Sulfonamide compounds as cav2.3 antagonists

Abstract

Disclosed are compounds of the formula (I) and pharmaceutically acceptable salts thereof: Formula (I) wherein R1, R2, R3, R4, R5, R6 and a are as defined herein. The compounds are antagonists of the resistant (R-type) voltage-gated calcium ion channel Cav 2.3. Also disclosed are pharmaceutical compositions comprising the compounds; and the compounds for use in the treatment of diseases modulated Cav 2.3, including epilepsy, neurodegenerative conditions such as Parkinson's disease, focal, drug-resistant forms of epilepsy, and other neurological disorders such as developmental and epileptic encephalopathies and Fragile X syndrome.

Description

SULFONAMIDE COMPOUNDS AS CAV2.3 ANTAGONISTS

[0001] This invention relates to compounds that are antagonists of the resistant (R-type) voltage-gated calcium ion channel Cav 2.3, and the use of the compounds in the treatment and prevention of diseases and conditions associated with Cav2.3, for example neurodegenerative conditions such as Parkinson’s disease, focal, drug-resistant forms of epilepsy, and other neurological disorders such as developmental and epileptic encephalopathies and Fragile X syndrome.BACKGROUND

[0002] Voltage-dependent calcium channels are multi-subunit complexes consisting of alpha-1 , alpha-2, beta, and delta subunits in a 1 : 1 : 1 : 1 ratio. Cav2.3 channels belong to the so called pharmaco-resistant or “residual” (R-type) membrane-bound voltage-gated calcium channels and are responsible for calcium ion influx into cells that express them. These channels are structurally only partially characterised. Nevertheless, it is well accepted that most of them are encoded by the CACNA1E gene (Gene ID 777) and are expressed as different Cav2.3 splice variants (variant Cav2.3a to Cav2.3e or f) as the ion conducting subunit (Schneider et al., Pflugers Arch. 2020; 472(7): 811-816).Cav2.3 is highly expressed in neuronal and endocrine tissues and has also been detected in heart, kidney, sperm, spleen and retina, and is associated with numerous physiologic and pathophysiologic processes in the central nervous system, vascular system and in endocrine systems (Schneider et al., Pharmaceuticals 2013, 6(6), 759-776, Schneider et al., Pflugers Arch. 2020; 472(7): 811-816).

[0003] Parkinson disease is the second-most common neurodegenerative disorder that affects 2-3% of the population >65 years of age. The primary motor symptoms of Parkinson’s are caused by the progressive degeneration of dopaminergic midbrain neurons, particularly those within the substantia nigra (SN) neurones (Giguere et al. 2018, Front. Neurol. 9, 455). This leads to a striatal dopamine deficiency, and intracellular inclusions containing aggregates of a-synuclein are the neuropathological hallmarks of Parkinson disease (Poewe et al, Nat Rev Dis Primers. 2017 Mar 23;3:17013). Currently there are no curative therapies available for Parkinson’s disease (Bloem et al, Lancet. 2021 Jun 12;397(10291):2284-2303). Parkinson’s disease is a multifactorial disease, and besides genetic risk-factors for Parkinson’s disease like PARK-gene mutations, numerous Parkinson’s disease-stressors have been identified, including inflammation, viral infections, trauma, gut bacteria, or environmental toxins. Most of these factors lead to mitochondria, proteasomal, and / or lysosomal dysfunction, and elevated metabolic stress, key pathophysiological events in Parkinson’s disease. As PARK mutations and also most external factors are global Parkinson’s disease-stressors, additional cell-specific features must also contribute to theParkinson’s disease-pathophysiology, and in particular to the differential neuronal vulnerability.

[0004] Dopaminergic midbrain neurons display pacemaker activity, which is important for dopamine release and e.g., voluntary movement control. In SN dopaminergic neurons (and other highly vulnerable neurons), this activity generates oscillatory increases in free cytosolic Ca2+levels, which are associated with oscillatory elevated levels of metabolic stress (Guzman et al, Nature. 2010 Dec 2;468(7324):696-700; Liss & Striessnig, Annu. Rev. Pharmacol Toxicol. 2019 Jan 6;59:263-289; Ortner, Front. Synaptic Neurosci. 2021 Feb 26; 13:636103; Zampese & Surmeier, Cells 2020 Sep 8;9(9):2045) . These increased stresses are thought to render SN neurons more vulnerable to degeneration by Parkinson’s disease stressors. Cav2.3 is highly expressed in adult SN dopaminergic neurons and accounts for -50% of somatic Ca2+oscillations in SN DA neurons (Benkert et al., 2019, Nat. Commun. 10, 5094).

[0005] In patch clamp electrophysiology experiments on brain slices from Cav2.3 knockout mice, the amplitude of the activity-related Ca2+oscillations were significantly reduced by -50% in somata of SN neurones compared to wild-type mice. Ca2+-dependent action potential after-hyperpolarizations (AHPs), were also significantly reduced in SN dopaminergic neurons of Cav2.3 knockout mice, consistent with the reduction in the Ca2+signals. Similar effects were also observed when Cav2.3 channels were partially blocked using low concentrations of the non-selective peptide antagonist SNX-482, blocking Cav2.3 but also A-type Kv4 potassium channels with protective effects in SN dopaminergic (DA) neurons (Kimm et al, 2014, 34 (28) 9182-9189). Cav 2.3 has also been shown to be implicated the preferential degeneration of these SN DA neurons in an in-vivo model of Parkinson’s disease (Benkert et al., 2019, Nat. Commun. 10, 5094).

[0006] In a mouse Cav2.3 knockout model in which mice were subjected to low-dose MPTP / probenecid (neurotoxin) knockout of Cav2.3 was shown to provide a significant 100% neuroprotective effect on SN dopaminergic neurons compared to wild-type mice. These data identify Cav2.3 as mediator of SN dopaminergic neuron vulnerability to a degenerative stressor and suggest that Cav2.3 antagonists would be useful in the treatment of Parkinson’s disease, for example by providing a neuroprotective treatment of the disease that prevents or inhibits disease progression (Benkert et al., 2019, Nat. Commun. 10, 5094).

[0007] In addition to neurodegenerative diseases such as Parkinson’s disease Cav2.3 channels are also associated with other diseases and medical disorders, for example Fragile X syndrome (Gray et al., J Neurosci. 2019 Sep 18;39(38):7453-7464), monogenic developmental and epileptic encephalopathies (DEEs) (Carvill, Epilepsy Curr. May-Jun 2019; 19(3): 199-201 ; Helbig et al., Am J Hum Genet. 2019 Mar 7; 104(3): 562; Ortiz Cabrera,Mol Syndromol. 2021 Mar;12(1):25-32), focal, drug-resistant forms of epilepsy (Weiergraber et al., Epilepsia, 2006, 47:839-50; Weiergraber et al., J. Neurophysiol., 2007, 97:3660-69; Zaman et al., Neuron, 2011 , 70:95-108), neurodevelopmental disorders, endocrine disorders such as diabetes (e.g., glucose-induced insulin release, glucose-mediated glucagon suppression, or glucose-mediated somatostatin-release) (Jing et al, 2005, The Journal of clinical investigation 115: 146-154, Rorsman et al, 2018, Physiological reviews 98: 117-214), the treatment of vasospasm following cerebral aneurism or subarachnoidal haemorrhage (Wang et al., 2010, Journal of Neurotrauma, vol. 27, no. 9, pp. 1723-1732), and pain (for example, chronic pain, inflammatory pain, neuropathic pain (e.g. peripheral neuropathic pain (Shan et al., ACS Chem. Neurosci. 2019, 10, 6, 2939-2955) or central neuropathic pain), or nociceptive pain) (Schneider et al.; Ishiguro et al, Circ. Res. 2005, 96, 419-426, Patel et al., British Journal of Pharmacology 2018, 175, 2173-2184; Wormuth et al., Open Neurol J. 2016;10:99-126).

[0008] WO2018 / 228692 discloses that Cav2.3 antagonists are beneficial in the neuroprotective treatment of Parkinson’s disease and other neurodegenerative diseases.

[0009] SNX-482 is a peptide antagonist of Cav2.3 derived from the venom of the tarantula Hysterocratis gigas. SNX-482 has an IC50 of 15-30 nM against Cav2.3, however at higher concentrations SNX-482 also inhibits N-type Ca2+currents Newcomb et al., Biochemistry 1998, 37, 15353-15362); while at similar low nM concentration it inhibits A- Type Kv4 Potassium Currents (Kim et al., J Neurosci. 2014 Jul 9;34(28):9182-9). The off- target effects of SNX-482 and its general toxicity renders it unsuitable as a neuroprotective treatment for a therapeutic treatment of humans with neurodegenerative conditions such as Parkinson’s disease.

[0010] Accordingly, there remains a need for Cav2.3 antagonists. Particularly desirable would be Cav2.3 antagonists that are also brain permeable.BRIEF SUMMARY OF THE DISCLOSURE

[0011] In accordance with the present invention there is provided a compound of the Formula (I), or a pharmaceutically acceptable salt thereof:wherein:R1is selected from: Ci-e alkyl, C3-6 cycloalkyl, and Cs-e cycloalkyl-Ci-e alkyl-, wherein R1is optionally substituted by one or more halo, and optionally wherein one or more H in R1is substituted by D;R2is selected from: H, D, Ci-e alkyl and Ci-e haloalkyl, optionally wherein one or more H in R2is substituted by D; orR1and R2together with the carbon atom to which they are attached form a C3-6 cycloalkyl optionally substituted with one or more halo;R3is selected from: H, Ci-e alkyl and Ci-e haloalkyl, optionally wherein one or more H in R3is substituted by D; each R4is independently selected from: halo, -CN, -NO2, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, -OR4A, -S(O)XR4A, -NR4AR4B, -C(O)R4A, - OC(O)R4A, -C(O)OR4A, -NR4AC(O)R4B, -C(O)NR4AR4B, -NR4AC(O)OR4B, -OC(O)NR4AR4B, - NR4ASO2R4B, and -SO2NR4AR4B, wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R9;R5is selected from: H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and Co-6 alkylene- R5a; wherein said Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci-e alkylene is optionally substituted by one or more R10;R6is selected from: Ci-e alkyl, Ci-e haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and Co-6 alkylene- R6a; wherein said Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci-e alkylene is optionally substituted by one or more R10; orR5and R6, together with the nitrogen atom to which they are attached form Ring A, wherein Ring A is selected from: a 4- to 12 membered heterocyclyl group and a 5- to 12- membered heteroaryl group; wherein Ring A is optionally substituted by one or more R6b; each R6bis independently selected from: halo, -CN, -NO2, =0, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, -OR7, -S(O)XR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, - NR7SO2R8, and -SO2NR7R8;wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl is optionally substituted by one or more R11;R5aand R6aare each independently selected from: C3-6 cycloalkyl, 4- to 12 membered heterocyclyl, 5- to 12-membered heteroaryl, and Ce- aryl; wherein R5aand R6aare optionally substituted by one or more R12; each R7and R8is independently selected from: H, Ci-e alkyl, Ci-e haloalkyl and C3-6 cycloalkyl; wherein said Ci-e alkyl and C3-6 cycloalkyl is optionally substituted by one or more R13; each R9, R10, R11, R13, and R14is independently selected from: halo, =0, -CN, -OR9A, - S(O)xR9A, -NR9AR9B, C(O)R9A, -OC(O)R9A, -C(O)OR9A, -NR9AC(O)R9B, -C(O)NR9AR9Band C3-6 cycloalkyl; each R12is independently selected from: halo, -CN, -NO2, =0, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, -OR7, -S(O)XR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, - NR7SO2R8, and -SO2NR7R8; wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl is optionally substituted by one or more R14;R4A, R4BR9A, and R9Bare at each occurrence independently selected from: H, C1.4 alkyl and C1.4 haloalkyl; and wherein any -NR7R8, -NR4AR4B, and -NR9AR9Bwithin 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, =0, C1.4 alkyl and C1.4 haloalkyl; each x is independently 0, 1 , or 2; and a is 0, 1 , 2, 3, 4 or 5; with the proviso that the compounds in List A are excluded:List A:

[0012] Also provided is a compound of the Formula (la), or a pharmaceutically acceptable salt thereof:wherein:R1is selected from: Ci-e alkyl, C3-6 cycloalkyl, and Cs-e cycloalkyl-Ci-e alkyl-, wherein R1is substituted by at least one fluorine, optionally wherein one or more H in R1is substituted by D;R2is selected from: H, D, Ci-e alkyl and Ci-e haloalkyl, optionally wherein one or more H in R2is substituted by D; orR1and R2together with the carbon atom to which they are attached form a C3-6 cycloalkyl substituted with at least one fluorine;R3is selected from: H, Ci-e alkyl and Ci-e haloalkyl; optionally wherein one or more H in R3is substituted by D; each R4is independently selected from: halo, -CN, -NO2, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, -OR4A, -S(O)XR4A, -NR4AR4B, -C(O)R4A, - OC(O)R4A, -C(O)OR4A, -NR4AC(O)R4B, -C(O)NR4AR4B, -NR4AC(O)OR4B, -OC(O)NR4AR4B, - NR4ASO2R4B, and -SO2NR4AR4B,wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R9;R5is selected from: H, Ci-e alkyl, Ci-e haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and Co-6 alkylene- R5a; wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 alkylene is optionally substituted by one or more R10;R6is selected from: C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and Co-6 alkylene- R6a; wherein said Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci-e alkylene is optionally substituted by one or more R10; orR5and R6, together with the nitrogen atom to which they are attached form Ring A, wherein Ring A is selected from: a 4- to 12 membered heterocyclyl group and a 5- to 12- membered heteroaryl group; wherein Ring A is optionally substituted by one or more R6b; each R6bis independently selected from: halo, -CN, -NO2, =0, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, -OR7, -S(O)XR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, - NR7SO2R8, and -SO2NR7R8; wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl is optionally substituted by one or more R11;R5aand R6aare each independently selected from: C3-6 cycloalkyl, 4- to 12 membered heterocyclyl, 5- to 12-membered heteroaryl, and Ce- aryl; wherein R5aand R6aare optionally substituted by one or more R12;R7and R8are each independently selected from: H, Ci-e alkyl, Ci-e haloalkyl and C3-6 cycloalkyl; wherein said Ci-e alkyl and C3-6 cycloalkyl is optionally substituted by one or more R13; each R9, R10, R11, R13, and R14is independently selected from: halo, =0, -CN, -OR9A, - S(O)xR9A, -NR9AR9B, C(O)R9A, -OC(O)R9A, -C(O)OR9A, -NR9AC(O)R9B, -C(O)NR9AR9Band C3-6 cycloalkyl; each R12is independently selected from: halo, -CN, -NO2, =0, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, -OR7, -S(O)XR7, -NR7R8,-C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, - NR7SO2R8, and -SO2NR7R8; wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2.6 alkenyl, C2.6 alkynyl, and C3-6 cycloalkyl is optionally substituted by one or more R14;R4A, R4BR9A, and R9Bare at each occurrence independently selected from: H, C1.4 alkyl and C1.4 haloalkyl; and wherein any -NR7R8, -NR4AR4B, and -NR9AR9Bwithin 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, =0, C1.4 alkyl and C1.4 haloalkyl; each x is independently 0, 1 , or 2; and a is 0, 1 , 2, 3, 4 or 5.

[0013] Also provided is a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, with the proviso that the compounds in List A are not excluded.

[0014] Also provided is a compound of the invention, or a pharmaceutically acceptable salt thereof, for use as a medicament, with the proviso that the compounds in List A are not excluded.

[0015] Also provided is a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or medical disorder mediated by Cav2.3, with the proviso that the compounds in List A are not excluded.

[0016] 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 of a disease or medical disorder mediated by Cav2.3, with the proviso that the compounds in List A are not excluded.

[0017] Also provided is a method of treating a disease or medical disorder mediated by Cav2.3 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, with the proviso that the compounds in List A are not excluded.

[0018] 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 disease or medical disorder selected from: a neurodegenerative disease, a neurodevelopmental disorder, epilepsy, an endocrine disorder, cerebral vasospasm, and pain. In certain embodiments there is provided a compound of the invention, or a pharmaceuticallyacceptable salt thereof for use in the treatment of a neurodegenerative disease, for example Parkinson's disease, Alzheimer's disease, Huntington's disease, dystonia, amyotrophic lateral sclerosis (ALS), and age-related neurodegeneration, with the proviso that the compounds in List A are not excluded. Further therapeutic uses of the compounds of the invention are set out in the Detailed Description.DETAILED DESCRIPTIONDefinitions

[0019] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0020] 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 (XXXXXIII), or a compound described in any of the Examples, or a pharmaceutically acceptable salt, solvate, or salt of a solvate of any thereof.

[0021] The term “antagonist” for example "Cav2.3 antagonist" refers to any molecule that is capable of blocking or decreasing the amount of ions, particularly calcium ions through Cav2.3 channels. An antagonist may prevent of inhibit opening of the channel, or otherwise disrupt the normal operation of the channel. The antagonist may act directly on the channel or indirectly, for example by binding to an allosteric site on the channel.

[0022] As used herein, the term "selective antagonist" refers to an antagonist having greater affinity for its target than for one or more related receptors. For example, a "Cav2.3- selective antagonist" has greater affinity for Cav2.3 than for one or more similar calcium-ion channels (e.g., other Cav2, L-type, or N-type family members. The greater affinity of its Cav2.3 target may be, for example, at least: 1.1 -fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 2- fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, 1000-fold, 10000-fold, etc. The selectivity of a compound of the invention for Cav2.3 over other ion channels (e.g. one or more other Cav channels selected from: Cav1.2, Cav1.2, Cav1.3, Cav1.4, Cav2.1 , and Cav 2.2) can be assessed using methods analogous to the Cav2.3 channel calcium-influx assay described herein, using cells which express the channels of interest and comparing the IC50 values.

[0023] 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 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 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 Cav2.3 (e.g., reducing or preventing symptoms or effects of the disease or condition or preventing or inhibiting progression of the disease or condition. For example, a compound of the invention may be for use in preventing, or reducing neurodegeneration in a neurodegenerative disease (e.g. Parkinson’s disease), or delaying the onset of symptoms, or delaying the progression of a neurodegenerative disease.

[0024] The term “associated” or “associated with”, “involving” or “mediated by” in the context of a Cav2.3 associated with a disease 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 Cav2.3 channels, or channel activity or function. For example, a symptom of a disease or condition associated with Cav2.3 activity may be a symptom that results (entirely or partially) from an increase in the level of activity of Cav2.3 channels and or increased expression of Cav2.3 channels. A disease or medical disorder associated with a Cav2.3 activity or expression, may be treated with a compound of the invention effective for decreasing the level of activity of Cav2.3 channels, for example by blocking or partially blocking the channel, inhibiting the function of the channel, preventing or inhibiting the expression of the channel and / or degrading the channel.

[0025] 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 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, 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 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 effectdoes not necessarily occur by administration of one dose and may occur only after 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 Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0026] 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, as measured using the methods described herein or known in the art.

[0027] 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 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.

[0028] 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 invention should be sufficient to effect 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 small increments until the optimum effect under circumstances is reached.

[0029] 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 disease state.

[0030] 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,relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration and the toxicity profile of the selected agent.

[0031] 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.

[0032] The term Cm-n refers to a group with m to n carbon atoms. For the avoidance of doubt, the term Co-n alkylene refers to a group where the alkylene group is absent, i.e. the Co-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.

[0033] The term “Ci-e 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, / so-propyl, n-butyl, / so- butyl, sec-butyl, terf-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. Furthermore, an alkylene group may, for example, correspond to one of those alkyl groups listed in this paragraph. For example, Ci-e alkylene may be -CH2-, -CH2CH2-, -CH2CH(CH3)- , -CH2CH2CH2- or -CH2CH(CHS)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, bromine and iodine, OH, C1-C4 alkoxy, -NR’R” amino, wherein R’ and R” are independently H or alkyl. Other substituents for the alkyl group may alternatively be used.

[0034] The term “Co-6 alkylene” encompasses a bond (i.e. “Co”) and a Ci-e alkylene group. Thus by way of an example, Co-6 alkylene-R5aencompasses -R5aand -Ci-e alkylene-R5a.

[0035] The term “Ci-e haloalkyl”, e.g., “C1.4 haloalkyl”, 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 position on the hydrocarbon chain. For example, Ci-e haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl e.g., 1 -chloromethyl and 2-chloroethyl, 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,-CH2CHX2 or -CX(CH3)CH3wherein X is a halo (e.g., F, Cl, Br, or I). A fluoroalkyl group, i.e., a hydrocarbon chain substituted with at least one fluorine atom (e.g., -CF3, -CHF2, -CH2CF3or -CH2CHF2).

[0036] 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 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-CHs,-CH2- 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,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).

[0037] 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 be present as the E or Z isomer. The double bond may be at any possible position of the hydrocarbon chain. For example, the “C2-6 alkenyl” 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, 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 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.

[0038] The term “C2-6 alkynyl” 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 at any possible position of the hydrocarbon chain. For example, the “C2-6 alkynyl” 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 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=CCH3. Alkynyl and alkynylenegroups may 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.

[0039] 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.

[0040] The term “heterocyclyl”, “heterocyclic” or “heterocycle” includes a non-aromatic 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. The 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 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 be share a bridgehead, i.e. the rings are 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, tetrahydropyridinyl, homopiperidinyl, homopiperazinyl, 2,5-diaza-bicyclo[2.2.1]heptanyl and the like. Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1 , 3-dithiol, 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. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxide and sulfone forms oftetrahydrothienyl 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 (=0), for example, 2 oxopyrrolidinyl, 2-oxoimidazolidinyl, 2-oxopiperidinyl, 2,5- 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, 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.

[0041] The term “bridged ring systems” includes ring systems in which two rings share more 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- bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane, and quinuclidine.

[0042] 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, 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.

[0043] “Heterocyclyl-Cm-n alkyl” includes a heterocyclyl group covalently attached to a Cm-n alkylene group, both of which are defined herein; and wherein the Heterocyclyl-Cm-n alkyl group is linked to the remainder of the molecule via a carbon atom in the alkylene group. The groups “aryl-Cm-n alkyl”, “heteroaryl-Cm-n alkyl” and “cycloalkyl-Cm-n alkyl” are defined in the same way.

[0044] “-Cm-n alkyl substituted by -NRR” and “Cm-n alkyl substituted by -OR” similarly refer to an -NRR” or -OR” group covalently attached to a Cm-n alkylene group and wherein the group is linked to the remainder of the molecule via a carbon atom in the alkylene group.

[0045] 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 TT system within the ring or ring system where all atoms contributing to the conjugated TT system are in the same plane.

[0046] The term “aryl” includes an aromatic hydrocarbon ring system. The ring system has 4n +2 electrons in a conjugated TT system within a ring where all atoms contributing to the conjugated TT 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 Ce-12 aryl, suitably phenyl 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.

[0047] The term “heteroaryl” includes an aromatic mono- or bicyclic ring incorporating one 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 TT system where all atoms contributing to the conjugated TT system are in the same plane.

[0048] 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 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 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. 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.

[0049] 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, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl,naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 1 H-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- 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, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl and pteridinyl.

[0050] “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 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, 2,3-dihydro-benzo[1 ,4]dioxi nyl , 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-2 / 7-pyrido[3,2-b][1 ,4]oxazinyl.

[0051] Examples of five-membered heteroaryl groups include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

[0052] Examples of six-membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0053] 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, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, pyrrolopyridine, and pyrazolopyridinyl groups.

[0054] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl,benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.

[0055] 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).

[0056] The term "optionally substituted" includes either groups, structures, or molecules that are substituted and those that are not substituted.

[0057] 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, 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).

[0058] 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 1 or 2 substituents on a group. Where there are two or more substituents, the substituents may be the same or different.

[0059] 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. For example, it will be recognised that when Ring A is pyridyl the ring nitrogen is not substituted and the ring may be optionally substituted with up to 4 substituents, similarly when Ring A is pyrimidyl, the ring may be optionally substituted up to 3 substituents.

[0060] Ortho, meta and para substitution are well understood terms in the art. For the 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 “

[0061] “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 another substituent. For example, the groups below are meta substituted:

[0062] “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 another substituent. For example, the groups below are para substituted:

[0063] Where Ring A comprises an NH group the NH group may be substituted by R6bto give NR6b. Similarly, where Ring B comprises an NH group, the NH group may be substituted by R12to give NR12.

[0064] 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, an -NRR’ group within a substituent may form a carbonyl-linked 4 to 6 membered 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.

[0065] For the avoidance of doubt, where R5and R6, together with the nitrogen atom to which they are attached, form Ring A, Ring A is attached to the remainder of the molecule via a ring nitrogen atom in Ring A, i.e.:. For example, where Ring A is heteroaryl, Ring A is N- linked to the remaining portion of the molecule via the sulfur atom to form a sulfonyl urea.

[0066] A bond terminating in, , represents that the bond is connected to 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 stated otherwise herein.

[0067] 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 1000. More usually, the molecular weight of the compound will be less than 750, for example less than 700, or less than 650, or less than 600, or less than 550.

[0068] Suitable or preferred features of any compounds of the present invention may also be suitable features of any other aspect.

[0069] 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.

[0070] 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, 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.

[0071] Suitable base salts are formed from bases which form non-toxic salts. Examples 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:Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0072] Pharmaceutically acceptable salts of compounds of the invention may be prepared by for example, one or more of the following methods:(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 appropriate acid or base or by means of a suitable ion exchange column.

[0073] 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 nonionised.

[0074] 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.

[0075] 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 “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 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 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 excess may be any of those disclosed above. Where the compound is a single stereoisomer,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%.

[0076] 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 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. Some of the compounds of the invention may have geometric isomeric centres (E and Z isomers). It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof

[0077] Z / E (e.g., cis / trans) isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.

[0078] Conventional techniques for the preparation / isolation of individual enantiomers when necessary include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). Thus, chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and for specific examples, 0 to 5% by volume of an alkylamine e.g., 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.

[0079] 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 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.

[0080] When any racemate crystallises, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein onehomogeneous 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.

[0081] 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. Wilen (Wiley, 1994).

[0082] 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” for deuterium),3H (also written as “T” for tritium),11C,13C,14C,15O,17O,18O,13N,15N,18F,36CI,123l,25l,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 some embodiments, the radionuclide is11C. And in some embodiments, the radionuclide is 18p

[0083] 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 previously employed.

[0084] 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 metabolites, thereby improving safety and tolerability. It is to be understood that the invention encompasses deuterated derivatives of compounds of formula (I). 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. For example, one or more hydrogen atoms in a Ci-4-alkyl group may be replaced by deuterium to form a deuterated Ci-4-alkyl group. By way of example, if any of R1, R2, R3, R4, R5or R6is methyl the invention also encompasses -CDs, -CHD2 and -CH2D. Similarly R2, R3or R5may be D.

[0085] 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.

[0086] It is also to be understood that certain compounds of the invention may exhibit polymorphism, and that the invention encompasses all such forms.

[0087] 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 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 enolate

[0088] 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.

[0089] 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, 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 of the invention contains a suitable group or substituent to which a property-modifying group can be attached. Examples of pro-drugs include in v / vo-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.

[0090] 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 syntheticmeans and also such compounds that are produced in the human or animal body 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.

[0091] A suitable pharmaceutically-acceptable pro-drug of a compound of the invention is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.

[0092] Various forms of pro-drug have been described, for example in the following documents:- 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. 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. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0093] A suitable pharmaceutically-acceptable pro-drug of a compound of the formula (I) that possesses a carboxy group is, for example, an in v / Vo-cleavable ester thereof. An in v / o-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 Ci-6 alkyl esters such as methyl, ethyl and terf-butyl, Ci-e alkoxymethyl esters such as methoxymethyl esters, Ci-e alkanoyloxymethyl esters such as pivaloyloxymethyl esters, 3- phthalidyl esters, C3-8 cycloalkylcarbonyloxy- Ci-e alkyl 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 C1.6 alkoxycarbonyloxy- Ci-e alkyl esters such as methoxycarbonyloxymethyl and 1 -methoxycarbonyloxyethyl esters.

[0094] A suitable pharmaceutically-acceptable pro-drug of a compound of the invention that possesses a hydroxy group is, for example, an in v / Vo-cleavable ester or ether thereof. An in v / o-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. Suitable 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 Ci- alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, Ci-io alkoxycarbonyl groups such as ethoxycarbonyl, / V, / V-(Ci-6 alkyl)2carbamoyl, 2- dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, / V-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin-1 -ylmethyl and 4-(CI-4 alkyl)piperazin-1- ylmethyl. Suitable pharmaceutically-acceptable ether forming groups for a hydroxy group include a-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl groups.

[0095] A suitable pharmaceutically-acceptable pro-drug of a compound of the invention that possesses a carboxy group is, for example, an in v / vo-cleavable amide thereof, for example an amide formed with an amine such as ammonia, a C1.4 alkylamine such as methylamine, a (Ci-4 alkyl)2amine such as dimethylamine, / V-ethyl- / V-methylamine or diethylamine, a C1.4 alkoxy- C2-4 alkylamine such as 2-methoxyethylamine, a phenyl-Ci-4 alkylamine such as benzylamine and amino acids such as glycine or an ester thereof.

[0096] A suitable pharmaceutically-acceptable pro-drug of a compound of the invention that possesses an amino group is, for example, an in v / vo-cleavable amide or carbamate derivative thereof. Suitable pharmaceutically-acceptable amides from an amino group include, for example an amide formed with Ci- 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, / V, / V-dialkylaminomethyl, morpholinomethyl, piperazin-1 -ylmethyl and 4-(CI-4 alkyl)piperazin-1 -ylmethyl. Suitable pharmaceutically-acceptable carbamates from an amino group include, for example acyloxyalkoxycarbonyl and benzyloxycarbonyl groups.

[0097] 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 plural unless the context otherwise requires. In particular, where the indefinite article isused, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[0098] Features, integers, characteristics, compounds, chemical moieties, or groups described in conjunction with a particular aspect, embodiment or example of the invention 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 this 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 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.

[0099] 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 which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.COMPOUNDS

[0100] The following paragraphs are applicable to the compounds of the invention, including compounds of the formulae (I) to (XXXXXIII).

[0101] In certain embodiments the compound of the formula (I) is a compound of the formula (II), or a pharmaceutically acceptable salt thereof:whereinR1, R2, R3, R4, a, and Ring A are as defined for formula (I).

[0102] In certain embodiments the compound of the formula (I) is a compound of the formula (III), or a pharmaceutically acceptable salt thereof:whereinR1, R2, R3, R4, a, and Ring A are as defined for formula (I).

[0103] In certain embodiments the compound of the formula (I) is a compound of the formula (IV), or a pharmaceutically acceptable salt thereof:whereinR3, R4, a, and Ring A are as defined for formula (I).

[0104] In certain embodiments the compound of the formula (I) is a compound of the formula (V), or a pharmaceutically acceptable salt thereof:whereinR3, R4, and Ring A are as defined for formula (I).

[0105] In certain embodiments the compound of the formula (I) is a compound of the formula (VI), or a pharmaceutically acceptable salt thereof:whereinR3, R4, and Ring A are as defined for formula (I).

[0106] In certain embodiments the compound of the formula (I) is a compound of the formula (VII), or a pharmaceutically acceptable salt thereof:whereinR3and Ring A are as defined for formula (I).

[0107] In certain embodiments the compound of the formula (I) is a compound of the formula (VIII), or a pharmaceutically acceptable salt thereof:wherein R3and Ring A are as defined for formula (I).

[0108] In certain embodiments the compound of the formula (I) is a compound of the formula (IX), or a pharmaceutically acceptable salt thereof:wherein R3, R4, a, and Ring A are as defined for formula (I).

[0109] In certain embodiments the compound of the formula (I) is a compound of the formula (X), or a pharmaceutically acceptable salt thereof:wherein R3, R4, and Ring A are as defined for formula (I).

[0110] In certain embodiments the compound of the formula (I) is a compound of the formula (XI), or a pharmaceutically acceptable salt thereof:wherein R3, R4, and Ring A are as defined for formula (I).

[0111] In certain embodiments the compound of the formula (I) is a compound of the formula (XII), or a pharmaceutically acceptable salt thereof:whereinR1, R2, R3, R4, a and R6bare as defined for formula (I); and b is O, 1 , 2, 3, 4, 5, or 6.

[0112] In certain embodiments the compound of the formula (I) is a compound of the formula (XIII), or a pharmaceutically acceptable salt thereof:whereinR1, R2, R3, R4, a and R6bare as defined for formula (I); and b is 0, 1 , 2, 3, 4, 5, or 6.

[0113] In certain embodiments the compound of the formula (I) is a compound of the formula (XIV), or a pharmaceutically acceptable salt thereof:whereinR3, R4, a and R6bare as defined for formula (I); and b is 0, 1 , 2, 3, 4, 5, or 6.

[0114] In certain embodiments the compound of the formula (I) is a compound of the formula (XV), or a pharmaceutically acceptable salt thereof:whereinR3, R4, and R6bare as defined for formula (I); and b is 0, 1 , 2, 3, 4, 5, or 6.

[0115] In certain embodiments the compound of the formula (I) is a compound of the formula (XVI), or a pharmaceutically acceptable salt thereof:whereinR3, R4, and R6bare as defined for formula (I); and b is 0, 1 , 2, 3, 4, 5, or 6.

[0116] In certain embodiments the compound of the formula (I) is a compound of the formula (XVII), or a pharmaceutically acceptable salt thereof:wherein R3and R6bare as defined for formula (I); and b is 0, 1 , 2, 3, 4, 5, or 6.

[0117] In certain embodiments the compound of the formula (I) is a compound of the formula (XVIII), or a pharmaceutically acceptable salt thereof:(XVIII) wherein R3and R6bare as defined for formula (I); and b is 0, 1 , 2, 3, 4, 5, or 6.

[0118] In certain embodiments the compound of the formula (I) is a compound of the formula (XIX), or a pharmaceutically acceptable salt thereof:wherein R3, R4, a and R6bare as defined for formula (I); and b is 0, 1 , 2, 3, 4, 5, or 6.

[0119] In certain embodiments the compound of the formula (I) is a compound of the formula (XX), or a pharmaceutically acceptable salt thereof:wherein R3, R4, and R6bare as defined for formula (I); and b is 0, 1 , 2, 3, 4, 5, or 6.

[0120] In certain embodiments the compound of the formula (I) is a compound of the formula (XXI), or a pharmaceutically acceptable salt thereof:wherein R3, R4, and R6bare as defined for formula (I); and b is 0, 1 , 2, 3, 4, 5, or 6.

[0121] In certain embodiments the compound of the formula (I) is a compound of the formula (XXII), or a pharmaceutically acceptable salt thereof:whereinR1, R2, R3, R4, R5, R12, and a are as defined for formula (I);Ring B is selected from: C3-6 cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 12- membered heteroaryl, and Ce- aryl; wherein Ring B is optionally substituted by one or more R12; and y is 0, 1 , 2, 3, 4, 5, or 6.

[0122] In certain embodiments the compound of the formula (I) is a compound of the formula (XXIII), or a pharmaceutically acceptable salt thereof:whereinR1, R2, R3, R4, R5, R12, and a are as defined for formula (I);Ring B is selected from: C3-6 cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 12- membered heteroaryl, and Ce- aryl; wherein Ring B is optionally substituted by one or more R12; and y is 0, 1, 2, 3, 4, 5, or 6.

[0123] In certain embodiments the compound of the formula (I) is a compound of the formula (XXIV), or a pharmaceutically acceptable salt thereof:whereinR3, R4, R5, R12, and a are as defined for formula (I);Ring B is selected from: C3-6 cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 12- membered heteroaryl, and Ce- aryl; wherein Ring B is optionally substituted by one or more R12; and y is 0, 1, 2, 3, 4, 5, or 6.

[0124] In certain embodiments the compound of the formula (I) is a compound of the formula (XXV), or a pharmaceutically acceptable salt thereof:(XXV) whereinR3, R4, R5, and R12are as defined for formula (I);Ring B is selected from: C3-6 cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 12- membered heteroaryl, and Ce- aryl; wherein Ring B is optionally substituted by one or more R12; and y is 0, 1 , 2, 3, 4, 5, or 6.

[0125] In certain embodiments the compound of the formula (I) is a compound of the formula (XXVI), or a pharmaceutically acceptable salt thereof:whereinR3, R4, R5, and R12are as defined for formula (I);Ring B is selected from: C3-6 cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 12- membered heteroaryl, and Ce- aryl; wherein Ring B is optionally substituted by one or more R12; and y is 0, 1 , 2, 3, 4, 5, or 6.

[0126] In certain embodiments the compound of the formula (I) is a compound of the formula (XXVII), or a pharmaceutically acceptable salt thereof:whereinR3, R5, and R12are as defined for formula (I);Ring B is selected from: C3-6 cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 12- membered heteroaryl, and Ce- aryl; wherein Ring B is optionally substituted by one or more R12; andy is 0, 1, 2, 3, 4, 5, or 6.

[0127] In certain embodiments the compound of the formula (I) is a compound of the formula (XXVIII), or a pharmaceutically acceptable salt thereof:whereinR3, R5, and R12are as defined for formula (I);Ring B is selected from: C3-6 cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 12- membered heteroaryl, and Ce- aryl; wherein Ring B is optionally substituted by one or more R12; and y is 0, 1, 2, 3, 4, 5, or 6.

[0128] In certain embodiments the compound of the formula (I) is a compound of the formula (XXIX), or a pharmaceutically acceptable salt thereof:whereinR3, R4, R5, R12, and a are as defined for formula (I);Ring B is selected from: C3-6 cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 12- membered heteroaryl, and Ce- aryl; wherein Ring B is optionally substituted by one or more R12; and y is 0, 1, 2, 3, 4, 5, or 6.

[0129] In certain embodiments the compound of the formula (I) is a compound of the formula (XXX), or a pharmaceutically acceptable salt thereof:whereinR3, R4, R5, and R12are as defined for formula (I);Ring B is selected from: C3-6 cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 12- membered heteroaryl, and Ce- aryl; wherein Ring B is optionally substituted by one or more R12; and y is 0, 1 , 2, 3, 4, 5, or 6.

[0130] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXI), or a pharmaceutically acceptable salt thereof:whereinR3, R4, R5, and R12are as defined for formula (I);Ring B is selected from: C3-6 cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 12- membered heteroaryl, and Ce- aryl; wherein Ring B is optionally substituted by one or more R12; and y is 0, 1 , 2, 3, 4, 5, or 6.

[0131] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXII), or a pharmaceutically acceptable salt thereof:whereinR3, R5, and R12are as defined for formula (I);Ring B is selected from: C3-6 cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 12- membered heteroaryl, and Ce- aryl; wherein Ring B is optionally substituted by one or more R12; and y is 0, 1, 2, 3, 4, 5, or 6.

[0132] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXIII), or a pharmaceutically acceptable salt thereof:(XXXIII) whereinR3, R5, and R12are as defined for formula (I);Ring B is selected from: C3-6 cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 12- membered heteroaryl, and Ce- aryl; wherein Ring B is optionally substituted by one or more R12; and y is 0, 1, 2, 3, 4, 5, or 6.

[0133] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXIV), or a pharmaceutically acceptable salt thereof:(XXXIV) whereinR3, R4, R6, and a are as defined for formula (I); andR5is C1.3 alkyl.

[0134] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXV), or a pharmaceutically acceptable salt thereof:whereinR3, R4, and R6, are as defined for formula (I); andR5is C1.3 alkyl.

[0135] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXVI), or a pharmaceutically acceptable salt thereof:(XXXVI) whereinR3, R4, and R6are as defined for formula (I); andR5is C1.3 alkyl.

[0136] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXVII), or a pharmaceutically acceptable salt thereof:(XXXVII) whereinR3and R6, are as defined for formula (I); andR5is C1.3 alkyl.

[0137] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXVIII), or a pharmaceutically acceptable salt thereof:(XXXVIII) whereinR3and R6are as defined for formula (I); andR5is C1.3 alkyl.

[0138] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXIX), or a pharmaceutically acceptable salt thereof:whereinR3, R4, R6, and a are as defined for formula (I); andR5is C1.3 alkyl.

[0139] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXX), or a pharmaceutically acceptable salt thereof:whereinR3, R4, and R6, are as defined for formula (I); andR5is C1.3 alkyl.

[0140] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXXI), or a pharmaceutically acceptable salt thereof:(XXXXI) whereinR3, R4, and R6are as defined for formula (I); andR5is C1.3 alkyl.

[0141] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXXII), or a pharmaceutically acceptable salt thereof:(XXXXII) whereinR3and R6, are as defined for formula (I); andR5is C1.3 alkyl.

[0142] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXXIII), or a pharmaceutically acceptable salt thereof:(XXXXII I) whereinR3and R6are as defined for formula (I); andR5is C1.3 alkyl.

[0143] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXXIV), or a pharmaceutically acceptable salt thereof:(XXXXIV) wherein R3, R4, R5and R12and a are as defined for formula (I).

[0144] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXXV), or a pharmaceutically acceptable salt thereof:(XXXXV) wherein R3, R4, R5and R12are as defined for formula (I).

[0145] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXXVI), or a pharmaceutically acceptable salt thereof:(XXXXVI) wherein R3, R4, R5and R12are as defined for formula (I).

[0146] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXXVII), or a pharmaceutically acceptable salt thereof:(XXXXVII) wherein R3, R5and R12are as defined for formula (I).

[0147] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXXVII I), or a pharmaceutically acceptable salt thereof:(XXXXVIII) wherein R3, R5and R12are as defined for formula (I).

[0148] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXXIX), or a pharmaceutically acceptable salt thereof:(XXXXIX) wherein R3, R4, R5and R12and a are as defined for formula (I).

[0149] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXXX), or a pharmaceutically acceptable salt thereof:(XXXXX) wherein R3, R4, R5and R12are as defined for formula (I).

[0150] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXXXI), or a pharmaceutically acceptable salt thereof:(XXXXXI) wherein R3, R4, R5and R12are as defined for formula (I).

[0151] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXXXI I), or a pharmaceutically acceptable salt thereof:(XXXXXII) wherein R3, R5and R12are as defined for formula (I).

[0152] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXXXIII), or a pharmaceutically acceptable salt thereof:(XXXXXIII) wherein R3, R5and R12are as defined for formula (I).

[0153] In certain embodiments compounds of the invention include, for example, compounds of formulae (I) to (XXXXXIII), or a pharmaceutically acceptable salt thereof, wherein, unless otherwise stated, each of Ring A, Ring B, R1, R2, R3, R4, R4A, R4B, R5, R5a, R6, R6a, R6b, R7, R8, R9, R10, R11, R12, R13, R14, R4A, R4B, R9A, R9B, a, b, y, and x has any of the meanings defined hereinbefore or in any of the following statements in the numbered paragraphs 1 to 277 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 in 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 invention in this specification.1. R1is selected from: Ci-e alkyl, C3-6 cycloalkyl, and Cs-ecycloalkyl-Ci-e alkyl-, wherein R1is optionally substituted by at least one fluorine and optionally wherein one or more H in R1is substituted by D.2. R1is selected from: Ci-e alkyl, Ci-e alkyl substituted by at least one fluorine, C3-6 cycloalkyl, C3-6 cycloalkyl substituted by at least one fluorine, Cs-e cycloalkyl-Ci-e alkyl-and C3-6 cycloalkyl-Ci-6 alkyl- substituted by at least one fluorine, optionally wherein one or more H in R1is substituted by D.3. R1is selected from: C1.3 alkyl, C1.3 alkyl substituted by at least one fluorine, C3-5 cycloalkyl, C3-5 cycloalkyl substituted by at least one fluorine, optionally wherein one or more H in R1is substituted by D.4. R1is selected from: Ci-e alkyl, C3-6 cycloalkyl, and Cs-ecycloalkyl-Ci-e alkyl-, wherein R1is substituted by at least one fluorine, optionally wherein one or more H in R1is substituted by D.5. R1is selected from: Ci-e alkyl, C3-6 cycloalkyl, and Cs-ecycloalkyl-Ci-e alkyl-, wherein R1is substituted by at least one fluorine.6. R1is selected from: C1.3 alkyl, C3-6 cycloalkyl, and Cs-ecycloalkyl-Ci-s alkyl-, wherein R1is substituted by at least one fluorine.7. R1is selected from: Ci-e alkyl, and C3-6 cycloalkyl, wherein R1is substituted by at least one fluorine.8. R1is selected from: C1.3 alkyl, and C3-6 cycloalkyl, wherein R1is substituted by at least one fluorine.9. R1is C1.6 alkyl, wherein R1is substituted by at least one fluorine.10. R1is C1.3 alkyl, wherein R1is substituted by at least one fluorine.11. R1is selected from: methyl, methyl substituted by at least one fluorine, ethyl and ethyl substituted by at least one fluorine.12. R1is selected from: ethyl and methyl, wherein the ethyl or methyl is substituted by at least one fluorine.13. R1is ethyl wherein the ethyl is substituted by at least one fluorine.14. R1is selected from: methyl, ethyl, -CH2F, -CHF2, and -CF3.15. R1is selected from: -CH2F, -CHF2, and -CF3.16. R1is methyl.17. R1is ethyl.18. R1is -CH2F.19. R1is -CHF2.20. R1is -CF3.21. R1is as defined in any of 1 to 19, wherein one or more H in R1is substituted by D.22. R2is selected from: H, C1.3 alkyl and C1.3 haloalkyl.23. R2is selected from: H, and C1.3 alkyl. Thus it may be that R2is selected from: H and methyl.24. R2is C1.3 alkyl.25. R2is methyl.26. R2is H or D.27. R2is D.28. R2is H.29. R1and R2together with the carbon atom to which they are attached form a C3 or C4 cycloalkyl. Thus, it may be that R1and R2together with the carbon atom to which they are attached form a cyclopropyl group. It may be that R1and R2together with the carbon atom to which they are attached form a cyclobutyl group.30. R1and R2together with the carbon atom to which they are attached form a C3 or C4 cycloalkyl substituted with at least one fluorine.31. R1and R2together with the carbon atom to which they are attached form a cyclobutyl group substituted with at least one fluorine. Thus, it may be that R1and R2together with the carbon atom to which they are attached form a cyclobutyl group substituted with one fluorine.32. R1and R2together with the carbon atom to which they are attached form a cyclopropyl group substituted with at least one fluorine. Thus, it may be that R1and R2together with the carbon atom to which they are attached form a cyclopropyl group substituted with one fluorine.33. R1is as defined in any of 1 to 21 and R2is methyl.34. R1is as defined in any of 1 to 21 and R2is H. Thus it may be that R1is selected from: methyl, -CH2F, -CHF2, and -CF3, and R2is H.35. R3is selected from: Ci-e alkyl and Ci-e haloalkyl, optionally wherein one or more H in R3is substituted by D36. R3is selected from: Ci-e alkyl and Ci-e haloalkyl.37. R3is selected from: C1.3 alkyl and C1.3 haloalkyl.38. R3is selected from: Ci-2alkyl and Ci-2haloalkyl.39. R3is methyl optionally substituted with 1 to 3 halo groups.40. R3is ethyl optionally substituted with 1 to 5 halo groups.41. R3is as defined in any of 35 to 40, wherein said halo is fluoro.42. R3is C1.3 alkyl.43. R3is selected from: methyl, ethyl, and 2-fluoroethyl.44. R3is methyl.45. R3is ethyl.46. R3is 2-fluoroethyl.47. R3is as defined in any of 35 to 46 wherein one or more hydrogen atoms in R3is deuterium. Thus, it may be that R3is selected from: methyl, -CDs, ethyl, and 2- fluoroethyl.48. R3is -CD3.49. R3is H.50. Each R4is independently selected from: halo, -CN, -NO2, Ci-e alkyl, Ci-e haloalkyl, - OR4A, -S(O)xR4A, and -NR4AR4B.51. Each R4is independently selected from: -C(O)R4A, -OC(O)R4A, -C(O)OR4A, - NR4AC(O)R4B, -C(O)NR4AR4B, -NR4AC(O)OR4B, -OC(O)NR4AR4B, -NR4ASO2R4B, and - SO2NR4AR4B.52. Each R4is independently selected from: halo, -CN, -NO2, Ci-e alkyl, Ci-e haloalkyl, - OR4A, and -S(O)XR4A53. Each R4is independently selected from: halo, -CN, -NO2, C1.3 alkyl, C1.3 haloalkyl, - OR4A, and -S(O)XR4A54. Each R4is independently selected from: halo, C1.3 alkyl, C1.3 haloalkyl, -OC1.3 alkyl and -O-C1.3 haloalkyl.55. Each R4is independently selected from: halo, C1.3 alkyl and C1.3 haloalkyl.56. Each R4is independently selected from: halo and C1.3 alkyl.57. Each R4is independently selected from: halo, -CN, -NO2, methyl, -CF3, -OH, -OMe, and -S(O)2Me.58. Each R4is independently selected from: fluoro, chloro, -CN, -NO2, methyl, -CF3, -OH, -OMe, and -S(O)2Me.59. Each R4is independently selected from: fluoro, chloro, methyl, -CF3, methoxy, -OCF3 and -OCHF2.60. Each R4is independently selected from: fluoro, chloro, and methyl.61. Each R4is independently selected from: halo and C1.3 haloalkyl.62. Each R4is independently selected from: fluoro, chloro and -CF363. R4is fluoro.64. R4is chloro.65. R4is -CF3.66. R4is as defined in any of 50 and 52 to 60, wherein said alkyl is substituted by one or more R9.67. Each R9is independently selected from: halo, -CN, -OR9A, -NR9AR9Band -SC>2R9A68. Each R9is independently selected from: halo, -CN, -OR9A, and -NR9AR9B.69. Each R9is independently selected from: halo and -OR9A.71. The group of the formulaselected from:72.10 74. The group of the formulaselected from:76. The group of the formulaselected from:77.-fluorophenyl.78.-chlorophenyl.79. The group of the formulai.e., 4- trifluoromethylphenyl.80. The group of the formula81. R5is selected from: Ci-e alkyl, Ci-e haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and Co-6 alkylene-R5a.82. R5is selected from: C1-6 alkyl, C1-6 haloalkyl, and Co-6 alkylene-R5a.83. R5is selected from: C1.3 alkyl, C1.3 haloalkyl, and C0-3 alkylene-R5a.84. R5is C1.3 alkyl. Thus, it may be that R5is methyl. It may be that R5is ethyl.85. R5is Co-6 alkylene-R5a. Thus, it may be that R5is C0-3 alkylene-R5a. It may be that R5is C1.3 alkylene-R5a. It may be that R5is Co alkylene-R5a, i.e. R5may be R5a.86. R5may be as defined in any of 80 to 84, wherein said alkyl, alkenyl, alkynyl, and alkylene is optionally substituted by one or more R10.87. Each R10is independently selected from: halo, =0, -CN, -OR9A, -NR9AR9B, C(O)R9A, - C(O)OR9A, -C(O)NR9AR9Band C3-6 cycloalkyl.88. Each R10is independently selected from: halo, =0, -CN, -OR9A, -NR9AR9B, and C3-6 cycloalkyl.89. Each R10is independently selected from: halo, =0, -CN, -OR9A, and -NR9AR9B.90. Each R10is independently selected from: halo, =0, and -CN.91. Each R10is independently halo. Thus, it may be that each R10is selected from: fluoro and chloro.92. R5ais selected from: C3-6 cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 12- membered heteroaryl and Ce- aryl.93. R5ais selected from: C3-6 cycloalkyl, 4- to 8-membered heterocyclyl, 5- to 10- membered heteroaryl, and Ce- aryl. Thus it may be that R5ais Ce- aryl, for example phenyl or naphthyl. It may be that R5ais phenyl.94. R5ais C3-6 cycloalkyl. Thus it may be that R5ais cyclopropyl, it may be that R5ais cyclobutyl. It may be that R5ais cyclopentyl. It may be that R5ais cyclohexyl.95. R5ais 4- to 8-membered heterocyclyl. Thus, it may be that R5ais 5-membered heterocyclyl. It may be that R5ais 5-membered heterocyclyl with 1 or 2 ring heteroatoms selected from: O, S and N. It may be that R5ais 6-membered heterocyclyl. It may be that R5ais 6-membered heterocyclyl with 1 or 2 ring heteroatoms selected from: O, S and N. It may be that R5ais 7-membered heterocyclyl. It may be that R5ais 7-membered heterocyclyl with 1 or 2 ring heteroatoms selected from: O, S and N. It may be that R5ais 8-membered heterocyclyl. It may be that R5ais 8-membered heterocyclyl with 1 or 2 ring heteroatoms selected from: O, S and N.96. R5ais 5- to 12-membered heteroaryl. Thus, it may be that R5ais 5- to 10-membered heteroaryl. It may be that R5ais 5-membered heteroaryl. It may be that R5ais 6- membered heteroaryl. It may be that R5ais 8-membered heteroaryl. It may be that R5ais 9-membered heteroaryl. It may be that R5ais 10-membered heteroaryl.97. R5ais a 4- to 12-membered heterocyclyl group.98. R5ais a 4- to 12-membered heterocyclyl group with 1 to 4 ring heteroatoms selected from: O, S and N.99. R5ais a 5- to 12-membered heterocyclyl group.100. R5ais a 5- to 12-membered heterocyclyl group with 1 to 4 ring heteroatoms selected from: O, S and N.101. R5ais a 5- to 10-membered heterocyclyl group.102. R5ais a 5- to 10-membered heterocyclyl group with 1 to 4 ring heteroatoms selected from: O, S and N.103. R5ais a 4- to 8-membered heterocyclyl or 5- to 12-membered heteroaryl.104. R5ais 5- to 12-membered heteroaryl. Thus, it may be that R5ais 5- to 10-membered heteroaryl. It may be that R5ais 5-membered heteroaryl. It may be that R5ais 6- membered heteroaryl. It may be that R5ais 8-membered heteroaryl. It may be that R5ais 9-membered heteroaryl. It may be that R5ais 10-membered heteroaryl.105. R5ais a monocyclic 5- or 6-membered heteroaryl or a 8- to 10-membered fused bicyclic heteroaryl, wherein R5ahas at least 1 (for example 1 to 4) ring nitrogen atom. Thus it may be that R5ais a monocyclic 6-membered heteroaryl or a 9- to 10- membered fused bicyclic heteroaryl, wherein R5ahas at least 1 (for example 1 to 4) ring nitrogen atom.106. R5ais a monocyclic 5- or 6-membered heteroaryl or a 9- to 10-membered fused bicyclic heteroaryl, wherein R5ahas 1 to 4 ring nitrogen atoms. Thus it may be that R5ais amonocyclic 6-membered heteroaryl or a 9-membered fused bicyclic heteroaryl, wherein R5ahas 1 to 4 ring nitrogen atoms.107. R5ais 5-membered heteroaryl, wherein said heteroaryl has 1 ring nitrogen atom and optionally one or more ring heteroatoms (for example 1 , 2 or 3) selected from: O, S and N.108. R5ais 5-membered heteroaryl, wherein said heteroaryl has 1 , 2, 3 or 4 ring nitrogen atoms.109. R5ais 6-membered heteroaryl.110. R5ais a monocyclic 6-membered heteroaryl, wherein said heteroaryl has 1 , 2 or 3 (for example 1 or 2) ring nitrogen atoms.111. R5ais 9-membered heteroaryl.112. R5ais 9-membered fused bicyclic heteroaryl, wherein said heteroaryl has 1 , 2, 3 or 4 ring nitrogen atoms.113. R5ais 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 6-membered ring. It may be that the 5- and 6-membered rings forming the 9-membered bicyclic heteroaryl are both heteroaryl rings.114. R5ais 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. It may be that the 5- and 6-membered rings forming the 9-membered bicyclic heteroaryl are both heteroaryl rings.115. R5ais selected from: a 6-membered heteroaryl and a 9-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. It may be that the 5- and 6-membered rings forming the 9- membered bicyclic heteroaryl are both heteroaryl rings.116. Where the R5adefined in any of 91 to 114 comprises one or more nitrogen atoms, said nitrogen atoms are not -N(H)-.117. R5ais as defined in any of 91 to 115, wherein R5ais optionally substituted with one or more R12.118. R6is selected from: Ci-e alkyl, Ci-e haloalkyl, and Co-6 alkylene-R6a.119. R6is selected from: C1.3 alkyl, C1.3 haloalkyl, and C0-3 alkylene-R6a.120. R6is C1-3 alkyl. Thus, it may be that R6is methyl. It may be that R6is ethyl.121. R6is Co-6 alkylene-R6a. Thus, it may be that R6is C0-3 alkylene-R6a. It may be that R6is C1.3 alkylene-R6a. It may be that R6is Co alkylene-R6a, i.e. R6may be R6a.122. R6may be as defined in any of 117 to 120, wherein said alkyl, alkenyl, alkynyl, and alkylene is optionally substituted by one or more R10; optionally wherein R10is as defined in any of 86 to 90.123. R6is selected from: C1.4 alkyl, -C2-4 alkyl-OR9A, -CH2-R6aand R6a.124. R6is selected from: C1.4 alkyl and -C2-4 alkyl-OR9A.125. R6is selected from: C1.4 alkyl, -C2-4 alkyl-OH and -C2-4 alkyl-OCHs Thus it may be that R6is selected from: methyl, ethyl, -CH2CH2OH and -CH2CH2OCH3.126. R6ais selected from: C3-6 cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 12- membered heteroaryl and Ce- aryl.127. R6ais selected from: C3-6 cycloalkyl, 4- to 8-membered heterocyclyl, 5- to 10- membered heteroaryl, and Ce- aryl. Thus it may be that R6ais Ce- aryl, for example phenyl or naphthyl. It may be that R6ais phenyl.128. R6ais C3-6 cycloalkyl. Thus it may be that R6ais cyclopropyl, it may be that R6ais cyclobutyl. It may be that R6ais cyclopentyl. It may be that R6ais cyclohexyl.129. R6ais 4- to 8-membered heterocyclyl. Thus, it may be that R6ais 5-membered heterocyclyl. It may be that R6ais 5-membered heterocyclyl with 1 or 2 ring heteroatoms selected from: O, S and N. It may be that R6ais 6-membered heterocyclyl. It may be that R6ais 6-membered heterocyclyl with 1 or 2 ring heteroatoms selected from: O, S and N. It may be that R6ais 7-membered heterocyclyl. It may be that R6ais 7-membered heterocyclyl with 1 or 2 ring heteroatoms selected from: O, S and N. It may be that R6ais 8-membered heterocyclyl. It may be that R6ais 8-membered heterocyclyl with 1 or 2 ring heteroatoms selected from: O, S and N.130. R6ais 5- to 12-membered heteroaryl. Thus, it may be that R6ais 5- to 10-membered heteroaryl. It may be that R6ais 5-membered heteroaryl. It may be that R6ais 6- membered heteroaryl. It may be that R6ais 8-membered heteroaryl. It may be that R6ais 9-membered heteroaryl. It may be that R6ais 10-membered heteroaryl.131. R6ais a 4- to 12-membered heterocyclyl group.R6ais a 4- to 12-membered heterocyclyl group with 1 to 4 ring heteroatoms selected from: O, S and N. R6ais a 5- to 12-membered heterocyclyl group. R6ais a 5- to 12-membered heterocyclyl group with 1 to 4 ring heteroatoms selected from: O, S and N. R6ais a 5- to 10-membered heterocyclyl group. R6ais a 5- to 10-membered heterocyclyl group with 1 to 4 ring heteroatoms selected from: O, S and N. R6ais a 4- to 8-membered heterocyclyl or 5- to 12-membered heteroaryl. R6ais 5- to 12-membered heteroaryl. Thus, it may be that R6ais 5- to 10-membered heteroaryl. It may be that R6ais 5-membered heteroaryl. It may be that R6ais 6- membered heteroaryl. It may be that R6ais 8-membered heteroaryl. It may be that R6ais 9-membered heteroaryl. It may be that R6ais 10-membered heteroaryl. R6ais a monocyclic 5- or 6-membered heteroaryl or a 8- to 10-membered fused bicyclic heteroaryl, wherein R6ahas at least 1 (for example 1 to 4) ring nitrogen atom. Thus it may be that R6ais a monocyclic 6-membered heteroaryl or a 9- to 10- membered fused bicyclic heteroaryl, wherein R6ahas at least 1 (for example 1 to 4) ring nitrogen atom. R6ais a monocyclic 5- or 6-membered heteroaryl or a 9- to 10-membered fused bicyclic heteroaryl, wherein R6ahas 1 to 4 ring nitrogen atoms. Thus it may be that R6ais a monocyclic 6-membered heteroaryl or a 9-membered fused bicyclic heteroaryl, wherein R6ahas 1 to 4 ring nitrogen atoms. R6ais 5-membered heteroaryl, wherein said heteroaryl has 1 ring nitrogen atom and optionally one or more ring heteroatoms (for example 1 , 2 or 3) selected from: O, S and N. R6ais 5-membered heteroaryl, wherein said heteroaryl has 1 , 2, 3 or 4 ring nitrogen atoms. R6ais 6-membered heteroaryl. R6ais a monocyclic 6-membered heteroaryl, wherein said heteroaryl has 1 , 2 or 3 (for example 1 or 2) ring nitrogen atoms. R6ais 9-membered heteroaryl. R6ais 9-membered fused bicyclic heteroaryl, wherein said heteroaryl has 1 , 2, 3 or 4 ring nitrogen atoms.147. R6ais 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 6-membered ring. It may be that the 5- and 6-membered rings forming the 9-membered bicyclic heteroaryl are both heteroaryl rings.148. R6ais 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. It may be that the 5- and 6-membered rings forming the 9-membered bicyclic heteroaryl are both heteroaryl rings.149. R6ais selected from: a 6-membered heteroaryl and a 9-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. It may be that the 5- and 6-membered rings forming the 9- membered bicyclic heteroaryl are both heteroaryl rings.150. Where the R6adefined in any of 125 to 148 comprises one or more nitrogen atoms, said nitrogen atoms are not -N(H)-.151. R6ais as defined in any of 125 to 149, wherein R6ais optionally substituted with one or more R12.152. R5aand / or R6aare each independently selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, and tetrahydropyranyl.153. R5aand / or R6aare each independently selected from: C3-6 cycloalkyl.154. R5aand / or R6aare each independently selected from: cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.155. R5aand / or R6aare each independently selected from: pyrrolidinyl, tetrahydrofuranyl, piperidinyl, and tetrahydropyranyl.156. R5aand / or R6aare each independently selected from: furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl.157. R5aand / or R6aare each independently selected from: furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, or a compound of the structure:wherein R5aand / or R6aare each independently optionally substituted with one or more R12. R5aand / or R6aare each independently selected from: thienyl, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, tetrahydropyranyl,wherein R5aand / or R6aare each independently optionally substituted with one or more R12. R5aand / or R6aare each independently selected from:wherein R5aand / or R6aare each independently optionally substituted with one or more R12. R5aand / or R6aare each independently a 9-membered fused bicyclic heteroaryl containing at least one ring nitrogen atom, wherein R5aand / or R6aare each independently substituted by one or more R12. Thus it may be that R5aand / or R6aare each independently selected from:wherein R5aand / or R6aare each independently optionally substituted with one or more R12. It may be that R5aand / or R6aare each independently attached to the remaining portion of the molecule via an atom in a 5-membered ring in R5aand / or R6a, respectively. R5aand / or R6aare each independently attached to the remaining portion of the molecule via an atom in a 6-membered ring in R5aand / or R6a, respectively.161. R5aand / or R6aare each independently selected from:substituted with one or more R12. It may be that Ring A is attached to the remaining portion of the molecule via a carbon atom in a benzo ring in R5aand / or R6a, respectively.162. R5aand / or R6aare each independently selected from:wherein R5aand / or R6aare each independently is optionally substituted with one or more R12.163. R5aand / or R6aare each independently selected from:wherein R5aand / or R6aare each independently optionally substituted with one or more R12.164. R5aand / or R6aare each independently selected from:wherein R5aand / or R6aare each independently optionally substituted with one or more R12.165. R5aand / or R6aare each independently selected from:wherein R5aand / or R6aare each independently optionally substituted with one or more R12.166. R5aand / or R6aare each independently selected from:wherein R5aand / or R6aare each independently optionally substituted with one or more R12.167. R5aand / or R6aare each independently selected from:wherein R5aand / or R6aare each independently optionally substituted with one or more R12.168. R5aand / or R6aare each independently selected from:wherein R5aand / or R6aare each independently optionally substituted with one or more R12.R5aand / or R6aare each independently selected from: thienyl and thiazolyl, wherein R5aand / or R6aare each independently optionally substituted with one or more R12. R5aand / or R6aare each independently selected from:171. R5aand / or R6aare each independently selected from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wherein R5aand / or R6aare each independently optionally substituted with one or more R12.172. R5aand / or R6aare each independently selected from: C3-6 cycloalkyl and a 6- membered heteroaryl containing 1 or 2 ring nitrogen atoms, wherein said C3-6 cycloalkyl and 6-membered heteroaryl containing 1 or 2 ring nitrogen atoms are each independently optionally substituted by one or more R12.173. R5aand / or R6aare each independently selected from: C3-6 cycloalkyl and pyridyl, wherein said C3-6 cycloalkyl and pyridyl are each independently optionally substituted by one or more R12.174. R5aand / or R6aare each independently selected from: cyclobutyl and 3-pyridyl, wherein said cyclobutyl and 3-pyridyl are each independently optionally substituted by one or more R12.175. R5aand / or R6aare each independently selected from:176. R6ais as defined in any of 151 to 174.177. R5ais as defined in any of 151 to 174.178. R5is C1.3 alkyl and R6and R6aare as defined in any of 117 to 175.179. R5is methyl and R6and R6aare as defined in any of 117 to 175.180. R5is ethyl and R6and R6aare as defined in any of 117 to 175.181. R5and R6, together with the nitrogen atom to which they are attached form Ring A.182. Ring A is a 4- to 12-membered heterocyclyl group.183. Ring A is a 4- to 12-membered heterocyclyl group with 1 , 2 or 3 ring heteroatoms selected from: O, S and N.184. Ring A is a 5- to 12-membered heterocyclyl group.185. Ring A is a 5- to 12-membered heterocyclyl group with 1, 2 or 3 ring heteroatoms selected from: O, S and N.186. Ring A is a 5- to 10-membered heterocyclyl group.187. Ring A is a 5- to 10-membered heterocyclyl group with 1, 2 or 3 ring heteroatoms selected from: O, S and N.188. Ring A is a 4- to 8-membered heterocyclyl group.189. Ring A is a 4- to 8-membered heterocyclyl group with 1 or 2 ring heteroatoms selected from: O, S and N.190. Ring A is 4- to 10-membered heterocyclyl. Thus, it may be that Ring A is 5-membered heterocyclyl. It may be that Ring A is 5-membered heterocyclyl with 1 or 2 ring heteroatoms selected from: O, S and N. It may be that Ring A is 6-membered heterocyclyl. It may be that Ring A is 6-membered heterocyclyl with 1 or 2 ring heteroatoms selected from: O, S and N. It may be that Ring A is 7-membered heterocyclyl. It may be that Ring A is 7-membered heterocyclyl with 1 or 2 ring heteroatoms selected from: O, S and N. It may be that Ring A is 8-membered heterocyclyl. It may be that Ring A is 8-membered heterocyclyl with 1, 2 or 3 ring heteroatoms selected from: O, S and N. It may be that Ring A is 9-membered heterocyclyl. It may be that Ring A is 9-membered heterocyclyl with 1, 2 or 3 ring heteroatoms selected from: O, S and N.191. Ring A is selected from:.192. Ring A is selected from:optionally whereinRing A is substituted with one or more R6b.193. Where the Ring A defined in any of 181 to 191 comprises one or more additional nitrogen atoms (i.e. in addition to the nitrogen atom to which R5and R6are attached), said nitrogen atoms are not -N(H)-.194. Ring A is as defined in any of 181 to 192, wherein Ring A is optionally substituted with one or more R6b.195. Each R6bis independently selected from: halo, -CN, -NO2, =0, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, -OR7, -S(O)XR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, - OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8.196. Each R6bis independently selected from: halo, -CN, -NO2, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, -OR7, -S(O)XR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, - NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8.197. Each R6bis independently selected from: halo, -CN, -NO2, Ci-e alkyl, Ci-e haloalkyl, - OR7, -NR7R8, -C(O)R7, -C(O)OR7, -C(O)NR7R8.198. Each R6bis independently selected from: halo, -CN, C1.4 alkyl, C1.4 haloalkyl, -OR7, - NR7R8, -C(O)R7, -C(O)OR7, and -C(O)NR7R8.199. Each R6bis independently selected from: halo, -CN, -NO2, =0, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, OR7, -NR7R8, -C(O)R7, -C(O)NR7R8, and -NR7C(O)R8.200. Each R6bis independently selected from: halo, -CN, C1.4 alkyl, -OR7, -NR7R8, -C(O)R7, -C(O)NR7R8and -NR7C(O)R8.201. Each R6bis independently selected from: halo, -CN, C1.4 alkyl, -C(O)R7and - C(O)NR7R8.202. Each R6bis independently selected from: halo (e.g. fluoro or chloro), -CN, C1.3 alkyl, - OC1.3 alkyl, -C(O)Ci-3alkyl, -C(O)NH2, -C(O)NH(CI-3alkyl) and -C(O)N(Ci-3alkyl)2.203. Each R6bis independently selected from: halo (e.g. fluoro or chloro), -CN, C1.3 alkyl and -OC1.3 alkyl. Thus it may be that each R6bis independently selected from: halo, - CN and C1.3 alkyl. Thus it may be that each R6bis independently selected from: fluoro, chloro, -CN, methyl and methoxy. For example each R6bis independently selected from: fluoro, chloro, -CN and methyl.204. R6bis as defined in any one of 194 to 202, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, or cycloalkyl is substituted by one or more R11.205. Each R11is independently selected from: halo, =0, -CN, -OR9A, -NR9AR9B, C(O)R9A, - C(O)OR9A, -C(O)NR9AR9Band C3-6 cycloalkyl.206. Each R11is independently selected from: halo, =0, -CN, -OR9A, -NR9AR9B, and C3-6 cycloalkyl.207. Each R11is independently selected from: halo, =0, -CN, -OR9A, and -NR9AR9B.208. Each R11is independently selected from: halo, =0, and -CN.209. Each R11is independently halo. Thus, it may be that each R11is selected from: fluoro and chloro.210. Each R12is independently selected from: halo, -CN, -NO2, =0, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2.6 alkenyl, C2.6 alkynyl, C3-6 cycloalkyl, -OR7, -S(O)XR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, - OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8.211. Each R12is independently selected from: halo, -CN, -NO2, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, -OR7, -S(O)XR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, - NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, -NR7SO2R8, and -SO2NR7R8.212. Each R12is independently selected from: halo, -CN, -NO2, Ci-e alkyl, Ci-e haloalkyl, - OR7, -NR7R8, -C(O)R7, -C(O)OR7, -C(O)NR7R8.213. Each R12is independently selected from: halo, -CN, C1.4 alkyl, C1.4 haloalkyl, -OR7, - NR7R8, -C(O)R7, -C(O)OR7, and -C(O)NR7R8.214. Each R12is independently selected from: halo, -CN, -NO2, =0, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, OR7, -NR7R8, -C(O)R7, -C(O)NR7R8, and -NR7C(O)R8.215. Each R12is independently selected from: halo, -CN, C1.4 alkyl, -OR7, -NR7R8, -C(O)R7, -C(O)NR7R8and -NR7C(O)R8.216. Each R12is independently selected from: halo, -CN, C1.4 alkyl, -C(O)R7and - C(O)NR7R8.217. Each R12is independently selected from: halo (e.g. fluoro or chloro), -CN, C1.3 alkyl, - OC1.3 alkyl, -C(O)Ci-3alkyl, -C(O)NH2, -C(O)NH(CI-3alkyl) and -C(O)N(Ci-3alkyl)2.218. Each R12is independently selected from: halo (e.g. fluoro or chloro), -CN, C1.3 alkyl and -OC1.3 alkyl. Thus it may be that each R12is independently selected from: halo, - CN and C1.3 alkyl. Thus it may be that each R12is independently selected from: fluoro, chloro, -CN, methyl and methoxy. For example each R12is independently selected from: fluoro, chloro, -CN and methyl.219. R12is as defined in any one of 209 to 217, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, or cycloalkyl is substituted by one or more R14.220. Each R14is independently selected from: halo, =0, -CN, -OR9A, -NR9AR9B, C(O)R9A, - C(O)OR9A, -C(O)NR9AR9Band C3-6 cycloalkyl.221. Each R14is independently selected from: halo, =0, -CN, -OR9A, -NR9AR9B, and C3-6 cycloalkyl.222. Each R14is independently selected from: halo, =0, -CN, -OR9A, and -NR9AR9B.223. Each R14is independently selected from: halo, =0, and -CN.224. Each R14is independently halo. Thus, it may be that each R14is selected from: fluoro and chloro.225. R7and R8are each independently selected from: H, Ci-e alkyl, Ci-e haloalkyl and C3-6 cycloalkyl.226. R7and R8are each independently selected from: H, C1.3 alkyl, C1.3 haloalkyl and C3 cycloalkyl.227. R7and R8are each independently selected from: H, C1.3 alkyl, and C1.3 haloalkyl.228. R7and R8are each independently selected from: H and C1.3 alkyl.229. R7and R8are as defined in 224 to 227, wherein said alkyl is substituted by one or more R13.230. Each R13is independently selected from: halo, =0, -CN, -OR9A, -NR9AR9B, C(O)R9A, - C(O)OR9A, -C(O)NR9AR9Band C3-6cycloalkyl.231. Each R13is independently selected from: halo, =0, -CN, -OR9A, -NR9AR9B, and C3-6 cycloalkyl.232. Each R13is independently selected from: halo, =0, -CN, -0R9A, and -NR9AR9B.233. Each R13is independently selected from: halo, =0, and -CN.234. Each R13is independently halo. Thus, it may be that each R13is selected from: fluoro and chloro.235. Each R4A, R4B, R9Aand R9Bis independently at each occurrence selected from: H, and C1.4 alkyl.236. Each R4A, R4B, R9Aand R9Bis independently at each occurrence selected from: H, methyl, and ethyl.237. Each R4A, R4B, R9Aand R9Bis independently at each occurrence selected from: H and methyl.238. Any -NR7R8, -NR4AR4B, and -NR9AR9Bwithin a substituent may form a 4-membered heterocyclyl. Thus it may be that a -NR7R8, -NR4AR4Bor -NR9AR9Bwithin a substituent may form azetidine.239. Any -NR7R8, -NR4AR4B, and -NR9AR9Bwithin a substituent may form a 5-membered heterocyclyl. Thus it may be that a -NR7R8, -NR4AR4Bor -NR9AR9Bwithin a substituent may form pyrrolidinyl.240. Any -NR7R8, -NR4AR4B, and -NR9AR9Bwithin a substituent may form a 6-membered heterocyclyl. Thus it may be that a -NR7R8, -NR4AR4Bor -NR9AR9Bwithin a substituent may form piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl or 1 ,1-dioxo- thiomorpholin-4-yl.241. -NR7R8, -NR4AR4B, and -NR9AR9Bmay be as defined in any of 237 to 239, wherein said heterocyclyl is optionally substituted by one or more substituents selected from: halo, =0, C1.4 alkyl and C1.4 haloalkyl.242. -NR7R8, -NR4AR4B, and -NR9AR9Bmay be as defined in any of 237 to 239, wherein said heterocyclyl is optionally substituted by one or more substituents selected from: halo, C1.3 alkyl and C1.3 haloalkyl.243. The group of the formula:244. The group of the formula:245. The group of the formula:246. The group of the formuladefined in any of 242 to 244 and R3is methyl or ethyl.247. a is an integer from 0 to 5.248. a is an integer from 0 to 3.249. a is 3.250. a is 2.251. a is 1.252. a is 0.253. Each x is independently 0.254. Each x is independently 1.255. Each x is independently 2.256. y is 0.257. y is 1.258. y is 2.259. y is 3.260. y is 4.261. y is 5.262. y is 6.263. Ring B is as defined for R6ain any of 125 to 174.264. R5is C1.3 alkyl and Ring B is as defined for R6ain any of 125 to 174.265. R5is methyl and Ring B is as defined for R6ain any of 125 to 174.266. R5is ethyl and Ring B is as defined for R6ain any of 125 to 174.267. R6is selected from: C1.4 alkyl, -C2-4 alkyl-OR9A, -CH2-R6aand R6a, wherein R6ais as defined in any one of 125 to 174.268. R6is selected from: C1.4 alkyl, -C2-4 alkyl-OR9A, -CH2-R6aand R6a, wherein R6ais selected from C3-6 cycloalkyl and a 6-membered heteroaryl containing 1 or 2 ring nitrogen atoms, wherein said C3-6 cycloalkyl and 6-membered heteroaryl containing 1 or 2 ring nitrogen atoms are each independently optionally substituted by one or more R12.269. R6is selected from: C1.4 alkyl, -C2-4 alkyl-OH, -C2-4 alkyl-OCHs, C3-6 cycloalkyl and pyridyl, wherein said C3-6 cycloalkyl and pyridyl are each independently optionally substituted by one or more R12.270. R6is selected from: C1.4 alkyl, -C2-4 alkyl-OH, -C2-4 alkyl-OCHs, cyclobutyl and 3-pyridyl, wherein said cyclobutyl and 3-pyridyl are each independently optionally substituted by one or more R12.271. R6is selected from: selected from: methyl, ethyl,272. R5is C1.4 alkyl and R6is selected from: C1.4 alkyl, -C2-4 alkyl-OR9A, -CH2-R6aand R6a, wherein R6ais as defined in any one of 125 to 174.273. R5is methyl and R6is selected from: C1.4 alkyl, -C2-4 alkyl-OR9A, -CH2-R6aand R6a, wherein R6ais as defined in any one of 125 to 174.274. R5is ethyl and R6is selected from: C1.4 alkyl, -C2-4 alkyl-OR9A, -CH2-R6aand R6a, wherein R6ais as defined in any one of 125 to 174.275. R5is methyl and R6is as defined in any one of 266 to 273.276. R5is ethyl and R6is as defined in any one of 266 to 273. 277. Ring A is selected from:278. It may be that compounds according to the invention comprise aR5R5R6structure, wherein the structure R6is selected from:

[0154] In certain embodiments, the compound is a compound according to any of formulae (I), (la), (II), (III), (XII), (XIII), (XXII), and (XXIII), wherein R1is selected from: -CH2F, -CHF2and -CF3. Suitably in this embodiment R2is H. Suitably in this embodiment, R3is selected from: methyl, ethyl, and -CH2CH2F.

[0155] In these embodiments it may be that R3is methyl or ethyl.

[0156] In these embodiments it may be that R3is methyl. In these embodiments it may be that R3is ethyl. In these embodiments it may be that R3is -CH2CH2F.

[0157] In certain embodiments, the compound is a compound according to any of formulae (I), (la), (II), (III), (XII), (XIII), (XXII), and (XXIII), wherein R1is methyl or ethyl. Suitably in this embodiment R2is H. Suitably in this embodiment, R3is selected from: methyl, ethyl, and - CH2CH2F.

[0158] In these embodiments it may be that R1is methyl.

[0159] In these embodiments it may be that R3is methyl or ethyl.

[0160] In these embodiments it may be that R3is methyl. In these embodiments it may be that R3is ethyl. In these embodiments it may be that R3is -CH2CH2F.

[0161] In certain embodiments in any of the compound of any of formulae (I), (la), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X) and (XI): R2(when present) is H; R3is selected from: methyl, ethyl and -CH2CH2F; and Ring A is as defined in any of 181 to 193 and 276.

[0162] In these embodiments it may be that Ring A is optionally substituted by one or more (e.g. 1 or 2) R6bwherein each R6bis independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, -OR7, -NR7R8, -C(O)R7, -C(O)OR7, -C(O)NR7R8. Thus it may be that Ring A is optionally substituted by one or more (e.g. 1 or 2) R6b, wherein each R6bis independently selected from: F, Cl, -CN, methyl, methoxy, -NH2, -NH(Me), -NH(Et), -N(Me)2 -C(O)Me, - C(O)NH2, -C(O)NH(Me), -C(O)N(Me)2 and -C(O)OMe. It may be that Ring A is optionally substituted by one or more (e.g. 1 or 2) R6b, wherein each R6bis independently selected from: F, Cl, -CN, methyl and methoxy. It may be that Ring A is optionally substituted by one or more (e.g. 1 or 2) R6b, wherein each R6bis independently selected from: F, Cl, -CN, methoxy and methyl.

[0163] In these embodiments it may be that R3is methyl or ethyl. In these embodiments it may be that R3is methyl. In these embodiments it may be that R3is ethyl. In these embodiments it may be that R3is -CH2CH2F.

[0164] In certain embodiments in any of the compound of any of formulae (XXII), (XXIII), (XXIV)), (XXV), (XXVI), (XXVII), (XXVIII), (XXIX), (XXX), (XXXI), (XXXII) and (XXXIII): R2(when present) is H; R3is selected from: methyl, ethyl and -CH2CH2F; and Ring B is as defined in 262.

[0165] In these embodiments it may be that y is 0 or 1. Thus it may be that y is 0. It may be that y is 1 .

[0166] In these embodiments it may be that Ring B is optionally substituted by one or more (e.g. 1 or 2) R12wherein each R12is independently selected from: halo, -CN, -NO2, C1.6 alkyl,Ci-6haloalkyl, -OR7, -NR7R8, -C(O)R7, -C(O)OR7, -C(O)NR7R8. Thus it may be that Ring B is optionally substituted by one or more (e.g. 1 or 2) R12, wherein each R12is independently selected from: F, Cl, -CN, methyl, methoxy, -NH2, -NH(Me), -NH(Et), -N(Me)2 -C(O)Me, - C(O)NH2, -C(O)NH(Me), -C(O)N(Me)2 and -C(O)OMe. It may be that Ring B is optionally substituted by one or more (e.g. 1 or 2) R12, wherein each R12is independently selected from: F, Cl, -CN, methyl and methoxy. It may be that Ring B is optionally substituted by one or more (e.g. 1 or 2) R12, wherein each R12is independently selected from: F, Cl, -CN, and methyl.

[0167] In these embodiments it may be that R3is methyl or ethyl. In these embodiments it may be that R3is methyl. In these embodiments it may be that R3is ethyl. In these embodiments it may be that R3is -CH2CH2F.

[0168] In these embodiments it may be that R5is not H.

[0169] In these embodiments it may be that R5is as defined in any one of 80 to 85. Thus it may be that R5is methyl. It may be that R5is ethyl.

[0170] In certain embodiments in any of the compound of any of formulae (I), (la), (XXXIV), (XXXV), (XXXVI), (XXXVII), (XXXVIII), (XXXIX), (XXXX), (XXXXI), (XXXXII) and (XXXXIII): R2(when present) is H; R3is selected from: methyl, ethyl and -CH2CH2F; and R6is as defined in any one of 117 to 124 .

[0171] In these embodiments R6is C1.6 alkyl substituted by one or more R10.

[0172] In these embodiments it may be that R6is C1.6 alkyl substituted by -OR9Aand optionally one or more further R10. Suitably, it may be that in these embodiments, R6is C1.6 alkyl substituted by -OMe and optionally one or more further R10. It may be that in these embodiments, R6is C2-4 alkyl substituted by -OMe. Thus it may be that R6is 2-methoxyethyl.

[0173] In these embodiments it may be that R3is methyl or ethyl. In these embodiments it may be that R3is methyl. In these embodiments it may be that R3is ethyl. In these embodiments it may be that R3is -CH2CH2F.

[0174] In these embodiments it may be that R5is not H.

[0175] In these embodiments it may be that R5is as defined in any one of 80 to 85. Thus it may be that R5is methyl. It may be that R5is ethyl.

[0176] In certain embodiments in any of the compound of any of formulae (XXXXIV), (XXXXV), (XXXXVI), (XXXXVII), (XXXXVIII), (XXXXIX), (XXXXX), (XXXXXI), (XXXXXII) and (XXXXXIII): R3is selected from: methyl, ethyl and -CH2CH2F; and R12is as defined in any one of 209 to 218.

[0177] In these embodiments it may be that R3is methyl or ethyl. In these embodiments it may be that R3is methyl. In these embodiments it may be that R3is ethyl. In these embodiments it may be that R3is -CH2CH2F.

[0178] In these embodiments it may be that R5is not H.

[0179] In these embodiments it may be that R5is as defined in any one of 80 to 85. Thus it may be that R5is methyl. It may be that R5is ethyl.

[0180] In certain embodiments in any of the compound of any of formulae (I), (la), (II), (III), (IV), (IX), (XII), (XIII), (XIV), (XIX), (XXII), (XXIII), (XXIV), (XXIX), (XXIV), (XXXIX), (XXXXIV) and (XXXXIX): R3is selected from: methyl, ethyl and -CH2CH2F; and the of the formula

[0181] In these embodiments it may be that R3is methyl or ethyl. In these embodiments it may be that R3is methyl. In these embodiments it may be that R3is ethyl. In these embodiments it may be that R3is -CH2CH2F.

[0182] In an embodiment, the compound of the invention does not contain an oxo (=0) substituent adjacent to a ring nitrogen in Ring A. Thus in this embodiment Ring A does not contain a lactam (-N(R)C(O)-) in the ring structure.

[0183] In one embodiment Ring A in a compound of the invention is not substituted by - OR7.

[0184] In another embodiment there is provided a compound selected from Compound List 1 , or a pharmaceutically acceptable salt thereof:Compound List 1

[0185] In another embodiment there is provided a compound selected from any one of the Examples herein, or a pharmaceutically acceptable salt thereof.

[0186] Particular compounds of the invention are those that have an pICso of greater than 5.5, preferably those with a pICso of 6, still more preferably those with a pICso of 7 or more when measured in the Human Cav2.3 channel calcium-influx assay described in the Examples.

[0187] Suitably the compounds of the invention exhibit a favourable pharmacokinetic and / or pharmacodynamic profile, for example, one or more of favourable oral bioavailability, metabolic stability, plasma half-life.PHARMACEUTICAL COMPOSITIONS

[0188] In accordance with another aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, with the proviso that the compounds in List A are not excluded.

[0189] It may be that the pharmaceutical composition comprises a compound selected from a compound according to any of formulae (I) to (XXXXXIII), or a pharmaceutically acceptable salt thereof.

[0190] In some embodiments the pharmaceutical composition does not include a compound from List A.

[0191] Conventional procedures for the selection and preparation of suitable pharmaceutical compositions are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.

[0192] 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 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).

[0193] 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.

[0194] 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.

[0195] 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 particular route of administration. For example, a formulation intended for oral administrationto 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.

[0196] 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.

[0197] In using a compound of the invention for therapeutic or prophylactic purposes it will 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 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 about 0.5 mg to 0.5 g of a compound of the invention. In a particular embodiment the compound of the invention is administered parenterally, for example by intravenous administration. In another particular embodiment the compound of the invention is administered orally.THERAPEUTIC USES AND APPLICATIONS

[0198] In this section describing therapeutic uses, applications and methods of treatment reference to “a compound of the invention” includes compounds according to any to any of formulae (I) to (XXXXXIII), or a pharmaceutically acceptable salt thereof, with the proviso that the compounds in List A are not excluded. However, in some embodiments of the uses, applications and methods of treatment described here reference to “a compound of the invention” excludes the compounds in List A.

[0199] In accordance with another aspect, the present invention provides a compound of the invention, for use as a medicament.

[0200] A further aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a disease or medical disorder mediated by Cav2.3.

[0201] Also provided is a method of preventing or treating a disease or medical disorder mediated by Cav2.3 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.

[0202] 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 Cav2.3.

[0203] 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 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 the subject a therapeutically effective amount of the compound of the invention, or pharmaceutically acceptable salt thereof.

[0204] In certain embodiments the disease or medical disorder mediated by Cav2.3 is selected from: a neurodegenerative disease, a neurodevelopmental disorder, epilepsy, an endocrine disorder, cerebral vasospasm, and pain.

[0205] In certain embodiments there is provided a compound of the invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or medical disorder selected from: a neurodegenerative disease, a neurodevelopmental disorder, epilepsy, an endocrine disorder, cerebral vasospasm, and pain.Neurodegenerative Diseases

[0206] In some embodiments the disease or medical disorder is a neurodegenerative disease. For example the disease or medical disorder is selected from: Parkinson's disease, Alzheimer's disease, Huntington's disease, dystonia, amyotrophic lateral sclerosis (ALS), multiple sclerosis, and age-related neurodegeneration. In a particular embodiment a compound of the invention is for use in the treatment of Parkinson’s disease.

[0207] It may be that a compound of the invention provides a neuroprotective effect in subjects with a neurodegenerative disease. Accordingly, a compound of the invention may be for use in the neuroprotective treatment of a neurodegenerative disease (e.g. Parkinson’s disease). In some embodiments a compound of the invention may be for use in preventing or delaying the onset of symptoms associated with a neurodegenerative disease. Thuscompound of the invention may be for use in preventing or reducing neurodegeneration associated with a neurodegenerative disease.

[0208] In certain embodiments a compound of the invention is for use in preventing or inhibiting degeneration of dopaminergic neurons in a subject with a neurodegenerative disease (e.g. Parkinson’s disease). Accordingly, it may be that a compound of the invention is for use in the prevention or inhibition of degeneration of dopaminergic substantia nigra (SN) neurones in a subject with Parkinson’s disease.

[0209] In certain embodiments a compound of the invention is for use in the treatment or prevention of one or more symptoms of a neurodegenerative disease. For example, a compound may be for use in the treatment or prevention of one or more symptoms of Parkinson’s disease selected from: tremor, bradykinesia, dystonia, stiffness, balance, coordination, cognitive impairment, and speech impairment.Neurodevelopmental Disorders

[0210] In certain embodiments a compound of the invention is for use in the treatment of a neurodevelopmental disorder. In certain embodiments the neurodevelopmental disorder is selected from: CACNA1E Gain-of-function Syndrome (DEE69), CDKL5 Deficiency (DEE2), Fragile X syndrome, Down syndrome, Rett syndrome, Angelman syndrome, autism, motor disorders (e.g., developmental coordination disorder, stereotypic movement disorder and tic disorders), and attention deficit hyperactivity disorder (ADHD).

[0211] As discussed in the introduction, Cav2.3 channels are associated with developmental and epileptic encephalopathies (DEEs). The term “DEE” refers to a group a heterogeneous group of rare neurodevelopmental disorders, characterised by (a) early- onset seizures that are often intractable, (b) electroencephalographic abnormalities, (c) developmental delay or regression and (d) in some cases, early death. DEE is classified by the 2017 International League Against Epilepsy (I LAE) Classification of the Epilepsies as an epilepsy associated with developmental impairment that may be due to both the underlying etiology (developmental encephalopathy) and superimposed epileptic activity (epileptic encephalopathy) (Scheffer et al. I LAE classification of the epilepsies: position paper of the I LAE commission for classification and terminology. Epilepsia. 2017;58:512-21).

[0212] In certain embodiments a compound of the invention is for use in the prevention or treatment of a developmental and epileptic encephalopathy. In certain embodiments a compound of the invention is for use in the prevention or treatment of a monogenic developmental and epileptic encephalopathy In certain embodiments a compound of the invention is for use in the treatment or prevention of CACNA1E Gain-of-function Syndrome (DEE69), CDKL5 Deficiency (DEE2), DEE9 (caused by mutation in the PCDH19 gene),DEE11 (SCN2A gain of function), DEE13 (SCN8A gain of function), Dravet syndrome (DEE6A) or a DEE caused by or associated with a loss of function of GABAa receptors (e.g. DEE19, DEE43, DEE45, DEE59, DEE74, DEE78, DEE79 or DEE92).

[0213] In one embodiment a compound of the invention is for use in the treatment or prevention of DEE is Dravet syndrome (DEE6A). In a particular embodiment a compound of the invention is for use in the treatment or prevention of CACNA1E Gain-of-function Syndrome (DEE69) or CDKL5 Deficiency (DEE2).

[0214] In another embodiment a compound of the invention is for use in the treatment of a DEE caused by or associated with a loss of function of GABAa receptors. For example a compound of the invention is for use in the treatment of a DEE selected from: DEE19, DEE43, DEE45, DEE59, DEE74, DEE78, DEE79 and DEE92.

[0215] The genetic phenotypes and clinical features of the DEEs described herein are set out in entry #30008 in the Online Mendelian Inheritance in Man® (OMIM) database (https: / / www.omim.org / about).Epilepsy

[0216] In certain embodiments a compound of the invention is for use in the treatment of epilepsy.

[0217] Epilepsy is a chronic brain disease in which unprovoked epileptic seizures are the predominant feature. Epileptic seizures can vary from brief and nearly undetectable to long periods of vigorous shaking. Epilepsy and its related syndromes may be classified according to whether seizures are partial or generalized, and whether the aetiology is idiopathic or symptomatic or cryptogenic. The term “epilepsy” comprises both generalized and focal forms, with generalized epilepsy affecting both hemispheres while focal epilepsy includes unifocal and multifocal disorders as well as seizures involving one hemisphere.

[0218] 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. Cryptogenic epilepsy occurs when the cause of epilepsy in a subject has not been identified despite investigation. Symptomatic epilepsy is epilepsy with a known cause. Causes of symptomatic epilepsy include, for example, brain injury, an bacterial or viral infection (e.g. meningitis), stroke or a tumour.

[0219] In some embodiments a compound of the invention is for use in the treatment of 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 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 non-familial neonatal-infantile seizures, Gastaut syndrome, sleep-related hypermotor epilepsy, and temporal lobe epilepsy.

[0220] In some embodiments a compound of the invention is for use in the treatment or prevention of drug-resistant epilepsy. Drug-resistant epilepsy (also known as “uncontrolled,” “intractable” or “refractory” epilepsy) refers to epilepsy that fails to respond to, or relapses following treatment with an anti-epileptic therapy. Accordingly, in subjects with drugresistant epilepsy seizures persist despite treatment with one or more anti-epileptic therapies. For example, a subject may not respond to, or relapses after treatment with one or more anti-epileptic therapy (for example the subject does not respond to, or relapses after treatment with at least two anti-epileptic therapies). In certain embodiments the subject fails to respond to, or relapses after treatment with one or more anti-epileptic drug (AED), for example one or more of the AEDs listed herein in relation to combination therapies. The drug-resistant epilepsy may be any of the forms of epilepsy described herein that is, or has become resistant to treatment with one or more (e.g. at least two) anti-epileptic therapy. In some embodiments the drug-resistant epilepsy is a drug-resistant focal epilepsy.

[0221] In certain embodiments a compound of the invention is for use in preventing or treating seizures. Thus in certain embodiments a compound of the invention is for use in preventing or treating an epileptic seizure. For example, a compound of the invention may reduce the occurrence of epileptic seizures, reduce the severity and / or duration of epileptic seizures, or reduce the frequency of seizures. In some embodiments a compound of the invention is for use in the prevention or treatment of partial, generalized, convulsive and non- convulsive seizures. In some embodiments a compound of the invention is for use in preventing or treating a seizure selected from: tonic-clonic, tonic, clonic, myoclonic, absence, and atonic seizures.Endocrine Disorders

[0222] In certain embodiments a compound of the invention is for use in the treatment of an endocrine disorder. For example, a compound of the invention may be for use in the treatment of an endocrine disorder selected from: diabetes (e.g., treating glucose-induced insulin release, glucose-mediated glucagon suppression, or glucose-mediated somatostatin-release), acromegaly, Addison’s disease, Cushing’s syndrome, Graves’disease, Hashimoto’s thyroiditis, hyperthyroidism, hypothyroidism (underactive thyroid), and prolactinoma.Pain

[0223] 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 treatment of chronic pain, inflammatory pain, neuropathic pain (e.g. peripheral neuropathic pain or central neuropathic pain), or nociceptive pain.Cerebral

[0224] Subjects which suffer a cerebral aneurism or aneurysmal subarachnoid haemorrhage (bleeding on the surface of the brain) often survive the initial trauma. However, often within a few days to two weeks subjects experience cerebral vasospasm, a constriction, or tightening, of arteries in the brain. Cerebral vasospasm restricts blood flow to the brain and may subsequently lead to the death of blood-starved brain tissue resulting in cerebral infarction. Expression of Cav2.3 may be increased following a cerebral aneurism or aneurysmal subarachnoid haemorrhage and may be implicated in cerebral vasospasm (Wang et al., supra). Accordingly, in some embodiments a compound of the invention is for use in the treatment or prevention of cerebral vasospasm. For example a compound of the invention is for use in the treatment or prevention of cerebral vasospasm in a subject who has suffered a cerebral aneurism or aneurysmal subarachnoid haemorrhage. In some embodiments a compound of the invention is for use in the treatment or prevention of cerebral infarction.

[0225] Without wishing to be bound by theory it is expected that the selective modulation of Cav2.3 will provide compounds with a desirable therapeutic effect whilst avoiding or minimising the side effects associated with a non-selective Cav2.3 antagonist.

[0226] In certain embodiments such selective compounds may be used in the treatment or prevention of any of the diseases or medical disorders described herein.Combination Therapies

[0227] The compounds of the invention may be used alone to provide a therapeutic effect. The compounds of the invention may also be used in combination with one or more additional therapeutic agents.

[0228] In some embodiments the additional therapeutic agent is selected from one or more of:• an anti-epileptic drug (AED), for example acetazolamide, benzodiazepine, cannabadiols, carbamazepine, clobazam, clonazepam, diazepam, eslicarbazepine acetate, ethosuximide, ethotoin, felbamate, fenfluramine, fosphenytoin, gabapentin, ganaxolone, huperzine A, lacosamide, lamotrigine, levetiracetam, nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin, potassium bromide, pregabalin, primidone, retigabine, rufinamide, valproic acid, sodium valproate, soticlestat, stiripentol, tiagabine, topiramate, vigabatrin, or zonisamide.® a drug for the treatment of Parkinson’s disease, for example a dopamine mimetic (substances which regulate / modulate the dopamine metabolism, e.g., levodopa or carbidopa); a dopamine receptor agonist (e.g. pramipexole, ropinirole, rotigotine or apomorphine); a monaminoxidase inhibitor, for example an MAO B inhibitor (e.g. selegiline, rasagiline or safinamide); a catechol O-methyltransferase (COMT) inhibitor (e.g. entacapone, opicapone or tolcapone); an anticholinergic (e.g. benztropine or trihexyphenidyl);adamantane; or an adenosine A2A receptor antagonist (e.g. istradefylline).

[0229] Such combination treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within a therapeutically effective dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.

[0230] Herein, where the term “combination” is used it is to be understood that this refers to simultaneous, separate or sequential administration. In one aspect of the invention “combination” refers to simultaneous administration. In another aspect of the invention “combination” refers to separate administration. In a further aspect of the invention “combination” refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination.

[0231] In some embodiments in which a combination treatment is used, the amount of the compound of the invention and the amount of the other pharmaceutically active agent(s) are, when combined, therapeutically effective to treat a targeted disorder in the patient. In this context, the combined amounts are “therapeutically effective amount” if they are, when combined, sufficient to reduce or completely alleviate symptoms or other detrimental effects of the disorder; cure the disorder; reverse, completely stop, or slow the progress of the disorder; or reduce the risk of the disorder getting worse. Typically, such amounts may be determined by one skilled in the art by, for example, starting with the dosage range describedin this specification for the compound of the invention and an approved or otherwise published dosage range(s) of the other pharmaceutically active compound(s).Biological Assays

[0232] The effect of a compound of the invention on inhibiting calcium ion influx into cells via human Cav2.3 channels can be assessed using the human Cav2.3 channel calcium- influx assay described in the examples section. The effects of compounds of the invention inhibiting the function of Cav2.3 ion channels in-vitro can be assessed by, for example using whole cell patch clamp methods such as that described in the example section.

[0233] The effects of the compounds blocking R-type calcium current with whole cell patch clamp electrophysiology in substantia nigra dopamine neurons in an ex vivo brain slice can be assessed using the methods described in Siller et al., Elife, 11:e67464 (2022) https: / / doi.org / 10.7554 / eLife.67464.

[0234] Effects of the compounds on diseases or medical disorders mediated by Cav2.3 may be assessed using suitable in-vitro and in-vivo models for such diseases and medical disorders. For example, the effects of a compound of the invention on Parkinson’s disease may be assessed using the methods and models described in WO2018 / 228692. Other suitable models for Parkinson’s disease include, for example, the MitoPark mouse model described in Gaiter et al. (Genes Brain Behav. 2010 March 1; 9(2): 173-181); and the SNCA- OVX transgenic mouse model described in Janezic et al. (Proceedings of the National Academy of Sciences, 2013, September, 201309143 DOI: 10.1073 / pnas.1309143110).

[0235] Suitable models for testing a compound of the invention for the treatment of seizures or epilepsy include, for example, one or more of the models described in Ldscher (Seizure, 2011 , (20), 359-368). Alternatively a compound of the invention may be tested in the Maximal Electroshock Stimulation (MES) model described in Kehne et al, Neurochemistry Research 42 : 1894-1903 (2017); https: / / doi.org / 10.1007 / s11064-017-2275-z.Further Embodiments

[0236] The following embodiments further exemplify the invention.1. A compound of the Formula (I), or a pharmaceutically acceptable salt thereof:wherein:R1is selected from: Ci-e alkyl, C3-6 cycloalkyl, and Cs-e cycloalkyl-Ci-e alkyl-, wherein R1is substituted by at least one fluorine, optionally wherein one or more H in R1is substituted by D;R2is selected from: H, D, Ci-e alkyl and Ci-e haloalkyl, optionally wherein one or more H in R2is substituted by D; orR1and R2together with the carbon atom to which they are attached form a C3-6 cycloalkyl substituted with at least one fluorine;R3is selected from: H, Ci-e alkyl and Ci-e haloalkyl; optionally wherein one or more H in R3is substituted by D; each R4is independently selected from: halo, -CN, -NO2, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, -OR4A, -S(O)XR4A, -NR4AR4B, -C(O)R4A, - OC(O)R4A, -C(O)OR4A, -NR4AC(O)R4B, -C(O)NR4AR4B, -NR4AC(O)OR4B, -OC(O)NR4AR4B, - NR4ASO2R4B, and -SO2NR4AR4B, wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R9;R5is selected from: H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and Co-6 alkylene- R5a; wherein said Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci-e alkylene is optionally substituted by one or more R10;R6is selected from: Ci-e alkyl, Ci-e haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and Co-6 alkylene- R6a; wherein said Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci-e alkylene is optionally substituted by one or more R10; orR5and R6, together with the nitrogen atom to which they are attached form Ring A, wherein Ring A is selected from: a 4- to 12 membered heterocyclyl group and a 5- to 12- membered heteroaryl group; wherein Ring A is optionally substituted by one or more R6b; each R6bis independently selected from: halo, -CN, -NO2, =0, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, -OR7, -S(O)XR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, - NR7SO2R8, and -SO2NR7R8; wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl is optionally substituted by one or more R11;R5aand R6aare each independently selected from: C3-6 cycloalkyl, 4- to 12 membered heterocyclyl, 5- to 12-membered heteroaryl, and Ce- aryl; wherein R5aand R6aare optionally substituted by one or more R12;R7and R8are each independently selected from: H, Ci-e alkyl, Ci-e haloalkyl and C3-6 cycloalkyl; wherein said Ci-e alkyl and C3-6 cycloalkyl is optionally substituted by one or more R13; each R9, R10, R11, R13, and R14is independently selected from: halo, =0, -CN, -OR9A, - S(O)xR9A, -NR9AR9B, C(O)R9A, -OC(O)R9A, -C(O)OR9A, -NR9AC(O)R9B, -C(O)NR9AR9Band C3-6 cycloalkyl; each R12is independently selected from: halo, -CN, -NO2, =0, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, -OR7, -S(O)XR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, - NR7SO2R8, and -SO2NR7R8; wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl is optionally substituted by one or more R14;R4A, R4BR9A, and R9Bare at each occurrence independently selected from: H, C1.4 alkyl and C1.4 haloalkyl; and wherein any -NR7R8, -NR4AR4B, and -NR9AR9Bwithin 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, =0, C1.4 alkyl and C1.4 haloalkyl; each x is independently 0, 1 , or 2; and a is 0, 1 , 2, 3, 4 or 5.2. The compound according to Embodiment 1 , wherein R5is selected from: C1.3 alkyl, C1.3 haloalkyl, and C0-3 alkylene-R5a; optionally wherein said alkyl and alkylene is substituted by one or more R10.3. The compound according to Embodiment 1 , wherein R6is selected from: C1.3 alkyl, C1.3 haloalkyl, and C0-3 alkylene-R6a; optionally wherein said alkyl and alkylene is substituted by one or more R10.4. The compound according to Embodiment 1 , wherein the compound is a compound of the formula (II), or a pharmaceutically acceptable salt thereof:optionally wherein Ring A is substituted with one or more R6b.5. The compound according to Embodiment 1 or Embodiment 4, wherein Ring A is 4- to 10-membered heterocyclyl; optionally wherein Ring A is substituted with one or more□ 6b6. The compound according to Embodiment 1 , or Embodiments 4 or 5, wherein Ring A is selected from:7. The compound according to Embodiment 1 , wherein the compound is a compound of the formula (VII), or a pharmaceutically acceptable salt thereof:wherein b is 0, 1 , 2, 3, 4, 5, or 6.8. The compound according to Embodiment 1 , wherein the compound is a compound of the formula (XII), or a pharmaceutically acceptable salt thereof:whereinRing B is selected from: C3-6 cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl, and Ce- aryl; wherein Ring B is optionally substituted by one or more R12; and y is 0, 1 , 2, 3, 4, 5, or 6.9. The compound according to any one of Embodiments 1 to 8, wherein the group of the formulaselected from:10. The compound according to any one of Embodiments 1 to 8, wherein the group of the formulaselected from:11. The compound according to any one of Embodiments 1 to 8, the group of the12. The compound according to any one of Embodiments 1 to 8, wherein the group of the formula-fluorophenyl.13. The compound according to any one of Embodiments 1 to 12, wherein R3is selected from: methyl, -CD3, ethyl, and 2-fluoroethyl.14. The compound according to any one of Embodiments 1 to 12, wherein R3is selected from: methyl and ethyl.15. The compound according to any one of Embodiments 1 to 14, wherein R1is selected from: Ci-e alkyl and C3-6 cycloalkyl, wherein R1is substituted by at least one fluorine.16. The compound according to any one of Embodiments 1 to 14, wherein R1is selected from: CH2F, -CHF2, and -CF3.17. The compound according to any one of Embodiments 1 to 14, wherein R1is -CF3.18. The compound according to any one of Embodiments 1 to 17, wherein R2is selected from: H and methyl.19. The compound according to any one of Embodiments 1 to 17, wherein R2is H.20. The compound of any one of Embodiments 1 to 19, wherein the group of the formula:21. The compound of any one of Embodiments 1 to 19, wherein the group of the formula:22. A compound selected from: Compound List 1 in the description, or a pharmaceutically acceptable salt thereof.23. A pharmaceutical composition comprising a compound according to any one of Embodiments 1 to 22, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.24. A compound according to any one of Embodiments 1 to 22, or a pharmaceutically acceptable salt thereof, for use as a medicament.25. A compound according to any one of Embodiments 1 to 22, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or medical disorder mediated by Cav2.3.26. A method of treating a disease or medical disorder mediated by Cav2.3 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of Embodiments 1 to 22, or a pharmaceutically acceptable salt thereof.27. A compound according to any one of Embodiments 1 to 22, or a pharmaceutically acceptable salt thereof, for use in in the treatment of a disease or medical disorder selected from: a neurodegenerative disease, a neurodevelopmental disorder, epilepsy, an endocrine disorder, cerebral vasospasm, and pain.28. A compound according to any one of Embodiments 1 to 22, or a pharmaceutically acceptable salt thereof, for use in a neuroprotective treatment of a neurodegenerative disease.29. A compound according to any one of Embodiments 1 to 22, or a pharmaceutically acceptable salt thereof, for use in the treatment of Parkinson’s disease.30. A compound according to any one of Embodiments 1 to 22, or a pharmaceutically acceptable salt thereof, for use in a preventing or inhibiting degeneration of dopaminergic neurons in a subject with Parkinson’s disease.31. A compound according to any one of Embodiments 1 to 22, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of epilepsy; optionally wherein the epilepsy is a drug-resistant epilepsy.32. A compound according to any one of Embodiments 1 to 22, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a developmental and epileptic encephalopathy; optionally wherein the developmental and epileptic encephalopathy is a monogenic developmental and epileptic encephalopathy (e.g. CACNA1E Gain-of-function Syndrome (DEE69), CDKL5 Deficiency (DEE2), Dravet syndrome (DEE6A), DEE9 (caused by mutation in the PCDH19 gene), DEE11 (SCN2A gain of function), DEE13, DEE19, DEE43, DEE45, DEE59, DEE74, DEE78, DEE79 or DEE92).Synthesis

[0237] 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 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.

[0238] 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 reaction conditions utilised.

[0239] 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 illustrated which are within the ordinary skill of an organic chemist.

[0240] It will be appreciated that during the synthesis of the compounds of the invention in the processes defined below, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed.

[0241] For examples of protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule.

[0242] Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.

[0243] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as acetyl or trifluoroacetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an acyl group such as a terf-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example BFs.OEt2. A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0244] A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, or sodium hydroxide, or ammonia. Alternatively, an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

[0245] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a f-butyl group which may beremoved, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.

[0246] Resins may also be used as a protecting group.General Synthetic Routes

[0247] Compounds of formula (v) may be prepared according to General Scheme 1 :wherein Ring A, R1, R2, R4and a are as defined above for any of formulae (I) to (XXXXXIII), except that any functional group is protected, if necessary; and Z is halo (e.g. I).

[0248] Oxazolidine protected sulfonamide compound (ii) may be obtained by reaction of the respective amine derivatives (i) in a sulfur-nitrogen bond forming reaction in an inert atmosphere in the presence of chlorosulfonyl isocyanate and 2-bromoethanol in the presence of organic base such as, TEA, DIPEA, NMM, etc. The reaction may be performed in a suitable solvent, such as, acetonitrile, 1 ,4-dioxane, toluene, benzene, DMF, DME, DMA solution preferably at temperatures between 0 °C and 100 °C.

[0249] Reaction of compounds of formula (ii) with an amine or it’s salt (iii), with or without base, under thermal condition, microwave irradiation condition preferably at temperatures between room temperature and 150 °C. The reaction may be performed in a suitable solvent, such as, acetonitrile, 1 ,4-dioxane, toluene, benzene, DME, DMA solvent and optionally in the presence of at least one suitable base thereof. Non-limiting examples of such reaction promoters include DIPEA, TEA, pyridine, NMM, 2,6-lutidine, DMAP or a functional derivative thereof.

[0250] Reaction of compounds of formula (iv) with R3-Z (e.g an alkylating reagent), is preferably carried out in the presence of a inorganic base under thermal condition preferably at temperatures between room temperature and 120 °C. The reaction of a compound of formula (iv), may be carried out in at least one reaction-inert solvent. Non-limiting examples of bases include K2CO3, CS2CO3, NaH or a functional derivative thereof. Suitable examples of reaction-inert solvents include, for example, one or more of DMF, DMSO or acetonitrile.

[0251] Analogous methods to those described in General Scheme 1 may be used to prepare compounds of the invention wherein the moiety -NR5R6is non-cyclic by reacting can by prepared with a compound of formula (ii) and a compound of formula (iiia):wherein R1, R2, R3, R4, R5, R6and a are as defined above for any of formulae (I) to (XXXXXIII), except that any functional group is protected, if necessary; Z is halo (e.g. I), and R’ is H or methyl.

[0252] Compounds of formula (v) may be prepared according to General Scheme 2:General Scheme 2 wherein R1, R2, R3, R4, R5, R6and a are as defined above for any of formulae (I) to (XXXXXIII), except that any functional group is protected, if necessary; Lg is a suitable leaving group (e.g. halo, such as Cl); and Z is halo (e.g. I).

[0253] The reaction of the compound of the formula (vi) with the compound of formula (vii) is suitably carried out in the presence of a suitable base. Examples of bases include DI PEA, TEA, pyridine, NMM, 2,6-lutidine, DMAP or a functional derivative thereof. The reaction is suitably performed at room temperature. The reaction may be performed in a suitable solvent, such as, DCM or THF.

[0254] Reaction of compounds of formula (viii) with R3-Z may be carried our as described for the reaction of compounds of formula (iv) with R3-Z in General Scheme 1 .

[0255] Compounds of the formulae (vi) and (vii) are commercially available or can be prepared using analogous methods to those described in the Examples herein.

[0256] Further methods for preparing compounds of the invention are described in the Examples. Analogous methods to those described in the Examples can be used to prepare compounds of the formulae (I) to (XXXXXIII), or a pharmaceutically acceptable salts thereof.

[0257] Certain of the intermediates described in General Scheme 1 , General Scheme 2 and the Examples, and salts thereof, form a further aspect of the invention.EXAMPLESAbbreviations:Ac - acetylACN - acetonitrileBINAP - 2,2'-bis(diphenylphosphino)-1 ,1'-binaphthylBn - benzylBoc - tert-butoxycarbonylCBz - benzyloxycarbonylCPME - cyclopentyl methyl ether dba - dibenzylideneacetoneDCM - dichloromethaneDIEA - N,N-diisopropylethylamineDIPA - diisopropylamineDMAc - dimethylacetamideDMAP - 4-dimethylaminopyridineDMF - N,N-dimethylformamideDMSO - dimethylsulfoxideEDCI - 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride salt ee - enantiomeric excess eq. - equivalentsEtl - ethyl iodideGhosez's Reagent - 1-chloro-N,N-2-trimethyl-1-propenylamineHATLI - 1-[bis(dimethylamino)methylene]-1 H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphateHOAt - 1-hydroxy-7-azabenzotriazoleHPLC - high performance liquid chromatographyI PA - isopropanolKHMDS - potassium bis(trimethylsilyl)amideLC-MS - liquid chromatograph-mass spectrometerLDA - lithium diisopropylamide mCPBA - 3-chloroperbenzoic acidMeCN - acetonitrileMel - methyl iodideMS - mass spectrometryMs - mesylMTBE - methyl tert-butyl etherMW - microwaveNBS - N-bromosuccinimideNMM - N-methylmorpholineNMP - N-methyl-2-pyrrolidoneNMR - nuclear magnetic resonance o / n - overnightPd / C - palladium-on-carbonPiv - pivaloylPrep - preparative pTSA - p-toluene sulfonic acidPy - pyridine rt - retention timeRT - room temperatureRM - reaction massSFC - supercritical fluid chromatographySEM - trimethylsilylethoxymethylSPE - solid phase extractionSu - succinimideTBAB - tetrabutylammonium bromideTBAF - tetrabutylammonium fluorideTEA - triethylamineTFA - trifluoroacetic acidTFAA - trifluoroacetic anhydrideTHF - tetrahydrofuranTLC - thin-layer chromatographyUPLC- ultra-performance liquid chromatographyReagents and Conditions

[0258] Unless syntheses are given, reagents and starting materials were obtained from commercial sources. All reactions, unless otherwise stated, were carried out under an inert atmosphere of either nitrogen or argon.Compound Names

[0259] New compounds were named using ChemDraw Ultra 14.0 from CambridgeSoft. Other compounds, particularly commercial reagents, either use names generated by ChemDraw Ultra 14.0 or names commonly found in online databases and catalogues.Analytical MethodsTCGLS LCMS methodMethod 1 (K84-3 min)

[0260] The HPLC measurement was performed using Waters Acquity H Class LIPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters SQ Detector 2) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L / Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on a Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm) with a flow rate of 0.800 ml / min. Two mobile phases were used, mobile phase A: 0.05% HCOOH in water; mobile phase B: 0.05% HCOOH in ACN: Water (90:10), and they were employed to run a gradient conditions from 10 % B for 0.75 minutes, from 10 % to 50 % in 0.25 minutes, and from 50 % to 98 % in 1.00 minutes, 98 % B for 0.25 minutes and then 10 % B in 0.35 minutes and hold these conditions for 0.40 minutes in order to re-equilibrate the column (Total Run Time 3.00 minutes). An injection volume of 0.5 pl was used.Method 2 (K84 / K92-5 min)

[0261] The HPLC measurement was performed using Waters Acquity H Class UPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters SQ Detector 2) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L / Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on a Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm) with a flow rate of 0.800 ml / min. Two mobile phases were used, mobile phase A: 0.05% HCOOH in water; mobile phase B: 0.05% HCOOH in ACN: Water (90:10), and they were employed to run a gradient conditions from 5 % B for 0.75 minutes, from 5 % to 25 % in 0.75 minutes, and from 25 % to 95 % in 1.50 minutes, 95 % B for 1.00 minutes and 5 % B in 0.50 minutes and hold these conditions for 0.60 minutes in order to re-equilibrate the column (Total Run Time 5.10 minutes). An injection volume of 0.5 pl was used.Method 3 (K70 / 71 / 55 / 63 3 min)

[0262] The HPLC measurement was performed using Waters Acquity UPLC comprising a binary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-arraydetector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters ZQ SQD) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 0.40 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L / Hour. Data acquisition was performed with Mass Lynx 4.1 Software. Reversed phase HPLC was carried out on a YMC Triart C18 column (3 pm, 33 x 2.1 mm) with a flow rate of 1.00 ml / min. Two mobile phases were used, mobile phase A: 0.05% HCOOH in water; mobile phase B: 0.05% HCOOH in ACN: Water (90:10), and they were employed to run a gradient conditions from 2 % B for 0.75 minutes, from 2 % to 10 % in 0.25 minutes, and from 10 % to 98 % in 1.00 minutes, 98 % B for 0.50 minutes and then 2 % B in 0.40 minutes and hold these conditions for 0.10 minutes in order to reequilibrate the column (Total Run Time 3.00 minutes). An injection volume of 0.5 to 3 pl was used (Depending on the sample concentration).Method 4 (K03 / 04 / 05 / 06 / 07 / 08 / 72 / 78 5 min)

[0263] The HPLC measurement was performed using Shimadzu HPLC comprising a binary pump with degasser, a sample manager a dual channel UV detector and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Applied Biosystems API2000 / 2000 Trap) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 800 in 0.40 second. The ion spray voltage 5500 V in positive and 4500 V in negative ionization mode and the source temperature was maintained at 300 °C and Declusturing Potential 8-50 V depending on compound. Data acquisition was performed with Analyst 1.6.3 Software. Reversed phase HPLC was carried out on a Waters Xbridge C18 / Agilent Zorbax C18 column (5 pm, 50 x 4.6 mm) with a flow rate of 1.20 ml / min. Two mobile phases were used, mobile phase A: 10mM Ammonium Acetate in water; mobile phase B: ACN, and they were employed to run a gradient condition from 10 % B to 30 % B in 1.50 minutes, and from 30 % to 90 % in 1.50 minutes, 90 % B for 1.00 minutes and 10 % B in 1.00 minutes and hold these conditions for 0.10 minutes. Pre run Equilibration Time 0.50 min (Total Run Time 5.10 minutes). An injection volume of 1 pl to 3 pl was used (Depending on the sample concentration).Method 5 (K03 / 04 / 05 / 06 / 07 / 08 / 72 / 78 5 min Nonpolar)

[0264] The HPLC measurement was performed using Shimadzu HPLC comprising a binary pump with degasser, a sample manager a dual channel UV detector and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Applied Biosystems API2000 / 2000 Trap) was configuredwith an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 800 in 0.40 second. The ion spray voltage 5500 V in positive and 4500 V in negative ionization mode and the source temperature was maintained at 300 °C and Declusturing Potential 8-50 V depending on compound. Data acquisition was performed with Analyst 1.6.3 Software. Reversed phase HPLC was carried out on a Waters Xbridge C18 / Agilent Zorbax C18 column (5 pm, 50 x 4.6 mm) with a flow rate of 1.20 ml / min. Two mobile phases were used, mobile phase A: 10mM Ammonium Acetate in water; mobile phase B: ACN, and they were employed to run a gradient condition from 50 % B to 95 % B in 1.50 minutes, and 95 % B for 2.50 minutes and 50 % B in 1.00 minutes and hold these conditions for 0.10 minutes. Pre run Equilibration Time 0.50 min (Total Run Time 5.10 minutes). An injection volume of 1 pl to 3 pl was used (Depending on the sample concentration).Method 6 ((K03 / 04 / 05 / 06 / 07 / 08 / 72 / 78 12 min)

[0265] The HPLC measurement was performed using Shimadzu HPLC comprising a binary pump with degasser, a sample manager a dual channel UV detector and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Applied Biosystems API2000 / 2000 Trap) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 800 in 0.40 second. The ion spray voltage 5500 V in positive and 4500 V in negative ionization mode and the source temperature was maintained at 300 °C and Declusturing Potential 8-50 V depending on compound. Data acquisition was performed with Analyst 1.6.3 Software. Reversed phase HPLC was carried out on a Waters Xbridge C18 / Agilent Zorbax C18 column (5 pm, 50 x 4.6 mm) with a flow rate of 1.00 ml / min. Two mobile phases were used, mobile phase A: 10mM Ammonium Acetate in water; mobile phase B: ACN, and they were employed to run a gradient condition from 5% B for 1 .00 min, from 5% B to 50 % B in 6.00 minutes, and 50% B to 90% B in 3.00 minutes and 90 % B for 1.00 minutes and 5 % B in 1.00 minutes and hold these conditions for 0.10 minutes. Pre run Equilibration Time 0.50 min (Total Run Time 12.10 minutes). An injection volume of 1 pl to 3 pl was used (Depending on the sample concentration).Method 7 (K70 / 71 / 55 / 63 12 min)

[0266] The HPLC measurement was performed using Waters Acquity UPLC comprising a binary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters ZQ SQD) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 0.40 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was usedas the desolvation gas, the flow was 750 L / Hour. Data acquisition was performed with Mass Lynx 4.1 Software. Reversed phase HPLC was carried out on a Waters YMC Triart C18 column (3 pm, 33 x 2.1 mm) with a flow rate of 1.00 ml / min. Two mobile phases were used, mobile phase A: 0.05% HCOOH in water; mobile phase B: 0.05% HCOOH in ACN: Water (90:10), and they were employed to run a gradient conditions from 5 % B for 1.00 minutes, from 5 % to 50 % in 4.00 minutes, and from 50 % to 90 % in 3.00 minutes, 90 % B for 2.00 minutes and then 5 % B in 1.50 minutes and hold these conditions for 0.50 minutes in order to re-equilibrate the column (Total Run Time 12.00 minutes). An injection volume of 0.5 to 3 pl was used (Depending on the sample concentration).Method 8 (K83 3 min)

[0267] The HPLC measurement was performed using Waters Acquity H Class UPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters SQ Detector 2) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L / Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on a Waters Xbridge C18 column (3.5 pm, 50 x 3 mm) with a flow rate of 1.20 ml / min. Two mobile phases were used, mobile phase A: 5 mM NH4OAC in water; mobile phase B: 5 mM NH4OAC in ACN: Water (90:10), and they were employed to run a gradient conditions from 5 % B for 0.75 minutes, from 5 % to 30 % in 0.25 minutes, and from 30 % to 98 % in 1.00 minutes, 98 % B for 0.25 minutes and 5 % B in 0.50 minutes and hold these conditions for 0.25 minutes in order to re-equilibrate the column (Total Run Time 3.00 minutes). An injection volume of 0.5 pl was used.Method 9 (K83 5 min)

[0268] The HPLC measurement was performed using Waters Acquity H Class UPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters SQ Detector 2) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L / Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on aWaters Xbridge C18 column (3.5 pm, 50 x 3 mm) with a flow rate of 1.20 ml / min. Two mobile phases were used, mobile phase A: 5 mM NH4OAC in water; mobile phase B: 5 mM NH4OAC in ACN: Water (90:10), and they were employed to run a gradient conditions from 5 % B for 0.75 minutes, from 5 % to 15 % in 0.50 minutes, from 15 % to 70 % in 1.25 minutes and from 70% to 98 % in 1 .25 minutes, 98 % B for 0.50 minutes and 5 % B in 0.25 minutes and hold these conditions for 0.60 minutes in order to re-equilibrate the column (Total Run Time 5.10 minutes). An injection volume of 0.5 pl was used.Method 10 (K83 12 min)

[0269] The HPLC measurement was performed using Waters Acquity H Class LIPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters SQ Detector 2) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L / Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on a Waters Xbridge C18 column (3.5 pm, 50 x 3 mm) with a flow rate of 1.00 ml / min. Two mobile phases were used, mobile phase A: 5 mM NH4OAC in water; mobile phase B: 5 mM NH4OAC in ACN: Water (90:10), and they were employed to run a gradient conditions from 2 % B for 1.00 minutes, from 2 % to 50 % in 4.00 minutes and from 50% to 98 % in 3.00 minutes, 98 % B for 2.00 minutes and 2 % B in 2.00 minutes and hold these conditions for 0.10 minutes in order to re-equilibrate the column (Total Run Time 12.10minutes). An injection volume of 0.5 pl was used.Method 11 (K84 12 min)

[0270] The HPLC measurement was performed using Waters Acquity H Class UPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters SQ Detector 2) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L / Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on a Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm) with a flow rate of 0.800 ml / min. Two mobile phases were used, mobile phase A: 0.05% HCOOH in water; mobile phase B: 0.05%HCOOH in ACN: Water (90:10), and they were employed to run a gradient conditions from 5 % B for 1.00 minutes, from 5 % to 50 % in 4.00 minutes, and from 50 % to 90 % in 3.00 minutes, 90 % B for 2.00 minutes and then 5 % B in 1.50 minutes and hold these conditions for 0.50 minutes in order to re-equilibrate the column (Total Run Time 12.00 minutes). An injection volume of 0.5 pl was used.Method 12 (K79 3 min)

[0271] The HPLC measurement was performed using Agilent 1260 Infinity II LIPLC comprising a quaternary pump with degasser, an sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Agilent SQD) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1200 in 0.20 second. The capillary needle voltage was 4.00 kV in positive and negative ionization mode and the source temperature was maintained at 350 °C. Nitrogen was used as the desolvation gas, the flow was 12 L / Min. Data acquisition was performed with Open Lab CDS. Reversed phase HPLC was carried out on a YMC Triart C18 column (3 pm, 33 x 2.1 mm) with a flow rate of 1 .00 ml / min. Two mobile phases were used, mobile phase A: 0.1 % HCOOH in water; mobile phase B: 0.1 % HCOOH in ACN, and they were employed to run a gradient condition from 2 % B for 0.50 minutes, from 2 % to 30 % in 0.50 minutes, and from 30 % to 98 % in 1.00 minutes, 98 % B for 0.25 minutes and then 2 % B in 0.75 minutes (Total Run Time 3.00 minutes). An injection volume of 0.5 pl was used.Method 13 (K83 3 min-BEH)

[0272] The HPLC measurement was performed using Waters Acquity H Class UPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters SQ Detector 2) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L / Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on a Waters Acquity BEH C18 column (1.7 pm, 30 x 2.1 mm) with a flow rate of 1.20 ml / min. Two mobile phases were used, mobile phase A: 5 mM NH4OAC in water; mobile phase B: 5 mM NH4OAC in ACN: Water (90:10), and they were employed to run a gradient conditions from 2 % B for 0.50 minutes, from2 % to 98 % in 1.00 minutes, 98 % B for 1.00 minutes and 2 %B in 0.25 minutes and hold these conditions for 0.25 minutes in order to re-equilibrate the column (Total Run Time 3.00 minutes). An injection volume of 0.5 pl was used.Method 14 (K83 12 min)-OLD

[0273] The HPLC measurement was performed using Waters Acquity H Class LIPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters SQ Detector 2) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L / Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on a Waters Xbridge C18 column (5 pm, 50 x 4.6 mm) with a flow rate of 1.50 ml / min. Two mobile phases were used, mobile phase A: 5 mM NH4OAC in water; mobile phase B: 5 mM NH4OAC in ACN: Water (90:10), and they were employed to run a gradient conditions from 2 % B for 0.75 minutes, from 2 % to 15 % in 0.50 minutes, from 15 % to 70 % in 1.25 minutes and from 70% to 98 % in 1 .25 minutes, 98 % B for 0.75 minutes and 2 % B in 0.50 minutes and hold these conditions for 0.10 minutes in order to re-equilibrate the column (Total Run Time 5.10 minutes). An injection volume of 0.5 pl was used.Method 15 (K83 12 min)-OLD

[0274] The HPLC measurement was performed using Waters Acquity H Class UPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters SQ Detector 2) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L / Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on a Waters Xbridge C18 column (5 pm, 50 x 4.6 mm) with a flow rate of 1.20 ml / min. Two mobile phases were used, mobile phase A: 5 mM NH4OAC in water; mobile phase B: 5 mM NH4OAC in ACN: Water (90:10), and they were employed to run a gradient conditions from 2 % B for 1 .00 minutes, from 2 % to 50 % in 4.00 minutes, from 50 % to 90 % in 3.00 minutes and 90 % B for 2.00 minutes and 2 % B in 2.00 minutes and hold these conditions for 0.10 minutes in order to re-equilibrate the column (Total Run Time 12.10 minutes). An injection volume of 0.5 pl was used.Method 16

[0275] The HPLC measurement was performed using Waters Acquity LIPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 50° C), a diodearray detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters ZQ) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L / Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on a Sunfire C18 column (5 pm, 100 x 4.6 mm) with a flow rate of 1.00 ml / min. Two mobile phases were used, mobile phase A: 0.05% HCOOH in water; mobile phase B: 0.05% HCOOH in ACN: Water (90:10), and they were employed to run a gradient condition from 2 % B for 1.00 minutes, from 2 % to 50 % in 4.00 minutes, and from 50 % to 95 % in 4.00 minutes, 95 % B for 3.00 minutes and then 5 % B in 0.50 minutes. (Total Run Time 12.50 minutes). An injection volume of 0.5 pl was used.Method 17

[0276] The HPLC measurement was performed using Shimadzu HPLC comprising a binary pump with degasser, a sample manager a dual channel UV detector and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Applied Biosystems API2000 / 2000 Trap) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 800 in 0.40 second. The ion spray voltage 5500 V in positive and 4500 V in negative ionization mode and the source temperature was maintained at 300 °C and Declusturing Potential 8-50 V depending on compound. Data acquisition was performed with Analyst 1.6.3 Software. Reversed phase HPLC was carried out on a Waters Xbridge C18 / Agilent Zorbax Ext C18 column (5 pm, 100 x 4.6 mm) with a flow rate of 1.00 ml / min. Two mobile phases were used, mobile phase A: 10mm Ammonium Acetate in water; mobile phase B: ACN, and they were employed to run a gradient condition from 50% B for 2.00 min, from 50% B to 95 % B in 6.00 minutes, and 95 % B for 3.00 minutes and 50 % B in 3.00 minutes and hold these conditions for 4.00 minutes. Pre run Equilibration Time 4.00 min (Total Run Time 18.00 minutes). An injection volume of 1 pl to 3 pl was used (Depending on the sample concentration).Method 18 (K84 3 min)-OLD

[0277] The HPLC measurement was performed using Waters Acquity H Class UPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 50°C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters SQ Detector 2) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L / Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on a YMC Triart C18 column (3 pm, 33 x 2.1 mm) with a flow rate of 1.00 ml / min. Two mobile phases were used, mobile phase A: 0.05% HCOOH in water; mobile phase B: 0.05% HCOOH in ACN: Water (90:10), and they were employed to run a gradient conditions from 2 % B for 0.75 minutes, from 2 % to 10 % in 0.25 minutes, and from 10 % to 98 % in 1.00 minutes, 98 % B for 0.50 minutes and then 2 % B in 0.40 minutes and hold these conditions for 0.10 minutes in order to re-equilibrate the column (Total Run Time 3.00 minutes).. An injection volume of 0.5 pl was used.Method 19 (K84 3 min)-OLD BEH POLAR

[0278] The HPLC measurement was performed using Waters Acquity H Class UPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters SQ Detector 2) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L / Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on a Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm) with a flow rate of 0.80 ml / min. Two mobile phases were used, mobile phase A: 0.05% HCOOH in water; mobile phase B: 0.05% HCOOH in ACN: Water (90:10), and they were employed to run a gradient conditions from 2 % B for 0.75 minutes, from 2 % to 10 % in 0.25 minutes, and from 10 % to 98 % in 1.00 minutes, 98 % B for 0.50 minutes and then 2 % B in 0.40 minutes and hold these conditions for 0.10 minutes in order to re-equilibrate the column (Total Run Time 3.00 minutes). An injection volume of 0.5 pl was used.Method 20 (K43 6 min)

[0279] The HPLC measurement was performed using Agilant HPLC comprising a binary pump with degasser, a sample manager a DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Applied Biosystems API2000 / 2000 Trap) was configured with an electrospray ionizationsource. Mass spectra were acquired by scanning from 100 to 800 in 0.40 second. The ion spray voltage 5500 V in positive and 4500 V in negative ionization mode and the source temperature was maintained at 300 °C and Declusturing Potential 8-50 V depending on compound. Data acquisition was performed with Analyst 1.6.3 Software. Reversed phase HPLC was carried out on a Waters Xbridge C18 / Agilent Zorbax C18 column (5 pm, 50 x 4.6 mm) with a flow rate of 1.20 ml / min. Two mobile phases were used, mobile phase A: 10mM Ammonium Acetate in water; mobile phase B: ACN, and they were employed to run a gradient condition from 10 % B to 30 % B in 1.50 minutes, and from 30 % to 90 % in 1.50 minutes, 90 % B for 1.00 minutes and 10 % B in 1.00 minutes and hold these conditions for 1.00 minutes. Pre run Equilibration Time 0.50 min (Total Run Time 6.00 minutes). An injection volume of 1 pl to 3 pl was used (Depending on the sample concentration).Method 22 (K91 12 min)

[0280] The HPLC measurement was performed using Waters Acquity H Class LIPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters SQ Detector 2) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L / Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on a Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm) with a flow rate of 0.60 ml / min. Two mobile phases were used, mobile phase A: 5 mM NH4OAC in water; mobile phase B: 5 mM NH4OAC in ACN: Water (90:10), and they were employed to run a gradient conditions from 2 % B for 1 .00 minutes, from 2 % to 50 % in 4.00 minutes, from 50 % to 98 % in 3.00 minutes 98 % B for 2.00 minutes and 2 % B in 1.00 minutes and hold these conditions for 1.00 minutes in order to re-equilibrate the column (Total Run Time 12.00 minutes). An injection volume of 0.5 pl was used.Method 23 (K91 3 min)

[0281] The HPLC measurement was performed using Waters Acquity H Class UPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 40° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters SQ Detector 2) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150°C. Nitrogen was used as the desolvation gas, the flow was 750 L / Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on a Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm) with a flow rate of 0.60 ml / min. Two mobile phases were used, mobile phase A: 5 mM NH4OAC in water; mobile phase B: 5 mM NH4OAC in ACN: Water (90:10), and they were employed to run a gradient conditions from 5 % B for 0.75 minutes, from 5 % to 30 % in 0.25 minutes, from 30 % to 98 % in 1.00 minutes 98 % B for 0.25 minutes and 5 % B in 0.25 minutes and hold these conditions for 0.50 minutes in order to re-equilibrate the column (Total Run Time 3.00 minutes). An injection volume of 0.5 pl was used.Method 24 (K91 5 min)

[0282] The HPLC measurement was performed using Waters Acquity H Class UPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 40° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters SQ Detector 2) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L / Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on a Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm) with a flow rate of 0.60 ml / min. Two mobile phases were used, mobile phase A: 5 mM NH4OAC in water; mobile phase B: 5 mM NH4OAC in ACN: Water (90:10), and they were employed to run a gradient conditions from 5 % B for 0.75 minutes, from 5 % to 15 % in 0.50 minutes, from 15 % to 70 % in 1.25 minutes, from 70 % to 98 % in 1.25 minutes, 98 % B for 0.50 minutes and 5 % B in 0.25 minutes and hold these conditions for 0.60 minutes in order to re-equilibrate the column (Total Run Time 5.10 minutes). An injection volume of 0.5 pl was used.Method 25 (K92-3 min)

[0283] The HPLC measurement was performed using Waters Acquity H Class UPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters SQ Detector 2) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L / Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on aWaters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm) with a flow rate of 0.600 ml / min. Two mobile phases were used, mobile phase A: 0.05% HCOOH in water; mobile phase B: 0.05% HCOOH in AON: Water (90:10), and they were employed to run a gradient conditions from 10 % B for 0.75 minutes, from 10 % to 50 % in 0.25 minutes, and from 50 % to 98 % in 1.00 minutes, 98 % B for 0.25 minutes and then 10 % B in 0.35 minutes and hold these conditions for 0.40 minutes in order to re-equilibrate the column (Total Run Time 3.00 minutes). An injection volume of 0.5 pl was used.Method 26 (TM)

[0284] The HPLC measurement was performed using Shimadzu HPLC comprising a binary pump with degasser, a sample manager a dual channel UV detector and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Applied Biosystems API2000 / 2000 Trap) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 800 in 0.40 second. The ion spray voltage 5500 V in positive and 4500 V in negative ionization mode and the source temperature was maintained at 300 °C and Declusturing Potential 8-50 V depending on compound. Data acquisition was performed with Analyst 1.6.3 Software. Reversed phase HPLC was carried out on a Gemini NX C18 (5 pm, 100 x 4.6 mm) with a flow rate of 1.00 ml / min. Two mobile phases were used, mobile phase A: 0.1 % NH3 in Water); mobile phase B: ACN, and they were employed to run a gradient condition from 2% B for 1.50 min, from 2% B to 40 % B in 3.50 minutes, and 40% B to 95% B in 3.00 minutes and 95 % B for 6.00 minutes and 2 % B in 1.00 minutes and hold these conditions for 4.00 minutes. Pre run Equilibration Time 4.00 min (Total Run Time 19.00 minutes). An injection volume of 1 pl to 3 pl was used (Depending on the sample concentration).Method 27 (K92-3 min-YMC)

[0285] The HPLC measurement was performed using Waters Acquity H Class UPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters SQ Detector 2) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L / Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on a YMC Triart C18 column (3 pm, 33 x 2.1 mm) with a flow rate of 1.00 ml / min. Two mobile phases were used, mobile phase A: 0.05% HCOOH in water; mobile phase B: 0.05% HCOOH in ACN: Water (90:10), and they were employed to run a gradient conditions from2 % B for 0.75 minutes, from 2 % to 10 % in 0.25 minutes, and from 10 % to 98 % in 1.00 minutes, 98 % B for 0.50 minutes and then 2 % B in 0.40 minutes and hold these conditions for 0.10 minutes in order to re-equilibrate the column (Total Run Time 3.00 minutes). An injection volume of 0.5 to 3 pl was used (Depending on the sample concentration).Method 28 (K92-5 min-YMC)

[0286] The HPLC measurement was performed using Waters Acquity H Class LIPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters SQ Detector 2) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L / Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on a YMC Triart C18 column (3 pm, 33 x 2.1 mm) with a flow rate of 1.00 ml / min. Two mobile phases were used, mobile phase A: 0.05% HCOOH in water; mobile phase B: 0.05% HCOOH in ACN: Water (90:10), and they were employed to run a gradient conditions from 5 % B for 0.75 minutes, from 5 % to 25 % in 0.75 minutes, and from 25 % to 95 % in 1.50 minutes, 95 % B for 1 .75 minutes and then 5 % B in 0.25 minutes and hold these conditions for 0.10 minutes in order to re-equilibrate the column (Total Run Time 5.10 minutes). An injection volume of 0.5 to 3 pl was used (Depending on the sample concentration).Method 29 (K70 / 71 / 55 / 63 5 min-YMC)

[0287] The HPLC measurement was performed using Waters Acquity UPLC comprising a binary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters ZQ SQD) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 0.40 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L / Hour. Data acquisition was performed with Mass Lynx 4.1 Software. Reversed phase HPLC was carried out on a YMC Triart C18 column (3 pm, 33 x 2.1 mm) with a flow rate of 1.00 ml / min. Two mobile phases were used, mobile phase A: 0.05% HCOOH in water; mobile phase B: 0.05% HCOOH in ACN: Water (90:10), and they were employed to run a gradient conditions from 5 % B for 0.75 minutes, from 5 % to 25 % in 0.75 minutes, and from 25 % to 95 % in 1.50 minutes, 95 % B for 1.75 minutes and then 5 % B in 0.25 minutes and hold these conditions for 0.10 minutes in order to re-equilibrate the column (Total Run Time 5.10 minutes). An injection volume of 0.5 to 3 pl was used (Depending on the sample concentration).Method 30 (K71 5 min-BEH)

[0288] The HPLC measurement was performed using Waters Acquity LIPLC comprising a binary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters ZQ SQD) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 0.40 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L / Hour. Data acquisition was performed with Mass Lynx 4.1 Software. Reversed phase HPLC was carried out on a Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm) with a flow rate of 0.50 ml / min. Two mobile phases were used, mobile phase A: 0.05% HCOOH in water; mobile phase B: 0.05% HCOOH in ACN: Water (90:10), and they were employed to run a gradient conditions from 2 % B for 0.50 minutes, from 2 % to 30 % in 1.00 minutes, and from 30 % to 95 % in 1.50 minutes, 95 % B for 1.00 minutes and then 2 % B in 0.50 minutes and hold these conditions for 0.60 minutes in order to re-equilibrate the column (Total Run Time 5.10 minutes). An injection volume of 0.5 to 3 pl was used (Depending on the sample concentration).Method 31 (K71 3 min-BEH)

[0289] The HPLC measurement was performed using Waters Acquity UPLC comprising a binary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters ZQ SQD) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 0.40 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L / Hour. Data acquisition was performed with Mass Lynx 4.1 Software. Reversed phase HPLC was carried out on a Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm) with a flow rate of 0.60 ml / min. Two mobile phases were used, mobile phase A: 0.05% HCOOH in water; mobile phase B: 0.05% HCOOH in ACN: Water (90:10), and they were employed to run a gradient conditions from 5 % B for 0.75 minutes, from 5 % to 50 % in 0.45 minutes, and from 50 % to 98 % in 0.80 minutes, 98 % B for 0.25 minutes and then 5 % B in 0.35 minutes and hold these conditions for 0.50 minutes in order to re-equilibrate the column (Total Run Time 3.10 minutes). An injection volume of 0.5 to 3 pl was used (Depending on the sample concentration).Method 32 (K103-3 min)

[0290] The HPLC measurement was performed using Waters Acquity H Class LIPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters QDA) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 0.20 second. The capillary needle voltage was 1.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 600 L / Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on a Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm) with a flow rate of 0.600 ml / min. Two mobile phases were used, mobile phase A: 0.05% HCOOH in water; mobile phase B: 0.05% HCOOH in ACN: Water (90:10), and they were employed to run a gradient conditions from 10 % B for 0.75 minutes, from 10 % to 50 % in 0.25 minutes, and from 50 % to 98 % in 1.00 minutes, 98 % B for 0.25 minutes and then 10 % B in 0.35 minutes and hold these conditions for 0.40 minutes in order to re-equilibrate the column (Total Run Time 3.00 minutes). An injection volume of 0.5 pl was used.NMRAll NMR spectra were obtained using Bruker Avance 400 MHz spectrometers running Topspin Software.GCMSGCMS-METHOD-1 :GC-MS was taken on Agilent 6890 and 5973 N MSD series instrument.Column: HP-5MS (30 x 250pm x 0.25pm)Carrier Gas:- HeliumInlet Temperature: 250 °CSplit ratio: 5 :1Carrier Gas flow: 1.0 ml / minSolvent Delay: 3minMass range: 50 to 550 amuInjection volume: 1 ulRamp Profile: -Oven temperature initial from 100°C held for 2 min then, 310°C increasing at the rate of 35°C held for 6min. Total run time is 14 min.GCMS-METHOD-2:GC-MS was taken on Agilent 7890B and 5977B MSD series instrument.Column: HP-5MS (30 x 250pm x 0.25pm)Carrier Gas:- HeliumInlet Temperature: 250 °CSplit ratio: 20 :1Carrier Gas flow: 1.0 ml / minRamp Profile:Oven temperature initial from 60°C held for 2 min then, 100°C increasing at the rate of 20°C held for 2min, 310°C increasing at the rate of 40°C held for 4min. Total run time is 15.25 min.SFCSupercritical fluid chromatography (SFC) analysis was performed on a WATERS SFC- analytical instrument. Column: Chiralpak IG 250 x 4.6mm, particle size 5pm. Method: mobile phase: A: carbon dioxide, mobile phase B: Hexane / IPA / Methanol 2 / 1 / 1 (0.3% Isopropyl amine), with isocratic flow 4.0 mL / min; 20% of B; wavelength: 240nm.Example 1( / ?)- / V-ethyl- / V-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)morpholine-4-sulfonamide (Example 1)Example 1Scheme 1

[0291] Synthesis of ( / ?)-2-oxo- / V-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)oxazolidine- 3-sulfonamide 1.1 : A solution of chlorosulfonyl isocyanate (0.4 mL, 4.14 mmol) in CH3CN (15 mL) was cooled at 0°C and 2-bromoethanol (0.3 mL, 4.14 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 30 min and then warmed to room temperature and stirred for another 1 h. The reaction mixture was cooled further at 0°C and a mixture of ( )-1-(4-fluorophenyl)-2,2,2-trifluoroethan-1-amine (800 mg, 4.14 mmol) and 4- methylmorpholine (1.8 mL, 16.56 mmol) in CH3CN (5 mL) was added dropwise to it. It was then stirred at 50°C for 18 h. Acetonitrile was evaporated under reduced pressure and the crude was diluted with 1 N HCI (5 mL). It was extracted with ethyl acetate (2 x 10 mL) and the combined organic part was washed with 1 N HCI (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was further purified by column chromatography over silica gel using 30% ethyl acetate in hexane to isolate desired compound 1.1 as a white solid (750 mg, 50% yield).1H NMR (400 MHz, DMSO-cfe) 6 10.22 (d, J = 10.0 Hz, 1 H), 7.68 (t, J = 7.3 Hz, 2H), 7.28 (t, J = 8.8 Hz, 2H), 5.52 - 5.41 (m, 1 H), 4.20 (q, J = 8.0 Hz, 1 H), 4.10 (q, J = 8.2 Hz, 1 H), 3.90 (t, J = 8.0 Hz, 2H).

[0292] Synthesis of ( / ?)- / V-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)morpholine-4- sulfonamide 1.2: To the solution of compound 1.1 (250 mg, 0.73 mmol) in CH3CN (1 mL) and Et3N (1 mL, 7.30 mmol) morpholine (0.1 mL, 0.88 mmol) was added and the reaction mixture was irradiated under microwave (MW) at 130°C for 30 min. The reaction mixture was diluted with ethyl acetate (10 mL) and the organic part was washed with 1 N HCI (10 mL) and brine (10 mL). The solution was dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane to isolate desired compound 1.2 as a colourless gum (190 mg, 70% yield).1H NMR (400 MHz, DMSO-cfe) 6 9.04 (d, J = 10.2 Hz, 1 H), 7.89 - 7.51 (m, 2H), 7.29 (t, J = 8.7 Hz, 2H), 5.27 - 5.16 (m, 1 H), 3.48 - 3.38 (m, 2H), 3.38 - 3.28 (m, 2H), 2.87 - 2.72 (m, 4H).

[0293] Synthesis of (R)-A / -ethyl-A / -(2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)morpholine-4-sulfonamide (Example 1): Compound 1.2 (190 mg, 0.55 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (217 mg, 0.66 mmol) was added to it. It was stirred and to it ethyl iodide (0.4 mL, 5.50 mmol) was added. The reaction mixture was then stirred at room temperature for 2 h, then quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product was isolated as a yellow sticky gum (100 mg, 48% yield). The compound was purified by PREP-HPLC-Chiral (SFC)to yield enantiomerically pure Example 1 as a yellow sticky gum (70 mg, 99.68% purity, 100% enantiomeric excess). LCMS: m / z found 371.2 [M+H]+, rt = 2.94 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)].1H NMR (400 MHz, DMSO-cfe) 6 7.74 - 7.52 (m, 2H), 7.33 (t, J = 8.7 Hz, 2H), 5.70 (q, J = 9.0 Hz, 1 H), 3.64 - 3.57 (m, 4H), 3.37 - 3.14 (m, 2H), 3.07 (t, J = 4.9 Hz, 4H), 0.96 (t, J = 6.9 Hz, 3H).

[0294] Chiral SFC PREP Method: SFC PREP purification was performed with a Waters Thar SFC-80 instrument equipped with Waters UV Detector 2489 by using CHIRALPAK-IG (30.0 mmx250mm), 5p Column operating at 35 °C temperature, maintaining a flow rate of 70 mL / min, using 65% CO2 in super critical state and 35% CH3OH as a mobile phase. This isocratic mixture ran up to 10.0 minutes while maintaining an isobaric condition of 100 bar at 214 nm wavelength.Example 2 and Example 3( / ?)-A / -(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-A / -methylmorpholine-4-sulfonamide(Example 2) and( / ?)-A / -(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-A / -ethylmorpholine-4-sulfonamide(Example 3)2-bromoethanol,Chlorosulfonyl isocyanate4-Methyl morpholine,CH3CN, 0°C to 50°C, 18Scheme 2

[0295] Synthesis of ( / ?)- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-2-oxo- oxazolidine-3-sulfonamide 2.1 : The solution of chlorosulfonyl isocyanate (2.1 mL, 23.85 mmol) in CH3CN (80 mL) was cooled at 0°C and 2-bromoethanol (1.7 mL, 23.85 mmol) was added dropwise at 0°C. The reaction mixture was stirred at 0°C for 30 min and it was warmed to room temperature and stirred for another 1 h. The reaction mixture was cooled further at 0°C and a mixture of ( )-1-(4-chlorophenyl)-2,2,2-trifluoroethan-1-amine (5 g, 23.85 mmol) and 4-methylmorpholine (10.5 mL, 95.42 mmol) in CH3CN (20 mL) was added dropwise to it. It was then stirred at 50°C for 18 h. Acetonitrile was evaporated under reduced pressure and the crude was diluted with 1 N HCI (50 mL). It was then extracted with ethyl acetate (2 x 50 mL) and the combined organic part was washed with 1 N HCI (30 mL) and brine (30 mL); dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crudewas further purified by column chromatography over silica gel using 30% ethyl acetate in hexane to isolate desired compound 2.1 as white solid (5.5 g, 64% yield).1H NMR (400 MHz, DMSO-cfe) 6 10.25 (d, J = 9.6 Hz, 1 H), 7.65 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 8.5 Hz, 2H), 5.48 (t, J = 7.7 Hz, 1 H), 4.22 (q, J = 8.1 Hz, 1 H), 4.12 (q, J = 8.4 Hz, 1 H), 3.91 (t, J = 8.5 Hz, 2H).

[0296] Synthesis of ( / ?)- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)morpholine-4- sulfonamide 3.1 : To the solution of compound 2.1 (150 mg, 0.41 mmol) in CH3CN (1 mL) and Et3N (0.6 mL, 4.18 mmol) morpholine (0.06 mL, 0.62 mmol) was added and the reaction mixture was irradiated under microwave (MW) at 130°C for 30 mins. The reaction mixture was diluted with ethyl acetate (10 mL) and the organic part was washed with 1 N HCI (10 mL) and brine (10 mL). It was dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane to isolate desired compound 3.1 as a colourless gum (100 mg, 66% yield).1H NMR (400 MHz, DMSO-cfe) 6 9.06 (d, J = 10.5 Hz, 1 H), 7.68 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 5.46 - 5.09 (m, 1 H), 3.50 - 3.39 (m, 2H), 3.39 - 3.32 (m, 2H), 2.81 (q, = 4.9 Hz, 4H).

[0297] Synthesis of ( / ?)- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V- methylmorpholine-4-sulfonamide (Example 2): Compound 3.1 (120 mg, 0.33 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (130 mg, 0.40 mmol) was added to it. The mixture was stirred and methyl iodide (0.2 mL, 3.34 mmol) was added. The reaction mixture was then stirred at room temperature for 30 min. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product was isolated as a yellow sticky gum (75 mg, 60% yield). The compound was purified by PREP-HPLC-Chiral (SFC) to yield enantiomerically pure Example 2 as a colourless sticky gum (32 mg, 99.05% purity,100% enantiomeric excess). LCMS: m / z found 373.1 [M+H]+, rt = 2.36 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)];1H NMR (400 MHz, DMSO-cfe) 6 7.57 (q, J = 8.7 Hz, 4H), 5.77 (q, J = 8.8 Hz, 1 H), 3.60 (t, J = 4.6 Hz, 4H), 3.09 (t, J = 4.8 Hz, 4H), 2.70 (s, 3H).

[0298] Chiral SFC PREP Method: SFC PREP purification was performed with a Waters Thar SFC-80 instrument equipped with UV Detector 40D by using CHIRALPAK-IG (30.0 mmx250mm), 5p Column operating at 35°C temperature, maintaining a flow rate of 60 mL / min, using 50% CO2 in super critical state and 50% CH3OH as a mobile phase. This isocratic mixture ran up to 9.0 minutes while maintaining an isobaric condition of 100 bar at 220 nm wavelength.

[0299] Synthesis of ( / ?)- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V- ethylmorpholine-4-sulfonamide (Example 3): Compound 3.1 (130 mg, 0.36 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (142 mg, 0.43 mmol) was added to it. It was stirred and ethyl iodide (0.3 mL, 3.62 mmol) was added to it. The reaction mixture was then stirred at room temperature for 2 h. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product was isolated as a yellow sticky gum (85 mg, 60% yield). The compound was purified by PREP-HPLC-Chiral (SFC) to yield enantiomerically pure Example 3 as a grey sticky gum (32 mg, 99.53% purity, 99.76% enantiomeric excess). LCMS: m / z found 387.1 [M+H]+, rt = 3.04 min (Method 2)[Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)];1H NMR (400 MHz, DMSO-cfe) 6 7.59 (q, J = 8.5 Hz, 4H), 5.71 (q, J = 8.6 Hz, 1 H), 3.61 (t, J = 4.7 Hz, 4H), 3.32 - 3.12 (m, 2H), 3.07 (t, J = 4.7 Hz, 4H), 0.97 (t, J = 6.9 Hz, 3H).

[0300] Chiral SFC PREP Method: SFC PREP purification was performed with a Waters Thar SFC-80 instrument equipped with UV Detector 40D by using CHIRALPAK-IG (30.0 mmx250mm), 5p Column operating at 35°C temperature, maintaining a flow rate of 60 mL / min, using 50% CO2 in super critical state and 50% CH3OH as a mobile phase. This isocratic mixture ran up to 9.0 minutes while maintaining an isobaric condition of 100 bar at 220 nm wavelength.Example 4 and Example 5( / ?)- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V,2,2-trimethylmorpholine-4- sulfonamide (Example 4) and( / ?)- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V-ethyl-2,2-dimethylmorpholine-4- sulfonamide (Example 5)Scheme 4 Example 4

[0301] Synthesis of ( / ?)- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-2,2- dimethylmorpholine-4-sulfonamide 4.1 : To the solution of compound 2.1 (200 mg, 0.55 mmol) in CH3CN (1 mL) and Et3N (0.8 mL, 5.57 mmol) 2,2-dimethylmorpholine (0.1 mL, 0.83 mmol) was added and the reaction mixture was irradiated under microwave (MW) at 130°C for 30 mins. The reaction mixture was diluted with ethyl acetate (10 mL) and the organic part was washed with 1 N HCI (10 mL) and brine (10 mL). It was dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane to isolate desired compound 4.1 as a colourless gum (150 mg, 68% yield).1H NMR (400 MHz, DMSO-cfe) 5 9.07 (d, J = 9.6 Hz, 1 H), 7.68 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.0 Hz, 2H), 5.29 - 5.23 (m, 1 H), 3.51 - 3.32 (m, 2H), 2.72 - 2.56 (m, 4H), 1.01 (d, = 6.4 Hz, 6H).

[0302] Synthesis of ( / ?)-A / -(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-A / ,2,2- trimethylmorpholine-4-sulfonamide (Example 4): Compound 4.1 (150 mg, 0.38 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (151 mg, 0.46 mmol) was added to it. The mixture was stirred and was added methyl iodide (0.25 mL, 3.87 mmol) to it. The reaction mixture was then stirred at room temperature for 30 min. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product was isolated as a yellow sticky gum (120 mg, 75% yield). The compound was purified by PREP- HPLC-Chiral (SFC) to yield enantiomerically pure Example 4 as a colourless sticky gum (70 mg, 96.26% purity, 100% enantiomeric excess). LCMS: m / z found 401.2 [M+H]+, rt = 3.21min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)].1H NMR (400 MHz, DMSO-cfe) 5 7.62 - 7.50 (m, 4H), 5.78 (q, J = 8.6 Hz, 1 H), 3.63 (t, J = 4.7 Hz, 2H), 3.16 - 2.80 (m, 4H), 2.68 (s, 3H), 1.14 (d, J = 5.7 Hz, 6H).

[0303] Chiral SFC PREP Method: SFC PREP purification was performed with a Waters Thar SFC-80 instrument equipped with UV Detector 40D by using CHIRALPAK-IG (30.0 mmx250mm), 5p Column operating at 35°C temperature, maintaining a flow rate of 70 mL / min, using 50% CO2 in super critical state and 50% CH3OH as a mobile phase. This isocratic mixture ran up to 12.0 minutes while maintaining an isobaric condition of 100 bar at 220 nm wavelength.

[0304] Synthesis of ( / ?)- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V-ethyl-2,2- dimethylmorpholine-4-sulfonamide (Example 5): Compound 4.1 (230 mg, 0.59 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (232 mg, 0.71 mmol) was added to it. It was stirred and to it was added ethyl iodide (0.5 mL, 5.94 mmol). The reaction mixture was then stirred at room temperature for 2 h. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product was isolated as yellow sticky gum (130 mg, 52% yield). The compound was purified by PREP-HPLC-Chiral (SFC) to yield enantiomerically pure Example 5 as a colourless sticky gum (70 mg, 99.66% purity, 100% enantiomeric excess). LCMS: m / z found 415.2 [M+H]+, rt = 3.31 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)].1H NMR (400 MHz, DMSO-cfe) 5 7.58 (s, 4H), 5.69 (q, J = 8.6 Hz, 1 H), 3.63 (t, J = 4.9 Hz, 2H), 3.30 - 3.10 (m, 2H), 3.07 - 2.84 (m, 4H), 1.16 (d, J = 2.4 Hz, 6H), 0.97 (t, J = 6.8 Hz, 3H).Chiral SFC PREP Method: SFC PREP purification was performed with a Waters Thar SFC- 80 instrument equipped with UV Detector 40D by using CAmylose A (30.0 mmx250mm), 5p Column operating at 35°C temperature, maintaining a flow rate of 70 mL / min, using 60% CO2 in super critical state and 40% CH3OH as a mobile phase. This isocratic mixture ran up to 6.0 minutes while maintaining an isobaric condition of 125 bar at 220 nm wavelength.Example 6 and Example 7( / ?)- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V-methyl-4-oxa-7-azaspiro[2.5]octane-7-sulfonamide (Example 6) and( / ?)- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V-ethyl-4-oxa-7-azaspiro[2.5]octane-7- sulfonamide (Example 7)

[0305] Synthesis of ( / ?)- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-4-oxa-7- azaspiro[2.5]octane-7-sulfonamide 5.1 : To the solution of compound 2.1 (200 mg, 0.55 mmol) in CH3CN (1 mL) and Et3N (0.8 mL, 5.57 mmol) 4-oxa-7-azaspiro[2.5]octane hydrochloride (125 mg, 0.83 mmol)was added and the reaction mixture was irradiated under microwave (MW) at 130°C for 30 mins. The reaction mixture was diluted with ethyl acetate (10 mL) and the organic part was washed with 1 N HCI (10 mL) and brine (10 mL). It was dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane to isolate desired compound 5.1 as a colourless gum (160 mg, 75% yield). LCMS: m / z found 385.2 [M+H]+, rt = 1.76 min (Method 3)[YMC Triart C18 column (3 m, 33 x 2.1 mm)].1H NMR (400 MHz, DMSO-cfe) 6 9.07 (d, J = 10.2 Hz, 1 H), 7.68 (d, J = 8.1 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 5.28 - 5.17 (m, 1 H), 3.54 - 3.44 (m, 1 H), 3.32 - 3.20 (m, 1 H), 2.92 - 2.78 (m, 4H), 0.68 - 0.45 (m, 3H), 0.40 - 0.31 (m, 1 H).

[0306] Synthesis of ( / ?)- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V-methyl-4-oxa-7- azaspiro[2.5]octane-7-sulfonamide (Example 6): Compound 5.1 (130 mg, 0.33 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (132 mg, 0.40 mmol) was added to it. It was stirred and to it was added methyl iodide (0.2 mL, 3.37 mmol). The reaction mixture was then stirred at room temperature for 30 mins. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product was isolated as yellow sticky gum (100 mg, 74% yield). The compound was purified by PREP-HPLC-Chiral (SFC) to yield enantiomerically pure Example 6 as a colourless sticky gum (70 mg, 99.34% purity,100% enantiomeric excess). LCMS: m / z found 399.2 [M+H]+, rt = 3.20 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)];1H NMR (400 MHz, DMSO-cfe) 6 7.57 (q, J = 8.6 Hz, 4H), 5.77 (q, J = 8.6 Hz, 1 H), 3.67 - 3.58 (m, 2H), 3.20 - 3.05 (m, 4H), 2.70 (s, 3H), 0.77 - 0.48 (m, 4H).

[0307] Chiral SFC PREP Method: SFC PREP purification was performed with a Waters Thar SFC-80 instrument equipped with UV Detector 40D by using Chiralpak-IG (30.0 mmx250mm), 5p column operating at 35°C temperature, maintaining a flow rate of 60 mL / min, using 50% CO2 in super critical state and 50% CH3OH as a mobile phase. This isocratic mixture ran up to 14.0 minutes while maintaining an isobaric condition of 100 bar at 220 nm wavelength.

[0308] Synthesis of ( / ?)- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V-ethyl-4-oxa-7- azaspiro[2.5]octane-7-sulfonamide (Example 7): Compound 5.1 (210 mg, 0.54 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (213 mg, 0.65 mmol) was added to it. It was stirred and to it was added ethyl iodide (0.4 mL, 5.45 mmol). The reaction mixture was then stirred at room temperature for 2 h. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product was isolated as yellow sticky gum (130 mg, 57% yield). The compound was purified by PREP-HPLC-Chiral (SFC) to yield enantiomerically pure Example 7 as a colourless sticky gum (70 mg, 99.57% purity, 100% enantiomeric excess). LCMS: m / z found 413.2 [M+H]+, rt = 3.29 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)];1H NMR (401 MHz, DMSO-cfe) 6 7.63 - 7.53 (m, 4H), 5.69 (q, J = 8.8 Hz, 1 H), 3.68 - 3.60 (m, 2H), 3.31 - 3.08 (m, 6H), 0.99 (t, J = 7.0 Hz, 3H), 0.77 - 0.55 (m, 4H).

[0309] Chiral SFC PREP Method: SFC PREP purification was performed with a Waters Thar SFC-80 instrument equipped with UV Detector 40D by using C Amylose A (30.0 mmx250mm), 5p column operating at 35°C temperature, maintaining a flow rate of 60 mL / min, using 60% CO2 in super critical state and 40% CH3OH as a mobile phase. This isocratic mixture ran up to 8.0 minutes while maintaining an isobaric condition of 100 bar at 220 nm wavelength.Example 8 and Example 9(S)- / V-(( / ?)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V,2-dimethylmorpholine-4- sulfonamide (Example 8) and(S)- / V-((R)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V-ethyl-2-methylmorpholine-4- sulfonamide (Example 9)Scheme 6Example 8

[0310] Synthesis of (S)-N-((R)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-2- methylmorpholine-4-sulfonamide 6.1 : To the solution of compound 2.1 (400 mg, 1.15 mmol) in CH3CN (1 mL) and Et3N (1.5 mL, 11.15 mmol) (S)-2-methylmorpholine (0.2 mL, 1 .67 mmol) was added and the reaction mixture was irradiated under microwave (MW) at 130°C for 30 mins. The reaction mixture was diluted with ethyl acetate (10 mL) and the organic part was washed with 1 N HCI (10 mL) and brine (10 mL). It was dried over anhydrous Na2SC>4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane to isolate desired compound 6.1 as a colourless gum (320 mg, 77% yield). LCMS: m / z found 371.0 [M-H], rt =2.05 min (Method 32) [Waters Acquity BEH C18 column (1 .7 pm, 50 x 2.1 mm)]; 1 H NMR (400 MHz, DMSO-d6): 5 9.03 (d, J = 10.1 Hz, 1 H), 7.67 (d, J = 7.8 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 5.54 - 4.93 (m, 1 H), 3.67 - 3.58 (m, 1 H), 3.29 - 3.19 (m, 1 H), 3.02 - 2.88 (m, 2H), 2.40 - 2.32 (m, 1 H), 2.21 (t, J = 10.9 Hz, 1 H), 1.17 (t, J = 7.2 Hz, 1 H)1.02 (d, J = 6.1 Hz, 3H).

[0311] (S)-N-((R)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-N,2-dimethylmorpholine-4- sulfonamide (Example 8): Compound 6.1 (140 mg, 0.37 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (146 mg, 0.45 mmol) was added to it. It was stirred and to it was added methyl iodide (0.2 mL, 3.75 mmol). The reaction mixture was then stirred at room temperature for 30 mins. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane to isolated compound Example 8 as a light-yellow sticky gum (100 mg,99.96% purity ,100% enantiomeric excess). LCMS: m / z found 387.2 [M+H]+, rt = 3.14 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)]; 1 H NMR (400 MHz, DMSO-d6) 5 7.57 (q, J = 8.6 Hz, 4H), 5.77 (q, J = 8.7 Hz, 1H), 3.81 (d, J = 11.6 Hz, 1 H), 3.54 - 3.30 (m, 5H), 2.83 - 2.72 (m, 1 H), 2.70 (s, 3H), 1.07 (d, J = 6.2 Hz, 3H).

[0312] (S)-A / -(( / ?)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-A / -ethyl-2- methylmorpholine-4-sulfonamide (Example 9): Compound 6.1 (180mg, 0.48 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (188 mg, 0.57 mmol) was added to it. It was stirred and to it was added ethyl iodide (0.4 mL, 4.82 mmol). The reaction mixture was then stirred at room temperature for 2 h. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product was isolated as yellow sticky gum (130 mg, 67.17% yield). The compound was purified by PREP-HPLC-Chiral (SFC) to yield enantiomerically pure Example 9 as a colourless sticky gum (74 mg, 99.68% purity 100% enantiomeric excess). LCMS: m / z found 401.2 [M+H]+, rt = 3.21 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x2.1 mm)] ; 1H NMR (400 MHz, Chloroform- d) 5 7.49 (d, J = 8.4 Hz, 2H), 7.43 - 7.34 (m, 2H), 5.49 (q, J = 8.4 Hz, 1 H), 3.98 - 3.89 (m, 1H), 3.69 - 3.54 (m, 2H), 3.51 - 3.40 (m, 2H), 3.33 - 3.19 (m, 1H), 3.13 - 3.00 (m, 1H), 3.04 - 2.92 (m, 1H), 2.69 - 2.58 (m, 1 H), 1.19 (d, = 6.2 Hz, 3H), 1.04 (t, J = 7.0 Hz, 3H).

[0313] Chiral SFC PREP Method: SFC PREP purification was performed with a Waters Thar SFC-80 instrument equipped with UV Detector 40D by using Chiralpak IG (21.0 mmx250mm), 5p column operating at 35°C temperature, maintaining a flow rate of 70 mL / min, using 60% CO2 in super critical state and 40% CH3OH as a mobile phase. This isocratic mixture ran up to 8.0 minutes while maintaining an isobaric condition of 100 bar at 220 nm wavelength.Example 10 and Example 11( / ?)- / V-(( / ?)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V,2-dimethylmorpholine-4- sulfonamide (Example 10) and( / ?)- / V-(( / ?)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V-ethyl-2-methylmorpholine-4- sulfonamide (Example 11)

[0314] Synthesis of ( / ?)- / V-(( / ?)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-2- methylmorpholine-4-sulfonamide 7.1 : To the solution of compound 2.1 (200 mg, 0.55 mmol) in CH3CN (1 mL) and Et3N (0.8 mL, 5.57 mmol) (R)-2-methylmorpholine (0.1 ml, 0.83 mmol) was added and the reaction mixture was irradiated under microwave (MW) at 130°C for 30 mins. The reaction mixture was diluted with ethyl acetate (10 mL) and the organic part was washed with 1 N HCI (10 mL) and brine (10 mL). It was dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane to isolate desired compound 7.1 as a colourless gum (150 mg, 72% yield). LCMS: m / z found 373.0 [M+H]+, rt = 1.71 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)] ;1H NMR (400 MHz, DMSO-cfe) 6 9.05 (d, J = 10.4 Hz, 1 H), 7.68 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 5.28 - 5.19 (m, 1 H), 3.80 - 3.72 (m, 1 H), 3.29 - 3.19 (m, 1 H), 3.02 (d, J = 11.5 Hz, 1 H), 2.98 - 2.89 (m, 1 H), 2.03 - 1.93 (m, 2H), 1.17 (t, J = 7.2 Hz, 1 H), 0.88 (d, J = 6.2 Hz, 3H).

[0315] Synthesis of ( / ?)-A / -(( / ?)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-A / ,2- dimethylmorpholine-4-sulfonamide (Example 10): Compound 7.1 (150 mg, 0.40 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (196 mg, 0.60 mmol) was added to it. It was stirred and to it was added methyl iodide (0.3 mL, 4.0 mmol). The reaction mixture was then stirred at room temperature for 30 min. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product Example 10 was isolated as a yellow sticky gum (100 mg, 64% yield, 99.77% purity, 98.14% enantiomeric excess). LCMS: m / z found 387.2 [M+H]+, rt = 3.12 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)] ;1H NMR (400 MHz, DMSO-cfe) 6 7.57 (q, J = 8.1 Hz, 4H), 5.82 - 5.73 (m, 1 H), 3.87 - 3.79 (m, 1 H), 3.54 - 3.33 (m, 3H), 2.88 - 2.77 (m, 1 H), 2.70 (s, 3H), 2.48 - 2.34 (m, 2H), 1.06 (d, J = 6.0 Hz, 3H).

[0316] Synthesis of (R)-A / -((R)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-A / -ethyl-2- methylmorpholine-4-sulfonamide (Example 11): Compound 7.1 (150 mg, 0.40 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (196 mg, 0.60 mmol) was added to it. It was stirred and to it was added ethyl iodide (0.3 mL, 4.0 mmol). The reaction mixture was then stirred at room temperature for 2 h. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product was isolated as a yellow sticky gum (90 mg, 56% yield). The compound was purified by PREP-HPLC-Chiral (SFC) to yield enantiomerically pure Example 11 as a colourless sticky gum (38 mg, 99.21 % purity, 100% enantiomeric excess). LCMS: m / z found 401.2 [M+H]+, rt = 3.24 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)] ;1H NMR (400 MHz, Chloroform-d) 5 7.49 (d, J = 8.3 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 5.49 (q, J = 8.4 Hz, 1 H), 4.03 - 3.82 (m, 1 H), 3.68 - 3.56 (m, 2H), 3.50 (d, J = 12.2 Hz, 1 H), 3.43 (d, J = 12.8 Hz, 1 H), 3.31 - 3.21 (m, 1 H), 3.14 - 2.91 (m, 2H), 2.63 (t, J = 10.6 Hz, 1 H), 1.18 (d, J = 6.2 Hz, 3H), 1.04 (t, J = 7.0 Hz, 3H).

[0317] Chiral SFC PREP Method: SFC PREP purification was performed with a Waters Thar SFC-80 instrument equipped with UV Detector 40D by using C Amylose A (30.0 mmx250mm), 5p column operating at 35°C temperature, maintaining a flow rate of 60 mL / min, using 60% CO2 in super critical state and 40% CH3OH as a mobile phase. This isocratic mixture ran up to 10.0 minutes while maintaining an isobaric condition of 100 bar at 220 nm wavelength.Example 12 and Example 13(S)- / V-(( / ?)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V,3-dimethylmorpholine-4- sulfonamide (Example 12) and(S)- / V-(( / ?)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V-ethyl-3-methylmorpholine-4- sulfonamide (Example 13)Scheme 8 Example 12

[0318] Synthesis of (S)-N-((R)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-2- methylmorpholine-4-sulfonamide 8.1 : To the solution of compound 2.1 (400 mg, 1.15 mmol) in CH3CN (1 mL) and Et3N (1.5 mL, 11.15 mmol) (S)-3-methylmorpholine (0.2 mL, 1 .67 mmol) was added and the reaction mixture was irradiated under microwave (MW) at 130°C for 30 mins. The reaction mixture was diluted with ethyl acetate (10 mL) and the organic part was washed with 1 N HCI (10 mL) and brine (10 mL). It was dried over anhydrous Na2SC>4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane to isolate desired compound 8.1 as colourless gum (300, 72% yield). LCMS: m / z found 371.0 [M-H], rt= 2.03 min (Method 32) [Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm)]; 1 H NMR (400 MHz, DMSO-d6) 5 9.18 - 8.90 (m, 1 H), 7.67 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.3 Hz, 2H), 5.34 - 5.11 (m, 1 H), 3.71 (d, J = 11.4 Hz, 1 H), 3.54 - 3.35 (m, 2H), 3.28 - 2.91 (m, 4H), 1.16 (d, J = 6.8 Hz, 3H).

[0319] (S)-N-((R)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-N-ethyl-3- methylmorpholine-4-sulfonamide (Example 12): Compound 8.1 (150 mg, 0.40 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (157 mg, 0.48 mmol) was added to it. It was stirred and to it was added methyl iodide (0.25 mL, 4.02 mmol). The reaction mixture was then stirred at room temperature for 30 mins. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane to obtain the product Example 12 as a light yellow sticky gum (110 mg, 98.79% purity ,100% enantiomeric excess). LCMS: m / z found 387.2 [M+H]+, rt = 6.37 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm]; 1 H NMR (400 MHz, DMSO-d6) 5 7.55 (q, J = 8.6 Hz, 4H), 5.77 (q, J = 8.8 Hz, 1 H), 3.83 - 3.74 (m, 1 H), 3.74 - 3.65 (m, 1 H), 3.59 (d, J = 11 .3 Hz, 1 H), 3.55 - 3.47 (m, 1 H),3.32 - 3.25 (m, 1 H), 3.25 - 3.13 (m, 1 H), 3.10 - 3.01 (m, 1H), 2.66 (s, 3H), 1.23 (d, J = 6.8 Hz, 3H).

[0320] (S)-N-((R)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-N-ethyl-2- methylmorpholine-4-sulfonamide (Example 13): Compound 8.1 (140 mg, 0.37 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (146 mg, 0.45 mmol) was added to it. It was stirred and to it was added ethyl iodide (0.2 ml, 3.75 mmol). The reaction mixture was then stirred at room temperature for 2 h. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane to isolate the product Example 13 as a colourless sticky gum (100 mg, 99.96% ,100% enantiomeric excess). LCMS: m / z found 401.2 [M+H]+ rt= 3.24 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)]; 1 H NMR (400 MHz, DMSO-d6) 5 7.59 (q, J = 8.6 Hz, 4H), 5.70 (q, J = 8.8 Hz, 1 H), 3.87 - 3.73 (m, 2H), 3.72 - 3.48 (m, 2H), 3.31 - 3.09 (m, 4H), 3.01 (d, J = 11.9 Hz, 1 H), 1 .25 (d, J = 6.7 Hz, 3H), 0.92 (t, J = 7.0 Hz, 3H).Example 14 and Example 15( / ?)- / V-(( / ?)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V,3-dimethylmorpholine-4- sulfonamide (Example 14) and( / ?)- / V-(( / ?)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V-ethyl-3-methylmorpholine-4- sulfonamide (Example 15)Scheme 9 Example 14

[0321] Synthesis of (R)-A / -((R)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-3- methylmorpholine-4-sulfonamide 9.1 : To the solution of compound 2.1 (200 mg, 0.55 mmol) in CH3CN (1 mL) and Et3N (0.8 mL, 5.57 mmol), ( )-3-methylmorpholine (0.1 ml, 0.83 mmol) was added and the reaction mixture was irradiated under microwave (MW) at 130°Cfor 30 min. The reaction mixture was diluted with ethyl acetate (10 mL) and the organic part was washed with 1 N HCI (10 mL) and brine (10 mL). It was dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane to isolate desired compound as colourless gum (160 mg, 77% yield). LCMS: m / z found 373.0 [M+H]+, rt = 1.69 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)];1H NMR (400 MHz, DMSO- cfe) 6 9.09 (d, J = 10.2 Hz, 1 H), 7.70 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 5.40 - 4.95 (m, 1 H), 3.70 - 3.56 (m, 1 H), 3.51 - 3.42 (m, 2H), 3.24 - 3.16 (m, 1 H), 2.91 - 2.79 (m, 1 H), 2.61 (d, = 12.0 Hz, 1 H), 2.29 - 2.18 (m, 1 H), 1.10 (d, J = 6.8 Hz, 3H).

[0322] Synthesis of ( / ?)-A / -(( / ?)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-A / ,3- dimethylmorpholine-4-sulfonamide Example 14: Compound 9.1 (160 mg, 0.43 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (209 mg, 0.64 mmol) was added to it. It was stirred and to it was added methyl iodide (0.3 mL, 4.29 mmol). The reaction mixture was then stirred at room temperature for 30 mins. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane to obtain the product Example 14 as a yellow sticky gum (10 mg, 68% yield, 99.64% purity, 97.33% enantiomeric excess). LCMS: m / z found 387.2 [M+H]+, rt = 3.14 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)] ;1H NMR (400 MHz, DMSO-cfe) 6 7.71 - 7.42 (m, 4H), 5.79 (q, J = 8.4 Hz, 1 H), 3.77 (d, J = 10.2 Hz, 1 H), 3.72 - 3.46 (m, 3H), 3.29 - 3.13 (m, 2H), 3.06 (d, J = 11.8 Hz, 1 H), 2.65 (s, 3H), 1.24 (d, J = 6.8 Hz, 3H).

[0323] Synthesis of (R)-A / -((R)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-A / -ethyl-3- methylmorpholine-4-sulfonamide (Example 15): Compound 9.1 (160 mg, 0.43 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (210 mg, 0.64 mmol) was added to it. It was stirred and to it was added ethyl iodide (0.3 mL, 4.29 mmol). The reaction mixture was then stirred at room temperature for 2 h. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane to isolate the product Example 15 as a yellow sticky gum (100 mg, 58% yield, 99.79% purity, 98.22% enantiomeric excess). LCMS: m / z found 401 .2 [M+H]+, rt = 3.24 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)] ;1H NMR (400 MHz, DMSO-cfe) 6 7.69 - 7.46 (m, 4H), 5.70 (q, J = 8.8 Hz,1 H), 3.81 - 3.69 (m, 2H), 3.60 (d, J = 11.4 Hz, 1 H), 3.55 - 3.47 (m, 1 H), 3.30 - 3.06 (m, 4H), 2.94 (d, J = 11.6 Hz, 1 H), 1.25 (d, J = 6.7 Hz, 3H), 1.02 (t, J = 7.0 Hz, 3H).Example 16 and Example 17( / ?)-A / -(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-A / -methyl-2-oxa-6- azaspiro[3.3]heptane-6-sulfonamide (Example 16) and( / ?)- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V-ethyl-2-oxa-6-azaspiro[3.3]heptane-6-sulfonamide (Example 17)Example 16Scheme 10

[0324] Synthesis of ( / ?)- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-2-oxa-6- azaspiro[3.3]heptane-6-sulfonamide 10.1 : To the solution of compound 2.1 (200 mg, 0.55 mmol) in CH3CN (1 mL) and Et3N (1.2 mL, 8.36 mmol), 2-oxa-6-azaspiro[3.3]heptane oxalate (158 mg, 0.83 mmol) was added and the reaction mixture was irradiated under microwave (MW) at 130°C for 30 mins. The reaction mixture was diluted with ethyl acetate (10 mL) and the organic part was washed with 1 N HCI (10 mL) and brine (10 mL). It was dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane to isolate desired compound 10.1 as a white solid (66 mg, 32% yield). LCMS: m / z found 371.0 [M+H]+, rt = 1.64 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)];1H NMR (400 MHz, DMSO-cfe) 6 9.00 (d, J = 9.5 Hz, 1 H), 7.68 (d, J = 8.2 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 5.49 - 5.18 (m, 1 H), 4.40 (d, J = 6.7 Hz, 2H), 4.32 (d, J = 6.7 Hz, 2H), 3.78 - 3.63 (m, 4H).

[0325] Synthesis of ( / ?)- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V-methyl-2-oxa-6- azaspiro[3.3]heptane-6-sulfonamide (Example 16): Compound 10.1 (100 mg, 0.27 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (105 mg, 0.32 mmol) was added to it. It was stirred and to it was added methyl iodide (0.1 mL, 1.35 mmol). The reaction mixture was then stirred at room temperature for 30 mins. The reaction was then quenchedwith water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product was isolated as yellow sticky gum (70 mg, 68% yield). The compound was purified by PREP-HPLC-Chiral (SFC) to yield enantiomerically pure Example 16 as a colourless sticky gum (40 mg, 99.68 % purity, 100% enantiomeric excess). LCMS: m / z found 385.2 [M+H]+, rt = 2.97 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)];1H NMR (400 MHz, DMSO-cfe) 6 7.58 (d, J = 8.2 Hz, 2H), 7.50 (d, J = 8.2 Hz, 2H), 5.74 (q, J = 7.4 Hz, 1 H), 4.64 (s, 4H), 3.96 (s, 4H), 2.66 (s, 3H).

[0326] Chiral SFC PREP Method: SFC PREP purification was performed with a Waters Thar SFC-80 instrument equipped with UV Detector 40D by using C Amylose A (30.0 mm x 250mm), 5p column operating at 35°C temperature, maintaining a flow rate of 70 mL / min, using 55% CO2 in super critical state and 45% CH3OH as a mobile phase. This isocratic mixture ran up to 10.0 minutes while maintaining an isobaric condition of 100 bar at 220 nm wavelength.

[0327] Synthesis of ( / ?)- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V-ethyl-2-oxa-6- azaspiro [3.3] heptane-6-sulfonamide (Example 17): Compound 10.1 (150 mg, 0.40 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (197 mg, 0.60 mmol) was added to it. It was stirred and to it was added ethyl iodide (0.2 mL, 2.02 mmol). The reaction mixture was then stirred at room temperature for 2 h. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product was isolated as a yellow sticky gum (50 mg, 31% yield). The compound was purified by PREP-HPLC-Chiral (SFC) to yield enantiomerically pure Example 17 as yellow sticky gum (25 mg, 98.34% purity, 100% enantiomeric excess). LCMS: m / z found 399.2 [M+H]+, rt = 3.06 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm) ];1H NMR (400 MHz, DMSO-cfe) 6 8.08 - 7.21 (m, 4H), 5.89 - 5.46 (m, 1 H), 4.66 (s, 4H), 3.95 (s, 4H), 3.24 - 3.09 (m, 2H), 0.90 (t, J = 7.0 Hz, 3H).

[0328] Chiral SFC PREP Method: SFC PREP purification was performed with a Waters Thar SFC-80 instrument equipped with UV Detector 40D by using C Amylose A (30.0 mmx250mm), 5p column operating at 35°C temperature, maintaining a flow rate of 70 mL / min, using 60% CO2 in super critical state and 35% CH3OH as a mobile phase.This isocratic mixture ran up to 15.0 minutes while maintaining an isobaric condition of 100 bar at 220 nm wavelength.Example 18 and Example 19(1 / ?)-1-(4-chlorophenyl)-2,2,2-trifluoro- / V-[2-methoxyethyl(methyl)sulfamoyl]- / V- methyl-ethanamine (Example 18) and(1 / ?)-1 -(4-chlorophenyl)- / V-ethyl-2,2,2-trifluoro- / V-[2- methoxyethyl(methyl)sulfamoyl]ethanamine (Example 19)

[0329] Synthesis1 -chloro-4-[(1 / ?)-2,2,2-trifluoro-1 -[[2- methoxyethyl(methyl)sulfamoyl]amino]ethyl]benzene 11.2: To the solution of compound 2.1 (500 mg, 1.39 mmol) in CH3CN (2 mL) and Et3N (1.9 mL, 13.93 mmol), 2- methoxy- / V, / V-dimethylethan-1 -amine (0.2 mL, 2.09 mmol) was added and the reaction mixture was stirred at 80°C for 18 h. The reaction mixture was diluted with ethyl acetate (20 mL) and the organic part was washed with 1 N HCI (2 x 15 mL) and brine (15 mL). It was dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane to isolate desired compound 11.2 as a colourless gum (250 mg, 45% yield).1H NMR (400 MHz, DMSO-cfe) 6 8.80 (d, J = 10.4 Hz, 1 H), 7.65 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 5.26 - 5.23 (m, 1 H), 3.33 - 3.29 (m, 5H), 3.19 (s, 3H), 3.06 - 3.01 (m, 1 H), 2.98 - 2.93 (m, 1 H).

[0330] Synthesis of (1R)-1-(4-chlorophenyl)-2,2,2-trifluoro-A / -[2- methoxyethyl(methyl)sulfamoyl]- / V-methyl-ethanamine (Example 18): Compound 11.2 (70 mg, 0.19 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (76 mg, 0.23 mmol) was added to it. Methyl iodide (0.15 mL, 1.94 mmol) was then added under stirring. The reaction mixture was allowed to stir at room temperature for 30 min. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried overanhydrous Na2SC>4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product was isolated as a yellow gum (45 mg, 96.19% purity, 95.86% ee). LCMS: m / z found 375.2 [M+H]+, rt = 3.19 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)].1H NMR (400 MHz, DMSO) 5 7.61 - 7.53 (m, 2H), 7.51 (d, J = 8.6 Hz, 2H), 5.78 (q, J = 8.8 Hz, 1 H), 3.47 (t, J = 5.4 Hz, 2H), 3.37 - 3.28 (m, 5H), 2.76 (s, 3H), 2.60 (s, 3H).

[0331] Synthesis of (1 / ?)-1-(4-chlorophenyl)- / V-ethyl-2,2,2-trifluoro- / V-[2- methoxyethyl(methyl)sulfamoyl]ethanamine (Example 19): Compound 11.2 (150 mg, 0.41 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (162 mg, 0.49 mmol) was added to it. Ethyl iodide (0.3 mL, 4.15 mmol) was added under stirring. The reaction mixture was then allowed to stir at 40°C for 2 h The reaction was quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product Example 19 was isolated as a yellow gum (60 mg, 96.08% purity, 96.86% ee). LCMS: m / z found 389.3 [M+H]+, rt = 3.18 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)].1H NMR (400 MHz, Chloroform-d) 5 7.50 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 5.63 (q, J = 8.4 Hz, 1 H), 3.64 - 3.50 (m, 3H), 3.35 (s, 4H), 3.29 - 3.15 (m, 1 H), 3.12 - 2.98 (m, 1 H), 2.86 (s, 3H), 1.01 (t, J = 6.9 Hz, 3H).Example 205-[[[(1 / ?)-1-(4-chlorophenyl)-2,2,2-trifluoro-ethyl]-methyl-sulfamoyl]-methyl- amino]pyridine-3-carbonitrile

[0332] Synthesis of 5-[[(1 / ?)-1-(4-chlorophenyl)-2,2,2-trifluoro- ethyl]sulfamoylamino]pyridine-3-carbonitrile 12.1 : To the solution of compound 2.1 (200 mg, 0.55 mmol) in CH3CN (1 mL) and Et3N (0.8 mL, 5.57 mmol) was added 5- aminonicotinonitrile (100 mg, 0.83 mmol) and the reaction mixture was stirred at 80°C for 18 h. The reaction mixture was diluted with ethyl acetate (20 mL) and the organic part was washed with 1 N HCI (2 x 15 mL) and brine (15 mL). It was dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane to isolate desired compound 12.1 as a colourless gum (140 mg, 64% yield).1H NMR (400 MHz, DMSO-cfe) 5 10.62 (s, 1 H), 9.60 (d, J = 10.3 Hz, 1 H), 8.53 (d, J = 1.3 Hz, 1 H), 8.23 (d, J = 2.4 Hz, 1 H), 7.59 (s, 1 H), 7.38 (d, J = 8.2 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 5.19 - 5.14 (m, 1 H).

[0333] Synthesis of 5-[[[(1 / ?)-1-(4-chlorophenyl)-2,2,2-trifluoro-ethyl]-methyl- sulfamoyl]-methyl-amino]pyridine-3-carbonitrile (Example 20): Compound 12.1 (140 mg, 0.35 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (256 mg, 0.78 mmol) was added to it. It was stirred and to it was added methyl iodide (0.1 mL, 1.43 mmol). The reaction mixture was then stirred at room temperature for 30 min. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product (Example 20) was isolated as a yellow gum (40 mg, 96.61% purity, 98.10% ee). LCMS: m / z found 419.2 [M+H]+, rt = 3.11 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1mm)].1H NMR (400 MHz, DMSO-cfe) 6 8.98 - 8.88 (m, 2H), 8.43 (s, 1 H), 7.53 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 8.3 Hz, 2H), 5.84 (q, J = 8.7 Hz, 1 H), 3.22 (s, 3H), 2.76 (s, 3H).Example 21 and Example 22( / ?)- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V-methylthiomorpholine-4- sulfonamide 1,1-dioxide (Example 21) and( / ?)- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V-ethylthiomorpholine-4-sulfonamide1,1-dioxide (Example 22)Scheme 13

[0334] Synthesis of ( / ?)- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)thiomorpholine-4- sulfonamide 13.1 : To the solution of compound 2.1 (600 mg, 1.67 mmol) in CH3CN (2.5 mL) and Et3N (2 mL, 16.72 mmol) was added thiomorpholine (0.2 mL, 2.50 mmol) and the reaction mixture was irradiated under microwave (MW) at 130°C for 30 min. The reaction mixture was diluted with ethyl acetate (30 mL) and the organic part was washed with 1 N HCI (30 mL) and brine (30 mL). It was dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane to isolate desired compound 13.1 as a colourless gum (400 mg, 64% yield). ; 1 H NMR (400 MHz, Chloroform-d) 5 7.41 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 4.99 (d, J = 8.7 Hz, 1 H), 4.85 - 4.72 (m, 1 H), 3.40 (t, J = 4.9 Hz, 4H), 2.72 - 2.48 (m, 4H).

[0335] Synthesis of -(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V- methylthiomorpholine-4-sulfonamide 13.2: Compound 13.1 (190 mg, 0.50 mmol) wasdissolved in DMF (2 mL) in a sealed tube and CS2CO3 (198 mg, 0.60 mmol) was added to it. It was stirred and to it was added methyl iodide (0.2 mL, 2.53 mmol). The reaction mixture was then stirred at room temperature for 30 mins. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product 13.2 was isolated as a yellow sticky gum (160 mg, 81 % yield).1H NMR (400 MHz, Chloroform-d) 5 7.60 - 7.32 (m, 4H), 5.60 (q, J = 8.4 Hz, 1 H), 3.56 (t, J = 5.0 Hz, 4H), 2.75 - 2.65 (m, 4H), 2.60 (s, 3H).

[0336] Synthesis of ( / ?)- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V- methylthiomorpholine-4-sulfonamide 1,1-dioxide (Example 21): Compound 13.2 (100 mg, 0.25 mmol) was dissolved in DCM (2 mL) and the solution was cooled at 0°C. m-CPBA (133 mg, 0.77 mmol) was added to it and the reaction mixture was stirred at room temperature for 2 h. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product Example 21 was isolated as a yellow sticky gum (90 mg, 83% yield, 98.58% purity, 95.39% ee). GCMS: m / z found 420.1 , rt = 9.25 min [GC-Mass was taken on Agilent 6890 series instrument with MSD 5973N; Method Name : CHE300H; Column: HP- 5MS (30 x 250pm x 0.25pm); Carrier Gas:- Helium; Inlet Temperature: 250 °C; Split ratio: 5 :1 ; Gas flow: 1.0 ml / min; Ramp Profile: Oven temperature initial from 100°C held for 2min then, 310°C increasing at the rate of 35°C held for 6min,. Total run time is 14 min.];1H NMR (401 MHz, DMSO-cfe) 6 7.57 (q, J = 8.7 Hz, 4H), 5.83 (q, J = 8.6 Hz, 1 H), 3.63 (t, J = 5.3 Hz, 4H), 3.23 (t, J = 4.8 Hz, 4H), 2.71 (s, 3H).

[0337] Synthesis of ( / ?)-A / -(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-Af- ethylthiomorpholine-4-sulfonamide 13.3: Compound 13.1 (200 mg, 0.53 mmol) was dissolved in DMF (2 mL) in a sealed tube and CS2CO3 (261 mg, 0.8 mmol) was added to it. It was stirred and to it was added ethyl iodide (0.4 mL, 5.33 mmol). The reaction mixture was then stirred at room temperature for 2 h. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product 13.3 was isolated as a yellow sticky gum (120 mg, 56% yield).1H NMR (400 MHz, Chloroform-d) 5 7.47 (d, J = 8.1 Hz, 2H), 7.38 (d, J =8.2 Hz, 2H), 5.46 (q, J = 8.0 Hz, 1 H), 3.61 - 3.54 (m, 4H), 3.27 - 3.13 (m, 1 H), 3.10 - 2.95 (m, 1 H), 2.70 (t, J = 4.4, 45.4 Hz, 4H), 1.01 (t, J = 7.0 Hz, 3H).

[0338] Synthesis of ( / ?)- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V- ethylthiomorpholine-4-sulfonamide 1,1-dioxide (Example 22): Compound 13.3 (120 mg, 0.29 mmol) was dissolved in DCM (2 mL) and the solution was cooled at 0°C. m-CPBA (154 mg, 0.89 mmol) was added to it and the reaction mixture was stirred at room temperature for 2 hr. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product Example 22 was isolated as a yellow sticky gum (50 mg, 39% yield, 98.63% purity, 95.36% ee). GCMS: m / z found 433.9, rt = 10.52 min [GC-Mass was taken on Agilent 7890B series instrument with MSD 5977B; Method Name : CHE300H; Column: HP-5MS (30 x 250|jm x 0.25|jm); Carrier Gas:- Helium; Inlet Temperature: 250 °C; Split ratio: 5 :1 ; Gas flow: 1.0 ml / min; Ramp Profile: Oven temperature initial from 100°C held for 2min then, 310°C increasing at the rate of 35°C held for 6min,. Total run time is 14 min];1H NMR (400 MHz, Chloroform-d) 5 7.49 - 7.37 (m, 4H), 5.45 (q, J = 8.3 Hz, 1 H), 4.03 - 3.66 (m, 4H), 3.31 - 3.15 (m, 5H), 3.15 - 3.01 (m, 1 H), 1.01 (t, J = 7.0 Hz, 3H).Example 23 and Example 24(1 / ?)-1-(4-chlorophenyl)- / V-methyl- / V-[ethyl(2-methoxyethyl)sulfamoyl]-2,2,2-trifluoro- ethanamine (Example 23) and(1 / ?)-1-(4-chlorophenyl)- / V-ethyl- / V-[ethyl(2-methoxyethyl)sulfamoyl]-2,2,2-trifluoro- ethanamine (Example 24)

[0339] Synthesis of 1-chloro-4-[(1 / ?)-1-[[ethyl(2-methoxyethyl)sulfamoyl]amino]- 2,2,2-trifluoro-ethyl]benzene 14.2: To the solution of ( )- / V-(1-(4-chlorophenyl)-2,2,2- trifluoroethyl)-2-oxooxazolidine-3-sulfonamide 2.1 (200 mg, 0.56 mmol) in CH3CN (1 mL) and Et3N (0.8 mL, 5.57 mmol) was added N-ethyl-2-methoxy-N-methylethan-1 -amine (0.1mL, 0.84 mmol) and the reaction mixture was stirred at 80°C for 18 h. The reaction mixture was diluted with ethyl acetate (20 mL) and the organic part was washed with 1 N HCI (2 x 15 mL) and brine (15 mL). It was dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane to isolate desired compound 14.2 as colourless gum (110 mg, 45% yield).1H NMR (400 MHz, DMSO) 5 8.80 (d, J = 10.2 Hz, 1 H), 7.64 (d, J = 7.9 Hz, 2H), 7.50 (d, J = 8.3 Hz, 2H), 5.27 - 5.20 (m, 1 H), 3.30 - 3.24 (m, 2H), 3.19 (s, 3H), 3.10 - 3.01 (m, 2H), 2.95 (t, J = 6.9 Hz, 2H), 0.92 (t, J = 7.0 Hz, 3H).

[0340] Synthesis of (1 / ?)-1-(4-chlorophenyl)- / V-ethyl- / V-[ethyl(2- methoxyethyl)sulfamoyl]-2,2,2-trifluoro-ethanamine (Example 23): Compound 14.2 (140 mg, 0.37 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (146 mg, 0.44 mmol) was added to it. It was stirred and to it was added ethyl iodide (0.3 mL, 3.73 mmol). The reaction mixture was then stirred at 40°C for 2 h The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product Example 23 was isolated as a yellow gum (60 mg, 96.14% purity, 95.94% ee, 40% yield). LCMS: m / z found 403.2 [M+H]+, rt = 3.40 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)];1H NMR (400 MHz, CDCI3) 6 7.51 (d, J = 8.3 Hz, 2H), 7.37 (d, J = 8.5 Hz, 2H), 5.68 (q, J = 8.7 Hz, 1 H), 3.62 - 3.48 (m, 3H), 3.40 - 3.31 (m, 5H), 3.27 - 3.16 (m, 2H), 3.13 - 2.99 (m, 1 H), 1.22 (t, J = 7.1 Hz, 3H), 1.00 (t, J = 7.1 Hz, 3H).

[0341] Synthesis of (1 / ?)-1-(4-chlorophenyl)- / V-[ethyl(2-methoxyethyl)sulfamoyl]- 2,2,2-trifluoro- / V-methyl-ethanamine (Example 24): Compound 14.2 (100 mg, 0.26 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (104 mg, 0.32 mmol) was added to it. It was stirred and to it was added methyl iodide (0.15 mL, 2.66 mmol). The reaction mixture was then stirred at room temperature for 30 mins. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product Example 24 was isolated as a yellow gum (50 mg, 99.43% purity, 95.54% ee, 48% yield). LCMS: m / z found 422.2 [M+H]+, rt = 3.23 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)];1H NMR (400 MHz, CDCh) 6 7.40 (q, J = 8.5 Hz, 4H), 5.71 (q, J = 8.7 Hz, 1 H), 3.54 - 3.30 (m, 9H), 2.57 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H).Example 25 and Example 26A / -[[(1 / ?)-1-(4-chlorophenyl)-2,2,2-trifluoro-ethyl]-methyl-sulfamoyl]-3-methoxy-Af- methyl-cyclobutanamine (racemic trans-cyclobutyl) (Example 25), andA / -[[(1 / ?)-1-(4-chlorophenyl)-2,2,2-trifluoro-ethyl]-ethyl-sulfamoyl]-3-methoxy-Af- methyl-cyclobutanamine (racemic trans-cyclobutyl) (Example 26)

[0342] Synthesis of 1-chloro-4-[(1 / ?)-2,2,2-trifluoro-1-[[(3-methoxycyclobutyl)- methyl-sulfamoyl]amino]ethyl]benzene (racemic trans-cyclobutyl) 15.1 : To the solution of compound 2.1 (200 mg, 0.55 mmol) in CH3CN (0.5 mL) and Et3N (1.9 mL, 13.93 mmol) was added (trans)-3-methoxy- / V-methylcyclobutan-1 -amine hydrochloride (126 mg, 0.83 mmol) and the reaction mixture was stirred at 80°C for 18 h. The reaction mixture was diluted with ethyl acetate (15 mL) and the organic layer was washed with 1 N HCI (2 x 10 mL) and brine (10 mL). It was dried over anhydrous Na2SO4, and the solvent evaporated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane to isolate desired compound 15.1 as a colorless gum (150 mg, 45% yield). LCMS: m / z found 387 [M+H]+, rt = 1.73 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)].

[0343] Synthesis of A / -[[(1 / ?)-1-(4-chlorophenyl)-2,2,2-trifluoro-ethyl]-methyl- sulfamoyl]-3-methoxy- / V-methyl-cyclobutanamine (racemic trans-cyclobutyl) (Example 25): Compound 15.1 (80 mg, 0.20 mmol) was dissolved in DMF (0.8 mL) in a sealed tube and CS2CO3 (80 mg, 0.24 mmol) was added to it. It was stirred and to it was added methyl iodide (0.1 mL, 2.06 mmol). The reaction mixture was then stirred at room temperature for 30 min. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and Example 25 was isolated as a yellow gum (40 mg, 99.86% purity, 100% ee). LCMS: m / z found 401.3 [M+H]+, rt = 3.08 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)];1H NMR (400 MHz, Chloroform-d) 5 7.46 - 7.34 (m, 4H), 5.60 (q, J= 8.0 Hz, 1 H), 4.62 - 4.48 (m, 1 H), 3.94 - 3.81 (m, 1 H), 3.23 (s, 3H), 2.80 (s, 3H), 2.54 (s, 3H), 2.48 - 2.17 (m, 4H).

[0344] Synthesis of A / -[[(1 / ?)-1-(4-chlorophenyl)-2,2,2-trifluoro-ethyl]-ethyl- sulfamoyl]-3-methoxy-A / -methyl-cyclobutanamine (racemic trans-cyclobutyl) (Example 26): Compound 15.1 (160 mg, 0.41 mmol) was dissolved in DMF (1.5 mL) in a sealed tube and CS2CO3 (162 mg, 0.49 mmol) was added to it. It was stirred and to it was added ethyl iodide (0.3 mL, 4.13 mmol). The reaction mixture was then stirred at 40°C for 2 h. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product was isolated as a yellow gum (80 mg, 99.05% purity, 96.56% ee). LCMS: m / z found 415.2 [M+H]+, rt = 3.25 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)];1H NMR (400 MHz, DMSO-cfe) 6 7.64 - 7.47 (m, 3H), 5.64 (q, J = 8.6 Hz, 1 H), 4.50 - 4.32 (m, 1 H), 3.81 (t, J = 6.6 Hz, 1 H), 3.16 - 3.03 (m, 5H), 2.71 (s, 3H), 2.41 - 2.31 (m, 3H), 2.12 - 2.01 (m, 2H), 0.90 (t, J = 6.8 Hz, 3H).Example 27 and Example 28A / -[[(1 / ?)-1-(4-chlorophenyl)-2,2,2-trifluoro-ethyl]-methyl-sulfamoyl]-3-methoxy- / V- methyl-cyclobutanamine (racemic cis-cyclobutyl) (Example 27), andA / -[[(1 / ?)-1-(4-chlorophenyl)-2,2,2-trifluoro-ethyl]-ethyl-sulfamoyl]-3-methoxy- / V- methyl-cyclobutanamine (racemic cis-cyclobutyl) (Example 28)

[0345] Synthesis of 1-chloro-4-[(1 / ?)-2,2,2-trifluoro-1-[[(3-methoxycyclobutyl)- methyl-sulfamoyl]amino]ethyl]benzene (racemic cis-cyclobutyl) 16.1 : To the solution of compound 2.1 (370 mg, 1.03 mmol) in CH3CN (1.5 mL) and Et3N (1.9 mL, 13.93 mmol) was added (c / s)-3-methoxy-N-methylcyclobutan-1-amine hydrochloride (187 mg, 1.23 mmol) and the reaction mixture was stirred at 80°C for 18 h. The reaction mixture was diluted with ethyl acetate (15 mL) and the organic part was washed with 1 N HCI (2 x 10 mL) andbrine (10 mL). It was dried over anhydrous Na2SO4, and the solvent evaporated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane to isolate desired compound 16.1 as colourless gum (200 mg, 50% yield). LCMS: m / z found 387 [M+H]+, rt = 1.73 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)].

[0346] Synthesis of A / -[[(1 / ?)-1-(4-chlorophenyl)-2,2,2-trifluoro-ethyl]-methyl- sulfamoyl]-3-methoxy-A / -methyl-cyclobutanamine (racemic c / s-cyclobutyl) (Example27): Compound 16.1 (120 mg, 0.31 mmol) was dissolved in DMF (1.2 mL) in a sealed tube and CS2CO3 (121 mg, 0.37 mmol) was added to it. It was stirred and to it was added methyl iodide (0.1 mL, 2.06 mmol). The reaction mixture was then stirred at room temperature for 30 mins. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and Example 27 was isolated as a yellow gum (80 mg, 99.95% purity, 96.73% ee). LCMS: m / z found 401.3 [M+H]+, rt = 3.16 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)];1H NMR (400 MHz, Chloroform-d) 5 7.45 - 7.35 (m, 4H), 5.61 (q, J = 8.5 Hz, 1 H), 4.00 - 3.87 (m, 1 H), 3.63 - 3.51 (m, 1 H), 3.23 (s, 3H), 2.79 (s, 3H), 2.68 - 2.37 (m, 5H), 2.13 - 2.00 (m, 2H).

[0347] Synthesis of A / -[[(1 / ?)-1-(4-chlorophenyl)-2,2,2-trifluoro-ethyl]-ethyl- sulfamoyl]-3-methoxy-A / -methyl-cyclobutanamine (racemic c / s-cyclobutyl) (Example28): Compound 16.1 (150 mg, 0.38 mmol) was dissolved in DMF (1.5 mL) in a sealed tube and CS2CO3 (152 mg, 0.46 mmol) was added to it. It was stirred and to it was added ethyl iodide (0.3 mL, 3.87 mmol). The reaction mixture was then stirred at 40°C for 2 h. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and Example 28 was isolated as a yellow gum (80 mg, 99.59% purity, 97.16% ee). LCMS: m / z found 415.2 [M+H]+, rt = 3.60 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)];1H NMR (400 MHz, Chloroform-d) 5 7.47 (d, J = 8.3 Hz, 2H), 7.38 (d, J = 8.5 Hz, 2H), 5.47 (q, J = 8.5 Hz, 1 H), 4.02 - 3.88 (m, 1 H), 3.64 - 3.52 (m, 1 H), 3.24 (s, 3H), 3.23 - 3.11 (m, 1 H), 3.07 - 2.95 (m, 1 H), 2.78 (s, 3H), 2.61 - 2.49 (m, 2H), 2.14 - 2.01 (m, 2H), 0.99 (t, J = 7.1 Hz, 3H).Example 29 and Example 30( / ?)-N-(2,2-difluoro-1-(4-(trifluoromethyl)phenyl)ethyl)-N-methylmorpholine-4- sulfonamide (Example 29), and( / ?)-N-(2,2-difluoro-1-(4-(trifluoromethyl)phenyl)ethyl)-N-ethylmorpholine-4- sulfonamide (Example 30)difluoro-1-(4-(trifluoromethyl)phenyl)ethyl)morpholine-4-sulfonamide 17.1 : To the stirred solution of morpholine-4-sulfonyl chloride (1.0 g, 4.42 mmol) in DCM (10 ml) pyridine (3.1 mL, 39.2 mmol) and ( )-2,2-difluoro-1-(4-(trifluoromethyl)phenyl)ethan-1 -amine (98 mg, 5.3 mmol) were added, and the reaction mixture was stirred at room temperature for 18 h. The reaction was quenched with water (10 mL) and extracted with DCM (2 x 15 ml). The combined organic layer was washed with water (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude compound was purified by flash column chromatography using 50 % EtOAC in hexane and the compound 17.1 was isolated as a yellow solid (150 mg, 10 % yield). LCMS: m / z found 424.8 [M+H]+, rt = 1.63 min (Method C) YMC Triart C18 column (3 pm, 33 x 2.1 mm).

[0349] Synthesis of (R)-N-(2,2-difluoro-1-(4-(trifluoromethyl)phenyl)ethyl)-N- methylmorpholine-4-sulfonamide (Example 29): The sulfonamide 17.1 (120 mg, 0.32 mmol) was dissolved in DMF (2.5 mL) and CS2CO3 (125 mg, 0.38 mmol) was added to it followed by Mel (0.02 mL, 0.32 mmol). The reaction mixture was stirred at RT for 30 min. The reaction was quenched with water (10 mL) and extracted with EtOAc (2 x 10 ml). The combined organic layer was washed with water (10 ml) and brine (10 ml), dried over anhydrous sodium sulphate, and concentrated under vacuum. The crude was purified by flash column chromatography over silica gel using 40% EtOAc in hexane and the compound Example 29 was isolated as white solid (30 mg, 24 % yield). LCMS: m / z 389.33 [M+H]+, rt= 2.93 min (Method B) Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm).1H NMR (400 MHz, DMSO) 5 7.85 (d, 2H), 7.70 (d, 2H), 6.84 (m, 1 H), 5.26(t, 1 H), 3.60 (t, 4H), 3.09 (t, 4H), 2.75 (s, 3H).

[0350] Synthesis of (R)-N-(2,2-difluoro-1-(4-(trifluoromethyl)phenyl)ethyl)-N- ethylmorpholine-4-sulfonamide (Example 30): The sulfonamide 17.1 (200 mg, 0.53 mmol) was dissolved in DMF (2.5 ml) and CS2CO3 (208 mg, 0.64 mmol) was added to it followed by Etl (0.033 ml, 0.53 mmol). The reaction mixture was stirred at RT for 16 h. The reaction was quenched with water (10 ml) and extracted with EtOAc (2 x 10 ml). The combined organic layer was washed with water (10 ml) and brine (10 ml), dried over anhydrous sodium sulphate and concentrated under vacuum. The crude was purified by flash column chromatography over silica gel using 40% EtOAc in hexane and the compound Example 30 was isolated as white solid (20 mg, 9 % yield). LCMS: m / z 403.3 [M+H]+, rt = 3.13 min (Method B) Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm).1H NMR (401 MHz, DMSO-ds) 6 7.83 (d, 2H), 7.77 (d, 2H), 6.89 (m, 1 H), 5.18 (m,1 H), 3.58 (t, 4H), 3.32 (m, 2H), 3.18 (m, 1 H), 3.05 (t, 4H), 1.02 (t, 3H).Example 31 and Example 32(S)-N-methyl-N-(1-(4-(trifluor°methyl)phenyl)ethyl)morpholine-4-sulfonamide, and(S)-N-ethyl-N-(1-(4-(triflu°r°methyl)phenyl)ethyl)morpholine-4-sulfonamideScheme 18

[0351] Synthesis of (S)-N-(2,2-difluoro-1-(4-(trifluoromethyl)phenyl)ethyl)morpholine-4-sulfonamide 18.1 : To the stirred solution of morpholine-4-sulfonyl chloride (0.13 g, 0.7 mmol) in THF (10 mL) was added pyridine (0.28 mL, 3.5 mmol) and (S)-1-(4-(trifluoromethyl)phenyl)ethan-1 -amine hydrochloride (132 mg, 0.7 mmol) and the reaction mixture was stirred at room temperature for 18 h. The reaction was quenched with water (10 mL) and extracted with DCM (2 x 15 mL). The combined organic layer was washed with water (10 mL), dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude compound was purified by flash columnchromatography using 50 % EtOAC in hexane and the compound 1.1 was isolated as yellow solid (70 mg, 26 % yield). LCMS: m / z found 339.10 [M+H]+, rt = 1.63 min (Method C) YMC Triart C18 column (3 pm, 33 x 2.1 mm).

[0352] Synthesis of (S)-N-methyl-N-(1-(4-(trifluor°methyl)phenyl)ethyl)morpholine- 4-sulfonamide (Example 31): The sulfonamide 18.1 (150 mg, 0.44 mmol) was dissolved in DMF (1 mL) and CS2CO3 (173 mg, 0.53 mmol) was added to it followed by Mel (0.27 mL, 4.43 mmol). The reaction mixture was stirred at RT for 30 min. The reaction was quenched with water (10 mL) and extracted with EtOAc (2 * 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulphate, and concentrated under vacuum. The crude was purified by flash column chromatography over silica gel using 40 % EtOAc in hexane and the compound Example 31 was isolated as a white solid (100 mg, 24 % yield). LCMS: m / z 353.3 [M+H]+, rt = 2.95 min (Method B) Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm). 1 H NMR (401 MHz, DMSO) 5 7.76 (d, J = 8.2 Hz, 2H), 7.61 (d, J = 8.1 Hz, 2H), 5.07 (q, J = 7.1 Hz, 1 H), 3.68 - 3.58 (m, 4H), 3.12 - 3.03 (m, 4H), 2.59 (s, 3H), 1.57 (d, J = 7.1 Hz, 3H).

[0353] Synthesis of (S)-N-ethyl-N-(1-(4-(trifluor°methyl)phenyl)ethyl)morpholine-4- sulfonamide (Example 32): The sulfonamide 18.1 (150 mg, 0.44 mmol) was dissolved in DMF (2.5 mL) and CS2CO3 (173 mg, 0.53 mmol) was added to it followed by Etl (0.35 mL, 4.43 mmol). The reaction mixture was stirred at 40 C for 2 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (2 * 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulphate, and concentrated under vacuum. The crude was purified by flash column chromatography over silica gel using 40 % EtOAc in hexane and the compound Example 32 was isolated as white solid (95 mg, 57 % yield). LCMS: m / z 367.3 [M+H]+, rt = 2.94 min (Method B) Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm). 1 H NMR (401 MHz, DMSO) 5 7.76 (d, J = 8.2 Hz, 2H), 7.67 (d, J = 8.2 Hz, 2H), 5.00 (q, J = 7.2 Hz, 1 H), 3.68 - 3.58 (m, 4H), 3.22 - 3.10 (m, 2H), 3.07 - 3.03 (m, 4H), 1.61 (d, J = 7.1 Hz, 3H), 0.87 (t, J = 7.0 Hz, 3H).Example 33 and Example 34(S)-N-(1-(4-chlorophenyl)ethyl)-N-methylmorpholine-4-sulfonamide (Example 33), and(S)-N-(1 -(4-chlorophenyl)ethyl)-N-ethylmorpholine-4-sulfonamide (Example 34)Scheme 19

[0354] Synthesis of (S)-N-(1-(4-chlorophenyl)ethyl)morpholine-4-sulfonamide 19.1 : To the stirred solution of morpholine-4-sulfonyl chloride (0.5 g, 2.69 mmol) in THF (2 mL) were added pyridine (1.5 mL, 18.85 mmol), (S)-1-(4-chlorophenyl)ethan-1 -amine hydrochloride (503 mg, 3.23 mmol) and DMAP (16 mg, 0.13 mmol) at RT and the reaction mixture was stirred at RT for 18 h. The reaction was quenched with water (10 mL) and extracted with DCM (2 x 15 mL). The combined organic layer was washed with water (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by flash column chromatography using 50 % EtOAC in hexane and the compound 2.1 was isolated as a yellow solid (70 mg, 26% yield). LCMS: m / z found 305.08 [M+H]+, rt = 1 .63 min (Method B) Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm).

[0355] Synthesis of (S)-N-(1-(4-chlorophenyl)ethyl)-N-methylmorpholine-4- sulfonamide (Example 33): The sulfonamide 19.1 (110 mg, 0.36 mmol) was dissolved in DMF (1 .5 mL) and CS2CO3 (141 mg, 0.43 mmol) was added to it followed by Mel (0.22 mL,3.6 mmol). The reaction mixture was stirred at RT for 30 min. The reaction was quenched with water (10 mL) and extracted with EtOAc (2 x 10 ml). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulphate, and concentrated under vacuum. The crude was purified by flash column chromatography over silica gel using 40% EtOAc in hexane and the compound Example 33 was isolated as a white solid (80 mg, 69% yield). LCMS: m / z 319.17 [M+H]+, rt = 3.24 min (Method AG) Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm). 1 H NMR (400 MHz, DMSO) 5 7.43 (q, J =8.7 Hz, 4H), 4.99 (q, J = 7.0 Hz, 1 H), 3.69 - 3.55 (m, 4H), 3.10 - 3.01 (m, 4H), 2.55 (s, 3H), 1.52 (d, J = 7.1 Hz, 3H).

[0356] Synthesis of (S)-N-(1-(4-chlorophenyl)ethyl)-N-ethylmorpholine-4- sulfonamide (Example 34): The sulfonamide 19.1 (150 mg, 0.49 mmol) was dissolved in DMF (2.5 mL) and CS2CO3 (192 mg, 0.59 mmol) was added to it followed by Etl (0.33 mL,4.92 mmol). The reaction mixture was stirred at 40°C for 2 h. The reaction was then quenched with water (10 mL) and extracted with EtOAc (2 * 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude was purified by flash column chromatography over silica gel using 40% EtOAc in hexane and the compound Example 34 was isolated as a white solid (95 mg, 52 % yield). LCMS: m / z 333.2 [M+H]+, rt = 3.30 min (Method AB) Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm). 1 H NMR (400 MHz, DMSO) 5 7.52 - 7.40 (m, 4H), 4.91 (q, J = 7.0 Hz, 1 H), 3.68 - 3.58 (m, 4H), 3.22 - 2.99 (m, 6H), 1.56 (d, J = 7.1 Hz, 3H), 0.85 (t, J = 7.0 Hz, 3H).Example 35 and Example 36(R)-N-(1-(4-chlorophenyl)-2,2-difluoroethyl)-N-methylmorpholine-4-sulfonamide (Example 35), and(R)-N-(1-(4-chlorophenyl)-2,2-difluoroethyl)-N-ethylmorpholine-4-sulfonamide (Example 36)Scheme 20

[0357] Synthesis of (R)-N-(1-(4-chlorophenyl)-2,2-difluoroethyl)morpholine-4- sulfonamide 20.1 : To the stirred solution of morpholine-4-sulfonyl chloride (150 mg, 0.8 mmol) in THF (5 mL) was added pyridine (0.35 mL, 4.04 mmol) and (R)-1-(4-chlorophenyl)- 2,2-difluoroethan-1-amine hydrochloride (180 mg, 0.8 mmol) and the reaction mixture was stirred at RT for 18 h. The reaction was then quenched with water (10 mL) and extracted with DCM (2 x 15 mL). The combined organic layer was washed with water (10 mL), dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude compound was purified by flash column chromatography using 50 % EtOAC in hexane and compound 3.1 was isolated as a yellow solid (120 mg, 43 % yield). LCMS: m / z found 341.05 [M+H]+, rt = 1.63 min (Method B) Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm).

[0358] Synthesis of (R)-N-(1-(4-chlorophenyl)-2,2-difluoroethyl)-N- methylmorpholine-4-sulfonamide (Example 35): The sulfonamide 20.1 (120 mg, 0.35 mmol) was dissolved in DMF (2 mL) and CS2CO3 (137 mg, 0.42 mmol) was added to it followed by Mel (0.03 mL, 0.52 mmol). The reaction mixture was stirred at RT for 30 min. The reaction was quenched with water (10 mL) and extracted with EtOAc (2 * 10 ml). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude was purified by flash column chromatography over silica gel using 40 % EtOAc in hexane and the compound Example 35 was isolated as a white solid (55 mg, 44 % yield). LCMS: m / z 355.2 [M+H]+, rt = 2.89min (Method B) Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm). 1 H NMR (400 MHz, DMSO) 5 7.44 - 7.59 (m, 4H), 6.69 - 6.90 (m, 1 H), 5.08 - 5.23 (m, 1 H), 3.60 (t, J = 4.8 Hz, 4H), 3.02 - 3.13 (m, 4H), 2.72 (s, 3H).

[0359] Synthesis of (R)-N-(1-(4-chlorophenyl)-2,2-difluoroethyl)-N-ethylmorpholine- 4-sulfonamide (Example 36): The sulfonamide 20.1 (100 mg, 0.29 mmol) was dissolved in DMF (2.5 mL) and CS2CO3 (208 mg, 0.43 mmol) was added to it followed by Etl (0.033 mL, 0.53 mmol). The reaction mixture was stirred at 40°C for 2 h. The reaction was then quenched with water (10 mL) and extracted with EtOAc (2 * 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude was purified by flash column chromatography over silica gel using 40% EtOAc in hexane and the compound Example 36 was isolated as white solid (22 mg, 12% yield). LCMS: m / z 369.21 [M+H]+, rt = 2.94 min (Method B) Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm). 1 H NMR (401 MHz, DMSO) 5 7.55 (q, J = 8.6 Hz, 4H), 6.93 - 6.72 (m, 1 H), 5.14 - 4.97 (m, 1 H), 3.59 (t, J = 4.8 Hz, 4H), 3.22 - 3.09 (m, 2H), 3.09 - 2.99 (m, 4H), 1.01 (t, J = 7.0 Hz, 3H).Example 37 and Example 38(R)-N-(2-fluoro-1-(4-(trifluoromethyl)phenyl)ethyl)-N-methylmorpholine-4- sulfonamide (Example 37), and(R)-N-ethyl-N-(2-fluoro-1-(4-(trifluoromethyl)phenyl)ethyl)morpholine-4-sulfonamide (Example 38)Scheme 21

[0360] Synthesis of (R)-N-(2-fluoro-1-(4-(trifluoromethyl)phenyl)ethyl)morpholine-4- sulfonamide 21.1 : To the stirred solution of morpholine-4-sulfonyl chloride (300 mg, 1.6 mmol) in DCM (2 mL) was added pyridine (1.3 mL, 16.3 mmol) and (R)-2-fluoro-1-(4- (trifluoromethyl)phenyl)ethan-1-amine hydrochloride (337 mg, 1.63 mmol) and the reaction mixture was stirred at RT for 18 h. The reaction was then quenched with water (10 mL) and extracted with DCM (2 x 15 mL). The combined organic layer was washed with water (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by flash column chromatography using 50% EtOAC in hexane and compound 21.1 was isolated as an off white solid (180 mg, 52 % yield). LCMS: m / z found 357.08 [M+H]+, rt = 1.63 min (Method B) Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm).

[0361] Synthesis of (R)-N-(2-fluoro-1-(4-(trifluoromethyl)phenyl)ethyl)-N- methylmorpholine-4-sulfonamide (Example 37): The sulfonamide 21.1 (120 mg, 0.33 mmol) was dissolved in DMF (1 mL) and CS2CO3 (132 mg, 0.4 mmol) was added to it followed by Mel (0.1 mL, 1.68 mmol). The reaction mixture was stirred at RT for 30 min. The reaction was quenched with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude was purified by flash column chromatography over silica gel using 40% EtOAc in hexane and the compound LTX- 001601 was isolated as a colourless sticky liquid (45 mg, 44 % yield). LCMS: m / z 371.21 [M+H]+, rt = 5.73 min (Method K) Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm). 1 H NMR (401 MHz, DMSO) 5 7.80 (d, J = 8.1 Hz, 2H), 7.63 (d, J = 8.1 Hz, 2H), 5.35 - 5.22 (m, 1 H), 5.05 - 4.85 (m, 2H), 3.68 - 3.53 (m, 4H), 3.16 - 3.02 (m, 4H), 2.78 (s, 3H).

[0362] Synthesis of (R)-N-ethyl-N-(2-fluoro-1-(4-(trifluoromethyl)phenyl)ethyl)morpholine-4-sulfonamide (Example 38): The sulfonamide 21.1 (120 mg, 0.33 mmol) was dissolved in DMF (2.5 mL) and CS2CO3 (131mg, 0.40 mmol) was added to it followed by Etl (0.10 mL, 1.68 mmol). The reaction mixture was stirred at 40°C for 2 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude was purified by flash column chromatography over silica gel using 40% EtOAc in hexane and the compound Example 38 was isolated as colourless sticky liquid (15 mg, 11 % yield). LCMS: m / z 385.8 [M+H]+, rt = 3.03 min (Method B) Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm). 1 H NMR (401 MHz, DMSO) 5 7.79 (d, J = 8.1 Hz, 2H), 7.69 (d, J = 8.2 Hz, 2H), 5.24 - 5.14 (m, 1 H), 5.13 - 5.04 (m, 1 H), 5.01 - 4.93 (m, 1 H), 3.65 - 3.55 (m, 4H), 3.37 - 3.34 (m, 1 H), 3.20 (dt, J = 7.2, 15.1 Hz, 1 H), 3.10 - 3.02 (m, 4H), 1.01 (t, J = 7.0 Hz, 3H).Example 39(S)-N-(1 -(3,4-difluorophenyl)ethyl)-N-methylmorpholine-4-sulfonamide (Example 39).Scheme 22

[0363] Synthesis of (S)-N-(1-(3,4-difluorophenyl)ethyl)morpholine-4-sulfonamide 22.1 : To the stirred solution of morpholine-4-sulfonyl chloride (110 mg, 0.79 mmol) in THF (2 mL) were added pyridine (0.3 mL, 3.95 mmol), (S)-1-(3,4-difluorophenyl)ethan-1-amine hydrochloride (337 mg, 1.63 mmol) and DMAP (9.5 mg, 0.07 mmol) at ambient temperature and then the whole reaction mixture was stirred at room temperature for 18 h. The reaction was quenched with water (10 mL) and extracted with DCM (2 x 15 mL). The combined organic layer was washed with water (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by flash column chromatography using 50 % EtOAC in hexane and compound 22.1 was isolated as colorless sticky liquid (110 mg, 62 % yield). LCMS: m / z found 307.10 [M+H]+, rt = 2.21 min (Method B) Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm).

[0364] Synthesis of (S)-N-(1-(3,4-difluorophenyl)ethyl)-N-methylmorpholine-4- sulfonamide (Example 39): The sulfonamide 22.1 (60 mg, 0.19 mmol) was dissolved in DMF (1 mL) and CS2CO3 (77 mg, 0.23 mmol) was added to it followed by Mel (0.10 mL, 1.95 mmol). The reaction mixture was stirred at RT for 30 min. The reaction was quenched with water (10 mL) and extracted with EtOAc (2 x 10 mL). The combined organic layer waswashed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude was purified by flash column chromatography over silica gel using 40 % EtOAc in hexane and the compound LTX-001606 was isolated as an off-white solid (30 mg, 4 % yield). LCMS: m / z 321.25 [M+H]+, rt = 2.84 min (Method B) Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm). 1H NMR (400 MHz, DMSO) 5 7.52 - 7.38 (m, 2H), 7.30 - 7.20 (m, 1 H), 4.98 (q, J = 7.1 Hz, 1 H), 3.63 (t, J = 4.8 Hz, 4H), 3.06 (t, J = 4.7 Hz, 4H), 2.57 (s, 3H), 1.52 (d, J = 7.1 Hz, 3H).Example 40 and Example 41(R)-N-(1-(3,4-difluorophenyl)-2,2,2-trifluoroethyl)-N-ethylmorpholine-4-sulfonamide(Example 40), and(R)-N-(1-(3,4-difluorophenyl)-2,2,2-trifluoroethyl)-N-methylmorpholine-4-sulfonamide(Example 41)

[0365] Synthesis of (R)-N-(1-(3,4-difluorophenyl)-2,2,2-trifluoroethyl)morpholine-4- sulfonamide 23.1 : To the stirred solution of morpholine-4-sulfonyl chloride (300 mg, 1.6 mmol) in DCM (2 mL) was added pyridine (1.31 mL, 16.3 mmol) and (R)-1-(3,4- difluorophenyl)-2,2,2-trifluoroethan-1-amine hydrochloride (337 mg, 1.63 mmol) and the reaction mixture was stirred at RT for 18 h. The reaction was quenched with water (10 mL) and extracted with DCM (2 x 15 mL). The combined organic layer was washed with water (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound was purified by flash column chromatography using 50% EtOAc in hexane and compound 6.1 was isolated as pale yellow solid (195 mg, 59% yield). LCMS: m / z found 361.1 [M+H]+, rt = 2.1 min (Method B) Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm).

[0366] Synthesis of (R)-N-(1-(3,4-difluorophenyl)-2,2,2-trifluoroethyl)-N- methylmorpholine-4-sulfonamide (Example 40): The sulfonamide 23.1 (110 mg, 0.3 mmol) was dissolved in DMF (2 mL) and CS2CO3 (120 mg, 0.36 mmol) was added to itfollowed by Mel (0.19 mL, 3.05 mmol). The reaction mixture was stirred at RT for 30 min. The reaction was quenched with water (10 mL) and extracted with EtOAc (2 * 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude was purified by flash column chromatography over silica gel using 40% EtOAc in hexane and the compound LTX- 001638 was isolated as colourless sticky liquid (35 mg, 28% yield). LCMS: m / z 375.21 [M+H]+, rt = 2.98 min (Method B) Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm). 1 H NMR (401 MHz, DMSO) 5 7.67 - 7.52 (m, 2H), 7.47 - 7.36 (m, 1 H), 5.80 (q, J = 8.7 Hz, 1 H), 3.60 (t, J = 4.7 Hz, 4H), 3.13 - 3.04 (m, 4H), 2.76 (s, 3H).

[0367] Synthesis of (R)-N-(1-(3,4-difluorophenyl)-2,2,2-trifluoroethyl)-N- ethylmorpholine-4-sulfonamide (Example 41): The sulfonamide 23.1 (180 mg, 0.5 mmol) was dissolved in DMF (2.5 mL) and CS2CO3 (195 mg, 0.6 mmol) was added to it followed by Etl (0.4 mL, 4.99 mmol). The reaction mixture was stirred at 40°C for 2 h. The reaction was quenched with water (10 ml) and extracted with EtOAc (2 * 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulphate, and concentrated under vacuum. The crude was purified by flash column chromatography over silica gel using 40 % EtOAc in hexane and the compound Example 41 was isolated as colourless sticky liquid (45 mg, 23% yield). LCMS: m / z 389.28 [M+H]+, rt = 3.07 min (Method B) Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm). 1 H NMR (401 MHz, DMSO) 5 7.72 - 7.53 (m, 2H), 7.53 - 7.40 (m, 1 H), 5.74 (q, J = 8.7 Hz, 1 H), 3.65 - 3.55 (m, 4H), 3.31 - 3.18 (m, 2H), 3.07 (dd, J = 3.6, 6.1 Hz, 4H), 0.99 (t, J = 7.0 Hz, 3H).Pharmacological ExamplesExample 42: Human Cav2.3 Channel Calcium-lnflux AssayCell Line

[0368] H EK-293 T-Rex cells were transfected with pcDNA3.1-Kir2.1 to generate a stable cell line. After antibiotic selection, the obtained stable pools were analysed using FLIPRTETRA(membrane potential assay), and a limiting dilution was performed and a HEK-293 T- Rex / Kir2.1 clone was selected. The clone was transfected with pcDNA3.1-Cav2.3e and pBud-Cav-p4-a251 to generate a stable cell line where the Cav2.3e expression is inducible. After antibiotic selection, functional clone pool analysis and two successive limiting dilutions, the final clone underwent a qPCR analysis and a biophysical and pharmacological validation using patch-clamp.Assay

[0369] A compound plate, containing 10 test compounds in eight-points dose response with n=4, was prepared. Test compounds dose response curves were prepared inautomated fashion in 100% DMSO at CyBio Felix and starting from a stock solution in 100% DMSO; a defined volume was serially moved into destination wells pre-filled with the desired DMSO volume; stock solution concentration volumes were dependent on the final compounds concentrations to be tested and the final DMSO content used in the assay. For the assay test compounds dose response curves ranged from 30 pM and half log dilution with 0.3% final DMSO. In order to obtain the 8-points dose response curve all the concentrations were created by starting from a 10 mM DMSO stock solution and then moving 9.5 pL into a destination well pre-filled with 20.5 pL of 100% DMSO and repeating this step seven times. This initial step was done into 96 MTP plates, 10 compounds / plate. One 384 MTP was then reformatted to contain all the 10 compounds at 8 concentrations, quadruplicate data points. This so obtained 384 MTP compound plate served as source plate in a “mother to child” process with a CyBi®-Well dispenser in which 0.7 pL of compounds were moved into a destination plate pre-filled with 57.6 pL of Tyrode’s buffer 0 mM K+, thus obtaining 4x concentrated compounds solution. In columns 1-2 and 23-24 the control wells were added. Both “source” compound plate and “destination” compound plate were barcoded and a relationship between the two plates was thus generated.

[0370] The day before the experiment, cells were detached by gentle wash with DPBS, followed by 5 min incubation at 37°C with Trypsin solution. Detached cells were diluted with OptiMEM + Doxycycline at 0.2 pg / mL, counted and plated in Poly-D-Lysine coated black / clear bottom (15.000 c / well in 20 pl / well) by the use of a MATRIX WellMate dispenser. Plates were placed into a humidified incubator at 37°C with 5% CO2 until the experimental day. 24h after seeding 10 pL / well of 1.5X Fluo8 NW dye solution prepared in Tyrode’s buffer 0 mM K+were added on top of the seeding medium. Cell plates were incubated for 40-60 min at RT in the dark. We then Injected off-line 10 pL / well of test compounds and controls 4X concentrated in Tyrode’s Buffer 0 mM K+ with the CyBi®-Well instrument. Cell plates were incubated 3 minutes at RT. Finally, we injected 20 pL / well of 3X concentrated activator solution (K20-Na130-Ca2 buffer: 20 mM KCI, 130 mM NaCI, 2 mM CaCI2, 10 mM HEPES, 10 mM Glucose, final concentrations, prepared starting from “K0-Na150-Ca2” and “K150- Na0-Ca2” buffers) at FDSS7000EX instrument and read emitted fluorescence for 130 seconds.

[0371] Data analysis was performed with Genedata Screener® software and reported compounds activity as % effect in relation to the normalization standards. The Kinetic Response Value (KRV) is calculated as follows:

[0372] KRV = Maximal fluorescence recorded from second 5 to second 130 minus baseline fluorescence, computed as average from second 1 to second 2, of the kinetic trace. The KRV was normalized versus Neutral Controls and Inhibitor Controls in order to obtainthe Activity[%] for each well. The normalization places the compound activity values on an equivalent scale and makes them comparable across plates or different compound batches. Therefore, the compound activity values were scaled (based on the two references) to a common range (two-point normalization). The following equation was used by the software to normalize the signal values to the desired signal range:N(x) = CR + [((x - < cr >) / (< sr > - < cr >)). (SR - CR)] where: x is the calculated signal value of a well (KRV); < cr > is the median of the calculated signal values (KRV) for the Central Reference wells of a plate (median of Neutral Controls); < sr > is the median of the calculated signal values (KRV) for the Scale Reference wells of a plate (median of Inhibitor Controls); CR is the desired median normalized value for the Central Reference (0) and SR is the desired median normalized value for the Scale Reference (-100).

[0373] The final equation to calculate the Activity% can be simplified as follow:% Activity = -100. (x - <NeutralControls>) I (<NeutralControls> - <lnhibitorControls>) where full inhibition corresponds to % Activity = -100

[0374] The fitting of the dose-response curve of each test compound is performed in the Analyzer module of the Screener software on the normalized values and applying the “smart fit” strategy. This strategy allowed an automatic selection between the “Constant Fit” and the “Hill Fit” model calculating which fit model best matched the experimental data. The Constant Fit was applied when no change of activity was detected across the measured concentrations, and the corresponding compounds were further classified as inactive. The Hill Fit was applied when the observed activity significantly changed with the compound concentration. In case of Hill Fit, Hill equation was used to determine the concentration at which activity reach...

Claims

CLAIMS1. A compound of the Formula (I), or a pharmaceutically acceptable salt thereof:wherein:R1is selected from: Ci-e alkyl, C3-6 cycloalkyl, and Cs-e cycloalkyl-Ci-e alkyl-, wherein R1is optionally substituted by one or more halo, and optionally wherein one or more H in R1is substituted by D;R2is selected from: H, D, Ci-e alkyl and Ci-e haloalkyl, optionally wherein one or more H in R2is substituted by D; orR1and R2together with the carbon atom to which they are attached form a C3-6 cycloalkyl optionally substituted with one or more halo;R3is selected from: H, Ci-e alkyl and Ci-e haloalkyl, optionally wherein one or more H in R3is substituted by D; each R4is independently selected from: halo, -CN, -NO2, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, -OR4A, -S(O)XR4A, -NR4AR4B, -C(O)R4A, - OC(O)R4A, -C(O)OR4A, -NR4AC(O)R4B, -C(O)NR4AR4B, -NR4AC(O)OR4B, -OC(O)NR4AR4B, - NR4ASO2R4B, and -SO2NR4AR4B, wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R9;R5is selected from: H, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and Co-6 alkylene- R5a; wherein said Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, and Ci-e alkylene is optionally substituted by one or more R10;R6is selected from: Ci-e alkyl, Ci-e haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and Co-6 alkylene- R6a;wherein said Ci-e alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1.6 alkylene is optionally substituted by one or more R10; orR5and R6, together with the nitrogen atom to which they are attached form Ring A, wherein Ring A is selected from: a 4- to 12 membered heterocyclyl group and a 5- to 12- membered heteroaryl group; wherein Ring A is optionally substituted by one or more R6b; each R6bis independently selected from: halo, -CN, -NO2, =0, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, -OR7, -S(O)XR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, - NR7SO2R8, and -SO2NR7R8; wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl is optionally substituted by one or more R11;R5aand R6aare each independently selected from: C3-6 cycloalkyl, 4- to 12 membered heterocyclyl, 5- to 12-membered heteroaryl, and Ce- aryl; wherein R5aand R6aare optionally substituted by one or more R12; each R7and R8is independently selected from: H, Ci-e alkyl, Ci-e haloalkyl and C3-6 cycloalkyl; wherein said Ci-e alkyl and C3-6 cycloalkyl is optionally substituted by one or more R13; each R9, R10, R11, R13, and R14is independently selected from: halo, =0, -CN, -OR9A, - S(O)xR9A, -NR9AR9B, C(O)R9A, -OC(O)R9A, -C(O)OR9A, -NR9AC(O)R9B, -C(O)NR9AR9Band C3-6 cycloalkyl; each R12is independently selected from: halo, -CN, -NO2, =0, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, -OR7, -S(O)XR7, -NR7R8, -C(O)R7, -OC(O)R7, -C(O)OR7, -NR7C(O)R8, -C(O)NR7R8, -NR7C(O)OR8, -OC(O)NR7R8, - NR7SO2R8, and -SO2NR7R8; wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-6 cycloalkyl is optionally substituted by one or more R14;R4A, R4BR9A, and R9Bare at each occurrence independently selected from: H, C1.4 alkyl and C1.4 haloalkyl; and wherein any -NR7R8, -NR4AR4B, and -NR9AR9Bwithin a substituent may form a4- to 6-membered heterocyclyl, wherein said 4- to 6-membered heterocyclyl is optionallysubstituted by one or more substituents selected from: halo, =0, C1.4 alkyl and C1.4 haloalkyl; each x is independently 0, 1 , or 2; and a is 0, 1 , 2, 3, 4 or 5; with the proviso that the compounds in List A are excluded:List A:

2. The compound according to claim 1 , wherein R5is selected from: C1.6 alkyl, C1.6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, and Co-6 alkylene-R5a, wherein said C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 alkylene is optionally substituted by one or more R10.

3. The compound according to claim 1 , wherein R5is selected from: C1.3 alkyl, C1.3 haloalkyl, and C0-3 alkylene-R5a; optionally wherein said alkyl and alkylene is substituted by one or more R10.

4. The compound according to claim 1 , wherein R5is C1.3 alkyl, for example R5is methyl or ethyl.

5. The compound according to any one of claims 1 to 4, wherein R6is selected from: C1-3 alkyl, C1-3 haloalkyl, and C0-3 alkylene-R6a; optionally wherein said alkyl and alkylene is substituted by one or more R10.

6. The compound according to any one of claims 1 to 4, wherein R6is selected from: C1-4 alkyl, -C2-4 alkyl-OR9A, -CH2-R6aand R6a,R6ais selected from C3-6 cycloalkyl and a 6-membered heteroaryl containing 1 or 2 ring nitrogen atoms, wherein said C3-6 cycloalkyl and 6-membered heteroaryl containing 1 or 2 ring nitrogen atoms are each independently optionally substituted by one or more R127. The compound according to claim 1 , wherein the compound is a compound of the formula (II), or a pharmaceutically acceptable salt thereof:optionally wherein Ring A is substituted with one or more R6b.

8. The compound according to claim 1 or claim 7, wherein Ring A is 4- to 10- membered heterocyclyl; optionally wherein Ring A is substituted with one or more R6b9. The compound according to any one of claims 1 , 7 or 8, wherein Ring A is selected from:

10. The compound according to claim 1 , wherein the compound is a compound of the formula (XII), or a pharmaceutically acceptable salt thereof:wherein b is 0, 1 , 2, 3, 4, 5, or 6; optionally wherein b is 0, 1 or 2.

11. The compound according to claim 1 or any one of claims 7 to 10, wherein each R6bis independently selected from: halo, -CN, -NO2, =0, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, OR7, -NR7R8, -C(O)R7, -C(O)NR7R8, and -NR7C(O)R8;optionally wherein each R6bis independently selected from: halo (e.g. fluoro or chloro), -CN, C1.3 alkyl and -OC1.3 alkyl.

12. The compound according to claim 1 , wherein the compound is a compound of the formula (XXII), or a pharmaceutically acceptable salt thereof:whereinRing B is selected from: C3-6 cycloalkyl, 4- to 12-membered heterocyclyl, 5- to 12-membered heteroaryl, and Ce- aryl; wherein Ring B is optionally substituted by one or more R12; and y is 0, 1 , 2, 3, 4, 5, or 6; optionally wherein:(i) y is 0 or 1 , preferably wherein y is 0; and(ii) R5is C1.3 alkyl, for example R5is methyl or ethyl.

13. The compound according to claim 12, wherein Ring B selected from: C3-6 cycloalkyl and a 6-membered heteroaryl containing 1 or 2 ring nitrogen atoms, wherein said C3-6 cycloalkyl and 6-membered heteroaryl containing 1 or 2 ring nitrogen atoms are each independently optionally substituted by one or more R12.

14. The compound according to any one of claims 1 to 13, wherein the group of the15. The compound according to any one of claims 1 to 14, wherein each R4is selected from: halo and C1.3 haloalkyl.

16. The compound according to any one of claims 1 to 13, wherein the group of the formulaselected from:

17. The compound according to any one of claims 1 to 13, wherein the group of the18. The compound according to any one of claims 1 to 13, wherein the group of the formula-fluorophenyl.

19. The compound according to any one of claims 1 to 18, wherein R3is selected from: Ci-6 alkyl and Ci-ehaloalkyl, optionally wherein one or more H in R3is substituted by D.

20. The compound according to any one of claims 1 to 18, wherein R3is selected from: methyl, -CDs, ethyl, and 2-fluoroethyl.

21. The compound according to any one of claims 1 to 18, wherein R3is selected from: methyl and ethyl.

22. The compound according to any one of claims 1 to 21 , whereinR1is selected from: Ci-e alkyl, C3-6 cycloalkyl, and Cs-e cycloalkyl-Ci-e alkyl-, wherein R1is substituted by at least one fluorine, optionally wherein one or more H in R1is substituted by D;R2is selected from: H, D, Ci-e alkyl and Ci-e haloalkyl, optionally wherein one or more H in R2is substituted by D; orR1and R2together with the carbon atom to which they are attached form a C3-6 cycloalkyl substituted with at least one fluorine.

23. The compound according to any one of claims 1 to 22, wherein R1is selected from: C1.6 alkyl and C3-6 cycloalkyl, wherein R1is substituted by at least one fluorine.

24. The compound according to any one of claims 1 to 22, wherein R1is selected from: CH2F, -CHF2, and -CF3.

25. The compound according to any one of claims 1 to 22, wherein R1is -CF3.

26. The compound according to any one of claims 1 to 21 , wherein R1is -methyl.

27. The compound according to any one of claims 1 to 26, wherein R2is selected from:H and methyl.

28. The compound according to any one of claims 1 to 26, wherein R2is H.

29. The compound of any one of claims 1 to 28, wherein the group of the formula:

31. A compound selected from Compound List 1 in the description, or a pharmaceutically acceptable salt thereof.

32. A pharmaceutical composition comprising a compound according to any one of claims 1 to 31, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, with the proviso that the compounds in List A are not excluded.

33. A compound according to any one of claims 1 to 31 , or a pharmaceutically acceptable salt thereof, for use as a medicament, with the proviso that the compounds in List A are not excluded.

34. A compound according to any one of claims 1 to 31 , or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or medical disorder mediated by Cav2.3, , with the proviso that the compounds in List A are not excluded.

35. A method of treating a disease or medical disorder mediated by Cav2.3 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound according to any one of claims 1 to 31 , or a pharmaceutically acceptable salt thereof, with the proviso that the compounds in List A are not excluded.

36. A compound according to any one of claims 1 to 31 , or a pharmaceutically acceptable salt thereof, for use in in the treatment of a disease or medical disorder selected from: a neurodegenerative disease, a neurodevelopmental disorder, epilepsy, an endocrine disorder, cerebral vasospasm, and pain, with the proviso that the compounds in List A are not excluded.

37. A compound according to any one of claims 1 to 31 , or a pharmaceutically acceptable salt thereof, for use in a neuroprotective treatment of a neurodegenerative disease, with the proviso that the compounds in List A are not excluded.

38. A compound according to any one of claims 1 to 31 , or a pharmaceutically acceptable salt thereof, for use in the treatment of Parkinson’s disease, with the proviso that the compounds in List A are not excluded.

39. A compound according to any one of claims 1 to 31 , or a pharmaceutically acceptable salt thereof, for use in a preventing or inhibiting degeneration of dopaminergic neurons in a subject with Parkinson’s disease, with the proviso that the compounds in List A are not excluded.

40. A compound according to any one of claims 1 to 31 , or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of epilepsy, with the proviso that the compounds in List A are not excluded; optionally wherein the epilepsy is a drug-resistant epilepsy.

41. A compound according to any one of claims 1 to 31 , or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a developmental and epileptic encephalopathy, with the proviso that the compounds in List A are not excluded; optionally wherein the developmental and epileptic encephalopathy is a monogenic developmental and epileptic encephalopathy (e.g. CACNA1E Gain-of-function Syndrome (DEE69), CDKL5 Deficiency (DEE2), Dravet syndrome (DEE6A), DEE9 (caused by mutation in the PCDH19 gene), DEE11 (SCN2A gain of function), DEE13, DEE19, DEE43, DEE45, DEE59, DEE74, DEE78, DEE79 or DEE92).

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