Indian Patents
Title of Invention

TETRAHYDROQUINOLINE ANALOGUES
Abstract The present invention relates to terahydroquinoline compounds as muscarinic receptor agonists; compositions comprising the same; methods of inhibiting an activity of a muscarinic receptor with said compounds; methods of treating a disease condition associated with a muscarinic receptor using said compounds; and methods for identifying subject suitable for treatment using said compounds.
Full Text FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
As amended by the Patents (Amendment) Act, 2005
&
The Patents Rules, 2003
As amended by the Patents (Amendment) Rules, 2005
COMPLETE SPECIFICATION
(See section 10 and rule 13)
TITLE OF THE INVENTION
Tetrahydroquinoline analogues as muscarinic agonists
APPLICANTS
Name : ACADIA PHARMACEUTICALS INC
Address : 3911 Sorrento Valley Blvd., San Diego, California 92121-1402, USA
Nationality : an US Company
INVENTORS
1) Name : SKJAERBAEK, Niels
Nationality : a Danish National
Address : Fagerparken 33, DK-2950 Vedbaek, Denmark
2) Name : KOCH Kristian Norup
Nationality : a Danish National
Address : Borthigsgade 11, DK-2100 Copenhagen, Denmark
3) Name : FRIBERG Bo Lennart
Nationality : a Swedish National
Address : Mikolaigatan 24, S-21421 Malmo, Sweden
4) Name : TOLF Bo-ragnar
Nationality : a Swedish National
Address : Ringstedgade 2, DK-2100 Copenhagen, Denmark
PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the nature of this invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
[0001] The present invention relates to compounds that affect cholinergic receptors, especially muscarinic receptors. The present invention provides compounds that are agonists of cholinergic receptors including muscarinic receptors, especially the Mi and M4 subtype of muscarinic receptors. The invention also provides methods of using the provided compounds for modulating conditions associated with cholinergic receptors, especially for treating or alleviating disease conditions associated with muscarinic receptors, such as the M1 and/or M4 receptor subtypes.
BACKGROUND
[0002] Muscarinic cholinergic receptors mediate the actions of the neurotransmitter acetylcholine in the central and peripheral nervous systems. Muscarinic receptors play a critical role in the central nervous system mediating higher cognitive functions, as well as in the peripheral parasympathetic nervous system where they mediate cardiac, respiratory, digestive, and endocrine and exocrine responses. Five distinct muscarinic receptor subtypes have been identified, M1-M5. The muscarinic Mi receptor subtype is predominantly expressed in the cerebral cortex and is believed to be involved in the control of higher cognitive functions; the M2 receptor is the predominant subtype found in heart and is involved in the control of heart rate; the M3 receptor is widely expressed in many peripheral tissues and is believed to be involved in gastrointestinal and urinary tract stimulation as well as sweating and salivation; the M4 receptor is present in brain and may be involved in locomotion; the M5, receptor is present in the brain where its role is at present poorly defined. Mi and M4 have been particularly associated with the dopaminergic system.
[0003] Conditions associated with cognitive impairment, such as Alzheimer's disease, are accompanied by a reduction of acetylcholine content in the brain. This is believed to be the result of degeneration of cholinergic neurons of the basal forebrain, which widely innervate multiple areas of the brain, including the association cortices and hippocampus, that are critically involved in higher processes.
[0004] Efforts to increase acetylcholine levels have focused on increasing levels of choline, the precursor for acetylcholine synthesis, and on blocking acetylcholineesterase (AChE), the enzyme that metabolizes acetylcholine. Attempts to
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augment central cholinergic function through the administration of choline or phosphatidylcholine have not been successful. AChE inhibitors have shown therapeutic efficacy, but have been found to have frequent cholinergic side effects due to peripheral acetylcholine stimulation, including abdominal cramps, nausea, vomiting, and diarrhoea. These gastrointestinal side effects have been observed in about a third of the patients treated. In addition, some AChE inhibitors, such as tacrine, have also been found to cause significant hepatotoxicity with elevated liver transaminases observed in about 30% of patients. The adverse effects of AChE inhibitors have severely limited their clinical utility.
[0005] The dopamine hypothesis of schizophrenia suggests that increased dopamine neurotransmission underlies the positive symptoms of the disease and is supported by the evidence that dopamine receptor blockade is effective in ameliorating such psychotic symptoms. Further, drugs that enhance dopamine neurotransmission in the brain cause psychotic-like episodes in man and exacerbate psychotic symptoms in schizophrenic patients. In animal studies, drugs that increase dopamine neurotransmission cause behavioural effects such as increased locomotion, climbing and deficits in prepulse inhibition. Known antipsychotics and dopamine receptor antagonists can block these behavioural effects. Unfortunately, dopamine receptor antagonists also cause severe extrapyramidal side effects in patients as predicted by induction of catalepsy in animal models. These extrapyramidal side effects include tremor, bradykinesia, akithesias, and tardive dyskinesias.
[0006] Due in part to these observations, the discovery of agents with Mi receptor agonist activity has been sought after for the treatment of dementia. However, existing agents lack specificity in their actions at the various muscarinic receptor subtypes. Known M1 muscarinic agonists such as arecoline have also been found to be weak agonists of M2 as well as M3 receptor subtypes and are ineffective in the treatment of cognitive impairment, due in large part to their dose-limiting M2 and M3 receptor mediated side effects.
[0007] Xanomeline (Shannon et al., J. Pharmacol. Exp. Ther. 1994, 269, 271; Shannon et al., Schizophrenia Res. 2000, 42, 249) is an M1/M4 preferring muscarinic receptor agonist with little or no affinity for dopamine receptors despite inhibiting A10 but not A9 dopamine cells. The thiadiazole derivative PTAC has been reported (Shannon et al., European Journal of Pharmacology, 1998, 356, 109) to have partial agonist effect
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at muscarinic M2 and M4 receptors and antagonist effect at muscarinic M1, M3, and M5 receptors as well as exhibiting functional dopamine antagonism.
[0008] Recently, muscarinic agonists including xanomeline have been shown to be active in animal models with similar profiles to known antipsychotic drugs, but without causing catalepsy (Bymaster et al., Eur. J. Pharmacol. 1998, 356, 109, Bymaster et al., Life Sci. 1999, 64, 527, Shannon et al., J. Pharmacol. Exp. Ther. 1999, 290, 901, Shannon et al., Schizophrenia Res. 2000, 42, 249). Further, xanomeline was shown to reduce psychotic behavioural symptoms such as delusions, suspiciousness, vocal outbursts, and hallucinations in Alzheimer's disease patients (Bodick et al., Arch. Neurol. 1997, 54, 465), however treatment induced side effects that severely limit the clinical utility of this compound.
[0009] Analogues of 1,2,5-thiadiazole have been reported (Sauerberg et al, J. Med Chem. 1998, 41, 4378) to have high affinity and selectivity for central muscarinic receptors as well as exhibiting functional dopamine antagonism despite lack of affinity for dopamine receptors.
[0010] The present investigators have, in part, focussed their efforts on the development of molecules that simultaneously reduced the positive symptoms and improved the negative symptoms and the cognitive impairments associated with schizophrenia as a novel treatment of mental disorders. It is the intent of the present investigators to demonstrate that muscarinic M1 and/or M4 agonists with combined D2 antagonist activity may possess superior antipsychotic efficacy without the side effects associated with high dose D2 antagonism alone. The D2 antagonist properties of some of the compounds of the present invention may contribute to a reduction in the positive symptoms of this disease.
[0011] Based on distribution of M1 and M4 receptors in the cerebral cortex and hippocampus (the areas involved in higher order cognitive functions), the M1 and/or M4 agonist properties of these compounds may reduce the cognitive dulling and perhaps ameliorate other negative symptoms associated with schizophrenia. (Friedman, Biol. Psychiatry, 1999, 45, 1; Rowley, J. Med. Chem. 2001, 44, All; Felder, J. Med. Chem. 2000, 43, 4333). This unique combination of central nervous system activities in one molecule is unprecedented and may lead to the development of an entirely new class of antipsychotic drugs, ones with the superior clinical properties without the limiting side-effect profile.
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[0012] US 3,324,137 and US 3,365,457 describe N-[indolyl-lower-alkanoyl]-1,5-iminocycloalkanes and iminocycloalkanes not encompassed by the invention.
[0013] EP 0 584 487 describes 4,5-dihydo-4-oxo-pyrroles with linked to piperazine rings not encompassed by the invention.
[0014] Mokrosz et al (Pharmazie, 52,1997, 6, p423) describes N[3-(4-aryl)-l-piperazinyl)propyl] derivatives of indolin-2(lH)-one, quinolin-2-(lH)-one and isoquinolin-l-(2H)-one, which are not encompassed by the invention.
SUMMARY OF THE INVENTION
[0015] The invention provides novel compounds of formula I, as well as salts and isomers thereof
R3 L'-L2
Ri_c^ N_c_c_c_N x
C3-|V R5 R5 R5 ]]
R2 Y
I
wherein R1 is a monoradical selected from the group consisting of optionally substituted C1-6-alkyl, optionally substituted C2-6-alkylidene, optionally substituted C2-6-alkenyl, optionally substituted C2-6-alkynyl, optionally substituted O-C1-6-alkyl, optionally substituted O-C2-6-alkenyl, optionally substituted O-C2-6-alkynyl; optionally substituted S-C1-6-alkyl, optionally substituted S-C2-6-alkenyl, optionally substituted S-C2-6-alkynyl;
m is 0,1 or 2;
C3-C4 is CH2-CH or CH=C or C4 is CH and C3 is absent;
R2 and R3 are independently selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, optionally substituted O-C1-6 alkyl, halogen, hydroxy or selected such that R2 and R3 together form a ring system;
each R4 and R5 is independently selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted C1-6 alkyl, optionally substituted O-Ci^alkyl, optionally substituted aryl-1-6 alkyl, and optionally substituted arylheteroalkyl;
L1 and L2 are biradicals independently selected from the group consisting of -C(R6)=C(R7), -C(R6)=N-, -N=C(R6)-, -S-, -NH- and -O-; wherein only one of L1 and L2 may be selected from the group consisting of-S-, -NH- and -O-;
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Y is selected from the group consisting of O, S, and H2;
X is a biradical selected from the group consisting of -C(R6)(R7)-C(R6)(R7)-, -C(R6)=C(R7)-, -O- C(R6)(R7)-, C(R6)(R7)-0-, -S-C(R6)(R7)-, -C(R6)(R7)-S-, -N(RN)-C(R6)(R7)-, -C(R6)(R7)-N(RN)-, -C(R6)(R7)-C(R6)(R7)-C(R6)(R7)-, -0-C(R6)(R7)-C(R6)(R7)-,S-C(R6)(R7)-C(R6)(R7)-, N(RN)-C(R6)(R7)-C(R6)(R7)-, -C(R6)(R7)-C(R6)(R7)-O, -C(R6)(R7)-C(R6)(R7)-S, -C(R6)(R7)-C(R6)(R7)-N(RN)-, -C(R6)(R7)- C(R6)=C(R7)--,and - C(R6)=C(R7)-C(R6)(R7),wherein R6 and R7 are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, NRNRN, N(RN)-C(O) N(RN), optionally substituted C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl,, optionally substituted O-C1-6-alkyl, optionally substituted O-aryl, optionally substituted O-C2-6-alkenyl, optionally substituted O-C2-6-alkynyl
wherein RN is selected from the group consisting of hydrogen, and optionally substituted C1-6-alkyl.
[0016] The invention further provides compositions comprising
i) one or more compounds of formula I, and;
ii) at least one pharmaceutically acceptable excipient or carrier.
[0017] The invention also provides methods of treating a disease in a mammal, such as a human, wherein modulation of the activity of a cholinergic receptor is associated with a physiologically beneficial response in said disease of said mammal. In one embodiment, a method includes administering an effective amount of a compound of formula I.
[0018] Thus, the invention provides methods of treating or preventing or alleviating one or more symptoms associated with a disorder in a mammal, such as a human, said disorder associated with a muscarinic receptor, for example, the Mi muscarinic receptor subtype. In one embodiment, a method includes the administration of an effective amount of the compound of formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a pharmaceutical composition comprising either entity. Particular disorders treatable by a method of the invention include, for example, Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's chorea, Friederich's ataxia, Gilles de la Tourette's Syndrome, Down Syndrome, Pick disease, dementia, clinical depression, age-related cognitive decline, cognitive impairment, forgetfulness, confusion, memory loss, attentional deficits, deficits in visual perception,
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depression, pain, sleep disorders, psychosis, sudden infant death syndrome, increased intraocular pressure and glaucoma.
[0019] The invention additionally provides a method of treating a mental disorder wherein the physiologically beneficial response is due to modulation in terms of M1 agonism; M1 and M4 agonism; both M1 agonism and D2 antagonism; or M1 and M4 agonism and D2 antagonism.
[0020] The invention additionally provides the use of a compound of formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a pharmaceutical composition comprising either entity, for the preparation of a medicament for the treatment of diseases or disorders associated with a cholinergic receptor or ligand thereof.
[0021] The invention therefore provides methods for the preparation of a medicament for the treatment of diseases or disorders selected from the group consisting of Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's chorea, Friederich's ataxia, Gilles de la Tourette's Syndrome, Down Syndrome, Pick disease, dementia, clinical depression, age-related cognitive decline, cognitive impairment, forgetfulness, confusion, memory loss, attentional deficits, deficits in visual perception, depression, pain, sleep disorders, psychosis, sudden infant death syndrome, increased intraocular pressure and glaucoma.
[0022] The invention further provides methods of increasing an activity of a cholinergic receptor. In one embodiment, a method includes contacting the cholinergic receptor or a system containing the cholinergic receptor with an effective amount of at least one compound of formula I to increase an activity of the cholinergic receptor.
[0023] The invention provides kits including one or more compounds of the invention, and instructions for practicing a method of the invention. In one embodiment, instructions are for treating or preventing or alleviating one or more symptoms associated with a disorder in a mammal, such as a human, said disorder associated with a muscarinic receptor, for example, the M1 muscarinic receptor subtype. In another embodiment, instructions are for increasing cholinergic receptor activity or activating cholinergic receptors.
DESCRIPTION OF THE INVENTION
[0024] For the purpose of the current disclosure, the following definitions shall in their entireties be used to define technical terms.
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[0025] The term "agonist" is defined as a compound that increases the activity of a receptor when it contacts the receptor.
[0026] The term "antagonist" is defined as a compound that competes with an agonist or inverse agonist for binding to a receptor, thereby inhibiting or blocking the action of an agonist or inverse agonist on the receptor. However, an antagonist (also known as a "neutral" antagonist) has no effect on constitutive receptor activity.
[0027] The term "inverse agonist" is defined as a compound that decreases the basal activity of a receptor (i.e., signaling mediated by the receptor). Such compounds are also known as negative antagonists. An inverse agonist is a ligand for a receptor that causes the receptor to adopt an inactive state relative to a basal state occurring in the absence of any ligand. Thus, while an antagonist can inhibit the activity of an agonist, an inverse agonist is a ligand that can alter the conformation of the receptor in the absence of an agonist. The concept of an inverse agonist has been explored by Bond et al. in Nature 374:272 (1995). More specifically, Bond et al. have proposed that unliganded β 2-adrenoceptor exists in an equilibrium between an inactive conformation and a spontaneously active conformation. Agonists are proposed to stabilize the receptor in an active conformation. Conversely, inverse agonists are believed to stabilize an inactive receptor conformation. Thus, while an antagonist manifests its activity by virtue of inhibiting an agonist, an inverse agonist can additionally manifest its activity in the absence of an agonist by inhibiting the spontaneous conversion of an unliganded receptor to an active conformation.
[0028] The "M1-receptor" is defined as a receptor having an activity corresponding to the activity of the ml muscarinic receptor subtype characterized through molecular cloning and pharmacology.
[0029] The term "subject" refers to an animal, for example a mammal, such as a human, who is the object of treatment, observation or experiment.
[0030] The term "selective" is defined as a property of a compound whereby an amount of the compound sufficient to effect a desired response from a particular receptor type, subtype, class or subclass causes a substantially smaller or no effect upon the activity of other receptor types.
[0031] The EC50 for an agonist is intended to denote the concentration of a compound needed to achieve 50% of a maximal response seen in an in vitro assay such as R-SAT. For inverse agonists, EC50 is intended to denote the concentration of a
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compound needed to achieve 50% inhibition of an R-SAT response from basal, no compound, levels.
[0032] As used herein, the term "coadministration" of pharmacologically active compounds refers to the delivery of two or more separate chemical entities, whether in vitro or in vivo. Coadministration refers to the simultaneous delivery of separate agents; to the simultaneous delivery of a mixture of agents; as well as to the delivery of one agent followed by delivery of a second agent or additional agents. In all cases, agents that are coadministered are intended to work in conjunction with each other.
[0033] In the present context, the term "C1-6-alkyl" means a linear or branched saturated hydrocarbon chain wherein the longest chain has from one to six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, and hexyl.
[0034] In the present context, the term "C2-8-alkenyl" means a linear or branched hydrocarbon group having from two to eight carbon atoms and containing one or more double bonds. Illustrative examples of C2-8-alkenyl groups include allyl, homo-allyl, vinyl, crotyl, butenyl, pentenyl, hexenyl, heptenyl and octenyl. Illustrative examples of C2-8-alkenyl groups with more than one double bond include butadienyl, pentadienyl, hexadienyl, heptadienyl, heptatrienyl and octatrienyl groups as well as branched forms of these. The position of the unsaturation (the double bond) may be at any position along the carbon chain.
[0035] In the present context the term " C2-8-alkynyl" means a linear or branched hydrocarbon group containing from two to eight carbon atoms and containing one or more triple bonds. Illustrative examples of C2-8-alkynyl groups include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl and octynyl groups as well as branched forms of these. The position of unsaturation (the triple bond) may be at any position along the carbon chain. More than one bond may be unsaturated such that the " C2-8-alkynyl" is a di-yne or enedi-yne as is known to the person skilled in the art.
[0036] In the present context, the term "C3-8-cycloalkyl" includes three-, four-, five-, six-, seven-, and eight-membered rings comprising carbon atoms only, whereas the term "heterocyclyl" means three-, four-, five-, six- seven-, and eight-membered rings wherein carbon atoms together with from 1 to 3 heteroatoms constitute said ring. The heteroatoms of such heterocyclyl groups are independently selected from oxygen, sulphur, and nitrogen.
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[0037] The term "Heterocyclyl" groups may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, and the like.
[0038] C3-8-cycloalkyl and heterocyclyl rings may optionally contain one or more unsaturated bonds situated in such a way, however, that an aromatic 7t-electron system does not arise.
[0039] Heterocyclyl rings may optionally also be fused to aryl rings, such that the definition includes bicyclic structures. Examples of such fused heterocyclyl groups share one bond with an optionally substituted benzene ring. Examples of benzo-fused heterocyclyl groups include, but are not limited to, benzimidazolidinone, tetrahydroquinoline, and methylenedioxybenzene ring structures.
[0040] Illustrative examples of " C3-8-cycloalkyl" are the carbocycles cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, cycloheptene, 1,2-cycloheptadiene, 1,3-cycloheptadiene, 1,4-cycloheptadiene and 1,3,5 cycloheptatriene.
[0041] Illustrative examples of "heterocyclyls" are the heterocycles tetrahydrothiopyran, 4H/-pyran, tetrahydropyran, piperidine, 1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine, 1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-l,2-oxazine , maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine, tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine, pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline, imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole, 1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine, thiazoline, thiazolidine, 1,3-oxathiolane,. Binding to the heterocycle may be at the position of a heteroatom or via a carbon atom of the heterocycle, or, for benzo-fused derivatives, via a carbon of the benzenoid ring.
[0042] In the present context the term "aryl" means a carbocyclic aromatic ring or ring system. Moreover, the term "aryl" includes fused ring systems wherein at least two aryl rings, or at least one aryl and at least one C3-8--cycloalkyl share at least one chemical bond. Illustrative examples of "aryl" rings include optionally substituted phenyl, naphthalenyl, phenanthrenyl, anthracenyl, tetralinyl, fluorenyl, indenyl, and indanyl. An example of an aryl group is phenyl. The term "aryl" relates to aromatic, typically
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benzenoid groups connected via one of the ring-forming carbon atoms, and optionally carrying one or more substituents selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, C1-6 alkoxy, C1-6 alkyl, C1-6 hydroxyalkyl, C1-6 aminoalkyl, C1-6 alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. As stated, aryl groups may be phenyl, and, most suitably, substituted phenyl groups, carrying one or two, same or different, of the substituents listed above. One pattern of substitution is para and/or meta. Representative examples of aryl groups include, but are not limited to, phenyl, 3-halophenyl, 4-halophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-aminophenyl, 4-aminophenyl, 3-methylphenyl, 4-methylphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3-cyanophenyl, 4-cyanophenyl, dimethylphenyl, naphthyl, hydroxynaphthyl, hydroxymethylphenyl, trifluoromethylphenyl, alkoxyphenyl.
[0043] In the present context the term "aryl(C1-6-alkyl)" means a carbocyclic aromatic ring as defined above connected via a C1-6-alkyl group.
[0044] The term arylheteroalkyl should be interpreted as an aryl group, as defined above, connected, as a substituent, via a C1-6 -alkyl tether which, additionally, contains, in the chain, at least one atom selected from the group consisting of oxygen, sulfur, and nitrogen.
[0045] In the present context, the term "heteroaryl" means a heterocyclic aromatic group where one or more carbon atoms in an aromatic ring have been replaced with one or more heteroatoms selected from the group comprising nitrogen, sulphur, phosphorous and oxygen.
[0046] Furthermore, the term "heteroaryl" comprises fused ring systems wherein at least one aryl ring and at least one heteroaryl ring, at least two heteroaryl rings, at least one heteroaryl ring and at least one heterocyclyl ring, or at least one heteroaryl ring and at least one C3-8-cycloalkyl ring share at least one chemical bond.
[0047] The term "heteroaryl" is understood to relate to aromatic, C2-6 cyclic groups further containing one O or S atom or up to four N atoms, or a combination of one O or S atom with up to two N atoms, and their substituted as well as benzo- and pyrido-fused derivatives, typically connected via one of the ring-forming carbon atoms. Heteroaryl groups may carry one or more substituents, selected from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl, C1-6-alkoxy, C1-6-alkyl, C1-6-hydroxyalkyl, C1-6-aminoalkyl, C1-6-alkylamino, alkylsulfenyl, alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. Particular heteroaryl groups are five- and six-membered aromatic
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heterocyclic systems carrying 0, 1, or 2 substituents, which may be the same as or different from one another, selected from the list above. Representative examples of heteroaryl groups include, but are not limited to, unsubstituted and mono- or di-substituted derivatives of furan, benzofuran, thiophene, benzothiophene, pyrrole, pyridine, indole, oxazole, benzoxazole, isoxazole, benzisoxazole, thiazole, benzothiazole, isothiazole, imidazole, benzimidazole, pyrazole, indazole, and tetrazole, as well as furazan, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, triazole, benzotriazole, quionoline, isoquinoline, pyridazine, pyrimidine, purine, pyrazine, pteridine, pyrrole, phenoxazole, oxazole, isoxazole, oxadiazole, benzopyrazole, indazole, quinolizine, cinnoline, phthalazine, quinazoline, and quinoxaline. The most typical substituents are halo, hydroxy, cyano, O-C1-6 -alkyl, C1-6 -alkyl, hydroxy- C1-6 -alkyl, amino- C1-6 -alkyl.
[0048] When used herein, the term "O-C1-6-alkyl" means C1-6-alkyloxy, or alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy and hexyloxy
[0049] The term "halogen" includes fluorine, chlorine, bromine and iodine.
[0050] When used herein, the term "optionally substituted" means that the group in question may be substituted one or several times, such as 1 to 5 times, 1 to 3 times, or 1 to 2 times, with one or more groups selected from C1-6-alkyl, C1-6-alkoxy, oxo (which may be represented in the tautomeric enol form), carboxyl, amino, hydroxy (which when present in an enol system may be represented in the tautomeric keto form), nitro, alkylsulfonyl, alkylsulfenyl, alkylsulfinyl, C1-6-alkoxycarbonyl, C1-6 -alkylcarbonyl, formyl, mono- and di(C1-6-alkyl)amino; carbamoyl, mono- and di(C1-6-alkyl)aminocarbonyl, amino-C1-6-alkyl-aminocarbonyl, mono- and di(C1-6-alkyl)amino-Ci-6-alkyl-aminocarbonyl, Ci-6-alkylcarbonylamino, cyano, guanidino, carbamido, Ci-6-alkanoyloxy, C1-6-alkylsulphonyloxy, dihalogen- C1-6-alkyl, trihalogen-C1-6-alkyl, and halo. In general, the above substituents may be susceptible to further optional substitution
[0051] The term "salt" means pharmaceutically acceptable acid addition salts obtainable by treating the base form of a functional group, such as an amine, with appropriate acids such as inorganic acids, for example hydrohalic acids; typically hydrochloric, hydrobromic, hydrofluoric, or hydroiodic acid; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example acetic, propionic, hydroacetic, 2-hydroxypropanoic acid, 2-oxopropanoic acid, ethandioic, propanediol, butanedioic, (Z)-2-butenedioic, (E)-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-
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hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic acid, cyclohexanesulfamic, 2-hydoxybenzoic, 4-amino-2-hydroxybenzoic, and other acids known to the skilled practitioner.
[0052] The method of the invention relates to the modulation of a cholinergic receptor. Typically, said cholinergic receptor is a muscarinic receptor; one example of a cholinergic receptor is a muscarinic receptor of M1-receptor subtype. As can be seen from the Examples, in suitable embodiments, the cholinergic receptor may be either or both the muscarinic Mi-receptor and the muscarinic M4-receptor subtypes. The physiologically beneficial response in the method of the invention is typically associated with the specific activation of the M1-receptor subtype over the M2- or M3-receptor subtype, or the specific activation of the M1-and M4- receptor subtypes over the M2- or M3-receptor subtype. Moreover, a physiologically beneficial response in a method of the invention is typically associated with the agonistic activity of the compound of formula I or IA. Thus, in one embodiment, the compound of formula I or IA is a muscarinic agonist, such as an Mi agonist or an M1 and M4 agonist.
[0053] A further aspect of the invention relates to a method of increasing the activity of a cholinergic receptor. In one embodiment, a method includes contacting a cholinergic receptor or a system containing a cholinergic receptor with an effective amount of at least one compound of formula I or IA, as defined supra.
[0054] A related aspect of the invention is directed to a method of treating or preventing or alleviating one or more symptoms associated with a disorder in a mammal, such as a human. In one embodiment, a method includes the administration of an effective amount of a compound of formula I or IA, said disorder associated with a muscarinic receptor, for example, M1 muscarinic receptor subtype.
[0055] The disorders associated with the M1 muscarinic receptor subtype are typically mental disorders. Suitable mental disorders which can be treated by the method of the invention may be selected from the group comprising of cognitive impairment, forgetfulness, confusion, memory loss, attentional deficits, deficits in visual perception, depression, pain, sleep disorders, psychosis, and increased intraocular pressure.
[0056] Disorders associated with the M1 muscarinic receptor subtype need not be a mental disorder. For instance, increased intraocular pressure is associated with the Mi muscarinic receptor subtype. Disorders to which the method of the invention are directed therefore include non-mental disorders.
13

[0057] Disorders to which the method of the invention are directed may be further selected from the group comprising neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's chorea, Friederich's ataxia, Gilles de la Tourette's Syndrome, Down Syndrome, Pick disease, dementia, clinical depression, age-related cognitive decline, attention-deficit disorder, sudden infant death syndrome, and glaucoma.
[0058] As stated, the compounds of the invention have high selectivity and affinity for the muscarinic Mi receptor subtypes. As can be seen from the Examples, the compounds also have high affinity for one or both of the M1 and M4 receptor subtypes, selectively over other receptors such as the M2, M3 and M5 receptor subtypes. The compounds of the invention typically act, at least in part, as an M1 agonist or as Mi and M4 agonist.
[0059] The compounds of the invention also have an affinity for the dopamine D2 receptor. As discussed supra in connection with the dopamine hypothesis in relation to schizophrenia, compounds which act as both muscarinic agonists and dopamine antagonists may be keys to adequately treat many mental disorders. Thus, the invention is also directed to methods of treating mental disorders, using compounds of the invention, said compounds acting as a D2 antagonist or D2 inverse agonist as well as a muscarinic agonist, particularly an M1 agonist or as M1 and M4 agonist. Thus, the method of the invention may be such that the disease in a mental disorder and the physiologically beneficial response to due to modulation in terms of M1 agonism; M1 and M4 agonism; both M1 agonism and D2 antagonism; or M1 and M4 agonism and D2 antagonism.
[0060] In one aspect of the invention, the compounds of the invention are antipsychotic agents, said anti-psychotic activity due to the compounds of the invention acting as Mi agonist; or as M1 and M4 agonists; or acting as an both Mi agonists and D2 antagonist; or as M1 and M4 agonists and D2 antagonists.
[0061] Another aspect of the invention relates to the use of a compound of formula IA, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising either entity, for the preparation of a medicament for the treatment of diseases or disorders associated with a cholinergic receptor or ligand thereof. The medicament may be for the treatment of diseases associated with the receptors as discussed supra and for disorders as discussed supra. A related aspect of the invention is directed to a pharmaceutical composition comprising an effective amount of a compound
14

of formula I, as defined supra, or pharmaceutically acceptable salts thereof, a stereoisomer thereof, or a pharmaceutical composition comprising either entity, together with pharmaceutically acceptable carriers or excipients.
[0062] The invention provides novel compounds of formula I, as well as salts and isomers thereof
R3 L1-L2
Ri_c^ N_C_C_C_N x
Cs-I-7 R5 R5 R5 Y
R2 Y
I
wherein R1 is a monoradical selected from the group consisting of optionally substituted C1-6-alkyl, optionally substituted C2-6-alkylidene, optionally substituted C2-6-alkenyl, optionally substituted C2-6-alkynyl, optionally substituted O- C1-6-alkyl, optionally substituted O-C2-6-alkenyl, optionally substituted O-C2-6-alkynyl; optionally substituted S- C1-6-alkyl, optionally substituted S-C2-6-alkenyl, optionally substituted S-C2-6-alkynyl;
m is 0, 1 or 2;
C3-C4 is CH2-CH or CH=C or C4 is CH and C3 is absent;
R2 and R3 are independently selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, optionally substituted O-C1-6 alkyl, halogen, hydroxy or selected such that R2 and R3 together form a ring system;
each R4 and R5 is independently selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted C1-6-alkyl, OC C1-6 alkyl, aryl-C C1-6 alkyl, and arylheteroalkyl;
L1 and L2 are biradicals independently selected from the group consisting of -C(R6)=C(R7), -C(R6)=N-, -N=C(R6)-, -S-, -NH- and -0-; wherein only one of L1 and L2 may be selected from the group consisting of-S-, -NH- and -0-;
Y is selected from the group consisting of O, S, and H2;
X is a biradical selected from the group consisting of -C(R6)(R7)-C(R6)(R7)-, -C(R6)=C(R7)-, -O- C(R6)(R7)-, C(R6)(R7)-0-, -S-C(R6)(R7)-, -C(R6)(R7)-S-, -N(RN)-C(R6)(R7)-, -C(R6)(R7)-N(RN)-, -C(R6)(R7)-C(R6)(R7)-C(R6)(R7)-, -0-C(R6)(R7)-C(R6)(R7)-,S-C(R6)(R7)-C(R6)(R7)-, N(RN)-C(R6)(R7)-C(R6)(R7)-, -C(R6)(R7)-C(R6)(R7)-O, -C(R6)(R7)-C(R6)(R7)-S, -C(R6)(R7)-C(R6)(R7)-N(RN)-, -C(R6)(R7)- C(R6)=C(R7)-
15

,and - C(R6)=C(R7)-C(R6)(R7),wherein R6 and R7 are independently selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, NRNRN, N(RN)-C(O) N(RN), optionally substituted C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl,, optionally substituted O- C1-6-alkyl, optionally substituted O-aryl, optionally substituted 0- C2-6-alkenyl, optionally substituted O-C2-6-alkynyl
wherein R is selected from the group consisting of hydrogen, and optionally substituted C1-6-alkyl.
[0063] The present investigators have found that the compounds of the invention have a high affinity and specificity for the M1 muscarinic receptor. The compounds of the invention may be of use in an array of conditions associated with the modulation of the M1 muscarinic receptor subtype.
[0064] Typically, the compounds of formula I are such that R1 is selected from the group consisting of optionally substituted C1-6-alkyl, optionally substituted C1-6-alkylidene, optionally substituted C2-6-alkenyl, optionally substituted C2-6-alkynyl, optionally substituted O-C1-6-alkyl, and optionally substituted O-C2-6-alkenyl. R1 can be selected from the group consisting of optionally substituted C1-6-alkyl, optionally substituted C1-6-alkylidene, optionally substituted C2-6-alkenyl, optionally substituted O- C1-6-alkyl. R1 can typically be selected from the group consisting of optionally substituted C1-6-alkyl, optionally substituted C1-6-alkylidene, and optionally substituted O- C1-6-alkyl. Most typically, R1 is selected from the group consisting of optionally substituted C4-alkyl, optionally substituted C5-alkyl, optionally substituted C4-alkylidene, and optionally substituted O- C1-6-alkyl. In a preferred embodiment, R1 may be unsubstituted C4-alkyl, unsubstituted C5-alkyl, or unsubstituted O-C3-alkyl, e.g. n-butyl, n-pentyl, , or n-propyloxy.
[0065] In a particular embodiment of the invention, the compounds of formula I are such that R1 is an optionally substituted C1-6-alkyl, selected from the group consisting of unsubstituted C1-6-alkyl, and C1-6-alkoxyalkyl. The C1-6-alkoxyalkyl may be C1-3-alkoxyC1-3-alkyl. Typically, the C1-6-alkoxyalkyl is selected from methoxypropyl, ethoxyethyl, propyloxymethyl, and methoxyethyl.
[0066] In one embodiment of the invention, the compounds of formula I are piperidines, bicyclic piperidines, 3-4-unsaturated piperidines or bicyclic 3-4-unsaturated piperidines. Within this embodiment, the C3-C4 bond may be a single bond to form either a piperidine ring or a bicylic piperidine. Alternatively, piperidine may be 3-4 unsaturated.
16

That is to say that C3-C4 may be a double bond (C3=C4) so as to form either a 3-4-unsaturated piperidine or bicylic 3-4-unsaturated piperidine.
[0067] In another embodiment of the invention, m is 0 and C3 is absent while C4 is CH, so as to result in an azetidine ring. Bicyclic analogues of azetidine are also included.
[0068] In an alternative embodiment, m is 0 so as to result in a pyrrolidine ring or a 3-pyrroline, when C3-C4 is a single bond or a double bond, respectively. Bicyclic analogues of pyrrolidine ring or a 3-pyrroline are further included. In a further suitable embodiment, m is 2 so as to form a 7-membered ring. In a particular embodiment, m is 1.
[0069] In one embodiment, R2 and R3 together form a bicyclic ring system such that
R3
R1-Cl m NH
C31^ R2
is selected from the group consisting of
R8 RB R8 R8 R8 R8
*Kt> « «-& «Kt> *K$> -Kt>
Q
wherein R8 is present 0, 1, or 2 times and is independently selected from the group consisting of optionally substituted C1-6 alkyl, optionally substituted O-C1-6 alkyl, halogen, hydroxy.
[0070] Within such an embodiment, R2 and R3 may preferably be selected such that R2 and R3 together form a ring system such that
R3
R1-citm_XNH
Gal/ R2
is selected from the group comprising
17

R8 R8
R,^CN R'^CN
9 "5
[0071] In a more preferred embodiment, the substituents R and R are selected so that the bicyclic ring is 3-substituted 8-azabicyclo[3.2.1]octane.
9 ^
[0072] However, in a particular embodiment, R2 and R3 are independently selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, optionally substituted O- C1-6 alkyl, halogen and hydroxy.
[0073] Thus, in a combination of embodiments of compounds of formula I,
C3-C4 is a single bond, R2 and R3 are independently selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, optionally substituted O- 1-6 alkyl, halogen and hydroxy, and m is 1. Suitably, R2 and R3 are hydrogen.
[0074] In a further combination, m can be 0, C3 can be absent, and C4 can be CH such that
R1-C; m N
C3-!-7
R2
is
R1 V
[0075] In a further combination of embodiments, C3-C4 and m are so as to
form a piperidine ring, for example, wherein R2 and R3 are hydrogen. In additional embodiments, C3-C4 and m are so as to form a piperidine ring, R and R are hydrogen, and R1 an unsubstituted C4-alkyl, an unsubstituted C5-alkyl, or an O-C3-alkyl, such as butyl, pentyl, or propyloxy.
[0076] Thus, in one embodiment
R3
(tK
R1-C> NH
R2

is a 4-butyl piperidine.
[0077] In another embodiment

18

R3 R1-C> NH
R2 is 4-butyl piperidine.
[0078] In one embodiment of the invention, C3-C4 and m are such as to form an azetidine ring,
[0079] R2 and R3 are hydrogen, and R is selected from unsubstitued C4-alkyl, unsubstituted C5-alkyl, and O-C3-alkyl. Thus, in one embodiment
R3 R1-C> NH
R2 is a 4-butylazetidine.
[0080] In one aspect of the invention a 3-carbon tether is linking the two nitrogen atoms of the two ring systems of the compounds of formula I. The present investigators have found that this optionally substituted propylene spacer unit provides for compounds with highly efficacious binding capacity to the cholinergic receptors. More specifically, the compounds of the invention show agonistic properties at cholinergic receptors, especially muscarinic receptors.
[0081] In one embodiment, the tether
R4 R4 R4
—c-c-c—
R5 R5 R5 is unsubstituted, meaning that all of R4 and R5 are hydrogen.
[0082] In another embodiment one of the substituents R4 is selected from the group consisting of C1-6-alkyl, O-C1-6-alkyl, and halogen, while the other two of the substituents R4 are hydrogen.
[0083] In a combination of embodiments one of the substituents R4 is selected from the group consisting of C-alkyl, O- C1-6-alkyl, and halogen, while the other two of the substituents R4 are hydrogen, and all of R5 are hydrogen.
[0084] In a preferred embodiment one of the substituents R4 is selected from the group consisting of methyl, methoxy, ethyl, and fluoro while the remaining R4 and R5 are all hydrogen.
19

[0085] Typically, when one of the substituents R4 is C1-6-alkyl, O- C1-6-alkyl, or halogen, the tether is a 2-substituted-1,3-propylene group.
[0086] In a further suitable embodiment, the tether is a 2,2-disubstituted-l,3-propylene group, in which one of R4 and one of R are typically C1-6-alkyl or fluoro.
[0087] Certain embodiments of the invention, wherein the propylene tether carries one or more substituents possess a stereogenic atom in the propylene tether. As set forth in the Examples, such chiral compounds may be preferred either in racemic or enantiomerically enriched form. Pure enantiomers and racemates are both included in the invention.
[0088] X may be a 1-, 2-, or 3-atom linear unit such that, together with the atoms in the ring comprising X, a 5-, 6- or 7-membered ring is formed. As stated, X, within the ring, is a biradical selected from the group consisting of-C(R6)(R7)-C(R6)(R7)-, -C(R6)=C(R7)-,-O- C(R6)(R7)-, C(R6)(R7)-O-, -S-C(R6)(R7)-, -C(R6)(R7)-S-, -N(RN)-C(R6)(R7)-, -C(R6)(R7)-N(RN)-, -C(R6)(R7)-C(R6)(R7)-C(R6)(R7)-, -O-C(R6)(R7)-C(R6)(R7)-,S-C(R6)(R7)-C(R6)(R7)-, N(RN)-C(R6)(R7)-C(R6)(R7)-, -C(R6)(R8)-C(R6)(R7)-O, -C(R6)(R7)-C(R6)(R7)-S, -C(R6)(R7)-C(R6)(R7)-N(RN)-, -C(R6)(R7)-CH=CH- and -CH=CH-C(R6)(R7).
[0089] In a preferred embodiment X is selected from the group consisting of -C(R6)(R7)-C(R6)(R7)-, -C(R6)=C(R7)-, -O- C(R6)(R7)-, C(R6)(R8)-0-, -S-C(R6)(R7)-, -C(R6)(R7)-S-, -N(RN)-C(R6)(R7)-, -C(R6)(R7)-N(RN)-.
[0090] In a more preferred embodiment X is selected from the group consisting of-C(R6)(R7)-C(R6)(R7)-, -O- C(R6)(R7)-, C(R6)(R8)-0-, and -C(R6)=C(R7)-.
[0091] R6 and R7 are optional substituents of the ring system. An array of substituents is anticipated by the present investigators and are known to the person skilled in the art. The substituents R and R may independently be selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, NRNRN, N(RN)-C(O) N(RN), optionally substituted C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, optionally substituted O-C1-6-alkyl, optionally substituted O-aryl, optionally substituted O-C2-6-alkenyl, optionally substituted O-C2-6-alkynyl.
[0092] Suitably, when the substituents R6 and R7 occur within the definition of X, they are typically selected from hydrogen, halogen, hydroxy and C1-6-alkyl. More typically, R6 and R7 , when consituting part of the definition of X, are both hydrogen.
20

[0093] In one embodiment, Y is selected from the group consisting of O, S and H2.
[0094] In a preferred embodiment, Y is O.
[0095] As stated, L1 and L2 are biradicals independently selected from the group consisting of -C(R7)=C(R8), -C(R7)=N-, -N=C(R7)-, -S-, -NH- and -O-; wherein
only one of L1 and L2 may be selected from the group consisting of-S- and -O-. Typically,
1 2
L and L are such that
LuL2
1 9
is an aromatic or heteroaromatic ring. In one embodiment, L and L are independently selected from the group consisting of -C(R6)=C(R7)-, -C(R6)=N-, -N=C(R7)-, and -S-;
wherein only one of L and L is -S-. In another embodiment, at least one of L and L is
C(R6 )=C(R7 ). In yet another embodiment, L and L are so as to form a 6-membered ring. In still another embodiment, both of L1 and L2 are -C(R6)=C(R7)-.
f\ 7
[0096] Suitably, when the substituents R and R occur within the definition of
Lb2
they are typically selected from hydrogen, halogen, hydroxy, C1-6-alkyl and O-C1-6-alkyl.
[0097] Preferably, when the substituents R6 and R7 occur within the definition of
Lb2
they are selected from hydrogen, fluoro, chloro, methyl, and methoxy.
[0098] Thus, in a combination of embodiments, the compounds of the invention are of formula la

R3
1 f l~\ Y

R7

R2
la
wherein R1 is selected from the group consisting of optionally substituted C1-6-alkyl, optionally substituted C1-6-alkylidene, optionally substituted C2-6-alkenyl, optionally substituted C2-6-alkynyl, optionally substituted O-C1-6-alkyl, optionally substituted O-C2-6-alkenyl; and R2, R3, R4, X, Y, R6, and R7 are as defined supra.
21

[0099] In another combination of embodiments, the compounds of the invention are of formula la, wherein X is selected from the group consisting of -C(R6)(R7)-C(R6)(R7)-, -C(R6)=C(R7)-, -O- C(R6)(R7)-, C(R6)(R8)-0-, -S-C(R6)(R7)-, -C(R6)(R7)-S-, -N(RN)-C(R6)(R7)-, -C(R6)(R7)-N(RN)-,
wherein R6 and R7 are suitably hydrogen.
[0100] In a further combination of embodiments, the compounds of the invention are of formula la, wherein Y is O.
[0101] In yet another combination of embodiments, the compounds of the invention are of formula la, wherein R4 is selected from hydrogen, C1-6-alkyl, O-C1-6-alkyl, and halogen.
[0102] In a further combination of embodiments, the compounds of the invention are of formula la, wherein R and R are selected from hydrogen, halogen, hydroxy, C1-6-alkyl and O-C1-6-alkyl.
[0103] In another combination of embodiments, the compounds of the invention are of formula la, wherein the optionally substituted C1-6-alkyl is selected from the list comprising unsubstituted C1-6-alkyl, and C1-6-alkoxyalkyl, and wherein Y is selected from the group consisting of O and H2, and wherein X is selected from the group consisting of -C(R6)(R7)-C(R6)(R7)-, -C(R6)=C(R7)-, -O-C(R6)(R7)-, -O-C(R6)(R7)-O-, -S-C(R6)(R7)-, -C(R6)(R7)-S-, and wherein L1 and L2 are independently selected from the group consisting of -C(R6)=C(R7)-, -C(R6)=N-, and -N=C(R7)-, and wherein R4 selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted C1-6-alkyl, and optionally substituted O-C1-6 alkyl.
[0104] In a further combination of embodiments, the compounds of the
invention are optionally substituted l-[3-(4-alkylpiperidin-l-yl)propyl]-l,2,3,4-
tetrahydroquinolines, optionally substituted l-[3-(4-alkylpiperidin-l-yl)propyl]-3,4-
dihydro-1H-quinolin-2-ones, optionally substituted l-[3-(4-alkylpiperidin-l-yl)propyl]-
1H-quinolin-2-ones, optionally substituted 4-[3-(4-alkylpiperidin-l-yl)propyl]-4H-
benzo[l,4]oxazin-3-ones, optionally substituted 4-[3-(4-alkylpiperidin-l-yl)propyl]--4#-
benzo[l,4]thiazin-3-ones; optionally substituted l-[3-(3-alkyl-8-azabicyclo[3.2.1]oct-8-
yl)propyl]-l,2,3,4-tetrahydroquinolines; optionally substituted l-[3-(3-alkyl-8-
azabicyclo[3.2.l]oct-8-yl)propyl]-3,4-dihydro-lH-quinolin-2-ones, optionally substituted
l-[3-(3-alkyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-lH-quinolin-2-ones optionally
substituted 4-[3-(3-alkyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[l,4]oxazin-3-
22

ones; optionally substituted 4-[3-(3-alkyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]--4H-benzo[l,4]thiazin-3-ones; optionally substituted 1-[3-(3-alkylazetidin-l-yl)propyl]-3,4-dihydro-lH-quinolin-2-ones, optionally substituted l-[3-(3-alkylazetidin-l-yl)propyl]-lH-quinolin-2-ones, optionally substituted l-[3-(3-alkylazetidin-l-yl)propyl]- 1,2,3,4-tetrahydroquinolines; optionally substituted 4-[3-(3-alkylazetidin-l-yl)propyl]--4H7-benzo[l,4]oxazin-3-ones; optionally substituted 4-[3-(3-alkylazetidin-l-yl)propyl]- -4H-benzo[ 1,4]thiazin-3-ones.
[0105] Suitable embodiments of the compounds of the invention may be
selected from the group consisting of l-[3-(4-Butyl-piperidin-l-yl)-propyl]-l,2,3,4-
tetrahydro-quinoline; l-[3-(4-Butyl-piperidin-l-yl)-propyl]-2-methyl-l,2,3,4-tetrahydro-
quinoline; l-[3-(4-Butyl-piperidin-l-yl)-propyl]-6-methyl-l,2,3,4-tetrahydro-quinoline; 1-
[3-(4-Butyl-piperidin-l-yl)-propyl]-8-methyl-l,2,3,4-tetrahydro-quinoline; l-[3-(4-Butyl-
piperidin-l-yl)-propyl]-7-fluoro-2-methyl-l,2,3,4-tetrahydro-quinoline; l-[3-(4-Butyl-
piperidin-1 -yl)-propyl]-7-trifluoromethyl-1,2,3,4-tetrahydro-quinoline; 1 -[3-(4-Butyl-
piperidin-1 -yl)-propyl] -3,4-dihydro-1H-quinolin-2-one; 1 - [3 -(4-Butyl-piperidin-1 -yl)-
propyl] -6-methoxy-3,4-dihydro-1H-quinolin-2-one; 4- [3-(4-Butyl-piperidin-1 -yl)-propyl]-
4H-benzo [ 1,4]thiazin-3 -one; 4- [3 -(4-Butyl-piperidin-1 -yl)-propyl] –4H-benzo [1,4] oxazin-
3 -one; 4- [3 -(4-Butyl-piperidin-1 -yl)-propyl] -6-methyl-4H-benzo [1,4] oxazin-3 -one; 6-
Acetyl-4- [3 -(4-butyl-piperidin-1 -yl)-propyl] –4H-benzo [ 1,4] oxazin-3 -one; 4- [3 -(4-Butyl-
piperidin- 1 -yl)-propyl] -6-methyl-3,4-dihydro-2H-benzo[1,4]oxazine; and 4-[3-(4-Butyl-
piperidin-l-yl)-propyl]-6-ethyl-3,4-dihydro-2H-benzo[l,4]oxazine; (i?)-4-[3-(4-
Butylpiperidin-l-yl)-2-methylpropyl]-4H-benzo[l,4]thiazin-3-one; (R)-4-[2-Methyl-3-(4-
propoxypiperidin-1 -yl)propyl] –4H-benzo [ 1,4] thiazin-3 -one; (R)-4-[3 -(4-Butylidene-
piperidin-l-yl)-2-methyl-propyl]-4H-benzo[l,4]thiazin-3-one; (R)-4-[3-(3-Butyl-8-aza-
bicyclo[3.2.l]oct-8-yl)-2-methyl-propyl]-4H-benzo[l,4]thiazin-3-one; (R)-4-[2-Methyl-3-
(3-pentyl-8-aza-bicyclo[3.2. l]oct-8-yl)propyl]-4H-benzo[l ,4]thiazin-3-one; 4-[3-(4-
Butylpiperidin-1 -yl)propyl] -6,8-dichloro-7-methyl-4H-benzo [1,4] oxazin-3 -one; 4- [3 -(4-
Butyl-piperidin-l-yl)propyl]-6,8-dimethyl-4H-benzo[l,4]oxazin-3-one (81MF2237F);6-
trert-Butyl-4-[3-(4-butyl-piperidin-l-yl)propyl]-4H-benzo[l,4]oxazin-3-one; 4-[3-(4-
Butylpiperidin-1 -yl)propyl] -5 -methyl-4H-benzo [1,4] oxazin-3 -one; 4- [3 -(4-
Butylpiperidin-l-yl)propyl]-7-methyl-4H-benzo[l,4]oxazin-3-one; 4-[3-(4-
Butylpiperidin-1 -yl)propyl] -6-chloro-7-nitro-4H-benzo [1,4] oxazin-3 -one ;4- [3 -(4-Butylpiperidin-1 -yl)propyl] -7-chloro-4H-benzo [ 1,4] oxazin-3 -one ;4- [3 -(4-Butylpiperidin-
23

l-yl)propyl]-6-fluoro-4H-benzo[l,4]oxazin-3-one; 4-[3-(4-Butylpiperidin-l-yl)propyl]-
7,8-difluoro-4H-benzo[ 1,4] oxazin-3-one; 4-[3-(4-Butylpiperidin-1 -yl)propyl]-4#-
pyrido[4,3-6] [ 1,4]thiazin-3-one; 4-[3-(4-Propoxypiperidin-1 -yl)propyl]-4H-
benzo [ 1,4] thiazin-3 -one; 4- [3 -(4-Propoxypiperidin-1 -yl)propyl] -4H-benzo [ 1,4] oxazin-3 -
one; 4-[3-(4-Butylpiperidin-1 -yl)propyl]-7-fluoro-4H-benzo[ 1,4]oxazin-3-one; 4-[3-(4-
Butylidenepiperidin-1 -yl)propyl] –4H-benzo [ 1,4] thiazin-3 -one; 4- [3 -(4-
Butylidenepiperidin-1 -yl)propyl] –4H-benzo [ 1,4] oxazin-3 -one; 4- [3 -(3 -Butylidene-8-aza-
bicyclo [3.2.1] oct- 8-yl)-propyl] -4H-benzo [1,4] oxazin-3 -one; 4- [3 -(4-Butylpiperidin-1 -
yl)propyl]-6-methoxy-4H-benzo[ 1,4]oxazin-3-one; 4-[3-(4-Butylpiperidin-1 -yl)propyl]-
6,8-dichloro-7-ethyl-4H-benzo[l,4]oxazin-3-one; 4-[3-(4-Butylpiperidin-l-yl)propyl]-8-
fluoro-4H-benzo [1,4] oxazin-3 -one; 6-Bromo-4- [3 -(4-butylpiperidin-1 -yl)propyl] -8-
fluoro-4H-benzo[ 1,4] oxazin-3-one; 4-[3-(4-Butylpiperidin-l-yl)propyl]-8-isopropyl-4H-
benzo[ 1,4] oxazin-3-one; (R,S)-4-[3-(4-Butylpiperidin-l-yl)-2-hydroxy-propyl]-6-methyl-
4H-benzo [ 1,4] oxazin-3 -one; (R,S)-4- [3-(4-Butylpiperidin-1-yl)-2-hydroxypropyl] -4H-
benzo [1,4] oxazin-3 -one; (-)-4- [3 -(4-Butylpiperidin-1-yl)-2-hydroxypropyl] -4H-
benzo [ 1,4] oxazin-3 -one; (R,S)-4- [3 -(4-Butylpiperidin)-2-methoxypropyl] -4H-
benzo [ 1,4] oxazin-3 -one; (R, S)-4- [2-Hydroxy-3 -(3 -pentylbicyclo [3.2.1] oct-8-yl)-propyl] -
4H-benzo[ 1,4] oxazin-3 -one; 4-[2-(4-Butylpiperidin-l-ylmethyl)allyl]-4H-
benzo [ 1,4] oxazin-3 -one; (R, S)-4- [3 -(4-Butylpiperidin-1 -yl)-2-fluoropropyl] -4H-
benzo [1,4] oxazin-3 -one; (S)-4- [3 -(4-Butyl-piperidin-1 -yl)-2-methyl -propyl] -4H-
benzo[l ,4]oxazin-3-one; (R)-4-[3-(4-Butylpiperidin-l -yl)-2-methylpropyl]-4H-
benzo[ 1,4] oxazin-3-one; (R)-4-[2-Methyl-3-(4-propoxypiperidin-l-yl)-propyl]-4H-
benzo[l ,4]oxazin-3-one; (R)-4-[3-(4-Butylidenepiperidin-l -yl)-2-methylpropyl]-4H/-
benzo[l,4]oxazin-3-one;(R)-4-[3-(3-Butyl-8-aza-bicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-
4#-benzo[l,4]oxazin-3-one; (R)-4-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-
yl)propyl] –4H-benzo [1,4] oxazin-3 -one; (R)-6-Fluoro-4- [2-methyl-3 -(4-propoxy-piperidin-1 -yl)-propyl] –4H-benzo [ 1,4] oxazin-3 -one; (R)-4- [3 -(4-Butylidenepiperidin-1 -yl)-2-methyl-propyl] -6-fluoro-4H-benzo[ 1,4] oxazin-3-one; (R)-4-[3-(4-Butylpiperidin-1 -yl)-2-methylpropyl]-6-fluoro-4J7-benzo[l,4]oxazin-3-one; (R)-4-[3-(3-Butyl-8-
azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-fluoro-4H-benzo[l,4]oxazin-3-one; (R)-6-Fluoro-4-[2-methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)-propyl]-4Hf-benzo[l ,4]oxazin-3-one; (R)-4-[3-(4-Butylpiperidin-l-yl)2-methylpropyl]-7-Fluoro-4H-benzo[l,4]oxazin-3-one; (R)-7-Fluoro-4-[2-methyl-3-(4-propoxypiperidin-l-yl)propyl]-
24

4H-benzo[l,4]oxazin-3-one; (R)-4-[3-(4-Butylidenepiperidin-l-yl)-2-methylpropyl]-7-
fluoro-4H-benzo[l,4]oxazin-3-one; (R)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-
methylpropyl]-7-fluoro-4H-benzo[l,4]oxazin-3-one; (R)-7-Fluoro-4-[2-methyl-3-(3-
pentyl-8-azabicyclo[3.2. l]oct-8-yl)-propyl]-4H-benzo[l ,4]oxazin-3-one; (R)-4-[3-(4-
Butylpiperidin-1 -yl)-2-methyl-propyl] -6-methoxy-4H-benzo [1,4] oxazin-3 -one; (R)-4- [3 -
(4-Butylidenepiperidin-l-yl)-2-methylpropyl]-6-methoxy-4H-benzo[l,4]oxazin-3-one;
(R)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-methoxy-4H-
benzo[l,4]oxazin-3-one; (R)-6-Methoxy-4-[2-methyl-3-(3-pentyl-8-aza-bicyclo[3.2. l]oct-
8-yl)propyl]-4H-benzo[l,4]oxazin-3-one; (R)-6-Methoxy-4-[2-methyl-3-(4-
propoxypiperidin-1 -yl)propyl] -4H-benzo [1,4] oxazin-3 -on; (R)-6-Methyl-4- [2-methyl-3 -
(4-propoxypiperidin-1 -yl)-propyl] –4H-benzo [ 1,4] oxazin-3 -one; (i?)-4- [3 -(4-
Butylidenepiperidin-1 -yl)-2 -methylpropyl] -6-methyl-4H-benzo [1,4] oxazin-3 -one; (i?)-4-
[3 -(4-Butylpiperidin-1 -yl)-2-methylpropyl] -6-methyl-4H-benzo [ 1,4] oxazin-3 -one; (i?)-4-
[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-methyl-4H-benzo[l,4]oxazin-
3-one; (i?)-4-[3-(3-Pentyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-methyl-4H-
benzo [1,4] oxazin-3 -one; 1 - [3 -(4-Propoxypiperidin-1 -yl)propyl] -3,4-dihydro-1 /f-quinolin-
2-one; 1 - [3 -(4-Butylpiperidin-1 -yl)propyl] -6-fluoro-3,4-dihydro-1 i7-quinolin-2-one; 6-
Fluoro-1 -[3-(4-propoxypiperidin-1 -yl)propyl] -3,4-dihydro-1 i7-quinolin-2-one; (R, S)-1 -[3-
(4-Butylpiperidin-1 -yl)-2-methylpropyl] -6-fluoro-3,4-dihydro-1 H-quinolin-2-one; (R,S)-
6-Fluoro-1 - [3 -(4-propoxypiperidin-1 -yl)-2 -methylpropyl] -3,4-dihydro-1 H-quinolin-2-one;
l-[3-(4-Butylpiperidin-l-yl)propyl]-6-chloro-3,4-dihydro-lH-quinolin-2-one; l-[3-(4-
Butylpiperidin-1 -yl)propyl] -6-methyl-3,4-dihydro-1 H-quinolin-2-one; 6-Methyl-1 - [3-(4-
propoxypiperidin-1 -yl)propyl] -3,4-dihydro-1 H-quinolin-2-one; 1 - [3 -(4-Butylpiperidin-1 -
yl)propyl] -7-fluoro-3,4-dihydro-1 H-quinolin-2-one; 1 - [3-(4-Butylpiperidin-1 -yl)propyl]-
5 -methyl-3,4-dihydro-1 H-quinolin-2-one; 1 - [3 -(4-Butylpiperidin-1 -yl)propyl] -7-methyl-
3,4-dihydro-1H-quinolin-2-one; l-[3-(4-Butylpiperidin-l-yl)propyl]-7-fluoro-6-methyl-
3,4-dihydro-1H-quinolin-2-one; l-[3-(4-Butylpiperidin-l-yl)propyl]-6,7-difluoro-3,4-
dihydro-1 H-quinolin-2-one; 6,7-Difluoro-1 - [3 -(4-propoxypiperidin-1 -yl)propyl] -3,4-
dihydro- 1H-quinolin-2-one; (R, S)-1 - [3 -(4-Butylpiperidin-1 -yl)-2-methylpropyl] -6,7-
difluoro-3,4-dihydro-lH-quinolin-2-one; (R,S)-6,7-Difluoro-l-[3-(4-propoxypiperidin-l-
yl)-2-methylpropyl] -3,4-dihydro-1H-quinolin-2-one; 1 - [3 -(4-Butylpiperidin-1 -yl)propyl] -
6-fluoro-7-methyl-3,4-dihydro-lH-quinolin-2-one; 6-Fluoro-7-methyl-l-[3-(4-
propoxypiperidin-1-yl)propyl] -3,4-dihydro-1 H-quinolin-2-one; (R, S)-1 - [3 -(4-
25

Butylpiperidin-1 -yl)-2-methylpropyl] -6-fluoro-7-methyl-3,4-dihydro-1 H-quinolin-2-one;
(R, S)-6-Fluoro-7-methyl-1 - [2-methyl-3 -(4-propoxypiperidin-1 -yl)-propyl] -3,4-dihydro-
1 H-quinolin-2-one; 1 - [3 -(4-Butyl-piperidin-1 -yl)propyl] -6-fluoro-5 -methyl-3,4-dihydro-
1 H-quinolin-2-one; 6-Fluoro-5 -methyl-1 - [3 -(4-propoxypiperidin-1 -yl)propyl] -3,4-
dihydro-lH-quinolin-2-one; (i?)-l-[3-(4-Butylpiperidin-l-yl)-2-methylpropyl]-3,4-
dihydro- lH-quinolin-2-one; (R)-1 -[2-Methyl-3-(4-propoxypiperidin-1-yl)propyl]-3,4-
dihydro-1H-quinolin-2-one; (R)-1 - [3 -(4-Butylidenepiperidin-1 -yl)-2-methyl)propyl] -3,4-
dihydro-lH-quinolin-2-one; (R)-l-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-
methylpropyl]-3,4-dihydro-lH-quinolin-2-one; (R)-l-[2-Methyl-3-(3-pentyl-8-
azabicyclo [3.2.1] oct-8-yl)propyl] -3,4-dihydro-1 H-quinolin-2-one; 1 - [3 -(4-Butylpiperidin-
1 -yl)propyl] -1 H-quinolin-2-one; 1 - [3 -(4-Propoxypiperidin-1 -y l)propyl] -1 H-quinolin-2-
one; 1 - [3 -(4-Butylpiperidin-1 -yl)propyl] -6-fluoro-1 H-quinolin-2-one; 1-[3-(4-
Butylpiperidin-1 -yl)propyl] -6-methyl-1 H-quinolin-2-one; 1 - [3-(4-Butylpiperidin-1 -
yl)propyl]-7-fluoro-lH-quinolin-2-one; 1-[3-(4-Butylpiperidin-l-yl)propyl]-6-methoxy-
1 H-quinolin-2-one; 1 - [3 -(4-Butylpiperidin-1 -yl)propyl] -6-chloro-1 H-quinolin-2-one; 1 -
[3 -(4-Butylpiperidin-1 -yl)propyl] -5 -methyl-1 H-quinolin-2-one; 1 - [3 -(4-Butyl-piperidin-1 -
yl)propyl]-7-methyl-lH-quinolin-2-one; (i?)-l-[3-(4-Butylpiperidin-l-yl)-2-
methylpropyl]-lH-quinolin-2-one; (i?)-l-[2-Methyl-3-(4-propoxypiperidin-l-yl)-propyl]-
1 H-quinolin-2-one; 1 - [3-(4-Allyloxypiperidin-1 -yl)propyl]-1 H-quinolin-2-one; (R,S)-4-
[3 -(4-Butylpiperidin-1 -yl)-2-methylpropyl] -6-methyl-4H-benzo [1.4] oxazin-3 -one; (R,S)-
4-[2-Methyl-3-(4-propoxypiperidin-l-yl)propyl]-6-methyl-4^-benzo[1.4]oxazin-3-one;
(R,S)-4-[3-(4-Butylidenepiperidin-l-yl)-2-methylpropyl]-6-methyl-4H-benzo[1.4]oxazin-
3-one; (R,S)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-methyl-4H-
benzo[l .4]oxazin-3-one; (R,S)-4-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2. l]oct-8-
yl)propyl] -6-methyl-4H-benzo [1.4] oxazin-3 -one; (R, S)-4- [3 -(4-Butylpiperidin-1 -yl)-2-
methylpropyl]-6-fluoro-4H-benzo[1.4]oxazin-3-one; (R,S)-6-Fluoro-4-[2-methyl-3-(4-
propoxypiperidin-1 -yl)propyl] -4H-benzo [1.4] oxazin-3 -one; (R, S)-4- [3 -(4-
Butylidenepiperidin-1 -yl)-2-methylpropyl] -6-fluoro-4H-benzo [1.4] oxazin-3 -one; (R, iS)-4-[3-(3-Butyl-8-azabicyclo[3.2.1 ]oct-8-yl)-2-methylpropyl]-6-fluoro-4H-benzo[ 1.4]oxazin-3-one; (R,S)-6-Fluoro-4-[2-methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo [1.4] oxazin-3 -one; (R, S)-4- [3 -(4-Butylpiperidin-1 -yl)-2-methylpropyl] -7-fluoro-4H-benzo[1.4]oxazin-3-one; (R, S)-7-Fluoro-4-[2-methyl-3-(4-propoxypiperidin-l-yl)propyl]-4H/-benzo [1.4] oxazin-3 -one; (R, S)-4- [3 -(4-Butylidenepiperidin-1 -yl)-2-methylpropyl] -7-
26

fluoro-4#-benzo[1.4]oxazin-3-one; (R,S)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-
methylpropyl] -7-fluoro-4H-benzo [1.4] oxazin-3 -one; (R, S)-7-Fluoro-4- [2-methyl-3 -(3 -
pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H/-benzo[1.4]oxazin-3-one; (R,S)-3-[3-(4-
Butylpiperidin-l-yl)-2-methylpropyl]-3H-benzothiazol-2-one; (R,S)-4-[2-Methyl-3-(4-
propoxypiperidin-1 -yl)propyl] -3H-benzothiazol-2-one; (R, 5)-4- [3 -(4-Butylidenepiperidin-
l-yl)-2-methylpropyl]-3H-benzothiazol-2-one; (R,S)-3-[3-(3-Butyl-8-
azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-3H-benzothiazol-2-one; (R,S)-3-[2-Methyl-3-
(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-3H-benzothiazol-2-one; (R,S)-4-[3-(4-
Butylpiperidin-1 -yl)-2-methylpropyl] -4H-benzo [ 1,4] oxazin-3 -one; (R, S)-4- [2-Methyl-3 -
(4-propoxypiperidin-1 -yl)propyl] –4H-benzo [ 1,4] oxazin-3 -one; (R, S)-4- [3 -(4-
Butylidenepiperidin-1 -yl)-2-methylpropyl] -4H-benzo [ 1,4] oxazin-3 -one; (R, S)-4- [3 -(3 -
Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-4H/-benzo[l,4]oxazin-3-one; (R,S)-4-
[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[l,4]oxazin-3-one;
(R,S)-4-[3-(4-Butylpiperidin-l-yl)-2-methylpropyl]-4H-benzo[l,4]thiazin-3-one; (J?,5)-l-
[2-Methyl-3-(4-propoxypiperidin-l-yl)propyl]-4H-benzo[l,4]thiazin-3-one; (R,S)-4-[3-(4-
Butylidenepiperidin-l-yl)-2-methylpropyl]-4H-benzo[l,4]thiazin-3-one; (i?,iS)-4-[3-(3-
Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-4H-benzo[l,4]thiazin-3-one; (R,S)-4-
[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[l,4]thiazin-3-one;
(R,S)-l-[3-(4-Butylpiperidin-l-yl)-2-methylpropyl]-3,4-dihydro-lH-quinolin-2-one;(R,S)-
1 -[2-Methyl-3-(4-propoxypiperidin-1 -yl)propyl]-3,4-dihydro-1 H-quinolin-2-one; (R,S)-\-
[3-(4-Butylidenepiperidin-1 -yl)-2-methylpropyl] -3,4-dihydro-1 H-quinolin-2-one; (R,S)-1 -
[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-3,4-dihydro-1H-quinolin-2-one;
(R,S)-l-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-3,4-dihydro-lH-
quinolin-2-one; (R, 5)-4- [3 -(4-Butylpiperidin-1 -yl)-2-methylpropyl] -6-methoxy-4H-
benzo [1,4] oxazin-3 -one; (R, S)-4- [2-Methyl-3 -(4-propoxypiperidin-1 -yl)-6-methoxy] -4H-
benzo [ 1,4] oxazin-3 -one; (R, S)-4- [3 -(4-Butylidenepiperidin-1 -yl)-2-methylpropyl] -6-
methoxy-4H-benzo[l,4]oxazin-3-one; (R,S)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-
methylpropyl] -6-methoxy-4H-benzo [ 1,4]oxazin-3 -one; (R, S)-1 -[2-Methyl-3 -(3-pentyl-8-
azabicyclo[3.2.1]oct-8-yl)propyl]-6-methoxy-4H-benzo[l,4]oxazin-3-one; (R,S)-4-[3-(4-
Butylpiperidin-l-yl)-2-methylpropyl]-6,7-difluoro-4H-benzo[l,4]oxazin-3-one; (R,S)-6,7-
Difluoro-4-[2-methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-
benzo[l,4]oxazin-3-one; (R,S)-4-[3-(3-Butoxy-8-azabicyclo[3.2.1]oct-8-yl)-2-
methylpropyl] -6-fluoro-4H-benzo [1,4] oxazin-3 -one; (R, 5)-6-Fluoro-4- { 3- [3 -(2-
27

methoxyethyl)-8-azabicyclo[3.2.1]oct-8-yl]-2-methylpropyl}-4H-benzo[l,4]oxazin-3-one,
(R, S)-4- [3 -(3 -Butylazetidin-1 -yl)-2-methylpropyl] -6-fluoro-4H-benzo [1,4] oxazin-3 -one;
(R, 5)-6-Fluoro-4- [2-methyl-3 -(3 -propoxyazetidin-1 -yl)propyl] -4H-benzo [ 1,4] oxazin-3 -
one; (R, 5)-4- [3 -(3 -Butylazetidin-1-yl)-2-methoxypropyl] -6-fluoro-4H-benzo [ 1,4] oxazin-
3-one; 4-[3-(4-Butyl-3-fluoropiperidin-l-yl)-2-methylpropyl]-6-fluoro-4H-
benzo[l,4]oxazin-3-one.
[0106] In another aspect, disclosed herein is a compound of formula (I), and salts and isomers thereof
L1—L2
R3
riJ— R4 R4 R4 J=
r*\ iii/
C4 N—C—C—C—NL :
v \J III Y
Ca-K R6 R5 R5 ||
R v
(I)
wherein:
m is 0,1 or 2;
C3-C4 is CH2-CR1R9 or CH=CR1 or C4 is CR1R9 and C3 is absent;
each R1 and each R9 is separately selected from the group consisting of hydrogen, halogen, hydroxy, straight- or branched-chain optionally substituted C1- 6 alkyl, straight- or branched-chain optionally substituted C2-6 alkenyl, straight- or branched-chain optionally substituted C2-6 alkynyl, straight- or branched-chain optionally substituted C1-6 alkylidene, straight- or branched-chain optionally substituted C1-6 alkoxy, straight- or branched-chain optionally substituted C1-6 heteroalkyl, straight- or branched-chain optionally substituted C1-6 aminoalkyl, straight- or branched-chain optionally substituted C1-6 haloalkyl, straight- or branched-chain optionally substituted C1-6 alkoxycarbonyl, straight- or branched-chain optionally substituted C1-6 hydroxyalkoxy, straight- or branched-chain optionally substituted C1-6 hydroxyalkyl, straight- or branched-chain optionally substituted C1-6 alkylthio, straight- or branched-chain optionally substituted -O-C2-6 alkenyl, straight- or branched-chain optionally substituted -O-C2-6 alkynyl, straight- or branched-chain optionally substituted C3-6 alkenylalkoxy, straight- or branched-chain optionally substituted C1-6 alkyloxyimino, straight- or branched-chain optionally substituted C1-6 alkyloxyamino, optionally substituted
28

-O-CH2-C5.6 aryl, -C(O)NR10Rn, -CR10RnR12, -OC(0)R10, straight- or branched-chain optionally substituted -(O)(CH2)SNR11R12, straight- or branched-chain optionally substituted -(CH2)sNRnR12, straight- or branched-chain optionally substituted -OC(O)O(CH2)sCH3, straight- or branched-chain optionally substituted -S-C1-6-alkyl, straight- or branched-chain optionally substituted -S-C2-6-alkenyl, and straight- or branched-chain optionally substituted -S-C2-6-alkynyl, each of which may be optionally substituted with one or more substituents Rx;
each R10 is separately selected from the group consisting of hydrogen, straight- or branched-chain C1-6 alkyl, straight- or branched-chain C2-6 alkenyl, straight- or branched-chain C2-6 alkynyl, straight- or branched-chain C2-6 heteroalkyl, straight- or branched-chain C2-6 aminoalkyl, straight- or branched-chain C2-6 haloalkyl, straight- or branched-chain C1-6 alkoxycarbonyl, straight- or branched-chain C2-6 hydroxyalkyl, C3-8 cycloalkyl, -C(O)-C5-6 aryl substituted with C1-3 alkyl or halo, C5-6 aryl, C5-6 heteroaryl, C5-6 cycloalkyl, C5-6 heterocycloalkyl, -C(0)NRnR12, -CRnR12R13, and straight- or branched-chain -(CH2)sNRnR12;
each s is separately selected to be an integer from 1 to 8;
11 19
each R and each R is separately selected from the group consisting of hydrogen, straight- or branched-chain C1-6 alkyl, C3-6 cycloalkyl, and C5-6 heteroaryl, or each R11 and R12 together form a C3-8 cycloalkyl or C3-8 heterocycloalkyl;
R13 is selected from the group consisting of hydrogen, halogen, straight- or branched-chain C1-6 alkyl, formyl, and C3-6 cycloalkyl;
each Rx is separately selected from the group consisting of hydrogen, halogen, hydroxy, straight- or branched-chain optionally substituted C1-6 alkyl, straight- or branched-chain optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 heterocyclyl, and straight-or branched-chain optionally substituted C1-6 alkylidene;
R2 and R3 are separately selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, optionally substituted O-C1-6 alkyl, halogen, hydroxy or selected such that R2 and R3 are covalently linked together to form a ring system;
29

each R4 and each R5 are separately selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted C1-6-alkyl, optionally substituted O-C1-6alkyl, optionally substituted aryl-C1-6alkyl, and optionally substituted arylheteroalkyl;
L1 and L2 are biradicals separately selected from the group consisting of-C(R6)=C(R7), -C(R6)=N-, -N=C(R6)-, -S-, -NH- and -O-; wherein only one of L1 and L2 may be selected from the group consisting of-S-, -NH- and -O-;
Y is selected from the group consisting of O, S, and H2; and
X is a biradical selected from the group consisting of -C(R6)(R7)-C(R6)(R7)-, -C(R6)=C(R7)-, -O- C(R6)(R7)-, C(R6)(R7)-0-, -S-C(R6)(R7)-, -C(R6)(R7)-S-, -N(RN)-C(R6)(R7)-, -C(R6)(R7)-N(RN)-, -C(R6)(R7)-C(R6)(R7)-C(R6)(R7)-, -0-C(R6)(R7)-C(R6)(R7)-, S-C(R6)(R7)-C(R6)(R7)-, N(RN)-C(R6)(R7)-C(R6)(R7)-, -C(R6)(R7)-C(R6)(R7)-0, -C(R6)(R7)-C(R6)(R7)-S, -C(R6)(R7)-C(R6)(R7)-N(RN)-, -C(R6)(R7)- C(R6)=C(R7)~,and - C(R6)=C(R7)-
C(R6)(R7),wherein R6 and R7 are separately selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, NRNRN, N(RN)-C(O) N(RN), optionally substituted C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl, optionally substituted O-C1-6-alkyl, optionally substituted O-aryl, optionally substituted O-C2-6-alkenyl, optionally substituted O-C2-6-alkynyl,
wherein RN is selected from the group consisting of hydrogen, and optionally substituted C1-6alkyl.
[0107] Disclosed herein is a pharmaceutical composition comprising an
effective amount of a compound of formula (I), as disclosed above, or a pharmaceutically
acceptable salt, ester, or prodrug thereof.
[0108] In some embodiments, disclosed herein is a compound of formula (I),
wherein:
at least one of R1 or R9 is selected from the group consisting of hydroxy, straight- or branched-chain optionally substituted C1-6 alkoxy, straight- or branched-chain optionally substituted C1-6 alkyl, straight- or branched-chain optionally substituted C2-6 alkenyl, straight- or branched-chain optionally substituted C3-6 alkenylalkoxy, straight- or branched-chain optionally substituted C1-6 alkyloxyimino, and straight- or branched-chain optionally substituted -OC(O)O(CH2)sCH3; and
30

Rx is selected from the group consisting of halogen, optionally substituted C3-8 cycloalkyl, optionally substituted straight- or branched-chain C1-6 alkyl, optionally substituted C1-6 alkoxy and optionally substituted straight- or branched-chain C2-6 alkenyl
[0109] Disclosed herein is a pharmaceutical composition comprising an effective amount of a compound disclosed in the above paragraph or a pharmaceutically acceptable salt, ester, or prodrug thereof.
[0110] In some embodiments, disclosed herein is a compound of formula (I), wherein:
the at least one of R1 or R9 is selected from the group consisting of hydroxyl methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, ethenylmethoxy, ethenylethoxy, ethenylpropoxy, iminobutoxy, iminomethoxy, iminoethoxy, iminopropoxy, iminobutoxy; and -OC(O)O(CH2)2CH3; and
Rx is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halogen, and ethenyl.
[0111] Disclosed herein is a pharmaceutical composition comprising an effective amount of a compound disclosed in the above paragraph or a pharmaceutically acceptable salt, ester, or prodrug thereof.
[0112] In some embodiments, disclosed herein is a compound of formula (I), wherein:
X is selected from the group consisting of-CH2O- and -CH2CH2-;
L1 and L2 is -C(R6)=C(R7)-; and
each R6 and each R7 are separately selected from the group consisting of H, halogen, methyl, and methoxy.
[0113] Disclosed herein is a pharmaceutical composition comprising an effective amount of a compound disclosed in the above paragraph or a pharmaceutically acceptable salt, ester, or prodrug thereof.
[0114] The compound according to claim 1, wherein R2, R3, R9, m, and C3-C4 are selected such that
31

R3
C4 N
R2 is selected from the group consisting of
R8 R8 R8 R8 R8 R8
■Kb RKfr ^ "Kb «K^> »Kb
Q
wherein R8 is present 0, 1, or 2 times and is independently selected from the group consisting of optionally substituted C1-6 alkyl, optionally substituted O-C1-6 alkyl, halogen, hydroxy.
[0115] Disclosed herein is a pharmaceutical composition comprising an effective amount of a compound disclosed in the above paragraph or a pharmaceutically acceptable salt, ester, or prodrug thereof.
[0116] The compound according to claim 1, wherein C3-C4, m, R2, R3, and R9 are hydrogen or selected such that R2 and R3 together form a ring system such that
R3
C4 N
VK
R2 is selected from the group consisting of
R8 R8
[0117] Disclosed herein is a pharmaceutical composition comprising an effective amount of a compound disclosed in the above paragraph or a pharmaceutically acceptable salt, ester, or prodrug thereof.
[0118] The compound according to claim 1, wherein R2 and R3 are separately selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, optionally substituted O-C1-6 alkyl, halogen and hydroxy.
32

[0119] Disclosed herein is a pharmaceutical composition comprising an effective amount of a compound disclosed in the above paragraph or a pharmaceutically acceptable salt, ester, or prodrug thereof.
[0120] The compound according to claim 1, wherein m is 1.
[0121] Disclosed herein is a pharmaceutical composition comprising an effective amount of a compound disclosed in the above paragraph or a pharmaceutically acceptable salt, ester, or prodrug thereof.
[0122] The compound according to claim 1, wherein m is 0, C3 is absent, and C4 is CH such that
R3
C4 N
R2 is
R3\^N
A!
R1 V
[0123] Disclosed herein is a pharmaceutical composition comprising an effective amount of a compound disclosed in the above paragraph or a pharmaceutically acceptable salt, ester, or prodrug thereof.
[0124] The compound according to claim 1 wherein X is selected from the group consisting of-C(R6)(R7)-C(R6)(R7)-, -C(R6)=C(R7)-, -O-C(R6)(R7)-, -C(R6)(R7)-O-, -S-C(R6)(R7)-, -C(R6)(R7)-S-, -N(RN)-C(R6)(R7)-, -C(R6)(R7)-N(RN)-.
[0125] Disclosed herein is a pharmaceutical composition comprising an effective amount of a compound disclosed in the above paragraph or a pharmaceutically acceptable salt, ester, or prodrug thereof.
[0126] The compound according to claim 1 wherein Y is selected from the group consisting of O and H2.
[0127] Disclosed herein is a pharmaceutical composition comprising an effective amount of a compound disclosed in the above paragraph or a pharmaceutically acceptable salt, ester, or prodrug thereof.
33

[0128] The compound according to claim 1 wherein L1 and L2 are independently selected from the group consisting of -C(R6)=C(R7)-, -C(R6)=N-, and -N=C(R7)-.
[0129] Disclosed herein is a pharmaceutical composition comprising an effective amount of a compound disclosed in the above paragraph or a pharmaceutically acceptable salt, ester, or prodrug thereof.
[0130] The compound according to claim 1, wherein R1 is selected from the group consisting of:
.F
v-o^y X^/0^A /v
\^o^ xo^ \^°^7
[0131] Disclosed herein is a pharmaceutical composition comprising an effective amount of a compound disclosed in the above paragraph or a pharmaceutically acceptable salt, ester, or prodrug thereof.
[0132] The compound according to claim 13 selected from the group consisting of:
34


o
v-
H,F

c^


^r
o

o^O



5.F ^


-k^N^^N^ F
,o^
Nk^^N

N^/^^N


H,F





^


^

o^ A/NA^

XXxM
H,F
0^A %
H,F

>^

35






r
N^x-^N
Nx^^N

Y^O


°N^F
F F

[0133] Disclosed herein is a pharmaceutical composition comprising an effective amount of a compound disclosed in the above paragraph or a pharmaceutically acceptable salt, ester, or prodrug thereof.

[0134] In another aspect, disclosed herein is a method of treating a disease in a mammal, wherein modulation of the activity of a cholinergic receptor is associated with a physiologically beneficial response in said disease of said mammal, said method comprising administering an effective amount of a compound of formula (I).

[0135] In some embodiments, the cholinergic receptor is a muscarinic receptor.
[0136] In some embodiments, the cholinergic receptor is a muscarinic M1-receptor subtype.
[0137] In some embodiments, the cholinergic receptor is the muscarinic M4-receptor subtype.
36

[0138] In some embodiments, the physiologically beneficial response is associated with the selective modulation of the muscarinic Mi-receptor subtype in relation to the muscarinic M2- or M3-receptor subtypes.
[0139] In some embodiments, the compound is a muscarinic agonist.
[0140] In another aspect, disclosed herein is a method of increasing an activity of a cholinergic receptor comprising contacting the cholinergic receptor or a system containing the cholinergic receptor with an effective amount of at least one compound of formula (I).
[0141] In another aspect, disclosed herein is a method of treating or preventing or alleviating the symptoms associated with a disorder in a mammal, comprising the administration of an effective amount of at least one compound of formula (I), said disorder associated with a muscarinic receptor, such as M1 muscarinic receptor subtype.
[0142] In some embodiments, the disorder is selected from the group consisting of cognitive impairment, forgetfulness, confusion, memory loss, attentional deficits, deficits in visual perception, depression, pain, sleep disorders, psychosis, and increased intraocular pressure.
[0143] In some embodiments, the disorder is selected from the group consisting of neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's chorea, Friederich's ataxia, Gilles de la Tourette's Syndrome, Downs Syndrome, Pick disease, dementia, clinical depression, age-related cognitive decline, attention-deficit disorder, sudden infant death syndrome, and glaucoma.
[0144] In some embodiments, the disease or disorder is a mental disorder and the physiologically beneficial response is due to modulation in terms of M1 agonism; M1 and M4 agonism; both M1 agonism and D2 antagonism; or M1 and M4 agonism and D2 antagonism.
[0145] The compounds of the invention have the ability to increase cholinergic receptor activity or activate cholinergic receptors. Cholinergic receptor activity includes signaling activity or any other activity that is directly or indirectly related to cholinergic signalling or activation. The cholinergic receptors include muscarinic receptors, especially the ml or m4 subtype of muscarinic receptors. The muscarinic receptor can be, for example, in the central nervous system, peripheral nervous system, gastrointestinal system, heart, endocrine glands, or lungs. The muscarinic receptor can be a wild-type, truncated, mutated, or modified cholinergic receptor.
37

[0146] Kits comprising the compounds of the present invention, and instructions for practicing a method of the invention, for example, increasing cholinergic receptor activity or activating cholinergic receptors, are also provided.
[0147] The system containing the cholinergic receptor may, for example, be a subject such as a mammal, non-human primate or a human. The system may also be an in vivo or in vitro experimental model, such as a cell culture model system that expresses a cholinergic receptor, a cell-free extract thereof that contains a cholinergic receptor, or a purified receptor. Non-limiting examples of such systems are tissue culture cells expressing the receptor, or extracts or lysates thereof.
[0148] Cells that may be used in a method of the invention include any cell capable of mediating signal transduction via cholinergic receptors, such as the ml muscarinic receptor, either via endogenous expression of receptor (certain types of neuronal cells lines, for example, natively express the ml receptor), or such as following introduction of an exogenous gene into the cell, for example, by transfection of cells with plasmids containing the receptor gene. Such cells are typically mammalian cells (or other eukaryotic cells, such as insect cells or Xenopus oocytes), because cells of lower life forms generally lack the appropriate signal transduction pathways for the present purpose. Specific non-limiting examples of suitable cells include: the mouse fibroblast cell line NIH 3T3 (ATCC CRL 1658), which responds to transfected ml receptors by increased growth; RAT 1 cells (Pace et al, Proc. Natl. Acad. Sci. USA 88:7031-35 (1991)); and pituitary cells (Vallar et al., Nature 330:556-58 (1987)). Other useful mammalian cells include but are not limited to HEK 293 cells, CHO cells and COS cells.
[0149] The compounds of the present invention also have the ability to reduce intraocular pressure and therefore can be used in the treatment of such diseases associated with intraocular pressure, e.g., glaucoma. Glaucoma is a disease in which an abnormality is observed in the circulation-control mechanism of the aqueous humor filling up the anterior chamber, i.e., the space formed between the cornea and the lens. This leads to an increase in the volume of the aqueous humor and an increase in intraocular pressure, consequently leading to visual field defects and even to loss of eyesight due to the compulsion and contraction of the papillae of the optic nerve.
[0150] Accordingly, the invention also provides methods of treating a disease in a mammal, such as a human, wherein modulation of the activity of a cholinergic receptor is associated with a physiologically beneficial response in said disease of said
38

mammal. In one embodiment, a method includes administering an effective amount of a compound of formula I, as defined supra, to achieve a physiologically beneficial response. Typically, the cholinergic receptor is a muscarinic receptor, more typically the cholinergic receptor is a muscarinic M1-receptor subtype. Alternatively, the cholinergic receptor is the muscarinic M4-receptor subtype.
[0151] The invention further provides methods of treating or preventing or alleviating the symptoms associated with a disorder in a mammal, such as a human. In one embodiment, a method includes the administration of an effective amount of the compound of formula I, said disorder associated with a muscarinic receptor, such as the M1 muscarinic receptor subtype, to treat or prevent or alleviate one or more symptoms associated with the disorder.
[0152] The physiologically beneficial response is typically associated with the selective modulation of the muscarinic Mi-receptor subtype in relation to the muscarinic M2- or M3-receptor subtypes. In one embodiment, the compound in the method of the invention is a muscarinic agonist.
[0153] The disease or disorder treated by the compounds of the invention is typically a mental disorder and the physiologically beneficial response is due to modulation in terms of M1 agonism; M1 and M4 agonism; both M1 agonism and D2 antagonism; or M1 and M4 agonism and D2 antagonism.
[0154] A further and related aspect of the invention relates to methods of increasing an activity of a cholinergic receptor. In one embodiment, a method includes contacting the cholinergic receptor or a system containing the cholinergic receptor with an effective amount of at least one compound as defined supra to increase an activity of a cholinergic receptor.
[0155] As can be ascertained from the above discussion, the compounds of the invention are intended, at least in part, for use as pharmaceutical medicaments. Thus, the invention provides compositions comprising i) one or more compounds of formula I, as defined supra; and ii) at least one pharmaceutically acceptable excipient or carrier. As the invention relates to the use of a compound of formula I, as defined supra, the invention also provides a compound of formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a pharmaceutical composition comprising either entity, for the preparation of a medicament for the treatment of diseases or disorders associated with a cholinergic receptor or ligand thereof.
39

[0156] The invention thus relates, in part, to a method of treating or preventing or alleviating one or more symptoms associated with a disorder in a mammal, such as a human. In one embodiment, a method includes the administration of an effective amount of the compound of formula I, said disorder associated with a muscarinic receptor, such as the M1 muscarinic receptor subtype, to prevent or alleviate one or more symptoms. Disorders include those selected from the group consisting of cognitive impairment, forgetfulness, confusion, memory loss, attentional deficits, deficits in visual perception, depression, pain, sleep disorders, psychosis, and increased intraocular pressure. Disorders also include those selected from the group consisting of neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's chorea, Friederich's ataxia, Gilles de la Tourette's Syndrome, Downs Syndrome, Pick disease, dementia, clinical depression, age-related cognitive decline, attention-deficit disorder, sudden infant death syndrome, and glaucoma. Consequently, the invention further relates to a use of a compound of formula I, a pharmaceutically acceptable salt thereof, a stereoisomer thereof, or a pharmaceutical composition comprising either entity, for the preparation of a medicament for the treatment of diseases or disorders including those selected from the group consisting of Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's chorea, Friederich's ataxia, Gilles de la Tourette's Syndrome, Down Syndrome, Pick disease, dementia, clinical depression, age-related cognitive decline, cognitive impairment, forgetfulness, confusion, memory loss, attentional deficits, deficits in visual perception, depression, pain, sleep disorders, psychosis, sudden infant death syndrome, increased intraocular pressure and glaucoma.
[0157] Compounds according to the invention may be used alone at appropriate dosages defined by routine testing in order to obtain optimal pharmacological effect on a muscarinic receptor, in particular the muscarinic Mi or M4 receptor subtype, while minimizing any potential toxic or otherwise unwanted effects. In addition, coadministration or sequential administration of other agents that improve the effect of the compound may, in some cases, be desirable.
[0158] The pharmacological properties and selectivity of the compounds of the invention for specific muscarinic receptor subtypes may be demonstrated by a number of different assay methods using, for example, recombinant receptor subtypes, the human receptors as available, e.g., conventional second messenger or binding assays. A particularly convenient functional assay system is the receptor selection and amplification
40

assay (R-SAT assay) in U.S. Patent No. 5,707,798, which describes a method of screening for bioactive compounds by utilizing the ability of cells transfected with receptor DNA, e.g., coding for the different muscarinic subtypes, to amplify in the presence of a ligand of the receptor. Cell amplification is detected as increased levels of a marker also expressed by the cells.
[0159] The invention is disclosed in further detail in the following examples.
EXAMPLES
Example 1
Synthetic Chemistry
General analytical LC-MS procedures
Procedure 1:
[0160] Spectra were obtained using a HP 1100 LC/MSD-instrument. A set-up with a binary pump, auto sampler, column oven, diode array detector, and electro spray ionisation interface was used. A reversed phase column (CI8 Luna 3m, 75 x 4.6 mm ID) with a guard column cartridge system was used. The mobile phase was MeCN/8 mM aqueous ammonium acetate. A 15-minute gradient program was used, starting at 70% MeCN over 12 minutes to 95% MeCN, over 1 minute to 70% MeCN, hold for 2 minutes. The flow rate was 0.6 ml/min.
Procedure 2:
[0161] Spectra were obtained using a Waters LC/ZMD-instrument. A set-up with a 600 gradient pump, 2700 sample manager, 996 diode array detector, and electro spray ionisation interface was used. A reversed phase column (CI8 X-Terra 5m, 50 x 4.6 mm ID) with a guard column cartridge system was used. The mobile phase was MeCN/10 mM aqueous ammonium acetate. A 14-minute gradient program was used; starting at 30% MeCN, over 10 minutes to 95% MeCN, hold for 2 minutes, over 0.5 minutes to 30% MeCN, hold for 4.5 minutes. The flow rate was 1 ml/min.
General preparative LC-MS procedures
41

Procedure 1:
[0162] Preparative purification was performed on a Waters auto purification system (600 pumps, 2700 sample manager, 996 PDA detector, ZMD mass spectrometer).
[0163] The columns used were YMC C18 J'sphere ODS H80. Buffer A was 0.15% TFA in water, buffer B was 0.15% TFA in MeCN/water 95/5. The columns were operated at 17 ml/min. Following an initial hold of 2.5 min at 30% buffer B, compounds were separated using a gradient af 30-100% buffer B in 8.5 min. A dual column set-up with two pumps was used to equilibrate one column, while running on the other.
Procedure 2:
[0164] Preparative purification was performed on Waters Delta 4000 preparative system, Water 2487 dual absorbance detector, and Waters Fraction collector II. The column used was a Luna 15 um CI8, 250x21.2 mm. The following mobile phases were used: H2O/MeCN ammonium acetate buffer (25 nM) or H2O/MeCN TFA buffer (25 nM).
[0165] Heating with microwave irradiation was performed with a Smith Creator single-mode cavity (Personal Chemistry AB, Uppsala, Sweden) producing continuous irradiation at 2.45 GHz. The microwave-assisted reactions were performed in caped Smith process vials with a magnetic stirring bar. To secure sufficient irradiation absorption the liquid sample volume was > 0.5 mL.
[0166] Cation exchange CC was performed with Varian BOND ELUT (mega BE-SCX, 1 g, 6 ml) columns. After applying the compound to the column, it was first washed with MeOH (2 column volumes) and thereafter the desired compound was eluted applying 2 column volumes of an NH4OH (25% NH3 in H2O)/MeOH mixture (1:9).
(R,S)-1-(4-Butylpiperidin-l-yl)-3-chloropropan-2-ol (101IS93-1)
[0167] A 4 mL vial was charged with 4-butylpiperidine (0.29 g, 2.0 mmol) and epichlorohydrin (0.190 g, 2.1 mmol) and was shaken at rt for 4 h. The resulting thick oil was purified by flash chromatography (SiO2; CH2Cl2/acetone/MeOH 85/10/5) to yield the title compound as an oil (0.31 g, 64%). lH NMR (CDCl3) 5 3.95 - 3.85 (m, 1H), 3.60 -3.48 (m, 1H), 2.97 - 2.88 (m, 1H), 2.82 - 2.72 (m, 1H), 2.46 - 2.35 (m, 1H), 2.30 - 2.20 (m, 1H), 1.98 -1.88 (m, 1H), 1.70 -1.58 (m, 2H), 1.35 -1.08 (m, 9H), 0.88 (t, J= 6.8 Hz,
42

3H); 13C NMR (CDC13) d 66.7, 61.5, 55.9, 53.1, 47.4, 36.4, 35.8, 32.9, 32.6, 29.2, 23.1, 14.3.
(R,S)-4-Butyl-1 -(3-chloro-2-fluoropropyl)piperidine (101IS93-2)
[0168] DAST (1.9 mmol, 230 ml) was added drop wise to a solution of l-(4-butylpiperidin-l-yl)-3-chloropropan-2-ol (101IS93) (0.31 g, 1.28 mmol) in CH2C12 (5 mL). After 2h the reaction was quenched by the addition water (5 mL) and the organic phase was extracted with CH2Cl2 (2x15 mL) and the combined organic phase was dried (Na2SO4), filtered, concentrated under reduced pressure and the residue was purified by flash chromatography (SiO2; heptane/EtOAc 60:40) to yield the title compound as an oil (0.025 g, 9 %); lH NMR (CDCl3) d 4.79 (dm, J= 48 Hz, 1H), 3.78 - 3.60 (m, 2H), 2.92 -2.83 (m, 2H), 2.72 - 2.56 (m, 2H), 2.15 - 2.00 (m, 2H), 1.69 - 1.58 (m, 2H), 1.35-1.16 (m, 9H), 0.88 (t, J= 6.8 Hz); 13C NMR (CDC13) 5 91.1 (d, J= 111 Hz), 59.9 (d, J =22 Hz), 55.2, 54.9, 44.9 (d, J= 25 Hz), 36.4, 35.6, 32.7, 32.6, 29.2, 23.1, 14.3.
General procedure 1 (GP1)
[0169] To a flask or vial was charged 2-aminophenol (1.0 equiv) disolved in DMF (0.1 g/mL) and 2-Chloroacetyl chloride (1.1 equiv) was added. The reaction was stirred in rt for 12-20 hours and K2CO3 (2.1 equiv) was added. The reaction was stirred in it for another 12-20 hours then evaporated to dryness, redisolved in water (10 mL) and extracted using EtOAc (3x 20 mL). The combined organic phases concentrated to a crude that was used directly or purified by CC (Heptane:EtOAc).
4H-Pyrido[4,3-b][1,4]thiazin-3-one(81MF939a)
[0170] 3-Amino-4-thiopyridine (0.10 g, 0.79 mmol) and 2-Chloroacetyl chloride (0.098 g, 0.87 mmol) and K2CO3 (0.23 g, 1.66 mmol) were mixed according to GP1 to give the title compound as a crude (81MF939a) (0.087 g)
8-Fluoro-4H-benzo[1,4]oxazin-3-one(95MF45)
[0171] 2-Amino-6-flourophenol (95MF2085) (0.256 g, 2.0 mmol), 2-chloroacetyl chloride (0.25 g, 2.2 mmol) and K2CO3 (0.583 g, 4.2 mmol) were mixed according to GP1 to give the title compound as a crude (95MF45) (0.29 g)
43

7-Fluoro-4H-benzo[1,4]oxazin-3-one (111MF12)
[0172] 2-Amino-5-flourophenol (111MF 10) (10.3 g, 81 mmol), 2-chloroacetyl chloride (10.1 g, 89 mmol) and K2CO3 (23.5 g, 170 mmol) were mixed according to GPL CC (Si02; Heptane/EtOAc 4:1-4) to give the title compound (111MF12) (12.6 g, 93%); 'H NMR (DMSO) 5 10.68 (s, 1 H), 6.83-6.91 (m, 2 H), 6.75-6.80 (m, 1 H), 4.57 (s, 2 H); I3C NMR (DMSO) 5 164.2, 157.8 (d, J = 238.6 Hz), 144.0 (d, J= 12.4 Hz), 123.9 (d, J = 2.7 Hz), 116.3 (d, J= 9.6 Hz), 108.6 (d, J= 22.7 Hz), 104.0 (d, J= 26.5 Hz), 66.7.
7,8-Difluoro-4H-benzo[l,4]oxazin-3-one(81MF2082A)
[0173] 6-Amino-2,3-diflourophenol (81KK30a) (0.113 g, 0.78 mmol), 2-chloroacetyl chloride (0.10g, 0.89 mmol) and K2CO3 (0.226 g, 1.6 mmol) were mixed according to GP1 to give the title compound as a crude (81MF2082A) (0.12 g)
6-Bromo-8-fluoro-4H-benzo[1,4]oxazin-3-one (95MF44)
[0174] 2-Amino-4-bromo-6-flourophenol (95MF2084) (0.078 g, 0.38 mmol), 2-chloroacetyl chloride (0.048 g, 0.42 mmol) and K2CO3 (0.11 g, 0.79 mmol) were mixed according to GP1 to give the title compound as a crude (95MF44) (0.091 g)
8-Isopropvl-4H-benzo[1.4]oxazin-3-one (95MF83)
[0175] Crude 2-Amino-6-isopropylphenol (95MF80(2240) (0.16 g, 1.1 mmol), 2-chloroacetyl chloride (0.14 g, 1.2 mmol) and K2CO3 (0.32 g, 2.3 mmol) were mixed according to GP1 to give the title compound as a crude (95MF83) (0.115 g).
6.8-Dichloro-7-methyl-4H-benzo[1,4]oxazin-3-one(81MF2225)
[0176] 6-Amino-2.4 dichloro-3-metylphenol (1.9 g, 10 mmol), 2-chloroacetyl chloride (1.2 g, 11 mmol) and K2CO3 (3.0 g, 22 mmol) were mixed according to GP1 to give the title compound as a crude (80MF2225) (2.33 g).
6.8-Dichloro-7-ethvl-4#-benzor 1.4]oxazin-3-one (95MF46)
[0177] 6-Amino-2.4-dichloro-3-etylphenol (95MF2226) (0.293 g, 1.5 mmol), 2-chloroacetyl chloride (0.19 g, 1.7 mmol) and K2CO3 (0.44 g, 3.2 mmol) were mixed according to GP1 to give the title compound as a crude (95MF46) (0.34 g).
44

7-fluoro-6-methyl-3.4-dihydro-1 H-quinolin-2-one (97KK40)
[0178] 3-Fluoro-4-methylaniline (1.247 g, 9.96 mmol), 3-chloropropionyl chloride (1.269 g, 9.99 mmol), and K2CO3 (1.450 g, 10.5 mmol) in MeCN (10 mL) were stirred at 40 °C for 3 h. The reaction mixture was quenched with 4M HC1 and the product extracted into CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue (1.168 g) was heated to 145 °C and small portions of AlCl3 (3.538 g, 26.5 mmol) were added over a period of 30 min. The reaction mixture was then cooled and 4M HC1 added under stirring followed by extraction of the product into CH2CI2. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by flash CC (SiO2; CH2Cl2/MeOH 40:1) to give the title compound (97KK40) (0.201 g, total yield 11%). 1H NMR (CDCI3) d 8.15 (br s, 1H), 6.94 (d, J= 7.8 Hz, 1H), 6.47 (d, J= 10.0 Hz, 1H), 2.91 - 2.87 (m, 2H), 2.62 - 2.60 (m, 2H), 2.19 (d, .7=1.8 Hz, CH3).
6-Fluoro-lH-quinolin-2-one(97KK38)
[0179] DDQ (0.38 g, 1.7 mmol) was added to a solution of 6-fluoro-3,4-dihydro-1H-quinolin-2-one (0.18 g, 1.1 mmol) in dioxane (25 mL) and the resulting solution was refluxed for 16 h. The mixture was concentrated, and sat aqueous Na2CO3 (25 mL) was added followed by extraction into an organic mixture (MeOH:CH2Cl2; 1:10, 3 x 50 mL). The combined organic phase was dried (Na2SO4), filtered, concentrated under reduced pressure and purified by flash CC (SiO2; CH2Cl2/MeOH 20:1) to give the title compound (0.056 g, 31%). 1H NMR (DMSO-D6) 11.8 (brs, 1H), 7.85 (d, J = 9.4 Hz), 7.50 (dd, J= 2.8, 9.2 Hz), 7.43 - 7.37 (m, 1H), 7.37 - 7.25 (m, 1H), 6.54 (d, J= 9.4 Hz).
7-Fluoro-lH-quinolin-2-one,(97KK34).
[0180] DDQ (0.42 g, 1.9 mmol) was added to a solution of 7-fluoro-3,4-dihydro-1H-quinolin-2-one (0.20 g 1.2 mmol) in dioxane (25 mL) and the resulting mixture was refluxed under an Argon atmosphere for 16 h. The mixture was concentrated under reduced pressure and sat aqueous Na2CO3 solution (25 mL) was added, and this was extracted with an organic mixture (MeOH/CH2Cl2 1:10, 3 x 50 mL). The combined organic phase was dried (Na2SO4), filtered, concentrated under reduced pressure and purified by combi flash LC (SiO2; CH2Cl2/MeOH 10:1) to give the title compound (0.037
45

g, 18%). 1H NMR (DMSO-D6) 8 11.8 (s, 1H), 7.88 (d, J= 9.6 Hz, 1H), 7.74 - 7.65 (m, 1H), 7.05 - 6.95 (m, 2H), 6.43, (d, J= 9.6 Hz); 13C NMR (CDMSO-D6) d 163.0 (d, J = 247 Hz), 161.9, 140.4 (d, J = 13 Hz), 130.4 (d, J= 11 Hz), 120.9,116.1,109.8 (d, J =23), 101.0(d,J=25Hz).
6-Fluoro-7-methyl-3.4-dihydro-lH-quinolin-2-one (10LH75-1) and 6-Fluoro-5-methyl-3.4-dihydro-lH-quinolin-2-one(107LH75-2)
[0181] 3-Chloro-iV-(4-fluoro-3-methyl-phenyl)-propionamide (3.8 g, 30 mmol), 3-chloropropionyl chloride (2.9 mL, 30 mmol) and K2CO3 (5.0 g, 36 mmol) were added to CH3CN (50 mL) and the mixture was stirred for 44 h at rt. Thereafter, the reaction was diluted with EtOAc (50 mL) and washed with water (20 mL), HCl (20 mL, 4N) and brine (20 mL). The organic phase was dried with Na2S04, filtered and concentrated under reduced pressure. The residue (5.9 g) was heated to 135 °C and small portions of AICI3 (11 g, 82 mmol) were added during 30 min, the reaction was then cooled to 50 °C and HCl (4N 20, mL) was added and the resulting mixture was stirred for 15 min. The mixture was extracted with EtOAc (50 mL) and the organic phase was washed with water (20 mL). The resulting organic phase was dried (Na2SO4), filtered concentrated under reduced pressure and purified by prep HPLC to yield 6-fluoro-7-methyl-3,4-dihydro-1H-quinolin-2-one (0.76 g, 14%) and 6-fluoro-5-methyl-3,4-dihydro-lH-quinolin-2-one (0.190 g, 4%). 6-Fluoro-7-methyl-3,4-dihydro-lH-quinolin-2-one (107LH75-1). lH NMR (CDC13) 8 8.86 (brs, 8.86, 1H), 6.81 (d, J= 9.2 Hz, 1H), 6.62 (d, J = 6.8 Hz, 1H), 2.91 (brt, J= 7.6 Hz, 3H), 2.94 - 2.87 (m, 2H), 2.20 (d, J =2.0 Hz). 6-Fluoro-5-methyl-3,4-dihydro-lH-quinolin-2-one (107LH75-2). 1H NMR (CDCI3) d 8.78 (brs, 1H), 6.85 (t, J= 8.8 Hz, 1H), 6.62 (dd, J= 4.5, 8.8 Hz, 1H), 2.92 (brt, J = 7.6 Hz, 2H), 2.64 - 2.58 (m, 2H), 2.20 (d, J= 2.4 Hz, 3H).
(R)-4-(3-Hydroxy-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one(108LM40-37)
[0182] A 25 mL flask was charged with 4H-benzo[l,4]oxazin-3-one (0.100 g, 0.670 mmol), (5)-3-bromo-2-methylpropanol (0.103 g, 0.670 mmol) and cesium carbonate (0.208 g, 0.670 mmol) in MeCN (10 mL) and stirred at 40°C for 2 days. The reaction mixture was quenched with water (5 mL), and the product extracted into EtOAc (2x10 mL). The combined organic layers were dried (Na2SO4) and evaporated to give the crude title compound (108LM40-37) (0.219 g).
46

GENERAL PROCEDURE 2 (GP2)
[0183] A dry 50 mL flask was charged with the appropriate heterocycle (1.1 equiv), (R)-(3-bromo-2-methyl-propoxy)-tert-butyl-dimethylsilane (95MF94) (1 equiv) and cesium carbonate (2.5 equiv) in DMF (20 mL) and stirred at 55°C for 20 h. The reaction mixture was quenched with water (10 mL), and the product extracted into EtOEt (3 x 20 mL). The combined organic layers were washed with brine, dried (Na2SO4), evaporated and purified by flash CC (SiO2; EtOAc/heptane 1:10).
(S)-4- [3 -(tert-Butyldimethylsilanyloxy)-2-methylpropyl] –4H-benzo[1,4] oxazin-3 -one (108LM24-21)
[0184] 4H-Benzo[l,4]oxazin-3-one (2.47 g, 16.5 mmol), (R)-(3-bromo-2-methyl-propoxy)-tert-butyldimethylsilane (95MF94) (4.01 g, 15.0 mmol) and CS2CO3 (12.2 g, 37.6 mmol) in DMF (20 mL) were reacted according to GP2 to give the title compound (108LM24-21) (3.92 g, 78%). lH NMR (CDC13) 5 7.15 - 7.11 (m, 1H), 6.99 -6.91 (m, 3H), 4.60 - 4.50 (m, 2H), 3.98 (dd, J= 8.3 Hz, J= 12.4 Hz, 1H), 3.81 (dd, J = 5.5 Hz, J= 12.4 Hz, 1H), 3.51 (dd, J= 4.1 Hz, J= 9.7 Hz, 1H), 3.40 (dd, J= 6.9 Hz, J = 9.7 Hz, 1H), 2.12 - 2.02 (m, 1H), 0.90 - 0.82 (m, 12H), 0.02 (s, 6H).
(S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-4H-benzo[1,4]thiazin-3-one (108LM25-22)
[0185] 4H-Benzo[l,4]thiazin-3-one (2.75 g, 16.7 mmol), (R)-(3-bromo-2-methylpropoxy)-ter/-butyldimethylsilane (95MF94) (4.04 g, 15.1 mmol) and cesium carbonate (12.3 g, 37.9 mmol) in DMF (20 mL) were reacted according to GP2 to give the title compound (108LM25-22) (3.74 g, 70%). 1H NMR (CDCI3) 6 7.35 (d, J= 7.6 Hz, 1H), 7.28-7.18 (m, 2H), 6.99 (t, J= 7.6 Hz, 1H), 4.13 (dd, J= 8.9 Hz, J= 13.3 Hz, 1H), 3.95 (dd, J= 5.9 Hz, J= 13.3 Hz, 1H), 3.52-3.40 (m, 2H), 3.37 (s, CH2), 1.96-2.07 (m, 1H), 0.92-0.83 (m, 12 H), 0.02 (s, 6H).
GENERAL PROCEDURE 3 (GP3)
[0186] A 50 mL flask was charged with the appropriate heterocycle (1 equiv) and tetrabutylammonium fluoride (TBAF) (1.3 equiv) in THF (30 mL) and stirred at rt for 20 h. The reaction mixture was concentrated to syrup and dissolved in EtOAc (30 mL).
47

The mixture was washed with brine (2 x 20 mL). The combined organic layers were dried (Na2SO4), evaporated and purified by flash CC (SiO2; EtOAc/heptane 7:3).
(S)-4-(3-Hydroxy-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one(108LM26-23)
[0187] The compound (S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-
methylpropyl]-4H-benzo[l,4]oxazin-3-one (108LM24-21) (3.92 g, 11.7 mmol) and TBAF (4.78 g, 15.2 mmol) in THF (30 mL) were reacted according to GP3 to give the title compound (108LM26-23) (2.52 g, 98%). lH NMR (CDC13) 8 7.05 - 6.95 (m, 4H), 4.63 (s, CH2), 4.23 (dd, J= 10.3 Hz, J= 13.9 Hz, IH), 3.56 (dd, J= 4.8 Hz, J= 13.9 Hz, IH), 3.52 - 3.49 (m, IH), 3.46 - 3.38 (m, IH), 2.92 - 2.85 (m, IH), 2.09 - 1.97 (m, IH), 1.06 (d, J=7.3Hz, CH3).
(S)-4- [3 -(tert/-Butyldimethylsilanyloxy)-2-methylpropyl] –4H-benzo [ 1,4] thiazin-3 -one
[0188] The compound (108LM25-22) (3.69 g, 10.5 mmol) and TBAF (4.30 g, 13.6 mmol) in THF (30 mL) were reacted according to GP3. Purified by flash CC (SiO2; EtOAc/heptane 7:3) to give the title compound (108LM34-31) (2.36 g, 95%). 1H NMR (CDCl3) d 7.38 (d, J= 7.9 Hz, IH), 7.28 - 7.18 (m, 2H), 7.03 (t, J= 7.0 Hz, IH), 4.32 (dd, J= 9.0 Hz, J= 15.2 Hz, IH), 3.70 (dd, J= 5.5 Hz, J= 15.2 Hz, IH), 3.52 (dd, J = 3.4 Hz, J= 11.7 Hz, IH), 3.34 - 3.42 (m, 3H), 2.82 (bs, OH), 1.92 -1.83 (m, IH), 0.98 (d, J= 6.9 Hz, CH3).
GENERAL PROCEDURE 4 (GP4)
[0189] A 50 mL flask was charged with the appropriate heterocycle (1 equiv), triphenylphosphine (2 equiv) and imidazole (2.5 equiv) in CHCI3 (30 mL). When all of the material was dissolved iodine (3 equiv) was added while stirring. Stirring was continued at rt for 20 h. The reaction mixture was washed with sat. aqueous sodium thiosulfate (30 mL), dried (Na2SO4), evaporated and purified by flash CC (SiO2; EtOAc/heptane 3:1).
(S)-4-(3-Iodo-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one(108LM27-24)
[0190] The compound (S)-4-(3-Hydroxy-2-methylpropyl]-4H-
benzo[l,4]oxazin-3-one (108LM26-23) (2.52 g, 11.4 mmol), triphenylphosphine (6.12 g, 23.3 mmol), imidazole (1.98 g, 29.1 mmol) and iodine (8.88 g, 35.0 mmol) in CHCI3 (30
48

mL) were reacted according to GP4 to give the title compound (108LM27-24) (3.02 g, 80%). 1H NMR (CDCI3) 6 7.07 - 7.00 (m, 4H), 4.65 - 4.55 (m, 2H), 3.94 (dd, J= 1.7 Hz, J= 6.7 Hz, CH2), 3.23 - 3.14 (m, 2H), 2.18 - 2.07 (m, 1H), 1.05 (d, J= 6.1 Hz, CH3).
(R)-4-(3-Iodo-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one(108LM46-43)
[0191] Crude (R)-4-(3-hydroxy-2-methylpropyl]-4#-benzo[ 1,4]oxazin-3-one (108LM40-37) (1.040 g), triphenylphosphine (0.99 g, 3.77 mmol), imidazole (0.32 g, 4.71 mmol) and iodine (1.43 g, 5.65 mmol) in CHCI3 (30 mL) were reacted according to GP4 to give the crude title compound (108LM46-43) (0.312 g).
(S)-4-(3-Iodo-2-methylpropyl]-4H-benzo[1,4]thiazin-3-one(108LM37-34)
[0192] The compound (S)-4-(3-Hydroxy-2-methylpropyl]-4H/-
benzo[l,4]thiazin-3-one (108LM34-31) (2.33 g, 9.82 mmol), triphenylphosphine (5.15 g, 19.7 mmol), imidazole (1.67 g, 24.6 mmol) and iodine (7.48 g, 29.5 mmol) in CHC13 (30 mL) were reacted according to GP4 to give the title compound (108LM37-34) (2.57 g, 75%). 1H NMR (CDCI3) d 7.37 (d, J= 7.8 Hz, 1H), 7.24 (t, J= 7.8 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.02 (t, J= 7.8 Hz, 1H), 4.02 (d, J= 6.8 Hz, CH2), 3.37 (s, CH2), 3.15-3.05 (m, CH2), 1.95 (m, 1H), 0.97 (d, J= 6.2 Hz, CH3).
GENERAL PROCEDURE 5 (GP5)
[0193] A 4 or 7 mL vial was charged with 4H-benzo[l,4]oxazin-3-one (1.0 equiv), CS2CO3 (1.5 equiv) and 3-chloro-l-iodopropane (1.1 equiv) in 3 mL dry MeCN and shaken at rt for 66 - 72 h. The reaction mixture was diluted with 10 mL H2O and extracted into CH2Cl2 or EtOAc (3 x 30 mL). The combined organic layers were dried over MgS04 or filtered through a PTFF Whatman filter and concentrated. The residue was purified by CC (Heptane/EtOAc) or used without further purification in the next step.
6-Bromo-4-(3-chloropropyl)-8-fluoro-4H-benzo[1,4]oxazin-3-one(95MF50(2084))
[0194] 6-Bromo-8-fluoro-4H-benzo[l,4]oxazin-3-one (95MF44) (0.091g, 0.37 mmol), Cs2CO3 (0.180 g, 0.55 mmol) and 3-chloro-l-iodopropane (0.083 g, 0.41 mmol) were mixed according to GP5. CC (SiO2;Heptane/EtOAc 9:1-4) gave the title compound (95MF50(2084)) (0.086 g, 72%). 1H NMR (CDC13) 5 7.02 - 6.96 (m, 1H), 6.85 (d, J= 5.2 Hz, 1 H), 4.65 (s, 2H), 4.04 - 4.11 (m, 2H), 3.62 (t, J= 6.2 Hz, 2H), 2.10 - 2.18 (m, 2H);
49

13C NMR (CDCI3) 5 163.8, 151.7 (d, J= 250.9 Hz), 133.1 (d, J= 14.6 Hz), 131.5 (d, J = 3.8 Hz), 115.1 (d, J-21.5 Hz), 114.2 (d, J = 10.0 Hz), 113.4 (d, J = 3.4 Hz), 67.6, 42.2, 39.5, 30.0.
4-(3-Chloropropyl)-8-fluoro-4H-benzo[1,4]oxazin-3-one(95MF51(2085))
[0195] 8-Fluoro-4H-benzo[l,4]oxazin-3-one (95MF45) (0.290g, 1.74 mmol), Cs2CO3 (0.848 g, 2.6 mmol) and 3-chloro-l-iodopropane (0.390 g, 1.91 mmol) were mixed according to GP5. CC (SiO2 Heptane/EtOAc 9:1-4) gave the title compound (95MF51(2082)) (0.254 g, 60%). 1H NMR (CDCI3) d 7.01 - 6.95 (m, 1H), 6.88 - 6.82 (m, 2H), 4.66 (s, 2H), 4.13 - 4.08 (m, 2H), 3.63 (t, J= 6.0 Hz, 2H), 2.19 - 2-12 (m, 2H); 13C NMR (CDCI3) d164.2, 152.1 (d, J= 246.8 Hz), 133.9 (d, J= 15.0 Hz), 130.6 (d, J- 3.1 Hz), 122.6 (d, J = 8.1 Hz), 111.8 (d, J= 18.4 Hz), 110.1 (d, J= 3.4 Hz), 67.8, 42.4, 39.5, 30.1.
6.8-Dichloro-4-(3-chloropropyl-7-ethyl-4H-benzo[1,4]oxazin-3-one((95MF52(2226))
[0196] 6,8-Dichloro-7-ethyl-4H-benzo[l,4]oxazin-3-one (95MF46) (0.342g, 1.39 mmol), Cs2CO3 (0.678 g, 2.08 mmol) and 3-chloro-l-iodopropane (0.313 g, 1.52 mmol) were mixed according to GP5. CC (SiO2;Heptane/EtOAc 9:1-4) gave the title compound (95MF52(2226)) (0.301 g, 67%). !H NMR (CDC13) 5 7.01 (s, 1H), 4.68 (s, 2H), 4.06 (t, J= 12 Hz, 2H), 3.62 (t, J= 6.0 Hz, 2H), 2.91 (q,J = 7.6 Hz, 2H), 2.10-2.18 (m, 2H), 1.16 (t, J= 7.6 Hz, 3H); 13C NMR (CDC13) 5 163.8, 140.6, 135.8, 127.9, 127.7, 123.6,113.8, 67.9, 42.2, 39.3, 30.0, 24.7, 12.7.
4-(3-Chloropropyl)-8-isopropyl-4H-benzo[1.4]oxazin-3-one(95MF98)
[0197] 8-Isopropyl-4H-benzo[l,4]oxazin-3-one (95MF83) (0.115g, 0.60 mmol), CS2CO3 (0.293 g, 0.90 mmol) and 3-chloro-l-iodopropane (0.135 g, 0.66 mmol) were mixed according to GP5. CC (SiO2;Heptane/EtOAc 9:1-4) gave the title compound (95MF98) (0.112 g, 70%). lH NMR (CDCI3) 8 7.03 - 6.95 (m, 2H), 6.93 - 6.90 (m, 1H), 4.57 (s, 2H), 4.09 (m, 2H), 3.62 (t, J= 6.2 Hz, 2H), 3.33 - 3.25 (m, 1H), 2.20 - 2.13 (m, 2H), 1.22 (d, J= 7.2 Hz, 6H); 13CNMR(CDC13) d 164.9, 142.8, 137.8, 128.5, 122.8, 121.4, 112.5, 67.7, 42.5, 39.3, 30.3, 27.2, 22.7.
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4-(3-Chloropropyl-6-fluoro-4H-benzo[1,4]oxazin-3-one (8173MF55b)
[0198] 6-Fluoro-4H-benzo[l,4]oxazin-3-one (8173MF55b) (0.090 g, 0.54 mmol), CS2CO3 (0.263 g, 0.81 mmol) and 3-chloro-l-iodopropane (0.121 g, 0.59 mmol) were mixed according to GP5. CC (SiO2;Heptane/EtOAc 10:1-5) gave the title compound (8173MF55b) (0.102 g, 78%). 1HNMRCCDCl3) 5 6.95 - 6.91 (m, 1H), 6.82 - 6.78 (m, 1H), 6.72 - 6.67 (m, 1H), 4.57 (s, 1H), 4.05 (t, J= 7.2 Hz, 2H), 3.62 (t, J= 6.2 Hz, 2H), 2.19 - 2.11 (m, 2H); 13CNMR(CDC13) 5 164.6, 158.6 (d, J= 240.7 Hz), 141.5 (d, J= 2.3 Hz), 129.6 (d, J= 10.5 Hz), 118.0 (d, J= 9.3 Hz), 110.0 (d, J= 23.1 Hz), 102.7 (d, J = 28.8 Hz), 67.8, 42.3, 39.3, 30.0.
4-(3-Chloropropyl-7.8-difluoro-4H-benzo[1,4]oxazin-3-one(81MF2082b)
[0199] 7,8-Difluoro-4H-benzo[l,4]oxazin-3-one (81MF2082a) (0.119 g, 0.64 mmol), CS2CO3 (0.314 g, 0.96 mmol) and 3-chloro-l-iodopropane (0.144 g, 0.70 mmol) were mixed according to GP5 giving the crude title compound (0.156 g); *H NMR (CDCI3) d 6.89 - 6.82 (m, 1H), 6.78 - 6.74 (m, 1H), 4.68 (s, 2H), 4.08 (t, J= 12 Hz, 2H), 3.62 (t, J= 6.4 Hz, 2H), 2.18 - 2.10 (m, 2H); 13CNMR (CDC13) 5 163.5, 147.7 (q, J = 245.6 Hz, J= 10.4 Hz), 141.0 (q, J= 249.4 Hz, J= 15.7 Hz), 135.5, 126.2, 109.9 (d, J = 18.4 Hz), 108.6 (q, J= 7.6 Hz, J= 4.2 Hz), 67.8, 42.3, 39.4, 30.0.
4-(3-Chloropropyl-6-methoxy-4H-benzo[1,4]oxazin-3-one(81MF2249b)
[0200] 6-Methoxy-4H-benzo[l,4]oxazin-3-one (81MF2249a) (0.212 g, 1.18 mmol), CS2CO3 (0.578 g, 1.77 mmol) and 3-chloro-l-iodopropane ( 0.265 g, 1.3 mmol) were mixed according to GP5. CC (SiO2 Heptane/EtOAc 10:1-2) gave the title compound (81MF2249b) (0.127 g, 42%). !H NMR (CDCI3) 5 6.88 (d, J= 8.8 Hz, 1H), 6.62 (d, J= 2.8 Hz, 1H), 6.50 (dd, J= 2.8 Hz, J= 8.8 Hz, 1H), 4.50 (s, 2H), 4.05 - 4.01 (m, 2H), 3.76 (s, 3H), 3.59 (t, J= 6.2 Hz, 2H), 2.16 - 2.09 (m, 2H); 13C NMR (CDC13) 8 164.8,155.5,139.3,129.2, 117.4, 107.8, 101.9, 67.8, 55.8,42.4, 38.9, 30.0.
4-(3-Chloropropyl)-fluoro-4H-benzo[l,4]oxazin-3-one (81MF763b)
[0201] 7-Fluoro-4H-benzo[l,4]oxazin-3-one (81MF763) (0.263 g, 1.57 mmol), CS2CO3 (0.769 g, 2.36 mmol) and 3-chloro-l-iodopropane (0.354 g, 1.73 mmol) were mixed according to GP5 giving the crude title compound (0.40 g); 1H NMR (CDCl3)
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d 7-01 - 6.91 (m, 1H), 6.79 - 6.73 (m, 2H), 4.60 (s, 2H), 4.08 (t, J= 7.2 Hz, 2H), 3.62 (t, J= 6.4 Hz, 2 H), 2.18 - 2.11 (m, 2H).
4-(3-Chloropropyl)-4H-pyrido[4.3-b][1,4]thiazin-3-one(81MF939b)
[0202] 4H-pyrido[4,3-6][l,4]thiazin-3-one (81MF939a) (0.087 g, 0.52 mmol), CS2CO3 (0.256 g, 0.78 mmol) and 3-chloro-l-iodopropane (0.116 g, 0.57 mmol) were mixed according to GP5 giving the crude title compound (0.139 g). 1H NMR (CDCI3) 5 8.43 (s, 1H), 8.17 (d, J= 5.2 Hz, 1H), 7.25 (d, J= 5.2 Hz, 1H), 4.20 - 4.15 (m, 2H), 3.55 (t, J= 6.2 Hz, 2H), 3.41 (s, 2H), 2.17 - 2.10 (m, 2H).
GENERAL PROCEDURE 6 (GP6)
[0203] A 100 mL flask was charged with 4H-benzo[l,4]oxazin-3-one (1.0 equiv), CS2CO3 (1.5 equiv) and 3-chloro-l-iodopropane (1.1 equiv) in 50 mL dry MeCN and stirred at rt for 72 h. The reaction mixture was evaporated to dryness and diluted with 100 mL H2O and extracted into EtOAc (3 x 100 mL). The combined organic layers were dried over MgSO4, filtrated, evaporated to dryness and purified by CC (Heptane/EtOAc).
6.8-Dichloro-4-(3-chloropropyl)-7-methyl-4H-benzo[1,4]oxazin-3-one(81MF2225b)
[0204] 6,8-Dichloro-7-methyl-4#-benzo[l,4]oxazin-3-one (81MF2225a)
(2.33 g, 10.0 mmol), Cs2CO3 (4.88 g, 15.0 mmol) and 3-chloro-l-iodopropane (2.25 g, 11.0 mmol) were mixed according to GP6. CC (Si02; Heptane/EtOAc 10:1-5) gave the title compound (81MF2225b) (2.44 g, 79%). 1H NMR (CDC13) 5 7.02 (s, 1H), 4.67 (s, 2H), 4.06 (t, J= 7.2 Hz, 2H), 3.62 (t,J = 6.2, 2H), 2.43 (s, 3H), 2.18 - 2.10 (m, 2H); 13C NMR (CDCl3) CS2CO3 163.7, 140.5, 130.3, 128.3, 127.6, 124.1, 113.5, 67.9, 42.2, 39.3, 30.0, 17.2.
4-(3-Chloropropyl)-6,8-dimethyl-4H-benzo[1,4]oxazin-3-one(81MF2237b)
[0205] 6,8-Dimethyl-4H-benzo[l,4]oxazin-3-one (81MF2237a) (1.70 g, 9.60 mmol), CS2CO3 (4.69 g, 14.4 mmol) and 3-chloro-l-iodopropane (2.15 g, 10.6 mmol) were mixed according to GP6. CC (SiO2; Heptane/EtOAc 10:1-5) gave the title compound (81MF2237b) (0.96 g, 39%). 1H NMR (CDC13) 8 6.72 - 6.69 (m, 2H), 4.56 (s, 2H), 4.07 (t, 2H), 3.62 (t, J= 6.4 Hz, 2H), 2.30 (s, 3H), 2.20 (s, 3H), 2.19 - 2.12 (m, 2H);
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13C NMR (CDCl3) d 164.9, 141.5, 131.9, 128.0, 126.7, 126.4, 113.1, 67.8, 42.5, 39.0, 30.3,21.2,15.5.
6-tert-Butyl-4-(3-chloropropyl-4H-benzo[1,4]oxazin-3-one(81MF2248b)
[0206] 6-tert-Butyl-4H-benzo[l,4]oxazin-3-one (81MF2248a) (2.07g, 10.0 mmol), CS2CO3 (4.88 g, 15.0 mmol) and 3-chloro-l-iodopropane (2.25 g, 11.0 mmol) were mixed according to GP6. CC (SiO2 Heptane/EtOAc 10:1-5) to give the title compound (81MF2248b) (1.39 g, 49%). 1H NMR (CDCI3) 5 7.12 (d, J= 2.0 Hz, 1H), 7.03 (dd, J= 8.4 Hz, J= 2.0 Hz, 1H), 6.92 (d, J= 8.4 Hz, 1H), 4.54 (s, 2H), 4.14 (t, J = 7.2 Hz, 2H), 3.65 (t, J= 6.0 Hz, 2H), 2.21 - 2.14 (m, 2H), 1.32 (s, 9H); 13C NMR (CDCI3) d 164.8,146.4, 143.1, 127.9,120.9,116.7,112.2,67.8,42.6,38.9,34.8,31.6,30.2.
6-Chloro-4-(3-chloropropyl)-7-nitro-4H-benzo[1,4]oxazin-3-one (8 lMF2253b)
[0207] Crude 6-Chloro-7-nitro-4H/-benzo[l,4]oxazin-3-one (81MF2253a) (2.60 g, 10.0 mmol), Cs2CO3 (4.88 g, 15.0 mmol) and 3-chloro-l-iodopropane (2.25 g, 11.0 mmol) were mixed according to GP6. CC (SiCh; Heptane/EtOAc 10:1-5) gave the title compound (81MF2253b) (1.23 g, 36%). !H NMR (CDCI3) 8 7.66 (s, 1H), 7.20 (s, 1H), 4.70 (s, 2H), 4.12 (t, J= 7.6 Hz, 2H), 3.67 - 3.59 (m, 2H), 2.21 - 2.13 (m, 2H); 13C NMR (CDCI3) 8 163.6, 143.5, 133.3, 133.2, 122.4, 117.2, 115.2, 67.4, 42.1, 39.6, 29.8.
7-Chloro-4-(3-Chloropropyl)-4H-benzo[1,4]oxazin-3-one(81MF2271b)
[0208] 7-Chloro-4H-benzo[l,4]oxazin-3-one (81MF2271a) (1.74g, 9.47 mmol), CS2CO3 (4.63 g, 14.2 mmol) and 3-chloro-l-iodopropane (2.13 g, 10.4 mmol) were mixed according to GP6. CC (SiO2 Heptane/EtOAc 10:1-5) gave the title compound (81MF2271b) (1.95 g, 79%). 1H NMR (CDC13) 8 7.03 - 6.96 (m, 3H), 4.59 (s, 2H), 4.07 (t, J= 7.2 Hz, 2H), 3.61 (t, J= 6.4 Hz, 2H), 2.17 - 2.10 (m, 2H); 13C NMR (CDCI3) 8 164.0,146.0,129.1,127.3,123.0,117.8, 115.5, 67.7,42.4, 39.2, 30.0.
4-(3-Chloropropyl)-5-methyl-4H-benzo[1,4]oxazin-3-one (81MF941 b)
[0209] 5-Methyl-4H-benzo[l,4]oxazin-3-one (81MF941a) (1.514 g, 9.28 mmol), CS2CO3 (4.53 g, 13.9 mmol) and 3-chloro-l-iodopropane (2.09 g, 10.21 mmol) were mixed according to GP6. CC (SiO2; Heptane/EtOAc 10:1-5) gave the title compound (81MF941b) (1.07 g, 48%). 1H NMR (CDC13) 8 6.99 - 6.87 (m, 3H), 4.42 (s,
53

2H), 4.17 (t, J= 7.2 Hz, 2 H), 3.45 (t, J = 6.4 Hz, 2H), 2,41 (s, 3H), 2.04 - 1.97 (m, 2H); 13C NMR (CDC13) 8 168.3, 149.9, 129.1, 128.7, 126.9, 125.1, 115.0, 69.4, 42.2, 42.1, 30.6,20.9.
4-(3-Chloropropyl-7-methyl-4H-benzo[1,4]oxazin-3-one(81MF2246b)
[0210] 7-Methyl-4H-benzo[l,4]oxazin-3-one (81MF2246a) (1.42 g, 8.7 mmol), CS2CO3 (4.24 g, 13.0 mmol) and 3-chloro-l-iodopropane (1.95 g, 9.5 mmol) were mixed according to GP6. CC (SiCh; Heptane/EtOAc 10:1-5) gave the title compound (81MF2246b) (1.64 g, 79%). !H NMR (CDC13) 5 6.98 - 6.81 (m, 3H), 4.59 (s, 2H), 4.06 -4.03 (m, 2H), 3.63 - 3.60 (m, 2H), 2.26 (s, 2H), 2.20 - 2.15 (m, 2H); 13C NMR (CDC13) 5 164.8,145.8,134.3,123.9,118.1,114.9, 68.0,42.8, 39.4, 30.5, 21.0
(R,S)-6-Methyl-4-oxiranylmethyl-4H/-benzo[1,4]oxazin-3-one (101IS84F1)
[0211] A dry 7 mL vial was charged with 6-methyl-4H-benzo[l,4]oxazin-3-one (160 mg, 1.0 mmol), epichlorohydrin (0.147 g, 1.6 mmol), Cs2CO3 (0.820 g, 2.5 mmol) and dry DMF (lmL), the mixture was then shaken at 60 °C for 36 h. The mixture was diluted with ether (20 mL) washed with water and brine (10 mL), dried, filtered and concentrated under reduced pressure to give an oil. Purification with flash CC (SiCh, CH2C12: acetone/MeOH 95:3:2) gave the title compound (0.127 g, 39%). lH NMR (CDCI3) 5 7.01 (d, J= 1.2 Hz, 1H), 6.84 (d, J= 8.4 Hz), 6.80 (dm, J= 8.4 Hz), 4.58 (ABq J= 15.2, 21.2 Hz, 2H), 4.50 (dd, J= 3.2, 15.2 Hz, 1H), 3.66 (dd, J= 6,15.2 Hz), 3.23 (m, 1H), 2.86 (dd, J= 4, 4.4 Hz, 1H), 2.69 (dd, J= 2.8, 4.8 Hz, 1H), 2.33 (s, 3H); 13C NMR (CDCI3) 5 156.2, 143.3, 132.9, 129.0, 124.9, 116.9, 116.6, 68.0, 50.2, 25.8, 44.0, 21.3.
GENERAL PROCEDURE 7 CGP7)
[0212] To a dry 100 mL flask was charged 4H-benzo[l,4]oxazin-3-one (1.0 equiv), (3-bromo-2-methyl-propoxy)-ter/-butyldimethylsilane (1.0 equiv), Cs2CO3 (2.5 equiv) dissolved in dry DMF (40 mL) and stirred under an inert atmosphere at 50 °C for 20-28 hours. To the reaction was added water (100 mL) and extraction using diethyl ether (3 x 150 mL). The combined organic layers were washed with brine (100 mL), dried over Na2S04, and concentrated followed by purification by CC (Heptane/EtOAc)
54

(S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-6-fluoro-4H-benzo[1.4]oxazin-3-one(1l1MF01)
[0213] 6-Fluoro-4#-benzo[l,4]oxazin-3-one (95MF88) (2.54 g, 15.2 mmol), (R)-3-bromo-2-methylpropoxy-ter/-butyldimethylsilane (4.07g, 15.2 mmol) and CS2CO3 (12.38 g, 38 mmol) were mixed according to GP7. CC (Si02; Heptane/EtOAc 9:1) gave the title compound (111MF01) (4.09 g, 76%). 1H NMR (CDC13) 5 6.93 - 6.87 (m, IH), 6.92 - 6.88 (m, IH), 6.68 - 6.63 (m, IH), 4.56 (m, 2H), 4.01 (m, IH), 3.78 (m, IH), 3.58 (m, IH), 3.45 (m, IH), 2.11 (m, IH), 0.92 (s, 12H), 0.06 (d, J= 0.8 Hz, 6H); 13C NMR (CDCI3) 8 164.8, 158.5 (d, J= 239.9 Hz), 141.6 (d, J= 2.7 Hz), 130.1 (d, J= 10.7 Hz), 117.6 (d, J= 9.3 Hz), 109.6 (d, J = 23.1 Hz), 103.6 (d, J = 28.8 Hz), 67.8, 65.9, 44.2, 34.5,26.0,18.4,14.9,-5.4,-5.4.
(S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-7-fluoro-4H-benzo[l,4]oxazin-3-one(lllMF14)
[0214] 7-Fluoro-4H-benzo[l,4]oxazin-3-one (111MF12) (2.52 g, 15.1 mmol), (S)-3-bromo-2-methylpropoxy-tert-butyldimethylsilane (4.03 g, 15.1 mmol) and CS2CO3 (12.3 g, 38 mmol) were mixed according to GP7. CC (SiO2; Heptane/EtOAc 9:1) gave the title compound (111MF14) (3.79 g, 71%). 1H NMR (CDCI3) 6 7.12 (dd, J= 5.2 Hz, J = 8.8 Hz, IH), 6.67 - 6.34 (m, 2H), 4.60 (q, J= 14.8 Hz, J= 25.4 Hz, 2H), 4.03 (dd, J= 8.4 Hz, J= 14.0 Hz, IH), 3.82 (dd, J= 5.6 Hz, J= 14.0 Hz, IH), 3.57 (dd, J= 4.8 Hz, J = 10.0 Hz, IH), 3.45 (dd, J= 7.0 Hz, J= 9.8 Hz, IH), 2.15 - 2.05 (m, IH), 0.93 - 0.89 (m, 12H), 0.06 (s, 6H); 13C NMR (CDC13) 8 164.1, 158.9 (d, J= 243.7 Hz), 146.4 (d, J= 11.6 Hz), 125.3 (d, J= 3.0 Hz), 116.4 (d, J= 9.6 Hz), 109.1 (d, J = 22.7 Hz), 105.1 (d, J= 25.8 Hz), 67.8, 66.0, 44.1, 34.5, 26.0, 18.4, 14.9, -5.3, -5.4.
(S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-6-methoxy-4H-benzo[l,4]oxazin-3-one (111MF32)
[0215] 6-Methoxy-4H-benzo[l,4]oxazin-3-one (111MF24) (2.7 g, 15.1 mmol), (S)-3-bromo-2-methylpropoxy-tert-butyldimethylsilane (4.03g, 15.1 mmol) and CS2CO3 (12.3 g, 38 mmol) were mixed according to GP7. CC (SiO2; Heptane/EtOAc 9:1) to give the title compound (111MF32) (4.03 g, 80%). ]H NMR (CDC13) d 6.89 (d, J= 8.8 Hz, IH), 6.71 (d, J= 2.8 Hz, IH), 6.50 (dd, J= 2.8 Hz, J= 8.6 Hz, IH), 4.53 (q, J= 14.8 Hz, J= 29.2 Hz, 2H), 3.98 (dd, J = 8.8 Hz, J= 14.0 Hz, IH), 3.85 (dd, J= 5.8 Hz, J =
55

14.2 Hz, IH), 3.77 (s, 3H), 3.57 (dd, J= 9.2 Hz, J= 10.0 Hz, IH), 3.47 (dd, J = 7.2 Hz, J = 10.0 Hz, IH), 2.20 - 2.12 (m, IH), 0.91 (s, 12H), 0.05 (d,J= 1.2 Hz, 6H); 13C NMR (CDC13) 5 165.3, 155.6, 139.7, 129.8, 117.2, 107.4, 103.3, 68.0, 66.2, 55.9, 43.9, 34.3, 26.1,18.5,14.7,-5.3,-5.4.
GENERAL PROCEDURE 8 (GP8)
[0216] To a 100 mL flask was charged 4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-4H-benzo[l,4]oxazin-3-one (1.0 equiv) and Tetrabutylammonium flouride monohydrate (1.3 equiv) and dissolved in 40 mL dry THF. The reaction was stirred in it under an inert atmosphere for 20-24 hours. The reaction mixture was concentrated and purified by CC (Heptane/EtOAc).
(S)-6-Fluoro-4-(3-hydroxy-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (111MF03)
[0217] The compound (S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-
methylpropyl]-6-fluoro-47/-benzo[l,4]oxazin-3-one (111MF01) (4.09 g, 11.6 mmol) and tetrabutylammonium flouride monohydrate (4.30 g, 15.4 mmol) were mixed according to GP8. CC (Si02; Heptane/EtOAc 4:1-4) gave the title compound (111MF03) (2.63 g, 95%). !H NMR (CDCI3) 5 6.92 (dd, J= 5.2 Hz, J =8.8 Hz, IH), 6.80 (dd, J= 2.8 Hz, J= 10.0 Hz, IH), 6.71 - 6.66 (m, IH), 4.59 (d, J= 0.8 Hz, 2H), 4.17 - 4.11 (m, IH), 3.58 -3.40 (m, 3H), 2.79 (s, IH), 2.08 - 1.96 (m, IH) 1.04 (d, J = 7.2 Hz, 3H); 13C NMR (CDCI3) 5 165.3, 158.4 (d, J= 238.44 Hz), 141.5 (d, J= 2.7 Hz), 129.5 (d, J= 10.4 Hz), 117.9 (d, J= 9.3 Hz),110.2 (d, J= 23.1 Hz), 103.1 (d, J= 28.4 Hz), 67.5, 63.85, 43.8, 34.0,14.9.
(S)-7-Fluoro-4-(3-hydroxy-2-methylpropyl-4H-benzo[1,4]oxazin-3-one (111MF18)
[0218] The compound (S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methy-propyl]-7-fluoro-4H-benzo[l,4]oxazin-3-one (111MF14) (3.79 g, 10.7 mmol) and tetrabutylammonium flouride monohydrate (3.99 g, 14.3 mmol) were mixed according to GP8. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF18) (2.57 g, 100%). 1H NMR (CDCI3) 8 6.99 - 6.95 (m, IH), 7.77 - 7.72 (m, 2H), 4.63 (m, 2H), 4.23 -4.16 (m, IH), 3.58 - 3.40 (m, 3H), 2.86 (s, IH), 2.05 - 1.97 (m, IH), 1.04 (d, J= 6.8 Hz, 3H); 13C NMR (CDCI3) 164.6, 159.2 (d, J= 244.5 Hz), 146.4 (d, J= 11.6 Hz), 124.9 (d, J
56

= 3.1 Hz), 115.9 (d, J= 9.6 Hz), 109.4 (d, J= 22.7 Hz), 105.3 (d, J= 26.1 Hz), 67.5, 63.8, 43.8,34.0,15.0.
(S)-4-(3-Hydroxy-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one (111MF34)
[0219] The compound (S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-
methylpropyl]-6-methoxy-4H/-benzo[l,4]oxazin-3-one (111MF32) (4.03 g, 12.0 mmol) and tetrabutylammonium flouride monohydrate (4.46 g, 16.0 mmol) were mixed according to GP8. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF34) (2.70 g, 100%). lK NMR (CDC13) 8 6.91 (d, J= 8.8 Hz, 1H), 6.63 (d, J= 2.8 Hz, 1H), 6.54 (dd, J= 2.8 Hz, J= 8.8 Hz, 1H), 4.57 (s, 2H), 4.19 (dd, J= 9.4 Hz, J= 14.6 Hz, 1H), 3.78 (s, 3H), 3.56 - 3.39 (m, 3H), 2.84 (s, 1H), 2.09 - 1.99 (m, 1H), 1.05 (d, J= 7.2 Hz, 3H); 13C NMR (CDC13) 165.8, 155.5, 139.5, 129.4, 117.4, 107.7, 103.0, 67.7, 63.8, 56.0, 43.6,34.1,15.0.
[0169] GENERAL PROCEDURE 9 (GP9)
[0220] A 250 mL flask was charged with 4-(3-hydroxy-2-methylpropyl)-4H-benzo[l,4]oxazin-3-one (1.0 equiv) dissolved in CHCI3 (100 mL). Then triphenylphosphine (2.2 equiv) and imidazole (2.4 equiv) was added. To the solution was added I2 (2.8 equiv) and the reaction was stirred in rt for 15 - 18 hours. The reaction mixture was quenched with Na2S2O3 (aqueous, sat) (100 mL). The phases were separated and the water phase washed with CH2Cl2 (150 mL). The combined organic layers were dried over Na2SO4, concentrated and purified by CC (Heptane/EtOAc).
(S)6-Fluoro-4-(3-iodo-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (111MF04)
[0221] The compound (S)-6-Fluoro-4-(3-hydroxy-2-methyl-propyl)-4H7-benzo[l,4]oxazin-3-one (111MF03) (2.63 g, 11.0 mmol), triphenylphosphine (6.35 g, 24.2 mmol), imidazole (1.8 g, 26.4 mmol) and I2 (7.81 g, 30.8 mmol) were mixed according to GP9. CC (Si02; Heptane/EtOAc 9:1-4) gave the title compound (111MF04) (3.86 g, 100 %). !H NMR (CDC13) 5 6.97 - 6.93 (m, 1H), 6.82 - 6.78 (m, 1H), 6.73 - 6.68 (m, 1H), 4.63 - 4.53 (m, 2H), 3.90 (d, J= 6.8 Hz, 2H), 3.20 - 3.16 (m, 2H), 2.15 - 2.04 (m, 1H), 1.06 (d, J= 6.4 Hz, 3H); 13C NMR (CDC13) 5 165.0, 158.5 (d, J = 240.2 Hz), 141.7 (d, J =2.3 Hz), 129.6 (d, J= 10.4 Hz), 118.1 (d,J=9.2Hz), 110.1 (d, J= 23.4 Hz), 103.1 (d,J= 28.7 Hz), 67.8, 46.3, 33.5, 18.9, 11.6.
57

(S)7-Fluoro-4-(3-iodo-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (111MF20)
[0222] The compound (S)-7-Fluoro-4-(3-hydroxy-2-methylpropyl)-4H-benzo[l,4]oxazin-3-one (111MF18) (2.57 g, 11.0 mmol), triphenylphosphine (6.61 g, 23.7 mmol), imidazole (1.76 g, 25.8 mmol) and I2 (7.64 g, 30.1 mmol) were mixed according to GP9. CC (SiO2; Heptane/EtOAc 9:1-4) gave the title compound (111MF20) (3.31 g, 89%). *H NMR (CDCI3) 5 7.00 - 6.96 (m, IH), 6.78 - 6.74 (m, 2H), 4.65 - 4.56 (m, 2H), 3.92 (d, J= 7.6 Hz, 2H), 3.21 - 3.13 (m, 2H), 2.13 - 2.03 (m, IH), 1.04 (d, J = 6.4 Hz, 3H); 13C NMR (CDCI3) 6 164.3, 159.0 (d, J= 244.4 Hz), 146.6 (d, J= 12.0 Hz), 125.0 (d, .7=3.0 Hz), 115.9 (d, .7=9.7 Hz), 109.4 (d,J= 22.5 Hz), 105.5 (d, J =26.0 Hz), 67.8,46.3,33.6,18.9,11.8.
(S)-4-(3-Iodo-2-methylpropyl)6-methoxy-4H-benzo[l,41oxazin-3-one (111MF36)
[0223] The compound (S)-4-(3-Hydroxy-2-methylpropyl)-6-methoxy-47/-benzo[l,4]oxazin-3-one (111MF34) (2.70 g, 12.0 mmol), triphenylphosphine (6.92 g, 26.4 mmol), Imidazole (1.96 g, 28.8 mmol) and I2 (8.53 g, 33.6 mmol) were mixed according to GP9. CC (SiO2; Heptane/EtOAc 9:1-4) gave the title compound (111MF36) (3.54 g, 82%). 1H NMR (CDCI3) 5 6.92 (d, J= 8.4 Hz, IH), 6.63 (d, J= 2.8 Hz, IH), 6.53 (dd, J= 2.8 Hz, J = 8.8 Hz, 1H),4.54 (q, J= 14.8 Hz, J = 23.6 Hz, 2H), 3.92 (d, 7= 7.4 Hz, 2 H), 3.80 (s, 3H), 3.18 (dd, J= 1.0 Hz, J= 6 Hz, 2H), 2.17 - 2.08 (m, IH), 1.05 (d, J = 6.8 Hz, 3H); 13C NMR (CDCI3) 8 165.4, 155.6, 139.6, 129.4, 117.7, 108.0, 102.5, 68.0, 56.1,46.1,33.6,18.9,12.0.
(S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-6-methyl-4H-benzo[1.4]oxazin-3-one (101IS60-1)
[0224] A dry 50 mL r-flask was charged with 6-Methyl-4H-benzo[l,4]oxazin-3-one (0.59 g, 3.6 mmol), (i?)-(3-bromo-2-methylpropoxy)-tert-butyldimethylsilane (1.0 g, 3.6 mmol), CS2CO3 (2.9 g, 8.9 mmol) and 10 mL of dry DMF. The mixture was stirred at 50 °C overnight (15 h) and dissolved in ether (50 mL) washed with water (20 mL) and the water phase was extracted with ether (20 mL). The combined organic phases were then washed with brine, dried (Na2SO4), filtered, concentrated under reduced pressure and the resulting oil was purified by flash chromatography (SiO2; Heptane/EtOAc 85:15) to
58

yield the title compound as an oil (1.1 g, 88 %). !H NMR (CDC13) 8 6.87 (d, 7= 1.6 Hz, IH), 6.81 (d, J= 8.0 Hz, IH), 6.72 (dm, J= 8.0 Hz, IH), 4.5 (bars, 2H), 3.93 (dd, J= 8.8, 14.0 Hz, IH), 3.81 (dd, J= 5.6, 14.0 Hz, IH), 3.53 (dd, J= 4.8, 10.2 Hz, IH), 3.41 (dd J = 7.2, 10.2 Hz, IH), 2.25 (s, 3H), 2.18 (m, IH), 0.87 (s, 9H), 0.83 (d, J = 6.8 Hz, 3H), 0.01 (s, 6H); 13C NMR (CDCI3) 8 170.5, 148.9, 137.8, 129.6, 122.2, 121.6, 73.3, 71.6, 49.0, 39.7, 31.5,26.6, 23.8, 20.1, 0.0.
(S)-4-(3-Hydroxy-2-methylpropyl)6-methyl-4H-benzo[1,4]oxazin-3-one(101IS60-2)
[0225] The compound (S)-4-[3-(tert-butyldimethylsilanyloxy)-2-
methylpropyl]-6-methyl-4H-benzo[l,4]oxazin-3-one (101IS60-1) (1.0 g, 2.9 mmol) was dissolved in dry THF (12 mL) and TBAF (1.2 g, 3.8 mmol) was added. The reaction was stirred at rt overnight and the solution was concentrated under reduced pressure, the remaining oil was diluted with EtOAc (60 mL) and washed with brine (3x30 mL), dried (Na2S04) filtered and concentrated under reduced pressure. The remaining oil was purified by flash chromatography (SiO2; Heptane/EtOAc 30:70) to yield an oil which crystallized upon standing (0.69 g, 76 %). 'H NMR (CDCI3) 8 6.88 (d, J= 8.4 Hz, IH), 6.83-6.78 (m, 2H), 4.59 (brs 2 H), 4.22 (dd J= 10.0, 14.4 Hz), 3.57-3.38 (m, 3H), 2.9 (vbrs, IH), 2.33 (s, 3H), 2.04 (m, IH), 1.08 (d, J= 7.2 Hz); 13C NMR (CDC13) 8 165.7, 143.4,132.3, 124.9,117.1, 115.9,67.6,63.7,43.5,34.2,21.3,15.1.
(S)-4-(3-Iodo-2-methylpropyl)6-methyl-4H-benzo[1,4]oxazin-3-one(101IS70)
[0226] A dry 50 mL r-flask was charged with (5)-4-(3-hydroxy-2-methylpropyl)-6-rnethyl-4#-benzo[l,4]oxazin-3-one (1.0 g, 4.2 mmol), PPh3 (2.2 g, 8.5 mmol), imidazole (0.58 g, 8.5 mmol) and dissolved with CH2CI2 (25 mL). Iodine (2.2 g, 8.4 mmol) was then added in small portions over 4h period. After the last addition the reaction was poured onto SiO2 and filtered. Concentration under reduced pressure yielded the crude title compound (1.5 g), which was used without further purification.
l-(3-Chloropropyl)-3,4-dihydro-lH-quinolin-2-one(85LM31)
[0227] A 50 mL flask was charged with 3,4-dihydro-lH-quinolin-2-one (2.00 g, 13.6 mmol) and sodium hydride (60% in oil, 0.712 g, 16.3 mmol) in DMF (50 mL, dry) and stirred at 0 °C for 1 h, followed by addition of l-chloro-3-iodo-propane (2.77 g, 13.6
59

mmol) and stirring at rt for 20 h. The reaction mixture was quenched with water (10 mL), and the product was extracted into EtOEt (3 x 25 mL). The combined organic layers were dried (Na2S04), evaporated and purified by flash CC (Si02; EtOAc/heptane 1:4) to give the crude title compound (85LM31) (2.25 g). *H NMR (CDC13) 8 7.29 - 7.22 (m, 1H), 7.17 (d, J= 7.4 Hz, 1H), 7.08 - 6.98 (m, 2H), 4.10 (t, J = 7.3 Hz, CH2), 3.62 (t, J= 5.9 Hz, CH2), 2.88 (t, J= 7.3 Hz, CH2), 2.63 (t, J= 7.3 Hz, CH2), 2.19 - 2.10 (m, 2H); 13C NMR (CDCI3) 8 170.5, 140.0, 128.2, 127.8, 126.3, 123.2, 115.0, 43.3, 40.2, 32.2, 30.5, 26.0.
1 –(3-Chloropropyl-6-fluoro-3.4-dihydro- lH-quinolin-2-one (92LH79)
[0228] A reaction flask was charged with 6-fluoro-3,4-dihydro-lH-quinolin-2-one (0.180 g, 1.09 mmol) in dry DMF (2 mL) under Argon. NaH (60% in oil, 0.048 g, 1.20 mmol) was added and the mixture was stirred at rt for 0.5 h. Then l-bromo-3-chloropropane (0.180 g, 1.14 mmol) was added followed by stirring at rt for 20 h. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2SC>4, filtered, and concentrated. The product was purified by flash CC (Si02; DCM) to give the title compound (92LH79) (0.193 g, 73%). ' H NMR (CDCI3) 8 7.02 - 6.88 (m, 3H), 4.09 - 4.05 (m, 2H), 3.61 (t, J= 6.3 Hz, CH2), 2.87 (t, J= 6.7 Hz, CH2), 2.65 - 2.61 (m, 2H), 2.16 - 2.09 (m, 2H); 13C NMR (CDCI3) 8 169.8, 158.4 (J= 242.9 Hz), 135.7 (J= 2.7 Hz), 128.5 (J= 7.7 Hz), 115.7 (J = 8.1 Hz), 115.1 (J= 22.7), 113.8 (J= 22.3 Hz), 42.6, 40.3, 31.5, 30.1,25.5.
(R,S)-l-(3-Chloro-2-methylpropyl-6-fluoro-3,4-dihydro-lH-quinolin-2-one(107LH68)
[0229] A reaction flask was charged with 6-fluoro-3,4-dihydro-l/7-quinolin-2-one (0.496 g, 3.0 mmol) in dry DMF (3 mL) under Argon. NaH (60% in oil, 0.132 g, 3.3 mmol) was added and the mixture was stirred at rt for 45 min. Then (R,S)-l-bromo-3-chloro-2-methylpropane (0.513 g, 3.0 mmol) was added followed by stirring at rt for 20 h. The reaction mixture was quenched with water, and the product extracted into EtO Ac. The combined organic layers were dried over Na2S04, filtered, and concentrated. The crude product was purified by flash CC (Si02; EtOAc/n-heptane 1:1) to give the crude title compound (107LH68) (0.308 g).
60

1 –(3-Chloropropyl)-6-methyl-3.4-dihydro-1 H-quinolin-2-one (107LH14)
[0230] A reaction flask was charged with 6-methyl-3,4-dihydro-lH-quinolin-2-one (107LH05) (0.300 g, 1.26 mmol) in dry DMF (5 mL) under Argon. NaH (60% in oil, 0.055 g, 1.38 mmol) was added and the mixture was stirred at rt for 1 h. Then 1-bromo-3-chloropropane (0.198 g, 1.24 mmol) was added followed by stirring at rt for 20 h. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. The crude product was purified by flash CC (SiO2; DCM) to give the crude title compound (107LH14) (0.257 g).
1-(3-Chloropropyl)-7-fluoro-6-methyl-3.4-dihydro-lH-quinolin-2-one (112KK01)
[0231] A reaction flask was charged with 7-fluoro-6-methyl-3,4-dihydro-lH-quinolin-2-one (97KK40) (0.102 g, 0.57 mmol) in dry DMF (5 mL) under an argon atmosphere. Washed NaH (0.015 g, 0.63 mmol) was added and the mixture was stirred at rt for 1 h. Then l-chloro-3-iodopropane (0.104 g, 0.51 mmol) dissolved in DMF (1 mL) was added followed by stirring at rt for 20 h. The reaction mixture was quenched with water, and the product extracted into Et20. The combined organic layers were washed with aqueous 4% MgSO4, dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (Si02; DCM/n-heptane 2:1, DCM, MeOH/DCM 1:10) to give the title compound (112KK01) (0.050 g, 38%). ' H NMR (CDC13) 5 6.95 - 6.93 (m, 1H), 6.73 (d, J = 11.5 Hz, 1H), 4.03 - 4.00 (m, 2H), 3.59 (t, J = 6.5 Hz, CH2), 2.83 - 2.79 (m, 2H), 2.62 - 2.58 (m, 2H), 2.20 (d, J= 1.8 Hz, CH3), 2.13 - 2.07 (m, 2H).
l-(3-Chloropropyl)-6.7-difluoro-3.4-dihydro-lH-quinolin-2-one(1l2KK03)
[0232] A reaction flask was charged with 6,7-difluoro-3,4-dihydro-lH-quinolin-2-one (97KK47) (0.181 g, 0.99 mmol) in dry DMF (5 mL) under an argon atmosphere. Washed NaH (0.026 g, 1.08 mmol) was added and the mixture was stirred at rt for 0.5 h. Then 3-chloro-l-iodopropane (0.205 g, 1.00 mmol) dissolved in DMF (1 mL) was added followed by stirring at rt for 20 h. The reaction mixture was quenched with water, and the product extracted into Et20. The combined organic layers were washed with aqueous 4% MgSO4, dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; DCM) to give the title compound (112KK03) (0.122 g, 47%).
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1 H NMR (CD3OD) 5 6.99 - 6.86 (m, 2H), 4.03 - 3.99 (m, 2H), 3.60 (t, J= 6.1, CH2), 2.84-2.81 (m, 2H), 2.63-2.59 (m, 2H), 2.13-2.06 (m, 2H).
l-(3-Chloropropyl)5-methyl-3.4-dihydro-lH-quinolin-2-one and l-(3-Chloropropyl)-7-methyl-3,4-dihydro-1 H-quinolin-2-one
[0233] Neat 2-chloro-N-m-tolylacetamide (92LH85) (1.7 g, 8.5 mmol) was heated to 135 °C and AICI3 (3.4 mg, 26 mmol) was added under an Argon atmosphere, in small portions, during 30 min. The reaction was allowed cool to 60 °C and then HC1 (10 mL, 4 M) was added. The mixture was extracted with EtOAc (2 x 30 mL) and the combined organic phase was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2; CH2CL2/MeOH 9:1) to yield The compound 7-Methyl-3,4-dihydro-lH-quinolin-2-one and 5-Methyl-3,4-dihydro-lH-quinolin-2-one (1.1 g). This mixture was dissolved in dry DMF(8 mL) and NaH (60% in oil, 310 mg, 7.7 mmol) was added and the solution was stirred under a N2 atmosphere at rt for 45 min. Thereafter, l-bromo-3-chloropropan was added and the reaction was stirred overnight at rt. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (10 mL). The organic phase was dried over Na2SO4 filtered, concentrated under reduced pressure and the residue was purified by prep RP-HPLC to yield l-(3-chloropropyl)-5-methyl-3,4-dihydro-lH-quinolin-2-one (0.057 g, 3%) and l-(3-chloropropyl)-7-methyl-3,4-dihydro-lH-quinolin-2-one (0.12 g, 6%). l-(3-Chloropropyl)-5-methyl-3,4-dihydro-lH-quinolin-2-one, (107LH27-11.7). Retention time =11.7 min. *H NMR (CD3OD) 8 7.12 (vbrt, 7.7 Hz, 1H), 6.98 (d, J= 8.0 Hz, 1H), 6.90 (d, J = 7.2 Hz, 1H), 4.09-4.02 (m, 2H), 3.59 (t, J= 6.4 Hz, 2H), 2.85-2.78 (m, 2H), 2.58-2.50 (m, 2H), 2.27 (s, 3H), 2.10-2.01 (m, 2H); 13C NMR (CD3OD) 8 171.5, 139.2, 135.9, 126.9, 125.4, 125.3, 113.1, 42.2, 40.1, 31.1, 30.3, 21.2, 18.5. l-(3-Chloropropyl)-7-methyl-3,4-dihydro-lH-quinolin-2-one, (107LH27-13.1). Retention time = 13.1 min. lH NMR (CD3OD) 8 7.02 (brd, J= 7.6 Hz, 1H), 6.94 (brs, 1H), 6.81 (brd, J= 7.6 Hz, 1H), 4.03 (brt, J= 7.2 Hz, 2H), 3.58 (t, J= 6.2 Hz, 2H), 2.78 (t, J= 1A Hz, 2H), 2.51 (t, J= 1A Hz), 2.30 (s, 3H), 2.09-2.00 (m, 2H); 13C NMR (CD3OD) 8 171.6, 139.0, 137.4, 127.8, 123.9, 115.7, 42.3, 39.8, 31.7, 30.3,24.6,20.4.
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(S)-l-[3-(t-Butyldimethylsilanyl)-2-methylpropyl-3,4-dihydro-lH-quinolin-2-one (122LH13)
[0234] A reaction flask was charged with 3,4-dihydro-lH-quinolin-2-one (1.60 g, 10.9 mmol) in dry DMF (30 mL) under Argon. NaH (60% in oil, 0.480 g, 12.0 mmol) was added and the mixture was stirred at rt for 1 h. Then (i?)-(3-bromo-2-methylpropoxy)-/-butyldimethylsilane (3.0 g, 10.9 mmol) was added followed by stirring at rt for 4 days. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. The product was purified by flash CC (Si02; DCM) to give the title compounds (122LH13) (2.685 g, 74%).
(S)-1 -(3-Hydroxy-2-methylpropyl-3.4-dihydro-1 H-quinolin-2-one (122LH16)
[0235] A reaction flask was charged with (S)-l-[3-(t-Butyldimethylsilanyl)-2-methylpropyl]-3,4-dihydro-lH-quinolin-2-one (122LH13) (2.685 g, 8.05 mmol) and tetrabutylammonium fluoride (2.70 g, 10.3 mmol) in dry THF (20 mL) and stirred at rt for 20 h under an Argon atmosphere. The reaction mixture was concentrated, and the product purified by flash CC (Si02; n-heptane/EtOAc 1:1) to give the title compound (122) (1.54 g, 87%).
(S)-1 -(3-Iodo-2-methylpropyl) 3.4-dihydro-1H-quinolin-2-one (122LH18)
[0236] A reaction flask was charged with (5)-l-(3-Hydroxy-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (122LH16) (1.54 g, 7.0 mmol) dissolved in 50 mL DCM. PPI13 (4.04 g, 15.4 mmol) and imidazole (1.14 g, 16.7 mmol) were added followed by stirring at rt for 15 min. The mixture was cooled with an ice-bath followed by addition of I2 (5.00 g, 19.7 mmol). The reaction mixture was slowly warmed to rt and stirred over night. The reaction mixture was washed with a Na2S2O3 solution, dried over Na2S04, and concentrated. The product was purified by flash CC (Si02; n-heptane/EtOAc 1:1) to give the title compound (122LH18) (2.140 g, 93%).
1 -(3-Chloropropyl-1 #-quinolin-2-one (107LH80).
[0237] A 7 mL vial was charged with lH-quinolin-2-one (0.62 g, 4.2 mmol), 4 mL dry DMF and NaH (60% in oil, 0.200 g, 5.1 mmol). The mixture was stirred under a N2 atmosphere at rt for 45 min, and thereafter l-bromo-3-chloropropane (0.42 mL, 4.2
63

mmol) was added and the reaction was stirred at rt overnight. The reaction was diluted with EtOAc (50 mL) and washed with water (15 mL). The water phase was extracted with EtOAc (25 mL) and the combined organic phase was dried (Na2S04), filtered, concentrated under reduced pressure and the residue was purified by flash chromatography (SiC^; CH2CI2) to yield the title compound (0.38 g, 41%), containing 15% of l-(3-bromopropyl)-1H-quinolin-2-one. *H NMR (CD3OD) 5 7.90 (d, J= 9.4 Hz, 1H), 7.73-7.57 (m, 3H), 7.34-7.28 (m, 1H), 6.66 (d, J= 9.4 Hz), 4.46 (t, J= 7.4 Hz, 2H), 3.71 (t, J= 6.4 Hz, 2H), 2.21-2.02 (m, 2H); 13C NMR (CD3OD) 8 163.2, 140.7, 138.8, 131.3,129.3, 122.8,121.4, 120.2,114.4,42.18,40.2,30.5.
l-(3-Chloropropyl-5-metyl-lH-quinolin-2-one, (107LH39).
[0238] A microwave vial was charged with l-(3-chloropropyl)-5-methyl-3,4-dihydro-1H-quinolin-2-one (0.081 g, 0.34 mmol), DDQ (0.116 g, 0.51 mmol), dioxane (2 mL) and sealed. After microwave irradiation, 175 °C, 10 min, the reaction was diluted with EtOAc (50 mL), washed with sat aqueous NaHCO3 (2 x 15 mL) and the organic phase was dried (Na2S04), filtered, concentrated under reduced pressure and the residue was purified with prep RP-HPLC to yield the crude title compound (0.053 g), which was used without further purification. HPLC-MS (ammonium acetate) [M+H]+ = 236.2.
l-(3-Chloropropyl-7-methyl-lH-quinolin-2-one('107LH40)
[0239] A microwave vial was charged with l-(3-chloropropyl)-7-methyl-3,4-dihydro-1H-quinolin-2-one (0.21 g, 0.88 mmol), DDQ (0.30 g, 1.3 mmol), dioxane (4 mL) and sealed. After microwave irradiation, 175 °C, 10 min, the reaction was diluted with EtOAc (50 mL), washed with sat aqueous NaHC03 (2 x 15 mL) and the organic phase was dried over Na2S04, filtered, and concentrated under reduced pressure. The residue was purified with prep RP-HPLC to yield the crude title compound (0.130 g), which was used without further purification. HPLC-MS (ammonium acetate) [M+H]+ -236.2.
(S)-1-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-1 H-quinolin-2-one (107LH43)
[0240] lH-Quinolin-2-one (1.9 g, 13 mmol) and NaH (60% in oil, 0.58 g, 15 mmol) were added to dry DMF (30 mL) and the reaction was stirred under a N2
64

atmosphere at rt for 45 min. Thereafter, (i?)-(3-bromo-2-methylpropyl)-tert-butyldimethylsilane (3.7 g, 13 mmol) was added and the reaction was stirred for 72 h at 50 °C. The reaction was poured onto water and extracted with EtOAc (2 x 50 mL) and the combined organic phase was dried, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (Si02; CH2CI2) to yield the title compound (2.10 g, 6.4 mmol, 48%). !H NMR (CDC13) 8 7.60-7.53 (m, 2H), 7.49-7.40 (m, 2H), 7.12 (dt, J= 0.9, 7.6 Hz, 1H), 6.62 (d, J= 9.6 Hz, 1H), 4.39 (dd, J= 8.4, 14.0 Hz, 1H), 4.15 (dd, J= 5.4, 14.0 Hz), 3.54 (dd, J= 4.4, 10.2 Hz, 1H), 3.45 (dd, J= 7.6, 10.2 Hz), 2.27-2.12 (m, 1H), 0.88 (s, 12 H), 0.01 (s, 6 H); 13C NMR (CDCI3) 8 168.2, 145.2, 144.5, 135.8, 134.3, 127.3, 127.2, 126.4,120.5, 71.7, 50.4,40.9, 31.4,23.8, 20.4, 0.0.
(S)-1-(3-Hydroxy-2-methylpropyl)-1H-quinolin-2-one (107LH62)
[0241] TBAF (1.2 g, 4.6 mmol) and (S)-1-[3-(tert-butyldimethylsilanyloxy)-2-methylpropyl]-lH-quinolin-2-one (0.31 g, 0.93 mmol) were dissolved in THF (5 mL) and stirred under an Argon atmosphere at rt overnight. The mixture was concentrated under reduced pressure and dissolved in EtOAc (30 mL). The solution was washed with water (15 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue thereof was filtered through silica to give the crude title compound (0.19 g), which was used without further purification.
(S)-1 –[3-Iodo-2-methylpropyl) 1 H-quinolin-2-one (107LH64)
[0242] Imidazole (0.14 g, 2.1 mmol), crude (5)-l-(3-hydroxy-2-methyl-propyl)-lH-quinolin-2-one (0.19 g, 0.87 mmol) and PPh3 (0.50 g, 1.9 mmol) were dissolved in CH2CI2 (5 mL) and the solution was cooled to 0 °C, thereafter I2 (0.61 g, 2.4 mmol) was added and the reaction reached rt overnight. The reaction diluted with CH2CI2 (25 mL) and washed with sat aqueous Na2SO4 (2 x 25 mL) and the organic phase was dried over Na2SC>4, filtered, concentrated under reduced pressure to yield the crude product that was used without further purification. HPLC-MS (ammonium acetate) [M+H]+ = 328.1.
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GENERAL PROCEDURE 10 (GP10)
[0243] A 4 mL vial was charged with the appropriate heterocycle (1 equiv) and the appropriate piperidine (1.2 or 2 equiv) in dry MeCN (1/2 mL) and shaken. The reaction mixture was quenched with water (1 mL), and the product extracted into EtOAc (2 x 1 mL). The combined organic layers were purified by cation exchange CC and by flash CC.
(R)-4-[3-(4-Butylpiperidin-l-yl)-2-methylpropyl-4H-benzo[1,41thiazin-3-one(108LM43-40}
[0244] The compound (S)-4-(3-Iodo-2-methyl-propyl]-4H-benzo[l,4]thiazin-3-one (108LM37-34) (0.105 g, 0.304 mmol) and 4-butyl-piperidine (0.052 g, 0.369 mmol) in MeCN (lA mL) were reacted according to GP10 shaking at 60 °C for 3 days. Purified by cation exchange CC and flash CC (Si02; MeOH/DCM 1:20) to give the title compound (108LM43-40) (0.082 g, 75%). *H NMR (CDC13) 5 7.34 (d, J= 9.1 Hz, 1H), 7.25-7.17 (m, 2H), 7.02-6.95 (m, 1H), 4.15-3.99 (m, 2H), 3.35 (s, CH2), 2.83 (bd, J= 10.4 Hz, 1H), 2.68 (bd, J= 10.4 Hz, 1H), 2.20-2.05 (m, 2H), 2.00-1.85 (m, 2H), 1.82-1.73 (m, 1H), 1.67-1.55 (m, 2H), 1.30-1.14 (m, 9H), 0.88 (t, J= 7.2, CH3), 0.82 (d, J- 6.5 Hz, CH3); 13C NMR (CDCI3) 5 166.0, 139.2, 128.8, 127.1, 124.8, 123.5, 118.9, 63.8, 55.5, 54.4, 47.7, 36.6, 36.1, 32.9, 32.8, 32.1, 29.4, 29.3, 23.2, 16.7, 14.4; HPLC-MS (ammonium acetate) [M+H]+=361.3.
(RV4- [2-Methyl-3 -("4-propoxypiperidin-1 - vDpropyl] -4H-benzo [1.4] thiazin-3 -one (108LM49-46)
[0245] The compound (S)-4-(3-Iodo-2-methyl-propyl]-4#-benzo[l,4]thiazin-3-one (108LM37-34) (0.433 g, 1.25 mmol) and 4-propoxypiperidine (79KS66) (0.225 g, 1.55 mmol) in MeCN QA mL) were reacted according to GP10 shaking at 60 °C for 4 days. Purified by cation exchange CC and flash CC (Si02; MeOH/DCM 1:20) to give the title compound (108LM49-46) (0.220 g, 49%). lH NMR (CDCI3) 8 7.37 (d, J= 8.1 Hz, 1H), 7.25 - 7.20 (m, 2H), 7.05 - 6.97 (m, 1H), 4.18 - 4.00 (m, 2H), 3.42 - 3.35 (m, 4H), 3.30 - 3.20 (m, 1H), 2.80 - 2.70 (m, 1H), 2.65 - 2.55 (m, 1H), 2.20 - 2.05 (m, 3H), 2.00 -1.82 (m, 4H), 1.62 - 1.50 (m, 4H), 0.92 (t, J= 7.4, CH3), 0.82 (d, J= 6.8 Hz, CH3), 13C NMR (CDCI3) 5 166.1, 139.2, 128.8, 127.1, 124.9, 123.5, 118.8, 75.5, 69.8, 63.3, 52.7,
66

51.9, 47.6, 32.1, 32.0, 29.6, 23.5, 16.6, 10.9; HPLC-MS (ammonium acetate) [M+H]+=363.3.
(R)-4- [3 –( 4-Butylidene-piperidin-1 –yl)-2-methyl-propyl] -4H-benzo [ 1,41 thiazin-3 -one (l08LM50-47)
[0246] The compound (S)-4-(3-Iodo-2-methyl-propyl]-4H-benzo[l,4]thiazin-3-one (108LM37-34) (0.432 g, 1.25 mmol) and 4-butylidenepiperidine (111MF05) (0.208 g, 1.49 mmol) in MeCN (1/2 mL) were reacted according to GP10 shaking at 60 °C for 4 days. Purified by cation exchange CC and flash CC (Si02; MeOH/DCM 1:20) to give the title compound (108LM50-47) (0.267 g, 60%). 1H NMR (CDC13) 8 7.35 (d, J= 7.5 Hz, 1H), 7.26 - 7.18 (m, 2H), 6.98 (t, J= 7.5 Hz, 1H), 5.10 (t, J= 7.4 Hz, CH), 4.17 - 4.03 (m, 2H), 3.36 (s, CH2), 2.43 - 2.33 (m, 2H), 2.30 - 2.08 (m, 8H), 2.00 - 1.90 (m, 3H), 1.28 -1.38 (m, 2H), 0.90 - 0.80 (m, 6H); 13C NMR (CDC13) 5 166.0,139.2, 136.4,128.8,127.1, 124.8, 123.5, 122.7, 118.8, 63.4, 56.4, 55.6, 47.7, 36.4, 32.1, 29.5, 29.4, 28.6, 23.4, 16.7, 14.0; HPLC-MS (ammonium acetate) [M+H]+=359.3.
(R)-4-[3-(3-Butyl-8-aza-bicyclo[3.2.1]oct-8-yl-2-methyl-propyl]-4H-benzo[1,4]thiazin-3-one(108LM51-48)
[0247] The compound (5)-4-(3-Iodo-2-methyl-propyl)-4H/-benzo[l,4]thiazin-3-one (108LM37-34) (0.093 g, 0.269 mmol) and 3-butyl-8-aza-bicyclo[3.2.1]octane (104KS29) (0.054 g, 0.323 mmol) in MeCN (1/2 mL) were reacted according to GP10 shaking at 40 °C for 5 days. Purified by cation exchange CC and flash CC (Si02; MeOH/DCM 1:10) to give the title compound (108LM51-48) (0.042 g, 40%). *H NMR (CDCI3) 5 7.38 (d, J= 7.8 Hz, 1H), 7.33 (d, J= 8.1 Hz, 1H), 7.22 (t, J= 7.9 Hz, 1H), 7.00 (t, J= 8.0 Hz, 1H), 4.18-4.10 (m, 2H), 3.38 (s, CH2), 3.15 - 3.00 (m, 2H), 2.30 - 2.22 (m, 1H), 2.20 - 2.10 (m, 1H), 1.90 - 1.75 (m, 3H), 1.60 - 1.40 (m, 5H), 1.40 - 1.15 (m, 8H), 0.90-0.82 (m, 6H); 13C NMR (CDCI3) 5 166.1, 139.2, 128.7, 127.2, 124.7, 123.5, 119.1, 61.4, 60.1, 57.3, 47.6, 38.3, 36.9, 32.1, 31.2, 29.9, 29.4, 28.2, 27.2, 26.5, 23.1, 16.7, 14.3; HPLC-MS (ammonium acetate) [M+H]+=387.3.
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(R)-4-[2-Methyl-3-(3-pentyl-8-aza-bicyclo[3.2.1]oct-8-vl)propyl]-4H-benzo[1,4]thiazin-3-one(108LM52-49)
[0248] The compound (5)-4-(3-Iodo-2-methylpropyl]-4H/-benzo[ 1,4]thiazin-3-one (108LM37-34) (0.080 g, 0.231 mmol) and 3-pentyl-8-azabicyclo[3.2.1]octane (104KS32-2) (0.050 g, 0.276 mmol) in MeCN 1/2 mL) were reacted according to GP10 shaking at 40 °C for 5 days. Purified by cation exchange CC and flash CC (SiO2; MeOH/DCM 1:50 + 1% Et3N) to give the title compound (108LM52-49) (0.045 g, 49%). 'H NMR (CDC13) 8 7.36 (d, J= 7.6 Hz, IH), 7.32 (d, J= 1.1 Hz, IH), 7.22 (t, J= 7.6 Hz, IH), 7.00 (t, J = 7.6 Hz, IH), 4.16 (d, J= 7.3 Hz, CH2), 3.34 (s, CH2), 3.10 - 2.95 (m, 2H), 2.25 - 2.17 (m, IH), 2.15 - 2.03 (m, 3H), 1.94 - 1.75 (m, 3H), 1.70 - 1.60 (m, IH), 1.60 - 1.50 (m, 2H), 1.40 -1.15 (m, 10H), 0.90 - 0.80 (m, 6H); 13C NMR (CDCI3) 8 166.1, 139.2, 128.7, 127.1, 124.7, 123.4, 119.1, 60.5, 59.0, 57.4, 47.5, 38.4, 36.4, 32.2, 32.1, 31.4, 29.9, 28.5, 28.4, 27.9, 27.2, 22.9, 16.7, 14.3; HPLC-MS (ammonium acetate) [M+H]+=401.3.
GENERAL PROCEDURE 11 (GP11)
[0249] A 100 mL flask was charged with 4-(3-chloropropyl)-4H-benzo[l,4]oxazin-3-one (1.0 equiv), K2CO3 (2.0 equiv), Nal (2.0 equiv) and 4-Butylpiperidine (1.05 equiv) in 25 mL dry MeCN and stirred at rt for 168 h under N2 atmosphere. The reaction mixture was evaporated to dryness and diluted with 100 mL H20 and extracted into EtOAc (3 x 120 mL). The combined organic layers were dried over MgSO4, evaporated to dryness, and purified by CC (Heptane:EtOAc or CH2Cl2:MeOH).
4- [3 -(4-Butylpiperidin-1-vl)propyl] -6,8-dichloro-7-methyl-4H/-benzo[1.4]oxazin-3 -one (81MF2225F)
[0250] 6,8-Dichloro-4-(3-chloropropyl)-7-methyl-4H/-benzo[ 1,4] oxazin-3-one (81MF2225b), (2.44 g, 7.92 mmol), K2C03 (2.19 g, 15.84 mmol), Nal (2.37 g, 15.84 mmol) and 4-butylpiperidine (1.172 g, 8.3 mmol) were mixed according to GPU. CC (Si02; Heptane/EtOAc 10:1-4) gave the title compound (81MF2225F) (1.55 g, 47%). lH NMR (CDCI3) 8 7.11 (s, IH), 4.65 (s, 2H), 3.93 (t, 2H), 2.86, (d, 2H), 2.41 (s, 3H), 2.41 (s, 3H), 2.33 (t, 2H), 1.92 - 1.77 (m, 4H), 1.65 (d, 2H), 1.31 - 1.19 (m, 9H), 0.88 (t, 3H);
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13C NMR (CDCI3) 5 163.5, 140.5,129.9, 128.1, 123.7,114.0, 67.9, 55.8, 54.4, 40.1, 36.4, 36.0, 32.6,29.2, 24.8,23.1, 17.2,14.2.
[0251] To the pure compound (0.235 g, 0.50 mmol) dissolved in diethyl ether (4 mL) was added oxalic acid (0.047 g, 0.52 mmol) in diethyl ether (2 mL). The formed crystals filtered and washed with diethyl ether to give the title compound as oxalic salt (0.24 g, 94%); HPLC-MS (ammonium acetate) [M+H]+= 413.2
4-[3-(4-Butyl-piperidin-l-yl)propyl]-6.8-dimethyl-4H-benzo[l,4]oxazin-3-one (81MF2237F)
[0252] 4-(3-Chloropropyl)-6,8-dimethyl-4H7-benzo[1,4]oxazin-3-one (81MF2237b) (0.96 g, 3.78 mmol), K2C03 (1.05 g, 7.57 mmol), Nal (1.14 g, 7.57 mmol) and 4-butylpiperidine (0.56 g, 3.97 mmol) were mixed according to GPU. CC (Si02; Heptane/EtOAc 10:1-4) gave the title compound (81MF2237F) (0.98 g, 72%). 'H NMR (CDCI3) 8 6.71 (s, 1H), 6.65 (s, 1H), 4.52 (s, 2H), 3.93 (t, J= 7.2,2H), 2.87 (d, J= 11.2,2 H), 2.36 (t, J= 7.2 Hz, 2H), 2.27 (s, 3H), 2.18 (s, 3H), 1.81-1.89 (m, 4H), 1.65 (d, J= 9.6 Hz, 2H), 1.28 - 1.17 (m, 9H), 0.87 (t, J= 6-8 Hz, 3H); 13C NMR (CDCI3) 5 164.6, 141.4, 131.6,128.3,126.3,126.1, 113.4, 67.8, 56.1, 54.3, 39.8, 36.4, 35.9, 32.7,29.1,25.0, 23.0, 21.1,15.5,14.2.
[0253] To the pure compound (0.193 g, 0.54 mmol) dissolved in diethyl ether (4 mL) was added oxalic acid (0.051 g, 0.57 mmol) in diethyl ether (2 mL). The formed crystals filtered and washed with diethyl ether to give the title compound as oxalic salt (0.22 g, 91%); HPLC-MS (ammonium acetate) [M+H]+= 359.3
6-tert-Butyl-4- [3 -(4-butyl-piperidin-1-yl)propyl]-4H-benzo [1,4] oxazin-3 -one (81MF2248F)
[0254] 6-tert-Butyl-4-(3-chloropropyl)-4H-benzo [ 1,4] oxazin-3 -one (81MF2248b) (1.39 g, 4.93 mmol), K2C03 (1.36 g, 9.85 mmol), Nal (1.48 g, 9.85 mmol) and 4-butylpiperidine (0.73 g, 5.17 mmol) were mixed according to GPU. CC (SiC^; Heptane/EtOAc 10:1-4) gave the title compound (81MF2248F) (1.66 g, 87%). lH NMR (CDCI3) 5 7.01 - 6.98 (m, 2H), 6.91 - 6.88 (m, 1H), 4.55 (s, 2H), 3.99 (t, J= 7.2 Hz, 2H), 2.89 (d, J= 6.4 Hz, 2H), 2.42 (t, J= 6.8 Hz, 2H), 1.92 - 1.82 (m, 4H), 1.65 (d, J= 9.6 Hz 2H), 1.31 (s, 9H), 1.29 - 1.17 (m, 9H), 0.88 (t, J= 6.8 Hz, 3H); 13C NMR (CDC13) d
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164.6, 146.1, 143.3, 128.1, 120.6, 116.6, 112.2, 67.9, 56.5, 54.4, 39.8, 36.4, 35.9, 34.7, 32.6,31.6,29.2,24.8,23.1,14.2.
[0255] To the pure compound (0.178 g, 0.46 mmol) dissolved in diethyl ether (4 mL) was added oxalic acid (0.044 g, 0.49 mmol) in diethyl ether (2 mL). The formed crystals filtered and washed with diethyl ether to give the title compound as oxalic salt (0.19 g, 87%); HPLC-MS (ammonium acetate) [M+H]+= 387.4
4-[3-(4-Butylpiperidin-1-yl)propyl] -5-methyl-4H-benzo [1,4]oxazin-3-one (81MF941 x)
[0256] 4-(3-Chloropropyl)-5-methyl-4H-benzo[l,4]oxazin-3-one (8lMF941b) (1.08 g, 4.48 mmol), K2CO3 (1.24 g, 8.95 mmol), Nal (1.34 g, 8.95 mmol) and 4-butylpiperidine (0.66 g, 4.70 mmol) were mixed according to GPU. CC (SiCh; Heptane/EtOAc 10:1-4) gave the title compound (81MF941x) (0.814 g, 53%). !H NMR (CDC13) 8 6.97 - 6.83 (m, 3H), 4.41 (s, 2H), 4.07 (t, J= 12 Hz, 2 H), 2.67 (d, J= 10.8 Hz, 2H), 2.39 (s, 3H), 2.18 (t, J = 7.2 Hz, 2 H), 1.76 (t, J = 10.8 Hz, 2H), 1.69 - 1.62 (m, 2H), 1.58 (d, J= 10.0 Hz, 2 H), 1.30 - 1.06 (m, 9H), 0.87 (t, J= 6.8 Hz, 3H); 13C NMR (CDCI3) 8 168.3, 150.0, 129.2, 128.9, 126.8, 124.8, 114.8, 69.5, 55.7, 54.2, 42.6, 36.4, 35.9, 32.6, 29.2, 25.3, 23.0, 20.9, 14.2.
[0257] To the pure compound (0.177 g, 0.52 mmol) dissolved in diethyl ether (4 mL) was added oxalic acid (0.047 g, 0.49 mmol) in diethyl ether (2 mL). The formed crystals were filtered and washed with diethyl ether to give the title compound as oxalic salt (0.21 g, 92%); HPLC-MS (ammonium acetate) [M+H]+= 345.1
4-[3-(4-Butylpiperidin-1-yl)-propyl]-7-methyl-4H-benzo[1.41 oxazin-3-one (81MF2246F)
[0258] 4-(3-Chloropropyl)-7-methyl-4H-benzo[ 1,4] oxazin-3-one (81MF2246b) (1.64 g, 6.84 mmol), K2C03 (1.89 g, 13.68 mmol), Nal (2.05 g, 13.68 mmol) and 4-butylpiperidine (1.02 g, 7.18 mmol) were mixed according to GPU. CC (Si02; Heptane/EtOAc 10:1-4) gave the title compound (81MF2246F) (1.85 g, 79%). 'H NMR (CDCI3) 5 6.97 (d, J= 8.0 Hz, 1H), 6.82 - 6.78 (m, 2H), 4.54 (s, 2H), 3.94 (t, J = 7.2 Hz, 2H), 2.86 (d, J= 10.8 Hz, 2H), 2.37 (t, J= 7.0 Hz, 2H), 2.28 (s, 3H), 1.92 - 1.79 (m, 4H), 1.66 (d, J= 9.2 Hz, 2H), 1.31 - 1.18 (m, 9H), 0.88 (t, J= 7.2 Hz, 3H) 13C NMR (CDCI3) 8 164.2, 145.3, 133.9, 126.3, 123.3, 117.7, 115.0, 67.8, 56.0, 54.3, 39.7, 36.5, 36.0, 32.7,29.2,24.9,23.1, 20.8,14.2.
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[0259] To the pure compound (0.156 g, 0.45 mmol) dissolved in diethyl ether (4 mL) was added oxalic acid (0.042 g, 0.47 mmol) in diethyl ether (2 mL). The formed crystals were filtered and washed with diethyl ether to give the title compound as oxalic salt (0.192 g, 97%); HPLC-MS (ammonium acetate) [M+H]+= 345.1
4- [3 -(4-Butyrpiperidin-1 –yl)propyl] -6-chloro-7-nitro-4H-benzo [1.4] oxazin-3 -one (81MF2253x)
[0260] 6-Chloro-4-(3-chloropropyl)-7-nitro-4H-benzo[ 1,4] oxazin-3-one (81MF2253b) (1.23 g, 4.05 mmol), K2C03 (1.12 g, 8.09 mmol), Nal (1.21 g, 8.09 mmol) and 4-butylpiperidine (0.60 g, 4.24 mmol) were mixed according to GPU. CC (SiC^; Heptane/EtOAc 10:1-4) gave the title compound (81MF2253x) (0.698 g, 42%). !H NMR (CDC13) 5 7.61 (s, 1H), 7.36 (s, 1H), 4.66, (s, 2H), 3.99 (t, J= 6.8 Hz, 2H), 2.85 (d, J = 11.2 Hz, 2H), 2.34 (t, J= 6.4 Hz, 2H), 1.94 - 1.80 (m, 4H), 1.67 (d, J= 10.0 Hz, 2H), 1.31-1.20 (m, 9H), 0.88 (t, J= 6.4 Hz, 3H); 13C NMR (CDCI3) 5 163.4, 143.4, 141.9, 133.9, 122.1, 117.7, 114.8, 67.5, 55.5, 54.4, 40.5, 36.4, 36.0, 32,6, 29.2, 24.6, 23.0, 14.2.
[0261] To the pure compound (0.128 g, 0.31 mmol) dissolved in diethyl ether (4 mL) was added oxalic acid (0.029 g, 0.33 mmol) in diethyl ether (2 mL). The formed crystals were filtered and washed with diethyl ether to give the title compound as oxalic salt (0.125 g, 80%); HPLC-MS (ammonium acetate) [M+H]+= 410.1
4- [3 -(4-Butylpiperidin-1 – yl)propyl]-7-chloro-4H-benzo[1,4] oxazin-3 -one (81MF2271 x)
[0262] 7-Chloro-4-(3-chloropropyl)-4H/-benzo[ 1,4]oxazin-3-one (81MF2271b) (1.953 g, 7.49 mmol), K2CO3 (2.07 g, 14.9 mmol), Nal (2.24 g, 14.9 mmol) and 4-butylpiperidine (1.11 g, 7.86 mmol) were mixed according to GPU. CC (SiC«2; Heptane/EtOAc 10:1-4) gave the title compound (81MF2271x) (2.46 g, 90%). *H NMR (CDCI3) 5 7.08 - 6-96 (m, 3H), 4.57 (s, 2H), 3.95 (t, J= 7.2 Hz, 2H), 2.85 (d, J= 10.8 Hz, 2H), 2.35 (t, J= 12 Hz, 2H), 1.93 - 1.78 (m, 4H), 1.66 (d, J= 9.2 Hz, 2H), 1.31 — 1.18 (m, 9H), 0.88 (t, J= 6.4 Hz, 3H); 13C NMR (CDC13) 5 163.7, 146.0, 128.7, 127.7, 122.7, 117.6, 116.1, 67.7, 55.9, 54.3, 39.9, 36.5, 36.0, 32.7, 29.2, 24.8, 23.1, 14.2.
[0263] To the pure compound (0.171 g, 0.47 mmol) dissolved in diethyl ether (4 mL) was added oxalic acid (0.043 g, 0.49 mmol) in diethyl ether (2 mL). The formed crystals were filtered and washed with diethyl ether to give the title compound as oxalic salt (0.206 g, 97%); HPLC-MS (ammonium acetate) [M+H]+= 365.1
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GENERAL PROCEDURE 12 (GP12)
[0264] A 4 mL vial was charged with 4-(3-chloropropyl)-4H-benzo[l,4]oxazin-3-one (1.0 equiv), K2CO3 (2.0 equiv), Nal (2.0 equiv) and amine (1.05 equiv) in 3 mL dry MeCN and shaken at 60 °C for 100 h. The reaction mixture was evaporated to dryness, diluted with 4 mL H2O, extracted into CH2Cl2 (3x10 mL), and filtered through a PTFF Whatman filter. The combined organic layers were evaporated to dryness and purified by CC (Heptane/EtOAc or CH2Cl2/MeOH) or Prep TLC (Heptane/EtOAc or CH2Cl2/MeOH).
4-[3-(4-Butylpiperidin-l-yl)propyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one(8173MF55F)
[0265] 4-(3-Chloropropyl)-6-fluoro-4J?/-benzo[l,4]oxazin-3-one(8173MF55b) (0.102 g, 0.42 mmol), K2CO3 (0.12 g, 0.84 mmol), Nal (0.13 g, 0.84 mmol) and 4-butylpiperidine (0.06 g, 0.44 mmol) were mixed according to GP12. CC (Si02; Heptane/EtOAc 10:1-4) gave the title compound (8183MF55F) (0.12 g, 80%). *H NMR (CDCl3) 5.6.96 (dd, J = 10.4 Hz, J= 2.8 Hz, 1H), 6.87 (dd, J= 9.6 Hz, J= 5.2 Hz, 1H), 6.66 - 6.12 (m, 1H), 4.51 (s, 2H), 3.91 (t, J= 12 Hz, 2H), 2.84 (d, J= 11.2 Hz, 2H), 2.32 (t, J= 12 Hz, 2H), 1.91-1.77 (m, 4H), 1.64 (d, J= 9.6 Hz, 2H), 1.29 - 1.16 (m, 9H), 0.86 (t, J= 6.8 Hz, 3H); 13C NMR (CDC13) 8 164.2, 158.5 (d, J= 239.5 Hz), 141.4 (d, J= 2.7 Hz), 130.0 (d, J= 10.4 Hz), 117.5 (J= 9.3 Hz), 109.5 (d, J= 23.5 Hz), 103.2 (d, J = 28.8 Hz), 67.7, 55.7, 54.3,40.0, 36.4, 35.9, 32.6,29.1, 24.7,23.0,14.2.
[0266] To the pure compound (0.12 g, 0.34 mmol) dissolved in diethyl ether (4 mL) was added oxalic acid (0.032 g, 0.37 mmol) in diethyl ether (2 mL). The formed crystals were filtered and washed with diethyl ether to give the title compound as oxalic salt (0.128 g, 87%). HPLC-MS (ammonium acetate) [M+H]+= 349.2.
4-[3-(4-Butylpiperidin-l-yl)propyl]-7.8-difluoro-4H-benzo[1,4]oxazin-3-one (81MF2082x)
[0267] 4-(3-Chloropropyl)-7,8-difluoro-4H-benzo[l ,4]oxazin-3-one (81MF2082b) (0.16 g, 0.60 mmol), K2C03 (0.17 g, 11.9 mmol), Nal (0.18 g, 11.9 mmol) and 4-butylpiperidine (0.09 g, 0.63 mmol) were mixed according to GP12. CC (SiO2; Heptane/EtOAc 10:1-4) gave the title compound (81MF2082x) (0.14 g, 65%). lH NMR (CDCI3) d 6.88 - 6.76 (m, 2H) 4.66 (s, 2H), 3.96 (t, J= 7.2 Hz, 2H), 2.84 (d, J= 11.2,
72

2H), 2.34 (t, J= 6.8 Hz, 2H), 1.91 - 1.78 (m, 4H), 1.67 (d J= 9.6 Hz, 2H), 1.30-1.15 (m, 9H);13C NMR (CDC13) 5 163.1, 147.4 (q, J = 245.0 Hz, J= 10.6 Hz), 140.1 (q, J = 248.7 Hz, J= 15.7 Hz), 135.4 (d, J= 12.0 Hz), 126.5, 109.5 (d, J= 18.4 Hz), 109.0 (q, J = 7.6 Hz, J= 3.8 Hz), 67.8, 55.8, 52,3,40.1, 36.4, 35.9, 32.7,29.1,24.8,23.0,14.2.
[0268] To the pure compound (0.14 g, 0.39 mmol) dissolved in diethyl ether (4 mL) was added oxalic acid (0.042 g, 0.46 mmol) in diethyl ether (2 mL). The formed crystals were filtered and washed with diethyl ether to give the title compound as oxalic salt (0.16 g, 89%). HPLC-MS (ammonium acetate) [M+H]+= 367.3.
4-[3-(4-Butylpiperidin-l-yl)propyl]-4H-pyrido[4,3-b][1,4]thiazin-3-one(81MF939)
[0269] 4-(3-Chloropropyl)-4H-pyrido[4,3-6][l,4]thiazin-3-one (81MF939b) (0.14 g, 0.57 mmol), K2CO3 (0.16 g, 11.4 mmol), Nal (0.18 g, 11.4 mmol) and 4-butylpiperidine (0.09 g, 0.60 mmol) were mixed according to GP12. CC (SiO2; Heptane/EtOAc 10:1-4) gave the title compound (81MF939) (0.064 g, 32%). 1H NMR (CDCI3) 6 8.48 (s, IH), 8.17 (d, J= 5.2 Hz, IH), 7.25 (d, J= 4.8 Hz, IH), 4.06-4.12 (m, 2H), 3.41 (s, 2H), 2.82 (d,J= 11.2, 2H), 2.33 (t, J= 6.8 Hz, 2H), 1.83-1.89 (m, 4H), 1.64 (d, J= 9.2 Hz, 2H), 1.16-1.29 (m, 9H), 0.87 (t, J= 6.8 Hz, 3H); 13C NMR (CDC13) 5 163.91, 143.84, 138.92, 136.20, 134.04, 122.31, 55.80, 54.32, 43.29, 36.43, 35.99, 32.68, 30.78,29.19,25.20,23.05, 14.24.
[0270] To the pure compound (0.064 g, 0.18 mmol) dissolved in diethyl ether (4 mL) was added oxalic acid (0.020 g, 0.22 mmol) in diethyl ether (2 mL). The formed crystals were filtered and washed with diethyl ether to give the title compound as oxalic salt (0.16 g, 89%); HPLC-MS (ammonium acetate) [M+H]+= 348.2
4-[3-(4-Propoxypiperidin-l-yl)propyl]-4H-benzo[1,4]thiazin-3-one (81MF07KS)
[0271] 4-(3-Chloropropyl)-4H-benzo[l,4]thiazin-3-one (81MF07) (0.18 g, 0.74 mmol), K2C03 (0.20 g, 14.8 mmol), Nal (0.22 g, 14.8 mmol) and 4-propoxypiperidine (0.12 g, 0.81 mmol) were mixed according to GP12. CC (SiC«2; Heptane/EtOAc 4:1-4) gave the title compound (81MF07KS) (0.205 g, 79%). lU NMR (CDCI3) 5 7.33 (d, J= 7.6 Hz, 2H), 7.21 (d, J= 3.2 Hz, 2H), 7.00 - 6.96 (m, IH), 4.03 (t, J= 7.2 Hz, 2H), 3.38 - 3.34 (m, 4H), 3.26 - 3.21 (m, IH), 2.69 (t, J= 5.6 Hz, 2H), 2.33 (t, J= 7.2 Hz, 2H), 2.04 (t, J= 9.8 Hz, 2H), 1.86 - 1.76 (m, 4H), 1.58-1.51 (m, 4H),
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0.90 (t, J = 7.2 Hz, 3H); 13C NMR (CDC13) 5 165.2, 139.7, 128.5, 127.2, 124.1, 123.4, 118.1, 75.2, 69.7, 55.4, 51.5,43.2, 31.8, 31.7,25.3,23.4, 10.8.
[0272] To the pure compound (0.205 g, 0.58 mmol) dissolved in diethyl ether (4 mL) was added oxalic acid (0.058 g, 0.64 mmol) in diethyl ether (2 mL). The formed crystals were filtered and washed with diethyl ether to give the title compound as oxalic salt (0.192 g, 74%). HPLC-MS (ammonium acetate) [M+H]+= 349.2.
4-[3-(4-Propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one (81(81MF08KS)
[0273] 4-(3-Chloropropyl)-4H-benzo[l,4]oxazin-3-one (81MF08) (0.13 g, 0.58 mmol), K2CO3 (0.16 g, 1.15 mmol), Nal (0.17 g, 1.15 mmol) and 4-propoxypiperidine (0.089 g, 0.60 mmol) were mixed according to GP12. CC (Si02; Heptane/EtOAc 4:1-4) gave the title compound (81(81MF08KS)) (0.147 g, 76%). 'H NMR (CDCI3) 5.7.11 - 7.08 (m, IH), 7.01 - 6.94 (m, 3H), 4.55 (s, 2H), 3.96 (t, J= 7.2 Hz, 2H), 3.37 (t, J= 6.8 Hz, 2H), 3.28 - 3.21 (m, IH), 2.74 - 2.69 (m, 2H), 2.36 (t, J = 7.2 Hz, 2H), 2.10 - 2.03 (m, 2H), 1.90 - 1.77 (m, 4H), 1.61 - 1.51 (m, 4H), 0.90 (t, J = 7.2 Hz, 3H); 13C NMR (CDC13) 5 164.3, 145.4, 128.7, 123.8, 122.8, 117.1, 115.1, 75.1, 69.6, 67.7, 55.5, 51.5, 39.6, 31.6, 24.9, 23.4,10.7.
[0274] To the pure compound (0.147 g, 0.44 mmol) dissolved in diethyl ether (4 mL) was added oxalic acid (0.048 g, 0.53 mmol) in diethyl ether (2 mL). The formed crystals were filtered and washed with diethyl ether to give the title compound as oxalic salt (0.160 g, 86%). HPLC-MS (ammonium acetate) [M+H]+= 333.3.
4- [3-(4-Butylpiperidin-1-yl)propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one (81MF763)
[0275] 4-(3-Chloropropyl)-7-fluoro-4H-benzo[l,4]oxazin-3-one (81MF763b) (0.40 g, 1.6 mmol), K2CO3 (0.44 g, 3.2 mmol), Nal (0.48 g, 3.2 mmol) and 4-butylpiperidine (0.24 g, 1.70 mmol) were mixed according to GP12. CC (Si02; Heptane/EtOAc 4:1-4) gave the title compound (81MF763) (0.26 g, 46%). *H NMR (CDCI3) 6. 7.09 - 7.04 (m, IH), 6.74 - 6.69 (m, 2H), 4.58 (s, 2H), 3.95 (t, J= 12 Hz, 2H), 2.84 (d, J= 11.2 Hz, 2H), 3.45 (t, J= 6.8 Hz, 2H), 1.91 - 1.78 (m, 4H), 1.66 (d, J = 9.2 Hz, 2H), 1.29 - 1.16 (m, 9H), 0.88 (t, 7.2 Hz, 3H); 13C NMR (CDCI3) 5 163.6, 158.9 (d, J = 243.7 Hz), 146.3 (d, J= 11.5 Hz), 125.2 (d, J= 3.0 Hz), 115.9 (d, J= 9.7 Hz), 109.1 (d, J= 22.8 Hz), 105.1 (d, J= 26.1 Hz), 67.8, 55.9, 54.3, 39.9, 36.5, 36.0, 32.7, 29.2,24.8,23.1,14.2.
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[0276] To the pure compound (0.26 g, 0.74 mmol) dissolved in diethyl ether (4 mL) was added oxalic acid (0.073 g, 0.818 mmol) in diethyl ether (2 mL). The formed crystals were filtered and washed with diethyl ether to give the title compound as oxalic salt (0.26 g, 78%) HPLC-MS (ammonium acetate) [M+H]+= 349.3.
4-[3-(4-Butylidenepiperidin-1-yl)propyl]-4H-benzo[1,4]thiazin-3-one (81MF26)
[0277] 4-(3-Chloropropyl)-4H-benzo[l,4]thiazin-3-one (81MF07) (0.073 g, 0.30 mmol), K2C03 (0.12 g, 0.90 mmol), Nal (0.090 g, 0.6 mmol) and 4-butylidenepiperidine (0.050 g, 0.28 mmol) were mixed according to GP12. Prep TLC (Si02; CH2Cl2/MeOH 10:1) gave the title compound (81MF26) (0.034 g, 33%). *H NMR (CDC13) 5 7.34 - 7.31 (m, 1H), 7.23 - 7.20 (m, 1H), 7.00 - 6.95 (m, 1H), 5.10 (t, J= 7.2 Hz, 1H), 4.04 (t, J= 7.2 Hz, 2H), 3.34 (s, 2H), 2.37 - 2.32 (m, 6H), 2.23 - 2.14 (m, 2H), 1.96 - 1.90 (m, 2H), 1.86 - 1.78 (m, 2H), 1.37 - 1.27 (m, 2H), 0.86 (t, J= 7.2 Hz, 3H); 13C NMR (CDCI3) 8 165.1, 139.6, 136.0, 128.5, 127.2, 124.1, 123.4, 122.7, 118.1, 55.6, 55.4, 54.8,43.2, 36.1, 31.7, 29.2,28.3,25.2,23.2,13.8.
[0278] To the pure compound (0.034 g, 0.10 mmol) dissolved in diethyl ether (4 mL) was added oxalic acid (0.010 g, 0.10 mmol) in diethyl ether (2 mL). The formed crystals were filtered and washed with diethyl ether to give the title compound as oxalic salt (0.030 g, 69%); HPLC-MS (ammonium acetate) [M+H]+= 345.2
4-[3-(4-Butylidenepiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one (81MF25)
[0279] 4-(3-Chloropropyl)-4H-benzo[l,4]oxazin-3-one (81MF08) (0.068 g, 0.30 mmol), K2CO3 (0.12 g, 0.90 mmol), Nal (0.090 g, 0.60 mmol) and 4-butylidenepiperidine (0.050 g, 0.28 mmol) were mixed according to GP12. Prep TLC (SiO2; CH2Cl2/MeOH 10:1) gave the title compound (81MF25) (0.070 g, 71%). 'H NMR (CDCI3) 5 7.12 (d, J= 6.8 Hz, 1H), 7.03 - 6.95 (m, 3H), 5.12 (J= 7.4 Hz, 1H), 4.56 (s, 1H), 3.99 (t, J = 7.6 Hz, 2H), 2.41 - 2.36 (m, 6H), 2.26 - 2.17 (m, 2H), 1.98 - 1.81 (m, 4H), 1.38 - 1.28 (m, 2H), 0.87 (t, J= 7.2 Hz, 3H); 13C NMR (CDCI3) 5 164.3, 145.5, 136.0, 128.7, 123.8, 122.8, 122.8, 117.1, 115.2, 67.7, 55.7, 55.6, 54.9, 39.7, 36.1, 29.2, 28.4,24.8,23.2,13.8.
[0280] To the pure compound (0.070 g, 0.21 mmol) dissolved in diethyl ether (4 mL) was added oxalic acid (0.020 g, 0.22 mmol) in diethyl ether (2 mL). The formed
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crystals were filtered and washed with diethyl ether to give the title compound as oxalic salt (0.087 g, 97%) HPLC-MS (ammonium acetate) [M+H]+= 329.3.
4- [3 -(3 -Butylidene-8-aza-bicyclo[3.2.1] oct-8 -yl)-propyl] -4H-benzo [ 1,4] oxazin-3 -one (81MF24)
[0281] 4-(3-Chloropropyl)-4H-benzo[l,4]oxazin-3-one (81MF08) (0.030 g, 0.13 mmol), K2C03 (0.037 g, 0.26 mmol), Nal (0.040 g, 0.27 mmol) and 3-butylidene-8-azabicyclo[3.2.1]octane (0.029 g, 0.17 mmol) were mixed according to GP12. Prep TLC (Si02; CH2Cl2/MeOH 10:1) gave the title compound (81MF24) (0.019 g, 41%). !H NMR (CDC13) 5 7.22 - 7.19 (m, 1H), 7.05 - 6.96 (m, 3H), 5.24 (t, J= 7.2 Hz, 1H), 5.08 (s, 2H), 4.06 (t, J= 6.4 Hz, 2H), 2.61 (t, J= 6.8 Hz, 2H), 2.30 (s, 2H), 2.03 - 1.83 (m, 7H), 1.58 -1.43 (m, 2H), 1.39 -1.22 (m, 3 H), 0.89 (m, 3 H); 13C NMR (CDCI3) 5 164.5, 145.5, 131.4, 128.7, 127.9, 124.0, 123.0, 117.1, 115.5, 67.8, 60.4, 60.2, 48.8, 41.0, 39.6, 33.7, 29.5,26.8, 26.4, 25.8,23.2, 13.9.
[0282] To the pure compound (0.019 g, 0.05 mmol) dissolved in diethyl ether (2 mL) was added oxalic acid (0.005 g, 0.006 mmol) in diethyl ether (1 mL). The formed crystals were filtered and washed with diethyl ether to give the title compound as oxalic salt (0.012 g, 50%); HPLC-MS (ammonium acetate) [M+H]+= 355.3
4-[3-(4-Butylpiperidin-l-yl)propyl]-6-methoxy-4H-benzo[l,4]oxazin-3-one(81MF2249)
[0283] 4-(3-Chloropropyl)-6-methoxy-4H-benzo[l,4]oxazin-3-one (81MF2249b) (0.127 g, 0.50 mmol), K2C03 (0.137 g, 1.0 mmol), Nal (0.149 g, 1.0 mmol) and 4-butylpiperidine (0.075 g, 0.52 mmol) were mixed according to GP12. CC (Si02; Heptane/EtOAc 4:1-4) gave the title compound (81MF2249) (0.14 g, 85%). *H NMR (CDCI3) 8. 6.88 (d, J= 8.8 Hz, 1H), 6.67 (d, J= 2.4 Hz, 1H), 6.49 (dd, J= 8.8 Hz, J= 2.4 Hz, 1H), 4.51 (s, 2H), 3.93 (t, 7.2 Hz, 2H), 3.77 (s, 3H), 2.86 (d, J = 10.8 Hz, 2H), 2.36 (t, J= 7.2 Hz, 2H), 1.90 - 1.80 (m, 4H), 1.64 (d J= 8.8 Hz, 2H), 1.29 - 1.17 (m, 9H), 0.88 (t, J = 6.2 Hz, 3H); 13C NMR (CDCI3) 6 168.8, 155.6, 139.6, 129.7, 117.2, 107.2, 102.9, 68.0, 56.1, 56.0, 54.4, 39.9, 36.5, 35.9, 32.6, 29.2, 24.9, 23.0, 14.2.
[0284] To the pure compound (0.14 g, 0.37 mmol) dissolved in diethyl ether (4 mL) was added oxalic acid (0.037 g, 0.41 mmol) in diethyl ether (2 mL). The formed crystals were filtered and washed with diethyl ether to give the title compound as oxalic salt (0.15 g, 90%). HPLC-MS (ammonium acetate) [M+H]+= 361.3.
76

GENERAL PROCEDURE 13 (GP13)
[0285] A 7 mL vial was charged with 4-(3-chloropropyl)-4H-benzo[l,4]oxazin-3-one (1.0 equiv), K2CO3 (2.0 equiv), Nal (2.0 equiv) and 4-Butylpiperidine (1.05 equiv) in 5 mL dry MeCN and shaken at 60 °C for 48 h. The reaction mixture was evaporated to dryness, diluted with 10 mL H2O, extracted into CH2Cl2 (3x13 mL), and filtered through a PTFF Whatman filter. The combined organic layers were evaporated to dryness and purified by CC (Heptane/EtOAc or CH2Cl2/MeOH) or prep TLC (Heptane/EtOAc or CH2Cl2/MeOH).
4-[3-(4-Butylpiperidin-l-yl)propyl]-6.8-dichloro-7-ethyl-4H-benzo[l,41oxazin-3-one (95MF60)
[0286] 6,8-Dichloro-4-(3-chloro-propyl)-7-ethyl-4H-benzo[l,4]oxazin-3-one ((95MF52(2226)) (0.30 g, 0.93 mmol), K2C03 (0.26 g, 1.86 mmol), Nal (0.28 g, 1.86 mmol) and 4-butylpiperidine (0.14 g, 0.98 mmol) were mixed according to GP13. CC (Si02; CH2Cl2/MeOH 10:0.2-4) gave the title compound (95MF60) (0.24 g, 59%). JH NMR (CDCI3) 5 7.10 (s, 1H), 4.65 (s, 2H), 3.93 (t, J= 6.8 Hz, 2H), 2.95 - 2.81 (m, 4H), 2.33 (t, J= 6.8 Hz, 2H), 1.90 - 1.78 (m, 4H), 1.66 (d, J= 10.0 Hz, 2H) 1.30 - 1.13 (m, 12H), 0.88 (s, 3H); 13C NMR (CDCI3) 5 163.5, 140.6, 135.3, 128.2, 127.7, 123.2, 114.3, 67.9, 55.8, 54.4, 40.1, 36.4, 36.0, 32.7, 29.2, 24.8, 24.6, 23.1, 14.2, 12.7; HPLC-MS (ammonium acetate) [M+H]+ = 427.2.
4-[3-(4-Butylpiperidin-l-yl)propyl]-8-fluoro-4H-benzo[1.41oxazin-3-one(,95MF59)
[0287] 4-(3-Chloropropyl)-8-fluoro-4H-benzo[l,4]oxazin-3-one (95MF51(2085)) (0.25 g, 1.04 mmol), K2C03 (0.29 g, 2.1 mmol), Nal (0.31 g, 2.1 mmol) and 4-butylpiperidine (0.15 g, 1.1 mmol) were mixed according to GP13. CC (Si02; CH2Cl2/MeOH 10:0.2-4) gave the title compound (95MF59) (0.29 g, 80%). lH NMR (CDCI3) 8 6.92 - 6.84 (m, 2H), 6.79 - 6.74 (m, 1H), 4.59 (s, 2H), 3.93 (t, J= 1A Hz, 2H), 2.81 (d, J=\ 0.8 Hz, 2H), 2.31 (t, J= 7.0 Hz, 2H), 1.87 - 1.75 (m, 4H), 1.62 (d, J= 9.2 Hz, 2H), 1.27 - 1.12 (m, 9H), 0.84 (t, J= 6.8 Hz, 3H); 13C NMR (CDCI3) 8 163.7, 151.8 (d, J = 246.0 Hz), 133.8 (d, J= 14.6 Hz), 130.7 (d, J= 3.5 Hz), 122.1 (d, J= 8.0 Hz), 111.2 (d, J= 18.4 Hz), 110.4 (d, J = 3.4 Hz), 67.6, 55.8, 54.2,40.0, 36.4, 35.8, 32.6,29.0, 24.8,22.9,14.1.
77

[0288] To the pure compound (0.29 g, 0.83 mmol) dissolved in diethyl ether (4 mL) was added oxalic acid (0.078 g, 0.86 mmol) in diethyl ether (2 mL). The formed crystals were filtered and washed with diethyl ether to give the title compound as oxalic salt (0.31 g, 85%). HPLC-MS (ammonium acetate) [M+H]+= 349.3.
6-Bromo-4-[3-(4-Butylpiperidin-1-yl)propyl]-8-fluoro-4H-benzo[1,4]oxazin-3-one (95MF58)
[0289] 6-Bromo-4-(3-chloropropyl)-8-fluoro-4H-benzo[ 1,4]oxazin-3-one (95MF50(2084)) (0.086 g, 0.27 mmol), K2C03 (0.074 g, 0.53 mmol), Nal (0.080 g, 0.53 mmol) and 4-butylpiperidine (0.039 g, 0.28 mmol) were mixed according to GP13. CC (Si02; CH2Cl2/MeOH 10:0.2-4) gave the title compound (95MF58) (0.040 g, 35%). *H NMR (CDC13) 5 6.92 - 6.84 (m, 2H), 6.79 - 6.74 (m, 1H), 4.59 (s, 2H), 3.93 (t, J= 7.4 Hz, 2H), 2.81 (d, J = 10.8 Hz, 2H), 2.31 (t, J= 7.0 Hz, 2H), 1.87 - 1.75 (m, 4H), 1.62 (d, J= 9.2 Hz, 2H), 1.27-1.12 (m, 9H), 0.84 (t, J= 6.8 Hz, 3H); 13C NMR (CDCI3) 5 163.7, 151.8 (d, J= 246.0 Hz), 133.8 (d, J= 14.6 Hz), 130.7 (d, J= 3.5 Hz), 122.1 (d, J= 8.0 Hz), 111.2 (d, J= 18.4 Hz), 110.4 (d, J- 3.4 Hz), 67.6, 55.8, 54.2, 40.0, 36.4, 35.8, 32.6, 29.0,24.8,22.9,14.1.
[0290] To the pure compound (0.040 g, 0.09 mmol) dissolved in diethyl ether (4 mL) was added oxalic acid (0.009 g, 0.098 mmol) in diethyl ether (2 mL). The formed crystals were filtered and washed with diethyl ether to give the title compound as oxalic salt (0.040 g, 82%). HPLC-MS (ammonium acetate) [M+H]+ = 427.2.
[0212] 4-[3-(4-Butylpiperidin-1-yl)propyl]-8-isopropvl-4H-benzo[l,4]oxazin-3-one (T11MF02)
[0291] 4-(3-Chloropropyl)-8-isopropyl-4#-benzo[l,4]oxazin-3-one (95MF98) (0.112 g, 0.42 mmol), K2CO3 (0.115 g, 0.84 mmol), Nal (0.125 g, 0.84 mmol) and 4-butylpiperidine (0.062 g, 0.44 mmol) were mixed according to GP13. Prep TLC (Si02; CH2Cl2/MeOH 10:1) gave the title compound (111MF02) (0.06 g, 39%). lH NMR (CDCI3) 8 6.99 - 6.91 (m, 3H), 4.55 (s, 2H), 3.96 (t, J= 7.4 Hz, 2H), 3.27 (m, 1H), 2.89 (d, J= 11.2 Hz, 2H), 2.40 (t, J= 7.2 Hz, 2H), 1.93 - 1.83 (m, 4H), 1.66 (d, J= 9.6 Hz, 2H); 1.27 - 1.20 (m, 15H), 0.88 (t, J= 6.8 Hz, 3H); 13C NMR (CDC13) 5 164.7, 142.9, 137.5, 128.7, 122.6, 121.1, 112.9, 67.7, 56.0, 54.2, 39.9, 36.4, 35.9, 32.5, 29.1, 27.2, 24.9, 23.0, 22.7,14.2.
78

[0292] To the pure compound (0.06 g, 0.16 mmol) dissolved in diethyl ether (4 mL) was added oxalic acid (0.016 g, 0.18 mmol) in diethyl ether (2 mL). The formed crystals were filtered and washed with diethyl ether to give the title compound as oxalic salt (0.07 g, 88%). HPLC-MS (ammonium acetate) [M+H]+= 373.3.
(R,S)-4-[3-(4-Butylpiperidin-l-yl)-2-hydroxy-propyl]-6-methyl-4H benzo[1,4]oxazin-3-one(101IS86)
[0293] A dry 4 mL vial was charged with (R,S)-6-methyl-4-oxiranylmethyl-4H-benzo[l,4]oxazin-3-one (0.090 g, 0.41 mmol), 4-butylpiperidine (0.090 g, 0.60 mmol), K2CO3 (0.097 g, 0.70 mmol) and dry THF (2 mL). The mixture was shaken at 40 °C for 74 h and was thereafter concentrated under reduced pressure and the residue was diluted with EtOAc (20 mL) and washed with water (10 mL), brine, dried over Na2SO4. Filtration, concentration under reduced pressure and purification of the residue with flash chromatography (SiO2; CH2Cl2/acetone/MeOH 85:10:5) gave the title product as an oil (0.080 g, 54%). 1H NMR (CD3OD) 5 7.12 (s, 1H), 6.85 (d, J= 8.2 Hz, 1H), 6.81 (brd, J= 8.2 Hz, 1H), 4.53 (ABq, 14.8, 18.0 Hz, 2H), 4.12 - 4.02 (m, 2H), 3.95 - 3.85 (m, 1H), 3.05 - 2.98 (m, 1H), 2,92 - 2.84 (m, 1H), 2.48 - 2,40 (m, 2H), 2.31 (s, 3H), 2.10 - 1.98 (m, 2H), 1.71 - 1.62, (m, 2H), 1.35 - 1.15 (m, 9H), 0.90 (t, J= 6.8 Hz). 13C NMR (CD3OD) 8 166.0, 143.7, 132.4, 128.8, 124.4, 116.5, 116.4, 67.5, 65.9, 62.8, 54.6, 54.5, 46.1, 36.3, 35.6, 32.2 (br), 29.0, 22.8,20.0,13.3.
[0294] The product was dissolved in diethyl ether and oxalic acid (1.1 equiv) dissolved in diethyl ether was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.033 g). HPLC-MS (ammonium acetate) [M+H]+= 361.3.
(R,S)-4-[3-(4-Butylpiperidin-l-yl)-2-hydroxypropyl]-4H-benzo[l,4]oxazin-3-one (101IS85)
[0295] Epichlorohydrin (0.48 g, 5.2 mmol), CS2CO3 (2.3 g, 7.0 mmol), 4H-benzo[l,4]oxazin-3-one (0.52 g, 3.5 mmol) were stirred with dry DMF (7 mL) for 22 h. Thereafter the mixture was diluted with ether (50 mL) and washed with water (10 mL) and brine (10 mL). The organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure and the residue was purified by flash chromatography (SiO2; CH2Cl2/acetone/MeOH 95:3:2). The resulting oil (0.50 g, 2.5 mmol) was dissolved in
79

THF, 4-butylpiperidine (0.43 g, 3.0 mmol) and K2C03 (0.83 g, 6.0 mmol) were added and the reaction was shaken at 40 °C for 72 h. The reaction was thereafter concentrated under reduced pressure, and the residue was purified by flash CC (SiO2; CH2Cl2/acetone/MeOH 85:10:5) to give the title compound (0.43 g, 1,2 mmol, 35%). 1H NMR (CD3OD) d 7.32 (brd, J= 7.2 Hz, 1H), 7.06-6.94 (m, 3H), 4.58 (ABq, J= 14.8, 17.6 Hz, 2H), 4.13-4.03 (m, 2H), 3.91 (dd, J= 8.8, 15.2 Hz), 3. 97 (brd, J= 10.7 Hz, 1H), 2.87 (brd, J= 10.1 Hz), 2.43 (d, J= 6 Hz, 2H), 2.09-1.96 (m, 2H), 1.69-1.60 (m, 2H), 1.34-1.16 (m, 9H), 0.90 (t, J = 6.8 Hz); 13C NMR (CD3OD) 5 165.8, 145.8, 129.2, 124.0, 122.6, 116.7, 116.2, 67.4, 65.9, 54.7, 54.5,46.2, 36.3, 35.6, 32.2 (br), 29.0, 22.8,13.3.
[0296] The product was dissolved in diethyl ether and oxalic acid (1.1 equiv) dissolved in diethyl ether was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.037 g). HPLC-MS (ammonium acetate) [M+H]+= 347.3.
(-)-4[3-(4-Butylpiperidin-l-yl)-2-hydroxypropyl]-4H-benzo[1,4]oxazin-3-one (1011895) [0297] Following the method outlined above for (i?/5)-4-[3-(4-butylpiperidin-l-yl)-2-hydroxypropyl]-4H-benzo[l,4]oxazin-3-one using (R)-(-)-epichlorohydrine (97% ee), (instead of racemic epichlorohydrin, gave the title compound. The optical purity was determined by HPLC analysis (Chiralpak AD, 250 x 4.6, 5 |im; hexane/j-PrOH/diethylamine 95:4.7:0.3, 0.5 mL/min) to be 96.3% ee. ([a]D20 = - 6, c = 0.5, EtOH). 'H NMR, 13C NMR and HPLC-MS spectral data were identical to those of the racemic compound.
(R,S)-4-[3-(4-Butylpiperidin)-2-methoxypropyl]-4H-benzo[1,4]oxazin-3-one (101IS91)
[0298] A dry 4 mL vial was charged with NaH (6.5 mg, 0.15 mmol) and then a solution of (R ,S)-4- [3 -(4-Butylpiperidin-1 -yl)-2-hydroxypropyl] -4H-benzo [ 1,4] oxazin-3 -one (101IS85) (0.043 g, 0.12 mmol) in dry THF (1 mL) was added and the mixture was allowed to stir at rt for 2 h. Thereafter, neat Mel (7.5 \d, 0.12 mmol) was added and after another 2h at rt the reaction mixture was quenched with water (2 mL) and extracted with EtOAc (3x10 mL). The organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure and the residue was purified by flash chromatography (SiO2; CH2Cl2/acetone/MeOH 90:6:4) to yield the title compound as an oil (5.1 mg, 12%). 1H
80

NMR (CD3OD) 5 7.25 (dm, J= 7.2 Hz, 1H), 7.00-6.88 (m, 3H), 4.49 (ABq, J= 15.2, 18.8 Hz, 2H), 4.06-3.94 (m, 2H), 3.69-3.61 (m, 1H), 3.25 (s, 3H), 2.94-2.82 (m, 2H), 2.54-2.36 (m, 2H), 2.10-1.94 (m, 2H), 1.64-1.55 (m, 2H), 1.25-1.05 (m, 9H), 0.81 (t, J= 6.8 Hz); 13C NMR (CD3OD) 5 165.9, 146.0, 129.1, 124.2, 122.7, 116.8, 116.1, 76.0, 67.5, 60.2, 57.2, 54.6, 54.5, 43.7, 36.2, 35.3, 31.8, 28.9, 22.8, 13.2; HPLC-MS (ammonium acetate) [M+H]+ = 361.3.
(R,S)-4-[2-Hydroxy-3-(3-pentylbicyclo[3.2.1]oct-8-yl)-propyl]-4H-benzo[1,4]oxazin-3-one (123IS03)
[0299] Epichlorohydrin (0.48 g, 5.2 mmol), Cs2CO3 (2.3 g, 7.0 mmol), 4H-benzo[l,4]oxazin-3-one (0.52 g, 3.5 mmol) were stirred with dry DMF (7 mL) for 22 h. Thereafter the mixture was diluted with ether (50 mL) washed with water (10 mL) and then brine (10 mL). The organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure and the residue was purified by flash CC (Si02; CH2Cl2/acetone/MeOH 95:3:2). Of the resulting oil (0.060 g, 0.29 mmol) was dissolved in DMF (1.5 mL), 3-pentyl-8-azabicyclo[3.2.1]octane (0.060 g, 0.33 mmol) and Cs2CO3 (0.30 g, 0.81 mmol) were added and the mixture was shaken at 65 °C for 72 h. The mixture was then poured into ether (25 mL) washed with water (10 mL) and the water phase was extracted with ether (20 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, concentrated under reduced pressure and the residue was purified by cation exchange CC, followed by flash CC (SiO2; CH2Cl2:acetone:MeOH 85/10/5) to yield the title compound (0.060 g, 33% (from 4H-benzo[l,4]oxazin-3-one)). *H NMR (CDCI3) 5 7.42 (dm, J = 7.2 Hz, 1H), 7.05-6.94 (m, 3H), 4.60 (ABq, J= 14.8, 16.8 Hz, 2H), 4.15 (dd, J= 3.2, 14.0 Hz, 1H), 3.86-3.78 (m, 3H), 3.14 (m, 2H), 2.54 (dd, J = 4.8, 12.5 Hz, 1H), 2.22 (dd, J= 9.2, 12.4 Hz), 2.16-1.98 (m, 2H), 1.98-1.83 (m, 2H), 1.72-1.55 (m, 3H), 1.43-1.34 (m, 2H), 1.42-1.15 (m, 8H), 0.87 (t, J= 12 Hz). 13C NMR (CDCI3) 8 165.3, 145.5, 129.7, 124.2, 122.9, 117.0, 116.6, 67.9, 67.4, 60.9, 58.6, 56.7, 46.7, 38.3, 36.7, 36.5, 28.5, 28.3, 28.2, 27.1, 22.9, 14.3. HPLC-MS (ammonium acetate) [M+H]+ = 387.3.
81

4-[2-(4-Butylpiperidin-1-ylmethyl)allyl]-4H-benzo[ 1.4]oxazin-3-one (123IS02)
[0300] 3-Chloro-2-chloromethyl-l-propene (0.20 g, 1.5 mmol), 4H-benzo[l,4]oxazin-3-one (0.15 g, 1.0 mmol) and CS2CO3 (0.65 g, 2.0 mmol) were mixed with 1 mL DMF and were shaken at 65 °C for 5 h. The mixture was diluted with ether (20 mL) and washed with water (20 mL) and the water phase was extracted with ether (20 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered concentrated under reduced pressure and the residue was purified by flash CC (Si02; heptane/EtOAc 70:30). This product (0.080 g, 0.34 mmol) was dissolved in DMF (1 mL), thereafter 4-butylpiperidine (0.053 g, 0.37 mmol) and Cs2CO3 (0.23 g, 0.71 mmol) were added and the mixture was shaken at 65 °C for 24 h. The mixture was then poured into ether (25 mL) washed with water (10 mL) and the water phase was extracted with ether (20 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, concentrated under reduced pressure and the residue was purified by cation exchange CC, followed by flash CC (Si02; EtOAc/MeOH/NH4OH (25% NH3 in water) 97.5:2:0.5), to yield the title compound (0.075 g, 21%). !H NMR (CDC13) 5 7.05-2.92 (m, 4H), 5.01 (brs, 1H), 4.82 (brs, 1H), 4.64 (brs 2H), 4.57 (brs, 2H), 2.94 (brs, 2H), 2.86 (brd, J= 10.4 Hz, 2H), 1,93-1.82 (m, 2H), 1.71-1.62 (m, 2H), 1.34-1.15 (m, 9H), 0.89 (t, J= 6.2 Hz, 3H); 13C NMR (CDC13) 5 1.64.5, 145.4, 129.2, 123.9, 122.8, 116.9, 113.2, 67.9, 63.2, 54.4, 44.8, 36.6, 36.0, 32.8, 29.3, 23.1, 14.3; HPLC-MS (ammonium acetate) [M+H]+ = 343.3.
(R,S)-4-[3-(-4-Butylpiperidin-l-yl)-2-fluoropropyl]-4H-benzo[1,4]oxazin-3-one(101IS96) [0301] A 4mL vial was charged with (R,S)-4-butyl-l-(3-chloro-2-fluoropropyl)piperidine (0.020 g, 85 umol) and 4H-benzo[l,4]oxazin-3-one (0.023 g 0.16 mmol) and CH3CN (1 mL). The mixture was stirred at 60 °C for 70 h and the mixture was diluted with MeOH and filtered through a small silica pad onto a cationic-exchange CC. Concentration under reduced pressure yielded an oil that was purified by flash chromatography (SiCh; heptane:EtOAc 50/50;) to yield the title compound as an oil (0.011 g, 38%). 1H NMR (CD3OD) 8 7.28-7.24 (m, 1H), 7.07-6.96 (m, 3H), 5.05 (dm, J= 50.4 Hz), (ABq, J= 15.2, 20.o Hz), 4.29-4.12 (m, 2H), 3.00-2.92 (m, 2H), 2.78-2.60 (m, 2H), 2.14-2.05 (m, 2H), 1.73-1.63 (m, 2H), 1.35-1.16 (m, 10H), 0.90 (t, J= 6.8 Hz, 3H). 13C NMR (CD3OD) 8 165.8, 145.8, 129,0, 124.2, 122.7, 116.8, 117.0, 116.8, 89.5 (d, J =
82

174 Hz), 67.4, 60.1 (d, J= 21 Hz), 54.5, 43.8 (d, J= 23 Hz), 36.2, 35.4, 32.0, 31.9, 28.9, 22.8,13.2.
[0302] The product was dissolved in diethyl ether and oxalic acid (1.1 equiv) dissolved in diethyl ether was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.037 g). HPLC-MS (ammonium acetate) [M+H]+= 349.3.
(S)-4-[3-(4-Butyl-piperidin-l-yl)-2-methyl-propyl]-4H-benzo[1.41oxazin-3-one (108LM53-50)
[0303] A 4 ml vial was charged with crude (R)-4-(3-iodo-2-methyl-propyl]-4H-benzo[l,4]oxazin-3-one (108LM46-43) (0.312 g) and 4-butyl-piperidine (0.210 g, 1.49 mmol) in dry MeCN QA ml) and shaken at 60°C for 3 days. The reaction mixture was quenched with water (1 ml), and the product extracted into EtOAc (2 x 1 ml). The combined organic layers were added a cation exchange column. The column was washed with MeOH (2 column volumes) then the product was eluded of the column using 8% ammonium hydroxide in MeOH (2 column volumes). The product was purified by flash CC (Si02; MeOH/DCM 1:20) to give the title compound (108LM53-50) (0.193 g, 17% -3 steps). *H NMR (CDC13) 5 7.18 (d, J = 7.8 Hz, IH), 7.03 - 6.96 (m, 3H), 4.58 (ABq, J =
14.3 Hz, J - 33.9 Hz, CH2), 4.05 - 3.90 (m, 2H), 2.88 (bd, J = 10.4 Hz, IH), 2.71 (bd, J =
10.3 Hz, IH), 2.25 - 2.01 (m, 3H), 2.00 - 1.92 (m, IH), 1.83 - 1.75 (m, IH), 1.68 - 1.56 (m, 2H), 1.33 -1.12 (m, 9H), 0.95 - 0.85 (m, 6H); 13C NMR (CDCI3) 8 164.9, 145.7, 128.9,123.8,122.7, 117.2, 115.8, 67.8, 64.2, 55.8, 54.4,45.4, 36.6, 36.1, 33.0, 32.8,29.3, 23.2,17.1,14.4; HPLC-MS (ammonium acetate) [M+H]+=345.3.
(R)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one H08LM22-20}
[0304] The compound (S)-4-(3-Iodo-2-methyl-propyl]-4H/-benzo[l,4]oxazin-3-one (108LM27-24) (0.063 g, 0.19 mmol) and 4-butyl-piperidine (0.053 g, 0.38 mmol) in MeCN (V2 mL) were reacted according to GP10 shaking at 50 °C for 1 day and at 70 °C for 2 days. Purified by cation exchange CC and flash CC (Si02; MeOH/DCM 1:50) to give the title compound (108LM22-20) (0.051 g, 79%). *H NMR (CDC13) 6 7.18 - 7.15 (m, IH), 7.02 - 6.96 (m, 3H), 4.60 (ABq, J= 15.0 Hz, J= 31.3 Hz, CH2), 3.99 (dd, J= 8.1 Hz, 13.8 Hz, IH), 3.92 (dd, J= 5.0 Hz, 13.8 Hz, IH), 2.88 (bd, J= 10.0 Hz, IH), 2.72
83

(bd, J= 10.0 Hz, 1H), 2.26-2.02 (m, 3H), 2.00 - 1.92 (m, 1H), 1.85 - 1.75 (m, 1H), 1.70 -1.59 (m, 2H), 1.32-1.14 (m, 9H), 0.92 - 0.85 (m, 6H); HPLC-MS (ammonium acetate) [M+H]+=345.3.
GENERAL PROCEDURE 14 (GP14)
[0305] A 4 mL vial was charged with the appropriate heterocycle (1 equiv) and the appropriate piperidine (1.1 equiv) and shaken at 60 °C for 2 days. EtsN (lA mL) was added and shaking was continued for 1 day. The reaction mixture was quenched with water (1 mL), and Et20 (1 mL) and sodium hydroxide (until pH 10) were added. The product was extracted into Et20 (2x1 mL). The combined organic layers were dried over Na2SC>4, and concentrated. The product was purified by cation exchange CC followed by flash CC (Si2O; MeOH/DCM 1:50).
(R)-4- [2-Methyl-3 -(4-Propoxypiperidin-1 -yl-propyl] –4H-benzo[1,4] oxazin-3 -one (108LM32-29)
[0306] The compound (5)-4-(3-Iodo-2-methyl-propyl]-4H-benzo[l,4]oxazin-3-one (108LM27-24) (0.202 g, 0.61 mmol) and 4-propoxy-piperidine (79KS66) (0.097 g, 0.67 mmol) in MeCN QA mL) were reacted according to GP14 to give the title compound (108LM32-29) (0.136 g, 65%). 1H NMR (CDC13) 6 7.15 (bd, J= 7.3 Hz, 1H), 7.03 - 6.95 (m, 3H), 4.60 (ABq, J= 13.9 Hz, J= 31.6 Hz, CH2), 4.05 - 3.90 (m, 2H), 3.48 (t, J= 7.0 Hz, CH2), 3.28 - 3.20 (m, 1H), 2.79 (bs, 1H), 2.63 (bs, 1H), 2.27 - 2.11 (m, 3H), 2.10 -1.93 (m, 2H), 1.92 - 1.83 (m, 2H), 1.63 - 1.52 (m, 4H), 0.94 - 0.86 (m, 6H); 13C NMR (CDC13) 8 164.5, 145.4, 128.5, 123.4, 122.3, 116.9, 115.2, 75.0, 69.4, 67.4, 63.2, 52.5, 51.5, 45.0, 31.6, 31.5, 29.1, 23.1, 16.6, 10.5; HPLC-MS (ammonium acetate) [M+H]+=347.3.
(R)-4-[3-(4-Butylidenepiperidin-l-yl)-2-methylpropyl]-4H-benzo[l,41oxazin-3-one (108LM33-30)
[0307] The compound (5)-4-(3-Iodo-2-methyl-propyl]-4H-benzo[l,4]oxazin-3-one (108LM27-24) (0.441 g, 1.33 mmol) and 4-butylidenepiperidine (111MF05) (0.204 g, 1.47 mmol) in MeCN QA mL) were reacted according to GP14 to give the title compound (108LM33-30) (0.293 g, 64%). 1H NMR (CDCI3) 6 7.19 (bd, J= 7.0 Hz, 1H), 7.04-6.97 (m, 3H), 5.13 (t, J= 7.9 Hz, CH), 4.60 (ABq, J =14.1 Hz, 7= 16.2 Hz, CH2),
84

4.00 (d, / = 7.0 Hz, CH2), 2.50-2.38 (m, 2H), 2.35-2.05 (m, 9H), 1.95 (dt, J= 7.0 Hz, CH2), 1.50 - 1.40 (m, 2H), 0.94-0.86 (m, 6H); 13C NMR (CDC13) 8 165.0, 145.8, 136.3, 128.9, 123.8, 122.8, 122.7, 117.3, 115.7, 67.9, 63.7, 56.5, 55.7, 45.5, 36.4, 29.4, 28.6, 23.4,17.1,13.9; HPLC-MS (ammonium acetate) [M+H]+=343.3.
GENERAL PROCEDURE 15 (GP15)
[0308] A 7 mL vial was charged with the appropriate heterocycle (1 equiv) and the appropriate piperidine (1.1 equiv) in Et3N QA mL) and shaken at 60°C for 4 days. The reaction mixture was quenched with water (1 mL), and Et20 (1 mL) and sodium hydroxide (until pH 10) were added. The product was extracted into Et20 (10x1 mL) and EtOAc (10x1 mL). The combined organic layers were dried (Na2S04), and concentrated. The product was purified by cation exchange CC followed by flash CC (Si20; MeOH/DCMl:20).
(R)-4-[3-(3-Butyl-8-aza-bicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (108LM38-35)
[0309] The compound (5)-4-(3-Iodo-2-methylpropyl]-4H-benzo[l,4]oxazin-3-one (108LM27-24) (0.092 g, 0.28 mmol) and 3-butyl-8-aza-bicyclo[3.2.1]octane (104KS29) (0.051 g, 0.31 mmol) in Et3N (1/2 mL) were reacted according to GP15 to give the title compound (108LM38-35) (0.068 g, 64%). lH NMR (CDCI3) 5 7.32 (d, J= 6.7 Hz, 1H), 7.03 - 6.95 (m, 3H), 4.60 (ABq, J =7.2 Hz, J= 10.8 Hz, CH2), 4.12-4.00 (m, 2H), 3.16 (bs, 1H), 3.07 (bs, 1H), 2.33 (dd, J= 6.1 Hz, J= 2.1 Hz, 1H), 2.12 (t, J= 4.7 Hz, 1H), 2.01 - 1.78 (m, 2H), 1.58 - 1.40 (m, 5H), 1.38 - 1.13 (m, 9H), 0.92 - 0.84 (m, 6H); 13C NMR (CDCI3) 5 164.9, 145.7, 128.9, 123.7, 122.7, 117.1, 116.2, 67.9, 61.8, 60.0, 58.1, 45.4, 38.7, 38.6, 37.1, 31.6, 29.4, 28.2, 27.4, 26.5, 23.1, 17.1, 14.3; HPLC-MS (ammonium acetate) [M+H]+=371.3.
(R)-4-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl-4H-benzo[1,4]oxazin-3-one (108LM39-36)
[0310] The compound (S)-4-(3-Iodo-2-methylpropyl]-4H/-benzo[l,4]oxazin-3-one (108LM27-24) (0.083 g, 0.25 mmol) and 3-pentyl-8-aza-bicyclo[3.2.1]octane (104KS32-2) (0.051 g, 0.28 mmol) in Et3N QA mL) were reacted according to GP15 to
85

give the title compound (108LM39-36) (0.061 g, 63%). !H NMR (CDC13) 5 7.33 - 7.29 (m, IH), 7.03 - 6.96 (m, 3H), 4.60 (ABq, J = 14.8 Hz, J =37A Hz, CH2), 4.14 - 4.00 (m, 2H), 3.13 (bs, IH), 3.05 (bs, IH), 2.63 - 2.50 (m, IH), 2.17 - 2.03 (m, 3H), 2.00 -1.80 (m, 3H), 1.72 - 1.53 (m, 3H), 1.42 - 1.15 (m, 10H), 0.93 - 0.85 (m, 6H); 13C NMR (CDCI3) 5 165.0, 145.7, 128.9, 123.7, 122.6, 117.1, 116.1, 67.9, 60.9, 58.9, 58.2, 45.3, 38.4, 37.0, 36.8, 32.2, 31.7, 28.5, 28.3, 27.2, 22.9, 17.1, 14.3; HPLC-MS (ammonium acetate) [M+H]+=385.3.
GENERAL PROCEDURE 16 (GP16)
[0311] A 7 mL vial charged with 4-(3-iodo-2-methylpropyl)-4#-benzo[l,4]oxazin-3-one (1.0 equiv) and amine (1.0 equiv) was shaken at 60 °C for 20 hours. The reaction mixture was added Et3N (2.5 equiv) and shaken at 60 °C for 60 - 80 hours. The reaction mixture was concentrated, dissolved in 1 M NaOH (10 mL), extracted into CH2CI2 (3x 15mL), and dried through a PTFF Whatman filter. The combined organic layers were concentrated and purified by cation exchange CC and CC (Heptane/EtOAc) or Prep HPLC.
(R)-6-Fluoro-4- [2-methyl-3 -(4-propoxy-piperidin-1-yl)-propyl]-4H-benzo [1.4] oxazin-3 -one (108LM30-27)
[0312] The compound (S)-6-Fluoro-4-(3-iodo-2-methyl-propyl)-4H-benzo[ 1,4] oxazin-3 -one (111MF04) (0.400 g, 1.15 mmol) and 4-propoxy-piperidine (79KS66) (0.332 g, 2.29 mmol) in MeCN (1/2 mL) were reacted according to GP10 shaking at 60 °C for 3 days and at 70 °C for 1 day. Purified by cation exchange CC and flash CC (Si02; MeOH/DCM 1:50 -+ 1:20) to give the title compound (108LM30-27) (0.263 g, 63%). 'H NMR (CDC13) 8 6.96 (dd, J= 9.7 Hz, J = 2.9 Hz, IH), 6.91 (dd, J = 8.9 Hz, J= 4.9 Hz, IH), 6.66 (dt, J= 8.9 Hz, J= 2.9 Hz, IH), 4.56 (ABq, J= 15.5 Hz, J= 31.7 Hz, CH2), 3.95 (dd, J= 13.5 Hz, J= 8.1 Hz, IH), 3.88 (dd, J= 13.5 Hz, J = 4.7 Hz, IH), 3.38 (t, J= 6.7 Hz, CH2), 3.32-3.23 (m, IH), 2.79 (bs, IH), 2.62 (bs, IH), 2.26-2.12 (m, 3H), 2.19-1.95 (m, 2H), 1.94-1.84 (m, 2H), 1.66-1.53 (m, 4H), 0.95-0.85 (m, 6H); 13C NMR (CDCI3) 5 164.9, 158.5 (d, J= 952.8 Hz, IH), 141.7 (d, J= 9.2 Hz, IH), 130.0 (d, J = 42.4 Hz, IH), 117.7 (d, J= 38.4 Hz, IH), 109.6 (d, J= 93.2 Hz, IH), 103.4 (d, J =
86

114.4 Hz, IH), 75.2, 69.8, 67.9, 63.7, 52.8, 52.0, 45.7, 31.8, 31.6, 29.5, 23.5, 17.1, 10.9; HPLC-MS (ammonium acetate) [M+H]+=365.3.
(R)-4-[3 -(4-Butylidenepiperidin-1-yl)2-methyl-propyl] -6-fluoro-4H-benzo [1.4] oxazin-3 –one(111MF06)
[0313] The compound (S)-6-Fluoro-4-(3-iodo-2-rnethyl-propyl)-4H-benzo[ 1,4] oxazin-3-one (111MF04)_(0.718 g, 2.06 mmol) and 4-Butylidenepiperidine (0.301 g, 2.16 mmol) were mixed according to GP16. CC (Si02; Heptane/EtOAc 4:1-4) gave the title compound (111MF06) (0.40 g, 54%). 'HNMRtCDCls) 5 7.01 (dd, J= 3.0 Hz, J= 10.2Hz, IH), 6.90(dd,.7=5.4Hz, J= 8.6Hz, IH), 6.89-6.63 (m, IH), 5.12 (t, J = 7.4 Hz, IH), 4.63 - 4.51 (m, 2H), 4.02 - 3.89 (m, IH), 2.51 - 2.44 (m, 2H), 2.32 - 2.23 (m, 5H), 2.21-2.15 (m, 5H), 2.11 - 2.03 (m, IH), 1.98 - 1.93 (m, 2H), 1.39 - 1.29 (m, 2H), 0.91 - 0.86 (m, 6H); 13C NMR (CDC13) 5 164.8, 158.5 (d, J= 239.4 Hz), 141.6 (d, J = 2.7 Hz), 136.2, 130.0 (d,J= 10.8 Hz), 122.7, 117.6 (d, J= 9.3 Hz), 109.5 (d, J = 23.1 Hz), 103.4 (d, J= 29.1 Hz), 67.8, 63.7, 56.6, 55.8, 45.7, 36.2, 29.4, 29.3,28.4, 23.3,17.0, 13.9.
[0314] To the pure compound (0.38 g, 1.0 mmol) dissolved in diethyl ether (4 mL) was added oxalic acid (0.104 g, 1.15 mmol) in diethyl ether (2 mL). The formed crystals filtered and washed with diethyl ether to give the title compound as oxalic salt (0.44 g, 92%); HPLC-MS (ammonium acetate) [M+H]+= 361.4
(R)-4- [3–(4-Butylpiperidin-1-yl-2-methylpropyl] -6-fluoro-4H-benzo[1,4] oxazin-3 -one (111MF08)
[0315] The compound (5)-6-Fluoro-4-(3-iodo-2-methyl-propyl)-4H-benzo[l,4]oxazin-3-one (111MF04).(0.873 g, 2.50 mmol) and 4-Butylpiperidine (0.371 g, 2.63 mmol) were mixed according to GP16. CC (SiCh; Heptane/EtOAc 4:1-4) gave the title compound (111MF08) (0.53 g, 58%). 1H NMR (CDCI3) 5 7.01 (d, J= 10.0 Hz, IH), 6.92 - 6.88 (m, IH), 6.68 - 6.64 (m, IH), 5.57 (q, J= 32.4 Hz, J= 15.2 Hz, 2H), 4.02 -3.83 (m, 2H), 2.92 - 2.70 (m, 2H), 2.23 - 2.10 (m, 2H), 2.04 - 1.97 (m, 2H), 1.81 (t, J = 10.8 Hz, IH), 1.72 - 1.61 (m, 2H), 1.36 - 1.19 (m, 9H), 0.90 - 0.88 (m, 6H); 13C NMR (CDCI3) 5 164.8, 158.5 (d, J = 239.4 Hz), 141.6 (d, J= 2.3 Hz), 130.0 (d, J= 10.4 Hz), 117.6 (d, J= 9.6 Hz), 109.4 (d, J= 23.1 Hz), 103.5 (d, J= 29.3 Hz), 67.8, 64.1, 56.0, 54.3, 45.7, 36.5, 36.0, 33.0, 32.5, 29.5, 29.2, 23.1, 17.1, 14.3.
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[0316] To the pure compound (0.53 g, 1.5 mmol) dissolved in diethyl ether (4 mL) was added oxalic acid (0.104 g, 1.15 mmol) in diethyl ether (2 mL). The formed crystals filtered and washed with diethyl ether to give the title compound as oxalic salt (0.614 g, 93%); HPLC-MS (ammonium acetate) [M+H]+= 363.3.
(i?V4-[3-(3-Butvl-8-azabicvclor3.2.11oct-8-vlV2-methylpropyl]-6-fluoro-4H-benzo|r,4]oxazin-3-one (111MF26)
[0317] The compound (S)-6-Fluoro-4-(3-iodo-2-methyl-propyl)-4H7-
benzo[l,4]oxazin-3-one (111MF04) (0.219 g, 0.6 mmol) and 3-butyl-8-azabicyclo[3.2.1]octane (0.10 g, 0.6 mmol) were mixed according to GP16. CC (Si02; Heptane/EtOAc (4:1-4) gave the title compound (111MF26) (0.16 g, 58%). *H NMR (CDC13) 5 7.16 (dd, J= 2.8 Hz, J= 10.0 Hz, 1H), 6.90 (dd, J= 5.0 Hz, J= 9.0 Hz, 1H), 6.69 - 6.63 (m, 1H), 4.58 (q, J= 14.8 Hz, J= 38.0 Hz, 2H), 4.10 - 3.93 (m, 2H), 3.16 -3.06 (m, 2H), 2.33 (dd, J= 4.0 Hz, J= 12.8 Hz, 1H), 2.05 (t, J= 11.6 Hz, 1H), 1.94 -1.82 (m, 2H), 1.58 - 1.43 (m, 6H), 1.39 - 1.32 (m, 2H), 1.31 - 1.15 (m, 6H), 0.90 - 0.87 (m, 6H); 13C NMR (CDC13) 5 164.9, 158.5 (d, J= 239.4 Hz), 141.6 (d, J= 2.7 Hz), 130.0 (d, J= 10.4 Hz), 117.5 (d, J= 9.3 Hz), 109.4 (d, J= 23.5 Hz), 103.9 (d, J= 28.9 Hz), 67.8, 61.9, 60.1, 58.2,45.6, 38.6, 38.5, 36.9, 31.8, 29.4,28.2, 27.4, 26.5, 23,1,17.1,14.3.
[0318] To the pure compound (0.16 g, 0.41 mmol) dissolved in diethyl ether (4 mL) was added oxalic acid (0.039 g, 0.43 mmol) in diethyl ether (2 mL). The formed crystals filtered and washed with diethyl ether to give the title compound as oxalic salt (0.173 g, 88%); HPLC-MS (ammonium acetate) [M+H]+= 389.3
(R)-6-Fluoro-4-[2-methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)-propyl]-4H-benzo[l,4]oxazin-3-one (111MF27)
[0319] The compound (5)-6-Fluoro-4-(3-iodo-2-methylpropyl)-4H/-
benzo[l,4]oxazin-3-one (111MF04) (0.208 g, 0.6 mmol) and 3-Pentyl-8-
azabicyclo[3.2.1]octane (0.10 g, 0.56 mmol) were mixed according to GP16. CC (Si02; Heptane/EtOAc 4:1-4) gave the title compound (111MF27) (0.16 g, 58%). !H NMR (CDCI3) 5 7.13 (dd, J= 2.8 Hz, J= 10.0 Hz, 1H), 6.90 (dd, J= 5.2 Hz, J- 8.8 Hz, 1H), 6.68 - 6.63 (m, 1H), 4.57 (q, J= 14.8 Hz, J = 40.0 Hz, 1H), 4.11 - 3.94 (m, 2H), 3.14 -3.04 (m, 2H), 2.30 (dd, J= 4.0 Hz, J= 12.8 Hz, 1H), 2.20 - 2.09 (m, 2H), 2.06 - 2.00 (m,
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IH), 1.95 - 1.82 (m, 3H), 1.71 - 1.52 (m, 3H), 1.40 - 1.34 (m, 2H), 1.32 - 1.19 (m, 8H), 0.89 - 0.85 (m, 6H); 13C NMR (CDC13) 8 164.9,158.5 (d, J= 239.4 Hz), 141.6 (d, J= 2.6 Hz), 130.0 (d, J= 10.8 Hz), 117.5 (d, J= 9.3 Hz), 109.4 (d, J= 23.4 Hz), 103.8 (d, J = 28.9 Hz), 67.8, 61.0, 59.0, 58.2, 45.5, 38.4, 36.6, 36.5, 32.8, 31.8, 28.4, 28.4, 28.2, 27.2, 22.8, 7.0, 14.2.
[0320] To the pure compound (0.16 g, 0.41 mmol) dissolved in diethyl ether (4 mL) was added oxalic acid (0.039 g, 0.43 mmol) in diethyl ether (2 mL). The formed crystals filtered and washed with diethyl ether to give the title compound as oxalic salt (0.198 g, 97%); HPLC-MS (ammonium acetate) [M+H]+= 403.3
(R )-4-[3-(4-Butyrpiperidin-1-yl)-2-methylpropyl] -7-Fluoro-4H-benzo [1.41 oxazin-3 -one (112KK04)
[0321] A microwave vial was charged with (iS)-7-fluoro-4-(3-Iodo-2-methylpropyl)-4H-benzo[l,4]oxazin-3-one (111MF20) (0.274 g, 0.78 mmol) and 4-butylpiperidine (0.226 g, 1.60 mmol) in MeCN (4 mL) and sealed. After microwave irradiation, 100 °C, 60 min, the reaction mixture was purified by cation exchange CC followed by flash CC (SiO2; CH2Cl2/MeOH 50:1) to give the title compound (112KK04) (0.180 g, 63%). 1H NMR (CD3OD) 8 7.24 - 7.21 (m, IH), 6.81 - 6.76 (m, 2H), 4.60 (ABq, J= 17.4 Hz, J= 15.1 Hz, CH2), 3.98 (dd, J= 14.3 Hz, J= 5.9 Hz, IH), 3.87 (dd, J = 14.3 Hz, J= 7.6 Hz, IH), 2.86 (d, J = 11.0 Hz, IH), 2.73 (d, J = 9.8 Hz, IH), 2.28 -2.23 (m, IH), 2.16 - 2.08 (m, 2H), 1.93 - 1.81 (m, 2H), 1.79 - 1.62 (m 2H), 1.32 - 1.13 (m, 9H), 0.93 - 0.88 (m, 2 CH3); 13C NMR (CD3OD) 8 166.1, 160.3 (d, J = 242.3 Hz), 148.1 (d, J= 11.9 Hz), 126.4 (d, J= 2.9 Hz), 117.8 (d, J= 9.4 Hz), 109.9 (d, J= 22.9 Hz), 105.7 (d, J= 26.1 Hz), 68.6, 65.1, 56.3, 55.4,46.6, 37.5, 37.0, 33.6, 33.4, 30.1, 29.9,24.0, 17.2,14.4.
[0322] The product was dissolved in MeOH/Et20 and oxalic acid dissolved in Et20 was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.176 g). HPLC-MS (ammonium acetate) [M+H]+= 363.29.
(R)-7-Fluoro-4-[2-methyl-3-(4-propoxypiperidin-1-yl)propyl]-4H-benzo[1,4]oxazin-3-one (111MF28)
[0323] The compound (S)-7-Fluoro-4-(3-iodo-2-methylpropyl)-4H-
benzo[l,4]oxazin-3-one (111MF20) (0.501 g, 1.43 mmol) and 4-propyloxypiperidine
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(0.205 g, 1.43 mmol) were mixed according to GP16. CC (Si02; Heptane/EtOAc 4:1-4) gave the title compound (111MF28) (0.375 g, 71%). 1H NMR (CDC13) 8 7.12 - 7.08 (m, 1H), 6.74 - 6.69 (m, 2H), 4.59 (q, J= 15.0 Hz, J= 31.0 Hz, 2H), 4.01 - 3.88 (m, 2H), 3.39 (t, J= 6.8 Hz, 2H), 3.29 - 3.22 (m, 1H), 2.77 (t, J= 6.3 Hz, 1H), 2.63 (t, J= 5.6 Hz, 1H), 2-26 - 2.12 (m, 3H), 2.04 - 1.96 (m, 2H), 1.88 - 1.84 (m, 2H), 1.62 - 1.50 (m, 4H), 0.93 - 0.87 (m, 6H); 13C NMR (CDC13) 5 164.2, 158.9 (d, J= 241.9 Hz), 146.5 (d, J = 12.1 Hz), 125.2 (d, J =3.0 Hz), 116.1 (d,J=9.6Hz), 109.0 (d, .7=22.3 Hz), 105.2 (d,J= 25.8 Hz), 75.2, 69.8, 67.8, 63.5, 52.8, 51.8,45.5, 31.9, 31.8, 29.4, 23.5, 17.0, 10.8.
[0324] To the pure compound (0.375 g, 1.03 mmol) dissolved in diethyl ether (4 mL) was added oxalic acid (0.097 g, 1.08 mmol) in diethyl ether (2 mL). The formed crystals filtered and washed with diethyl ether to give the title compound as oxalic salt (0.41 g, 88%); HPLC-MS (ammonium acetate) [M+H]+= 365.3.
(R )-4-[3-(4-Butyrpiperidin-1-yl)-2-methylpropyl] -7-fluoro-4H-benzo [ 1,4] oxazin-3 -one(lllMF29)
[0325] The compound (S)-7-Fluoro-4-(3-iodo-2-methylpropyl)-4H-
benzo[l,4]oxazin-3-one (111MF20)_(0.515 g, 1.47 mmol) and 4-butylidenepiperidine (0.205 g, 1.47 mmol) were mixed according to GP16. CC (Si02; Heptane/EtOAc 4:1-4) gave the title compound (111MF29) (0.393 g, 73%). *H NMR (CDC13) 8 7.17 - 7.12 (m, 1H), 6.74 - 6.69 (m, 2H), 5.15 - 5.11 (t, J= 7.2 Hz, 1H), 4.61 (q, J= 15.2 Hz, 2H), 4.04 -3.92 (m, 2H), 2.48 - 2.40 (m, 2H), 2.32 - 2.13 (m, 9H), 1.96 (q, J= 7.2 Hz, 2H), 1.38 -1.30 (m, 2H), 0.91 - 0.86 (m, 6H); 13C NMR (CDCI3) 8 164.1, 158.9 (d, J= 243 A Hz), 146.5 (d,J= 11.9 Hz), 136.1, 125.2 (d, J = 3.0 Hz), 128.9, 116.2 (d, J = 22.7 Hz), 109.0 (d, J= 22.7 Hz), 105.2 (d, J= 26.2 Hz), 67.8, 63.7, 56.5, 55.7, 54.6, 36.3, 29.3, 28.5, 23.3,17.1,13.9.
[0326] To the pure compound (0.393 g, 1.09 mmol) dissolved in diethyl ether (4 mL) was added oxalic acid (0.103 g, 1.14 mmol) in diethyl ether (2 mL). The formed crystals filtered and washed with diethyl ether to give the title compound as oxalic salt (0.46 g, 94%); HPLC-MS (ammonium acetate) [M+H]+= 361.3.
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(R)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl-7-fluoro-4H/-benzo[l,41oxazin-3-one (112KK05)
[0327] A microwave vial was charged with (iS)-7-fluoro-4-(3-Iodo-2-methylpropyl)-4#-benzo[l,4]oxazin-3-one (111MF20) (0.047 g, 0.13 mmol) and 3-butyl-8-azabicyclo[3,2,l]octane (0.039 g, 0.23 mmol) in MeCN (2 mL) and sealed. After microwave irradiation, 100 °C, 60 min, the reaction mixture was purified by cation exchange CC followed by flash CC (Si02; CH2Cl2/MeOH 50:1) to give the title compound (112KK05) (0.017 g, 33%). lU NMR (CD3OD) 5 7.34 - 7.30 (m, 1H), 6.80 -6.75 (m, 2H), 4.61 (ABq, J= 18.8 Hz, J= 15.1 Hz, CH2), 4.04 (dd, /= 14.3 Hz, J= 5.9 Hz, 1H), 3.93 (dd, J= 14.3 Hz, J= 8.2 Hz, 1H), 3.18-3.10 (m, 2H), 2.36 - 2.23 (m, 2H), 2.03 - 1.85 (m, 3H), 1.62 - 1.45 (m, 5H), 1.36-1.14 (m, 8H), 0.92 - 0.87 (m, 2 CH2); I3C NMR (CD3OD) 5 166.2,160.4 (d, J= 242.3 Hz), 148.1 (d, J= 11.9 Hz), 126.3 (d, J = 2.9 Hz), 118.1 (d, J= 9.7 Hz), 109.8 (d, J= 22.9 Hz), 105.7 (d, J= 26.5 Hz), 68.6, 62.5, 61.2, 58.3,46.4, 39.0, 37.9, 32.1, 30.2,29.0,27.8,27.2, 23.9, 17.2, 14.4.
[0328] The product was dissolved in MeOH/Et20 and oxalic acid dissolved in Et20 was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.016 g). HPLC-MS (ammonium acetate) [M+H]+= 389.34.
(R)-7-Fluoro-4-[2-methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl-propyl]-4H-benzo[1.41oxazin-3-one (111MF30)
[0329] The compound (5)-7-Fluoro-4-(3-iodo-2-methylpropyl)-4H-
benzo[l,4]oxazin-3-one (111MF20) (0.208 g, 0.59 mmol) and 3-Pentyl-8-azabicyclo[3.2.1]octane (0.106 g, 0.58 mmol) were mixed according to GP16. CC (Si02; Heptane/EtOAc 4:1-4) and prep HPLC gave the title compound (111MF30) (0.070 g, 29%). lH NMR (CDCI3) 5 7.23 - 7.19 (m, 1H), 6.66 - 6.60 (m, 2H), 4.60 - 4.46 (m, 2H), 4.05 - 3.99 (m, 1H), 3.95 - 3.90 (m, 1H), 3.06 - 3.03 (m, 1H), 2.99 - 2.96 (m, 1H), 2.24 -2.19 (m, 1H), 2.07 - 1.94 (m, 3H), 1.90 - 1.73 (m, 3H), 1.60 - 1.45 (m, 3H), 1.33 - 1.25 (m, 2H), 1.24 - 1.12 (m, 8H), 0.83 - 0.78 (m, 6H); 13C NMR (CDC13) 5 164.1,158.8 (d, J = 243.3 Hz), 146.4 (d,J= 11.5 Hz), 125.1 (d, J= 3.1 Hz), 116.6 (d, J= 9.3 Hz), 108.9 (d, J = 22.8 Hz), 105.0 (d, J= 25.7 Hz), 67.7, 60.9, 58.8, 58.1, 45.4, 38.3, 36.8, 36.6, 32.1, 31.6, 28.5, 28.4, 28.1, 27.0, 22.8, 17.0, 14.2.
[0330] To the pure compound (0.070 g, 0.17 mmol) dissolved in diethyl ether (1 mL) was added oxalic acid (0.016 g, 0.18 mmol) in diethyl ether (1 mL). The formed
91

crystals filtered and washed with diethyl ether to give the title compound as oxalic salt (0.082 g, 96 %); HPLC-MS (ammonium acetate) [M+H]+= 402.56
(R)-4-[3-(4-Butyrpiperidin-1-yl)-2-methylpropyl]-6-methoxv-4H-benzo[1,4]oxazin-3-one (111MF38)
[0331] The compound (S)-4-(3-Iodo-2-methylpropyl)-6-methoxy-4H-benzo[ 1,4] oxazin-3-one (111MF36) (0.636 g, 1.77 mmol) and 4-butylpiperidine (0.226 g, 1.6 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) and prep HPLC gave the title compound (111MF38) (0.245 g, 27%). 1H NMR (CDC13) 8 6.89 (d, J = 8.8 Hz, IH), 6.72 (d, J= 2.4 Hz, IH), 6.50 (dd, J = 2.8, J = 8.8 Hz, IH), 4.54 (q, J = 32.4, J= 14.8, 2H), 3.94 - 3.90 (m, 2H), 3.77 (s, 3H), 2.90 (d, J= 11.2 Hz, IH), 2.72 (d, J = 10.8 Hz, IH), 2.25 - 2.10 (m, 3H), 1.93 (t, J= 11.2 Hz, IH), 1.80 (t, J= 11.2 Hz, IH), 1.61 (d, J= 10.8 Hz, 2H), 1.31 - 1.19 (m, 9H), 0.90 - 0.86 (m, 6H); 13C NMR (CDC13) 8 165.3, 155.5, 139.7, 129.8, 117.2, 107.1, 103.3, 68.0, 64.2, 55.9, 55.7, 54.5, 45.5, 36.5, 36.0, 32.9, 32.5, 29.2,29.2,23.1,16.9,14.3.
[0332] To the pure compound (0.245 g, 0.65 mmol) dissolved in diethyl ether (2 mL) was added oxalic acid (0.062 g, 0.68 mmol) in diethyl ether (2 mL). The formed crystals filtered and washed with diethyl ether to give the title compound as oxalic salt (0.229 g, 75 %) HPLC-MS (ammonium acetate) [M+H]+= 375.3.
(R )-4-[3-(4-Butyrpiperidin-1-yl)-2-methylpropyl]-6-methoxy-4H-benzo[l,4]oxazin-3-one(111MF39)
[0333] The compound (5)-4-(3-Iodo-2-methylpropyl)-6-methoxy-4H-benzo[l,4]oxazin-3-one (111MF36) (0.612 g, 1.69 mmol) and 4-butylidenepiperidine (0.212 g, 1.5 mmol) were mixed according to GP16. CC (Si02; Heptane/EtOAc 4:1-4) gave the title compound (111MF39) (0.489 g, 77%). !H NMR (CDC13) 8 6.90 (d, J= 8.4 Hz, IH), 6.73 (d, J= 2.8 Hz, IH), 6.50 (dd, J= 8.4 Hz, J= 2.8 Hz, IH), 5.11 (t, J = 7.6 Hz, IH), 4.54 (q, J= 14.4 Hz, 2H), 3.97 - 3.94 (d, J= 6.8 Hz, 2H), 3.78 (s, 3H), 2.48 -2.41 (m, 2H), 2.33 - 2.23 (m, 5H), 2.20 - 2.13 (m, 4H), 1.96 (q, J= 7.4 Hz, 2H), 1.40 -1.29 (m, 2H), 0.91 - 0.86 (m, 6H); 13C NMR (CDCI3) 8 165.3, 155.5, 139.8, 136.5, 129.8, 122.5, 117.2, 107.0, 103.4, 68.1, 63.8, 56.5, 56.0, 55.7, 45.5, 36.2, 29.3, 29.2, 28.4, 23.3, 16.9,13.9; HPLC-MS; (ammonium acetate) [M+H]+= 373.3.
92

(R)-4-[3-3-Butyl-8-azabicyclo[3.2.1]oct-8-yl-2-methylpropyl]-6-methoxy-4H-benzo[1.4]oxazin-3-one (111MF40)
[0334] The compound (5)-4-(3-Iodo-2-methylpropyl)-6-methoxy-4H-benzo[l,4]oxazin-3-one (111MF36) (0.239 g, 0.66 mmol) and 3-Butyl-8-aza-bicyclo[3.2.1]octane (0.100 g, 0.60 mmol) were mixed according to GP16. CC (Si02; Heptane/EtOAc 4:1-4) gave the title compound (111MF40) (0.163 g, 61%). H NMR (CDC13) 5 6.88 (d, J= 8.8 Hz, 1H), 6.85 (d, J= 2.8 Hz, 1H), 6.49 (dd, J= 8.8 Hz, J= 2.8 Hz, 1H), 4.61 - 4.47 (m, 2H), 4.01 - 3.99 (m, 2H), 3.77 (s, 3H), 3.17 - 3.04 (m, 2H), 2.35 - 2.29 (m, 1H), 2.14 - 1.79 (m, 3H), 1.57 - 1.13 (m, 6H), 0.88 (m, 3H); 13C NMR (CDCI3) 5 165.4, 155.6, 139.8, 129.8, 117.1, 107.0, 103.8, 68.0, 61.6, 60.2, 58.1, 56.0, 45.4, 38.5, 38.4, 36.9, 31.6, 29.4, 28.2, 27.3, 26.5, 23.9, 14.3; HPLC-MS (ammonium acetate) [M+H]+= 401.3.
(R)-6-Methoxy-4-[2-methyl-3-(3-pentyl-8-aza-bicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]oxazin-3-one (111MF41)
[0335] The compound (S)-4-(3-Iodo-2-methylpropyl)-6-methoxy-4H-benzo[l,4]oxazin-3-one (111MF36) (0.226 g, 0.63 mmol) and 3-pentyl-8-azabicyclo[3.2.1]octane (0.101 g, 0.56 mmol) were mixed according to GP16. CC (SiC^; heptane/EtOAc 4:1-4) and prep HPLC gave the title compound (111MF41) (0.101 g, 39%). !H NMR (CDCI3) 8 6.89 (d, J= 8.8 Hz, 1H), 6.81 (d, J= 2.8 Hz, 1H), 6.49 (dd, J= 8.8 Hz, J= 2.8 Hz, 1H), 4.60 - 4.46 (m, 2H), 4.01 (d, J= 6.8 Hz, 2H), 3.77 (s, 3H), 3.15 -3.02 (m, 2H), 2.32 - 2.26 (m, 1H), 2.20 - 1.79 (m; 7H), 1.68 - 1.51 (m, 3H), 1.42 - 1.16 (m, 10H), 0.89 - 0.85 (m, 6H); 13C NMR (CDCI3) 6 168.4, 155.6, 139.8, 129.8, 117.0, 106.9, 103.8, 68.0, 60.6, 59.1, 58.1, 56.0, 45.3, 39.4, 36.6, 36.4, 32.2, 31.5, 28.4, 28.4, 28.0,27.3,22.8,16.8,14.2; HPLC-MS (ammonium acetate) [M+H]+= 415.3.
(R)-6-Methoxy-4-[2-methyl-3-(4-Propoxypiperidin-l-yl)propyl]-4H-benzo[1.4]oxazin-3-one(111MF42)
[0336] The compound (S)-4-(3-Iodo-2-methylpropyl)-6-methoxy-4H-benzo[l,4]oxazin-3-one (111MF36) (0.556 g, 1.5 mmol) and 4-propyloxypiperidine (0.20 g, 1.4 mmol) were mixed according to GP16. CC (SiCh; Heptane/EtOAc 4:1-4) gave the title compound (111MF42) (0.30 g, 53%). 1H NMR (CDC13) 5 6.89 (d, J= 8.8 Hz, 1H), 6.85 (d, 2.8 Hz, 1H), 6.49 (dd, 7 = 8.8 Hz, J=2.8 Hz, 1H), 4.53 (q, J= 14.6 Hz, 2H), 3.93
93

(d, J= 6.6 Hz, 2H), 3.77 (s, 3H), 3.38 (t, J= 6.8 Hz, 2H), 3.29 - 3.22 (m, 1H), 2.80 - 2.77 (t, 6.4 Hz, 1H), 2.65 - 2.61 (t, J= 6.0 Hz, 1H), 2.29 - 2.00 (m, 5H), 1.88 - 1.84 (m, 2H), 1.65 - 1.53 (m, 4H), 0.94 - 0.87 (m, 6H); 13C NMR (CDC13) 8 165.4,155.5,139.8,129.8, 117.2, 107.1, 103.3, 75.1, 69.7, 68.0, 63.7, 56.0, 52.5, 51.9, 45.4, 31.6, 31.5, 29.2, 23.5, 16.9,10.8; HPLC-MS (ammonium acetate) [M+H]+= 377.3.
GENERAL PROCEDURE 17 (GP17)
[0337] A 7 mL vial was charged with the crude 4-(3-iodo-2-methylpropyl)-6-methyl-4H-benzo[l,4]oxazin-3-one (1 equiv), Et3N (0.5 mL) and the secondary amine (1.2-1.5 equiv). This mixture was shaken at 60 °C for 72 h and thereafter diluted with MeOH (10 mL) and concentrated with basic AI2O3 (2 g) and purified by flash chromatography.
(R)-6-Methyl-4-[2-methyl-3-(4-Propoxypiperidin-l-yl)-propyl]-4H-benzo[1,4]oxazin-3-one (101IS69)
[0338] Crude (S)-4-(3-iodo-2-methylpropyl)-6-methyl-4H/-benzo[l,4]oxazin-3-one (0.23 g), 4-propyloxypiperidine (0.12 g, .81 mmol) and Et3N (0.5 mL) were reacted according to GP17. Flash CC (SiO2; CH2Cl2/acetone/MeOH 90:5:5) gave the title compound (0.20 g, 83%). lH NMR (CD3OD) 5 6.97 (brs, 1H), 6.79 (d, J= 8.0 Hz, 1H), 6.75 (dm, J= 8.0 Hz, 1H), 4.47 (brs, 2H), 3.97 (dd, J= 6.4, 14.4 Hz, 1H), 8.82 (dd, J = 7.2, 14.4 Hz, 1H), 3.44 (brs, 1H), 3.33 (t, J= 6.8 Hz, 2H), 3.10 - 2.90 (m, 2H), 2.90 - 2.6 (m, 3H), 2.29 (m, 1H), 2.24 (s, 3H), 1.98 - 1.86 (m, 2H), 1.78 - 1.64 (m, 2H), 1.47 (tq, J= 14.4, 7.2 Hz, 2H), 0.92 (d, J= 6.4 Hz), 0.83 (t, J= 7.2 Hz); 13C NMR (CD3OD) 8 166.4, 143.8, 132.8, 128.3, 124.7, 116.7, 116.1, 69.9, 67.4, 61.5, 50.7, 50.5, 44.1, 28.9, 28.6, 23.0, 20.0 15.6, 9.8.
[0339] The product was dissolved in diethyl ether and oxalic acid (1.1 equiv) dissolved in diethyl ether was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.204 g). HPLC-MS (ammonium acetate) [M+H]+= 361.3.
94

(R)-4-[3-(4-Butyrpiperidin-1-yl)-2-methylpropyl]-6-methoxy-4H-benzo[l,4]oxazin-3-one(101IS71-A)
[0340] Crude (S>4-(3-iodo-2-methylpropyl)-6-methyl-4H-benzo[l,4]oxazin-3-one (0.34 g), Et3N (0.5 mL) and 4-butylidenepiperidine (0.17 g, 1.2 mmol) were reacted according to GP17. Flash CC (Si02; CH2Cl2/acetone/MeOH 90:7:3) gave the title compound (0.22 g, 58%). !H NMR (CD3OD) 8 7.01 (s, 1H), 6.86 (d, J= 8.0 Hz, 1H), 6.82 (dm, J= 8.0 Hz, 1H), 5.12 (t, J= 7.2 Hz, 1H), 4.52 (ABq, J = 14.8, 20.8 Hz, 2H), 4.03 (dd, J= 5.6, 14.4 Hz, 1H), 3.91 (dd, J= 8.0, 14.4 Hz, 1H), 2.48 - 2.34 (m, 2H), 2.33 - 2.11 (m, 8H), 2.31 (s, 3H), 1.96 (q, J= 12 Hz, 2H), 1.34 (m, 2H), 0.91 - 0.86 (m, 6H); 13C NMR (CD3OD) 8 165.9, 143.9, 136.0, 132.4, 128.3, 124.3, 122.4, 116.6, 116.2, 67.4, 63.6, 56.3, 55.4, 45.0, 28.92, 28.85, 28.0, 23.0, 20.0, 15.9, 12.8.
[0341] The product was dissolved in diethyl ether and oxalic acid (1.1 equiv) dissolved in diethyl ether was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.236 g). HPLC-MS (ammonium acetate) [M+H]+= 367.3.
(R )-4-[3-(4-Butyrpiperidin-1-yl)-2-methylpropyl]-6-methoxy-4H-benzo[l,4]oxazin-3-one (101IS71-D)
[0342] Crude (S)-4-(3-iodo-2-methylpropyl)-6-methyl-4#-benzo[l,4]oxazin-3-one (0.30 g), Et3N (0.5 mL) and 4-butylpiperidine (0.15 g, 1.0 mmol) were reacted according to GP17. Flash CC (Si02; CH2Cl2/acetone/MeOH 90:7:3) gave the title compound (0.26 g, 84%). 'H NMR (CD3OD) 8 7.00 (s, 1H), 6.86 (d, J = 8.0 Hz, 1H), 6.81 (dm, J= 8.0Hz, 1H), 4.52 (ABq, J= 14.4, 20.8 Hz, 2H), 3.99 (dd, J= 6.0, 14.4 Hz, 1H), 3.90 (dd, J= 8.4, 14.4 Hz, 1H), 2.97 (brd, J= 11.2 Hz, 1H), 2.82 (brd, J= 8.4 Hz, 1H), 2.39 - 2.10 (m, 2H), 2.31 (s, 3H), 2.07 - 1.88 (m, 2H), 1.73 - 1.62 (m, 2H), 1.35 -1.18 (m, 9H), 0.94 - 0.08 (m, 6H); 13C NMR (CD3OD) 8 166.0, 143.8, 132.4, 128.3, 124.3, 116.6, 116.2, 67.4, 63.6, 55.0, 54.2, 44.8, 36.2, 35.6, 32.1 (br), 28.9, 28.8, 22.8, 20.0,15.9,13.2.
[0343] The product was dissolved in diethyl ether and oxalic acid (1.1 equiv) dissolved in diethyl ether was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.253 g). HPLC-MS (ammonium acetate) [M+H]+= 359.3.
95

(R )-4-[3-(4-Butyrpiperidin-1-yl)-2-methylpropyl]-6-methyl-4H-benzo[1.4]oxazin-3-one(101IS71-B3)
[0344] Crude (5)-4-(3-iodo-2-methylpropyl)-6-methyl-4H-benzo[ 1,4]oxazin-3-one (0.19 g, 0.54 mmol), Et3N (0.5 mL) and 3-butyl-8-azabicyclo[3.2.1]octane (0.10 g, 0.61 mmol) were reacted according to GP17. Flash CC (Si02; CH2Cl2H-PrOH 92:8) gave the title compound (0.13 g, 62%). *H NMR (CD3OD) 8 7.05 (s, IH), 6.86 (d, J= 8.4 Hz, 1 H), 6.81 (dm, J= 8.4 Hz, IH), 4.52 (ABq J= 14.8, 24.8 Hz, 2H), 4.05 (dd, J= 5.6, 14.0 Hz, IH), 3.94 (dd, J- 8.8, 14.0 Hz, IH), 3.05-3.16 (m, 2H), 2.35-2.14 (m, 2H), 2.31 (s, 3H), 2.05-1.78 (m, 3H), 1.63-1.40 (m, 5H), 1.36-1.12 (m, 5H), 0.99 (d, J= 6.4 Hz, 3H), 0.90 (t, J= 6.8 Hz, 3H); 13C NMR (CD3OD) 8 167.4, 144.9, 133.7, 129.2, 125.6, 117.7, 117.3, 68.5,63.2 (br),62.5(br), 56.0(Br), 43.3, 37.8 (br), 31.3, 30.5, 30.0, 28.3, 26.7, 26.4, 23.7,21.0,16.8,14.2.
[0345] The product was dissolved in diethyl ether and oxalic acid (1.1 equiv) dissolved in diethyl ether was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.104 g). HPLC-MS (ammonium acetate) [M+H]+= 349.3.
(R)-4-[3-(3-Pentyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-methyl-4H-benzo[1.4]oxazin-3-one(101IS71-C3)
[0346] Crude (5)-4-(3-Iodo-2-methylpropyl)-6-methyl-4H-benzo[l,4]oxazin-3-one (0.15 g), Et3N (0.5 mL) and 3-pentyl-8-azabicyelo[3.2.1]octane (95 mg, 5.2 mmol) were reacted according to GP17. Flash CC (SiO2; CH2Cl2/I-PrOH 92:8) gave the title compound (0.12 g, 68%). *H NMR (CD3OD) 8 7.06 (s, IH), 6.86 (d, J= 8.0 Hz, IH), 6.81 (brd, J= 8.0 Hz, IH), 4.52 (ABq, J= 14.8, 27.2 Hz, 2H), 4.06 (dd, J= 5.6, 14.2 Hz, IH), 4.96 (dd, y = 8.8, 14.2 Hz, IH), 3.16-3.02 (m, 2H), 2.34-2.07 (m, 7H), 2.3 l(s, 3H), 2.04-1.81 (m, 3H), 1.70-1.55 (m, 3H), 1.46-1.21 (m, 10H), 0.92-0.85 (m, 6H); 13C NMR (CD3OD) 8 167.2, 145.1, 133.6, 129.4, 125.5, 117.7, 117.5, 68.7, 61.6, 60.2, 58.6, 46.1, 39.6, 37.2, 36.9, 33.1, 32.4, 29.6, 29.5,28.5,27.8,23.7, 21.18,17.0,14.4.
[0347] The product was dissolved in diethyl ether and oxalic acid (1.1 equiv) dissolved in diethyl ether was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.128 g). HPLC-MS (ammonium acetate) [M+H]+= 399.3.
96

1-[3-(4-Propoxypiperidin-l-yl)propyl]-3,4-dihydro-1H-quinolin-2-one (85LM32)
[0348] A 4 mL vial was charged with crude l-(3-chloro-propyl)-3,4-dihydro-ltf-quinolin-2-one (85LM31) (0.200 g), 4-propoxy-piperidine (79KS-66) (0.130 g, 0.897 mmol), potassium carbonate (0.247 g, 1.79 mmol) and sodium iodide (0.269 g, 1.79 mmol) in MeCN (2 mL) and shaken at 50°C for 20 h. The reaction mixture was quenched with water (1 mL), and the product was extracted into EtOAc (3x1 mL). The combined organic layers were dried over Na2SO4, evaporated and purified by flash CC (SiC^; MeOH/DCM 0:1 -► 3:7) to give the title compound (85LM32) (0.012 g, total yield 3%). !H NMR (CDC13) 8 7.25 (t, J= 7.4 Hz, 1H), 7.18 - 7.08 (m, 2H), 6.98 (t, J= 7.4 Hz, 1H), 3.98 (t, J= 7.6 Hz, CH2), 3.38 (t, J= 6.8 Hz, CH2), 3.35 - 3.25 (m, 1H), 2.87 (t, J= 7.6 Hz, CH2), 2.80 - 2.70 (m, 2H), 2.65 - 2.60 (m, 2H), 2.45 - 2.35 (m, 2H), 2.20 - 2.10 (m, 2H), 1.95 - 1.80 (m, 4H), 1.65 - 1.50 (m, 4H), 0.95 (t, J = 7.6 Hz, CH3); 13C NMR (CDCI3) 5 170.2, 140.0, 128.2, 127.5, 126.6, 122.8, 115.3, 70.0, 56.0, 51.8, 40.5, 32.0, 31.5,25.8,25.2,22.8,10.7; HPLC-MS (ammonium acetate) [M+H]+= 331.3.
1 - [3-(4-Butylpiperidin-1-yl)propyl] -6-fluoro-3.4-dihydro-1H-quinolin-2-one (92LH81)
[0349] A 4 mL vial was charged with l-(3-chloropropyl)-6-fluoro-3,4-dihydro-lH-quinolin-2-one (92LH79) (0.090 g, 0.37 mmol), 4-butylpiperidine (0.078 g, 0.55 mmol), KI (0.091 g, 0.55 mmol), and K2C03 (0.076 g, 0.55 mmol) in MeCN and shaken at 50 ° for 20 h. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. The product was purified by flash CC (Si02; EtOAc) to give the title compound (92LH81) (0.090 g, 70%). XH NMR (CD3OD) 5 7.19 - 7.15 (m, 1H), 6.99 -6.97 (m, 2H), 3.97 (t, J= 6.4 Hz, CH2), 2.90 - 2.87 (m, 4H), 2.59 (t, J = 7.6 Hz, CH2), 2.38 (t, J= 7.6 Hz, CH2); 1.96 - 1.78 (m, 4H), 1.67 (d, / = 9.6 Hz, 2H), 1.29 - 1.22 (m, 9H), 0.90 - 0.88 (m, 3H); 13C NMR (CD3OD) 8 172.1, 160.0 (d, J= 241.8 Hz), 136.7 (d, .7=2.3 Hz), 130.6 (d, J =7.7 Hz), 117.8 (d,J= 8.1 Hz), 115.9 (d,J= 23.1 Hz), 114.6(d, J= 22.7 Hz), 57.0, 55.0, 41.6, 37.4, 36.9, 33.1, 32.4, 30.1, 26.2, 25.5, 23.9, 14.4; HPLC-MS (ammonium acetate) [M+H+] = 347.33.
97

6-Fluoro-1 - [3 -(4-Propoxypiperidin-1-yl)propyl] -3,4-dihydro-1 H-quinolin-2-one (107LH70)
[0350] A 4 mL vial was charged with 1 -(3 -chloropropyl)-6-fluoro-3,4-dihydro- 1H-quinolin-2-one (92LH79) (0.242 g, 1.00 mmol), 4-propoxypiperidine (0.143 g, 1.00 mmol), KI (0.250 g, 1.50 mmol), and K2C03 (0.207 g, 1.50 mmol) in MeCN (2 mL) and shaken at 40 ° for 20 h. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. The product was purified by flash CC (Si02; EtOAc, MeOH/EtOAc 1:4) to give the title compound (107LH70) (0.165 g, 47%). *H NMR (CD3OD) 8 7.19 - 7.15 (m, IH), 7.01 - 6.97 (m, 2H), 3.96 (t, J= 7.4 Hz, CH2), 3.40 (t, J = 6.6 Hz, CH2), 3.35 - 3.30 (m, 3H), 2.88 (t, J= 6.8 Hz, 2H), 2.76 (m, 2H), 2.60 - 2.57 (m, 2H), 2.43 - 2.39 (m, 2H), 2.22 - 2.17 (m, 2H), 1.90 - 1.78 (m, 4H), 1.61-1.50 (m, 4H), 0.91 (t, J = 7.4 Hz, CH3); 13C NMR (CD3OD) 5 172.2, 160.0 (d, J = 242.2 Hz), 136.7 (d, J= 2.3 Hz), 130.6 (d, J= 7.7 Hz), 117.8 (d, J= 8.5 Hz), 115.9 (d, J = 23.1 Hz), 114.64 (d, J= 22.3 Hz), 75.6, 70.7, 56.5, 52.0, 41.6, 32.4, 31.8, 26.1, 25.5, 24.2, 11.0; HPLC-MS (ammonium acetate) [M+H+] = 349.30.
(R )-4-[3-(4-Butyrpiperidin-1-yl)-2-methylpropyl]-6-fluoro-3,4-dihydro-1 H-quinolin-2-one (107LH71-1)
[0351] A 4 mL vial was charged with crude (R,S)-l-(3-chloro-2-memylpropyl)-6-fluoro-3,4-dihydro-lH-quinolin-2-one (107LH68) (0.154 g), 4-butylpiperidine (0.141 g, 1.0 mmol), KI (0.250 g, 1.5 mmol), and K2C03 (0.207 g, 1.5 mmol) in DMF (2 mL) and shaken at 100 ° for 20 h. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2SC>4, filtered, and concentrated. The crude product was purified by cation exchange CC and flash CC (Si02; EtOAc) to give the title compound (107LH77-1) (0.069 g, total yield 13%). !H NMR (CD3OD) 5 7.22 - 7.18 (m, IH), 7.00 - 6.93 (m, IH), 3.94 (d, J= 6.8 Hz, 2H), 2.91 - 2.86 (m, 3H), 2.74 (d, J= 10.2 Hz, IH), 2.62 - 2.58 (m, 2H), 2.24 - 2.02 (m, 3), 1.90 - 1.81 (m, 2H), 1.66 - 1.61 (m, 2H), 1.30-1.19 (m, 9H), 0.89 (t, J= 6.6 Hz, CH3), 0.86 (d, J= 6.1 Hz, CH3); 13C NMR (CD3OD) 8 172.7, 160.0 (d, J = 241.8Hz), 136.7 (d, J= 2.7 Hz), 130.9 (d, J= 8.1 Hz), 118.4 (d, J= 8.1 Hz), 115.9 (d, J= 23.5 Hz), 114.4 (d, J= 22.7 Hz), 65.0, 56.1, 55.6, 46.9, 37.5, 37.0, 33.5, 33.4, 32.6, 30.1, 30.1,26.2,24.0,17.2,14.4.
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[0352] The product was dissolved in acetone and oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.076 g). HPLC-MS (ammonium acetate) [M+H]+= 361.32.
(R,S)-6-Fluoro-1-[3–(4-Propoxypiperidin-1-yl )-2-methylpropyl] -3.4-dihydro-1 H-quinolin-2-one (107LH71-2)
[0353] A 4 mL vial was charged with crude (i?,iS)-l-(3-chloro-2-methylpropyl)-6-fluoro-3,4-dihydro-1H-quinolin-2-one (107LH68) (0.154 g), 4-propoxypiperidine (0.143 g, 1.0 mmol), KI (0.250 g, 1.5 mmol), and K2C03 (0.207 g, 1.5 mmol) in DMF (2 mL) and shaken at 100 ° for 20 h. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2SC>4, filtered, and concentrated. The crude product was purified by cation exchange CC and flash CC (Si02; EtOAc) to give the title compound (107LH77-2) (0.053 g, total yield 10%). *H NMR (CD3OD) 5 7.23 - 7.19 (m, 1H), 7.00 - 6.95 (m, 1H), 3.95 (d, J= 7.0 Hz, 2H), 3.41 (t, J= 6.6 Hz, CH2), 3.31 - 3.27 (m, 1H), 2.90 (t, J= 6.6 Hz, 2H), 2.74 - 2.71 (m, 1H), 2.64 - 2.58 (m, 3H), 2.26 - 2.00 (m, 5H), 1.89 - 1.85 (m, 2H), 1.60 - 1.49 (m, 4H), 0.91 (t, J = 7.4 Hz, CH3), 0.86 (d, J = 6.7 Hz, CH3); 13C NMR (CD3OD) 8 172.7, 160.0 (d, J= 242.2 Hz), 136.7 (d, J= 2.7 Hz), 130.9 (d, J= 7.7 Hz), 118.3 (d, J= 8.1 Hz), 115.9 (d, J= 23.1 Hz), 114.5 (d, J= 22.7 Hz), 76.4, 70.7, 64.4, 53.2, 52.8, 46.9, 32.5, 32.4, 32.3, 30.3, 26.17, 26.15, 24.2, 17.1, 11.0.
[0354] The product was dissolved in acetone and oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.048 g). HPLC-MS (ammonium acetate) [M+H]+= 363.30.
1 -[3-(4-Butylpiperidin-1 -vDpropyl]-6-chloro-3.4-dihydro-1 H-quinolin-2-one (107LH36)
[0355] A reaction flask was charged with 6-chloro-3,4-dihydro-lH-quinolin-2-one (107LH30) (0.100 g, 0.55 mmol) in dry DMF (2 mL) under Argon. NaH (60% in oil, 0.024 g, 0.60 mmol) was added and the mixture was stirred at rt for 0.5 h. Then 1-bromo-3-chloropropane (0.087 g, 0.55 mmol) was added followed by stirring at 30 ° for 20 h. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. The crude material was dissolved in MeCN (3 mL) followed by addition of 4-butylpiperidine (0.078 g, 0.055 mmol), KI (0.166 g, 1.00 mmol), and K2C03 (0.138 g, 1.00 mmol) and
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shaken at 50 ° for 2 days. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by prep RP-HPLC to give the title compound (107LH36) (0.047 g, 24%). !H NMR (CD3OD) 5 7.25 - 7.13 (m, 3H), 3.96 (t, J= 7.2 Hz, CH2), 2.95 - 2.86 (m, 4H), 2.61 - 2.57 (m, 2H), 2.45 - 2.41 (m, 2H), 2.04 - 1.98 (m, 2H), 1.87 - 1.79 (m, 2H), 1.28 - 1.18 (m, 9H), 0.90 (t, J= 7.0 Hz, CH3); 13C NMR (CD3OD) 5
172.3, 139.2, 130.2, 129.3, 128.9, 128.4, 117.8, 56.8, 54.9, 41.4, 37.2, 36.6, 32.9, 32.4,
30.0,26.0, 25.3, 23.9, 14.4; HPLC-MS (ammonium acetate) [M+H+] - 363.28.
1-[3-(4-Butylpiperidin-1-yl)propyl]-6-methyl-3.4-dihydro-1H-quinolin-2-one (107LH18-
I)
[0356] A 4 mL vial was charged with crude l-(3-chloropropyl)-6-methyl-3,4-dihydro-1H-quinolin-2-one (107LH14) (0.128 g), 4-butylpiperidine (0.076 g, 0.54 mmol), KI (0.166 g, 1.00 mmol), and K2CO3 (0.138 g, 1.00 mmol) in MeCN (2 mL) and shaken at 50 ° for 20 h. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. The product was purified by flash CC (SiCh; EtOAc, MeOH/EtOAc 1:4) to give the title compound (107LH18-1) (0.088 g, total yield 41%). *H NMR (CD3OD) 8 7.07 - 7.01 (m, 3H), 3.94 (t, J= 7.4 Hz, CH2), 2.90 - 2.80 (m, 4H), 2.57 - 2.53 (m, 2H), 2.39 - 2.33 (m, 2H), 2.27 (s, 3H, CH3), 1.95 - 1.90 (m, 2H), 1.85 - 1.79 (m, 2H), 1.66 (d, J= 9.8 Hz, 2H), 1.30 - 1.17 (m, 9H), 0.89 (t, J= 6.8 Hz, CH3); 13C NMR (CD3OD) 5
172.4, 137.9, 134.1, 129.8, 129.0, 128.0, 116.3, 57.1, 55.0, 41.3, 37.4, 36.8, 33.1, 32.8,
30.1, 26.2, 25.5, 23.9, 20.7, 14.4; HPLC-MS (ammonium acetate) [M+H+] = 343.33.
6-Methyl-1-[3 -(4-Propoxypiperidin-1-yl)propyl] -3,4-dihydro-1 H-quinolin-2-one (107LH18-2)
[0357] A 4 mL vial was charged with l-(3-Chloropropyl)-6-methyl-3,4-dihydro-lH-quinolin-2-one (107LH14) (0.128 g), 4-propoxypiperidine (0.079 g, 0.54 mmol), KI (0.166 g, 1.0 mmol), and K2C03 (0.138 g, 1.0 mmol) in MeCN (2 mL) and shaken at 50 ° for 20 h. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. The product was purified by flash CC (Si02; EtOAc, MeOH/EtOAc 1:4) to give the title compound (107LH18-2) (0.108 g, total yield 50%). lH NMR (CD3OD) 8
100
7.05 - 7.00 (m, 3H), 3.95 (t, J= 12, CH2), 3.41 - 3.30 (m, 3H), 2.84 - 2.76 (m, 4H), 2.57 - 2.53 (m, 2H), 2.47 - 2.43 (m, 2H), 2.27 (s, 3H, CH3), 2.27 - 2.22 (m, 2H), 1.90-1.81 (m, 4H), 1.63 - 1.52 (m, 4H), 0.91 (t, J= 7.4 Hz, CH3); 13C NMR (CD3OD) 8 172.4, 137.8, 134.0, 129.8, 129.0, 128.0, 116.2, 75.3, 70.7, 56.5, 51.9, 41.2, 32.8, 31.7, 26.2, 25.5, 24.3,20.7,11.0; HPLC-MS (ammonium acetate) [M+H+] = 345.30.
1 –[3-(4-Butylpiperidin-1-yl)propyl]-7-fluoro-3.4-dihydro-1H-quinolin-2-one (107LH21)
[0358] A reaction flask was charged with 7-fluoro-3,4-dihydro-lH-quinolin-2-one (97LH36) (0.080 g, 0.48 mmol) in dry DMF (2 mL) under Argon. NaH (60% in oil, 0.021 g, 0.53 mmol) was added and the mixture was stirred at rt for 0.5 h. Then 1-bromo-3-chloropropane (0.075 g, 0.48 mmol) was added followed by stirring at rt for 20 h. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was dissolved in MeCN (3 mL) followed by addition of 4-butylpiperidine (0.071 g, 0.50 mmol), KI (0.166 g, 1.00 mmol), and K2CO3 (0.138 g, 1.00 mmol) and shaken at 50 ° for 4 days. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. The product was purified by flash CC (Si02; EtOAc) to give the title compound (107LH21) (0.062 g, 37%). 1H NMR (CD3OD) 8 7.20 - 7.17 (m, IH), 7.01 -6.98 (m, IH), 6.76 - 6.72 (m, IH), 3.95 (t, J= 7.4 Hz, CH2), 2.93 - 2.84 (m, 4H), 2.61 -2.57 (m, 2H), 2.42 - 2.38 (m, 2H), 2.00 - 1.94 (m, 2H), 1.84 - 1.80 (m, 2H), 1.68 (d, J = 10.0 Hz, 2H), 1.30 - 1.22 (m, 9H), 0.89 (t, J= 6.8 Hz, CH3); HPLC-MS (ammonium acetate) [M+H+] = 347.31.
l-[3-(4-Butylpiperidin-1-yl)propyl]-5-methyl-3.4-dihydro-lH-quinolin-2-one(107LH28)
[0359] A 4 mL vial was charged with l-(3-chloropropyl)-5-methyl-3,4-dihydro-1H-quinolin-2-one (107LH27-11,3) (0.057 g, 0.24 mmol), 4-butylpiperidine (0.042 g, 0.30 mmol), KI (0.083 g, 0.50 mmol), and K2CO3 (0.069 g, 0.50 mmol) in MeCN and shaken at 50 °. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. The product was purified by flash CC (SiO2; EtOAc, MeOH/EtOAc 1:4) to give the title compound (107LH28) (0.060 g, 74%). 1H NMR (CD3OD) 8 7.15 (t, J= 8.0 Hz, IH), 7.03 (d, J= 8.2 Hz, IH), 6.92 (d, J= 7.4 Hz), 4.00 (t,
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J= 7.2 Hz, CH2), 3.10 (d, J = 12.1 Hz, 2H), 2.87 - 2.83 (m, 2H), 2.66 - 2.62 (m, 2H) 2.59 -2.55 (m, 2H), 2.31-2.25 (m, 2H), 2.29 (s, CH3), 1.93 - 1.87 (m, 2H), 1.76 (d, J= 11.7 Hz, 2H), 1.31 - 1.24 (m, 9H), 0.90 (t, J= 6.8 Hz, CH3); 13C NMR (CD3OD) 5 172.7, 140.2, 137.0, 128.1, 126.6, 126.5, 114.5, 56.5, 54.6, 41.2, 37.0, 36.0, 32.2, 32.2, 30.0, 25.0,23.9,22.4,19.7,14.4; HPLC-MS (ammonium acetate) [M+H+] = 343.36.
1-[3-(4-Butylpiperidin-1-yl)propyl]-7-methyl-3.4-dihydro-1H-quinolin-2-one (107LH29)
[0360] A 4 mL vial was charged with l-(3-chloropropyl)-7-methyl-3,4-dihydro-lH-quinolin-2-one (107LH27-13,1) (0.117 g, 0.49 mmol), 4-butylpiperidine (0.071 g, 0.50 mmol), KI (0.166 g, 1.00 mmol), and K2CO3 (0.138 g, 1.00 mmol) in MeCN and shaken at 50 °. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; EtOAc, MeOH/EtOAc 1:4) to give the title compound (107LH28) (0.060 g, 74%). *H NMR 5 7.06 (d, J= 7.4 Hz, 1H), 6.97 (s, 1H), 6.84 (d. J= 7.6 Hz, 1H), 3.97 (t, J- 7.4 Hz, CH2), 2.91 (d, J= 11.2 Hz, 2H), 2.82 (t, J= 6.8 Hz, CH2), 2.57 - 2.54 (m, 2H), 2.41 - 2.37 (m, 2H), 2.33 (s, CH3), 1.98 - 1.92 (m, 2H), 1.87 - 1.79 (m, 2H), 1.68 (d, J = 9.6 Hz, 2H), 1.30 - 1.17 (m, 9H), 0.89 (t, J= 6.8 Hz, CH3); 13C NMR (CD3OD) 5 172.7, 140.1, 138.5, 128.9, 125.1, 124.9, 117.0, 57.0, 55.0, 41.3, 37.3, 36.8, 33.1, 30.1, 25.8, 25.6, 23.9, 21.6, 14.4; HPLC-MS (ammonium acetate) [M+H]+ = 343.37.
1-[3-(4-Butylpiperidin-1-yl)propyl]-7-fluoro-6-methyl-3,4-dihydro-1 H-quinolin-2-one (112KK06)
[0361] A 4 mL vial was charged with l-(3-chloropropyl)-7-fiuoro-6-methyl-3,4-dihydro-lH-quinolin-2-one (112KK01) (0.047 g, 0.18 mmol), 4-butylpiperidine (0.039 g, 0.28 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in MeCN (2 mL) and shaken at 50 ° for 20 h. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were purified by cation exchange CC followed by purification by flash CC (SiO2; MeOH/DCM 1:10) to give the title compound (112KK06) (0.022 g, 34%). JH NMR (CD3OD) 5 7.05 (d, J = 8.4 Hz, 1H), 6.93 (d, J= 11.7 Hz, 1H), 3.93 (t, J= 7.2 Hz, CH2), 2.93 (d, J= 11.1 Hz, 2H), 2.83 (t, J= 6.9 Hz, CH2), 2.60 - 2.56 (m, 2H), 2.44 - 2.40 (m, 2H), 2.19 (D, J = 1.8 Hz, CH3) 2.03 - 1.98 (m, 2H), 1.86-1.79 (m, 2H), 1.69 (d, J= 11.0 Hz, 2H), 1.31 - 1.19 (m,
102

9H), 0.89 (t, J = 6.6 Hz, CH3); 13C NMR (CD3OD) 5 172.4, 161.7 (d, J = 241.0 Hz), 139.5 (d, J= 10.0 Hz), 131.7 (d,J= 6.1 Hz), 123.5 (d, J= 3.6 Hz), 119.9 (d, J= 17.4 Hz), 104.0 (d, J= 28.1 Hz), 56.8, 55.0,41.5, 37.3, 36.7, 33.0, 32.8, 30.1,25.5,25.3,23.9,14.4, 13.7.
[0362] The product was dissolved in MeOH/Et2O and oxalic acid dissolved in Et20 was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.018 g). HPLC-MS (ammonium acetate) [M+H]+= 361.35.
1-[3-(4-Butylpiperidin-1-yl)propyl]-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (112KK07)
[0363] A 4 mL vial was charged with l-(3-chloropropyl)-6,7-difluoro-3,4-dihydro-li7-quinolin-2-one (112KK03) (0.123 g, 0.47 mmol), 4-butylpiperidine (0.074 g, 0.52 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in MeCN (2 mL) and shaken at 50 ° for 20 h. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were purified by cation exchange CC followed by purification by flash CC (SiO2; MeOH/DCM 1:10) to give the title compound (112KK07) (0.097 g, 57%). 1H NMR (CD3OD) 5 7.20 - 7.09 (m, 2H), 3.91 (t, J= 7.2 Hz, CH2), 2.90 - 2.82 (m, 4H), 2.59 - 2.55 (m, 2H), 2.38 - 2.34 (m, 2H), 1.97 - 1.91 (m, 2H), 1.82 - 1.75 (m, 2H), 1.66 (d, J= 9.8 Hz, 2H), 1.28 - 1.16 (m, 9H), 0.87 (t, J= 6.7 Hz, CH3); 13C NMR (CD3OD) 8 172.1, 150.4 (q, J= 243.2 Hz, J= 13.2 Hz), 146.9 (q, J= 243.2 Hz, J- 12.6 Hz), 137.3 (q, J= 8.1 Hz, J= 2.9 Hz), 124.9 (q, J= 5.8 Hz, J= 3.9 Hz), 117.6 (d, J= 18.7 Hz), 106.4 (d, J= 22.6 Hz), 56.8, 55.0, 41.8, 37.4, 36.8, 33.1, 32.4, 30.1, 25.5, 25.3,23.9,14.4.
[0364] The product was dissolved in MeOH/Et2O and oxalic acid dissolved in Et20 was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.046 g). HPLC-MS (ammonium acetate) [M+H]+= 365.32.
6,7-Difluoro-l-[3-(4-propoxypiperidin-l-yl)propyl]-3,4-dihydro-1H-quinolin-2-one (122LH7)
[0365] A 4 mL vial was charged with l-(3-chloropropyl)-6,7-difluoro-3,4-dihydro-lif-quinolin-2-one (112KK03) (0.286 g, 1.1 mmol), 4-propoxypiperidine (0.160 g, 1.1 mmol), KI (0.250 g, 1.5 mmol), and K2CO3 (0.207 g, 1.54 mmol) in MeCN (2.5 mL) and shaken at 40 ° for 2 days. The reaction mixture was quenched with water, and the
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product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by cation exchange CC followed by flash CC (SiO2; EtOAc) and then prep RP-HPLC to give the title compound (122LH07) (0.165 g, 41%). lH NMR (CD3OD) 5 7.22 - 7.11 (m, 2H), 3.94 (t, J= 7.2 Hz, CH2), 3.42 - 3.35 (m, 3H), 2.89 - 2.83 (m, 4H), 2.62 - 2.51 (m, 4H), 2.40 - 2.36 (m, 2H), 1.95 -1.82 (m, 4H), 1.69-1.51 (m, 4H), 0.91 (t, J= 12 Hz, CH3); 13C NMR (CD3OD) 8 172.0, 150.3 (q, J= 243.3 Hz, J = 13.5 Hz), 146.9 (q, J = 243.3 Hz, J= 12.7 Hz), 137.3 (q, J= 8.1 Hz, J= 2.7 Hz), 124.9 (q, J= 5.8 Hz, J= 3.8 Hz), 117.6 (d,J= 18.8 Hz), 106.3 (d, J= 22.7 Hz), 74.8, 70.7, 56.1, 51.7,41.5, 32.3, 31.4,25.5,25.1,24.3,11.0.
[0366] The product was dissolved in acetone and oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.154 g). HPLC-MS (ammonium acetate) [M+H]+= 367.25.
(R,S)-1-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (122LH11-1)
[0367] A reaction flask was charged with 6,7-difluoro-3,4-dihydro-lH-quinolin-2-one (97KK47) (0.183 g, 1.0 mmol) in dry DMF (1 mL) under Argon. NaH (60% in oil, 0.050 g, 1.3 mmol) was added and the mixture was stirred at rt for 0.5 h. Then (/?,S)-l-bromo-3-chloro-2-methylpropane (0.172 g, 1.0 mmol) was added followed by stirring at rt for 20 h. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. After purification by flash CC (Si02; EtOAc/n-heptane 1:1), the crude product was solvated in DMF (0.5 mL) and added 4-butylpiperidine 0.085 g, 0.6 mmol), Nal (0.113 g, 0.075 mmol), and K2C03 (0.104 g, 0.075 mmol) followed by stirring at 50 ° for 3 days. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude product was purified by cation exchange CC and prep RP-HPLC to give the title compound (122LH11-1). lH NMR (CD3OD) 8 7.25 - 7.20 (m, 1H), 7.16 - 7.12 (m, 1H), 3.97 (dd, J= 14.3 Hz, J= 8.4 Hz, 1H), 3.85 (dd, J= 14.5 Hz, J= 5.1 Hz, 1H), 2.94 -2.85 (m, 3H), 2.78 (d, J= 9.4 Hz, 1H), 2.66 - 2.57 (m, 2H), 2.27 - 2.13 (m, 2H), 2.03 -1.85 (m, 3H), 1.67 - 1.65 (m, 2H), 1.31-1.22 (m, 9H), 0.90 (t, J= 6.6 Hz, CH3), 0.87 (d, J=6.7Hz,CH3).
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[0368] The crude product was dissolved in acetone and oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.025 g, 7%). HPLC-MS (ammonium acetate) [M+H]+ = 379.27.
(R, S)-6,7-Difluoro-1- [3 -(4-Propoxypiperidin-1-yl)-2-methylpropyl] -3,4-dihydro-1H-quinolin-2-one (122LH11-2)
[0369] A reaction flask was charged with 6,7-difluoro-3,4-dihydro-lH-quinolin-2-one (97KK47) (0.183 g, 1.0 mmol) in dry DMF (1 mL) under Argon. NaH (60% in oil, 0.050 g, 1.3 mmol) was added and the mixture was stirred at rt for 0.5 h. Then (R,S)-l-bromo-3-chloro-2-methylpropane (0.172 g, 1.0 mmol) was added followed by stirring at rt for 20 h. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. After purification by flash CC (SiO2; EtOAc/n-heptane 1:1), the crude product was solvated in DMF (0.5 mL) and added 4-butylpiperidine 0.085 g, 0.6 mmol), Nal (0.113 g, 0.075 mmol), and K2CO3 (0.104 g, 0.075 mmol) followed by stirring at 50 ° for 3 days. The reaction mixture was quenched with water, and the product extracted into EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. The crude product was purified by cation exchange CC and prep RP-HPLC to give the crude title compound (122LH11-2). 1H NMR (CD3OD) 5 7.24 - 7.12 (m, 2H), 3.97 (dd, / = 14.5 Hz, J= 8.6 Hz, 1H), 3.87 (dd, J= 14.3 Hz, J= 5.1 Hz, 1H), 3.41 (t, J= 6.7 Hz, CH2), 3.35 - 3.28 (m, 1H), 2.89 - 2.85 (m, 2H), 2.78 - 2.75 (m, 1H), 2.66 - 2.59 (m, 3H), 2.26 -2.21 (m, 1H), 2.17 - 2.11 (m, 2H), 2.07 - 1.97 (m, 2H), 1.90 - 1.86 (m, 2H), 1.61 -1.51 (m, 4H), 0.92 (t, J= 7.4 Hz, CH3), 0.86 (d, J= 6.6 Hz, CH3); 13C NMR (CD3OD) 8 172.5, 150.3 (q, J= 242.9 Hz, J= 13.1 Hz), 146.8 (q, J= 243.3 Hz, J= 13.1 Hz), 137.3 (q, J=8.1 Hz, J= 2.7 Hz), 125.1 (q, J= 5.8 Hz, J=3.8 Hz), 117.6 (d,J= 18.8 Hz), 106.7 (d, J= 22.7 Hz), 76.3, 70.9, 64.5, 53.4, 52.8,47.1, 32.5, 32.4, 30.5, 25.5, 24.3,17.2,11.0.
[0370] The crude product was dissolved in acetone and oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.030 g, 8%). HPLC-MS (ammonium acetate) [M+H]+ = 381.27.
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1 -[3-(4-Butylpiperidin-1 –yl)propyl] -6-fluoro-7-methyl-3,4-dihydro-1 H-quinolin-2-one (107LH93-1)
[0371] A reaction flask was charged with 6-fluoro-7-methyl-3,4-dihydro-lH-quinolin-2-one (0.150 g, 0.84 mmol) in dry DMF (1 mL) under N2. NaH (60% in oil, 0.038 g, 0.92 mmol) was added and stirred at rt for 30 min. Then 3-chloro-l-iodopropane (0.131 g, 0.84 mmol) was added followed by stirring at r.t for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was dissolved in MeCN (2 mL) followed by addition of 4-butylpiperidine (0.085 g, 0.6 mmol), Nal (0.150 g, 1.0 mmol), and K2C03 (0.138 g, 1.0 mmol) and shaken at 50 °C for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. The residue was purified by cation exchange CC followed by flash CC (SiO2; EtOAc) to give the title compound (107LH93-1) (0.166 g, total yield 55%). 1H NMR (CH3OD) 8 7.00 (d, J= 6.4 Hz, 1H), 6.88 (d, J= 9.2 Hz, 1H), 3.98 - 3.91 (m, 2H), 2.93 - 2.86 (m, 2H), 2.85 - 2.78 (m, 2H), 2.58 - 2.52 (m, 2H), 2.40 - 2.43 (m, 2H), 2.25 (d, J = 2.0 Hz, 3H), 1.98 - 1.76 (m, 4H), 1.70 - 1.62 (m, 2H), 1.35 - 1.22 (m, 9 H), 0.88 (t, J= 7.0 Hz, 3H); 13C NMR (CH3OD) 8 171.1, 157.2 (d, J= 241 Hz), 135.1 (d, J= 3 Hz), 126.5 (d, J= 8 Hz), 123.2 (d, J= 18 Hz), 118.1 (d, J= 5 Hz), 114.3 (d, J= 24 Hz), 55.8,43.9,40.4, 36.2, 35.7, 32.0, 31.5, 29.0, 24.6, 24.3, 22.8, 13.4 (br).
[0372] The product was dissolved in acetone and oxalic acid (1.1 equiv) dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.172 g). HPLC-MS (ammonium acetate) [M+H]+= 363.4.
6-Fluoro-7-methyl-l-[3-(4-propoxypiperidin-l-yl)propyl]-3.4-dihydro-1H-quinolin-2-one H07LH93-2)
[0373] A reaction flask was charged with 6-fluoro-7-methyl-3,4-dihydro-lH-quinolin-2-one (0.150 g, 0.84 mmol) in dry DMF (1 mL) under N2. NaH (60% in oil, 0.038 g, 0.92 mmol) was added and stirred at rt for 30 min. Then 3-chloro-l-iodopropane (0.131 g, 0.84 mmol) was added followed by stirring at r.t for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was
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dissolved in MeCN (2 mL) followed by addition of 4-propoxypiperidine (0.086 g, 0.6 mmol), Nal (0.150 g, 1.0 mmol), and K2CO3 (0.138 g, 1.0 mmol) and shaken at 50 °C for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. The residue was purified by cation exchange CC followed by flash CC (SiO2; EtOAc) to give the title compound (107LH93-2) (0.171 g, total yield 56%). lH NMR (CH3OD) 8 7.00 (d, J= 6.4 Hz, IH), 6.87 (d, J= 9.2 Hz, IH), 3.94 (brt, J= 7.2 Hz, 2H), 3.39 (t, J = 6.6 Hz, 2H), 3.35 - 3.26 (m, IH), 2.85 - 2.70 (m, 4 H), 2.58 - 2.51 (m, 2H), 2.39 (brt, 7.4 Hz, 2H), 2.24 (d, J= 1.6 Hz, 3H), 2.21 - 2.12 (m, 2 H), 1.92 - 1.75 (m, 4 H), 1.62 - 1.48 (m, 4H), 0.91 (t, J= 1A Hz); 13C NMR (CH3OD) 8 171.0, 157.1 (d, J = 241), 135.2 (d, J = 3 Hz), 126.5(d,J=8Hz), 123.2 (d, J = 18 Hz), 118.1 (d,J=5Hz), 114.3 (d,J= 24 Hz), 74.6, 69.5, 55.4, 51.0, 40.4, 31.5, 30.9, 24.7, 24.5, 23.2, 13.5 (br), 10.0.
[0374] The product was dissolved in acetone and oxalic acid (1.1 equiv) dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.172 g). HPLC-MS (ammonium acetate) [M+H]+= 364.3.
(R S)-1-[3 -(4-Butylpiperidin-1-yl)-2-methylpropyl -6-fluoro-7-methyl-3.4-dihydro-1H-quinolin-2-one (107LH94-1)
[0375] A reaction flask was charged with 6-fluoro-7-methyl-3,4-dihydro-lH-quinolin-2-one (0.150 g, 0.84 mmol) in dry DMF (1 mL) under N2. NaH (60% in oil, 0.038 g, 0.92 mmol) was added and stirred at it for 30 min. Then (R,S)-l-bromo-3-chloro-2-methylpropane (0.144 g, 0.84 mmol) was added followed by stirring at r.t for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. The crude material was dissolved in dry DMF (2 mL) followed by addition of 4-butylpiperidine (0.085 g, 0.6 mmol), Nal (0.150 g, 1.0 mmol), and K2CO3 (0.138 g, 1.0 mmol) and shaken at 100 °C for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. The residue was purified by cation-exchange CC followed by flash CC (Si02; EtOAc) to give the title compound (107LH94-1) (0.045 g, total yield 14%). lK NMR (CH3OD) d 7.01 (d, J= 6.4 Hz, IH), 6.90 (d, J= 9.2 Hz), 4.03 - 3.88 (m, 2H), 2.90 (brd, J= 10.8 Hz, 2H), 2.83 (brt, J= 7.0 Hz, 2 H), 2.75 (brd, J= 10.2 Hz), 2.64 - 2.50 (m,
107

2 H), 2.26 - 1.98 (m, 6H), 1.93 -1.78 (m, 2H), 1.68 - 1.58 (m, 2H), 1.35 -1.14 8 (m, 9H), 0.89 (t, J= 6.8 Hz, 3H), 0.84 (d, J= 6.8 Hz, 3H); 13C NMR (CH3OD) 8 171.6,156.1 (d, J = 241 Hz), 135.1 (d, J= 3 Hz), 126.9 (d, J= 8 Hz), 123.0, (d, J= 19 Hz), 118.6 (d, J= 5 Hz), 114.3 (d, J= 24 Hz), 63.9, 55.1, 54.4, 45.5, 36.3, 35.9, 32.4 (br), 31.6, 29.0, 28.8, 24.6,22.8,16.0,13.5 (br).
[0376] The product was dissolved in acetone and oxalic acid (1.1 equiv) dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.037 g). HPLC-MS (ammonium acetate) [M+H]+= 375.3.
(R,S)-6-Fluoro-7-methyl-l-[2-methyl-3-(4-Propoxypiperidin-l-yl)-propyl]-3,4-dihydro-1H-quinolin-2-one (T07LH94-2)
[0377] A reaction flask was charged with 6-fluoro-7-methyl-3,4-dihydro-lH-quinolin-2-one (0.150 g, 0.84 mmol) in dry DMF (1 mL) under N2. NaH (60% in oil, 0.038 g, 0.92 mmol) was added and stirred at rt for 30 min. Then (R,S)-l-bromo-3-chloro-2-methylpropane (0.144 g, 0.84 mmol) was added followed by stirring at r.t for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. The crude material was dissolved in dry DMF (2 mL) followed by addition of 4-propoxypiperidine (0.086 g, 0.6 mmol), Nal (0.150 g, 1.0 mmol), and K2CO3 (0.138 g, 1.0 mmol) and shaken at 100 °C for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by cation-exchange CC followed by flash CC (Si02; EtOAc) to give the title compound (107LH94-2) (0.033 g, total yield 10%). *H NMR (CH3OD) 8 7.02 (d, J= 6.8 Hz, 1H), 6.91 (d, J= 9.6 Hz, 1H), 3.95 (d, J= 12 Hz, 2H), 3.41 (t, J= 6.6 Hz, 2H), 3.33 - 3.25 (m, 1H), 2.84 (brt, J= 1A Hz), 2.79 - 2.71 (m, 1H), 2.67 - 2.51 (m, 3H), 2.28 - 1.98 (m, 8H), 1.92 - 1.83 (m, 2H), 1.60 - 1.48 (m, 4H), 0.91 (t, J= 7.6 Hz, 3H), 0.85 (d, J= 6.4 Hz, 3H); 13C NMR (CH3OD) 8 171.7, 157.2 (d, J = 241 Hz), 135.1 (d, J= 3 Hz), 126.9 (d, J= 8 Hz), 123.1 (d, J= 18 Hz), 114.3 (d, J= 24 Hz), 75.2, 69.5, 52.1, 51.7, 45.5, 31.6, 31.3, 29.0, 24.6, 23.1, 15.9, 13.5,13.3, 9.8.
[0378] The product was dissolved in acetone and oxalic acid (1.1 equiv) dissolved in acetone was added. The formed crystals were filtered and washed with
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acetone to give the title compound as oxalic salt (0.036 g). HPLC-MS (ammonium acetate) [M+H]+= 377.3.
l-[3-(4-Butyl-piperidin-1-yl)propyl]-6-fluoro-5-methyl-3.4-dihydro-lH-quinolin-2-one (107LH95-1)
[0379] A reaction flask was charged with 6-fluoro-5-methyl-3,4-dihydro-lH-quinolin-2-one (0.090 g, 0.50 mmol) in dry DMF (0.5 mL) under N2. NaH (60% in oil, 0.023 g, 0.55 mmol) was added and stirred at rt for 30 min. Then 3-chloro-l-iodopropane (0.079 g, 0.50 mmol) was added followed by stirring at r.t for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was dissolved in MeCN (2 mL) followed by addition of 4-butylpiperidine (0.085 g, 0.6 mmol), Nal (0.150 g, 1.0 mmol), and K2CO3 (0.138 g, 1.0 mmol) and shaken at 50 °C for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. The residue was purified by cation-exchange CC followed by flash CC (Si02; EtOAc) to give the title compound (107LH95-1) (0.059 g, total yield 33%). *H NMR (CH3OD) 8 7.02 (dd, J = 4.8, 9.2 Hz, 1H), 6.98 - 6.92 (m, 1H), 3.95 (brt, J= 1A Hz, 2H), 2.92 - 2.82 (m, 4H), 2.59 - 2.52 (m, 2H), 2.39 - 2.32 (m, 2H), 2.00 (d, J= 1.6 Hz, 3H), 1.97 - 1.75 (m, 4H), 1.66 (brd, 10.8 Hz, 2H), 1.35 -1.12 (m, 9H), 0.89 (t, J= 6.4 Hz); 13C NMR (CH3OD) 8 170.9, 157.6 (d, J= 240 Hz), 135.4 (d, J= 3 Hz), 128.1 (d, J= 4 Hz), 122.7 (d, J= 18 Hz), 114.2 (d, J = 8 Hz), 112.9, (d, J= 25 Hz), 55.9, 53.9, 40.6, 36.2, 35.7, 31.9, 30.9, 28.9, 24.4, 22.8,21.4 (br), 13.2, 9.7 (br).
[0380] The product was dissolved in acetone and oxalic acid (1.1 equiv) dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.058 g). HPLC-MS (ammonium acetate) [M+H]+= 361.3.
6-Fluoro-5 -methyl-1 - [3 -(4-Propoxypiperidin-1 –yl)propyl] -3,4-dihydro-1H-quinolin-2-one (107LH95-2)
[0381] A reaction flask was charged with 6-fluoro-5-methyl-3,4-dihydro-lH-quinolin-2-one (0.090 g, 0.50 mmol) in dry DMF (0.5 mL) under N2. NaH (60% in oil, 0.023 g, 0.55 mmol) was added and stirred at rt for 30 min. Then 3-chloro-l-iodopropane
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(0.079 g, 0.50 mmol) was added followed by stirring at r.t for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The crude material was dissolved in MeCN (2 mL) followed by addition of 4-propoxypiperidine (0.086 g, 0.6 mmol), Nal (0.150 g, 1.0 mmol), and K2C03 (0.138 g, 1.0 mmol) and shaken at 50 °C for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The residue was purified by cation-exchange CC followed by flash CC (Si02; EtOAc) to give the title compound (107LH95-2) (0.074 g, total yield 41%). !H NMR (CH3OD) 5 7.03 (dd, J= 4.8, 9.2 Hz, 1H), 6.99 - 6.92 (m, 1H), 3.98 (brt, J= 7.4 Hz, 2H), 3.46 - 3.38 (m, 3H), 2.95 - 2.84 (m, 4H), 2.64 - 2.42 (m, 6H), 2.20 (d, J= 2.0 Hz, 3H), 1.98 - 1.83 (m, 4H), 1.72 - 1.30 (m, 4H), 0.92 (t, J= 1A Hz, 3H); 13C NMR (CH3OD) 8 171.1, 157.7 (d, J= 240 Hz), 135.4 (d, J= 3 Hz), 128.1 (d, J= 4 Hz), 122.8 (d, J= 18 Hz), 114.1, (d, J = 9 Hz), 113.0 (d, J= 25 Hz), 73.1, 69.7, 55.0, 50.3, 40.3, 30.8, 29.9, 23.9, 23.1, 22.7, 21.4,9.8 (br).
[0382] The product was dissolved in acetone and oxalic acid (1.1 equiv) dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.067 g). HPLC-MS (ammonium acetate) [M+H]+= 363.3.
(R)-1- [3-(4-Butylpiperidin-1-yl)-2-methylpropyl] -3,4-dihydro-1H-quinolin-2-one (107LH47-A)
[0383] A 4 mL vial was charged with (5)-l-(3-iodo-2-methylpropyl)-3,4-dihydro-ltf-quinolin-2-one (122LH18) (0.329 g, 1.0 mmol) and 4-butylpiperidine (0.283 g, 2.0 mmol) in MeCN (2 mL) and shaken at 60 ° for 20 h. The reaction mixture was concentrated, and the product purified by flash CC (SiC^; EtOAc, EtOAc/MeOH 4:1) to give the title compound (107LH47-A) (0.186 g, 54%). 1H NMR (CD3OD) d 7.26 - 7.19 (M, 3H), 7.04 - 7.00 (m, 1H), 2.93 - 2.88 (m, 3H), 2.77 (d, J= 10.4 Hz, 2H), 2.62 - 2.58 (m, 2H), 2.29 - 2.06 (m, 3H), 1.93 - 1.86 (m, 2H), 1.68 - 1.62 (m, 2H), 1.31-1.22 (m, 9H), 0.91 - 0.86 (m, 2 CH3); 13C NMR (CD3OD) 8 173.2, 140.3, 129.1, 128.5, 128.4, 124.4, 166.9, 64.9, 56.0, 55.6, 37.5, 36.9, 33.4, 33.3, 32.9, 30.1, 30.1, 26.2, 24.0, 17.2, 14.4.
110

[0384] The product was dissolved in acetone and oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.222 g). HPLC-MS (ammonium acetate) [M+H]+= 343.33.
(R)-1- [2-Methyl-3 -(4-propoxypiperidin-1-yl)propyl] -3.4-dihydro-1H-quinolin-2-one (107LH48)
[0385] A 4 mL vial was charged with (S)-l-(3-iodo-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (122LH18) (0.493 g, 1.5 mmol) and 4-propoxypiperidine (0.430 g, 3.0 mmol) in MeCN (2 mL) and shaken at 60 ° for 20 h. The reaction mixture was quenched with water, basified with ammonium hydroxide, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiC>2; EtOAc, EtOAc/MeOH 4:1) to give the title compound (107LH48) (0.197 g, 38%). lH NMR (CD3OD) 5 7.26 - 7.19 (m, 3H), 7.03 - 6.98 (m, 1H), 3.96 (d, J= 7.0 Hz, 2H), 3.40 (t, J= 6.7 Hz, 2H), 2.90 - 2.86 (m, 2H), 2.74 - 2.71 (m, 1H), 2.65 - 2.54 (m, 3H), 2.26 - 1.99 (m, 6H), 1.87 - 1.84 (m, 2H), 1.59 - 1.49 (m, 4H), 0.91 (t, J= 1A Hz, CH3), 0.85 (d, J= 6.6 Hz, CH3); 13C NMR (CD3OD) 5 173.0, 140.3, 129.1, 128.4, 128.4, 124.3, 116.8, 76.3, 70.7, 64.5, 53.2, 52.8, 32.9, 32.4, 32.4, 30.3, 26.2, 24.3,17.1,11.0.
[0386] The product was dissolved in acetone and oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.189 g). HPLC-MS (ammonium acetate) [M+H]+= 345.31.
(R)-l-[3-(4-Butylidenepiperidin-l-yl)-2-methylpropyl]-3,4-dihydro-lH-quinolin-2-one (107LH53)
[0387] A 4 mL vial was charged with (S)-l-(3-iodo-2-methylpropyl)-3,4-dihydro-lH-quinolin-2-one (122LH18) (0.169 g, 0.51 mmol) and 4-butylidenepiperidine (0.200 g, 1.4 mmol) in MeCN (2 mL) and shaken at 40 ° for 20 h. The reaction mixture was quenched with water, basified with ammonium hydroxide, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (Si02; n-heptane/EtOAc 4:1) to give the title compound (107LH53) (0.116 g, 67%). !H NMR (CD3OD) 5 7.23 - 7.18 (m, 3H), 7.02 - 6.98 (m, 1H), 5.11 (t, J= 1A Hz, 1H), 3.98 (d, J= 6.8 Hz, 2H), 2.89 - 2.85 (m, 2H), 2.61 - 2.56 (m, 2H), 2.40 - 2.35 (m, 2H), 3.32 - 2.04 (m, 11H), 1.98 - 1.92 (m, 2H),
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1.36 - 1.29 (m, 2H), 0.90 - 0.85 (m, 2 CH3); 13C NMR (CD3OD) 8 173.0, 140.3, 137.1, 129.1, 128.4, 128.4, 124.3, 123.7, 116.9, 64.6, 57.4, 56.6, 46.5, 37.0, 32.9, 30.2, 30.1, 29.1,26.3,24.2,17.2,14.1.
[0388] The product was dissolved in acetone and oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.130 g). HPLC-MS (ammonium acetate) [M+H]+= 341.33.
(R)-l-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-3.4-dihydro-1H-quinolin-2-one (107LH54)
[0389] A 4 mL vial was charged with (5)-l-(3-iodo-2-methylpropyl)-3,4-dihydro-lH-quinolin-2-one (122LH18) (0.185 g, 0.56 mmol) and 3-butyl-8-azabicyclo[3.2.1]octane (0.100 g, 0.60 mmol) in MeCN (0.5 mL) and shaken at 40 ° for 20 h. The reaction mixture was quenched with water, basified with ammonium hydroxide, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; n-heptane/EtOAc 4:1) to give the title compound (107LH54) (0.063 g, 30%). 1H NMR (CD3OD) 8 7.29 - 7.19 (m, 3H), 7.03 - 6.99 (m, 1H), 4.03 - 4.00 (m, 2H), 3.14 - 3.13 (m, 1H), 3.07 - 3.05 (m, 1H), 2.90 - 2.86 (m, 2H), 2.62 - 2.57 (m, 2H), 2.28 - 2.19 (m, 2H), 1.97 - 1.82 (m, 3), 1.58 - 1.42 (m, 5H), 1.34 - 1.15 (m, 8H), 0.90 - 0.87 (m, 6H); 13C NMR (CD3OD) 8 173.1, 140.3, 129.1, 128.4, 128.3, 124.3, 117.2, 62.2, 61.2, 58.2, 46.5, 39.0, 38.0, 32.9, 32.1, 30.3,29.1,27.8,27.3, 26.3,24.0,17.1,14.5.
[0390] The product was dissolved in acetone and oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.064 g). HPLC-MS (ammonium acetate) [M+H]+ = 369.34.
(R)-1-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-3,4-dihydro-lH-quinolin-2-one (107LH55)
[0391] A 4 mL vial was charged with (5)-l-(3-iodo-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (122LH18) (0.185 g, 0.56 mmol) and 3-pentyl-8-azabicyclo[3.2.1]octane (0.112 g, 0.62 mmol) in MeCN (0.5 mL) and shaken at 40 ° for 20 h. The reaction mixture was quenched with water, basified with ammonium hydroxide, and the product extracted into EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. The product was purified by flash CC (Si02; n-
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heptane/EtOAc 4:1) to give the title compound (107LH55) (0.075 g, 35%). 1H NMR (CD3OD) 5 7.28 - 7.18 (m, 3H), 7.01 (t, J= 7.2 Hz, 1H), 4.03 (d, J= 7.0 Hz, 2H), 3.11 -3.04 (m, 2H), 2.90 - 2.85 (m, 2), 2.64 - 2.56 (m 2H), 2.28 - 2.11 (m, 4H), 1.97 - 1.84 (m, 3H), 1.66 - 1.54 (m, 3H), 1.42 - 1.21 (m, 10H), 0.90 - 0.85 (m, 2 CH3); 13C NMR (CD3OD) 8 173.1, 140.3, 129.1, 128.4, 128.3, 124.3, 117.1, 61.4, 60.2, 58.3, 46.4, 39.5, 37.1, 37.0, 33.1, 32.9, 32.2, 29.5,29.4,28.5,27.9, 26.3,23.7,17.1,14.4.
[0392] The product was dissolved in acetone and oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.054 g). HPLC-MS (ammonium acetate) [M+H]+= 383.35.
l-[3-(4-Butylpiperidin-l-yl)propyl]-lH-quinolin-2-one(092LH70-A)
[0393] A 7mL vial was charged with l-(3-chloropropyl)-lH-quinolin-2-one (0.450 g, 2.0 mmol), K2C03 (0.34 g, 2.5 mmol), KI (0.42 g, 2.5 mmol), 4-butylpiperidine (0.30 g, 2.1 mmol) and dry CH3CN (3 mL). The mixture was shaken at 50 °C for 60 h and thereafter diluted with EtOAc (50 mL) and washed with water (50 mL). The water phase was extracted with EtOAc (2 x 50 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash CC (Si02; EtOAc/MeOH 4:1) followed by prep RP-HPLC to give the title compound (0.32g, 49%). 'H NMR (CD3OD) 6 7.88 (d, J= 9.6 Hz), 7.68 (brd, J= 8.0 Hz), 7.65-7.61 (m, 2H), 7.33-7.25 (m, 1H), 6.64 (d, 9.6 Hz), 4.39-4.32 (m, 2H), 2.95-2.86 (m, 2H), 2.50-2.43 (m, 2H), 2.01-1.86 (m, 4H), 1.71-1.62 (m, 2H), 1.35-1.12 (m, 9H), 0.89 (t, J= 6.6 Hz); 13C NMR (CD3OD) 5 163.1, 140.4, 139.0, 131.1, 129.2, 122.6, 121.4, 120.3, 114.7, 55.8, 53.9,40.6, 36.2, 35.7, 32.0, 28.9,24.7,22.8,13.2.
[0394] The product was dissolved in acetone and oxalic acid (1.1 equiv) dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.356 g). HPLC-MS (ammonium acetate) [M+H]+= 327.3.
1-[3-(4-Butylpiperidin-l-yl)propyl]-lH-quinolin-2-one, (092LH69)
[0395] A 4 mL vial was charged with l-(3-chloropropyl)-1H-quinolin-2-one (0.069 g, 0.31 mmol), K2CO3 (0.069 g, 0.50 mmol), KI (0.083 g, 0.50 mmol), 4-propoxypiperidine (0.050 g, 0.35 mmol) and dry CH3CN (2 mL). The mixture was shaken
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at 50 °C for 24 h and thereafter diluted with water (25 mL) and EtOAc (25 mL). The phases were separated and the water phase was extracted with EtOAc (2 x 50 mL). The combined organic phase was then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash CC (SiO2; EtOAc/MeOH 4:1) followed by prep RP-HPLC to give the title compound (0.060 g, 59%). *H NMR (CD3OD) 5 7.85 (d, J= 9.4 Hz, 1H), 7.65 (brd, J= 12 Hz, 1H), 7.63 (m, 2 H), 7.29-7.22 (m, 1H), 6.62, (d, J= 9.4 Hz), 4.36-4.29 (m, 1H), 3.38 (t, J= 6.6 Hz, 2H), 3.34-3.24 (m, 1H), 2.78-2.69 (m, 2H), 2.48-2.41 (m, 2H), 2.18-2.09 (m, 2H), 1.94-1.82 (m, 4 H), 1.59-1.47 (m, 4H), 0.90 (t, J = 7.4 Hz); 13C NMR (CD3OD) 6 162.0, 140.3, 139.0, 131.1, 129.2, 122.6, 121.4, 120.3, 114.7, 74.7, 69.5, 55.4, 51.0, 40.6, 31.0, 24.9, 32.1, 9.9; HPLC-MS (ammonium acetate) [M+H]+ = 329.3.
1-[3-(4-Butylpiperidin-l-yl)propyl]-lH -6-fluoro-1 H-quinolin-2-one (107LH22)
[0396] A 4 mL vial was charged with 6-fluoro-lH-quinolin-2-one (00.56 g, 0.34 mmol), dry DMF (2 mL) and NaH (60% in oil, 0.015 g, 0.34 mmol). The mixture was stirred at rt for 1 h under a N2 atmosphere, and thereafter l-bromo-3-chloropropane (34 ul, 0.34 mmol) was added and the mixture was then shaken at rt for 20 h. The reaction was diluted with diethyl ether (25 mL) and washed with water (15 mL). The organic phase was washed with water (15 mL) and brine (15 mL), dried over Na2S04, and concentrated under reduced pressure. The oily residue was diluted with CH3CN (2 mL) and KI (0.083 g, 0.50 mmol), K2C03 (0.069 g, 0.50 mmol) and 4-butylpiperidine (0.048 g, 0.34 mmol) was added. The mixture was shaken at 50 °C for 72 h and then diluted with EtOAc (25 mL) and washed with water (15 mL). The water phase was extracted (2 x 25 mL) and the combined organic phase was dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by cation-exchange CC followed by flash CC (SiO2; EtOAc/MeOH 4:1) to yield the title compound (0.034 g, 29%). 1H NMR (CD3OD) 8 7.90 (d, J= 9.2 Hz, 1H), 7.69 (dd, J= 4.0, 8.8 Hz, 1H), 7.50-7.41 (m, 2H), 6.72 (d, ./ = 8.8 Hz, 1 H), 4.41 (t, J= 6.8 Hz, 2H), 3.02-2.95 (m, 2H), 2.65-2.60 (m, 2 H), 2.19-2.08 (m, 2H), 1.91-1.82 (m, 4 H), 1.53-1.21 (m, 9H), 0.90 (t, J= 7.0 Hz); 13C NMR (CD3OD) 8 169.9, 158.4 (d, J= 242 Hz), 139.8 (d, J= 3 Hz), 134.4 (d, J= 2 Hz), 122.5 (d, J= 9 Hz), 121.6, 119.9 (d, J= 24 Hz), 116.8 (d, J= 8 Hz), 113.9 (d = 23 Hz), 54.4, 53.0, 40.1, 34.5, 34.1, 30.1, 28.7, 23.3, 22.6, 13.2; HPLC-MS (ammonium acetate) [M+H]+ = 345.3.
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1-[3-(4-Butylpiperidin-1-yl)propyl]-6-methyl-lH-quinolin-2-one (107LH32-A)
[0397] A 4 mL vial was charged with 6-methyl-lH-quinolin-2-one (0.110 g, 0.71 mmol), dry DMF (2 mL) and NaH (60% in oil, 0.031 g, 0.78 mmol). The mixture was shaken under a N2 atmosphere for lh, and thereafter l-bromo-3-chloropropane (70 m, 0.71 mmol) was added. The reaction was shaken at rt for 20 h and then poured into diethyl ether (25 mL) and washed with water (15 mL). The ether phase was washed with water (15 mL) and brine (15 mL). The organic phase was dried over Na2SO4, and concentrated under reduced pressure. The residue was diluted with CH3CN (2 mL) and KI (0.160 g, 1.0 mmol), K2CO3 (0.140 g, 1.0 mmol) and 4-butylpiperidine (0.100 g, 0.71 mmol) was added. The mixture was shaken at 50 °C for 72 h and then poured onto The compound EtOAc (25 mL) and water (15 mL). The water phase was extracted (2 x 25 mL) and the combined organic phase was dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash CC (S1O2; EtOAc/MeOH 4:1) followed by prep RP-HPLC to give the title compound (0.058 g, 23%). 'H NMR (CD3OD) 8 7.78 (d, J= 9.2 Hz, IH), 7.52-7.40 (m, 3H), 6.60 (d, J= 9.2 Hz, 1 H), 4.3 (t, J = 7.6 Hz, 2H), 2.92-2.2.85 (m, 2H), 2.50-2.39 (m, 2H), 2.39 (s, 3H), 1.99-1.84 (m, 4H), 1.69-1.61 (m, 2H), 1.35-1.11 (m, 9H), 0.88 (t, J= 6.8 Hz); 13C NMR (CD3OD) 5 162.9, 140.1, 137.0, 132.5, 132.3, 128.8, 121.4, 120.2, 114.6, 55.8, 53.9, 40.6, 36.2, 35.7, 32.0, 28.9, 24.8,22.8,19.4,13.3; HPLC-MS (ammonium acetate) [M+H]+ = 341.3.
l-[3-(4-Butylpiperidin-1-yl)propyl]-7-fluoro-lH-quinolin-2-one(107LH33-A)
[0398] A 4 mL vial was charged with 7-fluoro-lH-quinolin-2-one (0.032 g, 0.19 mmol), NaH (60% in oil, 8.7 mg, .21 mmol) and dry DMF (2.5 mL). The mixture was shaken at rt for 1 h and then l-bromo-3-chloropropane (20 ml, 0.19 mmol) was added and the reaction was shaken overnight shaken at rt overnight. The mixture was then diluted with ether (25 mL) and washed water (15 mL), the ether phase was washed with water (15 mL) and brine (15 mL). The organic phase was dried over Na2SO4, and concentrated under reduced pressure. The oily residue was diluted with CH3CN (2 mL) and to the resulting solution was added: KI (0.050 g, 0.30 mmol), K2C03 (0.041 g, 0.30 mmol) and 4-butylpiperidine (0.028 g, 0.20 mmol). The mixture was shaken at 50 °C for 72 h and then poured onto The compound EtOAc (25 mL) and water (15 mL). The water
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phase was extracted (2 x 25 mL) and the combined organic phase was dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash CC (Si02; EtOAc/MeOH 4:1) followed by prep RP-HPLC to give the title compound (7.0 mg, 11%). lH NMR (CD3OD) 5 7.89 (d, J= 9.6 Hz, 1H), 7.73 (dd, J= 6.2, 8.6 Hz, 1H), 7.47 (dd, J= 2.4, 11.6 Hz, 1H), 7.08 (dt, J= 2.4, 8.6 Hz, 1H), 6.60 (dJ= 9.6 Hz, 1H), 4.33 (t, J= 7.6 Hz, 2 H), 2.98 - 2.00 (m, 2H), 2.50 - 2.42 (m, 2H), 2.05 - 1.86 (m, 4H), 1.55 - 1.64 (m, 2H), 1.36 - 1.15 (m, 9H), 0.90 (t, J= 6.8 Hz); 13C NMR (CD3OD) 8 164.7 (d, J= 248),
163.2, 140.9 (br), 139.9, 131.4 (d, J = 10 Hz), 119.3 (d, J=3Hz), 118.1 (br), 110.6 (d, J
= 23 Hz), 101.6 (d, J= 28 Hz), 55.5, 53.9, 41.0, 36.8, 35.6, 31.9, 28.9, 24.5, 22.7, 13.2;
HPLC-MS (ammonium acetate) [M+H]+ = 345.3
1-[3-(4-Butylpiperidin-l-yl)propyl]-6-methoxy-1H-quinolin-2-one (107LH3 7-A)
[0399] A 4 mL vial was charged with 6-methoxy-lH-quinolin-2-one (0.032 g, 0.18 mmol) dry DMF (2 mL) and NaH (60% in oil, 8 mg, 0.20 mmol), thereafter the mixture was stirred at 45 °C for 45 min under a N2 atmosphere, followed by the addition of l-bromo-3-chloropropane (18 ul, 0.18 mmol) and the mixture was shaken at 30 °C overnight. The reaction was then diluted with ether (25 mL) and washed with water (15 mL) and brine (15 mL), dried over Na2SO4, and concentrated under reduced pressure. The oily residue was diluted with CH3CN (3 mL) and KI (0.080 g, 0.50 mmol), K2CO3 (0.070 g, 0.50 mmol) and 4-butylpiperidine (0.028 g, 0.20 mmol) were added. The mixture was shaken at 50 °C for 48 h and then diluted with EtOAc (25 mL) and washed with water (15 mL). The water phase was extracted (2 x 25 mL) and the combined organic phase was dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep RP-HPLC to give the title compound (0.028 g, 44%). 1H NMR (CD3OD) 6 7.85 (d, J = 9.6 Hz, 1H), 7.56 (d, J= 9.2 Hz, 1H), 7.26 (dd, J= 2.8, 9.6 Hz, 1H), 7.19 (d./= 2.8 Hz, 1H), 6.65 (d, J= 9.6 Hz, 1H), 4.34 (t, J= 7.2 Hz, 2H), 3.85 (s, 3H), 3.07-2.98 (m, 2H), 2.64 - 2.58 (m, 2H), 2.19 - 2.10 (m, 2H), 2.04 - 1.94 (m, 2H), 1.76 - 1.66 (m, 2H), 1.35 -0.96 (m, 9H), 0.89 (t, J = 6.8 Hz); 13C NMR (CD3OD) 5 162.7, 155.5, 140.1, 133.3,
122.3, 120.6, 120.1, 116.1, 110.5, 55.3, 55.0, 53.6, 40.5, 36.0, 35.2, 31.4, 28.8 24.4, 22.7,
13.2; HPLC-MS (ammonium acetate) [M+H]+ = 357.3.
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1-[3-(4-Butylpiperidin-l-yl)propyl]-6-chloro-1H-quinolin-2-one (107LH38-A)
[0400] A 4 mL vial was charged with 6-chloro-lH-quinolin-2-one (107LH35) (0.085 g, 0.47 mmol), dry DMF (3 mL) and NaH (60% in oil, 0.023 g, 0.56 mmol) and the mixture was stirred at rt for 45 min under a N2 atmosphere. Thereafter, l-bromo-3-chloropropane (18 ml, 0.18 mmol) was added and the mixture was shaken at rt overnight, the reaction diluted with ether (25 mL) and washed with water (15 mL). The ether phase was washed with brine (15 mL), dried over Na2S04, concentrated under reduced pressure. The oily residue was diluted with dry CH3CN (2 mL) and KI (0.170 g, 1.0 mmol), K2C03 (0.140 g, 1.0 mmol) and 4-butylpiperidine (0.071 g, 0.50 mmol) were added. The mixture was shaken at 50 °C for 24 h and then diluted with EtOAc (25 mL) and washed with water (15 mL). The water phase was extracted (2 x 25 mL) and the combined organic phases were dried over Na2S04, and concentrated under reduced pressure. The residue was purified by prep RP-HPLC to give the title compound (32 mg, 89 umol, 19 %). *H NMR (CD3OD) 8 7.80 (d, J= 9.2Hz, 1H), 7.66 (brs, 1H), 7.60 - 7.51 (m, 2H), 6.65 (d,J= 9.6 Hz, 1H), 5.30 (t, J= 7.6 Hz, 2H), 3.09 - 2.95 (m, 2H), 2.68 - 2.57 (m, 2H), 2.24 -2.06 (m 2H), 2.00 - 1.90 (m, 2H), 1.75 - 1.64 (m, 2H), 1.32 - 1.12 (m, 9H), 0.84 (t, 6.4 Hz, 3H); 13C NMR (CD3OD) 5 162.6, 139.2, 137.4, 130.8, 128.0, 127.8, 122.4, 121.5, 116.3, 55.0, 53.3, 40.3, 35.7, 34.8, 31.0, 28.6, 23.9, 22.5, 13.0; HPLC-MS (ammonium acetate) [M+H]+ = 361.3.
1-[3-(4-Butylpiperidin-l-yl)propyl]-5-methyl-1H-quinolin-2-one(107LH45)
[0401] A 4mL vial was charged with l-(3-chloropropyl)-5-metyl-lH-quinolin-2-one (0.053 g, 0.23 mmol), KI (0.083 g, 0.5 mmol), K2C03 (0.069 g, 0.50 mmol) and 4-butylpiperidine (50 ul, 0.30 mmol) in CH3CN (2 mL). The mixture was shaken at 50 °C for 72 h and then diluted with EtOAc (25 mL) and washed with water (15 mL). The water phase was extracted (2 x 25 mL) and the combined organic phases were dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash CC (Si02; EtOAc/MeOH 1:4) to give the title compound (0.058 g, 74%). 1H NMR (CD3OD) 8 8.13 (d, J= 9.8 Hz, 1H), 7.56 - 7.46 (m, 2H), 7.15 (brd, 6.8 Hz, 2H), 6.67 (d, J= 9.8 Hz, 1H), 4.38 (t, J= 7.2 Hz, 2H), 3.10 - 3.03 (m, 2H), 2.68 - 2.61 (m, 2H), 2.57 (s, 3H), 2.25 - 2.15 (m, 2H), 2.04 - 1.95 (m, 2H), 1.78 - 1.69 (m, 2H), 1.36 - 1.16 (m, 9H), 0.89 (t, J= 7.0 Hz, 3H); 13C NMR (CD3OD) 5 162.3, 138.7, 136.6, 136.2, 130.4, 123.6, 119.4,
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118.9, 112.4, 54.7, 52.9, 39.9, 35.3, 34.5, 30.7, 28.2, 23.7, 22.1, 17.3, 12.6; HPLC-MS (ammonium acetate) [M+H]+ = 341.3.
1-[3-(4-Butyl-piperidin-l-yl)propyl]-7-methyl-lH -quinolin-2-one (107LH46-A)
[0402] A 4mL vial was charged with l-(3-chloro-propyl)-7-methyl-lH-quinolin-2-one 107LH40 (0.130 g, 0.56 mmol), KI (0.170 g, 1.0 mmol), K2CO3 (0.140 g, 1.0 mmol) and 4-butylpiperidine (100 ul, 0.60 mmol) in CH3CN (2 mL). The mixture was shaken at 50 °C for 72 h and then poured onto The compound EtOAc (25 mL) and water (15 mL). The water phase was extracted (2 x 25 mL) and the combined organic phases were dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash CC (Si02; EtOAc/MeOH 1:4) to give the title compound (0.017 g, 6%). *H NMR (CD3OD) 8 7.84 (d, J= 9.4 Hz), 7.56 (d, J= 8.0 Hz, 1H), 7.43 (brs, 1H), 7.14 (brd, J= 8 Hz, 1H), 6.58 (d, J= 9.4 Hz), 4.36 (d, J = 7.2 Hz, 2 H), 3.02 - 2.95 (m, 2H), 2.57 - 2.48 (m, 2H), 2.51 (s, 3H), 2.09 - 1.91 (m, 4H), 1.75 -1.65 (m, 2H9, 1.36 - 1.16 (m, 9H), 0.89 (t, J= 6.8 Hz, 3H); 13C NMR (CD3OD) 8 163.3, 142.2, 140.3, 139.1, 129.1, 124.1, 119.3, 119.0, 114.7, 55.6, 53.8, 40.4, 36.1, 35.5, 31.8, 28.9, 24.6, 22.7, 21.1, 13.2; HPLC-MS (ammonium acetate) [M+H]+ = 341.3.
(R)-1-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-1H-quinolin-2-one (107LH52)
[0403] A 4mL vial was charged with crude (S)-l-(3-iodo-2-methyl-propyl)-1H-quinolin-2-one (0.66 g), 4-butylpiperidine (0.43 g, 3.0 mmol) and dry CH3CN (1 mL). The mixture was shaken at 50 °C for 72 h and then poured onto The compound EtOAc (50 mL) and water (25 mL). The water phase was extracted (2 x 25 mL) and the combined organic phases were dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash CC (SiO2; EtOAc/MeOH 1:4) and then cation-exchange CC producing the title compound (0.300 g, 44%). lH NMR (CD3OD) 8 7.88 (d, J= 9.2 Hz, 1H), 7.73 - 7.66 (m, 2H), 7.61 (t, J= 8.0 Hz, 1H), 7.29 (t, J= 7.4 Hz, 1H), 6.65 (d, J= 9.2 Hz, 1H), 4.42 - 4.26 (m, 2H), 2.90 (brd, J= 11.4 Hz, 1H), 2.74 (brd, J= 11.4 Hz, 1H), 2.40 - 2.16 (m, 3 H), 1.94 - 1.78 (m, 2H), 1.64 - 1.54 (m, 2H), 1.35 - 1.00 (m, 9H), 0.96 -0.85 (m, 6H); 13C NMR (CD3OD) 8 163.7, 140.2, 139.5, 130.8, 129.1, 122.5, 121.4, 120.4,115.3, 64.0, 55.1, 54.2,46.8, 36.3, 35.8, 32.4, 32.3,29.8,28.9,22.8,16.1,13.2.
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[0404] The product was dissolved in acetone and tartric acid (1.1 equiv) dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.277 g). HPLC-MS (ammonium acetate) [M+H]+= 341.3.
(R)-1-[2-Methyl-3-(4-propoxypiperidin-1-yl)-propyl]-1 H-quinolin-2-one( 107LH65)
[0405] A 4mL vial was charged with crude (5)-l-(3-iodo-2-methylpropyl)-1H-quinolin-2-one (0.190 g), 4-propyloxypiperidine (0.137 g, 0.96 mmol) and dry CH3CN (2.5 mL). The mixture was shaken at 50 °C for 24 h and then purified by cation-exchange CC followed by flash CC (Si02; EtOAc/MeOH 1:4) to give the title compound (0.051 g, 17%). *H NMR (CD3OD) 5 7.85 (d, J= 9.6 Hz), 7.70 - 7.63 (m, 2H), 7.60 (brt, J = 7.8 Hz, 1H), 7.26 (brt, 7.6 Hz), 6.63 (d, J= 9.6 Hz, 1H), 4.39 - 4.23 (m, 2H), 3.37 (t, J= 6.6 Hz), 3.28 - 3.18 (m, 1H), 2.77-2.69 (m, 1H), 2.64 - 2.58 (m, 1H), 2.35 (dd, J= 8.4, 12.0 Hz), 2.51 - 2.21 (m, 1H), 2.18 (dd, J= 4.8, 12.0 Hz), 2.13 - 2.04 (m, 1H), 2.00 - 1.92 (m, 1H), 1.84 -1.75 (m, 2H), 1.58 - 1.32 (m, 4 H), 0.95 - 0.85 (m, 6H); 13C NMR (CD3OD) 8 163.7, 140.2, 139.5, 130.8, 129.2, 12.5, 121.4, 120.4, 115.2, 75.3, 69.5, 63.6, 52.3, 51.5, 46.8, 31.4, 31.3, 30.0,23.1,16.1, 9.8.
[0406] The product was dissolved in acetone and oxalic acid (1.1 equiv) dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.032 g). HPLC-MS (ammonium acetate) [M+H]+= 343.3.
1–[3-(4-Allyloxypiperidin-1-yl)propyl]-1H-quinolin-2-one (107LH85)
[0407] A 4 mL vial was charged with l-(3-chloropropyl)-lH-quinolin-2-one (0.130 g, 0.6 mmol), Nal (0.225 g, 1.5 mmol), K2C03 (0.210 g, 1.5 mmol), 4-allyloxypiperidine (0.085 g, 0.60 mmol) and dry CH3CN (1 mL). The mixture was shaken at 40 °C for 72 h and then poured onto The compound EtOAc (25 mL) and water (15 mL). The water phase was extracted (2 x 25 mL) and the combined organic phases were dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash CC (Si02; EtOAc/MeOH 4:1) followed by cation-exchange CC to yield the title compound (0.140 g, 70%). lH NMR (CD3OD) 6 7.81 (d, J= 9.6 Hz, 1H), 7.64-7.55 (m, 3H), 7.27-7.21 (m, 1H), 6.61 (d, J= 9.6 Hz, 1H), 5.93-5.82 (m, 1H), 5.27-5.20 (m, 1H),
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5.13-5.07 (m, 1H), 4.33-4.26 (m, 2H), 3.40-3.28 (m, 2H), 2.76-2.67 (m, 2H), 2.47-2.39 (m, 2H), 2.18-2.08 (m, 1H), 1.93-1.80 (m, 4H), 1.61-1.50 (m, 2H); 13C NMR (CD3OD) 5 162.9, 140.3, 139.0, 135.5, 131.1, 129.2, 122.6, 121.3, 120.4, 115.5, 114.7, 74.2, 68.7, 55.3,51.0,40.6,30.9,24.9.
[0408] The product was dissolved in acetone and oxalic acid (1.1 equiv) dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.140 g). HPLC-MS (ammonium acetate) [M+H]+= 327.3.
GENERAL PROCEDURE 18 (GP18)
[0409] A 7 mL vial was charged with heterocycle (1 equiv), (R,S)-l-bromo-3-chloro-2-methylpropane (1.2 equiv), and CS2CO3 (2 equiv) in MeCN (4 mL) and stirred at 50 ° for 20 h. The reaction mixture was added water, and the product extracted into EtOAc. The combined organic layers were filtered through a PTFF filter and concentrated. The product was used for the next reaction step without further purification.
(R,S)-4-(3-Chloro-2-methylpropyl-6-methyl-4H-benzo[1,4]oxazin-3-one(1l2KK19-a)
[0410] 6-Methyl-4/7-benzo[l,4]oxazin-3-one (0.512 g, 3.14 mmol), (R,S)-1-bromo-3-chloro-2-methylpropane (0.646 g, 3.77 mmol), and CS2CO3 (2.036 g, 6.25 mmol) in MeCN (4 mL) were reacted and worked up according to GP18 to give the crude title compound (112KK19-a) (0.692 g).
(i?.5)-4-(3-Chloro-2-methylpropyl)6-fluoro-4H/-benzo[1,4]oxazin-3-one(112KK19-b)
[0411] 6-Fluoro-4H-benzo[l,4]oxazin-3-one (0.502 g, 3.00 mmol), (R,S)-1-bromo-3-chloro-2-methylpropane (0.617 g, 3.60 mmol), and Cs2CO3 (1.983 g, 6.09 mmol) in MeCN (4 mL) were reacted and worked up according to GP18 to give the crude title compound (112KK19-b) (0.768 g).
(R,S)-4-(3-Chloro-2-methylpropyl-7-fluoro-4H-benzo[1,4]oxazin-3-one(112KK19-c)
[0412] 7-Fluoro-4H-benzo[l,4]oxazin-3-one (0.498 g, 2.98 mmol), (R,S)-1-bromo-3-chloro-2-methylpropane (0.613 g, 3.58 mmol), and CS2CO3 (1.985 g, 6.09 mmol) in MeCN (4 mL) were reacted and worked up according to GP18 to give the crude title compound (112KK19-c) (0.694 g).
120

(R.S)-3-(3-Chloro-2-methylpropyl)-3H-benzothiazol-2-one(112KK19-d)
[0413] Benzothiazol-2-ol (0.476 g, 3.15 mmol), (R,S)-l-bromo-3-chloro-2-methylpropane (0.648 g, 3.78 mmol), and Cs2CO3 (2.024 g, 6.21 mmol) in MeCN (4 mL) were reacted and worked up according to GP18 to give the crude title compound (112KK19-d) (0.804 g).
GENERAL PROCEDURE 19 (GP19)
[0414] A 7 mL vial was charged with heterocycle (1 equiv), (i?,iS)-l-bromo-3-chloro-2-methylpropane (1 equiv), and CS2CO3 (1.5 equiv) in MeCN (3 mL) and stirred at 50 ° for 20 h. The reaction mixture was added water and the product extracted into EtOAc. The combined org. layers were dried over Na2S04, filtered, and concentrated. The product was purified by flash CC (SiO2; EtOAc/n-heptane 1:1).
(R,S)-4-[3-Chloro-2-methylpropyl-4H-benzo[1,4]oxazin-3-one(107LH61-1)
[0415] 4H-benzo[1.4]oxazin-2-one (0.447 g, 3.0 mmol), (R,S)-l-bromo-3-chloro-2-methylpropane (0.514 g, 3.0 mmol), and Cs2CO3 (1.466 g, 4.5 mmol) in MeCN (3 mL) were reacted and purified according to GP19 to give the crude title compound (107LH61-1) (0.595 g).
(R,S)-4-(3-Chloro-2-methylpropyl-4H-benzo[1.4]thiazin-3-one (107LH61 -2)
[0416] 4H-Benzo[1.4]thiazin-3-one (0.496 g, 3.0 mmol), (R,S)-l-bromo-3-chloro-2-methylpropane (0.514 g, 3.0 mmol), and CS2CO3 (1.466 g, 4.5 mmol) in MeCN (3 mL) were reacted and purified according to GP19 to give the crude title compound (107LH61-2) (0.593 g).
(R,S)-4-(3-Chloro-2-methylpropyl)6-methoxy-4H-benzo[1,4]oxazin-3-one(107LH69)
[0417] 6-Methoxy-4H-benzo[l,4]oxazin-3-one (111MF24) (0.538 g, 3.0 mmol), (R,S)-l-bromo-3-chloro-2-methylpropane (0.514 g, 3.0 mmol), and CS2CO3 (1.466 g, 4.5 mmol) in MeCN (3 mL) were reacted and purified according to GP19 to give the crude title compound (107LH69) (0.658 g).
121

(R.S)-1-(3-Chloro-2-methylpropyl) 3.4-dihydro-1H-quinolin-2-one (107LH63)
[0418] A reaction flask was charged with 3,4-dihydro-lH-quinolin-2-one (1.00 g, 6.8 mmol) in dry DMF (10 mL). NaH 60% (0.300 g, 7.5 mmol) was added and the mixture was stirred at it for 1 h under an Argon atmosphere. Then (R,S)-l-bromo-3-chlor-2-methylpropane (1.165 g, 6.8 mmol) was added followed by stirring at rt for 20 h. The crude product was concentrated and purified by flash CC (Si02; EtOAc/n-heptane 1:1) to give the crude title compound (107LH63) (0.753 g)
GENERAL PROCEDURE 20 (GP20)
[0419] A 4 mL vial was charged with crude heterocycle, amine, Nal (0.100 g, 0.67 mmol), and K2C03 (0.075 g, 0.54 mmol) in DMF and stirred at 100 ° for 5 days. The reaction mixture was added water and the product extracted into EtOAc. The crude product was purified by cation exchange CC and then prep. RP-HPLC to give the title compound.
(R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6-methyl-4H-benzo[1.4]oxazin-3-one (112KK20-a1)
[0420] Crude (R,S)-4-(3-chloro-2-methylpropyl)-6-methyl-4H-
benzo[l,4]oxazin-3-one (112KK19-a) (0.046 g), 4-butylpiperidine (0.050 g, 0.35 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1.4 mL) were reacted and purified according to GP20 to give the title compound (112KK20-al) (0.007 g). HPLC-MS (ammonium acetate) [M+H]+ = 359.32.
(R, S)-4- [2-Methyl-3 -(4-propoxypiperidin-1-yl)propyl]-6-methyl-4H-benzo[1.4]oxazin-3-one(112KK20-a2)
[0421] Crude (R,S)-4-(3-chloro-2-methylpropyl)-6-methyl-4H-
benzo[l,4]oxazin-3-one (112KK19-a) (0.046 g), 4-propoxypiperidine (0.050 g, 0.35 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1.4 mL) were reacted and purified according to GP20 to give the title compound (112KK20-a2) (0.010 g). HPLC-MS (ammonium acetate) [M+H]+ = 361.29.
122

(R,S)-4-[3-(4-Butylidenepiperidin-l-yl)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one(112KK20-a3)
[0422] Crude (R,S)-4-(3-chloro-2-methylpropyl)-6-methyl 4H/- benzo[l,4]oxazin-3-one (112KK19-a) (0.046 g), 4-butylidenepiperidine (0.053 g, 0.38 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1.4 mL) were reacted and purified according to GP20 to give the title compound (112KK20-a3) (0.008 g). HPLC-MS (ammonium acetate) [M+H]+ = 357.30.

(R,S)-4-[3-(4-Butylidenepiperidin-l-yl)-2-methylpropyl]-6-methyl-4H-benzo[1,4]oxazin-3-one(112KK20-a3)
[0423] Crude (7?,S)-4-(3-chloro-2-methylpropyl)-6-methyl-4H/-
benzo[l,4]oxazin-3-one (112KK19-a) (0.023 g), 3-butyl-8-azabicyclo[3.2.1]octane (0.025 g, 0.15 mmol), Nal (0.100 g, 0.67 mmol), and K2C03 (0.075 g, 0.54 mmol) in DMF (1.2 mL) were reacted and purified according to GP20 to give the title compound (112KK20-a4) (0.007 g). HPLC-MS (ammonium acetate) [M+H]+ = 385.32.
(R,S)-4-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-6-methyl-4H-benzo[1,4]oxazin-3-one (112KK20-a5)
[0424] Crude (R,S)-4-(3-chloro-2-methylpropyl)-6-methyl-4H-
benzo[l,4]oxazin-3-one (112KK19-a) (0.023 g), 3-pentyl-8-azabicyclo[3.2.1]octane (0.024 g, 0.13 mmol), Nal (0.100 g, 0.67 mmol), and K2C03 (0.075 g, 0.54 mmol) in DMF (1.2 mL) were reacted and purified according to GP20 to give the title compound (112KK20-a5) (0.002 g). HPLC-MS (ammonium acetate) [M+H]+ = 399.35.
(R,S)-4-[3-(4-Butylpiperidin-1-yl)-2-methylpropyl]-6-fluoro-4H-benzo [1.4] oxazin-3 -one (112KK20-b1)
[0425] Crude (R,S)-4-(3-chloro-2-methylpropyl)-6-fluoro-4H-
benzo[l,4]oxazin-3-one (112KK19-b) (0.051 g), 4-butylpiperidine (0.050 g, 0.35 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1.4 mL) were reacted and purified according to GP20 to give the title compoimd (112KK20-M) (0.011 g). HPLC-MS (ammonium acetate) [M+H]+ = 363.28.
123

(R,S)-6-Fluoro-4-[2-methyl-3 -(4-Propoxypiperidin-1-yl)propyl]-4H-benzo [1.4] oxazin-3 –one(112KK20-b2)
[0426] Crude (R,S)-4-(3-chloro-2-methylpropyl)-6-fluoro-4H-
benzo[l,4]oxazin-3-one (112KK19-b) (0.051 g), 4-propoxypiperidine (0.050 g, 0.35 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1.4 mL) were reacted and purified according to GP20 to give the title compound (112KK20-b2) (0.010 g). HPLC-MS (ammonium acetate) [M+H]+ = 365.26.
(R,S)-4-\3 -(4-Butylidenepiperidin-1-yl)-2-methylpropyl] -6-fluoro-4H-benzo[1.4]oxazin-3-one(112KK20-b3)
[0427] Crude (R,S)-4-(3-chloro-2-methylpropyl)-6-fluoro-4H-
benzo[l,4]oxazin-3-one (112KK19-b) (0.051 g), 4-butylidenepiperidine (0.053 g, 0.38 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1.4 mL) were reacted and purified according to GP20 to give the title compound (112KK20-b3) (0.011 g). HPLC-MS (ammonium acetate) [M+H]+ = 361.27.
(R,S)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl-2-methylpropyl]-6-fluoro-4H-benzo[1,4]oxazin-3-one (112KK20-b4)
[0428] Crude (R,S)-4-(3-chloro-2-methylpropyl)-6-fluoro-4H-
benzo[l,4]oxazin-3-one (112KK19-b) (0.026 g), 3-butyl-8-azabicyclo[3.2.1]octane (0.025 g, 0.15 mmol), Nal (0.100 g, 0.67 mmol), and K2C03 (0.075 g, 0.54 mmol) in DMF (1.2 mL) were reacted and purified according to GP20 to give the title compound (112KK20-b4) (0.009 g). HPLC-MS (ammonium acetate) [M+H]+ = 389.30.
(R,S)-6-Fluoro-4-[2-methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]oxazin-3-one (112KK20-b5)
[0429] Crude (R,S)-4-(3-chloro-2-methylpropyl)-6-fluoro-4H-
benzo[l,4]oxazin-3-one (112KK19-b) (0.026 g), 3-pentyl-8-azabicyclo[3.2.1]octane (0.024 g, 0.13 mmol), Nal (0.100 g, 0.67 mmol), and K2C03 (0.075 g, 0.54 mmol) in DMF (1.2 mL) were reacted and purified according to GP20 to give the title compound (112KK20-b5) (0.009 g). HPLC-MS (ammonium acetate) [M+H]+ = 403.31.
124

(R. S)-4- [3 -(4-Butylpiperidin-1-yl)-2-methylpropyl] -7-fluoro-4H-benzo f 1.41 oxazin-3 -one (112KK20-c1)
[0430] Crude (R,S)-4-(3-chloro-2-methylpropyl)-7-fluoro-4H-
benzo[l,4]oxazin-3-one (112KK19-c) (0.046 g), 4-butylpiperidine (0.050 g, 0.35 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1.4 mL) were reacted and purified according to GP20 to give the title compound (112KK20-cl) (0.002 g). HPLC-MS (ammonium acetate) [M+H]+ = 363.29.
(R. S)-7-Fluoro-4- [2-methyl-3 -(4-propoxypiperidin-1-yl)propyl] -4H-benzo[1.4] oxazin-3-one(112KK20-c2)
[0431] Crude (R,S)-4-(3-chloro-2-methylpropyl)-7-fluoro-4H-
benzo[l,4]oxazin-3-one (112KK19-c) (0.046 g), 4-propoxypiperidine (0.050 g, 0.35 mmol), Nal (0.100 g, 0.67 mmol), and K2C03 (0.075 g, 0.54 mmol) in DMF (1.4 mL) were reacted and purified according to GP20 to give the title compound (112KK20-c2) (0.002 g). HPLC-MS (ammonium acetate) [M+H]+ = 365.28.
(R, S)-4- [3-(4-Butylidenepiperidin-1-yl)-2-methylpropyl]-7-fluoro-4H-benzo [1.4] oxazin-3-one(112KK20-c3)
[0432] Crude (R,S)-4-(3-chloro-2-methylpropyl)-7-fluoro-4H-
benzo[l,4]oxazin-3-one (112KK19-c) (0.046 g), 4-butylidenepiperidine (0.053 g, 0.38 mmol), Nal (0.100 g, 0.67 mmol), and K2C03 (0.075 g, 0.54 mmol) in DMF (1.4 mL) were reacted and purified according to GP20 to give the title compound (112KK20-c3) (0.008 g). HPLC-MS (ammonium acetate) [M+H]+ = 361.29.
(R,S)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one (112KK20-c4)
[0433] Crude (R,S)-4-(3-chloro-2-methylpropyl)-7-fluoro-4H-
benzo[l,4]oxazin-3-one (112KK19-c) (0.023 g), 3-butyl-8-azabicyclo[3.2.1]octane (0.025 g, 0.15 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1.2 mL) were reacted and purified according to GP20 to give the title compound (112KK20-c4) (0.004 g). HPLC-MS (ammonium acetate) [M+H]+ = 389.31.
125

(R,S)-7-Fluoro-4-[2-methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]oxazin-3-one (112KK20-c5)
[0434] Crude (R,S)-4-(3-chloro-2-methylpropyl)-7-fluoro-4H-
benzo[l,4]oxazin-3-one (112KK19-c) (0.023 g), 3-pentyl-8-azabicyclo[3.2.1]octane (0.024 g, 0.13 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1.2 mL) were reacted and purified according to GP20 to give the title compound (112KK20-c5) (0.002 g). HPLC-MS (ammonium acetate) [M+H]+ = 403.32.
(R,S)-3-[3-(4-Butylpiperidin-l-yl)-2-methylpropyl]-3H-benzothiazol-2-one (112KK20-d1)
[0435] Crude (R,S)-3-(3-chloro-2-methylpropyl)-3H-benzothiazol-2-one
(112KK19-d) (0.054 g), 4-butylpiperidine (0.050 g, 0.35 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1.4 mL) were reacted and purified according to GP20 to give the title compound (112KK20-dl) (0.012 g). HPLC-MS (ammonium acetate) [M+H]+ = 347.28.
(R,S)-4-[2-Methyl-3-(4-propoxypiperidin-1-yl)propyl]-3H-benzothiazol-2-one(112KK20-d2)
[0436] Crude (R,S)-3-(3-chloro-2-methylpropyl)-3H-benzothiazol-2-one
(112KK19-d) (0.054 g), 4-propoxypiperidine (0.050 g, 0.35 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1.4 mL) were reacted and purified according to GP20 to give the title compound (112KK20-d2) (0.011 g). HPLC-MS (ammonium acetate) [M+H]+ = 349.25.
(R,S)-4-[3-(4-Butylidenepiperidin-l-yl)-2-methylpropyl]-3H-benzothiazol-2-one (112KK20-d3)
[0437] Crude (R,S)-3-(3-chloro-2-methylpropyl)-3H-benzothiazol-2-one
(112KK19-d) (0.054 g), 4-butylidenepiperidine (0.053 g, 0.38 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1.4 mL) were reacted and purified according to GP20 to give the title compound (112KK20-d3) (0.011 g). HPLC-MS (ammonium acetate) [M+H]+ = 345.27.
126

(R,S)-3-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-3H-benzothiazol-2-one (112KK20-d4)
[0438] Crude (R,S)-3-(3-chloro-2-methylpropyl)-3H-benzothiazol-2-one
(112KK19-d) (0.027 g), 3-butyl-8-azabicyclo[3.2.1]octane (0.025 g, 0.15 mmol), Nal (0.100 g, 0.67 mmol), and K2C03 (0.075 g, 0.54 mmol) in DMF (1.2 mL) were reacted and purified according to GP20 to give the title compound (112KK20-d4) (0.011 g). HPLC-MS (ammonium acetate) [M+H]+ = 373.30.
(R,S)-3-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-3H-benzothiazol-2-one (112KK20-d5)
[0439] Crude (R,S)-3-(3-chloro-2-methylpropyl)-3i/-benzothiazol-2-one
(112KK19-d) (0.027 g), 3-pentyl-8-azabicyclo[3.2.1]octane (0.024 g, 0.13 mmol), Nal (0.100 g, 0.67 mmol), and K2C03 (0.075 g, 0.54 mmol) in DMF (1.2 mL) were reacted and purified according to GP20 to give the title compound (112KK20-d5) (0.011 g). HPLC-MS (ammonium acetate) [M+H]+ = 387.30.
(R, S)-4 [3 -(4-Butylpiperidin-1-yl)-2-methylpropyl]-4H-benzo[ 1,4] oxazin-3 -one (107LH74-a1)
[0440] Crude (R,S)-4-(3-chloro-2-methylpropyl)-4H-benzo[l ,4]oxazin-3-one (107LH61-1) (0.149 g), 4-butylpiperidine (0.042 g, 0.30 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1 mL) were reacted and purified according to GP20 to give the title compound (107LH74-al) (0.092 g). HPLC-MS (ammonium acetate) [M+H]+ = 345.30.
(R, S)-4- [2-Methyl-3 -(4-propoxypiperidin-1-yl)propyl]-4H-benzo [1,4] oxazin-3 -one (107LH74-a2)
[0441] Crude (R,S)-4-(3-chloro-2-methylpropyl)-4H-benzo[ 1,4] oxazin-3-one (107LH61-1) (0.149 g), 4-propoxypiperidine (0.043 g, 0.30 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1 mL) were reacted and purified according to GP20 to give the title compound (107LH74-a2) (0.077 g). HPLC-MS (ammonium acetate) [M+H]+ = 347.30.
127

(R,S)-4-[3-(4-Butylidenepiperidin-l-yl)-2-methylpropyl]-4H-benzo[l,4]oxazin-3-one H07LH74-a3)
[0442] Crude (R,S)-4-(3-chloro-2-methylpropyl)-4H-benzo[l,4]oxazin-3-one (107LH61-1) (0.149 g), 4-butylidenepiperidine (0.042 g, 0.30 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1 mL) were reacted and purified according to GP20 to give the title compound (107LH74-a3) (0.083 g). HPLC-MS (ammonium acetate) [M+H]+ = 343.30.
(R,S)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (107LH74-a4)
[0443] Crude (R,S)-4-(3-chloro-2-methylpropyl)-4H-benzo[l,4]oxazin-3-one (107LH61-1) (0.074 g), 3-butyl-8-azabicyclo[3.2.1]octane (0.025 g, 0.15 mmol), Nal (0.100 g, 0.67 mmol), and K2C03 (0.075 g, 0.54 mmol) in DMF (1 mL) were reacted and purified according to GP20 to give the title compound (107LH74-a4) (0.046 g). HPLC-MS (ammonium acetate) [M+H]+ = 371.33.
(R,S)-4-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]oxazin-3-one (107LH74-a5)
[0444] Crude (R,S)-4-(3-chloro-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one 107LH61-1) (0.074 g), 3-pentyl-8-azabicyclo[3.2.1]octane (0.027 g, 0.15 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1 mL) were reacted and purified according to GP20 to give the title compound (107LH74-a5) (0.053 g). HPLC-MS (ammonium acetate) [M+H]+ = 385.34.
(R,S)-4-[3-(4-Butylpiperidin-l-yl)-2-methylpropyl]-4H-benzo[l,4]thiazin-3-one (107LH74-b1)
[0445] Crude (R,S)-4-(3-chloro-2-methylpropyl)-4H-benzo[l,4]thiazin-3-one (107LH61-2) (0.148 g), 4-butylpiperidine (0.042 g, 0.30 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1 mL) were reacted and purified according to GP20 to give the title compound (107LH74-M) (0.083 g). HPLC-MS (ammonium acetate) [M+H]+ = 361.29.
128

(R. S)-1 - [2-Methyl-3 -(4-propoxypiperidin-1 –yl)propyl] -4H-benzo [ 1,4] thiazin-3 -one (107LH74-b2)
[0446] Crude (R,S)-1 -(3-chloro-2-methylpropyl)-4H-benzo[ 1,4]thiazin-3-one (107LH61-2) (0.148 g), 4-propoxypiperidine (0.043 g, 0.30 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1 mL) were reacted and purified according to GP20 to give the title compound (107LH74-b2) (0.071 g). HPLC-MS (ammonium acetate) [M+H]+ =363.27.
(R. S)-4- [3 -(4-Butylidenepiperidin-1-yl)-2-methylpropyl] -4H-benzo [1,41 thiazin-3 -one (107LH74-b3)
[0447] Crude (R,S)-4-(3-chloro-2-methylpropyl)-4Z7-benzo[ 1,4]thiazin-3-one (107LH61-2) (0.148 g), 4-butylidenepiperidine (0.042 g, 0.30 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1 mL) were reacted and purified according to GP20 to give the title compound (107LH74-b3) (0.064 g). HPLC-MS (ammonium acetate) [M+H]+ = 359.27.
(R,S)-4-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-4H-benzo[1.4]thiazin-3-one (l07LH74-b4)
[0448] Crude (R,S)-4-(3-chloro-2-methylpropyl)-4H-benzo[l,4]thiazin-3-one (107LH61-2) (0.074 g), 3-butyl-8-azabicyclo[3.2.1]octane (0.025 g, 0.15 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1 mL) were reacted and purified according to GP20 to give the title compound (107LH74-b4) (0.040 g). HPLC-MS (ammonium acetate) [M+H]+ =387.30.
(R,S)-4-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-4H-benzo[1,4]thiazin-3-one (107LH74-b5)
[0449] Crude (£S)-4-(3-chloro-2-methylpropyl)-4H-benzo[l,4]thiazin-3-one (107LH61-2) (0.074 g), 3-pentyl-8-azabicyclo[3.2.1]octane (0.027 g, 0.15 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1 mL) were reacted and purified according to GP20 to give the title compound (107LH74-b5) (0.040 g). HPLC-MS (ammonium acetate) [M+H]+ =401.30.
129

(R, S)-1 -[3-(4-Butylpiperidin-1-yl)-2-methylpropyl] -3.4-dihydro-1H-quinolin-2-one (107LH74-c1)
[0450] Crude(R,S)-l-(3-chloro-2-methylpropyl)-3,4-dihydro-lH-quinolin-2-one (107LH63) (0.188 g), 4-butylpiperidine (0.042 g, 0.30 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1 mL) were reacted and purified according to GP20 to give the title compound (107LH74-cl) (0.047 g). HPLC-MS (ammonium acetate) [M+H]+ = 343.32.
(R,S)-1-[2-Methyl-3 -(4-propoxypiperidin-1-yl)propyl] -3,4-dihydro-1H-quinolin-2-one (107LH74-c2)
[0451] Crude(R,S)-l-(3-chloro-2-methylpropyl)-3,4-dihydro-lH-quinolin-2-one (107LH63) (0.188 g), 4-propoxypiperidine (0.043 g, 0.30 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1 mL) were reacted and purified according to GP20 to give the title compound (107LH74-c2) (0.040 g). HPLC-MS (ammonium acetate) [M+H]+ = 345.32.
(R,S)-l-[3-(4-Butylidenepiperidin-l-yl)-2-methylpropyl]-3.4-dihydro-lH-quinolin-2-one (107LH74-c3)
[0452] Crude (R, S)-1 -(3-chloro-2-methylpropyl)-3,4-dihydro-1 H-quinolin-2-one (107LH63) (0.188 g), 4-butylidenepiperidine (0.042 g, 0.30 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1 mL) were reacted and purified according to GP20 to give the title compound (107LH74-c3) (0.038 g). HPLC-MS (ammonium acetate) [M+H]+ = 341.31.
(R,S)-l-[3-(3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-3.4-dihydro-lH-quinolin-2-one (107LH74-c4)
[0453] Crude (R,S)-l-(3-chloro-2-methylpropyl)-3,4-dihydro-lH-quinolin-2-one (107LH63) (0.094 g), 3-butyl-8-azabicyclo[3.2.1]octane (0.025 g, 0.15 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1 mL) were reacted and purified according to GP20 to give the title compound (107LH74-c4) (0.025 g). HPLC-MS (ammonium acetate) [M+H]+ = 369.33.
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(R,S)-l-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-3.4-dihydro-lH-quinolin-2-one (107LH74-c5)
[0454] Crude (R,S)-l-(3-chloro-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (107LH63) (0.094 g), 3-pentyl-8-azabicyclo[3.2.1]octane (0.027 g, 0.15 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1 mL) were reacted and purified according to GP20 to give the title compound (107LH74-c5) (0.023 g). HPLC-MS (ammonium acetate) [M+H]+ = 383.34.
(R, S)-4- [3 -(4-Butylpiperidin-1-yl)-2-methylpropyl] -6-methoxy-4H-benzo [ 1,4] oxazin-3-one (107LH74-d1)
[0455] Crude (R,S)-4-(3-chloro-2-methylpropyl)-6-methoxy-4H-
benzo[l,4]oxazin-3-one (107LH69) (0.165 g), 4-butylpiperidine (0.042 g, 0.30 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1 mL) were reacted and purified according to GP20 to give the title compound (107LH74-dl) (0.094 g). HPLC-MS (ammonium acetate) [M+H]+ = 375.31.
(R,S)-4-[2-Methyl-3-(4-propoxypiperidin-l-yl)-6-methoxy]-4H-benzo[l,4]oxazin-3-one 107LH74-d2)
[0456] Crude (R,S)-4-(3-chloro-2-methylpropyl)-6-methoxy-4H-
benzo[l,4]oxazin-3-one (107LH69) (0.165 g), 4-propoxypiperidine (0.043 g, 0.30 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1 mL) were reacted and purified according to GP20 to give the title compound (107LH74-d2) (0.086 g). HPLC-MS (ammonium acetate) [M+H]+ = 377.29.
(&.S)-4-[3-(4-Butylidenepiperidin-l-yl)-2-methylpropyl]-6-methoxY-4H-benzo[1,4]oxazin-3-one (107LH74-d3)
[0457] Crude (R,S)-4-(3-chloro-2-methylpropyl)-6-methoxy-4H-
benzo[l,4]oxazin-3-one (107LH69) (0.165 g), 4-butylidenepiperidine (0.042 g, 0.30 mmol), Nal (0.100 g, 0.67 mmol), and K2C03 (0.075 g, 0.54 mmol) in DMF (1 mL) were reacted and purified according to GP20 to give the title compound (107LH74-d3) (0.086 g). HPLC-MS (ammonium acetate) [M+H]+ = 373.29.
131

(R. ,S)-4-[3-f 3-Butyl-8-azabicyclo[3.2.1]oct-8-yl)-2-methylpropyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one (107LH74-d4)
[0458] Crude (R,S)-4-(3-chloro-2-methylpropyl)-6-methoxy-4H7-benzo[l,4]oxazin-3-one (107LH69) (0.082 g), 3-butyl-8-azabicyclo[3.2.1]octane (0.025 g, 0.15 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1 mL) were reacted and purified according to GP20 to give the title compound (107LH74-d4) (0.044 g). HPLC-MS (ammonium acetate) [M+H]+ = 401.32.
(R,S)-l-[2-Methyl-3-(3-pentyl-8-azabicyclo[3.2.1]oct-8-yl)propyl]-6-methoxy-4H-benzo[1,4]oxazin-3-one(107LH74-d5)
[0459] Crude (R,S)-4-(3-chloro-2-methylpropyl)-6-methoxy-4H-
benzo[l,4]oxazin-3-one (107LH69) (0.082 g), 3-pentyl-8-azabicyclo[3.2.1]octane (0.027 g, 0.15 mmol), Nal (0.100 g, 0.67 mmol), and K2CO3 (0.075 g, 0.54 mmol) in DMF (1 mL) were reacted and purified according to GP20 to give the title compound (107LH74-d5) (0.051 g). HPLC-MS (ammonium acetate) [M+H]+ = 415.34.
1-[3-(4-Butyl-piperidin-1-yl)-propyl]-1.2.3.4-tetrahydro-quinoline (55-LH-12-2)
[0460] A solution of H-butyllithium in hexane (1.5M, 7.3 mL, 11 mmol) was added drop wise to a solution of 1,2,3,4-tetrahydro-quinoline (1.256 mL, 10 mmol) in tetrahydrofuran (10 mL) at -78°C under an atmosphere of argon. The reaction mixture was stirred for Vi h then l-chloro-3-iodopropane (1.0 mL, 9.5 mmol) was added. The reaction mixture was stirred at -78°C for 14 h then stirred for additional 16 h at room temperature. Tetrahydrofuran was evaporated off and the solid was dissolved in acetonitrile (10 mL). KI (1.83 g, 11 mmol), K2C03 (2.76 g, 20 mmol) and 4-butylpiperidine (1.66 mL, 10 mmol) were added. The slurry was stirred at 50°C for 48 h then water (10 mL) was added and the product was extracted with ethyl acetate (2 x 20 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The product was purified by column chromatography (eluent: ethyl acetate) to give the title compound (1.11 g, 35%) Oxalate-salt was prepared from oxalic acid (1.1 eq.) in acetone. HPLC-MS: M+l+ = 315.1 (MS(%) = 95). !H NMR (400 MHz, CDC13): 8= 0.89 (3H, t), 1.18-1.34 (9H, m), 1.64-1.70 (2H, m), 1.79 (2H, quin.), 1.85-1.98 (4H, m), 2.36 (2H, t), 2.74 (2H, t), 2.92 (2H, broad d), 3.24-3.31 (4H, m), 6.54 (1H, ddd), 6.60 (1H, dd), 6.93 (1H, dd), 7.03
132

(IH, ddd).13C NMR (CDC13): d 14.3, 22.5, 23.1, 24.2, 28.4, 29.3, 32.7, 36.0, 36.5, 49.6, 49.8, 54.4, 56.7, 110.9, 115.5, 122.5, 127.3, 129.3, 145.6.
1-[3-(4-Butyl-piperidin-1-yl)-propyl]-2-methyl-1.2.3.4-tetrahydro-quinoline (55-LH-28-8) [0461] 2-Methyl-l,2,3,4-tetrahydroquinoline (346 mg, 2.35 mmol) was converted to the title product according to the procedure for the synthesis of l-[3-(4-butyl-piperidin-l-yl)-propyl]-l,2,3,4-tetrahydro-quinoline. Yield: 88.6 mg, 11%. HPLC-MS: M+l+= 329.5 (UV/MS(%) = 100/99). 1H NMR (400 MHz, CDC13): 6= 0.89 (3H, t), 1.11 (3H, d), 1.16-1.34 (9H, m), 1.67 (2H, broad d), 1.65-2.03 (8H, m), 2.39 (2H, t), 2.57-2.66 (IH, m), 2.74-2.85 (IH, m), 2.93 (2H, broad d), 3.12-3.21 (IH, m), 3.33-3.42 (IH, m), 3.44-3.52 (IH, m), 6.45 (IH, t), 6.54 (IH, d), 6.87 (IH, d), 6.97 (IH, t).13C NMR (CD3OD): 5 13.2, 17.8, 22.8, 23.7, 24.4, 28.0, 28.9, 31.9, 35.7, 36.2, 52.7, 53.9, 54.0, 56.4, 110.8, 115.1, 121.9, 126.7, 128.7, 144.2.
l-[3-(4-Butyl-piperidin-l-yl)-propyl]-6-methyl-1.2.3.4-tetrahydro-quinoline(55-LH-44A) [0462] 6-Methyl-l,2,3,4-tetrahydroquinoline (346 mg, 2.35 mmol) was converted to the title product according to the procedure for the synthesis of l-[3-(4-butyl-piperidin-l-yl)-propyl]-l,2,3,4-tetrahydro-quinoline. Yield: 137 mg, 18%. HPLC-MS: M+l+= 329.5 (UV/MS(%) = 98/99). 'H NMR (400 MHz, CDC13): 6= 0.89 (3H, t), 1.14-1.34 (9H, m), 1.68 (2H, broad d), 1.76 (2H, quin.), 1.85-1.99 (4H, m), 2.14 (3H, s), 2.34-2.39 (2H, m), 2.66 (2H, t), 2.92 (2H, broad d), 3.18-3.26 (4H, m), 6.49 (IH, d), 6.58 (IH, broad s), 6.76 (IH, broad d). 13C NMR (CD3OD): 5 13.2, 19.2, 22.5, 22.8, 23.2, 28.0, 28.9,31.9,35.7,36.2,49.4,49.6,53.9,56.5, 111.3,122.7,124.7, 127.2,129.6,143.2.
1–[3-(4-Butyl-piperidin-1-yl-propyl] -8-methyl-1,2,3.4-tetrahydro-quinoline (77-LH-1)
[0463] 8-Methyl-l,2,3,4-tetrahydroquinoline (125 mg, 0.85 mmol), 1-chloro-3-iodopropane (82 ml, 0.77 mmol) and CS2CO3 (415 mg, 1.27 mmol) in acetonitrile (2 mL) were shaken at 60°C for 7 days. Kl (140 mg, 0.85 mmol), K2CO3 (117 mg, 0.85 mmol) and 4-butylpiperidine (113 ml, 0.68 mmol) were added and the reaction mixture was shaken at 60°C for 2 days. Water (5 mL) was added and the product was extracted with ethyl acetate (2x10 mL). The organic layer was dried (Na2S04) and concentrated in vacuo. The product was purified by column chromatography (eluent: 20% methanol in ethyl acetate) to yield the title compound. Yield: 45.6 mg (20.4 %). HPLC-MS: M+l+ =
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329.5 (UV/MS(%) = 99/97). JH NMR (400 MHz, CDC13): 8= 0.89 (3H, t), 1.18-1.34 (9H, m), 1.70 (2H, broad d), 1.75-1.92 (4H, m), 1.99 (2H, broad t), 2.22 (3H, s), 2.38 (2H, dd), 2.70-2.81 (4H, m), 2.96 (2H, broad d), 3.04-3.10 (2H, m), 6.76 (IH, t), 6.80 (IH, broad d), 6.91 (IH, broad d). 13C NMR (CD3OD): 5 13.2, 17.2, 18.0, 18.1, 22.8, 25.7, 27.7, 28.9, 31.9, 35.7, 36.2, 52.7, 53.9, 56.3,121.5,127.1, 128.7,128.9, 131.0,148.0.
1-[3-(4-Butyl-piperidin-1-yl)-propyl]-7-fluoro-2-methyl-1,2,3,4-tetrahydro-quinoline (77-LH-2)
[0464] 7-Fluoro-2-methyl-1,2,3,4-tetrahydro-quinoline (165 mg, 1.0 mmol) was converted to the title product according to the procedure for the synthesis of l-[3-(4-butyl-piperidin-l-yl)-propyl]-8-methyl-l,2,3,4-tetrahydro-quinoline. Yield: 43.2 mg, 16%. HPLC-MS: M+l+ = 347.5 (UV/MS(%)= 95/92). 'HNMR (400 MHz, CDC13): 8= 0.89 (3H, t), 1.10 (3H, d), 1.18-1.36 (9H, m), 1.66-1.91 (6H, m), 2.00-2.10 (2H, m), 2.44 (2H, t), 2.62 (IH, dt), 2.74-2.85 (IH, m), 2.99 (2H, broad d), 3.16 (IH, q), 3.30-3.40 (IH, m), 3.41-3.49 (IH, m), 6.63-6.74 (IH, m), 6.63-6.74 (2H, m). 13C NMR (CD3OD): 8 13.2, 17.6, 22.7, 23.7, 23.8, 24.3, 29.9, 28.9, 31.7, 35.5, 36.1, 52.6, 53.8, 56.2, 112.7 (d), 114.8 (d), 123.7, 140.8, 153.5, 155.8.
l-[3-(4-Butyl-piperidin-l-yl)-propyl]-7-trifluoromethyl-l,2,3,4-tetrahydro-quinoline (55-LH-54)
[0465] 7-Trifiuoromethyl- 1,2,3,4-tetrahydro-quinoline (0.50 g, 2.5 mmol) was converted to the title product according to the procedure for the synthesis of l-[3-(4-butyl-piperidin-l-yl)-propyl]-1,2,3,4-tetrahydro-quinoline. Yield: 1.71 mg, 18%. HPLC-MS: M+l+= 347.5 (UV/MS(%)= 99/91). 1H NMR (400 MHz, CDC13): 8= 0.89 (3H, t), 1.14-1.36 (9H, m), 1.68 (2H, broad d), 1.79 (2H, quin.), 1.86-2.03 (4H, m), 2.38 (2H, dd), 2.75 (2H, dd), 2.94 (2H, broad d), 3.32 (4H, m), 6.71 (IH, d), 6.75 (IH, s), 6.99 (IH, d).
l-[3-(4-Butyl-piperidin-l-yl-propyl]-3.4-dihydro-lH-quinolin-2-one(77-LH-28-1)
[0466] A suspension of NaH in mineral oil (55-60%) (712 mg) was added to a solution of 3,4-dihydro-1H-quinolin-2-one (2.0 g, 13.6 mmol) in N,N-dimethylformamide (50 mL) at 0°C. The reaction mixture was stirred at 0°C for 1 h. then l-bromo-3-chloropropane (1.34 mL, 13.6 mmol) was added. The slurry was stirred for additional 16 h. at ambient temperature then water (50 mL) was added and the product was extracted
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with diethyl ether (2 x 50 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The product was purified by flash-chromatography (eluent: dichloromethane) to give l-[3-chloropropyl]-3,4-dihydro-1H-quinolin-2-one (2.41 g, 10.8 mmol). KI (2.5 g, 15 mmol), K2CO3 (2.1 g, 15 mmol) and 4-butylpiperidine (1.8 mL, 15 mmol) were added to a solution of l-[3-chloropropyl]-3,4-dihydro-1H-quinolin-2-one (2.41 g, 10.8 mmol) in acetonitrile (50 mL). The reaction mixture was stirred at 60°C for 16 h. The acetonitrile was evaporated in vacuo, water (50 mL) was added and the product was extracted with ethyl acetate (2 x 50 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. Purification by flash-chromatography (eluent: ethyl acetate) gave the title product. Yield: 2.06 g, 58%. Oxalate-salt was prepared from oxalic acid (1.1 eq.) in acetone. HPLC-MS: M+l+ = 329.5 (UV/MS(%) = 100/100). 1H NMR (400 MHz, CD3OD): 8= 0.89 (3H, t), 1.12-1.36 (9H, m), 1.67 (2H, broad d), 1.83 (2H, quin.), 1.97 (2H, broad t), 2.41 (2H, t), 2.59 (2H, t), 2.84-2.96 (4H, m), 3.99 (2H, t), 7.02 (1H, broad t), 7.16 (1H, broad d), 7.20 (1H, broad d), 7.25 (1H, broad t).13C NMR (CD3OD): 8 13.2, 22.8, 24.3, 25.0, 28.9, 31.6, 31.9 (2C), 35.6, 36.2, 40.1, 53.8 (2C), 55.9, 115,2, 123.2, 127.0,127.4,127.9,139.1,171.5
1 -[3-(4-Butyl-piperidin-1-yl-propyl] -6-methoxy-3.4-dihydro-1H-quinolin-2-one (77-LH-22A)
[0467] 6-Methoxy-3,4-dihydro-1H-quinolin-2-one (108 mg, 0.61 mmol), 1-chloro-3-iodopropane (64 ul, 0.6 mmol) and CS2CO3 (290 mg, 0.9 mmol) in acetonitrile (2 mL) were shaken at 60°C for 14 h then the reaction was cooled to room temperature. Water (5 mL) was added and the product was extracted with ethyl acetate (2x10 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The syrup was dissolved in acetonitrile (4 mL). KI (83 mg, 3.6 mmol), K2CO3 (100 mg, 0.6 mmol) and 4-butylpiperidine (83 ml, 0.5 mmol) were added and the reaction mixture was shaken at 60°C for 16 h. Water (5 mL) was added and the product was extracted with ethyl acetate (2 x 10 mL). The organic layer was dried (Na2S04) and concentrated in vacuo. The product was purified by column chromatography (eluent: 20% methanol in ethyl acetate) to yield the title compound. Yield: 24.8 mg, 11.3%. HPLC-MS: M+l+= 359.5 (UV/MS(%) = 90/78). 1H NMR (400 MHz, CDCl3): 8= 0.89 (3H, t), 1.12-1.34 (9H, m), 1.67 (2H, broad d), 1.85 (2H, quin.), 1.93 (2H, broad t), 2.39 (2H, t), 2.59 (2H, dd), 2.83 (2H, t), 2.90 (2H, broad d), 3.76 (3H, s), 3.94 (2H, t), 6.70 (1H, d), 6.74 (1H, dd), 7.01
135

(1H, d).13C NMR (CDCI3): 5 14.3, 23.0, 25.0, 26.1, 29.2, 32.1, 32.5 (2C), 35.9, 36.4, 40.8, 54.3 (2C), 55.8, 56.3, 112.2,114.2,116.2,128.3,133.4,155.4, 169.9
4-[3-(4-Butyl-piperidin-l-yl-propyl]-6-methyl-4H-benzo[1.4]oxazin-3-one 64-(LHY-89-6)
[0468] 6-Methyl-4H-benzo[l,4]oxazin-3-one (82 mg, 0.5 mmol), l-chloro-3-iodopropane (50 ml, 0.5 mmol) and CS2CO3 (163 mg, 0.5 mmol) in acetonitrile (2 mL) were shaken at 50°C for 24 h then the reaction mixture was concentrated in vacuo. The product (4-[3-chloropropyl]-6-methyl-4H-benzo[l,4]-oxazin-3-one) was purified on an Isco CombiFlash Sq 16x (4 g silica column, eluting 0-20% ethyl acetate in heptanes) then dissolved in acetonitrile (2 mL). K2CO3 (85 mg, 0.5 mmol) and 4-butylpiperidine (80 ul, 0.5 mmol) were added. The reaction mixture was shaken at 60°C for 16 h then cooled to room temperature. Dichloromethane (2 mL) and PS-isocyanate (loading 1.47 mmol/g, 100 mg) were added. The mixture was filtered after 5 h and the organic layer was loaded onto a Varian SCX ion exchange column. The column was washed with methanol (2x5 mL) then the product was eluted off the column using 10% ammonium hydroxide in methanol (6 mL). The solute was concentrated in vacuo to give the title product. Yield: 100 mg, 58%. HPLC-MS: M+l+= 345.5 (UV/MS(%) = 99/99). 1H NMR (400 MHz, CDCI3): 8= 0.89 (3H, t), 1.15-1.30 (9H, m), 1.65 (2H, broad d), 1.81-1.89 (4H, m), 2.30 (3H, s), 2.36 (2H, t), 2.86 (2H, broad d), 3.94 (2H, dd), 4.51 (2H, s), 6.76 (1H, dd), 6.84 (1H, d), 6.86 (1H, d).13C NMR (CDCI3): 8 14.3, 21.3, 23.1, 25.1, 29.2, 32.8 (2C), 36.0, 36.5, 39.8, 54.4 (2C), 56.1, 67.9,115.8,116.9,124.3,128.6,132.5, 143.4,164.6.
6-Acetyl-4-[3-(4-butyl-piperidin-l-yl)-propyl]-4H-benzo[1.4]oxazin-3-one (64-LHY-89-
5)
[0469] 6-Acetyl-4H-benzo[l,4]oxazin-3-one (96 mg, 0.5 mmol) was converted to the title product according to the procedure for the synthesis of 4-[3-(4-butyl-piperidin-l-yl)-propyl]-6-methyl-4H-benzo[l,4]-oxazin-3-one. Yield: 120 mg, 64%. HPLC-MS: M+l+ = 373.5 (UV/MS(%) = 99/100). 1H NMR (400 MHz, CDC13): 8= 0.89 (3H, t), 1.13-1.27 (9H, m), 1.63 (2H, broad d), 1.81-1.88 (4H, m), 2.37 (2H, t), 2.55 (3H, s), 2.84 (2H, broad d), 4.02 (2H, dd), 4.65 (2H, s), 6.99 (1H, d), 7.58 (1H, dd), 7.66 (1H, d).13C NMR (CDCl3): 8 14.3, 23.1, 24.7, 26.5, 29.2, 32.7 (2C), 36.0, 36.5, 39.9, 54.4 (2C), 56.3, 67.6,114.9,117.0,125.3,128.8,132.4,149.5,163.5,196.3.
136

4- [3 -(4-Butyl-piperidin-1–yl)-propyl]-6-methyl-3,4-dihydro-2H-benzo [ 1,41 oxazine (64-LHY-91-6)
[0470] A solution of borane in THF (1M, 0.5 mL, 0.5 mmol) was added to a solution of 4-[3-(4-butyl-piperidin-1-yl)-propyl] -6-methyl-4H-benzo[1,4]oxazin-3-one (50 mg, 0.15 mmol) in THF (6 mL). The reaction mixture was stirred at 40°C for 16 h then aqueous HC1 (4M, 10 mL) was added drop wise at room temperature. The reaction mixture was stirred for 16 h then concentrated in vacuo. A solution of K2CO3 (0.5 g) in water (5 mL) was added and the product was extracted with dichloromethane (2x10 mL). The organic layer was dried (Na2S04) and concentrated in vacuo. The product was purified on an Isco CombiFlash Sq 16x (4 g silica column, eluting 0-20% ethyl acetate in heptanes + 1% Et3N). Yield: 29.2 mg, 56%. HPLC-MS: M+l+ = 373.5 (UV/MS(%) = 95/90). lH NMR (400 MHz, CDC13): 6= 0.90 (3H, t), 1.18-1.35 (9H, m), 1.68 (2H, broad d), 1.78 (2H, quin.), 1.89 (2H, broad t), 2.24 (3H, s), 2.35 (2H, t), 2.89 (2H, broad d), 3.27 (2H, t), 3.31 (2H, t), 4.19 (2H, t), 6.39 (1H, broad d), 6.52 (1H, broad s), 6.66 (1H, d).13C NMR (CDCI3): 5 14.3, 21.4, 23.1, 24.2, 29.3, 32.8 (2C), 36.1, 36.6, 47.4, 49.3, 54.5 (2C), 56.5, 64.7,113.0,116.2,117.7,131.1,135.3,142.0.
4-[3-(4-Butyl-piperidin-l-yl)-propyl]-6-ethyl-3,4-dihydro-2H-benzo[1.4]oxazine (64-LHY-91-5)
[0471] 6-Acetyl-4-[3-(4-butyl-piperidin-l-yl)-propyl]-4H-benzo[l,4]oxazin-3-one (60 mg, 0.161 mmol) was converted to the title product according to the procedure for the synthesis of 4-[3-(4-butyl-piperidin-l-yl)-propyl]-6-methyl-3,4-dihydro-2i7-benzo[l,4]oxazine. Yield: 22 mg, 40%. HPLC-MS: M+l+= 373.5 (UV/MS(%) = 98/97). lH NMR (400 MHz, CDC13): 8= 0.89 (3H, t), 1.18-1.35 (12H, m), 1.68 (2H, broad d), 1.75 (2H, quin.), 1.89 (2H, broad t), 2.35 (2H, t), 2.53 (2H, qv), 2.89 (2H, broad d), 3.26-3.33 (4H, m), 4.20 (2H, t), 6.43 (1H, dd), 6.53 (1H, d), 6.69 (1H, d).13C NMR (CDC13): 5 14.3, 16.2, 23.1, 24.2, 28.9, 29.3, 32.8 (2C), 36.1, 36.6, 47.4, 49.4, 54.5 (2C), 56.5, 64.7, 112.0,116.2,116.5,135.3,137.7,142.2.
4-(3-Chloropropyl)-4H-benzo[1.4]thiazin-3-one (81MF07)
[0472] 2H-l,4-benzothiazine-3(4H)-one (1.0 g, 6.05 mmol) and Cs2CO3 (2.96 g, 9.08 mmol) were dissolved in dry acetonitrile (20 mL) under nitrogen atmosphere and stirred at rt for 30 min. 3-chloro-l-iodopropane (1.37 g, 6.66 mmol) dissolved in
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acetonitrile (4 mL) was added via a syringe. The reaction mixture was stirred at rt for 18 hours and concentrated in vacuo. Water (150 mL) was added and the reaction mixture was extracted with ethyl acetate (3 x 150 mL). The combined organic phases were dried (MgSO4) and concentrated in vacou to give 1.45 g of crude. The crude product was subjected to CC[eluent:Heptane:EtOAC(4:l)] to give the pure title compound as a slightly yellow oil. Yield 1.37 g, 90.2 %. Rf= 0.24 [Heptane:EtOAC(4:l)], 1H NMR (CDC13): d 2.14 (m, 2H), 3.38 (s, 2H), 3.36 (t, 2H), 4.17 (t, 2H),7.03 (t, 1H), 7.18 (d, 1H), 7.26 (t, 1H), 7.37 (d, 1H).13C NMR (CDC13): 5 30.61, 31.81, 42.48, 42.66, 117.87, 123.78, 124.29,127.52,127.52, 128.78,139.40, 165.51
4-[3-(4-Butyl-piperidin-l-yl)-propyl]-4H-beno[1,4]thiazin-3-one (81MF09)
[0473] Nal (1.24 g, §.27 mmol), K2CO3 (1.14 g, 8.27 mmol), and 4-butylpiperidine (0.62 g, 4.34 mmol) in acetonitrile (10 mL) were stirred at rt. 4-(3-chloropropyl)-4H-benzo[l,4]thiazin-3-one (1.0 g, 4.14 mmol) in acetonitrile (15 mL) was added via a syringe. The reaction was stirred at 60 °C for 13 hours and then at 80 °C for another 25 hours under nitrogen atmosphere and concentrated in vacuo. Water (150 mL) was added and the reaction mixture was extracted with ethyl acetate (3 x 150 mL). The combined organic phases were dried (Na2SO4) and concentrated in vacuo to give 1.63 g of crude. The crude product was subjected to CC[eluent:EtOAC:MeOH(100:l-5%)] to give the pure title compound. Yield 1.06 g 74.2 % HPLC-MS [M + H]+ 347 (UV/MS(%)=100/99. !H NMR (CDCI3): 5 0.88 (t, 3H), 1.23 (m, 9H), 1.64 (d, 2H), 1.85 (m, 4H), 2.34 (t, 2H), 2.83 (d, 2H), 3.36 (s, 1H), 4.03 (t, 2H), 6.99 (m, 1H), 7.22 (d, 2H), 7.34 (d, 1H), 13C NMR (CDCI3): 8 14.21, 23.03, 25.23, 29.15, 31.80, 32.63, 35.90, 36.44, 43.28, 54.26, 55.91, 118.18, 123.45, 124.17,127.27, 128.56, 139.63, 165.19.
[0474] To 4-[3-(4-butyl-piperidin-l-yl)-propyl]-4H-benzo[l,4]thiazin-3-one (1.06 g, mmol) in 30 ml diethyl ether was charged oxalic acid (0.28 g, 3.1 mmol) dissolved in diethyl ether (5 mL). The formed crystals were filtered of and washed with diethyl ethyl (5 x 10 mL) to give 1.21 g of the oxalic salt after drying. HPLC-MS [M + H]+ 347 (UV/MS(%)=100/99
4-(3-Chloropropyl-4H-benzo[1,4]oxazin-3-one (81MF08)
[0475] 2H-l,4 benzoxazine-3(4H)one (1.0 g, 6.70 mmol) and Cs2CO3 (3.28 g, 10.1 mmol) were dissolved in dry acetonitrile (20 mL) under nitrogen atmosphere and
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stirred at rt for 30 min. 3-chloro-l-iodopropane (1.58 g, 7.38 mmol) dissolved in acetonitrile (4 mL) was added via a syringe. The reaction mixture was stirred at rt for 18 hours and concentrated in vacuo. Water (150 mL) was added and the reaction mixture was extracted with ethyl acetate (3 x 150 mL). The combined organic phases were dried (MgSO4) and concentrated in vacou to give 1.65 g of crude. The crude product was subjected to CC[eluent:Heptane:EtOAC(4:l)] to give the pure title compound as a colorless oil. Yield 1.36 g, 89.2 %. Rf= 0.24 [Heptane:EtOAC(4:l)], 'HNMR (CDC13): 8 2.16 (m, 2H), 3.62 (t, 2H), 4.10 (t, 2H), 4.59 (s, 2H), 7.00 (m, 2H), 7.05 (m, 2H), 13C NMR (CDCI3): 5 30.16, 39.04, 42.45, 67.72, 114.80, 117.38, 123.07, 124.14, 128.49, 145.47, 164.58.
4-[3-r4-Butyl-piperidin-l-yl-propyl]-4H-benzo[1.4]oxazin-3-one(81MF10)
[0476] Nal (1.33 g, 8.87 mmol), K2C03 (1.23 g, 8.90 mmol), and 4-butylpiperidine (0.66 g, 4.71 mmol) in acetonitrile (10 mL) were stirred at rt. 4-(3-chloropropyl)-4H-benzo[l,4]oxazin-3-one (1.0 g, 4.43 mmol) in acetonitrile (15 mL) was added via a syringe. The reaction was stirred at 60 °C for 13 hours and then at 80 °C for another 5 hours under nitrogen atmosphere and concentrated in vacuo. Water (150 mL) was added and the reaction mixture was extracted with ethyl acetate (3 x 150 mL). The combined organic phases were dried (Na2SO4) and concentrated in vacuo to give 1.58 g of crude. The crude product was subjected to CC[eluent:EtOAC:MeOH(100:l-5%)] to give the pure title compound. Yield 0.82 g 56.0 % HPLC-MS [M + H]+ 331 (UV/MS(%)=100/99. 1HNMR (CDCI3): 8 0.88 (t, 3H), 1.21 (m, 6H), 1.26 (m, 3H), 1.66 (d, 2H), 1.86 (m, 4H), 2.37 (t, 2H), 2.86, (d, 2H), 3.97 (t, 2H), 4.58 (s, 2H), 6.99 (m, 3H), 7.11 (d, 1H), 13C NMR (CDCI3): 8 14.22, 23.04, 24.90, 29.17, 32.68, 35.95, 36.46, 39.74, 54.31, 56.02, 67.77, 115.26, 117.15, 122.83, 123.83, 128.78, 145.50, 164.34.
[0477] To 4-[3-(4-Butyl-piperidin-l -yl)-propyl]-4H-benzo[ 1,4]oxazin-3-one (0.82 g, mmol) in 30 ml diethyl ether was charged oxalic acid (0.25 g, 2.8 mmol) dissolved in diethyl ether (5 mL). The formed crystals were filtered of and washed with diethyl ether (5 x 10 mL) to give 0.75 g of the oxalic salt after drying. HPLC-MS [M + H]+ 331 (UV/MS(%)=100/99
Example 1
Additional Synthetic Chemistry
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General analytical LC-MS procedure Procedure 1:
[0478] Spectra were obtained using a HP 1100 LC/MSD-instrument. A set-up with a binary pump, auto sampler, column oven, diode array detector, and electro spray ionisation interface was used. A reversed phase column (CI8 Luna 3m., 75 x 4.6 mm ID) with a guard column cartridge system was used. The mobile phase was MeCN/8 mM aqueous ammonium acetate. A 15-minute gradient program was used, starting at 70% MeCN over 12 minutes to 95% MeCN, over 1 minute to 70% MeCN, hold for 2 minutes. The flow rate was 0.6 ml/min.
Procedure 2:
[0479] Spectra were obtained using a Waters LC/ZMD-instrument. A set-up with a 600 gradient pump, 2700 sample manager, 996 diode array detector, and electro spray ionisation interface was used. A reversed phase column (C18 X-Terra 5m., 50 x 4.6 mm ID) with a guard column cartridge system was used. The mobile phase was MeCN/10 mM aqueous ammonium acetate. A 14-minute gradient program was used; starting at 30% MeCN, over 10 minutes to 95% MeCN, hold for 2 minutes, over 0.5 minutes to 30% MeCN, hold for 4.5 minutes. The flow rate was 1 ml/min.
General preparative LC-MS procedure
[0480] Preparative purification was performed on Waters Delta 4000 preparative system, Water 2487 dual absorbance detector, and Waters Fraction collector II. The column used was a Luna 15 um CI8, 250x21.2 mm. The following mobile phases were used: H2O/MeCN ammonium acetate buffer (25 nM) or H2O/MeCN TFA buffer (25 nM).
[0481] Cation exchange column chromatography was performed with Varian BOND ELUT (mega BE-SCX, 1 g, 6 ml) columns. After applying the compound to the column, it was first washed with MeOH (2 column volumes) and thereafter the desired compound was eluted applying 2 column volumes of an NH4OH (25% NH3 in H2O)/MeOH mixture (1:9).
General procedure 1 (GP1)
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[0482] A flask or vial was charged with 2-aminophenol (1.0 equiv) dissolved in DMF (0.1 g/ml) and 2-chloroacetyl chloride (1.1 equiv) was added. The reaction was stirred at r.t. for 12-20 hours and K2CO3 (2.1 equiv) was added. The reaction was stirred at r.t. for another 12-20 hours then evaporated to dryness. The reaction mixture was redisolved redisolved in water (100 ml) and extracted using EtOAc (3x 150 ml) . The combined organic phases were dried over Na2SO4 and concentrated to a crude that was used directly or purified by column chromatography (heptanes/EtOAc) or (CH2Cl2/MeOH).
5,7-Difluoro-4H-benzo f 1,4] oxazin-3 -one
[0483] 2-Amino-3,5-diflourophenol (1.85 g, 12.7 mmol), 2-chloroacetyl chloride (1.58 g, 14 mmol) and K2CO3 (3.69 g, 26.7 mmol) were mixed according to GPL Purified by column chromatography (SiO2; heptanes/EtOAc 4:1) to give the title compound (111MF84) (0.49 g, 21%). Rf=0.21 (heptanes:EtOAc 4:1); *H NMR (CDCI3) 5 8.32 (s, 1H), 6.66 - 6.51 (m, 2H), 4.62 (s, 2H).
5,6-Difluoro-4H-benzo[ 1,4] oxazin-3-one
[0484] A crude of 2-amino-3,4-diflourophenol (0.68 g, 4.7 mmol), 2-chloroacetyl chloride (0.58 g, 5.2 mmol) and K2CO3 (1.36 g, 9.9 mmol) were mixed according to GPL Purified by prep RP-HPLC to give the title compound (0.127 g, 14.5%). Rf= 0.63 (heptanes/EtOAc 1:1). 1H NMR (CDCI3) 6.69 - 6.57 (m, 2H), 4.47 (s, 2H); 13C NMR (CDCI3) 5 165.0, 146.2 (dd, J = 241.8 Hz, J=10.4 Hz), 140.3 (t, J = 2.32 Hz), 138.7 (dd, J = 247.2 Hz, J = 17.3 Hz), 67.1 (t, J = 2.7 Hz).
6,7-Difluoro-4H-benzo[ 1,4] oxazin-3-one
[0485] A crude of 2-amino-4,5-diflourophenol (2.67 g, 18.4 mmol), 2-chloroacetyl chloride (2.28 g, 20 mmol) and K2CO3 (5.34 g, 38.6 mmol) were mixed according to GPL Purified by column chromatography (Si02; heptanes/EtOAc 4:1 to 1:1) to give the title compound (2.17 g, 64%). Rf= 0.43 (heptanes/EtOAc 1:1); Mp = 214.5-219.2°C; !H NMR (CD3OD) 5 6.90 (dd, J = 11.4 Hz, J = 7.2 Hz, 1H), 6.80 (dd, J = 11.0 Hz, J = 7.7 Hz, 1H), 4.56 (s, 2H); 13C NMR (CD3OD) d167.0, 147.0 (dd, J = 243.5 Hz, J = 13.8 Hz), 146.9 (dd, J = 240.0 Hz, J = 13.8 Hz), 141.2 (dd, J = 9.8 Hz, J = 3.0 Hz),
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124.8 (dd, J = 8.7 Hz, J = 3.0 Hz), 106.9 (dd, J = 22.0 Hz, J = 6.9 Hz), 105.5 (dd, J = 23.1 Hz, J = 4.6 Hz), 68.1 (t, J = 6.5 Hz).
6,8-Difluoro-4H-benzo[ 1.41 oxazin-3-one
[0486] 2-Amino-4,6-diflourophenol (1.98 g, 13.6 mmol), 2-chloroacetyl chloride (1.69 g, 15 mmol) and K2CO3 (3.95 g, 28.5 mmol) were mixed according to GPL Purified by column chromatography (SiO2; CH2Cl2/MeOH 99:1) to give the title compound (149MF24) (1.5 g, 59%). Rf= 0.50 (heptanes/EtOAc 1:1); 1HNMR (DMSO) 5 6.92 - 6.86 (m, 1H), 6.59 - 6.54 (m, 1H), 4.62 (s, 2H); 13C NMR (DMSO) 5 165.0, 156.4 (dd, J = 239.0 Hz, J = 13.1 Hz), 150.5 (dd, J = 267.3 Hz, J = 14.6 Hz), 130.1 (dd, J = 13.4 Hz, J = 5.8 Hz), 128.3 (dd, J = 14.6 Hz, J = 3.8 Hz), 98.8 (dd, J = 26.9 Hz, J = 3.5 Hz), 98.5 (dd, J = 27.6 Hz, J = 22.6 Hz), 67.0.
5,8-Difluoro-4H-benzo [ 1.4] oxazin-3 -one
[0487] 2-Amino-3,6-diflourophenol (0.44 g, 3.0 mmol), 2-chloroacetyl chloride (0.38 g, 3.3 mmol) and K2CO3 (0.88 g, 6.4 mmol) were mixed according to GP1. Purified by extraction gave the title compound (0.52 g, 93%). Rf = 0.57 (heptanes/EtOAc 1:1); 'H NMR (CDCI3) 5 8.02 (s, 1H), 7.78 - 6.69 (m, 2H), 4.72 (s, 2H); 13C NMR (CDCI3) 5 163.7, 148.0 (dd, J = 242.4 Hz, J = 2.1 Hz), 145.9 (d, J = 237.9 Hz), 132.9 (dd, J = 16.7 Hz, J = 4.4 Hz), 117.2 (dd, J = 16.9 Hz, J = 3.8 Hz), 110.2 (dd, J = 20.5 Hz, J = 8.6 Hz), 108.6 (dd, J = 20.0 Hz, J = 7.7 Hz), 67.4.
8-Ethyl-4H-benzo[ 1,4] oxazin-3-one
[0488] 6-Ethyl-2-aminophenol (0.88 g, 6.4 mmol), 2-chloroacetyl chloride (0.80 g, 7.0 mmol) and K2CO3 (1.86 g, 13.5 mmol) were mixed according to GP1. Purified by column chromatography (SiO2; CH2Cl2MeOH 99:1) to give the title compound (0.69 g, 61%). Rf = 0.54 (heptanes/EtOAc 1:1); 1H NMR (CDC13) 6 9.29 (s, 1H), 6.92 - 6.85 (m, 2H), 6.71 (dd, J = 7.0 Hz, J = 2.6 Hz), 4.62 (s, 2H), 2.65 (q, J = 7.6 Hz, 2H), 1.20 (t, J = 7.6 Hz, 3H); 13C NMR (CDCI3) 5 166.8, 141.6, 133.0, 126.1, 124.4, 122.5,114.0,67.3,22.9,14.4.
4-Cyclopropylmethoxypiperidine-l-carboxylic acid t-butyl ester
142

[0489] A reaction flask was charged with 4-hydroxypiperidine-l-carboxylic acid t-butyl ester (10.05 g, 49.9 mmol) in dry DMF (50 mL) under Argon. NaH (60% in oil, 2.0 g, 50.0 mmol) was added in portions and the mixture was stirred at 50° for 1 h. The mixture was cooled to rt and bromomethylcyclopropane (6.752 g, 50.0 mmol) was added followed by stirring at rt for 20 h under Argon. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (Si02; n-heptane/EtOAc 2:1) to give the title compound (6.809 g, 53%). *H NMR (CDC13) 5 3.66 - 3.58 (m, 2H), 3.31 - 3.24 (m, 1H), 3.12 (d, 2H), 2.90 - 2.83 (m, 2H), 1.68 - 1.60 (m, 2), 1.38 - 1.30 (m, 2H), 1.28 (s, 9H), 0.91 - 0.82 (m, 1H), 0.38 -0.33 (m, 2H), 0.04 - 0.00 (m, 2H); 13C NMR (CDCI3) d 154.8, 79.3, 74.4, 72.6, 41.4, 31.2,28.4,10.9,3.0
4-Cyclopropylmethoxypiperidine
[0490] A reaction flask was charged with 4-cyclopropylmethoxypiperidine-l-carboxylic acid /-butyl ester (6.80 g, 26.6 mmol) in DCM (15 mL). TFA (7 mL) was added and the reaction was stirred at rt for 4 h. The reaction mixture was quenched with 1 M NaOH and the product extracted into diethyl ether. The combined organic phases were dried over Na2SO4, filtered, and concentrated to give the title compound (3.949 g, 95%). 'H NMR (CD3CD) 5 3.34 - 3.24 (m, 1H), 3.15 (d, 2H), 2.88 - 2.82 (m, 2H), 2.44 - 2.37 (m, 2H), 1.78 - 1.70 (m, 2H), 1.31-1.21 (m, 2H), 0.89 - 0.79 (m, 1H), 0.37 - 0.32 (m, 2H), 0.04 - 0.00 (m, 2H); 13C NMR (CD3OD) 8 76.2, 73.6,44.7, 33.2,11.7, 3.5.
4-Cyclobutylmethoxypiperidine-l-carboxylic acid t-butyl ester and 4-cyclobutylmethoxycarbonvloxypiperidine-1-carboxylic acid t-butyl ester
[0491] A reaction flask was charged with 4-hydroxypiperidine-l-carboxylic acid /-butyl ester (1.00 g, 4.97 mmol) in dry DMF (5 mL) under Argon. NaH (60% in oil, 0.298 g, 7.5 mmol) was added in portions and the mixture was stirred at rt for 1 h under Argon. Then bromomethylcyclopropane (1.118 g, 7.5 mmol) was added followed by stirring at rt for 20 h under Argon.
[0492] A reaction flask was charged with 4-hydroxypiperidine-l-carboxylic acid /-butyl ester (0.201 g, 1.0 mmol) and Cs2CO3 (0.342 g, 1.05 mmol) in DMF (1 mL)
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and stirred at 95° for 1 h. bromomethylcyclobutane (0.149 g, 1.0 mmol) was then added and the reaction was stirred at 95° for another 20 h.
[0493] The two reaction mixtures were quenched with water and the products extracted into EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The reaction mixture was purified by flash column chromatography (SiO2; n-heptane/EtOAc 1:1) to give a mixture of the two title compounds (0.190 g).
4-Cyclobutylmethoxypiperidine and carbonic acid cyclobutylmethyl ester piperidine-4-yl ester
[0494] A reaction flask was charged with a mixture of 4-cyclobutylmethoxypiperidine-1-carboxylic acid f-butyl ester and 4-cyclobutylmethoxycarbonyloxypiperidine-1-carboxylic acid J-butyl ester (0.189 g) in DCM (2 mL). TFA (1 mL) was added and the reaction was stirred at rt for 4 h. The reaction mixture was quenched with 1 M NaOH and the products extracted into diethyl ether. The combined organic phases were dried over Na2SO4, filtered, and concentrated to give a mixture of the two title compounds (0.100 g)
2,2-Dimethylpropionic acid piperidin-4-ylmethyl ester
[0495] To 4-hydroxymethyl-piperidine-l-carboxylic acid tert-butylester (480 mg, 2.1 mmol) dissolved in dry DMF (10 ml) was added NaH (120 mg, 3.0 mmol, 55-65 % in mineral oil) and the mixture was warmed to 60 °C for 2 h. The mixture was allowed to cool to rt and then pivaloyl chloride (0.1.6 ml, 1.3 mmol) was added. The reaction was allowed to stir over night and then poured into water and the mixture was extracted with ether. The combined organic phases were washed with brine, dried (Na2S04), filtered, concentrated under reduced pressure and the oily residue was purified by Flash column chromatography (SiO2; heptane/EtOAc 70:30) to yield 4-(2,2-dimethylpropionyloxymethyl)piperidine-l-carboxylic acid ^-butyl ester as an oil. Deprotection of 4-(2,2-dimethylpropionyloxymethyl)piperidine-l-carboxylic acid f-butyl ester was conducted using the method (CH2Cl2:TFA; 1:1) to yield the title compound as an oil (85 mg, 0.43 mmol, 33 %). This crude was used without further purification.
2,2-Dimethylpropionic acid 2-piperidin-4-yl-ethyl ester
144

[0496] To 4-(2-hydroxyethyl)piperidine-l-carboxylic acid tert-butyl ester (480 mg, 2.1 mmol) dissolved in dry DMF (10 ml) was added NaH (120 mg, 3.0 mmol, 55-65 % in mineral oil) and the mixture was warmed to 60 °C for 2 h. The mixture was allowed to cool to rt and then pivaloyl chloride (0.1.6 ml, 1.3 mmol) was added. The reaction was allowed to stir over night and then poured into water and the mixture was extracted with ether. The combined organic phases were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The oily residue was purified by Flash column chromatography (SiO2; heptane/EtOAc 70:30) to yield 4-[2-(2,2-dimethylpropionyloxy)ethyl]-piperidine-l-carboxylic acid ter/-butyl ester as an oil, which was deprotected in CH2CI2/TFA, employing the standard procedure. This yielded the crude title compound as an oil (94 mg, 0.44 mmol, 34 %), which was used without further purification.
3a-Hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid t-butyl ester
[0497] A reaction flask was charged with 8-azabicyclo[3.2.1]octan-3α-ol (42.3 g, 0.33 mol) and di-r-butyldicarbonate (80 g, 0.37 mol) in MeCN (500 mL) and 1 M NaOH (150 mL). The reaction was stirred at rt for 20 h. Then water was added and the product extracted into EtOAc. The combined organic phases were washed with 5% aqueous citric acid and brine, then dried over Na2SO4, filtered, and concentrated. The solid material was washed with n-heptane and dried to give the crude title compound (76.19 g).
3a-Cyclopropylmethoxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid t-butyl ester
[0498] A reaction flask was charged with crude 3α-hydroxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid /-butyl ester (5.5 g) in dry DMF (25 mL) under Argon. NaH (60% in oil, 0.968 g, 24.2 mmol) was added in portions and the mixture was stirred at 50° for 1 h. The mixture was cooled to rt and bromomethylcyclopropane (3.252 g, 24.2 mmol) was added followed by stirring at rt for 20 h under Argon. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiC^; n-heptane/EtOAc 2:1) to give the title compound (3.354g). 1H NMR (CDC13) 6 3.98 - 3.94 (m, 2H), 3.44 - 3.40 (m, 1H), 3.05 (d, 2H), 1.96 - 1.88 (m, 2H), 1.79 - 1.62 (m, 6H), 1.29 (s, 9H), 0.88 - 0.79 (m, 1H), 0.35
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- 0.30 (m, 2H), 0.04 - 0.00 (m, 2H); 13C NMR (CDC13) 8 153.4, 78.9, 73.0, 72.5, 52.7,
34.9,28.5,28.1,10.9,2.8.
3a-Cyclopropylmethoxy-8-azabicyclo[3.2.1]octane
[0499] A reaction flask was charged with 3a-cyclopropylmethoxy-8-azabicyclo[3.2.1]octane-8-carboxylic acid /-butyl ester (3.35 g, 11.9 mmol) in DCM (5 mL). TFA (5 mL) was added and the reaction was stirred at rt for 4 h. The reaction mixture was quenched with 1 M NaOH and the product extracted into EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated to give the title compound (2.028 g, 94%). 1H NMR (CDCI3) δ3.38 - 3.37 (m, 1H), 3.33 - 3.28 (m, 2), 3.02 (d, J = 6.5 Hz, 2H), 2.62 (br s, 2H), 1.97 - 1.86 (m, 2H), 1.72 - 1.44 (m, 4H), 0.89 - 0.76 (m, 1H), 0.36 - 0.23 (m, 2H), 0.04 - 0.00 (m, 2H); 13C NMR (CDC13) 8 72.6, 72.2, 53.5, 36.5, 29.0,10.7, 2.6.
3-Ethoxycarbonylmethylene-8-azabicyclo[3.2.1]octane-8-carboxylic acid t-butyl ester
[0500] A reaction flask was charged with triethyl phosphonoacetate (7.458 g, 33.3 mmol) in dry THF (20 mL) under Argon. NaH (60% in oil, 1.33 g, 33.3 mmol) was added in portions and the mixture was stirred at rt for 1 h. The clear solution was cooled to - 5.74 (m, 1H), 4.28 (br s, 2H), 4.19 - 4.07 (m 2), 3.66 - 3.59 (m, 1H), 2.76 - 2.20 (m,
2H), 2.11 - 2.06 (m, 1H), 1.93 - 1.87 (m, 2H), 1.58 - 1.54 (m, 2H), 1.46 (m, 9H), 1.26 (t,
3H).
3-(2-Hydroxyethylidene)-8-azabicyclo[3.2.1]octane-8-carboxylic acid t-butyl ester
[0501] A reaction flask was charged with 3-ethoxycarbonylmethylene-8-azabicyclo[3.2.1]octane-8-carboxylic acid /-butyl ester (2.70 g, 9.1 mmol) in dry THF (15 mL) under Argon. The solution was cooled to -78° and DIBAL-H (1.5 M in toluene, 13.7
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mL, 20.5 mmol) was added dropwise over 20 min. The reaction was stirred at -78° for 1 h then the temperature was raised to rt. The reaction mixture was added z'-propanol (5 mL) and stirred at rt for 5 min followed by addition of water (10 mL). DCM was added and the suspension was stirred at rt for 15 min. The suspension was filtered and the collected organic phase was dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiCh; n-heptane/EtOAc 1:1; EtOAc) to give the title compound (1.908 g, 82%). 1H NMR (CDC13) 8 5.57 - 5.51 (m, 1H), 4.24 - 4.17 (m, 2H), 4.36 - 4.06 (m, 2H), 2.54 - 2.46 (m, 1H), 2.40 - 2.34 (m, 1H), 2.24 - 2.18 (m, 1H), 2.01 - 1.96 (m, 1H), 1.90 - 1.78 (m, 3H), 1.60 - 1.46 (m, 2H), 1.45 (s, 9H).
3-('2-Cyclopropylmethoxyethylidene)-8-azabicyclo[3.2.1]octane-8-carboxylic acid t-butyl ester
[0502] A reaction flask was charged with 3-(2-hydroxyethylidene)-8-azabicyclo[3.2.1]octane-8-carboxylic acid f-butyl ester (0.380 g, 1.5 mmol) in dry DMF (2 mL) under Argon. NaH (60% in oil, 0.060 g, 1.5 mmol) was added in portions and the mixture was stirred at 50° for 1 h. The mixture was cooled to rt and bromomethylcyclopropane (0.202 g, 1.5 mmol) was added followed by stirring at rt for 20 h under Argon. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiO2; n-heptane/EtOAc 1:1) to give the title compound (0.115 g, 25%). 1H NMR (CDC13) d 5.38 - 5.32 (m, 1H), 4.36 - 3.96 (m, 2H), 3.88 - 3.75 (m, 2H), 3.09 (d, 2H), 2.48 - 1.66 (m, 6H), 1.48 - 1.36 (m, 2H), 1.30 (s, 9H), 0.94 - 0.33 (m, 1H), 0.40 - 0.33 (m, 2H), 0.05 -0.00 (m, 2)
3-(2-Cyclopropylmethoxyethylidene)-azabicyclo[3.2.1)octane
[0503] A reaction flask was charged with 3-(2-cyclopropylmethoxyethylidene)-8-azabicyclo[3.2.1]octane-8-carboxylic acid f-butyl ester (138LH49) (0.115 g, 0.37 mmol) in DCM (2 mL). TFA (0.5 mL) was added and the reaction was stirred at rt for 3 h. The reaction mixture was quenched with 1 M NaOH and the product extracted into diethyl ether. The combined organic phases were dried over Na2SO4, filtered, and concentrated to give the crude title compound (0.090 g).
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3β-Butyl-3a-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
[0504] Dry CeCl3 (2.5 g, 10 mmol) was ground to a fine powder and was thereafter dried for 6 h at 100 °C under vacuum (>1 mm Hg). The powder was then cooled on an ice bath under an Ar atmosphere, then cold and dry THF (40 ml) was poured onto the white powder and was allowed to stir at 0 °C for 15 min and the stirring was then continued at rt overnight. The resulting thick slurry was cooled to -78 °C, and n-BuLi (7.1 ml, 1.4 M) was added. After stirring for lh at -78 °C the mixture had become slightly greenish and then 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.56 g, 2.5 mmol) dissolved in THF (10 ml) was slowly added. The reaction was allowed to reach rt overnight, quenched with sat aq NaCl (10 ml), the phases were separated and the water phase was extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2SO4), filtered, concentrated under reduced pressure and the oily residue was purified by flach column chromatography (SiO2;heptane/EtOAC, 90:10 to 25:75) to yield the title compound as a clear, colorless oil (0.48 g, 17 mmol, 68%). 13C NMR (CDC13) 8 153.8, 79.2, 71.6, 53.5 (vbr), 52.8 (vbr), 46.9, 42.9 (vbr), 42.3 (vbr), 28.7, 28.2 (vbr), 27.7 (vbr), 25.1, 23.3, 14.2; HPLC-MS (ammonium acetate) [M+H]+ = 228.20.
3-β-Butyl-8-aza-bicyclo[3.2.1]octan-3a-ol
[0505] Deprotection of 3p-butyl-3α-hydroxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.10 g, 0.35 mmol) was conducted using the method (CH2C12:TFA; 1:1) to yield the title compound as an oil (40 mg, 0.22 mmol, 62%). HPLC-MS (ammonium acetate) [M+H]+ = 184.19.
(8-Azabicyclo[3.2.1]oct-3-ylidene)acetic acid ethyl ester
[0506] To 3-ethoxycarbonylmethylene-8-azabicyclo[3.2.1 ]octane-8-carboxylic acid tert-butyl ester (12.3 g, 41.8 mmol) in CH2C12 was added TFA (10 ml) and the reaction was stirred for 8 h. The solution was concentrated under reduced pressure, diluted with CH2C12, and washed first with 2 M NaOH and followed by brine. The water phases were thereafter back-extracted with EtOAc and the combined organic phase was dried (Na2S04), filtered, and concentrated under reduced pressure. The crude title product was used without further purification (7.04 g, 37.9 mmol, 91%).
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(8-Azabicyclo[3.2.1]oct-3a-yl)acetic acid ethyl ester
[0507] A 250 ml reaction flask was charged with (8-azabicyclo[3.2.1]oct-3-ylidene)acetic acid ethyl ester (3.7 g, 19 mmol), ammonium formiate (14 g, 190 mmol), and Pd/C (0.32 g, 8.6 %) in 150 ml MeOH. When all of the ammonium formiate was dissolved a slight under pressure was applied on the mixture for 15 min. The reaction was stirred on under an inert atmosphere (N2) over night at rt. The reaction was filtered through celite, concentrated under reduced pressure, diluted with 2 M NaOH (ca pH 10), and extracted with EtOAc. The combined organic phases were washed with brine, dried (Na2S04), filtered, and concentrated under reduced pressure. The crude title product (3.1 g, 16 mmol, 83%; 85:15 a:P) that was used without further purification. Major isomer: lH NMR (CDCI3) 5 4.08 (q, J = 7.2 Hz, 2 H), 3.45-3.41 (m, 2 H), 2.40 (d, J = 8.0 Hz, 2 H), 2.25 - 2.18 (m, 1 H), 2.06 - 1.96 (m, 2 H), 1.82 - 1.55 (m, 5 H), 1.31 - 1.23 (m, 2 H), 1.21 (t, J = 7.2 Hz, 3 H); 13C NMR (CDC13) 5 173.3, 60.4, 53.6, 42.6, 36.7, 30.425.4, 14.4.
3a-Ethoxycarbonylmethyl-8-Azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
[0508] A solution of BOC-anhydride (4.3 g, 20 mmol) in THF (10 ml) was added to a cooled solution of (8-azabicyclo[3.2.1]oct-3α-yl)acetic acid ethyl ester (2.8 g, 14 mmol) in THF (40 ml). The reaction was stirred at rt for 14 h and concentrated under reduced pressure. The semi-solid residue was diluted with EtOAc, washed with brine, dried (Na2S04), filtered, and concentrated under reduced pressure. The oily residue was purified by flash column chromatography (SiO2; heptane/EtOAc 70:30) to yield the title compound as an oil (3.8 g, 11 mmol, 73%). Major isomer: 1H NMR (CDCI3) δ4.16 (vbr s, 2 H), 4.11 (q, J = 6.8 Hz, 2 H), 2.43 (d, J = 7.6 Hz, 2 H), 2.24 - 2.12 (m, 3 H), 2.00 -1.92 (m, 2 H), 1.70-1.61 (M, 2 H), 1.44 (s, 9 H), 1.23 (t, J = 6.8 Hz, 3 H).
3a-(2-Hydroxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
[0509] Under an inert atmosphere a solution of DIBAL-H (20 ml, 1.5 M) in toluene was slowly added to a -72 °C solution of 3α-ethoxycarbonylmethyl-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (3.7 g, 12 mmol) in dry THF (20 ml). The reaction was allowed to stir at -72 °C for 1 h and was then allowed to slowly rise in temperature. At -10 °C the reaction was quenched with i-PrOH, stirred for 15 min and the water was added. The resulting gel-like substance was filtered through celite with CH2CI2 and the eluent was washed with brine, dried (Na2SO4), filtered, and concentrated
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under reduced pressure. The oily residue was purified by flash column chromatography (SiCh; heptane/EtOAc 40:60) to yield the title compound as an oil (2.4 g, 9.4 mmol, 74%). Major isomer: lH NMR (CDC13) 6 4.15 (vbr s, 2H), 3.64 (t, J = 4.4 Hz, 2 H), 2.24 -2.15 (m, 2 H), 1.99 - 1,92 (m, 2 H), 1.77 - 1.61 (m, 5 H), 1.44 (s, 9 H), 1.28 - 1.17 (m, 2 H); 13C NMR (CDCI3) δ 154.2, 79.2, 61.7, 52.4,40.5, 35.9,29.9, 28.7,25.2.
3α-(2-Methanesulfonyloxyethyl)-8-azabicyclo[3.2.11 octane-8-carboxylic acid tert-butyl ester
[0510] To a solution of Et3N (5 ml) in CH2C12 (20 ml) 3α-(2-hydroxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ter/-butyl ester (2.3 g, 9.0 mmol) was dissolved and then cooled on an ice bath. Thereafter, neat MsCl (1.0 ml, 13.5 mmol) was slowly added. The reaction was stirred at 0 °C for 5 min and then at rt for 2h. The reaction was quenched with brine, the phases were separated, and the water phase was extracted with CH2CI2. The combined organic phases were washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The oily residue was purified by flash column chromatography (SiC^; heptane/EtOAc 50:50) to yield the title compound as an oil (2.9 g, 8.6 mmol, 95%), which solidified upon standing.
3a-(2-Methoxyethyl)-8-Azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
[0511] To a solution of 3α-(2-methanesulfonyloxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (1.0 g, 3.0 mmol) in dry MeOH (7 mL) was added to a solution of NaOMe (17 mL, 2.8 M in MeOH). The reaction was stirred under an inert atmosphere (N2) at 40 °C for 6 days, concentrated, poured into brine, and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and concentrated. The oily residue was purified by flash column chromatography (SiO2; heptane/ethyl acetate 7:3) to yield the title compound (0.7 g, 86%) as an oil. Major isomer: 1H NMR (CDCI3) 5 4.14 (vbr s, 2 H), 3.35 (t, J = 6.4 Hz, 2 H), 3.28 (s, 3 H), 2.16 (brs, 2 H), 1.98 -1.87 (m, 2 H), 1.74 -1.62 (m, 5 H), 1.44 (s, 9 H), 1.25 - 1.15 (m, 2 H); 13C NMR (CDC13) 8 154.1, 79.1, 71.8, 58.8, 52.6(br), 37.4, 35.8(br), 29.8(br), 28.7, 25.7.
3a-(2-Ethoxyethyl)-8-Azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester
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[0512] A solution of 3α-(2-methanesulfonyloxyethyl)-8-
azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.8 g, 8.4 mmol) in dry EtOH (15 ml) was added to a solution of NaOEt (17 ml, 2.8 M in EtOH). The reaction was stirred under an inert atmosphere at 40 °C for 64 h, concentrated under reduced pressure, poured onto brine and extracted with EtOAc. The organic phase was dried (Na2SO4), filtered, and concentrated under reduced pressure. The oily residue was purified by flash column chromatography (Si02; heptane/EtOAc 70:30) to yield the title compound as an oil (2.9 g, 7.1 mmol, 83%). Major isomer: 'H NMR (CDC13) 5 4.14 (vbr s, 2 H), 3.44 (t, J = 7.2 Hz, 2 H), 3.39 (q, J = 6.6 Hz, 2 H), 2.13 (m, 2 H), 1.98 - 1.90 (m, 2 H), 1.74 - 1.62 (m, 5 H), 1.44 (s, 9 H), 1.25 - 1.18 (m, 2 H), 1.17 (t, J, = 6.6 Hz); 13C NMR (CDC13) 5 154.1, 79.1, 69.6, 66.4, 52.5, 37.6, 35.9, 29.8, 28.7,25.7,15.4.
3α-(2-Methoxyethyl)-8-azabicyclo[ 3.2.1 ] octane
[0513] To 3α-(2-methoxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid ter/-butyl ester (0.7 g, 2.6 mmol) in CH2CI2 (2 ml) was added TFA (1 ml) and the reaction was stirred for 3 h. The solution was concentrated under reduced pressure, diluted with diethyl ether, and the solution was washed with aq NaOH (2M) and brine. The organic solution was dried (Na2S04), filtered, and concentrated under reduced pressure. The crude title product (0.400 g, 91%) was used without further purification.
3α-(2-Ethoxvethyl]-8-azabicyclo [3.2.1] octane
[0514] To 3α-(2-ethoxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (2.0 g, 7.1 mmol) in CH2CI2 (5 ml) was added TFA (5 ml) and the reaction was stirred for 4 h. The solution was concentrated under reduced pressure, diluted with EtOAc, and the solution was washed with aq NaOH (2M) and brine. The organic solution was dried (Na2S04), filtered, and concentrated under reduced pressure. The crude title product (1.2 g, 6.3 mmol, 88%) was used without further purification. Major isomer: 1H NMR (CDCI3) δ3.47-3.34 (m, 6 H), 2.04-1.94 (m, 2 H), 1.82-1.64 (m, 8 H), 1.30-1.23 (m, 2 H), 1.16 (t, J = 7.2 Hz, 3 H); 13C NMR (CDCI3) 5 69.8, 66.3, 53.7, 37.9, 37.3, 30.6, 25.3,15.4
3p-Ethoxycarbonylmethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid t-butyl ester
151

[0515] A reaction flask was charged with 3-ethoxycarbonylmethylene-8-azabicyclo[3.2.1]octane-8-carboxylic acid T-butyl ester (0.260 g, 0.88 mmol) and Pd/C (0.026 g) in MeOH (4 mL). The reaction flask was evacuated and purged with hydrogen twice followed by stirring under a hydrogen atmosphere for 20 h. The reaction mixture was filtered through Celite, washed with MeOH, and concentrated to give the crude title compound as the major isomer (0.255 g, 97%; 1:3 α β). Major isomer: lH NMR (CDC13) 8 4.17 - 4.15 (m, 2H), 4.13 - 4.06 (m, 2H), 2.32 - 2.26 (m, 1H), 2.13 (d, J = 7.0 Hz, 2H), 1.95 - 1.90 (m, 2H), 1.67 - 1.61 (m, 2H), 1.59 - 1.54 (m, 2H), 1.43 (s, 9H), 1.42 - 1.27 (m, 2), 1.22 (t, J = 7.2 Hz, 3H); 13C NMR (CDC13) 8 172.4, 153.3, 79.0, 60.2, 53.3, 41.3, 37.2,28.4,26.0,14.2
3P-Ethoxvcarbonvlmethyl-8-Azabicyclo[3.2.1]octane-8-carboxylic acid t-butyl ester
[0516] A reaction flask was charged with 3-ethoxycarbonylmethylene-8-azabicyclo[3.2.1]octane-8-carboxylic acid f-butyl ester (0.254 g, 0.86 mmol) and Pt02 (0.028 g) in MeOH (4 mL). The reaction flask was evacuated and purged with hydrogen twice followed by stirring under a hydrogen atmosphere for 20 h. The reaction mixture was filtered through Celite, washed with MeOH, and concentrated to give the crude title compound as the major isomer (0.256 g, 100%, 1:3 αβ).
3β-(2-Hydroxyethyl-8-Azabicyclo[3.2.1]octane-8-carboxylic acid t-butyl ester
[0517] A reaction flask was charged with 3p-Ethoxycarbonylmethyl-8-azabicyclo[3.2.1]octane-8-carboxylic acid r-butyl ester (0.497 g, 1.67 mmol) in dry THF (2 mL) and the solution was cooled to -78°. DIBAL-H (1.5 M in toluene, 2.2 mL, 3.34 mmol) was added dropwise and the reaction was stirred at -78° for 1 h. The temperature was raised to it, the reaction quenched with water, and the product extracted into DCM. The combined organic phases were dried over Na2S04, filtered, and concentrated. The product was purified by flash column chromatography (Si02; n-heptane/EtOAc 1:1) to give the title compound (0.242 g, 57%).
3P-(2-Methanesulfonyloxyethyl)-8-Azabicyclo[3.2.1]octane-8-carboxylic acid t-butyl ester
[0518] A reaction flask was charged with 3P-(2-hydroxyethyl)-8-
azabicyclo[3.2.1]octane-8-carboxylic acid /-butyl ester (0.154 g, 0.61 mmol),
methanesulfonyl chloride (0.105 g, 0.92 mmol), and TEA (1 mL) in dry DCM (6 mL) and
152

stirred at rt. After 30 min, more methanesulfonyl chloride (0.052, 0.45 mmol) was added and the reaction was stirred at rt for another 30 min. The reaction mixture was quenched with water and the product extracted into DCM. The combined organic layers were dried over Na2S04, filtered, and concentrated. The product was purified by flash column chromatography (Si02; n-heptane/EtOAc 2:1) to give the title compound (0.179 g, 89%).
3P-[2-Ethoxvethvl)-8-azabicyclo[3.2.1]octane-8-carboxvric acid t-butyl ester
[0519] A reaction flask was charged with 3β-(2-methanesulfonyloxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid /-butyl ester (0.179 g, 0.54 mmol) in EtOH (3 mL) and stirred at rt. An NaOEt solution (2.4 M in EtOH, 0.22 mL, 0.54 mmol) was added and the reaction was stirred at rt for 20 h then at 50° for 9 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiCh; n-heptane/EtOAc 2:1) to give the title compound (0.116 g, 76%).
3β-(2-Ethoxyethyl )-8-Azabicyclo[3.2.1]octane
[0520] A reaction flask was charged with 3P-(2-ethoxyethyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid /-butyl ester (0.115 g, 0.41 mmol) in DCM (1 mL). TFA (0.2 mL) was added and the reaction was stirred at rt for 4 h. The reaction mixture was concentrated to give the TFA salt of the title compound (0.182 g)
3-Ethoxyimino-8-azonia-bicvclo[3.2.1]octane chloride
[0521] To 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid ter/-butyl ester (0.50 g, 2.2 mmol) dissolved in MeOH (10 ml) was added o-ethyl-hydroxylamine hydrochloride (0.22 mg, 2.2 mmol) and the solution was stirred for 64 h at rt. The solution was concentrated under reduced pressure to yield the crude title compound that was used without further purification.
3-Cvclopropylmethoxvimino-8-azonia-bicvclo[3.2.1 ]octane chloride
[0522] To 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.15 g, 0.65 mmol) dissolved in MeOH (10 ml) was added O-cyclopropylmethyl-
153

hydroxylamine (80 mg, 0.65 mmol). The solution was concentrated under reduced pressure to yield the crude title compound that was used without further purification.
General Procedure 2 (GP2)
[0523] A reaction flask or vial was charged 4#-benzo[ 1,4] oxazin-3-one (1.0 equiv) dissolved in DMF (0.1 g/ml), Cs2CO3 (1.5 equiv) and l-chloro-3-iodopropane (1.1 equiv). The reaction was stirred in rt for 60-70 h and evaporated to dryness. The reaction was redisolved in H2O and extracted with EtOAc 3 x 150 ml. The combined organic phases were dried over Na2S04 and concentrated to a crude that was used directly or purified by column chromatography (heptanes/EtOAc).
4-(3 -Chloropropyl)-5.7-difluoro-4H-benzo f 1.4] oxazin-3 -one
[0524] 5,7-Difluoro-4H-benzo[l,4]oxazin-3-one (0.24 g, 1.3 mmol), Cs2CO3 (1.08 g, 3.3 mmol), and l-chloro-3-iodopropane (0.296 g, 1.45 mmol) were mixed according to GP2. Purified by column chromatography (Si02; heptanes/EtOAc, gradient 0 to 30% EtOAc) to give the title compound (0.17 g, 49%). Rf= 0.66 (heptanes/EtOAc 1:1); lH NMR (CDCI3) 5 6.67 - 6.58 (m, 2H), 4.55 (s, 2H), 4.16 - 4.10 (m, 2H), 3.59 - 3.52 (m, 2H), 2.21-2.10 (m,2H).
4-(3-Chloropropyl)-5.8-difluoro-4H-benzo[ 1,4] oxazin-3 -one
[0525] 5,8-Difluoro-4H-benzo[l,4]oxazin-3-one (1.86 g, 10 mmol), Cs2CO3 (4.91 g, 15 mmol), and l-chloro-3-iodopropane (2.04 g, 10 mmol) were mixed according to GP2. Purified by column chromatography (Si02; heptanes/EtOAc, gradient 0 to 50% EtOAc) to give the title compound (0.44 g, 17%). Rf = 0.74 (heptanes/EtOAc 1:1); *H NMR (CDCI3) 5 6.86 - 6.73 (m, 2H), 4.60 (s, 2H), 4.18 - 4.12 (m, 2H), 3.56 (t, J = 6.4 Hz, 2H), 2.20 - 2.12 (m, 2H); 13C NMR (CDCI3) δ164.7, 148.4 (dd, J = 243.9 Hz, J = 2.8 Hz), 147.5 (dd, J = 243.7 Hz, J = 3.0 Hz), 136.6 (dd, J = 16.2 Hz, J = 5.0 Hz), 119.8 (dd, J = 11.2 Hz, J = 2.7 Hz), 111.5 (dd, J = 20.4 Hz, J = 9.6 Hz), 110.4 (dd, J = 24.8 Hz, J = 7.9 Hz), 68.6, 42.4 (d, J = 10.0 Hz), 42.1, 31.1 (d, J = 3.5 Hz).
4-(3-Chloropropyl)-8-ethvl-4H-benzo[ 1.4] oxazin-3-one
[0526] 8-Ethyl-4H-benzo[l,4]oxazin-3-one (0.35 g, 2.0 mmol), Cs2CO3 (0.96 g, 2.9 mmol), and l-chloro-3-iodopropane (0.45 g, 2.2 mmol) were mixed according to
154

GP2. Purified by column chromatography (Si02; heptanes/EtOAc, gradient 0 to 50% EtOAc) to give the title compound (0.38 g, 74%). Rf = 0.64 (heptanes/EtOAc 1:1); *H NMR (CDC13) 8 7.01 - 6.89 (m, 2H), 4.58 (s, 2H), 4.12 - 4.07 (m, 2 H), 3.62 (t, J = 6.4 Hz, 2H), 2.65 (q, J = 7.6 Hz, 2H), 2.21-2.12 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H); 13C NMR (CDCI3) δ164.9, 143.3, 133.4, 128.4, 124.3, 122.6, 112.6, 67.2, 42.5, 39.2, 30.3, 23.0, 14.5.
4-(3-Chloropropyl)-6,8-difluoro-4H-benzo[ 1.4]oxazin-3-one
[0527] 6,8-Difluoro-4H-benzo[l,4]oxazin-3-one (0.80 g, 4.3 mmol), Cs2CO3 (2.12 g, 6.5 mmol), and l-chloro-3-iodopropane (0.98 g, 4.8 mmol) were mixed according to GP2. Purified by column chromatography (Si02; heptanes/EtOAc, gradient 0 to 50% EtOAc) to give the title compound (0.44 g, 39%). Rf = 0.65 (heptanes/EtOAc 1:1); lH NMR (CDCI3) δ6.66 - 6.59 (m, 2H), 4.64 (s, 2H), 4.09 - 4.03 (m, 2H), 3.62 (t, J = 6.0 Hz, 2H), 2.23 - 2.10 (m, 2H); 13C NMR (CDC13) 8 164.2, 157.5 (dd, J = 242.5 Hz, J = 12.7 Hz), 151.7 (dd, J = 248.5 Hz, J = 14.4 Hz), 131.0 (dd, J = 12.1 Hz, J = 4.8 Hz), 130.4 (dd, J = 15.0 Hz, J = 3.2 Hz), 99.7 (dd, J - 26.9 Hz, J = 22.4 Hz), 98.2 (dd, J = 28.4 Hz, J = 3.4 Hz), 67.8,42.2, 39.7, 30.0.
4-(3-Chloropropyl)-5.6-difluoro-4H-benzo[l,4]oxazin-3-one
[0528] 5,6-Difluoro-4H-benzo[l,4]oxazin-3-one (0.13 g, 0.69 mmol), Cs2CO3 (0.45 g, 1.4 mmol), and l-chloro-3-iodopropane (0.15 g, 0.76 mmol) were mixed according to GP2. Purified by column chromatography (Si02; heptanes/EtOAc, gradient 0 to 30% EtOAc) to give the title compound (0.13 g, 75%). Rf= 0.60 (heptanes/EtOAc 1:1); lH NMR (CDCI3) δ6.88 - 6.74 (m, 2H), 4.52 (s, 2H), 4.19 - 4.14 (m, 2H), 3.58 (t, J = 6.4 Hz, 2H), 2.22 - 2.14 (m, 2H); 13C NMR (CDCI3) δ165.1, 147.5 (dd, J = 242.5 Hz, J = 12.7 Hz), 143.8 (t, J = 3.0 Hz), 140.7 (dd, J = 249.8 Hz, J = 17.3 Hz), 119.8 (d, J = 4.6 Hz), 111.9 (dd, J = 7.4 Hz, J = 3.9 Hz), 111.2 (d, J = 18.8 Hz), 68.4, 42.4 (d, J = 9.7 Hz), 42.1, 31.1 (d, J = 3.5 Hz).
[R.S))-4-G-Chloro-2-methylpropyl)-8-ethvl-4H-berizor[14]oxazin-3-one
[0529] 8-Ethyl-4H-benzo[l,4]oxazin-3-one (0.34 g, 1.9 mmol), Cs2CO3 (0.94 g, 2.9 mmol), and l-bromo-3-chloro-2-methylpropane (0.36 g, 2.1 mmol) were mixed
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according to GP2. Purified by column chromatography (Si02; heptanes/EtOAc, gradient 0 to 50% EtOAc) to give the title compound (0.36 g, 69%). Rf = 0.76 (heptanes/EtOAc 1:1).
4-(3-Chloropropyl)-4H-benzo[1.4]oxazin-3-one
[0530] A reaction flask was charged with 4H-benzo[l .4]oxazin-3-one (1.48 g, 10 mmol), l-chloro-3-iodopropane (2.04 g, 10 mmol), and CS2CO3 (4.88 g, 15 mmol) in MeCN (10 mL) and stirred at rt for 40 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic phases were dried over Na2S04, filtered, and concentrated. The product was purified by flash column chromatography (SiCh; n-heptane/EtOAc 2:1) to give the title compound (1.97 g, 88%). !H NMR (CDCI3) 5 7.06 - 7.02 (m, 2H), 7.01 - 6.99 (m, 2H), 4.58 (s, 2H), 4.12 - 4.07 (m, 2H), 3.64 - 3.60 (m, 2H), 2.19 - 2.12 (m, 2); 13C NMR (CDCI3) 5 164.7, 145.6, 128.6, 124.2, 123.2, 117.5, 114.9, 67.8, 42.6, 39.1, 30.3.
4-(3-Chloropropyl)-7-fluoro-4H-benzo[1.4]oxazin-3-one
[0531] A reaction flask was charged with 6,7-difluoro-4H-benzo[1.4]oxazin-3-one (1.5 g, 8.1 mmol), l-chloro-3-iodopropane (1.44 g, 8.1 mmol), and CS2CO3 (4.0 g, 12.2 mmol) in MeCN (10 mL) and stirred at rt for 40 h. The reaction mixture was concentrated, water added, and the product extracted into EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiC>2; n-heptane/EtOAc 2:1) to give the title compound (1.88 g, 89%). lH NMR (CDCI3) 5 6.99 (dd, J = 8.0 Hz, J = 5.6 Hz, 1H), 6.79 - 6.72 (m, 2H), 4.59 (s, 2H), 4.08 (t, J = 7.2 Hz, 2H), 3.62 (t, J = 6.0 Hz, 2H) 2.18 - 2.10 (m, 2H); 13C NMR (CDCI3) 5 163.9, 159.1 (d, J = 244.1 Hz), 146.4 (d, J = 11.9 Hz), 124.9 (d, J = 3.0 Hz), 115.4 (d, J = 9.6 Hz), 109.5 (d, J = 22.7 Hz), 105.4 (d, J = 26.2 Hz), 67.7, 42.4, 39.2,30.1.
4-(3-Chloropropyl)-6-7-difluoro-4H-benzo[ 1,4]oxazin-3-one
[0532] A reaction flask was charged with 6,7-difluoro-4H-benzo[1.4]oxazin-3-one (9.0 g, 54 mmol), l-chloro-3-iodopropane (12.06 g, 59 mmol), and CS2CO3 (26.39 g, 81 mmol) in MeCN (150 mL) and stirred at rt for 40 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic phases were dried over Na2S04, filtered, and concentrated. The product was purified by flash
156

column chromatography (SiCh; n-heptane/EtOAc 4:1) to give the title compound (11.35 g, 86%). 'H NMR (CDC13) 8 6.93 - 6.82 (m, 2H), 4.57 (s, 2H), 4.05 - 4.01 (m, 2H), 3.62 (t, J = 6.1 Hz, 2H), 2.17 - 2.10 (m, 2H); HPLC-MS (ammonium acetate) [M+H]+ = 407.29
4-(3 -Chloropropyl-6-fluoro-4H-benzo [1.4] oxazin-3 -one
[0533] A reaction flask was charged with 6-fluoro-4H-benzo[ 1.4]oxazin-3-one (1.67 g, 10 mmol), l-chloro-3-iodopropane (2.04 g, 10 mmol), and Cs2CO3 (4.88 g, 15 mmol) in MeCN (10 mL) and stirred at rt for 3 days. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiC>2; n-heptane/EtOAc 2:1) to give the title compound (145LH20) (2.32 g, 95%). lH NMR (CDCI3) 5 6.95 - 6.91 (m, 1H), 6.82 - 6.78 (m, 1H), 6.72 - 6.67 (m, 1H), 4.57 (s, 1H), 4.05 (t, J = 7.2 Hz, 2H), 3.62 (t, J = 6.2 Hz, 2H), 2.19 - 2.11 (m, 2H); 13C NMR (CDCI3) δ164.6, 158.6 (d, J = 240.7 Hz), 141.5 (d, J = 2.3 Hz), 129.6 (d, J = 10.5 Hz), 118.0 (d, J = 9.3 Hz), 110.0 (d, J = 23.1 Hz), 102.7 (d, J = 28.8 Hz), 67.8, 42.3, 39.3, 30.0.
(R,S)-4-(3-Chloro-2-methylpropyl)-4H-benzo[1.4]oxazin-3-one
[0534] A reaction flask was charged with 4H-benzo[l .4]oxazin-3-one (3.85 g, 25.8 mmol), l-bromo-3-chloro-2-methylpropane (4.42 g, 25.8 mmol), and CS2CO3 (12.4 g, 38 mmol) in MeCN (50 mL) and stirred at rt for 20 h. The reaction mixture was quenched water and the product extracted into EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (Si02;n-heptane; n-heptane/EtOAc 4:1) to give the crude title compound (5.62 g, 60% pure).
(S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-4H-benzo[1.4]oxazin-3-one
[0535] A reaction flask was charged with 4H-Benzo[l ,4]oxazin-3-one (2.47 g, 16.5 mmol), (i?)-(3-bromo-2-methylpropoxy)-ter/-butyldimethylsilane (4.01 g, 15.0 mmol), and Cs2CO3 (12.2 g, 37.6 mmol) in DMF (20 mL) and stirred at 55° for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. The product
157

was purified by flash column chromatography (SiC>2; n-heptane/EtOAc 10:1) to give the title compound (3.92 g, 78%). !H NMR (CDC13) 8 7.15 - 7.11 (m, IH), 6.99 - 6.91 (m, 3H), 4.60 - 4.50 (m, 2H), 3.98 (dd, J= 8.3 Hz, J= 12.4 Hz, IH), 3.81 (dd, J= 5.5 Hz, J= 12.4 Hz, IH), 3.51 (dd, J= 4.1 Hz, J= 9.7 Hz, IH), 3.40 (dd, J= 6.9 Hz, J= 9.7 Hz, IH), 2.12 - 2.02 (m, IH), 0.90 - 0.82 (m, 12H), 0.02 (s, 6H).
(R)-4- [3 -(tert-Butyldimethylsilanyloxy)-2-methylpropyl] -4H-benzo [1.41 oxazin-3 -one
[0536] A reaction flask was charged with 4H-Benzo[l ,4] oxazin-3-one (1.49 g, 10.0 mmol), (iS)-(3-bromo-2-methylpropoxy)-/er?-butyldimethylsilane (2.67 g, 10.0 mmol), and Cs2CO3 (4.89 g, 15.0 mmol) in MeCN (15 mL) and stirred at rt for 7 days. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiC>2; n-heptane/EtOAc 2:1) to give the title compound (2.84 g, 85%).
(S)-4-[3 -Hydroxy-2-methylpropyl] -4H-benzo [ 1.41 oxazin-3 -one
[0537] A reaction flask was charged with (S)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-4H-berizo[l,4]oxazin-3-one (3.92 g, 11.7 mmol), and TBAF (4.78 g, 15.2 mmol) in THF (30 mL) and stirred at rt for 20 h. The reaction mixture was concentrated, dissolved in EtOAc, and washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (Si02; n-heptane/EtOAc 3:7) to give the title compound (2.52 g, 98%). *H NMR (CDCI3) δ7.05 - 6.95 (m, 4H), 4.63 (s, CH2), 4.23 (dd, J= 10.3 Hz, J = 13.9 Hz, IH), 3.56 (dd, J= 4.8 Hz, /= 13.9 Hz, IH), 3.52 - 3.49 (m, IH), 3.46 -3.38 (m, IH), 2.92- 2.85 (m, IH), 2.09-1.97 (m, IH), 1.06 (d, .7=7.3 Hz, CH3).
(R)-4-[3 -Hydroxy-2-methylpropyl] -4H-benzo f 1,41 oxazin-3 -one
[0538] A reaction flask was charged with (K)-4-[3-(tert-Butyldimethylsilanyloxy)-2-methylpropyl]-4H-benzo[l,4]oxazin-3-one (2.83 g, 8.5 mmol), and TBAF (11 mL, 1.0 M in THF, 11.0 mmol) in THF (10 mL) and stirred at rt for 20 h. The reaction mixture was concentrated, dissolved in EtOAc, and washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The product
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was purified by flash column chromatography (Si02; n-heptane/EtOAc 1:1) to give the title compound (1.72 g, 91%).
(s)-4(3-Iodo-2-methylpropyl] -4H-benzo f 1.4] oxazin-3 -one
[0539] A reaction flask was charged with (S)-4-(3-Hydroxy-2-methylpropyl]-4H-benzo[ 1,4] oxazin-3-one (2.52 g, 11.4 mmol), triphenylphosphine (6.12 g, 23.3 mmol), imidazole (1.98 g, 29.1 mmol), and iodine (8.88 g, 35.0 mmol) in CHC13 (30 mL) and stirred at rt for 20 h. The reaction mixture was washed with saturated sodium thiosulfate, dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (Si02; n-heptane/EtOAc 3:1) to give the title compound (3.02 g, 80%). *H NMR (CDCI3) δ7.07 - 7.00 (m, 4H), 4.65 - 4.55 (m, 2H), 3.94 (dd, J= 1.7 Hz, J = 6.7 Hz, CH2), 3.23 - 3.14 (m, 2H), 2.18 - 2.07 (m, 1H), 1.05 (d,J= 6.1 Hz, CH3).
(R-4-(3 -Iodo-2-methylpropyl] -4H-benzo [1,4] oxazin-3 -one
[0540] A reaction flask was charged with (i?)-4-(3-Hydroxy-2-methylpropyl]-4H-benzo[ 1,4] oxazin-3 -one (1.71 g, 7.77 mmol), triphenylphosphine (4.50 g, 17.2 mmol), imidazole (1.27, 18.7 mmol), and iodine (5.54 g, 21.8 mmol) in CH2C12 (20 mL) and stirred at rt for 20 h. The reaction mixture was washed with saturated sodium thiosulfate, dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (Si02; n-heptane/EtOAc 2:1) to give the title compound (2.25 g, 87%).
(R,S)-4-[3-(t-Butyldimethylsilanyloxy]2-hydroxvpropyl]-7-fluoro-4H-benzo[1.4]oxazin-3-one
[0541 ] A reaction flask was charged with 7-fluoro-4H-benzo [ 1,4] oxazin-3 -one (3.34 g, 20.0 mmol), /-butyldimethylsilyl glycidyl ether (4.685 g, 24.9 mmol), and Cs2CO3 (9.75 g, 29.9 mmol) in MeCN (25 mL) and stirred at rt for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (Si02; n-heptane/EtOAc 2:1) to give crude the title compound (2.048 g). lH NMR (CDCI3) 5 7.15 - 7.11 (m, 1H), 6.68 - 6.62 (m, 2H), 4.46 (s, 2H), 4.00 - 3.88 (m, 3H), 3.61 - 3.58 (m, 2H), 3.02 - 2.98 (m, 1H), 0.86 (s, 9H), 0.03 (s, 6H).
159

(R.S)-4-[3-(t-Butyldimethylsilanyloxy)-2-methoxvpropyl]-7-fluoro-4H-benzo[1.4]oxazin-3-one
[0542] A reaction flask was charged with crude (R,S)-4-[3-(f-butyldimethylsilanyloxy)-2-hydroxypropyl]-7-fluoro-4H-benzo[l.4]oxazin-3-one (2.04 g) in dry THF (10 mL) under Argon. NaH (60% in oil, 0.230 g, 5.76 mmol) was added in portions and the mixture was stirred at 0° for 1 h under Argon. Iodomethane (0.818 g g, 5.76 mmol) was added at 0° under stirring. The temperature was slowly raised to rt and the reaction was stirred for 20 h under Argon. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (Si02; n-heptane/EtOAc 2:1) to give the crude title compound (1.026 g).
CR. S V 7-Fluoro-4-(3 -hydroxv-2-methoxvpropyl]4H-benzo [1.41 oxazin-3 -one
[0543] A reaction flask was charged with crude (R,S)-4-[3-(f-Butyldimethylsilanyloxy)-2-methoxypropyl]-7-fluoro-4H-benzo[l.4]oxazin-3-one (1.026 g), and TBAF (0.940 g, 36.0 mmol) in THF (10 mL) and stirred at rt for 20 h. The reaction mixture was concentrated, dissolved in EtOAc, and washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiCh; n-heptane/EtOAc 1:1) to give the crude title compound (0.503 g). !H NMR (CDC13) 5 7.26 - 7.20 (m, 1), 6.76 - 6.70 (m, 2H), 4.65 -4.56 (m, 2H), 4.14 - 4.09 (m, 1H), 4.04 - 3.97 (m, 1H), 3.75 - 3.70 (m, 1H), 3.60 - 3.53 (m, 2H), 3.42 (s, 3H).
(R.S)-7-Fluoro-4-(3-iodo-2-methoxypropyl)-4H-benzo[1.4]oxazin-3-one
[0544] A reaction flask was charged with crude 7-fluoro-4-((R,S)-3-hydroxy-2-methoxypropyl)-4H-benzo[1.4]oxazin-3-one (0.503 g), triphenylphosphine (1.14 g, 4.33 mmol), imidazole (0.322 g, 4.73 mmol), and iodine (1.40 g, 5.52 mmol) in DCM (5 mL) and stirred at rt for 20 h. The reaction mixture was added DCM, washed with saturated sodium thiosulfate, dried over Na2SC«4, filtered, and concentrated. The product was purified by flash column chromatography (SiCh; n-heptane/EtOAc 2:1) to give the crude title compound (0.668 g).
General Procedure 3 (GP3)
160

[0545] A reaction flask or vial was charged with 4-cyclopropylmethoxypiperidine (1.0-1.05 equiv) dissolved in dry acetonitrile (0.1 g/ml), 4-(3-chloropropyl)-4H-benzo[l,4]oxazin-3-one (1.0 equiv), K2CO3 (2.0 equiv), and Nal (2.0 equiv) and stirred or shaken at 60 °C for 40-48 h. The reaction mixture was evaporated to dryness and purified by column chromatography (heptanes/EtOAc) or (CH2Cl2/MeOH) or Prep TLC (heptanes/EtOAc) or (CH2Cl2/MeOH).
4- [3 -(4-Cvclopropylmethoxvpiperidin-1 –vl) propyl] -7-fluoro-4H-benzo [1,41 oxazin-3 -one (AC 00262469^)
[0546] 4-Cyclopropylmethoxypiperidine (0.042 g, 0.27 mmol), 4-(3-chloropropyl)-7-fluoro-4H-benzo[l,4]oxazin-3-one (0.08 g, 0.32 mmol), K2C03 (0.075 g, 0.54 mmol) and KI (0.081 g, 0.54 mmol) were mixed according to GP3. Purified by prep TLC (Si02; heptanes/EtOAc 1:1) to give the title compound (0.049 g, 42%). Rf = 0.47 (CH2Cl2/MeOH 10:1); lH NMR (CDC13) 8 7.09 - 7.04 (m, 1H), 6.75 - 6.69 (m, 2H), 4.57 (s, 2H), 3.95 (t, J = 7.2 Hz), 3.34 - 3.25 (m, 3H), 2.77 - 2.70 (m, 2H), 2.36 (t, J = 6.8 Hz, 2H), 2.11 - 2.02 (m, 2H), 1.93 - 1.76 (m, 4H), 1.64 - 1.54 (m, 2H), 1.09 - 0.98 (m, 1H), 0.55 - 0.49 (m, 2H), 0.21 - 0.16 (m, 2H); 13C NMR (CDC13) 5 163.6, 158.9 (d, J = 243.7 Hz), 146.3 (d, J = 11.6 Hz), 125.2 (d, J = 3.1 Hz), 115.8 (t, J = 11.2 Hz), 109.2 (d, J = 22.3 Hz), 105.2 (dd, J = 25.7 Hz, J = 3.8 Hz), 75.0, 72.8, 67.8 (t, J = 8.1 Hz), 55.4, 51.6 (J = 9.2 Hz), 39.9 (t, J = 12.3 Hz), 31.7,24.9,11.1, 3.2.
[0547] The product was dissolved in ether and oxalic acid dissolved in ether was added. The formed crystals were filtered and washed with ether to give the title compound as oxalic salt (0.057 g); HPLC-MS (ammonium acetate) [M+H]+= 363.30; Mp 170.3-171.3 °C.
4-[3-(4-Cvclopropylmethoxvpiperidin-l-vl)propyl]-5.7-difluoro-4H-benzo[l,4]oxazin-3-one(AC0026247n
[0548] 4-Cyclopropylmethoxypiperidine (0.042 g, 0.27 mmol), 4-(3-chloropropyl)-7-fiuoro-4H-benzo[l,4]oxazin-3-one (0.078 g, 0.30 mmol), K2C03 (0.075 g, 0.54 mmol), and KI (0.081 g, 0.54 mmol) were mixed according to GP3. Purified by prep TLC (Si02; heptanes/EtOAc 1:1) to give the title compound (0.039 g, 38%). Rf = 0.47 (CH2Cl2/MeOH 10:1); lK NMR (CDCI3) 5 6.61 - 6.54 (m, 2H), 4.50 (s, 2H), 4.05 -4.00 (m, 2H), 3.30 - 3.23 (m, 3H), 2.72 - 2.65 (m, 2H), 2.31 (t, J = 7.2 Hz, 2H), 2.05 -
161

1.96 (m, 2H), 1.87 - 1.74 (m, 4H), 1.60 - 1.49 (m, 2H), 1.07 - 0.96 (m, 1H), 0.53 - 0.48 (m, 2H), 0.19 - 0.14 (m, 2H); 13C NMR (CDC13) 5 164.4, 158.5 (dd, J = 245.5 Hz, J = 15.0 Hz,), 151.7 (dd, J = 249.1 Hz, J = 14.2 Hz), 149.5 (q, J = 6.9 Hz), 115.1 (dd, J = 10.0 Hz, J = 4.6 Hz), 101.5 (dd, J = 25.8 Hz, J = 3.5 Hz), 99.7 (t, J = 26.9 Hz), 75.0, 72.7, 68.6 (t, J = 5.3 Hz), 55.6, 51.5 (d, J - 9.7 Hz), 42.7 (q, J = 10.4 Hz), 31.5, 25.6 (d, J = 2.3 Hz), 11.1,3.2
[0549] The product was dissolved in ether and oxalic acid dissolved in ether was added. The formed crystals were filtered and washed with ether to give the title compound as oxalic salt (0.044 g); HPLC-MS (ammonium acetate) [M+H]+= 381.28.
4-[3-(4-Cyclopropylmethoxvpiperidin-l-vl')propyl]-5.6-difluoro-4H-benzo[l,4]oxazin-3-one (AC00262696)
[0550] 4-Cyclopropylmethoxypiperidine (0.037 g, 0.24 mmol), 4-(3-chloropropyl)-5,6-difluoro-4H/-benzo[l,4]oxazin-3-one (0.065 g, 0.25 mmol), K2CO3 (0.066 g, 0.48 mmol), and KI (0.072 g, 0.48 mmol) were mixed according to GP3. Purified by prep TLC (SiC^; heptanes/EtOAc 1:1) to give the title compound (0.049 g, 54%). Rf = 0.21 (heptanes/EtOAc 1:1); 'H NMR (CDC13) 8 6.84 - 6.70 (m, 2H), 4.48 (s, 2H), 4.48 (s, 2H), 4.08 - 4.02 (m, 2H), 3.34 - 3.26 (m, 1H), 3.24 (d, J = 6.8 Hz, 2H), 2.75 - 2.68 (m 2H), 2.38 (t, J = 7.2 Hz, 2H), 2.18 - 2.06 (m, 2H), 1.92-1.81 (m, 4H), 1.63 -1.52 (m, 2H), 1.06 - 0.96 (m, 2H), 0.52 - 0.47 (m, 2H), 0.18-0.14 (m, 2H); 13C NMR (CDCI3) 5 165.0, 147.5 (dd, J = 242.3 Hz, J = 13.2 Hz), 143.9, 140.7 (dd, J = 250.2 Hz, J = 17.3 Hz), 119.9, 111.7 (dd, J = 7.3 Hz, J = 3.5 Hz), 110.9 (d, J = 18.9 Hz), 74.5, 72.7, 68.5, 55.5, 51.2,42.7 (d, J = 10.4 Hz), 31.1, 25.5, (d, J = 2.6 Hz), 11.1, 3.2.
[0551] The product was dissolved in ether and oxalic acid dissolved in ether was added. The formed crystals were filtered and washed with ether to give the title compound as oxalic salt (0.052 g); HPLC-MS (ammonium acetate) [M+H]+= 381.35.
4- [3-(4-Cyclopropylmethoxypiperidin-1 -yl) propyl] -6,8-difluoro-4H-benzo [ 1,4] oxazin-3-one [AC00262874)
[0552] 4-Cyclopropylmethoxypiperidine (0.076 g, 0.49 mmol), 4-(3-chloropropyl)-6,8-difluoro-4H-benzo[l,4]oxazin-3-one (0.143 g, 0.55 mmol), K2CO3 (0.136 g, 0.98 mmol) and KI (0.147 g, 0.98 mmol) were mixed according to GP3. Purified by prep TLC (Si02; heptanes/EtOAc 1:1) to give the title compound (0.094 g, 50%). lU
162

NMR (CDCI3) δ6.83 - 6.78 (m, IH), 6.60 - 6.54 (m, IH), 4.60 (s, IH), 3.92 (t, J = 6.8 Hz, 2H), 3.36 - 3.24 (m, 3H), 2.77 - 2.68 (m, 2H), 2.34 (t, J = 6.8 Hz, 2H), 2.09 (t, J = 9.6 Hz, 2H), 1.93 - 1.76 (m, 4H), 1.66 - 1.56 (m, 2H), 1.08 - 0.97 (m, IH), 0.53 - 0.48 (m, 2H), 0.19 - 0.15 (m, 2H); 13C NMR (CDCI3) 5 163.9, 157.4 (dd, J = 241.4 Hz, J = 12.7 Hz), 151.4 (dd, J = 247.6 Hz, J = 14.3 Hz), 131.4 (dd, J = 12.5 Hz, J = 4.7 Hz), 130.2 (dd, J =
14.6 Hz, J = 3.9 Hz), 99.3 (dd, J = 26.9 Hz, J = 22.3 Hz), 98.6 (dd, J = 28.4 Hz, J = 3.5
Hz), 74.8, 72.8, 67.8, 55.1, 51.5,40.3, 31.5,24.8,11.1, 3.2.
[0553] The product was dissolved in ether and oxalic acid dissolved in ether was added. The formed crystals were filtered and washed with ether to give the title compound as oxalic salt (0.099 g); HPLC-MS (ammonium acetate) [M+H]+= 381.33.
4- [3 -(4-Cvclopropylmethoxvpiperidin-1 –v)propyl] -5,8-difluoro-4H-benzo [1.4] oxazin-3 -one (AC00262869)
[0554] 4-Cyclopropylmethoxypiperidine (0.085 g, 0.55 mmol), 4-(3-chloropropyl)-5,8-difiuoro-4H-benzo[l,4]oxazin-3-one (0.146 g, 0.56 mmol), K2CO3 (0.152 g, 1.1 mmol), and KI (0.164 g, 1.1 mmol) were mixed according to GP3. Purified by prep TLC (Si02; Heptanes/EtOAc 1:1) to give the title compound (0.078 g, 37%). *H NMR (CDCI3) 5 6.82 - 6.69 (m, 2H), 4.57 (s, 2H), 4.07 - 4.03 (m, 2H), 3.31 - 3.22 (m, 3H), 2.72 - 2.64 (m, 2H), 2.32 (t, J = 7.2 Hz, 2H), 2.02 (t, J = 10.4 Hz, 2H), 1.88 - 1.76 (m, 4H), 1.59 - 1.48 (m, 2H), 1.07 - 0.95 (m, 2H), 0.53 - 0.47 (m, 2H), 0.19 - 0.14 (m, 2H); 13C NMR (CDCI3) δ164.6, 148.3 (dd, J = 243.3 Hz, J = 2.7 Hz), 147.7 (dd, J = 243.9, J = 2.8 Hz), 136.6 (dd, J = 11.2 Hz, J = 4.9 Hz), 120.0 (d, J = 11.1 Hz), 111.2 (dd, J = 20.4 Hz, J = 9.6 Hz), 110.3 (dd, J = 24.8 Hz, J = 7.7 Hz), 75.0, 72.6, 68.6, 55.6, 51.5,
42.7 (d, J = 10.8 Hz), 31.5, 25.7 (d, J = 2.7 Hz), 11.1, 3.2.
[0555] The product was dissolved in ether and oxalic acid dissolved in ether was added. The formed crystals were filtered and washed with ether to give the title compound as oxalic salt (0.075 g); HPLC-MS (ammonium acetate) [M+H]+= 381.33.
(R.S)-4-[3-(4-Cvclopropylmethoxvpiperidin-l-vl)-2-methylpropyl]-8-ethyl-4H-benzori .41 oxazin-3-one [ AC00262867)
[0556] 4-Cyclopropylmethoxypiperidine (0.091 g, 0.59 mmol), (R,S)-4-(3-Chloro-2-methylpropyl)-8-ethyl-4H-benzo[l,4]oxazin-3-one (0.175 g, 0.65 mmol), K2CO3 (0.162 g, 1.2 mmol), and KI (0.176 g, 1.2 mmol) were mixed according to GP3.
163

Purified by prep TLC (Si02; heptanes/EtOAc 1:1) to give the title compound (0.055 g, 24%). Rf=0.29 (heptanes/EtOAc 1:1); !HNMR (CDC13) 8 7.02 - 6.85 (m, 3H), 4.66 - 4.49 (m, 2H), 4.04 - 3.90 (m, 2H), 3.33 - 3.24 (m, 3H), 2.84 - 2.78 (m, 1H), 2.68 - 2.60 (m, 3H), 2.28 - 1.83 (m, 7H), 1.65 - 1.52 (m, 2H), 1.28 - 1.16 (m, 3H), 1.10 - 0.98 (m, 1H), 0.88 (d, J = 6.4 Hz, 3H), 0.56 - 0.50 (m, 2H), 0.21 - 0.16 (m, 2H); 13C NMR (CDC13) 5
165.1, 143.5, 133.1, 128.7, 123.9, 122.2, 113.4, 75.3, 72.7, 67.8, 63.5, 52.9, 51.9, 45.4,
31.9, 31.8,29.4,23.0,16.9, 14.5,11.1, 3.2
[0557] The product was dissolved in ether and oxalic acid dissolved in ether was added. The formed crystals were filtered and washed with ether to give the title compound as oxalic salt (0.055 g); HPLC-MS (ammonium acetate) [M+H]+= 387.40.
4-[3-(3-Cvclopropylmethoxv-8-aza-bicvclor3.2.1]oct-8-vl]propyl]-8-ethyl-4H-benzo[1,4]oxazin-3-one ("00264438)
[0558] A 7 ml vial was charged with 4-(3-chloropropyl)-8-ethyl-4H7-benzo[l,4]oxazin-3-one (0.21 g, 0.83 mmol), 3-cyclopropylmethoxy-8-aza-bicyclo[3,2,l]octane (0.16 g, 0.87 mmol), K2C03 (0.23 g, 1.7 mmol), acetonitrile (4 ml) and shaken at 60 °C for 90 hours The reaction mixture was evaporated to dryness and purified by prep TLC (SiCh; heptanes/EtOAc 1:1) followed by Prep HPLC to give the title compound (0.068 g, 20.5%). rH NMR (CDCI3) !H NMR (CDCI3) 5 7.05 - 6.84 (m, 3H), 4.56 (s, 2H), 4.04 - 3.98 (m, 2H), 3.53 - 3.49 (m, 1 H), 3.19 - 3.11 (m, 4H), 2.67 - 2.59 (m, 2H), 2.42 - 2.37 (m, 2H), 2.07 - 1.74 (m, 10H), 1.21 - 1.15 (m, 3H), 1.06 - 0.93 (m, 1H), 0.51 - 0.44 (m 2H), 0.21 - 0.14 (m, 2H); 13C NMR (CDC13) 8 164.60, 143.25,
133.02, 128.66, 123.99, 122.32, 113.20, 72.78, 72.23, 67.74, 58.59, 49.56, 39.83, 35.73,
26.45,26.17,23.03,14.50,11.04,2.94.
[0559] The product was dissolved in ether and oxalic acid dissolved in ether was added. The formed crystals were filtered and washed with ether to give the title compound as oxalic salt (0.075 g); HPLC-MS (ammonium acetate) [M+H]+= 399.52.
4- [3 -(4-Cvclopropylmethoxypiperidin-1 -yl) propyl] -4H-benzo [1.41 oxazin-3 -one (AC00262922)
[0560] A 4 mL vial was charged with 4-(3-chloropropyl)-4H-benzo[l,4]oxazin-3-one (0.068 g, 0.3 mmol), 4-cyclopropylmethoxypiperidine (0.047 g, 0.3 mmol), Nal (0.075 g, 0.5 mmol), and K2C03 (0.069 g, 0.5 mmol) in MeCN (1 mL)
164

and shaken at 50° for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by cation exchange column chromatography to give the title compound (0.076 g, 74%). *H NMR (CDC13) 5 6.96 - 6.93 (m, 1H), 6.87 -6.80 (m, 3H), 4.41 (s, 2H), 3.81 (t, J = 7.4 Hz, 2H), 3.16 - 3.10 (m, 1H), 3.11 (d, J = 6.8 Hz, 2H), 2.62 - 2.57 (m, 2H), 2.22 (t, J = 7.0 Hz, 2H), 1.94 - 1.89 (m, 2H), 1.75 - 1.64 (m, 4H), 1.48 - 1.39 (m, 2H), 0.89 - 0.86 (m, 1H), 0.38 - 0.33 (m, 2H), 0.04 - 0.00 (m, 2H); 13C NMR (CDC13) 5 164.2, 145.3, 128.6, 123.7, 122.7, 117.0, 115.0, 74.8, 72.6, 67.6, 55.3, 51.4, 39.5, 31.5, 24.8,11.0, 3.0.
[0561] The product was dissolved in acetone and 1.1 equiv oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.078 g). HPLC-MS (ammonium acetate) [M+H]+ = 344.00.
4-[3-(4-Cvclopropylmethoxvpiperidin-1-yl)propyl1-6-fluoro-4H-benzo[1.4]oxazin-3-one (AC00262635)
[0562] A 4 mL vial was charged with 4-(3-chloropropyl)-6-fluoro-4H-benzo[l,4]oxazin-3-one (0.097 g, 0.4 mmol), 4-cyclopropylmethoxypiperidine (0.042 g, 0.27 mmol), Nal (0.075 g, 0.5 mmol), and K2C03 (0.069 g, 0.5 mmol) in MeCN (1 mL) and shaken at 50° for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by cation exchange column chromatography followed by flash column chromatography (SiC>2; EtOAc) to give the title compound (0.056 g, 57%). 'H NMR (CDC13) 5 6.80 - 6.71 (m, 2H), 6.52 - 6.47 (m, 1H), 4.38 (s, 2H), 3.77 (t, J = 7.2 Hz, 2H), 3.17 - 3.13 (m, 1H), 3.11 (d, J = 6.8 Hz, 2H), 2.59 - 2.56 (m, 2H), 2.19 (t, J = 6.8 Hz, 2H), 1.95 - 1.89 (m, 2H), 1.75 - 1.62 (m, 4H), 1.50 - 1.41 (m, 2H), 0.89 - 0.86 (m, 1H), 0.38 - 0.33 (m, 2H), 0.04 - 0.00 (m, 2H); 13C NMR (CDCI3) δ164.1, 158.3, 141.2, 129.8, 117.4, 109.4, 102.9, 74.7, 72.5, 67.6, 55.1, 51.4, 39.8,31.3,24.6,10.9,3.0.
[0563] The product was dissolved in acetone and 1.1 equiv oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.062 g). HPLC-MS (ammonium acetate) [M+H]+ = 363.38.
165

4- [3 -(4-Cvclopropylmethoxvpiperidin-1 - yl)propyl] -6,7-difluoro-4H-benzo ("1.4] oxazin-3 -one (AC00262461)
[0564] A 4 mL vial was charged with 4-(3-chloropropyl)-6,7-difiuoro-4H-benzo[ 1,4] oxazin-3 -one (0.077 g, 0.3 mmol), 4-cyclopropylmethoxypiperidine (0.047 g, 0.3 mmol), Nal (0.075 g, 0.5 mmol), and K2C03 (0.069 g, 0.5 mmol) in MeCN (0.5 mL) and shaken at 60° for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by cation exchange column chromatography followed by flash column chromatography (SiCh; EtOAc) to give the title compound (0.050 g, 44%). lH NMR (CDC13) 5 6.98 - 6.93 (m, 1H), 6.66 - 6.62 (m, 1H), 4.39 (s, 2H), 3.74 (t, J = 7.2 Hz, 2H), 3.20 - 3.15 (m, 1H), 3.11 (d, J = 6.9 Hz, 2H), 2.61 - 2.55 (m, 2H), 2.21 (t, J = 6.8 Hz, 2H), 2.00 - 1.96 (m, 2H), 1.79 - 1.63 (m, 4H), 1.52 - 1.46 (m, 2H), 0.89 - 0.85 (m, 1H), 0.38 - 0.33 (m, 2H), 0.04 - 0.00 (m, 2H).
[0565] The product was dissolved in acetone and 1.1 equiv oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.052 g). HPLC-MS (ammonium acetate) [M+H]+ = 381.30.
4-(3-(3α-Cvclopropylmethoxv-8-azabicyclor3.2.1]oct-8--yl)propyl]-7-fluoro-4H-benzo[1,4]oxazin-3-one(AC00262571)
[0566] A 4 mL vial was charged with 4-(3-chloropropyl)-7-fluoro-4H-benzo[ 1,4] oxazin-3 -one (0.077 g, 0.3 mmol), 3α-cyclopropylmethoxy-8-azabicyclo[3.2.1]octane (0.054 g, 0.3 mmol), Nal (0.075 g, 0.5 mmol), and K2C03 (0.069 g, 0.5 mmol) in MeCN (0.5 mL) and shaken at 50° for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. The product was purified by cation exchange column chromatography to give the title compound (0.065 g, 56%). !H NMR (CDC13) 5 7.00 - 6.96 (m, 1H), 6.57 - 6.53 (m, 2H), 4.41 (s, 2H), 3.84 (t, J = 7.2 Hz, 2H), 3.35 (t, J = 4.9 Hz, 1H), 3.03 (d, J = 6.5 Hz, 2H), 2.97 - 2.88 (m, 2H), 2.22 (t, J = 6.9 Hz, 2H), 1.87 - 1.84 (m, 2H), 1.75 - 1.58 (m, 8H), 0.85 - 0.81 (m, 1H), 0.34 - 0.29 (m, 2H), 0.04 - 0.00 (m, 2H); 13C NMR (CDCI3) δ163.4, 158.7 (d, J = 243.7 Hz), 146.1 (d, J =
166

11.5 Hz), 125.1 (d, J = 3.1 Hz), 115.8 (d, J = 9.2 Hz), 108.9 (d, J = 22.7 Hz), 104.9 (d, J = 26.1 Hz), 72.6, 72.1, 67.6, 58.5,49.3, 39.7, 35.7, 26.2,26.0,10.9,2.7.
[0567] The product was dissolved in acetone and 1.1 equiv oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.065 g). HPLC-MS (ammonium acetate) [M+H]+ = 389.30.
4-[3-(3α-Cvclopropylmethoxv-8-Azabicyclo[3.2.1]oct-8-vl)propyl1-6,7-difluoro-4H-benz of 1,41oxazin-3-one (AC00262569)
[0568] A 4 mL vial was charged with 4-(3-chloropropyl)-6,7-difluoro-4H-benzo[l,4]oxazin-3-one (0.078 g, 0.3 mmol), 3α-cyclopropylmethoxy-8-azabicyclo[3.2.1]octane (0.054 g, 0.3 mmol), Nal (0.075 g, 0.5 mmol), and K2C03 (0.069 g, 0.5 mmol) in MeCN (0.5 mL) and shaken at 50° for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by cation exchange column chromatography to give the title compound (0.073 g, 60%). !H NMR (CDC13) 8 7.14 - 7.09 (m, 1H), 6.66 - 6.61 (m, 1H), 4.39 (s, 2H), 3.80 (t, J = 7.0 Hz, 2H), 3.36 (t, J = 5.1 Hz, 1H), 3.03 (d, J = 6.5 Hz, 2H), 2.93 (br s, 2H), 2.19 (t, J = 6.5 Hz, 2H), 1.88 - 1.83 (m, 2H), 1.80 - 1.74 (m, 2H), 1.68 - 1.57 (m, 6H), 0.85 - 0.81 (m, 1H), 0.34 - 0.29 (m, 2H), 0.04 - 0.00 (m, 2H).
[0569] The product was dissolved in acetone and 1.1 equiv oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.071 g). HPLC-MS (ammonium acetate) [M+H]+ = 407.29.
(R,S)-4-[3-(4-Cvclopropylmethoxvpiperidin-l-yl)-2-methylpropyl]-4H-benzo[1.4]oxazin-3-one (AC00262273)
[0570] A 4 mL vial was charged with (R,S)-4-(3-chloro-2-methylpropyl)-4H-benzo[l,4]oxazin-3-one (0.120 g, 60% pure, 0.3 mmol), 4-cyclopropylmethoxypiperidine (0.042 g, 0.27 mmol), Nal (0.075 g, 0.5 mmol), and K2C03 (0.069 g, 0.5 mmol) in DMF (1 mL) and shaken at 50° for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SC 167

chromatography followed by flash column chromatography (Si02; EtOAc) to give the title compound (0.063 g, 67%). 1H NMR 8 (CDC13) 8 6.99 - 6.97 (m, IH), 6.85 - 6.79 (m, 3H), 4.48 - 4.36 (m, 2H), 3.85 - 3.75 (m, 2H), 3.14 - 3.10 (m, 2H), 2.64 - 2.62 (m,lH), 2.49 - 2.46 (m, IH), 2.10 - 1.68 (m, 7H), 1.46 - 1.39 (m, 2H), 0.89 - 0.85 (m, IH), 0.71 (d, J = 6.7 Hz, 3H), 0.38 - 0.33 (m, 2H), 0.04 - 0.00 (m, 2H); 13C NMR (CDC13) 8 164.7, 145.5, 128.6, 123.5, 122.5, 117.0, 115.4, 75.1, 72.6, 67.6, 63.3, 52.7, 51.7, 45.1, 31.7, 31.6,29.2,16.8,11.0,3.0.
[0571] The product was dissolved in acetone and 1.1 equiv oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.060 g). HPLC-MS (ammonium acetate) [M+H]+ = 359.31.
4-[(R,S)-3-(4-Cvclobutylmethoxypiperidin-1 –yl)2-methylpropyl] -4H-benzo[ 1,4]oxazin-3-one (AC00262197) and carbonic acid cvclobutylmethyl ester l-[(R.S)2-methyl-3-f3-oxo-2,3-dihydrobenzo[1.4]oxazin-4-vl)propyl]piperidine-4-vl ester (A.C00262198)
[0572] A 4 mL vial was charged with 4-((R,S)-3-chloro-2-methylpropyl)-4H-benzo[l,4]oxazin-3-one (0.120 g, 60% pure 0.3 mmol), a mixture of 4-cyclobutylmethoxypiperidine and carbonic acid cyclobutylmethyl ester piperidine-4-yl ester (0.051 g), Nal (0.075 g, 0.5 mmol), and K2CO3 (0.069 g, 0.5 mmol) in DMF (1 mL) and shaken at 95° for 3 days. The reaction mixture was quenched with water and the products extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The products were purified by cation exchange column chromatography followed by flash column chromatography (SiCh; n-heptane/EtOAc 1:1) to give the title compounds 4-[(R,S)-3-(4-Cyclobutylmethoxypiperidin-l-yl)-2-methylpropyl]-4H-benzo[1.4]oxazin-3-one (0.033 g) and carbonic acid cyclobutylmethyl ester l-[(R,S)-2-methyl-3-(3-oxo-2,3-dihydrobenzo[1.4]oxazin-4-yl)propyl]piperidine-4-yl ester (0.014 g).
[0573] Data of 4-[(R,S)-3-(4-Cyclobutylmethoxypiperidin-l-yl)-2-
methylpropyl]-4H-benzo[1.4]oxazin-3-one: 1H NMR (CDCI3) δ7.16 - 7.14 (m, IH), 7.02 - 6.96 (m, 3H), 4.65 - 4.60 (m, 2H), 4.11 - 3.91 (m, 2H), 3.41 (d, J = 6.9 Hz), 3.27 - 3.22 (m, IH), 2.80 - 2.77 (m, IH), 2.26 - 1.82 (m, 11H), 1.75 - 1.68 (m, 2H), 1.61 - 1.54 (m, 2H), 0.88 (d, J = 6.7 Hz, 3H); 13C NMR (CDCI3) δ164.7, 145.5, 128.7, 123.6, 122.5,
168

117.0, 115.4, 75.3, 72.6, 67.6, 63.4, 52.7, 51.7, 45.1, 35.4, 31.7, 31.6, 29.3, 25.1, 18.6, 16.8.
[0574] The product was dissolved in acetone and 1.1 equiv oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.034 g). HPLC-MS (ammonium acetate) [M+H]+ = 373.23.
[0575] Data of carbonic acid cyclobutylmethyl ester l-[(R,S)-2-methyl-3-(3-oxo-2,3-dihydrobenzo[1.4]oxazin-4-yl)propyl]piperidine-4-yl ester: lH NMR (CDCI3) δ7.13 - 7.09 (m, 1H), 7.02 - 6.96 (m, 3H), 4.64 - 4.54 (m, 2H), 4.10 (d, 2H), 3.98 - 3.94 (m, 2H), 2.78 - 2.56 (m, 3H), 2.30 - 1.68 (m, 17H), 0.90 (d, 2H); 13C NMR (CDCI3) δ164.7, 154.9, 145.6, 128.7, 123.6, 122.5, 117.2, 115.3, 74.3, 71.7, 67.7, 63.3, 51.8, 51.2, 45.2, 34.1, 31.1, 30.9, 29.1, 24.7,18.4,16.8.
[0576] The product was dissolved in acetone and 1.1 equiv oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.010 g). HPLC-MS (ammonium acetate) [M+H]+ = 417.20.
(R.S)-4-[3-(3α-Cvclopropylmethoxv-8-Azabicyclor3.2.11oct-8-vn-2-methylpropyl-4H-benzori ,41oxazin-3-one (AC00262573)
[0577] A 4 mL vial was charged with (R,S)-4-(3-chloro-2-methylpropyl)-4H-benzo[l,4]oxazin-3-one (0.120 g, 60% pure, 0.3 mmol), 3α-cyclopropylmethoxy-8-azabicyclo[3.2.1]octane (0.054 g, 0.3 mmol), Nal (0.075 g, 0.5 mmol), and K2C03 (0.069 g, 0.5 mmol) in MeCN (0.5 mL) and shaken at 50° for 20 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. The product was purified by cation exchange column chromatography followed by flash column chromatography (SiCh; EtOAc) to give the title compound (0.067 g, 58%). *H NMR (CDC13) 8 7.10 - 7.07 (m, 1H), 6.84 - 6.79 (m, 3H), 4.49 - 4.36 (m, 2H), 3.89 - 3.84 (m, 2H), 3.34 (t, J = 4.9 Hz, 1H), 3.02 (d, J = 6.5 Hz, 2H), 2.92 - 2.90 (m, 1H), 2.84 - 2.82 (m, 1H), 2.16 - 2.11 (m, 1H), 1.95 - 1.89 (m, 1H), 1.83 - 1.58 (m, 9H), 0.85 - 0.81 (m, 1H), 0.70 (d, J = 6.7 Hz, 3H), 0.34 - 0.29 (m, 2H), 0.04 - 0.00 (m, 2H); 13C NMR (CDCI3) δ164.7, 145.5, 128.7, 123.5, 122.4, 116.9, 115.7, 72.6, 72.2, 67.6, 60.4, 58.7, 58.2, 45.0, 36.2, 36.1, 31.3, 26.7, 25.7,16.8,10.9,2.7.
169

[0578] The product was dissolved in acetone and 1.1 equiv oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.073 g). HPLC-MS (ammonium acetate) [M+H]+ = 385.35
4-{(R.S)-3-r3-(2-Cvclopropymethoxyethylidene)-8-aza-bicvclo[3.2.1]oct-8-vl]-2-methylpropyl)-4H-benzo[ 1.4]oxazin-3-one (AC00262357) (Diastereoisomers)
[0579] A 4 mL vial was charged with with 4-((R,S)-3-chloro-2-methylpropyl)-4H-benzo[l,4]oxazin-3-one (0.120 g, 60% pure, 0.3 mmol), 3-(2-cyclopropylmethoxyethylidene)-8-azabicyclo[3.2.1]octane (0.041 g, 0.2 mmol), Nal (0.075 g, 0.5 mmol), and K2C03 (0.069 g, 0.5 mmol) in DMF (1 mL) and stirred at 95° for 2 days. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by cation exchange column chromatography followed by flash column chromatography (Si02; EtOAc; EtOAc/MeOH 10:1) to give the title compound as a diastereoisomeric mixture (0.044 g, 51%). lH NMR (CDC13) 5 7.19 - 7.19 (m, 1H), 7.00 - 6.90 (m, 3H), 5.37 - 5.34 (m, 1H), 4.59 - 4.46 (m, 2H), 4.01 - 3.88 (m, 4H), 3.19 - 3.06 (m, 4H), 2.47 - 2.11, 1.93 - 1.70, 1.47 - 1.31 (m, 9H), 1.02 - 0.96 (m, 1H), 0.83 (d, J = 6.8 Hz, 3H), 0.48 - 0.44 (m, 2H), 0.15-0.12 (m, 2H); 13C NMR (CDCI3) δ164.7, 145.5, 137.9, 128.7, 128.6, 123.5, 123.3, 122.4, 117.0, 115.7, 74.8, 67.7, 67.6, 67.6, 66.1, 66.0, 61.3, 61.1, 60.2, 59.9, 57.3, 45.0, 41.8, 41.6, 34.8, 34.7, 31.2, 27.5, 27.2, 26.6, 26.2, 16.8,10.7,3.00.
[0580] The diastereoisomeric mixture was dissolved in acetone and 1.1 equiv oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.042 g). HPLC-MS (ammonium acetate) [M+H]+ = 411.31.
4- [(R)-3 -(4-Cvclopropylmethoxypiperidin-1 -yl)-2-methylpropyl] -4H-benzo [1.4] oxazin-3-one f AC00262908)
[0581] A reaction flask was charged with (S)-4-(3-Iodo-2-methylpropyl]-4H-benzo[l,4]oxazin-3-one (0.199 g, 0.6 mmol), 4-cyclopropylmethoxypiperidine (0.093 g, 0.6 mmol), and K2C03 (0.124 g, 0.9 mmol) in MeCN (2 mL) and stirred at 50° for 3 days. The reaction mixture was quenched with water and the product extracted into EtOAc. The
170

combined organic phases were dried over Na2SO4, filtered, and concentrated. The product was purified by cation exchange column chromatography followed by flash column chromatography (Si02; EtOAc) to give the title compound (0.138 g, 64%). *H NMR (CDCI3) δ6.99 - 6.97 (m, 1H), 6.85 - 6.79 (m, 3H), 4.47 - 4.35 (m, 2H), 3.85 - 3.74 (m, 2H), 3.14 - 3.08 (m, 1H), 3.11 (d, J = 6.8 Hz, 2H), 2.64 - 2.61 (m, 1H), 2.49 - 2.46 (m, 1H), 2.10 - 2.04 (m, 2H), 2.00 - 1.68 (m, 6H), 1.47 - 1.38 (m, 2H), 0.90 - 0.84 (m, 1H), 0.71 (d, J = 6.6 Hz, 3H), 0.37 - 0.33 (m, 2H), 0.04 - 0.00 (m, 2H); 13C NMR (CDC13) 5 164.6, 145.4, 128.5, 123.4, 122.4, 116.9, 115.3, 75.0, 72.5, 67.5, 63.3, 52.6, 51.6, 45.0, 31.6,31.5,29.1,16.7,10.9,2.9.
[0582] The product was dissolved in acetone and 1.1 equiv oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.172 g). HPLC-MS (ammonium acetate) [M+H]+ = 359.35.
(R)-4-[3-(3α-Cvclopropylmethoxv-8-Azabicyclor 3.2.1]oct-8-vl(-2-methylpropyl]-4H-benzo H ,41oxazin-3-one (AC00262909)
[0583] A reaction flask was charged with (S)-4-(3-Iodo-2-methylpropyl]-4H-benzo[l,4]oxazin-3-one (0.199 g, 0.6 mmol), 3α-cyclopropylmethoxy-8-azabicyclo[3.2.1]octane (0.109 g, 0.6 mmol), and K2C03 (0.124 g, 0.9 mmol) in MeCN (2 mL) and stirred at 50° for 3 days. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic phases were dried over Na2S04, filtered, and concentrated. The product was purified by cation exchange column chromatography followed by flash column chromatography (SiCh; EtOAc) to give the title compound (0.137 g, 59%). 1H NMR (CDC13) 5 7.10 - 7.07 (m, 1H), 6.86 - 6.80 (m, 3H), 4.49 - 4.36 (m, 2H), 3.88 (t, J = 3.9 Hz, 2H), 3.34 (t, J = 4.9 Hz, 1H), 3.02 (d, J = 6.5 Hz, 2H), 2.91 - 2.83 (m, 2H), 2.16 - 2.12 (m, 1H), 1.92 - 1.89 (m, 1H), 1.1.83 - 1.59 (m, 9H), 0.85 - 0.81 (m, 1H), 0.71 (d, J = 6.7 Hz, 3H), 0.34 - 0.29 (m, 2H); 0.04 - 0.00 (m, 2H); 13C (CDCI3) δ164.7, 145.5, 128.7, 123.5,122.4, 116.9,115.8, 72.6, 72.2, 67.6, 60.4, 58.7, 58.2, 45.1, 36.2, 36.1, 31.3, 26.7, 25.7, 16.8, 10.9, 2.8.
[0584] The product was dissolved in acetone and 1.1 equiv oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.138 g). HPLC-MS (ammonium acetate) [M+H]+ 385.37.
171

(R)-4-[3-(3B-Butyl-3α-hydroxy-8-aza-bicvclo[3.2.1]oct-8-vl)-2-methyl-propyl]-4H-benzo[1,4]oxazin-3-one(AC00261478)
[0585] A 7 ml vial was charged with 3-P-butyl-8-aza-bicyclo[3.2.1]octan-3α-
01 (37 mg, 0.20 mmol), 4-(3-iodo-2(S)-methyl-propyl)-4H-benzo[l,4]oxazin-3-one (130
mg, 0.40 mmol), and CS2CO3 (200 mg, 0.6 mmol) in dry DMF (4 ml) and the reaction
was shaken at 50 °C for 4 days. The reaction was then poured into water and extracted
with ether. The combined organic phases were washed with brine, dried (Na2S04),
filtered, concentrated under reduced pressure and the oily residue was purified by flash
column chromatography (SiC>2; EtOAc/MeOH 95:5) to yield the title compound as an oil
(63 mg, 16 mmol, 82 %). lH NMR (CDCI3) 5 7.28 - 7.21 (m, 1H), 7.02 - 6.95 (m, 3 H),
4.60 (ABq, J = 14.8, 34.0 Hz, 2H), 6.04 (d, J = 6.8 Hz, 2H), 3.17 - 3.04 (m, 2H), 2.32 dd,
J =4.4,12.8 Hz, 1H), 2.13 (dd, J = 9.2,12.8 Hz, 1 H), 2.08 -1.76 (m, 7 H), 1.62 -1.51 (m,
2 H), 1.38 - 1.24 (m, 6 H), 0.94 - 0.86 (m, 6 H);13C NMR (CDCI3) δ164.9, 145.7, 129.0,
123.8, 122.6, 117.2, 115.9, 71.1, 67.9, 60.7, 59.0, 58.1, 46.9, 45.4, 44.1, 31.6, 26.7, 25.7,
25.1,23.4,17.1,14.3; HPLC-MS (ammonium acetate) [M+H]+ = 359.46.
4-[3-(3-Ethoxvimino-8-aza-bicvclor3.2.11oct-8-vn-2( R)-methyl-propyl1-4H-benzo[1,4]oxazin-3-one(AC00261354)
[0586] A 7 ml vial was charged with 4-(3-iodo-2(S)-methyl-propyl)-4H7-benzo[l,4]oxazin-3-one (330 mg, 1.0 mmol), crude 3-ethoxyimino-8-azonia-bicyclo[3.2.1]octane chloride (200 mg, 0.98 mmol), and K2CO3 (290 mg, 2.1 mmol) in dry DMF (4 ml) and the reaction was shaken at 60 °C for 3 days. The reaction was then poured into water and extracted with ether. The combined organic phases were washed brine, dried (Tv SCU), filtered, concentrated under reduced pressure and the oily residue was purified by flash column chromatography (SiOa; CH2Cl2/acetone/MeOH, 90:7:3) to yield the diastereomeric mixture of the title compound as an oil (87 mg, 0.24 mmol, 24 %). 'H NMR (CD3OD) 5 7.28 (dd, J = 2.0, 7.6 Hz, 1 H), 7.07-6.93 (m, 3 H), 4.57 (ABq, J = 14.8, 19.6 Hz, 2 H), 4.12 (dd, J = 6.4, 14.4 Hz, 1 H), 4.05-3.92 (m, 3 H), 3.30-3.16 (m, 2 H), 2.92-2.82 (m, 1 H), 2.54-2.32 (m, 3 H), 2.18-1.81 (m, 2 H), 1.60-1.34 (m, 2 H), 1.20 (m, 3 H), 0.93 (d, J = 6.8 H); 13C NMR (CD3OD) 5165.8, 156.6, 146.0, 128.6, 124.0, 122.6, 116.8, 115.9, 68.5, 67.4, 60.2, 59.54, 59.48, 58.8, 56.5, 45.0, 37.0, 36.9, 31.9, 31.7,
172

30.99, 30.96,27.6,27.0, 26.7,26.1,15.9,13.7; HPLC-MS (ammonium acetate) [M+H]+ = 372.21.
[0587] The product (18 mg, 48 umol) was diluted in ether and oxalic acid (5.6 mg, 62 umol) dissolved in acetone was added. The resulting crystalline material was washed with ether to yield the corresponding oxalic salt (14 mg).
Separation of diastereoisomers (AC00261434 & AC00261435)
[0588] The diastereomeric mixture of 4-[3-(3-ethoxyimino-8-aza-bicyclo[3.2.l]oct-8-yl)-2(i?)-methyl-propyl]-4H-benzo[l,4]oxazin-3-one was separated with HPLC chiral phase chromatography. Retention times on an analytical column Chiralcel AD column ((250 x 4.6 mm, 10 u) eluting with hexane: EtOH (99:1, with 0.3 % diethylamine), 1 ml/min flow rate) are; the first isomer (AC00261434): 25.3 min, and the second isomer (AC00261435): 30.7 min.
4- [3 -(3 -Cvclopropylmethoxyimino-8 -aza-bicvclo [3.2.11 oct-8 -yl)-2(R)methyl-propyl] -4H-benzo[1.4]oxazin-3-one (diastereomeric mixture) (AC00261537)
[0589] A 7 ml vial was charged with 4-(3-iodo-2(S)-methyl-propyl)-4H-benzo[l,4]oxazin-3-one (330 mg, 1.0 mmol), crude (9-cyclopropylmethyl-hydroxylamine chloride, K2CO3 (290 mg, 2.1 mmol) and dry DMF (4 ml) and the reaction was shaken at 60 °C for 3 days. The reaction was then poured into water and extracted with ether. The combined organic phase was washed brine, dried (Na2S04), filtered, and concentrated under reduced pressure. The oily residue was purified by ion-exchange column chromatography to yield the diastereomeric mixture of the title compound as an oil (80 mg, 0.20 mmol, 31 % over two steps). 1H NMR (CDCI3) δ7.20 - 7.15 (m, 1 H), 7.02 -6.95 (m, 3 H), 4.65 - 4.51 (m, 2 H), 4.09 - 3.98 (m, 2 H), 3.85 - 3.76 (m, 2 H), 3.33 - 3.16 (m, 2 H), 2.95 (br t, J = 16 Hz, 1 H), 2.60 - 2.243 (m, 1 H), 2.42 - 2.35 (m, 1 H), 2.3 - 2.21 (m, 1 H), 2.20 - 2.04 (m, 2 H), 2.03 - 1.90 (m, 3 H), 1.66 - 1.38 (m, 2 H), 1.16 -1.02 (m, 1 H), 0.90 (d, J = 6.8 Hz, 3 H), 0.56 - 0.44 (m, 2 H), 0.32 - 0.18 (m, 2 H); 13C NMR (CDCI3) 5 161.9, 152.9, 142.8, 125.9, 120.8, 119.7, 119.6, 114.3, 112.64, 112.63, 75.09, 75.07, 64.8, 57.6, 56.8, 56.6, 55.9, 54.1, 54.0, 42.2, 34.7, 34.6, 29.6, 29.3, 28.34, 28.32, 25.3, 24.4, 24.3, 23.5, 14.01, 13.99, 7.5, 0.1, 0.02, 0.00 ; HPLC-MS (ammonium acetate) [M+H+] = 398.21.
173

('R.S)-4-[3-('4-Cvclopropylmethoxvpiperidin-l-vlV2-methoxvpropvn-7-fluoro-4H-benzoll.41oxazin-3-one (AC00262784)
[0590] A reaction vial was charged with crude (R,S)-7-Fluoro-4-(3-iodo-2-methoxypropyl)-4H-benzo[1.4]oxazin-3-one (0.113 g), cyclopropylmethoxypiperidine (145LH49) (0.047 g, 0.3 mmol), and K2C03 (0.062 g, 0.45 mmol) in MeCN (2 mL) and stored at 40° for 2 days. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The product was purified by cation exchange column chromatography followed by flash column chromatography (SiC^; EtOAc) and prep RP-HPLC to give the title compound (0.024 g). 'H NMR (CDC13) 8 7.11 - 7.07 (m, 1H), 6.58 - 6.53 (m, 2H), 4.48 - 4.35 (m, 2H), 3.97 - 3.93 (m, 1H), 3.83 - 3.77 (m, 1H), 3.48 (br s, 1H), 3.16 - 3.10 (m, 6H), 2.65 - 2.63 (m, 2H), 2.36 - 2.23 (m, 2H), 2.03 - 2.00 (m, 2H), 1.77 - 1.67 (m, 2H), 1.48 - 1.38 (m, 2H), 0.92 - 0.82 (m, 1H), 0.38 - 0.33 (m, 2H), 0.04 - 0.00 (m, 2H); 13C NMR (CDC13) 8 164.0, 158.8 (d, J = 243.7 Hz), 146.3 (d, J = 11.5 Hz), 125.8 (d, J = 3.5 Hz), 116.8 (d, J = 9.6 Hz), 109.0 (d, J = 22.7 Hz), 104.8 (d, J = 25.8 Hz), 76.7, 72.6, 67.8, 59.4, 58.0, 52.4, 52.1, 45.2, 31.5,11.0, 3.0.
[0591] The product was dissolved in acetone and 1.1 equiv oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.029 g). HPLC-MS (ammonium acetate) [M+H]+ = 393.33.
l-[3-(3α-Cvclopropylmethoxv-8-aza-bicvclo[3.2.1]oct-8-vl)propyl]-6,7-difluoro-3.4-dihydro-1 H-quinolin-2-one (AC00262572)
[0592] A 4 ml vial was charged with l-(3-chloropropyl)-6,7-difluoro-3,4-dihydro-lH-quinolin-2-one (78 mg, 0.30 mmol), 3 174

2.96 ( m, 2 H), 2.66 (t, J = 6.8 Hz, 2 H), 2.46 - 2.41 (m, 2 H), 2.22 (t, J = 6.8 Hz, 2 H), 1.93 - 1.15 (m, 10 H), 0.89 - 0.77 (m, 1 H), 0.40 - 0.27 (m, 2 H), 0.08 - (-)0.04 (m, 2 H); 13C NMR (CDC13) 5 166.7, 146.4 (dd, J = 13, 243 Hz), 142.6 (dd, J = 13 243 Hz), 133.7 (d, J = 8 Hz), 119.6 (br), 113.5 d, J = 18 Hz), 102.5 (d, J = 22 Hz), 69.9, 69.2, 55.9, 46.5, 38.3, 32.8,23.4,23.3,22.2, 8.1, 0.0 ; HPLC-MS (ammonium acetate) [M+H]+ = 405.30.
[0593] The product was dissolved in acetone and oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.049 g).
l-r3-(4-Cvclopropylmethoxvpiperidin-l-vl)propyl1-6,7-difluoro-3,4-dihydro-lH-quinolin-2-one ( AC00262272)
[0594] A 4 ml vial was charged with l-(3-chloropropyl)-6,7-difluoro-3,4-dihydro-lH-quinolin-2-one (78 mg, 0.30 mmol), 4-cyclopropylmethoxypiperidine (145LH49) (42 mg, 0.27 mmol), Nal (75 mg, 0.50 mmol), and K2C03 (69 mg, 0.50 mmol) in CH3CN/DMF (1 ml, 50:50). The reaction was shaken at 50 °C for 3 days and the reaction was poured into water and extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The oily residue was purified by ion-exchange column chromatography followed by flash column chromatography (SiCh; EtOAc) to yield the title compound as an oil (83 mg, 0.22 mmol, 81%). lH NMR (CDCI3) 5 6.90 (dd, J = 6.8, 12.0 Hz, 1 H), 6.82 - 6.75 (m, 1 H), 3.73 (t, J = 7.2 Hz, 2 H), 3.22 - 3.13 (m, 1 H), 3.11 (d, J = 6.8 Hz, 2 H), 2.69 - 2.54 (m, 4 H), 2.47 - 2.41 (m, 2 H), 2.23 - 2.17 (m, 2 H), 2.01-1.91 (m, 2 H), 1.78 - 1.58 (m, 4 H), 1.52 - 1.40 (m, 2 H), 0.94 - 0.82 (m, 1 H), 0.44 - 0.28 (m, 2 H), 0.06 - (-)0.03 (m, 2 H); 13C NMR (CDCI3) 5 166.4, 146.1 (dd, J = 13, 243 Hz), 142.3 (dd, J = 13, 243 Hz), 133.3 (dd, J = 3, 8 Hz), 119.4 (dd, J = 2, 5 Hz), 113.3 (d, J = 18 Hz), 102.0 (d, J = 22 Hz), 71.5 (br), 69.5, 52.2, 48.3, 38.0, 28.6, 28.2, 21.9, 21.7, 7.9, 0.0; HPLC-MS (ammonium acetate) [M+H]+ = 379.29.
[0595] The product was dissolved in acetone and oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.085 g).
175

1 -[3-(4-Cvclobutylmethoxypiperidin-1 –yl )propyl]-6.7-difluoro-3,4-dihydro-1 H-quinolin-2-one ^000262195) and carbonic acid cvclobutylmethyl ester l-[3-(6,7-difluoro-2-oxo-3.4-dihydro-2H-quinolin-l-vl-propyl]-piperidin-4-vlmethyl ester (AC00262296)
[0596] A 4 ml vial was charged with l-(3-chloropropyl)-6,7-difluoro-3,4-dihydro-1H-quinolin-2-one (130 mg, 60%, 0.30 mmol), a mixture of 4-cyclobutylmethoxypiperidine and carbonic acid cyclobutylmethyl ester piperidine-4-ylester (42 mg), Nal (75 mg, 0.50 mmol), and K2C03 (69 mg, 0.50 mmol) in CH3CN /DMF(1 ml, 50:50). The reaction was shaken at 50 °C for 3 days and the reaction was poured into water and extracted with EtOAc. The organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated under reduced pressure. The oily residue was purified by ion-exchange column chromatography followed by flash column chromatography (Si02; EtOAc) to yield two products: l-[3-(4-Cyclobutylmethoxypiperidin-1 -yl)propyl] -6,7-difluoro-3,4-dihydro-1 #-quinolin-2-one and carbonic (29 mg, 75 umol) and Carbonic acid cyclobutylmethyl ester l-[3-(6,7-difluoro-2-oxo-3,4-dihydro-2H-quinolin-1 -yl)-propyl] -piperidin-4-ylmethyl ester (12.2 mg, 36 umol).
[0597] 1 -[3-(4-Cyclobutylmethoxypiperidin-1 -yl)propyl]-6,7-difiuoro-3,4-dihydro-1H-quinolin-2-one and carbonic: !H NMR (CDC13) 5 7.08 (dd, J = 7.2, 12.4 Hz, 1 H), 6.94 (m, 1 H), 3.90 (t, J = 7.2 Hz, 2 H), 3.40 (d , J = 6.8 Hz, 2 H), 3.32 (m, 1 H), 2.82 (t, J = 6.8 Hz, 2 H), 2.76-2.68 (m, 2 H), 2.63-2.58 (m, 2 H), 2.57-2.46 (m, 1 H), 2.34 (t, J = 6.8 Hz, 2 H), 2.16-2.00 (m, 4 H), 1.94-1.56 (m, 11 H); 13C NMR (CDCI3) δ169.7, 149.4 (dd, J = 13, 243 Hz), 145.6 (dd, 13, 243 Hz) 136.6 (br), 122.7(br), 116.6 (d, J = 18 Hz), 105.3 (d, J = 23 Hz), 75.0 (br), 72.7, 55.5, 51.5, 41.3, 35.6, 31.8, 31.5, 25.325.2, 25.0,18.8; HPLC-MS (ammonium acetate) [M+H]+ = 393.20.
[0598] The product was dissolved in acetone and oxalic acid dissolved in acetone was added to the different solutions. The formed crystals were filtered and washed with acetone to give the corresponding oxalic salt (0.028 g).
[0599] Carbonic acid cyclobutylmethyl ester l-[3-(6,7-difluoro-2-oxo-3,4-dihydro-2i/-quinolin-l-yl)-propyl]-piperidin-4-ylmethyl ester: lH NMR (CDCI3) 5 7.05 (dd, J = 6.8, 12.4 Hz, 1 H), 6.95 (m, 1 H), 4.64 (m, 1 H), 4.10 (d, J = 7. 2 Hz, 2 H), 3.9 (t, J = 7.2 Hz, 2 H), 2.82 (t, J = 6.8 Hz, 2 H), 2.77-2.58 (m, 5 H), 2.36 (t, J = 7.2 Hz, 2 H), 2.28-2.18 (m, 2 H), 2.12- 2.02 (m, 2 H), 2.01-1.73 (m, 11 H); 13C NMR (CDC13) 5 169.7, 155.1,159.4 (dd, J = 13, 243 Hz), 145.6 (dd, J = 13,243 Hz), 136.6 (br), 122.7 (br), 116.7
176

(d, J = 18 Hz), 105.2 (d, J = 22 Hz), 74.3 (br), 55.4, 51.0, 41.2 (25.2, 25.0, 24.9, 18.6; HPLC-MS (ammonium acetate) [M+H]+ = 437.17.
[0600] The product was dissolved in acetone and oxalic acid dissolved in acetone was added to the different solutions. The formed crystals were filtered and washed with acetone to give the corresponding oxalic salt (0.012).
2,2-Dimethylpropionic acid l-[3-(6,7-difluoro-2-oxo-3,4-dihydro-2H-quinolin-l-yl)-propyl]piperidin-4-vl-methyl ester (AC00261673)
[0601] A 4 ml vial was charged with l-(3-chloropropyl)-6,7-difluoro-3,4-dihydro-lH-quinolin-2-one (52 mg, 0.20 mmol), 2,2-dimethylpropionic acid piperidin-4-ylmethyl ester (45 mg, 0.21 mmol) (40 mg, 0.20 mmol), and Cs2CO3 (200 mg, 0.60 mmol) in dry DMF (1 ml). The reaction was shaken at 80 °C for 3 days and the reaction was poured into water and extracted with EtOAc. The combined organic phase was washed with brine, dried (Na2S04), filtered, and concentrated under reduced pressure. The oily residue was purified by ion-exchange column chromatography to yield the title product as an oil (26 mg, 62 umol, 31%). !H NMR (CDC13) 8 7.07 (dd, J = 1.8, 3.1 Hz, 1 H), 6.98 - 6.91 (m, 1 H), 3.94 - 3.87 (m, 4 H), 2.94 - 2.86 (m, 2 H), 2.82 (br t, J = 6.8 Hz, 2 H), 2.02 (dd, J = 5.2, 7.6 Hz, 2 H), 2.35 (t, J = 6.8 Hz, 2 H), 1.94 (dt, J - 2.0, 11.6 Hz, 2 H), 1.74 - 1.58 (m, 3 H), 1.42 - 1.28 (m, 2 H), 1.91 (s, 9 H); 13C NMR (CDC13) 8178.7, 169.7,149.3 (dd, J = 13, 230 Hz), 145.6 (dd, J = 243,13 Hz), 136.7 (br), 122.7 (br), 116.6 (d, J = 18 Hz), 105.3 (d, J = 22 Hz), 68.8, 55.8, 53.7, 42.3, 39.1, 35.7, 31.1, 29.1, 25.2, 24.9; HPLC-MS (ammonium acetate) [M+H]+ = 423.20.
2,2-Dimethylpropionic acid 2-{l-[3-(6)-difluoro-2-oxo-3,4-dihydro-2H-quinolin-l-vl)-propyl]piperidin-4-vllethvl ester (AC00261939')
[0602] A 4 ml vial was charged with l-(3-chloropropyl)-6,7-difluoro-3,4-dihydro-lH-quinolin-2-one (52 mg, 0.20 mmol), 2,2-dimethyl-propionic acid 2-piperidin-4-yl-ethyl ester, and CS2CO3 (200 mg, 0.60 mmol) in dry DMF (1 ml). The reaction was shaken at 80 °C for 3 days and the reaction was poured into water and extracted with EtOAc. The organic phase was washed with brine, dried (Na2S04), filtered, and concentrated under reduced pressure. The oily residue was purified by ion-exchange column chromatography to yield the title product as an oil (21 mg, 48 umol, 24%). !H NMR (CD3OD) 8 7.23 - 7.12 (m, 2 H), 4.11 (t, J = 6.0 Hz, 2 H), 3.96 (t, J = 7.2 Hz, 2 H),
177

3.18 - 3.06 (m, 2 H), 2.88 (br t, 6.8 Hz, 2 H), 2.66 - 2.58 (m, 4 H), 2.29 (dt, J = 2.0, 12.0 Hz, 2 H), 1.94 - 1.85 (m, 2 H), 1.81 (br d, J = 13.6 Hz, 2 H), 1.64 - 1.57 (m, 2 H), 1.57 -1.45 (m, 1 H), 1.42 - 1.31 (m, 2 H), 1.18 (s, 9 H); 13C NMR (CD3OD) 5 178.9, 171.1, 149.2 (dd, J= 13, 241 Hz) 145.8 (dd, J = 13, 230 Hz), 135.0 (br), 123.8 (dd, J = 4, 6 Hz), 116.5 (d, J = 19 Hz), 105.1 (d, J = 23 Hz), 62.2, 55.0 53.2, 40.2, 38.6, 34.7, 31.1, 30.8, 26.4,24.3, 23.5; HPLC-MS (ammonium acetate) [M+H]+ = 437.22.
l-{3-f3-(2-Cvclopropylmethoxyethylidene)-8-Azabicyclo[3.2.1]oct-8-vl]-propyl]-6.7-difluoro-3,4-dihydro-1 H-quinolin-2-one (AC002623 56)
[0603] A 4 ml vial was charged with l-(3-chloropropyl)-6,7-difluoro-3,4-dihydro-lH-quinolin-2-one (78 mg, 0.30 mmol), 3-(2-cyclopropylmethoxyethylidene)-8-aza-bicyclo[3.2.1]octane (42 mg, 0.2 mmol), Nal (75 mg, 0.50 mmol), and K2CO3 (69 mg, 0.50 mmol) in CH3CN /DMF(1 ml, 50:50). The reaction was shaken at 50 °C for 3 days and the reaction was poured into water and extracted with EtOAc. The organic phase was washed with brine, dried (Na2S04), filtered, and concentrated under reduced pressure. The oily residue was purified by ion-exchange column chromatography followed by flash column chromatography (SiC^; EtOAc/MeOH, 90:10) to yield the title compound as an oil (46 mg, 0.11 mmol, 53 %). 2H NMR (CDCI3) 5 7.14 (dd, J = 6.8, 12.4 Hz, 1 H), 6.95 -6.88 (m, 1 H), 5.40 (t, J = 6.6 Hz, 1 H), 3.99 - 3.86 (m, 4 H), 3.33 - 3.25 (m, 2 H), 3.21 (d, J = 6.8 Hz, 2 H), 2.8 (t, J = 6.8 Hz, 2 H), 2.62 - 2.53 (m, 3 H), 2.48 (t, J = 6.8 Hz, 2 H), 2.25 (br s, 1 H), 1.95 - 1.74 (m, 5 H), 1.58 - 1.36 (m, 2 H), 1.08 - 0.96 (m, 1 H), 0.56 -0.44 (m, 2 H), 0.22 - 0.08 (m, 2 H); 13C NMR (CDC13) 8 166.5, 146.2 (dd, J = 13, 243 Hz), 142.4 (dd, J = 13, 243), 134.2, 133.4 (br), 120.7 (br), 119.4 (br), 113.3 (d, J = 18 Hz), 102.1 (br), 71.8, 63.0, 56.7, 56.4, 45.3, 38.0, 37.7, 30.9, 28.6, 23.9, 23.6, 23.0, 22.0, 7.7, 0.0; HPLC-MS (ammonium acetate) [M+H]+ = 398.21.
[0604] The product was dissolved in acetone and oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.046 g).
('R.S)-4-(3-3α-(2-Ethoxvethvl)-8-Azabicyclor3.2.1]oct-8-vl]-2-methylpropyl]-4H-benzo [1.4] oxazin-3 -one
[0605] A reaction flask was charged with (R,S)-4-(3-chloro-2-methylpropyl)-4H-benzo[l,4]oxazin-3-one (0.180 g, 60% pure, 0.45 mmol), 3α-(2-ethoxyethyl)-8-
178

azabicyclo[3.2.1]octane (0.078 g, 0.43 mmol), Nal (0.150 g, 1.0 mmol) and K2C03 (0.138 g, 1.0 mmol) in MeCN (1 mL) and stirred at 50° for 3 days. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. The product was purified by cation exchange column chromatography and flash column chromatography (Si02; EtOAc, EtOAc/MeOH 10:1) to give the 'title compound (0.045 g). Major isomer: lH NMR (CDC13) 5 7.32 - 7.26 (m, 1H), 7.02 - 6.95 (m, 3H), 4.66 - 4.52 (m, 2), 4.11 - 3.99 (m, 2H), 3.48 - 3.38 (m, 4H), 3.16 - 3.02 (m, 2), 2.33 - 2.25 (m, 1H), 2.17-1.20 (m, 13H), 1.19 (m, 3H), 0.88 - 0.86 (m, 3); 13C NMR (CDC13) 5 164.7, 145.5, 128.6, 123.5, 122.4, 116.9, 115.8, 69.7, 67.6, 66.1, 60.5, 58.7, 57.9, 45.0, 38.0, 36.6, 36.3, 31.4, 27.8, 26.8, 24.9,16.8,15.2.
[0606] The product was dissolved in acetone and 1.1 equiv oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.042 g). HPLC-MS (ammonium acetate) [M+H]+ = 387.43.
(TQ-4- (3- [3α-(2-Methoxyethyl)-8-Azabicyclo r3.2.11 oct-8-vl] -2-methylpropyl 1-4H-benzo[l .41oxazin-3-one (AC00263025)
[0607] A reaction flask was charged with (S)-4-(3-Iodo-2-methylpropyl]-4H-benzo[l,4]oxazin-3-one (0.199 g, 0.60 mmol), 3α-(2-methoxyethyl)-8-azabicyclo[3.2.1]octane (0.102 g, 0.60 mmol), and K2C03 (0.138 g, 1.00 mmol) in MeCN (2 mL) and stirred at 50° for 4 days. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2S04, filtered, and concentrated. The product was purified by cation exchange COLUMN CHROMATOGRAPHY and flash COLUMN CHROMATOGRAPHY (Si02; EtOAc) to give the title compound (0.184 g, 83%). Major isomer: !H NMR (CDC13) 8 7.31 - 7.28 (m, 1H); 7.02 - 6.93 (m, 3H); 4.70 - 4.52 (m, 2H); 4.08 - 4.05 (m, 2H); 3.38 (t, J = 6.6 Hz, 3H); 3.32 (s, 3H); 3.14 - 3.06 (m, 2H); 2.31 - 2.26 (m, 1H); 2.18 - 1.54 (m, 13H); 1.32 - 1.20 (m, 2H); 0.87 (d, J = 6.7, 3H); 13C (CDCI3) δ165.1, 145.9, 129.1, 123.9, 122.8, 117.3, 116.3, 72.3, 68.0, 61.0, 59.08, 58.98, 58.4, 45.5, 38.3, 37.0, 36.8, 31.8, 28.3, 27.6, 25.3, 17.3; HPLC-MS (ammonium acetate) [M+H]+ = 373.18.
179

[0608] The product was dissolved in acetone and 1.1 equiv oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.178 g).
('R)-4-{3-r3α-(2-Ethoxvethvl)-8-Azabicyclor3.2.1)oct-8-vl)-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one(AC0026320)
[0609] A reaction flask was charged with (S)-4-(3-Iodo-2-methylpropyl]-4H-benzo[l,4]oxazin-3-one (1.06 g, 3.2 mmol), 3α-(2-ethoxyethyl)-8-azabicyclo[3.2.1]octane (0.589 g, 3.2 mmol), and K2C03 (0.700 g, 5.1 mmol) in MeCN (4 mL) and stirred at 50° for 3 days. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by cation exchange column chromatography and flash column chromatography (SiC>2; EtOAc) to give the title compound (0.602 g, 49%). Major isomer: lH NMR (CDC13) 8 7.30 - 7.26 (m, 1H), 7.02 - 6.96 (m, 3H), 4.66 - 4.53 (m, 2H), 4.07 -4.04 (m, 2H), 3.48 - 3.39 (m, 4H), 3.13 - 3.05 (m, 2H), 2.30 - 2.26 (m, 1H), 2.16 - 2.03 (m, 3H), 1.95 - 1.80 (m, 4H), 1.74 - 1.68 (m, 2H), 1.63 - 1.56 (m, 2H), 1.30 - 1.23 (m, 2H), 1.19 (t, J = 4.5 Hz, 3H), 0.87 (d, J = 6.7 Hz, 3); 13C (CDCI3) δ164.7, 145.5, 128.7, 123.5, 122.4, 116.9, 115.8, 69.8, 67.6, 66.1, 60.6, 58.7, 57.9, 45.1, 38.0, 36.6, 36.3, 31.4, 27.8, 26.8,24.9,16.8,15.2; HPLC-MS (ammonium acetate) [M+H]+ = 387.39.
[0610] The product was dissolved in acetone and 1.1 equiv oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt
(S)-4-(3-r3α-(2-Ethoxvethvl)-8-Azabicyclor3.2.1]oct-8-vl]-2-methylpropyl>-4H-benzori ,41oxazin-3-one (AC00262993)
[0611] A reaction flask was charged with (i?)-4-(3-Iodo-2-methylpropyl]-4H-benzo[l,4]oxazin-3-one (1.06 g, 3.2 mmol), 3α-(2-ethoxyethyl)-8-azabicyclo[3.2.1]octane (0.589 g, 3.2 mmol), and K2C03 (0.700 g, 5.1 mmol) in MeCN (4 mL) and stirred at 50° for 3 days. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by cation exchange column chromatography and flash column chromatography (SiC>2; EtOAc) to give the title compound (0.914 g, 74%). Major isomer: lH NMR (CDCI3) δ7.29 - 7.26 (m 1H); 7.02 - 6.96 (m, 3H), 4.66 - 4.52 (m, 2H), 4.12 -
180

4.01 (m, 2H), 3.48 - 3.38 (m, 4H), 3.13 - 3.04 (m, 2H), 2.30 - 2.26 (m,lH), 2.16 - 2.03 (m, 3H), 1.96 - 1.79 (m, 4H), 1.73 - 1.68 (m, 2H), 1.65 - 1.56 (m, 2H), 1.31-1.23 (m, 2H), 1.17 (t, J = 4.3 Hz, 3), 0.86 (d, J = 6.6 Hz, 3H); 13C NMR (CDC13) 5 164.7, 145.5, 128.7, 123.5, 122.4, 116.9, 115.8, 69.8, 67.6, 66.1, 60.6, 58.7, 57.9, 45.0, 38.0, 36.6, 36.3, 31.4, 27.8, 26.8, 24.9, 16.8, 15.2 ; HPLC-MS (ammonium acetate) [M+H]+ = 387.41.
[0612] The product was dissolved in acetone and 1.1 equiv oxalic acid dissolved in acetone was added. The formed crystals were filtered and washed with acetone to give the title compound as oxalic salt (0.142 g).
(S)-4-(3-r3α-(2-Methoxvethvn-8-Azabicyclor3.2.11oct-8-vll-2-methylpropyl)-4H-benzori .41oxazin-3-one (AC00263035)
[0613] A reaction flask was charged with (i?)-4-(3-iodo-2-methylpropyl]-4/7-benzo[l,4]oxazin-3-one (0.265 g, 0.80 mmol), 3α-(2-methoxyethyl)-8-azabicyclo[3.2.1]octane (0.112 g, 0.66 mmol), and K2C03 (0.210 g, 1.5 mmol) in MeCN (2 mL) and stirred at 50° for 4 days. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SC«4, filtered, and concentrated. The product was purified by cation exchange column chromatography and flash column chromatography (SiC^; EtOAc) to give the title compound (0.151 g, 62%). Major isomer: 2H NMR (CDC13) 5 7.33 - 7.28 (m, 1H); 7.05 -6.98 (m, 3H); 4.69 - 4.54 (m, 2H); 4.10 - 4.06 (m, 2H; 3.39 (t, J = 6.7 Hz, 2H); 3.34 (s, 3H); 2.33 - 2.29 (m, 1H); 2.27 - 1.22 (m, 13H); 0.88 (d, J = 6.6 Hz, 3H); 13C NMR (CDCI3) 5 165.2, 145.9, 129.1, 123.9, 122.9, 117.3, 116.3, 72.4, 68.1, 61.1, 59.10, 59.00, 58.4, 45.5, 38.3, 37.0, 36.8, 31.8, 28.2, 27.2, 25.3, 17.3; HPLC-MS (ammonium acetate) [M+H]+ = 373.14.
(R)-4-{3-(3β-(2-Ethoxvethvn-8-Azabicyclor[3.2.1}oct-8-vl]-2-methylpropyl]-4H-benzo[l ,41oxazin-3-one (AC00262998)
[0614] A reaction flask was charged with (S)-4-(3-iodo-2-methylpropyl]-4H-benzo[l,4]oxazin-3-one (0.083 g, 0.25 mmol), TFA salt of 3p-(2-ethoxyethyl)-8-azabicyclo[3.2.1]octane (162LH20) (0.059. g, 0.20 mmol), and K2C03 (0.138 g, 1.0 mmol) in MeCN (2 mL) and stirred at 50° for 3 days. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SC 181

column chromatography and flash column chromatography (Si02; n-heptane/EtOAc 1:1, EtOAc) to give the title compound (0.039 g, 53%). Major isomer: !H NMR (CDC13) 8 7.26 - 7.19 (m, 1H), 6.96 - 6.90 (m, 3), 4.61 - 4.46 (m, 2H), 4.01 - 3.94 (m, 2H), 3.42 -3.32 (m, 4H), 3.14 - 3.00 (m, 2), 2.27 - 1.10 (m, 17H), 0.81 (d, J = 6.6 Hz, 3H); 13C NMR (CDCI3) δ164.7, 145.4, 128.6, 123.5, 122.4, 116.9, 115.9, 68.3, 67.6, 66.1, 61.5, 59.7, 58.0, 45.1, 38.5, 38.3, 36.9, 31.3, 27.1, 26.1, 25.1, 16.9, 15.2; HPLC-MS (ammonium acetate) [M+H]+ = 387.11.
(S)-4-(3-[3p-(2-Ethoxvethvl)-8-Azabicyclor3.2.1]oct-8-vl]-2-methylpropyl}-4H-benzo[l .41oxazin-3-one (AC00263034)
[0615] A reaction flask was charged with (R)-4-(3-iodo-2-methylpropyl]-4H-benzo[l,4]oxazin-3-one (0.099 g, 0.30 mmol), TFA salt of 3p-(2-ethoxyethyl)-8-azabicyclo[3.2.1]octane (0.059. g, 0.20 mmol), and K2C03 (0.138 g, 1.0 mmol) in MeCN (2 mL) and stirred at 50° for 4 days. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by cation exchange column chromatography and flash (Si02; EtOAc) to give the title compound (0.040 g, 49%). Major isomer: lK NMR (CDCI3) δ7.43 - 7.24 (m, 1H), 7.06 - 6.72 (m, 3H), 4.70 - 4.55 (m, 2H), 4.14 - 4.02 (m, 2H), 3.51 - 3.40 (m, 4H), 3.16 - 3.08 (m, 2H), 2.36 - 2.28 (m, 1H), 2.19 - 1.28 (m, 13H), 1.21 (t, J = 7.0 Hz, 3H), 0.90 (d, J = 6.6 Hz, 3H); HPLC-MS (ammonium acetate) [M+H]+ = 387.13.
Example 3 Pharmacological Data
[0616] Receptor Selection and Amplification (R-SAT) assays were carried out using the cloned Ml - M5 receptors essentially as described in: Brauner-Osborne H, Brann MR. Pharmacology of muscarinic acetylcholine receptor subtypes (ml-m5): high throughput assays in mammalian cells. Eur J Pharmacol 1996 Jan 4;295(1):93-102, and Spalding TA, Trotter C, Skjaerbaek N, Messier TL, Currier EA, Burstein ES, Li D, Hacksell U, Brann MR. Discovery of an ectopic activation site on the M(l) muscarinic receptor. Mol Pharmacol. 2002 Jun;61(6):1297-302.
182



184

We claim :
A compound of formula (I), and salts and isomers thereof





wherein:
m is 0,1 or 2;
C3-C4 is CH2-CR1R9 or CH=R1 or C4 is CR1R9 and C3 is absent;
each R1 and each R9 is separately selected from the group consisting of hydrogen, halogen, hydroxy, straight- or branched-chain optionally substituted C1-6 alkyl, straight- or branched-chain optionally substituted C2-6 alkenyl, straight- or branched-chain optionally substituted C2-6 alkynyl, straight- or branched-chain optionally substituted C1-6 alkylidene, straight- or branched-chain optionally substituted C1.6 alkoxy, straight- or branched-chain optionally substituted C1.6 heteroalkyl, straight- or branched-chain optionally substituted C1-6 aminoalkyl, straight- or branched-chain optionally substituted C1-6 haloalkyl, straight- or branched-chain optionally substituted C1-6 alkoxycarbonyl, straight- or branched-chain optionally substituted C1-6 hydroxyalkoxy, straight- or branched-chain optionally substituted C1-6hydroxyalkyl, straight- or branched-chain optionally substituted C1-6alkylthio, straight- or branched-chain optionally substituted -O-C2-6 alkenyl, straight- or branched-chain optionally substituted -O-C2-6 alkynyl, straight- or branched-chain optionally substituted C3.6 alkenylalkoxy, straight- or branched-chain optionally substituted C1-6alkyloxyimino, straight- or branched-chain optionally substituted C1-6alkyloxyamino, optionally substituted -O-CH2-C5.6 aryl, -C(O)NR10Ru, -CR10RnR12, -OC(0)R10, straight- or branched-chain optionally substituted -(0)(CH2)sNRnR12, straight- or branched-chain optionally substituted -(CH2)sNRnR12, straight- or branched-chain optionally substituted -OC(0)0(CH2)sCH3, straight- or branched-chain optionally
185

substituted -S-C1-6-alkyl, straight- or branched-chain optionally substituted -S-C2-6-alkenyl, and straight- or branched-chain optionally substituted -S-C2-6-alkynyl, each of which may be optionally substituted with one or more substituents Rx;
each R1 is separately selected from the group consisting of hydrogen, straight- or branched-chain C1.6 alkyl, straight- or branched-chain C2-6 alkenyl, straight- or branched-chain C2-6 alkynyl, straight- or branched-chain C2-6 heteroalkyl, straight- or branched-chain C2.6 aminoalkyl, straight- or branched-chain C2-6 haloalkyl, straight- or branched-chain C1-6 alkoxycarbonyl, straight- or branched-chain C2-6 hydroxyalkyl, C3.8 cycloalkyl, -C(0)-C5-6 aryl substituted with C1.3 alkyl or halo, C5.6 aryl, C5.6 heteroaryl, C5.6 cycloalkyl, C5.6 heterocycloalkyl, -C(0)NRnR12, -CRnR12R13, and straight- or branched-chain -(CH2)SNRUR12;
each s is separately selected to be an integer from 1 to 8;

each R and each R is separately selected from the group consisting of hydrogen, straight- or branched-chain C1-6 alkyl, C3.6 cycloalkyl, and C5.6 heteroaryl, or each R11 and R12 together form a C3-8 cycloalkyl or C3.8 heterocycloalkyl;
R is selected from the group consisting of hydrogen, halogen, straight- or branched-chain C1-6 alkyl, formyl, and C3.6 cycloalkyl;
each Rx is separately selected from the group consisting of hydrogen, halogen, hydroxy, straight- or branched-chain optionally substituted C1-6 alkyl, straight- or branched-chain optionally substituted C1-6 alkoxy, optionally substituted C3-8 cycloalkyl, optionally substituted C3-8 heterocyclyl, and straight-or branched-chain optionally substituted C1.6 alkylidene;
R2 and R3 are separately selected from the group consisting of hydrogen, optionally substituted C1.6 alkyl, optionally substituted O-C1-6 alkyl, halogen, hydroxy or selected such that R2 and R3 are covalently linked together to form a ring system;
each R4 and each R5 are separately selected from the group consisting of hydrogen, halogen, hydroxy, optionally substituted C1-6-alkyl, optionally substituted O-C1-6 alkyl, optionally substituted aryl-C1-6 alkyl, and optionally substituted arylheteroalkyl;
186

L1 and L2 are biradicals separately selected from the group consisting of -C(R6)=C(R7), -C(R6)=N-, -N=C(R6)-, -S-, -NH- and -0-; wherein only one of L1 and L2 may be selected from the group consisting of-S-, -NH- and -0-;
Y is selected from the group consisting of O, S, and H2; and
X is a biradical selected from the group consisting of -C(R )(R )-C(R6)(R7)-, -C(R6)=C(R7)-, -O- C(R6)(R7)-, C(R6)(R7)-0-, -S-C(R6)(R7)-, -C(R6)(R7)-S-, -N(RN)-C(R6)(R7)-, -C(R6)(R7)-N(RN)-, -C(R6)(R7)-C(R6)(R7)-C(R6)(R7)-, -0-C(R6)(R7)-C(R6)(R7)-, S-C(R6)(R7)-C(R6)(R7)-, N(RN)-C(R6)(R7)-C(R6)(R7)-, -C(R6)(R7)-C(R6)(R7)-0, -C(R6)(R7)-C(R6)(R7)-S, -C(R6)(R7)-C(R6)(R7)-N(RN)-, -C(R6)(R7)- C(R6)=C(R7)~,and - C(R6)=C(R7)-C(R6)(R7),wherein R6 and R7 are separately selected from the group consisting of hydrogen, halogen, hydroxy, nitro, cyano, NRNRN, N(RN)-C(0) N(RN), optionally substituted Ci^-alkyl, C2-6-alkenyl, C2-6-alkynyl, optionally substituted O-C1-6-alkyl, optionally substituted O-aryl, optionally substituted 0-C2-6-alkenyl, optionally substituted 0-C2-6-alkynyl,
wherein RN is selected from the group consisting of hydrogen, and optionally substituted C1-6-alkyl.
2. The compound of Claim 1, wherein:
at least one of Ri or R9 is selected from the group consisting of hydroxy, straight- or branched-chain optionally substituted C1-6 alkoxy, straight- or branched-chain optionally substituted C1-6 alkyl, straight- or branched-chain optionally substituted C2-6 alkenyl, straight- or branched-chain optionally substituted C3.6 alkenylalkoxy, straight- or branched-chain optionally substituted C1-6 alkyloxyimino, and straight- or branched-chain optionally substituted -OC(0)0(CH2)sCH3; and
Rx is selected from the group consisting of halogen, optionally substituted C3-8 cycloalkyl, optionally substituted straight- or branched-chain C1.6 alkyl, optionally substituted C1-6 alkoxy and optionally substituted straight- or branched-chain C2.6 alkenyl
3. The compound of Claim 2, wherein:
the at least one of R1 or R9 is selected from the group consisting of hydroxyl methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy,
187

ethenylmethoxy, ethenylethoxy, ethenylpropoxy, iminobutoxy, iminomethoxy, iminoethoxy, iminopropoxy, iminobutoxy; and -OC(0)0(CH2)2CH3; and
Rx is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halogen, and ethenyl.
4. The compound of Claim 1, wherein:
X is selected from the group consisting of-CH2O- and -CH2CH2-; L1 and L2 is -C(R6)=C(R7)-; and
each R6 and each R7 are separately selected from the group consisting of H, halogen, methyl, and methoxy.
5. The compound according to claim 1, wherein R2, R3, R9, m, and C3-C4 are
selected such that


selected from the group consisting of


wherein R8 is present 0,1, or 2 times and is independently selected from the group consisting of optionally substituted C1-6 alkyl, optionally substituted O-C1-6 alkyl, halogen, hydroxy.
6. The compound according to claim 1, wherein C3-C4, m, R2, R3, and R9 are
hydrogen or selected such that R and R together form a ring system such that


selected from the group consisting of
188


7. The compound according to claim 1, wherein R2 and R3 are separately selected from the group consisting of hydrogen, optionally substituted C1-6 alkyl, optionally substituted O-C4.6 alkyl, halogen and hydroxy.
8. The compound according to claim 1, wherein m is 1.
9. The compound according to claim 1, wherein m is 0, C3 is absent, and C4 is CH such that



10. The compound according to claim 1 wherein X is selected from the group consisting of -C(R6)(R7)-C(R6)(R7)-, -C(R6)=C(R7)-, -0-C(R6)(R7)-, -C(R6)(R7)-0-, -S-C(R6)(R7)-, -C(R6)(R7)-S-, -N(RN)-C(R6)(R7)-, -C(R6)(R7)-N(RN)-.
11. The compound according to claim 1 wherein Y is selected from the group consisting of O and H2.
12. The compound according to claim 1 wherein L1 and L2 are independently selected from the group consisting of-C(R6)=C(R7)-, -C(R6)=N-, and -N=C(R7)-.
13. The compound according to claim 1, wherein R1 is selected from the group consisting of:
189






14. The compound according to claim 13 selected from the group consisting
190



Y>








Ov ,



15. The compound according to Claim 1, wherein the compound is












16. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt, ester, or prodrug thereof.
17. A method of treating a disease in a mammal, wherein modulation of the activity of a cholinergic receptor is associated with a physiologically beneficial response in said disease of said mammal,
said method comprising administering an effective amount of a compound according to claim 1.
18. The method according to claim 17, wherein the cholinergic receptor is a
muscarinic receptor.
192

19. The method according to claim 17, wherein the cholinergic receptor is selected from the group consisting of a muscarinic Mi-receptor subtype and a muscarinic M4-receptor subtype.
20. The method according to claim 17, wherein the physiologically beneficial response is associated with the selective modulation of the muscarinic Mi-receptor subtype in relation to the muscarinic M2- or M3-receptor subtypes.
21. The method according to claim 17, wherein the compound is a muscarinic agonist.
22. A method of increasing an activity of a cholinergic receptor comprising contacting the cholinergic receptor or a system containing the cholinergic receptor with an effective amount of at least one compound according to claim 1.
23. A method of treating or preventing or alleviating the symptoms associated with a disorder in a mammal, comprising the administration of an effective amount of at least one compound according to claim 1, said disorder associated with a muscarinic receptor, such as Mi muscarinic receptor subtype.
24. The method of claim 23, wherein the disorder is selected from the group consisting of cognitive impairment, forgetfulness, confusion, memory loss, attentional deficits, deficits in visual perception, depression, pain, sleep disorders, psychosis, increased intraocular pressure, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, schizophrenia, Huntington's chorea, Friederich 's ataxia, Gilles de la Tourette's Syndrome, Downs Syndrome, Pick disease, dementia, clinical depression, age-related cognitive decline, attention-deficit disorder, sudden infant death syndrome, and glaucoma.
25. The method according to claim 23, wherein the disease or disorder is a mental disorder and the physiologically beneficial response is due to modulation in terms of Mi agonism; Mi and M4 agonism; both Mi agonism and D2 antagonism; or Mi and M4 agonism and D2 antagonism.
Dated 29th day of June 2007
193

Abstract of the Disclosure
The present invention relates to tetrahydroquinoline compounds as muscarinic receptor agonists; compositions comprising the same; methods of inhibiting an activity of a muscarinic receptor with said compounds; methods of treating a disease condition associated with a muscarinic receptor using said compounds; and methods for identifying a subject suitable for treatment using said compounds.

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Patent Number 253681
Indian Patent Application Number 1046/MUMNP/2007
PG Journal Number 33/2012
Publication Date 17-Aug-2012
Grant Date 13-Aug-2012
Date of Filing 12-Jul-2007
Name of Patentee ACADIA PHARMACEUTICALS INC
Applicant Address 3911 SORRENTO VALLEY BLVD., SAN DIEGO, CALIFORNIA 92121-1402
Inventors:
# Inventor's Name Inventor's Address
1 SKJAERBAEK NIELS FAGERPARKEN 33, DK-2950 VEDBAEK
2 KOCH KRISTIAN NORUP BORTHIGSGADE 11, DK-2100 COPENHAGEN
3 FRIBERG BO LENNART MIKOLAIGATAN 24, S-21421 MALMO
4 TOLF BO-RAGNAR RINGSTEDGADE 2, DK-2100 COPENHAGEN
PCT International Classification Number C07D413/06
PCT International Application Number PCT/US2005/045313
PCT International Filing date 2005-12-15
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 11/019556 2004-12-21 U.S.A.