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WO2025158150A1 - Heterocyclic compounds as modulators of cav2.3 - Google Patents

Heterocyclic compounds as modulators of cav2.3

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Publication number
WO2025158150A1
WO2025158150A1 PCT/GB2025/050117 GB2025050117W WO2025158150A1 WO 2025158150 A1 WO2025158150 A1 WO 2025158150A1 GB 2025050117 W GB2025050117 W GB 2025050117W WO 2025158150 A1 WO2025158150 A1 WO 2025158150A1
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alkyl
ring
compound
compound according
formula
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French (fr)
Inventor
Henning Steinhagen
Maria Pia Catalani
Paolo Pevarello
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Lario Therapeutics Ltd
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Lario Therapeutics Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C07D213/85—Nitriles in position 3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/18—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/38—One sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • 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, Phelan-McDermid and Fragile X syndromes.
  • 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.
  • 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 system0 and in endocrine systems (Schneider et al., Pharmaceuticals 2013, 6(6), 759-776, Schneider et al., Pflugers Arch. 2020; 472(7): 811-816).
  • 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, particularly5 those within the substantia nigra (SN) neurons (Giguere et al. 2018, Front. Neurol. 9, 455).
  • Currently there are no curative therapies available for Parkinson’s disease (Bloem et al, Lancet.
  • 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 in5 Parkinson’s disease. As PARK mutations and also most external factors are global Parkinson’s disease-stressors, additional cell-specific features must also contribute to the Parkinson’s disease-pathophysiology, and in particular to the differential neuronal vulnerability.
  • Dopaminergic midbrain neurons display pacemaker activity, which is important for dopamine release and e.g., voluntary movement control.
  • this activity generates oscillatory increases in free cytosolic Ca 2+ levels, which are associated with 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).
  • Cav2.3 is highly expressed in adult SN dopaminergic neurons and accounts for -50% of somatic Ca 2+ oscillations in SN DA neurons (Benkert et al., 2019, Nat. Commun. 10, 5094).
  • 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), Phelan McDermid syndrome (Reim et al., Front Mol Neurosci. 2017 Feb; 10:26), monogenic developmental and epileptic encephalopathies (DEEs) such as DEE2 and DEE69 (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.
  • Fragile X syndrome Gram et al., J Neurosci. 2019 Sep 18;39(38):7453-7464
  • Phelan McDermid syndrome Reim et al., Front Mol Neurosci. 2017 Feb; 10:26
  • monogenic developmental and epileptic encephalopathies DEE
  • diabetes e.g., glucose-induced insulin release, glucose-mediated glucagon suppression, or glucose-mediated somatostatin-release
  • WO2018/228692 discloses that Cav2.3 antagonists are beneficial in the neuroprotective treatment of Parkinson’s disease and other neurodegenerative diseases.
  • 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 Ca 2+ 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.
  • Cav2.3 antagonists that are also brain permeable.
  • R 1 is selected from: Ci-e alkyl, C3-6 cycloalkyl, and Cs-e cycloalkyl-Ci-e alkyl-, wherein R 1 is substituted by at least one fluorine; optionally wherein one or more H in R 1 is substituted by D;
  • R 2 is selected from: H, D, Ci-e alkyl and Ci-e haloalkyl; or
  • R 1 and R 2 together with the carbon atom to which they are attached form a C3-6 cycloalkyl substituted with at least one fluorine;
  • R 3 is selected from: H, Ci-e alkyl and Ci-e haloalkyl, and C3-6 cycloalkyl; optionally wherein one or more H in R 3 is substituted by D, and wherein the C3-6 cycloalkyl is optionally substituted by one or more substituent independently selected halo and C1.3 alkyl;
  • L is selected from: a bond and C1.3 alkylene
  • R 5 and R 6 are each independently selected from: H, Ci-e alkyl, Ci-e haloalkyl and Q 1 , wherein said Ci-e alkyl is optionally substituted by one or more R 8 ; each R 7 and R 8 is independently selected from: halo, -CN, -OR 7A , -S(O) X R 7A , -NR 7A R 7B , C(O)R 7A , -OC(O)R 7A , -C(O)OR 7A , -NR 7A C(O)R 7B , -C(O)NR 7A R 7B and Q 2 ; each Q 1 and Q 2 is independently selected from: C3-6 cycloalkyl, 4- to 7-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl, wherein said C3-6 cycloalkyl, 4- to 7-membered heterocyclyl, phenyl and 5- or 6- membered heteroaryl is optional
  • R 12 is independently selected from H, Ci-e alkyl, Ci-e haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-Ci-6 alkyl-, and COOR 13 ; optionally wherein one or more H in R 12 is substituted by D;
  • R 13 is independently selected from H, Ci-e alkyl, Ci-e haloalkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-Ci-6 alkyl; optionally wherein one or more H in R 13 is substituted by D;
  • composition comprising a compound of the invention, or a pharmaceutically acceptable salt or N-oxide thereof, and a pharmaceutically acceptable excipient.
  • a compound of the invention for use in the treatment of a disease or medical disorder mediated by Cav2.3.
  • a compound of the invention or a pharmaceutically acceptable salt or N-oxide thereof, for the manufacture of a medicament for the treatment of a disease or medical disorder mediated by Cav2.3.
  • a method of treating a disease or medical disorder mediated by Cav2.3 in a subject in need thereof comprising administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt or N-oxide thereof.
  • a compound of the invention 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.
  • a compound of the invention, or a pharmaceutically acceptable salt or N-oxide 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.
  • a neurodegenerative disease for example Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, dystonia, amyotrophic lateral sclerosis (ALS), and age-related neurodegeneration.
  • 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 (XXXXII), or a compound described in any of the Examples, or a pharmaceutically acceptable salt, N-oxide, solvate, or salt of a solvate of any thereof.
  • 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.
  • the term “selective antagonist” refers to an antagonist having greater affinity for its target than for one or more related receptors.
  • 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.
  • treating refers 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.
  • treating includes prevention of an injury, pathology, condition, or disease (i.e., prophylaxis or prevention).
  • 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.
  • 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.
  • a symptom of a disease or condition associated with Cav2.3 activity may be a symptom that results (entirely or partially) from an increase in the level of activity of Cav2.3 channels and or increased expression of Cav2.3 channels.
  • a disease or medical disorder associated with a Cav2.3 activity or expression may be treated with a compound of the invention effective for decreasing the level of activity of Cav2.3 channels, for example by blocking or partially blocking the channel, inhibiting the function of the channel, preventing or inhibiting the expression of the channel and/or degrading the channel.
  • 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.
  • a prophylactically effective amount may be administered in one or more administrations.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • halo refers to one of the halogens, group 17 of the periodic table.
  • the term refers to fluorine, chlorine, bromine and iodine.
  • the term refers to fluorine or chlorine.
  • C m -n refers to a group with m to n carbon atoms.
  • 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.
  • an alkylene group may, for example, correspond to one of those alkyl groups listed in this paragraph.
  • Ci-e alkylene may be -CH2-, -CH2CH2-, -CH2CH(CH 3 )- , -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.
  • substituents for an alkyl or alkylene group may be halogen, e.g.
  • 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.
  • 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, -CX 3 , -CHX 2 , -CH 2 CX3,-CH 2 CHX2 or -CX(CH 3 )CH 3 wherein 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., -CF 3 , -CHF 2 , -CH 2 CF 3 or -CH 2 CHF 2 ).
  • 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
  • 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.
  • a heteroalkyl moiety may include three optionally different heteroatoms (e.g.,
  • a heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • C 2 .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.
  • the “C 2 .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.
  • alkenylene group may, for example, correspond to one of those alkenyl groups listed in this paragraph.
  • Alkenyl and alkenylene groups may unsubstituted or substituted by one or more substituents. Possible substituents are described herein. For example, substituents may be those described above as substituents for alkyl groups.
  • C 2 .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.
  • the “C 2 .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.
  • an alkynylene group may, for example, correspond to one of those alkynyl groups listed in this paragraph.
  • 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.
  • C 3 .6 cycloalkyl includes a saturated hydrocarbon ring system containing 3, 4, 5 or 6 carbon atoms.
  • the “C 3 -Ce cycloalkyl” may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.1.1]hexane or bicyclo[1.1.1]pentane.
  • the “C 3 -Ce cycloalkyl” may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • heterocyclyl 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).
  • 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.
  • 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).
  • 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-2 H-thiopyran, and hexahydrothiepine.
  • Other heterocycles include dihydro oxathiolyl, tetrahydro oxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydro oxazinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl.
  • 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.
  • 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.
  • any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom.
  • piperidino or “morpholino” refers to a piperidin-1-yl or morpholin-4-yl ring that is linked via the ring nitrogen.
  • heterocyclyl may also include oxosubstituted partially saturated heterocyclic rings which contain a substituted ring nitrogen, such as N-alkyl pyridones.
  • heterocyclyl may also include oxosubstituted partially saturated heterocyclic rings which contain a substituted ring nitrogen, such as N-alkyl pyridones.
  • heterocyclyl may also include oxosubstituted partially saturated heterocyclic rings which contain a substituted ring nitrogen, such as N-alkyl pyridones.
  • heterocycle may include groups such
  • 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.
  • 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.
  • spiro ring systems examples 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.
  • Heterocyclyl-Cm-n alkyl includes a heterocyclyl group covalently attached to a C m -n alkylene group, both of which are defined herein; and wherein the Heterocyclyl-Cm-n alkyl group is linked to the remainder of the molecule via a carbon atom in the alkylene group.
  • the groups “aryl-C m -n alkyl”, “heteroaryl-C m -n alkyl” and “cycloalkyl-C m -n alkyl” are defined in the same way.
  • “-Cm-n alkyl substituted by -NRR” and “C m -n alkyl substituted by -OR” similarly refer to an -NRR” or -OR” group covalently attached to a C m -n alkylene group and wherein the group is linked to the remainder of the molecule via a carbon atom in the alkylene group.
  • 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.
  • 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.
  • the “aryl” may be a Ce-12 aryl, suitably phenyl or naphthyl.
  • the aryl system itself may be substituted with other groups.
  • 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.
  • 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.
  • 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.
  • the heteroaryl ring will contain up to 4, for example up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • 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.
  • the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring will be less than five.
  • heteroaryl examples 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, naphthy
  • 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.
  • 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]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,
  • 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.
  • Examples of six-membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.
  • 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
  • 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.
  • heteroaryl may also include groups that are tautomers of hydroxy substituted heteroaryl groups, such as pyridones.
  • heteroaryl may include groups such
  • 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.
  • substituents may refer to 1 or 2 or 3 substituents (e.g. 1 substituent or 2 substituents).
  • a moiety may be substituted at any point on the moiety where chemically possible and consistent with atomic valency requirements.
  • the moiety may be substituted by one or more substituents, e.g., 1 , 2, 3 or 4 substituents; optionally there are 1 or 2 substituents on a group. Where there are two or more substituents, the substituents may be the same or different.
  • ortho, meta and para substitution are well understood terms in the art.
  • “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 “ ”:
  • Metal 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.
  • the groups below are meta substituted:
  • “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.
  • the groups below are para substituted:
  • Ring A comprises an NH group
  • the NH group may be substituted by R 4 to give NR 4
  • Ring B comprises an NH group
  • the NH group may be substituted by R 10 to give NR 10 .
  • 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.
  • a -NR 5 R 6 , , -NR 7A R 7B , -NR 9A R 9B , -NR 9C R 9D , -NR 10A R 10B , - and -NR 11A R 11 B group may form:
  • an -NRR’ group within a substituent may form a carbonyl-linked 4 to 6 membered heterocyclyl, for example a -C(O)NRR’ group may form:
  • -NRR’ groups within substituents such as -OC(O)NRR’, -SO2NRR’, or -NRC(O)NRR’ may similarly form a 4 to 6 membered heterocyclyl within such substituents.
  • a bond terminating in represents that the bond is connected to another atom that is not shown in the structure.
  • a bond terminating inside a cyclic structure and not terminating at an atom of the ring structure represents that the bond may be connected to any of the atoms in the ring structure where allowed by valency, unless stated otherwise herein.
  • Ring A is the 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
  • 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.
  • Suitable or preferred features of any compounds of the present invention may also be suitable features of any other aspect.
  • 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.
  • 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, saccharide,
  • 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.
  • suitable salts see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
  • compositions of the invention may be prepared by for example, one or more of the following methods:
  • the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation in the resulting salt may vary from completely ionised to almost nonionised.
  • N-oxide compounds of the invention contemplates pharmaceutically acceptable N-oxide compounds of the invention.
  • Ring A comprises a nitrogencontaining heteroaromatic group
  • the nitrogen atom within said group may be in N-oxide form, e.g.:
  • N-oxide compounds may be prepared according to synthetic techniques known to those skilled in the art.
  • isomers 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.
  • a single stereoisomer does not necessarily have an enantiomeric excess (e.e.) or diastereomeric excess (d.e.) of 100% but could have an e.e. or d.e. of about at least 85%, for example at least 90%, at least 95%, at least 99%, or at least 99.9%.
  • 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.
  • Z/E e.g., cis/trans
  • Z/E e.g., cis/trans
  • chromatography e.g., chromatography and fractional crystallisation.
  • chiral compounds of the invention 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.
  • chromatography typically HPLC
  • 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.
  • 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.
  • 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.
  • racemic compound true racemate
  • the second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.
  • 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).
  • Radionuclides examples include 2 H (also written as “D” for deuterium), 3 H (also written as “T” for tritium), 11 C, 13 C, 14 C, 15 O, 17 O, 18 O, 13 N, 15 N, 18 F, 36 CI, 123 l, 25 l, 32 P, 35 S and the like. The radionuclide that is used will depend on the specific application of that radio-labelled derivative.
  • the radionuclide is 3 H. In some embodiments, the radionuclide is 14 C. In some embodiments, the radionuclide is 11 C. And in some embodiments, the radionuclide is
  • 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.
  • 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.
  • 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.
  • the invention encompasses deuterated derivatives of compounds of formula (I).
  • 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.
  • one or more hydrogen atoms in a Ci-4-alkyl group may be replaced by deuterium to form a deuterated C 1 -4-al ky I group.
  • R 1 , R 3 , R 4 or R 10 is methyl the invention also encompasses -CDs, -CHD2 and -CH2D.
  • R 2 or R 12 may be D.
  • 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.
  • 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
  • the compound may exist in different tautomeric forms, each of which is encompassed within the scope of the invention, e.g.:
  • the compound may exist in form (I’) and/or (I”), each of which is encompassed within the scope of the invention, e.g.:
  • 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.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the formula (I) also forms an aspect of the present invention.
  • 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.
  • pro-drugs examples 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.
  • the present invention includes those compounds of the invention as defined herein when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the formula (I) that are produced by organic synthetic means and also such compounds that are produced in the human or animal body 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.
  • 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.
  • pro-drug 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.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the formula (I) that possesses a carboxy group is, for example, an in v/ o-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.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the invention that possesses a hydroxy group is, for example, an in v/ o-cleavable ester or ether thereof.
  • An in v/ o-cleavable ester or ether of a compound of the invention containing a hydroxy group is, for example, a pharmaceutically-acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound.
  • Suitable pharmaceutically- acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters).
  • 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.
  • ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, /V-alkylaminomethyl, A/,A/- 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.
  • 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.
  • 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 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.
  • 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.
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the invention may include an in v/vo-cleavable group at the nitrogen depicted as N a in the structure below for compounds of formula (I):
  • a suitable pharmaceutically-acceptable pro-drug of a compound of the invention at N a 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 CMO alkanoyl groups such as an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups.
  • 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 carbamates from an amino group include, for example acyloxyalkoxycarbonyl and benzyloxycarbonyl groups.
  • the in-vivo cleavable group may be selected such that the pro-drug form of the compound is converted to a compound comprising the sulfonimidamide group present in compounds of the invention.
  • N a may be substituted with a -COOR X group, where R x is selected from substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl.
  • the compound of the formula (I) is a compound of the formula (la), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (I) is a compound of the formula (II), or a pharmaceutically acceptable salt or N-oxide thereof: wherein
  • R 3 , R 12 , L, Ring A, and Ring B are as defined for formula (I).
  • the compound of the formula (II) is a compound of the formula (Ila), or a pharmaceutically acceptable salt or N-oxide thereof:
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 12 , Q 1 , L, x, and Ring B are as defined for formula (I).
  • the compound of the formula (III) is a compound of the formula (Illa), or a pharmaceutically acceptable salt or N-oxide thereof:
  • R 3 , R 5 , R 6 , R 7 , R 12 , Q 1 , L, x, and Ring B are as defined for formula (I).
  • the compound of the formula (IV) is a compound of the formula (IVa), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (I) is a compound of the formula (V), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R 4a is independently selected from: H, halo, -CN, -NO 2 , Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C 2 .6 alkenyl, C 2 .6 alkynyl, Q 1 , -OR 5 , -S(O) X R 5 , -NR 5 R 6 , -C(O)R 5 , - OC(O)R 5 , -C(O)OR 5 , -NR 5 C(O)R 6 , -C(O)NR 5 R 6 , -NR 5 C(O)OR 6 , -OC(O)NR 5 R 6 , -NR 5 SO 2 R 6 , and -SO 2 NR 5 R 6 , wherein said Ci-e al
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 12 , Q 1 , L, x, and Ring B are as defined for formula (I).
  • the compound of the formula (V) is a compound of the formula (Va), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (I) is a compound of the formula (VI), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R 4a is independently selected from: H, halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q 1 , -OR 5 , -S(O) X R 5 , -NR 5 R 6 , -C(O)R 5 , - OC(O)R 5 , -C(O)OR 5 , -NR 5 C(O)R 6 , -C(O)NR 5 R 6 , -NR 5 C(O)OR 6 , -OC(O)NR 5 R 6 , -NR 5 SO 2 R 6 , and -SO 2 NR 5 R 6 , wherein said C1.6 alkyl, 2 to 8 membered
  • R 3 , R 5 , R 6 , R 7 , R 12 , Q 1 , L, x, and Ring B are as defined for formula (I).
  • the compound of the formula (VI) is a compound of the formula (Via), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (I) is a compound of the formula (VII), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R 4a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q 1 , -OR 5 , -S(O) X R 5 , -NR 5 R 6 , -C(O)R 5 , - OC(O)R 5 , -C(O)OR 5 , -NR 5 C(O)R 6 , -C(O)NR 5 R 6 , -NR 5 C(O)OR 6 , -OC(O)NR 5 R 6 , -NR 5 SO 2 R 6 , and -SO 2 NR 5 R 6 , wherein said C1.6 alkyl, 2 to 8 membered hetero
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 12 , Q 1 , L, x, and Ring B are as defined for formula (I).
  • the compound of the formula (VII) is a compound of the formula (Vila), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (I) is a compound of the formula (VIII), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R 4a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q 1 , -OR 5 , -S(O) X R 5 , -NR 5 R 6 , -C(O)R 5 , - OC(O)R 5 , -C(O)OR 5 , -NR 5 C(O)R 6 , -C(O)NR 5 R 6 , -NR 5 C(O)OR 6 , -OC(O)NR 5 R 6 , -NR 5 SO 2 R 6 , and -SO 2 NR 5 R 6 , wherein said Ci-e alkyl, 2 to 8 membered
  • R 3 , R 5 , R 6 , R 7 , R 12 , Q 1 , L, x, and Ring B are as defined for formula (I).
  • the compound of the formula (VIII) is a compound of the formula (Villa), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (I) is a compound of the formula (IX), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R 4a is independently selected from: halo, -CN, -NO2, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q 1 , -OR 5 , -S(O) X R 5 , -NR 5 R 6 , -C(O)R 5 , - OC(O)R 5 , -C(O)OR 5 , -NR 5 C(O)R 6 , -C(O)NR 5 R 6 , -NR 5 C(O)OR 6 , -OC(O)NR 5 R 6 , -NR 5 SO 2 R 6 , and -SO 2 NR 5 R 6 , wherein said Ci-e alkyl, 2 to 8 member
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 12 , Q 1 , L, x, and Ring B are as defined for formula (I).
  • the compound of the formula (IX) is a compound of the formula (IXa), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (I) is a compound of the formula (X), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R 4a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q 1 , -OR 5 , -S(O) X R 5 , -NR 5 R 6 , -C(O)R 5 , - OC(O)R 5 , -C(O)OR 5 , -NR 5 C(O)R 6 , -C(O)NR 5 R 6 , -NR 5 C(O)OR 6 , -OC(O)NR 5 R 6 , -NR 5 SO 2 R 6 , and -SO 2 NR 5 R 6 , wherein said C1.6 alkyl, 2 to 8 membered heteroal
  • the compound of the formula (X) is a compound of the formula (Xa), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (I) is a compound of the formula (XI), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R 4a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q 1 , -OR 5 , -S(O) X R 5 , -NR 5 R 6 , -C(O)R 5 , - OC(O)R 5 , -C(O)OR 5 , -NR 5 C(O)R 6 , -C(O)NR 5 R 6 , -NR 5 C(O)OR 6 , -OC(O)NR 5 R 6 , -NR 5 SO 2 R 6 , and -SO 2 NR 5 R 6 , wherein said C1.6 alkyl, 2 to 8 membered hetero
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 12 , Q 1 , L, x, and Ring B are as defined for formula (I).
  • the compound of the formula (XI) is a compound of the formula (Xia), or a pharmaceutically acceptable salt or N-oxide thereof: [00127] In certain embodiments the compound of the formula (I) is a compound of the formula (XII), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R 4a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q 1 , -OR 5 , -S(O) X R 5 , -NR 5 R 6 , -C(O)R 5 , - OC(O)R 5 , -C(O)OR 5 , -NR 5 C(O)R 6 , -C(O)NR 5 R 6 , -NR 5 C(O)OR 6 , -OC(O)
  • R 3 , R 5 , R 6 , R 7 , R 12 , Q 1 , L, x, and Ring B are as defined for formula (I).
  • the compound of the formula (XII) is a compound of the formula (XI la), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (I) is a compound of the formula (XIII), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R 4a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q 1 , -OR 5 , -S(O) X R 5 , -NR 5 R 6 , -C(O)R 5 , - OC(O)R 5 , -C(O)OR 5 , -NR 5 C(O)R 6 , -C(O)NR 5 R 6 , -NR 5 C(O)OR 6 , -OC(O)NR 5 R 6 , -NR 5 SO 2 R 6 , and -SO 2 NR 5 R 6 , wherein said C1.6 alkyl, 2 to 8 membered hetero
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 12 , Q 1 , L, x, and Ring B are as defined for formula (I).
  • the compound of the formula (XIII) is a compound of the formula (XI I la), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (I) is a compound of the formula (XIV), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R 4a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q 1 , -OR 5 , -S(O) X R 5 , -NR 5 R 6 , -C(O)R 5 , - OC(O)R 5 , -C(O)OR 5 , -NR 5 C(O)R 6 , -C(O)NR 5 R 6 , -NR 5 C(O)OR 6 , -OC(O)NR 5 R 6 , -NR 5 SO 2 R 6 , and -SO 2 NR 5 R 6 , wherein said C1.6 alkyl, 2 to 8 membered hetero
  • the compound of the formula (XIV) is a compound of the formula (XlVa), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (I) is a compound of the formula (XV), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R 4a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q 1 , -OR 5 , -S(O) X R 5 , -NR 5 R 6 , -C(O)R 5 , - OC(O)R 5 , -C(O)OR 5 , -NR 5 C(O)R 6 , -C(O)NR 5 R 6 , -NR 5 C(O)OR 6 , -OC(O)NR 5 R 6 , -NR 5 SO 2 R 6 , and -SO 2 NR 5 R 6 , wherein said C1.6 alkyl, 2 to 8 membered hetero
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 12 , Q 1 , L, x, and Ring B are as defined for formula (I).
  • the compound of the formula (XV) is a compound of the formula (XVa), or a pharmaceutically acceptable salt or N-oxide thereof: (XVa)
  • the compound of the formula (I) is a compound of the formula (XVI), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R 4a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q 1 , -OR 5 , -S(O) X R 5 , -NR 5 R 6 , -C(O)R 5 , - OC(O)R 5 , -C(O)OR 5 , -NR 5 C(O)R 6 , -C(O)NR 5 R 6 , -NR 5 C(O)OR 6 , -OC(O)NR 5 R 6 , -NR 5 SO 2 R 6 , and -SO 2 NR 5 R 6 , wherein said C1.6 alkyl, 2 to 8 membered hetero
  • R 3 , R 5 , R 6 , R 7 , R 12 , Q 1 , L, x, and Ring B are as defined for formula (I).
  • the compound of the formula (XVI) is a compound of the formula (XlVa), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (I) is a compound of the formula (XVII), or a pharmaceutically acceptable salt or N-oxide thereof: wherein:
  • Ring D is phenyl or a 6-membered heteroaryl containing 1 , 2 or 3 ring nitrogen atoms and Ring E is a 5-membered heteroaryl containing 1 or more (e.g. 1 to 4) ring nitrogen atoms and optionally one or two ring heteroatoms selected from O and S, and wherein Rings D and E together form a 9-membered fused bicyclic heteroaryl ring;
  • each R 4a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q 1 , -OR 5 , -S(O) X R 5 , -NR 5 R 6 , -C(O)R 5 , - OC(O)R 5 , -C(O)OR 5 , -NR 5 C(O)R 6 , -C(O)NR 5 R 6 , -NR 5 C(O)OR 6 , -OC(O)NR 5 R 6 , -NR 5 SO 2 R 6 , and -SO 2 NR 5 R 6 , wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R 7 ;
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 12 , Q 1 , L, x, and Ring B are as defined for formula (I).
  • the compound of the formula (XVII) is a compound of the formula (XVIIa), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (XVII) is a compound of the formula (XVIII), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (XVIII) is a compound of the formula (XVI I la), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (I) is a compound of the formula (XIX), or a pharmaceutically acceptable salt or N-oxide thereof: wherein:
  • Ring F is a 5-membered heteroaryl containing 1 or more (e.g. 1 to 3) ring nitrogen atoms and optionally one or two ring heteroatoms selected from O and S
  • Ring G is phenyl or a 6- membered heteroaryl containing 1 , 2 or 3 ring nitrogen atoms, and wherein Rings F and G together form a 9-membered fused bicyclic heteroaryl ring;
  • each R 4a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q 1 , -OR 5 , -S(O) X R 5 , -NR 5 R 6 , -C(O)R 5 , - OC(O)R 5 , -C(O)OR 5 , -NR 5 C(O)R 6 , -C(O)NR 5 R 6 , -NR 5 C(O)OR 6 , -OC(O)NR 5 R 6 , -NR 5 SO 2 R 6 , and -SO 2 NR 5 R 6 , wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R 7
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 12 , Q 1 , L, x, and Ring B are as defined for formula (I).
  • the compound of the formula (XIX) is a compound of the formula (XIXa), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (XIX) is a compound of the formula (XX), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (XX) is a compound of the formula (XXa), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (I) is a compound of the formula (XXI), or a pharmaceutically acceptable salt thereof: wherein:
  • X 3 is N or CR 4a ;
  • R 4a is selected from: halo, -CN, -NO2, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, Q 1 , -OR 5 , -S(O) X R 5 , -NR 5 R 6 , -C(O)R 5 , -OC(O)R 5 , - C(O)OR 5 , -NR 5 C(O)R 6 , -C(O)NR 5 R 6 , -NR 5 C(O)OR 6 , -OC(O)NR 5 R 6 , -NR 5 SO 2 R 6 , and - SO 2 NR 5 R 6 , wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C 2 .6 alkenyl and C 2 .6 alkynyl is optionally substituted by one or more R 7 ;
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , Q 1 , L, x, and Ring B are as defined for formula (I).
  • the compound of the formula (XXI) is a compound of the formula (XXIa), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (I) is a compound of the formula (XXII), or a pharmaceutically acceptable salt or N-oxide thereof: wherein:
  • X 3 is N or CR 4a ;
  • R 4a is selected from: H, halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, Q 1 , -OR 5 , -S(O) X R 5 , -NR 5 R 6 , -C(O)R 5 , -OC(O)R 5 , - C(O)OR 5 , -NR 5 C(O)R 6 , -C(O)NR 5 R 6 , -NR 5 C(O)OR 6 , -OC(O)NR 5 R 6 , -NR 5 SO 2 R 6 , and - SO 2 NR 5 R 6 , wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C 2 .6 alkenyl and C 2 .6 alkynyl is optionally substituted by
  • R 3 , R 5 , R 6 , R 7 , R 12 , Q 1 , L, x, and Ring B are as defined for formula (I).
  • the compound of the formula (XXII) is a compound of the formula (XXIIa), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (I) is a compound of the formula (XXIII), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: a is an integer from 0 to 4; and R 1 , R 2 , R 3 , R 4 , R 12 , L and Ring B are as defined for formula (I).
  • the compound of the formula (XIII) is a compound of the formula (XXI I la), or a pharmaceutically acceptable salt or N-oxide thereof: (XXI 11 a)
  • the compound of the formula (I) is a compound of the formula (XXIV), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: a is an integer from 0 to 4; and R 3 , R 4 , R 12 , L and Ring B are as defined for formula (I).
  • the compound of the formula (XXIV) is a compound of the formula (XXI Va), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (I) is a compound of the formula (XXV), or a pharmaceutically acceptable salt or N-oxide thereof: wherein each R 10a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, -OR 10A , -S(O) x R 10A , -NR 10A R 10B , - C(O)R 10A , -OC(O)R 10A , -C(O)OR 10A , -NR 10A C(O)R 10B , -C(O)NR 10A R 10B , -NR 10A C(O)OR 10B , -OC(O)NR 10A R 10B , -NR 10A SO 2 R 10B , and -SO 2 NR 10A R 10B , wherein each R 10a is independently selected
  • R 1 , R 2 , R 3 , R 10A , R 10B , R 11 , R 12 , L, x, and Ring A are as defined for formula (I).
  • the compound of the formula (XXV) is a compound of the formula (XXVa), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (I) is a compound of the formula (XXVI), or a pharmaceutically acceptable salt or N-oxide thereof: wherein each R 10a is independently selected from: halo, -CN, -NO2, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, -OR 10A , -S(O) x R 10A , -NR 10A R 10B , - C(O)R 10A , -OC(O)R 10A , -C(O)OR 10A , -NR 10A C(O)R 10B , -C(O)NR 10A R 10B , -NR 10A C(O)OR 10B , -OC(O)NR 10A R 10B , -NR 10A SO 2 R 10B , and -SO 2 NR 10A R 10B
  • R 3 , R 10A , R 10B , R 11 , R 12 , L, x, and Ring A are as defined for formula (I).
  • the compound of the formula (XXVI) is a compound of the formula (XXVIa), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (I) is a compound of the formula (XXVII), or a pharmaceutically acceptable salt or N-oxide thereof:
  • R 10a is selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 10A , -S(O) x R 10A , -NR 10A R 10B , -C(O)R 10A , - OC(O)R 10A , -C(O)OR 10A , -NR 10A C(O)R 10B , -C(O)NR 10A R 10B , -NR 10A C(O)OR 10B , - OC(O)NR 10A R 10B , -NR 10A SO 2 R 10B , and -SO 2 NR 10A R 10B , wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C 2 .6 alkenyl and C 2 .6 alkynyl is optionally substituted
  • R 1 , R 2 , R 3 , R 10A , R 10B , R 11 , R 12 , L, x, and Ring A are as defined for formula (I).
  • the compound of the formula (XXVII) is a compound of the formula (XXVI la), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (I) is a compound of the formula (XXVIII), or a pharmaceutically acceptable salt or N-oxide thereof:
  • R 10a is selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 10A , -S(O) x R 10A , -NR 10A R 10B , -C(O)R 10A , - OC(O)R 10A , -C(O)OR 10A , -NR 10A C(O)R 10B , -C(O)NR 10A R 10B , -NR 10A C(O)OR 10B , - OC(O)NR 10A R 10B , -NR 10A SO 2 R 10B , and -SO 2 NR 10A R 10B , wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C 2 .6 alkenyl and C 2 .6 alkynyl is optionally substituted
  • R 3 , R 10A , R 10B , R 11 , R 12 , L, x, and Ring A are as defined for formula (I).
  • the compound of the formula (XXVIII) is a compound of the formula (XXVI I la), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (I) is a compound of the formula (XXIX), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R 10a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, -OR 10A , -S(O) x R 10A , -NR 10A R 10B , - C(O)R 10A , -OC(O)R 10A , -C(O)OR 10A , -NR 10A C(O)R 10B , -C(O)NR 10A R 10B , -NR 10A C(O)OR 10B , -OC(O)NR 10A R 10B , -NR 10A SO 2 R 10B , and -SO 2 NR 10A R 10B
  • R 1 , R 2 , R 3 , R 10A , R 10B , R 11 , R 12 , L, x, and Ring A are as defined for formula (I).
  • the compound of the formula (I) is a compound of the formula (XXX), or a pharmaceutically acceptable salt or N-oxide thereof: wherein each R 10a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, -OR 10A , -S(O) x R 10A , -NR 10A R 10B , -
  • R 3 , R 10A , R 10B , R 11 , R 12 , L, x, and Ring A are as defined for formula (I).
  • the compound of the formula (XXX) is a compound of the formula (XXXa), or a pharmaceutically acceptable salt or N-oxide thereof:
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 10A , R 10B , R 11 , R 12 , Q 1 , L, and x are as defined for formula (I).
  • the compound of the formula (XXXI) is a compound of the formula (XXXIa), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (XXXI) is a compound of the formula (XXXI b), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (XXXI) is a compound of the formula (XXXIc), or a pharmaceutically acceptable salt or N-oxide thereof:
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 10A , R 10B , R 11 , R 12 , Q 1 , L, and x are as defined for formula (I).
  • the compound of the formula (XXXII) is a compound of the formula (XXXI la), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (XXXII) is a compound of the formula (XXXIIb), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (XXXII) is a compound of the formula (XXXIIc), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (I) is a compound of the formula (XXXIII), or a pharmaceutically acceptable salt or N-oxide thereof: wherein:
  • X 3 is N or CR 4a ;
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 10A , R 10B , R 11 , R 12 , Q 1 , L, and x are as defined for formula (I).
  • the compound of the formula (XXXIII) is a compound of the formula (XXXI I la), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (XXXIII) is a compound of the formula (XXXI 11 b), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (XXXIII) is a compound of the formula (XXXI He), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (I) is a compound of the formula (XXXIV), or a pharmaceutically acceptable salt or N-oxide thereof:
  • X 3 is N or CR 4a ;
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 10A , R 10B , R 11 , R 12 , Q 1 , L, and x are as defined for formula (I).
  • the compound of the formula (XXXIV) is a compound of the formula (XXXIVa), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (XXXIV) is a compound of the formula (XXXIVb), or a pharmaceutically acceptable salt or N-oxide thereof: (XXXIVb)
  • the compound of the formula (XXXIV) is a compound of the formula (XXXI Vc), or a pharmaceutically acceptable salt or N-oxide thereof:
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 10A , R 10B , R 11 , R 12 , Q 1 , L, and x are as defined for formula (I).
  • the compound of the formula (XXXV) is a compound of the formula (XXXVa), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (XXXV) is a compound of the formula (XXXVb), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (XXXV) is a compound of the formula (XXXVc), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (I) is a compound of the formula (XXXVI), or a pharmaceutically acceptable salt or N-oxide thereof:
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 10A , R 10B , R 11 , R 12 , Q 1 , L, and x are as defined for formula (I).
  • the compound of the formula (XXXVI) is a compound of the formula (XXXVIa), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (XXXVI) is a compound of the formula (XXXVIb), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (XXXVI) is a compound of the formula (XXXVIc), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (I) is a compound of the formula (XXXVII), or a pharmaceutically acceptable salt or N-oxide thereof:
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 10A , R 10B , R 11 , R 12 , Q 1 , L, and x are as defined for formula (I).
  • the compound of the formula (XXXVII) is a compound of the formula (XXXVI la), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (XXXVII) is a compound of the formula (XXXVIlb), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (I) is a compound of the formula (XXXVIII), or a pharmaceutically acceptable salt or N-oxide thereof:
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 10A , R 10B , R 11 , R 12 , Q 1 , L, and x are as defined for formula (I).
  • the compound of the formula (XXXVIII) is a compound of the formula (XXXVI I la), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (XXXVIII) is a compound of the formula (XXXVIHb), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (I) is a compound of the formula (XXXIX), or a pharmaceutically acceptable salt or N-oxide thereof: wherein
  • R 10a and R 10b are each independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, -OR 10A , -S(O) x R 10A , - NR 10A R 10B , -C(O)R 10A , -OC(O)R 10A , -C(O)OR 10A , -NR 10A C(O)R 10B , -C(O)NR 10A R 10B , - NR 10A C(O)OR 10B , -OC(O)NR 10A R 10B , -NR 10A SO 2 R 10B , and -SO 2 NR 10A R 10B , wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally
  • the compound of the formula (XXXIX) is a compound of the formula (XXXIXa), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (XXXIX) is a compound of the formula (XXXIXb), or a pharmaceutically acceptable salt or N-oxide thereof:
  • R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 10A , R 10B , R 11 , R 12 , Q 1 , L, and x are as defined for formula (I).
  • the compound of the formula (XXXX) is a compound of the formula (XXXXI), or a pharmaceutically acceptable salt or N-oxide thereof:
  • the compound of the formula (XXXX) is a compound of the formula (XXXXII), or a pharmaceutically acceptable salt or N-oxide thereof:
  • compounds of the invention include, for example, compounds of formulae (I) to (XXXXII), or a pharmaceutically acceptable salt or N-oxide thereof, wherein, unless otherwise stated, each of Ring A, Ring B, R 1 , R 2 , R 3 , R 4 , R 4a , R 4b , p4c p5 p6 p7 p8 p9 10 R11 p7A p7B p9A p9B R9C p9D f ⁇ 10a f ⁇ 10b f ⁇ 10A f ⁇ 10B f ⁇ 1 1A p1 1 B
  • R 12 , Q 1 , Q 2 , L, a, c, and x has any of the meanings defined hereinbefore or in any of the following statements in the numbered paragraphs 1 to 252 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.
  • R 1 is selected from: Ci-e alkyl, C3-6 cycloalkyl, and Cs-ecycloalkyl-Ci-e alkyl-, wherein R 1 is substituted by at least one fluorine.
  • R 1 is selected from: C1.3 alkyl, C3-6 cycloalkyl, and Cs-ecycloalkyl-Ci-s alkyl-, wherein R 1 is substituted by at least one fluorine.
  • R 1 is selected from: Ci-e alkyl, and C3-6 cycloalkyl, wherein R 1 is substituted by at least one fluorine.
  • R 1 is selected from: C1.3 alkyl, and C3-6 cycloalkyl, wherein R 1 is substituted by at least one fluorine.
  • R 1 is C1.6 alkyl, wherein R 1 is substituted by at least one fluorine.
  • R 1 is C1.3 alkyl, wherein R 1 is substituted by at least one fluorine.
  • R 1 is selected from ethyl and methyl, wherein the ethyl or methyl is substituted by at least one fluorine.
  • R 1 is ethyl wherein the ethyl is substituted by at least one fluorine.
  • R 1 is selected from -CH2F, -CHF2, and -CF3.
  • R 1 is -CH 2 F.
  • R 1 is -CHF 2 .
  • R 1 is -CF 3 .
  • R 2 is selected from: H, C1.3 alkyl and C1.3 haloalkyl.
  • R 2 is selected from: H, and C1.3 alkyl.
  • R 2 is C1.3 alkyl.
  • R 2 is methyl
  • R 2 is H or D. It may be that R 2 is D. It may be that R 2 is H.
  • R 1 and R 2 together with the carbon atom to which they are attached form a C3 or C4 cycloalkyl substituted with at least one fluorine.
  • R 1 and R 2 together with the carbon atom to which they are attached form a cyclobutyl group substituted with at least one fluorine.
  • R 1 and R 2 together with the carbon atom to which they are attached form a cyclobutyl group substituted one fluorine.
  • R 1 and R 2 together with the carbon atom to which they are attached form a cyclopropyl group substituted with at least one fluorine.
  • R 1 and R 2 together with the carbon atom to which they are attached form a cyclopropyl group substituted with one fluorine.
  • R 1 is as defined in any of 1 to 12 and R 2 is methyl.
  • R 1 is as defined in any of 1 to 12 and R 2 is H.
  • R 3 is selected from: H, Ci-e alkyl and Ci-e haloalkyl; optionally wherein one or more H in R 3 is substituted by D.
  • R 3 is selected from: C1.3 alkyl and C1.3 haloalkyl.
  • R 3 is selected from: C1.2 alkyl and C1.2 haloalkyl.
  • R 3 is methyl optionally substituted with 1 to 3 halo groups.
  • R 3 is ethyl optionally substituted with 1 to 5 halo groups.
  • R 3 is as defined in any of 23 to 27, wherein said halo is fluoro.
  • R 3 is C1.3 alkyl. 30. R 3 is selected from: methyl, ethyl, and 2-fluoroethyl.
  • R 3 is methyl
  • R 3 is ethyl
  • R 3 is 2-fluoroethyl.
  • R 3 is as defined in any of 23 to 33 wherein one or more hydrogen atoms in R 3 is deuterium. Thus, it may be that R 3 is selected from: methyl, -CDs, ethyl, and 2- fluoroethyl.
  • R 3 is -CD 3 .
  • R 12 is independently selected from H, Ci-e alkyl, Ci-e haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-Ci-6 alkyl-, and COOR 13 .
  • R 12 is independently selected from H, Ci-e alkyl, Ci-e haloalkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-Ci-6 alkyl-.
  • R 12 is independently selected from H, Ci-e alkyl, Ci-e haloalkyl, and C3-6 cycloalkyl.
  • R 12 is H.
  • R 12 is C1.6 alkyl, e.g. C1.3 alkyl.
  • R 12 is C1.6 haloalkyl, e.g. C1.3 haloalkyl.
  • R 12 is C3-6 cycloalkyl, e.g. C3 cycloalkyl.
  • R 12 is as defined in any of 36 to 42, wherein one or more H in R 12 is substituted by D.
  • R 12 is COOR 13 .
  • R 13 is independently selected from Ci-e alkyl, Ci-e haloalkyl, C3-6 cycloalkyl, and C3- 6 cycloalkyl-Ci-6 alkyl.
  • R 13 is independently selected from H, Ci-e alkyl, Ci-e haloalkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-Ci-6 alkyl.
  • R 13 is independently selected from Ci-e alkyl, Ci-e haloalkyl, and C3-6 cycloalkyl.
  • R 13 is C1.6 alkyl, e.g. C1.3 alkyl.
  • R 13 is C1.6 haloalkyl, e.g. C1.3 haloalkyl.
  • R 13 is C3-6 cycloalkyl, e.g. C3 cycloalkyl.
  • R 13 is as defined in any of 45 to 50, wherein one or more H in R 13 is substituted by
  • D. 52. L is selected from: a bond and C1.2 alkyl.
  • L is selected from: a bond, -CH2-, and -CH2CH2-.
  • L is selected from: a bond and -CH2-.
  • L is -CH2-.
  • L is a bond
  • Ring A is selected from: 4- to 7-membered heterocyclyl, 5- to 12-membered heteroaryl and Ce- aryl.
  • Ring A is selected from: 4- to 7-membered heterocyclyl and 5- to 12-membered heteroaryl.
  • Ring A is selected from: 5- or 6-membered heterocyclyl, 5- to 10-membered heteroaryl and Ce-8 aryl.
  • Ring A is selected from: 5- or 6-membered heterocyclyl, and 5- to 10-membered heteroaryl.
  • Ring A is selected from: 5- or 6-membered heterocyclyl, 5- to 9-membered heteroaryl and phenyl.
  • Ring A is selected from: 5- or 6-membered heterocyclyl and 5- to 9-membered heteroaryl.
  • Ring A is selected from: 5- to 10-membered heteroaryl and phenyl.
  • Ring A is a 5- to 10-membered heteroaryl.
  • Ring A is a 6- to 10-membered heteroaryl.
  • Ring A is selected from: 5-membered heteroaryl, 6-membered heteroaryl, 9- membered heteroaryl, and phenyl.
  • Ring A is a monocyclic 5- or 6-membered heteroaryl or a 8- to 10-membered fused bicyclic heteroaryl, wherein Ring A has at least 1 (for example 1 to 4) ring nitrogen atom.
  • Ring A is a monocyclic 6-membered heteroaryl or a 9- to 10-membered fused bicyclic heteroaryl, wherein Ring A has at least 1 (for example 1 to 4) ring nitrogen atom.
  • Ring A is a monocyclic 5- or 6-membered heteroaryl or a 9- to 10-membered fused bicyclic heteroaryl, wherein Ring A has 1 to 4 ring nitrogen atoms.
  • Ring A is a monocyclic 6-membered heteroaryl or a 9-membered fused bicyclic heteroaryl, wherein Ring A has 1 to 4 ring nitrogen atoms.
  • Ring A is 5-membered heteroaryl.
  • Ring A is 5-membered heteroaryl, wherein Ring A said heteroaryl has 1 ring nitrogen atom and optionally one or more ring heteroatoms (for example 1 , 2 or 3) selected from O, S and N.
  • Ring A is 5-membered heteroaryl, wherein said heteroaryl has 1 , 2, 3 or 4 ring nitrogen atoms.
  • Ring A is 6-membered heteroaryl.
  • Ring A is a monocyclic 6-membered heteroaryl, wherein said heteroaryl has 1 , 2 or 3 (for example 1 or 2) ring nitrogen atoms.
  • Ring A is 9-membered heteroaryl.
  • Ring A is 9-membered fused bicyclic heteroaryl, wherein said heteroaryl has 1 , 2, 3 or 4 ring nitrogen atoms.
  • Ring A is 9-membered bicyclic heteroaryl, wherein said heteroaryl has 1 , 2, 3 or 4 (for example 1 , 2 or 3) ring nitrogen atoms and is a 6-membered ring fused to a 5- membered ring, wherein the 9-membered bicyclic heteroaryl is attached to the group L by a ring atom in the 6-membered ring. It may be that the 5- and 6- membered rings forming the 9-membered bicyclic heteroaryl are both heteroaryl rings.
  • Ring A is 9-membered bicyclic heteroaryl, wherein said heteroaryl has 1 , 2, 3 or 4 (for example 1 , 2 or 3) ring nitrogen atoms and is a 6-membered ring fused to a 5- membered ring, wherein the 9-membered bicyclic heteroaryl is attached to the group L by a ring atom in the 5-membered ring. It may be that the 5- and 6- membered rings forming the 9-membered bicyclic heteroaryl are both heteroaryl rings.
  • Ring A is selected from: a 6-membered heteroaryl and a 9-membered bicyclic heteroaryl, wherein said 6-membered heteroaryl has 1 , 2 or 3 (for example 1 or 2) ring nitrogen atoms, and said 9-membered bicyclic heteroaryl has 1 , 2, 3 or 4 (for example 1 , 2 or 3) ring nitrogen atoms. It may be that the 5- and 6-membered rings forming the 9-membered bicyclic heteroaryl are both heteroaryl rings.
  • Ring A is phenyl
  • Ring A is a 4- to 6-membered heterocyclyl.
  • Ring A is a 5- or 6-membered heterocyclyl containing at least one ring oxygen atom and optionally 1 further ring heteroatom selected from S and N.
  • Ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, and tetrahydropyranyl.
  • Ring A is selected from pyrrolidinyl, tetrahydrofuranyl, piperidinyl, and tetrahydropyranyl. 84. Ring A is tetrahydropyranyl.
  • Ring A is selected from furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl.
  • Ring A is selected from furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, or a compound of the structure: wherein Ring A is optionally substituted with one or more R 4 .
  • Ring A is selected from: thienyl, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, tetrahydropyranyl,
  • Ring A is optionally substituted with one or more R 4 .
  • Ring A is selected from: ; wherein Ring A is optionally substituted with one or more R 4 .
  • Ring A is a 9-membered fused bicyclic heteroaryl containing at least one ring nitrogen atom, wherein Ring A is substituted by one or more R 4 .
  • Ring A is attached to L via an atom in a 5-membered ring in Ring A.
  • Ring A is attached to L via an atom in a 6-membered ring in Ring A.
  • Ring A is selected from: ; wherein Ring A is optionally substituted with one or more R 4 .
  • Ring A is attached to L via a carbon atom in a benzo ring.
  • Ring A is selected from: wherein Ring A is optionally substituted with one or more R 4 .
  • Ring A is selected from: wherein Ring A is optionally substituted with one or more R 4 .
  • Ring A is selected from: wherein Ring A is optionally substituted with one or more R 4 .
  • Ring A is selected from: wherein Ring A is optionally substituted with one or more R 4 .
  • Ring A is selected from: 96. Ring A is selected from: ; wherein Ring A is optionally substituted with one or more R 4 . Ring A is selected from: wherein Ring A is optionally substituted with one or more Ring A is selected from: ; wherein Ring A is optionally substituted with one or more R 4 .
  • Ring A is selected from: optionally substituted with one or more R 4 .
  • Ring A is selected from thienyl and thiazolyl, wherein Ring A is optionally substituted with one or more R 4 .
  • Ring A is selected from: wherein Ring A is optionally substituted with one or more R 4 .
  • Ring A is selected from: wherein Ring A is optionally substituted with one or more R 4 . Ring A is selected from: 107. Ring A is selected from:
  • Ring A is selected from: 108.
  • Ring A is selected from:
  • Ring A is selected from:
  • Ring A is selected from:
  • Ring A is as defined in any of 57 to 104 and is substituted by one or more R 4 .
  • Ring A is as defined in any of 57 to 104 and is substituted by one or two R 4 .
  • Ring A is as defined in any of 57 to 104 and is unsubstituted. 114. Ring A is selected from:
  • Ring A is optionally substituted with one or more R 4 .
  • Ring A is selected from:
  • Ring A is selected from:
  • Ring A is selected from:
  • Ring A is as defined in any of 115 to 118, wherein y is an integer from 0 to 10, where chemically possible.
  • Ring A is as defined in any of 115 to 118, wherein y is an integer from 0 to 5, where chemically possible.
  • Ring A is as defined in any of 115 to 118, wherein y is an integer from 0 to 3, where chemically possible. 122. Ring A is as defined in any of 115 to 118, wherein y is 0.
  • Ring A is as defined in any of 115 to 118, wherein y is 1.
  • Ring A is as defined in any of 115 to 118, wherein y is 2.
  • Ring A defined in any of 57 to 124 comprises an NH group
  • said NH group may be substituted by R 4 to give NR 4 .
  • Each R 4 is independently selected from: halo, -CN, -NO 2 , Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, Q 1 , -OR 5 , -S(O) X R 5 , -NR 5 R 6 , -C(O)R 5 , -OC(O)R 5 , - C(O)OR 5 , -NR 5 C(O)R 6 , -C(O)NR 5 R 6 , -NR 5 SO 2 R 6 , and -SO 2 NR 5 R 6 .
  • each R 4 is independently selected from: halo, -CN, -NO 2 , C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, Q 1 , -OR 5 , -S(O) X R 5 , -NR 5 R 6 , -C(O)R 5 , - OC(O)R 5 , -C(O)OR 5 , -C(O)NR 5 R 6 , -NR 5 SO 2 R 6 , and -SO 2 NR 5 R 6 .
  • Each R 4 is independently selected from: halo, -CN, C1.4 alkyl, C1.4 haloalkyl, -OR 5 , -NR 5 R 6 , -C(O)R 5 , -C(O)OR 5 , and -C(O)NR 5 R 6 .
  • Each R 4 is independently selected from: halo, -CN, C1.4 alkyl, -OR 5 , -NR 5 R 6 , - C(O)R 5 , -C(O)NR 5 R 6 and -NR 5 C(O)R 6 .
  • Each R 4 is independently selected from: halo, -CN, C1.4 alkyl, -C(O)R 5 and - C(O)NR 5 R 6 .
  • Each R 4 is independently selected from halo (e.g. fluoro or chloro), -CN, C1.3 alkyl, -OC1.3 alkyl, -C(O)Ci-3 alkyl, -C(O)NH 2 , -C(O)NH(CI- 3 alkyl) and -C(O)N(Ci. 3 alkyl) 2 .
  • halo e.g. fluoro or chloro
  • Each R 4 is independently selected from halo (e.g. fluoro or chloro), -CN, C1.3 alkyl and -OC1.3 alkyl. Thus it may be that each R 4 is independently selected from halo, - CN and C1.3 alkyl. Thus it may be that each R 4 is independently selected from fluoro, chloro, -CN, methyl and methoxy. For example each R 4 is independently selected from fluoro, chloro, -CN and methyl.
  • R 4 is as defined in any one of 126 to 131 , wherein said Ci-e alkyl or 2 to 8 membered heteroalkyl is substituted by one or more R 7 .
  • R 5 and R 6 are each independently selected from: H, Ci-e alkyl, and Q 1 .
  • R 5 and R 6 are each independently selected from: H, C1.3 alkyl and Q 1 .
  • R 5 and R 6 are each independently selected from: H and C1.3 alkyl.
  • R 5 and R 6 are as defined in 136 to 138, wherein said alkyl is substituted by one or more R 8 .
  • R 7 and R 8 are each independently selected from: -C(O)R 7A , -OC(O)R 7A , -C(O)OR 7A , -NR 7A C(O)R 7B and -C(O)NR 7A R 7B
  • R 7 and R 8 are each independently selected from: halo, -CN, -OR 7A , -NR 7A R 7B and Q 2 .
  • R 7 and R 8 are each independently selected from: halo, -OR 7A and Q 2 .
  • Q 1 and Q 2 are each independently selected from: C3-6 cycloalkyl and 4- to 7- membered heterocyclyl.
  • Q 1 and Q 2 are each independently 4- to 6-membered heterocyclyl.
  • Q 1 and Q 2 are each independently selected from: oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl and dihydropyranyl.
  • Q 1 and Q 2 are each independently selected from: phenyl and 5- or 6-membered heteroaryl.
  • Q 1 and Q 2 are as defined in any of 143 or 146, wherein Q 1 and Q 2 are substituted by one or more R 9 .
  • R 9 is as defined in 148, wherein said C1.4 alkyl is substituted by 1 or 2 substituents selected from: halo, -CN, -OR 9C , -NR 9C R 9D and -SO2R 9C
  • R 7A , R 7B , R 9A , R 9B , R 9C , and R 9D are at each occurrence independently selected from: H, and C1.4 alkyl.
  • R 7A , R 7B , R 9A , R 9B , R 9C , and R 9D are at each occurrence independently selected from: H, methyl, and ethyl.
  • R 7A , R 7B , R 9A , R 9B , R 9C , and R 9D are at each occurrence independently selected from: H and methyl.
  • Each R 4 is independently selected from:
  • Each R 4 or R 4a is independently selected from: F, Cl, -CN, methyl, methoxy, -NH2, -NH(Me), -NH(Et), -N(Me) 2 -C(O)Me, -C(O)NH 2 , -C(O)NH(Me), -C(O)n(Me) 2 , - C(O)OMe, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl and dihydropyranyl.
  • Each R 4 or R 4a is independently selected from: F, Cl, -CN, methyl, methoxy, -NH 2 , -NH(Me), -NH(Et), -N(Me) 2 -C(O)Me, -C(O)NH 2 , -C(O)NH(Me), -C(O)N(Me) 2 and - C(O)OMe.
  • Each R 4 or R 4a is independently selected from: F, -CN, methyl, -C(O)Me, -C(O)NH 2 , -C(O)NH(Me) and -C(O)N(Me) 2 .
  • Each R 4 or R 4a is independently selected from: halo (e.g. fluoro), -CN and C1.3 alkyl (e.g. methyl). This it may be that each R 4 is independently selected from: fluoro, - CN and methyl.
  • Ring A is selected from:
  • Ring A is selected from: . y It may be that Ring A is It may be that Ring may be that Ring A is . It may be that Ring A is may be that Ring A is 65. Ring A is selected from: . may be that Ring
  • Ring A is . It may be that Ring may be that Ring A is
  • 166. a is an integer from 0 to 5.
  • 167. a is an integer from 0 to 3.
  • x is 1. 174. x is 2.
  • R 4a and R 4b are each independently selected from: halo, -CN, -NO2, C1.6 alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, Q 1 , -OR 5 , - S(O) X R 5 , -NR 5 R 6 , -C(O)R 5 , -OC(O)R 5 , -C(O)OR 5 , -C(O)NR 5 R 6 , -NR 5 SO 2 R 6 , and - SO 2 NR 5 R 6 .
  • Each R 4a and R 4b is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, -OR 5 , -S(O) X R 5 , -NR 5 R 6 , -C(O)R 5 , -OC(O)R 5 , -C(O)OR 5 , -NR 5 C(O)R 6 , - C(O)NR 5 R 6 , -NR 5 SO 2 R 6 , and -SO 2 NR 5 R 6 .
  • Each R 4a and R 4b is independently selected from: halo, -CN, C1.6 alkyl, C1.6 haloalkyl, Q 1 , -OR 5 , -NR 5 R 6 , -C(O)R 5 , -C(O)OR 5 , and -C(O)NR 5 R 6 .
  • Each R 4a and R 4b is selected from: halo (e.g. fluoro or chloro), -CN, C1.3 alkyl, -OC1.3 alkyl, -C(O)Ci-3 alkyl, -C(O)NH 2 , -C(O)NH(CI- 3 alkyl) and -C(O)N(Ci. 3 alkyl) 2 .
  • halo e.g. fluoro or chloro
  • Each R 4a and R 4b is selected from: halo (e.g. fluoro), -CN and C1.3 alkyl (e.g. methyl).
  • R 4a and R 4b are each as defined in any one of 175 to 179, wherein said Ci-e alkyl is substituted by one or more R 7 .
  • R 4c is independently selected from: H, Ci-e alkyl, Ci-e haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.
  • R 4c is independently selected from: Ci-e alkyl, Ci-e haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.
  • R 4c is independently selected from: Ci-e alkyl and Ci-e haloalkyl.
  • R 4c is as defined in any of 183 to 185, wherein said Ci-e alkyl is optionally substituted by one or more R 7 .
  • Ring B is selected from phenyl or 6-membered heteroaryl.
  • Ring B is 6-membered heteroaryl.
  • Ring B is 5-membered heteroaryl.
  • Ring B is selected from furanyl, thienyl furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, phenyl, pyridyl, pyrimidinyl, and pyrazinyl.
  • Ring B is selected from furanyl, thienyl furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, phenyl, pyrimidinyl, and pyrazinyl.
  • Ring B is selected from furanyl, pyrazolyl, oxazolyl, isoxazolyl and phenyl.
  • Ring B is furanyl
  • Ring B is pyrazolyl
  • Ring B is oxazolyl
  • Ring B is isoxazolyl.
  • Ring B is phenyl
  • Ring B is as defined in any of 187 to 197 and is substituted by one or more R 10 .
  • Ring B is selected from:
  • Ring B is selected from:
  • Ring B is selected from:
  • Ring B is as defined in any of 199 to 203, wherein z is an integer from 0 to 5, where chemically possible. Thus it may be that Ring B is as defined in any of 199 to 203, wherein z is 0, 1 or 2. It may be that Ring B is as defined in any of 199 to 203, wherein z s 1 or 2. . Ring B is as defined in any of 199 to 203, wherein z is 2. . Ring B is as defined in any of 199 to 203, wherein z is 1. . Ring B is as defined in any of 199 to 203, wherein z is 0. . Ring B is selected from: . Ring B is phenyl substituted by one or two R 10 selected from halo and Ci-shaloalkyl.
  • Ring B is 4-fluorophenyl or 4-trifluoromethylphenyl. It may be that Ring B is 4-fluorophenyl. It may be that Ring B is 4-trifluoromethylphenyl.. Ring B is selected from: . Ring B is selected from:
  • Ring B defined in any of 187 to 201 comprises an NH group
  • said NH group may be substituted by R 10 to give NR 10 .
  • Each R 10 , R 10a , and R 10b is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, -OR 10A , -S(O) x R 10A , and -NR 10A R 10B .
  • Each R 10 , R 10a , and R 10b is independently selected from -C(O)R 10A , -OC(O)R 10A , - C(O)OR 10A , -NR 10A C(O)R 10B , -C(O)NR 10A R 10B , -NR 10A C(O)OR 10B , -OC(O)NR 10A R 10B , - NR 10A SO 2 R 10B , and -SO 2 NR 10A R 10B .
  • Each R 10 , R 10a , and R 10b is independently selected from: halo, -CN, -NO 2 , Ci-e alkyl, C1.6 haloalkyl, -OR 10A , and -S(O) x R 10A
  • Each R 10 , R 10a , and R 10b is independently selected from: halo, -CN, -NO 2 , C1.3 alkyl, C1.3 haloalkyl, -OR 10A , and -S(O) x R 10A
  • Each R 10 , R 10a , and R 10b is independently selected from: halo, C1.3 alkyl, C1.3 haloalkyl, -OC1.3 alkyl and -OC1.3 haloalkyl.
  • Each R 10 , R 10a , and R 10b is independently selected from: halo and C1.3 alkyl.
  • Each R 10 , R 10a , and R 10b is independently selected from: halo, -CN, -NO 2 , methyl, CF 3 , -OH, -OMe, and -S(O) 2 Me.
  • Each R 10 , R 10a , and R 10b is independently selected from: fluoro, chloro, -CN, -NO 2 , methyl, -CF3, -OH, -OMe, and -S(O) 2 Me. 223.
  • Each R 10 , R 10a , and R 10b is independently selected from: fluoro, chloro, methyl, - CF3, methoxy, -OCF3 and -OCHF2.
  • Each R 10 , R 10a , and R 10b is independently selected from: fluoro and methyl.
  • R 10 and R 10a are fluoro.
  • R 10 , R 10a , and R 10b are fluoro.
  • R 10a and R 10b are fluoro.
  • R 10 and R 10a are -CF 3 .
  • R 10 , R 10a , and R 10b are as defined in any of 215 and 217 to 220, wherein said alkyl is substituted by one or more R 11 .
  • Each R 11 is independently selected from: halo, -CN, -OR 11A , -NR 11A R 11B and - SO 2 R 11A .
  • Each R 11 is independently selected from: halo, -CN, -OR 11A , and -NR 11A R 11B .
  • Each R 11 is independently selected from: halo and -OR 11A .
  • R 10A , R 10B , R 11A and R 11B are at each occurrence independently selected from: H, and C1.4 alkyl.
  • R 10A , R 10B , R 11A and R 11B are at each occurrence independently selected from: H, methyl, and ethyl.
  • R 10A , R 10B , R 11A and R 11B are at each occurrence independently selected from: H and methyl.
  • c is an integer from 0 to 5.
  • c is an integer from 0 to 4.
  • c is an integer from 0 to 3.
  • Any -NR 5 R 6 , -NR 7A R 7B , -NR 9A R 9B , -NR 9C R 9D , -NR 10A R 10B , and -NR 11A R 11B within a substituent may form a 4-membered heterocyclyl.
  • Any -NR 5 R 6 , -NR 7A R 7B , -NR 9A R 9B , -NR 9C R 9D , -NR 10A R 10B , and -NR 11A R 11B within a substituent may form a 5-membered heterocyclyl. 245. Any -NR 5 R 6 , -NR 7A R 7B , -NR 9A R 9B , -NR 9C R 9D , -NR 10A R 10B , and -NR 11A R 11B within a substituent may form a 6-membered heterocyclyl.
  • Any 4- to 6-membered heterocyclyl defined in any of 243 to 245 is substituted by one or more substituents selected from: halo and C1.4 alkyl.
  • the compound of formula (I) is a compound of any of formulae (I) to (XXXXII), wherein L is a bond.
  • the compound of formula (I) is a compound of any of formulae (I) to (XXXXII), wherein L is -CH 2 -.
  • the compound of formula (I) is a compound of any of formulae (I) to (XXXXII), wherein L is a bond and R 3 is selected from methyl, ethyl, and -CH2CH2F.
  • the compound of formula (I) is a compound of any of formulae (I) to (XXXXII), wherein L is a bond and R 3 is methyl or ethyl.
  • the compound of formula (I) is a compound of any of formulae (I) to (XXXXII), wherein R 12 is H.
  • the compound is a compound according to any of formulae (I), (la), (III), (Illa), (V), (VII), (Vila), (IX), (IXa), (XI), (Xia), (XIII), (Xllla), (XV), (XVa), (XVII), (XVIIa), (XIX), (XIXa), (XXI), (XXIa), (XXIII), (XXIIIa), (XXV), (XXVa), (XXVII), (XVIla), (XXIX), (XXI), (XXXII), (XXXIIa), (XXXIII), (XXIIIa), (XXIV), (XXXIVa), (XXXV), (XXXVa), (XXXVI), (XVIa), (XXVII), (XXVII), (XXVII), (XXVIII), (XXIIIa), (XXIV), (XXXIV
  • R 3 is methyl or ethyl.
  • R 3 is methyl. In these embodiments it may be that R 3 is ethyl. In these embodiments it may be that R 3 is -CH2CH2F. In these embodiments it may be that R 12 is H.
  • Ring B is unsubstituted or is substituted by one or two R 10 (or R 10a and/or R 10b as appropriate for each formula), wherein each R 10 , R 10a and R 10b is independently as defined in any of 215 to 229.
  • Ring B is unsubstituted or is substituted by one or two R 10 (or R 10a as appropriate for each formula), wherein each R 10 and R 10a is independently selected from: halo, C1.3 alkyl, C1.3 haloalkyl, - OC1.3 alkyl and -OC1.3 haloalkyl.
  • Ring B is unsubstituted phenyl or phenyl substituted by one or two R 10 (or R 10a and/or R 10b as appropriate for each formula), wherein each R 10 , R 10a and R 10b is independently as defined in any of 215 to 229.
  • each R 10 , R 10a and R 10b is independently selected from: halo, C1.3 alkyl, C1.3 haloalkyl, - OC1.3 alkyl and -OC1.3 haloalkyl.
  • Ring B is phenyl substituted by one or two R 10 (or R 10a and/or R 10b as appropriate for each formula), wherein each R 10 , R 10a and R 10b is independently as defined in any of 215 to 229; and R 3 is methyl or ethyl.
  • each R 10 , R 10a and R 10b is independently selected from: halo, C1.3 alkyl, C1.3 haloalkyl, -OC1.3 alkyl and -OC1.3 haloalkyl.
  • each R 10 , R 10a and R 10b is independently selected from: fluoro, chloro, methyl, -CF3, methoxy and -OCF3
  • L is a bond
  • R 2 when present is H
  • R 3 is selected from methyl, ethyl and -CH2CH2F
  • Ring A is as defined in any of 57 to 118. In these embodiments it may be that R 12 is H.
  • Ring A is optionally substituted by one or more (e.g. 1 or 2) R 4 (or R 4a as appropriate for each formula), wherein each R 4 or R 4a is independently selected from: halo, -CN, Ci-e alkyl, Ci-e haloalkyl, -OR 5 , , -NR 5 R 6 , -C(O)R 5 , -C(O)OR 5 , and -C(O)NR 5 R 6 .
  • R 4 or R 4a as appropriate for each formula
  • each R 4 or R 4a is independently selected from: halo, -CN, Ci-e alkyl, Ci-e haloalkyl, -OR 5 , , -NR 5 R 6 , -C(O)R 5 , -C(O)OR 5 , and -C(O)NR 5 R 6 .
  • Ring A is optionally substituted by one or more (e.g.
  • R 4 or R 4a as appropriate for each formula
  • each R 4 or R 4a is independently selected from: F, Cl, -CN, methyl, methoxy, -NH2, -NH(Me), -NH(Et), - N(Me) 2 -C(O)Me, -C(O)NH 2 , -C(O)NH(Me), -C(O)N(Me) 2 and -C(O)OMe.
  • Ring A is optionally substituted by one or more (e.g. 1 or 2) R 4 (or R 4a as appropriate for each formula), wherein each R 4 or R 4a is independently selected from: F, Cl, -CN, methyl and methoxy.
  • R 3 is methyl or ethyl. In these embodiments it may be that R 3 is methyl. In these embodiments it may be that R 3 is ethyl. In these embodiments it may be that R 3 is -CH 2 CH 2 F.
  • L is a bond;
  • R 2 when present is H;
  • R 3 is selected from methyl, ethyl and -CH 2 CH 2 F;
  • Ring A is as defined in any of 158 to 164.
  • R 3 is methyl or ethyl.
  • R 3 is methyl.
  • R 3 is ethyl.
  • R 3 is - CH 2 CH 2 F.
  • R 12 is H.
  • the compound of any of formulae (I), (la), (II), (Ila), (XXV), (XXVa), (XXVI), (XXVIa), (XXVII), (XXVIla), (XXVIII), (XXVIlla), (XIX), (XIXa), (XXX) and (XXXa) is a compound wherein Ring A is not a ring according to the structure: wherein:
  • Y 1 , Y 2 , Y 3 and Y 4 are each independently CH or N, provided no more than two of Y 1 , Y 2 , Y 3 and Y 4 are N; t and u are each independently 0, 1 , 2, or 3; optionally wherein the ring system is substituted by one or more R 4 , wherein R 4 is as defined for formula (I).
  • the compound of any of formulae (I), (la), (II), (Ila), (XXV), (XXVa), (XXVI), (XXVIa), (XXVII), (XXVIla), (XXVIII), (XXVIlla), (XIX), (XiXa), (XXX) and (XXXa) is a compound wherein Ring A is not a structure selected from: optionally wherein the ring system is substituted by one or more R 4 , wherein R 4 is as defined for formula (I).
  • the compound is a compound according to any of formulae (I), (la), (II), (Ila), (III), (Illa), (IV), (IVa), (V), (Va), (VI), (Via), (VII), (Vila), (VIII), (Villa), (IX), (IXa) (X), (Xa), (XI), (Xia), (XII), (Xlla), (XIII), (Xllla), (XIV), (XlVa), (XV), (XVa), (XVI), (XVIa), (XVII), (XVIIa) , (XVIII) , (XVIIIa), (XIX), (XIXa), (XX), (XXa), (XXa), (XXII), (XXIIa), (XXIII), (XXII la), (XXIV) and (XXIVa), wherein Ring B is
  • the compound is a compound according to any of formulae (I), (la), (II), (Ila), (III), (Illa), (IV), (IVa), (V), (Va), (VI), (Via), (VII), (Vila), (VIII), (Villa), (IX), (IXa) (X), (Xa), (XI), (Xia), (XII), (Xlla), (XIII), (Xllla), (XIV), (XlVa), (XV), (XVa), (XVI), (XVIa), (XVII), (XVIIa) , (XVIII) , (XVIIIa), (XIX), (XIXa), (XX), (XXa), (XXI), (XVIIa) , (XVIII) , (XVIIIa), (XIX), (XIXa), (XX), (Xa), (XXa), (XXI), (XIa), (X
  • the compound is a compound according to any of formulae (I), (la), (II), (Ila), (III), (Illa), (IV), (IVa), (V), (Va), (VI), (Via), (VII), (Vila), (VIII), (Villa), (IX), (IXa) (X), (Xa), (XI), (Xia), (XII), (Xlla), (XIII), (Xllla), (XIV), (XlVa), (XV), (XVa), (XVI), (XVIa), (XVII), (XVIIa) , (XVIII) , (XVIIIa), (XIX), (XiXa), (XX), (Xa), (XXI), (XVIIa) , (XVIII) , (XVIIIa), (XIX), (XiXa), (XX), (Xa), (XXI), (XIa), (XVIII) , (
  • the compound is a compound according to any of formulae (I), (la), (II), (Ila), (III), (Illa), (IV), (IVa), (V), (Va), (VI), (Via), (VII), (Vila), (VIII), (Villa), (IX), (IXa) (X), (Xa), (XI), (Xia), (XII), (Xlla), (XIII), (Xllla), (XIV), (XlVa), (XV), (XVa), (XVI), (XVIa), (XVII), (XVIIa) , (XVIII) , (XVIIIa), (XIX), (XiXa), (XX), (Xa), (XXI), (XVIIa) , (XVIII) , (XVIIIa), (XIX), (XiXa), (XX), (Xa), (XXI), (XIa), (XVIII) , (
  • the compound is a compound according to any of formulae (III), (Illa), (IV), (IVa), (V), (Va), (VI), (Via), (VII), (Vila), (VIII), (Villa), (IX), (IXa) (X), (Xa), (XI), (Xia), (XII), (Xlla), (XIII), (Xllla), (XIV), (XlVa), (XV), (XVa), (XVI), (XVIa), (XVII), (XVIIa) , (XVIII) , (XVIIIa), (XIX), (XIXa), (XX) and (XXa), wherein each R 4a is independently as defined in any of 175 to 181.
  • L is a bond; R 2 (when present) is H; and R 3 is selected from methyl, ethyl and -CH2CH2F.
  • L is a bond; R 2 (when present) is H; and R 3 is methyl.
  • R 2 (when present) is H; and R 3 is ethyl.
  • L is a bond; R 2 (when present) is H; and R 3 is -CH2CH2F. In these embodiments it may be that R 12 is H.
  • the compound is a compound according to any of formulae (XXV), (XXVa), (XXVI), (XXVIa), (XXVII), (XXVIla), (XXVIII), (XXVIlla), (XIX), (XIXa), (XXX), (XXXa), (XXXI), (XXXIa), (XXXIb), (XXXIc), (XXXII), (XXXIIa), (XXXIIb) (XXXIIc), (XXXIII), (XXXIIIa), (XXXIIIb), (XXIIIc) (XXXIV), (XXXIVa), (XXXIVb), (XXIVc), (XXXV), (XXXVa), (XXXVb), (XXXVc), (XXXVI), (XXVIa), (XXVIb) (XXXVI), (XVIa), (XXVIb) (
  • L is a bond; R 2 (when present) is H; and R 3 is selected from methyl, ethyl and -CH2CH2F.
  • L is a bond; R 2 (when present) is H; and R 3 is methyl.
  • R 2 (when present) is H; and R 3 is ethyl.
  • L is a bond; R 2 (when present) is H; and R 3 is -CH2CH2F. In these embodiments it may be that R 12 is H.
  • the compound is a compound according to any of formulae (XXXI), (XXXIa), (XXXIb), (XXXIc), (XXXII), (XXXIIa), (XXXIIb), (XXXIIc), (XXXV), (XXXVa), (XXXVb), (XXXVc), (XXXVI), (XXXVIa), (XXXVIb) and (XXXVIc), wherein each R 4a is independently selected from: halo (e.g.
  • each R 10a is independently selected from: halo, C1.3 alkyl, C1.3 haloalkyl, -OC1.3 alkyl and -OC1.3 haloalkyl.
  • each R 4a is independently selected from: halo, - CN and C1.3 alkyl
  • each R 10a is independently selected from: halo, C1.3 alkyl, C1.3 haloalkyl, -OC1.3 alkyl and -OC1.3 haloalkyl.
  • each R 4a is independently selected from: fluoro, chloro, -CN, methyl and -OMe; and each R 10a is independently selected from: fluoro, chloro, methyl, -CF3, methoxy, -OCF3 and -OCHF2.
  • L is a bond; R 2 (when present) is H; and R 3 is selected from methyl, ethyl and -CH2CH2F.
  • R 2 (when present) is H; and R 3 is methyl.
  • R 2 (when present) is H; and R 3 is ethyl.
  • L is a bond; R 2 (when present) is H; and R 3 is -CH2CH2F.
  • R 12 is H.
  • the compound is of the formula (XXXII), (XXXIIa), (XXXIIb) or (XXXIIc), wherein the group of the formula: this embodiment it may be that each R 10a is independently as defined in any of 215 to 228.
  • each R 10a may be independently selected from: fluoro, chloro, methyl, -CF3, methoxy, -OCF3 and -OCHF2.
  • L is a bond
  • R 2 (when present) is H
  • R 3 is selected from methyl, ethyl and -CH2CH2F.
  • L is a bond; R 2 (when present) is H; and R 3 is selected from methyl, ethyl and -CH2CH2F.
  • L is a bond; R 2 (when present) is H; and R 3 is methyl.
  • R 2 (when present) is H; and R 3 is ethyl.
  • L is a bond; R 2 (when present) is H; and R 3 is -CH2CH2F. In these embodiments it may be that R 12 is H.
  • the compound is of the formula (XXXII), (XXXIIa), (XXXIIb) or (XXXIIc), wherein the group of the formula: independently as defined in any of 215 to 228.
  • each R 10a may be independently selected from: fluoro, chloro, methyl, -CF3, methoxy, -OCF3 and -OCHF2.
  • L is a bond; R 2 (when present) is H; and R 3 is selected from methyl, ethyl and -CH2CH2F.
  • L is a bond; R 2 (when present) is H; and R 3 is methyl.
  • R 2 (when present) is H; and R 3 is ethyl.
  • L is a bond; R 2 (when present) is H; and R 3 is -CH2CH2F. In these embodiments it may be that R 12 is H.
  • the compound is of the formula (XXI), (XXIa), (XII), (Xlla), (XXXIII), (XXXIIIa), (XXXIIIb), (XXXIIIc) (XXXIV), (XXXIVa), (XXXIVb) or (XXXIVc) wherein the group of the formula: , wherein R 4a is selected from: halo, -CN, Ci- 6 alkyl, Ci- 6 haloalkyl, -OR 5 , -NR 5 R 6 , -C(O)R 5 , -C(O)OR 5 , and - C(O)NR 5 R 6 ; and each R 10 (or R 10a or R 10b as appropriate for each formula) is independently as defined in any of 215 to 228.
  • R 4a is selected from: halo, -CN and C1.3 alkyl.
  • R 4a is selected from: F, -CN and methyl.
  • each R 10 (or R 10a or R 10b as appropriate for each formula) is independently selected from: halo, C1.3 alkyl, C1.3 haloalkyl, -OC1.3 alkyl and -OC1.3 haloalkyl.
  • each R 10a or R 10b may be independently selected from: fluoro, chloro, methyl, -CF3, methoxy and -OCF3.
  • L is a bond; R 2 (when present) is H; and R 3 is selected from methyl, ethyl and -CH2CH2F.
  • L is a bond; R 2 (when present) is H; and R 3 is methyl.
  • R 2 (when present) is H; and R 3 is ethyl.
  • L is a bond; R 2 (when present) is H; and R 3 is -CH2CH2F.
  • the compound is of the formula (I), (la), (II), (Ila), (XXV), (XXVa), (XXVI), (XXVIa), (XXVII), (XXVIla), (XXVIII), (XXVIlla), (XXIX), (XXX) and (XXXa), Ring A is selected from: and L is a bond.
  • L is a bond; R 2 (when present) is H; and R 3 is selected from methyl, ethyl and -CH2CH2F.
  • L is a bond; R 2 (when present) is H; and R 3 is methyl.
  • R 2 (when present) is H; and R 3 is ethyl.
  • L is a bond; R 2 (when present) is H; and R 3 is -CH2CH2F. In these embodiments it may be that R 12 is H.
  • the compound is of the formula (XVII), (XVIIa), (XVIII) or (XVI I la),
  • Ring D is selected from: benzene, pyridine, pyrimidine, pyridazine and pyrazine
  • Ring E is selected from: pyrrole, imidazole, pyrazole, triazole and tetrazole, and wherein the 9-membered fused bicyclic heteroaryl ring formed by Ring D and Ring E is attached to -L- by a ring atom in Ring D.
  • the compound is of the formula (XVII), (XVIIa), (XVIII) or
  • each R 4a is independently as defined in any of 175 to 181 , and wherein the 9-membered fused bicyclic heteroaryl ring formed by Ring D and Ring E is attached to -L- by a ring atom in Ring D.
  • the compound is of the formula (XVII), (XVIIa), (XVIII) or
  • Ring D and Ring E is attached to -L- by a ring atom in Ring D.
  • the compound is of the formula (XVII), (XVIIa), (XVIII) or
  • XVI I la the group of the formula: wherein: Xi and X2 are each independently N, or C, provided at least one of Xi and X2 is N; and Ring E is a fused 5-membered heteroaryl containing at least one (e.g. 1 , 2, or 3) ring nitrogen, and wherein the 9-membered fused bicyclic heteroaryl ring formed by Ring D and Ring E is attached to -L- by a ring atom in Ring D.
  • each of which is optionally substituted with 1 , 2 or 3 (e.g. 1 or 2) R 4a , wherein each R 4a is independently as defined in any of 175 to 181.
  • R 4a is independently as defined in any of 175 to 181.
  • the 9-membered fused bicyclic heteroaryl ring formed by Ring D and Ring E is selected from: optionally substituted with 1 , 2 or 3 (e.g. 1 or 2) R 4a , wherein each R 4a is independently as defined in any of 175 to 181 .
  • each R 4a is independently selected from: halo, C1.3 alkyl and -OC1.3 alkyl.
  • each R 4a is independently selected from: F, Cl, methyl and methoxy.
  • L is a bond; R 2 (when present) is H; and R 3 is selected from methyl, ethyl and -CH2CH2F.
  • R 2 (when present) is H; and R 3 is methyl.
  • L is a bond; R 2 (when present) is H; and R 3 is ethyl.
  • L is a bond; R 2 (when present) is H; and R 3 is -CH2CH2F.
  • the compound is of the formula (XIX), (XIXa), (XX) or (XXa)
  • Ring F is selected from: pyrrole, imidazole, pyrazole, triazole and tetrazole
  • Ring G is selected from: benzene, pyridine, pyrimidine, pyridazine and pyrazine, and wherein the 9-membered fused bicyclic heteroaryl ring formed by Ring F and Ring G is attached to -L- by a ring atom in Ring F.
  • the compound is of the formula (XIX), (XIXa), (XX) or
  • (XXa) the group of the formula: wherein the 9-membered fused bicyclic heteroaryl ring formed by Ring G and the imidazole ring is attached to -L- by a ring atom in the imidazole ring.
  • each of which is optionally substituted with 1, 2 or 3 (e.g. 1 or 2) R 4a , wherein each R 4a is independently as defined in any of 175 to 181, wherein the 9-membered fused bicyclic heteroaryl ring formed by Ring G and the imidazole ring is attached to -L- by a ring atom in the imidazole ring.
  • the 9-membered fused bicyclic heteroaryl ring formed by Ring G and the imidazole ring is selected from: ptionally substituted with 1 , 2 or 3 (e.g. 1 or 2) R 4a , wherein each R 4a is independently as defined in any of 175 to 181.
  • each R 4a is independently as defined in any of 175 to 181, wherein the ring is attached to -L- by a ring atom in the imidazole ring.
  • the ring may be o which is optionally substituted with 1 , 2 or 3
  • R 4a (e.g. 1 or 2) R 4a , wherein each R 4a is independently as defined in any of 175 to 181.
  • each R 4a is independently selected from: halo, C1.3 alkyl and -OC1.3 alkyl.
  • each R 4a is independently selected from: F, Cl, methyl and methoxy.
  • L is a bond; R 2 (when present) is H; and R 3 is selected from: methyl, ethyl and -CH2CH2F.
  • R 2 (when present) is H; and R 3 is methyl.
  • L is a bond; R 2 (when present) is H; and R 3 is ethyl.
  • L is a bond; R 2 (when present) is H; and R 3 is -CH2CH2F.
  • R 4a , and a are as defined for each formula therein.
  • R 12 , R 4a , and a are as defined for each formula therein.
  • R 4a , and a are as defined for each formula therein.
  • R 12 , R 4a , and a are as defined for each formula therein. [00268] In certain embodiments of the formulae (I), (la), (II), (Ila), (XIII), (Xllla), (XIV), and
  • R 12 , R 4a , and a are as defined for each formula therein.
  • R 12 , R 4a , and a are as defined for each formula therein.
  • 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.
  • 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.
  • Compounds of the invention may exhibit one or more beneficial properties.
  • compounds of the invention demonstrate one or more beneficial Absorption, Distribution, Metabolism, and Excretion (ADME) property.
  • ADME Absorption, Distribution, Metabolism, and Excretion
  • compounds of the invention exhibit one or more beneficial PK and or PD property.
  • compounds of the invention may exhibit improved solubility, plasma protein binding, mouse liver microsomes (MLM), human liver microsomes (HLM), CYP inhibition, and/or selectivity for Cav2.3 over Cav2.1.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt or N-oxide thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises a compound selected from a compound according to any of formulae (I) to (XXXXII) or a pharmaceutically acceptable salt or N-oxide thereof.
  • the pharmaceutical composition comprises a compound selected from a compound according to any of formulae (I) to (XXXXII), or a pharmaceutically acceptable salt or N-oxide thereof,.
  • 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).
  • oral use for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups
  • compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • lower doses will be administered when a parenteral route is employed.
  • a dose in the range for example, 0.1 mg/kg to 30 mg/kg body weight may be suitable.
  • a dose in the range for example, 0.05 mg/kg to 25 mg/kg body weight may be suitable.
  • 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.
  • unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of the invention.
  • the compound of the invention is administered parenterally, for example by intravenous administration.
  • the compound of the invention is administered orally.
  • the present invention provides a compound of the invention, or a pharmaceutically acceptable salt or N-oxide thereof, for use as a medicament.
  • a further aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt or N-oxide thereof, for use in the prevention or treatment of a disease or medical disorder mediated by Cav2.3.
  • a compound of the invention or a pharmaceutically acceptable salt or N-oxide thereof, for the manufacture of a medicament for the prevention or treatment of a disease or medical disorder mediated by Cav2.3.
  • 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 or N-oxide 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 or N-oxide thereof.
  • 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.
  • a compound of the invention 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.
  • the disease or medical disorder is a neurodegenerative disease.
  • 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.
  • a compound of the invention is for use in the treatment of Parkinson’s disease.
  • 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. [00296] 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.
  • SN dopaminergic substantia nigra
  • a compound of the invention is for use in the treatment or prevention of one or more symptoms of a neurodegenerative disease.
  • 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.
  • a compound of the invention is for use in the treatment of a neurodevelopmental disorder.
  • the neurodevelopmental disorder is selected from: CACNA1E Gain-of-function Syndrome (DEE69), CDKL5 Deficiency (DEE2), Phelan-McDermid syndrome, 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).
  • DEE developmental and epileptic encephalopathies
  • 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).
  • ILAE International League against Epilepsy
  • 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).
  • DEE69 CACNA1E Gain-of-function Syndrome
  • DEE2A CDKL5 Deficiency
  • DEE9 caused by mutation
  • a compound of the invention is for use in the treatment or prevention of DEE is Dravet syndrome (DEE6A).
  • a compound of the invention is for use in the treatment or prevention of CACNA1E Gain-of-function Syndrome (DEE69) or CDKL5 Deficiency (DEE2).
  • 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.
  • 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.
  • a compound of the invention is for use in the treatment of epilepsy.
  • 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.
  • 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.
  • a compound of the invention is for use in the treatment of an epilepsy syndrome.
  • 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, Je arms 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
  • 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).
  • 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.
  • AED anti-epileptic drug
  • the drug-resistant epilepsy may be any of the forms of epilepsy described herein that is, or has become resistant to treatment with one or more (e.g. at least two) anti-epileptic therapy.
  • the drug- resista nt epilepsy is a drug-resistant focal epilepsy.
  • a compound of the invention is for use in preventing or treating seizures.
  • a compound of the invention is for use in preventing or treating an epileptic seizure.
  • 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.
  • a compound of the invention is for use in the prevention or treatment of partial, generalized, convulsive and non- convulsive seizures.
  • 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.
  • a compound of the invention is for use in the treatment of an endocrine disorder.
  • 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.
  • 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.
  • neuropathic pain e.g. peripheral neuropathic pain or central neuropathic pain
  • nociceptive pain e.g. nociceptive pain.
  • a compound of the invention is for use in the treatment or prevention of cerebral vasospasm.
  • a compound of the invention is for use in the treatment or prevention of cerebral vasospasm in a subject who has suffered a cerebral aneurism or aneurysmal subarachnoid haemorrhage.
  • a compound of the invention is for use in the treatment or prevention of cerebral infarction.
  • such selective compounds may be used in the treatment or prevention of any of the diseases or medical disorders described herein.
  • 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.
  • 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,
  • AED anti-ep
  • 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).
  • a dopamine mimetic substances which regulate/modulate the dopamine metabolism, e.g
  • Such combination treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment.
  • Such combination products employ the compounds of this invention within a therapeutically effective dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
  • 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.
  • 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.
  • 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).
  • R 1 is selected from: Ci-e alkyl, C3-6 cycloalkyl, and Cs-e cycloalkyl-Ci-e alkyl-, wherein R 1 is substituted by at least one fluorine; optionally wherein one or more H in R 1 is substituted by D;
  • R 2 is selected from: H, D, Ci-e alkyl and Ci-e haloalkyl; or
  • R 1 and R 2 together with the carbon atom to which they are attached form a C3-6 cycloalkyl substituted with at least one fluorine;
  • R 3 is selected from: H, Ci-e alkyl and Ci-e haloalkyl; optionally wherein one or more H in R 3 is substituted by D;
  • L is selected from: a bond and C1.3 alkylene
  • R 5 and R 6 are each independently selected from: H, Ci-e alkyl, Ci-e haloalkyl and Q 1 , wherein said Ci-e alkyl is optionally substituted by one or more R 8 ; each R 7 and R 8 is independently selected from: halo, -CN, -OR 7A , -S(O) X R 7A , -NR 7A R 7B , C(O)R 7A , -OC(O)R 7A , -C(O)OR 7A , -NR 7A C(O)R 7B , -C(O)NR 7A R 7B and Q 2 ; each Q 1 and Q 2 is independently selected from: C3-6 cycloalkyl, 4- to 7-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl, wherein said C3-6 cycloalkyl, 4- to 7-membered heterocyclyl, phenyl and 5- or 6- membered heteroaryl is optional
  • R 12 is independently selected from H, Ci-e alkyl, Ci-e haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-Ci-6 alkyl-, and COOR 13 ; optionally wherein one or more H in R 12 is substituted by D;
  • R 13 is independently selected from H, Ci-e alkyl, Ci-e haloalkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-Ci-6 alkyl; optionally wherein one or more H in R 13 is substituted by D;
  • Ring A is a monocyclic 6-membered heteroaryl or a 9-membered fused bicyclic heteroaryl, wherein Ring A has 1 to 4 ring nitrogen atoms and wherein Ring A is optionally substituted with one or more R 4 .
  • Ring A is a monocyclic 6-membered heteroaryl, wherein Ring A has 1 , 2 or 3 ring nitrogen atoms and wherein Ring A is optionally substituted with one or more R 4 .
  • Ring A is selected from: thienyl, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, tetrahydropyranyl, optionally substituted with one or more R 4 .
  • P5. The compound according to P1 or P2, wherein Ring A is selected from: substituted with one or more R 4 .
  • each R 4 is independently selected from: halo, -CN, -NO 2 , Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, Q 1 , -OR 5 , -S(O) X R 5 , -NR 5 R 6 , -C(O)R 5 , -OC(O)R 5 , -C(O)OR 5 , -C(O)NR 5 R 6 , -NR 5 SO 2 R 6 , and - SO 2 NR 5 R 6 .
  • each R 4 is independently selected from: halo (e.g. fluoro or chloro), -CN, C1.3 alkyl, -OC1.3 alkyl, -C(O)Ci-3 alkyl, - C(O)NH 2 , -C(O)NH(CI-3 alkyl) and -C(O)N(Ci- 3 alkyl) 2 ; optionally wherein each R 4 is independently selected from: fluoro and -CN.
  • halo e.g. fluoro or chloro
  • -CN C1.3 alkyl, -OC1.3 alkyl, -C(O)Ci-3 alkyl, - C(O)NH 2 , -C(O)NH(CI-3 alkyl) and -C(O)N(Ci- 3 alkyl) 2 ; optionally wherein each R 4 is independently selected from: fluoro and -CN.
  • Ring A is selected from:
  • each R 4a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q 1 , -OR 5 , -S(O) X R 5 , -NR 5 R 6 , -C(O)R 5 , - OC(O)R 5 , -C(O)OR 5 , -NR 5 C(O)R 6 , -C(O)NR 5 R 6 , -NR 5 C(O)OR 6 , -OC(O)NR 5 R 6 , -NR 5 SO 2 R 6 , and -SO 2 NR 5 R 6 , wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl,
  • each R 4a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q 1 , -OR 5 , -S(O) X R 5 , -NR 5 R 6 , -C(O)R 5 , - OC(O)R 5 , -C(O)OR 5 , -NR 5 C(O)R 6 , -C(O)NR 5 R 6 , -NR 5 C(O)OR 6 , -OC(O)NR 5 R 6 , -NR 5 SO 2 R 6 , and -SO 2 NR 5 R 6 , wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q 1
  • X 3 is N or CR 4a ;
  • R 4a is selected from: halo, -CN, -NO2, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C 2-6 alkenyl, C 2-6 alkynyl, Q 1 , -OR 5 , -S(O) X R 5 , -NR 5 R 6 , -C(O)R 5 , -OC(O)R 5 , - C(O)OR 5 , -NR 5 C(O)R 6 , -C(O)NR 5 R 6 , -NR 5 C(O)OR 6 , -OC(O)NR 5 R 6 , -NR 5 SO 2 R 6 , and - SO 2 NR 5 R 6 , wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C 2 .6 alkenyl and C 2 .6 alkynyl is optionally substituted by one or more R 7 .
  • each R 4a is independently selected from: halo (e.g. fluoro or chloro), -CN, C1.3 alkyl, -OC1.3 alkyl, - C(O)Ci- 3 alkyl, -C(O)NH 2 , -C(O)NH(CI- 3 alkyl) and -C(O)N(Ci- 3 alkyl) 2 ; optionally wherein each R 4 is independently selected from: fluoro and -CN.
  • halo e.g. fluoro or chloro
  • -CN C1.3 alkyl, -OC1.3 alkyl, - C(O)Ci- 3 alkyl, -C(O)NH 2 , -C(O)NH(CI- 3 alkyl) and -C(O)N(Ci- 3 alkyl) 2 ; optionally wherein each R 4 is independently selected from: fluoro and -CN.
  • Ring B is selected from:
  • Ring B is selected from:
  • P22 The compound according to any one of P1 to P21 , wherein L is selected from a bond and -CH2-.
  • P24 The compound according to any one of P1 to P23, wherein R 3 is selected from methyl, -CD3, ethyl, and 2-fluoroethyl.
  • P28 The compound according to any one of P1 to P27, wherein R 1 is selected from Ci-e alkyl and C3-6 cycloalkyl, wherein R 1 is substituted by at least one fluorine.
  • P29 The compound according to any one of P1 to P27, wherein R 1 is selected from CH 2 F, -CHF 2 , and -CF 3 .
  • P35 A compound selected from: pharmaceutically acceptable salt or N-oxide thereof.
  • P36 A compound selected from Compound List 1 in the description, or a pharmaceutically acceptable salt or N-oxide thereof.
  • a pharmaceutical composition comprising a compound according to any one of P1 to P36, or a pharmaceutically acceptable salt or N-oxide thereof, and a pharmaceutically acceptable excipient.
  • P40 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 P1 to P36, or a pharmaceutically acceptable salt or N-oxide thereof.
  • P41 A compound according to any one of P1 to P36, or a pharmaceutically acceptable salt or N-oxide 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.
  • a 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
  • R 1 is selected from: Ci-e alkyl, C3-6 cycloalkyl, and Cs-e cycloalkyl-Ci-e alkyl-, wherein R 1 is substituted by at least one fluorine; optionally wherein one or more H in R 1 is substituted by D;
  • R 2 is selected from: H, D, Ci-e alkyl and Ci-e haloalkyl; or
  • R 1 and R 2 together with the carbon atom to which they are attached form a C3-6 cycloalkyl substituted with at least one fluorine;
  • R 3 is selected from: H, Ci-e alkyl, and Ci-e haloalkyl; optionally wherein one or more H in R 3 is substituted by D;
  • L is selected from: a bond and C1.3 alkylene
  • R 5 and R 6 are each independently selected from: H, Ci-e alkyl, Ci-e haloalkyl and Q 1 , wherein said Ci-e alkyl is optionally substituted by one or more R 8 ; each R 7 and R 8 is independently selected from: halo, -CN, -OR 7A , -S(O) X R 7A , -NR 7A R 7B , C(O)R 7A , -OC(O)R 7A , -C(O)OR 7A , -NR 7A C(O)R 7B , -C(O)NR 7A R 7B and Q 2 ; each Q 1 and Q 2 is independently selected from: C3-6 cycloalkyl, 4- to 7-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl, wherein said C3-6 cycloalkyl, 4- to 7-membered heterocyclyl, phenyl and 5- or 6- membered heteroaryl is optional
  • R 12 is independently selected from H, Ci-e alkyl, Ci-e haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-Ci-6 alkyl-, and COOR 13 ; optionally wherein one or more H in R 12 is substituted by D;
  • R 13 is independently selected from H, Ci-e alkyl, Ci-e haloalkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-Ci-6 alkyl; optionally wherein one or more H in R 13 is substituted by D;
  • Ring A is a monocyclic 6-membered heteroaryl or a 9-membered fused bicyclic heteroaryl, wherein Ring A has 1 to 4 ring nitrogen atoms and wherein Ring A is optionally substituted with one or more R 4 .
  • each R 10 is independently selected from: halo, C1.3 alkyl, C1.3 haloalkyl, -OC1.3 alkyl and -OC1.3 haloalkyl.
  • Q5 The compound according to any one of Q1 to Q4, wherein R 3 is selected from methyl, -CD3, ethyl, and 2-fluoroethyl.
  • a pharmaceutical composition comprising a compound according to any one of Q1 to Q8, or a pharmaceutically acceptable salt or N-oxide thereof, and a pharmaceutically acceptable excipient.
  • 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.
  • 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.
  • 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).
  • 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-
  • MES Maximal Electroshock Stimulation
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • a suitable acid such as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid
  • an aryl methoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example BFs.OEt2.
  • a suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
  • 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.
  • 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.
  • an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon.
  • 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.
  • a base such as sodium hydroxide
  • 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.
  • Resins may also be used as a protecting group.
  • Compounds of formula (la’) can be obtained from compounds of formula (lc’) and/or (lg’) wherein R 1 , R 2 , R 3 , ring A, ring B, and L are as defined above for any of formulae (I) to (XXXXII), and a suitable oxo transfer reagent such as iodosobenzene in the presence of a suitable nitrogen source such as ammonium formate.
  • reaction of a compound of formula (lc’) is carried out in a protic solvent for example, MeOH, EtOH in the presence of AcOH, and using an oxo transfer reagent such as iodosobenzene and suitable nitrogen source such as ammonium formate.
  • a protic solvent for example, MeOH, EtOH in the presence of AcOH, and using an oxo transfer reagent such as iodosobenzene and suitable nitrogen source such as ammonium formate.
  • oxo transfer reagent such as iodosobenzene and suitable nitrogen source such as ammonium formate.
  • reaction of a compound of formula (Id’) is carried out with compound (le’/lf’) in an aprotic solvent, for example THF or DCM, in the presence of an organic base such as pyridine, DIPEA, TEA, or DBU.
  • an organic base such as pyridine, DIPEA, TEA, or DBU.
  • the reaction may conveniently be carried out at ambient temperature for 2h to 16h.
  • reaction of a compound of formula (lid”) is carried out with compound (le’/lf’) in an aprotic solvent, for example MeOH, DCM, CHCI3 and mixture of both MeOH/DCM or CHCI3 in the presence of an AgNO3.
  • an aprotic solvent for example MeOH, DCM, CHCI3 and mixture of both MeOH/DCM or CHCI3 in the presence of an AgNO3.
  • the reaction may conveniently be carried out at ambient temperature for 1 h to 16h.
  • Sulfide compound (lib’) wherein M is defined as an aliphatic long-chain ester, may be obtained by reaction of the respective bromo derivatives (Ila’) with an appropriate thiol compound in a sulfur-carbon bond forming reaction in an inert atmosphere in the presence of Pd catalyst.
  • Examples of such reaction include reaction of an aromatic bromo, chloro or iodo compound with a sulfur compound, e.g. 2-ethylhexyl-3- mercaptopropanoate.
  • the reaction may be performed in a suitable solvent, such as, 1 ,4- dioxane, toluene, benzene, DMF, DME, DMA, preferably at temperatures between RT and 150 0C.
  • a suitable solvent such as, 1 ,4- dioxane, toluene, benzene, DMF, DME, DMA, preferably at temperatures between RT and 150 0C.
  • 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, Pd(dba)2, or Pd2(dba)s can undergo ligand dissociation to form the active species.
  • Phosphines can be added to ligandless Pd(0).
  • Sulfide compounds can be obtained by the reaction of the respective sulfide derivatives (lib’) in a sulfur-carbon bond cleavage reaction in an inert atmosphere in the presence of a Lewis acid, such as AlCh.
  • Suitable solvents for this type of conversion include, toluene, benzene, DCM, preferably at 0 °C to RT.
  • Hypochlorothioites may be obtained by reaction of the respective mercapto derivatives (He’) in a sulfur-chlorine bond forming reaction.
  • Non-limiting examples of such reaction include reaction with chlorine source in the presence of ACN using NCS, at ambient temperature.
  • the reaction may be performed in a suitable solvent, such as, DCM, THF, acetic acid, diethyl ether, toluene preferably at temperatures between -20°C and RT.
  • Disulfane (Hd”) may be obtained by reaction of the respective thiol derivatives (He’) in a sulfur-sulfur bond forming reaction.
  • Non-limiting examples of such reaction include reaction with:
  • halogen or iodine 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.
  • the reaction may be performed in a suitable solvent, such as, acetonitrile, DCM, tetrahydrofuran, acetic acid, diethyl ether, toluene preferably at temperatures between 0°C and RT.
  • a suitable solvent such as, acetonitrile, DCM, tetrahydrofuran, acetic acid, diethyl ether, toluene preferably at temperatures between 0°C and RT.
  • Aminothioderivative (lc’) can be synthesized by reaction of the corresponding hypochlorothioite (Id’) with the amine part of compound formula (le’) or (If’) using an aprotic solvent for example THF, 1 ,4-Dioxane in the presence of an organic base such as pyridine, TEA, DI PEA, DBU at RT for 2h to 16h.
  • an aprotic solvent for example THF, 1 ,4-Dioxane
  • organic base such as pyridine, TEA, DI PEA, DBU
  • Aminothioderivative (lc’) can also be synthesized by reaction of the corresponding disulfide derivative (lid”) with the amine part of compound formula (le’) or (If’) using an protic solvent for example MeOH, chlorinated solvent such as DCM, CHCI3 or mixture of both protic and chlorinated solvent in the presence of AgNO3 at RT for 1h to 16h.
  • an protic solvent for example MeOH, chlorinated solvent such as DCM, CHCI3 or mixture of both protic and chlorinated solvent in the presence of AgNO3 at RT for 1h to 16h.
  • Sulfonimidamides (la’) can be synthesized by reaction of corresponding aminothioderivative (lc’) using an oxo transfer reagent such as iodosobenzene and a suitable nitrogen source such as ammonium formate in the presence of a catalytic amount of AcOH in, e.g., MeOH or EtOH at ambient temperature for 12 h.
  • an oxo transfer reagent such as iodosobenzene and a suitable nitrogen source such as ammonium formate
  • Sulfonimidamides of formula (I) where R 12 is selected from Ci-e alkyl, Ci-e haloalkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-Ci-6 alkyl- can be synthesized by reaction of corresponding sulfonimidamides (la’), by reaction with an R 12 -X species where X is a suitable leaving group such as Br, Cl, methanesulfonyl using an aprotic solvent for example THF, 1 ,4-Dioxane in the presence of an organic base such as pyridine, TEA, DIPEA, DBU at RT for 2h to 16h.
  • an organic base such as pyridine, TEA, DIPEA, DBU at RT for 2h to 16h.
  • Compounds of formula (la’) can also be obtained from compounds of formula (lg’) wherein ring A, ring B, R 1 , R 2 , R 3 and L are as defined above for any of formulae (I) to (XXXXII), and a suitable urea deprotecting reagent such as pTSA and TFA, MsOH and TFA, CAS and TFA or a derivative thereof in the presence of a suitable polar, strongly hydrogen bond-donating solvent such as 1 ,1 ,1 ,3,3,3-Hexafluoroisopropanol (HFIP).
  • a suitable urea deprotecting reagent such as pTSA and TFA, MsOH and TFA, CAS and TFA or a derivative thereof in the presence of a suitable polar, strongly hydrogen bond-donating solvent such as 1 ,1 ,1 ,3,3,3-Hexafluoroisopropanol (HFIP).
  • Compounds of formula (Ig’) can be obtained from compounds of formula (lh’) wherein ring A, ring B, R 1 , R 2 , R 3 and L are as defined above for any of formulae (I) to (XXXXII), and a suitable alkyl halide such as R3-X in the presence of a suitable organic and inorganic base such as CS2CO3, NaH, tBuOK.
  • Compounds of formula (lh’) can be obtained by reacting compounds of formula (li’) with corresponding amine sources (If), wherein R 1 , R 2 , L, ring A and ring B are as defined above for any of formulae (I) to (XXXXII), except that any functional group is protected, if necessary.
  • Suitable bases for this type of conversion include LiHMDS, NaHMDS, KHMDS and turbo Grignard.
  • Suitable aprotic solvents for this type of conversion include THF, 1 ,4- Dioxane, DMSO, and DMAc preferably at temperature 0 oC to rt for 8h to 24h.
  • Compounds of formula (li’) can be obtained from compounds of formula (lj”) and a suitable halogenating agent such as NCS, NBS and NFSI in the presence of a suitable organic and inorganic base such as CS2CO3, NaH, tBuOK, LiHMDS, iPrMgBr, wherein ring A and L are as defined above for any of formulae (I) to (XXXXII).
  • a suitable halogenating agent such as NCS, NBS and NFSI
  • a suitable organic and inorganic base such as CS2CO3, NaH, tBuOK, LiHMDS, iPrMgBr, wherein ring A and L are as defined above for any of formulae (I) to (XXXXII).
  • Compounds of formula (lj”) can be obtained from compounds of formula (lj’) and a suitable sulfinamide protecting agent such as TBDMS-CI, TBDPS-CI and DIPC-CI in the presence of a suitable inorganic base such as CS2CO3, NaH, tBuOK, wherein ring A and L are as defined above for any of formulae (I) to (XXXXII).
  • a suitable sulfinamide protecting agent such as TBDMS-CI, TBDPS-CI and DIPC-CI in the presence of a suitable inorganic base such as CS2CO3, NaH, tBuOK, wherein ring A and L are as defined above for any of formulae (I) to (XXXXII).
  • Compounds of formula (lj’) can be obtained from compounds of formula (Ik’”) and a suitable S-C bond cleaved product in the presence of a suitable organic and inorganic base such as K2CO3, Na2COs, NaOMe and NaOEt, wherein M is defined as an aliphatic long-chain ester, e.g. 2-ethylhexyl 3-mercaptopropanoate and ring A, and L, are as defined above for any of formulae (I) to (XXXXII).
  • a suitable organic and inorganic base such as K2CO3, Na2COs, NaOMe and NaOEt
  • M is defined as an aliphatic long-chain ester, e.g. 2-ethylhexyl 3-mercaptopropanoate and ring A, and L, are as defined above for any of formulae (I) to (XXXXII).
  • Compounds of formula (Ik’”) can be obtained from compounds of formula (Ik”) and a suitable oxo transfer reagent such as iodosobenzene in the presence of a suitable nitrogen source such as ammonium formate, wherein M is an aliphatic long-chain ester, e.g. 2-ethylhexyl 3-mercaptopropanoate and ring A and L, are as defined above for any of formulae (I) to (XXXXII).
  • a suitable oxo transfer reagent such as iodosobenzene in the presence of a suitable nitrogen source such as ammonium formate
  • M is an aliphatic long-chain ester, e.g. 2-ethylhexyl 3-mercaptopropanoate and ring A and L, are as defined above for any of formulae (I) to (XXXXII).
  • Sulfide compound (Ik”) may be obtained by reaction of the respective bromo derivatives (Ila’) in a sulfur-carbon bond forming reaction in an inert atmosphere in the presence of Pd catalyst.
  • Examples of such reaction include reaction with aromatic bromo, chloro or iodo compound react with sulfur compound e.g. 2-ethylhexyl 3- mercaptopropanoate.
  • the reaction may be performed in a suitable solvent, such as, 1 ,4- dioxane, toluene, benzene, DMF, DME, DMA solution preferably at temperatures between rt and 150 °C.
  • the active palladium catalyst is believed to be Pd (0) complex, which can be generated in a variety of ways.
  • Pd (0) sources such as, Pd(PPhs)4 or Pd2(dba)scan undergo ligand dissociation to form the active species.
  • Phosphines can be added to ligand less palladium (0).
  • Sulfonimidoyl propanoate (Ik’”) can be synthesized by reaction of corresponding thioderivative (Ik”) using oxo transfer reagent iodosobenzene and suitable amine source such as ammonium formate, ammonia in the presence of catalytic amount of AcOH under protic solvent MeOH, EtOH, HFIP, IPA at ambient temperature for 30 min to 2h.
  • Sulfinamide compound (lj’) can be obtained by the reaction of the respective sulfide derivatives (Ik’”) in a sulfur-carbon bond cleavage reaction under inert atmosphere in the presence of inorganic or organic base.
  • Suitable bases for this type of conversion used include, for example, NaOEt, NaOMe, K2CO3, Na2COs, ‘BuONa and ‘BuOK.
  • Suitable solvents for this type of conversion include, for example, EtOH, MeOH, THF, MeCN preferably at temperatures between 0°C and RT.
  • Sulfinamide protection compound (lj”) can be obtained by the reaction of the respective Sulfinamide compound (lj’) with corresponding protecting reagent such as TBDMS-CI, TBDPS-CI and DIPC-CI in the presence of a suitable inorganic base such as CS2CO3, NaH, ‘BuOK.
  • suitable inorganic base such as CS2CO3, NaH, ‘BuOK.
  • suitable solvents for this type of conversion include, for example, THF, DMF, DMAc, DMSO preferably at temperatures between 0°C and RT.
  • Sulfonimidoyl halide (li’) can be obtained by the reaction of respective sulfinamide protection compound (lj”) with corresponding halogenating reagent such as NCS, NBS and NFSI or a derivative thereof; in the presence of a suitable inorganic base such as CS2CO3, NaH, ‘BuOK.
  • suitable solvents for this type of conversion include, for example, THF, DMF, DMAc, DMSO preferably at temperatures between 0°C and RT.
  • Sulfonimidamide (lh’) can be synthesized by reaction of corresponding sulfonimidoyl halide (li’) with amine part of compound formula (If).
  • Suitable bases for this type of conversion include LiHMDS, NaHMDS, KHMDS and turbo Grignard.
  • Suitable aprotic solvents for this type of conversion include THF, 1 ,4-Dioxane, DMSO, and DMAc preferably at temperature 0 °C to rt for 8h to 24h.
  • N-alkylation sulfonimidamide (lg’) can be performed by reaction of corresponding sulfonimidamide (lh’) with alkyl halide part of compound formula (R3-X).
  • Suitable bases for this type of conversion include CS2CO3, NaH, LiHMDS, and turbo Grignard.
  • Suitable aprotic solvents for this type of conversion include THF, DMF, DMSO, and DMAc preferably at temperature 0 °C to rt for 1h to 4h.
  • Sulfonimidamide (Ila’) can be obtained by deprotection of corresponding N- alkylated sulfonimidamide (lg’) using mixture of acids such as pTSA and TFA, MsOH and TFA, CAS and TFA or a derivative thereof; In the presence of a polar, strongly hydrogen bond-donating solvent such as 1 ,1 ,1 ,3,3,3-Hexafluoroisopropanol (HFIP) at elevated temperature 40 °C to 70 °C rt for 16h to 48h.
  • a polar, strongly hydrogen bond-donating solvent such as 1 ,1 ,1 ,3,3,3-Hexafluoroisopropanol (HFIP)
  • HATLI 1-[bis(dimethylamino)methylene]-1 H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate
  • 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.
  • 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.
  • 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.
  • the HPLC measurement was performed using Shimadzu HPLC comprising a binary pump with degasser, a sample manager a dual channel UV detector and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer.
  • the MS detector (Applied Biosystems API2000/2000 Trap) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 800 in 0.40 second. The ion spray voltage 5500 V in positive and 4500 V in negative ionization mode and the source temperature was maintained at 300 °C and Declusturing Potential 8-50 V depending on compound. Data acquisition was performed with Analyst 1.6.3 Software.
  • Reversed phase HPLC was carried out on a Waters Xbridge C18/ Agilent Zorbax C18 column (5 pm, 50 x 4.6 mm) with a flow rate of 1.20 ml/min.
  • Two mobile phases were used, mobile phase A: 10mm Ammonium Acetate in water; mobile phase B: ACN, and they were employed to run a gradient condition from 10 % B to 30 % B in 1.50 minutes, and from 30 % to 90 % in 1.50 minutes, 90 % B for 1.00 minutes and 10 % B in 1.00 minutes and hold these conditions for 0.10 minutes.
  • Pre run Equilibration Time 0.50 min (Total Run Time 5.10 minutes). An injection volume of 1 pl to 3 pl was used (Depending on the sample concentration).
  • 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).
  • 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 wate); 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Method 12 (K79 3 min) [00381] The HPLC measurement was performed using Agilent 1260 Infinity II LIPLC comprising a quaternary pump with degasser, an sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Agilent SQD) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1200 in 0.20 second. The capillary needle voltage was 4.00 kV in positive and negative ionization mode and the source temperature was maintained at 350 °C.
  • Agilent 1260 Infinity II LIPLC comprising a quaternary pump with degasser, an sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS
  • 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.
  • 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.
  • 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.
  • 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.
  • the HPLC measurement was performed using Waters Acquity UPLC 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.
  • 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 wate); mobile phase B: ACN, and they were employed to run a gradient condition from 50% B for 2.00 min, from 50% B to 95 % B in 6.00 minutes, and 95 % B for 3.00 minutes and 50 % B in 3.00 minutes and hold these conditions for 4.00 minutes.
  • Pre run Equilibration Time 4.00 min (Total Run Time 18.00 minutes). An injection volume of 1 pl to 3 pl was used (Depending on the sample concentration).
  • 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.
  • 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.
  • 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 wate); 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • Carrier Gas - Helium
  • 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.
  • Carrier Gas - Helium Inlet Temperature: 250 °C
  • Example 1 Example 1 and Example 3

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Abstract

Disclosed are compounds of the formula (I) and pharmaceutically acceptable salts thereof, wherein Ring A, Ring B, R1, R2, R3, R12, and L 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 Phelan-McDermid and Fragile X syndromes.

Description

HETEROCYCLIC COMPOUNDS AS MODULATORS OF CAV2.3
[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
5 neurodegenerative conditions such as Parkinson’s disease, focal, drug-resistant forms of epilepsy, and other neurological disorders such as developmental and epileptic encephalopathies, Phelan-McDermid and Fragile X syndromes.
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 as5 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).
[0003] 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 system0 and in endocrine systems (Schneider et al., Pharmaceuticals 2013, 6(6), 759-776, Schneider et al., Pflugers Arch. 2020; 472(7): 811-816).
[0004] 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, particularly5 those within the substantia nigra (SN) neurons (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 in5 Parkinson’s disease. As PARK mutations and also most external factors are global Parkinson’s disease-stressors, additional cell-specific features must also contribute to the Parkinson’s disease-pathophysiology, and in particular to the differential neuronal vulnerability.
[0005] 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 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).
[0006] 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 in 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).
[0007] 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).
[0008] 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), Phelan McDermid syndrome (Reim et al., Front Mol Neurosci. 2017 Feb; 10:26), monogenic developmental and epileptic encephalopathies (DEEs) such as DEE2 and DEE69 (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; Sampedro-Castaneda et al., Nat Comms. 2023 Dec 2023; 14:7830), 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).
[0009] WO2018/228692 discloses that Cav2.3 antagonists are beneficial in the neuroprotective treatment of Parkinson’s disease and other neurodegenerative diseases.
[0010] 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.
[0011] 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
[0012] In accordance with the present inventions there is provided a compound of the formula (I), or a pharmaceutically acceptable salt or N-oxide thereof: wherein:
R1 is selected from: Ci-e alkyl, C3-6 cycloalkyl, and Cs-e cycloalkyl-Ci-e alkyl-, wherein R1 is substituted by at least one fluorine; optionally wherein one or more H in R1 is substituted by D;
R2 is selected from: H, D, Ci-e alkyl and Ci-e haloalkyl; or
R1 and R2 together with the carbon atom to which they are attached form a C3-6 cycloalkyl substituted with at least one fluorine;
R3 is selected from: H, Ci-e alkyl and Ci-e haloalkyl, and C3-6 cycloalkyl; optionally wherein one or more H in R3 is substituted by D, and wherein the C3-6 cycloalkyl is optionally substituted by one or more substituent independently selected halo and C1.3 alkyl;
L is selected from: a bond and C1.3 alkylene;
Ring A is selected from: C3-6 cycloalkyl, 4- to 7-membered heterocyclyl, 5- to 12-membered heteroaryl and Ce- aryl; wherein Ring A is optionally substituted by one or more R4; each R4 is independently selected from: halo, -CN, -NO2, =0, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7;
R5 and R6 are each independently selected from: H, Ci-e alkyl, Ci-e haloalkyl and Q1, wherein said Ci-e alkyl is optionally substituted by one or more R8; each R7 and R8 is independently selected from: halo, -CN, -OR7A, -S(O)XR7A, -NR7AR7B, C(O)R7A, -OC(O)R7A, -C(O)OR7A, -NR7AC(O)R7B, -C(O)NR7AR7B and Q2; each Q1 and Q2 is independently selected from: C3-6 cycloalkyl, 4- to 7-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl, wherein said C3-6 cycloalkyl, 4- to 7-membered heterocyclyl, phenyl and 5- or 6- membered heteroaryl is optionally substituted by one or more R9; each R9 is independently selected from: halo, =0, -CN, -NO2, C1.4 alkyl, C1.4 haloalkyl, - OR9A, -S(O)2R9A, -NR9AR9B, -C(O)R9A, -OC(O)R9A, -C(O)OR9A, -NR9BC(O)R9A, - C(O)NR9AR9B, -NR9BC(O)OR9A, -OC(O)NR9AR9B, -NR9BSO2R9A and -SO2NR9AR9B, wherein said C1.4 alkyl is optionally substituted by 1 or 2 substituents selected from: halo, -CN, -OR9C, -NR9CR9D and -SO2R9C; Ring B is phenyl or a 5- or 6-membered heteroaryl, wherein Ring B is optionally substituted by one or more R10; each R10 is independently selected from: halo, -CN, -NO2, =0, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, -OR10A, -S(O)xR10A, -NR10AR10B, - C(O)R10A, -OC(O)R10A, -C(O)OR10A, -NR10AC(O)R10B, -C(O)NR10AR10B, -NR10AC(O)OR10B, - OC(O)NR10AR10B, -NR10ASO2R10B, and -SO2NR10AR10B, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R11; each R11 is independently selected from: halo, -CN, -OR11A, -NR11AR11B and -SC>2R11A;
R12 is independently selected from H, Ci-e alkyl, Ci-e haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-Ci-6 alkyl-, and COOR13; optionally wherein one or more H in R12 is substituted by D;
R13 is independently selected from H, Ci-e alkyl, Ci-e haloalkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-Ci-6 alkyl; optionally wherein one or more H in R13 is substituted by D;
R7A, R7B, R9A, R9B, R9C, R9D, R10A, R10B, R11A and R11 B are at each occurrence independently selected from: H, C1.4 alkyl and C1.4 haloalkyl; and wherein any -NR5R6, -NR7AR7B, -NR9AR9B, -NR9CR9D, -NR10AR10B, and - NR11AR11B within 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.
[0013] Also provided is a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt or N-oxide thereof, and a pharmaceutically acceptable excipient.
[0014] Also provided is a compound of the invention, or a pharmaceutically acceptable salt or N-oxide thereof, for use as a medicament.
[0015] Also provided is a compound of the invention, or a pharmaceutically acceptable salt or N-oxide thereof, for use in the treatment of a disease or medical disorder mediated by Cav2.3.
[0016] Also provided is the use of a compound of the invention, or a pharmaceutically acceptable salt or N-oxide thereof, for the manufacture of a medicament for the treatment of a disease or medical disorder mediated by Cav2.3. [0017] Also provided is a method of treating a disease or medical disorder mediated by Cav2.3 in a subject in need thereof, the method comprising administering to the subject an effective amount of a compound of the invention, or a pharmaceutically acceptable salt or N-oxide thereof.
[0018] In certain embodiments there is provided a compound of the invention, or a pharmaceutically acceptable salt or N-oxide 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 or N-oxide 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. Further therapeutic uses of the compounds of the invention are set out in the Detailed Description.
DETAILED DESCRIPTION
Definitions
[0019] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.
[0020] Reference herein to a “compound of the invention” is a reference to any of the compounds disclosed herein including compounds of the formulae (I) to (XXXXII), or a compound described in any of the Examples, or a pharmaceutically acceptable salt, N-oxide, solvate, or salt of a solvate of any thereof.
[0021] The term “antagonist” for example “Cav2.3 antagonist” refers to any molecule that is capable of blocking or decreasing the amount of ions, particularly calcium ions through Cav2.3 channels. An antagonist may prevent of inhibit opening of the channel, or otherwise disrupt the normal operation of the channel. The antagonist may act directly on the channel or indirectly, for example by binding to an allosteric site on the channel.
[0022] As used herein, the term “selective antagonist” refers to an antagonist having greater affinity for its target than for one or more related receptors. For example, a “Cav2.3- selective antagonist” has greater affinity for Cav2.3 than for one or more similar calcium-ion channels (e.g., other Cav2, L-type, or N-type family members). The greater affinity of its Cav2.3 target may be, for example, at least: 1.1 -fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 2- fold, 3-fold, 4-fold, 5-fold, 10-fold, 20-fold, 50-fold, 100-fold, 1000-fold, 10000-fold, etc. The selectivity of a compound of the invention for Cav2.3 over other ion channels (e.g. one or more other Cav channels selected from Cav1.2, Cav1.2, Cav1.3, Cav1.4, Cav2.1 , and Cav 2.2) can be assessed using methods analogous to the Cav2.3 channel calcium-influx assay described herein, using cells which express the channels of interest and comparing the IC50 values.
[0023] The terms “treating”, or “treatment” refer to any beneficial effect in the treatment or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; modifying the progression of a disease or condition, making the final point of degeneration less debilitating; improving a patient’s physical or mental 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.
[0024] The term “associated” or “associated with”, “involving” or “mediated by” in the context of a Cav2.3 associated with a disease means that the disease is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) by Cav2.3 channels, or channel activity or function. For example, a symptom of a disease or condition associated with Cav2.3 activity may be a symptom that results (entirely or partially) from an increase in the level of activity of Cav2.3 channels and or increased expression of Cav2.3 channels. A disease or medical disorder associated with a Cav2.3 activity or expression, may be treated with a compound of the invention effective for decreasing the level of activity of Cav2.3 channels, for example by blocking or partially blocking the channel, inhibiting the function of the channel, preventing or inhibiting the expression of the channel and/or degrading the channel.
[0025] An “effective amount” is an amount sufficient to accomplish a stated purpose. For example, an amount sufficient to achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce receptor signalling, increase receptor signalling, reduce one or more symptoms of a disease or condition, or to provide a disease modifying effect (i.e. alter the underlying pathophysiology of the disease). An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, or modify the progression of a disease, which could also be referred to as a “therapeutically effective amount.” A “reduction” of a symptom or symptoms means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s). A “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology, or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms. The full prophylactic 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).
[0026] The therapeutically effective amount of a compound of the invention can be initially estimated from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of achieving the therapeutic effect described herein, as measured using the methods described herein or known in the art.
[0027] Therapeutically effective amounts for use in humans can also be determined from animal models using known methods. For example, a dose for humans can be formulated to achieve a concentration that has been found to be effective in animals. The dosage in humans can be adjusted by monitoring compound effectiveness and adjusting the dosage upwards or downwards, as described above. Adjusting the dose to achieve maximal efficacy in humans based on the methods described above and other methods is well within the capabilities of the ordinarily skilled artisan.
[0028] Dosages may be varied depending upon the requirements of the patient and the compound being employed. The dose administered to a patient, in the context of the present invention should be sufficient to effect a beneficial therapeutic response in the patient over time. The size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. [0029] Dosage amounts and intervals can be adjusted individually to provide levels of the administered compound effective for the particular clinical indication being treated, or in response to a biomarker or other correlate or surrogate end-point of the disease. This will provide a therapeutic regimen that is commensurate with the severity of the individual’s disease state.
[0030] A prophylactic or therapeutic treatment regimen is suitably one that does not cause substantial toxicity and yet is effective to treat the clinical symptoms demonstrated by the particular patient. This determination of a dosage regimen is generally based upon an assessment of the active compound by considering factors such as compound potency, relative bioavailability, patient body weight, presence and severity of adverse side effects, preferred mode of administration and the toxicity profile of the selected agent.
[0031] The term “halo” or “halogen” refers to one of the halogens, group 17 of the periodic table. In particular the term refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to fluorine or chlorine.
[0032] The term Cm-n refers to a group with m to n carbon atoms.
[0033] The term “Ci-e alkyl” refers to a linear or branched hydrocarbon chain containing 1 , 2, 3, 4, 5 or 6 carbon atoms, for example methyl, ethyl, n-propyl, /so-propyl, n-butyl, /so- butyl, sec-butyl, terf-butyl, n-pentyl and n-hexyl. “C1.4 alkyl” similarly refers to such groups containing up to 4 carbon atoms. Alkylene groups are divalent alkyl groups and may likewise be linear or branched and have two points of attachment to the remainder of the molecule. Furthermore, an alkylene group may, for example, correspond to one of those alkyl groups listed in this paragraph. For example, Ci-e alkylene may be -CH2-, -CH2CH2-, -CH2CH(CH3)- , -CH2CH2CH2- or -CH2CH(CHS)CH2-. The alkyl and alkylene groups may be unsubstituted or substituted by one or more substituents. Possible substituents are described herein. For example, substituents for an alkyl or alkylene group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, C1-C4 alkoxy, -NR’R” amino, wherein R’ and R” are independently H or alkyl. Other substituents for the alkyl group may alternatively be used.
[0034] The term “Ci-e haloalkyl”, e.g., “C1.4 haloalkyl”, refers to a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence, for example fluorine, chlorine, bromine, and iodine. The halogen atom may be present at any position on the hydrocarbon chain. For example, Ci-e haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl e.g., 1 -chloromethyl and 2-chloroethyl, trichloroethyl e.g., 1 ,2,2-trichloroethyl, 2,2,2-trichloroethyl, fluoroethyl e.g., 1 -fluoromethyl and 2-fluoroethyl, trifluoroethyl e.g., 1 ,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl. A haloalkyl group may be, for example, -CX3, -CHX2, -CH2CX3,-CH2CHX2 or -CX(CH3)CH3 wherein 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, -CH2CF3 or -CH2CHF2).
[0035] 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- OCH3 and -CH2-O-Si(CH3)3. A heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety may include two optionally different heteroatoms (e.g., O,
N, S, Si, or P). A heteroalkyl moiety may include three optionally different heteroatoms (e.g.,
O, N, S, Si, or P). A heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P).
[0036] The term “C2.6 alkenyl” includes a branched or linear hydrocarbon chain containing at least one double bond and having 2, 3, 4, 5 or 6 carbon atoms. The double bond(s) may be present as the E or Z isomer. The double bond may be at any possible position of the hydrocarbon chain. For example, the “C2.6 alkenyl” may be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl. Alkenylene groups are divalent alkenyl groups and may likewise be linear or branched and have two points of attachment to the remainder of the molecule. Furthermore, an alkenylene group may, for example, correspond to one of those alkenyl groups listed in this paragraph. For example, alkenylene may be -CH=CH-, -CH2CH=CH-, -CH(CH3)CH=CH- or -CH2CH=CH-. Alkenyl and alkenylene groups may unsubstituted or substituted by one or more substituents. Possible substituents are described herein. For example, substituents may be those described above as substituents for alkyl groups.
[0037] 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.
[0038] The term “C3.6 cycloalkyl” includes a saturated hydrocarbon ring system containing 3, 4, 5 or 6 carbon atoms. For example, the “C3-Ce cycloalkyl” may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.1.1]hexane or bicyclo[1.1.1]pentane. Suitably the “C3-Ce cycloalkyl” may be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
[0039] 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-2 H-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.
[0040] The term “heterocyclyl”, “heterocyclic” or “heterocycle” may also include oxosubstituted partially saturated heterocyclic rings which contain a substituted ring nitrogen, such as N-alkyl pyridones. For example, the term “heterocyclyl”, “heterocyclic” or
“heterocycle” may include groups such
[0041] The term “bridged ring systems” includes ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 131-133, 1992. Suitably the bridge is formed between two non- adjacent carbon or nitrogen atoms in the ring system. The bridge connecting the bridgehead atoms may be a bond or comprise one or more atoms. Examples of bridged heterocyclyl ring systems include, aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza- bicyclo[2.2.2]octane, aza-bicyclo[3.2.1]octane, and quinuclidine.
[0042] The term “spiro bi-cyclic ring systems” includes ring systems in which two ring systems share one common spiro carbon atom, i.e., the heterocyclic ring is linked to a further carbocyclic or heterocyclic ring through a single common spiro carbon atom. Examples of spiro ring systems include 3,8-diaza-bicyclo[3.2.1]octane, 2,5-diaza-bicyclo[2.2.1]heptane, 6-azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptane, 2-oxa-6- azaspiro[3.3]heptane, 6-oxa-2-azaspiro[3.4]octane, 2,7-diaza-spiro[4.4]nonane, 2- azaspiro[3.5]nonane, 2-oxa-7-azaspiro[3.5]nonane and 2-oxa-6-azaspiro[3.5]nonane. [0043] “Heterocyclyl-Cm-n alkyl” includes a heterocyclyl group covalently attached to a Cm-n alkylene group, both of which are defined herein; and wherein the Heterocyclyl-Cm-n alkyl group is linked to the remainder of the molecule via a carbon atom in the alkylene group. The groups “aryl-Cm-n alkyl”, “heteroaryl-Cm-n alkyl” and “cycloalkyl-Cm-n alkyl” are defined in the same way.
[0044] “-Cm-n alkyl substituted by -NRR” and “Cm-n alkyl substituted by -OR” similarly refer to an -NRR” or -OR” group covalently attached to a Cm-n alkylene group and wherein the group is linked to the remainder of the molecule via a carbon atom in the alkylene group.
[0045] The term “aromatic” when applied to a substituent as a whole includes a single ring or polycyclic ring system with 4n + 2 electrons in a conjugated TT system within the ring or ring system where all atoms contributing to the conjugated TT system are in the same plane.
[0046] The term “aryl” includes an aromatic hydrocarbon ring system. The ring system has 4n +2 electrons in a conjugated TT system within a ring where all atoms contributing to the conjugated TT system are in the same plane. An aryl may be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently. A fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring. For example, the “aryl” may be a Ce-12 aryl, suitably phenyl or naphthyl. The aryl system itself may be substituted with other groups. The term “aryl” also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring.
[0047] The term “heteroaryl” includes an aromatic mono- or bicyclic ring incorporating one or more (for example 1-4, particularly 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. The ring or ring system has 4n + 2 electrons in a conjugated TT system where all atoms contributing to the conjugated TT system are in the same plane.
[0048] Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members. The heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10-membered bicyclic ring, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings, also referred to as a “fused bicyclic heteroaryl”. Bicyclic heteroaryl groups can be vicinally fused, i.e., where the rings are linked to each other through two adjacent carbon and/or nitrogen atoms. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically, the heteroaryl ring will contain up to 4, for example up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
[0049] Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]-pyranyl, 1 H-pyrazolo[4,3-d]-oxazolyl,
4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, imidazo[1 ,2-b][1 ,2,4]triazinyl, imidazo[1 ,2-a]pyridine, imidazo[1 ,2-a]pyrazine, imidazo[1 ,2- a]pyrimidine, imidazo[1 ,2-b]pyridazine, triazolo[1 ,5-a]pyridine, [1 ,2,3]triazolo[1 ,5-a]pyridine,. Examples of heteroaryl groups comprising at least one nitrogen in a ring position include pyrrolyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,3,5-triazenyl, indolyl, isoindolyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl and pteridinyl.
[0050] “Heteroaryl” also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a non-aromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or sulfur. Partially aromatic heteroaryl bicyclic ring systems can be vicinally fused, i.e. , where the rings are linked to each other through two adjacent carbon and/or nitrogen atoms. Examples of partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1 , 2,3,4- tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 1 ,3-dihydroisobenzofuran, 2,3-dihydro-benzo[1 ,4]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.
[0051] Examples of five-membered heteroaryl groups include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.
[0052] Examples of six-membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl. [0053] Particular examples of bicyclic heteroaryl groups containing a six-membered ring fused to a five-membered ring include but are not limited to benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl, pyrrolopyridine, and pyrazolopyridinyl groups.
[0054] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.
[0055] The term “heteroaryl” may also include groups that are tautomers of hydroxy substituted heteroaryl groups, such as pyridones. For example, the term “heteroaryl” may include groups such
[0056] The term “oxo,” or “=O” as used herein, means an oxygen that is double bonded to a carbon atom.
[0057] The term "optionally substituted" includes either groups, structures, or molecules that are substituted and those that are not substituted.
[0058] 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).
[0059] Where a moiety is substituted, it may be substituted at any point on the moiety where chemically possible and consistent with atomic valency requirements. The moiety may be substituted by one or more substituents, e.g., 1 , 2, 3 or 4 substituents; optionally there are 1 or 2 substituents on a group. Where there are two or more substituents, the substituents may be the same or different.
[0060] 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.
[0061] 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 “ ”:
[0062] “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:
[0063] “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:
[0064] Where Ring A comprises an NH group the NH group may be substituted by R4 to give NR4. Similarly, where Ring B comprises an NH group, the NH group may be substituted by R10 to give NR10.
[0065] 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 -NR5R6, , -NR7AR7B, -NR9AR9B, -NR9CR9D, -NR10AR10B, - and -NR11AR11 B group may form: Similarly, an -NRR’ group within a substituent may form a carbonyl-linked 4 to 6 membered heterocyclyl, for example a -C(O)NRR’ group may form:
-NRR’ groups within substituents such as -OC(O)NRR’, -SO2NRR’, or -NRC(O)NRR’, may similarly form a 4 to 6 membered heterocyclyl within such substituents.
[0066] A bond terminating in , , represents that the bond is connected to another atom that is not shown in the structure. A bond terminating inside a cyclic structure and not terminating at an atom of the ring structure represents that the bond may be connected to any of the atoms in the ring structure where allowed by valency, unless stated otherwise herein. For example if Ring A is the 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
[0067] The various functional groups and substituents making up the compounds of the present invention are typically chosen such that the molecular weight of the compound does not exceed 1000. More usually, the molecular weight of the compound will be less than 750, for example less than 700, or less than 650, or less than 600, or less than 550.
[0068] Suitable or preferred features of any compounds of the present invention may also be suitable features of any other aspect.
[0069] The invention contemplates pharmaceutically acceptable salts of the compounds of the invention. These may include the acid addition and base salts of the compounds. These may be acid addition and base salts of the compounds.
[0070] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 1 ,5- naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.
[0071] Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts. For a review on suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).
[0072] Pharmaceutically acceptable salts of compounds of the invention may be prepared by for example, one or more of the following methods:
(i) by reacting the compound of the invention with the desired acid or base;
(ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of the invention or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or
(iii) by converting one salt of the compound of the invention to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.
[0073] These methods are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost nonionised.
[0074] The invention contemplates pharmaceutically acceptable N-oxide compounds of the invention. For example, in compounds of the invention where Ring A comprises a nitrogencontaining heteroaromatic group, the nitrogen atom within said group may be in N-oxide form, e.g.:
O i . Such N-oxide compounds may be prepared according to synthetic techniques known to those skilled in the art.
[0075] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric centre, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterised by the absolute configuration of its asymmetric centre and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e. , as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”. Where a compound of the invention has two or more stereo centres any combination of (R) and (S) stereoisomers is contemplated. The combination of (R) and (S) stereoisomers may result in a diastereomeric mixture or a single diastereoisomer. The compounds of the invention may be present as a single stereoisomer or may be mixtures of stereoisomers, for example racemic mixtures and other enantiomeric mixtures, and diasteroemeric mixtures. Where the mixture is a mixture of enantiomers the enantiomeric excess may be any of those disclosed above. Where the compound is a single stereoisomer, the compounds may still contain other diasteroisomers or enantiomers as impurities. Hence a single stereoisomer does not necessarily have an enantiomeric excess (e.e.) or diastereomeric excess (d.e.) of 100% but could have an e.e. or d.e. of about at least 85%, for example at least 90%, at least 95%, at least 99%, or at least 99.9%.
[0076] The compounds of this invention may possess one or more asymmetric centres; such compounds can therefore be produced as individual (R) or (S)stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well known in the art (see discussion in Chapter 4 of “Advanced Organic Chemistry”, 4th edition J. March, John Wiley and Sons, New York, 2001), for example by synthesis from optically active starting materials or by resolution of a racemic form. Some of the compounds of the invention may have geometric isomeric centres (E and Z isomers). It is to be understood that the present invention encompasses all optical, diastereoisomers and geometric isomers and mixtures thereof.
[0077] Z/E (e.g., cis/trans) isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallisation.
[0078] Conventional techniques for the preparation/isolation of individual enantiomers when necessary include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). Thus, chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% by volume of isopropanol, typically from 2% to 20%, and for specific examples, 0 to 5% by volume of an alkylamine e.g., 0.1% diethylamine. Concentration of the eluate affords the enriched mixture.
[0079] Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of the invention contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person.
[0080] When any racemate crystallises, crystals of two different types are possible. The first type is the racemic compound (true racemate) referred to above wherein one homogeneous form of crystal is produced containing both enantiomers in equimolar amounts. The second type is the racemic mixture or conglomerate wherein two forms of crystal are produced in equimolar amounts each comprising a single enantiomer.
[0081] While both of the crystal forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures may be separated by conventional techniques known to those skilled in the art - see, for example, “Stereochemistry of Organic Compounds” by E. L. Eliel and S. H. Wilen (Wiley, 1994).
[0082] Compounds and salts described in this specification may be isotopically-labelled (or “radio-labelled”). Accordingly, one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature. Examples of radionuclides that may be incorporated include 2H (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 or 14C are often useful. For radio-imaging applications, 11C or 18F are often useful. In some embodiments, the radionuclide is 3H. In some embodiments, the radionuclide is 14C. In some embodiments, the radionuclide is 11C. And in some embodiments, the radionuclide is
18p [0083] Isotopically-labelled compounds can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described using an appropriate isotopically-labelled reagent in place of the non-labelled reagent previously employed.
[0084] The selective replacement of hydrogen with deuterium in a compound may modulate the metabolism of the compound, the PK/PD properties of the compound and/or the toxicity of the compound. For example, deuteration may increase the half-life or reduce the clearance of the compound in vivo. Deuteration may also inhibit the formation of toxic metabolites, thereby improving safety and tolerability. It is to be understood that the invention encompasses deuterated derivatives of compounds of formula (I). As used herein, the term deuterated derivative refers to compounds of the invention where in a particular position at least one hydrogen atom is replaced by deuterium. Accordingly, in a compound of the invention one or more hydrogen atom is optionally replaced by deuterium. For example, one or more hydrogen atoms in a Ci-4-alkyl group may be replaced by deuterium to form a deuterated C 1 -4-al ky I group. By way of example, if any of R1 , R3, R4 or R10 is methyl the invention also encompasses -CDs, -CHD2 and -CH2D. Similarly R2 or R12 may be D.
[0085] Certain compounds of the invention may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms.
[0086] It is also to be understood that certain compounds of the invention may exhibit polymorphism, and that the invention encompasses all such forms.
[0087] Compounds of the invention may exist in a number of different tautomeric forms and references to compounds of the invention include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by compounds of the invention. Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, and nitro/aci- nitro. keto enol enolate
[0088] Suitably, in compounds of the invention where R3 is H, the compound may exist in different tautomeric forms, each of which is encompassed within the scope of the invention, e.g.:
[0089] In compounds of the invention where R3 is H, the compound may exist in form (I’) and/or (I”), each of which is encompassed within the scope of the invention, e.g.:
[0090] 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.
[0091] 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.
[0092] Accordingly, the present invention includes those compounds of the invention as defined herein when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the formula (I) that are produced by organic synthetic means and also such compounds that are produced in the human or animal body 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. [0093] 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.
[0094] 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 a!., 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.
[0095] A suitable pharmaceutically-acceptable pro-drug of a compound of the formula (I) that possesses a carboxy group is, for example, an in v/ o-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.
[0096] A suitable pharmaceutically-acceptable pro-drug of a compound of the invention that possesses a hydroxy group is, for example, an in v/ o-cleavable ester or ether thereof. An in v/ o-cleavable ester or ether of a compound of the invention containing a hydroxy group is, for example, a pharmaceutically-acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically- acceptable ester forming groups for a hydroxy group include inorganic esters such as phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically-acceptable ester forming groups for a hydroxy group include Ci- alkanoyl groups such as acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, Ci-io alkoxycarbonyl groups such as ethoxycarbonyl, /V,/V-(Ci-6 alkyl)2carbamoyl, 2- dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, /V-alkylaminomethyl, A/,A/- 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.
[0097] 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.
[0098] 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.
[0099] In particular, a suitable pharmaceutically-acceptable pro-drug of a compound of the invention may include an in v/vo-cleavable group at the nitrogen depicted as Na in the structure below for compounds of formula (I): [00100] A suitable pharmaceutically-acceptable pro-drug of a compound of the invention at Na 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 CMO 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, /V-alkylaminomethyl, N,N- 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.
[00101] The in-vivo cleavable group may be selected such that the pro-drug form of the compound is converted to a compound comprising the sulfonimidamide group present in compounds of the invention. For example, Na may be substituted with a -COORX group, where Rx is selected from substituted or unsubstituted alkyl and substituted or unsubstituted cycloalkyl.
[00102] 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 is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.
[00103] 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.
[00104] 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
[00105] The following paragraphs are applicable to the compounds of the invention, including compounds of the formulae (I) to XXXXII.
[00106] In certain embodiments the compound of the formula (I) is a compound of the formula (la), or a pharmaceutically acceptable salt or N-oxide thereof:
[00107] In certain embodiments the compound of the formula (I) is a compound of the formula (II), or a pharmaceutically acceptable salt or N-oxide thereof: wherein
R3, R12, L, Ring A, and Ring B are as defined for formula (I).
[00108] In certain embodiments the compound of the formula (II) is a compound of the formula (Ila), or a pharmaceutically acceptable salt or N-oxide thereof:
[00109] In certain embodiments the compound of the formula (I) is a compound of the formula (III), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R4a is independently selected from: halo, -CN, -NO2, =0, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said C1.6 alkyl, C1.6 heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; a is an integer from 0 to 3; and
R1, R2, R3, R5, R6, R7, R12, Q1, L, x, and Ring B are as defined for formula (I).
[00110] In certain embodiments the compound of the formula (III) is a compound of the formula (Illa), or a pharmaceutically acceptable salt or N-oxide thereof:
[00111] In certain embodiments the compound of the formula (I) is a compound of the formula (IV), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R4a is independently selected from: halo, -CN, -NO2, =0, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2.6 alkenyl and C2.6 alkynyl is optionally substituted by one or more R7; a is an integer from 0 to 3; and
R3, R5, R6, R7, R12, Q1, L, x, and Ring B are as defined for formula (I).
[00112] In certain embodiments the compound of the formula (IV) is a compound of the formula (IVa), or a pharmaceutically acceptable salt or N-oxide thereof:
[00113] In certain embodiments the compound of the formula (I) is a compound of the formula (V), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R4a is independently selected from: H, halo, -CN, -NO2, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2.6 alkenyl, C2.6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2.6 alkenyl and C2.6 alkynyl is optionally substituted by one or more R7; and
R1, R2, R3, R5, R6, R7, R12, Q1, L, x, and Ring B are as defined for formula (I).
[00114] In certain embodiments the compound of the formula (V) is a compound of the formula (Va), or a pharmaceutically acceptable salt or N-oxide thereof:
[00115] In certain embodiments the compound of the formula (I) is a compound of the formula (VI), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R4a is independently selected from: H, halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; and
R3, R5, R6, R7, R12, Q1, L, x, and Ring B are as defined for formula (I).
[00116] In certain embodiments the compound of the formula (VI) is a compound of the formula (Via), or a pharmaceutically acceptable salt or N-oxide thereof:
[00117] In certain embodiments the compound of the formula (I) is a compound of the formula (VII), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R4a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; a is an integer from 0 to 5; and
R1, R2, R3, R5, R6, R7, R12, Q1, L, x, and Ring B are as defined for formula (I).
[00118] In certain embodiments the compound of the formula (VII) is a compound of the formula (Vila), or a pharmaceutically acceptable salt or N-oxide thereof:
[00119] In certain embodiments the compound of the formula (I) is a compound of the formula (VIII), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R4a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; a is an integer from 0 to 5; and
R3, R5, R6, R7, R12, Q1, L, x, and Ring B are as defined for formula (I).
[00120] In certain embodiments the compound of the formula (VIII) is a compound of the formula (Villa), or a pharmaceutically acceptable salt or N-oxide thereof:
(Villa)
[00121] In certain embodiments the compound of the formula (I) is a compound of the formula (IX), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R4a is independently selected from: halo, -CN, -NO2, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; a is an integer from 0 to 3; each R4b is independently selected from: H, halo, -CN, -NO2, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; and
R1, R2, R3, R5, R6, R7, R12, Q1, L, x, and Ring B are as defined for formula (I).
[00122] In certain embodiments the compound of the formula (IX) is a compound of the formula (IXa), or a pharmaceutically acceptable salt or N-oxide thereof:
[00123] In certain embodiments the compound of the formula (I) is a compound of the formula (X), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R4a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; a is an integer from 0 to 3; each R4b is independently selected from: H, halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; and R3, R5, R6, R7, R12, Q1, L, x, and Ring B are as defined for formula (I).
[00124] In certain embodiments the compound of the formula (X) is a compound of the formula (Xa), or a pharmaceutically acceptable salt or N-oxide thereof:
[00125] In certain embodiments the compound of the formula (I) is a compound of the formula (XI), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R4a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; a is an integer from 0 to 4; and
R1, R2, R3, R5, R6, R7, R12, Q1, L, x, and Ring B are as defined for formula (I).
[00126] In certain embodiments the compound of the formula (XI) is a compound of the formula (Xia), or a pharmaceutically acceptable salt or N-oxide thereof: [00127] In certain embodiments the compound of the formula (I) is a compound of the formula (XII), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R4a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; a is an integer from 0 to 4; and
R3, R5, R6, R7, R12, Q1, L, x, and Ring B are as defined for formula (I).
[00128] In certain embodiments the compound of the formula (XII) is a compound of the formula (XI la), or a pharmaceutically acceptable salt or N-oxide thereof:
(XI I a)
[00129] In certain embodiments the compound of the formula (I) is a compound of the formula (XIII), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R4a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; a is an integer from 0 to 3; and
R1, R2, R3, R5, R6, R7, R12, Q1, L, x, and Ring B are as defined for formula (I).
[00130] In certain embodiments the compound of the formula (XIII) is a compound of the formula (XI I la), or a pharmaceutically acceptable salt or N-oxide thereof:
[00131] In certain embodiments the compound of the formula (I) is a compound of the formula (XIV), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R4a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; a is an integer from 0 to 3; and R3, R5, R6, R7, R12, Q1, L, x, and Ring B are as defined for formula (I).
[00132] In certain embodiments the compound of the formula (XIV) is a compound of the formula (XlVa), or a pharmaceutically acceptable salt or N-oxide thereof:
[00133] In certain embodiments the compound of the formula (I) is a compound of the formula (XV), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R4a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; a is an integer from 0 to 3; and
R1, R2, R3, R5, R6, R7, R12, Q1, L, x, and Ring B are as defined for formula (I).
[00134] In certain embodiments the compound of the formula (XV) is a compound of the formula (XVa), or a pharmaceutically acceptable salt or N-oxide thereof: (XVa)
[00135] In certain embodiments the compound of the formula (I) is a compound of the formula (XVI), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R4a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; a is an integer from 0 to 3; and
R3, R5, R6, R7, R12, Q1, L, x, and Ring B are as defined for formula (I).
[00136] In certain embodiments the compound of the formula (XVI) is a compound of the formula (XlVa), or a pharmaceutically acceptable salt or N-oxide thereof:
(XVI a)
[00137] In certain embodiments the compound of the formula (I) is a compound of the formula (XVII), or a pharmaceutically acceptable salt or N-oxide thereof: wherein:
Ring D is phenyl or a 6-membered heteroaryl containing 1 , 2 or 3 ring nitrogen atoms and Ring E is a 5-membered heteroaryl containing 1 or more (e.g. 1 to 4) ring nitrogen atoms and optionally one or two ring heteroatoms selected from O and S, and wherein Rings D and E together form a 9-membered fused bicyclic heteroaryl ring;
L is attached to an atom in Ring D; each R4a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; a is an integer from 0 to 4; and
R1, R2, R3, R5, R6, R7, R12, Q1, L, x, and Ring B are as defined for formula (I).
[00138] In certain embodiments the compound of the formula (XVII) is a compound of the formula (XVIIa), or a pharmaceutically acceptable salt or N-oxide thereof:
(XVI la)
[00139] In certain embodiments the compound of the formula (XVII) is a compound of the formula (XVIII), or a pharmaceutically acceptable salt or N-oxide thereof:
(XVIII)
[00140] In certain embodiments the compound of the formula (XVIII) is a compound of the formula (XVI I la), or a pharmaceutically acceptable salt or N-oxide thereof:
(XVI 11 a)
[00141] In certain embodiments the compound of the formula (I) is a compound of the formula (XIX), or a pharmaceutically acceptable salt or N-oxide thereof: wherein:
Ring F is a 5-membered heteroaryl containing 1 or more (e.g. 1 to 3) ring nitrogen atoms and optionally one or two ring heteroatoms selected from O and S, Ring G is phenyl or a 6- membered heteroaryl containing 1 , 2 or 3 ring nitrogen atoms, and wherein Rings F and G together form a 9-membered fused bicyclic heteroaryl ring;
L is attached to an atom in Ring F; each R4a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; a is an integer from 0 to 4; and
R1, R2, R3, R5, R6, R7, R12, Q1, L, x, and Ring B are as defined for formula (I). [00142] In certain embodiments the compound of the formula (XIX) is a compound of the formula (XIXa), or a pharmaceutically acceptable salt or N-oxide thereof: [00143] In certain embodiments the compound of the formula (XIX) is a compound of the formula (XX), or a pharmaceutically acceptable salt or N-oxide thereof:
[00144] In certain embodiments the compound of the formula (XX) is a compound of the formula (XXa), or a pharmaceutically acceptable salt or N-oxide thereof:
[00145] In certain embodiments the compound of the formula (I) is a compound of the formula (XXI), or a pharmaceutically acceptable salt thereof: wherein:
X3 is N or CR4a;
R4a is selected from: halo, -CN, -NO2, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, -OC(O)R5, - C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and - SO2NR5R6, wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2.6 alkenyl and C2.6 alkynyl is optionally substituted by one or more R7;
R1, R2, R3, R5, R6, R7, Q1, L, x, and Ring B are as defined for formula (I).
[00146] In certain embodiments the compound of the formula (XXI) is a compound of the formula (XXIa), or a pharmaceutically acceptable salt or N-oxide thereof:
[00147] In certain embodiments the compound of the formula (I) is a compound of the formula (XXII), or a pharmaceutically acceptable salt or N-oxide thereof: wherein:
X3 is N or CR4a; R4a is selected from: H, halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, -OC(O)R5, - C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and - SO2NR5R6, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2.6 alkenyl and C2.6 alkynyl is optionally substituted by one or more R7; and
R3, R5, R6, R7, R12, Q1, L, x, and Ring B are as defined for formula (I).
[00148] In certain embodiments the compound of the formula (XXII) is a compound of the formula (XXIIa), or a pharmaceutically acceptable salt or N-oxide thereof:
[00149] In certain embodiments the compound of the formula (I) is a compound of the formula (XXIII), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: a is an integer from 0 to 4; and R1, R2, R3, R4, R12, L and Ring B are as defined for formula (I).
[00150] In certain embodiments the compound of the formula (XIII) is a compound of the formula (XXI I la), or a pharmaceutically acceptable salt or N-oxide thereof: (XXI 11 a)
[00151] In certain embodiments the compound of the formula (I) is a compound of the formula (XXIV), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: a is an integer from 0 to 4; and R3, R4, R12, L and Ring B are as defined for formula (I).
[00152] In certain embodiments the compound of the formula (XXIV) is a compound of the formula (XXI Va), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXIVa)
[00153] In certain embodiments the compound of the formula (I) is a compound of the formula (XXV), or a pharmaceutically acceptable salt or N-oxide thereof: wherein each R10a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, -OR10A, -S(O)xR10A, -NR10AR10B, - C(O)R10A, -OC(O)R10A, -C(O)OR10A, -NR10AC(O)R10B, -C(O)NR10AR10B, -NR10AC(O)OR10B, - OC(O)NR10AR10B, -NR10ASO2R10B, and -SO2NR10AR10B, wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R11; c is an integer from 0 to 5; and
R1, R2, R3, R10A, R10B, R11, R12, L, x, and Ring A are as defined for formula (I).
[00154] In certain embodiments the compound of the formula (XXV) is a compound of the formula (XXVa), or a pharmaceutically acceptable salt or N-oxide thereof:
[00155] In certain embodiments the compound of the formula (I) is a compound of the formula (XXVI), or a pharmaceutically acceptable salt or N-oxide thereof: wherein each R10a is independently selected from: halo, -CN, -NO2, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, -OR10A, -S(O)xR10A, -NR10AR10B, - C(O)R10A, -OC(O)R10A, -C(O)OR10A, -NR10AC(O)R10B, -C(O)NR10AR10B, -NR10AC(O)OR10B, - OC(O)NR10AR10B, -NR10ASO2R10B, and -SO2NR10AR10B, wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R11; c is an integer from 0 to 5; and
R3, R10A, R10B, R11, R12, L, x, and Ring A are as defined for formula (I).
[00156] In certain embodiments the compound of the formula (XXVI) is a compound of the formula (XXVIa), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXVI a)
[00157] In certain embodiments the compound of the formula (I) is a compound of the formula (XXVII), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXVII) wherein
R10a is selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, -OR10A, -S(O)xR10A, -NR10AR10B, -C(O)R10A, - OC(O)R10A, -C(O)OR10A, -NR10AC(O)R10B, -C(O)NR10AR10B, -NR10AC(O)OR10B, - OC(O)NR10AR10B, -NR10ASO2R10B, and -SO2NR10AR10B, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2.6 alkenyl and C2.6 alkynyl is optionally substituted by one or more R11;
R1, R2, R3, R10A, R10B, R11, R12, L, x, and Ring A are as defined for formula (I).
[00158] In certain embodiments the compound of the formula (XXVII) is a compound of the formula (XXVI la), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXVI la)
[00159] In certain embodiments the compound of the formula (I) is a compound of the formula (XXVIII), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXVIII) wherein:
R10a is selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, -OR10A, -S(O)xR10A, -NR10AR10B, -C(O)R10A, - OC(O)R10A, -C(O)OR10A, -NR10AC(O)R10B, -C(O)NR10AR10B, -NR10AC(O)OR10B, - OC(O)NR10AR10B, -NR10ASO2R10B, and -SO2NR10AR10B, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2.6 alkenyl and C2.6 alkynyl is optionally substituted by one or more R11; and
R3, R10A, R10B, R11, R12, L, x, and Ring A are as defined for formula (I).
[00160] In certain embodiments the compound of the formula (XXVIII) is a compound of the formula (XXVI I la), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXVI 11 a)
[00161] In certain embodiments the compound of the formula (I) is a compound of the formula (XXIX), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R10a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, -OR10A, -S(O)xR10A, -NR10AR10B, - C(O)R10A, -OC(O)R10A, -C(O)OR10A, -NR10AC(O)R10B, -C(O)NR10AR10B, -NR10AC(O)OR10B, - OC(O)NR10AR10B, -NR10ASO2R10B, and -SO2NR10AR10B, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R11 ; c is an integer from 0 to 3; and
R1 , R2, R3, R10A, R10B, R11 , R12, L, x, and Ring A are as defined for formula (I).
[00162] In certain embodiments the compound of the formula (I) is a compound of the formula (XXX), or a pharmaceutically acceptable salt or N-oxide thereof: wherein each R10a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, -OR10A, -S(O)xR10A, -NR10AR10B, -
C(O)R10A, -OC(O)R10A, -C(O)OR10A, -NR10AC(O)R10B, -C(O)NR10AR10B, -NR10AC(O)OR10B, - OC(O)NR10AR10B, -NR10ASO2R10B, and -SO2NR10AR10B, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R11 ; c is an integer from 0 to 3; and
R3, R10A, R10B, R11 , R12, L, x, and Ring A are as defined for formula (I).
[00163] In certain embodiments the compound of the formula (XXX) is a compound of the formula (XXXa), or a pharmaceutically acceptable salt or N-oxide thereof: [00164] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXI), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R4a is independently selected from: halo, -CN, -NO2, =0, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; a is an integer from 0 to 3; each R10a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, -OR10A, -S(O)xR10A, -NR10AR10B, - C(O)R10A, -OC(O)R10A, -C(O)OR10A, -NR10AC(O)R10B, -C(O)NR10AR10B, -NR10AC(O)OR10B, - OC(O)NR10AR10B, -NR10ASO2R10B, and -SO2NR10AR10B, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R11 ; c is an integer from 0 to 5; and
R1 , R2, R3, R5, R6, R7, R10A, R10B, R11 , R12, Q1, L, and x are as defined for formula (I).
[00165] In certain embodiments the compound of the formula (XXXI) is a compound of the formula (XXXIa), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXXIa) [00166] In certain embodiments the compound of the formula (XXXI) is a compound of the formula (XXXI b), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXXI b)
[00167] In certain embodiments the compound of the formula (XXXI) is a compound of the formula (XXXIc), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXXIc)
[00168] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXII), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R4a is independently selected from: halo, -CN, -NO2, =0, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; a is an integer from 0 to 4; each R10a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, -OR10A, -S(O)xR10A, -NR10AR10B, - C(O)R10A, -OC(O)R10A, -C(O)OR10A, -NR10AC(O)R10B, -C(O)NR10AR10B, -NR10AC(O)OR10B, - OC(O)NR10AR10B, -NR10ASO2R10B, and -SO2NR10AR10B, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R11; c is an integer from 0 to 5; and
R1, R2, R3, R5, R6, R7, R10A, R10B, R11, R12, Q1, L, and x are as defined for formula (I).
[00169] In certain embodiments the compound of the formula (XXXII) is a compound of the formula (XXXI la), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXXI I a)
[00170] In certain embodiments the compound of the formula (XXXII) is a compound of the formula (XXXIIb), or a pharmaceutically acceptable salt or N-oxide thereof:
[00171] In certain embodiments the compound of the formula (XXXII) is a compound of the formula (XXXIIc), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXXIIc) [00172] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXIII), or a pharmaceutically acceptable salt or N-oxide thereof: wherein:
X3 is N or CR4a;
R4a is selected from: halo, -CN, -NO2, =0, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, -OC(O)R5, - C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and - SO2NR5R6, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2.6 alkenyl and C2.6 alkynyl is optionally substituted by one or more R7; each R10a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2.6 alkenyl, C2.6 alkynyl, -OR10A, -S(O)xR10A, -NR10AR10B, -
C(O)R10A, -OC(O)R10A, -C(O)OR10A, -NR10AC(O)R10B, -C(O)NR10AR10B, -NR10AC(O)OR10B, - OC(O)NR10AR10B, -NR10ASO2R10B, and -SO2NR10AR10B, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2.6 alkenyl and C2.6 alkynyl is optionally substituted by one or more R11; c is an integer from 0 to 5; and
R1, R2, R3, R5, R6, R7, R10A, R10B, R11, R12, Q1, L, and x are as defined for formula (I).
[00173] In certain embodiments the compound of the formula (XXXIII) is a compound of the formula (XXXI I la), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXXI 11 a) [00174] In certain embodiments the compound of the formula (XXXIII) is a compound of the formula (XXXI 11 b), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXXI I lb)
[00175] In certain embodiments the compound of the formula (XXXIII) is a compound of the formula (XXXI He), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXXI lie)
[00176] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXIV), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXXIV) wherein:
X3 is N or CR4a;
R4a is selected from: halo, -CN, -NO2, =0, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, -OC(O)R5, - C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and - SO2NR5R6, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2.6 alkenyl and C2.6 alkynyl is optionally substituted by one or more R7; R10a is selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, -OR10A, -S(O)xR10A, -NR10AR10B, -C(O)R10A, - OC(O)R10A, -C(O)OR10A, -NR10AC(O)R10B, -C(O)NR10AR10B, -NR10AC(O)OR10B, - OC(O)NR10AR10B, -NR10ASO2R10B, and -SO2NR10AR10B, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2.6 alkenyl and C2.6 alkynyl is optionally substituted by one or more R11;
R1, R2, R3, R5, R6, R7, R10A, R10B, R11, R12, Q1, L, and x are as defined for formula (I).
[00177] In certain embodiments the compound of the formula (XXXIV) is a compound of the formula (XXXIVa), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXXIVa)
[00178] In certain embodiments the compound of the formula (XXXIV) is a compound of the formula (XXXIVb), or a pharmaceutically acceptable salt or N-oxide thereof: (XXXIVb)
[00179] In certain embodiments the compound of the formula (XXXIV) is a compound of the formula (XXXI Vc), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXXIVc) [00180] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXV), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R4a is independently selected from: halo, -CN, -NO2, =0, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; a is an integer from 0 to 3; each R10a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, -OR10A, -S(O)xR10A, -NR10AR10B, - C(O)R10A, -OC(O)R10A, -C(O)OR10A, -NR10AC(O)R10B, -C(O)NR10AR10B, -NR10AC(O)OR10B, - OC(O)NR10AR10B, -NR10ASO2R10B, and -SO2NR10AR10B, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R11 ; c is an integer from 0 to 5; and
R1 , R2, R3, R5, R6, R7, R10A, R10B, R11 , R12, Q1, L, and x are as defined for formula (I).
[00181] In certain embodiments the compound of the formula (XXXV) is a compound of the formula (XXXVa), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXXVa) [00182] In certain embodiments the compound of the formula (XXXV) is a compound of the formula (XXXVb), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXXVb)
[00183] In certain embodiments the compound of the formula (XXXV) is a compound of the formula (XXXVc), or a pharmaceutically acceptable salt or N-oxide thereof:
[00184] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXVI), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXXVI) wherein: each R4a is independently selected from: halo, -CN, -NO2, =0, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; a is an integer from 0 to 3; each R10a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, -OR10A, -S(O)xR10A, -NR10AR10B, - C(O)R10A, -OC(O)R10A, -C(O)OR10A, -NR10AC(O)R10B, -C(O)NR10AR10B, -NR10AC(O)OR10B, - OC(O)NR10AR10B, -NR10ASO2R10B, and -SO2NR10AR10B, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R11; c is an integer from 0 to 5; and
R1, R2, R3, R5, R6, R7, R10A, R10B, R11, R12, Q1, L, and x are as defined for formula (I).
[00185] In certain embodiments the compound of the formula (XXXVI) is a compound of the formula (XXXVIa), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXXVI a)
[00186] In certain embodiments the compound of the formula (XXXVI) is a compound of the formula (XXXVIb), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXXVI b)
[00187] In certain embodiments the compound of the formula (XXXVI) is a compound of the formula (XXXVIc), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXXVIc) [00188] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXVII), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXXVII) wherein: each R4a is independently selected from: halo, -CN, -NO2, =0, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; a is an integer from 0 to 3; each R4c is independently selected from: H, C1.6 alkyl, C1.6 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein said C1.6 alkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; each R10a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, -OR10A, -S(O)xR10A, -NR10AR10B, - C(O)R10A, -OC(O)R10A, -C(O)OR10A, -NR10AC(O)R10B, -C(O)NR10AR10B, -NR10AC(O)OR10B, - OC(O)NR10AR10B, -NR10ASO2R10B, and -SO2NR10AR10B, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R11 ; c is an integer from 0 to 5; and
R1 , R2, R3, R5, R6, R7, R10A, R10B, R11 , R12, Q1, L, and x are as defined for formula (I).
[00189] In certain embodiments the compound of the formula (XXXVII) is a compound of the formula (XXXVI la), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXXVI la)
[00190] In certain embodiments the compound of the formula (XXXVII) is a compound of the formula (XXXVIlb), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXXVIlb)
[00191] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXVIII), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXXVIII) wherein: each R4a is independently selected from: halo, -CN, -NO2, =0, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; a is an integer from 0 to 2; each R4c is independently selected from: H, Ci-e alkyl, Ci-e haloalkyl, C2-6 alkenyl, and C2-6 alkynyl; wherein said Ci-e alkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; each R10a is independently selected from: halo, -CN, -NO2, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, -OR10A, -S(O)xR10A, -NR10AR10B, - C(O)R10A, -OC(O)R10A, -C(O)OR10A, -NR10AC(O)R10B, -C(O)NR10AR10B, -NR10AC(O)OR10B, - OC(O)NR10AR10B, -NR10ASO2R10B, and -SO2NR10AR10B, wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R11 ; c is an integer from 0 to 5; and
R1 , R2, R3, R5, R6, R7, R10A, R10B, R11 , R12, Q1, L, and x are as defined for formula (I).
[00192] In certain embodiments the compound of the formula (XXXVIII) is a compound of the formula (XXXVI I la), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXXVI I la)
[00193] In certain embodiments the compound of the formula (XXXVIII) is a compound of the formula (XXXVIHb), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXXVI I lb)
[00194] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXIX), or a pharmaceutically acceptable salt or N-oxide thereof: wherein
R10a and R10b are each independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, -OR10A, -S(O)xR10A, - NR10AR10B, -C(O)R10A, -OC(O)R10A, -C(O)OR10A, -NR10AC(O)R10B, -C(O)NR10AR10B, - NR10AC(O)OR10B, -OC(O)NR10AR10B, -NR10ASO2R10B, and -SO2NR10AR10B, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R11; and R1, R2, R3, R10A, R10B, R11 , R12, L, and x are as defined for formula (I).
[00195] In certain embodiments the compound of the formula (XXXIX) is a compound of the formula (XXXIXa), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXXIXa) [00196] In certain embodiments the compound of the formula (XXXIX) is a compound of the formula (XXXIXb), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXXIXb) [00197] In certain embodiments the compound of the formula (I) is a compound of the formula (XXXX), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R4a is independently selected from: halo, -CN, -NO2, =0, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; a is an integer from 0 to 5; each R10a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, -OR10A, -S(O)xR10A, -NR10AR10B, - C(O)R10A, -OC(O)R10A, -C(O)OR10A, -NR10AC(O)R10B, -C(O)NR10AR10B, -NR10AC(O)OR10B, - OC(O)NR10AR10B, -NR10ASO2R10B, and -SO2NR10AR10B, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R11 ; c is an integer from 0 to 5; and
R1 , R2, R3, R5, R6, R7, R10A, R10B, R11 , R12, Q1, L, and x are as defined for formula (I).
[00198] In certain embodiments the compound of the formula (XXXX) is a compound of the formula (XXXXI), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXXXI) [00199] In certain embodiments the compound of the formula (XXXX) is a compound of the formula (XXXXII), or a pharmaceutically acceptable salt or N-oxide thereof:
(XXXXII)
[00200] In certain embodiments compounds of the invention include, for example, compounds of formulae (I) to (XXXXII), or a pharmaceutically acceptable salt or N-oxide thereof, wherein, unless otherwise stated, each of Ring A, Ring B, R1, R2, R3, R4, R4a, R4b, p4c p5 p6 p7 p8 p9 10 R11 p7A p7B p9A p9B R9C p9D f^10a f^10b f^10A f^10B f^1 1A p1 1 B
R12, Q1, Q2, L, a, c, and x has any of the meanings defined hereinbefore or in any of the following statements in the numbered paragraphs 1 to 252 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. R1 is selected from: Ci-e alkyl, C3-6 cycloalkyl, and Cs-ecycloalkyl-Ci-e alkyl-, wherein R1 is substituted by at least one fluorine.
2. R1 is selected from: C1.3 alkyl, C3-6 cycloalkyl, and Cs-ecycloalkyl-Ci-s alkyl-, wherein R1 is substituted by at least one fluorine.
3. R1 is selected from: Ci-e alkyl, and C3-6 cycloalkyl, wherein R1 is substituted by at least one fluorine.
4. R1 is selected from: C1.3 alkyl, and C3-6 cycloalkyl, wherein R1 is substituted by at least one fluorine.
5. R1 is C1.6 alkyl, wherein R1 is substituted by at least one fluorine.
6. R1 is C1.3 alkyl, wherein R1 is substituted by at least one fluorine.
7. R1 is selected from ethyl and methyl, wherein the ethyl or methyl is substituted by at least one fluorine. 8. R1 is ethyl wherein the ethyl is substituted by at least one fluorine.
9. R1 is selected from -CH2F, -CHF2, and -CF3.
10. R1 is -CH2F.
11. R1 is -CHF2.
12. R1 is -CF3.
13. R2 is selected from: H, C1.3 alkyl and C1.3 haloalkyl.
14. R2 is selected from: H, and C1.3 alkyl.
15. R2 is C1.3 alkyl.
16. R2 is methyl.
17. R2 is H or D. It may be that R2 is D. It may be that R2 is H.
18. R1 and R2 together with the carbon atom to which they are attached form a C3 or C4 cycloalkyl substituted with at least one fluorine.
19. R1 and R2 together with the carbon atom to which they are attached form a cyclobutyl group substituted with at least one fluorine. Thus it may be that R1 and R2 together with the carbon atom to which they are attached form a cyclobutyl group substituted one fluorine.
20. R1 and R2 together with the carbon atom to which they are attached form a cyclopropyl group substituted with at least one fluorine. Thus it may be that R1 and R2 together with the carbon atom to which they are attached form a cyclopropyl group substituted with one fluorine.
21. R1 is as defined in any of 1 to 12 and R2 is methyl.
22. R1 is as defined in any of 1 to 12 and R2 is H.
23. R3 is selected from: H, Ci-e alkyl and Ci-e haloalkyl; optionally wherein one or more H in R3 is substituted by D.
24. R3 is selected from: C1.3 alkyl and C1.3 haloalkyl.
25. R3 is selected from: C1.2 alkyl and C1.2 haloalkyl.
26. R3 is methyl optionally substituted with 1 to 3 halo groups.
27. R3 is ethyl optionally substituted with 1 to 5 halo groups.
28. R3 is as defined in any of 23 to 27, wherein said halo is fluoro.
29. R3 is C1.3 alkyl. 30. R3 is selected from: methyl, ethyl, and 2-fluoroethyl.
31. R3 is methyl.
32. R3 is ethyl.
33. R3 is 2-fluoroethyl.
34. R3 is as defined in any of 23 to 33 wherein one or more hydrogen atoms in R3 is deuterium. Thus, it may be that R3 is selected from: methyl, -CDs, ethyl, and 2- fluoroethyl.
35. R3 is -CD3.
36. R12 is independently selected from H, Ci-e alkyl, Ci-e haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-Ci-6 alkyl-, and COOR13.
37. R12 is independently selected from H, Ci-e alkyl, Ci-e haloalkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-Ci-6 alkyl-.
38. R12 is independently selected from H, Ci-e alkyl, Ci-e haloalkyl, and C3-6 cycloalkyl.
39. R12 is H.
40. R12 is C1.6 alkyl, e.g. C1.3 alkyl.
41. R12 is C1.6 haloalkyl, e.g. C1.3 haloalkyl.
42. R12 is C3-6 cycloalkyl, e.g. C3 cycloalkyl.
43. R12 is as defined in any of 36 to 42, wherein one or more H in R12 is substituted by D.
44. R12 is COOR13.
45. R13 is independently selected from Ci-e alkyl, Ci-e haloalkyl, C3-6 cycloalkyl, and C3- 6 cycloalkyl-Ci-6 alkyl.
46. R13 is independently selected from H, Ci-e alkyl, Ci-e haloalkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-Ci-6 alkyl.
47. R13 is independently selected from Ci-e alkyl, Ci-e haloalkyl, and C3-6 cycloalkyl.
48. R13 is C1.6 alkyl, e.g. C1.3 alkyl.
49. R13 is C1.6 haloalkyl, e.g. C1.3 haloalkyl.
50. R13 is C3-6 cycloalkyl, e.g. C3 cycloalkyl.
51. R13 is as defined in any of 45 to 50, wherein one or more H in R13 is substituted by
D. 52. L is selected from: a bond and C1.2 alkyl.
53. L is selected from: a bond, -CH2-, and -CH2CH2-.
54. L is selected from: a bond and -CH2-.
55. L is -CH2-.
56. L is a bond.
57. Ring A is selected from: 4- to 7-membered heterocyclyl, 5- to 12-membered heteroaryl and Ce- aryl.
58. Ring A is selected from: 4- to 7-membered heterocyclyl and 5- to 12-membered heteroaryl.
59. Ring A is selected from: 5- or 6-membered heterocyclyl, 5- to 10-membered heteroaryl and Ce-8 aryl.
60. Ring A is selected from: 5- or 6-membered heterocyclyl, and 5- to 10-membered heteroaryl.
61. Ring A is selected from: 5- or 6-membered heterocyclyl, 5- to 9-membered heteroaryl and phenyl.
62. Ring A is selected from: 5- or 6-membered heterocyclyl and 5- to 9-membered heteroaryl.
63. Ring A is selected from: 5- to 10-membered heteroaryl and phenyl.
64. Ring A is a 5- to 10-membered heteroaryl.
65. Ring A is a 6- to 10-membered heteroaryl.
66. Ring A is selected from: 5-membered heteroaryl, 6-membered heteroaryl, 9- membered heteroaryl, and phenyl.
67. Ring A is a monocyclic 5- or 6-membered heteroaryl or a 8- to 10-membered fused bicyclic heteroaryl, wherein Ring A has at least 1 (for example 1 to 4) ring nitrogen atom. Thus it may be that Ring A is a monocyclic 6-membered heteroaryl or a 9- to 10-membered fused bicyclic heteroaryl, wherein Ring A has at least 1 (for example 1 to 4) ring nitrogen atom.
68. Ring A is a monocyclic 5- or 6-membered heteroaryl or a 9- to 10-membered fused bicyclic heteroaryl, wherein Ring A has 1 to 4 ring nitrogen atoms. Thus, it may be that Ring A is a monocyclic 6-membered heteroaryl or a 9-membered fused bicyclic heteroaryl, wherein Ring A has 1 to 4 ring nitrogen atoms.
69. Ring A is 5-membered heteroaryl. 70. Ring A is 5-membered heteroaryl, wherein Ring A said heteroaryl has 1 ring nitrogen atom and optionally one or more ring heteroatoms (for example 1 , 2 or 3) selected from O, S and N.
71. Ring A is 5-membered heteroaryl, wherein said heteroaryl has 1 , 2, 3 or 4 ring nitrogen atoms.
72. Ring A is 6-membered heteroaryl.
73. Ring A is a monocyclic 6-membered heteroaryl, wherein said heteroaryl has 1 , 2 or 3 (for example 1 or 2) ring nitrogen atoms.
74. Ring A is 9-membered heteroaryl.
75. Ring A is 9-membered fused bicyclic heteroaryl, wherein said heteroaryl has 1 , 2, 3 or 4 ring nitrogen atoms.
76. Ring A is 9-membered bicyclic heteroaryl, wherein said heteroaryl has 1 , 2, 3 or 4 (for example 1 , 2 or 3) ring nitrogen atoms and is a 6-membered ring fused to a 5- membered ring, wherein the 9-membered bicyclic heteroaryl is attached to the group L by a ring atom in the 6-membered ring. It may be that the 5- and 6- membered rings forming the 9-membered bicyclic heteroaryl are both heteroaryl rings.
77. Ring A is 9-membered bicyclic heteroaryl, wherein said heteroaryl has 1 , 2, 3 or 4 (for example 1 , 2 or 3) ring nitrogen atoms and is a 6-membered ring fused to a 5- membered ring, wherein the 9-membered bicyclic heteroaryl is attached to the group L by a ring atom in the 5-membered ring. It may be that the 5- and 6- membered rings forming the 9-membered bicyclic heteroaryl are both heteroaryl rings.
78. Ring A is selected from: a 6-membered heteroaryl and a 9-membered bicyclic heteroaryl, wherein said 6-membered heteroaryl has 1 , 2 or 3 (for example 1 or 2) ring nitrogen atoms, and said 9-membered bicyclic heteroaryl has 1 , 2, 3 or 4 (for example 1 , 2 or 3) ring nitrogen atoms. It may be that the 5- and 6-membered rings forming the 9-membered bicyclic heteroaryl are both heteroaryl rings.
79. Ring A is phenyl.
80. Ring A is a 4- to 6-membered heterocyclyl.
81. Ring A is a 5- or 6-membered heterocyclyl containing at least one ring oxygen atom and optionally 1 further ring heteroatom selected from S and N. 82. Ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, and tetrahydropyranyl.
83. Ring A is selected from pyrrolidinyl, tetrahydrofuranyl, piperidinyl, and tetrahydropyranyl. 84. Ring A is tetrahydropyranyl.
85. Ring A is selected from furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl.
86. Ring A is selected from furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl, or a compound of the structure: wherein Ring A is optionally substituted with one or more R4.
87. Ring A is selected from: thienyl, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, tetrahydropyranyl,
wherein Ring A is optionally substituted with one or more R4. Ring A is selected from: ; wherein Ring A is optionally substituted with one or more R4. Ring A is a 9-membered fused bicyclic heteroaryl containing at least one ring nitrogen atom, wherein Ring A is substituted by one or more R4. Thus it may be that Ring A selected from: wherein Ring A is optionally substituted with one or more R4. It may be that Ring A is attached to L via an atom in a 5-membered ring in Ring A. It may be that Ring A is attached to L via an atom in a 6-membered ring in Ring A. Ring A is selected from: ; wherein Ring A is optionally substituted with one or more R4. It may be that Ring A is attached to L via a carbon atom in a benzo ring. in Ring A. Ring A is selected from: wherein Ring A is optionally substituted with one or more R4. Ring A is selected from: wherein Ring A is optionally substituted with one or more R4.
93. Ring A is selected from: wherein Ring A is optionally substituted with one or more R4.
94. Ring A is selected from: wherein Ring A is optionally substituted with one or more R4.
95. Ring A is selected from: 96. Ring A is selected from: ; wherein Ring A is optionally substituted with one or more R4. Ring A is selected from: wherein Ring A is optionally substituted with one or more Ring A is selected from: ; wherein Ring A is optionally substituted with one or more R4.
99. Ring A is selected from: optionally substituted with one or more R4. Ring A is selected from thienyl and thiazolyl, wherein Ring A is optionally substituted with one or more R4. Ring A is selected from: wherein Ring A is optionally substituted with one or more R4.
104. Ring A is selected from: wherein Ring A is optionally substituted with one or more R4. Ring A is selected from: 107. Ring A is selected from:
Thus it may be that Ring A is selected from: 108. Ring A is selected from:
109. Ring A is selected from:
110. Ring A is selected from:
111. Ring A is as defined in any of 57 to 104 and is substituted by one or more R4.
112. Ring A is as defined in any of 57 to 104 and is substituted by one or two R4.
113. Ring A is as defined in any of 57 to 104 and is unsubstituted. 114. Ring A is selected from:
wherein Ring A is optionally substituted with one or more R4.
5 115. Ring A is selected from:
10
117. Ring A is selected from:
118. Ring A is selected from:
119. Ring A is as defined in any of 115 to 118, wherein y is an integer from 0 to 10, where chemically possible. 120. Ring A is as defined in any of 115 to 118, wherein y is an integer from 0 to 5, where chemically possible.
121. Ring A is as defined in any of 115 to 118, wherein y is an integer from 0 to 3, where chemically possible. 122. Ring A is as defined in any of 115 to 118, wherein y is 0.
123. Ring A is as defined in any of 115 to 118, wherein y is 1.
124. Ring A is as defined in any of 115 to 118, wherein y is 2.
125. Where the Ring A defined in any of 57 to 124 comprises an NH group, said NH group may be substituted by R4 to give NR4.
126. Each R4 is independently selected from: halo, -CN, -NO2, =0, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5SO2R6, and -SO2NR5R6.
127. Each R4 is independently selected from: halo, -CN, -NO2, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, -OC(O)R5, - C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5SO2R6, and -SO2NR5R6. Thus it may be that each R4 is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -C(O)NR5R6, -NR5SO2R6, and -SO2NR5R6.
128. Each R4 is independently selected from: halo, -CN, =0, C1.6 alkyl, C1.6 haloalkyl, Q1, -OR5, -NR5R6, -C(O)R5, -C(O)OR5, and -C(O)NR5R6.
129. Each R4 is independently selected from: halo, -CN, C1.4 alkyl, C1.4 haloalkyl, -OR5, -NR5R6, -C(O)R5, -C(O)OR5, and -C(O)NR5R6.
130. Each R4 is independently selected from: halo, -CN, =0, C1.6 alkyl, 2 to 8 membered heteroalkyl, Q1, -OR5, -NR5R6, -C(O)R5, -C(O)NR5R6 and -NR5C(O)R6
131. Each R4 is independently selected from: halo, -CN, C1.4 alkyl, -OR5, -NR5R6, - C(O)R5, -C(O)NR5R6 and -NR5C(O)R6.
132. Each R4 is independently selected from: halo, -CN, C1.4 alkyl, -C(O)R5 and - C(O)NR5R6.
133. Each R4 is independently selected from halo (e.g. fluoro or chloro), -CN, C1.3 alkyl, -OC1.3 alkyl, -C(O)Ci-3 alkyl, -C(O)NH2, -C(O)NH(CI-3 alkyl) and -C(O)N(Ci.3alkyl)2.
134. Each R4 is independently selected from halo (e.g. fluoro or chloro), -CN, C1.3 alkyl and -OC1.3 alkyl. Thus it may be that each R4 is independently selected from halo, - CN and C1.3 alkyl. Thus it may be that each R4 is independently selected from fluoro, chloro, -CN, methyl and methoxy. For example each R4 is independently selected from fluoro, chloro, -CN and methyl.
135. R4 is as defined in any one of 126 to 131 , wherein said Ci-e alkyl or 2 to 8 membered heteroalkyl is substituted by one or more R7. 136. R5 and R6 are each independently selected from: H, Ci-e alkyl, and Q1.
137. R5 and R6 are each independently selected from: H, C1.3 alkyl and Q1.
138. R5 and R6 are each independently selected from: H and C1.3 alkyl.
139. R5 and R6 are as defined in 136 to 138, wherein said alkyl is substituted by one or more R8.
140. R7 and R8 are each independently selected from: -C(O)R7A, -OC(O)R7A, -C(O)OR7A, -NR7AC(O)R7B and -C(O)NR7AR7B
141. R7 and R8 are each independently selected from: halo, -CN, -OR7A, -NR7AR7B and Q2.
142. R7 and R8 are each independently selected from: halo, -OR7A and Q2.
143. Q1 and Q2 are each independently selected from: C3-6 cycloalkyl and 4- to 7- membered heterocyclyl.
144. Q1 and Q2 are each independently 4- to 6-membered heterocyclyl.
145. Q1 and Q2 are each independently selected from: oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl and dihydropyranyl.
146. Q1 and Q2 are each independently selected from: phenyl and 5- or 6-membered heteroaryl.
147. Q1 and Q2 are as defined in any of 143 or 146, wherein Q1 and Q2 are substituted by one or more R9.
148. Each R9 is independently selected from: halo, =0, -CN, -NO2, C1.4 alkyl, C1.4 haloalkyl, -OR9A, and -NR9AR9B.
149. R9 is as defined in 148, wherein said C1.4 alkyl is substituted by 1 or 2 substituents selected from: halo, -CN, -OR9C, -NR9CR9D and -SO2R9C
150. R7A, R7B, R9A, R9B, R9C, and R9D are at each occurrence independently selected from: H, and C1.4 alkyl.
151. R7A, R7B, R9A, R9B, R9C, and R9D are at each occurrence independently selected from: H, methyl, and ethyl.
152. R7A, R7B, R9A, R9B, R9C, and R9D are at each occurrence independently selected from: H and methyl.
153. Each R4 is independently selected from:
154. Each R4 or R4a is 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, - C(O)OMe, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl and dihydropyranyl.
155. Each R4 or R4a is 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.
156. Each R4 or R4a is independently selected from: F, -CN, methyl, -C(O)Me, -C(O)NH2, -C(O)NH(Me) and -C(O)N(Me)2.
157. Each R4 or R4a is independently selected from: halo (e.g. fluoro), -CN and C1.3 alkyl (e.g. methyl). This it may be that each R4 is independently selected from: fluoro, - CN and methyl.
158. Ring A is selected from:
159. Ring A is selected from: . y It may be that Ring A is It may be that Ring may be that Ring A is . It may be that Ring A is may be that Ring A is 65. Ring A is selected from: . may be that Ring
A is . It may be that Ring may be that Ring A is
166. a is an integer from 0 to 5. 167. a is an integer from 0 to 3.
168. a is 3.
169. a is 2.
170. a is 1.
171. a is 0. 172. x is 0.
173. x is 1. 174. x is 2.
175. R4a and R4b are each independently selected from: halo, -CN, -NO2, =0, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, Q1, -OR5, -S(O)XR5, -NR5R6, - C(O)R5, -OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5SO2R6, and - SO2NR5R6. Thus it may be that R4a and R4b are each independently selected from: halo, -CN, -NO2, C1.6 alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, Q1, -OR5, - S(O)XR5, -NR5R6, -C(O)R5, -OC(O)R5, -C(O)OR5, -C(O)NR5R6, -NR5SO2R6, and - SO2NR5R6.
176. Each R4a and R4b is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, -OC(O)R5, -C(O)OR5, -NR5C(O)R6, - C(O)NR5R6, -NR5SO2R6, and -SO2NR5R6.
177. Each R4a and R4b is independently selected from: halo, -CN, =0, C1.6 alkyl, C1.6 haloalkyl, Q1, -OR5, , -NR5R6, -C(O)R5, -C(O)OR5, and -C(O)NR5R6.
178. Each R4a and R4b is independently selected from: halo, -CN, C1.6 alkyl, C1.6 haloalkyl, Q1, -OR5, -NR5R6, -C(O)R5, -C(O)OR5, and -C(O)NR5R6.
179. Each R4a and R4b are each independently selected from: halo, -CN, =0, C1.6 alkyl, Q1, -OR5, -NR5R6, -C(O)R5, and -NR5C(O)R6
180. Each R4a and R4b is selected from: halo (e.g. fluoro or chloro), -CN, C1.3 alkyl, -OC1.3 alkyl, -C(O)Ci-3 alkyl, -C(O)NH2, -C(O)NH(CI-3 alkyl) and -C(O)N(Ci.3alkyl)2 .
181. Each R4a and R4b is selected from: halo (e.g. fluoro), -CN and C1.3 alkyl (e.g. methyl).
182. R4a and R4b are each as defined in any one of 175 to 179, wherein said Ci-e alkyl is substituted by one or more R7.
183. R4c is independently selected from: H, Ci-e alkyl, Ci-e haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.
184. R4c is independently selected from: Ci-e alkyl, Ci-e haloalkyl, C2-6 alkenyl, and C2-6 alkynyl.
185. R4c is independently selected from: Ci-e alkyl and Ci-e haloalkyl.
186. R4c is as defined in any of 183 to 185, wherein said Ci-e alkyl is optionally substituted by one or more R7.
187. Ring B is selected from phenyl or 6-membered heteroaryl.
188. Ring B is 6-membered heteroaryl. 189. Ring B is 5-membered heteroaryl.
190. Ring B is selected from furanyl, thienyl furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, phenyl, pyridyl, pyrimidinyl, and pyrazinyl.
191. Ring B is selected from furanyl, thienyl furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, phenyl, pyrimidinyl, and pyrazinyl.
192. Ring B is selected from furanyl, pyrazolyl, oxazolyl, isoxazolyl and phenyl.
193. Ring B is furanyl.
194. Ring B is pyrazolyl.
195. Ring B is oxazolyl.
196. Ring B is isoxazolyl.
197. Ring B is phenyl.
198. Ring B is as defined in any of 187 to 197 and is substituted by one or more R10.
199. Ring B is selected from:
200. Ring B is selected from:
202. Ring B is selected from:
204. Ring B is as defined in any of 199 to 203, wherein z is an integer from 0 to 5, where chemically possible. Thus it may be that Ring B is as defined in any of 199 to 203, wherein z is 0, 1 or 2. It may be that Ring B is as defined in any of 199 to 203, wherein z s 1 or 2. . Ring B is as defined in any of 199 to 203, wherein z is 2. . Ring B is as defined in any of 199 to 203, wherein z is 1. . Ring B is as defined in any of 199 to 203, wherein z is 0. . Ring B is selected from: . Ring B is phenyl substituted by one or two R10 selected from halo and Ci-shaloalkyl.
Thus it may be that Ring B is 4-fluorophenyl or 4-trifluoromethylphenyl. It may be that Ring B is 4-fluorophenyl. It may be that Ring B is 4-trifluoromethylphenyl.. Ring B is selected from: . Ring B is selected from:
214. Where the Ring B defined in any of 187 to 201 comprises an NH group, said NH group may be substituted by R10 to give NR10.
215. Each R10, R10a, and R10b is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, -OR10A, -S(O)xR10A, and -NR10AR10B.
216. Each R10, R10a, and R10b is independently selected from -C(O)R10A, -OC(O)R10A, - C(O)OR10A, -NR10AC(O)R10B, -C(O)NR10AR10B, -NR10AC(O)OR10B, -OC(O)NR10AR10B, - NR10ASO2R10B, and -SO2NR10AR10B.
217. Each R10, R10a, and R10b is independently selected from: halo, -CN, -NO2, Ci-e alkyl, C1.6 haloalkyl, -OR10A, and -S(O)xR10A
218. Each R10, R10a, and R10b is independently selected from: halo, -CN, -NO2, C1.3 alkyl, C1.3 haloalkyl, -OR10A, and -S(O)xR10A
219. Each R10, R10a, and R10b is independently selected from: halo, C1.3 alkyl, C1.3 haloalkyl, -OC1.3 alkyl and -OC1.3 haloalkyl.
220. Each R10, R10a, and R10b is independently selected from: halo and C1.3 alkyl.
221. Each R10, R10a, and R10b is independently selected from: halo, -CN, -NO2, methyl, CF3, -OH, -OMe, and -S(O)2Me.
222. Each R10, R10a, and R10b is independently selected from: fluoro, chloro, -CN, -NO2, methyl, -CF3, -OH, -OMe, and -S(O)2Me. 223. Each R10, R10a, and R10b is independently selected from: fluoro, chloro, methyl, - CF3, methoxy, -OCF3 and -OCHF2.
224. Each R10, R10a, and R10b is independently selected from: fluoro and methyl.
225. R10 and R10a are fluoro.
226. R10, R10a, and R10b are fluoro.
227. R10a and R10bare fluoro.
228. R10 and R10a are -CF3.
229. R10, R10a, and R10b are as defined in any of 215 and 217 to 220, wherein said alkyl is substituted by one or more R11.
230. Each R11 is independently selected from: halo, -CN, -OR11A, -NR11AR11B and - SO2R11A.
231. Each R11 is independently selected from: halo, -CN, -OR11A, and -NR11AR11B.
232. Each R11 is independently selected from: halo and -OR11A.
233. R10A, R10B, R11A and R11B are at each occurrence independently selected from: H, and C1.4 alkyl.
234. R10A, R10B, R11A and R11B are at each occurrence independently selected from: H, methyl, and ethyl.
235. R10A, R10B, R11A and R11B are at each occurrence independently selected from: H and methyl.
236. c is an integer from 0 to 5.
237. c is an integer from 0 to 4.
238. c is an integer from 0 to 3.
239. c is 3.
240. c is 2.
241. c is 1.
242. c is 0.
243. Any -NR5R6, -NR7AR7B, -NR9AR9B, -NR9CR9D, -NR10AR10B, and -NR11AR11B within a substituent may form a 4-membered heterocyclyl.
244. Any -NR5R6, -NR7AR7B, -NR9AR9B, -NR9CR9D, -NR10AR10B, and -NR11AR11B within a substituent may form a 5-membered heterocyclyl. 245. Any -NR5R6, -NR7AR7B, -NR9AR9B, -NR9CR9D, -NR10AR10B, and -NR11AR11B within a substituent may form a 6-membered heterocyclyl.
246. Any 4- to 6-membered heterocyclyl defined in any of 243 to 245 is substituted by one or more substituents selected from: halo, =0, C1.4 alkyl and C1.4 haloalkyl. 247. Any 4- to 6-membered heterocyclyl defined in any of 243 to 245 is substituted by one or more substituents selected from: halo, C1.4 alkyl and C1.4 haloalkyl.
248. Any 4- to 6-membered heterocyclyl defined in any of 243 to 245 is substituted by one or more substituents selected from: halo and C1.4 alkyl.
249. The group of the formula:
250. The group of the formula:
251. The group of the formula:
252. The group of the formula:
[00201] In an embodiment, the compound of formula (I) is a compound of any of formulae (I) to (XXXXII), wherein L is a bond.
[00202] In an embodiment, the compound of formula (I) is a compound of any of formulae (I) to (XXXXII), wherein L is -CH2-.
[00203] In an embodiment, the compound of formula (I) is a compound of any of formulae (I) to (XXXXII), wherein L is a bond and R3 is selected from methyl, ethyl, and -CH2CH2F.
[00204] In an embodiment, the compound of formula (I) is a compound of any of formulae (I) to (XXXXII), wherein L is a bond and R3 is methyl or ethyl.
[00205] In an embodiment, the compound of formula (I) is a compound of any of formulae (I) to (XXXXII), wherein R12 is H.
[00206] In certain embodiments, the compound is a compound according to any of formulae (I), (la), (III), (Illa), (V), (VII), (Vila), (IX), (IXa), (XI), (Xia), (XIII), (Xllla), (XV), (XVa), (XVII), (XVIIa), (XIX), (XIXa), (XXI), (XXIa), (XXIII), (XXIIIa), (XXV), (XXVa), (XXVII), (XXVIla), (XXIX), (XXXI), (XXXII), (XXXIIa), (XXXIII), (XXXIIIa), (XXXIV), (XXXIVa), (XXXV), (XXXVa), (XXXVI), (XXXVIa), (XXXVII), (XXXVIII), (XXXIV), and (XXXX), wherein R1 is selected from -CH2F, -CHF2 and -CF3. [00207] Suitably in this embodiment R2 is H. Suitably in this embodiment L is a bond and R3 is selected from methyl, ethyl, and -CH2CH2F.
[00208] In certain embodiments in any of the compounds of formulae (I), (la), (II), (Ila), (III), (Illa), (IV), (IVa), (V), (Va), (VI), (Via), (VII), (Vila), (VIII), (Villa), (IX), (IXa) (X), (Xa), (XI), (Xia), (XII), (Xlla), (XIII), (Xllla), (XIV), (XlVa), (XV), (XVa), (XVI), (XVIa), (XVII), (XVIIa) , (XVIII) , (XVIIIa), (XIX), (XIXa), (XX), (XXa), (XXI), (XXIa), (XXII), (XXIIa), (XXIII), (XXI Ila), (XXIV) and (XXIVa) L is a bond; R2 (when present) is H; R3 is selected from methyl, ethyl and -CH2CH2F; and Ring B is as defined in any of 187 to 213.
[00209] In these embodiments it may be that R3 is methyl or ethyl.
[00210] In these embodiments it may be that R3 is methyl. In these embodiments it may be that R3 is ethyl. In these embodiments it may be that R3 is -CH2CH2F. In these embodiments it may be that R12 is H.
[00211] In these embodiments it may be that Ring B is unsubstituted or is substituted by one or two R10 (or R10a and/or R10b as appropriate for each formula), wherein each R10, R10a and R10b is independently as defined in any of 215 to 229. Thus it may be that Ring B is unsubstituted or is substituted by one or two R10 (or R10a as appropriate for each formula), wherein each R10 and R10a is independently selected from: halo, C1.3 alkyl, C1.3 haloalkyl, - OC1.3 alkyl and -OC1.3 haloalkyl.
[00212] In these embodiments it may be that Ring B is unsubstituted phenyl or phenyl substituted by one or two R10 (or R10a and/or R10b as appropriate for each formula), wherein each R10, R10a and R10b is independently as defined in any of 215 to 229. For example each R10, R10a and R10b is independently selected from: halo, C1.3 alkyl, C1.3 haloalkyl, - OC1.3 alkyl and -OC1.3 haloalkyl.
[00213] In these embodiments it may be that Ring B is phenyl substituted by one or two R10 (or R10a and/or R10b as appropriate for each formula), wherein each R10, R10a and R10b is independently as defined in any of 215 to 229; and R3 is methyl or ethyl. For example each R10, R10a and R10b is independently selected from: halo, C1.3 alkyl, C1.3 haloalkyl, -OC1.3 alkyl and -OC1.3 haloalkyl. Thus it may be that each R10, R10a and R10b is independently selected from: fluoro, chloro, methyl, -CF3, methoxy and -OCF3
[00214] In certain embodiments in any of the compound of any of formulae (I), (la), (II), (Ila), (XXV), (XXVa), (XXVI), (XXVIa), (XXVII), (XXVIla), (XXVIII), (XXVIlla), (XXIX), (XXIXa), (XXX) and (XXXa): L is a bond; R2 (when present) is H; R3 is selected from methyl, ethyl and -CH2CH2F; and Ring A is as defined in any of 57 to 118. In these embodiments it may be that R12 is H. [00215] In these embodiments it may be that Ring A is optionally substituted by one or more (e.g. 1 or 2) R4 (or R4a as appropriate for each formula), wherein each R4 or R4a is independently selected from: halo, -CN, Ci-e alkyl, Ci-e haloalkyl, -OR5, , -NR5R6, -C(O)R5, -C(O)OR5, and -C(O)NR5R6. Thus it may be that Ring A is optionally substituted by one or more (e.g. 1 or 2) R4 (or R4a as appropriate for each formula), wherein each R4 or R4a is 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) R4 (or R4a as appropriate for each formula), wherein each R4 or R4a is independently selected from: F, Cl, -CN, methyl and methoxy.
[00216] In these embodiments it may be that R3 is methyl or ethyl. In these embodiments it may be that R3 is methyl. In these embodiments it may be that R3 is ethyl. In these embodiments it may be that R3 is -CH2CH2F.
[00217] In certain embodiments in any of the compounds of the formulae (I), (la), (II), (Ila), (XXV), (XXVa), (XXVI), (XXVIa), (XXVII), (XXVIla), (XXVIII), (XXVIlla), (XXIX), (XXIXa), (XXX) and (XXXa): L is a bond; R2 (when present) is H; R3 is selected from methyl, ethyl and -CH2CH2F; and Ring A is as defined in any of 158 to 164. In these embodiments it may be that R3 is methyl or ethyl. In these embodiments it may be that R3 is methyl. In these embodiments it may be that R3 is ethyl. In these embodiments it may be that R3 is - CH2CH2F. In these embodiments it may be that R12 is H.
[00218] In certain embodiments the compound of any of formulae (I), (la), (II), (Ila), (XXV), (XXVa), (XXVI), (XXVIa), (XXVII), (XXVIla), (XXVIII), (XXVIlla), (XIX), (XIXa), (XXX) and (XXXa) is a compound wherein Ring A is not a ring according to the structure: wherein:
Y1, Y2, Y3 and Y4 are each independently CH or N, provided no more than two of Y1, Y2, Y3 and Y4 are N; t and u are each independently 0, 1 , 2, or 3; optionally wherein the ring system is substituted by one or more R4, wherein R4 is as defined for formula (I). [00219] In certain embodiments the compound of any of formulae (I), (la), (II), (Ila), (XXV), (XXVa), (XXVI), (XXVIa), (XXVII), (XXVIla), (XXVIII), (XXVIlla), (XIX), (XiXa), (XXX) and (XXXa) is a compound wherein Ring A is not a structure selected from: optionally wherein the ring system is substituted by one or more R4, wherein R4 is as defined for formula (I).
[00220] In certain embodiments, the compound is a compound according to any of formulae (I), (la), (II), (Ila), (III), (Illa), (IV), (IVa), (V), (Va), (VI), (Via), (VII), (Vila), (VIII), (Villa), (IX), (IXa) (X), (Xa), (XI), (Xia), (XII), (Xlla), (XIII), (Xllla), (XIV), (XlVa), (XV), (XVa), (XVI), (XVIa), (XVII), (XVIIa) , (XVIII) , (XVIIIa), (XIX), (XIXa), (XX), (XXa), (XXI), (XXIa), (XXII), (XXIIa), (XXIII), (XXII la), (XXIV) and (XXIVa), wherein Ring B is not pyridyl.
[00221] In certain embodiments, the compound is a compound according to any of formulae (I), (la), (II), (Ila), (III), (Illa), (IV), (IVa), (V), (Va), (VI), (Via), (VII), (Vila), (VIII), (Villa), (IX), (IXa) (X), (Xa), (XI), (Xia), (XII), (Xlla), (XIII), (Xllla), (XIV), (XlVa), (XV), (XVa), (XVI), (XVIa), (XVII), (XVIIa) , (XVIII) , (XVIIIa), (XIX), (XIXa), (XX), (XXa), (XXI), (XXIa),
(XXII), (XXIIa), (XXIII), (XXIIIa), (XXIV) and (XXIVa), wherein Ring B is not
[00222] In certain embodiments, the compound is a compound according to any of formulae (I), (la), (II), (Ila), (III), (Illa), (IV), (IVa), (V), (Va), (VI), (Via), (VII), (Vila), (VIII), (Villa), (IX), (IXa) (X), (Xa), (XI), (Xia), (XII), (Xlla), (XIII), (Xllla), (XIV), (XlVa), (XV), (XVa), (XVI), (XVIa), (XVII), (XVIIa) , (XVIII) , (XVIIIa), (XIX), (XiXa), (XX), (XXa), (XXI), (XXIa),
(XXII), (XXIIa), (XXIII), (XXIIIa), (XXIV) and (XXIVa), wherein Ring B is not
[00223] In certain embodiments, the compound is a compound according to any of formulae (I), (la), (II), (Ila), (III), (Illa), (IV), (IVa), (V), (Va), (VI), (Via), (VII), (Vila), (VIII), (Villa), (IX), (IXa) (X), (Xa), (XI), (Xia), (XII), (Xlla), (XIII), (Xllla), (XIV), (XlVa), (XV), (XVa), (XVI), (XVIa), (XVII), (XVIIa) , (XVIII) , (XVIIIa), (XIX), (XiXa), (XX), (XXa), (XXI), (XXIa),
(XXII), (XXIIa), (XXIII), (XXIIIa), (XXIV) and (XXIVa), wherein Ring B is not
[00224] In certain embodiments, the compound is a compound according to any of formulae (III), (Illa), (IV), (IVa), (V), (Va), (VI), (Via), (VII), (Vila), (VIII), (Villa), (IX), (IXa) (X), (Xa), (XI), (Xia), (XII), (Xlla), (XIII), (Xllla), (XIV), (XlVa), (XV), (XVa), (XVI), (XVIa), (XVII), (XVIIa) , (XVIII) , (XVIIIa), (XIX), (XIXa), (XX) and (XXa), wherein each R4a is independently as defined in any of 175 to 181.
[00225] Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is selected from methyl, ethyl and -CH2CH2F. Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is methyl. Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is ethyl. Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is -CH2CH2F. In these embodiments it may be that R12 is H.
[00226] In certain embodiments, the compound is a compound according to any of formulae (XXV), (XXVa), (XXVI), (XXVIa), (XXVII), (XXVIla), (XXVIII), (XXVIlla), (XIX), (XIXa), (XXX), (XXXa), (XXXI), (XXXIa), (XXXIb), (XXXIc), (XXXII), (XXXIIa), (XXXIIb) (XXXIIc), (XXXIII), (XXXIIIa), (XXXIIIb), (XXXIIIc) (XXXIV), (XXXIVa), (XXXIVb), (XXXIVc), (XXXV), (XXXVa), (XXXVb), (XXXVc), (XXXVI), (XXXVIa), (XXXVIb) (XXXVIc), (XXXVII), (XXXVIla), (XXXVIlb), (XXXVIII), (XXXVIlla), (XXXVIHb), (XXXIX), (XXXIXa), (XXXIXb), (XXXX), (XXXXI), and (XXXXII), wherein each R10a is independently as defined in any of 215 to 229.
[00227] Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is selected from methyl, ethyl and -CH2CH2F. Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is methyl. Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is ethyl. Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is -CH2CH2F. In these embodiments it may be that R12 is H.
[00228] In certain embodiments, the compound is a compound according to any of formulae (XXXI), (XXXIa), (XXXIb), (XXXIc), (XXXII), (XXXIIa), (XXXIIb), (XXXIIc), (XXXV), (XXXVa), (XXXVb), (XXXVc), (XXXVI), (XXXVIa), (XXXVIb) and (XXXVIc), wherein each R4a is independently selected from: halo (e.g. fluoro or chloro), -CN, C1.3 alkyl, -OC1.3 alkyl, -C(O)Ci-3 alkyl, -C(O)NH2, -C(O)NH(CI-3 alkyl) and -C(O)N(Ci.3 alkyl)2 ; and each R10a is independently selected from: halo, C1.3 alkyl, C1.3 haloalkyl, -OC1.3 alkyl and -OC1.3 haloalkyl.
[00229] In this embodiment it may be that each R4a is independently selected from: halo, - CN and C1.3 alkyl, and each R10a is independently selected from: halo, C1.3 alkyl, C1.3 haloalkyl, -OC1.3 alkyl and -OC1.3 haloalkyl.
[00230] In this embodiment it maybe that each R4a is independently selected from: fluoro, chloro, -CN, methyl and -OMe; and each R10a is independently selected from: fluoro, chloro, methyl, -CF3, methoxy, -OCF3 and -OCHF2. [00231] Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is selected from methyl, ethyl and -CH2CH2F. Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is methyl. Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is ethyl. Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is -CH2CH2F. In these embodiments it may be that R12 is H.
[00232] In certain embodiments the compound is of the formula (XXXII), (XXXIIa), (XXXIIb) or (XXXIIc), wherein the group of the formula: this embodiment it may be that each R10a is independently as defined in any of 215 to 228.
[00233] Suitably in these embodiments each R10a may be independently selected from: fluoro, chloro, methyl, -CF3, methoxy, -OCF3 and -OCHF2.
[00234] Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is selected from methyl, ethyl and -CH2CH2F.
[00235] Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is selected from methyl, ethyl and -CH2CH2F. Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is methyl. Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is ethyl. Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is -CH2CH2F. In these embodiments it may be that R12 is H.
[00236] In certain embodiments the compound is of the formula (XXXII), (XXXIIa), (XXXIIb) or (XXXIIc), wherein the group of the formula: independently as defined in any of 215 to 228.
[00237] Suitably in these embodiments each R10a may be independently selected from: fluoro, chloro, methyl, -CF3, methoxy, -OCF3 and -OCHF2.
[00238] Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is selected from methyl, ethyl and -CH2CH2F. Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is methyl. Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is ethyl. Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is -CH2CH2F. In these embodiments it may be that R12 is H. [00239] In certain embodiments the compound is of the formula (XXI), (XXIa), (XII), (Xlla), (XXXIII), (XXXIIIa), (XXXIIIb), (XXXIIIc) (XXXIV), (XXXIVa), (XXXIVb) or (XXXIVc) wherein the group of the formula: , wherein R4a is selected from: halo, -CN, Ci-6 alkyl, Ci-6 haloalkyl, -OR5, -NR5R6, -C(O)R5, -C(O)OR5, and - C(O)NR5R6; and each R10 (or R10a or R10b as appropriate for each formula) is independently as defined in any of 215 to 228.
[00240] Suitably in these embodiments R4a is selected from: halo, -CN and C1.3 alkyl. For example, it may be that R4a is selected from: F, -CN and methyl.
[00241] Thus it may be that the group of the formula:
[00243] Suitably in these embodiments the group of the formula: each R10 (or R10a or R10b as appropriate for each formula) is independently selected from: halo, C1.3 alkyl, C1.3 haloalkyl, -OC1.3 alkyl and -OC1.3 haloalkyl. Thus each R10a or R10b may be independently selected from: fluoro, chloro, methyl, -CF3, methoxy and -OCF3.
[00244] Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is selected from methyl, ethyl and -CH2CH2F. Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is methyl. Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is ethyl. Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is -CH2CH2F. [00245] In certain embodiments the compound is of the formula (I), (la), (II), (Ila), (XXV), (XXVa), (XXVI), (XXVIa), (XXVII), (XXVIla), (XXVIII), (XXVIlla), (XXIX), (XXX) and (XXXa), Ring A is selected from: and L is a bond.
[00246] Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is selected from methyl, ethyl and -CH2CH2F. Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is methyl. Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is ethyl. Suitably in these embodiments L is a bond; R2 (when present) is H; and R3 is -CH2CH2F. In these embodiments it may be that R12 is H.
[00247] In certain embodiments the compound is of the formula (XVII), (XVIIa), (XVIII) or (XVI I la), Ring D is selected from: benzene, pyridine, pyrimidine, pyridazine and pyrazine, and Ring E is selected from: pyrrole, imidazole, pyrazole, triazole and tetrazole, and wherein the 9-membered fused bicyclic heteroaryl ring formed by Ring D and Ring E is attached to -L- by a ring atom in Ring D.
[00248] In certain embodiments the compound is of the formula (XVII), (XVIIa), (XVIII) or
(XVI I la), the group of the formula: or 2) R4a, wherein each R4a is independently as defined in any of 175 to 181 , and wherein the 9-membered fused bicyclic heteroaryl ring formed by Ring D and Ring E is attached to -L- by a ring atom in Ring D. [00249] In certain embodiments the compound is of the formula (XVII), (XVIIa), (XVIII) or
(XVI I la), the group of the formula: , which is optionally substituted with 1 , 2 or 3 (e.g. 1 or 2) R4a, wherein each R4a is independently as defined in any of 175 to 181 , and wherein the 9-membered fused bicyclic heteroaryl ring formed by
Ring D and Ring E is attached to -L- by a ring atom in Ring D.
[00250] In certain embodiments the compound is of the formula (XVII), (XVIIa), (XVIII) or
(XVI I la), the group of the formula: wherein: Xi and X2 are each independently N, or C, provided at least one of Xi and X2 is N; and Ring E is a fused 5-membered heteroaryl containing at least one (e.g. 1 , 2, or 3) ring nitrogen, and wherein the 9-membered fused bicyclic heteroaryl ring formed by Ring D and Ring E is attached to -L- by a ring atom in Ring D.
[00251] Thus it may be that is selected from: each of which is optionally substituted with 1 , 2 or 3 (e.g. 1 or 2) R4a, wherein each R4a is independently as defined in any of 175 to 181. For example, the 9-membered fused bicyclic heteroaryl ring formed by Ring D and Ring E is selected from: optionally substituted with 1 , 2 or 3 (e.g. 1 or 2) R4a, wherein each R4a is independently as defined in any of 175 to 181 . [00252] Suitably in these embodiments of the formulae (XVII), (XVIIa), (XVIII) and (XVI Ila), each R4a is independently selected from: halo, C1.3 alkyl and -OC1.3 alkyl. For example, each R4a is independently selected from: F, Cl, methyl and methoxy.
[00253] Suitably in these embodiments of the formulae (XVII), (XVIIa), (XVIII) and (XVII la) the fused bicyclic heteroaryl formed by Ring D and Ring E is unsubstituted.
[00254] Suitably in these embodiments of these embodiments of the formulae (XVII), (XVIIa), (XVIII) and (XVI Ila), L is a bond; R2 (when present) is H; and R3 is selected from methyl, ethyl and -CH2CH2F. Thus it may be that L is a bond; R2 (when present) is H; and R3 is methyl. It may be that L is a bond; R2 (when present) is H; and R3 is ethyl. It may be that L is a bond; R2 (when present) is H; and R3 is -CH2CH2F.
[00255] In certain embodiments the compound is of the formula (XIX), (XIXa), (XX) or (XXa) Ring F is selected from: pyrrole, imidazole, pyrazole, triazole and tetrazole and Ring G is selected from: benzene, pyridine, pyrimidine, pyridazine and pyrazine, and wherein the 9-membered fused bicyclic heteroaryl ring formed by Ring F and Ring G is attached to -L- by a ring atom in Ring F.
[00256] In certain embodiments the compound is of the formula (XIX), (XIXa), (XX) or
(XXa), the group of the formula: wherein the 9-membered fused bicyclic heteroaryl ring formed by Ring G and the imidazole ring is attached to -L- by a ring atom in the imidazole ring.
[00257] Thus it may be that selected from: each of which is optionally substituted with 1, 2 or 3 (e.g. 1 or 2) R4a, wherein each R4a is independently as defined in any of 175 to 181, wherein the 9-membered fused bicyclic heteroaryl ring formed by Ring G and the imidazole ring is attached to -L- by a ring atom in the imidazole ring. For example, the 9-membered fused bicyclic heteroaryl ring formed by Ring G and the imidazole ring is selected from: ptionally substituted with 1 , 2 or 3 (e.g. 1 or 2) R4a, wherein each R4a is independently as defined in any of 175 to 181.
[00258] Thus it may be that , which is optionally substituted with 1 , 2 or 3 (e.g. 1 or 2) R4a, wherein each R4a is independently as defined in any of 175 to 181, wherein the ring is attached to -L- by a ring atom in the imidazole ring.
For example, the ring may be o which is optionally substituted with 1 , 2 or 3
(e.g. 1 or 2) R4a, wherein each R4a is independently as defined in any of 175 to 181.
[00259] Suitably in these embodiments of formulae (XIX), (XIXa), (XX) or (XXa) each R4a is independently selected from: halo, C1.3 alkyl and -OC1.3 alkyl. For example, each R4a is independently selected from: F, Cl, methyl and methoxy.
[00260] Suitably in these embodiments of the formulae (XIX), (XIXa), (XX) or (XXa) the fused bicyclic heteroaryl formed by Ring F and Ring G is unsubstituted.
[00261] Suitably in these embodiments of the formulae (XIX), (XIXa), (XX) or (XXa), L is a bond; R2 (when present) is H; and R3 is selected from: methyl, ethyl and -CH2CH2F. Thus it may be that L is a bond; R2 (when present) is H; and R3 is methyl. It may be that L is a bond; R2 (when present) is H; and R3 is ethyl. It may be that L is a bond; R2 (when present) is H; and R3 is -CH2CH2F.
[00262] In certain embodiments of the compounds of formulae (I) to (XXXXII), the group of the formula: Suitably, in certain embodiments of the compounds of formulae (I) to (XXXXII), where L is a bond, the group of the formula:
[00263] In certain embodiments of the compounds of formulae (I) to (XXXXII), the group of Suitably, in certain embodiments of the compounds of formulae (I) to (XXXXII), where L is a bond, the group of the formula:
[00264] In certain embodiments of the formulae (I), (la), (II), (Ila), (XI), (Xia), (XII), (Xlla),
(XXI), (XXIa), (XXII), (XXIIa), (XXV), (XXVa), (XXVI), (XXVIa), (XXVII), (XXVIla), (XVIII),
(XVIIIa), (XXIX), (XXX), (XXXa), (XXXII), (XXXIIa), (XXXIIb), (XXXIIc), (XXXIII), (XXXIIIa), (XXXI I lb), (XXXI He), (XXXIV), (XXXI Va), (XXXI Vb), (XXXI Vc), (XXXIX), (XXXIXa), and
(XXXXII), the group of the formula:
R4a, and a are as defined for each formula therein.
[00265] In certain embodiments of the formulae (I), (la), (II), (Ila), (XIII), (Xllla), (XIV), and (XlVa), (XXI), (XXIa), (XXII), (XXIIa), (XXV), (XXVa), (XXVI), (XXVIa), (XXVII), (XXVIla), (XVIII), (XVIIIa), (XXIX), (XXX), (XXXa), (XXXIII), (XXXIIIa), (XXXIIIb), (XXXIIIc), (XXXIV), (XXXI Va), (XXXI Vb), (XXXI Vc), (XXXV), (XXXVa), (XXXVb), (XXXVc), (XXXIX), (XXXIXa), and (XXXIXb), the group of the formula: wherein
R12, R4a, and a are as defined for each formula therein.
[00266] In certain embodiments of the formulae (I), (la), (II), (Ila), (XI), (Xia), (XII), (Xlla),
(XXI), (XXIa), (XXII), (XXIIa), (XXV), (XXVa), (XXVI), (XXVIa), (XXVII), (XXVIla), (XVIII), (XVIIIa), (XXIX), (XXX), (XXXa), (XXXII), (XXXIIa), (XXXIIb), (XXXIIc), (XXXIII), (XXXIIIa),
(XXXI I lb), (XXXI He), (XXXIV), (XXXI Va), (XXXI Vb), (XXXI Vc), (XXXIX), (XXXIXa), and
(XXXIXb), the group of the formula:
R4a, and a are as defined for each formula therein.
[00267] In certain embodiments of the formulae (I), (la), (II), (Ila), (XIII), (Xllla), (XIV), and (XlVa), (XXI), (XXIa), (XXII), (XXIIa), (XXV), (XXVa), (XXVI), (XXVIa), (XXVII), (XXVIla), (XVIII), (XVIIIa), (XXIX), (XXX), (XXXa), (XXXIII), (XXXIIIa), (XXXIIIb), (XXXIIIc), (XXXIV), (XXXI Va), (XXXI Vb), (XXXI Vc), (XXXV), (XXXVa), (XXXVb), (XXXVc), (XXXIX), (XXXIXa), and (XXXIXb), the group of the formula: wherein
R12, R4a, and a are as defined for each formula therein. [00268] In certain embodiments of the formulae (I), (la), (II), (Ila), (XIII), (Xllla), (XIV), and
(XlVa), (XXI), (XXIa), (XXII), (XXIIa), (XXV), (XXVa), (XXVI), (XXVIa), (XXVII), (XXVIla), (XVIII), (XVIIIa), (XXIX), (XXX), (XXXa), (XXXIII), (XXXIIIa), (XXXIIIb), (XXXIIIc), (XXXIV), (XXXI Va), (XXXI Vb), (XXXI Vc), (XXXV), (XXXVa), (XXXVb), (XXXVc), (XXXIX), (XXXIXa), and (XXXIXb), the group of the formula: wherein
R12, R4a, and a are as defined for each formula therein.
[00269] In certain embodiments of the formulae (I), (la), (II), (Ila), (XIII), (Xllla), (XIV), and (XlVa), (XXI), (XXIa), (XXII), (XXIIa), (XXV), (XXVa), (XXVI), (XXVIa), (XXVII), (XXVIla), (XVIII), (XVIIIa), (XXIX), (XXX), (XXXa), (XXXIII), (XXXIIIa), (XXXIIIb), (XXXIIIc), (XXXIV), (XXXI Va), (XXXI Vb), (XXXI Vc), (XXXV), (XXXVa), (XXXVb), (XXXVc), (XXXIX), (XXXIXa), and (XXXIXb), the group of the formula: wherein
R12, R4a, and a are as defined for each formula therein.
[00270] In another embodiment there is provided a compound selected from Compound List 1 , or a pharmaceutically acceptable salt or N-oxide thereof:
Compound List 1
[00271] In another embodiment there is provided a compound selected from any one of the Examples herein, or a pharmaceutically acceptable salt or N-oxide thereof.
[00272] In another embodiment there is provided a compound selected from any one of the Examples 2, 4, 6, 8, 10, 24, and 38, or a pharmaceutically acceptable salt or N-oxide thereof.
[00273] 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. [00274] 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.
[00275] Compounds of the invention may exhibit one or more beneficial properties. In embodiments, compounds of the invention demonstrate one or more beneficial Absorption, Distribution, Metabolism, and Excretion (ADME) property. In embodiments, compounds of the invention exhibit one or more beneficial PK and or PD property. For example, compounds of the invention may exhibit improved solubility, plasma protein binding, mouse liver microsomes (MLM), human liver microsomes (HLM), CYP inhibition, and/or selectivity for Cav2.3 over Cav2.1.
PHARMACEUTICAL COMPOSITIONS
[00276] In accordance with another aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt or N-oxide thereof, and a pharmaceutically acceptable excipient.
[00277] It may be that the pharmaceutical composition comprises a compound selected from a compound according to any of formulae (I) to (XXXXII) or a pharmaceutically acceptable salt or N-oxide thereof.
[00278] It may be that the pharmaceutical composition comprises a compound selected from a compound according to any of formulae (I) to (XXXXII), or a pharmaceutically acceptable salt or N-oxide thereof,.
[00279] 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.
[00280] 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).
[00281] 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.
[00282] 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.
[00283] 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.
[00284] 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.
[00285] 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 intravenous administration. In another particular embodiment the compound of the invention is administered orally.
THERAPEUTIC USES AND APPLICATIONS
[00286] 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 (XXXXII), or a pharmaceutically acceptable salt or N-oxide thereof.
[00287] In accordance with another aspect, the present invention provides a compound of the invention, or a pharmaceutically acceptable salt or N-oxide thereof, for use as a medicament.
[00288] A further aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt or N-oxide thereof, for use in the prevention or treatment of a disease or medical disorder mediated by Cav2.3.
[00289] 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 or N-oxide thereof.
[00290] Also provided is the use of a compound of the invention, or a pharmaceutically acceptable salt or N-oxide thereof, for the manufacture of a medicament for the prevention or treatment of a disease or medical disorder mediated by Cav2.3.
[00291] In the following sections of the application reference is made to a compound of the invention, or a pharmaceutically acceptable salt or N-oxide 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 or N-oxide 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 or N-oxide thereof.
[00292] 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.
[00293] In certain embodiments there is provided a compound of the invention, or a pharmaceutically acceptable salt or N-oxide 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
[00294] 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.
[00295] 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. [00296] 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.
[00297] 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
[00298] 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), Phelan-McDermid syndrome, 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).
[00299] 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).
[00300] 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).
[00301] 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).
[00302] 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.
[00303] 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).
[00304] In certain embodiments a compound of the invention is for use in the treatment of epilepsy.
[00305] 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.
[00306] 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.
[00307] 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.
[00308] In some embodiments a compound of the invention is for use in the treatment or prevention of drug-resistant epilepsy. Drug-resistant epilepsy (also known as “uncontrolled,” “intractable” or “refractory” epilepsy) refers to epilepsy that fails to respond to, or relapses following treatment with an anti-epileptic therapy. Accordingly, in subjects with drugresistant epilepsy seizures persist despite treatment with one or more anti-epileptic therapies. For example, a subject may not respond to, or relapses after treatment with one or more anti-epileptic therapy (for example the subject does not respond to, or relapses after treatment with at least two anti-epileptic therapies). In certain embodiments the subject fails to respond to, or relapses after treatment with one or more anti-epileptic drug (AED), for example one or more of the AEDs listed herein in relation to combination therapies. The drug-resistant epilepsy may be any of the forms of epilepsy described herein that is, or has become resistant to treatment with one or more (e.g. at least two) anti-epileptic therapy. In some embodiments the drug- resista nt epilepsy is a drug-resistant focal epilepsy.
[00309] 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
[00310] 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
[00311] 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
[00312] Subjects which suffer a cerebral aneurism or aneurysmal subarachnoid haemorrhage (bleeding on the surface of the brain) often survive the initial trauma. However, often within a few days to two weeks subjects experience cerebral vasospasm, a constriction, or tightening, of arteries in the brain. Cerebral vasospasm restricts blood flow to the brain and may subsequently lead to the death of blood-starved brain tissue resulting in cerebral infarction. Expression of Cav2.3 may be increased following a cerebral aneurism or aneurysmal subarachnoid haemorrhage and may be implicated in cerebral vasospasm (Wang et al., supra). Accordingly, in some embodiments a compound of the invention is for use in the treatment or prevention of cerebral vasospasm. For example a compound of the invention is for use in the treatment or prevention of cerebral vasospasm in a subject who has suffered a cerebral aneurism or aneurysmal subarachnoid haemorrhage. In some embodiments a compound of the invention is for use in the treatment or prevention of cerebral infarction.
[00313] 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.
[00314] 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
[00315] 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.
[00316] 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).
[00317] Such combination treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within a therapeutically effective dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
[00318] 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.
[00319] 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).
FURTHER EMBODIMENTS
[00320] The invention is further illustrated by the following embodiments.
P1. A compound of the formula (I), or a pharmaceutically acceptable salt or N-oxide thereof: wherein:
R1 is selected from: Ci-e alkyl, C3-6 cycloalkyl, and Cs-e cycloalkyl-Ci-e alkyl-, wherein R1 is substituted by at least one fluorine; optionally wherein one or more H in R1 is substituted by D;
R2 is selected from: H, D, Ci-e alkyl and Ci-e haloalkyl; or
R1 and R2 together with the carbon atom to which they are attached form a C3-6 cycloalkyl substituted with at least one fluorine;
R3 is selected from: H, Ci-e alkyl and Ci-e haloalkyl; optionally wherein one or more H in R3 is substituted by D;
L is selected from: a bond and C1.3 alkylene;
Ring A is selected from: C3-6 cycloalkyl, 4- to 7-membered heterocyclyl, 5- to 12-membered heteroaryl and Ce- aryl; wherein Ring A is optionally substituted by one or more R4; each R4 is independently selected from: halo, -CN, -NO2, =0, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7;
R5 and R6 are each independently selected from: H, Ci-e alkyl, Ci-e haloalkyl and Q1, wherein said Ci-e alkyl is optionally substituted by one or more R8; each R7 and R8 is independently selected from: halo, -CN, -OR7A, -S(O)XR7A, -NR7AR7B, C(O)R7A, -OC(O)R7A, -C(O)OR7A, -NR7AC(O)R7B, -C(O)NR7AR7B and Q2; each Q1 and Q2 is independently selected from: C3-6 cycloalkyl, 4- to 7-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl, wherein said C3-6 cycloalkyl, 4- to 7-membered heterocyclyl, phenyl and 5- or 6- membered heteroaryl is optionally substituted by one or more R9; each R9 is independently selected from: halo, =0, -CN, -NO2, C1.4 alkyl, C1.4 haloalkyl, - OR9A, -S(O)2R9A, -NR9AR9B, -C(O)R9A, -OC(O)R9A, -C(O)OR9A, -NR9BC(O)R9A, - C(O)NR9AR9B, -NR9BC(O)OR9A, -OC(O)NR9AR9B, -NR9BSO2R9A and -SO2NR9AR9B, wherein said C1.4 alkyl is optionally substituted by 1 or 2 substituents selected from: halo, -CN, -OR9C, -NR9CR9D and -SO2R9C;
Ring B is phenyl or a 5- or 6-membered heteroaryl, wherein Ring B is optionally substituted by one or more R10; each R10 is independently selected from: halo, -CN, -NO2, =0, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2.6 alkenyl, C2.6 alkynyl, -OR10A, -S(O)xR10A, -NR10AR10B, - C(O)R10A, -OC(O)R10A, -C(O)OR10A, -NR10AC(O)R10B, -C(O)NR10AR10B, -NR10AC(O)OR10B, - OC(O)NR10AR10B, -NR10ASO2R10B, and -SO2NR10AR10B, wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2.6 alkenyl and C2.6 alkynyl is optionally substituted by one or more R11 ; each R11 is independently selected from: halo, -CN, -OR11A, -NR11AR11B and -SO2R11A;
R12 is independently selected from H, Ci-e alkyl, Ci-e haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-Ci-6 alkyl-, and COOR13; optionally wherein one or more H in R12 is substituted by D;
R13 is independently selected from H, Ci-e alkyl, Ci-e haloalkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-Ci-6 alkyl; optionally wherein one or more H in R13 is substituted by D;
R7A, R7B, R9A, R9B, R9C, R9D, R10A, R10B, R11A and R11 B are at each occurrence independently selected from: H, C1.4 alkyl and C1.4 haloalkyl; and wherein any -NR5R6, -NR7AR7B, -NR9AR9B, -NR9CR9D, -NR10AR10B, and - NR11AR11B within 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. P2. The compound according to P1 , wherein Ring A is a monocyclic 6-membered heteroaryl or a 9-membered fused bicyclic heteroaryl, wherein Ring A has 1 to 4 ring nitrogen atoms and wherein Ring A is optionally substituted with one or more R4.
P3. The compound according to P1 , wherein Ring A is a monocyclic 6-membered heteroaryl, wherein Ring A has 1 , 2 or 3 ring nitrogen atoms and wherein Ring A is optionally substituted with one or more R4.
P4. The compound according to P1 , wherein Ring A is selected from: thienyl, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, tetrahydropyranyl, optionally substituted with one or more R4. P5. The compound according to P1 or P2, wherein Ring A is selected from: substituted with one or more R4.
P6. The compound according to P1 or P3, wherein Ring A is selected from:
P7. The compound according to P1 or P3, wherein Ring A is selected from:
P8. The compound according to any one of P1 to P7, wherein each R4 is independently selected from: halo, -CN, -NO2, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, -OC(O)R5, -C(O)OR5, -C(O)NR5R6, -NR5SO2R6, and - SO2NR5R6.
P9. The compound according to any one of P1 to P7, wherein each R4 is independently selected from: halo (e.g. fluoro or chloro), -CN, C1.3 alkyl, -OC1.3 alkyl, -C(O)Ci-3 alkyl, - C(O)NH2, -C(O)NH(CI-3 alkyl) and -C(O)N(Ci-3alkyl)2; optionally wherein each R4 is independently selected from: fluoro and -CN.
P10. The compound according to claim 1 , wherein Ring A is selected from:
P11. The compound according to P1 , wherein the compound is a compound of the formula (XI), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R4a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; and a is an integer from 0 to 4.
P12. The compound according to P1 , wherein the compound is a compound of the formula (XIII), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R4a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; and a is an integer from 0 to 3.
P13. The compound according to P1 , wherein the compound is a compound of the formula (XXI), or a pharmaceutically acceptable salt or N-oxide thereof: wherein:
X3 is N or CR4a;
R4a is selected from: halo, -CN, -NO2, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, -OC(O)R5, - C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and - SO2NR5R6, wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2.6 alkenyl and C2.6 alkynyl is optionally substituted by one or more R7.
P14. The compound according to any one of P11 to P13, wherein each R4a is independently selected from: halo (e.g. fluoro or chloro), -CN, C1.3 alkyl, -OC1.3 alkyl, - C(O)Ci-3 alkyl, -C(O)NH2, -C(O)NH(CI-3 alkyl) and -C(O)N(Ci-3alkyl)2; optionally wherein each R4 is independently selected from: fluoro and -CN.
P15. The compound according to P13, wherein the group of the formula:
P16. The compound according to any one of P1 to P15, wherein Ring B is phenyl optionally substituted by one or more R10.
P17. The compound according to any one of P1 to P15, wherein Ring B is selected from:
P18. The compound according to any one of P1 to P15, wherein Ring B is P19. The compound according to any one of P1 to P18, wherein each R10 is independently selected from: halo, C1.3 alkyl, C1.3 haloalkyl, -OC1.3 alkyl and -OC1.3 haloalkyl.
P20. The compound according to any one of P1 to P19, wherein each R10 is fluoro.
P21. The compound according to any one of P1 to P15, wherein Ring B is selected from:
P22. The compound according to any one of P1 to P21 , wherein L is selected from a bond and -CH2-.
P23. The compound according to any one of P1 to P22, wherein L is a bond.
P24. The compound according to any one of P1 to P23, wherein R3 is selected from methyl, -CD3, ethyl, and 2-fluoroethyl.
P25. The compound according to any one of P1 to P23, wherein R3 is selected from methyl and ethyl.
P26. The compound according to any one of P1 to P25, wherein R12 is H.
P27. The compound according to any one of claims 1 to 25, wherein R12 is selected from
C1.6 alkyl, C1.6 haloalkyl, and C3-6 cycloalkyl.
P28. The compound according to any one of P1 to P27, wherein R1 is selected from Ci-e alkyl and C3-6 cycloalkyl, wherein R1 is substituted by at least one fluorine. P29. The compound according to any one of P1 to P27, wherein R1 is selected from CH2F, -CHF2, and -CF3.
P30. The compound according to any one of P1 to P27, wherein R1 is -CF3.
P31. The compound according to any one of P1 to P30, wherein R2 is selected from H and methyl.
P32. The compound according to any one of P1 to P30, wherein R2 is H.
P33. The compound of any one of P1 to P32, wherein the group of the formula:
P35. A compound selected from: pharmaceutically acceptable salt or N-oxide thereof.
P36. A compound selected from Compound List 1 in the description, or a pharmaceutically acceptable salt or N-oxide thereof.
P37. A pharmaceutical composition comprising a compound according to any one of P1 to P36, or a pharmaceutically acceptable salt or N-oxide thereof, and a pharmaceutically acceptable excipient.
P38. A compound according to any one of P1 to P36, or a pharmaceutically acceptable salt or N-oxide thereof, for use as a medicament.
P39. A compound according to any one of P1 to P36, or a pharmaceutically acceptable salt or N-oxide thereof, for use in the treatment of a disease or medical disorder mediated by Cav2.3.
P40. 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 P1 to P36, or a pharmaceutically acceptable salt or N-oxide thereof. P41. A compound according to any one of P1 to P36, or a pharmaceutically acceptable salt or N-oxide 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.
P42. A compound according to any one of P1 to P36, or a pharmaceutically acceptable salt or N-oxide thereof, for use in a neuroprotective treatment of a neurodegenerative disease.
P43. A compound according to any one of P1 to P36, or a pharmaceutically acceptable salt or N-oxide thereof, for use in the treatment of Parkinson’s disease.
P44. A compound according to any one of P1 to P36, or a pharmaceutically acceptable salt or N-oxide thereof, for use in a preventing or inhibiting degeneration of dopaminergic neurons in a subject with Parkinson’s disease.
P45. A compound according to any one of P1 to P36, or a pharmaceutically acceptable salt or N-oxide thereof, for use in the prevention or treatment of epilepsy; optionally wherein the epilepsy is a drug-resistant epilepsy.
P46. A compound according to any one of P1 to P36, or a pharmaceutically acceptable salt or N-oxide 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).
[00321] The invention is further illustrated by the following embodiments.
Q1. A compound of the formula (I), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: R1 is selected from: Ci-e alkyl, C3-6 cycloalkyl, and Cs-e cycloalkyl-Ci-e alkyl-, wherein R1 is substituted by at least one fluorine; optionally wherein one or more H in R1 is substituted by D;
R2 is selected from: H, D, Ci-e alkyl and Ci-e haloalkyl; or
R1 and R2 together with the carbon atom to which they are attached form a C3-6 cycloalkyl substituted with at least one fluorine;
R3 is selected from: H, Ci-e alkyl, and Ci-e haloalkyl; optionally wherein one or more H in R3 is substituted by D;
L is selected from: a bond and C1.3 alkylene;
Ring A is selected from: C3-6 cycloalkyl, 4- to 7-membered heterocyclyl, 5- to 12-membered heteroaryl and Ce- aryl; wherein Ring A is optionally substituted by one or more R4; each R4 is independently selected from: halo, -CN, -NO2, =0, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7;
R5 and R6 are each independently selected from: H, Ci-e alkyl, Ci-e haloalkyl and Q1, wherein said Ci-e alkyl is optionally substituted by one or more R8; each R7 and R8 is independently selected from: halo, -CN, -OR7A, -S(O)XR7A, -NR7AR7B, C(O)R7A, -OC(O)R7A, -C(O)OR7A, -NR7AC(O)R7B, -C(O)NR7AR7B and Q2; each Q1 and Q2 is independently selected from: C3-6 cycloalkyl, 4- to 7-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl, wherein said C3-6 cycloalkyl, 4- to 7-membered heterocyclyl, phenyl and 5- or 6- membered heteroaryl is optionally substituted by one or more R9; each R9 is independently selected from: halo, =0, -CN, -NO2, C1.4 alkyl, C1.4 haloalkyl, - OR9A, -S(O)2R9A, -NR9AR9B, -C(O)R9A, -OC(O)R9A, -C(O)OR9A, -NR9BC(O)R9A, - C(O)NR9AR9B, -NR9BC(O)OR9A, -OC(O)NR9AR9B, -NR9BSO2R9A and -SO2NR9AR9B, wherein said C1.4 alkyl is optionally substituted by 1 or 2 substituents selected from: halo, -CN, -OR9C, -NR9CR9D and -SO2R9C;
Ring B is phenyl or a 5- or 6-membered heteroaryl, wherein Ring B is optionally substituted by one or more R10; each R10 is independently selected from: halo, -CN, -NO2, =0, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, -OR10A, -S(O)xR10A, -NR10AR10B, - C(O)R10A, -OC(O)R10A, -C(O)OR10A, -NR10AC(O)R10B, -C(O)NR10AR10B, -NR10AC(O)OR10B, - OC(O)NR10AR10B, -NR10ASO2R10B, and -SO2NR10AR10B, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R11; each R11 is independently selected from: halo, -CN, -OR11A, -NR11AR11B and -SC>2R11A;
R12 is independently selected from H, Ci-e alkyl, Ci-e haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-Ci-6 alkyl-, and COOR13; optionally wherein one or more H in R12 is substituted by D;
R13 is independently selected from H, Ci-e alkyl, Ci-e haloalkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-Ci-6 alkyl; optionally wherein one or more H in R13 is substituted by D;
R7A, R7B, R9A, R9B, R9C, R9D, R10A, R10B, R11A and R11 B are at each occurrence independently selected from: H, C1.4 alkyl and C1.4 haloalkyl; and wherein any -NR5R6, -NR7AR7B, -NR9AR9B, -NR9CR9D, -NR10AR10B, and - NR11AR11B within 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.
Q2. The compound according to Q1, wherein Ring A is a monocyclic 6-membered heteroaryl or a 9-membered fused bicyclic heteroaryl, wherein Ring A has 1 to 4 ring nitrogen atoms and wherein Ring A is optionally substituted with one or more R4.
Q3. The compound according to Q1 or Q2, wherein Ring B is phenyl optionally substituted by one or more R10.
Q4. The compound according to any one of Q1 to Q3, wherein each R10 is independently selected from: halo, C1.3 alkyl, C1.3 haloalkyl, -OC1.3 alkyl and -OC1.3 haloalkyl.
Q5. The compound according to any one of Q1 to Q4, wherein R3 is selected from methyl, -CD3, ethyl, and 2-fluoroethyl.
Q6. The compound according to any one of Q1 to Q5, wherein R12 is H.
Q7. The compound according to any one of Q1 to Q6, wherein R1 is selected from
CH2F, -CHF2, and -CF3. Q8. A compound selected from: pharmaceutically acceptable salt or N-oxide thereof.
Q9. A pharmaceutical composition comprising a compound according to any one of Q1 to Q8, or a pharmaceutically acceptable salt or N-oxide thereof, and a pharmaceutically acceptable excipient.
Q10. A compound according to any one of Q1 to Q8, or a pharmaceutically acceptable salt or N-oxide thereof, for use in the treatment of a disease or medical disorder mediated by Cav2.3; optionally wherein the disease or medical disorder is selected from: a neurodegenerative disease, a neurodevelopmental disorder, epilepsy, an endocrine disorder, cerebral vasospasm, and pain.
Biological Assays
[00322] 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.
[00323] 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.
[00324] 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).
[00325] 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.
Synthesis
[00326] In the description of the synthetic methods described below and in the referenced synthetic methods that are used to prepare the staring materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art.
[00327] 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.
[00328] 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.
[00329] 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.
[00330] 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.
[00331] 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.
[00332] 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 aryl methoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid for example BFs.OEt2. A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.
[00333] 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.
[00334] 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.
[00335] Resins may also be used as a protecting group.
General Synthetic Routes [00336] Compounds of formula (I) can generally be prepared by reacting a compound of formula (la’) wherein R1, R2, R3, ring A, ring B, and L are as defined above for any of formulae
(I) to (XXXXII), with a compound of formula (lb’):
R12-X
(lb’) wherein X is a suitable leaving group.
[00337] Compounds of formula (la’) can be obtained from compounds of formula (lc’) and/or (lg’) wherein R1, R2, R3, ring A, ring B, and L are as defined above for any of formulae (I) to (XXXXII), and a suitable oxo transfer reagent such as iodosobenzene in the presence of a suitable nitrogen source such as ammonium formate.
Compounds of formula (lc’) can be obtained by reacting compounds of formula (Id’) and/or (lid”) wherein ring A and L are as defined above for any compound of formulae (I) to (XXXXII) and LG is suitable leaving group, with compounds of formulae (le’) or (If’)
(le’) (If’) wherein Ri, R2, R3, and ring B are as defined above for any of formulae (I) to (XXXXII), 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 (I) into another compound of formula (I); removing any protecting groups; forming a pharmaceutically acceptable salt; and/or preparing stereochemically isomeric forms thereof.
[00338] The reaction of a compound of formula (lc’) is carried out in a protic solvent for example, MeOH, EtOH in the presence of AcOH, and using an oxo transfer reagent such as iodosobenzene and suitable nitrogen source such as ammonium formate. The reaction may conveniently be carried out at ambient temperature for 12h.
[00339] The reaction of a compound of formula (Id’) is carried out with compound (le’/lf’) in an aprotic solvent, for example THF or DCM, in the presence of an organic base such as pyridine, DIPEA, TEA, or DBU. The reaction may conveniently be carried out at ambient temperature for 2h to 16h.
[00340] The reaction of a compound of formula (lid”) is carried out with compound (le’/lf’) in an aprotic solvent, for example MeOH, DCM, CHCI3 and mixture of both MeOH/DCM or CHCI3 in the presence of an AgNO3. The reaction may conveniently be carried out at ambient temperature for 1 h to 16h.
[00341] Compounds of formula (la’) may be prepared according to the following Scheme 1 : sulfur
Scheme 1 [00342] Sulfide compound (lib’), wherein M is defined as an aliphatic long-chain ester, may be obtained by reaction of the respective bromo derivatives (Ila’) with an appropriate thiol compound in a sulfur-carbon bond forming reaction in an inert atmosphere in the presence of Pd catalyst. Examples of such reaction include reaction of an aromatic bromo, chloro or iodo compound with a sulfur compound, e.g. 2-ethylhexyl-3- mercaptopropanoate. The reaction may be performed in a suitable solvent, such as, 1 ,4- dioxane, toluene, benzene, DMF, DME, DMA, preferably at temperatures between RT and 150 0C. In a palladium-catalyzed coupling reaction, 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, Pd(dba)2, or Pd2(dba)s can undergo ligand dissociation to form the active species. Phosphines can be added to ligandless Pd(0).
[00343] Sulfide compounds (He’) can be obtained by the reaction of the respective sulfide derivatives (lib’) in a sulfur-carbon bond cleavage reaction in an inert atmosphere in the presence of a Lewis acid, such as AlCh. Suitable solvents for this type of conversion include, toluene, benzene, DCM, preferably at 0 °C to RT.
[00344] Hypochlorothioites (lid’) may be obtained by reaction of the respective mercapto derivatives (He’) in a sulfur-chlorine bond forming reaction. Non-limiting examples of such reaction include reaction with chlorine source in the presence of ACN using NCS, at ambient temperature. The reaction may be performed in a suitable solvent, such as, DCM, THF, acetic acid, diethyl ether, toluene preferably at temperatures between -20°C and RT.
[00345] Disulfane (Hd”) may be obtained by reaction of the respective thiol derivatives (He’) in a sulfur-sulfur bond forming reaction. Non-limiting examples of such reaction include reaction with:
- a halogen or iodine 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.
The reaction may be performed in a suitable solvent, such as, acetonitrile, DCM, tetrahydrofuran, acetic acid, diethyl ether, toluene preferably at temperatures between 0°C and RT.
[00346] Aminothioderivative (lc’) can be synthesized by reaction of the corresponding hypochlorothioite (Id’) with the amine part of compound formula (le’) or (If’) using an aprotic solvent for example THF, 1 ,4-Dioxane in the presence of an organic base such as pyridine, TEA, DI PEA, DBU at RT for 2h to 16h.
[00347] Aminothioderivative (lc’) can also be synthesized by reaction of the corresponding disulfide derivative (lid”) with the amine part of compound formula (le’) or (If’) using an protic solvent for example MeOH, chlorinated solvent such as DCM, CHCI3 or mixture of both protic and chlorinated solvent in the presence of AgNO3 at RT for 1h to 16h.
[00348] Sulfonimidamides (la’) can be synthesized by reaction of corresponding aminothioderivative (lc’) using an oxo transfer reagent such as iodosobenzene and a suitable nitrogen source such as ammonium formate in the presence of a catalytic amount of AcOH in, e.g., MeOH or EtOH at ambient temperature for 12 h.
[00349] Sulfonimidamides of formula (I) where R12 is selected from Ci-e alkyl, Ci-e haloalkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-Ci-6 alkyl-, can be synthesized by reaction of corresponding sulfonimidamides (la’), by reaction with an R12-X species where X is a suitable leaving group such as Br, Cl, methanesulfonyl using an aprotic solvent for example THF, 1 ,4-Dioxane in the presence of an organic base such as pyridine, TEA, DIPEA, DBU at RT for 2h to 16h.
[00350] Certain of the intermediates described herein, and salts and N-oxides thereof, form a further aspect of the invention.
[00351] Compounds of formula (la’) can also be obtained from compounds of formula (lg’) wherein ring A, ring B, R1, R2, R3 and L are as defined above for any of formulae (I) to (XXXXII), and a suitable urea deprotecting reagent such as pTSA and TFA, MsOH and TFA, CAS and TFA or a derivative thereof in the presence of a suitable polar, strongly hydrogen bond-donating solvent such as 1 ,1 ,1 ,3,3,3-Hexafluoroisopropanol (HFIP).
[00352] Compounds of formula (Ig’) can be obtained from compounds of formula (lh’) wherein ring A, ring B, R1, R2, R3 and L are as defined above for any of formulae (I) to (XXXXII), and a suitable alkyl halide such as R3-X in the presence of a suitable organic and inorganic base such as CS2CO3, NaH, tBuOK.
[00353] Compounds of formula (lh’) can be obtained by reacting compounds of formula (li’) with corresponding amine sources (If), wherein R1, R2, L, ring A and ring B are as defined above for any of formulae (I) to (XXXXII), except that any functional group is protected, if necessary. Suitable bases for this type of conversion include LiHMDS, NaHMDS, KHMDS and turbo Grignard. Suitable aprotic solvents for this type of conversion include THF, 1 ,4- Dioxane, DMSO, and DMAc preferably at temperature 0 oC to rt for 8h to 24h. wherein ring A and L are as defined above for any compound of formulae (I) to (XXXXII) and LG is suitable leaving group (e.g. F, Cl and Br), with compounds of formulae (If) wherein R1, R2 and ring B are as defined above for any of formulae (I) to (XXXXII), except that any functional group is protected, if necessary.
[00354] Compounds of formula (li’) can be obtained from compounds of formula (lj”) and a suitable halogenating agent such as NCS, NBS and NFSI in the presence of a suitable organic and inorganic base such as CS2CO3, NaH, tBuOK, LiHMDS, iPrMgBr, wherein ring A and L are as defined above for any of formulae (I) to (XXXXII).
[00355] Compounds of formula (lj”) can be obtained from compounds of formula (lj’) and a suitable sulfinamide protecting agent such as TBDMS-CI, TBDPS-CI and DIPC-CI in the presence of a suitable inorganic base such as CS2CO3, NaH, tBuOK, wherein ring A and L are as defined above for any of formulae (I) to (XXXXII).
[00356] Compounds of formula (lj’) can be obtained from compounds of formula (Ik’”) and a suitable S-C bond cleaved product in the presence of a suitable organic and inorganic base such as K2CO3, Na2COs, NaOMe and NaOEt, wherein M is defined as an aliphatic long-chain ester, e.g. 2-ethylhexyl 3-mercaptopropanoate and ring A, and L, are as defined above for any of formulae (I) to (XXXXII).
[00357] Compounds of formula (Ik’”) can be obtained from compounds of formula (Ik”) and a suitable oxo transfer reagent such as iodosobenzene in the presence of a suitable nitrogen source such as ammonium formate, wherein M is an aliphatic long-chain ester, e.g. 2-ethylhexyl 3-mercaptopropanoate and ring A and L, are as defined above for any of formulae (I) to (XXXXII).
[00358] Compounds of formula (la’) may be prepared according to the following Scheme 2: da')
Scheme 2
[00359] Sulfide compound (Ik”) may be obtained by reaction of the respective bromo derivatives (Ila’) in a sulfur-carbon bond forming reaction in an inert atmosphere in the presence of Pd catalyst. Examples of such reaction include reaction with aromatic bromo, chloro or iodo compound react with sulfur compound e.g. 2-ethylhexyl 3- mercaptopropanoate. The reaction may be performed in a suitable solvent, such as, 1 ,4- dioxane, toluene, benzene, DMF, DME, 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 Pd2(dba)scan undergo ligand dissociation to form the active species. Phosphines can be added to ligand less palladium (0).
[00360] Sulfonimidoyl propanoate (Ik’”) can be synthesized by reaction of corresponding thioderivative (Ik”) using oxo transfer reagent iodosobenzene and suitable amine source such as ammonium formate, ammonia in the presence of catalytic amount of AcOH under protic solvent MeOH, EtOH, HFIP, IPA at ambient temperature for 30 min to 2h.
[00361] Sulfinamide compound (lj’) can be obtained by the reaction of the respective sulfide derivatives (Ik’”) in a sulfur-carbon bond cleavage reaction under inert atmosphere in the presence of inorganic or organic base. Suitable bases for this type of conversion used include, for example, NaOEt, NaOMe, K2CO3, Na2COs, ‘BuONa and ‘BuOK. Suitable solvents for this type of conversion include, for example, EtOH, MeOH, THF, MeCN preferably at temperatures between 0°C and RT.
[00362] Sulfinamide protection compound (lj”) can be obtained by the reaction of the respective Sulfinamide compound (lj’) with corresponding protecting reagent such as TBDMS-CI, TBDPS-CI and DIPC-CI in the presence of a suitable inorganic base such as CS2CO3, NaH, ‘BuOK. Suitable solvents for this type of conversion include, for example, THF, DMF, DMAc, DMSO preferably at temperatures between 0°C and RT.
[00363] Sulfonimidoyl halide (li’) can be obtained by the reaction of respective sulfinamide protection compound (lj”) with corresponding halogenating reagent such as NCS, NBS and NFSI or a derivative thereof; in the presence of a suitable inorganic base such as CS2CO3, NaH, ‘BuOK. Suitable solvents for this type of conversion include, for example, THF, DMF, DMAc, DMSO preferably at temperatures between 0°C and RT.
[00364] Sulfonimidamide (lh’) can be synthesized by reaction of corresponding sulfonimidoyl halide (li’) with amine part of compound formula (If). Suitable bases for this type of conversion include LiHMDS, NaHMDS, KHMDS and turbo Grignard. Suitable aprotic solvents for this type of conversion include THF, 1 ,4-Dioxane, DMSO, and DMAc preferably at temperature 0 °C to rt for 8h to 24h.
[00365] N-alkylation sulfonimidamide (lg’) can be performed by reaction of corresponding sulfonimidamide (lh’) with alkyl halide part of compound formula (R3-X). Suitable bases for this type of conversion include CS2CO3, NaH, LiHMDS, and turbo Grignard. Suitable aprotic solvents for this type of conversion include THF, DMF, DMSO, and DMAc preferably at temperature 0 °C to rt for 1h to 4h.
[00366] Sulfonimidamide (Ila’) can be obtained by deprotection of corresponding N- alkylated sulfonimidamide (lg’) using mixture of acids such as pTSA and TFA, MsOH and TFA, CAS and TFA or a derivative thereof; In the presence of a polar, strongly hydrogen bond-donating solvent such as 1 ,1 ,1 ,3,3,3-Hexafluoroisopropanol (HFIP) at elevated temperature 40 °C to 70 °C rt for 16h to 48h.
[00367] Certain of the intermediates described herein, and salts and N-oxides thereof, form a further aspect of the invention.
EXAMPLES
Abbreviations:
Ac - acetyl
ACN - acetonitrile
BINAP - 2,2'-bis(diphenylphosphino)-1 ,1'-binaphthyl Bn - benzyl
Boc - tert-butoxycarbonyl
CBz - benzyloxycarbonyl
CPME - cyclopentyl methyl ether dba - dibenzylideneacetone
DCM - dichloromethane
DIEA - N,N-diisopropylethylamine
DIPA - diisopropylamine
DMAc - dimethylacetamide
DMF - N,N-dimethylformamide
DMSO - dimethylsulfoxide
EDCI - 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride salt ee - enantiomeric excess eq. - equivalents
Ghosez's Reagent - 1-chloro-N,N-2-trimethyl-1-propenylamine
HATLI - 1-[bis(dimethylamino)methylene]-1 H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate
HOAt - 1-hydroxy-7-azabenzotriazole
HFIP - hexafluoroisopropanol
HPLC - high performance liquid chromatography
I PA - isopropanol
KHMDS - potassium bis(trimethylsilyl)amide
LC-MS - liquid chromatograph-mass spectrometer
LDA - lithium diisopropylamide mCPBA - 3-chloroperbenzoic acid
MeCN - acetonitrile
MS - mass spectrometry
Ms - mesyl
MTBE - methyl tert-butyl ether
MW - microwave
NBS - N-bromosuccinimide
NCS - N-chlorosuccinimide
NMM - N-methylmorpholine
NMP - N-methyl-2-pyrrolidone
NMR - nuclear magnetic resonance o/n - overnight
Pd/C - palladium-on-carbon Piv - pivaloyl
Prep - preparative pTSA - p-toluene sulfonic acid
Py - pyridine rt - retention time
RT - room temperature
RM - reaction mass
SFC - supercritical fluid chromatography
SEM - trimethylsilylethoxymethyl
SPE - solid phase extraction
Su - succinimide
TBAB - tetrabutylammonium bromide
TBAF - tetrabutylammonium fluoride
TEA - triethylamine
TFA - trifluoroacetic acid
TFAA - trifluoroacetic anhydride
THF - tetrahydrofuran
TLC - Thin-layer chromatography
Reagents and Conditions
[00368] 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
[00369] 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 Methods
TCGLS LCMS method
Method 1 (K84-3 min)
[00370] 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)
[00371] The HPLC measurement was performed using Waters Acquity H Class UPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters SQ Detector 2) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L/Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on a Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm) with a flow rate of 0.800 ml/min. Two mobile phases were used, mobile phase A: 0.05% HCOOH in water; mobile phase B: 0.05% HCOOH in ACN: Water (90:10)], and they were employed to run a gradient conditions from 5 % B for 0.75 minutes, from 5 % to 25 % in 0.75 minutes, and from 25 % to 95 % in 1.50 minutes, 95 % B for 1.00 minutes and 5 % B in 0.50 minutes and hold these conditions for 0.60 minutes in order to re-equilibrate the column (Total Run Time 5.10 minutes). An injection volume of 0.5 pl was used.
Method 3 (K70/71/55/63 3 min)
[00372] The HPLC measurement was performed using Waters Acquity UPLC comprising a binary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters ZQ SQD) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 0.40 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L/Hour. Data acquisition was performed with Mass Lynx 4.1 Software. Reversed phase HPLC was carried out on a YMC Triart C18 column (3 m, 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)
[00373] The HPLC measurement was performed using Shimadzu HPLC comprising a binary pump with degasser, a sample manager a dual channel UV detector and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Applied Biosystems API2000/2000 Trap) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 800 in 0.40 second. The ion spray voltage 5500 V in positive and 4500 V in negative ionization mode and the source temperature was maintained at 300 °C and Declusturing Potential 8-50 V depending on compound. Data acquisition was performed with Analyst 1.6.3 Software. Reversed phase HPLC was carried out on a Waters Xbridge C18/ Agilent Zorbax C18 column (5 pm, 50 x 4.6 mm) with a flow rate of 1.20 ml/min. Two mobile phases were used, mobile phase A: 10mm Ammonium Acetate in water; mobile phase B: ACN, and they were employed to run a gradient condition from 10 % B to 30 % B in 1.50 minutes, and from 30 % to 90 % in 1.50 minutes, 90 % B for 1.00 minutes and 10 % B in 1.00 minutes and hold these conditions for 0.10 minutes. Pre run Equilibration Time 0.50 min (Total Run Time 5.10 minutes). An injection volume of 1 pl to 3 pl was used (Depending on the sample concentration).
Method 5 (K03/04/05/06/07/08/72/78 5 min Nonpolar)
[00374] 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)
[00375] 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 wate); 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)
[00376] 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 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)
[00377] The HPLC measurement was performed using Waters Acquity H Class LIPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters SQ Detector 2) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L/Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on a Waters Xbridge C18 column (3.5 pm, 50 x 3 mm) with a flow rate of 1 .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)
[00378] 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)
[00379] The HPLC measurement was performed using Waters Acquity H Class LIPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters SQ Detector 2) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L/Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on a Waters Xbridge C18 column (3.5 pm, 50 x 3 mm) with a flow rate of 1.00 ml/min. Two mobile phases were used, mobile phase A: 5 Mm NH4oAc in water; mobile phase B: 5 Mm NH4oAc in ACN: Water (90:10)], and they were employed to run a gradient conditions from 2 % B for 1.00 minutes, from 2 % to 50 % in 4.00 minutes and from 50% to 98 % in 3.00 minutes, 98 % B for 2.00 minutes and 2 % B in 2.00 minutes and hold these conditions for 0.10 minutes in order to re-equilibrate the column (Total Run Time 12.10minutes). An injection volume of 0.5 pl was used.
Method 11 (K84 12 min)
[00380] The HPLC measurement was performed using Waters Acquity H Class UPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters SQ Detector 2) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L/Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on a Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm) with a flow rate of 0.800 ml/min. Two mobile phases were used, mobile phase A: 0.05% HCOOH in water; mobile phase B: 0.05% HCOOH in ACN: Water (90:10)], and they were employed to run a gradient conditions from 5 % B for 1.00 minutes, from 5 % to 50 % in 4.00 minutes, and from 50 % to 90 % in 3.00 minutes, 90 % B for 2.00 minutes and then 5 % B in 1 .50 minutes and hold these conditions for 0.50 minutes in order to re-equilibrate the column (Total Run Time 12.00 minutes). An injection volume of 0.5 pl was used.
Method 12 (K79 3 min) [00381] The HPLC measurement was performed using Agilent 1260 Infinity II LIPLC comprising a quaternary pump with degasser, an sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Agilent SQD) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1200 in 0.20 second. The capillary needle voltage was 4.00 kV in positive and negative ionization mode and the source temperature was maintained at 350 °C. Nitrogen was used as the desolvation gas, the flow was 12 L/Min. Data acquisition was performed with Open Lab CDS. Reversed phase HPLC was carried out on a YMC Triart C18 column (3 pm, 33 x 2.1 mm) with a flow rate of 1.00 ml/min. Two mobile phases were used, mobile phase A: 0.1% HCOOH in water; mobile phase B: 0.1 % HCOOH in ACN, and they were employed to run a gradient condition from 2 % B for 0.50 minutes, from 2 % to 30 % in 0.50 minutes, and from 30 % to 98 % in 1.00 minutes, 98 % B for 0.25 minutes and then 2 % B in 0.75 minutes (Total Run Time 3.00 minutes). An injection volume of 0.5 pl was used.
Method 13 (K83 3 min-BEH)
[00382] The HPLC measurement was performed using Waters Acquity H Class UPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters SQ Detector 2) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L/Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on a Waters Acquity BEH C18 column (1.7 pm, 30 x 2.1 mm) with a flow rate of 1.20 ml/min. Two mobile phases were used, mobile phase A: 5 Mm NH4oAc in water; mobile phase B: 5 Mm NH4oAc in ACN: Water (90:10)], and they were employed to run a gradient conditions from 2 % B for 0.50 minutes, from2 % to 98 % in 1.00 minutes, 98 % B for 1.00 minutes and 2 % B in 0.25 minutes and hold these conditions for 0.25 minutes in order to re-equilibrate the column (Total Run Time 3.00 minutes). An injection volume of 0.5 pl was used.
Method 14 (K83 12 min)-OLD
[00383] 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
[00384] The HPLC measurement was performed using Waters Acquity H Class UPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters SQ Detector 2) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L/Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on a Waters Xbridge C18 column (5 pm, 50 x 4.6 mm) with a flow rate of 1 .20 ml/min. Two mobile phases were used, mobile phase A: 5 Mm NH4oAc in water; mobile phase B: 5 Mm NH4oAc in ACN: Water (90:10)], and they were employed to run a gradient conditions from 2 % B for 1.00 minutes, from 2 % to 50 % in 4.00 minutes, from 50 % to 90 % in 3.00 minutes and 90 % B for 2.00 minutes and 2 % B in 2.00 minutes and hold these conditions for 0.10 minutes in order to re-equilibrate the column (Total Run Time 12.10 minutes). An injection volume of 0.5 pl was used.
Method 16
[00385] The HPLC measurement was performed using Waters Acquity UPLC 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
[00386] 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 wate); mobile phase B: ACN, and they were employed to run a gradient condition from 50% B for 2.00 min, from 50% B to 95 % B in 6.00 minutes, and 95 % B for 3.00 minutes and 50 % B in 3.00 minutes and hold these conditions for 4.00 minutes. Pre run Equilibration Time 4.00 min (Total Run Time 18.00 minutes). An injection volume of 1 pl to 3 pl was used (Depending on the sample concentration).
Method 18 (K84 3 min)-OLD
[00387] The HPLC measurement was performed using Waters Acquity H Class UPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters SQ Detector 2) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L/Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on a YMC Triart C18 column (3 pm, 33 x 2.1 mm) with a flow rate of 1.00 ml/min. Two mobile phases were used, mobile phase A: 0.05% HCOOH in water; mobile phase B: 0.05% HCOOH in ACN: Water (90:10)], and they were employed to run a gradient conditions from 2 % B for 0.75 minutes, from 2 % to 10 % in 0.25 minutes, and from 10 % to 98 % in 1.00 minutes, 98 % B for 0.50 minutes and then 2 % B in 0.40 minutes and hold these conditions for 0.10 minutes in order to re-equilibrate the column (Total Run Time 3.00 minutes).. An injection volume of 0.5 pl was used.
Method 19 (K84 3 min)-OLD BEH POLAR
[00388] The HPLC measurement was performed using Waters Acquity H Class LIPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters SQ Detector 2) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L/Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on a Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm) with a flow rate of 0.80 ml/min. Two mobile phases were used, mobile phase A: 0.05% HCOOH in water; mobile phase B: 0.05% HCOOH in ACN: Water (90:10)], and they were employed to run a gradient conditions from 2 % B for 0.75 minutes, from 2 % to 10 % in 0.25 minutes, and from 10 % to 98 % in 1.00 minutes, 98 % B for 0.50 minutes and then 2 % B in 0.40 minutes and hold these conditions for 0.10 minutes in order to re-equilibrate the column (Total Run Time 3.00 minutes).. An injection volume of 0.5 pl was used.
Method 20 (K43 6 min)
[00389] 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 wate); 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)
[00390] The HPLC measurement was performed using Waters Acquity H Class LIPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters SQ Detector 2) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L/Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on a Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm) with a flow rate of 0.60 ml/min. Two mobile phases were used, mobile phase A: 5 Mm NH4oAc in water; mobile phase B: 5 Mm NH4oAc in ACN: Water (90:10)], and they were employed to run a gradient conditions from 2 % B for 1.00 minutes, from 2 % to 50 % in 4.00 minutes, from 50 % to 98 % in 3.00 minutes 98 % B for 2.00 minutes and 2 % B in 1.00 minutes and hold these conditions for 1.00 minutes in order to re-equilibrate the column (Total Run Time 12.00 minutes). An injection volume of 0.5 pl was used.
Method 23 (K91 3 min)
[00391] The HPLC measurement was performed using Waters Acquity H Class UPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 40° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters SQ Detector 2) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L/Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on a Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm) with a flow rate of 0.60 ml/min. Two mobile phases were used, mobile phase A: 5 Mm NH4oAc in water; mobile phase B: 5 Mm NH4oAc in ACN: Water (90:10)], and they were employed to run a gradient conditions from 5 % B for 0.75 minutes, from 5 % to 30 % in 0.25 minutes, from 30 % to 98 % in 1 .00 minutes 98 % B for 0.25 minutes and 5 % B in 0.25 minutes and hold these conditions for 0.50 minutes in order to re-equilibrate the column (Total Run Time 3.00 minutes). An injection volume of 0.5 pl was used.
Method 24 (K91 5 min)
[00392] 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 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)
[00393] 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 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 26 (TM)
[00394] 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)
[00395] The HPLC measurement was performed using Waters Acquity H Class UPLC comprising a quaternary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters SQ Detector 2) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 160 to 1200 in 0.20 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L/Hour. Data acquisition was performed with Mass Lynx 4.2 Software. Reversed phase HPLC was carried out on a YMC Triart C18 column (3 pm, 33 x 2.1 mm) with a flow rate of 1.00 ml/min. Two mobile phases were used, mobile phase A: 0.05% HCOOH in water; mobile phase B: 0.05% HCOOH in ACN: Water (90:10)], and they were employed to run a gradient conditions from 2 % B for 0.75 minutes, from 2 % to 10 % in 0.25 minutes, and from 10 % to 98 % in 1.00 minutes, 98 % B for 0.50 minutes and then 2 % B in 0.40 minutes and hold these conditions for 0.10 minutes in order to re-equilibrate the column (Total Run Time 3.00 minutes). An injection volume of 0.5 to 3 pl was used (Depending on the sample concentration).
Method 28 (K92-5 min-YMC)
[00396] 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)
[00397] The HPLC measurement was performed using Waters Acquity UPLC comprising a binary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters ZQ SQD) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 0.40 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L/Hour. Data acquisition was performed with Mass Lynx 4.1 Software. Reversed phase HPLC was carried out on a YMC Triart C18 column (3 pm, 33 x 2.1 mm) with a flow rate of 1.00 ml/min. Two mobile phases were used, mobile phase A: 0.05% HCOOH in water; mobile phase B: 0.05% HCOOH in ACN: Water (90:10)], and they were employed to run a gradient conditions from 5 % B for 0.75 minutes, from 5 % to 25 % in 0.75 minutes, and from 25 % to 95 % in 1.50 minutes, 95 % B for 1.75 minutes and then 5 % B in 0.25 minutes and hold these conditions for 0.10 minutes in order to 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)
[00398] 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)
[00399] The HPLC measurement was performed using Waters Acquity UPLC comprising a binary pump with degasser, a sample manager, a column oven (set at 50° C), a diode-array detector DAD and a column as specified in the respective methods below. Flow from the column was split to a MS spectrometer. The MS detector (Waters ZQ SQD) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 1000 in 0.40 second. The capillary needle voltage was 3.50 kV in positive and negative ionization mode and the source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, the flow was 750 L/Hour. Data acquisition was performed with Mass Lynx 4.1 Software. Reversed phase HPLC was carried out on a Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm) with a flow rate of 0.60 ml/min. Two mobile phases were used, mobile phase A: 0.05% HCOOH in water; mobile phase B: 0.05% HCOOH in ACN: Water (90:10)], and they were employed to run a gradient conditions from 5 % B for 0.75 minutes, from 5 % to 50 % in 0.45 minutes, and from 50 % to 98 % in 0.80 minutes, 98 % B for 0.25 minutes and then 5 % B in 0.35 minutes and hold these conditions for 0.50 minutes in order to re-equilibrate the column (Total Run Time 3.10 minutes). An injection volume of 0.5 to 3 pl was used (Depending on the sample concentration).
Method 32 (K103-3 min)
[00400] 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 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.
NMR
All NMR spectra were obtained using Bruker Avance 400 MHz spectrometers running Topspin Software.
GCMS
GCMS-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:- Helium
Inlet Temperature: 250 °C
Split ratio: 5 : 1
Carrier Gas flow: 1 .0 ml/min
Solvent Delay: 3min
Mass range: 50 to 550 amu
Injection volume: 1 ul
Ramp 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:- Helium Inlet Temperature: 250 °C
Split ratio: 20 :1
Carrier Gas flow: 1 .0 ml/min
Ramp 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.
Example 1, Example 2 and Example 3
5-cyano-/V-methyl-(R,S)-/V-(( )-2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)pyridine-3- sulfonimidamide (Example 1), 5-cyano-N-methyl-(S)-N-((R)-2,2,2-trifluoro-1-(4-
(trifluoromethyl)phenyl)ethyl)pyridine-3-sulfonimidamide (Example 2), and 5-cyano-N- methyl-(R)-N-((R)-2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)pyridine-3- sulfonimidamide (Example 3).
Synthesis of 5-(benzylthio)nicotinonitrile (1.1):
[00401] 5-bromonicotinonitrile (10 g, 54.64 mmol) was dissolved in toluene (100 mL) and phenyl methanethiol (8.1 g, 65.57mmol) was added to it. The solution was stirred and degasified with argon. DIPEA (30.2 mL, 163.93 mmol) was added to the solution followed by Xantphos (0.95 g, 1.63 mmol). The reaction mixture was further degasified with argon. Pd2(dba)s (1 g, 1.09 mmol) was added to it under the inert atmosphere and the reaction mixture was stirred at 130°C for 16 h under argon atmosphere. After completion (monitored by TLC and LCMS), the mixture was filtered through a 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 product 1.1 was isolated as a gum (10.0 g, 81% yield). LCMS: m/z found ((227.3 [M+H]+), rt = 3.79 min (Method 4)[ Waters Xbridge C18 column (5 pm, 50 x 4.6 mm)].
Synthesis of 5-mercaptonicotinonitrilechloride (1.2):
[00402] To a stirred solution of intermediate 1.1 (2.0 g, 8.85 mmol) in toluene (20 mL) was added AlCh (11.8 g, 88.5 mmol) portion wise at RT. Stirring was continued at the same temperature for 1 h. The mixture was cooled, diluted with ice cold water (25 mL) and extracted with DCM (35 mL). The organic layer was separated, washed with cold water (10 mL) dried over anhydrous Na2SO4 and the solvent evaporated under reduced pressure to afford crude product, which was triturated with hexane to get desired product compound 1.2 (0.9 g, 75 % yield) as a solid. The crude product was used immediately in the next step.
Synthesis of 5-cyanopyridin-3-yl hypochlorothioite (1.3):
[00403] The 5-mercaptonicotinonitrile chloride 1.2 (0.25 g, 1.83 mmol) was dissolved in CH3CN (10 mL) and NCS (0.3 g, 2.2 mmol) was added portion wise to it at 0°C. The stirring was continued at RT for 1 h. The reaction mixture was then diluted with ice cold water (25 mL) and extracted with ethyl acetate (2 x 50 mL). The organic layer was separated, washed with brine (50 mL) dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound 1.3 (0.3 g) which was quickly used in the next step without further purification.
Synthesis of (R)-5-((methyl(2,2,2-trifluoro-1-(4-
(trifluoromethyl)phenyl)ethyl)amino)thio)nicotinonitrile 1.4:
[00404] To a solution of 5-cyanopyridin-3-ylhypochlorothioite 1.3 in DCM, ( )-2,2,2- trifluoro-N-methyl-1-(4-(trifluoromethyl)phenyl)ethan-1-amine (1.2 g, 4.68 mmol) was added followed by pyridine (0.8 mL, 9.38 mmol). The reaction mixture was stirred at room temperature for 2 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 Na2SO4 and the solvent was evaporated under reduced pressure. The crude was purified by column chromatography over silica gel and the compound 1.4 was isolated as a colourless sticky gum (120 mg, 6% yield). LCMS: m/z found ((392.05 [M+H]+), rt = 1.91 min (Method 2)[YMC Triart C18 column (3 pm, 33 x 2.1 mm);
Synthesis of 5-cyano-N-methyl-N-((R)-2,2,2-trifluoro-1-(4- (trifluoromethyl)phenyl)ethyl)pyridine-3-sulfonimidamide (Example 1):
[00405] To a stirred solution of intermediate 20.4 (120 mg, 0.33 mmol) in MeOH (1 mL), acetic acid (0.04 mL, 0.67 mmol) was added followed by (diacetoxyiodo)benzene (270 mg, 0.84 mmol). The mixture was stirred at 0°C and Ammonium carbamate (104 mg, 1.34 mmol) was added. The reaction mixture was then stirred at room temperature for 12 h. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain a crude compound which was purified by combiflash chromatography to obtain compound Example 1 as a mixture of two diastereomers (60 mg, 94.46% purity, 50% enantiomeric excess). LCMS: m/z found ((423.15 [M+H]+), rt= 2.86 min (Method 9)[Waters Xbridge C18 column (3.5 pm, 50 x 3 mm); 1H NMR (400 MHz, DMSO) 5 9.30 - 9.21 (m, 2H), 8.83 - 8.76 (m, 1 H), 7.84 - 7.71 (m, 2H), 7.67 - 7.56 (m, 2H), 6.19 (q, J = 8.7 Hz, 1 H), 5.71 - 5.67 (m, 1 H), 2.82 (d, J = 19.9 Hz, 3H). The diastereomeric mixture of the above compound was separated by SFC method to obtain diastereomeric pure compounds Example 2 and Example 3.
Peak-1 : (Example 2):
[00406] LCMS: m/z found ((423.15 [M+H]+), rt = 3.06 min (Method 9)[Waters Xbridge C18 column (3.5 pm, 50 x 3 mm))); 1H NMR (400 MHz, DMSO) 5 9.27 - 9.24 (m, 2H), 8.79 (s, 1 H), 7.80 (d, J = 8.12 Hz, 2H), 7.64 (d, J = 8.15 Hz, 2H), 6.21 (q, J = 8.7 Hz, 1 H), 5.69 (m, 1 H), 2.84 (s, 1 H).
Peak-2: (Example 3):
[00407] LCMS: m/z found ((423.15 [M+H]+), rt= 3.06 min (Method 9)[Waters Xbridge C18 column (3.5 pm, 50 x 3 mm); 1H NMR (400 MHz, DMSO) 5 9.27 - 9.23 (m, 2H), 8.78 (s, 1 H), 7.76 (d, J = 8.12 Hz, 2H), 7.59 (d, J = 8.15 Hz, 2H), 6.22 (q, J = 8.7 Hz, 1 H), 5.84 (m, 1 H), 2.79 (s, 1 H).
[00408] SFC PREP Purification was performed in a Waters SFC Prep 80 instrument equipped with Waters 2489 UV/Visible Detector by using Chiralpak-IG (30.0mm x 250mm), 5p column operating at 35°C temperature, maintaining a flow rate of 70 mL/min, using 50% CO2 in super critical state and 50% of 100% (methanol) as mobile phase, running this isocratic mixture up to 15.0 minutes and maintaining the isobaric condition of 100 bar at 220 nm.
Example 4 and Example 5
[00409] (S)-5-cyano-N-methyl-N-((R)-2,2,2-trifluoro-1-(4-(chlorophenyl)ethyl)pyridine-3- sulfonimidamide (Example 4) and (R)-5-cyano-N-methyl-N-((R)-2,2,2-trifluoro-1-(4- (chlorophenyl)ethyl)pyridine-3-sulfonimidamide (Example 5)
[00410] Synthesis of (/?)-5-(((1-(4-chlorophenyl)-2,2,2- trifluoroethyl)(methyl)amino)thio)nicotinonitrile 2.4: To a solution of 5-cyanopyridin-3- ylhypochlorothioite 1.3 (0.3 g, 1.75 mmol) in DCM (10 mL) was added ( )-1-(4- chlorophenyl)-2,2,2-trifluoro-/V-methylethan-1-amine (Amine-2a) (0.44 g, 1.93 mmol) followed by pyridine (0.7 mL, 8.75 mmol). The reaction mixture was stirred at RT for 3 h. It was diluted with water (15 mL) and extracted with DCM (2 x 15 mL). The combine 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 2.4 was isolated as a sticky gum (0.12 g, 20 % yield). LCMS: m/z found 358.05 [M+H]+,rt= 1.91 min (Method 2)[YMC Triart C18 column (3 pm, 33 x 2.1 mm)).
[00411] Synthesis of 5-cyano-/V-methyl-/V-((/?)-2,2,2-trifluoro-1-(4-
(trifluoromethyl)phenyl)ethyl)pyridine-3-sulfonimidamide 2.5: To a stirred solution of intermediate 2.4 (0.2 g, 0.55 mmol) in MeOH (1.5 mL) was added acetic acid (63 pL, 1.1 mmol), Phl(OAc)2 (0.45 g, 1.4 mmol) and ammonium carbamate (0.17 g, 2.23 mmol) at RT. The reaction mixture was then stirred at same temperature 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 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 2.5 (0.12 g) was isolated as its diastereomeric mixture. [00412] The diastereomers were separated by SFC purification method to obtain both the diastereomers.
[00413] Example 4: 37 mg; LCMS: m/z found 389.2 [M+H]+, rt= 3.04 min (Method B)[ Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm)]; 1H NMR (400 MHz, DMSO): 5 9.24 (dd, J = 7.8, 2.1 Hz, 2H), 8.80 - 8.74 (m, 1 H), 7.48 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 6.05 (q, J = 8.8 Hz, 1 H), 2.81 (s, 3H). Absolute stereochemistry not confirmed.
[00414] Example 5: 31 mg; LCMS: m/z found 389.1 [M+H]+, rt= 3.02 min (Method B)[Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm)]; 1H NMR (400 MHz, DMSO): 5 9.24 (dd, J = 11.0, 1.9 Hz, 2H), 8.80 - 8.74 (m, 1 H), 7.44 (d, J = 8.6 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H), 6.06 (q, = 8.8 Hz, 1 H), 5.79 - 5.74 (m, 1 H), 2.77 (s, 3H). Absolute stereochemistry not confirmed.
[00415] HPLC SFC Prep Purification was done on Waters SFC PREP 80 instruments equipped with Waters 2489 UV/Visible Detector 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 55% CO2 in super critical state & 45% of 100% MEOH as Mobile phase. Run this isocratic mixture up to 16.0 minutes and also maintained the isobaric condition of 100 bar at 226 nm wavelength.
Example 6 and Example 7
[00416] (S)-5-cyano-A/-methyl-A/-(( )-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyridine-3- sulfonimidamide (Example 6) and ( )-5-cyano-A/-methyl-A/-(( )-2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)pyridine-3-sulfonimidamide (Example 7) [00417] Synthesis of (R)-5-((methyl(2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)amino)thio)nicotinonitrile 3.1 : To a solution of 5-cyanopyridin-3- ylhypochlorothioite 1.3 (0.3 g, 1.75 mmol) in DCM (10 mL) was added ( )-1-(4-fluorophenyl)- 2,2,2-trifluoro-/V-methylethan-1-amine (Amine-1a) (0.44 g, 1.93 mmol) followed by pyridine (0.7 mL, 8.75 mmol). The reaction mixture was stirred at RT for 3 h. It was then diluted with water (15 mL) and extracted with DCM (2 x 15 mL). The combine 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 3.1 was isolated as a sticky gum (0.12 g, 20 % yield). LCMS: m/z found 342.06 [M+H]+, rt= 1.91 min (Method 2)[YMC Triart C18 column (3 pm, 33 x 2.1 mm)).
[00418] Synthesis of (/?)-5-cyano-/V-methyl-/V-(2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)pyridine-3-sulfonimidamide 3.2: To a stirred solution of intermediate 3.1 (0.32 g, 0.93 mmol) in MeOH (2 mL) acetic acid was added (100 pL, 1.8 mmol), Phl(OAc)2 (0.75 g, 2.3 mmol) and ammonium carbamate (0.29 g, 3.75 mmol) at RT. The reaction mixture was then stirred at same temperature 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 Na2SC>4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20 % ethyl acetate in hexane to obtain product 3.2 (0.18 g) as a diastereomeric mixture.
[00419] The diastereomers were separated by SFC purification method to obtain both the diastereomers Example 6 (83 mg): LCMS: m/z found 373.1 [M+H]+, rt= 3.0 min (Method B)[ Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm)]; 1H NMR (400 MHz, DMSO) 5 9.24 (dd, J = 7.6, 2.0 Hz, 2H), 8.79 - 8.73 (m, 1 H), 7.44 (dd, J = 8.5, 5.3 Hz, 2H), 7.23 (t, J = 8.7 Hz, 2H), 6.04 (q, J = 8.8 Hz, 1 H), 5.63 (s, 1 H), 2.82 (s, 3H) (absolute stereochemistry not confirmed) and Example 7 (72 mg): LCMS: m/z found 373.1 [M+H]+, rt= 2.98 min (Method B)[ Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm)]; 1H NMR (401 MHz, DM SO) 5 9.23 (dd, J = 11 .9, 2.0 Hz, 2H), 8.78 - 8.73 (m, 1 H), 7.42 (dd, J = 8.5, 5.3 Hz, 2H), 7.20 (t, J = 8.7 Hz, 2H), 6.04 (q, J = 8.8 Hz, 1 H), 5.73 (s, 1 H), 2.77 (s, 3H) (absolute stereochemistry not confirmed).
[00420] SFC Prep Purification was done on Waters SFC 80 instruments equipped with Waters 2489 UVA/isible Detector by using CHIRALPAK IG (30mm x 250 mm), 5p Column operating at 35°C temperature, maintaining flow rate of 70 ml/min, using 50% CO2 in super critical state & 50% of 100% METHANOL as Mobile phase. Run this isocratic mixture up to 12.0 minutes and also maintained the isobaric condition of 100 bar at 214 nm wavelength. Example 8 and Example 9
[00421] (S)-5-cyano-A/-methyl-A/-(( )-2,2,2-trifluoro-1-(3,4-difluorophenyl)ethyl)pyridine-3- sulfonimidamide (Example 8) and ( )-5-cyano-/V-methyl-/V-(( )-2,2,2-trifluoro-1-(3,4- difluorophenyl)ethyl)pyridine-3-sulfonimidamide (Example 9)
[00422] Synthesis of (/?)-5-(((1-(3,4-difluorophenyl)-2,2,2- trifluoroethyl)(methyl)amino)thio)nicotinonitrile 4.1 : To a solution of 5-cyanopyridin-3- ylhypochlorothioite 1.3 (0.30 g, 1.75 mmol) in DCM (10 mL) (R)-1-(3,4-difluorophenyl)-2,2,2- trifluoro-/V-methylethan-1-amine (0.44 g, 1.93 mmol) was added, followed by pyridine (0.7 mL, 8.75 mmol). The reaction mixture was stirred at RT for 3 h. It was diluted with water (15 mL) and extracted with DCM (2 x 15 mL). The combine organic layerwas 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 4.1 was isolated as a sticky gum (0.18 g, 35 % yield). LCMS: m/z found 360.06 [M+H]+,rt= 1.91 min (Method 2)[YMC Triart C18 column (3 pm, 33 x 2.1 mm)).
[00423] Synthesis of (R)-5-cyano-A/-methyl-A/-(2,2,2-trifluoro-1-(3,4- difluorophenyl)ethyl)pyridine-3-sulfonimidamide 4.2: To a stirred solution of intermediate 4.1 (0.18 g, 0.50 mmol) in MeOH (2 mL) acetic acid was added (57 pL, 1.0 mmol), Phl(OAc)2 (0.4 g, 1.25 mmol) and ammonium carbamate (0.16 g, 2.0 mmol) at RT. The reaction mixture was then stirred at same temperature 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 % ethyl acetate in hexane to obtain product 4.2 (110 mg) as a diastereomeric mixture.
[00424] The diastereomers were separated by SFC purification method to obtain both the diastereomers, Example 8 (83 mg): LCMS: m/z found 391.2 [M+H]+, rt= 2.99 min (Method B)[ Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm)], 1H NMR (400 MHz, DM SO) 5 9.26 (dd, J = 7.7, 2.0 Hz, 2H), 8.80 (t, J = 2.1 Hz, 1H), 7.56 - 7.42 (m, 2H), 7.34 - 7.24 (m, 1H), 6.07 (q, J = 8.6 Hz, 1 H), 5.67 (s, 1 H), 2.84 (s, 3H) (absolute stereochemistry confirmed by X-ray crystallography) and Example 9 (72 mg): LCMS: m/z found 391.2 [M+H]+, rt= 2.98 min (Method B)[ Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm)], 1H NMR (400 MHz, DMSO) 5 9.29 - 9.21 (m, 2H), 8.82 - 8.76 (m, 1 H), 7.51 - 7.43 (m, 2H), 7.32 - 7.23 (m, 1H), 6.06 (q, J = 7.8 Hz, 1 H), 5.77 (s, 1 H), 2.83 (s, 3H).
[00425] SFC Prep Purification was done on Waters SFC 80 instruments equipped with Waters 2489 UV/Visible Detector by using (R,R)WHELK O-1 (21.1 mm x 250 mm ), 5p Column operating at 35°C temperature, maintaining flow rate of 70 ml/min, using 75% CO2 in super critical state & 25% of 100% METHANOL as Mobile phase. Run this isocratic mixture up to 10.0 minutes and also maintained the isobaric condition of 100 bar at 260 nm wavelength.
Example 10 and Example 11
[00426] (S)-5-cyano-N-methyl-N-((R)-2,2,2-trifluoro-1-(3-fluoro-4-chloro- phenyl)ethyl)pyridine-3-sulfonimidamide (Example 10) and (R)-5-cyano-N-methyl-N-((R)- 2,2,2-trifluoro-1-(3-fluoro-4-chloro-phenyl)ethyl)pyridine-3-sulfonimidamide (Example 11)
Scheme 5 [00427] Synthesis of (/?)-5-(((1-(4-chloro-3-fluorophenyl)-
2,2,2trifluoroethyl)(methyl)amino)thio)nicotinonitrile 5.1 : To a solution of 5- cyanopyridin-3-ylhypochlorothioite 1.3 (0.56 g, 3.28 mmol) in DCM (10 mL) ( )-1-(4-chloro- 3-fluorophenyl)-2,2,2-trifluoro-/V-methylethan-1-amine (Amine-5a) was added (0.95 g, 3.93 mmol), followed by pyridine (1.3 mL, 16.41 mmol). The reaction mixture was stirred at RT for 3 h. It was then diluted with water (25 mL) and extracted with DCM (2 x 25 mL). The combine organic layer was washed with water (25 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 5.1 was isolated as a sticky gum (360 mg, 30 % yield). LCMS: m/z found 376.05 [M+H]+,rt= 1.89 min (Method 2)[YMC Triart C18 column (3 pm, 33 x 2.1 mm)].
[00428] Synthesis of (/?)-/V-(1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethyl)-5-cyano- A/-methylpyridine-3-sulfonimidamide 5.2: To a stirred solution of intermediate 5.1 (0.36 g, 0.95 mmol) in MeOH (5 mL) was added acetic acid (109 pL, 1.91 mmol), Phl(OAc)2 (0.77 g, 2.39 mmol) and ammonium carbamate (0.3 g, 3.83 mmol) at RT. The reaction mixture was then stirred at same temperature for 3 h. The reaction was then quenched with water (25 mL) and extracted with ethyl acetate (2 x 25 mL). The combined organic layer was washed with water (25 mL) and brine (25 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20 % ethyl acetate in hexane to obtain product 5.2 (180 mg) as a diastereomeric mixture.
[00429] The diastereomers were separated by SFC purification method to obtain both the diastereomers, Example 10 (66 mg): LCMS: m/z found 407.2 [M+H]+, rt= 3.16 min (Method B)[ Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm)]; 1H NMR (400 MHz, DM SO) 5 9.30 - 9.23 (m, 2H), 8.83 - 8.78 (m, 1 H), 7.66 (t, J = 8.0 Hz, 1 H), 7.43 (d, J = 10.6 Hz, 1 H), 7.28 (d, J = 8.3 Hz, 1 H), 6.10 (q, J = 8.6 Hz, 1 H), 5.68 (s, 1 H), 2.84 (s, 3H) (absolute stereochemistry not confirmed) and Example 11 (41 mg): LCMS: m/z found 407.2 [M+H]+, rt= 3.16 min (Method B)[ Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm)]; 1H NMR (400 MHz, DMSO) 5 9.29 - 9.23 (m, 2H), 8.83 - 8.77 (m, 1 H), 7.62 (t, J = 8.1 Hz, 1 H), 7.41 (d, J = 10.4 Hz, 1 H), 7.26 (d, J = 8.4 Hz, 1 H), 6.08 (q, J = 8.6 Hz, 1 H), 5.79 (s, 1 H), 2.80 (s, 3H) (absolute stereochemistry not confirmed).
[00430] SFC Prep Purification was done on Waters SFC 80 instruments equipped with Waters 2489 UV/Visible Detector by using CHIRALPAK IG (30mm x 250 mm), 5p Column operating at 35°C temperature, maintaining flow rate of 70 ml/min, using 50% CO2 in super critical state & 50% of 100% METHANOL as Mobile phase. Run this isocratic mixture up to 12.0 minutes and also maintained the isobaric condition of 100 bar at 220 nm wavelength
Example 12 and Example 13
[00431] (R)-5-cyano-N-ethyl-N-((R)-2,2,2-trifluoro-1-(3-fluoro-4-chloro- phenyl)ethyl)pyridine-3-sulfonimidamide (Example 12) and (S)-5-cyano-N-ethyl-N-((R)- 2,2,2-trifluoro-1-(3-fluoro-4-chloro-phenyl)ethyl)pyridine-3-sulfonimidamide (Example 13)
Example 12
Chiral SFC
Separation
Scheme 6
[00432] Synthesis of (/?)-5-(((1-(3,4-difluorophenyl)-2,2,2- trifluoroethyl)(ethyl)amino)thio)nicotinonitrile 6.1 : To the solution of [(1 )-1-(3,4- difluorophenyl)-2,2,2-trifluoroethyl](ethyl)amine (Amine-4b) (0.7 g , 2.94 mmol) in pyridine (1.5 mL, 18.34 mmol) was added compound 1.3 (0.63 g , 3.67 mmol) in THF (4 mL) and the reaction was stirred at 45°C for 3 h. The reaction mixture was cooled at RT, diluted with water (10 mL) and extracted with ethyl acetate (2 x 15 mL). The organic part was washed with water (10 mL) and brine (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 desired compound 6.1 (140 mg, 11 % yield). LCMS: m/z found 374.29 [M+H]+, rt= 1.88 min; 1H NMR (400 MHz, DMSO) 5 8.71 (brs, 1 H), 8.43 (brs, 1 H), 7.86 (brs, 1 H), 7.65 (t, J = 9.6 Hz, 1 H), 7.45 (s, 2H), 5.53-5.46 (m, 1 H), 3.36-3.32 (m, 2H), 1.16 (t, J = 6.9 Hz, 3H).
[00433] Synthesis of 5-cyano-A/-((/?)-1-(3,4-difluorophenyl)-2,2,2-trifluoroethyl)-Af- ethylpyridine-3-sulfonimidamide 6.2: Compound 6.1 (0.09 g, 0.24 mmol) was dissolved in HFIP (1 mL) and MeOH (1 mL) (0.1 M) (taken in a sealed vessel) and AcOH (28 uL , 0.43 mmol) was added to it. It was stirred and (diacetoxyiodo)benzene (0.47 g , 1.45 mmol) was added to the solution followed by ammonium carbamate (0.15 g , 1.93 mmol). The reaction mixture was stirred for 3 h. It was diluted with water (pH = neutral) and extracted with DCM (15 mL). The organic part was washed with water (10 mL), dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The crude was further purified by column chromatography over silica gel to obtain product 5.2 (70 mg) as a diastereomeric mixture.
[00434] The diastereomers were separated by SFC purification method to obtain both the diastereomers.
[00435] SFC Prep Purification was performed on Waters SFC 80 instruments equipped with Waters 2489 UV/Visible Detector by using CHIRALPAK IG (30 mm x 250mm), 5p Column operating at 35°C temperature, maintaining flow rate of 70 ml/min, using 65% CO2 in super critical state and 35% of 100% methanol as Mobile phase. This isocratic mixture ran up to 10.0 minutes and also maintained the isobaric condition of 120 bar at 220 nm wavelength.
[00436] (S)-5-cyano-N-ethyl-N-((R)-2,2,2-trifluoro-1-(3-fluoro-4-chloro- phenyl)ethyl)pyridine-3-sulfonimidamide (Example 12): 20 mg, brown sticky gum, LCMS: m/z found 405.2 [M+H]+, rt= 3.22 min (Method B)[Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm)]; 1H NMR (400 MHz, DMSO) 5 9.27 (d, J = 1.0 Hz, 1 H), 9.22 (d, J = 1.5 Hz, 1 H), 8.80 (s, 1 H), 7.52-7.41 (m, 2H), 7.28-7.27 (m, 1 H), 6.1-6.07 (m, 1 H), 5.73 (s, 1 H), 3.53-3.47 (m, 1 H), 3.33-3.25 (m, 1 H), 0.99 (t, J = 6.8 Hz, 3H) (absolute stereochemistry not confirmed).
(R)-5-cyano-N-ethyl-N-((R)-2,2,2-trifluoro-1-(3-fluoro-4-chloro-phenyl)ethyl)pyridine- 3-sulfonimidamide (Example 13): 20 mg, brown sticky gum, LCMS: m/z found 405.2 [M+H]+, rt= 3.22 min (Method B)[Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm)]; 1H NMR (400 MHz, DMSO) 5 9.31 (d, J = 1.9 Hz, 1 H), 9.23 (d, J = 1.6 Hz, 1 H), 8.85 (s, 1 H), 7.54-7.47 (m, 2H), 7.33 (d, J = 8.1 Hz, 1 H), 6.1-6.08 (m, 1 H), 5.83 (s, 1 H), 3.40-3.26 (m, 2H), 0.91 (t, J = 6.9 Hz, 3H) (absolute stereochemistry not confirmed).
Example-14 and Example 15
[00437] (S)-A/-(( )-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-5-fluoro-A/-methylpyridine-3- sulfonimidamide (Example 14) and (R)-/V-((R)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-5- fluoro-/V-methylpyridine-3-sulfonimidamide (Example 15)
[00438] Synthesis of 3-(benzylthio)-5-fluoropyridine 7.1 : 3-bromo-5-fluoropyridine (10.0 g, 56.82 mmol) was dissolved in toluene (100 mL) and phenyl methanethiol (8.5 g, 68.19 mmol) was added to it. The solution was stirred and degassed with Argon. DI PEA (31.5 mL, 170.47 mmol) was added to the solution followed by Xantphos (985 mg, 1.70 mmol). The reaction mixture was further degassed with Argon. Pd2(dba)s (1.1 g, 1.14 mmol) was added to it under the inert atmosphere and the reaction mixture was stirred at 100 °C for 18h under argon atmosphere. After completion (monitored by TLC and LCMS), the 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 20% ethyl acetate in hexane and product 1.1 was isolated as a yellow gum (10.0 g, 81 % yield).
[00439] LCMS: m/z found ((220.05 [M+H]+), rt= 3.79 min (Method 4)[ Waters Xbridge C18 column (5 pm, 50 x 4.6 mm)];
[00440] Synthesis of 5-fluoropyridine-3-thiol 7.2: AlCh (16.7 g, 77.52 mmol) was dissolved in toluene (20 mL) and a solution of intermediate 7.1 (10.0 g, 45.6 mmol) was added portion wise to it at 0 °C. The stirring was continued at RT for 1 h. The mixture was then diluted with ice cold water (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was separated, washed with water (50 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude product 7.2, which was forwarded to the next step reaction. [00441] Synthesis of 5-fluoropyridin-3-yl hypochlorothioite 7.3: The 5-fluoropyridine-3- thiol 7.2 was dissolved in acetonitrile (5 mL) and NCS (2.5 g, 11.6 mmol) was added portion wise to it at 0 °C. The stirring was continued at RT for 24h. The mixture was then diluted with ice cold water (25 mL) and extracted with dichloromethane (35 mL). The organic layer was separated, washed with water (5 mL) dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound 7.3 which was quickly used for next step reaction without any purification.
[00442] Synthesis of (/?)-/V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-S-(5- fluoropyridin-3-yl)-/V-methylthiohydroxylamine 7.4: To a solution of 5-fluoropyridin-3-yl hypochlorothioite 7.3 in THF ( )-1-(4-chlorophenyl)-2,2,2-trifluoro-/V-methylethan-1-amine (2.46 g, 11.0 mmol) was added, followed by pyridine (1.1 mL, 13.75 mmol). The reaction mixture was stirred at 45 °C for 2h. It was then diluted with water (15 mL) and extracted with dichloromethane (2 x 15 mL). The combined organic layer was washed with water (10 mL), dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The product was purified by column chromatography over silica gel and the compound 7.4 was isolated as colorless sticky gum (300 mg, 10% yield).
[00443] LCMS: m/z found ((351 .25 [M+ H]+) , rt= 1 .93 min (Method 2)[YMC Triart C18 column (3 pm, 33 x 2.1 mm)).
[00444] Synthesis of (/?)-/V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-5-fluoro-/V- methylpyridine-3-sulfonimidamide 7.5: To a solution of intermediate 7.4 (250 mg, 0.71 mmol) in methanol (4 mL) was added acetic acid (0.08 mL, 1.42 mmol), followed by (diacetoxyiodo) benzene (1 g, 1.78 mmol). The mixture was stirred at 0 °C and ammonium carbamate (223 mg, 2.86 mmol) was added. The reaction mixture was then stirred at ambient temperature for 3h. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and intermediate product 7.5 (150 mg) was isolated as a diastereomeric mixture.
[00445] The diastereomers were separated by SFC purification method to obtain Example 14 (40.11 mg), LCMS: m/z found ((382.1 [M+H]+), rt= 3.16 min (Method 2)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)). 1H NMR (400 MHz, DMSO) 5 8.93 - 8.87 (m, 1 H), 8.84 (d, J = 2.7 Hz, 1 H), 8.22 - 8.14 (m, 1 H), 7.51 - 7.44 (m, 2H), 7.41 (d, J = 8.4 Hz, 2H), 6.04 (q, J = 8.8 Hz, 1 H), 5.52 (s, 1 H), 2.80 (s, 3H) (absolute stereochemistry not confirmed) and Example 15: (34.57 mg, 99.87%)LCMS: m/z found ((382.1 [M+H]+),rt= 3.13 min (Method 2)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, DMSO) 5 8.93 - 8.87 (m, 1 H), 8.83 (d, J = 2.7 Hz, 1 H), 8.22 - 8.15 (m, 1 H), 7.47 - 7.34 (m, 4H), 6.05 (q, J = 8.9 Hz, 1H), 5.64 (s, 1 H), 2.75 (s, 3H) (absolute stereochemistry not confirmed).
[00446] SFC method:
[00447] SFC Prep Purification of compound 7.5 was done on Waters SFC PREP 80 instruments equipped with Waters 2489 UV/Visible Detector 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 50% CO2 in super critical state & 50% of 100% MeOH as Mobile phase. Run this isocratic mixture up to 14.0 minutes and maintain the isobaric condition of 100 bar at 220 nm wavelength.
Example 16 and Example 17
[00448] (S)-5-fluoro-/V-methyl-/V-((R)-2,2,2-trifluoro-1-(4-
(trifluoromethyl)phenyl)ethyl)pyridine-3-sulfonimidamide (Example 16) and ( )-5-fluoro-/V- methyl-/V-(( )-2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)pyridine-3-sulfonimidamide (Example 17).
[00449] Synthesis of ( )-S-(5-fluoropyridin-3-yl)-A/-methyl-A/-(2,2,2-trifluoro-1-(4- (trifluoromethyl)phenyl)ethyl)thiohydroxylamine 8.1 : To a solution of 5-fluoropyridin-3-yl hypochlorothioite 7.3 in THF (3 mL) (R)-2,2,2-trifluoro-/V-methyl-1-(4- (trifluoromethyl)phenyl)ethan-1 -amine (1.8 g, 6.97 mmol) was added followed by pyridine (0.7 mL, 8.71 mmol). The reaction mixture was stirred at 45 °C for 2 h. The mixture was diluted with water (15 mL) and extracted with dichloromethane (2 x 15 mL). The combined organic layer was washed with water (10 mL), dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The product was purified by column chromatography over silica gel and the compound 2.1 was isolated as colorless sticky gum (200 mg, 9% yield).
[00450] LCMS: m/z found ((385.2 [M+H]+),rt= 1.94 min (Method 2)[YMC Triart C18 column (3 pm, 33 x 2.1 mm));
[00451] Synthesis of (/?)-5-fluoro-/V-methyl-/V-(2,2,2-trifluoro-1-(4-
(trifluoromethyl)phenyl)ethyl)pyridine-3-sulfonimidamide 8.2 : To a solution of intermediate 8.1 (200 mg, 0.52 mmol) in methanol (3 mL), acetic acid (0.06 mL, 1.04 mmol) was added followed by (Diacetoxyiodo)benzene (419 mg, 1.3 mmol). The mixture was stirred at 0 °C and to it was added ammonium carbamate (163 mg, 2.08 mmol). The reaction mixture was then stirred at ambient temperature for 3 h. The reaction was then quenched with water (15 mL) and extracted with ethyl acetate (2 x 20 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% ethyl acetate in hexane and the product 8.2 (80 mg) was isolated as diastereomeric mixture.
[00452] The diastereomers were separated by SFC purification method to obtain compounds Example 16 (6 mg, 99.58%). LCMS: m/z found ((416.2 [M+H]+),rt= 3.23 min (Method 2)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, DMSO) 5 8.94 - 8.89 (m, 1 H), 8.83 (d, J = 2.7 Hz, 1 H), 8.23 - 8.15 (m, 1 H), 7.76 (d, J = 8.2 Hz, 2H), 7.60 (d, J= 8.1 Hz, 2H), 6.19 (q, J = 8.7 Hz, 1 H), 5.70 (s, 1 H), 2.78 (s, 3H) (absolute stereochemistry not confirmed) and Example 17: (22 mg, 98.86%). LCMS: m/z found ((416.2 [M+H]+),rt= 3.21 min (Method 2)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, DMSO) 5 8.92 (s, 1 H), 8.85 (d, J = 2.8 Hz, 1 H), 8.23 - 8.16 (m, 1 H), 7.80 (d, J = 8.1 Hz, 2H), 7.64 (d, J = 7.9 Hz, 2H), 6.18 (q, J = 8.8 Hz, 1 H), 5.57 (s, 1 H), 2.83 (s, 3H) (absolute stereochemistry not confirmed).
[00453] SFC method:
[00454] SFC Prep Purification of compound 8.2 was done on Waters SFC PREP 80 instruments equipped with Waters 2489 UV/Visible Detector by using CHIRALPAK IG (30.0 mm x 250 mm), 5p Column operating at 35 °C temperature, maintaining a flow rate of 70 mL/min, using 50% CO2 in super critical state and 50% of 100% MeOH as mobile phase. Run this isocratic mixture up to 14.0 minutes and maintain the isobaric condition of 100 bar at 220 nm wavelength.
Example 18 and Example 19 [00455] (S)-5-fluoro-/V-rnethyl-/V-((/?)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyridine-3- sulfonimidamide (Example 18) and (/?)-5-fluoro-/V-methyl-/V-((/?)-2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)pyridine-3-sulfonimidamide (Example 19)
7.3 9.1
Scheme 9
[00456] Synthesis of (/?)-S-(5-fluoropyridin-3-yl)-/V-methyl-/V-(2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)thiohydroxylamine 9.1 : To a solution of 5-fluoropyridin-3-yl hypochlorothioite 7.3 in THF (3 mL) (/?)-2,2,2-trifluoro-/V-methyl-1-(4- (trifluoromethyl)phenyl)ethan-1 -amine (1.52 g, 7.33 mmol was added followed by pyridine (3 mL, 36.65 mmol). The reaction mixture was stirred at 45 °C for 2h. It was then diluted with water (15 mL) and extracted with dichloromethane (2 x 15 mL). The combined organic layer was washed with water (10 mL), dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The product was purified by column chromatography over silica gel and the compound 7.3 was isolated as colorless sticky gum (180 mg, 8% yield).
[00457] LCMS: m/z found ((335.26 [M+H]+),rt= 1.86 min (Method 2)[YMC Triart C18 column (3 pm, 33 x 2.1 mm)).
[00458] Synthesis of (/?)-5-fluoro-/V-methyl-/V-(2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)pyridine-3-sulfonimidamide 9.2: To a solution of intermediate 9.1 (180 mg, 0.54 mmol) in methanol (3 mL) was added acetic acid (0.065 mL, 1.08 mmol) followed by (Diacetoxyiodo)benzene (436 mg, 1.35 mmol). It was stirred at 0 °C and to it was added ammonium carbamate (169 mg, 2.16 mmol). The reaction mixture was then stirred at ambient temperature for 3h. 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 9.2 (75 mg) was isolated as diastereomeric mixture.
[00459] The diastereomers were separated by SFC purification method to obtain compounds Example 18: (18 mg, 98.96%). LCMS: m/z found ((366.2 [M+H]+),rt= 3.09 min (Method 2)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, DMSO) 5 8.92 (s, 1H), 8.85 (d, J = 2.8 Hz, 1 H), 8.23 - 8.16 (m, 1H), 7.80 (d, J = 8.1 Hz, 2H), 7.64 (d, J = 7.9 Hz, 2H), 6.18 (q, J = 8.8 Hz, 1 H), 5.57 (s, 1H), 2.83 (s, 3H) (absolute stereochemistry not confirmed) and Example 19: (20 mg, 99.21%); LCMS: m/z found ((366.2 [M+H]+),rt= 3.03 min (Method 2) [ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, DMSO) 5 8.94 - 8.89 (m, 1H), 8.83 (d, J = 2.7 Hz, 1 H), 8.23 - 8.15 (m, 1 H), 7.76 (d, J= 8.2 Hz, 2H), 7.60 (d, J= 8.1 Hz, 2H), 6.19 (q, J= 8.7 Hz, 1 H), 5.70 (s, 1 H), 2.78 (s, 3H) (absolute stereochemistry not confirmed).
[00460] SFC method:
[00461] SFC Prep Purification of compound 3.2 is currently running on Waters SFC PREP 80 instruments equipped with Waters 2489 UV/Visible Detector 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 60% CO2 in super critical state and 40% of 100% MeOH as mobile phase. Run this isocratic mixture up to 10.0 minutes and maintain the isobaric condition of 100 bar at 210 nm wavelength.
Example 20 and Example 21
[00462] (S)-5-cyano-A/-ethyl-A/-((R)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyridine-3- sulfonimidamide (Example 20) and ( )-5-cyano-/V-ethyl-/V-(( )-2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)pyridine-3-sulfonimidamide (Example 21)
Scheme 10
[00463] Synthesis of (F?)-5-((ethyl(2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)amino)thio)nicotinonitrile 10.1 : To a solution of 5-cyanopyridin-3-yl hypochlorothioite 1.3 in THF (3 mL) (F?)-N-ethyl-2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1- amine (0.75 g, 3.63 mmol) was added followed by pyridine (1.4 mL, 18.17 mmol). The reaction mixture was stirred at 45 °C for 2 h. It was then diluted with water (15 mL) and extracted with dichloromethane (2 x 15 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 10.1 was isolated as colorless sticky gum (250 mg, 15% yield).
[00464] LCMS: m/z found ((356.08 [M+H]+),rt= 1.92 min (Method 2)[YMC Triart C18 column (3 pm, 33 x 2.1 mm)).
[00465] Synthesis of (/?)-5-cyano-A/-ethyl-A/-(2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)pyridine-3-sulfonimidamide 10.2 : To a solution of intermediate 10.1 (250 mg, 0.7 mmol) in methanol (5 mL) and HFIP (1.5 mL), acetic acid (0.08 mL, 1.41 mmol) was added followed by diacetoxyiodobenzene (1.4 g, 4.22 mmol). The reaction was stirred at ambient temperature and ammonium carbamate (439 mg, 5.63 mmol) was added. The reaction mixture was then stirred at ambient temperature for 2h. The reaction was then quenched with water (15 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 product was purified by column chromatography over silica gel using 20% ethyl acetate in hexane to obtain product 10.2 (110 mg) as diastereomeric mixtures.
[00466] The diastereomers were separated by SFC purification method to obtain compound Example 20: (26 mg, 99.75%),LCMS: m/z found ((387.1 [M+H]+),rt= 2.99 min (Method 2)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (401 MHz, DMSO) 5 9.28 - 9.24 (m, 1 H), 9.22 - 9.18 (m, 1 H), 8.76 (s, 1 H), 7.43 (t, J = 5.2 Hz, 2H), 7.22 (t, J = 8.8 Hz, 2H), 6.05 (q, J = 9.0 Hz, 1 H), 5.68 (s, 1 H), 3.50 - 3.43 (m, 1 H), 3.29 - 3.21 (m, 1 H), 0.99 (t, J = 7.0 Hz, 3H) (absolute stereochemistry not confirmed) and Example 21 : (30 mg, 98.76%), LCMS: m/z found ((387.1 [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 9.32 - 9.28 (m, 1 H), 9.24 - 9.19 (m, 1 H), 8.87 - 8.79 (m, 1 H), 7.50 (t, J = 5.4 Hz, 2H), 7.23 (t, J = 8.7 Hz, 2H), 6.08 (q, J = 8.9 Hz, 1 H), 5.79 (s, 1 H), 3.48 - 3.35 (m, 1 H), 3.29 - 3.20 (m, 1 H), 0.89 (t, J = 7.0 Hz, 3H). (absolute stereochemistry not confirmed).
[00467] SFC Method:
[00468] SFC Prep Purification of compound 10.2 was done on Waters SFC 80 instruments equipped with Waters 2489 UV/Visible Detector by using CHIRALPAK IG (30 mm x 250 mm), 5p column operating at 35 °C temperature, maintaining flow rate of 70 mL/min, using 55% CO2 in super critical state and 45% of 100%M ETHANOL as Mobile phase. Run this isocratic mixture up to 16.0 minutes and maintained the isobaric condition of 120 bar at 220 nm wavelength.
Example 22 and Example 23
[00469] (S)-N-((R)-1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethyl)-5-cyano-A/- ethylpyridine-3-sulfonimidamide: (Example 22) and ( )-/V-(( )-1-(4-chloro-3-fluorophenyl)- 2,2,2-trifluoroethyl)-5-cyano-A/-ethylpyridine-3-sulfonimidamide: (Example 23)
[00470] Synthesis of (R)-5-(((1-(4-chloro-3-fluorophenyl)-2,2,2- trifluoroethyl)(ethyl)amino)thio)nicotinonitrile 11.1 : To a solution of 5-cyanopyridin-3-yl hypochlorothioite 1.3 in THF (3 mL) (R)-1-(4-chloro-3-fluorophenyl)-/V-ethyl-2,2,2- trifluoroethan-1-amine (1.2 g, 4.68 mmol) was added followed by pyridine (0.8 mL, 9.38 mmol). The reaction mixture was stirred at 45 °C for 2 h then diluted with water (15 mL) and extracted with dichloromethane (2 x 15 mL). The combined organic layer was washed with water (10 mL), dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The product was purified by column chromatography over silica gel and the compound 11.1 (300 mg, 6% yield) was isolated as colourless sticky gum.
[00471] LCMS: m/z found ((390.04 [M+H]+),rt= 1.96 min (Method 2)[YMC Triart C18 column (3 pm, 33 x 2.1 mm))
[00472] Synthesis of (/?)-/V-(1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethyl)-5-cyano- A/-ethylpyridine-3-sulfonimidamide 11.2: To a solution of intermediate 11.1 (300 mg, 0.77 mmol) in methanol (5 mL) and HFIP (2 mL) acetic acid (0.09 mL, 1.54 mmol) was added followed by diacetoxyiodobenzene (1.5 g, 4.63 mmol). Ammonium carbamate (500 mg, 6.16 mmol) was then added. The reaction mixture was stirred at RT for 2h. 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 isolated 11.2 (70 mg) as a diastereomeric mixture. [00473] The diastereomers were separated by SFC purification method to obtain compounds Example 22: (12 mg, 99.26%), LCMS: m/z found ((421.2 [M+H]+),rt= 3.24 min (Method 2)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (401 MHz, CDCI3) 5 9.39 - 9.31 (m, 1 H), 9.09 - 8.98 (m, 1 H), 8.55 - 8.47 (m, 1 H), 7.43 (t, J = 7.7 Hz, 1H), 7.19 (d, J = 9.9 Hz, 1 H), 7.12 (d, J = 8.4 Hz, 1 H), 5.86 (q, J = 8.9 Hz, 1 H), 3.41 - 3.35 (m, 1 H), 3.32 - 3.24 (m, 1 H), 0.99 (t, J = 7.1 Hz, 3H), 0.92 (t, J = 7.2 Hz, 1 H) (absolute stereochemistry not confirmed) and Example 23: (9 mg, 99%), LCMS: m/z found ((421.2 [M+H]+),rt= 3.24 min (Method 2)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (401 MHz, CDCI3) 5 9.35 - 9.24 (m, 1H), 9.10 - 8.97 (m, 1 H), 8.52 - 8.43 (m, 1H), 7.46 (t, J = 7.7 Hz, 1H), 7.31 - 7.26 (m, 1 H), 7.19 (d, J = 8.6 Hz, 1 H), 6.05 (q, J = 8.4 Hz, 1H), 5.61 (q, J = 8.9 Hz, 1H), 3.46 - 3.34 (m, 1 H), 3.30 - 3.14 (m, 1 H), 1.00 (t, J = 7.1 Hz, 3H) (absolute stereochemistry not confirmed).
[00474] SFC Method:
[00475] SFC Prep Purification of compound 11.2 was done on Pic Solutions 175 instrument equipped with Knauer 40D UV/Visible Detector by using Chiralpak-IG (30mm x 250 mm), 5p Column operating at 35 °C temperature, maintaining flow rate of 100 mL/min, using 70% CO2 in super critical state and 30% of 100% Methanol as mobile phase. This isocratic mixture was run up to 10.0 minutes and maintained the isobaric condition of 100 bar at 229 nm wavelength.
Example 24 and Example 25
[00476] (S)-A/-(( )-1-(3,4-difluorophenyl)-2,2,2-trifluoroethyl)-5-fluoro-A/-methylpyridine-3- sulfonimidamide (Example 24) and (R)-/V-(( )-1-(3,4-difluorophenyl)-2,2,2-trifluoroethyl)-5- fluoro-/V-methylpyridine-3-sulfonimidamide (Example 25)
[00477] Synthesis of 1,2-bis(5-fluoropyridin-3-yl)disulfane, 12.3: The 5-fluoropyridine- 3-thiol 7.2 (2.0 g, 15.48 mmol) was dissolved in acetonitrile (80 mL) and NCS (4.55 g, 34.068 mmol) was added portion wise to it at 0 °C. The stirring continued at RT for 16 h. The mixture was then diluted with ice cold water (50 mL) and extracted with ethyl acetate (100 mL). The organic layer was separated, washed with brine (10 mL) dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude compound which was purified by column chromatography over silica gel using 30% ethyl acetate in hexane and product 12.3 was isolated as an off white solid (800 mg, 20 % yield).
[00478] LCMS: m/z found ((257.0 [M+H]+), rt= 1.92 min (Method 4)[ Waters Xbridge C18 column (5 pm, 50 x 4.6 mm)];
[00479] Synthesis of (/?)-A/-(1-(3,4-difluorophenyl)-2,2,2-trifluoroethyl)-S-(5- fluoropyridin-3-yl)-/V-methylthiohydroxylamine, 12.4: To a solution of 1 ,2-bis(5- fluoropyridin-3-yl)disulfane (400.0 mg, 1.56 mmol) 12.3 in methanol (20.0 mL) was added silver nitrate (530.23, 3.12 mmol) followed by addition of (R)-1-(3,4-difluorophenyl)-2,2,2- trifluoro-/V-methylethan-1-amine (702.81 mg, 3.121 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at RT for 16 h. Consumption of starting material was monitored by TLC and LCMS. The reaction mixture was filtered through a celite pad and the solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by combiflash column chromatography over silica gel using 20% ethyl acetate in hexane and intermediate 12.4 was isolated as colorless sticky gum (200 mg, 36 % yield).
[00480] LCMS: m/z found ((353.1 [M+H]+),rt= 2.30 min (Method 2)[YMC Triart C18 column (3 pm, 33 x 2.1 mm)); [00481] Synthesis of (/?)-/V-(1-(3,4-difluorophenyl)-2,2,2-trifluoroethyl)-5-fluoro-/V- methylpyridine-3-sulfonimidamide, 12.5: To a solution of intermediate 12.4 (200 mg, 0.57 mmol) in methanol (4 mL) and HFIP (2 mL) acetic acid (0.065 mL, 1.13 mmol)was added followed by diacetoxyiodobenzene (1.1 g, 3.41 mmol). The mixture was stirred at 0 °C and ammonium carbamate (354.56 mg, 4.54 mmol) was added to it. The reaction mixture was then stirred at ambient temperature 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 product was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product 12.5 (100 mg) was isolated as a diastereomeric mixture.
[00482] The diastereomers were separated by SFC purification method to obtain compounds Example24 (34.29 mg, 99.46 % ). LCMS: m/z found ((384.2 [M+H]+), rt= 3.07 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, CDCI3) 6 8.98 (s, 1 H), 8.67 (d, J = 2 Hz, 1 H), 7.93 (d, J = 2 Hz,1 H), 7.21-7.15 (m, 2H), 7.09 (s,1 H), 5.87-5.85 (m, 1 H) , 2.84 (s, 4H) (absolute stereochemistry not confirmed) and Example 25: (33.31 mg, 98.26 %) LCMS: m/z found ((384.2 [M+H]+),rt= 3.06 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, CDCI3) 6 8.94 (s, 1 H), 8.65 (d, J = 2 Hz, 1 H), 7.90 (d, J = 2 Hz, 1 H), 7.16-7.22 (m, 2H), 7.11(s, 1 H), 6.00-6.4 (m, 1 H), 2.99 (s, 1 H), 2.79 (s, 3H) (absolute stereochemistry not confirmed).
[00483] SFC method:
[00484] SFC Prep Purification of compound 12.5 was done on Pic Solutions-175 instrument equipped with Knauer 40D UV/Visible Detector by using Chiralpak IG (30.0 mm x 250 mm), 5p Column operating at 35°C temperature, maintaining flow rate of 90 mL/min, using 65% CO2 in super critical state and 35% of 100%MeOH as Mobile phase. Run this isocratic mixture up to 10.0 minutes and maintain the isobaric condition of 100 bar at 264nm wavelength.
Example 26 and Example 27
[00485] (S)-A/-((R)-1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethyl)-5-fluoro-A/- methylpyridine-3-sulfonimidamide (Example 26) and (S)-/V-(( )-1-(4-chloro-3- fluorophenyl)-2,2,2-trifluoroethyl)-5-fluoro-A/-methylpyridine-3-sulfonimidamide (Example 27)
[00486] Synthesis of ( )-/V-(1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethyl)-S-(5- fluoropyridin-3-yl)-/V-methylthiohydroxylamine 13.1 : To a solution of 1 ,2-bis(5-fluoropyridin- 3-yl)disulfane (400.0 mg, 1.56 mmol) 12.3 in methanol (20.0 mL) silver nitrate (530.23 mg, 3.12 mmol) was added, followed by addition of (R)-1-(4-chloro-3-fluorophenyl)-2,2,2- trifluoro-/V-methylethan-1-amine (754.17 mg, 3.121 mmol) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred at RT for 16 h. Consumption of starting material was monitored by TLC and LCMS. The reaction mixture was filtered through celite pad, and the solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by combiflash column chromatography over silica gel using 20% ethyl acetate in hexane and the compound 13.1 was isolated as a colorless sticky gum (200 mg, 34 % yield).
[00487] LCMS: m/z found ((369.25 [M+H]+),rt= 2.00 min (Method 2)[YMC Triart C18 column (3 pm, 33 x 2.1 mm));
[00488] Synthesis of (/?)-/V-(1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethyl)-5-fluoro- A/-methylpyridine-3-sulfonimidamide 13.2 : To a solution of intermediate 13.1 (200 mg, 0.54 mmol) in methanol (4 mL) and HFIP (2 mL) .acetic acid (0.062 mL, 1.08 mmol) was added followed by diacetoxyiodobenzene (1048.18 mg, 3.25 mmol). The mixture was stirred at 0 °C and to it was added ammonium carbamate (338.74 mg, 4.33 mmol). The reaction mixture was then stirred at RT 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 13.2 (100 mg) was isolated as a diastereomeric mixture.
[00489] The diastereomers were separated by SFC purification method to obtain compounds Example 26 (36.37 mg, 99.57%). LCMS: m/z found ((400.1 [M+H]+),rt= 3.16 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, DMSO) 5 8.92 (s, 1 H), 8.86-8.85 (m, 1 H), 8.22 (d, J = 8.4 Hz, 1 H), 7.66 (t, J = 8.4 Hz, 1 H), 7.41 (d, J = 10.4 Hz, 1 H), 7.28 (d, J = 8 Hz, 1 H), 6.11-6.07 (m, 1 H), 5.56 (s, 1 H), 2.82 (s, 3H) (absolute stereochemistry not confirmed) and Example 27: (43.98 mg, 99.75 %). LCMS: m/z found ((400.2 [M+H]+), rt= 3.15 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, DMSO) 5 8.92 (s, 1 H), 8.84 (d, J = 2.4 Hz, 1H), 8.22 (d, J = 8.4 Hz, 1 H), 7.62 (t, J = 8.4 Hz, 1 H), 7.39 (d, J = 10.4 Hz ,1 H), 7.25 (d, J = 8.4 Hz, 1 H), 6.12-6.06 (m, 1 H), 5.67 (s, 1 H), 2.79 (s, 3H) (absolute stereochemistry not confirmed).
[00490] SFC method:
[00491] SFC Prep Purification of compound 13.2 was done on a Waters SFC 80 instruments equipped with Waters 2489 UV/Visible Detector by using CHIRALPAK IG (30 mm x 250 mm), 5p Column operating at 35°C temperature, maintaining flow rate of 70 mL/min, using 60% CO2 in super critical state and 40% of 100% MeOH as mobile phase. Run this isocratic mixture up to 10.0 minutes and maintain the isobaric condition of 100 bar at 220 nm wavelength.
Example 28 and Example 29
[00492] (S)-/V,1-dimethyl-6-oxo-/V-(( )-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-1 ,6- dihydropyridazine-4-sulfonimidamide (Example 28) and ( )-/V,1-dimethyl-6-oxo-/V-(( )- 2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-1 ,6-dihydropyridazine-4-sulfonimidamide (Example 29)
[00493] Synthesis of 5-chloro-2-methylpyridazin-3(2H)-one, 3.1 : 5-chloro-2,3- dihydropyridazin-3-one 14.0 (15 g, 114.91 mmol) was dissolved in ACN (150 mL) K2CO3 (19.06 g, 137.9 mmol) and n-BiuNBr (0.74 g, 2.3 mmol) followed by iodomethane (10.73 mL, 172.37 mmol) were added at RT under nitrogen atmosphere. The resulting reaction mixture was allowed to stir at 115 °C for 4 h. Upon reaction completion, the mixture was evaporated in vacuo. The residue was diluted by dichloromethane and washed with water followed by brine wash. Combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography over silica gel using 30% ethyl acetate in hexane and product 14.1 was isolated as an off white solid (9.9 g, 60 % yield).
[00494] LCMS: m/z found ((145.0 [M+H]+), rt= 1.66 min (Method 4)[ Waters Xbridge C18 column (5 pm, 50 x 4.6 mm)];
[00495] Synthesis of 5-(benzylthio)-2-methylpyridazin-3(2H)-one 14.2: 5-chloro-2- methylpyridazin-3(2H)-one (7.0 g, 48.42 mmol) was dissolved in toluene (100 mL) and phenyl methanethiol (7.22 g, 58.11 mmol) was added to it. The solution was stirred and degassed with Argon. DIPEA (18.74 mL, 145.27 mmol) was added to the solution followed by Xantphos (840 mg, 1.45 mmol). The reaction mixture was further degassed with Argon. Pd2(dba)s (890 mg, 0.97 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) the mixture was filtered through a 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 product 14.2 was isolated as yellow solid (9.0 g, 80 % yield). [00496] LCMS: m/z found ((233.0 [M+H]+), rt= 1.83min (Method 4)[ Waters Xbridge C18 column (5 pm, 50 x 4.6 mm)]
[00497] Synthesis of 5-mercapto-2-methylpyridazin-3(2H)-one 14.3: AICL (38.74 g, 290.57 mmol) was dissolved in toluene (120 mL) and a solution of intermediate 14.2 (9.0 g, 38.74 mmol) was added portion wise to it at 0°C . The stirring continued at RT for 1 h. The mixture was then diluted with ice cold water (100 mL) and extracted with ethyl acetate (200 mL). The organic layer was separated, washed with water (50 mL), dried over anhydrous Na2SC>4 and evaporated under reduced pressure to get crude product 14.3, which was forwarded to the next step reaction.
[00498] LCMS: m/z found ((143.09 [M+H]+), rt= 0.37min (Method 4)[ Waters Xbridge C18 column (5 pm, 50 x 4.6 mm)];
[00499] Synthesis of 5,5'-disulfanediylbis(2-methylpyridazin-3(2H)-one) 14.4: The 5- mercapto-2-methylpyridazin-3(2/7)-one (2.5 g, 17.58 mmol) 14.3 was dissolved in ethanol (50 mL) and iodine (8.93 g, 35.17 mmol) was added portion wise to it at RT. The stirring continued at RT for 18 h. Consumption of starting material was monitored by TLC and LCMS. The reaction mixture was filtered through celite pad and the residue was dried under reduced pressure to get 14.4 as qn off white solid (1.05 g, 20 % yield).
[00500] LCMS: m/z found ((283.26 [M+H]+),rt= 1.23 min (Method 2)[YMC Triart C18 column (3 pm, 33 x 2.1 mm));
[00501] Synthesis of (R)-2-methyl-5-((methyl(2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)amino)thio)pyridazin-3(2H)-one 14.5: To a solution of 5,5'- disulfanediylbis(2-methylpyridazin-3(2H)-one) (500.0 mg, 1.77 mmol) 14.4 in methanol (20.0 mL) silver nitrate (601.65 , 3.54 mmol) was added followed by (R)-2,2,2-trifluoro-1-(4- fluorophenyl)-N-methylethan-1 -amine (733.37 mg, 3.54 mmol) at 0°C under nitrogen atmosphere. The reaction mixture was stirred at RT for 16 h. Consumption of starting material was monitored by TLC and LCMS. The reaction mixture was filtered through a celite pad, and the solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by combiflash column chromatography over silica gel using 50% ethyl acetate in hexane and the compound 14.5 was isolated as colorless sticky gum (200 mg, 32 % yield).
[00502] LCMS: m/z found ((348.29 [M+H]+),rt= 1.73 min (Method 2)[YMC Triart C18 column (3 pm, 33 x 2.1 mm))
[00503] Synthesis of ( )-A/,1-dimethyl-6-oxo-A/-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-1 ,6- dihydropyridazine-4-sulfonimidamide 14.6: To a solution of intermediate 14.5 (200 mg, 0.575 mmol) in methanol (4 mL) and HFIP (2 mL) was added acetic acid (0.066 mL, 1.15 mmol), followed by (diacetoxyiodo)benzene (1111.25 mg, 3.45 mmol). The mixture was stirred at 0°C and ammonium carbamate (359.122 mg, 4.6 mmol) was added to it. The reaction mixture was then stirred at RT 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 product was purified by column chromatography over silica gel using 50 % ethyl acetate in hexane and the product 14.6 (75 mg) was isolated as a diastereomeric mixture.
[00504] The diastereomers were separated by SFC purification method to obtain Example 28: (10.49 mg, 96.04 % ). LCMS: m/z found ((379.1 [M+H]+), rt= 2.85 min (Method B)[ Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, DMSO) 5 8.18 - 8.18 (m, 1 H), 7.53 - 7.49 (m, 2H), 7.29 - 7.25 (m, 3H), 6.08 - 6.01 (m, 1 H), 5.88 (s, 1 H), 3.67 (s, 3H), 2.78(s, 3H) (absolute stereochemistry not confirmed) and Example 29: (9.26 mg, 96 %) LCMS: m/z found ((379.2 [M+H]+),rt= 7.81 min (Method 2)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, DMSO) 5 8.17 (s, 1 H), 7.50-7.47 (m, 2H), 7.28 - 7.23 (m, 3H), 6.03-5.97 (m, 1 H), 5.72 (s, 1 H), 3.65-3.62 (s, 3H), 2.80 (s, 3H) (absolute stereochemistry not confirmed).
[00505] SFC method:
[00506] SFC Prep Purification of compound 14.6 was done on Waters SFC PREP 80 instruments equipped with Waters 2489 UV/Visible Detector by using CHIRALPAK IC (30 mm x 250 mm), 5p column operating at 35°C temperature, maintaining flow rate of 70 mL/min, using 60% CO2 in super critical state and 40% of 100%MeOH as Mobile phase. Run this isocratic mixture up to 10.0 minutes and maintain the isobaric condition of 100 bar at 225 nm wavelength.
Example30 and Example 31
[00507] (S)-/V-(( )-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-/V,1-dimethyl-6-oxo-1 ,6- dihydropyridazine-4-sulfonimidamide (Example 30) and ( )-/V-(( )-1-(4-chlorophenyl)- 2,2,2-trifluoroethyl)-A/,1-dimethyl-6-oxo-1 ,6-dihydropyridazine-4-sulfonimidamide (Example 31)
[00508] Synthesis of (/?)-5-(((1-(4-chlorophenyl)-2,2,2- trifluoroethyl)(methyl)amino)thio)-2-methylpyridazin-3(2/7)-one 15.1 : To a solution of 5,5'-disulfanediylbis(2-methylpyridazin-3(2/7)-one) (500.0 mg, 1.77 mmol) 14.4 in methanol (20.0 mL) silver nitrate (601.65 , 3.54 mmol) was added followed by of ( )-1-(4- chlorophenyl)-2,2,2-trifluoro-/V-methylethan-1-amine (792 mg, 3.54 mmol) at 0°C under nitrogen atmosphere. The reaction mixture was stirred at RT for 16 h. Consumption of starting material was monitored by TLC and LCMS. The reaction mixture was filtered through celite pad and the solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by combiflash column chromatography over silica gel using 50% ethyl acetate in hexane and compound 15.1 was isolated as a colorless sticky gum (200 mg, 31 % yield).
[00509] LCMS: m/z found ((364.15 [M+H]+),rt= 1.80 min (Method 2)[YMC Triart C18 column (3 pm, 33 x 2.1 mm))
[00510] Synthesis of (/?)-/V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-/V,1-dimethyl-6- oxo-1, 6-dihydropyridazine-4-sulfonimidamide 15.2: To a solution of intermediate 15.1 (200 mg, 0.55 mmol) in methanol (4 mL) and HFIP (2 mL) acetic acid (0.063 mL, 1.1 mmol)was added, followed by (diacetoxyiodo)benzene (1062.49 mg, 3.29 mmol). The mixture was stirred at 0°C and ammonium carbamate (343.36 mg, 4.398 mmol) was added to it. The reaction mixture was then stirred at RT for 1 h. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 50% ethyl acetate in hexane and the product 15.2 (80 mg) was isolated as a diastereomeric mixture. [00511] The diastereomers were separated by SFC purification method to obtain compounds Example 30: (22.71 mg, 95.06 % ). LCMS: m/z found ((395.2 [M+H]+), rt= 3.06 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, DMSO) 58.18 (s, 1 H), 7.52- 7.46 (m, 4H), 7.29 (s, 1 H), 6.09-6.03 (m, 1 H), 5.89 (s, 1 H), 3.67 (s, 3H), 2.78 (s, 3H) (absolute stereochemistry not confirmed) and Example 31 : (12.28 mg, 98.39%) LCMS: m/z found ((395.2 [M+H]+),rt= 3.05 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, DMSO) 5 8.20-8.20 (m, 1 H), 7.54 - 7.47 (m, 4H), 7.27-7.26 (m, 1 H), 6.05-6.03 (m, 1 H), 5.75 (s, 1 H), 3.68 (s, 3H), 2.82 (s, 3H). (absolute stereochemistry not confirmed).
[00512] SFC method:
[00513] SFC Prep Purification of compound 4.2 was done on a Waters SFC PREP 80 instruments equipped with a Waters 2489 UV/Visible Detector by using CHIRALPAK IC(30 mm x 250 mm ), 5p column operating at 35°C temperature, maintaining flow rate of 70 mL/min, using 60% CO2 in super critical state and 40% of 100%MeOH as mobile phase. Run this isocratic mixture up to 10.0 minutes and maintain the isobaric condition of 100 bar at 225 nm wavelength.
Example 32 and Example 33
[00514] (S)-A/-((R)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-A/-ethyl-5-fluoropyridine-3- sulfonimidamide (Example 32) and ( )-A/-(( )-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-A/- ethyl-5-fluoropyridine-3-sulfonimidamide (Example 33)
[00515] Synthesis of (/?)-/V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-/V-ethyl-S-(5- fluoropyridin-3-yl)thiohydroxylamine 16.1 : To a solution of 1 ,2-bis(5-fluoropyridin-3- yl)disulfane 12.3 in methanol (5 mL) AgNOs (929 mg, 5.46 mmol) was added was added portion wise to it at 0°C. The reaction mixture was stirred at 0°C for 15 minutes. ( )-1-(4- chlorophenyl)-/V-ethyl-2,2,2-trifluoroethan-1-amine (650 mg, 2.73 mmol) was added to it and the reaction mixture was stirred at RT for 24 h. After completion (monitored by TLC and LCMS), the 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 and the compound 16.1 was isolated as a colorless sticky gum (100 mg, 10 % yield).
[00516] LCMS: m/z found ((365.29 [M+H]+),rt= 2.03 min (Method 2)[YMC Triart C18 column (3 pm, 33 x 2.1 mm));
[00517] Synthesis of (/?)-/V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-/V-ethyl-5- fluoropyridine-3-sulfonimidamide 16.2: A solution of intermediate 16.1 (100 mg, 0.3 mmol) in methanol (2.4 mL) and HFIP (0.5 mL) acetic acid (0.03 mL, 0.55 mmol) was added followed by (diacetoxyiodo)benzene (531 mg, 1.64 mmol). Ammonium carbamate (171 mg, 2.19 mmol) was then added. The reaction mixture was then stirred at RT for 2 h. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product was isolated 35 mg as diastereomeric mixture.
[00518] The diastereomers were separated by SFC purification method to obtain compounds Example 32 (6.54 mg, 98.16%). LCMS: m/z found ((396.2 [M+H]+), rt= 3.21 min (Method 2)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, CDCh) 6 9.02 (s, 1 H), 8.64 (d, J = 2.7 Hz, 1 H), 7.99 - 7.92 (m, 1 H), 7.36 - 7.29 (m, 2H), 7.25 - 7.22 (m, 2H), 5.83 (q, J = 8.6 Hz, 1 H), 3.43 - 3.32 (m, 1 H), 3.31 - 3.19 (m, 1 H), 1.00 (t, J = 7.1 Hz, 3H). (NH proton is absent in CDCI3 the NMR) (absolute stereochemistry not confirmed) and Example 33: (10.62 mg, 99.86%)LCMS: m/z found ((396.2 [M+H]+),rt= 3.21 min (Method 2)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, CDCh) 6 8.98 (s, 1 H), 8.63 (d, J = 2.7 Hz, 1 H), 7.92 (d, J = 7.8 Hz, 1 H), 7.36 (s, 4H), 6.02 (q, J = 8.6 Hz, 1 H), 3.44 - 3.30 (m, 1 H), 3.27 - 3.13 (m, 1 H), 0.99 (t, J = 7.1 Hz, 3H). (NH proton is absent in CDCh the NMR) (absolute stereochemistry not confirmed).
[00519] SFC method:
[00520] SFC Prep Purification of of compound 16.2 was done ona Waters SFC 80 instruments equipped with a Waters 2489 UV/Visible Detector by using CHIRALPAK IG (30 mm x 250 mm), 5p column operating at 35°C temperature, maintaining flow rate of 70 mL/min, using 55% CO2 in super critical state and 45% of 100%Methanol as mobile phase. Run this isocratic mixture up to 20.0 minutes and maintain the isobaric condition of 120 bar at 220 nm wavelength.
Example 34 and Example 35
[00521] (S)-/V-ethyl-5-fluoro-/V-(( )-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyridine-3- sulfonimidamide (Example 34) and (R)-A/-ethyl-5-fluoro-A/-((R)-2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)pyridine-3-sulfonimidamide (Example 35)
[00522] Synthesis of (/?)-/V-ethyl-S-(5-fluoropyridin-3-yl)-/V-(2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)thiohydroxylamine 17.1 : To a solution of 1,2-bis(5-fluoropyridin-3- yl)disulfane 12.3 in methanol (5 mL) AgNOs (531 mg, 3.12 mmol) was added portion wise at 0°C. The reaction mixture was stirred at 0°C for 15 minutes. ( )-/V-ethyl-2,2,2-trifluoro-1- (4-fluorophenyl)ethan-1-amine (691 mg, 3.12 mmol) was added then to it and the reaction mixture was stirred at RT for 24 h. After completion (monitored by TLC and LCMS), the 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 and the compound 17.1 was isolated as a colorless sticky gum (110 mg, 20 % yield).
[00523] LCMS: m/z found ((349.3 [M+H]+),rt= 1.97 min (Method 2)[YMC Triart C18 column (3 pm, 33 x 2.1 mm))
[00524] Synthesis of (R)-A/-ethyl-5-fluoro-A/-(2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)pyridine-3-sulfonimidamide 17.2: Solution of intermediate 17.1 (110 mg, 0.32 mmol) in methanol (2.5 mL) and HFIP (0.6 mL) acetic acid (0.04 mL, 0.64 mmol) was added followed by (diacetoxyiodo)benzene (612 mg, 1.90 mmol) and ammonium carbamate (198 mg, 2.53 mmol). The reaction mixture was then stirred at RT for 2 h. The reaction was then quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane and the product was isolated 17.2 (50 mg) as a diastereomeric mixture.
[00525] The diastereomers were separated by SFC purification method to obtain compounds Example 34 (11.84 mg, 99.66%). LCMS: m/z found ((380.2 [M+H]+),rt= 3.11 min (Method 2)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, CDCh) 6 9.02 (s, 1 H), 8.64 (d, J = 2.6 Hz, 1 H), 7.99 - 7.91 (m, 1 H), 7.34 - 7.26 (m, 2H), 7.04 (t, J = 8.4 Hz, 2H), 5.84 (q, J = 8.7 Hz, 1 H), 3.45 - 3.33 (m, 1 H), 3.31 - 3.19 (m, 1 H), 2.95 (s, 1 H), 0.99 (t, J = 7.1 Hz, 3H) (absolute stereochemistry not confirmed) and Example 35: (17.88 mg, 99.53%). LCMS: m/z found ((380.1 [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, CDCh) 6 9.00 - 8.95 (m, 1 H), 8.62 (d, J = 2.8 Hz, 1 H), 7.95 - 7.88 (m, 1 H), 7.45 - 7.36 (m, 2H), 7.08 (t, J = 8.6 Hz, 2H), 6.08 - 5.97 (m, 1 H), 3.43 - 3.30 (m, 1 H), 3.29 - 3.15 (m, 1 H), 3.01 (s, 1 H), 0.99 (t, J = 7.1 Hz, 3H) (absolute stereochemistry not confirmed).
[00526] SFC method:
[00527] SFC Prep Purification of compound 6.2 was done on a Waters SFC 80 instruments equipped with a Waters 2489 UV/Visible Detector by using CHIRALPAK IG (30 mm x 250 mm), 5p column operating at 35°C temperature, maintaining flow rate of 70 mL/min, using 55% CO2 in super critical state and 45% of 100% MeOH as mobile phase. Run this isocratic mixture up to 10.0 minutes and maintained the isobaric condition of 100 bar at 269 nm wavelength.
Example 36 and Example 37
[00528] (S)-5-cyano-/V-ethyl-/V-((R)-2,2,2-trifluoro-1-(4- (trifluoromethyl)phenyl)ethyl)pyridine-3-sulfonimidamide (Example 36) and ( )-5-cyano-/V- ethyl-/V-(( )-2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)pyridine-3-sulfonimidamide (Example 37)
[00529] Synthesis of (R)-5-((ethyl(2,2,2-trifluoro-1-(4-
(trifluoromethyl)phenyl)ethyl)amino)thio)nicotinonitrile 18.1 : To a solution of 5-cyanopyridin- 3-yl hypochlorothioite 2.3 in THF (3 mL) (R)-/V-ethyl-2,2,2-trifluoro-1-(4- (trifluoromethyl)phenyl)ethan-1 -amine (1.8 g, 6.61 mmol) was added followed by pyridine (2.3 mL, 27.56 mmol). The reaction mixture was stirred at 45°C for 2 h. The mixture was diluted with water (15 mL) and extracted with dichloromethane (2x15 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 18.1 was isolated as a colorless sticky gum (250 mg, 11 % yield).
[00530] LCMS: m/z found ((406.08 [M+H]+),rt= 1.92 min (Method 2)[YMC Triart C18 column (3 pm, 33 x 2.1 mm))
[00531] Synthesis of (/?)-5-cyano-A/-ethyl-A/-(2,2,2-trifluoro-1-(4-
(trifluoromethyl)phenyl)ethyl)pyridine-3-sulfonimidamide 18.2 : To a solution of intermediate 18.1 (250 mg, 0.7 mmol) in methanol (5 mL) and HFIP(1.5 mL), acetic acid (0.07 mL, 1.23 mmol) was added followed by (diacetoxyiodo)benzene (1.2 g, 3.70 mmol). The mixture was stirred at RT and to it was added ammonium carbamate (385 mg, 4.94 mmol). The reaction mixture was then stirred at RT for 2 h. The reaction was then quenched with water (15 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by column chromatography over silica gel using 20% ethyl acetate in hexane to obtain product 18.2 (60 mg) as a diastereomeric mixture. [00532] The diastereomers were separated by SFC purification method to obtain compound Example 36: (21.64 mg, 98.04%), LCMS: m/z found ((437.3 [M+H]+),rt= 3.23 min (Method 2)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, CDC ) 6 9.39-9.34 (m, 1H), 9.04-9.00 (m, 1H), 8.52 (s, 1H), 7.80-7.70 (m, 1H), 7.66 (d, J= 8.1 Hz, 2H), 7.52 (d, J= 8.4 Hz, 2H), 5.95 (q, J= 8.2 Hz, 1H), 5.65 (m, 1H), 3.47-3.12 (m, 1H), 0.97 (t, J = 7.1 Hz, 3H) (absolute stereochemistry not confirmed) and Example 37: (14.03 mg, 98.52%), LCMS: m/z found ((437.3 [M+H]+),rt= 3.24 min (Method 2)[ Waters Acquity BEH C8 column (1.7 pm, 50x2.1 mm)); 1H NMR (400 MHz, CDCh) 69.32 (d, J= 2.3 Hz, 1H), 9.01 (d, J = 2.0 Hz, 1H), 8.49 (d, J= 2.8 Hz, 1H), 7.73-7.69 (m, 1H), 7.69-7.65 (m, 1H), 7.58 (d, J= 8.1 Hz, 2H), 6.13 (q, J = 8.4 Hz, 1H), 5.65 (m, 1H), 3.53-3.35 (m, 1H), 3.30 - 3.16 (m, 1H), 0.98 (t, J = 7.1 Hz, 3H) (absolute stereochemistry not confirmed).
[00533] SFC Method:
[00534] SFC Prep Purification of of compound 18.2 was done on a Waters SFC PREP 150 instruments equipped with Waters 2489 UV/Visible Detector by using CHIRALPAK IG (30.0 mm x 250 mm), 5p column operating at 35°C temperature, maintaining flow rate of 90 mL/min, using 65% CO2 in super critical state and 35% of 100% MeOH as mobile phase. Run this isocratic mixture up to 7.0 minutes and maintain the isobaric condition of 100 bar at 247 nm wavelength
Example 38 and Example 39
[00535] (S)-A/-((R)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-5-cyano-A/-ethylpyridine-3- sulfonimidamide (Example 38) and (R)-/V-((R)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-5- cyano-/V-ethylpyridine-3-sulfonimidamide (Example 39)
Example 39
Scheme 19 [00536] Synthesis of (F?)-5-(((1-(4-chlorophenyl)-2,2,2- trifluoroethyl)(ethyl)amino)thio)nicotinonitrile 19.1 : To a solution of 5-cyanopyridin-3-yl hypochlorothioite 2.3 in THF (3 mL) was added (R)-1-(4-chlorophenyl)-/V-ethyl-2,2,2- trifluoroethan-1-amine (858 mg, 3.62 mmol) followed by pyridine (1.3 mL, 16.45 mmol). The reaction mixture was stirred at 45°C for 2 h. The reaction mixture was diluted with water (15 mL) and extracted with dichloromethane (2 x 15 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 19.1 was isolated as a colorless sticky gum (250 mg, 20 % yield).
[00537] LCMS: m/z found ((372.05 [M+H]+),rt= 1.96 min (Method 2)[YMC Triart C18 column (3 pm, 33 x 2.1 mm));
[00538] Synthesis of (/?)-/V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-5-cyano-/V- ethylpyridine-3-sulfonimidamide 19.2: To a solution of intermediate 19.1 (250 mg, 0.7 mmol) in methanol (5 mL) and HFIP (2 mL) was added acetic acid (0.08 mL, 1.35 mmol) followed by (diacetoxyiodo)benzene (1 .3 g, 4.04 mmol) and ammonium carbamate (420 mg, 5.39 mmol). The reaction mixture was then stirred at RT 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 isolated 19.2 (35 mg) as a diastereomeric mixture.
[00539] The diastereomers were separated by SFC purification method to obtain compounds Example 38: (8.42 mg, 98.52%), LCMS: m/z found ((403.2[M+H]+),rt= 3.18 min (Method 2)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm); 1H NMR (400 MHz, CDCI3) 6 9.37 - 9.32 (m, 1 H), 9.03 - 8.98 (m, 1 H), 8.52 - 8.46 (m, 1 H), 7.36 (d, J = 8.5 Hz, 2H), 7.29 (d, J = 8.3 Hz, 2H), 5.90 - 5.79 (m, 1 H), 3.43 - 3.22 (m, 2H), 0.98 (t, J = 7.1 Hz, 3H). (NH proton is absent in CDCI3 the NMR) (absolute stereochemistry not confirmed) and Example 39: (8.28 mg, 96.80%); LCMS: m/z found ((403.2 [M+H]+),rt= 3.18 min (Method 2)[ Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, CDCI3) 6 9.33 - 9.25 (m, 1 H), 9.02 - 8.97 (m, 1 H), 8.48 - 8.43 (m, 1 H), 7.46 - 7.33 (m, 4H), 5.99 (q, J = 8.5 Hz, 1 H), 5.62(m, 1 H), 3.49 - 3.20 (m, 2H), 0.99 (t, J = 7.0 Hz, 3H) (absolute stereochemistry not confirmed).
[00540] SFC Method:
[00541] SFC Prep Purification of compound 19.2 was done on a Waters SFC PREP 150 instruments equipped with a Waters 2489 UV/Visible Detector by using CHIRALPAK IG (30.0 mm x 250 mm), 5p column operating at 35°C temperature, maintaining flow rate of 100 mL/min, using 65% CO2 in super critical state and 35% of 100% MeOH as mobile phase. Run this isocratic mixture up to 10.0 minutes and maintain the isobaric condition of 100 bar at 255 nm wavelength
Example 40 and Example 41
[00542] (S)-/V-((/?)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-/V-methylimidazo[1 ,2-a]pyridine-
7-sulfonimidamide (Example 40) and ( )-A/-(( )-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-A/- methylimidazo[1 ,2-a]pyridine-7-sulfonimidamide (Example 41)
[00543] Synthesis of 2-ethylhexyl 3-(imidazo[1,2-a]pyridin-7-ylthio)propanoate 20.1 : 7-bromoimidazo[1 ,2-a]pyridine 20.0 (5.0 g, 25.377 mmol) was dissolved in toluene (40 mL) and 2-ethylhexyl 3-mercaptopropanoate (6.09 g, 27.914mmol) was added to it. The solution was stirred and degassed with Argon. DI PEA (40 mL, 76.13 mmol) was added to the solution followed by Xantphos (440 mg, 0.761 mmol). The reaction mixture was further degassed with Argon, Pd2(dba)s (464 mg, 0.51 mmol) was added to it under the inert atmosphere and the reaction mixture was stirred was continued at 100 °C for 16 h under Argon. After completion (monitored by TLC and LCMS), 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 15% ethyl acetate in hexane to afford 2- ethylhexyl 3-(imidazo[1 ,2-a]pyridin-7-ylthio)propanoate 20.1 (7.08 g, 82 % yield) as a brown liquid.
[00544] LCMS: m/z found ((335 [M+H]+), rt= 2.11 min (Method H) Waters Xbridge C18 column (3.5 pm, 50 x 3 mm);
[00545] Synthesis of imidazo[1,2-a]pyridine-7-thiol 20.2: 2-ethylhexyl 3-(imidazo[1 ,2- a]pyridin-7-ylthio)propanoate 20.1 (4.5 g, 13.454 mmol) was dissolved in methanol (40 mL) and cooled to 0° C. Then K2CO3 (2.79 g, 20.18 mmol) was added portion wise to it maintaining the same temperature. The stirring was then continued at RT for 2 h. After completion, the reaction mixture was filtered through sintered funnel. The filtrate was concentrated under reduced pressure to get imidazo[1 ,2-a]pyridine-7-thiol as crude product 20.2 (1 .70 g, 84 % yield) which was forwarded to the next step reaction.
[00546] LCMS: m/z found ((151 [M+H]+), rt= 0.29 min (Method H) Waters Xbridge C18 column (3.5 pm, 50 x 3 mm);
[00547] Synthesis of 1,2-bis(imidazo[1,2-a]pyridin-7-yl)disulfane 20.3: The imidazo[1 ,2-a]pyridine-7-thiol 20.2 (900 mg, 5.992 mmol) was dissolved in acetonitrile (10 mL) and NCS (956 mg, 7.19 mmol) was added portion wise to it at -20°C. The stirring continued at RT for 16 h. The mixture was then diluted with ice cold water (25 mL) and extracted with dichloromethane (35 mL). The organic layer was separated, washed with water (5 mL) dried over anhydrous Na2SO4 and concentrated under reduced pressure and the crude product was purified by column chromatography over silica gel using 2% methanol in dihloromethane to afford 1 ,2-bis(imidazo[1 ,2-a]pyridin-7-yl)disulfane 20.3 (600 mg, 67 % yield) as a brown solid.
[00548] LCMS: m/z found ((299 [M+H]+), rt= 2.87 min (Method D) Waters Xbridge C18 column (5 pm, 50 x 4.6 mm);
[00549] Synthesis of (/?)-/V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-S-(imidazo[1,2- a]pyridin-7-yl)-/V-methylthiohydroxylamine 20.4: A solution of 1 ,2-bis(imidazo[1 ,2- a]pyridin-7-yl)disulfane 20.3 (600 mg, 2.01 mmol) in methanol (6 mL) was cooled to 0°C. Then AgNOs (681 mg, 4.02 mmol) was added to it followed by (R)-1-(4-chlorophenyl)-2,2,2- trifluoro-/V-methylethan-1-amine (717 mg, 3.216 mmol). The stirring continued at RT for 16 h. After completion, 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 5% methanol in dichloromethane to afford ( )-A/-(1-(4- chlorophenyl)-2,2,2-trifluoroethyl)-S-(imidazo[1 ,2-a]pyridin-7-yl)-A/- methylthiohydroxylamine 20.4 (160 mg, 21 % yield) as a brown liquid.
[00550] LCMS: m/z found ((372.2 [M+H]+),rt= 1.85 min (Method Y) Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm)
[00551] Synthesis of A/-((/?)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-/V- methylimidazo[1 ,2-a]pyridine-7-sulfonimidamide 20.5: To a solution of ( )-N-(1-(4- chlorophenyl)-2,2,2-trifluoroethyl)-S-(imidazo[1 ,2-a]pyridin-7-yl)-A/- methylthiohydroxylamine 20.4 (160 mg, 0.43 mmol) in methanol (4 mL) was added acetic acid (0.048 mL, 0.861 mmol), followed by (diacetoxyiodo) benzene (326 mg, 1.076 mmol). The mixture was stirred at 0°C and then ammonium carbamate (134 mg, 1.721 mmol)was added. Stirring was continued at RT 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 product was purified by column chromatography over silica gel using 5% methanol in dichloromethane to afford A/-((R)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-A/- methylimidazo[1 ,2-a]pyridine-7-sulfonimidamide 20.5 (60 mg, 35 % yield) was isolated as a diastereomeric mixture.
[00552] The diastereomers were separated by SFC purification method to obtain compounds Example 40: (14 mg); LCMS: m/z found ((403.2 [M+H]+), rt= 2.63 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm]; 1H NMR (400 MHz, DMSO) 5 8.65 (d, J = 7.1 Hz, 1 H), 8.13 (s, 1 H), 8.10 - 8.05 (m, 1 H), 7.81 - 7.77 (m, 1 H), 7.47 - 7.35 (m, 4H), 7.27 - 7.20 (m, 1 H), 6.09 (q, J = 8.8 Hz, 1 H), 5.39 (s, 1 H), 2.72 (s, 3H) (absolute stereochemistry not confirmed) and Example 41 : (12 mg); LCMS: m/z found ((403.1 [M+H]+),rt= 2.64 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm]; 1 H NMR (400 MHz, DMSO) 5 8.66 (d, J = 7.3 Hz, 1 H), 8.13 (s, 1 H), 8.08 - 8.03 (m, 1 H), 7.81 - 7.77 (m, 1 H), 7.45 (s, 4H), 7.28 - 7.21 (m, 1 H), 6.05 (q, J = 9.0 Hz, 1 H), 5.26 (s, 1 H), 2.77 (s, 3H) (absolute stereochemistry not confirmed).
[00553] SFC method:
[00554] SFC Prep Purification of compound 20-6 was done on a Waters SFC 150 instruments equipped with a Waters 2489 UV/Visible Detector by using CHIRALPAK IC (30 mm x 250 mm), 5p column operating at 35°C temperature, maintaining flow rate of 100 mL/min, using 60% CO2 in super critical state and 40% of 100%Methanol as mobile phase. Run this isocratic mixture up to 12.0 minutes and maintained the isobaric condition of 100 bar at 232 nm wavelength.
Example 42 and Example 43
[00555] ( )-/V-methyl-/V-(( )-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)imidazo[1 ,2-a]pyridine- 7-sulfonimidamide (Example 42) and (S)-/V-methyl-/V-((R)-2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)imidazo[1 ,2-a]pyridine-7-sulfonimidamide (Example 43)
[00556] Synthesis of (/?)-S-(imidazo[1,2-a]pyridin-7-yl)-/V-methyl-/V-(2,2,2-trifluoro-1- (4-fluorophenyl)ethyl)thiohydroxylamine, 21.1 : A solution of 1 ,2-bis(imidazo[1 ,2- a]pyridin-7-yl)disulfane 20.3 (500 mg, 1.68 mmol) in methanol (6 mL) was cooled to 0°C. Then, AgNOs (569 mg, 3.35 mmol) was added to it followed by (R)-2,2,2-trifluoro-1-(4- fluorophenyl)-/V-methylethan-1-amine (520 mg, 2.51 mmol). The stirring continued at RT for 16 h. After completion, the reaction mixture was filtered through a sintered funnel. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography over silica gel using 5% methanol in dichloromethane to afford (R)-S- (imidazo[1 ,2-a]pyridin-7-yl)-A/-methyl-A/-(2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)thiohydroxylamine 21.1 (200 mg, 33 % yield) as a brown liquid.
[00557] LCMS: m/z found ((356.2 [M+H]+),rt= 1.92 min (Method Y) Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm);
[00558] Synthesis of /V-methyl-/V-(( )-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)imidazo[1 ,2- a]pyridine-7-sulfonimidamide 21.2:
[00559] To a solution of afford ( )-S-(imidazo[1 ,2-a]pyridin-7-yl)-A/-methyl-A/-(2,2,2- trifluoro-1-(4-fluorophenyl)ethyl)thiohydroxylamine 21.1 (200 mg, 0.563 mmol) in methanol (4 mL) was added acetic acid (0.064 mL, 1.126 mmol), followed by (diacetoxyiodo)benzene (453 mg, 1.407 mmol). The mixture was stirred at 0 °C and ammonium carbamate (176 mg, 2.251 mmol) was added to it. The reaction mixture was then stirred at RT 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 product was purified by column chromatography over silica gel using 5% methanol in dichloromethane to afford N- methyl-/V-(( )-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)imidazo[1 ,2-a]pyridine-7- sulfonimidamide 21.2 (90 mg, 41 % yield) was isolated as diastereomeric mixture.
[00560] The diastereomers were separated by SFC purification method to obtain compounds Example 42: (34 mg); LCMS: m/z found ((387.2 [M+H]+), rt= 2.52 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm]; 1H NMR (400 MHz, DMSO) 5 8.64 (d, J = 7.1 Hz, 1 H), 8.12 (s, 1 H), 8.07 (s, 1 H), 7.79 (s, 1 H), 7.49 - 7.41 (m, 2H), 7.26 - 7.19 (m, 1 H), 7.14 (t, J = 8.6 Hz, 2H), 6.07 (q, J = 9.0 Hz, 1 H), 5.36 (s, 1 H), 2.72 (s, 3H) (absolute stereochemistry not confirmed) and Example 43: (24 mg) LCMS: m/z found ((387.2 [M+H]+),rt= 2.52 min (Method B)[ Waters Acquity BEH C8 column (1 .7 pm, 50 x 2.1 mm]; 1H NMR (400 MHz, DMSO) 5 8.65 (d, J = 7.2 Hz, 1 H), 8.13 (s, 1 H), 8.05 (s, 1 H), 7.79 (s, 1 H), 7.52 - 7.44 (m, 2H), 7.27 - 7.16 (m, 3H), 6.04 (q, J = 8.9 Hz, 1 H), 5.25 (s, 1 H), 2.77 (s, 3H) (absolute stereochemistry not confirmed).
[00561] SFC method:
[00562] SFC Prep Purification of compound 21.2 was done on a Waters SFC 150 instruments equipped with Waters 2489 UV/Visible Detector by using CHIRALPAK IC (30 mm x 250 mm), 5p column operating at 35°C temperature, maintaining flow rate of 100 mL/min, using 60% CO2 in super critical state and 40% methanol as mobile phase. Run this isocratic mixture up to 12.0 minutes and maintain the isobaric condition of 100 bar at 232 nm wavelength.
Example 44 and Example 45
[00563] (/?)-N-((/?)-1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethyl)-/V-methylimidazo[1 ,2- a]pyridine-7-sulfonimidamide (Example 44) and (S)-/V-((R)-1-(4-chloro-3-fluorophenyl)- 2,2,2-trifluoroethyl)-/V-methylimidazo[1 ,2-a]pyridine-7-sulfonimidamide (Example 45) [00564] Synthesis of (/?)-/V-(1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethyl)-S- (imidazo[1,2-a]pyridin-7-yl)-A/-methylthiohydroxylamin, 22.1 : A solution of 1 ,2- bis(imidazo[1 ,2-a]pyridin-7-yl)disulfane 20.3 (500 mg, 1.67 mmol) in methanol (6 mL) was cooled to 0°C. Then AgNOs (569 mg, 3.35 mmol) was added to it followed by ( )-1-(4-chloro- 3-fluorophenyl)-2,2,2-trifluoro-/V-methylethan-1-amine (607 mg, 2.514 mmol). The stirring continued at RT for 16 h. After completion, 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 5% methanol in dichloromethane to afford ( )-A/-(1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethyl)-(imidazo[1 ,2-a]pyridin-7-yl)-A/- methylthiohydroxylamine 22.1 (150 mg, 23 % yield) as a brown liquid.
LCMS: m/z found ((390.2 [M+H]+),rt= 1.44 min (Method Y) Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm);
[00565] Synthesis of A/-((/?)-1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethyl)-Af- methylimidazo[1 ,2-a]pyridine-7-sulfonimidamide 22.2:
[00566] To a solution of ( )-/V-(1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethyl)-S- (imidazo[1 ,2-a]pyridin-7-yl)-/V-methylthiohydroxylamine (21.1 , 150 mg, 0.385 mmol) in methanol (4 mL) was added acetic acid (0.044 mL, 0.77 mmol), followed by (diacetoxyiodo) benzene (309 mg, 0.962 mmol). The mixture was stirred at O °C and to it was added ammonium carbamate (120 mg, 1.539 mmol). The reaction mixture was then stirred at RT 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 product was purified by column chromatography over silica gel using 5% methanol in dichloromethane to afford A/-((R)-1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethyl)-A/- methylimidazo[1 ,2-a]pyridine-7-sulfonimidamide 22.2 (65 mg, 40 % yield) was isolated as a diastereomeric mixture.
[00567] The diastereomers were separated by SFC purification method to obtain compounds Example 44: (21 mg); LCMS: m/z found ((421.2 [M+H]+), rt= 2.72 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm]; 1H NMR (400 MHz, DMSO) 5 8.67 - 8.61 (m, 1 H), 8.13 - 8.05 (m, 2H), 7.77 (s, 1 H), 7.61 - 7.52 (m, 1 H), 7.40 - 7.33 (m, 1 H), 7.33 - 7.26 (m, 1 H), 7.25 - 7.19 (m, 1 H), 6.15 - 6.08 (m, 1 H), 5.14 (s, 1 H), 2.80 (s, 3H) (absolute stereochemistry not confirmed) and Example 45: (17 mg) LCMS: m/z found ((421.2 [M+H]+),rt= 2.72 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm]; 1H NMR (400 MHz, DMSO) 5 8.64 (d, J = 7.1 Hz, 1 H), 8.08 (d, J = 13.1 Hz, 2H), 7.77 (s, 1 H), 7.59 (t, J = 8.1 Hz, 1 H), 7.39 (d, J = 10.5 Hz, 1 H), 7.31 (d, J = 8.4 Hz, 1 H), 7.22 (d, J = 7.3 Hz, 1 H), 6.07 (q, J = 8.8 Hz, 1 H), 5.04 (s, 1 H), 2.83 (s, 3H) (absolute stereochemistry not confirmed).
[00568] SFC method:
[00569] SFC Prep Purification of compound 22.2 was done on a Waters SFC 80 instruments equipped with a Waters 2489 UV/Visible Detector by using CELLULOSE SC (21 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% MeOH as mobile phase. Run this isocratic mixture up to 6.0 minutes and maintain the isobaric condition of 100 bar at 230 nm wavelength.
Example 46 and Example 47
[00570] ( )-A/-(( )-1-(3,4-difluorophenyl)-2,2,2-trifluoroethyl)-A/-methylimidazo[1 ,2- a]pyridine-7-sulfonimidamide (Example 46) and (S)-/V-(( )-1-(3,4-difluorophenyl)-2,2,2- trifluoroethyl)-/V-methylimidazo[1 ,2-a]pyridine-7-sulfonimidamide (Example 47)
Scheme 23
[00571] Synthesis of (/?)-/V-(1-(3,4-difluorophenyl)-2,2,2-trifluoroethyl)-S-(imidazo[1,2- a]pyridin-7-yl)-/V-methylthiohydroxylamine, 23.1 : To a solution of 1 ,2-bis(imidazo[1 ,2- a]pyridin-7-yl)disulfane 20.3 (500 mg, 1.67 mmol) in methanol (6 mL) was cooled to 0°C. Then AgNOs (569 mg, 3.35 mmol) was added to it followed by (R)-1-(3,4-difluorophenyl)- 2,2,2-trifluoro-/V-methylethan-1-amine (377 mg, 1.676 mmol). The stirring continued at RT for 16 h. After completion, 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 5% methanol in dichloromethane to afford ( )- A/-(1-(3,4-difluorophenyl)-2,2,2-trifluoroethyl)-S-(imidazo[1 ,2-a]pyridin-7-yl)-/V- methylthiohydroxylamine 12.1 (200 mg, 32 % yield) as a brown liquid.
[00572] LCMS: m/z found ((374.2 [M+H]+),rt= 1.40 min (Method Y) Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm);
[00573] Synthesis of A/-((R)-1-(3,4-difluorophenyl)-2,2,2-trifluoroethyl)-N- methylimidazo[1 ,2-a]pyridine-7-sulfonimidamide, 23.2: To a solution of ( )-/V-(1-(3,4- difluorophenyl)-2,2,2-trifluoroethyl)-S-(imidazo[1 ,2-a]pyridin-7-yl)-A/- methylthiohydroxylamine 23.1 (170 mg, 0.455mmol) in methanol (4 mL) was added acetic acid (0.052 mL, 0.911 mmol), followed by (diacetoxyiodo) benzene (366 mg, 1.138 mmol). The mixture was stirred at 0 °C and to it was added ammonium carbamate (142 mg, 1.821 mmol). The reaction mixture was then stirred at RT 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 product was purified by column chromatography over silica gel using 5% methanol in dichloromethane to afford A/-(( )-1-(3,4-difluorophenyl)- 2,2,2-trifluoroethyl)-/V-methylimidazo[1 ,2-a]pyridine-7-sulfonimidamide 23.2 (65 mg, 35 % yield) was isolated as diastereomeric mixture.
[00574] The diastereomers were separated by SFC purification method to obtain compounds Example 46: (27 mg) LCMS: m/z found ((405.2 [M+H]+), rt= 2.64 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm]; 1H NMR (400 MHz, DMSO) 5 8.66 (d, J = 7.1 Hz, 1 H), 8.11 (d, J = 15.0 Hz, 2H), 7.82 - 7.77 (m, 1 H), 7.47 - 7.34 (m, 2H), 7.31 - 7.20 (m, 2H), 6.09 (q, J = 8.8 Hz, 1 H), 5.39 (s, 1 H), 2.76 (s, 3H) (absolute stereochemistry not confirmed) and Example 47: (19 mg) LCMS: m/z found ((405.2 [M+H]+),rt= 2.64 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm]; 1 H NMR (400 MHz, DMSO) 5 8.67 (d, J = 7.2 Hz, 1 H), 8.14 (s, 1 H), 8.08 (s, 1 H), 7.79 (s, 1 H), 7.51 - 7.40 (m, 2H), 7.33 - 7.29 (m, 1 H), 7.29 - 7.22 (m, 1 H), 6.07 (q, J = 8.8 Hz, 1 H), 5.29 (s, 1 H), 2.80 (s, 3H) (absolute stereochemistry not confirmed).
[00575] SFC method:
[00576] SFC Prep Purification of compound 12.2 was done on a Waters SFC PREP 80 instruments equipped with a Waters 2489 UV/Visible Detector by using CHIRALPAK IC (30 mm x 250 mm), 5p column operating at 35°C temperature, maintaining flow rate of 70 mL/min, using 55% CO2 in super critical state and 45% MeOH as mobile phase. Run this isocratic mixture up to 12.0 minutes and maintained the isobaric condition of 100 bar at 235 nm wavelength.
Example 48 and Example 49 [00577] (S)-A/-(( )-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-A/-methylpyrimidine-5- sulfonimidamide (Example 48) and ( )-A/-(( )-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-A/- methylpyrimidine-5-sulfonimidamide (Example 49)
[00578] Synthesis of 2-ethylhexyl 3-(pyrimidin-5-ylthio)propanoate 24.1 : 5- bromopyrimidine 24.0 (5.0 g, 31.45 mmol) was dissolved in toluene (50 mL) and 2-ethylhexyl 3-mercaptopropanoate (6.9 g, 31.45 mmol) was added to it. The solution was stirred and degassed with Argon. DIPEA (16.4 mL, 94.35 mmol) was added to the solution followed by Xantphos (545 mg, 0.95 mmol). The reaction mixture was further degassed with Argon. Pd2(dba)s (576 mg, 0.63 mmol) was added to it and the reaction mixture was stirred at 100°C for 16 h under argon atmosphere. After completion (monitored by TLC and LCMS), the mixture was filtered through a sintered funnel. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography over silica gel using 60% ethyl acetate in hexane and product 24.1 was isolated as yellow gum (7.0 g, 75 % yield).
[00579] LCMS: m/z found ((297.375 [M+H]+), rt= 1.80 min (Method l)[ Waters Xbridge C18 column (3.5 pm, 50 x 3 mm)];
[00580] Synthesis of pyrimidine-5-thiol 24.2: To a stirred solution of intermediate 24.1 (5 g, 16.87 mmol) in methanol (50 mL) K2CO3 (4.66 g, 33.73 mmol) was added portion wise at 0°C. The stirring was then continued at RT for 2 h. The reaction mixture was filtered through a celite bed and washed with methanol. Combined filtrate was concentrated under reduced pressure to get crude product 24.2, which was forwarded to the next step reaction.
[00581] Synthesis of 1,2-di(pyrimidin-5-yl)disulfane 24.3: The pyrimidine-5-thiol 24.2 (500 mg, 4.46 mmol) was dissolved in acetonitrile (10 mL). Triethylamine (1.87 mL, 13.38 mmol) and NCS (712 mg, 5.35 mmol) were added portion wise to it at 0°C. The stirring was continued at RT for 16 h. The mixture was then diluted with ice cold water (50 mL) and extracted with dichloromethane (100 mL). The organic layer was separated, washed with water (25 mL) dried over anhydrous Na2SO4 and concentrated under reduced pressure and the crude product was purified by column chromatography over silica gel using 60% ethyl acetate in hexane and product 24.3 was isolated as a yellow gum (200 mg, 21 % yield).
[00582] LCMS: m/z found ((223.15 [M+H]+), rt= 1.43 min (Method H)[ Waters Xbridge C18 column (3.5 pm, 50 x 3 mm)];
[00583] Synthesis of (/?)-/V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-/V-methyl-S- (pyrimidin-5-yl)thiohydroxylamine 24.4: A solution of 1 ,2-di(pyrimidin-5-yl)disulfane 24.3 (50 mg, 0.23 mmol) in methanol (1 mL) was cooled to 0°C. Then AgNOs (77 mg, 0.45 mmol) was added to it and the mixture was stirred at 0°C for 15 min. (R)-1-(4-chlorophenyl)-2,2,2- trifluoro-/V-methylethan-1-amine (100 mg, 0.45 mmol) was added to it and reaction mixture was stirred at RT for 16 h. After completion, the reaction mixture was filtered through a sintered funnel. The filtrate was concentrated under reduced pressure and the crude product was purified by column chromatography over silica gel using 90% ethyl acetate in hexane and product 24.4 was isolated as a yellow gum (20 mg, 26 % yield).
[00584] LCMS: m/z found ((334.26 [M+H]+),rt= 2.01 min (Method H) [Waters Xbridge C18 column (3.5 pm, 50 x 3 mm)];
[00585] Synthesis of A/-((/?)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-/V- methylpyrimidine-5-sulfonimidamide 24.5: To a solution of intermediate 24.4 (70 mg, 0.21 mmol) in methanol (2 mL) was added acetic acid (0.024 mL, 0.42 mmol), followed by (diacetoxyiodo)benzene (136 mg, 0.42 mmol). The mixture was stirred at 0°C and added ammonium carbamate (66 mg, 0.84 mmol) was then added. The reaction mixture was stirred at RT 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 product was purified by column chromatography over silica gel using 90% ethyl acetate in hexane and the product 24.5 (25 mg, 32% yield) was isolated as a diastereomeric mixture.
[00586] The diastereomers 24.5 (70 mg) were separated by SFC purification method to obtain compounds Example 48 (15.98 mg, 99.21%). LCMS: m/z found ((365.2 [M+H]+), rt= 3.07 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (401 MHz, DMSO) 5 9.41 (d, J = 6.3 Hz, 1 H), 9.23 (s, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.6 Hz, 2H), 6.07 (q, J = 8.8 Hz, 1 H), 5.63 (s, 1 H), 2.81 (s, 3H) (absolute stereochemistry not confirmed) and Example 49: (15.86 mg, 99.63 %)LCMS: m/z found ((365.2 [M+H]+),rt= 3.05 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, DMSO) 5 9.39 (s, 1 H), 9.23 (s, 2H), 7.48 - 7.40 (m, 4H), 6.08 (q, J = 8.9 Hz, 1 H), 5.75 (s, 1 H), 2.77 (s, 3H) (absolute stereochemistry not confirmed).
[00587] SFC method:
[00588] SFC Prep Purification of compound 24.5 was performed on a Waters SFC 150 instruments equipped with Waters 2489 UV/Visible Detector by using CHIRALPAK IG (30 mm x 250 mm ), 5p column operating at 35°C temperature, maintaining flow rate of 110 mL/min, using 55% CO2 in super critical state and 45% MeOH as mobile phase. Run this isocratic mixture up to 12.0 minutes and maintained the isobaric condition of 100 bar at 220 nm wavelength.
Example 50 and Example 51
[00589] (S)-/V-((/?)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-/V-methyl-[1 ,2,4]triazolo[1 ,5- a]pyridine-7-sulfonimidamide (Example 50) and ( )-/V-(( )-1-(4-chlorophenyl)-2,2,2- trifluoroethyl)-A/-methyl-[1 ,2,4]triazolo[1 ,5-a]pyridine-7-sulfonimidamide (Example 51 )
[00590] Synthesis of 2-ethylhexyl 3-([1,2,4]triazolo[1,5-a]pyridin-7-ylthio)propanoate 25.1 : To a stirred solution of 7-bromo-[1 ,2,4]triazolo[1 ,5-a]pyridine (5.0 g, 25.25 mmol) and 2-ethylhexyl 3-mercaptopropanoate (5.51 g , 25.25 mmol) in toluene (25 mL) was added DI PEA (13.2 mL, 75.75 mmol) and the reaction mixture was degassed with N2 for 10 min. Then, Xanthphos (440 mg, 0.76 mmol) and Pd2(dba)s (460 mg, 0.51 mmol) were added to the reaction mixture and stirred at 100 °C for 12 h. The reaction was monitored by TLC and LCMS. After completion, the reaction mixture was filtered through celite bed, washed with ethyl acetate and concentrated under reduced pressure. The crude was dissolved with ethyl acetate and washed with water. The organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 40% ethyl acetate in hexane to afford 25.1 as a yellow gum (7.0 g, 83 % yield). LCMS: m/z found ((336.39 [M+H]+), rt= 1.92 min) (Method C)[ YMC Triart C18 column (3 pm, 33 x 2.1 mm)].
[00591] Synthesis of [1,2,4]triazolo[1,5-a]pyridine-7-thiol 25.2: To a stirred solution of 25.1 (5.0 g , 14.91 mmol) in methanol (30 mL) was added 30% NaOMe (w/w) in methanol (10 mL, 2.42 g , 44.72 mmol) at 0 °C and stirred the mixture at rt for 2 h. After completion, confirmed by TLC and LCMS the reaction mixture was concentrated under reduced pressure. Then the mixture was acidified with 1 N HCI and concentrated under reduced pressure. The crude was dissolved in 10% methanol in dichloromethane and filtered. The filtrate was concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 10% methanol in dichloromethane to afford 25.2 as yellow solid (1.8 g, 80 % yield). LCMS: m/z found ((152.12 [M+H]+), rt= 0.80 min) (Method C)[ YMC Triart C18 column (3 pm, 33 x 2.1 mm)].
[00592] Synthesis of 1,2-bis([1,2,4]triazolo[1,5-a]pyridin-7-yl)disulfane 25.3: To a stirred solution of 25.2 (2.5 g , 16.54 mmol) in acetonitrile (25 mL), DI PEA (1.4 mL , 8.27 mmol) and CuCl2 (110 mg, 0.83 mmol) were added and the mixture was stirred under an oxygen atmosphere at RT for 16 h. After completion, confirmed by TLC and LCMS the reaction mixture was concentrated under reduced pressure. The crude was dissolved in water and extracted with dichloromethane. The organic extract was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 10% methanol in dichloromethane to afford 25.3 as a light-yellow solid (1.6 g, 64 % yield). LCMS: m/z found ((301.27 [M+H]+), rt= 1.29 min) (Method C)[ YMC Triart C18 column (3 pm, 33 x 2.1 mm)].
[00593] Synthesis of (/?)-S-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-/V-(1-(4-chlorophenyl)- 2,2,2-trifluoroethyl)-/V-methylthiohydroxylamine 25.4: A stirred solution of AgNOs (115 mg , 0.67 mmol) in methanol was cooled to 0°C and 25.3 (100 mg, 0.33 mmol) was added and the mixture stirred at same temperature for 20 min. Then [(1 )-1-(4-chlorophenyl)-2,2,2- trifluoroethyl](methyl)amine (150 mg, 0.67 mmol) and PTSA (7 mg, 0.04 mmol) were added in ice cold condition. The reaction mixture was stirred at rt for 16 h. The reaction was monitored by TLC and LCMS. After completion, the reaction mixture was filtered through celite bed, washed with methanol and concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 40% to 90% ethyl acetate in hexane to afford 25.4 as a gum (30 mg, 24 % yield). LCMS: m/z found ((373.25 [M+H]+), rt= 1.82 min) (Method C)[ YMC T riart C18 column (3 pm, 33 x 2.1 mm)].
[00594] Synthesis of (/?)-/V-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-/V-methyl- [1 ,2, 4]triazolo[1 ,5-a]pyridine-7-sulfoni midamide 25.5: To a stirred solution of 24.4(80 mg, 0.22 mmol) in methanol (3 mL) acetic acid (0.03 mL, 0.43 mmol), (diacetoxyiodo)benzene (175 mg, 0.55 mmol) and ammonium carbamate (70 mg, 0.87 mmol) were added at ice cold condition and the mixture was stirred at RT for 1 h. After completion, confirmed by TLC and LCMS, the reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 70% ethyl acetate in hexane to afford 25.5 as a diastereomeric mixture (35 mg, 39% yield). LCMS: m/z found ((404.2 [M+H]+), rt= 5.52 and 5.59 min) (Method K)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)].
[00595] The diastereomers were separated by SFC purification of 25.5 (75 mg) to obtain compounds Example 50 (24.52 mg, 99.20%); LCMS: m/z found ((4.4.2 [M+H]+), rt= 3.04 min) (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)]; 1H NMR (400 MHz, DMSO) 5 9.12 (d, J = 7.1 Hz, 1 H), 8.71 (s, 1 H), 8.33 (d, J = 1.9 Hz, 1 H), 7.58 - 7.51 (m, 1 H), 7.45 (s, 4H), 6.09 (q, J = 8.9 Hz, 1 H), 5.55 (s, 1 H), 2.81 (s, 3H) (absolute stereochemistry not confirmed) and Example 51 (21.55 mg, 99.52%); LCMS: m/z found ((4.4.2 [M+H]+), rt= 3.04 min) (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)]; 1H NMR (400 MHz, DMSO) 5 9.07 (d, J = 7.1 Hz, 1 H), 8.68 (s, 1 H), 8.31 (d, J = 1.9 Hz, 1 H), 7.54 - 7.48 (m, 1 H), 7.43 - 7.33 (m, 4H), 6.09 (q, J = 8.8 Hz, 1 H), 5.65 (s, 1 H), 2.73 (s, 3H) (absolute stereochemistry not confirmed).
[00596] SFC method: SFC Prep Purification of compound 25.5 was done on a Waters SFC PREP 80 instruments equipped with a Waters 2489 UV/Visible Detector 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 50% CO2 in super critical state and 50% MeOH as mobile phase. Run this isocratic mixture up to 22.0 minutes and maintain the isobaric condition of 100 bar at 220 nm wavelength.
Example 52 and Example 53
[00597] (S)-/V-(( )-1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethyl)-/V-methyl- [1 ,2,4]triazolo[1 ,5-a]pyridine-7-sulfonimidamide (Example 52) and ( )-/V-(( )-1-(4-chloro-3- fluorophenyl)-2,2,2-trifluoroethyl)-A/-methyl-[1 ,2,4]triazolo[1 ,5-a]pyridine-7-sulfonimidamide (Example 53).
Scheme 26
[00598] Synthesis of (R)-S-([1,2,4]triazolo[1,5-a]pyridin-7-yl)-A/-(1-(4-chloro-3- fluorophenyl)-2,2,2-trifluoroethyl)-/V-methylthiohydroxylamine 26.1 : A stirred solution of AgNOs (226 mg, 1.33 mmol) in methanol (6 mL) was cooled to 0 °C and 25.3 (200 mg, 0.67 mmol) was added and stirred the mixture at same temperature for 20 min. Then, (/?)- 1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoro-A/-methylethan-1-amine (320 mg, 1.33 mmol) and PTSA monohydrate (13 mg, 0.07 mmol) were added at ice cold temperature. The reaction mixture was stirred at RT for 16 h. The reaction was monitored by TLC and LCMS. After completion, the reaction mixture was filtered through celite bed, washed with methanol and concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 40% to 90% ethyl acetate in hexane to afford 26.1 as a gum (25 mg, 10% yield). LCMS: m/z found ((391.22 [M+H]+), rt= 1.81 min) (Method C)[ YMC Triart C18 column (3 pm, 33 x 2.1 mm)].
[00599] Synthesis of A/-((/?)-1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethyl)-/V-methyl- [1 ,2, 4]triazolo[1 ,5-a]pyridine-7-sulfoni midamide 26.2: To a stirred solution of 26.1 (130 mg, 0.33 mmol) in methanol (4 mL) were added acetic acid (0.04 mL, 0.67 mmol), (diacetoxyiodo) benzene (270 mg, 0.83 mmol) and ammonium carbamate (105 mg, 1.33 mmol) at ice cold temperature and stirred the mixture at RT for 1 h. After reaction completion, confirmed by TLC and LCMS, the reaction mixture was diluted with DCM, washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 85% ethyl acetate in hexane to afford 26.2 as a diastereomeric mixture (50 mg, 36% yield). LCMS: m/z found ((422.2 [M+H]+), rt= 5.70 and 5.76 min) (Method K)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)]. [00600] The diastereomers were separated by SFC purification method of 26.2 (50 mg) to obtain compounds Example 52 (12 mg, 99.21% HPLC purity); LCMS: m/z found ((422.2 [M+H]+), rt= 3.01 min) (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)]; 1H NMR (400 MHz, DMSO) 5 9.13 (d, J = 7.2 Hz, 1 H), 8.72 (s, 1 H), 8.36 (s, 1 H), 7.65 - 7.61 (m, 1 H), 7.60-7.55 (m, 1 H), 7.43 (d, J = 10.4 Hz, 1 H), 7.31 (d, J = 8.9 Hz,1 H), 6.14 (q, J = 8.7 Hz, 1 H), 5.59 (s, 1 H), 2.84 (s, 3H) (absolute stereochemistry not confirmed) and Example 53 (11 mg, 98.64% HPLC purity); LCMS: m/z found ((422.2 [M+H]+), rt= 2.99 min) (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)]; 1H NMR (400 MHz, DMSO) 5 9.11 (d, J = 7.2 Hz, 1 H), 8.72 (s, 1 H), 8.36 (s, 1 H), 7.59 - 7.51 (m, 2H), 7.39 (d, J = 8.6 Hz, 1 H), 7.28 (d, J = 8.5 Hz,1 H), 6.15 (q, J = 8.7 Hz, 1 H), 5.69 (s, 1 H), 2.80 (s, 3H) (absolute stereochemistry not confirmed).
[00601] SFC method: SFC Prep Purification of 26.2 (50 mg) was done on a Waters SFC 80 instruments equipped with Waters 2489 UV/visible detector by using CHIRALPAK IG (30 mm x 250 mm), 5p Column operating at 35 °C temperature, maintaining a flow rate of 70 mL/min, using 55% CO2 in super critical state and 45% of 0.2M methanolic ammonia in methanol as Mobile phase. Run this isocratic mixture up to 20.0 minutes and maintained the isobaric condition of 100 bar at 220 nm wavelength.
Example 54 and Example 55
[00602] (S)-/V-methyl-/V-((/?)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-[1 ,2 ,4]triazolo[1 ,5- a]pyridine-7-sulfonimidamide (Example 54) and ( )-A/-methyl-A/-(( )-2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)-[1 ,2,4]triazolo[1 ,5-a]pyridine-7-sulfonimidamide (Example 55)
Example 55
Scheme 27 [00603] Synthesis of ( )-S-([1 ,2,4]triazolo[1 ,5-a]pyridin-7-yl)-A/-methyl-A/-(2,2,2-trifluoro-1- (4-fluorophenyl)ethyl)thiohydroxylamine 27.1 : A stirred solution of AgNOs (226 mg, 1.33 mmol) in methanol (6 mL) was cooled to 0 °C and 25.1 (200 mg, 0.67 mmol) was added and the mixture stirred at same temperature for 20 min. Then (A?)-2,2,2-trifluoro-1-(4- fluorophenyl)-/V-methylethan-1 -amine (276 mg, 1.33 mmol) and PTSA monohydrate (13 mg, 0.07 mmol) were added at ice cold condition. The reaction mixture was stirred at RT for 16 h. The reaction was monitored by TLC and LCMS. After completion, the reaction mixture was filtered through celite bed, washed with methanol and concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 40% to 90% ethyl acetate in hexane to afford 27.1 as a gum (30 mg, 13% yield). LCMS: m/z found ((357.2 [M+H]+), rt= 2.22 min) (Method A)[ Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm)].
[00604] Synthesis of /V-methyl-/V-(( )-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)- [1 ,2,4]triazolo[1 ,5-a]pyridine-7-sulfonimidamide 27.2: To a stirred solution of 27.1 (160 mg, 0.45 mmol) in methanol (4 mL) were added acetic acid (0.05 mL, 0.9 mmol), (diacetoxyiodo)benzene (360 mg, 1.12 mmol) and ammonium carbamate (140 mg, 1.8 mmol) at ice cold temperature and the mixture was stirred at RT for 1 h. After completion, confirmed by TLC and LCMS, the reaction mixture was diluted with DCM, washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 85% ethyl acetate in hexane to afford 27.2 as diastereomeric mixture (75 mg, 43% yield). LCMS: m/z found ((388.2 [M+H]+), rt= 2.84 and 2.87 min) (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)].
[00605] The diastereomers were separated by SFC purification method of 2.2 (75 mg) to obtain compounds Example 54 (21 mg, 98.69% HPLC purity); LCMS: m/z found ((388.2 [M+H]+), rt= 2.87 min) (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)]; 1H NMR (400 MHz, DMSO) 5 9.11 (d, J = 7.2 Hz, 1 H), 8.71 (s, 1 H), 8.32 (s, 1 H), 7.53 (d, J = 7.2 Hz, 1 H), 7.49-7.46 (m, 2H), 7.21 (t, J = 8.4 Hz, 2H), 6.08 (q, J = 8.7 Hz, 1 H), 5.54 (s, 1 H), 2.82 (s, 3H) (absolute stereochemistry not confirmed) and Example 55 (17 mg, 96.30% HPLC purity); LCMS: m/z found ((388.2 [M+H]+), rt= 2.84 min) (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)]; 1H NMR (400 MHz, DMSO) 5 9.09 (d, J = 7.2 Hz, 1 H), 8.71 (s, 1 H), 8.33 (s, 1 H), 7.52 (d, J = 7.2 Hz, 1 H), 7.47-7.43 (m, 2H), 7.21 (t, J = 8.8 Hz, 2H), 6.09 (q, J = 8.7 Hz, 1 H), 5.66 (s, 1 H), 2.76 (s, 3H) (absolute stereochemistry not confirmed).
[00606] SFC method: SFC Prep Purification of compound 27.2 was done on a Waters SFC PREP 80 instruments equipped with Waters 2489 UV/Visible Detector 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 55% CO2 in super critical state and 45% MeOH as mobile phase. Run this isocratic mixture up to 20.0 minutes and maintain the isobaric condition of 100 bar at 220 nm wavelength.
Example 56 and Example 57
[00607] (S)-/V-(( )-1-(3,4-difluorophenyl)-2,2,2-trifluoroethyl)-/V-methyl-[1 ,2,4]triazolo[1 ,5- a]pyridine-7-sulfonimidamide (Example 56) and ( )-/V-(( )-1-(3,4-difluorophenyl)-2,2,2- trifluoroethyl)-/ -methyl-[1 ,2,4]triazolo[1 ,5-a]pyridine-7-sulfonimidamide (Example 57)
Scheme 28
[00608] Synthesis of (R)-S-([1 ,2,4]triazolo[1 ,5-a]pyridin-7-yl)-A/-(1-(3,4-difluorophenyl)-
2.2.2-trifluoroethyl)-/V-methylthiohydroxylamine 28.1 : A stirred solution of AgNOs (226 mg, 1.33 mmol) in methanol (6 mL) was cooled to 0 °C and 25.1 (200 mg, 0.67 mmol) was added and the mixture was stirred at same temperature for 20 min. Then (R)-1-(3,4-difluorophenyl)-
2.2.2-trifluoro-/V-methylethan-1-amine (300 mg, 1 .33 mmol) and PTSA monohydrate (13 mg, 0.07 mmol) were added at ice cold temperature. The reaction mixture was stirred at RT for 16 h. The reaction was monitored by TLC and LCMS. After completion, the reaction mixture was filtered through celite bed, washed with methanol and concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 40% to 90% ethyl acetate in hexane to afford 28.1 as agum (20 mg, 8% yield). LCMS: m/z found ((375.29 [M+H]+), rt= 1.77 min) (Method C)[ YMC Triart C18 column (3 pm, 33 x 2.1 mm)].
[00609] Synthesis of /V-(( )-1-(3,4-difluorophenyl)-2,2,2-trifluoroethyl)-/V-methyl- [1 ,2,4]triazolo[1 ,5-a]pyridine-7-sulfonimidamide 28.2: To a stirred solution of 28.1 (130 mg, 0.35 mmol) in methanol (4 mL) were added acetic acid (0.04 mL, 0.69mmol), (diacetoxyiodo)benzene (280 mg, 0.87 mmol) and ammonium carbamate (110 mg, 1.39mmol) at ice cold temperature and stirred the mixture at RT for 1 h. After completion, confirmed by TLC and LCMS the reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 85% ethyl acetate in hexane to afford 28.2 as adiastereomeric mixture (50 mg, 36% yield). LCMS: m/z found ((406.2 [M+H]+), rt= 5.28 and 5.35 min) (Method K)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)].
[00610] The diastereomers were separated by SFC purification method of 28.2 (50 mg) to obtain compounds Example 56 (13 mg, 97.68% HPLC purity); LCMS: m/z found ((406.2 [M+H]+), rt= 2.91 min) (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)]; 1H NMR (400 MHz, DMSO) 5 9.13 (d, J = 7.2 Hz, 1 H), 8.72 (s, 1 H), 8.35 (s, 1 H), 7.59 - 7.52 (m, 1 H), 7.48 (q, J = 8.8 Hz, 2H), 7.38 - 7.24 (m, 1 H), 6.12 (q, J = 8.9 Hz, 1 H), 5.58 (s, 1 H), 2.84 (s, 3H) (absolute stereochemistry not confirmed) and Example 57 (11 mg, 98.55% HPLC purity); LCMS: m/z found ((406.2 [M+H]+), rt= 2.90 min) (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)]; 1H NMR (400 MHz, MeOD) 5 8.97 - 8.90 (m, 1 H), 8.57 (s, 1 H), 8.39 - 8.34 (m, 1 H), 7.62 (dd, J = 1.9, 7.2 Hz, 1 H), 7.39 - 7.30 (m, 1 H), 7.30 - 7.18 (m, 2H), 6.14 (q, J= 8.5 Hz, 1 H), 2.89 (s, 3H) (absolute stereochemistry not confirmed).
[00611] SFC method: SFC Prep Purification of compound 28.2 was done on a Waters SFC PREP 80 instruments equipped with Waters 2489 UV/Visible Detector 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 60% CO2 in super critical state and 40% MeOH as mobile phase. Run this isocratic mixture up to 20.0 minutes and maintain the isobaric condition of 100 bar at 220 nm wavelength.
Example 58 and Example 59
[00612] (S)-/V-(( )-1-(3,4-difluorophenyl)-2,2,2-trifluoroethyl)-N,1-dimethyl-6-oxo-1 ,6- dihydropyridazine-4-sulfonimidamide [Example 58] and (R)-N-((R)-1-(3,4-difluorophenyl)- 2,2,2-trifluoroethyl)-N,1-dimethyl-6-oxo-1 ,6-dihydropyridazine-4-sulfonimidamide [Example 59],
[00613] Synthesis of (R)-5-(((1-(3,4-difluorophenyl)-2,2,2- trifluoroethyl)(methyl)amino)thio)-2-methylpyridazin-3(2H)-one 29.1 : To a solution of 5,5'-disulfanediylbis(2-methylpyridazin-3(2/7)-one) (14.4, 500.0 mg, 1.77 mmol) in methanol (20.0 mL) was added silver nitrate (601.65 , 3.54 mmol) followed by addition of (R)-1-(3,4- difluorophenyl)-2,2,2-trifluoro-N-methylethan-1-amine (797.47 mg, 3.54 mmol) at O°C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h. Consumption of starting material was monitored by TLC and LCMS. The reaction mixture was filtered through celite pad, and the solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by combiflash column chromatography over silica gel using 50% ethyl acetate in hexane and compound 29.1 was isolated as a colorless sticky gum (200 mg, 31% yield). LCMS: m/z found ((366.29 [M+H]+), rt= 1.73 min (Method C)[ YMC T hart C18 column (3 pm, 33 x 2.1 mm));
[00614] Synthesis of (R)-N-(1-(3,4-difluorophenyl)-2,2,2-trifluoroethyl)-N,1-dimethyl-6-oxo- 1 ,6-dihydropyridazine-4-sulfonimidamide 29.2: To a solution of intermediate 29.1 (200 mg, 0.55 mmol) in methanol (4 mL) and HFIP (2 mL) was added acetic acid (0.063 mL, 1.09 mmol), followed by (diacetoxyiodo)benzene (1058.03 mg, 3.29 mmol). The mixture was stirred at 0 °C then to it was added ammonium carbamate (341.92 mg, 4.38 mmol). The reaction mixture was then stirred at ambient temperature 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 Na2SC>4 and concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 50% ethyl acetate in hexane and the product 29.2 (100 mg) was isolated as a diastereomeric mixture. [00615] The diastereomers were separated by SFC purification method to obtain compounds Example 58: (14 mg, 98.67 % HPLC purity). LCMS: m/z found ((397.2 [M+H]+), rt= 2.90 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, DMSO) 5 8.20 (d, 1 H), 7.57- 7.49 (m, 2H), 7.34 (d, 1 H), 7.30 (d, 1 H), 6.10-6.03 (m, 1 H), 5.89 (s, 1 H), 3.67 (s, 3H), 2.81 (s, 3H) (absolute stereochemistry not confirmed) and Example 59 : (33 mg, 99.46% HPLC purity) LCMS: m/z found ((397.2 [M+H]+),rt= 2.91 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, DMSO) 58.22 (d, 1 H), 7.59- 7.51 (m, 2H), 7.35-7.33 (m, 1 H), 7.28 (d, 1 H), 6.07-6.03 (m, 1 H), 5.76 (s, 1 H), 3.68 (s, 3H), 2.85 (s, 3H) (absolute stereochemistry not confirmed).
[00616] SFC method:
[00617] SFC prep purification of compound 29.2 was done on Pic Solutions- 175 instrument equipped with Knauer 40D UV/Visible Detector by using Chiralpak IC (30mm x 250 mm), 5p Column operating at 35°C temperature, maintaining flow rate of 100 mL/min, using 50% CO2 in super critical state and 50% of 100% MeOH as mobile phase. Run this isocratic mixture up to 7.0 minutes and maintained the isobaric condition of 100 bar at 220 nm wavelength.
Example 60 and Example 61
[00618] (S)-N,1-dimethyl-6-oxo-N-((R)-2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)- 1 ,6-dihydropyridazine-4-sulfonimidamide [Example 60] and (R)-N,1-dimethyl-6-oxo-N-((R)- 2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)-1 ,6-dihydropyridazine-4-sulfonimidamide [Example 61]
Scheme 30
[00619] Synthesis of (R)-2-methyl-5-((methyl(2,2,2-trifluoro-1-(4-
(trifluoromethyl)phenyl)ethyl)amino)thio)pyridazin-3(2H)-one 30.1 : To a solution of 5,5'- disulfanediylbis(2-methylpyridazin-3(2/7)-one) (500.0 mg, 1.77 mmol) 14.4 in methanol (20.0 mL) was added silver nitrate (601.65 , 3.54 mmol) followed by addition of (R)-2,2,2-trifluoro- N-methyl-1-(4-(trifluoromethyl)phenyl)ethan-1-amine at 0°C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h. Consumption of starting material was monitored by TLC and LCMS. The reaction mixture was filtered through a celite pad, and the solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by combiflash column chromatography over silica gel using 50% ethyl acetate in hexane and compound 5.1 was isolated as a sticky gum (150.0 mg, 21% yield). LCMS: m/z found ((398.20 [M+H]+), rt= 2.15 min (Method AF)[ Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm));
[00620] Synthesis of (R)-N,1-dimethyl-6-oxo-N-(2,2,2-trifluoro-1-(4-
(trifluoromethyl)phenyl)ethyl)-1 ,6-dihydropyridazine-4-sulfonimidamide 30.2: To a solution of intermediate 30.1 (150 mg, 0.377 mmol) in methanol (4 mL) and HFIP (2 mL) acetic acid (0.043 mL, 0.45 mmol) was added, followed by (diacetoxyiodo)benzene (728.59 mg, 2.26 mmol). The mixture was stirred at 0°C and to it ammonium carbamate (235.45 mg, 3.016 mmol) was added. The reaction mixture was then stirred at ambient temperature for 1 h. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (10 mL) and brine (10 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 50% ethyl acetate in hexane and the product 30.2 (70 mg) was isolated as a diastereomeric mixture.
[00621] The diastereomers were separated by SFC purification method to obtain compounds [Example 60]: (19 mg, 98.66 % HPLC purity). LCMS: m/z found ((429.2 [M+H]+), rt= 3.08 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, MeOD) 5 8.25 (d, 1 H), 7.76 (d, 2H), 7.72 (d, 2H), 7.38 (d, 1 H), 6.18- 6.12 (m, 1 H), 3.79 (s, 3H), 2.91 (s, 3H) (absolute stereochemistry not confirmed) and [Example 61] : (19 mg, 96.08% HPLC purity) LCMS: m/z found ((429.2 [M+H]+),rt= 3.07 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, MeOD) 5 8.23 (d, 1 H), 7.76 (d, 2H), 7.70 (d, 2H), 7.38 (d, 1 H), 6.25-6.18 (m, 1 H), 3.78 (s, 3H), 2.91 (s, 3H) (absolute stereochemistry not confirmed).
[00622] SFC method:
[00623] SFC Prep Purification of compound 5.2 was done on Waters SFC PREP 80 instruments equipped with Waters 2489 UV/Visible Detector by using CHIRALPAK IG (30 mm x 250 mm), 5p Column operating at 35°C temperature, maintaining flow rate of 70 mL/min, using 60% CO2 in super critical state and 40% methanol as mobile phase. Run this isocratic mixture up to 15.0 minutes and maintain the isobaric condition of 100 bar at 215 nm wavelength.
Example 62 and Example 63
[00624] (S)-A/-((R)-1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethyl)-N, 1-dimethyl-6-oxo-1 ,6- dihydropyridazine-4-sulfonimidamide [Example 62] and ( )-/V-(( )-1-(4-chloro-3- fluorophenyl)-2,2,2-trifluoroethyl)-A/,1-dimethyl-6-oxo-1 ,6-dihydropyridazine-4- sulfonimidamide [Example 63]
Scheme 31
[00625] Synthesis of (R)-5-(((1-(4-chloro-3-fluorophenyl)-2,2,2- trifluoroethyl)(methyl)amino)thio)-2-methylpyridazin-3(2H)-one 31.1 : To a solution of 5,5'-disulfanediylbis(2-methylpyridazin-3(2/-/)-one) 14.4, 500.0 mg, 1.8 mmol) in methanol (20.0 mL) was added silver nitrate (601.65, 3.54 mmol) followed by the addition of ( )-1-(4- chloro-3-fluorophenyl)-2,2,2-trifluoro-N-methyl-ethan-1-amine (855.75 mg, 3.54 mmol) at 0°C under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 16 h. Consumption of starting material was monitored by TLC and LCMS. The reaction mixture was filtered through celite pad, and the solvent was evaporated under reduced pressure to get the crude product. The crude product was purified by combiflash column chromatography over silica gel using 50% ethyl acetate in hexane and compound 6.1 was isolated a sticky gum (200.0 mg, 30 % yield). LCMS: m/z found ((382.15 [M+H]+), rt= 1.82 min (Method C)[ YMC Triart C18 column (3 pm, 33 x 2.1 mm));
[00626] Synthesis of ( )-A/-(1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethyl)-A/,1-dimethyl- 6-oxo-1 ,6-dihydropyridazine-4-sulfonimidamide 31.2: To a solution of intermediate 31.1 (200 mg, 0.523 mmol) in methanol (4 mL) and HFIP (2 mL) was added acetic acid (0.059 mL, 1.047 mmol), followed by (diacetoxyiodo)benzene (1010.74 mg, 3.13 mmol). The mixture was stirred at 0 °C and to it was added ammonium carbamate (326.64 mg, 4.184 mmol). The reaction mixture was then stirred at ambient temperature 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 Na2SC>4 and concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 50% ethyl acetate in hexane and the product 31 .2 (100 mg) was isolated as a diastereomeric mixture.
[00627] The diastereomers were separated by SFC purification method to obtain compounds [Example 62]: (35.5 mg, 97.89 % HPLC purity). LCMS: m/z found ((413.2 [M+H]+), rt= 3.03 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, MeOD) 5 8.27 (d, 1 H), 7.59 (t, 1 H), 7.43-7.40 (m, 2H), 7.34 (d, 1 H), 6.12-6.06 (m, 1 H), 3.81 (s, 3H), 2.93 (s, 3H) (absolute stereochemistry not confirmed) and [Example 63] : (28 mg, 99.83% HPLC purity) LCMS: m/z found ((413.2 [M+H]+),rt= 3.02 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, MeOD) 5 8.21 (d, 1 H), 7.55 (t, 1 H), 7.39-7.36 (m, 2H), 7.29 (d, 1 H), 6.15-6.09 (m, 1 H), 3.77 (s, 3H), 2.88 (s, 3H) (absolute stereochemistry not confirmed).
[00628] SFC method:
[00629] SFC Prep Purification of compound 31.2 was done on a Waters SFC PREP 150 instruments equipped with a Waters 2489 UV/Visible Detector by using CHIRALPAK IG(30 mm x 250 mm), 5p column operating at 35°C temperature, maintaining a flow rate of 100 mL/min, using 50% CO2 in super critical state and 50% methanol as mobile phase. Run this isocratic mixture up to 15.0 minutes and maintained the isobaric condition of 100 bar at 240 nm wavelength.
Example 64 and Example 65
[00630] (S)-N-((R)-1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethyl)-N-methylpyrimidine-5- sulfonimidamide (Example 64) and (R)-N-((R)-1-(4-chloro-3-fluorophenyl)-2,2,2- trifluoroethyl)-N-methylpyrimidine-5-sulfonimidamide (Example 65)
[00631] Synthesis of (R)-N-(1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethyl)-N-methyl- S-(pyrimidin-5-yl)thiohydroxylamine 32.1 : A solution of 1 ,2-di(pyrimidin-5-yl)disulfane (24.3, 120 mg, 0.54 mmol) in methanol (3 mL) was cooled to 0°C. Then AgNOs (185 mg, 1.08 mmol) was added to it and stirred at the same temperature for 15 min. (R)-1-(4-chloro- 3-fluorophenyl)-2,2,2-trifluoro-N-methylethan-1-amine (260 mg, 1.08 mmol) was added to it and reaction mixture was stirred at ambient temperature for 16 h. After completion, 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 90% ethyl acetate in hexane and product 32.1 was isolated as a gum. (23 mg, 12% yield). LCMS: m/z found ((352.2 [M+H]+),rt= 3.21 min (Method B) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)];
[00632] Synthesis of N-((R)-1-(4-chloro-3-fluorophenyl)-2,2,2-trifluoroethyl)-N- methylpyrimidine-5-sulfonimidamide 32.2: To a solution of intermediate 32.1 (120 mg, 0.341 mmol) in methanol (3 mL) was added acetic acid (0.039 mL, 0.682 mmol), followed by (diacetoxyiodo)benzene (220 mg, 0.682 mmol). The mixture was stirred at 0°C and to it was added ammonium carbamate (107 mg, 1.36 mmol). The reaction mixture was stirred at rt 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 (20 mL) and brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 90% ethyl acetate in hexane and the product 32.2 (70 mg) was isolated as a diastereomeric mixture.
[00633] The diastereomer mixture 32.2 (70 mg) was separated by SFC purification method to obtain compounds Example 64 (22 mg, 98.58% HPLC purity). LCMS: m/z found ((383.2 [M+H]+), rt= 3.03 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (401 MHz, MEOD) 5 9.34 (s, 1 H), 9.26 (s, 2H), 7.55 (t, J = 8.0 Hz, 1 H), 7.38 (d, J = 10.2 Hz, 1 H), 7.29 (d, J = 8.44 Hz, 1 H), 6.12 (q, J = 8.5 Hz, 1 H), 2.89 (s, 3H) (absolute stereochemistry not confirmed) and Example 65 (20 mg, 99.81% HPLC purity) LCMS: m/z found ((383.2 [M+H]+),rt= 3.02 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, DMSO) 5 9.40 (s, 1H), 9.24 (s, 2H), 7.63 (t, J = 8.0 Hz, 1 H), 7.47 - 7.39 (m, 1 H), 7.28 (d, J = 8.3 Hz, 1 H), 6.12 (q, J = 8.4 Hz, 1 H), 5.79 (s, 1 H), 2.80 (s, 3H) (absolute stereochemistry not confirmed).
[00634] SFC method
[00635] SFC Prep Purification of 32.2 was done on a Waters SFC 150 instruments equipped with a Waters 2489 UV/Visible Detector by using CHIRALPAK IG (30 mm x 250 mm ), 5p column operating at 35°C temperature, maintaining a flow rate of 100 mL/min, using 60% CO2 in super critical state and 40% of methanol as a mobile phase. Run this isocratic mixture up to 10.0 minutes and maintained the isobaric condition of 100 bar at 220 nm wavelength.
Example 66 and Example 67
[00636] (S)-N-((R)-1-(3,4-difluorophenyl)-2,2,2-trifluoroethyl)-N-methylpyrimidine-5- sulfonimidamide (Example 66) and (R)-N-((R)-1-(3,4-difluorophenyl)-2,2,2-trifluoroethyl)-N- methylpyrimidine-5-sulfonimidamide (Example 67)
[00637] Synthesis of (/?)-/V-(1-(3,4-difluorophenyl)-2,2,2-trifluoroethyl)-/V-methyl-S- (pyrimidin-5-yl)thiohydroxylamine 33.1 : A solution of 1 ,2-di(pyrimidin-5-yl)disulfane (24.3, 50 mg, 0.23 mmol) in methanol (1 mL) was cooled to 0°C. Then, AgNOs (77 mg, 0.45 mmol) was added to it and stirred at 0°C for 15 min. (R)-1-(3,4-difluorophenyl)-2,2,2- trifluoro-N-methylethan-1-amine (100 mg, 0.45 mmol) was added to the reaction mixture and stirring was continued at rt for 16 h. After completion, 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 90% ethyl acetate in hexane and product 33.1 was isolated as a gum. (15 mg, 19% yield). LCMS: m/z found ((336.32 [M+H]+),rt= 2.0 min (Method H) [Waters Xbridge C18 column (3.5 pm, 50 x 3 mm)];
[00638] Synthesis of N-((R)-1-(3,4-difluorophenyl)-2,2,2-trifluoroethyl)-N-methylpyrimidine- 5-sulfonimidamide 33.2: To a solution of intermediate 33.1 (160 mg, 0.48 mmol) in methanol (4 mL) acetic acid (0.055mL, 0.954 mmol) was added, followed by (diacetoxyiodo)benzene (310 mg, 0.954 mmol). The mixture was stirred at 0°C and to it ammonium carbamate (150 mg, 1.90 mmol) was added. The reaction mixture was stirred at ambient temperature for 3 h, then it was quenched with water (10 mL) and extracted with EtAc (2 x 10 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 product was purified by column chromatography over silica gel using 90% EtAc in hexane and the product 33.2 (70 mg) was isolated as a diastereomeric mixture.
[00639] The diastereomeric mixture 33.2 (70 mg) was separated by SFC purification method to obtain compounds Example 66 (15 mg, 99.61% HPLC purity). LCMS: m/z found ((367.2 [M+H]+), rt= 2.95 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (401 MHz, DMSO) 5 9.40 (s, 1 H), 9.24 (s, 2H), 7.56 - 7.43 (m, 2H), 7.38 - 7.21 (m, 1 H), 6.10 (q, J = 8.6 Hz, 1 H), 5.65 (s, 1 H), 2.85 (s, 3H) (absolute stereochemistry not confirmed) and Example 67: (15 mg, 99.22% HPLC purity); LCMS: m/z found ((367.2 [M+H]+),rt= 2.93 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, DMSO) 5 9.40 (s, 1 H), 9.24 (s, 2H), 7.53 - 7.41 (m, 2H), 7.31 - 7.24 (m, 1 H), 6.10 (q, J = 8.6 Hz, 1 H), 5.77 (s, 1 H), 2.80 (s, 3H) (absolute stereochemistry not confirmed).
[00640] SFC method
[00641] SFC Prep Purification of 33.2 waqs done on a Waters SFC 150 instruments equipped with a Waters 2489 UV/Visible Detector by using CHIRALPAK IG (30 mm x 250 mm ), 5p column operating at 35°C temperature, maintaininga flow rate of 100 mL/min, using 60% CO2 in super critical state and 40% MeOH as a mobile phase. Run this isocratic mixture up to 8.0 minutes and maintained the isobaric condition of 100 bar at 234 nm wavelength.
Example 68 and Example 69 [00642] (S)-/V-methyl-/V-((/?)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyrimidine-5- sulfonimidamide (Example 68) and (/?)-/V-methyl-/V-((/?)-2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)pyrimidine-5-sulfonimidamide (Example 69)
[00643] Synthesis of (/?)-/V-methyl-S-(pyrimidin-5-yl)-/V-(2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)thiohydroxylamine 34.1 : A solution of 1 ,2-di(pyrimidin-5-yl)disulfane (24.3, 50 mg, 0.23 mmol) in methanol (1 mL) was cooled to 0 °C. Then AgNOs (77 mg, 0.45 mmol) was added to it and stirred at 0 °C for 15 min. (/?)-2,2,2-trifluoro-1-(4-fluorophenyl)- A/-methylethan-1-amine (95 mg, 0.45 mmol) was added to it and reaction mixture was stirred at ambient temperature for 16 h. After completion, 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 90% EtAc in hexane and product 9.1 was isolated as a gum. (15 mg, 21 % yield). LCMS: m/z found ((318.31 [M+H]+),rt= 1.92 min (Method H) [Waters Xbridge C18 column (3.5 pm, 50 x 3 mm)];
[00644] Synthesis of A/-methyl-A/-((R)-2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)pyrimidine-5-sulfonimidamide 34.2: To a solution of intermediate 34.1 (200 mg, 0.63 mmol) in methanol (4 mL) acetic acid (0.072 mL, 1.26 mmol) was added, followed by (diacetoxyiodo)benzene (407 mg, 1.26 mmol). The mixture was stirred at 0°C and to it ammonium carbamate (197 mg, 2.52 mmol) was added. Stirring was continued at rt 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 (20 mL) and brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 90% ethyl acetate in hexane and the product 34.2 (60 mg) was isolated as a diastereomeric mixture. [00645] The diastereomeric mixture 34.2 (60 mg) was separated by SFC purification method to obtain compounds Example 68 (14 mg, 99.38% HPLC purity). LCMS: m/z found ((349.1 [M+H]+), rt= 2.77 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (401 MHz, DMSO) 5 9.39 (s, 1 H), 9.22 (s, 2H), 7.46 (t, J = 5.7 Hz, 2H), 7.25 (t, J = 8.7 Hz, 2H), 6.06 (q, J = 9.0 Hz, 1 H), 5.62 (s, 1 H), 2.82 (s, 3H) (absolute stereochemistry not confirmed) and Example 69 (14 mg, 99.75% HPLC purity); LCMS: m/z found ((349.1 [M+H]+),rt= 2.77 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, DMSO) 5 9.38 (s, 1 H), 9.22 (d, J = 2.3 Hz, 2H), 7.43 (t, J = 5.9 Hz, 2H), 7.20 (t, J = 8.7 Hz, 2H), 6.06 (q, J = 9.0 Hz, 1 H), 5.73 (s, 1 H), 2.77 (s, 3H) (absolute stereochemistry not confirmed).
[00646] SFC method
[00647] SFC Prep Purification of 34.2 was done on a Pic Solutions- 175 instrument equipped with a Knauer 40D UV/Visible Detector by using Chiralpak IG (30mm x 250 mm), 5p column operating at 35°C temperature, maintaining a flow rate of 100 mL/min, using 50% CO2 in super critical state and 50% MeOH as a mobile phase. Run this isocratic mixture up to 11.0 minutes and maintained the isobaric condition of 100 bar at 235 nm wavelength.
Example 70 and Example 71
[00648] (S)-N-methyl-N-((R)-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyridine-3- sulfonimidamide (Example 70) and ( )-N-methyl-N-((R)-2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)pyridine-3-sulfonimidamide (Example 71)
[00649] Synthesis of (1/?,2S,5/?)-2-isopropyl-5-methylcyclohexyl pyridine-3-sulfinate 35.1 : To a stirred solution of pyridine-3-sulfonyl chloride (35.0, 2 g, 11.26 mmol) in DCM (25 mL), TEA (15.7 mL, 112.61 mmol), L-Menthol (1.75 g, 11.26 mmol) and triphenylphosphine (3 g, 11.26 mmol) were added at 0°C and the mixture stirred for 16 h at rt. After completion of the reaction as indicated by TLC, the reaction mixture was poured into water and extracted with DCM. The combined organic layer was washed with brine, dried over anhydrous MgSC and evaporated under vacuum to obtain crude compound which was purified by flash chromatography (eluent EtAc) to obtain desired compound 35.1 (1.6 g, 51% yield). LCMS: m/z found ((282.05 [M+H]+), rt= 3.79 min (Method 4)[ Waters Xbridge C18 column (5 pm, 50 x 4.6 mm)];
[00650] Synthesis of pyridine-3-sulfinamide 35.2: To a stirred solution of compound (1 ?,2S,5 ?)-2-isopropyl-5-methylcyclohexyl pyridine-3-sulfinate 35.1 (1.2 g, 4.26 mmol) in THF (15 mL) LiHMDS (1M, 6.39 mmol) was added dropwise at 0 °C and then allowed to stir for 1.5 h at the same temperature. To this mixture, a saturated aqueous solution of NH4CI (3.5 mL) was added at 0 °C and then stirring was continued for 4 h at rt. The reaction mass was partitioned between EtAc (3x 25 mL) and H2O (25 mL). The overall organic layer was washed with brine, dried over anhydrous MgSC and evaporated under vacuum to obtain crude compound which was purified by flash chromatography (eluent-ethyl acetate) to obtain desired compound 35.2 (450 mg, 74% yield). LCMS: m/z found ((143.05 [M+H]+), rt= 3.79 min (Method D)[ Waters Xbridge C18 column (5 pm, 50 x 4.6 mm)]; [00651] Synthesis of N-(diisopropylcarbamoyl)pyridine-3-sulfinamide 35.3: To a stirred solution of compound 35.2 (800 mg, 5.62 mmol) in THF (30 mL) NaH (560 mg, 14.06 mmol) was added portion wise at 0 °C and then allowed to stir at the same temperature for 20 min before DIPC-CI (920 mg, 5.62 mmol) was added portion wise to it. The overall reaction mass was then allowed to stir for 1.5 h at 0 °C. To the reaction mass was then added NFSI (1.95 g, 6.18 mmol) in one portion and then further stir for 2 h at 0 °C. TLC showed total consumption of SM has taken place. The reaction mass was then diluted with 50% EA in Hexane and then filtered through celite. The filtrate was concentrated under reduced pressure to afford crude compound which was then purified by combi flash chromatography (20% EtAc in Hexane) to afford desired compound 35.3 (500 mg, 31% yield). LCMS: m/z found ((288.21 [M+H]+),rt= 1.93 min (Method B) [Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm).
[00652] Synthesis of (/?)-N'-(diisopropylcarbamoyl)-N-(2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)pyridine-3-sulfonimidamide 35.4: To a flame dried round bottomed flask equipped with magnetic stir bar and argon balloon was added amine 7 (800 mg, 4.17 mmol) and get dissolved in anhydrous THF (25 mL). To it was added /-PrMgCl-LiCI (3.2 mL, 4.17 mmol, 1.3 M) dropwise at 0°C. After 30 min of stirring sulfonimidoyl fluoride (600 mg, 2.08 mmol) in THF (0.5 M, 4 mL) was added dropwise then warmed to room temperature. Upon completion (checked by TLC after 16 h) the reaction mass was quenched with saturated aqueous solution of NH4CI (50 mL) and then extracted with EA (3 x 25 mL). The overall organic layer was washed with brine, dried over anhydrous MgSCU, filtered and concentrated under reduced pressure to afford crude compound which was then purified by combi flash chromatography (eluent- 20% EA in Hexane) to get desired compound 35.4 (400 mg, 41%). LCMS: m/z found ((461.35 [M+H]+),rt= 1.93 min (Method B) [Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm).
[00653] Synthesis of (S)-N'-(diisopropylcarbamoyl)-N-methyl-N-((/?)-2,2,2-trifluoro-1- (4-fluorophenyl)ethyl)pyridine-3-sulfonimidamide 35.5and (/?)-N'-
(diisopropylcarbamoyl)-N-methyl-N-((/?)-2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)pyridine-3-sulfonimidamide 35.6: To a solution of intermediate 35.4 (430 mg, 0.93 mmol) in DMF (5 mL) CS2CO3 (457 mg, 1.40 mmol, was added, followed by Mel (116 pL, 1.86 mmol) at 0°C. The mixture was stirred at same temperature for 3 h. The reaction was then quenched with water (50 mL) and extracted with EtAc (2 x 25 mL). The combined organic layer was washed with water (50 mL) and brine (25 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to get crude compound, which was purified by combi-flash chromatography (30% EtAc in Hexane) to afford the two diastereomers which were separated by combi-flash chromatography to obtain compounds 35.5 (95 mg, 25%) and 35.6 (120 mg, 29%).
[00654] 35.5: LCMS: m/z found ((475.32 [M+HJ+), rt= 3.16 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1 H NMR (400 MHz, DMSO) 5 9.00 (s, 1 H), 8.83 (d, J = 4.6 Hz, 1 H), 8.21 (d, J = 7.7 Hz, 1 H), 7.69 - 7.61 (m, 1 H), 7.40 (t, J = 5.9 Hz, 2H), 7.20 (t, J = 8.6 Hz, 2H), 6.28 - 5.79 (m, 1 H), 4.42 - 4.12 (m, 1 H), 3.79 - 3.49 (m, 1 H), 2.80 (s, 3H), 1.26 - 1.10 (m, 12H) (absolute stereochemistry not confirmed); 35.6: LCMS: m/z found ((475.32[M+H]+),rt= 3.13 min (Method B) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, DMSO) 5 9.01 (s, 1 H), 8.87 (d, J = 3.5 Hz, 1 H), 8.25 (d, J = 9.2 Hz, 1 H), 7.74 - 7.68 (m, 1 H), 7.67 - 7.57 (m, 2H), 7.29 (t, J = 9.3 Hz, 2H), 6.24 - 5.91 (m, 1 H), 4.53 - 4.15 (m, 1 H), 3.93 - 3.51 (m, 1 H), 2.69 (s, 3H), 1.44 - 0.91 (m, 12H) (absolute stereochemistry not confirmed).
[00655] Synthesis of (S)-N-methyl-N-((R)-2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)pyridine-3-sulfonimidamide (Example 70): To a stirred solution of compound 10.5-Dia-1 (120 mg, 0.50 mmol) in HFIP (0.1M, 3.2 mL) (±)- 10-Camphorsulfonic acid (120 mg, 1.01 mmol) was added in a seal cap tube and then heated to 70 °C for 16 h. Crude LCMS showed desired product mass peak along with unreacted SM. The reaction mass was then concentrated under reduced pressure to afford crude compound which was purified by normal phase SFC to afford desired compound Example 70 (15 mg, 17% yield). LCMS: m/z found ((348.2 [M+H]+),rt= 2.91 min (Method B)[ Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm)); 1 H NMR (400 MHz, DMSO) 5 9.02 (d, J = 1.9 Hz, 1 H), 8.80 - 8.74 (m, 1 H), 8.27 - 8.19 (m, 1 H), 7.61 - 7.53 (m, 1 H), 7.46 - 7.38 (m, 2H), 7.21 (t, J = 8.8 Hz, 2H), 6.00 (q, J = 9.0 Hz, 1 H), 5.30 (s, 1 H), 2.75 (s, 3H) (absolute stereochemistry not confirmed).
[00656] Synthesis of (R)-N-methyl-N-((R)-2,2,2-trifluoro-1-(4- fluorophenyl)ethyl)pyridine-3-sulfonimidamide (Example 71): To a stirred solution of compound 35.6 (180 mg, 0.37 mmol) in HFIP (0.1M, 4.2 mL) (±)- 10-Camphorsulfonic acid (176 mg, 0.75 mmol) was added in a seal cap tube and then heated to 70 °C for 16 h. Crude LCMS showed desired product mass peak along with unreacted SM. The reaction mass was then concentrated under reduced pressure to afford crude compound which was purified by normal phase SFC to afford desired compound Example 71 (32 mg, 26% yield). LCMS: m/z found ((348.2 [M+H]+),rt= 2.89 min (Method B)[ Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm)); 1 H NMR (401 MHz, DMSO) 5 9.02 (s, 1 H), 8.76 (d, J = 4.0 Hz, 1 H), 8.27 - 8.20 (m, 1 H), 7.62 - 7.50 (m, 1 H), 7.42 - 7.35 (m, 2H), 7.18 (t, J = 8.7 Hz, 2H), 6.03 (q, J = 8.8 Hz, 1 H), 5.62 - 5.19 (m, 1 H), 2.70 (s, 3H) (absolute stereochemistry not confirmed).
Example 72 and Example 73 [00657] (S)-N-((R)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-6-fluoro-N-methylimidazo[1 ,2- a]pyridine-3-sulfonimidamide (Example 72) and (R)-N-((R)-1-(4-chlorophenyl)-2,2,2- trifluoroethyl)-6-fluoro-N-methylimidazo[1 ,2-a]pyridine-3-sulfonimidamide (Example 73)
Example 73 Scheme 37
[00658] Synthesis of 2-ethylhexyl 3-((6-fluoroimidazo[1,2-a]pyridin-3- yl)thio)propanoate 37.1 : To a stirred solution of 37.0 (7.5 g, 34.88 mmol) and 2-ethylhexyl 3-mercaptopropanoate (7.62 g, 34.88 mmol) in toluene (50 mL) was added DIPEA (18.2 mL, 104.64 mmol) and the reaction mixture was degassed with N2 for 10 min. Then Xantphos (605 mg, 1.05 mmol) and Pd2(dba)3 (640 mg, 0.7 mmol) were added to the reaction mixture and stirring was continued at 100 °C for 12 h. The reaction was monitored by TLC and LCMS. After completion, the reaction mixture was filtered through celite bed, washed with ethyl acetate and concentrated under reduced pressure. The crude was dissolved with ethyl acetate and washed with water. The organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 40% ethyl acetate in hexane to afford 37.1 as a gum (12 g, 97% yield). LCMS: m/z found ((353.46 [M+H]+), rt= 1.96 min) (Method C)[ YMC Triart C18 column (3 pm, 33 x 2.1 mm)]. [00659] Synthesis of 6-fluoroimidazo[1,2-a]pyridine-3-thiol 37.2: To a stirred solution of
37.1 (7.0 g, 19.86 mmol) in methanol (40 mL), K2CO3 (4.12 g, 29.79 mmol) was added at 0°C and stirred the mixture at rt for 2 h. After completion, confirmed by TLC and LCMS, the reaction mixture was concentrated under reduced pressure. Then the mixture was acidified with 1 N HCI and again concentrated under reduced pressure. The crude was dissolved in 10% methanol in dichloromethane and filtered. The filtrate was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 10% methanol in dichloromethane to afford
37.2 as a solid (3.0 g, 90% yield). LCMS: m/z found ((169.05 [M+HJ+), rt= 0.47 min) (Method C)[ YMC Triart C18 column (3 pm, 33 x 2.1 mm)].
[00660] Synthesis of 1,2-bis(6-fluoroimidazo[1,2-a]pyridin-3-yl)disulfane 37.3: To a stirred solution of 37.2 (3.0 g, 17.84 mmol) in acetonitrile (20 mL) were added DI PEA (3.1 mL, 17.84 mmol) and CuCh (240 mg, 1.78 mmol) and the mixture was stirred under oxygen atmosphere at rt for 16 h. After completion, confirmed by TLC and LCMS, the reaction mixture was concentrated under reduced pressure. The crude was dissolved in water and extracted with 10% methanol in dichloromethane. The organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 10% methanol in dichloromethane to afford 37.3 as a solid (2.0 g, 67% yield). LCMS: m/z found ((335.29 [M+H]+), rt= 1.46 min) (Method C)[ YMC T hart C18 column (3 pm, 33 x 2.1 mm)].
[00661] Synthesis of (/?)-A/-(1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-S-(6- fluoroimidazo[1,2-a]pyridin-3-yl)-/V-methylthiohydroxylamine 37.4: To a stirred solution of 37.3 (150 mg, 0.45 mmol) and (/?)-1-(4-chlorophenyl)-2,2,2-trifluoro-/V-methylethan-1- amine (200 mg, 0.9 mmol) in methanol (3 mL) and chloroform (3 mL) mixture, AgNOs (152 mg, 0.9 mmol) was added at ice cold condition and the mixture was stirred at rt for 16 h. The reaction was monitored by TLC and LCMS. After completion, the reaction mixture was filtered through celite bed, washed with methanol and concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 40% to 90% ethyl acetate in hexane to afford 37.4 as gum (17 mg, 10% yield). LCMS: m/z found ((390.32 [M+H]+), rt= 1.89 min) (Method C)[ YMC Triart C18 column (3 pm, 33 x 2.1 mm)].
[00662] Synthesis of A/-((/?)-1-(4-chlorophenyl)-2,2,2-trifluoroethyl)-6-fluoro-/V- methylimidazo[1 ,2-a]pyridine-3-sulfonimidamide 37.5: To a stirred solution of 37.4 (130 mg, 0.33 mmol) in methanol (4 mL) were added acetic acid (0.04 mL, 0.84 mmol), (diacetoxyiodo) benzene (270 mg, 0.84 mmol) and ammonium carbamate (105 mg, 1.33 mmol) at ice cold condition and stirred the mixture at rt for 1 h. After completion, confirmed by TLC and LCMS the reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 85% ethyl acetate in hexane to afford 37.5 as a diastereomeric mixture (40 mg, 29% yield). LCMS: m/z found ((421.2 [M+H]+), rt= 3.12 min) (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)].
[00663] The diastereomers were separated by SFC purification method of 37.5 (40 mg) to obtain compounds Example 72 (4.63 mg, 97.56%); LCMS: m/z found ((421.2 [M+H]+), rt= 3.11 min) (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)]; 1H NMR (400 MHz, DMSO) 5 8.93 (d, J = 7.2 Hz, 1 H), 8.16 (s, 1 H), 7.87-7.84 (m, 1 H), 7.64 (t, J = 10.2 Hz, 1 H), 7.44-7.38 (m, 4H), 6.16 (q, J = 8.7 Hz, 1 H), 5.86 (s, 1 H), 2.82 (s, 3H) (absolute stereochemistry not confirmed) and Example 73 (3.05 mg, 98.62%); LCMS: m/z found ((421.2 [M+H]+), rt= 5.98 min) (Method K)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)]; 5 8.98 (d, J = 7.2 Hz, 1 H), 8.19 (s, 1 H), 7.86-7.84 (m, 1 H), 7.64 (t, J = 8.0 Hz, 1 H), 7.42-7.37 (m, 4H), 6.23 (q, J = 8.7 Hz, 1 H), 5.96 (s, 1 H), 2.73 (s, 3H) (absolute stereochemistry not confirmed).
[00664] SFC method:
[00665] SFC Prep Purification of 37.5 (40 mg) was done on a Waters SFC prep 150 instruments equipped with a Waters 2489 UV/visible detector by using C-Amylose A (30 mm x 250 mm), 5p column operating at 35 °C temperature, maintaining a flow rate of 100 mL/min, using 65% CO2 in super critical state and 35% of 100% methanol as mobile phase. Run this isocratic mixture up to 9.0 minutes and maintained the isobaric condition of 100 bar at 230 nm wavelength.
Example 74 and Example 75
[00666] (S)-N-methyl-N-((R)-2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)-
[1 ,2,4]triazolo[1 ,5-a]pyridine-7-sulfonimidamide (Example 74) and (R)-N-methyl-N-((R)- 2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)-[1 ,2,4]triazolo[1 ,5-a]pyridine-7- sulfonimidamide (Example 75)
Scheme 38
[00667] Synthesis of 2-ethylhexyl 3-([1,2,4]triazolo[1,5-a]pyridin-7-ylthio)propanoate 38.1 : To a stirred solution of 38.0 (5.0 g, 25.25 mmol) and 2-ethylhexyl 3- mercaptopropanoate (5.51 g, 25.25 mmol) in toluene (25 mL) was added DI PEA (13.2 mL, 75.75 mmol) and the reaction mixture was degassed with N2 for 10 min. Then Xantphos (440 mg, 0.76 mmol) and Pd2(dba)s (460 mg, 0.51 mmol) were added to the reaction mixture and stirred at 100 °C for 12 h. The reaction was monitored by TLC and LCMS. After completion, the reaction mixture was filtered through celite bed, washed with ethyl acetate and concentrated under reduced pressure. The crude was dissolved with ethyl acetate and washed with water. The organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 40% ethyl acetate in hexane to afford 38.1 as a gum (7.0 g, 83% yield). LCMS: m/z found ((336.39 [M+H]+), rt= 1.92 min) (Method C)[ YMC Triart C18 column (3 m, 33 x 2.1 mm)].
[00668] Synthesis of [1,2,4]triazolo[1,5-a]pyridine-7-thiol 38.2: To a stirred solution of 38.1 (5.0 g, 14.91 mmol) in methanol (30 mL) 30% NaOMe (w/w) in methanol (10 mL, 2.42 g, 44.72 mmol) was added at 0°C and the mixture was stirred at rt for 2 h. After completion, confirmed by TLC and LCMS, the reaction mixture was concentrated under reduced pressure. Then the mixture was acidified with 1 N HCI and concentrated under reduced pressure. The crude residue was dissolved in 10% methanol in dichloromethane and filtered. The filtrate was concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 10% methanol in dichloromethane to afford 38.2 as a solid (1.81 g, 80% yield). LCMS: m/z found ((152.12 [M+H]+), rt= 0.80 min) (Method C)[ YMC Triart C18 column (3 pm, 33 x 2.1 mm)].
[00669] Synthesis of 1,2-bis([1,2,4]triazolo[1,5-a]pyridin-7-yl)disulfane 38.3: To a stirred solution of 2.2 (2.5 g, 16.54 mmol) in acetonitrile (25 mL), DIPEA (1 .4 mL, 8.27 mmol) and CuCh (110 mg, 0.83 mmol) were added and stirred the mixture under oxygen atmosphere at rtfor 16 h. After completion, confirmed by TLC and LCMS the reaction mixture was concentrated under reduced pressure. The crude was dissolved in water and extracted with dichloromethane. The organic extract was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 10% methanol in dichloromethane to afford 38.3 as a solid (1.6 g, 64% yield). LCMS: m/z found ((301.27 [M+H]+), rt= 1.29 min) (Method C)[ YMC Triart C18 column (3 pm, 33 x 2.1 mm)].
[00670] Synthesis of (/?)-S-([1 ,2,4]triazolo[1 ,5-a]pyridin-7-yl)-A/-methyl-A/-(2,2,2-trifluoro-1- (4-(trifluoromethyl)phenyl)ethyl)thiohydroxylamine 38.4: A stirred solution of AgNOs (170 mg, 1.0 mmol) in methanol (6 mL) was cooled to 0°C and 38.3 (150 mg, 0.5 mmol) was added and stirred the mixture at same temperature for 20 min. Then (A?)-2,2,2-trifluoro-A/- methyl-1-(4-(trifluoromethyl)phenyl)ethan-1-amine (257 mg, 1.0 mmol) and PTSA monohydrate (10 mg, 0.05 mmol) was added at ice cold temperature. The reaction mixture was stirred at rt for 16 h. The reaction was monitored by TLC and LCMS. After completion, the reaction mixture was filtered through celite bed, washed with methanol and concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 40% to 90% ethyl acetate in hexane to afford 38.4 as a gum (15 mg, 7% yield). LCMS: m/z found ((407.46 [M+H]+), rt= 1.83 min) (Method C)[ YMC Triart C18 column (3 pm, 33 x 2.1 mm)].
[00671] Synthesis of /V-methyl-/V-((/?)-2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)- [1 ,2,4]triazolo[1 ,5-a]pyridine-7-sulfonimidamide 38.5: To a stirred solution of 38.4 (170 mg, 0.42 mmol) in methanol (4 mL) acetic acid (0.05 mL, 0.84 mmol), (diacetoxyiodo)benzene (337 mg, 1.05 mmol) and ammonium carbamate (130 mg, 1.67 mmol) were added at ice cold condition and stirred the mixture at rt for 1 h. After completion, confirmed by TLC and LCMS the reaction mixture was diluted with dichloromethane, washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 85% ethyl acetate in hexane to afford 38.5 as diastereomeric mixture (65 mg, 36% yield). LCMS: m/z found ((438.2 [M+H]+), rt= 3.02 min) (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)]. [00672] The diastereomers were separated by SFC purification method of 38.5 (65 mg) to obtain compounds Example 74 (18.21 mg, 98.80%); LCMS: m/z found ((438.3 [M+H]+), rt= 3.00 min) (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)]; 1H NMR (400 MHz, DMSO) 5 9.13 (d, J = 7.2 Hz, 1 H), 8.72 (s, 1 H), 8.35 (s, 1 H), 7.78 (d, J = 8.1 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 7.4 Hz, 1 H), 6.23 (q, J = 8.8 Hz, 1 H), 5.60 (s, 1 H), 2.84 (s, 3H) (absolute stereochemistry not confirmed) and Example 75 (16.31 mg, 98.21%); LCMS: m/z found ((438.2 [M+H]+), rt= 2.99 min) (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)]; 5 9.11 (d, J = 7.2 Hz, 1 H), 8.72 (s, 1 H), 8.35 (s, 1 H), 7.72 (d, J = 8.2 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 7.1 Hz, 1 H), 6.26 (q, J = 8.4 Hz, 1 H), 5.75 (s, 1 H), 2.79 (s, 3H) (absolute stereochemistry not confirmed).
[00673] SFC method:
[00674] SFC Prep Purification of 38.5 (65 mg) was done on a Waters SFC prep 150 instruments equipped with a Waters 2489 UV/visible detector by using CHIRALPAK IG (30 mm x 250 mm), 5p column operating at 35 °C temperature, maintaining flow rate of 100 mL/min, using 50% CO2 in super critical state and 50% methanol as mobile phase. Run this isocratic mixture up to 7.0 minutes and also maintained the isobaric condition of 90 bar at 220 nm wavelength.
Example 76 and Example 77
[00675] (S)-N-methyl-N-((R)-2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)pyrimidine-5- sulfonimidamide (Example 76) and (R)-N-methyl-N-((R)-2,2,2-trifluoro-1-(4- (trifluoromethyl)phenyl)ethyl)pyrimidine-5-sulfonimidamide (Example 77)
Example 77
Scheme 39
[00676] Synthesis of (/?)-A/-methyl-S-(pyrimidin-5-yl)-N-(2,2,2-trifluoro-1-(4- (trifluoromethyl)phenyl)ethyl)thiohydroxylamine 39.1 : A solution of 1 ,2-di(pyrimidin-5- yl)disulfane (24.3, 100 mg, 0.45 mmol) in methanol (3 mL) was cooled to 0°C. Then, AgNOs (155 mg, 0.9 mmol) was added to it and stirring was continued at 0°C for 15 min. ( )-2,2,2- trifluoro-/V-methyl-1-(4-(trifluoromethyl)phenyl)ethan-1-amine (230 mg, 0.9 mmol) was added to it and reaction mixture was stirred at ambient temperature for 16 h. After completion, 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 90% ethyl acetate in hexane and product 39.1 was isolated as yellow gum. (20 mg, 12% yield). LCMS: m/z found ((368.2 [M+H]+),rt= 2.26 min (Method A) [Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)].
[00677] Synthesis of A/-methyl-A/-((R)-2,2,2-trifluoro-1-(4-
(trifluoromethyl)phenyl)ethyl)pyrimidine-5-sulfonimidamide 39.2: To a solution of intermediate 39.1 (140 mg, 0.38 mmol) in methanol (3 mL) was added acetic acid (0.044 mL, 0.76 mmol), followed by (diacetoxyiodo)benzene (250 mg, 0.76 mmol). The mixture was stirred at 0 °C and to it ammonium carbamate (120 mg, 1.52 mmol) was added. The reaction mixture was then stirred at ambient temperature for 3 h. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic layer was washed with water (20 mL) and brine (20 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by column chromatography over silica gel using 90% ethyl acetate in hexane and the product 39.2 (70 mg) was isolated as a diastereomeric mixture.
[00678] The diastereomeric mixture 39.2 (70 mg) was separated by SFC purification method to obtain compounds Example 76 (15 mg, 97.02%. LCMS: m/z found ((399.2 [M+H]+), rt= 3.10 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (401 MHz, MEOD) 5 9.34 (s, 1 H), 9.27 (s, 2H), 7.74 (d, J = 8.36 Hz, 2H), 7.68 (d, J = 8.32 Hz, 2H), 6.20 (q, J = 8.52 Hz, 1 H), 2.89 (s, 3H) (absolute stereochemistry not confirmed)and Example 77: (10 mg, 94.13%)LCMS: m/z found ((399.2 [M+H]+),rt= 3.09 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm)); 1H NMR (400 MHz, MEOD) 5 9.30 (s, 1 H), 9.23 (s, 2H), 7.70 (d, J = 8.32 Hz, 2H), 7.62 (d, J = 8.2 Hz, 2H), 6.23 (q, J = 8.56 Hz, 1 H), 2.87 (s, 3H) (absolute stereochemistry not confirmed).
[00679] SFC method:
[00680] SFC Prep Purification of 39.2 is running on a Waters SFC PREP 80 instruments equipped with a Waters 2489 UV/Visible Detector by using Chiralpak IG (30.0 mm x 250.0 mm), 5p column operating at 35°C temperature, maintaining flow rate of 70 mL/min, using 60% CO2 in super critical state and 40 % methanol as mobile phase. This isocratic mixture was run up to 11.0 minutes, maintained the isobaric condition of 100 bar at 220 nm wavelength.
Example 78 and Example 79
[00681] (R)-N-methyl-N-((R)-2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)imidazo[1 ,2- a]pyridine-7-sulfonimidamide (Example 78) and (S)-N-methyl-N-((R)-2,2,2-trifluoro-1-(4- (trifluoromethyl)phenyl)ethyl)imidazo[1 ,2-a]pyridine-7-sulfonimidamide (Example 79)
Example 79
Scheme 40
[00682] Synthesis of (/?)-S-(imidazo[1 ,2-a]pyridin-7-yl)-A/-methyl-A/-(2,2,2-trifluoro-1-(4- (trifluoromethyl)phenyl)ethyl)thiohydroxylamine, 40.1 : A solution of 1 ,2-bis(imidazo[1 ,2- a]pyridin-7-yl)disulfane (20.3, 500 mg, 1.68 mmol) in methanol (6 mL) was cooled to 0°C. Then AgNOs (570 mg, 3.35 mmol) was added to it followed by (/?)-2,2,2-trifluoro-/V-methyl- 1-(4-(trifluoromethyl)phenyl)ethan-1-amine (430 mg, 1.7 mmol). Stirring was continued at rt for 16 h. After completion, the reaction mixture was filtered through sintered funnel. The filtrate was concentrated under reduced pressure and the product was purified by column chromatography over silica gel using 5% methanol in dichloromethane to afford (R)-S- (imidazo[1 ,2-a]pyridin-7-yl)-A/-methyl-A/-(2,2,2-trifluoro-1-(4-
(trifluoromethyl)phenyl)ethyl)thiohydroxylamine 40.1 (150 mg, 22 % yield) as a liquid. LCMS: m/z found ((406.2 [M+H]+),rt= 2.05min (Method Y) Waters Acquity BEH C18 column (1.7 pm, 50 x 2.1 mm);
[00683] Synthesis of N-methyl-N-((R)-2,2,2-trifluoro-1-(4-
(trifluoromethyl)phenyl)ethyl)imidazo[1,2-a]pyridine-7-sulfonimidamide, 40.2: To a solution of afford (/?)-S-(imidazo[1 ,2-a]pyridin-7-yl)-A/-methyl-A/-(2,2,2-trifluoro-1-(4- (trifluoromethyl)phenyl)ethyl)thiohydroxylamine 40.1 (150 mg, 0.37 mmol) in methanol (4 mL) was added acetic acid (0.042 mL, 0.74 mmol), followed by (diacetoxyiodo)benzene (298 mg, 0.925 mmol). The mixture was stirred at 0 °C and to it ammonium carbamate (116 mg, 1.48 mmol)was added. The reaction mixture was then stirred at ambient temperature 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 product was purified by column chromatography over silica gel using 5% methanol in dichloromethane to afford N-methyl-N-((R)-2,2,2-trifluoro-1-(4-(trifluoromethyl)phenyl)ethyl)imidazo[1 ,2- a]pyridine-7-sulfonimidamide 40.2 (50 mg, 31 % yield) was isolated as diastereomeric mixture. The diastereomers were separated by SFC purification method to obtain compounds Example 78 (10 mg); LCMS: m/z found ((437.2 [M+H]+), rt= 2.81 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm];1H NMR (400 MHz, DMSO) 5 8.66 (d, J = 7.12 Hz, 1 H), 8.13 (s, 1 H), 8.07 (s, 1 H), 7.77 (t, 3H), 7.67 (d, J=8.08, 2H), 7.26 (d, J=8.08, 1 H), 6.19-6.17 (m, 1 H), 5.31 (s, 1 H), 2.79 (s, 3H) (absolute stereochemistry not confirmed); and Example 79 (11 mg) LCMS: m/z found ((437.2 [M+H]+),rt= 2.80 min (Method B)[ Waters Acquity BEH C8 column (1.7 pm, 50 x 2.1 mm]; 1H NMR (400 MHz, DMSO) 5 8.65 (d, J = 7 Hz, 1 H), 8.12 (s, 1 H), 8.08 (s, 1 H), 7.79 (s, 1 H), 7.70 (d, J =7.92, 2H), 7.63 (d, J=7.92, 2H), 7.24(d, J=7.2, 1 H), 6.22-6.20 (m, 1 H), 5.45 (s, 1 H), 2.79 (s, 3H) (absolute stereochemistry not confirmed).
[00684] SFC method:
[00685] SFC Prep Purification of compound 40.2 was done on a Pic Solutions 175 instrument equipped with a Knauer 40D UV/Visible Detector by using CHIRALPAK IG (30 mm x 250 mm ),5p column operating at 35°C, maintaining a flow rate of 100 mL/min, using 70% CO2 in super critical state and 30% of 100% Methanol as mobile phase. Run this isocratic mixture up to 15.0 minutes and maintained the isobaric condition of 100 bar at 234 nm wavelength.
Pharmacological Examples
Example 80: Human Cav2.3 Channel Calcium-lnflux Assay
Cell Line
[00686] HEK-293 T-Rex cells were transfected with pcDNA3.1-Kir2.1 to generate a stable cell line. After antibiotic selection, the obtained stable pools were analysed using FLIPRTETRA (membrane potential assay), and a limiting dilution was performed and a HEK-293 T- Rex/Kir2.1 clone was selected. The clone was transfected with pcDNA3.1-Cav2.3e and pBud-Cav-p4-a251 to generate a stable cell line where the Cav2.3e expression is inducible. After antibiotic selection, functional clone pool analysis and two successive limiting dilutions, the final clone underwent a qPCR analysis and a biophysical and pharmacological validation using patch-clamp.
Assay
[00687] A compound plate, containing 10 test compounds in eight-points dose response with n=4, was prepared. Test compounds dose response curves were prepared in automated fashion in 100% DMSO at CyBio Felix and starting from a stock solution in 100% DMSO; a defined volume was serially moved into destination wells pre-filled with the desired DMSO volume; stock solution concentration volumes were dependent on the final compounds concentrations to be tested and the final DMSO content used in the assay. For the assay test compounds dose response curves ranged from 30 pM and half log dilution with 0.3% final DMSO. In order to obtain the 8-points dose response curve all the concentrations were created by starting from a 10 mM DMSO stock solution and then moving 9.5 pL into a destination well pre-filled with 20.5 pL of 100% DMSO and repeating this step seven times. This initial step was done into 96 MTP plates, 10 compounds/plate. One 384 MTP was then reformatted to contain all the 10 compounds at 8 concentrations, quadruplicate data points. This so obtained 384 MTP compound plate served as source plate in a “mother to child” process with a CyBi®-Well dispenser in which 0.7 pL of compounds were moved into a destination plate pre-filled with 57.6 pL of Tyrode’s buffer 0 mM K+, thus obtaining 4x concentrated compounds solution. In columns 1-2 and 23-24 the control wells were added. Both “source” compound plate and “destination” compound plate were barcoded and a relationship between the two plates was thus generated.
[00688] The day before the experiment, cells were detached by gentle wash with DPBS, followed by 5 min incubation at 37°C with Trypsin solution. Detached cells were diluted with OptiMEM + Doxycycline at 0.2 pg/mL, counted and plated in Poly-D-Lysine coated black/clear bottom (15.000 c/well in 20 pl/well) by the use of a MATRIX WellMate dispenser. Plates were placed into a humidified incubator at 37°C with 5% CO2 until the experimental day. 24h after seeding 10 pL/well of 1.5X Fluo8 NW dye solution prepared in Tyrode’s buffer 0 mM K+ were added on top of the seeding medium. Cell plates were incubated for 40-60 min at RT in the dark. We then Injected off-line 10 pL/well of test compounds and controls 4X concentrated in Tyrode’s Buffer 0 mM K+ with the CyBi®-Well instrument. Cell plates were incubated 3 minutes at RT. Finally, we injected 20 pL/well of 3X concentrated activator solution (K20-Na130-Ca2 buffer: 20 mM KCI, 130 mM NaCI, 2 mM CaCI2, 10 mM HEPES, 10 mM Glucose, final concentrations, prepared starting from “K0-Na150-Ca2” and “K150- Na0-Ca2” buffers) at FDSS7000EX instrument and read emitted fluorescence for 130 seconds.
[00689] Data analysis was performed with Genedata Screener® software and reported compounds activity as % effect in relation to the normalization standards. The Kinetic Response Value (KRV) is calculated as follows:
[00690] KRV = Maximal fluorescence recorded from second 5 to second 130 minus baseline fluorescence, computed as average from second 1 to second 2, of the kinetic trace. The KRV was normalized versus Neutral Controls and Inhibitor Controls in order to obtain the Activity[%] for each well. The normalization places the compound activity values on an equivalent scale and makes them comparable across plates or different compound batches. Therefore, the compound activity values were scaled (based on the two references) to a common range (two-point normalization). The following equation was used by the software to normalize the signal values to the desired signal range:
N(x) = CR + [((x - < cr >)/ (< sr > - < cr >)). (SR - CR)] where: x is the calculated signal value of a well (KRV); < cr > is the median of the calculated signal values (KRV) for the Central Reference wells of a plate (median of Neutral Controls); < sr > is the median of the calculated signal values (KRV) for the Scale Reference wells of a plate (median of Inhibitor Controls); CR is the desired median normalized value for the Central Reference (0) and SR is the desired median normalized value for the Scale Reference (-100).
[00691] The final equation to calculate the Activity% can be simplified as follow:
% Activity = -100. (x - <NeutralControls>) I (<NeutralControls> - <lnhibitorControls>) where full inhibition corresponds to % Activity = -100
[00692] The fitting of the dose-response curve of each test compound is performed in the Analyzer module of the Screener software on the normalized values and applying the “smart fit” strategy. This strategy allowed an automatic selection between the “Constant Fit” and the “Hill Fit” model calculating which fit model best matched the experimental data. The Constant Fit was applied when no change of activity was detected across the measured concentrations, and the corresponding compounds were further classified as inactive. The Hill Fit was applied when the observed activity significantly changed with the compound concentration. In case of Hill Fit, Hill equation was used to determine the concentration at which activity reaches 50% of maximum level, i.e. , ACso.
Y = So + ((Sinf -So) I (1 + (10L°9AC5° 1 10x)n)) where X is Log10 of compound concentration. The equation has four parameters: Zero Activity (SO) - Activity level at zero concentration of test compound; Infinite Activity (Smf) - Activity level at infinite concentration of test compound; ACso - Concentration at which activity reaches 50% of maximum level. This term corresponds to ICso in this assay; AND Hill coefficient (n) - Measure of the slope at ACso.
[00693] The pICso values measured in this assay for the exemplified compounds is set out in the table below:
[00694] The inventors have found that for some high affinity compounds, the addition of pluronic acid (0.05%) aided solubility and in doing so increased the measured pICso values by approximately 0.5 units. However, all of the reported pICso values presented above did not include pluronic acid.
Example 81 : Whole-Cell Patch Clamp Assay
[00695] HEK-293 T-Rex/Kir2.1/Cav2.3e-p4-a251 cells were seeded 96 hours before experiment and doxycycline at 0.2 pg/mL was added 24 hours before experiment. Just before the experiments cells were washed twice with D-PBS w/o Ca2+/Mg2+ and gently detached from the flask with Detachin. Cells were then re-suspended in the suspension solution (25 mL EX-CELL ACF CHO medium; 0.25 mL of 100x Penicillin/Streptomycin) and placed on the Automated Patch-clamp platform (QPatch 16X). [00696] Standard whole-cell voltage clamp experiments were performed at room temperature using the single hole technology and the following intracellular and extracellular solutions (ICS and ECS, respectively) were used. ICS (mM): CsF 60, CsCI 50, NaCI 10, EGTA 20, BAPTA 5, HEPES 10, NaGTP 0.3, MgATP 5 (pH 7.2; ECS (mM): NMDG-CI 120, BaCI2 20, HEPES 10, EGTA 7 (pH 7.4). After establishment of the seal and the passage in the whole-cell configuration, the Cav2.3 dependent current was evoked by challenging the cells with the following voltage protocol: the plasma membrane was held at -80 mV then a 50ms-long depolarizing pulse at OmV, followed by a 50ms-long hyperpolarizing pulse at - 100mV were applied and finally the plasma membrane was held back to -80 mV. This voltage protocol was applied every 10 seconds. Cav2.3 dependent current was first measured in control condition (vehicle, 0.1 % DMSO), in the presence of increasing concentration of the compound under investigation and finally SNX 482 was added to fully block any R-type Cav2.3 dependent current.
[00697] For data collection, the Sophion proprietary software was used while the analysis was performed off-line using Excel and GraphPad Prism. The inward current (Area Under Curve) measured during each depolarizing pulse was normalized to cell membrane capacitance (Cm) to obtain the average inward current density in each condition (control, compound under investigation and SNX 482). Then, the inhibitory effect of the compound under investigation was evaluated as % of the remaining inward current, normalized to the internal control. When the percentage of inhibition exerted by the highest concentration tested was superior to 50 %, the dose-response curves data was fitted with the following equation: Y=100/(1+10A((LoglC50-X)*Hillslope)); where X: log of concentration; Y: normalized response, 100% down to 0%, decreasing as X increases; LoglC50: same log units as X; Hillslope: slope factor or hill slope, unit less. All data were expressed as mean ± S.E.
[00698] The pICso values measured in this assay for the exemplified compounds are set out in the table below: Example 82: Ex vivo activity in Substantia nigra dopamine neurons in mouse brain slice experiments
[00699] Compounds of the invention may be tested on R-type calcium current with whole cell patch clamp electrophysiology in substantia nigra dopamine neurons in an ex vivo brain slice preparation according to the methods described in Siller et al., Elife, 11 :e67464 (2022) https://doi.org/10.7554/eLife.67464.
Example 83: In vivo activity in the Maximal Electroshock Stimulation model (MES) in mouse
[00700] Compounds of the invention may be tested in an in vivo model of epilepsy, the MES model in mouse, according to the method described in Kehne et al, Neurochemistry Research 42 : 1894-1903 (2017) | https://doi.org/10.1007/s11064-017-2275-z.

Claims

Claims
1. A compound of the formula (I), or a pharmaceutically acceptable salt or N-oxide thereof: wherein:
R1 is selected from: Ci-e alkyl, C3-6 cycloalkyl, and Cs-e cycloalkyl-Ci-e alkyl-, wherein R1 is substituted by at least one fluorine; optionally wherein one or more H in R1 is substituted by D;
R2 is selected from: H, D, Ci-e alkyl and Ci-e haloalkyl; or
R1 and R2 together with the carbon atom to which they are attached form a C3-6 cycloalkyl substituted with at least one fluorine;
R3 is selected from: H, Ci-e alkyl and Ci-e haloalkyl, and C3-6 cycloalkyl; optionally wherein one or more H in R3 is substituted by D, and wherein the C3-6 cycloalkyl is optionally substituted by one or more substituent independently selected halo and C1.3 alkyl;
L is selected from: a bond and C1.3 alkylene;
Ring A is selected from: C3-6 cycloalkyl, 4- to 7-membered heterocyclyl, 5- to 12-membered heteroaryl and Ce- aryl; wherein Ring A is optionally substituted by one or more R4; each R4 is independently selected from: halo, -CN, -NO2, =0, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7;
R5 and R6 are each independently selected from: H, Ci-e alkyl, Ci-e haloalkyl and Q1, wherein said Ci-e alkyl is optionally substituted by one or more R8; each R7 and R8 is independently selected from: halo, -CN, -0R7A, -S(O)XR7A, -NR7AR7B, C(O)R7A, -OC(O)R7A, -C(O)OR7A, -NR7AC(O)R7B, -C(O)NR7AR7B and Q2; each Q1 and Q2 is independently selected from: C3-6 cycloalkyl, 4- to 7-membered heterocyclyl, phenyl and 5- or 6-membered heteroaryl, wherein said C3-6 cycloalkyl, 4- to 7-membered heterocyclyl, phenyl and 5- or 6- membered heteroaryl is optionally substituted by one or more R9; each R9 is independently selected from: halo, =0, -CN, -NO2, C1.4 alkyl, C1.4 haloalkyl, - OR9A, -S(O)2R9A, -NR9AR9B, -C(O)R9A, -OC(O)R9A, -C(O)OR9A, -NR9BC(O)R9A, - C(O)NR9AR9B, -NR9BC(O)OR9A, -OC(O)NR9AR9B, -NR9BSO2R9A and -SO2NR9AR9B, wherein said C1.4 alkyl is optionally substituted by 1 or 2 substituents selected from: halo, -CN, -OR9C, -NR9CR9D and -SO2R9C;
Ring B is phenyl or a 5- or 6-membered heteroaryl, wherein Ring B is optionally substituted by one or more R10; each R10 is independently selected from: halo, -CN, -NO2, =0, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2.6 alkenyl, C2.6 alkynyl, -OR10A, -S(O)xR10A, -NR10AR10B, - C(O)R10A, -OC(O)R10A, -C(O)OR10A, -NR10AC(O)R10B, -C(O)NR10AR10B, -NR10AC(O)OR10B, - OC(O)NR10AR10B, -NR10ASO2R10B, and -SO2NR10AR10B, wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2.6 alkenyl and C2.6 alkynyl is optionally substituted by one or more R11 ; each R11 is independently selected from: halo, -CN, -OR11A, -NR11AR11B and -SO2R11A;
R12 is independently selected from H, Ci-e alkyl, Ci-e haloalkyl, C3-6 cycloalkyl, C3-6 cycloalkyl-Ci-6 alkyl-, and COOR13; optionally wherein one or more H in R12 is substituted by D;
R13 is independently selected from H, Ci-e alkyl, Ci-e haloalkyl, C3-6 cycloalkyl, and C3-6 cycloalkyl-Ci-6 alkyl; optionally wherein one or more H in R13 is substituted by D;
R7A, R7B, R9A, R9B, R9C, R9D, R10A, R10B, R11A and R11 B are at each occurrence independently selected from: H, C1.4 alkyl and C1.4 haloalkyl; and wherein any -NR5R6, -NR7AR7B, -NR9AR9B, -NR9CR9D, -NR10AR10B, and - NR11AR11B within 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.
2. The compound according to claim 1 , wherein Ring A is a monocyclic 6-membered heteroaryl or a 9-membered fused bicyclic heteroaryl, wherein Ring A has 1 to 4 ring nitrogen atoms and wherein Ring A is optionally substituted with one or more R4.
3. The compound according to claim 1, wherein Ring A is a monocyclic 6-membered heteroaryl, wherein Ring A has 1, 2 or 3 ring nitrogen atoms and wherein Ring A is optionally substituted with one or more R4.
4. The compound according to claim 1, wherein Ring A is selected from: thienyl, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, tetrahydropyranyl, optionally substituted with one or more R4.
5. The compound according to claim 1 or claim 2, wherein Ring A is selected from: substituted with one or more R4.
6. The compound according to claim 1 or claim 3, wherein Ring A is selected from:
7. The compound according to claim 1 or claim 3, wherein Ring A is selected from:
8. The compound according to any one of claims 1 to 7, wherein each R4 is independently selected from: halo, -CN, -NO2, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, -OC(O)R5, -C(O)OR5, -C(O)NR5R6, - NR5SO2R6, and -SO2NR5R6.
9. The compound according to any one claims 1 to 7, wherein each R4 is independently selected from: halo (e.g. fluoro or chloro), -CN, C1.3 alkyl, -OC1.3 alkyl, - C(O)Ci-3 alkyl, -C(O)NH2, -C(O)NH(CI-3 alkyl) and -C(O)N(Ci-3alkyl)2; optionally wherein each R4 is independently selected from: fluoro and -CN.
10. The compound according to claim 1 , wherein Ring A is selected from:
11. The compound according to claim 1 , wherein the compound is a compound of the formula (XI), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R4a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; and a is an integer from 0 to 4.
12. The compound according to claim 1 , wherein the compound is a compound of the formula (XIII), or a pharmaceutically acceptable salt or N-oxide thereof: wherein: each R4a is independently selected from: halo, -CN, -NO2, C1.6 alkyl, C1.6 haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, - OC(O)R5, -C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and -SO2NR5R6, wherein said C1.6 alkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl and C2-6 alkynyl is optionally substituted by one or more R7; and a is an integer from 0 to 3.
13. The compound according to claim 1 , wherein the compound is a compound of the formula (XXI), or a pharmaceutically acceptable salt or N-oxide thereof: wherein:
X3 is N or CR4a;
R4a is selected from: halo, -CN, -NO2, Ci-e alkyl, Ci-e haloalkyl, 2 to 8 membered heteroalkyl, C2-6 alkenyl, C2-6 alkynyl, Q1, -OR5, -S(O)XR5, -NR5R6, -C(O)R5, -OC(O)R5, - C(O)OR5, -NR5C(O)R6, -C(O)NR5R6, -NR5C(O)OR6, -OC(O)NR5R6, -NR5SO2R6, and - SO2NR5R6, wherein said Ci-e alkyl, 2 to 8 membered heteroalkyl, C2.6 alkenyl and C2.6 alkynyl is optionally substituted by one or more R7.
14. The compound according to any one of claims 11 to 13, wherein each R4a is independently selected from: halo (e.g. fluoro or chloro), -CN, C1.3 alkyl, -OC1.3 alkyl, - C(O)Ci-3 alkyl, -C(O)NH2, -C(O)NH(CI-3 alkyl) and -C(O)N(Ci-3alkyl)2; optionally wherein each R4 is independently selected from: fluoro and -CN.
15. The compound according to claim 13, wherein the group of the formula:
16. The compound according to any one of claims 1 to 15, wherein Ring B is phenyl optionally substituted by one or more R10.
17. The compound according to any one of claims 1 to 15, wherein Ring B is selected from:
18. The compound according to any one of claims 1 to 15, wherein Ring B is
19. The compound according to any one of claims 1 to 18, wherein each R10 is independently selected from: halo, C1.3 alkyl, C1.3 haloalkyl, -OC1.3 alkyl and -OC1.3 haloalkyl.
20. The compound according to any one of claims 1 to 19, wherein each R10 is fluoro.
21. The compound according to any one of claims 1 to 15, wherein Ring B is selected from:
22. The compound according to any one of claims 1 to 21, wherein L is selected from a bond and -CH2-.
23. The compound according to any one of claims 1 to 22, wherein L is a bond.
24. The compound according to any one of claims 1 to 23, wherein R3 is selected from methyl, -CD3, ethyl, and 2-fluoroethyl.
25. The compound according to any one of claims 1 to 23, wherein R3 is selected from methyl and ethyl.
26. The compound according to any one of claims 1 to 25, wherein R12 is H.
27. The compound according to any one of claims 1 to 25, wherein R12 is selected from Ci-6 alkyl, Ci-6 haloalkyl, and C3-6 cycloalkyl.
28. The compound according to any one of claims 1 to 27, wherein R1 is selected from C1.6 alkyl and C3-6 cycloalkyl, wherein R1 is substituted by at least one fluorine. 29. The compound according to any one of claims 1 to 27, wherein R1 is selected from
CH2F, -CHF2, and -CF3.
30. The compound according to any one of claims 1 to 27, wherein R1 is -CF3.
31. The compound according to any one of claims 1 to 30, wherein R2 is selected from H and methyl. 32. The compound according to any one of claims 1 to 30, wherein R2 is H.
33. The compound of any one of claims 1 to 32, wherein the group of the formula:
35. A compound selected from:
, or a pharmaceutically acceptable salt or N-oxide thereof.
36. A compound selected from Compound List 1 in the description, or a pharmaceutically acceptable salt or N-oxide thereof.
37. A pharmaceutical composition comprising a compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or N-oxide thereof, and a pharmaceutically acceptable excipient.
38. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or N-oxide thereof, for use as a medicament.
39. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or N-oxide thereof, for use in the treatment of a disease or medical disorder mediated by Cav2.3.
40. 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 36, or a pharmaceutically acceptable salt or N-oxide thereof.
41. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or N-oxide 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.
42. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or N-oxide thereof, for use in a neuroprotective treatment of a neurodegenerative disease.
43. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or N-oxide thereof, for use in the treatment of Parkinson’s disease.
44. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or N-oxide thereof, for use in a preventing or inhibiting degeneration of dopaminergic neurons in a subject with Parkinson’s disease.
45. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or N-oxide thereof, for use in the prevention or treatment of epilepsy; optionally wherein the epilepsy is a drug-resistant epilepsy.
46. A compound according to any one of claims 1 to 36, or a pharmaceutically acceptable salt or N-oxide 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).
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