GB2558975A

GB2558975A - New compounds

Info

Publication number: GB2558975A
Application number: GB1714049.2A
Authority: GB
Inventors: Micheli Fabrizio; Bertani Barbara; Richard Gibson Karl; Di Fabio Romano; Raveglia Luca; Zanaletti Riccardo; Cremonesi Susanna; Pozzan Alfonso; Semeraro Teresa; Tarsi Luca; Luker Tim
Original assignee: Chronos Therapeutics Ltd
Current assignee: Chronos Therapeutics Ltd
Priority date: 2017-09-01
Filing date: 2017-09-01
Publication date: 2018-07-25
Anticipated expiration: 2037-09-01
Also published as: GB2558975B; GB201714049D0

Abstract

A compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof; Wherein L1 represents a bond or [CR5R6]-; L2 represents a bond or C(=O)-; L3 represents CH2- or CH2CH2-; X represents O, N(Rx), CH2 or S; A and B each independently represent an aryl, heteroaryl, cycloalkyl, heterocycloalkyl group, each of which is optionally substituted with one or more Q1 or Q2 groups respectively; R1 and R2 independently represent H, halogen, OR7, NR8R9; or optionally substituted as herein defined C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl or C5-12 cycloalkyl; or R1 and R2 together with the carbon atom to which they are attached form C=O, C=C(R10)r11 or an optionally substituted as herein defined cycloalkyl group; wherein Q1, Q2 and R3-11 are as herein defined. L2 is preferably carbonyl. Compositions comprising the disclosed compounds, along with uses of and methods of treatment comprising the compounds and compositions thereof for treating diseases via anatagonism of orexin-1 or orexin-2 receptors are also disclosed. Methods of preparing the disclosed compounds are also provided. The compounds are disclosed to have use in treating substance dependence, addiction; anxiety, panic, compulsive or impulse control disorders; cognitive impairment and Alzheimers disease, particularly binge eating or alcohol, nicotine and/or cocaine addiction.

Description

(71) Applicant(s):

Chronos Therapeutics Limited

CIO Mercer Lewin, 41 Cornmarket Street, Oxford.

OX1 3HA, United Kingdom (72) Inventor(s):

Fabrizio Micheli Barbara Bertani Karl Richard Gibson Romano Di Fabio Luca Raveglia Riccardo Zanaletti Susanna Cremonesi Alfonso Pozzan Teresa Semeraro Luca Tarsi Tim Luker (56) Documents Cited:

WO 2016/040789 A1 WO 2014/165070 A1 WO 2013/139730 A1 WO 2013/119639 A1 WO 2012/089607 A1 WO 2012/089606 A1 WO 2011/006960 A1 WO 2010/122151 A1 WO 2009/104155 A1 (58) Field of Search:

INT CL A61P, C07D

Other: WPI, EPODOC, CAS ONLINE, MARPAT (74) Agent and/or Address for Service:

Potter Clarkson LLP

The Belgrave Centre, Talbot Street, NOTTINGHAM, NG1 5GG, United Kingdom (54) Title of the Invention: New compounds

Abstract Title: Substituted 2-azabicyclo[3.1.1]heptanes and 2-axabicyclo[3.2.1]octanes as orexin receptor antagonists (57) A compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof;

Wherein L¹ represents a bond or -[CR⁵R⁶]-; L² represents a bond or -C(=O)-; L³ represents -CH2- or -CH2CH2-; X represents O, N(R^X), CH2 or S; Aand B each independently represent an aryl, heteroaryl, cycloalkyl, heterocycloalkyl group, each of which is optionally substituted with one or more Q¹ or Q² groups respectively; R¹and R² independently represent H, halogen, OR⁷, NR⁸R⁹; or optionally substituted as herein defined Ci_i₂ alkyl, C₂.,₂alkenyl, C₂_i₂ alkynyl or C₅_i₂ cycloalkyl; or R¹ and R² together with the carbon atom to which they are attached form

11 12 3-11

C=O, C=C(R )r or an optionally substituted as herein defined cycloalkyl group; wherein Q , Q and R are as herein defined. L² is preferably carbonyl. Compositions comprising the disclosed compounds, along with uses of and methods of treatment comprising the compounds and compositions thereof for treating diseases via anatagonism of orexin-1 or orexin-2 receptors are also disclosed. Methods of preparing the disclosed compounds are also provided. The compounds are disclosed to have use in treating substance dependence, addiction; anxiety, panic, compulsive or impulse control disorders; cognitive impairment and Alzheimer's disease, particularly binge eating or alcohol, nicotine and/or cocaine addiction.

NEW COMPOUNDS

Field of the Invention

This invention relates to novel pharmaceutically-useful compounds, which compounds are useful as antagonists of the orexin-1 and orexin-2 receptors or as selective antagonists of the orexin-1 receptor. The compounds are of potential utility in the treatment of addictive diseases, such as binge eating, and behavioural disorders, such as obsessive-compulsive disorders and impulse control disorder. The invention also relates to the use of such compounds as medicaments, to pharmaceutical compositions containing them, and to synthetic routes for their production.

Background of the Invention

There are a number of addictive behaviours that represent a significant unmet medical need requiring novel treatments. These include binge eating, alcohol use disorder and nicotine addiction.

Binge eating is an eating disorder where a person feels compelled to overeat on a regular basis through regular “binges” or consumption of very large quantities of food over a very short period of time, even when they are not hungry. The condition tends to develop first in young adults, although many people do not seek help until they are in their 30s or 40s. There is a 1 in 30 to 1 in 50 chance of a person developing binge eating disorder at some point during their life and it can lead to a variety of health problems that can, in extreme circumstances, be life-threatening. Whilst more women suffer from the condition than men, binge eating is not particularly uncommon in men with the prevalence ratio of approximately 1.5 women for every man with the disorder.

Binge eating disorder (BED), one of three formal eating-disorder diagnoses in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5, 2013), is defined by recurrent binge eating (i.e., eating unusually large quantities of food accompanied by subjective feelings of loss of control), marked distress about the binge eating, and the absence of inappropriate weight compensatory behaviours (e.g., purging, laxative misuse, excessive exercise, or extreme restraint) that characterize bulimia nervosa. BED is a common clinical problem, with an estimated lifetime prevalence rate of roughly 2.8% in adults, and common in both sexes and across minority groups. BED is associated strongly with obesity and is associated with elevated rates of medical and psychiatric co-morbidity. BED is frequently associated with increased depressive and body-image psychopathology and with psychosocial impairment. BED shares many features with, but is distinct from, the other eating disorders and obesity.

Since BED was first introduced as a research category in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), the treatment literature has grown considerably for this eating disorder. BED represents a clinical challenge and effective treatments need to address binge eating, weight loss, and associated eatingdisorder (e.g., body image concerns) and depressive psychopathology.

In the USA, clinicians treat approximately 80% of both their adolescent and adult BED patients with pharmacotherapy (based on physician recall of their past 6 months’ caseload). The remaining patients received only behavioural therapy. Although Vyvanse is considered ‘a big step forward’, there is still a desire for new treatments mainly driven by side-effect profile being the ‘big issue’ with Vyvanse (currently, the only drug treatment that has been recently approved by the regulatory agencies for managing BED - a stimulant pro-drug). Individuals seeking treatment may also have co-morbid mood and/or anxiety disorder, or substance abuse disorder which preclude the use of Vyvanse.

Nicotine and alcohol addiction involves repeated use of a psychoactive substance (nicotine or alcohol) causing a user to be intoxicated with a compulsion to take the preferred substance and often a determination to obtain the substance by almost any means. Addicts also have difficulty in modifying or stopping substance use. They build up tolerance to the addictive substance, sometimes requiring more and more for the same effect and develop withdrawal syndromes when use is interrupted.

Tobacco smoking results in greater than 5 million deaths each year. Even when using the most clinically efficacious smoking cessation agents available, approximately 80% of smokers attempting to quit will relapse within one year, highlighting the need to develop safe yet more clinically effective smoking cessation agents

Addiction to nicotine via tobacco kills one person prematurely every six seconds and 50% of long-term smokers according to World Health Organisation (WHO) reports, with tobacco attributed deaths predicted to rise to 8 million globally a year by 2030. The US Centers for Disease Control and Prevention (CDC) also note that about 480,000 Americans die every year from smoking related causes involving cancers (chiefly lung cancer), stroke, heart disease and chronic obstructive pulmonary disease (COPD).

Excessive alcohol use (as caused by addiction or binging) has caused 10% of deaths among working-age adults aged 20-64 years in the USA with economic costs in 2010 in the USA alone of $249 billion. WHO also estimates that harmful alcohol use causes 3.3 million deaths a year, globally. Short-term health risks, most often the result of binge drinking, include accidents, injuries, alcohol poisoning and risky sexual behaviours. Over a longer time, excessive alcohol use can lead to chronic diseases including high blood pressure, cancers, mental health and social problems.

Dependence on illicit drugs accounted for 3.6 million years of life lost through premature death globally in 2010, as well as 16.4 million years of life lived with disability, mainly caused by cardiovascular and liver disease, infection with HIV, hepatitis B and C and a range of other conditions. Of the estimated 183,100 reported deaths from drug abuse related causes in 2012, 44,600 were in North America, where the drug related mortality rate was estimated to be 142 per million aged 15-64 (UNODC World Drug Report 2014 (available at unodc.org)). Data from 2012 estimate there to be 297 million drug abusers worldwide, of whom 17.24 million abuse cocaine. Currently there are no FDA approved drugs for the treatment of cocaine addiction and dependence, and the development of efficacious, safe therapies is a societal priority.

The orexin system has been demonstrated to play a key role in substance seeking and craving. When conditioned animals received cues for cocaine, morphine or food, orexigenic neurons in the lateral hypothalamus are activated; in addition, when the reward seeking behaviour is extinguished, it can be reinstated by administration of an orexin agonist, and blocked by a selective orexin 1 receptor (OX1R) antagonist tool compound.

The orexin neuropeptides (OxA and OxB) are 33- and 28-amino acid peptides, respectively, produced by proteolysis of a common precursor, prepro-orexin. Production takes place in neurons of the hypothalamus which project to areas of the brain involved in sleep-wake state, regulation of food intake, panic, anxiety, emotion, reward and addictive behaviours. The role in reward, feeding behaviour and anxiety is attributed to the orexin 1 receptor subtype, while the role in sleep has been attributed to the orexin 2 receptor (OX2R). The orexin 1 receptors are found in the brain, the enteric nervous system and the gut.

There has been extensive preclinical validation of this mechanism of action in animal models of addictive disorders using first generation 0X1R antagonists.

Several 0X1R antagonists have been tested in preclinical models relevant to BED such as unpredictable, intermittent access to highly palatable food (with or without stress), whereby animals are trained to binge eat. Selective 0X1R antagonists have been shown to be highly efficacious in reducing binge behaviour.

Selective 0X1R antagonists have also been shown to be highly efficacious in animal models of alcohol dependence and binge drinking. In a model of voluntary ethanol intake mice treated with a selective 0X1R antagonist showed a significantly reduced ethanol consumption which decreased in a dose dependent manner, (Lopez M. F. et al., Brain Res., 2016 April 1, 1636, 74-80). In another publication utilising the drinking in the dark paradigm, which models binge-like drinking, central infusion of an 0X1R antagonist blunted the early stages of binge drinking (Olney J. J., et al., Alcohol Clin. Exp. Res., 2017, 41(3):551-561; Olney J. J., et al., Alcohol Clin. Exp. Res., 2015; 39(1):21-29).

In smoking cessation efficacy has been demonstrated in rodent models of nicotine seeking behaviour whereby 0X1R antagonists were shown to block stress induced reinstatement as well as nicotine induced anxiety response (Plaza-Zabala A., et al., Neuropsychopharmacology, 2013, 38, 1724-1736). In a separate study it was shown that 0X1R antagonism blocked nicotine related reward as measured by reversal of nicotineinduced lowering of intracranial self-stimulation thresholds (Hollander J. A., et al., PNAS, 2008, 105(49), 19480-19485).

Supporting the likely utility of 0X1R antagonism as a likely therapeutic for broad addictive disorders orexigenic signalling via the 0X1 receptor has been implicated in several other addictive disorders and 0X1R antagonists have demonstrated efficacy in several animal models of addiction including cocaine, heroin and amphetamine (Smith and Aston-Jones, Eur. J. Neurosci., 2012; 35(5):798-804; Hutcheson D. M., et al., Behavioural Pharmacology, 2011, 22(2), 173-181; Smith R. et al., Eur. J. Neurosci., 2009; 30(3):493-503).

The involvement of orexins in the modulation of fear has been demonstrated in rodent models. Mice lacking 0X1R showed impaired freezing responses and reduced expression of zif268 (an I EG (immediate-early gene) that is considered a marker of neuronal activation) in the lateral amygdala in both cued and contextual fear-conditioning paradigms. The dual orexin antagonist almorexant has been shown to reduce fearpotentiated startle responses in rats. (Flores A. et al., Trends in Neurosciences, September 2015, Vo. 38, No. 9, 550-559). Orexins also modulate the extinction of acquired aversive memory. For example, OX1R blockade with a centrally active 0X1R antagonist SB334867 facilitated the consolidation of fear extinction in both contextual and cued tests, while orexin A infusion impaired this response.

The role of orexin in panic disorder has also been confirmed. Panic-prone rats that were systematically pre-treated with SB334867 showed attenuated anxiety-like behaviour, locomotor and cardioexcitatory responses induced by the lactate challenge. SB408124 (another 0X1R antagonist) also attenuated the sodium lactate-induced increases in locomotor activity and tachycardia responses in another group of panic-prone rats when compared to vehicle (Johnson P. L., et al., Progress in Brain Research, Vol. 198, Chapter 9, A. Shekhar Ed.).

While no proof of concept has been achieved with 0X1R antagonists in the clinic, several dual orexin receptor antagonist (DORA) compounds (generally equipotent at 0X1R and OX2R) have been extensively tested in large scale clinical trials. The only adverse events reported (sleep and dependence related) are attributable to OX2R antagonism. This emphasises the need for a selective 0X1R antagonist and also indicates that such a compound would be safe and well tolerated.

With the elucidation of distinct roles for 0X1R and 0X2R, 0X1R antagonists have received a great deal of attention for the treatment of addictive and anxiety related disorders. 0X1R antagonists are believed to be particularly useful in treating addictive disorders, specifically binge eating disorder (BED), alcohol use disorder (AUD) and smoking due to the fact that reward stimuli are known to trigger dopamine release and orexins enhance this signalling while 0X1R antagonism normalises it (Narita M. et al., J. Neurosci., 2006, 26(2): 398-405).

Confirming the specificity of this response as an 0X1R driven effect, 0X2R antagonists were not efficacious in preclinical models relevant to BED and dual orexin receptor antagonists (DORAs), while having efficacy, were burdened by sedative effects like the 0X2R antagonists (Piccoli L., et al., Neuropsychopharmacology, 2012, 37, 1999-2011; Vickers S. P. et al., J. Psychopharmacology, 2015, 29(12):1290-1307).

0X1R antagonists have also been shown to block binge eating without affecting normal food consumption. This is a potential highly differentiating factor for 0X1R antagonists in BED as other potential mechanisms such as opioid antagonists are likely to cause anhedonia and stimulants are likely to affect appetite and result in sleep disturbance.

We have identified a number of 0X1R antagonists, many of which are highly selective for 0X1R over other targets and have favourable drug like qualities.

The listing or discussion of an apparently prior-published document in this specification 10 should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.

Disclosure of the Invention

According to the invention, there is provided a compound of formula I,

wherein:

L¹ represents a direct bond or -[CR⁵R⁶]-;

X represents a direct bond, -0-, -N(R^X)-, -CH2- or -S-;

A represents an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, each of which is optionally substituted with one or more Q¹ groups;

L² represents a direct bond or -C(=0)-;

B represents an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, each of which is optionally substituted with one or more Q² groups;

L³ represents -CH2- or -CH2CH2-;

R¹ and R² independently represent hydrogen, halogen, -OR⁷, -NR⁸R⁹, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl or C3-12 cycloalkyl (which latter four groups are optionally substituted by one or more E¹ substituents); or R¹ and R² together with the carbon atom to which they are bound form C=O, C=C(R¹⁰)R¹¹ or a C3-6 cycloalkyl group optionally substituted by one or more E² substituents;

R³, R⁴, R⁵ and R⁶ independently represent hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl or C3-6 cycloalkyl (which latter four groups are optionally substituted by one or more E³ substituents); or any relevant pair of R³, R⁴, R⁵ and R⁶ form, together with the carbon atom to which they are bound, C=O or a C3-6 cycloalkyl group optionally substituted by one or more E⁴ substituents;

R⁷, R⁸, R⁹, R¹⁰ and R¹¹ independently represent hydrogen or a C1-6 alkyl group optionally substituted by one or more halo atoms;

R^x represents hydrogen, C1-6 alkyl, or C3-6 cycloalkyl (which latter two groups are optionally substituted by one or more halo atoms);

Q¹ and Q² independently represent halogen, -CN, -NHCOR¹², C1-6 alkyl, C3-6 cycloalkyl, -O-C1-6 alkyl, aryl or heteroaryl (which latter five groups are optionally substituted by one or more substituents selected from halogen, methyl and halomethyl (e.g. trifluoromethyl));

E¹, E², E³ and E⁴ independently represent halogen or a C1-6 alkyl group optionally substituted by one or more halo atoms;

R¹² represents C1-6 alkyl or phenyl;

or a pharmaceutically acceptable salt, solvate or prodrug thereof;

which compounds, salts, solvates and prodrugs are referred to hereinafter as “the compounds of the invention”.

Pharmaceutically-acceptable salts include acid addition salts and base addition salts. Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.

By “pharmaceutically acceptable salt, solvate or prodrug thereof”, we include solvates of such salts.

For the purposes of this invention, prodrugs of compounds of the invention are also included within the scope of the invention. Prodrugs may include, for example, pharmaceutically acceptable esters and amides of the compounds of the invention (as well as salt or solvates of those pharmaceutically acceptable esters and amides). Pharmaceutically acceptable esters and amides of compounds of formula I may have an appropriate group, for example an acid group, an alcohol group or an amine group, converted to the appropriate ester or amide. For example, pharmaceutically acceptable esters (of carboxylic acids or alcohols) that may be mentioned include optionally substituted C1-6 alkyl, C5-10 aryl and/or C5-10 aryl-Ci-6 alkyl- esters. Pharmaceutically acceptable amides (of carboxylic acids or amines) that may be mentioned include those of the formula -C(O)N(R^z1)R^z2 or -N(R^z3)C(O)R^z4, in which R^z1, R²², R^z3 and R^z4independently represent optionally substituted C1-6 alkyl, C5-10 aryl, or C5-10 aryl-Ci-6 alkylene-. Preferably, C1-6 alkyl groups that may be mentioned in the context of such pharmaceutically acceptable esters and amides are not cyclic, e.g. linear and/or branched.

Further prodrug compounds of the invention that may be mentioned include carbamate, carboxamido or ureido derivatives, e.g. such derivatives of existing amino functional groups.

More broadly, the term “prodrug” of a relevant compound of the invention includes any compound that, following oral or parenteral administration, is metabolised in vivo to form that compound in an experimentally-detectable amount, and within a predetermined time (e.g. within a dosing interval of between 6 and 24 hours (i.e. once to four times daily)).

For the avoidance of doubt, the term “parenteral” administration includes all forms of administration other than oral administration.

Prodrugs of compounds of the invention may be prepared by modifying functional groups present on the compound in such a way that the modifications are cleaved, in vivo when such prodrug is administered to a mammalian subject. The modifications typically are achieved by synthesising the parent compound with a prodrug substituent. Prodrugs include compounds of the invention wherein a hydroxyl, amino, sulfhydryl, carboxy or carbonyl group in a compound of the invention is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, sulfhydryl, carboxy or carbonyl group, respectively.

Examples of prodrugs include, but are not limited to, esters and carbamates of hydroxy functional groups, esters groups of carboxyl functional groups, N-acyl derivatives and NMannich bases. General information on prodrugs may be found e.g. in Bundegaard, H. “Design of Prodrugs” p. I-92, Elesevier, New York-Oxford (1985).

Compounds of the invention may contain double bonds and may thus exist as E (entgegeri) and Z (zusammeri) geometric isomers about each individual double bond. Positional isomers may also be embraced by the compounds of the invention. All such isomers (e.g. if a compound of the invention incorporates a double bond or a fused ring, the cis- and trans- forms, are embraced) and mixtures thereof are included within the scope of the invention (e.g. single positional isomers and mixtures of positional isomers may be included within the scope of the invention).

Compounds of the invention may also exhibit tautomerism. All tautomeric forms (or tautomers) and mixtures thereof are included within the scope of the invention. The term tautomer or tautomeric form refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerisations. Valence tautomers include interconversions by reorganisation of some of the bonding electrons.

Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism. Diastereoisomers may be separated using conventional techniques, e.g. chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e. a ‘chiral pool’ method), by reaction of the appropriate starting material with a ‘chiral auxiliary’ which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as chromatography, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person.

All stereoisomers (including but not limited to diastereoisomers, enantiomers and atropisomers) and mixtures thereof (e.g. racemic mixtures) are included within the scope of the invention.

In the structures shown herein, where the stereochemistry of any particular chiral atom is not specified, then all stereoisomers are contemplated and included as the compounds of the invention. Where stereochemistry is specified by a solid wedge or dashed line representing a particular configuration, then that stereoisomer is so specified and defined.

The compounds of the present invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.

The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature (or the most abundant one found in nature). All isotopes of any particular atom or element as specified herein are contemplated within the scope of the compounds of the invention. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶CI, ¹²³l, and ¹²⁵l. Certain isotopically-labelled compounds of the present invention (e.g., those labelled with ³H and ¹⁴C) are useful in compound and for substrate tissue distribution assays. Tritiated (³H) and carbon-14 (¹⁴C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., ²H may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances. Positron emitting isotopes such as ¹⁵O, ¹³N, ¹¹C and ¹⁸F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Isotopically labelled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the Examples herein below, by substituting an isotopically labelled reagent for a non-isotopically labelled reagent.

Unless otherwise stated, the terms Ci-_q alkyl, and Ci-_q alkylene, groups (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number of carbon atoms, be branched-chain. Similarly, unless otherwise stated, the terms C₂._q alkenyl, C₂._q alkenylene, C₂._q alkynyl, and C₂._q alkynylene, groups (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number of carbon atoms, be branched-chain.

C3-_q cycloalkyl groups (where q is the upper limit of the range) that may be mentioned may be monocyclic or bicyclic alkyl groups, which cycloalkyl groups may further be bridged (so forming, for example, fused ring systems such as three fused cycloalkyl groups). Such cycloalkyl groups may be saturated or unsaturated containing one or more double or triple bonds (forming for example a cycloalkenyl or cycloalkynyl group). Substituents may be attached at any point on the cycloalkyl group. Further, where there is a sufficient number (i.e. a minimum of four) such cycloalkyl groups may also be part cyclic, e.g. forming an alkyl-cycloalkyl group. For the avoidance of doubt, optional substituents may also be other cyclic groups, which may be attached via a single carbon atom common to both rings, so forming a spiro-cycle.

The term “halo”, when used herein, includes fluoro, chloro, bromo and iodo.

Heterocycloalkyl groups that may be mentioned include non-aromatic monocyclic and bicyclic heterocycloalkyl groups in which at least one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom), and in which the total number of atoms in the ring system is from five to ten. Such heterocycloalkyl groups may also be bridged. Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C₂._qheterocycloalkenyl (where q is the upper limit of the range) or a C7-_q heterocycloalkynyl group. C₂._q heterocycloalkyl groups that may be mentioned include 7azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.2.1]-octanyl, 811 azabicyclo-[3.2.1]octanyl, aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyl and 1,4-dioxanyl), dithianyl (including 1,4-dithianyl), dithiolanyl (including 1,3-dithiolanyl), imidazolidinyl, imidazolinyl, morpholinyl, 7-oxabicyclo[2.2.1]heptanyl, 6-oxabicyclo-[3.2.1]octanyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sulfolenyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridyl (such as

1.2.3.4- tetrahydropyridyl and 1,2,3,6-tetrahydropyridyl), thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including 1,3,5-trithianyl), tropanyl and the like. Substituents on heterocycloalkyl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heterocycloalkyl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heterocycloalkyl groups may also be in the N- or S- oxidised form (i.e. those heteroatoms may be substituted with one or two =0 substituents, as appropriate). As stated herein other carbon atoms of the heterocycloalkyl groups mentioned herein may also be substituted by one or more =0 substituents. For the avoidance of doubt, optional substituents may also be other cyclic groups, which may be attached via a single carbon atom common to both rings (so forming a spiro-cycle).

For the avoidance of doubt, the term “bicyclic” (e.g. when employed in the context of heterocycloalkyl groups) refers to groups in which the second ring of a two-ring system is formed between two adjacent atoms of the first ring. The term “bridged” (e.g. when employed in the context of cycloalkyl or heterocycloalkyl groups) refers to monocyclic or bicyclic groups in which two non-adjacent atoms are linked by either an alkylene or heteroalkylene chain (as appropriate).

Aryl groups that may be mentioned include Ce-io aryl groups. Such groups may be monocyclic or bicyclic and have between 6 and 10 ring carbon atoms, in which at least one ring is aromatic. Ce-ιο aryl groups include phenyl, naphthyl and the like, such as

1.2.3.4- tetrahydronaphthyl. The point of attachment of aryl groups may be via any atom of the ring system. However, when aryl groups are bicyclic, they are linked to the rest of the molecule via an aromatic ring. For the avoidance of doubt, optional substituents include those defined herein and also include =0 substituents that may be attached to any non-aromatic rings of a polycyclic (e.g. bicyclic) aryl group (however, in an embodiment, =0 substituents are not included). For the avoidance of doubt, optional substituents may also be other cyclic groups, which may be, when attached to a non12 aromatic ring of an aryl group, attached via a single carbon atom common to both rings (so forming a spiro-cycle).

benzimidazolyl,

1,3-benzodioxolyl), benzodioxolyl benzothiadiazolyl (including (including (including

Unless otherwise specified, the term “heteroaryl” when used herein refers to an aromatic group containing one or more heteroatom(s) (e.g. one to four heteroatoms) preferably selected from N, O and S. Heteroaryl groups include those which have from 5 to 10 members and may be monocyclic or bicyclic, provided that at least one of the rings is aromatic (so forming, for example, a mono- or bicyclic heteroaromatic group). However, when heteroaryl groups are bicyclic, they are linked to the rest of the molecule via an aromatic ring. Heteroaryl groups that may be mentioned include acridinyl, benzodioxanyl, benzodioxepinyl, benzofuranyl, benzofurazanyl,

2.1.3- benzothiadiazolyl), benzothiazolyl, benzoxadiazolyl

2.1.3- benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro-2/7-1,4-benzoxazinyl), benzoxazolyl, benzomorpholinyl, benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazo[1,2-a]pyridyl, indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiaziolyl, isothiochromanyl, isoxazolyl, naphthyridinyl (including 1,6-naphthyridinyl or, preferably, 1,5-naphthyridinyl and 1,8-naphthyridinyl), oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl and

1.3.4- oxadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroisoquinolinyl (including

1.2.3.4- tetrahydroisoquinolinyl and 5,6,7,8-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including 1,2,3,4-tetrahydroquinolinyl and 5,6,7,8-tetrahydroquinolinyl), tetrazolyl, thiadiazolyl (including 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl and 1,3,4-thiadiazolyl), thiazolyl, thiochromanyl, thiophenetyl, thienyl, triazolyl (including 1,2,3-triazolyl,

1.2.4- triazolyl and 1,3,4-triazolyl) and the like. Substituents on heteroaryl groups may, where appropriate, be located on any atom in the ring system including a heteroatom. For the avoidance of doubt, optional substituents include those defined herein and also include =0 substituents that may be attached to any non-aromatic rings of a bicyclic heteroaryl group (but, in an embodiment, =0 substituents are not included). The point of attachment of heteroaryl groups may be via any atom in the ring system including (where appropriate) a heteroatom (such as a nitrogen atom), or an atom on any fused carbocyclic ring that may be present as part of the ring system.

In the case where it is specified that the heteroaryl is bicyclic, then it may consist of a five-, six- or seven-membered monocyclic ring (e.g. a monocyclic heteroaryl ring) fused with another a five-, six- or seven-membered ring (e.g. a monocyclic aryl or heteroaryl ring).

Heteroatoms that may be mentioned include phosphorus, silicon, boron and, preferably, oxygen, nitrogen and sulphur.

For the avoidance of doubt, in cases in which the identity of two or more substituents in a compound of the invention may be the same, the actual identities of the respective substituents are not in any way interdependent. For example, in the situation in which there is more than one Q² substituent present, then those Q² substituents may be the same or different. Further, in the case where there are two R⁷ substituents present, in which one R⁷ is present in the context of R¹ and the other is present in the context of R², then those R⁷ groups may or may not be the same.

For the avoidance of doubt, in the instance where cyclic substituents (e.g. cycloalkyl or heterocycloalkyl groups) are present on groups (such as alkyl groups), then those cyclic substituents may be attached to the same carbon atom, so forming for example a spirocyclic group.

All individual features (e.g. preferred features) mentioned herein may be taken in isolation or in combination with any other feature (including preferred feature) mentioned herein (hence, preferred features may be taken in conjunction with other preferred features, or independently of them).

The skilled person will appreciate that compounds of the invention that are the subject of this invention include those that are stable. That is, compounds of the invention include those that are sufficiently robust to survive isolation from e.g. a reaction mixture to a useful degree of purity.

For the avoidance of doubt, when a term such as “E¹ to E⁴” is employed herein, this will be understood by the skilled person to mean E¹, E², E³ and E⁴, inclusively.

Where a phrase such as “any relevant pair of R³, R⁴, R⁵ and R^e is used, this will be understood by the skilled person to refer to any pair of such groups where those groups are bonded to the same atom. Thus, the aforementioned phrase refers to either the pair R³ and R⁴ or the pair R⁵ and R⁶ (or both pairs simultaneously).

In an embodiment of the invention, there is provided compounds of the invention as hereinbefore defined but in which X represents -0-, -N(R^X)- or -CH2- (such as X represents -O- or -N(R^X)-). In these and other embodiments, R^x is preferably H. In another embodiment, there is provided compounds of the invention as hereinbefore defined but in which X does not represents -N(R^X)-, preferably wherein X represents -0-.

Compounds of the invention that may be mentioned include those in which -L¹-Xtogether represent -0-, -N(R^X)-, -CH2- or -[CR⁵R⁶]-O-. In another embodiment, -L¹-Xtogether represent -0-, -N(R^X)- or-[CR⁵R⁶]-O- (e.g. -0-, -NH- or-CH2-O-).

In an embodiment of the invention, R^x represents hydrogen, methyl, ethyl, propyl, or methyl cyclopropyl (e.g. -Cbb-OsHs).

Further compounds of the invention that may be mentioned include those in which L²represents -0(=0)-.

Preferred compounds of the invention that may be mentioned include those in which L³represents -CH₂-.

In one embodiment, R¹ and R² independently represent hydrogen, halogen, -OR⁷, -NR⁸R⁹, C1-6 alkyl, or C3-6 cycloalkyl (which latter two groups are optionally substituted by one or more E¹ substituents); or R¹ and R² together with the carbon atom to which they are bound form C=0.

In another embodiment, R¹ and R² independently represent hydrogen, halogen, -OR⁷ or C1-4 alkyl optionally substituted by one or more halo atoms.

In yet another embodiment, R¹ and R² independently represent hydrogen, methyl or fluoro.

Preferred compounds of the invention that may be mentioned include those in which R³, R⁴, R⁵ and R⁶ (if present) independently represent hydrogen, fluoro, C1-6 alkyl, or C3-6 cycloalkyl (which latter two groups are optionally substituted by one or more E³substituents); or any relevant pair of R³, R⁴, R⁵ and R⁶ form, together with the carbon atom to which they are bound, C=0.

Further preferred compounds include those in which R³, R⁴, R⁵ and R⁶ independently represent hydrogen or a C1-4 alkyl group optionally substituted by one or more halo atoms.

Ina particular embodiment, each R³, R⁴, R⁵ and R⁶ independently represents hydrogen or methyl. Most preferably, R³, R⁴, R⁵ and R⁶ (if present) all represent hydrogen.

The linker between the core bridged ring system and A (i.e. the linker represented by -[CR³R⁴]-L¹-X-) preferably has one of the following structures:

More preferably, the linker represented by -[CR³R⁴]-L¹-X- has one of the following structures:

The most preferred of these linkers is -CH2-O-.

Particularly compounds of the invention that may be mentioned include compounds of formula IA:

wherein R¹, R², L¹, A and B are as defined in respect of the compounds of formula I, and X represents -S-, -CH2- or preferably -0-, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

Compounds of the invention that may be mentioned include those in which R⁷ to R¹¹independently represent hydrogen or methyl.

Other compounds of the invention that may be mentioned include those in which E¹ to E⁴independently represent a C1-6 alkyl group or preferably a halogen.

In one embodiment (e.g. for compounds of formula I or IA), A represents an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group (particularly an aromatic group (i.e. an aryl or heteroaryl group)), each of which is substituted with at least one Q¹ group.

In another embodiment, the heteroaryl and heterocycloalkyl groups represented by A are monocyclic or bicyclic groups each containing one or two heteroatoms selected from O, S and, most preferably, N. Said groups may be optionally substituted with one or more Q¹ groups as indicated above.

In preferred embodiments, A represents an aryl or heteroaryl group, each of which is optionally substituted by one or more Q¹ groups. Particular aryl and heteroaryl groups that may be mentioned in this respect include naphthyl, benzimidazolyl, imidazolyl, pyrimidinyl, thiazolyl, pyrazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyrrolyl, indazolyl, indolyl, isoindolyl, isoxazolyl, pyranyl, thiazolyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl and 1,3,4-triazolyl), and most preferably phenyl, pyridyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl and benzothiazolyl.

In one embodiment (e.g. for compounds of formula I or ΙΑ), B represents a monocyclic group. For example, B may represent phenyl or a monocyclic heteroaryl or heterocycloalkyl group containing one or two heteroatoms selected from O, S and N.

In preferred embodiments, B represents an aryl or heteroaryl group (e.g. a monocyclic aromatic group), each of which is optionally substituted by one or more Q² substituents. Particular aryl and heteroaryl groups that may be mentioned in this respect include naphthyl, benzimidazolyl, imidazolyl, pyrimidinyl, thiazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyrrolyl, quinolinyl, isoquinolinyl, quinoxalinyl, indazolyl, indolyl, isoindolyl, isoxazolyl, pyranyl, quinazolinyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl and 1,3,4-triazolyl), and most preferably phenyl, pyrazolyl, pyridyl and thiazolyl.

In a yet further preferred embodiment (e.g. for compounds of formula I or IA), both A and B are aromatic groups. That is, A and B preferably independently represent an aryl or heteroaryl group, each of which is optionally substituted with one or more Q¹ or Q²groups, as appropriate.

Preferred compounds of the invention include those in which Q¹ represents halogen, -CN, C1-4 alkyl, -O-C1-4 alkyl, aryl or heteroaryl (which latter four groups are optionally substituted by one or more substituents selected from halogen, methyl and halomethyl (e.g. trifluoromethyl)). For example, Q¹ may represent halogen or C1-4 alkyl optionally substituted by one or more halo atoms. In yet further preferred compounds, Q¹represents halogen or a methyl group optionally substituted by one or more halo atoms.

Other preferred compounds of the invention include those in which Q² represents halogen, -CN, C1-4 alkyl, C3-6 cycloalkyl, -O-C1-4 alkyl, aryl or heteroaryl (which latter five groups are optionally substituted by one or more substituents selected from halogen, methyl and halomethyl (e.g. trifluoromethyl)). For example, Q² may represent halogen, C1-4 alkyl, C3-6 cycloalkyl, -O-C1-4 alkyl, phenyl or monocyclic heteroaryl (which latter five groups are optionally substituted by one or more substituents selected from halogen, methyl and halomethyl (e.g. trifluoromethyl)) wherein said monocyclic heteroaryl groups contain from one to three heteroatoms selected N, S and O. In further preferred compounds, Q² represents halogen, methyl, cyclopropyl or methoxy (which latter three groups are optionally substituted by one or more halo atoms), or phenyl, fluorophenyl, pyridinyl, pyrazinyl, pyrazolyl, pyrimidinyl, thiazolyl or triazolyl (which latter eight groups are optionally substituted by one or more substituents selected from halogen, methyl and halomethyl (e.g. trifluoromethyl)).

Preferred compounds of the invention include those in which:

X represents -0-, -N(R^X)- or -CH2-;

L² represents -C(=O)-;

L³ represents -CH2-;

R¹ and R² independently represent hydrogen, halogen, -OR⁷, -NR⁸R⁹, C1-6 alkyl, or C3-6 cycloalkyl (which latter two groups are optionally substituted by one or more E¹substituents); or R¹ and R² together with the carbon atom to which they are bound form C=O;

R³, R⁴, R⁵ and R⁶ (if present) independently represent hydrogen, C1-6 alkyl, or C3-6 cycloalkyl (which latter two groups are optionally substituted by one or more E³substituents); or any relevant pair of R³, R⁴, R⁵ and R⁶ form, together with the carbon atom to which they are bound, C=O;

R⁷ to R¹¹ and R^x (if present) independently represent hydrogen or methyl;

E¹ to E⁴ (if present) independently represent a C1-6 alkyl group or preferably a halogen;

A represents an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group (particularly an aryl or heteroaryl group), each of which is substituted with at least one Q¹ group;

B represents phenyl or a monocyclic heteroaryl or heterocycloalkyl group containing one or two heteroatoms selected from O, S and N, and which cyclic group is optionally substituted with at least one Q² group; and

Q¹ and Q² independently represent halogen, -CN, C1-4 alkyl, C3-6 cycloalkyl, -O-C1-4 alkyl, aryl or heteroaryl (which latter five groups are optionally substituted by one or more substituents selected from halogen, methyl and halomethyl (e.g. trifluoromethyl)).

More preferred compounds include those in which:

L² represents -C(=0)-;

L³ represents -CH2-;

R¹ and R² independently represent hydrogen, halogen, -OR⁷ or C1-4 alkyl optionally 20 substituted by one or more halo atoms;

the linker between the core bridged ring system and A (i.e. the linker represented by -[CR³R⁴]-L¹-X-) has one of the following structures:

R⁷ represents hydrogen or methyl;

A and B each independently represent an aryl or heteroaryl group, each of which is optionally substituted with one or more Q¹ or Q² groups, as appropriate;

Q¹ represents halogen or C1-4 alkyl optionally substituted by one or more halo atoms; and Q² represents halogen, C1-4 alkyl, C3-6 cycloalkyl, -O-C1-4 alkyl, phenyl or monocyclic heteroaryl (which latter five groups are optionally substituted by one or more substituents selected from halogen, methyl and halomethyl (e.g. trifluoromethyl)) further wherein said monocyclic heteroaryl group contain from one to three heteroatoms selected N, S and 0.

Still more preferred compounds include those in which:

L¹ represents a direct bond or CH₂;

L² represents -C(=O)-;

L³ represents -CH₂-;

R¹ and R² independently represent hydrogen, halogen or methyl;

R³ and R⁴ represent hydrogen;

X represents -O- or -NH- (preferably -0-);

A represents a monocyclic or bicyclic aromatic group which is optionally substituted with one or more Q¹ groups;

B represents a monocyclic aromatic group which is optionally substituted with one or more Q² groups;

Q¹ represents halogen or Ci-4 alkyl optionally substituted by one or more halo atoms; and Q² represents halogen, Ci-4 alkyl, C3-6 cycloalkyl, -O-Ci-₄ alkyl, phenyl or monocyclic heteroaryl (which latter two groups are optionally substituted by one or more substituents selected from halogen, methyl and halomethyl (e.g. trifluoromethyl)) further wherein said monocyclic heteroaryl group contain from one to three heteroatoms selected N, S and O.

Particularly preferred compounds of the invention include those of the examples described hereinafter, including:

3-[(4-fluorophenoxy)methyl]-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 ]heptane;

(3R)-3-[(4-fluorophenoxy)methyl]-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 ]heptane;

(3S)-3-[(4-fluorophenoxy)methyl]-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 ]heptane;

3-(4-fluorophenoxymethyl)-2-{[6-methyl-3-(1,3-thiazol-2-yl)pyridin-2-yl]carbonyl}-2azabicyclo[3.1.1 ]heptane;

(3R)-3-(4-fluorophenoxymethyl)-2-{[6-methyl-3-(1,3-thiazol-2-yl)pyridin-2-yl]carbonyl}-2azabicyclo[3.1.1 ]heptane;

(3S)-3-(4-fluorophenoxymethyl)-2-{[6-methyl-3-(1,3-thiazol-2-yl)pyridin-2-yl]carbonyl}-2azabicyclo[3.1.1 ]heptane;

3-(4-fluorophenoxymethyl)-2-{[5-methyl-2-(1,3-thiazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 ]heptane;

(3R)-3-(4-fluorophenoxymethyl)-2-{[5-methyl-2-(1,3-thiazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 ]heptane;

(3S)-3-(4-fluorophenoxymethyl)-2-{[5-methyl-2-(1,3-thiazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 ]heptane;

3-(4-fluorophenoxymethyl)-2-{[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 ]heptane;

(3R)-3-(4-fluorophenoxymethyl)-2-{[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 ]heptane;

(3S)-3-(4-fluorophenoxymethyl)-2-{[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 ]heptane;

3-(4-fluorophenoxymethyl)-2-{[6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl]carbonyl}-2azabicyclo[3.1.1 ]heptane;

(3R)-3-(4-fluorophenoxymethyl)-2-{[6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl]carbonyl}-2azabicyclo[3.1.1 ]heptane;

(3S)-3-(4-fluorophenoxymethyl)-2-{[6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl]carbonyl}-2azabicyclo[3.1.1 ]heptane;

3-(4-fluorophenoxymethyl)-2-{[5-methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 ]heptane;

(3S)-3-(4-fluorophenoxymethyl)-2-{[5-methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 ]heptane;

(3R)-3-(4-fluorophenoxymethyl)-2-{[5-methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 ]heptane;

3-(4-chlorophenoxymethyl)-2-{[5-methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 ]heptane;

3-(4-chlorophenoxymethyl)-2-{[5-methyl-2-(1,3-thiazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 ]heptane;

3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl]carbonyl}2- azabicyclo[3.1.1]heptane;

(3S)-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[6-methyl-3-(pyrimidin-2-yl)pyridin-2yl]carbonyl}-2-azabicyclo[3.1.1]heptane;

(3R)-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[6-methyl-3-(pyrimidin-2-yl)pyridin-2yl]carbonyl}-2-azabicyclo[3.1.1]heptane;

3- {[(5-fluoropyridin-2-yl)oxy]methyl}-2-[(2-methyl-5-phenyl-1,3-thiazol-4-yl)carbonyl]-2azabicyclo[3.1.1 ]heptane;

3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[5-methyl-2-(1,3-thiazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 ]heptane;

(3S)-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[5-methyl-2-(1,3-thiazol-2yl)phenyl]carbonyl}-2-azabicyclo[3.1.1]heptane;

(3R)-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[5-methyl-2-(1,3-thiazol-2yl)phenyl]carbonyl}-2-azabicyclo[3.1.1]heptane;

3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[5-methyl-2-(2H-1,2,3-triazol-2yl)phenyl]carbonyl}-2-azabicyclo[3.1.1]heptane;

(3S)-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[5-methyl-2-(2H-1,2,3-triazol-2yl)phenyl]carbonyl}-2-azabicyclo[3.1.1]heptane;

(3R)-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[5-methyl-2-(2H-1,2,3-triazol-2yl)phenyl]carbonyl}-2-azabicyclo[3.1.1]heptane;

3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[6-methyl-3-(1,3-thiazol-2-yl)pyridin-2-yl]carbonyl}

2- azabicyclo[3.1.1]heptane;

3- {[(5-chloropyridin-2-yl)oxy]methyl}-2-{[5-methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}-210 azabicyclo[3.1.1]heptane;

(3S)-3-{[(5-chloropyridin-2-yl)oxy]methyl}-2-{[5-methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}· 2-azabicyclo[3.1.1]heptane;

(3R)-3-{[(5-chloropyridin-2-yl)oxy]methyl}-2-{[5-methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}

2- azabicyclo[3.1.1]heptane;

2-{[5-methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}-3-({[5-(trifluoromethyl)pyridin-2yl]oxy}methyl)-2-azabicyclo[3.1.1]heptane;

(3S)-2-{[5-methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}-3-({[5-(trifluoromethyl)pyridin-2yl]oxy}methyl)-2-azabicyclo[3.1.1]heptane;

(3R)-2-{[5-methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}-3-({[5-(trifluoromethyl)pyridin-220 yl]oxy}methyl)-2-azabicyclo[3.1.1]heptane;

3- {[2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptan-3yl]methoxy}isoquinoline;

3-[(4-fluorophenoxy)methyl]-2-[6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carbonyl]-2azabicyclo[3.1.1 jheptane;

3-[(4-fluorophenoxy)methyl]-2-[5-(2-fluorophenyl)-2-methyl-1,3-thiazole-4-carbonyl]-2azabicyclo[3.1.1 jheptane;

3-[2-(4-fluorophenoxy)ethyl]-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]-2azabicyclo[3.1.1 jheptane;

(3S)-3-[2-(4-fluorophenoxy)ethyl]-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]-230 azabicyclo[3.1.1]heptane;

(3R)-3-[2-(4-fluorophenoxy)ethyl]-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]-2azabicyclo[3.1.1 jheptane;

3-(3-fluorophenoxymethyl)-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 jheptane;

3-(2-fluorophenoxymethyl)-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 jheptane;

3-(4-bromophenoxymethyl)-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 jheptane;

3-(3,4-difluorophenoxymethyl)-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 jheptane;

2- (2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-3-(4-methylphenoxymethyl)-2azabicyclo[3.1.1 jheptane;

3- (4-chlorophenoxymethyl)-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 jheptane;

3-(4-fluorophenoxymethyl)-2-[5-(4-fluorophenyl)-2-methyl-1,3-thiazole-4-carbonyl]-2azabicyclo[3.1.1 jheptane;

2- (2-chloro-5-phenyl-1,3-thiazole-4-carbonyl)-3-[(4-fluorophenoxy)methyl]-2azabicyclo[3.1.1 jheptane;

3- [(4-fluorophenoxy)methyl]-2-(2-methoxy-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 jheptane;

2-(2-cyclopropyl-5-phenyl-1,3-thiazole-4-carbonyl)-3-[(4-fluorophenoxy)methyl]-2azabicyclo[3.1.1 jheptane;

6-fluoro-2-{[2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptan-3yl]methoxy}-1,3-benzothiazole;

2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-3-({[5-(trifluoromethyl)pyridin-2yl]oxy}methyl)-2-azabicyclo[3.1.1]heptane;

2-{[2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptan-3yl]methoxy}quinoline;

2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-3-[({7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2yl}oxy)methyl]-2-azabicyclo[3.1.1]heptane;

2-{[2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptan-3yl]methoxy}quinoxaline ;

N-{[2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptan-3yl]methyl}isoquinolin-3-amine;

N-{[2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptan-3yl]methyl}quinolin-2-amine;

6-fluoro-N-{[2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptan-3yl]methyl}-1,3-benzothiazol-2-amine;

(3S,4R)-4-fluoro-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-(2-methyl-5-phenyl-1,3-thiazole-4carbonyl)-2-azabicyclo[3.1.1]heptane;

(3R,4S)-4-fluoro-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-(2-methyl-5-phenyl-1,3-thiazole-4carbonyl)-2-azabicyclo[3.1.1]heptane;

3-(4-fluorophenoxymethyl)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 jheptane;

(3R,4R)-3-(4-fluorophenoxymethyl)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4carbonyl)-2-azabicyclo[3.1.1]heptane;

(3R,4S)-3-(4-fluorophenoxymethyl)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4carbonyl)-2-azabicyclo[3.1.1]heptane;

(35.45) -3-(4-fluorophenoxymethyl)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4carbonyl)-2-azabicyclo[3.1.1]heptane;

(3S,4R)-3-(4-fluoiOphenoxymethyl)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-41 o carbonyl)-2-azabicyclo[3.1.1]heptane;

3-(4-fluorophenoxymethyl)-4-methyl-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]-2azabicyclo[3.1.1 jheptane;

(35.45) -3-(4-fluorophenoxymethyl)-4-methyl-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]-2azabicyclo[3.1.1 jheptane;

(3R,4S)-3-(4-fluorophenoxymethyl)-4-methyl-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]-2azabicyclo[3.1.1 jheptane;

(3R,4R)-3-(4-fluorophenoxymethyl)-4-methyl-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]-2azabicyclo[3.1.1 jheptane;

(3S,4R)-3-(4-fluorophenoxymethyl)-4-methyl-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]-220 azabicyclo[3.1.1]heptane;

Racemic mixture of cis-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[5-methyl-2 (pyrimidin-2-yl)benzoyl]-2-azabicyclo[3.1.1]heptane;

(3S,4R)-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[5-methyl-2-(pyrimidin-2yl)benzoyl]-2-azabicyclo[3.1.1]heptane;

(3R,4S)-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[5-methyl-2-(pyrimidin-2yl)benzoyl]-2-azabicyclo[3.1.1]heptane;

3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4carbonyl)-2-azabicyclo[3.1.1]heptane;

3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[6-methyl-3-(pyrimidin-2-yl)pyridine-230 carbonyl]-2-azabicyclo[3.1.1 jheptane;

(3R,4S)-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[6-methyl-3-(pyrimidin-2yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane;

(3R,4R)-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[6-methyl-3-(pyrimidin-2yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane;

(3S,4R)-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[6-methyl-3-(pyrimidin-2yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane;

(35.45) -3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[6-methyl-3-(pyrimidin-2yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane;

1- {[4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptan-3yl]methoxy}isoquinoline;

7-chloro-2-{[4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 ]heptan-3-yl]methoxy}quinoxaline;

3-{[4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptan-3yl]methoxy}isoquinoline;

3-{[(3R,4R)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 ]heptan-3-yl]methoxy}isoquinoline;

3-{[(3R,4S)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 ]heptan-3-yl]methoxy}isoquinoline;

3-{[(3S,4S)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 ]heptan-3-yl]methoxy}isoquinoline;

3-{[(3S,4R)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 ]heptan-3-yl]methoxy}isoquinoline;

(3R,4S)-3-(4-fluorophenoxymethyl)-4-methyl-2-[6-methyl-3-(pyrimidin-2-yl)pyridine-2carbonyl]-2-azabicyclo[3.1.1 ]heptane;

(3S,4R)-3-(4-fluorophenoxymethyl)-4-methyl-2-[6-methyl-3-(pyrimidin-2-yl)pyridine-2carbonyl]-2-azabicyclo[3.1.1 ]heptane;

(3R,4R)-3-(4-fluorophenoxymethyl)-4-methyl-2-[6-methyl-3-(pyrimidin-2-yl)pyridine-2carbonyl]-2-azabicyclo[3.1.1 ]heptane;

(35.45) -3-(4-fluorophenoxymethyl)-4-methyl-2-[6-methyl-3-(pyrimidin-2-yl)pyridine-2carbonyl]-2-azabicyclo[3.1.1 ]heptane;

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[2-methyl-5-(pyrimidin-2yl)-1,3-thiazole-4-carbonyl]-2-azabicyclo[3.1.1]heptane;

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(2H-1,2,3triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane;

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(1,3-thiazol2- yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane;

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[5-methyl-2-(2H-1,2,3triazol-2-yl)benzoyl]-2-azabicyclo[3.1.1]heptane;

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[5-methyl-2-(1,3-thiazol2-yl)benzoyl]-2-azabicyclo[3.1.1 ]heptane;

Racemic mixture of cis-3-{[(5-chloropyridin-2-yl)oxy]methyl}-4-methyl-2-[6-methyl-3-(2H1,2,3-triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane;

Racemic mixture of cis-4-methyl-2-[6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carbonyl]3-{[(5-methylpyridin-2-yl)oxy]methyl}-2-azabicyclo[3.1.1]heptane;

Racemic mixture of trans-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[5-methyl-2-(1,3thiazol-2-yl)benzoyl]-2-azabicyclo[3.1.1]heptane;

Racemic mixture of trans-3-{[(5-chloropyridin-2-yl)oxy]methyl}-4-methyl-2-e-methyl-3(2H-1,2,3-e-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane;

Racemic mixture of trans-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(2H-1,2,3triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane; (3R,4R)-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(2H-1,2,3-triazol-2yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1 ]heptane;

(35.45) -3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(2H-1,2,3-triazol-2yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1 ]heptane;

Racemic mixture of trans-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(1,3thiazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane;

(3R,4R)-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(1,3-thiazol-2-yl)pyridine-2carbonyl]-2-azabicyclo[3.1.1 ]heptane;

(35.45) -3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(1,3-thiazol-2-yl)pyridine-2carbonyl]-2-azabicyclo[3.1.1 ]heptane;

Racemic mixture of trans-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[5-methyl-2-(2H-1,2,3triazol-2-yl)benzoyl]-2-azabicyclo[3.1.1]heptane;

Racemic mixture of trans-6-fluoro-2-({4-methyl-2-[6-methyl-3-(2H-1,2,3-triazol-2yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptan-3-yl}methoxy)-1,3-benzothiazole; Racemic mixture of trans-3-[(3,4-difluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(2H1.2.3- triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane;

Racemic mixture of trans-3-[(4-chlorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(2H-1,2,3triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane;

Racemic mixture of trans-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[2-methyl-5-(pyrimidin2-yl)-1,3-thiazole-4-carbonyl]-2-azabicyclo[3.1.1]heptane;

Racemic mixture of trans-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[2-methyl-5(pyrimidin-2-yl)-1,3-thiazole-4-carbonyl]-2-azabicyclo[3.1.1]heptane;

Racemic mixture of trans-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[2-methyl-5(pyridin-2-yl)-1,3-thiazole-4-carbonyl]-2-azabicyclo[3.1.1]heptane;

Racemic mixture of cis-2'-(3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2azabicyclo[3.1.1]heptane-2-carbonyl)-6'-methyl-2,3'-bipyridine;

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[2-methyl-5-(pyridin-2-yl)1.3- thiazole-4-carbonyl]-2-azabicyclo[3.1.1]heptane;

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-{6-methyl-3-[5(trifluoromethyl)pyrimidin-2-yl]pyridine-2-carbonyl}-2-azabicyclo[3.1.1 jheptane;

(3R,4R)-3-[(4-chlorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(2H-1,2,3-triazol-2yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane;

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-2-[3-(5-fluoropyrimidin-2-yl)-6methylpyridine-2-carbonyl]-4-methyl-2-azabicyclo[3.1.1 jheptane;

(3S,4S)-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[2-methyl-5-(pyrimidin-2-yl)-1,3-thiazole4-carbonyl]-2-azabicyclo[3.1.1]heptane;

(3R,4R)-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[2-methyl-5-(pyrimidin-2-yl)-1,3-thiazole4-carbonyl]-2-azabicyclo[3.1.1]heptane;

Racemic mixture of trans-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[2-methyl-5-(pyrazin-2yl)-1,3-thiazole-4-carbonyl]-2-azabicyclo[3.1.1]heptane;

Racemic mixture of trans-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(1Hpyrazol-1-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane;

Racemic mixture of cis-N-({4-methyl-2-[6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridine-2carbonyl]-2-azabicyclo[3.1.1 ]heptan-3-yl}methyl)isoquinolin-3-amine;

Racemic mixture of cis-6-fluoro-N-({4-methyl-2-[6-methyl-3-(2H-1,2,3-triazol-2yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptan-3-yl}methyl)-1,3-benzothiazol-2-amine; Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(4-methyl1 H-pyrazol-1 -yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1 jheptane;

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[2-methyl-5-(pyrazin-2yl)-1,3-thiazole-4-carbonyl]-2-azabicyclo[3.1.1]heptane;

Racemic mixture of cis-N-({4-methyl-2-[6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridine-2carbonyl]-2-azabicyclo[3.1.1]heptan-3-yl}methyl)quinazolin-2-amine;

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[2-methyl-5-(6methylpyridin-2-yl)-1,3-thiazole-4-carbonyl]-2-azabicyclo[3.1.1 jheptane;

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(5methylpyrimidin-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane;

Racemic mixture of cis-2-[5-(5-chloropyridin-3-yl)-2-methyl-1,3-thiazole-4-carbonyl]-3-[(4fluorophenoxy)methyl]-4-methyl-2-azabicyclo[3.1.1]heptane;

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[2-methyl-5-(2H-1,2,3triazol-2-yl)-1,3-thiazole-4-carbonyl]-2-azabicyclo[3.1.1]heptane; and

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[2-methyl-5-(1H-pyrazol1-yl)-1,3-thiazole-4-carbonyl]-2-azabicyclo[3.1.1]heptane.

Other compounds that may be mentioned include:

3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-[5-methyl-2-(1H-pyrazol-1-yl)benzoyl]-2azabicyclo[3.1.1 jheptane;

3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-[6-methyl-3-(pyrimidin-2-yl)pyridine-2-carbonyl]-2azabicyclo[3.1.1 jheptane;

6-({2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]-2-azabicyclo[3.1.1]heptan-3yl}methoxy)pyridine-2-carbonitrile;

3-[(4-fluorophenoxy)methyl]-2-[2-(pyrimidin-2-yl)benzoyl]-2-azabicyclo[3.1.1]heptane; 2-[5-methyl-2-(1,3-thiazol-2-yl)benzoyl]-3-{[4-(trifluoromethyl)phenoxy]methyl}-2azabicyclo[3.1.1 jheptane;

2- [5-fluoro-2-(pyrimidin-2-yl)benzoyl]-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2azabicyclo[3.1.1 jheptane;

3- {[(5-fluoropyridin-2-yl)oxy]methyl}-2-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-2azabicyclo[3.1.1 jheptane;

2- [5-(4-fluorophenyl)-2-methyl-1,3-thiazole-4-carbonyl]-3-{[(5-fluoropyridin-2yl)oxy]methyl}-2-azabicyclo[3.1.1]heptane;

3- {[(5-fluoropyridin-2-yl)oxy]methyl}-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]-2azabicyclo[3.1.1 jheptane;

Racemic mixture of cis-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-[5-methyl-2-(pyrimidin-2yl)benzoyl]-2-azabicyclo[3.2.1]octane; and

Racemic mixture of cis-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-(2-methyl-5-phenyl-1,3thiazole-4-carbonyl)-2-azabicyclo[3.2.1]octane.

Particularly preferred compounds are those which are antagonists of 0X1R and/or OX1R/OX2R, as defined herein.

In the case of a discrepancy between the names and structures of any of the compounds disclosed herein, the structures provided should prevail.

Compounds of the invention may be made in accordance with techniques that are well known to those skilled in the art, for example as described hereinafter. Moreover, by utilising the procedures described herein, one of ordinary skill in the art can readily prepare additional compounds that fall within the scope of the present invention claimed herein. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.

The compounds of the invention may be isolated in the form of their pharmaceutically acceptable salts, such as those described previously herein above.

According to a further aspect of the invention there is provided a process for the preparation of a compound of formula I which process comprises:

(i) for compounds of formula I in which L² represents -C(=O)-, reaction of a corresponding compound of formula II,

wherein L¹, L³, R¹, R², R³, R⁴, X and A are as hereinbefore defined, with a compound of formula III,

B-C(O)OH III wherein B is as hereinbefore defined, in the presence of a suitable coupling reagent (e.g. 1,T-carbonyldiimidazole, Λ/,Λ/'-dicyclohexylcarbodiimide, 1-hydroxy-benzotriazole (HOBt), 1-hydroxy-7-aza-benzotriazole (HOAt), (1-[Bis(dimethylamino)methylene]-1H1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 2,4,6-Tripropyl30 1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P), or the like), or, alternatively the -C(O)OH group may first be activated to the corresponding acyl halide (e.g -C(O)CI, by treatment with oxalyl chloride, thionyl chloride, phosphorous pentachloride, phosphorous oxychloride, or the like), together with a suitable base such as, Na₂CO3, K3PO4, Cs₂CC>3, NaOH, KOH, K₂CC>3, CsF, EtsN, (/-Pr)₂NEt, f-BuONa or t-BuOK (or mixtures thereof) in a suitable solvent such as dioxane, toluene, ethanol, dimethylformamide, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, /V-methylpyrrolidinone, tetrahydrofuran, dimethoxyethane (DME) or mixtures thereof (preferably a polar aprotic solvent is employed, e.g. dioxane or DME) under standard conditions known to those skilled in the art (e.g. optionally in an inert atmosphere);

(ii) for compounds of formula compound of formula IV,

I in which X represents -0-, reaction of a corresponding

wherein L¹, L², L³, R¹, R², R³, R⁴ and B are as hereinbefore defined, with a compound of formula V,

A-OH V wherein A is as hereinbefore defined, in the presence of a suitable coupling reagent (e.g. a dialkylazodicarboxylate (or another similar agent as is appropriate for the Mitsunobu reaction) and a triphenylphosphine) under standard conditions known to those skilled in the art (e.g. optionally in an inert atmosphere);

(iii) for compounds of formula I in which X represents -0-, reaction of a corresponding compound of formula IV, as hereinbefore defined, with a compound of formula VI,

A-L^x VI wherein A is as hereinbefore defined and L^x represents a suitable leaving group, such as iodo, bromo, chloro or a sulfonate group (e.g. -OS(O)2CF3, -OS(O)2CH3 or -OS(O)2PhMe) (most preferably L^x represents fluoro or chloro), in the presence of a suitable base such as, Na2CO₃, KsPCU, Cs2CO₃, NaH, NaOH, KOH, K2CO₃, CsF, Et₃N, (/-Pr)2NEt, f-BuONa or f-BuOK (or mixtures thereof) in a suitable solvent such as dioxane, toluene, ethanol, dimethylformamide, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, /V-methylpyrrolidinone, tetrahydrofuran, dimethoxyethane (DME) or mixtures thereof (preferably a polar aprotic solvent is employed, e.g. dioxane or DME);

(iv) for compounds of formula I in which X represents -0-, reaction of a corresponding compound of formula VII,

wherein L¹, L², L³, R¹, R², R³, R⁴ and B are as hereinbefore defined and L^y represents a suitable leaving group, e.g. as hereinabove defined in respect of L^x, with a compound of formula V as hereinbefore defined, and under conditions as defined above for step (iii); or (v) for compounds of formula I in which X represents -NH-, reaction of a corresponding compound of formula VIII,

wherein L², L³, R¹, R², and B are as hereinbefore defined, with a compound of formula

IX,

A-NH₂

IX wherein A is as hereinbefore defined, under appropriate reaction conditions, for example in “one-pot” procedure in the presence of an appropriate reducing agent, such as a chemoselective reducing agent such as sodium cyanoborohydride or, preferably, sodium triacetoxyborohydride, or the like. Alternatively, such reactions may be performed in two steps, for example a condensation step (in the presence of e.g. a dehydrating agent such as trimethyl orthoformate or MgSO₄ or molecular sieves, etc) followed by a reduction step (e.g. by reaction in the presence of a reducing agent such as a chemoselective one mentioned above or NaBH₄, AIH₄, or the like).

Compounds of formulae II, IV, VII and VIII may be prepared by reactions that are analogous to those described herein (particularly in the preparations and Examples), e.g. using one or more of the following specific transformations:

(i) reductions, for example of a carboxylic acid (or ester) to either an aldehyde or an alcohol, using appropriate reducing conditions (e.g. -C(O)OH (or an ester thereof), may be converted to a -C(O)H or -CH2-OH group, using DI BAL and LiAIH₄, respectively (or similar chemoselective reducing agents));

(ii) reductions of an aldehyde (-C(O)H) group to an alcohol group (-CH2OH), using appropriate reduction conditions such as those mentioned at point (i) above;

(iii) oxidations, for example of a moiety containing an alcohol group (e.g. -CH₂OH) to an aldehyde (e.g. -C(O)H) or of a -S- moiety to a -S(O)- or -S(O)2- moiety (or the reverse reduction reaction), for example in the presence of a suitable oxidising agent, e.g. ΜηΟ₂or mcpba or the like;

(iv) reductive amination of an aldehyde and an amine, under appropriate reaction conditions, for example in “one-pot” procedure in the presence of an appropriate reducing agent, such as a chemoselective reducing agent such as sodium cyanoborohydride or, preferably, sodium triacetoxyborohydride, or the like. Alternatively, such reactions may be performed in two steps, for example a condensation step (in the presence of e.g. a dehydrating agent such as trimethyl orthoformate or MgSO₄ or molecular sieves, etc.) followed by a reduction step (e.g. by reaction in the presence of a reducing agent such as a chemoselective one mentioned above or NaBH₄, AIH₄, or the like), for instance the conversion of -NH2 to -N(H)-isopropyl by condensation in the presence of acetone (H3C-C(O)-CH3) followed by reduction in the presence of a reducing agent such as sodium cyanoborohydride (i.e. overall a reductive amination);

(v) formation of an amide or sulfonamide, for example by reaction of a sulfonyl chloride with an amine or by an amide coupling reaction, i.e. the formation of an amide from a carboxylic acid (or ester thereof), for example -C(O)OH (or an ester thereof), may be converted to -C(O)NR₂ group, and which reaction may (e.g. for -COOH) be performed in the presence of a suitable coupling reagent (e.g. 1,T-carbonyldiimidazole, Λ/,Λ/'-dicyclohexylcarbodiimide, or the like) or, in the case of an ester (e.g. -C(O)OCH3 or -C(O)OCH2CH3), be performed in the presence of e.g. trimethylaluminium, or, alternatively the -C(O)OH group may first be activated to the corresponding acyl halide (e.g. -C(O)CI, by treatment with oxalyl chloride, thionyl chloride, phosphorous pentachloride, phosphorous oxychloride, or the like), and, in all cases, the relevant compound is reacted with a compound of formula HNR₂, under standard conditions known to those skilled in the art (e.g. optionally in the presence of a suitable solvent, suitable base and/or in an inert atmosphere);

(vi) conversion of a primary amide to a nitrile functional group, for example under dehydration reaction conditions, e.g. in the presence of POCb, or the like;

(vii) nucleophilic substitution (e.g. aromatic nucleophilic substitution) reactions, where any nucleophile replaces a leaving group, e.g. an amine may replace a -S(O)CH3 leaving group;

(viii) transformation of a methoxy group to a hydroxy group, by reaction in the presence of an appropriate reagent, such as boron fluoride-dimethyl sulfide complex or BBr3 (e.g. in the presence of a suitable solvent such as dichloromethane);

(ix) alkylation, acylation or sulfonylation reactions, which may be performed in the presence of base and solvent (such as those described hereinbefore);

(x) specific deprotection steps, such as deprotection of an /V-Boc protecting group by reaction in the presence of an acid, or, a hydroxy group protected as a silyl ether (e.g. a te/Y-butyl-dimethylsilyl protecting group) may be deprotected by reaction with a source of fluoride ions, e.g. by employing the reagent tetrabutylammonium fluoride (TBAF);

(xi) hydrogenation of an unsaturated system (e.g. a carbon-carbon double bond) by reduction in the presence of a source of hydrogen and a suitable catalyst (such as a palladium-based catalyst, e.g. Pd/C);

(xii) transformation of a hydroxyalkane into an alkene (a dehydration reaction), by reaction in the presence of an appropriate reagent, such as one which converts the alcohol into a suitable leaving group, optionally together with a base.

The compounds of formula I which contain a 2-azabicyclo[3.1.1]heptane core can be prepared using conventional synthetic methods for example, but not limited to, those which include the routes outlined in Scheme 1 below for the formation of 2-tert-butyl 3methyl 4-oxo-2-azabicyclo[3.1.1]heptane-2,3-dicarboxylate moiety.

Scheme 1

Η

N—Boc

Boc O (XVIII)

Step 1

Compound of formula XI may be obtained by esterification of a compound of formula X (commercially available from Sigma-Aldrich) under standard literature conditions such as by reaction with triethylorthoacetate in a suitable solvent, such as toluene, under reflux.

Step 2

Compound of formula XII may be obtained by reductive amination and of compound XI with a benzylamine, in a suitable solvent, such as THF, in presence of a reducing agent like Na(AcO)₃BH,

Step 3

Compound of formula XIII may be obtained from compound XII by removing the benzyl groups by hydrogenolysis, e. g. using ammonium formate and palladium on carbon, in a suitable solvent such as methanol under reflux.

Step 4

Compound of formula XIV may be obtained by N-protection of compound XIII under standard literature conditions such as by reaction with Di-ferf-butyl dicarbonate in a mixture of THF/water, in presence of a suitable base, such as Na₂CC>3, at a temperature around 0 °C.

Step 5

Compound of formula XV may be obtained by hydrolysis of a compound of formula XIV in the presence of bases such as lithium or sodium hydroxide.

Step 6

Compound of formula XVI may be obtained by reaction of a compound of formula XV with an acetyl ester derivative, such as Meldrum’s acid in the presence of a suitable base, such as DMAP.

Step 7

Compound of formula XVII may be obtained via a diazotransfer reaction starting from a compound of formula XVI in the presence of a suitable base, e.g. triethylamine, carrying out the reaction at a temperature between 0 °C and room temperature.

Step 8

Compound of formula XVIII (2-tert-butyl 3-methyl 4-oxo-2-azabicyclo[3.1.1]heptane-2,3dicarboxylate) may be obtained by cyclisation of a compound of formula XVII using a suitable catalyst, such as a Rhodium II catalyst, in a suitable solvent, such as toluene, typically at reflux temperature.

The substituents R¹ to R⁶, A and B (or substituents thereon, e.g. defined by Q¹ or Q²) in final compounds of the invention or relevant intermediates may be modified one or more times, after or during the processes described above by way of methods that are well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, alkylations, acylations, hydrolyses, esterifications, etherifications, halogenations or nitrations. Such reactions may result in the formation of a symmetric or asymmetric final compound of the invention or intermediate. The precursor groups can be changed to a different such group, or to the groups defined in formula I, at any time during the reaction sequence. For example, in cases in which there is a -CO2H present, the skilled person will appreciate that at any stage during the synthesis (e.g. the final step), the relevant ester group may be hydrolysed to form a carboxylic acid functional group.

Compounds of the invention may be isolated from their reaction mixtures using conventional techniques (e.g. recrystallisations).

It will be appreciated by those skilled in the art that, in the processes described above and hereinafter, the functional groups of intermediate compounds may need to be protected by protecting groups.

The protection and deprotection of functional groups may take place before or after a reaction in the above-mentioned schemes.

Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be converted chemically to unprotected compounds using standard deprotection techniques.

The type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis.

The use of protecting groups is fully described in “Protective Groups in Organic Synthesis”, 3^rd edition, T.W. Greene & P.G.M. Wutz, Wiley-lnterscience (1999).

Medical and Pharmaceutical Uses

Compounds of the invention are indicated as pharmaceuticals. According to a further aspect of the invention there is provided a compound of the invention, for use as a pharmaceutical.

For the avoidance of doubt, although compounds of the invention may possess pharmacological activity as such, certain pharmaceutically-acceptable (e.g. “protected”) derivatives of compounds of the invention may exist or be prepared which may not possess such activity, but may be administered parenterally or orally and thereafter be metabolised in the body to form compounds of the invention. Such compounds (which may possess some pharmacological activity, provided that such activity is appreciably lower than that of the “active” compounds to which they are metabolised) may therefore be described as “prodrugs” of compounds of the invention.

A “prodrug of a compound of the invention” is as hereinbefore defined, including compounds that form a compound of the invention, in an experimentally-detectable amount, within a predetermined time (e.g. about 1 hour), following oral or parenteral administration. All prodrugs of the compounds of the invention are included within the scope of the invention.

Furthermore, certain compounds of the invention may possess no or minimal pharmacological activity as such, but may be administered parenterally or orally, and thereafter be metabolised in the body to form compounds of the invention that possess pharmacological activity as such. Such compounds (which also includes compounds that may possess some pharmacological activity, but that activity is appreciably lower than that of the “active” compounds of the invention to which they are metabolised), may also be described as “prodrugs”.

Thus, the compounds of the invention are useful because they possess pharmacological activity, and/or are metabolised in the body following oral or parenteral administration to form compounds which possess pharmacological activity.

Compounds of the invention may be antagonists of 0X1R and/or 0X1R/0X2R, for example as may be shown in the tests described below and/or in tests known to the skilled person. Thus, the compounds of the invention may be useful in the treatment of those disorders in an individual in which antagonism of the orexin-1 and/or both the orexin-1 and orexin-2 receptors is desired and/or required. Said antagonist compounds may be described herein as being “active”. Compounds are typically considered to be effective as antagonists of 0X1R and/or 0X1R/0X2R if they exhibit a pKi of at least 6, e.g. when tested using the scintillation proximity assay (SPA) binding assay described herein. Similarly, compounds may be considered to be effective as antagonists of 0X1R and/or 0X1R/0X2R if they exhibit a fpKi of at least 6, e.g. when tested using the intracellular calcium measurement method described herein.

The term “antagonism” may refer to any measurable blocking or dampening of a biological response by binding to a particular receptor. The blocking or dampening of a biological response may be measured by the binding assays described herein (particularly the intracellular calcium measurement assay), as would be apparent to those skilled in the art. The measurable change may be objective (e.g. measurable by some test or marker, for example in an in vitro or in vivo assay or test, such as one described hereinafter, or otherwise another suitable assay or test known to those skilled in the art) or subjective (e.g. the subject gives an indication of or feels an effect).

The compounds of the invention may also be useful in the treatment of disorders in an individual in which selective antagonism of the orexin-1 receptor is desired and/or required. A compound may be considered to be selective for 0X1R (e.g. preferentially selective for 0X1R over 0X2R) when the antagonistic effect with 0X1R is at least 50 times (e.g. at least 100 times) greater than a that with second receptor (e.g. 0X2R). Selectivity may similarly be determined using the binding assays described herein (particularly the intracellular calcium measurement assay) for the receptors under consideration. Compounds showing a high degree of selectivity may possess additional advantages in the clinic as their use would be less likely to give rise to biological effects that are associated with antagonism of the second receptor. In the case of compounds that are selective for 0X1R over 0X2R, such compounds would advantageously be less likely to induce sedation in a subject, which is an effect associated with OX2R antagonism.

Compounds of the invention are thus expected to be useful in the treatment or prevention of a disorder in which orexin-1 and/or orexin-2 receptors are known to play a role and which are characterised by or associated with an overall elevated activity of those receptors. The compounds of the invention are particularly expected to be useful in the treatment or prevention of disorders in which selective antagonism of the orexin-1 receptor is desired and/or required. Such conditions/disorders include substance dependence, addiction, an anxiety disorder, a panic disorder, binge eating, a compulsive disorder, an impulse control disorder, cognitive impairment and Alzheimer’s disease.

The compounds of the invention are expected to be particularly effective in the treatment or prevention of substance dependence and addiction. Particular examples that may be mentioned include binge eating, binge drinking, alcohol addiction, nicotine addiction, gambling addiction, and cocaine addiction.

Anxiety disorders that may be treated or prevented using the compounds of the invention include generalized anxiety disorder, specific phobias, panic disorder, agoraphobia, social anxiety disorder, post-traumatic stress disorder, separation anxiety disorder, situational anxiety, obsessive-compulsive disorder, and selective mutism.

Compulsive disorders that may be treated or prevented using the compounds of the invention include obsessive-compulsive disorders, and disorders on the OCD spectrum, such as obsessive body dysmorphic disorder, delusional disorder, eating disorders (including anorexia nervosa, bulimia nervosa and binge eating disorder) hypochondriasis, impulse control disorders in general, olfactory reference syndrome, paraphilias, pathological gambling, pica, non-paraphilic sexual addictions, Tourette’s syndrome, body-focused repetitive behaviours (such as trichotillomania), Asperger’s syndrome (autism spectrum), social phobia and compulsive hoarding. The compounds of the invention may also be useful in treating or preventing the compulsive and/or impulsive behaviour associated with movement disorders such as Parkinson’s disease and Alzheimer’s disease.

Impulse control disorders that may be treated or prevented using the compounds of the invention include sexual compulsion (e.g. sex addiction), internet addiction, compulsive shopping, pyromania, intermittent explosive disorder, kleptomania (e.g. compulsive shoplifting) and attention deficit hyperactivity disorder (ADHD).

Cognitive impairments that may be treated or prevented using the compounds of the invention include deficits in overall intelligence, deficits in cognitive abilities (such as learning disorders, dyslexia, dyscalculia, and the like), or neuropsychological deficits (such as in attention, working memory or executive function).

Particular patient groups that may be mentioned include those which have co-morbid mood and/or anxiety disorder, or substance abuse disorder which precludes the use of existing therapies, such as Vyvanse.

Compounds of the invention are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions.

According to a further aspect of the present invention, there is provided a method of treating or preventing of a disease or condition (e.g. substance dependence or addiction) in which antagonism of the orexin-1 and/or orexin-2 receptors (e.g. selective antagonism of the orexin-1 receptor) is desired and/or required, which method comprises administration of a therapeutically effective amount of a compound of the invention, as hereinbefore defined to a patient suffering from, or susceptible to, such a condition.

“Patients” include mammalian (including human) patients. Hence, the method of treatment discussed above may include the treatment of a human or animal body.

The term “effective amount” refers to an amount of a compound, which confers a therapeutic effect on the treated patient. The effect may be objective (e.g. measurable by some test or marker) or subjective (e.g. the subject gives an indication of or feels an effect).

Compounds of the invention may be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, by any other parenteral route or via inhalation, in a pharmaceutically acceptable dosage form.

Compounds of the invention may be administered alone, but are preferably administered by way of known pharmaceutical formulations, including tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like. The type of pharmaceutical formulation may be selected with due regard to the intended route of administration and standard pharmaceutical practice. Such pharmaceutically acceptable carriers may be chemically inert to the active compounds and may have no detrimental side effects or toxicity under the conditions of use.

Such formulations may be prepared in accordance with standard and/or accepted pharmaceutical practice. Otherwise, the preparation of suitable formulations may be achieved non-inventively by the skilled person using routine techniques and/or in accordance with standard and/or accepted pharmaceutical practice.

According to a further aspect of the invention there is thus provided a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.

Depending on e.g. potency and physical characteristics of the compound of the invention (i.e. active ingredient), pharmaceutical formulations that may be mentioned include those in which the active ingredient is present in at least 1% (or at least 10%, at least 30% or at least 50%) by weight. That is, the ratio of active ingredient to the other components (i.e. the addition of adjuvant, diluent and carrier) of the pharmaceutical composition is at least 1:99 (or at least 10:90, at least 30:70 or at least 50:50) by weight.

The amount of compound of the invention in the formulation will depend on the severity of the condition, and on the patient, to be treated, as well as the compound(s) which is/are employed, but may be determined non-inventively by the skilled person.

The invention further provides a process for the preparation of a pharmaceutical formulation, as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, or a pharmaceutically acceptable salt, solvate or prodrug thereof with a pharmaceutically-acceptable adjuvant, diluent or carrier.

Compounds of the invention may also be combined with other therapeutic agents that are antagonists of the orexin-1 and/or orexin-2 receptors (e.g. selective antagonism of the orexin-1 receptor) and/or useful in the treatment or prevention of substance dependence, addiction, an anxiety disorder, a panic disorder, binge eating, a compulsive disorder, an impulse control disorder, cognitive impairment or Alzheimer’s disease. Compounds of the invention may also be combined with other therapies.

According to a further aspect of the invention, there is provided a combination product comprising:

(A) a compound of the invention, as hereinbefore defined; and (B) another therapeutic agent that is useful in the treatment of a disease or disorder in which antagonism of the orexin-1 and/or orexin-2 receptors is desired and/or required, wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.

Such combination products provide for the administration of a compound of the invention in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises a compound of the invention, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including a compound of the invention and the other therapeutic agent).

Thus, there is further provided:

(1) a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, another therapeutic agent that is useful in the treatment of a disease or disorder in which antagonism of the orexin-1 and/or orexin-2 receptors is desired and/or required, and a pharmaceutically-acceptable adjuvant, diluent or carrier; and (2) a kit of parts comprising components:

(a) a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and (b) a pharmaceutical formulation including another therapeutic that is useful in the treatment of a disease or disorder in which antagonism of the orexin-1 and/or orexin-2 receptors is desired and/or required in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.

The invention further provides a process for the preparation of a combination product as hereinbefore defined, which process comprises bringing into association a compound of the invention, as hereinbefore defined, or a pharmaceutically acceptable salt, solvate or prodrug thereof with the other therapeutic agent that is useful in the treatment of a disease or disorder in which antagonism of the orexin-1 and/or orexin-2 receptors is desired and/or required, and at least one pharmaceutically-acceptable adjuvant, diluent or carrier.

By “bringing into association”, we mean that the two components are rendered suitable for administration in conjunction with each other.

Thus, in relation to the process for the preparation of a kit of parts as hereinbefore defined, by bringing the two components “into association with” each other, we include that the two components of the kit of parts may be:

(i) provided as separate formulations (i.e. independently of one another), which are subsequently brought together for use in conjunction with each other in combination therapy; or (ii) packaged and presented together as separate components of a “combination pack” for use in conjunction with each other in combination therapy.

Depending on the disorder, and the patient, to be treated, as well as the route of administration, compounds of the invention may be administered at varying therapeutically effective doses to a patient in need thereof. However, the dose administered to a mammal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the mammal over a reasonable timeframe. One skilled in the art will recognize that the selection of the exact dose and composition and the most appropriate delivery regimen will also be influenced by inter alia the pharmacological properties of the formulation, the nature and severity of the condition being treated, and the physical condition and mental acuity of the recipient, as well as the potency of the specific compound, the age, condition, body weight, sex and response of the patient to be treated, and the stage/severity of the disease.

Administration may be continuous or intermittent (e.g. by bolus injection). The dosage may also be determined by the timing and frequency of administration. In the case of oral or parenteral administration the dosage can vary from about 0.01 mg to about 2000 mg per day of a compound of the invention.

In any event, the medical practitioner, or other skilled person, will be able to determine routinely the actual dosage, which will be most suitable for an individual patient. The above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

Compounds of the invention may also have the advantage that they may be more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, whether for use in the above-stated indications or otherwise.

Biological Test Methods

Scintillation Proximity Assay (SPA) binding assays

CHO cells stably transfected with human Orexin type 1 receptors (CHO-hOXi) or HEK-293 cells transiently transfected with human Orexin type 2 receptors (HEK-hOX2) were collected after 16 h induction with 5 mM sodium butyrate. The cell pellets were re-suspended, homogenized in 15 mM Tris/HCI pH=7.5, 1 mM EGTA, 0.3 mM EDTA, 2 mM MgCb, protease inhibitors and centrifuged at 40,000 g (20 min, 4°C). After re-suspension, homogenization and centrifugation as above, the final pellets were re-suspended in 75 mM Tris/HCI pH=7.5, 1 mM EGTA, 0.3 mM EDTA, 12.5 mM MgCb, 250 mM Sucrose, protease inhibitors, divided into aliquots and frozen down at-80 °C.

Compounds of invention were serially diluted in neat DMSO at 100-fold concentrations (1% DMSO final in the assay) and 2 μΙ/well were plated into 96-well Isoplates (Perkin Elmer).

CHO-hOXi cell membranes (6 pg ml^-1) or HEK-hOX2 membranes (8 pg ml^-1) were pre-coupled with 1.0 mg ml^-1 of Wheatgerm Agglutinin-coated Yttrium Silicate (YSi-WGA) SPA beads (Perkin Elmer) in buffer containing 25 mM HEPES pH=7.4, 1 mM CaCb, 5 mM MgCb, 0.01% (w/v) BSA, 0.02% (w/v) Pluronic F-127 by shaking at room temperature for 2.5-3 h.

The binding was performed in a final volume of 200 pi. 100 μΙ of hOXi or hOX2 beadsmembranes suspension were added to 100 μΙ of [³H]SB-674042 or [³H]EMPA solutions (radioligand concentration 2 nM final in the assay), into the 96-well Isoplates containing the 2 μΙ/well of compounds to be tested. Nonspecific binding was measured in the presence of 1 μΜ Almorexant. Assay plates were then incubated at room temperature for 3 h before being counted in a Microbeta scintillation counter (PerkinElmer).

Data were analysed by non-linear regression analysis using XLfit Software. The pKi was calculated from the ICso using the Cheng-Prusoff correction: pKi = ICso/(1⁺([L]/Kd)) where [L] is the radioligand concentration in the displacement assay, and Kd is the dissociation constant of the radioligand as calculated from previous saturation binding experiments which were performed similarly to the competition binding experiments using increasing radioligand concentrations.

Intracellular Calcium measurement

Intracellular calcium increase was measured by using FLIPR-384 (Molecular Devices). CHO-hOXi and CHO-hOX2 cells were seeded into black walled clear-bottom 384-well plates at a density of 8,000 cells/well in F12K medium supplemented with 10% heatinactivated foetal bovine serum and cultured overnight. Cells were then washed with assay buffer (20 mM HEPES, 145 mM NaCI, 5 mM KCI, 5.5 mM D-(+)-glucose, 1 mM MgCE and 2 mM CaCE, pH 7.4) containing 2.5 mM probenecid and incubated at 37 °C for 60 min in assay buffer containing 2.5 mM probenecid, 0.01% (w/v) Pluronic F-127 and 1 μΜ of the calcium dye Fluo-4 AM. After a further washing step with assay buffer containing 2.5 mM probenecid plates were the placed into FLI PR to monitor cell fluorescence (A_ex=488 nm, A_em=510-570 nm).

Compounds of invention were serially diluted in neat DMSO at 200-fold concentrations (0.5% DMSO final in the assay), plated into 384-well plates and then diluted with assay buffer containing 0.05% Pluronic F-127 to reach 4 times the final assay concentration (4X, 2% DMSO).

A dual read-out FLIPR protocol was applied allowing for antagonist characterization. In the first, compound solution was added and the ability to increase intracellular calcium levels with respect to the agonist standard Orexin-A was monitored. After a 15 min compound incubation, a second addition containing Orexin-A at ECso concentration (concentration producing 80% of the maximal response) follows. Inhibition of the agonist evoked signal indicates antagonist activity of the compound and allows for the calculation of the compounds ICso (concentration of the antagonist required for 50% inhibition of the agonist effect).

A CRC (Concentration-response curves) of Orexin-A was tested in each experiment to estimate the ECso (concentration of the agonist needed to produce 50% of the maximum response) value to be used for functional pKi calculation and to calculate the ECso (EC₅₀x4).

Orexin-A CRCs were analysed by using GraphPad Prism5 Software to estimate ECso whereas antagonist inhibitory curves were analysed by using XLfit Software. Curve fitting and ECso/ICso estimations were carried out using a four-parameter logistic model. In the case of antagonist activity, an estimation of the functional pKi (-logwKi) can be calculated from the IC50 using the Cheng-Prusoff correction: functional ki= -log (IC50 /1+([A]/ECso)) where [A] is the Orexin-A concentration (ECso) in the inhibition assay.

Examples

The invention is further illustrated by the following non-limiting examples.

In the procedures that follow, after each starting material, reference to a Preparation or Example by number is typically provided. This is provided merely for assistance to the skilled chemist. The starting material may not necessarily have been prepared from the batch referred to.

Where reference is made to the use of a “similar or analogous or as” procedure, as will be appreciated by those skilled in the art, such procedure may involve minor variation, for example reaction temperature, reagent/solvent amount, reaction time, work-up conditions or chromatographic purification conditions.

All temperatures refer to °C.

Proton Magnetic Resonance (NMR) spectra may be typically recorded either on Varian instruments at 400 or 500 MHz, or on a Bruker instrument at 400 MHz. Chemical shifts are expressed in parts of million (ppm, δ units). Chemical shifts are reported in ppm downfield (δ) from Me₄Si, used as internal standard, and are typically assigned as singlets (s), broad singlets (br.s.), doublets (d), doublets of doublets (dd), doublets of doublets of doublets (ddd), doublets of triplets (dt), triplets (t), triplets of doublets (td), quartets (q), or multiplets (m).

LCMS may be recorded under the following conditions:

DAD chromatographic traces, mass chromatograms and mass spectra may be taken on UPLC/PDA/MS AcquityTM system coupled with Micromass ZQ™ or Waters SQD single quadrupole mass spectrometer operated in positive and/or negative ES ionisation mode. The QC methods used were two, one operated under low pH conditions and another one operated under high pH conditions. Details of the method operated under low pH conditions were: column, Acquity BEH Cw, 1.7 pm, 2.1 x 50 mm or Acquity CSH Cw, 1.7 pm, 2.1 x 50 mm, the temperature column was 40 °C; mobile phase solvent A was milliO water + 0.1% HCOOH, mobile phase solvent B MeCN + 0.1% HCOOH. The flow rate was 1 ml/min. The gradient table was t= 0 min 97% A - 3% B, t= 1.5 min 0.1% A 99.9% B, t= 1.9 min 0.1% A - 99.9% B and t= 2 min 97% A - 3% B. The UV detection range was 210 - 350 nm and the ES7ES' range was 100 - 1000 amu. Details of the method operated under high pH conditions were the same of those listed above for the low pH method apart from: column Acquity BEH Cw, 1.7 pm, 2.1 x 50 mm; mobile phase solvent A was 10 mM acqueous solution of NH4HCO3 adjusted to pH= 10 with ammonia, mobile phase solvent B MeCN.

Semipreparative mass directed autopurifications (MDAP) were carried out using Waters Fractionlynx™ systems operated under low or high pH chromatographic conditions. The stationary phases used were, XTerra C18, XBridge C18, Sunfire C18, XSelect C18, Gemini AXIA C18. The length of the columns was 5, 10 or 15 cm, while the internal diameter was 19, 21 or 30 mm. The particle size of the stationary phases was 5 or 10 pm. The purifications were carried out using low pH or high pH chromatographic conditions. The mobile phase solvent composition was the same used for OC analysis. The combinations stationary/mobile phases used were: XTerra, XBridge, Sunfire, XSelect - low pH mobile phases and XTerra, XBridge, Gemini AXIA - high pH mobile phases. All the purifications were carried out with the column kept at room T. The flow rate used was 17 or 20 ml/min for columns of internal diameter 19 or 21 mm and 40 or 43 ml/min for columns of internal diameter 30 mm. The trigger for the collection of the target species was the presence of the target m/z ratio value in the TIC MS signal. The gradient timetable was customised on the Rt behaviour of the target species.

Purification may also be performed using Biotage® Isolera or Biotage® SP1 flash chromatography systems, these instruments work with Biotage® KP-SIL cartridges, Biotage® KP-NH cartidges or Biotage® KP-C18 cartridges.

The order of compounds obtained from a chiral separation is given based on the order of elution from the chiral column. This means that when a racemate is resolved into single enantiomers, the terms “Enantiomer 1” or “Enantiomer 2”, as reported in the descriptions, refer to “first eluted” or “second eluted” respectively. When a mixture of diastereoisomers is purified via chiral HPLC to separate single enantiomers for each diastereoisomer of the mixture, the order is given based on the order of elution. In this case the indication of relative stereochemistry is determined by NMR analyses and the terms “Enantiomer 1” or “Enantiomer 2”, as reported in the descriptions, refer to “first eluted” or “second eluted” respectively for each diastereomer.

Relative stereochemistry “cis” is represented by using the bold highlight of the bonds, while the “trans” relative stereochemistry is represented by using bold and dotted highlight of the bonds.

Unless otherwise stated, all reactions are typically performed under inert atmosphere (for example under Nitrogen).

The following abbreviations are used in the text:

EtOAc, AcOEt, EA = ethyl acetate,

Et2<D = diethyl ether,

MeOH = methanol;

THF = tetrahydrofuran,

Tic = thin layer chromatography on silica plates, and dried refers to a solution dried over anhydrous sodium sulphate, r.t. (RT) = room temperature,

DMSO = dimethyl sulfoxide;

DMF = Λ/,Λ/’-dimethylformamide,

DCM = dichloromethane,

EtOH = ethanol,

RP = reverse phase FA = formic acid DCE = dichloroethane,

DME = 1,2-Dimethoxyethane,

Cy, cHex = cyclohexane,

TEA = triethylamine,

DI PEA = Λ/,/V-Diisopropylethylamine,

BOC2O = Di-terf-butyl dicarbonate;

TFA = trifluoroacetic acid,

DIAD = Diisopropyl azodicarboxylate,

HATU = 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate,

DAST = Diethylaminosulfur trifluoride,

TPP = triphenylphosphine,

AcOH = acetic acid,

LAH = Lithium aluminum hydride,

T3P = Propylphosphonic anhydride,

SCX Cartridge = Strong Cation Exchange Cartridge.

FC = Flash chromatography

Preparation 1: ethyl 3-oxocyclobutane-1-carboxylate

Triethyl orthoacetate (95 mL, 516 mmol) was added to a solution of 3-oxocyclobutane-1carboxylic acid (20 g, 172 mmol) in toluene (400 mL) and the reaction was refluxed for 6h. The reaction mixture was cooled down to RT, quenched with a 1 N solution of HCI (100 mL x 2) and the layers were separated. The organic phase was washed with s.s. of NaHCCb (100 mL) and Brine (100 mL). HCI and NaHCCb aqueous phases were back15 extracted several times with DCM until complete disappearance of the desired product (check by TLC, Cy/EtOAC 8/2, Ninhydrin). Combined organics were dried over Na2SC>4, filtered and concentrated under vacuum affording ethyl 3-oxocyclobutane-1-carboxylate (P1, 23.3 g) as yellow oil that was used as crude without further purification.

NMR (¹H, Chloroform-d): δ 4.24 (q, 1 H) 3.39 - 3.50 (m, 2 H) 3.18 - 3.37 (m, 3 H) 1.29 - 1.36 (m, 3 H)

Preparation 2: ethyl 3-(dibenzylamino)cyclobutane-1-carboxylate

A mixture of ethyl 3-oxocyclobutane-1-carboxylate (p1, 23.3 g, 164 mmol), Dibenzylamine (35 mL, 180 mmol), Sodium triacetoxyborohydride (70 g, 328 mmol) and AcOH (18.8 mL, 328 mmol) in THF dry (230 mL) was stirred at RT under nitrogen overnight. THF was partially concentrated (until -100 mL) and the residue was diluted with AcOEt; the resulting solution was washed with NaHCO3 ss, and brine. Aqueous phase was basified to pH 7-8 with solid NaHCO3 and extracted with EtOAC. Combined organics were dried over Na₂SO4, filtered and evaporated to give ethyl 3(dibenzylamino)cyclobutane-l-carboxylate (p2, 55 g), that was used as such in the next step.

MS (zn/z): 324.3 [MH]⁺.

Preparation 3: ethyl 3-aminocyclobutane-1-carboxylate

O

Ethyl 3-aminocyclobutane-1-carboxylate (p2, 55g, 170 mmol), ammonium formate (54 g,

850 mmol) and Pd(OH)₂ (5.5 g) were suspended in MeOH (360 ml_) and the reaction mixture was stirred at reflux for 1 h. The mixture was cooled down to RT, filtered through a pad of Celite and concentrated under reduced pressure to afford ethyl 3aminocyclobutane-1-carboxylate (p3, 23.5 g) as white solid. Presence of ammonium formate detected, but material was used as such in the next step.

MS(/n/z): 144.1 [MH]⁺.

Preparation 4: ethyl 3-{[(tert-butoxy)carbonyl]amino}cyclobutane-1-carboxylate

HN⁷ \

Boc

Ditert-butyl dicarbonate (45 g, 197 mmol) was added portionwise to a solution of ethyl 3aminocyclobutane-1-carboxylate (p3, 23.5 g, 164 mmol) and TEA (68.5 ml_, 492 mmol) in THF dry (400 ml_) at RT under nitrogen. The resulting mixture was stirred at RT overnight. The mixture was concentrated under vacuum, diluted with DCM and washed with s.s. of NaHCC>3. Then the organic phase was washed with 5% solution of KHSO4, then dried, filtered and concentrated under vacuum affording ethyl 3-{[(tertbutoxy)carbonyl]amino}cyclobutane-1-carboxylate (p4, 45.5 g) as yellow oil that was used in the next step without further purification.

NMR (¹H, Chloroform-d): δ 4.11 - 4.18 (m, 1 H) 4.04 - 4.23 (m, 4 H) 2.72 - 2.82 (m, 1

H) 2.57-2.68 (m, 2 H) 2.04-2.15 (m, 2 H) 1.42-1.50 (m, 9 H) 1.24- 1.30 (m, 2 H).

Preparation 5: 3-{[(tert-butoxy)carbonyl]amino}cyclobutane-1-carboxylic acid hi\t \

Boc

A mixture of ethyl 3-{[(tert-butoxy)carbonyl]amino}cyclobutane-1-carboxylate (p4, 45.5 g,

164 mmol) and Ι_ίΟΗ·Η2θ (13.8 g, 328 mmol) in THF (350 ml_) and water (350 ml_) was stirred at RT overnight. Then the mixture was heated to 55 °C and stirred at that temperature for 24 hrs. Still presence of starting material detected, therefore volatiles were removed under reduced pressure, THF/MeOH (150 ml_/50 ml_) was added and the mixture stirred at 55 °C for further 3 hrs. Organic phase was evaporated, the aqueous phase was extracted with DCM and the DCM was discarded. The aqueous mixture was acidified with a 2 M solution of citric acid until pH 3 and was extracted with DCM (x 3). Combined organics were dried and concentrated affording 3-{[(tertbutoxy)carbonyl]amino}cyclobutane-1-carboxylic acid (p5, 30.3 g)

NMR (¹H, DMSO-c/6): δ ppm 12.04 (br. s., 1 H) 7.18 (br. s., 1 H) 7.13 (d, 1 H) 3.84 (d, 1 H) 2.59-2.67 (m, 1 H) 2.33 (m, 2 H) 2.18-2.18 (m, 1 H) 1.95-2.07 (m, 2 H) 1.33- 1.40 (m, 2 H)

Preparation 6: methyl 3-(3-{[(tert-butoxy)carbonyl]amino}cyclobutyl)-320 oxopropanoate

Boc

EDC.HCI (37.8 g, 197.4 mmol) was added slowly at 0 °C to a solution of 3-{[(tertbutoxy)carbonyl]amino}cyclobutane-1-carboxylic acid (p5, 30.3 g, 141 mmol), DMAP (25.8 g, 211.5 mmol) and Meldrum’s acid (22.4 g, 155.1 mmol) in DCM dry (350 ml_) under nitrogen. The mixture was stirred at RT for 2.5h. The mixture was quenched with 5% solution of KHSO4 until pH ~3. Phases were separated and the organic phase was washed with 5% solution of KHSO4, then dried over Na2SO4, filtered and concentrated under vacuum to afford a dark brown solid. The crude was taken up with MeOH (350 ml_) and stirred at reflux (70 °C) for 2 h. The reaction was cooled down to RT and concentrated under vacuum affording methyl 3-(3-{[(tertbutoxy)carbonyl]amino}cyclobutyl)-3-oxopropanoate (p6, 39 g) as brown solid.

NMR (¹H, Chloroform-d): δ 4.70 (br. s., 1 H) 4.13 (br. s., 1 H) 3.72 - 3.77 (m, 2 H) 3.49 5 - 3.49 (m, 1 H) 3.41 - 3.46 (m, 2 H) 3.00 - 3.13 (m, 1 H) 2.51 - 2.65 (m, 2 H) 2.03 - 2.14 (m, 2 H) 1.40- 1.50 (m, 6 H).

Preparation 7: methyl 3-(3-{[(tert-butoxy)carbonyl]amino}cyclobutyl)-2-diazo-3 oxopropanoate

Boc

Methyl 3-(3-{[(tert-butoxy)carbonyl]amino}cyclobutyl)-3-oxopropanoate (p6, 39 g, 141 mmol) was dissolved in MeCN dry (500 ml_) at 0 °C under nitrogen, then 4acetamidobenzene-1-sulfonyl azide (37.2 g, 155 mmol) was added. TEA (59 ml_, 423 mmol) was added dropwise and the solution turned into a suspension in 10 min. The resulting mixture was allowed to reach RT and stirred for 1.5h. The mixture was filtered washing with MeCN and concentrated under vacuum. The residue was suspended in DCM, filtered and the filtrate was purified by a pad of silica using Cy/EtOAc 7:3 as eluent. The product was concentrated under vacuum to afford methyl 3-(3-{[(tertbutoxy)carbonyl]amino}cyclobutyl)-2-diazo-3-oxopropanoate (p7, 35.3 g) as yellow solid.

_

MS (zn/z): 298.3 [MH]⁺.

Preparation 8: 2-tert-butyl 3-methyl 4-oxo-2-azabicyclo[3.1.1]heptane-2,3 dicarboxylate

Methyl 3-(3-{[(tert-butoxy)carbonyl]amino}cyclobutyl)-2-diazo-3-oxopropanoate (p7, 35.3 g, 118.7 mmol) was dissolved in toluene dry (400 ml_) under nitrogen, and Rhodium(ll)acetate dimer (681 mg, 1.54 mmol) was added, and the mixture was immediately stirred in a preheated bath at 90 °C. The mixture immediately developed some bubbling, which stopped after 10 minutes. Therefore it was cooled down to RT and the catalyst was filtered off. The filtrate was evaporated affording a green oil that was purified by a pad of silica (eluent DCM/AcOEt 95: 5) affording 2-tert-butyl 3-methyl 4-oxo2-azabicyclo[3.1.1]heptane-2,3-dicarboxylate (p8, 21.5 g) as yellow solid.

NMR (¹H, Chloroform-d): δ 4.94 - 5.07 (m, 2 H) 3.85 (s, 3 H) 3.14 (q, 1 H) 2.64 - 2.81 (m, 2 H) 2.24 - 2.37 (m, 1 H) 1.89 (dd, 1 H) 1.40 - 1.52 (m, 9 H)

Preparation 9: CIS/TRANS 3-(hydroxymethyl)-2-azabicyclo[3.1.1]heptan-4-ol

Step a:

2-tert-butyl 3-methyl 4-oxo-2-azabicyclo[3.1.1]heptane-2,3-dicarboxylate (p8, 3 g, 11.14 mmol) was dissolved in THF/MeOH (25/5 ml_) and NaBFL (2.5 g, 66.84 mmol) was added portion wise and then the mixture was stirred at RT for 4 hrs. The reaction was quenched with H₂O and volatiles were removed under vacuum. pH was adjusted to 7 with 1N HCI, EtOAc was added and the product was extracted several times. The organic solvent was concentrated under vacuum affording CIS/TRANS tert-butyl 4hydroxy-3-(hydroxymethyl)-2-azabicyclo[3.1.1]heptane-2-carboxylate (Int. a, 2.7 g) which was used as such in the next step

Step b:

Int a (2.39 g, 9.82 mmol) was dissolved in DCM (16 ml_) and TFA (4 ml_) was added. The mixture was stirred at RT for 3 hrs. Volatiles were removed under vacuum, the residue was charged on SCX, eluting with 1N NH3 in MeOH affording CIS/TRANS 3(hydroxymethyl)-2-azabicyclo[3.1.1]heptan-4-ol (p9, 1.4 g, mixture of cis and trans diastereoisomers) that was used as such in the next step.

MS (zn/z): 143.9 [MH]⁺.

Preparation 10: CIS/TRANS 2-tert-butyl 3-methyl 4-hydroxy-2azabicyclo[3.1.1]heptane-2,3-dicarboxylate

Boc O

To a cooled solution of 2-tert-butyl 3-methyl 4-oxo-2-azabicyclo[3.1.1]heptane-2,3dicarboxylate (p8, 5 g, 18.56 mmol) in MeOH (120 ml_) at 0°C NaBH4 (1.4 g, 37.13 mmol) was added portionwise. The reaction was left to stir at RT for 2 h, cooled at 0°C and HCI 1 N was added (50 ml_). The mixture was diluted with water (200 ml_) and extracted with DCM (5 x 50 mL). The organic phase was washed with Brine dried over Na2SC>4, filtered and concentrated under vacuum affording CIS/TRANS 2-tert-butyl 3methyl 4-hydroxy-2-azabicyclo[3.1.1]heptane-2,3-dicarboxylate (p10, 4.65 g, y = 92%, mixture of cis and trans diastereoisomers) as colourless oil that was used in the next step as such.

NMR (¹H, Chloroform-d): δ 5.31-5.34 (m, 1H), 4.33-4.50 (m, 1H), 4.33-4.90 (m, 3H), 4.33-4.53 (m, 1H), 3.81 (s, 3H), 2.56-2.66 (m, 1H), 2.19-2.44 (m, 3H), 2.01-2.15 (m, 1H), 1.43 (br. s., 9H)

Preparation 11 and 12: CIS/TRANS 2-tert-butyl 3-methyl 4-[(1H-imidazol-1 yl)carbothioyloxy]-2-azabicyclo[3.1.1]heptane-2,3-dicarboxylate (p11) and 2-tert butyl 3-methyl 2-azabicyclo[3.1.1]hept-3-ene-2,3-dicarboxylate (p12)

To a solution of CIS/TRANS 2-tert-butyl 3-methyl 4-hydroxy-2-azabicyclo[3.1.1]heptane2,3-dicarboxylate (p10, 5.7 g, 21.00 mmol) in DCM dry (100 mL) at 0 °C DMAP (3.85 g, 31.5 mmol) and 1,T-Thiocarbonyldiimidazole (10.29 g, 57.75 mmol) were added. The reaction was stirred at RT for 4 hrs and then concentrated under vacuum. The residue was purified by FC on silica gel (eluent: from DCM 100% to DCM/AcOEt 8:2) affording

CIS/TRANS 2-tert-butyl 3-methyl 4-[(1H-imidazol-1-yl)carbothioyloxy]-2azabicyclo[3.1.1]heptane-2,3-dicarboxylate (p11, 4 g, y = 50%, mixture of cis and trans diastereoisomers) and 2-tert-butyl 3-methyl 2-azabicyclo[3.1.1]hept-3-ene-2,3dicarboxylate (p12, 1.3 g, y = 25%) as yellow solids.

p11: MS(m/z): 382.0 [MH]⁺. p12: MS (zn/z): 276.0 [M+Na]⁺.

Preparation 13: 2-tert-butyl 3-methyl 2-azabicyclo[3.1.1]heptane-2,3-dicarboxylate

Method A:

To a solution of CIS/TRANS 2-tert-butyl 3-methyl 4-[(1H-imidazol-1-yl)carbothioyloxy]-2azabicyclo[3.1.1]heptane-2,3-dicarboxylate (p11, 3.7 g, 9.7 mmol) in toluene dry (80 mL) were added Tributyltin hydride (4.1 g, 13.97 mmol) and AIBN (0.350 g, 2.13 mmol). The reaction was stirred for 2 hrs at 90 °C. Then it was cooled down to RT, the mixture was concentrated under vacuum and the residue was purified by pad of silica using as eluent a solution of DCM/AcOEt 95:5 affording 2-tert-butyl 3-methyl 2-azabicyclo[3.1.1]heptane5 2,3-dicarboxylate (p13, 2.07 g, y= 83 %) as yellow oil.

Method B:

To a solution of 2-tert-butyl 3-methyl 2-azabicyclo[3.1.1]hept-3-ene-2,3-dicarboxylate (p12, 1.3 g, 5.13 mmol) in EtOH (60 ml_) was added Pd/C 10% (1.0 g) and the reaction was stirred at RT O/N under H2 atmosphere at 6 bar. The reaction was filtered over celite and concentrated under vacuum affording 2-tert-butyl 3-methyl 2azabicyclo[3.1.1]heptane-2,3-dicarboxylate (p13, 1.10 g, y= 84%) as colourless oil and used without further purifications

MS (m/z): 256.0 [MH]⁺.

Preparation 14: tert-butyl 3-(hydroxymethyl)-2-azabicyclo[3.1.1]heptane-2 carboxylate

Boc

2-tert-butyl 3-methyl 2-azabicyclo[3.1.1]heptane-2,3-dicarboxylate (p13, 0.100 g, 0.392 mmol) was dissolved in THF (5 ml_) and cooled to -20°C. Lithium aluminium hydride 2M in THF (0.314 mL, 0.627 mmol) was added dropwise at -20 °C, and then the mixture was stirred at same temperature for 2 h. The reaction was quenched with Na2SO₄ *10 H2O. The mixture was filtered to remove the solid and concentrated under vacuum to afford tert-butyl 3-(hydroxymethyl)-2-azabicyclo[3.1.1]heptane-2-carboxylate (p14, 90 mg, 0.395 mmol), which was used without further purification.

MS (m/z): 228.2 [MH]⁺.

Preparation 15: tert-butyl 3-({[5-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-2 azabicyclo[3.1.1]heptane-2-carboxylate

A mixture of tert-butyl 3-(hydroxymethyl)-2-azabicyclo[3.1.1]heptane-2-carboxylate (p14, 150 mg, 0.66 mmol), 2-fluoro-5-(trifluoromethyl)pyridine (120 mg, 0.72 mmol), and cesium carbonate (254 mg, 0.78 mmol) in DMF dry (5 ml_) was stirred at RT under nitrogen for 3h, then more 2-fluoro-5-(trifluoromethyl)pyridine (60 mg, 0.36 mmol) was added, and the mixture was stirred at RT for 3h.

The mixture was combined with crude material from similar preparation and the combined crudes were diluted with AcOEt and washed several times with brine. The organic phase was dried over Na₂SC>4 and filtered, and the solvent was evaporated. Crude was purified by silica gel chromatography (eluent: Cy/AcOEt 80:20 to 60:40) affording tert-butyl 3-({[5-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-2azabicyclo[3.1.1]heptane-2-carboxylate (p15, 100 mg, 30% recovery on combined batches) as a colourless oil.

MS (m/z): 373.2 [MH]⁺.

Preparation 16: tert-butyl 3-[(isoquinolin-3-yloxy)methyl]-2-azabicyclo[3.1.1]heptane

2-carboxylate

tert-butyl 3-(hydroxymethyl)-2-azabicyclo[3.1.1]heptane-2-carboxylate (p14, 100 mg,

0.44 mmol) was dissolved in THF (7 mL). PPh3 (174 mg, 0.66 mmol) was added, followed by 3-hydroxyisoquinoline (96 mg, 0.66 mmol). The mixture was stirred at RT for 15’, then cooled to 0 °C. Di-tert-butyl azodicarboxylate (152 mg, 0.66 mmol) was added portionwise and, after 10’, the ice bath was removed, allowing the mixture to stir at RT for 1.5h. The mixture was concentrated under vacuum to obtain a crude that was combined with crude from a similar preparation. Combined crude material was purified by FC on silica gel (eluent from Cy to EtOAc 20%) to afford tert-butyl 3-[(isoquinolin-3yloxy)methyl]-2-azabicyclo[3.1.1]heptane-2-carboxylate (p16, 72 mg, 30% recovery on combined batches) as colourless oil.

MS (m/z): 355.3 [MH]⁺.

Preparation 17: 3-({[5-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-2azabicyclo[3.1,1]heptane trifluoroacetate

A mixture of tert-butyl 3-({[5-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-25 azabicyclo[3.1.1]heptane-2-carboxylate (p15, 100 mg, 0.27 mmol) and TFA (0.75 ml_) in

DCM (5 ml.) was stirred at RT for 1h 30 minutes, then the solution was evaporated to give 3-({[5-(trifluoromethyl)pyridin-2-yl]oxy}methyl)-2-azabicyclo[3.1.1]heptane trifluoroacetate (p17, 104 mg, recovery assumed quantitative) as pale yellow oil.

MS (zn/z): 273.1 [MH]⁺.

Preparation 18: 3-{2-azabicyclo[3.1.1]heptan-3-ylmethoxy}isoquinoline

To a solution of tert-butyl 3-[(isoquinolin-3-yloxy)methyl]-2-azabicyclo[3.1.1]heptane-215 carboxylate (p16, 72 mg, 0.20 mmol) in DCM (3 ml_), TFA (1 ml_) was added and the reaction was stirred at RT for 30’. It was concentrated under vacuum; the residue was purified by SCX washing with MeOH and eluting with NH3 1M in MeOH to obtain 3-{2azabicyclo[3.1.1]heptan-3-ylmethoxy}isoquinoline (p18, 44 mg, y= 83%) as pale yellow oil.

_

MS (zn/z): 255.2 [MH]⁺.

Preparation 19: 2-azabicyclo[3.1.1]heptan-3-ylmethanol

H

To a solution of tert-butyl 3-(hydroxymethyl)-2-azabicyclo[3.1.1]heptane-2-carboxylate (p14, 440 mg, 1.94 mmol) in DCM (21 ml_), TFA (7 ml_) was added and the reaction was stirred at RT for 1 h. Then it was concentrated under vacuum and the residue was purified by SCX washing with MeOH and eluting with NH₃ 1M in MeOH to obtain 25 azabicyclo[3.1.1]heptan-3-ylmethanol (p19, 240 mg, 1.89 mmol, y= 97 %) as pale yellow oil.

MS (zn/z): 128.1 [MH]⁺.

Preparation 20: 2-azabicyclo[3.1.1]heptan-3-ylmethanol hydrochloride

^hhci

A 4N solution of HCI in dioxane (7 ml_, 28 mmol) was added to tert-butyl 3(hydroxymethyl)-2-azabicyclo[3.1.1]heptane-2-carboxylate (p14, 223 mg, 1 mmol) and the resulting reaction mixture was stirred at RT for 2 hrs. The reaction mixture was concentrated under reduced pressure affording 2-azabicyclo[3.1.1]heptan-3-ylmethanol hydrochloride (p20, 144 mg) as beige solid.

MS (zn/z): 128.1 [MH]⁺.

Preparation 21: 3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-azabicyclo[3.1.1]heptanes

NaH (60% in mineral oil, 53 mg, 1.32 mmol) was added to a solution of 2azabicyclo[3.1.1]heptan-3-ylmethanol (p19, 152 mg,1.1 mmol) in DMF dry (5 ml_) at 0 °C under nitrogen, then the suspension was stirred at RT for 45 minutes. 2,525 difluoropyridine (0.14 ml_, 1.21 mmol) was added, and the mixture was stirred at RT for 30 minutes, then at 60 °C for 1h 30 minutes. The mixture was cooled to RT, then it was partitioned between AcOEt and brine. The aqueous phase was extracted with more AcOEt, then the combined organics were washed with brine, dried over Na2SO₄, and filtered. The solvent was evaporated to give a crude yellow oil that was purified by FC on

NH column (eluent: DCM: MeOH 100% to 98:2), to give 3-{[(5-fluoropyridin-2yl)oxy]methyl}-2-azabicyclo[3.1.1]heptanes (p21, 95 mg, y= 47%) as a yellow oil.

MS (m/z): 223.1 [MH]⁺.

Preparation 22: 3-{[(5-chloropyridin-2-yl)oxy]methyl}-2-azabicyclo[3.1.1]heptane

NaH (60% in mineral oil, 81 mg, 2 mmol) was added to a solution of 2azabicyclo[3.1.1]heptan-3-ylmethanol (p19, 215 mg, 1.69 mmol) in DMF dry (5 ml_) at 0 °C under nitrogen, then the suspension was stirred at RT for 45 minutes. 5-Chloro-2fluoropyridine (0.195 ml_, 1.94 mmol) was added, and the mixture was stirred at 60 °C for 1h. The mixture was cooled to RT, then it was partitioned between AcOEt and brine. The aqueous phase was extracted with more AcOEt, then the combined organics were washed with brine, dried over Na₂SO4, and filtered. The solvent was evaporated to give a crude yellow oil that was purified by FC on NH column (eluent: CyAcOEt 90:10 to 70:30), to give 3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-azabicyclo[3.1.1]heptanes (p22, 254 mg, y= 63%) as a colourless oil.

MS (m/z): 238.9 [MH]⁺.

Preparation 23: methyl 2-azabicyclo[3.1.1]heptane-3-carboxylate

O

A mixture of 2-tert-butyl 3-methyl 2-azabicyclo[3.1.1]heptane-2,3-dicarboxylate (p13, 1.5 g, 5.9 mmol) and TFA (7.5 ml_) in DCM (50 ml_) was stirred at RT for 1h, then the solution was concentrated, and the residue was purified by SCX cartridge (10g, 0.9 meq/g), first eluting with MeOH, then with NH3 1M in MeOH affording methyl 2azabicyclo[3.1.1]heptane-3-carboxylate (p23, 816 mg, y= 89%) as a yellow oil.

MS (m/z): 156.0 [MH]⁺.

Preparation 24: methyl 2-[(4-methoxyphenyl)methyl]-2-azabicyclo[3.1.1]heptane-3 carboxylate

A mixture of methyl 2-azabicyclo[3.1.1]heptane-3-carboxylate (p23, 816 mg, 5.26 mmol), 5 potassium carbonate (1.09 g, 7.9 mmol), and 1-(chloromethyl)-4-methoxybenzene (0.85 mL, 6.3 mmol) in acetonitrile dry (35 mL) was stirred under nitrogen at 50 °C for 3h. The mixture was filtered to remove the excess potassium carbonate, and the filtrate was evaporated. The crude material was purified by SCX cartridge (10 g, 0.9 meq/g), first eluting with MeOH, then with NH3 1N in MeOH affording methyl 2-[(410 methoxyphenyl)methyl]-2-azabicyclo[3.1.1]heptane-3-carboxylate (p24, 1.29 g, y= 89%) as a yellow oil.

MS(m/z): 276.1 [MH]⁺.

Preparation 25: {2-[(4-methoxyphenyl)methyl]-2-azabicyclo[3.1.1]heptan-3yljmethanol

L1AIH4 (sol 2M in THF, 3.5 mL, 7 mmol) was added to a solution of methyl 2-[(4methoxyphenyl)methyl]-2-azabicyclo[3.1.1]heptane-3-carboxylate (p24, 1.29 g, 4.7 mmol) in THF dry (40 mL) at 0 °C under nitrogen. The mixture was stirred for 45 minutes, then solid sodium sulphate decahydrate was added. The resulting mixture was stirred for 4h, allowing temperature to reach RT. Solid was filtered off and the organic solution was evaporated to give {2-[(4-methoxyphenyl)methyl]-2-azabicyclo[3.1.1]heptan-3yljmethanol (p25, 1.13 g, y= 97%) as a colourless oil.

MS (zn/z): 248.1 [MH]⁺.

Preparation 26: 3-(4-fluorophenoxymethyl)-2-[(4-methoxyphenyl)methyl]-2azabicyclo[3.1,1]heptane

A solution of {2-[(4-methoxyphenyl)methyl]-2-azabicyclo[3.1.1]heptan-3-yl}methanol (p25, 1.13 g, 4.56 mmol), 4-fluorophenol (613 mg, 5.47 mmol), and Ph₃P (1.2 g, 4.56 mmol) in THF dry (35 ml_) was prepared at 0 °C under nitrogen, then a solution of DIAD (1.35 ml_, 6.84 mmol) in THF dry (5 ml_) was added dropwise at 0 °C. The mixture was allowed to reach RT, and stirred at RT overnight. The mixture was partitioned between AcOEt and aqueous NaHCC>3, then the organic phase was dried over Na2SC>4 and filtered. The solvent was evaporated to give a yellow oil which was purified by FC on NH column (eluent: Cy/AcOEt 99:1 to 95:5) affording 3-(4-fluorophenoxymethyl)-2-[(4methoxyphenyl)methyl]-2-azabicyclo[3.1.1]heptane (p26, 1.03 g, y= 66%).

MS (zn/z): 342.1 [MH]⁺.

Preparation 27: 3-(4-chlorophenoxymethyl)-2-[(4-methoxyphenyl)methyl]-2azabicyclo[3.1,1]heptane

A solution of {2-[(4-methoxyphenyl)methyl]-2-azabicyclo[3.1.1]heptan-3-yl}methanol (P25, 233 mg, 0.94 mmol), 4-chlorophenol (407 uL, 1.13 mmol), and Ph₃P (369 mg, 1.41 mmol) in THF dry (8 ml_) was prepared at 0 °C under nitrogen, then a solution of DIAD (0.277 ml_, 1.41 mmol) in THF dry (2 ml_) was added dropwise at 0 °C. The mixture was allowed to reach RT, and stirred at RT overnight. The solvent was evaporated and the crude material was purified by SCX cartridge first eluting with MeOH, then with NH₃1N in MeOH then further purified by FC on silica gel (eluent: cyclohexane:ethyl acetate 100:0 to 85:15) affording 3-(4-chlorophenoxymethyl)-2-[(4-methoxyphenyl)methyl]-2azabicyclo[3.1.1]heptane (p27, 185 mg, y= 55%).

MS (zn/z): 358.1 [MH]⁺.

Preparation 28: 3-(4-fluorophenoxymethyl)-2-azabicyclo[3.1.1]heptane

To a solution of 3-(4-fluorophenoxymethyl)-2-[(4-methoxyphenyl)methyl]-2azabicyclo[3.1.1]heptanes (p26, 420 mg, 1.23 mmol) in MeOH (30 ml_) ammonium formate (775 mg, 12.3 mmol) and Pd(0H)2 20 wt. % (84 mg, 0.12 mmol) were added. The solution was stirred at 65 °C for 1 h, cooled to RT, filtered over celite and concentrated under vacuum. The crude was purified by SCX washing with MeOH and eluting with NH₃ 1M in MeOH affording 3-(4-fluorophenoxymethyl)-2azabicyclo[3.1.1]heptane (p28, 280 mg, y = 50%) as yellow oil.

MS (ZT7/Z): 222.0 [MH]⁺.

Preparation 29: 3-(4-chlorophenoxymethyl)-2-azabicyclo[3.1.1]heptane

To a solution of 3-(4-chlorophenoxymethyl)-2-[(4-methoxyphenyl)methyl]-2azabicyclo[3.1.1]heptane (p27, 150 mg, 0.14 mmol) in DCE (5 ml_), ACE-CI (16 uL,

0.153 mmol) and DI PEA (73 uL, 0.42 mmol) were added. The reaction mixture was irradiated by MW (T=120 °C, 25 min). Then solvent was removed under reduced pressure and the residue was dissolved in MeOH (2 ml_). The solution was irradiated by MW (T=90 °C, 20 min). Solvent was removed and crude was purified by SCX cartridge first eluting with MeOH, then with NH₃1M in MeOH affording 3-(4-chlorophenoxymethyl)25 2-azabicyclo[3.1.1]heptane (p29, 86 mg, y= 85%) as a colourless oil.

NMR (¹H, Chloroform-d): δ 7.25 (d, 2H), 6.89 (d, 2H), 3.96-4.03 (m, 1H), 3.87-3.95 (m, 2H), 3.65-3.71 (m, 1H), 2.52-2.60 (m, 1H), 2.24-2.33 (m, 1H), 2.15-2.23 (m, 1H), 1.952.13 (m, 2H), 1.81-1.93 (m, 1H), 1.33-1.41 (t, 1H)

Preparation 30: tert-butyl 3-formyl-2-azabicyclo[3.1.1]heptane-2-carboxylate

Boc

Dess-Martin periodinane (1.026 g, 2.42 mmol) was added portionwise to a stirred solution of tert-butyl 3-(hydroxymethyl)-2-azabicyclo[3.1.1]heptane-2-carboxylate (p14,

460 mg, 2.02 mmol) in DCM (10 ml_) at 0°C. The reaction mixture was stirred for 2 hours at RT. The reaction mixture was diluted with DCM (10 ml_) and quenched with 5% sodium thiosulphate in saturated NaHCOs aqueous solution (25 ml_). The resulting biphasic mixture was stirred vigorously for 15 minutes then extracted with DCM (3 x 20 ml_). The combined organic phases were evaporated under reduced pressure and the residue was purified by FC on silica gel (EtOAc/Cyclohexane 95:5 to 70:30) to give tertbutyl 3-formyl-2-azabicyclo[3.1.1]heptane-2-carboxylate (p30, 350 mg, y= 77%) as colourless oil.

MS (zn/z): 226.1 [MH]⁺.

Preparation 31: tert-butyl 3-[2-methoxyethenyl]-2-azabicyclo[3.1.1]heptane-2carboxylate

I

Boc

A solution of potassium tert-butoxide (278.3 mg, 2.48 mmol) in THF (3 ml_) was added dropwise to a stirred suspension of the (methoxymethyl)triphenylphosphonium chloride (935.8 mg, 2.73 mmol) in THF (3 ml_) cooled in an ice bath. After stirring the red solution at room temperature for 30 minutes, tert-butyl 3-formyl-2-azabicyclo[3.1.1]heptane-2carboxylate (p30, 280 mg, 1.24 mmol) in THF (3 ml_) was added and the reaction stirred at room temperature for 16 hours. The reaction was partitioned between saturated aqueous ammonium chloride solution and Ethyl Acetate. Combined organic extracts were washed with water, dried and concentrated and the residue purified by FC on silica gel (Cyclohexane/EtOAc 10:0 to 7:3) affording tert-butyl 3-[2-methoxyethenyl]-2azabicyclo[3.1.1]heptane-2-carboxylate (p31, 250 mg, y= 80%) in a 80% purity due to presence of 20% of already deprotected homologated aldehyde.

MS (zn/z): 254.1 [MH]⁺.

Preparation 32: tert-butyl 3-(2-oxoethyl)-2-azabicyclo[3.1.1]heptane-2-carboxylate

Boc tert-butyl 3-[2-methoxyethenyl]-2-azabicyclo[3.1.1]heptane-2-carboxylate (p31, 250 mg, 0.99 mmol) was dissolved in acetonitrile (10 ml_) then 0.4 M trifluoroacetic acid in water (100 uL, 0.099 mmol) was added to the reaction mixture and the reaction was stirred at RT for 1 hour. After this period of time, the reaction was complete. A saturated solution of sodium bicarbonate (10 ml_) was added to quench the reaction and then the solvent was evaporated. The resultant aqueous layer was then extracted with ethyl acetate (3 x 50 ml_), and the combined organic layers dried with sodium sulfate, filtered and concentrated in vacuo to afford tert-butyl 3-(2-oxoethyl)-2-azabicyclo[3.1.1]heptane-2carboxylate (p32, 190 mg, y= 91%) as colorless oil, that was used as crude in the next step.

_

MS (zn/z): 240.1 [MH]⁺.

Preparation 33: tert-butyl 3-(2-hydroxyethyl)-2-azabicyclo[3.1.1]heptane-2carboxylate

Boc

A mixture of tert-butyl 3-(2-oxoethyl)-2-azabicyclo[3.1.1]heptane-2-carboxylate (p32, 190 mg, 0.79 mmol) and sodium borohydride (32.8 mg, 0.87 mmol) in methanol (3 ml_) were stirred at RT for 2 hours. Water was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with brine, dried, concentrated, and purified by FC on silica gel (Cyclohexane/EtOAc 90:10 to 60:40) affording tert-butyl 3-(2hydroxyethyl)-2-azabicyclo[3.1.1]heptane-2-carboxylate (p33, 140 mg, y= 73%).

MS (zn/z): 242.1 [MH]⁺.

Preparation 34: tert-butyl 3-[2-(4-fluorophenoxy)ethyl]-2-azabicyclo[3.1.1]heptane2-carboxylate

Boc

To a solution of tert-butyl 3-(2-hydroxyethyl)-2-azabicyclo[3.1.1]heptane-2-carboxylate 5 (p33, 140 mg, 0.58 mmol), 4-fluorphenol (90.8 mg, 0.81 mmol) and triphenylphosphine (212 mg, 0.81 mmol) in anhydrous tetrahydrofuran (5 ml_) at 0° C under an atmosphere of nitrogen was added diisopropyl azodicarboxylate (147.6 uL, 0.75 mmol) and the resulting mixture was stirred at ambient temperature for about 2 hours. The clear colourless solution was concentrated in vacuo The crude liquid was purified by FC on silica gel (Cyclohexane/EtOAc 95:5 to 7:3) to give tert-butyl 3-[2-(4-fluorophenoxy)ethyl]2-azabicyclo[3.1.1]heptane-2-carboxylate (p34, 170 mg, y= 88%) as a white powder.

MS (zn/z): 336.1 [MH]⁺.

Preparation 35: 3-[2-(4-fluorophenoxy)ethyl]-2-azabicyclo[3.1.1]heptane

H tert-butyl 3-[2-(4-fluorophenoxy)ethyl]-2-azabicyclo[3.1.1]heptane-2-carboxylate (p34, 20 170 mg, 0.51 mmol) was treated with TFA (1 ml_) in DCM (3 ml_) and stirred at RT for 1 hour. The solvent was evaporated and the crude was purified by SCX cartridge first washing with MeOH then eluting with NH3 1M in MeOH affording 3-[2-(4fluorophenoxy)ethyl]-2-azabicyclo[3.1.1]heptane (p35, 120 mg, y= quantitative).

MS (zn/z): 236.0 [MH]⁺.

Preparation 36: 2-tert-butyl 3-methyl 4-methylidene-2-azabicyclo[3.1.1]heptane-2,3dicarboxylate

To an ice-bath cooled suspension of t-ButO'K⁺ (2.9 g, 25.98 mmol) in THF (35 ml_) (methyl) triphenylphosphonium bromide (9.9 g, 27.85 mmol) was added. After 15 minutes the mixture was allowed to reach RT and stirred at that temperature for 45 minutes then cooled down again to 0°C. Then a solution of 2-tert-butyl 3-methyl 4-oxo-210 azabicyclo[3.1.1]heptane-2,3-dicarboxylate (p8, 5.0g, 18.56 mmol) in THF (10 ml_) was slowly added and the mixture was allowed to reach RT and stirred at that temperature for 1 h, then heated at 60°C and stirred at that temperature for further 2 hours. The mixture was then cooled down to RT and quenched with water, extracted with AcOEt, dried and evaporated. The crude was purified by FC on silica gel (eluent: Cy:AcOEt 85:15) affording 2-tert-butyl 3-methyl 4-methylidene-2-azabicyclo[3.1.1]heptane-2,3dicarboxylate (p36, 2.0 g, y = 40%) as yellow oil.

MS (m/z): 268.0 [MH]⁺.

Preparation 37: CIS/TRANS 2-tert-butyl 3-methyl 4-methyl-2azabicyclo[3.1.1]heptane-2,3-dicarboxylate

2-tert-butyl 3-methyl 4-methylidene-2-azabicyclo[3.1.1]heptane-2,3-dicarboxylate (p36,

1.75 g, 6.5 mmol) was dissolved in EtOH (60 ml_). Then Pd/C [10%] (1.0 g) was added and the mixture was hydrogenated at 6 atm. After 4h Pd/C 10% was added (1.0 g) and the reaction was stirred under H2 atmosphere (6 atm) overnight. The day after further Pd/C 10% (1.0 g) was added and the reaction was stirred for additional 4 h at 6 atm. The catalyst was filtered off over a pad of celite and the reaction was concentrated under vacuum affording CIS/TRANS 2-tert-butyl 3-methyl 4-methyl-2-azabicyclo[3.1.1]heptane2,3-dicarboxylate (p37, 1.66 g, y = 95%, mixture of cis and trans diastereoisomers) as brown oil that was used as crude in the next step.

MS (m/z): 268.0 [MH]⁺.

Preparation 38: CIS/TRANS tert-butyl 3-(hydroxymethyl)-4-methyl-2azabicyclo[3.1.1]heptane-2-carboxylate

Boc

CIS/TRANS 2-tert-butyl 3-methyl 4-methyl-2-azabicyclo[3.1.1]heptane-2,3-dicarboxylate (p37, 0.3 g, 1.11 mmol) was dissolved in anhydrous THF (8.5 ml_) and cooled to -20°C. LiAIHU 2M in THF (0.9 ml_, 1.78 mmol) was added dropwise and reaction was stirred at 20 ° for 4 h. The reaction was quenched with Ν3₂504·10Η₂0 and warmed to RT. The reaction was filtered and concentrated under vacuum affording CIS/TRANS tert-butyl 310 (hydroxymethyl)-4-methyl-2-azabicyclo[3.1.1]heptane-2-carboxylate (p38, 0.25 g, y= 93%, mixture of cis and trans diastereoisomers) as yellow solid, that was used as such in the next step.

MS (zn/z): 236.0 [MH]⁺.

Preparation 39: CIS/TRANS {4-methyl-2-azabicyclo[3.1.1]heptan-3-yl}methanol

To a solution of CIS/TRANS tert-butyl 3-(hydroxymethyl)-4-methyl-2azabicyclo[3.1.1]heptane-2-carboxylate (p38, 0.25 g, 1.03 mmol) in DCM (3 ml_) TFA (0.5 ml_) was added. The reaction was stirred at RT for 2 h. The mixture was concentrated under vacuum and the residue was purified by SCX, washing with MeOH and eluting with NH₃ 1M in MeOH affording CIS/TRANS {4-methyl-2azabicyclo[3.1.1]heptan-3-yl}methanol (p39, 0.15 g, y = 99%, mixture of cis and trans diastereoisomers) as colourless oil.

MS (zn/z): 141.9 [MH]⁺.

Preparation 40: azabicyclo[3.1.1]heptane

CIS/TRANS

3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-

NaH (60% in mineral oil, 84 mg, 1.38 mmol) was added to a solution of CIS/TRANS {45 methyl-2-azabicyclo[3.1.1]heptan-3-yl}methanol (p39, 150 mg, 1.06 mmol) in DMF dry (3 ml_) at 0 °C under nitrogen, then the suspension was stirred at RT for 45 minutes. 2,5-Difluoropyridine (0.126 ml_, 1.38 mmol) was added, and the mixture was stirred at 70 °C for 3 hours. The reaction was then quenched with methanol. Solvents were removed under reduced pressure and crude was purified by SCX washing first with MeOH and then eluting with NH₃ 1M in MeOH to give CIS/TRANS 3-{[(5-fluoropyridin-2yl)oxy]methyl}-2-azabicyclo[3.1.1]heptane (p40, 0.11 g, mixture of cis and trans diastereoisomers) that was used as such in the next step.

MS (zn/z): 237.0 [MH]⁺.

Preparation 41: CIS/TRANS 1-({4-methyl-2-azabicyclo[3.1.1]heptan-3yl}methoxy)isoquinoline

NaH (60% in mineral oil, 50 mg, 1.27 mmol) was added to a solution of CIS/TRANS {4methyl-2-azabicyclo[3.1.1]heptan-3-yl}methanol (p39, 150 mg, 1.06 mmol) in DMF dry (4 ml_) at 0 °C under nitrogen, then the suspension was stirred at RT for 45 minutes.

1-Chloroisoquinoline (0.85 ml_, 1.27 mmol) was added, and the mixture was stirred at 80 °C for 6h. The mixture was cooled to RT, then it was partitioned between AcOEt and brine. The aqueous phase was extracted again with AcOEt, then the combined organics were washed with brine, dried over Na2SO4, and filtered.

The solvent was evaporated and crude was purified by FC on silica gel (eluent: DCM/ EtOH 100:0 to 9:1) affording CIS/TRANS 1-({4-methyl-2-azabicyclo[3.1.1]heptan-368 yl}methoxy)isoquinoline (p41, 0.1 g, y= 42%, mixture of cis and trans diastereoisomers) as a yellow oil.

NMR (¹H, DMSO-c/6): δ 8.26-8.32 (m, 1H), 7.99-8.05 (m, 1H), 7.88-7.93 (m, 1H), 7.755 7.82 (m, 1H), 7.62-7.69 (m, 1H), 7.37-7.43 (m, 1H), 4.35-4.47 (m., 2H), 4.00-4.11 (m,

1H), 3.50-3.61 (m, 1H), 2.44-2.51 (m, 1H), 2.32-2.42 (m, 1H), 2.10-2.21 (m, 1H), 1.992.07 (m, 1H), 1.84-1.96 (m, 1H), 1.51-1.61 (t, 1H), 1.01-1.07 (m, 3H)

Preparation 42: CIS/TRANS 7-chloro-2-({4-methyl-2-azabicyclo[3.1.1]heptan-3-

NaH (60% in mineral oil, 38 mg, 0.95 mmol) was added to a solution of CIS/TRANS {4methyl-2-azabicyclo[3.1.1]heptan-3-yl}methanol (p39, 112 mg, 0.79 mmol) in DMF dry (4 mL) at 0 °C under nitrogen, then the suspension was stirred at RT for 45 minutes. 2,715 dichloroquinoxaline (173.2 mg, 0.87 mmol) was added, and the mixture was stirred at RT for 30 minutes, then at 60 °C for 1h 30 minutes. The mixture was cooled to RT, then it was partitioned between AcOEt and brine. The aqueous phase was extracted with more AcOEt, and then the combined organics were washed with brine, dried over Na2SO4, and filtered. The solvent was evaporated and the crude was purified by FC on NH column (eluent: DCM/ MeOH 100% to 98:2) affording CIS/TRANS 7-chloro-2-({4-methyl-2azabicyclo[3.1.1]heptan-3-yl}methoxy)quinoxaline (p42, 194.4 mg, y= 81%, mixture of cis and trans diastereoisomers).

MS (m/z): 303.93 [MH]⁺.

Preparation 43: CIS/TRANS methyl 4-methyl-2-azabicyclo[3.1.1]heptane-3carboxylate

To a solution of CIS/TRANS 2-tert-butyl 3-methyl 4-methyl-2-azabicyclo[3.1.1]heptane30 2,3-dicarboxylate (p37, 535 mg, 1.99 mmol) in DCM (10 mL), TFA (1 mL) was added and the mixture was stirred at RT overnight. The solvent was then removed and the crude mixture was purified by SCX first washing with MeOH then eluting with NH31M in MeOH, affording CIS/TRANS methyl 4-methyl-2-azabicyclo[3.1.1]heptane-3-carboxylate (p43,

305 mg, y= 91%, mixture of cis and trans diastereoisomers).

MS (m/z): 170.0 [MH]⁺.

Preparation 44: CIS/TRANS methyl 2-[(4-methoxyphenyl)methyl]-4-methyl-2azabicyclo[3.1.1]heptane-3-carboxylate

A mixture of CIS/TRANS methyl 4-methyl-2-azabicyclo[3.1.1]heptane-3-carboxylate (p43, 305 mg, 1.8 mmol), potassium carbonate (373 mg, 2.7 mmol), and 1(chloromethyl)-4-methoxybenzene (0.292 ml_, 2.16 mmol) in acetonitrile dry (11 ml_) was stirred under nitrogen at 50 °C overnight. Then the mixture was filtered to remove the excess potassium carbonate, and the filtrate was evaporated.

The crude material was purified by SCX cartridge, first washing with MeOH, then eluting with NH₃ 1N in MeOH, affording CIS/TRANS methyl 2-[(4-methoxyphenyl)methyl]-4methyl-2-azabicyclo[3.1.1]heptane-3-carboxylate (p44, 457 mg, y= 87%, mixture of cis and trans diastereoisomers) as colourless oil.

MS (m/z): 290.3 [MH]⁺.

Preparation 45: CIS/TRANS {2-[(4-methoxyphenyl)methyl]-4-methyl-2azabicyclo[3.1.1]heptan-3-yl}methanol

CIS/TRANS 2-[(4-methoxyphenyl)methyl]-4-methyl-2-azabicyclo[3.1.1]heptane-3carboxylate (p44, 457 mg, 1.58 mmol) was dissolved in anhydrous THF (12 ml_) and cooled at 0 °C. LiAIHU 1M in THF (2.5 mL, 2.5 mmol) was added dropwise to the solution at 0 °C, then the mixture was stirred at 0 °C for 2 hours and at RT for 1 hour. Then the reaction was quenched at 0 °C with Na₂SO4*10 H₂O and left stirring overnight at RT. Then it was filtered and concentrated under reduced pressure. The residue was purified by SCX first washing with MeOH and then eluting with NH3 1M in MeOH affording CIS/TRANS {2-[(4-methoxyphenyl)methyl]-4-methyl-2-azabicyclo[3.1.1]heptan-3yljmethanol (p45, 400 mg, y= 97%, mixture of cis and trans diastereoisomers) as colourless oil.

MS (m/z): 262.3 [MH]⁺.

Preparation 46 and Preparation 47: CIS-{2-[(4-methoxyphenyl)methyl]-4-methyl-2azabicyclo[3.1.1]heptan-3-yl}methanol (p46) and TRANS-{2-[(4methoxyphenyl)methyl]-4-methyl-2-azabicyclo[3.1.1]heptan-3-yl}methanol (p47)

CIS/TRANS {2-[(4-methoxyphenyl)methyl]-4-methyl-2-azabicyclo[3.1.1]heptan-3yljmethanol was synthesized following analogue procedure as in preparation 45 on a

19.7 g scale of CIS/TRANS 2-[(4-methoxyphenyl)methyl]-4-methyl-2azabicyclo[3.1.1]heptane-3-carboxylate. Crude material was then purified by FC on RP using basic conditions (eluent: 100% ammonium bicarbonate aqueous solution adjusted to pH 10 with ammonia to CH3CN 100%) affording CIS-{2-[(4-methoxyphenyl)methyl]-4methyl-2-azabicyclo[3.1.1]heptan-3-yl}methanol (p46, 11 g, y= 62%) and TRANS-{2-[(425 methoxyphenyl)methyl]-4-methyl-2-azabicyclo[3.1.1]heptan-3-yl}methanol (p47, 2.6 g, y= 15%) ρ46Ϊ

NMR (¹H, Chloroform-d): δ 7.19 (d, 2 H), 6.85 (d, 2 H), 3.80 (s, 3 H), 3.74 - 3.78 (m, 1

H), 3.71 (d, 1 H), 3.62 (dd, 1 H), 3.54 (br. s, 1 H), 3.42 (d, 1 H), 3.29 (m, 1 H), 2.96 - 3.11 (m, 1 H), 2.43 - 2.58 (m, 1 H), 2.20 - 2.28 (m, 1 H), 1.45 - 2.01 (m, 4 H), 1.12 (d, 3 H).

p47:

NMR (¹H, Chloroform-d): δ 7.18 (d, 2 H), 6.85 (d, 2 H), 3.80 (s, 3 H), 3.75 (dd, 1 H),

3.70 (d, 1 H), 3.41 (d, 1 H), 3.32 (d, 1 H), 3.23 - 3.31 (m, 1 H), 2.32 (dd, 1 H), 2.07 - 2.26 (m, 2H), 1.64-1.82 (m, 2 H), 1.17-2.21 (m, 2 H), 0.97 (d, 3 H).

Preparation 48: CIS/TRANS 3-(4-fluorophenoxymethyl)-2-[(4methoxyphenyl)methyl]-4-methyl-2-azabicyclo[3.1.1]heptane

CIS/TRANS {2-[(4-methoxyphenyl)methyl]-4-methyl-2-azabicyclo[3.1.1]heptan-35 yl}methanol (p45, 400 mg, 1.53 mmol) was dissolved in anhydrous THF (8 mL). Then triphenylphosphine (600 mg, 2.3 mmol) was added, followed by 4-fluorophenol (257 mg, 2.3 mmol). The mixture was stirred at RT for 15 minutes, then cooled to 0 °C. DIAD (0.453 mL, 2.3 mmol) was added dropwise and after 10 minutes the ice bath was removed, allowing the mixture to stir at RT for 30 minutes; then it was heated to 55 °C for

1.5 hours. The reaction was cooled down to RT and solvent removed under reduced pressure. The crude was then purified by FC on silica gel (eluent: Cy:AcOEt 8:2) affording CIS/TRANS 3-(4-fluorophenoxymethyl)-2-[(4-methoxyphenyl)methyl]-4-methyl2-azabicyclo[3.1.1]heptane (p48, 492 mg, mixture of cis and trans diastereoisomers). Material used as crude in the next step.

_

MS (m/z): 356.1 [MH]⁺.

Preparation 49: CIS/TRANS 3-(4-fluorophenoxymethyl)-4-methyl-2azabicyclo[3.1,1]heptane

To a solution of CIS/TRANS 3-(4-fluorophenoxymethyl)-2-[(4-methoxyphenyl)methyl]-4methyl-2-azabicyclo[3.1.1]heptane (p48, 492 mg, crude material: assumed 1.38 mmol) in MeOH (10 mL) ammonium formate (1.89 g, 30 mmol) and Pd(OH)2 20% (200 mg) were added. The mixture was stirred at 65 °C for 20 minutes, then cooled down to RT. The catalyst was filtered off, and the solvent was evaporated. Water was added, and pH was corrected at 7 with NaHCO₃, then the aqueous solution was extracted with AcOEt. The organic phase was washed with brine, dried over Na2SO₄ and filtered. The solvent was evaporated and crude was purified by SCX first washing with MeOH, then eluting with

NH₃ 1M in MeOH affording CIS/TRANS 3-(4-fluorophenoxymethyl)-4-methyl-272 azabicyclo[3.1.1]heptane (p49, 181 mg, y= 56%, mixture of cis and trans diastereoisomers).

MS (zn/z): 236.0 [MH]⁺.

Preparation 50: CIS-3-(4-fluorophenoxymethyl)-2-[(4-methoxyphenyl)methyl]-4methyl-2-azabicyclo[3.1.1]heptane

To an ice cooled solution of CIS-[4-[(4-methoxyphenyl)methyl]-2-methyl-410 azabicyclo[3.1.1]heptan-3-yl]methanol (p46, 500 mg, 1.91 mmol),4-fluorophenol (0.25 mL, 2.87 mmol) and triphenylphosphine (752.67 mg, 2.87 mmol) in THF (12 mL),DIAD (0.57 mL, 2.87 mmol) was added. Reaction was left to warm to room temperature and then heated to 55 °C and stirred at the same temperature for 2 hrs. Further triphenylphosphine (752.67 mg, 2.87 mmol) and DIAD (0.57 mL, 2.87 mmol) were added and the reaction was heated at 55 °C for 1h and then left at RT overnight. Solvent was removed under reduced pressure, crude was loaded on a SCX cartridge washing with MeOH and eluting with 1N ammonia solution in MeOH. Material obtained was purified by FC on silica gel (eluent: Cy to Cy/AcOEt 7:3) affording CIS-3-[(4-fluorophenoxy)methyl]2-[(4-methoxyphenyl)methyl]-4-methyl-4-azabicyclo[3.1.1]heptane (p50, 400 mg,1.125 mmol, y= 59%) as a transparent oil.

MS (m/z): 356.4 [MH]⁺.

Preparation 51: CIS-3-(4-fluorophenoxymethyl)-4-methyl-2azabicyclo[3.1,1]heptane

To a solution of CIS-3-[(4-fluorophenoxy)methyl]-2-[(4-methoxyphenyl)methyl]-4-methyl4-azabicyclo[3.1.1]heptane (p50, 400 mg, 1.13 mmol) in Methanol (20 mL), ammonium formate (709.64 mg, 11.25 mmol) and palladium hydroxide (80.15 mg, 0.110 mmol) were added. Reaction was refluxed for 30min then the mixture was cooled to room temperature and the catalyst was filtered out. Filtrate was evaporated under reduced pressure and crude obtained was loaded on a SCX cartridge, washing with MeOH and eluting with 1N ammonia solution in MeOH to afford CIS-3-[(4-fluorophenoxy)methyl]-4methyl-2-azabicyclo[3.1.1]heptane (p51, 265 mg, y= quant).

MS (m/z): 236.4 [MH]⁺.

Preparation 52: TRANS-3-(4-fluorophenoxymethyl)-2-[(4-methoxyphenyl)methyl]-4-

methyl-2-azabicyclo[3.1.1]heptane
r
To a solution of	TRANS-[2-[(4-methoxyphenyl)methyl]-4-methyl-4-
azabicyclo[3.1.1]heptan-3-yl]methanol (p47, 164 mg, 0.63 mmol) THF (5 ml_)

triphenylphosphine (246.88 mg, 0.94 mmol) and 4-fluorophenol (105.51 mg, 0.94 mmol) were added. The solution was cooled at 0°C and DIAD (0.19 ml_, 0.94 mmol) was added dropwise. The reaction was warmed to RT and after 5 min heated at 55 °C for 2 hrs. The reaction was concentrated under vacuum and the residue was purified by FC on silica gel (eluent: from cHex 100% to cHex/AcOEt 1:1) and then further purified by SCX washing with MeOH and then eluting with NH₃ 1M in MeOH affording TRANS-3-[(4fluorophenoxy)methyl]-2-[(4-methoxyphenyl)methyl]-4-methyl-4-azabicyclo[3.1.1]heptane (p52, 140 mg, y= 63%) as yellow solid.

MS (m/z): 356.4 [MH]⁺.

Preparation 53: TRANS-3-(4-fluorophenoxymethyl)-4-methyl-2azabicyclo[3.1,1]heptane

To a solution of TRANS-3-[(4-fluorophenoxy)methyl]-2-[(4-methoxyphenyl)methyl]-4methyl-4-azabicyclo[3.1.1]heptane (p52, 140 mg, 0.39 mmol) in Methanol (10 ml_) ammonium formate (248.37 mg, 3.94 mmol) and palladium dihydroxide (27.66 mg, 0.04 mmol) were added. The reaction was stirred at 65 °C for 1 h. The mixture was cooled down then filtered over celite and concentrated under vacuum. The residue was purified by SCX cartridge first washing with MeOH and then eluting with NH₃ 1M in MeOH affording TRANS-3-[(4-fluorophenoxy)methyl]-4-methyl-2-azabicyclo[3.1.1]heptane (p53, mg,y= quant) as yellow oil. The product was used in the next step without further purification.

MS (zn/z): 236.3 [MH]⁺.

Preparation 54: CIS-{4-methyl-2-azabicyclo[3.1.1]heptan-3-yl}methanol ¢0

H

To a solution of CIS-[2-[(4-methoxyphenyl)methyl]-4-methyl-2-azabicyclo[3.1.1]heptan-3yl]methanol (p46, 300 mg, 1.15 mmol) in Methanol (8.5 ml_), ammonium formate (723.83 mg, 11.48 mmol) and palladium dihydroxide (81.76 mg, 0.110 mmol) were added. Reaction was heated to reflux and stirred at the same temperature for 30min. Then it was cooled down to RT, the catalyst was filtered out and filtrate was evaporated to dryness. Crude was loaded on a SCX cartridge washing with MeOH and eluting with 1N ammonia solution in MeOH to afford CIS-(4-methyl-2-azabicyclo[3.1.1]heptan-315 yl)methanol (p54, 155 mg, y= 95%).

MS (zn/z): 142.2 [MH]⁺.

Preparation 55: TRANS-{4-methyl-2-azabicyclo[3.1.1]heptan-3-yl}methanol

H

To a solution of TRANS-[2-[(4-methoxyphenyl)methyl]-4-methyl-2azabicyclo[3.1.1]heptan-3-yl]methanol (p47, 600 mg, 2.3 mmol) in Methanol (50 ml_) ammonium formate (1447.66 mg, 22.96 mmol) and palladium dihydroxide (161.19 mg, 0.23 mmol) were added. The reaction was left to stir at 60 °C for 1 h. The reaction was filtered over celite and concentrated under vacuum. The residue was purified by SCX cartridge first washing with MeOH and then eluting with NH3 1M in MeOH affording TRANS-(4-methyl-2-azabicyclo[3.1.1]heptan-3-yl)methanol (p55, 311 mg, y= 96%) as yellow oil. The product was used in the next step without further purifications.

MS (zn/z): 142.1 [MH]⁺.

Preparation 56: methyl 3-bromo-6-methylpyridine-2-carboxylate

Br O

3-Bromo-6-methylpyridine-2-carboxylic acid (1.5 g, 6.94 mmol) was dissolved in MeOH 5 (25 ml_) and SOCI2 (0.6 ml_, 8.33 mmol) was added dropwise. The resulting solution was refluxed ON. The day after volatiles were removed under vacuum, the residue was dissolved with water, the pH was adjusted to 7 with NaHCOs, and the product was extracted with DCM (2x). The organic phase was dried and evaporated affording methyl

3-bromo-6-methylpyridine-2-carboxylate (p56, 1.35 g, y=84%) as yellow oil.

NMR (¹H, DMSO-c/6): δ ppm 8.07-8.14 (m, 1H), 7.36-7.44 (m, 1H), 3.90 (s, 3H), 2.47 (s,

3H)

Preparation 57: methyl 6-methyl-3-(pyrimidin-2-yl)pyridine-2-carboxylate methyl 3-bromo-6-methylpyridine-2-carboxylate (p56, 0.5 g, 2.17 mmol), 2(Tributylstannyl)pyrimidine (0.76 ml_, 2.39 mmol), Pd(PPh3)4 (250 mg, 0.22 mmol) were mixed in dioxane (10 ml_) in a microwave vial. The solution was degassed for 2 min then irradiated for 1h at 160 °C. After cooling down the solution was filtered over Celite, rinsing with EtOAc. The solvent was removed under vacuum and the residue was purified by FC on silica gel (eluting from cHex to 40% AcOEt) to afford methyl 6-methyl3-(pyrimidin-2-yl)pyridine-2-carboxylate (p57, 100 mg, y=20%).

MS (m/z): 230.0 [MH]⁺.

Preparation 58: 6-methyl-3-(pyrimidin-2-yl)pyridine-2-carboxylic acid

methyl 6-methyl-3-(pyrimidin-2-yl)pyridine-2-carboxylate (p57, 100 mg, 0.43 mmol) was dissolved in EtOH/H₂O (4/1 ml_) then NaOH (86 mg, 2.15 mmol) was added. The resulting mixture was stirred at 100 °C for 3 hrs. Then the solution was cooled down, EtOH was removed under vacuum and the aqueous phase was acidified with 1N HCI until pH 2/3. Volatiles were removed under vacuum, the residue was purified by RP on C18 cartridge (from H₂O +0.1% HCOOH to 20% AcCN +0.1% HCOOH) to afford 6methyl-3-(pyrimidin-2-yl)pyridine-2-carboxylic acid (p58, 80 mg, y=87%) as white solid.

MS (zn/z): 216.1 [MH]⁺.

Preparation 59: methyl 5-methyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate

B. O

To a solution of methyl 2-iodo-5-methylbenzoate in 2-MeTHF (25 ml_) triethylamine (3.0 ml_, 21.7 mol) was added and the solution was degassed with N₂. Pinacol borane (1.56 ml_, 10.8 mol) was added slowly (over 15 minutes) to the stirring solution while maintaining the purge. The solution was further degassed for 10 minutes and Tri-otolylphosphine (110 mg, 0.36 mol) was added followed by Palladium (II) acetate (50 mg,

0.22mol). This caused the reaction to turn black immediately with a slow exothermic from °C to 25 °C. At this point a delayed exothermic was observed and the reaction temperature increased to 60 °C (over 45 minutes). The reaction temperature was increased to IT °C and aged for 2 hours. The heat source was removed and the reaction was cooled for 1 hour. A 26 w/w% ammonium chloride solution was added very slowly to

IT control gas evolution and exothermic which caused a black precipitated to form. The supernatant was transferred to the extractor which already contained 43 ml_ of water. The remaining black slurry was filtered and washed with diethyl ether. The solution was transferred to a separatory funnel and the layers were separated The crude was purified by FC on silica gel (eluent: Cy/EtoAc 8/2) affording methyl 5-methyl-2-(tetramethyl-1,3,2dioxaborolan-2-yl)benzoate (p59, 1.51 g, y=76%).

MS (m/z): 276.0 [M]⁺.

Preparation 60: methyl 5-methyl-2-(pyrimidin-2-yl)benzoate

To a solution of methyl 5-methyl-2-(tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (p59, 1.51 g, 5.5 mmol) in 2-MeTHF (20 ml_), 2-chloropyrimidine (0.756 g, 6.6 mmol) and Sodium carbonate (1.75 g, 16.5 mmol) were added. To this stirring suspension water (4 ml_) was added. The thick slurry was degassed with nitrogen for 40 minutes, then PdCbidppfj-CFLCb adduct (0.163 g, 0.2 mmol) was added. The internal temperature was set to 74°C and the mixture stirred for 16 hrs. The reaction was gone to completion therefore it was cooled to room temperature and treated with water (6 ml_) and diethyl ether (12 ml_) while maintaining stirring for 10 minutes. This solution was filtered washing with further diethyl ether (12 ml_) and water (8 ml_) then 12 ml_ of diethyl ether more. The layers was separated, organic one was dried and concentrated and the crude purified by FC on silica gel (eluent: Cy/EtoAc 7/3) affording methyl 5-methyl-2-(pyrimidin-2yl)benzoate (p60, 231 mg, y= 18%).

MS (mlz): 228.0 [MH]⁺.

Preparation 61: 5-methyl-2-(pyrimidin-2-yl)benzoic acid

To a solution of methyl 5-methyl-2-(pyrimidin-2-yl)benzoate (p60, 231 mg, 1.01 mmol) in

2-Me-THF (4 ml_) water (2.5 ml_) and sodium hydroxide solution (10 N) (1.25 ml_) were added.

The reaction turned red, the mixture was heated to 72°C and stirred at that temperature overnight. The reaction was gone to completion; therefore it was cooled down to RT and transferred to an extractor washing with water and diethyl ether. The layers were separated and the aqueous phase was back-extracted twice with diethyl ether. The aqueous layer was acidified with HCI (12 N). A precipitated was formed, that was filtered washing with water and dried affording 5-methyl-2-(pyrimidin-2-yl)benzoic acid (p61, 140 mg, y= 65%) as white solid.

MS (zn/z): 214.0 [MH]⁺.

Preparation 62: 5-methyl-2-(2H-1,2,3-triazol-2-yl)-benzoic acid

-OH

To a solution of methyl 2-iodo-5-methylbenzoate (1.00 g, 3.6 mmol) in DMF (3.5 ml_), 1 /7-1,2,3-triazole (530 mg, 7.7 mmol), cesium carbonate (2.49 g, 7.6 mmol), copper (I) iodide (40 mg, 0.21 mmol) and (R,R)-(-)-/\/,/\/'-Dimethyl-1,2-cyclohexanediamine (110 mg, 0.77 mmol) were added. The mixture was stirred at 120 °C microwave irradiation for 20 min, then an additional run of 10 min was performed. The mixture was diluted with water (50 ml_) and washed with ethyl acetate (2x30 ml_). The aqueous layer was acidified by adding of HCI 1N and extracted with ethyl acetate (3x25 mL). The combined organic layers were dried over anhydrous sodium sulphate, filtered and concentrated in vacuo. The residue was purified by FC on silica gel (eluting from DCM/MeOH 95:5 to

85:15) affording 5-methyl-2-(2/7-1,2,3-triazol-2-yl)-benzoic acid (p62, 495 mg, y= 51%) as pale orange solid.

MS (m/z): 204.0 [MH]⁺.

Preparation 63: methyl 3-amino-6-methylpyridine-2-carboxylate o

Step a:

6-methylpyridine-2,3-dicarboxylic acid (5.50 g, 30.36 mmol) was dissolved in Acetic anhydride (14.3 mL) and the mixture heated at 100 °C under nitrogen for 5 hours. Volatiles were removed under vacuum to give 2-methyl-5H,7H-furo[3,4-b]pyridine-5,715 dione (Int. a, 4.97 g).

Step b:

2-methyl-5H,7H-furo[3,4-b]pyridine-5,7-dione (Int. a, 4.97 g, 30,47 mmol) was added portion wise over 5 minutes to MeOH (30 mL) at 0 °C under stirring. The mixture was stirred at 0 °C for 30 minutes, then at room temperature for other 2.5 hrs. The solution was evaporated under reduced pressure and the residue recrystallized from toluene (60 mL). Recrystallization was repeated three times affording a mixture of 2(methoxycarbonyl)-6-methylpyridine-3-carboxylic acid and 3-(methoxycarbonyl)-6methylpyridine-2-carboxylic acid (Int. b, 2.7 g) as yellow solid.

Step c:

Int. b (2.7 g, 13.85 mmol) was suspended in toluene (100 mL) and DIPEA (2.9 mL, 16.64 mmol) was added. The mixture was stirred 10 minutes at room temperature, then Diphenyl azidophospate (4.05 g, 14.7 mmol) was added in one portion and the mixture was heated to reflux and stirred at that temperature for 1 hour. The solution was cooled to room temperature and t-BuOH (5.82 mL, 61 mmol) was added in one portion. The mixture was then stirred at 70 °C for 1 hour and then cooled to room temperature. Et2<D was added and the resulting solution washed with NaHCC>3 satured solution. The water phases were combined and back-extracted with Et20. The combined orgnics were then dried over Na₂SO4and evaporated under reduced pressure. Crude was purified by FC on silica gel (eluent: Cy/EtOAc 7/3) affording methyl 3-{[(tert-butoxy)carbonyl]amino}-6methylpyridine-2-carboxylate (Int. c, 2 g) as a white solid.

Step d:

Int. c (2 g, 7.5 mmol) was dissolved in DCM (50 ml_) and then TFA (7.5 ml_, 97.5 mmol) was added and the mixture stirred at RT overnight. Solvent was removed under reduced pressure and crude purified by SCX cartridge washing with MeOH and eluting with NH₃1M in MeOH affording methyl 3-amino-6-methylpyridine-2-carboxylate (p63, 1.2 g, y= o 24% over 4 steps).

MS (mlz)·. 166.9 [MH]⁺.

Preparation 64: methyl 3-iodo-6-methylpyridine-2-carboxylate

HCI 6N solution in water (30.75 ml_, 41 mmol) was added to methyl 3-amino-6methylpyridine-2-carboxylate (p63, 1.2 g, 7.22 mmol) and the resulting pale yellow mixture was diluted with water (2 X 10 ml_) and then cooled to 0 °C (internal temperature).

A solution of sodium nitrite (0.730 g, 10.6 mmol) in water (5 ml_) was dropped into the mixture over 1 minute. The mixture was stirred at 0 °C for 30 minutes, then a solution of Kl (2.6 g, 15.5 mmol) in water (5 ml_) was added over 1 minute and the mixture was left under stirring for 1 hour (temperature between 0 °C and +5 °C). AcOEt and water were added, phases were separated and the aqueous one was back-extracted with AcOEt. Combined organics were washed with NaHCOs saturated solution; aqueous solution from previous extraction was neutralised with NaHCOs satured solution and extracted with EtOAc. All the combined organic phases were dried over Na₂SO4 and concentrated under reduced pressure. Crude was purified by FC on silica gel (eluent: Cy/EtOAc 7/3) affording methyl 3-iodo-6-methylpyridine-2-carboxylate (p64, 1.2 g, y= 60%).

MS (mlz)·. 277.8 [M]⁺.

Preparation 65: 6-methyl-3-(1,3-thiazol-2-yl)pyridine-2-carboxylic acid o

ΌΗ

Step a:

A mixture of methyl 3-iodo-6-methylpyridine-2-carboxylate (p64, 1.2 g, 4.33 mmol), 2(tributylstannyl)-1,3-thiazole (1.5 ml_, 4.64 mmol) and Pd(PhsP)4 (0.500 g, 0.433 mmol) in 1,4-Dioxane (10 ml_) was stirred at RT overnight. The mixture was diluted with EtOAc and washed with NH4CI (saturated solution) and corrected with HCI 1N until pH about 56. The organic phase was separated and the aqueous phase was further extracted with

EtOAc. The combined organics were washed, dried over Na2SO4, and filtered. The crude was purified by FC on silica gel (eluent: Cy/ EtOAc 7/3) affording methyl 6-methyl-3-(1,3thiazol-2-yl)pyridine-2-carboxylate (Int. a, 0.61 g).

Step b:

A mixture of Int. a (0.61 g, 2.60 mmol) and LiOH (0.164 g, 3.90 mmol) in THF (10 ml_) and water (10 ml_) was stirred at RT overnight. The mixture was diluted with EtOAc and washed with NH4CI (saturated solution) and pH adjusted to 5-6 with HCI. The organic phase was separated and the aqueous phase was back-extracted with EtOAc. The combined organics were washed, dried over Na2SO4, and filtered. The solvent was evaporated affording 6-methyl-3-(1,3-thiazol-2-yl)pyridine-2-carboxylic acid (p65, 0.6 g, y= 63% over 2 steps) as a white solid.

MS (mlz)\ 176.9 [MH]⁺.

Preparation 66: 5-methyl-2-(1,3-thiazol-2-yl)benzoic acid

Step a:

2-(tributylstannyl)-1,3-thiazole (0.629 mL, 2 mmol) was dissolved in dioxane (4 ml_) in a microwave tube, then methyl 2-iodo-5-ethylbenzoate (0.568 mL, 2.4 mmol) and Palladium Tetrakis (232 mg, 0.1 mmol) were added. Once the solid dissolved, the mixture was heated to 120 °C in a microwave reactor for 60 minutes. The mixture was then quenched with water and extracted with DCM. The organic phase was dried and concentrated under reduced pressure and the crude purified by FC on NH column (eluent: Cy:AcOEt 7:3) affording methyl 5-methyl-2-(1,3-thiazol-2-yl)benzoate (Int. a, 0.46 g).

Step b:

A mixture of Int. a (0.46 g, 1.97 mmol) and LiOH (0.124 g, 2.96 mmol) in THF (10 mL) and water (10 mL) was stirred at RT overnight. The mixture was diluted with EtOAc and washed with NH4CI (saturated solution) and pH adjusted to 5-6 with HCI 1N. The organic phase was separated and the aqueous phase was back-extracted with EtOAc. The combined organics were washed, dried over Na₂SO4, and filtered. The solvent was evaporated affording 5-methyl-2-(1,3-thiazol-2-yl)benzoic acid (p66, 0.43 g, y= quant) as a white solid.

MS (m/z): 176.9 [MH]⁺.

Preparation 67: 6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxylic acid

To a 3-necked, round-bottomed flask equipped with an overhead magnetic stirrer, reflux condenser, and nitrogen inlet were added 3-bromo-6-methylpyridine-2-carboxylic acid (5.0 g, 23.14 mmol), copper iodide (0.221 g, 1.16 mmol), and Cs₂CO3 (15.08 g, 46.28 mmol). To these solids was added dioxane (25 mL), then water (1 mL), then 1H-1,2,3triazole (2.7 mL, 46.28 mmol), and finally Trans-N,N’-dimethyl-cyclohexane-1,2-diamine (0.730 mL, 4.63 mmol). The mixture was then heated to 100 °C and stirred at that temperature overnight. The day after the mixture was cooled down to RT and MTBE and water were added. After vigorous mixing, the layers were separated and the bottom aqueous layer was acidified to pH 2 with 6N HCI. The resulting precipitate was removed by filtration affording a first crop of target compound (1 g). The mother-liquors were concentrated and purified by FC on C18 cartridge (eluent: from H₂O+0.1% formic acid to

H2O/ACN + 0.1% formic acid 95:5). The fractions containing desired product were evaporated and combined with the previous crop affording 6-methyl-3-(2H-1,2,3-triazol2-yl)pyridine-2-carboxylic acid (p67, 2.3 g, y= 49%). Mixed fractions from FC were evaporated affording a less pure batch of target compound (1.2 g, 95 % purity).

MS (zn/z): 205.1 [M]⁺.

Preparation 68: ethyl 5-bromo-2-methyl-1,3-thiazole-4-carboxylate

To a solution of 2-methyl-4-thiazolecarboxylic acid ethyl ester (3 g, 17.52 mmol) in MeCN (30 ml_), 1-bromopyrrolidine-2,5-dione (6.24 g, 35.04 mmol) was added. Reaction was heated to reflux and stirred at the same temperature for 20 hrs. Then it was cooled down to RT and then cooled to 0 °C. ss NaHCOs (aq) was added and mixture was stirred for

15 min at the same temperature. MeCN was removed under reduced pressure and DCM was added. Aqueous layer was extracted several times with DCM, Combined organic layers were dried and concentrated under reduced pressure. Crude was purified by FC on silica gel (eluent: Cy/EtOAcfrom 100:0 to 70:30) to afford ethyl 5-bromo-2-methyl-1,3thiazole-4-carboxylate (p68, 2.95 g, y= 67%) as a pale orange solid.

MS (zn/z): 249.8 [M]⁺.

Preparation 69: ethyl 2-methyl-5-pyrimidin-2-yl-1,3-thiazole-4-carboxylate

To a solution of ethyl 5-bromo-2-methyl-1,3-thiazole-4-carboxylate (p68, 250.11 mg, 1 mmol) in DMF (12 ml_), cesium fluoride (305.82 mg, 2 mmol), Copper(l) iodide (19.05 mg, 0.100 mmol) and palladium triphenylphosphine (115.56 mg, 0.100 mmol) were added and mixture was degassed with nitrogen for 20min. tributyl(2-pyrimidinyl)stannane (0.32 ml_, 1 mmol) was added and the reaction was sealed and stirred under microwave irradiation at 130 °C for 30 min. Reaction was diluted with EtOAC and 1M KF aq. solution was added. The two phases were stirred at room temperature for 1 h and then separated. Organic layer was dried over Na2SO4 and solvent was removed under reduced pressure. Crude was purified by FC on silica gel (eluent: Cy/EtOAc from 100:0 to 50:50) to afford ethyl 2-methyl-5-pyrimidin-2-yl-1,3-thiazole-4-carboxylate (p69, 92.5 mg, y= 37%).

MS (m/z): 250.0 [MH]⁺.

Preparation 70: 2-methyl-5-pyrimidin-2-yl-1,3-thiazole-4-carboxylic acid

A solution of ethyl 2-methyl-5-pyrimidin-2-yl-1,3-thiazole-4-carboxylate (p69, 92.5 mg, 0.370 mmol) and 1M sodium hydroxide (1 ml_, 1 mmol) in Ethanol (2.5 ml_) was heated to 80 °C and stirred at that temperature for 30 min. The reaction was allowed to reach room temperature and then 2M HCI (aq.) was added until pH 4-5. The precipitate formed was filtered out, washed with water and dried under high vacuum to afford 2-methyl-515 pyrimidin-2-yl-1,3-thiazole-4-carboxylic acid (p70, 81.6 mg, y= quant).

MS(m/z): 221.9 [MH]⁺.

Preparation 71: 5-(2-fluorophenyl)-2-methyl-1,3-thiazole-4-carboxylic acid

Step a:

A solution of 2-fluorobenzaldehyde (4.24 ml_, 40.29 mmol) and methyl 2,2dichloroacetate (4.17 ml_, 40.29 mmol) in THF (15 ml_) was added drop-wise to a stirred suspension of t-BuOK (4.52 g, 40.29 mmol) in THF (40 ml_), at - 60 °C and under a nitrogen atmosphere. The resulting reaction mixture was stirred 4 h at - 60 °C then it was allowed to reach RT and stirred overnight. The mixture was concentrated in vacuo, DCM and ice-cold water were added, the organic phase was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by FC on silica gel (eluting with Cy/EA from 100/0 to 1/1) affording the product methyl 3-chloro-3-(2-fluorophenyl)-2-oxopropanoate (Int. a, 7.5 g) as brown oil. The product was used in the next step without further purifications.

Step b:

To a solution of Int. a (7.5 g, 32.52 mmol) in MeOH dry (60 ml_) thioacetamide (2.44 g, 32.52 mmol) was added. The solution was stirred at 60 °C overnight. The reaction was concentrated under vacuum affording methyl 5-(2-fluorophenyl)-2-methyl-1,3-thiazole-4carboxylate (Int. b, 9 g) as crude wich was used in the next step without further purification.

Step c:

To a solution of Int. b (8.17 g, 32.52 mmol) in THF/H₂O/MeOH (50 mL/10 ml_/50 mL) was added LiOH.H₂O (6.8 g, 162.6 mmol). The mixture was stirred overnight at RT then it was concentrated under reduced pressure, a s.s. of NaHCO₃ was added and the mixture diluted with DCM. Phases were separated and the aqueous phase was acified with HCI 1 N until pH = 3 and extracted with AcOEt. The organic phase was washed with brine, dried over Na₂SO4, filtered and concentrated under vacuum. The residue was purified by FC on C18 column (eluent: from 100 % water + 0.1 % FA to 100% CH₃CN + 0.1 % FA) affording 5-(2-fluorophenyl)-2-methyl-1,3-thiazole-4-carboxylic acid (p71, 504 mg, y = 6.5%) as yellow solid.

MS (zn/z): 238.1 [MH]⁺.

Preparation 72: 5-(4-fluorophenyl)-2-methyl-1,3-thiazole-4-carboxylic acid

Step a:

A solution of 4-fluorobenzaldehyde (3.46 mL, 32.25 mmol) and methyl 2,2dichloroacetate (3.67 mL, 35.5 mmol) in THF (10 mL) was added by dropping funnel to a cooled suspension of t-ButOK (4.34 g, 38.7 mmol) in THF (40 mL) (T= -78 °C). After 4 hours at -78 °C, the mixture was warmed to RT, and then stirred at that temperature overnight. The volatiles were then removed and the crude partitioned between water and DCM. Phases were separated and organic phase was dried and concentrated affording methyl 3-chloro-3-(4-fluorophenyl)-2-oxopropanoate (Int. a, 7.6 g) as crude material.

Step b:

Int. a (7.6 g, crude assumed 32.25 mmol) was dissolved in CH3CN (60 ml_) then Thioacetamide (2.42 g, 32.25 mmol) and molecular sieves (4 A) were added and the mixture stirred at RT overnight. Molecular sieves were removed and solvent evaporated. The residual yellow oil was dissolved in MeOH (50 ml_) and the mixture heated at reflux for 4 hours. Then the mixture was cooled down to RT, 2 ml_ of HCI -1.25 M solution in MeOH were added and the mixture was refluxed for further 2 hours. The mixture was then cooled down to RT, solvent eliminated under reduced pressure and the residue partitioned between water and DCM. Phases were separated and the organic one was dried and concentrated affording methyl 5-(4-fluorophenyl)-2-methyl-1,3-thiazole-4carboxylate (Int. b, 1 g) that was used as crude in the next step.

Step c:

To a solution of Int. b (0.6 g, crude assumed 2.38 mmol) in THF (5 ml_), water (5 ml_) and lithium hydroxide (0.15 g, 3.57 mmol) were added and the solution was stirred overnight at RT. THF was eliminated under reduced pressure and the aqueous phase was acidified by addition of 6 N HCI. Water was removed under reduced pressure and the crude was purified by RP on C18 cartridge (from H₂O +0.1% HCOOH to 100% ACN +0.1% HCOOH) affording 5-(4-fluorophenyl)-2-methyl-1,3-thiazole-4-carboxylic acid (P72, 430 mg) as white solid.

MS (m/z): 238.1 [MH]⁺.

Preparation 73: methyl 2-amino-5-phenyl-1,3-thiazole-4-carboxylate

Step a:

A solution of benzaldehyde (9.6 ml_, 94.23 mmol) and methyl 2,2-dichloroacetate (9.8 30 ml_, 94.23 ml_) in THF (30 ml_) was added drop-wise to a stirred suspension of t-BuOK (10.57 g, 94.23 mmol) in THF (100 ml_), at - 60 °C and under a nitrogen atmosphere. The resulting reaction mixture was stirred 4 h at - 60 °C then it was allowed to reach RT and stirred overnight. The mixture was concentrated in vacuo, DCM and ice-cold water were added, the organic phase was washed with water, dried over sodium sulfate and concentrated under reduced pressure.

The crude material was purified by FC on silica gel in portions (eluting with Cy/EA from 5 100/0 to 78/22) affording methyl 3-chloro-2-oxo-3-phenylpropanoate (Int. a, 5 g overall) as colourless oil.

Step b:

A solution of Int. a (1.01 g, 4.75 mmol) in acetone (6 ml_) was added to a suspension of 10 thiourea (0.36 g, 4.75 mmol) in acetone (10 ml_) and the resulting reaction mixture was stirred overnight at 58 °C (external temperature). The mixture was filtered, the solid was washed with acetone and dried under vacuum affording methyl 2-amino-5-phenyl-1,3thiazole-4-carboxylate (p73, 0.70 g, y= 16% over 2 steps) as white solid.

MS (m/z): 235.0 [MH]⁺._

Preparation 74: methyl 2-chloro-5-phenyl-1,3-thiazole-4-carboxylate

To a stirred mixture of methyl 2-amino-5-phenyl-1,3-thiazole-4-carboxylate (p73, 0.35 g, 1.49 mmol) in MeCN (6 ml_), at RT and under a nitrogen atmosphere, CuCb (260 mg, 1.94 mmol) was added followed by slow drop-wise addition of 3-methylbutyl nitrite (0.3 ml_, 2.24 mmol) and the resulting reaction mixture was stirring at RT for 5 hrs. The mixture was filtered and the solution concentrated under reduced pressure. The residue was taken up with DCM and water, the organic phase was washed with water, dried over sodium sulfate and concentrated under vacuum. The crude material was purified by FC on silica gel (eluent: Cy/acetone from 100/0 to 85/15) affording methyl 2-chloro-5-phenyl1,3-thiazole-4-carboxylate (p74, 195 mg, y= 51%) as white solid.

MS (m/z): 254.0 [MH]⁺.

Preparation 75: 2-chloro-5-phenyl-1,3-thiazole-4-carboxylic acid

To a solution of methyl 2-chloro-5-phenyl-1,3-thiazole-4-carboxylate (p74, 310 mg, 1.22 5 mmol) in THF/MeOH (7 /4 ml_) was added a solution of LiOH.FLO (513 mg, 12.22 mmol) in water (2 ml_) and the resulting mixture was stirred overnight at RT. The mixture was concentrated under vacuum and the residue was taken up with DCM and aqueous 1N solution of HCI up to ~ pH 5-6. The mixture was submitted to a phase separator cartridge and the solution was concentrated under vacuum affording 2-chloro-5-pheny 1-1,310 thiazole-4-carboxylic acid (p75, 241 mg, y= 82%) as white solid.

MS (mlz): 240.0 [MH]⁺.

Preparation 76: 2-methoxy-5-phenyl-1,3-thiazole-4-carboxylic acid

To a stirred solution of methyl 2-chloro-5-phenyl-1,3-thiazole-4-carboxylate (p75, 383 mg, 1.51 mmol) in MeOH (8 ml_), at RT and under a nitrogen atmosphere, MeONa (163 mg, 3.02 mmol) was added portion-wise and the resulting reaction mixture was stirred overnight at 50 °C and then for 36 hrs at RT. The mixture was concentrated under reduced pressure and the residue taken up with DCM and water (aqueous 1 M HCI was added to the mixture up to pH ~6), the organic phase was dried over phase separartor cartridge and concentrated under reduced pressure. Crude was first purified by FC on silica gel (eluent: DCM/MeOH from 100/0 to 98/2) , then by RP on C18 cartridge (from

H₂O +0.1% HCOOH to 100% ACN +0.1% HCOOH) affording 2-methoxy-5-phenyl-1,3thiazole-4-carboxylic acid (p76, 100 mg, y= 27%) as pale yellow solid.

MS (zn/z): 236.1 [MH]⁺.

Preparation 77: 2-cyclopropyl-5-phenyl-1,3-thiazole-4-carboxylic acid o

Step a:

A solution of benzaldehyde (9.6 mL, 94.23 mmol) and methyl 2,2-dichloroacetate (9.8 mL, 94.23 mL) in THF (30 mL) was added drop-wise to a stirred suspension of t-BuOK (10.57 g, 94.23 mmol) in THF (100 mL), at - 60 °C and under a nitrogen atmosphere. The resulting reaction mixture was stirred 4 h at - 60 °C then it was allowed to reach RT and stirred overnight. The mixture was concentrated in vacuo, DCM and ice-cold water were added, the organic phase was washed with water, dried over sodium sulfate and concentrated under reduced pressure.

The crude material was purified by FC on silica gel in portions (eluting with Cy/EA from 100/0 to 78/22) affording methyl 3-chloro-2-oxo-3-phenylpropanoate (Int. a, 5 g overall) as colourless oil.

Step b:

A solution of Int. a (360 mg, 1.69 mmol) in MeCN (4 mL), cyclopropanecarbothioamide (171 mg, 1.69 mmol) and molecular sieves (0.2 g) were added and the reaction mixture was shaken overnight at RT. No reaction was detected by UPLC analysis. The mixture was concentrated under reduced pressure, methanol (5 mL) was added and the mixture was shaken overnight at 60 °C. The mixture was filtered and the filtrate concentrated under reduced pressure. The residue was purified by FC on silica gel (eluent: Cy/EA from 100/0 to 85/15) affording methyl 2-cyclopropyl-5-phenyl-1,3-thiazole-4-carboxylate (Int. b, 135 mg).

Step c:

To a solution of Int. b (135 mg, 0.52 mmol) in THF/H₂O/MeOH (2.5 mL/1 mL/0.5 mL) was added LiOH.H2O (109 mg, 2.60 mmol). The mixture was stirred overnight at RT. The mixture was concentrated under reduced pressure, the residue was taken up with HCI 1 N aqueous solution and the resulting mixture was extracted with DCM. The organic phase was dried over a phase separator cartridge and the solution was concentrated under vacuum. Crude was purified by RP on C18 cartridge (from H₂O +0.1% HCOOH to

70% ACN +0.1% HCOOH) affording 2-cyclopropyl-5-phenyl-1,3-thiazole-4-carboxylic acid (p77, 53 mg) as white solid.

MS (zn/z): 235.0 [MH]⁺.

Preparation 78: [2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1]heptan-3-yl]methanol

2-methyl-5-phenyl-1,3-thiazole-4-carboxylic acid (235 mg, 1.07 mmol) was dissolved in DMF (5 ml_), then HATU (479 mg, 1.26 mmol) was added followed by DIPEA (0.370 ml_, 2.13 mmol). The resulting solution was stirred for 10 min then 2-azabicyclo[3.1.1]heptan3-ylmethanol (p19, 123 mg, 0.97 mmol) in DMF (1 ml_) was added and the mixture stirred for 1 hr. The mixture was diluted with NH4CI ss and DCM, the two phases were separated and the product was extracted twice with DCM. Combined organics were dried over phase separator and evaporated. The residue was purified by FC on NH column (eluent: from Cy to EtOAc 100%) affording [2-(2-methyl-5-phenyl-1,3-thiazole-4carbonyl)-2-azabicyclo[3.1.1]heptan-3-yl]methanol (p78, 160 mg, y= 50%) as pale yellow foam.

MS (zn/z): 329.2 [MH]⁺.

Preparation 79: {2-[5-(4-fluorophenyl)-2-methyl-1,3-thiazole-4-carbonyl]-2azabicyclo[3.1.1]heptan-3-yl}methanol

To a solution of 5-(4-fluorophenyl)-2-methyl-1,3-thiazole-4-carboxylic acid (p72, 78.3 mg, 0.33 mmol) in DMF (2 mL) HATU (148 g, 0.39 mmol) and DIPEA (0.1 mL, 0.66 mmol) were added. The mixture was stirred at room temperature for 30 min and added to a solution of 2-azabicyclo[3.1.1]heptan-3-yl}methanol hydrochloride (p20, 50 mg, 0.30 mmol) and DIPEA (0.07 mL, 0.36 mmol) in DMF (1 mL). The reaction was stirred at room temperature for 1 h, water was added and the reaction was concentrated under vacuum. The residue was purified by FC C18 cartridge (eluent from 100 % H₂O + 0.1 % FA to CH₃CN + 0.1 % 100 %) affording {2-[5-(4-fluorophenyl)-2-methyl-1,3-thiazole-4carbonyl]-2-azabicyclo[3.1.1]heptan-3-yl}methanol (p79, 0.076 g, y = 73%) as yellow oil.

MS (m/z): 347.0 [MH]⁺.

The following intermediates were prepared using an analogue procedure as in Preparation 79, reacting 2-azabicyclo[3.1.1]heptan-3-ylmethanol hydrochloride (p20) with the appropriate carboxylic acid (RCOOH) as reported in the table below.

Prep. number	Structure	Name	RCOOH	MS (m/z): [MH]⁺	Y%
	Tv	[2-(2-chloro-5-phenyl- 1,3-thiazole-4-
p80	o	carbonyl)-2azabicyclo[3.1.1 jhepta n-3-yl]methanol	p75	349.2	73

p81	MeO___ o	[2-(2-methoxy-5phenyl-1,3-thiazole-4carbonyl)-2azabicyclo[3.1.1 jhepta n-3-yl]methanol	p76	345.2	60
p82	ex- o	[2-(2-cyclopropyl-5phenyl-1,3-thiazole-4carbonyl)-2azabicyclo[3.1.1 jhepta n-3-yl]methanol	p77	355.4	84

Preparation 83: CIS/TRANS [4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4carbonyl)-2-azabicyclo[3.1.1]heptan-3-yl]methanol

2-methyl-5-phenyl-1,3-thiazole-4-carboxylic acid (426 mg, 1.95 mmol) was dissolved in DMF (5 ml_), then HATU (875 mg, 2.3 mmol) was added followed by DI PEA (0.4 ml_, 2.3 mmol). The resulting solution was stirred for 30 min then it was added to a solution of

CIS/TRANS {4-methyl-2-azabicyclo[3.1.1]heptan-3-yl}methanol (p39, 250 mg, 1.77 mmol) in DMF (2 ml_) and stirred for 1 hr at RT. The mixture was diluted with s.s. of NaHCOs and extracted with AcOEt. The organic layer was washed with Brine, dried, filtered and concentrated under vacuum. The crude was purified by FC on silica gel (eluent: DCM to DCM/MeOH 8: 2) and then by RP C18 cartridge (from Water/CFbCN

95:5 with 0.1% of Formic acid to Water/CFbCN 5:95 with 0.1% of Formic acid) affording

CIS/TRANS [4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1]heptan-3-yl]methanol (p83, 390 mg, y = 64 %,mixture of cis and trans diastereoisomers).

MS (mlz)\ 343.3 [MH]⁺.

Preparation 84: CIS/TRANS {4-methyl-2-[6-methyl-3-(pyrimidin-2-yl)pyridine-2carbonyl]-2-azabicyclo[3.1.1]heptan-3-yl}methanol

-OH

To a solution of 6-methyl-3-(pyrimidin-2-yl)pyridine-2-carboxylic acid (p58, 703 mg, 3.27 mmol) in DMF (10 mL), HATU (1.24 g, 3.27 mmol) and DIPEA (1.14 mL, 6.53 mmol) were added. The mixture was stirred at room temperature for 30 min and then it was added to a solution of CIS/TRANS {4-methyl-2-azabicyclo[3.1.1]heptan-3-yl}methanol (p39, 419 mg, 2.97 mmol) in DMF (4 mL). The reaction was stirred at room temperature for 1 h. The reaction was concentrated under vacuum and the residue was purified by RP on C18 cartridge (eluent: from 100 % H₂O + 0.1 % FA to CH₃CN + 0.1 % 100 %) affording CIS/TRANS {4-methyl-2-[6-methyl-3-(pyrimidin-2-yl)pyridine-2-carbonyl]-2azabicyclo[3.1.1]heptan-3-yl}methanol (p84, 230 mg, y = 22%, mixture of cis and trans diastereoisomers).

MS (m/z): 339.1 [MH]⁺.

Preparation 85: CIS-{4-methyl-2-[6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridine-220 carbonyl]-2-azabicyclo[3.1.1]heptan-3-yl}methanol

OH

To a solution of 6-methyl-3-(triazol-2-yl)pyridine-2-carboxylic acid (p67, 478.05 mg, 2.34 mmol) and Ν,Ν-Diisopropylethylamine (0.39 mL, 2.34 mmol) in DMF (4 mL), HATU (890.19 mg, 2.34 mmol) was added. Mixture was stirred at room temperature for 30 min then it was added dropwise to a stirring solution of CIS-{4-methyl-294 azabicyclo[3.1.1]heptan-3-yl}methanol (p54, 290 mg, 1.95 mmol) in DMF (8 ml_). The reaction was stirred at room temperature for 2 hrs. EtOAc was added and organic layer was washed with ss NaHCC>3, ss NH4CI and brine. Aqueous phases were back-extracted with EtOAc, organic layers were combined, dried and evaporated. Crude obtained was purified by FC on RP (eluent: H₂O + 0.1% HCOOH/ MeCN + 0.1% HCOOH from 95:5 to 50:50) affording CIS-{4-methyl-2-[6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carbonyl]2-azabicyclo[3.1.1]heptan-3-yl}methanol (p85, 353 mg, y = 55%) as a white solid.

MS (m/z): 328.1 [MH]⁺.

Preparation 86: TRANS-{4-methyl-2-[6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridine-2carbonyl]-2-azabicyclo[3.1.1]heptan-3-yl}methanol

To a solution of 6-methyl-3-(triazol-2-yl)pyridine-2-carboxylic acid (p67, 540 mg, 2.64 15 mmol) and HATU (1 g, 2.64 mmol) in DMF (12 ml_) DIPEA (0.46 ml_, 2.64 mmol) was added. The reaction was stirred at RT for 30 min and then added to a pre-cooled (0 °C) solution of TRANS-(2-methyl-4-azabicyclo[3.1.1]heptan-3-yl)methanol (p55, 311 mg, 2.2 mmol) in DMF (6 ml_). The reaction was stirred at RT for 3 h, then s. s. solution of

NaHCO3 was added and the reaction was extracted with AcOEt. The organic phase was 20 dried, filtered and concentrated under vacuum. The residue was purified by FC on silica gel (eluent: from cHex 100 % to AcOEt 100 %) TRANS-{4-methyl-2-[6-methyl-3-(2H1,2,3-triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptan-3- yljmethanol (p86, 700 mg, y= 97%) as yellow oil.

MS (m/z): 328.3 [MH]⁺.

Preparation 87: tert-butyl 3-{[(isoquinolin-3-yl)amino]methyl}-2azabicyclo[3.1.1]heptane-2-carboxylate

tert-butyl 3-formyl-2-azabicyclo[3.1.1]heptane-2-carboxylate (p30, 100 mg, 0.44 mmol) and isoquinolin-3-amine (63 mg, 0.44 mmol) were dissolved in DCM (3 mL), followed by AcOH (25 pL, 0.44 mmol). The mixture was stirred at RT for 15min, then NaBH(OAc)3 (131 mg, 0.62 mmol) was added and the reaction was shaken in a PLS apparatus at RT overnight. The reaction mixture was diluted with DCM, water was added and the two phases were separated. The organic one was concentrated and the crude was combined with crude from analogous preparation then purified by FC on NH column (eluent: Cy to EtOAc 30%) affording tert-butyl 3-{[(isoquinolin-3-yl)amino]methyl}-2azabicyclo[3.1.1]heptane-2-carboxylate (p87, 94 mg) as green gum.

MS (m/z): 354.3 [MH]⁺.

The following intermediates were prepared using an analogue procedure as in Preparation 87, reacting tert-butyl 3-formyl-2-azabicyclo[3.1.1]heptane-2-carboxylate (p30) with the appropriate amine (R-NH2) as reported in the table below.

Prep.	Structure	Name	RNH₂	MS (m/z): [MH]⁺	y%
p88	^b°^c	tert-butyl 3-{[(quinolin2-yl)amino]methyl}-2azabicyclo[3.1.1 jhepta ne-2-carboxylate	H 2 N \	354.4	22
p89	Boc N__/ \ \\ r	Tert-butyl 3-{[(6fluoro-1,3benzothiazol-2yl)amino]methyl}-2azabicyclo[3.1.1 jhepta ne-2- carboxylate	^H2N—	378.3	31

Preparation 90: N-{2-azabicyclo[3.1.1]heptan-3-ylmethyl}isoquinolin-3-amine

To a solution of tert-butyl 3-{[(isoquinolin-3-yl)amino]methyl}-2-azabicyclo[3.1.1]heptane5 2-carboxylate (p87, 95 mg, 0.27 mmol) in DCM (3 ml_), TFA (1 ml_) was added and the reaction was stirred at RT for 2h. Then it was concentrated under reduced pressure and the residue purified by SCX washing with MeOH and eluting with NH₃ 1M in MeOH, affording N-{2-azabicyclo[3.1.1]heptan-3-ylmethyl}isoquinolin-3-amine (p90, 61.7 mg, y=

88%) as green gum.

MS (m/z): 254.3 [MH]⁺.

The following intermediates were prepared using an analogue procedure as in Preparation 90, from the appropriate starting material as reported in the table below.

Prep.	Structure	Name	SM	MS (m/z): [MH]⁺	y%
p91	<T,^:: uu	N-{2- azabicyclo[3.1.1 jhepta n-3-ylmethyl}quinolin2-amine	p88	254.3	89
p92		N-{2- azabicyclo[3.1.1 jhepta n-3-ylmethyl}-6-fluoro1,3-benzothiazol-2amine	p89	278.2	90

EXAMPLES

The following examples were synthesised following one of the general procedures reported below as indicated in the table.

GENERAL PROCEDURE A:

A mixture of 2-azabicyclo[3.1.1]heptanes (p17-18, p21-22, p28-29, p35 as reported; 1 eq), carboxylic acid (p58, 61, 62, 65-67, 71 or commercially available if not specified in the table; 1.2 eq), DI PEA (3 eq), and T3P (3 eq) in DMF dry (33 vol) was stirred at 90 °C for 40 minutes then left stirring at RT for 1h. The solvent was evaporated and crude material purified by FC on C18 cartridge (eluent: water +0.1 % HCOOH/acetonitrile +0.1 % HCOOH) then the compound was dissolved in 3-5 mL NaHCC>3 saturated aqueous solution and extracted with DCM. Organic layers were dried and solvent removed under reduced pressure to give the title compound.

GENERAL PROCEDURE B:

A mixture of 2-azabicyclo[3.1.1]heptanes (p17-18, p21-22, p28-29, p35 as reported; 1 eq), carboxylic acid (p58, 61, 62, 65-67, 71 or commercially available if not specified in the table; 1.1 eq), DI PEA (4 eq), and T3P (3 eq) in DMF dry (33 vol) was stirred at 90-95 °C for 20-45 minutes. The solvent was evaporated and crude material purified by FC either on silica gel or aminic silica using Cy/AcOEt as eluting mixture. Then the product was triturated with Et20 to give the target compound

GENERAL PROCEDURE C:

A mixture of 2-azabicyclo[3.1.1]heptanes (p17-18, p21-22, p28-29, p35 as reported; 1 eq), carboxylic acid (p58, 61, 62, 65-67, 71 or commercially available if not specified in the table; 0.9 eq), DI PEA (4 eq), and T3P (3 eq) in DMF dry (33 vol) was stirred at 90 °C for 15 minutes. The reaction mixture was partitioned between AcOEt and a NaOH solution (0.5 N). The aqueous phase was extracted with AcOEt, and the combined organics were washed with brine, dried over Na2SO₄, and filtered. The solvent was evaporated and crude material purified by FC on silica gel using Cy/AcOEt as eluting mixture. Then the product was triturated with Et20 to give the target compound.

GENERAL PROCEDURE D:

A mixture of 2-azabicyclo[3.1.1]heptanes (p17-18, p21-22, p28-29, p35 as reported; 1 eq), carboxylic acid (p58, 61, 62, 65-67, 71 or commercially available if not specified in the table; 1.2 eq), DI PEA (2 eq), and T3P (1 eq) in DMF dry (100 vol) was stirred at 80 °C for 18 hrs. The mixture was concentrated under reduced pressure and extracted with DCM and iced water. The organic phase washed with Brine, then it was concentrated under reduced pressure and the crude was purified by FC on aminic silica using Cy/AcOEt as eluting mixture. Then the product further purified by FC on C18 cartridge (eluent: water +0.1 % HCOOH/acetonitrile +0.1 % HCOOH) to give the target compound

GENERAL PROCEDURE E:

A mixture of 2-azabicyclo[3.1.1]heptanes (p17-18, p21-22, p28-29, p35 as reported; 1 eq), carboxylic acid (p58, 61, 62, 65-67, 71 or commercially available if not specified in the table; 1.2 eq), DIPEA (1.5 eq), and T3P (3 eq) in DMF dry (100 vol) was stirred at 50 °C for 1 hr. The mixture was treated with 1N NaOH, and then extracted with AcOEt, the extract was dried over Na2SC>4, evaporated and purified by FC on silica gel using Cy/AcOEt as eluting mixture. Then the product further purified by FC on C18 cartridge (eluent: water +0.1 % HCOOH/acetonitrile +0.1 % HCOOH) to give the target compound.

GENERAL PROCEDURE F:

To a solution of carboxylic acid (p58, 61, 62, 65-67, 71 or commercially available if not specified in the table; 1.1 eq) in DMF (40 vol), HATU (1.3 eq) and DI PEA (2.2 eq) were added. Mixture was stirred at RT for 30 min and then added dropwise to a solution of Σι 5 azabicyclo[3.1.1]heptanes (p17-18, p21-22, p28-29, p35 as reported; 1 eq) in DMF (20 vol) and DIPEA (1.1 eq). The reaction was stirred at room temperature for 1 h, then solvent was removed under reduced pressure and crude purified by FC on either C18,

NH or silica column with the appropriate eluent mixture to give the title compound.

Example	Starting materials	Gen. procedure	Yield (%)
1	p28	B	50
	MS (m/z): 423.0 [MH	+
.n ϊ °χχ	NMR (¹H, DMSO-c/6]	: δ 7.26 - 7.47 (m, 5 H), 6.96 -
	7.22 (m, 4 H), 4.63 (d, 1 H), 4.09 - 4.28 (m, 2 H), 3.88 -
	3.96 (m, 1 H), 2.67 (s, 3H), 2.39 - 2.46 (m, 1 H), 2.31
o	(d, 1 H), 2.02 - 2.21 (m, 3 H), 1.69 (t, 1 H), 1.03 (t, 1 H)
3-[(4-fluorophenoxy)methyl]-2-(2-me	thyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-
azabicyclo[3.1.1 jheptane
The racemic mixture was separated into the single enantiomers by preparative chiral HPLC
Column	Chiralpak IC (25 x 2.0 cm), 5 μ
_. .. . . , Mobile phase n-Hexane / Ethanol 60/40 % v/v . . . Flow rate (ml/min) 15ml/min chromatography DAD detection 220 nm
protocol: , ^r Loop	2500 μΙ
Injection	30 mg (each injection)

Enantiomer 1

Rt: 8.9 min

100% ee

MS (m/z): 423.1 [MH]⁺.

(3R or 3S) 3-[(4-fluorophenoxy)methyl]-2-(2-methyl-5phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 jheptane

3S or 3R enantiomer

Example_

Enantiomer 2

Rt: 13.9 min

100% ee

MS (m/z): 423.1 [MH]⁺.

(3S or 3R) 3-[(4-fluorophenoxy)methyl]-2-(2-methyl-5phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 jheptane

Starting materials	Gen. procedure	Yield (%)
p28 + p65	B	71

MS (m/z): 424.0 [MH]⁺.

NMR (¹H, DMSO-c/6): δ 8.19 (d, 1 H), 7.92 (d, 1 H), 7.80 (d, 1 H), 7.44 (d, 1 H), 6.95 - 7.20 (m, 4 H),4.56 4.65 (m, 1 H), 4.40 (dd, 1 H), 4.17 (t, 1 H), 3.77 (q, 1 H), 2.53 (s, 3 H), 2.42 - 2.48 (m, 1 H), 2.32 - 2.39 (m, 1 H),2.22 (d, J=13.7 Hz, 1 H), 2.14 (dt, 1 H), 2.02 - 2.08 (m, 1 H), 1.80 (t, 1 H), 1.15 - 1.27 (m, 1 H)

3-(4-fluorophenoxymethyl)-2-{[6-methyl-3-(1,3-thiazol-2-yl)pyridin-2-yl]carbonyl}-2azabicyclo[3.1.1 jheptane

The racemic mixture was separated into the single enantiomers by preparative chiral HPLC

Preparative chiral chromatography protocol:

Column Mobile phase

Flow rate (ml/min) DAD detection Loop Injection

Chiralpak AD-H (25 x 2.0 cm), 5 μ n-Hexane I (Ethanol/Methanol+0.1 % ipa) 85/15 % v/v ml/min 220 nm 2500 μΙ mg (each injection)

Enantiomer 1

Rt: 8.1 min

MS (m/z): 424.3 [MH]⁺.

99% ee (3R or 3S) 3-(4-fluorophenoxymethyl)-2-{[6-methyl-3(1,3-thiazol-2-yl)pyridin-2-yl]carbonyl}-2azabicyclo[3.1.1 jheptane

100

3S or 3R enantiomer

Example_

Enantiomer 2

Rt: 10.3 min

MS (m/z): 424.3 [MH]⁺.

99% ee (3S or 3R) 3-(4-fluorophenoxymethyl)-2-{[6-methyl-3(1,3-thiazol-2-yl)pyridin-2-yl]carbonyl}-2azabicyclo[3.1.1 jheptane

Starting materials	Gen. procedure	Yield (%)
p28 + p66	B	57
MS (m/z): 423.0 [MH	+

NMR (¹ H, DMSO-c/6): δ 7.88 (d, 1 H), 111 (d, 1 H),

7.72 (d, 1 H), 7.31 -7.37 (m, 1 H), 7.04 - 7.19 (m, 4 H), 7.02 (s, 1 H), 4.53 - 4.61 (m, 1 H), 4.48 (dd, 1 H), 4.00 (t, 1 H), 3.82 (m, 1 H), 2.37 - 2.42 (m, 1 H), 2.35 - 2.36 (m,3H), 2.11 -2.33 (m, 3 H), 1.84- 1.92 (m, 1 H), 1.57 (t, 1 H), 0.85 (t, 1 H)

3-(4-fluorophenoxymethyl)-2-{[5-methyl-2-(1,3-thiazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 jheptane

Preparative chiral chromatography protocol:

Column Mobile phase

Flow rate (ml/min) DAD detection Loop Injection

Chiralpak AD-H (25 x 2.0 cm), 5 μ n-Hexane I (Ethanol/Methanol+0.1 % ipa) 80/20 % v/v ml/min 220 nm 2700 μΙ mg (each injection)

Enantiomer 1

Rt: 7.3 min

99% ee

MS (m/z): 423.3 [MH]⁺.

(3R or 3S) 3-(4-fluorophenoxymethyl)-2-{[5-methyl-2(1,3-thiazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 jheptane

Enantiomer 2

Rt: 12.0 min

99% ee

3S or 3R enantiomer

MS (m/z): 423.3 [MH]⁺.

(3S or 3R) 3-(4-fluorophenoxymethyl)-2-{[5-methyl-2(1,3-thiazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 jheptane

101

Example

Starting materials

Gen, procedure Yield (%) p28 + p62

MS (m/z): 407.0 [MH

NMR (¹H, DMSO-c/6): δ 7.98 - 8.08 (m, 2 H), 7.71 (d, 1 H), 7.34 - 7.45 (m, 1 H), 7.24 (s, 1 H), 7.03 - 7.20 (m, 4 H), 4.60 (t, 1 H), 4.37 (dd, 1 H), 3.88 (t, 1 H), 3.82 (q, 1 H), 2.42 - 2.47 (m, 1 H), 2.35 - 2.38 (m, 3 H), 2.10 2.33 (m, 2 H), 1.91- 2.07 (m, 2 H), 1.44 - 1.49 (m, 1 H), 1.14 (t, 1 H)

3-(4-fluorophenoxymethyl)-2-{[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 ]heptane

Preparative chiral chromatography protocol:	Column Chiralpak AD-H (25x2.0 cm), 5 μ Mobile phase n-Hexane I (Ethanol/Methanol+0.1 % ipa) 80/20 % v/v Flow rate (ml/min) 14 ml/min DAD detection 220 nm Loop 750 μΙ Injection 30 mg (each injection)
¹¹	Enantiomer 1	Rt: 7.6 min	99% ee
MS (m/z): 407.4 [MH]⁺.

(3R or 3S) 3-(4-fluorophenoxymethyl)-2-{[5-methyl-2(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 ]heptane

3R or 3S enantiomer

Enantiomer 2

Rt: 13.6 min

MS (m/z): 407.3 [MH]⁺.

99% ee (3S or 3R) 3-(4-fluorophenoxymethyl)-2-{[5-methyl-2(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 ]heptane

3S or 3R enantiomer

102

Example

Starting materials	Gen. procedure	Yield (%)
p28 + p58	B	52
MS (m/z): 419.0 [MH	+

N

NMR (¹H, DMSO-c/6): δ 8.84 - 8.92 (m, 2 H), 8.46 (d, 1 H), 7.42 - 7.49 (m, 2 H), 7.07 - 7.18 (m, 4 H), 4.56 4.63 (m, 1 H), 4.43 (dd, 1 H), 4.17 (t, 1 H), 3.88 (q, 1 H), 2.54 (s, 3 H), 2.50 (m, 1 H), 2.39 - 2.46 (m, 1 H), 2.20 - 2.27 (m, 1 H), 2.13 -2.19 (m, 1 H), 2.05 - 2.13 (m, 1 H), 1.79- 1.86 (m, 1 H), 1.48 (t, 1 H)

3-(4-fluorophenoxymethyl)-2-{[6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl]carbonyl}-2azabicyclo[3.1.1 jheptane

Preparative chiral chromatography protocol:

Column Mobile phase

Flow rate (ml/min) DAD detection Loop Injection

Chiralpak AD-H (25 x 2.0 cm), 5 μ n-Hexane / (Ethanol/Methanol 1/1 + 0.1% ipa) 85/15 % v/v 14 ml/min

220 nm 2000 μΙ mg (each injection)

Enantiomer 1

Rt: 7.6 min

100% ee

N

MS (m/z): 419.1 [MH]⁺.

(3R or 3S) 3-(4-fluorophenoxymethyl)-2-{[6-methyl-3(pyrimidin-2-yl)pyridin-2-yl]carbonyl}-2azabicyclo[3.1.1 jheptane

3R or 3S enantiomer

Enantiomer 2

Rt: 9.4 min

97.8% ee

N jl MS (m/z): 419.1 [MH]⁺.

(3S or 3R) 3-(4-fluorophenoxymethyl)-2-{[6-methyl-3(pyrimidin-2-yl)pyridin-2-yl]carbonyl}-2azabicyclo[3.1.1 jheptane

3S or 3R enantiomer

103

Example

Starting materials	Gen. procedure	Yield (%)
p28 + p61	B	26
MS (m/z): 418.1 [MH	+

NMR (¹H, DMSO-c/6): δ 8.79 - 8.87 (m, 1 H), 8.06 (d,

N

H), 7.40 (t, 2 H), 7.33 - 7.37 (m, 1 H), 7.05 - 7.20 (m, 5 H), 4.61 (d, 1 H), 4.49 - 4.56 (m, 1 H), 4.01 -4.08 (m, 1 H), 3.87 (d, 1 H), 2.44 - 2.54 (m, 1 H), 2.36 (s, 3 H), 2.29 - 2.43 (m, 1 H), 2.12 - 2.27 (m,2 H), 1.93 - 2.05 (m, 1 H), 1.74- 1.81 (m, 1 H), 1.28- 1.36 (m, 1 H)

3-(4-fluorophenoxymethyl)-2-{[5-methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 jheptane

Preparative chiral chromatography protocol:

Column Mobile phase Flow rate (ml/min) DAD detection Loop Injection

Chiralpak IC (25 x 2.0 cm), 5 μ n-Hexane/Ethanol 70/30 % v/v 15 ml/min

220 nm 2500 pL 7.5 mg/injection

Enantiomer 1

Rt: 11.2 min

99% ee

N

MS (m/z): 418.1 [MH]⁺.

(3S or 3R) 3-(4-fluorophenoxymethyl)-2-{[5-methyl-2(pyrimidin-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 jheptane

3S or 3R enantiomer

Enantiomer 2

Rt: 18.8 min

99% ee

MS (m/z): 418.1 [MH]⁺.

N (3R or 3S) 3-(4-fluorophenoxymethyl)-2-{[5-methyl-2(pyrimidin-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 jheptane

3R or 3S enantiomer

104

Example	Starting materials	Gen. procedure	Yield (%)
19	p29 + p61	A	33
MS (m/z): 434.3 [MH	+
NMR (¹H, DMSO-c/6): δ 8.83 (d, 2 H), 8.11 (d, 1 H), 7.40 (t, 2 H), 6.94 (s, 5 H), 4.49 - 4.66 (m, 2 H), 4.05 4.11 (m, 1 H), 3.93 (q, 1 H), 2.34 (br. s., 3 H),2.29 2.47 (m, 2 H), 2.13 - 2.24 (m, 2 H), 1.93 - 2.00 (m, 1 H), 1.57 (t, 1 H), 1.32 (t, 1 H)
3-(4-chlorophenoxymethyl)-2-{[5-me azabicyclo[3.1.1 jheptane	thyl-2-(pyrimidin-2-yl)phenyl]carbonyl}-2-
20 Χή	p29 + p66	B	33
MS (m/z): 439.2 [MH	+
NMR (¹H, DMSO-c/6): δ 7.86 (dd, 1H), 7.65-7.79 (m, 2H), 7.26-7.41 (m, 3H), 6.95-7.24 (m, 3H), 4.53-4.72 (m, 1H), 4.32-4.52 (m, 1H), 3.99-4.29 (m, 1H), 3.743.97 (m, 1H), 2.38-2.48 (m, 1H), 2.36 (d, 3H), 2.102.33 (m, 3H), 1.84-2.08 (m, 1H), 1.52-1.80 (m, 1H), 0.77-1.49 (m, 2H)
3-(4-chlorophenoxymethyl)-2-{[5-me azabicyclo[3.1.1 jheptane	thyl-2-(1,3-thiazol-2-yl)phenyl]carbonyl}-2-
Example	Starting materials	Gen. procedure	Yield (%)
21 A)	p21 + p58	B	37
MS (m/z): 420.1 [MH	+
NMR (¹H, DMSO-c/6): δ 8.89 (d, 2 H), 8.44 - 8.50 (m, 1 H), 8.19 (d, 1 H), 7.67 - 7.78 (m, 1 H), 7.46 - 7.51 (m, 1 H), 7.44(d, 1 H), 6.97 (d, 1 H), 4.60 - 4.72 (m, 2 H), 4.38 (t, 1 H), 3.87 (q, 1 H), 2.56 (br. s., 3 H), 2.46 2.51 (m, 2 H), 2.07- 2.27 (m, 3 H), 1.76 (t, 1 H), 1.49 (t, 1 H)
3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl]carbonyl}-2azabicyclo[3.1.1 jheptane
The racemic mixture was separated into the single enantiomers by preparative chiral HPLC
Preparative chiral chromatography protocol:	Column Chiralpak AS-H (25 x 2.0 cm), 5 μ Mobile phase n-Hexane I Ethanol 50/50 % v/v Flow rate (ml/min) 14 ml/min DAD detection 220 nm Loop 1000 pi Injection 20 mg (each injection)

105

Enantiomer 1

Rt: 5.2 min

100% ee

MS (m/z): 420.3 [MH]⁺.

(3S or 3R) 3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[6methyl-3-(pyrimidin-2-yl)pyridin-2-yl]carbonyl}-2azabicyclo[3.1.1 jheptane

3S or 3R enantiomer

3R or 3S enantiomer

Example_

Enantiomer 2

Rt: 8.8 min

100% ee

MS (m/z): 420.3 [MH]⁺.

(3R or 3S) 3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[6methyl-3-(pyrimidin-2-yl)pyridin-2-yl]carbonyl}-2azabicyclo[3.1.1 jheptane

Starting materials	Gen. procedure	Yield (%)
p21	B	17
MS (m/z): 424.3 [MH	+

p,

NMR (¹H, DMSO-c/6): δ 8.17 (d, 1 H), 7.72 (td, 1 H), 7.29 - 7.46 (m, 5 H), 6.91 (dd, 1 H), 4.67 (dd, 1 H), 4.41 - 4.48 (m, 2 H), 3.93 (q, 1 H), 2.68 (s, 3 H), 2.37 - 2.45 (m, 1 H), 2.29 - 2.38 (m, 1 H), 2.02 - 2.19 (m, 3 H), 1.65 (t,1 H), 1.04 (t,1 H)

3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-[(2-methyl-5-phenyl-1,3-thiazol-4-yl)carbonyl]-2azabicyclo[3.1.1 jheptane

Example	Starting materials	Gen. procedure	Yield (%)
25		p21 + p66	B	47
		MS (m/z): 424.1 [MH	+
	jA> Mk ,ό	NMR (¹H, DMSO-c/6): δ 8.17 (d, 1 H), 7.60 - 7.96 (m, 4 H), 7.27 - 7.41 (m, 1 H), 7.15 (s, 1 H), 6.97 (s, 1 H), 4.61 - 4.72 (m, 2 H),4.29 - 4.38 (m, 1 H), 3.81 (t, 1 H), 2.42 - 2.47 (m, 1 H), 2.35 (s, 3 H), 2.25 - 2.40 (m, 1 H), 2.15 (d, 2 H), 1.99 - 2.08 (m, 1 H), 1.68 -1.80 (m, 1 H), 1.39- 1.48 (m, 1 H)

3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[5-methyl-2-(1,3-thiazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 jheptane

Preparative chiral chromatography protocol:

Column Mobile phase Flow rate (ml/min) DAD detection Loop Injection

Chiralpak IC (25 x 2.0 cm), 5 μ n-Hexane I Ethanol 60/40 % v/v 14 ml/min

220 nm

1000 μΙ mg (each injection)

106

Enantiomer 1

Rt: 11.6 min

100% ee

MS (m/z): 424.2 [MH]⁺.

(3S or 3R) 3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[5methyl-2-(1,3-thiazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 ]heptane

o

3R or 3S enantiomer

Enantiomer 2

Rt: 14.6 min

100% ee

Example

MS (m/z): 424.2 [MH]⁺.

(3R or 3S) 3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[5methyl-2-(1,3-thiazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 ]heptane

Starting materials p21 + p62

Gen, procedure Yield (%)

MS (m/z): 408.3 [MH

NMR (¹H, DMSO-c/6): δ 8.16 (d, 1 H), 7.93 (s, 2 H), 111 (d, 1 H), 7.68 - 7.74 (m, 1 H), 7.39 (dd, 1 H), 7.23 (d, 1 H), 6.94 (td, 1 H), 4.59 - 4.68 (m, 1 H), 4.56 (d, 1 H), 4.22 (t, 1 H), 3.83 (q, 1 H), 2.41 - 2.48 (m, 1 H), 2.35 (s, 3 H), 2.32 (m, 1 H), 2.10-2.23 (m, 2 H), 1.932.05 (m, 1 H), 1.77 (t, 1 H), 1.40 - 1.48 (m, 1 H)

Column Mobile phase Flow rate (ml/min) DAD detection Loop Injection

3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 ]heptane_

Chiralpak IC (25 x 2.0 cm), 5 μ n-Hexane I Ethanol 60/40 % v/v 14 ml/min

220 nm 1000 pi mg (each injection)

Preparative chiral chromatography protocol:

Enantiomer 1

Rt: 9.9 min

100% ee

MS (m/z): 408.2 [MH]⁺.

(3S or 3R) 3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[5methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 ]heptane

3S or 3R enantiomer

107

30	0/	Enantiomer 2	Rt: 12.2 min	100% ee
		MS (m/z): 408.2 [MH]⁺.
	ul	(3R or 3S) 3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[5-
	I 5	methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-2-
		azabicyclo[3.1.1 jheptane
	3S or 3R enantiomer
Example	Starting materials	Gen. procedure Yield (%)
31		p21 + p65	A	46
		MS (m/z): 425.0 [MH ⁺.
		NMR (¹H, DMSO-c/6): δ 8.14 - 8.23 (m, 2 H), 7.90 (d,
	j. i il	1 H), 7.81 (d, 1 H)	7.72 (td, 1 H), 7.41 - 7.45 (m, 1H),
		6.95 (dd, 1 H), 4.57 - 4.69 (m, 2 H), 4.40 -4.49 (m, 1
		H), 3.76 (q, 1 H),	2.52 (s, 3 H), 2.31	- 2.47 (m, 2 H),
	ό	2.00-2.22 (m, 3 H),1.77 (t, 1 H), 1.18	- 1.27 (m, 1 H)

3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[6-methyl-3-(1,3-thiazol-2-yl)pyridin-2-yl]carbonyl}-2azabicyclo[3.1.1 jheptane

Example

Starting materials	Gen. procedure	Yield (%)
p22 + p61	B	55
MS (m/z): 435.3 [MH	+

NMR (¹H, DMSO-c/6): δ 8.85 (m, 2 H), 8.23 (d, 1 H), 8.09 (d, 1 H), 7.84 (d, 1 H), 7.40 (t, 1 H), 7.33 (d, 1 H), 6.96 (d, 1 H), 6.86 (s, 1 H), 4.81 (dd, 1 H), 4.61 - 4.70 (m, 1 H), 4.26 (t, 1 H), 3.93 (q,1 H), 2.41 - 2.46 (m, 1 H), 2.38 (s, 3 H), 2.33 - 2.36 (m, 1 H), 2.17 (d, 2 H), 1.93-2.02 (m, 1 H), 1.75 (t, 1 H), 1.40- 1.51 (m,1 H)

3-{[(5-chloropyridin-2-yl)oxy]methyl}-2-{[5-methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 jheptane

Preparative chiral chromatography protocol:

Column	Chiralpak IC (25 x 2.0 cm), 5 μ
Mobile phase	n-Hexane / Ethanol 50/50 % v/v
Flow rate (ml/min)	18 ml/min
DAD detection	220 nm
Loop	3300 μΙ
Injection	30 mg (each injection)

108

Enantiomer 1

Rt: 8.4 min

100% ee

MS (m/z): 424.2 [MH]⁺.

(3S or 3R) 3-{[(5-chloropyridin-2-yl)oxy]methyl}-2-{[5methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 jheptane

Enantiomer 2

Rt: 13.8 min

100% ee

Example

3R or 3S enantiomer

MS (m/z): 424.2 [MH]⁺.

(3R or 3S) 3-{[(5-chloropyridin-2-yl)oxy]methyl}-2-{[5methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 jheptane

Starting materials Gen, procedure Yield (%) p17 + p61

MS (m/z): 469.3 [MH

NMR (¹H, DMSO-c/6): δ 8.84 (d, 2 H), 8.61 (s, 1 H), 8.05 - 8.16 (m, 2 H), 7.40 (t, 1 H), 7.33 (d, 1 H), 7.10 (d, 1 H), 6.87 (s, 1 H), 4.92 (dd, 1 H), 4.64 - 4.70 (m, 1

H), 4.33 - 4.39 (m, 1 H), 3.94 (q, 1 H), 2.42 - 2.48 (m, 1

H), 2.34 (s, 3H), 2.31 - 2.42 (m, 1 H), 2.14 - 2.22 (m, 2

H), 1.95 - 2.03 (m, 1 H), 1.76 (t, 1 H), 1.41 - 1.51 (m, 1

H)

2-{[5-methyl-2-(pyrimidin-2-yl)pheny ]carbonyl}-3-({[5-(trifluoromethyl)pyridin-2yl]oxy}methyl)-2-azabicyclo[3.1.1]heptane

The racemic mixture was separated into the single enantiomers by preparative chiral SFC

Preparative chiral chromatography protocol:

Column

Modifier

Flow rate (ml/min) Pressure (bar) Temperature (°C) UV detection Loop Injection

Chiralcel OD-H (25 x 2.0 cm), 5 μ Methanol 17 %

120

220 nm 650 pL 9.75 mg

3S or 3R enantiomer

Enantiomer 1

Rt: 3.7 min

MS (m/z): 469.3 [MH]⁺.

99% ee (3S or 3R) 2-{[5-methyl-2-(pyrimidin-2yl)phenyl]carbonyl}-3-({[5-(trifluoromethyl)pyridin-2yl]oxy}methyl)-2-azabicyclo[3.1.1]heptane

109

³⁷ a»	Enantiomer 2 Rt: 5.4 min 99% ee
γΑ ⁿA^cf₃	MS (m/z): 469.3 [MH]⁺.
3R or 3S enantiomer	(3R or 3S) 2-{[5-methyl-2-(pyrimidin-2- yl)phenyl]carbonyl}-3-({[5-(trifluoromethyl)pyridin-2- yl]oxy}methyl)-2-azabicyclo[3.1.1]heptane
Example	Starting materials	Gen. procedure	Yield (%)
38	p18	D	37
	MS (m/z): 456.1 [MH	+
0	NMR (¹H, DMSO-c/6): δ 8.82 - 9.16 (m, 1 H), 8.04 (d, 1 H), 7.83 (d, 1 H), 7.61 - 7.71 (m, 1 H), 7.42 - 7.47 (m, 1 H),7.26 - 7.42 (m, 5 H), 7.24 (s, 1 H), 4.67 - 5.03 (m, 1 H), 4.53 (d, 2 H), 3.94 (q, 1 H), 2.66 (s, 3 H), 2.26 2.45 (m, 2 H), 2.17 - 2.25 (m,1 H), 2.02 - 2.16 (m, 2 H), 1.00- 1.90 (m, 2 H)
3-{[2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptan-3- yl]methoxy}isoquinoline
Example	Starting materials	Gen. procedure	Yield (%)
39	p28 + p67	F	6
	MS (m/z): [MH]⁺.
Ύ^Νγ4₀ A Ν=ζ/	NMR (¹H, DMSO-c/6): δ 8.17 (d, 1H), 7.69 (s, 2H), 7.30 (d, 1H), 7.06 - 6.96 (m, 4H), 4.85 - 4.79 (m, 1H), 4.58 (dd, 1H), 4.19 (dd, 1H), 3.94 (q, 1H), 2.63 (s, 3H), 2.56 - 2.52 (m, 1H), 2.40 - 2.38 (m, 2H), 2.16 - 2.07 (m, 2H), 1.89 - 1.85 (m, 1H), 1.45 (t, 1H).
3-[(4-fluorophenoxy)methyl]-2-[6-me azabicyclo[3.1.1 jheptane	thyl-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carbonyl]-2-
40	p28 + p71	F	56
	MS (m/z): 441.1 [MH	+
^f	NMR(¹H, Chloroform-d): δ 7.45-7.41 (m, 1H), 7.33 - 7.27 (m, 1H), 7.09 - 7.02 (m, 2H), 6.99 - 6.92 (m, 4H), 4.77 - 4.71 (m, 1H), 4.38 (dd, 1H), 4.16 (q, 1H), 4.03 (dd, 1H), 2.74 (s, 3H), 2.46 - 2.44 (m, 1H), 2.29 2.26 (m, 2H), 2.07 (dt, 2H), 1.58-1.53 (m, 1H), 1.07 1.02 (m, 1H).
3-[(4-fluorophenoxy)methyl]-2-[5-(2-f azabicyclo[3.1.1 jheptane	uorophenyl)-2-methyl-1,3-thiazole-4-carbonyl]-2-

110

Example	Starting materials	Gen. procedure	Yield (%)
41		p35 + p61	E	36
	Λ J=	MS (m/z): 432.2 [MH	+
'θ'ύ	NMR (¹H, DMSO-c/6): δ 8.74 (d, 2 H), 8.18 (d, 1 H), 7.30 (d,1 H), 7.15 (t, 1 H), 7.11 (d,1 H), 6.84- 7.00 (m, 4 H), 4.51 - 4.65 (m, 1 H), 4.13 - 4.34 (m, 2 H), 4.03 4.09 (m, 1 H), 2.83 - 2.93 (m, 1 H), 2.43 - 2.58 (m, 2 H), 2.41 (s, 3 H),2.08 - 2.28 (m, 3 H), 1.88 - 1.96 (m, 1 H), 1.79 (t, 1 H), 1.11 (t, 1 H)
3-[2-(4-fluorophenoxy)ethyl]-2-[5-me azabicyclo[3.1.1 jheptane	thyl-2-(pyrimidin-2-yl)benzoyl]-2-
The racemic mixture was separated into the single enantiomers by preparative chiral HPLC
Preparative chiral chromatography protocol:	Column Chiralpak IC (25 x2.0 cm), 5 μ Mobile phase n-Hexane 1 Ethanol 40/60 % v/v Flow rate (ml/min) 14ml/min DAD detection 220 nm Loop 3000 μΙ Injection 40 mg (each injection)
⁴² m rV	Enantiomer 1	Rt: 10 min	100% ee

		MS (m/z): 432.2 [MH]⁺.
	(3S or 3R) 3-[2-(4-fluorophenoxy)ethyl]-2-[5-methyl-2(pyrimidin-2-yl)benzoyl]-2-azabicyclo[3.1.1]heptane
3S or 3R enantiomer
⁴³ ιίΥ	Enantiomer 2	Rt: 16.3 min	100% ee

		MS (m/z): 432.2 [MH]⁺.
	(3R or 3S) 3-[2-(4-fluorophenoxy)ethyl]-2-[5-methyl-2(pyrimidin-2-yl)benzoyl]-2-azabicyclo[3.1.1]heptane
3R or 3S enantiomer

GENERAL PROCEDURE G:

To a stirred suspension of NaH 60% w/w (1.3 eq) in dry DMF (~30 vol), the desired alcohol intermediate (p78-82 as reported on the table, 1 eq) was added at RT. After 30’, the corresponding aryl chloride (1.1 eq) was added and the reaction mixture was stirred at room temperature for 2 hrs. The reaction was quenched adding iced water and the mixture was extracted with dichloromethane. Combined organics were dried and

111 concentrated. The crude was purified by FC on silica gel and/or NH column (eluting mixture Cy/AcOEt) and/or C18 cartridge (eluent from water + 0.1% formic acid I MeCN + 0.1% formic acid) and/or preparative HPLC to afford the title compound.

GENERAL PROCEDURE H:

The desired alcohol intermediate (p78-82 as reported in the table, 1 eq) was dissolved in THF (~40 vol). PPh3 (1.5 eq) was added, followed by the desired phenol (commercially available, 1.5 eq). The mixture was stirred at RT for 15’, then cooled to 0 °C. DIAD (1.5 eq) was added dropwise and, after 10’, the ice bath was removed and the mixture was allowed to reach RT and stirred for at that temperature for 1.5-2.5 hrs. The mixture was concentrated and the crude obtained was purified by FC on silica gel and/or NH column (eluting mixture Cy/AcOEt) and/or C18 cartridge (eluent from water + 0.1% formic acid I MeCN + 0.1% formic acid) to afford the title compound.

GENERAL PROCEDURE I:

The desired alcohol intermediate (p78-82 as reported in the table, 1 eq) was dissolved in THF (~40 vol). PPh₃ (1.5 eq) was added, followed by the desired phenol (commercially available, 1.5 eq). The mixture was stirred at RT for 15’, then cooled to 0 °C. DIAD (1.5 eq) was added dropwise and, after 10’, the ice bath was removed and the mixture was heated to 55 °C and stirred for 1.5-2.5 hrs. The mixture was concentrated and the crude obtained was purified by FC on silica gel and/or NH column (eluting mixture Cy/AcOEt) and/or C18 cartridge (eluent from water + 0.1% formic acid I MeCN + 0.1% formic acid) to afford the title compound.

GENERAL PROCEDURE L:

To a stirred suspension of NaH 60% w/w (1.3 eq) in dry DMF (~30 vol), the desired alcohol intermediate (p78-82 as reported on the table, 1 eq) was added at RT. After 30’, the corresponding aryl fluoride (1.1 eq) was added and the reaction mixture was stirred at room temperature for 2 hrs. The reaction was quenched adding iced water and the mixture was extracted with dichloromethane. Combined organics were dried and concentrated. The crude was purified by FC on silica gel and/or NH column (eluting mixture Cy/AcOEt) and/or C18 cartridge (eluent from water + 0.1% formic acid I MeCN + 0.1% formic acid) and/or preparative HPLC to afford the title compound.

112

113

47	p78	H	55
	MS (m/z): 441.3	MH]⁺.
lx o	NMR (¹H, CHLOROFORM-d) δ 7.41 - 7.46 (m, 2 H) 7.27 - 7.34 (m, 3 H) 7.09 (q, 1 H) 6.89 (ddd, 1 H) 6.76 - 6.82 (m, 1 H) 4.73 - 4.82 (m, 1 H) 4.45 (dd, 1 H) 4.02 - 4.13 (m, 2 H) 2.75 (s, 3 H) 2.42 - 2.49 (m, 1 H) 2.26 - 2.32 (m, 2 H) 1.97 - 2.09 (m, 2 H) 1.53 - 1.61 (m, 1 H) 0.92 0.99 (m, 1 H)
3-(3,4-difluorophenoxymethyl)-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 ]heptane
48	p78	H	55
	MS (m/z): 419.3	MH]⁺.
Uk Ο	NMR (¹H, CHLOROFORM-d) δ 7.42 - 7.47 (m, 2 H) 7.26 - 7.32 (m, 3 H) 7.09 - 7.15 (m, 2 H) 6.92 - 6.98 (m, 2 H) 4.78 - 4.86 (m, 1 H) 4.47 (dd, 1 H) 4.10 - 4.16 (m, 1 H) 4.05 (q, 1 H) 2.74 (s, 3 H) 2.40 - 2.48 (m, 1 H) 2.24 - 2.37 (m, 5 H) 1.96 - 2.06 (m, 2 H) 1.61 - 1.69 (m, 1 H) 0.98 (t, 1 H)
2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-3-(4-methylphenoxymethyl)-2azabicyclo[3.1.1 ]heptane
49	p78	H	70
	MS (m/z): 439.2	MH]⁺.
	NMR (¹H, CHLOROFORM-d) δ 7.40 - 7.50 (m, 2 H) 7.23 - 7.36 (m, 5 H) 6.97 - 7.07 (m, 2 H) 4.75 - 4.85 (m, 1 H) 4.44 - 4.53 (m, 1 H) 4.09 4.19 (m, 1 H) 4.01 - 4.09 (m, 1 H) 2.74 (s, 3 H) 2.41 - 2.51 (m, 1 H) 2.26 - 2.36 (m, 2 H) 1.96 2.10 (m, 2 H) 1.53- 1.67 (m, 1 H) 0.92- 1.03 (m,1 H)
3-(4-chlorophenoxymethyl)-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2 azabicyclo[3.1.1 ]heptane
50	p79	H	63
	MS (m/z): 441.0	MH]⁺.
	NMR (¹H, CHLOROFORM-d) δ 7.37-7.47 (m, 2H), 6.88-7.07 (m, 5H), 4.74-4.86 (m, 1H), 4.37 (d, 1H), 4.15-4.24 (m, 1H), 4.05 (d, 1H), 2.74 (s, 3H), 2.45-2.53 (m, 1H), 2.33 (br. s., 2H), 2.00-2.13 (m, 2H), 1.63-1.75 (m, 1H), 0.991.11 (m, 1H)
3-(4-fluorophenoxymethyl)-2-[5-(4-fluorophenyl)-2-methyl-1,3-thiazole-4-carbonyl]-2azabicyclo[3.1.1 ]heptane

114

51	p80	H 17
MS(m/z): 443.3	MH]⁺.
NMR (¹H, CHLOROFORM-d) δ 7.42 (d, 2H), 7.28 (s, 4H), 6.90-7.06 (m, 3H), 4.73-4.85 (m, 1H), 4.37 (dd, 1H), 4.16 (dd, 1H), 4.08 (d, 1H), 2.44-2.58 (m, 1H), 2.29-2.38 (m, 2H), 2.002.18 (m, 2H), 1.65-1.78 (m, 1H), 0.98-1.12 (m, 1H)
2-(2-chloro-5-phenyl-1,3-thiazole-4-carbonyl)-3-[(4-fluorophenoxy)methyl]-2azabicyclo[3.1.1 jheptane
52	p81	H \| 48
MS(m/z): 439.3	MH]⁺.

NMR (¹H, CHLOROFORM-d) δ 7.34-7.46 (m, 2H), 7.19-7.30 (m, 4H), 6.96-7.06 (m, 3H), 4.73-4.84 (m, 1H), 4.38-4.50 (m, 1H), 4.074.20 (m, 5H), 2.43-2.53 (m, 1H), 2.24-2.37 (m, 2H), 1.99-2.13 (m, 2H), 1.52-1.63 (m, 1H), 1.02-1.13 (m, 1H)

3-[(4-fluorophenoxy)methyl]-2-(2-methoxy-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 jheptane p82

MH]⁺.

NMR (¹H, Chloroform-c/) δ 7.40-7.47 (m, 2H), 7.23-7.28 (m, 3H), 7.01 (d, 4H), 4.73-4.85 (m,

1H), 4.41-4.50 (m, 1H), 4.07-4.17 (m, 1H), 3.99-4.07 (m, 1H), 2.41-2.50 (m, 1H), 2.272.38 (m, 3H), 1.98-2.10 (m, 2H), 1.58-1.68 (m, 1H), 1.11-1.23 (m, 4H), 0.96-1.09 (m, 1H)

2-(2-cyclopropyl-5-phenyl-1,3-thiazole-4-carbonyl)-3-[(4-fluorophenoxy)methyl]-2azabicyclo[3.1.1 jheptane p78

MS(m/z): 479.0

MH]⁺.

NMR (¹H, DMSO-ofe) δ 7.82 - 7.89 (1 H, m) 7.68 - 7.75 (1 H, m) 7.22 - 7.49 (5 H, m) 4.69 4.87 (2 H, m) 3.92 - 4.00 (1 H, m) 2.68 (3 H, s) 2.27 - 2.46 (3 H, m) 2.04 - 2.20 (3 H, m) 1.53 1.62 (1 H, m) 1.03-1.15 (1 H, m).

6-fluoro-2-{[2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptan-3yl]methoxy}-1,3-benzothiazole

115

55 aA ⁿ^K_F3	p78	L 15
MS (m/z): 474.3	MH]⁺.
NMR (¹H, DMSO-de) δ 8.63 (1 H, s) 8.06 8.14 (1 H, m) 7.29 - 7.46 (5 H, m) 7.05 (1 H, d) 4.67 - 4.78 (1 H, m) 4.50 - 4.67 (2 H, m) 3.91 3.98 (1 H, m) 2.68 (3 H, s) 2.28 - 2.46 (3 H, m) 2.04-2.18(3 H, m) 1.60- 1.69(1 H, m) 1.021.11 (1 H, m).
2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-3-({[5-(trifluoromethyl)pyridin-2yl]oxy}methyl)-2-azabicyclo[3.1.1]heptane
56 A	p78	H \| 29
MS (m/z): 456.3	MH]⁺.
NMR(¹H, CHLOROFORM-d) δ 8.01 (d, 1 H) 7.88 (d, 1 H) 7.74 (d, 1 H) 7.65 (t, 1 H) 7.50 (d, 2 H) 7.40 (t, 1 H) 7.30 - 7.36 (m, 3 H) 6.93 (d, 1 H) 4.83 - 5.01 (m, 2 H) 4.69 - 4.76 (m, 1 H) 4.07 (q, 1 H) 2.75 (s, 3 H) 2.41 - 2.48 (br. s., 1 H) 2.23 - 2.41 (m, 2 H) 2.00 - 2.1 (br. s., 2 H) 1.67- 1.76 (m, 1 H) 1.06 (t, 1 H)
2-{[2-(2-methyl-5-phenyl-1,3-thiazole-4 yl]methoxy}quinoline	FcarbonyOb-azabicyclolO. 1.1 ]heptan-3-
57 l\L Ax. N·. A--'/ Aj’ s-—	p78	H \| 8
MS (m/z): 460.3	MH]⁺.
NMR (¹H, CHLOROFORM-d) δ 8.72 (s, 1 H) 7.49 (dd, 2 H) 7.29 - 7.38 (m, 3 H) 7.00 (d, 1 H) 6.46 - 6.49 (m, 1 H) 4.90 - 4.99 (m, 2 H) 4.54 4.61 (m, 1 H) 4.06 (q, 1 H) 3.82 (s, 3 H) 2.74 (s, 3 H) 2.30 - 2.48 (m, 3 H) 1.96 - 2.09 (m, 2 H) 1.73- 1.80 (m, 1 H) 0.98 (t, 1 H)
2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-3-[({7-methyl-7H-pyrrolo[2,3-d]pyrimidin- 2-yl}oxy)methyl]-2-azabicyclo[3.1.1]heptane
58	p78 H 54

MS (m/z): 457.3 [M]⁺.

NMR (¹H, CHLOROFORM-d) δ 8.43 (s, 1H), 8.02 (dd, 1H), 7.85 (dd, 1H), 7.72 -7.64 (m, 1H), 7.63 -7.51 (m, 1H), 7.50 -7.38 (m, 2H), 7.32 -7.27 (m, 3H), 4.97 -4.90 (m, 1H), 4.84 (dd, 1H), 4.70 (dd, 1H), 4.06 (q, 1H), 2.72 (s, 3H), 2.59 -2.18 (m, 3H), 2.13-1.95 (m, 2H), 1.73-1.51 (m, 2H), 1.02 (t, 1H).

2-{[2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptan-3yl]methoxy}quinoxaline

116

The following examples were synthesised following the general procedure reported below as indicated in the table.

GENERAL PROCEDURE M:

2-methyl-5-phenyl-1,3-thiazole-4-carboxylic acid (1.1 eq) was dissolved in DMF (~ 25 vol), then HATU (1.3 eq) was added followed by DIPEA (2.2 eq). The resulting solution was stirred for 10 min at RT then desired intermediate (p90-92 as reported in the table, 1 eq) in DMF (~25 vol) was added and stirred at RT for 1 hr. The mixture was diluted with iced NH4CI ss and DCM, the two phases were separated and aqueous phase was backextracted twice with DCM. Combined organics were dried and concentrated under reduced pressure. The residue was purified by FC on C18 cartridge (eluent from water + 0.1% formic ac. I MeCN + 0.1% formic ac. 40%) to afford the title compound.

Example number	Intermediate	General procedure	Yield (%)
59		p90	M	87
		MS (m/z): 455.3 [MH]⁺.
		NMR (¹H, CHLOROFORM-c/): δ	8.83 (s, 1
	H) 7.76 (d, 1 H) 7.70 (d, 1 H) 7.54 (t, 1 H)
		7.43 - 7.50 (m, 2 H) 7.33 - 7.41 (m, 3 H)
		7.21 - 7.31 (m, 2 H) 5.65 - 5.96 (m, 1 H) 4.64 - 4.77 (m, 1 H) 4.03 - 4.13 (m, 2 H)
		3.38 - 3.51 (m,	1 H) 2.77 (s, 3 H) 2.43 -
		2.52 (m, 1 H) 2.26 - 2.37 (m, 1	H) 2.14 -
V		2.24 (m, 1 H) 2.02 - 2.11 (m 1	H) 1.94 -
	2.02 (m, 1 H) 1.44 - 1.53 (m, 1 H) 0.89 (t, 1
		H)
N-{[2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptan-3-
yl]methyl}isoquinolin-3-amine
60		p91	M	48
		MS (m/z): 455.3 [MH]⁺.
¢1 N N		NMR (¹H, DMSO-d6): δ 9.99 (br. s., 1 H),
		7.31 - 8.52 (m, 5 H), 7.26 - 7.60 (m, 5 H),
X L. JL		6.97 - 7.27 (m,	1 H), 4.59 (t, 1	H), 3.99 -
s—\		4.15(m, 1 H), 3.62 - 3.97 (m, 2 H), 2.71 (s,
	3 H), 2.43- 2.49 (m, 1 H), 2.27-	2.40 (m, 1
		H), 2.13 - 2.25 (m, 1 H), 2.00 -	2.12 (m, 2
		H), 1.58 - 1.69 (m, 1 H), 0.86(br. s., 1 H)
N-{[2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptan-3-
yl]methyl}quinolin-2-amine

117

p92	M	34
MS (m/z): 479.3	[M]⁺.

NMR (¹H, CHLOROFORM-d) δ 7.42-7.51 (m, 3 H) 7.26 - 7.34 (m, 3 H) 6.98 - 7.07 (m,

H) 4.86 - 4.94 (m, 1 H) 4.10 (d, 1 H) 3.90 - 3.99 (m, 1 H) 3.78 - 3.86 (m, 1 H) 2.74 (s,

H) 2.41 - 2.51 (m, 2 H) 2.04 - 2.13 (m, 2 H) 1.96 - 2.04 (m, 1 H) 1.58 - 1.63 (m, 1 H) 1.11 (t, 1 H)

6-fluoro-N-{[2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptan3-yl]methyl}-1,3-benzothiazol-2-amine

Example 62 and 63: (3S,4R or 3R,4S)-4-fluoro-3-{[(5-fluoropyridin-2-yl)oxy]methyl}2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptane (E62) and (3R,4S or 3S,4R)-4-fluoro-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-(2-methyl-55 phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptane (E63)

Step a:

2-methyl-5-phenyl-1,3-thiazole-4-carboxylic acid (1.18 g, 5.38 mmol) was dissolved in

DMF (5 mL), then HATU (2.4 g, 6.36 mmol) was added followed by DIPEA (1.87 mL, 10.76 mmol). The resulting solution was stirred for 10 min cis/trans 3-(hydroxymethyl)-2azabicyclo[3.1.1]heptan-4-ol (p9, 700 mg, 4.89 mmol) in DMF (0.5 mL) was added and stirred for 1 hr. The mixture was diluted with NHLCIss and DCM, the two phases were separated and the product was extracted several times with DCM. The combined organic phases were dried and evaporated. The residue was purified by FC on silica gel (from DCM to 10% MeOH) to afford CIS-3-(hydroxymethyl)-2-(2-methyl-5-phenyl-1,3-thiazole4-carbonyl)-2-azabicyclo[3.1.1]heptan-4-ol (Int. a, 900 mg) and TRANS-3(hydroxymethyl)-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1]heptan-4-ol (100 mg).

Step b:

Int. a (850 mg, 2.47 mmol) and imidazole (670 mg, 9.88 mmol) were dissolved in DMF (5 mL). A solution of tert-Butyldimethylsilyl chloride (744 mg, 4.93 mmol) in DMF (3 mL) was added dropwise and the mixture was stirred at RT for 30 min until completion.

Reaction was quenched with water and extracted with DCM. Organic layers were dried

118 and solvent was removed under reduced pressure. The residue was purified by FC on silica gel (eluting from cHex to 60% EtOAc) to afford 3-{[(tertbutyldimethylsilyl)oxy]methyl}-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1]heptan-4-ol (Int. b, 600 mg).

Step c:

Int. b (250 mg, 0.54 mmol) was dissolved in DCM (8 ml_) and cooled with an ice bath. DAST (0.144 ml_, 1.09 mmol) was added dropwise and mixture was stirred at RT 1h. Reaction was quenched carefully with water and extracted with DCM. Organic layers were dried and solvent was removed under reduced pressure. The residue was dissolved in DCM (8 ml_) and HCI 1.25M in MeOH (1.25 ml_, 1.25 mmol) was added dropwise. The mixture was stirred at RT 2 hrs. Solvent was removed under vacuum and the residue was purified by FC on silica gel (from DCM to 10% MeOH) to afford [4fluoro-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptan-315 yljmethanol (Int. c, 120 mg) as mixture of target intermediate and by-products due to carbocation rearrangement during the fluorination step.

Step d:

Int. c (120 mg, 0.346 mmol) was dissolved in DMF (3 ml_) and cooled with an ice bath. 20 NaH 60% w/w dispersion in mineral oil (21 mg, 0.52 mmol) was added and mixture was stirred 10 min before adding 2,5-difluoropyridine (0.05 ml_, 0.52 mmol). The mixture was stirred at RT for 3 hrs. The mixture was diluted with water and extracted several times with DCM. Organic layers were dried and solvent was removed under reduced pressure to afford crude which was purified by FC on silica gel (eluting from DCM to 5% MeOH) then further purified by chiral prep HPLC:

Column Mobile phase Flow rate (ml/min) DAD detection Loop Injection

Chiralpak AD-H (25 x 2.0 cm), 5 μ n-Hexane/ (2-propanol + 0.1% isopropylamine) 83/17 % v/v 17 ml/min 220 nm 400 pL

7.8 mg/injection affording:

(3S,4R or 3R,4S)-4-fluoro-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-(2-methyl-530 phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptane (E62):

Enantiomer 1, Rt = 24.7 min, 100% ee MS (m/z): 442.0 [MH]⁺.

119

NMR (¹H, CHLOROFORM-d): δ 1.35 - 1.78 (m, 2 H), 1.81 - 2.32 (m, 1 H), 2.12 (dd, 1

H), 2.61 - 2.91 (m, 4 H), 4.09 (q, 1 H), 4.49 - 4.77 (m, 2 H), 4.78 - 4.94 (m, 1 H), 5.01 5.39 (m, 1 H), 6.75 (dd, 1 H), 7.28 - 7.49 (m, 6 H), 8.01 (d, 1H) (3R,4S or 3S,4R)-4-fluoro-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-(2-methyl-5phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptane (E63):

Enantiomer 2, Rt = 32.7 min, 100% ee

MS (mlz): 442.0 [MH]⁺.

NMR (¹H, CHLOROFORM-d): δ 1.36 - 1.71 (m, 1 H), 1.49 - 1.79 (m, 1 H), 1.81 - 2.28 (m, 1 H), 2.12 (dq, 1 H), 2.61 - 2.87(m, 4 H), 3.96 - 4.15 (m, 1 H), 4.42 - 4.77 (m, 2 H), 4.77 - 4.95 (m, 1 H), 4.99 - 5.43 (m, 1 H), 6.75 (dd, 1 H), 7.28 - 7.57 (m, 5 H), 7.33 -7.40 (m, 1 H), 8.01 (d, 1 H)

GENERAL PROCEDURE N:

4-methyl-2-azabicyclo[3.1.1 jheptane (p40-42, p49, 51, 53 as reported; 1 eq) was dissolved in DMF (~50 vol), then the carboxylic acid (p58, p61-62, p65-67, p70 or commercially available if not specified in the table; 1.2 eq) was added followed by T3P (2 eq) and DI PEA (2 eq). The mixture was heated at 90 °C and left stirring at the same temperature 1-18 hrs, then the solvent was evaporated and the crude material purified by FC either on silica gel or aminic silica using Cy/AcOEt as eluting mixture to give the title compound.

GENERAL PROCEDURE O:

A mixture of 4-methyl-2-azabicyclo[3.1.1 jheptane (p40-42, p49, 51, 53 as reported; 1 eq), carboxylic acid (p58, p61-62, p65-67, p70 or commercially available if not specified in the table; 1.2 eq), DIPEA (3 eq), and T3P (3 eq) in DMF dry (~33 vol) was stirred at 90 °C for 40 minutes then left stirring at RT for 1h. The solvent was evaporated and crude material purified by FC either on silica gel or aminic silica using Cy/AcOEt as eluting mixture to give the title compound.

GENERAL PROCEDURE P:

A mixture of 2-azabicyclo[3.1.1]heptanes (p40-42, p49, 51, 53 as reported; 1 eq), carboxylic acid (p58, p61-62, p65-67, p70 or commercially available if not specified in

120 the table; 1.2 eq), DIPEA (1.5 eq), and T3P (3 eq) in DMF dry (100 vol) was stirred at 50 °C for 1 hr. The mixture was treated with 1N NaOH, and then extracted with AcOEt, the extract was dried over Na₂SO4, evaporated and purified by FC on silica gel using Cy/AcOEt as eluting mixture. Then the product further purified by FC on C18 cartridge (eluent: water +0.1 % HCOOH/acetonitrile +0.1 % HCOOH) to give the target compound.

GENERAL PROCEDURE Q:

To a stirred solution of carboxylic acid (1.2 eq) and HATU (1.2 eq) in DMF (2 mL) dipea (2 eq) was added. The reaction was stirred at RT for 30 min-1h and then added to a solution of azabicyclo[3.1,1]heptane (1 eq) in DMF (1 mL). The reaction was stirred for 3 h at RT. A saturated aqueous solution of NaHCO₃ was added and the reaction was extracted with AcOEt. The combined organic phases were washed with a saturated solution of NH4CI and Brine. The organic phase was dried, filtered and concentrated under vacuum. The residue crude material was purified by FC either on silica gel or aminic silica or C18 column using the appropriate eluents.

GENERAL PROCEDURE R:

The desired alcohol intermediate (p83-86 as reported in the table, 1 eq) was dissolved in THF (—40 vol). PPh₃ (1.5 eq) was added, followed by the desired phenol (commercially available, 1.5 eq). The mixture was stirred at RT for 15’, then cooled to 0 °C. DIAD (1.5 eq) was added dropwise and, after 10’, the ice bath was removed and the mixture was allowed to reach RT and stirred for at that temperature for 1.5-2.5 hrs. The mixture was concentrated and the crude obtained was purified by FC on silica gel and/or NH column (eluting mixture Cy/AcOEt) and/or C18 cartridge (eluent from water + 0.1% formic acid I MeCN + 0.1% formic acid) to afford the title compound.

GENERAL PROCEDURE S:

To a solution of aryl halide (1.5 eq), NaH 60% dispersion in mineral oil (1.5 eq) and desired alcohol intermediate (p83-86 as reported in the table, 1 eq) were added. The reaction was stirred at 60 °C O/N. the reaction mixture was cooled down to RT, quenched with water and extracted with AcOEt. The organic phase was washed with Brine, dried and concentrated under vacuum. The residue was purified by FC on silica gel and/or NH column (eluting mixture Cy/AcOEt) and/or C18 cartridge (eluent from water + 0.1% formic acid / MeCN + 0.1% formic acid) to afford the title compound

121

Example	Starting materials	Gen. procedure	Yield (%)
64		p49	N	82
		MS (m/z): 437.0 [MH	+
cc	ΤΊι	NMR (¹H, DMSO-c/6): δ 7.26 - 7.48 (m, 5 H), 6.95 -
'XT		7.20 (m, 4 H), 4.74 -	4.81 (m, 1 H), 4.33 - 4.39 (m, 1
	H), 3.98 - 4.03 (m, 1 H), 3.87 - 3.95(m, 1 H), 2.65 -
		2.70 (m, 3 H), 2.60 -	2.65 (m, 1 H), 2.17 - 2.24 (m, 1
V		H), 2.02 - 2.16 (m, 1 H), 1.82 - 1.95 (m, 1 H), 1.03 -
	1.13 (m, 4 H), 0.95- 1.01 (m, 1 H)
CIS/TRANS 3-(4-fluorophenoxymethyl)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4-
carbonyl)-2-azabicyclo[3.1.1]heptane
The diastereomeric mixture was	separated into the	single enantiomers for each
diastereomer by preparative chiral HPLC
	Column	Chiralpak IC (25 x 2.0 cm), 5 μ
Preparative chiral chromatography	Mobile phase n-Hexane/Ethanol 75/25 % v/v Flow rate (ml/min) 14ml/min DAD detection 220 nm
protocol:	Loop	1000 pL
	Injection	9.6 mg/injection
65		TRANS Enantiomer 1	Rt: 10.7 min	100% ee
		MS (m/z): 437.0 [MH	+
	ΎΊ
0
	NMR (¹H, DMSO-c/6): δ 7.29 - 7.46 (m, 5 H), 7.11 -
		7.19 (m, 2 H), 7.00 -	7.07 (m, 2 H), 4.25 - 4.29 (m, 1
or		H), 4.17 - 4.23 (m, 1 H), 4.02 - 4.09(m, 1 H), 3.92 (d, 1
		H), 2.67 (s, 3 H), 2.38 - 2.47 (m, 1 H),	2.20 (dd, 1 H),
		2.09 - 2.17 (m, 1 H), 1.85 - 1.94 (m, 1 H), 1.63 (t, 1 H),
	1.07- 1.12 (m, 1 H), 1.06 (d, 3 H)
TA	AJA

V
(3R,4R or 3S,4S) 3-(4-fluorophenoxymethyl)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4-
carbonyl)-2-azabicyclo[3.1.1]heptane

122

CIS Enantiomer 1	Rt: 11.7 min	98.4% ee
MS (m/z): 437.0 [MH	+

NMR (¹H, DMSO-c/6): δ 7.27 - 7.45 (m, 5 H), 7.15 (t, 2 H), 6.98 - 7.04 (m, 2 H), 4.78 (t, 1 H), 4.33 - 4.40 (m, 1 H), 4.01(dd, 1 H), 3.90 (q, 1 H), 2.65 - 2.70 (m, 3 H), 2.60 - 2.66 (m, 1 H), 2.02 - 2.15 (m, 3 H), 1.86 (t, , 1 H), 1.09 (d, 3H), 0.98 (t, 1 H) (3R,4S or 3S,4R) 3-(4-fluorophenoxymethyl)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4carbonyl)-2-azabicyclo[3.1.1 jheptane

TRANS Enantiomer 2	Rt: 13.5 min	100% ee
MS (m/z): 437.0 [MH	+

NMR (¹H, DMSO-c/6): δ 7.29 - 7.46 (m, 5 H), 7.11 7.19 (m, 2 H), 7.00 - 7.07 (m, 2 H), 4.25 - 4.29 (m, 1 H), 4.17 - 4.23 (m, 1 H), 4.02 - 4.09(m, 1 H), 3.92 (d, 1 H), 2.67 (s, 3 H), 2.38 - 2.47 (m, 1 H), 2.20 (dd, 1 H), 2.09 - 2.17 (m, 1 H), 1.85 - 1.94 (m, 1 H), 1.63 (t, 1 H), 1.07- 1.12 (m, 1 H), 1.06 (d, 3 H) (3S,4S or 3R,4R) 3-(4-fluorophenoxymethyl)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4carbonyl)-2-azabicyclo[3.1.1 jheptane

123

CIS Enantiomer 2	Rt: 22.1 min	100% ee
MS (m/z): 437.0 [MH	+

NMR (¹H, DMSO-c/6): δ 7.27 - 7.45 (m, 5 H), 7.15 (t, 2 H), 6.98 - 7.04 (m, 2 H), 4.78 (t, 1 H), 4.33 - 4.40 (m, 1 H), 4.01(dd, 1 H), 3.90 (q, 1 H), 2.65 - 2.70 (m, 3 H), 2.60 - 2.66 (m, 1 H), 2.02 - 2.15 (m, 3 H), 1.86 (t, , 1 H), 1.09 (d, 3H), 0.98 (t, 1 H) (3S,4R or 3R,4S) 3-(4-fluorophenoxymethyl)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4carbonyl)-2-azabicyclo[3.1.1 jheptane

Example	Starting materials	Gen. procedure	Yield (%)
69 'W	p49 + p61	N	76
MS (m/z): 432.1 [MH	+
NMR (¹H, DMSO-c/6): δ 8.68 - 8.97 (m, 1 H), 8.03 8.20 (m, 1 H), 7.38 - 7.43 (m, 1 H), 7.30 - 7.37 (m, 1 H), 6.85 - 7.22 (m, 6 H), 4.68 - 4.80(m, 1 H), 4.22 4.42 (m, 2 H), 3.81 - 3.97 (m, 1 H), 2.64 - 2.72 (m, 1 H), 2.36 (br. s., 3 H), 1.40 - 2.25 (m, 5 H), 1.09 - 1.18 (m, 3 H)

CIS/TRANS 3-(4-fluorophenoxymethyl)-4-methyl-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]-2azabicyclo[3.1.1 jheptane_

The diastereomeric mixture was separated into the single enantiomers for each diastereomer by preparative chiral HPLC

Preparative chiral chromatography protocol:

Column	Chiralpak IC (25 x 2.0 cm), 5 μ
Mobile phase	n-Hexane/Ethanol 70/30 % v/v
Flow rate (ml/min)	14 ml/min
DAD detection	220 nm
Loop	1000 μι
Injection	9.5 mg/injection

124

TRANS Enantiomer 1	Rt: 10.1 min	100% ee
MS (m/z): 432.1 [MH	+

NMR (¹H, Acetone): δ 1.16 - 1.25 (m, 3 H), 1.46 1.88 (m, 3 H), 1.94 - 2.01 (m, 1 H), 2.11 - 2.14 (m, 1

H), 2.25 - 2.46 (m, 4 H), 2.54 - 2.70 (m, 1 H), 3.94 4.13 (m, 1 H), 4.14 - 4.29 (m, 1 H), 4.33 - 4.89 (m, 2

H), 6.94 - 7.00 (m, 1 H), 7.03 - 7.25 (m, 4 H), 7.30 7.44 (m, 2 H), 8.12 - 8.26 (m, 1 H), 8.73 - 8.91 (m, 2 H) (3S,4S or 3R,4R) 3-(4-fluorophenoxymethyl)-4-methyl-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]2-azabicyclo[3.1.1 ]heptane

F

CIS Enantiomer 1	Rt: 12.0 min	100% ee
MS (m/z): 432.1 [MH	+

NMR (¹H, Acetone): δ 1.21 - 1.27 (m, 3 H), 1.40 2.01 (m, 2 H), 2.11 - 2.35 (m, 3 H), 2.36 - 2.42 (m, 3 H), 3.92 - 4.13 (m, 1 H), 4.29 - 4.60 (m, 2 H), 4.81 5.00 (m, 1 H), 6.92 - 7.18 (m, 5 H), 7.33 (d, 2 H), 8.19 (s, 1 H), 8.72-8.91 (m, 2 H) (3S,4R or 3R,4S) 3-(4-fluorophenoxymethyl)-4-methyl-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]2-azabicyclo[3.1.1 ]heptane

125

TRANS Enantiomer 2	Rt: 13.7 min	95.2% ee
MS (m/z): 432.1 [MH	+

NMR (¹H, Acetone): δ 1.23 (d,3 H), 1.53 - 2.00 (m, 3 H), 2.09 - 2.28 (m, 2 H), 2.29 - 2.36 (m, 1 H), 2.37 2.45 (m, 3 H), 2.54 - 2.68 (m, 1 H), 3.95 - 4.14 (m, 1

H), 4.14 - 4.31 (m, 1 H), 4.33 - 4.86 (m, 2 H), 6.92 7.00 (m, 1 H), 7.08 (s, 4 H), 7.28 - 7.42 (m, 2 H), 8.09 8.26 (m, 1 H), 8.84 (d, 1 H) (3R,4R or 3S,4S) 3-(4-fluorophenoxymethyl)-4-methyl-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]2-azabicyclo[3.1.1 jheptane

F

CIS Enantiomer 2	Rt: 22.5 min	100% ee
MS (m/z): 432.1 [MH	+

NMR (¹H, Acetone): δ 1.24 (d, J=7.34 Hz, 3 H), 1.41 - 2.03 (m, 3 H), 2.11 - 2.35 (m, 4 H), 2.36 - 2.45 (m, 3 H), 3.96 - 4.13 (m, 1 H), 4.27 - 4.61 (m, 2 H), 4.78 5.04 (m, 1 H), 6.88 - 7.19 (m, 5 H), 7.25 - 7.45 (m, 2 H), 8.11 - 8.30 (m, 1 H), 8.81 (d, 1 H) (3R,4S or 3S,4R) 3-(4-fluorophenoxymethyl)-4-methyl-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]2-azabicyclo[3.1.1 jheptane

126

Example	Starting materials	Gen. procedure	Yield (%)
74			p40 + p61	N	58
			MS (m/z): 433.1 [MH	+
X	'o ‘	X	NMR (¹H, DMSO-c/6): δ 8.78 - 8.93 (m, 2 H), 8.25 (d, 1 H), 8.05 - 8.19 (m, 1 H), 7.71 (td, 1 H), 7.45 (t, 1H), 7.35 (d, 1 H), 7.11 (s, 1 H), 6.93 (dd, 1 H), 4.79 (t, 1 H), 4.65 (d, 1 H), 4.50 (t, 1 H), 3.86 (d, 1 H), 2.66 - 2.77 (m, 1 H), 2.35 - 2.42 (m, 3 H), 2.13 - 2.25 (m, 1 H), 1.96 2.03 (m, 1 H), 1.90 - 1.97 (m, 1 H), 1.57 (t, 1 H), 1.16 1.23(m, 1 H), 1.08- 1.15 (m, 3 H)
mixture of c/s-isomers
Racemic	mixture of	cis-3-{	(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[5-methyl-2-

(pyrimidin-2-yl)benzoyl]-2-azabicyclo[3.1.1]heptane

Preparative chiral chromatography protocol:

Column	Chiralpak IC (25 x 2.0 cm), 5 μ
Mobile phase	n-Hexane / Ethanol 50/50 % v/v
Flow rate (ml/min)	14 ml/min
DAD detection	220 nm
Loop	500 μΙ
Injection	14.5 mg (each injection)

75	XX	Enantiomer 1	Rt: 10.1 min	100 ee %
	<7	X,	MS (m/z): 433.1 [MH]⁺.
X	Vj		(3S,4R or 3R,4S) 3-{[(5-fluoropyridin-2-yl)oxy]methyl}4-methyl-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]-2azabicyclo[3.1.1 jheptane
(3S.4R) or enantiomer	(3R.4S)
76			Enantiomer 2	Rt: 15.7 min	100 ee %
	'XX	MS (m/z): 433.1 [MH]⁺.
X	X)		(3R,4S or 3S,4R) 3-{[(5-fluoropyridin-2-yl)oxy]methyl}4-methyl-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]-2azabicyclo[3.1.1 jheptane
(3R,4S) or enantiomer	(3S,4R)

127

Example	Starting materials	Gen. procedure	Yield (%)
77		p40	N	40
		MS (m/z): 438.1 [MH	+
¢0¾
.n. L I I	NMR (¹H, DMSO-d6): δ 8.17 (s, 1H),	7.60-7.76 (m,
		1H), 7.25-7.47 (m, 5H), 6.85-6.95 (m,	1H), 3.85-5.07
S-A		(m, 4H), 2.65-2.65 (m, 3H), 1.53-2.72 (m, 6H), 1.04-
o		1.13 ppm (m, 3H)
CIS/TRANS 3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-
4-carbonyl)-2-azabicyclo[3.1.1 jheptane
Example	Starting materials	Gen. procedure	Yield (%)
78		p40 +p58	N	98
		MS (m/z): 434.4 [MH	+
		NMR (¹H, DMSO-c/6]	: δ 8.79 - 8.97 (m, 1 H), 8.34 -
. L	8.53 (m, 1 H), 7.82 -	8.26 (m, 1 H), 7.55 - 7.76 (m, 1
		H), 7.29 - 7.53 (m, 2 H), 6.54 - 7.03(m, 1 H), 3.78 -
		4.99 (m, 4 H), 2.64 - 2.81 (m, 1 H), 2.53 (s, 3 H), 2.02 -
		2.39 (m, 3 H), 1.40-	1.98 (m, 2 H), 0.89	- 1.29 (m, 3 H)
CIS/TRANS 3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[6-methyl-3-(pyrimidin-2-
yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1 jheptane
The diastereomeric mixture was	separated into the	single enantiomers for each
diastereomer by preparative chiral HPLC
	Column	Chiralpak AD-H (25 x 2.0 cm), 5 μ
	Mobile phase n-Hexane / (2-Propanol/Methanol
Preparative chiral		1/1) 90/10 % v/v
chromatography	Flow rate (ml/min) 15 ml/min
protocol:	DAD detection 220 nm
	Loop	1500 μΙ
	Injection	35 mg (each injection)

128

CIS Enantiomer 1	Rt: 14.4 min	100% ee
MS (m/z): 434.4 [MH	+

or (X,

NMR (¹H, DMSO-c/6): δ 8.82 - 8.96 (m, 2 H), 8.47 (d,

H), 8.21 (d, 1 H), 7.67 - 7.76 (m, 1 H), 7.46 - 7.52 (m, 1 H), 7.44(d, 1 H), 6.94 (dd, 1 H), 4.74 - 4.83 (m, 1 H), 4.49 - 4.63 (m, 2 H), 3.85 (q, 1 H), 2.72 - 2.80 (m, 1 H), 2.53 (s, 3 H), 1.99 -2.41 (m, 3 H), 1.41 - 1.83 (m, 2 H),

1.13 (d, 3 H) (3R,4S or 3S,4R) 3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[6-methyl-3-(pyrimidin-2yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane

TRANS Enantiomer 1	Rt: 19.3 min	100% ee
MS (m/z): 434.4 [MH	+

F

NMR (¹H, DMSO-c/6): δ 8.88 (d, 2 H), 8.46 (d, 1 H), 8.18 (d, 1 H), 7.72 (td, 1 H), 7.39 - 7.50 (m,2 H), 6.96 (dd, 1 H), 4.66 (dd, 1 H), 4.41 (t, 1 H), 4.03 - 4.13 (m, 1 H), 3.88 (q, 1 H), 2.54 (s, 3 H), 2.48(br. s., 1 H), 2.24 2.32 (m, 1 H), 2.14 - 2.22 (m, 1 H), 1.94 (dt, 1 H), 1.68 - 1.75 (m, 1 H), 1.59- 1.66 (m, 1 H), 1.22 (d, 3 H) (3R,4R or 3S,4S) 3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[6-methyl-3-(pyrimidin-2yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane

129

CIS Enantiomer 2	Rt: 24.2 min	100% ee
MS (m/z): 434.4 [MH	+

or

NMR (¹H, DMS0-d6): δ 8.82 - 8.96 (m, 2 H), 8.47 (d,

1.13 (d, 3 H) (3S,4R or 3R,4S) 3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[6-methyl-3-(pyrimidin-2yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1 jheptane

TRANS Enantiomer 2	Rt: 37.4 min	100% ee
MS (m/z): 434.4 [MH	+

F

NMR (¹H, DMSO-c/6): δ 8.88 (d, 2 H), 8.46 (d, 1 H), 8.18 (d, 1 H), 7.72 (td, 1 H), 7.39 - 7.50 (m,2 H), 6.96 (dd, 1 H), 4.66 (dd, 1 H), 4.41 (t, 1 H), 4.03 - 4.13 (m, 1 H), 3.88 (q, 1 H), 2.54 (s, 3 H), 2.48(br. s., 1 H), 2.24 2.32 (m, 1 H), 2.14 - 2.22 (m, 1 H), 1.94 (dt, 1 H), 1.68 - 1.75 (m, 1 H), 1.59- 1.66 (m, 1 H), 1.22 (d, 3 H) (3S,4S or 3R,4R) 3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[6-methyl-3-(pyrimidin-2yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1 jheptane

130

Example	Starting materials	Gen. procedure	Yield (%)
83		p41	0	76
		MS (m/z): 470.1 [MH	+
a
		NMR (¹H, CHLOROFORM-d): δ 0.94	1.41 (m, 5 H)
		1.64 - 2.62 (m, 6 H) 3.89 - 5.44 (m, 1 H) 7.07 - 7.26 (m,
S-A		4 H) 7.41 - 8.39 (m, 7 H)
O
CIS/TRANS	1-{[4	-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-

azabicyclo[3.1.1 ]heptan-3-yl]methoxy}isoquinoline

Example	Starting materials	Gen. procedure	Yield (%)
84	p42	P	57
/Tx/**	MS (m/z): 505.1 [MH	+
-yDYOY	NMR (¹H, DMSO-c/6): δ 8.26 - 8.67 (m, 1 H), 8.06 (d, 1 H), 7.95 (d, 1 H), 7.70 (dd, 1 H), 7.18 - 7.51 (m, 5H),
^s \	3.77 - 5.12 (m, 4 H), 2.44 - 2.76 (m, 4 H), 1.54 - 2.40
0	(m, 4 H), 0.83- 1.22 (m, 4 H)

CIS/TRANS 7-chloro-2-{[4	-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-

azabicyclo[3.1.1 ]heptan-3-yl]methoxy}quinoxaline

Example	Starting materials	Gen. procedure	Yield (%)
85 0	p83	R	85
MS (m/z): 470.3 [MH	+
NMR (¹H, DMSO-c/6): δ 9.09 (s, 1H), 8.10 - 7.99 (m, 1H), 7.90 - 7.79 (m, 1H), 7.71 - 7.61 (m, 1H), 7.50 7.33 (m, 4H), 7.32 - 7.20 (m, 3H), 4.79 - 4.53 (m, 1H), 4.95 - 4.18 (m, 1H), 4.45 - 4.09 (m, 1H), 5.10 - 3.85 (m, 1H), 2.77 - 2.43 (m, 1H), 2.74 - 2.27 (m, 3H), 2.27 2.04 (m, 1H), 1.16 - 1.08 (m, 3H), 2.30 - 0.91 (m, 4H)

CIS/TRANS 3-{[4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 ]heptan-3-yl]methoxy}isoquinoline

Preparative chiral chromatography protocol:	Column Mobile phase Flow rate (ml/min) DAD detection Loop Injection	Chiralpak AD-H (25 x 2.0 cm), 5 μ n-Hexane I (2-Propanol/Methanol 1/1) 90/10 % v/v 15 ml/min 220 nm 1500 μΙ 35 mg (each injection)
86	\|TRANS	\| Rt: 15.9 min 100% ee

131

Enantiomer 1
MS (m/z): 470.3 [MH	+

NMR (¹H, DMS0-d6): δ 9.09 (s, 1 H), 8.06 (d, 1 H), 7.86 (d, 1 H), 7.68 (t, 1 H), 7.18 - 7.50 (m, 7 H), 4.55 4.65 (m, 2 H), 4.09 - 4.16 (m, 1 H), 3.94 (d, 1 H), 2.67 (s, 3 H), 2.45 - 2.53 (m, 1 H), 2.10 - 2.25 (m, 2 H), 1.86 - 1.96 (m, 1 H), 1.73 (t, 1H), 1.12 (d, 3 H), 1.08 - 1.16 (m,1 H)

3-{[(3R,4R or 3S,4S)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 ]heptan-3-yl]methoxy}isoquinoline

CIS Enantiomer 1	Rt: 18.0 min	98.6% ee
MS (m/z): 470.3 [MH	+

NMR (¹H, CHLOROFORM-d): δ 0.87 - 1.39 (m, 1 H), 0.99 - 1.24 (m, 3 H), 1.70 - 2.31 (m, 2 H), 1.92 - 2.45 (m, 1 H), 2.10 - 2.74 (m, 1 H),2.10 - 2.20 (m, 1 H), 2.39 - 2.75 (m, 3 H), 3.96 - 5.16 (m, 1 H), 4.14 - 4.57 (m, 1 H), 4.22 - 5.16 (m, 1 H), 4.56 - 4.86 (m, 1 H), 6.77 7.15 (m, 1 H), 7.17 -7.33 (m, 3 H), 7.38 (t, 1 H), 7.43 7.51 (m, 2 H), 7.58 (t, 1 H), 7.63 - 7.75 (m, 1 H), 7.89 (d, 1 H), 8.82-9.01 (m, 1 H)

3-{[(3R,4S or 3S, 4R)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 ]heptan-3-yl]methoxy}isoquinoline

132

TRANS

Enantiomer 2__

MS (m/z): 470.3 [MH]⁺

Rt: 22.0 min

100% ee

NMR (¹H, DMSO-d6): δ 9.09 (s, 1 H), 8.06 (d, 1 H), 7.86 (d, 1 H), 7.68 (t, 1 H), 7.18 - 7.50 (m, 7 H), 4.55 4.65 (m, 2 H), 4.09 - 4.16 (m, 1 H), 3.94 (d, 1 H), 2.67 (s, 3 H), 2.45 - 2.53 (m, 1 H), 2.10 - 2.25 (m, 2 H), 1.86 - 1.96 (m, 1 H), 1.73 (t, 1H), 1.12 (d, 3 H), 1.08 - 1.16 (m,1 H)

3-{[(3S, 4S or 3R,4R)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 ]heptan-3-yl]methoxy}isoquinoline

CIS	Rt: 30.0 min	100% ee
Enantiomer 2

MS (m/z): 470.3 [MH]⁺.

3-{[(3S, 4R or 3R,4S)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 ]heptan-3-yl]methoxy}isoquinoline

133

Example

Starting materials

Gen, procedure Yield (%)

p84

MS (m/z): 433.3 [MH

NMR (¹H, DMSO-d6): δ 8.82-8.97 (m, 2H), 8.38-8.49 (m, 1H), 7.29-7.55 (m, 2H), 6.62-7.18 (m, 4H), 3.814.84 (m, 4H), 2.52-2.56 (m, 3H), 1.39-2.85 (m, 6H), 0.95-1.20 ppm (m, 3H)

CIS/TRANS 3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(pyrimidin-2-yl)pyridine-2carbonyl]-2-azabicyclo[3.1.1 jheptane

The diastereomeric mixture was separated into the single enantiomers for each

diastereomer by preparative chiral HPLC
	Column	Chiralpak IC (25 x 3.0 cm), 5 μ
	Mobile phase	n-Hexane/(Ethanol + 0.1%
Preparative chiral		isopropylamine) 70/30 % v/v
chromatography	Flow rate (ml/min)	40 ml/min
protocol:	DAD detection	220 nm
	Loop	1300 pL
	Injection	25.4 mg/injection

Rt: 5.9 min

100% ee

CIS

Enantiomer 1 or

MS (m/z): 433.3 [MH]

NMR (¹H, CHLOROFORM-d): δ 1.01 - 1.27 (m, 3 H), 1.49 - 1.92 (m, 1 H), 1.69 - 2.08 (m, 1 H), 1.98 2.41 (m, 1 H), 2.20 (s, 1 H), 2.16 - 2.65(m, 3 H), 2.21 - 2.33 (m, 1 H), 2.65 - 2.87 (m, 1 H), 3.88 - 5.08 (m, 1 H), 4.45 (s, 1 H), 4.23 - 4.64 (m, 2 H), 6.59 - 7.07 (m, 4 H), 7.08 - 7.25 (m, 1 H), 7.14 -7.35 (m, 1 H), 8.47 8.58 (m, 1 H), 8.58- 8.88 (m, 2 H) (3R,4S or 3S, 4R)-3-(4-fluorophenoxymethyl)-4-methyl-2-[6-methyl-3-(pyrimidin-2yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane

134

CIS or

Enantiomer 2__

MS (m/z): 433.3 [MH]⁺.

Rt: 6.8 min

97.6% ee

NMR (¹H, CHLOROFORM-d): δ 0.98 - 1.34 (m, 3 H), 1.46 - 1.93 (m, 1 H), 1.69 - 2.07 (m, 1 H), 1.97 2.41 (m, 1 H), 2.07 - 2.51 (m, 1 H),2.17 - 2.65 (m, 3

H), 2.21 - 2.32 (m, 1 H), 2.66 - 2.86 (m, 1 H), 3.81 5.05 (m, 1 H), 4.07 - 5.18 (m, 1 H), 4.23 - 4.64 (m, 2

H), 6.57 - 7.06 (m, 4 H), 7.07 -7.25 (m, 1 H), 7.13 7.35 (m, 1 H), 8.49 - 8.57 (m, 1 H), 8.58 - 8.87 (m, 2 H) (3S, 4R or 3R,4S)-3-(4-fluorophenoxymethyl)-4-methyl-2-[6-methyl-3-(pyrimidin-2yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane or

TRANS

Enantiomer 1__

MS (m/z): 433.3 [MH]⁺.

Rt: 7.6 min

100% ee

NMR (¹H, CHLOROFORM-d): δ 1.02 - 1.24 (m, 3 H), 1.60 - 1.96 (m, 2 H), 1.73 - 2.22 (m, 2 H), 2.25 - 2.37 (m, 1 H), 2.46 - 2.68 (m, 3 H),2.58 - 2.74 (m, 1 H), 3.89 - 3.98 (m, 1 H), 4.18 - 4.77 (m, 2 H), 4.29 - 4.40 (m, 1 H), 6.53 - 7.11 (m, 2 H), 6.82 - 7.04 (m, 2 H), 7.15 (t, 1 H), 7.26- 7.32 (m, 1 H), 8.48 - 8.63 (m, 1 H), 8.64 - 8.87 (m, 2 H) (3R,4R or 3S,4S)-3-(4-fluorophenoxymethyl)-4-methyl-2-[6-methyl-3-(pyrimidin-2-yl)pyridine2-carbonyl]-2-azabicyclo[3.1.1]heptane

135

TRANS Enantiomer 2	Rt: 8.2 min	98.4% ee
MS (m/z): 433.3 [M	HL

NMR(^{* 1}H, CHLOROFORM-d): δ 0.98 - 1.24 (m, 3 H), 1.63 - 2.22 (m, 5 H), 2.31 (dd, 1 H), 2.41 - 2.73 (m, 4 H), 3.79 - 4.78(m, 4 H), 6.51 - 7.11 (m, 4 H),

7.15 (t, 1 H), 8.53 (d, 1 H), 8.64 - 8.86 (m, 2 H) (3S,4S or 3R,4R)-3-(4-fluorophenoxymethyl)-4-methyl-2-[6-methyl-3-(pyrimidin-2-yl)pyridine2-carbonyl]-2-azabicyclo[3.1.1]heptane

Example	Starting materials	Gen. procedure	Yield (%)
94	p51 + p70	Q	54
	MS (m/z): 439.1 [MH	+
NMR (¹H, CHLOROFORM-d): δ 8.53 (d, 2H), 6.67-
-<4	7.15 (m, 5H), 3.97-5.18 (m, 4H), 2.34-2.86 (m, 2H),
^s	2.76 (s, 3H), 1.65-2.21 (m, 4H), 1.28 (d, 3H)
“O
mixture of c/s-isomers

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[2-methyl-5-(pyrimidin-2-yl)1,3-thiazole-4-carbonyl]-2-azabicyclo[3.1.1]heptane

p51 + p67	Q	18
MS (m/z): 422.1 [MH	+

NMR (¹H, CHLOROFORM-d): δ 1.00 -1.31 (m, 3 H) 1.45-1.54 (m, 1 H) 1.69-2.11 (m, 2 H) 2.11-2.66 (m, 5 H) 2.67-2.84 (m, 1 H) 3.91-4.17 (m, 1 H) 4.24-4.39 (m,

H) 4.41-4.55 (m, 1 H) 4.87-5.04 (m, 1 H) 6.60-7.05 (m, 4 H) 7.19 - 7.31 (m, 1 H) 7.55-7.88 (m, 2 H) 8.108.26 (m, 1 H) mixture of c/'s-isomers__

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(2H-1,2,3-triazol2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane

136

96	p51 + p65	Q	3
MS (m/z): 438.1 [MH	+
NMR (¹H, CHLOROFORM-c/): δ 0.96-1.45 (m, 4 H) 1.65-1.84 (m, 1 H) 2.00-2.15 (m, 2 H) 2.14-2.64 (m, 4 H) 2.63-2.80 (m, 1 H) 3.80-4.15 (m, 1 H) 4.20-4.38 (m, 1 H) 4.38-4.52 (m, 1 H) 4.92-5.07 (m, 1 H) 6.59-7.19 (m, 4 H) 7.27 (s, 1 H) 7.71-7.89 (m, 1 H) 7.98-8.15 (m, 1 H)
Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(1,3-thiazol-2yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1 jheptane
97 Us Νΐΐ/ mixture of c/s-isomers	p51 + p62	Q	17
MS (m/z): 421.1 [MH	+
NMR (¹H, CHLOROFORM-of): δ 1.22 (dd, 3 H) 1.39 1.48 (m, 1 H) 1.64 - 2.27 (m, 4 H) 2.39 (m, 3 H) 2.51 2.78 (m, 1 H) 3.85 - 4.62 (m, 3 H) 4.87 - 5.04 (m, 1 H) 6.54 - 7.22 (m, 5 H) 7.28 - 7.33 (m, 1 H) 7.50 (s, 1 H) 7.67- 7.88 (m, 2 H)
Racemic mixture of cis-3-[(4-fluorop 2-yl)benzoyl]-2-azabicyclo[3.1.1 jhep	ienoxy)methyl]-4-methyl-2-[5-methyl-2-(2H-1,2,3-triazol- tane
mixture of c/s-isomers	p51 + p66	Q	4
MS (m/z): 437.3 [MF	]⁺-
NMR (¹H, CHLOROFORM-of): δ 7.72 (s, 2H), 7.327.63 (m, 1H), 7.10-7.27 (m, 2H), 6.94-7.08 (m, 4H), 3.84-5.06 (m, 4H), 2.59-2.82 (m, 2H), 2.40 (d, 3H), 1.83-2.31 (m, 4H), 0.97-1.49 (m, 3H)
Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[5-methyl-2-(1,3-thiazol-2yl)benzoyl]-2-azabicyclo[3.1.1 jheptane
99 XO'y'A Vy N=s/ mixture of c/s-isomers	p85	S	34
MS (m/z): 439.1 [MH	+
NMR (¹H, CHLOROFORM-of): δ 8.16-8.25 (m, 1H), 8.06-8.15 (m, 1H), 7.72-7.85 (m, 2H), 7.44-7.58 (m, 1H), 7.20-7.33 (m, 1H), 6.38-6.82 (m, 1H), 4.54-5.09 (m, 4H), 2.27-2.83 (m, 5H), 1.80-2.26 (m, 4H), 1.001.20 (m, 3H)
Racemic mixture of cis-3-{[(5-chloropyridin-2-yl)oxy]methyl}-4-methyl-2-[6-methyl-3-(2H1,2,3-triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1. Ijheptane

137

100

mixture of c/s-isomers

p85	S	28
MS (m/z): 419.1 [MF	r

NMR (¹H, CHLOROFORM-d): δ 8.17 (d, 1H), 7.938.03 (m, 1H), 7.70-7.86 (m, 2H), 7.32-7.43 (m, 1H),

7.19-7.32 (m, 1H), 6.75 (d, 1H), 3.93-5.10 (m, 4H),

2.27-2.83 (m, 2H), 2.62 (s, 3H), 1.84-2.26 (m, 4H),

1.01-1.22 (m, 3H)

Racemic mixture of cis-4-methyl-2-[6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carbonyl]-3{[(5-methylpyridin-2-yl)oxy]methyl}-2-azabicyclo[3.1.1 jheptane

101

mixture of frans-isomers

p52 + p66	Q \| 19
MS (m/z): 437.4 [MF	r

NMR (¹H, CHLOROFORM-d): δ 8.10-8.36 (m, 2H), 7.77 (s, 2H), 7.51-7.61 (m, 1H), 7.27-7.37 (m, 3H), 6.76-6.86 (m, 1H), 4.76 (d, 1H), 4.56-4.64 (m, 1H), 4.31-4.37 (m, 1H), 3.93-4.01 (m, 1H), 2.51-2.69 (m, 4H), 2.28-2.36 (m, 1H), 2.13-2.24 (m, 1H), 1.89-1.98 (m, 1H), 1.85 (t, 1H), 1.64 (d, 1H), 1.24 (d, 3H)

Racemic mixture of trans-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[5-methyl-2-(1,3-thiazol-2yl)benzoyl]-2-azabicyclo[3.1.1 jheptane

102

mixture of frans-isomers p86

MS (m/z): 439.4 [MH]

NMR (¹H, CHLOROFORM-d): δ 8.13-8.32 (m, 2H), TIT (s, 2H), 7.54-7.60 (m, 1H), 7.30-7.34 (m, 1H), 6.80-6.87 (m, 1H), 4.74-4.81 (m, 1H), 4.57-4.68 (m, 1H), 4.32-4.39 (m, 1H), 3.93-4.04 (m, 1H), 2.64 (s, 4H), 2.26-2.34 (m, 1H), 2.11-2.23 (m, 1H), 1.80-1.98 (m, 2H), 1.60-1.68 (m, 1H), 1.24 (d, 3H)

Racemic mixture of trans-3-{[(5-chloropyridin-2-yl)oxy]methyl}-4-methyl-2-[6-methyl-3-(2H1,2,3-triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1. Ijheptane

Example	Starting materials	Gen. procedure	Yield (%)
103			p52 + p67	Q	32
			MS (m/z): 422.3 [MH	+
c	Xr \|	°Ά	NMR (¹H, CHLOROFORM-d): δ 8.17 (d, 1H), 7.67 (s,
			2H), 7.29 (d, 1H), 7.07 - 6.94 (m, 4H),	4.57 (dd, 1H),
TI			4.29 (dt, 1H), 4.23 (dd, 1H), 3.93 (q, 1H), 2.62 (s, 4H),
			2.35 - 2.26 (m, 1H),	2.16 (dt, 1H), 1.92 (dt, 1H), 1.80
	w		(dd, 1H), 1.27-1.12 (m,4H).
mixture of frans-isomers
Racemic	mixture	of trans-3-[(4-	Fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(2H-1,2,3-

triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane_

138

Preparative chiral chromatography protocol:	Column Mobile pha Flow rate ( DAD detec Loop Injection	Chiralpak IA (25 x 2.0 cm), 5 μ se n-Hexane/2-Propanol 60/40 % v/v ml/min) 17 ml/min tion 220 nm 1000 pL 11.5 mg/injection
¹⁰⁴ γΤύ''	Enantiomer 1	Rt: 6.2 min	100 ee %
MS (m/z): 422.4 [MH]⁺.
3R,4R or 3S,4S enantiomer	(3R,4R or 3S,4S)-3-[(4-fluorophenoxy)methyl]-4methyl-2-[6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridine-2carbonyl]-2-azabicyclo[3.1. Ijheptane
¹⁰⁵ f’TY	Enantiomer 2	Rt: 8.9 min	96 ee %
MS (m/z): 422.4 [MH]⁺.
N^s/ 3S,4S or 3R,4R enantiomer	(3S,4S or 3R,4R)-3-[(4-fluorophenoxy)methyl]-4methyl-2-[6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridine-2carbonyl]-2-azabicyclo[3.1. Ijheptane
Example	Starting materials	Gen. procedure	Yield (%)
106		p52 + p65	Q	62
.0''		MS (m/z): 438.3 [MH	+
γ^Ν·\|Α mixture of frans-isomers	NMR (¹H, CHLOROFORM-d): δ 8.09 (d, 1 H), 7.71 7.93 (m, 1 H), 7.16 - 7.48 (m, 2 H), 6.90 - 7.09 (m, 4 H), 4.55 (d, 1 H), 4.20 - 4.35 (m, 2 H), 3.84 (d, 1 H), 2.55 - 2.67 (m, 4 H), 2.22 - 2.35 (m, 1 H), 1.27 - 2.21 (m, 4 H), 1.15 (d, 3 H)
Racemic mixture of trans-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(1,3-thiazol-2yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane
The racemic mixture was separated into the single enantiomers by preparative chiral HPLC
Preparative chiral chromatography protocol:	Column Chiralpak IA (25 x 2.0 cm), 5 μ Mobile phase n-Hexane/2-Propanol 60/40 % v/v Flow rate (ml/min) 17 ml/min DAD detection 220 nm Loop 500 pL Injection 10 mg/injection

139

107

3R,4R or 3S,4S enantiomer

Enantiomer 1

Rt: 7.3 min

MS (m/z): 438.4 [MH]⁺.

108

100 ee % (3R,4R or 3S,4S)-3-[(4-fluorophenoxy)methyl]-4methyl-2-[6-methyl-3-(1,3-thiazol-2-yl)pyridine-2carbonyl]-2-azabicyclo[3.1.1]heptane

Enantiomer 2

Rt: 10.5 min

94.6 ee %

MS (m/z): 438.4 [MH]⁺.

(3S,4S or 3R,4R)-3-[(4-fluorophenoxy)methyl]-4methyl-2-[6-methyl-3-(1,3-thiazol-2-yl)pyridine-2carbonyl]-2-azabicyclo[3.1.1]heptane

3S,4S or 3R,4R enantiomer

Example	Starting materials	Gen. procedure	Yield (%)
109			p52 + p62	Q	18
			MS (m/z): 421.1 [MH	+
	Tr 'n^V-	Ό.	NMR (¹H, CHLOROFORM-d): δ 7.49 -	7.95 (m, 3 H),
K	Λ	6.83 - 7.37 (m, 6 H), 3.83 - 4.64 (m, 4 H), 2.35 - 2.46
			(m, 3 H), 2.21 - 2.68 (m, 2 H), 1.40 -	2.21 (m, 4 H),
			1.09- 1.19 (m, 3 H)
	f >
mixture of frans-isomers
Racemic	mixture	of trans-3-[(4-	Fluorophenoxy)methyl]-4-methyl-2-[5-methyl-2-(2H-1,2,3-

triazol-2-yl)benzoyl]-2-azabicyclo[3.1	,1]heptane
110 N \_ N=~/ mixture of frans-isomers	p86	S 24
MS (m/z): 479.1 [MH	+
NMR (¹H, CHLOROFORM-d): δ 8.17 (d, 1H), 7.76 (s, 2H), 7.63 (dd, 1H), 7.36 (dd, 1H), 7.29 (d, 1H), 7.09 (td, 1H), 5.14 - 4.82 (m, 2H), 4.36 (dt, 1H), 3.98 (q, 1H), 2.61 (s, 3H), 2.38 - 2.26 (m, 1H), 2.19 (dt, 1H), 1.94 (dd, 1H), 1.84 - 1.74 (m, 1H), 1.63 (t, 1H), 1.25 (d, 3H).

Racemic mixture of trans-6-fluoro-2-({4-methyl-2-[6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridine2-carbonyl]-2-azabicyclo[3.1.1]heptan-3-yl}methoxy)-1,3-benzothiazole

140

111 GCvy mixture of frans-isomers	p86	R	18
MS (m/z): 440.4 [MH	+
NMR(¹H, CHLOROFORM-d): δ 8.17 (d, 1H), 7.71 (s, 2H), 7.30 (d, 1H), 7.07 (q, 1H), 6.95 - 6.89 (m, 1H), 6.86 - 6.79 (m, 1H), 4.57 (dd, 1H), 4.30 - 4.25 (m, 1H), 4.21 (dd, 1H), 3.93 (q, 1H), 2.62 (s, 3H), 2.33 2.28 (m, 1H), 2.17 (dt, 1H), 1.92 (dt, 1H), 1.80 - 1.71 (m, 1H), 1.17 (d, 3H).
Racemic mixture of trans-3-[(3,4-di triazol-2-yl)pyridine-2-carbonyl]-2-az	Fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(2H-1,2,3abicyclo[3.1.1 jheptane
112 CCy. Νί;/ mixture of frans-isomers	p86	R	17
MS (m/z): 438.3 [MH	+
NMR (¹H, CHLOROFORM-d): δ 8.17 (d, 1H), 7.67 (s, 3H), 7.31-7.23 (m, 2H), 7.05-7.02 (m, 2H), 4.59 (dd, 1H), 4.30-4.22 (m, 2H), 3.93 (q, 1H), 2.62 (s, 4H), 2.31-2.29 (m, 1H), 2.19-2.13 (m, 1H), 1.95-1.91 (m, 1H), 1.81-1.77 (m, 1H), 1.16 (d, 3H).
Racemic mixture of trans-3-[(4-chlorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(2H-1,2,3triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1 jheptane

Example 113:

Compounds of the examples were assayed for their Orexin type 1 and type 2 receptor 5 binding activity using the Scintillation Proximity Assay and Intracellular Calcium

Measurement methods described above. Results are shown in Table 1.

Table 1: OXi and OX₂ binding and functional antagonist values for representative examples.

Example	OX1 pKi (SPA binding)	OX2 pKi (SPA binding)	OX1 fpKi (FLIPR)	OX2 fpKi (FLIPR)
1	8.14	6.97	8.20	6.53
3			8.63	7.09
4			8.24	6.79
6			8.29	7.03
7			8.15	6.85
9			8.4	7.1
10			7.83	6.46
12			7.56	5.98
13			8.11	6.77
15			8.39	7.28
16			7.54	6.27
17			7.82	6.45
19			7.04	6.01

141

Example	0X1 pKi (SPA binding)	0X2 pKi (SPA binding)	0X1 fpKi (FLIPR)	0X2 fpKi (FLIPR)
20			7.64	6.41
22			7.46	6.76
24			7.33	6.12
25			7.52	6.68
26			7.74	6.74
29			7.33	6.21
31			7.01	6.11
32			7.14	6.29
33			7.62	6.96
35			7.13	6.2
36			7.17	6.7
38	7.61	6.9
39	7.64	6.19
40	7.33	6.19
41			7.65	6.65
42			7.74	6.97
44	7.15	6.38
45	7.22	7.12
46	7.62	6.51
47	7.61	6.91
48	7.45	6.53
49	7.88	6.81
50	7.66	6.52
51	7.22	ND
52	7.71	6.79
53	7.58	7.13
54	111	7.03
55	7.38	6.49
56	7.98	7.12
57	7.35	6.86
58	7.4	6.76
59	8.1	7.46
60	8.27	7.39
61	9.12	8.03
63	8.06	6.37
64			8.5	6.55
67			8.86	6.25
68			9.13	6.86
69			7.89	6.53
70			7.87	5.61
71			8.47	7.05
74			7.54	6.23
75			7.98	6.98
77			7.66	<6
78			7.45	6.63
81			8.01	7.23
82			8	5.65
83			8.46	7.33
84			7.12	5.73
85			8.2	5.98
86	7.05	5.89

142

Example	0X1 pKi (SPA binding)	0X2 pKi (SPA binding)	0X1 fpKi (FLIPR)	0X2 fpKi (FLIPR)
88	7.92	6.56
89	8.86	6
91	8.46	7.45
93	8.71	6.39
94	8.04	6.35
95	8.09	6.6
96	8.18	6.88
97	7.74	6.51
98	7.86	6.75
99	7.37	6.18
100	7.03	5.96
101	8.02	6.15
102	7.23	5.71
103	8	5.6
105	8.2	5.88
106	8.16	6.12
108	8.49	6.39
109	7.51	5.89
110	7	6.06
111	7.53	5.99
112	7.83	5.92

ND: Not determined

143

Claims

1. A compound of formula I, wherein:

L1 represents a direct bond or -[CR5R6]-;

X represents a direct bond, -0-, -N(RX)-, -CH2- or -S-;

A represents an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, each of which is optionally substituted with one or more Q1 groups;

L2 represents a direct bond or -C(=O)-;

B represents an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, each of which is optionally substituted with one or more Q2 groups;

L3 represents -CH2- or -CH2CH2-;

R1 and R2 independently represent hydrogen, halogen, -OR7, -NR8R9, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl or C3-12 cycloalkyl (which latter four groups are optionally substituted

25 by one or more E1 substituents); or R1 and R2 together with the carbon atom to which they are bound form C=O, C=C(R10)R11 or a C3-6 cycloalkyl group optionally substituted by one or more E2 substituents;

144

R3, R4, R5 and R6 independently represent hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl,

C2-12 alkynyl or C3-6 cycloalkyl (which latter four groups are optionally substituted by one or more E3 substituents); or any relevant pair of R3, R4, R5 and R6 form, together with the carbon atom to which they are bound, C=O or a C3-6 cycloalkyl group optionally

5 substituted by one or more E4 substituents;

R7, R8, R9, R10 and R11 independently represent hydrogen or a C1-6 alkyl group optionally substituted by one or more halo atoms;

10 Rx represents hydrogen, C1-6 alkyl, or C3-6 cycloalkyl (which latter two groups are optionally substituted by one or more halo atoms);

Q1 and Q2 independently represent halogen, -CN, -NHCOR12, C1-6 alkyl, C3-6 cycloalkyl, -O-C1-6 alkyl, aryl or heteroaryl (which latter five groups are optionally substituted by one

15 or more substituents selected from halogen, methyl and halomethyl (e.g. trifluoromethyl));

E1, E2, E3 and E4 independently represent halogen or a C1-6 alkyl group optionally substituted by one or more halo atoms;

R12 represents C1-6 alkyl or phenyl;

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

25

2. A compound as claimed in Claim 1, wherein X represents -0-, -N(RX)- or -CH2-.

3. A compound as claimed in Claim 2, wherein the -[CR3R4]-L1-X- linker has one of the following structures:

4. A compound as claimed in any one of the preceding claims, wherein L2 represents -C(=0)-.

145

5. A compound as claimed in any one of the preceding claims, wherein R1 and R2 independently represent hydrogen, halogen, -OR7 or C1-4 alkyl optionally substituted by one or more halo atoms.

6. A compound as claimed in any one of the preceding claims, wherein A represents an aryl or heteroaryl group, each of which is optionally substituted by one or more Q1 groups.

7. A compound as claimed in any one of the preceding claims, wherein B represents an aryl or heteroaryl group, each of which is optionally substituted by one or more Q2 substituents.

8. A compound as claimed in any one of the preceding claims, wherein the compound is an antagonist of 0X1R and/or OX1R/OX2R selected from the group consisting of:

3-[(4-fluorophenoxy)methyl]-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 jheptane;

(3R)-3-[(4-fluorophenoxy)methyl]-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 jheptane;

(3S)-3-[(4-fluorophenoxy)methyl]-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 jheptane;

3-(4-fluorophenoxymethyl)-2-{[6-methyl-3-(1,3-thiazol-2-yl)pyridin-2-yl]carbonyl}-2azabicyclo[3.1.1 jheptane;

(3R)-3-(4-fluorophenoxymethyl)-2-{[6-methyl-3-(1,3-thiazol-2-yl)pyridin-2-yl]carbonyl}-2azabicyclo[3.1.1 jheptane;

(3S)-3-(4-fluorophenoxymethyl)-2-{[6-methyl-3-(1,3-thiazol-2-yl)pyridin-2-yl]carbonyl}-2azabicyclo[3.1.1 jheptane;

3-(4-fluorophenoxymethyl)-2-{[5-methyl-2-(1,3-thiazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 jheptane;

(3R)-3-(4-fluorophenoxymethyl)-2-{[5-methyl-2-(1,3-thiazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 jheptane;

(3S)-3-(4-fluorophenoxymethyl)-2-{[5-methyl-2-(1,3-thiazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 jheptane;

3-(4-fluorophenoxymethyl)-2-{[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 jheptane;

146 (3R)-3-(4-fluorophenoxymethyl)-2-{[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 jheptane;

(3S)-3-(4-fluorophenoxymethyl)-2-{[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 jheptane;

3-(4-fluorophenoxymethyl)-2-{[6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl]carbonyl}-2azabicyclo[3.1.1 jheptane;

(3R)-3-(4-fluorophenoxymethyl)-2-{[6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl]carbonyl}-2azabicyclo[3.1.1 jheptane;

(3S)-3-(4-fluorophenoxymethyl)-2-{[6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl]carbonyl}-2azabicyclo[3.1.1 jheptane;

3-(4-fluorophenoxymethyl)-2-{[5-methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 jheptane;

(3S)-3-(4-fluorophenoxymethyl)-2-{[5-methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 jheptane;

(3R)-3-(4-fluorophenoxymethyl)-2-{[5-methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 jheptane;

3-(4-chlorophenoxymethyl)-2-{[5-methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 jheptane;

3-(4-chlorophenoxymethyl)-2-{[5-methyl-2-(1,3-thiazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 jheptane;

3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl]carbonyl}2- azabicyclo[3.1.1 jheptane;

(3S)-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[6-methyl-3-(pyrimidin-2-yl)pyridin-2yl]carbonyl}-2-azabicyclo[3.1.1 jheptane;

(3R)-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[6-methyl-3-(pyrimidin-2-yl)pyridin-2yl]carbonyl}-2-azabicyclo[3.1.1 jheptane;

3- {[(5-fluoropyridin-2-yl)oxy]methyl}-2-[(2-methyl-5-phenyl-1,3-thiazol-4-yl)carbonyl]-2azabicyclo[3.1.1 jheptane;

3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[5-methyl-2-(1,3-thiazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 jheptane;

147 (3S)-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[5-methyl-2-(2H-1,2,3-triazol-2yl)phenyl]carbonyl}-2-azabicyclo[3.1.1]heptane;

5 3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[6-methyl-3-(1,3-thiazol-2-yl)pyridin-2-yl]carbonyl}

2- azabicyclo[3.1.1]heptane;

3- {[(5-chloropyridin-2-yl)oxy]methyl}-2-{[5-methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 jheptane;

(3S)-3-{[(5-chloropyridin-2-yl)oxy]methyl}-2-{[5-methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}· 10 2-azabicyclo[3.1.1]heptane;

(3R)-3-{[(5-chloropyridin-2-yl)oxy]methyl}-2-{[5-methyl-2-(pyrimidin-2-yl)phenyl]carbonyl} 2-azabicyclo[3.1.1]heptane;

2- {[5-methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}-3-({[5-(trifluoromethyl)pyridin-2yl]oxy}methyl)-2-azabicyclo[3.1.1]heptane;

15 (3S)-2-{[5-methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}-3-({[5-(trifluoromethyl)pyridin-2yl]oxy}methyl)-2-azabicyclo[3.1.1]heptane;

(3R)-2-{[5-methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}-3-({[5-(trifluoromethyl)pyridin-2yl]oxy}methyl)-2-azabicyclo[3.1.1]heptane;

3- {[2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptan-320 yl]methoxy}isoquinoline;

25 3-[2-(4-fluorophenoxy)ethyl]-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]-2azabicyclo[3.1.1 jheptane;

(3S)-3-[2-(4-fluorophenoxy)ethyl]-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]-2azabicyclo[3.1.1 jheptane;

(3R)-3-[2-(4-fluorophenoxy)ethyl]-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]-230 azabicyclo[3.1.1]heptane;

35 3-(4-bromophenoxymethyl)-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 jheptane;

148

2- {[2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptan-3yl]methoxy}quinoxaline ;

3- (4-fluorophenoxymethyl)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 jheptane;

149 (3R,4R)-3-(4-fluorophenoxymethyl)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4carbonyl)-2-azabicyclo[3.1.1]heptane;

5 (3S,4S)-3-(4-fluorophenoxymethyl)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4carbonyl)-2-azabicyclo[3.1.1]heptane;

(3S,4R)-3-(4-fluorophenoxymethyl)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4carbonyl)-2-azabicyclo[3.1.1]heptane;

3-(4-fluorophenoxymethyl)-4-methyl-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]-210 azabicyclo[3.1.1]heptane;

(3S,4S)-3-(4-fluorophenoxymethyl)-4-methyl-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]-2azabicyclo[3.1.1 ]heptane;

(3R,4S)-3-(4-fluorophenoxymethyl)-4-methyl-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]-2azabicyclo[3.1.1 ]heptane;

15 (3R,4R)-3-(4-fluorophenoxymethyl)-4-methyl-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]-2azabicyclo[3.1.1 ]heptane;

(3S,4R)-3-(4-fluorophenoxymethyl)-4-methyl-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]-2azabicyclo[3.1.1 ]heptane;

Racemic mixture of cis-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[5-methyl-2 20 (pyrimidin-2-yl)benzoyl]-2-azabicyclo[3.1.1]heptane;

25 3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4carbonyl)-2-azabicyclo[3.1.1]heptane;

3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[6-methyl-3-(pyrimidin-2-yl)pyridine-2carbonyl]-2-azabicyclo[3.1.1 ]heptane;

(3R,4S)-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[6-methyl-3-(pyrimidin-230 yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane;

35 (3S,4S)-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[6-methyl-3-(pyrimidin-2yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane;

150

(3R,4S)-3-(4-fluorophenoxymethyl)-4-methyl-2-[6-methyl-3-(pyrimidin-2-yl)pyridine-2carbonyl]-2-azabicyclo[3.1.1 jheptane;

(3S,4R)-3-(4-fluorophenoxymethyl)-4-methyl-2-[6-methyl-3-(pyrimidin-2-yl)pyridine-2carbonyl]-2-azabicyclo[3.1.1 jheptane;

(3R,4R)-3-(4-fluorophenoxymethyl)-4-methyl-2-[6-methyl-3-(pyrimidin-2-yl)pyridine-2carbonyl]-2-azabicyclo[3.1.1 jheptane;

(3S,4S)-3-(4-fluorophenoxymethyl)-4-methyl-2-[6-methyl-3-(pyrimidin-2-yl)pyridine-2carbonyl]-2-azabicyclo[3.1.1 jheptane;

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[2-methyl-5-(pyrimidin-2yl)-1,3-thiazole-4-carbonyl]-2-azabicyclo[3.1.1 jheptane;

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(2H-1,2,3triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1 jheptane;

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(1,3-thiazol2- yl)pyridine-2-carbonyl]-2-azabicyclo[3.1. Ijheptane;

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[5-methyl-2-(2H-1,2,3triazol-2-yl)benzoyl]-2-azabicyclo[3.1.1 jheptane;

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[5-methyl-2-(1,3-thiazol2- yl)benzoyl]-2-azabicyclo[3.1.1 jheptane;

Racemic mixture of cis-3-{[(5-chloropyridin-2-yl)oxy]methyl}-4-methyl-2-[6-methyl-3-(2H1,2,3-triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1. Ijheptane;

Racemic mixture of cis-4-methyl-2-[6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carbonylj3- {[(5-methylpyridin-2-yl)oxy]methyl}-2-azabicyclo[3.1.1 jheptane;

151

Racemic mixture of trans-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(2H-1,2,3triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane; (3R,4R)-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(2H-1,2,3-triazol-2yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1 jheptane;

(35.45) -3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(2H-1,2,3-triazol-2yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1 jheptane;

(3R,4R)-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(1,3-thiazol-2-yl)pyridine-2carbonyl]-2-azabicyclo[3.1.1 jheptane;

(35.45) -3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(1,3-thiazol-2-yl)pyridine-2carbonyl]-2-azabicyclo[3.1.1 jheptane;

152

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-{6-methyl-3-[5(trifluoromethyl)pyrimidin-2-yl]pyridine-2-carbonyl}-2-azabicyclo[3.1.1 ]heptane;

(35.45) -3-[(4-chlorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(2H-1,2,3-triazol-2yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane;

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-2-[3-(5-fluoropyrimidin-2-yl)-6methylpyridine-2-carbonyl]-4-methyl-2-azabicyclo[3.1.1 ]heptane;

(35.45) -3-[(4-fluorophenoxy)methyl]-4-methyl-2-[2-methyl-5-(pyrimidin-2-yl)-1,3-thiazole4-carbonyl]-2-azabicyclo[3.1.1]heptane;

Racemic mixture of cis-6-fluoro-N-({4-methyl-2-[6-methyl-3-(2H-1,2,3-triazol-2yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptan-3-yl}methyl)-1,3-benzothiazol-2-amine; Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(4-methyl1 H-pyrazol-1 -yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1 ]heptane;

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[2-methyl-5-(6methylpyridin-2-yl)-1,3-thiazole-4-carbonyl]-2-azabicyclo[3.1.1 ]heptane;

153

9. A compound of formula I as defined in any one of the preceding claims, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for use in medicine.

10. A pharmaceutical formulation including a compound of formula I, as defined in any one of Claims 1 to 8, or a pharmaceutically acceptable salt, solvate or prodrug thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.

11. A compound, as defined in any one of Claims 1 to 8, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for use in treating or preventing a disease or disorder in which antagonism of the orexin-1 and/or orexin-2 receptors is desired and/or required.

12. Use of a compound of formula I, as defined in any one of Claims 1 to 8, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for the manufacture of a medicament for treating or preventing a disease or disorder in which antagonism of the orexin-1 and/or orexin-2 receptors is desired and/or required.

13. A method of treating or preventing a disease or disorder in which antagonism of the orexin-1 and/or orexin-2 receptors is desired and/or required, which method comprises administration of a therapeutically effective amount of a compound of formula I as defined in any one of Claims 1 to 8, or a pharmaceutically-acceptable salt, solvate or prodrug thereof, to a patient suffering from, or susceptible to, such a condition.

14. A compound for use as claimed in Claim 11, a use as claimed in Claim 12, or a method as claimed in Claim 13, wherein the disease or disorder is selected from the group consisting of substance dependence, addiction, an anxiety disorder, a panic disorder, binge eating, a compulsive disorder, an impulse control disorder, cognitive impairment and Alzheimer’s disease.

15. The compound for use, use or method, as claimed in any one of Claims 11 to 14, wherein the disease or disorder is binge eating, alcohol addiction, nicotine addiction, or cocaine addiction.

16. A combination product comprising:

154 (A) a compound of formula I as defined in any one of Claims 1 to 8, or a pharmaceutically-acceptable salt, solvate or prodrug thereof; and (B) another therapeutic agent that is useful in the treatment of a disease or disorder as defined in any one of Claims 11 to 15,

5 wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.

17. A process for the preparation of a compound of formula I as defined in Claim 1, which process comprises:

(i) for compounds of formula I in which L2 represents -C(=O)-, reaction of a corresponding compound of formula II, wherein L1, L3, R1, R2, R3, R4, X and A are as defined in Claim 1, with a compound of 15 formula III,

B-C(O)OH III wherein B is as defined in Claim 1, optionally wherein the -C(O)OH group in the 20 compound of formula III is first activated to the corresponding acyl halide;

(ii) for compounds of formula compound of formula IV,

I in which X represents -0-, reaction of a corresponding

155 wherein L1, L2, L3, R1, R2, R3, R4 and B are as defined in Claim 1, with a compound of formula V,

A-OH V wherein A is as defined in Claim 1;

(iii) for compounds of formula I in which X represents -0-, reaction of a corresponding compound of formula IV, with a compound of formula VI,

A-Lx VI wherein A is as defined in Claim 1 and Lx represents a suitable leaving group;

(iv) for compounds of formula I in which X represents -0-, reaction of a corresponding compound of formula VII, wherein L1, L2, L3, R1, R2, R3, R4 and B are as defined in Claim 1, and Ly represents a suitable leaving group, with a compound of formula V; or (v) for compounds of formula I in which X represents -NH-, reductive amination of a corresponding compound of formula VIII, wherein L2, L3, R1, R2, and B are as defined in Claim 1, using a compound of formula IX,

156 a-nh2

IX wherein A is as defined in Claim 1.

157

Amendment to Claims have been filed as follows

Claims

1. A compound of formula I, wherein:

1506 18

L1 represents a direct bond or -[CR5R6]-;

X represents a direct bond, -0-, -N(RX)-, -CH2- or -S-;

A represents an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, each of which is optionally substituted with one or more O1 groups;

L2 represents a direct bond or -C(=O)-;

B represents an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, each of which is optionally substituted with one or more O2 groups;

L3 represents -CH2- or -CH2CH2-;

158

1506 18

5 substituted by one or more E4 substituents;

Ε1, E2, E3 and E4 independently represent halogen or a C1-6 alkyl group optionally substituted by one or more halo atoms;

R12 represents C1-6 alkyl or phenyl;

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

25 2. A compound as claimed in Claim 1, wherein X represents -0-, -N(RX)- or -CH2-.

y^ov y^A.

4. A compound as claimed in any one of the preceding claims, wherein L2 represents -C(=O)-.

159

1506 18

10 7. A compound as claimed in any one of the preceding claims, wherein B represents an aryl or heteroaryl group, each of which is optionally substituted by one or more Q2 substituents.

8. A compound as claimed in any one of the preceding claims, wherein the

15 compound is an antagonist of 0X1R and/or OX1R/OX2R selected from the group consisting of:

(3R)-3-[(4-fluorophenoxy)methyl]-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-220 azabicyclo[3.1.1 jheptane;

25 (3R)-3-(4-fluorophenoxymethyl)-2-{[6-methyl-3-(1,3-thiazol-2-yl)pyridin-2-yl]carbonyl}-2azabicyclo[3.1.1 jheptane;

3-(4-fluorophenoxymethyl)-2-{[5-methyl-2-(1,3-thiazol-2-yl)phenyl]carbonyl}-230 azabicyclo[3.1.1 jheptane;

35 3-(4-fluorophenoxymethyl)-2-{[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 jheptane;

160

1506 18 (3R)-3-(4-fluorophenoxymethyl)-2-{[5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 jheptane;

5 3-(4-fluorophenoxymethyl)-2-{[6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl]carbonyl}-2azabicyclo[3.1.1 jheptane;

(3S)-3-(4-fluorophenoxymethyl)-2-{[6-methyl-3-(pyrimidin-2-yl)pyridin-2-yl]carbonyl}-210 azabicyclo[3.1.1]heptane;

15 (3R)-3-(4-fluorophenoxymethyl)-2-{[5-methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}-2azabicyclo[3.1.1 jheptane;

3-(4-chlorophenoxymethyl)-2-{[5-methyl-2-(1,3-thiazol-2-yl)phenyl]carbonyl}-220 azabicyclo[3.1.1]heptane;

25 (3R)-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[6-methyl-3-(pyrimidin-2-yl)pyridin-2yl]carbonyl}-2-azabicyclo[3.1.1 jheptane;

3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[5-methyl-2-(1,3-thiazol-2-yl)phenyl]carbonyl}-230 azabicyclo[3.1.1]heptane;

35 3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[5-methyl-2-(2H-1,2,3-triazol-2yl)phenyl]carbonyl}-2-azabicyclo[3.1.1]heptane;

161

1506 18 (3S)-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[5-methyl-2-(2H-1,2,3-triazol-2yl)phenyl]carbonyl}-2-azabicyclo[3.1.1 jheptane;

(3R)-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[5-methyl-2-(2H-1,2,3-triazol-2yl)phenyl]carbonyl}-2-azabicyclo[3.1.1 jheptane;

5 3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-{[6-methyl-3-(1,3-thiazol-2-yl)pyridin-2-yl]carbonyl}2- azabicyclo[3.1.1 jheptane;

(3S)-3-{[(5-chloropyridin-2-yl)oxy]methyl}-2-{[5-methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}10 2-azabicyclo[3.1.1 jheptane;

(3R)-3-{[(5-chloropyridin-2-yl)oxy]methyl}-2-{[5-methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}2-azabicyclo[3.1.1 jheptane;

2- {[5-methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}-3-({[5-(trifluoromethyl)pyridin-2yl]oxy}methyl)-2-azabicyclo[3.1.1 jheptane;

15 (3S)-2-{[5-methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}-3-({[5-(trifluoromethyl)pyridin-2yl]oxy}methyl)-2-azabicyclo[3.1.1 jheptane;

(3R)-2-{[5-methyl-2-(pyrimidin-2-yl)phenyl]carbonyl}-3-({[5-(trifluoromethyl)pyridin-2yl]oxy}methyl)-2-azabicyclo[3.1.1 jheptane;

3- {[2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptan-320 yljmethoxyjisoquinoline;

(3R)-3-[2-(4-fluorophenoxy)ethyl]-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]-230 azabicyclo[3.1.1 jheptane;

162

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5 3-(4-chlorophenoxymethyl)-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 jheptane;

3- (4-fluorophenoxymethyl)-2-[5-(4-fluorophenyl)-2-methyl-1,3-thiazole-4-carbonyl]-2azabicyclo[3.1.1 jheptane;

2- (2-chloro-5-phenyl-1,3-thiazole-4-carbonyl)-3-[(4-fluorophenoxy)methyl]-210 azabicyclo[3.1.1 jheptane;

15 6-fluoro-2-{[2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptan-3yl]methoxy}-1,3-benzothiazole;

2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-3-({[5-(trifluoromethyl)pyridin-2yl]oxy}methyl)-2-azabicyclo[3.1.1 jheptane;

2-{[2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptan-320 yljmethoxyjquinoline;

2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-3-[({7-methyl-7H-pyrrolo[2,3-d]pyrimidin-2yl}oxy)methyl]-2-azabicyclo[3.1.1 jheptane;

2-{[2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptan-3yljmethoxyjquinoxaline ;

25 N-{[2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptan-3yl]methyl}isoquinolin-3-amine;

6-fluoro-N-{[2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptan-330 yljmethyl}-1,3-benzothiazol-2-amine;

(3S,4R)-4-fluoro-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-(2-methyl-5-phenyl-1,3-thiazole-4carbonyl)-2-azabicyclo[3.1.1 jheptane;

(3R,4S)-4-fluoro-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-2-(2-methyl-5-phenyl-1,3-thiazole-4carbonyl)-2-azabicyclo[3.1.1 jheptane;

35 3-(4-fluorophenoxymethyl)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 jheptane;

163

1506 18 (3R,4R)-3-(4-fluorophenoxymethyl)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4carbonyl)-2-azabicyclo[3.1. Ijheptane;

(3R,4S)-3-(4-fluorophenoxymethyl)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4carbonyl)-2-azabicyclo[3.1. Ijheptane;

5 (3S,4S)-3-(4-fluorophenoxymethyl)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4carbonyl)-2-azabicyclo[3.1. Ijheptane;

(3S,4R)-3-(4-fluorophenoxymethyl)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4carbonyl)-2-azabicyclo[3.1. Ijheptane;

3-(4-fluorophenoxymethyl)-4-methyl-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]-210 azabicyclo[3.1.1 jheptane;

(3S,4S)-3-(4-fluorophenoxymethyl)-4-methyl-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]-2azabicyclo[3.1.1 jheptane;

15 (3R,4R)-3-(4-fluorophenoxymethyl)-4-methyl-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]-2azabicyclo[3.1.1 jheptane;

(3S,4R)-3-(4-fluorophenoxymethyl)-4-methyl-2-[5-methyl-2-(pyrimidin-2-yl)benzoyl]-2azabicyclo[3.1.1 jheptane;

Racemic mixture of cis-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[5-methyl-220 (pyrimidin-2-yl)benzoyl]-2-azabicyclo[3.1.1 jheptane;

(3S,4R)-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[5-methyl-2-(pyrimidin-2yl)benzoyl]-2-azabicyclo[3.1.1 jheptane;

(3R,4S)-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[5-methyl-2-(pyrimidin-2yl)benzoyl]-2-azabicyclo[3.1.1 jheptane;

25 3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4carbonyl)-2-azabicyclo[3.1.1 jheptane;

3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[6-methyl-3-(pyrimidin-2-yl)pyridine-2carbonyl]-2-azabicyclo[3.1.1 jheptane;

(3R,4S)-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[6-methyl-3-(pyrimidin-230 yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1 jheptane;

(3R,4R)-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[6-methyl-3-(pyrimidin-2yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1 jheptane;

(3S,4R)-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[6-methyl-3-(pyrimidin-2yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1 jheptane;

35 (3S,4S)-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[6-methyl-3-(pyrimidin-2yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1 jheptane;

164

1506 18

5 3-{[4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2-azabicyclo[3.1.1]heptan-3yl]methoxy}isoquinoline;

3-{[(3R,4R)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-2azabicyclo[3.1.1 ]heptan-3-yl]methoxy}isoquinoline; 3-{[(3R,4S)-4-methyl-2-(2-methyl-5-phenyl-1,3-thiazole-4-carbonyl)-21 o azabicyclo[3.1.1 ]heptan-3-yl]methoxy}isoquinoline;

15 (3R,4S)-3-(4-fluorophenoxymethyl)-4-methyl-2-[6-methyl-3-(pyrimidin-2-yl)pyridine-2carbonyl]-2-azabicyclo[3.1.1 jheptane;

(3R,4R)-3-(4-fluorophenoxymethyl)-4-methyl-2-[6-methyl-3-(pyrimidin-2-yl)pyridine-220 carbonyl]-2-azabicyclo[3.1.1 jheptane;

25 Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(2H-1,2,3triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane;

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[5-methyl-2-(2H-1,2,330 triazol-2-yl)benzoyl]-2-azabicyclo[3.1.1 jheptane;

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[5-methyl-2-(1,3-thiazol2- yl)benzoyl]-2-azabicyclo[3.1.1]heptane;

Racemic mixture of cis-3-{[(5-chloropyridin-2-yl)oxy]methyl}-4-methyl-2-[6-methyl-3-(2H1,2,3-triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1 jheptane;

35 Racemic mixture of cis-4-methyl-2-[6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridine-2-carbonyl]3- {[(5-methylpyridin-2-yl)oxy]methyl}-2-azabicyclo[3.1.1 jheptane;

165

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Racemic mixture of trans-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[5-methyl-2-(1,3thiazol-2-yl)benzoyl]-2-azabicyclo[3.1.1 jheptane;

Racemic mixture of trans-3-{[(5-chloropyridin-2-yl)oxy]methyl}-4-methyl-2-e-methyl-3(2H-1,2,3-e-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1 jheptane;

5 Racemic mixture of trans-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(2H-1,2,3triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1 jheptane; (3R,4R)-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(2H-1,2,3-triazol-2yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1 jheptane;

(3S,4S)-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(2H-1,2,3-triazol-210 yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane;

Racemic mixture of trans-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(1,3thiazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1 jheptane;

15 (3S,4S)-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(1,3-thiazol-2-yl)pyridine-2carbonyl]-2-azabicyclo[3.1.1 jheptane;

Racemic mixture of trans-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[5-methyl-2-(2H-1,2,3triazol-2-yl)benzoyl]-2-azabicyclo[3.1.1 jheptane;

Racemic mixture of trans-6-fluoro-2-({4-methyl-2-[6-methyl-3-(2H-1,2,3-triazol-220 yl)pyridine-2-carbonyl]-2-azabicyclo[3.1,1]heptan-3-yl}methoxy)-1,3-benzothiazole;

Racemic mixture of trans-3-[(3,4-difluorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(2H1.2.3- triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1 jheptane;

Racemic mixture of trans-3-[(4-chlorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(2H-1,2,3triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1 jheptane;

25 Racemic mixture of trans-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[2-methyl-5-(pyrimidin2-yl)-1,3-thiazole-4-carbonyl]-2-azabicyclo[3.1.1 jheptane;

Racemic mixture of trans-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[2-methyl-5(pyri m id i n-2-yl)-1,3-thiazole-4-carbonyl]-2-azabicyclo[3.1.1 jheptane;

Racemic mixture of trans-3-{[(5-fluoropyridin-2-yl)oxy]methyl}-4-methyl-2-[2-methyl-530 (pyridin-2-yl)-1,3-thiazole-4-carbonyl]-2-azabicyclo[3.1.1 jheptane;

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[2-methyl-5-(pyridin-2-yl)1.3- thiazole-4-carbonyl]-2-azabicyclo[3.1. Ijheptane;

35 Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-{6-methyl-3-[5(trifluoromethyl)pyrimidin-2-yl]pyridine-2-carbonyl}-2-azabicyclo[3.1. Ijheptane;

166

1506 18

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-{6-methyl-3-[5(trifluoromethyl)pyrimidin-2-yl]pyridine-2-carbonyl}-2-azabicyclo[3.1.1]heptane;

5 (3S,4S)-3-[(4-chlorophenoxy)methyl]-4-methyl-2-[6-methyl-3-(2H-1,2,3-triazol-2yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptane;

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-2-[3-(5-fluoropyrimidin-2-yl)-61 o methylpyridine-2-carbonyl]-4-methyl-2-azabicyclo[3.1.1 jheptane;

15. A process for the preparation of a compound of formula I as defined in Claim 1, which process comprises:

(i) for compounds of formula I in which L2 represents -C(=O)-, reaction of a

35 corresponding compound of formula II,

168

1506 18 wherein L1, L3, R1, R2, R3, R4, X and A are as defined in Claim 1, with a compound of formula III,

B-C(O)OH III wherein B is as defined in Claim 1, optionally wherein the -C(O)OH group in the compound of formula III is first activated to the corresponding acyl halide;

(ii) for compounds of formula I in which X represents -0-, reaction of a corresponding compound of formula IV, wherein L1, L2, L3, R1, R2, R3, R4 and B are as defined in Claim 1, with a compound of formula V,

A-OH wherein A is as defined in Claim 1;

A-Lx

VI

169 wherein A is as defined in Claim 1 and Lx represents a suitable leaving group;

(iv) for compounds of formula I in which X represents -0-, reaction of a corresponding compound of formula VII, wherein L1, L2, L3, R1, R2, R3, R4 and B are as defined in Claim 1, and Ly represents a suitable leaving group, with a compound of formula V; or

1506 18 (v) for compounds of formula I in which X represents -NH-, reductive amination of a corresponding compound of formula VIII, wherein L2, L3, R1, R2, and B are as defined in Claim 1, using a compound of formula IX,

A-NH2 IX wherein A is as defined in Claim 1.

170

171

Intellectual

Property

Office

Application No: GB1714049.2 Examiner: Mr Aaron Butt

15 Racemic mixture of trans-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[2-methyl-5-(pyrazin-2yl)-1,3-thiazole-4-carbonyl]-2-azabicyclo[3.1.1]heptane;

Racemic mixture of cis-N-({4-methyl-2-[6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridine-220 carbonyl]-2-azabicyclo[3.1.1]heptan-3-yl}methyl)isoquinolin-3-amine;

25 Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[2-methyl-5-(pyrazin-2yl)-1,3-thiazole-4-carbonyl]-2-azabicyclo[3.1.1]heptane;

Racemic mixture of cis-N-({4-methyl-2-[6-methyl-3-(2H-1,2,3-triazol-2-yl)pyridine-2carbonyl]-2-azabicyclo[3.1.1 ]heptan-3-yl}methyl)quinazolin-2-amine;

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[2-methyl-5-(630 methylpyridin-2-yl)-1,3-thiazole-4-carbonyl]-2-azabicyclo[3.1.1]heptane;

35 Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[2-methyl-5-(2H-1,2,3triazol-2-yl)-1,3-thiazole-4-carbonyl]-2-azabicyclo[3.1.1]heptane; and

167

1506 18

Racemic mixture of cis-3-[(4-fluorophenoxy)methyl]-4-methyl-2-[2-methyl-5-(1 H-pyrazol1-yl)-1,3-thiazole-4-carbonyl]-2-azabicyclo[3.1.1]heptane.

9. A compound of formula I as defined in any one of the preceding claims, or a

5 pharmaceutically acceptable salt, solvate or prodrug thereof, for use in medicine.

11. A compound as defined in any one of Claims 1 to 8, or a pharmaceutically acceptable salt, solvate or prodrug thereof, for use in treating or preventing a disease or disorder in which antagonism of the orexin-1 and/or orexin-2 receptors is desired and/or required.

12. The compound for use as claimed in Claim 11, wherein the disease or disorder is selected from the group consisting of substance dependence, addiction, an anxiety disorder, a panic disorder, binge eating, a compulsive disorder, an impulse control disorder, cognitive impairment and Alzheimer’s disease.

13. The compound for use as claimed in Claim 11 or Claim 12, wherein the disease or disorder is binge eating, alcohol addiction, nicotine addiction, or cocaine addiction.

14. A combination product comprising:

25 (A) a compound of formula I as defined in any one of Claims 1 to 8, or a pharmaceutically-acceptable salt, solvate or prodrug thereof; and (B) another therapeutic agent that is useful in the treatment of a disease or disorder as defined in any one of Claims 11 to 13, wherein each of components (A) and (B) is formulated in admixture with a

30 pharmaceutically-acceptable adjuvant, diluent or carrier.