NZ619258B2 - Phenyl-3-aza-bicyclo[3.1.0]hex-3-yl-methanones and the use thereof as medicament - Google Patents

Phenyl-3-aza-bicyclo[3.1.0]hex-3-yl-methanones and the use thereof as medicament Download PDF

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NZ619258B2
NZ619258B2 NZ619258A NZ61925812A NZ619258B2 NZ 619258 B2 NZ619258 B2 NZ 619258B2 NZ 619258 A NZ619258 A NZ 619258A NZ 61925812 A NZ61925812 A NZ 61925812A NZ 619258 B2 NZ619258 B2 NZ 619258B2
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Barbara Bertani
Marco Ferrara
Riccardo Giovannini
Iain Lingard
Rocco Mazzaferro
Holger Rosenbrock
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Boehringer Ingelheim International Gmbh
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    • 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
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/52—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring condensed with a ring other than six-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 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
    • C07D413/04—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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

Provided are phenyl-3-aza-bicyclo[3.1.0]hex-3-yl-methanone derivative compounds of general formula (I), wherein the variables are as described in the specification. Examples of the compounds include [5-Methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[1-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)-3-aza-bicyclo[3.1.0]hex-3-yl]-methanone and [5-Methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy) phenyl]-{1-[5-(3-methyl-oxetan-3-yl)-[1,2,4]oxadiazol-3-yl]-3-aza-bicyclo[3.1.0]hex-3-yl}-methanone. The compounds are glycine transporter-1 (GlyT1) inhibitors. The compounds may be useful in the treatment of the positive and negative symptoms of schizophrenia as well as cognitive impairments associated with schizophrenia, Alzheimer’s disease and other neurological and psychiatric disorders. -3-yl)-3-aza-bicyclo[3.1.0]hex-3-yl]-methanone and [5-Methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy) phenyl]-{1-[5-(3-methyl-oxetan-3-yl)-[1,2,4]oxadiazol-3-yl]-3-aza-bicyclo[3.1.0]hex-3-yl}-methanone. The compounds are glycine transporter-1 (GlyT1) inhibitors. The compounds may be useful in the treatment of the positive and negative symptoms of schizophrenia as well as cognitive impairments associated with schizophrenia, Alzheimer’s disease and other neurological and psychiatric disorders.

Description

Phenylaza-bicyclo[3.1.0]hexyl-methanones and the use thereof as medicament The present inventions relate to substituted aza-bicyclo[3. l .0]heXyl- methanones of general formula (I) N R7 R2 R1 wherein l 2 3 4 5 6 . . .
R R R R R and R are as here1n descr1bed or salts thereof, preferably pharmaceutl- , , , , cally acceptable salts thereof.
The invention r relates to the manufacture of said compounds, pharmaceutical com- positions comprising a compound according to general formula (I), and the use of said compounds for the treatment of various conditions such as conditions concerning positive and negative ms of schizophrenia as well as ive impairments associated with schizophrenia, Alzheimer’s Disease and other neurological and psychiatric disorders.
The compounds ofthe invention according to general formula (I) show glycine transporter- l (GlyTl) inhibiting properties.
Another subject ofthe present invention concerns intermediates for the manufacture of the pharmaceutically active nds ofthe invention.
BACKGROUND OF THE INVENTION A general overview ofthe role of glycine transporter-l (GlyTl) inhibitors for the treatment of diseases can be taken for example from W02010/086251. This role of glycine transpor- ter-l (GlyTl) inhibitors is applicable for the present invention as well. In the following section, which is printed in italics, pages 1 to 4 of WO2010/086251 will be cited in parts, literally or modified and wherever considered appropriate fiarther details, which are known in the art, are added, in order to e state of the art background information for the present invention: phrenia is a progressive and devastating psychiatric disease characterized by epi- sodic positive symptoms such as delusions, hallucinations, thought disorders andpsychosis and persistent negative symptoms such as flattened aflect, impaired attention and social withdrawal, and cognitive impairments (Lewis DA and Lieberman JA, 2000, Neuron, 28: 325-33). For decades research has d on the inergic hyperactivity" hypothe- sis which has led to therapeutic interventions involving blockade of the nergic sys- tem (Vandenberg RJ and Aubrey KR, 2001, Exp. Opin. Ther. Targets, 5(4): 507-518; Na- kazato A and Okuyama S, et al., 2000, Exp. Opin. Ther. Patents, 10(1): 75-98). However, this pharmacological approach does not eflectively treat negative and cognitive symptoms which are the best predictors tional outcome (Sharma T., 1999, Br. J. Psychiatry, ppl. 28).‘44-5I).
A complementary model of schizophrenia was proposed in the mid-1960’ based upon the psychotomimetic action caused by the blockade ofthe glutamate system by compounds like phencyclidine (PCP) and related agents (e.g. ne) which are non-competitive anta- gonists of the glutamate N—methyl—D-aspartate (NMDA) receptor. Interestingly in y volunteers, PCP-inducedpsychotomimetic action incorporates positive and negative symp- toms as well as cognitive dysfunction, thus y resembling phrenia in patients (Javitt DC et al., 1999, Biol. Psychiatry, 453668-679; see also Jentsch and Roth, 1999, sychopharmacology 20:201-225. Therefore, sing NMDA-receptor neuro- transmission in the l nervous system oflers an opportunityfor the development of novel treatment approachesfor schizophrenia and also other neurological and psychiatric diseases related to NMDA-receptor and/or glutamatergic dysfunction. The NMDA- or is a ligand-gated ion channel composed of a combination of two NR] and two NR2 subunits and requires the concomitant binding of glutamate at the NR2 subunit and glycine as a co-agonist at the NR1 subunit to be activated (Johnson and , 198 7, Na- ture 325:529-531). While glutamate is ed in an activity-dependent mannerfrom syn- aptic terminals, glycine is apparently present at a more constant level and seems to mod- ulate/control the orfor its response to glutamate. One of the most efi’ective ways to control synaptic concentrations of neurotransmitter is to influence their re-uptake at the synapses. In forebrain areas like prefrontal andfrontal cortex, hippocampus, striatum and us, glycine has been shown to be necessary for atergic NMDA-receptor ac- tivity and to modulate NMDA-receptor dependent excitatory neurotransmission (Johnson and Ascher, 1987, Nature 325: 529-531; Danysz and Parsons, 1998, Pharmacol. Rev. 50.‘ 597-664). The ability ofglycine to modulate NMDA-receptor ed neurotransmis- sion suggests that pharmacological manipulation ofsynaptic glycine could prove eflective in the ent of conditions involving a hypofunction of the NMDA-receptor such as schizophrenia. Thus, one strategy to enhance NMDA receptor activity is to e the gly- cine concentration in the local microenvironment of synaptic NMDA receptors by inhibi- tion of GlyTI (Bergeron R. et al., 1998, Proc. Natl. Acad. Sci. USA 95:15730—15734). In fact, clinical studies with direct glycine site agonists D-serine and a prototype GlyTI- inhibitor, sarcosine, which increases glycine in the synaptic cleft, have demonstrated some efi’icacyfor the treatment of negative symptoms and to a lesser extent, positive and cogni- tive symptoms zophrenia (Tsai et al., 2004, Biol. Psychiatry 44:1081-1089,‘ Lane et al., 2005, Biol. Psychiatry 6339-12). Recently, clinical efi’icacy regarding negative symp- toms in schizophrenia patients was reported for the GlyTI—inhibitor RG1678 tested in a clinical phase II trial as adjunctive treatment to marketed antipsychotics (Umbricht et al., 2011, Schizophr. Bull. pl.1).‘324).
Efi’icacy in various animal models/tests for positive and negative symptoms ofschizophre- nia as well as in l memory tasks has been reported in the literature for difi’erent GlyTI—inhibitors. In detail, the ive GlyTI—inhibitors 734 and SSR103800 were shown to be efi’icacious in two modelsfor antipsychotic ty, i.e. reversal of NMDA-receptor antagonist induced hyperlocomotion andpre-pulse-inhibition, well known models for positive symptoms of schizophrenia rtere et al., 2005, Neuropsycho- pharmacology 63-1985; Boulay et al., 2008, Pharmacol. Biochem. Behav. 91:47-58).
Regarding negative symptoms, SSR504 734 was demonstrated to increase dopamine in the prefrontal cortex, a mechanistic in-vivo model for negative symptoms in schizophrenia rtere et al., 2005, Neuropsychopharmacology 30:1963-1985). Regarding memory enhancement, both GlyTI—inhibitors were efi’icacious in the social recognition test (De- poortere et al., 2005, Neuropsychopharmacology 30:1963-1985,‘ Boulay et al., 2008, Pharmacol. Biochem. Behav. 91:47-58). Another GlyTI-inhibitor, NFPS, was shown to be active in the object recognition and social recognition test regarding reversal ofMK induced cognitive deficits (Karasawa et al., 2008, Behav. Brain Res. 186378-83; Shimaza- ki et al., 2010, Psychopharmacology 209:263-2 70). In addition, an enhancing efi’ect on long-term potentiation in hippocampal slices could be shown with NFPS demonstrating that inhibition of GlyTI leads to strengthening of synaptic plasticity which is crucial for formation on a ar level y et al., 2003, J. Neurosci. 23:7586-7591). In fact, glutamate neurotransmission, in ular NMDA or ty, plays a critical role in synaptic plasticity, learning and , such as the NMDA receptors appears to serve as a graded switch for gating the threshold ofsynaptic plasticity and memoryforma- tion (Bliss TVand gridge GL, 1993, Nature, 361331-39).
In addition, GlyTI-inhibitors were shown to be efiicacious in animal models ofdepression, anxiety and sleep, such as chronic mild stress, ultrasonic distress calls in rat pups and in- creased latency ofparadoxical sleep (Depoortere et al., 2005, Neuropsychopharmacology :1963-1985).
Two distinct glycine transporter genes have been cloned (GlyTI and GlyT2) from mamma- lian brain, which give rise to two orters with-50 % amino acid sequence homology.
GlyTI presents four isoforms arising from alternative splicing and alternative promoter usage (la, lb, Ic and ld). Only two of these isoforms have beenfound in rodent brain (GlyT- la and GlyTlb). GlyT2 also presents some degree of heterogeneity. Two GlyT2 isoforms (2a and 2b) have been identified in rodent brains. GlyTI is known to be located in CNS and in some peripheral s, whereas GlyT2 is specific to the CNS, primarily in the hindbrain and spinal cord (Zafra et al., 1995, J. Neurosci. 153952-3969). GlyTI is ex- 2012/065140 pressed in glia and neurons, and it isfound to be d at glutamatergic synapses (Cube- los et al., 2005, Cereb. Cortex 153448-459).
Glycine transporter inhibitors are suitable for the ent of neurological and psychia- tric disorders. The majority ofdiseases states implicated are psychoses, schizophrenia (Armer RE and Miller D], 2001, Exp. Opin. Ther. Patents 11: 563-5 72), psychotic mood ers such as severe major depressive disorder, mood disorders associated with psy- chotic disorders such as acute mania or depression, associated with bipolar ers and mood disorders, ated with schizophrenia, (Pralong ET et al., 2002, Prog. Neuro- biol., 67:] 73-202), autistic disorders (Carlsson ML, 1998, J. Neural Trans. [05:525-535), cognitive disorders such as ias, ing age related dementia and senile dementia ofthe Alzheimer type, memory disorders in a mammal, including a human, attention deficit disorders and pain (Armer RE and Miller D], 2001, Exp. Opin. Ther. Patents, 11:563- 72).
Thus, increasing activation ofNMDA receptors via GlyTI inhibition may lead to agents that treat psychosis, schizophrenia (positive, negative and cognitive symptoms), dementia and other diseases in which cognitive ses are impaired, such as attention deficit dis- orders, Alzheimer's disease, or other neurological and psychiatric disorders.
All these concepts to medicinally benefit from the inhibition of GlyTl are of high interest, in particular with respect to cognitive impairment associated with Alzheimer’s disease or Schizophrenia.
BRIEF SUMMARY OF THE INVENTION The t inventions relate to substituted phenylaza-bicyclo[3. l .0]heXyl- methanones of general formula (I) N R7 R2 R1 wherein 1 2 3 4 5 6 7 R , R , R , R , R , R and R are as herein described or salts thereof, preferably a pharmaceutically acceptable salt thereof.
The invention further s to the manufacture of said active compounds, pharmaceutical compositions comprising a compound according to general a (I), and the use of said active nds for the treatment of various conditions such as conditions concerning positive and negative symptoms of schizophrenia as well as cognitive impairments associated with schizophrenia, Alzheimer’s Disease and other neurological and psychiatric disorders.
The use comprises the manufacture of medicaments for the treatment of the corresponding According to a first aspect of the present invention there is provided a compound of general formula (I) or a salt thereof N R7 R2 R1 wherein R is ed from the group of (10728446_1):JJC a) 5 or 6 membered monocyclic heteroaryl, having 1, 2, 3 or 4 heteroatoms independently selected from the group of O, N and S(O)r, b) 5 or 6 ed clic partially saturated heterocycloalkyl, having 1, 2 or 3 heteroatoms independently selected from the group of O, N and S(O)r, and c) 9 or 10 membered bicyclic heteroaryl, having 1, 2 or 3 heteroatoms independently selected from the group of O, N and S(O)r, wherein r is 0, 1 or 2; wherein each of said groups a), b) and c) is optionally substituted with 1 or more substituents ndently selected from the group of C1alkyl-, C1alkyl-O-, yl, tetrahydrofuranyl, tetrahydropyranyl, C3cycloalkyl- and C3cycloalkyl-O- and in case a substituent is attached to a nitrogen ring atom said substituent is selected from the group of C1alkyl-, C1alkyl-CO-, C3cycloalkyl- and C3cycloalkyl-CO-, and wherein each of said C1alkyl-, C1alkyl-O-, C1alkyl-CO-, yl, tetrahydrofuranyl, tetrahydropyranyl, C3cycloalkyl-, C3cycloalkyl-CO- or C3 cycloalkyl-O- substituents may be substituted by 1 or more substituents independently selected from the group of fluoro, -CF3, -CHF2, -CH2F and –CN; R is selected from the group of hydrogen, C1alkyl-, C1alkyl-O-, -CN and C3 lkyl-, wherein each of said C1alkyl-, C1alkyl-O- and C3cycloalkyl-group may be optionally substituted with 1, 2, 3 or more substituents independently selected from the group of fluoro, -CF3, -CHF2, -CH2F and -CN; R is selected from the group of C1alkyl-O-, C3cycloalkyl-O-, morpholino, pyrazolyl and a 4 to 7 membered, monocyclic cycloalkyl-O- with 1 oxygen atom as ring member and ally 1 or 2 heteroatoms independently selected from the group of O, N and S(O)s with s = 0,1 or 2, , (10728446_1):JJC wherein said C1alkyl-O- and said C3cycloalkyl-O- may be optionally substituted with 1, 2, 3 or more substituents independently selected from the group of , -CF3, -CHF2, -CH2F, -CN, C1alkyl-, C3cycloalkyl-, C1alkyl-O- and C3cycloalkyl-O-; R is hydrogen; 3 4 or R and R together with the ring atoms of the phenyl group to which they are bound may form a 4, 5 or 6 membered, monocyclic, partially saturated heterocycloalkyl or a heteroaryl each of which having 1, 2 or 3 heteroatoms ndently selected from the group of O, N and S(O)s with s = 0, 1 or 2, n there must be 1 ring oxygen atom that is directly attached to the ring carbon atom of said phenyl group to which R is attached to in general formula (I); wherein said heterocycloalkyl group may be optionally substituted with 1, 2, 3 or more substituents independently selected from the group of fluoro, -CF3, -CHF2, -CH2F, -CN, C1alkyl-, C3cycloalkyl-, C1alkyl-O-, C3cycloalkyl-O-, oxetanyl-O-, ydrofuranyl-O- and tetrahydropyranyl-O-; R is hydrogen; R is selected from the group of hydrogen, C1alkyl-SO2-, C3cycloalkyl-SO2- and -CN; R is hydrogen; 6 7 6 5 or one of the pairs a) R and R or b) R and R form er with the ring atoms of the phenyl group to which they are bound, a 5 or 6 membered, partially saturated monocyclic cycloalkyl group having 1, 2 or 3 heteroatoms independently selected from the group (10728446_1):JJC of O, N and S(O)u with u = 0, 1 or 2, n there must be 1 -SO2- member that is directly attached to the ring carbon atom of said phenyl group to which R is attached to in general formula (I), wherein said heterocycloalkyl group may be optionally substituted with 1, 2, 3 or more substituents independently selected from the group of fluoro, -CF3, -CHF2, -CH2F, -CN, C1alkyl-, C1alkyl-O- and C3cycloalkyl-O-; 6 7 6 5 or one of the pairs a) R and R or b) R and R form together with the ring atoms of the phenyl group to which they are bound a partially ted monocyclic heterocycloalkyl group having 1, 2 or 3 heteroatoms independently selected from the group of O, N and S(O)u with u = 0, 1 or 2, wherein there must be 1 -SO2- member that is directly ed to the ring carbon atom of said phenyl group to which R is attached to in general formula (I), wherein said heterocycloalkyl group may be optionally substituted with 1, 2, 3 or more substituents independently selected from the group of fluoro, -CF3, -CHF2, -CH2F and - C1alkyl-. ing to a second aspect of the present invention, there is provided a compound of the formula 3 3 F F O O O O 2 F F 2 F H N H N 1 1 N O S O N O S O F N N F O O F F F F (10728446_1):JJC 3 3 F F O O O O F F F 2 2 F H N H N 1 1 F N O S O N O S O F N N F , 3 3 F F O O O O 2 F F 2 F H N H N 1 1 N O S O O O S O N N O , F F , 3 3 F F O O O O F F 2 F 2 F H N H N 1 1 N O S O N O S O N N 446_1):JJC 3 3 F F O O O O F F 2 F 2 F H N H N 1 1 N O S O N O S O 3 3 F F O O O O F F F 2 2 F H N H N 1 1 N O S O N O S O S N , , 3 3 F F O O O O F F F 2 2 F H N H N 1 1 O S O N O S O N F F S F F , 446_1):JJC 3 3 F F O O O O F F 2 F 2 F H N H N 1 1 N O S O O S O F O F N F F , F , 3 3 F F O O O O F F 2 F 2 F H N H N 1 1 N O S O N O S O O N 3 3 F F O O O O F F F 2 2 F H N H N 1 1 O O S O O O S O F N N F , 446_1):JJC 3 3 F F O O O O F F F 2 2 F H N H N 1 1 O S O N F N F N N F O F O F , F , 3 3 F F O O O O F F F 2 2 F H N H N 1 1 O S O N O S O N N O F O , F F , 3 3 F F O O O O F F F 2 2 F H N H N 1 1 N O S O N O S O N F N O F N F F F F , 446_1):JJC O O 3 2 O O H N F 2 F H N N O S O 1 F N N O S O F O N F , O , O O O O 2 F 2 H N H N 1 1 N O S O N O S O F N F O F F F , 3 3 F F O O F O O F 2 F 2 F H N H N 1 1 N O S O N O S O N N F F , 446_1):JJC O O F O O F H N 2 F H N N O S O F N N O S O F O F , F F F , 3 3 F F O O F O O F 2 F 2 F H N H N 1 1 N O S O N F N N O O F O , F 3 3 F F O O F O O F 2 F 2 F H N H N 1 1 O S O O O S O N N F O F F F , F , 446_1):JJC 3 3 F F O O F O O F 2 F 2 F H N H N 1 1 N O S O O S O O N N O , 3 3 F F O O F O O F 2 F 2 F H N H N 1 1 N O S O O O S O N N O O N 3 3 F F O O F O O F 2 F 2 F H N H N 1 1 F O S O O O S O N F N O , F N F , 446_1):JJC O O F O O 2 F 2 H N H N 1 1 O O S O O O S O N N F F F F F F , , 3 3 F F O O F O O F 2 F 2 F H N H N 1 1 O O S O N O S O N N F O F , , O O O O 2 2 H N H N 1 1 N O S O F N O S O F N F F O O F , 446_1):JJC 3 3 F F O O F O O F 2 F 2 F H N N 1 1 F N O S O N O S O F O F N N F O F , F F F O O F N 2 F O N H N H N 1 O S O 1 F N F O N O S O F N F O , F , O O or H N F N O S O F F n said compound is selected from the group consisting of: (10728446_1):JJC the stereoisomer with R-configuration at the chiral carbon atom designated by the numeral 1 and R-configuration at the chiral carbon atom designated by the numeral the stereoisomer with S-configuration at the chiral carbon atom ated by the numeral 1 and S-configuration at the chiral carbon atom designated by the numeral the stereoisomer with R-configuration at the chiral carbon atom designated by the numeral 1 and S-configuration at the chiral carbon atom designated by the numeral the stereoisomer with S-configuration at the chiral carbon atom designated by the numeral 1 and iguration at the chiral carbon atom designated by the l wherein, in each such stereoisomer, the chiral carbon atom designated by the l 2 is always in the syn configuration with respect to the chiral carbon atom designated by the numeral 1; or a mixture of two or more of the foregoing stereoisomer.
According to a third aspect of the present invention, there is provided a pharmaceutical composition or medicament comprising a compound according to the first or second aspect above.
According to a fourth aspect of the present invention, there is provided use of a compound ing to the first or second aspect above for the manufacture of a medicament for: (a) the treatment of a CNS disease, the treatment of which is accessible by the inhibition of GlyT1, (b) the treatment of a disease that is accessible by the tion of GlyT1, (c) the treatment, amelioration or prevention of a condition selected from the group consisting of positive and negative symptoms of schizophrenia, psychoses and cognitive impairments associated with schizophrenia, mer’s Disease, mal Alzheimer’s disease, amnestic mild cognitive ment and psychiatric disorders; (10728446_1):JJC (d) the treatment of Alzheimer’s disease, prodromal mer’s disease, amnestic mild ive impairment or cognitive impairment associated with Alzheimer’s (e) the treatment of schizophrenia or cognitive impairment associated with schizophrenia, or (f) the treatment of psychoses.
According to a fifth aspect of the t invention, there is provided a compound of general formula (II), (III), (IV), (V) or (VI): PG PG PG N O N N O O R2 R2 R2 R8 OH l formula (II) general formula (III) general formula (IV) R2 O N N R2 R1 R7 OH R6 general formula (V) general formula (VI) wherein in each of those independent formulas 1 4 5 6 7 R , R , R , R , and R have the meaning as in the first or second aspect above, R in general formula (II) to (V) is selected from the group consisting of C1alkyl-, C1 alkyl-O-, -CN and C3cycloalkyl-, R in general formula (VI) is selected from the group consisting of hydrogen, C1alkyl-, C1alkyl-O-, -CN and C3cycloalkyl-, (10728446_1):JJC wherein each of said C1alkyl-, C1alkyl-O- and C3cycloalkyl-group may be optionally substituted with 1, 2, 3 or more substituents independently ed from the group of fluoro, -CF3, -CHF2, -CH2F and -CN; R is C1-4 alkyl-O-, optionally substituted by 1 or more substituents independently selected from each other from the group of fluoro, chloro, bromo, -CN, C1-4 alkyl-O-, C1-4 alkyl-, phenyl and , wherein phenyl and benzyl optionally may be tuted with one or more substituents independently selected from each other from the group of fluoro, chloro, bromo, -CN, C1-4 alkyl-O-, C1-4 alkyl-; and PG is ed from the group consisting of tert- butoxycarbonyl-, 9- fluorenylmethoxycarbonyl-, benzyl-, 2,4-dimethoxybenzyl-.
DETAILED DESCRIPTION OF THE INVENTION The present inventions relate to substituted phenylaza-bicyclo[3.1.0]hexylmethanones of general formula (I) N R7 R2 R1 (10728446_1):JJC 2012/065140 wherein 1 . . . . b R is defined according to a definition selected from a group of Rla, R1 R1c and Rld; 2 b R . . . . is defined according to a definition selected from a group of Rza, R2 and R“; R3 is defined according to a definition selected from a group of R321, R3b R3c and R“; R . . . . 4 is defined according to definition R a; 3 4 3/4 . . . or R and R together are defined according to ion R. which is se-. lected from the group of R3/4a, R3/4b and ; R . . . . 5 is defined according to definition R a; R6 is defined according to a definition ed from a group of R621, R6 and R“; 7 . . . . 7 R is defined according to definition R a; or one of the pairs a) R6 and R7 or b) R6 and R5 er are defined according . . 5/6/7 5/6/7a . to definition R which is selected from the group ofR. and R5/6/7b; and Wherever appropriate the salts, preferably pharmaceutically acceptable salts, solvates and the so lvates of the salts thereof.
Definitions of tuents according to general formula 11) Definitions for R. .
Rla: R1 is selected from the group of a) 5 or 6 membered nionocyclic heteroaryl, having 1, 2, 3 or 4 heteroatonis indepen- dently selected from the group of O, N and S(O)r, b) 5 or 6 membered nionocyclic partially ted heterocycloalkyl, having 1, 2 or 3 heteroatonis independently selected from the group of O, N and S(O)r, and c) 9 or 10 membered bicyclic heteroaryl, having 1, 2 or 3 heteroatonis independently selected from the group of O, N and S(O)r, wherein r is 0, l or 2; wherein each of said groups a), b) and c) is optionally substituted with l or more substitu- ents independently selected from the group of C1_4-alkyl-, lkyl-O-, oxetanyl, tetra- hydrofilranyl, tetrahydropyranyl, C3_6-cycloalkyl- and C3_6-cycloalkyl-O- and in case a substituent is attached to a nitrogen ring atom said tuent is selected from the group of C1_4-alkyl-, lkyl-CO-, C3_6-cycloalkyl- and ycloalkyl-CO-, and wherein each of said C1_4-alkyl-, C1_4-alkyl-O-, C1_4-alkyl-CO-, oxetanyl, tetrahydro- furanyl, tetrahydropyranyl, C3_6-cycloalkyl-, C3_6-cycloalkyl-CO- or C3_6-cycloalkyl-O- substituents may be substituted by l or more substituents independently other from the group of fluoro, -CF3, -CHF2, -CH2F and —CN; Examples for the 5 or 6 membered heteroaryls according to group a) in definition Rla above are: 0 H H 0 S g O\‘s’p H s @ U U N‘N \ / \ 4 U M D H H H o S \ , ER o\ 0‘ ,o\ \ \ /N U N\\_//N \ /N M’N M NM S O O\ S\ S\ /S\ MW N‘N N\\_//N M l—E M’N MN l—é’ WO 17657 Rlb: R1 is a 5 or 6 ed monocyclic heteroaryl, having 1, 2 or 3 heteroatoms independently selected from the group of O, N or S, wherein said heteroaryl is optionally substituted with l or more substituents independently selected from the group of C1_2-alkyl-, C1_2-alkyl-O-, oxetanyl, tetrahydrofuranyl, tetrahy- dropyranyl, ropyl-, cyclobutyl-, cyclopropyl-O- and cyclobutyl-O- and in case a substituent is attached to a nitrogen ring atom said substituent is selected from the group of C 1_2-alkyl- and C 1_2—alkyl-CO-, and wherein each of said lkyl-, lkyl-O-, C1_2-alkyl-CO-, oxetanyl, tetrahydro- fiaranyl, tetrahydropyranyl, cyclopropyl- or cyclopropyl-O- substituents may be substituted with l or more substituents independently selected from the group of fluoro, -CF3, -CHF2, -CH2F and —CN, preferably fluoro; Examples for the 5 or 6 membered heteroaryls according to group a) in definition Rlb above are: O H H O S g s \‘S” H U o o m o m oN\N @ O o o S H H H £3 \ ’ ‘ \N \N N’ \ /N U N\\_//N \ / \ N’ M LE /8\ S O S\N ”U“ M M MO\N M MS\N 1. 1 R c: R . . . 1s a 5 or 6 membered monocycllc heteroaryl be1ng selected from the group of oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, lyl, triazoyl, pyridinyl and pyrimi- dinyl, wherein said heteroaryl is optionally substituted with l or more tuents ndently selected from the group of C1_2-alkyl-, C1_2-alkyl-O-, cyclopropyl— and cyclopropyl-O- and in case it is a substituent of a nitrogen ring atom said substituent is selected from the group of C1_2-alkyl- and C1_2-alkyl-CO-, and wherein each of said C1_2-alkyl-, C1_2-alkyl-O-, C1_2-alkyl-CO-, ropyl— or cyc- lopropyl-O- substituents may be substituted with l or more substituents independently se- lected from the group of fluoro, -CF3, -CHF2, -CH2F and —CN, preferably fluoro; R d: R 1 . . . 1s a 5 or 6 membered monocycllc heteroaryl be1ng selected from the group of oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl and pyrimidinyl, n said heteroaryl is optionally substituted with l or more substituents independently selected from the group of lkyl-, C1_2-alkyl-O-, cyclopropyl-, cyclopropyl-O- and in case it is a substituent of a nitrogen ring atom is selected from the group of C1_2-alkyl- and C1_2-alkyl-CO-, and n each of said C1_2-alkyl-, C1_2-alkyl-O-, C1_2-alkyl-CO-, , cyclobutyl, cyclo- propyl—O- or cyclobutyl-O- substituents may be substituted with l or more tuents in- dependently selected from the group of fluoro, -CF3, -CHF2, -CH2F and —CN, preferably fluoro ; -1]- Definitions for R2 R221: R2 is selected from the group of hydrogen, C1_4-alkyl-, C1_4-alkyl-O-, -CN and C3_6-cycloalkyl-, wherein each of said C1_4-alkyl-, C1_4-alkyl-O- and C3_6-cycloalkyl-group may be option- ally tuted with l, 2, 3 or more substituents independently ed from the group of fluoro, -CF3, -CHF2, -CH2F and -CN; R2b: R2 is selected from the group of hydrogen, methyl, ethyl, methoxy, ethoxy, - CN and ropyl-, wherein each of said groups may be optionally substituted with l, 2 or 3 substituents inde- pendently selected from the group of fluoro, -CF3, -CHF2, -CH2F and -CN; RR: R2 is hydrogen or methyl; R“: R2 is en; Definitions for R3 R321: R3 is selected from the group of C1_6-alkyl-O-, C3_6-cycloalkyl-O-, morpholi- no, pyrazolyl and a 4 to 7 membered, monocyclic heterocycloalkyl-O- with 1 oxygen atom as ring member and optionally l or 2 heteroatoms independently selected from the group of O, N and S(O)S with s = 0,1 or 2, ably with 1 oxygen atom as the only heteroatom in said heterocycloalkyl—O- ring, wherein said C1_6-alkyl-O- and said C3_6-cycloalkyl-O- may be optionally substituted with l, 2, 3 or more tuents independently selected from the group of fluoro, -CF3, -CHF2, -CH2F, -CN, C1_4-alkyl-, C3_6-cycloalkyl-, C1_6-alkyl-O- and C3_6-cycloalkyl-O-; 2012/065140 R3b: R3 is ed from the group of C1_6-alkyl-O-, oxetanyl-O-, tetrahydrofuranyl-O-, tetrahydropyranyl-O- wherein said C1_6-alkyl-O-, oxetanyl-O-, tetrahydrofuranyl-O-, te- trahydropyranyl-O-may be optionally tuted with 1, 2 or 3 substituents independently selected from the group of fluoro, -CF3, -CHF2, -CH2F, -CN, lkyl and C1_6-alkyl-O- R3c: R3 is selected from the group of C1_3-alkyl-O-, oxetanyl-O-, tetrahydrofuranyl-O- and tetrahydropyranyl-O-, wherein said C1_3-alkyl-O-, oxetanyl-O-, tetrahydrofuranyl-O-, tetrahydropyranyl-O-may be optionally substituted with 1, 2 or 3 substituents independent- ly selected from the group of fluoro and -CF3; R“: R3 is selected from the group of R-l,l,l-trifluoroethoxy and l-trifluoro ethoxy and isopropOXy; whenever R3 is a representative of a member of the group selected from C1_6-alkyl-O-, a C3_6-cycloalkyl-O- or the 4 to 7 membered, monocyclic heterocycloalkyl—O- and if there is a substituent selected from the group of C1_6-alkyl-O- or ycloalkyl-O- substituent, said substituent preferably is not attached geminal to the “oxy” group () by which said R3 is connected to the remaining part of the molecule. Specifically, if R3 is a heterocyc- loalkyl—O- with l or more oxygen atom(s) as ring member, such as oxetanyl-O-, tetrahy- drofiJranyl-O-, tetrahydropyranyl-O-, i.e. as defined in R321, R3b, R3c’ an oxygen atom that is a ring member preferably shall not be directly attached to said carbon atom to which the oxy substituent is bound by which said heterocycloalkyl-O- is attached to the group to which it is a substituent in order to avoid a geminal diether motif.
In case of oxetanyl-O- the preferred isomer is always 3-oxetanyl—O-, in case of tetrahydro- filranyl-O- the preferred isomer is always 3-tetrahydrofi1ranyl and in case oftetrahydropyranyl-O- the preferred isomers are always 3- or 4- tetrahydropyranyl-O-.
The analogue principle shall apply in case of other heteroatoms in a heterocycloalkyl-O- group.
Definitions for R. .
R4°a: R4 is hydrogen Definitions for R3/4 R3/4a: R3 and R4 together with the ring atoms of the phenyl group to which they are bound may form a 4, 5 or 6 membered, monocyclic, partially saturated heterocycloalkyl or a heteroaryl each ofwhich having 1, 2 or 3 heteroatoms ndently selected from the group of O, N and S(O)S with s = 0, l or 2, wherein there must be 1 ring oxygen atom that is directly attached to the ring carbon atom of said phenyl group to which R3 is attached to in general a (I); wherein with respect to oxetanyl-O- the preferred isomer is 3-oxetanyl-O-, with respect to tetrahydrofiJranyl-O- the preferred isomer is 3-tetrahydrofi1ranyl and with respect to tetrahydropyranyl-O- the preferred isomers are 3- or 4- tetrahydropyranyl- wherein said heterocycloalkyl group may be ally substituted with l, 2, 3 or more tuents ndently selected from the group of fluoro, -CF3, -CHF2, -CH2F, -CN, C1_4-alkyl-, C3_6-cycloalkyl-, C1_6-alkyl-O-, C3_6-cycloalkyl-O-, oxetanyl-O-, tetrahydro- filranyl-O- and tetrahydropyranyl-O-; 2012/065140 R3/4b: R3 and R4 together with the ring atoms of the phenyl group to which they are bound may form a 4, 5 or 6 membered, monocyclic, partially saturated heterocycloalkyl group having 1 or 2 oxygen atoms, wherein 1 ring oxygen atom is directly attached to the ring carbon atom of said phenyl group to which R3 is attached to in l formula (I); wherein said heterocycloalkyl group may be optionally substituted with l, 2, 3 or more substituents independently selected from the group of fluoro, -CF3, -CHF2, -CH2F, -CN, C1_3-alkyl-, cyclopropyl-, C1_3-alkyl-O- and cyclopropyl—O-; R3/4c: R3 and R4 together with the ring atoms of the phenyl group to which they are bound may form a oxetan—, tetrahydrofilran-, tetrahydropyran- or dioxolan-group, n l oxy- gen atom is directly attached to the ring carbon atom of said phenyl group to which R3 is attached to in general formula (I); wherein said oxetan—, ydro fiaran—, tetrahydropyran- or dioxolan-group, may be op- tionally substituted with l, 2, 3 or more substituents independently selected from the group of fluoro, -CF3, -CHF2, -CH2F, -CN, C1_3-alkyl-, cyclopropyl-, C1_3-alkyl-O and cyclo- pr0py1-O-; . . 5 Definitions for R R521: R5 is hydrogen; ions for R6 R621: R6 is selected from the group of hydrogen, C1_4-alkyl-SOz-, C3_6-cycloalkyl-SOz- and -CN; 2012/065140 R6b: R6 is selected from the group of C1_4-alkyl-SOz- and -CN; R“: R6 is selected from the group of methyl-SOz-, ethyl-SOz-g CN; preferably being se- lected from the group of methyl-SOz- and ethyl-SOz-g . . 7 Definitions for R R721: R7 is hydrogen Definitions for R5/6/7 R5/6/7a: one of the pairs a) R6 and R7 or b) R6 and R5 form together with the ring atoms of the phenyl group to which they are bound, a 5 or 6 membered, partially saturated mo- nocyclic heterocycloalkyl group having 1, 2 or 3 heteroatoms independently selected from the group of O, N and S(O)u with u = 0, l or 2, wherein there must be 1 -SOZ- member that is directly ed to the ring carbon atom of said phenyl group to which R6 is attached to in general formula (I), wherein said heterocycloalkyl group may be optionally substituted with l, 2, 3 or more substituents independently ed from the group of fluoro, -CF3, -CHF2, -CH2F, -CN, C1_4-alkyl-, C1_6-alkyl-O- and C3_6-cycloalkyl-O-; R5/6/7b: one of the pairs a) R6 and R7 or b) R6 and R5 form together with the ring atoms of the phenyl group to which they are bound, a 5 or 6 membered, lly ted mo- nocyclic heterocycloalkyl group having 1, 2 or 3 heteroatoms independently selected from the group of O, N and S(O)u with u = 0, l or 2, wherein there must be 1 -SOZ- member that is directly attached to the ring carbon atom of said phenyl group to which R6 is attached to in general formula (I), wherein said heterocycloalkyl group may be optionally substituted with l, 2, 3 or more substituents independently selected from the group of fiuoro, -CF3, -CHF2, -CH2F and - C1_4-alkyl-,.
Embodiments according to the invention General remark: 1 2 Substituents are defined herein as R. . R . . . etc. The ions for these substituents are ab- breviated by the name ofthe substituent directly followed by a superscript Latin .
To illustrate this princ1ple, the herein irrelevant tuent R shall be taken as an exam- . . . . . . 0 . 0a ple: If the corresponding definition for said substituent is “R is as defined by R “, the . . . 0a wording means that the definition R applies in order to define substituent R. . . 0 If R021 defines: R0 is hydrogen, then the term “R0 is as defined by Roa“ is to be read “R0 is hydrogen”.
Embodiment l g genius 1 A compound according to general formula (I), n R . is as defined by Rla; R2 is as defined by Rza; R3 is as defined by R3a, preferably R3b; more preferably R3c, more preferably R“; R4 . 4 is defined by R a; 3/421 or R3 and R4 er are as defined by ; . . . . 521 R is defined according to definition R ; R6 is as defined by R621; R7 is as defined by R”; W0 2013/017657 or one of the pairs a) R6 and R7 or b) R6 and R5 together are defined by R5/6/7a; prefera- bly by R5/6/7b; and er appropriate a specific diastereoisomer or a mixture thereof, a salt, preferably a pharmaceutically able salt, a solvate and the solvate of a salt thereof.
Embodiment 2 ggenius) A compound according to general formula (I), wherein R1 is as defined by Rlb R is as defined by RZb; preferably by ch R3 is as defined by R3b; ably by R3c R is as defined by R421 or R3 and R4 together are as defined by R3/4b; R5 a is as defined according to definition R R6 is as defined by R621; preferably R6b R7 is as defined by R721 and Wherever appropriate a specific diastereoisomer or a mixture thereof, a salt, preferably a ceutically acceptable salt, a solvate and the solvate of a salt thereof Embodiment 3 according to the invention 1genius) A compound according to general formula (I), wherein R1 is as defined by R1c R is as defined by RZb; preferably by ch R3 is as defined by R3b; preferably by R3c R is as defined by R421 or R3 and R4 together are as defined by R3/4c; . . . . 5 R 1s as defined 1ng to definition R a; WO 17657 R6 is as defined by R6a; preferably R6b; more preferably R“; R7 is as defined by R”; and Wherever appropriate a specific diastereoisomer or a mixture thereof, a salt, preferably a pharmaceutically acceptable salt, a e and the e of a salt thereof Embodiment 4 according to the invention 1genius) A compound according to general formula (I), wherein R1 is as defined by Rld; R2 is as defined by R“, preferably R“; R3 is as defined by R3b; preferably by R3c; R4 . 4 1s as defined by R a; 3/4c or R3 and R4 together are as defined by ‘ R5 is as defined according to definition Rsa; R6 is as defined by R6b; ably R“; R7 is as defined by R”; and Wherever appropriate a specific diastereoisomer or a mixture thereof, a salt, preferably a pharmaceutically acceptable salt, a solvate and the solvate of a salt thereof Embodiment 5 according to the invention 1genius) A compound according to general formula (I), n R1 is as defined by Rld; 2 . 2c 2d W 1s as defined by R ; preferably as defined by R ; W . 3c 1s as defined by R ; W is as defined by R4a; . . . . 5 W 1s as defined accord1ng to defin1t1on R a; W is as defined by R6b; preferably R6c; R7 is as defined by R”; and wherever appropriate a specific diastereoisomer or a mixture thereof, a salt, ably a pharmaceutically acceptable salt, a solvate and the e of a salt thereof.
Embodiment 6 according to the invention 1genius) A compound according to general formula (I), wherein R1 is as defined by Rld; R2 is as defined by R“; R3 is as defined by R“; R4 is as defined by R421; R5 . . . . 5 is as defined according to definition R a; R6 is as defined by R6b; preferably R“; R7 is as defined by R721; and wherever appropriate a specific diastereoisomer or a mixture thereof, a salt, preferably a pharmaceutically able salt, a solvate and the solvate of a salt thereof Used Terms and Definitions General definitions Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the spe- cification, however, unless specified to the contrary, the following terms have the meaning indicated and the following tions are adhered to.
In case a compound ofthe present invention is depicted in form of a al name and as a formula in case of any discrepancy the formula shall prevail.
An asterisk is may be used in rmulas to indicate the bond which is connected to the core molecule as defined.
Scope of the term compound/ scope of a chemical structure / stereochemistry/ solvates/ hydrates Unless specifically indicated, hout the specification and the ed claims, a giv- en chemical formula or name shall ass tautomers and all stereo, optical and geome- trical isomers (e.g. enantiomers, diastereomers, E/Z isomers etc.) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diaste- reomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and es the- reof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the nd.
The terms “compound ofthe invention” or “compound according to formula (I)” and the like refer to the compounds according to general formula (I) — be it generically or specifi- cally. Such compounds are also called “active compounds”, g that they are sup- posed to be the active ingredients of medicaments or pharmaceutical compositions.
These “active compounds” shall not be mixed up with the term “intermediate compounds” as defined by the general formulas (II), (III), (IV), (V) and (VI).
Whenever the term compound is used it may be any compound or specifically an active compound, what will be t fiom the context. An intermediate compound according to the general as (II), (III), (IV), (V) and (VI) will be addressed “intermediate com- pound”. -2]- Bonds “Bonds”: Ifwithin a al formula of a ring system or a defined group a tuent is directly linked to an atom or a group like “RyR” in below formula this shall mean that the substituent is only attached to the corresponding atom. If r from another substituent like “RxR” a bond is not specifically linked to an atom of the ring system but drawn to- wards the centre of the ring or group this means that this substituent “RxR” may be linked to any meaningful atom of the ring system / group unless stated otherwise.
IIRyRII IIRXRII The bond symbol “-“ (= minus sign) or the symbol “— *” (= minus sign followed by an aste- risk sign) stands for the bond through which a tuent is bound to the corresponding remaining part of the molecule / scaffold. In cases in that the minus sign does not seem to be sufficiently clear, there may be added an asterisk to the bond symbol “-“ in order to determine the point of attachment of said bond with the corresponding main part of the molecule / scaffold.
In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for e, C1_6-alkyl means an alkyl group or radical having 1 to 6 carbon atoms. In general, for groups comprising two or more subgroups, the last named subgroup is the radical attachment point, for example, the substituent " C1_4- alkyl-O-C1_3-alkyl-" means a C1_4-alkyl-group that is bound to an oxygen that with its second valence is bound to another C1_3-alkyl-group or in other word an alkoxyalkyl group. If to a substituent a hyphen is added with a loose end, this end indicates the position of said substituent which is connected to the remaining part of the compound as defined. In the above example "C1_4-alkyl-O-C1_3-alkyl-" it is the C1_3-alkyl group that is bound to the remaining part of the compound, while the C1_4-alkyl-O- group is a substituent for the lkyl group. In the following rative examples “-CN”, “-CF3” it is the carbon atom that is attached to the remaining part of the compound. An alternative writing of the groups such as the latter two ones is: “NC-“ or “F3C-“ for addressing a C-bound cyano or romethyl-group.
Metabo lites “Metabolites” are considered derivatives of the active compounds according to the present invention that are formed in-vz‘vo. Active metabolites are such metabolites that cause a pharmacological . It will be appreciated that metabolites of the active compounds according to the t inventions are subject to the present invention as well, in particular active metabolites. gs A “Prodrug” is considered a compound that is designed to release a biologically active nd according to the present invention in-vz’vo when such prodrug is administered to a mammalian subject. Prodrugs of active compounds ing to the present invention are prepared by modifying fianctional groups present in the active compound ofthe invention in such a way that these modifications are retransformed to the original functional groups under physiological conditions. It will be appreciated that prodrugs of the compounds ac- cording to the present inventions are subject to the present invention as well.
Prevention / Prophylaxis Expressions like "prevention , laxis , prophylactic treatment" or "preventive treatment" used herein should be understood synonymous and in the sense that the risk to develop a condition mentioned before is reduced, especially in a patient having ele- vated risk for said conditions or a corresponding sis. Thus the expression "preven- tion of a disease" as used herein means the management and care of an individual at risk of developing the disease prior to the clinical onset of the disease. The purpose of prevention is to combat the development of the e, condition or er and includes the admin- istration of the active compounds to prevent or delay the onset of the symptoms or compli- cations and to prevent or delay the pment of related diseases, conditions or disord- ers. Success of said preventive treatment is reflected statistically by d incidence of said condition within a patient population at risk for this condition in comparison to an equivalent patient tion without preventive treatment.
Solvates Some ofthe compounds ofthe invention may form “solvates”. For the purposes ofthe in- vention the term “solvates” refers to those forms of the nds which form, in the so 1- id or liquid state, a complex by coordination with t molecules. Hydrates are a specif- ic form of solvates in which the coordination takes place with water. According to the present invention, the term preferably is used for solid solvates, such as amorphous or more preferably crystalline solvates.
Treatment / therapy The expression "treatment" or "therapy" preferably means therapeutic treatment of (e.g. ably human) patients having already developed one or more of said conditions in manifest, acute or chronic form, including symptomatic treatment in order to relieve symp- toms of the specific indication or causal treatment in order to reverse or partially reverse the condition or to delay the progression of the indication as far as this may be possible, depending on the ion and the severity thereof Thus the expression ment of a disease" as used herein means the management and care of a t having developed the disease, condition or disorder. The purpose of treatment is to combat the disease, ion , disorder or a symptom thereof Treatment es the stration of the active compounds to eliminate or control the disease, condition or disorder as well as to alleviate the symptoms or complications associated with the e, condition or disorder. m The following a represents the scaffold of the compounds according to the present inventions, specifically the compounds according to general formula (I), inclusively the numbering of the atoms (position numbers) in the two ring systems, the 3-aza- bicyclo[3. l .0]hexyl— ring system and the phenyl ring system: 2 4 o\ 5 4 2 1 The positions 1 and 5 of the 3-aza-bicyclo[3. l .0]hexane ring are the bridgehead positions.
Specifically R1 is ed to one of said bridgehead positions.
Salts: The active compounds of the present ion shall provide a pharmacological effect in an animal or a human being. The pharmacological effect may be provided by the l ac- tive compound or in the case of some active compound according to the invention by a salt thereof Among salt forms, pharmaceutically acceptable salts are red for the final destination of the active compound, i.e. as pharmacologically active ingredient in a drug product. The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, itions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in t with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or com- plication, and commensurate with a able benefit/risk ratio.
As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed active compounds wherein the parent compound is modified by making acid or base salts thereof Examples ofpotential pharmaceutically acceptable salts can be found in: Pharma- al salts, Berge, S.M. et al., J. Pharm. Sci., (1977), @, 1-19.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical me- thods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount ofthe appropriate base or acid in water or in an or- ganic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.
Salts of other acids than those mentioned above which for e are useful for purifying or isolating the nds ofthe present invention (e. g. trifluoro acetate salts,) also com- prise a part of the invention.
Solvates Some ofthe compounds may form “solvates”. For the purposes ofthe invention the term “solvates” refers to those forms of the compounds which form, in the solid or liquid state, a complex by coordination with solvent molecules. Hydrates are a specific form of so lvates in which the coordination takes place with water. According to the present invention, the term preferably is used for solid so lvates, such as amorphous or more preferably crystalline solvates.
Substitution The term "substituted" as used herein itly or implicitly, means that any one or more hydrogen(s) on the designated atom is replaced with a member ofthe ted group of substituents, provided that the designated atom's normal valence is not ed. In case a substituent is bound via a double bond, e.g. an oxo substituent, such tuent replaces two hydrogen atoms on the designated atom. The substitution shall result in a stable com- pound. “Stable” in the t with an active compound preferably means a nd that from a pharmaceutical point of view is chemically and physically sufficiently stable under ambient conditions in order to be used as an active pharmaceutical ingredient of a pharma- ceutical composition. If a substituent is not defined, it shall be hydrogen. By the term "op- tionally substituted" is meant that either the corresponding group is substituted or it is not.
A characterization that substituents of the same group may be “selected independently” shall mean that the corresponding substituents may be the same or may be different.
Definitions for substituents Alkyl: The term “C1_n-all<yl”, wherein n is an integer from 2 to 11, either alone or in combination with another l denotes an acyclic, saturated, branched or linear hydrocarbon radical with l to n C atoms. For example the term ll<yl es the radicals: Cl-alkyl: H3C-, C2-alkyl: H3C-CH2-, C3-alkyl: H3C-CH2-CH2-, (CH3)-, C4-alkyl: 2-CH2-CH2-, H3C-CH2-CH(CH3)-, (CH3)-CH2-, H3C- C(CH3)2-.
Cycloalkyl: The term “C3_n-cycloall<yl”, wherein n is an integer from 4 to 11, either alone or in combi- nation with another radical denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C atoms. For example the term C3_6-cycloalkyl includes cyclopropyl, cyclo- butyl, cyclopentyl and cyclohexyl.
The term "heteroaryl" means an aromatic-ring systems containing heteroatoms. A hete- roaryl comprises at least one heteroatom selected from N, O or S, wherein an atom like S may be oxidized without disturbing the aromatic ter of the ring system which is why it is referred to as S(O)r, wherein r = 0, l or 2. The ring is composed of atoms or groups of atoms such as carbon, oxygen, nitrogen, sulfur, -S(O)- or -S(O)2-. Such atoms or groups are ring members. For example, a 5 membered heteroaryl is composed by 5 such atoms/groups. The term “heteroaryl” is intended to include all the le isomeric forms.
In cases in which there is tautomeric forms are le which allow an aromatic and a non-aromatic character, the system shall be considered aromatic if the aromatic form do- minates under ambient and/or in-vz’vo conditions.
In principle, a “heteroaryl” may be attached to the group of which it is a substituent either by a carbon ring atom or a nitrogen ring atom.
Heterocycloalkyl The term "heterocycloalkyl" means a cycloalkyl ring in which one or more carbon atoms are replaced by heteroatoms. A heterocycloalkyl comprises at least one heteroatom se- lected from N, O or S, wherein an atom like S may be oxidized, which is why it is referred to as S(O)r, wherein r = 0, l or 2. The ring is composed of atoms or groups of atoms such as carbon, oxygen, en, sulfur, -S(O)- or -S(O)2-. Such atoms or groups are ring members. A 5 ed heterocycloalkyl is ed by 5 such atoms/groups. The term “heterocycloalkyl” is intended to include all the possible isomeric forms. A heterocycloal— kyl is a non-aromatic ring system, that even if substituted will maintain its non-aromatic character. If not specified otherwise it is a saturated ring system.
PREFERRED EMBODIMENTS Specifically preferred in the context of the present invention are the ing compound family groups (compound family groups of active compounds). The following compound family groups and individual isomers (= compound family members) are particularly pre- ferred embodiments of compounds according to the ion. Each such compound family group and individual isomer is an individual embodiment ofthe ion. For each of these compound family groups one or more (s) or mixture of specific isomers is/are among the compounds as ified in the section “Exemplary embodiments of active compounds”.
The following tabular scheme is used to list said active compound families and their mem- bers individually. In the presentation, the structure prevails the chemical name in case of discrepancy.
Compound family with alphanumerical abbreviation: chemical name thereof chemical structure 1 ) Compound ifled s3) family membersz) (R;R) and (S;S) and (R;S) and (S;R) and and mixtures thereofga) 1) Structure of nd family is presented as diastereomeric or racemic mixture. 2) The compound family encompasses all stereoisomers that are encompassed by the chemical structure of the left hand column as well as the mixtures of the corresponding ste- reoisomers. In the table form only the individualized stereoisomers are presented as the preferred representatives of the compound family. The specific stereochemistry is pre- . l 3 sented With respect to R and R according to a (I). Stereochem1stry of the two ste-. . . l l; and the one w1th1n R. . 3 . l; 3 3 . reocentres bear1ng R is presented as (R R ), wherein (R R ) = (configuration at R. l . 3 ). The name and the structure are directly deter-. ; configuration at R e from the remaining information provided. While the absolute configuration for R3 is known, as this is R-l, l ,l-trifluoro-2—propoxy substituent, S-1, 1 , uoropropoxy, (S)-Tetrahydro-furanoxy or (R)-Tetrahydro-fi1ran—3-oxy, the absolute configuration for l . l R ’ only the relative configuration With respect to R2. . . . the1r. is not known. For R is known: relative configuration is always syn.
The following abbreviations for the absolute configuration of the corresponding stereocen- tres are used: M: mixture of compounds with R and S configuration at the corresponding 1 3 . 3 . stereocentres R and R ; R: R-conf1guration at R ; S: S-conf1guration at R3; X,Y,U,V: . . 1 spec1fic configuratlon R r the absolute configuration is not known. X and Y are. . 2012/065140 used to indicate the two different stereoisomers with regard to R1 if R3 has S- configuration, U and V are used to indicate the two ent stereoisomers with regard to R1 if R3 has R-configuration. The te configuration behind X,Y,U and Y may vary over the different compound families. For example the configurations (X; S) and (Y,S) de- cr1bes the two stere01smers where1n for both compounds R. . . 3 shows S-configuratlon whlle. . l . l for one of them R shows R-configuratlon and for the other one R shows S-configuratlon;.
In case R3 lacks a stereogenic , only the specific stereochemistry at R1 is presented by the capital letters W for enantiomer 1, Z for enantiomer 2; M1 indicates a mixture at R1.
This is as again the absolute configuration is not known. Consequently for a compound family lacking a stereogenic center at R3 only the stereochemical property for R1 is to be . . . . . 1 3 cons1dered. In the below table th1s 1s 1nd1cated as (R .
; R = no stereogen1c center). In case R1 in itself includes a stereogenic center, stereochemistry is presented by a pair of three time of the corresponding letters for R and S configuration: as before the first letter stands for the stereochem1stry of the carbon atom bear1ng R. . the second letter stands for the ste- reochem1stry w1th1n subst1tutent R. . . . 3 . . . . l and the th1rd one for the stereochem1stry w1th1n R .
For example: ) means at the bridgehead bearing R1 is R; stereo- , stereochemistry chemistry within substituent R3 is S and stereochemistry within R1 is R. The absolute con- . . . l and the stereogen1c center w1th1n R may. . . l figuratlon for the stereogen1c center bear1ng R be not known. In these cases the following abbreviations for the te configuration of the ponding stereocentres are used: M: mixture of nds with R and S configu- ration at the ponding stereocentres. 2a) The compound family encompasses all mixtures of the corresponding stereoisomers of said family, i.e. mixtures of 2, 3 or 4 stereoisomers that belong to the same compound fam- ily.(= binary, y and quaternary mixtures). Example of the binary mixtures (in the terminology (R1;R3) as discussed above) : (S;S) and (R;R); (S;S) and (R;S); (S;S) and (S;R); (R;R) and (R;S); (R;R) and (S;R)- 2012/065140 3) For details it is referred to the experimental part, section “Exemplary embodiments3, .
The example number and the stereochemistry are presented as discussed above under 2).
List of active com ound families and the dual famil members as further ed embodiments ofthe invention Table l Table l nd family A: [5-Methanesulfonyl(2,2,2-trifluoro- l -methyl-ethoxy)-phenyl]- [l-(S -trifluoromethyl-[ l ,2,4]oxadiazolyl)aza-bicyclo [3. l .0]hexyl]-methanone example 1, (M;S); example 2, (X;S); example 3, (Y;S); example 4, (U;R); example 5, (VgR) example 58, (MR) Compound family B: [5-Methanesulfonyl(2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]- [l-(S -methyl-[ 1 ,2,4]oxadiazolyl)aza-bicyclo [3. l .0]hexyl]-methanone example 6, (M;S); example 7, (X;S); example 8, (Y;S); example 42, (U;R); example 43, (V;R); example 101, (MR) Compound family C: Cyclopropyl—[l,2,4]0xadiazolyl)aza-bicyclo[3. l .0]hexyl] - [5 -methanesulf0nyl(2,2,2-trifluor0- l -methyl-ethoxy)-phenyl]-methan0ne e 9, (M;S); example 10, (X;S), example 11, (Y;S); example 41, (MR); example 44, (U;R); example 45, (V;R); Compound family D: [5-Methanesulfonyl(2,2,2-triflu0r0- l -methyl-eth0xy)-phenyl]— { l -[5-(2,2,2-trifluoro- l , l -dimethyl-ethyl)-[ l ,2,4]0xadiaz0 lyl]aza-bicyclo [3 . l .0]hexyl} -methan0ne example 12, (M;S); Compound family E: (3 ,3-Diflu0r0-cyclobuty1)-[ 1 ,2,4]oxadiaz01y1]aza- bicyclo [3. 1 .0]heX-3 -y1}-[5 -rnethanesu1f0ny1—2-(2,2,2-trifluor0rnethy1—eth0xy)-pheny1]— methanone example 13, (M;S); Compound family F: [5-Methanesulfonyl(2,2,2-trifluorornethy1—ethoxy)-phenyl]— (1-pyrimidin—2-y1—3-aza-bicyclo[3. 1 .0]heXy1)-rnethanone example 14, (M;S); Compound family G: [5-Methanesulfonyl(2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]— [l-(4-trifluor0methyl-pyrimidin-Z-yl)aza-bicyclo [3. l .0]hexyl]—methanone example 15, (MS); example 16, (X;S); example 17, (Y;S); e 18, (UgR); example 19, (VgR); example 72 (MR) Compound family H: [5-Methanesulfonyl(2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]— (l-0xaz0lylaza-bicyclo [3. l .0]hexyl)-methan0ne example 20, (M;S); Compound family I: [5-Methanesulf0nyl—2-(2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]— [l-(5 -methyl-0xaz0 lyl)-3 -aza-bicyclo [3. l .0]hex-3 -yl]-methan0ne example 21, (M;S); example 22, (X;S); example 23, (Y;S); Compound family J: (l-Imidazo [ l ,2-a]pyridinylaza-bicyclo [3 - . l .0]hex-3 -yl)- [5 methanesulfonyl(2,2,2-triflu0ro- l - l -eth0xy)-phenyl]-methan0ne example 24, (M;S); Compound family K: [5-Methanesulf0nyl(2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]— [l-(2-methyl-thiazo lyl)-3 icyclo [3. l .0]hex-3 -yl]-methanone example 25, (M;S); Compound family L: [5-Methanesulf0nyl—2-(2,2,2-triflu0r0- l -methyl-eth0xy)-phenyl]— [l-(2-triflu0romethyl-thiazolyl)aza-bicyclo [3 . l .0]hexyl]—methanone example 26, (MS); example 27, (X;S); example 28, (Y;S); example 29, (MR); example 30, (UgR); example 31, (V;R); Compound family M: [5-Methanesulf0nyl(2,2,2-triflu0r0- l -methyl-eth0xy)-phenyl]— methyl-0xaz0lyl)aza-bicyclo[3. l .0]hexyl]—methan0ne example 32, (M;S); Compound family N: [5-Methanesulf0nyl(2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]— [l-(4-methyl-oxaz0 lyl)-3 -aza-bicyclo [3. l .0]hex-3 -yl]-methan0ne example 33, (M;S); Compound family 0: [5-Methanesulf0nyl(2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]— [l-(3 l-[ 1 ,2,4]0xadiaz0lyl)aza-bicyclo [3. l .0]hexyl]—methanone example 34, (M;S); example 35, (MR); Compound family P: [5-Methanesulf0nyl—2-(2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]— [l-(3 -trifluor0methyl-[ l ,2,4]0xadiazolyl)aza-bicyclo [3. l .0]hexyl]—methan0ne example 36, (M;S); example 37, (M;R); example 84 (X;S) example 85 (Y;S) example 86 (U;R) example 87 (VgR) Compound family Q: [5-Methanesulf0nyl(2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]— [l-(S -methyl-[ 1 ,3 diaz0lyl)aza-bicyclo [3. l .0]hexyl]—methan0ne example 38, (M;S); WO 17657 Compound family R: 4-(2,2,2-Trifluoromethyl-ethoxy)[1-(5-trifluoromethyl— [l,2,4]0xadiaz0lyl)aza-bicyclo [3. l .0]hexanecarb0nyl]—benz0nitrile example 39, (MgM); example 88 (M;S) e 89 (X;S) example 90 (Y;S) example 91 (MR) Compound family S: anesulf0nyl(2,2,2-triflu0r0- l -methyl-eth0xy)-phenyl]-[ l - (5 -trifluor0methyl—[ l ,2,4]0xadiaz0lyl)aza-bicyclo [3. l .0]hexyl]—methan0ne example 40, (M;S); example 92 (MR) example 93 (UgR) example 94 (V;R) Compound family T: [5-Methanesulf0nyl—2-(2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]— [l-(5 -trifluor0methyl-isoxazolyl)aza-bicyclo [3. l .0]hexyl]—methan0ne example 46, (MS); example 47, (X;S); example 48, (Y;S); example 49, (MR); example 50, (UgR); example 51, (V;R); Compound family U: [5-Methanesulfonyl(2,2,2-triflu0r0- l -methyl-eth0xy)-phenyl]— [l-(S -methyl-isoxazolyl)aza-bicyclo[3. l .0]hexyl]—methan0ne example 52, (M;S); nd family V: [5-Methanesulfonyl(2,2,2-triflu0r0- l l-eth0xy)-phenyl]— [l-(S -trifluor0methyl-pyridinyl)aza-bicyclo [3. l .0]hexyl]—methan0ne example 53, (M;S); Compound family W: [5-Methanesulf0nyl(2,2,2-trifluoro-l-methyl-ethoxy)-phenyl]— [l-(6-trifluor0methyl-pyridinyl)aza-bicyclo[3. l .0]hexyl]—methan0ne example 54, (M;S); example 55, (X;S); example 56, (Y;S); Compound family X: [5-Methanesu1fonyl(2,2,2-trifluoromethyl-ethoxy)-phenyl]- [1-(5 -trifluoromethy1—4,5-dihydr0-oxaz01y1)aza-bicyclo [3. 1 .0]hexyl]—methanone (R;R;R) and example 57, (M;S;M) (R;R;S) and (R;S;S) and (R;S;R) and ) and (S;R;S) and (S;S;S) and (S;S;R) Compound family Y: [5-Methanesu1fonyl(2,2,2-trifluoromethyl-ethoxy)-phenyl]- (2,2,2-trifluoro-ethyl)-[1,2,4]oxadiaz01y1]aza-bicyc10[3.1.0]heXyl}- methanone Example 61 (M;S) Compound family Z: [5-Methanesulf0nyl—2-(2,2,2-triflu0r0- l -methyl-eth0xy) phenyl]— { l -[5-(3-methyl-0xetan—3-yl)-[ l xadiaz0 lyl]aza-bicyclo [3 - . l .0]hexyl} methanone Example 62 (M;S) Compound family Za: {l-[5-(2,2-Difluoro-cyclopropyl)-[l,2,4]oxadiazol—3-yl]aza- bicyclo [3. l .0]hex-3 -yl} - [5 -methanesulf0nyl(2,2,2-triflu0r0- l -methyl-eth0xy) -phenyl]—methan0ne (R;R;R) and Example 63 (M;S;M) ) and Example 64 (M:R;M) ) and (R;S;R) and (S;R;R) and (S;R;S) and (S;S;S) and (S;S;R) Compound family lb: [5 -Methanesulfonyl(2,2,2-trifluoro- l -methyl-ethoxy)-phenyl] - {l- [5 -( l -trifluor0methyl—cyclopropyl)-[ l ,2,4]0xadiaz01-3 -yl] -3 -aza-bicyclo [3. l .0]hexyl} -methan0ne Example 65 (MS) Example 66 (XS) Example 67(Y:S) Example 68 (MR) e 69 (UiR) Example 70 (ViR) Compound family Zc: [5-Methanesulf0nyl—2-(2,2,2-triflu0r0- l -methyl-eth0xy)-phenyl]— [l-( l -methyltrifluor0methyl- l H-[ l ,2,4]triazolyl)aza-bicyclo [3. l yl]— methanone Example 71 (M;S) Compound family Zd: [5-Ethanesulf0nyl(2,2,2-trifluor0- l -methyl-eth0xy)-phenyl]— [l-(4-trifluor0methyl-pyrimidin-Z-yl)aza-bicyclo [3. l .0]hexyl]—methanone Example 73 (M;S) Example 74 (X;S) Example 75 (Y;S) Example 76 (MR) Example 77 (UiR) Example 78 (ViR) Compound family Ze: Cyclopropyl—pyrimidin—Z-yl)aza-bicyclo[3.l.0]hexyl]— [5 -methanesulf0nyl(2,2,2-triflu0r0methyl—ethoxy)-phenyl]-methan0ne Example 79 (MR) Compound family Zf: [l-(2-Cyclopropyl—oxazolyl)aza-bicyclo[3. l yl]—[5- methanesulfonyl((S)-2,2,2-trifluor0 methyl-ethoxy)-phenyl]-methan0ne Example 80 (M;S) Example 81 (MR) Example 82(U;R) Example 83 (VgR) Compound family Zg: but0xymethanesulf0nyl-phenyl)-[l-(S-trifluoromethyl- [l,2,4]0xadiaz0lyl)aza-bicyclo [3. l .0]hexyl]—methanone (R; R3: no stereo- Example 95 (M1) genie center) and (S; R3: no stereoge- nic center) Compound family Zh: (2-Isopropoxymethanesu1f0nyl-pheny1)-[1-(5-triflu0r0methyl- [1,2,4]oxadiaz01y1)aza-bicyc10[3. 1 .0]heXy1]-methanone (R; R3: no stereo- Example 96 (M1) genic center) and Example 97 (W) (S; R3: no stereoge- Example 98 (Z) nic center) Compound family Zi: hanesu1f0ny1—2,2-dimethy1—2,3-dihydr0-benz0fi1ran—7-yl)- [1-(5-trifluor0methy1—[1,2,4]oxadiazo1y1)aza-bicyc10[3. 1 .0]heXy1]-methanone (R; R3: no stereo- e 99 (M1) genic center) and (S; R3: no stereoge- nic center) W0 2013/017657 Compound family Zj: [5-Oxazolyl(2,2,2-trifluoromethyl-ethoxy)-phenyl]-[1-(5- trifluoromethyl-[ 1 ,2,4]0xadiaz0 1-3 -yl)-3 -aza-bicyclo [3. 1 .0]hex-3 -yl]-methan0ne Example 100 (M;S) Compound family Zl: [5-Ethanesulfonyl—2-(2,2,2-trifluoromethyl—ethoxy)—phenyl]- [1-(5-trifluoromethyl-isoxazolyl)aza-bicyclo[3.1.0]hexyl]-methanone e 102, (M;S); example 103, (X;S); example 104, (Y;S); example 105, (MR); example 106, (U;R); example 107, (VgR) Compound family Zm: [5-Methanesulfonyl(2,2,2-triflu0r0- l -methyl-eth0xy)-phenyl]— [l-(4-methyl-isoxaz0lyl)aza-bicyclo[3. l .0]hexyl]—methan0ne example 108, (MS); Compound family Zn: [5-Methanesulfonyl(2,2,2-triflu0r0- l -methyl-eth0xy)-phenyl]— [l-(4-trifluor0methyl-isoxazo1yl)aza-bicyclo[3. l .0]hexyl]—methanone example 109, (MS); Compound family Zo: (2-Isopr0p0xymethanesulfonyl-phenyl)-[l-(4-trifluor0methyl- oxazol—2-yl)aza-bicyclo [3. l yl]—methan0ne (R; R3: no - example 110, (M1); genie center) and example 111, (W) (S; R3: no stereoge- example 112’ (Z) nic center) W0 2013/017657 Compound family Zp: [5-Methanesulfonyl(2,2,2-trifluor0methyl-eth0xy)-phenyl]— [1-(4-triflu0r0methyl-0xazolyl)aza-bicyclo [3 . 1 .0]hexyl]—methanone example 113, (MR); example 114, (UgR) example 115, (VgR); example 136, (X;S); example 137, (Y;S); Compound family: Zq: hanesulfonyl(2,2,2-trifluoromethyl-ethoxy)- phenyl]—{1-[5-(1-meth0xy-cyclopr0pyl)-[1,2,4]0xadiaz0lyl]aza-bicyclo[3.1.0]hex yl} -methan0ne example 116, (M;S); example 117, (X;S); e 118, (Y;S); example 119, (MR); example 120, (U,R); example 121, (V,R); Compound family: Zr: [5-Methanesulf0nyl(2,2,2-trifluor0methyl-eth0xy)-phenyl]— [1-(5 -trifluor0methyl-[1,3 diaz0 lyl)-3 -aza-bicyclo [3. 1 .0]hex-3 -yl]-methan0ne example 122, (MR); example 123, (UgR); example 124, (VgR); example 125, (M;S); example 126, (X,S); example 127, (Y,S); Compound family: Zs: [5-Methanesulf0nyl—2-(2,2,2-trifluor0methyl-eth0xy)-phenyl]— [1-(5-trifluor0methyl-0xazolyl)aza-bicyclo[3.1.0]hexyl]—methan0ne example 128, (MR); example 129, (UgR); e 130, (V;R); example 131, (M;S); example 132, (X,S); example 133, (Y,S); 2012/065140 Compound family: Zt: [5-Methanesulfonyl(2,2,2-trifluoromethyl-ethoxy)-phenyl]— {1-[5-(1-methyl-cyclopr0pyl)-[1,2,4]0xadiazolyl]aza-bicyclo[3.1.0]hexyl}- methanone example 134, (M;S); example 135, (MR); Compound family: Zu: [5-Methanesulf0nyl(tetrahydr0-fi1ran—3-yloxy)-phenyl]—[1-(5- trifluoromethyl-[l,2,4]0xadiazolyl)aza-bicyclo[3.1.0]hexyl]—methan0ne example 138, (M,R); example 139, (U;R); example 140, (V;R) Compound : ZV: [5-Methanesu1fony1—2-(3-trifluoron1ethy1—pyrazol—1-y1)-pheny1]— [1-(5-trifluoron1ethy1—[1,2,4]oxadiazo1y1)aza-bicyclo[3. 1 .0]heXy1]-n1ethanone (R; R3: no stereo- example 141, (M1); genic center) and (S; R3: no stereoge- nic center) Compound family: Zw: (2-Isopropoxyn1ethanesu1fonyl-pheny1)- { 1-[5-(1-trifluoro- methyl-cyclopropyl)-[ 1 ,2,4]oxadiazol—3-y1]aza-bicyclo [3. 1 .0]hexy1} -n1ethanone (R; R3: no stereo- example 142’ (W) genic center) and (S; R3: no ge- nic center) W0 2013/017657 Compound family: Zx: [1-(3-Cyclopropyl—[1,2,4]oxadiazolyl)aza-bicyclo[3.1.0] hex-3 -yl] - [5 -methanesulf0nyl(2,2,2-trifluor0methyl-ethoxy)-phenyl]-methan0ne example 143, (X;S); example 144, (Y;S); example 145, (MR) nd family: Zy: [1-(5-Cyclopr0pyl—[1,3,4]0xadiaz0lyl)aza-bicyclo[3.1.0] hexyl]-[5-methanesulfonyl(2,2,2-trifluor0methyl-eth0xy)-phenyl]-methan0ne example 146, (MR); example 147, (M;S) W0 2013/017657 Compound family: Zz: [5-Methanesulf0nyl(2,2,2-trifluor0methyl-eth0xy)-phenyl]— {1-[5-(1-triflu0romethyl—cyclopropyl)-[1,3 ,4]0xadiazolyl]aza-bicyclo [3 . 1 .0]hex yl} -methan0ne example 148, (MR); example 149, (UgR); example 150, (V;R); example 151, (M;S); example 152, (X;S); e 153, (Y;S) Compound family: Zza: (2-Isopr0poxymethanesulf0nyl-phenyl)-{1-[3-(1-trifluor0- -cyclopropyl)-[ 1 ,2,4]0xadiazolyl]aza-bicyclo [3. 1 .0]hexyl} -methan0ne (R; R3: no stereo- example 154, (M1) genie center) and (S; R3: no stereoge- nic center) Compound family: Zzb: hanesulfonyl(2,2,2-triflu0r0methyl-eth0xy)- phenyl] - { 1 - [3 -(1-triflu0r0methyl-cyclopropyl)-[1,2,4]0xadiazol-5 -yl] -3 -aza- bicyclo [3 . l .0]hexyl} none example 155, (MS); example 156, (MR) Compound family: ch: [5-Methanesulf0nyl—2-(2,2,2-trifluoromethyl-eth0xy)- phenyl]—[1-methyl(5-triflu0romethyl—[1,2,4]0xadiaz0lyl)aza-bicyclo[3. 1 .0]hex yl] -methan0ne example 157, (MS); example 158, (X;S); example 159, (Y;S) W0 2013/017657 Compound : sz: [5-Methanesulfonyl(2,2,2-trifluoromethyl-ethoxy)- phenyl]-[ 1 -(4-methyltrifluoromethyl—isoxazo1yl)aza-bicyclo[3. l .0]hexyl]— methanone example 160, (MR); example 161, (UgR); example 162, (VgR); example 163, (M;S); example 164, (X;S); example 165, (Y;S) and wherever appropriate the salts, ably pharmaceutically able salts, solvates and the so lvates of the salts thereof.
PREPARATION The following schemes shall illustrate generally how to manufacture the nds ac- cording to general formula (I) and the corresponding intermediate compounds by way of example. The abbreviated substituents may be as defined above if not defined otherwise within the context of the schemes.
Scheme 1 o R2 o R2 RS 2 0 R CDI, NH4OH HCI fox THF %O dioxane N R4 HATU,TEA R2 0 2 O 3 /; R3 s reagent y/ R N R4 N 4 R 7 O R N R5 DCM,35°C 5 NH2 R (path 2) (path 1) AcCI, EtOH, CHCI3 NHZOH (50% in water) then NH3, EtOH EtOH, 100°C (microwave) R2 O HN§R%Z/5R3 R2 0 R3 R4 N 7 I R HN§ R fi/R“ /NH 5 R6 NH R 2 R6 HO R"NHNH2 MeOH, rt O (R'CO)ZO, TEA R2 0 / R3 R'MOK ACN, 100-150°C (microwave) R4 O or R'MONa R2 O $95GR3 HN R7 N R R4 /NH R6 \0 R"—N H 0r R'AO/N \ R6 ‘0 (R'c0)20, TEA ACN, 100-150°C (microwave) J if R' is hydrogen 70-175°C (microwave) R2 0 R3 R2 O R3 N R4 '7‘ R RA \ R5 N‘ R7 N’N R6 5 | MN R" R' . l In scheme 1 all substituents R . to R7 have the meaning as defined for general formula (I) and all embodiments ofthe invention that directly refer thereto. R' and R’ ’= substituents as de- fined for R1.
Scheme 1: In a first step a derivative of 3-azabicyclo[3. l .0]hexane-l,3-dicarboxylic acid tert-butyl ester is coupled with ammonium hydroxyde in the presence of l,l’- carbonyldiimidazole in an riate solvent like THF. The Boc protecting group of the ing primary amide is deprotected with hydrochloric acid in an appropriate solvent like dioxane. The resulting product is d with c acid derivatives in an appropri- ate solvent like DMF and in the presence of a coupling agent (e. g. HATU or TBTU) and a base (e.g. TEA or DIPEA). The primary amide functional group of the resulting benzamide is converted into a e filnctional group using Burgess reagent in DCM. These com- pounds are reacted with hydroxylamine (50% in water) in EtOH at elevated temperatures under microwave irradiation to give the corresponding amidoximes (path 1). These deriva- tives are then converted to 1,2,4-oxadiazole derivatives upon treatment with anhydrides, a base (e.g. TEA) and an appropriate solvent like ACN at elevated temperature under mi- crowave irradiation. atively, nitriles are converted to the corresponding amidines upon treatment with AcCl in EtOH and CHCl3 followed by ent with ammonia in EtOH (path 2). These compounds are reacted with a l,3-dicarbonyl derivative or a synthet- ic equivalent (e.g. l,1,3,3-tetramethoxypropane or 4-ethoxy-l,l,l-trifiuorobuten—2-one) to form the corresponding pyrimidines. Alternatively, amidines are reacted with ines in MeOH to give the corresponding amidrazones. These derivatives are then converted to 1,2,4-triazole derivatives upon treatment with ides, a base (e. g. TEA) and an appro- priate solvent like ACN at elevated temperature under microwave irradiation.
Scheme 2 O R2 conditions: R2 HCI R2 % see table below R% dioxane R% HO —> N24) N>FO or TFA H 0 K 0 K DCM O R3 HO R4 ng reagent, base DCM or DMF N R7 In scheme 2 all substituents R1 to R7 have the meaning as defined for l formula (I), all embodiments ofthe invention that directly refer thereto and specifically the meaning as de- fined in the following table.
Scheme 2: a derivative of 3-azabicyclo[3. l .0]hexane-l,3-dicarboxylic acidtert-butyl es- ter is treated under ions listed in the table below to form heteroaryl substituted 3- azabicyclo[3. l .0]hexanecarboxylic -tert-butyl ester. Ra is a substituent of Het.
Reaction with a coupling agent (e. g. TBTU, etc.) and a base (e. g. TEA) followed by a 2- amino-alcohol.
Oxidation with Dess-Martin—Periodinane in H-, H3C-, F3C- dichloromethane or acetonitrile.
Treatment with Burgess-reagent in THF at elevated temperatures.
Reaction with oxalylchloride in THF fol- lowed by treatment with trimethylsilydiazo- methane followed by hydrochloric acid in Reaction with a 2-amino-pyridine in 1,2- dimethoxyethane at elevated temperatures.
Reaction with oxalylchloride in THF fol- lowed by treatment with trimethylsilydiazo- methane followed by hydrochloric acid in dioxane.
Reaction with a thioamide in EtOH. on with oxalylchloride in THF or DCM followed by treatment with trimethylsilydia- ane followed by hydrochloric or hy- drobromic acid. H3C-, cyclopropyl Reaction with an amide in l-methyl pyrrolidinone or EtOH at ed tempera- tUIGS Reaction with a coupling agent (e. g. CD1, etc.) in THF followed by ammonium hydroxyde Reaction with a tone in ethanol at ele- vated temperatures in ethanol or in dioxane optionally followed by treatment with metha- nesulfonylchloride and TEA in DCM on with a coupling agent (e.g. CD1, etc) H3C-, F3C-, in DMF followed by a N—hydroxyamidine cyclopropyl, derivative (which may be obtained from the *: CF3 corresponding nitrile upon treatment with hy- droxylamine and potassium carbonate in wa- ter/EtOH or from the corresponding amide upon treatment with an anhydride in THF at elevated temperatures followed by hydrox- ylamine and potassium ate in MeOH) at elevated temperatures on with a coupling agent (e. g. TBTU, etc.) and a base (e.g.DIPEA) followed by a H3C-, CYCIOPTOPYL carboxylic acid hydrazide. *: CF3 Treatment with Burgess-reagent in 1,2- F3C-, dichloroethane at elevated temperatures F3C-, cyclopropyl-, CH3-, on with a coupling agent (e.g.CDI) in CF3C(CH3)2-, THF followed by ammonium hydroxyde F Treatment with Burgess-reagent in DCM at elevated temperatures Reaction with hydroxylamine in ethanol at 0: elevated temperatures Reaction an anhydride and TEA in ACN at ed temperatures Reaction with CD1 in DCM followed by TEA and N,O-dimethylhydroxylamine Reaction with methylmagnesium e in Reaction with lithium bis(trimethylsilyl)amide followed by treat- ment with an ester in THF Reaction with hydroxylamine hydrochloride in methanol at ed temperatures Treatment with a TEA followed by a sulfonyl chloride in DCM a. Reaction with a coupling agent (e. g. CD1, etc.) in DCM followed by a base (e. g. TEA) and methylhydroxylamine Reaction with ethylmagnesium bromide in Reaction with Lithium diisopropylamide fol- lowed by ent with an acylimidazole in Reaction with hydroxylamine hydrochloride in methanol at elevated temperatures Treatment with a TEA followed by a sulfonyl de in DCM; Reaction with lithium aluminium hydride in Reaction with Dess-Martin periodinane in Reaction with hydroxylamine hydrochloride and sodium acetate in EtOH and water Reaction with N—chlorosuccinimide in DMF at 40°C Treatment with a haloalkene and TEA in DCM or CHC13 Reaction with lithium aluminium hydride in Reaction with Dess-Martin periodinane in Reaction with hydroxylamine hydrochloride and sodium acetate in EtOH and water Reaction with N—chlorosuccinimide in DMF at 40°C ent with an enolether and TEA in The resulting Het-substituted 3-azabicyclo[3. l .0]hexanecarboxylic acidtert-butyl es- ter derivatives are deprotected with hydrochloric acid or TFA in an appropriate solvent like dioxane. The resulting products are coupled with benzoic acid derivatives in an appropriate t like DMF and in the presence of a coupling agent (e.g. HATU or TBTU) and a base (e. g. TEA or .
Scheme 3 diethyl malonate, 082003 O 1 N-Bromosuccinimide 1 R O R—Br \/[< R1 Pd(0) cat, phosphine O gox Dimethoxyethane K (320)20 cat., CC|4 Br 150°C (microwave) reflux R2 NaH, EtOH, EtZO R1 CH38020| R1 LIA|H4 PASR2 R2 R1 2 HO OH THF CH3028 osoch3 TEA, DCM R0 4-MeO-benzylamine O 3 DIPEA, DMF, 80°C CI R7 R1 2%R2 1 2,-dichloroethane N HATU, TEA J then MeOH, 60°C RON;;: \O: H -62— In scheme 3 all substituents R1 to R7 have the meaning as defined for l formula (I) and all embodiments of the invention that directly refer thereto. R -Br 1n the first step: the Br is. . . . l . . attached to a carbon atom.
Scheme 3: In a first step heteroaryl bromides are treated with a malonate derivative, a base (e.g. cesium carbonate), a Pd(0) catalyst (e.g. Pd2dba3) and a phosphine (e. g. t-Bu3P) in an appropriate solvent like dimethoxyethane at elevated temperatures. The resulting - substituted tives are brominated with a Bromine source (e.g. N—bromosuccinimide) and a radical initiator (e. g. benzoyl peroxide) in an appropriate solvent like carbon tetrach- loride at elevated temperatures. The ing bromides are in turn treated with an acrylate tive, a base (e. g. NaH) and ethanol in l ether affording a cyclopropane deriva- tive. The two ester fianctional groups of such compounds are converted to a diol coupled using a reducing agent (e. g. lithium aluminium hydride) in an appropriate solvent like THF. The diols are in turn converted to leaving groups such as mesylates upon ent with methanesulfonyl chloride, a base (e. g. TEA) in DCM. Ring closure to pyrrolidine de- rivatives is carried out employing an amine (e. g. 4-MeO-benzylamine), a base (e. g. DI- PEA) in an appropriate solvent like DMF at elevated temperatures. NH-pyrrolidines are ed by deprotection of such compounds, e. g. in the case of 4-MeO-benzyl-protection by treatment with l-chloroethyl chloroformate in l,2-dichloroethane followed by MeOH at elevated temperatures. The resulting products are coupled with c acid tives in an appropriate solvent like DMF and in the presence of a coupling agent (e. g. HATU or TBTU) and a base (e. g. TEA or DIPEA).
Scheme4 O>< HO\fNHZ o>< O 0 R O HOAX;Nko k0 HCI NJKQN HO HO 2 TBTU,TEA ”AKA;H R fH 2 fH R dloxane. R O R3 HO 4 HATU, TEA 6 R NJK 2 0 R3 N R4 \ N Nonafluorobutanesulfonyl fluoride R7 0)) R5 1, 8-Diazabicyclo[5.4.0]undecene R' DCM HO—(H In scheme 4 all substituents R2 to R7 have the meaning as defined for general formula (I) and all embodiments of the invention that directly refer o. R' = a substituent as defined for R1, e.g. -CF3.
Scheme 4: In a first step a derivative of 3-azabicyclo[3. l .0]hexane-l,3-dicarboxylic acid utyl ester is coupled with an amino alcohol in the presence of a coupling agent (e.g.
TBTU), a base (e. g. TEA) an appropriate solvent like DMF. The Boc protecting group of the resulting amides are ected with hydrochloric acid in an riate solvent like dioxane. The resulting products are coupled with benzoic acid derivatives in an appropriate solvent like DMF and in the presence of a coupling agent (e. g. HATU or TBTU) and a base (e. g. TEA or DIPEA). The formation ofthe dihydro-oxazole is accomplished upon treatment with orobutanesulfonyl fluoride, a base (e.g. 1,8- diazabicyclo[5.4.0]undecene) in DCM.
Scheme 5 R R6 R1 HATU, TEA R R Base DCM e R R R1 R2 In scheme 5 all substituents R1 to R7 have the meaning as defined for general formula (I) and all embodiments ofthe invention that ly refer thereto.
Scheme 5: In a first step a derivative of roarylaza-bicyclo[3.1.0]hexane is coupled with fluoro-benzoic acid derivatives in an appropriate solvent like DMF and in the pres- ence of a coupling agent (e. g. HATU) and a base (e. g. DIPEA). R3 is subsequently in- stalled by substitution of the Fluorine upon treatment with R3-H and a base (e. g. NaH or KOtBu) in an appropriate solvent like THF or DMF. 3-azabicyclo[3. l .0]hexane-l,3-dicarboxylic -tert-butyl ester derivates are available from commercial vendors or, alternatively, can be synthesised following the approach de- scribed in Scheme 6.
Scheme6 2 O Br TEA, EtOH WWW R2 0 * Who V O O \ 2,4-dimethoxyanilineNaCNBHa AcOH, THF \l/ | o 0\ 0Y0 m | N H2’ Pd(OH)2 N BH3.Me28 R SVA (BOC)20 RZSVA :(j/O\ OH N Dess-Martin 2 O periodinane R 0Y0 NaCIOZ, NaHZPO4 0Y0 2 o HZO R 5V1]? 2-methyIbutene RZSVZfO In scheme 6 substituent R2 has the meaning as defined for general a (I) and all embo- diments ofthe invention that ly refer thereto.
Scheme 6: In a first step a malonate derivative is treated with an acrylate deriva- tive, a base (e. g. TEA) in ethanol affording a cyclopropane derivative. A pyrrolidone ring is then constructed by subjecting this compound to reductive amination conditions. The pyrrolidone is in turn converted to a pyrrolidine derivative with a reducing agent (e.g. bo- rane-dimethylsulfide complex). N—Boc-pyrrolidines are obtained by ection of such compounds, e. g. in the case of 2,4-dimethoxy-benzyl-protection by metal-catalysed hydro- genation, in the presence of di-tert-butyl dicarbonate. Derivatives of 3- azabicyclo[3. l .0]hexane- l ,3-dicarboxylic -tert-butyl ester are prepared by oxydation ofthe corresponding alcohols, e.g. by treatment with artin periodinane followed by Sodium chlorite.
The above processes for manufacture according to schemes 1, 2, 3, 4, 5 or 6 are among other aspects of the present invention.
The ediate nds as outlined in the above processes for manufacture according to s 1, 2, 3, 4, 5 or 6 constitute another aspect of the present invention, specifically with regard to intermediate compounds according to any ofthe following l formulas (11), (111), (IV), (V) and (v1): TG T6 We N N N 2 O o R R2 R2 R OH H general formula (11) general formula (111) general formula (IV) FI’G R2 O N N 2 o R7 6 R5 general formula (V) general formula (VI) wherein in each ofthose independent formulas R1, R2, R4, R5, R6, and R7 have the meaning as d for general formula (I), all embodi- ments referring thereto and specifically the meaning as defined in the table as outlined for scheme 2, R8 is C1_4 alkyl-O-, optionally substituted by l or more substituents independently se- lected from each other from the group of fluoro, chloro, bromo, -CN, C1_4 all<yl-O-, C1_4 alkyl-, phenyl and benzyl, wherein phenyl and benzyl optionally may be substituted with one or more substituents independently selected from each other from the group of fluoro, chloro, bromo, -CN, C1_4 all<yl-O-, C1_4 all<yl-; PG is a ting group for an amino fianction such as outlined in: Peter G.M. Wuts, Theodora W. Greene, Greene’s Protective Groups in Organic Synthesis, Wiley- Interscience; 4 edition (October 30, 2006).
Preferred protecting groups are tert- butoxycarbonyl-, 9-fluorenylmethoxycarbonyl-, ben- zyl-, 2,4-dimethoxybenzyl-.
Specifically preferred are those intermediate compounds according to general formulas (11), (111), (IV), (V) and (VI), in which any ofthe substituents R1, R2, R4, R5, R6, and R7 have the meaning according to the exemplified specific compounds ofthe compound families e l in ation with PG being tert-butoxycarbonyl-, 9- fluorenylmethoxycarbonyl-, benzyl-, 2,4-dimethoxybenzyl-.
Among the more preferred intermediate compounds are those according to general formu- las (111), (V) and (VI).
The intermediate compounds according to general as (II), (III), (IV), (V) and (VI) can be made according to or in analogy to the processes outlined by schemes 1 to 6 and with respect to protecting groups for the nitrogen fianction of the 3- azabicyclo[3. l .0]hexane- template, by the conditions for addition of these protecting groups and l thereof as outlined by the entioned book of Peter G.M. Wuts and ra W. Greene.
METHOD OF TREATMENT The present invention refers to compounds, which are considered effective in the treatment of diseases (active compounds according to general formula (I) and specifically the com- pound family classes and the members thereof). These active compounds according to the invention are effective and selective inhibitors of glycine transporter-l (GlyTl). Thus, the nal concepts discussed above, specifically in the section “Background of the Inven- tion” at the uction part of this description, are considered of high interest as field of application for the active compounds of the present ion. The active compounds of the present invention can be used for the development of medicaments. Such medicaments shall preferably be used for the treatment of diseases in which the inhibition of GlyTl can evolve a therapeutic, prophylactic or disease ing . Preferably the medicaments shall be used to treat illnesses such as psychoses, dysfianction in memory and learning, schizophrenia (positive and ve symptoms and cognitive impairment associated with schizophrenia), dementia like Alzheimer's disease and other diseases in which cognitive processes are impaired, such as attention deficit disorders, epilepsy and/or bipolar disorder.
The medicaments are for use in a method, preferably a therapeutic method, or a method for to improve perception, concentration, ion, learning or memory, like those occurring in particular in conditions, diseases and/or syndromes such as: mild cognitive impairment, amnestic mild cognitive impairment, age-associated learning and memory ments, age-associated memory losses, vascular dementia, craniocere- bral trauma, stroke, dementia occurring after strokes (post stroke dementia), post-traumatic dementia, general concentration ments, concentration impairments in children with learning and memory problems, Alzheimer's disease, prodromal mer’s disease, Lewy body dementia, dementia with degeneration of the frontal lobes, including Pick's syndrome, Parkinson's disease, ssive nuclear palsy, dementia with obasal de- generation, amyotropic lateral sclerosis (ALS), Huntington's e, multiple sclerosis, thalamic degeneration, Creutzfeld-Jacob dementia, HIV dementia, epilepsy, temporal lobe epilepsy, Korsakoffs psychosis or cognitive impairment associated with schizophrenia, sion, epilepsy, schizo-affective disorder or r disorder.
Another aspect of the present invention concerns the treatment of a disease which is ac- cessible by inhibition, in particular sleep disorders like insomnia or narcolepsy, bi- polar disorder, depression, substance use disorders / abuse disorders, hearing disorders, attention deficit (hyperactive) disorder, inflammatory pain, neuropathic pain or autism spectrum disorders.
Thus the medical aspect ofthe present invention can be summarized in that it is considered that a compound according to formula (I) as herein , in particular the specifically defined species active compounds for use in or as a medicament.
Such a medicament preferably is for a therapeutic or lactic, ably therapeutic method in the treatment of a CNS disease.
In an alternative use, the medicament is for the treatment of a CNS disease, the treatment ofwhich is accessible by the inhibition of GlyTl.
In an alternative use, the ment is for the treatment of a disease that is accessible by the inhibition of GlyTl.
In an alternative use, the medicament is for the use in a method for the treatment ofAlz- heimer’s disease, schizophrenia (positive and negative symptoms) or cognitive impair- ment ated with Alzheimer’s disease or associated with schizophrenia.
In a filrther aspect of the invention, the present invention relates to the method of treatment or prevention of a condition or disease selected from the above listed groups of conditions and es, wherein the method comprises the administration of a eutically effec- tive amount of an active compound according to the invention in a human being in need thereof The dose range of an active compound ofthe present invention applicable per day is usual- ly fiom 0.1 to 5000 mg, preferably from 0.1 to 1000 mg, preferably from 2 to 500 mg, more ably from 5 to 250 mg, most preferably from 10 to 100 mg. A dosage unit (e.g. a tablet) preferably may contain n 2 and 250 mg, particularly preferably between 10 and 100 mg ofthe active compounds according to the invention.
Another aspect ofthe invention concerns the active nds ofthe inventions for use in a therapeutic method or for use as a ment. If indicated the therapeutic method or the medicament is preferably for the ent of a condition or a disease selected from the group of conditions or a diseases as outlined above in this section, which is entitled “ME- THOD OF TREATMENT”.
PHARMACEUTICAL COMPOSITION Suitable preparations for administering the active compounds according to the invention will be apparent to those with ordinary skill in the art and include for example s, pills, capsules, suppositories, lozenges, troches, solutions, syrups, s, sachets, ables, inhalatives and powders etc. The t of the pharmaceutically active nd(s) should be in the range from 0.05 to 90 wt.-%, preferably 0.1 to 50 wt.-% of the composi- tion as a whole.
Suitable tablets may be obtained, for example, by mixing one or more active compounds according to a (I) with known ents, for example inert diluents, carriers, disin- tegrants, adjuvants, surfactants, binders and/or lubricants . The tablets may also consist of several layers.
Examples Examples which might illustrate possible pharmaceutical formulations, without being meant to be limiting: The term "active substance" denotes one or more active compounds according to the inven- tion including the salts thereof In the case of one of the aforementioned combinations with one or more other active substances the term "active substance" may also include the addi- tional active substances. Standard procedures should be considered for the preparation of any the herein mentioned pharmaceutical formulations HARD GELATINE SUPPOSITORY ITION active substance 150.0 mg active substance 150.0 mg lactose 87.0 mg polyethyleneglycol 1500 550.0 mg corn starch (dried) 80.0 mg polyethyleneglycol 6000 460.0 mg magnesium stearate 3.0 mg polyoxyethylene sorbitan 840.0 mg monostearate m m TABLETS active substance 100.0 mg 150 mg lactose 80.0 mg 89.0 mg corn starch 34.0 mg 40.0 mg polyvinylpyrrolidone 4.0 mg 10 mg magnesium stearate 2.0 mg 1.0 mg 220.0 mg 300.0 mg COMBINATION THERAPY / COMBINATION WITH OTHER ACTIVE SUBSTANCES In another aspect the present invention relates to a combination therapy in which an active compound according to the present invention is administered together with r active compound. Accordingly, the invention also refers to pharmaceutical formulations that pro- vide such a ation of active ients, wherein one ofwhich is an active compound of the present invention. Such combinations may be fixed dose combinations (the active ingredients that are to be combined are t of the same pharmaceutical formulation) or free dose combinations (active ingredients are in separate pharmaceutical formulations).
Consequently, a r aspect of the present invention refers to a combination of each of the active compounds of the present invention, preferably at least one active nd according to the present invention, with another active compound for example selected from the group of antipsychotics such as haloperidol, clozapine, risperidone, quetiapine, aripripazole, asenapine and olanzapine; antidepressants such as selective serotonin re- uptake inhibitors and dual nin/noradrenaline re-uptake inhibitors; mood stabilizers such as lithium valproate and lamotrigine; beta-secretase inhibitors; gamma-secretase inhi- bitors; gamma-secretase modulators; amyloid aggregation inhibitors such as e.g. scyllo- inositol; directly or indirectly acting rotective and/or disease-modifying substances; anti-oxidants, such as e.g. vitamin E, ginko biloba or ginkolide; anti-inflammatory sub- s, such as e. g. Cox inhibitors, NSAIDs additionally or exclusively having AB (Abeta) ng properties; HMG-CoA reductase inhibitors, such as statins; acetylcholine esterase tors, such as donepezil, rivastigmine, tacrine, galantamine; NMDA receptor antagon- ists such as e.g. memantine; AMPA receptor ts; AMPA receptor positive modula- tors, es, glycine transporter 1 inhibitors; monoamine receptor reuptake inhibitors; substances modulating the concentration or release of neurotransmitters; substances induc- ing the secretion of growth hormone such as ibutamoren te and capromorelin; CB-l receptor antagonists or e agonists; antibiotics such as minocyclin or rifampicin; PDEl, PDE2, PDE4, PDES, PDE9 or PDElO inhibitors, GABAA receptor e agon- ists; GABAA alpha5 receptor inverse agonists; GABAA receptor antagonists; nicotinic receptor agonists or partial agonists or positive modulators; alpha4beta2 nic receptor agonists or l agonists or positive modulators; alpha7 nicotinic receptor agonists or partial ts; histamine receptor H3 antagonists; 5-HT4 receptor agonists or partial agonists; 5-HT6 receptor antagonists; alpha2-adrenoreceptor antagonists, calcium antagon- ists; muscarinic receptor Ml agonists or partial agonists or positive modulators; muscarinic receptor M2 antagonists; muscarinic receptor M4 antagonists; muscarinic receptor M4 pos- itive allosteric modulators; tropic glutamate receptor 5 positive allosteric - tors; metabotropic glutamate receptor 2 antagonists; metabotropic glutamate or 2/3 agonists; metabotropic glutamate receptor 2 positive allosteric modulators and other sub- stances that modulate receptors or enzymes in a manner such that the efficacy and/or safety of the active compounds according to the invention is increased and/or unwanted side ef- fects are reduced.
The active compounds according to the invention may also be used in combination with immunotherapies such as e. g. active immunisation with Abeta or parts thereof or passive immunisation with sed anti-Abeta antibodies or antibody fragments for the treat- ment ofthe above mentioned diseases and ions.
The active compounds according to the ion also may be combined with antipsychot- ics like ridol, flupentixol, fluspirilene, chlorprothixene, prothipendyl, levomeproma- zine, clozapine, olanzapine, pine, risperidone, paliperidone, amisulpride, ziprasidone, aripiprazol, sulpiride, zotepine, sertindole, fluphenazine, perphenazine, perazine, proma- zine, romazine, levomepromazine, benperidol, bromperidol, pimozid, melperone, pipamperone, iloperidone, asenapine, perospirone, blonanserin, lurasidone.
The active compounds according to the invention also may be combined with antidepres- sants like amitriptyline imipramine hloride (TOFRANIL), imipramine maleate (SURMONTIL), lofepramine, desipramine (NORPRAMIN), doxepin (SINEQUAN, ZONALON ), trimipramine (SURMONTIL).
Or the active nds according to the ion also may be combined with serotonin (5-HT) reuptake inhibitors such as alaproclate, citalopram (CELEXA, CIPRAMIL) lopram (LEXAPRO, CIPRALEX), clomipramine (ANAFRANIL), tine (CYM- BALTA), femoxetine (MALEXIL), fenfluramine (PONDIMIN), norfenfluramine, fluoxe- tine (PROZAC), fluvoxamine (LUVOX), indalpine, milnacipran (IXEL), paroxetine (PAXIL, SEROXAT), sertraline (ZOLOFT, LUSTRAL), trazodone (DESYREL, XIN ), venlafaxine (EFFEXOR), dine D, ZELMID), bicifadine, desven— lafaxine (PRISTIQ), brasofensme and tesofensine.
The combinations according to the present invention may be provided simultaneously in one and the same dosage form, i.e. in form of a combination preparation, for example the two components may be incorporated in one tablet, e. g. in different layers of said tablet.
The ation may be also provided separately, in form of a free combination, i.e. the active compounds of the present invention are provided in one dosage form and one or more of the above mentioned combination partners is provided in another dosage form.
These two dosage forms may be equal dosage forms, for example a co-administration of two tablets, one containing a therapeutically effective amount of the active compound of the t invention and one containing a therapeutically effective amount of the above mentioned combination r. It is also possible to combine different administration forms, if desired. Any type of suitable administration forms may be provided.
The active compound according to the invention, or a physiologically acceptable salt the- reof, in combination with another active substance may be used simultaneously or at stag- gered times, but particularly close together in time. If administered aneously, the two active substances are given to the patient together; if administered at red times the two active substances are given to the patient successively within a period of less than or equal to 12, particularly less than or equal to 6 hours.
The dosage or stration forms are not limited, in the frame of the t invention any suitable dosage form may be used. Exemplarily the dosage forms may be selected from solid preparations such as patches, tablets, capsules, pills, pellets, dragees, powders, troches, suppositories, liquid preparations such as solutions, suspensions, emulsions, drops, syrups, s, or gaseous preparations such as aerosols, sprays and the like.
The dosage forms are advantageously formulated in dosage units, each dosage unit being adapted to supply a single dose of each active component being present. ing from the administration route and dosage form the ingredients are selected accordingly.
The dosage for the above-mentioned combination partners may be expediently 1/5 of the normally recommended lowest dose up to 1/1 of the normally recommended dose.
The dosage forms are administered to the patient for example 1, 2, 3, or 4 times daily de- pending on the nature of the formulation. In case of ing or extended release formula- tions or other pharmaceutical formulations, the same may be applied differently (e. g. once weekly or monthly etc.). It is preferred that the active compounds of the invention be ad- ministered either three or fewer times, more preferably once or twice daily.
BIOLOGICAL ASSAY ro effect: The in-vz’tro effect of the active compounds of the ion can be shown with the follow- ing biological assay.
GlyTl assay protocol: Cells expressing either endogenously the GlyTl orter like JAR cells (human placen- tal choriocarcinoma cells; e.g. ) or SK—N—MC cells (human neuroblasto- ma cells; Depoortere et al., 2005, Neuropsychopharmacology 30:1963-1985) or primary neurons or cells which have been transfected with a plasmid encoding the cDNA of a fianc- tional GlyTl transporter and stably or transiently express GlyTl (e.g. ) can be used to r glycine uptake in cells. Different protocols for determination of the e uptake into the cells described above can be applied in order to identify and rank compounds which interfere with glycine uptake in the selected cell.
Compounds outlined in the examples below were characterized using human SK—N—MC cells (ATCC number HTB-lO) endogenously expressing the GlyTl transporter which is responsible for the uptake of glycine into these cells and the uptake of glycine into these cells is monitored using the Cytostar-T assay format (GE care, RPNQOl62) which is based on the radioactive glycine taken up by the cells and brought into ity with the llant contained within the base of the plate. The radioactive decay is converted to a light signal based on the integration of the scintillation matrix into the assay plate. The up- take is recorded as kinetic and the slope of the measured counts over time is used to calcu- late IC50.
In detail, SK—N—MC cells are seeded into l Cytostar-T assay plates at a density of 200,000 cells/well and grown for 16-18 hours to confluence in growth medium as recom- mended by ATCC. Before starting the assay, cells are washed once with HBSS (Hank’s buffered salt solution; Sigma, H8264) cont. 5 mM alanine (referred in here as HBSS/Ala) and afterwards the following reagents are added: 1. 80 ul/well HBSS/Ala 2. 20 ul/well of la containing 6x the concentration of compound in 6% DMSO 3. approx. 5-10 min incubation 4. 20 ul/well 3 uM glycine (3H-glycine (Perkin Elmer, NET00400lMC, specific ac- tiVity: 52 l; diluted 1:1 with unlabelled glycine) in HBSS/Ala.
In the final assay, glycine concentration is 500 nM (250 nM derived from the 3H-glycine Perkin Elmer, 250 nM lled glycine), DMSO concentration is 1%.
The assay plate is immediately after addition of the cine placed into a Beta Counter (Perkin Elmer) and the signal is recorded over 60 min.
To calculate uptake, the slope in the linear range ofthe kinetics is determined using GraphPadPrism and for the ent slopes at the selected concentrations IC50 are calcu- lated by curve fitting using the software GraphPadPrism.
Maximal glycine uptake in every experiment is determined by incubation of SK—N—MC cells with substrate but without inhibitor. Unspecific uptake of glycine by the cells is de- termined by incubating the cells with substrate and a reference GlyTl inhibitor e. g. 10 uM RG-l678 d et al., 2010, J. Med. Chem. 53(12):4603-l4).
Compounds are diluted from 10 mM stocks and in general, for IC50 determination 8 com- pound concentrations are used.
Example Example Example number number number WO 17657 WO 17657 Compounds with an IC50 value of between >1 and 1000 nM are preferred, more red are active compounds with an IC50 value of between >1 and 500 nM, more preferred are compounds with an IC50 value of between >1 and 150 nM.
In-vivo effect: It is believed that the positive in-vz’tro efficacy results of the active compounds of the present invention translate in ve in-vivo efficacy.
The in-vz’vo effect of the active compounds of this invention can be tested regarding gly- cine increase in CSF according to Perry et al. 2008 pharmacology 55:743-754), in the psychostimulant-induced hyperlocomotion test according to Boulay et al. 2008 (Phar- macol. Biochem. Behav. 91 :47-5 8) or the social recognition test according to Shimazaki et al. 2010 (Psychopharmacology 209:263-270). For fithher information concerning biologi- cal testing, it is also referred to these three citations. s the inhibition property toward the target GlyTl transporter, active compounds ac- g to the present invention may provide fithher advantageous pharmacokinetic prop- erties.
E.g. active compounds according to the invention may show one or more advantages in the area of safety, balanced metabolism, low risk of causing drug - drug interaction and/or ba- lanced clearance.
Active compounds also might show one or more additional or alternative advantages in the area of bioavailability, high fraction absorbed, blood brain ort properties, a fa- vourable (e. g. high mean) residence time (mrt), favourable exposure in the effect com- partment and so on.
WO 17657 2012/065140 CHEMICAL MANUFACTURE Abbreviations: Ac Acetyl ACN itrile APCI Atmospheric pressure chemical ionization Boc ter—butyloxycarbony Burgess reagent: methoxycarbonylsulfamoyl-triethyl ammonium hydroxide inner salt CD1 1 l ’-carbonyldiimidazole d day dba ylideneacetone DCM dichloromethane DIPEA diisopropylethylamine DME l ,2-dimethoxyethane DMF dimethylformamide ESI electrospray ionization (in MS) EtOAc ethylacetate EtOH ethanol Exp. example h hour(s) HATU O-(7-azabenzotriazo l- l -yl)-N,N,N’,N’-tetramethyluronium— hexafluorophosphate HPLC high performance liquid chromatography HPLC-MS coupled high performance liquid chromatography-mass spectrometry M molar (mo l/L) MeOH methanol min minute(s) MS mass spectrometry NMP l -methylpyrrolidinone RP reverse Phase rt room temperature Rt retention time (in HPLC) -8l- TBTU O-(benzotriazo lyl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate TEA triethylamine TFA trifluoroacetic acid THF tetrahydro filran TLC ayer chromatography UPLC- MS ultra performance liquid chromatography - mass spectrometry Methods: UPLC-MS methods: Method 1 (acidic analytics) Instrument: LC/MS Waters Acquity UPLC System DAD, SQD single quadrupole; : HSS C18 1,8 um 2,1 x 50 mm, Temp 35°C; mobile phase: A = H20 90% + 10% CH3CN + CF3COOH 0,1%, B = CH3CN 90% + H20 10%; gradient: 0.0 min 0% B —> 1.20 min 100% B —> 1.45 min 100% B —> 1.55 min 0% B —> 1.75 min 0% B; flow rate: 0.70 mL/min; detection: UV 254 nm; detection: SQD, single quadrupole; ion source: ES+/ ES-; scan range: 90-900 amu Method 2 (NH4COOH) Instrument: LC/MS Waters Acquity UPLC System DAD, SQD single quadrupole; column: BEH C18 1,7um 2,1 x 50 mm, Temp 35°C; mobile phase: A = H20 90% + 10% CH3CN + NH4COOH 5 mmol, B = CH3CN 90% + H20 10%; nt: 0.0 min 0% B —> 1.20 min 100% B —> 1.45 min 100% B —> 1.55 min 0% B —> 1.75 min 0% B; flow rate: 0.70 mL/min; detection: UV 254 nm; ion: SQD, single quadrupole; ion source: ES+/ ES-; scan range: 90-900 amu Method 3 (QC_TFA_50mm) Instrument: LC/MS Waters Acquity UPLC System DAD, ELSD detector, SQD single qu- adrupole; column: HSS C18 1,8 um 2,1 X 50 mm, Temp 35°C; mobile phase: A = H20 90% + 10% CH3CN + CF3COOH 0,1%, B = CH3CN 90% + H20 10%; gradient: 0.0 min 0% B —> 2.40 min 100% B —> 2.70 min 100% B —> 2.80 min 0% B —> 3.00 min 0% B; flow rate: 0.70 ; ion: UV 254 nm; detection: ELSD detector; detection: SQD, single quadrupole; ion source: ES+/ ES-; scan range: 90-900 amu Method 4 (QC_ NH4COOH _50mm) Instrument: LC/MS Waters Acquity UPLC System DAD, ELSD detector, SQD single qu- adrupole; column: HSS C18 1,8 um 2,1 X 50 mm, Temp 35°C; mobile phase: A = H20 90% + 10% CH3CN + NH4COOH 5 mmol, B = CH3CN 90% + H20 10%; gradient: 0.0 min 0% B —> 2.40 min 100% B —> 2.70 min 100% B —> 2.80 min 0% B —> 3.00 min 0% B; flow rate: 0.70 mL/min; detection: UV 254 nm; ion: ELSD detector; detection: SQD, single quadrupole; ion source: ES+/ ES-; scan range: 90-900 amu HPLC-MS methods: Method 5 (lEh) Instrument: LC/MS ThermoFinnigan. lec Surveyor DAD, MSQ Quadrupole; column: i Hydro-RP80A, 4 um, 4.60 X 100 mm; eluent A: 90% water + 10% ACN + ammo- nium formate 10 mM; eluent B = ACN 90%+10% H20 + NH4COOH 10 mM; gradient: A (100) for 1.5 min, then to B (100) in 10 min for 1.5 min; flow rate: 1.2 mL/min; UV Detec- tion: 254nm; Ion source: APCI.
Method 6 (2FF) Instrument: LC/MS ThermoFinnigan HPLC Surveyor DAD, LCQ Fleet Ion Trap; column: ry Shield RP8, 5um, 4,6 x 150 mm; eluent A: 90% water + 10% ACN + HCOOH 0.1%; eluent B = ACN 90%+10% H20 + HCOOH 0.1%; gradient: 0.0 min 5% B —> 1.5 min 5% B —> 11.5 min 95% B —> 13.0 min 95% B —> 13.3 min 5% B —> 15.0 min 5% B; flow rate: 1.0 mL/min; UV Detection: 254 nm; Detection: Finnigan Fleet, Ion Trap; ion source: ES+; scan range: 100-900 amu Method 7 (2LF) Instrument: LC/MS ThermoFinnigan. lec Surveyor DAD, MSQ Quadrupole; column: Synergi Hydro-RP8, 4 um, 4.60 X 100 mm; eluent A: 90% water + 10% ACN + ammo- nium formate 10 mM; eluent B = ACN 90%+10% H20 + NH4COOH 10 mM; gradient: 0.0 min 30% B —> 1.50 min 50% B —> 8.50 min 100% B —> 13.50 min 100% B —> 14.00 min 30% B —> 15.00 min 30% B; flow rate: 0.85 mL/min; UV Detection: 254 nm; Ion source: ES+.
Method 7a Instrument: LC/MS ThermoFinnigan. lec Surveyor DAD, MSQ Quadrupole; column: Synergi Hydro RP100A, 2.5 um, 3 X 50 mm; eluent A: 90% water + 10% ACN + ammo- nium formate 10 mM; eluent B = ACN 90%+10% H20 + NH4COOH 10 mM; nt: 0.0 min 0% B —> 1.50 min 0% B —> 8.00 min 100% B —> 10.00 min 100% B —> 11.00 min 0% B —> 12.00 min 0% B; flow rate: 0.7 mL/min; UV Detection: 254 nm; Ion source: AP- CI+.
Method 7b Instrument: LC/MS ThermoFinnigan. lec or DAD, MSQ Quadrupole; column: Synergi Hydro RP100A, 2.5 um, 3 X 50 mm; eluent A: 90% water + 10% ACN + ammo- nium formate 10 mM; eluent B = ACN % H20 + NH4COOH 10 mM; gradient: 0.0 min 0% B —> 4.00 min 100% B —> 5.30 min 100% B —> 5.50 min 0% B —> 6.00 min 0% B; flow rate: 1.2 mL/min; UV ion: 254 nm; Ion source: APCI+.
GC-MS s: Method 8 (3A.2) Instrument: GC/MS Thermo Scientific TRACE GC ULTRA, DSQ II MS single quadru- pole; column: Agilent DB-5MS, 25m X 0.2 5 mmol X 0.25 um; carrier gas:Helium, 1 mL/min costant flow; oven m: 50°C, to 100°C in 10°C/min, to 200°C in 20°C/min, to 320°C in 30°C/min (hold 10 min); detection: DSQ II MS single quadrupole; ion source: EI; scan range: 50- 450 amu Chiral HPLC methods: Method 9: HPLC tus type: Agilent 1100; column: Daicel chiralpack AD-H, 5.0 um, 250 mm x mm; method: eluent hexane/IPA 70:30; flow rate: 1 mL/min, Temperature: 25°C; UV Detection: 210 nm Method 10: HPLC apparatus type: Agilent 1100; column: Daicel chiralpack AD-H, 5.0 um, 250 mm x mm; method: eluent hexane/IPA 70:30; flow rate: 1 mL/min, ature: 25°C; UV Detection: 230 nm Method 11: HPLC apparatus type: Agilent 1100; column: Daicel chiralpack AD-H, 5.0 um, 250 mm x 4.6 mm; method: eluent hexane/IPA 75:25; flow rate: 1 mL/min, Temperature: 25°C; UV Detection: 230 nm Method 12: HPLC apparatus type: Agilent 1100; column: Daicel chiralpack AD-H, 5.0 um, 250 mm x 4.6 mm; method: eluent hexane/IPA 70:30; flow rate: 1 mL/min, Temperature: 25°C; UV Detection: 230 nm Method 13: HPLC apparatus type: Agilent 1100; column: Daicel chiralpack AD-H, 5.0 um, 250 mm x 4.6 mm; method: eluent hexane/IPA 80:20; flow rate: 1 mL/min, Temperature: 25°C; UV Detection: 230 nm Method 14: HPLC apparatus type: t 1100; column: Daicel chiralpack AS-H, 5.0 um, 250 mm x 4.6 mm; : eluent hexane/IPA 70:30; flow rate: 0.8 , Temperature: 25°C; UV Detection: 230 nm Method 15: HPLC apparatus type: Agilent 1100; column: Daicel chiralpack AS-H, 5.0 um, 250 mm x 4.6 mm; method: eluent hexane/EtOH 70:30; flow rate: 0.8 mL/min, Temperature: 25°C; UV Detection: 230 nm Method 16: HPLC apparatus type: Agilent 1100; column: Daicel pack AD-H, 5.0 um, 250 mm x 4.6 mm; method: eluent hexane/IPA 95:5; flow rate: 1 mL/min, Temperature: 25°C; UV ion: 210 nm Method 17: HPLC apparatus type: Agilent 1100; column: Daicel chiralpack AS-H, 5.0 um, 250 mm x 4.6 mm; method: eluent hexane/IPA 75:25; flow rate: 0.9 mL/min, Temperature: 25°C; UV Detection: 230 nm Method 18: HPLC apparatus type: Agilent 1100; column: Daicel chiralpack AS-H, 5.0 um, 250 mm x 4.6 mm; method: eluent hexane/IPA 80:20; flow rate: 1 , Temperature: 25°C; UV Detection: 230 nm Method 19: HPLC tus type: Agilent 1100; column: Daicel chiralpack AS-H, 5.0 um, 250 mm x 4.6 mm; method: eluent /IPA 90:10; flow rate: 1 mL/min, Temperature: 25°C; UV Detection: 230 nm Method 20: HPLC apparatus type: Agilent 1100; column: Daicel chiralpack AD-H, 5.0 um, 250 mm x 4.6 mm; method: eluent hexane/IPA 85:15; flow rate: 1 mL/min, Temperature: 25°C; UV Detection: 230 nm Method 21: HPLC apparatus type: Agilent 1100; column: Daicel chiralpack OJ-H, 5.0 um, 250 mm x 4.6 mm; method: eluent hexane/IPA 80:20; flow rate: 1 mL/min, Temperature: 25°C; UV Detection: 230 nm Method 22: HPLC apparatus type: t 1100; column: Daicel chiralpack IA, 5.0 um, 250 mm x 4.6 mm; method: eluent hexane/IPA 80:20; flow rate: 1 mL/min, Temperature: 25°C; UV De- tection: 230 nm Method 23: HPLC apparatus type: Agilent 1100; column: Daicel pack IA, 5.0 um, 250 mm x 4.6 mm; method: eluent hexane/IPA 70:30; flow rate: 1 mL/min, Temperature: 25°C; UV De- tection: 230 nm Method 24: HPLC apparatus type: Agilent 1100; column: Daicel chiralpack IA, 5.0 um, 250 mm x 4.6 mm; method: eluent hexane/IPA 75:25; flow rate: 1 mL/min, Temperature: 25°C; UV De- tection: 230 nm Method 25: HPLC apparatus type: t 1100; column: Daicel chiralpack IA, 5.0 um, 250 mm x 4.6 mm; : eluent /IPA 85:15; flow rate: 1 mL/min, Temperature: 25°C; UV De- tection: 230 nm Microwave heating: Discover® CEM instruments, equipped with 10 and 35 mL vessels; General comment concerning the tation of the structures Some active compounds have stereogenic center(s). The structures ed in the experi- mental examples will not necessarily show all the possible chemical possibilities of said compounds but only one. 1 . . . 2 For R ’ only the relat1ve configuratlon w1th respect to R . . 1s known: the1r relat1ve configu-. ration is always syn .
The structural presentations of the compounds of the present inventions will not show a stereochemlcal bond With regard to the bond of the scaffold to R. . 1 but a plain one plus an. additional comment, that indicates if the described compound is a mixture of diastereiso- mers, a mixture of enantiomers, a specific diastereomer or a specific enantiomer of which the absolute configuratlon at sa1d R bond 1s not determmed. The 0n of R1 1s the bridgehead position.
Experimental: e 1a 1,1,1-Trifluoroacetone (25 g, 216.419 mmol) in ethyl ether (20 mL) is added se to (- )-beta-chlorodiisopinocampheylborane (81 g, 252.53 mmol) in ethyl ether (125 mL) cooled to -24°C. Stirring is continued at -24°C for 5d. 3-Phenyl propionaldehyde (35.4 mL, 259.7 mmol) is added dropwise and the reaction mixture is warmed to room temperature. After 24h, the reaction mixture is cooled to 0°C and 4N NaOH is added dropwise until pH > 10.
The reaction mixture is warmed to room temperature and stirred at that temperature for 30 min. KH2PO4, is added until pH=7/8. The layers are separated and the aqueous layer is extracted twice with ethyl ether . The combined organic layers are dried over Na2SO4 and distilled twice to obtain the title compound (b.p. 30-75°C, 18.3 g, content 65%, 48%).
Example 2a O=S=O Trimethylsilyldiazomethane in hexanes (2M, 2.153 mL, 4.3 mrnol) is added dropwise to 5- (ethanesulfonyl)fluorobenzoic acid (500 mg, 2.15 mmol) in DCM (5 mL) and MeOH (2.5 mL) cooled to 0°C. Stirring is continued for 120 min, then the reaction mixture is washed with ted . The organic layer is separated, dried and evaporated un- der reduced pressure to h the title compound (420 mg, 79%).
GC-MS (Method 8): Rt = 11.36 min MS (EI pos): m/z = 246 (M)+ Example 2b | F O O e 1a (1748 mg, 77% content, 11,80 mrnol) is added to sodium hydride (60% sion in mineral oil, 472 mg, 11.80 mmol) in THF (5 mL). Stirring is continued at room temperature for 45 min. Methyl 5-bromofluorobenzoate (1100 mg, 4.72 mmol) in THF (5 mL) is added and stirring is continued at room temperature overnight. Example la (65 mg, 75% t, 0.43 mmol) is added to sodium hydride (60% suspension in mineral oil, 17 mg, 0.43 mmol) in THF (1 mL) and the ing mixture added to the reaction mixture and stirring is continued at room temperature overnight. The reaction mixture is diluted with DCM, washed with saturated NH4C1, dried and concentrated under reduced pressure giving a residue. Trimethylsilyldiazomethane in hexanes (2M, 2.153 mL, 4.3 mmol) is added dropwise to the residue in DCM (5 mL) and MeOH (2.5 mL) cooled to 0°C. Stirring is continued for 120 min, then the reaction mixture is ated under reduced re to fiamish the title compound (200 mg, 50% content, 7%).
HPLC-MS (Method 2): Rt = 1.38 min MS (ESI pos): m/z = 327 (M+H)+ Example 3a F F O:\S e 1a (278 mg, 75% content, 1.83 mmol) is added to sodium hydride (60% suspen- sion in mineral oil, 62 mg, 1.54 mmol) in THF (1 mL). ng is continued at room tem- perature for 45 min. Example 2a (150 mg, 0.61 mmol) in THF (1 mL) is added and stirring is continued at room temperature overnight. Example 1a (65 mg, 75% content, 0.43 mmol) is added to sodium hydride (60% suspension in mineral oil, 17 mg, 0.43 mmol) in THF (1 mL) and the resulting mixture added to the reaction e and stirring is continued at room temperature overnight. Volatiles are evaporated under reduced pressure and the resi- due treated with DCM, washed with saturated NH4C1, dried with a phase separator car- tridge, d and concentrated under reduced pressure giving a residue that is purified by flash chromatography (eluent 80-100% DCM/cyclohexane) to filmish the title compound (130 mg, 63%).
HPLC-MS (Method 6): Rt = 11.04 min MS (ESI pos): m/z = 341 (M+H)+ Example 3b Example 2b (200 mg, 50% content, 0.31 mmol), 2-(tri-n-butylstannyl)-oxazole (806 ul, 3.82 mmol) and tetrakis(triphenylphosphine)palladium(0) (106 mg, 0.09 mmol) in toluene (4 mL) are degassed with a flow of nitrogen for 5 minutes and then heated to 130°C in a microwave oven for 1 hour. Volatiles are evaporated under reduced pressure, the resulting residue redissolved in dichloromethane, washed with water, dried using a phase tor cartridge, and concentrated under reduced pressure. The ing residue is purified by flash chromatography (eluent 20% ethyl acetate/cyclohexane) to furnish the title compound (30 mg, 31%).
HPLC-MS (Method 2): R = 1.25 min MS (ESI pos): m/z = 316 (M+H)+ Literature Examples Structure Reference S-Methane- yl((S)- /107334 2,2,2-trifluoro (using example methyl-ethoxy)- 1 a) benzoic acid -Methane- US2006/160788 sulfonyl((R)- (using (R)-1,1,1- 2,2,2-trifluoro trifluoro-propan— methyl-ethoxy)- 2-o 1) benzoic acid ane- sulfonyl(2,2,2- trifluoromethyl- US2005/209241 ethoxy)-benzoic acid Example 4d ic mixture) Potassium tert-butoxide (0.666 g, 5.93 mmol) followed by 5-cyanofluorobenzoic acid (700 mg, 4.24 mmol) are added portionwise to 1,1,1-trifluoropropanol (0.594 mL, 6.36 mmol) in THF (15 mL). ng is continued for 3 h at room temperature followed by 1h at reflux. The reaction mixture is diluted with THF (5 mL) and DMF (5 mL), and d at room temperature overnight. Potassium tert-butoxide (0.666 g, 5.93 mmol) is added to 1,1,1-trifluoropropanol (0.594 mL, 6.36 mmol) in THF (5 mL) and the resulting mixture added to the on mixture dropwise. Stirring is continued for 6h at 80°C. Volatiles are removed under reduced pressure and the resulting residue partitioned between 10% citric acid and DCM. The organic layer is separated, washed with brine and evaporated under WO 17657 reduced pressure to give a residue which is triturated with eum ether to fiamish the title compound (0.95 g, 87%).
HPLC-MS (Method 7): Rt = 6.41 min MS (ESI pos): m/z = 260 (M+H)+ Example 4e Lithium hydroxide monohydrate (48 mg, 1.15 mmol) is added to example 3a (130 mg, 0.38 mmol) in THF (5 mL) and water (5 mL). Stirring is continued at rt ght, then the reaction mixture is diluted with EtOAc and water. The aqueous layer is separated and the organic layer extracted with 5% NaHCO3. The combined aqueous layers are acidified to pH=3 with lN HCl and extracted with EtOAc. The organic layer is separated, dried and evaporated under reduced pressure to filI'IllSh the title nd (112 mg, 90%).
HPLC-MS (Method 2): Rt =0.8l min MS (ESI pos): m/z = 327 (M+H)+ Example 4f Cesium carbonate (2.240 g, 6.87 mrnol) is added to 2-fluoromethanesulfonyl—benzoic acid (500 mg, 2.29 mmol) in 2-propanol (15 mL). Stirring is continued for 72h at 80 CC.
Volatiles are removed under reduced pressure and the resulting residue partitioned between 4N HCl and DCM. The organic layer is separated, dried using a phase separator cartridge and evaporated under vacuum to h the title compound (0.60 g, 80% content, 81%).
HPLC-MS (Method 2): Rt = 0.52 min MS (ESI pos): m/z = 259 (M+H)+ Example 4g Potassium ide (27 mg, 0.48 mrnol) is added to example 3b (30 mg, 0.09 mrnol) in EtOH (20 mL). The reaction mixture is ed with 4N HCl and extracted with DCM.
The organic layer is separated and evaporated under reduced re to filrnish the title compound (20 mg, 70%).
HPLC-MS (Method 2): Rt =0.88 min MS (ESI neg): m/z = 320 (M-H)" The following es are synthesized in analogy to the preparation of example 4d: MS (ESI pos): Example Structure Reactant(s) 2-methy1propanol (326 111, 3.53 mmol); 2-fluoro 9.27, methanesulfonyl- + 273 (M+H) method 6 benz01c ac1d (700_ _ mg, 3.21 mmol) 2-methy1propen— 1-ol (1283 111, 15.12 mmol); 2-fluoro 0.97, methanesulfonyl- + 271 (M+H) method 1 benzoic acid (3000 mg, 13.75 mmol) 1a (2.159 g, 64% content, 12.11 mmol); 5-cyano 1.03, 260 (M+H) fluorobenz01c ac1d_ _ method 1 (500 mg, 3.03 mmol) (R)- 1 , 1, 1 -trifluoropropan —2-ol (1.842 g, 75% content, 12.11mmol);5- 1.04, 260 (M+H) 2- method 1 fluorobenzoic acid (500 mg, 3.03 mmol) (R)- 1 , 1, 1 -trifluoropropanol , (216 mg, 75% content, 1.42 mol); 5- 1.00, 326 (M+H) (ethanesulfonyl) method 1 fluorobenzoic acid (300 mg, 1.29 mmol) 2-Fluoro methanesulfonyl- c acid (350 6.91, mg, 1.60 mmol); method 6 + 287 (M+H) (R)-(-) hydroxytetrahydro- furan (145 L, 1.76 mmol) O=S=O Example 4i (500 mg, 1.85 mmol) is heated in NMP for 3h at 175 CC followed by 3h at 210°C. The reaction mixture is cooled to room ature and diluted with aq. NH4Cl and DCM. The organic layer is separated and extracted with 1N NaOH. The aqueous layer is acidified with 1N HCl and extracted with DCM. The resulting organic layer is separated, The organic layer is separated, dried and evaporated under reduced pressure to fiamish a e that is purified by preparative HPLC (stationary phase: Sunfire C18 ODB 5 um 19 x 100 mm. Mobile phase: ACN/H20 + NH4COOH 5 mmol). Fractions containing the title compound are combined and freeze dried to fiamish the title compound (120 mg, 24%).
HPLC-MS (Method 1): Rt = 0.95 min MS (ESI pos): m/z = 271 (M+H)+ Exam le 5a racemic mixture To a solution ofracemic icyclo[3.1.0]hexane-1,3-dicarboxylic acidtert-butyl ester (600 mg, 2.64 mmol) in dry THF (12 mL), CDI (471 mg, 2.90 mmol) is added. Mixture is stirred at room temperature for 1.5 h, then ammonium ide (6 mL of a 30% solution in water) is added and the mixture stirred for additional 15 min. Solvents are evaporated, crude ved in EtOAc, washed with 0.1 N hydrochloric acid, sat. NaHCO3 and brine.
Organic phases are separated, dried and evaporated under vacuum to obtain the title com- pound (505 mg, 85%) used in the next step without any fiarther purification.
S d 5): Rt = 6.43 min MS (APCI): m/z = 127 (M-tBuOCO+H)+ Example 6a gracemic mixture) Example 5a (505 mg, 2.23 mmol) is dissolved in 14.4 mL of hydrochloric acid (4M solu- tion in dioxane) cooled to 0°C. Stirring is continued for 2h at rt. Solvent is removed under vacuum to obtain the title compound (260 mg, 72%) used in the next step Without any filr- ther purification.
S (Method 5): Rt = 1.74 min MS (APCI): m/z = 127 (M+H)+ Exam le 7a diastereomeric mixture N O O F o=s\\ To a solution of example 6a (210 mg, 1.29 mmol) in dry DCM (12 mL), HATU (638 mg, 1.68 mmol) and dry TEA (0.540 mL, 3.874 mmol) are added. Mixture is stirred at room temperature for 10 min, then example 4a (403 mg, 1.29 mmol) is added and the mixture stirred at room ature for additional 2 h. 0.1 N hydrochloric acid and DCM are add- ed, organic phase is separated, washed with brine, dried using a phase separator cartridge and evaporated under vacuum. The crude is purified by flash cromatography (eluent 0-5% MeOH/DCM) to obtain the title compound as a White solid (370 mg, 68%) S (Method 2): Rt = 0.72 min MS (ESI pos): m/z = 421 (M+H)+ Exam le 7b diastereomeric mixture N O *‘ o 3W F F /‘O\ The title compound is prepared as described for example 7a, using example 4b (90 mg, 0.29 mmol).
HPLC-MS (Method 2): Rt = 0.69 min MS (ESI pos): m/z = 421 (M+H)+ Example 8a gdiastereomeric mixture) / 04FF N/ F F o=s\\ To a solution of example 7a (370 mg, 0.88 mmol) in dry DCM (12 mL), Burgess reagent (294 mg, 1.23 mmol) is added and the e stirred at 35°C for 3 h. Burgess reagent (50 mg, 0.21 mmol) is added and the mixture stirred at 35°C for 2 h. A diluted solution of HCl (0.2 M) is added, organics separated, washed with brine, dried using a phase separator car- tridge and evaporated under vacuum. The crude is d by flash cromatography (eluent 50-70% AcOEt/cyclohexane) to obtain the title compound (253 mg, 71%) HPLC-MS (Method 6): Rt = 9.72 min MS (ESI pos): m/z = 403 (M+H)+ Exam le 8b diastereomeric mixture The title compound is prepared as described above for example 8a, starting from example 7b (82 mg, 0.19 mmol).
HPLC-MS (Method 2): Rt =0.9l min MS (ESI pos): m/z = 403 (M+H)+ Example 9a (diastereomeric mixture) N O HN F F F O=S\\ To a solution of example 8a (0.16 g, 0.4 mmol) in EtOH (3 mL), hydroxylamine (49 ul of a 50% solution in water, 0.79 mmol) is added and the mixture stirred under ave ir- radation for 30 min at 100°C. After evaporation of the solvent, the title compound (0.17 g, 98%) is used in the next step t any fiarther purification.
HPLC-MS (Method 2): Rt =0.73 min MS (ESI pos): m/z = 436 (M+H)+ Exam le 9b diastereomeric mixture N O HN ‘BVF F F 07830 The title compound is prepared as described above for example 9a using example 8b (60 mg, 0.15 mmol).
HPLC-MS (Method 1): Rt =0.73 min MS (ESI pos): m/z = 436 (M+H)+ WO 17657 Exam le 10a diastereomeric mixture OOJ>/F H N N H O:f=O H2 N Acetyl chloride (1.082 mL, 14.91 mmol) is added to EtOH (1.5 mL) and chloroform (2.0 mL) cooled to 0°C. After 20 min a solution of example 8a (200 mg, 0.49 mmol) in chloro- form (2.0 mL) is added and the mixture warmed to room temperature overnight. Volatiles are evaporated under reduced pressure and ammonia solution (7N in MeOH, 2.13 mL, 14.91 mmol) is added to resulting e redissolved in EtOH (2.0 mL). The reaction mix- ture is warmed to room temperature and stirring continued overnight. After evaporation of the solvent, the title compound (208 mg, 100%) is used in the next step without any further ation.
HPLC-MS d 2): Rt =0.87 min MS (ESI pos): m/z = 420 (M+H)+ Exam le 10b diastereomeric mixture H2N 0:?20 Example 10b is prepared as described for example 10a using example 8b (145 mg, 0.36 mmol).
HPLC-MS (Method 2): Rt =0.85 min MS (ESI pos): m/z = 420 (M+H)+ - l 0 l - Exam le lla racemic mixture ~—/< Ho/\/NH ; \ To a on ofracemic 3-azabicyclo[3. l .0]hexane-l,3-dicarboxylic acidtert-butyl ester (0.1 g, 0.44 mmol) in dry DMF (3 mL), TBTU (0.17 g, 0.52 mmol) and dry TEA (0.079 mL, 0.57 mmol) are added. e is stirred at room temperature for l h, then ethanola- mine (0.03 mL, 0.48 mmol) is added and the mixture stirred for additional 30 min. Sol- vents are evaporated, crude dissolved in EtOAc, washed with a saturated solution of so- dium bicarbonate and brine. Organic phases are separated, dried and evaporated under va- cuum to obtain the title compound (55 mg) used in the next step Without any fiarther purifi- cation.
HPLC-MS (Method 1): Rt = 6.34min MS (ESI pos): m/z = 269 (M+H-tBu)+ Exam le llb diastereomeric mixture 0 ZI O 3 Example llb is prepared as described for example lla, using racemic 3- azabicyclo[3. l .0]hexane-l,3-dicarboxylic acidtert-butyl ester (200 mg, 0.88 mmol) and )-l-aminopropanol (73 mg, 0.968 mmol).
HPLC-MS (Method 2): Rt = 0.77 min MS (ESI pos): m/z = 285 (M+H)+ Exam le l2a racemic mixture To a solution of example lla (55 mg) in dry DCM (2 mL) Dess-Martin periodinane (0.95 g) is added and the mixture stirred at room temperature for lh. A saturated solution of NaHCO3 is added, mixture is diluted with DCM, c phases are separated, dried and evaporated under vacuum to obtain the title compound (53 mg) used in the next step with- out any filrther ation.
HPLC-MS (Method 2): Rt = 0.72 min MS (ESI pos): m/z = 269 (M+H)+ Exam le 12b racemic mixture Example 12b is prepared as described for example l2a using e llb (224 mg, 80% content, 0.630 mmol).
HPLC-MS (Method 2): Rt = 0.83 min MS (ESI pos): m/z = 283 (M+H)+ Exam le 13a racemic mixture [0/ MkO To a solution of example 12a (0.053 g) in dry THF (0.5 mL) Burgess reagent (0.05 g, 0.24 mmol) is added. Mixture is heated under microwave tion for l min at 110°C. Burgess reagent (0.024 g, 0.10 mmol) is added. Mixture is heated under microwave irradation for l min at 110°C. t is evaporated, crude dissolved in DCM, organics washed with water and brine, dried and evaporated under vacuum. The crude is d by flash cromatogra- phy (cyclohexane/EtOAc from 50:50 to 0:100) to obtain the title compound (0.015 g, puri- ty 50%).
HPLC-MS (Method 2): Rt =l.05 min MS (ESI pos): m/z = 195 (M-tBu+H)+ Exam le 13b racemic mixture Example 13b is prepared as described for example 13a using example 12b (176 mg).
HPLC-MS (Method 6): Rt =10.9l min MS (ESI pos): m/z = 265 (M+H)+ —104— Exam le 14a racemic mixture DMF (1 drop) and oxalyl chloride (82 ul, 0.97 mmol) are added to a solution ofracemic 3- azabicyclo[3. l .0]hexane-l,3-dicarboxylic acidtert-butyl ester (200 mg, 0.88 mmol) in THF (2.5 mL) cooled to 0°C. After stirring for 2h at 0°C, ACN (2.5 mL) and trimethylsi- lyldiazomethane in hexanes (2M, 880 ul, 1.76 mmol) are added and the reaction mixture stirred at 0°C for 2h. Hydrochloric acid in dioxane (4M, 440 ul, 1.76 mmol) is added and the reaction mixture warmed to room temperature. After stirring for 15 min at room tem- perature, the on mixture is diluted with EtOAc and washed with saturated NaHCO3 and brine, dried over Na2804. After evaporation of the solvent, the resulting residue is dis- soled in DME (2.5 mL) and 2-aminopyridine (145 mg, 1.54 mmol) is added. The reaction mixture is heated at 90°C for 2h and les are evaporated under reduced pressure. The resulting e is redissolved in DCM, washed twice with water and brine and dried over Na2804. After evaporation ofthe solvent, the title nd (172 mg, 65%) is used in the next step without any fiarther ation.
HPLC-MS (Method 2): Rt = 1.03 min MS (ESI pos): m/z = 300 (M+H)+ WO 17657 Exam le 14b racemic mixture DMF (1 drop) and oxalyl chloride (41 ul, 0.48 mmol) are added to a solution ofracemic 3- azabicyclo[3. l .0]hexane-l,3-dicarboxylic -tert-butyl ester (100 mg, 0.44 mmol) in THF (1.25 mL) cooled to 0°C. After stirring for 2h at 0°C, ACN (1.25 mL) and trimethyl- silyldiazomethane in hexanes (2M, 440 ul, 0.88 mmol) are added and the reaction mixture stirred at 0°C for 2h. Hydrochloric acid in e (4M, 220 ul, 0.88 mmol) is added and the reaction mixture warmed to room temperature. After stirring for 15 min at room tem- perature, the reaction mixture is diluted with EtOAc and washed with saturated NaHCO3 and brine, dried over . After evaporation of the solvent, the resulting residue is dis- solved in absolute EtOH (2 mL) and thioacetamide (52 mg, 0.69 mmol) is added. Mixture stirred at room temperature overnight. Solvent evaporated, crude purified by flash croma- tography (0-50% EtOAc:cyclohexane) to obtain 0.044 g ofthe title compound.
HPLC-MS (Method 6): Rt = 11.50 min MS (ESI pos): m/z = 281 (M+H)+ Exam le 14c racemic mixture o>_N Oxalyl de (410 ul, 4.84 mmol) and a drop ofDMF are added to c 3- azabicyclo[3. l .0]hexane-l,3-dicarboxylic -tert-butyl ester (1000 mg, 4.40 mmol) in DCM (12 mL) cooled to 0°C. After stirring at that temperature for 2h, ACN (12 mL) fol- lowed by trimethylsilyldiazomethane in hexanes (2M, 4.4 mL, 8.80 mmol) are added dropwise. The reaction mixture is stirred at 0°C for 2h and then at room temperature over- night. The reaction mixture is then cooled to 0°C, hydrobromic acid (48%, 989 ul, 8.80 mmol) is added dropwise and stirring is continued at rt for 10 min. Solid NaHCO3 is added until basic pH and stirring is continued for 5 min. The reaction mixture is diluted with EtOAc, washed with water and saturated NaHCO3, brine, dried over Na2SO4 and evapo- rated under reduced pressure to obtain a residue, 980 mg. 200 mg of such residue are mixed with trifluoroethanethioamide (170 mg, 1.31 mmol) in EtOH (1 mL) and heated at 70°C overnight. Volatiles are evaporated under d pressure and the result- ing residue purified by flash chromatography (eluent 10% EtOAc/cyclohexane) to furnish the title compound (146 mg, 49%).
HPLC-MS (Method 2): Rt =1 .48 min MS (ESI pos): m/z = 279 (M-tBu+H)+ Exam le l4d racemic mixture O>_N 1O /N DMF (1 drop) and oxalyl chloride (410 ul, 4.84 mmol) are added to a solution of racemic 3-azabicyclo[3. l .0]hexane-l,3-dicarboxylic acidtert-butyl ester (1000 mg, 4.40 mmol) in THF (12.5 mL) cooled to 0°C. After stirring for 2h at 0°C, ACN (12.5 mL) and trime- thylsilyldiazomethane in s (2M, 4.4 mL, 8.80 mmol) are added. After stirring for 2h at 0°C, hydrochloric acid in dioxane (4M, 2.2 mL, 8.80 mmol) is added and the reaction mixture warmed to room temperature. After stirring for 15 min at room temperature, the reaction e is diluted with EtOAc and washed with saturated NaHCO3 and brine, dried over Na2804. 200 mg out of the 1200 mg obtained after evaporation ofthe t are dissolved in NMP (4 mL) and acetamide (80 mg, 1.35 mmol) is added. The reaction mixture stirred at 100°C for 34 h and then diluted with EtOAc, washed with water, brine, dried over NaZSO4, filtered and concentrated under reduced pressure giving a residue that is purified by flash chromatography (eluent 0-30% EtOAc/cyclohexane) to filmish the title compound (9 mg, 13%).
HPLC-MS (Method 5): Rt = 9.02 min MS : m/z = 165 tBu +H)+ Exam le 14e racemic mixture o>_N Example 5a (100 mg, 0.442 mmol) and chloroacetone (106 ul, 1.32 mmol) in EtOH (2 mL) are stirred at 70°C for 2.5 d. Volatiles are evaporated under reduced pressure to furnish the title compound that is used as such (70 mg, 44% content, 27%).
HPLC-MS (Method 2): Rt = 1.22 min MS (ESI pos): m/z = 209 (M-tBu +H)+ Exam le 14f racemic mixture o>_N DMF (1 drop) and oxalyl de (696 ul, 8.23 mmol) are added to a solution of racemic 3-azabicyclo[3.1.0]hexane-1,3-dicarboxylic acidtert-butyl ester (1700 mg, 7.48 mmol) in DCM (20 mL) cooled to 0°C. After stirring for 2h at 0°C, ACN (20 mL) and trimethylsi- lyldiazomethane in hexanes (2M, 7.5 mL, 14.96 mmol) are added. After stirring for 2h at 0°C and overnight at room temperature, hydrobromic acid (1.7 mL, 48%, 14.96 mmol) is added and the on mixture warmed to room temperature. After stirring for 20 min at room temperature, the reaction e is diluted with EtOAc and washed with saturated NaHCO3 and brine, dried over Na2804. The residue obtained after evaporation of vola- tiles, 1370 mg, is split in two equal aliquots and each ofthem dissolved in EtOH (3 mL) and cyclopropanecarboxamide (372 mg, 4.37 mmol) is added. The reaction mixture stirred at 70°C for 32 h and then diluted with EtOAc, washed with ted NaHCOg, brine, dried using a phase separator cartridge and concentrated under reduced pressure giving a e that is purified by flash chromatography (eluent 0-25% EtOAc/cyclohexane) to filmish the title compound (163 mg, 13%).
HPLC-MS (Method 2): Rt = 1.20 min MS (ESI pos): m/z = 291 (M+H)+ Exam le 14 c mixture Example 5a (980 mg, 4.33 mmol) and o-1,1,1-trifluoroacetone (1.38 ml, 13.00 mmol) in anhydrous dioxan (10 mL) are stirred at 100°C for 3 hours and volatiles are evaporated under reduced pressure. The residue is ved in anhydrous DCM (5ml), cooled at 0°C, a solution of methansulfonylchloride (0.50 ml, 6.50 mmol) in 1ml of anhy- drous DCM is added and the reaction mixture is then stirred overnight at room temperature then purified by Si flash chromatography (eluent 5-10% EtOAc/cyclohexane) to furnish the title compound (515 mg, content 95%, 35%).
GC-MS (Method 8): Rt = 10.59 min MS (ESI pos): m/z = 318 (M)+ Exam le 15a racemic mixture 7L0M \N Racemic 3-azabicyclo[3. l .0]hexane-l,3-dicarboxylic acidtert-butyl ester (200 mg, 0.88 mmol) and CD1 (214 mg, 1.320 mmol) in DMF (5 mL) are stirred at rt for 45 min; N- hydroxyacetamidine (93 mg, 1.258 mmol) is then added to the reaction mixture and stirring is continued over weekend. The reaction mixture is then heated under microwave irra- dation (100°C) for 20 min. les are evaporated under reduced pressure and the result- ing residue partitioned between EtOAc and water. The organic layer is separated, washed with brine, dried using a phase tor cartridge and trated under reduced pressure to give a residue that is purified by flash chromatography t 0-30% EtOAc/petroleum ether) to fiarnish the title compound (169 mg, 72%).
HPLC-MS (Method 5): Rt = 8.51 min MS (APCI): m/z = 166 (M-COztBu +H)+ Exam le 15b racemic mixture +0M \N O\Na/F Racemic 3-azabicyclo[3.1.0]hexane-l,3-dicarboxylic acidtert-butyl ester (200 mg, 0.88 mmol) and CD1 (214 mg, 1.32 mmol) in DMF (5 mL) are stirred at room temperature for 45 min. 2,2,2-Trifluoro-N'-hydroxy-acetamidine (161 mg, 1.26 mmol) is then added and the on mixture stirred at room temperature overnight and then heated to 110°C in a microwave oven for 4 hours and 40 min. Volatiles are removed under reduced pressure and the residue olved in EtOAc, washed with water and brine. The organic layer is then concentrated under reduced pressure and the resulting residue purified by flash chromato- graphy (eluent 0-30% EtOAc/cyclohexane) to fiarnish the title compound (202 mg, 72%).
S (Method 5): Rt = 10.28 min MS (APCI): m/z = 220 (M-COztBu+H)+ Exam le 15c racemic mixture +0M \N O\ / The title compound is prepared in analogy to example 15b starting from N‘- ycyclopropanecarboximidamide (207.3 mg, 1.76 mmol) in place of 2,2,2-Trifluoro- N'-hydroxy-acetamidine and heating, after the intermediate formation, into a ave oven at 110°C for 2 hours to obtain 150 mg of product (58%) HPLC-MS (Method 7): Rt = 7.78 min MS (ESI pos): m/z = 236 (M-tBu+H)+ -l l 1- Exam le 15d racemic mixture 1,1-carbonyldiimidazole (1.26 g, 7.79 mmol) is added to a solution of 1- trifiuoromethylcyclopropanecarboxylic acid (1.00 g, 6.49 mmol) in 10 ml of anhydrous ACN and stirred at room temperature for 2 hours. 30% aqueous ammonium hydroxide so- lution (6 ml, 46.22 mmol) is added and the reaction e is stirred overnight. EtOAc and brine are added, organic layer is separated, washed with 1N aqueous HCl solution, dried over Na2S04 and concentrated under reduced pressure to obtain 0.81 g ofprimary am- ide. 400 mg of this amide are dissolved, under nitrogen atmosphere, in 5 ml of THF, roacetic ide (1.82 ml, 13.06 mmol) is added and the reaction mixture is heated overnight at 60°C; after cooling to room temperature potassium carbonate (3.25 g, 23.51 mmol), hydroxylamine hydrochloride (556 mg, 7.84 mmol) and MeOH (30 ml) are added and the reaction mixture is heated at 65°C and stirred overnight.
The cooled mixture is filtered and concentrated under reduced pressure, the residue is sus- pended in EtOH and stirred cooling with an ice-water bath. A precipitate is filtered out over a celite pad then the e is concentrated under reduced pressure. The ed residue is added, after lh hour stirring, to a solution ofracemic 3-azabicyclo[3.1.0]hexane- l,3-dicarboxylic acidtert-butyl ester (227 mg, 1.00 mmol) and 1,1-carbonyldiimidazole (176 mg, 1.08 mmol) in DMF (2ml) and the reaction mixture is d overnight at room temperature then heated under ave irradation (110°C) for 30 minutes. Solvent is concentrated under reduced pressure, residue is partitioned between DCM and 10% aque- ous citric acid solution, organic layer is separated, washed with saturated aqueous NaHC03 solution and brine then concentrated under reduced pressure to obtain the title compound (240 mg, 51%).
S (Method 2): Rt = 1.39 min MS (ESI pos): m/z = 377 (M+NH4)+ -1 12- Exam le 16a racemic mixture H N\A\O Racemic 3-azabicyclo[3.1.0]hexane-1,3-dicarboxylic acidtert-butyl ester (300 mg, 1.32 mmol), TBTU (636 mg, 1.980 mmol) and DIPEA (1.15 mL, 6.60 mmol) in DMF (4 mL) are stirred at rt for 10 min; acetic hydrazide (196 mg, 2.64 mmol) is then added to the reac- tion mixture and stirring is ued for 4h. Volatiles are evaporated under reduced pres- sure and the resulting e partitioned between EtOAc and saturated . The or- ganic layer is separated, washed with 10% citric acid and brine, dried over NaZSO4 and concentrated under reduced pressure to give a residue that is purified by flash chromato- graphy (e1uent 0-5% MeOH/DCM) to fiamish the title compound (72 mg, 19%).
S (Method 5): Rt = 5.97 min MS (APCI): m/z = 184 (M-COztBu +H)+ Exam le 17a racemic mixture :0 $0 Burgess reagent (335 mg, 1.40 mmol) is added to example 16a (100 mg, 0.35 mmol) in 1,2-dichloroethane (2.5 mL) and the reaction mixture is then heated under microwave irra- dation (120°C) for 20 min. les are evaporated under reduced pressure and the result- -ll3- ing residue partitioned between EtOAc and water. The organic layer is separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give a residue that is purified by flash chromatography (eluent 20-50% EtOAc/cyclohexane) to filmish the title nd (77 mg).
HPLC-MS (Method 5): Rt = 7.86 min MS (APCI): m/z = 266 (M+H)+ Example 18a gracemic mixture) o>_N +0 Oi Burgess reagent (2.890 g, 12.13 mmol) is added to example 5a (1.960 g, 90% content, 7.79 mmol) in DCM (28 mL) and the reaction mixture is d at 35°C for 3h. The reaction mixture is diluted with DCM, washed with 0.N HCl and brine, dried using a phase separa- tor cartridge. The organic layer is then concentrated under reduced pressure and the result- ing residue purified by flash tography (eluent 0-20% EtOAc/cyclohexane) to flir- nish the title compound (1.590 g, 98%).
HPLC-MS (Method 2): Rt = 1.09 min MS (ESI pos): m/z = 209 (M+H)+ The enantiomers ofthe title compound are separated by HPLC using a chiral stationary phase.
Method for separation: HPLC apparatus type: Agilent 1100; column: Daicel chiralpack AD-H, 5.0 um, 250 mm x mm; method: eluent /IPA 95:5; flow rate: 15 mL/min, ature: 25°C; UV Detection: 210 nm —114— Chiral HPLC Example structure Rt [mm]_ Exp. l8b Enantiomer l 6.3 5 3 Unknown absolute d 16) stereochemistry at head Exp. l8c Enantiomer 2 7. l 99 Unknown absolute (Method 16) stereochemistry at bridgehead Exam le l9a racemic mixture O H HN OH To a solution of e l8a (300 mg, 1.44 mmol) in EtOH (2 mL), hydroxylamine (l77 ul, 50% solution in water, 2.88 mmol) is added and the mixture stirred under microwave irradation for 30 min at 100°C. After evaporation of the solvent, the title compound (340 mg, 98%) is used in the next step without any further purification.
HPLC-MS (Method 2): Rt =0.90 min MS (ESI pos): m/z = 242 (M+H)+ -l 15- Exam le 19b sin le enantiomer unknown absolute stereochemistr at brid ehead 7L0M H HN OH The title compound is prepared as described for example 19a, starting from example 18b (45 mg, 0.21 mmol).
HPLC-MS (Method 2): Rt =0.92 min MS (ESI pos): m/z = 242 (M+H)+ Exam le 19c sin le enantiomer unknown absolute stereochemistr at brid ehead 7L0M H HN OH The title compound is prepared as described for e 19a, starting from e 18c (45 mg, 0.21 mmol).
HPLC-MS (Method 2): Rt =0.95 min MS (ESI pos): m/z = 242 (M+H)+ Exam le 20a racemic mixture Example 19a (1.160 g, 4.81 mmol), is dissolved in ACN (10 mL) in a microwave vessel and trifluoroacetic anhydride (2.005 mL, 14.42 mmol) and dry TEA (2.680 mL, 19.23 mmol) are added. The reaction e is heated under microwave irradation for two cycles at 100°C for 30 min. Volatiles are evaporated under reduced pressure and the resi- due purified by flash tography (eluent 7-60% EtOAc/cyclohexane) to fiamish the title compound (1.000 g, 65%).
HPLC-MS (Method 2): Rt = 1.43 min MS (ESI pos): m/z = 320 (M+H)+ Exam le 20b racemic mixture o>\_N N\ 0 To a solution of example 19a (350 mg, 1.45 mmol) in dry ACN (2.5 mL) dicyclopropyl ide (1.240 g, 75% content, 6.03 mmol; prepared as described in.]. Org. Chem, 67, 5226-5231; 2002) and dry TEA (1.415 mL, 10.15 mmol) are added and the mixture heated under microwaves irradation (100°C) for 20 min and then heated at 150°C for additional 30 min. Solvents are evaporated under reduced pressure and the resulting residue is d by flash chromatography (eluent 0-20% EtOAc/cyclohexane) to filmish the title compound (353 mg, 84%).
HPLC-MS (Method 5): Rt = 9.60 min MS : m/z = 192 (M-COztBu +H)+ Exam le 20c racemic mixture +0M \N N \ The title compound is prepared as described for example 20a, starting from example 19a (340 mg, 1.409 mmol) using acetic anhydride (200 ul, 2.11 mmol) S (Method 2): Rt = 1.17 min MS (ESI pos): m/z = 266 (M+H)+ Exam le 20d sin le omer unknown absolute stereochemistr at brid ehead o>_N N\ o The title compound is prepared as described for example 20b, starting from example 19b (46 mg, 0.19 mmol).
HPLC-MS (Method 2): Rt =1.34 min MS (ESI pos): m/z = 236 (M-tBu+H)+ -l 18- Exam le 20e sin le enantiomer unknown absolute stereochemistr at brid ehead +3)” N\ o The title compound is prepared as described for e 20b, starting from example 19c (45 mg, 0.18 mmol).
HPLC-MS (Method 2): Rt =l.33 min MS (ESI pos): m/z = 236 (M-tBu+H)+ Exam le 20f sin le enantiomer unknown absolute stereochemistr at brid ehead) The title compound is prepared as described for example 20b starting from e l9c (60.3 mg, 0.25 mmol), l-trifluoromethylcyclopropane-l-carboxylic acid anhydride (250 mg, prepared following the procedure described in J. Org. Chem, 67, 5226-5231; 2002 starting from 1 -trifluoromethylcyclopropane- l xylic acid) and 0-40% cyclohexane as purification eluent to give 70 mg (78%) ofproduct.
HPLC-MS (Method 2): Rt = 1.41 min MS (ESI pos): m/z = 377 (M+NH4)+ -1 19- Exam le 21a racemic mixture o ‘0‘ CD1 (313 mg, 1.93 mmol) is added to racemic icyclo[3.1.0]hexane-1,3-dicarboxylic acidtert-butyl ester (337 mg, 1.48 mmol) dissolved in DCM (5 mL) under stirring at room temperature. TEA (0.289 mL, 2.07 mmol) followed by N,O-dimethylhydroxylamine hydrochloride (203 mg, 2.076 mmol) are added to the on mixture after 1 hour. After 2 hours the reaction mixture is diluted with DCM, washed with 0.2 M HCl, saturated NaH- CO3 and brine and then dried over Na2SO4 before being evaporated to fiamish the title nd (373 mg, 93%), that is used as such.
HPLC-MS (Method 5): Rt = 7.64 min MS (APCI): m/z = 171 (M-COztBu +H)+ Example 22a gracemic mixture) Methylmagnesium bromide (3M in ethyl ether, 920 uL, 2.76 mmol) is added dropwise to e 21a (373 mg, 1.38 mmol) dissolved in THF (5 mL) cooled to 0°C. Stirring is con- tinued at 0°C for 15 min followed by 2h at room temperature. The reaction mixture is cooled to 0°C and methylmagnesium bromide (3M in ethyl ether, 920 uL, 2.76 mmol) is added dropwise. Stirring is continued at 0°C for 15 min followed by overnight at room temperature. The reaction mixture is cooled to 0°C, 1N HCl (6 mL) is added dropwise and WO 17657 -l20- stirring is continued for 15 min. EtOAc is added, the organic layer separated, washed with brine, dried over Na2SO4 and trated under reduced pressure to fiamish a residue.
Lithium bis(trimethylsilyl)amide (1M in THF, 1.25 mL, 1.27 mmol) is added dropwise to such residue dissolved in THF (8 mL) and cooled to -78°C. Stirring is continued at -20°C for 1h. The reaction mixture is cooled to -60°C and ethyl trifluoroacetate (273 uL, 2.28 mmol) is added. Stirring is continued at room temperature overnight. Water and EtOAc are added, the organic layer separated, dried over Na2SO4 and concentrated under reduced pressure to filI'IllSh a residue. ylamine hydrochloride (1.048 g, 15.00 mmol) is add- ed to such e dissolved in MeOH (40 mL) and the on mixture refluxed for 2h.
Volatiles are evaporated under reduced pressure, the residue partitioned between EtOAc and saturated NaHCO3, the organic layer separated, washed with saturated NaHCO3, dried over Na2SO4 and concentrated under reduced pressure to fiamish a residue. TEA (147 uL, 1.057 mmol) followed by methanesulfonyl chloride (76 uL, 0.98 mmol) are added to such residue dissolved in DCM (11 mL) and cooled to 0°C. Stirring is continued for 5h at room temperature. Water and DCM are added, the aqueous layer further extracted with DCM, the organic layers combined, dried using a phase separator cartridge and concentrated un- der reduced pressure. The resulting residue is purified by flash tography (eluent 0- % EtOAc/cyclohexane) to filmish the title compound (195 mg, 44%).
HPLC-MS (Method 5): Rt = 10.41 min MS (APCI): m/z = 219 tBu +H)+ Exam le 22a racemic mixture alternative rocedure 2012/065140 N—Chlorosuccinimide (212 mg, 1.59 mmol) is added to example 23a (vide infra) (360 mg, 1.59 mmol) in DMF (8 mL) cooled to 0°C. Stirring is continued overnight. The reaction mixture is partitioned n water and AcOEt. The organic layer is washed with brine, dried over Na2SO4 and ated under reduced pressure to furnish a residue (386 mg). 100 mg of such residue are ved in anhydrous chloroform (5 mL) and cooled to 0°C. 2-Bromo-3,3,3-trifluoropropene (671 mg, 3.84 mmol) followed by TEA (160 ul, 1.15 mmol) are added to the reaction mixture and stirring is continued 3 hours. The reaction mixture is partitioned between water and DCM. The organic layer is washed with brine, dried over Na2SO4 and evaporated under reduced pressure to give residue, which is puri- fied by Si-flash chromatography, using Cyclohexan/EtOAc 85: 15 as eluent, to obtain 76 mg (62%) ofproduct.
S (Method 7b): Rt = 3.67 min MS (APCI pos): m/z = 219 (M-Boc+H)+ Example 22b gracemic mixture) Ethylmagnesium bromide (3M in ethyl ether, 3.95 ml, 11.84 mmol) is added dropwise to example 21a (1.6 g, 5.92 mmol) dissolved in anhydrous THF (20 mL) cooled to 0°C. Stir- ring is continued at 0°C for 15 min then overnight at room temperature. The reaction mix- ture is cooled to 0°C and methylmagnesium bromide (3M in ethyl ether, 1.97 ml, 5.92 mmol) is added dropwise. Stirring is continued at 0°C for 15 min followed by 2h at room temperature. The reaction mixture is cooled to 0°C, aqueous NH4C1 is added dropwise and stirring is continued for 5 min. EtOAc is added, the organic layer separated, washed with brine, dried over Na2SO4 and concentrated under d pressure to fiarnish 1.37 g of crude ketone. Lithium bis(trimethylsilyl)amide (1,8M, 1.03 mL, 1.86 mmol) is added dropwise to the crude ketone (370 mg, 1.55 mmol) dissolved in anhydrous THF (10 mL) and cooled to -78°C. Stirring is continued at -20°C for 1h. The reaction mixture is cooled to -78°C and l-(trifluoroacetyl)imidazole (0.70 ml, 6.18 mmol) is added. Stirring is contin- ued 3 h at room temperature. Aqueous NH4Cl solution and EtOAc are added, the organic layer is separated, dried over a separator cartridge and concentrated under reduced pressure to filI'IllSh a residue that is purified by Si flash chromatography (5-40% EtOAc/Hexane as eluent) to obatain 190 mg of intermediate. Hydroxylamine hydrochlo- ride (512 mg, 7.37 mmol) is added to such product dissolved in MeOH (20 mL) and the reaction mixture refluxed for 2h. Volatiles are evaporated under d pressure, the resi- due is partitioned between EtOAc and ted NaHCO3, the organic layer is separated, washed with saturated , dried over phase separator cartridge and concentrated un- der reduced re to furnish a 90mg of residue. TEA (50 uL, 0.36 mmol) followed by methanesulfonyl chloride (26 uL, 0.33 mmol) are added to such residue dissolved in DCM (10 mL) and cooled to 0°C. Stirring is continued at room temperature then flirther TEA (50 uL, 0.36 mmol) and methanesulfonyl chloride (26 uL, 0.33 mmol) are added and stirring is continued for 2h. Water and DCM are added, the aqueous layer is further extracted with DCM, the organic layers are ed, dried over a phase-separator cartridge and concen- trated under reduced pressure. The resulting residue is d by flash chromatography t 0-10% EtOAc/hexane) to furnish the title compound (20 mg, 23% on the last step).
Exam le 23a racemic mixture #0M ~ Lithium aluminium hydride (50 mg, 1.30 mmol) is added portionwise to racemic 3- azabicyclo[3. l .0]hexane-l,3-dicarboxylic acidtert-butyl ester (315 mg, 1.30 mmol) in THF (6 mL) cooled to 0°C. ng is continued for 10 min at 0°C followed by 1h at rt.
The reaction mixture is cooled to 0°C and water (100 uL), 1M NaOH (100 uL) and water (300 uL) are added. Stirring is continued for 15 min at rt. Solids are d away on celite and the filtrate dried over Na2SO4 before being evaporated to fiamish a residue that is dis- solved in DCM (7 mL), cooled to 0°C and d with Dess-Martin periodinane (679 mg, 1.60 mmol) portionwise. Stirring is continued for 3h at rt. Saturated NaHCO3 and sodium thiosulphate (2 g in 5 mL ofwater) are added and stirring is continued for 30 min. The or- ganic layer is separated, dried using a phase separator cartridge and evaporated under re- duced pressure. The resulting residue is dissolved in EtOH (13 mL) and added to hydrox- ylamine hydrochloride (387 mg, 5.56 mmol) and sodium acetate (730 mg, 8.9 mmol) in water (5 mL). Afier stirring overnight at room temperature the reaction mixture is parti- tioned between water and AcOEt. The organic layer is washed with brine, dried over Na2SO4 and evaporated under d pressure to fiamish the title compound (265 mg, 90% content, 79%) that is used as such.
HPLC-MS d 2): Rt = 1.05 min MS (ESI pos): m/z = 227 (M+H)+ e 24a gracemic mixture) +O>—N N—Chlorosuccinimide (148 mg, 1.10 mmol) is added to example 23a (265 mg, 90% con- tent, 1.05 mmol) in DMF (5 mL) cooled to 0°C. Stirring is continued for 2h at 40°C. N- Chlorosuccinimide (72 mg, 0.538 mmol) is added to the reaction mixture and stirring is ued for 1h at 40°C. The reaction mixture is partitioned between water and AcOEt.
The organic layer is washed with brine, dried over Na2SO4 and evaporated under reduced pressure to fiarnish a residue (270 mg). 135 mg of such residue are dissolved in DCM (5 —124— mL) and cooled to 0°C. 2-Chloropropene (1 mL, 11.75 mmol) followed by TEA (217 ul, 1.553 mmol) are added to the reaction mixture and stirring is continued overnight. The on mixture is partitioned between water and DCM. The organic layer is washed with brine, dried over Na2SO4 and evaporated under d pressure to give residue, which is purified by flash chromatography (eluent 0-10% cyclohexane) to furnish the title compound (69 mg, 50%).
HPLC-MS (Method 6): Rt = 11.20 min MS (ESI pos): m/z = 265 (M+H)+ Example 24b gracemic mixture) 7L0>—N ‘ '1 rosuccinimide (148 mg, 1.10 mmol) is added to example 23a (265 mg, 90% con- tent, 1.05 mmol) in DMF (5 mL) cooled to 0°C. Stirring is continued for 2h at 40°C. N- Chlorosuccinimide (72 mg, 0.538 mmol) is added to the reaction mixture and stirring is continued for 1h at 40°C. The reaction mixture is ioned between water and AcOEt.
The organic layer is washed with brine, dried over Na2SO4 and evaporated under reduced pressure to furnish a residue (270 mg). 67 mg of such residue are dissolved in DCM (2.5 mL) and cooled to 0°C. Ethyl propenyl ether (0.654 mL, 5,91 mmol) followed by TEA (72 ul, 0,51 mmol) are added to the reaction e and stirring is continued overnight at room temperature. The reaction mixture is partitioned between water and DCM. The or- ganic layer is washed with brine, dried over Na2SO4 and evaporated under reduced pres- sure to give residue, which is purified by flash chromatography (eluent 5-30% EtOAc/cyclohexane) to fiamish the title compound (68 mg).
HPLC-MS (Method 8): Rt = 6.82 min MS (ESI pos): m/z = 165 (M-COztBu +H)+ -l25- Exam le 24c racemic mixture F \o N—Chlorosuccinimide (148 mg, 1.10 mmol) is added to example 23a (265 mg, 90% con- tent, 1.05 mmol) in DMF (5 mL) cooled to 0°C. Stirring is ued for 2h at 40°C. N- Chlorosuccinimide (72 mg, 0.54 mmol) is added to the reaction mixture and stirring is con- tinued for lh at 40°C. The reaction mixture is ioned between water and AcOEt. The organic layer is washed with brine, dried over NaZSO4 and evaporated under reduced pres- sure to fiamish a e (270 mg). 67 mg of such residue are dissolved in DCM (2.5 mL) and cooled to 0°C. (E)-l-Methoxy—3,3,3-trifluoropropene (746 mg, 5.91 mmol) followed by TEA (72 ul, 0.51 mmol) are added to the reaction mixture and stirring is continued overnight at room temperature.
The reaction mixture is partitioned n water and DCM. The organic layer is washed with brine, dried over NaZSO4 and evaporated under d pressure to give residue, which is purified by flash chromatography (eluent 0-20% EtOAc/cyclohexane) to furnish the title compound (41 mg).
HPLC-MS (Method 8): Rt = 10.41 min MS (ESI pos): m/z = 219 (M-COztBu +H)+ Example 25a gracemic mixture) / CI [jigN 2012/065140 e 13a (0.015 mg, purity 50%) is dissolved in dry 1,4-dioxane (0.5 mL) and hy- drochloric acid (1 mL of a 4N solution in dioxane) is added. Mixture is stirred at room temperature for 1h, solvent evaporated to obtain the title compound (15 mg) used in the next step Without any fiarther purification.
HPLC-MS (Method 2): Rt = 0.28 min MS (ESI pos): m/z = 150 (M+H)+ The following examples are synthesized in analogy to the preparation of example 25a: MS (ESI pos Reactant, Example Structure or APCI) : amount 25b (racemic 13b, 7.35, 165 (M+H) mixture) 115 mg method 5 25c ic 14a, 7.88, 200 (M+H) mixture) 172 mg method 5 25d (racemic 14b, 1.42, 1 8 1 (M+H) mixture) 44 mg Method 6 MS (ESI pos Reactant, Example Structure or APCI) : amount 25e (racemic 8.53, 235 (M+H) mixture) method 5 25f (racemic 0.39, 165 (M+H) e) Method 2 0.8 1 , + 25g (racemic 165 (M+H) Method 2 mixture) 25h (racemic 0.34, 166 (M+H) mixture) Method 2 MS (ESI pos Reactant, Example Structure or APCI) : amount 25i (racemic 15b, 7.77, 220 (M+H) mixture) 200 mg Method 5 25j ic 17a, 5.15, 166 (M+H) mixture) 77 mg Method 5 25k (racemic 20a, 0.96, 220 (M+H) mixture) 1000 mg Method 2 20b, 6.81, 251 (racemic + 192 (M+H) 353 mg Method 5 mixture)_ -l29- MS (ESI pos Reactant, Example Structure or APCI) : amount / CI 20c, 25m (racemic 296 mg 0.34, 165 (M+H) mixture). (90% Method 2 content) 25n (single omer, n ab- 0.86, 192 (M+H) solute stereo- Method 2 chemistry at bridgehead) 250 (single enantiomer, Unknown ab- 0.86, 192 (M+H) solute stereo- Method 2 chemistry at bridgehead) 25p (racemic 7.96, 219 (M+H)+ mixture) Method 5 MS (ESI pos Reactant, Example Structure or APCI) : amount 25q (racemic 24a, 0.69, 165 (M+H) mixture) 69 mg Method 2 25r ic 14 f, 0.57, 1 9 1 (M+H)+ mixture) 163 mg method 2 0.38 and 25u (racemic 24b, 0.58, 165 (M+H)+ mixture) 68 mg method 2 25V (racemic 24c 0.88, 2 1 9 (M+H)+ mixture) 41 mg method 2 Rt = 4.54; 25W (racemic 515mg, Method 721 219 (M+H)+ mixture) content 2012/065140 MS (ESI pos Reactant, _ Example Structure or APCI) : amount 25x (single enantiomer, Rt = 0.77; Unknown abmethod 2 260 (M+H)+ solute stereo- chemistry at bridgehead) Rt = 4.00; 25y (racemic_ 150, Method 7a 192 (M+H)+ mixture) Rt = 0.85; 25z (racemic 15d, method 2 260 (M+H)+ mixture) 25za (racemic Rt = 5.27; 233 (M+H)+ mixture) method 7a -l32- Example 26a: F \ 3-Bromo(trifluoromethyl)pyridine (6.0 g, 26.55 mmol), diethyl te (4.8 mL, 0.032 mol) and cesium carbonate (11.2 g, 0.035 mol) in DME (30 mL) are degassed with a flow of en for 5 min. Tris(dibenzylideneacetone)dipalladium(0) (486 mg, 0.531 mmol) and tri-tert—butylphosphine (644 ul, 2.65 mmol) are the added and the reaction mixture split in six equal portions. Each portion is heated to 150°C in a microwave oven for 1 hour.
The combined portions are mixed with saturated NH4Cl and extracted three times with ethyl ether .The combined organic layers are dried using a phase separator dge, and concentrated under reduced pressure to give a residue that is purified by flash chromato- graphy (eluent 0-25% EtOAc/petroleum ether) to fiamish the title compound (2.63 g, 43%).
HPLC-MS (Method 2): Rt =1 .02 min MS (ESI pos): m/z = 233 (M+H)+ Example 27a gracemic e) F | F Br Benzoyl peroxide (24 mg, 0.1 mmol) and N—bromosuccinimide (0.885 g, 4.97 mmol) are added to example 26a (1 . 160 g, 4.97 mmol) in carbon tetrachloride (30 mL) and the reac- tion mixture is refluxed overnight. The reaction mixture is cooled to room temperature, undissolved material is filtered away and washed with EtOAc. The filtrate and the EtOAc washings are evaporated under reduced pressure to give a residue that is purified by flash chromatography (eluent 0-10% EtOAc/petroleum ether) to fill'IllSh the title nd (1.000 g, 64%).
HPLC-MS (Method 2): Rt =l.l8 min MS (ESI pos): m/z = 312 (M+H)+ Example 27b gracemic mixture) The title nd is prepared as described for example 27a, using 2-pyridineacetic acid, fluoromethyl)-, ethyl ester (3.000 g, 88% content, 11.32 mrnol, prepared as described in WO2009/121919).
HPLC-MS (Method 2): Rt =1.24 min MS (ESI pos): m/z = 312 (M+H)+ Example 28a (diastereomeric mixture) i OW EtOH (416 ul) followed by a solution of e 27a (1.000 g, 3.20 mmol) in ethyl acry- late (662 ul, 6.09 mmol) and EtOH (125 ul) are added to sodium hydride (60% suspension in mineral oil, 128 mg, 3.20 mmol) in diethyl ether (12 mL) cooled to 0°C. Stirring is con- tinued at room temperature over weekend. EtOH (5 mL), ethyl ether (50 mL) and water are added and the organic layer separated, dried using a phase separator cartridge and - trated under reduced pressure to give a residue that is purified by flash chromatography (eluent 0-20% EtOAc/petroleum ether) to filI'IllSh the title compound (0.96 g, 90%).
HPLC-MS (Method 7): Rt =7.33-7.52 min MS (ESI pos): m/z = 332 (M+H)+ —134— e 28b gdiastereomeric mixture) z o\\ The title compound is prepared as bed for example 28a, using example 27b (1.780 g, .70 mmol).
GC-MS (Method 8): Rt = 10.76 min MS (EI pos): m/z = 331 (M)+ Exam le 29a s ' racemic mixture F | F \ Lithium aluminum hydride (149 mg, 3.92 mmol) is added portionwise to example 28a (1000 mg, 3.02 mmol) in THF cooled to 0°C. Stirring is continued for 10 min at 0°C and then for 1 h at room temperature. Lithium um hydride (22 mg, 0.58 mmol) is added and stirring is continued overnight. Lithium aluminum hydride (23 mg, 0.60 mmol) is add- ed and stirring is continued for 3h. Water (194 ul), 1M NaOH (194 ul) and water (5 82 ul) are added to the reaction mixture cooled to 0°C and stirring is continued for 40 min at room temperature. Solids are filtered away on celite and washed with EtOAc. The e and the EtOAc washings are evaporated under reduced pressure to give a residue that is purified by flash chromatography t 0-10% MeOH/DCM) to filmish the title com- pound (209 mg, 28%).
HPLC-MS (Method 6): Rt = 7.18 min MS (ESI pos): m/z = 248 (M+H)+ -l35- Example 29b (diastereomeric mixture) The title compound is prepared as described for example 29a, using example 28b (200 mg, 0.60 mmol).
HPLC-MS (Method 5); Rt =7.18 min MS (APCI): m/z = 248 (M+H)+ Exam le 30a s ' racemic mixture FF \| F o o\\ lo O\é’=o o \ | TEA (280 ul, 2.01 mmol) followed by methanesulfonyl chloride (143 ul, 1.84 mmol) are added to example 29a (207 mg, 0.84 mmol) in DCM (5 mL) at 0°C. After ng for 30 min at room ature the reaction mixture is diluted with DCM, washed with sat.
NaHCO3 and brine, dried using a phase separator cartridge and concentrated under re- duced pressure to filI'IllSh the title nd (319 mg, 94%) that is used as such.
HPLC-MS (Method 6): Rt = 9.84 min MS (ESI pos): m/z = 404 (M+H)+ Example 30b (diastereomeric e) The title compound is prepared as bed for example 30a, using example 29b (213 mg, 0.86 mmol).
HPLC-MS (Method 2): Rt = 1.07 min MS (ESI pos): m/z = 404 (M+H)+ Example 31a gracemic mixture) \\©\O Example 30a (318 mg, 0.788 mmol), 4-methoxybenzylamine (206 ul, 1.58 mmol) and DI- PEA (343 ul, 1.97 mmol) in DMF (5 mL) are stirred at 80°C for 2.5h. The reaction mixture is cooled to room temperature, volatiles are evaporated under reduced pressure and the re- sulting residue partitioned between EtOAc and water. The organic layer is separated, washed with NaHCO3 and brine, dried using a phase separator cartridge and concentrated under reduced pressure to give a residue that is purified by flash chromatography (eluent 0- % petroleum ether) to filI'IllSh the title compound (182 mg, 66%).
S (Method 6): Rt = 6.41 min MS (ESI pos): m/z = 349 (M+H)+ Example 31b gracemic mixture) The title nd is prepared as described for example 31a, using example 30b (345 mg, 0.85 mol).
HPLC-MS (Method 5): Rt = 10.09 min MS (APCI): m/z = 349 (M+H)+ Example 32a gracemic mixture) /\ H FF fi l-Chloroethyl chloroformate (68 ul, 0.62 mmol) is added to e 31a (180 mg, 0.52 mmol) in 1,2-dichloroethane (3.3 mL) cooled to 0°C. Stirring is continued for 2.5 h at room temperature. l-Chloroethyl chloroformate (25 ul, 0.23 mmol) is added to the reaction mixture and stirring is ued for 1h. MeOH (6.6 mL) is added to the reaction mixture and ng is continued for 1h at 60°C. The reaction mixture is cooled to room tempera- ture and concentrated under reduced pressure to give a residue that is purified by flash chromatography (eluent 5% MeOH in DCM + 0.5% ofNH3) to furnish the title compound (113 mg, 96%).
HPLC-MS (Method 5): Rt = 8.22 min MS (APCI): m/z = 229 (M+H)+ -13 8- Example 32b (racemic mixture) / \ H F \N F F n The title compound is prepared as described for Example 32a, using example 3 lb (165 mg, 0.47 mmol).
HPLC-MS (Method 5): Rt = 8.81 min MS (APCI): m/z = 229 (M+H)+ Example 33a (racemic mixture 2 F F H To a solution mic 3-azabicyclo[3.1.0]hexane-1,3-dicarboxylic -tert-butyl ester (200 mg, 0.88 mmol) in DMF (5 mL), TBTU (339 mg, 1.056 mmol) and TEA (160 uL, 1.14 mmol) are added. e is stirred at room temperature for 10 min, then racemic 3- amino-1,1,1-trifluoropropanol (125 mg, 0.97 mmol) is added and the mixture d at room temperature overnight. AcOEt and saturated NaHCO3 are added, the organic phases separated and washed with 10% citric acid and brine. The organic layer is then dried using a phase separator cartridge and evaporated under reduced pressure to fiamish the title com- pound (330 mg, 90% content, 100%), that is used as such.
HPLC-MS (Method 2): Rt = 0.94 min MS (ESI pos): m/z = 339 (M+H)+ -l39- Example 34a (racemic mixture) 0 H F F H Example 33a (310 mg, 94% content, 0.86 mmol) is dissolved in dry oxane (5 mL) and hydrochloric acid (5 mL of a 4N solution in dioxane) is added. Mixture is stirred at room ature for 2.5 h, solvent evaporated to obtain the title compound (310 mg, 64% content, 84%) used in the next step Without any fiarther purification.
HPLC-MS (Method 2): Rt = 0.35 min MS (ESI pos): m/z = 239 (M+H)+ Exam le 35a racemic mixture O /8\ I2 O F F To a solution of example 34a (310 mg, 64% content, 0.72 mmol) in DMF (5 mL), example 4a (226 mg, 0.72 mmol), TBTU (255 mg, 0.79 mmol) and DIPEA (618 uL, 3.61 mmol) are added. Stirring is ued at room temperature overnight. AcOEt and saturated NaH- CO3 are added, the c phases separated and washed with brine, dried and evaporated under reduced pressure. The resulting residue is purified by flash chromatography (eluent 0-5% MeOH/DCM) to fiamish the title compound (270 mg, 70%). —140— HPLC-MS (Method 5): Rt = 7.08 min MS (APCI): m/z = 533 (M+H)+ Example 36a O \\ To a solution of methacrolein (2.61 mL, 30 mmol) in dry EtOH (40 mL), dry TEA (3.47 mL, 25 mmol) and diethlybromomalonate (4.63 mL, 25 mmol) are added at room temper- ature. The resulting clear solution is stirred at room temperature for 20h. A White ate is formed. Solvent is reduced under vacuum. The White solid suspended in pen- tane/diethylehter 90:10 and the suspension d under vacuum. The solution is evapo- rated to give 5.5 g of colorless oil. Crude is purified by flash cromatography t from pentane/diethylehter 90:10 to 75:25) to fiamish the title compound (3.49 g, purity 60%, 36.7% yield) as colorless oil.
GC-MS (Method 8): R = 8.99 min Example 37a gracemic mixture= SE) —141— To a on ofExample 36a (2.8 g, 60% purity, 7.36 mmol) in dry THF (30 mL) , 2,4- dimethoxybenzylamine (1.24 mL, 8.1 mmol) is added followed by AcOH (0.49 mL, 8.1 mmol). The mixture is stirred at room temperature for 20 min, then cooled at 00C and so- dium cianoborohydride (0.54 g, 8.1 mmol) is added. Afler 30 min, the ice bath is removed and reaction mixture lefl under stirring overnight. A ted solution 03 is add- ed, mixture extracted with EtzO, phases separated and organics washed with brine and dried over sodium sulphate. Evaporation of the solvent give a yellow oil purified by flash cromotagraphy (eluent from 7% to 63% e/Cyclohexane ) to fiamish the title compound as colorless oil (0.89 g, 36%) HPLC-MS (Method 2): R = 1.15 min MS (ESI pos): m/z = 334 (M+H)+ Example 38a gracemic mixture= SE) To a solution of e 37a (0.87 g, 2.61 mmol) in dry THF (20 mL) under reflux, bo- rane dimethlysulflde complex (2M solution in THF, 5.22 mL, 10.44 mmol) is added drop- wise. Afler 1h, mixture is cooled at 00C and 5mL of a solution ofMeOH/HCl 36% (9:1) are added dropwise and mixture then refluxed overnight. ts are evaporated, the re- sidue is loaded on SCX cartridge and ammonia fractions are evaporated to furnish the title compound as colorless oil (0.63 g, 87%) HPLC-MS (Method 2): R = 0.91 min MS (ESI pos): m/z = 278 (M+H)+ Exam le 39a racemic mixture s NJOLO To a solution of Example 38a (0.42 g, 1.51 mmol) in absolute EtOH (20 mL), di-tert- buthyldicarbonate (0.33 g, 1.51 mmol) and palladium hydroxide (0.06 g, 0.03 mmol) are added and the mixture hydrogenated at 20 psi for 20h. Catalyst is removed by filtration, solvent evaporated and the crude is purified by flash cromatography t gradient from 0% to 100% exane in AcOEt) to fiamish the title compound as colorless oil (0.19 g, 55%) GC-MS (Method 8): R = 10.19 min Exam le 40a racemic mixture s 29 1 To a solution of Example 39a (0.095 g, 0.42 mmol) in dry DCM (5 mL) at 00C, Dess- Martin periodinane (0.25 g, 0.59 mmol) is added and the mixture then stirred for 3h at room temperature. A saturated solution ofNaHC03 is added followed by 2.5 mL of a 5% solution ofNa2S203 and the mixture stirred at room temperature for 30 min. Phases are se- d, organics dried over sodium te and evaporated to filmish the title compound, used in the next steo Without fiarther ation. (0.08 g, 85%) GC-MS (Method 8): R = 9.85 min —143— Exam le 4la racemic mixture s To a solution of Example 40a (0.08g, 0.36 mmol) in t-BuOH (2mL) and ylbutene (0.65mL of a 2N solution in THF) at room temperature sodiumhydrogenphosphate (0.133 g, ol) in water (1.5mL) is added followed by sodiumchlorite (0.112g, 0.99mmol) and the mixture then stirred at room ature for 5hrs, then a solution of citric acid (5% in water) is added. Mixture is extracted with DCM, phased separated, dried over sodium sulphate and evaporated to fiamish the title compound (0.065 g, 76%) GC-MS (Method 8): R = 10.66 min MS (EI pos): m/z = 241 (M)+ Example 42a gracemic mixture) Example 18a (550 mg, 2.64 mmol) is dissolved in dry l,4-dioxane (2 mL) and hydrochlor- ic acid (1 mL of a 4N solution in dioxane) is added. e is stirred at room temperature for 3h, solvent evaporated to obtain the title compound (380 mg, 100%) used in the next step Without any fiarther purification.
HPLC-MS (Method 2): Rt = 0.24 min MS (ESI pos): m/z = 109 (M+H)+ —144— Exam le 43a diastereomeric mixture / 04FF N/ F F O=S\\ To a solution of example 4e (210 mg, 0.64 mmol) in dry DMF (5 mL), HATU (318 mg, 0.84 mmol) and dry TEA (269 ul, 1.93 mmol) are added. Mixture is stirred at room tem- perature for 20 min, then example 42a (93 mg, 0.64 mmol) is added and the mixture stirred at room temperature for additional 2 h. The reaction mixture is treated with basic alumina and volatiles are evaporated under reduced pressure. The residue is dissolved in EtOAc, washed with 10% citric acid and then with brine, dried using a phase separator cartridge and evaporated under vacuum. The crude is d by flash cromatography t 50- 70% EtOAc/Cyclohexane) to obtain the title compound as a white solid (235 mg, 88%) HPLC-MS (method 2): Rt = 0.93 min MS (ESI pos): m/z = 417 (M+H)+ Exam le 43b diastereomeric mixture / O}F N/ F F o=s\\ The title compound is ed as described above for example 43a, starting from example 42a (53 mg, 0.36 mmol) and example 41 (118 mg, 0.36 mmol) HPLC-MS (method 2): Rt = 1.07 min MS (ESI pos): m/z = 417 (M+H)+ WO 17657 —145— Exam le 45a diastereomeric mixture NHO; Example 45a is ed as described for example lOa using example 43a (235 mg, 0.56 mmol).
HPLC-MS (method 2): Rt =0.68 min MS (ESI pos): m/z = 434 (M+H)+ Exam le 45b diastereomeric mixture NHO; Example 45b is prepared as described for example lOa using example 43b (121 mg, 0.26 mmol).
HPLC-MS (method 2): Rt =0.87 min MS (ESI pos): m/z = 434 (M+H)+ WO 17657 Exam le 46a diastereomeric mixture Methylhydrazine (29 ul, 0.55 mmol) is added to example 10a (208 mg, 0,50 mmol) in MeOH (2 mL) cooled to 0°C. ng is continued for 2.5 days at room temperature fol- lowed by 1h at 40°C. After evaporation of volatiles, the title compound (244 mg, 85% con- tent, 93%) is used in the next step Without any fiarther purification.
HPLC-MS (Method 2): Rt =0.87 min MS (ESI pos): m/z = 449 (M+H)+ Exam le 47a racemic mixture O\ O /N f0 o\N/ A solution of 1-methoxycyclopropanecarboxylic acid (750 mg, 6.46 mmol) and N,N‘- dicyclohexylcarbodiimide (670.2 mg, 3.25 mmol) is stirred under nitrogen atmosphere for 20 hours then EtZO is added to the mixture, the solid is filtered out and solvent is removed under reduced pressure. The obtained anhydride is added to a on of example 19a (490 mg, 2.03 mmol) and TEA (1.4 ml, 10.06 mmol) in ACN (4 ml) and heated under micro- waves irradation (100°C) for 30 min and then at 150°C for additional 30 min. Solvents are WO 17657 —147— evaporated under reduced re, the residue is partitioned between EtOAc and water, the organic layer is separated, dried over NaZSO4 and concentrated under reduced pressure.
The crude is d by Si-flash chromatography (eluent n-Hexane/EtOAc 8:2) to obtain the title compound (450 mg, content 90%, 69%).
HPLC-MS (Method 2): Rt = 1.26 min MS (ESI pos): m/z = 322 (M+H)+ Exam le 47b racemic mixture EM/]>/ O F Dess-Martin inane (2.63 g, 6.20 mmol) is added to a solution of example 33a (1.50 g, 4.43 mmol) in ACN and stirred for 6 hours at room temperature. The reaction e is poured into 10% NaHC03 + 5% Na2803 aqueous solution and extracted with EtOAc, or- ganic layer is separated, washed with water, dried over NaZSO4 and concentrated under re- duced pressure. An aliquote of crude ketone (900 mg, 2.68 mrnol) is dissolved into anhy- drous THF, Burgess reagent (2.50 g, 10.49 mmol) is added and the reaction mixture is then heated under microwave irradation (120°C) for 30 min. EtOAc is added to the reaction mixture and the organic layer is washed with water, dried over NaZSO4, concentrated under reduced pressure to give a residue that is purified by Si flash tography (eluent EtOAc/cyclohexane 2:8) to filI'IllSh the title compound (140 mg, 16%).
HPLC-MS (Method 2): Rt = 0.93 min MS (ESI pos): m/z = 319 (M+H)+ Exam le 47c racemic mixture The title compound is ed in analogy to example 47a starting from 1- methylcyclopropaneCarboxylic acid (550 mg, 5.49 mmol) in place of 1- methoxycyclopropanecarboxylic acid to obtain 340 mg (84% on the last step) of prod- uct.
HPLC-MS (Method 2): Rt = 1.40 min MS (ESI pos): m/z = 306 (M+H)+ Example 48a (racemic mixture) 7L0M H 0 NH2 Trimethylsilyldiazomethane (3.63 ml, 7.26 mmol) is added dropwise into a stirred on of racemic 3-azabicyclo[3.1.0]hexane-1,3-dicarboxylic -tert-butyl ester (1.50 g, 6.60 mmol) dissolved in anhydrous Toluene/anhydrous MeOH mixture at 0°C under nitrogen atmosphere then the reaction e is stirred at room temperature for 2 hours. A small amount of glacial acetic acid is added, solvent is removed under reduced pressure and the residue is partitioned between water and EtOAc. Organic layer is separated, washed with water, dried over NaZSO4 and concentrated under reduced pressure. The obtained ester is dissolved in anhydrous MeOH and hydrazine hydrate (6.00 ml, 123.45 mmol) is added; the reaction e is refluxed for 16 hours, solvent is removed and the residue is partitioned between water and DCM. c layer is separated, dried over NaZSO4 and concentrated under reduced pressure to obtain the title compound (1.40 g, 87%). —149— HPLC-MS (Method 2): Rt = 0.74 min MS (ESI pos): m/z = 242 (M+H)+ Exam le 49a racemic mixture Racemic 3-azabicyclo[3.1.0]hexane-1,3-dicarboxylic acidtert-butyl ester (300 mg, 1.32 mmol), HATU (552 mg, 1.45 mmol) and DIPEA (0.25 mL, 1.45 mmol) in DMF (15 mL) are d at rt for 15 min; cyclopropyl ide hydrochloride (198 mg, 1.45 mmol) fol- lowed by DIPEA (0.25ml, 1.45 mmol) is then added to the reaction mixture and stirring is continued for 1h. 100ml of water are added, the reaction mixture is extracted with EtzO (2x100 ml), EtOAc/EtzO (1:1 mixture, 2x100 ml), EtOAc (1x50 ml) then the ted or- ganic phases are washed with 0.5N HCl, 10% aqueous NaHCOg, dried over a phase- separator cartridge and trated under reduced pressure to fiamish the title compound (290 mg, 70%) used for the following step without fiarther purification HPLC-MS (Method 1): Rt = 0.79 min MS (ESI pos): m/z = 254 (M-tBu +H)+ Exam le 49b racemic mixture o>\_N +0 H Trifluoroacetic anhydride (0.20 ml, 1.41 mmol) is added dropwise into a solution of exam- ple 48a (340 mg, 1.41 mmol) and DIPEA (0.27 ml, 1.55 mmol) in ACN at 0°C then the -l50- reaction mixture is stirred at room temperature for 2 hours. Solvent is eliminated under re- duced pressure and the residue is partitioned between water and EtOAc, organic layer is separated, washed with water, dried over Na2S04 and concentrated under reduced re to obtain the title compound (450 mg, 95%) HPLC-MS (Method 2): Rt = 0.79 min MS (ESI pos): m/z = 355 (M+NH4)+ e 49c (racemic mixture) HATU (997 mg, 2.62 mmol) and DIPEA (450 ul, 2.62 mmol) are added into a solution of uomethylcyclopropanecarboxylic acid (404 mg, 2.62 mmol) in 20 ml of anhy- drous DMF and the on mixture is stirred for 30 minutes; Tert-butyl carbazate (315 mg, 2.38 mmol) is added and the resulting mixture is stirred 3 hours. Water and EtzO are added and phases are separated; organic layer is washed with 0.5M HCl, 10% aqueous NaHC03, dried over phase-separator cartridge and concentrated under reduced pressure.
The residue is dissolved in 5ml of oxane, 4M HCl dioxane solution (9.7 ml, 38.8 mmol) is slowly added and the reaction mixture is stirred overnight. Solvent is removed under reduced pressure to obtain 403 mg of 1-Trifluoromethyl-cyclopropanecarboxylic acid hydrazide hydrochloride. Title compound is then prepared in analogy to example 49a using 410 mg (1.80 mmol) of racemic 3-azabicyclo[3.1.0]hexane-1,3-dicarboxylic - tert-butyl ester, DIPEA (0.68 ml, 3.97 mmol), HATU (754 mg, 1.98 mol), 1- Trifluoromethyl-cyclopropanecarboxylic acid hydrazide hydrochloride (403 mg, 1.97 mmol) to obtain 637 mg (94%) ofproduct.
HPLC-MS (Method 2): Rt = 0.94 min MS (ESI pos): m/z = 395 (M+NH4)+ - l 5 1- Exam le 50a racemic mixture :0 $0 Burgess reagent (894 mg, 3.75 mrnol) is added to example 49a (290 mg, 0.94 mmol) in anhydrous THF (5 mL) and the reaction mixture is then heated under microwave irradation (120°C) for 25 min. EtOAc is added to the reaction e and the organic layer is washed with water, brine, dried over phase separator cartridge and concentrated under re- duced pressure to give a residue that is purified by Si flash chromatography (eluent 25- 100% EtOAc/cyclohexane) to fiamish the title nd (162 mg, 59%).
HPLC-MS (Method 1): Rt = 1.08 min MS (ESI pos): m/z = 292 (M+H)+ Exam le 50b c mixture The title compound is prepared in analogy to example 50a, ng from example 49b (100 mg, 0.30 mmol) in place of example 49a to obtain 50mg ofproduct (53%) HPLC-MS (Method 2): Rt = 1.25 min MS (ESI pos): m/z = 337 (M+NH4)+ Exam le 50c racemic mixture F o>< N\/ N\A\O Title compound is prepared in analogy to example 50a starting from example 49c (637 mg,1.69 mmol) in place of example 49a to obtain 546 mg (94%) ofproduct.
HPLC-MS (Method 2): Rt = 1.23 min MS (ESI pos): m/z = 360 (M+H)+ Exam le 51a racemic mixture s +0M NH2 Title compound is prepared in analogy to example 5a ng from example 41a (185.0 mg, 0.77 mmol) in place ofracemic 3-azabicyclo[3.1.0]hexane-l,3-dicarboxylic - tert-butyl ester to obtain 130 mg (71%) of product.
S (Method 8): Rt = 11.34 min MS (ESI pos): m/z = 184 (M-tBu)+ WO 17657 Exam le 52a racemic mixture s o>\_N +0 9% Title compound is prepared in analogy to e 8a starting from example 51a (128 mg, 0.53 mmol) in place of example 7a, using 10% citric acid aqueous solution in place of aqueous HCl to obtain 138 mg (content 80%, 93%) of product used Without fiarther purifi- cation.
HPLC-MS (Method 8): Rt = 9.71 min MS (ESI pos): m/z = 166 (M-tBu)+ Exam le 53a racemic mixture s +0M pH Title compound is prepared in analogy to example 19a ng from example 52a (138mg, content 80%, 0.50 mmol) in place of example 18a to obtain 127 mg (100%) ofproduct.
HPLC-MS (Method 6): Rt = 2.00 min MS (ESI pos): m/z = 200 (M-tBu+H)+ —154— Exam le 54a racemic mixture s +0>LN —N F F Title compound is ed in y to example 20a starting from example 53a (125mg, 0.49 mmol) in place of example 19a and using 0-40% EtOAc/Cyclohexan as purification eluent to obtain 100 mg (61%) ofproduct.
HPLC-MS (Method 8): Rt = 9.76 min MS (ESI pos): m/z = 277 (M-tBu)+ Example 55a gracemic mixture 2 /N N O\N/ Title compound is prepared in analogy to example 25a, ng from example 47a (450 mg, content 90%, 1.26 mmol) in place of 13a. After basic work-up the free amine is ob- tained (230 mg, 82%).
HPLC-MS (Method 1): Rt = 0.59 min MS (ESI pos): m/z = 222 (M+H)+ Example 55b gracemic mixture) O F The title compound is ed in analogy to example 55a starting from example 47b (310 mg, 0.97 mmol) in place of example 47a to obtain 130 mg (61%) ofproduct.
HPLC-MS (Method 2): Rt = 0.70 min MS (ESI pos): m/z = 219 (M+H)+ Example 55c gracemic e 2 / H HCI o\ /W9 Title compound is prepared in analogy to example 25a, ng from example 47c (340 mg, content 90%, 1.0 mmol) in place of example 13a to obtain (190 mg, 80%).
HPLC-MS (Method 1): Rt = 0.73 min MS (ESI pos): m/z = 206 (M+H)+ Example 55d gracemic mixture 2 -l56- The title compound is ed in analogy to example 55a starting from example 50b (330 mg, 1.03 mmol) in place of e 47a to obtain 200 mg (88%) ofproduct.
HPLC-MS (Method 1): Rt = 0.61 min MS (ESI pos): m/z = 220 (M+H)+ Example 55e gracemic mixture 2 /\ ZI Example 50a (162 mg, 0.56 mmol) is dissolved in dichloromethane (5 mL) and trifluoroacetic acid (0.5 mL) is added. Mixture is stirred overnight at room temperature, solvent is evaporated and the crude is first purified over SCX cartridge then by RP chroma- hy (eluent 5-40% ACN/Water ) to fiamish the title compound (100 mg, 94%).
HPLC-MS (Method 2): Rt = 0.49 min, broad MS (ESI pos): m/z = 192 (M+H)+ Example 55f gracemic mixture) ZI HCI Title compound is prepared in analogy to e 25a, starting from example 50c (546 mg, 1.52 mmol) to obtain 450 mg (100%) ofproduct.
HPLC-MS (Method 1): Rt = 0.65 min MS (ESI pos): m/z = 260 (M+H)+ -l57- Exam le 55 racemic mixture s Title compound is prepared in analogy to example 25a starting from example 54a (100 mg, 0.30 mmol) in place of example 13a to obtain 90 mg (81%) uct.
HPLC-MS (Method 6): Rt = 2.01 min MS (ESI pos): m/z = 234 (M+H)+ Example 56a gracemic mixture) 2-Fluoromethanesulfonyl-benzoic acid (563.0 mg, 2.58 mmol), HATU (1064 mg, 2,80 mmol) and DIPEA (1.12 ml, 6.45 mmol) are added to example 25k (550.0 mg, 2.15 mmol) in DMF (10 mL). The reaction mixture is stirred at room temperature overnight.
Volatiles are ated under reduced pressure and the resulting residue partitioned be- tween DCM and saturated NaHCO3. The organic layer is washed with brine, trated under reduced pressure giving a residue that is purified by flash chromatography (eluent 12-100% EtOAc/cyclohexane) to fiamish the title compound (690 mg, 77%).
S (Method 6): Rt = 10.69 min MS (ESI pos): m/z = 420 (M+H)+ Exemplary embodiments of active compounds Exam le 1 diastereomeric mixture e 9a (54 mg, 0.12 mmol), is dissolved in ACN (2 mL) in a microwave vessel and roacetic anhydride (23 ul, 0.16 mmol) and dry TEA (52 ul, 0.37 mmol) are added.
Mixture is heated under microwave irradation at 100°C for 20 min. Trifluoroacetic anhy- dride (100 pl, 0.70 mmol) is added and the mixture is heated under microwave irradation at 100°C for 30 min. Solvents are evaporated and the crude purified by flash cromatography (eluent DCM/MeOH 98:2) to obtain the title compound (54 mg, 85%).
HPLC-MS d 5): Rt = 9.72 min MS (APCI): rn/z = 514 (M+H)+ The diastereoisorners of the title compound are separated by HPLC using a chiral statio- nary phase.
Method for separation: HPLC apparatus type: Agilent 1100; column: Daicel chiralpack AD-H, 5.0 urn, 250 mm x mm; method: eluent hexane/IPA 70:30; flow rate: 12 mL/min, temperature: 25°C; UV Detection: 230 nm e of separation by chiral HPLC: Surnitted to separation: 78 mg of e 1; Obtained: 27 mg of Diastereoisomer 1 (Exp. 2) and 42 mg of Diastereoisomer 2 (Exp.3) -lS9- Example 2: Diastereoisomer 1 Example 3: Diastereoisomer 2 Unknown absolute chemistry Unknown absolute stereochemistry at bridgehead at bridgehead Example Chiral HPLC HPLC-MS (Method 6): MS (ESI pos): Rt [min] Rt [min] Exam le 4 diastereoisomer 1 unknown absolute stereochemist at brid ehead and ex- am le 5 diastereoisomer 2 unknown absolute stereochemistr at brid ehead The mixture ofthe title compounds is prepared as described for example 1, starting from example 9b (73 mg, 0.17 mmol); Obtained: 54 mg of diatereomeric mixture (62%) .
The title compounds are ed by separation of such mixture by HPLC using a chiral stationary phase.
Method for separation: HPLC tus type: Agilent 1100; : Daicel chiralpack AD-H, 5.0 um, 250 mm x mm; method: eluent hexane/IPA 70:30; flow rate: 12 mL/min, temperature: 25°C; UV Detection: 230 nm Example of tion by chiral HPLC: Sumitted to separation: 54 mg of Diastereomeric mixture; Obtained: 23 mg of Diastereoisomer 1 (exp. 4) and 23 mg of reoisomer 2 (Exp.5) -l60- e 4: Diastereoisomer 1 Example 5: reoisomer 2 Unknown absolute stereochemistry Unknown absolute stereochemistry at bridgehead at bridgehead Example Chiral HPLC HPLC-MS (Method 6): MS (ESI pos): Rt [min] Rt [min] Example 6 gdiastereomeric mixture) Example 9a (54 mg, 0.12 mmol) is dissolved in ACN (2 mL) in a microwave vessel and acetic anhydride (15 ul, 0.16 mmol) and dry TEA (52 ul, 0.37 mmol) are added. The reac- tion mixture is heated under microwave irradation at 100°C for 20 min. Dry TEA (100 ul, 0.71 mmol) is added and the reaction mixture is heated under microwave irradation at 150°C for 30 min. Solvents are evaporated and the crude d by flash ography (eluent DCM/MeOH 98:2) to obtain the title compound (38 mg, 67%) HPLC-MS (Method 5): Rt = 7.97 min MS : m/z = 460 (M+H)+ The diastereoisomers ofthe title compound are separated by HPLC using a chiral statio- nary phase.
Method for separation: HPLC apparatus type: Agilent 1100; column: Daicel chiralpack AD-H, 5.0 um, 250 mm x mm; method: eluent hexane/IPA 70:30; flow rate: 10 mL/min, Temperature: 25°C; UV Detection: 230 nm Example of separation by chiral HPLC: Sumitted to tion: 200 mg of Example 6; Obtained: 61 mg of Diastereoisomer 1 (Exp. 7) and 75 mg of Diastereoisomer 2 (Exp.8) Example 7: Diastereoisomer 1 Example 8: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute chemistry at bridgehead at bridgehead Chiral HPLC HPLC-MS (Method 6): MS (APCI pos): 11661 66666666) 16 66 16) To a solution of example 9a (0.055 g, 0.12 mmol) in dry ACN (2 mL), dicyclopropyl an- hydride (0.075 g, 90% content, 0.44 mrnol, prepared as described in.]. Org. Chem, 67, 5226-5231; 2002) and dry TEA (0088 mL, 0.62 mmol) are added and the mixture heated under microwaves tion (100°C) for 50 min and then heated at 150°C for additional 30 min. Solvents evaporated, crude purified by flash cromatography (cycloheane/EtOAc from 50:50 to 20:80) to obtain the title compound (0.033 g, 54%).
HPLC-MS d 6): Rt = 10.80 min MS (ESI pos): m/z = 486 (M+H)+ The diastereoisomers ofthe title compound are separated by HPLC using a chiral statio- nary phase.
Method for tion: HPLC apparatus type: Agilent 1100; column: Daicel chiralpack AS-H, 5.0 um, 250 mm x mm; method: eluent hexane/EtOH 70:30; flow rate: 15 mL/min, Temperature: 25°C; UV Detection: 230 nm WO 17657 -l63- Example of separation by chiral HPLC: Sumitted to separation: 200 mg of Example 9 ed: 84 mg of Diastereoisomer 1 (Exp. 10) and 78 mg of Diastereoisomer 2 (Exp. 1 1) Example 10: Diastereoisomer 1 Example 11: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute stereochemistry at bridgehead at bridgehead Chiral HPLC - : MS (APCI pos): Exp 10 10736 (Method 15) Exp 11 12824 (Method 15) Example 12 (diastereomeric mixture) N,N'-Dicyclohexylcarbodiimide (330 mg, 1.60 mmol) is added to 3,3,3-trifluoro-2,2- dimethylpropionic acid (500 mg, 3.20 mmol) in DCM and stirring is continued for 2d at room ature. Volatiles are evaporated under reduced pressure and the resulting resi- due, example 9a (100 mg, 0.23 mmol) and TEA (160 ul, 0.15 mmol) in ACN (2 mL) are heated under microwave irradiation (100°C) for two 30 min cycles. Solvents are evapo- rated under d pressure and the ing residue purified by flash cromatography (cyclohexane/EtOAc from 100:0 to 20:80) followed by preparative HPLC (stationary phase: Xterra C18 5 um 30 X 100 mm. Mobile phase: ACN/HzO + H 5 mmol).
Fractions containing the title compound are combined and freeze dried to filmish the title compound (35 mg, 27%).
HPLC-MS (Method 5): Rt = 9.63 min MS (APCI): m/z = 556 (M+H)+ Example 13 (diastereomeric mixture) a“?0:8:0N\ The title compound is prepared as bed for example 12, employing example 9a (100 mg, 96% content, 0.22 mmol) and 3,3-difluorocyclobutanecarboxylic acid (142 mg, 1.04mmol) in the place of trifluoro-2,2-dimethylpropionic acid. Obtained: 80 mg (70%).
HPLC-MS (Method 6): Rt = 11.15 min MS (ESI pos): m/z = 536 (M+H)+ Example 14 (diastereomeric mixture) Example 10a (150 mg, 83% content, 0.3 mmol) and 1,1,3,3-tetramethoxypropane (1.5 mL) are heated to 175°C in a microwave oven for 1 hour. Water and DCM are added to the on mixture and the c layer dried over NaZSO4, d and concentrated under reduced pressure giving a residue that is purified by flash chromatography (eluent 70- 100% EtOAc/petroleum ether) to filrnish the title compound (44 mg, 33%).
HPLC-MS d 5): Rt = 9.35 min MS (APCI): m/z = 456 (M+H)+ Example 15 (diastereomeric mixture) Example 10a (95 mg, 0.23 mmol) in 4-ethoxy-1,1,1-trifiuorobuten—2-one (3.0 mL) is heated under microwave irradation at 70°C for 5 min and then at 110°C for 5 min. Vola- tiles are evaporated under reduced pressure and the resulting residue purified by flash chromatography (eluent 50-80% cyclohexane/EtOAc) to fiamish the title compound (100 mg, 84%) HPLC-MS (Method 6): Rt = 11.56 min MS (ESI pos): m/z = 524 (M+H)+ The diastereoisomers ofthe title compound are separated by HPLC using a chiral statio- nary phase.
Method for separation: -l67- HPLC apparatus type: t 1100; column: Daicel pack AS-H, 5.0 um, 250 mm x mm; method: eluent hexane/IPA 75:25; flow rate: 15 mL/min, Temperature: 25°C; UV Detection: 230 nm Example of separation by chiral HPLC: Sumitted to tion: 100 mg of Example 15; Obtained: 45 mg of Diastereoisomer 1 (Exp. 16) and 48 mg of Diastereoisomer 2 (Exp.l7) Example 16: Diastereoisomer 1 Example 17: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute stereochemistry at bridgehead at bridgehead Chiral HPLC - : MS (APCI pos): Exp 16 9184 (Method 14) Exp 17 10943 (Method 14) Exam le 18 diastereoisomer 1 unknown absolute stereochemist at brid ehead and ex- ample 19 ereoisomer 2: unknown absolute stereochemistry at bridgehead) The mixture ofthe title compounds is prepared as bed for example 15, starting from example 10b (95 mg, 0.23 mmol); obtained 75 mg ofthe diastereomeric mixture (59%).
The title compounds are obtained by separation of such mixture by HPLC using a chiral stationary phase.
Method for separation: HPLC apparatus type: Agilent 1100; column: Daicel chiralpack AS-H, 5.0 um, 250 mm x mm; method: eluent hexane/EtOH 75:25; flow rate: 15 mL/min, Temperature: 25°C; UV Detection: 230 nm Example of separation by chiral HPLC: Sumitted to tion: 70 mg of Diastereomeric e; Obtained: 33 mg of Diastereoisomer 1 (exp. 18) and 33 mg of reoisomer 2 (Exp. 19) Example 18: Diastereoisomer 1 Example 19: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute stereochemistry at bridgehead at bridgehead Example Chiral HPLC - : MS (APCI): Rt [min] ' Exam le 20 diastereomeric mixture o F N F F g/o O:S\ Example 4a (19 mg, 0.061 mmol), HATU (27 mg, 0.072 mmol) and TEA (39 ul, 0.266 mmol) are added to example 25a (15 mg) in DMF (1 mL). The reaction mixture is stirred at room temperature overnight. Volatiles are evaporated under reduced pressure and the resulting residue partitioned between EtOAc and saturated NaHCO3. The organic layer is washed with brine, dried over NaZSO4, filtered and trated under d pressure giving a residue that is d by flash chromatography (eluent 50-100% EtOAc/cyclohexane) to fiamish the title compound (8 mg).
HPLC-MS (Method 5): Rt = 7.75 min MS (APCI): m/z = 445 (M+H)+ Example 21 (diastereomeric mixture) O F H o % N F F N O BK 028‘\O / The title compound is prepared in analogy to example 20, starting from example 25b (87 mg, 95% content, 0.41 mmol) and employing TBTU (146 mg, 0.45 mmol) in the place of HATU and DIPEA (354 ul, 2.067 mmol) in the place of TEA. Obtained: 140 mg (73 %). -l70- HPLC-MS (Method 5): Rt = 7.98 min MS (APCI): m/z = 459 (M+H)+ The diastereoisomers ofthe title compound are separated by HPLC using a chiral statio- nary phase.
Method for separation: HPLC apparatus type: Waters 600 Pump; column: Daicel Chiralpack AD-H, 5.0 um, 250 mm x 20 mm; method: eluent hexane/ IPA 75:25; flow rate: 10 , Temperature: °C; UV Detection: 230 nm Example of separation by chiral HPLC: ed to tion: 110 mg of Example 21 prepared as described above; Obtained: 43 mg of Diastereoisomer 1 (Exp. 22) and 47 mg of Diastereoisomer 2 (Exp.23) Example 22: Diastereoisomer 1 Example 23: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute stereochemistry at bridgehead at bridgehead e Chiral HPLC HPLC-MS (Method 5): MS (APCI): Rt [min] Rt [min] m/z nWMd) Wild) - l 7 l - Example 24 (diastereomeric mixture) o o F F '7\ O=S|=O The title compound is prepared as bed for example 20, starting from example 25c (180 mg, 75% content, 0.57 mmol). Obtained: 180 mg (63 %).
HPLC-MS (Method 5): Rt = 7.77 min MS (APCI): m/z = 494 (M+H)+ Exam le 25 diastereomeric mixture O F N F F A\ =sl\ S /l The title compound is prepared as described for example 20, starting from example 25d (33 mg, 0.15 mmol). Obtained: 52 mg (72%) S (Method 5): Rt = 8.48 min MS (APCI): m/z = 475 (M+H)+ -l72- e 26 (diastereomeric mixture) O F H o N F F / 0:8:O s F / F F The title compound is prepared in analogy to example 20, starting from example 25e (87 mg, 0.32 mmol) and ing TBTU (1 14 mg, 0.35 mmol) in the place ofHATU and DIPEA (275 ul, 1.607 mmol) in the place of TEA. Obtained: 102 mg (70% ).
HPLC-MS (Method 6): Rt = 12.00 min MS (ESI): m/z = 529 (M+H)+ The diastereoisomers ofthe title compound are separated by HPLC using a chiral statio- nary phase.
Method for separation: HPLC apparatus type: Waters 600 Pump; column: Daicel Chiralpack AD-H, 5.0 um, 250 mm x 20 mm; method: eluent hexane/ IPA 70:30; flow rate: 15 mL/min, Temperature: °C; UV Detection: 230 nm Example of separation by chiral HPLC: Sumitted to tion: 100 mg of Example 26 prepared as described above; Obtained: 40 mg of Diastereoisomer 1 (Exp. 27) and 43 mg of Diastereoisomer 2 (Exp.28) -l73- Example 27: Diastereoisomer 1 Example 28: Diastereoisomer 2 Unknown absolute stereochemistry Unknown te stereochemistry at bridgehead at bridgehead Example Chiral HPLC MS (APCI): Rt [min] ' m/z Example 29 gdiastereomeric mixture) —174— The title compound is prepared as described for example 20, starting from example 25e (87 mg, 0.32 mmol) and employing e 4b (110 mg, 0.35 mmol) in the place of example 4a, TBTU (114 mg, 0.35 mmol) in the place of HATU and DIPEA (275 ul, 1.607 mmol) in the place of TEA. Obtained: 104 mg (60%).
HPLC-MS (Method 6): Rt = 12.01 min MS (ESI): m/z = 529 (M+H)+ The diastereoisomers ofthe title compound are separated by HPLC using a chiral statio- nary phase.
Method for separation: HPLC apparatus type: Waters 600 Pump; column: Daicel Chiralpack AD-H, 5.0 um, 250 mm x 20 mm; method: eluent hexane/ IPA 70:30; flow rate: 12 mL/min, Temperature: °C; UV Detection: 210 nm Example of separation by chiral HPLC: Sumitted to separation: 100 mg of Example 29 ed as described above; Obtained: 37 mg of Diastereoisomer 1 (Exp. 30) and 52 mg of Diastereoisomer 2 1) Example 30: Diastereoisomer 1 Example 31: Diastereoisomer 2 Unknown absolute chemistry Unknown te stereochemistry at bridgehead at bridgehead 2012/065140 -l75- Example Chiral HPLC HPLC-MS (Method 6): MS (ESI): Rt [min] Rt [min] m/z Wild) Wad) Example 32 gdiastereomeric mixture) O F H o N F F N O\\S: The title compound is prepared in analogy to example 20, starting from example 25f (l3 mg, 0.063 mmol) and employing TBTU (22 mg, 0.070 mmol) in the place ofHATU and DIPEA (54 pl, 0.316 mmol) in the place of TEA. Obtained: 17 mg (58 %).
S (Method 5): Rt = 7.70 min MS (APCI): m/z = 459 (M+H)+ Example 33 gdiastereomeric mixture) -l76- The title compound is prepared in analogy to example 20, starting from example 25g (34 mg, 82% content, 0.14 mmol) and employing TBTU (49 mg, 0.15 mmol) as coupling agent and DIPEA (119 ul, 0.69 mmol) as base. Obtained: 21 mg (33%).
HPLC-MS (Method 6): Rt = 10.06 min MS (ESI pos): m/z = 459 (M+H)+ Example 34 (diastereomeric mixture) N/ O ’ [\1 0‘820 The title compound is prepared in analogy to e 20, ng from example 25h (64 mg, 0.31 mmol) and employing TBTU (111 mg, 0.35 mmol) as coupling agent and DIPEA (270 ul, 1.574 mmol) as base. Obtained: 124 mg (85% ).
HPLC-MS (Method 5): Rt = 7.65 min MS (APCI): m/z = 460 (M+H)+ Exam le 35 reomeric mixture -l77- The title compound is prepared in analogy to example 20, starting from example 25h (64 mg, 0.31 mmol) and employing example 4b (103 mg, 0.33 mmol) in the place of example 4a, TBTU (111 mg, 0.35 mmol) as ng agent and DIPEA (270 ul, 1.574 mmol) as base. Obtained: 90 mg (62%).
HPLC-MS (Method 5): Rt = 7.63 min MS : m/z = 460 (M+H)+ Example 36 (diastereomeric mixture) O F H O N \l : F F _, 0:8:0 N F / F F The title compound is prepared in analogy to e 20, starting from example 25i (80 mg, 0.31 mmol) and employing TBTU (111 mg, 0.35 mmol) as coupling agent and DIPEA (268 ul, 1.565 mmol) as base. Obtained: 102 mg (63 %).
HPLC-MS (Method 5): Rt = 9.14 min MS (APCI): m/z = 514 (M+H)+ -l78- Exam le 37 diastereomeric mixture The title compound is prepared in analogy to example 20, starting from example 25i (80 mg, 0.313 mmol) and employing example 4b (98 mg, 0.31 mmol) in the place of e 4a, TBTU (111 mg, 0.35 mmolas coupling agent and DIPEA (268 ul, 1.56 mmol) as base.
Obtained: 120 mg (74%).
HPLC-MS (Method 5): Rt = 9.14 min MS (APCI): m/z = 514 (M+H)+ Exam le 38 diastereomeric e O O :Nkfi:F €§ 2‘2’ O=S=O YO ' The title compound is prepared as described for example 20, starting from example 25j (58 mg, 0.29 mmol). ed: 11 mg (8%).
HPLC-MS (Method 5): Rt = 7.14 min MS (APCI): m/z = 460 (M+H)+ -l79- Exam le 39 diastereomeric mixture O\—/)fi\lk?N H H The title compound is ed in analogy to e 20, starting from e 25k (50 mg, 0.19 mmol) and employing example 4d (61 mg, 0.23 mmol) in the place of example 4a and DIPEA (234 ul, 1.37 mmol) as base. Obtained: 71 mg (78%).
HPLC-MS (Method 5): Rt = 9.76 min MS (APCI): m/z = 461 (M+H)+ Exam le 40 diastereomeric mixture 0:850 The title compound is prepared in analogy to example 20, starting from example 25k (50 mg, 0.19 mmol) and employing example 4e (77 mg, 0.235 mmol) in the place of example 4a and DIPEA (268 ul, 1.565 mmol) as base. Obtained: 75 mg (73%) HPLC-MS (Method 6): Rt = 11.77 min MS (ESI pos): m/z = 528 (M+H)+ Exam le 41 diastereomeric mixture The title compound is prepared as described for example 20, starting from example 251 (135 mg, 0.59 mmol) and employing example 4b (185 mg, 0.59 mmol) in the place ofex- ample 4a. Obtained: 190 mg (66%).
HPLC-MS (Method 5): Rt = 8.31 min MS : m/z = 486 (M+H)+ Exam 1e 42 diastereoisomer 1 unknown absolute stereochemist at brid ehead and ex- ample 43 (diastereoisomer 2: unknown absolute chemistry at bridgehead) The mixture ofthe title compounds is prepared as bed for example 20, starting from example 25m (100 mg) and employing example 4b (207 mg, 75% content, 0.498 mmol) in the place of e 4a; obtained 145 mg. The single diastereoisomers are obtained by se- paration of such mixture by HPLC using a chiral stationary phase.
Method for separation: HPLC apparatus type: Agilent 1100; column: Daicel chiralpack AD-H, 5.0 um, 250 mm x mm; : eluent /IPA 80:20; flow rate: 15 mL/min, Temperature: 25°C; UV Detection: 230 nm Example of separation by chiral HPLC: Sumitted to separation: 145 mg of the mixture; Obtained: 55 mg of Diastereoisomer 1 (Exp. 42) and 60 mg of Diastereoisomer 2 (Exp.43) Example 42: Diastereoisomer 1 e 43: Diastereoisomer 2 Unknown absolute chemistry Unknown absolute stereochemistry at bridgehead at bridgehead Example Chiral HPLC: HPLC-MS (Method 5): MS (APCI): Rt [min] Rt [min] Exam le 44 sin le stereoisomer unknown absolute stereochemistr at brid ehead The title compound is prepared in analogy to example 20, starting from example 25n (35 mg, 94% content, 0.14 mmol) and employing e 4b (48 mg, 0.15 mmol) in the place of example 4a and HATU (76 mg, 0.20 mmol) as ng Obtained: 26 mg (37%).
HPLC-MS (Method 6): Rt = 10.74 min MS (ESI pos): m/z = 486 (M+H)+ HPLC (chiral stationary phase, Method 10): Rt = 13.704 min Exam le 45 sin le stereoisomer unknown absolute stereochemistr at brid ehead O‘z N / 0:8\ The title compound is prepared in analogy to example 20, starting from example 250 (35 mg, 88% content, 0.13 mmol) and employing example 4b (42 mg, 0.13 mmol) in the place of example 4a and HATU (67 mg, 0.17 mmol) as coupling agent.Obtained: 15 mg (22 %): HPLC-MS (Method 6): Rt = 10.71 min MS (ESI pos): m/z = 486 (M+H)+ HPLC (chiral stationary phase, Method 10): Rt = 13.665 min Example 46 gdiastereomeric mixture) O F H N The title compound is prepared as described for example 20, starting from example 25p (83 mg, 90% content, 0.29 mmol). Obtained: 102 mg (68%).
HPLC-MS (Method 5): Rt = 9.22 min MS : m/z = 513 (M+H)+ The single diastereoisomers were obtained by HPLC tion using a chiral stationary phase.
Method for separation: HPLC apparatus type: Agilent 1100; column: Daicel chiralpack AD-H, 5.0 um, 250 mm x mm; method: eluent hexane/IPA 70:30; flow rate: 15 mL/min, Temperature: 25°C; UV Detection: 230 nm Example of separation by chiral HPLC: Sumitted to separation: 72 mg of the Example 46; Obtained: 25 mg of reoisomer 1 (Exp. 47) and 30 mg of Diastereoisomer 2 (Exp.48) Example 47: Diastereoisomer 1 Example 48: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute chemistry at bridgehead at head Example Chiral HPLC: HPLC-MS (Method 6): MS (ESI): Rt [min] Rt [min] m/z 0010100100130 00033 0010010000130 1110 Exam le 49 diastereomeric mixture :2 F o o/WLF The title compound is prepared as described for example 20, starting from example 25p (83 mg, 90% content, 0.29 mmol) and ing example 4b (91 mg, 0.29 mmol) in the place of example 4a. Obtained: 130 mg (87%).
HPLC-MS (Method 6): Rt = 11.76 min MS (ESI pos): m/z = 513 (M+H)+ Method for separation: HPLC apparatus type: Agilent 1100; column: Daicel chiralpack AD-H, 5.0 um, 250 mm x mm; method: eluent hexane/IPA 70:30; flow rate: 15 mL/min, Temperature: 25°C; UV Detection: 230 nm e of separation by chiral HPLC: Sumitted to separation: 100 mg of the Example 49; Obtained: 40 mg of Diastereoisomer 1 (Exp. 50) and 35 mg of reoisomer 2 (Exp.51) e 50: Diastereoisomer 1 Example 51: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute stereochemistry at bridgehead at bridgehead Example Chiral HPLC: S (Method 6): MS (ESI): Rt [min] Rt [min] m/Z We (Method 12) (Method 12) Example 52 (diastereomeric mixture) O F H N 0:850 The title compound is prepared in analogy to example 20, starting from example 25q (50 mg, 90% content, 0.22 mmol) and employing HATU (1 11 mg, 0.29 mmol) as coupling agent. ed: 82 mg (79 %).
HPLC-MS (Method 6): Rt = 10.28 min MS (ESI pos): m/z = 459 (M+H)+ -l87- Exam le 53 diastereomeric mixture O F H N/b FO F \ / O=Is\ F O The title compound is ed in analogy to example 20, starting from example 32a (150 mg, 0.48 mmol) and employing TBTU (164 mg, 0.51 mmol) as coupling agent and DIPEA (419 ul, 2.402 mmol) as base. Obtained: 161 mg (64 %).
HPLC-MS (Method 5): Rt = 8.92 min MS (APCI): m/z = 523 (M+H)+ Exam le 54 diastereomeric mixture The title compound is prepared in analogy to example 20, ng from example 32b (97 mg, 0.31 mmol) and employing TBTU (106 mg, 0.33 mmol) as coupling agent and DIPEA (271 ul, 1.553 mmol) as base. Obtained: 108 mg (66%).
HPLC-MS (Method 7): Rt = 7.96 min MS (ESI pos): m/z = 523 (M+H)+ WO 17657 The diastereoisomers ofthe title compound are separated by HPLC using a chiral statio- nary phase.
Method for separation: HPLC apparatus type: Agilent 1100; column: Daicel chiralpack AD-H, 50 um, 250 mm x mm; method: eluent hexane/ IPA 70:30; flow rate: 12 mL/min, Temperature: 25°C; UV Detection: 228 nm Example of separation by chiral HPLC: Sumitted to separation: 78 mg of the Example 54; Obtained: 31 mg of Diastereoisomer 1 (Exp. 55) and 33 mg of Diastereoisomer 2 (Exp.56) Example 55: Diastereoisomer 1 Example 56: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute stereochemistry at head at bridgehead Example Chiral HPLC: S d 6): MS (ESI): Rt [min] Rt [min] m/Z 55 5555555555) 55555 55555555555555 -l89- Exam le 57 diastereomeric mixture Nonafluorobutanesulfonyl fluoride (136 mg, 0.45 mmol) and 1,8- diazabicyclo[5.4.0]undecene (l35 uL, 0.90 mmol) are added to example 35a (160 mg, 0.300 mmol) in DCM (1 mL). Stirring is continued for lh at rt. Volatiles are evaporated under reduced re to give a residue, which is purified by flash chromatography (elu- ent 60-90% EtOAc/cyclohexane) to filI'IllSh the title compound (90 mg, 58%).
HPLC-MS (Method 5): Rt = 8.29 min MS (APCI): m/z = 515 (M+H)+ Exam le 58 diastereomericmixture F / \ IN O=s\ F II F o The title compounds is ed as described for example 1, starting from example 9b (73 mg, 0.17 mmol); Obtained: 54 mg (63%) .
HPLC-MS (Method 2): Rt = 1.19 min MS (ESI pos): m/z = 514 (M+H)+ -l90- Exam le 59 diastereoisomer 1 unknown te stereochemist at brid ehead and Exam le 60 diastereoisomer 2 unknown absolute stereochemist at brid ehead The diastereoisomers of e 13 are separated by HPLC using a chiral stationary phase.
Method for separation: HPLC apparatus type: Agilent 1100; column: Daicel chiralpack AS-H, 5.0 um, 250 mm x mm; method: eluent hexane/IPA 75:15; flow rate: 15 mL/min, temperature: 25°C; UV Detection: 230 nm Example of separation by chiral HPLC: Submitted to separation: 60 mg of Example 13 Obtained: 21 mg of Diastereoisomer 1 (Exp. 59) and 23 mg of Diastereoisomer 2 (Exp.60) Example 59: reoisomer 1 Example 60: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute stereochemistry at head at bridgehead - l 9 l - Chiral HPLC HPLC-MS (Method 7): MS (ESI pos): Exp 59 14 180 d 17) Exp 60 18.345 (Method 17) The title compound is prepared as described for example 12, employing example 9a (150 mg, 98% content, 0,34 mmol) and 3,3,3-trifluoropropionic anhydride (198mg, content 81%, 0.68 mmol) coming from a crude anhydride batch of 830mg synthetized from 3,3,3- trifluoropropionic acid (500 “1, 5.66 mmol) in the place of 3,3,3-trifluoro-2,2- dimethylpropionic acid. Obtained: 38 mg (21%).
HPLC-MS (Method 7). Rt: 6. 81 min MS (ESI pos): m/z = 528 (M+H)+ -l92- Exam le 62 diastereomeric mixture The title compound is prepared as bed for example 12, employing example 9a (122 mg, 98% content, 0.28 mmol) and 3-methyloxetanecarboxylic acid anhydride (300mg of a 450mg crude ide batch) synthetized from 3-methyloxetanecarboxylic acid (300 mg, 2,58 mmol) in the place of 3,3,3-trifluoro-2,2-dimethylpropionic acid. Obtained: 91 mg (64%).
HPLC-MS (Method 7): Rt = 5.82 min MS (ESI pos): m/z = 516 (M+H)+ Exam le 63 diastereomeric mixture O O H N \N 028:0 N\ l l -l93- The title compound is prepared as described for example 12, employing example 9a (180 mg, 96% content, 0.40 mrnol) and 2,2-difluorocyclopropanecarboxylic acid anhydride (46% of a batch obtained from 544 mg, 4.46 mmol of 2,2-difluorocyclopropanecarboxylic acid) in the place of 3,3,3-trifluoro-2,2-dimethylpropionic acid. ed: 76 mg (37%).
HPLC-MS (Method 7): Rt = 6.64 min MS (ESI pos): m/z = 522 (M+H)+ Exam le 64 diastereomeric e The title compound is prepared as described for example 12, employing example 9b (260 mg, 93% content, 0.55 mrnol) and fluorocyclopropanecarboxylic acid anhydride (88% of a batch obtained from 700 mg, 5.73 mmol, of 2,2-difluorocyclopropanecarboxylic acid) in the place of 3,3,3-trifluoro-2,2-dimethylpropionic acid. Obtained: 160 mg (55%).
HPLC-MS (Method 7a): Rt = 6.14 min MS (APCI pos): m/z = 522 (M+H)+ 2012/065140 Exam le 65 diastereomeric mixture 29*5;NO=SN\6 The title compound is prepared as described for example 12, employing example 9a (120 mg, 0.28 mmol) and 1-(Trifluoromethyl)cyclopropanecarboxylic acid anhydride (67% of a batch obtained from 500 mg, 3.24 mmol, of 1- (Trifluoromethyl)cyclopropanecarboxylic acid) in the place of 3,3,3-trifluoro-2,2- dimethylpropionic acid. Obtained: 71 mg (47%).
HPLC-MS (Method 7). Rt: 7.56 min MS (ESI pos): m/z = 554 (M+H)+ The diastereoisomers ofthe title compound are separated by HPLC using a chiral statio- nary phase.
Method for separation: HPLC apparatus type: Agilent 1100; : Daicel chiralpack AD-H, 5.0 um, 250 mm x mm; method: eluent hexane/IPA 73:27; flow rate: 15 mL/min, temperature: 25°C; UV ion: 230 nm Example of separation by chiral HPLC: Submitted to separation: 65 mg of Example 65; Obtained: 21 mg of Diastereoisomer 1 (Exp. 66) and 31 mg of Diastereoisomer 2 (Exp.67) -l95- Example 66: Diastereoisomer 1 Example 67: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute chemistry at bridgehead at bridgehead Example Chiral HPLC - : MS (ESI pos): Rt [min] ' Exp 66 9516 (Method 9) Exp 67 10452 (Method 9) Exam le 68 diastereomeric mixture The title compound is prepared as described for example 12, employing example 9b (173 mg, 93% t, 0.37 mmol) and 1-(Trifluoromethyl)cyclopropanecarboxylic acid ide (89% of a batch obtained from 500 mg, 3.24 mmol, of 1- (Trifluoromethyl)cyclopropanecarboxylic acid) in the place of 3,3,3-trifluoro-2,2- dimethylpropionic acid. Obtained: 85 mg (42%).
HPLC-MS d 7a): Rt = 6.71 min MS (APCI pos): m/z = 554 (M+H)+ The diastereoisomers ofthe title compound are separated by HPLC using a chiral statio- nary phase.
Method for separation: HPLC apparatus type: Agilent 1100; column: Daicel chiralpack AD-H, 5.0 um, 250 mm x 20 mm; method: eluent hexane/IPA 70:30; flow rate: 15 mL/min, ature: 25°C; UV Detection: 230 nm Example of separation by chiral HPLC: Submitted to separation: 64 mg of Example 68; Obtained: 27 mg of Diastereoisomer 1 (Exp. 69) and 22 mg of Diastereoisomer 2 (Exp.70) -l97- Example 69: Diastereoisorner 1 e 70: Diastereoisorner 2 Unknown absolute stereochernistry at Unknown absolute stereochemistry at bridgehead bridgehead HPLC-MS (Me- Exam le Ch1ralHPLC thod 7a): MS (APCI pos): m/z Rt [min] Exp. 69 9.785 (Method 9) 6.73 554 Exp. 70 11.430 (Method 9) 2 6.71 3 554 2012/065140 Example 71 (diastereomeric mixture) O O \N 02820 N\ I l F \ Example 46a (110 mg, 85% content, 0.21 mmol), is dissolved in ACN (2 mL) in a micro- wave vessel and roacetic anhydride (59 ul, 0.42 mmol) and dry TEA (87 ul, 0.62 mmol) are added. Mixture is heated under microwave irradation at 100°C for 20 min. Sol- vents are evaporated and the crude purified by flash cromatography (eluent 60-90% EtOAc/Cyclohexane) then by preparative HPLC (stationary phase: Xbridge C18 5 um 19 x 100 mm. Mobile phase: ACN/HzO + NH4COOH 5 mmol). to obtain the title compound (11 mg, 10%).
HPLC-MS (Method 5): Rt = 9.72 min MS (APCI): m/z = 514 (M+H)+ 2012/065140 Example 72 gdiastereomeric mixture) Example 10b (95 mg, 0.23 mmol) in 4-ethoxy-1,1,1-trifluorobuten—2-one (6.0 mL) is heated under ave irradation at 120°C for 60 min. Volatiles are evaporated under reduced pressure and the resulting residue purified by flash chromatography (eluent 50- 80% cyclohexane/EtOAc) to fiamish the title compound (70 mg, 59%) HPLC-MS (Method 6): Rt = 11.56 min MS (ESI pos): m/z = 524 (M+H)+ Example 73 gdiastereomeric mixture) The title compound is prepared as described for example 15, employing example 45a (240 mg, 0.55 mmol) in the place of example 10a. Obtained: 160 mg (54%).
HPLC-MS (Method 7a): Rt = 6.79 min MS (APCI pos): m/z = 538 (M+H)+ The diastereoisomers ofthe title compound are separated by HPLC using a chiral statio- nary phase.
Method for separation: HPLC apparatus type: Agilent 1100; column: Daicel chiralpack AD-H, 5.0 um, 250 mm x 20 mm; : eluent hexane/IPA 70:30; flow rate: 12 mL/min, Temperature: 25°C; UV Detection: 230 nm Example of separation by chiral HPLC: Submitted to separation: 137 mg of Example 73; Obtained: 53 mg of Diastereoisomer l 4) and 59 mg of Diastereoisomer 2 5) e 74: Diastereoisomer 1 Example 75: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute stereochemistry at bridgehead at bridgehead WO 17657 Chiral HPLC HPLC-MS (Method 7): MS (ESIpos): Exp 74 9737 (Method 9) Exp 75 12472 (Method 9) Exam le 76 diastereomeric mixture The title compound is prepared as described for example 15, employing example 45b (125 mg, 76% content, 0.22 mmol) in the place of example 10a. Obtained: 53 mg (45%).
HPLC-MS (Method 7a): Rt: 6.79 min MS (APCI pos): m/z = 538 (M+H)+ The diastereoisomers ofthe title compound are separated by HPLC using a chiral statio- nary phase.
Method for tion: HPLC apparatus type: Agilent 1100; column: Daicel chiralpack AS-H, 5.0 um, 250 mm x mm; method: eluent /IPA 80:20; flow rate: 15 mL/min, Temperature: 25°C; UV Detection: 230 nm Example of separation by chiral HPLC: Submitted to separation: 45 mg of Example 76; ed: 21 mg of Diastereoisomer 1 (Exp. 77) and 20 mg of Diastereoisomer 2 (Exp. 78) -202— Example 77: reoisomer 1 Example 78: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute stereochemistry at bridgehead at bridgehead Example Chiral HPLC - : MS (ESI pos): Rt [min] ' m/z 78 8488888888888 Exam le 79 diastereomeric mixture O O/WLF H N 0:8:0 N l“ \ Example 10b (450 mg, 93% content, 1.00 mmol) and sodium 3-cyclopropyl—3-oxoprop-l- en-l-olate (700 mg, 5.22 mmol) in EtOH (9.0 mL) is heated under microwave irradation at 120°C for 2 h. Volatiles are evaporated under reduced pressure and the resulting residue partitioned between ethyl acetate and sat. NaHCOg. The organic layer is washed with brine dried and evaporated under d pressure to fiamish a e that is purified by prepar- ative HPLC (stationary phase: Xbridge C18 5 um 19 x 100 mm. Mobile phase: ACN/HzO + NH4COOH 5 mmol). Fractions containing the title nd are combined and freeze dried to fiamish a residue that is fiarther purified by flash chromatography (eluent 70% cyc- lohexane/EtOAc) to afford the title compound (22 mg, 4%) HPLC-MS d 7a): Rt = 6.54 min MS (APCI pos): m/z = 496 (M+H)+ Exam le 80 diastereomeric mixture \ 43¢ N\O olo The title compound is prepared in analogy to example 20, starting from example 25r (30 mg, 0.13 mmol). Obtained: 45 mg (71 %).
HPLC-MS (Method 7): Rt = 6.50 min MS (ESI pos): m/z = 485 (M+H)+ —204— Example 81 (diastereomeric mixture) éfé0 The title compound is prepared in analogy to example 20, starting from example 25r (42 mg, 0.18 mmol) and example 4b (64 mg, 90% content, 0.18 mmol). Obtained: 53 mg (59 HPLC-MS (Method 7a): Rt = 6.23 min MS (APCI): m/z = 485 (M+H)+ The diastereoisomers ofthe title compound are separated by HPLC using a chiral statio- nary phase.
Method for separation: HPLC apparatus type: Agilent 1100; column: Daicel pack AS-H, 5.0 um, 250 mm x mm; method: eluent /IPA 90: 10; flow rate: 15 mL/min, Temperature: 25°C; UV ion: 230 nm Example of separation by chiral HPLC: Submitted to separation: 51 mg of Example 81; Obtained: 9 mg of Diastereoisomer 1 (Exp. 82) and 11 mg of Diastereoisomer 2 (Exp. 83) WO 17657 Example 82: Diastereoisomer 1 Example 83: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute stereochemistry at bridgehead at head Example Chiral HPLC HPLC-MS (Method 7a): MS (APCIpos): Rt [min] ' m/z 44 444444444444) :“ .44 4444444444444) Exam le 84 diastereoisomerl unknown absolute chemistr at brid ehead and Exam le 85 diastereoisomer 2 unknown absolute stereochemistr at brid ehead The diastereoisomers of example 36 are separated by HPLC using a chiral stationary phase.
Method for separation: HPLC apparatus type: Agilent 1100; column: Daicel chiralpack AD-H, 5.0 um, 250 mm x mm; : eluent hexane/IPA 70:30; flow rate: 15 mL/min, Temperature: 25°C; UV Detection: 230 nm Example of separation by chiral HPLC: Submitted to separation: 68 mg of Example 36; Obtained: 24 mg of Diastereoisomer 1 (Exp. 84) and 29 mg of Diastereoisomer 2 (Exp. 85) Example 84: reoisomer 1 Example 85: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute stereochemistry at bridgehead at bridgehead Example Chiral HPLC - : MS (ESI pos): Rt [min] ' WMW) WMethodg) Exam le 86 diastereoisomerl unknown absolute stereochemistr at brid ehead and Exam le 87 diastereoisomer 2 unknown absolute stereochemistr at brid ehead The reoisomers of example 37 are separated by HPLC using a chiral stationary phase.
Method for separation: HPLC apparatus type: Agilent 1100; column: Daicel chiralpack AD-H, 5.0 um, 250 mm x mm; method: eluent hexane/IPA 70:30; flow rate: 15 mL/min, Temperature: 25°C; UV Detection: 230 nm Example of separation by chiral HPLC: ted to tion: 84 mg of Example 37; Obtained: 36 mg of Diastereoisomer 1 (Exp. 86) and 31 mg of Diastereoisomer 2 (Exp. 87) 2012/065140 Example 86: Diastereoisomer 1 Example 87: Diastereoisomer 2 Unknown absolute stereochemistry at Unknown te stereochemistry at bridgehead bridgehead Example Chiral HPLC - : MS (ESI pos): Rt [min] ' 7362(Meth0d9) 9002(Meth0d9) Exam le 88 diastereomeric mixture H \\ The title compound is prepared in analogy to example 20, starting from example 25k (80 mg, 0.31 mmol) and employing e 4j, 97 mg, 0.38 mmol) in the place of example 4a, DIPEA (429 ul, 2.50 mmol) as base and TBTU (151 mg, 0.47 mmol) as coupling agent.
Obtained: 32 mg (22%).
HPLC-MS (Method 6): Rt = 12.11 min MS (ESI pos): m/z = 461 (M+H)+ The diastereoisomers ofthe title compound are separated by HPLC using a chiral statio- nary phase.
Method for separation: HPLC apparatus type: Agilent 1100; column: Daicel chiralpack AD-H, 5.0 um, 250 mm x mm; method: eluent hexane/IPA 70:30; flow rate: 12 , Temperature: 25°C; UV Detection: 230 nm e of separation by chiral HPLC: Submitted to separation: 160 mg of Example 88; Obtained: 55 mg of Diastereoisomer 1 (Exp. 89) and 62 mg of Diastereoisomer 2 (Exp. 90) e 89: Diastereoisomer 1 Example 90: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute stereochemistry at bridgehead at bridgehead Example Chiral HPLC HPLC-MS (Method 7): MS (ESI pos): Rt [min] Rt [min] Exam le 91 diastereomeric mixture \II“‘ F: 9;“! fiF F N H \\ The title compound is prepared in analogy to example 20, starting from e 25k (80 mg, 0.31 mmol) and employing example 4k (97 mg, 0.38 mmol) in the place of example 4a, DIPEA (429 ul, 2.50 mmol) as base and TBTU (151 mg, 0.47 mmol) as coupling agent. Obtained: 56 mg (39%).
HPLC-MS (Method 6): Rt = 12.12 min MS (ESI pos): m/z = 461 (M+H)+ Exam le 92 diastereomeric mixture F F F:i ' F 0 0% \N F O\ / F Oj=0 The title compound is prepared in analogy to example 20, starting from example 25k (90 mg, 0.35 mmol) and employing example 41 (138 mg, 0.42 mmol) in the place of example 4a, DIPEA (482 ul, 2.82 mmol) as base and TBTU (170 mg, 0.53 mmol) as ng agent. ed: 59 mg (32%).
HPLC-MS (Method 6): Rt = 11.81 min MS (ESI pos): m/z = 528 (M+H)+ The diastereoisomers ofthe title compound are separated by HPLC using a chiral statio- nary phase.
Method for tion: HPLC apparatus type: Agilent 1100; column: Daicel chiralpack AD-H, 5.0 um, 250 mm x mm; method: eluent hexane/IPA 70:30; flow rate: 12 mL/min, Temperature: 25°C; UV Detection: 230 nm Example of separation by chiral HPLC: Submitted to separation: 54 mg of e 92; Obtained: 25 mg of Diastereoisomer 1 (Exp. 93) and 35 mg of Diastereoisomer 2 (Exp. 94) Example 93: Diastereoisomer 1 Example 94: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute stereochemistry at head at bridgehead Chiral HPLC HPLC-MS(Method 7): MS (ESI p05); Example Rt [min] Rt [min] WO 17657 -2l 1- Example 95 gracemic mixture) The title nd is prepared in analogy to example 20, starting from example 25k (70 mg, 0.27 mmol) and employing example 4h (75 mg, 0.27 mmol) in the place of example 4a. Obtained: 110 mg (85%).
HPLC-MS (Method 7): Rt = 7.54 min MS (ESI pos): m/z = 474 (M+H)+ Exam le 96 racemic mixture The title compound is prepared in analogy to example 20, starting from example 25k (100 mg, 0.39 mmol) and employing example 4f (126 mg, 80% t, 0.39 mmol) in the place of example 4a and DIPEA (204 111, 1.17 mmol) as base. Obtained: 116 mg (65%).
HPLC-MS (Method 6): Rt = 6.85 min MS (ESI pos): m/z = 460 (M+H)+ The enantiomers ofthe title compound are separated by HPLC using a chiral stationary phase.
Method for tion: HPLC apparatus type: Agilent 1100; column: Daicel chiralpack AD-H, 5.0 um, 250 mm x mm; method: eluent hexane/IPA 70:30; flow rate: 15 mL/min, Temperature: 25°C; UV Detection: 230 nm Example of tion by chiral HPLC: Submitted to separation: 116 mg of e 96; Obtained: 46 mg of enantiomer 1 (Exp. 97) and 44 mg of enantiomer 2 (Exp. 98) Example 97: Enantiomer 1 Example 98: Enantiomer 2 Unknown absolute stereochemistry at Unknown absolute stereochemistry at bridgehead bridgehead Example Chiral HPLC HPLC-MS (Method 7): MS (ESI pos): Rt [min]' m/z Rt [min] -2l3- Example 99 gracemic mixture) The title compound is prepared in analogy to example 20, starting from example 25k (80 mg, 0.31 mmol) and employing example 4n (97 mg, 0.38 mmol) in the place of example 4a, DIPEA (429 ul, 2.50 mmol) as base and TBTU (151 mg, 0.47 mmol) as coupling agent. Obtained: 23 mg (16%).
HPLC-MS (Method 6): Rt = 11.27 min MS (ESI pos): m/z = 472 (M+H)+ Example 100 gdiastereomeric mixture) H O OJug [I\]/ N The title nd is prepared in analogy to e 20, ng from example 25k (18 mg, 0.07 mmol) and employing example 4g (20 mg, 0.07 mmol) in the place of example 4a, DIPEA (73 mg, 0.56 mmol) as base and TBTU (29 mg, 0.09 mmol) as coupling agent.
Obtained: 12 mg (34%).
HPLC-MS (Method 7): Rt = 8.21 min MS (ESI pos): m/z = 503 (M+H)+ —214— Exam le 101 diastereomeric mixture The title compound is prepared in y to example 20, starting from example 25m (100 mg, 0.50 mmol) and employing example 4b (207 mg, 75% content, 0.50 mmol) in the place of example 4a. Obtained: 145 mg (64%).
S (Method 5): Rt = 7.60 min MS (APCI): m/z = 460 (M+H)+ Exam le 102 diastereomeric mixture H N \N 0:820 \ l O K The title compound is prepared in analogy to example 20, starting from example 25p (16 mg, 0.46 mmol) and employing example 4e (149 mg, 0.46 mmol) in the place of example 4a. ed: 208 mg (87%).
HPLC-MS (Method 7): Rt = 7.79 min MS (ESI pos): m/z = 527 (M+H)+ 2012/065140 The diastereoisomers ofthe title compound are separated by HPLC using a chiral statio- nary phase.
Method for separation: HPLC apparatus type: Agilent 1100; column: Daicel pack AD-H, 5.0 um, 250 mm x mm; : eluent hexane/IPA 70:30; flow rate: 15 mL/min, Temperature: 25°C; UV Detection: 230 nm Example of separation by chiral HPLC: Submitted to separation: 62 mg of Example 102; Obtained: 20 mg of Diastereoisomer 1 (Exp. 103) and 30 mg of Diastereoisomer 2 (Exp. 104) Example 103: Diastereoisomer 1 Example 104: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute stereochemistry at bridgehead at bridgehead Example Chiral HPLC HPLC-MS (Method 7a): MS (APCI pos): Rt [min] Rt [min] -2l6- Exam le 105 diastereomeric mixture H N \N 02820 \ I The title compound is prepared in analogy to example 20, ng from example 25p (70 mg, 0.27 mmol) and employing example 41 (87 mg, 0.27 mmol) in the place of example 4a. ed: 71 mg (49%).
HPLC-MS (Method 7): Rt = 7.82 min MS (ESI pos): m/z = 527 (M+H)+ The reoisomers ofthe title compound are separated by HPLC using a chiral statio- nary phase.
Method for separation: HPLC apparatus type: Agilent 1100; column: Daicel pack OJ-H, 5.0 um, 250 mm x mm; method: eluent hexane/IPA 80:20; flow rate: 12 mL/min, Temperature: 25°C; UV Detection: 230 nm Example of separation by chiral HPLC: Submitted to separation: 60 mg of Example 105; Obtained: 24 mg of Diastereoisomer 1 (Exp. 106) and 27 mg of Diastereoisomer 2 (Exp. 107) Example 106: reoisomer 1 Example 107: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute stereochemistry at bridgehead at bridgehead -2l7- Example Chiral HPLC HPLC-MS (Method 7): MS (ESI pos): Rt [min] m/z Rt [min] Exam le 108 diastereomeric mixture o o H%NN \ I =0 The title compound is prepared in analogy to example 20, starting from example 25u (50 mg, 0.25 mmol) and employing example 4a (78 mg, 0.25 . Obtained: 6 mg (5%).
HPLC-MS (Method 7): Rt = 5.86 min MS (ESI pos): m/z = 459 (M+H)+ Exam le 109 reomeric mixture The title compound is prepared in analogy to example 20, starting from example 25V (30 mg, 0.12 mmol) and employing example 4a (37 mg, 0.12 mmol). Obtained: 57 mg (94%).
HPLC-MS (Method 7): Rt = 6.86 min MS (ESI pos): m/z = 513 (M+H)+ Exam le 110 racemic mixture OWP | TEA (70uL, 0.53 mmol) is added to a suspension of example 25W (90 mg, 0.35 mmol) in anhydrous DCM (4ml); after 30 s stirring example 4f (100 mg, 0.39 mmol), N—(3- dimethylaminopropyl)-N'-ethylcarbodiimidehydrochloride (74.5 mg, 0.39 mmol) and l- Hydroxybenzotriazole (4.78 mg, 0.04 mmol) are added and the e is stirred overnight.
Water is added, phases are separated then the organic layer is washed with 10% -2l9- aqueous NaHCOg, dried over phase-separator cartridge and solvent is eliminated under re- duced pressure. Crude product is ed by preparative HPLC (stationary phase: Xterra C18 5 um 30 x 100 mm. Mobile phase: ACN/HzO + NH4COOH 5 mmol) to obtain 71mg (43%) ofproduct.
HPLC-MS (Method 7a): Rt = 6.42 min MS (APCI pos): m/z = 459 (M+H)+ The enantiomers of the title compound are separated by HPLC using a chiral stationary phase.
Method for separation: HPLC apparatus type: Waters 600 Pump; column: Daicel Chiralpack IA, 5.0 um, 250 mm x 20 mm; method: eluent hexane/ IPA 70:30; flow rate: 15 mL/min, Temperature: 25°C; UV ion: 230 nm Example of separation by chiral HPLC: ted to tion: 56 mg of Example 110 prepared as described above; Obtained: 25 mg of enantiomer 1 (Exp. 111) and 24 mg of enantiomer 2 (Exp. 1 12) Example 111: Enantiomer 1 e 112: Enantiomer 2 Unknown absolute stereochemistry Unknown absolute stereochemistry at bridgehead at bridgehead 2012/065140 Example Chiral HPLC HPLC-MS(Method 7b): MS (APCI): Rt [min] ' m/Z Example 113 (diasteromeric mixture) F F O O- /\N *J O=?=O Title compound is prepared in analogy to e 110, starting from example 4b (81 mg, 0.26 mmol) in place of example 4f to obtain the title compound (59 mg, 48%).
HPLC-MS (Method 7a): Rt = 6.63 min MS (APCI pos): m/z = 513 (M+H)+ The diasteromers of the title compound are separated by HPLC using a chiral nary phase.
Method for separation: HPLC apparatus type: Waters 600 Pump; column: Daicel Chiralpack IA, 5.0 um, 250 mm x 20 mm; method: eluent hexane/ IPA 80:20; flow rate: 15 mL/min, Temperature: 25°C; UV Detection: 230 nm Example of separation by chiral HPLC: Submitted to separation: 40 mg of Example 113 prepared as bed above; Obtained: 17 mg of Diastereoisomer 1 (Exp. 114) and 19 mg of Diastereoisomer 2 (Exp.115) Example 114: Diastereoisomer 1 Example 115: Diastereoisomer 2 Unknown te stereochemistry Unknown absolute stereochemistry at bridgehead at bridgehead Example Chiral HPLC HPLC-MS (Method 7b): MS (APCI): Rt [mm] Rt [min] Exam le 116 diasteromeric mixture N—(3-dimethylaminopropyl)-N'-ethylcarbodiimidehydrochloride (110 mg, 0.57 mmol) is added to a stirred e ofexample 55a (110 mg, 0.50 mmol), example 4a (159 mg, 0.51 mmol) and 1-Hydroxybenzotriazole (10 mg, 0.07 mmol) in THF/DMF mixture. After stir- ring 18 hours the mixture is poured in water and extracted with EtOAc. Organic layer is separated, washed with 5% aqueous NaHC03 solution, dried over Na2S04 and - trated under reduced pressure. The residue is purified by Si flash chromatography (Eluent EtOAc/n—Hexane/MeOH 80:20: 1) to obtain the title compound (200 mg, 78%).
HPLC-MS (Method 6): Rt = 11.00 min MS (ESI pos): m/z = 516 (M+H)+ The diasteromers of the title compound are separated by HPLC using a chiral stationary phase.
Method for separation: HPLC apparatus type: Waters 600 Pump; column: Daicel Chiralpack IA, 5.0 um, 250 mm x 20 mm; method: eluent / IPA 80:20; flow rate: 15 mL/min, Temperature: 25°C; UV Detection: 230 nm Example of separation by chiral HPLC: Submitted to separation: 120 mg of Example 116 ed as described above; Obtained: 50 mg of reoisomer 1 (Exp. 117) and 54 mg of Diastereoisomer 2 (Exp. 1 18) Example 117: Diastereoisomer 1 Example 118: Diastereoisomer 2 Unknown te stereochemistry Unknown absolute stereochemistry at bridgehead at bridgehead Example Chiral HPLC HPLC-MS (Method 7a): MS (APCI): Rt [min] ' m/Z Exam le 119 diasteromeric e Title nd is prepared in y to example 116 starting from example 4b (158.7 mg, 0.51 mmol) in place of example 4a to obtain 180 mg (70%) ofproduct.
HPLC-MS (Method 7a): Rt = 6.23 min MS (APCI pos): m/z = 516 (M+H)+ The diasteromers of the title compound are separated by HPLC using a chiral stationary phase.
Method for separation: HPLC apparatus type: Waters 600 Pump; column: Daicel Chiralpack IA, 5.0 um, 250 mm x 20 mm; method: eluent hexane/ IPA 80:20; flow rate: 15 mL/min, Temperature: 25°C; UV Detection: 230 nm Example of separation by chiral HPLC: Submitted to separation: 70 mg of Example 119 prepared as described above; Obtained: 31 mg of Diastereoisomer 1 (Exp. 120) and 29 mg of Diastereoisomer 2 (Exp. 121) WO 17657 —224— Example 120: Diastereoisomer 1 Example 121: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute stereochemistry at bridgehead at bridgehead Example Chiral HPLC MS (APCI): Rt [min] ' m/z Example 122 gdiasteromeric mixture) The title compound is prepared in analogy to example 116 starting from e 55d (90 mg, 0.41 mmol) in place of example 55a and example 4b (131 mg, 0.42 mmol) in place of example 4a and EtOAc/n—Hexane/MeOH 70:30:1 as eluent for the Si—flash chromatogra- phy to obtain 150 mg (71%) ofproduct.
HPLC-MS (Method 7a): Rt = 6.20 min MS (APCI pos): m/z = 514 (M+H)+ The diasteromers of the title compound are separated by HPLC using a chiral stationary phase.
Method for separation: HPLC apparatus type: Waters 600 Pump; column: Daicel Chiralpack IA, 5.0 um, 250 mm x 20 mm; method: eluent hexane/ IPA 75:25; flow rate: 15 , Temperature: 25°C; UV ion: 230 nm Example of separation by chiral HPLC: Submitted to separation: 110 mg of Example 122 prepared as described above; Obtained: 49 mg of reoisomer 1 (Exp. 123) and 50 mg of Diastereoisomer 2 (Exp. 124) e 123: Diastereoisomer 1 Example 124: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute stereochemistry at bridgehead at bridgehead Example Chiral HPLC HPLC-MS (Method 7a): MS : Rt [min] ' m/Z Example 125 (diasteromeric mixture) The title compound is prepared in analogy to example 116 starting from example 55d (90 mg, 0.41 mmol) in place of example 55a and EtOAc/n—Hexane/MeOH 70:30:1 as eluent for the Si—flash chromatography to obtain 140 mg (66%) ofproduct.
S d 7a): Rt = 6.22 min MS (APCI pos): m/z = 514 (M+H)+ The diasteromers of the title compound are separated by HPLC using a chiral stationary phase.
Method for separation: HPLC apparatus type: Waters 600 Pump; column: Daicel Chiralpack IA, 5.0 um, 250 mm x 20 mm; method: eluent hexane/ IPA 70:30; flow rate: 15 mL/min, Temperature: 25°C; UV Detection: 230 nm WO 17657 Example of separation by chiral HPLC: Submitted to tion: 100 mg of Example 125 prepared as described above; Obtained: 39 mg of Diastereoisomer 1 (Exp. 126) and 45 mg of Diastereoisomer 2 (Exp. 127) Example 126: Diastereoisomer 1 Example 127: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute stereochemistry at bridgehead at bridgehead Example Chiral HPLC S (Method 7a): MS (APCI): Rt [min] Rt [min] m/z 126 8.23(Method23) swallow) Example 128 eromeric mixture) 02820 / | The title compound is prepared in analogy to e 116 starting from example 55b (50 mg, 0.23 mmol) in place of example 55a, example 4b (73.2 mg, 0.23 mmol) in place of example 4a and EtOAc/n—Hexane/MeOH 70:30:1 as eluent for the Si—flash chromatogra- phy to obtain 90 mg (77%) ofproduct.
HPLC-MS (Method 7a): Rt = 6.68 min MS (APCI pos): m/z = 513 (M+H)+ The diasteromers of the title compound are ted by HPLC using a chiral stationary phase.
Method for separation: HPLC apparatus type: Waters 600 Pump; column: Daicel Chiralpack AD-H, 5.0 um, 250 mm x 20 mm; method: eluent hexane/ IPA 70:30; flow rate: 15 mL/min, Temperature: 25°C; UV Detection: 230 nm Example of separation by chiral HPLC: Submitted to separation: 70 mg of Example 128 prepared as described above; Obtained: 28 mg of reoisomer 1 (Exp. 129) and 24 mg of Diastereoisomer 2 (Exp. 130) Example 129: Diastereoisomer 1 Example 130: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute chemistry at bridgehead at head Chiral HPLC MS (APCI): Example ' m/Z 656666666155 - Example 131 (diasteromeric mixture) WO 17657 The title compound is prepared in analogy to example 116 starting from example 55b (50 mg, 0.23 mmol) in place of example 55a and EtOAc/n—Hexane/MeOH 70:30:1 as eluent for the Si—flash chromatography to obtain 75 mg (64%) ofproduct.
HPLC-MS (Method 2): Rt = 1.14 min MS (ESI pos): m/z = 513 (M+H)+ The diasteromers of the title compound are separated by HPLC using a chiral stationary phase.
Method for separation: HPLC apparatus type: Waters 600 Pump; column: Daicel Chiralpack IA, 5.0 um, 250 mm x 20 mm; method: eluent hexane/ IPA 80:20; flow rate: 15 , Temperature: 25°C; UV Detection: 230 nm Example of separation by chiral HPLC: Submitted to separation: 75 mg of Example 131 prepared as described above; Obtained: 32 mg of reoisomer 1 (Exp. 132) and 30 mg of Diastereoisomer 2 (Exp. 133) Example 132: Diastereoisomer 1 Example 133: Diastereoisomer 2 n absolute stereochemistry Unknown absolute stereochemistry at head at bridgehead -23 1- Example Chiral HPLC HPLC-MS(Method 7a): MS (ESI pos): Rt [min] Rt [min] m/z Example 134 gdiasteromeric e) DIPEA (0.15 ml, 0.88 mmol) is added to a stirred solution of example 55c (90 mg, 0.37 mmol) and e 4a (140 mg, 0.45 mmol) in DMF; after 10 minutes HATU (190 mg, 0.50 mmol) is added and the on is stirred for 18 hours. The reaction mixture is poured into water and extracted with EtOAc, organic layer is separated, washed With 5% NaHC03 aqueous solution, dried over NaZSO4 and concentrated under reduced pressure. The crude is purified by flash chromatography using EtOAc/n—Hexane/MeOH 60:40:l as eluent to obtain the title compound (130 mg, 70%) HPLC-MS (Method 7a): Rt: 6. 19 min MS (APCI pos): m/z = 500 (M+H)+ WO 17657 Exam le 135 diastereomeric mixture The title compound is prepared in analogy to example 134 starting from example 4b (140 mg, 0.45 mmol) in place of example 4a to obtain 140 mg (76%) ofproduct.
HPLC-MS (Method 7a): Rt = 6.17 min MS (APCI pos): m/z = 500 (M+H)+ Exam le 136 diastereoisomerl unknown absolute stereochemistr at brid ehead and Example 137 (diastereoisomer 2, unknown absolute chemistry at bridgehead) The mixture of the title compounds is prepared in analogy to example 110, starting from e 4a (81mg, 0.26 mmol) in place of example 4f and example 25W (60 mg, 0.24 mmol) to obtain the title compound (45 mg, 37%).
HPLC-MS (Method 7a): Rt = 6.63 min MS (APCI pos): m/z = 513 (M+H)+ The diasteromers are separated by HPLC using a chiral stationary phase.
Method for separation: HPLC tus type: Waters 600 Pump; column: Daicel Chiralpack IA, 5.0 um, 250 mm x 20 mm; method: eluent hexane/ IPA 75:25; flow rate: 15 mL/min, Temperature: 25°C; UV Detection: 230 nm Example of separation by chiral HPLC: ted to separation: 38 mg of diastereomeric mixture prepared as described above; Obtained: 17 mg of Diastereoisomer 1 (Exp.136) and 18 mg of Diastereoisomer 2 (Exp.137) Example 136: reoisomer 1 Example 137: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute stereochemistry at bridgehead at bridgehead Example Chiral HPLC HPLC-MS (Method 7a): MS (APCI): Rt [min] Rt [min] 2012/065140 —234— Exam le 138 diasteromeric mixture 0:?20 The title compound is prepared in analogy to example 20 starting from example 4m (121.0 mg, 0.42 mmol) in place of example 4a, example 25k (80.0 mg, 0.31 mmol) in place of example 25a and DIPEA (0.18 ml, 1.06 mmol) in place of TEA to obtain 118 mg (77%) of product.
HPLC-MS (Method 6): Rt = 10.15 min MS (ESI pos): m/z = 488 (M+H)+ The diasteromers of the title compound are separated by HPLC using a chiral stationary phase.
Method for tion: HPLC tus type: Waters 600 Pump; column: Daicel Chiralpack AD-H, 5.0 um, 250 mm x 20 mm; method: eluent / IPA 70:30; flow rate: 15 mL/min, Temperature: °C; UV Detection: 230 nm Example of tion by chiral HPLC: Submitted to separation: 110 mg of Example 138 prepared as described above; Obtained: 53 mg of Diastereoisomer 1 (Exp. 139) and 54 mg of Diastereoisomer 2 (Exp. 140) Example 139: Diastereoisomer 1 Example 140: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute stereochemistry at bridgehead at bridgehead e Chiral HPLC HPLC-MS (Method 7a): MS (APCI): Rt [min] Rt [min] Exam le l4l racemic mixture O=S=O Potassium tert-butoxide (44.2 mg, 0.39 mmol) is added, under nitrogen here, to a solution of e 56a (150 mg, 0.36 mmol) and l-(3-trifluoromethyl)pyrazole (58.4 mg, 0.43 mmol) in anhydrous THF (2 ml) then the reaction mixture is stirred overnight at room temperature. Solvent is concentrated under reduced pressure then the residue is partitioned between DCM and 10% citric acid aqueous solution, organic layer is separated over a phase-separator cartridge and concentrated under reduced pressure.
The cude is d by RP-flash chromatography using ACN/water 20-100% as eluent to obtain the title product (87 mg, 45%) HPLC-MS (Method 7): Rt = 7.88 min MS (ESI pos): m/z = 536 (M+H)+ Example 142 (sin le enantiomer unknown te stereochemistr at brid ehead ) The title compound is prepared in analogy to example 20 starting from e 25x (54 mg, 0.18 mmol) in place of example 25a, example 4f(65 mg, content 80%, 0.20 mmol) in place of example 4a and 10-100% EtOAc/Cyclohexane as purification eluent to obtain 60 mg (66%) ofproduct.
HPLC-MS (Method 7a): Rt = 6.21 min MS (APCI pos): m/z = 500 (M+H)+ Exam le 143 reoisomer1 unknown absolute stereochemistr at brid ehead and example 144 (diastereoisomer 21 unknown absolute stereochemistry at bridgehead) The mixture of the title compounds is prepared in analogy to example 20 starting from ex- ample 4a (75.0 mg, 0.24 mmol), example 25y (55.0 mg, 0.24 mmol) in place of e 25a and DIPEA (0.21 ml, 1.20 mmol) in place of TEA to obtain 85 mg (content 88%, 64%) ofproduct.
The diasteromers are separated by HPLC using a chiral stationary phase. 2012/065140 Method for separation: HPLC apparatus type: Waters 600 Pump; column: Daicel Chiralpack AD-H, 5.0 um, 250 mm x 20 mm; method: eluent hexane/ IPA 70:30; flow rate: 15 mL/min, Temperature: °C; UV Detection: 230 nm e of separation by chiral HPLC: Submitted to separation: 85 mg ofthe diasteromeric mixture prepared as described above; Obtained: 28 mg of Diastereoisomer 1 (Exp. 143) and 34 mg of Diastereoisomer 2 (Exp. 144) Example 143: Diastereoisomer 1 Example 144: Diastereoisomer 2 Unknown te stereochemistry Unknown absolute stereochemistry at bridgehead at bridgehead Example Chiral HPLC HPLC-MS (Method 7): MS (ESI pos): Rt [min] Rt [min] Exam le 145 diastereomeric mixture The title compound is prepared in analogy to example 20 starting from example 4b (75.0 mg, 0.24 mmol) in place of example 4a, example 25y (55.0 mg, 0.24 mmol) in place of example 25a and DIPEA (0.21 ml, 1.20 mmol) in place of TEA to obtain 68 mg (58%) of product.
S (Method 7): Rt = 6.58 min MS (ESI pos): m/z = 486 (M+H)+ Exam le 146 diasteromeric mixture HATU (109 mg, 0.29 mmol) and DIPEA (49 ul, 0.29 mmol) are added into a solution of example 4b (90 mg, 0.29 mmol) in 3ml of ous DMF and the reaction mixture is stirred for 30 minutes; example 55e (50 mg, 0.26 mmol) dissolved into 3ml of anhydrous DMF is added and the resulting mixture is stirred overnight. EtOAc and water are added, phases are separated then the organic layer is washed With 0.5M HCl, 10% s Na- HCOg, brine, dried over a phase-separator cartridge and concentrated under reduced pres- sure. e is purified by Si flash chromatography (eluent 20-100% EtOAc/cyclohexane) to fiamish the title compound (36.5 mg, 29%).
HPLC-MS (Method 7a): Rt = 5.28 min MS (APCI pos): m/z = 486 (M+H)+ Exam le l47 diasteromeric mixture The title nd is prepared in analogy to example 146, starting from example 4a (90 mg, 0.29 mmol) in place of example 4b to obtain 41 mg ofproduct (32%) HPLC-MS (Method 7a): Rt = 5.28 min MS (APCI pos): m/z = 486 (M+H)+ —240— Exam le 148 romeric mixture :5 F O o/WLF 0:8:0 o 'I“ \ The title nd is prepared in analogy to example 146, starting from example 4b (80 mg, 0.28 mmol), e 55f(83 mg, 0.28mmol) in place of example 55e, DIPEA (0.096 ml, 0.56 mmol), HATU (107 mg, 0.28 mmol) to obtain 102 mg ofproduct (72%).
HPLC-MS (Method 7a): Rt = 6.05 min MS (APCI pos): m/z = 554 (M+H)+ The diastereoisomers of the title compound are separated by HPLC using a chiral station- ary phase.
Method for separation: HPLC apparatus type: Waters 600 Pump; column: Daicel Chiralpack IA, 5.0 um, 250 mm x 20 mm; method: eluent hexane/ IPA 75:25; flow rate: 15 mL/min, Temperature: 25°C; UV Detection: 230 nm Example of separation by chiral HPLC: Submitted to separation: 75 mg of e 148 prepared as described above; Obtained: 33 mg of Diastereoisomer 1 (Exp. 149) and 35 mg of Diastereoisomer 2 (Exp.150) —241— Example 149: Diastereoisomer 1 Example 150: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute stereochemistry at bridgehead at bridgehead Example Chiral HPLC - : MS (ESI pos): Rt [min] ' Exp 149 2050 (Method 22) Exp 150 2451 d 22 Exam le lSl diasteromeric mixture 2012/065140 —242— The title compound is prepared in analogy to example 148, starting from example 4a (80 mg, 0.28 mmol) in place of example 4b to obtain 100 mg ofproduct (71%).
HPLC-MS (Method 7a): Rt = 6.03 min MS (APCI pos): m/z = 554 (M+H)+ The diastereoisomers of the title compound are separated by HPLC using a chiral station- ary phase.
Method for separation: HPLC tus type: Waters 600 Pump; column: Daicel Chiralpack IA, 5.0 um, 250 mm x 20 mm; method: eluent hexane/ IPA 75:25; flow rate: 15 mL/min, ature: 25°C; UV Detection: 230 nm Example of separation by chiral HPLC: Submitted to separation: 75 mg of Example 151 prepared as described above; Obtained: 30 mg of Diastereoisomer 1 (Exp. 152) and 34 mg of Diastereoisomer 2 (Exp.153) Example 152: Diastereoisomer 1 e 153: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute stereochemistry at bridgehead at bridgehead —243— Example Chiral HPLC S (Method 6): MS (ESI pos): Rt [min] Rt [min] m/z 1900116110122) 11.03 -554 Exp. 153 33.02 (Method 22) 11.03 Exam le 154 racemic mixture KEN/fl:N/ Title compound is prepared in analogy to example 20 starting from example 4f (58 mg, 0.22 mmol) in place of example 4a, example 25z (63 mg, 0.21 mmol) in place of example 25a and anhydrous ACN (2 ml) in place of DMF. The crude is purified by RP-flash chro- aphy using 20-100% ACN/Water as eluent then by Si—flash chromatography using -100% EtOAc/Cyclohexan as eluent to obtain 15 mg (14%) ofproduct.
HPLC-MS (Method 7a): Rt = 6.50 min MS (APCI pos): m/z = 500 (M+H)+ —244— Exam le 155 diasteromeric mixture N/o | Title compound is prepared in analogy to example 20 starting from example 4a (70 mg, 0.22 mmol), example 25z (63 mg, 0.21 mmol) in place of example 25a and anhydrous ACN (2 ml) in place ofDMF. The crude is purified by RP-flash tography using 20- 100% ACN/Water as eluent then by Si-flash chromatography using % EtOAc/Cyclohexan as eluent to obtain 30 mg (25%) ofproduct.
HPLC-MS (Method 6): Rt = 11.91 min MS (ESI pos): m/z = 554 (M+H)+ Example 156 gdiasteromeric mixture) o o H: 3 :Nkfi; N/ O / O=S|3=O Title compound is prepared in analogy to example 20 starting from e 4b (70mg, 0.22 mmol) in place of example 4a, example 25z (63 mg, 0.21 mmol) in place of example 25a and anhydrous ACN (2ml) in place of DMF. The crude is d by RP-flash chro- —245— matography using 20-100% ACN/Water as eluent then by Si—flash chromatography using -100% EtOAc/Cyclohexan as eluent to obtain 26 mg (22%) ofproduct.
HPLC-MS (Method 7a): Rt = 6.67 min MS (APCI pos): m/z = 554 (M+H)+ Exam le 157 diasteromeric mixture 0:?20 The title compound is prepared in analogy to example 20 starting from example 4a (110 mg, 0.35 mrnol), example 55g (79 mg, 0.29 mmol) in place of example 25a, DIPEA (153 ul, 0.88 mmol) in place of TEA and purifying by RP-flash chromatography using 20- 100% ACN/Water as eluent to obtain 115 mg (74%) uct.
S d 7a): Rt = 7.07 min MS (APCI pos): m/z = 528 (M+H)+ The diasteromers of the title compound are separated by HPLC using a chiral stationary phase.
Method for separation: HPLC apparatus type: Waters 600 Pump; column: Daicel Chiralpack AD-H, 5.0 um, 250 mm x 20 mm; method: eluent hexane/IPA 75:25; flow rate: 15 mL/min, Temperature: °C; UV Detection: 230 nm e of tion by chiral HPLC: Submitted to separation: 110 mg of Example 157 prepared as described above; Obtained: 50 mg of Diastereoisomer 1 (Exp. 158) and 53 mg of Diastereoisomer 2 (Exp. 159) Example 158: Diastereoisomer 1 Example 159: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute stereochemistry at bridgehead at bridgehead Example Chiral HPLC HPLC-MS d 7): MS (ESI pos): Rt [min] Rt [min] Exam le 160 diastereomeric mixture —247— The title nd is prepared as described for example 20, starting from example 25za (22 mg, 0.08 mmol) in place of example 25a and example 4b (25.6 mg, 0.08 mmol) in place ofexample 4a to obtain 4.5 mg (10 %).
HPLC-MS (Method 7a): Rt = 6.88 min MS (APCI): m/z = 527 (M+H)+ The diastereomers of the title compound are separated by HPLC using a chiral stationary phase.
Method for separation: HPLC apparatus type: Waters 600 Pump; : Daicel Chiralpack AD-H, 5.0 um, 250 mm x 20 mm; method: eluent hexane/ IPA 85:15; flow rate: 15 mL/min, Temperature: °C; UV Detection: 210 nm Example of separation by chiral HPLC: Submitted to separation: 60 mg of example 160 prepared as described above; ed: 19 mg of Diastereoisomer 1 (Exp. 161) and 17 mg of Diastereoisomer 2 (Exp. 162) Example 161: reoisomer 1 Example 162: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute stereochemistry at bridgehead at bridgehead Example Chiral HPLC HPLC-MS (Method 7a): MS (APCI): Rt [min] ' m/Z Exam le l63 reomeric mixture HATU (100 mg, 0.26 mmol) and DIPEA (120 ul, 0.69 mmol) are added into a solution of example 4a (80 mg, 0.26 mmol) in 3ml of anhydrous ACN and the reaction mixture is d for 15 minutes; e 25za (62 mg, 0.23 mmol) is added and the resulting mix- ture is stirred overnight. The on mixture is filtered over basic alumina pad concen- trated under reduced pressureand purified by Si flash chromatography (eluent 0-100% EtOAc/cyclohexane) then by RP flash chromatography (eluent 20-100 ACN/Water) to flir- nish the title compound (63.8 mg, 53%).
HPLC-MS (Method 7a): Rt = 6.80 min MS (APCI): m/z = 527 (M+H)+ The diastereomers of the title compound are separated by HPLC using a chiral stationary phase. —249— Method for separation: HPLC apparatus type: Waters 600 Pump; column: Daicel Chiralpack IA, 5.0 um, 250 mm x 20 mm; method: eluent hexane/ IPA 85:15; flow rate: 12 mL/min, Temperature: 25°C; UV ion: 230 nm Example of tion by chiral HPLC: Submitted to separation: 54 mg of Example 163 prepared as described above; Obtained: 24 mg of Diastereoisomer 1 (Exp. 164) and 26 mg of Diastereoisomer 2 (Exp. 165) Example 164: Diastereoisomer 1 Example 165: Diastereoisomer 2 Unknown absolute stereochemistry Unknown absolute chemistry at bridgehead at bridgehead Example Chiral HPLC MS (APCI): Rt [min] ' m/z WE

Claims (47)

CLAIM :
1. A compound of general formula (I) or a salt thereof N R7 R2 R1 wherein R is selected from the group of a) 5 or 6 membered monocyclic heteroaryl, having 1, 2, 3 or 4 heteroatoms independently selected from the group of O, N and S(O)r, b) 5 or 6 ed monocyclic partially saturated heterocycloalkyl, having 1, 2 or 3 heteroatoms independently selected from the group of O, N and S(O)r, and c) 9 or 10 membered bicyclic heteroaryl, having 1, 2 or 3 heteroatoms independently selected from the group of O, N and S(O)r, wherein r is 0, 1 or 2; wherein each of said groups a), b) and c) is optionally substituted with 1 or more substituents independently selected from the group of C1alkyl-, C1alkyl-O-, yl, tetrahydrofuranyl, tetrahydropyranyl, C3cycloalkyl- and C3cycloalkyl-O- and in case a substituent is attached to a en ring atom said substituent is selected from the group of C1alkyl-, C1alkyl-CO-, C3cycloalkyl- and C3cycloalkyl-CO-, and wherein each of said C1alkyl-, C1alkyl-O-, lkyl-CO-, oxetanyl, ydrofuranyl, tetrahydropyranyl, C3cycloalkyl-, C3cycloalkyl-CO- or C3 cycloalkyl-O- substituents may be substituted by 1 or more substituents independently selected from the group of , -CF3, -CHF2, -CH2F and –CN; (10728446_1):JJC R is selected from the group of hydrogen, lkyl-, C1alkyl-O-, -CN and C3 cycloalkyl-, n each of said C1alkyl-, C1alkyl-O- and ycloalkyl-group may be ally substituted with 1, 2, 3 or more substituents independently selected from the group of fluoro, -CF3, -CHF2, -CH2F and -CN; R is selected from the group of C1alkyl-O-, C3cycloalkyl-O-, morpholino, pyrazolyl and a 4 to 7 membered, monocyclic heterocycloalkyl-O- with 1 oxygen atom as ring member and optionally 1 or 2 heteroatoms independently selected from the group of O, N and S(O)s with s = 0,1 or 2, , wherein said C1alkyl-O- and said C3cycloalkyl-O- may be optionally substituted with 1, 2, 3 or more substituents independently selected from the group of fluoro, -CF3, -CHF2, -CH2F, -CN, C1alkyl-, C3cycloalkyl-, lkyl-O- and C3cycloalkyl-O-; R is hydrogen; 3 4 or R and R together with the ring atoms of the phenyl group to which they are bound may form a 4, 5 or 6 membered, monocyclic, partially saturated heterocycloalkyl or a heteroaryl each of which having 1, 2 or 3 heteroatoms independently selected from the group of O, N and S(O)s with s = 0, 1 or 2, wherein there must be 1 ring oxygen atom that is directly attached to the ring carbon atom of said phenyl group to which R is attached to in general formula (I); wherein said cycloalkyl group may be optionally substituted with 1, 2, 3 or more substituents independently selected from the group of fluoro, -CF3, -CHF2, -CH2F, -CN, C1alkyl-, C3cycloalkyl-, C1alkyl-O-, C3cycloalkyl-O-, yl-O-, tetrahydrofuranyl-O- and tetrahydropyranyl-O-; (10728446_1):JJC R is hydrogen; R is ed from the group of hydrogen, C1alkyl-SO2-, C3cycloalkyl-SO2- and -CN; R is hydrogen; 6 7 6 5 or one of the pairs a) R and R or b) R and R form together with the ring atoms of the phenyl group to which they are bound, a 5 or 6 membered, partially saturated monocyclic heterocycloalkyl group having 1, 2 or 3 heteroatoms independently selected from the group of O, N and S(O)u with u = 0, 1 or 2, wherein there must be 1 -SO2- member that is directly attached to the ring carbon atom of said phenyl group to which R is attached to in general formula (I), wherein said heterocycloalkyl group may be optionally substituted with 1, 2, 3 or more substituents independently ed from the group of fluoro, -CF3, -CHF2, -CH2F, -CN, C1alkyl-, C1alkyl-O- and C3cycloalkyl-O-; 6 7 6 5 or one of the pairs a) R and R or b) R and R form together with the ring atoms of the phenyl group to which they are bound a partially saturated monocyclic cycloalkyl group having 1, 2 or 3 atoms independently ed from the group of O, N and S(O)u with u = 0, 1 or 2, wherein there must be 1 -SO2- member that is directly attached to the ring carbon atom of said phenyl group to which R is attached to in general formula (I), wherein said heterocycloalkyl group may be optionally substituted with 1, 2, 3 or more substituents independently selected from the group of fluoro, -CF3, -CHF2, -CH2F and - C1alkyl-. (10728446_1):JJC
2. A compound according to claim 1, wherein R is a 5 or 6 membered monocyclic heteroaryl, having 1, 2 or 3 heteroatoms independently selected from the group of O, N or S, wherein said heteroaryl is optionally tuted with 1 or more substituents independently selected from the group of C1alkyl-, C1alkyl-O-, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, cyclopropyl-, cyclobutyl-, cyclopropyl-O- and cyclobutyl-O- and in case a substituent is attached to a nitrogen ring atom said substituent is ed from the group of C1alkyl- and C1alkyl-CO-, and wherein each of said C1alkyl-, C1alkyl-O-, C1alkyl-CO-, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, cyclopropyl- , cyclobutyl, cyclopropyl-O- or cyclobutyl-O- substituents may be substituted with 1 or more tuents independently selected from the group of fluoro, -CF3, -CHF2, -CH2F and –CN; R is selected from the group of hydrogen, methyl, ethyl, methoxy, ethoxy, -CN and cyclopropyl-, wherein each of said groups may be optionally tuted with 1, 2 or 3 substituents independently selected from the group of fluoro, -CF3, -CHF2, -CH2F and -CN; R is as is selected from the group of C1alkyl-O-, oxetanyl-O-, tetrahydrofuranyl-O-, tetrahydropyranyl-O- n said C1alkyl-O-, may be ally substituted with 1, 2 or 3 substituents independently selected from the group of fluoro, -CF3, -CHF2, -CH2F, - CN, C1alkyl- and C1alkyl-O-; R is hydrogen; (10728446_1):JJC 3 4 or R and R together with the ring atoms of the phenyl group to which they are bound may form a 4, 5 or 6 membered, monocyclic, partially saturated heterocycloalkyl group having 1 or 2 oxygen atoms, wherein 1 ring oxygen atom is directly attached to the ring carbon atom of said phenyl group to which R is ed to in general formula (I); wherein said cycloalkyl group may be optionally substituted with 1, 2, 3 or more substituents independently selected from the group of fluoro, -CF3, -CHF2, -CH2F, -CN, C1alkyl-, cyclopropyl-, C1alkyl-O- and cyclopropyl-O-; R is hydrogen; R is selected from the group of hydrogen, C1alkyl-SO2-, C3cycloalkyl-SO2- and -CN; R is hydrogen.
3. A compound according to claim 1, n R is a 5 or 6 ed monocyclic heteroaryl being selected from the group of oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, pyrazolyl, triazoyl, pyridinyl and pyrimidinyl, wherein said aryl is optionally substituted with 1 or more substituents independently selected from the group of C1alkyl-, C1alkyl-O-, cyclopropyl- and cyclopropyl-O- and in case it is a substituent of a nitrogen ring atom said substituent is selected from the group of lkyl- and C1alkyl-CO-, and wherein each of said C1alkyl-, C1alkyl-O-, C1alkyl-CO-, cyclopropyl- or cyclopropyl-O- substituents may be substituted with 1 or more substituents independently selected from the group of fluoro, -CF3, -CHF2, -CH2F and –CN; (10728446_1):JJC R is selected from the group of hydrogen, methyl, ethyl, methoxy, ethoxy, -CN and ropyl-, wherein each of said groups may be optionally substituted with 1, 2 or 3 substituents ndently selected from the group of fluoro, -CF3, -CHF2, -CH2F and -CN; R is as is selected from the group of C1alkyl-O-, oxetanyl-O-, tetrahydrofuranyl-O-, ydropyranyl-O- wherein said C1alkyl-O-may be optionally tuted with 1, 2 or 3 substituents independently selected from the group of fluoro, -CF3, -CHF2, -CH2F, -CN, C1alkyl-, and C1alkyl-O-; R is en; 3 4 or R and R er with the ring atoms of the phenyl group to which they are bound may form a oxetan-, tetrahydrofuran-, tetrahydropyran- or dioxolan-group, wherein 1 oxygen atom is directly attached to the ring carbon atom of said phenyl group to which R is attached to in general formula (I); wherein said oxetan-, tetrahydrofuran-, tetrahydropyran- or dioxolan-group, may be optionally substituted with 1, 2, 3 or more substituents independently selected from the group of fluoro, -CF3, -CHF2, -CH2F, -CN, C1alkyl-, cyclopropyl-, C1alkyl-O and cyclopropyl-O-; R is hydrogen; R is selected from the group of hydrogen, C1alkyl-SO2-, C3cycloalkyl-SO2- and - R is hydrogen. (10728446_1):JJC
4. A compound according to claim 1, wherein R is a 5 or 6 membered monocyclic heteroaryl being selected from the group of oxadiazolyl, yl, isoxazolyl, lyl, pyridinyl and pyrimidinyl, wherein said heteroaryl is optionally substituted with 1 or more substituents independently selected from the group of C1alkyl-, C1alkyl-O-, cyclopropyl-, cyclopropyl-O- and in case it is a substituent of a nitrogen ring atom is selected from the group of C1alkyl- and C1alkyl-CO-, and wherein each of said C1alkyl-, C1alkyl-O-, C1alkyl-CO-, cyclopropyl- or cyclopropyl-O- substituents may be substituted with 1 or more substituents independently ed from the group of , -CF3, -CHF2, -CH2F and –CN; R is hydrogen or methyl; R is as is selected from the group of C1alkyl-O-, oxetanyl-O-, tetrahydrofuranyl-O-, tetrahydropyranyl-O- wherein said C1alkyl-O- may be optionally substituted with 1, 2 or 3 substituents independently selected from the group of , -CF3, -CHF2, -CH2F, -CN, C1alkyl- and C1alkyl-O-; R is hydrogen; 3 4 or R and R together with the ring atoms of the phenyl group to which they are bound may form a oxetan-, ydrofuran-, tetrahydropyran- or dioxolan-group, wherein 1 oxygen atom is directly attached to the ring carbon atom of said phenyl group to which R is attached to in general formula (I); (10728446_1):JJC wherein said oxetan-, tetrahydrofuran-, tetrahydropyran- or dioxolan-group, may be optionally substituted with 1, 2, 3 or more substituents ndently selected from the group of fluoro, -CF3, -CHF2, -CH2F, -CN, lkyl-, cyclopropyl-, C1alkyl-O- and cyclopropyl-O-; R is hydrogen; R is selected from the group of C1alkyl-SO2- and -CN; R is hydrogen.
5. A compound according to claim 1, n R is a 5 or 6 membered monocyclic heteroaryl being selected from the group of oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl and pyrimidinyl, wherein said heteroaryl is optionally tuted with 1 or more substituents independently selected from the group of lkyl-, C1alkyl-O-, ropyl-, cyclopropyl-O- and in case a substituent is attached to a nitrogen ring atom said substituent is selected from the group of C1alkyl- and C1alkyl-CO-, and wherein each of said C1alkyl-, C1alkyl-O-, C1alkyl-CO-, cyclopropyl- or cyclopropyl-O- substituents may be substituted with 1 or more substituents independently selected from the group of fluoro, -CF3, -CHF2, -CH2F and –CN; R is hydrogen or methyl; (10728446_1):JJC R is selected from the group of C1alkyl-O-, oxetanyl-O-, tetrahydrofuranyl-O-, tetrahydropyranyl-O-wherein said C1alkyl-O-may be optionally tuted with 1, 2 or 3 substituents independently selected from the group of fluoro and -CF3; R is en; R is hydrogen; R is ed from the group of C1alkyl-SO2- and -CN; R is hydrogen.
6. A compound according to claim 1, wherein R is a 5 or 6 membered monocyclic heteroaryl being selected from the group of oxadiazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl and pyrimidinyl, wherein said heteroaryl is optionally substituted with 1 or more substituents independently selected from the group of C1alkyl-, C1alkyl-O-, cyclopropyl-, ropyl-O- and in case a substituent is attached to a nitrogen ring atom said substituent is selected from the group of C1alkyl- and C1alkyl-CO-, and wherein each of said C1alkyl-, C1alkyl-O-, C1alkyl-CO-, cyclopropyl- or cyclopropyl-O- substituents may be substituted with 1 or more substituents independently ed from the group of fluoro, -CF3, -CHF2, -CH2F and –CN; R is hydrogen; R is selected from the group of (S)-2,2,2-trifluoromethyl-ethoxy and (R)-2,2,2- oromethyl-ethoxy; (10728446_1):JJC R is hydrogen; R is hydrogen; R is selected from the group of C1alkyl-SO2- and -CN; R is hydrogen.
7. A compound of the a 3 3 F F O O O O F F F 2 2 F H N H N 1 1 N O S O N O S O F N N F O O F F F F 3 3 F F O O O O F F F 2 2 F H N H N 1 1 F N O S O N O S O F N N F , (10728446_1):JJC 3 3 F F O O O O F F F 2 2 F H N H N 1 1 N O S O O O S O N N O , F F , 3 3 F F O O O O F F F 2 2 F H N H N 1 1 N O S O N O S O N N 3 3 F F O O O O F F F 2 2 F H N H N 1 1 N O S O N O S O 446_1):JJC 3 3 F F O O O O F F 2 F 2 F H N H N 1 1 N O S O N O S O S N , , 3 3 F F O O O O F F F 2 2 F H N H N 1 1 O S O N O S O N F F S F F , 3 3 F F O O O O F F 2 F 2 F H N H N 1 1 N O S O O S O F O F N F F , F , 446_1):JJC 3 3 F F O O O O F F 2 F 2 F H N H N 1 1 N O S O N O S O O N 3 3 F F O O O O F F F 2 2 F H N H N 1 1 O O S O O O S O F N N F , 3 3 F F O O O O 2 F F 2 F H N H N 1 1 O S O N F N F N N F O F O F , F , 446_1):JJC 3 3 F F O O O O F F F 2 2 F H N H N 1 1 O S O N O S O N N O F O , F F , 3 3 F F O O O O F F 2 F 2 F H N H N 1 1 N O S O N O S O N F N O F N F F F F , O O 3 2 O O H N F 2 F H N N O S O 1 F N N O S O F O N F , O , 446_1):JJC O O O O 2 F 2 H N H N 1 1 N O S O N O S O F N F O F F F , 3 3 F F O O F O O F 2 F 2 F H N H N 1 1 N O S O N O S O N N F F , O O F O O F H N 2 F H N N O S O F N N O S O F O F , F F F , 446_1):JJC 3 3 F F O O F O O F 2 F 2 F H N H N 1 1 N O S O N F N N O O F O , F 3 3 F F O O F O O F 2 F 2 F H N H N 1 1 O S O O O S O N N F O F F F , F , 3 3 F F O O F O O F 2 F 2 F H N H N 1 1 N O S O O S O O N N O , 446_1):JJC 3 3 F F O O F O O F 2 F 2 F H N H N 1 1 N O S O O O S O N N O O N 3 3 F F O O F O O F 2 F 2 F H N H N 1 1 F O S O O O S O N F N O , F N F , O O F O O 2 F 2 H N H N 1 1 O O S O O O S O N N F F F F F F , , 446_1):JJC 3 3 F F O O F O O F 2 F 2 F H N H N 1 1 O O S O N O S O N N F O F , , O O O O 2 2 H N H N 1 1 N O S O F N O S O N F N F O O F , 3 3 F F O O F O O F 2 F 2 F H N N 1 1 N O S O N O S O F F O F N N F O F , 446_1):JJC F F F O O F N 2 F O N H N H N 1 O S O 1 F N F O N O S O F N F O , F , O O or H N F N O S O F F wherein said compound is selected from the group consisting of: the stereoisomer with R-configuration at the chiral carbon atom designated by the numeral 1 and iguration at the chiral carbon atom designated by the numeral the stereoisomer with S-configuration at the chiral carbon atom designated by the numeral 1 and S-configuration at the chiral carbon atom designated by the numeral (10728446_1):JJC the isomer with R-configuration at the chiral carbon atom designated by the l 1 and iguration at the chiral carbon atom designated by the numeral the stereoisomer with S-configuration at the chiral carbon atom designated by the numeral 1 and R-configuration at the chiral carbon atom designated by the numeral wherein, in each such stereoisomer, the chiral carbon atom designated by the numeral 2 is always in the syn uration with respect to the chiral carbon atom designated by the numeral 1; or a mixture of two or more of the foregoing stereoisomer.
8. A compound according to any one of claims 1 to 6, wherein the absolute configuration at R is R.
9. A compound according to any one of claims 1 to 6, wherein the absolute configuration at R is S.
10. A compound according to any one of claims 1 to 9, wherein the compound is in the form of a salt.
11. A compound according to any one of claims 1 to 10, wherein the compound is in the form of a solvate. (10728446_1):JJC
12. A compound according to claim 1, of the formula O O F 2 F H N O O S O F , wherein said compound is selected from the group ting of: the stereoisomer with R-configuration at the chiral carbon atom designated by the l 1 and R-configuration at the chiral carbon atom designated by the l the stereoisomer with S-configuration at the chiral carbon atom designated by the numeral 1 and S-configuration at the chiral carbon atom designated by the numeral the stereoisomer with R-configuration at the chiral carbon atom designated by the numeral 1 and S-configuration at the chiral carbon atom designated by the numeral 3; and the stereoisomer with S-configuration at the chiral carbon atom designated by the numeral 1 and R-configuration at the chiral carbon atom designated by the numeral n, in each such stereoisomer, the chiral carbon atom designated by the numeral 2 is always in the syn configuration with respect to the chiral carbon atom designated by the numeral 1; (10728446_1):JJC or a mixture of two or more of the ing stereoisomers.
13. A compound according to claim 1, of the a O O F 2 F H N O O S O F , with R-configuration at the chiral carbon atom designated by the numeral 1; wherein the chiral carbon atom designated by the numeral 2 is in the syn configuration with respect to the chiral carbon atom designated by the numeral 1.
14. A compound according to claim 1, of the formula O O F 2 F H N O O S O F , with S-configuration at the chiral carbon atom ated by the numeral 1; wherein the chiral carbon atom designated by the numeral 2 is in the syn configuration with respect to the chiral carbon atom designated by the numeral 1. (10728446_1):JJC
15. A compound according to claim 1, of the formula O O F 2 F H N O O S O F , with R-configuration at the chiral carbon atom designated by the numeral 1; wherein the chiral carbon atom designated by the numeral 2 is in the syn configuration with respect to the chiral carbon atom designated by the l 1.
16. A compound according to claim 1, of the formula O O F 2 F H N O O S O F , with S-configuration at the chiral carbon atom ated by the numeral 1; wherein the chiral carbon atom designated by the numeral 2 is in the syn configuration with respect to the chiral carbon atom designated by the numeral 1. (10728446_1):JJC
17. A compound according to claim 1, of the formula O O 2 F H N N O S O F S F , wherein said compound is selected from the group consisting of: the stereoisomer with R-configuration at the chiral carbon atom designated by the numeral 1 and R-configuration at the chiral carbon atom designated by the numeral the isomer with S-configuration at the chiral carbon atom designated by the numeral 1 and S-configuration at the chiral carbon atom designated by the numeral the stereoisomer with iguration at the chiral carbon atom designated by the numeral 1 and S-configuration at the chiral carbon atom designated by the numeral 3; and the stereoisomer with S-configuration at the chiral carbon atom designated by the numeral 1 and R-configuration at the chiral carbon atom designated by the numeral wherein, in each such stereoisomer, the chiral carbon atom ated by the numeral 2 is always in the syn configuration with t to the chiral carbon atom designated by the numeral 1; (10728446_1):JJC or a mixture of two or more of the foregoing stereoisomers.
18. A compound according to claim 1, of the a O O 2 F H N N O S O F S F , with R-configuration at the chiral carbon atom designated by the numeral 1; wherein the chiral carbon atom designated by the l 2 is in the syn configuration with respect to the chiral carbon atom designated by the numeral 1.
19. A compound according to claim 1, of the formula O O 2 F H N N O S O F S F , with S-configuration at the chiral carbon atom designated by the numeral 1; wherein the chiral carbon atom designated by the numeral 2 is in the syn configuration with respect to the chiral carbon atom ated by the numeral 1. (10728446_1):JJC
20. A compound according to claim 1, of the formula O O 2 F H N N O S O F S F , with R-configuration at the chiral carbon atom designated by the numeral 1; wherein the chiral carbon atom designated by the numeral 2 is in the syn configuration with respect to the chiral carbon atom ated by the numeral 1.
21. A compound according to claim 1, of the formula O O 2 F H N N O S O F S F , with S-configuration at the chiral carbon atom designated by the numeral 1; wherein the chiral carbon atom designated by the numeral 2 is in the syn configuration with respect to the chiral carbon atom designated by the l 1. (10728446_1):JJC
22. A nd according to claim 1, of the formula O O 2 F H N O S O F N F O F , wherein said nd is selected from the group consisting of: the stereoisomer with R-configuration at the chiral carbon atom designated by the numeral 1 and R-configuration at the chiral carbon atom designated by the numeral the isomer with S-configuration at the chiral carbon atom designated by the numeral 1 and S-configuration at the chiral carbon atom designated by the numeral the diastereomer with R-configuration at the chiral carbon atom designated by the numeral 1 and S-configuration at the chiral carbon atom designated by the numeral 3; and the stereoisomer with S-configuration at the chiral carbon atom designated by the numeral 1 and R-configuration at the chiral carbon atom designated by the numeral wherein, in each such stereoisomer, the chiral carbon atom designated by the numeral 2 is always in the syn configuration with respect to the chiral carbon atom designated by the l 1; (10728446_1):JJC or a mixture of two or more of the foregoing stereoisomers.
23. A compound according to claim 1, of the formula O O 2 F H N O S O F N F O F , with R-configuration at the chiral carbon atom designated by the numeral 1; wherein the chiral carbon atom designated by the numeral 2 is in the syn uration with respect to the chiral carbon atom designated by the l 1.
24. A compound according to claim 1, of the formula O O 2 F H N O S O F N F O F , with S-configuration at the chiral carbon atom designated by the numeral 1; wherein the chiral carbon atom designated by the numeral 2 is in the syn configuration with respect to the chiral carbon atom designated by the numeral 1. (10728446_1):JJC
25. A compound according to claim 1, of the formula O O 2 F H N O S O F N F O F , with R-configuration at the chiral carbon atom designated by the numeral 1; wherein the chiral carbon atom designated by the numeral 2 is in the syn configuration with respect to the chiral carbon atom designated by the numeral 1.
26. A compound according to claim 1, of the formula O O 2 F H N O S O F N F O F , with iguration at the chiral carbon atom ated by the numeral 1; wherein the chiral carbon atom designated by the numeral 2 is in the syn configuration with respect to the chiral carbon atom designated by the numeral 1. (10728446_1):JJC
27. A compound according to claim 1, of the formula O O F 2 F H N N O S O F F , wherein said compound is selected from the group ting of: the isomer with R-configuration at the chiral carbon atom designated by the numeral 1 and R-configuration at the chiral carbon atom designated by the numeral the isomer with S-configuration at the chiral carbon atom designated by the numeral 1 and S-configuration at the chiral carbon atom designated by the numeral the isomer with R-configuration at the chiral carbon atom designated by the numeral 1 and S-configuration at the chiral carbon atom designated by the numeral 3; and the stereoisomer with S-configuration at the chiral carbon atom designated by the numeral 1 and R-configuration at the chiral carbon atom designated by the numeral wherein, in each such stereoisomer, the chiral carbon atom designated by the numeral 2 is always in the syn configuration with respect to the chiral carbon atom designated by the numeral 1; (10728446_1):JJC or a mixture of two or more of the foregoing stereoisomers.
28. A compound according to claim 1, of the formula O O F 2 F H N N O S O F F , with R-configuration at the chiral carbon atom designated by the numeral 1; n the chiral carbon atom designated by the numeral 2 is in the syn configuration with respect to the chiral carbon atom designated by the numeral 1.
29. A compound according to claim 1, of the formula O O F 2 F H N N O S O F F , with S-configuration at the chiral carbon atom ated by the numeral 1; (10728446_1):JJC wherein the chiral carbon atom designated by the numeral 2 is in the syn configuration with t to the chiral carbon atom designated by the numeral 1.
30. A compound according to claim 1, of the formula O O F 2 F H N N O S O F F , with iguration at the chiral carbon atom designated by the numeral 1; wherein the chiral carbon atom designated by the numeral 2 is in the syn configuration with respect to the chiral carbon atom designated by the numeral 1.
31. A compound according to claim 1, of the formula O O F 2 F H N N O S O F F , with S-configuration at the chiral carbon atom designated by the numeral 1; (10728446_1):JJC wherein the chiral carbon atom designated by the numeral 2 is in the syn configuration with respect to the chiral carbon atom designated by the numeral 1.
32. A compound according to claim 1, of the formula O O 2 F H N F F N O S O F , wherein said compound is selected from the group ting of: the stereoisomer with R-configuration at the chiral carbon atom designated by the numeral 1 and R-configuration at the chiral carbon atom designated by the numeral the stereoisomer with S-configuration at the chiral carbon atom designated by the numeral 1 and S-configuration at the chiral carbon atom designated by the numeral the isomer with R-configuration at the chiral carbon atom designated by the numeral 1 and S-configuration at the chiral carbon atom designated by the numeral 3; and the isomer with S-configuration at the chiral carbon atom designated by the numeral 1 and R-configuration at the chiral carbon atom designated by the numeral (10728446_1):JJC n, in each such stereoisomer, the chiral carbon atom designated by the numeral 2 is always in the syn configuration with respect to the chiral carbon atom designated by the l 1; or a mixture of two or more of the foregoing stereoisomers.
33. A compound according to claim 1, of the formula O O 2 F H N F N O S O F N F , with R-configuration at the chiral carbon atom designated by the numeral 1; wherein the chiral carbon atom designated by the numeral 2 is in the syn configuration with respect to the chiral carbon atom designated by the numeral 1.
34. A compound according to claim 1, of the a O O 2 F H N N O F F O S F , with S-configuration at the chiral carbon atom designated by the numeral 1; (10728446_1):JJC wherein the chiral carbon atom designated by the numeral 2 is in the syn configuration with respect to the chiral carbon atom designated by the numeral 1.
35. A compound according to claim 1, of the formula O O 2 F H N F N O S O F N F , with R-configuration at the chiral carbon atom designated by the numeral 1; wherein the chiral carbon atom designated by the l 2 is in the syn uration with respect to the chiral carbon atom designated by the numeral 1.
36. A compound according to claim 1, of the formula O O 2 F H N N O F F S O F , with S-configuration at the chiral carbon atom ated by the numeral 1; wherein the chiral carbon atom designated by the numeral 2 is in the syn configuration with respect to the chiral carbon atom designated by the numeral 1. (10728446_1):JJC
37. A compound according to claim 1, of the formula O O F 2 F H N O S O F N F O F , wherein said compound is selected from the group consisting of: the stereoisomer with R-configuration at the chiral carbon atom designated by the l 1 and R-configuration at the chiral carbon atom designated by the numeral the stereoisomer with S-configuration at the chiral carbon atom designated by the numeral 1 and S-configuration at the chiral carbon atom ated by the numeral the stereoisomer with iguration at the chiral carbon atom designated by the numeral 1 and S-configuration at the chiral carbon atom designated by the numeral 3; and the stereoisomer with S-configuration at the chiral carbon atom designated by the numeral 1 and R-configuration at the chiral carbon atom designated by the numeral wherein, in each such stereoisomer, the chiral carbon atom designated by the numeral 2 is always in the syn configuration with respect to the chiral carbon atom designated by the numeral 1; (10728446_1):JJC or a mixture of two or more of the foregoing stereoisomers.
38. A nd according to claim 1, of the formula O O F 2 F H N O S O F N F O F , with iguration at the chiral carbon atom designated by the numeral 1; wherein the chiral carbon atom designated by the numeral 2 is in the syn configuration with respect to the chiral carbon atom designated by the numeral 1.
39. A compound according to claim 1, of the formula O O F 2 F H N O S O F N F O F , with S-configuration at the chiral carbon atom designated by the numeral 1; wherein the chiral carbon atom designated by the numeral 2 is in the syn configuration with respect to the chiral carbon atom ated by the numeral 1. (10728446_1):JJC
40. A compound according to claim 1, of the formula O O F 2 F H N O S O F N F O F , with iguration at the chiral carbon atom designated by the numeral 1; wherein the chiral carbon atom ated by the numeral 2 is in the syn configuration with respect to the chiral carbon atom designated by the numeral 1.
41. A compound according to claim 1, of the formula O O F 2 F H N O S O F N F O F , with S-configuration at the chiral carbon atom designated by the numeral 1; wherein the chiral carbon atom designated by the numeral 2 is in the syn configuration with respect to the chiral carbon atom designated by the numeral 1. (10728446_1):JJC
42. A nd according to any one of claims 1 to 41 for use in or for use as a medicament, wherein the use of the medicament or the medicament is for a therapeutic or prophylactic method (a) for the treatment of a CNS disease, the treatment of which is accessible by the inhibition of GlyT1, (b) for the treatment of a disease that is accessible by the inhibition of GlyT1, (c) for the treatment, amelioration or prevention of a condition ed from the group consisting of positive and negative symptoms of schizophrenia, psychoses and cognitive impairments associated with schizophrenia, Alzheimer’s e, prodromal Alzheimer’s disease, amnestic mild cognitive impairment and psychiatric disorders; (d) for the ent of Alzheimer’s disease, prodromal mer’s e, amnestic mild cognitive impairment or cognitive impairment associated with Alzheimer’s disease, (e) for the treatment of schizophrenia or cognitive impairment associated with schizophrenia, (f) for the ent of psychoses.
43. A pharmaceutical composition or medicament comprising a compound according to any one of claims 1 to 41.
44. Use of a compound according to any one of claims 1 to 41 for the manufacture of a medicament for: (a) the ent of a CNS disease, the treatment of which is accessible by the inhibition of GlyT1, (b) the treatment of a disease that is accessible by the inhibition of GlyT1, (c) the treatment, amelioration or prevention of a condition ed from the group consisting of positive and negative symptoms of phrenia, psychoses and cognitive impairments associated with schizophrenia, Alzheimer’s Disease, (10728446_1):JJC prodromal Alzheimer’s disease, amnestic mild cognitive impairment and psychiatric disorders; (d) the ent of Alzheimer’s disease, prodromal Alzheimer’s disease, amnestic mild cognitive impairment or cognitive impairment associated with Alzheimer’s disease, (e) the treatment of schizophrenia or cognitive impairment associated with schizophrenia, or (f) the treatment of psychoses.
45. A combination of a compound according to any one of claims 1 to 41 with another active agent, that (a) is useful for the therapeutic treatment of a disease or condition as defined in claim 42 under (a) or (b) or (c) or (d) or (e) or (f) or (b) is useful for the prophylactic ent of a condition or e as defined in claim 42 under (a) or (b) or (c) or (d) or (e) or (f) or (c) is useful for the manufacture of a medicament for the treatment of a condition or e as d in claim 42 under (a) or (b) or (c) or (d) or (e) or (f).
46. A combination of a compound according to any one of claims 1 to 41 with an acetylcholine esterase inhibitor, such as donepezil, rivastigmine, e or galantamine.
47. A compound of general a (II), (III), (IV), (V) or (VI): PG PG PG N N O N O O R2 R2 R2 R8 OH general formula (II) general formula (III) general formula (IV) (10728446_1):JJC R2 O N N R2 R1 R7 OH R6 l formula (V) general formula (VI) wherein in each of those independent formulas 1 4 5 6 7 R , R , R , R , and R have the meaning as in any one of claims 1 to 9, R in general formula (II) to (V) is selected from the group consisting of C1alkyl-, C1 O-, -CN and C3cycloalkyl-, R in general formula (VI) is selected from the group consisting of en, C1alkyl-, C1alkyl-O-, -CN and C3cycloalkyl-, wherein each of said C1alkyl-, C1alkyl-O- and C3cycloalkyl-group may be optionally substituted with 1, 2, 3 or more substituents independently ed from the group of fluoro, -CF3, -CHF2, -CH2F and -CN; R is C1-4 alkyl-O-, optionally substituted by 1 or more substituents independently ed from each other from the group of fluoro, chloro, bromo, -CN, C1-4 alkyl-O-, C1-4 alkyl-, phenyl and benzyl, wherein phenyl and benzyl optionally may be substituted with one or more substituents independently selected from each other from the group of fluoro, chloro, bromo, -CN, C1-4 alkyl-O-, C1-4 alkyl-; and PG is selected from the group consisting of tert- carbonyl-, 9- fluorenylmethoxycarbonyl-, benzyl-, 2,4-dimethoxybenzyl-. Boehringer Ingelheim International GmbH By the Attorneys for the Applicant SPRUSON & FERGUSON Per: (10728446_1):JJC
NZ619258A 2011-08-03 2012-08-02 Phenyl-3-aza-bicyclo[3.1.0]hex-3-yl-methanones and the use thereof as medicament NZ619258B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP11176468 2011-08-03
EP11176468.4 2011-08-03
PCT/EP2012/065140 WO2013017657A1 (en) 2011-08-03 2012-08-02 Phenyl-3-aza-bicyclo[3.1.0]hex-3-yl-methanones and the use thereof as medicament

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NZ619258A NZ619258A (en) 2015-12-24
NZ619258B2 true NZ619258B2 (en) 2016-03-30

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