman]-6'-yl)
cyanopicolinamide,
(R)-N-(2'-amino-5',5'-difluoro-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazine]yl)
chloropicolinamide,
(R)-N-(2'-amino-5',5'-difluoro-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazine]yl)
cyanopicolinamide,
(R)-N-(2'-amino-5',5'-difluoro-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazine]yl)chloro-1H-
pyrazolecarboxamide,
(R)-N-(3'-amino-6',6'-difluoro-3,4,6',7'-tetrahydro-2H,2'H-spiro[naphthalene-1,5'-
[1,4]oxazepine]yl)cyanopicolinamide,
(R)-N-(3'-amino-6',6'-difluoro-3,4,6',7'-tetrahydro-2H,2'H-spiro[naphthalene-1,5'-
[1,4]oxazepine]yl)chloropicolinamide,
(R)-N-(3'-amino-6',6'-difluoro-6',7'-dihydro-2'H-spiro[chroman-4,5'-[1,4]oxazepine]yl)
cyanopicolinamide,
(R)-N-(3'-amino-6',6'-difluoro-6',7'-dihydro-2'H-spiro[chroman-4,5'-[1,4]oxazepine]yl)
chloropicolinamide,
(R)-N-(3'-amino-6',6'-difluoro-6',7'-dihydro-2'H-spiro[chroman-4,5'-[1,4]oxazepine]yl)-3,5-
dichloropicolinamide,
3-((2RS,4R)-2'-amino-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazine]
yl)benzonitrile,
3-((2RS,4R)-3'-amino-6',6'-difluorophenyl-6',7'-dihydro-2'H-spiro[chroman-4,5'-
[1,4]oxazepine]yl)benzonitrile,
3-[(2'R,4R)amino-5,5-difluoro-5,5'',6,6''-tetrahydro-4''H-dispiro[1,3-oxazine-4,4'-chromene-
2',3''-pyran]-6'-yl]benzonitrile formate,
-((2RS,4R)-2'-amino-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazine]
yl)nicotinonitrile,
-((2RS,4R)-3'-amino-6',6'-difluorophenyl-6',7'-dihydro-2'H-spiro[chroman-4,5'-
[1,4]oxazepine]yl)nicotinonitrile,
N-((2R or 2S,4R)-2'-amino-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazine]yl)chloropicolinamide,
N-((2R or 2S,4R)-2'-amino-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazine]yl)cyanopicolinamide,
N-((2R or 2S,4R)-2'-amino-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazine]yl)fluoropicolinamide,
N-((2R or 2S,4R)-2'-amino-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazine]yl)(trifluoromethyl)picolinamide,
N-((2RS,4R)-3'-amino-6',6'-difluorophenyl-6',7'-dihydro-2'H-spiro[chroman-4,5'-
[1,4]oxazepine]yl)(trifluoromethyl)picolinamide,
N-((2RS,4R)-3'-amino-6',6'-difluorophenyl-6',7'-dihydro-2'H-spiro[chroman-4,5'-
[1,4]oxazepine]yl)cyanopicolinamide,
N-[(2'R,4R)amino-5,5-difluoro-5,5'',6,6''-tetrahydro-4''H-dispiro[1,3-oxazine-4,4'-chromene-
2',3''-pyran]-6'-yl]cyanopyridinecarboxamide,
N-[(4R)amino-5,5-difluoro-1',1'-dioxido-2',3',5,6-tetrahydrospiro[1,3-oxazine-4,4'-
thiochromen]-6'-yl]chloropyridinecarboxamide, and
N-[(4R)amino-5,5-difluoro-1',1'-dioxido-2',3',5,6-tetrahydrospiro[1,3-oxazine-4,4'-
thiochromen]-6'-yl]cyanoopyridinecarboxamide,
or a pharmaceutical acceptable salt thereof.
A certain embodiment is a compound as described herein,, selected from the group
consisting of
(R)-N-(2'-Amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]yl)
cyanopicolinamide,
(R)(5-Chloropyridinyl)-5',5'-difluoro-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-
amine,
(R)-N-(2'-Amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]yl)
chloropicolinamide, and
(R)-N-(2'-Amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]yl)
fluoropicolinamide,
or a pharmaceutical acceptable salt thereof.
A certain embodiment of the invention provides a process as described below,
Z-COOH N
H N 3
R Y 3
I' I
1 2 3 4 5 6
wherein V, W, Y, Z, n, p, R , R , R , R , R and R are as described herein and m is 1.
A certain embodiment of the invention provides a compound of formula I as described
herein, whenever prepared by a process as defined above.
A certain embodiment of the invention provides a compound of formula I as described
herein for use as therapeutically active substance.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use as inhibitor of BACE1 and/or BACE2 activity.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use as inhibitor of BACE1 activity.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use as inhibitor of BACE2 activity.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use as inhibitor of BACE1 and BACE2 activity.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use as therapeutically active substance for the therapeutic and/or prophylactic
treatment of diseases and disorders characterized by elevated β-amyloid levels and/or β-amyloid
oligomers and/or β-amyloid plaques and further deposits or Alzheimer's disease.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use as therapeutically active substance for the therapeutic and/or prophylactic
treatment of Alzheimer's disease.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use as therapeutically active substance for the therapeutic and/or prophylactic
treatment of diabetes or type 2 diabetes.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use as therapeutically active substance for the therapeutic and/or prophylactic
treatment of diabetes.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use as therapeutically active substance for the therapeutic and/or prophylactic
treatment of diabetes or type 2 diabetes.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use as therapeutically active substance for the therapeutic and/or prophylactic
treatment of Alzheimer's disease, diabetes or type 2 diabetes.
A certain embodiment of the invention provides a pharmaceutical composition comprising
a compound of formula I as described herein and a pharmaceutically acceptable carrier and/or a
pharmaceutically acceptable auxiliary substance.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the use in inhibition of BACE1 and/or
BACE2 activity.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the use in inhibition of BACE1
activity.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the use in inhibition of BACE2
activity.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the use in inhibition of BACE1 and
BACE2 activity.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the therapeutic and/or prophylactic
treatment of diseases and disorders characterized by elevated β-amyloid levels and/or β-amyloid
oligomers and/or β-amyloid plaques and further deposits or Alzheimer's disease.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the therapeutic and/or prophylactic
treatment of Alzheimer's disease.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the therapeutic and/or prophylactic
treatment of diabetes or type 2 diabetes.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the therapeutic and/or prophylactic
treatment of diabetes.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the therapeutic and/or prophylactic
treatment of diabetes or type 2 diabetes.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the therapeutic and/or prophylactic
treatment of Alzheimer's disease, diabetes or type 2 diabetes.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the therapeutic and/or prophylactic
treatment of Alzheimer's disease.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the therapeutic and/or prophylactic
treatment of diabetes or type 2 diabetes.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the therapeutic and/or prophylactic
treatment of diabetes.
A certain embodiment of the invention provides the use of a compound of formula I as
described herein for the manufacture of a medicament for the therapeutic and/or prophylactic
treatment of type 2 diabetes.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use in inhibition of BACE1 and/or BACE2 activity.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use in inhibition of BACE1 activity.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use in inhibition of BACE2 activity.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use in inhibition of BACE1 and BACE2 activity.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use in the therapeutic and/or prophylactic treatment of diseases and disorders
characterized by elevated β-amyloid levels and/or β-amyloid oligomers and/or β-amyloid
plaques and further deposits or Alzheimer's disease.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use in the therapeutic and/or prophylactic treatment of Alzheimer's disease.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use in the therapeutic and/or prophylactic treatment of diabetes or type 2 diabetes.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use in the therapeutic and/or prophylactic treatment of diabetes.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use in the therapeutic and/or prophylactic treatment of diabetes or type 2 diabetes.
A certain embodiment of the invention provides a compound of formula I as described
herein for the use in the therapeutic and/or prophylactic treatment of Alzheimer's disease,
diabetes or type 2 diabetes.
Also described herein is a method for the use in inhibition of BACE1 and/or BACE2
activity, particularly for the therapeutic and/or prophylactic treatment of diseases and disorders
characterized by elevated β-amyloid levels and/or β-amyloid oligomers and/or β-amyloid
plaques and further deposits, Alzheimer's disease, diabetes or type 2 diabetes, which method
comprises administering compound of formula I as described herein to a human being or animal.
Also described herein is a method for the use in the therapeutic and/or prophylactic
treatment of Alzheimer's disease, diabetes or type 2 diabetes, which method comprises
administering a compound of formula I as described herein to a human being or animal.
Also described herein is a method for the use in the therapeutic and/or prophylactic
treatment of Alzheimer's disease, which method comprises administering a compound of formula
I as described herein to a human being or animal.
Also described herein is a method for the use in the therapeutic and/or prophylactic
treatment of diabetes, which method comprises administering a compound of formula I as
described herein to a human being or animal.
Also described herein is a method for the use in the therapeutic and/or prophylactic
treatment of type 2 diabetes, which method comprises administering a compound of formula I as
described herein to a human being or animal.
Furthermore, the invention includes all optical isomers, i.e. diastereoisomers,
diastereomeric mixtures, racemic mixtures, all their corresponding enantiomers and/or tautomers
as well as their solvates of the compounds of formula I.
The skilled person in the art will recognize that the compounds of formula I can exist in
tautomeric forms, e.g. in the following tautomeric form:
All tautomeric forms are encompassed in the present invention.
The compounds of formula I can contain one or more asymmetric centers and can therefore
occur as racemates, racemic mixtures, single enantiomers, diastereomeric mixtures and
individual diastereomers. Additional asymmetric centers can be present depending upon the
nature of the various substituents on the molecule. Each such asymmetric centre will
independently produce two optical isomers and it is intended that all of the possible optical
isomers and diastereomers in mixtures and as pure or partially purified compounds are included
within this invention. The present invention is meant to encompass all such isomeric forms of
these compounds. The independent syntheses of these diastereomers or their chromatographic
separations can be achieved as known in the art by appropriate modification of the methodology
disclosed herein. Their absolute stereochemistry can be determined by the x-ray crystallography
of crystalline products or crystalline intermediates which are derivatized, if necessary, with a
reagent containing an asymmetric centre of known absolute configuration. If desired, racemic
mixtures of the compounds can be separated so that the individual enantiomers are isolated. The
separation can be carried out by methods well known in the art, such as the coupling of a racemic
mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture,
followed by separation of the individual diastereomers by standard methods, such as fractional
crystallization or chromatography. Particular examples of isomers of a compound of formula I is
a compound of formula Ia wherein the residues have the meaning as described in any of the
embodiments.
In the embodiments, where optically pure enantiomers are provided, optically pure
enantiomer means that the compound contains > 90 % of the desired isomer by weight,
particularly > 95 % of the desired isomer by weight, or more particularly > 99 % of the desired
isomer by weight, said weight percent based upon the total weight of the isomer(s) of the
compound. Chirally pure or chirally enriched compounds can be prepared by chirally selective
synthesis or by separation of enantiomers. The separation of enantiomers can be carried out on
the final product or alternatively on a suitable intermediate.
The compounds of formula I can be prepared in accordance with the following schemes. The
starting material is commercially available or can be prepared in accordance with known
methods. Any previously defined residues and variables will continue to have the previously
defined meaning unless otherwise indicated.
1a 1b 1a 1b
Sulfinyl imines of general formula A2, wherein X is -CR R (R , R are hydrogen,
2a 2b 2a 2b
lower alkyl or fluorine) and W is –CR R (with p = 1, R , R are hydrogen), can be prepared
in analogy to T.P. Tang & J.A. Ellman, J. Org. Chem. 1999, 64, 12, by condensation of an aryl
ketone A1 and a sulfinamide, e.g. an alkyl sulfinamide, most particularly (R)-(+)-tert-
butylsulfinamide, in the presence of a Lewis acid such as e.g. a titanium(IV)alkoxide, more
particularly titanium(IV)ethoxide in a solvent such as an ether, e.g. diethyl ether or more
particularly tetrahydrofuran.
The conversion of the sulfinyl imine A2 to the sulfinamide ester A3 proceeds
stereoselectively by the chiral directing group as described by Tang & Ellman. The sulfinyl
imine A2 can be reacted in a Reformatsky reaction with a zinc enolate generated from e.g. an
alkyl bromodifluoroacetate, particularly ethyl bromodifluoroacetate, and activated zinc powder
at ambient to elevated temperature, particularly at 23 to 60 °C in a solvent such as an ether, e.g.
diethyl ether or more particularly tetrahydrofuran.
The alcohol of formula A4 can be prepared by the reduction of an ethylester of formula A3
with an alkali hydride, particularly lithium borohydride or lithium aluminium hydride, in a
solvent such as an ether, e.g. diethyl ether or more particularly tetrahydrofuran.
Hydrolysis of the chiral directing group in the sulfinamide alcohol of formula A4 to give
the aminoalcohol of formula A5 can be accomplished with a mineral acid, e.g. sulfuric acid or
particularly hydrochloric acid, in a solvent such as an ether, e.g. diethyl ether, tetrahydrofuran or
more particularly 1,4-dioxane.
The aminooxazine of formula A6 can be prepared by reaction of an aminoalcohol of
formula A5 with cyanogen bromide in a solvent such as an alcohol, particularly ethanol.
The reduction of derivatives of formula A6, wherein Q is a nitro group, to give anilines of
formula A7 can be accomplished by hydrogenation using a catalyst, such as palladium on carbon,
in protic solvents, such as alcohols, in particular ethanol or methanol.
S COOEt
O + N R
S HN
H N R
(W) (W)
p p p
1a 1b
1a 1b 1a 1b
R R R R
A1 A2 A3
Q = Br, NO
R = C -alkyl, in particular t-butyl
H N O OH R O OH
N H N HN
Q Q Q
F F F
(W) (W) (W)
1a 1b 1a 1b 1a 1b
R R R R R R
A6 A5
for Q = Br for Q : NO
H N O H N O H N O
2 2 2
F F F
N N N
H N Z-COOH
F F F
(W) (W) (W)
p p p
1a 1b 1a 1b 1a 1b
R R R R R R
I.1 A7
Scheme A: Synthesis of compounds of formula I.1 and I.2.
Target amines of formula I.1 can be prepared by palladium-catalyzed cross coupling
between compounds of formula A6 and derivatives of formula Z-R , wherein R has the meaning
of a boronic acid or ester under conditions (Suzuki-Miyaura-coupling) known to those skilled in
the art.
Target amides of formula I.2 can be prepared by selective coupling of anilines of formula
A7 and a carboxylic acid of formula Z-COOH with 4-(4,6-dimethoxy[1.3.5]triazinyl)
methylmorpholinium chloride hydrate (DMTMM) as the condensating agent in a solvent such as
methanol.
Another typical procedure for the preparation of anilines of formula A7 via N-protected
intermediates is illustrated in Scheme A.1.
Protection of the amino group in compounds of formula A6, wherein Q is bromine, to
produce aryl bromides of formula A6.1 can be performed with triarylmethyl chlorides, such as
triphenylmethyl chloride (Tr-Cl), p-methoxyphenyldiphenylmethyl chloride (MMTr-Cl), di(p-
methoxyphenyl)phenylmethyl chloride (DMTr-Cl) or tri(p-methoxyphenyl)methyl chloride
(TMTr-Cl), particularly DMTr-Cl, under basic conditions, e.g. in the presence of an amine, such
as triethylamine or diisopropylethylamine, in a chlorinated solvent, such as dichloromethane or
chloroform, at temperatures between 0 °C and ambient temperature.
Aryl bromides of formula A6.1 can be reacted with ammonia equivalents, such as
benzophenone imine, in the presence of a suitable transition metal catalyst, such as
bis(dibenzylideneacetone)palladium (0) ((dba) Pd) or tris(dibenzylideneacetone)dipalladium (0)
((dba) Pd )), and a suitable ligand, such as rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (rac-
BINAP), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-PHOS) or 2-di-tert-
butylphosphino-2',4',6'-triisopropylbiphenyl (t-Bu X-PHOS), in the presence of a base, such as
sodium tert-butoxide, potassium phosphate or cesium carbonate, in a suitable solvent, such as
toluene or 1,4-dioxane, under an inert atmosphere, such as nitrogen or argon, at temperatures
between 80 and 110 °C, to produce compounds of formula A6.2.
Deprotection of both amino groups in compounds of formula A6.2 can be achieved by a one-
pot procedure by first reacting it with a strong organic acid, such as trifluoroacetic acid, in
chlorinated solvents, such as dichloromethane or chloroform, under anhydrous conditions at
temperatures between 0 °C and ambient temperature to cleave the P -group. Then the addition of
water to cleave the benzophenone imine and reaction at ambient temperature produces diamines
of formula A7.
H N O P -HN O
P -HN O
F F F
N N N
Q Q N
F F F
for Q = Br
(W) (W) (W)
1a 1b 1a 1b
1a 1b
R R R R
A6 A6.1 A6.2
P : e.g. Tr, MMTr, DMTr, TMTr
H N O
1a 1b
Scheme A.1: Alternative synthesis of intermediate anilines of formula A7.
2a 2b
Sulfinyl imines of general formula B2, wherein X is O or S and W is –CR R (with p = 1,
2a 2b
R , R are hydrogen. lower alkyl, phenyl, or taken together with the C they are attached to form
a heterocyclyl) can form a heterocycloalkyl), can be prepared in analogy to T.P. Tang & J.A.
Ellman, J. Org. Chem. 1999, 64, 12, by condensation of an aryl ketone B1 and a sulfinamide, e.g.
an alkyl sulfinamide, most particularly (R)-(+)-tert-butylsulfinamide, in the presence of a Lewis
acid such as e.g. a titanium(IV)alkoxide, more particularly titanium(IV)ethoxide in a solvent
such as an ether, e.g. diethyl ether or more particularly tetrahydrofuran.
The conversion of the sulfinyl imine B2 to the sulfinamide ester B3 proceeds
stereoselectively by the chiral directing group as described by Tang & Ellman. The sulfinyl
imine B2 can be reacted in a Reformatsky reaction with a zinc enolate generated from e.g. an
alkyl bromodifluoroacetate, particularly ethyl bromodifluoroacetate, and activated zinc powder
at ambient to elevated temperature, particularly at 23 to 60 °C in a solvent such as an ether, e.g.
diethyl ether or more particularly tetrahydrofuran.
The alcohol of formula B4 can be prepared by the reduction of an ethylester of formula B3
with an alkali hydride, particularly lithium borohydride or lithium aluminium hydride, in a
solvent such as an ether, e.g. diethyl ether or more particularly tetrahydrofuran.
Hydrolysis of the chiral directing group in the sulfinamide alcohol of formula B4 to give
the aminoalcohol of formula B5 can be accomplished with a mineral acid, e.g. sulfuric acid or
particularly hydrochloric acid, in a solvent such as an ether, e.g. diethyl ether, tetrahydrofuran or
more particularly 1,4-dioxane.
The aminooxazine of formula B6 can be prepared by reaction of an aminoalcohol of
formula B5 with cyanogen bromide in a solvent such as an alcohol, particularly ethanol.
The reduction of derivatives of formula B6, wherein Q is a nitro group, to give anilines of
formula B7 can be accomplished by hydrogenation using a catalyst, such as palladium on carbon,
in protic solvents, such as alcohols, in particular ethanol or methanol.
S COOEt
S HN
H N R
Q Q Q
(W) (W)
B1 B2 B3
Q = Br, NO
R = C alkyl, in particular t-butyl
X = O, S
H N O OH R O OH
F F F
H N HN
Q Q Q
F F F
(W) (W) (W)
p p p
X X X
B6 B5
for Q = Br for Q : NO
H N O H N O H N O
2 2 2
F F F
N N N
H N Z-COOH Y
F 2 F F
(W) (W) (W)
p p p
X X X
I.3 B7
Scheme B: Synthesis of compounds of formula I.3 and I.4.
Target amines of formula I.3 can be prepared by palladium-catalyzed cross coupling
between compounds of formula B6 and derivatives of formula Z-R , wherein R has the meaning
of a boronic acid or ester under conditions (Suzuki-Miyaura-coupling) known to those skilled in
the art.
Target amides of formula I.4 can be prepared by selective coupling of anilines of formula
B7 and a carboxylic acid of formula Z-COOH with 4-(4,6-dimethoxy[1.3.5]triazinyl)
methylmorpholinium chloride hydrate (DMTMM) as the condensating agent in a solvent such as
methanol.
Target amides of formula I.3 or I.4, wherein X is SO , can be prepared from compounds of
formula I.3 or I.4, wherein X is S, by oxidation in inert solvents at temperatures between 0 °C
and ambient temperature using e.g. potassium peroxomonosulphate as the oxidizing agent.
Alternatively, anilines of formula B7 can be prepared via N-protected intermediates as
illustrated in Scheme B.1.
Protection of the amino group in compounds of formula A6, wherein Q is bromine, to
produce aryl bromides of formula B6.1 can be performed with triarylmethyl chlorides, such as
triphenylmethyl chloride (Tr-Cl), p-methoxyphenyldiphenylmethyl chloride (MMTr-Cl), di(p-
methoxyphenyl)phenylmethyl chloride (DMTr-Cl) or tri(p-methoxyphenyl)methyl chloride
(TMTr-Cl), particularly DMTr-Cl, under basic conditions, e.g. in the presence of an amine, such
as triethylamine or diisopropylethylamine, in a chlorinated solvent, such as dichloromethane or
chloroform, at temperatures between 0 °C and ambient temperature.
Aryl bromides of formula B6.1 can be reacted with ammonia equivalents, such as
benzophenone imine, in the presence of a suitable transition metal catalyst, such as
bis(dibenzylideneacetone)palladium (0) ((dba) Pd) or tris(dibenzylideneacetone)dipalladium (0)
((dba) Pd )), and a suitable ligand, such as rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (rac-
BINAP), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (X-PHOS) or 2-di-tert-
butylphosphino-2',4',6'-triisopropylbiphenyl (t-Bu X-PHOS), in the presence of a base, such as
sodium tert-butoxide, potassium phosphate or cesium carbonate, in a suitable solvent, such as
toluene or 1,4-dioxane, under an inert atmosphere, such as nitrogen or argon, at temperatures
between 80 and 110 °C, to produce compounds of formula B6.2.
Deprotection of both amino groups in compounds of formula B6.2 can be achieved by a one-
pot procedure by first reacting it with a strong organic acid, such as trifluoroacetic acid, in
chlorinated solvents, such as dichloromethane or chloroform, under anhydrous conditions at
temperatures between 0 °C and ambient temperature to cleave the P -group. Then the addition of
water to cleave the benzophenone imine and reaction at ambient temperature produces diamines
of formula B7.
H N O P -HN O
P -HN O
F F F
N N N
Q Q N
F F F
for Q = Br
(W) (W) (W)
X X X
B6 B6.1 B6.2
P : e.g. Tr, MMTr, DMTr, TMTr
H N O
Scheme B.1: Alternative synthesis of intermediate anilines of formula B7.
Alkylation of alcohols of formula A4 or B4 to nitriles of formula C1 can be accomplished
with a suitable mild base particularly silver(I) oxide in a solvent such as tetrahydrofuran or
dichloromethane, more particularly dichloromethane, in the presence of an alkylating catalyst
such as tetra-butyl ammonium iodide.
Hydrolysis of the chiral directing group in nitriles of formula C1 to give amino nitriles of
formula C2 can be accomplished with a mineral acid, e.g. sulfuric acid or particularly
hydrochloric acid in a solvent such as an ether, e.g. diethyl ether or more particularly 1,4-dioxane.
Aminooxazepines of formula C3 can be prepared by the reaction of amino nitriles of
formula C2 and trimethyl aluminium in a solvent such as a xylene or toluene, particularly
toluene.
The reduction of derivatives of formula C3, wherein Q is a nitro group, to give anilines of
formula C4 can be accomplished by hydrogenation using a catalyst, such as palladium on carbon,
in protic solvents, such as alcohols, in particular ethanol or methanol.
S COOEt
O + N R
S HN
H N R
(W) (W)
p p p
A1/B1 A2/B2 A3/B3
Q = Br, NO
R = C alkyl, in particular t-butyl
1a 1b
X = CR R , O, S, SO
R CN R O OH
O O +
NC O +
(W) (W)
C1 A4/B4
H N H N
H N Z-COOH Y
for Q : NO
(W) (W)
(W) p
C3 C4
for Q = Br
Scheme C: Synthesis of compounds of formula I.5 and I.6.
Target amines of formula I.5 can be prepared by palladium-catalyzed cross coupling
between compounds of formula C3 and derivatives of formula Z-R , wherein R has the meaning
of a boronic acid or ester under conditions (Suzuki-Miyaura-coupling) known to those skilled in
the art.
Target amides of formula I.6 can be prepared by selective coupling of anilines of formula
C4 and a carboxylic acid of formula Z-COOH with 4-(4,6-dimethoxy[1.3.5]triazinyl)
methylmorpholinium chloride hydrate (DMTMM) as the condensating agent in a solvent such as
methanol.
The corresponding pharmaceutically acceptable salts with acids can be obtained by standard
methods known to the person skilled in the art, e.g. by dissolving the compound of formula I in a
suitable solvent such as e.g. dioxane or tetrahydrofuran (THF) and adding an appropriate amount
of the corresponding acid. The products can usually be isolated by filtration or by
chromatography. The conversion of a compound of formula I into a pharmaceutically acceptable
salt with a base can be carried out by treatment of such a compound with such a base. One
possible method to form such a salt is e.g. by addition of 1/n equivalents of a basic salt such as
e.g. M(OH) , wherein M = metal or ammonium cation and n = number of hydroxide anions, to a
solution of the compound in a suitable solvent (e.g. ethanol, ethanol-water mixture,
tetrahydrofuran-water mixture) and to remove the solvent by evaporation or lyophilisation.
Particular salts are hydrochloride, formate and trifluoroacetate.
Insofar as their preparation is not described in the examples, the compounds of formula I as
well as all intermediate products can be prepared according to analogous methods or according
to the methods set forth herein. Starting materials are commercially available, known in the art or
can be prepared by methods known in the art or in analogy thereto.
It will be appreciated that the compounds of general formula I in this invention can be
derivatised at functional groups to provide derivatives which are capable of conversion back to
the parent compound in vivo.
Pharmacological Tests
The compounds of formula I and their pharmaceutically acceptable salts possess valuable
pharmacological properties. It has been found that the compounds of the present invention are
associated with inhibition of BACE1 and/or BACE2 activity. The compounds were investigated
in accordance with the test given hereinafter.
Cellular Aβ-lowering assay:
a) Human HEK293 cells which are stably transfected with a vector expressing a cDNA of
the human APP wt gene (APP695) were used to assess the potency of the compounds in a
cellular assay. The cells were seeded in 96-well microtiter plates in cell culture medium (Iscove,
plus 10% (v/v) fetal bovine serum, glutamine, penicillin/streptomycin) to about 80% confluence
and the compounds were added at a 10x concentration in 1/10 volume of medium without FCS
containing 8% DMSO (final concentration of DMSO was kept at 0.8% v/v). After 18-20 hrs
incubation at 37 °C and 5% CO in a humidified incubator the culture supernatant was harvested
for the determination of Aβ40 concentrations. 96well ELISA plates (e.g., Nunc MaxiSorb) were
coated with monoclonal antibody which specifically recognize the C-terminal end of Aβ40
(Brockhaus et al., NeuroReport 9, 1481-1486; 1998). After blocking of non-specific binding sites
with e.g. 1% BSA and washing, the culture supernatants were added in suitable dilutions
together with a horseradish peroxidase-coupled Aβ detection antibody (e.g., antibody 4G8,
Senetek, Maryland Heights, MO) and incubated for 5 to 7 hrs. Subsequently the wells of the
microtiter plate were washed extensively with Tris-buffered saline containing 0.05% Tween 20
and the assay was developed with tetramethylbenzidine/H O in citric acid buffer. After stopping
the reaction with one volume of 1N H SO the reaction was measured in an ELISA reader at 450
nm wavelength. The concentrations of Aβ in the culture supernatants were calculated from a
standard curve obtained with known amounts of pure Aβ peptide.
b) Alternatively, the Abeta 40 AlphaLISA Assay can be used. The HEK293 APP cells were
seeded in 96 well Microtiter plates in cell culture medium (Iscove’s, plus 10% (v/v) fetal bovine
serum, penicillin/streptomycin ) to about 80% confluency and the compounds were added at a 3x
concentration in 1/3 volume of culture medium ( final DMSO concentration was kept at 1 % v/v).
After 18-20 hrs incubation at 37°C and 5% CO in a humidified incubator, the culture
supernatants were harvested for the determination of Aβ 40 concentrations using Perkin-Elmer
Human Amyloid beta 1-40 ( high specificity ) Kit ( Cat# AL275C ).
In a Perkin-Elmer White Optiplate-384 ( Cat# 6007290 ), 2ul culture supernatants were
combined with 2μl of a 10X AlphaLISA Anti-hAβAcceptor beads + Biotinylated Antibody
Anti-Aβ 1-40 Mix ( 50 μg/mL / 5nM ). After 1 hour room temperature incubation, 16μl of a 1.25
X preparation of Streptavidin (SA) Donor beads (25μg/mL ) were added and incubated for 30
minutes in the Dark. Light Emission at 615 nm was then recorded using EnVision-Alpha Reader.
Levels of Aβ 40 in the culture supernatants were calculated as percentage of maximum signal
(cells treated with 1% DMSO without inhibitor). The IC50 values were calculated using the
Excel XLfit software.
Assay for BACE inhibition by measuring cellular TMEM27 cleavage:
The assay uses the principle of inhibition of human TMEM27 cleavage by endogenous
cellular BACE2 in the Ins1e rat cell line and shedding from the cell surface into the culture
medium, followed by detection in an ELISA assay. Inhibition of BACE2 prevents the cleavage
and shedding in a dose-dependent manner.
The stable cell line “INS-TMEM27” represents an INS1e-derived cell line with inducible
expression (using the TetOn system) of full-length hTMEM27 in a doxycycline-dependent
manner. The cells are cultured throughout the experiment in RPMI1640 + Glutamax (Invitrogen)
Penicillin/Streptomycin, 10% Fetal bovine serum, 100 mM pyruvate, 5 mM beta-
mercatptoethanol, 100 micrograms/ml G418 and 100 microgram/ml hygromycin and are grown
inadherent culture at 37 °C in a standard CO cell culture incubator.
INS-TMEM27 cells are seeded in 96-well plates. After 2 days in culture, BACE2 inhibitor
is added in a range of concentrations as required by the assay and after a further two hours,
doxycycline is added to a final concentration of 500 ng/ml. The cells are incubated for a further
46 hours and the supernatant harvested for detection of shed TMEM27.
An ELISA assay (using a pair of mouse anti-human-TMEM27 antibodies, raised against
the extracellular domain of TMEM27) is used for detection of TMEM27 in the culture medium.
An EC for BACE2 inhibition is calculated using the ELISA readout for each inhibitor
concentration with standard curve-fitting software such as XLFit for the Excel spreadsheet
program.
BACE1 BACE2
cell act. cell act.
Exam. Structure
Aβ40
[μM]
[μM]
H N O
1 F 0.100 0.543
H N O
2 F 0.080 0.526
H N O
3 2.550 -
BACE1 BACE2
cell act. cell act.
Exam. Structure
Aβ40
[μM]
[μM]
H N O
4 5.690 -
H N O
2.770 -
H N O
6 F 1.360 -
H N O
7 2.370 -
H N O
8 2.450 2.730
H N O
F 0.790 3.580
BACE1 BACE2
cell act. cell act.
Exam. Structure
Aβ40
[μM]
[μM]
H N O
0.960 -
11 3.380 -
H N O
12 F 0.022 -
H N O
13 F 0.005 0.116
H N O
N a)
14 1.110 13.034
H N O
F 0.510 -
H N O
16 N 2.490 -
BACE1 BACE2
cell act. cell act.
Exam. Structure
Aβ40
[μM]
[μM]
H N O
18 N 0.660 -
19 0.380 0.124
H N O
N a)
2.020 3.995
HN O
.140 -
HN O
22 2.780 0.926
23 0.420 -
BACE1 BACE2
cell act. cell act.
Exam. Structure
Aβ40
[μM]
[μM]
H N O
24 0.098 -
H N O
1.580 -
H N O
26 2.868 -
27 0.260 -
H N O
28 2.530 -
BACE1 BACE2
cell act. cell act.
Exam. Structure
Aβ40
[μM]
[μM]
H N O
29 4.430 -
H N O
6.580 -
H N O
31 9.000 -
H N O
0.676 1.947
H N O
33 0.360 0.986
34 0.080 1.924
BACE1 BACE2
cell act. cell act.
Exam. Structure
Aβ40
[μM]
[μM]
H N O
1.250 -
H N O
36 0.195 -
HN O
37 0.070 -
38 0.510 -
H N O
39 0.280 -
BACE1 BACE2
cell act. cell act.
Exam. Structure
Aβ40
[μM]
[μM]
H N O
40 2.260 -
HN O
41 0.230 -
H N O
42 0.035 0.438
HN O
43 0.010 0.148
HN O
44 5.172 -
H N O
F a)
45 6.960 -
BACE1 BACE2
cell act. cell act.
Exam. Structure
Aβ40
[μM]
[μM]
HN O
F a)
46 3.400 -
N a)
47 0.240 -
48 0.450 -
49 N 0.830 -
50 N 2.130 -
51 F 1.691 5.866
BACE1 BACE2
cell act. cell act.
Exam. Structure
Aβ40
[μM]
[μM]
52 3.380 -
53 0.470 -
N a)
54 1.160 -
3.830 10.525
56 2.100 -
BACE1 BACE2
cell act. cell act.
Exam. Structure
Aβ40
[μM]
[μM]
57 6.280 -
58 1.290 -
59 0.340 -
60 1.040 -
a) b)
Table 1: IC values of selected examples, and indicate the respective cellular assay used
Pharmaceutical Compositions
The compounds of formula I and the pharmaceutically acceptable salts can be used as
therapeutically active substances, e.g. in the form of pharmaceutical preparations. The
pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets,
dragées, hard and soft gelatin capsules, solutions, emulsions or suspensions. The administration
can, however, also be effected rectally, e.g. in the form of suppositories, or parenterally, e.g. in
the form of injection solutions.
The compounds of formula I and the pharmaceutically acceptable salts thereof can be
processed with pharmaceutically inert, inorganic or organic carriers for the production of
pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acids or its
salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragées
and hard gelatin capsules. Suitable carriers for soft gelatin capsules are, for example, vegetable
oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the
active substance no carriers are however usually required in the case of soft gelatin capsules.
Suitable carriers for the production of solutions and syrups are, for example, water, polyols,
glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or
hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
The pharmaceutical preparations can, moreover, contain pharmaceutically acceptable
auxiliary substances such as preservatives, solubilizers, stabilizers, wetting agents, emulsifiers,
sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents
or antioxidants. They can also contain still other therapeutically valuable substances.
Medicaments containing a compound of formula I or a pharmaceutically acceptable salt
thereof and a therapeutically inert carrier are also provided by the present invention, as is a
process for their production, which comprises bringing one or more compounds of formula I
and/or pharmaceutically acceptable salts thereof and, if desired, one or more other
therapeutically valuable substances into a galenical administration form together with one or
more therapeutically inert carriers.
The dosage can vary within wide limits and will, of course, have to be adjusted to the
individual requirements in each particular case. In the case of oral administration the dosage for
adults can vary from about 0.01 mg to about 1000 mg per day of a compound of general formula
I or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage
can be administered as single dose or in divided doses and, in addition, the upper limit can also
be exceeded when this is found to be indicated.
The following examples illustrate the present invention without limiting it, but serve
merely as representative thereof. The pharmaceutical preparations conveniently contain about 1-
500 mg, particularly 1-100 mg, of a compound of formula I. Examples of compositions
according to the invention are:
Example A
Tablets of the following composition are manufactured in the usual manner:
ingredient mg/tablet
25 100 500
Compound of formula I 5 25 100 500
Lactose Anhydrous DTG 125 105 30 150
Sta-Rx 1500 6 6 6 60
Microcrystalline Cellulose 30 30 30 450
Magnesium Stearate 1 1 1 1
Total 167 167 167 831
Table 2: possible tablet composition
Manufacturing Procedure
1. Mix ingredients 1, 2, 3 and 4 and granulate with purified water.
2. Dry the granules at 50°C.
3. Pass the granules through suitable milling equipment.
4. Add ingredient 5 and mix for three minutes; compress on a suitable press.
Example B-1
Capsules of the following composition are manufactured:
ingredient mg/capsule
25 100 500
Compound of formula I 5 25 100 500
Hydrous Lactose 159 123 148 -
Corn Starch 25 35 40 70
Talk 10 15 10 25
Magnesium Stearate 1 2 2 5
Total 200 200 300 600
Table 3: possible capsule ingredient composition
Manufacturing Procedure
1. Mix ingredients 1, 2 and 3 in a suitable mixer for 30 minutes.
2. Add ingredients 4 and 5 and mix for 3 minutes.
3. Fill into a suitable capsule.
The compound of formula I, lactose and corn starch are firstly mixed in a mixer and then in
a comminuting machine. The mixture is returned to the mixer; the talc is added thereto and
mixed thoroughly. The mixture is filled by machine into suitable capsules, e.g. hard gelatin
capsules.
Example B-2
Soft Gelatin Capsules of the following composition are manufactured:
ingredient mg/capsule
Compound of formula I 5
Yellow wax 8
Hydrogenated Soya bean oil 8
Partially hydrogenated plant oils 34
Soya bean oil 110
Total 165
Table 4: possible soft gelatin capsule ingredient composition
ingredient mg/capsule
Gelatin 75
Glycerol 85 % 32
Karion 83 8 (dry matter)
Titan dioxide 0.4
Iron oxide yellow 1.1
Total 116.5
Table 5: possible soft gelatin capsule composition
Manufacturing Procedure
The compound of formula I is dissolved in a warm melting of the other ingredients and the
mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are
treated according to the usual procedures.
Example C
Suppositories of the following composition are manufactured:
ingredient mg/supp.
Compound of formula I 15
Suppository mass 1285
Total 1300
Table 6: possible suppository composition
Manufacturing Procedure
The suppository mass is melted in a glass or steel vessel, mixed thoroughly and cooled to
45°C. Thereupon, the finely powdered compound of formula I is added thereto and stirred until it
has dispersed completely. The mixture is poured into suppository moulds of suitable size, left to
cool; the suppositories are then removed from the moulds and packed individually in wax paper
or metal foil.
Example D
Injection solutions of the following composition are manufactured:
ingredient mg/injection solution.
Compound of formula I 3
Polyethylene Glycol 400 150
acetic acid q.s. ad pH 5.0
water for injection solutions ad 1.0 ml
Table 7: possible injection solution composition
Manufacturing Procedure
The compound of formula I is dissolved in a mixture of Polyethylene Glycol 400 and water
for injection (part). The pH is adjusted to 5.0 by acetic acid. The volume is adjusted to 1.0 ml by
addition of the residual amount of water. The solution is filtered, filled into vials using an
appropriate overage and sterilized.
Example E
Sachets of the following composition are manufactured:
ingredient mg/sachet
Compound of formula I 50
Lactose, fine powder 1015
Microcrystalline cellulose (AVICEL PH 102) 1400
Sodium carboxymethyl cellulose 14
Polyvinylpyrrolidon K 30 10
Magnesium stearate 10
Flavoring additives 1
Total 2500
Table 8: possible sachet composition
Manufacturing Procedure
The compound of formula I is mixed with lactose, microcrystalline cellulose and sodium
carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidone in water. The
granulate is mixed with magnesium stearate and the flavoring additives and filled into sachets.
Experimental Part
The following examples are provided for illustration of the invention. They should not be
considered as limiting the scope of the invention, but merely as being representative thereof.
MS: Mass spectra (MS) were measured either with ion spray positive or negative (ISP or
ISN) method on a Perkin-Elmer SCIEX API 300 or with electron impact method (EI, 70 eV) on
a Finnigan MAT SSQ 7000 spectrometer.
Synthesis of the intermediate sulfinyl imines A2
General procedure
To a solution of the (R)-(+)-tert-butylsulfinamide (66 mmol) in tetrahydrofuran (350 ml)
was added subsequently the ketone A1 (72.6 mmol) and titanium(IV)ethoxide (132 mmol) and
the solution was stirred at reflux temperature for 5 h. The mixture was cooled to 22 °C, treated
with brine (400 ml), the suspension was stirred for 10 min and filtered over Dicalite®. The layers
were separated, the aqueous layer was extracted with ethyl acetate, the combined organic layers
were washed with water, dried and concentrated in vacuo. The residue was purified by
chromatography on silica using cylohexane/ethyl acetate as the eluent to give the pure sulfinyl
imine A2.
1a 1b 1a 1b 2a 2b 2a 2b
Intermediate A2.1 (X = -CR ,R ; R , R = H; W = -CR ,R ; R , R = H; p = 1)
Starting from 7-bromo-3,4-dihydro-2H-naphthalenone {CAS[322813]}
(intermediate A1.1), the product (R)methyl-propanesulfinic acid [7-bromo-3,4-dihydro-
2H-naphthalen-(1E)-ylidene]-amide (64% yield) was obtained as a yellow solid. MS (ISP): m/z
= 328.1 [M+H] and 329.9 [M+2+H] .
1a 1b 1a 1b 2a 2b 2a 2b
Intermediate A2.2 (X = -CR ,R ; R , R = H; W = -CR ,R ; R , R = H; p = 1)
Starting from 7-nitro-3,4-dihydro-2H-naphthalenone {CAS[403532]} (intermediate
A1.2), the product (R)methyl-propanesulfinic acid [7-nitro-3,4-dihydro-2H-naphthalen-
(1E)-ylidene]-amide (62% yield) was obtained as a yellow solid.
1a 1b 1a 1b 2a 2b 2a 2b
Intermediate A2.3 (X = -CR ,R ; R , R = CH ; W = -CR ,R ; R , R = H; p = 1)
Starting from 4,4-dimethylnitro-3,4-dihydro-2H-naphthalenone (WO03095430)
(intermediate A1.3), the product (R)methyl-propanesulfinic acid [4,4-dimethylnitro-3,4-
dihydro-2H-naphthalen-(1E)-ylidene]-amide (66% yield) was obtained as a yellow solid. MS
(ISP): m/z = 323.5 [M+H] .
1a 1b 1a 1b 2a 2b 2a 2b
Intermediate A2.4 (X = -CR ,R ; R , R = F; W = -CR ,R ; R , R = H; p = 1)
Starting from 7-bromo-4,4-difluoro-3,4-dihydro-2H-naphthalenone (intermediate A1.4),
the product (R)methyl-propanesulfinic acid [7-bromo-4,4-difluoro-3,4-dihydro-2H-
naphthalen-(1E)-ylidene]-amide (97% yield) was obtained as a light brown solid. MS (ISP): m/z
= 365.9 [M+H] .
The 7-bromo-4,4-difluoro-3,4-dihydro-2H-naphthalenone (intermediate A1.4) was
obtained as follows:
a) 6'-Bromo-3',4'-dihydro-2'H-spiro[[1,3]dithiolane-2,1'-naphthalene]
A solution of 6-bromo-3,4-dihydro-2H-naphthalenone (CAS[663619]) (0.9 g, 4.00
mmol) in dichloromethane (8 ml) was cooled to 0 °C and treated with 1,2-ethandithiol (769 mg,
686 µl, 8.00 mmol) and boron trifluoro etherate (284 mg, 247 µl, 2.00 mmol). The reaction
mixture was left to warm to room temperature and stirred for 15 hours. For the workup, the
reaction mixture was poured into a solution of sodium hydroxide (1N) followed by extraction
with dichloromethane (40 ml). The organic layer was dried over sodium sulphate and evaporated.
The crude product was purified by chromatography on silica gel usinga gradient of heptane/ethyl
acetate = 100:0 to 70:30 as the eluent. The 6'-bromo-3',4'-dihydro-2'H-spiro[[1,3]dithiolane-2,1'-
naphthalene] (1.06 g, 88% yield) was obtained as a light red oil.
b) 6-Bromo-1,1-difluoro-1,2,3,4-tetrahydro-naphthalene
A suspension of N-iodosuccinimide (1.78 g, 7.9 mmol) in dichloromethane (15 ml) was
cooled to -70 °C. Hydrogen fluoride-pyridine (1.57 g, 1.42 ml, 15.8 mmol) was added dropwise.
A cold solution (-70 °C) of 6'-bromo-3',4'-dihydro-2'H-spiro[[1,3]dithiolane-2,1'-naphthalene]
(1.19 g, 3.95 mmol) in dichloromethane (10 ml) was added dropwise and the white suspension
changed to a brown. The mixture was stirred at -70°C for 15 minutes. For the workup, the dark
red solution was poured into a mixture of hexane (50 ml) and dichloromethane (10 ml). The
deeply colored solution was first passed through a layer of silica gel, then through a layer of a
silica-NH phase and Dicalite®. The resulting colorless solution was evaporated and the crude
product purified by chromatography on silica gel using a gradient of heptane/ethyl acetate =
100:0 to 90:10 as the eluent. The 6-bromo-1,1-difluoro-1,2,3,4-tetrahydro-naphthalene (668 mg,
68% yield) was obtained as a pale yellow oil.
c) 7-Bromo-4,4-difluoro-3,4-dihydro-2H-naphthalenone
A solution of 6-bromo-1,1-difluoro-1,2,3,4-tetrahydro-naphthalene (691 mg, 2.8 mmol) in
tert-butanol (7 ml). A solution of potassium dihydrogenphosphate (769 mg, 5.59 mmol) in water
(2 ml) and a solution of sodium phosphate heptahydrate (1.51 g, 5.59 mmol) in water (2 ml)
were added. Thereafter, potassium permanganate (670 mg, 4.2 mmol) was added and the
reaction mixture stirred at room temperature for 15 hours. For the workup, the mixture was
diluted with ethyl acetate (200 ml), the organic layer separated, washed with water (10 ml) and
brine (10 ml), finally dried over sodium sulphate and evaporated at reduced pressure. The crude
product was purified by chromatography on silica gel using a gradient of heptane/ethyl acetate =
100:0 to 80:20 as the eluent. The 7-bromo-4,4-difluoro-3,4-dihydro-2H-naphthalenone (515
mg, 71% yield) was obtained as a colorless oil.
1a 1b 1a 1b
Intermediate A2.5 (X = -CR ,R ; R , R = H; p = 0)
Starting from 6-bromo-indanone {CAS[145481]} (intermediate A1.5), the product
(R)methyl-propanesulfinic acid [6-bromo-indan-(1E)-ylidene]-amide (34% yield) was
obtained as a yellow solid. MS (ISP): m/z = 314.2 [M+H] .
1a 1b 1a 1b
Intermediate A2.6 (X = -CR ,R ; R , R = H; p = 0)
Starting from 6-nitro-indanone {CAS [246233]} (intermediate A1.6), the product
(R)methyl-propanesulfinic acid [6-nitro-indan-(1E)-ylidene]-amide (51% yield) was
obtained as a blackish semi-solid. MS (ISP): m/z = 281.0 [M+H] .
Synthesis of the intermediate sulfinamide esters A3
General procedure (via Reformatsky reaction)
In a dry apparatus a suspension of freshly activated zinc powder (1.63 g, 24.9 mmol) in dry
tetrahydrofuran (70 ml) was heated under an inert atmosphere to reflux. A solution of the
sulfinyl imine A2 (24.9 mmol) and the bromo-acetate (24.9 mmol) in dry tetrahydrofuran (15 ml)
was added dropwise over a period of 15 min and the suspension was heated to reflux for 5 h (5
hours). The cooled mixture was partitioned between a saturated aqueous solution of ammonium
chloride and ethyl acetate, the organic layer was dried and evaporated. The crude material was
purified by flash chromatography using heptane/ethyl acetate as the eluent to give the
sulfinamide ester A3.
Intermediate A3.1
COOEt
Starting from (R)methyl-propanesulfinic acid [7-bromo-3,4-dihydro-2H-naphthalen-
(1E)-ylidene]-amide (intermediate A2.1), the product [(R)bromo((R)methyl-propane
sulfinylamino)-1,2,3,4-tetrahydro-naphthalenyl]-difluoro-acetic acid ethyl ester (90% yield)
was obtained as a light brown oil. MS (ISP): m/z = 452.1 [M+H] and 454.1 [M+2+H] .
Intermediate A3.2
S COOEt
Starting from (R)methyl-propanesulfinic acid [7-nitro-3,4-dihydro-2H-naphthalen-
(1E)-ylidene]-amide (intermediate A2.2), the product difluoro-[(R)((R)methyl-propane
sulfinylamino)nitro-1,2,3,4-tetrahydro-naphthalenyl]-acetic acid ethyl ester (83% yield)
was obtained as a yellow oil. MS (ISP): m/z = 419.2 [M+H] .
Intermediate A3.3
S COOEt
Starting from (R)methyl-propanesulfinic acid [4,4-dimethylnitro-3,4-dihydro-2H-
naphthalen-(1E)-ylidene]-amide (intermediate A2.3), the product [(R)-4,4-dimethyl((R)
methyl-propanesulfinylamino)nitro-1,2,3,4-tetrahydro-naphthalenyl]-difluoro-acetic
acid ethyl ester (73% yield) was obtained as a yellow oil. MS (ISP): m/z = 447.5 [M+H] .
Intermediate A3.4
S COOEt
Starting from (R)methyl-propanesulfinic acid [7-bromo-4,4-difluoro-3,4-dihydro-2H-
naphthalen-(1E)-ylidene]-amide (intermediate A2.4) and ethyl 2-bromo-2,2-difluoroacetate, the
product [(R)bromo-4,4-difluoro((R)methyl-propanesulfinylamino)-1,2,3,4-
tetrahydro-naphthalenyl]-difluoro-acetic acid ethyl ester (58% yield) was obtained as a brown
solid. MS (ISP): m/z = 488.1 [M+H] and 490.0 [M+H] .
Intermediate A3.5
S COOEt
Starting from (R)methyl-propanesulfinic acid [6-bromo-indan-(1E)-ylidene]-amide
(intermediate A2.5), the product [(R)bromo((R)methyl-propanesulfinylamino)-indan-
1-yl]-difluoro-acetic acid ethyl ester (43% yield) was obtained as a deep brown solid. MS (ISP):
m/z = 438.0 [M+H] .
Intermediate A3.6
S COOEt
Starting from (R)methyl-propanesulfinic acid [6-nitro-indan-(1E)-ylidene]-amide
(intermediate A2.6), the product difluoro-[(R)((R)methyl-propanesulfinylamino)
nitro-indanyl]-acetic acid ethyl ester (60% yield) was obtained as a blackish semi-solid. MS
(ISP): m/z = 405.0 [M+H] .
Synthesis of the intermediate sulfinamide alcohols A4
General procedure
A solution of the sulfinamide ester A3 (12.7 mmol) in dry tetrahydrofuran (50 ml) was
treated at 0 °C with lithium borohydride (25.3 mmol) and stirring was continued at 0 °C for 4 h.
The reaction mixture was quenched by addition of acetic acid (2 ml) and water (50 ml), extracted
with ethyl acetate and the organic layer was dried and evaporated. The residue was purified by
chromatography on silica using a mixture of n-heptane and ethyl acetate as the eluent to give the
pure intermediate sulfinamide alcohol A4.
Intermediate A4.1
Starting from [(R)bromo((R)methyl-propanesulfinylamino)-1,2,3,4-tetrahydro-
naphthalenyl]-difluoro-acetic acid ethyl ester (intermediate A3.1), the product (R)methyl-
propanesulfinic acid [(R)bromo(1,1-difluorohydroxy-ethyl)-1,2,3,4-tetrahydro-
naphthalenyl]-amide (45% yield) was obtained as a white solid. MS (ISP): m/z = 410.1
[M+H] and 412.1 [M+2+H] .
Intermediate A4.2
Starting from difluoro-[(R)((R)methyl-propanesulfinylamino)nitro-1,2,3,4-
tetrahydro-naphthalenyl]-acetic acid ethyl ester (intermediate A3.2), the product (R)
methyl-propanesulfinic acid [(R)(1,1-difluorohydroxy-ethyl)nitro-1,2,3,4-tetrahydro-
naphthalenyl]-amide (92% yield) was obtained as a brown solid. MS (ISP): m/z = 377.4
[M+H] .
Intermediate A4.3
Starting from [(R)-4,4-dimethyl((R)methyl-propanesulfinylamino)nitro-1,2,3,4-
tetrahydro-naphthalenyl]-difluoro-acetic acid ethyl ester (intermediate A3.3), the product (R)-
2-methyl-propanesulfinic acid [(R)(1,1-difluorohydroxy-ethyl)-4,4-dimethylnitro-
1,2,3,4-tetrahydro-naphthalenyl]-amide (50% yield) was obtained as a light brown solid. MS
(ISP): m/z = 405.5 [M+H] .
Intermediate A4.4
Starting from [(R)bromo-4,4-difluoro((R)methyl-propanesulfinylamino)-
1,2,3,4-tetrahydro-naphthalenyl]-difluoro-acetic acid ethyl ester (intermediate A3.4), the
product (R)methyl-propanesulfinic acid [(R)bromo(1,1-difluorohydroxy-ethyl)-
4,4-difluoro-1,2,3,4-tetrahydro-naphthalenyl]-amide (100% yield) was obtained as a grey
foam. MS (ISP): m/z = 446.0 [M+H] and 447.9 [M+H] .
Intermediate A4.5
Starting from [(R)bromo((R)methyl-propanesulfinylamino)-indanyl]-
difluoro-acetic acid ethyl ester (intermediate A3.5), the product (R)methyl-propanesulfinic
acid [(R)bromo(1,1-difluorohydroxy-ethyl)-indanyl]-amide (77% yield) was obtained
as a deep brown solid. MS (ISP): m/z = 395.8 [M+H] .
Intermediate A4.6
Starting from difluoro-[(R)((R)methyl-propanesulfinylamino)nitro-indanyl]-
acetic acid ethyl ester (intermediate A3.6), the product (R)methyl-propanesulfinic acid
[(R)(1,1-difluorohydroxy-ethyl)nitro-indanyl]-amide (84% yield) was obtained as a
deep brown solid. MS (ISP): m/z = 363.2 [M+H] .
Synthesis of the intermediate amino alcohols A5
General Procedure:
A solution of the sulfinamide alcohols A4 (10.3 mmol) in methanol or tetrahydrofuran (30
to 60 ml) was treated with a solution of hydrochloric acid in 1,4-dioxane (4 M, 10-13 ml) and
stirring was continued at 23 °C for 2 to 18 h. The mixture was partitioned between ethyl acetate
and an aqueous solution of sodium carbonate (2 M), the organic layer was dried over sodium
sulphate, filtered and evaporated to give a residue which was purified by chromatography on
silica using a mixture of n-heptane and ethyl acetate as the eluent to give the pure aminoalcohols
Intermediate A5.1
Starting from (R)methyl-propanesulfinic acid [(R)bromo(1,1-difluoro
hydroxy-ethyl)-1,2,3,4-tetrahydro-naphthalenyl]-amide (intermediate A4.1), the product 2-
((R)aminobromo-1,2,3,4-tetrahydro-naphthalenyl)-2,2-difluoro-ethanol (25% yield) was
obtained as a pale yellow gum. MS (ISP): m/z = 306.0 [M+H] and 308.1 [M+2+H] .
Intermediate A5.2
Starting from (R)methyl-propanesulfinic acid [(R)(1,1-difluorohydroxy-ethyl)-
7-nitro-1,2,3,4-tetrahydro-naphthalenyl]-amide (intermediate A4.2), the product 2-((R)
aminonitro-1,2,3,4-tetrahydro-naphthalenyl)-2,2-difluoro-ethanol (74% yield) was
obtained as a pale yellow solid. MS (ISN): m/z = 271.3 [M-H] .
Intermediate A5.3
Starting from (R)methyl-propanesulfinic acid [(R)(1,1-difluorohydroxy-ethyl)-
4,4-dimethylnitro-1,2,3,4-tetrahydro-naphthalenyl]-amide (intermediate A4.3), the product
2-((R)amino-4,4-dimethylnitro-1,2,3,4-tetrahydro-naphthalenyl)-2,2-difluoro-ethanol
(49% yield) was obtained as an off-white foam. MS (ISP): m/z = 301.4 [M+H] .
Intermediate A5.4
Starting from (R)methyl-propanesulfinic acid [(R)bromo(1,1-difluoro
hydroxy-ethyl)-4,4-difluoro-1,2,3,4-tetrahydro-naphthalenyl]-amide (intermediate A4.4), the
product 2-((R)aminobromo-4,4-difluoro-1,2,3,4-tetrahydro-naphthalenyl)-2,2-difluoro-
ethanol (44% yield) was obtained as a yellow oil. MS (ISP): m/z = 342.0 [M+H] and 344.0
[M+2+H] .
Intermediate A5.5
Starting from (R)methyl-propanesulfinic acid [(R)bromo(1,1-difluoro
hydroxy-ethyl)-indanyl]-amide (intermediate A4.5), the product 2-((R)aminobromo-
indanyl)-2,2-difluoro-ethanol (81% yield) was obtained as a deep brown solid. MS (ISP): m/z
= 291.0 [M+H] .
Intermediate A5.6
Starting from (R)methyl-propanesulfinic acid [(R)(1,1-difluorohydroxy-ethyl)-
6-nitro-indanyl]-amide (intermediate A4.6), the product 2-((R)aminonitro-indanyl)-
2,2-difluoro-ethanol (70% yield) was obtained as a deep brown solid. MS (ISP): m/z = 258.9
[M+H] .
Syntheses of the intermediate amino oxazines A6
General procedure
A dried tube was charged with a mixture of the amino alcohol A5 (18.8 mmol), cyanogen
bromide (33.9 mmol) and ethanol (61 ml). The tube was sealed and heated at 90 °C for 16 hours.
For the workup, the reaction mixture was cooled and evaporated at reduced pressure. The residue
was partitioned between ethyl acetate (150 ml) and a saturated aqueous solution of sodium
carbonate (50 ml). The aqueous layer was separated and re-extracted with ethyl acetate (2 x 50
ml). The organic layers were washed with brine (50 ml), then combined, dried over sodium
sulphate and evaporated at reduced pressure. The product was used in the next step without
further purification.
Intermediate A6.1
H N O
Starting from 2-((R)aminobromo-1,2,3,4-tetrahydro-naphthalenyl)-2,2-difluoro-
ethanol (intermediate A5.1), the product (R)bromo-5',5'-difluoro-3,4,5',6'-tetrahydro-2H-
spiro[naphthalene-1,4'-[1,3]oxazin]-2'-amine (50% yield) was obtained as a white solid. MS
(ISP): m/z = 331.0 [M+H] and 333.0 [M+2+H] .
Intermediate A6.2
H N O
Starting from 2-((R)aminonitro-1,2,3,4-tetrahydro-naphthalenyl)-2,2-difluoro-
ethanol (intermediate A5.2), the product (R)-5',5'-difluoronitro-3,4,5',6'-tetrahydro-2H-
spiro[naphthalene-1,4'-[1,3]oxazin]-2'-amine (62% yield) was obtained as a white solid. MS
(ISP): m/z = 298.2 [M+H] .
Intermediate A6.3
H N O
Starting from 2-((R)amino-4,4-dimethylnitro-1,2,3,4-tetrahydro-naphthalenyl)-
2,2-difluoro-ethanol (intermediate A5.3), the product (R)-5',5'-difluoro-4,4-dimethylnitro-
3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'-[1,3]oxazin]-2'-amine (51% yield) was obtained
as a pale yellow gum. MS (ISP): m/z = 326.5 [M+H] .
Intermediate A6.4
H N O
Starting from 2-((R)aminobromo-4,4-difluoro-1,2,3,4-tetrahydro-naphthalenyl)-
2,2-difluoro-ethanol (intermediate A5.4), the product (R)bromo-4,4,5',5'-tetrafluoro-3,4,5',6'-
tetrahydro-2H-spiro[naphthalene-1,4'-[1,3]oxazin]-2'-amine (65% yield) was obtained as a white
solid. MS (ISP): m/z = 366.9 [M+H] and 369.0 [M+H] .
Intermediate A6.5
H N O
Starting from 2-((R)aminobromo-indanyl)-2,2-difluoro-ethanol (intermediate
A5.5), the product (R)bromo-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazin]-
2'-amine (64% yield) was obtained as an off-white solid. MS (ISP): m/z = 346.8 [M+H] .
Intermediate A6.6
H N O
a) (R)(1,1-Difluorohydroxy-ethyl)nitro-indanyl-cyanamide
A mixture of 2-((R)aminonitro-indanyl)-2,2-difluoro-ethanol (intermediate A5.6),
(1.6 g, 6.2 mmol) and sodium acetate (1.54 g, 18.6 mmol) in ethanol (30 ml) was warmed to
40°C. The mixture was then treated with cyanogen bromide (724 mg, 6.82 mmol) and allowed to
stir at 40°C for 16 hours. Removal of the solvent at reduced pressure followed by purification of
the resultant crude material by column chromatography on silica gel using a 3:2-mixture of
hexane and ethyl acetate as the eluent yielded the (R)(1,1-difluorohydroxy-ethyl)nitro-
indanyl-cyanamide (800 mg, 42% yield) as colorless sticky solid. MS (ISP): m/z = 284.0
[M+H] .
b) (R)-5',5'-Difluoronitro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazin]-2'-amine
In a tube, a solution of (R)(1,1-difluorohydroxy-ethyl)nitro-indanyl-cyanamide
(1.0 g, 3.55 mmol) in methanol (10 ml) was treated with ammonium hydroxide (25% in water, 3
ml). The tube was sealed and heated at 60°C for 16 hours. For the workup, the reaction mixture
was evaporated at reduced pressure. The crude material was purified by column chromatography
(NH-biotage) using a 95:5-mixture of dichloromethane and methanol as the eluent. The (R)-5',5'-
difluoronitro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazin]-2'-amine (500 mg, 50% yield)
was obtained as a white solid. MS (ISP): m/z = 283.4 [M+H] .
Syntheses of the intermediate anilines A7
General procedure
A solution of the nitro oxazine A6 (3 mmol) in ethanol (31 ml) was hydrogenated at
atmospheric pressure using palladium (10% on carbon) (159 mg, 150 µmol) as the catalyst. After
90 minutes the reaction was complete. The reaction mixture was filtrated over a layer of Dicalit,
which was washed with ethanol (3 x 20 ml). The combined solutions of ethanol were evaporated
at reduced pressure. The product was engaged in the step without further purification.
Intermediate A7.1
H N O
Starting from (R)-5',5'-difluoronitro-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'-
[1,3]oxazin]-2'-amine (intermediate A6.2), the product (R)-5',5'-difluoro-3,4,5',6'-tetrahydro-2H-
spiro[naphthalene-1,4'-[1,3]oxazine]-2',7-diamine (58% yield) was obtained as a light brown
solid. MS (ISP): m/z = 268.3 [M+H] .
Intermediate A7.2
Starting from (R)-5',5'-difluoro-4,4-dimethylnitro-3,4,5',6'-tetrahydro-2H-
spiro[naphthalene-1,4'-[1,3]oxazin]-2'-amine (intermediate A6.3), the product (R)-5',5'-difluoro-
4,4-dimethyl-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'-[1,3]oxazine]-2',7-diamine (88%
yield) was obtained as a pale yellow foam. MS (ISP): m/z = 296.4 [M+H] .
Intermediate A7.3
HN O
Starting from (R)-5',5'-difluoronitro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazin]-
2'-amine (intermediate A6.6), the product (R)-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-
[1,3]oxazine]-2',6-diamine (75% yield) was obtained as a yellow sticky liquid. MS (ISP): m/z =
254.0 [M+H] .
Example 1
(R)(5-Chloropyridinyl)-5',5'-difluoro-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'-
[1,3]oxazin]-2'-amine
In a tube a mixture of (R)bromo-5',5'-difluoro-3,4,5',6'-tetrahydro-2H-
spiro[naphthalene-1,4'-[1,3]oxazin]-2'-amine (intermediate A6.1) (35 mg, 106 µmol), 5-
chloropyridinylboronic acid (17 mg, 106 µmol), and cesium carbonate (138 mg, 423 µmol) in
tetrahydrofuran (2.8 ml) and water (1.4 ml) was purged with argon for 5 minutes. Thereafter,
[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (3.9 mg, 5.3 µmol) was added, the
tube was sealed and the mixture heated at 80 °C for 25 minutes. For the workup, the reaction
mixture was diluted with ethyl acetate and washed with water. The organic layer was separated,
dried over sodium sulphate and evaporated at reduced pressure. The residue was purified by
chromatography on silica gel using a gradient of heptane/ethyl acetate = 100:0 to 0:100 as the
eluent. The (R)(2'-amino-4,4,5',5'-tetrafluoro-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'-
[1,3]oxazine]yl)nicotinonitrile (24 mg, 63% yield) was obtained as an off-white solid. MS
(ISP): m/z = 364.1 [M+H] .
Example 2
(R)(2'-Amino-5',5'-difluoro-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'-
[1,3]oxazine]yl)nicotinonitrile
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-
7-bromo-5',5'-difluoro-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'-[1,3]oxazin]-2'-amine
(intermediate A6.1) with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)nicotinonitrile yielded
the title compound (72% yield) as an off-white solid. MS (ISP): m/z = 355.2 [M+H] .
Example 3
(R)(5-Chloropyridinyl)-4,4,5',5'-tetrafluoro-3,4,5',6'-tetrahydro-2H-
spiro[naphthalene-1,4'-[1,3]oxazin]-2'-amine
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-
7-bromo-4,4,5',5'-tetrafluoro-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'-[1,3]oxazin]-2'-
amine (intermediate A6.4) with 5-chloropyridinylboronic acid yielded the title compound
(28% yield) as a white solid. MS (ISP): m/z = 399.9 [M+H] .
Example 4
(R)-4,4,5',5'-Tetrafluoro(5-fluoropyridinyl)-3,4,5',6'-tetrahydro-2H-
spiro[naphthalene-1,4'-[1,3]oxazin]-2'-amine
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-
7-bromo-4,4,5',5'-tetrafluoro-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'-[1,3]oxazin]-2'-
amine (intermediate A6.4) with 5-fluoropyridinylboronic acid yielded the title compound
(32% yield) as a pale yellow solid. MS (ISP): m/z = 384.0 [M+H] .
Example 5
(R)(2'-Amino-4,4,5',5'-tetrafluoro-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'-
[1,3]oxazine]yl)nicotinonitrile
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-
7-bromo-4,4,5',5'-tetrafluoro-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'-[1,3]oxazin]-2'-
amine (intermediate A6.4) with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl)nicotinonitrile
yielded the title compound (51% yield) as a yellow solid. MS (ISP): m/z = 390.3 [M] .
Example 6
(R)(2-Chloropyridinyl)-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-
[1,3]oxazin]-2'-amine
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-
6-bromo-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazin]-2'-amine (intermediate
A6.5) with 5-chloropyridinylboronic acid in a 3:1-mixture of 1,2-dimethoxyethane and water
as the solvent yielded the title compound (25% yield) as an off-white solid. MS (ISP): m/z =
349.8 [M+H] .
Example 7
(R)-5',5'-Difluoro(pyrimidinyl)-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazin]-2'-
amine
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-
6-bromo-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazin]-2'-amine (intermediate
A6.5) with pyrimidinylboronic acid in a 3:1-mixture of 1,2-dimethoxyethane and water as the
solvent yielded the title compound (19% yield) as an off-white solid. MS (ISP): m/z = 317.0
[M+H] .
Example 8
(R)(3,5-Dichlorophenyl)-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazin]-
2'-amine
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-
6-bromo-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazin]-2'-amine (intermediate
A6.5) with 3,5-dichlorophenylboronic acid in a 3:1-mixture of 1,2-dimethoxyethane and water as
the solvent yielded the title compound (15% yield) as an off-white solid. MS (ISP): m/z = 382.8
[M+H] .
Example 9
(R)(5-Chloropyridinyl)-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-
[1,3]oxazin]-2'-amine
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-
6-bromo-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazin]-2'-amine (intermediate
A6.5) with 5-chloropyridinylboronic acid in a 3:1-mixture of 1,2-dimethoxyethane and water
as the solvent yielded the title compound (19% yield) as a white solid. MS (ISP): m/z = 349.8
[M+H] .
Example 10
(R)(2'-Amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]
yl)benzonitrile
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-
6-bromo-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazin]-2'-amine (intermediate
A6.5) with 3-cyanophenylboronic acid in a 3:1-mixture of 1,2-dimethoxyethane and water as the
solvent yielded the title compound (10% yield) as an off-white solid. MS (ISP): m/z = 340.2
[M+H] .
Example 11
(R)(2'-Amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]
yl)nicotinonitrile
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-
6-bromo-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazin]-2'-amine (intermediate
A6.5) with 5-cyanopyridinylboronic acid in a 3:1-mixture of 1,2-dimethoxyethane and water
as the solvent yielded the title compound as an off-white solid.
General procedure for the preparation of amides of formula I.2:
A solution of the carboxylic acid (0.23 mmol) in methanol (5 ml) was cooled to 0 °C. 4-
(4,6-Dimethoxy[1.3.5]triazinyl)methylmorpholinium chloride hydrate (DMTMM) (80 mg,
0.27 mmol) was added and the solution was stirred at 0 °C for 30 minutes. Thereafter, a solution
of the intermediate diamine A8 (0.21 mmol) in methanol (5 ml) was added dropwise at 0 °C via
syringe. The reaction mixture was stirred at 23 °C for 18-60 hours. For the workup, the reaction
mixture was poured into a solution of sodium carbonate (1M) followed by the extraction with
ethyl acetate. The organic layer was separated, washed with brine and dried over sodium
sulphate. Removal of the solvent at reduced pressure left a residue which was purified by
chromatography on silica gel or on a silica-NH phase using a mixture of dichloromethane and
methanol (0-10%) to give the pure amides of formula I.
Example 12
(R)-N-(2'-Amino-5',5'-difluoro-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'-
[1,3]oxazine]yl)chloropicolinamide
The condensation of (R)-5',5'-difluoro-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'-
[1,3]oxazine]-2',7-diamine (intermediate A7.1) and 5-chloropicolinic acid yielded the title
compound (42% yield) as a white solid. MS (ISP): m/z = 407.2 [M+H] .
Example 13
(R)-N-(2'-Amino-5',5'-difluoro-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'-
[1,3]oxazine]yl)cyanopicolinamide
The condensation of (R)-5',5'-difluoro-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'-
[1,3]oxazine]-2',7-diamine (intermediate A7.1) and 5-cyanopicolinic acid yielded the title
compound (38% yield) as a white solid. MS (ISP): m/z = 398.2 [M+H] .
Example 14
(R)-N-(2'-Amino-5',5'-difluoro-4,4-dimethyl-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-
1,4'-[1,3]oxazine]yl)cyanopicolinamide
The condensation of (R)-5',5'-difluoro-4,4-dimethyl-3,4,5',6'-tetrahydro-2H-
spiro[naphthalene-1,4'-[1,3]oxazine]-2',7-diamine (intermediate A7.2) and 5-cyanopicolinic acid
yielded the title compound (65% yield) as a pale yellow solid. MS (ISP): m/z = 426.0 [M+H] .
Example 15
(R)-N-(2'-Amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]yl)
cyanopicolinamide
The condensation of (R)-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]-
2',6-diamine (intermediate A7.3) and 5-cyanopicolinic acid yielded the title compound (27%
yield) as an off-white solid. MS (ISP): m/z = 384.2 [M+H] .
Example 16
(R)-N-(2'-Amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]yl)
chloropicolinamide
The condensation of (R)-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]-2',6-
diamine (intermediate A7.3) and 5-chloropicolinic acid yielded the title compound (16% yield)
as an off-white solid. MS (ISP): m/z = 393.0 [M+H] .
Example 17
(R)-N-(2'-Amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]yl)
fluoropicolinamide
The condensation of (R)-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]-
2',6-diamine (intermediate A7.3) and 5-fluoropicolinic acid yielded the title compound (17%
yield) as an off-white solid. MS (ISP): m/z = 377.2 [M+H] .
Example 18
(R)-N-(2'-Amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]yl)
(trifluoromethyl)picolinamide
The condensation of (R)-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]-
2',6-diamine (intermediate A7.3) and 5-(trifluoromethyl)picolinic acid yielded the title
compound (15% yield) as an off-white solid. MS (ISP): m/z = 427.2 [M+H] .
Synthesis of the intermediate sulfinyl imines B2
General procedure
To a solution of the (R)-(+)-tert-butylsulfinamide (66 mmol) in tetrahydrofuran (350 ml)
was added subsequently the ketone B1 (72.6 mmol) and titanium(IV)ethoxide (132 mmol) and
the solution was stirred at reflux temperature for 5 h. The mixture was cooled to 22 °C, treated
with brine (400 ml), the suspension was stirred for 10 min and filtered over Dicalite®. The layers
were separated, the aqueous layer was extracted with ethyl acetate, the combined organic layers
were washed with water, dried and concentrated in vacuo. The residue was purified by
chromatography on silica using cylohexane/ethyl acetate as the eluent to give the pure sulfinyl
imine B2.
2a 2b 2a 2b
Intermediate B2.1 (X = O; W = -CR ,R ; R , R = H; p = 1)
Starting from 6-bromo-chromanone {CAS[496603]} (intermediate B1.1), the
product (R)methyl-propanesulfinic acid [6-bromo-chroman-(4E)-ylidene]-amide (69%
yield) was obtained as a pale yellow oil. MS (ISP): m/z = 332.0 [M+H] .
2a 2b 2a 2b
Intermediate B2.2 (X = O; W = -CR ,R ; R , R = H; p = 1)
Starting from 6-nitro-chromanone {CAS[680438]} (intermediate B1.2), the product
(R)methyl-propanesulfinic acid [6-nitro-chroman-(4E)-ylidene]-amide (85% yield) was
obtained as a yellow oil. MS (ISP): m/z = 297.2 [M+H] .
2a 2b 2a 2b
Intermediate B2.3 (X = O; W = -CR ,R ; R = phenyl, R = H; p = 1)
Starting from (RS)bromophenyl-chromanone {CAS[564140];
WO2010021680} (intermediate B1.3), the product (R)methyl-propanesulfinic acid [(RS)-
6-bromophenyl-chroman-(4E)-ylidene]-amide (64% yield) was obtained as a yellow solid.
MS (ISP): m/z = 407 [M+H] .
2a 2b 2a 2b
Intermediate B2.4 (X = O; W = -CR ,R ; R = phenyl, R = H; p = 1)
Starting from (RS)nitrophenyl-chromanone {CAS[30345]} (intermediate
B1.4), the product (R)methyl-propanesulfinic acid [(RS)nitrophenyl-chroman-(4E)-
ylidene]-amide (43% yield) was obtained as a yellow solid. MS (ISP): m/z = 373 [M+H] .
2a 2b 2a 2b 2b
Intermediate B2.5 (X = O; W = -CR ,R ; R , R = methyl, R = H; p = 1)
Starting from 6-bromo-2,2-dimethyl-chromanone {CAS[998531]; WO2010021680}
(intermediate B1.5), the product (R)methyl-propanesulfinic acid [6-bromo-2,2-dimethyl-
chroman-(4E)-ylidene]-amide (55% yield) was obtained as a yellow solid. MS (ISP): m/z =
358.1 [M+H] and 360.2 [M+2+H] .
2a 2b 2a 2b 2b
Intermediate B2.6 (X = O; W = -CR ,R ; R , R = methyl, R = H; p = 1)
Starting from 2,2-dimethylnitro-chromanone {CAS[11147801]} (intermediate
B1.6), the product (R)methyl-propanesulfinic acid [2,2-dimethylnitro-chroman-(4E)-
ylidene]-amide (64% yield) was obtained as a yellow solid. MS (ISP): m/z = 325.2 [M+H] .
Intermediate B2.7
Starting from 6-bromo-2',4',5',6'-tetrahydrospiro[chroman-2,3'-pyran]one
{CAS[12120179]; WO2010021680} (intermediate B1.7), the product (R,E)-N-(6-bromo-
2',4',5',6'-tetrahydrospiro[chroman-2,3'-pyran]ylidene)methylpropanesulfinamide (67%
yield) was obtained as a yellow solid. MS (ISP): m/z = 400.1 [M+H] and 402.2 [M+H] .
2a 2b 2a 2b
Intermediate B2.8 (X = S; W = -CR ,R ; R , R = H; p = 1)
Starting from 6-bromo-thiochromanone {CAS[137352]} (intermediate B1.8), the
product (R)methyl-propanesulfinic acid [6-bromo-thiochroman-(4E)-ylidene]-amide (73%
yield) was obtained as a yellow solid. MS (ISP): m/z = 346.0 [M+H] .
Synthesis of the intermediate sulfinamide esters B3
General procedure (via Reformatsky reaction)
In a dry apparatus a suspension of freshly activated zinc powder (1.63 g, 24.9 mmol) in dry
tetrahydrofuran (70 ml) was heated under an inert atmosphere to reflux. A solution of the
sulfinyl imine B2 (24.9 mmol) and the bromo-acetate (24.9 mmol) in dry tetrahydrofuran (15 ml)
was added dropwise over a period of 15 min and the suspension was heated to reflux for 5 h. The
cooled mixture was partitioned between aqueous saturated ammonium chloride and ethyl acetate,
the organic layer was dried and evaporated. The crude material was purified by flash
chromatography using heptane/ethyl acetate as the eluent to give the sulfinamide ester B3.
Intermediate B3.1
COOEt
Starting from (R)methyl-propanesulfinic acid [6-bromo-chroman-(4E)-ylidene]-
amide (intermediate B2.1), the product [(R)bromo((R)methyl-propanesulfinylamino)-
chromanyl]-difluoro-acetic acid ethyl ester (63% yield) was obtained as a yellow oil. MS
(ISP): m/z = 456.1 [M+H] .
Intermediate B3.2
S COOEt
Starting from (R)methyl-propanesulfinic acid [6-nitro-chroman-(4E)-ylidene]-amide
(intermediate B2.2), the product difluoro-[(R)((R)methyl-propanesulfinylamino)
nitro-chromanyl]-acetic acid ethyl ester (52% yield) was obtained as a red oil.
Intermediate B3.3
S COOEt
Starting from (R)methyl-propanesulfinic acid [(RS)bromophenyl-chroman-
(4E)-ylidene]-amide (intermediate B2.3), the product [(2RS,4R)bromo((R)methyl-
propanesulfinylamino)phenyl-chromanyl]-difluoro-acetic acid ethyl ester (82% yield)
was obtained as a yellow solid. MS (ISP): m/z = 532 [M+H] .
Intermediate B3.4
S COOEt
Starting from (R)methyl-propanesulfinic acid [(RS)nitrophenyl-chroman-(4E)-
ylidene]-amide (intermediate B2.4), the product difluoro-[(2RS,4R)((R)methyl-propane
sulfinylamino)nitrophenyl-chromanyl]-acetic acid ethyl ester (42% yield) was obtained
as a yellow solid. MS (ISP): m/z = 497 [M+H] .
Intermediate B3.5
S COOEt
Starting from (R)methyl-propanesulfinic acid [6-bromo-2,2-dimethyl-chroman-(4E)-
ylidene]-amide (intermediate B2.5), the product [(R)bromo-2,2-dimethyl((R)methyl-
propanesulfinylamino)-chromanyl]-difluoro-acetic acid ethyl ester (53% yield) was
obtained as a pale yellow solid. MS (ISP): m/z = 482.2 [M+H] and 484.3 [M+2+H] .
Intermediate B3.6
COOEt
Starting from (R)methyl-propanesulfinic acid [2,2-dimethylnitro-chroman-(4E)-
ylidene]-amide (intermediate B2.6), the product [(R)-2,2-dimethylnitro((R)methyl-
propanesulfinylamino)-chromanyl]-difluoro-acetic acid ethyl ester (56% yield) was
obtained as a red oil. MS (ISP): m/z = 449.2 [M+H] .
Intermediate B3.7
COOEt
Starting from (R,E)-N-(6-bromo-2',4',5',6'-tetrahydrospiro[chroman-2,3'-pyran]ylidene)-
2-methylpropanesulfinamide (intermediate B2.7), the product ethyl 2-((4R)bromo((R)-
1,1-dimethylethylsulfinamido)-2',4',5',6'-tetrahydrospiro[chroman-2,3'-pyran]yl)-2,2-
difluoroacetate (58% yield) was obtained as a pale yellow foam. MS (ISP): m/z = 524.2 [M+H]
and 526.1 [M+H] .
Intermediate B3.8
S COOEt
Starting from (R)methyl-propanesulfinic acid [6-bromo-thiochroman-(4E)-ylidene]-
amide (intermediate B2.8), the product [(R)bromo((R)methyl-propanesulfinylamino)-
thiochromanyl]-difluoro-acetic acid ethyl ester (77% yield) was obtained as a yellow, viscous
oil. MS (ISP): m/z = 470.2 [M+H] and 472.2 [M+2+H] .
Synthesis of the intermediate sulfinamide alcohols B4
General procedure
A solution of the sulfinamide ester B3 (12.7 mmol) in dry tetrahydrofuran (50 ml) was
treated at 0 °C with lithium borohydride (25.3 mmol) and stirring was continued at 0 °C for 4 h.
The reaction mixture was quenched by addition of acetic acid (2 ml) and water (50 ml), extracted
with ethyl acetate and the organic layer was dried and evaporated. The residue was purified by
chromatography on silica using a mixture of n-heptane and ethyl acetate as the eluent to give the
pure intermediate sulfinamide alcohol B4.
Intermediate B4.1
Starting from [(R)bromo((R)methyl-propanesulfinylamino)-chromanyl]-
difluoro-acetic acid ethyl ester (intermediate B3.1), the product (R)methyl-propanesulfinic
acid [(R)bromo(1,1-difluorohydroxy-ethyl)-chromanyl]-amide (96% yield) was
obtained as a white solid. MS (ISP): m/z = 414.1 [M+H] .
Intermediate B4.2
Starting from difluoro-[(R)((R)methyl-propanesulfinylamino)nitro-chroman
yl]-acetic acid ethyl ester (intermediate B3.2), the product (R)methyl-propanesulfinic acid
[(R)(1,1-difluorohydroxy-ethyl)nitro-chromanyl]-amide (78% yield) was obtained as
a red oil. MS (ISP): m/z = 379.2 [M+H] .
Intermediate B4.3
Starting from [(2RS,4R)bromo((R)methyl-propanesulfinylamino)phenyl-
chromanyl]-difluoro-acetic acid ethyl ester (intermediate B3.3), the product (R)methyl-
propanesulfinic acid [(2RS,4R)bromo(1,1-difluorohydroxy-ethyl)phenyl-
chromanyl]-amide (78% yield) was obtained as a white solid. MS (ISP): m/z = 490 [M+H] .
Intermediate B4.4
Starting from difluoro-[(2RS,4R)((R)methyl-propanesulfinylamino)nitro
phenyl-chromanyl]-acetic acid ethyl ester (intermediate B3.4), the product (R)methyl-
propanesulfinic acid [(2RS,4R)(1,1-difluorohydroxy-ethyl)nitrophenyl-chroman-
4-yl]-amide (64% yield) was obtained as a yellow sticky liquid. MS (ISP): m/z = 455 [M+H] .
Intermediate B4.5
Starting from [(R)bromo-2,2-dimethyl((R)methyl-propanesulfinylamino)-
chromanyl]-difluoro-acetic acid ethyl ester (intermediate B3.5), the product (R)methyl-
propanesulfinic acid [(R)bromo(1,1-difluorohydroxy-ethyl)-2,2-dimethyl-chroman
yl]-amide (99% yield) was obtained as a white powder. MS (ISP): m/z = 440.2 [M+H] and
442.2 [M+2+H] .
Intermediate B4.6
Starting from [(R)-2,2-dimethylnitro((R)methyl-propanesulfinylamino)-
chromanyl]-difluoro-acetic acid ethyl ester (intermediate B3.6), the product (R)methyl-
propanesulfinic acid [(R)(1,1-difluorohydroxy-ethyl)-2,2-dimethylnitro-chroman
yl]-amide (59% yield) was obtained as a red oil. MS (ISP): m/z = 407.3 [M+H] .
Intermediate B4.7
Starting from ethyl 2-((4R)bromo((R)-1,1-dimethylethylsulfinamido)-2',4',5',6'-
tetrahydrospiro[chroman-2,3'-pyran]yl)-2,2-difluoroacetate (intermediate B3.7), the product
(R)-N-((4R)bromo(1,1-difluorohydroxyethyl)-2',4',5',6'-tetrahydrospiro[chroman-2,3'-
pyran]yl)methylpropanesulfinamide (98% yield) was obtained as a white solid. MS
(ISP): m/z = 482.2 [M+H] and 484.1 [M+H] .
Intermediate B4.8
Starting from [(R)bromo((R)methyl-propanesulfinylamino)-thiochromanyl]-
difluoro-acetic acid ethyl ester (intermediate B3.8), the product (R)methyl-propanesulfinic
acid [(R)bromo(1,1-difluorohydroxy-ethyl)-thiochromanyl]-amide (94% yield) was
obtained as a white foam. MS (ISP): m/z = 428.2 [M+H] and 430.2 [M+2+H] .
Synthesis of the intermediate amino alcohols B5
General Procedure:
A solution of the sulfinamide alcohols B4 (10.3 mmol) in methanol or tetrahydrofuran (30
to 60 ml) was treated with a solution of hydrochloric acid in 1,4-dioxane (4 M, 10-13 ml) and
stirring was continued at 23 °C for 2 to 18 h. The mixture was partitioned between ethyl acetate
and an aqueous solution of sodium carbonate (2 M), the organic layer was dried over sodium
sulphate, filtered and evaporated to give a residue which was purified by chromatography on
silica using a mixture of n-heptane and ethyl acetate as the eluent to give the pure aminoalcohols
Intermediate B5.1
Starting from (R)methyl-propanesulfinic acid [(R)bromo(1,1-difluoro
hydroxy-ethyl)-chromanyl]-amid (intermediate B4.1), the product 2-((R)aminobromo-
chromanyl)-2,2-difluoro-ethanol (73% yield) was obtained as a pale yellow oil.
Intermediate B5.2
Starting from (R)methyl-propanesulfinic acid [(R)(1,1-difluorohydroxy-ethyl)-
6-nitro-chromanyl]-amide (intermediate B4.2), the product 2-((R)aminonitro-chroman-
4-yl)-2,2-difluoro-ethanol (25% yield) was obtained as a yellow oil. MS (ISP): m/z = 275.1
[M+H] .
Intermediate B5.3
Starting from (R)methyl-propanesulfinic acid [(2RS,4R)bromo(1,1-difluoro
hydroxy-ethyl)phenyl-chromanyl]-amide (intermediate B4.3), the product 2-((2RS,4R)
aminobromophenyl-chromanyl)-2,2-difluoro-ethanol (70% yield) was obtained.
Intermediate B5.4
Starting from (R)methyl-propanesulfinic acid [(2RS,4R)(1,1-difluorohydroxy-
ethyl)nitrophenyl-chromanyl]-amide (intermediate B4.4), the product 2-((2RS,4R)
aminonitrophenyl-chromanyl)-2,2-difluoro-ethanol (50% yield) was obtained as a pale
yellow solid. MS (ISP): m/z = 351.2 [M+H] .
Intermediate B5.5
Starting from (R)methyl-propanesulfinic acid [(R)bromo(1,1-difluoro
hydroxy-ethyl)-2,2-dimethyl-chromanyl]-amide (intermediate B4.5), the product 2-((R)
aminobromo-2,2-dimethyl-chromanyl)-2,2-difluoro-ethanol (47% yield) was obtained as a
viscous, pale yellow oil. MS (ISP): m/z = 319.0 [M+H] and 321.0 [M+2+H] .
Intermediate B5.6
Starting from (R)methyl-propanesulfinic acid [(R)(1,1-difluorohydroxy-ethyl)-
2,2-dimethylnitro-chromanyl]-amide (intermediate B4.6), the product 2-((R)amino-2,2-
dimethylnitro-chromanyl)-2,2-difluoro-ethanol (69% yield) was obtained as a red oil. MS
(ISP): m/z = 303.1 [M+H] .
Intermediates B5.7A and B5.7B
OH OH
H N H N
Br Br
B5.7A
B5.7B
Starting from (R)-N-((4R)bromo(1,1-difluorohydroxyethyl)-2',4',5',6'-
tetrahydrospiro[chroman-2,3'-pyran]yl)methylpropanesulfinamide (intermediate B4.7),
and after chromatography on silica gel using a gradient of heptane/ethyl acetate = 100:0 to =:100
as the eluent the 2-((2R,4R)aminobromo-2',4',5',6'-tetrahydrospiro[chroman-2,3'-pyran]
yl)-2,2-difluoroethanol (47% yield) (intermediate B5.7A) was obtained as the first eluting isomer
as a white foam; MS (ISP): m/z = 378.0 [M+H] and 380.0 [M+2+H] . The second eluting
isomer, 2-((2S,4R)aminobromo-2',4',5',6'-tetrahydrospiro[chroman-2,3'-pyran]yl)-2,2-
difluoroethanol (27% yield) (intermediate B5.7B) was also obtained as a white foam; MS (ISP):
m/z = 378.0 [M+H] and 380.0 [M+2+H] .
Intermediate B5.8
Starting from (R)methyl-propanesulfinic acid [(R)bromo(1,1-difluoro
hydroxy-ethyl)-thiochromanyl]-amide (intermediate B4.8), the product 2-((R)amino
bromo-thiochromanyl)-2,2-difluoro-ethanol (85% yield) was obtained as a colorless, viscous
oil. MS (ISP): m/z = 324.0 [M+H] .
Syntheses of the intermediate amino oxazines B6
General procedure
A dried tube was charged with a mixture of the amino alcohol B5 (18.8 mmol), cyanogen
bromide (33.9 mmol) and ethanol (61 ml). The tube was sealed and heated at 90 °C for 16 hours.
For the workup, the reaction mixture was cooled and evaporated at reduced pressure. The residue
was partitioned between ethyl acetate (150 ml) and a saturated aqueous solution of sodium
carbonate (50 ml). The aqueous layer was separated and re-extracted with ethyl acetate (2 x 50
ml). The organic layers were washed with brine (50 ml), then combined, dried over sodium
sulphate and evaporated at reduced pressure. The product was used in the next step without
further purification.
Intermediate B6.1
H N O
Starting from 2-((R)aminobromo-chromanyl)-2,2-difluoro-ethanol (intermediate
B5.1), the product (R)bromo-5',5'-difluoro-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-
amine (15% yield) was obtained as a colorless. MS (ISP): m/z = 331.1 [M+H] .
Intermediate B6.2
H N O
Starting from 2-((R)aminonitro-chromanyl)-2,2-difluoro-ethanol (intermediate
B5.2), the product (R)-5',5'-difluoronitro-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-
amine (24% yield) was obtained as a pale yellow solid. MS (ISP): m/z = 300.1 [M+H] .
Intermediate B6.3
H N O
Starting from 2-((2RS,4R)aminobromophenyl-chromanyl)-2,2-difluoro-ethanol
(intermediate B5.3), the product (2RS,4R)bromo-5',5'-difluorophenyl-5',6'-
dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-amine (30% yield) was obtained.
Intermediate B6.4
HN O
Starting from 2-((2RS,4R)aminonitrophenyl-chromanyl)-2,2-difluoro-ethanol
(intermediate B5.4), the product (2RS,4R)-5',5'-difluoronitrophenyl-5',6'-
dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-amine was obtained.
Intermediate B6.5
H N O
Starting from 2-((R)aminobromo-2,2-dimethyl-chromanyl)-2,2-difluoro-ethanol
(intermediate B5.5), the product (R)bromo-5',5'-difluoro-2,2-dimethyl-5',6'-
dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-amine (35% yield) was obtained as a pale yellow
solid. MS (ISP): m/z = 361.1 [M+H] and 363.1 [M+2+H] .
Intermediate B6.6
H N O
Starting from 2-((R)amino-2,2-dimethylnitro-chromanyl)-2,2-difluoro-ethanol
(intermediate B5.6), the product (R)-5',5'-difluoro-2,2-dimethylnitro-5',6'-
dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-amine (50% yield) was obtained as a yellow oil. MS
(ISP): m/z = 328.1 [M+H] .
Intermediate B6.7
H N O
Starting from 2-((2R,4R)aminobromo-2',4',5',6'-tetrahydrospiro[chroman-2,3'-pyran]-
4-yl)-2,2-difluoroethanol (intermediate B5.7A), the product (2'R,4R)-6'-bromo-5,5-difluoro-
,5'',6,6''-tetrahydro-4''H-dispiro[1,3-oxazine-4,4'-chromene-2',3''-pyran]amine (49% yield)
was obtained as a white foam; MS (ISP): m/z = 403.3 [M+H] and 405.2 [M+2+H] .
Intermediate B6.8
H N O
Starting from 2-((2S,4R)aminobromo-2',4',5',6'-tetrahydrospiro[chroman-2,3'-pyran]-
4-yl)-2,2-difluoroethanol (intermediate B5.7B), the product (2'S,4R)-6'-bromo-5,5-difluoro-
5,5'',6,6''-tetrahydro-4''H-dispiro[1,3-oxazine-4,4'-chromene-2',3''-pyran]amine (47% yield)
was obtained as a white foam; MS (ISP): m/z = 403.0 [M+H] and 405.0 [M+2+H] .
Intermediate B6.9
H N O
Starting from 2-((R)aminobromo-thiochromanyl)-2,2-difluoro-ethanol
(intermediate B5.9), the product (R)-6'-bromo-5,5-difluoro-5,6-dihydrospiro[[1,3]oxazine-4,4'-
thiochroman]amine (29% yield) was obtained as a colorless, waxy solid. MS (ISP): m/z =
349.1 [M+H] and 351.0 [M+2+H] .
Syntheses of intermediate anilines B7 (via reduction of nitro oxazines)
General procedure
A solution of the nitro oxazine B6 (3 mmol) in ethanol (31 ml) was hydrogenated at
atmospheric pressure using palladium (10% on carbon) (159 mg, 150 µmol) as the catalyst. After
90 minutes the reaction was complete. The reaction mixture was filtrated over a layer of Dicalit,
which was washed with ethanol (3 x 20 ml). The combined solutions of ethanol were evaporated
at reduced pressure. The product was engaged in the step without further purification.
Intermediate B7.1
H N O
Starting from (R)-5',5'-difluoronitro-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-
amine (intermediate B6.2), the product (R)-5',5'-difluoro-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazine]-2',6-diamine (67% yield) was obtained as a yellow solid. MS (ISP): m/z = 270.3
[M+H] .
Intermediate B7.2
H N O
Starting from (2RS,4R)-5',5'-difluoronitrophenyl-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazin]-2'-amine (intermediate B6.4), the product (2RS,4R)-5',5'-difluorophenyl-5',6'-
dihydrospiro[chroman-4,4'-[1,3]oxazine]-2',6-diamine (81% yield) was obtained as a brown
solid.
Intermediate B7.3
HN O
Starting from (R)-5',5'-difluoro-2,2-dimethylnitro-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazin]-2'-amine (intermediate B6.6), the product (R)-5',5'-difluoro-2,2-dimethyl-5',6'-
dihydrospiro[chroman-4,4'-[1,3]oxazine]-2',6-diamine (64% yield) was obtained as a yellow oil.
MS (ISP): m/z = 298.2 [M+H] .
Syntheses of intermediate anilines B7 (via Buchwald-Hartwig cross coupling reaction)
Intermediate B7.4
H N O
(R)-5,5-Difluoro-5,6-dihydrospiro[[1,3]oxazine-4,4'-thiochroman]-2,6'-diamine
a) (R)-N-(bis(4-methoxyphenyl)(phenyl)methyl)-6'-bromo-5,5-difluoro-5,6-dihydrospiro-
[[1,3]oxazine-4,4'-thiochroman]amine (intermediate B6.1)
A solution of (R)-6'-bromo-5,5-difluoro-5,6-dihydrospiro[[1,3]oxazine-4,4'-thiochroman]-
2-amine (intermediate B6.9) (460 mg, 1.32 mmol) and triethylamine (267 mg, 2.63 mmol) in
dichloromethane (10 ml) was cooled to 0 °C and 4,4’-dimethoxytritylchloride (469 mg, 1.38
mmol) was added. The reaction mixture was left to warm to room temperature and stirred for 15
hours. For the workup, the reaction mixture was evaporated and the residue directly purified by
chromatography on silica gel using a gradient of heptane/ethyl acetate = 0:100 to 60:40 as the
eluent. The (R)-N-(bis(4-methoxyphenyl)(phenyl)methyl)-6'-bromo-5,5-difluoro-5,6-
dihydrospiro[[1,3]oxazine-4,4'-thiochroman]amine (789 mg, 92% yield) was obtained as a
yellow foam. MS (ISP): m/z = 651.0 [M+H] and 353.0 [M+2+H] .
b) (R)-N2-(bis(4-methoxyphenyl)(phenyl)methyl)-N6'-(diphenylmethylene)-5,5-difluoro-
5,6-dihydrospiro[[1,3]oxazine-4,4'-thiochroman]-2,6'-diamine (intermediate B6.2)
In a dry tube under an atmosphere of argon to a solution of (R)-N-(bis(4-
methoxyphenyl)(phenyl)methyl)-6'-bromo-5,5-difluoro-5,6-dihydrospiro[[1,3]oxazine-4,4'-
thiochroman]amine (789 mg, 1.21 mmol) in toluene (10 ml) were added consecutively
benzophenone imine (439 mg, 2.42 mmol), sodium tert-butoxide (349 mg, 3.63 mmol), 2-di-tert-
butylphosphino-2',4',6'-triisopropylbiphenyl {CAS [5644838]} (51.4 mg, 121 µmol), and
tris(dibenzylideneacetone)dipalladium(0) chloroform adduct {CAS [525224]} (37.6 mg,
36.3 µmol). The tube was sealed and the reaction mixture stirred at 110 °C for 15 hours. For the
workup, the solvent was evaporated at reduced pressure and the residue purified by
chromatography on silica gel using a gradient of heptane/ethyl acetate = 0:100 to 70:30 as the
eluent. The (R)-N2-(bis(4-methoxyphenyl)(phenyl)methyl)-N6'-(diphenylmethylene)-5,5-
difluoro-5,6-dihydrospiro[[1,3]oxazine-4,4'-thiochroman]-2,6'-diamine (613 mg, 67% yield) was
obtained as a yellow solid. MS (ISP): m/z = 752.5 [M+H] .
c) (R)-5,5-Difluoro-5,6-dihydrospiro[[1,3]oxazine-4,4'-thiochroman]-2,6'-diamine
A solution of (R)-N2-(bis(4-methoxyphenyl)(phenyl)methyl)-N6'-(diphenylmethylene)-
5,5-difluoro-5,6-dihydrospiro[[1,3]oxazine-4,4'-thiochroman]-2,6'-diamine (613 mg, 815 µmol)
in dichloromethane (10 ml) was treated with trifluoroacetic acid (930 mg, 8.15 mmol). The
orange colored solution was stirred at room temperature for 15 hours. Thereafter, the reaction
mixture was diluted with dichloromethane (10 ml) and washed with a 1M-solution of sodium
carbonate (5 ml). The organic layer was separated, dried over sodium sulphate and evaporated.
The resulting yellow oil was dissolved in dioxane (8 ml), then hydrochloric acid (4N in dioxane,
2.04 ml) was added dropwise. A precipitate was formed, which dissolved after addition of
hydrochloric acid (4N in dioxane, 2.0 ml). The orange colored solution was stirred at room
temperature for 15 hours. For the workup, the solution was evaporated at reduced pressure and
the residue dissolved in ethyl acetate (30 ml). The organic layer was washed with hydrochloric
acid (1N, 8 ml), the aqueous layer was separated and adjusted to pH 9 by addition of sodium
hydroxide (2N). Thereafter, the aqueous layer was extracted with ethyl acetate (3 x 30 ml), the
organic layers combined and dried over sodium sulphate. After evaporation at reduced pressure,
the (R)-5,5-difluoro-5,6-dihydrospiro[[1,3]oxazine-4,4'-thiochroman]-2,6'-diamine (230 mg,
89% yield) was obtained as a yellow solid pure enough to be used in the next step without
further purification. MS (ISP): m/z = 286.1[M+H] .
Intermediate B7.5
H N O
In close analogy to the procedure described for the synthesis of Intermediate B7.4 , the
(2'R,4R)-5,5-difluoro-5,5'',6,6''-tetrahydro-4''H-dispiro[1,3-oxazine-4,4'-chromene-2',3''-pyran]-
2,6'-diamine was obtained as follows:
a) (2'R,4R)-N-[bis(4-methoxyphenyl)(phenyl)methyl]-6'-bromo-5,5-difluoro-5,5'',6,6''-
tetrahydro-4''H-dispiro[1,3-oxazine-4,4'-chromene-2',3''-pyran]amine
Starting from (2'R,4R)-6'-bromo-5,5-difluoro-5,5'',6,6''-tetrahydro-4''H-dispiro[1,3-
oxazine-4,4'-chromene-2',3''-pyran]amine (intermediate B6.7), the title compound (80% yield)
was obtained as a white foam. MS (ISP): m/z = 705.2 [M+H] and 707.2 [M+2+H] .
b) (2'R,4R)-N~2~-[bis(4-methoxyphenyl)(phenyl)methyl]-N~6~'-(diphenylmethylidene)-
,5-difluoro-5,5'',6,6''-tetrahydro-4''H-dispiro[1,3-oxazine-4,4'-chromene-2',3''-pyran]-2,6'-
diamine
Starting from (2'R,4R)-N-[bis(4-methoxyphenyl)(phenyl)methyl]-6'-bromo-5,5-difluoro-
,5'',6,6''-tetrahydro-4''H-dispiro[1,3-oxazine-4,4'-chromene-2',3''-pyran]amine, the title
compound (54% yield) was obtained as a yellow solid. MS (ISP): m/z = 806.5 [M+H] .
c) (2'R,4R)-5,5-difluoro-5,5'',6,6''-tetrahydro-4''H-dispiro[1,3-oxazine-4,4'-chromene-2',3''-
pyran]-2,6'-diamine
Starting from (2'R,4R)-N~2~-[bis(4-methoxyphenyl)(phenyl)methyl]-N~6~'-
(diphenylmethylidene)-5,5-difluoro-5,5'',6,6''-tetrahydro-4''H-dispiro[1,3-oxazine-4,4'-chromene-
2',3''-pyran]-2,6'-diamine, the title compound (34% yield) was obtained as a pale yellow solid.
MS (ISP): m/z = 340.1 [M+H] .
Example 19
(R)(5-Chloropyridinyl)-5',5'-difluoro-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-
amine
In a tube a mixture of (R)bromo-5',5'-difluoro-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazin]-2'-amine (intermediate B6.1) (20 mg, 60 µmol), 5-chloropyridinylboronic acid
(11 mg, 72 µmol), and cesium carbonate (78 mg, 240 µmol) in tetrahydrofuran (1.2 ml) and
water (0.59 ml) was purged with argon for 5 minutes. Thereafter, [1,1′-
bis(diphenylphosphino)ferrocene]dichloropalladium(II) (2.2 mg, 3.0 µmol) was added, the tube
was sealed and the mixture heated at 80 °C for 30 minutes. For the workup, the reaction mixture
was diluted with ethyl acetate and washed with water. The organic layer was separated, dried
over sodium sulphate and evaporated at reduced pressure. The residue was purified by
chromatography on a silica-NH phase using a gradient of heptane/ethyl acetate = 100:0 to 0:100
as the eluent. The (R)(2'-amino-4,4,5',5'-tetrafluoro-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-
1,4'-[1,3]oxazine]yl)nicotinonitrile (12 mg, 55% yield) was obtained as a pale yellow solid.
MS (ISP): m/z = 366.0 [M+H] .
Example 20
(R)(3,5-dichlorophenyl)-5',5'-difluoro-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-
amine
In a manner analogous to that described in Example 19, the cross coupling reaction of
(R)bromo-5',5'-difluoro-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-amine (intermediate
B6.1) with 3,5-dichlorophenylboronic acid yielded the title compound (58% yield) as a pale
yellow solid. MS (ISP): m/z = 399.1 [M+H] .
Example 21
(R)-5',5'-difluoro(pyrimidinyl)-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-amine
In a manner analogous to that described in Example 19, the cross coupling reaction of
(R)bromo-5',5'-difluoro-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-amine (intermediate
B6.1) with pyrimidinylboronic acid yielded the title compound (55% yield) as a pale yellow
solid. MS (ISP): m/z = 333.1 [M+H] .
Example 22
(R)-5',5'-difluoro(5-methoxypyridinyl)-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazin]-
2'-amine
In a manner analogous to that described in Example 19, the cross coupling reaction of
(R)bromo-5',5'-difluoro-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-amine (intermediate
B6.1) with 5-methoxypyridinylboronic acid yielded the title compound (60% yield) as a pale
yellow solid. MS (ISP): m/z = 362.2 [M+H] .
Example 23
(2RS,4R)(5-chloropyridinyl)-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazin]-2'-amine
In a manner analogous to that described in Example 19, the cross coupling reaction of
(2RS,4R)bromo-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-
amine (intermediate B6.3) with 5-chloropyridinylboronic acid yielded the title compound
(16% yield) as a grey solid. MS (ISP): m/z = 442.3 [M+H] .
Example 24
-((2RS,4R)-2'-amino-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazine]yl)nicotinonitrile
In a manner analogous to that described in Example 19, the cross coupling reaction of
(2RS,4R)bromo-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-
amine (intermediate B6.3) with 5-cyanopyridinylboronic acid yielded the title compound
(16% yield) as a white solid. MS (ISP): m/z = 433.3 [M+H] .
Example 25
(2RS,4R)-5',5'-difluorophenyl(pyrimidinyl)-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazin]-2'-amine
In a manner analogous to that described in Example 19, the cross coupling reaction of
(2RS,4R)bromo-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-
amine (intermediate B6.3) with pyrimidinylboronic acid yielded the title compound (22%
yield) as a white solid. MS (ISP): m/z = 409.3 [M+H] .
Example 26
(2RS,4R)(3,5-dichlorophenyl)-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazin]-2'-amine
In a manner analogous to that described in Example 19, the cross coupling reaction of
(2RS,4R)bromo-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-
amine (intermediate B6.3) with 3,5-dichlorophenylboronic acid yielded the title compound (17%
yield) as a white solid. MS (ISP): m/z = 475.0 [M+H] .
Example 27
3-((2RS,4R)-2'-amino-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazine]yl)benzonitrile
In a manner analogous to that described in Example 19, the cross coupling reaction of
(2RS,4R)bromo-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-
amine (intermediate B6.3) with 3-cyanophenylboronic acid yielded the title compound (13%
yield) as a white solid. MS (ISP): m/z = 432.2 [M+H] .
Example 28
(R)(5-chloropyridinyl)-5',5'-difluoro-2,2-dimethyl-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazin]-2'-amine
In a manner analogous to that described in Example 19, the cross coupling reaction of
(R)bromo-5',5'-difluoro-2,2-dimethyl-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-amine
(intermediate B6.5) with 5-chloropyridinylboronic acid yielded the title compound (78% yield)
as a white powder. MS (ISP): m/z = 394.1 [M+H] .
Example 29
(2'R,4R)-6'-(5-Chloropyridinyl)-5,5-difluoro-5,5'',6,6''-tetrahydro-4''H-dispiro[1,3-
oxazine-4,4'-chromene-2',3''-pyran]amine formate
In a manner analogous to that described in Example 19, the cross coupling reaction of
(2'R,4R)-6'-bromo-5,5-difluoro-5,5'',6,6''-tetrahydro-4''H-dispiro[1,3-oxazine-4,4'-chromene-
2',3''-pyran]amine (intermediate B6.7) with 5-chloropyridinylboronic acid and
chromatography on preparative HPLC yielded the title compound (66% yield) as an off-white,
amorphous material. MS (ISP): m/z = 436 [M+H] and 438 [M+2+H] .
Example 30
3-[(2'R,4R)Amino-5,5-difluoro-5,5'',6,6''-tetrahydro-4''H-dispiro[1,3-oxazine-4,4'-
chromene-2',3''-pyran]-6'-yl]benzonitrile formate
In a manner analogous to that described in Example 19, the cross coupling reaction of
(2'R,4R)-6'-bromo-5,5-difluoro-5,5'',6,6''-tetrahydro-4''H-dispiro[1,3-oxazine-4,4'-chromene-
2',3''-pyran]amine (intermediate B6.7) with 3-cyanophenylboronic acid and chromatography
on preparative HPLC yielded the title compound (25% yield) as a pale yellow solid. MS (ISP):
m/z = 426.2 [M+H] .
Example 31
(2'S,4R)-6'-(5-Chloropyridinyl)-5,5-difluoro-5,5'',6,6''-tetrahydro-4''H-dispiro[1,3-
oxazine-4,4'-chromene-2',3''-pyran]amine formate
In a manner analogous to that described in Example 19, the cross coupling reaction of
(2'S,4R)-6'-bromo-5,5-difluoro-5,5'',6,6''-tetrahydro-4''H-dispiro[1,3-oxazine-4,4'-chromene-
2',3''-pyran]amine (intermediate B6.8) with 5-chloropyridinylboronic acid and
chromatography on preparative HPLC yielded the title compound (66% yield) as an off-white,
amorphous material. MS (ISP): m/z = 436 [M+H] and 438 [M+2+H] .
Example 32
(R)-6'-(5-Chloropyridinyl)-5,5-difluoro-5,6-dihydrospiro[[1,3]oxazine-4,4'-
thiochroman]amine
In a manner analogous to that described in Example 19, the cross coupling reaction of
(R)-6'-bromo-5,5-difluoro-5,6-dihydrospiro[[1,3]oxazine-4,4'-thiochroman]amine
(intermediate B6.9) with 5-chloropyridinylboronic acid yielded the title compound (70% yield)
as a white solid. MS (ISP): m/z = 382.0 [M+H] .
General procedure for the preparation of amides of formula I.4:
A solution of the carboxylic acid (0.23 mmol) in methanol (5 ml) was cooled to 0 °C. 4-
(4,6-Dimethoxy[1.3.5]triazinyl)methylmorpholinium chloride hydrate (DMTMM) (80 mg,
0.27 mmol) was added and the solution was stirred at 0 °C for 30 minutes. Thereafter, a solution
of the intermediate diamine B7 (0.21 mmol) in methanol (5 ml) was added dropwise at 0 °C via
syringe. The reaction mixture was stirred at 23 °C for 18-60 hours. For the workup, the reaction
mixture was poured into a solution of sodium carbonate (1M) followed by the extraction with
ethyl acetate. The organic layer was separated, washed with brine and dried over sodium
sulphate. Removal of the solvent at reduced pressure left a residue which was purified by
chromatography on silica gel or on a silica-NH phase using a mixture of dichloromethane and
methanol (0-10%) to give the pure amides of formula I.
Example 33
(R)-N-(2'-Amino-5',5'-difluoro-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazine]yl)
chloropicolinamide
The condensation of (R)-5',5'-difluoro-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazine]-
2',6-diamine (intermediate B7.1) and 5-chloropicolinic acid yielded the title compound (56%
yield) as a white solid. MS (ISP): m/z = 409.2 [M+H] .
Example 34
(R)-N-(2'-Amino-5',5'-difluoro-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazine]yl)
cyanopicolinamide
The condensation of (R)-5',5'-difluoro-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazine]-
2',6-diamine (intermediate B7.1) and 5-cyanopicolinic acid yielded the title compound (74%
yield) as a yellow solid. MS (ISP): m/z = 400.2 [M+H] .
Example 35
(R)-N-(2'-Amino-5',5'-difluoro-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazine]yl)
cyanopicolinamide
The condensation of (R)-5',5'-difluoro-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazine]-
2',6-diamine (intermediate B7.1) and 4-chloro-1H-pyrazolecarboxylic acid yielded the title
compound (34% yield) as a pale yellow solid. MS (ISP): m/z = 398.1 [M+H] .
Example 36
N-((2R or 2S,4R)-2'-Amino-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazine]yl)chloropicolinamide
The condensation of (2RS,4R)-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazine]-2',6-diamine (intermediate B7.2) and 5-chloropicolinic acid yielded the title
compound (21% yield) as an off-white solid. MS (ISP): m/z = 485.1 [M+H] .
Example 37
N-((2R or 2S,4R)-2'-Amino-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazine]yl)cyanopicolinamide
The condensation of (2RS,4R)-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazine]-2',6-diamine (intermediate B7.2) and 5-cyanopicolinic acid yielded the title
compound (33% yield) as an off-white solid. MS (ISP): m/z = 476.1 [M+H] .
Example 38
N-((2R or 2S,4R)-2'-Amino-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazine]yl)fluoropicolinamide
The condensation of (2RS,4R)-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazine]-2',6-diamine (intermediate B7.2) and 5-fluoropicolinic acid yielded the title
compound (26% yield) as an off-white solid. MS (ISP): m/z = 469.2 [M+H] .
Example 39
N-((2R or 2S,4R)-2'-Amino-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazine]yl)(trifluoromethyl)picolinamide
The condensation of (2RS,4R)-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazine]-2',6-diamine (intermediate B7.2) and 5-fluoropicolinic acid yielded the title
compound (27% yield) as an off-white solid.
Example 40
(R)-N-(2'-Amino-5',5'-difluoro-2,2-dimethyl-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazine]-
6-yl)chloropicolinamide
The condensation of (R)-5',5'-difluoro-2,2-dimethyl-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazine]-2',6-diamine (intermediate B7.3) and 5-chloropicolinic acid yielded the title
compound (85% yield) as a white solid. MS (ISP): m/z = 437.1 [M+H] .
Example 41
(R)-N-(2'-Amino-5',5'-difluoro-2,2-dimethyl-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazine]-
6-yl)cyanopicolinamide
The condensation of (R)-5',5'-difluoro-2,2-dimethyl-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazine]-2',6-diamine (intermediate B7.3) and 5-cyanopicolinic acid yielded the title
compound (78% yield) as a yellow solid. MS (ISP): m/z = 428.3 [M+H] .
Example 42
(R)-N-(2-Amino-5,5-difluoro-5,6-dihydrospiro[[1,3]oxazine-4,4'-thiochroman]-6'-yl)
chloropicolinamide
The condensation of (R)-5',5'-difluoro-2,2-dimethyl-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazine]-2',6-diamine (intermediate B7.4) and 5-chloropicolinic acid yielded the title
compound (55% yield) as a white solid. MS (ISP): m/z = 424.9 [M+H] .
Example 43
(R)-N-(2-Amino-5,5-difluoro-5,6-dihydrospiro[[1,3]oxazine-4,4'-thiochroman]-6'-yl)
cyanopicolinamide
The condensation of (R)-5',5'-difluoro-2,2-dimethyl-5',6'-dihydrospiro[chroman-4,4'-
[1,3]oxazine]-2',6-diamine (intermediate B7.4) and 5-cyanopicolinic acid yielded the title
compound (57% yield) as a yellow solid. MS (ISP): m/z = 415.9 [M+H] .
Example 44
N-[(2'R,4R)Amino-5,5-difluoro-5,5'',6,6''-tetrahydro-4''H-dispiro[1,3-oxazine-4,4'-
chromene-2',3''-pyran]-6'-yl]cyanopyridinecarboxamide
The condensation of (2'R,4R)-5,5-difluoro-5,5'',6,6''-tetrahydro-4''H-dispiro[1,3-oxazine-
4,4'-chromene-2',3''-pyran]-2,6'-diamine (intermediate B7.5) and 5-cyanopicolinic acid yielded
the title compound (64% yield) as a yellow solid. MS (ISP): m/z = 470.3 [M+H] .
Example 45
N-[(4R)amino-5,5-difluoro-1',1'-dioxido-2',3',5,6-tetrahydrospiro[1,3-oxazine-4,4'-
thiochromen]-6'-yl]chloropyridinecarboxamide
A solution of (R)-N-(2-amino-5,5-difluoro-5,6-dihydrospiro[[1,3]oxazine-4,4'-
thiochroman]-6'-yl)chloropicolinamide (Example 42) (30 mg, 70.6 µmol) in methanol (2 ml)
was treated with potassium peroxomonosulphate (52.1 mg, 84.7 µmol). The suspension was
stirred at room temperature for 5 days. For the workup, the reaction mixture was evaporated at
reduced pressure and the residue directly purified by chromatography on a silica-NH phase
using a gradient of heptane/ethyl acetate = 100:0 to 20:80 as the eluent. The title compound (30
mg, 93% yield) was obtained as a white solid. MS (ISP): m/z = 457.2 [M+H] .
Example 46
N-[(4R)amino-5,5-difluoro-1',1'-dioxido-2',3',5,6-tetrahydrospiro[1,3-oxazine-4,4'-
thiochromen]-6'-yl]cyanoopyridinecarboxamide
In a manner analogous to that described in Example 45, the oxidation of the N-[(2'R,4R)-
2-amino-5,5-difluoro-5,5'',6,6''-tetrahydro-4''H-dispiro[1,3-oxazine-4,4'-chromene-2',3''-pyran]-
6'-yl]cyanopyridinecarboxamide (Example 44) yielded the title compound (74% yield) as a
white solid. MS (ISP): m/z = 448.2 [M+H] .
Synthesis of the intermediate sulfinamide nitrile C1
General procedure
A solution of the sulfinamide alcohol A4 (4.1 mmol) in dichloromethane (23 ml) was
subsequently treated at 22 °C with 2-bromoacetonitrile (6.2 mmol), silver(I) oxide (1.9 g) and
tetrabutylammonium iodide (0.30 g), and stirring was continued for 2 hours. For the workup, the
suspension was filtered and the filtrate was washed with an aqueous saturated solution of sodium
hydrogencarbonate. The organic layer was dried and evaporated to give the crude sulfinamide
nitrile C1 which was used without further purification.
Intermediate C1.1
Starting from (R)methyl-propanesulfinic acid [(R)(1,1-difluorohydroxy-ethyl)-
7-nitro-1,2,3,4-tetrahydro-naphthalenyl]-amide (intermediate A4.2), the product (R)
methyl-propanesulfinic acid [(R)(2-cyanomethoxy-1,1-difluoro-ethyl)nitro-1,2,3,4-
tetrahydro-naphthalenyl]-amide (68% yield) was obtained as a brown oil. MS (ISP): m/z =
416.3 [M+H] .
Intermediate C1.2
O CN
Starting from (R)methyl-propanesulfinic acid [(R)bromo(1,1-difluoro
hydroxy-ethyl)-chromanyl]-amide (intermediate B4.1), the product (R)methyl-propane
sulfinic acid [(R)bromo(2-cyanomethoxy-1,1-difluoro-ethyl)-chromanyl]-amide (64%
yield) was obtained as an off-white waxy solid. MS (ISP): m/z = 451.0 [M+H] and 453.0
[M+2+H] .
Intermediate C1.3
O CN
Starting from (R)methyl-propanesulfinic acid [(R)(1,1-difluorohydroxy-ethyl)-
6-nitro-chromanyl]-amide (intermediate B4.2), the product (R)methyl-propanesulfinic
acid [(R)(2-cyanomethoxy-1,1-difluoro-ethyl)nitro-chromanyl]-amide (79% yield) was
obtained as a brown oil. MS (ISP): m/z = 418.2 [M+H] .
Intermediate C1.4
Starting from (R)methyl-propanesulfinic acid [(2RS,4R)bromo(1,1-difluoro
hydroxy-ethyl)phenyl-chromanyl]-amide (intermediate B4.3), the product (R)methyl-
propanesulfinic acid [(2S,4R)bromo(2-cyanomethoxy-1,1-difluoro-ethyl)phenyl-
chromanyl]-amide (79% yield)was obtained as a white solid.
Intermediate C1.5
O CN
Starting from (R)methyl-propanesulfinic acid [(2RS,4R)(1,1-difluorohydroxy-
ethyl)nitrophenyl-chromanyl]-amide (intermediate B4.4), the product (R)methyl-
propanesulfinic acid [(2RS,4R)(2-cyanomethoxy-1,1-difluoro-ethyl)nitrophenyl-
chromanyl]-amide (76% yield) was obtained as a sticky yellow liquid.
Synthesis of the intermediate amino nitrile C2
General procedure
A solution of the sulfinamide nitrile C1 (4.25 mmol) in 1,4-dioxane (20 ml) was treated
with a solution of hydrochloric acid in 1,4-dioxane (4 M, 5.3 ml), and stirring was continued at
22 °C for 1 hour. For the workup, the mixture was diluted with ethyl acetate and washed with a
saturated aqueous solution of sodium carbonate. The organic layer was dried and evaporated.
The crude material was purified on silica using a mixture of n-heptane and ethyl acetate as the
eluent to give the pure amino nitrile C2.
Intermediate C2.1
O CN
Starting from (R)methyl-propanesulfinic acid [(R)(2-cyanomethoxy-1,1-difluoro-
ethyl)nitro-1,2,3,4-tetrahydro-naphthalenyl]-amide (intermediate C1.1), the product [2-
((R)aminonitro-1,2,3,4-tetrahydro-naphthalenyl)-2,2-difluoro-ethoxy]-acetonitrile (76%
yield) was obtained as a light brown oil. MS (ISP): m/z = 312.1 [M+H] .
Intermediate C2.2
Starting from (R)methyl-propanesulfinic acid [(R)bromo(2-cyanomethoxy-1,1-
difluoro-ethyl)-chromanyl]-amide (intermediate C1.2), the product [2-((R)aminobromo-
chromanyl)-2,2-difluoro-ethoxy]-acetonitrile (50% yield) was obtained as an off-white oil.
MS (ISP): m/z = 347.0 [M+H] and 349.2 [M+2+H] .
Intermediate C2.3
Starting from (R)methyl-propanesulfinic acid [(R)(2-cyanomethoxy-1,1-difluoro-
ethyl)nitro-chromanyl]-amide (intermediate C1.3), the product [2-((R)aminonitro-
chromanyl)-2,2-difluoro-ethoxy]-acetonitrile (87% yield) was obtained as a yellow oil. MS
(ISP): m/z = 313.9 [M+H] .
Intermediate C2.4
O CN
Starting from (R)methyl-propanesulfinic acid [(2RS,4R)bromo(2-
cyanomethoxy-1,1-difluoro-ethyl)phenyl-chromanyl]-amide (intermediate C1.4), the
product [2-((2RS,4R)aminobromophenyl-chromanyl)-2,2-difluoro-ethoxy]-
acetonitrile (62% yield) was obtained as a pale yellow solid.
Intermediate C2.5
Starting from (R)methyl-propanesulfinic acid [(2RS,4R)(2-cyanomethoxy-1,1-
difluoro-ethyl)nitrophenyl-chromanyl]-amide (intermediate C1.5), the product [2-
((2RS,4R)aminonitrophenyl-chromanyl)-2,2-difluoro-ethoxy]-acetonitrile (63% yield)
was obtained as a brown solid.
Synthesis of the intermediate 1,4-oxazepine C3
General procedure
A solution of the amino nitrile C2 (2.20 mmol) in toluene (38 ml) was treated at 22 °C with
a solution of trimethylaluminium in toluene (2 M, 1.2 ml) and the mixture was heated to 80 °C
for 1 hour. For the workup, the mixture was cooled to 0 °C, diluted with a saturated aqueous
solution of sodium carbonate. The aqueous layer was extracted with ethyl acetate, the organic
layers were combined, dried, and evaporated. The residue was purified by chromatography on a
silica-NH phase using a mixture of n-heptane and ethyl acetate as the eluent to give the pure
1,4-oxazepine C3.
Intermediate C3.1
Starting from [2-((R)aminonitro-1,2,3,4-tetrahydro-naphthalenyl)-2,2-difluoro-
ethoxy]-acetonitrile (intermediate C2.1), the product (R)-6',6'-difluoronitro-3,4,6',7'-
tetrahydro-2H,2'H-spiro[naphthalene-1,5'-[1,4]oxazepin]-3'-amine (70% yield) was obtained as a
light brown foam. MS (ISP): m/z = 312.1 [M+H] .
Intermediate C3.2
Starting from [2-((R)aminobromo-chromanyl)-2,2-difluoro-ethoxy]-acetonitrile
(intermediate C2.2), the product (R)bromo-6',6'-difluoro-6',7'-dihydro-2'H-spiro[chroman-
4,5'-[1,4]oxazepin]-3'-amine was obtained in quantitative yield as an off-white foam. MS (ISP):
m/z = 347.1 [M+H] and 349.1 [M+2+H] .
Intermediate C3.3
Starting from [2-((R)aminonitro-chromanyl)-2,2-difluoro-ethoxy]-acetonitrile
(intermediate C2.3), the product (R)-6',6'-difluoronitro-6',7'-dihydro-2'H-spiro[chroman-4,5'-
[1,4]oxazepin]-3'-amine (98% yield) was obtained as a red oil. MS (ISP): m/z = 313.9 [M+H] .
Intermediate C3.4
Starting from [2-((2RS,4R)aminobromophenyl-chromanyl)-2,2-difluoro-
ethoxy]-acetonitrile (intermediate C2.4), the product (2RS,4R)bromo-6',6'-difluorophenyl-
6',7'-dihydro-2'H-spiro[chroman-4,5'-[1,4]oxazepin]-3'-amine (67% yield) was obtained as a
yellow semi-solid. MS (ISP): m/z = 422.9 [M+H] .
Intermediate C3.5
Starting from [2-((2RS,4R)aminonitrophenyl-chromanyl)-2,2-difluoro-ethoxy]-
acetonitrile (intermediate C2.5), the product (2RS,4R)-6',6'-difluoronitrophenyl-6',7'-
dihydro-2'H-spiro[chroman-4,5'-[1,4]oxazepin]-3'-amine (37% yield) was obtained as a brown
solid. MS (ISP): m/z = 390.0 [M+H] .
Syntheses of intermediate anilines C4 (via reduction of nitro 1,4-oxazepines)
General procedure
A solution of the nitro oxazepine C3 (3 mmol) in ethanol (31 ml) was hydrogenated at
atmospheric pressure using palladium (10% on carbon) (159 mg, 150 µmol) as the catalyst. After
90 minutes the reaction was complete. The reaction mixture was filtrated over a layer of Dicalit,
which was washed with ethanol (3 x 20 ml). The combined solutions of ethanol were evaporated
at reduced pressure. The product was engaged in the step without further purification.
Intermediate C4.1
Starting from (R)-6',6'-difluoronitro-3,4,6',7'-tetrahydro-2H,2'H-spiro[naphthalene-1,5'-
[1,4]oxazepin]-3'-amine (intermediate C3.1), the product (R)-6',6'-difluoro-3,4,6',7'-tetrahydro-
2H,2'H-spiro[naphthalene-1,5'-[1,4]oxazepine]-3',7-diamine was obtained in quantitative yield as
a yellow foam. MS (ISP): m/z = 282.2 [M+H] .
Intermediate C4.2
Starting from (R)-6',6'-difluoronitro-6',7'-dihydro-2'H-spiro[chroman-4,5'-
[1,4]oxazepin]-3'-amine (intermediate C3.3), the product (R)-6',6'-difluoro-6',7'-dihydro-2'H-
spiro[chroman-4,5'-[1,4]oxazepine]-3',6-diamine (95% yield) was obtained as a yellow solid. MS
(ISP): m/z = 284.1 [M+H] .
Intermediate C4.3
Starting from (2RS,4R)-6',6'-difluoronitrophenyl-6',7'-dihydro-2'H-spiro[chroman-
4,5'-[1,4]oxazepin]-3'-amine (intermediate C3.5), the product (2RS,4R)-6',6'-difluorophenyl-
6',7'-dihydro-2'H-spiro[chroman-4,5'-[1,4]oxazepine]-3',6-diamine (54% yield) was obtained as a
brown solid. MS (ISP): m/z = 360.0 [M+H] .
In analogy to the general procedure for the preparation of amides of formula I, the reaction
of the intermediate anilines of formula C4 with acids by 4-(4,6-dimethoxy[1.3.5]triazinyl)
methylmorpholinium chloride hydrate (DMTMM) as the condensating agent yielded the
following compounds:
Example 47
(R)-N-(3'-Amino-6',6'-difluoro-3,4,6',7'-tetrahydro-2H,2'H-spiro[naphthalene-1,5'-
[1,4]oxazepine]yl)cyanopicolinamide
The condensation of (R)-6',6'-difluoro-3,4,6',7'-tetrahydro-2H,2'H-spiro[naphthalene-1,5'-
[1,4]oxazepine]-3',7-diamine (intermediate C4.1) and 5-cyanopicolinic acid yielded the title
compound (37% yield) as an off-white solid. MS (ISP): m/z = 412.2 [M+H] .
Example 48
(R)-N-(3'-Amino-6',6'-difluoro-3,4,6',7'-tetrahydro-2H,2'H-spiro[naphthalene-1,5'-
[1,4]oxazepine]yl)chloropicolinamide
The condensation of (R)-6',6'-difluoro-3,4,6',7'-tetrahydro-2H,2'H-spiro[naphthalene-1,5'-
[1,4]oxazepine]-3',7-diamine (intermediate C4.1) and 5-chloropicolinic acid yielded the title
compound (45% yield) as an off-white solid. MS (ISP): m/z = 421.1 [M+H] .
Example 49
(R)-N-(3'-Amino-6',6'-difluoro-6',7'-dihydro-2'H-spiro[chroman-4,5'-[1,4]oxazepine]yl)-
-cyanopicolinamide
The condensation of (R)-6',6'-difluoro-6',7'-dihydro-2'H-spiro[chroman-4,5'-
[1,4]oxazepine]-3',6-diamine (intermediate C4.2) and 5-cyanopicolinic acid yielded the title
compound (51% yield) as a yellow solid. MS (ISP): m/z = 414.3 [M+H] .
Example 50
(R)-N-(3'-Amino-6',6'-difluoro-6',7'-dihydro-2'H-spiro[chroman-4,5'-[1,4]oxazepine]yl)-
-chloropicolinamide
The condensation of (R)-6',6'-difluoro-6',7'-dihydro-2'H-spiro[chroman-4,5'-
[1,4]oxazepine]-3',6-diamine (intermediate C4.2) and 5-chloropicolinic acid yielded the title
compound (54% yield) as a pale yellow solid. MS (ISP): m/z = 423.2 [M+H] .
Example 51
(R)-N-(3'-Amino-6',6'-difluoro-6',7'-dihydro-2'H-spiro[chroman-4,5'-[1,4]oxazepine]yl)-
3,5-dichloropicolinamide
The condensation of (R)-6',6'-difluoro-6',7'-dihydro-2'H-spiro[chroman-4,5'-
[1,4]oxazepine]-3',6-diamine (intermediate C4.2) and 3,5-chloropicolinic acid yielded the title
compound (38% yield) as a pale yellow solid. MS (ISP): m/z = 457.2 [M+H] and 459.2
[M+2+H] .
Example 52
N-((2RS,4R)-3'-Amino-6',6'-difluorophenyl-6',7'-dihydro-2'H-spiro[chroman-4,5'-
[1,4]oxazepine]yl)(trifluoromethyl)picolinamide
The condensation of (2RS,4R)-6',6'-difluorophenyl-6',7'-dihydro-2'H-spiro[chroman-
4,5'-[1,4]oxazepine]-3',6-diamine (intermediate C4.3) and 5-trifluoromethyl-pyridine
carboxylic acid yielded the title compound (7% yield) as a light brown solid. MS (ISP): m/z =
532.8 [M+H] .
Example 53
N-((2RS,4R)-3'-Amino-6',6'-difluorophenyl-6',7'-dihydro-2'H-spiro[chroman-4,5'-
[1,4]oxazepine]yl)cyanopicolinamide
The condensation of (2RS,4R)-6',6'-difluorophenyl-6',7'-dihydro-2'H-spiro[chroman-
4,5'-[1,4]oxazepine]-3',6-diamine (intermediate C4.3) and 5-cyanopicolinic acid yielded the title
compound as an off-white solid. MS (ISP): m/z = 490.2 [M+H] .
In a manner analogous to that described in Example 19, the following compounds were
obtained:
Example 54
(R)(5-Chloropyridinyl)-6',6'-difluoro-6',7'-dihydro-2'H-spiro[chroman-4,5'-
[1,4]oxazepin]-3'-amine
The cross coupling reaction of (R)bromo-6',6'-difluoro-6',7'-dihydro-2'H-
spiro[chroman-4,5'-[1,4]oxazepin]-3'-amine (intermediate C3.2) with 5-chloropyridin
ylboronic acid yielded the title compound (35% yield) as a light brown, amorphous material. MS
(ISP): m/z = 380.2 [M+H] .
Example 55
(R)(3,5-Dichlorophenyl)-6',6'-difluoro-6',7'-dihydro-2'H-spiro[chroman-4,5'-
[1,4]oxazepin]-3'-amine
The cross coupling reaction of (R)bromo-6',6'-difluoro-6',7'-dihydro-2'H-
spiro[chroman-4,5'-[1,4]oxazepin]-3'-amine (intermediate C3.2) with 3,5-dichlorophenylboronic
acid yielded the title compound (40% yield) as a light brown foam. MS (ISP): m/z = 413.2
[M+H] and 415.2 [M+2+H] .
Example 56
(2RS,4R)(5-Chloropyridinyl)-6',6'-difluorophenyl-6',7'-dihydro-2'H-
spiro[chroman-4,5'-[1,4]oxazepin]-3'-amine
The cross coupling reaction of (2RS,4R)bromo-6',6'-difluorophenyl-6',7'-dihydro-
2'H-spiro[chroman-4,5'-[1,4]oxazepin]-3'-amine (intermediate C3.4) with 5-chloropyridin
ylboronic acid yielded the title compound (7% yield) as a white solid.
Example 57
(2RS,4R)(3,5-Dichlorophenyl)-6',6'-difluorophenyl-6',7'-dihydro-2'H-spiro[chroman-
4,5'-[1,4]oxazepin]-3'-amine
The cross coupling reaction of (2RS,4R)bromo-6',6'-difluorophenyl-6',7'-dihydro-
2'H-spiro[chroman-4,5'-[1,4]oxazepin]-3'-amine (intermediate C3.4) with 3,5-
dichlorophenylboronic acid yielded the title compound (8% yield) as a white solid. MS (ISP):
m/z = 489.4 [M+H] .
Example 58
(2RS,4R)-6',6'-difluorophenyl(pyrimidinyl)-6',7'-dihydro-2'H-spiro[chroman-4,5'-
[1,4]oxazepin]-3'-amine
The cross coupling reaction of (2RS,4R)bromo-6',6'-difluorophenyl-6',7'-dihydro-
2'H-spiro[chroman-4,5'-[1,4]oxazepin]-3'-amine (intermediate C3.4) with pyrimidinylboronic
acid yielded the title compound (12% yield). MS (ISP): m/z = 423.0 [M+H] .
Example 59
-((2RS,4R)-3'-amino-6',6'-difluorophenyl-6',7'-dihydro-2'H-spiro[chroman-4,5'-
[1,4]oxazepine]yl)nicotinonitrile
The cross coupling reaction of (2RS,4R)bromo-6',6'-difluorophenyl-6',7'-dihydro-
2'H-spiro[chroman-4,5'-[1,4]oxazepin]-3'-amine (intermediate C3.4) with 5-cyanopyridin
ylboronic acid yielded the title compound (15% yield) as a colorless solid. MS (ISP): m/z =
447.4 [M+H] .
Example 60
3-((2RS,4R)-3'-amino-6',6'-difluorophenyl-6',7'-dihydro-2'H-spiro[chroman-4,5'-
[1,4]oxazepine]yl)benzonitrile
The cross coupling reaction of (2RS,4R)bromo-6',6'-difluorophenyl-6',7'-dihydro-
2'H-spiro[chroman-4,5'-[1,4]oxazepin]-3'-amine (intermediate C3.4) with 3-cyanophenylboronic
acid yielded the title compound (10% yield) as a colorless solid. MS (ISP): m/z = 446.0 [M+H] .
Claims (28)
1. A compound of formula I, wherein 7a 7b 5 V is -CR R -; 2a 2b W is -CR R -; 1a 1b X is -CR R -, -O-, -S- or -SO -; Y -NH-C=O-; Z is selected from the group consisting of 10 i) heteroaryl, ii) heteroaryl substituted by 1-4 substituents individually selected from R , iii) aryl, and iv) aryl substituted by 1-4 substituents individually selected from R , R is selected from the group consisting of 15 i) hydrogen, ii) halogen, and iii) C -alkyl; R is selected from the group consisting of i) hydrogen, 20 ii) halogen, and iii) C -alkyl; R is selected from the group consisting of i) hydrogen, and ii) C -alkyl; 25 R is selected from the group consisting of i) hydrogen, ii) aryl, and iii) C -alkyl; 2a 2b or R and R together with the C they are attached form a heterocyclyl; 30 R is selected from the group consisting of i) hydrogen, and ii) halogen, R is selected from the group consisting of i) hydrogen, and ii) halogen, 5 R is selected from the group consisting of i) hydrogen, and ii) C -alkyl, R is selected from the group consisting of i) hydrogen, and 10 ii) C -alkyl, R is selected from the group consisting of i) hydrogen, and ii) C -alkyl; R is selected from the group consisting of 15 i) hydrogen, and ii) C -alkyl; R is selected from the group consisting of i) cyano, ii) cyano-C -alkyl, 20 iii) halogen, iv) halogen-C -alkoxy, v) halogen-C -alkyl, vi) C -alkoxy, vii) C -alkoxy-C -alkyl, 1-6 1-6 25 viii) C -alkynyl, and ix) C -alkyl; n is 0 or 1; m is 0 or 1; p is 0 or 1; 30 or pharmaceutically acceptable salts thereof.
2. A compound according to claim 1, wherein 7a 7b V is -CR R -; 2a 2b W is -CR R -; 1a 1b X is -CR R -, -O-, -S- or -SO -; 35 Y -NH-C=O-; Z is selected from the group consisting of i) heteroaryl, ii) heteroaryl substituted by 1-2 substituents individually selected from R , and iii) aryl substituted by 1-2 substituents individually selected from R , R is selected from the group consisting of i) hydrogen, ii) halogen, and 5 iii) C -alkyl; R is selected from the group consisting of i) hydrogen, ii) halogen, and iii) C -alkyl; 10 R is selected from the group consisting of i) hydrogen, and ii) C -alkyl; R is selected from the group consisting of i) hydrogen, 15 ii) phenyl, and iii) C -alkyl; 2a 2b or R and R together with the C they are attached form tetrahydropyranyl; R is halogen; R is halogen; 20 R is hydrogen; R is hydrogen; R is hydrogen; R is hydrogen; R is selected from the group consisting of 25 i) cyano, ii) halogen, iii) halogen-C -alkyl, and iv) C -alkoxy, n is 0 or 1; 30 m is 0 or 1; p is 0 or 1; or pharmaceutically acceptable salts thereof.
3. A compound according to any of claims 1-2, wherein n is 0. 1a 1b 1a 1b
4. A compound according to any of claims 1-3, wherein X is -CR R - and R and R are 35 both hydrogen.
5. A compound according to any of claims 1-4, wherein p is 0.
6. A compound according to any of claims 1-3, wherein X is -O-. 2a 2b
7. A compound according to any one of claims 1-2 and 6, wherein p is 1, W is –CR R - and 2a 2b R and R are both hydrogen.
8. A compound according to any of claims 1-7, wherein R is halogen. 5
9. .A compound according to any of claims 1-8, wherein R is F.
10. A compound according to any of claims 1-9, wherein R is halogen.
11. .A compound according to any of claims 1-10, wherein R is F.
12. A compound according to any of claims 1-11, wherein R is hydrogen.
13. .A compound according to any of claims 1-12, wherein R is hydrogen. 10
14. A compound according to any of claims 1-13, wherein m is 0.
15. A compound according to any of claims 1-13, wherein m is1.
16. A compound according to any of claims 1-15, wherein Z is heteroaryl substituted by halogen or cyano.
17. A compound according to any of claims 1-16, selected from the group consisting of 15 (R)(5-chloropyridinyl)-5',5'-difluoro-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'- [1,3]oxazin]-2'-amine, (2'R,4R)-6'-(5-chloropyridinyl)-5,5-difluoro-5,5'',6,6''-tetrahydro-4''H-dispiro[1,3-oxazine- 4,4'-chromene-2',3''-pyran]amine formate, (2RS,4R)-5',5'-difluorophenyl(pyrimidinyl)-5',6'-dihydrospiro[chroman-4,4'- 20 [1,3]oxazin]-2'-amine, (2RS,4R)(3,5-dichlorophenyl)-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'- [1,3]oxazin]-2'-amine, (2RS,4R)(3,5-dichlorophenyl)-6',6'-difluorophenyl-6',7'-dihydro-2'H-spiro[chroman-4,5'- [1,4]oxazepin]-3'-amine, 25 (2RS,4R)(5-chloropyridinyl)-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'- [1,3]oxazin]-2'-amine, (2RS,4R)(5-chloropyridinyl)-6',6'-difluorophenyl-6',7'-dihydro-2'H-spiro[chroman-4,5'- [1,4]oxazepin]-3'-amine, (2RS,4R)-6',6'-difluorophenyl(pyrimidinyl)-6',7'-dihydro-2'H-spiro[chroman-4,5'- 30 [1,4]oxazepin]-3'-amine, (2'S,4R)-6'-(5-chloropyridinyl)-5,5-difluoro-5,5'',6,6''-tetrahydro-4''H-dispiro[1,3-oxazine- 4,4'-chromene-2',3''-pyran]amine formate, (R)(2'-amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine] yl)benzonitrile, 5 (R)-4,4,5',5'-tetrafluoro(5-fluoropyridinyl)-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'- [1,3]oxazin]-2'-amine, (R)(2'-amino-4,4,5',5'-tetrafluoro-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'- [1,3]oxazine]yl)nicotinonitrile, (R)(2'-amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine] 10 yl)nicotinonitrile, (R)(2'-amino-5',5'-difluoro-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'-[1,3]oxazine] yl)nicotinonitrile, (R)-5',5'-difluoro(5-methoxypyridinyl)-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'- amine, 15 (R)-5',5'-difluoro(pyrimidinyl)-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazin]-2'-amine, (R)-5',5'-difluoro(pyrimidinyl)-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-amine, (R)(2-chloropyridinyl)-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazin]-2'- amine, (R)(3,5-dichlorophenyl)-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazin]-2'- 20 amine, (R)(3,5-dichlorophenyl)-5',5'-difluoro-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-amine, (R)(3,5-dichlorophenyl)-6',6'-difluoro-6',7'-dihydro-2'H-spiro[chroman-4,5'-[1,4]oxazepin]-3'- amine, (R)(5-chloropyridinyl)-5',5'-difluoro-2,2-dimethyl-5',6'-dihydrospiro[chroman-4,4'- 25 [1,3]oxazin]-2'-amine, (R)(5-chloropyridinyl)-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazin]-2'- amine, (R)-6'-(5-chloropyridinyl)-5,5-difluoro-5,6-dihydrospiro[[1,3]oxazine-4,4'-thiochroman] amine, 30 (R)(5-chloropyridinyl)-5',5'-difluoro-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-amine, (R)(5-chloropyridinyl)-6',6'-difluoro-6',7'-dihydro-2'H-spiro[chroman-4,5'-[1,4]oxazepin]- 3'-amine, (R)(5-chloropyridinyl)-4,4,5',5'-tetrafluoro-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'- [1,3]oxazin]-2'-amine, (R)-N-(2'-amino-5',5'-difluoro-2,2-dimethyl-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazine]yl)- 5-chloropicolinamide, (R)-N-(2'-amino-5',5'-difluoro-2,2-dimethyl-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazine]yl)- 5-cyanopicolinamide, 5 (R)-N-(2'-amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]yl) cyanopicolinamide, (R)-N-(2'-amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]yl) chloropicolinamide, (R)-N-(2'-amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]yl) 10 fluoropicolinamide, (R)-N-(2'-amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]yl) (trifluoromethyl)picolinamide, (R)-N-(2'-amino-5',5'-difluoro-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'-[1,3]oxazine] yl)chloropicolinamide, 15 (R)-N-(2'-amino-5',5'-difluoro-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'-[1,3]oxazine] yl)cyanopicolinamide, (R)-N-(2'-amino-5',5'-difluoro-4,4-dimethyl-3,4,5',6'-tetrahydro-2H-spiro[naphthalene-1,4'- [1,3]oxazine]yl)cyanopicolinamide, (R)-N-(2-amino-5,5-difluoro-5,6-dihydrospiro[[1,3]oxazine-4,4'-thiochroman]-6'-yl) 20 chloropicolinamide, (R)-N-(2-amino-5,5-difluoro-5,6-dihydrospiro[[1,3]oxazine-4,4'-thiochroman]-6'-yl) cyanopicolinamide, (R)-N-(2'-amino-5',5'-difluoro-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazine]yl) chloropicolinamide, 25 (R)-N-(2'-amino-5',5'-difluoro-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazine]yl) cyanopicolinamide, (R)-N-(2'-amino-5',5'-difluoro-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazine]yl)chloro-1H- pyrazolecarboxamide, (R)-N-(3'-amino-6',6'-difluoro-3,4,6',7'-tetrahydro-2H,2'H-spiro[naphthalene-1,5'- 30 [1,4]oxazepine]yl)cyanopicolinamide, (R)-N-(3'-amino-6',6'-difluoro-3,4,6',7'-tetrahydro-2H,2'H-spiro[naphthalene-1,5'- [1,4]oxazepine]yl)chloropicolinamide, (R)-N-(3'-amino-6',6'-difluoro-6',7'-dihydro-2'H-spiro[chroman-4,5'-[1,4]oxazepine]yl) cyanopicolinamide, (R)-N-(3'-amino-6',6'-difluoro-6',7'-dihydro-2'H-spiro[chroman-4,5'-[1,4]oxazepine]yl) chloropicolinamide, (R)-N-(3'-amino-6',6'-difluoro-6',7'-dihydro-2'H-spiro[chroman-4,5'-[1,4]oxazepine]yl)-3,5- dichloropicolinamide, 5 3-((2RS,4R)-2'-amino-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazine] yl)benzonitrile, 3-((2RS,4R)-3'-amino-6',6'-difluorophenyl-6',7'-dihydro-2'H-spiro[chroman-4,5'- [1,4]oxazepine]yl)benzonitrile, 3-[(2'R,4R)amino-5,5-difluoro-5,5'',6,6''-tetrahydro-4''H-dispiro[1,3-oxazine-4,4'-chromene- 10 2',3''-pyran]-6'-yl]benzonitrile formate, 5-((2RS,4R)-2'-amino-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazine] yl)nicotinonitrile, 5-((2RS,4R)-3'-amino-6',6'-difluorophenyl-6',7'-dihydro-2'H-spiro[chroman-4,5'- [1,4]oxazepine]yl)nicotinonitrile, 15 N-((2R or 2S,4R)-2'-amino-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'- [1,3]oxazine]yl)chloropicolinamide, N-((2R or 2S,4R)-2'-amino-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'- [1,3]oxazine]yl)cyanopicolinamide, N-((2R or 2S,4R)-2'-amino-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'- 20 [1,3]oxazine]yl)fluoropicolinamide, N-((2R or 2S,4R)-2'-amino-5',5'-difluorophenyl-5',6'-dihydrospiro[chroman-4,4'- [1,3]oxazine]yl)(trifluoromethyl)picolinamide, N-((2RS,4R)-3'-amino-6',6'-difluorophenyl-6',7'-dihydro-2'H-spiro[chroman-4,5'- [1,4]oxazepine]yl)(trifluoromethyl)picolinamide, 25 N-((2RS,4R)-3'-amino-6',6'-difluorophenyl-6',7'-dihydro-2'H-spiro[chroman-4,5'- [1,4]oxazepine]yl)cyanopicolinamide, N-[(2'R,4R)amino-5,5-difluoro-5,5'',6,6''-tetrahydro-4''H-dispiro[1,3-oxazine-4,4'-chromene- 2',3''-pyran]-6'-yl]cyanopyridinecarboxamide, N-[(4R)amino-5,5-difluoro-1',1'-dioxido-2',3',5,6-tetrahydrospiro[1,3-oxazine-4,4'- 30 thiochromen]-6'-yl]chloropyridinecarboxamide, and N-[(4R)amino-5,5-difluoro-1',1'-dioxido-2',3',5,6-tetrahydrospiro[1,3-oxazine-4,4'- thiochromen]-6'-yl]cyanoopyridinecarboxamide, or a pharmaceutical acceptable salt thereof.
18. A compound according to any of claims 1-17, selected from the group consisting of (R)-N-(2'-amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]yl) cyanopicolinamide, (R)(5-chloropyridinyl)-5',5'-difluoro-5',6'-dihydrospiro[chroman-4,4'-[1,3]oxazin]-2'-amine, 5 (R)-N-(2'-amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]yl) chloropicolinamide, and (R)-N-(2'-amino-5',5'-difluoro-2,3,5',6'-tetrahydrospiro[indene-1,4'-[1,3]oxazine]yl) fluoropicolinamide, or a pharmaceutical acceptable salt thereof. 10
19. A process for preparing a compound of formula I as defined in any of claims 1 to 16, which process comprises reacting a compound of formula I’ to a compound of formula I Z-COOH N H N 3 R Y 3 I' I 1 2 3 4 5 6 wherein V, W, Y, Z, n, p, R , R , R , R , R and R are as defined in any of claim 1 to 16 and m is 1. 15
20. A compound of formula I according to any of claims 1-18, whenever prepared by a process as defined in claim 19.
21. A compound of formula I according to any of claims 1-18 for use as therapeutically active substance.
22. A compound of formula I according to claims 1-18 for the use as therapeutically active 20 substance for the therapeutic and/or prophylactic treatment of diseases and disorders characterized by elevated β-amyloid levels and/or β-amyloid oligomers and/or β-amyloid plaques and further deposits or Alzheimer's disease.
23. A compound of formula I claims 1-18 for the use as therapeutically active substance for the therapeutic and/or prophylactic treatment of diabetes or type 2 diabetes.
24. A pharmaceutical composition comprising a compound of formula I according to any of claims 1-18 and a pharmaceutically acceptable carrier and/or a pharmaceutically acceptable auxiliary substance.
25. Use of a compound of formula I according to any of claims 1-18 for the manufacture of a 5 medicament for the therapeutic and/or prophylactic treatment of Alzheimer's disease.
26. Use of a compound of formula I according to any of claims 1-18 for the manufacture of a medicament for the therapeutic and/or prophylactic treatment of diabetes.
27. A process according to claim 19 for preparing a compound of formula I substantially as herein described with reference to any example thereof. 10
28. A pharmaceutical composition according to claim 24 substantially as herein described with reference to any example thereof.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP11167835.5 | 2011-05-27 | ||
EP11167835 | 2011-05-27 | ||
PCT/EP2012/059688 WO2012163790A1 (en) | 2011-05-27 | 2012-05-24 | Spiro-[1,3]-oxazines and spiro-[1,4]-oxazepines as bace1 and/or bace2 inhibitors |
Publications (2)
Publication Number | Publication Date |
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NZ616817A NZ616817A (en) | 2015-12-24 |
NZ616817B2 true NZ616817B2 (en) | 2016-03-30 |
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