Diazabicyclic modulators of monoamine transporters

Abstract

Disclosed are compounds of the formulae (II) and (III), and pharmaceutically acceptable salts thereof: (II) (III) wherein * represents the relative cis- or trans- conformations in formulae (II) and (III) respectively and R1, R2, each R3, each R4, n and m are as defined herein. The compounds are modulators of norepinephrine transporters (NET), dopamine transporters (DAT), serotonin transporters (SERT), sigma-1 receptor (σ1R), muscarinic M1 receptors and / or muscarinic M2 receptors and are expected to be useful in the treatment of pain, neuropsychiatric or neurodegenerative diseases, sleep disorders, as a sedative or as an anaesthetic.

Description

P382113WO 1 COMPOUNDS

[0001] This invention relates to compounds which are modulators of one or more of the dopamine transporter (DAT), the serotonin transporter (SERT), the norepinephrine transporter (NET) and sigma-1 receptor(σ1R), and the use of the compounds in the 5 treatment and prevention of pain, and diseases and conditions associated with neuropsychiatric and neurodegenerative disorders associated with monoamine dysregulation, for example depression, anxiety, panic disorders, attention deficit hyperactivity disorder, psychosis and insomnia. BACKGROUND 10

[0002] Dopamine transporters (DAT), serotonin transporters (SERT) and norepinephrine transporters (NET) are monoamine transporters primarily responsible for controlling the neurotransmission mediated by their respective monoamine substrates, dopamine (DA), serotonin (5-HT) and norepinephrine (NE also known as noradrenaline (NA)). The sigma-1 receptor (σ1R) is a transmembrane protein found in various tissue types, with a notable 15 concentration in specific regions of the central nervous system. It has been linked to numerous conditions and functions, including cardiovascular health, schizophrenia, clinical depression, the impact of substance abuse and bipolar disorder. The sigma-1 receptor (σ1R) does play a role in modulating the monoaminergic systems, which include neurotransmitters like dopamine, serotonin, and norepinephrine. The receptor's activity 20 can influence the release, reuptake, and synthesis of these neurotransmitters, thereby affecting their levels and activity in the brain. This modulation is thought to contribute to the receptor's involvement in various neuropsychiatric conditions, such as schizophrenia, depression, and bipolar disorder.

[0003] Monoamine transporters are targets of a wide range of inhibitors that have been 25 developed as therapeutic treatments for various neuropsychiatric and neurodegenerative disorders such as depression, attention deficit hyperactivity disorder (ADHD) neuropathic pain, anxiety disorders, stimulant use disorders, epilepsy, and Parkinson's disease (Aggarwal & Mortensen, 2023). Preclinical evidence of the role of sigma-1 receptors in pain has led to the development of the first selective sigma-1 antagonist with an intended 30 indication for pain treatment. The sigma-1 receptor (σ1R) is involved in excessive drug and food seeking (Knowles et al., 2023) and cognitive impairment in neuropsychiatric diseases (Albayrak & Hashimoto, 2017).

[0004] The locus coeruleus (LC), a small brainstem nucleus, is the primary source of the neuromodulator norepinephrine (NE) in the brain. Norepinephrine (NE), also known as 35 noradrenaline (NA) originating from the locus coeruleus (LC) sends widespreadP382113WO 2 norepinephrine projections throughout the central nervous system, exerting a global influence on arousal states and adaptive behaviours. The LC plays a pivotal role in modulating both ascending visceral and descending cortical neurocognitive information. Dysregulation of NE signalling via the LC contributes to various neuropsychiatric 5 conditions, including anxiety, insomnia, and is regulated by the activity of the norepinephrine transporter (NET) (Hamon & Plier, 2013).

[0005] Pharmacological inhibition of the LC is a promising target for inhibiting negative memory formation in post-traumatic stress disorders (PTSD), obsessive-compulsive disorders (OCDs) and Tourette syndrome (Alsene & Bakshi, 2011, Giustino et al., 2020). 10

[0006] The LC also plays a crucial role in anxiety, pain perception, sleep disorders (Morris et al., 2020; Van Egroo et al., 2022) and mediates anaesthesia states.

[0007] Dysregulated NE activity through the LC is implicated in neurodegenerative disorders, for example, Alzheimer’s disease (AD) and Parkinson’s disease (PD) (Kula et al., 2021; Krohn et al., 2023, Alsene & Bakshi, 2011). 15

[0008] Cocaine and amphetamines (e.g. methamphetamine, 3,4-methylenedioxy– methamphetamine and cathinones) are NET and / or DAT inhibitors, however these agents increase synaptic neurotransmission leading to stimulatory effects thereby promoting substance abuse and / or addiction. These compounds are also anxiogenic and can result in anxiety, paranoia, social disorders, obsessive behaviour and these effects are 20 particularly pronounced in subjects with pre-existing anxiety or panic disorders such as PTSD. Therefore, there remains a need for alternative monoamine transporter modulators such as NET and / or DAT inhibitors which avoid some or all of the negative side effects associated with cocaine and amphetamines.

[0009] The inventors have identified compounds which inhibit NET and / or DAT and also25 target SERT and sigma-1 receptor (σ1R) and therefore exhibit an atypical non- amphetamine-type neuropharmacology. Acute dosing of the compounds in mice results in sedation, which is not observed with cocaine or amphetamine NET inhibitors. When dosed chronically the compounds exhibit antidepressant-like effects without chronic sedative effects. 30 BRIEF SUMMARY OF THE DISCLOSURE

[0010] In accordance with the present inventions there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof:P382113WO 3wherein X is selected from -CH2-, -CH2CH2- and -CH2CH2CH2-; 5 R1is selected from H, -CN, C1-6 alkyl, C1-6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)2R5, -C(O)R5, -C(O)OR5, -C(O)NR5R6and -SO2NR5R6, wherein said C1-6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; R2is selected from H, -CN, C1-6 alkyl, C1-6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 10 alkenyl, C2-6 alkynyl, Q2, -OR8, -S(O)2R8, -C(O)R8, -C(O)OR8, -C(O)NR8R9and -SO2NR8R9, wherein said C1-6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R10; each R3and each R4is independently selected from halo, =O, C1-6 alkyl and C1-6 haloalkyl; R5and R6are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, 2 to 8 15 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, and Q1, wherein said C1-6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R11; R7and R11are each independently selected from halo, -CN, -OR7A, -S(O)xR7A, -NR7AR7B, C(O)R7A, -OC(O)R7A, -C(O)OR7A, -NR7AC(O)R7B, -C(O)NR7AR7Band Q1; 20 R8and R9are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6alkenyl, C2-6alkynyl, and Q2, wherein said C1-6alkyl, 2 to 8 membered heteroalkyl, C2-6alkenyl and C2-6alkynyl is optionally substituted by one or more R12; R10and R12are each independently selected from halo, -CN, -OR10A, -S(O)xR10A, - 25 NR10AR10B, C(O)R10A, -OC(O)R10A, -C(O)OR10A, -NR10AC(O)R10B, -C(O)NR10AR10Band Q2; each Q1and each Q2is independently selected from C3-6cycloalkyl, 3- to 12-membered heterocyclyl, C6-10aryl and 5- to 10-membered heteroaryl, wherein said C3-6cycloalkyl and 3- to 12-membered heterocyclyl is optionally substituted by one or more R13, andP382113WO 4 wherein said C6-10aryl and 5- to 10-membered heteroaryl is optionally substituted by one or more R14; each R13is independently selected from halo, =O, -CN, -NO2, C1-4alkyl, C1-4haloalkyl, -OR13A, -S(O)xR13A, -NR13AR13B, -C(O)R13A, -OC(O)R13A, -C(O)OR13A, - 5 NR13BC(O)R13A, -C(O)NR13AR13B, -NR13BC(O)OR13A, -OC(O)NR13AR13B, -NR13BSO2R13Aand -SO2NR13AR13B, wherein said C1-4 alkyl is optionally substituted by 1 or 2 substituents selected from halo, -CN, -OR13C, -NR13CR13Dand -S(O)xR13C; each R14is independently selected from halo, -CN, -NO2, C1-4 alkyl, C1-4 haloalkyl, -OR14A, -10 S(O)xR14A, -NR14AR14B, -C(O)R14A, -OC(O)R14A, -C(O)OR14A, -NR14BC(O)R14A, - C(O)NR14AR14B, -NR14BC(O)OR14A, -OC(O)NR14AR14B, -NR14BSO2R14Aand -SO2NR14AR14B, wherein said C1-4 alkyl is optionally substituted by 1 or 2 substituents selected from halo, -CN, -OR14C, -NR14CR14Dand -S(O)xR14C; R7A, R7B, R10A, R10B, R13A, R13B, R13C, R13D, R14A, R14B, R14C, R14Dare at each occurrence 15 independently selected from H, C1-4 alkyl and C1-4 haloalkyl; and wherein any -NR5R6, -NR8R9, -NR7AR7B, -NR10AR10B,-NR13AR13B, -NR13CR13D, - NR14AR14Band -NR14CR14Dwithin a substituent may form a 4- to 6-membered heterocyclyl, wherein said 4- to 6-membered heterocyclyl is optionally substituted by one or more substituents selected from halo, =O, C1-4 alkyl and C1-4 haloalkyl; 20 each x is independently 0, 1 or 2; n is an integer from 0 to 8; and m is an integer from 0 to 4.

[0011] Also provided is a compound of the formula (I) wherein the compound is a cis- isomer of the formula (II) or a trans-isomer of the formula (III), or a pharmaceutically 25 acceptable salt thereof:wherein R1, R2, R3, R4, n and m are as defined for formula (I); and * represents the relative cis- or trans- conformations in formulae (II) and (III) respectively.P382113WO 5

[0012] Also provided is a compound of the formula (I) wherein the compound is of the formula (XVII) or a pharmaceutically acceptable salt thereof:wherein R1, R3, R4, Q2, n and m are as defined for formula (I); and L2is selected 5 from a bond, -CH2-, -C(O)-, -C(O)-CH2-**, -S(O)2-, -S(O)2-CH2-**, wherein ** shows the point of attachment to Q2.

[0013] Also provided is a compound of the formula (I) wherein the compound is of the formula (XXII) or a pharmaceutically acceptable salt thereof:, 10 wherein R1, each R3, each R4, each R14, X, n and m are as defined for formula (I), and p is an integer 0 to 5.

[0014] Also provided is a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 15

[0015] Also provided is a compound of the invention, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0016] Also provided is a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or medical disorder mediated by one or more of a monoamine transporter, sigma-1 receptor (σ1R) and muscarinic receptors 20 (e.g. muscarinic M1 or M3 receptors).

[0017] Also provided is the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment or prevention of a disease or medical disorder mediated by one or more of a monoamine transporter, sigma-1 receptor (σ1R) and muscarinic receptors (e.g. muscarinic M1 or M3 receptors).P382113WO 6

[0018] Also provided is a method of treating a disease or medical disorder mediated by one or more of a monoamine transporter, sigma-1 receptor (σ1R) and muscarinic receptors (e.g. muscarinic M1 or M3 receptors) in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the invention, or a 5 pharmaceutically acceptable salt thereof.

[0019] Also provided is a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease or medical disorder mediated by one or more of a norepinephrine transporter (NET), a dopamine transporter (DAT), and / or a serotonin transporter (SERT) and / or a sigma-1 receptor (σ1R). 10

[0020] In certain embodiments there is provided a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a neuropsychiatric or neurodegenerative disease or medical disorder.

[0021] In certain embodiments there is provided a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of cognitive 15 impairment associated with a neuropsychiatric or neurodegenerative disease or medical disorder.

[0022] In certain embodiments there is provided a compound of the invention, or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a neurodegenerative disease, for example Parkinson's disease, Alzheimer's disease, 20 Huntington's disease, dystonia, amyotrophic lateral sclerosis (ALS), and age-related neurodegeneration.

[0023] In certain embodiments there is provided a compound of the invention, or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of depression (including major depressive disorder (MDD), schizophrenia, bipolar disorder, 25 an anxiety disorder, a panic disorder, attention deficit hyperactivity disorder (ADHD), a post-traumatic stress disorder (PTSD), an obsessive-compulsive disorder (OCD), Tourette syndrome, epilepsy, psychosis (including psychostimulant-induced psychosis), pain (including neuropathic pain) or a sleep disorder (e.g. insomnia).

[0024] Also provided is a compound of the invention for use as a sedative, an 30 anaesthetic or an antinociceptive agent.

[0025] Also provided is a compound of the invention for use in inducing or maintaining anaesthesia in a subject.

[0026] Further therapeutic uses of the compounds of the invention are set out in the Detailed Description.P382113WO 7

[0027] Also provided is a compound library comprising a plurality of compounds of the invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Embodiments of the invention are further described hereinafter with reference to 5 the accompanying drawings, in which: Figure 1A shows the structures of the compounds tested in radioligand binding assays for activity against DAT, NET and SERT. Figure 1B is a bar plot showing the % competition at a compound concentration of 10 µM in radioligand assays against DAT,NET and SERT. The y-axis shows the 10 compound number tested. Figure 1C shows the IC50 of compound (R,R)-1a against NET, DAT, SERT. The sigma-1 receptor (σ1R)is radioligand binding assays measuring competition with [³H] haloperidol. Figure 1D shows the in-vitro activity as % inhibition for compound (R,R)-1a 15 against the targets shown of the y-axis in radioligand binding assays. The % inhibition was measured at a compound concentration of 5 µM.

[0029] Figure 2A, Figure 2B and Figure 2C show the effects of (R,R)-1a in cellular assays in PC12 cells.(A and B) Norepinephrine (NE, Figure 2A) and dopamine (DA, Figure 2B) cellular uptake inhibition assays. NE and DA levels were measured by LC- 20 MS / MS in the assay buffer after 30 min incubation with (R,R)-1a (0.001, 0.1 or 1.0 μM), atomoxetine (10 μM) (“10 atom” in Figures) or (S,S)-1a (10 μM) and DMSO vehicle control and adding 1 μM of NE or DA, respectively, for 60 minutes. Figure 2C shows the comparative effects of 0.1 µM (R,R)-1a, (R,R)-ACA480, (R,R)-ACA481, (R,R)-ACA502, (R,R)-ACA504 and (R,R)-ACA505 compared to 10 µM of atomoxetine (10 atom. in 25 Figure) on DA and NE levels compared to vehicle control upon 120 min incubation with PC12 cells. NE and DA levels were measured by LC-MS / MS. Figure 3 shows the results from a 5-HT uptake assay in PC12 cells with vehicle (DMSO), (R,R)-1a (0.001, 0.1 or 1.0 μM), atomoxetine (10 μM (atom.)) or the enantiomer (S, S)-1a (10 μM). Ordinary one-way analysis of variance (ANOVA) followed by Tukey’s 30 multiple-comparison test. ns, not significant, *P < 0.05, **P < 0.01 and ***P < 0.001. Data were expressed as means ± SD. Figure 4 shows the cellular dopamine (DA) release assay in PC12 cells measured by LC-MS / MS. DA was measured in the assay buffer and normalized to the constitutive secretion. (R, R)-1a (10 μM) was incubated for 24 h and the DA release wasP382113WO 8 then stimulated by adding 59 mM. K+ for 15 min. Experiments show data from at least 3 independent experiments. “B” refers to assay buffer. Figure 5 shows the effects of acute administration of (R,R)-1a (10 or 1 mg / kg, i.p., n=7) in mice compared to control vehicle (n=6). (A) Body temperature decrease. (B) 5 Decreased latency in rotatory rod performance. (C) Decrease in the overall distance travelled and (D) in the zone alteration frequency during the dark / light box test indicative of reduced activity. Figure 6 shows behavioural examination following acute administration of two doses of (R, R)-1a in mice. Behavioural data captured during the light / dark box task: A) 10 Mobility. B) Mean Velocity. C) Time spent in dark and light compartments. D) Meandering. Results displayed as means ± SEM. P<0.05*, P<0.01**, P<0.001***, P<0.0001****. E) Body weight of adult male mice treated acutely with 10 and 1 mg / kg (R, R)-1a (n=7), and control vehicle treated animals (n=6). Figure 7 shows the schedule of drug administration and testing used for chronic 15 dosing in-vivo in mice. Figure 8: shows the results of behavioural examination during a 4-week chronic administration of 0.5 mg / kg (R, R)-1a in mice (5 males and 5 females / treatment group). (A) Body temperature. (B) Body temperature in response to acute administration of 1.0- or 10mg / kg (R, R)-1a on days 19 and 26 (Week 3 and 4), respectively. 20 Figure 9 shows the time spent immobile in the tail suspension assay was unaffected at week 3 and decreased slightly at week 4 following chronic dosing of (R,R)- 1a. Figure 10 shows the observed latency in the rotatory rod performance only slightly decreased in week 1 during chronic dosing of compound (R,R)-1a. 25 Figure 11 shows the mean body weight on days 19 and 26 of chronic dosing of compound (R,R)-1a. Figure 12 shows representative heatmaps of movement in mice treated with compound (R,R)-1a and control groups from light / dark box sessions on days 9 (Week 2) and 24 (Week 4) of chronic dosing. 30 Figure 13 shows behavioural data captured during the light / dark box task shows Distance travelled (A). Mobility (B). Velocity (C). Time spent in dark and light compartments (D). Meandering (E). Figure 14 shows neurotransmitter concentrations in the midbrain following acute treatment of mice with vehicle control (V) or (R,R)-1a (R), measured by LC-MS / MS.P382113WO 9 Results are based on data from two independent LC-MS / MS measurements on each tissue sample. Statistical differences were calculated using the two-tailed unpaired student’s t-test. ns, not significant, *P < 0.05, **P < 0.01 and ***P < 0.001. Data are plotted as means ± SD. 5 Figure 15 shows neurotransmitter concentrations in the brainstem following acute treatment of mice with vehicle control (V) or (R, R)-1a (R), measured by LC-MS / MS. Results are based on data from two independent LC-MS / MS measurements on each tissue sample. Statistical differences were calculated using the two-tailed unpaired student’s t-test. ns, not significant, *P < 0.05, **P < 0.01 and ***P < 0.001. Data are plotted 10 as means ± SD. Figure 16 shows neurotransmitter concentrations in the midbrain region in mice sacrificed after chronic administration of vehicle control (V) or (R,R)-1a (R). Figure 17 shows neurotransmitter concentrations in the brainstem in mice sacrificed after chronic administration of vehicle control (V) or (R,R)-1a (R). 15 Figure 18 shows the concentration (ng / mL) of compound number (R,R)-62 (Example 43, ACA502) over time (hours) in blood following intravenous (i.v.) and per oral (p.o.) to C57BL / 6JRj mice. Figure 19 shows the biodistribution of compound number (R,R)-1a 30 minutes after per oral administration to C57BL / 6JRj mice. 20 Figure 20 shows the biodistribution of compound number (R,R)-62 (Example 43, ACA502) 30 minutes after per oral administration to C57BL / 6JRj mice. Figures 21 and 22 show the X-ray crystal structures of 2b, 3a, 4b, 17a, 1b, 44b and (R,R) -1a confirming the ring fusion stereochemistry. The structures are shown as ORTEP with ellipsoids drawn at the 50% probability level. Hydrogen atoms (white spheres, arbitrary radius) 25 were located in the difference. DETAILED DESCRIPTION Definitions

[0030] Unless otherwise stated, the following terms used in the specification and claims 30 have the following meanings set out below.

[0031] Reference herein to a “compound of the invention” is a reference to any of the compounds disclosed herein including compounds of the formulae (I) to (XXXXXXXI), or a compound described in any of the Examples, or a pharmaceutically acceptable salt, solvate, or salt of a solvate of any thereof.P382113WO 10

[0032] The terms “treating”, or “treatment” refer to any beneficial effect in the treatment or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of 5 degeneration or decline; modifying the progression of a disease or condition, making the final point of degeneration less debilitating; improving a patient’s physical or mental well- being. The treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric examinations, and / or a psychiatric evaluation. The term "treating" and conjugations thereof, includes 10 prevention of an injury, pathology, condition, or disease (i.e., prophylaxis or prevention). For example, the term "treating" and conjugations thereof, include prevention of a pathology, condition, or disease associated with a transporter or receptor disclosed herein(e.g., reducing or preventing symptoms or effects of the disease or condition or preventing or inhibiting progression of the disease or condition). 15

[0033] The term “associated” or “associated with”, “involving” or “mediated by” in the context of a transporter or receptor means that the disease or medical condition is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) by the activity or function of the transporter or receptor. For example, when the transporter is a norepinephrine transporter (NET), reference to a disease or medical condition associated 20 with NET means that the disease is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) by NET activity or function. For example, a symptom of a disease or condition associated with NET may be a symptom that results (entirely or partially) from an increase in the level of activity of NET. A disease or medical disorder associated with NET activity or expression, may be treated with a compound of the 25 invention effective for decreasing the level of activity of NET, inhibiting the function of NET, preventing or inhibiting the expression of the NET and / or degrading the NET. Reference to “associated” or “associated with”, “involving” or “mediated by” is equally applicable to other transporters and receptors described herein such as DAT, SERT, sigma-1 receptor, or muscarinic receptors (e.g. muscarinic M1and / or M2receptors) are to be construed in the 30 same way.

[0034] An “effective amount” is an amount sufficient to accomplish a stated purpose. For example, an amount sufficient to achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce receptor signalling, increase receptor signalling, reduce one or more symptoms of a disease or condition, or to 35 provide a disease modifying effect (i.e. alter the underlying pathophysiology of the disease). An example of an “effective amount” is an amount sufficient to contribute to the treatment,P382113WO 11 prevention, or reduction of a symptom or symptoms of a disease, or modify the progression of a disease, which could also be referred to as a “therapeutically effective amount.” A “reduction” of a symptom or symptoms means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A “prophylactically effective amount” of a 5 drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology, or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic effect does not necessarily occur by administration of one dose and may occur only after 10 administration of a series of doses. Thus, a prophylactically effective amount may be administered in one or more administrations. The exact amounts will depend on the purpose of the treatment and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage 15 Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0035] The therapeutically effective amount of a compound of the invention can be initially estimated from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the therapeutic effect described herein, 20 as measured using the methods described herein or known in the art.

[0036] Therapeutically effective amounts for use in humans can also be determined from animal models using known methods. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compound effectiveness and adjusting the dosage 25 upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.

[0037] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present 30 invention should be sufficient to affect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by 35 small increments until the optimum effect under circumstances is reached.P382113WO 12

[0038] Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated, or in response to a biomarker or other correlate or surrogate end-point of the disease. This will provide a therapeutic regimen that is commensurate with the severity of the individual's 5 disease state.

[0039] A prophylactic or therapeutic treatment regimen is suitably one that does not cause substantial toxicity and yet is effective to treat the clinical symptoms demonstrated by the particular patient. This determination of a dosage regimen is generally based upon an assessment of the active compound by considering factors such as compound potency, 10 relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration and the toxicity profile of the selected agent.

[0040] The term “halo” or “halogen” refers to one of the halogens, group 17 of the periodic table. In particular the term refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to fluorine or chlorine. 15

[0041] The term Cm-n refers to a group with m to n carbon atoms. For the avoidance of doubt, the term C0-n alkylene refers to a group where the alkylene group is absent, i.e. the C0-n group is a bond, or an alkylene group comprising up to ‘n’ number of carbon atoms. Similarly, and by way of example, where y is 0 in compounds according to formula XII, the structure in parentheses between N and Ring B is a bond. 20

[0042] The term “C1-6 alkyl” refers to a linear or branched hydrocarbon chain containing 1, 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. “C1-4 alkyl” similarly refers to such groups containing up to 4 carbon atoms. Alkylene groups are divalent alkyl groups and may likewise be linear or branched and have two points of attachment to the remainder of the molecule. 25 Furthermore, an alkylene group may, for example, correspond to one of those alkyl groups listed in this paragraph. For example, C1-6alkylene may be –CH2-, -CH2CH2-, -CH2CH(CH3)- , -CH2CH2CH2- or -CH2CH(CH3)CH2-. The alkyl and alkylene groups may be unsubstituted or substituted by one or more substituents. Possible substituents are described herein. For example, substituents for an alkyl or alkylene group may be halogen, e.g. fluorine, chlorine, 30 bromine and iodine, OH, C1-C4alkoxy, -NR’R’’ amino, wherein R’ and R’’ are independently H or alkyl. Other substituents for the alkyl group may alternatively be used.

[0043] The term “C1-6haloalkyl”, e.g., “C1-4haloalkyl”, refers to a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence, for example fluorine, chlorine, bromine, and iodine. The halogen atom may be present at any 35 position on the hydrocarbon chain. For example, C1-6haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl e.g., 1-chloromethyl and 2-chloroethyl,P382113WO 13 trichloroethyl e.g., 1,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl e.g., 1-fluoromethyl and 2-fluoroethyl, trifluoroethyl e.g., 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl. A haloalkyl group may be, for example, -CX3, -CHX2, -CH2CX3,-CH2CHX2or -CX(CH3)CH3wherein X is a halo (e.g., F, Cl, 5 Br, or I). A fluoroalkyl group, i.e., a hydrocarbon chain substituted with at least one fluorine atom (e.g., -CF3, -CHF2, -CH2CF3 or -CH2CHF2).

[0044] The term “heteroalkyl,” refers to a stable linear or branched chain alkyl, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may 10 optionally be quaternized. The heteroatom(s) (e.g., N, S, Si, or P) may be placed at any interior position of the heteroalkyl group. The heteroalkyl is a non-cyclic group. “2 to 8 membered heteroalkyl” refers to a heteroalkyl in which there are a total of 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms and heteroatoms (e.g., O, N, P, Si, and S) in the heteroalkyl group. Examples include, but are not limited to: -CH2-O-CH3,-CH2-CH2-O-CH3, -CH2-NH-CH3,-CH2- 15 CH2-NH-CH3, -CH2-N(CH3)-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -CH2-S(O)-CH3, -CH2-S(O)2-CH3, -CH2-CH2-S-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH2-CH=N- OCH3, Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH- OCH3 and -CH2-O-Si(CH3)3. A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, 20 N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P).

[0045] The term “C2-6 alkenyl” includes a branched or linear hydrocarbon chain containing at least one double bond and having 2, 3, 4, 5 or 6 carbon atoms. The double bond(s) may 25 be present as the E or Z isomer. The double bond may be at any possible position of the hydrocarbon chain. For example, the “C2-6alkenyl” may be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl. Alkenylene groups are divalent alkenyl groups and may likewise be linear or branched and have two points of attachment to the remainder of the molecule. Furthermore, an alkenylene group may, for example, 30 correspond to one of those alkenyl groups listed in this paragraph. For example, alkenylene may be –CH=CH-, -CH2CH=CH-, -CH(CH3)CH=CH- or -CH2CH=CH-. Alkenyl and alkenylene groups may be unsubstituted or substituted by one or more substituents. Possible substituents are described herein. For example, substituents may be those described above as substituents for alkyl groups. 35

[0046] The term “C2-6alkynyl” includes a branched or linear hydrocarbon chain containing at least one triple bond and having 2, 3, 4, 5 or 6 carbon atoms. The triple bond may be atP382113WO 14 any possible position of the hydrocarbon chain. For example, the “C2-6alkynyl” may be ethynyl, propynyl, butynyl, pentynyl and hexynyl. Alkynylene groups are divalent alkynyl groups and may likewise be linear or branched and have two points of attachment to the remainder of the molecule. Furthermore, an alkynylene group may, for example, correspond 5 to one of those alkynyl groups listed in this paragraph. For example, alkynylene may be – C≡C-, -CH2C≡C-, -CH2C≡CCH2-, -CH(CH3)CH≡C- or -CH2C≡CCH-. Alkynyl and alkynylene groups may be unsubstituted or substituted by one or more substituents. Possible substituents are described herein. For example, substituents may be those described above as substituents for alkyl groups. 10

[0047] The term “C3-6 cycloalkyl” includes a saturated hydrocarbon ring system containing 3, 4, 5 or 6 carbon atoms. For example, the “C3-C6 cycloalkyl” may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.1.1]hexane or bicyclo[1.1.1]pentane. Suitably the “C3-C6 cycloalkyl” may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0048] The term “heterocyclyl”, “heterocyclic” or “heterocycle” includes a non-aromatic 15 saturated or partially saturated monocyclic or fused, bridged, or spiro bicyclic heterocyclic ring system. Monocyclic heterocyclic rings may contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Bicyclic heterocycles may contain from 7 to 12-member atoms in the ring. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems. The20 heterocyclyl group may be a 3-12, for example, a 3- to 9- (e.g. a 3- to 7-) membered non- aromatic monocyclic or bicyclic saturated or partially saturated group comprising 1, 2 or 3 heteroatoms independently selected from O, S and N in the ring system (in other words 1, 2 or 3 of the atoms forming the ring system are selected from O, S and N). By partially saturated it is meant that the ring may comprise one or two double bonds. This applies 25 particularly to monocyclic rings with from 5 to 7 members. The double bond will typically be between two carbon atoms but may be between a carbon atom and a nitrogen atom. Bicyclic systems may be spiro-fused, i.e. where the rings are linked to each other through a single carbon atom; vicinally fused, i.e. where the rings are linked to each other through two adjacent carbon and / or nitrogen atoms; or they may share a bridgehead, i.e. the rings are 30 linked to each other through two non-adjacent carbon or nitrogen atoms (a bridged ring system). Examples of heterocyclic groups include cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Heterocycles comprising at least one nitrogen in a ring position include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, 35 tetrahydropyridinyl, homopiperidinyl, homopiperazinyl, 2,5-diaza-bicyclo[2.2.1]heptanyl and the like. Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol,P382113WO 15 tetrahydro-2H-thiopyran, and hexahydrothiepine. Other heterocycles include dihydro oxathiolyl, tetrahydro oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydro oxazinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. 5 For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1,1-dioxide and thiomorpholinyl 1,1-dioxide. A suitable value for a heterocyclyl group which bears 1 or 2 oxo (=O), for example, 2 oxopyrrolidinyl, 2-oxoimidazolidinyl, 2-oxopiperidinyl, 2,5- 10 dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, 15 homopiperidinyl, piperazinyl or homopiperazinyl. As the skilled person will appreciate, any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom. For example, the term “piperidino” or “morpholino” refers to a piperidin-1-yl or morpholin-4-yl ring that is linked via the ring nitrogen.

[0049] The term “bridged ring systems” includes ring systems in which two rings share more 20 than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 131-133, 1992. Suitably the bridge is formed between two non- adjacent carbon or nitrogen atoms in the ring system. The bridge connecting the bridgehead atoms may be a bond or comprise one or more atoms. Examples of bridged heterocyclyl ring systems include, aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza- 25 bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane, and quinuclidine.

[0050] The term “spiro bi-cyclic ring systems” includes ring systems in which two ring systems share one common spiro carbon atom, i.e., the heterocyclic ring is linked to a further carbocyclic or heterocyclic ring through a single common spiro carbon atom. Examples of spiro ring systems include 3,8-diaza-bicyclo[3.2.1]octane, 2,5-diaza-bicyclo[2.2.1]heptane,30 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 2-oxa-6- azaspiro[3.3]heptane, 6-oxa-2-azaspiro[3.4]octane, 2,7-diaza-spiro[4.4]nonane, 2- azaspiro[3.5]nonane, 2-oxa-7-azaspiro[3.5]nonane and 2-oxa-6-azaspiro[3.5]nonane.

[0051] “Heterocyclyl-Cm-nalkyl” includes a heterocyclyl group covalently attached to a Cm-nalkylene group, both of which are defined herein; and wherein the Heterocyclyl-Cm-nalkyl 35 group is linked to the remainder of the molecule via a carbon atom in the alkylene group.P382113WO 16 The groups “aryl-Cm-nalkyl”, “heteroaryl-Cm-nalkyl” and “cycloalkyl-Cm-nalkyl” are defined in the same way.

[0052] “-Cm-nalkyl substituted by –NRR” and “Cm-nalkyl substituted by –OR” similarly refer to an –NRR’’ or –OR’’ group covalently attached to a Cm-nalkylene group and wherein the 5 group is linked to the remainder of the molecule via a carbon atom in the alkylene group.

[0053] The term “aromatic” when applied to a substituent as a whole includes a single ring or polycyclic ring system with 4n + 2 electrons in a conjugated π system within the ring or ring system where all atoms contributing to the conjugated π system are in the same plane.

[0054] The term “aryl” includes an aromatic hydrocarbon ring system. The ring system has 10 4n +2 electrons in a conjugated π system within a ring where all atoms contributing to the conjugated π system are in the same plane. An aryl may be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. For example, the “aryl” may be a C6-12 aryl, suitably phenyl 15 or naphthyl. The aryl system itself may be substituted with other groups. The term “aryl” also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring.

[0055] The term “heteroaryl” includes an aromatic mono- or bicyclic ring incorporating one 20 or more (for example 1-4, particularly 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. The ring or ring system has 4n + 2 electrons in a conjugated π system where all atoms contributing to the conjugated π system are in the same plane.

[0056] Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members. The heteroaryl 25 group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings, also referred to as a “fused bicyclic heteroaryl”. Bicyclic heteroaryl groups can be vicinally fused, i.e., where the rings are linked to each other through two adjacent carbon and / or nitrogen atoms. Each ring may contain up to about four 30 heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically, the heteroaryl ring will contain up to 4, for example up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. 35 In general, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.P382113WO 17

[0057] Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, 5 purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 1H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-b][1,2,4]triazinyl, imidazo[1,2-a]pyridine, imidazo[1,2-a]pyrazine, imidazo[1,2- 10 a]pyrimidine, imidazo[1,2-b]pyridazine, triazolo[1,5-a]pyridine, [1,2,3]triazolo[1,5-a]pyridine,. Examples of heteroaryl groups comprising at least one nitrogen in a ring position include pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazenyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, 15 purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl and pteridinyl.

[0058] “Heteroaryl” also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring, provided at least one ring contains one or more 20 heteroatoms selected from nitrogen, oxygen or sulfur. Partially aromatic heteroaryl bicyclic ring systems can be vicinally fused, i.e., where the rings are linked to each other through two adjacent carbon and / or nitrogen atoms. Examples of partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4- tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 1,3-dihydroisobenzofuran, 25 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl, 2,2-dioxo-1,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, 1,2,3,4-tetrahydro-1,8-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl and 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazinyl.

[0059] Examples of five-membered heteroaryl groups include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, 30 isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

[0060] Examples of six-membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0061] Particular examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include but are not limited to benzofuranyl, benzothiophenyl, 35 benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,P382113WO 18 isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, pyrrolopyridine, and pyrazolopyridinyl groups.

[0062] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, 5 chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.

[0063] The term “oxo,” or “=O” as used herein, means an oxygen that is double bonded to the atom to which is it attached (e.g. a carbon atom or a sulfur atom). 10

[0064] The term "optionally substituted" includes either groups, structures, or molecules that are substituted and those that are not substituted.

[0065] Where optional substituents are chosen from “one or more” groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups, 15 which may be the same or different. For example, “one or more optional substituents” may refer to 1 or 2 or 3 substituents (e.g.1 substituent or 2 substituents).

[0066] Where a moiety is substituted, it may be substituted at any point on the moiety where chemically possible and consistent with atomic valency requirements. The moiety may be substituted by one or more substituents, e.g., 1, 2, 3 or 4 substituents; optionally there are 20 1 or 2 substituents on a group. Where there are two or more substituents, the substituents may be the same or different.

[0067] Substituents are only present at positions where they are chemically possible, the person skilled in the art being able to decide (either experimentally or theoretically) without undue effort which substitutions are chemically possible and which are not. 25

[0068] It is to be understood that the R4substituent(s) in the compounds of the invention may be present on any carbon atom in the left-hand ring containing the group X, including carbon atoms in the group X. The R3substituent(s) may be present on any carbon in the right-hand azepane ring.

[0069] Ortho, meta and para substitution are well understood terms in the art. For the 30 absence of doubt, “ortho” substitution is a substitution pattern where adjacent carbons possess a substituent, whether a simple group, for example the fluoro group in the example below, or other portions of the molecule, as indicated by the bond ending in “”:P382113WO 19.

[0070] “Meta” substitution is a substitution pattern where two substituents are on carbons one carbon removed from each other, i.e., with a single carbon atom between the substituted carbons. In other words, there is a substituent on the second atom away from the atom with 5 another substituent. For example, the groups below are meta substituted:.

[0071] “Para” substitution is a substitution pattern where two substituents are on carbons two carbons removed from each other, i.e., with two carbon atoms between the substituted carbons. In other words, there is a substituent on the third atom away from the atom with 10 another substituent. For example, the groups below are para substituted:.

[0072] Any R3group in a compound of the invention is located on the azepane ring containing the NR2group. Any R4group in a compound of the invention (when present) is located on the ring containing X. 15

[0073] Reference to a -NRR’ group forming a 4 to 6 membered heterocyclyl refers to R and R’ together with the nitrogen atom to which they are attached forming a 4 to 6 membered heterocyclyl group. For example, a -NR7R8, -NR4AR4B, and -NR9AR9Bgroup may form:. Similarly, a -NRR’ group within a substituent may form a carbonyl-linked 4 to 6 membered 20 heterocyclyl, for example a -C(O)NRR’group may form:-NRR’ groups within substituents such as -OC(O)NRR’, -SO2NRR’, or -NRC(O)NRR’, may similarly form a 4 to 6 membered heterocyclyl within such substituents.P382113WO 20

[0074] For the avoidance of doubt, the R3substituents, when present, are located on the 7-membered ring containing the N(R2) group. The R4substituents (when present) are located on the ring containing the NR1group. The R4substituents may be present at any location on the ring containing the NR1group, including X. Thus, one or more hydrogen 5 atom in an X group may be independently substituted by an R4group.

[0075] A bond terminating in a “”, i.e. “ ”, represents that the bond is connectedto another atom that is not shown in the structure. A bond terminating inside a cyclic structure and not terminating at an atom of the ring structure represents that the bond may be connected to any of the atoms in the ring structure where allowed by valency, unless 10 stated otherwise herein.

[0076] The various functional groups and substituents making up the compounds of the present invention are typically chosen such that the molecular weight of the compound does not exceed 750. More usually, the molecular weight of the compound will be less than 700 fore example less than 650, or less than 600, less than 550 or preferably less than 500. 15

[0077] Suitable or preferred features of any compounds of the present invention may also be suitable features of any other aspect.

[0078] The invention contemplates pharmaceutically acceptable salts of the compounds of the invention. These may include the acid addition and base salts of the compounds. These may be acid addition and base salts of the compounds. 20

[0079] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate,25 malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 1,5- naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.

[0080] Suitable base salts are formed from bases which form non-toxic salts. Examples 30 include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts. For a review on suitable salts, see "Handbook of Pharmaceutical Salts:P382113WO 21 Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0081] Pharmaceutically acceptable salts of compounds of the invention may be prepared by for example, one or more of the following methods: 5 (i) by reacting the compound of the invention with the desired acid or base; (ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of the invention or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) by converting one salt of the compound of the invention to another by reaction with an 10 appropriate acid or base or by means of a suitable ion exchange column.

[0082] These methods are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non- ionised. 15

[0083] In so far as the compounds of the invention are able to form N-oxides, such N-oxide compounds are also considered to form part of the invention.

[0084] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed 20 “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterised by the absolute configuration of its asymmetric centre and is described by the 25 R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”. Where a compound of the invention has two or more stereo centres any 30 combination of (R) and (S) stereoisomers is contemplated. The combination of (R) and (S) stereoisomers may result in a diastereomeric mixture or a single diastereoisomer. The compounds of the invention may be present as a single stereoisomer or may be mixtures of stereoisomers, for example racemic mixtures and other enantiomeric mixtures, and diasteroemeric mixtures. Where the mixture is a mixture of enantiomers the enantiomeric 35 excess may be any of those disclosed above. Where the compound is a single stereoisomer,P382113WO 22 the compounds may still contain other diasteroisomers or enantiomers as impurities. Hence a single stereoisomer does not necessarily have an enantiomeric excess (e.e.) or diastereomeric excess (d.e.) of 100% but could have an e.e. or d.e. of about at least 85%, for example at least 90%, at least 95%, at least 99%, or at least 99.9%. 5

[0085] The compounds of this invention may possess one or more asymmetric centres; such compounds can therefore be produced as individual (R) or (S) stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of 10 stereochemistry and the separation of stereoisomers are well known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof. 15

[0086] The compounds of the invention have geometric isomeric centres (cis- and trans - isomers). In some embodiments a compound of the invention may be represented with relative cis- or trans- conformation. A “*” or “(±)” indicates a compound is represented by relative cis- or trans- conformation as in, for example, the cis- compound of the formula (II):20 wherein the compound comprises a mixture (e.g. a racemic mixture) of the (R,R) and (S,S) cis-enantiomers. Similarly compounds of the formula (III) show compounds with a relative trans- conformation and includes a mixture (including a racemic mixture) of the (S,R) and (R,S) trans-enantiomers. Accordingly, it is to be understood that cis- compound of formula (II) encompasses the individual cis-enantiomers and that the trans- compound of formula 25 (III) encompasses the individual trans-enantiomers. Also disclosed herein and in the Examples are compounds in the absolute cis- or trans- conformation. Such compounds are shown without “*” or “(±)”. Thus, by way of an example the compound (±) 1a refers to a compound with relative cis-conformation (4-benzyldecahydropyrrolo[3,2-b]azepine ((±)- 1a):P382113WO 23whereas the compound (R,R)-1a refers to the (R,R)-cis enantiomer ((3aR,8aR)-4- benzyldecahydropyrrolo[3,2-b]azepine ((R,R)-1a): 5

[0087] Z / E and cis / trans isomers may be separated by, for example, chromatography and fractional crystallisation.

[0088] Known techniques for the preparation / isolation of individual enantiomers, when necessary, include chiral synthesis from a suitable optically pure precursor or resolution of 10 the racemate (e.g. the separation of the cis-enantiomers of the compound of formula (II), or the trans-enantiomers of the trans-compound of formula (III)) using, for example, chiral high- pressure liquid chromatography (HPLC).

[0089] Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of 15 the invention contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and / or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.

[0090] When any racemate crystallises, crystals of two different types are possible. The 20 first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.P382113WO 24

[0091] While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, “Stereochemistry of Organic Compounds” by E. L. Eliel and S. H. 5 Wilen (Wiley, 1994).

[0092] Compounds and salts described in this specification may be isotopically-labelled (or “radio-labelled”). Accordingly, one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of radionuclides that may be incorporated include2H (also written as “D” 10 for deuterium),3H (also written as “T” for tritium),11C,13C,14C,15O,17O,18O,13N,15N,18F, 36Cl,123I,25I,32P,35S and the like. The radionuclide that is used will depend on the specific application of that radio-labelled derivative. For example, for in vitro competition assays,3H or14C are often useful. For radio-imaging applications,11C or18F are often useful. In some embodiments, the radionuclide is3H. In some embodiments, the radionuclide is14C. In 15 some embodiments, the radionuclide is11C. And in some embodiments, the radionuclide is 18F.

[0093] Isotopically-labelled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described using an appropriate isotopically-labelled reagent in place of the non-labelled reagent 20 previously employed.

[0094] The selective replacement of hydrogen with deuterium in a compound may modulate the metabolism of the compound, the PK / PD properties of the compound and / or the toxicity of the compound. For example, deuteration may increase the half-life or reduce the clearance of the compound in vivo. Deuteration may also inhibit the formation of toxic 25 metabolites, thereby improving safety and tolerability. It is to be understood that the invention encompasses deuterated derivatives of compounds described herein. As used herein, the term deuterated derivative refers to compounds of the invention where in a particular position at least one hydrogen atom is replaced by deuterium. Accordingly, in a compound of the invention one or more hydrogen atom is optionally replaced by deuterium. 30 For example, one or more hydrogen atoms in a C1-4-alkyl group may be replaced by deuterium to form a deuterated C1-4-alkyl group.

[0095] Certain compounds of the invention may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms. 35

[0096] It is also to be understood that certain compounds of the invention may exhibit polymorphism, and that the invention encompasses all such forms.P382113WO 25

[0097] Compounds of the invention may exist in a number of different tautomeric forms and references to compounds of the invention include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by compounds of the 5 invention. Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci- nitro.keto enol enolate10

[0098] The in vivo effects of a compound of the invention may be exerted in part by one or more metabolites that are formed within the human or animal body after administration of a compound of the invention.

[0099] It is further to be understood that a suitable pharmaceutically-acceptable pro-drug of a compound of the formula (I) also forms an aspect of the present invention. Accordingly, 15 the compounds of the invention encompass pro-drug forms of the compounds and the compounds of the invention may be administered in the form of a pro-drug (i.e., a compound that is broken down in the human or animal body to release a compound of the invention). A pro-drug may be used to alter the physical properties and / or the pharmacokinetic properties of a compound of the invention. A pro-drug can be formed when the compound 20 of the invention contains a suitable group or substituent to which a property-modifying group can be attached. Examples of pro-drugs include in vivo-cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the invention and in vivo- cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the invention. 25

[0100] Accordingly, the present invention includes those compounds of the invention as defined herein when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the formula (I) that are produced by organic synthetic means and also such compounds that are produced in the human or animal body 30 by way of metabolism of a precursor compound, that is a compound of the formula (I) may be a synthetically-produced compound or a metabolically-produced compound.

[0101] A suitable pharmaceutically-acceptable pro-drug of a compound of the invention is one that is based on reasonable medical judgement as being suitable forP382113WO 26 administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.

[0102] Various forms of pro-drug have been described, for example in the following documents:- 5 a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 10 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. 15 Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0103] A suitable pharmaceutically-acceptable pro-drug of a compound of the formula (I) that possesses a carboxy group is, for example, an in vivo-cleavable ester 20 thereof. An in vivo-cleavable ester of a compound of the invention containing a carboxy group is, for example, a pharmaceutically-acceptable ester which is cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically-acceptable esters for carboxy include C1-6 alkyl esters such as methyl, ethyl and tert-butyl, C1-6 alkoxymethyl esters such as methoxymethyl esters, C1-6 alkanoyloxymethyl esters such as pivaloyloxymethyl 25 esters, 3-phthalidyl esters, C3-8cycloalkylcarbonyloxy- C1-6alkyl esters such as cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters, 2-oxo-1,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl esters and C1-6alkoxycarbonyloxy- C1-6alkyl esters such as methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl esters. 30

[0104] A suitable pharmaceutically-acceptable pro-drug of a compound of the invention that possesses a hydroxy group is, for example, an in vivo-cleavable ester or ether thereof. An in vivo-cleavable ester or ether of a compound of the invention containing a hydroxy group is, for example, a pharmaceutically-acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. SuitableP382113WO 27 pharmaceutically-acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically-acceptable ester forming groups for a hydroxy group include C1-10alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl 5 groups, C1-10 alkoxycarbonyl groups such as ethoxycarbonyl, N,N–(C1-6 alkyl)2carbamoyl, 2- dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-4 alkyl)piperazin-1- ylmethyl. Suitable pharmaceutically-acceptable ether forming groups for a hydroxy group 10 include ^-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0105] A suitable pharmaceutically-acceptable pro-drug of a compound of the invention that possesses a carboxy group is, for example, an in vivo-cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C1-4 alkylamine such as methylamine, a (C1-4 alkyl)2amine such as dimethylamine, N-ethyl-N-methylamine 15 or diethylamine, a C1-4 alkoxy- C2-4 alkylamine such as 2-methoxyethylamine, a phenyl-C1-4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

[0106] A suitable pharmaceutically-acceptable pro-drug of a compound of the invention that possesses an amino group is, for example, an in vivo-cleavable amide or carbamate derivative thereof. Suitable pharmaceutically-acceptable amides from an amino 20 group include, for example an amide formed with C1-10 alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-4 alkyl)piperazin-1-ylmethyl. Suitable pharmaceutically-acceptable carbamates from 25 an amino group include, for example acyloxyalkoxycarbonyl and benzyloxycarbonyl groups.

[0107] Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of them mean “including but not limited to”, and they are not intended to (and do not) exclude other moieties, additives, components, integers, or steps. Throughout the description and claims of this specification, the singular encompasses the 30 plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0108] Features, integers, characteristics, compounds, chemical moieties, or groups described in conjunction with a particular aspect, embodiment or example of the invention 35 are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in thisP382113WO 28 specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention 5 extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0109] The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and 10 which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference. COMPOUNDS

[0110] The following paragraphs are applicable to the compounds of the invention, including compounds of the formulae (I) to (XXXXXXXI), or a pharmaceutically acceptable 15 salt thereof.

[0111] In certain embodiments the compound of the invention is a cis-isomer of the formula (II), or a pharmaceutically acceptable salt thereof:wherein R1, R2, each R3, each R4, n and m are as defined herein, and * represents the 20 relative cis- conformation. Suitably in this embodiment X is -CH2- or -CH2CH2-.

[0112] In certain embodiments the compound of formula (I) is a compound of the formula (IV), or a pharmaceutically acceptable salt thereof:wherein R1, R2, each R3, each R4, n and m are as defined for formula (I), and * represents 25 the relative cis- conformation.

[0113] In certain embodiments the compound of formula (I) is a compound of the formula (V), or a pharmaceutically acceptable salt thereof:P382113WO 29wherein R1, R2, each R3, each R4, n and m are as defined for formula (I), and * represents the relative cis- conformation.

[0114] In certain embodiments the compound of formula (I) is a compound of the formula 5 (VI), or a pharmaceutically acceptable salt thereof:wherein R1, R2, each R3, each R4, n and m are as defined for formula (I). Suitably in this embodiment X is -CH2- or -CH2CH2-.

[0115] In certain embodiments the compound of formula (I) is a compound of the formula 10 (VII), or a pharmaceutically acceptable salt thereof:wherein R1, R2, each R3, each R4, n and m are as defined for formula (I).

[0116] In certain embodiments the compound of formula (I) is a compound of the formula (VIII), or a pharmaceutically acceptable salt thereof: 15wherein R1, R2, each R3, each R4, n and m are as defined for formula (I).

[0117] In certain embodiments the compound of formula (I) is a compound of the formula (VIX), or a pharmaceutically acceptable salt thereof:P382113WO 30wherein R1, R2, each R3, each R4, n and m are as defined for formula (I).

[0118] In certain embodiments the compound of formula (I) is a trans-isomer of the formula (III), or a pharmaceutically acceptable salt thereof: 5wherein R1, R2, each R3, each R4, n and m are as defined for formula (I), and * represents the relative trans- conformation.

[0119] In certain embodiments the compound of formula (I) is a compound of the formula (X), or a pharmaceutically acceptable salt thereof: 10wherein R1, R2, each R3, each R4, n and m are as defined for formula (I), and * represents the relative trans- conformation.

[0120] In certain embodiments the compound of formula (I) is a compound of the formula (XI), or a pharmaceutically acceptable salt thereof: 15wherein R1, R2, each R3, each R4, n and m are as defined for formula (I), and * represents the relative trans- conformation.P382113WO 31

[0121] In certain embodiments the compound of formula (I) is a compound of the formula (XII), or a pharmaceutically acceptable salt thereof:wherein R1, R2, each R3, each R4, n and m are as defined for formula (I), and * represents 5 the relative trans- conformation.

[0122] In certain embodiments the compound of formula (I) is a compound of the formula (XII), or a pharmaceutically acceptable salt thereof:wherein R1, R2, each R3, each R4, n and m are as defined for formula (I). 10

[0123] In certain embodiments the compound of formula (I) is a compound of the formula (XIII), or a pharmaceutically acceptable salt thereof:wherein R1, R2, each R3, each R4, n and m are as defined for formula (I).

[0124] In certain embodiments the compound of formula (I) is a compound of the formula 15 (XIV), or a pharmaceutically acceptable salt thereof:wherein R1, R2, each R3, each R4, n and m are as defined for formula (I).P382113WO 32

[0125] In certain embodiments the compound of formula (I) is a compound of the formula (XV), or a pharmaceutically acceptable salt thereof:wherein R1, R2, each R3, each R4, n and m are as defined for formula (I). 5

[0126] In certain embodiments the compound of formula (I) is a compound of the formula (XVI), or a pharmaceutically acceptable salt thereof:wherein R1, R2, each R3, each R4, n and m are as defined for formula (I).

[0127] In certain embodiments the compound of the formula (I) is a compound of the 10 formula (XVII), or a pharmaceutically acceptable salt thereof:wherein R1, each R3, each R4, Q2, X, n and m are as defined for formula (I); and L2is selected from a bond, -CH2-, -C(O)-, -C(O)-CH2-**, -S(O)2-, -S(O)2-CH2-**, wherein ** shows the point of attachment to Q2. 15

[0128] In certain embodiments the compound of formula (I) is a compound of the formula (XVIII), or a pharmaceutically acceptable salt thereof:P382113WO 33 wherein R1, each R3, each R4, Q2, X, n and m are as defined for formula (I); and L2is selected from a bond, -CH2-, -C(O)-, -C(O)-CH2-**, -S(O)2-, -S(O)2-CH2-**, wherein ** shows the point of attachment to Q2, and * represents the relative cis- conformation. Suitably in this embodiment X is -CH2- or -CH2CH2-. In certain embodiments X is - 5 CH2CH2CH2-.

[0129] In certain embodiments the compound of formula (I) is a compound of the formula (XIX), or a pharmaceutically acceptable salt thereof:wherein R1, each R3, each R4, Q2, X, n and m are as defined for formula (I); and L2is 10 selected from a bond, -CH2-, -C(O)-, -C(O)-CH2-**, -S(O)2-, -S(O)2-CH2-**, wherein ** shows the point of attachment to Q2, and * represents the relative trans- conformation.

[0130] In certain embodiments the compound of formula (I) is a compound of the formula (XX), or a pharmaceutically acceptable salt thereof:15 wherein R1, each R3, each R4, Q2, X, n and m are as defined for formula (I); and L2is selected from a bond, -CH2-, -C(O)-, -C(O)-CH2-**, -S(O)2-, and -S(O)2-CH2-**, wherein **is the point of attachment to Q2. Suitably in this embodiment X is -CH2- or -CH2CH2-. In certain embodiments X is -CH2CH2CH2-.

[0131] In certain embodiments the compound of formula (I) is a compound of the formula 20 (XXI), or a pharmaceutically acceptable salt thereof:P382113WO 34 wherein R1, each R3, each R4, Q2, X, n and m are as defined for formula (I); and L2is selected from a bond, -CH2-, -C(O)-, -C(O)-CH2-**, -S(O)2-, -S(O)2-CH2-**, wherein ** is the point of attachment to Q2.

[0132] In certain embodiments the compound of formula (I) is a compound of the formula 5 (XXII), or a pharmaceutically acceptable salt thereof:wherein R1, each R3, each R4, each R14, X, n and m are as defined for formula (I), and p is an integer 0 to 5.

[0133] In certain embodiments the compound of formula (I) is a compound of the formula 10 (XXIII), or a pharmaceutically acceptable salt thereof:wherein R1, each R3, each R4, each R14, X, n and m are as defined for formula (I), p is an integer 0 to 5, and * represents the relative cis- conformation. Suitably in this embodiment X is -CH2- or -CH2CH2-. In certain embodiments X is -CH2CH2CH2-. 15

[0134] In certain embodiments the compound of formula (I) is a compound of the formula (XXIV), or a pharmaceutically acceptable salt thereof:wherein R1, each R3, each R4, each R14, X, n and m are as defined for formula (I), p is an integer 0 to 5, and * represents the relative trans- conformation.P382113WO 35

[0135] In certain embodiments the compound of formula (I) is a compound of the formula (XXV), or a pharmaceutically acceptable salt thereof:, wherein R1, each R3, each R4, each R14, X, n and m are as defined for formula (I), and 5 p is an integer 0 to 5. Suitably in this embodiment X is -CH2- or -CH2CH2-. In certain embodiments X is -CH2CH2CH2-.

[0136] In certain embodiments the compound of formula (I) is a compound of the formula (XXVI), or a pharmaceutically acceptable salt thereof:10 wherein R1, each R3, each R4, each R14, X, n and m are as defined for formula (I), and p is an integer 0 to 5.

[0137] In certain embodiments the compound of formula (I) is a compound of the formula (XXVII), or a pharmaceutically acceptable salt thereof:15 wherein R1, each R3, each R4, each R14, n and m are as defined for formula (I), and p is an integer 0 to 5.

[0138] In certain embodiments the compound of formula (I) is a compound of the formula (XXVIII), or a pharmaceutically acceptable salt thereof:P382113WO 36wherein R1, each R3, each R4, each R14, n and m are as defined for formula (I), and p is an integer 0 to 5.

[0139] In certain embodiments the compound of formula (I) is a compound of the formula 5 (XXIX), or a pharmaceutically acceptable salt thereof:wherein R1, each R3, each R4, each R14, n and m are as defined for formula (I), and p is an integer 0 to 5.

[0140] In certain embodiments the compound of formula (I) is a compound of the formula 10 (XXX), or a pharmaceutically acceptable salt thereof:wherein R1, each R3, each R4, each R14, n and m are as defined for formula (I), and p is an integer 0 to 5.

[0141] In certain embodiments the compound of formula (I) is a compound of the formula 15 (XXXI), or a pharmaceutically acceptable salt thereof:P382113WO 37wherein R1, each R3, each R4, each R14, n and m are as defined for formula (I), and p is an integer 0 to 5.

[0142] In certain embodiments the compound of formula (I) is a compound of the formula 5 (XXXII), or a pharmaceutically acceptable salt thereof:, wherein R1, each R3, each R4, R14, X, n and m are as defined for formula (I).

[0143] In certain embodiments the compound of formula (I) is a compound of the formula (XXXIII), or a pharmaceutically acceptable salt thereof: 10wherein R1, each R3, each R4, R14, X, n and m are as defined for formula (I) and * represents the relative cis- conformation. Suitably in this embodiment X is -CH2- or - CH2CH2-. In certain embodiments X is -CH2CH2CH2-.

[0144] In certain embodiments the compound of formula (I) is a compound of the formula 15 (XXXIV), or a pharmaceutically acceptable salt thereof:P382113WO 38wherein R1, each R3, each R4, R14, X, n and m are as defined for formula (I) and * represents the relative trans- conformation.

[0145] In certain embodiments the compound of formula (I) is a compound of the formula 5 (XXXV), or a pharmaceutically acceptable salt thereof:wherein R1, each R3, each R4, R14, X, n and m are as defined for formula (I). Suitably in this embodiment X is -CH2- or -CH2CH2-. In certain embodiments X is -CH2CH2CH2-.

[0146] In certain embodiments the compound of formula (I) is a compound of the formula 10 (XXXVI), or a pharmaceutically acceptable salt thereof:wherein R1, each R3, each R4, R14, X, n and m are as defined for formula (I).

[0147] In certain embodiments the compound of formula (I) is a compound of the formula (XXXVII), or a pharmaceutically acceptable salt thereof:P382113WO 39wherein R1, each R3, each R4, R14, X, n and m are as defined for formula (I).

[0148] In certain embodiments the compound of formula (I) is a compound of the formula (XXXVIII), or a pharmaceutically acceptable salt thereof: 5wherein R1, each R3, each R4, R14, X, n and m are as defined for formula (I), and * represents the relative cis- conformation. Suitably in this embodiment X is -CH2- or - CH2CH2-. In certain embodiments X is -CH2CH2CH2-

[0149] In certain embodiments the compound of formula (I) is a compound of the formula 10 (XXXIX), or a pharmaceutically acceptable salt thereof:wherein R1, each R3, each R4, R14, X, n and m are as defined for formula (I), and * represents the relative trans- conformation.

[0150] In certain embodiments the compound of formula (I) is a compound of the formula 15 (XXXX), or a pharmaceutically acceptable salt thereof:P382113WO 40wherein R1, each R3, each R4, R14, X, n and m are as defined for formula (I). Suitably in this embodiment X is -CH2- or -CH2CH2-. In certain embodiments X is -CH2CH2CH2-.

[0151] In certain embodiments the compound of formula (I) is a compound of the formula 5 (XXXXI), or a pharmaceutically acceptable salt thereof:wherein R1, each R3, each R4, R14, X, n and m are as defined for formula (I).

[0152] In certain embodiments the compound of formula (I) is a compound of the formula (XXXXII), or a pharmaceutically acceptable salt thereof: 10wherein R1, each R3, each R4, R14, X, n and m are as defined for formula (I).

[0153] In certain embodiments the compound of formula (I) is a compound of the formula (XXXXIII), or a pharmaceutically acceptable salt thereof:P382113WO 41wherein R1, each R3, each R4, R14, X, n and m are as defined for formula (I), and * represents the relative cis- conformation. Suitably in this embodiment X is -CH2- or - CH2CH2-. In certain embodiments X is -CH2CH2CH2-. 5

[0154] In certain embodiments the compound of formula (I) is a compound of the formula (XXXXIV), or a pharmaceutically acceptable salt thereof:wherein R1, each R3, each R4, R14, X, n and m are as defined for formula (I), and * represents the relative trans- conformation. 10

[0155] In certain embodiments the compound of formula (I) is a compound of the formula (XXXXV), or a pharmaceutically acceptable salt thereof:wherein R1, each R3, each R4, R14, X, n and m are as defined for formula (I). Suitably in this embodiment X is -CH2- or -CH2CH2-. In certain embodiments X is -CH2CH2CH2-. 15

[0156] In certain embodiments the compound of formula (I) is a compound of the formula (XXXXVI), or a pharmaceutically acceptable salt thereof:P382113WO 42wherein R1, each R3, each R4, R14, X, n and m are as defined for formula (I).

[0157] In certain embodiments the compound of formula (I) is a compound of the formula (XXXXVII), or a pharmaceutically acceptable salt thereof: 5wherein R1, each R3, each R4, each R14, X, n and m are as defined for formula (I).

[0158] In certain embodiments the compound of formula (I) is a compound of the formula (XXXXVIII), or a pharmaceutically acceptable salt thereof:10 wherein R1, each R3, each R4, each R14, X, n and m are as defined for formula (I) and * represents the relative cis- conformation. Suitably in this embodiment X is -CH2- or - CH2CH2-. In certain embodiments X is -CH2CH2CH2-.

[0159] In certain embodiments the compound of formula (I) is a compound of the formula (XXXXIX), or a pharmaceutically acceptable salt thereof:P382113WO 43, wherein R1, each R3, each R4, each R14, X, n and m are as defined for formula (I) and * represents the relative trans- conformation.

[0160] In certain embodiments the compound of formula (I) is a compound of the formula 5 (XXXXX), or a pharmaceutically acceptable salt thereof:wherein R1, each R3, each R4, each R14, X, n and m are as defined for formula (I). Suitably in this embodiment X is -CH2- or -CH2CH2-. In certain embodiments X is -CH2CH2CH2-.

[0161] In certain embodiments the compound of formula (I) is a compound of the formula 10 (XXXXXI), or a pharmaceutically acceptable salt thereof:wherein R1, each R3, each R4, each R14, X, n and m are as defined for formula (I).

[0162] In certain embodiments the compound of formula (I) is a compound of the formula (XXXXXII), or a pharmaceutically acceptable salt thereof:P382113WO 44wherein R1, each R3, each R4, each R14, X, n and m are as defined for formula (I).

[0163] In certain embodiments the compound of formula (I) is a compound of the formula (XXXXXIII), or a pharmaceutically acceptable salt thereof: 5(XXXXXIII), wherein R1, each R3, each R4, each R14, X, n and m are as defined for formula (I) and * represents the relative cis- conformation. Suitably in this embodiment X is -CH2- or - CH2CH2-. In certain embodiments X is -CH2CH2CH2-.

[0164] In certain embodiments the compound of formula (I) is a compound of the formula 10 (XXXXXIV), or a pharmaceutically acceptable salt thereof:wherein R1, each R3, each R4, each R14, X, n and m are as defined for formula (I) and * represents the relative trans- conformation.

[0165] In certain embodiments the compound of formula (I) is a compound of the formula 15 (XXXXXV), or a pharmaceutically acceptable salt thereof:P382113WO 45wherein R1, each R3, each R4, each R14, X, n and m are as defined for formula (I). Suitably in this embodiment X is -CH2- or -CH2CH2-. In certain embodiments X is -CH2CH2CH2-.

[0166] In certain embodiments the compound of formula (I) is a compound of the formula 5 (XXXXXVI), or a pharmaceutically acceptable salt thereof:wherein R1, each R3, each R4, each R14, X, n and m are as defined for formula (I).

[0167] In certain embodiments the compound of formula (I) is a compound of the formula (XXXXXVII), or a pharmaceutically acceptable salt thereof: 10wherein R1, each R3, each R4, X, n and m are as defined for formula (I).

[0168] In certain embodiments the compound of formula (I) is a compound of the formula (XXXXXVIII), or a pharmaceutically acceptable salt thereof:P382113WO 46 wherein R1, each R3, each R4, X, n and m are as defined for formula (I), and * represents the relative cis- conformation. Suitably in this embodiment X is -CH2- or -CH2CH2-. In certain embodiments X is -CH2CH2CH2-.

[0169] In certain embodiments the compound of formula (I) is a compound of the formula 5 (XXXXXIX), or a pharmaceutically acceptable salt thereof:, wherein R1, each R3, each R4, X, n and m are as defined for formula (I), and * represents the relative trans- conformation.

[0170] In certain embodiments the compound of formula (I) is a compound of the formula 10 (XXXXXX), or a pharmaceutically acceptable salt thereof:, wherein R1, each R3, each R4, X, n and m are as defined for formula (I). Suitably in this embodiment X is -CH2- or -CH2CH2-. In certain embodiments X is -CH2CH2CH2-.

[0171] In certain embodiments the compound of formula (I) is a compound of the formula 15 (XXXXXXI), or a pharmaceutically acceptable salt thereof:wherein R1, each R3, each R4, X, n and m are as defined for formula (I).

[0172] In certain embodiments the compound of formula (I) is a compound of the formula (XXXXXXII), or a pharmaceutically acceptable salt thereof:P382113WO 47(XXXXXXII), wherein R1, each R3, each R4, n and m are as defined for formula (I).

[0173] In certain embodiments the compound of formula (I) is a compound of the formula (XXXXXXIII), or a pharmaceutically acceptable salt thereof: 5wherein R1, each R3, each R4, n and m are as defined for formula (I).

[0174] In certain embodiments the compound of formula (I) is a compound of the formula (XXXXXXIV), or a pharmaceutically acceptable salt thereof: thereof:(XXXXXXIV) 10 wherein R1, each R3, each R4, n and m are as defined for formula (I).

[0175] In certain embodiments the compound of formula (I) is a compound of the formula (XXXXXXV), or a pharmaceutically acceptable salt thereof:P382113WO 48 wherein R1, each R3, each R4, n and m are as defined for formula (I).

[0176] In certain embodiments the compound of formula (I) is a compound of the formula (XXXXXXVI), or a pharmaceutically acceptable salt thereof:5 wherein R1, each R3, each R4, n and m are as defined for formula (I).

[0177] In certain embodiments the compound of formula (I) is a compound of the formula (XXXXXXVII), or a pharmaceutically acceptable salt thereof:wherein R1, each R3, each R4, n and m are as defined for formula (I). 10

[0178] In certain embodiments the compound of formula (I) is a compound of the formula (XXXXXXVIII), or a pharmaceutically acceptable salt thereof:wherein R1, R2, each R3, each R4, n and m are as defined for formula (I), and * represents the relative cis- conformation. 15

[0179] In certain embodiments the compound of formula (I) is a compound of the formula (XXXXXXIX), or a pharmaceutically acceptable salt thereof:P382113WO 49(XXXXXXIX) wherein R1, R2, each R3, each R4, n and m are as defined for formula (I).

[0180] In certain embodiments the compound of formula (I) is a compound of the formula (XXXXXXX), or a pharmaceutically acceptable salt thereof: 5wherein R1, each R3, each R4, each R14, n and m are as defined for formula (I), and p is an integer 0 to 5.

[0181] In certain embodiments the compound of formula (I) is a compound of the formula (XXXXXXXI), or a pharmaceutically acceptable salt thereof: 10(XXXXXXXI)

[0182] wherein R1, each R3, each R4, n and m are as defined for formula (I).

[0183] In certain embodiments compounds of the invention include, for example, compounds of formulae (I) to (XXXXXXXI), or a pharmaceutically acceptable salt thereof, wherein, unless otherwise stated, each of R1, R2, R3, R4, R5, R6, R7, R7A, R7B, R8, R9, R10, 15 R10A, R10B, R11, R12, R13, R13A, R13B, R13C, R13D, R14, R14A, R14B, R14C, R14D, X, m, n , p, and x has any of the meanings defined hereinbefore or in any of the following statements in the numbered paragraphs 1 to 198 hereinafter. These statements are independent and interchangeable. In other words, any of the features described in any one of the following statements may (where chemically allowable) be combined with the features described inP382113WO 50 one or more other statements below. In particular, where a compound is exemplified or illustrated in this specification, any two or more of the statements below which describe a feature of that compound, expressed at any level of generality, may be combined so as to represent subject matter which is contemplated as forming part of the disclosure of this 5 invention in this specification. 1. X is selected from -CH2- and -CH2CH2-. 2. X is selected from -CH2CH2- and -CH2CH2CH2-. 3. X is -CH2-. 4. X is -CH2CH2-. 10 5. X is -CH2CH2CH2-. 6. Q1and Q2are each independently selected from C3-6 cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 10-membered heteroaryl and C6-10 aryl; wherein said C3-6 cycloalkyl and 4- to 12-membered heterocyclyl is optionally substituted by one or more R13, and wherein said C6-10 aryl and 5- to 10-membered heteroaryl is optionally substituted by one or more 15 R14. 7. Q1and Q2are each independently selected from C3-6 cycloalkyl, 4- to 8-membered heterocyclyl, 5- to 10-membered heteroaryl, and C6-10 aryl; wherein said C3-6 cycloalkyl and 4- to 8-membered heterocyclyl is optionally substituted by one or more R13, and wherein said C6-10 aryl and 5- to 10-membered heteroaryl is optionally substituted by one or more 20 R14. 8. Q1and Q2are each independently selected from C3-6 cycloalkyl, 5- or 6-membered heteroaryl, and C6-10 aryl; wherein said C3-6 cycloalkyl is optionally substituted by one or more R13, and wherein said C6-10 aryl and 5- or 6-membered heteroaryl is optionally substituted by one or more R14. 25 9. Q1and Q2are each independently selected from 5- to 10-membered heteroaryl and C6-10aryl; wherein said C6-10aryl and 5- to 10-membered heteroaryl is optionally substituted by one or more R14. 10. Q1and Q2are each independently selected from 5- or 6-membered heteroaryl, phenyl and naphthyl; wherein said and 5- or 6-membered heteroaryl, phenyl and naphthyl 30 is optionally substituted by one or more R14. 11. Q1and Q2are each independently selected from 5- or 6-membered heteroaryl, and phenyl; wherein said and 5- or 6-membered heteroaryl and phenyl is optionally substituted by one or more R14.P382113WO 51 12. Q1and Q2are each independently selected from C3-6cycloalkyl optionally substituted by one or more R13. Thus, it may be that Q1and / or Q2are cyclopropyl. It may be that Q1and / or Q2are cyclobutyl. It may be that Q1and / or Q2are cyclopentyl. It may be that Q1and / or Q2is cyclohexyl. 5 13. Q1and Q2are each independently selected from 4- to 8-membered heterocyclyl optionally substituted by one or more R13. Thus, it may be that Q1and Q2are each independently 5-membered heterocyclyl substituted by one or more R13. It may be that Q1and Q2are each independently 5-membered heterocyclyl with 1 or 2 ring heteroatoms selected from O, S and N optionally substituted by one or more R13. It may be that Q1and 10 Q2are each independently 6-membered heterocyclyl optionally substituted by one or more R13. It may be that Q1and Q2are each independently 6-membered heterocyclyl with 1 or 2 ring heteroatoms selected from O, S and N optionally substituted by one or more R13. It may be that Q1and Q2are each independently 7-membered heterocyclyl optionally substituted by one or more R13. It may be that Q1and Q2are each independently 7- 15 membered heterocyclyl with 1 or 2 ring heteroatoms selected from O, S and N optionally substituted by one or more R13. It may be that Q1and Q2are each independently 8- membered heterocyclyl optionally substituted by one or more R13. It may be that Q1and Q2are each independently 8-membered heterocyclyl with 1 or 2 ring heteroatoms selected from O, S and N optionally substituted by one or more R13. 20 14. Q1and Q2are each independently C6-10 aryl optionally substituted by one or more R14. Thus, it may be that Q1and Q2are each independently phenyl optionally substituted by one or more R14. It may be that Q1and Q2are each independently naphthyl optionally substituted by one or more R14. 15. Q1and Q2are each independently 5- to 10-membered heteroaryl optionally25 substituted by one or more R14. It may be that Q1and Q2are each independently 5- membered heteroaryl optionally substituted by one or more R14. It may be that Q1and Q2are each independently 6-membered heteroaryl optionally substituted by one or more R14. It may be that Q1and Q2are each independently 8-membered heteroaryl optionally substituted by one or more R14. It may be that Q1and Q2are each independently 9- 30 membered heteroaryl optionally substituted by one or more R14. It may be that Q1and Q2are each independently 10-membered heteroaryl optionally substituted by one or more R14. 16. Q1and Q2are each independently a monocyclic 5- or 6-membered heteroaryl or an 8- to 10-membered fused bicyclic heteroaryl, wherein said heteroaryl has at least 1 (for 35 example 1 to 4) ring nitrogen atom and is optionally substituted by one or more R14. Thus, it may be that Q1and Q2are each independently a monocyclic 6-membered heteroaryl or aP382113WO 52 9- to 10-membered fused bicyclic heteroaryl, wherein said heteroaryl has at least 1 (for example 1 to 4) ring nitrogen atom and is optionally substituted by one or more R14. 17. Q1and Q2are each independently a monocyclic 5- or 6-membered heteroaryl or a 9- to 10-membered fused bicyclic heteroaryl, wherein said heteroaryl has 1 to 4 ring 5 nitrogen atoms and is optionally substituted by one or more R14. Thus, it may be that Q1and Q2are each independently a monocyclic 6-membered heteroaryl or a 9-membered fused bicyclic heteroaryl, wherein said heteroaryl has 1 to 4 ring nitrogen atoms and is optionally substituted by one or more R14. 18. Q1and Q2are each independently 5-membered heteroaryl, wherein said heteroaryl 10 has 1 ring nitrogen atom and optionally one or more ring heteroatoms (for example 1, 2 or 3) selected from O, S and N and is optionally substituted by one or more R14. 19. Q1and Q2are each independently 5-membered heteroaryl, wherein said heteroaryl has 1, 2, 3 or 4 ring nitrogen atoms and is optionally substituted by one or more R14. 20. Q1and Q2are each independently 6-membered heteroaryl and is optionally 15 substituted by one or more R14. 21. Q1and Q2are each independently a monocyclic 6-membered heteroaryl, wherein said heteroaryl has 1, 2 or 3 (for example 1 or 2) ring nitrogen atoms and is optionally substituted by one or more R14. 22. Q1and Q2are each independently 9-membered heteroaryl and is optionally 20 substituted by one or more R14. 23. Q1and Q2are each independently 9-membered fused bicyclic heteroaryl, wherein said heteroaryl has 1, 2, 3 or 4 ring nitrogen atoms and is optionally substituted by one or more R14. 24. Q1and Q2are each independently 9-membered bicyclic heteroaryl, wherein said 25 heteroaryl has 1, 2, 3 or 4 (for example 1, 2 or 3) ring nitrogen atoms and is a 6-membered ring fused to a 5-membered ring, wherein the 9-membered bicyclic heteroaryl is attached to the remaining portion of the molecule by a ring atom in the 6-membered ring and wherein said heteroaryl is optionally substituted by one or more R14. It may be that the 5- and 6-membered rings forming the 9-membered bicyclic heteroaryl are both heteroaryl 30 rings. 25. Q1and Q2are each independently 9-membered bicyclic heteroaryl, wherein said heteroaryl has 1, 2, 3 or 4 (for example 1, 2 or 3) ring nitrogen atoms and is a 6-membered ring fused to a 5-membered ring, wherein the 9-membered bicyclic heteroaryl is attached to the remaining portion of the molecule by a ring atom in the 5-membered ring, andP382113WO 53 wherein said heteroaryl is optionally substituted by one or more R14. It may be that the 5- and 6-membered rings forming the 9-membered bicyclic heteroaryl are both heteroaryl rings. 26. Q1and Q2are each independently selected from a 6-membered heteroaryl and a 9- 5 membered bicyclic heteroaryl, wherein said 6-membered heteroaryl has 1, 2 or 3 (for example 1 or 2) ring nitrogen atoms, and said 9-membered bicyclic heteroaryl has 1, 2, 3 or 4 (for example 1, 2 or 3) ring nitrogen atoms, and wherein said heteroaryl optionally substituted by one or more R14. It may be that the 5- and 6-membered rings forming the 9- membered bicyclic heteroaryl are both heteroaryl rings. It may be that Q1and Q2are each 10 independently selected from a 6-membered heteroaryl, and wherein said heteroaryl optionally substituted by one or more R14. It may be that Q1and Q2are each independently selected from a 6-membered heteroaryl containing 1, 2 or 3 ring nitrogen atoms, and wherein said heteroaryl optionally substituted by one or more R14. 27. Q1and Q2are each independently selected from cyclopropyl, cyclobutyl, 15 cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, and tetrahydropyranyl, each of which is optionally substituted by one or more R13. 28. Q1and Q2are each independently selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, each of which is optionally substituted by one or more R13. 29. Q1and Q2are each independently selected from pyrrolidinyl, tetrahydrofuranyl, 20 piperidinyl, and tetrahydropyranyl, each of which is optionally substituted by one or more R14. 30. Q1and Q2are each independently selected from furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl and quinazolinyl, each of which 25 is optionally substituted by one or more R14. 31. Q1and Q2are each independently selected from imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl and quinazolinyl, each of which is optionally substituted by one or more R14.P382113WO 54 32. Q1and Q2are each independently selected from:, each of which is optionally substituted by one or more R14. 33. Q1and Q2are each independently selected from: 5. 34. Q1is as defined in any one of 6 to 33. 35. Q2is as defined in any one of 6 to 33. 36. R1is selected from -CN, C1-6alkyl, C1-6haloalkyl, 2 to 8 membered heteroalkyl, C2-610 alkenyl, C2-6alkynyl, Q1, -OR5, -S(O)2R5, -C(O)R5, -C(O)OR5, -C(O)NR5R6and -SO2NR5R6, wherein said C1-6alkyl, 2 to 8 membered heteroalkyl, C2-6alkenyl and C2-6alkynyl is optionally substituted by one or more R7. 37. R1is selected from -CN, C1-6alkyl, C1-6haloalkyl, 2 to 8 membered heteroalkyl, C2-6alkenyl, C2-6alkynyl, Q1, -OR5, -S(O)2R5, -C(O)R5, -C(O)OR5, -C(O)NR5R6and -SO2NR5R6, 15 wherein said C1-6alkyl, 2 to 8 membered heteroalkyl, C2-6alkenyl and C2-6alkynyl is optionally substituted by one or more R7, and wherein Q1is as defined in any one of 6 to 33. 38. R1is selected from H, -CN, C1-6 alkyl, C1-6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)2-C1-6 alkyl, -C(O)R5, -C(O)NR5R6and -SO2NR5R6; 20 wherein said C1-6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7.P382113WO 55 39. R1is selected from H, -CN, C1-6alkyl, C1-6haloalkyl, 2 to 8 membered heteroalkyl, C2-6alkenyl, C2-6alkynyl, Q1, -OR5, -S(O)2-C1-6alkyl, -C(O)R5, -C(O)NR5R6and -SO2NR5R6; wherein said C1-6alkyl, 2 to 8 membered heteroalkyl, C2-6alkenyl and C2-6alkynyl is optionally substituted by one or more R7; and wherein Q1is as defined in any one of 6 to 5 33. 40. R1is selected from H, -CN, C1-6 alkyl, C1-6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)2R5, -C(O)R5, -C(O)NR5R6and -SO2NR5R6, wherein said C1-6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7. 10 41. R1is selected from H, -CN, C1-6 alkyl, C1-6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)2R5, -C(O)R5, -C(O)NR5R6and -SO2NR5R6, wherein said C1-6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7, and wherein Q1is as defined in any one of 6 to 33. 15 42. R1is selected from H, -CN, C1-4 alkyl, C1-4 haloalkyl, 2 to 6 membered heteroalkyl, C2-4 alkenyl, C2-4 alkynyl, Q1, -OR5, -S(O)2R5, -C(O)R5, -C(O)OR5, -C(O)NR5R6and - SO2NR5R6, wherein said C1-6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7. 20 43. R1is selected from H, -CN, C1-4 alkyl, C1-4 haloalkyl, 2 to 6 membered heteroalkyl, C2-4 alkenyl, C2-4 alkynyl, Q1, -OR5, -S(O)2R5, -C(O)R5, -C(O)OR5, -C(O)NR5R6and - SO2NR5R6, wherein said C1-6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7, and wherein Q1is as defined in any one of 6 to 25 33. 44. R1is selected from C1-4alkyl, C1-4haloalkyl, 2 to 6 membered heteroalkyl, C2-4alkenyl, C2-4alkynyl, Q1, -OR5, -S(O)2R5, -C(O)R5, -C(O)NR5R6and -SO2NR5R6, wherein said C1-6alkyl, 2 to 8 membered heteroalkyl, C2-6alkenyl and C2-6alkynyl is optionally substituted by one or more R7. 30 45. R1is selected from C1-4alkyl, C1-4haloalkyl, 2 to 6 membered heteroalkyl, C2-4alkenyl, C2-4alkynyl, Q1, -OR5, -S(O)2R5, -C(O)R5, -C(O)NR5R6and -SO2NR5R6,P382113WO 56 wherein said C1-6alkyl, 2 to 8 membered heteroalkyl, C2-6alkenyl and C2-6alkynyl is optionally substituted by one or more R7, and wherein Q1is as defined in any one of 6 to 33. 46. R1is selected from H, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, Q1, -S(O)2R5and - 5 C(O)R5, wherein said C1-4 alkyl is optionally substituted by one or more R7. 47. R1is selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, Q1, -S(O)2R5and - C(O)R5, wherein said C1-4 alkyl is optionally substituted by one or more R7, and wherein Q1is as defined in any one of 6 to 33. 48. R1is selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, Q1, -S(O)2R5and -C(O)R5, 10 wherein said C1-4 alkyl is optionally substituted by one or more R7. 49. R1is selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, Q1, -S(O)2R5and -C(O)R5, wherein said C1-4 alkyl is optionally substituted by one or more R7, and wherein Q1is as defined in any one of 6 to 33. 50. R1is selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, Q1and -C(O)R5, wherein 15 said C1-4 alkyl is optionally substituted by one or more R7. 51. R1is selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, Q1, and -C(O)R5, wherein said C1-4 alkyl is optionally substituted by one or more R7, and wherein Q1is as defined in any one of 6 to 33. 52. R1is selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, -S(O)2R5and -C(O)R5, 20 wherein said C1-4 alkyl is optionally substituted by one or more R7. 53. R1is selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, -S(O)2R5and -C(O)R5, wherein said C1-4 alkyl is optionally substituted by one or more R7. 54. R1is selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, -S(O)2R5and -C(O)R5, wherein R5is C1-4 alkyl. 25 55. R1is selected from H, C1-4alkyl, -C1-4alkyl-CN, -C2-4alkyl-OR7A, -C2-4alkyl- NR7AR7B, C2-4alkenyl, C2-4alkynyl, -S(O)2R5and -C(O)R5. 56. R1is selected from C1-4alkyl, -C1-4alkyl-CN, -C2-4alkyl-OR7A, -C2-4alkyl-NR7AR7B, C2-4alkenyl, C2-4alkynyl, -S(O)2R5and -C(O)R5. 57. R1is selected from C1-4alkyl, -C1-4alkyl-CN, -C2-4alkyl-OR7A, -C2-4alkyl-NR7AR7B, 30 C2-4alkenyl, C2-4alkynyl and -C(O)R5. 58. R1is selected from H, C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4alkynyl, Q1, -C1-4alkyl-Q1, -S(O)2R5, -C(O)R5, -C(O)OR5, -C(O)NR5R6and -SO2NR5R6,P382113WO 57 wherein R5is selected from H, C1-4alkyl, -C1-4alkyl-Q1, C1-4haloalkyl, C2-4alkenyl, C2-4alkynyl, and Q1; and R6is H or C1-4alkyl. 59. R1is selected from H, C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4alkynyl, Q1, -C1-4alkyl-Q1, -S(O)2R5, -C(O)R5, -C(O)OR5, -C(O)NR5R6and -SO2NR5R6, 5 wherein R5is selected from H, C1-4 alkyl, -C1-4 alkyl-Q1, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, and Q1; R6is H or C1-4 alkyl; and wherein each Q1is independently as defined in any one of 6 to 33. 60. R1is selected from C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, Q1, -C1-4 alkyl- Q1, -S(O)2R5, -C(O)R5, -C(O)NR5R6and -SO2NR5R6, 10 wherein R5is selected from H, C1-4 alkyl, -C1-4 alkyl-Q1, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, and Q1; and R6is H or C1-4 alkyl. 61. R1is selected from C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, Q1, -C1-4 alkyl- Q1, -S(O)2R5, -C(O)R5, -C(O)NR5R6and -SO2NR5R6, wherein R5is selected from H, C1-4 alkyl, -C1-4 alkyl-Q1, C1-4 haloalkyl, C2-4 alkenyl, 15 C2-4 alkynyl, and Q1; R6is H or C1-4 alkyl; and wherein each Q1is independently as defined in any one of 6 to 33. 62. R1is selected from H, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, -S(O)2R5, - C(O)R5, -C(O)NR5R6and -SO2NR5R6, wherein R5is selected from H, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, 20 and Q1; and R6is H or C1-4 alkyl. 63. R1is selected from H, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, -S(O)2R5, - C(O)R5, -C(O)NR5R6and -SO2NR5R6, wherein R5is selected from H, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, and Q1; R6is H or C1-4 alkyl; and Q1is independently as defined in any one of 6 to 33. 25 64. R1is selected from C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4alkynyl, -S(O)2R5, - C(O)R5, -C(O)NR5R6and -SO2NR5R6, wherein R5is selected from H, C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4alkynyl, and Q1; and R6is H or C1-4alkyl. It may be that Q1is as defined in any one of 6 to 33. 65. R1is selected from Q1, -C1-4alkyl-Q1, -S(O)2R5, -C(O)R5, -C(O)OR5, -C(O)NR5R630 and -SO2NR5R6, wherein R5is selected from Q1and -C1-4alkyl-Q1; and R6is H or C1-4alkyl. It may be that each Q1is independently as defined in any one of 6 to 33.P382113WO 58 66. R1is selected from Q1, -C1-4alkyl-Q1, -S(O)2R5and -C(O)R5, wherein R5is selected from Q1and -C1-4alkyl-Q1. It may be that each Q1is independently as defined in any one of 6 to 33. 67. R1is selected from Q1, -CH2-Q1, -S(O)2R5and -C(O)R5, wherein R5is selected from 5 Q1and -CH2-Q1. It may be that each Q1is independently as defined in any one of 6 to 33. 68. R1is -L1-Q1, wherein L1is selected from a bond, -CH2-, -C(O)-, -C(O)-CH2-**, - S(O)2-, and -S(O)2-CH2-**, wherein **is the point of attachment to Q1. It may be that L1is a bond, -CH2-, -C(O)-, or -S(O)2-. It may be that L1is a bond. It may be that L1is -CH2-. It may be that L1is -C(O)-. It may be that L1is -S(O)2-. 10 69. R1is -L1-Q1, wherein Q1is as defined in any one of 6 to 33, L1is selected from a bond, -CH2-, -CH(CH3)-, -C(O)-, -C(O)-CH2-**, -S(O)2- and -S(O)2-CH2-**, wherein **is the point of attachment to Q1. It may be that L1is selected from a bond, -CH2-, -C(O)-, -C(O)- CH2-**, -S(O)2- and -S(O)2-CH2-**, wherein **is the point of attachment to Q1. It may be that L1is a bond, -CH2-, -C(O)-, or -S(O)2-. It may be that L1is a bond. It may be that L1is 15 -CH2-. It may be that L1is -C(O)-. It may be that L1is -S(O)2-. 70. R1is C1-4 alkyl. Thus, it may be that R1is methyl or ethyl. 71. R1is C2-4 alkenyl. 72. R1is C2-4 alkynyl. 73. R1is -C(O)R5. Thus, it may be that R1is -C(O)C1-4 alkyl. 20 74. R1is -S(O)2R5. Thus, it may be that R1is -S(O)2C1-4 alkyl. 75. R1is Q1. It may be that Q1is as defined in any one of 6 to 33. 76. R1is -CH2-Q1. It may be that Q1is as defined in any one of 6 to 33. 77. R1is -C(O)-Q1. It may be that Q1is as defined in any one of 6 to 33. 78. R1is -C(O)-CH2-Q1. It may be that Q1is as defined in any one of 6 to 33. 25 79. R1is -S(O)2-Q1. It may be that Q1is as defined in any one of 6 to 33. 80. R1is -S(O)2-CH2-Q1. It may be that Q1is as defined in any one of 6 to 33. 81. R1is H, C1-3alkyl, C1-3haloalkyl, C2-3alkenyl, C2-3alkynyl, -C(O)C1-3alkyl, -S(O)2C1-3alkyl, phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, -CH2-phenyl, -CH2- naphthyl, -CH2-pyridyl, -CH2-pyrimidyl, -CH2-pyridazinyl, -CH2-pyrazinyl, -C(O)-phenyl, -30 C(O)-naphthyl, -C(O)-pyridyl, -C(O)-pyrimidyl, -C(O)-pyridazinyl, -C(O)-pyrazinyl, -S(O)2- phenyl, -S(O)2-naphthyl, -S(O)2-pyridyl, -S(O)2-pyrimidyl, -S(O)2-pyridazinyl, and -S(O)2- pyrazinyl; wherein any phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl in R1P382113WO 59 is optionally substituted by one or more R14(e.g.1 or 2 R14). It may be that each R14is independently selected from halo, C1-4alkyl, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, and C1-4alkoxy. Thus, it may be that each R14is selected from F, C-, Br, methyl, ethyl, - CF3, -CHF2, -CH2F and methoxy. It may be that R1is not H. 5 82. R1is selected from phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl, each of which is optionally substituted by one or more R14(e.g.1 or 2 R14). It may be that each R14is independently selected from halo, C1-4 alkyl, -CF3, -CHF2, -CH2F, -OCF3, - OCHF2, -OCH2F, and C1-4 alkoxy. Thus, it may be that each R14is selected from F, C-, Br, methyl, ethyl, -CF3, -CHF2, -CH2F and methoxy. 10 83. R1is selected from:wherein q1 is 0, 1 or 2. It may be that each R14is independently selected from halo, C1-4 alkyl, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, and C1-4alkoxy. Thus, it may be that each R14is selected from F, C-, Br, methyl, ethyl, -CF3, -CHF2, -CH2F and methoxy. 15 84. R1is selected from:, wherein q1 is 0, 1 or 2. It may be that each R14is independently selected from halo, C1-4 alkyl, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, and C1-4alkoxy. Thus, it may be that 20 each R14is selected from F, C-, Br, methyl, ethyl, -CF3, -CHF2, -CH2F and methoxy. 85. R1is selected from:P382113WO 60, wherein q1 is 0, 1 or 2. It may be that each R14is independently selected from halo, C1-4 alkyl, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F and C1-4 alkoxy. Thus, it may be that 5 each R14is selected from F, C-, Br, methyl, ethyl, -CF3, -CHF2, -CH2F and methoxy. 86. R1is selected from: ,10wherein L1is selected from a bond, -C(CH3)-, -CH2-,-C(O)- and -S(O)2-. It may be that L1is selected from a bond, -CH2-,-C(O)- and -S(O)2-. It may be that L1is selected from -CH2-,-C(O)- and -S(O)2-. It may be that L1is a bond. It may be that L1is -CH2-. It may be that 15 L1is -C(O)-. It may be that L1is -S(O)2-.P382113WO 61 87. R1is selected from: 590. R1is selected from H, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, -C(O)C1-3alkyl, -S(O)2C1-3alkyl. It may be that R1is C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, -C(O)C1-3 alkyl, -S(O)2C1-3 10 alkyl. 91. R1is methyl, ethyl, isopropyl, propyl, allyl, propynyl, acetyl, -C(O)CH2CH3, methylsulfonyl and ethysulfonyl. 92. R1is H or R1is as defined in any one of 36 to 91. 93. R1is H. 15 94. R1is not H. 95. R2is selected from -CN, C1-6 alkyl, C1-6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q2, -OR8, -S(O)2R8, -C(O)R8, -C(O)OR8, -C(O)NR8R9and -SO2NR9R9, wherein said C1-6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R10. 20 96. R2is selected from -CN, C1-6 alkyl, C1-6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q2, -OR8, -S(O)2R8, -C(O)R8, -C(O)OR8, -C(O)NR8R9and -SO2NR8R9,P382113WO 62 wherein said C1-6alkyl, 2 to 8 membered heteroalkyl, C2-6alkenyl and C2-6alkynyl is optionally substituted by one or more R10, and wherein Q2is as defined in any one of 6 to 33. 97. R2is selected from -CN, C1-6alkyl, C1-6haloalkyl, 2 to 8 membered heteroalkyl, C2-65 alkenyl, C2-6 alkynyl, Q2, -OR8, -S(O)2R8, -C(O)R8, -C(O)NR8R9and -SO2NR8R9, wherein said C1-6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R10. 98. R2is selected from -CN, C1-6 alkyl, C1-6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q2, -OR8, -S(O)2R8, -C(O)R8, -C(O)NR8R9and -SO2NR8R9, 10 wherein said C1-6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R10, and wherein Q2is as defined in any one of 6 to 33. 99. R2is selected from H, -CN, C1-4 alkyl, C1-4 haloalkyl, 2 to 6 membered heteroalkyl, C2-4 alkenyl, C2-4 alkynyl, Q2, -OR8, -S(O)2R8, -C(O)R8, -C(O)OR8, -C(O)NR8R9and - 15 SO2NR8R9, wherein said C1-6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R10. 100. R2is selected from H, -CN, C1-4 alkyl, C1-4 haloalkyl, 2 to 6 membered heteroalkyl, C2-4 alkenyl, C2-4 alkynyl, Q2, -OR8, -S(O)2R8, -C(O)R8, -C(O)OR8, -C(O)NR8R9and - 20 SO2NR8R9, wherein said C1-6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R10, and wherein Q2is as defined in any one of 6 to 33. 101. R2is selected from C1-4 alkyl, C1-4 haloalkyl, 2 to 6 membered heteroalkyl, C2-4 25 alkenyl, C2-4alkynyl, Q2, -OR8, -S(O)2R8, -C(O)R8, -C(O)NR8R9and -SO2NR8R9, wherein said C1-6alkyl, 2 to 8 membered heteroalkyl, C2-6alkenyl and C2-6alkynyl is optionally substituted by one or more R10. 102. R2is selected from C1-4alkyl, C1-4haloalkyl, 2 to 6 membered heteroalkyl, C2-4alkenyl, C2-4alkynyl, Q2, -OR8, -S(O)2R8, -C(O)R8, -C(O)NR8R9and -SO2NR8R9, 30 wherein said C1-6alkyl, 2 to 8 membered heteroalkyl, C2-6alkenyl and C2-6alkynyl is optionally substituted by one or more R10, and wherein Q2is as defined in any one of 6 to 33.P382113WO 63 103. R2is selected from H, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, Q2, -S(O)2R8and - C(O)R8, wherein said C1-4alkyl is optionally substituted by one or more R10. 104. R2is selected from H, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, Q2, -S(O)2R8and - C(O)R8, wherein said C1-4alkyl is optionally substituted by one or more R10, and wherein 5 Q2is as defined in any one of 6 to 33. 105. R2is selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, Q2, -S(O)2R8and -C(O)R8, wherein said C1-4 alkyl is optionally substituted by one or more R10. 106. R2is selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, Q2, -S(O)2R8and -C(O)R8, wherein said C1-4 alkyl is optionally substituted by one or more R10, and wherein Q2is as 10 defined in any one of 6 to 33. 107. R2is selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, Q2and -C(O)R8, wherein said C1-4 alkyl is optionally substituted by one or more R10. 108. R2is selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, Q2, and -C(O)R8, wherein said C1-4 alkyl is optionally substituted by one or more R10, and wherein Q2is as defined in 15 any one of 6 to 33. 109. R2is selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, -S(O)2R8and -C(O)R8, wherein said C1-4 alkyl is optionally substituted by one or more R10. 110. R2is selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, -S(O)2R8and -C(O)R8, wherein said C1-4 alkyl is optionally substituted by one or more R10. 20 111. R2is selected from C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, -S(O)2R8and -C(O)R8, wherein R8is C1-4 alkyl. 112. R2is selected from H, C1-4 alkyl, -C1-4 alkyl-CN, -C2-4 alkyl-OR10A, -C2-4 alkyl- NR10AR10B, C2-4 alkenyl, C2-4 alkynyl, -S(O)2R8and -C(O)R8. 113. R2is selected from C1-4 alkyl, -C1-4 alkyl-CN, -C2-4 alkyl-OR10A, -C2-4 alkyl-NR10AR10B, 25 C2-4alkenyl, C2-4alkynyl, -S(O)2R8and -C(O)R8. 114. R2is selected from C1-4alkyl, -C1-4alkyl-CN, -C2-4alkyl-OR10A, -C2-4alkyl-NR10AR10B, C2-4alkenyl, C2-4alkynyl and -C(O)R8. 115. R2is selected from H, C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4alkynyl, Q2, -C1-4alkyl-Q2, -S(O)2R8, -C(O)R8, -C(O)OR8, -C(O)NR8R9and -SO2NR8R9, 30 wherein R8is selected from H, C1-4alkyl, -C1-4alkyl-Q2, C1-4haloalkyl, C2-4alkenyl, C2-4alkynyl, and Q2; and R9is H or C1-4alkyl. 116. R2is selected from H, C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4alkynyl, Q2, -C1-4alkyl-Q2, -S(O)2R8, -C(O)R8, -C(O)OR8, -C(O)NR8R9and -SO2NR8R9,P382113WO 64 wherein R8is selected from H, C1-4alkyl, -C1-4alkyl-Q2, C1-4haloalkyl, C2-4alkenyl, C2-4alkynyl, and Q2; R9is H or C1-4alkyl; and wherein each Q2is independently as defined in any one of 6 to 33. 117. R2is selected from C1-4alkyl, C1-4haloalkyl, C2-4alkenyl, C2-4alkynyl, Q2, -C1-4alkyl- 5 Q2, -S(O)2R8, -C(O)R8, -C(O)NR8R9and -SO2NR8R9, wherein R8is selected from H, C1-4 alkyl, -C1-4 alkyl-Q2, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, and Q2; and R9is H or C1-4 alkyl. 118. R2is selected from C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, Q2, -C1-4 alkyl- Q2, -S(O)2R8, -C(O)R8, -C(O)NR8R9and -SO2NR8R9, 10 wherein R8is selected from H, C1-4 alkyl, -C1-4 alkyl-Q2, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, and Q2; R9is H or C1-4 alkyl; and wherein each Q2is independently as defined in any one of 6 to 33. 119. R2is selected from H, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, -S(O)2R8, - C(O)R8, -C(O)NR8R9and -SO2NR8R9, 15 wherein R8is selected from H, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, and Q2; and R9is H or C1-4 alkyl. 120. R2is selected from H, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, -S(O)2R8, - C(O)R8, -C(O)NR8R9and -SO2NR8R9, wherein R8is selected from H, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, 20 and Q2; R9is H or C1-4 alkyl; and Q2is independently as defined in any one of 6 to 33. 121. R2is selected from C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, -S(O)2R8, - C(O)R8, -C(O)NR8R9and -SO2NR8R9, wherein R8is selected from H, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, C2-4 alkynyl, and Q2; and R9is H or C1-4 alkyl. It may be that Q2is as defined in any one of 6 to 33. 25 122. R2is selected from Q2, -C1-4alkyl-Q2, -S(O)2R8, -C(O)R8, -C(O)OR8, -C(O)NR8R9and -SO2NR8R9, wherein R8is selected from Q2and -C1-4alkyl-Q2; and R9is H or C1-4alkyl. It may be that each Q2is independently as defined in any one of 6 to 33. 123. R2is selected from Q2, -C1-4alkyl-Q2, -S(O)2R8and -C(O)R8, wherein R8is selected 30 from Q2and -C1-4alkyl-Q2. It may be that each Q2is independently as defined in any one of 6 to 33. 124. R2is selected from Q2, -CH2-Q2, -S(O)2R8and -C(O)R8, wherein R8is selected from Q2and -CH2-Q2. It may be that each Q2is independently as defined in any one of 6 to 33.P382113WO 65 125. R2is -L2-Q2, wherein L2is selected from a bond, -CH2-, -C(O)-, -C(O)-CH2-**, - S(O)2-, and -S(O)2-CH2-**, wherein ** is the point of attachment to Q2. It may be that L2is a bond, -CH2-, -C(O)-, or -S(O)2-. It may be that L2is a bond. It may be that L2is -CH2-. It may be that L2is -C(O)-. It may be that L2is -S(O)2-. 5 126. R2is -L2-Q2, wherein Q2is as defined in any one of 6 to 33, L2is selected from a bond, -CH2-, -CH(CH3)-, -C(O)-, -C(O)-CH2-**, -S(O)2- and -S(O)2-CH2-**, wherein ** is the point of attachment to Q2. It may be that L2is selected from a bond, -CH2-, -C(O)-, -C(O)- CH2-**, -S(O)2- and -S(O)2-CH2-**, wherein **is the point of attachment to Q2. It may be that L2is a bond, -CH2-, -C(O)-, or -S(O)2-. It may be that L2is a bond. It may be that L2is 10 -CH2-. It may be that L2is -C(O)-. It may be that L2is -S(O)2-. 127. R2is C1-4 alkyl. Thus, it may be that R2is methyl or ethyl. 128. R2is C2-4 alkenyl. 129. R2is C2-4 alkynyl. 130. R2is -C(O)R8. Thus, it may be that R2is -C(O)C1-4 alkyl. 15 131. R2is -S(O)2R8. Thus, it may be that R2is -S(O)2C1-4 alkyl. 132. R2is Q2. It may be that Q2is as defined in any one of 6 to 33. 133. R2is -CH2-Q2. It may be that Q2is as defined in any one of 6 to 33. 134. R2is -C(O)-Q2. It may be that Q2is as defined in any one of 6 to 33. 135. R2is -C(O)-CH2-Q2. It may be that Q2is as defined in any one of 6 to 33. 20 136. R2is -S(O)2-Q2. It may be that Q2is as defined in any one of 6 to 33. 137. R2is -S(O)2-CH2-Q2. It may be that Q2is as defined in any one of 6 to 33. 138. R2is H, C1-3 alkyl, C1-3 haloalkyl, C2-3 alkenyl, C2-3 alkynyl, -C(O)C1-3 alkyl, -S(O)2C1-3 alkyl, phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, -CH2-phenyl, -CH2- naphthyl, -CH2-pyridyl, -CH2-pyrimidyl, -CH2-pyridazinyl, -CH2-pyrazinyl, -C(O)-phenyl, -25 C(O)-naphthyl, -C(O)-pyridyl, -C(O)-pyrimidyl, -C(O)-pyridazinyl, -C(O)-pyrazinyl, -S(O)2- phenyl, -S(O)2-naphthyl, -S(O)2-pyridyl, -S(O)2-pyrimidyl, -S(O)2-pyridazinyl, and -S(O)2- pyrazinyl; wherein any phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl in R2is optionally substituted by one or more R14(e.g.1 or 2 R14). It may be that each R14is independently selected from halo, C1-4alkyl, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F,30 and C1-4alkoxy. Thus, it may be that each R14is selected from F, Cl, Br, methyl, ethyl, - CF3, -CHF2, -CH2F and methoxy. It may be that R2is not H. 139. R2is selected from phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl and pyrazinyl, each of which is optionally substituted by one or more R14(e.g.1 or 2 R14). It may be thatP382113WO 66 each R14is independently selected from halo, C1-4alkyl, -CF3, -CHF2, -CH2F, -OCF3, - OCHF2, -OCH2F, and C1-4alkoxy. Thus, it may be that each R14is selected from F, Cl, Br, methyl, ethyl, -CF3, -CHF2, -CH2F and methoxy. 140. R2is selected from: 5wherein q2 is 0, 1 or 2. It may be that each R14is independently selected from halo, C1-4alkyl, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, C1-4alkoxy. Thus, it may be that each R14is selected from F, Cl, Br, methyl, ethyl, -CF3, -CHF2, -CH2F and methoxy. 141. R2is selected from:10, wherein q2 is 0, 1 or 2. It may be that each R14is independently selected from halo, C1-4 alkyl, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F, C1-4 alkoxy. Thus, it may be that each R14is selected from F, Cl, Br, methyl, ethyl, -CF3, -CHF2, -CH2F and methoxy. 15 142. R2is selected from:, wherein q1 is 0, 1 or 2. It may be that each R14is independently selected from halo, C1-4alkyl, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, -OCH2F and C1-4alkoxy. Thus, it may be that 20 each R14is selected from F, Cl, Br, methyl, ethyl, -CF3, -CHF2, -CH2F and methoxy.P382113WO 67 143. R2is selected from: ,5wherein L2 is selected from a bond, -CH2-, -CH(CH3)-, -C(O)- and -S(O)2-. It may be that L2 is selected from -CH2-, -C(O)- and -S(O)2-. It may be that L2 is selected from a bond, - CH2-, -CH(CH3)-, -C(O)- and -S(O)2-. It may be that L2 is selected from -CH2-, -C(O)- and - 10 S(O)2-. It may be that L2 is selected from -CH2- and -C(O)-. It may be that L2 is a bond. It may be that L2 is -CH2-. It may be that L2 is -C(O)-. It may be that L2 is -S(O)2-. 144. R2is selected from:15 145. R2is selected from:P382113WO 68147. R2is selected from H, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, -C(O)C1-3alkyl, -S(O)2C1-35 alkyl. It may be that R1is C1-3alkyl, C2-3alkenyl, C2-3alkynyl, -C(O)C1-3alkyl, -S(O)2C1-3alkyl. 148. R2is methyl, ethyl, isopropyl, propyl, allyl, propynyl, acetyl, -C(O)CH2CH3, methylsulfonyl and ethysulfonyl. 149. R2is H or R2is as defined in any one of 95 to 148. 10 150. R2is H. 151. R2is not H. 152. R1is selected from H, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, -C(O)C1-3alkyl, and -S(O)2C1-3alkyl, and R2is as defined in any one of 95 to 151. 153. R1is H and R2is as defined in any one of 95 to 151. 15 154. R2is selected from H, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, -C(O)C1-3alkyl, and - S(O)2C1-3alkyl, and R1is as defined in any one of 36 to 94. 155. R1is H and R2is as defined in any one of 95 to 151. 156. each R3and each R4is independently selected from halo, =O, C1-4 alkyl and C1-4 haloalkyl. 20 157. each R3and each R4is independently selected from halo, C1-4 alkyl and C1-4 haloalkyl. 158. each R3and each R4is independently selected from F, Cl, methyl, -CF3, -CHF2, and -CH2F. Thus, it may be that each R3and each R4is independently selected from F and methyl. It may be that each R3is methyl. It may be that each R3is F. It may be that 25 each R4is methyl. It may be that each R4is fluoro.P382113WO 69 159. One R3is =O. 160. One R3is =O and is located in the ortho position to the ring nitrogen. Thus, it may be that the compound of formula (II) is of the formula (IIa) and the compound of formula (III) is of the formula (IIIa): 5(IIIa), wherein each n1 is an integer from 0 to 6. It may be that n1 is 0 or 1. It may be that n1 is 0. 161. m is 0 and n is 0, 1 or 2. It may be that m is 0 and n is 1 or 2. 162. m is 0, 1 or 2 and n is 0. It may be that m is 1 or 2 and n is 0. 163. m and n are both 0. 10 164. R5and R6are each independently selected from H, C1-4alkyl, C1-4haloalkyl, 2 to 6 membered heteroalkyl, C2-4 alkenyl, C2-4 alkynyl, and Q1; wherein said C1-4 alkyl, 2 to 6 membered heteroalkyl, C2-4 alkenyl and C2-4 alkynyl is optionally substituted by one or more R11. 165. R5is selected from H, C1-4 alkyl, C1-4 haloalkyl, 2 to 6 membered heteroalkyl, C2-4 15 alkenyl, C2-4 alkynyl, and Q1; wherein said C1-4 alkyl, 2 to 6 membered heteroalkyl, C2-4 alkenyl and C2-4 alkynyl is optionally substituted by one or more R11; and Q1is as defined in any one of 6 to 33; and R6is selected from H and C1-4 alkyl. 166. R5is selected from H, C1-4 alkyl, -C1-4 alkyl-CN, -C1-4 alkyl-OR7A, -C1-4 alkyl- NR7AR7B, -C1-4 alkyl-Q1, C1-4 haloalkyl, and Q1; wherein Q1is as defined in any one of 6 to 20 33; and R6is selected from H and C1-4 alkyl. 167. R5and R6are each independently selected from H and C1-4 alkyl. It may be that R5and R6are each independently selected from H, methyl and ethyl. 168. R7and R11are each independently selected from halo, -CN, -OR7A, -S(O)xR7A, - NR7AR7B, C(O)R7A, -OC(O)R7A, -C(O)OR7A, -NR7AC(O)R7B, -C(O)NR7AR7Band Q1; wherein 25 Q1is as defined in any one of 6 to 33. 169. R7and R11are each independently selected from halo, -CN, -OR7A, -SO2R7Aand - NR7AR7B. 170. R8and R9are each independently selected from H, C1-4 alkyl, C1-4 haloalkyl, 2 to 6 membered heteroalkyl, C2-4 alkenyl, C2-4 alkynyl, and Q2; wherein said C1-4 alkyl, 2 to 6P382113WO 70 membered heteroalkyl, C2-4alkenyl and C2-4alkynyl is optionally substituted by one or more R12. 171. R8and R9are each independently selected from H, C1-4alkyl, C1-4haloalkyl, 2 to 6 membered heteroalkyl, C2-4alkenyl, C2-4alkynyl, and Q2; wherein said C1-4alkyl, 2 to 6 5 membered heteroalkyl, C2-4 alkenyl and C2-4 alkynyl is optionally substituted by one or more R12; and Q2is as defined in any one of 6 to 33; and R6is selected from H and C1-4 alkyl. 172. R8is selected from H, C1-4 alkyl, -C1-4 alkyl-CN, -C1-4 alkyl-OR10A, -C1-4 alkyl- NR10AR10B, -C1-4 alkyl-Q2, C1-4 haloalkyl, and Q2; wherein Q2is as defined in any one of 6 to 10 33; and R9is selected from H and C1-4 alkyl. 173. R8and R9are each independently selected from H and C1-4 alkyl. It may be that R8and R9are each independently selected from H, methyl and ethyl. 174. R10and R12are each independently selected from halo, -CN, -OR10A, -SO2R10Aand -NR10AR10B. 15 175. each R13is independently selected from halo, =O, -CN, C1-4 alkyl, -C1-4 alkyl-CN, - C1-4 alkyl-OR13C, -C1-4 alkyl-NR13CR13D, C1-4 haloalkyl, -OR13A, -S(O)xR13A, -NR13AR13B, - C(O)R13A, -C(O)OR13A, -C(O)NR13AR13B, and -SO2NR13AR13B. 176. each R13is independently selected from halo, =O, C1-4 alkyl, C1-4 haloalkyl, -OR13A, -S(O)2R13Aand -C(O)R13A. 20 177. each R13is independently selected from halo, =O, C1-4 alkyl, -CF3, -CHF2, -CH2F, - OCF3, -OCHF2, -OCH2F, C1-4 alkoxy. 178. each R13is independently selected from halo, =O, C1-3 alkyl, -CF3, -CHF2, -CH2F, - OCF3, -OCHF2, -OCH2F, -OH, methoxy and ethoxy. 179. each R13is independently selected from F, Cl, C1-3 alkyl, -CF3, -CHF2, -CH2F, - 25 OCF3, -OCHF2, -OCH2F, -OH, methoxy and ethoxy. 180. each R14is independently selected from halo, -CN, C1-4alkyl, -C1-4alkyl-CN, -C1-4alkyl-OR14C, -C1-4alkyl-NR14CR14D, C1-4haloalkyl, -OR14A, -S(O)xR14A, -NR14AR14B, - C(O)R14A, -C(O)OR14A, -NR14BC(O)R14A, -C(O)NR14AR14B, -NR14BC(O)OR14A, - OC(O)NR14AR14B, -NR14BSO2R14Aand -SO2NR14AR14B. 30 181. each R14is independently selected from halo, -CN, C1-4alkyl, -C1-4alkyl-OR14C, C1-4haloalkyl, -OR14A, -S(O)xR14Aand -C(O)R14A. 182. each R14is independently selected from halo, C1-4alkyl, -CF3, -CHF2, -CH2F, - OCF3, -OCHF2, -OCH2F, C1-4alkoxy.P382113WO 71 183. each R14is independently selected from halo, C1-3alkyl, -CF3, -CHF2, -CH2F, - OCF3, -OCHF2, -OCH2F, -OH, methoxy and ethoxy. 184. each R14is independently selected from halo, methyl, -CF3, -CHF2, -CH2F, -OCF3, - OCHF2, -OCH2F, and methoxy. 5 185. each R14is independently selected from halo, methyl, -CF3 and methoxy. 186. each R14is independently selected from halo. 187. each R14is independently selected from F, Cl and Br. 188. each R7A, R7B, R10A, R10B, R13A, R13B, R13C, R13D, R14A, R14B, R14C, R14Dare at each occurrence independently selected from H, and C1-4 alkyl. 10 189. each R7A, R7B, R10A, R10B, R13A, R13B, R13C, R13D, R14A, R14B, R14C, R14Dare at each occurrence independently selected from H, methyl and ethyl. 190. Any -NR5R6, -NR8R9, -NR7AR7B, -NR10AR10B,-NR13AR13B, -NR13CR13D, -NR14AR14Band -NR14CR14Dwithin a substituent may form a heterocyclyl selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, wherein said heterocyclyl is optionally 15 substituted by one or two substituents selected from halo and C1-4 alkyl. Thus, it may be that said heterocyclyl is optionally substituted by one or two substituents selected from F, Cl, methyl and ethyl. 191. m is 0, 1 or 2. 192. m is 1 or 2. 20 193. n is 0, 1 or 2. 194. n is 1 or 2. 195. m and n are both 0. 196. Each x is independently 0. 197. Each x is independently 1. 25 198. Each x is independently 2.

[0184] In certain embodiments the compound of formula (I) is a compound of the formula (Ia), (Ib) or (Ic), or a pharmaceutically acceptable salt thereof:P382113WO 72wherein R1, R2, each R3, each R4, n and m are as defined for formula (I), including in any of paragraphs 1 to 198. Thus, it may be that the compound of formula (I) is a compound of the formula (Ia), or a pharmaceutically acceptable salt thereof. It may be that the 5 compound of formula (I) is a compound of the formula (Ib), or a pharmaceutically acceptable salt thereof. It may be that the compound of formula (I) is a compound of the formula (Ic), or a pharmaceutically acceptable salt thereof.

[0185] In certain embodiments the compound of the invention is a compound according to any one of formulae (I), (Ia), (Ib), (Ic), or (II) to (XXXXXXXI) wherein m and n are 10 independently 0, 1 or 2. suitably in this embodiment each R3and each R4is independently as defined in any one of 156 to 160. It may be that m is 0 and n is 1 or 2. It may be that m is 1 or 2 and n is 0. In some embodiments m and n are both 0.

[0186] In certain embodiments the compound of the invention is a compound of the formula (I), (II), (VI), (XVII), (XVIII), (XX), (XXII), (XXIII), (XXV), (XXXII), (XXXIII), (XXXV), 15 (XXXVII), (XXXVIII), (XXXX), (XXXXII), (XXXXIII), (XXXXV), (XXXXVII), (XXXXVIII), (XXXXX), (XXXXXII), (XXXXXIII), (XXXXXV), (XXXXXVII), (XXXXXVIII) or (XXXXXX), wherein X is -CH2- or -CH2CH2-.Thus, it may be that X is -CH2-. It may be that X is - CH2CH2-.

[0187] In certain embodiments the compound of the invention is a compound of the 20 formula (I), (Ia), (Ib), (Ic), (II), (III), (XXII), (XXIII), (XXIV), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII), (XXXIII), (XXXIV), (XXXV), (XXXVI), (XXXVII), (XXXVIII), (XXXIX), (XXXX), (XXXXI), (XXXXII), (XXXXIII), (XXXXIV), (XXXXV), (XXXXVI), (XXXXVII), (XXXXVIII), (XXXXIX), (XXXXX), (XXXXXI), (XXXXXII), (XXXXXIII), (XXXXXIV), (XXXXXV) or (XXXXXVI), wherein R14is as defined in any one of 180 to 187. 25

[0188] In this embodiment R1may be as defined in any one of 36 to 94. Thus it may be that R1is selected from H, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, -C(O)-C1-3alkyl, -S(O)2-C1-3alkyl, -C(O)NR5R6and -SO2NR5R6, wherein R5and R6are independently selected from H and C1-3alkyl, and each R14is independently selected from halo, C1-4alkyl, -CF3, -CHF2, - CH2F, -OCF3, -OCHF2, -OCH2F and C1-4alkoxy. 30

[0189] In this embodiment it may be that R1is selected from H, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, -C(O)-C1-3alkyl, and -S(O)2-C1-3alkyl; and each R14is independently selectedP382113WO 73 from F, Cl, Br, methyl, ethyl, -CF3, -CHF2, -CH2F and methoxy. For example, each R14may be selected from F, Cl, Br, and -CF3.

[0190] Suitably in this embodiment it may be that each R3and each R4is independently as defined in any one of 156 to 160 (for example R3is oxo, halo or C1-3alkyl and R4is halo 5 or C1-3 alkyl). It may be that m is 0 and n is 1 or 2. It may be that m is 1 or 2 and n is 0. In some embodiments m and n are both 0.

[0191] In certain embodiments the compound of the invention is a compound of the formula (I), (Ia), (Ib), (Ic), (II), (III), (IV), (V), (VI), (VII), (VIII), (VIX), (X), (XI), (XII), (XIII), (XIV), (XV) or (XVI), wherein 10 R1is -L1-Q1, wherein Q1is as defined in any one of 6 to 33; L1is selected from a bond, -CH2-, -C(O)-, -C(O)-CH2-**, -S(O)2- and -S(O)2-CH2-**, wherein **is the point of attachment to Q1; and R2is selected from H, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, -C(O)-C1-3 alkyl, -S(O)2- C1-3 alkyl, -C(O)NR8R9and -SO2NR8R9, wherein R8and R9are independently selected 15 from H and C1-3 alkyl.

[0192] In this embodiment it may be that L1is a bond, -CH2-, -C(O)-, or -S(O)2-. Thus, it may be that L1is a bond. It may be that L1is -CH2-. It may be that L1is -C(O)-. It may be that L1is -S(O)2-.

[0193] In this embodiment it may be that it may be that R2is selected from H, C1-3 alkyl, 20 C2-3 alkenyl, C2-3 alkynyl, -C(O)-C1-3 alkyl, and -S(O)2-C1-3 alkyl. Thus it may be that R2is selected from H, C1-3 alkyl, C2-3 alkenyl, C2-3 alkynyl, -C(O)-C1-3 alkyl, and -S(O)2-C1-3 alkyl; R1is -L1-Q1, wherein Q1is as defined in any one of 6 to 33; and L1is selected from a bond, -CH2-, -C(O)- and -S(O)2-.

[0194] Suitably in this embodiment it may be that each R3and each R4is independently 25 as defined in any one of 156 to 160 (for example R3is oxo, halo or C1-3alkyl and R4is halo or C1-3alkyl). It may be that m is 0 and n is 1 or 2. It may be that m is 1 or 2 and n is 0. In some embodiments m and n are both 0.

[0195] In certain embodiments the compound of the invention is a compound of the formula (I), (Ia), (Ib), (Ic),(II), (III), (XVII), (XVIII), (XIX), (XX), (XXI), (XXII), (XXIII), (XXIV), 30 (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXIII), (XXXIV), (XXXV), (XXXVI), (XXXVII), (XXXVIII), (XXXIX), (XXXX), (XXXXI), (XXXXII), (XXXXIII), (XXXXIV), (XXXXV), (XXXXVI), (XXXXVII), (XXXXVIII), (XXXXIX), (XXXXX), (XXXXXI), (XXXXXII), (XXXXXIII), (XXXXXIV), (XXXXXV), (XXXXXVI), (XXXXXVII), (XXXXXVIII), (XXXXXIX), (XXXXXX), (XXXXXXI), (XXXXXXII), (XXXXXXIII), (XXXXXXIV), (XXXXXXV), 35 (XXXXXXVI), (XXXXXXVII), (XXXXXXVIII), (XXXXXXIX), (XXXXXXX), or (XXXXXXXI),P382113WO 74 wherein R1is as defined in any one of 36 to 94. Thus it may be that R1is selected from H, C1-3alkyl, C2-3alkenyl, C2-3alkynyl, -C(O)-C1-3alkyl, -S(O)2-C1-3alkyl, -C(O)NR5R6and - SO2NR5R6, wherein R5and R6are independently selected from H and C1-3alkyl, and each R14is independently selected from halo, C1-4alkyl, -CF3, -CHF2, -CH2F, -OCF3, -OCHF2, - 5 OCH2F and C1-4 alkoxy.

[0196] In this embodiment it may be that R1is selected from H, C1-3 alkyl, C2-3 alkenyl, C2- 3 alkynyl, -C(O)-C1-3 alkyl, and -S(O)2-C1-3 alkyl.

[0197] Suitably in this embodiment it may be that each R3and each R4is independently as defined in any one of 156 to 160 (for example R3is oxo, halo or C1-3 alkyl and R4is halo 10 or C1-3 alkyl). It may be that m is 0 and n is 1 or 2. It may be that m is 1 or 2 and n is 0. In some embodiments m and n are both 0.

[0198] In certain embodiments the compound of the invention is a compound wherein: R1is selected from H, -CN, C1-6 alkyl, C1-6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)2-C1-6 alkyl, -C(O)R5, -C(O)NR5R6and -SO2NR5R6; 15 wherein said C1-6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; R2has any of the values defined herein provided R2is not hydrogen; with the proviso that when R1is H, then R2is not methyl or tert-butoxycarbonyl (BOC). In this embodiment it may be that R2is as defined in any one of 95 to 151, provided R2is 20 not hydrogen.

[0199] In certain embodiments, when X is -CH2- in a compound of the invention R1and R2are not both H.

[0200] In certain embodiments when X is -CH2-, R1is not. In certain embodiments when X is -CH2-, R1is not isoquinolinyl-S(O)2- . In certain embodiments 25 when X is -CH2-, Q1is not isoquinolinyl. In certain embodiments Q1is not isoquinolinyl.

[0201] In certain embodiments R1and R2are not both H.

[0202] In another embodiment there is provided a compound selected from Compound List 1, or a pharmaceutically acceptable salt thereof: Compound List 1P382113WO 78

[0203] In another embodiment there is provided a compound selected from Compound List 2, or a pharmaceutically acceptable salt thereof:Compound List 2:P382113WO 83.

[0204] In another embodiment there is provided a compound selected from Compound 5 List 3, or a pharmaceutically acceptable salt thereof: Compound List 3P382113WO 845

[0205] In another embodiment there is provided a compound selected from Compound List 4, or a pharmaceutically acceptable salt thereof: Compound List 4P382113WO 85.

[0206] In another embodiment there is provided a compound selected from Compound 5 List 5, or a pharmaceutically acceptable salt thereof: Compound List 510

[0207] In another embodiment there is provided a compound selected from Compound List 6, or a pharmaceutically acceptable salt thereof: Compound List 6:P382113WO 86

[0208] In another embodiment there is provided a compound selected from Compound List 7, or a pharmaceutically acceptable salt thereof: Compound List 7:

[0209] In another embodiment there is provided a compound selected from any one of the Examples herein, or a pharmaceutically acceptable salt thereof.

[0210] In some embodiments the compound of the invention is not one or more of the following compounds:P382113WO 87.

[0211] Also provided is a composition comprising an enantiomeric excess of a compound of the invention. Reference to an “enantiomeric excess” of a compound of the invention 5 refers to an excess of a cis- or trans- enantiomer of a compound of the invention. By way of an example and enantiomeric excess of the compound of formula (V) means that there is an excess of the enantiomer (V) relative to the compound of formula (VI):

[0212] It is recognised that a compound of the invention may have stereocenters in other 10 substituent groups in the compound. However, unless stated otherwise, references herein to enantiomeric excess is a reference to the two cis- enantiomers or the two trans- enantiomers on the fused azepane core of the compounds of the invention.

[0213] In some embodiments the compound of the invention is present in the composition in an enantiomeric excess of at least 60%. It may be that the compound of 15 the invention is in an enantiomeric excess of at least 70%. It may be that the compound of the invention is in an enantiomeric excess of at least 80%. It may be that the compound of the invention is in an enantiomeric excess of at least 85%. It may be that the compound of the invention is in an enantiomeric excess of at least 90%. It may be that the compound of the invention is in an enantiomeric excess of at least 95%. It may be that the compound of 20 the invention is in an enantiomeric excess of at least 98%. It may be that the compound of the invention is in an enantiomeric excess of at least 99%. It may be that the compound of the invention is in an enantiomeric excess of at least 99.9% It may be that the compound of the invention is enantiomerically pure (i.e. substantially free of other enantiomers).P382113WO 88

[0214] Suitably the composition comprising the enantiomeric excess of the compound of the invention is also present in a diastereomeric excess. For example, when the compound of the invention is a cis-isomer, the composition comprises a diastereomeric excess of the cis-isomer relative to trans isomers of the compound. Suitably the 5 composition comprises the compound of the invention in a diastereomeric excess of at least 60%. For example, a diastereomeric excess of at least 70%, at least 80% at least 90% at least 95%, at least 98%, at least 99%, or at least 99.9%. Preferably the composition is diastereomerically pure (i.e. substantially free of other diastereoisomers).

[0215] In some embodiments there is provided a composition comprising a 10 diastereomeric excess of a compound of the invention with the cis-conformation. For example, it may be that the composition comprises a compound of the invention in the cis- conformation (e.g. a compound of formula (I)) in a diastereomeric excess over the corresponding trans-compound of the invention (e.g. a compound of formula (II)). In other embodiments there is provided a composition comprising a diastereomeric excess of a 15 compound of the invention with the trans-conformation. For example, a composition comprising a compound of the invention in the trans-conformation (e.g. a compound of formula (II)) in a diastereomeric excess over the corresponding cis-compound (e.g. compound of the formula (II)). Suitably the composition comprises the desired cis- or trans- isomer in a diastereomeric excess of at least 60 %. For example, a diastereomeric 20 excess of at least 70%, at least 80% at least 90% at least 95%, at least 98%, at least 99%, or at least 99.9%. Preferably the composition is diastereomerically pure (i.e. substantially free of other diastereoisomers).

[0216] In another embodiment, there is provided a composition comprising a compound of the invention optionally together with one or more of the other stereoisomeric forms of the 25 compound, if any, wherein the compound of the invention is present within the composition with an enantiomeric excess (%ee) of ≥ 90% and a diastereomeric excess (%de) of ≥ 90%.

[0217] In another embodiment, there is provided a composition comprising a compound of the invention optionally together with one or more of the other stereoisomeric forms of the compound, if any, wherein the %ee and %de of the compound of the invention take any 30 combination of values, e.g., the %ee is ≤5% and the %de is ≥ 80%; the %ee is ≤5% and the %de is ≥ 90%; the %ee is ≤5% and the %de is ≥ 95%; the %ee is ≤5% and the %de is ≥ 98%; the %ee is ≥ 95% and the %de is ≥ 95%; the %ee is ≥ 98% and the %de is ≥ 98%; or the %ee is ≥ 99% and the %de is ≥ 99%.

[0218] The enantiomeric enrichment or enantiomeric purity can be measured using 35 known methods. For example, by resolution and detection of the enantiomericP382113WO 89 components of a composition using chiral HPLC separation techniques and calculating the enantiomeric excess according to the formula [^^^^^^^ ^^^^^^^^^^ ^^^^ ^ ^ ^%^^ = ^^^^ − ^^^^^^^^^^^ ^^^^^^^^^^ ^^^^ ^^^^ ][^^^^^^^ ^^^^^^^^^^ ^^^^ ^^^^^ + ^^^^^^^^^^^^ ^^^^^^^^^^ ^^^^ ^^^^^] × 100

[0219] Diasteroemeric excess may also be determined by comparison of HPLC peak 5 areas of the target cis- diastereomer with the corresponding trans- diastereomer.

[0220] Certain compounds according to the invention may exhibit one or more benefits including, inter alia, advantageous levels of biological activity which may be useful in the prophylaxis and / or treatment of one or more disease, improved safety characteristics (e.g. relating to hERG inhibition, drug-drug interaction (DDI) or CYP-interaction characteristics, 10 etc), improved selectivity for one or more disease-associated biological target (e.g. reduced off-target effects, etc), improved pharmacokinetic properties (e.g. relating to dosing, solubility, absorption, etc), improved pharmacodynamic properties (e.g. relating to permeability, efflux, etc) or superior properties for use as pharmaceutical active ingredients alone or in pharmaceutical compositions (e.g. stability), or advantageous physico-chemical 15 properties useful in the manufacturability of such aforementioned pharmaceutical compositions. PHARMACEUTICAL COMPOSITIONS

[0221] In accordance with another aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt 20 thereof, and a pharmaceutically acceptable excipient.

[0222] It may be that the pharmaceutical composition comprises a compound selected from a compound according to any of formulae (I) to (XXXXXXXI), or a pharmaceutically acceptable salt thereof.

[0223] Conventional procedures for the selection and preparation of suitable 25 pharmaceutical compositions are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.

[0224] The pharmaceutical composition may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for sublingual use, for topical use (for 30 example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intraperitoneal dosing or as a suppository for rectal dosing).P382113WO 90

[0225] The pharmaceutical composition may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and / or preservative agents. 5

[0226] An effective amount of a compound of the invention for use in therapy of a condition is an amount sufficient to symptomatically relieve in a warm-blooded animal, particularly a human the symptoms of the condition or to slow the progression of the condition.

[0227] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the 10 particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.1 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. 15

[0228] The size of the dose for therapeutic or prophylactic purposes of a compound of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well- known principles of medicine.

[0229] In using a compound of the invention for therapeutic or prophylactic purposes it will 20 generally be administered so that a daily dose in the range, for example, a daily dose selected from: 0.1 mg / kg to 100 mg / kg, 1 mg / kg to 75mg / kg, 1 mg / kg to 50 mg / kg, 1 mg / kg to 20 mg / kg and 5 mg / kg to 10 mg / kg body weight is received, given if required in divided doses. In general, lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous, subcutaneous, intramuscular or intraperitoneal 25 administration, a dose in the range, for example, 0.1 mg / kg to 30 mg / kg body weight may be suitable. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg / kg to 25 mg / kg body weight may be suitable. When administered orally a total daily dose of a compound of the invention may be, for example, selected from: 1 mg to 1000 mg, 5 mg to 1000 mg, 10 mg to 750 mg or 25 mg to 500 mg. Typically, unit dosage forms will contain 30 about 0.5 mg to 0.5 g of a compound of the invention.

[0230] The compound may be administered according to a dosage regimen which provides or maintains a therapeutically effective concentration of the compound in a subject. For example, a compound of the invention may be administered once or twice daily.

[0231] In some embodiments the compound of the invention is administered to provide an 35 acute effect in a subject, for example as a sedative, to induce anaesthesia. Therefore, alsoP382113WO 91 contemplated is the administration of a single dose of a compound of the invention, for example a single oral dose or a single parenteral dose (e.g. bolus dose or a single parenteral (e.g. intravenous) infusion). Route of Administration 5

[0232] The compound of the invention may be administered by topical (local), enteral (system-wide effect, but delivered through the gastrointestinal tract), or parenteral (systemic action, but delivered by routes other than the GI tract) routes.

[0233] In some embodiments a compound of the invention may be administered by, for example, enteral administration, such as oral, sublingual, buccal, and rectal administration; 10 parenteral administration, including bolus injection or continuous infusion, intravenous, intra-arterial, intraperitoneal, intraosseous, intramuscular, intrathecal, intracerebroventricular, vaginal, ocular, nasal, cutaneous, topical, otic, ocular, transdermal, and subcutaneous administration.

[0234] In some embodiments, a compound of the invention is administered as oral solid 15 and oral liquid dosage forms; sublingually or buccally; as injections, including intravenous, intra-arterial, intraperitoneal, intraosseous, intramuscular, intrathecal, and intracerebroventricular; rectally, vaginally, ocularly, nasally, cutaneously, topically, optically, transdermally, and subcutaneously.

[0235] In a particular embodiment a compound of the invention is administered by 20 intravenous administration. In another particular embodiment a compound of the invention is administered orally. THERAPEUTIC USES AND APPLICATIONS

[0236] In the following sections of the application reference is made to a compound of the invention, or a pharmaceutically acceptable salt thereof for use in the treatment of certain 25 diseases or medical disorders. It is to be understood that any reference herein to a compound for a particular use is also intended to be a reference to (i) the use of the compound of the invention, or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of that disease or disorder; and (ii) a method for the treatment of the disease or disorder in a subject, the method comprising administering to 30 the subject a therapeutically effective amount of the compound of the invention, or pharmaceutically acceptable salt thereof.

[0237] Another aspect, the present invention provides a compound of the invention, for use as a medicament.P382113WO 92

[0238] Compounds of the invention have been shown to exhibit inhibitory effects against several targets, including norepinephrine transporters (NET), dopamine transporters (DAT), serotonin transporters (SERT), sigma-1 receptor (σ1R), muscarinic M1receptors and muscarinic M2receptors. The Examples herein show that compounds of the invention inhibit 5 norepinephrine (NE) and dopamine (DA) uptake in a cellular assay using PC-12 cells.

[0239] Monoamine transporters such as NET DAT and SERT are the targets of a wide range of inhibitors that have been developed as therapeutic treatments for various neuropsychiatric and neurodegenerative disorders, including but not limited to depression, ADHD, neuropathic pain, anxiety disorders, panic disorders, stimulant use disorders, 10 epilepsy, and Parkinson's disease (Aggarwal & Mortensen, 2023).

[0240] Sigma-1 receptor antagonists have been shown to be useful in the treatment of pain (including neuropathic pain, inflammatory pain and ischemic pain) (Sánchez- Fernández C et al, 2017). The sigma-1 receptor (σ1R) is involved in excessive drug and food seeking (Knowles et al., 2023) and cognitive impairment in neuropsychiatric diseases 15 (Albayrak & Hashimoto, 2017).

[0241] The locus coeruleus (LC), a small brainstem nucleus, is the primary source of the neuromodulator norepinephrine (NE) in the brain. NE influences almost all cortical and subcortical brain regions. Neurons in the locus coeruleus release NE sending widespread norepinephrine projections throughout the central nervous system, exerting a global 20 influence on arousal states and adaptive behaviours. The LC plays a pivotal role in modulating both ascending visceral and descending cortical neurocognitive information.

[0242] Dysfunction in the LC-NE system contributes to various neuropsychiatric and neurodegenerative disorders conditions and is regulated by the activity of the norepinephrine transporter (NET). Conditions associated with dysregulated NA signalling 25 via the LC include, for example, anxiety, depression, ADHA, insomnia, schizophrenia, and cognitive decline associated with neurodegenerative diseases, including cognitive decline associated with Alzheimer’s disease and Parkinson’s disease (Hamon & Plier, 2013, McCal, 2019; Borodovitsyna et al.2017, Morris et al., 2020). Inhibition of the LC may also inhibit negative memory formation in post-traumatic stress disorders (PTSD), obsessive- 30 compulsive disorders (OCDs) and Tourette syndrome (Alsene & Bakshi, 2011, Giustino et al., 2020). Dysregulated NA activity mediated by the LC is also implicated in neurodegenerative disorders, for example Alzheimer’s disease (AD) and Parkinsons disease (PD) (Kula et al., 2021; Krohn et al., 2023, Alsene & Bakshi, 2011).

[0243] Significantly studies in mice using compounds of the invention have unexpectedly 35 shown that compounds of the invention do not induce the stimulant and anxiogenic effectsP382113WO 93 typically associated with other NET and DAT inhibitors such a cocaine or amphetamines (Yang et al., 1992). Instead, the tested compound elicit sedative and antinociceptive effects by inhibiting LC activity). This finding suggests the potential for using compounds of the invention to restore the dysregulated LC function observed in, for example, anxiety, 5 panic disorder, the manic phase of depression, psychoses, and insomnia. Given the opposing effect on the LC compared to classical psychostimulants such as cocaine and amphetamines, a compound of the invention may be used to treat psychostimulant- induced psychosis.

[0244] The LC also plays a crucial role in anxiety, pain perception, sleep disorders 10 (Morris et al., 2020; Van Egroo et al., 2022) and mediates anaesthesia states (Morena et al., 2020). The Examples herein show that compounds of the invention tested in mice induced acute sedative effects in the mice and significantly reduced levels of the neurotransmitters NE, 5-hydroxy tryptamine and adenosine in the midbrain and brainstem. These observations suggest that compounds of the invention could be used to treat 15 anxiety, pain perception or sleep disorders. Alternatively, a compound of the invention may be used as a sedative or to induce anaesthesia in a subject.

[0245] In contrast chronic dosing of the compounds of the invention showed anti- depressant like effects and the absence of chronic sedative effects. Mice treated with a compound of the invention tended to display increased mobility compared to controls in the 20 tail suspension test which is indicative of increased stress resilience and antidepressant activity.

[0246] NET inhibitors can induce anxiogenic and / or weight loss. Certain compounds of the invention exhibit reduced anxiogenic and / or reduced weight loss compared to known NET inhibitors. Accordingly in some embodiments administration of a 25 compound of the invention to a subject does not induce anxiogenic effects in the subject. For example, administration of a compound of the invention does not induce anxiety or panic attacks in the subject. In some embodiments administration of a compound of the invention to a subject does not induce weight loss in the subject.

[0247] A further aspect of the invention provides a compound of the invention, or a 30 pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a disease or medical disorder mediated by one or more of norepinephrine transporters (NET), dopamine transporters (DAT), serotonin transporters (SERT), sigma-1 receptor (σ1R), muscarinic M1receptors and / or muscarinic M2receptors.

[0248] Also provided is a method of preventing or treating a disease or medical disorder 35 mediated by one or more of norepinephrine transporters (NET), dopamine transportersP382113WO 94 (DAT), serotonin transporters (SERT), sigma-1 receptor (σ1R), muscarinic M1receptors and / or muscarinic M2receptors in a subject, the method comprising administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof. 5

[0249] Also provided is the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of a disease or medical disorder mediated by one or more of norepinephrine transporters (NET), dopamine transporters (DAT), serotonin transporters (SERT), sigma-1 receptor (σ1R), muscarinic M1receptors and / or muscarinic M2receptors. 10

[0250] In certain embodiments the compound of the invention is for use in the treatment or prevention of a disease or medical disorder mediated by one or more of norepinephrine transporters (NET), dopamine transporters (DAT) and / or serotonin transporters (SERT).

[0251] In certain embodiments the compound of the invention is for use in the treatment or prevention of a disease or medical disorder mediated by dysfunction of the locus 15 coeruleus noradrenergic system.

[0252] In certain embodiments the compound of the invention is for use as a neuromodulatory agent in the treatment of a disease or disorder selected from a neuropsychiatric or neurodegenerative disorder associated with monoamine dysregulation.

[0253] In certain embodiments the compound of the invention is for use in the treatment 20 or prevention of a neuropsychiatric or a neurodegenerative disease or condition. Neuropsychiatric Diseases and Conditions

[0254] Also provided is a compound of the invention for use in the prevention or treatment of a neuropsychiatric disease or condition.

[0255] In some embodiments a compound of the invention is for use in the treatment or25 prevention of a neuropsychiatric disease or condition selected from attention- deficit / hyperactivity disorder (ADHD), depression (including for example, major depressive disorder (MDD) and the treatment of manic phases of depression), an anxiety disorder (including general anxiety disorder (GAD) and social anxiety disorder (SAD)),panic attacks, a substance use disorder, a stimulant use disorder (including disorders associated with 30 cocaine, amphetamines, adderall or ritalin), substance abuse (including alcohol abuse and opioid abuse), an eating disorder (e.g. binge eating disorder or bulimia nervosa), addiction, aggression, paranoia, psychosis (including psychostimulant-induced psychosis (e.g. cocaine induced psychosis or amphetamine induced psychosis)), delusional disorders, hallucinations, post-traumatic stress disorder (PTSD), an obsessive-compulsive disorderP382113WO 95 (OCD), Tourette syndrome, inhibition of negative memory formation (for example inhibition of negative memory formation associated with PTSD, OCD or Tourette syndrome), cognitive impairment (e.g. age-related cognitive decline) and schizophrenia.

[0256] In some embodiments the compound of the invention is for use in the treatment or 5 prevention of cognitive impairment associated with a neuropsychiatric disease or condition. For example, cognitive impairment associated with schizophrenia.

[0257] In some embodiments a compound of the invention is for use in the treatment or prevention of paranoia or anxiety associated with a neuropsychiatric disease or condition. For example, a compound of the invention may be for use in the treatment or prevention of 10 paranoia or anxiety associated with schizophrenia. Neurodegenerative Disorders

[0258] Also provided is a compound of the invention for use in the treatment or prevention of a neurodegenerative disease.

[0259] In certain embodiments a compound of the invention is for use in the treatment or 15 prevention of a neurodegenerative disease selected from Parkinson's disease, Alzheimer's disease, Huntington's disease, dystonia, amyotrophic lateral sclerosis (ALS), age-related neurodegeneration and Lewy body dementia. In some embodiments the neurodegenerative disease is selected from Parkinson's disease and Alzheimer's disease.

[0260] In some embodiments a compound of the invention is for use in the prevention or 20 treatment of cognitive impairment associated with a neurodegenerative disease (for example cognitive impairment associated with Alzheimer’s disease or Parkinson’s disease).

[0261] In some embodiments a compound of the invention is for use in the prevention or treatment of insomnia associated with a neurodegenerative disease (for example insomnia 25 associated with Alzheimer’s disease or Parkinson’s disease).

[0262] In some embodiments a compound of the invention is for use in the treatment or prevention of paranoia or anxiety associated with a neurodegenerative disease or condition. For example, a compound of the invention may be for use in the treatment or prevention of paranoia or anxiety associated with Alzheimer’s disease, Parkinson’s 30 disease or schizophrenia. Epilepsy and Seizures

[0263] In certain embodiments a compound of the invention is for use in the treatment of epilepsy or seizures.P382113WO 96

[0264] In certain embodiments a compound of the invention is for use in the treatment of an epilepsy selected from: idiopathic epilepsy, cryptogenic epilepsy and symptomatic epilepsy. Idiopathic epilepsy is epilepsy with no apparent cause.

[0265] In some embodiments a compound of the invention is for use in the treatment of 5 an epilepsy syndrome. For example a compound of the invention may be for use in the treatment of an epilepsy syndrome selected from: childhood absence epilepsy, benign Rolandic epilepsy, Doose syndrome, Dravet syndrome, early myoclonic encephalopathy, epilepsy in infancy with migrating focal seizures, Jeavons syndrome, epilepsy with myoclonic absences, epilepsy with generalised tonic-clonic seizures, epileptic 10 encephalopathy with continuous spike and wave during sleep, febrile illness-related epilepsy syndrome, genetic epilepsy with febrile seizures plus, West syndrome, juvenile absence epilepsy, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox- Gastaut syndrome, myoclonic epilepsy of infancy, Ohtahara syndrome, Panayiotopoulos syndrome, progressive myoclonic epilepsies, reflex epilepsies, self-limited familial and 15 non-familial neonatal-infantile seizures, Gastaut syndrome, sleep-related hypermotor epilepsy, and temporal lobe epilepsy. Pain

[0266] In certain embodiments a compound of the invention is for use in the treatment or prevention of pain. In some embodiments a compound of the invention is for use in the 20 treatment of chronic pain, neuropathic pain (e.g. peripheral neuropathic pain or central neuropathic pain), or nociceptive pain. In some embodiments the pain is neuropathic pain. In some embodiments the pain is peripheral neuropathic pain. In some embodiments the pain is central neuropathic pain. Sedation and anaesthesia 25

[0267] In certain embodiments a compound of the invention is for use as a sedative. In some embodiments a compound of the invention is for use is sedating a subject. For example, a compound of the invention may be for use in sedating a subject undergoing a surgical procedure.

[0268] Also provided is a method of sedating a subject, the method comprising 30 administering an effective amount of a compound of the invention.

[0269] In certain embodiments a compound of the invention is for use as an anaesthetic. In some embodiments a compound of the invention is for use in inducing or maintaining anaesthesia in a subject. For example, a compound of the invention is for use in inducing or maintaining anaesthesia in a subject undergoing a surgical procedure. In someP382113WO 97 embodiments the compound of the invention prevents or inhibits pain or discomfort associated with a surgical procedure.

[0270] In some embodiments the compound of the invention provides both anaesthetic effects and analgesic effects when administered to a subject. 5

[0271] In some embodiments the compound of the invention may be used to provide acute anaesthesia during, for example a surgical procedure.

[0272] Also provided is a method of inducing or maintaining anaesthesia in a subject, the method comprising administering to the subject an effective amount of a compound of the invention. 10

[0273] The compound of the invention may be used alone or together with another anaesthetic agent. The compound of the invention may potentiate the anaesthetic effect of the other anaesthetic agent, for example by increasing one or more of the depth and / or duration of anaesthesia. Therefore, in some embodiments a compound of the invention is for use in combination with another anaesthetic agent to induce or maintain anaesthesia in 15 a subject.

[0274] The compound of the invention may be used together with an adjuvant to supplement or enhance the anaesthetic effect of the compound of the invention. Suitable adjuvants include, for example, opioids, lidocaine or a benzodiazepine (e.g. midazolam or remimazolam). 20

[0275] In some embodiments the use of a compound of the invention together with another anaesthetic agent may enable a satisfactory depth of anaesthesia to be achieved at a reduced level of the other anaesthetic agent (compared to use of the other anaesthetic alone). This has the advantage of reducing the risk of side effects and / or the discomfort associated with recovery from the use of higher amounts of anaesthetic compounds. For 25 instance, known anaesthetics can be associated with respiratory depression whereby patients stop spontaneous breathing. Therefore, administration of a compound of the invention with a reduced level of a known anaesthetic may result in an acceptable level of anaesthesia without respiratory depression.

[0276] The compound of the invention may be administered separately sequentially or 30 simultaneously with the other anaesthetic agent.

[0277] The other anaesthetic agent may be, for example, propofol, fospropofol, etomidate ketamine, dexmedetomidine or methohexital. Alternatively, the other anaesthetic agent may be an inhaled anaesthetic, for example, nitrous oxide, isoflurane sevoflurane or desflurane.P382113WO 98 Sleep Disorders

[0278] In some embodiments the compound of the invention is for use in the treatment or prevention of a sleep disorder.

[0279] It may be that the compound of the invention reduces the onset of sleep, the 5 duration of sleep and / or quality of sleep.

[0280] There are a number of ways to determine whether the onset, duration or quality of sleep (e.g. non-restorative or restorative sleep) is impaired or improved. One method is a subjective determination by the subject themselves (e.g., do they feel drowsy or rested upon waking. Other methods involve the observation of the patient by a third-party during 10 sleep to assess, for example, how long it takes the patient to fall asleep, how many times the patient wakes up during the night or restlessness during sleep. Another method is to objectively measure the stages of sleep. Polysomnography is the monitoring of multiple electrophysiological parameters during sleep and generally includes measurement of EEG activity, electrooculographic (EOG) activity and electromyographic activity, as well as other 15 measurements. These results, along with observations, can measure not only sleep latency (the amount of time required to fall asleep) , but also sleep continuity (overall balance of sleep and wakefulness) which may be an indication of the quality of sleep.

[0281] There are five distinct sleep stages which can be measured by polysomnography: rapid eye movement (REM) sleep and four stages of no-rapid eye movement (NREM) 20 sleep (stages 1, 2, 3 and 4) . Stage 1 NREM sleep is a transition from wakefulness to sleep and occupies about 5% of time spent asleep in healthy adults. Stage 2 NREM sleep, which is characterized by specific EEG waveforms (sleep spindles and K complexes) , occupies about 50% of time spent asleep. Stages 3 and 4 NREM sleep (also known collectively as slow-wave sleep) are the deepest levels of sleep and occupy about 10-20% 25 of sleep time. REM sleep, during which the majority of typical story-like dreams occur, occupies about 20-25% of total sleep.

[0282] These sleep stages have a characteristic temporal organization across the night. NREM stages 3 and 4 tend to occur in the first one-third to one-half of the night and increase in duration in response to sleep deprivation. REM sleep occurs cyclically through 30 the night. Alternating with NREM sleep about every 80-100 minutes. REM sleep periods increase in duration toward the morning. Human sleep also varies characteristically across the life span. After relative stability with large amounts of slow-wave sleep in childhood and early adolescence, sleep continuity and depth deteriorate across the adult age range. This deterioration is reflected by increased wakefulness and stage 1 sleep and decreased 35 stages 3 and 4 sleep.P382113WO 99

[0283] In some embodiments the compound of the invention enhances or prolongs REM sleep.

[0284] In some embodiments the sleep disorder is insomnia. For example, a compound of the invention may be for use in the treatment or prevention of primary Insomnia, 5 insomnia related to a neurodegenerative disease or insomnia associated with a neuropsychiatric disease or condition.

[0285] In some embodiments the compound of the invention is for use in the prevention or treatment of insomnia associated with a neurodegenerative disease (for example insomnia associated with Alzheimer’s disease or Parkinson’s disease). 10

[0286] In some embodiments the compound of the invention is for use in the treatment or prevention of substance-induced insomnia, for example insomnia induced by one or more of caffeine, alcohol, amphetamine, opioids, sedatives, hypnotics and anxiolytics.

[0287] In some embodiments the compound of the invention is for use on the prevention or treatment of insomnia associated with depression, anxiety or schizophrenia. 15 Biological Assays

[0288] The effect of a compound of the invention on inhibiting norepinephrine transporters (NET), dopamine transporters (DAT), serotonin transporters (SERT), sigma-1 receptors, muscarinic M1 receptors and / or muscarinic M2 receptors may be assessed in-vitro using the assays described in the Examples. 20

[0289] The effect of a compound of the invention in inhibiting monoamine uptake (e.g. NE and DE) may be assessed using the PC12 Cellular Assay described in the Examples.

[0290] The effects of the compound in-vivo may be assessed using, for example the behavioural rodent models described in the Examples. Compound Library 25

[0291] Also provided is a compound library comprising a plurality of compounds of the invention. In some embodiments, the library can be encoded to provide the identity of the compound. The library can include a plurality of compounds (e.g., including one or more of any compounds herein) provided in any useful format (e.g., beads, wells, arrays, etc.). The compound library comprises a plurality of different compounds of the invention, for 30 example at least 10, at least 100, at least 1000 or at least 10,000 compounds or more.

[0292] The compound library may be used in screening methods, for example high throughput screening to identify compounds that bind to, degrade, inhibit, agonise, antagonise or otherwise modulate a biological target (e.g. a receptor, enzyme or cell).P382113WO 100 Use as Intermediates

[0293] The compounds of the invention may also be used as intermediates in the synthesis of larger molecules, for example larger pharmacologically active compounds. Accordingly, also provided is the use of a compound of the invention as an intermediate in 5 the synthesis of another compound, for example another pharmacologically active compound. Synthesis

[0294] In the description of the synthetic methods described below and in the referenced synthetic methods that are used to prepare the staring materials, it is to be understood that 10 all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art.

[0295] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and 15 reaction conditions utilised.

[0296] Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively, necessary starting materials are obtainable by analogous procedures to those 20 illustrated which are within the ordinary skill of an organic chemist. General Synthetic Routes

[0297] Compounds of the invention may be prepared by the methods summarised in General Reaction Scheme 1: General Reaction Scheme 1P382113WO 101

[0298] The compounds shown in General Reaction Scheme 1 are shown with the relative (±) cis- or trans- conformation. The individual enantiomers may be separated using chiral 5 HPLC.P382113WO 102

[0299] The cis-fused (5,7) diamine 2a shown in General Reaction Scheme 1 may be prepared from the pyrrolocyclohexanone 5, which is converted to 6 by Boc protection followed by hydrogenation of the pyrrole ring under mild conditions (PtO2, 10 bar H2, 2 eq. AcOH, iPrOH, 50°C, 6 h) to form the cis-fused pyrrolidinocyclohexanol intermediate 7, and 5 reoxidation to form ketone 8. Oxime formation, tosylation, and Beckmann rearrangement provides lactams 9 and 10 as 1:1.3 mixture of regioisomers, reflecting the Z / E ratio of the oxime intermediate. Lactam 10 is separated from its regioisomer and reduced with LiAlH4 to the corresponding azepane 11, which was deprotected to yield the cis-fused (5,7)- diamine 2a. This method is illustrated in General Reaction Scheme 2: 10 General Reaction Scheme 2Conditions: a) Boc2O, DIPEA, DMAP, ACN, 22 °C, 24 h, quant.; b) PtO2, H2 (10 bar), 2 eq. 15 AcOH, iPrOH, 50 °C, 6 h, 71%; c) DMP, DCM, 22 °C, 30 min, quant.; d) NH2OH^HCl, pyr, 22 °C, 2 h; e) p-TsCl, pyr, 22 °C, 2 h; f) KOAc, EtOH / H2O, 100 °C, 16 h, 10: 57% over three steps, 10:91.3:1; g) LiAlH4, THF, 0 °C then 22 °C, 4 h, 46%; h) TFA, DCM, 22 °C, 2 h, 89%.

[0300] Alternatively, the (5,7)-cis fused diamine may be prepared using a diphenylmethyl 20 protecting group according to General Reaction Scheme 3: General Reaction Scheme 3P382113WO 103Conditions: a) TFA, DCM, 22 °C, 2 h; b) Bromodiphenylmethane, Cs2CO3, DMF, 60 °C, 24 h, 8% over two steps; c) NH2OH^HCl, pyr, 22 °C, 2 h; d) p-TsCl, pyr, 22 °C, 2 h; e) KOAc, 5 EtOH / H2O, 100 °C, 16 h, 24% over three steps; f) LiAlH4, THF, 0 °C then 22 °C, 4 h, quant.

[0301] Synthesis of the (5,7)-cis fused diamine 2b is illustrated in the second row of General Reaction Scheme 1. Beckmann rearrangement on tosylate 13, obtained from 5 via the separable E-oxime 12 (E-12 / Z-124:1), provides pyrrololactam 14. In this case, hydrogenation required harsher conditions (25 bar H2, Pd / C, AcOH, 100°C, 3 d) to form 10 the trans-fused lactam 15, which was N-benzylated to 16. Reduction of lactam 16 (e.g. with LiAlH4) provides the mono-benzylated (5,7)-diamine 17b, which may be hydrogenated to the trans-fused (5,7)-diamine 2b, as illustrated in General Reaction Scheme 4: General Reaction Scheme 4: 15Conditions: a) NH2OH^HCl, pyr, 22 °C, 2 h, quant., E:Z 4:1; b) p-TsCl, pyr, 22 °C, 2 h, 89%; c) KOAc, EtOH / H2O, reflux, 12 h, 71%; d) 10% Pd / C, H2 (25 bar), AcOH, 100 °C, 3 d, 46%; e) BnBr, K2CO3, MeOH, 22 °C, 2 h, 95%, f) LiAlH4, THF, 0 °C then reflux, 16 h, 73%; g) 20 Pd / C, H2 (1 bar), AcOH, MeOH, 24 h, quant.P382113WO 104

[0302] The (6,7) cis-fused diamine 3a may be prepared from dihydroquinolinone 18, which is reacted stereoselectively with hydroxylamine to the E-oxime 19. Tosylation to the corresponding E-tosylate 20 and Beckmann rearrangement then provides lactam 21. Reducing lactam 21 with LiAlH4 to the pyridinoazepane 22 and trifluoroacetylation 5 of the formed secondary amine gives trifluoroacetamide 23. The pyridine ring in 23 is reduced under mild conditions (10 bar H2, Rh / C, iPrOH, 70 °C, 5 d) to yield the cis- fused piperidine 24, and finally the corresponding cis-fused (6,7)-diamine 3a after deprotection. This synthesis is illustrated in General Reaction Scheme 5A.

[0303] The (6,7) trans-fused diamine 3b may be prepared by hydrogenation of lactam 10 21 under somewhat stronger conditions (20 bar H2, Pd / C, AcOH, 100 °C, 2 d) to provide the trans-fused piperidine 25, which is N-benzylated to 26, reduced (e.g. with LiAlH4) to 27b, and deprotected to the free trans-(6,7)-diamine 3b. This synthesis is illustrated in General Reaction Scheme 5B. General Reaction Scheme 5 15Conditions: a) NH2OH^HCl, NaOAc, MeOH / H2O, reflux, 4 h, 98%; b) p-TsCl, KOH, acetone / H2O, reflux, 2 h, 65%; c) KOAc, MeOH / H2O, reflux, 24 h, 91%; d) LiAlH4, THF, 0P382113WO 105 °C then reflux, 6 h, 81%; e) TFAA, pyr, DCM, 22 °C, 2 h, 90%; f) Rh / C, H2(10 bar), iPrOH, 70 °C, 5 d, 98%; g) LiOH, THF / H2O, reflux, 24 h, 78%; h) 10% Pd / C, H2(20 bar), AcOH, 100 °C, 2 d, 32%; i) BnBr, K2CO3, MeOH, 22 °C, 2 h, 64%, j) LiAlH4, THF, 0 °C then 22 °C, 22 h, 79%; k) Pd / C, H2(1 bar), AcOH, MeOH, 22°C 24 h, quant. 5

[0304] The (7,7)-trans-fused diamine 4b may be obtained starting from 5- methoxytetralone 28 by ring expansion via E-oxime 29 and oxime tosylate 30 to gave lactam 31. Demethylation with BBr3 provides phenol 32, which is then hydrogenated to provide the trans-fused cyclohexanol 33 and ketone 34 after reoxidation of the alcohol. A Schmidt reaction followed by reduction of the crude bis-lactam with LiAlH4, provides 10 the trans-fused (7,7)-diamine 4b. This synthesis is illustrated in General Reaction Scheme 6: General Reaction Scheme 615 Conditions: a) NH2OH^HCl, NaOH, EtOH, reflux, 2 h, quant.; b) p-TsCl, pyr, acetone / H2O, 22 °C, 24 h, quant.; c) AcOH, H2O, 70 °C, 24 h, 75%; d) BBr3, DCM, -78 °C to 22 °C, 24 h, 84%; e) Rh / C, H2(20 bar), 2 eq. AcOH, iPrOH, 70 °C, 5 d, 43%; f) DMP, DCM, 22 °C, 1 h, 82%; g) H2SO4, NaN3, CHCl3, 0 °C to 22 °C, 24 h; h) LiAlH4, THF, 0 °C then reflux, 24 h.

[0305] The cis-fused (7,7)-diamine 4a was not obtained using analogous methods. 20 However, it may be possible to prepare the cis-fused (7,7)-diamine using a Schmidt reaction starting from the Boc-protected ketone 53 as illustrated in Potential Reaction Scheme 7: Potential Reaction Scheme 7:P382113WO 106a)NaN3, H2SO4, CHCl3, 0 °C then 22 °C, 24 h; b) LiAlH4, THF, 0 °C then reflux, 24 h. The Boc group is expected to be removed under acidic conditions. Subsequent treatment of the crude lactam with LiAlH4 is expected to provide the unexplored cis-(7,7)-diamine 4a. 5

[0306] In summary General Reaction Schemes 1 to 7 the cis-fused azepanes resulted from hydrogenations of aromatic precursors conducted with only small amounts or no acid (Scheme 1, steps b and f’), while trans-fused azepanes were formed when hydrogenation of the aromatic rings required more forcing conditions, sometimes using acetic acid as 10 solvent (Scheme 1, steps l, h’ and e’’).

[0307] Compounds of the invention wherein R1and R2are not H may be prepared by modifying a compound 2a, 2b, 3a, 3b or 4a to introduce the R1 / R2group using an appropriate orthogonal protection strategy. Alternatively, the R1and R2groups can be introduced earlier in the synthesis as illustrated in the Examples herein. By way of illustration compounds of 15 the invention wherein R1or R2is benzyl may be prepared using General Reaction Schemes 8 to 11: General Reaction Scheme 8: Synthesis of (5,7)-cis- and trans-fused diamine mono-benzylatesP382113WO 107A) Conditions: a) BnBr, K2CO3, MeOH, 22 °C, 2 h, 89%; b) TFA, DCM, 22 °C, 2 h, 64%; c) TFAA, pyr, DCM, 22 °C, 2 h; d) TFA, DCM, 22 °C, 2 h, 48% over two steps; e) BnBr, K2CO3, 5 MeOH, 22 °C, 2 h; f) LiOH, THF / H2O, reflux, 24 h, 39% over two steps; B) Conditions: g) Boc2O, NEt3, DMAP, DCM, 22 °C, 2 h, 64%; h) LiAlH4, THF, 0 °C then 22 °C, 3 h, 45%; i) BnBr, K2CO3, MeOH, 22 °C, 2 h; j) TFA, DCM, 22 °C, 2 h, 70% over two steps. General Reaction Scheme 9: 10 Synthesis of (6,7)-cis and trans-fused diamine mono-benzylatesP382113WO 108A) Conditions: a) Boc2O, NEt3, DMAP, DCM, 22 °C, 2 h; b) LiOH, THF / H2O, reflux, 24 h, 76% over two steps; c) BnBr, K2CO3, MeOH, 22 °C, 2 h; d) TFA, DCM, 22 °C, 2 h, 79% over 5 two steps; e) BnBr, K2CO3, MeOH, 22 °C, 2 h; f) LiOH, THF / H2O, reflux, 24 h, 45% over two steps; B) Conditions: g) Boc2O, NEt3, DCM, 22 °C; 80% h) LiAlH4, THF, 0 °C, 4 h, 45%; i) BnBr, K2CO3, MeOH, 22°C, 2 h; j) TFA, DCM, 22 °C, 2 h 76% over two steps. General Reaction Scheme 10: 10 Synthesis of (7,7)-trans-fused diamine mono-benzylatesConditions: a) Boc2O, NEt3, DMAP, DCM, 22 °C, 24 h; b) TFA, CHCl3, 0°C, 90 min, 10% over two steps; c) BnBr, K2CO3, MeOH, 22 °C, 24 h; d) TFA, DCM, 22 °C, 2 h, 67% over 15 two steps.P382113WO 109 General Reaction Scheme 11: Addition of N-substituents using reductive amination.(R,R)-57 (R = 2-chloro) (R,R)-60 (R = 2-chloro) a, b,c or d then e3-bromo) 3-fluoro) ,3-dichloro),5-dichloro) 5 Synthesis of halogenated derivatives of compound (R,R)-1a. A) Conditions: a) Pd / C, H2(1 bar), MeOH, 22 °C, 24 h; b) 4-chlorobenzaldehyde, NaBH3CN, MeOH, reflux, 24 h, 8% over two steps; c) 3-chlorobenzaldehyde, NaBH3CN, AcOH, MeOH, reflux, 24 h, 56% over two steps; d) 2-chlorobenzaldehyde, NaBH3CN, AcOH, MeOH, reflux,10 24 h, 56% over two steps; e) TFA, DCM, 22 °C, 2 h, (R,R)-58 quant., (R,R)-59: 80%, (R,R)- 60: 46%; B) Conditions: a) 3-bromobenzaldehyde, NaBH3CN, AcOH, MeOH, reflux, 24 h; b) 3- fluorobenzaldehyde, NaBH3CN, AcOH, MeOH, reflux, 24 h; c) 2,3-dichlorobenzaldehyde, 15 NaBH3CN, AcOH, MeOH, reflux, 24 h; d) 3,5-dichlorobenzaldehyde, NaBH3CN, AcOH, MeOH, reflux, 24 h; e) TFA, DCM, 22 °C, 2 h, 29% over two steps for (R,R)-61, (R,R)-62, (R,R)-63, (R,R)-64.

[0308] (7,7)-cis compounds of the invention wherein R1or R2is benzyl may be prepared using Potential Reaction Scheme 12:P382113WO 110 Potential Reaction Scheme 12min; e) BnBr, K2CO3, MeOH, 22 °C, 24 h; f) TFA, DCM, 22 °C, 2 h. 5

[0309] To derivatize the C2-symmetrical diamine 4a, a bis-Boc protection / mono deprotection sequence could be used to access the mono-Boc-protected diamine (±)-43a. Benzylation of (±)-43a and subsequent Boc-deprotection could give (±)-44a.

[0310] Analogous methods to those described in General Reaction Schemes 7 to 12 10 may be used to introduce other R1and / or R2substituents into the compounds of the invention.

[0311] Certain of the intermediates described in General Reaction Schemes 1 to 10 and in the Examples, and salts thereof, form a further aspect of the invention. EXAMPLES 15 Abbreviations: Ac – acetyl Bn - benzyl Boc – tert-butoxycarbonyl d - day 20 DCM – dichloromethane Deion - deionised DMAP – 4-dimethylaminopyridine DMF – N,N-dimethylformamide DMP - Dess-Martin periodinane 25 DMSO – dimethylsulfoxide ee – enantiomeric excess eq. – equivalents h - hour HPLC – high performance liquid chromatography 30 LCMS – liquid chromatograph-mass spectrometry MS – mass spectrometryP382113WO 111 NMR – nuclear magnetic resonance o.n. – over night Pd / C – palladium-on-carbon rt – retention time 5 TFA – trifluoroacetic acid TFAA – trifluoroacetic anhydride THF – tetrahydrofuran TLC – thin-layer chromatography Ts - tosyl 10 Reagents. Commercially available chemicals were purchased from commercial suppliers: Sigma Aldrich, Fluorochem, Alfa Aesar, Combi-Blocks, Toronto Research Chemicals, Apollo Scientific and others. They were used without further purification unless otherwise stated. 15 Solvents. Dry solvents for reaction (DCM, THF, toluene) were obtained by an in-house dry solvent system (filtration over alumina under a positive pressure of argon). Other dry solvents (DMF, pyridine) were purchased form commercial sources. Solvents used for non- anhydrous reactions, extractions and chromatography (acetic acid, acetone, CHCl3, CH3CN, DCM, EtOAc, EtOH, heptane,iPrOH, MeOH, THF) were bought in technical quality and 20 distilled before use or bought in HPLC grade from commercial suppliers. Reactions. If necessary, reactions were performed using standard Schlenk techniques in flame- dried flasks under a positive pressure of argon. Reactions were monitored by thin- layer chromatography (TLC) or by analytical liquid chromatography mass spectrometry (-). 25 Thin-layer chromatography (TLC). TLC was conducted on pre-coated aluminum sheets (0.2 mm silica gel 60 with fluorescent indicator, ALUGRAM®Xtra SIL G / UV254by Macherey- Nagel). Visualization was performed by either UV light (254 nm) or by staining with potassium permanganate solution or ninhydrin solution. 30 Column chromatography. Adsorption column chromatography was carried out with SiO2(pore size: 60 Å, 230-400 mesh particle size by Sigma Aldrich) and distilled technical solvents. 35 NMR spectra (1H,13C). NMR spectra were recorded at 22 °C unless otherwise stated. Chemical shifts (δ) are reported in ppm relative to the signal of tetramethylsilane (TMS) and residual solvent signals in1H and13C NMR spectra were used as internal reference.P382113WO 112 Coupling constants (J) are given in Hz. The apparent resonance multiplicity is described as s (singlet), d (doublet), t (triplet), q (quartet), quint. (quintet), m (multiplet), or combinations thereof and broad signals are indicated as br (broad). Atom to peak assignment was performed through standard 2D NMR techniques such as COSY, HSQC, HMBC, and 5 NOESY.1H and13C -NMR spectra were measured either on a Bruker Avance III 300 spectrometer (at 300 MHz and 75 MHz, respectively) or on a Bruker Avance II 400 spectrometer (at 400 MHz and 101 MHz, respectively). High-resolution mass spectrometry (HR-MS). HR-MS analyses were performed by the 10 mass spectrometry service of the department of chemistry and biochemistry at the University of Bern on an LTQ Orbitrap XL with nano ESI (Thermo). Single Crystal X-ray diffraction. Single crystal X-ray diffractions were measured by the XRD-service of the University of Bern and the experiments are carried out using Oxford 15 Diffraction (now Agilent) SuperNova, equipped with Mo micro-source and Oxford cryosystem 700 for low / high temperature measurements. Recrystallization of p-TsCl. Upon prolonged standing the chemical develops impurities of p-toluenesulfonic acid and HCl. Therefore, tosyl chloride was purified by dissolving 10 g in 20 CHCl3 (25 mL), filtering and diluting with petroleum ether (125 mL) to precipitate impurities. The solution was clarified with charcoal, filtered and concentrated to yield 8 g of white crystals. Fieser work-up. The following procedure was used to work-up reactions with x g of LiAlH4. 25 1. Dilute with THF and cool to 0°C 2. Slowly add x mL deion. H2O 3. Add x mL aq. NaOH (15%) 4. Add 3x mL deion. H2O 5. Warm to room temperature and stir 15 min 30 6. Add some anhydrous MgSO47. Stir 15 min and filter to remove salts HCl and TFA salt formation. The HCl and TFA salts disclosed in these Examples were obtained by treatment of the dried purified diamines with HCl in MeOH or TFA in MeOH (3 M solutions), 3 eq. per amine. The solvent was evaporated and the procedure repeated 35 once. SynthesisP382113WO 113 tert-butyl 4-oxo-4,5,6,7-tetrahydro-1H-indole-1-carboxylate (6)qua . Boc5 To a solution of commercially available 1,5,6,7-tetrahydro-4H-indol-4-one 5 (10.0 g, 74.0 mmol, 1.0 eq.) in CH3CN (370 mL, 0.2 M) was added Boc2O (17.7 g, 81.1 mmol, 1.1 eq.), DIPEA (19.3 mL, 111 mmol, 1.5 eq.) and DMAP (cat.). The mixture was stirred at 22 °C for 24 hours. Then the solvent was evaporated and the crude was purified by flash column chromatography on silica gel (30% EtOAc in heptane) to isolate Boc-protected 10 amine 6 (17.4 g, 74.0 mmol, quant.) as an orange solid; Rf= 0.25 (30% EtOAc in heptane); 1H-NMR (400 MHz, CDCl3, 298 K): δ [ppm] = 7.13 (d, J = 3.5 Hz, 1H); 6.51 (d, J = 3.5 Hz, 1H), 3.10 (t, J = 6.2 Hz, 2H), 2.44 (t, J = 4.4 Hz, 2H), 2.12 (quint., J = 6.4 Hz, 2H), 1.58 (s, 9H); HR-MS (ESI): (m / z) = calculated for C13H17NO3Na+[M+Na]+: 258.1101, found: 258.1097. 15 tert-butyl-4-hydroxyoctahydro-1H-indole-1-carboxylate ((±)-7) OH 3 PtO 3a 2, H2(10 bar), AcOH 5 46 Boc7A mixture of ketone 6 (8.93 g, 38.0 mmol, 1.0 eq.), PtO2 (PtO2 on activated charcoal, 890 mg, 10 wt% of substrate) and AcOH (2.40 mL, 41.8 mmol, 1.1 eq.) iniPrOH (50 mL) was 20 stirred in a sealed autoclave at 50 °C under H2 pressure (10 bar) for 6 hours. After cooling to room temperature, the reaction mixture was carefully filtered over celite, washed with MeOH and evaporated to dryness. The crude was purified by flash column chromatography on silica gel (30%-60% EtOAc in heptane) to afford aliphatic bicycle (±)-7 (6.54 g, 27.1 mmol, 71%) as a yellow oil; Rf = 0.20 (30% EtOAc in heptane);1H-NMR (400 MHz, MeOD-d4, 298 25 K): δ [ppm] = 3.88-3.93 (m, 1.4H), 3.73-3.80 (m, 0.6H), 3.43-3.49 (m, 0.6H) 3.36-3.40 (m, 0.5H), 3.25-3.28 (m, 0.4H), 2.42-2.55 (m, 0.6H), 2.20 (br, 0.4H), 1.84-1.98 (m, 3H), 1.59- 1.70 (m, 2.5H), 1.45 (s, 9H), 1.00-1.40 (m, 3H);13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 156.1, 2X 80.6, 2X 70.3, 69.0, 58.6, 58.2, 56.0, 46.1, 46.0, 45.6, 45.3, 2X 30.0, 28.8, 28.1, 27.6, 23.5, 22.7, 22.4, 18.7; due to the presence of alcohol isomers in the NMR 30 measurement, structural assignment is not possible; HR-MS (ESI): (m / z) = calculated for C13H23NO3Na+[M+Na]+: 264.1570, found: 264.1566. tert-butyl-4-oxooctahydro-1H-indole-1-carboxylate ((±)-8)P382113WO 114A solution of alcohol (±)-7 (6.70 g, 27.8 mmol, 1.0 eq.) in DCM (275 mL, 0.1 M) was cooled to 0 °C and DMP (23.5 g, 55.4 mmol, 2.0 eq.) was added. The reaction was stirred at 22 °C 5 for 30 minutes. Then it was quenched by addition of sat. NaHCO3solution (125 mL) and Na2S2O3solution (2 M, 125 mL). The water phase was washed with DCM (3x 250 mL). The combined organic phases were washed with deion. H2O (250 mL), dried over Na2SO4, filtered and the solvent was evaporated in vacuo. The crude was purified by column chromatography on silica gel (30% EtOAc in heptane) to yield ketone (±)-8 (6.63 g, 27.7 10 mmol, quant.) as a white solid; Rf= 0.20 (25% EtOAc in heptane);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 4.07-4.12 (m, 1H; H-C(7a)), 3.34-3.44 (m, 2H; H-C(2)), 2.87- 2.93 (m, 1H; H-C(3a)), 2.38-2.47 (m, 1H; H-C(5)), 2.27-2.34 (m, 1H; H-C(5)), 2.16-2.25 (m, 2H; H-C(3 and 7)), 1.95-2.03 (m, 1H; H-C(3)), 1.84-1.91 (m, 1H; H-C(6)), 1.58-1.72 (m, 2H; H-C(6 and 7)), 1.47 (s, 9H; H3-CBoc);13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 213.3 15 (C(4)), 156.1 ((C=O)Boc), 81.1 ((Cq)Boc), 60.3 (C(7a)), 53.1 (C(3a)), 46.4 (C(2)), 39.4 (C(5)), 28.7 ((CH3)Boc), 2X 28.0 (C(3 and 7)), 22.0 (C(6)); HR-MS (ESI): (m / z) = calculated for C13H21NO3Na+[M+Na]+: 262.1414, found: 262.1408. Example 1: (±)-cis-tert-butyl-5-oxooctahydropyrrolo[3,2-b]azepine-1(2H)- 20 carboxylate ((±)-10)Ketone (±)-8 (2.0 g, 8.36 mmol, 1.0 eq.) was dissolved in pyridine (25 mL) and NH2OH•HCl (1.16 g, 16.7 mmol, 2.0 eq.) was added. The reaction mixture was stirred at 22 °C for 2 hours. Then the pyridine was evaporated, and the residue was taken up in deion. H2O (25 25 mL) and extracted with EtOAc (3x 50 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was evaporated to afford a mixture of oxime isomers as white sticky solid. The intermediate product was dissolved in pyridine (25 mL) was added freshly recrystallized p-TsCl (1.81 g, 9.49 mmol, 1.2 eq.) and the solution was stirred at 22 °C for 2 hours. After completion the solvent was evaporated, and the crude was taken up inP382113WO 115 deion. H2O (25 mL) and extracted with EtOAc (3x 50 mL). The organic phases were dried over Na2SO4, filtered and the solvent was evaporated to yield a mixture of tosyl isomers as yellow sticky solid. The intermediate product was further reacted with potassium acetate (2.34 g, 23.8 mmol, 3.0 eq.) in a mixture of EtOH (50 mL) and deion. H2O (50 mL). The 5 reaction was stirred and refluxed for 16 hours. After cooling to room temperature and evaporation of the EtOH, the remaining aqueous solution was adjusted to pH = 10 by addition of aqueous NaOH solution (1 M, 6 mL). The aqueous phase was extracted with DCM (3x 200 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash 10 column chromatography on silica gel (80% EtOAc in heptane to EtOAc) to isolate the major lactam regioisomer (±)-10 (690 mg, 2.70 mmol, 32%, ratio 1.3:1) as a white solid. tert-butyl (3aS,8aS)-4-oxooctahydropyrrolo[3,2-c]azepine-1 -carboxylate ((±)-9)15 Minor lactam regioisomer (±)-9 (523 mg, 2.06 mmol, 25%, ratio 1:1.3) was isolated as a white solid from the above reaction; Rf= 0.20 (80% EtOAc in heptane);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 3.93-3.99 (m, 1H), 3.44-3.52 (m, 2H), 3.38-3.42 (m, 1H), 3.18- 3.23 (m, 1H), 3.10-3.16 (m, 1H), 2.29-2.36 (m, 1H), 2.22 (br, 1H), 1.84-2.09 (m, 2H), 1.72- 20 1.82 (m, 1H), 1.62-1.67 (m, 1H), 1.46 (s, 9H; H3-CBoc);13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 176.6 (C(4)), 155.9 ((C=O)Boc), 81.20 ((Cq)Boc), 56.8 (CH), 47.3 (CH), 46.4 (CH2), 39.1 (CH2), 28.7 ((CH3)Boc), 27.3 ((CH2), 27.0 ((CH2), 25.2 (CH2); HR-MS (ESI): (m / z) = calculated for C13H23N2O3+[M+H]+: 255.1703, found: 255.1687. 25 Example 2: (±)-cis-tert-butyl-octahydropyrrolo[3,2-b]azepine-1(2H)-carboxylate (±)- 11)A solution of lactam (±)-10 (568 mg, 2.23 mmol, 1.0 eq.) in dry THF (24 mL, 0.1 M) was cooled to 0 °C, LiAlH4(1 M in THF, 3.4 mL, 3.40 mmol, 1.5 eq.) was added dropwise and 30 the reaction was stirred at 22 °C for 4 hours. The reaction was then worked up using Fieser’sP382113WO 116 protocol and the crude was purified by flash column chromatography on silica gel (10% MeOH in DCM + 0.1% NEt3) to give azepane (±)-11 (248 mg, 1.03 mmol, 46%) as a colorless oil; Rf= 0.20 (10% MeOH in DCM + 0.1% NEt3);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 3.76-3.81 (m, 1H; H-C(8a)), 3.53-3.59 (m, 1H; H-C(3a)), 3.39 (t, J = 8.9 Hz, 1H; H- 5 C(2)), 3.22-3.29 (m, 1H; H-C(2)), 3.03-3.06 (m, 1H; H-C(5)), 2.46-2.53 (m, 1H; H-C(5)), 2.03- 2.10 (m, 1H; H-C(3)), 1.70-1.92 (m, 4H; H-C(3, 6, 7 and 8)), 1.59-1.61 (m, 1H; H-C(8)), 1.45 (m, 11H; H3-CBoc and H-C(6, 7)),13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 156.4 ((C=O)Boc), 80.8 ((Cq)Boc), 64.0 (C(8a)), 61.9 (C(3a)), 49.0 (C(5)), 45.3 (C(2)), 32.9 (C(6 or 7)), 31.3 (C(3)), 30.1 (C(8)), 28.8 ((CH3)Boc), 27.4 (C(6 or 7)); HR-MS (ESI): (m / z) = 10 calculated for C13H25N2O2+[M+H]+: 241.1911, found: 241.1912. Example 3: (±)-cis-Decahydropyrrolo[3,2-b]azepine ((±)-2a) 4 Bo(±) (±) To a solution of mono-Boc-protected diamine (±)-11 (90.0 mg, 0.37 mmol, 1.0 eq.) in DCM 15 (4 mL, 0.1 M) was added TFA (0.4 mL, 10 vol%). The reaction was stirred at 22 °C for 2 hours. Then it was washed with NaOH (1 M, 2x 4 mL) and the organic phase was dried over Na2SO4, filtered and the solvent was evaporated to obtain final free diamine (±)-2a (46.5 mg, 0.33 mmol, 89%) as a yellow oil;1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 3.59-3.64 (m, 1H; H-C(3a)), 3.50-3.56 (m, 1H; H-C(8a)), 3.32-3.37 (m, 1H; H-C(2)), 3.18-3.23 (m, 1H; 20 H-C(5)), 3.04-3.11 (m, 1H; H-C(2)), 2.51-2.58 (m, 1H; H-C(5)), 2.36-2.45 (m, 1H; H-C(3)), 2.04-2.11 (m, 1H; H-C(8)), 1.94-1.95 (m, 1H; H-C(7)), 1.74-1.84 (m, 3H; H-C(3, 6 and 8)), 1.52-1.63 (m, 1H; H-C(6)), 1.35-1.45 (m, 1H; H-C(7));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 65.0 (C(8a)), 62.8 (C(3a)), 51.4 (C(5)), 45.3 (C(2)), 33.7 (C(3)), 32.7 (C(6)), 29.7 (C(8)), 25.5 (C(7)); HR-MS (ESI): (m / z) = calculated for C8H17N2+[M+H]+: 141.1386, 25 found: 141.1381. (E)-1,5,6,7-teo-4H-indol-4-one oxime (E-1To a solution of commercially available 1,5,6,7-tetrahydro-4H-indol-4-one 5 (10.4 g, 76.9 mmol, 1.0 eq.) in pyridine (80 mL, 1 M) was added NH2OH•HCl (10.7 g, 154 mmol,P382113WO 117 2.0 eq.). The mixture was stirred at 22 °C for 2 hours, then the pyridine was evaporated, and the residue was diluted with deion. H2O (150 mL) and extracted with EtOAc (3x 200 mL). The organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude product was purified by flash column chromatography on silica gel (50% EtOAc 5 in heptane) to isolate the major (E)-oxime isomer E-12 (9.24 g, 61.5 mmol, 80%; E / Z 4:1) as a yellow solid; Rf = 0.31 (50% EtOAc in heptane);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 6.57 (d, J = 3.0 Hz, 1H; H-C(2)), 6.30 (d, J = 3.0 Hz, 1H; H-C(3)), 2.67 (t, J = 6.5 Hz, 2H; H2-C(5 or 7)), 2.63 (t, J = 6.2 Hz, 2H; H2-C(5 or 7)), 1.89 (quint., J = 6.3 Hz, 2H; H2- C(6));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 156.0 (C(4)), 135.8 (C(7a)), 118.7 10 (C(2)), 114.4 (C(3a)), 103.8 (C(3)), 23.8 (C(5, 6 or 7)), 23.7 (C(5, 6 or 7)), 23.3 (C(5, 6 or 7)); HR-MS (ESI): (m / z) = calculated for C8H11N2O+[M+H]+: 151.0866, found: 151.0863. -tetrahydro-4H-indol-4-one oxime (Z-115 Minor (Z)-oxime isomer Z-12 (2.31, 15.4 mmol, 13%, Z / E 1:4) was isolated as a white solid from the above reaction ; Rf = 0.18 (50% EtOAc in heptane);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 6.84 (d, J = 3.0 Hz, 1H; H-C(2)), 6.62 (d, J = 3.0 Hz, 1H; H-C(3)), 2.72 (t, J = 6.2 Hz, 2H; H2-C(7)), 2.38-2.42 (m, 2H; H2-C(5)), 1.96 (quint., J = 3.7 Hz, 2H; H2-C(6)); 13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 152.8 (C(4)), 136.9 (C(7a)), 117.7 (C(3)), 20 112.3 (C(3a)), 111.4 (C(2)), 30.6 (C(5)), 24.9 (C(6)), 24.2 (C(7)); HR-MS (ESI): (m / z) = calculated for C8H11N2O+[M+H]+: 151.0866, found: 151.0863. (E)-1,5,6,7-tetrahydro-4H-indol-4-one O-tosyl oxime (13)25 To a solution of (E)-oxime isomer E-12 (2.18 g, 14.5 mmol, 1.0 eq.) in pyridine (20 mL) was added freshly recrystallized p-TsCl (3.32 g, 17.4 mmol, 1.2 eq.). The mixture was stirred at 22 °C for 2 hours, then the pyridine was evaporated in vacuo and the crude product was purified by flash column chromatography on silica gel (EtOAc) to afford tosylate 13 (3.94 g, 12.9 mmol, 89%) as a yellow solid; Rf = 0.23 (60% EtOAc in heptane);1H-NMR (400 MHz, 30 CDCl3, 298 K): δ [ppm] = 7.91 (d, J = 8.3 Hz, 2H; H-Ctos., 7.31 (d, J = 8.0 Hz, 2H; H-Ctos.,P382113WO 118 6.62 (t, J = 2.7 Hz, 1H; H-C(3)), 6.37 (t, J = 2.8 Hz, 1H; H-C(2)), 2.72 (t, J = 6.5 Hz, 2H; H2- C(5)), 2.63 (t, J = 6.2 Hz, 2H; H2-C(7)), 2.42 (s, 3H; H3-Ctos), 1.91 (quint., J = 6.3 Hz, 2H; H2- C(6));13C-NMR (100 MHz, CDCl3, 298 K): δ [ppm] = 161.0 (C(4)), 144.6 ((Cq)tos.), 137.1 (C(7a)), 133.3 ((Cq)tos.), 129.5 ((CH)tos.), 129.1 ((CH)tos.), 118.3 (C(3)), 111.9 (C(3a)), 104.8 5 (C(2)), 24.3 (C(5)), 22.3 (C(6 or 7)), 22.3 (C(6 or 7)), 21.8 ((CH3)tos.); HR-MS (ESI): (m / z) = calculated for C15H17N2O3S+[M+H]+: 305.0954, found: 305.0945. 4,6,7,8-tetrahydropyrrolo[3,2-b]azepin-5(1H)-one (14)10 A mixture of tosylate 13 (2.04 g, 6.70 mmol, 1.0 eq.) and KOAc (1.98 g, 20.2 mmol, 3.0 eq.) in EtOH (50 mL) and deion. H2O (50 mL) was stirred and refluxed for 12 hours. After cooling to room temperature and evaporation of the EtOH, the remaining aqueous solution was adjusted to pH = 10 by addition of aqueous NaOH solution (1 M, 6 mL). The aqueous phase was extracted with DCM (3x 200 mL). The combined organic layers were dried over Na2SO4, 15 filtered and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel (EtOAc) to afford lactam 14 (0.71 g, 4.73 mmol, 71%) as a white solid; Rf= 0.27 (EtOAc);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 6.51 (d, J = 2.9 Hz, 1H; H-C(3), 5.76 (d, J = 2.9 Hz, 1H; H-C(2)), 2.83 (t, J = 6.8 Hz, 2H; H2-C(8)), 2.52-2.55 (m, 2H; H2-C(6)) 1.99-2.05 (m, 2H; H2-C(7));13C-NMR (100 20 MHz, MeOD-d4, 298 K): δ [ppm] = 176.7 (C(5)), 120.4 (C(3a)), 119.0 (C(8a)), 116.6 (C(3)), 102.0 (C(2)), 37.0 (C(6)), 27.5 (C(8)), 21.8 (C(7)); HR-MS (ESI): (m / z) = calculated for C8H11N2O+[M+H]+: 151.0866, found: 151.0862, C8H10N2ONa+[M+Na]+: 173.0691, found: 173.0680. Example 4: (±)-trans-Octahydropyrrolo[3,2-b]azepin-5(1H)-one ((±)-15) 25To a solution of lactam 14 (380 mg, 2.53 mmol, 1.0 eq.) in AcOH (5 mL) was added Pd / C (10% Pd on activated charcoal, 38.0 mg, 10 wt% of substrate). The solution was stirred in a sealed autoclave at 100 °C under H2pressure (25 bar) for 3 days. After cooling to room temperature, the reaction mixture was diluted with MeOH and the catalyst was removed by 30 filtration over celite. The crude product was purified by flash column chromatography onP382113WO 119 silica gel (10%-20% MeOH in DCM + 1% NH3) to afford aliphatic bicycle (±)-15 (181 mg, 1.17 mmol, 46%) as a light brown solid; Rf= 0.20 (20% MeOH in DCM + 1% NH3);1H-NMR (400 MHz, CDCl3, 298 K): δ [ppm] = 6.70 (br, 1H; H-N(4), 3.37 (qd, J = 9.0, 4.2 Hz, 1H; H- C(3a)), 3.05-3.11 (m, 2H; H-C(2)), 2.57-2.63 (m, 1H; H-C(8a)), 2.54 (s, 1H; H-N(1)), 2.44- 5 2.48 (m, 2H; H2-C(6)), 2.28-2.37 (m, 1H; H-C(3)), 2.20-2.26 (m, 1H; H-C(8)), 1.88-1.96 (m, 1H; H-C(7)), 1.60-1.77 (m, 2H; H-C(3 and 7)), 1.29-1.39 (m, 1H; H-C(8));13C-NMR (100 MHz, CDCl3, 298 K): δ [ppm] = 178.3 (C(5)), 65.2 (C(8a)), 58.0 (C(3a)), 43.7 (C(2)), 37.2 (C(6)), 35.1 (C(8)), 31.90 (C(3)), 21.9 (C(7)); HR-MS (ESI): (m / z) = calculated for C8H15N2O+[M+H]+: 155.1179, found: 155.1176. 10 Example 5: (±)-trans-1-benzyloctahydropyrrolo[3,2-b]azepin-5(1H)-one ((±)-16)To a solution of amine (±)-15 (455 mg, 2.95 mmol, 1.0 eq.) in MeOH (25 mL) was added benzyl bromide (530 µL, 4.45 mmol, 1.5 eq.) and K2CO3 (629 mg, 4.55 mmol, 1.5 eq.). The 15 mixture was stirred at 22 °C for 2 hours. Then the solvent was evaporated, and the residue was diluted with deion. H2O and extracted with DCM (3x 50 mL). The organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo to give benzylated amine (±)-16 (682 mg, 2.79 mmol, 95%) as a colourless oil; Rf = 0.20 (2% MeOH in DCM + 0.1% NEt3);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 7.24-7.31 (m, 5H; H-Carom.), 4.05 (d, 20 J = 12.8 Hz, 1H; H-Cbenz.), 3.69-3.75 (m, 1H; H-C(3a)), 3.20 (d, J = 12.8 Hz, 1H; H-Cbenz.), 2.87 (td, J = 9.3, 3.6 Hz, 1H; H-C(2)), 2.62-2.70 (m, 1H; H-C(6)), 2.32-2.43 (m, 3H; H-C(2, 6 and 8)), 2.12-2.22 (m, 1H; H-C(3)), 2.00-2.07 (m, 2H; H-C(7 and 8a)), 1.65-1.73 (m, 1H; H- C(3)), 1.56-1.63 (m, 1H; H-C(7)), 1.42-1.52 (m, 1H; H-C(8));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 180.6 (C(5)), 139.2 ((Cq)arom.), 130.4 ((CH)arom.), 129.3 ((CH)arom.), 128.3 25 ((CH)arom.), 71.5 (C(8a)), 58.4 ((CH2)benz.), 58.1 (C(3a)), 52.2 (C(2)), 37.6 (C(6)), 34.0 (C(8)), 28.1 (C(3)), 22.7 (C(7)); HR-MS (ESI): (m / z) = calculated for C15H21N2O+[M+H]+: 245.1648, found: 245.1645. Example 6: (±)-trans-1-benzyldecahydropyrrolo[3,2-b]azepine ((±)-17b) 30P382113WO 120 A solution of lactam (±)-16 (660 mg, 2.70 mmol, 1.0 eq.) in dry THF (27 mL, 0.1 M) was cooled to 0 °C and LiAlH4(1 M in THF, 24.3 mL, 24.3 mmol, 9.0 eq.) was added dropwise. The reaction was heated to reflux and stirred for 16 hours. The reaction mixture was then 5 cooled to room temperature and worked up using Fieser’s protocol. The crude was purified by flash column chromatography on silica gel (10% MeOH in DCM + 1% NH3) to give azepane (±)-17 (451 mg, 1.96 mmol, 73%) as a colorless oil; Rf = 0.20 (10% MeOH in DCM + 1% NH3);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 7.26-7.36 (m, 5H; H-Carom.), 4.04 (d, J = 12.6 Hz, 1H; H-Cbenz.), 3.13-3.20 (m, 2H; H-Cbenz. and H-C(3a)), 2.95-3.01 (m,10 1H; H-C(5, 6, 7 or 8)), 2.80-2.87 (m, 2H; H-C(2 and 5, 6, 7 or 8)), 2.36 (q, J = 9.4 Hz, 1H; H- C(2)), 2.22-2.30 (m, 2H; H-C(8a and H-C(5, 6, 7 or 8)), 2.09-2.17 (m, 1H; H-C(3)), 1.82-1.89 (m, 1H; H-C(5, 6, 7 or 8)), 1.69-1.79 (m, 3H; H-C(5, 6, 7 or 8)), 1.39-1.48 (m, 2H; H-C(3 and 5, 6, 7 or 8);13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 138.9 ((Cq)arom.), 130.7 ((CH)arom.), 129.3 ((CH)arom.), 128.3 ((CH)arom.), 72.4 (C(8a)), 62.5 (C(3a)), 59.2 (CH2)benz.), 15 52.9 (C(2)), 49.6 (C(5, 6, 7 or 8)), 31.1 (C(5, 6, 7 or 8)), 30.6 (C(3)), 28.9 (C(5, 6, 7 or 8)), 26.1 (C(5, 6, 7 or 8)); HR-MS (ESI): (m / z) = calculated for C15H23N2+[M+H]+: 231.1856, found: 231.1854. Example 7: (±)-trans-Decahydropyrrolo[3,2-b]azepine ((±)-2b) 20To a solution of mono-benzylated diamine (±)-17 (147 mg, 0.64 mmol, 1.0 eq.) in MeOH (7 mL, 0.1 M) was added Pd / C (10% Pd on activated charcoal, 15.2 mg, 10 wt% of substrate) and AcOH (75 µL, 1.30 mmol, 2.0 eq.). The reaction mixture was stirred at 22 °C under an atmosphere of hydrogen (1 bar, balloon) for 24 hours. It was then filtered over celite, washed 25 with MeOH and evaporated to dryness. The residue was taken up in DCM and washed with NaOH (1 M, 2x 4 mL) and the organic phase was dried over Na2SO4 to give final free diamine (±)-2b as a yellow oil (90.0 mg, 0.64 mmol, quant.);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 2.88-3.01 (m, 4H), 2.79-2.85 (m, 1H), 2.67-2.73 (m, 1H), 2.13-2.22 (m, 1H), 2.04- 2.11 (m, 1H), 1.63-1.82 (m, 4H), 1.52-1.61 (m, 1H), 1.29-1.40 (m, 1H);13C-NMR (100 MHz, 30 MeOD-d4, 298 K): δ [ppm] = 66.8 (CH), 64.2 (CH), 49.3 (CH2), 44.9 (CH2), 34.5 (CH2), 32.9 (CH2), 29.2 (CH2), 25.8 (CH2); HR-MS (ESI): (m / z) = calculated for C8H17N2+[M+H]+: 141.1386, found: 141.1385. (E)-7,8-dihydroquinolin-5(6H)-one oxime (19)P382113WO 121To a solution of commercially available 7,8-Dihydroquinolin-5(6H)-one 18 (4.90 g, 33.3 mmol, 1.0 eq.) in MeOH (27 mL) and deion. H2O (9 mL) was added NH2OH•HCl (7.09 g, 102 mmol, 3.0 eq.) and sodium acetate (13.7 g, 167 mmol, 5.0 eq.). The mixture was 5 refluxed for 4 hours. The reaction was allowed to cool to room temperature and concentrated under reduced pressure. The formed solid was collected by vacuum filtration and washed with deion. H2O to give (E)-oxime isomer 19 (5.32 g, 32.8 mmol, 98%) as a white solid; Rf= 0.24 (60% EtOAc in heptane);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 8.37 (dd, J = 4.9, 1.7 Hz, 1H; H-C(2)), 8.31 (dd, J = 8.0, 1.7 Hz, 1H; H-C(4)), 7.25 (dd, J = 8.0, 4.8 Hz, 10 1H; H-C(3)), 2.92 (t, J = 6.2 Hz, 2H; H2-C(8)), 2.79 (t, J = 6.6 Hz, 2H; H2-C(6)), 1.93 (quint., J = 6.4 Hz, 2H; H2-C(7));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 159.2 (C(8a)), 153.3 (C(5)), 149.6 (C(2)), 133.6 (C(4)), 129.2 (C(4a)), 123.3 (C(3)), 33.0 (C(8)), 23.9 (C(6)), 21.7 (C(7)); HR-MS (ESI): (m / z) = calculated for C9H11N2O+[M+H]+: 163.0866, found: 163.0866. 15 (E)-7,8-dihydroquinolin-5(6H)-one O-tosyl oxime (20)To a solution of oxime 19 (1.51 g, 9.31 mmol, 1.0 eq.) in acetone (70 mL) and deion. H2O (29 mL) was added freshly recrystallized p-TsCl (2.67 g, 14.0 mmol, 1.5 eq.) and KOH (0.52 g, 9.31 mmol, 1.0 eq.). After heating the mixture to reflux for 2 hours, it was cooled 20 down, concentrated under reduced pressure and the resulting solid was taken up in deion. H2O (50 mL). The aqueous phase was extracted with EtOAc (3x 100 mL). The organic layers were washed with Na2CO3(100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo to obtain tosylate 20 (1.90 g, 6.01 mmol, 65%) as a white solid; Rf= 0.22 (60% EtOAc in heptane);1H-NMR (400 MHz, CDCl3, 298 K): δ [ppm] = 8.55 (dd, J = 4.8, 1.7 25 Hz, 1H; H-C(2 or 4)), 8.15 (dd, J = 8.0, 1.5 Hz, 1H; H-C(2 or 4)), 7.93 (d, J = 8.3 Hz, 2H; H-Ctos.), 7.36 (d, J = 8.2 Hz, 2H; H-Ctos.), 7.17 (dd, J = 8.1, 4.8 Hz, 1H; H-C(3)), 2.96 (t, J = 6.2 Hz, 2H; H2-C(8)), 2.86 (t, J = 6.6 Hz, 2H; H2-C(6)), 2.45 (s, 3H; H3-Ctos.), 1.94 (quint., J = 6.5 Hz, 2H; H2-C(7));13C-NMR (100 MHz, CDCl3, 298 K): δ [ppm] = 161.5 (C(5)), 159.9 (C(8a)), 151.8 (C(2 or 4)), 145.4 ((Cq)tos.), 133.2 (C(2 or 4)), 132.7 ((Cq)tos.), 129.8 ((CH)tos.), 30 129.1 ((CH)tos.), 124.4 (C(4a)), 122.1 (C(3)), 32.3 (C(8)), 25.0 (C(6)), 21.9 ((CH3)tos.), 20.5 (C(7)), HR-MS (ESI): (m / z) = calculated for C16H17N2O3S+[M+H]+: 317.0954, found:P382113WO 122 317.0947, C16H16N2O3SNa+[M+Na]+: 339.0779, found: 339.0765. 5,7,8,9-tetrahydro-6H-pyrido[3,2-b]azepin-6-one (21)Tosylate 20 (2.69 g, 8.50 mmol, 1.0 eq.) was dissolved in EtOH (40 mL) and deion. H2O (80 5 mL), potassium acetate (2.56 g, 25.6 mmol, 3.0 eq.) was added and the mixture was refluxed for 24 hours. After cooling to room temperature and evaporation of the EtOH, the remaining aqueous solution was adjusted to pH = 10 by addition of aqueous NaOH solution (1 M, 10 mL). The aqueous phase was extracted with chloroform (3x 150 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed under reduced 10 pressure to yield lactam 21 (1.25 g, 7.70 mmol, 91%) as a light brown solid; Rf= 0.25 (80% EtOAc in heptane);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 8.28 (dd, J = 4.9, 1.5 Hz, 1H; H-C(2 or 4), 7.45 (dd, J = 8.0, 1.5 Hz, 1H; H-C(2 or 4)), 7.34 (dd, J = 8.0, 4.9 Hz, 1H; H-C(3)), 2.98-3.02 (m, 2H; H2-C(9)) 2.32-2.35 (m, 4H; H2-C(7 and 8));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 176.7 (C(6)), 155.6 (C(9a)), 146.4 (C(2 or 4)), 136.615 (C(4a)), 131.1 (C(2 or 4)), 124.1 (C(3)), 33.8 (C(7 or 8)), 33.5 (C(9)), 28.7 (C(7 or 8)); HR- MS (ESI): (m / z) = calculated for C9H11N2O+[M+H]+: 163.0866, found: 163.0864, C9H10N2ONa+[M+Na]+: 185.0691, found: 185.0683. 620 A solution of lactam 21 (1.25 g, 7.70 mmol, 1.0 eq.) in dry THF (31 mL) was cooled to 0 °C. Then LiAlH4 (1 M in THF, 69.4 mL, 69.4 mmol, 9.0 eq.) was added dropwise. The mixture was stirred at reflux for 6 hours. The reaction was cooled down and worked up using Fieser’s protocol. The crude product was purified by flash column chromatography on silica gel (2% MeOH in DCM + 0.1% NEt3) to afford azepane 22 (0.92 g, 6.21 mmol, 81%) as a white 25 solid; Rf = 0.25 (2% MeOH in DCM + 0.1% NEt3);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 7.88 (dd, J = 4.8, 1.5 Hz, 1H; H-C(4)), 7.23 (dd, J = 8.0, 1.3 Hz, 1H; H-C(2)), 7.06 (dd, J = 8.0, 4.8 Hz, 1H; H-C(3)), 3.02-3.05 (m, 2H; H2-C(6)), 2.94-2.97 (m, 2H; H2-C(9)), 1.80-1.85 (m, 2H; H2-C(7)), 1.67-1.73 (m, 2H; H2-C(8));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 154.3 (C(9a)), 148.6 (C(4a)), 140.7 (C(4)), 128.0 (C(2)) 123.2 (C(3)), 49.1 30 (C(6)), 38.8 (C(9)), 32.4 (C(7)), 26.2 (C(8)); HR-MS (ESI): (m / z) = calculated for C9H13N2+[M+H]+: 149.1073, found: 149.1075.P382113WO 123 trifluoro-1-(6,7,8,9-tetrahydro-5H-pyrido[3,2-b]azepin-5-yl)ethanone (23)To a solution of amine 22 (1.58 g, 10.7 mmol, 1.0 eq.) in DCM (164 mL) was added TFAA (1.78 mL, 12.8 mmol, 1.2 eq.) and pyridine (1.12 mL, 13.9 mmol, 1.3 eq.). The mixture was 5 stirred at 22 °C for 2 hours. The organic phase was washed with deion. H2O (100 mL) and brine (100 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo to give protected amine 23 (2.34 g, 9.58 mmol, 90%) as a light yellow solid; Rf = 0.18 (20% EtOAc in heptane);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 8.46 (dd, J = 4.9, 1.4 Hz, 1H; H-C(2 or 4); 7.75-7.78 (m, 1H; H-C(2 or 4), 7.38 (dd, J = 7.9, 4.9 Hz, 1H; H-C(3), 4.62-4.67 10 (m, 1H; H-C(6)), 2.98-3.10 (m, 2H; H2-C(9)), 2.85-2.92 (m, 1H; H-C(6)), 1.97-2.10 (m, 2H; H-C(7 / 8)), 1.88-1.94 (m, 1H; H-C(7)), 1.48-1.59 (m, 1H; H-C(8));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 162.0 (C(9a)), 156.6 (q, JC-F = 35.7 Hz, COCF3), 150.0 (C(2 or 4)), 138.0 (C(4a)), 137.4 (C(2 or 4)), 123.7 (C(3)), 117.6 (q, JC-F = 287.9 Hz, COCF3), 50.8 (C(6)), 37.4 (C(9)), 29.6 (C(7)), 25.7 (C(8));19F-NMR (300 MHz, MeOD-d4, 15 298 K): δ [ppm] = -69.6; HR-MS (ESI): (m / z) = calculated for C11H12N2OF3+[M+H]+: 245.0896, found: 245.0897. Example 8: (±)-cis-1-(decahydro-5H-pyrido[3,2-b]azepin-5-yl)-trifluoroethanone 20To a solution of protected amine 23 (1.34 g, 5.49 mmol, 1.0 eq.) iniPrOH (28 mL) was added Rh / C (5%, Rh on activated charcoal, 134 mg, 10 wt% of substrate). The mixture was stirred in a sealed autoclave at 70 °C under H2 pressure (10 bar) for 24 hours. After cooling to room temperature, the reaction mixture was diluted with MeOH and the catalyst was removed by 25 filtration over celite. The filtrate was concentrated to yield the aliphatic bicycle (±)-24 (1.35 g, 5.39 mmol, 98%) as a yellow solid; Rf = 0.17 (5% MeOH in DCM + 0.1% NEt3);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 4.40 (quint., J = 4.1 Hz, 1H), 4.07-4.12 (m, 0.6H), 3.90-3.96 (m, 1.6H), 3.73-3.77 (m, 1H), 3.41-3.48 (m, 0.6H), 3.09-3.13 (m, 1H), 2.99-3.03 (m, 0.7H), 2.91-2.97 (m, 1H), 2.65-2.80 (m, 2H), 2.00-2.26 (m, 3H), 1.78-1.95 (m, 4H), 1.53-P382113WO 124 1.75 (m, 7H), 1.29-1.44 (m, 2H);13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 158.3 (q, JC-F= 36.0 Hz, COCF3), 118.3 (q, JC-F= 287.3 Hz, COCF3), 60.0 (CH)rot., 57.4 (CH)rot., 57.0 (CH)rot., 56.7 (CH)rot., 43.7 (CH2)rot., 43.6 (CH2)rot., 41.9 (CH2)rot., 41.3 (CH2)rot., 31.2 (CH2)rot., 30.7 (CH2)rot., 28.5 (CH2)rot., 27.1 (CH2)rot., 26.4 (CH2)rot., 26.3 (CH2)rot., 25.5 (CH2)rot., 25.3 5 (CH2)rot., 23.1 (CH2)rot., 22.6 (CH2)rot.;19F-NMR (300 MHz, MeOD-d4, 298 K): δ [ppm] = -68.2, -68.3; due to the presence of trifluoroacetamide rotamers in the NMR measurement, structural assignment is not possible; HR-MS (ESI): (m / z) = calculated for C11H18N2OF3+[M+H]+: 251.1366, found: 251.1367, C11H17N2OF3Na+[M+Na]+: 273.1191, found: 273.1186. 10 Example 9: (±)-cis-Decahydro-1H-pyrido[3,2-b]azepine ((±)-3a)Mono-trifluoroacetamide-protected diamine (±)-24 (100 mg, 0.40 mmol, 1.0 eq.) was dissolved in a mixture of THF and deion. H2O (4 mL, 1:1, 0.1 M) and LiOH (48.0 mg, 2.00 mmol, 5.0 eq.) was added. The mixture was refluxed for 24 hours. Then it was cooled to 15 room temperature and concentrated under reduced pressure. The aqueous phase was extracted with EtOAc (3x 10 mL). The organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo to obtain final free diamine (±)-3a (47.7 mg, 0.31 mmol, 78%) as a brown solid;1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 3.01-3.07 (m, 1H); 2.94-2.99 (m, 1H), 2.87 (td, J = 6.5, 2.9 Hz, 1H), 2.77-2.80 (m, 1H), 2.58-2.67 (m, 2H), 1.92- 20 1.99 (m, 1H), 1.35-1.85 (m, 9H);13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 59.0 (CH), 57.4 (CH), 49.7 (CH2), 46.7 (CH2), 35.0 (CH2), 32.9 (CH2), 32.4 (CH2), 23.2 (CH2), 22.3 (CH2); HR-MS (ESI): (m / z) = calculated for C9H19N2+[M+H]+: 155.1543, found: 155.1536. 25To a solution of lactam 21 (2.02 g, 12.5 mmol, 1.0 eq.) in AcOH (25 mL) was added Pd / C (10% Pd on activated charcoal, 200 mg, 10 wt% of substrate). The solution was stirred in a sealed autoclave at 100 °C under H2pressure (20 bar) for 2 days. After cooling to room temperature, the reaction mixture was diluted with MeOH and the catalyst was removed byP382113WO 125 filtration over celite. The crude product was purified by flash column chromatography on silica gel (5% MeOH in DCM + 1% NH3) to afford aliphatic bicycle (±)-25 (676 mg, 4.02 mmol, 32%) as a white solid; Rf= 0.20 (5% MeOH in DCM + 1% NH3);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 4.66-4.70 (m, 1H; H-C(2), 3.50-3.54 (m, 1H; H-C(4a)), 3.07- 5 3.08 (m, 1H; H-C(8a)), 2.49-2.56 (m, 1H; H-C(2)), 2.33-2.35 (m, 2H; H-C(7)), 1.84-1.94 (m, 3H; H-C(3, 4, 8 or 9)), 1.70-1.83 (m, 3H; H-C(3, 4, 8 or 9)), 1.58-1.68 (m, 2H; H-C(3 or 9)); 13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 173.6 (C(6)), 60.5 (C(4a)), 50.5 (C(8a)), 43.2 (C(2)), 33.7 (C(7)), 31.6 (C(4 or 8)), 27.2 (C(4 or 8)), 20.2 (C(3 or 9)), 19.8 (C(3 or 9)); HR-MS (ESI): (m / z) = calculated for C9H17N2O+[M+H]+: 169.1335, found: 169.1339. 10 Example 11: (±)-trans-1-benzyldecahydro-6H-pyrido[3,2-b]azepin-6-one ((±)-26)To a solution of amine (±)-25 (98 mg, 0.59 mmol, 1.0 eq.) in MeOH (5.8 mL) was added benzyl bromide (83 μL, 0.70 mmol, 1.2 eq.) and K2CO3(120 mg, 0.87 mmol, 1.5 eq.). The mixture was stirred at 22 °C for 22 hours. Then the solvent was evaporated, and the residue 15 was diluted with deion. H2O and extracted with EtOAc (3x 20 mL). The organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude product was purified by flash chromatography on silica gel (80% EtOAc in heptane) to afford benzylated amine (±)-26 (99 mg, 0.38 mmol, 64%) as a colorless oil; Rf = 0.22 (80% EtOAc in heptane); 1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 7.35-7.37 (m, 2H; H2-Carom.), 7.28-7.31 20 (m, 2H; H2-Carom.), 7.20-7.24 (m, 1H; H-Carom.), 4.61-4.65 (m, 1H; H-C(2)), 3.88 (d, J = 13.4 Hz, 1H; H-Cbenz.,), 3.68 (d, J = 13.4 Hz, 1H; H-Cbenz.), 3.42-3.46 (m, 1H; H-C(4a)), 2.65-2.67 (m, 1H; H-C(9a)), 2.47-2.54 (m, 1H; H-C(2)), 2.26-2.32 (m, 2H; H-C(7)), 2.04-2.16 (m, 2H; H-C(4 and 9)), 1.95-1.99 (m, 1H; H-C(8)), 1.70-1.81 (m, 2H; H-C(3 and 4)), 1.43- 1.63 (m, 3H; H-C(3, 8 and 9));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 173.5 25 (C(6)), 142.0 ((Cq)arom.), 1294 ((CH)arom.), 129.3 ((CH)arom.), 127.9 ((CH)arom.), 61.7 (C(4a)), 55.6 C(9a)), 52.3 ((CH2)benz.), 43.6 (C(2)), 33.7 (C(7)), 28.0 (C(9)), 27.0 (C(4)), 20.3 (C(3 or 8)), 20.2 (C(3 or 8)); HR-MS (ESI): (m / z) = calculated for C16H23N2O+[M+H]+: 259.1805, found: 259.1805. 30 Example 12: (±)-trans-1-benzyldecahydro-1H-pyrido[3,2-b]azepine ((±)-27b)P382113WO 126A solution of lactam (±)-26 (220 mg, 0.85 mmol, 1.0 eq.) in dry THF (8.5 mL, 0.1 M) was cooled to 0 °C and LiAlH4(1 M in THF, 1.3 mL, 1.3 mmol, 1.5 eq.) was added dropwise. The reaction was stirred at 22 °C for 16 hours. The reaction mixture was then cooled to room 5 temperature and worked up using Fieser’s protocol. The crude was purified by flash column chromatography on silica gel (5% MeOH in DCM + 1% NH3) to give azepane (±)-27b (164 mg, 0.67 mmol, 79%) as a colorless oil; Rf= 0.18 (5% MeOH in DCM + 1% NH3);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 7.35-7.37 (m, 2H; H2-Carom.), 7.27-7.31 (m, 2H; H2-Carom.), 7.19-7.23 (m, 1H; H-Carom.), 3.86 (d, J = 13.2 Hz, 1H; H-Cbenz.), 3.66 (m, J =10 13.2 Hz, 1H; H-Cbenz.), 2.79-2.82 (m, 2H; H-C(2, 3, 4, 6, 7, 8)), 2.60 (m, 1H; H-C(9a)), 1.96- 2.08 (m, 4H; H-C(2, 3, 4, 6, 7, 8)), 1.77-1.91 (m, 3H; H-C(4a and H-C(2, 3, 4, 6, 7, 8)), 1.54- 1.59 (m, 2H; H-C(2, 3, 4, 6, 7, 8)), 1.44-1.50 (m, 1H; H-C(2, 3, 4, 6, 7, 8)), 1.30-1.40 (m, 3H; H-C(9 and 2, 3, 4, 6, 7, 8));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 142.0 ((Cq)arom.), 129.3 ((CH)arom.), 129.2 ((CH)arom.), 127.8 ((CH)arom.), 2X 58.0 (C(8a and 15 2, 3, 4, 6, 7 or 8)), 56.4 (C(9a)), 52.3 (CH2)benz.), 2X 28.4 (C(9 and 2, 3, 4, 6, 7 or 8)), 26.0 (C(2, 3, 4, 6, 7 or 8)), 2X 25.6 (C(2, 3, 4, 6, 7 or 8)), 21.2 (C(2, 3, 4, 6, 7 or 8)); HR-MS (ESI): (m / z) = calculated for C16H25N2+[M+H]+: 245.2012, found: 245.2011. Example 13: Decahydro-1H-pyrido[3,2-b]azepine ((±)-3b)20 To a solution of mono-benzylated diamine (±)-27b (50 mg, 0.20 mmol, 1.0 eq.) in MeOH (2 mL, 0.1 M) was added Pd / C (10% Pd on activated charcoal, 5.0 mg, 10 wt% of substrate) and AcOH (23 µL, 0.04 mmol, 2.0 eq.). The reaction mixture was stirred at 22 °C under an atmosphere of hydrogen (1 bar, balloon) for 24 hours. It was then filtered over celite, washed with MeOH and evaporated to dryness. The residue was taken up in DCM and washed with 25 NaOH (1 M, 2x 4 mL) and the organic phase was dried over Na2SO4to give final free diamine (±)-3b as a yellow oil (30.9 mg, 0.20 mmol, quant.);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 2.77-2.86 (m, 2H), 1.98-2.10 (m, 2H), 1.75-1.86 (m, 3H), 1.45-1.65 (m, 6H), 1.29- 1.41 (m, 4H);13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 66.8 (CH), 57.9 (CH2), 50.9P382113WO 127 (CH), 32.5 (CH2), 30.8 (CH2), 30.3 (CH2), 26.5 (CH2), 25.4 (CH2), 20.6 (CH2); HR-MS (ESI): (m / z) = calculated for C9H19N2+[M+H]+: 155.1543, found: 155.1542 (E)-5-methoxy-3,4-dihydronaphthalen-1(2H)-one oxime (29) 5To a solution of commercially available 5-methoxy-3,4-dihydronaph-thalen-1(2H)-one 28 (25 g, 142 mmol, 1.0 eq.) in EtOH (285 mL, 0.2 M) was added NH2OH•HCl (23.7 g, 341 mmol, 2.4 eq.) and grinded NaOH (30 g, 750 mmol, 5.3 eq.). The mixture was stirred under reflux for 2 hours. The mixture was allowed to cool to room temperature and the solvent was 10 evaporated. Deion. water (300 mL) was added, and the mixture was extracted with chloroform (3x 300 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo to give (E)-oxime isomer 29 (27.1 g, 142 mmol, quant.) as a white solid; Rf = 0.21 (10% EtOAc in heptane);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 7.50 (d, J = 8.0, 1H; H-C(8)), 7.11 (t, J = 8.1 Hz, 1H; H-C(7)), 6.87 (d, J = 8.0, 1H; 15 H-C(6)), 3.81 (s, 3H; H3-C), 2.68-2.74 (m, 4H; H2-C(2 and 4)), 1.79 (quint., J = 6.4 Hz, 2H; H2-C(3));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 158.1 (C(5)), 155.6 (C(1)), 133.4 (C(8a)), 129.5 (C(4a)), 127.3 (C(7)), 117.2 (C(8)), 111.0 (C(6)), 55.9 (CH3), 24.1 (C(2 or 4)), 23.3 (C(2 or 4)), 22.2 (C(3)); HR-MS (ESI): (m / z) = calculated for C11H14NO2+[M+H]+: 192.1019, found: 192.1010. 20 (E)-5-methoxy-3,4-dihydronaphthalen-1(2H)-one O-tosyl oxime (30)25 To a solution of oxime 29 (27.1 g, 142 mmol, 1.0 eq.) in pyridine (285 mL, 0.5 M) was added freshly recrystallized p-TsCl (32.4 g, 170 mmol, 1.2 eq.) and the mixture was stirred at 22 °C for 24 hours. Then the pyridine was evaporated, and the residue was taken up in deion. H2O (250 mL) and extracted with DCM (3x 250 mL). The organic layers were washed with 30 HCl (1 M, 250 mL) and sat. NaHCO3(250 mL), dried over Na2SO4, filtered and evaporated to yield tosylate 30 (49.2 g, 142 mmol, quant.) as a yellow solid; Rf = 0.22 (60% EtOAc in heptane);1H-NMR (400 MHz, CDCl3, 298 K): δ [ppm] = 7.94 (d, J = 8.3 Hz, 2H; H-Ctos.), 7.48 (d, J = 7.9 Hz, 1H; H-C(8)), 7.35 (d, J = 8.1 Hz, 2H; H-Ctos.), 7.14 (t, J = 8.1 Hz, 1H; H-C(7)), 6.86 (d, J = 8.1 Hz, 1H; H-C(6)), 3.81 (s, 3H; H3-C), 2.79 (t, J = 6.7 Hz, 2H; H2-C(2)), 2.69P382113WO 128 (t, J = 6.2 Hz, 2H; H2-C(4)), 2.44 (s, 3H; H3-Ctos.), 1.80 (quint., J = 6.4 Hz, 2H; H2-C(3)); 13C-NMR (100 MHz, CDCl3, 298 K): δ [ppm] = 162.7 (C(1)) 156.8 (C(5)), 145.0 ((Cq)tos.), 133.0 ((Cq)tos.), 130.5 (C(4a)), 129.7 ((CH)tos.), 129.2 (C(8a)), 129.1 ((CH)tos.), 126.8 (C(7)), 117.3 (C(8)), 112.0 (C(6)), 55.7 (CH3), 25.0 (C(2)), 22.1 (C(4)), 21.8 ((CH3)tos.), 20.6 (C(3)); 5 HR-MS (ESI): (m / z) = calculated for C18H20NO4S+[M+H]+: 346.1108, found: 346.1100. 6-methoxy-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one (31) 10To tosylate 30 (49.0 g, 142 mmol, 1.0 eq.) in deion. H2O (600 mL) was added AcOH (760 mL), and the mixture was stirred at 70 °C for 24 hours. Then the solvent was evaporated, and the remaining brown oil was cooled to 0 °C and quenched by addition of NaHCO3 (500 15 mL) and Na2CO3 (600 mL). Then the aqueous phase was extracted with EtOAc (3x 400 mL) and the organic phases were dried over Na2SO4, filtered and the solvent was evaporated to yield lactam 31 (20.2 g, 106 mmol, 75%) as a brown solid; Rf = 0.24 (50% EtOAc in heptane); 1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 7.18 (t, J = 8.1, 1H; H-C(8)), 6.83 (d, J = 8.3 Hz, 1H; H-C(7)), 6.64 (d, J = 2.9, 1H; H-C(9)), 3.83 (s, 3H; H3-C), 2.83 (t, J = 7.1 Hz, 2H; 20 H2-C(5)), 2.24-2.28 (m, 2H; H2-C(3)), 2.13-2.19 (m, 2H; H2-C(4));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 177.7 (C(2)), 158.9 (C(6)), 140.7 (C(9a)), 128.5 (C(8)), 123.7 (C(5a)), 115.6 (C(9)), 109.0 (C(7)), 56.3 (CH3), 34.0 (C(3)), 29.3 (C(4)), 22.6 (C(5)); HR-MS (ESI): (m / z) = calculated for C11H14NO2+[M+H]+: 192.1019, found: 192.1019. 6-hydroxy-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one (32) 25To a solution of lactam 31 (5.00 g, 26.1 mmol, 1.0 eq.) in dry DCM (260 mL, 0.1 M) was added BBr3 (1 M in DCM, 40 mL, 40 mmol, 1.5 eq.) at -78 °C. The mixture was warmed to 22 °C and stirred for 24 hours. Then it was cooled to 0 °C and quenched by addition of deion. H2O (60 mL). The precipitate was filtered, washed with deion. H2O, dried and purified by 30 flash column chromatography on silica gel (EtOAc to 10% MeOH in EtOAc) to yield alcohol 32 (3.90 g, 22.0 mmol, 84%) as a light brown solid; Rf = 0.24 (EtOAc);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 7.02 (t, J = 8.0, 1H; H-C(8)), 6.66 (dd, J = 8.2, 1.0, 1H; H-C(7 or 9)), 6.52 (dd, J = 7.8, 0.8 Hz, 1H; H-C(7 or 9)), 2.81 (t, J = 7.1 Hz, 2H; H2-C(5)), 2.25-2.29 (m, 2H; H2-C(3)), 2.12-2.20 (m, 2H; H2-C(4));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm]P382113WO 129 = 177.8 (C(2)), 156.5 (C(6 or 9a)), 140.8 (C(6 or 9a)), 128.2 (C(8)), 122.1 (C(5a)), 114.3 (C(7 or 9)), 113.4 (C(7 or 9)), 34.0 (C(3)), 29.2 (C(4)), 22.7 (C(5)); HR-MS (ESI): (m / z) = calculated for C10H12NO2+[M+H]+: 178.0863, found: 178.0857, C10H11NO2Na+[M+Na]+: 200.0687, found: 200.0676. 5 6-hydroxydecahydro-2H-benzo[b]azepin-2-one ((±)-33) 1A mixture of aromatic compound 32 (1.53 g, 8.63 mmol, 1.0 eq.), Rh / C (5%, Rh on activated charcoal, 153 mg, 10 wt% of substrate) and AcOH (1.0 mL, 17.3 mmol, 2.0 eq.) iniPrOH (50 mL) was stirred in a sealed autoclave at 70 °C under H2pressure (20 bar) for 5 days. After 10 cooling to room temperature, the reaction mixture was filtered over celite, washed with MeOH and evaporated to dryness. The crude was purified by flash column chromatography on silica gel (80% EtOAc in heptane to EtOAc to 10% MeOH in EtOAc) to afford aliphatic bicycle (±)-33 (684 mg, 3.73 mmol, 43%) as a yellow oil; Rf= 0.20 (80% EtOAc in heptane); 1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 3.70-3.75 (m, 1H; H-C(6)), 3.13-1.16 (m, 15 1H; H-C(9a)), 2.42-2.54 (m, 2H; H2-C(3)), 1.90-2.05 (m, 4H; H-C(4, 5a, 5 and 9)), 1.72-1.85 (m, 2H; H-C(5 and 8)), 1.45-1.61 (m, 4H; H-C(4, 7 and 9)), 1.29-1.42 (m, 1H; H-C(8));13C- NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 180.6 (C(2)), 73.1 (C(6)), 54.6 (C(9a)), 46.5 (C(5a)), 38.2 (C(3)), 29.5 (C(7)), 27.9 (C(4, 5 or 9)), 24.7 (C(4, 5 or 9)), 23.6 (C(4, 5 or 9)), 22.8 (C(8)); HR-MS (ESI): (m / z) = calculated for C10H18NO2+[M+H]+: 184.1332, found: 20 184.1326. Octahydro-1H-benzo[b]azepine-2,6-dione ((±)-34)A solution of alcohol (±)-33 (1.10 g, 6.00 mmol, 1.0 eq.) in DCM (60 mL, 0.1 M) was cooled to 0 °C and DMP (3.30 g, 7.78 mmol, 1.3 eq.) was added. The reaction was stirred at 22 °C 25 for 1 hour. Then it was quenched by addition of sat. NaHCO3solution (35 mL) and Na2S2O3solution (2 M, 35 mL). The water phase was washed twice with DCM (3x 100 mL). The combined organic phases were washed with deion. H2O, dried over Na2SO4, filtered and the solvent was evaporated in vacuo. The crude was purified by column chromatography on silica gel (5%-10% MeOH in EtOAc) to yield ketone (±)-34 (0.89 g, 4.91 mmol, 82%) as aP382113WO 130 white solid; Rf= 0.20 (5% MeOH in EtOAc);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 4.27-4.28 (m, 1H; H-C(5a)), 2.90-2.92 (m, 1H; H-C(9a)), 2.49-2.56 (m, 1H; H-C(3)), 2.42- 2.48 (m, 1H; H-C(7)), 2.23-2.36 (m, 3H; H-C(3, 7 and 9)), 2.07-2.19 (m, 2H; H-C(5 and 8)), 1.98-2.06 (m, 2H; H-C(5 and 8)), 1.79-1.86 (m, 1H; H-C(4)), 1.68-1.77 (m, 1H; H-C(4)), 1.52- 5 1.61 (m, 1H; H-C(9));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 212.8 (C(6)), 181.1 (C(2)), 55.8 (C(5a)), 52.3 (C(9a)), 41.6 (C(7)), 37.2 (C(3)), 30.9 (C(5 or 8)), 29.0 (C(9)), 22.4 (C(5 or 8)), 20.2 (C(4)); HR-MS (ESI): (m / z) = calculated for C10H16NO2+[M+H]+: 182.1176, found: 182.1170, C20H33N2O4+[2M+H]+: 363.2284, found: 363.2267. 10 Example 14: Dodecahydroazepino[3,2-b]azepine (meso-4b)Ketone (±)-34 (471 mg, 2.60 mmol, 1.0 eq.) was dissolved in CHCl3 (26 mL, 0.1 M) and the solution was cooled to 0 °C. Then conc. H2SO4 (1.11 mL, 20.8 mmol, 8.0 eq.) was added dropwise. Upon completion of addition, NaN3 (372 mg, 5.72 mmol, 2.2 eq.) was added 15 portionwise at 0 °C. It is critical that the temperature during addition is maintained at 0 °C. The reaction mixture was then warmed to 22 °C and stirred vigorously for 24 hours. The viscous bottom layer (aqueous) was separated from the top layer, cooled to 0 °C and carefully quenched by dropwise addition of a sat. NaHCO3 solution to pH 12. It is critical that the pH of the aqueous phase is > 10 so that residual HN3 (toxic, explosive) is deprotonated. 20 Upon completion of addition, 25%iPrOH in CHCl3 (25 mL) was added and the reaction mixture was stirred vigorously for 1 hour. The filtrate was then separated, and the aqueous phase was extracted with 25%iPrOH in CHCl3 (3x 25 mL). All organic layers were combined, dried over Na2SO4, filtered and the solvent was evaporated to yield a yellow solid. The intermediate product was dissolved in in dry THF (26 mL, 0.1 M) and cooled to 0 °C. Then 25 LiAlH4 (1 M in THF, 23.4 mL, 23.4 mmol, 9.0 eq.) was added dropwise. The mixture was stirred at reflux for 24 hours. Then it was cooled down and worked up using Fieser’s protocol. The crude product was purified by flash column chromatography on silica gel (10%-15% MeOH in DCM + 1% NH3) to afford final free diamine meso-4b (186 mg, 1.11 mmol, 43%) as a white solid;1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 3.01-3.07 (m, 2H), 2.72- 30 2.79 (m, 2H), 2.66-2.67 (m, 2H), 1.89-1.94 (m, 2H), 1.60-1.75 (m, 10H);13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 65.9 (CH), 49.6 (CH2), 36.2 (CH2), 29.7 (CH2), 24.4 (CH2); HR- MS (ESI): (m / z) = calculated for C10H21N2+[M+H]+: 169.1699, found: 169.1696.P382113WO 131 Example 15: (±)-cis-tert-butyl-4-benzyloctahydropyrrolo[3,2-b]azepine-1(2H)-To a solution of mono-Boc-protected diamine (±)-11 (397 mg, 1.65 mmol, 1.0 eq.) in MeOH 5 (17 mL, 0.1 M) was added benzyl bromide (235 µL, 1.98 mmol, 1.2 eq.) and K2CO3(343 mg, 2.48 mmol, 1.5 eq.). The mixture was stirred at 22 °C for 2 hours. Then the solvent was evaporated, and the residue was diluted with deion. H2O (25 mL) and extracted with EtOAc (3x 50 mL). The organic layer was dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude was purified by column chromatography on silica gel (10% EtOAc in 10 heptane) to give orthogonally protected diamine (±)-35 (487 mg, 1.47 mmol, 89%) as a yellow oil; Rf= 0.20 (10% EtOAc in heptane);1H-NMR (400 MHz MeOD-d4, 298 K): δ [ppm] = 7.35-7.37 (m, 2H; H2-Carom.), 7.27-7.31 (m, 2H; H2-Carom.), 7.19-7.23 (m, 1H; H-Carom.), 3.96 (d, J = 13.7, 1H; H2-Cbenz), 3.77-3.83 (m, 1H; H-C(8a)), 3.42-3.49 (m, 1H; H-C(2)), 3.35 (d, J = 13.7, 1H; H2-Cbenz.), 3.14-3.27 (m, 2H; H-C(2 and 3a)), 2.62-2.65 (m, 1H; H-C(5)), 2.34- 15 2.40 (m, 1H; H-C(5)), 2.25-2.28 (m, 1H; H-C(3)), 1.89-2.07 (m, 2H; H-C(3 and 8)), 1.65-1.75 (m, 2H; H-C(7 and 8)), 1.50-1.52 (m, 1H; H-C(6)), 1.46 (s, 9H, H3-CBoc), 1.29-1.34 (m, 2H; H-C(6 and 7));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 156.2 ((C=O)Boc-rot., 156.1((C=O)Boc-rot., 141.2 ((Cq)arom.), 129.9 ((CH)arom.), 129.2 ((CH)arom.), 127.9 ((CH)arom.), 80.8 ((Cq)Boc)rot., 80.7 ((Cq)Boc)rot., 68.0 (C(3a))rot, 67.4 (C(3a))rot., 64.2 (C(8a))rot., 63.8 20 (C(8a))rot., 61.3 (CH2)benz.)), 53.5 (C(5)), 45.5 (C(2)rot., 44.9 (C(2)rot., 32.4 (C(6), 31.1 (C(3 or 8), 30.4 (C(3 or 8))rot., 30.3 (C(3 or 8))rot., 28.8 ((CH3)Boc), 28.1 (C(7))rot., 28.0 (C(7))rot.; HR- MS (ESI): (m / z) = calculated for C20H31N2O2+[M+H]+: 331.2380, found: 331.2374. 25To a solution of orthogonally protected diamine (±)-35 (50 mg, 0.15 mmol, 1.0 eq.) in DCM (1.5 mL, 0.1 M) was added TFA (0.15 mL, 10 vol%). The reaction was stirred at 22 °C for 2 hours. Then it was washed with NaOH (1 M, 2x 4 mL) and the organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The crude was purified by column 30 chromatography on silica gel (10% MeOH in DCM + 0.1% NH3) to yield mono-benzylatedP382113WO 132 diamine (±)-1a (22.0 mg, 0.96 mmol, 64%) as a yellow oil; Rf= 0.20 (10% MeOH in DCM + 0.1% NH3);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 7.35-7.37 (m, 2H; H2-Carom.), 7.27-7.30 (m, 2H; H2-Carom.), 7.19-7.22 (m, 1H; H-Carom.), 3.92 (d, J = 13.7, 1H; H2-Cbenz.), 3.39 (d, J = 13.7, 1H; H2-Cbenz.), 3.21-3.26 (m, 1H; H-C(3a)), 3.18-3.21 (m, 1H; H-C(8a)), 5 3.06-3.11 (m, 1H; H-C(2)), 2.77-2.82 (m, 1H; H-C(2)), 2.70-2.75 (m, 1H; H-C(5)), 2.26-2.33 (m, 1H; H-C(5)), 2.13-2.20 (m, 1H; H-C(3)), 2.00-2.09 (m, 1H; H-C(8)), 1.74-1.83 (m, 2H; H- C(3 and 7)), 1.58-1.63 (m, 1H; H-C(8)), 1.42-1.54 (m, 2H; H2-C(6)), 1.29-1.40 (m, 1H; H-C(7));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 141.4 ((Cq)arom.), 129.9 ((CH)arom.), 129.2 ((CH)arom.), 127.9 ((CH)arom.), 69.7 (C(3a)), 64.5 (C(8a)), 61.4 (CH2)benz.), 54.7 (C(5)), 10 45.2 (C(2), 33.2 (C(3), 32.3 (C(8), 31.9 (C(6), 27.7 (C(7)); HR-MS (ESI): (m / z) = calculated for C15H23N2+[M+H]+: 231.1856, found: 231.1847. Enantiomeric separation of (±)-35 was performed by dissolving the sample in MeOH (50 mg / mL) and was purified by preparative chiral-HPLC (Conditions: Chiralcel OD-H (30 mm x 15 250 mm, 5 μm), ambient column temperature, flow rate: 42 mL / min, wavelength detector: 210 nm, injection volume: 2000 μL, isocratic conditions: MeOH). Combined fractions of Examples 17 and 18 were then evaporated to near dryness using a rotary evaporator. The resultant solids were transferred into vessels with MeOH, which was removed on a Biotage V10 at 35 °C before being stored in a vacuum oven at 35 °C and 5 mbar until constant 20 weight. The absolute assignment of each enantiomer was confirmed by single crystal X-ray diffraction using the hydrochloride salts of the two enantiomers. Example 17: tert-butyl-(3aR,8aR)-4-benzyloctahydropyrrolo[3,2-b]azepine-1(2H)- carboxylate ((R,R)-35) 25More active enantiomer, see (±)-35 (Example 16) for full assignment. Chiral-HPLC: tR= 3.691 min, Conditions: Chiralcel OD-H (30 mm x 250 mm, 5 μm), ambient, 42 mL / min, MeOH). 30P382113WO 133Less active enantiomer, see (±)-35 (Example 16) for full assignment. Chiral-HPLC: tR= 5.019 min, Conditions: Chiralcel OD-H (30 mm x 250 mm, 5 μm), ambient, 42 mL / min, MeOH). 5 Example 19: (3aR,8aR)-4-benzyldecahydropyrrolo[3,2-b]azepine ((R,R)-1a)Orthogonally protected diamine (R,R)-35 (102 mg, 0.31 mmol, 1.0 eq.) was dissolved in DCM (3.1 mL, 0.1 M) and TFA (0.3 mL, 10 vol%) was added. The reaction was stirred at 22 10 °C for 2 hours. Then it was washed with NaOH (1 M, 2x 5 mL) and the organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The crude was purified by column chromatography on silica gel (10% MeOH in DCM + 1% NH3) to yield mono- benzylated diamine (R,R)-1a (49 mg, 0.21 mmol, 68%) as a yellow oil. See racemate (±)-1a (Example 16) for full assignment. 15 3,2-b]azepine ((S,S)-1a)Orthogonally protected diamine (S,S)-35 (105 mg, 0.32 mmol, 1.0 eq.) was dissolved in DCM (3.2 mL, 0.1 M) and TFA (0.3 mL, 10 vol%) was added. The reaction was stirred at 22 20 °C for 2 hours. Then it was washed with NaOH (1 M, 2x 5 mL) and the organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The crude was purified by column chromatography on silica gel (10% MeOH in DCM + 1% NH3) to yield mono- benzylated diamine (S,S)-1a (54 mg, 0.23 mmol, 72%) as a yellow oil. Diffusion controlled crystallization of an analytical sample from HCl in MeOH and Et2O yielded the title compound 25 as HCl salt and allowed to determine the (S,S) stereochemistry at the bridgehead by x-ray diffraction studies. See racemate (±)-1a (Example 16) for full assignment.P382113WO 134 Example 21: (±)-cis-Trifluoro-1-octahydropyrrolo[3,2-b]azepin-4(1H)-yl)ethanone ((±)-36)5 To a solution of mono-Boc-protected diamine (±)-11 (115 mg, 0.48 mmol, 1.0 eq.) in DCM (5 mL, 0.1 M) was added TFAA (100 µL, 0.72 mmol, 1.5 eq.) and pyridine (46 µL, 0.58 mmol, 1.2 eq.). The reaction mixture was stirred at 22 °C for 2 hours. The organic phase was washed with deion. H2O (5 mL) and NaHCO3 (5 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo to give a light-yellow oil. The intermediate product was 10 dissolved in DCM (5 mL, 0.1 M) and TFA (0.5 mL, 10 vol%) was added. The reaction was stirred at 22 °C for 2 hours. Then it was washed with NaOH (1 M, 2x 5 mL) and the organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The crude was purified by column chromatography on silica gel (5% MeOH in DCM + 0.1% NH3) to give mono-trifluoroacetamide-protected diamine (±)-36 (55.0 mg, 0.23 mmol, 48%) as a yellow 15 oil; Rf = 0.18 (5% MeOH in DCM + 0.1% NH3);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 4.70-4.74 (m, 1H), 4.54-4.56 (m, 1.3H), 3.94 (d, J = 13.5, 1.3H), 3.74-3.78 (m, 1.2H), 3.48-3.61 (m, 3H), 3.39-3.43 (m, 1.8H), 3.23-3.27 (m, 1.3H), 3.00-3.11 (m, 2.3H), 2.69-2.76 (m, 1.4H), 2.37-2.44 (m, 1.2H), 2.27-2.35 (m, 1.5H), 2.12-2.21 (m, 2.5H), 1.97-2.04 (m, 1.4H), 1.70-1.93 (m, 8H), 1.51-1.67 (m, 4H);13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] 20 = 157.5 (COCF3), 118.1 (q, COCF3), 63.5 (CH)rot., 63.0 (CH)rot., 62.3 (CH)rot., 60.4 (CH)rot., 49.3 (CH2)rot., 46.5 (CH2)rot., 45.9 (CH2)rot., 44.6 (CH2)rot., 32.8 (CH2)rot., 32.4 (CH2)rot., 30.0 (CH2)rot., 29.3 (CH2)rot., 28.9 (CH2)rot., 28.6 (CH2)rot., 23.2 (CH2)rot., 22.6 (CH2)rot.; due to the presence of trifluoroacetamide rotamers in the NMR measurement, structural assignment is not possible; HR-MS (ESI): (m / z) = calculated for C10H16N2OF3+[M+H]+: 237.1209, found: 25 237.1206. Example 22: (±)-cis-1-benzyldecahydropyrrolo[3,2-b]azepine ((±)-17a)P382113WO 135 To a solution of mono-trifluoroacetamide-protected diamine (±)-36 (55.0 mg, 0.23 mmol, 1.0 eq.) in MeOH (2.3 mL, 0.1 M) was added benzyl bromide (33 µL, 0.28 mmol, 1.2 eq.) and K2CO3(48.4 mg, 0.35 mmol, 1.5 eq.). The mixture was stirred at 22 °C for 2 hours. Then the solvent was evaporated, and the residue was diluted with deion. H2O and extracted with 5 EtOAc (3x 10 mL). The organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo to give a yellow oil. The intermediate product was dissolved in a mixture of THF and deion. H2O (3 mL, 1:1) and LiOH (27.5 mg, 1.15 mmol, 5.0 eq.) was added. The mixture was refluxed for 24 hours. Then it was cooled to room temperature and concentrated under reduced pressure. The aqueous phase was extracted with EtOAc (3x 6 mL). The 10 organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude was purified by column chromatography on silica gel (10% MeOH in DCM + 0.1% NH3) to give mono-benzylated diamine (±)-17a (21.0 mg, 0.09 mmol, 39%) as a yellow oil; Rf = 0.20 (10% MeOH in DCM + 0.1% NH3);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 7.24-7.31 (m, 5H; H-Carom.), 3.97 (d, J = 12.6, 1H; H-Cbenz.), 3.45-3.46 (m, 1H; H-C(3a)) 15 3.12-3.19 (m, 2H; H-Cbenz. and C(5)), 2.81-2.85 (m, 1H; H-C(2)), 2.45-2.52 (m, 2H; H-C(5 and 8a)), 2.06-2.17 (m, 2H; H-C(2 and 3)), 1.97-2.02 (m, 1H; H-C(6)), 1.88-1.91 (m, 1H; H- C(7)), 1.77-1.81 (m, 1H; H-C(8)), 1.54-1.64 (m, 2H; H-C(6 and 8)), 1.40-1.46 (m, 1H; H- C(3)), 1.29-1.37 (m, 1H; H-C(7));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 139.5 ((Cq)arom.), 130.5 ((CH)arom.), 129.3 ((CH)arom.), 128.3 ((CH)arom.), 70.9 (C(8a)), 63.8 (C(3a)),20 59.9 (CH2)benz.), 53.5 (C(2)), 50.9 (C(5), 33.6 (C(8), 32.6 (C(3), 30.4 (C(6), 25.7 (C(7)); HR- MS (ESI): (m / z) = calculated for C15H23N2+[M+H]+: 231.1856, found: 231.1851. Example 23: (±)-trans-tert-butyl-5-oxooctahydropyrrolo[3,2-b]azepine-1(2H)- carboxylate ((±)-37) 4Boc 25 (±) (±) To a solution of amine (±)-15 (181 mg, 1.17 mmol, 1.0 eq.) in DCM (12 mL, 0.1 M) was added Boc2O (308 mg, 1.41 mmol, 1.2 eq.), NEt3(213 µL, 1.53 mmol, 1.3 eq.) and DMAP (cat.). The reaction mixture was stirred at 22 °C for 2 hours. Then the solvent was evaporated, and the crude was purified by column chromatography on silica gel (10% MeOH 30 in DCM + 1% NH3) to give Boc-protected amine (±)-37 (191 mg, 0.75 mmol, 64%) as a white solid; Rf= 0.20 (10% MeOH in DCM + 1% NH3);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 3.81-3.88 (m, 1H; H-C(3a)), 3.69-3.74 (m, 1H; H-C(2)), 3.22-3.28 (m, 1H; H-C(2)) 3.07-3.13 (m, 1H; H-C(8a)), 2.79 (br, 1H; H-C(8)), 2.68-2.75 (m, 1H; H-C(6)), 2.36 (dd, J = 14.2, 6.9P382113WO 136 Hz, 1H; H-C(6)), 2.05-2.11 (m, 1H; H-C(3)), 1.95-1.99 (m, 1H; H-C(7)), 1.76-1.87 (m, 1H; H- C(3)), 1.56-1.66 (m, 1H; H-C(7)), 1.46 (s, 9H; H3-CBoc), 1.37-1.40 (m, 1H; H-C(8));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 180.4 (C(5)), 156.6 ((C=O)Boc, 81.2 ((Cq)Boc), 65.0 (C(8a)), 59.5 (C(3a)), 46.6 (C(2)), 37.6 (C(6)), 35.8 (C(8)), 29.8 (C(3)), 28.7 ((CH3)Boc), 22.7 5 (C(7)); HR-MS (ESI): (m / z) = calculated for C13H23N2O3+[M+H]+: 255.1703, found: 255.1679. Example 24: (±)-trans-tert-butyl-octahydropyrrolo[3,2-b]azepine-1(2H)-carboxylate10 A solution of lactam (±)-37 (141 mg, 0.55 mmol, 1.0 eq.) in dry THF (5.5 mL, 0.1 M) was cooled to 0 °C and LiAlH4 (1 M in THF, 0.83 mL, 0.83 mmol, 1.5 eq.) was added dropwise. The reaction was stirred at 22 °C for 3 hours. Then it was worked up using Fieser’s protocol and the crude was purified by flash column chromatography on silica gel (10% MeOH in DCM + 0.1% NEt3) to give azepane (±)-38 (60.0 mg, 0.25 mmol, 45%) as a white solid; Rf = 15 0.20 (10% MeOH in DCM + 0.1% NEt3);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 3.67 (dd, J = 11.1, 8.2 Hz, 1H; H-C(2)), 3.39-3.45 (m, 1H; H-C(8a)), 3.14-3.25 (m, 2H; H- C(2 and 3a)) 2.95-3.01 (m, 1H; H-C(5)), 2.84-2.90 (m, 1H; H-C(5)), 2.55 (br, 1H; H-C(8)), 1.99 (quint, J = 5.8 Hz, 1H; H-C(3)), 1.54-1.83 (m, 5H; H-C(3, 6 and 7)), 1.45 (s, 9H; H3- CBoc), 1.26-1.29 (m, 1H; H-C(8));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 156.4 20 ((C=O)Boc, 80.9 ((Cq)Boc), 64.5 (C(3a or 8a)), 64.0 (C(3a or 8a)), 50.0 (C(5)), 46.3 (C(2)), 33.6 (C(8)), 32.6 (C(3)), 28.8 ((CH3)Boc), 28.5 (C(6)), 26.2 (C(7)); HR-MS (ESI): (m / z) = calculated for C13H25N2O2+[M+H]+: 241.1911, found: 241.1905. Example 25: (±)-trans-4-benzyldecahydropyrrolo[3,2-b]azepine ((±)-1b) Boc , , 70 1 25 (±) % over two steps (±) To a solution of mono-Boc-protected diamine (±)-38 (49.2 mg, 0.20 mmol, 1.0 eq.) in MeOH (2 mL, 0.1 M) was added benzyl bromide (29 µL, 0.24 mmol, 1.2 eq.) and K2CO3 (41.5 mg, 0.30 mmol, 1.5 eq.). The mixture was stirred at 22 °C for 2 hours. Then the solvent was evaporated, and the residue was diluted with deion. H2O and extracted with EtOAc (3x 10 30 mL). The organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo to give a white solid. The intermediate product was dissolved in DCM (2 mL, 0.1 M)P382113WO 137 and TFA (0.2 mL, 10 vol%) was added. The reaction was stirred at 22 °C for 2 hours. Then it was washed with NaOH (1 M, 2x 4 mL) and the organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The crude was purified by column chromatography on silica gel (10% MeOH in DCM + 0.1% NH3) to give mono-benzylated diamine (±)-1b (33.3 5 mg, 0.14 mmol, 70%) as a yellow oil; Rf = 0.20 (10% MeOH in DCM + 0.1% NH3);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 7.25-7.33 (m, 5H; H-Carom., 3.83 (d, J = 13.4, 1H; H- Cbenz.), 3.46 (d, J = 13.4, 1H; H-Cbenz.) 2.90-3.04 (m, 3H; H-C(2 and 8a)), 2.67-2.83 (m, 3H; H-C(3a and 5)), 2.25-2.34 (m, 1H; H-C(3)), 2.02-2.06 (m, 1H; H-C(8)), 1.81-1.88 (m, 1H; H- C(3)), 1.75-1.80 (m, 1H; H-C(6)), 1.62-1.71 (m, 1H; H-C(7)), 1.39-1.55 (m, 3H; H-C(6, 7 and 10 8));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 139.8 ((Cq)arom.), 130.6 ((CH)arom.), 129.3 ((CH)arom.), 128.3 ((CH)arom.), 72.0 (C(3a)), 62.4 (C(8a)), 60.6 (CH2)benz.), 53.6 (C(5)), 45.0 (C(2), 35.1 (C(3), 34.0 (C(8), 27.2 (C(6), 23.8 (C(7)); HR-MS (ESI): (m / z) = calculated for C15H23N2+[M+H]+: 231.1856, found: 231.1847. 15 Example 26: (±)-cis-tert-butyl-decahydro-1H-pyrido[3,2-b]azepine-1-carboxylate ((±)- 39)To a solution of mono-trifluoroacetamide-protected diamine (±)-24 (102 mg, 0.41 mmol, 1.0 eq.) in DCM (4 mL, 0.1 M) was added Boc2O (107 mg, 0.49 mmol, 1.2 eq.), NEt3 (74 µL, 20 0.53 mmol, 1.3 eq.) and DMAP (cat.). The reaction mixture was stirred at 22 °C for 2 hours. Then the solvent was evaporated to give a white solid. The intermediate product was dissolved in a mixture of THF and deion. H2O (4 mL, 1:1) and LiOH (49.1 mg, 2.05 mmol, 5.0 eq.) was added. The mixture was refluxed for 24 hours. Then it was cooled to room temperature and concentrated under reduced pressure. The aqueous phase was extracted 25 with EtOAc (3x 15 mL). The organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude was purified by column chromatography on silica gel (10% MeOH in DCM + 0.1% NEt3) to give mono-Boc-protected diamine (±)-39 (79.3 mg, 0.31 mmol, 76%) as a yellow oil; Rf = 0.20 (10% MeOH in DCM + 0.1% NEt3);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 4.33-4.35 (t, J = 8.0 Hz, 1H), 3.88-3.92 (m, 1H), 2.91-2.99 (m, 30 2H) 2.63-2.72 (m, 2H), 1.96-2.05 (m, 1H), 1.84-1.86 (m, 2H), 1.74-1.78 (m, 1H), 1.66-1.69 (m, 1H), 1.46 (s, 9H; H3-CBoc), 1.36-1.44 (m, 5H);13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 156.7 ((C=O)Boc, 81.2 ((Cq)Boc), 57.0 (CH), 55.6 (CH), 44.4 (CH2), 40.8 (CH2), 32.6P382113WO 138 (CH2), 29.0 (CH2), 28.7 ((CH3)Boc), 28.5 (CH2), 28.3 (CH2), 25.5 (CH2); HR-MS (ESI): (m / z) = calculated for C14H27N2O2+[M+H]+: 255.2067, found: 255.2046. Example 27: (±)-cis-5-benzyldecahydro-1H-pyrido[3,2-b]azepine ((±)-40a) 5To a solution of mono-Boc-protected diamine (±)-39 (74.4 mg, 0.29 mmol, 1.0 eq.) in MeOH (3 mL, 0.1 M) was added benzyl bromide (42 µL, 0.35 mmol, 1.2 eq.) and K2CO3 (48.4 mg, 0.35 mmol, 1.2 eq.). The mixture was stirred at 22 °C for 2 hours. Then the solvent was 10 evaporated, and the residue was diluted with deion. H2O and extracted with EtOAc (3x 10 mL). The organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo to give a yellow oil. The intermediate product was dissolved in DCM (3 mL, 0.1 M) and TFA (0.3 mL, 10 vol%) was added. The reaction was stirred at 22 °C for 2 hours. Then it was washed with NaOH (1 M, 2x 4 mL) and the organic phase was dried over Na2SO4, 15 filtered and the solvent was evaporated. The crude was purified by column chromatography on silica gel (10% MeOH in DCM + 0.1% NEt3) to give mono-benzylated diamine (±)-40a (56.8 mg, 0.23 mmol, 79%) as a brown oil; Rf = 0.20 (DCM / MeOH 9:1 + 0.1% NEt3);1H- NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 7.33-7.35 (m, 2H; H2-Carom.), 7.26-7.29 (m, 2H; H2-Carom.), 7.18-7.21 (m, 1H; H-Carom), 3.89 (d, J = 14.1, 1H; H-Cbenz.), 3.56 (d, J = 14.1, 1H; 20 H-Cbenz.) 3.12-3.16 (m, 1H; H-C(9a)), 2.74-2.80 (m, 1H; H-C(4a)), 2.59-2.73 (m, 4H; H2-C(2 and 6)), 2.08-2.18 (m, 1H; H-C(9)), 1.85-1.89 (m, 1H; H-C(4)), 1.68-1.80 (m, 4H; H-C(3, 4, 7, 8 or 9)), 1.55-1.60 (m, 1H; H-C(8)), 1.39-1.54 (m, 3H; H-C(3, 4, 7, 8 or 9));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 141.9 ((Cq)arom.), 129.7 ((CH)arom.), 129.2 ((CH)arom.), 127.8 ((CH)arom.), 62.9 (C(4a)), 60.2 (CH2)benz.), 58.7 (C(9a)), 49.2 (C(2 or 6)), 41.3 (C(2 or 6)), 30.6 25 (C(3, 4, 7, 8 or 9), 30.4 (C(3, 4, 7, 8 or 9), 26.7 (C(3, 4, 7, 8 or 9), 26.4 (C(3, 4, 7, 8 or 9), 26.2 (C(3, 4, 7, 8 or 9)); HR-MS (ESI): (m / z) = calculated for C16H25N2+[M+H]+: 245.2012, found: 245.1990. Example 28: (±)-cis-1-benzyldecahydro-1H-pyrido[3,2-b]azepine ((±)-27a)P382113WO 139To a solution of mono-trifluoroacetamide-protected diamine (±)-24 (50.0 mg, 0.20 mmol, 1.0 eq.) in MeOH (2 mL, 0.1 M) was added benzyl bromide (29 µL, 0.24 mmol, 1.2 eq.) and K2CO3(41.5 mg, 0.30 mmol, 1.5 eq.). The mixture was stirred at 22 °C for 2 hours. Then the 5 solvent was evaporated, and the residue was diluted with deion. H2O and extracted with EtOAc (3x 10 mL). The organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo to give a yellow oil. The intermediate product was dissolved in a mixture of THF and deion. H2O (4 mL, 1:1) and LiOH (24.0 mg, 1.0 mmol, 5.0 eq.) was added. The mixture was refluxed for 24 hours. Then it was cooled to room temperature and concentrated 10 under reduced pressure. The aqueous phase was extracted with EtOAc (3x 10 mL). The organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude was purified by column chromatography on silica gel (10% MeOH in DCM + 1% NH3) to give mono-benzylated diamine (±)-27a (22.2 mg, 0.09 mmol, 45%) as a yellow oil; Rf= 0.20 (10% MeOH in DCM + 1% NH3);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 15 7.20-7.36 (m, 5H; H-Carom.), 3.82 (d, J = 13.3, 1H; H-Cbenz.), 3.38 (d, J = 13.3, 1H; H-Cbenz.), 2.97 (quint. J = 4.1 Hz, 1H; H-C(4a)), 2.90 (dt, J = 14.2, 4.3 Hz, 1H; H-C(6)), 2.78-2.80 (m, 1H; H-C(9a)), 2.52-2.59 (m, 1H; H-C(6)), 2.43-2.49 (m, 1H; H-C(2)), 2.20-2.25 (m, 1H; H- C(2)), 1.40-1.86 (m, 9H; H-C(3, 4, 7, 8 and 9)), 1.22-1.29 (m, 1H; H-C(3, 4, 7, 8 or 9));13C- NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 140.4 ((Cq)arom.), 130.1 ((CH)arom.), 129.2 20 ((CH)arom.), 128.0 ((CH)arom.), 64.3 (C(9a)), 59.6 (CH2)benz.), 57.2 (C(4a)), 49.9 (C(2)), 45.8 (C(6), 33.0 (C(7, 8 or 9), 30.4 (C(3 or 4)), 25.8 (C(7, 8 or 9)), 24.5 (C(3, 4, 7, 8 or 9)), 24.3 (C(3, 4, 7, 8 or 9)); HR-MS (ESI): (m / z) = calculated for C16H25N2+[M+H]+: 245.2012, found: 245.2006. 25 Example 29: (±)-trans-tert-butyl-6-oxodecahydro-1H-pyrido[3,2-b]azepine-1- carboxylate ((±)-41)To a solution of amine (±)-25 (50.0 mg, 0.30 mmol, 1.0 eq.) in DCM (3 mL, 0.1 M) was added Boc2O (79 mg, 0.36 mmol, 1.2 eq.) and NEt3(54 µL, 0.39 mmol, 1.3 eq.). The 30 reaction mixture was stirred at 22 °C for 2 hours. Then the solvent was evaporated and theP382113WO 140 crude was purified by column chromatography on silica gel (80% EtOAc in heptane) to give Boc-protected amine (±)-41 (65 mg, 0.24 mmol, 80%) as a white solid; Rf= 0.21 (80% EtOAc in heptane);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 4.64-4.67 (m, 1H; H- C(2)), 3.79 (m, 1H; H-C(9a)), 3.49-3.54 (m, 1H; H-C(4a)), 2.48-2.54 (m, 1H; H-C(2)), 2.28- 5 2.31 (m, 2H; H-C(7)), 1.57-1.89 (m, 8H; H-C(3, 4, 8 and 9)), 1.46 (m, 9H; H3-CBoc);13C- NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 173.3 (C(6)), 158.3 ((C=O)Boc, 80.4 ((Cq)Boc), 60.3 (C(4a)), 50.4 (C(9a)), 43.3 (C(2)), 33.6 (C(7)), 31.1 (C(3, 4, 8 or 9)), 28.8 (C(3, 4, 8 or 9)), 27.2 (C(3, 4, 8 or 9)), 20.6 (C(3, 4, 8 or 9)), 19.9 ((CH3)Boc); HR-MS (ESI): (m / z) = calculated for C14H25N2O3+[M+H]+: 269.1860, found: 269.1958. 10 Example 30: (±)-trans-tert-butyl-decahydro-1H-pyrido[3,2-b]azepine-1-carboxylate ((±)-42)15 A solution of lactam (±)-41 (199 mg, 0.74 mmol, 1.0 eq.) in dry THF (7.5 mL, 0.1 M) was cooled to 0 °C, LiAlH4(1 M in THF, 1.11 mL, 1.11 mmol, 1.5 eq.) was added dropwise and the reaction was stirred at 0 °C for 4 hours. The reaction was then worked up using Fieser’s protocol and the crude was purified by flash column chromatography on silica gel (EtOAc) to give azepane (±)-42 (85 mg, 0.33 mmol, 45%) as a colorless oil; Rf = 0.20 (EtOAc);1H-20 NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 3.59 (s, 1H; H-C(9a)), 2.76-2.83 (m, 2H; H2- C(2 or 6)), 1.98-2.08 (m, 3H; H-C(4a and H2-C(2 or 6)), 1.69-1.78 (m, 3H; H-C(9 and 3, 4, 7 or 8)), 1.62-1.68 (m, 1H; H-C(3, 4, 7 or 8)), 1.48-1.58 (m, 4H; H-C(9 and 3, 4, 7 or 8)), 1.44 (m, 9H; H3-CBoc), 1.29-1.43 (m, 2H; H-C(3, 4, 7 or 8));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 157.9 ((C=O)Boc), 80.2 ((Cq)Boc), 66.0 (C(4a)), 57.8 (C(2 or 6)), 57.4 (C(2 or 6)), 25 50.6 (C(9a)), 31.1 (C(3, 4, 7 or 8)), 29.9 (C(3, 4, 7 or 8)), 28.7 ((CH3)Boc), 26.5 (C(3, 4, 7 or 8)), 25.1 (C(3, 4, 7 or 8)), 21.2 (C(9)); HR-MS (ESI): (m / z) = calculated for C14H27N2O2+[M+H]+: 255.2067, found: 255.2064. Example 31: (±)-trans-5-benzyldecahydro-1H-pyrido[3,2-b]azepine ((±)-40b)30 o e o sepsP382113WO 141 To a solution of mono-Boc-protected diamine (±)-42 (85 mg, 0.33 mmol, 1.0 eq.) in MeOH (3.5 mL, 0.1 M) was added benzyl bromide (48 µL, 0.40 mmol, 1.2 eq.) and K2CO3(55 mg, 0.40 mmol, 1.2 eq.). The mixture was stirred at 22 °C for 2 hours. Then the solvent was evaporated, and the residue was diluted with deion. H2O and extracted with EtOAc (3x 10 5 mL). The organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo to give a yellow oil. The intermediate product was dissolved in DCM (3.5 mL, 0.1 M) and TFA (0.35 mL, 10 vol%) was added. The reaction was stirred at 22 °C for 2 hours. Then it was washed with NaOH (1 M, 2x 4 mL) and the organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The crude was purified by column chromatography 10 on silica gel (10% MeOH in DCM + 0.1% NEt3) to give mono-benzylated diamine (±)-40b (86 mg, 0.25 mmol, 76%) as a brown oil; Rf = 0.20 (10% MeOH in DCM + 0.1% NEt3);1H- NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 7.67-7.68 (m, 2H; H2-Carom.), 7.53-7.54 (m, 3H; H-Carom.), 4.68-4.71 (m, 1H; H-Cbenz.), 4.53-4.56 (m, 1H; H-Cbenz.), 4.16-4.20 (m, 1H; H-C(4a or 9a)), 3.93-3.96 (m, 1H; H-C(4a or 9a)), 3.60-3.65 (m, 1H; H-C(2, 3, 4, 6, 7, 8, or 9)), 3.46-15 3.52 (m, 1H; H2-C(2, 3, 4, 6, 7, 8, or 9)), 3.19-3.22 (m, 1H; H-C(2, 3, 4, 6, 7, 8, or 9)), 3.01- 3.08 (m, 1H; H-C(2, 3, 4, 6, 7, 8, or 9)), 1.92-3.32 (m, 8H; H-C(2, 3, 4, 6, 7, 8, or 9)), 1.65- 1.82 (m, 2H; H-C(2, 3, 4, 6, 7, 8, or 9));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 133.2 ((CH)arom.), 131.7 ((Cq)arom.), 130.6 ((CH)arom.), 130.0 130.6 ((CH)arom.), 2X 62.3 (CH2)benz.) and (C(4a)) or (C(9a)), 54.5 (C(4a)) or (C(9a)), 53.4 (C(2, 3, 4, 6, 7, 8, or 9), 39.4 20 (C(2, 3, 4, 6, 7, 8, or 9)), 2X 26.6 (C(2, 3, 4, 6, 7, 8, or 9)), 25.7 (C(2, 3, 4, 6, 7, 8, or 9), 23.3 (C(2, 3, 4, 6, 7, 8, or 9), 22.3 (C(2, 3, 4, 6, 7, 8, or 9); HR-MS (ESI): (m / z) = calculated for C16H25N2+[M+H]+: 245.2012, found: 245.2010.Example 32: (±)-trans-tert-butyl-decahydroazepino[3,2-b]azepine-1(2H)-carboxylate 25To a solution of free diamine meso-4b (75.0 mg, 0.62 mmol, 1.0 eq.) in DCM (6 mL, 0.1 M) was added Boc2O (406 mg, 1.86 mmol, 3.0 eq.), NEt3 (259 µL, 1.86 mmol, 3.0 eq.) and DMAP (cat.). The reaction mixture was stirred at 22 °C for 24 hours. Then the solvent was 30 evaporated, and the crude product was purified by column chromatography on silica gel (heptane / EtOAc 8:2) to give bis-Boc-protected diamine (65.4 mg, 0.18 mmol, 29%). Due to the presence of Boc rotamers in the NMR measurement, no proper data could be obtained. The intermediate product was dissolved in CHCl3(7.3 mL, 0.024 mol / l) and TFA (0.73 mL, 10 vol%) was added at 0 °C. The reaction was stirred at this temperature for 90 minutes.P382113WO 142 Then it was quenched by addition of NaOH (1 M, 5.7 mL) and extracted with DCM (3x 6 mL). The organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude was purified by column chromatography on silica gel (5% MeOH in DCM + 1% NH3) to give mono-Boc-protected diamine (±)-43 (16.7 mg, 0.06 mmol, 10%) as a 5 yellow oil; Rf = 0.20 (5% MeOH in DCM + 1% NH3);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 3.82-3.95 (m, 1H), 3.55-3.67 (m, 2H), 2.80-3.01 (m, 4H) 1.62-1.84 (m, 11H), 1.47 (m, 9H);13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 157.0, 156.7, 81.2, 81.1, 73.7, 71.6, 64.4, 62.9, 62.2, 60.9, 48.4, 44.4, 36.8, 36.0, 34.3, 33.9, 29.4, 29.2, 2X 28.8, 28.3, 27.9, 27.3, 24.8, 24.5; due to the presence of Boc rotamers in the NMR measurement, 10 structural assignment is not possible; HR-MS (ESI): (m / z) = calculated for C15H29N2O2+[M+H]+: 269.2224, found: 269.2224. Example 33: (±)-trans-6-benzyldodecahydroazepino[3,2-b]azepine ((±)-44b)15 To a solution of mono-Boc protected diamine (±)-43 (15.4 mg, 0.06 mmol 1.0 eq.) in MeOH (1 mL) was added benzyl bromide (8 µL, 0.07 mmol, 1.2 eq.) and K2CO3 (12.4 mg, 0.09 mmol, 1.5 eq.). The mixture was stirred at 22 °C for 24 hours. Then the solvent was evaporated, and the residue was diluted with deion. H2O and extracted with EtOAc (3x 5 mL). The organic layers were dried over Na2SO4, filtered and the solvent was removed in 20 vacuo to give a yellow oil. The intermediate product was dissolved in DCM (1 mL) and TFA (0.1 mL, 10 vol%) was added. The reaction was stirred at 22 °C for 2 hours. Then it was washed with NaOH (1 M, 2x 2 mL) and the organic phase was dried over Na2SO4, filtered and the solvent was evaporated. The crude was purified by column chromatography on silica gel (5% MeOH in DCM + 1% NH3) to give mono-benzylated diamine (±)-44b (9.3 mg, 0.04 25 mmol, 67%) as a brown oil; Rf= 0.20 (5% MeOH in DCM + 1% NH3);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 7.33-7.35 (m, 2H; H2-Carom.), 7.26-7.29 (m, 2H; H2-Carom.), 7.19- 7.21 (m, 1H; H-Carom), 3.83 (d, J = 13.7, 1H; H-Cbenz.), 3.69 (d, J = 13.7, 1H; H-Cbenz.) 2.84- 2.92 (m, 3H; H-C(5a and 7)), 2.73-2.79 (m, 2H; H-C(2 and 10a)), 2.53-2.59 (m, 1H; H-C(2)), 2.07-2.13 (m, 1H; H-C(3, 4, 5, 8, 9 or 10)), 1.97-2.05 (m, 1H; H-C(3, 4, 5, 8, 9 or 10)), 1.75- 30 1.83 (m, 2H; H-C(3, 4, 5, 8, 9 or 10)), 1.62-1.74 (m, 4H; H-C(3, 4, 5, 8, 9 or 10)), 1.41-1.61 (m, 4H; H-C(3, 4, 5, 8, 9 or 10));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 142.1 ((Cq)arom.), 129.7 ((CH)arom.), 129.2 ((CH)arom.), 127.8 ((CH)arom.), 68.4 (C(10a)), 64.9 (C(5a)), 58.1 (CH2)benz.), 50.4 (C(2)), 48.5 (C(7)), 35.6 (C(3, 4, 5, 8, 9 or 10), 31.0 (C(3, 4, 5, 8, 9 orP382113WO 143 10), 28.5 (C(3, 4, 5, 8, 9 or 10), 28.4 (C(3, 4, 5, 8, 9 or 10), 27.2 (C(3, 4, 5, 8, 9 or 10)), 25.9 (C(3, 4, 5, 8, 9 or 10)); HR-MS (ESI): (m / z) = calculated for C17H27N2+[M+H]+: 259.2169, found: 259.2165. 5To a solution of Boc-protected amine (±)-8 (1.19 g, 4.97 mmol, 1.0 eq.) in DCM (50 mL, 0.1 M) was added TFA (5.0 mL, 10 vol%). The reaction was stirred at 22 °C for 2 hours. Then it was evaporated to yield a colorless oil. To a solution of intermediate product in DMF 10 (18 mL) was added Cs2CO3 (4.20 g, 12.9 mmol, 2.5 eq.) and bromodiphenylmethane (3.19 g, 12.9 mmol, 2.5 eq.). The reaction mixture was stirred at 60 °C for 24 hours. Then the solvent was evaporated, and the residue was taken up in deion. H2O (50 mL) and extracted with EtOAc (3x 100 mL). The organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude was purified by column chromatography on silica gel (4% 15 acetone in heptane) to give diphenylmethane protected amine (±)-45 (117 mg, 0.38 mmol, 8%) as an orange solid; Rf = 0.20 (4% acetone in heptane);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 7.13-7.42 (m, 10H; H-Carom.), 4.82 (s, 1H; CH), 3.16-3.23 (m, 1H; H-C(7a)), 2.78-2.89 (m, 2H; H-C(2 and 3a)), 2.34-2.50 (m, 2H; H-C(2 and 5)), 2.24-2.31 (m, 1H; H- C(5)), 2.07-2.22 (m, 1H; H-C(3)), 1.74-1.93 (m, 2H; H-C(3 and 6)), 1.63-1.71 (m, 2H; H2- 20 C(7)), 1.42-1.53 (m, 1H; H-C(6));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 215.3 (C(4)), 144.8 ((Cq)arom.), 143.1 ((Cq)arom.), 129.6 ((CH)arom.), 129.3 ((CH)arom.), 129.2 ((CH)arom.), 129.0 ((CH)arom.), 128.1 ((CH)arom.), 127.9 ((CH)arom.), 71.3 (CH), 64.5 (C(7a)), 52.8 (C(3a)), 49.7 (C(2)), 40.1 (C(5)), 26.2 (C(3)), 25.9 (C(7)), 22.1 (C(6)); HR-MS (ESI): (m / z) = calculated for C21H24NO+[M+H]+: 306.1852, found: 306.1842. 25 Example 34: (±)-cis-1-benzhydryloctahydro-4H-indol-4-one ((±)-46)P382113WO 144Ketone (±)-45 (85.5 mg, 0.28 mmol, 1.0 eq.) was dissolved in pyridine (3 mL, 0.1 M) and NH2OH•HCl (38.9 mg, 0.56 mmol, 2.0 eq.) was added. The mixture was stirred at 22 °C for 2 hours, then the solvent was evaporated, and the residue was taken up in deion. H2O (5 5 mL) and extracted with EtOAc (3x 10 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was evaporated to yield a yellow solid. To a solution of oxime isomers in pyridine (2 mL, 0.1 M) was added freshly recrystallized p-TsCl (64.8 mg, 0.34 mmol, 1.2 eq.) and the solution was stirred at 22 °C for 2 hours. After completion the solvent was evaporated, and the crude was taken up in deion. H2O (5 mL) and extracted 10 with EtOAc (3x 10 mL). The organic phases were dried over Na2SO4, filtered and the solvent was evaporated to yield a yellow sticky solid. The intermediate product was further reacted with potassium acetate (50.1 mg, 0.51 mmol, 3.0 eq.) in a mixture of EtOH (2.5 mL) and deion. H2O (2.5 mL). The reaction was stirred and refluxed for 16 hours. After cooling to room temperature and evaporation of the EtOH, the remaining aqueous solution was 15 adjusted to pH = 10 by addition of aqueous NaOH solution (1 M, 0.5 mL). The aqueous phase was extracted with DCM (3x 10 mL). The combined organic layers were dried over Na2SO4, filtered and the solvent was removed under reduced pressure. The crude product was purified by flash column chromatography on silica gel (80% EtOAc in heptane) to isolate lactam (±)-46 (21.4 mg, 0.07 mmol, 24%) as a white solid; Rf = 0.20 (80% EtOAc in heptane); 201H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 7.18-7.41 (m, 10H; H-Carom.), 4.81 (s, 1H; CH), 4.00 (q, J = 7.8 Hz, 1H; H-C(3a)), 2.89-2.96 (m, 1H; H-C(2)), 2.63-2.70 (m, 1H; H- C(8a)), 2.43-2.53 (m, 1H; H-C(6)), 2.06-2.23 (m, 3H; H-C(2, 3 and 6)), 1.67-1.80 (m, 1H; H- C(3)), 1.52-1.63 (m, 2H; H-C(7 and 8)), 1.33-1.49 (m, 2H; H-C(7 and 8));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 177.6 (C(5)), 144.4 ((Cq)arom.), 142.0 ((Cq)arom.), 130.2 25 ((CH)arom.), 129.4 ((CH)arom.), 129.2 ((CH)arom.), 129.1 ((CH)arom.), 128.2 ((CH)arom.), 128.0 ((CH)arom.), 72.1 (CH), 64.5 (C(8a)), 55.7 (C(3a)), 50.2 (C(2)), 33.3 (C(6)), 31.1 (C(3)), 26.8 (C(7)), 19.7 (C(8)); HR-MS (ESI): (m / z) = calculated for C21H25N2O+[M+H]+: 321.1961, found: 321.1955. 30 Example 35: (±)-cis-1-benzhydryldecahydropyrrolo[3,2-b]azepine ((±)-47)P382113WO 145A solution of lactam (±)-46 (7.7 mg, 0.02 mmol, 1.0 eq.) in dry THF (1 mL) was cooled to 0 °C, then LiAlH4(1 M in THF, 60 µL, 0.06 mmol, 3.0 eq.) was added dropwise and the reaction was stirred at 22 °C for 4 hours. The reaction was then worked up using Fieser’s protocol 5 and the crude was purified by flash column chromatography on silica gel (5% MeOH in DCM + 0.1% NEt3) to give azepane (±)-47 (6.6 mg, 0.02 mmol, quant.) as a light brown oil; Rf= 0.20 (5% MeOH in DCM + 0.1% NEt3);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 7.16-7.43 (m, 10H; H-Carom.), 4.83 (s, 1H; CH), 3.50 (q, J = 8.3 Hz, 1H; H-C(3a)), 3.11-3.16 (m, 1H; H-C(5)), 2.81-2.89 (m, 2H; H-C(2 and 8a)), 2.48-2.55 (m, 1H; H-C(5)), 2.19-2.25 (m, 10 1H; H-C(2)), 2.04-2.10 (m, 1H; H-C(3)), 1.62-1.72 (m, 4H; H-C(3, 6, 7 and 8)), 1.48-1.61 (m, 2H; H-C(6 and 8)), 1.00-1.10 (m, 1H; H-C(7));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 144.5 ((Cq)arom.), 142.2 ((Cq)arom.), 130.1 ((CH)arom.), 129.4 ((CH)arom.), 129.2 ((CH)arom.), 129.1 ((CH)arom.), 128.1 ((CH)arom.), 127.9 ((CH)arom.), 71.9 (CH), 67.2 (C(8a)), 63.0 (C(3a)), 50.0 (C(2)), 49.5 (C(5)), 31.9 (C(3 or 6)), 31.7 (C(3 or 6)), 29.5 (C(8)), 26.2 (C(7)); 15 HR-MS (ESI): (m / z) = calculated for C21H27N2+[M+H]+: 307.2169, found: 307.2173. 6-methoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepine (48)A solution of lactam 31 (5.67 g, 29.7 mmol, 1.0 eq.) in dry THF (120 mL) was cooled to 0 20 °C. Then LiAlH4 (1M in THF, 267 mL, 267 mmol, 9.0 eq.) was added dropwise through a dropping funnel. The mixture was stirred at reflux for 15 hours. Then it was cooled down and worked up using Fieser’s protocol. The crude product was purified by flash column chromatography on silica gel (20% EtOAc in heptane + 0.1% NEt3) to afford azepane 48 (4.29 g, 24.2 mmol, 81%) as a yellow solid; Rf = 0.16 (20% EtOAc in heptane + 0.1% NEt3); 251H-NMR (400 MHz, CDCl3, 298 K): δ [ppm] = 6.99 (t, J = 8.0 Hz, 1H; H-C(8)), 6.52 (dd, 4H, J = 8.1 Hz, 1H; H-C(7 and 9)), 3.80 (s, 3H; H3-C), 3.10 (t, J = 5.5 Hz, 2H; H-C(2)), 2.90 (t, J = 5.6 Hz, 2H; H-C(5)), 1.82-1.88 (m, 2H; H-C(3)), 1.60-1.65 (m, 2H; H-C(4));13C-NMR (100 MHz, CDCl3, 298 K): δ [ppm] = 158.1 (C(6)), 150.6 (C(9a)), 126.6 (C(8)), 122.6 (C(5a)),P382113WO 146 113.0 (C(7 or 9)), 104.8 (C(7 or 9)), 56.0 (CH3), 49.0 (C(2)), 31.5 (C(3)), 26.0 (C(4)), 24.8 (C(5)); HR-MS (ESI): (m / z) = calculated for C11H16NO+[M+H]+: 178.1226, found: 178.1221. trifluoro-1-(6-methoxy-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)ethanone (49) 5To a solution of azepane 48 (4.28 g, 24.1 mmol, 1.0 eq.) in DCM (240 mL, 0.1 M) was added TFAA (4.02 mL, 28.9 mmol, 1.2 eq.) and pyridine (2.33 mL, 28.9 mmol, 1.2 eq.). The mixture was stirred at 22 °C for 2 hours. The organic phase was washed with deion. H2O (130 mL) and brine (130 mL), dried over Na2SO4, filtered and the solvent was removed in vacuo to 10 give trifluoroacetamide-protected amine 49 (6.49 g, 23.8 mmol, 99%) as a yellow solid; Rf= 0.24 (20% EtOAc in heptane);1H-NMR (400 MHz, CDCl3, 298 K): δ [ppm] = 7.20-7.25 (m, 1H; H-C(8); 7.02-7.05 (m, 1H; H-C(7), 6.83 (d, J = 7.8 Hz, 1H; H-C(9), 4.55-4.59 (m, 1H; H- C(2)), 3.85 (s, 3H; H3-C), 3.38-3.44 (m, 1H; H-C(5)), 2.80-2.87 (m, 1H; H-C(2)), 2.22-2.30 (m, 1H; H-C(5)), 1.90-2.01 (m, 2H; H-C(3 and 4)), 1.81-1.85 (m, 1H; H-C(3)), 1.26-1.37 (m, 15 1H; H-C(4));13C-NMR (100 MHz, CDCl3, 298 K): δ [ppm] = 158.6 (C(6)), 156.8 (q, JC-F = 35.3 Hz, COCF3), 142.7 (C(9a)), 130.2 (C(5a)), 128.3 (C(8)), 120.4 (C(9)), 117.8 (q, JC-F = 287.7 Hz, COCF3), 112.7 (C(7)), 56.5 (CH3), 51.0 (C(2)), 29.6 (C(3)), 26.6 (C(4)), 24.8 (C(5)); 19F-NMR (300 MHz, CDCl3, 298 K): δ [ppm] = -69.7; HR-MS (ESI): (m / z) = calculated for C13H15NO2F3+[M+H]+: 274.1049, found: 274.1049, C13H14NO2Na+[M+Na]+: 296.0874, found: 20 296.0866. trifluoro-1-(6-hydroxy-2,3,4,5-tetrahydro-1H-benzo[b]azepin-1-yl)ethanone (50)To a solution of 49 (5.73 g, 21.0 mmol, 1.0 eq.) in dry DCM (125 mL) was added BBr3 (1 M 25 in DCM, 63 mL, 63 mmol, 3 eq.) at -78 °C. The mixture was warmed to 22 °C and stirred for 24 hours. Then it was cooled to 0 °C and quenched by addition of deion. H2O (40 mL). The precipitate was filtered, washed with deion. H2O, dried and purified by flash column chromatography on silica gel (20% EtOAc in heptane to EtOAc) to yield alcohol 50 (5.07 g, 19.6 mmol, 93%) as a light brown solid; Rf= 0.23 (20% EtOAc in heptane);1H-NMR (400 30 MHz, MeOD-d4, 298 K): δ [ppm] = 7.04 (t, J = 8.0 Hz, 1H; H-C(8); 6.83-6.85 (m, 1H; H-C(7P382113WO 147 or 9), 6.68-6.70 (m, 1H; H-C(7 or 9), 4.57 (dt, J = 13.2, 3.3 Hz, 1H; H-C(2)), 3.38 (dd, J = 13.7, 5.8 Hz, 1H; H-C(5)), 2.80-2.87 (m, 1H; H-C(2)), 2.25 (t, J = 9.06 Hz, 1H; H-C(5)), 1.89- 2.01 (m, 2H; H-C(3 and 4)), 1.81-1.87 (m, 1H; H-C(3)), 1.29-1.40 (m, 1H; H-C(4));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 156.9 (q, JC-F= 34.1 Hz, COCF3), 156.4 (6), 142.9 5 (C(9a)), 128.3 (C(5a)), 127.9 (C(8)), 119.1 (C(7 or 9)), 117.9 (q, JC-F = 284.6 Hz, COCF3), 117.0 (C(7 or 9)), 51.1 (C(2)), 29.6 (C(3)), 26.8 (C(4)), 25.0 (C(5));19F / NMR (300 MHz, MeOD-d4, 298 K): δ [ppm] = -69.6; HR-MS (ESI): (m / z) = calculated for C12H13NO2F3+[M+H]+: 260.0893, found: 260.0888, C12H12NO2F3Na+[M+Na]+: 282.0718, found: 282.0705. trifluoro-1-(6-hydroxydecahydro-1H-benzo[b]azepin-1-yl)ethanone ((±)-51) 10A mixture of aromatic compound (±)-50 (5.07 g, 19.6 mmol, 1.0 eq.), Rh / C (5%, Rh on activated charcoal, 0.51 g, 10 wt% of substrate) and AcOH (2.24 mL, 39.2 mmol, 2.0 eq.) in iPrOH (50 mL) was stirred in a sealed autoclave at 70 °C under H2 pressure (25 bar) for 2 days. After cooling to room temperature, the reaction mixture was filtered over celite, washed 15 with MeOH and evaporated to dryness to afford aliphatic bicycle (±)-51 (5.20 g, 19.6 mmol, quant.) as a colorless oil; Rf = 0.23 (20% EtOAc in heptane);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 4.96-5.01 (m, 0.6H), 4.45-4.49 (m, 1H), 3.90-4.03 (m, 1.7H), 3.81-3.85 (m, 1.5H), 3.69-3.78 (m, 1.6H), 3.64-3.68 (m, 0.3H), 3.42-3.50 (m, 1H), 3.26-3.28 (m, 1H), 3.23- 3.24 (m, 0.3H), 1.14-2.08 (m, 35H);13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 158.0 20 (q, JC-F = 45.9 Hz, COCF3), 118.3 (q, JC-F = 288.8 Hz, COCF3), 75.2, 73.9, 73.5, 72.9, 72.4, 70.0, 2X 58.7, 57.8, 2X 54.9, 54.4, 51.5, 51.3, 46.8, 46.6, 46.1, 42.6, 2X 41.9, 2X 41.7, 41.3, 40.7, 36.7, 34.0, 32.9, 32.3, 32.1, 31.4, 30.2, 30.1, 29.5, 2X 29.3, 2X 28.5, 28.3, 27.9, 27.8, 26.7, 26.6, 26.3, 26.2, 26.1, 25.7, 25.4, 2X 25.3, 2X 25.1, 25.0, 24.8, 24.3, 23.3, 23.0, 21.8, 21.7, 21.0, 20.9, 20.6, 20.5, 19.2; due to the presence of alcohol isomers and 25 trifluoroacetamide rotamers in the NMR measurement, structural assignment is not possible; HR-MS (ESI): (m / z) = calculated for C12H19NO2F3+[M+H]+: 266.1373, found: 266.1363, C12H18NO2F3Na [M+Na]+: 288.1187, found: 288.1179. tert-butyl-6-hydroxydecahydro-1H-benzo[b]azepine-1-carboxylate ((±)-52)P382113WO 148Trifluoroacetamide-protected amine (±)-51 (1.05 g, 3.96 mmol, 1.0 eq.) was dissolved in a mixture of THF and deion. H2O (20 mL, 1:1) and LiOH (0.47 mg, 19.8 mmol, 5.0 eq.) was added. The mixture was refluxed for 24 hours. Then it was cooled to room temperature and 5 concentrated under reduced pressure. The aqueous phase was extracted with EtOAc (3x 25 mL). The organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo to obtain a brown solid. To a solution of intermediate product in DCM (40 mL, 0.1 M) was added Boc2O (1.30 g, 5.94 mmol, 1.5 eq.), NEt3(658 µL, 4.75 mmol, 1.2 eq.) and DMAP (cat.). The mixture was stirred at 22 °C for 24 hours. Then the solvent was evaporated 10 and the crude was purified by flash column chromatography on silica gel (20% EtOAc in heptane) to isolate Boc-protected amine (±)-52 (0.67 g, 2.49 mmol, 63%) as a colorless oil; Rf= 0.23 (20% EtOAc in heptane);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 4.52 (br, 0.5H), 3.98-4.09 (m, 0.5H), 3.67-3.81 (m, 2H), 3.01-3.09 (m, 1H), 1.73-1.93 (m, 6H), 1.19-1.66 (m, 22H);13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 157.4, 80.8, 75.2, 15 73.4, 72.7, 70.0, 56.1, 52.5, 46.1, 42.7, 41.3, 40.3, 36.7, 36.6, 34.0, 33.0, 32.4, 31.4, 30.8, 29.7, 29.0, 28.8, 27.9, 27.4, 26.8, 26.2, 26.1, 25.3, 24.8, 23.5; due to the presence of alcohol isomers and Boc rotamers in the NMR measurement, structural assignment is not possible; HR-MS (ESI): (m / z) = calculated for C15H28NO3+[M+H]+: 270.2064, found: 270.2064. tert-butyl-6-oxodecahydro-1H-benzo[b]azepine-1-carboxylate ((±)-53) Boc Boc 20A solution of alcohol (±)-52 (0.67 g, 2.49 mmol, 1.0 eq.) in DCM (25 mL, 0.1 M) was cooled to 0 °C and DMP (1.58 g, 3.74 mmol, 1.5 eq.) was added. The reaction was stirred at 22 °C for 2 hours. Then it was quenched by addition of sat. NaHCO3solution (10 mL) and Na2S2O3solution (2 M, 10 mL). The water phase was washed three times with EtOAc (3x 20 mL). 25 The combined organic phases were washed with deion. H2O, dried over Na2SO4, filtered and the solvent was evaporated in vacuo. The crude was purified by column chromatography on silica gel (20% EtOAc in heptane) to yield ketone (±)-53 (0.36 g, 1.35 mmol, 54%) as a yellow solid; Rf= 0.23 (20% EtOAc in heptane);1H-NMR (400 MHz, MeOD- d4, 298 K): δ [ppm] = 4.41 (quint., J = 5.1 Hz, 1H; H-C(9a)), 3.68-3.72 (m, 1H; H-C(2)), 3.00-P382113WO 149 3.04 (m, 1H; H-C(2)), 2.64-2.69 (m, 1H; H-C(9a)), 2.36-2.45 (m, 1H; H-C(7)), 2.25-2.33 (m, 1H; H-C(7)), 2.07-2.15 (m, 1H), 1.87-2.02 (m, 3H), 1.76-1.84 (m, 2H), 1.66-1.72 (m, 1H), 1.53-1.65 (m, 2H), 1.46 (s, 9H; H3-CBoc), 1.37-1.44 (m, 1H);13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 214.3 (C(6)), 157.1 ((C=O)Boc, 81.4 ((Cq)Boc), 57.9 (C(9a)), 56.2 (C(5a)), 5 43.7 (C(2)), 39.9 (C(7)), 28.9 (CH2), 28.8 (CH2), 28.7 ((CH3)Boc), 28.1 (CH2), 25.1 (CH2), 22.2 (CH2); HR-MS (ESI): (m / z) = calculated for C15H26NO3+[M+H]+: 268.1907, found: 268.1900.To a solution of ketone (±)-53 (687 mg, 2.57 mmol, 1.0 eq.) in MeOH (10 mL) and deion. 10 H2O (10 mL) was added NH2OH•HCl (536 mg, 7.71 mmol, 3.0 eq.) and sodium acetate (632 mg, 7.71 mmol, 5.0 eq.). The mixture was refluxed for 4 hours. The reaction was allowed to cool to room temperature and the MeOH was evaporated. The remaining aqueous phase was extracted with EtOAc (3x 20 mL), the organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude product was purified by flash column 15 chromatography on silica gel (20% EtOAc in heptane) to isolate (E)-oxime isomer (±)-54 (139 mg, 0.49 mmol, 19%, ratio 1:1.3) was isolated as a colorless oil; Rf= 0.23 (60% EtOAc in heptane);1H-NMR (400 MHz, DMSO-d6, 333 K): δ [ppm] = 10.05 (s, 1H, OH), 4.02-4.05 (m, 1H; H-C(5a or 9a)), 3.62 (br, 1H), 3.00-3.08 (m, 2H), 1.75-1.99 (m, 5H), 1.62-1.70 (m, 1H), 1.48-1.53 (m, 2H), 1.41 (s, 9H; H3C-Boc), 1.17-1.19 (m, 3H);13C-NMR (100 MHz, 20 DMSO-d6, 333 K): δ [ppm] = 159.2 (C(6)), 154.3 ((C=O)Boc), 78.2 ((Cq)Boc), 46.7 (CH), 39.8 (CH2), 2X 27.8 ((CH3)Boc) and (CH2), 26.0 (CH2), 24.9 (CH2), 24.0 (CH2), 22.6 (CH2), 19.9 (CH2); 1 X CH is hidden behind the DMSO peak, 1 CH is not visible; HR-MS (ESI): (m / z) = calculated for C15H27N2O3+[M+H]+: 282.2016, found: 283.2013, C15H26N2O3Na [M+Na]+: 305.1841, found: 305.1832. 25 tert-butyl-(Z)-6-(hydroxyimino)decahydro-1H-benzo[b]azepine-1-carboxylate ((±)-Z-54)P382113WO 150(Z)-oxime isomer (±)-54 (181 mg, 0.64 mmol, 25%, ratio 1.3:1) was isolated as a white solid from the above reaction. The (Z)-oxime crystallized spontaneously and allowed to determine the syn ring junction by x-ray diffraction studies; Rf= 0.24 (60% EtOAc in heptane);1H-NMR 5 (400 MHz, DMSO-d6, 333 K): δ [ppm] = 10.08 (s, 1H, OH), 3.99 (br, 1H; H-C(5a or 9a)), 3.62 (br, 1H), 3.44 (br, 1H; H-C(5a or 9a)), 3.04-3.10 (m, 1H), 2.00-2.12 (m, 2H), 1.84-1.98 (m, 3H), 1.76-1.80 (m, 1H), 1.57-1.66 (m, 1H), 1.45-1.52 (m, 2H), 1.41 (s, 9H; H3C-Boc), 1.29- 1.34 (m, 1H), 1.16-1.27 (m, 2H);13C-NMR (100 MHz, DMSO-d6, 333 K): δ [ppm] = 158.6 (C(6)), 154.3 ((C=O)Boc), 78.1 ((Cq)Boc), 39.7 (CH2), 2X 27.8 ((CH3)Boc) and (CH2), 27.7 (CH2), 10 25.8 (CH2), 24.9 (CH2), 24.3 (CH2), 23.8 (CH2); 2 CH are not visible; HR-MS (ESI): (m / z) = calculated for C15H27N2O3+[M+H]+: 282.2016, found: 283.2012, C15H26N2O3Na [M+Na]+: 305.1841, found: 305.1831. Example 36: tert-butyl-(3aR,8aR)-4-(4-chlorobenzyl)octahydropyrrolo[3,2-b]azepine- 15 1(2H)-carboxylate ((R,R)-55) 1) Pd / C, H2(1 bar)2) 4-chlorobenzaldehyde, NaBH3CNMeOH, reflux, 24 h8% over two steps To a solution of orthogonally protected (R,R)-35 (43.0 mg, 0.13 mmol, 1.0 eq.) in MeOH (1.5 mL, 0.1 M) was added Pd / C (10%, Pd on activated charcoal, 4.5 mg, 10 wt% of 20 substrate). The mixture was stirred at 22 °C under an atmosphere of hydrogen (1 atm, balloon) for 24 hours. Then it was filtered over celite and evaporated to dryness to yield a colorless oil. To a solution of intermediate product in MeOH (1.5 mL, 0.1 M) was added 4-chlorobenzaldehyde (22.5 mg, 0.16 mmol, 1.2 eq.) and NaBH3CN (10.1 mg, 0.16 mmol, 1.2 eq.). The mixture was refluxed for 24 hours. After cooling to room temperature, it was 25 quenched by addition of NaOH (1 M, 2 mL). Then the solvent was concentrated under reduced pressure and the aqueous phase was extracted with EtOAc (3x 10 mL). The organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude product was purified by flash chromatography on silica gel (5% EtOAc in heptane) to affordP382113WO 151 derivatized diamine (R,R)-55 (4.2 mg, 0.01 mmol, 8%) as a yellow oil; Rf = 0.20 (5% EtOAc in heptane);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 7.35-7.38 (m, 2H; H2- Carom.), 7.29-7.31 (m, 2H; H2-Carom.), 3.92 (d, J = 13.9 Hz, 1H; H-CCl.-benz.), 3.77-3.83 (m, 1H; H-C(8a)), 3.42-3.49 (m, 1H; H-C(2)), 3.35 (d, J = 14.0, 1H; H-CCl.-benz.), 5 3.17-3.27 (m, 2H; H-C(2 and 3a)), 2.56-2.60 (m, 1H; H-C(5)), 2.36-2.42 (m, 1H; H- C(5)), 2.21-2.26 (m, 1H; H-C(8)), 1.90-2.04 (m, 2H; H-C(3 and 8)), 1.65-1.78 (m, 2H; H-C(3 and 7)), 1.51-1.52 (m, 1H; H-C(6)), 1.46 (s, 9H; H3-CBoc), 1.33-1.38 (m, 2H; H-C(6 and 7));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 156.3 ((C=O)Boc, 140.2 ((Cq)arom.), 135.6 ((Cq)arom.), 131.4 ((CH)arom.), 129.2 ((CH)arom.), 80.8 ((Cq)Boc),1068.0 (C(3a))rot., 67.5 (C(3a))rot., 64.1 (C(8a))rot., 63.7 (C(8a))rot., 60.5 (CH2)Cl.-benz.), 53.6 (C(5)), 45.5 (C(2))rot., 44.9 (C(2))rot., 32.4 (C(6)), 31.1 (C(3 or 8))rot., 30.4 (C(3 or 8))rot., 30.3 (C(3 or 8))rot., 28.8 ((CH3)Boc), 28.1 (C(7))rot., 28.0 (C(7))rot.; HR-MS (ESI): (m / z) = calculated for C20H30N2O2Cl+[M+H]+: 365.1990, found: 365.1981. 15 Example 37: (3aR,8aR)-4-(4-chlorobenzyl)decahydropyrrolo[3,2-b]azepine ((R,R)-58)To a solution of Boc-protected amine (R,R)-55 (4.2 mg, 0.01 mmol, 1.0 eq.) in DCM (1 mL) was added TFA (0.1 mL, 10 vol%). The reaction was stirred at 22 °C for 2 hours. Then the solvent was evaporated and the crude was purified by flash chromatography on silica gel 20 (5%-10% MeOH in DCM + 1% NH3) to afford derivatized diamine (R,R)-58 (4.9 mg, 0.01 mmol, quant.) as a TFA salt and yellow solid; Rf= 0.20 (10% MeOH in DCM + 1% NH3);1H- NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 7.36-7.38 (m, 2H; H2-Carom.), 7.31-7.33 (m, 2H; H2-Carom.), 3.90 (d, J = 13.9 Hz, 1H; H-CCl.-benz.), 3.72-3.77 (m, 1H; H-C(8a)), 3.41-3.50 (m, 3H; H-CCl.-benz. and H-C(2 and 3a), 3.15-3.24 (m, 1H; H-C(2)), 2.71-2.77 (m, 1H; H-C(5)),25 2.34-2.44 (m, 2H; H-C(3 and 5)), 2.17-2.27 (m, 1H; H-C(8)), 1.96-2.06 (m, 1H; H-C(3)), 1.78- 1.89 (m, 2H; H-C(7 and 8)), 1.54-1.58 (m, 1H; H-C(6)), 1.42-1.50 (m, 2H; H-C(6 and 7));13C- NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 139.8 ((Cq)arom.), 133.8 ((Cq)arom.), 131.3 ((CH)arom.), 129.4 ((CH)arom.), 66.9 (C(3a)), 64.5 (C(8a)), 60.0 (CH2)Cl.-benz.)), 54.6 (C(5)), 44.5 (C(2)), 31.3 (C(6)), 31.0 (C(3)), 29.3 (C(8)), 26.8 (C(7)); HR-MS (ESI): (m / z) = calculated for 30 C15H22N2Cl+[M+H]+: 265.1466, found: 265.1463.P382113WO 152 Example 38: tert-butyl (3aR,8aR)-4-(3-chlorobenzyl)octahydropyrrolo[3,2-b]azepine- 1(2H)-carboxylate ((R,R)-56)56% over two steps To a solution of orthogonally protected (R,R)-35 (90 mg, 0.27 mmol, 1.0 eq.) in MeOH 5 (2.7 mL, 0.1 M) was added Pd / C (10%, Pd on activated charcoal, 10 mg, 10 wt% of substrate). The mixture was stirred at 22 °C under an atmosphere of hydrogen (1 atm, balloon) for 24 hours. Then it was filtered over celite and evaporated to dryness to yield a colorless oil. To a solution of intermediate product in MeOH (2.5 mL, 0.1 M) was added 3-chlorobenzaldehyde (58 mg, 0.41 mmol, 1.5 eq.), NaBH3CN (26 mg, 0.41 mmol, 1.5 eq.) 10 and AcOH (23 µL, 0.38 mmol, 1.5 eq.). The mixture was refluxed for 24 hours. After cooling to room temperature, it was quenched by addition of NaOH (1 M, 4 mL). Then the solvent was concentrated under reduced pressure and the aqueous phase was extracted with EtOAc (3x 20 mL). The organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude product was purified by flash chromatography on silica gel 15 (10% EtOAc in heptane) to afford derivatized diamine (R,R)-56 (56 mg, 0.15 mmol, 56%) as a colorless oil; Rf= 0.22 (5% EtOAc in heptane);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 7.41 (s, 1H; H-Carom.), 7.27-7.29 (m, 2H; 2X H-Carom.), 7.21-7.24 (m, 1H; H-Carom.), 3.94 (d, J = 14.1 Hz, 1H; H-Cbenz.), 3.78-3.84 (m, 1H; H-C(8a)), 3.42-3.48 (m, 1H; H-C(3)), 3.36 (d, J = 14.1, 1H; H-Cbenz.), 3.16-3.28 (m, 2H; H-C(3 and 3a)), 2.55-2.59 (m, 1H; H-C(5)),20 2.44-2.41 (m, 1H; H-C(5)), 2.21-2.23 (m, 1H; H-C(2)), 1.90-2.01 (m, 2H; H-C(2 and 8)), 1.69- 1.76 (m, 2H; H-C(7 and 8)), 1.52-1.53 (m, 1H; H-C(6)), 1.46 (s, 9H; H3-CBoc), 1.30-1.42 (m, 2H; H-C(6 and 7));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 156.1 ((C=O)Boc, 144.0 ((Cq)arom.), 135.2 ((Cq)arom.), 130.7 ((CH)arom.), 129.7 ((CH)arom.), 128.2 ((CH)arom.), 128.0 ((CH)arom.), 80.8 ((Cq)Boc), 68.0 (C(3a))rot., 67.5 (C(3a))rot., 64.1 (C(8a))rot., 63.7 (C(8a))rot., 60.8 25 (CH2)benz.), 53.8 (C(5)), 45.4 (C(3))rot., 44.9 (C(3))rot., 32.4 (C(6)), 31.1 (C(2 or 8)), 30.4 (C(2 or 8))rot., 30.3 (C(2 or 8))rot., 28.8 ((CH3)Boc), 28.0 (C(7))rot., 27.9 (C(7))rot.; HR-MS (ESI): (m / z) = calculated for C20H30N2O2Cl+[M+H]+: 365.1990, found: 365.1983. Example 39: (3aR,8aR)-4-(3-chlorobenzyl)decahydropyrrolo[3,2-b]azepine ((R,R)-59) 30P382113WO 153To a solution of Boc-protected amine (R,R)-56 (38 mg, 0.10 mmol, 1.0 eq.) in DCM (1 mL) was added TFA (0.1 mL, 10 vol%). The reaction was stirred at 22 °C for 2 hours. Then the solvent was evaporated and the crude was purified by flash chromatography on silica gel 5 (5%-10% MeOH in DCM + 1% NH3) to afford derivatized diamine (R,R)-59 (19.9 mg, 0.08 mmol, 80%) as an orange oil; Rf= 0.25 (10% MeOH in DCM + 1% NH3);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 7.41 (s, 1H; H-Carom.), 7.28-7.31 (m, 2H; H-Carom.), 7.21-7.26 (m, 1H; H-Carom.), 3.90 (d, J = 14.1 Hz, 1H; H-Cbenz.), 3.33-3.43 (m, 3H; H-Cbenz.and H-C(3a and 8a)), 3.17-3.23 (m, 1H; H-C(2), 2.88-2.95 (m, 1H; H-C(2)), 2.66-2.71 (m, 1H; H-C(5)), 2.32- 10 2.38 (m, 1H; H-C(5)), 2.20-2.27 (m, 1H; H-C(3)), 2.05-2.15 (m, 1H; H-C(8)), 1.78-1.89 (m, 2H; H-C(3 and 7)), 1.66-1.71 (m, 1H; H-C(8)), 1.51-1.57 (m, 1H; H-C(6)), 1.35-1.49 (m, 2H; H-C(6 and 7));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 144.0 ((Cq)arom.), 135.2 ((Cq)arom.), 130.8 ((CH)arom.), 129.6 ((CH)arom.), 128.0 ((CH)arom.), 128.0 ((CH)arom.), 68.7 (C(3a)), 64.5 (C(8a)), 60.5 (CH2)benz.)), 54.9 (C(5)), 45.0 (C(2)), 32.5 (C(3)), 31.7 (C(6)), 31.2 15 (C(8)), 27.3 (C(7)); HR-MS (ESI): (m / z) = calculated for C15H22N2Cl+[M+H]+: 265.1466, found: 265.1472. Example 40: tert-butyl (3aR,8aR)-4-(2-chlorobenzyl)octahydropyrrolo[3,2-b]azepine- 1(2H)-carboxylate ((R,R)-57)20 56% over two steps To a solution of orthogonally protected (R,R)-35 (90.0 mg, 0.27 mmol, 1.0 eq.) in MeOH (2.7 mL, 0.1 M) was added Pd / C (10%, Pd on activated charcoal, 10 mg, 10 wt% of substrate). The mixture was stirred at 22 °C under an atmosphere of hydrogen (1 atm, balloon) for 24 hours. Then it was filtered over celite and evaporated to dryness to yield a 25 colorless oil. To a solution of intermediate product in MeOH (2.5 mL, 0.1 M) was added 2-chlorobenzaldehyde (58 mg, 0.41 mmol, 1.5 eq.), NaBH3CN (26 mg, 0.41 mmol, 1.5 eq.)P382113WO 154 and AcOH (23 µL, 0.38 mmol, 1.5 eq.). The mixture was refluxed for 24 hours. After cooling to room temperature, it was quenched by addition of NaOH (1 M, 4 mL). Then the solvent was concentrated under reduced pressure and the aqueous phase was extracted with EtOAc (3x 20 mL). The organic layers were dried over Na2SO4, filtered and the solvent was 5 removed in vacuo. The crude product was purified by flash chromatography on silica gel (10% EtOAc in heptane) to afford derivatized diamine (R,R)-57 (56 mg, 0.15 mmol, 56%) as a colorless oil; Rf = 0.22 (5% EtOAc in heptane);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 7.62-7.64 (m, 1H; H-Carom.), 7.33-7.36 (m, 1H; H-Carom.), 7.26-7.30 (m, 1H; H-Carom.), 7.19-7.23 (m, 1H; H-Carom.), 3.90 (d, J = 14.6 Hz, 1H; H-Cbenz.), 3.80-3.88 (m, 1H; H-C(8a)), 10 3.66 (d, J = 14.6, 1H; H-Cbenz.), 3.41-3.47 (m, 1H; H-C(3)), 3.22-3.26 (m, 2H; H-C(3 and 3a)), 2.44-2.58 (m, 2H; H-C(5)), 2.21-2.24 (m, 1H; H-C(2)), 1.93-2.05 (m, 2H; H-C(2 and 8)), 1.62- 1.75 (m, 2H; H-C(7 and 8)), 1.51-1.55 (m, 1H; H-C(6)), 1.47 (s, 9H; H3-CBoc), 1.35-1.44 (m, 2H; H-C(6 and 7));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 156.2 ((C=O)Boc, 138.7 ((Cq)arom.), 135.0 ((Cq)arom.), 132.2 ((CH)arom.), 130.4 ((CH)arom.), 129.2 ((CH)arom.), 127.7 15 ((CH)arom.), 80.8 ((Cq)Boc), 68.5 (C(3a))rot., 68.0 (C(3a))rot., 64.1 (C(8a))rot., 63.7 (C(8a))rot., 58.2 (CH2)benz.), 53.8 (C(5)), 45.5 (C(3))rot., 44.9 (C(3))rot., 32.3 (C(6)), 31.1 (C(2 or 8))rot., 30.9 (C(2 or 8))rot., 30.4 (C(2 or 8))rot., 30.1 (C(2 or 8))rot., 28.8 ((CH3)Boc), 28.0 (C(7))rot., 27.9 (C(7))rot.; HR-MS (ESI): (m / z) = calculated for C20H30N2O2Cl+[M+H]+: 365.1990, found: 365.1984.20 Example 41: (3aR,8aR)-4-(2-chlorobenzyl)decahydropyrrolo[3,2-b]azepine ((R,R)-60)To a solution of Boc-protected amine (R,R)-57 (46 mg, 0.13 mmol, 1.0 eq.) in DCM (1.3 mL) was added TFA (0.13 mL, 10 vol%). The reaction was stirred at 22 °C for 2 hours. Then the solvent was evaporated and the crude was purified by flash chromatography on silica gel 25 (5%-10% MeOH in DCM + 1% NH3) to afford derivatized diamine (R,R)-60 (16.2 mg, 0.06 mmol, 46%) as an orange oil; Rf = 0.20 (10% MeOH in DCM + 1% NH3);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 7.60-7.62 (m, 1H; H-Carom.), 7.33-7.35 (dd, J = 7.8, 1.3 Hz, 1H; H-Carom.), 7.26-7.30 (m, 1H; H-Carom.), 7.19-7.23 (m, 1H; H-Carom.), 3.89 (d, J = 14.6 Hz, 1H; H-Cbenz.), 3.67 (d, J = 14.6 Hz, 1H; H-Cbenz.), 3.33-3.40 (m, 2H; H-C(3a and 8a)), 3.14-3.1930 (m, 1H; H-C(2)), 2.85-2.92 (m, 1H; H-C(2)), 2.64-2.69 (m, 1H; H-C(5)), 2.37-2.43 (m, 1H; H- C(5)), 2.17-2.24 (m, 1H; H-C(3)), 2.05-2.14 (m, 1H; H-C(8)), 1.84-1.92 (m, 1H; H-C(3)), 1.76- 1.82 (m, 1H; H-C(6)), 1.65-1.70 (m, 1H; H-C(7)), 1.35-1.56 (m, 3H; H-C(6, 7 and 8));13C-P382113WO 155 NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 138.8 ((Cq)arom.), 134.9 ((Cq)arom.), 132.0 ((CH)arom.), 130.4 ((CH)arom.), 129.3 ((CH)arom.), 127.8 ((CH)arom.), 69.2 (C(3a or 8a)), 64.5 (C(3a or 8a)), 58.0 (CH2)benz.)), 54.9 (C(5)), 45.1 (C(2)), 32.4 (C(3)), 31.6 (C(7 or 8)), 31.4 (C(7 or 8)), 27.2 (C(6)); HR-MS (ESI): (m / z) = calculated for C15H22N2Cl+[M+H]+: 265.1466, 5 found: 265.1472. Example 42: (3aR,8aR)-4-(3-bromobenzyl)de lo[3,2-b]azepine -61)1) 3-bromobenzaldehyde, NaBH3CN, AcOH MeOH, reflux, 24 h29% over two steps10 To a solution of mono-Boc protected amine (R,R)-11 (16.0 mg, 0.07 mmol, 1.0 eq.) in MeOH (1 mL, 0.1 M) was added 3-bromobenzaldehyde (13 µL, 0.11 mmol, 1.5 eq.), NaBH3CN (6.9 mg, 0.11 mmol, 1.5 eq.) and AcOH (6 µL, 0.11 mmol, 1.5 eq.). The mixture was refluxed for 24 hours. After cooling to room temperature, it was quenched by addition of NaOH (1 M, 1 mL). Then the solvent was concentrated under reduced pressure and the aqueous phase 15 was extracted with EtOAc (3x 10 mL). The organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. The intermediate product was dissolved in DCM (1 mL) and TFA (0.1 mL, 10 vol%) was added. The reaction was stirred at 22 °C for 2 hours. Then the solvent was evaporated and the crude was purified by flash chromatography on silica gel (5%-10% MeOH in DCM + 1% NH3) to afford derivatized diamine (R,R)-61 as 20 double TFA salt (11.2 mg, 0.02 mmol, 29%) and yellowish oil; Rf = 0.20 (5% MeOH in DCM + 1% NH3);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 7.57 (s, 1H; H-Carom.), 7.40 (m, 1H; H-Carom.), 7.34 (m, 1H; H-Carom.), 7.24 (t, J = 7.8 Hz, 1H; H-Carom.), 3.93 (d, J = 14.1 Hz, 1H; H-Cbenz.), 3.71-3.77 (m, 1H; H-C(8a)), 3.40-3.51 (m, 3H; H-C(3a, 5 and H-Cbenz.)), 3.15- 3.22 (m, 1H; H-C(5)), 2.71-2.77 (m, 1H; H-C(3)), 2.36-2.44 (m, 2H; H-C(3 and 6)), 2.17-2.27 25 (m, 1H; H-C(8)), 1.97-2.05 (m, 1H; H-C(6)), 1.79-1.88 (m, 2H; H-C(7 and 8)), 1.57-1.61 (m, 1H; H-C(2)), 1.42-1.52 (m, 2H; H-C(2 and 7));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 143.8 ((Cq)arom.), 132.6 ((CH)arom.), 2X 131.2 ((2X CH)arom.), 128.5 ((CH)arom.), 123.4 ((Cq)arom.), 66.9 (C(3a)), 64.5 (C(8a)), 60.1 (CH2)benz.)), 54.7 (C(3)), 44.5 (C(5)), 31.3 (C(2 or 6)), 31.1 (C(2 or 6)), 29.4 (C(8)), 26.8 (C(7));19F-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] 30 = -77.0; HR-MS (ESI): (m / z) = calculated for C15H22N2Br+[M+H]+: 309.0961, found: 309.0959.P382113WO 156 Example 43: (3aR,8aR)-4-(3-fluorobenzyl)de o[3,2-b]azepine ((R,R)-62)1) 3-fluorobenzaldehyde, NaBH3CN, AcOH MeOH, reflux, 24 h29% over two stepsTo a solution of mono-Boc protected amine (R,R)-11 (16.0 mg, 0.07 mmol, 1.0 eq.) in MeOH 5 (1 mL, 0.1 M) was added 3-fluorobenzaldehyde (11 µL, 0.11 mmol, 1.5 eq.), NaBH3CN (6.9 mg, 0.11 mmol, 1.5 eq.) and AcOH (6 µL, 0.11 mmol, 1.5 eq.). The mixture was refluxed for 24 hours. After cooling to room temperature, it was quenched by addition of NaOH (1 M, 1 mL). Then the solvent was concentrated under reduced pressure and the aqueous phase was extracted with EtOAc (3x 10 mL). The organic layers were dried over Na2SO4, filtered 10 and the solvent was removed in vacuo. The intermediate product was dissolved in DCM (1 mL) and TFA (0.1 mL, 10 vol%) was added. The reaction was stirred at 22 °C for 2 hours. Then the solvent was evaporated and the crude was purified by flash chromatography on silica gel (5%-10% MeOH in DCM + 1% NH3) to afford derivatized diamine (R,R)-62 as double TFA salt (10.0 mg, 0.02 mmol, 29%) and yellowish oil; Rf= 0.20 (5% MeOH in DCM15 + 1% NH3);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 7.30-7.36 (s, 1H; H-Carom.), 7.15- 7.20 (m, 2H; H-Carom.), 6.96-7.01 (m, 1H; H-Carom.), 3.98 (d, J = 14.1 Hz, 1H; H-Cbenz.), 3.75- 3.80 (m, 1H; H-C(8a)), 3.50-3.56 (m, 2H; H-C(3a and H-Cbenz.)), 3.42-3.48 (m, 1H; H-C(2)), 3.16-3.24 (m, 1H; H-C(2)), 2.78-2.83 (m, 1H; H-C(5)), 2.39-2.47 (m, 2H; H-C(3 and 5)), 2.19- 2.28 (m, 1H; H-C(8)), 1.99-2.10 (m, 1H; H-C(3)), 1.81-1.91 (m, 2H; H-C(7 and 8)), 1.58-1.62 20 (m, 1H; H-C(6)), 1.43-1.56 (m, 1H; H-C(6 and 7));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 164.3 ((Cq)arom.), 131.2 ((CH)arom.), 125.6 ((CH)arom.), 118.2 ((Cq)arom.), 116.3 ((CH)arom.), 115.0 ((CH)arom.), 66.9 (C(3a)), 64.3 (C(8a)), 60.3 (CH2)benz.)), 54.9 (C(5)), 44.5 (C(2)), 32.1 (C(3 or 6)), 30.9 (C(3 or 6)), 29.3 (C(8)), 26.7 (C(7));19F-NMR (100 MHz, MeOD- d4, 298 K): δ [ppm] = -77.0; HR-MS (ESI): (m / z) = calculated for C15H22N2F+[M+H]+: 25 249.1762, found: 249.1762. Example 44: (3aR,8aR)-4-(2,3-dichlorobenzyl)decahydropyrrolo[3,2-b]azepine ((R,R)-63)P382113WO 157 1) 2,3-dichlorobenzaldehyde, NaBH3CN, AcOH MeOH, reflux, 24 h29% over two stepsTo a solution of mono-Boc protected amine (R,R)-11 (16.0 mg, 0.07 mmol, 1.0 eq.) in MeOH (1 mL, 0.1 M) was added 2,3-dichlorobenzaldehyde (19 mg, 0.11 mmol, 1.5 eq.), NaBH3CN 5 (6.9 mg, 0.11 mmol, 1.5 eq.) and AcOH (6 µL, 0.11 mmol, 1.5 eq.). The mixture was refluxed for 24 hours. After cooling to room temperature, it was quenched by addition of NaOH (1 M, 1 mL). Then the solvent was concentrated under reduced pressure and the aqueous phase was extracted with EtOAc (3x 10 mL). The organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. The intermediate product was dissolved in DCM (1 10 mL) and TFA (0.1 mL, 10 vol%) was added. The reaction was stirred at 22 °C for 2 hours. Then the solvent was evaporated and the crude was purified by flash chromatography on silica gel (5%-10% MeOH in DCM + 1% NH3) to afford derivatized diamine (R,R)-63 as double TFA salt (9.3 mg, 0.02 mmol, 29%) and yellowish oil; Rf= 0.20 (5% MeOH in DCM + 1% NH3);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 7.36-7.37 (m, 2H; H-Carom.), 15 7.32-7.33 (m, 1H; H-Carom.), 3.91 (d, J = 14.4 Hz, 1H; H-Cbenz.), 3.73-3.79 (m, 1H; H-C(8a)), 3.41-3.53 (m, 3H; H-C(2, 3a and H-Cbenz.)), 3.16-3.23 (m, 1H; H-C(2)), 2.69-2.74 (m, 1H; H- C(5)), 2.37-2.47 (m, 2H; H-C(3 and 5)), 2.17-2.26 (m, 1H; H-C(8)), 1.96-2.05 (m, 1H; H-C(3), 1.81-1.90 (m, 2H; H-C(7 and 8)), 1.58-1.62 (m, 1H; H-C(6)), 1.44-1.53 (m, 2H; H-C(6 and 7));13C-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 145.4 ((Cq)arom.), 2X 136.1 ((Cq)arom.), 20 3X 128.1 ((3X CH)arom.), 66.8 (C(3a)), 64.4 (C(8a)), 59.6 (CH2)benz.)), 55.0 (C(5)), 44.5 (C(2)), 31.3 (C(3 or 6)), 31.0 (C(3 or 6)), 29.3 (C(8)), 26.7 (C(7));19F-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = -77.0; HR-MS (ESI): (m / z) = calculated for C15H21N2Cl2+[M+H]+: 299.1075, found: 299.1076. 25 Example 45: (3aR,8aR)-4-(3,5-dichlorobenzyl)decahydropyrrolo[3,2-b]azepine ((R,R)-64)P382113WO 158 Cl 2 TFA Cl 1) 3,5-dichlorobenzaldehyde, H NaBH CN, A N3cOH 3 3a5MeOH, reflux, 24 h N 47 Boc DCM, 22 °C, 2 h H 8 (R,R) 29% over two steps (R,R) To a solution of mono-Boc protected amine (R,R)-11 (16.0 mg, 0.07 mmol, 1.0 eq.) in MeOH (1 mL, 0.1 M) was added 3,5-dichlorobenzaldehyde (19 mg, 0.11 mmol, 1.5 eq.), NaBH3CN (6.9 mg, 0.11 mmol, 1.5 eq.) and AcOH (6 µL, 0.11 mmol, 1.5 eq.). The mixture was refluxed 5 for 24 hours. After cooling to room temperature, it was quenched by addition of NaOH (1 M, 1 mL). Then the solvent was concentrated under reduced pressure and the aqueous phase was extracted with EtOAc (3x 10 mL). The organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. The intermediate product was dissolved in DCM (1 mL) and TFA (0.1 mL, 10 vol%) was added. The reaction was stirred at 22 °C for 2 hours. 10 Then the solvent was evaporated and the crude was purified by flash chromatography on silica gel (5%-10% MeOH in DCM + 1% NH3) to afford derivatized diamine (R,R)-64 as double TFA salt (9.0 mg, 0.02 mmol, 29%) and yellowish oil; Rf= 0.20 (5% MeOH in DCM + 1% NH3);1H-NMR (400 MHz, MeOD-d4, 298 K): δ [ppm] = 7.54-7.57 (m, 1H; H-Carom.), 7.44-7.46 (m, 1H; H-Carom.), 7.29 (t, J = 7.9 Hz, 1H; H-Carom.), 3.96 (d, J = 14.7 Hz, 1H; H- 15 Cbenz.), 3.73-3.80 (m, 2H; H-Cbenz.and H-C(8a)), 3.55-3.61 (m, 1H; H-C(3a)), 3.41-3.46 (m, 1H; H-C(2)), 3.15-3.23 (m, 1H; H-C(2)), 2.70-2.75 (m, 1H; H-C(5)), 2.45-2.52 (m, 1H; H- C(5)), 2.37-2.42 (m, 1H; H-C(3)), 2.18-2.24 (m, 1H; H-C(8)), 2.03-2.10 (m, 1H; H-C(3)), 1.83- 1.88 (m, 2H; H-C(7 and 8)), 1.57-1.60 (m, 1H; H-C(6)), 1.44-1.50 (m, 2H; H-C(6 and 7));13C- NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = 141.0 ((Cq)arom.), 134.1 ((Cq)arom.), 133.0 20 ((Cq)arom.), 2X 130.2 ((CH)arom.), 128.5 ((CH)arom.), 67.1 (C(3a)), 64.4 (C(8a)), 58.3 (CH2)benz.)), 54.8 (C(5)), 44.5 (C(2)), 31.0 (C(3 or 6)), 30.6 (C(3 or 6)), 29.2 (C(8), 26.6 (C(7));19F-NMR (100 MHz, MeOD-d4, 298 K): δ [ppm] = -77.0; HR-MS (ESI): (m / z) = calculated for C15H21N2Cl2+[M+H]+: 299.1076, found: 299.1074. 25 Example 46: (3aRS,8aRS)-4-(3,5-bis(trifluoromethyl)benzyl)decahydropyrrolo[3,2- b]azepine ((±)-65)P382113WO 159To a solution of (±)-11 (53 mg, 1 Eq, 0.22 mmol) in dry MeOH (5 mL) was added 3,5- bis(trifluoromethyl)benzaldehyde (80 mg, 55 μL, 1.5 Eq, 0.33 mmol), sodium cyanoborohydride (21 mg, 1.5 Eq, 0.33 mmol) and acetic acid (20 mg, 19 μL, 1.5 Eq, 0.33 5 mmol). The mixture was stirred at reflux for 20 hours. After cooling to room temperature, the reaction was quenched by addition of NaOH (1 M, 2 mL). The mixture was concentrated under reduced pressure to remove MeOH. The aqueous phase was extracted with EtOAc (3x 10 mL). The organic layers were dried over Na2SO4, filtered and the solvent was removed in vacuo. The crude product was purified by flash 10 chromatography on silica gel (5% EtOAc in heptane) to afford tert-butyl (3aRS,8aRS)-4- (3,5-bis(trifluoromethyl)benzyl)octahydropyrrolo[3,2-b]azepine-1(2H)-carboxylate (44.1 mg). This intermediate was dissolved in DCM (1.5 mL) and 2,2,2-trifluoroacetic acid (224 mg, 0.150 mL, 21 Eq, 1.96 mmol) was added. The mixture was stirred at 22 °C for 24 hours. The mixture was concentrated under reduced pressure and purified on reverse 15 phase HPLC (0-100% ACN in H2O + 0.1% TFA) to afford (±)-65 mono-TFA as a white solid (29 mg, 60 μmol, 28% over 2 steps);1H-NMR (300 MHz, CD2Cl2, 298K) δ [ppm] = 7.23 – 7.10 (m, 3H), 6.84 – 6.70 (m, 3H), 4.08 – 3.92 (m, 1H), 3.89 – 3.63 (m, 2H), 3.69 (s, 4H), 3.48 (s, 3H), 2.83 – 2.73 (m, 1H), 2.73 – 2.56 (m, 2H), 2.43 – 2.25 (m, 2H), 2.29 – 1.65 (m, 5H), 1.65 – 1.49 (m, 1H), 1.41 (ddd, J = 8.3, 4.8, 2.3 Hz, 1H), 1.36 (s, 13H), 1.29 20 (dt, J = 7.8, 4.7 Hz, 1H), 1.18 (s, 1H).13C-NMR (101 MHz, MeOD, 298K) δ [ppm] = 144.52, 132.93, 132.61, 130.03, 126.25, 123.55, 122.05, 122.01, 67.02, 64.27, 59.61, 55.08, 44.52, 31.11, 30.99, 29.26, 26.57. HR-MS (ESI): (m / z) = calculated for C₁₇H₂₁N₂F₆ [M+H]+: 367.16034 Found mass: 367.1601 Example 47: 1-((3aRS,8aRS)-4-(3,5-bis(trifluoromethyl)benzyl)octahydropyrrolo[3,2- 25 b]azepin-1(2H)-yl)ethan-1-one ((±)-66)P382113WO 160To a solution of (±)-65 (22.8 mg, 1 Eq, 47.5 μmol) in DCM (1 mL) was added triethylamine (12.6 mg, 17.3 μL, 2 Eq, 124 μmol) 4-Dimethylaminopyridine (3.80 mg, 0.5 Eq, 31.1 μmol) and acetic anhydride (7.62 mg, 7.06 μL, 1.2 Eq, 74.7 μmol). The reaction was stirred at 5 22 °C for 4 hours. The reaction was concentrated and purified on HPLC reverse phase (5- 100% ACN in water 0.1%TFA) (±)-66 mono-TFA salt as a white solid (2.2 mg, 4.2 μmol, 8.9 %);1H-NMR (400 MHz, MeOD, 298K) δ [ppm] = 8.31 – 7.96 (m, 3H), 4.56 (d, J = 57.0 Hz, 1H), 4.37 – 4.06 (m, 2H), 3.85 – 3.38 (m, 3H), 3.05 (m, 1H), 2.57 (m, 1H), 2.40 – 2.25 (m, 1H), 2.10 (s, 1H), 2.04 (s, 2H), 1.89 (d, J = 35.8 Hz, 4H), 1.57 (t, J = 10.4 Hz, 2H), 1.31 10 (d, J = 16.2 Hz, 1H).13C-NMR (101 MHz, MeOD, 298K) δ [ppm] = 172.08, 171.93, 146.30, 138.92, 132.33, 125.98, 123.27, 114.64, 76.96, 68.27, 67.73, 60.36, 60.28, 46.08, 32.68, 31.55, 29.40, 21.85. HR-MS (ESI): (m / z) = calculated for C₁₉H₂₃ON₂F₆+[M+H]+: 409.17091, found: 409.1705 Example 48: (3aRS,8aRS)-4-benzyl-1-(propylsulfonyl)decahydropyrrolo[3,2- 15 b]azepine ((±)-67)(±)-1a (22.9 mg, 1 Eq, 99.4 μmol) was dissolved in THF (1 mL) under argon, triethylamine (30.2 mg, 41.6 μL, 3 Eq, 298 μmol) was added and the reaction was cooled to 0 °C. Under flow of argon, propane-1-sulfonyl chloride (15.6 mg, 12.3 μL, 1.1 Eq, 109 μmol) was 20 added. The reaction was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was added to saturated aqueous solution of NH4Cl. The mixture was extracted with DCM. The organic layers were dried over Na2SO4, filtered and the solventP382113WO 161 was removed in vacuo. The crude product was purified by flash chromatography on silica gel (10-30% EtOAc in Heptane) to yield (±)-67 (15.1 mg, 44.9 μmol, 45.1 %) as a yellow oil;1H-NMR (400 MHz, MeOD, 298K) δ [ppm] = 7.39 – 7.34 (m, 2H), 7.33 – 7.27 (m, 2H), 7.25 – 7.18 (m, 1H), 3.97 (d, J = 13.7 Hz, 1H), 3.79 (ddd, J = 11.3, 8.0, 1.5 Hz, 1H), 3.51 – 5 3.37 (m, 2H), 3.30 – 3.15 (m, 2H), 3.10 – 2.96 (m, 2H), 2.68 (ddd, J = 14.5, 5.5, 2.4 Hz, 1H), 2.46 – 2.25 (m, 2H), 2.19 – 2.08 (m, 1H), 2.07 – 1.93 (m, 1H), 1.89 – 1.69 (m, 4H), 1.55 – 1.45 (m, 1H), 1.39 – 1.27 (m, 2H), 1.08 (t, J = 7.5 Hz, 3H).13C-NMR (101 MHz, MeOD, 298K) δ [ppm] = 140.98, 129.92, 129.22, 128.00, 68.24, 65.70, 61.31, 53.50, 50.65, 46.91, 33.58, 32.08, 31.16, 27.60, 18.06, 13.36. HR-MS (ESI): (m / z) = calculated 10 for C₁₈H₂₉O₂N₂³²S [M+H]+: 337.19443, found: 337.1947 Example 49: 1-((3aRS,8aRS)-4-benzyloctahydropyrrolo[3,2-b]azepin-1(2H)-yl)ethan- 1-one ((±)-68)15 To a solution of (±)-1a (40 mg, 1 Eq, 0.17 mmol) in DCM (1.7 mL) was added triethylamine (70 mg, 97 μL, 4 Eq, 0.69 mmol) and acetic...

Claims

P382113WO 189 CLAIMS 1. A compound of which is a cis-isomer of the formula (II) or a trans-isomer of the formula (III), or a pharmaceutically acceptable salt thereof:wherein: * represents the relative cis- or trans- conformations in formulae (I) and (II) respectively; X is selected from -CH2-, -CH2CH2- and -CH2CH2CH2-; R1is selected from H, -CN, C1-6alkyl, C1-6haloalkyl, 2 to 8 membered heteroalkyl, C2-6alkenyl, C2-6alkynyl, Q1, -OR5, -S(O)2R5, -C(O)R5, -C(O)OR5, -C(O)NR5R6and -SO2NR5R6, wherein said C1-6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; R2is selected from H, -CN, C1-6 alkyl, C1-6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q2, -OR8, -S(O)2R8, -C(O)R8, -C(O)OR8, -C(O)NR8R9and -SO2NR8R9, wherein said C1-6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R10; each R3and each R4is independently selected from halo, =O, C1-6 alkyl and C1-6 haloalkyl; R5and R6are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, and Q1, wherein said C1-6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R11; R7and R11are each independently selected from halo, -CN, -OR7A, -S(O)xR7A, -NR7AR7B, C(O)R7A, -OC(O)R7A, -C(O)OR7A, -NR7AC(O)R7B, -C(O)NR7AR7Band Q1; R8and R9are each independently selected from H, C1-6 alkyl, C1-6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, and Q2, wherein said C1-6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R12;P382113WO 190 R10and R12are each independently selected from halo, -CN, -OR10A, -S(O)xR10A, - NR10AR10B, C(O)R10A, -OC(O)R10A, -C(O)OR10A, -NR10AC(O)R10B, -C(O)NR10AR10Band Q2; each Q1and each Q2is independently selected from C3-6cycloalkyl, 3- to 12-membered heterocyclyl, C6-10aryl and 5- to 10-membered heteroaryl, wherein said C3-6 cycloalkyl and 3- to 12-membered heterocyclyl is optionally substituted by one or more R13, and wherein said C6-10 aryl and 5- to 10-membered heteroaryl is optionally substituted by one or more R14; each R13is independently selected from halo, =O, -CN, -NO2, C1-4 alkyl, C1-4 haloalkyl, -OR13A, -S(O)xR13A, -NR13AR13B, -C(O)R13A, -OC(O)R13A, -C(O)OR13A, - NR13BC(O)R13A, -C(O)NR13AR13B, -NR13BC(O)OR13A, -OC(O)NR13AR13B, -NR13BSO2R13Aand -SO2NR13AR13B, wherein said C1-4 alkyl is optionally substituted by 1 or 2 substituents selected from halo, -CN, -OR13C, -NR13CR13Dand -S(O)xR13C; each R14is independently selected from halo, -CN, -NO2, C1-4 alkyl, C1-4 haloalkyl, -OR14A, - S(O)xR14A, -NR14AR14B, -C(O)R14A, -OC(O)R14A, -C(O)OR14A, -NR14BC(O)R14A, - C(O)NR14AR14B, -NR14BC(O)OR14A, -OC(O)NR14AR14B, -NR14BSO2R14Aand -SO2NR14AR14B, wherein said C1-4 alkyl is optionally substituted by 1 or 2 substituents selected from halo, -CN, -OR14C, -NR14CR14Dand -S(O)xR14C; R7A, R7B, R10A, R10B, R13A, R13B, R13C, R13D, R14A, R14B, R14C, R14Dare at each occurrence independently selected from H, C1-4 alkyl and C1-4 haloalkyl; and wherein any -NR5R6, -NR8R9, -NR7AR7B, -NR10AR10B,-NR13AR13B, -NR13CR13D, - NR14AR14Band -NR14CR14Dwithin a substituent may form a 4- to 6-membered heterocyclyl, wherein said 4- to 6-membered heterocyclyl is optionally substituted by one or more substituents selected from halo, =O, C1-4alkyl and C1-4haloalkyl; each x is independently 0, 1 or 2; n is an integer from 0 to 8; and m is an integer from 0 to 4.

2. The compound of claim 1, wherein the compound is a compound of the formula (II) is a compound of formula (IV) or formula (V), or a pharmaceutically acceptable salt thereof:P382113WO 191wherein * represents the relative cis- conformation.

3. The compound of claim 1, wherein the compound is a compound of the formula (III) selected from a compound of the formula (X), (XI) and (XII), or a pharmaceutically acceptable salt thereof:wherein * represents the relative trans- conformation.

4. The compound of any one of claims 1 to 3, wherein R1and R2are not both H.

5. The compound of any one of claims 1 to 3, wherein R2is -L2-Q2, wherein L2is selected from a bond, -CH2-, -C(O)-, -C(O)-CH2-**, -S(O)2-, and -S(O)2-CH2-**, wherein ** is the point of attachment to Q2.

6. A compound of the formula (XVII), or a pharmaceutically acceptable salt thereof:wherein R1, each R3, each R4, Q2, X, n and m are as defined in claim 1; and L2is selected from a bond, -CH2-, -C(O)-, -C(O)-CH2-**, -S(O)2-, -S(O)2-CH2-**, wherein ** shows the point of attachment to Q2; optionally wherein the compound is a compound of the formula (XXII), or a pharmaceutically acceptable salt thereof:P382113WO 192wherein p is an integer 0 to 5.

7. The compound of claim 5 or claim 6, wherein Q2is selected from 5- to 10- membered heteroaryl and C6-10 aryl; wherein said C6-10 aryl and 5- to 10-membered heteroaryl is optionally substituted by one or more R14.

8. The compound of any one of claims 1, 2, or 5 to 7, wherein the compound is selected a compound of the formula (XXVII) or (XXVIII), or a pharmaceutically acceptable salt thereof:

9. The compound of any one of claims 6 to 8, wherein the group of the formula.

10. The compound of any one of claims 1 to 9, wherein R1is selected from H, -CN, C1-6 alkyl, C1-6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, - S(O)2-C1-6 alkyl, -C(O)R5, -C(O)NR5R6and -SO2NR5R6; wherein said C1-6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; optionally wherein R1is selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, -S(O)2- C1-4 alkyl and -C(O)C1-4 alkyl.P382113WO 19312. The compound of any one of claims 1 to 11, wherein m and n are both 0.

13. A compound selected from Compound List 3, or a pharmaceutically acceptable salt thereof: Compound List 3:P382113WO 19414. The compound of claim 13, wherein the compound is selected from:thereof.

15. The compound of claim 13, wherein the compound is selected from:P382113WO 195pharmaceutically acceptable saltthereof.

16. A pharmaceutical composition comprising a compound of any one of claims 1 to 15, or a or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

17. A compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof for use as a medicament.

18. A compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof for use in Method A, Method B, Method C, Method D, Method E, Method F, Method G, Method H or Method I: Method A: the prevention or treatment of a disease or medical disorder mediated by one or more of norepinephrine transporters (NET), dopamine transporters (DAT), serotonin transporters (SERT), sigma-1 receptor (σ1R), muscarinic M1 receptors and / or muscarinic M2 receptors; Method B: the treatment or prevention of a disease or medical disorder mediated by dysfunction of the locus coeruleus noradrenergic system; Method C: the treatment or prevention of a neuropsychiatric or a neurodegenerative disease or condition; Method D: as a neuromodulatory agent in the treatment or prevention of a disease or disorder selected from a neuropsychiatric or neurodegenerative disorder associated with monoamine dysregulation Method E: the treatment or prevention of cognitive impairment associated with a neuropsychiatric or a neurodegenerative disease or condition; Method F: the sedation of a subject; Method G: to induce or maintain anaesthesia in a subject; Method H: the treatment or prevention of a sleep disorder, optionally wherein the sleep disorder is insomnia; or Method I: the treatment of pain, optionally wherein the pain is neuropathic pain (e.g. peripheral neuropathic pain or central neuropathic pain).P382113WO 196 19. A method of treatment, the method comprising administering to a subject a therapeutically effective amount of a compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein the method of treatment is selected from Method A, Method B, Method C, Method D, Method E, Method F, Method G, Method H and Method I: Method A: the prevention or treatment of a disease or medical disorder mediated by one or more of norepinephrine transporters (NET), dopamine transporters (DAT), serotonin transporters (SERT), sigma-1 receptor (σ1R), muscarinic M1 receptors and / or muscarinic M2 receptors; Method B: the treatment or prevention of a disease or medical disorder mediated by dysfunction of the locus coeruleus noradrenergic system; Method C: the treatment or prevention of a neuropsychiatric or a neurodegenerative disease or condition; Method D: treatment or prevention of a disease or disorder selected from a neuropsychiatric or neurodegenerative disorder associated with monoamine dysregulation; Method E: the treatment or prevention of cognitive impairment associated with a neuropsychiatric or a neurodegenerative disease or condition; Method F: sedating the subject; Method G: inducing or maintaining anaesthesia in the subject; Method H: the treatment or prevention of a sleep disorder, optionally wherein the sleep disorder is insomnia; and Method I: the treatment of pain, optionally wherein the pain is neuropathic pain (e.g. peripheral neuropathic pain or central neuropathic pain).

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