Sulfonamide compounds beneficial in neuroprotective treatment

Abstract

Disclosed are compounds of the formula (I) and pharmaceutically acceptable salts thereof: Formula (I) wherein Ring A, R1, R2, R3, R4 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 BENEFICIAL IN NEUROPROTECTIVE TREATMENT

[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 inParkinson’s disease. As PARK mutations and also most external factors are global Parkinson’s disease-stressors, additional cell-specific features must also contribute to the Parkinson’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), monogenicdevelopmental 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:(I) wherein:R1is selected from: Ci-e alkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-Ci-6 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;L is selected from: a bond and C1.3 alkylene;Ring A is a 4- to 12-membered heterocyclyl group comprising agroup; optionally wherein Ring A is substituted by one or more R5; or Ring A is phenyl or a 5- or 6-membered heteroaryl, wherein said phenyl or 5- or 6- membered heteroaryl is substituted by Ring B and is optionally substituted by one or more R5;Ring B is; wherein Ring B is a 4- to 12-membered heterocyclyl group, optionally wherein Ring B is substituted by one or more R5; each R5is 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 R10;R6is selected from: Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, and a 4- to 7-membered heterocyclyl group, wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, and 4- to 7-membered heterocyclyl group, is optionally substituted by one or more R11; or R6and one R5, together with the atoms to which they are attached form a 4- to 7- membered heterocyclyl group; optionally wherein the heterocyclyl group is substituted by one or more R5a; each R5ais 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 R10a;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 R12; each R9, R10, R10a, R11, and R12is independently selected from: halo, =0, -CN, -0R9A, - S(O)XR9A, -NR9AR9B, C(O)R9A, -OC(O)R9A, -C(O)OR9A, -NR9AC(O)R9B, -C(O)NR9AR9Band C3- 6 cycloalkyl;R4A, R4B, R9A, 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; a is 0, 1 , 2, 3, 4 or 5; with the proviso that the compounds in List A and List B are excluded:List A:

[0012] 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 and / or List B are not excluded.

[0013] 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 and / or List B are not excluded.

[0014] 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 and / or List B are not excluded.

[0015] 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 and / or List B are not excluded.

[0016] 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 and / or List B are not excluded.

[0017] 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 pharmaceutically acceptable 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 and / or List B are not excluded. Further therapeutic uses of the compounds of the invention are set out in the Detailed Description.DETAILED DESCRIPTIONDefinitions

[0018] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0019] 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 (XVII), or a compound described in any of the Examples, or a pharmaceutically acceptable salt, solvate, or salt of a solvate of any thereof.

[0020] 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.

[0021] 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.

[0022] 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 wellbeing. 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.

[0023] 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 Cav2.3channels, 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.

[0024] 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 effect does 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).

[0025] 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.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] The term Cm-n refers to a group with m to n carbon atoms.

[0032] 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(CHs)- , -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.

[0033] 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,-CH2CHX2or -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).

[0034] 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-CH3,-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- OCH3and -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).

[0035] 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 andalkenylene 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.

[0036] 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 alkynylene 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.

[0037] 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.

[0038] 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 of tetrahydrothienyl and thiomorpholinyl such as tetrahydrothiene 1 ,1 -dioxide and thiomorpholinyl 1 , 1 -dioxide. A suitable value for a heterocyclyl group which bears 1 or 2 oxo (=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.

[0039] The term “heterocyclyl”, “heterocyclic” or “heterocycle” also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is a non-aromatic, saturated or partially saturated ring and one or more of the other ring(s) is an aromatic ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Partially aromatic heterocyclyl 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 heterocyclyl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1 ,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 1 ,3-dihydroisobenzofuran, 2,3-dihydro-benzo[1 ,4]dioxinyl , benzo[1 , 3]dioxolyl , 2,2-dioxo-1 ,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl, 1 ,2,3,4-tetrahydro-1 ,8-naphthyridinyl, 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl and 3,4-dihydro-2 / 7-pyrido[3,2-b][1 ,4]oxazinyl.

[0040] 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.

[0041] 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.

[0042] “Heterocyclyl-Cm-n alkyl” includes a heterocyclyl group covalently attached to a Cm-nalkylene 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.

[0043] “-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.

[0044] 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] “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.

[0050] 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.

[0051] Examples of six-membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0052] 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.

[0053] 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.

[0054] The term “oxo,” or “=O” as used herein, means an oxygen that is double bonded to the atom to which it is attached (e.g. a carbon atom or a sulfur atom).

[0055] The term "optionally substituted" includes either groups, structures, or molecules that are substituted and those that are not substituted.

[0056] 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).

[0057] 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 moietymay 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.

[0058] 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.

[0059] 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 “”:

[0060] “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:

[0061] “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:

[0062] Where Ring A comprises an NH group the NH group may be substituted by R5to give NR5.

[0063] For the avoidance of doubt, the R6' group in Ring A is an integral structure of the ring. In other words, both the nitrogen and carbon atoms in -N(R6)- and -C(=O)- are ring atoms. For example, Ring A may be represented by the structure:whereinRing A is as defined elsewhere herein. Thus, example Ring A structures include:

[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:O-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] A bond terminating in a “. . 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 beconnected to any of the atoms in the ring structure where allowed by valency, unless stated otherwise herein. For example if Ringthe ring may be attached to the remainder of the compound via either the 5 membered ring or the 6-membered ring, including, but not limited

[0066] 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.

[0067] Suitable or preferred features of any compounds of the present invention may also be suitable features of any other aspect.

[0068] 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.

[0069] 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.

[0070] 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).

[0071] 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.

[0072] These methods are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.

[0073] 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.

[0074] 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.) ordiastereomeric 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%.

[0075] 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

[0076] 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.

[0077] 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.

[0078] 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.

[0079] When any racemate crystallises, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolaramounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.

[0080] 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).

[0081] 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 is18F.

[0082] 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.

[0083] 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, R5, R6, R7, or R8is methyl the invention also encompasses -CDs, -CHD2 and -CH2D. Similarly R2, R3, R7, or R8may be D.

[0084] 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.

[0085] It is also to be understood that certain compounds of the invention may exhibit polymorphism, and that the invention encompasses all such forms.

[0086] 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

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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.

[0092] 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.

[0093] 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 / Vo-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.

[0094] 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 (C1.4 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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

[0099] The following paragraphs are applicable to the compounds of the invention, including compounds of the formulae (I) to (XVII).

[0100] 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, L, and Ring A are as defined for formula (I).

[0101] In certain embodiments the compound of the formula (I) is a compound of the formula (III), or a pharmaceutically acceptable salt thereof:whereinR3, R4, a, L, 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 (IV), or a pharmaceutically acceptable salt thereof:wherein R3, R4, L, 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 (V), or a pharmaceutically acceptable salt thereof:whereinR3, R4, L, 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 (VI), or a pharmaceutically acceptable salt thereof:(VI) whereinR1, R2, R3, R4, R5, R6, a, and L are as defined for formula (I); and b is 0, 1 , 2, or 3.

[0105] In certain embodiments the compound of the formula (I) is a compound of the formula (VII), or a pharmaceutically acceptable salt thereof:whereinR1, R2, R3, R4, R5, R6, a, and L are as defined for formula (I); and b is 0, 1 , or 2.

[0106] In certain embodiments the compound of the formula (I) is a compound of the formula (VIII), or a pharmaceutically acceptable salt thereof:whereinR1, R2, R3, R4, R5, R6, a, and L are as defined for formula (I); and b is 0, 1 , or 2.

[0107] In certain embodiments the compound of the formula (I) is a compound of the formula (IX), or a pharmaceutically acceptable salt thereof:whereinR1, R2, R3, R4, R5, R6, a, and L are as defined for formula (I); and b is 0, 1 , or 2.

[0108] In certain embodiments the compound of the formula (I) is a compound of the formula (X), or a pharmaceutically acceptable salt thereof:whereinR1, R2, R3, R4, R5, R6, a, and L are as defined for formula (I); and b is 0, 1 , 2, 3, or 4.

[0109] In certain embodiments the compound of the formula (I) is a compound of the formula (XI), or a pharmaceutically acceptable salt thereof:whereinR1, R2, R3, R4, R5, R6, a, and L are as defined for formula (I); and b is 0, 1 , 2, 3, or 4.

[0110] 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, R5, R6, a, and L are as defined for formula (I); and b is 0, 1 , 2, or 3.

[0111] 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, R5, R6, a, and L are as defined for formula (I); and b is 0, 1 , or 2.

[0112] In certain embodiments the compound of the formula (I) is a compound of the formula (XIV), or a pharmaceutically acceptable salt thereof:whereinR1, R2, R3, R4, R5, R6, a, and L are as defined for formula (I); andb is 0, 1 , 2, or 3.

[0113] In certain embodiments the compound of the formula (I) is a compound of the formula (XV), or a pharmaceutically acceptable salt thereof:whereinR1, R2, R3, R4, R5, R6, a, and L are as defined for formula (I); and b is 0, 1 , 2, or 3.

[0114] In certain embodiments the compound of the formula (I) is a compound of the formula (XVI), or a pharmaceutically acceptable salt thereof:whereinR1, R2, R3, R4, R5, R6, a, and L are as defined for formula (I); and b is 0, 1 , or 2.

[0115] In certain embodiments the compound of the formula (I) is a compound of the formula (XVII), or a pharmaceutically acceptable salt thereof:whereinR1, R2, R3, R4, R5, R6, a, and L are as defined for formula (I); andb is 0, 1, 2, 3, 4, 5, or 6.

[0116] In certain embodiments compounds of the invention include, for example, compounds of formulae (I) to (XVII), 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, R7, R8, R9, R10, R10a, R11, R12, R9A, R9B, L, a, b, and x has any of the meanings defined hereinbefore or in any of the following statements in the numbered paragraphs 1 to 183 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 substituted by at least one fluorine.2. R1is selected from: C1.3 alkyl, C3-6 cycloalkyl, and Cs-ecycloalkyl-Ci-s alkyl-, wherein R1is substituted by at least one fluorine.3. R1is selected from: Ci-e alkyl, and C3-6 cycloalkyl, wherein R1is substituted by at least one fluorine.4. R1is selected from: C1.3 alkyl, and C3-6 cycloalkyl, wherein R1is substituted by at least one fluorine.5. R1is C1.6 alkyl, wherein R1is substituted by at least one fluorine.6. R1is C1.3 alkyl, wherein R1is substituted by at least one fluorine.7. R1is selected from ethyl and methyl, wherein the ethyl or methyl is substituted by at least one fluorine.8. R1is ethyl wherein the ethyl is substituted by at least one fluorine.9. R1is selected from -CH2F, -CHF2, and -CF3.10. R1is -CH2F.11. R1is -CHF2.12. R1is -CF3.13. R1is as defined in any of 1 to 12, wherein one or more H in R1is substituted by D.14. R2is selected from: H, C1.3 alkyl and Ci-s haloalkyl.15. R2is selected from: H, and C1.3 alkyl.16. R2is C1.3 alkyl.17. R2is methyl.18. R2is H or D. It may be that R2is D. It may be that R2is H.19. R1and R2together with the carbon atom to which they are attached form a C3 or C4 cycloalkyl substituted with at least one fluorine.20. 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.21. 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.22. R1is as defined in any of 1 to 13 and R2is methyl.23. R1is as defined in any of 1 to 13 and R2is H.24. R3is selected from: Ci-e alkyl and Ci-e haloalkyl.25. R3is selected from: C1.3 alkyl and C1.3 haloalkyl.26. R3is selected from: C1.2 alkyl and C1.2 haloalkyl.27. R3is methyl optionally substituted with 1 to 3 halo groups.28. R3is ethyl optionally substituted with 1 to 5 halo groups.29. R3is as defined in any of 24 to 28, wherein said halo is fluoro.30. R3is C1.3 alkyl.31. R3is selected from: methyl, ethyl, and 2-fluoroethyl.32. R3is methyl.33. R3is ethyl.34. R3is 2-fluoroethyl.35. R3is as defined in any of 24 to 34 wherein one or more hydrogen atoms in R3is deuterium. Thus, it may be that R3is selected from: methyl, -CD3, ethyl, and 2- fluoroethyl.36. R3is -CD3.37. Each R4is independently selected from: halo, -CN, -NO2, Ci-e alkyl, Ci-e haloalkyl, - OR4A, -S(O)xR4A, and -NR4AR4B38. 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 - SO2NR4AR4B39. Each R4is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, - OR4A, and -S(O)XR4A40. Each R4is independently selected from: halo, -CN, -NO2, C1.3 alkyl, C1.3 haloalkyl, - OR4A, and -S(O)XR4A41. Each R4is independently selected from: halo, C1.3 alkyl, C1.3 haloalkyl, -OC1.3 alkyl and -O-C1.3 haloalkyl.42. Each R4is independently selected from: halo and C1.3 alkyl.43. Each R4is independently selected from: halo, -CN, -NO2, methyl, CF3, -OH, -OMe, and -S(O)2Me.44. Each R4is independently selected from: fluoro, chloro, -CN, -NO2, methyl, -CF3, -OH, -OMe, and -S(O)2Me.45. Each R4is independently selected from: fluoro, chloro, methyl, -CF3, methoxy, -OCF3 and -OCHF2.46. Each R4is independently selected from: fluoro, chloro, and methyl.47. R4is fluoro.48. R4is chloro.49. R4is -CF3.50. R4is as defined in any of 37 and 39 to 46, wherein said alkyl is substituted by one or more R9.51. Each R9is independently selected from: halo, -CN, -OR9A, -NR9AR9Band -SO2R9A.52. Each R9is independently selected from: halo, -CN, -OR9A, and -NR9AR9B.53. Each R9is independently selected from: halo and -OR9A.54. The group of the formulaselected from:55. The group of the formulaselected from:56. The group of the formulaselected from:from:The group of the formulaselected from:60. The group of the formula-fluorophenyl.61. The group of the formula-chlorophenyl.62. The group of the formulatrifluoromethylphenyl.63. L is selected from: a bond and C1.2 alkylene.64. L is selected from: a bond, -CH2-, and -CH2CH2-.65. L is selected from: a bond and -CH2-.66. L is -CH2-.67. L is a bond.68. Ring A is a 4- to 12-membered heterocyclyl group comprising69. Ring A is a 6- to 12-membered heterocyclyl group comprising70. Ring A is a 6- to 10-membered heterocyclyl group comprising71. Ring A is a 4- to 8-membered monocyclic heterocyclyl group comprisinggroup.72. Ring A is a 7- to 12-membered bicyclic heterocyclyl group comprisinggroup.73. Ring A is a 7- to 10-membered bicyclic heterocyclyl group comprising a Rgroup.74. Ring A is a 9- or 10-membered bicyclic heterocyclyl group comprising a R .66' group.75. Ring A is as defined in any of 67 to 73, where Ring A is a non-aromatic saturated or partially saturated monocyclic or fused, bridged, or spiro bicyclic heterocyclic ring system.76. Ring A is as defined in any of 67 to 73, where Ring A is an aromatic mono- or bicyclic ring system.77. Ring A is as defined in any of 67 to 73, where Ring A is a partially aromatic mono- or bicyclic ring system.78. Ring A is selected from: a 5- or 6-membered non-aromatic saturated or partially saturated monocyclic heterocyclic ring, and a 9- or 10-membered partially aromatic bicyclic heterocyclic ring system.79. Ring A is a 6-membered non-aromatic saturated or partially saturated monocyclic heterocyclic ring.80. Ring A is 9--membered partially aromatic bicyclic heterocyclic ring system.81. Ring A is 10--membered partially aromatic bicyclic heterocyclic ring system.82. Ring A is as defined in any of 67 to 80, wherein Ring A is optionally substituted with one or more R5.83. Ring A is selected from:85. Ring A is as defined in any of 82 to 83, wherein b is 0, 1, 2, 3, or 4.86. Ring A is as defined in any of 82 to 83, wherein b is 0, 1 , 2, or 3.87. Ring A is as defined in any of 82 to 83, wherein b is 3.88. Ring A is as defined in any of 82 to 83, wherein b is 2.89. Ring A is as defined in any of 82 to 83, wherein b is 1.90. Ring A is as defined in any of 82 to 83, wherein b is 0.91. Ring A is phenyl or a 5- or 6-membered heteroaryl, wherein said phenyl or 5- or 6- membered heteroaryl is substituted by Ring B.92. Ring A is phenyl substituted by Ring B.93. Ring A is 5-membered heteroaryl substituted by Ring B.94. Ring A is 6-membered heteroaryl substituted by Ring B. Thus, it may be that Ring A is pyridyl substituted by Ring B.95. Ring A is as defined in any of 90 to 93, wherein Ring A is substituted by one or more R5.97. Ring B is a 4- to 12-membered heterocyclyl group.98. Ring B is a 5- to 10-membered heterocyclyl group.99. Ring B is a 5-membered heterocyclyl group.100. Ring B is a 6-membered heterocyclyl group. Thus, it may be that Ring B is101. Ring B is as defined in any of 95 to 99, wherein Ring B is substituted by one or moreR5102. Ring A substituted by Ring B may have the structure:103.optionally substituted by one or more R5. Thus, it may be thatRing A substituted by Ring B has the structure:; optionally substituted with one or more R5.104. Each R5is 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 -SO2NR7R8.105. Each R5is 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 -SO2NR7R8.106. Each R5is independently selected from: halo, -CN, -NO2, Ci-e alkyl, Ci-e haloalkyl, - OR7, -NR7R8, -C(O)R7, -C(O)OR7, -C(O)NR7R8.107. Each R5is independently selected from: halo, -CN, C1.4 alkyl, C1.4 haloalkyl, -OR7, - NR7R8, -C(O)R7, -C(O)OR7, and -C(O)NR7R8.108. Each R5is 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)R8.109. Each R5is independently selected from: halo, -CN, C1.4 alkyl, -OR7, -NR7R8, -C(O)R7, -C(O)NR7R8and -NR7C(O)R8.110. Each R5is independently selected from: halo, -CN, C1.4 alkyl, -C(O)R7and - C(O)NR7R8.111. Each R5is 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)2.112. Each R5is independently selected from halo (e.g. fluoro or chloro), -CN, C1.3 alkyl and -OC1.3 alkyl. Thus it may be that each R5is independently selected from halo, -CN and C1.3 alkyl. Thus it may be that each R5is independently selected from fluoro, chloro, -CN, methyl and methoxy. For example each R5is independently selected from fluoro, chloro, -CN and methyl. For example, each R5is independently selected from fluoro, chloro, and methyl.113. R5is as defined in any one of 103 to 111 , wherein said alkyl, heteroalkyl, alkenyl, alkynyl, or cycloalkyl is substituted by one or more R10.114. Each R10is independently selected from: halo, -CN, -OR9A, -NR9AR9Band -SO2R9A.115. Each R10is independently selected from: halo, -CN, -OR9A, and -NR9AR9B.116. Each R10is independently selected from: halo and -OR9A.117. R6is selected from: Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2.6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, and a 4- to 7-membered heterocyclyl group.118. R6is selected from: Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2.6 alkenyl, C2-6 alkynyl and C3-6 cycloalkyl.119. R6is selected from: C1.3 alkyl, C1.3 haloalkyl, 2 to 4 membered heteroalkyl, C2.3 alkenyl, C2-3 alkynyl, C3 cycloalkyl and 4-membered heterocyclyl.120. R6is selected from: C1.3 alkyl, C1.3 haloalkyl, 2 to 4 membered heteroalkyl, C2.3 alkenyl, C2-3 alkynyl and C3 cycloalkyl.121. R6is selected from: Ci-e alkyl, Ci-e haloalkyl, and 2 to 8 membered heteroalkyl.122. R6is selected from: C1.3 alkyl, C1.3 haloalkyl, and 2 to 4 membered heteroalkyl.123. R6is C1.3 alkyl. Thus, it may be that R6is methyl. It may be that R6is ethyl.124. R6is 3 or 4 membered heteroalkyl. Thus, it may be that R6is an oxygen containing 3 or 4 membered heteroalkyl, e.g., -Ci-2alkyl-O-Ci-2alkyl. R6may be -CH2CH2OMe. R6may be -CH2CH2OEt.125. R6is 1 to 3 membered heteroalkyl. Thus, it may be that R6is an oxygen containing 1 to 3 membered heteroalkyl, e.g., -C1.3 alkyl-OH, or -Ci-2alkyl-OH R6may be - CH2CH2OH. R6may be -CH2CH2CH2OH.126. R6is C3-6 cycloalkyl. Thus, it may be that R6is C3 cycloalkyl.127. R6is a 4- to 7-membered heterocyclyl group. Thus, it may be that R6is a 4-membered heterocyclyl group.128. R6may be as defined in any of 116 to 126, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl is optionally substituted by one or more R11.129. Each R11is independently selected from: halo, -CN, -OR9A, -NR9AR9Band -SC>2R9A.130. Each R11is independently selected from: halo, -CN, -OR9A, and -NR9AR9B.131. Each R11is independently selected from: halo and -OR9A.132. R6and one R5, together with the atoms to which they are attached form a 4- to 7- membered heterocyclyl group.133. R6and one R5, together with the atoms to which they are attached form a 5-membered heterocyclyl group.134. R6and one R5, together with the atoms to which they are attached form a 6-membered heterocyclyl group.135. The heterocyclyl group as defined in one of 131 to 133, wherein the heterocyclyl is optionally substituted with one or more R5a.136. Each R5ais 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 -SO2NR7R8.137. Each R5ais 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 -SO2NR7R8.138. Each R5ais independently selected from: halo, -CN, -NO2, Ci-e alkyl, Ci-e haloalkyl, - OR7, -NR7R8, -C(O)R7, -C(O)OR7, -C(O)NR7R8.139. Each R5ais independently selected from: halo, -CN, C1.4 alkyl, C1.4 haloalkyl, -OR7, - NR7R8, -C(O)R7, -C(O)OR7, and -C(O)NR7R8.140. Each R5ais 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)R8.141. Each R5ais independently selected from: halo, -CN, C1.4 alkyl, -OR7, -NR7R8, -C(O)R7, -C(O)NR7R8and -NR7C(O)R8.142. Each R5ais independently selected from: halo, -CN, C1.4 alkyl, -C(O)R7and - C(O)NR7R8.143. Each R5ais 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)2.144. Each R5ais independently selected from halo (e.g. fluoro or chloro), -CN, C1.3 alkyl and -OC1.3 alkyl. Thus it may be that each R5ais independently selected from halo, -CN and C1.3 alkyl. Thus it may be that each R5ais independently selected from fluoro, chloro, -CN, methyl and methoxy. For example each R5ais independently selected from fluoro, chloro, -CN and methyl. For example, each R5ais independently selected from fluoro, chloro, and methyl.145. R5ais as defined in any of 135 to 143, wherein said alkyl, heteroalkyl, alkenyl, alkynyl, or cycloalkyl is substituted by one or more R10a.146. Each R10ais independently selected from: halo, -CN, -OR9A, -NR9AR9Band -SO2R9A147. Each R10ais independently selected from: halo, -CN, -OR9A, and -NR9AR9B148. Each R10ais independently selected from: halo and -OR9A.149. Ring A is selected from:wherein R5ais as defined in any of 135 to 144 and c is an integer from 0 to 6.150. Ring A is selected from:defined in any of 135 to 144 and c is an integer from 0 to 6.151. Ring A is selected from:152. R7and R8are each independently selected from: H, Ci-e alkyl, Ci-e haloalkyl and C3-6 cycloalkyl.153. R7and R8are each independently selected from: H, C1.3 alkyl, C1.3 haloalkyl and C3 cycloalkyl.154. R7and R8are each independently selected from: H, C1.3 alkyl, and C1.3 haloalkyl.155. R7and R8are each independently selected from: H and C1.3 alkyl.156. R7and R8are as defined in 151 to 154, wherein said alkyl is substituted by one or more R12.157. Each R12is independently selected from: halo, -CN, -OR9A, -NR9AR9Band -SC>2R9A.158. Each R12is independently selected from: halo, -CN, -OR9A, and -NR9AR9B.159. Each R12is independently selected from: halo and -OR9A.160. Each R4A, R4B, R9Aand R9Bis independently at each occurrence selected from: H, and C1.4 alkyl.161. Each R4A, R4B, R9Aand R9Bis independently at each occurrence selected from: H, methyl, and ethyl.162. Each R4A, R4B, R9Aand R9Bis independently at each occurrence selected from: H and methyl.163. Any -NR7R8, -NR4AR4B, and -NR9AR9Bwithin a substituent may form a 4-membered heterocyclyl.164. Any -NR7R8, -NR4AR4B, and -NR9AR9Bwithin a substituent may form a 5-membered heterocyclyl.165. Any -NR7R8, -NR4AR4B, and -NR9AR9Bwithin a substituent may form a 6-membered heterocyclyl.166. -NR7R8, -NR4AR4B, and -NR9AR9Bmay be as defined in any of 162 to 164, wherein said heterocyclyl is optionally substituted by one or more substituents selected from: halo, =0, C1.4 alkyl and C1.4 haloalkyl.167. -NR7R8, -NR4AR4B, and -NR9AR9Bmay be as defined in any of 162 to 164, wherein said heterocyclyl is optionally substituted by one or more substituents selected from: halo, C1.3 alkyl and C1.3 haloalkyl.168. Ring A is selected from:169. a is an integer from 0 to 5.170. a is an integer from 0 to 3.171. a is 3.172. a is 2.173. a is 1. 174. a is 0.175. c is 6.176. c is 5.177. c is 4.178. c is 3. 179. c is 2.180. c is 1.181. c is 0.182. Each x is independently 0.183. Each x is independently 1.184. Each x is independently 2.

[0117] In an embodiment, the compound of formula (I) is a compound of any of formulae (I) to (XVII), wherein L is a bond.

[0118] In an embodiment, the compound of formula (I) is a compound of any of formulae (I) to (XVII), wherein L is -CH2-.

[0119] In an embodiment, the compound of formula (I) is a compound of any of formulae (I) to (XVII), wherein L is a bond and R3is selected from methyl, ethyl, and -CH2CH2F.

[0120] In an embodiment, the compound of formula (I) is a compound of any of formulae (I) to (XVII), wherein L is a bond and R3is methyl or ethyl.

[0121] In certain embodiments, the compound is a compound according to any of formulae (I), (II), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), and (XVII), wherein R1is selected from -CH2F, -CHF2 and -CF3. Suitably in this embodiment R2is H. Suitably in this embodiment L is a bond and R3is selected from methyl, ethyl, and -CH2CH2F.

[0122] In these embodiments it may be that R3is methyl or ethyl.

[0123] 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.

[0124] In certain embodiments in any of the compound of any of formulae (I), (II), (III), (IV), and (V): L is a bond; R2is H; R3is selected from methyl, ethyl and -CH2CH2F; and Ring A is as defined in any of 67 to 94, 101 to 102, 148 to 150, and 167.

[0125] In these embodiments it may be that Ring A is optionally substituted by one or more (e.g. 1 or 2) R5wherein each R5is independently selected from: halo, -CN, -NO2, Ci-e 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) R5, wherein each R5is 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) R5, wherein each R5is 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) R5, wherein each R5is independently selected from: F, Cl, -CN, and methyl.

[0126] 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.

[0127] In certain embodiments the compound of any of formulae (I), (II), (III), (IV), and (V) is a compound wherein Ring A is not a structure selected from:

[0129] In an embodiment, the compound of formula (I) is a compound of any of formulae (I) to (XVII), wherein Ring A is attached to the sulfur atom of the sulfonamide group via a carbon atom within Ring A, i.e. ,

[0130] In another embodiment there is provided a compound selected from Compound List 1 , or a pharmaceutically acceptable salt thereof: Compound List 1

[0131] In an embodiment, the compound of the invention is not a compound selected from:

[0132] In another embodiment there is provided a compound selected from any one of the Examples herein, or a pharmaceutically acceptable salt thereof.

[0133] 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.

[0134] 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

[0135] 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.

[0136] It may be that the pharmaceutical composition comprises a compound selected from a compound according to any of formulae (I) to (XVII), or a pharmaceutically acceptable salt thereof.

[0137] 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.

[0138] The compositions of the invention 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).

[0139] The compositions of the invention 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.

[0140] An effective amount of a compound of the present 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.

[0141] 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 administration to humans will generally contain, for example, from 0.1 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.

[0142] 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.

[0143] 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 or 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 intravenousadministration. In another particular embodiment the compound of the invention is administered orally.THERAPEUTIC USES AND APPLICATIONS

[0144] 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 (XVII), or a pharmaceutically acceptable salt thereof, with the proviso that the compounds in List A and / or List B are not excluded.

[0145] It may be that, in the described 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 (XVII), or a pharmaceutically acceptable salt thereof, wherein compounds in List A and / or List B are excluded.

[0146] In accordance with another aspect, the present invention provides a compound of the invention, for use as a medicament.

[0147] 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.

[0148] 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.

[0149] 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.

[0150] 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.

[0151] 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.

[0152] 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

[0153] 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.

[0154] 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. Thus compound of the invention may be for use in preventing or reducing neurodegeneration associated with a neurodegenerative disease.

[0155] 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.

[0156] 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

[0157] 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).

[0158] 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 (ILAE) 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. ILAE classification of the epilepsies: position paper of the ILAE commission for classification and terminology. Epilepsia. 2017;58:512-21).

[0159] 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).

[0160] 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).

[0161] 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.

[0162] 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

[0163] In certain embodiments a compound of the invention is for use in the treatment of epilepsy.

[0164] 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.

[0165] 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.

[0166] 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.

[0167] 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. Thedrug-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.

[0168] 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

[0169] 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

[0170] 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 Vasospasm

[0171] 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 theinvention 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.Selectivity

[0172] 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.

[0173] 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

[0174] 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.

[0175] 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).

[0176] 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 therapeuticallyeffective dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.

[0177] 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.

[0178] 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 described in 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

[0179] 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.

[0180] 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.

[0181] 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).

[0182] 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

[0183] 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 C3-6 cycloalkyl-Ci-6 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;L is selected from: a bond and C1.3 alkylene;Ring A is a 4- to 12-membered heterocyclyl group comprising agroup; optionally wherein Ring A is substituted by one or more R5; or Ring A is phenyl or a 5- or 6-membered heteroaryl, wherein said phenyl or 5- or 6- membered heteroaryl is substituted by Ring B and is optionally substituted by one or more R5;Ring B is; wherein Ring B is a 4- to 12-membered heterocyclyl group, optionally wherein Ring B is substituted by one or more R5; each R5is 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 R10;R6is selected from: Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl and C3-6 cycloalkyl, 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; or R6and one R5, together with the atoms to which they are attached form a 4- to 7- membered heterocyclyl group; optionally wherein the heterocyclyl group is substituted by one or more R5a; each R5ais 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 R10a;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 R12; each R9, R10, R10a, R11, and R12is 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;R4A, R4B, R9A, 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; a is 0, 1 , 2, 3, 4 or 5; with the proviso that the compound according to formula (I) is not:2. The compound according to Embodiment 1 , wherein Ring A is selected from: a 5- or 6-membered non-aromatic saturated or partially saturated monocyclic heterocyclic ring, and a 9- or 10-membered partially aromatic bicyclic heterocyclic ring system; wherein RingA comprises comprisinggroup, and wherein Ring A is optionally substituted by one or more R5.3. The compound according to Embodiment 1, wherein Ring A is a 6-membered nonaromatic saturated or partially saturated monocyclic heterocyclic ring; wherein Ring A comprises comprisinggroup, and wherein Ring A is optionally substituted by one or more R5. 4. The compound according to any one of Embodiments 1 to 7, wherein each R5is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 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 -SO2NR7R8.5. The compound according to any one of Embodiments 1 to 7, wherein each R5is 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; optionally wherein each R5is independently selected from: fluoro, chloro, -CN, and methyl.6. The compound according to Embodiment 1 , wherein Ring A is selected from:7. The compound according to Embodiment 1 , wherein the compound is a compound10 of the formula (VI), or a pharmaceutically acceptable salt thereof:wherein b is 0, 1, 2, or 3.8. The compound according to Embodiment 1, wherein the compound is a compound of the formula (IX), or a pharmaceutically acceptable salt thereof:wherein b is 0, 1, or 2.9. The compound according to Embodiment 1, wherein the compound is a compound of the formula (XIV), or a pharmaceutically acceptable salt thereof:wherein b is 0, 1, 2, or 3.10. The compound according to any one of Embodiments 1 to 9, wherein the group of11. The compound according to any one of Embodiments 1 to 9, wherein the group of the formulaselected from:12. The compound according to any one of Embodiments 1 to 9, the group of the13. The compound according to any one of Embodiments 1 to 9, wherein the group of the formula-fluorophenyl.14. The compound according to any one of Embodiments 1 to 13, wherein L is selected from a bond and -CH2-. 15. The compound according to any one of Embodiments 1 to 13, wherein L is a bond.16. The compound according to any one of Embodiments 1 to 15, wherein R3is selected from methyl, -CDs, ethyl, and 2-fluoroethyl.17. The compound according to any one of Embodiments 1 to 15, wherein R3is selected from methyl and ethyl.18. The compound according to any one of Embodiments 1 to 17, wherein R1is selected from Ci-e alkyl and C3-6 cycloalkyl, wherein R1is substituted by at least one fluorine.19. The compound according to any one of Embodiments 1 to 17, wherein R1is selected from CH2F, -CHF2, and -CF3.20. The compound according to any one of Embodiments 1 to 17, wherein R1is -CF3.21. The compound according to any one of Embodiments 1 to 20, wherein R2is selected from H and methyl.22. The compound according to any one of Embodiments 1 to 20, wherein R2is H.23. The compound of any one of Embodiments 1 to 22, wherein the group of the formula:24. The compound of any one of Embodiments 1 to 22, wherein the group of the formula:25. A compound selected from Compound List 1 in the description, or a pharmaceutically acceptable salt thereof.26. A pharmaceutical composition comprising a compound according to any one of Embodiments 1 to 25, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.27. A compound according to any one of Embodiments 1 to 25, or a pharmaceutically acceptable salt thereof, for use as a medicament.28. A compound according to any one of Embodiments 1 to 25, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or medical disorder mediated by Cav2.3.29. 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 25, or a pharmaceutically acceptable salt thereof.30. A compound according to any one of Embodiments 1 to 25, 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.31. A compound according to any one of Embodiments 1 to 25, or a pharmaceutically acceptable salt thereof, for use in a neuroprotective treatment of a neurodegenerative disease.32. A compound according to any one of Embodiments 1 to 25, or a pharmaceutically acceptable salt thereof, for use in the treatment of Parkinson’s disease.33. A compound according to any one of Embodiments 1 to 25, or a pharmaceutically acceptable salt thereof, for use in a preventing or inhibiting degeneration of dopaminergic neurons in a subject with Parkinson’s disease.34. A compound according to any one of Embodiments 1 to 25, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of epilepsy; optionally wherein the epilepsy is a drug-resistant epilepsy.35. A compound according to any one of Embodiments 1 to 25, 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

[0184] 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, reactiontemperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art.

[0185] 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.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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.

[0190] 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 catalystsuch 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.

[0191] 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.

[0192] 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 be removed, 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.

[0193] Resins may also be used as a protecting group.General Synthetic Routes

[0194] Compounds of formula (vi) can generally be prepared by reacting a compound of formula (iv)wherein ring A, L, and R6are as defined above for any of formulae (I) to (XVII), and LG is a leaving group, with a compound of formula (vii) or with a compound of formula (vii- a):(vii-a) (vii) wherein R1, R2, R3, R4and a are as defined above for any of formulae (I) to (XVII), except that any functional group is protected, if necessary; and optionally thereafter carrying out one or more of the following procedures: converting a compound of formula (vi) into another compound of formula (vi); removing any protecting groups; forming a pharmaceutically acceptable salt; and / or preparing stereochemically isomeric forms thereof.

[0195] In the compound of formula (iv), LG is an appropriate leaving group such as, for example, halo, e.g., fluoro, chloro, bromo and the like.

[0196] Compounds of formula (iv) may be prepared according to the following scheme (General Scheme 1):

[0197] Sulfide compound (ii) may be obtained by reaction of the respective bromo derivatives (i) through a sulfur-carbon bond forming reaction in an inert atmosphere in the presence of Pd catalyst. Examples of such reaction include reaction of aromatic bromo, chloro or iodo compound with sulphur compound e.g. phenylmethanethiol, (4- methoxyphenyhmethanethiol and 2-ethylhexyl 3-mercaptopropanoate. The reaction may be performed in a suitable solvent, such as, 1 ,4-dioxane, toluene, benzene, DMF, DI E,DMA solution preferably at temperatures between RT and 150 °C. Palladium- catalyzed coupling reactions, the active palladium catalyst is believed to be Pd (0) complex, which can be generated in a variety of ways. Suitable Pd (0) sources such as, Pd(PPhs)4 or Pd(dba)2, can undergo ligand dissociation to form the active species. Phosphines can be added to ligandless palladium (0).

[0198] Compounds of formula (iii) may be obtained by reaction of compounds of formula(ii) with alkylating reagent, preferably with inorganic base under thermal condition preferably at temperatures between 50 °C and 120 °C. The reaction of a compound of formula (ii), may be carried out in a at least one reaction-inert solvent and optionally in the presence of at least one suitable base thereof. Non-limiting examples of such reaction promoters include K2CO3, CS2CO3, NaH or a functional derivative thereof; may be performed in a reaction-inert solvent such as, for example, DMF, DMSO, acetonitrile.

[0199] Sulfonyl chloride (iv) may be obtained by reaction of the respective thiol derivatives(iii) in a sulfur-oxygen and sulfur-chlorine bond forming reaction. Non-limiting examples of such reaction include reaction with:- halogen or a chlorine source in the presence of acid water such as chlorine gas, NaOCI, NCS, NBS, 1 ,3-Dibromo-5,5-Dimethylhydantoin, oxone, isocyanuric chloride or a derivative thereof;- an oxygen source such as ammonium nitrate, an aqueous solution of AcOH, HCI and HBr and oxygen as a terminal oxidant was developed in that process.

[0200] The reaction may be performed in a suitable solvent, such as, DCM, tetrahydrofuran, acetic acid, diethyl ether, toluene preferably at temperatures between -20°C and RT.

[0201] Compounds of formula (v) may generally be prepared by reacting a compound of formula (iv) and formula (vii), using the protocol described above. Compounds according to formula (vi) can be prepared from a single step procedure form formula (iv) using N-alkylated compound (vii-a) as mentioned below the following scheme (General Scheme 2):where Z in the alkylating compound (R3-Z) is an appropriate leaving group, such as, for example, halo, e.g., fluoro, chloro, bromo, iodo and the like.

[0202] Reaction of compounds of formula (v) with alkylating reagent, preferably with inorganic base under thermal condition preferably at temperatures between room temperature and 120 °C. The reaction of a compound of formula (v), may be carried out in at least one reaction-inert solvent and optionally in the presence of at least one suitable base thereof. Non-limiting examples of such reaction promoters include K2CO3, CS2CO3, NaH or a functional derivative thereof; may be performed in a reaction-inert solvent such as, for example, DMF, DMSO, acetonitrile.

[0203] 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 (XVII), or a pharmaceutically acceptable salts thereof.

[0204] Certain of the intermediates described in General Scheme 1 and the Examples, and salts thereof, form a further aspect of the invention.EXAMPLESAbbreviations:Ac - acetylBINAP - 2,2'-bis(diphenylphosphino)-1 ,1'-binaphthylBn - benzylBoc - tert-butoxycarbonylCBz - benzyloxycarbonylCPME - cyclopentyl methyl ether dba - dibenzylideneacetoneDCM - dichloromethaneDIEA - N,N-diisopropylethylamineDIPA - diisopropylamineDMAc - dimethylacetamideDMF - N,N-dimethylformamideDMSO - dimethylsulfoxideEDCI - 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride salt ee - enantiomeric excess eq. - equivalentsGhosez'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 - acetonitrileMS - 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 chromatographyReagents and Conditions

[0205] 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

[0206] 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)

[0207] 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 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)

[0208] 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 1.50minutes, 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)

[0209] 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 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)

[0210] 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 RunTime 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)

[0211] 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 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)

[0212] 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)

[0213] 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 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)

[0214] 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)

[0215] 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 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)

[0216] 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 1.00 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 12.10 minutes). An injection volume of 0.5 pl was used.Method 11 (K84 12 min)

[0217] 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 Detector2) 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)

[0218] The HPLC measurement was performed using Agilent 1260 Infinity II UPLC 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)

[0219] 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, from 2 % 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

[0220] 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 1.50 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

[0221] 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 mobilephases 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

[0222] 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

[0223] 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 minutesand 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

[0224] 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 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

[0225] 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 conditionsfor 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)

[0226] 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 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 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)

[0227] 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, 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)

[0228] 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 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)

[0229] 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)

[0230] 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, 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)

[0231] 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)

[0232] 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 byscanning 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 to 3 pl was used (Depending on the sample concentration).Method 28 (K92-5 min-YMC)

[0233] 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 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)

[0234] 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 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 reequilibrate 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)

[0235] 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 0.50 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)

[0236] 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 C18column (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)

[0237] 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.

[0238] Example 1

[0239] f / ?J-N-ethyl-1 -methyl-2-oxo-N-(2,2,2-trifluoro-1 -(4-fluorophenyl)ethyl)-1 ,2- dihydroquinoxaline-6-sulfonamideScheme 1

[0240] Synthesis of 6-bromoquinoxalin-2(1H)-one 1.1 : To stirring solution of 6- bromoquinoxalin-2(1 H)-one (1 g, 4.35 mmol) in DMF (10 mL) cooled 0 °C, K2CO3 (1.5 g, 10.87 mmol) and Mel (0.32 mL, 5.22 mmol) was added. Stirring was continued at room temperature for 3 h. The reaction was monitored by TLC. After completion, the reaction was quenched with cold water and extracted with EtOAc (2 x 20 mL) and the combined organic layer were washed with water (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (silica gel 100-200 mesh as stationary phase and 15-50% EtOAc in hexane as eluent to afford 1.1 as orange solid (851 mg, 81% yield). LCMS: m / z found 239.1 [M+H]+, rt 1.61 min, (Method 8), {Waters Xbridge C18 column (3.5 pm, 50 x 3 mm)}.

[0241] Synthesis of 6-((4-methoxybenzyl) thio)-1-methylquinoxalin-2(1 H)-one 1.2:Compound 1.1 (800 mg, 3.38 mmol) was dissolved in toluene (8 mL) and (4- methoxyphenyl)methanethiol (0.56 mL, 4.05 mmol) was added to it. The solution was stirred and degasified with argon. DIPEA (1.8 mL, 4.05 mmol) was added to the solution followed by xanthphos (97 mg, 0.17 mmol). The reaction mixture was further degasified with argon. Pd2(dba)s (152 mg, 0.17 mmol) was added to it under an inert atmosphere and the reaction mixture was stirred at 110 °C for 16 h under argon atmosphere. After completion (monitored by TLC and LCMS), it was filtered through sintered funnel. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography over silica gel using 15-25% EtOAc in hexane and the product 1.2 was isolated as a yellow solid(650 mg, 61% yield). LCMS: m / z found 313.2 [M+H]+, rt 1.89 min, (Method 8), {Waters Xbridge C18 column (3.5 pm, 50 x 3 mm)}.

[0242] Synthesis of 1-methyl-2-oxo-1,2-dihydroquinoxaline-6-sulfonyl chloride 1.3: A solution of intermediate 1.2 (300 mg, 0.96 mmol) in CH3CN (5 mL) was cooled at -10 °C and a mixture of added 2 N HCI (1.5 mL) was added to the solution. 1 ,3-Dichloro-5,5- dimethyl hydantoin (473 mg, 2.40 mmol) was added to this solution portion wise to it under stirring. Stirring was continued at the same temperature for 30 min. The reaction mixture was then diluted with ice cold water (50 mL) and extracted with DCM (2x50 mL). The organic layer was separated, washed with water (5 mL) dried over anhydrous Na2SO4 and concentrated under reduced pressure to get the crude as yellow solid (235 mg, crude). It was used in the forwarding step without further purification.

[0243] Synthesis of (7?9-1-methyl-2-oxo-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)- 1 ,2-dihydroquinoxaline-6-sulfonamide 1.4: To mixture of 1.3 (235 mg, 0.91 mmol) and pyridine (0.4 mL, 4.55 mmol) in DCM (2.3 mL) (R)-2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1- amine (246 mg, 1.00 mmol) was added drop-wise in DCM (4 mL) under stirring. The reaction mixture was stirred at room temperature for 16 h. The reaction was monitored by TLC. After completion the reaction was quenched with water (30 mL) and extracted with DCM (2 x 30 mL), the organic layer dried over sodium sulphate and concentrated under vacuum. The crude compound was purified by flash column chromatography (silica gel 100-200 mesh as stationary phase and 15-20% EtOAc in hexane as eluent) to provide compound 1.4 as a white solid (240 mg, 63% yield). LCMS: m / z found (414.1 [M+H]+), rt 1.76 min, (Method 8), {Waters Xbridge C18 column (3.5 pm, 50 x 3 mm)}.

[0244] (7?9-N-ethyl-1 -methyl-2-oxo-N-(2,2,2-trifluoro-1 -(4-fluorophenyl)ethyl)-1 ,2- dihydroquinoxaline-6-sulfonamide (Example 1): To a stirred solution of (R)-1-methyl-2- oxo-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-1 ,2-dihydroquinoxaline-6-sulfonamide 1.4 (150 mg, 0.35 mmol) in DMF (1.5 mL) CS2CO3 (135 mg, 0.42 mmol) was added and the reaction mixture was stirred for 10 min. To this resulting solution ethyl iodide was added (0.04 mL, 0.521 mmol) at room temperature within 30 min. The reaction was monitored by TLC. After completion the reaction was quenched with water (30 mL) and extracted with EtOAc (2 x 30 mL) dried over sodium sulphate and concentrated under vacuum. The crude compound was purified by flash column chromatography (silica gel 100-200 mesh as stationary phase and 20-50% EtOAc in hexane as eluent). The product was further purified by PREP-HPLC-Chiral (SFC) to yield enantiomerically pure Example 1 as a white solid (43.7 mg, 26% yield). LCMS: m / z found (444.0 [M+H]+), rt 2.82 min (Method 9), {Waters Xbridge C18 column (3.5 pm, 50 x 3 mm)}. 1 H NMR (400 MHz, Chloroform-d) 5 8.45 - 8.35 (m, 2H), 8.04 (dd, J = 1.9, 8.8 Hz, 1 H), 7.50 (t, J = 5.2, 8.2 Hz, 2H), 7.44 (d, J = 8.9 Hz, 1 H), 7.10 (t,J = 8.6 Hz, 2H), 5.87 (q, J = 8.6 Hz, 1 H), 3.72 (s, 3H), 3.44 - 3.30 (m, 1 H), 3.24 - 3.10 (m, 1 H), 0.92 (t, J = 7.0 Hz, 3H).

[0245] SFC PREP Method: SFC PREP PURIFICATION of Example 1 was run on a Waters Thar SFC-80 equipped with Waters UV Detector 2489 by using Chiralpak-IG column (30.0 mm x 250 mm), 5p operating at 35 °C temperature, maintaining flow rate of 70 mL / min, using 55% CO2 in super critical state & 45% of [100% Methanol] as mobile phase. This isocratic mixture was run up to 12.0 minutes and the isobaric condition of 100 bar at 220 nm wavelength was maintained.

[0246] Example 2

[0247] (7?9-5-chloro-N,1-dimethyl-6-oxo-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)- 1,6-dihydropyridine-3-sulfonamide:Scheme 2

[0248] 3-chloro-5-((4-methoxybenzyl)thio)-1-methylpyridin-2(1 H)-one(3) 2.1 : In a sealed tube, 5-bromo-3-chloro-1-methylpyridin-2(1 H)-one (1.0 g, 8.17 mmol) and 4- Methoxy-a-toluenethiol (0.90 mL, 6.53 mmol) were taken in toluene(10.0 mL) and the reaction mixture was bubbled with nitrogen for 5 min. DI PEA (4.52 mL, 24.50 mmol) was added to it followed by xanthphos (0.47 mg, 0.82 mmol). The reaction mixture was further degasified with argon. Pd2(dba)s (0.37 mg, 0.41 mmol) was added to it under an inert atmosphere and the reaction mixture was stirred at 100 °C for 12 h under argon atmosphere. After completion (monitored by TLC and LCMS), the reaction mixture was quenched with cold water and extracted with EtOAc (2 x 20 mL) and the combined organic layer was washed with water (20 mL), dried over Na2SO4 and concentrated through reduced pressure to get a crude residue. The crude was purified by column chromatography over silica gel using 30% EtOAc -Hexane, and 3-chloro-5-((4-methoxybenzyl)thio)-1-methylpyridin-2(1 H)-one 2.1 was obtained as a yellow solid. (610 mg, 26% yield). LCMS: m / z found (296.0 [M- H]), rt = 3.32 min (Method 4) Waters Xbridge C18 column (5 pm, 50 x 4.6 mm).

[0249] 5-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-sulfonyl chloride 2.2: To a stirred solution of 3-chloro-5-((4-methoxybenzyl)thio)-1-methylpyridin-2(1 H)-one 2.1 (620 mg, 2.10 mmol) in ACN (5.0 mL) 2N HCI (0.5 mL) and 1 ,3-Dichloro-5,5-dimethyl hydantoin (495.21 mg, 2.51 mmol) were added portion wise at -10 °C. The reaction mass was then allowed to stir for 1h at cooling condition. The crude sulfonyl chloride was used immediately in the forwarding step without further purification.

[0250] (7?9-5-chloro-N-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-1-methyl-6-oxo-1,6- dihydropyridine-3-sulfonamide 2.3: To a stirred solution (R)-1-(4-chlorophenyl)-2,2,2- trifluoroethan-1 -amine (780.99 mg, 3.72 mmol) in DCM (3.0 mL) pyridine (900 mg, 3.72 mmol), and then 5-chloro-1-methyl-6-oxo-1 ,6-dihydropyridine-3-sulfonyl chloride 2.2 (700 mg, 2.89 mmol) was added. The reaction mixture was then allowed to stir for 16 h at room temperature. After completion (monitored by TLC and LCMS), it was diluted with water (10 mL) and extracted with EtOAc (2 * 10 mL). The combined organic layer was washed with water (10 mL), dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The crude residue was purified by column chromatography over silica gel and the compound (R)-5-chloro-N-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-1-methyl-6-oxo-1 ,6- dihydropyridine-3-sulfonamide 2.3 was isolated as a white solid (600 mg, 39% yield). LCMS: m / z found (413.0 [M-H]), rt 2.56 min, Waters Xbridge C18 column (3.5 pm, 50 x 3 mm) (Method 9).

[0251] (7?9-5-chloro-N-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-N,1-dimethyl-6-oxo- 1,6-dihydropyridine-3-sulfonamide (Example 2): (R)-5-chloro-N-(1-(4-chlorophenyl)- 2,2,2-trifluoroethyl)-1-methyl-6-oxo-1 ,6-dihydropyridine-3-sulfonamide (200.0 mg, 0.48 mmol) was dissolved in DMF (2 mL) in a sealed tube and CS2CO3 (204.03 mg, 0.63 mmol) was added to it. Under stirring methyl iodide (0.3 mL, 4.82 mmol) was added. The reaction mixture was stirred at room temperature for 30 min 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% EtOAc in hexane and the product was further purified by PREP-HPLC-Chiral (SFC) to yield enantiomerically pure product Example 2 as a white solid (100 mg, 48% yield, 98.34 purity, 100% enantiomeric excess). LCMS: m / z found (429.1 [M+H]+), rt 3.07 min, Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm), (Method 2).1H NMR (400 MHz, DMSO-d6) 5 8.51 (d, J = 2.3 Hz, 1 H), 8.00 (d, J = 2.3 Hz, 1 H), 7.51 (q, J = 8.6 Hz, 4H), 5.98 (q, J = 8.6 Hz, 1 H), 3.57 (s, 3H), 2.77 (s, 3H).

[0252] SFC PREP PURIFICATION of 2.4 was run on a Waters Thar SFC-80 equipped with Waters UV Detector 2489 by using Chiralpak-IG column (30.0 mm x 250 mm), 5p operating at 35 °C temperature, maintaining a flow rate of 70 mL / min, using 80% CO2 in super critical state and 20% of [100% Methanol ] as a mobile phase. This isocratic mixture was run up to 7.0 minutes maintaining the isobaric condition of 100 bar at 250 nm wavelength.

[0253] Example 3

[0254] ( / ?9-N-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-N,4-dimethyl-5-oxo-4,5- dihydropyrazine-2-sulfonamideScheme 3

[0255] Synthesis of 5-((4-methoxybenzyl)thio)-1-methylpyrazin-2(1 H)-one 3.1 : 5- bromo-1-methylpyrazin-2(1 H)-one (1 g, 5.34 mmol) was dissolved in toluene (10 mL) and (4-methoxyphenyl)methanethiol (1.11 mL, 8.02 mmol) was added to it. The solution was stirred and degasified with argon. DIPEA (4.64 mL, 26.73 mmol) was added to the solution followed by Xanthaphos (155 mg, 0.26 mmol). The reaction mixture was further degasified with argon. Pd2(dba)s (147 mg, 0.16 mmol) was added to it under the inert atmosphere and the reaction mixture was stirred at 100 °C for 16 h under argon atmosphere. After completion (monitored by TLC and LCMS) it was filtered through sintered funnel. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography over silica gel using 40% EtOAc in hexane and 5-((4-methoxybenzyl)thio)- 1-methylpyrazin-2(1 H)-one 3.1 was isolated as a brown solid (1.3 g, 92% yield). LCMS: m / z found 263.0 [M+H]+, rt = 1.43 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)];1H NMR (400 MHz, DMSO-cfe) 6 8.01 (s, 1 H), 7.70 (s, 1 H), 7.14 (d, J = 8.3 Hz, 2H), 6.84 (d,J = 8.4 Hz, 2H), 4.05 (s, 2H), 3.70 (s, 3H), 3.34 (s, 3H).

[0256] Synthesis of 4-methyl-5-oxo-4,5-dihydropyrazine-2-sulfonyl chloride 3.2: A solution of 5-((4-methoxybenzyl)thio)-1-methylpyrazin-2(1 H)-one 3.1 (500 mg, 1.90 mmol) in CH3CN (5 mL) was cooled to -10 °C and to the solution a mixture of added 2 N HCI (1 mL) was added. The solution was stirred and 1 ,3-dichloro-5,5-dimethyl hydantoin (752 mg, 3.81 mmol) was added portion-wise to it. Stirring was continued at the same temperature for 30 min. The mixture was then diluted with ice cold water (5 mL) and extracted with DCM (2 x 5 mL). The organic layer was separated, washed with water (5 mL) dried over anhydrous Na2SC>4 and the volatiles were evaporated under reduced pressure at room temperature. The crude was used immediately in the forwarding step.

[0257] Synthesis of (7?9-N-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-4-methyl-5-oxo- 4,5-dihydropyrazine-2-sulfonamide 3.3: To a solution of sulfonyl chloride 3.2 in DCM (R)- 1-(4-chlorophenyl)-2,2,2-trifluoroethan-1-amine hydrochloride (357 mg, 1.27 mmol) was added followed by pyridine (1 .47 mL, 18.26 mmol). The reaction mixture was stirred at room temperature for 16 h. It was then diluted with water (10 mL) and extracted with DCM (2 x 10 mL). The combined organic layer was washed with water (10 mL), dried over anhydrous Na2SC>4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel to afford 3.3 as an off-white solid (600 mg, 86% yield). LCMS: m / z found 382.0 [M+H]+, rt = 1.56 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)].

[0258] Synthesis of f(7?9-N-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-N,4-dimethyl-5- oxo-4, 5-dihydropyrazine-2-sulfonamide (Example 3): The sulfonamide 3.3 (200 mg, 0.52 mmol) was dissolved in DMF (2.0 mL) in a sealed tube and CS2CO3 (205 mg, 0.63 mmol) was added to it. The mixture was stirred and methyl iodide (0.19 mL, 2.62 mmol) was added. The reaction mixture was further 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% EtOAc in hexane and the product was isolated as a colourless sticky gum (130 mg, 62% yield). The product was further purified by PREP-Singleton (RP) to yield enantiomerically pure Example 3 as a white solid (80 mg, 98.77% purity, 100% enantiomeric excess). LCMS: m / z found 456.0 [M+H]+, rt = 2.81 min (Method 2) [Waters Acuity BEH C8 column (1.7 pm, 50 x 2.1 mm)];1H NMR (400 MHz, DMSO-cfe) 6 8.49 (s, 1 H), 7.98 (s, 1 H), 7.59 - 7.40 (m, 4H), 5.83 (q, J = 8.6 Hz, 1 H), 3.48 (s, 3H), 2.74 (s, 3H).

[0259] Example 4

[0260] ( / ?9-N-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-5-fluoro-N,1-dimethyl-6-oxo- 1,6-dihydropyridine-3-sulfonamideExample 4 (crude)Scheme 4

[0261] Synthesis of 5-bromo-3-fluoro-1-methylpyridin-2(1 H)-one 4.1 : To a solution of 5-bromo-3-fluoropyridin-2(1 H)-one (1.5 g, 7.86 mmol) in DMF (20 mL) NaH was added (0.19 g, 7.86 mmol) in ice cold condition. To this reaction mixture, Mel (0.73 mL, 11.79 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. Reaction mixture was quenched with saturated NH4CI solution (5 mL). It was then extracted with EtOAc (3 x 20 mL), the combined organic part was washed with water (2 x 15 mL), dried over anhydrous Na2SC>4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel using 30% EtOAc in hexane and 5-bromo-3- fluoro-1-methylpyridin-2(1 H)-one 4.1 was isolated as white solid (1.0 g, 62% yield). NMR (400 MHz, DMSO) 5 7.9 (s, 1 H), 7.67 (dd, J = 9.6, 2.4 Hz, 1 H), 3.47 (s, 3H).

[0262] 3-fluoro-5-((4-methoxybenzyl)thio)-1-methylpyridin-2(1 H)-one 4.2: 5-bromo-3- fluoro-1-methylpyridin-2(1 H)-one 4.1 (500 mg, 2.44 mmol) was dissolved in toluene (5 mL) and (4-methoxyphenyl)methanethiol (0.23 mL, 1.7 mmol) was added to it. The solution was stirred and degasified with argon. DI PEA (1.35 mL, 7.32 mmol) was added to the solution followed by Xanthphos (42.3 mg, 0.07 mmol). The reaction mixture was further degasified with argon. Pd2(dba)s (44.65 mg, 0.05 mmol) was added to it under the inert atmosphere and the reaction mixture was stirred at 100 °C for 18 h under argon atmosphere. After completion (monitored by TLC and LCMS), it was filtered through sintered funnel. The filtratewas concentrated under reduced pressure and the crude product was purified by column chromatography over silica gel using 20% EtOAc in hexane and 3-fluoro-5-((4- methoxybenzyl)thio)-1-methylpyridin-2(1 H)-one 4.2 was isolated as yellow gum (600 mg, 88% yield). LCMS: m / z found (280.2 [M+H]+),rt=1 .57 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)]

[0263] Synthesis of 5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-sulfonyl chloride 4.3: Solution of intermediate 4.2 (300 mg, 1.07 mmol) in DCM (2.5 mL) was cooled at -10 °C and to the solution was added a mixture of 2 N HCI (2.5 mL). The solution was stirred and 1 ,3-Dichloro-5,5-dimethyl hydantoin (254.29 mg, 1.29 mmol) was added portion-wise to it. The stirring was continued at the same temperature for 30 min. It was then diluted with ice cold water (5 mL) and extracted with DCM (5 mL). The organic layer was separated, washed with water (5 mL) dried over anhydrous Na2SO4 and used in the forwarding step without evaporation.

[0264] Synthesis of (7?9-N-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-5-fluoro-1-methyl- 6-oxo-1,6-dihydropyridine-3-sulfonamide 4.4: To a solution of sulfonyl chloride 4.3 in DCM (F?)-2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1 -amine (290 mg, 1.18 mmol) was added followed by pyridine (0.6 mL, 7.53 mmol). The reaction mixture was stirred at room temperature for 16 h. It was diluted with water (10 mL) and extracted with DCM (2 * 10 mL). The combined organic layer was washed with water (10 mL), dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel and the compound 4.4 was isolated as a white solid (90 mg, 20% yield). LCMS: m / z found (399.0 [M+H]+), rt= 1.59 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)]

[0265] Synthesis of (7?9-N-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-5-fluoro-N,1- dimethyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Example 4): The sulfonamide 4.4 (90 mg, 0.23 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (88.19 mg, 0.27 mmol) was added to it and stirred at room temperature for 10 min. To this reaction mixture methyl iodide (0.42 mL, 0.68 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% EtOAc in hexane and the product was isolated as colourless sticky gum (45 mg, 48% yield). The product was further purified by PREP-HPLC-Chiral (SFC) to yield enantiomerically pure Example 4 as a sticky gum (30 mg, 99.7% purity, 99.29% enantiomeric excess).

[0266] LCMS: m / z found (413.1 [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) 5 8.42 - 8.36 (m, 1 H), 7.75 (dd, J = 9.5, 2.5 Hz, 1 H), 7.57 - 7.50 (m, 2H), 7.46 (d, J = 8.4 Hz, 2H), 5.94 (q, J = 8.5 Hz, 1 H), 3.57 (s, 3H), 2.77 (s, 3H).

[0267] SFC-PREP purification method:

[0268] SFC PREP PURIFICATION was run in a Pic Solution 175 instrument equipped with Knauer UV Detector 40D by using Chiralpak IG (30.0 mm x 250mm), 5p Column operating at 35 °C temperature, maintaining flow rate of 70 ml / min, using 75 % CO2 in super critical state & 25% of (MeOH) as mobile phase, running this isocratic mixture up to 7.0 minutes and maintaining the isobaric condition of 100 bar at 215 nm wavelength.

[0269] Example 5

[0270] (7?9-5-fluoro-N,1-dimethyl-6-oxo-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)- 1,6-dihydropyridine-3-sulfonamide100 °C, 16 hChiral EnrichmentScheme 5

[0271] 3-fluoro-5-((4-methoxybenzyl)thio)-1-methylpyridin-2(1 H)-one-3-fluoro-5-((4- methoxybenzyl)thio)-1-methylpyridin-2(1 H)-one 5.1 : 5-bromo-3-fluoro-1-methylpyridin- 2(1 H)-one (500 mg, 2.44 mmol) was dissolved in toluene (5 mL) and (4- methoxyphenyl)methanethiol (0.23 mL, 1.7 mmol) was added to it. The solution was stirred and degasified with argon. DIPEA (1.35 mL, 7.32 mmol) was added to the solution followed by Xanthphos (42.3 mg, 0.07 mmol). The reaction mixture was further degasified with argon.Pd2(dba)s (44.65 mg, 0.05 mmol) was added to it under the inert atmosphere and thereaction mixture was stirred at 100 °C for 18 h under argon atmosphere. After completion (monitored by TLC and LCMS), it was filtered through sintered funnel. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography over silica gel using 20% EtOAc in hexane and the product 5.1 was isolated as yellow gum (600 mg, 88% yield). LCMS: m / z found (280.2 [M+H]+), rt=1.57 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)].

[0272] Synthesis of 5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-sulfonyl chloride 5.2: Solution of intermediate 5.1 (300 mg, 1.073 mmol) in DCM (2.5 mL) was cooled at -10 °C and to the solution was added a mixture of 2 N HCI (2.5 mL). The solution was stirred and 1 ,3-Dichloro-5,5-dimethyl hydantoin (254.29 mg, 1.29 mmol) was added portion-wise to it. The stirring was continued at the same temperature for 30 min. It was then diluted with ice cold water (5 mL) and extracted with DCM (5 mL). The organic layer was separated, washed with water (5 mL), dried over anhydrous Na2SO4 and used in the forwarding step without evaporation.

[0273] Synthesis of (7?9-5-fluoro-1-methyl-6-oxo-N-(2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)-1,6-dihydropyridine-3-sulfonamide 5.3: To a solution of sulfonyl chloride 5.2 in DCM (F?)-2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1 -amine (270.98 mg, 1.18 mmol)was added followed by pyridine (0.6 mL, 7.53 mmol). The reaction mixture was stirred at room temperature for 16 h. It was diluted with water (10 mL) and extracted with DCM (2 x 10 mL). The combined organic layerwas washed with water (10 mL), dried over anhydrous Na2SC>4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel and the compound 5.3 was isolated as white solid (90 mg, 23% yield). LCMS: m / z found (383.0 [M+H]+), rt= 1.53 min (Method 3) [(YMC Triart C18 column (3 pm, 33 x 2.1 mm)].

[0274] Synthesis of (7?9-5-fluoro-N,1-dimethyl-6-oxo-N-(2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)-1,6-dihydropyridine-3-sulfonamide (Example 5): The sulfonamide 5.3 (70 mg, 0.18 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (71.4 mg, 0.22 mmol) was added to it. To the stirred solution methyl iodide (0.03 mL, 0.55 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 colourless sticky gum (43 mg, 59% yield). The product was further purified by PREP-HPLC-Chiral (SFC) to yield enantiomerically pure Example 5 as a sticky gum (17 mg, 99.22% purity, 100% enantiomeric excess). LCMS: m / z found (397.2 [M+H]+),rt= 2.88min (Method 2)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm);1H NMR (400 MHz, DMSO) 5 8.39 (s, 1 H), 7.78 - 7.70 (m, 1 H), 7.51 (dd, J = 8.6, 5.2 Hz, 2H), 7.33 - 7.25 (m, 2H), 5.91 (q, J = 8.5 Hz, 1 H), 3.57 (s, 3H), 2.77 (s, 3H).

[0275] SFC-PREP purification method:

[0276] SFC PREP PURIFICATION was run in a Waters Thar SFC-80 instrument equipped with Knauer UV Detector 2489 by using Chiralpak IG (30.0 mm x 250mm), 5p Column operating at 35 °C temperature, maintaining flow rate of 70 mL / min, using 75 % CO2 in super critical state and 20% of MeOH as mobile phase, running this isocratic mixture up to 7.0 minutes and maintaining the isobaric condition of 100 bar at 250 nm wavelength.

[0277] Example 6

[0278] (7?)-N-ethyl-5-fluoro-1 -methyl-6-oxo-N-(2,2,2-trifluoro-1 -(4- fluorophenyl)ethyl)-1,6-dihydropyridine-3-sulfonamideExample 6 (Crude)Chiral EnrichmentScheme 6

[0279] Synthesis of 3-fluoro-5-((4-methoxybenzyl)thio)-1-methylpyridin-2(1 H)-one6.1 : 5-bromo-3-fluoro-1-methylpyridin-2(1 H)-one (500 mg, 2.44 mmol) was dissolved in toluene (5 mL) and (4-methoxyphenyl)methanethiol (0.23 mL, 1.7 mmol) was added to it. The solution was stirred and degasified with argon. DIPEA (1.35 mL, 7.32 mmol) was added to the solution followed by Xanthphos (42.3 mg, 0.07 mmol). The reaction mixture wasfurther degasified with argon. Pd2(dba)s (44.65 mg, 0.05 mmol) was added to it under the inert atmosphere and the reaction mixture was stirred at 100 °C for 18 h under argon atmosphere. After completion (monitored by TLC and LCMS), it was filtered through sintered funnel. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography over silica gel using 20% EtOAc in hexane and the product 6.1 was isolated as yellow gum (600 mg, 88% yield). LCMS: m / z found (280.2 [M+H]+), rt=1.57 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)].

[0280] Synthesis of 5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-sulfonyl chloride: A solution of intermediate 6.2 (800 mg, 2.87 mmol) in DCM (2.5 mL) was cooled at -10 °C and to the solution was added a mixture of 2N HCI (2.5 mL). The solution was stirred and 1 ,3-Dichloro-5,5-dimethyl hydantoin (677.9 mg, 3.44 mmol) was added portion-wise to it. The stirring was continued at the same temperature for 30 min. It was then diluted with ice cold water (5 mL) and extracted with DCM (5 mL). The organic layer was separated, washed with water (5 mL) dried over anhydrous Na2SO4 and used in the forwarding step without evaporation.

[0281] Synthesis of (7?9-5-fluoro-1-methyl-6-oxo-N-(2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)-1,6-dihydropyridine-3-sulfonamide 6.3: To a solution of sulfonyl chloride 6.2 in DCM (F?)-2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1 -amine (723.36 mg, 3.16 mmol)was added followed by pyridine (1.6 mL, 20.10 mmol). The reaction mixture was stirred at room temperature for 16 h. It was diluted with water (20 mL) and extracted with DCM (2 x 20 mL). The combined organic layer was washed with water (10 mL), dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel and the compound 6.3 was isolated as white solid as white solid (210 mg, 19% yield). LCMS: m / z found (383.0 [M+H]+), rt= 1.53 min (Method 3) [(YMC Triart C18 column (3 pm, 33 x 2.1 mm)].

[0282] Synthesis of (7?9-N-ethyl-5-fluoro-1-methyl-6-oxo-N-(2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)-1,6-dihydropyridine-3-sulfonamide (Example 6). The sulfonamide 6.3 (210 mg, 0.55 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (214.39 mg, 0.66 mmol) was added to it. It was stirred and ethyl iodide (0.42 mL, 0.68 mmol) was added to it. The reaction mixture was then stirred at 50 °C 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% EtOAc in hexane and the product was isolated as colourless sticky gum (45 mg, 20% yield). The product was further purified by PREP-HPLC-Chiral (SFC) to yield enantiomerically pure Example 6 as sticky gum (30 mg,97.64% purity, 98.84% enantiomeric excess). LCMS: m / z found (411.2 [M+H]+), rt= 2.95 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)];1H NMR (400 MHz, DMSO) 5 8.39 (s, 1 H), 7.74 (dd, J = 9.6, 2.5 Hz, 1 H), 7.55 - 7.47 (m, 2H), 7.29 (t, J = 8.8 Hz, 2H), 5.90 (q, = 8.7 Hz, 1 H), 3.56 (s, 3H), 3.42 - 3.32 (m, 1 H), 3.29 - 3.18 (m, 1 H), 1.00 (t, J = 7.0 Hz, 3H).

[0283] SFC-PREP purification method:

[0284] SFC PREP PURIFICATION of Example 6 (45mg) was carried on a Pic Solution 175 instrument equipped with Knauer UV Detector 40D by using Chiralpak IG (30.0 mm x 250mm), 5p column operating at 35 °C temperature, maintaining flow rate of 60 mL / min, using 85 % CO2 in super critical state and 15% of MeOH as mobile phase, running this isocratic mixture up to 7.0 minutes and maintaining the isobaric condition of 100 bar at 250 nm wavelength.

[0285] Example 7

[0286] ( / ?)-2-amino- / V-ethyl- / V-(2,2,2-trifluoro-1 -(4- fluorophenyl)ethyl)benzo[d]thiazole-6-sulfonamideExample 7 (Crude) Example 7Scheme 7

[0287] Synthesis of 5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-sulfonyl chloride 7.1 : Solution of intermediate 6.1 (2.3 g, 8.24 mmol) in DCM (30 mL) was cooled at -10 °C and to the solution was added a mixture of added 2 N HCI (5 mL). The solution was stirred and 1 ,3-Dichloro-5,5-dimethyl hydantoin (1.94 g, 9.89 mmol) was added portion-wise to it. The stirring was continued at the same temperature for 30 min. It was then diluted with ice cold water (5 mL) and extracted with DCM (2 x 25 mL). The organic layer was separated,washed with water (25 mL) dried over anhydrous Na2SC>4 and used in the forwarding step without evaporation.

[0288] Synthesis of ( / ?9-N-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-5-fluoro-1-methyl- 6-oxo-1,6-dihydropyridine-3-sulfonamide 7.2 To a solution of sulfonyl chloride 7.1 in DCM was added (R)-2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1 -amine (2.2 g, 9.05 mmol) to it followed by pyridine (4.6 mL, 57.57 mmol). The reaction mixture was stirred at room temperature for 16 h. It was diluted with water (20 mL) and extracted with DCM (2 x 50 mL). The combined organic layer was washed with water (10 mL), dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel and the compound 7.2 was isolated as white solid (1.2 g, 35% yield). LCMS: m / z found (399.0 [M+H]+),rt= 1.59 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)]

[0289] Synthesis of (7?9-N-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-5-fluoro-N,1- dimethyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Example 7): The sulfonamide 7.2 (800 mg, 2.01 mmol) was dissolved in DMF (5 mL) in a sealed tube and CS2CO3 (783.9 mg, 2.41 mmol) was added to it. It was stirred and to it was added Ethyl iodide (0.48 mL, 6.03 mmol). The reaction mixture was then stirred at 50 °C for 2h. The reaction was then quenched with water (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% EtOAc in hexane and the product was isolated as colourless sticky gum (270 mg, 31 % yield). The product was further purified by PREP-HPLC-Chiral (SFC) to yield enantiomerically pure Example 7 as a sticky gum (140 mg, 98.14 % purity, 100% enantiomeric excess). LCMS: m / z found (427.2 [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) 5 8.41 - 8.36 (m, 1 H), 7.75 (dd, J = 9.6, 2.5 Hz, 1 H), 7.56 - 7.44 (m, 4H), 5.92 (q, J = 8.7 Hz, 1 H), 3.56 (s, 3H), 3.43 - 3.32 (m, 1 H), 3.28 - 3.18 (m, 1 H), 1.00 (t, J = 7.0 Hz, 3H).

[0290] SFC-PREP purification method:

[0291] SFC PREP PURIFICATION of Example 7 (45mg) was carried on a Waters Thar SFC-80 equipped with Waters UV Detector 2489 by using Chiralpak IG (30.0 mm x 250mm), 5p column operating at 35 °C temperature, maintaining flow rate of 60 mL / min, using 65 % CO2 in super critical state and 35% of MeOH as mobile phase, running this isocratic mixture up to 10.0 minutes and maintaining the isobaric condition of 100 bar at 249 nm wavelength.

[0292] Example 8

[0293] ( / ?9-N-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-N-ethyl-4-methyl-5-oxo-4,5- dihydropyrazine-2-sulfonamideScheme 8

[0294] Synthesis of ( / ?94\l-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-N-ethyl-4-methyl- 5-oxo-4,5-dihydropyrazine-2-sulfonamide (Example 8): ( / ?)-N-(1-(4-chlorophenyl)-2,2,2- trifluoroethyl)-4-methyl-5-oxo-4,5-dihydropyrazine-2-sulfonamide (200 mg, 0.52 mmol) was dissolved in DMF (2.0 mL) in a sealed tube and CS2CO3 (205 mg, 0.63 mmol) was added to it. It was stirred and ethyl iodide (0.21 mL, 2.62 mmol) was added to it. The reaction mixture was then stirred at 50 °C for 3 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% EtOAc in hexane and the product to isolate Example 8 as a colourless sticky pure (80 mg, 37% yield, 98.77% purity, 100% enantiomeric excess). LCMS: m / z found 410.1 [M+H]+, rt = 2.93 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)];1H NMR (401 MHz, DMSO-cfe) 6 8.45 (s, 1 H), 8.00 (s, 1 H), 7.68 - 7.34 (m, 4H), 5.85 - 5.73 (m, 2H), 3.47 (s, 3H), 3.25 - 3.13 (m, 1 H), 1.01 (t, J = 7.0 Hz, 3H).

[0295] Example 9 and Example 10

[0296] (7?)-N-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-A / ,1,3,3-tetramethyl-2-oxo-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-5-sulfonamide (Example 9) and (R)-N-{^-{4- chlorophenyl)-2,2,2-trifluoroethyl)- / V-ethyl-1,3,3-trimethyl-2-oxo-2,3-dihydro-1H- pyrrolo[2,3-b]pyridine-5-sulfonamide (Example 10)Scheme 9

[0297] Synthesis of 5-bromo-1,3,3-trimethyl-1,3-dihydro-2 / 7-pyrrolo[2,3-b]pyridin-2- one 9.1 : 5-bromo-1,3-dihydro-2 / 7-pyrrolo[2,3-b]pyridin-2-one (1 g, 4.71 mmol) was dissolved in DMF (10 mL) and potassium carbonate (1.95 g, 14.15 mmol) was added to it. After stirring for 15 minutes, iodomethane (1.5 mL, 23.58 mmol) was added and stirred for 16 h at 25°C. After completion (monitored by TLC and LCMS), water (20 mL) was added to the reaction mixture and extracted with EtOAc (2 x 20 mL). Combined organic part was washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure and the crude was purified by column chromatography over silica gel using 15% EtOAc in hexane and the product 9.1 was isolated as an off-white solid (500 mg, 41% yield). LCMS: m / z found 255.1 [M+H]+, rt = 1.77 min (Method 8) [ Waters Xbridge C18 column (3.5 pm, 50 x 3 mm)];1H NMR (400 MHz, DMSO) 5 8.28 (d, J = 1.6 Hz, 1 H), 8.03 (d, J = 1.7 Hz, 1 H), 3.12 (s, 3H), 1.31 (s, 6H).

[0298] Synthesis of 5-((4-methoxybenzyl)thio)-1,3,3-trimethyl-1,3-dihydro-2H- pyrrolo[2,3-b]pyridin-2-one 9.2: 5-bromo-1,3,3-trimethyl-1,3-dihydro-2 / 7-pyrrolo[2,3- b]pyridin-2-one 9.1 (500 mg, 1.96 mmol) was dissolved in toluene (5 mL) and (4- methoxyphenyl)methanethiol (0.35 mL, 2.36 mmol) was added to it. The solution was stirred and degasified with argon. DI PEA (1 mL, 5.90 mmol) was added to the solutionfollowed by Xanthphos (114 mg, 0.19 mmol). The reaction mixture was further degasified with argon. Pd2(dba)s (90 mg, 0.10 mmol) was added to it under the inert atmosphere and the reaction mixture was stirred at 100°C for 18 h under argon atmosphere. After completion (monitored by TLC and LCMS), it was filtered through sintered funnel. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography over silica gel using 20% EtOAc in hexane and the product 9.2 was isolated as yellow gum (500 mg, 77% yield). LCMS: m / z found 329.2 [M+H]+, rt = 1.96 min (Method 8) [Waters Xbridge C18 column (3.5 pm, 50 x 3 mm)];1H NMR (400 MHz, DMSO) 5 8.06 (d, J = 1.6 Hz, 1 H), 7.65 (d, J = 1.6 Hz, 1 H), 7.13 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.4 Hz, 2H), 4.08 (s, 2H), 3.70 (s, 3H), 3.11 (s, 3H), 1.26 (s, 6H).

[0299] Synthesis of 1,3,3-trimethyl-2-oxo-2,3-dihydro-1 H-pyrrolo[2,3-b]pyridine-5- sulfonyl chloride 9.3: Solution of intermediate 9.2 (250 mg, 0.76 mmol) in DCM (2.5 mL) was cooled at -10 °C and to the solution was added a mixture of added 2 N HCI (2.5 mL). The solution was stirred and 1 ,3-dichloro-5,5-dimethyl hydantoin (375 mg, 1.90 mmol) was added portion wise to it. The stirring was continued at the same temperature for 30 min. It was then diluted with ice cold water (5 mL) and extracted with DCM (5 mL). The organic layer was separated, washed with water (5 mL) dried over anhydrous sodium sulphate and used in the forwarding step without evaporation.

[0300] Synthesis of (R)-N-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-1,3,3-trimethyl-2- oxo-2, 3-dihydro-1 H-pyrrolo[2,3-b]pyridine-5-sulfonamide 9.4: To a solution of sulfonyl chloride 9.3 in DCM, (R)-1-(4-chlorophenyl)-2,2,2-trifluoroethan-1-amine (157 mg, 0.63 mmol) was added followed by pyridine (0.7 mL, 9.12 mmol). The reaction mixture was stirred at room temperature overnight. It was then diluted with water (10 mL) and extracted with DCM (2 x 10 mL). The combined organic layer was washed with water (10 mL), dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel and the compound 9.4 was isolated as a yellow sticky gum (140 mg, 34% yield). LCMS: m / z found 448.1 [M+H]+, rt = 1.94 min (Method 8) [Waters Xbridge C18 column (3.5 pm, 50 x 3 mm)].

[0301] Synthesis of (R)-A / -(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-A / ,1,3,3- tetramethyl-2-oxo-2,3-dihydro-1 H-pyrrolo[2,3-b]pyridine-5-sulfonamide (Example 9):The sulfonamide 9.4 (140 mg, 0.31 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (122 mg, 0.37 mmol) was added to it. It was stirred and to it was added methyl iodide (0.1 mL, 1.56 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 EtOAc (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 waspurified by column chromatography over silica gel using 40% EtOAc in hexane and the product was isolated as colourless sticky gum (100 mg,). The product was further purified by PREP-HPLC-Chiral (SFC) to yield enantiomerically pure Example 9 as an off-white solid (16 mg, 99.75% purity, 100% enantiomeric excess). LCMS: m / z found 462.0 [M+H]+, rt = 2.91 min (Method 9) [Waters Xbridge C18 column (3.5 pm, 50 x 3 mm)];1H NMR (401 MHz, DMSO-d6) 5 8.63 (d, J = 2.1 Hz, 1 H), 8.26 (d, J = 2.2 Hz, 1 H), 7.48 - 7.40 (m, 2H), 7.36 (d, J = 8.6 Hz, 2H), 6.00 (q, J = 8.4 Hz, 1 H), 3.19 (s, 3H), 2.74 (s, 3H), 1.36 (s, 3H), 1.30 (s, 3H).

[0302] SFC PREP PURIFICATION was carried on a Waters Thar SFC-80 equipped with Waters UV Detector 40D by using Chiralpak IG (30.0 mm x 250 mm), 5p column operating at 35 °C temperature, maintaining flow rate of 50 mL / min, using 65 % CO2 in super critical state and 35% of MeOH as mobile phase, running this isocratic mixture up to 10.0 minutes and maintaining the isobaric condition of 100 bar at 265 nm wavelength.

[0303] (R)-N-{^ -(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V-ethyl-1 ,3,3-trimethyl-2-oxo- 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-sulfonamide (Example 10): The sulfonamide 9.4 (200 mg, 0.44 mmol) was dissolved in DMF (2 mL) in a sealed tube and CS2CO3 (174 mg, 0.53 mmol) was added to it. It was stirred and to it was added ethyl iodide (0.18 mL, 2.23 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 EtOAc (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 40% EtOAc in hexane and the product was isolated as colourless sticky gum (110 mg). The product was further purified by PREP-HPLC-Chiral (SFC) to yield enantiomerically pure Example 10 as an off-white solid (20 mg, 99.7% purity, 97.26 % enantiomeric excess). LCMS: m / z found 476.0 [M+H]+, rt = 3.02 min (Method 9) [Waters Xbridge C18 column (3.5 pm, 50 x 3 mm)];1H NMR (400 MHz, DMSO-d6) 5 8.66 (s, 1 H), 8.30 (s, 1 H), 7.45 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 7.8 Hz, 2H), 6.16 - 5.87 (m, 1 H), 3.19 (s, 3H), 1.33 (d, J = 11.3 Hz, 6H), 1.00 (t, J = 7.1 Hz, 3H), Note: three protons are merged with solvent peak.

[0304] SFC PREP PURIFICATION was carried on a Waters Thar SFC-80 equipped with Waters UV Detector 40D by using Chiralpak IG (30.0 mm x 250 mm), 5p column operating at 35 °C temperature, maintaining flow rate of 60 mL / min, using 65 % CO2 in super critical state and 35% of MeOH as mobile phase, running this isocratic mixture up to 7.0 minutes and maintaining the isobaric condition of 100 bar at 265 nm wavelength.

[0305] Example 11 and Example 12

[0306] (7?)-A / -(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-A / ,2-dimethyl-3-oxo-2,3- dihydro-[1 ,2,4]triazolo[4,3-b]pyridazine-6-sulfonamide (Example 11) and (R)-N-{^-{4- chlorophenyl)-2,2,2-trifluoroethyl)-A / -ethyl-2-methyl-3-oxo-2,3-dihydro-[1 ,2,4]triazolo[4,3-b]pyridazine-6-sulfonamide (Example 12)Scheme 10

[0307] Synthesis of 6-chloro-2-methyl-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one 10.1 : 6-chloro-[1 ,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (1 g, 5.88 mmol) was dissolved in DMF (10 mL) and potassium carbonate (2.44 g, 17.64 mmol) was added to it. After stirring for 15 min, methyl iodide (3.7 mL, 58.82 mmol) was added and stirred for 15 h at 25°C. After completion (monitored by TLC and LCMS), water (20 mL) was added to the reaction mixture and extracted with EtOAc (2 x 20 mL). Total organic part was washed with brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure and the crude was purified by column chromatography over silica gel using 20% EtOAc in hexane and the product 10.1 was isolated as an off-white solid (400 mg, 36% yield). LCMS: m / zfound 185.1 [M+H]+, rt = 1.11 min (Method 8) [Waters Xbridge C18 column (3.5 pm, 50 x 3 mm)];1H NMR (400 MHz, DMSO-d6) 5 7.93 (d, J = 9.8 Hz, 1 H), 7.26 (d, J = 9.8 Hz, 1 H), 3.57 (s, 3H).

[0308] Synthesis of 6-((4-methoxybenzyl)thio)-2-methyl-[1,2,4]triazolo[4,3- b]pyridazin-3(2H)-one 10.2: Intermediate 10.1 (400 mg, 2.17) was dissolved in toluene (5 mL) and (4-methoxyphenyl)methanethiol (0.4 ml, 2.60 mmol) was added to it. The solution was stirred and degasified with argon. DIPEA (1.1 mL, 6.50 mmol) was added to the solution followed by Xanthphos (126 mg, 0.22 mmol). The reaction mixture was further degasified with argon. Pd2(dba)s (100 mg, 0.11 mmol) was added to it under the inert atmosphere and the reaction mixture was stirred at 100°C for 18 h under argon atmosphere. After completion (monitored by TLC and LCMS), it was filtered through sintered funnel. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography over silica gel using 40% EtOAc in hexane and the product 10.2 was isolated as a yellow gum (550 mg, 83% yield). LCMS: m / z found 303.2 [M+H]+, rt = 2.96 min (Method 4) Waters Xbridge C18 column (5 pm, 50 x 4.6 mm);1H NMR (400 MHz, DMSO- d6) 5 7.68 (d, J = 9.8 Hz, 1 H), 7.42 (d, J = 8.5 Hz, 2H), 7.04 (d, J = 9.8 Hz, 1 H), 6.88 (d, J = 8.5 Hz, 2H), 4.35 (s, 2H), 3.72 (s, 3H), 3.55 (s, 3H).

[0309] Synthesis of 2-methyl-3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-b]pyridazine-6- sulfonyl chloride 10.3: Solution of intermediate 10.2 (200 mg, 0.66 mmol) in DCM (2 mL) was cooled at -10 °C and to the solution was added a mixture of added 2 N HCI (0.4 mL). The solution was stirred and 1 ,3-dichloro-5,5-dimethyl hydantoin (326 mg, 1.66 mmol) was added portion wise to it. The stirring was continued at the same temperature for 30 min. It was then diluted with ice cold water (5 mL) and extracted with DCM (5 mL). The organic layer was separated, washed with water (5 mL) dried over anhydrous Na2SC>4 and used in the forwarding step without evaporation.

[0310] Synthesis of (R)-N-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-2-methyl-3-oxo- 2,3-dihydro-[1,2,4]triazolo[4,3-b]pyridazine-6-sulfonamide 10.4: To a solution of sulfonyl chloride 10.3 in DCM, (R)-1-(4-chlorophenyl)-2,2,2-trifluoroethan-1-amine (111 mg, 0.45 mmol) was added, followed by pyridine (0.5 mL, 6.45 mmol). The reaction mixture was stirred at room temperature for 4 h. It was then diluted with water (10 mL) and extracted with DCM (2 x 10 mL). The combined organic layer was washed with water (10 mL), dried over anhydrous Na2SC>4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel and the compound 10.4 was isolated as yellow sticky gum (100 mg, 36% yield). LCMS: m / z found 422.1 [M+H]+, rt = 1.49 min (Method 8) [Waters Xbridge C18 column (5 pm, 50 x 4.6 mm].Synthesis of (Rj-N- -(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V,2-dimethyl-3-oxo-2,3- dihydro-[1 ,2,4]triazolo[4,3-b]pyridazine-6-sulfonamide (Example 11): The sulfonamide 10.4 (200 mg, 0.47 mmol) was dissolved in DMF (2 mL) in a sealed tube and CS2CO3 (185 mg, 0.57 mmol) was added to it. It was stirred and to it was added methyl iodide (0.15 mL, 2.37 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 EtOAc (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 40% EtOAc in hexane and the product was isolated as colourless sticky gum (80 mg). The product was further purified by PREP-HPLC- Chiral (SFC) to yield enantiomerically pure Example 11 as a yellow solid (14 mg, 96.07% purity, 100% enantiomeric excess). LCMS: m / z found 436.11 [M+H]+, rt = 7.13 min (Method 8) [Luna Omega Polar C18 column (3 pm, 100 x 4.6 mm)];1H NMR (400 MHz, DMSO-cfe) 5 8.08 (d, J = 9.9 Hz, 1 H), 7.60 - 7.46 (m, 5H), 6.08 (q, J = 8.4 Hz, 1 H), 3.60 (s, 3H), 2.83 (s, 3H).

[0311] SFC PREP PURIFICATION was carried on a Waters Thar SFC-80 equipped with Waters UV Detector 40D by using Chiralpak IG (30.0 mm x 250 mm), 5p column operating at 35 °C temperature, maintaining flow rate of 70 mL / min, using 65 % CO2 in super critical state and 35% of MeOH as mobile phase, running this isocratic mixture up to 7.0 minutes and maintaining the isobaric condition of 100 bar at 220 nm wavelength.

[0312] Synthesis of ( / ?9- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V-ethyl-2-methyl- 3-oxo-2,3-dihydro-[1,2,4]triazolo[4,3-b]pyridazine-6-sulfonamide (Example 12): The sulfonamide 10.4 (300 mg, 0.71 mmol) was dissolved in DMF (2 mL) in a sealed tube and CS2CO3 (278 mg, 0.85 mmol) was added to it. The mixture was stirred and ethyl iodide (0.3 mL, 3.56 mmol) was added to it. Stirring was continued at room temperature for 30 min. The reaction was then 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 Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 40% EtOAc in hexane and the product was isolated as colourless sticky gum (120 mg). The product was further purified by PREP- HPLC-Chiral (SFC) to yield enantiomerically pure Example 12 as yellow solid (10 mg, 99.65% purity, 100% enantiomeric excess). LCMS: m / z found 450.0 [M+H]+, rt = 2.69 min (Method 9) [Waters Xbridge C18 column (5 pm, 50 x 4.6 mm)];1H NMR (401 MHz, DMSO- d6) 6 8.06 (d, J = 9.9 Hz, 1 H), 7.61 (d, J = 8.5 Hz, 2H), 7.55 - 7.45 (m, 3H), 6.04 (q, J = 8.6 Hz, 1 H), 3.61 (s, 3H), 3.53 - 3.33 (m, 2H), 0.96 (t, J = 7.0 Hz, 3H).

[0313] SFC PREP PURIFICATION was carried on a Waters Thar SFC-80 equipped with Waters UV Detector 40D by using Chiralpak IG (30.0 mm x 250 mm), 5p column operating at 35 °C temperature, maintaining flow rate of 70 mL / min, using 65 % CO2 in super critical state and 35% of MeOH as mobile phase, running this isocratic mixture up to 10.0 minutes and maintaining the isobaric condition of 100 bar at 220 nm wavelength.Example 13 and Example 14

[0314] ( / ?9- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-5-cyano- / V,1-dimethyl-6-oxo- 1,6-dihydropyridine-3-sulfonamide (Example 13) and ( / ?9- / V-(1-(4-chlorophenyl)-2,2,2- trifluoroethyl)-5-cyano- / V-ethyl-1-methyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Example 14)Example 14Scheme 11

[0315] Synthesis of 5-bromo-1-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile 11.1 : To a stirred solution of 5-bromo-2-oxo-1 ,2-dihydropyridine-3-carbonitrile (1.5 gm, 7.54 mmol), K2COs (2 gm, 15.08 mmol) in DMF (5 mL) was added methyl iodide (2.35 mL, 37.68 mmol) in a sealed tube under ice cold condition and the reaction mixture was stirred at roomtemperature for 16 h. The reaction was then quenched with ice cold water (20 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layer was washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 30% ethyl acetate in hexane and the compound 11.1 was isolated as white solid (1.2 g,75% yield). LCMS: m / z found 212.8 [M+H]+, rt = 1.13 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)].1H NMR (400 MHz, DMSO-cfe) 6 8.47 (d, J = 2.6 Hz, 1 H), 8.40 (d, J = 2.6 Hz, 1 H), 3.48 (s, 3H).

[0316] 5-((4-methoxybenzyl)thio)-1-methyl-2-oxo-1,2-dihydropyridine-3-carbonitrile 11.2: Compound 11.1 (1.2 g, 5.63 mmol) was dissolved in toluene (10 mL) and (4- methoxyphenyl)methanethiol (0.95 mL, 6.76 mmol) was added to it. The solution was stirred and degasified with argon. DIPEA (2.9 mL, 16.89 mmol) was added to the solution followed by Xanthphos (326 mg, 0.56 mmol). The reaction mixture was further degasified with argon. Pd2(dba)s (258 mg, 0.28 mmol) was added to it under the inert atmosphere and the reaction mixture was stirred at 100°C for 12 h under argon atmosphere. After completion (monitored by TLC and LCMS), it was filtered through sintered funnel. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography over silica gel using 50% ethyl acetate in hexane and the product 11.2 was isolated as white solid (1.4 g, 87% yield). LCMS: m / z found 287.2 [M+H]+, rt = 1.55 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)].1H NMR (400 MHz, DMSO-cfe) 6 8.09 (d, J = 2.4 Hz, 1 H), 8.03 (d, J = 2.8 Hz, 1 H), 7.11 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 3.97 (s, 2H), 3.72 (s, 3H), 3.42 (s, 3H).

[0317] Synthesis of 5-cyano-1-methyl-6-oxo-1,6-dihydropyridine-3-sulfonyl chloride 11.3: Solution of intermediate 11.2 (600 mg, 2.09 mmol) in CH3CN (6 mL) was cooled at - 10 °C and to the solution was added a mixture of added 2 N HCI (1 mL). The solution was stirred and 1 ,3-Dichloro-5,5-dimethyl hydantoin (826 mg, 4.19 mmol) was added portion wise to it. The stirring was continued at the same temperature for 30 min. It was then diluted with ice cold water (5 mL) and extracted with DCM (5 mL). The organic layer was separated, washed with water (5 mL) dried over anhydrous Na2SC>4 and used in the forwarding step without evaporation.

[0318] Synthesis of ( / ?9- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-5-cyano-1-methyl- 6-oxo-1,6-dihydropyridine-3-sulfonamide 11.4: To a solution of sulfonyl chloride 11.3 in DCM was added ( )-1-(4-chlorophenyl)-2,2,2-trifluoroethan-1-amine (258 mg, 1.05 mmol) to it followed by pyridine (1.7 mL, 20.95 mmol). The reaction mixture was stirred at room temperature for 18 h. It was diluted with water (10 mL) and extracted with DCM (2 * 10 mL). The combined organic layer was washed with water (10 mL), dried over anhydrous Na2SC>4and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel and the compound 11.4 was isolated as white solid (320 mg, 38% yield).1H NMR (400 MHz, DMSO-cfe) 6 9.41 (d, J = 10.4 Hz, 1 H), 8.47 (d, J = 2.7 Hz, 1 H), 7.98 (d, J = 2.0 Hz, 1 H), 7.45 (q, J = 8.3 Hz, 4H), 5.63 - 5.01 (m, 1 H), 3.46 (s, 3H).

[0319] Synthesis of ( / ?9- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-5-cyano- / V,1- dimethyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Example 13): The sulfonamide 11.4 (150 mg, 0.37 mmol) was dissolved in DMF (0.5 mL) in a sealed tube and CS2CO3 (181 mg, 0.55 mmol) was added to it. It was stirred and to it was added Methyl iodide (0.23 mL, 3.69 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 EtOAc (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% EtOAc in hexane and (Example 13) isolated as colourless sticky gum (60 mg, 97.6% purity, 99.5% enantiomeric excess). LCMS: m / z found 420.2 [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 8.81 (d, J = 2.5 Hz, 1 H), 8.55 (d, J = 2.6 Hz, 1 H), 7.53 (d, J = 8.6 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 5.95 (q, J = 8.6 Hz, 1 H), 3.56 (s, 3H), 2.80 (s, 3H).

[0320] Synthesis of (R)-N-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-5-cyano-N-ethyl- 1-methyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Example 14): The sulfonamide 11.4 (170 mg, 0.42 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (205 mg, 0.63 mmol) was added to it. It was stirred and to it was added ethyl iodide (0.3 mL, 4.19 mmol). The reaction mixture was then stirred at 50°C for 30 min. The reaction was then 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 Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% EtOAc in hexane and the product was isolated as white solid (130 mg, 72% yield). The product was further purified by PREP-HPLC-Chiral (SFC) to yield enantiomerically pure (Example 14) as white solid (60 mg, 99.32% purity, 99.8% enantiomeric excess). LCMS: m / z found 434.1 [M+H]+, rt = 3.03 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)]; 1 H NMR (400 MHz, DMSO-d6) 5 8.81 (d, J = 2.8 Hz, 1 H), 8.54 (d, J = 2.7 Hz, 1 H), 7.53 (d, J = 8.3 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 5.94 (q, J = 8.5 Hz, 1 H), 3.56 (s, 3H), 3.48 - 3.33 (m, 1 H), 3.30 - 3.19 (m, 1 H), 1.03 (t, J = 6.7 Hz, 3H).

[0321] SFC PREP PURIFICATION was carried on a Waters Thar SFC-80 equipped with Waters UV Detector 40D by using Chiralpak IG (30.0 mm x 250 mm), 5p column operatingat 35 °C temperature, maintaining flow rate of 60 mL / min, using 65 % CO2 in super critical state and 40% of MeOH as mobile phase, running this isocratic mixture up to 6.0 minutes and maintaining the isobaric condition of 100 bar at 220 nm wavelength.

[0322] Example 15 and Example 165

[0323] (7?)-A / -(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-3,3-difluoro-A / ,1-dimethyl-2- oxo-2, 3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-sulfonamide (Example 15) and (R)-N-{^- (4-chlorophenyl)-2,2,2-trifluoroethyl)- / V-ethyl-3,3-difluoro-1-methyl-2-oxo-2,3- dihydro-1H-pyrrolo[2,3-b]pyridine-5-sulfonamide (Example 16)Example 15 Example 16-| Q Scheme 12

[0324] Synthesis of 5-bromo-3,3-difluoro-1-methyl-1,3-dihydro-2H-pyrrolo[2,3- b]pyridin-2-one 12.1 : To a stirred solution of 5-bromo-3,3-difluoro-1 ,3-dihydro-2 / 7- pyrrolo[2,3-b]pyridin-2-one (850 mg, 3.41 mmol), K2COs( 943 mg , 6.83 mmol) in DMF (5 mL) was added methyl iodide (1.3 mL, 20.48 mmol) in a sealed tube under ice cold condition15 and the reaction mixture was stirred at room temperature for 16 h. The reaction was then quenched with ice cold water (25 mL) and extracted with EtOAc (2 x 25 mL). The combined organic layer was washed with water (25 mL) and brine (20 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 30% EtOAc in hexane and the compound 12.1 wasisolated as white solid (760 mg, 84% yield). LCMS: m / z found 262.9 [M+H]+, rt = 1.61 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)];1H NMR (400 MHz, DMSO-cfe) 6 8.63 (s, 1 H), 8.53 (s, 1 H), 3.15 (s, 3H).

[0325] Synthesis of 3,3-difluoro-5-((4-methoxybenzyl)thio)-1-methyl-1,3-dihydro-2H- pyrrolo[2,3-b]pyridin-2-one 12.2: Compound 12.1 (760 mg, 2.89 mmol) was dissolved in toluene (8 mL) and (4-methoxyphenyl)methanethiol (0.5 ml, 3.47 mmol) was added to it. The solution was stirred and degasified with argon. DIPEA (1.5 mL, 8.66 mmol) was added to the solution followed by Xanthphos (167 mg, 0.29 mmol). The reaction mixture was further degasified with argon. Pd2(dba)s (132 mg, 0.14 mmol) was added to it under the inert atmosphere and the reaction mixture was stirred at 100°C for 16 h under argon atmosphere. After completion (monitored by TLC and LCMS), it was filtered through sintered funnel. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography over silica gel using 50% EtOAc in hexane and the product 12.2 was isolated as white solid (700 mg, 72% yield). LCMS: m / z found 337.0 [M+H]+, rt = 1.85 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)];1H NMR (400 MHz, DMSO- cfe) 6 8.33 (s, 1 H), 8.18 (s, 1 H), 7.20 (d, J = 8.4 Hz, 2H), 6.84 (d, J = 8.3 Hz, 2H), 4.20 (s, 2H), 3.70 (s, 3H), 3.13 (s, 3H).

[0326] Synthesis of 3,3-difluoro-1-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3- b]pyridine-5-sulfonyl chloride 12.3: Solution of intermediate 12.2 (660 mg, 1.96 mmol) in CH3CN (6 mL) was cooled at -10°C and to the solution was added a mixture of added 2 N HCI (1.2 mL). The solution was stirred and 1 ,3-dichloro-5,5-dimethyl hydantoin (703 mg, 3.57 mmol) was added portion wise to it. The stirring was continued at the same temperature for 30 mins. It was then diluted with ice cold water (5 mL) and extracted with DCM (5 mL). The organic layer was separated, washed with water (5 mL) dried over anhydrous Na2SC>4 and used in the forwarding step without evaporation.

[0327] Synthesis of ( / ?9- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-3,3-difluoro-1- methyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-sulfonamide 12.4: To a solution of sulfonyl chloride 12.3 in DCM was added (R)-1-(4-chlorophenyl)-2,2,2-trifluoroethan-1- amine (289 mg, 1.18 mmol) to it followed by pyridine (1.6 mL, 19.6 mmol). The reaction mixture was stirred at room temperature for 18 h. It was diluted with water (10 mL) and extracted with DCM (2 * 10 mL). The combined organic layer was washed with water (10 mL), dried over anhydrous Na2SC>4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel and the compound 12.4 was isolated as white solid (210 mg, 24% yield). LCMS: m / z found 456.0 [M+H] +, rt = 1.76 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)];1H NMR (400 MHz, DMSO-cfe) 6 9.59 (d, J = 10.1 Hz, 1 H), 8.67 (s, 1 H), 8.16 (s, 1 H), 7.43 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.3 Hz, 2H), 5.64 - 5.40 (m, 1 H), 3.16 (s, 3H).

[0328] Synthesis of ( / ?9- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-3,3-difluoro- / V,1- dimethyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-sulfonamide (Example 15): The sulfonamide 12.4 (80 mg, 0.18 mmol) was dissolved in DMF (0.5 mL) in a sealed tube and CS2CO3 (86 mg, 0.26 mmol) was added to it. It was stirred and to it was added methyl iodide (0.1 mL, 1.76 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 EtOAc (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 desired product Example 15 as a colourless sticky gum (30 mg, 93% purity, 100% enantiomeric excess). LCMS: m / z found 470.1 [M+H]+, rt = 3.14 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)];1H NMR (401 MHz, DMSO-cfe) 6 8.95 (d, J = 2.0 Hz, 1 H), 8.71 (d, J = 1 .6 Hz, 1 H), 7.48 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.6 Hz, 2H), 6.09 (q, J = 8.6 Hz, 1 H), 3.20 (s, 3H), 2.80 (s, 3H).

[0329] Synthesis of (R)-A / -(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-A / -ethyl-3,3- difluoro-1-methyl-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-sulfonamide(Example 16): The sulfonamide 12.4 (130 mg, 0.29 mmol) was dissolved in DMF (0.5 mL) in a sealed tube and CS2CO3 (139 mg, 0.43 mmol) was added to it. It was stirred and to it was added ethyl iodide (0.2 mL, 2.85 mmol). The reaction mixture was then stirred at 50°C for 4 h. The reaction was then 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 Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% EtOAc in hexane to isolate the product Example 16 as a white solid (70 mg, 97.72% purity, 97.9% enantiomeric excess). LCMS: m / z found 484.2 [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 8.97 (s, 1 H), 8.71 (s, 1 H), 7.49 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.5 Hz, 2H), 6.10 (q, J = 8.7 Hz, 1 H), 3.48 - 3.34 (m, 1 H), 3.30 - 3.21 (m, 1 H), 3.20 (s, 3H), 0.99 (t, J = 6.9 Hz, 3H).

[0330] Example 17, Example 18 and Example 19

[0331] ( / ?9- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V-ethyl-1-methyl-6-oxo-1,6- dihydropyridazine-4-sulfonamide (Example 17), (R)-N, 1 -di methyl -6-oxo- / V-(2, 2,2- trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)-1,6-dihydropyridazine-4-sulfonamide (Example 18) and (7?9-A / -ethyl-1-methyl-6-oxo-A / -(2,2,2-trifluoro-1-(4- (trifluoromethyl)phenyl)ethyl)-1,6-dihydropyridazine-4-sulfonamide (Example 19)Scheme 13

[0332] Synthesis of 5-((4-methoxybenzyl)thio)-2-methylpyridazin-3(2H)-one 13.1 : Compound 8.1 (3.7 g, 14.90 mmol) was dissolved in DMF (15 mL) and the solution was cooled in ice bath. NaH (60%) (893 mg, 22.35 mmol) was added portion wise to the solution and the reaction mixture was stirred in ice bath for 30 mins. Methyl iodide (2.8 mL, 44.70 mmol) was added slowly to the reaction mixture at 0°C and stirring was continued at room temperature for 3 h. The reaction mixture was then cooled in ice bath and was quenched with cold saturated aqueous NH4CI solution (20 mL). It was further diluted with aqueous NH4CI solution (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with saturated aqueous NH4CI solution (30 mL) and brine (30 mL), dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% EtOAc in hexane to yield the desired compound 13.1 as off white solid (3.2 g, 81 % yield). LCMS: m / z found 263.0 [M+H]+, rt = 1.51 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)]; 1 H NMR (400 MHz,DMSO) 5 7.78 (d, J = 2.2 Hz, 1 H), 7.36 (d, J = 8.6 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 6.73 (d, J = 2.1 Hz, 1 H), 4.30 (s, 2H), 3.73 (s, 3H), 3.56 (s, 3H).

[0333] Synthesis of 1-methyl-6-oxo-1,6-dihydropyridazine-4-sulfonyl chloride 13.2: To a stirred solution of compound 13.1 (400 mg, 1.52 mmol) in CH3CN (5 mL) at -5°C was added a mixture of water and AcOH (2:1) (0.5 mL). 1 ,3-Dichloro-5,5-dimethylhydantoin (600 mg, 3.05 mmol) was added portion wise to the reaction mixture at -5°C and it was stirred at the same temperature for 30 min. After dilution with ice cold water (15 mL) and extraction with DCM (10 mL) the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure at 25 °C. The crude sulfonyl chloride 13.2 was used immediately in the forwarding step.

[0334] Synthesis of ( / ?9- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-1-methyl-6-oxo- 1 ,6-dihydropyridazine-4-sulfonamide 13.3: To the solution of sulfonyl chloride 13.2 in DCM (10 mL) was added ( )-1-(4-chlorophenyl)-2,2,2-trifluoroethan-1-amine hydrochloride (283 mg, 1.15 mmol) followed by pyridine (1 mL, 13.08 mmol) and the reaction mixture was stirred at room temperature for 4 h. The volatiles were evaporated under reduced pressure and the crude was purified column chromatography over silica gel using 40% ethyl acetate in hexane to yield the compound 13.3 as a yellow gum (127 mg, 23% yield). LCMS: m / z found 382.2 [M+H]+, rt = 1.74 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)];1H NMR (400 MHz, DMSO) 5 10.05 - 10.00 (m, 1 H), 7.93 (s, 1 H), 7.51 (d, J = 7.9 Hz, 2H), 7.43 (d, J = 8.2 Hz, 2H), 7.03 (s, 1 H), 5.56 (s, 1 H), 3.58 (s, 3H).

[0335] Synthesis of (R)-N-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-N-ethyl-1-methyl- 6-oxo-1,6-dihydropyridazine-4-sulfonamide (Example 17): The sulfonamide 13.3 (120 mg, 0.31 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (123 mg, 0.37 mmol) was added to it. It was stirred and to it was added ethyl iodide (0.25 mL, 3.14 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 EtOAc (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% EtOAc in hexane to yield the desired compound Example 17 as a colourless sticky gum (40 mg, 30% yield, 96.39% purity, 94.95% ee). LCMS: m / z found410.2 [M+H]+, rt = 3.00 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)]; 1 H NMR (400 MHz, DMSO) 5 8.34 - 8.29 (m, 1 H), 7.58 - 7.47 (m, 4H), 7.43 (d, J =2.2 Hz, 1 H), 6.15 - 6.08 (m, 1 H), 3.69 (s, 3H), 3.49 - 3.35 (m, 2H), 0.98 (t, J = 7.0 Hz, 3H).

[0336] Synthesis of (R)-1-methyl-6-oxo-N-(2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)-1,6-dihydropyridazine-4-sulfonamide 13.4: To the solution of sulfonyl chloride 13.2 in DCM (10 mL) was added (R)-2,2,2-trifluoro-1-(4- (trifluoromethyl)phenyl)ethan-1 -amine hydrochloride (418 mg, 1.15 mmol) followed by pyridine (1 mL, 13.08 mmol) and the reaction mixture was stirred at room temperature for 4h. The volatiles were evaporated under reduced pressure and the crude was purified column chromatography over silica gel using 40% ethyl acetate in hexane to yield the compound 13.4 as yellow gum (120 mg, 23% yield). LCMS: m / z found 416.12 [M+H]+, rt = 1.94 min (Method 32) [Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm)]; 1 H NMR (400 MHz, DMSO) 5 10.15 (d, J = 9.5 Hz, 1 H), 7.93 (d, J = 2.3 Hz, 1 H), 7.87 - 7.75 (m, 1 H), 7.74 (s, 3H), 7.07 (d, J = 2.0 Hz, 1 H), 5.78 - 5.66 (m, 1 H), 3.54 (s, 3H).

[0337] Synthesis of (R)-N,1-dimethyl-6-oxo-N-(2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)-1,6-dihydropyridazine-4-sulfonamide (Example 18):The sulfonamide 13.4 (120 mg, 0.28 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (113 mg, 0.34 mmol) was added to it. It was stirred and to it was added methyl iodide (0.2 mL, 2.88 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 EtOAc (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% EtOAc in hexane to yield the desired compound Example 18 as a colourless sticky gum (30 mg, 24% yield, 98.51% purity, 98.08% ee). LCMS: m / z found 430.2 [M+H]+, rt = 2.97 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)]; 1 H NMR (400 MHz, DMSO) 5 8.33 - 8.28 (m, 1 H), 7.86 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 7.8 Hz, 2H), 7.44 (d, J = 8.8 Hz, 1 H), 6.27 (d, J = 8.4 Hz, 1 H), 3.69 (s, 3H), 2.90 (s, 3H).

[0338] Synthesis of (R)-A / -ethyl-1-methyl-6-oxo-A / -(2,2,2-trifluoro-1-(4- (trifluoromethyl)phenyl)ethyl)-1,6-dihydropyridazine-4-sulfonamide (Example 19):The sulfonamide 13.4 (320 mg, 0.77 mmol) was dissolved in DMF (3 mL) in a sealed tube and CS2CO3 (300 mg, 0.92 mmol) was added to it. It was stirred and to it was added ethyl iodide (0.6 mL, 7.70 mmol). The reaction mixture was then stirred at 40°C for 2 h. The reaction was then quenched with water (15 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layer was washed with water (15 mL) and brine (15 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% EtOAc in hexane to yield the desired compound (100 mg), which was further purified by Normal Phase Prep-HPLC-Chiral to yield the compound Example 19 as a yellow sticky gum (55 mg, 16% yield, 97.79% purity, 100% ee). LCMS: m / z found 444.12 [M+H]+, rt = 3.38 min (Method 2)[Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)].1H NMR (400 MHz, DMSO) 5 8.32 (d, J = 2.3 Hz, 1 H), 7.86 (d, J = 8.2 Hz, 2H), 7.72 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 2.3 Hz, 1 H), 6.27 (q, J = 8.4 Hz, 1 H), 3.69 (s, 3H), 3.55 - 3.33 (m, 2H), 1 .00 (t, J = 7.0 Hz, 3H).

[0339] SFC PREP PURIFICATION was carried on an Agilent 1200 series instrument by using Chiralpak IC (20.0 mm x 250 mm), 5p column operating at room temperature, maintaining flow rate of 18 mL / min, 90% hexane, 5%dischloromethane and 5% ethanol as mobile phase, running this isocratic mixture up to 15.0 minutes at 314 nm wavelength.

[0340] Example 20 and Example 21

[0341] (R)-N-(1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethyl)-N,1-dimethyl-6-oxo-1 ,6-dihydropyridazine-4-sulfonamide (Example 20) and (R)-N-(1-(4-chloro-3- fluorophenyl)-2,2,2-trifluoroethyl)-N-ethyl-1-methyl-6-oxo-1,6-dihydropyridazine-4- sulfonamide (Example 21)

[0342] (R)-1 -(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethan-1 -amine hydrochloride 14.3Scheme 14

[0343] Synthesis of (R)-N-(1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethylidene)-2- methylpropane-2-sulfinamide 14.1 : (R)-2-methylpropane-2-sulfinamide (1.34 g, 11.03 mmol) was dissolved in THF (20 mL) and Ti(OiPr)4 (7.2 mL) was added to it and stirred for 10 mins at room temperature. 1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethan-1-one (2 g) was added to the reaction mixture and was stirred at 60°C for 18 h. The reaction mixture was cooled and forwarded to the next step.

[0344] Synthesis of A / -(( / ?)-1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethyl)-2- methylpropane-2-sulfinamide 14.2: The reaction mixture of previous step was cooled at - 78°C and NaBH4 (1 g, 26.47 mmol) was added portion wise. The reaction mixture was stirred for 3 h keeping the temperature under -40°C. The reaction mass was poured slowly into ice cold aqueous saturated NaCI solution and stirred vigorously. Ethyl acetate (50 mL) was added and the mixture was filtered through celite bed. The celite bed was washed withEtOAc (2 x 50 mL) and the combined organic layer was washed with brine (2 x 50 mL). The organic part was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% EtOAc in hexane to yield the desired compound 14.2 (2 g, 68% yield) as colourless oil. LCMS: m / z found 332.0 [M+H]+, rt = 1.71 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)].1H NMR (400 MHz, DMSO) 5 7.67 (t, J = 8.5 Hz, 2H), 7.46 (d, J = 8.5 Hz, 1 H), 6.74 (d, J = 9.9 Hz, 1 H), 5.36 (s, 1 H), 1.06 (s, 9H).

[0345] Synthesis of ( / ?9-1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethan-1-amine hydrochloride 14.3: Compound 14.2 (1.5 g, 4.52 mmol) was dissolved in MeOH (10 mL) and cooled in ice water bath. 4 N HCI in dioxane (15 mL) was added to it and was stirred for 1 h. The volatiles were evaporated under reduced pressure and the crude was further triturated with 50% diethyl ether in pentane to obtain desired amine 14.3 (1.2 g) as white solid as hydrochloride salt.1H NMR (400 MHz, DMSO) 5 9.66 (s, 3H), 7.85 - 7.74 (m, 2H), 7.53 (d, J = 8.0 Hz, 1 H), 5.62 (q, J = 7.6 Hz, 1 H).

[0346] Synthesis of ( / ?9- / V-(1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethyl)-1-methyl- 6-oxo-1,6-dihydropyridazine-4-sulfonamide 15.1 : To the solution of sulfonyl chloride 13.2 in DCM (10 mL), ( )-1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethan-1-amine hydrochloride (394 mg, 1 .49 mmol) was added, followed by pyridine (1 .0 mL, 13.08 mmol) and the reaction mixture was stirred at room temperature for 4 h. The volatiles were evaporated under reduced pressure and the crude was purified column chromatography over silica gel using 40% EtOAc in hexane to yield the compound 15.1 as a yellow gum (270 mg, 36% yield). LCMS: m / z found 400.2 [M+H]+, rt = 1.80 min (Method 1) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)];1H NMR (400 MHz, DMSO) 5 10.06 (s, 1 H), 7.94 (d, = 2.0 Hz, 1 H),7.66 - 7.59 (m, 1 H), 7.56 (d, J = 10.3 Hz, 1 H), 7.37 (d, J = 8.4 Hz, 1 H), 7.04 (d, J = 2.4 Hz, 1 H), 5.63 (d, J = 7.0 Hz, 1 H), 3.58 (s, 3H).

[0347] Synthesis of ( / ?9 V-(1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethyl)- / V,1- dimethyl-6-oxo-1,6-dihydropyridazine-4-sulfonamide (Example 20): The sulfonamide 15.1 (100 mg, 0.25 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (98 mg, 0.30 mmol) was added to it. It was stirred and to it was added methyl iodide (0.15 mL, 2.50 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 EtOAc (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% EtOAc in hexane to yield the desired compound (70 mg) which was further purified by Prep-HPLC-SFC to yield the compound Example 20 as a white solid (30 mg, 16% yield, 97.0% purity, 100% ee). LCMS: m / z found 414.2 [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) 5 8.20 (d, J = 1.8 Hz, 1 H), 7.59 (t, J = 8.0 Hz, 1 H), 7.43 - 7.36 (m, 2H), 7.32 (d, J = 8.1 Hz, 1 H), 6.06 (q, J = 8.2 Hz, 1 H), 3.79 (s, 3H), 2.91 (s, 3H).

[0348] Chiral SFC method: Chiral SFC has been completed in Waters Thar SFC-80 instrument equipped with UV Detector 40D by using Chiralpak IG (30.0 mm x 250mm), 5p Column operating at 35 °C, maintaining a flow rate of 70 mL / min, using 45% CO2 in super critical state and 55% MeOH as mobile phase, this isocratic mixture ran up to 16.0 minutes and maintained the isobaric condition of 100 bar at 230 nm wavelength.

[0349] Synthesis of (R)-N-{^ -(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethyl)- / V-ethyl-1 - methyl-6-oxo-1,6-dihydropyridazine-4-sulfonamide (Example 21): The sulfonamide 15.1 (300 mg, 0.75 mmol) was dissolved in DMF (3 mL) in a sealed tube and CS2CO3 (293 mg, 0.90 mmol) was added to it. It was stirred and to it was added ethyl iodide (0.6 mL, 7.5 mmol). The reaction mixture was then stirred at 40 °C for 2 h. The reaction was then quenched with water (15 mL) and extracted with EtOAc (2 x 15 mL). The combined organic layer was washed with water (15 mL) and brine (15 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% EtOAc in hexane to yield the desired compound (110 mg), which was further purified by Normal Phase Prep-HPLC-Chiral to yield the compound Example 21 as light yellow sticky gum (60 mg, 99.19% purity, 99.05% ee). LCMS: m / z found 428.2 [M+H]+, rt = 3.10 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)];1H NMR (400 MHz, DMSO) 5 8.31 (d, J = 2.2 Hz, 1 H), 7.72 (t, J = 8.2 Hz, 1 H), 7.50 (d, J = 10.4 Hz, 1 H), 7.45 (d, J = 2.3 Hz, 1 H), 7.38 (d, J = 8.4 Hz, 1 H), 6.14 (q, J = 8.4 Hz, 1 H), 3.69 (s, 3H), 3.59 - 3.34 (m, 2H), 1 .02 (t, J = 7.0 Hz, 3H).

[0350] Chiral method: Chiral separation was done on Agilent 1200 series instrument. Column name: CHIRALPAK IG (250 X 21 mm) 5p, operating at ambient temperature and flow rate of 21.0 mL / min. Mobile phase was a mixture of 70% hexane, 15% dichloromethane and 15% isopropyl alcohol, held this isocratic mixture run up to 15 min at a wavelength of 225 nm.

[0351] Example 22 and Example 23

[0352] (7?)-A / -(1 -(4-chlorophenyl)-2,2,2-trifluoroethyl)-A / ,1,4-trimethyl-6-oxo-1 ,6- dihydropyridine-3-sulfonamide (Example 22) and ( / ?9- / V-(1-(4-chlorophenyl)-2,2,2- trifluoroethyl)- / V-ethyl-1,4-dimethyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Example 23)Example 23Scheme 16

[0353] Synthesis of 5-bromo-1,4-dimethylpyridin-2(1H)-one 16.1 : To a stirred solution of 5-bromo-4-methylpyridin-2-ol (1.0 g, 5.32 mmol) in DMF (5 mL), K2CO3 (2.20 g, 15.96 mmol) was added. Methyl iodide (0.40 mL, 5.85 mmol) was added to it and the reaction mixture was stirred at room temperature for 12 h. It was then quenched with ice cold 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 30% ethyl acetate in hexane and the product 16.1 was isolated as whitesolid (600 mg, 56% yield). LCMS: m / z found 202.0 [M+H]+, rt = 1.69 min (Method 12) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)].

[0354] Synthesis of 5-((4-methoxybenzyl)thio)-1,4-dimethylpyridin-2(1H)-one 1.2 (Buchwald coupling): Compound 16.1 (600 mg, 2.97 mmol) was dissolved in toluene (5 mL) and (4-methoxyphenyl)methanethiol (0.40 mL, 2.67 mmol) was added to it. The solution was stirred and degasified with argon. DIPEA (1.0 mL, 5.94 mmol) was added to the solution followed by Xanthphos (86 mg, 0.15 mmol). The reaction mixture was further degasified with argon. Pd2(dba)s (81 mg, 0.09 mmol) was added to it under the inert atmosphere and the reaction mixture was stirred at 100°C for 16 h under argon atmosphere. After completion (monitored by TLC and LCMS), it was filtered through sintered funnel. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography over silica gel using 50% ethyl acetate in hexane and the product 16.2 was isolated as a white solid (600 mg, 73% yield). LCMS: m / z found 276.0 [M+H]+, rt = 1.57 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)].

[0355] Synthesis of 1,4-dimethyl-6-oxo-1,6-dihydropyridine-3-sulfonyl chloride 16.3: Solution of intermediate 16.2 (300 mg, 1.09 mmol) in CH3CN (3 mL) was cooled at -10°C and to the solution 2 N HCI (0.6 mL) was added. The solution was stirred and 1 ,3-dichloro- 5,5-dimethyl hydantoin (429 mg, 2.18 mmol) was added portion wise to it. Stirring was continued at the same temperature for 30 min. It was then diluted with ice cold water (5 mL) and extracted with DCM (5 mL). The organic layerwas separated, washed with water (5 mL) dried over anhydrous Na2SO4 and used in the forwarding step without evaporation.

[0356] Synthesis of ( / ?9- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-1,4-dimethyl-6- oxo-1, 6-dihydropyridine-3-sulfonamide 16.4: To a solution of sulfonyl chloride 16.3 in DCM, (R)-1-(4-chlorophenyl)-2,2,2-trifluoroethan-1-amine (265 mg, 1.08 mmol) was added, followed by pyridine (0.90 mL, 10.83 mmol). The reaction mixture was stirred at room temperature for 18 h. It was then diluted with water (10 mL) and extracted with DCM (2 * 10 mL). The combined organic layer was washed with water (10 mL), dried over anhydrous Na2SC>4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel and the compound 16.4 was isolated as a white solid (200 mg, 48% yield). LCMS: m / z found 394.9 [M+H]+, rt = 1.59 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)].

[0357] Synthesis of (7?9-A / -(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-A / ,1,4-trimethyl-6- oxo-1, 6-dihydropyridine-3-sulfonamide (Example 22): The sulfonamide 16.4 (80 mg, 0.20 mmol) was dissolved in DMF (0.5 mL) in a sealed tube and CS2CO3 (99 mg, 0.30 mmol) was added to it. It was stirred and to it was added methyl iodide (0.10 mL, 2.02 mmol). The reaction mixture was then stirred at 50°C for 30 min. It was then quenched with water (10mL) 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 compound Example 22 as a sticky gum (35 mg, 98.76% purity, 99.9% ee). LCMS: m / z found 409.1 [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 8.43 (s, 1 H), 7.59 - 7.48 (m, 4H), 6.34 (s, 1 H), 5.86 (q, J = 8.7 Hz, 1 H), 3.49 (s, 3H), 2.79 (s, 3H), 2.19 (s, 3H).

[0358] Synthesis of ( / ?9- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V-ethyl-1,4- dimethyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Example 23): The sulfonamide 16.4 (260 mg, 0.66 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (322 mg, 0.99 mmol) was added to it. It was stirred and to it was added ethyl iodide (0.25 mL, 3.29 mmol). The reaction mixture was then stirred at 60°C for 40 min. It 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 white solid (100 mg, 36% yield). The product was further purified by PREP-HPLC-Chiral (SFC) to yield enantiomerically pure Example 23 as a white solid (20 mg, 99.90% purity, 99.8% ee). LCMS: m / z found 423.2 [M+H]+, rt = 2.98 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)];1H NMR (400 MHz, DMSO-cfe) 6 8.44 (s, 1 H), 7.61 - 7.51 (m, 4H), 6.32 (s, 1 H), 5.76 (d, J = 7.6 Hz, 1 H), 3.49 (s, 3H), 3.49 - 3.34 (m, 2H), 2.20 (s, 3H), 0.78 (t, J = 6.9 Hz, 3H).

[0359] Example 24

[0360] (7?)-A / -(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-A / ,8-dimethyl-7-oxo-7,8- dihydroimidazo[1,2-a]pyrimidine-3-sulfonamide (Example 24)xamp eScheme 17

[0361] Synthesis of 4-amino-1-methylpyrimidin-2(1H)-one 17.1 : 4-aminopyrimidin- 2(1 / 7)-one (2.50 g, 22.50 mmol) was dissolved in DMF (100 mL) and 1 M methanolic tetrabutylammonium hydroxide (21.1 mL, 67.49 mmol) was added dropwise to it. To the resulting solution methyl iodide (1 mL, 15.75 mmol) was added at room temperature and the reaction mixture was allowed to stir at 115°C for 2 h. The volatiles were evaporated under reduced pressure and the crude product was purified by column chromatography over silica gel using 10% MeOH in DCM as eluent to get 17.1 as reddish brown solid (1.0 g, 36% yield). LCMS: m / z found 125.8 [M+H]+, rt = 0.12 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)].

[0362] Synthesis of 6-methylimidazo[1,2-c]pyrimidin-5(6H)-one 17.2: Compound 17.1 (2.0 g, 15.99 mmol) was dissolved in EtOH:Water (1.5:1) (10 mL), taken in a sealed tube and 2-bromo-1 ,1 -diethoxyethane (4.80 mL, 31.98 mmol) was added dropwise to this solution. Aqueous HBr (1.90 ml, 23.99 mmol) was added to it and the reaction mixture was stirred at 100°C for 48 h. The reaction mixture was concentrated under reduced pressure and the crude was diluted with 30% isopropanol in chloroform (50 mL). The organic part was washed with saturated Na2COs (25 mL) and dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to get the crude which was purified by column chromatography over silica gel using 10% MeOH in DCM to isolate compound 17.2 as a reddish brown solid (250 mg, 11 % yield). LCMS: m / z found 150.1 [M+H], rt = 1.17 min (Method 8) [Waters Xbridge C18 column (3.5 pm, 50 x 3 mm)].

[0363] Synthesis of 3-bromo-6-methylimidazo[1,2-c]pyrimidin-5(6 / 7)-one 17.3: Compound 17.2 (1 g, 6.71 mmol) was dissolved in chloroform (10 mL) and NBS (1.2 g, 6.71 mmol) was added to it. Reaction mixture was stirred at room temperature for 2 h. The volatiles were evaporated under reduced pressure and the crude was purified by column chromatography over silica gel using 50% ethyl acetate in hexane to obtain the compound 17.3 as yellow solid (550 mg, 36% yield). LCMS: m / z found 228.0 [M+H]+, rt = 1.38 min (Method 8) [Waters Xbridge C18 column (3.5 pm, 50 x 3 mm)].

[0364] Synthesis of 3-((4-methoxybenzyl)thio)-6-methylimidazo[1,2-c]pyrimidin- 5(6H)-one 17.4: Compound 17.3 (430 mg, 1.89 mmol) and 4-methoxy-a-toluenethiol (0.20 mL, 1.51 mmol) were taken in toluene (5 mL) and the reaction mixture was degasified with nitrogen. DIPEA (1.2 mL, 5.66 mmol) was added it and degasified further. Xanthphos (110 mg, 0.19 mmol) was added to the reaction mixture under inert atmosphere followed by Pd2(dba)s (87 mg, 0.09 mmol). Stirring was continued at 100°C for 16 h. The reaction mixture was filtered through sintered funnel. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography over silica gel using 30% ethyl acetate in hexane and the product 17.4 as yellow solid (110 mg, 19% yield). LCMS: m / z found 302.2 [M+H]+, rt = 1.65 min (Method 8) [Waters Xbridge C18 column (3.5 pm, 50 x 3 mm)].

[0365] Synthesis of 6-methyl-5-oxo-5,6-dihydroimidazo[1,2-c]pyrimidine-3-sulfonyl chloride 17.5: To a stirred solution of 17.4 (380 mg, 1.26 mmol) in CH3CN (3 mL) at -10°C were added 2 N HCI (0.5 mL) and 1 ,3-dichloro-5,5-dimethyl hydantoin (298 mg, 1.51 mmol). The reaction mass was stirred for 30 min at the same temperature. It was then diluted with ice cold water (10 mL) and extracted with DCM (2 x 10 mL). The organic layer was separated, washed with water (5 mL), dried over anhydrous Na2SO4 and the volatiles were evaporated under reduced pressure at room temperature. The crude was used immediately in the forwarding step.

[0366] Synthesis of ( / ?9- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-6-methyl-5-oxo- 5,6-dihydroimidazo[1,2-c]pyrimidine-3-sulfonamide 17.6: To a stirred solution (R)-1-(4- chlorophenyl)-2,2,2-trifluoroethan-1-amine (187 mg, 0.88 mmol) in pyridine (0.80 mL, 8.88 mmol) was added 17.5 in DCM. The reaction mixture was allowed to stir at room temperature for 18 h. It was diluted with water (10 mL) and extracted with DCM (2 x 10 mL). The combined organic layer was washed with water (10 mL), dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel to obtain the compound 17.6 as white solid (130 mg, 35% yield). LCMS: m / z found 421.0 [M+H]+, rt = 1.59 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)];1H NMR (400 MHz, DMSO-cfe) 5 11.14 - 10.14 (m, 3H), 8.70 (d, J = 11.2Hz, 1 H), 8.08 - 7.87 (m, 4H), 7.79 (s, 1 H), 7.58 (d, J = 7.8 Hz, 1 H), 7.31 (d, J = 7.8 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 6.59 (d, J = 7.7 Hz, 1 H), 5.73 - 4.90 (m, 1 H), 3.39 (s, 3H).

[0367] Synthesis of ( / ?9- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V,6-dimethyl-5- oxo-5, 6-dihydroimidazo[1,2-c]pyrimidine-3-sulfonamide (Example 24): Sulfonamide 17.6 (80 mg, 0.19 mmol) was dissolved in DMF (2 mL) in a sealed tube and CS2CO3 (80 mg, 0.25 mmol) was added to it. It was stirred and to it was added methyl iodide (0.05 mL, 1.9 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 cold 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 further purified by SFC-Prep-HPLC- chiral to yield pure compound Example 24 as a white solid (30 mg, 36% yield, 99.62% purity, 100% ee). LCMS: m / z found 435.2 [M+H]+, rt = 7.82 min (Method 34) [Luna Omega Polar C18 column (3 pm, 100 x 4.6 mm)];1H NMR (400 MHz, DMSO-cfe) 6 7.99 (s, 1 H), 7.71 (d, J = 7.7 Hz, 1 H), 7.46 (d, J = 8.7 Hz, 2H), 7.39 (d, J = 8.4 Hz, 2H), 6.75 (d, J = 7.6 Hz, 1 H), 5.92 (q, J = 8.5 Hz, 1 H), 3.46 (s, 3H), 2.94 (s, 3H).

[0368] SFC chiral method: SFC purification was done in Waters Thar SFC-80 equipped with Waters UV Detector 2489 by using CHIRALPAK-IG (30.0mm x 250mm), 5p column operating at 35°C, maintaining a flow rate of 70 ml / min, using 60% CO2 in super critical state and 40% of methanol) as mobile phase. This isocratic mixture ran up to 10.0 minutes, maintaining the isobaric condition of 100 bar at 220 nm wavelength.

[0369] Example 25

[0370] (7?)-A / -(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-N,8-dimethyl-7-oxo-7,8- dihydroimidazo[1,2-a]pyrimidine-3-sulfonamide (Example 25)11.5Example 25Scheme 18

[0371] Synthesis of 8-methylimidazo[1,2-a]pyrimidin-7(8H)-one 18.1 : 2-amino-3- methylpyrimidin-4(3 / 7)-one (2.0 g, 15.99 mmol) was dissolved in EtOH:Water (1.5:1) (10 mL), taken in a sealed tube and 2-bromo-1 ,1 -diethoxyethane (6 mL, 31.98 mmol) was added dropwise to this solution. Aqueous HBr (1.9 mL, 23.99 mmol) was added to it and the reaction mixture was stirred at 100°C for 48 h. The reaction mixture was concentrated under reduced pressure and the crude was diluted with 30% isopropanol in chloroform (50 mL). The organic part was washed with saturated Na2COs (25 mL) and dried over anhydrous sodium sulphate and the solvent was evaporated under reduced pressure to get the crude which was purified by column chromatography over silica gel using 10% MeOH in DCM to isolate compound 18.1 as brown solid (350 mg, 15% yield). LCMS: m / z found 149.9 [M+H]+, rt = 0.37 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)].

[0372] Synthesis of 3-bromo-8-methylimidazo[1,2-a]pyrimidin-7(8H)-one 18.2: Compound 18.1 (400 mg, 2.68 mmol) was dissolved in chloroform (4 mL) and NBS (477 mg, 2.68 mmol) was added to it. Reaction mixture was stirred at room temperature for 12 h. The volatiles were evaporated under reduced pressure and the crude was purified by column chromatography over silica gel using 50% ethyl acetate in hexane to obtain the compound18.2 as yellow solid (110 mg, 18% yield). LCMS: m / z found 228.1 [M+H]+, rt = 1.28 min (Method 8) [Waters Xbridge C18 column (3.5 pm, 50 x 3 mm)].

[0373] Synthesis of 3-((4-methoxybenzyl)thio)-8-methylimidazo[1,2-a]pyrimidin- 7(8H)-one 18.3: Compound 18.2 (200 mg, 0.87 mmol) and 4-methoxy-a-toluenethiol (0.1 mL, 0.70 mmol) were taken in toluene (4 mL) and the reaction mixture was degasified with nitrogen. DI PEA (0.5 mL, 2.63 mmol) was added it and degasified further. Xanthphos (65 mg, 0.11 mmol) was added to the reaction mixture under inert atmosphere followed by Pd2(dba)s 41 mg, 0.04 mmol). It was stirred at 100°C for 16 h. Itwas filtered through sintered funnel. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography over silica gel using 30% ethyl acetate in hexane and compound 18.3 was isolated as a yellow solid. (95 mg, 36% yield). LCMS: m / z found 302.3 [M+H]+, rt = 1.63 min (Method 8) [Waters Xbridge C18 column (3.5 pm, 50 x 3 mm)].

[0374] Synthesis of 8-methyl-7-oxo-7,8-dihydroimidazo[1,2-a]pyrimidine-3-sulfonyl chloride 18.4: To a stirred solution of 18.3 (380 mg, 1.26 mmol) in CH3CN (3 mL) at -10°C were added 2 N HCI (0.5 mL) and 1 ,3-dichloro-5,5-dimethyl hydantoin (298 mg, 1.51 mmol). The reaction mass was stirred for 30 min at the same temperature. It was then diluted with ice cold water (10 mL) and extracted with DCM (2 x 10 mL). The organic layer was separated, washed with water (5 mL), dried over anhydrous Na2SO4 and the volatiles were evaporated under reduced pressure at room temperature. The crude was used immediately in the forwarding step.

[0375] Synthesis of ( / ?9- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-8-methyl-7-oxo- 7,8-dihydroimidazo[1,2-a]pyrimidine-3-sulfonamide 18.5: To a stirred solution (7?)-1-(4- chlorophenyl)-2,2,2-trifluoroethan-1-amine (323 mg, 1.53 mmol) in pyridine (1.25 mL, 15.34 mmol) was added 18.4 in DCM. The reaction mixture was allowed to stir at room temperature for 18 h. It was diluted with water (10 mL) and extracted with DCM (2 x 10 mL). The combined organic layer was washed with water (10 mL), dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel using 30% ethyl acetate in hexane to obtain the compound 18.5 (110 mg, 17% yield). LCMS: m / z found 412.2 [M+H]), rt = 1.63 min (Method 8) [Waters Xbridge C18 column (3.5 pm, 50 x 3 mm)];1H NMR (400 MHz, DMSO-cfe) 6 9.76 (d, J = 10.2 Hz, 1 H), 8.10 (d, J = 7.4 Hz, 1 H), 7.54 (d, J = 10.8 Hz, 2H), 7.43 - 7.29 (m, 2H), 7.24 (d, J = 8.0 Hz, 2H), 6.34 (d, J = 8.1 Hz, 1 H), 5.34 - 5.29 (m, 1 H), 3.37 (s, 3H), 2.56 (s, 2H).

[0376] Synthesis of ( / ?9- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V,8-dimethyl-7- oxo-7, 8-dihydroimidazo[1,2-a]pyrimidine-3-sulfonamide (Example 25): Sulfonamide 18.5 (80 mg, 0.19 mmol) was dissolved in DMF (2 mL) in a sealed tube and CS2CO3 (81 mg, 0.24 mmol) was added to it. It was stirred and to it was added methyl iodide (0.1 mL, 0.57mmol). 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 layerwas washed with cold water 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 further purified by Reverse Phase Prep-HPLC to obtain compound Example 25 as white solid (30 mg, 36% yield, 99.81 purity, 100% ee). LCMS: m / z found 435.2 [M+H]+, rt = 2.94 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)] ;1H NMR (401 MHz, DMSO-cfe) 6 8.41 (d, J = 7.9 Hz, 1 H), 7.92 (s, 1 H), 7.51 (d, J = 8.6 Hz, 2H), 7.43 (d, J = 8.3 Hz, 2H), 6.34 (d, J = 7.9 Hz, 1 H), 6.14 (q, J = 8.5 Hz, 1 H), 3.50 (s, 3H), 2.78 (s, 3H).

[0377] Preparative HPLC was done in WATERS BGM 2545 equipped with WATERS PDA Detector 2998 set to multiple-wavelength UV (200-400nm) detection. Column name: YMC Actus Triart C18 (250 x 20 mm, 5p) operating at ambient temperature and flow rate of 16 ml / min. Mobile phase: A =0.1 % Formic acid in water, Mobile phase: B= Acetonitrile; Gradient Profile: Mobile phase initial composition of 80% A and 20% B, then to 60% A and 40% B in 3 min, then to 30% A and 70% B in 20 min, then to 5% A and 95% B in 20.5 min held this composition up to 23.5 min. for column washing, then returned to initial composition in 24 min. and held for 27 min.

[0378] Example 26 and Example 27

[0379] (7?)-A / -f1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-A / ,1-dimethyl-2-oxo-1,2- dihydropyrimidine-5-sulfonamide (Example 26) and (7?9-A / -(1-(4-chlorophenyl)-2,2,2- trifluoroethyl)- / V-ethyl-1-methyl-2-oxo-1,2-dihydropyrimidine-5-sulfonamide (Example 27),DIPEA, Toluene19.1100 °C, 18 h 19.2Scheme 19

[0380] Synthesis of 5-((4-methoxybenzyl)thio)-1-methylpyrimidin-2(1H)-one 19.1 :The solution of compound 5-bromo-1-methylpyrimidin-2(1 / 7)-one (700 mg, 3.0 mmol) and (4-methoxyphenyl)methanethiol (500 mg, 3.6 mmol) in toluene (5 mL) was degasified with argon and to it were added Pd2(dba)s (140 mg, 0.15 mmol), Xanthphos (170 mg, 0.3 mmol) and DIPEA (1.6 mL, 9.2 mmol) under inert atmosphere. It was heated at 100°C for 18 h. The reaction mass was cooled to room temperature, filtered through sintered funnel and the filtrate was concentrated under reduced pressure to afford crude compound which was purified by column chromatography over silica gel using 20% ethyl acetate in hexane to afford pure compound 19.1 (600 mg, 70% yield). LCMS: m / z found 263.2 [M+H]+, rt = 1.55 min (Method 8) [Waters Xbridge C18 column (3.5 pm, 50 x 3 mm)].

[0381] Synthesis of 1-methyl-2-oxo-1,2-dihydropyrimidine-5-sulfonyl chloride 19.2: Solution of intermediate 19.1 (250 mg, 0.92 mmol) in CH3CN (2.5 mL) was cooled at -10°C and to the solution was added 2 N HCI (2.5 mL). The solution was stirred and 1 ,3-dichloro- 5,5-dimethyl hydantoin (363 mg, 1.84 mmol) was added portion wise to it. The stirring was continued at the same temperature for 30 min. It was then diluted with ice cold water (5 mL) and extracted with DCM (5 mL). The organic layerwas separated, washed with water (5 mL) dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound which was used for forwarding step without purification.

[0382] Synthesis of ( / ?9- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-1-methyl-2-oxo- 1 ,2-dihydropyrimidine-5-sulfonamide 19.3: To a solution of sulfonyl chloride 19.2 in DCM was added ( )-2,2,2-trifluoro-1-(4-chlorophenyl) ethan-1-amine (124 mg, 0.64 mmol) followed by pyridine (1.5 mL, 18.38 mmol). The reaction mixture was stirred at room temperature for 18 h. It was diluted with water (10 mL) and extracted with DCM (2 * 10 mL). The combined organic layer was washed with water (10 mL), dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel and the compound 19.3 was isolated as yellow sticky gum (70 mg, 20% yield). LCMS: m / z found 382.0 [M+H]+, rt = 1.48 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)].

[0383] Synthesis of ( / ?9- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V,1-dimethyl-2- oxo-1, 2-dihydropyrimidine-5-sulfonamide (Example 26): The sulfonamide 19.3 (165 mg, 0.44 mmol) was dissolved in DMF (0.5 mL) in a sealed tube and CS2CO3 (215 mg, 0.66 mmol) was added to it. It was stirred and to it was added methyl iodide (0.3 mL, 4.39 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 26 was isolated as a white solid (25 mg, 98.95% purity, 100% ee). LCMS: m / z found 396.1 [M+H]+, rt = 2.76 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)];1H NMR (400 MHz, DMSO-cfe) 6 9.01 - 8.73 (m, 2H), 7.57 - 7.45 (m, 4H), 5.99 (q, J = 7.6 Hz, 1 H), 3.50 (s, 3H), 2.78 (s, 3H).

[0384] Synthesis of (7?9-A / -(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-A / -ethyl-1-methyl- 2-oxo-1,2-dihydropyrimidine-5-sulfonamide (Example 27): Sulfonamide 19.3 (150 mg, 0.26 mmol) was dissolved in DMF (0.5 mL) in a sealed tube and CS2CO3 (215 mg, 0.31 mmol) was added to it. It was stirred and to it was added ethyl iodide (0.30 mL, 0.39 mmol). The reaction mixture was then stirred at 60°C for 1 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 27 was isolated as white solid (25 mg, 98.95% purity, 100% ee). LCMS: m / z found 410.0 [M+H]+, rt = 1.67 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)];1H NMR (400 MHz, Chloroform-d) 5 8.86 (d, J = 3.0 Hz, 1 H), 8.21 (d, = 3.1 Hz, 1 H), 7.49 - 7.34 (m, 4H), 5.86 - 5.62 (m, 1 H), 3.63 (s, 3H), 3.28 - 3.04 (m, 2H), 0.96 (t, J = 7.0 Hz, 3H).

[0385] Example 28 and Example 29

[0386] ( / ?9 V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-5-fluoro-A / ,1-dimethyl-2-oxo- 1 ,2-dihydropyridine-4-sulfonamide (Example 28) and ( / ?)- / V-(1-(4-chlorophenyl)-2,2,2- trifluoroethyl)-A / -ethyl-5-fluoro-1-methyl-2-oxo-1,2-dihydropyridine-4-sulfonamide (Example 29)Scheme 20

[0387] Synthesis of 4-bromo-5-fluoro-1-methylpyridin-2(1H)-one 20.1 : To the solution of 4-bromo-5-fluoropyridin-2(1 / 7)-one (950 mg, 4.94 mmol) in DMF (20 mL) was added K2CO3 (1.37 g, 9.89 mmol) at room temperature. To this solution, methyl iodide (1.5 mL, 24.74 mmol) was added and the reaction mixture was stirred at room temperature for 16 h.It was quenched with saturated NH4CI solution (20 mL), then extracted with ethyl acetate (3 x 20 mL). The combined organic part was washed with water (2 x 25 mL), dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel using 30% ethyl acetate in hexane and compound 20.1 was isolated as white solid (900 mg, 62% yield). LCMS: m / z found 205.8 [M+H]+, rt= 1.16 min (Method 3)[YMC Triart C18 column (3 pm, 33 x 2.1 mm)].

[0388] Synthesis of 5-fl uoro-4-((4-methoxybenzyl )thio)-1 -methyl pyridin-2(1 / 7)-one 20.2: Compound 20.1 (900 mg, 4.36 mmol) was dissolved in toluene (15 mL) and (4- methoxyphenyl)methanethiol (0.7 mL , 5.24 mmol) was added to it. The solution was stirred and degasified with argon. DI PEA (2.3 mL, 13.10 mmol) was added to the solution followed by Xanthphos (253 mg, 0.43 mmol). The reaction mixture was further degasified with argon. Pd2(dba)s (200 mg, 0.21 mmol) was added to it under the inert atmosphere and the reaction mixture was stirred at 100°C for 16 h under argon atmosphere. After completion (monitored by TLC and LCMS), it was filtered through sintered funnel. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product 20.2 was isolated as a yellow gum (700 mg, 57% yield). LCMS: m / z found 280 [M+H]+, rt= 1.54 min (Method 3)[YMC Triart C18 column (3 pm, 33 x 2.1 mm)].

[0389] Synthesis of 5-fluoro-1-methyl-2-oxo-1,2-dihydropyridine-4-sulfonyl chloride 20.3: To the solution of intermediate 20.2 (900 mg, 3.22 mmol) in CH3CN (5 mL) was added 2 N HCI (1.2 mL). The solution was stirred at room temperature and 1 ,3-dichloro-5,5- dimethyl hydantoin (1.90 g, 9.67 mmol) was added portion wise to it. Stirring was continued at the same temperature for 30 min. It was then diluted with ice cold water (10 mL) and extracted with DCM (15 mL). The organic layer was separated, washed with water (10 mL) dried over anhydrous Na2SO4 and used in the forwarding step without evaporation.

[0390] Synthesis of ( / ?9- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-5-fluoro-1-methyl- 2-oxo-1,2-dihydropyridine-4-sulfonamide 20.4: To a solution of sulfonyl chloride 20.3 in DCM was added ( / ?)-2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1 -amine (476 mg, 1.93 mmol) followed by pyridine (2.6 mL, 32.22 mmol). The reaction mixture was stirred at room temperature overnight. It was diluted with water (15 mL) and extracted with DCM (2 x 15 mL). The combined organic layer was washed with water (20 mL), dried over anhydrous Na2SC>4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel and the compound 20.4 was isolated as white solid (110 mg, 9% yield). LCMS: m / z found 399.0 [M+H]+, rt= 1.50 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)].

[0391] Synthesis of ( / ?)- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-5-fluoro- / V,1- dimethyl-2-oxo-1,2-dihydropyridine-4-sulfonamide (Example 28): The sulfonamide 20.4 (60 mg, 0.15 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (59 mg, 0.18 mmol) was added to it. It was stirred and to it was added methyl iodide (0.03 mL, 0.45 mmol). The reaction mixture was then stirred at room temperature for 30 min. It 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 andconcentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product was isolated Example 28 as a white solid (35 mg, 94.45% purity, 95.78% enantiomeric excess).1H NMR (400 MHz, DMSO-cfe) 6 8.23 (d, J = 6.4 Hz, 1 H), 7.55 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 6.6 Hz, 1 H), 6.01 (q, J = 8.2 Hz, 1 H), 3.43 (s, 3H), 2.89 (s, 3H).

[0392] Synthesis of (R)-N-( 1 -(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V-ethyl-5-fluoro-1 - methyl-2-oxo-1,2-dihydropyridine-4-sulfonamide (Example 29): The sulfonamide 20.4 (70 mg, 0.17 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (69 mg, 0.21 mmol) was added to it. It was stirred and to it was added ethyl iodide (0.04 mL, 0.52 mmol). The reaction mixture was then stirred at 50°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 30% ethyl acetate in hexane and the product was isolated Example 29 as a sticky gum (9 mg, 91 % purity, 95.56 % enantiomeric excess).1H NMR (400 MHz, DMSO-cfe) 6 8.22 (d, J = 6.4 Hz, 1 H), 7.53 (q, J = 8.6 Hz, 4H), 6.85 (d, J = 6.6 Hz, 1 H), 5.95 (q, J = 8.4 Hz, 1 H), 3.55 - 3.38 (m, 5H), 0.93 (t, J = 6.9 Hz, 3H).

[0393] Example 30 and Example 31

[0394] (R)-5-Chloro-A / -ethyl-1 -methyl-6-oxo- / V-(2,2,2-trifluoro-1 -(4- fluorophenyl)ethyl)-1,6-dihydropyridine-3-sulfonamide (Example 30) and (R)-5- chloro- / V,1-dimethyl-6-oxo- / V-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-1,6- dihydropyridine-3-sulfonamide (Example 31)Example 30Scheme 21

[0395] Synthesis of 5-bromo-3-chloro-1-methylpyridin-2(1H)-one 21.1 : To solution of a 5-bromo-3-chloropyridin-2-ol (2.0 g, 9.59 mmol) in DMF (20 mL), K2COs (4 g, 28.78 mmol) and methyl iodide (0.70 mL, 10.55 mmol) were added at RT. The mixture was quenched with saturated NH4CI solution (30 mL), then extracted with ethyl acetate (3 x 25 mL). The combined organic part was washed with water (2 x 25 mL), dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel using 30% ethyl acetate in hexane and compound 21.1 as white solid (1.2 g, 56% yield). LCMS: m / z found 222.1 [M+H]+, rt = 1.45 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)].

[0396] Synthesis of 3-chloro-5-((4-methoxybenzyl)thio)-1-methylpyridin-2(1H)-one 21.2: Compound 21.1 (1.50 g, 12.25 mmol) was dissolved in toluene (15 mL) and (4- methoxyphenyl)methanethiol (1 .35 mL, 9.80 mmol) was added to it. The solution was stirred and degasified with argon. (6.8 mL, 36.74 mmol) was added to the solution followed by Xanthphos (700 mg, 1.22 mmol). The reaction mixture was further degasified with argon.Pd2(dba)s (560 mg, 0.61 mmol) was added to it under the inert atmosphere and the reaction mixture was stirred at 100°C for 16 h under argon atmosphere. After completion (monitoredby TLC and LCMS), it was filtered through sintered funnel. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product 21.2 was isolated obtained as yellow solid (1.9 g, 52% yield). LCMS: m / z found 296.1 [M+H]+, rt = 1.79 min (Method 8) [Waters Xbridge C18 column (3.5 pm, 50 x 3 mm)].

[0397] Synthesis of 5-chloro-1-methyl-6-oxo-1,6-dihydropyridine-3-sulfonyl chloride 21.3: Solution of intermediate 21.2 (700 mg, 0.39 mmol) in CH3CN (5 mL) was added 2 N HCI (0.5 mL). The solution was cooled at -10°C and 1 ,3-dichloro-5,5-dimethyl hydantoin (559 mg, 0.78 mmol) was added portion wise to it. Stirring was continued at the same temperature for 30 min. It was then diluted with ice cold water (5 mL) and extracted with DCM (15 mL). The organic layer was separated, washed with water (5 mL) dried over anhydrous Na2SO4 and used in the forwarding step without evaporation.

[0398] Synthesis of ( / ?9-5-chloro-1-methyl-6-oxo- / V-(2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)-1,6-dihydropyridine-3-sulfonamide 21.4: To a solution of sulfonyl chloride 21.3 in DCM was added (R)-2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1 -amine (558 mg, 2.89 mmol) followed by pyridine (2.3 mL, 28.93 mmol). The reaction mixture was stirred at room temperature 18 h. It was diluted with water (15 mL) and extracted with DCM (2 x 15 mL). The combined organic layer was washed with water (10 mL), dried over anhydrous Na2SC>4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography using 30% ethyl acetate-hexane over silica gel and the compound 21.4 as white solid (530 mg, 46% yield). LCMS: m / z found 399.1 [M+H]+, rt = 1 .73 min (Method 8) [Waters Xbridge C18 column (3.5 pm, 50 x 3 mm)].

[0399] Synthesis of ( / ?9-5-chloro- / V-ethyl-1-methyl-6-oxo- / V-(2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)-1,6-dihydropyridine-3-sulfonamide (Example 30): Sulfonamide21.4 (100 mg, 0.25 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (106 mg, 0.33 mmol) was added to it. It was stirred and to it was added ethyl iodide (0.2 mL, 2.51 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 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 further purified by SFC-Prep-HPLC to yield the desired compound Example 30 as a white sticky solid (40 mg, 37% yield, 99.57 purity, 100% ee). LCMS: m / z found 427.10 [M+H]+, rt = 3.34 min (Method 1) [Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm)];1H NMR (400 MHz, DMSO-cfe) 6 8.51 (d, J = 1.8 Hz, 1 H), 8.00 (d, J = 2.6 Hz, 1 H), 7.52 (t, J = 5.4 Hz,2H), 7.28 (t, J = 8.6 Hz, 2H), 5.97 (q, J = 8.1 Hz, 1 H), 3.57 (s, 3H), 3.17 (d, J = 6.4 Hz, 2H), 2.77 (s, 3H).

[0400] Chiral separation method: SFC PREP purification was run on a Waters Thar SFC- 80 instrument equipped with Waters UV Detector 2489, by using Chiralpak-IG column (30.0 mm x 250mm), 5p, operating at 35°C, at a flow rate of 70 mL / min, using 80% CO2 in super critical state and 20% of Methanol as mobile phase. This isocratic mixture was run up to 7.0 minutes and maintaining the isobaric condition of 100 bar at 250 nm wavelength.

[0401] Synthesis of (7?9-5-chloro-A / ,1-dimethyl-6-oxo-A / -(2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)-1,6-dihydropyridine-3-sulfonamide (Example 31): Sulfonamide 21.4 (100 mg, 0.25 mmol) was dissolved in DMF (1 mL) in a sealed tube and CS2CO3 (106 mg, 0.32 mmol) was added to it. It was stirred and to it was added methyl iodide (0.15 mL, 2.51 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 31 was isolated as a colourless gum (95 mg, 45% yield, 99.72 purity, 100% ee). LCMS: m / z found 413.0 [M+H]+, rt = 2.74 min (Method 9) [Waters Xbridge C18 column (3.5 pm, 50 x 3 mm)];1H NMR (400 MHz, DMSO-cfe) 6 8.52 (d, J = 2.4 Hz, 1 H), 7.95 (d, J = 2.4 Hz, 1H), 7.57 - 7.46 (m, 2H), 7.28 (t, J = 8.8 Hz, 2H), 5.93 (t, J = 8.9 Hz, 1 H), 3.56 (s, 3H), 1.00 (t, J = 6.9 Hz, 3H).

[0402] Example 32

[0403] (7?)-5-chloro-A / -ethyl-1 -methyl-6-oxo-N-(2,2,2-trifluoro-1 -(4- fluorophenyl)ethyl)-1 ,6-dihydropyridine-3-sulfonamide (Example 32)Scheme 22

[0404] Synthesis of ( / ?9-5-chloro- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-1- methyl-6-oxo-1,6-dihydropyridine-3-sulfonamide 22.1 : To a solution of sulfonyl chloride 21.3 in DCM was added (R)-2,2,2-trifluoro-1-(4-chlorophenyl)ethan-1 -amine (781 mg, 3.72 mmol) to it followed by pyridine (2.3 mL, 28.93 mmol). The reaction mixture was stirred atroom temperature 18 h. It was diluted with water (15 mL) and extracted with DCM (2 x 15 mL). The combined organic layer was washed with water (10 mL), dried over anhydrous Na2SC>4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography using 30% ethyl acetate-hexane over silica gel and the compound 22.1 was isolated as white solid (600 mg, 39% yield). LCMS: m / z found 413.0 [M-H], rt = 2.56 min (Method 9) [Waters Xbridge C18 column (3.5 pm, 50 x 3 mm)].

[0405] Synthesis of ( / ?9-5-chloro- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)- / V,1- dimethyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Example 32): Sulfonamide 22.1 (200 mg, 0.48 mmol) was dissolved in DMF (2 mL) in a sealed tube and CS2CO3 (204 mg, 0.63 mmol) was added to it. It was stirred and to it was added ethyl iodide (0.3 mL, 4.82 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 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 further purified by SFC Prep-HPLC to obtain compound Example 32 as white solid (100 mg, 48% yield, 98.34 purity, 100% ee). LCMS: m / z found 443.1[M+H]+, rt = 3.09 min, (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)]; 1 H NMR (400 MHz, DMSO-d6) 5 8.51 (d, J = 2.4 Hz, 1 H), 7.94 (d, J = 2.4 Hz, 1 H), 7.50 (q, J = 8.6 Hz, 4H), 5.97 (q, J = 8.6 Hz, 1 H), 4.03 (q, J= 7.1 Hz, 1 H), 3.56 (s, 3H), 3.45 - 3.31 (m, 1 H), 3.32 - 3.18 (m, 1 H), 1.99 (s, 2H), 1.17 (t, J = 7.1 Hz, 2H), 1.01 (t, J = 7.0 Hz, 3H).

[0406] SFC PREP purification is currently running on Waters Thar SFC-80 equipped with Waters UV Detector 2489 by using Chiralpak-IG column (30.0 mm x 250mm), 5p operating at 35 °C temperature, maintaining flow rate of 70 mL / min, using 80% CO2 in super critical state & 20% of [100% Methanol] as mobile phase. This isocratic mixture ran up to 7.0 minutes and also maintained the isobaric condition of 100 bar at 250 nm wavelength.

[0407] Example 33 and Example 34

[0408] ( / ?)- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-1-ethyl- / V-methyl-6-oxo-1,6- dihydropyridine-3-sulfonamide (Example 33) and ( / ?)- / V-(1-(4-chlorophenyl)-2,2,2- trifluoroethyl)- / V,1-diethyl-6-oxo-1,6-dihydropyridine-3-sulfonamide (Example 34)Scheme 23

[0409] Synthesis of 5-bromo-1-ethylpyridin-2(1H)-one 23.1 : 5-bromopyridin-2-ol (5 g, 28.36 mmol) was dissolved in DMF (50 mL) and CS2CO3 (23.34 g, 71.83 mmol) was added to it. Ethyl iodide (2.35 mL, 28.73 mmol) was then added under inert atmosphere and the reaction mixture was stirred at room temperature for 2 h under argon atmosphere. After completion (monitored by TLC and LCMS), it was filtered through sintered funnel. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product 23.1 was isolated as yellow solid (3.5 g, 70% yield). LCMS: m / z found 201.9 [M+H]+, rt = 1.2 min (Method 4) [YMC Triart C18 column (3 pm, 33 x 2.1 mm).

[0410] Synthesis of 1-ethyl-5-((4-methoxybenzyl)thio)pyridin-2(1H)-one 23.2: Compound 23.1 (2.5 g, 12.36 mmol) was dissolved in toluene (50 mL) and (4- methoxyphenyl)methanethiol (2.3 mL, 14.85 mmol) was added to it. The solution was stirred and degasified with argon. DI PEA (6.4 mL, 37.12 mmol) was added to the solution followed by xanthphos (715 mg, 1.23 mmol). The reaction mixture was further degasified with argon. Pd2(dba)s (566 mg, 0.69 mmol) was added to it under the inert atmosphere and the reaction mixture was stirred at 100°C for 18 h under argon atmosphere. After completion (monitored by TLC and LCMS), it was filtered through sintered funnel. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography over silica gel using 40% ethyl acetate in hexane and the product 23.2 was isolated as yellowgum (1.98 g, 62% yield). LCMS: m / z found 276.0 [M+H]+, rt = 1.59 min, (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)].

[0411] Synthesis of 1-ethyl-6-oxo-1,6-dihydropyridine-3-sulfonyl chloride 23.3: The solution of compound 23.2 (500 mg, 1 .81 mmol) in CH3CN (10 mL) was cooled at -5°C and 2 N HCI (2 mL) was added to it. 1 ,3-Dichloro-5,5-dimethylhydantoin (662 mg, 2.70 mmol) was added portion wise to the reaction mixture and it was stirred at 0°C for 1 h. The reaction was quenched with water (10 ml) and extracted with DCM (2 x 10 ml). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure at 25°C. The crude compound was forwarded without further purification.

[0412] Synthesis of A / -(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-1-ethyl-6-oxo-1,6- dihydropyridine-3-sulfonamide 23.4: To the stirred solution of 23.3 in DCM (10 ml) was added pyridine (1.7 ml, 22.26 mmol) and (F?)-1-(4-chlorophenyl)-2,2,2-trifluoroethan-1- amine hydrochloride (662 mg, 2.7 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 column chromatography using 50% EtOAC in hexane and the compound 23.4 was isolated as yellow solid (180 mg, 20% yield). LCMS: m / z found 394.9 [M+H]+, rt = 1.62 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)].

[0413] Synthesis of ( / ?)- / V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-1-ethyl- / V-methyl- 6-oxo-1,6-dihydropyridine-3-sulfonamide (Example 33): The sulfonamide 23.4 (180 mg, 0.45 mmol) was dissolved in DMF (2.5 mL) and CS2CO3 (178 mg, 0.54 mmol) was added to it followed by methyl iodide (0.03 mL, 0.47 mmol). The reaction mixture was stirred at room temperature for 30 mins. 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 sodium sulphate and concentrated under vacuum. The crude was purified by flash column chromatography over silica gel using 40% ethyl acetate in hexane to isolate the desired compound Example 33 as a yellow solid (110 mg, 58% yield). LCMS: m / z found 409.1 [M+H]+, rt = 2.97 min rt = 1.32 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)].1H NMR (400 MHz, DMSO) 5 8.51 (d, J = 2.6 Hz, 1 H), 7.64 (dd, J = 2.8, 9.7 Hz, 1 H), 7.50 (d, J = 8.5 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 6.45 (d, J = 9.6 Hz, 1 H), 5.94 (q, J = 8.6 Hz, 1 H), 4.00 (q, J = 7.4 Hz, 2H), 2.73 (s, 3H), 1.23 (t, J = 7.0 Hz, 3H).

[0414] Synthesis of ( / ?9- / V,1-diethyl-6-oxo- / V-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)- 1,6-dihydropyridine-3-sulfonamide (Example 34): The sulfonamide 23.4 (180 mg, 0.45 mmol) was dissolved in DMF (2.5 mL) and CS2CO3 (185 mg, 0.57 mmol) was added to itfollowed by ethyl iodide (0.04 mL, 0.47 mmol). The reaction mixture was stirred at room temperature for 18 h. It 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 sodium sulphate and concentrated under vacuum. The crude was purified by Reverse Phase Prep-HPLC to obtain compound Example 34 as yellow solid (25 mg, 17% yield). LCMS: m / z found 423.1 [M+H]+, rt = 1.62 min (Method 2) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)];1H NMR (400 MHz, DMSO-cfe) 6 8.53 (d, J = 2.5 Hz, 1 H), 7.68 (dd, J = 2.7, 9.7 Hz, 1 H), 7.55 - 7.42 (m, 4H), 6.46 (d, J = 9.6 Hz, 1 H), 5.93 (q, J = 8.7, 9.2 Hz, 1 H), 3.99 (q, J = 7.4 Hz, 2H), 3.41 - 3.32 (m, 1 H), 3.27 - 3.15 (m, 1 H), 1 .22 (t, J = 7.0 Hz, 3H), 0.97 (t, J = 7.0 Hz, 3H).

[0415] Preparative HPLC was done on a WATERS BGM 2545 instrument equipped with WATERS PDA Detector 2998 set to multiple-wavelength UV (200-400nm) detection. Column name: YMC Actus Triart PFP (250 x 20 mm, 5p) operating at ambient temperature and flow rate of 16 mL / min. Mobile phase: A =0.1 % Formic acid in water, Mobile phase: B= Methanol; Gradient Profile: Mobile phase initial composition of 40% A and 60% B, then to 40% A and 60% B in 3 min, then to 10% A and 90% B in 25 min, then to 5% A and 95% B in 25.5 min held this composition up to 28.5 min. for column washing, then returned to initial composition in 29 min, and held for 31 min.

[0416] Example 35

[0417] (7?)-A / ,1-diethyl-6-oxo-A / -(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-1,6- dihydropyridine-3-sulfonamide (Example 35)Scheme 24

[0418] Synthesis of 1-ethyl-6-oxo- / V-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-1,6- dihydropyridine-3-sulfonamide 24.1 : To the stirred solution of 23.3 (650 mg, 2.94 mmol) in DCM (10 mL), pyridine (2.3 mL, 29.4 mmol) and (R)-2,2,2-trifluoro-1-(4- fluorophenyl)ethan-1 -amine hydrochloride (808 mg, 3.52 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 sulphate and concentrated under reducedpressure. The crude compound was purified by flash column chromatography using 50% ethyl acetate in hexane and the compound 24.1 was isolated as yellow solid (300 mg, 26% yield). LCMS: m / z found 379.2 [M+H]+, rt = 1.55 min (Method 3) [YMC Triart C18 column (3 pm, 33 x 2.1 mm)].

[0419] Synthesis of ( / ?)- / V,1-diethyl-6-oxo- / V-(2,2,2-trifluoro-1-(4-...

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 C3-6 cycloalkyl-Ci-6 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;L is selected from: a bond and C1.3 alkylene;Ring A is a 4- to 12-membered heterocyclyl group comprising agroup; optionally wherein Ring A is substituted by one or more R5;or Ring A is phenyl or a 5- or 6-membered heteroaryl, wherein said phenyl or 5- or 6- membered heteroaryl is substituted by Ring B and is optionally substituted by one or more R5;Ring B is; wherein Ring B is a 4- to 12-membered heterocyclyl group, optionally wherein Ring B is substituted by one or more R5; each R5is 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 R10;R6is selected from: Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, and a 4- to 7-membered heterocyclyl group, wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl and 4- to 7-membered heterocyclyl group is optionally substituted by one or more R11; or R6and one R5, together with the atoms to which they are attached form a 4- to 7- membered heterocyclyl group; optionally wherein the heterocyclyl group is substituted by one or more R5a; each R5ais 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 R10a;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 moreeach R9, R10, R10a, R11, and R12is independently selected from: halo, =0, -CN, -0R9A, - S(O)xR9A, -NR9AR9B, C(O)R9A, -OC(O)R9A, -C(O)OR9A, -NR9AC(O)R9B, -C(O)NR9AR9Band C3- 6 cycloalkyl;R4A, R4B, R9A, 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; a is 0, 1 , 2, 3, 4 or 5; with the proviso that the compounds in List A and List B are excluded:List A:

2. The compound according to claim 1 , wherein Ring A is selected from: a 5- or 6- membered non-aromatic saturated or partially saturated monocyclic heterocyclic ring, anda 9- or 10-membered partially aromatic bicyclic heterocyclic ring system; wherein Ring A comprises comprisinggroup, and wherein Ring A is optionally substituted by one or more R5.

3. The compound according to claim 1 , wherein Ring A is a 6-membered nonaromatic saturated or partially saturated monocyclic heterocyclic ring; wherein Ring A comprises comprisinggroup, and wherein Ring A is optionally substituted by one or more R5.

4. The compound according to any one of claims 1 to 7, wherein each R5is 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.

5. The compound according to any one of claims 1 to 7, wherein each R5is 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; optionally wherein each R5is independently selected from: fluoro, chloro, -CN, and methyl.

6. The compound according to claim 1 , wherein Ring A is selected from:

7. The compound according to claim 1, wherein the compound is a compound of the formula (VI), or a pharmaceutically acceptable salt thereof:wherein b is 0, 1, 2, or 3.

8. The compound according to claim 1, wherein the compound is a compound of the formula (IX), or a pharmaceutically acceptable salt thereof:wherein b is 0, 1, or 2.

9. The compound according to claim 1 , wherein the compound is a compound of the formula (XIV), or a pharmaceutically acceptable salt thereof:(XIV) wherein b is 0, 1 , 2, or 3.

10. The compound according to any one of claims 1 to 9, wherein the group of the formula11 . The compound according to any one of claims 1 to 9, wherein the group of the formulaselected from:

12. The compound according to any one of claims 1 to 9, the group of the formulaselected from:

13. The compound according to any one of claims 1 to 9, wherein the group of the formula-fluorophenyl.

14. The compound according to any one of claims 1 to 13, wherein L is selected from a bond and -CH2-.

15. The compound according to any one of claims 1 to 13, wherein L is a bond.

16. The compound according to any one of claims 1 to 15, wherein R3is selected from methyl, -CD3, ethyl, and 2-fluoroethyl.

17. The compound according to any one of claims 1 to 15, wherein R3is selected from methyl and ethyl.

18. The compound according to any one of claims 1 to 17, wherein R1is selected from C1.6 alkyl and C3-6 cycloalkyl, wherein R1is substituted by at least one fluorine.

19. The compound according to any one of claims 1 to 17, wherein R1is selected from CH2F, -CHF2, and -CF3.

20. The compound according to any one of claims 1 to 17, wherein R1is -CF3.

21. The compound according to any one of claims 1 to 20, wherein R2is selected fromH and methyl.

22. The compound according to any one of claims 1 to 20, wherein R2is H.

23. The compound of any one of claims 1 to 22, wherein the group of the formula:

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

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, with the proviso that the compounds in List A and List B are not excluded.

27. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, for use as a medicament, with the proviso that the compounds in List A and List B are not excluded.

28. A compound according to any one of claims 1 to 25, 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 and List B are not excluded.

29. 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 25, or a pharmaceutically acceptable salt thereof, with the proviso that the compounds in List A and List B are not excluded.

30. A compound according to any one of claims 1 to 25, 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 and List B are not excluded.

31. A compound according to any one of claims 1 to 25, 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 and List B are not excluded.

32. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, for use in the treatment of Parkinson’s disease, with the proviso that the compounds in List A and List B are not excluded.

33. A compound according to any one of claims 1 to 25, 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 and List B are not excluded.

34. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of epilepsy, with the proviso that the compounds in List A and List B are not excluded;optionally wherein the epilepsy is a drug-resistant epilepsy.

35. A compound according to any one of claims 1 to 25, 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 and List B 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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