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Title:
2-AZABICYCLO[3.1.1] DERIVATIVES AS ANTAGONISTS OF THE OREXIN-1 AND OREXIN-2 RECEPTORS
Document Type and Number:
WIPO Patent Application WO/2019/081939
Kind Code:
A1
Abstract:
There is provided a compound of formula I, wherein L1, R1, R2, R5, X, A and B have meanings given in the description, and pharmaceutically acceptable salts, solvates and prodrugs thereof, which compounds are useful as antagonists of the orexin-1 and orexin-2 receptors or as selective antagonists of the orexin-1 receptor, and thus, in particular, in the treatment or prevention of inter alia substance dependence, addiction, anxiety disorders, panic disorders, binge eating, compulsive disorders, impulse control disorders, cognitive impairment and Alzheimer's disease.

Inventors:
MICHELI, Fabrizio (Aptuit, Srl Via Alessandro Fleming 4, Verona, 37135, IT)
CREMONESI, Susanna (Aptuit, Srl Via Alessandro Fleming 4, Verona, 37135, IT)
SEMERARO, Teresa (Aptuit, Srl Via Alessandro Fleming 4, Verona, 37135, IT)
TARSI, Luca (Aptuit, Srl Via Alessandro Fleming 4, Verona, 37135, IT)
GIBSON, Karl Richard (Sandexis Medicinal Chemistry Ltd, Innovation HouseDiscovery Park,Ramsgate Road, Sandwich Kent CT13 9FF, CT13 9FF, GB)
Application Number:
GB2018/053093
Publication Date:
May 02, 2019
Filing Date:
October 25, 2018
Export Citation:
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Assignee:
CHRONOS THERAPEUTICS LIMITED (Mercer Lewin, 41 Cornmarket Street, Oxford OX1 3HA, OX1 3HA, GB)
International Classes:
C07D471/08; A61K31/46; A61P25/30
Domestic Patent References:
WO2010122151A12010-10-28
WO2013139730A12013-09-26
WO2014176146A12014-10-30
Other References:
KOSUGE S ET AL: "Synthesis of thromboxane A"2 analog, dl-(9,11)-methano-(11,12)-amino thromboxane A"2", TETRAHEDRON LETTERS, ELSEVIER, AMSTERDAM, NL, vol. 23, no. 39, 1 January 1982 (1982-01-01), pages 4027 - 4030, XP026596662, ISSN: 0040-4039, [retrieved on 19820101], DOI: 10.1016/S0040-4039(00)88687-6
HE SHUWEN ET AL: "Synthesis of novel 2-azabicyclo[3.1.1]heptane-5-carboxylic acid", TETRAHEDRON LETTERS, vol. 57, no. 11, 4 February 2016 (2016-02-04), pages 1268 - 1269, XP029440084, ISSN: 0040-4039, DOI: 10.1016/J.TETLET.2016.02.024
Attorney, Agent or Firm:
CARLING, David Andrew (Potter Clarkson LLP, The Belgrave CentreTalbot Street, Nottingham NG1 5GG, NG1 5GG, GB)
Download PDF:
Claims:
Claims

1. A compound of formula I,

wherein:

L1 represents a direct bond or -[CR3R4]-;

X represents a direct bond, -0-, -NKR")-, -CH2- or -S-;

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

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

R5 represents hydrogen, halogen, -OR6, -NR7R8, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl or C3-12 cycloalkyi (which latter four groups are optionally substituted by one or more E1 substituents);

R1 , R2, R3 and R4 independently represent hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl or C3-6 cycloalkyi (which latter four groups are optionally substituted by one or more E2 substituents); or any relevant pair of R1 , R2, R3 and R4 form, together with the carbon atom to which they are bound, C=0 or a C3-6 cycloalkyi group optionally substituted by one or more E3 substituents; R6, R7 and R8 independently represent hydrogen or a Ci-e alkyl group optionally substituted by one or more halo atoms;

Rx represents hydrogen, Ci-e 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 and E3 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.

2. A compound as claimed in Claim 1 , wherein X represents -0-, -N(R*)- or -CH2-.

3. A compound as claimed in Claim 2, wherein the -[CR1 R2]-L1-X- linker has either of the following structures:

4. A compound as claimed in any one of the preceding claims, wherein R5 represents hydrogen, halogen or C1-4 alkyl optionally substituted by one or more halo atoms.

5. 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.

6. 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 groups.

7. A compound as claimed in any one of the preceding claims, wherein Q1 and Q2 independently represent halogen, Ci-e alkyl, C3-6 cycloalkyl, -O-C1-6 alkyl, phenyl or a 5- or 6-membered monocyclic heteroaryl group, wherein said alkyl, cycloalkyl, -O-alkyl, phenyl and heteroaryl groups are optionally substituted by one or more substituents selected from halogen, methyl and halomethyl (e.g. trifluoromethyl).

8. A compound as claimed in any one of the preceding claims, wherein the compound is an antagonist of 0X1 R and/or OX1 R/OX2R selected from the group consisting of:

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

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

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

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

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

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

3-({2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptan-1- yl}methoxy)isoquinoline;

2- [6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-1-{[4- (trifluoromethyl)phenoxy]methyl}-2-azabicyclo[3.1.1]heptane;

2- [6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-1-({[5-(trifluoromethyl)pyridin-2- yl]oxy}methyl)-2-azabicyclo[3.1.1 ]heptane;

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

3- ({2-[6-methyl-3-(pyrimidin-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptan-1- yl}methoxy)isoquinoline;

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

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

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

1-{[(5-chloropyridin-2-yl)oxy]methyl}-2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2- carbonyl]-2-azabicyclo[3.1.1 ]heptane;

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

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

2- azabicyclo[3.1.1 ]heptane;

4-fluoro-N-({2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2- azabicyclo[3.1.1]heptan-1-yl}methyl)aniline;

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

6-fluoro-N-({2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2- azabicyclo[3.1.1]heptan-1-yl}methyl)-1 ,3-benzothiazol-2-amine;

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

N-({2-[6-methyl-3-(1 H-pyrazol-1-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptan-1- yl}methyl)isoquinolin-3-amine;

N-({2-[6-methyl-3-(pyrimidin-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptan-1- yl}methyl)isoquinolin-3-amine;

5- fluoro-N-({2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2- azabicyclo[3.1.1]heptan-1-yl}methyl)pyridin-2-amine;

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

2,4-difluoro-N-({2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2- azabicyclo[3.1.1]heptan-1-yl}methyl)aniline;

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

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

4-fluoro-N-({2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2- azabicyclo[3.1.1]heptan-1-yl}methyl)pyridin-2-amine; 4-fluoro-N-({2-[4-methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoyl]-2-azabicyclo[3.1.1]heptan-1- yl}methyl)aniline;

4-fluoro-N-({2-[5-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2- azabicyclo[3.1.1]heptan-1-yl}methyl)aniline;

N-{[2-(3-ethoxy-6-methylpyridine-2-carbonyl)-2-azabicyclo[3.1.1]heptan-1-yl]methyl}-4- fluoroaniline;

4- fluoro-N-({2-[2-methyl-5-(pyrazin-2-yl)-1 ,3-thiazole-4-carbonyl]-2- azabicyclo[3.1.1]heptan-1-yl}methyl)aniline;

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

4-chloro-N-({2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2- azabicyclo[3.1.1]heptan-1-yl}methyl)aniline;

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

4- chloro-N-({2-[2-methyl-5-(pyrimidin-2-yl)-1 ,3-thiazole-4-carbonyl]-2- azabicyclo[3.1.1]heptan-1-yl}methyl)aniline;

5- chloro-N-({2-[2-methyl-5-(pyrimidin-2-yl)-1 ,3- thiazole-4-carbonyl]-2 azabicycl [3.1.1]heptan-1 - yl}methyl)pyridin-2-amine;

5-chloro-N-({2-[6-methyl-3-(1 ,3-thiazol-2-yl)pyridine-2-carbonyl]-2- azabicyclo[3.1.1]heptan-1-yl}methyl)pyridin-2-amine;

5-chloro-N-({2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2- azabicyclo[3.1.1]heptan-1-yl}methyl)pyridin-2-amine;

N-({2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptan-1 yl}methyl)-5-phenyl-1 ,3-thiazol-2-amine;

N-({2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptan-1 yl}methyl)-5-(trifluoromethyl)pyridin-2-amine;

N-({2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptan-1 yl}methyl)-5-(trifluoromethyl)pyrimidin-2-amine;

N-({2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]heptan-1 yl}methyl)-5-(trifluoromethyl)pyrazin-2-amine;

4-chloro-N-({2-[6-methyl-3-(4-methyl-2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2- azabicyclo[3.1.1]heptan-1 -yl}methyl)aniline;

4-chloro-N-({2-[2-methyl-5-(pyridin-2-yl)-1 ,3-thiazole-4-carbonyl]-2- azabicyclo[3.1.1]heptan-1 - yl}methyl)aniline;

4-chloro-N-({2-[2-methyl-5-(pyridin-3-yl)-1 ,3-thiazole-4-carbonyl]-2- azabicyclo[3.1.1]heptan-1 -yl}methyl)aniline; 4-chloro-N-({2-[5-fluoro-2-(2H-1 ,2,3-triazol-2-yl)benzoyl]-2-azabicyclo[3.1.1]heptan-1 - yl}methyl)aniline;

4-chloro-N-{[2-(1 -methyl-4^henyl-1 H^yrazole-3-carbonyl)-2-azabicyclo[3.1.1]heptan-1 - yl]methyl}aniline;

4-chloro-N-({2-[1 -methyl-4-(pyrimidin-2-yl)-1 H-pyrazole-3-carbonyl]-2- azabicyclo[3.1.1]heptan-1 -yl}methyl)aniline;

4-chloro-N-({2-[1 ,5-dimethyl-4-(pyrimidin-2-yl)-1 H-pyrazole-3-carbonyl]-2- azabicyclo[3.1.1]heptan-1 -yl}methyl)aniline;

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

N-({2-[1 ,5-dimethyl-4-(pyrimidin-2-yl)-1 H-pyrazole-3-carbonyl]-2-azabicyclo[3.1.1]heptan- 1-yl}methyl)-5-(trifluoromethyl)pyridin-2-amine; and

1-[2-(4-fluorophenyl)ethyl]-2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2- azabicyclo[3.1.1 ]heptane.

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.

1 1. 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 1 1 , 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 1 1 to 14, wherein the disease or disorder is binge eating, alcohol addiction, nicotine addiction, or cocaine addiction.

16. A combination product comprising:

(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,

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) reaction of a compo

wherein L1 , R1 , R2, R5, X and A are as defined in Claim 1 , with a compound of formula III,

B-C(0)OH wherein B is as defined in Claim 1 , optionally wherein the -C(0)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 formul

wherein L1 , R1 , R2, R5 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 -N(RX)-, reaction of a corresponding compound of formul

wherein L1 , R1 , R2, R5, Rx and B are as defined in Claim 1 , with a compound of formula VII,

A-Lx VII 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 IV with a compound of formula VII; or (v) for compounds of formula I in which X represents -NH-, reaction of a corresponding compound of formula VIII,

wherein R5 and B are as defined in Claim 1 , with a compound of formula IX,

A-NH2 IX wherein A is as defined in Claim 1 , and a reducing agent.

Description:
-AZABICYCLO[3.1.1] DERIVATIVES AS ANTAGONISTS OF THE OREXIN-1 AND OREXIN-2 RECEPTORS 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 eating- disorder (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 (OX1 R) 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 0X1 R antagonists.

Several 0X1 R 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 0X1 R antagonists have been shown to be highly efficacious in reducing binge behaviour.

Selective 0X1 R 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 0X1 R 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 0X1 R 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 0X1 R 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 0X1 R antagonism blocked nicotine related reward as measured by reversal of nicotine-induced lowering of intracranial self-stimulation thresholds (Hollander J. A., et al., PNAS, 2008, 105(49), 19480-19485).

Supporting the likely utility of 0X1 R antagonism as a likely therapeutic for broad addictive disorders orexigenic signalling via the 0X1 receptor has been implicated in several other addictive disorders and 0X1 R 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 0X1 R showed impaired freezing responses and reduced expression of zif268 (an IEG (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 fear- potentiated 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, 0X1 R blockade with a centrally active 0X1 R 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 0X1 R 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 0X1 R antagonists in the clinic, several dual orexin receptor antagonist (DORA) compounds (generally equipotent at 0X1 R 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 0X1 R antagonist and also indicates that such a compound would be safe and well tolerated.

With the elucidation of distinct roles for 0X1 R and 0X2R, 0X1 R antagonists have received a great deal of attention for the treatment of addictive and anxiety related disorders. 0X1 R 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 0X1 R antagonism normalises it (Narita M. et al., J. Neurosci., 2006, 26(2): 398-405).

Confirming the specificity of this response as an 0X1 R driven effect, OX2R 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 OX2R antagonists (Piccoli L, et al., Neuropsychopharmacology, 2012, 37, 1999-201 1 ; Vickers S. P. et al., J. Psychopharmacology, 2015, 29(12):1290-1307). 0X1 R antagonists have also been shown to block binge eating without affecting normal food consumption. This is a potential highly differentiating factor for 0X1 R 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 0X1 R antagonists, many of which are highly selective for 0X1 R over other targets and have favourable drug like qualities.

The listing or discussion of an apparently prior-published document in this specification 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:

L 1 represents a direct bond or -[CR 3 R 4 ]-;

X represents a direct bond, -0-, -NKR")-, -CH2- or -S-; A represents an aryl, heteroaryl, cycloalkyl or heterocycloalkyl group, each of which is optionally substituted with one or more Q 1 groups; B represents an aryl, heteroaryl, cycloalkyi or heterocycloalkyi group, each of which is optionally substituted with one or more Q 2 groups;

R 5 represents hydrogen, halogen, -OR 6 , -NR 7 R 8 , C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl or C3-12 cycloalkyi (which latter four groups are optionally substituted by one or more E 1 substituents);

R 1 , R 2 , R 3 and R 4 independently represent hydrogen, halogen, C1-12 alkyl, C2-12 alkenyl, C2-12 alkynyl or C3-6 cycloalkyi (which latter four groups are optionally substituted by one or more E 2 substituents); or any relevant pair of R 1 , R 2 , R 3 and R 4 form, together with the carbon atom to which they are bound, C=0 or a C3-6 cycloalkyi group optionally substituted by one or more E 3 substituents;

R 6 , R 7 and R 8 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 cycloalkyi (which latter two groups are optionally substituted by one or more halo atoms); Q 1 and Q 2 independently represent halogen, -CN, -NHCOR 12 , C1-6 alkyl, C3-6 cycloalkyi, -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)); E 1 , E 2 and E 3 independently represent halogen or a C1-6 alkyl group optionally substituted by one or more halo atoms;

R 12 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 Ci-e 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(0)N(R z1 )R z2 or -N(R z3 )C(0)R z4 , in which R z1 , R z2 , R z3 and R z4 independently 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 N- Mannich 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 (entgegen) and Z (zusammen) 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 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 0, 17 0, 18 0, 32 P, 33 P, 35 S, 18 F, 36 CI, 123 l, and 125 l. Certain isotopically-labelled compounds of the present invention (e.g., those labelled with 3 H and 14 C) are useful in compound and for substrate tissue distribution assays. Tritiated ( 3 H) and carbon-14 ( 14 C) isotopes are useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2 H 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 15 0, 13 N, 11 C and 18 F 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 cycloalkyi groups (where q is the upper limit of the range) that may be mentioned may be monocyclic or bicyclic alkyl groups, which cycloalkyi groups may further be bridged (so forming, for example, fused ring systems such as three fused cycloalkyi groups). Such cycloalkyi 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 cycloalkyi group. Further, where there is a sufficient number (i.e. a minimum of four) such cycloalkyi 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- q heterocycloalkenyl (where q is the upper limit of the range) or a C 7 . q heterocycloalkynyl group. C2- q heterocycloalkyl groups that may be mentioned include 7- azabicyclo[2.2.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.2.1]-octanyl, 8- 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 heterocycloalkyi groups may, where appropriate, be located on any atom in the ring system including a heteroatom. The point of attachment of heterocycloalkyi 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. Heterocycloalkyi 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 heterocycloalkyi 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 heterocycloalkyi 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 cycloalkyi or heterocycloalkyi 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-io 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 non- aromatic ring of an aryl group, attached via a single carbon atom common to both rings (so forming a spiro-cycle). 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, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including 1 ,3-benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiadiazolyl (including 2,1 ,3-benzothiadiazolyl), benzothiazolyl, benzoxadiazolyl (including

2.1.3- benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro-2/-/-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 Q 2 substituent present, then those Q 2 substituents may be the same or different. Further, in the case where there are two R 7 substituents present, in which one R 7 is present in the context of R 1 and the other is present in the context of R 2 , then those R 7 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 spiro- cyclic 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 "R 1 to R 4 " is employed herein, this will be understood by the skilled person to mean R 1 , R 2 , R 3 and R 4 , inclusively. Where a phrase such as "any relevant pair of R 1 , R 2 , R 3 and R 4 " 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 R 1 and R 2 or the pair R 3 and R 4 (or both pairs simultaneously). In one embodiment of the invention, L 1 represents a direct bond. In an embodiment of the invention, there is provided compounds of the invention as hereinbefore defined but in which X represents -0-, -N(R*)- or -CH2-, and preferably X represents -O- or -N(R X )-. In these and other embodiments, R x is methyl or, preferably, H. Compounds of the invention which may be mentioned include those in which X does not represents -N R*)-, preferably wherein X represents -0-. Other compounds of the invention which may be mentioned include those in which X represents -N(R X )- (e.g. -NH-).

Further embodiments of the invention include those in which X represents -O- or -N(R X )- and B represents an aryl, heteroaryl, cycloalkyi or heterocycloalkyi group (preferably an aryl or heteroaryl group), each of which is substituted with at least one Q 2 group. A yet further embodiment of the invention that may be mentioned in one in which X represents -O- or -N(R X )- and B represents an aryl or heteroaryl group, each of which aryl or heteroaryl group is substituted with at least two Q 2 groups.

Compounds of the invention that may be mentioned include those in which -L 1 -X- together represent -0-, -N(R X )-, -CH 2 - or -[CR 5 R 6 ]-0-. In another embodiment, -U-X- together represent -CH2-, -O- and -N(R X )-. In yet another embodiment, -L 1 -X- together represent -O- and -N(R X )- (e.g. -O- and -NH-).

In an embodiment of the invention, R x represents hydrogen, methyl, ethyl, propyl, or methyl cyclopropyl (e.g. -CH2-C3H5).

In one embodiment, R 5 represents hydrogen, halogen, -OR 6 , -NR 7 R 8 , C1-6 alkyl, or C3-6 cycloalkyi (which latter two groups are optionally substituted by one or more E 1 substituents).

In another embodiment, R 5 represents hydrogen, halogen or C1-4 alkyl optionally substituted by one or more halo atoms.

In yet another embodiment, R 5 represents methyl, fluoro or preferably hydrogen.

Preferred compounds of the invention that may be mentioned include those in which R 1 , R 2 , R 3 and R 4 (if present) independently represent hydrogen, fluoro, C1-6 alkyl, or C3-6 cycloalkyi (which latter two groups are optionally substituted by one or more E 2 substituents); or any relevant pair of R 1 , R 2 , R 3 and R 4 form, together with the carbon atom to which they are bound, C=0. Further preferred compounds include those in which R 1 , R 2 , R 3 and R 4 independently represent hydrogen or a C1-4 alkyl group optionally substituted by one or more halo atoms.

In a particular embodiment, each R 1 , R 2 , R 3 and R 4 independently represents hydrogen or methyl. Most preferably, R 1 , R 2 , R 3 and R 4 (if present) all represent hydrogen.

The linker between the core bridged ring system and A (i.e. the linker represented by -[CR 1 R 2 ]-L 1 -X-) preferably is any of the following structures:

More preferably, the linker represented by -[CR 1 R 2 ]-L 1 -X- has either of the following structures:

Still more preferably, the linker represented by -[CR 1 R 2 ]-L 1 -X- has either of the following structures:

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

Compounds of the invention that may be mentioned include those in which R 6 to R 8 independently represent hydrogen or methyl.

Other compounds of the invention that may be mentioned include those in which E 1 to E 3 independently represent a C1-6 alkyl group or preferably a halogen. In one embodiment, A represents an aryl, heteroaryl, cycloalkyl or heterocycloalkyi group (particularly an aromatic group (i.e. an aryl or heteroaryl group)), each of which is substituted with at least one Q 1 group.

In another embodiment, the heteroaryl and heterocycloalkyi 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 Q 1 groups as indicated above.

In preferred embodiments, A represents an aryl or heteroaryl group (e.g. a monocyclic or bicyclic aromatic group), each of which is optionally substituted by one or more Q 1 groups. Particular aryl and heteroaryl groups that may be mentioned in this respect include naphthyl, benzimidazolyl, imidazolyl, thiazolyl, pyrazolyl, oxazolyl, pyrazinyl, pyridazinyl, pyrrolyl, indazolyl, indolyl, isoindolyl, isoxazolyl, pyranyl, quinolinyl, quinoxalinyl, quinazolinyl, thiazolyl, triazolyl (including 1 ,2,3-triazolyl, 1 ,2,4-triazolyl and 1 ,3,4-triazolyl), and most preferably phenyl, pyrazinyl, pyridyl, pyrimidinyl, isoquinolinyl and benzothiazolyl. In one embodiment, B represents an optionally substituted monocyclic group. For example, B may represent phenyl or a monocyclic heteroaryl or heterocycloalkyi group containing one or two heteroatoms selected from O, S and N, which cyclic group is optionally substituted by one or more Q 2 groups. 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 Q 2 groups. In a particular embodiment, B represents an optionally substituted heteroaryl group. 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), more particularly pyrazolyl, and most particularly phenyl, pyridyl and thiazolyl. In a yet further preferred embodiment, 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 Q 1 or Q 2 groups, as appropriate. In a particular example of such compounds, A represents an aryl or heteroaryl group optionally substituted with one or more Q 1 groups, and B represents a heteroaryl group optionally substituted with one or more Q 2 groups. Compounds of the invention include those in which Q 1 and Q 2 independently represent halogen, Ci-e 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)). In one embodiment, the aryl and heteroaryl groups represented by Q 1 and Q 2 are phenyl or a 5- or 6-membered monocyclic heteroaryl group (each of which is optionally substituted with one or more substituents selected from halogen, methyl and halomethyl (e.g. trifluoromethyl)).

Preferred compounds of the invention include those in which Q 1 represents halogen, -CN, C1-4 alkyl, -O-C1-4 alkyl, aryl or heteroaryl (which latter four groups are optionally substituted with one or more substituents selected from halogen, methyl and halomethyl (e.g. trifluoromethyl)). For example, Q 1 may represent halogen, phenyl or C1-4 alkyl (which latter two groups are optionally substituted by one or more halo atoms). In yet further preferred compounds, Q 1 represents halogen, phenyl or a methyl group optionally substituted by one or more halo atoms.

Other preferred compounds of the invention include those in which Q 2 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, Q 2 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 is a 5- or 6-membered aromatic group containing from one to three heteroatoms selected from N, S and O. In further preferred compounds, Q 2 represents halogen, methyl or ethoxy (which latter two groups are optionally substituted by one or more halo atoms), or phenyl, 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)). Particular compounds of the invention that may be mentioned include those which contain at least one Q 2 group, preferably at least two Q 2 groups (e.g. two Q 2 groups). Where two or more Q 2 groups are present on the same compound, said Q 2 groups may be the same or different, though preferably at least two different Q 2 groups are present. In one embodiment, at least one Q 2 group is present which is phenyl or a monocyclic heteroaryl group and at least one other Q 2 group is present which is halogen, -CN, C1-4 alkyl, or -O-C1-4 alkyl.

Preferred compounds of the invention include those in which:

X represents -0-, -N(R^- or -CH 2 -;

R x represents methyl or H;

R 5 represents hydrogen, halogen, -OR 6 , -NR 7 R 8 , C1-6 alkyl or C3-6 cycloalkyi (which latter two groups are optionally substituted by one or more E 1 substituents);

R 1 , R 2 , R 3 and R 4 (if present) independently represent hydrogen, fluoro, C1-6 alkyl, or C3-6 cycloalkyi (which latter two groups are optionally substituted by one or more E 2 substituents); or any relevant pair of R 1 , R 2 , R 3 and R 4 form, together with the carbon atom to which they are bound, C=0;

R 6 to R 8 independently represent hydrogen or methyl;

E 1 to E 3 (if present) independently represent a C1-6 alkyl group or a halogen;

A represents an aryl, heteroaryl, cycloalkyi or heterocycloalkyi group (particularly an aryl or heteroaryl group), each of which is substituted with at least one Q 1 group;

B represents phenyl, or a monocyclic heteroaryl or heterocycloalkyi group containing one or two heteroatoms selected from O, S and N, which cyclic group is optionally substituted with at least one Q 2 group;

Q 1 and Q 2 independently represent halogen, C1-6 alkyl, C3-6 cycloalkyi, -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)).

More preferred compounds include those in which:

R 5 represents methyl, fluoro or hydrogen;

the linker between the core bridged ring system and A (i.e. the linker represented by -[CR 1 R 2 ]-L 1 -X-

A and B each independently represent an aryl or heteroaryl group, each of which is optionally substituted with one or more Q 1 or Q 2 groups, as appropriate; Q 1 represents halogen, phenyl or C1-4 alkyl (which latter two groups are optionally substituted by one or more halo atoms);

Q 2 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)) wherein said monocyclic heteroaryl groups contain from one to three heteroatoms selected from N, S and O.

Still more preferred compounds include those in which:

-L 1 -X- together represent -CH2-, -O- and -NH- (preferably -0-);

R 1 , R 2 and R 5 represent hydrogen;

A represents a monocyclic or bicyclic aromatic group which is optionally substituted with one or more Q 1 groups;

B represents a monocyclic aromatic group which is optionally substituted by one or more Q 2 groups;

Q 1 represents halogen, phenyl or C1-4 alkyl (which latter two groups are optionally substituted by one or more halo atoms);

Q 2 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)) wherein said monocyclic heteroaryl groups contain from one to three heteroatoms selected from N, S and O.

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

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

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

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

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

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

1-[(4-fluorophenoxy)methyl]-2-[2-methyl-5-(pyridin-2-yl)-1 ,3-thiazole-4-carbonyl]-2- azabicyclo[3.1.1 ]heptane; 3-({2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]he ptan-1- yl}methoxy)isoquinoline;

2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-1-{[4- (trifluoromethyl)phenoxy]methyl}-2-azabicyclo[3.1.1]heptane;

2- [6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-1-({[5-(trifluorometh yl)pyridi yl]oxy}methyl)-2-azabicyclo[3.1.1 ]heptane;

1-[(4-fluorophenoxy)methyl]-2-[6-methyl-3-(pyrimidin-2-yl)py ridine-2-carbonyl]-2- azabicyclo[3.1.1 ]heptane;

3- ({2-[6-methyl-3-(pyrimidin-2-yl)pyridine-2-carbonyl]-2-azabi cyclo[3.1.1]heptan-1- yl}methoxy)isoquinoline;

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

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

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

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

1-{[(5-chloropyridin-2-yl)oxy]methyl}-2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2- carbonyl]-2-azabicyclo[3.1.1 ]heptane;

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

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

2- azabicyclo[3.1.1 ]heptane;

4- fluoro-N-({2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2- azabicyclo[3.1.1]heptan-1-yl}methyl)aniline;

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

6-fluoro-N-({2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2- azabicyclo[3.1.1]heptan-1-yl}methyl)-1 ,3-benzothiazol-2-amine;

N-({2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]he ptan-1- yl}methyl)isoquinolin-3-amine;

N-({2-[6-methyl-3-(1 H-pyrazol-1-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]hepta n-1- yl}methyl)isoquinolin-3-amine;

N-({2-[6-methyl-3-(pyrimidin-2-yl)pyridine-2-carbonyl]-2-aza bicyclo[3.1.1]heptan-1- yl}methyl)isoquinolin-3-amine; 5-fluoro-N-({2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2- azabicyclo[3.1.1]heptan-1-yl}methyl)pyridin-2-amine;

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

2,4-difluoro-N-({2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2- azabicyclo[3.1.1]heptan-1-yl}methyl)aniline;

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

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

4-fluoro-N-({2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2- azabicyclo[3.1.1]heptan-1-yl}methyl)pyridin-2-amine;

4-fluoro-N-({2-[4-methyl-2-(2H-1 ,2,3-triazol-2-yl)benzoyl]-2-azabicyclo[3.1.1]heptan-1- yl}methyl)aniline;

4-fluoro-N-({2-[5-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2- azabicyclo[3.1.1]heptan-1-yl}methyl)aniline;

N-{[2-(3-ethoxy-6-methylpyridine-2-carbonyl)-2-azabicyclo[3. 1.1]heptan-1-yl]methyl}-4- fluoroaniline;

4- fluoro-N-({2-[2-methyl-5-(pyrazin-2-yl)-1 ,3-thiazole-4-carbonyl]-2- azabicyclo[3.1.1]heptan-1-yl}methyl)aniline;

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

4-chloro-N-({2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2- azabicyclo[3.1.1]heptan-1-yl}methyl)aniline;

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

4- chloro-N-({2-[2-methyl-5-(pyrimidin-2-yl)-1 ,3-thiazole-4-carbonyl]-2- azabicyclo[3.1.1]heptan-1-yl}methyl)aniline;

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

5-chloro-N-({2-[6-methyl-3-(1 ,3-thiazol-2-yl)pyridine-2-carbonyl]-2- azabicyclo[3.1.1]heptan-1-yl}methyl)pyridin-2-amine;

5-chloro-N-({2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2- azabicyclo[3.1.1]heptan-1-yl}methyl)pyridin-2-amine;

N-({2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]he ptan-1- yl}methyl)-5-phenyl-1 ,3-thiazol-2-amine; N-({2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]he ptan-1- yl}methyl)-5-(trifluoromethyl)pyridin-2-amine;

N-({2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]he ptan-1- yl}methyl)-5-(trifluoromethyl)pyrimidin-2-amine;

N-({2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]he ptan-1- yl}methyl)-5-(trifluoromethyl)pyrazin-2-amine;

4-chloro-N-({2-[6-methyl-3-(4-methyl-2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2- azabicyclo[3.1.1]heptan-1 -yl}methyl)aniline;

4-chloro-N-({2-[2-methyl-5-(pyridin-2-yl)-1 ,3-thiazole-4-carbonyl]-2- azabicyclo[3.1.1]heptan-1 - yl}methyl)aniline;

4-chloro-N-({2-[2-methyl-5-(pyridin-3-yl)-1 ,3-thiazole-4-carbonyl]-2- azabicyclo[3.1.1]heptan-1 -yl}methyl)aniline;

4-chloro-N-({2-[5-fluoro-2-(2H-1 ,2,3-triazol-2-yl)benzoyl]-2-azabicyclo[3.1.1]heptan-1 - yl}methyl)aniline;

4-chloro-N-{[2-(1 -methyl-4-phenyl-1 H-pyrazole-3-carbonyl)-2-azabicyclo[3.1.1]heptan-1 - yl]methyl}aniline;

4-chloro-N-({2-[1 -methyl-4-(pyrimidin-2-yl)-1 H-pyrazole-3-carbonyl]-2- azabicyclo[3.1.1]heptan-1 -yl}methyl)aniline;

4-chloro-N-({2-[1 ,5-dimethyl-4-(pyrimidin-2-yl)-1 H-pyrazole-3-carbonyl]-2- azabicyclo[3.1.1]heptan-1 -yl}methyl)aniline;

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

N-({2-[1 ,5-dimethyl-4-(pyrimidin-2-yl)-1 H-pyrazole-3-carbonyl]-2-azabicyclo[3.1.1]heptan- 1-yl}methyl)-5-(trifluoromethyl)pyridin-2-amine; and

1-[2-(4-fluorophenyl)ethyl]-2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2- azabicyclo[3.1.1 ]heptane.

Other compounds that may be mentioned include:

[5-[(6-fluoro-1 ,3-benzothiazol-2-yl)oxymethyl]-4-azabicyclo[3.1.1]heptan-4- yl]-[6-methyl- 3-(triazol-2-yl)pyridin-2-yl]methanone;

[6-methyl-3-(triazol-2-yl)pyridin-2-yl]-[5-[[6-(trifluoromet hyl)pyridin-3-yl]oxymethyl]-4- azabicyclo[3.1.1]heptan-4-yl]methanone;

[6-methyl-3-(triazol-2-yl)pyridin-2-yl]-[5-[[(4-phenyl-1 ,3-thiazol-2-yl)amino]methyl]-4- azabicyclo[3.1.1]heptan-4-yl]methanone; and

Racemic mixture of 4-chloro-N-(1-{2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2- carbonyl]-2-azabicyclo[3.1.1 ]heptan-1 -yl}ethyl)aniline. Particularly preferred compounds are those which are antagonists of 0X1 R and/or OX1 R/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) reaction of a compo

wherein L 1 , R 1 , R 2 , R 5 , X and A are as hereinbefore defined, with a compound of formula III,

B-C(0)OH wherein B is as hereinbefore defined, in the presence of a suitable coupling reagent (e.g. 1 , 1 '-carbonyldiimidazole, Λ/,Λ/'-dicyclohexylcarbodiimide, 1-hydroxy-benzotriazole (HOBt), 1-hydroxy-7-aza-benzotriazole (HOAt), (1-[Bis(dimethylamino)methylene]-1 H- 1 ,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), 2,4,6-Tripropyl- 1 ,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P), or the like), or, alternatively the -C(0)OH group may first be activated to the corresponding acyl halide (e.g -C(0)CI, by treatment with oxalyl chloride, thionyl chloride, phosphorous pentachloride, phosphorous oxychloride, or the like), together with a suitable base such as, Na2CC>3, K3PO4, CS2CO3, NaOH, KOH, K2CO3, CsF, Et 3 N, (/-Pr) 2 NEt, 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) under standard conditions known to those skilled in the art (e.g. optionally in an inert atmosphere);

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

wherein L 1 , R 1 , R 2 , R 5 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 -N(R X )-, reaction of a corresponding compound of formul

wherein L 1 , R 1 , R 2 , R 5 , R x and B are as hereinbefore defined, with a compound of formula VII,

A-L x VII 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(0)2CF3, -OS(0)2CH3 or -OS(0)2PhMe) (most preferably L x represents fluoro or chloro), in the presence of a suitable base such as, Na 2 C0 3 , K 3 P0 4 , Cs 2 C0 3 , NaH, NaOH, KOH, K 2 C0 3 , CsF, Et 3 N, (/ ' -Pr) 2 NEt, 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). This reaction may be performed, for example in the presence of a suitable catalyst system, e.g. a metal (or a salt or complex thereof) such as PdCI 2 , Pd(OAc) 2 , Pd(Ph 3 P) 2 CI 2 , Pd(Ph 3 P) 4 (i.e. palladium tetrakistriphenylphosphine), Pd 2 (dba) 3 and a ligand such as f-Bu 3 P, (CeHn) 3 P, Ph 3 P, AsPh 3 , P(o-Tol) 3 , 1 ,2-bis(diphenylphosphino)ethane, 2,2'-bis(di-te/f-butylphosphino)-1 ,V- biphenyl, 2,2'-bis(diphenylphosphino)-1 ,1'-bi-naphthyl, 1 ,1'-bis(diphenyl-phosphino- ferrocene), 1 ,3-bis(diphenylphosphino)propane, xantphos, or a mixture thereof; (iv) 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 VII as hereinbefore defined, in the presence of a suitable base such as, Na 2 C0 3 , K 3 P0 4 , Cs 2 C0 3 , NaH, NaOH, KOH, K 2 C0 3 , CsF, Et 3 N, (/-Pr) 2 NEt, 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); or

(v) for compounds of formula I in which X represents -NH-, reaction of a corresponding compound of formul

wherein R 5 and B are as hereinbefore defined, with a compound of formula IX,

A-NH 2 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 MgSCU 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 NaBhU, AIH4, or the like).

Compounds of formulae II , IV, VI and VII I 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(0)OH (or an ester thereof), may be converted to a -C(0)H or -CH2-OH group, using DI BAL and UAIH4, 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(0)2- moiety (or the reverse reduction reaction), for example in the presence of a suitable oxidising agent, e.g. Mn02 or 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 MgSCU 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 NaBhU, AIH4, or the like), for instance the conversion of -NH2 to -N(H)-isopropyl by condensation in the presence of acetone (H3C-C(0)-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(0)OH (or an ester thereof), may be converted to -C(0)NR2 group, and which reaction may (e.g. for -COOH) be performed in the presence of a suitable coupling reagent (e.g. 1 ,1'-carbonyldiimidazole, Λ/,Λ/'-dicyclohexylcarbodiimide, or the like) or, in the case of an ester (e.g. -C(0)OCH3 or -C(0)OCH2CH3), be performed in the presence of e.g. trimethylaluminium, or, alternatively the -C(0)OH group may first be activated to the corresponding acyl halide (e.g. -C(0)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 POCI3, 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(0)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 A/-Boc protecting group by reaction in the presence of an acid, or, a hydroxy group protected as a silyl ether (e.g. a te/f-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 the 4-benzyl-4- azabicyclo[3.1.1 ]heptane-5-carbonitrile moiety.

Scheme 1

Step 1

Step 1

Compound of formula XII may be obtained by halogenation of a compound of formula XI (commercially available from Sigma-Aldrich) under standard literature conditions such as by reaction with SOC in a suitable solvent, such as pyridine, under cooling. Step 2

Compound of formula XIII may be obtained from compound XII by cyclisation with a haloacetic acid derivative, such as trichloroacetylchloride, e.g. in the presence of a suitable metal catalyst, such as a zinc-copper couple.

Step 3

Compound of formula XIV may be obtained by zinc-promoted reduction of compound XIII under standard literature conditions such as by reaction zinc in the presence of an organic acid, such as acetic acid.

Step 4

Compound of formula XVI may be obtained by alkylation of a compound of formula XV (commercially available from Sigma-Aldrich) under standard literature conditions.

Step 5

Compound of formula XVII may be obtained via a reaction of a compound of formula XIV with a compound of formula XVI in the presence of a suitable base, e.g. phenylmethylamine, in a suitable solvent, such as methanol, under reflux.

The substituents R 1 to R 5 , A and B (or substituents thereon, e.g. defined by Q 1 or Q 2 ) 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 0X1 R and/or OX1 R/OX2R, 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 0X1 R and/or OX1 R/OX2R 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 0X1 R and/or OX1 R/OX2R 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 0X1 R (e.g. preferentially selective for 0X1 R over OX2R) when the antagonistic effect with 0X1 R is at least 50 times (e.g. at least 100 times) greater than a that with second receptor (e.g. OX2R). 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 0X1 R over OX2R, 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-I-1OX2) 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 MgC , 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 MgCI 2 , 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 2μΙ/ννβΙΙ were plated into 96-well Isoplates (Perkin Elmer).

CHO-hOXi cell membranes (6 ml -1 ) or HEK-hOX2 membranes (8 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 CaCI 2 , 5 mM MgCI 2 , 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 μΙ. 100 μΙ of hOXi or hOX 2 beads- membranes suspension were added to 100 μΙ of [ 3 H]SB-674042 or [ 3 H]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 IC50 using the Cheng-Prusoff correction: pKi = IC5O/(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% heat- inactivated 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 MgC and 2 mM CaC , 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 FLIPR 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 IC50 (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 EC50 (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 (EC 50 x4).

Orexin-A CRCs were analysed by using GraphPad Prism5 Software to estimate EC50 whereas antagonist inhibitory curves were analysed by using XLfit Software. Curve fitting and EC50/IC50 estimations were carried out using a four-parameter logistic model. In the case of antagonist activity, an estimation of the functional pKi (-logioKi) 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.

Were 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 Me 4 Si, 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 Cis, 1.7 μηι, 2.1 x 50 mm or Acquity CSH Cis, 1.7 μηι, 2.1 x 50 mm, the temperature column was 40 °C; mobile phase solvent A was milliQ 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 Cis, 1.7 μηι, 2.1 x 50 mm; mobile phase solvent A was 10 mM aqueous solution of NH 4 HC03 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 μηι. The purifications were carried out using low pH or high pH chromatographic conditions. The mobile phase solvent composition was the same used for QC 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.

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,

Et 2 0 = diethyl ether,

MeOH = methanol;

THF = tetrahydrofuran,

MeCN=acetonitrile

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,

DIPEA = A/,A/-Diisopropylethylamine,

B0C2O = Di-te/f-butyl dicarbonate;

TFA = trifluoroacetic acid,

DIAD = Diisopropyl azodicarboxylate, HATU = 1-[Bis(dimethylamino)methylene]-1 H-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

ss = saturated solution

BINAP = (±)-2,2'-Bis(diphenylphosphino)-1 , 1 '-binaphthalene Preparation 1 : 4-chlorobut-1 -ene

A stirred mixture of but-3-en-1-ol (36 mL, 416 mmol) with 18 drops of pyridine, under a nitrogen atmosphere, was cooled to 0 °C and SOC (30 mL, 416 mmol) was carefully added drop-wise. The ice-bath was removed and the reaction mixture was allowed to reach RT, then it was refluxed (external T = 82 °C) for 0.5 h. The mixture was then submitted to fraction distillation at ambient pressure (vapour T = 73 °C) to give 4- chlorobut-1-ene (p1 , 32.94 g, y= 87%) as colourless oil.

NMR ( 1 H, Chloroform-d): δ 5.84 (tdd, 1 H), 5.07-5.26 (m, 2H), 3.58 (t, 2H), 2.55 (tq, 2H).

Preparation 2: 2,2-dichloro-3-(2-c utan-1 -one

Step a:

In a 500 mL two-necked flask zinc (50 g, 765 mmol) was vigorously stirred in 200 mL of distilled water, while nitrogen gas was bubbled through. After this period, copper (II) sulphate (3.75 g, 23.49 mmol) was added at once, and the resulting suspension was stirred for another 45 minutes while the bubbling with nitrogen gas continued. The resulting zinc-copper couple was filtered under a nitrogen atmosphere and washed with respectively 500 mL of degassed water and 500 mL of degassed acetone. The black powder was transferred to a flask and dried under vacuum obtaining the desired zinc- copper couple (51.49 g, Int a.) as grey solid. Step b:

A stirred mixture of 4-chlorobut-1-ene (p1 , 7 mL, 71 mmol) and zinc-copper couple (Step a, 18.57 g, 284 mmole) in diethylether (1 10 mL) was cooled to 0 °C under a nitrogen atmosphere. A solution of trichloroacetylchloride (15.8 mL, 142 mmole) and 1 ,2- dimethoxyethane (14.8 mL, 142 mmole) in diethylether (65 mL) was added dropwise, then the reaction mixture was stirred overnight at room temperature. The solution was filtered over celite and washed with diethylether. The filtrate was washed twice with water, twice with a concentrated NaHCC>3 solution and brine. The organic phase was 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 80/20) to give 2,2- dichloro-3-(2-chloroethyl)cyclobutan-1-one (p2, 7.39 g, y= 52%) as orange oil.

NMR ( 1 H, Chloroform-tf): δ 3.63-3.78 (m, 2H), 3.39-3.52 (m, 1 H), 3.04-3.27 (m, 2H), 2.46 (qd, 1 H), 2.13 (dtd, 1 H).

Preparation 3: 3-(2-chloroethyl)cyclobutan-1 -one

To a stirred solution of 2,2-dichloro-3-(2-chloroethyl)cyclobutan-1-one (p2, 7.39 g, 36.68 mmol) in Acetic acid (80 mL), at 60 °C, zinc (14.39 g, 220.07 mmol) (powder) was added portion-wise then the reaction mixture was heated to 90 °C and stirred for 2 hrs. The reaction mixture was allowed to reach RT, then filtered on celite and washed with diethylether. The filtrate was washed with water, saturated sodium bicarbonate solution until basic, dried over sodium sulfate and concentrated under reduced pressure affording 3-(2-chloroethyl)cyclobutan-1-one (p3, 3.69 g, y= 76%) as colourless oil.

NMR ( 1 H, Chloroform-d): δ 3.53-3.64 (m, 2H), 3.16-3.31 (m, 2H), 2.71-2.86 (m, 2H), 2.56-2.70 (m, 1 H), 2.04-2.16 (m, 2H).

Preparation 4: 2-(benzylamino)-2-methylpropanenitrile

To a stirred solution of phenylmethanamine (12.84 mL, 1 17.59 mmol) in methanol (20 mL), at RT and under a nitrogen atmosphere, 2-hydroxy-2-methylpropanenitrile (10.74 mL, 117.59 mmol) was added portion-wise and the resulting reaction mixture was stirred for 24 hrs at RT. The mixture was concentrated under vacuum and the crude material was purified by FC on silica gel (eluting with Cy/EA from 100/0 to 85/15) affording 2- (benzylamino)-2-methylpropanenitrile (p4, 10.75 g, y= 52%) as colourless oil.

NMR ( 1 H, DMSO-c/6): δ 7.20-7.42 (m, 5H), 3.71-3.85 (m, 2H), 3.13 (t, J=7.15 Hz, 1 H), 1 .38-1 .47 (m, 6H). Preparation 5: 2-benzyl-2-azabicycl ne-1 -carbonitrile

Method a:

To a solution of 3-(2-chloroethyl)cyclobutan-1 -one (p3, 4.03 g, 30.39 mmol) in Methanol (40 mL), 2-(benzylamino)-2-methylpropanenitrile (p4, 10.59 g, 60.79 mmol) and phenylmethanamine (2.19 mL, 20.06 mmol) were added and the resulting reaction mixture was stirred at reflux for 72 hrs. The mixture was concentrated and taken up with ether. The mixture was filtered, the solid was further triturated with ether and the mixture filtered. The combined organic phases were concentrated under vacuum and the crude material was purified by FC on silica gel (eluting with Cy/EA from 100/0 to 85/15) affording 2-benzyl-2-azabicyclo[3.1.1]heptane-1 -carbonitrile (p5, 3.59 g, y= 56%) as orange oil.

NMR ( 1 H, Chloroform-d): δ ppm 7.17-7.51 (m, 5H), 3.82-3.96 (m, 2H), 2.82-2.97 (m, 2H), 2.51 -2.59 (m, 1 H), 2.41 -2.51 (m, 2H), 2.22-2.36 (m, 2H), 1 .89-2.01 (m, 2H).

Preparation 6: 2-benzyl-2-azabicyclo[3.1.1]heptane-1 -carboxylic acid hydrochloride

To a 2-benzyl-2-azabicyclo[3.1.1]heptane-1 -carbonitrile (p5, 3.07g, 13.3mmol) was dissolved in aqueous 6N HCI (80 mL) and the mixture was refluxed overnight. The mixture was concentrated under reduced pressure affording 2-benzyl-2- azabicyclo[3.1 .1 ]heptane-1 -carboxylic acid hydrochloride (p6, 3.56 g, y= quant) that was used as such in the next step.

MS (mlz): 232.2 [MH] + . Preparation 7: {2-benzyl-2-azabicyc n-1 -yl}methanol

Bn

To a stirred mixture of 2-benzyl-2-azabicyclo[3.1.1]heptane-1-carboxylic acid hydrochloride (p6, 1.78 g, 6.65 mmol) in THF (28 ml_), at RT, 4-methylmorpholine (1.46 ml_, 13.3 mmol) was added and the resulting mixture was stirred 10 min at RT then cooled to 0 °C. Isobutylchloroformate (0.86 ml_, 6.65 mmol) was added portion-wise, the ice-bath was removed and the resulting reaction mixture was stirred at RT for 30 min. The precipitate formed was removed by filtration and washed with THF then the solution so obtained was cooled to -10 °C. A solution of sodium borohydride (0.38 g, 9.97 mmol) in Water (6 ml_) was added portion-wise, the cooling bath was removed and the reaction mixture was stirred at RT. The reaction mixture was cooled to 0 °C, quenched with methanol and stirred for 0.5 h at RT then concentrated under reduced pressure. The crude material was taken up with DCM and saturated sodium bicarbonate. The organic phase was washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The crude material was combined with crude material obtained with analogue procedure and purified by NH column (eluting with Cy/EA from 100/0 to 82/18) affording {2-benzyl-2-azabicyclo[3.1.1]heptan-1-yl}methanol (p7, 1.56 g, y= 54 % overall on the 2 batches).

MS (/77/z): 218.2 [MH] + .

Preparation 8: 2-benzyl-1 -[(4-fluorophenoxy)methyl]-2-azabicyclo[3.1.1]heptane

To a solution of {2-benzyl-2-azabicyclo[3.1.1]heptan-1-yl}methanol (p7, 600 mg, 2.76 mmol) and 4-fluorophenol (464.27 mg, 4.14 mmol) in THF (20 ml_), triphenylphosphine

(1.09 g, 4.14 mmol) was added. The mixture was stirred at room temperature for 15 min then cooled to 0 °C and DIAD (0.82 ml_, 4.14 mmol) was added. The reaction was stirred at 0 °C for 15 min and then allowed to reach room temperature. Then it was heated to reflux and stirred at the same temperature for 2 hrs. Solvent was removed under reduced pressure and crude was loaded on SCX cartridge, washing with MeOH and eluting with 1 N ammonia solution in MeOH. Opportune fractions were evaporated to afford 2-benzyl- 1-[(4-fluorophenoxy)methyl]-2-azabicyclo[3.1.1]heptane (p8, 740 mg, y= 86%) that was used for the following step without further purification. MS (/T7/z): 312.3 [MH] + .

Preparation 9: 1 -[(4-fluoroph [3.1.1]heptane

To a solution of 2-benzyl-1-[(4-fluorophenoxy)methyl]-2-azabicyclo[3.1.1]hept ane (p8, 740 mg, 2.38 mmol) in Methanol (40 ml_), ammonium formate (1.5 g, 23.76 mmol) and Pd(OH)2 (166.86 mg, 0.240 mmol) were added . The reaction was left to stir at reflux for 1 h. No reaction occurred, further Pd(OH)2 (83 mg) was added and the mixture refluxed for 3 h. The mixture was cooled and filtered over celite and the solvent removed under vacuum. The residue was purified by SCX eluting with MeOH/NH3 1 M in MeOH. Crude material was then purified by FC on silica gel (eluting from 100/0 Cy/EtOAc to 80/20 Cy/EtOAC) affording 1-[(4-fluorophenoxy)methyl]-2-azabicyclo[3.1.1]heptane (p9, 30 mg, y= 6%).

NMR ( 1 H, Methanol-^): δ ppm 1.70 - 1.77 (m, 2 H), 2.01 (td, 2 H), 2.12 (td, 2 H), 2.50 (tt, 1 H), 3.20 - 3.24 (m, 2 H), 3.76 (s, 2 H), 6.88 - 6.93 (m, 2 H), 6.96 - 7.01 (m, 2 H).

Preparation 10: {2-azabicyclo[3.1.1 hanol

H

To s solution of {2-benzyl-2-azabicyclo[3.1.1]heptan-1-yl}methanol (p7, 1.55 g, 6.64 mmol) in Methanol (80 ml_), ammonium formate (2.51 g, 39.85 mmol) and Pd(OH) 2 (372 mg, 2.65 mmol) were subsequently added, then the reaction mixture was stirred under reflux for 2 hrs. Further ammonium formate (1 g) and Pd(OH)2 (148 mg) were added and the reaction mixture was refluxed for additional 0.5 h until complete conversion. The reaction mixture was filtered on celite and the solvent removed under vacuum. The residue was dissolved in MeOH and the solution was loaded on a SCX cartridge (eluting with MeOH and 1 M NH 3 /MeOH) to give {2-azabicyclo[3.1.1]heptan-1-yl}methanol (p10, 560 mg, y= 66%) as white solid.

NMR ( 1 H, Chloroform-d): δ 3.34-3.40 (m, 2H), 3.18-3.27 (m, 2H), 2.45-2.53 (m, 1 H), 2.20-2.39 (m, 1 H), 1.92-2.00 (m, 2H), 1.83-1.92 (m, 2H), 1.59-1.69 (m, 2H). Preparation 11 : tert-butyl 1 -(hydroxymethyl)-2-azabicyclo[3.1.1]heptane-2- carboxylate

Boc

To a solution {2-azabicyclo[3.1.1]heptan-1-yl}methanol (p10, 0.64 g, 4.53 mmol) in DCM (15 ml_), at RT, Di-tert-butyl dicarbonate (1.09 g, 4.98 mmol) was added portion-wise and the resulting reaction mixture was stirred overnight at RT. The mixture was then concentrated under reduced pressure and the residue was purified by FC on silica gel (eluting with Cy/EA from 100/0 to 60/40) tert-butyl 1-(hydroxymethyl)-2- azabicyclo[3.1.1]heptane-2-carboxylate (p11 , 930 mg, y= 90%) as colourless oil.

NMR ( 1 H, Chloroform-d): δ 3.70-3.89 (m, 4H), 2.46-2.54 (m, 1 H), 2.05-2.15 (m, 2H), 1.94-2.02 (m, 2H), 1.84-1.92 (m, 2H), 1.49 (s, 8H)

Preparation 12: tert-butyl 1 -formyl-2-azabicyclo[3.1.1]heptane-2-carboxylate

Boc

To a stirred solution of tert-butyl 1-(hydroxymethyl)-2-azabicyclo[3.1.1]heptane-2- carboxylate (p11 , 200 mg, 0.84 mmol) in DCM (6 ml_), at RT and under a nitrogen atmosphere, Dess Martin reagent (390 mg, 0.92 mmol) was added portion-wise and the resulting reaction mixture was stirred at RT. An aqueous concentrated solution (14 ml_) of sodium thiosulfate was added and the mixture was stirred for 15 min, then a concentrated solution of sodium bicarbonate (5 ml_) was added and the mixture was stirred for additional 5 min. Phases were separated, the aqueous phase was extracted with DCM and the organic phases were combined, dried over sodium sulphate and concentrated under reduced pressure. The crude material was purified by FC on silica gel (eluting with Cy/EA from 100/0 to 80/20) affording tert-butyl 1-formyl-2- azabicyclo[3.1.1]heptane-2-carboxylate (p12, 140 mg, y= 74%) as white solid.

NMR ( 1 H, Chloroform-d): δ 9.37-9.47 (m, 1 H), 3.80-3.97 (m, 2H), 2.47-2.56 (m, 1 H), 2.36-2.46 (m, 2H), 1.97-2.10 (m, 2H), 1.74-1.87 (m, 2H), 1.43 (s, 9H) Preparation 13: methyl 3-bromo-6-methylpyridine-2-carboxylate

3-Bromo-6-methylpyridine-2-carboxylic acid (1.5 g, 6.94 mmol) was dissolved in MeOH (25 mL) and SOC (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 NaHCC>3, and the product was extracted with DCM (2x). The organic phase was dried and evaporated affording methyl 3-bromo-6-methylpyridine-2-carboxylate (p13, 1.35 g, y=84%) as yellow oil.

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

Preparation 14: methyl 6-methyl-3-(pyrimidin-2-yl)pyridine-2-carboxylate

methyl 3-bromo-6-methylpyridine-2-carboxylate (p13, 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 1 h 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-methyl- 3-(pyrimidin-2-yl)pyridine-2-carboxylate (p14, 100 mg, y=20%).

MS (/T7/z): 230.0 [MH] + . Preparation 15: 6-methyl-3-(pyrimidin-2-yl)pyridine-2-carboxylic acid

methyl 6-methyl-3-(pyrimidin-2-yl)pyridine-2-carboxylate (p14, 100 mg, 0.43 mmol) was dissolved in EtOH/H 2 0 (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 1 N HCI until pH 2/3. Volatiles were removed under vacuum, the residue was purified by RP on

C18 cartridge (from H 2 0 +0.1 % HCOOH to 20% AcCN +0.1 % HCOOH) to afford 6- methyl-3-(pyrimidin-2-yl)pyridine-2-carboxylic acid (p15, 80 mg, y=87%) as white solid.

MS (mlz): 216.1 [MH] + .

Preparation 16: 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 Cs 2 C0 3 (15.08 g, 46.28 mmol). To these solids was added dioxane (25 mL), then water (1 mL), then I H-1 ,2,3- triazole (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-triazol- 2-yl)pyridine-2-carboxylic acid (p16, 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 (mlz): 205.1 [M] + . Preparation 17: 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 NaHCC>3 (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/EtOAc from 100:0 to 70:30) to afford ethyl 5-bromo-2-methyl-1 ,3- thiazole-4-carboxylate (p17, 2.95 g, y= 67%) as a pale orange solid.

MS (mlz): 249.8 [M] + .

Preparation 18: 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 (p17, 250.1 1 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 (1 15.56 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 1 M KF aq. solution was added. The two phases were stirred at room temperature for 1 h and then separated. Organic layer was dried over Na2S0 4 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 (p18, 92.5 mg, y= 37%). MS (/T7/z): 250.0 [MH] + .

Preparation 19: 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 (p18, 92.5 mg, 0.370 mmol) and 1 M 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-5- pyrimidin-2-yl-1 ,3-thiazole-4-carboxylic acid (p19, 81 .6 mg, y= quant).

MS (mlz): 221 .9 [MH] + .

Preparation 20: ethyl 2-methyl-5-pyridin-2-yl-1 ,3-thiazole-4-carboxylate

To a solution of ethyl 5-bromo-2-methyl-1 ,3-thiazole-4-carboxylate (p17, 1 g, 3.64 mmol) in DMF (50 ml_), cesium fluoride (1.1 1 g, 7.28 mmol), Copper(l) iodide (69.29 mg, 0.360 mmol) and palladium triphenylphosphine (420.44 mg, 0.360 mmol) were added and mixture was degassed with nitrogen for 20min. tributyl(2-pyridinyl)stannane (1.18 ml_, 3.64 mmol) was added and reaction was stirred at 100 °C overnight. The reaction mixture was diluted with EtOAC and 1 M KF aq. solution was added. The two phases were stirred at room temperature for 1 h and then separated. Organic layer was dried over Na2S0 4 and solvent was removed under reduced pressure. Crude was purified by FC on silica gel (eluent from Cy to EtOAc 50%) to afford ethyl 2-methyl-5-pyridin-2-yl- 1 ,3-thiazole-4-carboxylate (p20, 400 mg, y= 44% yield).

MS (mlz): 249.0 [MH] + . Preparation 21 : 2-methyl-5-pyridin-2-yl-1 ,3-thiazole-4-carboxylic acid

A solution of ethyl 2-methyl-5-pyridin-2-yl-1 ,3-thiazole-4-carboxylate (p20, 400 mg, 1.61 mmol) and 1 M sodium hydroxide (4.82 ml_, 4.82 mmol) in Ethanol (12.5 ml_) was heated to 80 °C and stirred at that temperature for 30 min, then at RT overnight. Ethanol was removed under reduced pressure and 2M HCI was added dropwise until pH 4-5.

Water was concentrated and the residue was dissolved in a mixture of DCM and MeOH.

The suspension obtained was filtered and the solid discarded. Solvents were concentrated and the residue purified by FC on C18 cartridge (eluent from water + 0.1 % formic ac. to MeCN + 0.1 % formic ac. 10%) to afford 2-methyl-5-pyridin-2-yl-1 ,3-thiazole-

4-carboxylic acid (p21 , 262 mg, y= 74%) as white solid.

NMR ( 1 H, DMSO-c/6): δ ppm 13.67 (br. s., 1 H) 8.61 (dt, 1 H) 7.88 - 7.97 (m, 2 H) 7.42 (ddd, 1 H) 2.65 - 2.72 (m, 3 H)

Preparation 22: ethyl 2-methyl-5-pyrazin-2-yl-1 ,3-thiazole-4-carboxylate

To a solution of ethyl 5-bromo-2-methyl-1 ,3-thiazole-4-carboxylate (p17, 1 g, 3.64 mmol) in DMF (50 ml_), Copper(l) iodide (69.29 mg, 0.36 mmol), palladium triphenylphosphine (420.44 mg, 0.36 mmol) and cesium fluoride (1.1 1 g, 7.28 mmol) were added and the mixture was degassed with nitrogen for 20 min. tributyl(2- pyrazinyl)stannane (1.15 ml_, 3.64 mmol) was added and reaction was stirred at 100 °C overnight. The reaction was cooled down to RT and diluted with EtOAC and then 1 M KF aq. solution was added. The two phases were left stirring at RT for 1 h and then separated. Aqueous layer was extracted twice with EtOAc. Combined organics were dried over Na2S0 4 and solvent was removed under reduced pressure. Crude was dissolved in DCM and the resulting suspension was filtered through a phase separator. The filtrate was concentrated under vacuum and the residue was purified by FC on silica gel (eluent from Cy to EtOAc 30%) to afford ethyl 2-methyl-5-pyrazin-2-yl-1 ,3-thiazole-4- carboxylate (p22, 368 mg, y= 41 %) as yellow solid.

MS (mlz): 250.2 [MH] + . Preparation 23: 2-methyl-5-pyrazin-2-yl-1 ,3-thiazole-4-carboxylic acid

A solution of ethyl 2-methyl-5-pyrazin-2-yl-1 ,3-thiazole-4-carboxylate (p22, 368 mg, 1.48 mmol) and 1 M sodium hydroxide (3.98 mL, 3.98 mmol) in Ethanol (12 mL) was stirred at RT overnight. Ethanol was removed under reduced pressure and 2M HCI (aq.) was added until pH 4-5. Precipitate formation was observed. Precipitate was filtered out, washed with water and dried under high vacuum to afford 2-methyl-5-pyrazin-2-yl-1 , 3- thiazole-4-carboxylic acid (1 16.6 mg) as white solid. Mother liqueur were purified by RP FC on C18 cartridge (eluent from water + 0.1 % formic ac. to MeCN + 0.1 % formic ac. 17%) to afford a second batch of 2-methyl-5-pyrazin-2-yl-1 ,3-thiazole-4-carboxylic acid (187 mg) as white solid.

2-methyl-5-pyrazin-2-yl-1 ,3-thiazole-4-carboxylic acid (p23, 303.6 mg, y= 93%).

NMR ( 1 H, DMSO-c/6): δ ppm 13.34 (br. s. , 1 H) 9.13 (d, 1 H) 8.68 - 8.71 (m, 1 H) 8.63 (d, 1 H) 2.72 (s, 3 H)

Preparation 24: 6-methyl-3-pyrazol-1 -ylpyridine-2-carboxylic acid

To a solution of 3-bromo-6-methylpyridine-2-carboxylic acid (500 mg, 2.31 mmol) in 1 ,4- Dioxane (2.5 mL)/ Water (0.1 ml) 1 H-pyrazole (157.57 mg, 2.31 mmol) was added, followed by Copper (I) iodide (22.04 mg, 0.120 mmol), (1 R,2R)-N 1 , N2- dimethylcyclohexane-1 ,2-diamine (65.84 mg, 0.460 mmol) and cesium carbonate (1 .52 g, 4.63 mmol). The reaction mixture was refluxed (100 °C) overnight. After cooling, MTBE and water were added. After vigorously stirring, the layers were separated and the bottom aqueous one was acidified to pH 2 with HCI 6N. It was extracted several times with EtOAc then combined organics were dried and concentrated to afford 6-methyl-3- pyrazol-1 -ylpyridine-2-carboxylic acid (p24, 393 mg, y= 84%).

MS (mlz): 204.1 [MH] + . Preparation 25: 4-methyl-2-(triazol-2-yl)benzoic acid

To a 3-necked, round bottomed flask equipped with a magnetic stirrer, reflux condenser, and nitrogen inlet 2-bromo-4-methylbenzoic acid (500 mg, 2.33 mmol), iodocopper (22.14 mg, 0.12 mmol) and cesium carbonate (1524.55 mg, 4.65 mmol) were added. To these solids were added 1 ,4-Dioxane (2.5 ml_), Water (0.25 ml_), 2H-triazole (0.27 ml_, 4.65 mmol), and (1 R,2R)-N 1 , N2-dimethylcyclohexane-1 ,2-diamine (66.15 mg, 0.47 mmol). The reaction mixture was stirred overnight at 100 °C. The mixture was cooled down to RT and water and DCM were added and phases separated. The aqueous layer was acidified with HCI 3N and extracted with DCM. Combined organics were dried and concentrated. The crude material was purified by FC on silica gel (eluent from DCM to DCM/MeOH 9/1), to afford 4-methyl-2-(triazol-2-yl)benzoic acid (p25, 250 mg, y= 53%) as a light yellow powder.

MS (mlz): 203.9 [MH] + .

Preparation 26: 5-methyl-3-(triazol-2-yl)pyridine-2-carbonitrile

potassium carbonate (0.77 g, 5.58 mmol) and 3-bromo-5-methylpyridine-2-carbonitrile (1 g, 5.08 mmol) were mixed in DMF (10 ml_) then 1 H-1 ,2,3-Triazole (0.29 ml_, 5.08 mmol) was added and the reaction mixture was heated at 100 °C O/N. After cooling to RT the mixture was diluted with water and EtOAc, the organic phase was washed with brine, dried and evaporated. The crude material was purified by FC on silica gel (eluting from cHex to 80% EtOAc) affording 5-methyl-3-(triazol-2-yl)pyridine-2-carbonitrile (p26, 490 mg, y= 52%) as white solid.

MS (mlz): 186.2 [MH] + . Preparation 27: 5-methyl-3-(triazol-2-yl)pyridine-2-carboxylic acid

5-methyl-3-(triazol-2-yl)pyridine-2-carbonitrile (p26, 490 mg, 2.65 mmol) was suspended in Ethanol (7 ml_) and Water (3 ml_) and sodium hydroxide (108.51 mg, 2.65 mmol) was added. The mixture was refluxed for 4 hrs. It was cooled, EtOH was removed under vacuum and HCI 1 N was added until a precipitate was observed (pH 2). The precipitate was collected by filtration, washed with pentane, dried under vacuum to afford 5-methyl- 3-(triazol-2-yl)pyridine-2-carboxylic acid (p27, 455 mg, y= 84%) as white solid.

MS (mlz): 205.0 [MH] + .

Preparation 28: 3-ethoxy-6-methylpyridine-2-carboxylic acid

Step a:

To a solution of 2-(hydroxymethyl)-6-methylpyridin-3-ol (2.0 g, 14.37 mmol) in DMF (20 ml_) iodoethane (1 .38 ml_, 17.24 mmol) and potassium carbonate (9.92 g, 71.8 mmol) were added. The reaction mixture was stirred at room temperature for 24 hrs then the mixture was partitioned between diethyl ether and water. The organics were washed with brine, dried with Na2S0 4 , filtered and concentrated under vacuum to afford (3-ethoxy-6- methylpyridin-2-yl)methanol (Int. a, 1 .05 g), which was used in the next step without purification. Step b:

To a suspension of Int a (1 .05 g, 6.3 mmol) in water (5 ml_) potassium hydroxide (0.353 g, 6.3 mmol) and KMn0 4 (2.0 g, 12.6 mmol) were added and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was acidified to pH 4, filtered through a pad of Celite and concentrated under vacuum. The crude was purified by RP FC on C18 column (eluent: Water+0.1 % formic acid/ACN+0.1 % formic acid 90/10) to afford 3- ethoxy-6-methylpyridine-2-carboxylic acid (p28, 0.410 g, y= 36%). MS (/T7/z): 182.1 [MH] + .

Preparation 29: 1 -{[(tert-butyl l}-2-azabicyclo[3.1.1]heptane

{2-azabicyclo[3.1 .1]heptan-1 -yl}methanol (p10, 440 mg, 3.46 mmol) was dissolved in DMF (10 ml_) then 1 H-imidazole (824.37 mg, 12.1 1 mmol) and tert-butyl-chloro- diphenylsilane (0.99 ml_, 3.81 mmol) were subsequently added and the resulting reaction mixture was stirred overnight a RT. The mixture was diluted with water and extracted with EA, the organic phase was washed with water, dried over sodium sulphate and concentrated under vacuum. The crude material was purified by FC on silica gel (eluting with Cy/EA from 100/0 to 30/70), then further purified by FC on NH column (eluting with Cy/EA from 100/0 to 80/20) to give 1-{[(tert-butyldiphenylsilyl)oxy]methyl}-2- azabicyclo[3.1 .1 ]heptane (p29, 0.86 g, y= 68%) as colourless oil.

MS (/T7/z): 366.4 [MH] + .

Preparation 30: 1 -{[(tert-butyldiphenylsilyl)oxy]methyl}-2-[6-methyl-3-(pyrim idin-2- yl)pyridine-2-carbonyl]-2

To a stirred mixture of 6-methyl-3-pyrimidin-2-ylpyridine-2-carboxylic acid (p15, 123.93 mg, 0.550 mmol), 1 -{[(tert-butyldiphenylsilyl)oxy]methyl}-2-azabicyclo[3.1 .1 ]heptane (p29, 200 mg, 0.55 mmol) in DCM (3 ml_), N, N-Diisopropylethylamine (0.27 ml_, 1.64 mmol) and HATU (193.22 mg, 0.6 mmol) were subsequently added and the mixture was stirred overnight at RT. The mixture was diluted with EA and washed with saturated sodium bicarbonate solution; the organic phase was dried over sodium sulphate and concentrated under vacuum. The crude material was purified by FC on NH column (eluting with Cy/EA from 100/0 to 75/25) affording the product 1 -{[(tert- butyldiphenylsilyl)oxy]methyl}-2-[6-methyl-3-(pyrimidin-2-yl )pyridine-2-carbonyl]-2- azabicyclo[3.1 .1]heptane (p30, 250 mg, y= 81 %).

MS (mlz): 563.5 [MH] + . Preparation 31 : {2-[6-methyl-3-(pyrimidin-2-yl)pyridine-2-carbonyl]-2- azabicyclo[3.1.1]heptan-1 -yl}methanol

To a solution of 1 -{[(tert-butyldiphenylsilyl)oxy]methyl}-2-[6-methyl-3-(pyrim idin-2- yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1 ]heptane (p30, 250 mg, 0.44 mmol) in THF (2 mL), at RT, a 1 M/THF solution of tetrabutylammonium fluoride (0.53 mL, 0.53 mmol) was added and the resulting reaction mixture was stirred overnight at RT. The mixture was concentrated under vacuum and the residue was purified by FC on silica gel (eluting with DCM/MeOH from 100/0 to 95/5) affording {2-[6-methyl-3-(pyrimidin-2-yl)pyridine-2- carbonyl]-2-azabicyclo[3.1.1 ]heptan-1 -yl}methanol (p31 , 1 14 mg, y= 79%)

MS (mlz): 325.3 [MH] + .

Preparation 32: [2-(2-methyl-5-phenyl-1 ,3-thiazole-4-carbonyl)-2- azabicyclo[3.1.1]heptan-1 -yl]methanol

2-methyl-5-phenyl-1 ,3-thiazole-4-carboxylic acid (101 mg, 0.46 mmol) was dissolved in DMF (2 mL) then HATU (208 mg, 0.55 mmol) was added followed by DI PEA (0.16 mL, 0.92 mmol). The mixture was stirred for 15 min then 2-azabicyclo[3.1.1 ]heptan-1 - yimethanol (p10, 53 mg, 0.42 mmol) in DMF (0.5 mL) was added and the resulting reaction mixture was stirred overnight at RT. The mixture was diluted with water and EA, the organic phase was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by NH column (eluting with Cy/EA from 100/0 to 70/30) affording [2-(2-methyl-5-phenyl-1 ,3-thiazole-4-carbonyl)-2- azabicyclo[3.1 .1]heptan-1 -yl]methanol (p32, 71 mg, y= 51 %).

MS (mlz): 329.2 [MH] + . Preparation 33: riazol-2-yl)pyridine-2-carbonyl]-2- azabicyclo[3.1.1]heptan-1

To a solution of {2-azabicyclo[3.1.1 ]heptan-1 -yl}methanol (p10, 120 mg, 0.94 mmol) and HATU (466.39 mg, 1 .23 mmol) in DMF (4 ml_), N, N-Diisopropylethylamine (0.34 ml_, 2.08 mmol) was added and the mixture was stirred for 15 min at RT. A solution of 6-methyl-3- (triazol-2-yl)pyridine-2-carboxylic acid (p16, 21 1.93 mg, 1.04 mmol) in DMF (1 ml_) was added and the resulting reaction mixture was stirred overnight . The mixture was diluted with DCM and washed with water. The aqueous phase was extracted with DCM and the two organic phases were combined, washed with brine, dried over sodium sulphate and concentrated under vacuum. The residue was purified by N H column (eluting with Cy/EA from 100/0 to 34/66) affording {2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]- 2-azabicyclo[3.1.1 ]heptan-1 -yl}methanol (p33, 188 mg, y= 64%) as white solid.

MS (mlz): 314.3 [MH] + .

Preparation 34: {2-benzyl-2-azabi -1 -yl}methanamine

Bn

A solution of 2-benzyl-2-azabicyclo[3.1.1]heptane-1 -carbonitrile (p5, 1 g, 4.71 mmol) in THF (15 ml_) was cooled at -78 °C and 1 M lithium aluminium hydride (9.42 ml_, 9.42 mmol) in THF was added drop wise over 10 min. The cooling equipment was removed and the reaction mixture was allowed to reach RT and stirred 4 hrs. The reaction was cooled with ice bath and quenched with NaaSC OhbO until gas evolution ceased. The mixture was filtered, washing with EtOAc. Solvent was removed under vacuum affording {2-benzyl-2-azabicyclo[3.1.1 ]heptan-1 -yl}methanamine (p34, 840 mg, y= 82%) as colourless oil that was used as such in the next step.

MS {mlz): 217.3 [MH] + . Preparation 35: N-({2-benzyl-2-azabicyclo[3.1.1]heptan-1 -yl}methyl)isoquinolin-3- amine

{2-benzyl-2-azabicyclo[3.1.1 ]heptan-1 -yl}methanamine (p34, 300 mg, 1 .39mmol), 3- chloroisoquinoline (249.57 mg, 1.53 mmol), sodium tert-butoxide (266.55 mg, 2.77 mmol) and [1 -(2-diphenylphosphino-1 -naphthalenyl)-2-naphthalenyl]-diphenylphosphine (86.35 mg, 0.140 mmol) were dissolved in Toluene (5 ml_) and degassed for 10 min, then Pd2(dba)3 (38.1 mg, 0.040 mmol) was added. The resulting mixture was stirred at 100 °C overnight. The day after it was cooled to RT and diluted with water and EtOAc. The organic phase was dried and evaporated, the residue was purified by FC on NH column (eluting from cHex to 50% EtOAc) to afford N-({2-benzyl-2-azabicyclo[3.1 .1 ]heptan-1 - yl}methyl)isoquinolin-3-amine (p35, 300 mg, y= 63%).

MS (/T7/z): 344.1 [MH] + . Preparation 36: N-({2-aza soquinolin-3-amine

N-({2-benzyl-2-azabicyclo[3.1.1 ]heptan-1 -yl}methyl)isoquinolin-3-amine (p35, 300 mg, 0.870 mmol) was dissolved in Methanol (10 ml_) and Ethyl acetate (5 ml_) , ammonium formate (330.48 mg, 5.24 mmol) was added. The solution was degassed with N2 before adding 10% palladium/C (92.95 mg, 0.090 mmol). The resulting mixture was stirred at reflux for 3 hrs. Then it was cooled down to RT and filtered over celite. The solution was evaporated and charged on SCX cartridge eluting with 1 N NH3 in MeOH to afford N-({2- azabicyclo[3.1.1 ]heptan-1 -yl}methyl)isoquinolin-3-amine (p36, 100 mg, y= 45%) that was used as such in the next step.

MS (mlz): 254.3 [MH] + .

Preparation 37: N-({2-benzyl-2-azabicyclo[3.1.1]heptan-1 -yl}methyl)-4-fluoroaniline A mixture of (±)-2,2'-Bis(diphenylphosphino)-1 , 1 '-binaphthalene (86.35 mg, 0.140 mmol), Sodium tert-butoxide (266.55 mg, 2.77 mmol), Pd 2 (dba) 3 (38.1 mg, 0.040 mmol), {2-benzyl-2-azabicyclo[3.1.1 ]heptan-1 -yl}methanamine (p34, 300 mg, 1 .39 mmol), and 1 - bromo-4-fluorobenzene (0.15 ml_, 1.39 mmol) in toluene (5 ml_) was degassed and heated under nitrogen at 80 °C overnight. The mixture was cooled down to RT, then diluted with ethyl acetate and washed with water. The organic phase was dried and evaporated, and crude was purified by FC on NH column (eluent: cyclohexane to 15% ethylacetate) affording N-({2-benzyl-2-azabicyclo[3.1 .1]heptan-1 -yl}methyl)-4- fluoroaniline (p37, 270 mg, y= 63%) as yellow oil.

MS (/T7/z): 31 1 .3 [MH] + .

Preparation 38: N-({2-azabi )-4-fluoroaniline

N-({2-benzyl-2-azabicyclo[3.1.1 ]heptan-1 -yl}methyl)-4-fluoroaniline (p37, 100 mg, 0.320 mmol) was dissolved in Methanol (5 ml_), the solution was degassed with N2 before adding ammonium formate (203.15 mg, 3.22 mmol) and palladium/C (68.57 mg, 0.060 mmol). The reaction mixture was heated at reflux for 30 min. Then it was allowed to reach RT and filtered over celite, the methanol solution was concentrated and loaded on a SCX cartridge eluting with 1 N NH3 in MeOH affording, after evaporation, N-({2- azabicyclo[3.1 .1]heptan-1 -yl}methyl)-4-fluoroaniline (p38, 60 mg, y= 85%) as white off solid.

Partial defluorination observed. The compound was used as such in the next step.

MS (mlz): 221 .0 [MH] + . Preparation 39: N-({2-benzyl-2-azabicyclo[3.1.1]heptan-1 -yl}methyl)-2,4- difluoroaniline

{2-benzyl-2-azabicyclo[3.1.1 ]heptan-1 -yl}methanamine (p34, 150 mg, 0.62 mmol) was dissolved in Toluene (2.5 ml_), 1 -bromo-2,4-difluorobenzene (0.08 ml_, 0.69 mmol), [1 - (2-diphenylphosphino-1 -naphthalenyl)-2-naphthalenyl]-diphenylphosphine (38.86 mg, 0.06 mmol) and sodium tert-butoxide (1 19.95 mg, 1 .25 mmol) were added, the solution was degassed with nitrogen before adding Pd2(dba)3 (17.14 mg, 0.02 mmol) . The reaction mixture was heated at 100 °C O/N. The day after it was diluted with water and EtOAc, the organic phase was separated, dried and evaporated under vacuum. The residue was purified by FC on silica gel (eluting from cHex to 50 % EtOAc) to afford N- ({2-benzyl-2-azabicyclo[3.1.1 ]heptan-1 -yl}methyl)-2,4-difluoroaniline (p39, 80 mg, y= 39%) as yellow oil.

MS (mlz): 329.3 [MH] + .

Preparation 40: N-({2-azabi )-2,4-difluoroaniline

N-({2-benzyl-2-azabicyclo[3.1.1 ]heptan-1 -yl}methyl)-2,4-difluoroaniline (p39, 80 mg, 0.24 mmol) was dissolved in Methanol (5 mL), the solution was degassed with N2 before adding Pd(OH)2 (17.35 mg, 0.02 mmol). The reaction mixture was stirred at reflux for 90 min. It was cooled to RT and filtered over celite, the methanolic solution was concentrated and charged on SCX eluting with 1 N NH3 in MeOH to afford, after evaporation, N-({2-azabicyclo[3.1.1 ]heptan-1 -yl}methyl)-2,4-difluoroaniline (p40, 60 mg, y= quant) as orange brown oil, that was used as such in the next step.

MS (mlz): 239.3 [MH] + . Preparation 41 : N-({2-benzyl-2-azabicyclo[3.1.1]heptan-1 -yl}methyl)-5-chloropyridin- 2-amine

To a solution of {2-benzyl-2-azabicyclo[3.1.1 ]heptan-1 -yl}methanamine (p34, 100 mg, 0.42 mmol) in DMF (2 mL), potassium carbonate (172.51 mg, 1.25 mmol) and 5-chloro- 2-fluoropyridine (0.05 mL, 0.5 mmol) were added. The resulting mixture was stirred at 120 °C for 6 hrs. The mixture was cooled and diluted with water and EtOAc. The organic phase was washed several times with brine, then dried and evaporated. The residue was purified by FC on NH cartridge (eluting from cHex to 50 % EtOAc) to afford N-({2-benzyl- 2-azabicyclo[3.1.1 ]heptan-1 -yl}methyl)-5-chloropyridin-2-amine (p41 , 30 mg, y= 22%) as yellow oil.

MS (mlz): 328.4 [MH] + . Preparation 42: N-({2-azabicy yl)pyridin-2-amine

To a solution of N-({2-benzyl-2-azabicyclo[3.1 .1 ]heptan-1 -yl}methyl)-5-chloropyridin-2- amine (p41 , 30 mg, 0.09 mmol) in Methanol (5 mL) Platinum(IV) oxide (4.16 mg, 0.02 mmol) was added. The resulting mixture was stirred under H2 atmosphere for 1 h. Then 10% Pd/C (15 mg) was added and the mixture was stirred for 45 min under H2 atmosphere. Debenzylation and dehalogenation occurred during the reaction. The mixture was then filtered over a pad of celite and the methanolic solution was removed under vacuum to afford N-({2-azabicyclo[3.1.1 ]heptan-1 -yl}methyl)pyridin-2-amine (p42, 18 mg, y= 97%) that was used as such in the next step.

MS (mlz): 204.2 [MH] + .

Preparation 43: N-({2-benzyl-2-azabicyclo[3.1.1]heptan-1 -yl}methyl)-5-fluoropyridin- 3-amine

A mixture of (±)-2,2'-Bis(diphenylphosphino)-1 , 1 '-binaphthalene (54.69 mg, 0.09 mmol), Sodium tert butoxide (168.81 mg, 1 .76 mmol), Pd 2 (dba) 3 (24.13 mg, 0.03 mmol), (4- benzyl-4-azabicyclo[3.1.1 ]heptan-5-yl)methanamine (p34, 200 mg, 0.88 mmol), and 3- bromo-5-fluoropyridine (0.09 mL, 0.88 mmol) in toluene (5 mL) was degassed and heated under nitrogen at 80 °C overnight. The mixture was diluted with ethyl acetate, washed with water. The organic phase was dried and evaporated, the crude mixture was purified by FC on NH column (eluent from Cy to 40% AcOEt) affording N-({2-benzyl-2- azabicyclo[3.1 .1]heptan-1 -yl}methyl)-5-fluoropyridin-3-amine (p43, 230 mg, y=84%) as an orange oil.

MS (mlz): 312.4 [MH] + . Preparation 44: N-({2-azabic l)-5-fluoropyridin-3-amine

N-({2-benzyl-2-azabicyclo[3.1.1 ]heptan-1 -yl}methyl)-5-fluoropyridin-3-amine (p43, 230 mg, 0.74 mmol) was dissolved in Methanol (8 ml_), ammonium formate (279.46 mg, 4.43 mmol) was added, the mixture was degassed before adding Pd(OH)2 (52.61 mg, 0.07 mmol). The resulting solution was refluxed 30 min, then cooled to RT and filtered over celite rinsing with MeOH. The methanolic solution was concentrated under vacuum and purified by SCX eluting with 1 N NH3 in MeOH to afford after evaporation N-({2- azabicyclo[3.1 .1]heptan-1 -yl}methyl)-5-fluoropyridin-3-amine (p44, 130 mg, y= 79%).

MS (mlz): 222.3 [MH] + .

Preparation 45: N-({2-benzyl-2-azabicyclo[3.1.1]heptan-1 -yl}methyl)-4-fluoropyridin- 2-amine

A mixture of (±)-2,2'-Bis(diphenylphosphino)-1 , 1 '-binaphthalene (54.69 mg, 0.09 mmol), Sodium tert butoxide (168.81 mg, 1.76 mmol), Pd 2 (dba) 3 (24.13 mg, 0.03 mmol), {2-benzyl-2-azabicyclo[3.1.1 ]heptan-1 -yl}methanamine (p34, 200 mg, 0.88 mmol), and 2- chloro-4-fluoropyridine (0.08ml_, 0.88 mmol) in toluene (5 ml_) was degassed and heated under nitrogen at 80 °C overnight. The mixture was diluted with ethyl acetate and washed with water. The organic phase was dried and evaporated, the crude mixture was purified by FC on NH column (eluent: from Cy to 15% AcOEt) affording N-({2-benzyl-2- azabicyclo[3.1 .1]heptan-1 -yl}methyl)-4-fluoropyridin-2-amine (p45, 100 mg, y= 37%) as a yellow oil containing 20% of diaryl by-product. It was used as such in the next step.

MS (mlz): 312.1 [MH] + .

Preparation 46: N-({2-azabic l)-4-fluoropyridin-2-amine

N-({2-benzyl-2-azabicyclo[3.1.1 ]heptan-1 -yl}methyl)-4-fluoropyridin-2-amine (p45, 100 mg, 0.32 mmol) was dissolved in Methanol (7 ml_), ammonium formate (121 .5 mg, 1.93 mmol) was added, the mixture was degassed before adding Pd(OH)2 (22.87 mg, 0.03 mmol). The resulting solution was refluxed 30 min, then cooled to RT and filtered over celite rinsing with MeOH. The methanolic solution was concentrated under vacuum and purified by SCX eluting with 1 N NH 3 in MeOH to afford after N-({2- azabicyclo[3.1 .1]heptan-1 -yl}methyl)-4-fluoropyridin-2-amine (p46, 80 mg, y= quant) that was used as such in the next step. MS (mlz): 222.0 [MH] + .

Preparation 47: rophenyl)amino]methyl}-2- azabicyclo[3.1.1]heptane-2-

tert-butyl 1 -formyl-2-azabicyclo[3.1.1]heptane-2-carboxylate (p12, 170 mg, 0.75 mmol) and 4-chloroaniline (105.89 mg, 0.83 mmol) were mixed in DCM (4 ml_), acetic acid (0.02 ml_, 0.38 mmol) was added and the mixture was stirred for 20 min at RT before adding sodium triacetoxyborohydride (240 mg, 1 .13 mmol), the resulting mixture was stirred at RT O/N. An aqueous solution of NaHCC ss was added to quench the reaction, then phases were separated and the organic one was dried and evaporated. The crude material was purified by FC on silica gel (eluent: from cHex to 25% EtOAc) to afford tert- butyl 1 -{[(4-chlorophenyl)amino]methyl}-2-azabicyclo[3.1 .1 ]heptane-2-carboxylate (p47, 200 mg, y= 79%) as oil.

MS (mlz): 337.1 [MH] + .

Preparation 48: N-({2-azabi )-4-chloroaniline

tert-butyl 1 -{[(4-chlorophenyl)amino]methyl}-2-azabicyclo[3.1 .1 ]heptane-2-carboxylate (p47, 200 mg, 0.59 mmol) was dissolved in DCM (5 ml_) and Trifluoroacetic acid (0.44 ml_, 5.94 mmol) was added. The resulting mixture was stirred for 3 hrs at RT, and then volatiles were removed under vacuum. The residue was purified by SCX eluting with 1 N NH 3 in MeOH to afford N-({2-azabicyclo[3.1.1 ]heptan-1 -yl}methyl)-4-chloroaniline (p48, 130 mg, y= 92% yield) that was used as such in the next step.

MS (/T7/z): 237.0 [MH] + . Preparation 49: N-({2-azabi )-5-chloropyridin-2-amine

Step a:

tert-butyl 1 -formyl-2-azabicyclo[3.1.1]heptane-2-carboxylate (p12, 140 mg, 0.62 mmol) and 5-chloro-2-pyridinamine (87.88 mg, 0.68 mmol) were mixed in DCE (5 mL) at RT, after stirring for 20 min sodium triacetoxyborohydride (197.56 mg, 0.93 mmol) was added and the resulting mixture was stirred at RT O/N. Solids were filtered off and the solution was evaporated, the crude material was purified by FC on silica gel (eluent: from cHex to 25% EtOAc) to afford tert-butyl 1 -{[(5-chloropyridin-2-yl)amino]methyl}-2- azabicyclo[3.1 .1]heptane-2-carboxylate (Int. a, 130 mg, purity 30%) as oil.

Step b:

tert-butyl 1 -{[(5-chloropyridin-2-yl)amino]methyl}-2-azabicyclo[3.1.1]he ptane-2- carboxylate (Int. a, 130 mg, purity 30%) was dissolved in DCM (4 mL) and Trifluoroacetic acid (0.29 mL, 3.85 mmol) was added. The resulting mixture was stirred for 2 hrs at RT, then volatiles were removed under vacuum. The residue was purified by SCX eluting with 1 N NHs in MeOH to afford N-({2-azabicyclo[3.1 .1 ]heptan-1 -yl}methyl)-5- chloropyridin-2-amine (p49, 80 mg, purity 30%) that was used as such in the next step.

MS (mlz): 238.3 [MH] + .

Preparation 50: tert-butyl N-({2-benzyl-2-azabicyclo[3.1.1]heptan-1 - yl}methyl)carbamate

Bn

{2-benzyl-2-azabicyclo[3.1.1 ]heptan-1 -yl}methanamine (p34, 200 mg, 0.92 mmol) was dissolved in DCM (6 mL) and Di-tert-butyl dicarbonate (221.96 mg, 1.02 mmol) was added. The resulting mixture was stirred at RT O/N. The day after the solvent was removed under vacuum and the residue was purified by FC on NH column (eluting from cHex to 20% EtOAc) affording tert-butyl N-({2-benzyl-2-azabicyclo[3.1.1 ]heptan-1 - yl}methyl)carbamate (p50, 250 mg, y= 85%) as colourless oil. NMR ( 1 H, Acetone-c/6): δ ppm 7.37-7.44 (m, 2H), 7.28-7.34 (m, 2H), 7.16-7.26 (m, 1 H), 5.60-5.74 (m, 1 H), 3.69 (s, 2H), 3.17 (d, 2H), 2.93 (t, 2H), 2.79 (d, 1 H), 2.41 (s, 1 H), 1 .89-1 .99 (m, 4H), 1 .77-1.86 (m, 2H), 1.42 (s, 9H) Preparation 51 : tert-butyl N-({2- an-1 -yl}methyl)carbamate

A solution of tert-butyl N-({2-benzyl-2-azabicyclo[3.1.1 ]heptan-1 -yl}methyl)carbamate (p50, 250 mg, 0.790 mmol) in Methanol (8 mL) was degassed with N2, then palladium/C (84.08 mg, 0.080 mmol) was added and the mixture was stirred for 1 h at RT under H2 atmosphere. The catalyst was filtered off over a pad of celite and the methanol solution was evaporated under vacuum affording tert-butyl tert-butyl N-({2- azabicyclo[3.1 .1]heptan-1 -yl}methyl)carbamate (p51 , 180 mg, y= quant) as wax.

MS (mlz): 227.3 [MH] + . Preparation 52: 2,3-triazol-2-yl)pyridine-2- carbonyl]-2-azabicycl

6-methyl-3-(triazol-2-yl)pyridine-2-carboxylic acid (p16, 69.47 mg, 0.340 mmol) was dissolved in DMF (2 mL), then HATU (152.88 mg, 0.4 mmol) and N, N- Diisopropylethylamine (0.1 1 mL, 0.680 mmol) were added and the mixture was stirred at RT for 15 min before adding tert-butyl tert-butyl N-({2-azabicyclo[3.1.1 ]heptan-1 - yl}methyl)carbamate (p51 , 70 mg, 0.310 mmol). The resulting solution was stirred at RT ON. The day after it was diluted with EtOAc and washed several times with NH4CI ss. The organic phase was dried and evaporated, the residue was purified by FC on silica gel (eluting from cHex to 90 % EtOAc) affording tert-butyl N-({2-[6-methyl-3-(2H-1 ,2,3- triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1 ]heptan-1 -yl}methyl)carbamate (p52, 100 mg, y= 78%).

MS (mlz): 413.1 [MH] + . Preparation 53: {2-[6-methyl-3-(2H-1 ,2,3-triazol-2-yl)pyridine-2-carbonyl]-2- azabicyclo[3.1.1]heptan-1 -yl}methanamine

tert-butyl N-[[4-[6-methyl-3-(triazol-2-yl)pyridine-2-carbonyl]-4-azabi cyclo[3.1.1 ]heptan-5- yl]methyl]carbamate (p52, 100 mg, 0.24 mmol) was dissolved in DCM (4 mL), then Trifluoroacetic acid (0.18 mL, 2.42 mmol) was added and the resulting solution was stirred at RT for 1 h. Volatiles were removed under vacuum and the residue was charged on a SCX cartridge eluting with 1 N NH 3 in MeOH affording {2-[6-methyl-3-(2H-1 , 2,3- triazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1 ]heptan-1 -yl}methanamine (p53, 60 mg, y= 79%).

MS (mlz): 313.0 [MH] + .

Preparation 54: 6-methyl-3-(1 , -2-carbonitrile

Step a:

2,2,6,6-tetramethylpiperidine (8.72mL, 51 .7mmol) was dissolved in dry THF (62mL) under argon and stirred at -30 °C; n-Butyllithium (21.33mL, 53.32mmol) 2.5 M in hexane was added over 5 m. The yellow solution was stirred at -30 °C for 20 min, then chilled at -78 °C and tripropan-2-yl borate (10.94mL, 47.4mmol) was added over 5 min. After 10 min at -78 °C, 6-methyl-2-pyridinecarbonitrile (5000mg, 42.32mmol) dissolved in dry THF (35mL) was added dropwise (over 20 min) maintaining internal temperature below -73 °C and the mixture became dark-brown. The mixture was stirred at -73 °C for 6 hrs. The mixture was quenched with acetic acid (5.94mL, 103.75mmol) dropwise at -73 °C (the temperature never exceeded -60 °C). The cooling bath was removed and the mixture left to reach the room temperature: during this period the mixture became thick and new THF (15 mL) had to be added in order to have a better stirring. The mixture was stirred 10 min at RT then 2,2-dimethylpropane-1 ,3-diol (6022.5mg, 57.83mmol) was added in one portion and the mixture stirred at RT overnight. The solvent was evaporated and the orange residue taken-up with DCM and 10 % water solution of ΚΉ2ΡΟ4. The phases were separated and the water phase was back-extracted with DCM. The combined organic phases were washed with 10 % water solution of KH2PO4 (50 ml). The DCM was evaporated. The residue was dissolved in Et20 and extracted with NaOH 0.05 M (5 x 250 ml_, boronic ester in water phase). The aqueous phases were joined together and the pH was adjusted between pH = 4 and pH = 5 with 10 % water solution of KH2PO4 (50 ml_). The so obtained yellow solution was extracted with EtOAc and DCM. All the organics joined together were dried (Na2S0 4 ) and evaporated to afford 3-(5,5-dimethyl-1 ,3,2- dioxaborinan-2-yl)-6-methylpyridine-2-carbonitrile (Int a: 3816 mg) which was used in the next step without purification.

Step b:

To a stirred solution of Int a (1.43g, 6.22mmol), cesium fluoride (1.9g, 12.43mmol) and copper (I) iodide (202.3mg, 1.06mmol) in 1 ,4-Dioxane (30m L), 2-bromothiazole (0.67ml_, 7.46mmol) and palladium triphenylphosphine (359.12mg, 0.310mmol) were subsequently added. The mixture was submitted to repeated cycles of vacuum/nitrogen then was heated to 65 °C (external temperature 70 °C) and stirred 3 hrs at this temperature. The residue was taken up with EA and a concentrated solution of NaHC03, the organic phase was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude material was purified by FC on silica (Snap 100, eluting with Cy/EA from 100/0 to 66/34) to afford 6-methyl-3-(1 ,3-thiazol-2-yl)pyridine-2- carbonitrile (p54, 0.840 g, y= 33%).

MS (/T7/z): 202.1 [MH] + .

Preparation 55: 6-methyl-3-(1 ,3-thiazol-2-yl)pyridine-2-carboxylic acid

A mixture of 6-methyl-3-(1 ,3-thiazol-2-yl)pyridine-2-carbonitrile (p54, 790. mg, 3.93mmol) and HCI (6 N aqueous solution) (47.76ml_, 286.56mmol) was stirred at 80 °C overnight. The reaction mixture was concentrated under reduced pressure and the crude material so obtained was purified by C18 FC (eluting with Water+0.1 % formic acid/ MeCN +0.1 % formic acid 22/78) affording 6-methyl-3-(1 ,3-thiazol-2-yl)pyridine-2-carboxylic acid (p55, 410 mg, y=47.42%). MS [mlz): 202.1 [MH] + .

Preparation 56: 3-(1 ,3-thiazol-2-yl)pyridine-2-carbonyl]-2-azabicyclo[3.1.1]hept an-1 - yl}methanol

To a stirred mixture of {2-azabicyclo[3.1.1 ]heptan-1 -yl}methanol (p10, 80. mg, 0.630mmol), 6-methyl-3-(1 ,3-thiazol-2-yl)pyridine-2-carboxylic acid (p55, 152.4mg, 0.690mmol) and HATU (310.93mg, 0.820mmol) in DMF (3m L), at RT, N, N- Diisopropylethylamine (0.23mL, 1 .38mmol) was added and the reaction mixture was stirred overnight at RT. The mixture was diluted with water and extracted twice with EA, the combined organic phases washed with brine, dried over sodium sulphate and concentrated under reduced pressure. The crude material was purified by NH column (eluting with Cy/EA from 100/0 to 42/58) affording [5-(hydroxymethyl)-4- azabicyclo[3.1 .1]heptan-4-yl]-[6-methyl-3-(1 ,3-thiazol-2-yl)pyridin-2-yl]methanone (p56, 90 mg,0.273mmol, y=43.4) as white foam.

MS (mlz): 330.3 [MH] + .

Preparation 57: N-({2-azabicyclo[3.1.1]heptan-1 -yl}methyl)-5-phenyl-1 ,3-thiazol-2- amine

Step a

tert-butyl 1 -formyl-2-azabicyclo[3.1 .1 ]heptane-2-carboxylate (p12, 130.mg, 0.580mmol) and 5-phenyl-1 ,3-thiazol-2-amine (1 1 1.87mg, 0.630mmol) were mixed in DCM (5ml_), acetic acid (0.02m L, 0.290mmol) was added and the mixture was stirred for 60 min at RT before adding sodium triacetoxyborohydride (183.45mg, 0.870mmol), the resulting mixture was stirred at RT ON. The day after further 2 eq of Na(OAc)3BH were added and the mixture was refluxed for 3hrs. Then it was cooled to RT, an aqueous solution of NaHCC>3 ss was added to quench, phases were separated, the organic one was dried and evaporated. The crude material was purified by FC on Si02 (from cHex to 35% EtOAc) to afford tert-butyl 5-[[(5-phenyl-1 ,3-thiazol-2-yl)amino]methyl]-4- azabicyclo[3.1.1]heptane-4-carboxylate (Int a,: 60 mg,0.156mmol) as oil.

Step b

tert-butyl 5-[[(5-phenyl-1 ,3-thiazol-2-yl)amino]methyl]-4-azabicyclo[3.1.1 ]heptane-4- carboxylate (Int a,60.mg, 0.160mmol) was dissolved in DCM (4ml_) and Trifluoroacetic acid (0.12ml_, 1.56mmol) was added. The resulting mixture was stirred for 1 hr then volatiles were removed under vacuum. The residue was purified by SCX eluting with 1 N NHs in MeOH to afford N-(4-azabicyclo[3.1.1]heptan-5-ylmethyl)-5-phenyl-1 ,3-thiazol-2- amine (p57, 35 mg) used as such in the next step.

MS (/T7/z): 286.1 [MH] + .

Preparation 58: .1.1]heptan-1 -yl}methyl)-5-

(trifluoromethyl)pyrimidin-

To a solution of {2-benzyl-2-azabicyclo[3.1.1]heptan-1-yl}methanamine (p34, 85. mg, 0.390mmol) in DMF (1.5ml_), potassium carbonate (162.92mg, 1.18mmol) and 2-chloro- 5-(trifluoromethyl)pyrimidine (86.07mg, 0.470mmol) were added. The resulting mixture was stirred at 120 °C for 6 hrs. The mixture was cooled and diluted with water and EtOAc. The organic phase was washed several times with brine, then dried and evaporated. The residue was purified by FC on NH cartridge (eluting from cHex to 50 % EtOAc) to afford N-[(4-benzyl-4-azabicyclo[3.1.1]heptan-5-yl)methyl]-5- (trifluoromethyl)pyrimidin-2-amine (p58, 73 mg,0.201 mmol, y=51.3%). MS (/T7/z): 363.1 [MH] + .

Preparation 59: N-({2-azabicyclo[3.1.1]heptan-1 -yl}methyl)-5-

(trifluoromethyl)pyrimidin-2-amine

A solution of N-[(4-benzyl-4-azabicyclo[3.1.1 ]heptan-5-yl)methyl]-5- (trifluoromethyl)pyrimidin-2-amine (p58, 73. mg, 0.200mmol), ammonium formate (76.22mg, 1.21 mmol), and 20% Pd(OH) 2 (14.14mg, 0.020mmol) in methanol (2mL) was degassed and refilled with nitrogen (x3), then it was heated at reflux for 1 h. After being cooled at RT, it was filtrated through a path of celite and concentrated under reduced pressure. The crude mixture was purified by SCX cartridge eluting with 1 N NH3 in MeOH, to afford N-(4-azabicyclo[3.1.1 ]heptan-5-ylmethyl)-5-(trifluoromethyl)pyrimidin-2- amine (p59, 42 mg, y= 76.6%).

MS (mlz): 273.3 [MH] + .

Preparation 60: .1.1]heptan-1 -yl}methyl)-5-

(trifluoromethyl)pyrazin-2-

To a solution of {2-benzyl-2-azabicyclo[3.1 .1 ]heptan-1 -yl}methanamine (p34, 79. mg, 0.370mmol) in DMF (1 .5ml_), potassium carbonate (151.42mg, 1.1 mmol) and 2-chloro- 5-(trifluoromethyl)pyrazine (0.05ml_, 0.440mmol) were added. The resulting mixture was stirred at 120 °C for 6 hrs. The mixture was cooled and diluted with water and EtOAc. The organic phase was washed several times with brine, then dried and evaporated. The reside was purified by FC on NH column (eluting from cHex to 50 % EtOAc) to afford N-[(4-benzyl-4-azabicyclo[3.1.1 ]heptan-5-yl)methyl]-5- (trifluoromethyl)pyrazin-2-amine (p60, 61 mg, y=46%).

MS (mlz): 363.1 [MH] + . Preparation 6 .1.1]heptan-1 -yl}methyl)-5-

(trifluoromethyl)pyrazin-2

A solution of N-[(4-benzyl-4-azabicyclo[3.1.1 ]heptan-5-yl)methyl]-5- (trifluoromethyl)pyrazin-2-amine (p60, 61. mg, 0.170mmol), ammonium formate (63.69mg, 1.01 mmol), and 20% Pd(OH) 2 (1 1.82mg, 0.020mmol) in methanol (2 mL) was degassed and refilled with nitrogen (x3), then it was heated at reflux for 1 h. After being cooled at RT, it was filtrated through a path of celite and concentrated under reduced pressure. The crude mixture was purified by SCX cartridge eluting with 1 N NH3 in MeOH, to afford N-(4-azabicyclo[3.1.1 ]heptan-5-ylmethyl)-5-(trifluoromethyl)pyrazin- 2-amine (p61 , 32 mg, y= 69.8%).

MS (mlz): 273.3 [MH] + .

Preparation 62: .1.1]heptan-1 -yl}methyl)-5-

(trifluoromethyl)pyridin-2-a

To a solution of {2-benzyl-2-azabicyclo[3.1.1 ]heptan-1 -yl}methanamine (p34, 80 mg, 0.370 mmol) in DMF (1 .5 mL), potassium carbonate (153 mg, 1.1 mmol) and 2-chloro-5-

(trifluoromethyl)pyridine (80.5 mg, 0.44 mmol) were added. The resulting mixture was stirred at 120 °C for 2 hrs. The mixture was cooled and diluted with water and EtOAc.

The organic phase was washed several times with brine, then dried and evaporated.

The reside was purified by FC on NH column (eluting from cHex to 70% EtOAc) to afford N-({2-benzyl-2-azabicyclo[3.1.1 ]heptan-1 -yl}methyl)-5-(trifluoromethyl)pyridin-2- amine (p62, 40 mg, y= 30%).

MS (mlz): 362.2 [MH] + .

Preparation 63: N-({2-azabicyclo[3.1.1]heptan-1 -yl}methyl)-5-(trifluoromethyl)pyridin- 2-amine

N-({2-benzyl-2-azabicyclo[3.1.1 ]heptan-1 -yl}methyl)-5-(trifluoromethyl)pyridin-2-amine (p62, 40. mg, 0.1 10 mmol) was dissolved in Methanol (4 mL), the solution was degassed with N2 before adding ammonium formate (55.84 mg, 0.890 mmol) and 10% Pd/C (1 1.78 mg, 0.010 mmol). The reaction mixture was refluxed for 45 min. After cooling to RT it was filtered over celite, the methanolic solution was concentrated and charged on SCX eluting with 1 N NH3 in MeOH to afford, after evporation, N-({2- azabicyclo[3.1 .1]heptan-1 -yl}methyl)-5-(trifluorornethyl)pyridin-2-arnine (p63, 25 mg, y= 83%) as oil.

MS (mlz): 272.1 [MH] + .

Preparation 64: 6-methyl-3-(4-methyl-2H-1 ,2,3-triazol-2-yl)pyridine-2-carboxylic acid

4-Methyl-1 H-1 ,2,3-triazole (0.1 1 mL, 1 .85mmol) was added to a solution of 3-bromo-6- methylpyridine-2-carboxylic acid (200. mg, 0.930mmol) in 1 ,4-Dioxane (1 mL)/ Water (0.1 ml_), followed by Cul (8.86mg, 0.050mmol), (1 R,2R)-N 1 , N2-dimethylcyclohexane-1 ,2- diamine (26.34mg, 0.190mmol) and cesium carbonate (607.03mg, 1 .85mmol The mixture was stirred at 120 °C for 5 h. Reaction mixture was cooled to room temperature and then water and MTBE were added. After vigorously stirring, the layers were separated and the aqueous one was acidified to pH 2 with HCI 6N. The acidic solution was concentrated and purified by RP on C18 column [H20 (0.1 % HCOOH)/Acetonitrile=60/40] affording 6-methyl-3-(4-methyltriazol-2-yl)pyridine-2- carboxylic acid (p64, 139 mg, y= 69% yield) as a white solid.

MS (mlz): 219.2 [MH] + .

Preparation 65: ethyl 2-methyl-5-(pyridin-3-yl)-1 ,3-thiazole-4-carboxylate

To a mixture of ethyl 5-bromo-2-methyl-1 ,3-thiazole-4-carboxylate (p17, 300 mg, 1 .08mmol) and 3-pyridinylboronic acid (146 mg, 1 .19mmol) in 1 ,4-Dioxane (12 mL) and water (4 mL), sodium carbonate (343 mg, 3.24mmol) was added. The mixture was degassed with N2 and then Pd(P i3) 4 (62.37mg, 0.050mmol) was added. The reaction mixture was degassed again with N2 and stirred at 90 °C for 2 hrs. It was cooled and diluted with EtOAc and NH4CI ss. Phases were separated and the aqueous one was extracted with EtOAc (2x). The organic phases were collected, dried and evaporated under vacuum. The crude material was purified by FC on S1O2 column (eluting from cHex to EtOAc) to afford ethyl 2-methyl-5-pyridin-3-yl-1 ,3-thiazole-4-carboxylate (p65, 200 mg, y=75% yield).

MS (mlz): 249.0 [MH] +

Preparation 66: 2-methyl-5-(pyridin-3-yl)-1 ,3-thiazole-4-carboxylic acid

A solution of 2M NaOH (1 .01 ml_, 2.01 mmol) and ethyl 2-methyl-5-pyridin-3-yl-1 ,3- thiazole-4-carboxylate (p65, 200 mg, 0.810mmol) in ethanol (5mL) was stirred at RT for 3 hrs. Ethanol was removed under reduced pressure and 1 M HCI (aq.) was added until pH 4-5. No precipitation was observed. Volatiles were removed under vacuum and the crude material was purified by RP on C18 column (eluting from water + 0.1 % HCOOH. to 50% MeCN + 0.1 % HCOOH.) to afford 2-methyl-5-pyridin-3-yl-1 ,3-thiazole-4-carboxylic acid (p66, 160 mg, y= 90%) as white solid.

MS (mlz): 221.0 [MH] +

Preparation 67: 5-fluoro-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid

To a round-bottomed flask equipped with an overhead magnetic stirrer, reflux condenser, and nitrogen inlet were added 2-Bromo-5-fluorobenzoic acid (1 g, 4.57 mmol), copper iodide (0.045 g, 0.23 mmol), and Cs 2 C0 3 (2.98 g, 9.13 mmol). To these solids were added dioxane (7 ml_), water (0.035 ml), 1 H-1 ,2,3-triazole (0.52 ml_, 9.13 mmol), and finally trans-1 ,2-dimethylcyclohexane-1 ,2-diamine (0.145 ml_, 0.91 mmol). The mixture was then warmed to 100 °C for 4 hrs. Then the mixture was cooled 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 aqueous phase was then extracted with DCM (3x). The combined organic layers were dried, and concentrated. The residue was purified by FC on Si0 2 column (eluent : from DCM to DCM : MeOH: 95: 5) to afford 5- fluoro-2-(2H-1 ,2,3-triazol-2-yl)benzoic acid (p67, 0.52 g, y= 55%) as white solid.

MS (mlz): 208.2 [MH] + Preparation 68: methyl 4-nitro-1 H-pyrazole-3-carboxylate

Thionyl chloride (6.28ml_, 86.07mmol) was added to an ice cooled solution of 4-nitro-1 H- pyrazole-3-carboxylic acid (10.4 g, 66.21 mmol) in methanol (150 ml_). The resulting solution was stirred at RT ON. The day after MeOH was removed under vacuum; toluene was added and dried again. The solid was suspended in pentane and filtered under vacuum to afford methyl 4-nitro-1 H-pyrazole-3-carboxylate (p68, 1 1.15 g, y= 98%) as creamy solid.

MS (mlz): 171 .9 [MH] +

Preparation 69: methyl 1 -methyl-4-nitro-1 H-pyrazole-3-carboxylate

Step a

NaH 60% dispersion in oil (3.13 g, 78.2 mmol) was added portionwise to an ice cooled suspension of methyl 4-nitro-1 H-pyrazole-3-carboxylate (p68, 1 1.15 g, 65.16 mmol) in THF (100 ml_) and the resulting mixture was stirred for 30min. lodomethane (6.09 ml_, 97.74mmol) was added to the mixture and the reaction was stirred at RT ON. The day after UPLC showed mainly hydrolysis of the methyl ester and presence of the corresponding carboxilic acid. The reaction was quenced with water and diluted with EtOAc, but no product was present in the organic phase so the organic phase was discarded. The water phase was acidified until pH 4 with 6N HCI, then extracted several times with EtOAc, but only traces of product were detected in organic phase. The water phase was then dried under vacuum, the orange residue was triturated with Et20/MeOH 9/1 to afford 1 -methyl-4-nitropyrazole-3-carboxylic acid (Int A, 20 g, 1 16.88 mmol) as pale yellow solid in mixture with inorganic salts that was used as such. Step b

1 -methyl-4-nitropyrazole-3-carboxylic acid (Int A, 20 g, 64.29 mmol) was suspended in methanol (200 ml_), sulfuric acid (2.4 ml_, 45mmol) was added dropwise and the resulting suspension was refluxed ON. The day after it was cooled, diluted with water, and then MeOH was removed under vacuum. The aqueous phase was extracted several times with EtOAc, the organic phase was dried and evaporated. The residue was triturated with pentane, and then with ether to afford methyl 1 -methyl-4-nitro-1 H-pyrazole-3-carboxylate (p69, 8.15 g, y=68%) as yellow-orange solid.

MS (/T7/z): 186.0 [MH] +

Preparation 70: methyl 4-amino-1 -methyl-1 H-pyrazole-3-carboxylate

10% palladium/C (2.87 g, 2.7 mmol) was added to a stirred solution of methyl 1 -methyl- 4-nitro-1 H-pyrazole-3-carboxylate (p69, 7.15 g, 38.6 mmol) in methanol (250 ml_) and stirred at RT under H2 atmosphere for 4 hrs. The catalyst was filtered off and the solvent was evaporated under vacuum to afford methyl 4-amino-1 -methyl-1 H-pyrazole- 3-carboxylate (p70, 6 g, y= quant) as purple wax used as such in the next step.

MS (/T7/z): 156.1 [MH] + Preparation 71 : methyl 4-bromo-1 -methyl-1 H-pyrazole-3-carboxylate

Isoamyl nitrite (1 .3 ml_, 9.67mmol) was added drop-wise to a suspension of methyl 4- amino-1 -methyl-1 H-pyrazole-3-carboxylate (p70, 1 g, 6.45 mmol), CuBr2 (1 .44 g, 6.45 mmol) and CuBr (924 mg, 6.45 mmol) in MeCN (25 ml_). The resulting mixture was stirred at 80 °C for 2 hrs. After cooling to RT the volatiles were evaporated under vacuum and the residue was purified by FC on S1O2 column (eluting from cHex to 40% EtOAc) to afford methyl 4-bromo- 1 -methyl- 1 H-pyrazole-3-carboxylate (p71 , 500 mg, y= 35 %) as brown solid.

MS (mlz): 220.9 [MH] +

Preparation 72: methyl 1 -methyl-4-phenyl-1 H-pyrazole-3-carboxylate

To a mixture of methyl 4-bromo-1 -methyl-1 H-pyrazole-3-carboxylate (p71 , 80 mg, 0.37 mmol) and phenylboronic acid (57.9 mg, 0.47 mmol) in 1 ,4-Dioxane (2 ml_) and Water (0.7 ml_) potassium carbonate (151.44 mg, 1 .1 mmol) was added. The mixture was degassed with N2 and then Pd(P i3) 4 (42 mg, 0.04 mmol) was added. The reaction mixture was degassed again with N2 and stirred at 120 °C for 3 hrs. It was cooled and diluted with EtOAc and water. Phases were separated and the aqueous one was extracted with EtOAc (2x). The organic phases were collected, dried and evaporated under vacuum. The crude material was purified by FC on S1O2 column (eluting from cHex to 60% EtOAc) to afford methyl 1 -methyl-4-phenyl-1 H-pyrazole-3-carboxylate (p72, 50 mg, y=63%).

MS (mlz): 217.0 [MH] +

Preparation 73: lithium 1 -methyl-4-phenyl-1 H-pyrazole-3-carboxylate

methyl 1 -methyl-4-phenyl-1 H-pyrazole-3-carboxylate (p72, 50 mg, 0.23 mmol) was dissolved in THF (3 ml_) and Water (0.5 ml_) then lithium hydroxide hydrate (1 1.9 mg, 0.28 mmol) was added and the reaction mixture was stirred at RT ON. The day after volatiles were removed under vacuum to afford lithium 1 -methyl-4-phenyl -1 H-pyrazole -3-carboxylate (p73, 56 mg, y= quant) as white off solid used as such in the next step. MS (mlz): 203.1 [MH] +

Preparation 74: methyl 1 -methyl-4-(pyrimidin-2-yl)-1 H-pyrazole-3-carboxylate

To a solution of methyl 4-bromo- 1 -methyl- 1 H-pyrazole-3-carboxylate (p71 , 270. mg, 1.23 mmol) in DMF (8 mL), Cul (23.6 mg, 0.12 mmol) and Pd(Ph 3 )4 (142.4 mg, 0.12 mmol) were added and the mixture was degassed with nitrogen for 20min before adding tributyl(2-pyrimidinyl)stannane (0.5 mL, 1 .51 mmol). The reaction was stirred at 1 10 °C for 4hrs. Reaction was cooled to RT and diluted with EtOAC and 1 M KF aq. solution. Phases were stirred at RT for 1 h and then separated. Organic layer was dried and solvent was removed under reduced pressure. Crude material was purified by FC on N H column (eluting from Cy to 60%EtOAc) to afford methyl 1 -methyl-4-(pyrimidin-2-yl)-1 H- pyrazole-3-carboxylate (p74, 90 mg, y= 33% yield) as white solid.

MS (/T7/z): 219.0 [MH] +

Preparation 75: lithium 1 -methyl-4-(pyrimidin-2-yl)-1 H-pyrazole-3-carboxylate

methyl 1 -methyl-4-(pyrimidin-2-yl)-1 H-pyrazole-3-carboxylate (p74, 90 mg, 0.41 mmol) was dissolved in THF (3 mL) and Water (1 mL) then lithium hydroxide hydrate (21 mg, 0.49 mmol) was added and the reaction mixture was stirred at RT ON. The day after volatiles were removed under vacuum to afford lithium 1 -methyl-4-(pyrimidin-2-yl)-1 IH- pyrazole-S-carboxylate (p75, 90 mg, y= quant) as white off solid used as such in the next step.

MS (mlz): 205.0 [MH] +

Preparation 76: ethyl 4-bromo-5-methyl-1 H-pyrazole-3-carboxylate

To an ice cooled solution of ethyl 5-methyl-1 H-pyrazole-3-carboxylate (625. mg, 4.05mmol) in MeCN (8ml_) N-Bromosuccinimide (760 mg, 4.27 mmol) was added portion-wise. The resulting reaction mixture was stirred at RT for 2 hrs then solvent was removed under vacuum and the residue was purified by FC on S1O2 column (eluting from cHex to 40% EtOAc) affording ethyl 4-bromo-5-methyl-1 H-pyrazole-3-carboxylate (p76, 900 mg, y= 95%) as white solid.

MS (/T7/z): 233.1 [MH] +

Preparation 77: ethyl 4-bromo-1 ,5-dimethyl-1 H-pyrazole-3-carboxylate

ethyl 4-bromo-5-methyl-1 H-pyrazole-3-carboxylate (p76, 900 mg, 3.86 mmol) was dissolved in DMF (6 mL) and cooled with an ice bath. Then NaH 60% dispersion in oil (309 mg, 7.72 mmol) was added portion-wise and the resulting mixture was stirred for 30 min before adding iodomethane (0.29 mL, 4.63 mmol). The reaction mixture was stirred at RT for 3 hrs. It was diluted with water and extracted with EtOAc (3x). The organic phase was dried and evaporated and the residue was purified by S1O2 column (eluting from cHex to 50% EtOAc) to afford ethyl 4-bromo-2,5-dimethyl-1 H-pyrazole-3- carboxylate (260 mg) as oil and ethyl 4-bromo-1 ,5-dimethyl-1 H-pyrazole-3-carboxylate (p77, y= 44% yield) as white solid.

NMR ( 1 H, DMSO-c/6) δ 4.26 (q, 2H), 3.86 (s, 3H), 2.27 (s, 3H), 1.28 (t, 3H)

Preparation 78: ethyl 1,5-dimethyl-4-(pyrimidin-2-yl)-1 H-pyrazole-3-carboxylate

To a solution of ethyl 4-bromo-1 ,5-dimethyl-1 H-pyrazole-3-carboxylate (p77, 420 mg, 1.7 mmol) in DMF (8 mL), copper (I) iodide (32.5 mg, 0.17 mmol) and Pd(Ph 3 )4 (196.4 mg, 0.17 mmol) were added and the mixture was degassed with nitrogen for 20min before adding tributyl(2-pyrimidinyl)stannane (0.68 mL, 2.08 mmol). The reaction was stirred at 1 10 °C for 4hrs. Reaction was cooled to RT and diluted with EtOAC and 1 M KF aq. solution. Two phases were stirred at RT for 1 h and then separated. Organic layer was dried and solvent was removed under reduced pressure. Crude material was purified by FC on NH column (eluent from Cy to 60% EtOAc) to afford 380 mg further purified by FC on S1O2 column (eluent from 50% Cy to 85% EtOAc+15%MeOH) to afford ethyl 1 ,5-dimethyl-4-(pyrimidin- 2-yl)-1 H-pyrazole-3-carboxylate (p78, 180 mg, y=43%) as white solid.

MS (mlz): 247.0 [MH] +

Preparation 79: lithium 1 ,5-dimethyl-4-(pyrimidin-2-yl)-1 H-pyrazole-3-carboxylate

ethyl 1 ,5-dimethyl-4-(pyrimidin-2-yl)-1 H-pyrazole-3-carboxylate (p78, 180 mg, 0.73 mmol) was dissolved in THF (4 ml_) and water (1 ml_) then lithium hydroxide hydrate (38 mg, 0.88 mmol) was added and the reaction mixture was stirred at RT 4hrs. Then volatiles were removed under vacuum to afford lithium 1 1 ,5-dimethyl-4-(pyrimidin-2-yl)- 1 H-pyrazole-3-carboxylate (p79, 175 mg, y=quant) as white off solid used as such in the next step.

MS (mlz): 247.0 [MH] + Preparation 80: tert-butyl l)-1 ,3-thiazole-4-carbonyl]- 2-azabicyclo[3.1.1]heptan-

2-methyl-5-pyrimidin-2-yl-1 ,3-thiazole-4-carboxylic acid (p19, 71 mg, 0.32 mmol) was dissolved in DMF (2.5 ml_), then HATU (131 mg, 0.34 mmol) and N,N- Diisopropylethylamine (0.1 ml_, 0.63 mmol) were added and the mixture was stirred at RT for 15 min before adding tert-butyl N-({2-azabicyclo[3.1.1 ]heptan-1 - yl}methyl)carbamate (p51 , 65 mg, 0.29 mmol). The resulting solution was stirred at RT 1 h. Then it was diluted with EtOAc and washed several times with NH4CI ss. The organic phase was dried and evaporated, the residue was purified by FC on NH column (eluting from cHex to 50 % EtOAc) to afford tert-butyl N-({2-[2-methyl-5-(pyrimidin-2-yl)- 1 ,3-thiazole-4-carbonyl]-2-azabicyclo[3.1.1 ]heptan-1 -yl}methyl)carbamate (p80, 1 10 mg, y=89%).

MS (mlz): 430.4 [MH] +

Preparation 81 : {2-[2-methyl-5-(pyrimidin-2-yl)-1 ,3-thiazole-4-carbonyl]-2- azabicyclo[3.1.1]heptan-1 -y

tert-butyl N-({2-[2-methyl-5-(pyrimidin-2-yl)-1 ,3-thiazole-4-carbonyl]-2- azabicyclo[3.1 .1]heptan-1 -yl}methyl)carbamate (p80, 1 10 mg, 0.26 mmol) was dissolved in DCM (5 ml_) and Trifluoroacetic acid (0.19 ml_, 2.56 mmol) was added. The resulting solution was stirred at RT for 2 hrs, then volatiles were removed and the residue was purified by SCX eluting withI N NH3 in MeOH, fractions containing the wanted product were evaporated and further purified by FC on NH column (eluting from cHex to 85% EtOAc/15% MeOH ) affording {2-[2-methyl-5-(pyrimidin-2-yl)-1 ,3-thiazole-4-carbonyl]-2- azabicyclo[3.1 .1]heptan-1 -yl}methanamine (p81 , 60 mg, y=71 %) as white solid.

MS (mlz): 330.3 [MH] +

Preparation 82: tert-butyl 1 -ethyn l-2-azabicyclo[3.1.1]heptane-2-carboxylate

To a stirred mixture of tert-butyl 1 -formyl-2-azabicyclo[3.1 .1 ]heptane-2-carboxylate (p12, 200 mg, 0.89 mmol) and K 2 C0 3 (245.4 mg, 1.78 mmol) in Methanol (2.5 ml_), at RT, dimethyl (1 -diazo-2-oxopropyl)phosphonate (0.19 ml_, 1.24 mmol) was added and the resulting reaction mixture was stirred 24 hrs at RT. The mixture was diluted and filtered, the solid was washed with MeOH and the filtrate was concentrated under reduced pressure. The residue was taken up with EA and concentrated ammonium chloride solution. The organic phase was dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by FC on S1O2 column (eluting with Cy/EA from 100/0 to 80/20) affording the product tert-butyl 1 -ethynyl-2-azabicyclo[3.1.1]heptane- 2-carboxylate (p82, 78 mg, y= 40%) as colourless oil.

1 H NMR (CDCU-d) δ 3.85 (t, 2H), 2.38-2.53 (m, 4H), 2.1 1 -2.20 (m, 2H), 1.91 (td, 2H), 1 .48-1 .53 (m, 9H)

Preparation 83: tert-butyl 1 -[2-(4-fluorophenyl)ethynyl]-2-azabicyclo[3.1.1]heptane-2- carboxylate

A vial was charged with tert-butyl 1 -ethynyl-2-azabicyclo[3.1 .1 ]heptane-2-carboxylate (p82, 84 mg, 0.38 mmol), 1 -fluoro-4-iodobenzene (0.09 ml_, 0.760 mmol), Cul (14.46 mg, 0.08 mmol), PPh 3 (43.86 mg, 0.04 mmol) then DMF (2.2 ml_) was added followed by N, N- Diisopropylethylamine (0.31 ml_, 1.9 mmol) and the resulting reaction mixture was shaken ON at RT. The mixture was diluted with ether and a saturated solution of sodium bicarbonate was added. The organic phase was washed with water, dried over sodium sulphate and concentrated under reduced pressure. The crude material was purified by FC on Si0 2 column (eluting with Cy/EA from 100/0 to 75/25) affording tert-butyl 1 -[2-(4- fluorophenyl)ethynyl]-2-azabicyclo[3.1 .1 ]heptane-2-carboxylate (p83, 61 mg, y= 51 %) as dark yellow foam.

MS (mlz): 316.3 [MH] + Preparation 84: tert-butyl 1 -[2-(4-fluorophenyl)ethyl]-2-azabicyclo[3.1.1]heptane-2- carboxylate

tert-butyl 1 -[2-(4-fluorophenyl)ethynyl]-2-azabicyclo[3.1 .1 ]heptane-2-carboxylate (p83, 65 mg, 0.21 mmol) was dissolved in Methanol (9 mL), 10% Pd/C (22 mg, 0.21 mmol) was added and the stirred mixture was submitted to hydrogenation (at atmospheric pressure)

ON. Further 10% Pd/C (21 mg) was added and the mixture was hydrogenated for 8 hrs.

The mixture was filtered and the filtrate concentrated under reduced pressure. The crude material was purified by FC on NH column (eluting with Cy/EA from 100/0 to 80/20) affording tert-butyl 1 -[2-(4-fluorophenyl)ethyl]-2-azabicyclo[3.1 .1 ]heptane-2-carboxylate

(p84, 30 mg, y= 45%) as white wax.

MS (mlz): 320.3 [MH] +

Preparation 85: 1 -[2-(4-fluoro henyl)ethyl]-2-azabicyclo[3.1.1]heptane

To a solution of tert-butyl 1 -[2-(4-fluorophenyl)ethyl]-2-azabicyclo[3.1 .1 ]heptane-2- carboxylate (p84, 30 mg, 0.09 mmol) in DCM (0.30 mL), at RT, trifluoroacetic acid (0.14 mL, 1.88 mmol) was added and the resulting reaction mixture was stirred at RT for 1 .5 h. The mixture was concentrated under reduced pressure then the residue was taken up with DCM and a concentrated solution of NaHC03. The mixture was separated and the filtrate was concentrated under reduce pressure to give 1 -[2-(4-fluorophenyl)ethyl]-2- azabicyclo[3.1.1]heptane (p85, 20 mg, y=97%) as pale yellow wax.

MS {mlz): 220.2 [MH] +

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

The desired alcohol intermediate (p31 -33 and p56 as reported in the table, 1 eq), PP (1.5 eq) and the desired phenol (commercially available, 1.5 eq) were dissolved in THF (-40 vol). The mixture was then cooled to 0 °C and DIAD (1.5 eq) was added dropwise; the ice bath was removed and the mixture was heated to 55 °C and stirred at that temperature for 1-2.5 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 / MeCN + 0.1 % formic acid) to afford the title compound.

GENERAL PROCEDURE B:

A solution of carboxylic acid (p15-16, p19, p23-25, p27-28 or commercially available if not specified in the table; 1.05 eq), HATU (1.3 eq) and N,N-Diisopropylethylamine (2.2 eq) in DMF (1 mL) was stirred at room temperature for 30 min and then added dropwise to a stirring solution of 4-azabicyclo[3.1.1]heptanes (p9 as reported; 1 eq) in DMF (2mL). After 1 h, solvent was partially removed under reduced pressure and residue was partitioned between ss NH4CI (aq) and EtOAc. Organic layer was dried and solvent was removed under reduced pressure. 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 / MeCN + 0.1 % formic acid) to afford the title compound.

GENERAL PROCEDURE C:

A solution of carboxylic acid (p15-16, p19, p23-25, p27-28, p55 or commercially available if not specified in the table; 1.1 eq), HATU (1.2-1.3 eq) and N,N- Diisopropylethylamine (2-2.2 eq) in DMF (40-45 vol) was stirred at room temperature for 15-30 min and then 4-azabicyclo[3.1.1]heptanes (p36, p38, p40, p42, p44, p46, p48-49, p57, p59, p61 , p63 as reported; 1 eq) were added. The resulting solution was stirred at RT from 1 hr to 18 hrs, then it was diluted with EtOAc and washed several times with NH4CI ss. The organic phase was dried and evaporated, and 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 / MeCN + 0.1 % formic acid) to afford the title compound.

GENERAL PROCEDURE D:

To a solution of desired amine (p53 as reported; 1 eq) and the desired aryl halide (commercially available, 1.1 eq) in DMSO (30-35 vol), N,N-Diisopropylethylamine (1 eq) was added. The reaction was stirred at 100° C for 3 hrs. Then it was partitioned between water and EtOAc and the organic phase was washed with brine (x2). The organic layer was dried and evaporated, 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. GENERAL PROCEDURE E:

To a solution of carboxylic acid (p15-16, p19, p23-25, p27-28 or commercially available if not specified in the table; 2 eq) in DCM (~ 38 vol) cooled at 0 °C oxalyl chloride (4 eq) and DMF (1.5 eq) were added. The reaction was allowed to warm to room temperature and stirred for 20 min. This solution was added dropwise to a mixture of desired amine (p36, p38, p40, p42, p44, p46, p48-49 as reported; 1 eq) and TEA (10 eq) in DCM (100 vol), and the resulting reaction mixture was stirred at RT for 4 hrs. The reaction mixture was washed with water. The organic layer was dried and concentrated to dryness. The crude material 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.

GENERAL PROCEDURE F:

Desired amine (p53 as reported; 1 eq), sodium tert-butoxide (2 eq), BINAP (0.1 eq) and aryl halide (commercially available, 1.1 eq) were dissolved in Toluene (28 vol), the mixture was degassed before adding Pd2(dba)3 (0.03 eq). The resulting mixture was heated at 100 °C for 6 hrs. It was diluted with EtOAc and water, the organic phase was dried and evaporated. 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.

aza cyco . . epane

y oxy me y - -aza cyco . . epane

aza cyco . . epane

azabicyclo[3.1.1 ]heptane

y me y soquno n- -amne

y me y pyr n- -amne

aza cyco . . epan- -y me y an ne

aza cyco . . epan- -y me y an ne

aza cyco . . epan- -y me y pyr n- -amne

y me y - - r uorome y pyrazn- -amne

aza cyco . . epan- -y me y an ne

aza cyc o . . ep ane

Example 56:

Compounds of the examples were assayed for their Orexin type 1 and type 2 receptor binding activity using the Scintillation Proximity Assay described above. Results are shown in Table 1.

Table 1 : OXi and OX2 binding and functional antagonist values for representative examples. 0X1 pKi 0X2 pKi

Example

(SPA binding) (SPA binding)

1 8.87 6.8

2 9.15 7.6

3 7.56 5.65

4 8.38 6.59

5 7.84 5.76

6 7.77 5.84

7 7.55 6.84

8 7.47 6.24

9 8.08 6.49

10 7.48 5.76

11 7.31 6.43

12 9.33 7.35

13 9.12 7.12

14 8.18 6.13

15 8.74 7.08

16 8.24 6.27

17 8.36 6.31

18 8.53 6.83

19 7.99 5.83

20 8.95 6.94

21 8.45 7.55

22 8.1 1 6.98

23 7.75 6.52

24 7.86 6.68

25 7.47 5.77

26 7.62 6.15

27 7.55 5.82

28 7.67 6.08

29 8.27 6.74

30 7 5.61

31 7.54 6.52

32 6.98 5.7

33 6.97 5.3

34 7.43 5.71

35 9.22 7.21

36 8.39 6.6

37 9.17 7.31

38 8.47 6.45

39 8.21 6.1

40 8.53 6.91

41 8.24 6.31

42 7.17 5.8

43 8.25 6.78

44 7.05 5.88

45 7.71 6.52

46 7.93 6.44

47 8.67 6.7

48 7.97 6.14

49 7.43 6.59

50 8.2 6.6

51 7.56 5.76 52 9.06 7.28

53 8.44 7.15

54 8.73 7.23

55 7.49 6.04




 
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