Sulfonamide Compounds for the Treatment of Neurological Conditions - Patent application

Abstract

Formula (I) [Case 1] TIFF2024542610000434.tif20170(in the formula, ring A, ring B, R 1 , R 2 , R 3 and L is as defined herein. The compounds and pharma- ceutically acceptable salts thereof are disclosed. The compounds are antagonists of the resistant (R-type) voltage-gated calcium ion channel Cav2.3. Pharmaceutical compositions containing the compounds and compounds for use in treating diseases modulated by Cav2.3, including epilepsy, neurodegenerative conditions such as Parkinson's disease, focal and drug-resistant forms of epilepsy, and other neurological disorders such as developmental and epileptic encephalopathies and fragile X syndrome, are also disclosed.

Description

[Technical Field]

[0001] The present invention relates to compounds that are antagonists of the resistant (R-type) voltage-gated calcium ion channel Cav2.3 and to their use in the treatment and prevention of diseases and conditions associated with Cav2.3, such as neurodegenerative conditions such as Parkinson's disease, focal and drug-resistant forms of epilepsy, and other neurological disorders such as developmental and epileptic encephalopathies and fragile X syndrome. [Background technology]

[0002] Voltage-gated calcium channels are multisubunit complexes consisting of α-1, α-2, β, and δ subunits in a 1:1:1:1 ratio. Cav2.3 channels belong to the drug-resistant, or "residual" (R-type), membrane-bound voltage-gated calcium channels and are responsible for calcium ion influx in cells that express them. These channels are only partially characterized structurally. Nevertheless, it is well established that the majority of them are encoded by the CACNA1E gene (gene ID 777) and are expressed as different Cav2.3 splice variants (variants Cav2.3a to Cav2.3e or f) as ion-conducting subunits (Schneider et al., Pfluegers Arch. 2020;472(7):811-816). Cav2.3 is highly expressed in neurons and endocrine tissues, and is also detected in the heart, kidney, semen, spleen, and retina, and is involved in numerous physiological and pathophysiological processes in the central nervous system, vascular system, and endocrine system (Schneider et al., Pharmaceuticals 2013,6(6),759-776, Schneider et al., Pfluegers Arch. 2020;472(7):811-816).

[0003] Parkinson's disease (PD) is the second most common neurodegenerative disorder, affecting 2-3% of the population aged 65 years and older. The primary motor symptoms of PD are caused by progressive degeneration of dopaminergic midbrain neurons, particularly those within the substantia nigra (SN) (Giguere et al. 2018, Front. Neurol. 9, 455). This results in striatal dopamine deficiency. Intracellular inclusions containing aggregates of α-synuclein are a novel pathological hallmark of PD (Poewe et al., Nat Rev Dis Primers. 2017 Mar 23;3:17013). Currently, no curative therapy is available for PD (Bloem et al., Lancet. 2021 Jun 12;397(10291):2284-2303). Parkinson's disease is a multifactorial disease. In addition to genetic risk factors for Parkinson's disease, such as PARK gene mutations, many stressors for Parkinson's disease have been identified, including inflammation, viral infection, trauma, intestinal bacteria, or environmental toxins. Most of these factors lead to mitochondrial, proteasome, and / or lysosomal dysfunction and increased metabolic stress, which are key pathophysiological events in Parkinson's disease. PARK mutations and most external factors are global stressors for Parkinson's disease, and additional cell-specific features also contribute to the pathophysiology of Parkinson's disease, particularly the vulnerability of different neuronal cells.

[0004] Dopaminergic midbrain neurons exhibit pacemaker activity, which is important for dopamine release and the control of, for example, voluntary movements. In SN dopaminergic neurons (and other highly vulnerable neurons), this activity is driven by the release of free cytosolic Ca 2+This leads to enhanced oscillations at the SN level, which is associated with elevated oscillatory 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 may make SN neurons more vulnerable to degeneration due to Parkinson's disease stressors. Cav2.3 is highly expressed in adult SN dopaminergic neurons and regulates somatic Ca in SN DA neurons. 2+ It accounts for approximately 50% of vibrations (Benkert et al., 2019, Nat. Commun. 10, 5094).

[0005] Patch clamp electrophysiology experiments in brain slices from Cav2.3 knockout mice revealed activity-related Ca 2+ The amplitude of oscillations was significantly reduced by approximately 50% in the soma of SN neurons compared to wild-type mice. 2+ Ca-dependent action potentials (AHPs) were also significantly reduced in SN dopaminergic neurons of Cav2.3 knockout mice. 2+ This coincided with a decrease in signaling. A similar effect was observed when Cav2.3 channels were partially blocked using low concentrations of the nonselective peptide antagonist SNX-482, which blocks Cav2.3 but also A-type Kv4 potassium channels, which have protective effects in SN dopaminergic (DA) neurons (Kimm et al., 2014, 34(28)9182-9189). Cav2.3 has also been shown to be associated with preferential degeneration of these SN DA neurons in an in vivo model of Parkinson's disease (Benkert et al., 2019, Nat. Commun. 10, 5094).

[0006] A mouse Cav2.3 knockout model, in which mice were subjected to low-dose MPTP / probenecid (neurotoxin) knockout of Cav2.3, demonstrated significant 100% neuroprotection in SN dopaminergic neurons compared to wild-type mice. These data identify Cav2.3 as a mediator of SN dopaminergic neuron vulnerability to degenerative stressors and suggest that Cav2.3 antagonists may be useful in the treatment of Parkinson's disease, for example, by providing neuroprotective treatments that prevent or halt disease progression (Benkert et al., 2019, Nat. Commun. 10, 5094).

[0007] In addition to neurodegenerative diseases such as Parkinson's disease, Cav2.3 channels have been implicated in other diseases and medical disorders, such as fragile X syndrome (Gray et al., J Neurosci. 2019 Sep 18;39(38):7453-7464), genetic developmental and epileptic encephalopathies (DEE) (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), and focal and drug-resistant forms of epilepsy (Weiergraber et al., Epilepsy, 2006,47:839-50; Weiergraber et al. 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), treatment of vasospasm after cerebral ischemia or subarachnoid hemorrhage (Wang et al., 2010, Journal of Neurotrauma, vol. 27, no. 9, pp. 1723-1732), and pain (e.g., 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 injury pain) (Schneider et al.; Ishiguro et al, Circ. Res. 2005, 96, 419-426, Patel et al., British Journal of Pharmacology 2018, 175, 2173-2184; Wormuth et al., Open Neurol J. 2016; 10:99-126).

[0008] WO 2018 / 228692 discloses that Cav2.3 antagonists are useful for the neuroprotective treatment of Parkinson's disease and other neurodegenerative diseases.

[0009] SNX-482 is a peptide antagonist of Cav2.3 derived from the venom of the tarantula Hysterocratis gigas. SNX-482 has an IC50 of 15–30 nM against Cav2.3. 50 However, at high concentrations, SNX-482 inhibits N-type Ca 2+ It also inhibits A-type Kv4 potassium currents (Newcomb et al., Biochemistry 1998, 37, 15353-15362). Meanwhile, at similarly low nM concentrations, 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 make it unsuitable as a neuroprotective treatment for the therapeutic treatment of humans with neurodegenerative conditions such as Parkinson's disease. Summary of the Invention [Problem to be solved by the invention]

[0010] Thus, there remains a need for Cav2.3 antagonists. Cav2.3 antagonists that are also brain penetrant would be particularly desirable. [Means for solving the problem]

[0011] In the context of the present invention, compounds of formula (I): [ka] (In the formula, R 1 is C 1~6 Alkyl, C 3~6 Cycloalkyl and C 3~6 Cycloalkyl-C 1~6alkyl-, and R 1 is substituted with at least one fluorine, and optionally R 1 wherein one or more H is replaced by D; R 2 H, D, C 1~6 Alkyl and C 1~6 haloalkyl; or R 1 and R 2 are C groups substituted with at least one fluorine atom along with the carbon atom to which they are attached. 3~6 forming a cycloalkyl, R 3 is C 1~6 Alkyl and C 1~6 haloalkyl, and optionally R 3 wherein one or more H is replaced by D; L is a bond and C 1~3 alkylene; Ring A is C 3~6 Cycloalkyl, 4- to 7-membered heterocyclyl, 5- to 12-membered heteroaryl and C 6~10 aryl, and ring A is selected from one or more R 4 and optionally substituted by Each R 4 Halo, -CN, -NO2, =O, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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)NR5 R 6 , -NR 5 SO2R 6 and -SO2NR 5 R 6 are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 Alkynyl is a group consisting of one or more R 7 and optionally substituted by R 5 and R 6 is H, C 1~6 Alkyl, C 1~6 Haloalkyl and Q 1 are each independently selected from Said C 1~6 Alkyl is one or more R 8 and optionally substituted by Each R 7 and R 8 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 are independently selected from Each Q 1 and Q 2 is C 3~6 independently selected from cycloalkyl, 4- to 7-membered heterocyclyl, phenyl, and 5- or 6-membered heteroaryl; Said C 3~6 Cycloalkyl, 4- to 7-membered heterocyclyl, phenyl, and 5- or 6-membered heteroaryl may be substituted by one or more R 9 and optionally substituted by Each R 9 Halo, =O, -CN, -NO2, C 1~4 Alkyl, C1~4 Haloalkyl, -OR 9A , -S(O)2R 9A , -NR 9A R 9B , -C(O)R 9A , -OC(O)R 9A , -C(O)OR 9A , -NR 9B C(O)R 9A , -C(O)NR 9A R 9B , -NR 9B C(O)OR 9A , -OC(O)NR 9A R 9B , -NR 9B SO2R 9A and -SO2NR 9A R 9B are independently selected from Said C 1~4 Alkyl is a group that can be substituted with halo, -CN, -OR 9C , -NR 9C R 9D and -SO2R 9C and optionally substituted by one or two substituents selected from Ring B is phenyl or 5- or 6-membered heteroaryl, and Ring B contains one or more R 10 and optionally substituted by Each R 10 Halo, -CN, -NO2, =O, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 10AR 10B , -NR 10A SO2R 10B and -SO2NR 10A R 10B are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 Alkynyl is a group consisting of one or more R 11 and optionally substituted by Each R 11 Halo, -CN, -OR 11A , -NR 11A R 11B and -SO2R 11A are independently selected from R 7A , R 7B , R 9A , R 9B , R 9C , R 9D , R 10A , R 10B , R 11A and R 11B In each occurrence, H, C 1~4 Alkyl and C 1~4 haloalkyl; Any -NR in the substituent 5 R 6 , -NR 7A R 7B , -NR 9A R 9B , -NR 9C R 9D , -NR 10A R 10B and -NR 11A R 11B can form a 4- to 6-membered heterocyclyl, and the 4- to 6-membered heterocyclyl is selected from halo, ═O, C 1~4 Alkyl and C 1~4 optionally substituted by one or more substituents selected from haloalkyl; each x is independently 0, 1, or 2; however, (i) Group [ka] but, [ka] and R 41 is H, -CH3, -CF3 or cyclopropyl, R 42 is -NHC(O)R 6 and (ii) Compounds A and B: [ka] be excluded (Subject to or a pharmaceutically acceptable salt thereof.

[0012] Also provided is a pharmaceutical composition comprising a compound of the invention, or a pharmaceutically acceptable salt thereof, except that compounds A and B are not excluded, and a pharmaceutically acceptable excipient.

[0013] Also provided are compounds of the invention, or pharmaceutically acceptable salts thereof, with the exception of compounds A and B, for use as pharmaceuticals.

[0014] Also provided is a compound of the invention, or a pharmaceutically acceptable salt thereof, except that compounds A and B are not excluded, for use in the treatment of a disease or medical disorder mediated by Cav2.3.

[0015] There is also provided the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, except that compounds A and B are not excluded, for the manufacture of a medicament for the treatment of a disease or medical disorder mediated by Cav2.3.

[0016] Also provided is 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 present invention, or a pharmaceutically acceptable salt thereof, except that compounds A and B are not excluded.

[0017] In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are provided for use in the prevention or treatment of a disease or medical disorder selected from neurodegenerative diseases, neurodevelopmental disorders, epilepsy, endocrine disorders, cerebral vasospasm, and pain. In certain embodiments, the compounds of the present invention or pharmaceutically acceptable salts thereof are provided for use in the treatment of neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease, Huntington's disease, dystonia, amyotrophic lateral sclerosis (ALS), multiple sclerosis, and age-related neurodegeneration. Further therapeutic uses of the compounds of the present invention are described in the detailed description below. DETAILED DESCRIPTION OF THE INVENTION

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

[0019] References herein to "a compound of the invention" are references to any of the compounds disclosed herein, including a compound of Formulas (I)-(XXXVIc), a compound selected from Compound A or Compound B, a compound described in any of the Examples, or a pharmaceutically acceptable salt, solvate, or salt of a solvate of any of these.

[0020] The term "antagonist," e.g., "Cav2.3 antagonist," refers to any molecule capable of blocking or reducing the amount of ions, particularly specific calcium ions, passing through the Cav2.3 channel. Antagonists can prevent or inhibit the opening of the channel or otherwise interfere with the normal operation of the channel. Antagonists can act directly or indirectly on the channel, for example, by binding to the allotropic site of the channel.

[0021] As used herein, the term "selective antagonist" refers to an antagonist that has 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 for the Cav2.3 target can 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, 10,000-fold, etc. The selectivity of the compounds of the invention for Cav2.3 relative to other ion channels (e.g., one or more other Cav channels selected from Cav1.2, Cav1.2, Cav1.3, Cav1.4, Cav2.1 and Cav2.2) can be assessed using methods similar to the Cav2.3 channel calcium influx assay described herein, using cells expressing the channel of interest to compare IC50 values.

[0022] The terms "treat" or "treatment" refer to any effect beneficial to the treatment or alleviation of an injury, disease, lesion, or condition, including objective or subjective parameters such as attenuation; amelioration; reduction of symptoms or making the injury, lesion, or condition more tolerable to the patient; slowing the rate of degeneration or decline; altering the progression of the disease or condition so that the degenerative endpoint is less debilitating; or improving the physical or mental well-being of the patient. The treatment or alleviation of symptoms may be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation. The term "treat" and its conjugations include prevention of an injury, lesion, condition, or disease (i.e., prophylaxis or prevention). For example, the term "treat" and its conjugations include prevention of a lesion, prevention of a condition, or disease associated with Cav2.3 (e.g., reduction or prevention of the effects or condition of a symptom or disease, or prevention or arrest of the progression of a disease or condition). For example, the compounds of the invention may be for use in preventing or reducing neurodegeneration in neurodegenerative diseases (eg Parkinson's disease), delaying the onset of symptoms or slowing the progression of neurodegenerative diseases.

[0023] In relation to Cav2.3 associated with a disease, the terms "associated" or "associated with," "involved," or "mediated by" mean that the disease is caused (in whole or in part) or the symptoms of the disease are caused (in whole or in part) by the Cav2.3 channel or channel activity or function. For example, the symptoms of a disease or condition associated with Cav2.3 activity may result (in whole or in part) from an increased level of Cav2.3 channel activity and / or enhanced expression of the Cav2.3 channel. Diseases or medical disorders associated with Cav2.3 activity or expression can be treated with compounds of the present invention that are effective in reducing the activity level of the Cav2.3 channel, for example, by blocking or partially blocking the Cav2.3 channel, inhibiting channel function, preventing or inhibiting channel expression, and / or attenuating the channel.

[0024] An "effective amount" is an amount sufficient to achieve a stated purpose. For example, it is an amount sufficient to achieve the intended effect for which it is administered, treat a disease, reduce enzyme activity, enhance enzyme activity, reduce receptor signaling, increase receptor signaling, reduce one or more symptoms of a disease or condition, or produce a disease-modifying effect (i.e., alter the underlying pathophysiology of the disease). One example of an "effective amount" is an amount sufficient to contribute to the treatment, prevention, or reduction of one or more symptoms of a disease or modify the progression of a disease, which may also be referred to as a "therapeutically effective amount." "Reduction" of one or more symptoms means a decrease in the severity or frequency of the symptoms, or elimination of the symptoms. A "prophylactically effective amount" of a drug, when administered to a subject, has an intended prophylactic effect, such as preventing or delaying the onset (or recurrence) of an injury, disease, lesion, or condition, or reducing the likelihood of the onset (or recurrence) of an injury, disorder, lesion, or condition, or a symptom thereof. A complete prophylactic effect does not necessarily occur with the administration of a single dose, but may occur only after the administration of a series of doses. Thus, a prophylactically effective amount can be administered in one or more administrations. The exact amount will vary depending on the purpose of the treatment, and can be ascertained by one of ordinary skill in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0025] Therapeutically effective amounts of compounds of the invention can be estimated initially from cell culture assays. The target concentration is the concentration of active compound that is capable of achieving the therapeutic effects described herein, as measured using methods described herein or known in the art.

[0026] Therapeutically effective amounts for use in humans can also be determined from animal models using known methods. For example, a human dose can be formulated to achieve a concentration found to be effective in animals. The human dosage can be adjusted by monitoring the effectiveness of the compound and adjusting the dosage upward or downward, as described above. Adjusting the dosage to achieve maximum efficacy in humans based on the above and other methods is well within the capabilities of those skilled in the art.

[0027] Dosage can vary depending on the patient's requirements and the compound being utilized. In the context of the present invention, the dosage administered to a patient should be sufficient to produce a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the existence, nature, and extent of any adverse side effects. Determining the appropriate dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages that are less than the optimal dose of the compound. Thereafter, the dosage is increased by small increments until the optimal effect under the circumstances is reached.

[0028] Dosage amount and interval may be individually adjusted to provide levels of the administered compound effective for the particular clinical indication being treated, or in response to biomarkers or other correlates or surrogate endpoints of the disease, thereby providing a treatment regimen proportional to the severity of the individual's disease state.

[0029] A prophylactic or therapeutic treatment regimen preferably does not produce substantial toxicity and is effective in treating the clinical symptoms demonstrated in a particular patient. Determination of a dosing regimen is generally based on an evaluation of the active compound by considering factors such as compound potency, relative bioavailability, patient weight, the presence and severity of adverse side effects, the preferred mode of administration, and the toxicity profile of the selected agent.

[0030] The terms "halo" or "halogen" refer to one of the halogens in Group 17 of the periodic table. In particular, the term refers to fluorine, chlorine, bromine, and iodine. Preferably, the term refers to fluorine or chlorine.

[0031] C m~n Terms such as refer to groups having m to n carbon atoms.

[0032] "C 1~6 Terms such as "alkyl" refer to straight or branched hydrocarbon chains containing 1, 2, 3, 4, 5 or 6 carbon atoms, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. 1~4 "Alkyl" similarly refers to such groups containing up to four carbon atoms. Alkylene groups are divalent alkyl groups, which may also be straight or branched, and have two points of attachment to the remainder of the molecule. Furthermore, the alkylene group may correspond, for example, to one of the alkyl groups listed in this paragraph. For example, C 1~6 Alkylene can be -CH-, -CHCH-, -CHCH(CH)-, -CHCHCH-, or -CHCH(CH)CH-. Alkyl and alkylene groups can be unsubstituted or substituted with one or more substituents. Possible substituents are described herein. For example, substituents on an alkyl or alkylene group can be halogen (e.g., fluorine, chlorine, bromine, and iodine), -OH, C 1~4 It can be alkoxy, -NR'R''amino, where R' and R'' are independently H or alkyl. Other substituents of the alkyl group can alternatively be used.

[0033] For example, "C 1~4 "C" such as haloalkyl 1~6 The term "haloalkyl" refers to a hydrocarbon chain substituted with at least one halogen atom, independently selected at each occurrence, such as fluorine, chlorine, bromine, and iodine. The halogen atom may be located at any position on the hydrocarbon chain. For example, C 1~6Haloalkyl can refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl, such as 1-chloromethyl and 2-chloroethyl, trichloroethyl, such as 1,2,2-trichloroethyl and 2,2,2-trichloroethyl, fluoroethyl, such as 1-fluoromethyl and 2-fluoroethyl, trifluoroethyl, such as 1,2,2-trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl. Haloalkyl groups can be, for example, -CX, -CHX, -CHCX, -CHCHX, or -CX(CH)CH, where X is halo (e.g., F, Cl, Br, or I). Fluoroalkyl groups, i.e., hydrocarbon chains substituted with at least one fluorine atom (e.g., -CF, -CHF, -CHCF, or -CHCHF).

[0034] The term "heteroalkyl" refers to a stable straight- or branched-chain alkyl containing at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), wherein the nitrogen and sulfur atoms can be optionally oxidized, and the nitrogen heteroatom can be optionally quaternized. The heteroatom (e.g., N, S, Si, or P) can be placed at any interior position of the heteroalkyl group. The heteroalkyl is an acyclic group. A "2- to 8-membered heteroalkyl" refers to a heteroalkyl having a total of 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms and heteroatoms (e.g., O, N, P, Si, and S) present 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-CH2-S-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH=N-OCH3, and up to two to three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. The heteroalkyl moiety may contain one heteroatom (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain two optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain three optionally different heteroatoms (e.g., O, N, S, Si, or P). A heteroalkyl moiety can contain four optionally different heteroatoms (e.g., O, N, S, Si, or P).

[0035] "C 2~6 The term "alkenyl" includes branched or straight hydrocarbon chains containing at least one double bond and having 2, 3, 4, 5, or 6 carbon atoms. The double bond may exist as an E or Z isomer. The double bond may be in any reasonable position on the hydrocarbon chain. For example, "C 2~6"Alkenyl" can be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, and hexadienyl. Alkenylene groups are divalent alkenyl groups, which can also be straight or branched and have two points of attachment to the rest of the molecule. Furthermore, alkenylene groups can correspond, for example, to one of the alkenyl groups listed in this paragraph. For example, alkenylene can be -CH=CH-, -CHCH=CH-, -CH(CH)CH=CH-, or -CHCH=CH-. Alkenyl and alkenylene groups can be unsubstituted or substituted with one or more substituents. Possible substituents are described herein. For example, the substituents can be those described above as substituents for alkyl groups.

[0036] "C 2~6 The term "alkynyl" includes branched or straight hydrocarbon chains containing at least one triple bond and having 2, 3, 4, 5, or 6 carbon atoms. The triple bond can be located at any reasonable position on the hydrocarbon chain. For example, "C 2~6 "Alkynyl" can be ethynyl, propynyl, butynyl, pentynyl, and hexynyl. Alkynylene groups are divalent alkynyl groups, which can also be straight or branched and have two points of attachment to the remainder of the molecule. Furthermore, alkynylene groups can correspond, for example, to one of the alkynyl groups listed in this paragraph. For example, alkylene can be -C≡C, -CHC≡C-, -CHC≡CCH-, -CH(CH)CH≡C-, or -CHC≡CCH. Alkynyl and alkynylene groups can be unsubstituted or substituted with one or more substituents. Possible substituents are described herein. For example, the substituents can be those described above as substituents for alkyl groups.

[0037] "C 3~6The term "cycloalkyl" includes saturated hydrocarbon ring systems containing 3, 4, 5, or 6 carbon atoms. For example, "C3-C6 cycloalkyl" can be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo[2.1.1 hexane], or bicyclo[1.1.1]pentane. Suitably, "C3-C6 cycloalkyl" can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0038] The terms "heterocyclyl," "heterocyclic," or "heterocycle" include non-aromatic saturated or partially saturated monocyclic heterocyclic ring systems or fused, bridged, or spiro bicyclic heterocyclic ring systems. Monocyclic heterocycles can contain about 3 to 12 (preferably 3 to 7) ring atoms with 1 to 5 (preferably 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur in the ring. Bicyclic heterocycles can contain 7 to 12 member atoms in the ring. Bicyclic heterocycles can be fused, spiro, or bridged ring systems. Heterocyclyl groups can be 3- to 12-membered, e.g., 3- to 9- (e.g., 3- to 7-) membered non-aromatic monocyclic or bicyclic saturated or partially saturated groups containing 1, 2, or 3 heteroatoms independently selected from O, S, and N in the ring system (in other words, 1, 2, or 3 atoms forming the ring system are selected from O, S, and N). Partially saturated means that the ring may contain one or two double bonds. This applies particularly to 5- to 7-membered monocyclic rings. The double bond is typically between two carbon atoms, but may also be between a carbon atom and a nitrogen atom. Bicyclic ring systems may be spiro-fused, i.e., the rings are bonded to each other by a single carbon atom; closely fused, i.e., bonded to each other by two adjacent carbon atoms and / or nitrogen atoms; or shared bridgeheads, i.e., bonded to each other by two non-adjacent carbon atoms or nitrogen atoms (bridged ring systems). Examples of heterocyclic groups include cyclic ethers and substituted cyclic ethers such as oxiranyl, oxetanyl, tetrahydrofuranyl, and dioxanyl. Heterocycles containing 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, etc. Exemplary sulfur-containing heterocycles include tetrahydrothienyl, dihydro-1,3-dithiol, tetrahydro-2H-thiopyran, and hexahydrothiepin.Other heterocycles include dihydrooxathiolyl, tetrahydrooxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydroxazinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing sulfur, sulfur-oxidized heterocycles containing SO or SO are also included. Examples include sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl, such as tetrahydrothienyl, 1,1-dioxide, and thiomorpholinyl 1,1-dioxide. Suitable values ​​for heterocyclyl groups containing one or two oxo (=O) are, for example, 2oxopyrrolidinyl, 2-oxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3- to 7-membered heterocyclyl containing one, two or three heteroatoms selected from nitrogen, oxygen or sulfur, such as azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1,1-dioxide, thiomorpholinyl, thiomorpholinyl 1,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As will be appreciated by those skilled in the art, any heterocyclic ring can be attached to another group through any suitable atom, such as through a carbon atom or a nitrogen atom. For example, the terms "piperidino" or "morpholino" refer to a piperidin-1-yl or morpholin-4-yl ring attached through the ring nitrogen.

[0039] The term "bridged ring system" includes ring systems in which two rings share three or more atoms. See, for example, Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 131-133, 1992. Preferably, the bridge is formed between two non-adjacent carbon or nitrogen atoms of the ring system. The bridge connecting the bridgehead atoms can be a bond or can include 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.

[0040] The term "spiro bicyclic ring system" includes ring systems in which two rings share one common spiro carbon atom, i.e., a heterocyclic ring is linked to a further carbocyclic or heterocyclic ring by a single common spiro carbon atom. Examples of spirocyclic 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]heptane, 2-azaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]octane, 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.

[0041] "Heterocyclyl-C m~n "Alkyl" is C m~n Heterocyclyl-C includes a heterocyclyl group covalently linked to an alkylene group, both of which are defined herein. m~n The alkyl group is attached to the rest of the molecule through a carbon atom in the alkylene group. m~n alkyl" group, "heteroaryl-C m~n "Alkyl" groups and "cycloalkyl-C m~n An "alkyl" group is similarly defined.

[0042] -C replaced by -NRR m~n C substituted by alkyl and OR m~n "Alkyl" is similar to C m~n refers to an -NRR'' or -OR'' group covalently attached to an alkyl group, which group is attached to the remainder of the molecule through a carbon atom in the alkylene group.

[0043] When applied to a substituent as a whole, the term "aromatic" includes monocyclic or polycyclic ring systems having 4n+2 electrons in a conjugated pi system within the ring or ring system, where all atoms contributing to the conjugated pi system lie in the same plane.

[0044] Terms such as "aryl" include aromatic hydrocarbon ring systems. The ring system has 4n+2 electrons in a conjugated π system within the ring, with all atoms contributing to the conjugated π system lying in the same plane. An aryl can be a single ring or multiple rings (preferably 1 to 3 rings) that are fused or covalently bonded together (i.e., a fused-ring aryl). A fused-ring aryl refers to multiple rings that are fused together, where at least one of the fused rings is an aryl ring. For example, "aryl" refers to C 6~12 It may be aryl, preferably phenyl or naphthyl. The aryl system itself may be substituted by other groups. The term "aryl" also encompasses partially aromatic bicyclic or polycyclic ring systems, in which at least one ring is aromatic and one or more of the other rings are non-aromatic, saturated or partially saturated.

[0045] The term "heteroaryl" includes aromatic monocyclic or bicyclic rings incorporating one or more (e.g., 1 to 4, particularly 1, 2, or 3) heteroatoms selected from nitrogen, oxygen, or sulfur. The ring or ring system has 4n+2 electrons in a conjugated π system in which all atoms contributing to the conjugated π system are in the same plane.

[0046] Examples of heteroaryl groups are monocyclic and bicyclic groups containing 5 to 12 ring members, more typically 5 to 10 ring members. Heteroaryl groups can be, for example, 5- or 6-membered monocyclic or 9- or 10-membered rings. For example, bicyclic structures formed from fused 5- and 6-membered rings or two fused 6-membered rings are also referred to as "fused bicyclic heteroaryls." Bicyclic heteroaryl groups can be vicinal fused; that is, the rings are connected to each other by two adjacent carbon and / or nitrogen atoms. Each ring can contain up to about four heteroatoms, typically selected from nitrogen, sulfur, and oxygen. Typically, heteroaryl rings contain up to four, e.g., up to three, heteroatoms, more typically up to two, e.g., one, heteroatom. In one embodiment, heteroaryl groups contain at least one ring nitrogen atom. The nitrogen atom of a heteroaryl ring can be basic, as in the case of an imidazole or pyridine, or non-basic, as in the case of an indole or pyrrole nitrogen. Generally, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents on the ring, will be four or less.

[0047] 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, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, and carbazolyl. phenyl, phenazinyl, benzoisoquinolinyl, pyridopyrazinyl, thieno[2,3-b]furanyl, 2H-furo[3,2-b]pyranyl, 1H-pyrazolo[4,3-d]oxazolyl, 4H-imidazo[4,5-d]thiazolyl, pyrazino[2,3-d]pyridazinyl, imidazo[2,1-b]thiazolyl, imidazo[1,2-b][1,2,4]thiazinyl, imidazo[1,2-a]pyridine, imidazo[1,2-a]pyrazine, imidazo[1,2-a]pyrimidine, imidazo[1,2-b]pyridazine, thiazolo[1,5-a]pyridine, [1,2,3]triazolo[1,5-a]pyridine. Examples of heteroaryl groups containing 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.

[0048] The term "heteroaryl" also encompasses partially aromatic bicyclic or polycyclic ring systems, in which at least one ring is aromatic and one or more of the other rings are non-aromatic, saturated, or partially saturated, provided that at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, or sulfur. Partially aromatic heteroaryl bicyclic ring systems may be vicinal fused, i.e., the rings are joined to each other by two adjacent carbon and / or nitrogen atoms. Partially aromatic heteroaryl groups include, for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1,2,3,4-tetrahydroquinolinyl, dihydrobenzothienyl, dihydrobenzofuranyl, 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-2H-pyrido[3,2-b][1,4]oxazinyl.

[0049] Examples of 5-membered heteroaryl groups include, but are not limited to, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxathiazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, thiazolyl, and tetrazolyl groups.

[0050] Examples of 6-membered heteroaryl groups include, but are not limited to, pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl, and triazinyl.

[0051] Specific examples of bicyclic heteroaryl groups containing a 6-membered ring fused to a 5-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.

[0052] Specific examples of bicyclic heteroaryl groups containing two fused 6-membered rings include, but are not limited to, quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolidinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, and pteridinyl groups.

[0053] The terms "oxo" or "=O" as used herein refer to an oxygen that is double bonded to a carbon atom.

[0054] The term "optionally substituted" includes groups, structures, or molecules that are substituted as well as those that are not substituted.

[0055] When an optional substituent is selected from "one or more" groups, this definition includes all substituents selected from one of the specified groups or substituents selected from two or more of the specified groups, which can be the same or different, and it is understood that these can be the same or different. For example, "one or more optional substituents" can refer to one, or two, or three substituents (e.g., one substituent or two substituents).

[0056] When a moiety is substituted, it can be substituted at any point on the moiety, where chemically possible and consistent with valence requirements. A moiety can be substituted with one or more substituents, for example, one, two, three, or four substituents, optionally with one or two substituents per group. When two or more substituents are present, the substituents can be the same or different.

[0057] Substituents are present only at chemically feasible positions, and those skilled in the art can determine (either experimentally or theoretically) whether a substitution is chemically feasible without undue effort. For example, when ring A is pyridyl, the ring nitrogen is unsubstituted and the ring can be optionally substituted with up to four substituents; similarly, when ring A is pyrimidyl, the ring can be optionally substituted with up to three substituents.

[0058] Ortho, meta, and para substitution are terms well understood in the art. For the avoidance of doubt, "ortho" substitution refers to a single group, e.g., a fluoro group in the examples below, or a bond, where the other part of the molecule is [ka] A substitution pattern in which adjacent carbons have substituents, whether or not they terminate in a substituted group. [ka]

[0059] A "meta" substitution is a substitution pattern in which two substituents are present on one carbon atom removed from each other, i.e., there is a single carbon atom between the substituted carbons. In other words, a substituent is present on a second atom separated from an atom bearing another substituent. For example, the following group is meta-substituted: [ka]

[0060] "Para" substitution is a substitution pattern in which two substituents are on carbons that are two carbons removed from each other, i.e., there are two carbon atoms between the substituted carbons. In other words, a substituent is on a third atom that is separated from an atom that bears another substituent. For example, the following group is para-substituted: [ka]

[0061] When ring A contains an NH group, the NH group is 4 Replaced by NR 4 Similarly, ring B contains an NH group, and the NH group can be 10 Replaced by NR 10 can be obtained.

[0062] Reference to an -NRR' group forming a 4- to 6-membered heterocyclyl refers to R and R' together with the nitrogen atom to which they are attached to form the 4- to 6-membered heterocyclyl group. For example, -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 teeth, [ka] Similarly, the -NRR' group in a substituent may form a carbonyl-linked 4-6 membered heterocyclyl. For example, the -C(O)NRR' group may form [ka] and an -NRR' group within a substituent such as -OC(O)NRR', -SO2NRR' or -NRC(O)NRR' can similarly form a 4- to 6-membered heterocyclyl within such substituent.

[0063] [ka] A bond terminating in, i.e., [ka] represents that the bond is attached to another atom not shown in the structure. Bonds that terminate within the ring structure and bonds that do not terminate on an atom of the ring structure represent that they may be attached to any atom of the ring structure as allowed by valence, unless otherwise stated herein. For example, if ring A is [ka] If [ka] The aryl group may be linked to the remainder of the compound by either a five-membered or six-membered ring, including, but not limited to:

[0064] The various functional groups and substituents comprising the compounds of the present invention are typically selected so that the molecular weight of the compound does not exceed 1000. More generally, the molecular weight of the compound is less than 750, for example, less than 700, or less than 650, or less than 600, or less than 550.

[0065] A suitable or preferred feature of any compound of the invention may also be a suitable feature of any other embodiment.

[0066] The present invention contemplates pharmaceutically acceptable salts of the compounds of the present invention. These can include acid addition and base salts of the compounds. These can be acid addition or base salts of the compounds.

[0067] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, 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 / hydrogenphosphate / dihydrogenphosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate.

[0068] Suitable base salts are formed from bases that form non-toxic salts.Examples include aluminum salt, arginine salt, benzathine salt, calcium salt, chlorine salt, diethylamine salt, diolamine salt, glycine salt, lysine salt, magnesium salt, meglumine salt, olamine salt, potassium salt, sodium salt, tromethamine salt and zinc salt.Half-salts of acids and bases can also be formed, such as hemisulfate and hemicalcium salt.For a summary of suitable salts, refer to "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0069] Pharmaceutically acceptable salts of the compounds of the present invention can be prepared, for example, by the following method: (i) reacting a compound of the present invention with a desired acid or base; (ii) removing an acid- or base-labeled protecting group from a suitable precursor of a compound of the invention or opening a suitable cyclic precursor, such as a lactone or lactam, using a desired acid or base; or (iii) converting one salt of a compound of the invention into another in reaction with an appropriate acid or base or by a suitable ion exchange column; It may be prepared with one or more of the following:

[0070] These methods are typically carried out in solution. The resulting salts may be precipitated and recovered by filtration or may be recovered by evaporation of the solvent. The degree of ionization of the resulting salts may vary from completely ionized to nearly non-ionized.

[0071] 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 each other are termed "diastereoisomers," and those that are non-superimposable mirror images of each other are termed "enantiomers." When a compound has an asymmetric center, for example, it can be bonded to four different groups and form a pair of enantiomers. Enantiomers can be characterized by the absolute configuration of their asymmetric center and described according to the Cahn and Prelog R- and S-arrangements or in the manner in which the molecule rotates about the plane of polarized light, and are termed dextrorotatory or levorotatory (i.e., (+)- or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture." When a compound of the present invention has two or more stereocenters, any combination of (R) and (S) stereoisomers is contemplated. Combinations of (R) and (S) stereoisomers can result in diastereomeric mixtures or single diastereoisomers. The compounds of the present invention can exist as a single stereoisomer or as a mixture of stereoisomers, such as racemic mixtures and other enantiomeric and diastereomeric mixtures. When the mixture is a mixture of enantiomers, the enantiomeric excess can be any of those disclosed above. When the compound is a single stereoisomer, the compound contains other diastereoisomers or enantiomers as impurities. Thus, a single stereoisomer does not necessarily have 100% enantiomeric excess (ee) or diastereomeric excess (de), but can have an ee or de of at least about 85%, e.g., at least 90%, at least 95%, at least 99%, or at least 99.9%.

[0072] The compounds of the present invention may have one or more asymmetric centers, and therefore, such compounds may be produced as individual (R) or (S) stereoisomers or mixtures thereof. Unless otherwise indicated, the description or name of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures thereof, racemic or otherwise. Methods for the determination of stereochemistry and separation of stereoisomers are well known in the art, for example, by synthesis from optically active starting materials or by resolution of racemates (see Chapter 4 of "Advanced Organic Chemistry," 4th edition, J. March, John Wiley and Sons, New York, 2001). Some of the compounds of the present invention may have geometric isomeric centers (E and Z isomers). It is understood that the present invention encompasses all optical, diastereomeric and geometric isomers, and mixtures thereof.

[0073] Z / E (eg, cis / trans) isomers can be separated by conventional techniques well known to those skilled in the art, such as, for example, chromatography and fractional crystallization.

[0074] Conventional methods for preparing / isolating individual enantiomers, if desired, include chiral synthesis from suitable optically pure precursors, followed by separation of the racemate (or racemate or derivative salts) using, for example, chiral high-performance liquid chromatography (HPLC). Thus, chiral compounds of the present invention (and their chiral precursors) can 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 0-50% by weight, typically 2-20% by weight, of isopropanol, and, for certain instances, 0-5% by weight of an alkylamine, e.g., 0.1% diethylamine. Depending on the concentration of the eluent, an enriched mixture can be obtained.

[0075] Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound, such as, for example, an alcohol, or, if the compound of the invention contains an acidic or basic moiety, with a base or acid, such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture can be separated by chromatography and / or fractional crystallization, and one or both of the diastereoisomers can be converted to the corresponding pure enantiomer by means well known to those skilled in the art.

[0076] When any racemate crystallizes, two different types of crystals are possible: the first type is the racemate (true racemate) mentioned above, where a uniform form of crystal is produced, which contains both enantiomers in equimolar amounts; the second type is a racemic mixture or conglomerate, where two forms of crystal are produced in equimolar amounts, each containing a single enantiomer.

[0077] Although any crystalline forms present in a racemic mixture have identical physical properties, they may have different physical properties compared to the true racemate. Racemic mixtures can be separated by conventional techniques known to those skilled in the art. See, for example, "Stereochemistry of Organic Compounds" by EL Eliel and SH Wilen (Wiley, 1994).

[0078] The compounds and salts described herein may be isotopically labeled (or "radiolabeled"). Thus, one or more atoms are replaced with 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: 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 Cl, 123 I, 25 I, 32 P, 35 The radionuclide used will vary depending on the particular application of the radiolabeled derivative. For example, for in vitro competitive assays, 3 H or 14 C is often useful. For radiographic applications, 11 C or 18 F is often useful. In some embodiments, the radionuclide is 3 H. In some embodiments, the radionuclide is 14 C. In some embodiments, the radionuclide is 11 C. In some embodiments, the radionuclide is 18 It's F.

[0079] Isotopically labeled compounds may generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described, substituting an appropriate isotopically labeled reagent for a previously used non-labeled reagent.

[0080] 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 specific metabolites, thereby improving safety and tolerability. It should be understood that the present invention encompasses deuterated derivatives of the compounds of formula (I). As used herein, the term deuterated derivative refers to a compound of the present invention in which at least one hydrogen atom is replaced with deuterium at a specific position. Thus, in the compounds of the present invention, one or more hydrogen atoms are optionally replaced with deuterium. For example, C 1~4 One or more hydrogen atoms in the alkyl group are replaced with deuterium, resulting in deuterated C 1~4 It can form an alkyl group. For example, R 1 , R 3 , R 4 or R 10is methyl, the present invention also encompasses -CD, -CHD, and -CHD. Similarly, when R 2 can be D.

[0081] Certain compounds of the present invention can exist in solvated as well as unsolvated forms, such as, for example, hydrated forms, and it will be understood that the present invention encompasses all such solvated forms.

[0082] It will also be understood that certain compounds of the present invention may exhibit polymorphism and that the present invention encompasses all such forms.

[0083] The compounds of the present invention may exist in several different tautomeric forms, and reference to a compound of the present invention includes all such forms. For the avoidance of doubt, where a compound may exist in one of several tautomeric forms and only one is specifically described or shown, all others are nevertheless encompassed by the compounds of the present invention. Examples of tautomers include keto, enol, and enolate forms, such as the following tautomeric pairs: keto / enol (described below), imine / enamine, amide / iminoalcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / acintro. [ka]

[0084] The in vivo effects of the compounds of the invention may be exerted in part by one or more metabolic products formed in the human or animal body following administration of the compounds of the invention.

[0085] It should be further understood that suitable pharmaceutically acceptable prodrugs of the compounds of formula (I) also form an aspect of the present invention. Thus, the compounds of the present invention encompass prodrug forms of the compounds, and the compounds of the present invention may be administered in prodrug form (e.g., compounds that are broken down in the human or animal body to release a compound of the present invention). Prodrugs may be used to alter the physical and / or pharmacokinetic properties of the compounds of the present invention. Prodrugs can be formed when the compounds of the present invention contain a suitable group or substituent that can be attached to a suitable modifying group. Examples of prodrugs include biocleavable ester derivatives that can be formed at a carboxy or hydroxy group of the compounds of the present invention, and biocleavable amide derivatives that can be formed at a carboxy or amino group of the compounds of the present invention.

[0086] The present invention therefore includes such compounds of the invention as defined herein when made available by organic synthesis and when made available in the human or animal body by cleavage of their prodrugs. Thus, the present invention includes these compounds of formula (I) produced by organic synthetic means, and also such compounds produced in the human or animal body by metabolism of precursor compounds that are compounds of formula (I), which may be synthetically produced compounds or metabolically produced compounds.

[0087] Suitable pharmaceutically acceptable prodrugs of the compounds of the present invention are those that, based on sound medical judgment, are free from undesired pharmacological activity and are free from undue toxicity and are suitable for administration to the human or animal body.

[0088] Various prodrug mechanisms are described, for example, in the following references: a)Methods in Enzymology,Vol.42,p.309-396,edited by K.Widder,et al.(Academic Press,1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c)A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.Bundgaard,Chapter 5 "Design and Application of Pro-drugs", by H.Bundgaard p.113-191(1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N.Kakeya,et al.,Chem.Pharm.Bull.,32,692(1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, ACSSymposium Series, Volume 14; and h) E. Roche (editor), "Bioreversible Carriers in Drug Design", Pergamon Press, 1987 is described in.

[0089] Suitable pharmaceutically acceptable prodrugs of the compounds of formula (I) having a carboxy group are, for example, biocleavable esters thereof. Biocleavable esters of the compounds of the present invention containing a carboxy group are, for example, pharmaceutically acceptable esters that are cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters for carboxy include C methyl, ethyl, and tert-butyl. 1~6 C alkyl esters, methoxymethyl esters, etc. 1~6 C such as alkoxymethyl ester and pivaloyloxymethyl ester 1~6 C alkanoyloxymethyl esters, 3-phthalidyl esters, cyclopentylcarbonyloxymethyl and 1-cyclohexylcarbonyloxyethyl esters3~8 Cycloalkylcarbonyloxy-C 1~6 esters, 2-oxo-1,3-dioxolenylmethyl esters such as 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl ester, and C esters such as methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl esters. 1~6 Alkoxycarbonyloxy-C 1~6 Alkyl esters are included.

[0090] Suitable pharmaceutically acceptable prodrugs of the compounds of the present invention having a hydroxy group are, for example, biocleavable esters or ethers thereof. The biocleavable esters or ethers of the compounds of the present invention containing a hydroxy group are, for example, pharmaceutically acceptable esters or ethers that are cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester-forming groups for the hydroxy group include inorganic esters such as phosphate esters (including phosphoramido cyclic esters). Further suitable pharmaceutically acceptable ester-forming groups for the hydroxy group include C esters such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 1~10 Alkanoyl group, ethoxycarbonyl group, N,N-(C 1~6 C such as alkyl) 2-carbamoyl group, 2-dialkylaminoacetyl group, and 2-carboxyacetyl group 1~10 Examples of ring substituents in the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C 1~4 Suitable pharmaceutically acceptable ether-forming groups for a hydroxy group include α-acyloxyalkyl groups such as acetoxymethyl and pivaloyloxymethyl.

[0091] Suitable pharmaceutically acceptable prodrugs of compounds of the invention having a carboxy group include, for example, biocleavable amides thereof, e.g., amides formed with amines such as ammonia, C methylamines, etc. 1~4 alkylamines, dimethylamine, N-ethyl-N-methylamine, or diethylamine (C 1~4 C alkyl)2 amine, 2-methoxyethylamine, etc. 1~4 Alkoxy-C 2~4 Phenyl-C such as alkylamines and benzylamines 1~4 Alkylamines and amino acids such as glycine or their esters.

[0092] Suitable pharmaceutically acceptable prodrugs of the compounds of the invention having an amino group are, for example, biocleavable amide or carbamate derivatives thereof. Suitable pharmaceutically acceptable amides derived from an amino group include, for example, C acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. 1~10 Included are amides formed with alkanoyl groups. Ring substituents in phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl, and 4-(C 1~4 Suitable pharmaceutically acceptable carbamates derived from an amino group include, for example, acyloxyalkoxycarbonyl and benzyloxycarbonyl groups.

[0093] Throughout the description and claims of this specification, the words "comprise" and "contain" and variations thereof mean "including, but not limited to," and are not intended to (and do not) exclude other moieties, additives, components, integers, or steps. Throughout the description and claims of this invention, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification should be understood as contemplating both the plural and the singular unless the context otherwise requires.

[0094] It should be understood that any feature, integer, property, compound, chemical moiety, or group described in connection with a particular aspect, embodiment, or example of the invention applies to any other aspect, embodiment, or example, unless inconsistent. All features disclosed in this specification (including any accompanying claims, abstract, and drawings) and / or steps of any method or process so disclosed may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any of the foregoing embodiments. The invention also applies to any novel or any novel combination of features disclosed in this specification (including any accompanying claims, abstract, and drawings) or any novel or any novel combination of steps of any method or process so disclosed.

[0095] The reader's attention is directed to all articles and documents in connection with this application that have been filed contemporaneously with or prior to this application and that are open to public inspection hereof, the contents of all such articles and documents being incorporated herein by reference in their entirety.

[0096] compound The following paragraphs are applicable to compounds of the present invention, including compounds of Formulas (I)-(XXXVIc).

[0097] In certain embodiments, the compound of formula (I) has formula (Ia): [ka] or a pharmaceutically acceptable salt thereof.

[0098] In certain embodiments, the compound of formula (I) has formula (II): [ka] (In the formula, R 3 , L, ring A and ring B are as defined for formula (I). or a pharmaceutically acceptable salt thereof.

[0099] In certain embodiments, the compound of formula (II) has the formula (IIa): [ka] or a pharmaceutically acceptable salt thereof.

[0100] In certain embodiments, the compound of formula (I) has formula (III): [ka] (In the formula, Each R 4a Halo, -CN, -NO2, =O, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 6 and -SO2NR 5 R 6 are independently selected from Said C 1~6 Alkyl, C 1~6 Heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 7 is replaced by a is an integer from 0 to 3, 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). or a pharmaceutically acceptable salt thereof.

[0101] In certain embodiments, the compound of formula (III) has the formula (IIIa): [ka] or a pharmaceutically acceptable salt thereof.

[0102] In certain embodiments, the compound of formula (I) has formula (IV): [ka] (In the formula, Each R 4a Halo, -CN, -NO2, =O, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 6 and -SO2NR 5 R 6are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 7 is replaced by a is an integer from 0 to 3, R 3 , R 5 , R 6 , R 7 , Q 1 , L, x and ring B are as defined for formula (I). or a pharmaceutically acceptable salt thereof.

[0103] In certain embodiments, the compound of formula (IV) has the formula (IVa): [ka] or a pharmaceutically acceptable salt thereof.

[0104] In certain embodiments, the compound of formula (I) has formula (V): [ka] (In the formula, Each R 4a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 6 and -SO2NR 5 R 6 are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 7 is replaced by 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). or a pharmaceutically acceptable salt thereof.

[0105] In certain embodiments, the compound of formula (V) has the formula (Va): [ka] or a pharmaceutically acceptable salt thereof.

[0106] In certain embodiments, the compound of formula (I) has formula (VI): [ka] (In the formula, Each R 4a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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)OR5 , -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 SO2R 6 and -SO2NR 5 R 6 are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 7 is replaced by R 3 , R 5 , R 6 , R 7 , Q 1 , L, x and ring B are as defined for formula (I). or a pharmaceutically acceptable salt thereof.

[0107] In certain embodiments, the compound of formula (VI) has formula (VIa): [ka] or a pharmaceutically acceptable salt thereof.

[0108] In certain embodiments, the compound of formula (I) has formula (VII): [ka] (In the formula, Each R 4a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 6 and -SO2NR 5 R 6 are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 7 is replaced by a is an integer from 0 to 5, 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). or a pharmaceutically acceptable salt thereof.

[0109] In certain embodiments, the compound of formula (VII) has formula (VIIa): [ka] or a pharmaceutically acceptable salt thereof.

[0110] In certain embodiments, the compound of formula (I) has formula (VIII): [ka] (In the formula, Each R 4a Halo, -CN, -NO2, C 1~6Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 6 and -SO2NR 5 R 6 are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 7 is replaced by a is an integer from 0 to 5, R 3 , R 5 , R 6 , R 7 , Q 1 , L, x and ring B are as defined for formula (I). or a pharmaceutically acceptable salt thereof.

[0111] In certain embodiments, the compound of formula (VIII) has the formula (VIIIa): [ka] or a pharmaceutically acceptable salt thereof.

[0112] In certain embodiments, the compound of formula (I) has formula (IX): [ka] (In the formula, Each R 4a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 6 and -SO2NR 5 R 6 are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 7 is replaced by a is an integer from 0 to 3, Each R 4b H, halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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)OR5 , -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 SO2R 6 and -SO2NR 5 R 6 are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 Alkynyl is a group consisting of one or more R 7 and optionally substituted by 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). or a pharmaceutically acceptable salt thereof.

[0113] In certain embodiments, the compound of formula (IX) has formula (IXa): [ka] or a pharmaceutically acceptable salt thereof.

[0114] In certain embodiments, the compound of formula (I) has formula (X): [ka] (In the formula, Each R 4a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 6 and -SO2NR 5 R 6 are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 7 is replaced by a is an integer from 0 to 3, Each R 4b H, halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 6 and -SO2NR 5 R 6are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 Alkynyl is a group consisting of one or more R 7 and optionally substituted by R 3 , R 5 , R 6 , R 7 , Q 1 , L, x and ring B are as defined for formula (I). or a pharmaceutically acceptable salt thereof.

[0115] In certain embodiments, the compound of formula (X) has the formula (Xa): [ka] or a pharmaceutically acceptable salt thereof.

[0116] In certain embodiments, the compound of formula (I) has formula (XI): [ka] (In the formula, Each R 4a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 R6 , -NR 5 SO2R 6 and -SO2NR 5 R 6 are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 7 is replaced by a is an integer from 0 to 4, 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). or a pharmaceutically acceptable salt thereof.

[0117] In certain embodiments, the compound of formula (XI) has formula (XIa): [ka] or a pharmaceutically acceptable salt thereof.

[0118] In certain embodiments, the compound of formula (I) has formula (XII): [ka] (In the formula, Each R 4a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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)OR5 , -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 SO2R 6 and -SO2NR 5 R 6 are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 7 is replaced by a is an integer from 0 to 4, R 3 , R 5 , R 6 , R 7 , Q 1 , L, x and ring B are as defined for formula (I). or a pharmaceutically acceptable salt thereof.

[0119] In certain embodiments, the compound of formula (XII) has formula (XIIa): [ka] or a pharmaceutically acceptable salt thereof.

[0120] In certain embodiments, the compound of formula (I) has formula (XIII): [ka] (In the formula, Each R 4a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 6 and -SO2NR 5 R 6 are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 7 is replaced by a is an integer from 0 to 3, 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). or a pharmaceutically acceptable salt thereof.

[0121] In certain embodiments, the compound of formula (XIII) has formula (XIIIa): [ka] or a pharmaceutically acceptable salt thereof.

[0122] In certain embodiments, the compound of formula (I) has formula (XIV): [ka] (In the formula, Each R4a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 6 and -SO2NR 5 R 6 are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 7 is replaced by a is an integer from 0 to 3, R 3 , R 5 , R 6 , R 7 , Q 1 , L, x and ring B are as defined for formula (I). or a pharmaceutically acceptable salt thereof.

[0123] In certain embodiments, the compound of formula (XIV) has formula (XIVa): [ka] or a pharmaceutically acceptable salt thereof.

[0124] In certain embodiments, the compound of formula (I) has formula (XV): [ka] (In the formula, Each R 4a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 6 and -SO2NR 5 R 6 are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 7 is replaced by a is an integer from 0 to 3, 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). or a pharmaceutically acceptable salt thereof.

[0125] In certain embodiments, the compound of formula (XV) has formula (XVa): [ka] or a pharmaceutically acceptable salt thereof.

[0126] In certain embodiments, the compound of formula (I) has formula (XVI): [ka] (In the formula, Each R 4a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 6 and -SO2NR 5 R 6 are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 7 is replaced by a is an integer from 0 to 3, R 3 , R 5 , R 6 , R 7 , Q1 , L, x and ring B are as defined for formula (I). or a pharmaceutically acceptable salt thereof.

[0127] In certain embodiments, the compound of formula (XVI) has formula (XIVa): [ka] or a pharmaceutically acceptable salt thereof.

[0128] In certain embodiments, the compound of formula (I) has formula (XVII): [ka] (In the formula, Ring D is phenyl or a 6-membered heteroaryl containing 1, 2, or 3 ring nitrogen atoms; Ring E is a 5-membered heteroaryl containing one or more (e.g., 1 to 4) ring nitrogen atoms and optionally 1 or 2 ring heteroatoms selected from O and S; and Rings D and E together form a 9-membered fused bicyclic heteroaryl ring; L is bonded to an atom of ring D, Each R 4a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 , -NR5 SO2R 6 and -SO2NR 5 R 6 are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 7 is replaced by a is an integer from 0 to 4, 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). or a pharmaceutically acceptable salt thereof.

[0129] In certain embodiments, the compound of formula (XVII) has formula (XVIIa): [ka] or a pharmaceutically acceptable salt thereof.

[0130] In certain embodiments, the compound of formula (XVII) has formula (XVIII): [ka] or a pharmaceutically acceptable salt thereof.

[0131] In certain embodiments, the compound of formula (XVIII) has formula (XVIIIa): [ka] or a pharmaceutically acceptable salt thereof.

[0132] In certain embodiments, the compound of formula (I) has formula (XIX): [ka] (In the formula, Ring F is a 5-membered heteroaryl containing one or more (e.g., 1 to 3) ring nitrogen atoms and optionally 1 or 2 ring heteroatoms selected from O and S; Ring G is a phenyl or 6-membered heteroaryl containing 1, 2, or 3 ring nitrogen atoms; and Rings F and G together form a 9-membered fused bicyclic heteroaryl ring; L is bonded to an atom of ring F, Each R 4a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 6 and -SO2NR 5 R 6 are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 7 is replaced by a is an integer from 0 to 4, 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). or a pharmaceutically acceptable salt thereof.

[0133] In certain embodiments, the compound of formula (XIX) has formula (XIXa): [ka] or a pharmaceutically acceptable salt thereof.

[0134] In certain embodiments, the compound of formula (XIX) has formula (XX): [ka] or a pharmaceutically acceptable salt thereof.

[0135] In certain embodiments, the compound of formula (XX) has the formula (XXa): [ka] or a pharmaceutically acceptable salt thereof.

[0136] In certain embodiments, the compound of formula (I) has formula (XXI): [ka] (In the formula, X3 is N or CR 4a is selected from Each R 4a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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)OR5 , -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 SO2R 6 and -SO2NR 5 R 6 are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 7 is replaced by 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). or a pharmaceutically acceptable salt thereof.

[0137] In certain embodiments, the compound of formula (XXI) has formula (XXIa): [ka] or a pharmaceutically acceptable salt thereof.

[0138] In certain embodiments, the compound of formula (I) has formula (XXII): [ka] (In the formula, X3 is N or CR 4a is selected from Each R 4a H, halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 membered heteroalkyl, C 2~6 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 SO2R 6 and -SO2NR 5 R 6 are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 7 is replaced by R 3 , R 5 , R 6 , R 7 , Q 1 , L, x and ring B are as defined for formula (I). or a pharmaceutically acceptable salt thereof.

[0139] In certain embodiments, the compound of formula (XXII) has the formula (XXIIa): [ka] or a pharmaceutically acceptable salt thereof.

[0140] In certain embodiments, the compound of formula (I) has formula (XXIII): [ka] (wherein a is an integer of 0 to 4, and R 1, R 2 , R 3 , R 4 , L and ring B are as defined for formula (I). or a pharmaceutically acceptable salt thereof.

[0141] In certain embodiments, the compound of formula (XIII) has the formula (XXIIIa): [ka] or a pharmaceutically acceptable salt thereof.

[0142] In certain embodiments, the compound of formula (I) has formula (XXIV): [ka] (wherein a is an integer of 0 to 4, and R 3 , R 4 , L and ring B are as defined for formula (I). or a pharmaceutically acceptable salt thereof.

[0143] In certain embodiments, the compound of formula (XXIV) has the formula (XXIVa): [ka] or a pharmaceutically acceptable salt thereof.

[0144] In certain embodiments, the compound of formula (I) has formula (XXV): [ka] (In the formula, Each R 10a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, -OR 10A , -S(O) x R 10A , -NR10A 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 SO2R 10B and -SO2NR 10A R 10B are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 11 is replaced by c is an integer from 0 to 5, R 1 , R 2 , R 3 , R 10A , R 10B , R 11 , L, x and ring A are as defined for formula (I). or a pharmaceutically acceptable salt thereof.

[0145] In certain embodiments, the compound of formula (XXV) has the formula (XXVa): [ka] or a pharmaceutically acceptable salt thereof.

[0146] In certain embodiments, the compound of formula (I) has formula (XXVI): [ka] (In the formula, Each R 10a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6Haloalkyl, 2-8 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 SO2R 10B and -SO2NR 10A R 10B are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 11 is replaced by c is an integer from 0 to 5, R 3 , R 10A , R 10B , R 11 , L, x and ring A are as defined for formula (I). or a pharmaceutically acceptable salt thereof.

[0147] In certain embodiments, the compound of formula (XXVI) has formula (XXVIa): [ka] or a pharmaceutically acceptable salt thereof.

[0148] In certain embodiments, the compound of formula (I) has formula (XXVII): [ka] (In the formula, R 10a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 10B and -SO2NR 10A R 10B is selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 11 is replaced by R 1 , R 2 , R 3 , R 10A , R 10B , R 11 , L, x and ring A are as defined for formula (I). or a pharmaceutically acceptable salt thereof.

[0149] In certain embodiments, the compound of formula (XXVII) has the formula (XXVIIa): [ka] or a pharmaceutically acceptable salt thereof.

[0150] In certain embodiments, the compound of formula (I) has formula (XXVIII): [ka] (In the formula, R 10a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 10B and -SO2NR 10A R 10B is selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 11 is replaced by R 3 , R 10A , R 10B , R 11 , L, x and ring A are as defined for formula (I). or a pharmaceutically acceptable salt thereof.

[0151] In certain embodiments, the compound of formula (XXVIII) has the formula (XXVIIIa): [ka] or a pharmaceutically acceptable salt thereof.

[0152] In certain embodiments, the compound of formula (I) has formula (XXIX): [ka] (In the formula, Each R 10a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 10B and -SO2NR 10A R 10B are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 11 is replaced by c is an integer from 0 to 3, R 1 , R 2 , R 3 , R 10A , R 10B , R 11 , L, x and ring A are as defined for formula (I). or a pharmaceutically acceptable salt thereof.

[0153] In certain embodiments, the compound of formula (I) has the formula (XXX): [ka] (In the formula, Each R 10a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 10B and -SO2NR 10A R 10B are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 11 is replaced by c is an integer from 0 to 3, R 3 , R 10A , R 10B , R 11 , L, x and ring A are as defined for formula (I). or a pharmaceutically acceptable salt thereof.

[0154] In certain embodiments, the compound of formula (XXX) has formula (XXXa): [ka] or a pharmaceutically acceptable salt thereof.

[0155] In certain embodiments, the compound of formula (I) has the formula (XXXI): [ka] (In the formula, Each R 4a Halo, -CN, -NO2, =O, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 6 and -SO2NR 5 R 6 are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 7 is replaced by a is an integer from 0 to 3, Each R 10a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl, C 2~6Alkynyl, -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 SO2R 10B and -SO2NR 10A R 10B are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 Alkynyl is a group consisting of one or more R 11 and optionally substituted by c is an integer from 0 to 5, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 10A , R 10B , R 11 , Q 1 , L and x are as defined for formula (I). or a pharmaceutically acceptable salt thereof.

[0156] In certain embodiments, the compound of formula (XXXI) has formula (XXXIa): [ka] or a pharmaceutically acceptable salt thereof.

[0157] In certain embodiments, the compound of formula (XXXI) has formula (XXXIb): [ka] or a pharmaceutically acceptable salt thereof.

[0158] In certain embodiments, the compound of formula (XXXI) has formula (XXXIc): [ka] or a pharmaceutically acceptable salt thereof.

[0159] In certain embodiments, the compound of formula (I) has formula (XXXII): [ka] (In the formula, Each R 4a Halo, -CN, -NO2, =O, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 6 and -SO2NR 5 R 6 are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 7is replaced by a is an integer from 0 to 4, Each R 10a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 10B and -SO2NR 10A R 10B are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 Alkynyl is a group consisting of one or more R 11 and optionally substituted by c is an integer from 0 to 5, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 10A , R 10B , R 11 , Q 1 , L and x are as defined for formula (I). or a pharmaceutically acceptable salt thereof.

[0160] In certain embodiments, the compound of formula (XXXII) has the formula (XXXIIa): [ka] or a pharmaceutically acceptable salt thereof.

[0161] In certain embodiments, the compound of formula (XXXII) has formula (XXXIIb): [ka] or a pharmaceutically acceptable salt thereof.

[0162] In certain embodiments, the compound of formula (XXXII) has formula (XXXIIc): [ka] or a pharmaceutically acceptable salt thereof.

[0163] In certain embodiments, the compound of formula (I) has formula (XXXIII): [ka] (In the formula, X 3 is N or CR 4a is selected from R 4a Halo, -CN, -NO2, =O, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 6 and -SO2NR 5 R 6 are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 7 is replaced by Each R 10a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 10B and -SO2NR 10A R 10B are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 Alkynyl is a group consisting of one or more R 11 and optionally substituted by c is an integer from 0 to 5, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R10A , R 10B , R 11 , Q 1 , L and x are as defined for formula (I). or a pharmaceutically acceptable salt thereof.

[0164] In certain embodiments, the compound of formula (XXXIII) has the formula (XXXIIIa): [ka] or a pharmaceutically acceptable salt thereof.

[0165] In certain embodiments, the compound of formula (XXXIII) has formula (XXXIIIb): [ka] or a pharmaceutically acceptable salt thereof.

[0166] In certain embodiments, the compound of formula (XXXIII) has formula (XXXIIIc): [ka] or a pharmaceutically acceptable salt thereof.

[0167] In certain embodiments, the compound of formula (I) has formula (XXXIV): [ka] (In the formula, X 3 is N or CR 4a is selected from R 4a Halo, -CN, -NO2, =O, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, Q 1 , -OR 5 , -S(O) x R5 , -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 SO2R 6 and -SO2NR 5 R 6 are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 7 is replaced by R 10a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 10B and -SO2NR 10A R 10B is selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C2~6 Alkenyl and C 2~6 Alkynyl is a group consisting of one or more R 11 and optionally substituted by R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 10A , R 10B , R 11 , Q 1 , L and x are as defined for formula (I). or a pharmaceutically acceptable salt thereof.

[0168] In certain embodiments, the compound of formula (XXXIV) has formula (XXXIVa): [ka] or a pharmaceutically acceptable salt thereof.

[0169] In certain embodiments, the compound of formula (XXXIV) has formula (XXXIVb): [ka] or a pharmaceutically acceptable salt thereof.

[0170] In certain embodiments, the compound of formula (XXXIV) has formula (XXXIVc): [ka] or a pharmaceutically acceptable salt thereof.

[0171] In certain embodiments, the compound of formula (I) has the formula (XXXV): [ka] (In the formula, Each R 4a Halo, -CN, -NO2, =O, C 1~6 Alkyl, C1~6 Haloalkyl, 2-8 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 SO2R 6 and -SO2NR 5 R 6 are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 7 is replaced by a is an integer from 0 to 3, Each R 10a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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)NR10A R 10B , -NR 10A SO2R 10B and -SO2NR 10A R 10B are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 Alkynyl is a group consisting of one or more R 11 and optionally substituted by c is an integer from 0 to 5, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 10A , R 10B , R 11 , Q 1 , L and x are as defined for formula (I). or a pharmaceutically acceptable salt thereof.

[0172] In certain embodiments, the compound of formula (XXXV) has the formula (XXXVa): [ka] or a pharmaceutically acceptable salt thereof.

[0173] In certain embodiments, the compound of formula (XXXV) has formula (XXXVb): [ka] or a pharmaceutically acceptable salt thereof.

[0174] In certain embodiments, the compound of formula (XXXV) has the formula (XXXVc): [ka] or a pharmaceutically acceptable salt thereof.

[0175] In certain embodiments, the compound of formula (I) has the formula (XXXVI): [ka] (In the formula, Each R 4a Halo, -CN, -NO2, =O, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 6 and -SO2NR 5 R 6 are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 7 is replaced by a is an integer from 0 to 3, Each R 10a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 10B and -SO2NR 10A R 10B are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 Alkynyl is a group consisting of one or more R 11 and optionally substituted by c is an integer from 0 to 5, R 1 , R 2 , R 3 , R 5 , R 6 , R 7 , R 10A , R 10B , R 11 , Q 1 , L and x are as defined for formula (I). or a pharmaceutically acceptable salt thereof.

[0176] In certain embodiments, the compound of formula (XXXVI) has formula (XXXVIa): [ka] or a pharmaceutically acceptable salt thereof.

[0177] In certain embodiments, the compound of formula (XXXVI) has formula (XXXVIb): [ka] or a pharmaceutically acceptable salt thereof.

[0178] In certain embodiments, the compound of formula (XXXVI) has formula (XXXVIc): [ka] or a pharmaceutically acceptable salt thereof.

[0179] In certain embodiments, the compounds of the present invention include, for example, compounds of Formula (I)-(XXXVIc) or pharmaceutically acceptable salts thereof, and unless otherwise specified, ring A, ring B, R 1 , R 2 , R 3 , R 4 , R 4a , R 4b , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 7A , R 7B , R 9A , R 9B , R 9C , R 9D , R 10A , R 10B , R 11A , R 11B , Q 1 , Q 2 , L, a, c, and x have the meanings defined above or any of the meanings described in any of the following numbered paragraphs 1 to 223. These descriptions are independent and interchangeable. In other words, any feature described in any one of the following descriptions may be combined (where chemically possible) with features described in one or more of the other descriptions below. In particular, when a compound is exemplified or shown herein, any two or more of the following descriptions describing the characteristics of this compound may be combined, expressed to any degree of generality, to describe the subject matter contemplated herein as forming part of the disclosure of the present invention. 1.R 1 is C 1~6 Alkyl, C 3~6 Cycloalkyl and C 3~6 Cycloalkyl-C 1~6alkyl-, and R 1 is substituted with at least one fluorine atom. 2.R 1 is C 1~3 Alkyl, C 3~6 Cycloalkyl and C 3~6 Cycloalkyl-C 1~3 alkyl-, and R 1 is substituted with at least one fluorine atom. 3.R 1 is C 1~6 Alkyl and C 3~6 cycloalkyl, R 1 is substituted with at least one fluorine atom. 4.R 1 is C 1~3 Alkyl and C 3~6 cycloalkyl, R 1 is substituted with at least one fluorine atom. 5.R 1 is C 1~6 alkyl, and R 1 is substituted with at least one fluorine atom. 6.R 1 is C 1~3 alkyl, and R 1 is substituted with at least one fluorine atom. 7.R 1 is selected from ethyl and methyl, the ethyl and methyl being substituted by at least one fluorine. 8.R 1 is ethyl, which is substituted with at least one fluorine. 9.R 1 is selected from —CH2F, —CHF2 and —CF3. 10.R 1 is -CH2F. 11.R 1 is -CHF2. 12.R 1 is -CF3. 13.R 2 is H, C 1~3Alkyl and C 1~3 haloalkyl. 14.R 2 is H and C 1~3 alkyl. 15.R 2 is C 1~3 It is alkyl. 16.R 2 is methyl. 17.R 2 are H and D. R 2 can be D. R 2 can also be H. 18.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. 19.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. 1 and R 2 can form, together with the carbon atom to which they are attached, a cyclobutyl group substituted by one fluorine. 20.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. 1 and R 2 can form, together with the carbon atom to which they are attached, a cyclopropyl group substituted by one fluorine. 21.R 1 is as defined in any of 1 to 12, and R 2 is methyl. 22.R 1 is as defined in any of 1 to 12, and R 2 is H. 23.R 3 is C 1~3 Alkyl and C 1~3 haloalkyl. 24.R 3 is C 1~2 Alkyl and C 1~2 haloalkyl. 25.R 3 is methyl optionally substituted with one to three halo groups. 26.R 3 is ethyl optionally substituted with 1 to 5 halo groups. 27.R 3 is as defined in any one of 23 to 26, and said halo is fluoro. 28.R 3 is C 1~3 It is alkyl. 29.R 3 is selected from methyl, ethyl and 2-fluoroethyl. 30.R 3 is methyl. 31.R 3 is ethyl. 32.R 3 is 2-fluoroethyl. 33.R 3 is as defined in any of 23 to 32, and R 3 One or more hydrogen atoms in R are deuterium. 3 may be selected from methyl, -CD3, ethyl and 2-fluoroethyl. 34.R 3 -CD 3 is. 35.L is a bond and C 1~2 alkyl. 36. L is selected from a bond, -CH2- and -CH2CH2-. 37. L is selected from a bond and -CH2-. 38.L is -CH2-. 39.L is a bond. 40. Ring A is selected from the group consisting of 4- to 7-membered heterocyclyl, 5- to 12-membered heteroaryl, and C 6~10 aryl. 41. Ring A is selected from 4- to 7-membered heterocyclyl and 5- to 12-membered heteroaryl. 42. Ring A is selected from the group consisting of 5- and 6-membered heterocyclyl, 5- to 10-membered heteroaryl, and C 6~8 aryl. 43. Ring A is selected from 5- or 6-membered heterocyclyl and 5- to 10-membered heteroaryl. 44. Ring A is selected from 5- or 6-membered heterocyclyl, 5- to 9-membered heteroaryl, and phenyl. 45. Ring A is selected from 5- or 6-membered heterocyclyl and 5- to 9-membered heteroaryl. 46. ​​Ring A is selected from 5-10 membered heteroaryl and phenyl. 47. Ring A is a 5- to 10-membered heteroaryl. 48. Ring A is a 6- to 10-membered heteroaryl. 49. Ring A is selected from 5-membered heteroaryl, 6-membered heteroaryl, 9-membered heteroaryl and phenyl. 50. Ring A is a monocyclic 5- or 6-membered heteroaryl or an 8- to 10-membered fused bicyclic heteroaryl, and ring A has at least one (e.g., 1 to 4) ring nitrogen atom. Therefore, ring A can be a monocyclic 6-membered heteroaryl or a 9- to 10-membered fused bicyclic heteroaryl, and ring A can have at least one (e.g., 1 to 4) ring nitrogen atom. 51. Ring A is a monocyclic 5- or 6-membered heteroaryl or a 9- to 10-membered fused bicyclic heteroaryl, and ring A has 1 to 4 ring nitrogen atoms. Therefore, ring A can be a monocyclic 6-membered heteroaryl or a 9-membered fused bicyclic heteroaryl, and ring A can have 1 to 4 ring nitrogen atoms. 52. Ring A is a 5-membered heteroaryl. 53. Ring A is a 5-membered heteroaryl, said heteroaryl of Ring A having one ring nitrogen atom and optionally one or more ring heteroatoms (e.g., 1, 2, or 3) selected from O, S, and N. 54. Ring A is a 5-membered heteroaryl, said heteroaryl having 1, 2, 3 or 4 ring nitrogen atoms. 55. Ring A is a 6-membered heteroaryl. 56. Ring A is a monocyclic 6-membered heteroaryl, said heteroaryl having 1, 2 or 3 (eg, 1 or 2) ring nitrogen atoms. 57. Ring A is a 9-membered heteroaryl. 58. Ring A is a 9-membered fused bicyclic heteroaryl, said heteroaryl having 1, 2, 3 or 4 ring nitrogen atoms. 59. Ring A is a 9-membered bicyclic heteroaryl, wherein the heteroaryl has 1, 2, 3, or 4 (e.g., 1, 2, or 3) ring nitrogen atoms and is a 6-membered ring fused to a 5-membered ring, and the 9-membered bicyclic heteroaryl is bonded to group L by a ring atom of the 6-membered ring. The 5-membered and 6-membered rings forming the 9-membered bicyclic heteroaryl can both be heteroaryl rings. 60. Ring A is a 9-membered bicyclic heteroaryl, wherein the heteroaryl has 1, 2, 3, or 4 (e.g., 1, 2, or 3) ring nitrogen atoms and is a 6-membered ring fused to a 5-membered ring, and the 9-membered bicyclic heteroaryl is bonded to group L by a ring atom of the 5-membered ring. The 5-membered and 6-membered rings forming the 9-membered bicyclic heteroaryl can both be heteroaryl rings. 61. Ring A is selected from a 6-membered heteroaryl and a 9-membered bicyclic heteroaryl, wherein the 6-membered heteroaryl has 1, 2, or 3 (e.g., 1 or 2) ring nitrogen atoms, and the 9-membered bicyclic heteroaryl has 1, 2, 3, or 4 (e.g., 1, 2, or 3) ring nitrogen atoms. The 5-membered and 6-membered rings forming the 9-membered bicyclic heteroaryl can both be heteroaryl rings. 62. Ring A is phenyl. 63. Ring A is a 4- to 6-membered heterocyclyl. 64. Ring A is a 5- or 6-membered heterocyclyl containing at least one ring oxygen atom and optionally one further ring heteroatom selected from S and N. 65. Ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, and tetrahydropyranyl. 66. Ring A is selected from pyrrolidinyl, tetrahydrofuranyl, piperidinyl and tetrahydropyranyl. 67. Ring A is tetrahydropyranyl. 68. Ring A is selected from furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl. 69. Ring A is furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl or the structure: [ka] wherein ring A is optionally selected from compounds of the formula: 4 has been replaced by 70. Ring A is thienyl, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, or tetrahydropyranyl. [ka] and ring A is optionally selected from one or more R 4 has been replaced by 71. Ring A is [ka] and ring A is selected from one or more R 4 is optionally substituted by 72. Ring A is a 9-membered fused bicyclic heteroaryl containing at least one ring nitrogen atom, and Ring A is one or more R 4 Therefore, ring A is substituted by [ka] and ring A is optionally selected from one or more R 4Ring A can be bonded to L through a 5-membered ring atom of ring A. Ring A can be bonded to L through a 6-membered ring atom of ring A. 73. Ring A is [ka] and ring A is selected from one or more R 4 Ring A can be bonded to L via a carbon atom of the benzo ring of Ring A. 74. Ring A is [ka] and ring A is selected from one or more R 4 is optionally substituted by 75. Ring A is [ka] and ring A is selected from one or more R 4 is optionally substituted by 76. Ring A is [ka] and ring A is selected from one or more R 4 is optionally substituted by 77. Ring A is [ka] and ring A is selected from one or more R 4 is optionally substituted by 78. Ring A is [ka] and ring A is selected from one or more R 4 is optionally substituted by 79. Ring A is [ka] and ring A is selected from one or more R 4 is optionally substituted by 80. Ring A is [ka] and ring A is selected from one or more R 4 is optionally substituted by 81. Ring A is selected from thienyl and thiazolyl, and Ring A is selected from one or more R 4 is optionally substituted by 82. Ring A is [ka] [ka] and ring A is selected from one or more R 4 is optionally substituted by 83. Ring A is [ka] and ring A is selected from one or more R 4 is optionally substituted by 84. Ring A is [ka] and ring A is selected from one or more R 4 is optionally substituted by 85. Ring A is [ka] is selected from. 86. Ring A is [ka] is selected from. 87. Ring A is [ka] is selected from. Therefore, ring A is [ka] It may be selected from: 88. Ring A is [ka] is selected from. 89. Ring A is [ka] is selected from. 90. Ring A is [ka] is selected from. 91. Ring A is as defined in any of 40 to 84 and contains one or more R 4 has been replaced by 92. Ring A is as defined in any of 40 to 84, and one or two R 4 has been replaced by 93. Ring A is as defined in any of 40-84 and is unsubstituted. 94. Ring A is [ka] and ring A is selected from one or more R 4 is optionally substituted by 95. Ring A is [ka] is selected from. 96. Ring A is [ka] is selected from. 97. Ring A is [ka] is selected from. 98. Ring A is [ka] is selected from. 99. Ring A is as defined in any of 95 to 98, and, if chemically possible, y is an integer from 0 to 10. 100. Ring A is as defined in any of 95 to 98, and, if chemically possible, y is an integer from 0 to 5. 101. Ring A is as defined in any of 95 to 98, and, if chemically possible, y is an integer from 0 to 3. 102. Ring A is as defined in any of 95 to 98, and y is 0. 103. Ring A is as defined in any of 95 to 98, and y is 1. 104. Ring A is as defined in any of 95 to 98, and y is 2. 105. Ring A as defined in any one of 40 to 104 contains an NH group, and said NH group is R 4 Replaced by NR 4 can be obtained. 106.Each R 4 Halo, -CN, -NO2, =O, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 6 and -SO2NR 5 R 6 are independently selected from 107.Each R 4 Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 6 and -SO2NR 5 R 6 are independently selected from each R 4 Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 6 and -SO2NR 5 R 6 may be independently selected from 108.Each R 4 Halo, -CN, =O, C 1~6 Alkyl, C 1~6 Haloalkyl, Q 1 , -OR 5 , -NR 5 R 6 , -C(O)R 5 , -C(O)OR 5 and -C(O)NR 5 R 6are independently selected from 109.Each R 4 Halo, -CN, C 1~4 Alkyl, C 1~4 Haloalkyl, -OR 5 , -NR 5 R 6 , -C(O)R 5 , -C(O)OR 5 and -C(O)NR 5 R 6 are independently selected from 110.Each R 4 Halo, -CN, =O, C 1~6 Alkyl, 2-8 membered heteroalkyl, Q 1 , -OR 5 , -NR 5 R 6 , -C(O)R 5 , -C(O)NR 5 R 6 and -NR 5 C(O)R 6 are independently selected from 111.Each R 4 Halo, -CN, C 1~4 Alkyl, -OR 5 , -NR 5 R 6 , -C(O)R 5 , -C(O)NR 5 R 6 and -NR 5 C(O)R 6 are independently selected from 112.Each R 4 Halo, -CN, C 1~4 Alkyl, -C(O)R 5 and -C(O)NR 5 R 6 are independently selected from 113.Each R 4 is halo (e.g., fluoro or chloro), -CN, C 1~3 Alkyl, -OC 1~3 Alkyl, -C(O)C 1~3 Alkyl, -C(O)NH2, -C(O)NH(C 1~3 alkyl) and -C(O)N(C 1~3alkyl)2. 114.Each R 4 is halo (e.g., fluoro or chloro), -CN, C 1~3 Alkyl and -OC 1~3 alkyl. Therefore, each R 4 Halo, -CN and C 1~3 alkyl. Thus, each R 4 may be independently selected from fluoro, chloro, —CN, methyl, and methoxy. For example, each R 4 may be independently selected from fluoro, chloro, —CN, and methyl. 115.Each R 4 is as defined in any one of 106 to 111, and 1~6 The alkyl or 2- to 8-membered heteroalkyl may be one or more R 7 has been replaced by 116.R 5 and R 6 is H, C 1~6 Alkyl and Q 1 are each independently selected from 117.R 5 and R 6 is H, C 1~3 Alkyl and Q 1 are each independently selected from 118.R 5 and R 6 is H and C 1~3 alkyl. 119.R 5 and R 6 is as defined in 116-118, and said alkyl is one or more R 8 has been replaced by 120.R 7 and R 8 is -C(O)R 7A , -OC(O)R 7A , -C(O)OR 7A , -NR 7A C(O)R 7B and -C(O)NR 7AR 7B are each independently selected from 121.R 7 and R 8 Halo, -CN, -OR 7A , -NR 7A R 7B and Q 2 are each independently selected from 122.R 7 and R 8 , halo, -OR 7A and Q 2 are each independently selected from 123.Q 1 and Q 2 is C 3~6 are each independently selected from cycloalkyl and 4- to 7-membered heterocyclyl. 124.Q 1 and Q 2 are each independently 4- to 6-membered heterocyclyl. 125.Q 1 and Q 2 are each independently selected from oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, and dihydropyranyl. 126.Q 1 and Q 2 are each independently selected from phenyl and 5- or 6-membered heteroaryl. 127.Q 1 and Q 2 is as defined in either 123 or 126, and Q 1 and Q 2 is one or more R 9 has been replaced by 128.Each R 9 Halo, =O, -CN, -NO2, C 1~4 Alkyl, C 1~4 Haloalkyl, -OR 9A and -NR 9A R 9B are independently selected from 129.R 9 is as defined in 128, and1~4 Alkyl is a group that can be substituted with halo, -CN, -OR 9C , -NR 9C R 9D and -SO2R 9C is substituted by one or two substituents selected from: 130.R 7A , R 7B , R 9A , R 9B , R 9C and R 9D In each occurrence, H and C 1~4 alkyl. 131.R 7A , R 7B , R 9A , R 9B , R 9C and R 9D is, at each occurrence, independently selected from H, methyl and ethyl. 132.R 7A , R 7B , R 9A , R 9B , R 9C and R 9D is, at each occurrence, independently selected from H and methyl. 133.Each R 4 teeth, [ka] are independently selected from 134.R 4 or R 4a are independently selected from F, Cl, -CN, methyl, methoxy, -NH, -NH(Me), -NH(Et), -N(Me), -C(O)Me, -C(O)NH, -C(O)NH(Me), -C(O)N(Me), -C(O)OMe, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, tetrahydropyranyl, and dihydropyranyl. 135.Each R 4 or R 4aare independently selected from F, Cl, —CN, methyl, methoxy, —NH, —NH(Me), —NH(Et), —N(Me), —C(O)Me, —C(O)NH, —C(O)NH(Me), —C(O)N(Me), —C(O)OMe. 136.Each R 4 or R 4a are independently selected from F, —CN, methyl, —C(O)Me, —C(O)NH, —C(O)NH(Me), —C(O)N(Me) 137.Each R 4 or R 4a is halo (e.g., fluoro), -CN and C 1~3 alkyl (e.g., methyl). 4 may be independently selected from fluoro, —CN, and methyl. 138. Ring A is [ka] is selected from. 139. Ring A is [ka] is selected from. 140. Ring A is [ka] is selected from. 141. Ring A is [ka] is selected from. 142. Ring A is [ka] [ka] is selected from. 143. Ring A is [ka] [ka] [ka] is selected from. 144. Ring A is [ka] Therefore, ring A is selected from [ka] Therefore, ring A can be [ka] Therefore, ring A can be [ka] Therefore, ring A can be [ka] Therefore, ring A can be [ka] Therefore, ring A can be [ka] It is possible that: 145.a is an integer between 0 and 5. 146.a is an integer between 0 and 3. 147.a is 3. 148.a is 2. 149.a is 1. 150.a is 0. 151.x is 0. 152.x is 1. 153.x is 2. 154.Each R 4a and R 4b Halo, -CN, -NO2, =O, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 6 and -SO2NR 5 R 6 Therefore, each R 4a and R 4b Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 6 and -SO2NR 5 R 6 may be independently selected from 155.Each R 4a and R 4b Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, -OR 5 , -S(O) x R 5 , -NR 5 R 6 , -C(O)R5 , -OC(O)R 5 , -C(O)OR 5 , -NR 5 C(O)R 6 , -C(O)NR 5 R 6 , -NR 5 SO2R 6 and -SO2NR 5 R 6 are independently selected from 156.Each R 4a and R 4b Halo, -CN, =O, C 1~6 Alkyl, C 1~6 Haloalkyl, Q 1 , -OR 5 , -NR 5 R 6 , -C(O)R 5 , -C(O)OR 5 and -C(O)NR 5 R 6 are independently selected from 157.Each R 4a and R 4b Halo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, Q 1 , -OR 5 , -NR 5 R 6 , -C(O)R 5 , -C(O)OR 5 and -C(O)NR 5 R 6 are independently selected from 158.Each R 4a and R 4b Halo, -CN, =O, C 1~6 Alkyl, Q 1 , -OR 5 , -NR 5 R 6 , -C(O)R 5 and -NR 5 C(O)R 6 are each independently selected from 159.Each R 4a and R 4b is halo (e.g., fluoro or chloro), -CN, C 1~3Alkyl, -OC 1~3 Alkyl, -C(O)C 1~3 Alkyl, -C(O)NH2, -C(O)NH(C 1~3 alkyl) and -C(O)N(C 1~3 alkyl)2. 160.Each R 4a or R 4b is halo (e.g., fluoro), -CN and C 1~3 alkyl (eg, methyl). 161.R 4a or R 4b is as defined in any one of 154 to 158, and 1~6 Alkyl is one or more R 7 has been replaced by 162. Ring B is selected from phenyl or 6-membered heteroaryl. 163. Ring B is a 6-membered heteroaryl. 164. Ring B is a 5-membered heteroaryl. 165. Ring B is selected from furanyl, thienyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, phenyl, pyridyl, pyrimidinyl and pyrazinyl. 166. Ring B is selected from furanyl, thienyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, phenyl, pyrimidinyl and pyrazinyl. 167. Ring B is selected from furanyl, pyrazolyl, oxazolyl, isoxazolyl, and phenyl. 168. Ring B is furanyl. 169. Ring B is pyrazolyl. 170. Ring B is oxazolyl. 171. Ring B is isoxazolyl. 172. Ring B is phenyl. 173. Ring B is as defined in any of 162 to 172, and is substituted with one or more R 10 has been replaced by 174. Ring B is [ka] is selected from. 175. Ring B is [ka] is selected from. 176. Ring B is [ka] is selected from. 177. Ring B is [ka] is selected from. 178. Ring B is [ka] is. 179. Ring B is as defined in any of 174 to 178, and, if chemically possible, z is an integer from 0 to 5. Thus, ring B is as defined in any of 174 to 178, and z can be 0, 1, or 2. Ring B is as defined in any of 174 to 178, and z can be 1 or 2. 180. Ring B is as defined in any of 174 to 178, and z is 2. 181. Ring B is as defined in any of 174 to 178, and z is 1. 182. Ring B is as defined in any of 174 to 178, and z is 0. 183. Ring B is [ka] is selected from. 184. Ring B is [ka] Ring B is selected from [ka] It is possible that: 185. Ring B is halo and C 1~3 one or two R selected from haloalkyl 10 Thus, Ring B can be 4-fluorophenyl or 4-trifluoromethylphenyl. Ring B can be 4-fluorophenyl. Ring B can be 4-trifluoromethylphenyl. 186. Ring B is [ka] is selected from. 187. Ring B is [ka] is selected from. 188. Ring B is [ka] Therefore, ring B is selected from [ka] It may be selected from: Ring B as defined in any one of 189.162 to 176 contains an NH group, and said NH group is R 10 Replaced by NR 10 can be obtained. 190.Each R 10 and R 10a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, -OR 10A , -S(O) x R 10A and -NR 10A R 10B are independently selected from 191.Each R 10 and R10a is -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 SO2R 10B and -SO2NR 10A R 10B are independently selected from 192.Each R 10 and R 10a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, -OR 10A and -S(O) x R 10A are independently selected from 193.Each R 10 and R 10a Halo, -CN, -NO2, C 1~3 Alkyl, C 1~3 Haloalkyl, -OR 10A and -S(O) x R 10A are independently selected from 194.Each R 10 and R 10a Ha, Halo, C 1~3 Alkyl, C 1~3 Haloalkyl, -OC 1~3 Alkyl and -OC 1~3 haloalkyl. 195.Each R 10 and R 10a Halo and C 1~3 alkyl. 196.Each R 10 and R 10a are independently selected from halo, —CN, —NO 2 , methyl, CF 3 , —OH, —OMe, and —S(O) 2 Me. 197.Each R 10 and R10a are independently selected from fluoro, chloro, —CN, —NO 2 , methyl, CF 3 , —OH, —OMe, and —S(O) 2 Me. 198.Each R 10 and R 10a are independently selected from fluoro, chloro, methyl, —CF 3 , methoxy, —OCF 3 and —OCHF 2 . 199.Each R 10 and R 10a is independently selected from fluoro and methyl. 200.R 10 and R 10a is fluoro. 201.R 10 and R 10a is -CF3. 202.R 10 and R 10a is as defined in 190 and 192-195, and the alkyl is one or more R 11 has been replaced by 203.Each R 11 Halo, -CN, -OR 11A , -NR 11A R 11B and -SO2R 11A are independently selected from 204.Each R 11 Halo, -CN, -OR 11A and -NR 11A R 11B are independently selected from 205.Each R 11 Halo and -OR 11A are independently selected from 206.R 10A , R 10B , R 11A and R 11B In each occurrence, H and C 1~4 alkyl. 207.R 10A , R 10B , R 11A and R 11B is, at each occurrence, independently selected from H, methyl and ethyl. 208.R10A , R 10B , R 11A and R 11B is, at each occurrence, independently selected from H and methyl. 209.c is an integer between 0 and 5. 210.c is an integer between 0 and 4. 211.c is an integer between 0 and 3. 212.c is 3. 213.c is 2. 214.c is 1. 215.c is 0. 216. Any -NR in the substituent 5 R 6 , -NR 7A R 7B , -NR 9A R 9B , -NR 9C R 9D , -NR 10A R 10B and -NR 11A R 11B can form a four-membered heterocyclyl. 217. Any -NR in a substituent 5 R 6 , -NR 7A R 7B , -NR 9A R 9B , -NR 9C R 9D , -NR 10A R 10B and -NR 11A R 11B can form a 5-membered heterocyclyl. 218. Any -NR in a substituent 5 R 6 , -NR 7A R 7B , -NR 9A R 9B , -NR 9C R 9D , -NR 10A R 10B and -NR 11A R 11B can form a 6-membered heterocyclyl. 219. Any 4- to 6-membered heterocyclyl as defined in any of 216 to 218 is not limited to halo, ═O, C 1~4 Alkyl and C 1~4 and substituted by one or more substituents selected from haloalkyl. 220. Any 4- to 6-membered heterocyclyl as defined in any of 216 to 218 is not limited to halo, C 1~4 Alkyl and C 1~4 and substituted by one or more substituents selected from haloalkyl. Any 4- to 6-membered heterocyclyl as defined in any of 221.216 to 218 is substituted with halo and C 1~4 and substituted by one or more substituents selected from alkyl. 222.Formula: [ka] The basis of [ka] Therefore, the expression: [ka] The basis of [ka] It is possible that: 223.Formula: [ka] The basis of [ka] Therefore, the expression: [ka] The basis of [ka] It is possible that:

[0180] In one embodiment, the compound of Formula (I) is a compound of any of Formulas (I)-(XXXVIc), wherein L is a bond.

[0181] In one embodiment, the compound of Formula (I) is a compound of any of Formulas (I)-(XXXVIc), wherein L is -CH2-.

[0182] In one embodiment, the compound of Formula (I) is any compound of Formulas (I)-(XXXVIc), wherein L is a bond and R 3 is selected from methyl, ethyl and —CH2CH2F.

[0183] In one embodiment, the compound of Formula (I) is any compound of Formulas (I)-(XXXVIc), wherein L is a bond and R 3 is methyl or ethyl.

[0184] In certain embodiments, the compound is a compound according to any of Formulas (I), (Ia), (III), (IIIa), (V), (VII), (VIIa), (IX), (IXa), (XI), (XIa), (XIII), (XIIIa), (XV), (XVa), (XVII), (XVIIa), (XIX), (XIXa), (XXI), (XXIa), (XXIII), (XXIIIa), (XXV), (XXVa), (XXVII), (XXVIIa), (XXIX), (XXXI), (XXXII), (XXXIIa), (XXXIII), (XXXIIIa), (XXXIV), (XXXIVa), (XXXV), (XXXVa), (XXXVI), and (XXXVIa); 1 is selected from —CH2F, —CHF2 and —CF3.

[0185] Preferably, in this embodiment, R 2 is H. Preferably, in this embodiment, L is a bond and R 3 is selected from methyl, ethyl and —CH2CH2F.

[0186] In certain embodiments, a compound of formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X), (Xa), (XI), (XIa), (XII), (XIIa), (XIII), (XIIIa), (XIV), In any of compounds (XIVa), (XV), (XVa), (XVI), (XVIa), (XVII), (XVIIa), (XVIII), (XVIIIa), (XIX), (XIXa), (XX), (XXa), (XXI), (XXIa), (XXII), (XXIIa), (XXIII), (XXIIIa), (XXIV), and (XXIVa), L is a bond and R 2 (if present) is H and R 3 is selected from methyl, ethyl and -CH2CH2F, and ring B is as defined in any of 162 to 188.

[0187] In these embodiments, R 3 can be methyl or ethyl.

[0188] In these embodiments, R 3 can be methyl. In these embodiments, R 3 In these embodiments, R 3 can be -CH2CH2F.

[0189] In these embodiments, ring B is unsubstituted or contains one or two R 10 (or R where appropriate for each formula) 10a ) and each R 10 and R 10a can be independently as defined in any of 190-202. Thus, ring B can be unsubstituted or can contain one or two R 10 (or R where appropriate for each formula) 10a ) and each R 10 and R 10a Ha, Halo, C1~3 Alkyl, C 1~3 Haloalkyl, -OC 1~3 Alkyl and -OC 1~3 haloalkyl.

[0190] In these embodiments, ring B is unsubstituted phenyl or one or two R 10 (or R where appropriate for each formula) 10a phenyl substituted by phenyl, and each R 10 and R 10a can independently be as defined in any of 190-202. For example, each R 10 and R 10a Ha, Halo, C 1~3 Alkyl, C 1~3 Haloalkyl, -OC 1~3 Alkyl and -OC 1~3 haloalkyl.

[0191] In these embodiments, ring B is selected from one or two R 10 (or R where appropriate for each formula) 10a phenyl substituted by phenyl, and each R 10 and R 10a are independently as defined in any of 190-202; R 3 can be methyl or ethyl. For example, each R 10 and R 10a Ha, Halo, C 1~3 Alkyl, C 1~3 Haloalkyl, -OC 1~3 Alkyl and -OC 1~3 haloalkyl. Therefore, each R 10 and R 10a may be independently selected from fluoro, chloro, methyl, —CF 3 , methoxy, and —OCF 3 .

[0192] In certain embodiments, in any of the compounds of any of Formulas (I), (Ia), (II), (IIa), (XXV), (XXVa), (XXVI), (XXVIa), (XXVII), (XXVIIa), (XXVIII), (XXVIIIa), (XXIX), (XXIXa), (XXX), and (XXXa), L is a bond and R 2 (if present) is H and R 3 is selected from methyl, ethyl and -CH2CH2F, and ring A is as defined in any of 40 to 98.

[0193] In these embodiments, ring A contains one or more (e.g., one or two) R 4 (or R where appropriate for each formula) 4a ), and each R 4 or R 4a Halo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, -OR 5 , -NR 5 R 6 , -C(O)R 5 , -C(O)OR 5 and -C(O)NR 5 R 6 Thus, ring A can be independently selected from one or more (e.g., one or two) R 4 (or R where appropriate for each formula) 4a ), and each R 4 or R 4a can be independently selected from F, -Cl, -CN, methyl, methoxy, -NH, -NH(Me), -NH(Et), -N(Me)-C(O)Me, -C(O)NH, -C(O)NH(Me), -C(O)N(Me) and -C(O)OMe. Ring A can be independently selected from one or more (e.g., one or two) R 4 (or R where appropriate for each formula) 4a ), and each R 4 or R 4a may be independently selected from F, Cl, —CN, methyl and methoxy.

[0194] In these embodiments, R 3 can be methyl or ethyl. In these embodiments, R 3 can be methyl. In these embodiments, R 3 In these embodiments, R 3 can be -CH2CH2F.

[0195] In certain embodiments, in any of the compounds of Formula (I), (Ia), (II), (IIa), (XXV), (XXVa), (XXVI), (XXVIa), (XXVII), (XXVIIa), (XXVIII), (XXVIIIa), (XXIX), (XXIXa), (XXX), and (XXXa), L is a bond and R 2 (if present) is H and R 3 is selected from methyl, ethyl, and —CH2CH2F, and ring A is as defined in any of 138-144. In these embodiments, R 3 can be methyl or ethyl. In these embodiments, R 3 can be methyl. In these embodiments, R 3 In these embodiments, R 3 can be -CH2CH2F.

[0196] In certain embodiments, compounds of any of Formulae (I), (Ia), (II), (IIa), (XXV), (XXVa), (XXVI), (XXVIa), (XXVII), (XXVIIa), (XXVIII), (XXVIIIa), (XIX), (XIXa), (XXX), and (XXXa) are compounds wherein ring A has the structure: [ka] (In the formula, Y 1 , Y 2 , Y 3 and Y 4 is Y 1 , Y2 , Y 3 and Y 4 are each independently CH or N, with the proviso that no more than two of are N; t and u are each independently 0, 1, 2, or 3. is a non-cyclic compound of Optionally, the ring system may comprise one or more R 4 is replaced by R 4 is as defined for formula (I).

[0197] In certain embodiments, compounds of any of Formulae (I), (Ia), (II), (IIa), (XXV), (XXVa), (XXVI), (XXVIa), (XXVII), (XXVIIa), (XXVIII), (XXVIIIa), (XIX), (XIXa), (XXX), and (XXXa) are compounds wherein ring A is: [ka] and optionally the ring system is not a structure selected from one or more R 4 is replaced by R 4 is as defined for formula (I).

[0198] In certain embodiments, the compound is represented by formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X), (Xa), (XI), (XIa), (XII), (XIIa), (XIII), (XIIIa), (XIV), A compound according to any of (XIVa), (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 pyridyl.

[0199] In certain embodiments, the compound has formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X), (Xa), (XI), (XIa), (XII), (XIIa), (XIII), (XIIIa), (X IV), (XIVa), (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 [ka] isn't it.

[0200] In certain embodiments, the compound has formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X), (Xa), (XI), (XIa), (XII), (XIIa), (XIII), (XIIIa), (X IV), (XIVa), (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 [ka] isn't it.

[0201] In certain embodiments, the compound has formula (I), (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X), (Xa), (XI), (XIa), (XII), (XIIa), (XIII), (XIIIa), (X IV), (XIVa), (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 [ka] isn't it.

[0202] In certain embodiments, the compound is according to any of formulas (III), (IIIa), (IV), (IVa), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIII), (VIIIa), (IX), (IXa), (X), (Xa), (XI), (XIa), (XII), (XIIa), (XIII), (XIIIa), (XIV), (XIVa), (XV), (XVa), (XVI), (XVIa), (XVII), (XVIIa), (XVIII), (XVIIIa), (XIX), (XIXa), (XX), and (XXa), wherein each R 4a are independently as defined in any of 154-160.

[0203] Suitably, in these embodiments, L is a bond and R 2 (if present) is H and R 3 is selected from methyl, ethyl and —CH2CH2F. Suitably, in these embodiments, L is a bond and R 2 (if present) is H and R 3 is methyl. Suitably, in these embodiments, L is a bond and R 2(if present) is H and R 3 is ethyl. Preferably, in these embodiments, L is a bond and R 2 (if present) is H and R 3 is -CH2CH2F.

[0204] In certain embodiments, the compound is a compound according to any of formulas (XXV), (XXVa), (XXVI), (XXVIa), (XXVII), (XXVIIa), (XXVIII), (XXVIIIa), (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), and (XXXVIc); 10a are independently as defined in any of 190-201.

[0205] Suitably, in these embodiments, L is a bond and R 2 (if present) is H and R 3 is selected from methyl, ethyl and —CH2CH2F. Suitably, in these embodiments, L is a bond and R 2 (if present) is H and R 3 is methyl. Suitably, in these embodiments, L is a bond and R 2 (if present) is H and R 3 is ethyl. Preferably, in these embodiments, L is a bond and R 2 (if present) is H and R 3 is -CH2CH2F.

[0206] In certain embodiments, the compound is according to any of formulas (XXXI), (XXXIa), (XXXIb), (XXXIc), (XXXII), (XXXIIa), (XXXIIb), (XXXIIc), (XXXV), (XXXVa), (XXXVb), (XXXVc), (XXXVI), (XXXVIa), (XXXVIb), and (XXXVIc), wherein each R 4a is halo (e.g., fluoro or chloro), -CN, C 1~3 Alkyl, -OC 1~3 Alkyl, -C(O)C 1~3 Alkyl, -C(O)NH2, -C(O)NH(C 1~3 alkyl) and -C(O)N(C 1~3 alkyl)2; R 10a Ha, Halo, C 1~3 Alkyl, C 1~3 Haloalkyl, -OC 1~3 Alkyl and -OC 1~3 haloalkyl.

[0207] In this embodiment, each R 4a Halo, -CN and C 1~3 alkyl; R 10a Ha, Halo, C 1~3 Alkyl, C 1~3 Haloalkyl, -OC 1~3 Alkyl and -OC 1~3 haloalkyl.

[0208] In this embodiment, each R 4a is independently selected from fluoro, chloro, —CN, methyl, and —OMe; R 10a are independently selected from fluoro, chloro, methyl, —CF 3 , methoxy, —OCF 3 and —OCHF 2 .

[0209] Suitably, in these embodiments, L is a bond and R 2 (if present) is H and R 3is selected from methyl, ethyl and —CH2CH2F. Suitably, in these embodiments, L is a bond and R 2 (if present) is H and R 3 is methyl. Suitably, in these embodiments, L is a bond and R 2 (if present) is H and R 3 is ethyl. Preferably, in these embodiments, L is a bond and R 2 (if present) is H and R 3 is -CH2CH2F.

[0210] In certain embodiments, the compound is of formula (XXXII), (XXXIIa), (XXXIIb), or (XXXIIc), and is a group of the formula: [ka] teeth, [ka] In this embodiment, each R 10a may independently be as defined in any of 190-201.

[0211] Preferably, in these embodiments, each R 10a are independently selected from fluoro, chloro, methyl, —CF 3 , methoxy, —OCF 3 and —OCHF 2 .

[0212] Suitably, in these embodiments, L is a bond and R 2 (if present) is H and R 3 is selected from methyl, ethyl and —CH2CH2F.

[0213] Suitably, in these embodiments, L is a bond and R 2 (if present) is H and R 3 is selected from methyl, ethyl and —CH2CH2F. Suitably, in these embodiments, L is a bond and R 2(if present) is H and R 3 is methyl. Suitably, in these embodiments, L is a bond and R 2 (if present) is H and R 3 is ethyl. Preferably, in these embodiments, L is a bond and R 2 (if present) is H and R 3 is -CH2CH2F.

[0214] In certain embodiments, the compound is of formula (XXXII), (XXXIIa), (XXXIIb), or (XXXIIc), and is a group of the formula: [ka] teeth, [ka] In this embodiment, each R 10a may independently be as defined in any of 190-201.

[0215] Preferably, in these embodiments, each R 10a are independently selected from fluoro, chloro, methyl, —CF 3 , methoxy, —OCF 3 and —OCHF 2 .

[0216] Suitably, in these embodiments, L is a bond and R 2 (if present) is H and R 3 is selected from methyl, ethyl and —CH2CH2F. Suitably, in these embodiments, L is a bond and R 2 (if present) is H and R 3 is methyl. Suitably, in these embodiments, L is a bond and R 2 (if present) is H and R 3 is ethyl. Preferably, in these embodiments, L is a bond and R 2 (if present) is H and R 3 is -CH2CH2F.

[0217] In certain embodiments, the compound is of formula (XXI), (XXIa), (XII), (XIIa), (XXXIII), (XXXIIIa), (XXXIIIb), (XXXIIIc), (XXXIV), (XXXIVa), (XXXIVb), or (XXXIVc), and is a compound of formula: [ka] teeth, [ka] Selected from R 4a Halo, -CN, C 1~6 Alkyl, C 1~6 Haloalkyl, -OR 5 , -NR 5 R 6 , -C(O)R 5 , -C(O)OR 5 and -C(O)NR 5 R 6 Each R 10 (or R where appropriate for each formula) 10a ) are independently as defined in any of 190-201.

[0218] Preferably, in these embodiments, R 4a Halo, -CN and C 1~3 For example, R 4a can be selected from F, —CN and methyl.

[0219] Therefore, the basis of the formula: [ka] The basis of [ka] It may be selected from:

[0220] Therefore, the basis of the formula: [ka] teeth, [ka] It may be selected from:

[0221] Preferably, in these embodiments, the group of formula: [ka] teeth, [ka] is selected from Each R 10 (or R where appropriate for each formula) 10a ) is a halo, C 1~3 Alkyl, C 1~3 Haloalkyl, -OC 1~3 Alkyl and -OC 1~3 haloalkyl. Therefore, each R 10a may be independently selected from fluoro, chloro, methyl, —CF 3 , methoxy, and —OCF 3 .

[0222] Suitably, in these embodiments, L is a bond and R 2 (if present) is H and R 3 is selected from methyl, ethyl and —CH2CH2F. Suitably, in these embodiments, L is a bond and R 2 (if present) is H and R 3 is methyl. Suitably, in these embodiments, L is a bond and R 2 (if present) is H and R 3 is ethyl. Preferably, in these embodiments, L is a bond and R 2 (if present) is H and R 3 is -CH2CH2F.

[0223] In certain embodiments, the compound is of formula (I), (Ia), (II), (IIa), (XXV), (XXVa), (XXVI), (XXVIa), (XXVII), (XXVIIa), (XXVIII), (XXVIIIa), (XXIX), (XXX), and (XXXa), wherein ring A is [ka] and L is a bond.

[0224] Suitably, in these embodiments, L is a bond and R 2 (if present) is H and R 3 is selected from methyl, ethyl and —CH2CH2F. Suitably, in these embodiments, L is a bond and R 2 (if present) is H and R 3 is methyl. Suitably, in these embodiments, L is a bond and R 2 (if present) is H and R 3 is ethyl. Preferably, in these embodiments, L is a bond and R 2 (if present) is H and R 3 is -CH2CH2F.

[0225] In certain embodiments, the compound is of Formula (XVII), (XVIIa), (XVIII), or (XVIIIa), wherein Ring D is selected from benzene, pyridine, pyrimidine, pyridazine, and pyrazine; Ring E is selected from pyrrole, imidazole, pyrazole, triazole, and tetrazole; and the 9-membered fused bicyclic heteroaryl ring formed by Ring D and Ring E is bonded to L at a ring atom of Ring D.

[0226] In certain embodiments, the compound is of formula (XVII), (XVIIa), (XVIII) or (XVIIIa), and is a group of formula: [ka] teeth, [ka] each of which is selected from one, two, or three (e.g., one or two) R 4a and each R is optionally substituted by 4a are independently as defined in any of 154 to 160, and the 9-membered fused bicyclic heteroaryl ring formed by ring D and ring E is bonded to L at a ring atom of ring D.

[0227] In certain embodiments, the compound is of formula (XVII), (XVIIa), (XVIII) or (XVIIIa), and is a group of formula: [ka] teeth, [ka] wherein X and X are each independently N or C, with the proviso that at least one of X and X is N; ring E is a fused 5-membered heteroaryl containing at least one (e.g., 1, 2, or 3) ring nitrogen; and the 9-membered fused bicyclic heteroaryl ring formed by ring D and ring E is bonded to L at a ring atom of ring D.

[0228] Therefore, [ka] teeth, [ka] each of which is selected from one, two, or three (e.g., one or two) R 4a and each R is optionally substituted by 4a may be independently as defined in any of 154 to 160. For example, the 9-membered fused bicyclic heteroaryl ring formed by ring D and ring E may be [ka] each of which is selected from one, two, or three (e.g., one or two) R 4a and each R is optionally substituted by 4a are independently as defined in any of 154-160.

[0229] Suitably, in these embodiments of formula (XVII), (XVIIa), (XVIII) or (XVIIIa), each R 4a Ha, Halo, C 1~3 Alkyl and -OC 1~3 alkyl. For example, each R 4a may be independently selected from F, Cl, methyl and methoxy.

[0230] Suitably, in these embodiments of formula (XVII), (XVIIa), (XVIII) or (XVIIIa), the fused bicyclic heteroaryl formed by ring D and ring E is unsubstituted.

[0231] Suitably, in these embodiments of formula (XVII), (XVIIa), (XVIII) or (XVIIIa), L is a bond and R 2 (if present) is H and R 3 is selected from methyl, ethyl and —CH2CH2F, so that L is a bond and R 2 (if present) is H and R 3 can be methyl; L is a bond; R 2 (if present) is H and R 3 can be ethyl; L is a bond; R 2 (if present) is H and R 3 can be -CH2CH2F.

[0232] In certain embodiments, the compound is of Formula (XIX), (XIXa), (XX) or (XXa), wherein ring F is selected from pyrrole, imidazole, pyrazole, triazole and tetrazole, ring G is selected from benzene, pyridine, pyrimidine, pyridazine and pyrazine, and the 9-membered fused bicyclic heteroaryl ring formed by ring F and ring G is bonded to L at a ring atom of ring F.

[0233] In certain embodiments, the compound is of formula (XIX), (XIXa), (XX) or (XXa), and is a group of the formula: [ka] teeth, [ka] and the 9-membered fused bicyclic heteroaryl ring and the imidazole ring formed by ring G are bonded to L at a ring atom of the imidazole ring.

[0234] Therefore, [ka] teeth, [ka] each of which is selected from one, two, or three (e.g., one or two) R 4a and each R is optionally substituted by 4a are independently as defined in any one of 154 to 160, and the 9-membered fused bicyclic heteroaryl ring formed by ring G and the imidazole ring is bonded to L at a ring atom of the imidazole ring. For example, the 9-membered fused bicyclic heteroaryl ring formed by ring G and the imidazole ring is [ka] each of which is selected from one, two, or three (e.g., one or two) R 4a and each R is optionally substituted by 4aare independently as defined in any of 154-160.

[0235] Suitably, in these embodiments of formula (XIX), (XIXa), (XX) or (XXa), each R 4a Ha, Halo, C 1~3 Alkyl and -OC 1~3 alkyl. For example, each R 4a may be independently selected from F, Cl, methyl and methoxy.

[0236] Suitably, in these embodiments of formula (XIX), (XIXa), (XX) or (XXa), the fused bicyclic heteroaryl formed by ring F and ring G is unsubstituted.

[0237] Suitably, in these embodiments of formula (XIX), (XIXa), (XX) or (XXa), L is a bond and R 2 (if present) is H and R 3 is selected from methyl, ethyl and —CH2CH2F, so that L is a bond and R 2 (if present) is H and R 3 can be methyl; L is a bond; R 2 (if present) is H and R 3 can be ethyl; L is a bond; R 2 (if present) is H and R 3 can be -CH2CH2F.

[0238] In another embodiment, there is provided a compound selected from Compound List 1 or a pharmaceutically acceptable salt thereof.

[0239] [Table 1]

[0240] [Table 2]

[0241]

Table 3

[0242]

Table 4

[0243]

Table 5

[0244]

Table 6

[0245]

Table 7

[0246]

Table 8

[0247]

Table 9

[0248]

Table 10

[0249]

Table 11

[0250]

Table 12

[0251] [Table 13]

[0252] [Table 14]

[0253] [Table 15]

[0254] [Table 16]

[0255] [Table 17]

[0256] [Table 18]

[0257] [Table 19]

[0258] [Table 20]

[0259] [Table 21]

[0260] In another embodiment, there is provided a compound selected from any one of the Examples herein, or a pharmaceutically acceptable salt thereof.

[0261] Certain compounds of the present invention have a pIC of greater than 5.5 as measured in the human Cav2.3 channel calcium influx assay described in the Examples. 50 Preferably, pIC 50 is 6, more preferably pIC 50 is 7 or more.

[0262] Suitably, compounds of the invention exhibit a favourable pharmacokinetic and / or pharmacodynamic profile, for example favourable oral bioavailability, metabolic stability, plasma half-life or more.

[0263] Pharmaceutical Composition In accordance with another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, except that compounds A and B are not excluded, and a pharmaceutically acceptable excipient.

[0264] The pharmaceutical composition may comprise a compound selected from the compounds according to any of Formulas (I) to (XXXVIc) and Compound A or Compound B, or a pharmaceutically acceptable salt thereof.

[0265] The pharmaceutical composition may comprise a compound selected from the compounds according to any of Formulas (I) to (XXXVIc), or a pharmaceutically acceptable salt thereof, with the proviso that Compound A and Compound B are excluded.

[0266] The pharmaceutical composition can include Compound A or Compound B.

[0267] Conventional procedures for the selection and preparation of suitable pharmaceutical compositions are described, for example, in "Pharmaceuticals - The Science of Dosage Form Designs", MEAulton, Churchill Livingstone, 1988.

[0268] Compositions of the invention may be in a form suitable for oral use (for example, tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), in a form suitable for sublingual use, in a form suitable for topical use (for example, creams, ointments, gels or aqueous or oily solutions or suspensions), in a form suitable for administration by inhalation (for example, as a finely divided powder or liquid aerosol), in a form suitable for administration by insufflation (for example, as a finely divided powder) or in a form suitable for parenteral administration (for example, as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intraperitoneal administration or as a suppository for rectal administration).

[0269] 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 coloring agents, sweeteners, flavoring agents and / or preservatives.

[0270] An effective amount of a compound of the invention for use in the treatment of a condition is an amount sufficient to symptomatically alleviate the symptoms of or slow the progression of the condition in a warm-blooded animal, especially a human.

[0271] 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, 0.1 mg to 0.5 g of active agent (more preferably 0.5 to 100 mg, e.g., 1 to 30 mg), compounded with an appropriate and convenient amount of excipient, which may vary from about 5 percent to about 98 percent by weight of the total composition.

[0272] The size of a dose of the compounds of the invention for therapeutic or prophylactic purposes will naturally vary according to well-known medical principles, depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

[0273] When using the compounds of the present invention for therapeutic or prophylactic purposes, they are generally administered to receive a daily dose ranging from, for example, 0.1 mg / kg to 100 mg / kg, 1 mg / kg to 75 mg / kg, 1 mg / kg to 50 mg / kg, 1 mg / kg to 20 mg / kg, or 5 mg / kg to 10 mg / kg of body weight, if necessary in divided doses. Generally, when parenteral routes are used, lower doses are administered. Thus, for example, for intravenous, subcutaneous, intramuscular, or intraperitoneal administration, a dose ranging from, for example, 0.1 mg / kg to 30 mg / kg of body weight may be suitable. Similarly, for administration by inhalation, a dose ranging from, for example, 0.05 mg / kg to 25 mg / kg of body weight may be suitable. When administered orally, the total daily dose of the compounds of the present invention may be selected from, for example, 1 mg to 1000 mg, 5 mg to 1000 mg, 10 mg to 750 mg, or 25 mg to 500 mg. Typically, a unit dosage form contains about 0.5 mg to 0.5 g of a compound of the invention. In certain embodiments, the compounds of the invention are administered parenterally, for example, intravenously. In another particular embodiment, the compounds of the invention are administered orally.

[0274] Therapeutic uses and applications In this section describing therapeutic uses, applications and methods of treatment, references to "compounds of the invention" include compounds according to any of Formulas (I) through (XXXVIc) or pharmaceutically acceptable salts thereof, except that Compound A and Compound B1 are not excluded. Thus, in this section, "compounds of the invention" can be compounds according to any of Formulas (I) through (XXXVIc), Compound A and Compound B, or pharmaceutically acceptable salts thereof.

[0275] However, it should be understood that in some embodiments of this chapter, the compound of the invention may be a compound according to any of Formulas (I) through (XXXVIc), or a pharmaceutically acceptable salt thereof, with the proviso that Compound A and Compound B are excluded. In other embodiments in this chapter, the compound of the invention may be a compound selected from Compound A and Compound B, or a pharmaceutically acceptable salt thereof.

[0276] In accordance with another aspect, the present invention provides a compound of the present invention for use as a pharmaceutical.

[0277] A further aspect of the present invention provides a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of a disease or medical disorder mediated by Cav2.3.

[0278] Also provided is a method for preventing or treating a disease or medical disorder mediated by Cav2.3 in a subject, comprising administering to the subject an effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.

[0279] There is also provided the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention or treatment of a disease or medical disorder mediated by Cav2.3.

[0280] In the following sections of this application, reference is made to compounds of the invention, or pharmaceutically acceptable salts thereof, for use in treating specific diseases or medical disorders. It should also be understood that any reference herein to a compound for a specific use is also intended to be a reference to (i) the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a disease or disorder, and (ii) a method for treating a disease or disorder in a subject, comprising administering to the subject a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof.

[0281] 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, a cerebral vasospasm, and pain.

[0282] In certain embodiments, there is provided a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or medical disorder selected from a neurodegenerative disease, a neurodevelopmental disorder, epilepsy, an endocrine disorder, a cerebral vasospasm, and pain.

[0283] Neurodegenerative diseases 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 certain embodiments, the compounds of the present invention are for use in treating Parkinson's disease.

[0284] The compounds of the present invention can provide neuroprotective effects to subjects with neurodegenerative diseases. Thus, the compounds of the present invention can be used for the neuroprotective treatment of neurodegenerative diseases (e.g., Parkinson's disease). In some embodiments, the compounds of the present invention can be used to prevent or delay the onset of symptoms associated with neurodegenerative diseases. Thus, the compounds of the present invention can be used to prevent or reduce symptoms associated with neurodegenerative diseases.

[0285] In certain embodiments, the compounds of the invention are for use in preventing or inhibiting the degeneration of dopaminergic neurons in a subject with a neurodegenerative disease (e.g., Parkinson's disease). Thus, the compounds of the invention are for use in preventing or inhibiting the degeneration of dopaminergic substantia nigra (SN) neurons in a subject with Parkinson's disease.

[0286] In certain embodiments, the compounds of the invention are for use in the treatment or prevention of one or more symptoms of a neurodegenerative disease, for example, the compounds may be for use in the treatment or prevention of one or more symptoms of Parkinson's disease selected from tremor, bradykinesia, dystonia, rigidity, balance disorders, coordination disorders, cognitive disorders, and speech disorders.

[0287] Neurodevelopmental disorders In certain embodiments, the compounds of the invention are for use in treating a neurodevelopmental disorder, hi certain embodiments, the neurodevelopmental disorder is selected from CACNA1E hyperactivity (DEE69), CDKL5 deficiency (DEE2), fragile X syndrome, Down syndrome, Rett syndrome, Angelman syndrome, autism, movement disorders (e.g., developmental coordination disorder, stereotypic movements, and tics), and attention deficit hyperactivity disorder (ADHD).

[0288] As mentioned in the introduction, Cav2.3 channels are associated with developmental and epileptic encephalopathies (DEEs). The term "DEEs" refers to a heterogeneous group of rare neurodevelopmental disorders characterized by (a) early-onset epileptic seizures that are often intractable, (b) electroencephalographic abnormalities, (c) developmental delay or regression, and (d) in some cases, early death. DEEs are classified by the 2017 International League Against Epilepsy (ILAE) classification of epilepsies as transformations associated with developmental disorders that can result from both an underlying cause (developmental encephalopathy) and additional 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).

[0289] In certain embodiments, the compounds of the present invention are for use in the prevention or treatment of developmental and epileptic encephalopathies. In certain embodiments, the compounds of the present invention are for use in the prevention or treatment of developmental and epileptic encephalopathies. In certain embodiments, the compounds of the present invention are for use in the treatment or prevention of CACNA1E hyperactivity (DEE69), CDKL5 deficiency (DEE2), DEE9 (caused by mutations in the PCDH19 gene), DEE11 (SCN2A hyperactivity), DEE13 (SCN8A hyperactivity), Dravet syndrome (DEE6A), or DEE due to or associated with loss of function of the GABAa receptor (e.g., DEE19, DEE43, DEE45, DEE59, DEE74, DEE78, DEE79, or DEE92).

[0290] In one embodiment, the compounds of the invention are for use in the treatment or prevention of a DEE that is Dravet syndrome (DEE6A). In particular embodiments, the compounds of the invention are for use in the treatment or prevention of CACNA1E hyperactivity (DEE69) or CDKL5 deficiency (DEE2).

[0291] In another embodiment, the compounds of the invention are for use in treating DEEs caused by or associated with loss of function of GABAa receptors, for example, the compounds of the invention are for use in treating DEEs selected from DEE19, DEE43, DEE45, DEE59, DEE74, DEE78, DEE79, and DEE92.

[0292] The genetic phenotypic and clinical features of DEE described herein are those of the Online Mendelian Inheritance in Man® (OMIM) database (https: / / www.omim.org / about), entry number 30008.

[0293] epilepsy In certain embodiments, the compounds of the invention are for use in the treatment of epilepsy.

[0294] Epilepsy is a chronic brain disorder primarily characterized by unprovoked epileptic seizures. Epileptic seizures can range from short and nearly undetectable to long and violent concussions. Epilepsy and its associated symptoms can be classified according to whether the seizures are partial or generalized and whether the pathology is idiopathic, symptomatic, or cryptogenic. The term "epilepsy" includes both generalized and focal types, with generalized epilepsy affecting both hemispheres, while focal epilepsy includes unifocal and multifocal disorders and seizures involving one hemisphere.

[0295] In certain embodiments, the compounds of the present invention are for use in treating epilepsy selected from idiopathic epilepsy, cryptogenic epilepsy, and symptomatic epilepsy. Idiopathic epilepsy is epilepsy without a clear cause. Cryptogenic epilepsy occurs when the cause of epilepsy in a subject cannot be classified despite investigation. Symptomatic epilepsy is epilepsy with a known cause. Causes of symptomatic epilepsy include, for example, brain injury, bacterial or viral infection (e.g., meningitis), stroke, or major encephalopathy.

[0296] In some embodiments, the compounds of the invention are for use in treating epileptic conditions. For example, the compounds of the invention may be for use in the treatment of an epileptic condition selected from childhood absence epilepsy, benign rolandic epilepsy, Doze syndrome, Dravet syndrome, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, Jeavons syndrome, epilepsy with myoclonic absences, epilepsy with generalized tonic-clonic seizures, epileptic encephalopathy with sustained spike-and-wave events during sleep, febrile illness-related epilepsy, genetic epilepsy with febrile seizures, West syndrome, juvenile absence epilepsy, juvenile myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, myoclonic epilepsy of infancy, Ohtahara syndrome, Panayiotopolous syndrome, progressive myoclonic epilepsy, reflex epilepsy, self-limited familial and non-familial neonatal infantile seizures, Gastaut syndrome, sleep-related hyperkinetic epilepsy and temporal lobe epilepsy.

[0297] In some embodiments, the compounds of the present invention are for use in the treatment or prevention of drug-resistant epilepsy. Drug-resistant epilepsy (also known as "uncontrolled," "refractory," or "resistant" epilepsy) refers to epilepsy that fails to respond to or recurs after treatment with an antiepileptic therapy. Thus, a subject with drug-resistant epilepsy has persistent seizures despite treatment with one or more antiepileptic therapies. For example, a subject may fail to respond to or recur after treatment with one or more antiepileptic therapies (e.g., a subject fails to respond to or recurs after treatment with at least two antiepileptic therapies). In certain embodiments, a subject fails to respond to or recurs after treatment with one or more antiepileptic drugs (AEDs), such as one or more AEDs listed herein in connection with combination therapy. Drug-resistant epilepsy can be any of the forms of epilepsy described herein that are resistant to or have become resistant to treatment with one or more (e.g., at least two) antiepileptic therapies. In some embodiments, the drug-resistant epilepsy is drug-resistant focal epilepsy.

[0298] In certain embodiments, the compounds of the present invention are for use in the prevention or treatment of seizures. Thus, in certain embodiments, the compounds of the present invention are for use in the prevention or treatment of epileptic seizures. For example, the compounds of the present invention reduce the occurrence of epileptic seizures, decrease the severity and / or duration of epileptic seizures, or reduce seizure frequency. In some embodiments, the compounds of the present invention are for use in the prevention or treatment of partial, generalized, convulsive, and non-convulsive seizures. In some embodiments, the compounds of the present invention are for use in the prevention or treatment of seizures selected from tonic-clonic seizures, tonic seizures, clonic seizures, myoclonic seizures, absence seizures, and atonic seizures.

[0299] Endocrine disorders In certain embodiments, the compounds of the invention are for use in treating an endocrine disorder. For example, the compounds of the invention can be for use in treating an endocrine disorder selected from diabetes (e.g., 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 (low thyroid function), and prolactinoma.

[0300] pain In certain embodiments, the compounds of the invention are for use in the treatment or prevention of pain, hi some embodiments, the compounds of the invention are for use in the treatment of chronic pain, inflammatory pain, neuropathic pain (e.g., peripheral neuropathic pain or central neuropathic pain), or nociceptive pain.

[0301] Cerebral vasospasm Subjects suffering from cerebral aneurysms or aneurysmal subarachnoid hemorrhage (bleeding on the surface of the brain) often survive the initial trauma. However, within a few days to two weeks, the subject experiences cerebral vasospasm, a spasm or constriction of the cerebral blood vessels. Cerebral vasospasm can restrict blood flow to the brain, causing the death of blood-deprived brain tissue, which subsequently leads to cerebral infarction. Cav2.3 expression can be increased after cerebral anemia or aneurysmal subarachnoid hemorrhage and may be involved in cerebral vasospasm (Wang et al., supra). Thus, in some embodiments, the compounds of the present invention are for use in the treatment or prevention of cerebral vasospasm. For example, the compounds of the present invention are for use in the treatment or prevention of cerebral vasospasm in subjects suffering from cerebral aneurysms or aneurysmal subarachnoid hemorrhage. In some embodiments, the compounds of the present invention are for use in the treatment or prevention of cerebral infarction.

[0302] Selectivity Without wishing to be bound by theory, selective modulation of Cav2.3 results in compounds that have desirable therapeutic effects while avoiding or minimizing the side effects associated with non-selective Cav2.3 antagonists.

[0303] In certain embodiments, such selective compounds may be used in the treatment or prevention of any of the diseases or medical disorders described herein.

[0304] Combination therapy The compounds of the invention may be used alone to provide therapeutic benefit. The compounds of the invention may also be used in combination with one or more additional therapeutic agents.

[0305] In some embodiments, the additional therapeutic agent is antiepileptic drugs (AEDs), such as acetazolamide, benzodiazepines, cannabadiol, 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, stripentol, tiagapine, topiramate, vigabatrin or zonisamide, a drug for the treatment of Parkinson's disease, for example selected from one or more of: a dopamine mimetic (a substance that controls / regulates dopamine metabolism, for example levodopa or carbidopa); a dopamine receptor agonist (for example pramipexole, ropinirole, rotigotine or apomorphine); a monamine oxidase inhibitor, for example an MAO B inhibitor (for example selegiline, rasagiline or safinamide), a catechol O-methyltransferase (COMT) inhibitor (for example entacapone, opicapone or tolcapone), an anticholinergic (for example benztropine or trihexyphenidyl); an adamantane; or an adenosine A2A receptor antagonist (for example istradefylline).

[0306] Such combination treatment may be achieved by the simultaneous, sequential or separate administration of the individual components of the treatment. Such combination products utilize the compounds of this invention within the therapeutically effective dosage range described herein above and other pharmaceutically active agents within their approved dosage ranges.

[0307] As used herein, when the term "combination" is used, it should be understood that this refers to simultaneous administration, separate administration, or sequential administration. In one aspect of the present invention, "combination" refers to simultaneous administration. In another aspect of the present invention, "combination" refers to separate administration. In a further aspect of the present invention, "combination" refers to sequential administration. When administration is sequential or separate, the timing of administration of the second component should not impair the beneficial effects of the combination.

[0308] In some embodiments in which combination therapy is used, the amounts of the compounds of the present invention and the other pharmaceutically active agent, when combined, are therapeutically effective to treat the targeted disorder in a patient. In this context, a combined amount is a "therapeutically effective amount" if, when combined, it is sufficient to reduce or completely alleviate the symptoms or other damaging effects of the disorder, cure the disorder, reverse, completely halt, or slow the progression of the disorder, or reduce the risk of the disorder worsening. Typically, such amounts can be determined by one of skill in the art, for example, by starting with the dosage ranges described herein for the compounds of the present invention or approved or otherwise published dosage ranges for other pharmaceutically active compounds.

[0309] Biological assays The effect of the compounds of the present invention on inhibiting calcium ion influx into cells through human Cav2.3 channels was evaluated using the human Cav2.3 channel calcium influx assay described in the Examples section. The effect of the compounds of the present invention on inhibiting the function of Cav2.3 ion channels in vitro can be evaluated using whole-cell patch clamp methods, such as those described in the Examples section.

[0310] The effects of compounds that block R-type calcium currents using whole-cell patch clamp electrophysiology in nigral dopamine neurons in ex vivo brain slice preparations can be assessed using the methods described in Siller et al., Elife, 11:e67464 (2022) https: / / doi.org / 10.7554 / eLife.67464.

[0311] The effects of compounds on diseases or medical disorders mediated by Cav2.3 can be evaluated using suitable in vitro and in vivo models for such diseases and medical disorders. For example, the effects of compounds of the present invention on Parkinson's disease can be evaluated using the methods and models described in WO 2018 / 228692. Other suitable models of Parkinson's disease include, for example, the MitoPark mouse model described by Galter et al. (Genes Brain Behav. 2010 March 1;9(2):173-181) and the SNCA-OVX transgenic mouse model described by Janezic et al. (Proceedings of the National Academy of Sciences, 2013, September, 201309143 DOI:10.1073 / pnas.1309143110).

[0312] Suitable models for testing compounds of the invention for the treatment of seizures or epilepsy include, for example, one or more of the models described in Loescher (Seizure, 2011, (20), 359-368). Alternatively, compounds of the invention can 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.

[0313] synthesis In describing the synthetic methods described below or the reference synthetic methods used to prepare starting materials, it is understood that all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, duration of experiment and work-up procedures, can be selected by one skilled in the art.

[0314] 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 employed.

[0315] Necessary starting materials can be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variations and within the accompanying Examples. Alternatively, necessary starting materials can be obtained by analogous procedures to those illustrated, which are within the skill of an organic chemist.

[0316] It will be understood that during the synthesis of the compounds of the invention, or of certain starting materials, in the processes defined below, it may be desirable to protect certain substituents to prevent undesired reactions. Those skilled in the art will understand how such protecting groups may be put in place and subsequently removed when such protection is required.

[0317] For examples of protecting groups, see one of the many general texts on the subject, such as "Protective Groups in Organic Synthesis" by Theodora Green (publisher: John Wiley & Sons). Protecting groups can be removed by any convenient method described in the literature or known to those skilled in the art as suitable for removing the protecting group in question, with such method being chosen so that removal of the protecting group has minimal effect on the disruption of groups elsewhere in the molecule.

[0318] Thus, when reactants include groups such as amino, carboxy or hydroxy, it may be desirable to protect the group in some of the reactions mentioned herein.

[0319] For example, suitable protecting groups for amino or alkylamino groups include, for example, acyl groups, such as alkanoyl groups (e.g., acetyl or trifluoroacetyl), alkoxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, or t-butoxycarbonyl), arylmethoxycarbonyl groups (e.g., benzyloxycarbonyl), or aroyl groups (e.g., benzoyl). The deprotection conditions for the above protecting groups necessarily vary depending on the choice of protecting group. Thus, for example, acyl groups (e.g., alkanoyl, alkoxycarbonyl, or aroyl) can be removed by hydrolysis using a suitable base, such as an alkali metal hydroxide (e.g., lithium hydroxide or sodium hydroxide). Alternatively, acyl groups such as tert-butoxycarbonyl groups may be removed by treatment with a suitable acid, for example hydrochloric, sulfuric or phosphoric acid, or trifluoroacetic acid, and arylmethoxycarbonyl groups such as benzyloxycarbonyl groups may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid, for example BF3.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 hydrazine.

[0320] Suitable protecting groups for hydroxy groups are, for example, acyl groups, e.g., acetyl, alkanoyl groups such as aroyl groups, e.g., benzoyl, or arylmethyl groups, e.g., benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, acyl groups, e.g., alkanoyl or aroyl groups, can be removed by hydrolysis with a suitable base, e.g., an alkali metal hydroxide, e.g., lithium hydroxide or sodium hydroxide, or ammonia. Alternatively, arylmethyl groups, e.g., benzyl groups, can be removed by hydrogenation over a catalyst, e.g., palladium on carbon.

[0321] Suitable protecting groups for carboxy groups are, for example, esterifying groups such as a methyl or ethyl group which may be removed by hydrolysis with a base such as sodium hydroxide, or a t-butyl group which may be removed by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or a benzyl group which may be removed by hydrogenation over a catalyst such as palladium on carbon.

[0322] Resins may also be used as protecting groups.

[0323] General synthetic route [ka] Compounds of formula (I) generally have the formula (Ia') [ka] wherein rings A and L are as defined above for any of formulas (I) to (XXXVIc), and LG is a leaving group. with a compound of formula (Ib) or a compound of formula (Ic): [ka] (In the formula, R 1 , R 2 , R 3 and Ring B is as defined above for any of Formulas (I) through (XXXVIc), as appropriate, except that any functional groups are protected, and optionally performing one or more of the following steps: converting a compound of Formula (I) into another compound of Formula (I), removing any protecting groups, forming a pharmaceutically acceptable salt and / or preparing a stereochemical isomer thereof. It can be prepared by reacting

[0324] The compound of formula (I) has the formula (Id) [ka] (Wherein, rings A, L and R 3is as defined above for any of Formulas (I) to (XXXVIc). and a compound of formula (Ie): [ka] (In the formula, rings B, R 1 and R 2 is as defined above for any of Formulas (I) to (XXXVIc) as appropriate, except that any functional groups are protected, and optionally performing one or more of the following steps: converting a compound of Formula (I) into another compound of Formula (I), removing any protecting groups, forming a pharmaceutically acceptable salt and / or preparing a stereochemical isomer thereof. It can also be prepared by reacting a compound of the formula:

[0325] The reaction of the compound of formula (Ia') with the compound of formula (Ib / Ic) can be carried out in a reaction-inert solvent such as DCM, THF, acetonitrile, and optionally in the presence of at least one suitable base. Non-limiting examples of such reaction promoters include DIPEA, TEA, pyridine, NMM, 2,6-lutidine, DMAP, or functional derivatives thereof.

[0326] In compounds of formula (Ia), LG is a suitable leaving group such as, for example, halo (eg, fluoro, chloro, bromo, etc.).

[0327] The reaction of a compound of formula (Ia') with a compound of formula (Ib) can be carried out in a reaction-inert solvent such as DCM, THF, acetonitrile, or pyridine, and optionally in the presence of a suitable base such as sodium carbonate, potassium carbonate, or trimethylamine, DIPEA, or pyridine. Stirring can improve the reaction rate. The reaction can conveniently be carried out at a temperature ranging between the freezing point of water (0°C) and the reflux temperature of the reaction mixture.

[0328] Compounds of formula (Ia') can be prepared according to the following scheme (general scheme 1): [ka] It can be prepared according to

[0329] The sulfide compounds (IIb) can be obtained by reacting the respective bromo derivatives (IIa') in a sulfur-carbon bond-forming reaction in the presence of a Pd catalyst under an inert atmosphere. Examples of such reactions include the reaction with aromatic bromo, aromatic chloro, or aromatic iodo compounds, which react with sulfur compounds such as phenylmethanethiol, (4-methoxyphenyl)methanethiol, and 2-ethylhexyl 3-mercaptopropanoate. The reaction can be carried out in a suitable solvent, such as 1,4-dioxane, toluene, benzene, DMF, DME, or DMA solution, preferably at temperatures between room temperature and 150°C. For palladium-catalyzed coupling reactions, the active palladium catalyst is considered to be a Pd(0) complex, which can be generated in various ways. Suitable Pd(0) sources, such as Pd(PPh3)4 or Pd(dba)2, can undergo ligand dissociation to form the active species. Phosphine can be added to ligand-free palladium(0).

[0330] The sulfide compounds (IIc) can be obtained by the reaction of the respective sulfide derivatives (IIb) in a sulfur-carbon bond cleavage reaction in the presence of a base under an inert atmosphere. Suitable bases for this type of transformation include, for example, NaOEt, NaOMe, K2CO3, Na2CO3, tBuONa, and tBuOK. Suitable solvents for this type of transformation include, for example, EtOH, MeOH, THF, DCE, DCM, MeCN, preferably at temperatures between -78°C and room temperature.

[0331] The sulfonyl chlorides (Ia') can be obtained by reaction of the respective thiol derivatives (IIc) in sulfur-oxygen and sulfur-chlorine bond forming reactions. Non-limiting examples of such reactions include: - halogen or chlorine sources in the presence of acidic water, such as chlorine gas, NaOCl, NCS, NBS, 1,3-dibromo-5,5-dimethylhydantoin, oxone, cyanuric chloride or their derivatives; - The reaction of ammonium nitrate with an aqueous solution of AcOH, HCl or HBr and oxygen with the acid as the terminal oxidant is developed in this process.

[0332] The reaction may be carried out in a suitable solvent such as DCM, tetrahydrofuran, acetic acid, diethyl ether, toluene, preferably at a temperature between −20° C. and room temperature.

[0333] Compounds of formula (Id) comprising rings A, R 3 Compounds of formula (Id), in the sense that L is as defined above for any of formulae (I) to (XXXVIc) and LG is a leaving group, can be prepared by a one-step procedure of formula (II) and can be prepared according to the following scheme (general scheme 2): [ka] can be converted to the title compound of formula (I) using a Mitsunobu reaction as mentioned in

[0334] The reaction of the compound of formula (Ia') with an amine or a salt thereof under thermal conditions, with or without a base, is preferably carried out at a temperature between 0°C and room temperature. The reaction can be carried out in a reaction-inert solvent, optionally in the presence of at least one suitable base. Non-limiting examples of such reaction promoters include DIPEA, TEA, pyridine, NMM, 2,6-lutidine, DMAP, or functional derivatives thereof.

[0335] LG in compounds of formula (Ia) is a suitable leaving group such as, for example, halo (eg, fluoro, chloro, bromo, etc.).

[0336] Reaction of a compound of formula (Id) with a substituted benzyl alcohol reagent of the type of formula (Ie):

[0337] Commonly used phosphine sources for this type of transformation are triphenylphosphine, tricyclohexylphosphine, tributylphosphine, trihexylphosphine, or functional derivatives thereof. Commonly used azo compound sources for this type of reaction are DEAD, DIAD, DTAB, ADDP, or functional derivatives thereof. The transformation can be preferably carried out in a reaction-inert solvent such as dioxane, THF, or diethyl ether.

[0338] Compounds of formula (If) can generally be prepared by reacting compounds of formula (Ia') with compounds of formula (Ic) using the above protocol. Compounds according to formula (I) can be prepared according to the following scheme (general scheme 3): [ka] wherein the alkylated compound (R 3 -Z), where Z is a suitable leaving group, for example, halo (fluoro, chloro, bromo, iodo, etc.). can be prepared in a single step procedure from formula (If) using N-alkylation as mentioned below in

[0339] The reaction of the compound of formula (If) with an alkylating agent, preferably an inorganic base, under thermal conditions is preferably carried out at a temperature of 50° C. to 120° C. The reaction of the compound of formula (If) can be carried out in at least one reaction-inert solvent, optionally in the presence of at least one suitable base thereof. Non-limiting examples of such reaction promoters include K2CO3, Cs2CO3, NaH or functional derivatives thereof, and can be carried out in a reaction-inert solvent such as DMF, DMSO, or acetonitrile.

[0340] Certain intermediates described herein, such as intermediate (If) and salts thereof, form further aspects of the present invention. In intermediates of formula (If), ring A, ring B, R 1 , R 2and L is as defined for formula (I), including any of the values ​​in the above numbered paragraphs 1-223. In certain embodiments, the intermediate of formula (If) is a compound of formula (If) or a salt thereof described in any of the Examples herein.

[0341] Some compounds of formula (If) have activity as Cav2.3 antagonists. Thus, in another embodiment, a compound according to any of formulas (I) to (XXXVIc) or a pharmaceutically acceptable salt thereof, wherein R 3 H, C 1~6 Alkyl and C 1~6

[0023] There is provided a compound according to any of Formulas (I) to (XXXVIc), or a pharmaceutically acceptable salt thereof, wherein R is selected from haloalkyl. Suitably, in this embodiment, 3 is H. In these embodiments, ring A, ring B, R 1 , R 2 and L is as defined for formula (I), including any of the values ​​in the above numbered paragraphs 1 to 223. Thus, the compound may be a compound of formula (If) above, such as, for example, one of the compounds of formula (If) used in the preparation of any of the Examples herein.

[0342] Further embodiments The present invention is further described in the following embodiments. P1.Formula (I): [ka] (In the formula, R 1 is C 1~6 Alkyl, C 3~6 Cycloalkyl and C 3~6 Cycloalkyl-C 1~6 alkyl-, and R 1 is substituted by at least one fluorine atom, R 2 is H, C 1~6 Alkyl and C 1~6 haloalkyl; or R 1 and R2 are, together with the carbon atoms to which they are attached, optionally substituted by at least one fluorine. 3~6 forming a cycloalkyl, R 3 is C 1~6 Alkyl and C 1~6 haloalkyl; L is a bond and C 1~3 alkylene; Ring A is C 3~6 Cycloalkyl, 4- to 7-membered heterocyclyl, 5- to 12-membered heteroaryl and C 6~10 aryl, and ring A is selected from one or more R 4 and optionally substituted by Each R 4 Halo, -CN, -NO2, =O, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 6 and -SO2NR 5 R 6 are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 Alkynyl is a group consisting of one or more R 7 and optionally substituted by R5 and R 6 is H, C 1~6 Alkyl, C 1~6 Haloalkyl and Q 1 are each independently selected from Said C 1~6 Alkyl is one or more R 8 and optionally substituted by Each R 7 and R 8 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 are independently selected from Each Q 1 and Q 2 is C 3~6 independently selected from cycloalkyl, 4- to 7-membered heterocyclyl, phenyl, and 5- or 6-membered heteroaryl; Said C 3~6 Cycloalkyl, 4- to 7-membered heterocyclyl, phenyl, and 5- or 6-membered heteroaryl may be substituted by one or more R 9 and optionally substituted by Each R 9 Halo, =O, -CN, -NO2, C 1~4 Alkyl, C 1~4 Haloalkyl, -OR 9A , -S(O)2R 9A , -NR 9A R 9B , -C(O)R 9A , -OC(O)R 9A , -C(O)OR 9A , -NR 9B C(O)R 9A , -C(O)NR 9A R 9B , -NR 9B C(O)OR 9A, -OC(O)NR 9A R 9B , -NR 9B SO2R 9A and -SO2NR 9A R 9B are independently selected from Said C 1~4 Alkyl is a group that can be substituted with halo, -CN, -OR 9C , -NR 9C R 9D and -SO2R 9C and optionally substituted by one or two substituents selected from Ring B is phenyl or 5- or 6-membered heteroaryl, and Ring B contains one or more R 10 and optionally substituted by Each R 10 Halo, -CN, -NO2, =O, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 10B and -SO2NR 10A R 10B wherein C is independently selected from 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 Alkynyl is a group consisting of one or more R 11 and optionally substituted by Each R 11 Halo, -CN, -OR11A , -NR 11A R 11B and -SO2R 11A are independently selected from R 7A , R 7B , R 9A , R 9B , R 9C , R 9D , R 10A , R 10B , R 11A and R 11B In each occurrence, H, C 1~4 Alkyl and C 1~4 haloalkyl; Any -NR in the substituent 5 R 6 , -NR 7A R 7B , -NR 9A R 9B , -NR 9C R 9D , -NR 10A R 10B and -NR 11A R 11B can form a 4- to 6-membered heterocyclyl, and the 4- to 6-membered heterocyclyl is selected from halo, ═O, C 1~4 Alkyl and C 1~4 optionally substituted by one or more substituents selected from haloalkyl; each x is independently 0, 1, or 2; However, compounds A and B: [ka] (subject to exclusion) or a pharmaceutically acceptable salt thereof. P2. Ring A is furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, phenyl, pyridyl, pyrimidinyl, pyrazinyl or the structure: [ka] wherein ring A is optionally selected from compounds of the formula:4 The compound of embodiment 1, wherein P3.Each R 4 Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 6 and -SO2NR 5 R 6 The compound of embodiment 1 or 2, independently selected from: P4.Formula (III): [ka] (In the formula, Each R 4a Halo, -CN, -NO2, =O, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 6 and -SO2NR5 R 6 are independently selected from Said C 1~6 Alkyl, C 1~6 Heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 7 is replaced by, and a is an integer from 0 to 3. or a pharmaceutically acceptable salt thereof. P5.Formula (VII): [ka] (In the formula, Each R 4a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 6 and -SO2NR 5 R 6 are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 7 is replaced by, and a is an integer from 0 to 5. or a pharmaceutically acceptable salt thereof. P6.Formula (XI): [ka] (In the formula, Each R 4a Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, 2-8 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 SO2R 6 and -SO2NR 5 R 6 are independently selected from Said C 1~6 Alkyl, 2-8 membered heteroalkyl, C 2~6 Alkenyl and C 2~6 The alkynyl may optionally be one or more R 7 is replaced by, and a is an integer from 0 to 4. or a pharmaceutically acceptable salt thereof. The compound of any one of embodiments 1-6, wherein P7.L is selected from a bond and -CH2-. The compound of any one of embodiments 1-6, wherein P8.L is a bond. P9.R1 is C 1~6 Alkyl and C 3~6 cycloalkyl, R 1 The compound of any one of embodiments 1-8, wherein is substituted with at least one fluorine. P10.R 1 The compound of any one of embodiments 1-8, wherein is selected from —CH 2 F, —CHF 2 , and —CF 3 . P11.R 1 The compound of any one of embodiments 1-8, wherein is —CF 3 . P12.R 1 and R 2 The compound of any one of embodiments 1-8, wherein together with the carbon atom to which they are attached, form a C3 or C4 cycloalkyl substituted with at least one fluorine. P13.R 2 The compound of any one of embodiments 1-12, wherein is selected from H and methyl. P14.R 2 The compound of any one of embodiments 1-12, wherein is H. P15.R 3 is C 1~3 The compound of any one of embodiments 1-14, wherein the alkyl is selected from alkyl and optionally substituted with one or more halo groups. P16. Ring B is selected from furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, phenyl, pyrimidinyl, and pyrazinyl, and Ring B optionally contains one or more R 10 The compound of any one of embodiments 1-15, substituted by: P17. Ring B is one or more R 10 The compound of any one of embodiments 1-15, wherein R is phenyl optionally substituted by: P18.Each R 10 Halo, -CN, -NO2, C 1~6 Alkyl, C 1~6 Haloalkyl, -OR 10A , -S(O)x R 10A and -NR 10A R 10B 18. The compound of any one of embodiments 1-17, independently selected from: P19.Each R 10 Halo and C 1~4 The compound of any one of embodiments 1-17, wherein: P20. Ring B is halo and C 1~4 one or two R selected from alkyl 10 16. The compound of any one of embodiments 1-15, wherein Ring B is phenyl substituted by, for example, Ring B is 4-fluorophenyl. P21. A compound selected from Compound List 1 herein or a pharmaceutically acceptable salt thereof. P22. A pharmaceutical composition comprising a compound according to any one of embodiments 1-21, except that compounds A and B are not excluded, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. P23. A compound according to any one of embodiments 1-21, except that compounds A and B are not excluded, or a pharmaceutically acceptable salt thereof, for use as a pharmaceutical. P24. A compound according to any one of embodiments 1 to 21, except that compounds A and B are not excluded, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or medical disorder mediated by Cav2.3. A method of treating a disease or medical disorder mediated by P25.Cav2.3 in a subject in need thereof, comprising administering to the subject an effective amount of a compound according to any one of embodiments 1 to 21, except that compounds A and B are not excluded, or a pharmaceutically acceptable salt thereof. P26. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1-21, except that compounds A and B are not excluded, for use in the treatment of a disease or medical disorder selected from a neurodegenerative disease, a neurodevelopmental disorder, epilepsy, an endocrine disorder, a cerebral vasospasm, and pain. P27. A compound according to any one of embodiments 1-21, except that compounds A and B are not excluded, or a pharmaceutically acceptable salt thereof, for use in the neuroprotective treatment of a neurodegenerative disease. P28. A compound according to any one of embodiments 1-21, except that compounds A and B are not excluded, or a pharmaceutically acceptable salt thereof, for use in the treatment of Parkinson's disease. P29. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1 to 21, except that compounds A and B are not excluded, for use in preventing or arresting degeneration of dopaminergic neurons in a subject with Parkinson's disease. [Example]

[0343] Abbreviation: Ac - acetyl 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 - Dimethyl Sulfoxide EDCI - 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride salt ee - enantiomeric excess eq.- equivalent Ghosez Reagent - 1-Chloro-N,N-2-trimethyl-1-propenylamine HATU - 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate HOAt - 1-hydroxy-7-azabenzotriazole HPLC - High Performance Liquid Chromatography IPA - 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 - Mesir MTBE - Methyl tert-butyl ether MW - microwave NBS - N-Bromosuccinimide NMM - N-methylmorpholine NMP - N-methyl-2-pyrrolidone NMR - Nuclear Magnetic Resonance Spectroscopy o / n - overnight Pd / C - Palladium on carbon Piv - Pivaloyl Prep - preparative pTSA - p-toluenesulfonic acid Py - pyridine rt - retention time RT - room temperature RM - reactant 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

[0344] Reagents and conditions Unless synthesized, reagents and starting materials were obtained from commercial sources. All reactions were performed under an inert atmosphere of either nitrogen or argon unless otherwise noted.

[0345] Compound name New compounds were named using CambridgeSoft's ChemDraw Ultra 14.0. For other compounds, particularly commercially available reagents, either names generated by ChemDraw Ultra 14.0 or names commonly found in online databases and catalogs are used.

[0346] Analysis method TCGLS LCMS Method Method 1 (K84-3 minutes) HPLC measurements were performed using a Waters Acquity H-class UPLC equipped with four pumps equipped with a degasser, a sample manager, a column oven (set at 50 °C), a diode array detector (DAD), and the column specified for each method below. The flow from the column was split to an MS mass 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 s. The capillary needle voltage was 3.50 kV for positive and negative ionization modes, and the ion source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, with a flow rate of 750 L / h. Data acquisition was performed using Mass Lynx 4.2 Software. Reversed-phase HPLC was performed on a Waters Acquity BEH C8 column (1.7 μm, 50 × 2.1 mm) at 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)) using a gradient of 10% B in 0.75 min, 10% to 50% in 0.25 min, 50% to 98% in 1.00 min, 98% B in 0.25 min, then 10% B in 0.35 min, which was maintained at these conditions for 0.40 min to re-equilibrate the column (total run time 3.00 min). An injection volume of 0.5 μL was used.

[0347] Method 2 (K84 / K92-5 minutes) HPLC measurements were performed using a Waters Acquity H-class UPLC equipped with four pumps equipped with a degasser, a sample manager, a column oven (set at 50 °C), a diode array detector (DAD), and the column specified for each method below. The flow from the column was split to an MS mass 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 s. The capillary needle voltage was 3.50 kV for positive and negative ionization modes, and the ion source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, with a flow rate of 750 L / h. Data acquisition was performed using Mass Lynx 4.2 Software. Reversed-phase HPLC was performed on a Waters Acquity BEH C8 column (1.7 μm, 50 × 2.1 mm) at 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)) using a gradient of 5% B in 0.75 min, 5% to 25% in 0.75 min, 25% to 95% in 1.50 min, 95% B in 1.00 min, and 5% B in 0.50 min, which was held at these conditions for 0.60 min to re-equilibrate the column (total run time 5.10 min). An injection volume of 0.5 μL was used.

[0348] Method 3 (K70 / 71 / 55 / 63 3 minutes) HPLC measurements were performed using a Waters Acquity UPLC equipped with two pumps equipped with a degasser, a sample manager, a column oven (set at 50 °C), a diode array detector (DAD), and the column specified for each method below. The flow from the column was split to an MS mass 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 s. The capillary needle voltage was 3.50 kV for positive and negative ionization modes, and the ion source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, with a flow rate of 750 L / h. Data acquisition was performed using Mass Lynx 4.1 Software. Reversed-phase HPLC was performed on a YMC Triart C18 column (3 μm, 33 × 2.1 mm) at 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)) with a gradient of 2% B in 0.75 min, 2% to 10% in 0.25 min, 10% to 98% in 1.00 min, 98% B in 0.50 min, and then 2% B in 0.40 min, with a 0.10 min hold time for re-equilibration (total run time 3.00 min). Injection volumes of 0.5–3 μL (depending on sample concentration) were used.

[0349] Method 4 (K03 / 04 / 05 / 06 / 07 / 08 / 72 / 78 5 minutes) HPLC measurements were performed using a Shimadzu HPLC equipped with two pumps equipped with a degasser, a sample manager, a dual-channel UV detector, and the column specified in each method below. The flow from the column was split to an MS mass spectrometer. The MS detector (Applied Biosystems API2000 / 2000Trap) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 800 in 0.40 seconds. The ion spray voltage was 5500 V for positive ionization mode and 4500 V for negative ionization mode. The ion source temperature was maintained at 300 °C, and the dextering potential was 8 to 50 V, depending on the compound. Data acquisition was performed using Analyst 1.6.3 Software. Reversed-phase HPLC was performed on a Waters Xbridge C18 / Agilent Zorbax C18 column (5 μm, 50 × 4.6 mm) at a flow rate of 1.20 mL / min. Two mobile phases were used (Mobile Phase A: 10 mm ammonium acetate in water; Mobile Phase B: ACN). These were used to run a gradient from 10% to 30% in 1.50 min, from 30% to 90% in 1.50 min, to 90% B in 1.00 min, then to 10% B in 1.00 min, and held at these conditions for 0.10 min. The pre-run equilibration time was 0.50 min (total run time: 5.10 min). Injection volumes of 1–3 μL (depending on sample concentration) were used.

[0350] Method 5 (K03 / 04 / 05 / 06 / 07 / 08 / 72 / 78.5 minutes non-polar) HPLC measurements were performed using a Shimadzu HPLC equipped with two pumps equipped with a degasser, a sample manager, a dual-channel UV detector, and the column specified in each method below. The flow from the column was split to an MS mass spectrometer. The MS detector (Applied Biosystems API2000 / 2000Trap) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 800 in 0.40 seconds. The ion spray voltage was 5500 V for positive ionization mode and 4500 V for negative ionization mode. The ion source temperature was maintained at 300 °C, and the dextering potential was 8 to 50 V, depending on the compound. Data acquisition was performed using Analyst 1.6.3 Software. Reversed-phase HPLC was performed on a Waters Xbridge C18 / Agilent Zorbax C18 column (5 μm, 50 × 4.6 mm) at a flow rate of 1.20 mL / min. Two mobile phases were used (Mobile Phase A: 10 mm ammonium acetate in water; Mobile Phase B: ACN). These were used to run a gradient from 50% to 95% B in 1.50 min, to 95% B in 2.50 min, then to 50% B in 1.00 min, and held at these conditions for 0.10 min. The pre-run equilibration time was 0.50 min (total run time: 5.10 min). Injection volumes of 1–3 μL (depending on sample concentration) were used.

[0351] Method 6 (K03 / 04 / 05 / 06 / 07 / 08 / 72 / 78 12 minutes) HPLC measurements were performed using a Shimadzu HPLC equipped with two pumps equipped with a degasser, a sample manager, a dual-channel UV detector, and the column specified in each method below. The flow from the column was split to an MS mass spectrometer. The MS detector (Applied Biosystems API2000 / 2000Trap) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 800 in 0.40 seconds. The ion spray voltage was 5500 V for positive ionization mode and 4500 V for negative ionization mode. The ion source temperature was maintained at 300 °C, and the dextering potential was maintained between 8 and 50 V, depending on the compound. Data acquisition was performed using Analyst 1.6.3 Software. Reversed-phase HPLC was performed on a Waters Xbridge C18 / Agilent Zorbax C18 column (5 μm, 50 × 4.6 mm) at a flow rate of 1.00 mL / min. Two mobile phases were used (Mobile Phase A: 10 mM ammonium acetate in water; Mobile Phase B: ACN). These were used to perform a gradient of 5% B in 1.00 min, 5% B to 50% B in 6.00 min, 50% B to 90% B in 3.00 min, 90% B in 1.00 min, and 5% B in 1.00 min, with a 0.10 min hold time. The pre-run equilibration time was 0.50 min (total run time: 12.10 min). Injection volumes of 1–3 μL (depending on sample concentration) were used.

[0352] Method 7 (K70 / 71 / 55 / 63 12 minutes) HPLC measurements were performed using a Waters Acquity UPLC equipped with two pumps equipped with a degasser, a sample manager, a column oven (set at 50 °C), a diode array detector (DAD), and the column specified in each method below. The flow from the column was split to an MS mass 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 s. The capillary needle voltage was 3.50 kV for positive and negative ionization modes, and the ion source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, with a flow rate of 750 L / h. Data acquisition was performed using Mass Lynx 4.1 Software. Reversed-phase HPLC was performed on a Waters YMC Triart C18 column (3 μm, 33 × 2.1 mm) at 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)) with a gradient of 5% B in 1.00 min, 5% to 50% in 4.00 min, 50% to 90% in 3.00 min, 90% B in 2.00 min, and then 5% B in 1.50 min, with a 0.50 min hold time for re-equilibration (total run time 12.00 min). Injection volumes of 0.5–3 μL (depending on sample concentration) were used.

[0353] Method 8 (K83 3 minutes) HPLC measurements were performed using a Waters Acquity H-class UPLC equipped with four pumps equipped with a degasser, a sample manager, a column oven (set at 50 °C), a diode array detector (DAD), and the column specified for each method below. The flow from the column was split to an MS mass 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 s. The capillary needle voltage was 3.50 kV for positive and negative ionization modes, and the ion source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, with a flow rate of 750 L / h. Data acquisition was performed using Mass Lynx 4.2 Software. Reversed-phase HPLC was performed on a Waters Xbridge C18 column (3.5 μm, 50 × 3 mm) at 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)) using a gradient of 5% B in 0.75 min, 5% to 30% in 0.25 min, 30% to 98% in 1.00 min, 98% B in 0.25 min, and 5% B in 0.50 min, with a 0.25 min hold at these conditions to allow the column to re-equilibrate (total run time 3.00 min). An injection volume of 0.5 μL was used.

[0354] Method 9 (K83 5 minutes) HPLC measurements were performed using a Waters Acquity H-class UPLC equipped with four pumps equipped with a degasser, a sample manager, a column oven (set at 50 °C), a diode array detector (DAD), and the column specified for each method below. The flow from the column was split to an MS mass 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 s. The capillary needle voltage was 3.50 kV for positive and negative ionization modes, and the ion source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, with a flow rate of 750 L / h. Data acquisition was performed using Mass Lynx 4.2 Software. Reversed-phase HPLC was performed on a Waters Xbridge C18 column (3.5 μm, 50 × 3 mm) at 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)) using a gradient of 5% B in 0.75 min, 5% to 15% in 0.50 min, 15% to 70% in 1.25 min, 70% to 98% in 1.25 min, 98% B in 0.50 min, and 5% B in 0.25 min, which were held at these conditions for 0.60 min to re-equilibrate the column (total run time 5.10 min). An injection volume of 0.5 μL was used.

[0355] Method 10 (K83 12 minutes) HPLC measurements were performed using a Waters Acquity H-class UPLC equipped with four pumps equipped with a degasser, a sample manager, a column oven (set at 50 °C), a diode array detector (DAD), and the column specified for each method below. The flow from the column was split to an MS mass 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 s. The capillary needle voltage was 3.50 kV for positive and negative ionization modes, and the ion source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, with a flow rate of 750 L / h. Data acquisition was performed using Mass Lynx 4.2 Software. Reversed-phase HPLC was performed on a Waters Xbridge C18 column (3.5 μm, 50 × 3 mm) at 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)) using a gradient of 2% B in 1.00 min, 2% to 50% in 4.00 min, 50% to 98% in 3.00 min, 98% B in 2.00 min, and 2% B in 2.00 min, held at these conditions for 0.10 min to re-equilibrate the column (total run time 12.10 min). An injection volume of 0.5 μL was used.

[0356] Method 11 (K84 12 minutes) HPLC measurements were performed using a Waters Acquity H-class UPLC equipped with four pumps equipped with a degasser, a sample manager, a column oven (set at 50 °C), a diode array detector (DAD), and the column specified for each method below. The flow from the column was split to an MS mass 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 s. The capillary needle voltage was 3.50 kV for positive and negative ionization modes, and the ion source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, with a flow rate of 750 L / h. Data acquisition was performed using Mass Lynx 4.2 Software. Reversed-phase HPLC was performed on a Waters Acquity BEH C8 column (1.7 μm, 50 × 2.1 mm) at 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)) using a gradient of 5% B in 1.00 min, 5% to 50% in 4.00 min, 50% to 90% in 3.00 min, 90% B in 2.00 min, then 5% B in 1.50 min, with a 0.50 min hold at these conditions to allow the column to re-equilibrate (total run time 12.00 min). An injection volume of 0.5 μL was used.

[0357] Method 12 (K79 3 minutes) HPLC measurements were performed using an Agilent 1260 Infinity II UPLC equipped with four pumps equipped with a degasser, a sample manager, a column oven (set at 50 °C), a diode array detector (DAD), and the column specified for each method below. The flow from the column was split to an MS mass 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 s. The capillary needle voltage was 4.00 kV for positive and negative ionization modes, and the ion source temperature was maintained at 350 °C. Nitrogen was used as the desolvation gas, with a flow rate of 12 L / min. Data acquisition was performed with an Open Lab CDS. Reversed-phase HPLC was performed on a YMC Triart C18 column (3 μm, 33 × 2.1 mm) at 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) with a gradient of 2% B in 0.50 min, 2% to 30% in 0.50 min, 30% to 98% in 1.00 min, 98% B in 0.25 min, and then 2% B in 0.75 min (total run time 3.00 min). An injection volume of 0.5 μL was used.

[0358] Method 13 (K83 3 minutes-BEH) HPLC measurements were performed using a Waters Acquity H-class UPLC equipped with four pumps equipped with a degasser, a sample manager, a column oven (set at 50 °C), a diode array detector (DAD), and the column specified for each method below. The flow from the column was split to an MS mass 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 s. The capillary needle voltage was 3.50 kV for positive and negative ionization modes, and the ion source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, with a flow rate of 750 L / h. Data acquisition was performed using Mass Lynx 4.2 Software. Reversed-phase HPLC was performed on a Waters Acquity C18 column (1.7 μm, 30 × 2.1 mm) at 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)) using a gradient of 2% B in 0.50 min, 2% to 98% in 1.00 min, 98% B in 1.00 min, 2% B in 0.25 min, and held at these conditions for 0.25 min to re-equilibrate the column (total run time 3.00 min). An injection volume of 0.5 μL was used.

[0359] Method 14 (K83 12 minutes) - OLD HPLC measurements were performed using a Waters Acquity H-class UPLC equipped with four pumps equipped with a degasser, a sample manager, a column oven (set at 50 °C), a diode array detector (DAD), and the column specified for each method below. The flow from the column was split to an MS mass 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 s. The capillary needle voltage was 3.50 kV for positive and negative ionization modes, and the ion source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, with a flow rate of 750 L / h. Data acquisition was performed using Mass Lynx 4.2 Software. Reversed-phase HPLC was performed on a Waters Xbridge C18 column (5 μm, 50 × 4.6 mm) at 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)) to run a gradient of 2% B in 0.75 min, 2% to 15% in 0.50 min, 15% to 70% in 1.25 min, 70% to 98% in 1.25 min, 98% B in 0.75 min, and 2% B in 0.50 min, with a 0.10 min hold at these conditions to allow the column to re-equilibrate (total run time 5.10 min). An injection volume of 0.5 μL was used.

[0360] Method 15 (K83 12 minutes) - OLD HPLC measurements were performed using a Waters Acquity H-class UPLC equipped with four pumps equipped with a degasser, a sample manager, a column oven (set at 50 °C), a diode array detector (DAD), and the column specified for each method below. The flow from the column was split to an MS mass 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 s. The capillary needle voltage was 3.50 kV for positive and negative ionization modes, and the ion source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, with a flow rate of 750 L / h. Data acquisition was performed using Mass Lynx 4.2 Software. Reversed-phase HPLC was performed on a Waters Xbridge C18 column (5 μm, 50 × 4.6 mm) at 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)) using a gradient of 2% B in 1.00 min, 2% to 50% in 4.00 min, 50% to 90% in 3.00 min, 90% B in 2.00 min, and 2% B in 2.00 min, held at these conditions for 0.10 min to re-equilibrate the column (total run time 12.10 min). An injection volume of 0.5 μL was used.

[0361] Method 16 HPLC measurements were performed using a Waters Acquity UPLC equipped with four pumps equipped with a degasser, a sample manager, a column oven (set at 50 °C), a diode array detector (DAD), and the column specified for each method below. The flow from the column was split to an MS mass 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 s. The capillary needle voltage was 3.50 kV for positive and negative ionization modes, and the ion source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, with a flow rate of 750 L / h. Data acquisition was performed using Mass Lynx 4.2 Software. Reversed-phase HPLC was performed on a Sunfire C18 column (5 μm, 100 × 4.6 mm) at 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)) with a gradient of 2% B in 1.00 min, 2% to 50% in 4.00 min, 50% to 95% in 4.00 min, 95% B in 3.00 min, then 5% B in 0.50 min (total run time 12.50 min). An injection volume of 0.5 μL was used.

[0362] Method 17 HPLC measurements were performed using a Shimadzu HPLC equipped with two pumps equipped with a degasser, a sample manager, a dual-channel UV detector, and the column specified in each method below. The flow from the column was split to an MS mass spectrometer. The MS detector (Applied Biosystems API2000 / 2000Trap) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 800 in 0.40 seconds. The ion spray voltage was 5500 V for positive ionization mode and 4500 V for negative ionization mode. The ion source temperature was maintained at 300 °C, and the dextering potential was maintained between 8 and 50 V, depending on the compound. Data acquisition was performed using Analyst 1.6.3 Software. Reversed-phase HPLC was performed on a Waters Xbridge C18 / Agilent Zorbax Ext C18 column (5 μm, 100 × 4.6 mm) at a flow rate of 1.00 mL / min. Two mobile phases were used (Mobile Phase A: 10 mm ammonium acetate in water; Mobile Phase B: ACN). These were used to perform a gradient of 50% B in 2.00 min, 50% B to 95% B in 6.00 min, 95% B in 3.00 min, and 50% B in 3.00 min, which was maintained at these conditions for 4.00 min. The pre-run equilibration time was 4.00 min (total run time: 18.00 min). Injection volumes of 1–3 μL (depending on sample concentration) were used.

[0363] Method 18 (K84 3 minutes) - OLD HPLC measurements were performed using a Waters Acquity H-class UPLC equipped with four pumps equipped with a degasser, a sample manager, a column oven (set at 50 °C), a diode array detector (DAD), and the column specified for each method below. The flow from the column was split to an MS mass 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 s. The capillary needle voltage was 3.50 kV for positive and negative ionization modes, and the ion source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, with a flow rate of 750 L / h. Data acquisition was performed using Mass Lynx 4.2 Software. Reversed-phase HPLC was performed on a YMC Triart C18 column (3 μm, 33 × 2.1 mm) at 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)) using a gradient of 2% B in 0.75 min, 2% to 10% in 0.25 min, 10% to 98% in 1.00 min, 98% B in 0.50 min, and then 2% B in 0.40 min, with a 0.10 min hold time for re-equilibration (total run time 3.00 min). An injection volume of 0.5 μL was used.

[0364] Method 19 (K84 3 minutes) - OLD BEH polarity HPLC measurements were performed using a Waters Acquity H-class UPLC equipped with four pumps equipped with a degasser, a sample manager, a column oven (set at 50 °C), a diode array detector (DAD), and the column specified for each method below. The flow from the column was split to an MS mass 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 s. The capillary needle voltage was 3.50 kV for positive and negative ionization modes, and the ion source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, with a flow rate of 750 L / h. Data acquisition was performed using Mass Lynx 4.2 Software. Reversed-phase HPLC was performed on a Waters Acquity BEH C8 column (1.7 μm, 50 × 2.1 mm) at 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)) using a gradient of 2% B in 0.75 min, 2% to 10% in 0.25 min, 10% to 98% in 1.00 min, 98% B in 0.50 min, then 2% B in 0.40 min, with a 0.10 min hold at these conditions to allow the column to re-equilibrate (total run time 3.00 min). An injection volume of 0.5 μL was used.

[0365] Method 20 (K43 6 minutes) HPLC measurements were performed using an Agilant HPLC equipped with two pumps equipped with a degasser, a sample manager, a DAD, and the column specified in each method below. The flow from the column was split to an MS mass spectrometer. The MS detector (Applied Biosystems API2000 / 2000Trap) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 800 in 0.40 seconds. The ion spray voltage was 5500 V for positive ionization mode and 4500 V for negative ionization mode. The ion source temperature was maintained at 300 °C, and the dextering potential was 8 to 50 V, depending on the compound. Data acquisition was performed using Analyst 1.6.3 Software. Reversed-phase HPLC was performed on a Waters Xbridge C18 / Agilent Zorbax C18 column (5 μm, 50 × 4.6 mm) at a flow rate of 1.20 mL / min. Two mobile phases were used (Mobile Phase A: 10 mm ammonium acetate in water; Mobile Phase B: ACN). These were used to run a gradient of 10% to 30% in 1.50 min, 30% to 90% in 1.50 min, 90% B in 1.00 min, and then 10% B in 1.00 min, with a 1.00 min hold time. The pre-run equilibration time was 0.50 min (total run time 6.00 min). Injection volumes of 1–3 μL (depending on sample concentration) were used.

[0366] Method 22 (K91 12 minutes) HPLC measurements were performed using a Waters Acquity H-class UPLC equipped with four pumps equipped with a degasser, a sample manager, a column oven (set at 50 °C), a diode array detector (DAD), and the column specified for each method below. The flow from the column was split to an MS mass 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 s. The capillary needle voltage was 3.50 kV for positive and negative ionization modes, and the ion source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, with a flow rate of 750 L / h. Data acquisition was performed using Mass Lynx 4.2 Software. Reversed-phase HPLC was performed on a Waters Acquity BEH C18 column (1.7 μm, 50 × 2.1 mm) at 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)) to run a gradient of 2% B in 1.00 min, 2% to 50% in 4.00 min, 50% to 98% in 3.00 min, 98% B in 2.00 min, and 2% B in 1.00 min, which was held at these conditions for 1.00 min to re-equilibrate the column (total run time 12.00 min). An injection volume of 0.5 μL was used.

[0367] Method 23 (K91 3 minutes) HPLC measurements were performed using a Waters Acquity H-class UPLC equipped with four pumps equipped with a degasser, a sample manager, a column oven (set at 40 °C), a diode array detector (DAD), and the column specified for each method below. The flow from the column was split to an MS mass 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 s. The capillary needle voltage was 3.50 kV for positive and negative ionization modes, and the ion source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, with a flow rate of 750 L / h. Data acquisition was performed using Mass Lynx 4.2 Software. Reversed-phase HPLC was performed on a Waters Acquity C18 column (1.7 μm, 50 × 2.1 mm) at 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)) using a gradient of 5% B in 0.75 min, 5% to 30% in 0.25 min, 30% to 98% in 1.00 min, 98% B in 0.25 min, and 5% B in 0.25 min, which was held at these conditions for 0.50 min to re-equilibrate the column (total run time 3.00 min). An injection volume of 0.5 μL was used.

[0368] Method 24 (K91 5 minutes) HPLC measurements were performed using a Waters Acquity H-class UPLC equipped with four pumps equipped with a degasser, a sample manager, a column oven (set at 40 °C), a diode array detector (DAD), and the column specified for each method below. The flow from the column was split to an MS mass 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 s. The capillary needle voltage was 3.50 kV for positive and negative ionization modes, and the ion source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, with a flow rate of 750 L / h. Data acquisition was performed using Mass Lynx 4.2 Software. Reversed-phase HPLC was performed on a Waters Acquity C18 column (1.7 μm, 50 × 2.1 mm) at 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)) using a gradient of 5% B in 0.75 min, 5% to 15% in 0.50 min, 15% to 70% in 1.25 min, 70% to 98% in 1.25 min, 98% B in 0.50 min, and 5% B in 0.25 min, which were held at these conditions for 0.60 min to re-equilibrate the column (total run time 5.10 min). An injection volume of 0.5 μL was used.

[0369] Method 25 (K92-3 minutes) HPLC measurements were performed using a Waters Acquity H-class UPLC equipped with four pumps equipped with a degasser, a sample manager, a column oven (set at 50 °C), a diode array detector (DAD), and the column specified for each method below. The flow from the column was split to an MS mass 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 seconds. The capillary needle voltage was 3.50 kV for positive and negative ionization modes, and the ion source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, with a flow rate of 750 L / h. Data acquisition was performed using Mass Lynx 4.2 Software. Reversed-phase HPLC was performed on a Waters Acquity BEH C18 column (1.7 μm, 50 × 2.1 mm) at 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)) using a gradient of 10% B in 0.75 min, 10% to 50% in 0.25 min, 50% to 98% in 1.00 min, 98% B in 0.25 min, then 10% B in 0.35 min, which was maintained at these conditions for 0.40 min to re-equilibrate the column (total run time 3.00 min). An injection volume of 0.5 μL was used.

[0370] Method 26(TM) HPLC measurements were performed using a Shimadzu HPLC equipped with two pumps equipped with a degasser, a sample manager, a dual-channel UV detector, and the column specified in each method below. The flow from the column was split to an MS mass spectrometer. The MS detector (Applied Biosystems API2000 / 2000Trap) was configured with an electrospray ionization source. Mass spectra were acquired by scanning from 100 to 800 in 0.40 seconds. The ion spray voltage was 5500 V for positive ionization mode and 4500 V for negative ionization mode. The ion source temperature was maintained at 300 °C, and the dextering potential was 8 to 50 V, depending on the compound. Data acquisition was performed using Analyst 1.6.3 Software. Reversed-phase HPLC was performed on a Gemini NX C18 column (5 μm, 100 × 4.6 mm) at 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). These were used to perform a gradient of 2% B in 1.50 min, 2% B to 40% B in 3.50 min, 40% B to 95% B in 3.00 min, 95% B in 6.00 min, and 2% B in 1.00 min, which was maintained for 4.00 min. The pre-run equilibration time was 4.00 min (total run time: 19.00 min). Injection volumes of 1–3 μL (depending on sample concentration) were used.

[0371] Method 27 (K92-3 minutes-YMC) HPLC measurements were performed using a Waters Acquity H-class UPLC equipped with four pumps equipped with a degasser, a sample manager, a column oven (set at 50 °C), a diode array detector (DAD), and the column specified for each method below. The flow from the column was split to an MS mass 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 s. The capillary needle voltage was 3.50 kV for positive and negative ionization modes, and the ion source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, with a flow rate of 750 L / h. Data acquisition was performed using Mass Lynx 4.2 Software. Reversed-phase HPLC was performed on a YMC Triart C18 column (3 μm, 33 × 2.1 mm) at 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)) with a gradient of 2% B in 0.75 min, 2% to 10% in 0.25 min, 10% to 98% in 1.00 min, 98% B in 0.50 min, and then 2% B in 0.40 min, with a 0.10 min hold time for re-equilibration (total run time 3.00 min). Injection volumes of 0.5–3 μL (depending on sample concentration) were used.

[0372] Method 28 (K92-5 minutes-YMC) HPLC measurements were performed using a Waters Acquity H-class UPLC equipped with four pumps equipped with a degasser, a sample manager, a column oven (set at 50 °C), a diode array detector (DAD), and the column specified for each method below. The flow from the column was split to an MS mass 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 s. The capillary needle voltage was 3.50 kV for positive and negative ionization modes, and the ion source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, with a flow rate of 750 L / h. Data acquisition was performed using Mass Lynx 4.2 Software. Reversed-phase HPLC was performed on a YMC Triart C18 column (3 μm, 33 × 2.1 mm) at 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)) with a gradient of 5% B in 0.75 min, 5% to 25% in 0.75 min, 25% to 95% in 1.50 min, 95% B in 1.75 min, and then 5% B in 0.25 min. These conditions were maintained for 0.10 min to re-equilibrate the column (total run time 5.10 min). Injection volumes of 0.5–3 μL (depending on sample concentration) were used.

[0373] Method 29 (K70 / 71 / 55 / 63.5 minutes-YMC) HPLC measurements were performed using a Waters Acquity UPLC equipped with two pumps equipped with a degasser, a sample manager, a column oven (set at 50 °C), a diode array detector (DAD), and the column specified for each method below. The flow from the column was split to an MS mass 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 s. The capillary needle voltage was 3.50 kV for positive and negative ionization modes, and the ion source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, with a flow rate of 750 L / h. Data acquisition was performed using Mass Lynx 4.1 Software. Reversed-phase HPLC was performed on a YMC Triart C18 column (3 μm, 33 × 2.1 mm) at 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)) with a gradient of 5% B in 0.75 min, 5% to 25% in 0.75 min, 25% to 95% in 1.50 min, 95% B in 1.75 min, and then 5% B in 0.25 min. These conditions were maintained for 0.10 min to re-equilibrate the column (total run time 5.10 min). Injection volumes of 0.5–3 μL (depending on sample concentration) were used.

[0374] Method 30 (K71 5 minutes-BEH) HPLC measurements were performed using a Waters Acquity UPLC equipped with two pumps equipped with a degasser, a sample manager, a column oven (set at 50 °C), a diode array detector (DAD), and the column specified in each method below. The flow from the column was split to an MS mass 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 s. The capillary needle voltage was 3.50 kV for positive and negative ionization modes, and the ion source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, with a flow rate of 750 L / h. Data acquisition was performed using Mass Lynx 4.1 Software. Reversed-phase HPLC was performed on a Waters Acquity BEH C18 column (1.7 μm, 50 × 2.1 mm) at 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)) with a gradient of 2% B in 0.50 min, 2% to 30% in 1.00 min, 30% to 95% in 1.50 min, 95% B in 1.00 min, and then 2% B in 0.50 min, held at these conditions for 0.60 min to re-equilibrate the column (total run time 5.10 min). Injection volumes of 0.5–3 μL (depending on sample concentration) were used.

[0375] Method 31 (K71 3 minutes-BEH) HPLC measurements were performed using a Waters Acquity UPLC equipped with two pumps equipped with a degasser, a sample manager, a column oven (set at 50 °C), a diode array detector (DAD), and the column specified for each method below. The flow from the column was split to an MS mass 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 s. The capillary needle voltage was 3.50 kV for positive and negative ionization modes, and the ion source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, with a flow rate of 750 L / h. Data acquisition was performed using Mass Lynx 4.1 Software. Reversed-phase HPLC was performed on a Waters Acquity BEH C18 column (1.7 μm, 50 × 2.1 mm) at 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)) with a gradient of 5% B in 0.75 min, 5% to 50% in 0.45 min, 50% to 98% in 0.80 min, 98% B in 0.25 min, and then 5% B in 0.35 min, with a 0.50 min hold at these conditions to re-equilibrate the column (total run time 3.10 min). Injection volumes of 0.5–3 μL (depending on sample concentration) were used.

[0376] Method 32 (K103-3 minutes) HPLC measurements were performed using a Waters Acquity H-class UPLC equipped with four pumps equipped with a degasser, a sample manager, a column oven (set at 50 °C), a diode array detector (DAD), and the column specified for each method below. The flow from the column was split to an MS mass 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 seconds. The capillary needle voltage was 1.50 kV for positive and negative ionization modes, and the ion source temperature was maintained at 150 °C. Nitrogen was used as the desolvation gas, with a flow rate of 600 L / h. Data acquisition was performed using Mass Lynx 4.2 Software. Reversed-phase HPLC was performed on a Waters Acquity BEH C18 column (1.7 μm, 50 × 2.1 mm) at 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)) using a gradient of 10% B in 0.75 min, 10% to 50% in 0.25 min, 50% to 98% in 1.00 min, 98% B in 0.25 min, then 10% B in 0.35 min, which was maintained at these conditions for 0.40 min to re-equilibrate the column (total run time 3.00 min). An injection volume of 0.5 μL was used.

[0377] NMR All NMR spectra were obtained using a Bruker Avance 400 MHz spectrometer running Topspin Software.

[0378] GCMS GCMS-Method-1: GC-MS was performed on Agilent 6890 and 5973 N MSD series instruments. Column: HP-5MS (30 x 250 μm x 0.25 μm) Carrier gas: Helium Inlet temperature: 250℃ Split ratio: 5:1 Carrier gas flow rate: 1.0 mL / min Solvent delay time: 3 minutes Mass range: 50 to 550 amu Injection volume: 1uL Tilt Profile: The oven temperature was initially held at 100°C for 2 minutes, then increased at a rate of 35°C to 310°C for 6 minutes, for a total run time of 14 minutes. GCMS-Method-2: GC-MS was performed on Agilent 7890B and 5977B MSD series instruments. Column: HP-5MS (30 x 250 μm x 0.25 μm) Carrier gas: Helium Inlet temperature: 250℃ Split ratio: 20:1 Carrier gas flow rate: 1.0 mL / min Tilt Profile: The oven temperature was initially held at 60°C for 2 minutes, then increased at a rate of 20°C to 100°C for 2 minutes, and increased at a rate of 40°C to 310°C for 4 minutes, for a total run time of 15.25 minutes.

[0379] SFC Supercritical fluid chromatography (SFC) analysis was performed on a WATERS SFC analyzer. Column: Chiralpak IG 250 × 4.6 mm, particle size 5 μm. Method: Mobile phase A: carbon dioxide, Mobile phase B: hexane / IPA / methanol 2 / 1 / 1 (0.3% isopropylamine), isocratic flow rate 4.0 mL / min, 20% B, wavelength: 240 nm.

[0380] Example 1 5-chloro-N-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide [ka] General Method for Sulfonamide Formation (Method A): To a suspension of 2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine hydrochloride (528.8 mg, 2.3 mmol) in DCM (5 mL), DIPEA (1.2 mL, 6.9 mmol) was added, and the solution was cooled to 0 °C. A solution of 5-chlorothiophene-2-sulfonyl chloride (500 mg, 2.3 mmol) in DCM (0.3 mL) was added thereto. The reaction mixture was stirred at room temperature for 1 hour. The volatiles were evaporated under reduced pressure, and the crude product was purified by column chromatography on silica gel using 15% ethyl acetate in hexanes to isolate 1.1 as a colorless sticky gum (140 mg, 16% yield). 1 H NMR(400MHz,DMSO-d6)ae 9.68(d,J=9.96Hz,1H),7.55-7.49(m,2H),7.31(d,J=3.96Hz,1H),7.14(t,J=8.76Hz,2H),7.04(d,J=3.96Hz,1H),5.44-5.39(m,1H).

[0381] 5-chloro-N-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide (Example 1): General Method for Sulfonamide-N-Alkylation (Method B): To a stirred solution of secondary sulfonamide (0.307 mmol) and MeI (3.067 mmol) in DMF (2 mL), K2CO3 or Cs2CO3 (0.46 mmol) was added, and the RM was stirred at room temperature for 8 h. The reaction was diluted with cold water (10 mL) and extracted with ethyl acetate (2 x 10 mL). The combined organic portions were washed with water (10 mL) and brine (10 mL), dried (anhydrous Na2SO4), and concentrated under reduced pressure to give the crude product. The crude product was further purified by column chromatography on silica gel using 25% ethyl acetate in hexanes to give the desired compound.

[0382] Methylation of intermediate 1.1 was carried out using CsCO at 70 °C according to the protocol described in Method B. The compound was purified by column chromatography on silica gel using 20% ​​ethyl acetate in hexanes, and Example 1 was isolated as a light yellow gum (22 mg, 42% yield, 95.04% purity). 1 H NMR(400MHz,DMSO-d6)ae 7.71(d,J=4.1Hz,1H),7.44(dd,J=5.4,8.6Hz,2H),7.32(d,J=4.0Hz,1H),7.26(t,J=8.8Hz,2H),6.00(q,J=8.6Hz,1H),2.78(s,3H).

[0383] Examples 2 to 7 [ka] 5-cyano-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide 2.1: The synthesis of intermediate 2.1 was carried out essentially as described in Method A using 2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine hydrochloride and 5-cyanothiophene-2-sulfonyl chloride. Pyridine was used as the base and THF was used as the solvent. The compound was purified by column chromatography on silica gel using 40% ethyl acetate:hexane and isolated as a yellow solid (90 mg, 51% yield). 1 H NMR(400MHz,DMSO-d6):δ 10.10-9.94(m,1H),7.82(d,J=4.0Hz,1H),7.54-7.46(m,4H),7.15(t,J=8.8Hz,2H),5.59-5.43(m,1H).

[0384] Example 2 5-cyano-N-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide [ka] Methylation of intermediate 2.1 was preformed at 70 °C using CsCO as the base according to the protocol described in Method B. The crude product was purified by column chromatography on silica gel using 35% ethyl acetate in hexanes, and compound Example 2 was isolated as a yellow oil (15 mg, 48% yield, 99.40% purity). 1 H NMR(400MHz,DMSO-d6):δ 8.09(d,J=4.0Hz,1H),7.92(d,J=4.0Hz,1H),7.43(dd,J=5.3,8.6Hz,2H),7.27(t,J=8.8Hz,2H),6.07(q,J=8.4Hz,1H),2.82(s,3H).

[0385] Example 3 5-cyano-N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide [ka] Ethylation of intermediate 2.1 was carried out using CsCO as the base according to the protocol described in Method B at 70 °C. The crude product was purified by column chromatography on silica gel using 35% ethyl acetate in hexanes to isolate compound Example 3 as a yellow oil (15 mg, 46% yield, 99.73% purity). GCMS: m / z found 392.1 (CHE 300-Method-1); 1 H NMR(400MHz,DMSO-d6):δ 8.06(d,J=4.0Hz,1H),7.92(d,J=4.0Hz,1H),7.44(t,J=5.3Hz,2H),7.27(t,J =8.8Hz,2H),6.05(q,J=8.6Hz,1H),3.45-3.31(m,2H),1.01(t,J=6.8Hz,3H).

[0386] Examples 4 and 5 (S)-5-cyano-N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide (Example 4) and (R)-5-cyano-N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide (Example 5): [ka] Chiral separation of 5-cyano-N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide (Example 3) resulted in both enantiomers as mentioned below: Chiral separation method 1: CHIRALPAK IA (250 x 20 mm) 5μ, flow rate - 18 mL / min, mobile phase - hexane / ETOH-95 / 05, solubility - DCM, wavelength - 268 nm, run time - 22 min.

[0387] (Example 4): Yellow oil (4 mg, 99.41% purity). GCMS: m / z found 392.0 (CHE 300-Method-3); 1 H NMR(400MHz,DMSO-d6):δ 8.06(d,J=4.0Hz,1H),7.92(d,J=4.0Hz,1H),7.45(dd,J=5.2,8.6Hz,2H),7.27( t,J=8.8Hz,2H),6.05(q,J=8.7Hz,1H),3.48-3.33(m,2H),1.01(t,J=7.0Hz,3H).

[0388] (Example 5): Yellow oil (5 mg, 99.15% purity). GCMS: m / z found 392.0 (CHE 300-Method-3); 1 H NMR(400MHz,DMSO-d6):δ 8.06(d,J=4.0Hz,1H),7.92(d,J=4.0Hz,1H),7.45(dd,J=5.3,8.6Hz,2H),7.27( t,J=8.8Hz,2H),6.04(q,J=8.6Hz,1H),3.47-3.31(m,2H),1.01(t,J=7.0Hz,3H).

[0389] Examples 6 and 7 (R)-5-cyano-N-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide (Example 6) and (S)-5-cyano-N-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide (Example 7) [ka] Chiral separation of 5-cyano-N-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide (Example 2) yielded both enantiomers as mentioned below. Chiral separation method: CHIRALPAK IG (250 x 21 mm) 5μ, flow rate - 21 mL / min, mobile phase - hexane / MEOH / MTBE-96 / 02 / 02, solubility - DCM, wavelength - 268 nm, run time - 25 min.

[0390] (Example 6): Yellow oil (4 mg, 99.35% purity). GCMS: m / z found 377.9 (CHE 300-Method-2); 1 H NMR(400MHz,DMSO-d6):δ 8.08(d,J=4.0Hz,1H),7.92(d,J=4.0Hz,1H),7.43(dd,J=5.3,8.6Hz,2H),7.26(t,J=8.7Hz,2H),6.07(q,J=8.5Hz,1H),2.82(s,3H).

[0391] (Example 7): Yellow oil (4 mg, 98.51% purity). GCMS: m / z found 378.1 (CHE 300-Method-2); 1 H NMR(400MHz,DMSO-d6):δ 8.09(d,J=4.0Hz,1H),7.92(d,J=4.1Hz,1H),7.43(dd,J=5.3,8.6Hz,2H),7.26(t,J=8.8Hz,2H),6.07(q,J=8.6Hz,1H),2.82(s,3H).

[0392] Examples 8 to 13 [ka] 5-Methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide 3.1: Intermediate 3.1 was synthesized from 5-methylthiophene-2-sulfonyl chloride using 2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine and pyridine as the base according to the procedure described in Method A. The compound was purified by flash chromatography on silica gel using 20% ​​ethyl acetate in hexanes and isolated as a light yellow oil (100 mg, 56% yield). 1 H NMR(400MHz,DMSO-d6)δ 9.41(d,J=9.9Hz,1H),7.50(t,J=8.2Hz,2H),7.22(d,J=3.7Hz,1H),7.12(t,J=8.7Hz,2H),6.67(d,J=3.4Hz,1H),5.56-5.03(m,1H),2.37(s,3H).

[0393] Example 8 N-ethyl-5-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide Ethylation of intermediate 3.1 was carried out using CsCO as the base according to the protocol described in Method B at 70 °C. The crude product was purified by column chromatography on silica gel using 35% ethyl acetate in hexanes, and the desired compound, Example 8, was isolated as a pale yellow gum (15 mg, 55% yield, 98.88% purity). LCMS: m / z found 382.1 [M+H] + , room temperature, 3.85 min (Method 1) [Xbridge C18 column 5 μm, 50 × 4.6 mm]; 1 H NMR(400MHz,chloroform-d)δ 7.42(d,J=3.7Hz,1H),7.39(dd,J=5.2,8.6Hz,2H),7.11-7.00(m,2H),6.74(dd,J=1.1,3.8Hz,1H) ,5.74(q,J=8.4Hz,1H),3.40-3.26(m,1H),3.21-3.07(m,1H),2.52(s,3H),1.00(t,J=7.0Hz,3H).

[0394] (S)—N-ethyl-5-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide (Example 9) and (R)—N-ethyl-5-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide (Example 10): [ka] Chiral separation of N-ethyl-5-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide gave both enantiomers as noted below. Chiral Separation Method: Chiral separation was performed on an Agilent 1200 series instrument. Column: Chiralcel OJ-H (250 x 21 mm), 5μ, operated at ambient temperature with a flow rate of 21.0 mL / min. Mobile Phase: A mixture of 95% hexane and 5% ethanol, and this isocratic mixture was maintained at a wavelength of 264 nm for up to 35 minutes.

[0395] Example 9: Colorless sticky solid (10 mg, 99.26% purity). LCMS: m / z found 382.1 [M+H] + , room temperature = 3.73 min (Method 1) [Xbridge C8 column 5 μm, 50 × 4.6 mm]; 1 H NMR(400MHz,chloroform-d)δ 7.42(d,J=3.8Hz,1H),7.39(dd,J=5.2,8.6Hz,2H),7.06(t,J=8.6Hz,2H),6.74(dd,J=1.2,3.7Hz,1 H),5.74(q,J=8.5Hz,1H),3.39-3.26(m,1H),3.21-3.07(m,1H),2.52(s,3H),1.00(t,J=7.0Hz,3H).

[0396] Example 10: Colorless sticky solid (10 mg, 98.33% purity). LCMS: m / z found 382.2 [M+H] + , room temperature = 3.74 min (Method 1) [Xbridge C8 column 5 μm, 50 × 4.6 mm]. 1H NMR (400 MHz, chloroform-d) δ 7.43 (d, J = 3.7 Hz, 1H), 7.39 (dd, J = 5.1, 8.4 Hz, 2H), 7.06 (t, J = 8.6 Hz, 1H), 6.73 (d, J = 3.8 Hz, 1H), 5.74 (q, J = 8.3 Hz, 1H), 3.40-3.26 (m, 1H), 3.21-3.07 (m, 1H), 2.52 (s, 3H), 1.00 (t, J = 7.1 Hz, 3H).

[0397] Example 11 N,5-dimethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide Methylation of intermediate 3.1 was carried out using CsCO as the base according to the protocol described in Method B at 70 °C. The crude product was purified by column chromatography on silica gel using 35% ethyl acetate in hexanes, and the desired compound, Example 11, was isolated as a pale yellow gum (15 mg, 57% yield, 96.26% purity). LCMS: m / z found 368.0 [M+H] + , room temperature = 3.72 min (Method 1) [Xbridge C18 column 5 μm, 50 × 4.6 mm]; 1 H NMR (400 MHz, chloroform-d) δ 7.41 (d, J = 3.7 Hz, 1H), 7.37 (dd, J = 5.1, 8.5 Hz, 2H), 7.07 (t, J = 8.6 Hz, 2H), 6.78-6.72 (m, 1H), 5.80 (q, J = 8.2 Hz, 1H), 2.72 (s, 3H), 2.52 (s, 3H).

[0398] Examples 12 and 13 (S)—N,5-dimethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide (Example 12) and (R)—N,5-dimethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide (Example 13) [ka] Chiral separation of N,5-dimethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide gave both enantiomers as noted below. Chiral Separation Method: Chiral separation was performed on an Agilent 1200 series instrument. Column: Chiralcel OJ-H (250 x 21 mm), 5μ, operated at ambient temperature with a flow rate of 21.0 mL / min. Mobile Phase: A mixture of 95% hexane and 5% ethanol, and this isocratic mixture was maintained at a wavelength of 264 nm for up to 20 minutes.

[0399] (Example 12): Colorless sticky solid (10 mg, 99.09% purity). LCMS: m / z found 367.9 [M+H] + , room temperature = 3.64 min (Method 1) [Xbridge C8 column 5 μm, 50 × 4.6 mm]; 1 H NMR (400 MHz, chloroform-d) δ 7.42 (d, J = 3.6 Hz, 1H), 7.37 (dd, J = 5.2, 8.5 Hz, 2H), 7.07 (t, J = 8.8 Hz, 2H), 6.74 (d, J = 3.6 Hz, 1H), 5.79 (q, J = 8.4 Hz, 1H), 2.72 (s, 3H), 2.52 (s, 3H).

[0400] (Example 13): Colorless sticky solid (10 mg, 99.63% purity). LCMS: m / z found 368.0 [M+H] + , room temperature = 3.74 min (Method 1) [Xbridge C8 column 5 μm, 50 × 4.6 mm]; 1 H NMR (400 MHz, chloroform-d) δ 7.41 (d, J = 4.0 Hz, 1H), 7.37 (dd, J = 5.2, 8.4 Hz, 2H), 7.07 (t, J = 8.4 Hz, 2H), 6.78-6.72 (m, 1H), 5.79 (q, J = 8.4 Hz, 1H), 2.72 (s, 3H), 2.52 (s, 3H).

[0401] Examples 14 to 16 N-ethyl-5-fluoro-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide (Example 14), (S)-N-ethyl-5-fluoro-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide (Example 15), and (R)-N-ethyl-5-fluoro-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide (Example 16). [ka] 5-Fluoro-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide 4.1: Intermediate 4.1 was synthesized from 5-fluorothiophene-2-sulfonyl chloride using 2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine hydrochloride according to the procedure described in Method A. The compound was purified by flash chromatography on silica gel using 20% ​​ethyl acetate in hexanes and isolated as a colorless oil (300 mg, 42% yield). 1 H NMR(400MHz,DMSO-d6)δ 9.62(d,J=9.0Hz,1H),7.52(dd,J=5.4,8.5Hz,2H),7.21(t,J=4.0Hz,1H),7.16(t,J=8.8Hz,2H),6.69(d,J=4.3Hz,1H),5.39(t,J=8.0Hz,1H).

[0402] Example 14 N-ethyl-5-fluoro-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide: [ka] Ethylation of intermediate 4.1 was preformed at 70 °C using CsCO as the base according to the protocol described in Method B. The compound (Example 14) was purified by column chromatography on silica gel using 20% ​​ethyl acetate in hexanes and isolated as a light yellow oil (25 mg, 50% yield, 93.93% purity). 1 H NMR(400MHz,DMSO-d6):δ 7.62(t,J=4.0Hz,1H),7.44(dd,J=5.4,8.6Hz,2H),7.27(t,J=8.7Hz,2H),6.96(dd, J=1.5,4.3Hz,1H),5.95(q,J=8.6Hz,1H),3.30-3.15(m,2H),0.99(t,J=7.0Hz,3H).

[0403] Chiral separation of racemic Example 14 yielded both enantiomers as noted below. Chiral Separation Method: Chiral separation was performed on an Agilent 1200 series instrument. Column Name: Chiralcel OJ-H (250 x 20 mm), 5μ, operated at ambient temperature with a flow rate of 18.0 mL / min. Mobile Phase: 0.1% isopropylamine in a mixture of 85% hexane and 15% ethanol, and the isocratic mixture was maintained at a wavelength of 258 nm for up to 30 minutes.

[0404] Example 15: Pale yellow liquid (20 mg, purity 98.35%). 1 H NMR(400MHz,DMSO-d6):δ 7.62(t,J=4.1Hz,1H),7.44(dd,J=5.3,8.6Hz,2H),7.27(t,J=8.8Hz,2H),6.96(dd,J=1.6,4. 4Hz,1H), 5.95(q,J=8.4Hz,1H),3.40-3.29(m,1H),3.27-3.17(m,1H),0.99(t,J=7.0Hz,3H).

[0405] Example 16: Light yellow oil (20 mg, 97.94% purity). 1H NMR(400MHz,DMSO-d6):δ 7.62(t,J=4.0Hz,1H),7.45(dd,J=5.3,8.6Hz,2H),7.28(t,J=8.8Hz,2H),6.96(dd,J=1.6,4. 3Hz,1H), 5.95(q,J=8.8Hz,1H),3.42-3.31(m,1H),3.27-3.15(m,1H),1.00(t,J=7.2Hz,3H).

[0406] Example 17 5-Fluoro-N-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide [ka] Synthesis of 5-fluoro-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide (5.1): Intermediate (5.1) was synthesized from 5-fluorothiothiophene-2-sulfonyl chloride using 2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine hydrochloride according to the procedure described in Method A. Pyridine was used as a base in THF solvent. The compound was purified by column chromatography on silica gel using 20% ​​ethyl acetate in hexane and isolated as a colorless oil (300 mg, 42% yield). 1 H NMR (400MHz, DMSO-d6): δ 9.78-9.53(m,1H),7.58-7.46(m,2H),7.25-7.08(m,4H),5.54-5.29(m,1H).

[0407] 5-Fluoro-N-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide (Example 17): Methylation of intermediate 5.1 was preformed at 70 °C using CsCO as the base according to the protocol described in Method B. The compound (Example 17) was purified by column chromatography on silica gel using 20% ​​ethyl acetate in hexanes and isolated as a colorless oil (20 mg, 43% yield, 99.40% purity). LCMS: m / z found 371.2 [M+H] + , room temperature = 3.67 min (Method 1) [Xbridge C8 column 5 μm, 50 × 4.6 mm] 1 H NMR(400MHz,DMSO-d6):δ 7.62(t,J=4.1Hz,1H),7.44(dd,J=5.3,8.6Hz,2H),7.27(t,J=8.8Hz,2H),6.98(dd,J=1.6,4.4Hz,1H),6.00(q,J=8.4Hz,1H),2.76(s,3H)

[0408] Examples 18 and 19 5-Fluoro-N-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide (Example 18) and 5-fluoro-N-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide (Example 19) [ka] 5-Fluoro-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide 6.1: Intermediate 6.1 was synthesized from 5-fluorothiophene-2-sulfonyl chloride using 2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine hydrochloride according to the procedure described in Method A. The compound was purified by flash chromatography on silica gel using 20% ​​ethyl acetate in hexanes and isolated as a colorless oil (300 mg, 42% yield). 1H NMR(400MHz,DMSO-d6)δ 9.62(d,J=9.0Hz,1H),7.52(dd,J=5.4,8.5Hz,2H),7.21(t,J=4.0Hz,1H),7.16(t,J=8.8Hz,2H),6.69(d,J=4.3Hz,1H),5.39(t,J=8.0Hz,1H).

[0409] Chiral separation of the racemic compound Example 17 gave both enantiomers as noted below. Chiral Separation Method: Chiral separation was performed on an Agilent 1200 series instrument. Column Name: Chiralcel OJ-H (250 x 20 mm), 5μ, operated at ambient temperature with a flow rate of 18 mL / min. Mobile Phase: A mixture of 98% hexane and 2% ethanol, and this isocratic mixture was maintained at a wavelength of 256 nm for up to 25 minutes.

[0410] Example 18: Colorless sticky gum (10 mg, 99.35% purity). GCMS: m / z Found 371.1 (CHE 300-Method) (HP-5MS (30 x 250 μm x 0.25 μm); 1 H NMR(400MHz,DMSO-d6):δ 7.62(t,J=4.0Hz,1H),7.43(dd,J=5.3,8.6Hz,2H),7.27(t,J=8.8Hz,2H),6.99(dd,J=1.6,4.4Hz,1H),5.98(q,J=8.6Hz,1H),2.76(s,3H).

[0411] Example 19: Colorless sticky gum (10 mg, 99.35% purity). GCMS: m / z Found 371.1 (CHE 300-Method) (HP-5MS (30 x 250 μm x 0.25 μm); 1 H NMR(400MHz,DMSO-d6):δ 7.62(t,J=4.1Hz,1H),7.43(dd,J=5.4,8.7Hz,2H),7.27(t,J=8.8Hz,2H),6.99(dd,J=1.5,4.4Hz,1H),5.99(q,J=8.6Hz,1H),2.76(s,3H).

[0412] Example 20 N-ethyl-1-(tetrahydro-2H-pyran-4-yl)-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)methanesulfonamide [ka] 1-(tetrahydro-2H-pyran-4-yl)-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)methanesulfonamide 7.1: Intermediate 7.1 was synthesized from (tetrahydro-2H-pyran-4-yl)methanesulfonyl chloride using 2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine according to the protocol described in Method A. Pyridine was used as the base, and THF was used as the solvent. The compound was purified by column chromatography on silica gel using 25% ethyl acetate in hexanes and isolated as a colorless solid (45 mg, 50% yield). 1 H NMR(400MHz,DMSO-d6):δ 8.89(d,J=9.7Hz,1H),7.69(d,J=7.9Hz,2H),7.30(d,J=7.7Hz,2H),5.50-5.17(m ,1H),3.91-3.49(m,2H),3.23-2.67(m,4H),1.86-1.55(m,2H),1.36-0.97(m,3H).

[0413] N-ethyl-1-(tetrahydro-2H-pyran-4-yl)-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)methanesulfonamide: [ka] Ethylation of intermediate 7.1 was carried out at 70 °C according to the protocol described in Method B. The crude product was purified by column chromatography on silica gel using 25% ethyl acetate in hexanes, and the desired compound, Example 20, was isolated as a colorless gum (19 mg, 45% yield, 98.81% purity). GCMS: m / z found 383.1 (CHE 300-Method) (HP-5MS (30 × 250 μm × 0.25 μm); 1H NMR(400MHz,DMSO-d6):δ 7.62(dd,J=5.3,8.5Hz,2H),7.33(t,J=8.8Hz,2H),5.81(q,J=8.7Hz,1H),3.81(d,J=11.3Hz,2H), 3.29-3.05(m,4H),2.18-1.97(m,1H),1.83-1.63(m,3H),1.42-1.27(m,3H),0.95(t,J=7.0Hz,3H).

[0414] Examples 21 and 22 5-cyano-N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide (Example 21) and 5-(N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)sulfamoyl)thiophene-2-carboxamide (Example 22) [ka] 5-cyano-N-(1-(4-fluorophenyl)-2,2-dimethylpropyl)thiophene-2-sulfonamide 7.1: The synthesis of Intermediate 7.1 was essentially preformed as described in Method A using 2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine hydrochloride and 5-cyanothiophene-2-sulfonyl chloride. Pyridine was used as the base and THF was used as the solvent. The compound was purified by column chromatography on silica gel using 40% ethyl acetate:hexane and isolated as a yellow solid (90 mg, 51% yield). 1 H NMR(400MHz,DMSO-d6):δ 10.10-9.94(m,1H),7.82(d,J=4.0Hz,1H),7.54-7.46(m,4H),7.15(t,J=8.8Hz,2H),5.59-5.43(m,1H).

[0415] 5-cyano-N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide (Example 21) Ethylation of intermediate 7.1 was preformed at 70 °C using CsCO as the base according to the protocol described in Method B. The crude product was purified by column chromatography on silica gel using 35% ethyl acetate in hexanes to isolate compound Example 21 as a yellow oil (15 mg, 46% yield, 99.73% purity). GCMS: m / z found 392.1 (CHE 300-Method-1); 1 H NMR(400MHz,DMSO-d6):δ 8.06(d,J=4.0Hz,1H),7.92(d,J=4.0Hz,1H),7.44(t,J=5.3Hz,2H),7.27(t,J =8.8Hz,2H),6.05(q,J=8.6Hz,1H),3.45-3.31(m,2H),1.01(t,J=6.8Hz,3H).

[0416] 5-(N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)sulfamoyl)thiophene-2-carboxamide (Example 22) Nitrile Hydrolysis: Method N: To a stirred solution of Example 21 (55 mg, 0.14 mmol) in ethanol:water (9:1) (2 mL) was added Ghaffar Parkins' catalyst (6 mg, 0.014 mmol), and the reaction mixture was heated at 70° C. for 2 hours. Volatiles were evaporated under reduced pressure, and the crude product was purified by column chromatography using 50% ethyl acetate in hexanes. The desired compound, Example 22, was isolated as a white sticky solid (39 mg, 68% yield, 99.10% purity). LCMS: m / z found 409.11 [MH], room temperature = 2.70 min (Method 4) [Xbridge C18 column (3.5 μm, 50 × 3 mm)]; 1 H NMR(400MHz,DMSO-d6)δ 8.27(s,1H),7.79(d,J=4.0Hz,1H),7.74(d,J=4.0Hz,1H),7.43(dd,J=5.3,8.6Hz,2H),7.25(t,J =8.8Hz,2H),5.97(q,J=8.5Hz,1H),3.43-3.32(m,1H),3.30-3.17(m,1H),1.00(t,J=7.0Hz,3H).

[0417] Example 23 5-chloro-N-(2,2,-difluoro-1-(4-fluorophenyl)ethyl)-N-methylthiophene-2-sulfonamide [ka] 5-Fluoro-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide (6.1): Intermediate 6.1 was synthesized from 5-fluorothiophene-2-sulfonyl chloride using 2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine hydrochloride according to the procedure described in Method A. Pyridine was used as the base, and THF was used as the solvent. The compound was purified by flash chromatography on silica gel using 20% ​​ethyl acetate in hexanes and isolated as a colorless oil (300 mg, 42% yield). 1 H NMR (400MHz, DMSO-d6): δ 9.78-9.53(m,1H),7.58-7.46(m,2H),7.25-7.08(m,4H),5.54-5.29(m,1H).

[0418] Methylation of Intermediate 6.1 was carried out according to the protocol described in Method B. The crude product was purified by column chromatography on silica gel using 25% ethyl acetate in hexanes, and the desired compound, Example 23, was isolated as a brown oil (50 mg, 48% yield, 99.51% purity). GCMS: m / z found 369.0 (CHE 300-Method); H NMR (400 MHz, DMSO-d): δ 7.61 (d, J = 4.8 Hz, 1H), 7.41 (dd, J = 5.3, 8.6 Hz, 2H), 7.36-7.20 (m, 3H), 6.92-6.54 (m, 1H), 5.40-5.27 (m, 1H), 2.79 (s, 3H).

[0419] Examples 24 and 25 N,N-dimethyl-5-(N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)sulfamoyl)thiophene-2-carboxamide (Example 24) and 5-(N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)sulfamoyl)-N,N-dimethylthiophene-2-carboxamide (Example 25) [ka] The desired compound, Example 24, was synthesized from 5-(dimethylcarbamoyl)thiophene-2-sulfonyl chloride using 2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine hydrochloride according to the protocol described in Method A. Pyridine was used as the base, and THF was used as the solvent. The compound was purified by column chromatography on silica gel using 25% ethyl acetate in hexanes and isolated as a white solid (150 mg, 33% yield, 95.06% purity). 1 H NMR(400MHz,DMSO-d6)δ 9.69(d,J=9.9Hz,1H),7.52(dd,J=5.4,8.5Hz,2H),7.35(d,J=3.9Hz,1H),7 .23(d,J=4.0Hz,1H),7.11(t,J=8.7Hz,2H),5.49-5.40(m,1H),2.98(s,6H).

[0420] 5-(N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)sulfamoyl)-N,N-dimethylthiophene-2-carboxamide (Example 25): Ethylation of intermediate Example 24 was carried out at 70° C. following the protocol described in Method D. The crude product was purified by column chromatography on silica gel using 25% ethyl acetate in hexanes, and the desired compound, Example 25, was isolated as a pale yellow sticky gum (70 mg, 52% yield, 98.7% purity). LCMS: m / z found 439.0 [M+H] + , room temperature = 3.48 min (Method 4) [Xbridge C18 column (5 μm, 50 × 4.6 mm)]; 1H NMR(400MHz,DMSO-d6)δ 7.76(d,J=4.0Hz,1H),7.50(d,J=4.0Hz,1H),7.42(dd,J=5.2,8.5Hz,2H),7.23(t,J=8.9Hz,2H),5. 99(q,J=8.8Hz,1H),3.42-3.33(m,1H),3.30-3.19(m,1H),3.21-2.95(m,6H),1.02(t,J=7.0Hz,3H).

[0421] Example 26 5-cyano-N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyridine-3-sulfonamide [ka] 5-cyano-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyridine-3-sulfonamide: Intermediate 9.1 was synthesized from 5-cyanopyridine-3-sulfonyl chloride using 2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine hydrochloride according to the protocol described in Method A. Pyridine was used as the base and THF was used as the solvent. The compound was purified by column chromatography on silica gel using 25% ethyl acetate in hexanes and isolated as a colorless oil (300 mg, 34% yield). 1 H NMR(400MHz,DMSO-d6):δ 9.96-9.65(m,1H),9.13(d,J=1.5Hz,1H),9.00(d,J=2.0Hz,1H),8.43(t,J=2.1H z,1H),7.44(dd,J=5.3,8.6Hz,2H),7.11(t,J=8.8Hz,2H),5.50(d,J=7.7Hz,1H).

[0422] Ethylation of intermediate 9.1 was carried out at 70° C. following the protocol described in Method B. The crude product was purified by column chromatography on silica gel using 25% ethyl acetate in hexanes, and the desired compound, Example 26, was isolated as a colorless gum (25 mg, 28% yield, 97.40% purity). LCMS: m / z found 388.1 [M+H] + , room temperature = 3.62 min (Method 4) [Xbridge C18 column (5 μm, 50 × 4.6 mm)]; 1 H NMR(400MHz,DMSO-d6)δ 9.31(dd,J=1.9,9.8Hz,2H),8.90(t,J=1.8Hz,1H),7.45(dd,J=5.3,8.6Hz,2H),7.2 6(t,J=8.8Hz,2H),6.07(q,J=8.8Hz,1H),3.56-3.32(m,2H),0.99(t,J=7.0Hz,3H).

[0423] Example 27 N-ethyl-6-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyridine-2-sulfonamide [ka] 6-Methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyridine-2-sulfonamide 10.1: Intermediate 10.1 was synthesized from 6-methylpyridine-2-sulfonyl chloride using 2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine hydrochloride according to the protocol described in Method A. Pyridine was used as the base and THF was used as the solvent. The compound was purified by column chromatography on silica gel using 25% ethyl acetate in hexanes and isolated as a colorless oil (300 mg, 34% yield). 1H NMR(400MHz,DMSO-d6)δ 9.41(d,J=9.8Hz,1H),7.80(t,J=7.8Hz,1H),7.64(d,J=7.8Hz,1H),7.47(dd,J=5.3,8. 4Hz,2H),7.33(d,J=7.3Hz,1H),7.10(t,J=8.8Hz,2H),5.45-5.15(m,1H),2.27(s,3H).

[0424] Example 27: Ethylation of intermediate 6.1 was preformed at 70° C. following the protocol described in Method D. The crude product was purified by column chromatography on silica gel using 25% ethyl acetate in hexanes to isolate the desired compound, Example 27, as an off-white solid (10 mg, 23% yield, 99.70% purity). LCMS: m / z found 377.31 [M+H] + , room temperature for 3.20 minutes (Method 2) [Acquity BEH C8 column (1.7 μm, 50 × 2.1 mm)]; 1 H NMR(400MHz,DMSO-d6)δ 7.93(t,J=8.0Hz,1H),7.79(d,J=7.6Hz,1H),7.52(t,J=8.8Hz,3H),7.21(t,J =8.8Hz,2H),5.80(q,J=9.2Hz,1H),3.44-3.29(m,2H),0.94(t,J=6.8Hz,3H).

[0425] Example 28 N-Ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-2,3-dihydrobenzo[b]thiophene-6-sulfonamide 1,1-dioxide [ka] N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-2,3-dihydrobenzo[b]thiophene-6-sulfonamide 1,1-dioxide 11.1: Intermediate 11.1 was synthesized from 2,3-dihydrobenzo[b]thiophene-6-sulfonyl chloride 1,1-dioxide using 2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine hydrochloride according to the protocol described in Method A. Pyridine was used as the base and THF was used as the solvent. The compound was purified by column chromatography on silica gel using 25% ethyl acetate in hexanes and isolated as a brown oil (40 mg, 50% yield). 1 H NMR(400MHz,DMSO-d6)δ 9.48(d,J=10.2Hz,1H),7.92(s,1H),7.88(d,J=8.2Hz,1H),7.59(d,J=8.0Hz,1H),7.43(t,J=5. 1Hz,2H),7.06(t,J=8.5Hz,2H),5.59-5.40(m,1H),3.62(t,J=7.0Hz,2H),3.36(d,J=6.8Hz,2H).

[0426] Ethylation of intermediate 11.1 was carried out at 70° C. following the protocol described in Method B. The crude product was purified by column chromatography on silica gel using 25% ethyl acetate in hexanes to isolate the desired compound, Example 28, as an off-white solid (50 mg, 47% yield, 99.44% purity). LCMS: m / z found 1 H NMR(400MHz,DMSO-d6)δ 8.32(s,1H),8.17(d,J=7.8Hz,1H),7.76(d,J=8.2Hz,1H),7.52-7.44(m,2H),7.21(t,J=8.7Hz,2H),6. 27-6.05(m,1H),3.70(t,J=7.0Hz,2H),3.46(t,J=6.8Hz,2H),3.29-3.17(m,2H),0.93(t,J=7.0Hz,3H).

[0427] Example 29 N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)isochroman-7-sulfonamide [ka] N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)isochroman-7-sulfonamide 12.1: Intermediate 12.1 was synthesized from isochroman-7-sulfonyl chloride using 2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine hydrochloride according to the protocol described in Method A. Pyridine was used as the base and THF was used as the solvent. The compound was purified by column chromatography on silica gel using 25% ethyl acetate in hexanes and isolated as a colorless oil (370 mg, 74% yield). 1 H NMR(400MHz,DMSO-d6)δ 9.15(d,J=10.0Hz,1H),7.44-7.36(m,3H),7.23(s,1H),7.13(d,J=8.0Hz,1H),7.06(t,J= 8.8Hz,2H),5.28(t,J=8.0Hz,1H),4.54(s,2H),3.86-3.72(m,2H),2.72(t,J=5.4Hz,2H).

[0428] Ethylation of intermediate 12.1 was preformed at 70° C. following the protocol described in Method D. The crude product was purified by column chromatography on silica gel using 25% ethyl acetate in hexanes, and the desired compound, Example 29, was isolated as a colorless gum (50 mg, 47% yield, 99.63% purity). LCMS: m / z found 418.25 [M+H] + , 3.27 min at room temperature (Method 2) [Acquity BEH C8 column (1.7 μm, 50 × 2.1 mm)]; 1 H NMR(400MHz,DMSO-d6)δ 7.62(d,J=8.0Hz,1H),7.54(s,1H),7.43(t,J=5.2Hz,2H),7.34(d,J=8.0Hz,1H),7.20(t,J=8.4Hz,2H),5.84(q,J =8.8Hz,1H),4.71(s,2H),3.91(t,J=5.6Hz,2H),3.38-3.15(m,2H),2.89(t,J=5.6Hz,2H),0.97(t,J=7.1Hz,3H).

[0429] Example 30 6-cyano-N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyridine-2-sulfonamide [ka] 6-cyano-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyridine-2-sulfonamide: Intermediate 13.1 was synthesized from 6-cyanopyridine-2-sulfonyl chloride using 2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine hydrochloride according to the protocol described in Method A. Pyridine was used as the base and THF was used as the solvent. The compound was purified by column chromatography on silica gel using 25% ethyl acetate in hexanes and isolated as a colorless oil (310 mg, 34% yield). 1 H NMR(400MHz,DMSO-d6)δ 9.82(d,J=9.9Hz,1H),8.27-8.19(m,1H),8.18-8.10(m,2H),7.46(dd,J=5.4,8.6Hz,2H),7.10(t,J=8.8Hz,2H),5.37(q,J=8.5Hz,1H).

[0430] Ethylation of intermediate 13.1 was preformed at 70° C. following the protocol described in Method D. The crude product was purified by column chromatography on silica gel using 25% ethyl acetate in hexanes, and the desired compound, Example 30, was isolated as a colorless gum (25 mg, 58% yield, 96.19% purity). LCMS: m / z found 388.2 [M+H] + , 3.12 min at room temperature (Method 2) [Acquity BEH C18 column (1.7 μm, 50 × 2.1 mm)]; 1 H NMR(400MHz,DMSO-d6)δ 8.41-8.26(m,3H),7.57-7.47(m,2H),7.28-7.17(m,2H),7.27-7.19(m, 2H),5.94(q,J=8.7Hz,1H),3.40(q,J=7.0Hz,2H),0.91(t,J=7.0Hz,3H).

[0431] Example 31 5-chloro-N-ethyl-4-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide [ka] 5-chloro-4-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide 14.1: Intermediate 14.1 was synthesized from 5-chloro-4-methylthiophene-2-sulfonyl chloride using 2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine hydrochloride according to the protocol described in Method A. Pyridine was used as the base and THF was used as the solvent. The compound was purified by column chromatography on silica gel using 25% ethyl acetate in hexanes and isolated as a colorless oil (360 mg, 71% yield). 1 H NMR(400MHz,DMSO-d6)δ 9.62(s,1H),7.49(dd,J=5.5,8.5Hz,2H),7.13(t,J=8.8Hz,3H),5.31(s,1H),1.98(s,3H).

[0432] Ethylation of intermediate 14.1 was preformed at 70° C. following the protocol described in Method D. The crude product was purified by column chromatography on silica gel using 25% ethyl acetate in hexanes, and the desired compound, Example 31, was isolated as a colorless gum (50 mg, 47% yield, 98.18% purity). LCMS: m / z found 415.9 [M+H] + , room temperature = 4.06 min (Method 4) [Xbridge C18 column (5 μm, 50 × 4.6 mm)]; 1H NMR(400MHz,DMSO-d6)δ 7.63(s,1H),7.45(dd,J=5.3,8.6Hz,2H),7.27(t,J=8.8Hz,2H),5.92(q,J=8.7H z,1H),3.39-3.32(m,1H),3.27-3.19(m,1H),2.16(s,3H),1.01(t,J=7.0Hz,3H).

[0433] Examples 32 and 33 (S)—N-ethyl-6-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyridine-2-sulfonamide (Example 32) and (R)—N-ethyl-6-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyridine-2-sulfonamide (Example 33) [ka] Chiral separation of racemic Example 30 yielded both enantiomers as noted below. Chiral Separation Method: Chiral separation was performed on an Agilent 1200 series instrument. Column Name: Chiralcel OJ-H (250 x 21 mm), 5μ, operated at ambient temperature with a flow rate of 21.0 mL / min. Mobile Phase: A mixture of 85% hexane and 15% ethanol, and this isocratic mixture was maintained at a wavelength of 268 nm for up to 20 minutes.

[0434] Example 32: 10 mg (colorless sticky gum, 99.84% purity). LCMS: m / z found 377.1 [M+H] + , room temperature = 3.71 min (Method 4) [Xbridge C18 column (5 μm, 50 × 4.6 mm)]; 1 H NMR(400MHz,chloroform-d)δ 7.81(d,J=7.7Hz,1H),7.74(t,J=7.7Hz,1H),7.57(dd,J=5.2,8.6Hz,2H),7.30(d,J=7.6Hz,1H),7 .04(t,J=8.6Hz,2H),5.84(q,J=8.4Hz,1H),3.45-3.27(m,2H),2.60(s,3H),0.93(t,J=6.8Hz,3H).

[0435] Example 33: 10 mg (light yellow sticky gum, 99.27% ​​purity). LCMS: m / z found 377.1 [M+H] + , room temperature = 3.73 min (Method 4) [Xbridge C18 column (5 μm, 50 × 4.6 mm)]; 1 H NMR(400MHz,chloroform-d)δ 7.80(d,J=7.7Hz,1H),7.74(t,J=7.6Hz,1H),7.57(dd,J=5.2,8.5Hz,2H),7.30(d,J=7.7Hz,1H),7 .04(t,J=8.6Hz,2H),5.84(q,J=8.2Hz,1H),3.41-3.31(m,2H),2.60(s,3H),0.94(t,J=7.2Hz,3H).

[0436] Examples 34 and 35 (S)-5-cyano-N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyridine-3-sulfonamide (Example 34) and (R)-5-cyano-N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyridine-3-sulfonamide (Example 35) [ka] Chiral separation of racemic Example 26 afforded both enantiomers as shown in Scheme 16. Chiral Separation Method: Chiral separation was performed on an Agilent 1200 series instrument. Column Name: Chiralpak IG (250 x 21 mm), 5μ, operated at ambient temperature with a flow rate of 21.0 mL / min. Mobile Phase: A mixture of 80% hexane, 10% dichloromethane, and 10% ethanol, and this isocratic mixture was maintained for up to 18 minutes at a wavelength of 230 nm.

[0437] Example 34: Pale yellow sticky gum (10 mg, 99.88% purity). LCMS: m / z found 386.1 [M+H] + , room temperature = 3.57 min (Method 4) [Xbridge C18 column (5 μm, 50 × 4.6 mm)]; 1H NMR(400MHz,DMSO-d6)δ 9.31(dd,J=1.9,9.8Hz,2H),8.90(t,J=1.8Hz,1H),7.45(dd,J=5.3,8.6Hz,2H),7.2 6(t,J=8.8Hz,2H),6.07(q,J=8.8Hz,1H),3.52-3.32(m,2H),0.99(t,J=7.0Hz,3H).

[0438] Example 35: Pale yellow sticky gum (10 mg, 94.36% purity). LCMS: m / z found 386.1 [M+H] + , room temperature = 3.60 min (Method 4) [Xbridge C18 column (5 μm, 50 × 4.6 mm)]; 1 H NMR(400MHz,DMSO-d6)δ 9.31(dd,J=2.1,9.4Hz,2H),8.89(t,J=2.1Hz,1H),7.45(dd,J=5.3,8.6Hz,2H),7.2 6(t,J=8.8Hz,2H),6.08(q,J=8.8Hz,1H),3.56-3.31(m,2H),1.00(t,J=7.2Hz,3H).

[0439] Example 36: N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-1,3-dihydroisobenzofuran-5-sulfonamide [ka] N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-1,3-dihydroisobenzofuran-5-sulfonamide 15.2: Method O: To a stirred solution of dihydroisobenzofuran-5-sulfonyl chloride 17.1 (250.0 mg, 1.14 mmol) in THF (1 mL) and 2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine hydrochloride (262 mg, 1.14 mmol) in THF (1 mL) was added pyridine (0.7 mL, 8.01 mmol). The reaction mixture was stirred at room temperature overnight. The volatiles were evaporated under reduced pressure, and the residue was purified by column chromatography (100–200 mesh silica gel, eluent 30% EtOAc in hexanes) to give N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-1,3-dihydroisobenzofuran-5-sulfonamide 17.2 as a colorless oil (220 mg, 47% yield). 1 H NMR(400MHz,DMSO-d6):δ 9.23(d,J=10.4Hz,1H),7.59-7.49(m,2H),7.41(t,J=5.7Hz,2H),7.31(d,J= 7.8Hz,1H),7.07(t,J=8.8Hz,2H),5.43-5.19(m,1H),4.92(d,J=18.2Hz,4H)

[0440] N-Ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-1,3-dihydroisobenzofuran-5-sulfonamide: Method D: To a stirred solution of compound N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-1,3-dihydroisobenzofuran-5-sulfonamide 17.2 (220.0 mg, 0.58 mmol) in DMF (0.5 mL) was added CsCO (286 mg, 0.88 mmol) and ethyl iodide (0.07 mL, 0.88 mmol). The reaction mixture was stirred at 70 °C for 2 h. The reaction mixture was diluted with water (5 mL) and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by Combiflash column to give N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-1,3-dihydroisobenzofuran-5-sulfonamide as an off-white solid (80 mg, 33% yield, 99.59% purity). LCMS: m / z found 404.2 [M+H] + , room temperature = 3.54 min (Method 4) [Waters Xbridge C18 column (5 μm, 50 × 4.6 mm)]; 1 H NMR (400MHz, chloroform-d):δ 7.80(d,J=8.0Hz,1H),7.73(s,1H),7.46(dd,J=5.2,8.6Hz,2H),7.37(d,J=8.0Hz,1H),7.08(t,J=8.6Hz,2 H),5.83(q,J=8.4Hz,1H),5.34-4.95(m,4H),3.40-3.26(m,1H),3.19-3.04(m,1H),0.90(t,J=7.0Hz,3H).

[0441] Examples 37 and 38 (S)—N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-1,3-dihydroisobenzofuran-5-sulfonamide (Example 37 (EN-1)) and (R)—N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)1,3-dihydroisobenzofuran-5-sulfonamide (Example 38 (EN-2)) Chiral separation of racemic Example 36 afforded both enantiomers as noted below. Chiral Separation Method: Chiral separation was performed on an Agilent 1200 series instrument. Column: CHIRALCEL OJ-H (250 x 21 mm), 5μ, operated at ambient temperature with a flow rate of 21.0 mL / min. Mobile Phase: 0.1% isopropylamine in a mixture of 90% hexane and 10% ethanol, and the isocratic mixture was maintained at a wavelength of 250 nm for up to 24 minutes.

[0442] Example 37 [EN-1]: Off-white solid (96.80% purity). LCMS: m / z found 404.2 [M+H] + , room temperature = 3.62 min (Method 4) [Waters Xbridge C18 column (5 μm, 50 × 4.6 mm)]; 1 H NMR (400 MHz, chloroform-d): δ 7.80 (d, J = 8.4 Hz, 1H), 7.73 (s, 1H), 7.46 (t, J = 5.6 Hz, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.08 (t, J = 8.6 Hz, 2H), 5.82 (q, J = 8.5 Hz, 1H), 5.15 (d, J = 4.0 Hz, 4H), 3.38-3.28 (m, 1H), 3.17-3.07 (m, 1H), 0.91 (t, J = 7.1 Hz, 3H).

[0443] Example 38 [EN-2]: Off-white solid (98.40% purity). LCMS: m / z found 404.2 [M+H] + , room temperature = 3.74 min (Method 4) [Waters Xbridge C18 column (5 μm, 50 × 4.6 mm)]; 1H NMR(400MHz,DMSO-d6):δ 7.88-7.79(m,2H),7.51(d,J=7.8Hz,1H),7.42(dd,J=5.4,8.6Hz,2H),7.23(t,J =8.8Hz,2H),5.95(q,J=8.7Hz,1H),5.05(d,J=9.4Hz,4H),0.93(t,J=7.0Hz,3H).

[0444] Example 39 N-Ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-2,3-dihydrobenzofuran-6-sulfonamide [ka] N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-2,3-dihydrobenzofuran-6-sulfonamide 18.2: Intermediate 18.2 was synthesized from 2,3-dihydrobenzofuran-6-sulfonyl chloride 18.1 using 2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine hydrochloride according to the protocol described in Method O. The crude product was purified by CombiFlash column to give N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-2,3-dihydrobenzofuran-6-sulfonamide as a colorless oil (200 mg, 43% purity). 1 H NMR(400MHz,DMSO-d6):δ 9.14(d,J=10.4Hz,1H),7.43(dd,J=5.5,8.6Hz,2H),7.21(d,J=7.7Hz,1H),7.16-7.03(m,3 H),6.91(d,J=1.6Hz,1H),5.38-5.21(m,1H),4.51(t,J=8.8Hz,2H),3.13(t,J=8.8Hz,2H).

[0445] N-Ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-2,3-dihydrobenzofuran-6-sulfonamide Example 39: Ethylation of 18.2 was preformed using CsCO according to the protocol described in Method D. The crude product was purified by CombiFlash column chromatography to give N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-2,3-dihydrobenzofuran-6-sulfonamide as an off-white solid (70 mg, 32% purity, 99.25% purity). LCMS: m / z found 404.2 [M+H] + , room temperature = 3.52 min (Method 4) [Waters Xbridge C18 column (5 μm, 50 × 4.6 mm)]; 1 H NMR (400 MHz, chloroform-d) δ 7.48-7.34 (m, 3H), 7.32-7.20 (m, 2H), 7.06 (t, J = 8.6 Hz, 2H), 5.79 (q, J = 8.6 Hz, 1H), 4.65 (t, J = 8.9 Hz, 2H), 3.38-3.23 (m, 3H), 3.16-3.02 (m, 1H), 0.92 (t, J = 7.1 Hz, 3H).

[0446] Examples 40 and 41 (R)-N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-2,3-dihydrobenzofuran-6-sulfonamide (Example 40 [EN-1] and (S)-N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)-2,3-dihydrobenzofuran-6-sulfonamide (Example 41 [EN-2]): Chiral separation of racemic Example 39 yielded both enantiomers as noted below. Chiral Separation Method: Chiral separation was performed on an Agilent 1200 series instrument. Column Name: CHIRALPAK IG (250 x 21 mm), 5μ, operated at ambient temperature with a flow rate of 21.0 mL / min. Mobile Phase: A mixture of 95% hexane and 5% isopropyl alcohol, and operation with this isocratic mixture was maintained for up to 35 minutes at a wavelength of 228 nm.

[0447] Example 40: Off-white solid (99.81% purity). LCMS: m / z found 404.2 [M+H] + , room temperature = 3.76 min (Method 4) [Waters Xbridge C18 column (5 μm, 50 × 4.6 mm)]; 1 H NMR (400MHz, chloroform-d):δ 7.48-7.35(m,3H),7.28(d,J=7.5Hz,1H),7.26-7.16(m,2H),7.06(t,J=8.4Hz,2H),5.79(q,J=8. 4Hz,1H),4.66(t,J=8.8Hz,2H),3.28(t,J=8.6Hz,2H),3.17-3.02(m,1H),0.92(t,J=7.0Hz,3H).

[0448] Example 4: Off-white sticky gum (99.90% purity). LCMS: m / z found 404.2 [M+H] + , room temperature = 3.74 min (Method 4) [Waters Xbridge C18 column (5 μm, 50 × 4.6 mm)]; 1 H NMR(400MHz,DMSO-d6)δ 7.46-7.35(m,4H),7.30-7.18(m,3H),5.95(q,J=8.8Hz,1H),4.61(t,J= 8.8Hz,2H),3.36-3.20(m,4H),3.19-3.05(m,1H),0.90(t,J=7.0Hz,3H).

[0449] Example 42 5-cyano-N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-3-sulfonamide [ka] Synthesis of 4-((4-methoxybenzyl)thio)thiophene-2-carbonitrile 19.2: Intermediate 19.2 was synthesized from 4-bromothiophene-2-carbonitrile 19.1 using (4-methoxyphenyl)methanethiol at 70 °C following a similar method as described in Method I. The crude product was purified by Combi-Flash column using 0-30% ethyl acetate-hexanes, and 4-((4-methoxybenzyl)thio)thiophene-2-carbonitrile was isolated as a yellow oil (600 mg, 86% yield). 1 H NMR (400MHz, DMSO-d6): δ 7.94(d,J=1.2Hz,1H),7.80(d,J=1.2Hz,1H),7.22(d,J=8.5Hz,2H),6.86(d,J=8.5Hz,2H),4.17(s,2H),3.71(s,3H).

[0450] 5-Cyanothiophene-3-sulfonyl chloride 19.3 Method T: Intermediate 19.2 (227 mg, 0.906 mmol) was dissolved in CHCN (5 mL), and a mixture of water (0.3 mL) and AcOH (0.1 mL) was added to the solution. This was then cooled to −5° C., and 1,3-dichloro-5,5-dimethylhydantoin (268 mg, 1.359 mmol) was added to it. The RM was then stirred at −5° C. for 30 min. The RM was then quenched with water and extracted with DCM (10 mL). The organic portion was washed with brine, and the solvent was evaporated under reduced pressure at room temperature. The crude product was used immediately in the subsequent step without further purification. The crude sulfonyl chloride 19.3 was used immediately in the subsequent step without further purification.

[0451] Synthesis of 5-cyano-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-3-sulfonamide 19.4: Intermediate 19.4 was synthesized from sulfonyl chloride 19.3 using 2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine hydrochloride according to the protocol described in Method O. The compound was purified on a CombiFlash column using 30% EA-hexane to give 5-cyano-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-3-sulfonamide as a bright yellow gum (100 mg, 38% yield). 1 H NMR(400MHz,DMSO-d6)δ 9.54(d,J=9.8Hz,1H),8.37(s,1H),7.82(s,1H),7.46(dd,J=5.4,8.5Hz,2H),7.14(t,J=8.8Hz,2H),5.44-5.35(m,1H).

[0452] 5-Cyano-N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-3-sulfonamide (Example 42): Ethylation of intermediate 19.4 was preformed at 70° C. according to the protocol described in Method D. The crude product was purified on a CombiFlash column using 10% EA-hexanes, and the compound 5-cyano-N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-3-sulfonamide (Example 42) was isolated as an off-white sticky gum (30 mg, 28% yield, 98.18% purity). LCMS: m / z found 390.9 [M+H] + , room temperature = 3.70 min (Method 4) [Waters Xbridge C18 column (5 μm, 50 × 4.6 mm)]; 1 H NMR (400 MHz, chloroform-d): δ 8.16 (d, J = 1.3 Hz, 1H), 7.80 (d, J = 1.2 Hz, 1H), 7.46 (dd, J = 5.1, 8.6 Hz, 2H), 7.17-7.06 (m, 2H), 5.78 (q, J = 8.4 Hz, 1H), 3.44-3.30 (m, 1H), 3.24-3.10 (m, 1H), 0.93 (t, J = 7.0 Hz, 3H).

[0453] Examples 43 and 44 5-cyano-N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-3-sulfonamide (Example 43 [EN-1]) and 5-cyano-N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-3-sulfonamide (Example 44 [EN-2]) Chiral separation of racemic Example 42 yielded both enantiomers as noted below. Chiral Separation Method: Chiral separation was performed on an Agilent 1200 series instrument. Column Name: CHIRALCEL OJ-H (250 x 21 mm), 5μ, operated at ambient temperature with a flow rate of 21.0 mL / min. Mobile Phase: 0.1% isopropylamine in a mixture of 90% hexane and 10% ethanol, and this isocratic mixture was maintained at a wavelength of 250 nm for up to 24 minutes.

[0454] Example 43: Off-white sticky gum (99.78% purity). LCMS: m / z found 391.2 [M+H] - , room temperature = 9.61 min (Method 6) [Waters Xbridge C18 column (5 μm, 50 × 4.6 mm)]; 1 H NMR (400 MHz, chloroform-d): δ 8.16 (d, J = 0.8 Hz, 1H), 7.79 (s, 1H), 7.46 (dd, J = 5.1, 8.5 Hz, 2H), 7.11 (t, J = 8.6 Hz, 2H), 5.77 (q, J = 8.4 Hz, 1H), 3.44-3.30 (m, 1H), 3.24-3.10 (m, 1H), 0.94 (t, J = 7.1 Hz, 3H).

[0455] Example 44: Light brown sticky gum (99.44% purity). LCMS: m / z found 391.2 [M−H] - , room temperature = 9.63 min (Method 6) [Waters Xbridge C18 column (5 μm, 50 × 4.6 mm)]; 1H NMR (400 MHz, chloroform-d): δ 8.16 (s, 1H), 7.80 (s, 1H), 7.46 (t, J = 5.1 Hz, 2H), 7.11 (t, J = 8.4 Hz, 2H), 5.79 (q, J = 8.4 Hz, 1H), 3.46-3.29 (m, 1H), 3.24-3.10 (m, 1H), 0.94 (t, J = 6.8 Hz, 3H).

[0456] Example 45 5-cyano-N-ethyl-3-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide [ka] Synthesis of 5-((4-methoxybenzyl)thio)-4-methylthiophene-2-carbonitrile 20.2: Intermediate 20.2 was synthesized from 5-bromo-4-methylthiophene-2-carbonitrile 20.1 using (4-methoxyphenyl)methanethiol following a similar method as described in Method I at 80° C. The crude product was purified by Combi-Flash column chromatography using 30% ethyl acetate in hexanes, and 5-((4-methoxybenzyl)thio)-4-methylthiophene-2-carbonitrile was isolated as a yellow gum (250 mg, 74% yield). 1 H NMR (400MHz, DMSO-d6): δ 7.85-7.75(m,1H),7.11(d,J=8.7Hz,2H),6.85(d,J=8.6Hz,2H),4.07(s,2H),3.72(s,3H),2.03(s,3H).

[0457] 5-Cyano-3-methylthiophene-2-sulfonyl chloride 20.3: Sulfonyl chloride 20.3 was synthesized from intermediate 20.2 according to the procedure described in Method T. The crude sulfonyl chloride was used immediately in the subsequent step without further purification.

[0458] Synthesis of 5-cyano-3-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide 20.4: Intermediate 20.4 was synthesized from sulfonyl chloride 20.3 using 2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine hydrochloride according to the protocol described in Method O. The compound was purified on a CombiFlash column using 30% EA-hexane to give 5-cyano-3-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide as a colorless gum (80 mg, 39% yield). LCMS: m / z found 377 [MH], rt = 3.43 min (Method 4) Waters Xbridge C18 column (5 μm, 50 × 4.6 mm).

[0459] 5-Cyano-N-ethyl-3-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide: Ethylation of intermediate 20.4 was preformed at 70° C. according to the protocol described in Method D. The crude product was purified on a Combi-Flash column using 15% EA-hexanes, and the compound 5-cyano-N-ethyl-3-methyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide (Example 45) was isolated as an off-white sticky gum (20 mg, 34% yield, 99.98% purity). LCMS: m / z found 424.1 [M+H] + 17, room temperature = 3.70 min (Method 4) [Waters Xbridge C18 column (5 μm, 50 × 4.6 mm)]; 1 H NMR (400 MHz, chloroform-d): δ 7.47 (dd, J = 5.1, 8.4 Hz, 2H), 7.38 (s, 1H), 7.11 (t, J = 8.6 Hz, 2H), 5.66 (q, J = 8.3 Hz, 1H), 3.68-3.19 (m, 2H), 2.48 (s, 3H), 0.93 (t, J = 7.1 Hz, 3H).

[0460] Example 46 5-(N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)sulfamoyl)thiazole-2-carboxamide [ka] Synthesis of 5-((4-methoxybenzyl)thio)thiazole-2-carboxylate 21.2: Intermediate 21.2 was synthesized from methyl 5-bromothiazole-2-carboxylate 21.1 using (4-methoxyphenyl)methanethiol following a similar method as described in Method I at 80° C. The crude product was purified by Combi-Flash column chromatography using 30% ethyl acetate in hexanes to give methyl 5-((4-methoxybenzyl)thio)thiazole-2-carboxylate as a yellow solid (1 g, 94% yield). 1 H NMR (400MHz, DMSO-d6): δ 7.92(s,1H),7.21(d,J=8.4Hz,2H),6.87(d,J=8.6Hz,2H),4.22(s,2H),3.88(s,3H),3.72(s,3H).

[0461] Methyl 5-(chlorosulfonyl)thiazole-2-carboxylate 21.3: Sulfonyl chloride 21.3 was synthesized from intermediate 21.2 according to the procedure described in Method T. The crude sulfonyl chloride was purified by Combi-Flash column chromatography using 10% EA-hexane to give methyl 5-(chlorosulfonyl)thiazole-2-carboxylate as a white solid (700 mg, 85% yield). 1 H NMR (400MHz, DMSO-d6): δ 7.99(s,1H),3.90(s,3H).

[0462] Synthesis of methyl 5-(N-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)sulfamoyl)thiazole-2-carboxylate 21.4: Intermediate 21.4 was synthesized from sulfonyl chloride 21.3 using 2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine hydrochloride according to the protocol described in Method O. The compound was purified on a Combi-Flash column using 50% EA-hexane to give methyl 5-(N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)sulfamoyl)thiazole-2-carboxylate (500 mg, 43% yield). 1 H NMR (400MHz, DMSO-d6): δ 10.14(d,J=8.9Hz,1H),8.29(s,1H),7.52(dd,J=5.3,8.6Hz,2H),7.16(t,J=8.7Hz,2H),5.67-5.47(m,1H),3.91(s,3H).

[0463] Synthesis of methyl 5-(N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)sulfamoyl)thiazole-2-carboxylate 21.5: Ethylation of intermediate 21.4 was preformed at 70° C. according to the protocol described in Method D. The crude product was purified on a Combi-Flash column using 20% ​​EA-hexane, and the compound methyl 5-(N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)sulfamoyl)thiazole-2-carboxylate was isolated as an off-white solid (120 mg, 70% yield). 1 H NMR (400 MHz, chloroform-d): δ 8.34 (s, 1H), 7.44 (t, J = 6.9 Hz, 3H), 7.11 (t, J = 8.3 Hz, 2H), 5.90-5.66 (m, 1H), 4.04 (s, 3H), 3.45-3.34 (m, 1H), 3.32-3.20 (m, 1H), 1.01 (t, J = 7.0 Hz, 3H).

[0464] 5-(N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)sulfamoyl)thiazole-2-carboxamide: Intermediate 21.5 (40 mg, 0.09 mmol) was heated in a sealed tube with NH in THF (1.5 mL) at 70 °C for 12 h. Volatiles were evaporated under reduced pressure and the crude product was purified by Combi-Flash column chromatography using 50% EA-hexane to give 5-(N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)sulfamoyl)thiazole-2-carboxamide (Example 46, 10 mg, 26% yield, 95.12% purity) as a white solid. LCMS: m / z found 412 [M+H] + 17, room temperature = 2.79 min (Method 9) [Waters Xbridge C18 column (3.5 μm, 50 × 3 mm)]; 1 H NMR(400MHz,DMSO-d6):δ 8.57(s,1H),8.49(s,1H),8.19(s,1H),7.47(dd,J=5.3,8.7Hz,2H),7.27(t,J =8.8Hz,2H),6.06(q,J=8.7Hz,1H),3.49-3.32(m,2H),1.03(t,J=7.0Hz,3H).

[0465] Example 47 5-(azetidin-3-yl)-N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide [ka] Synthesis of tert-butyl 3-(5-bromothiophen-2-yl)azetidine-1-carboxylate 22.2: To a stirred solution of 3-(5-bromothiophen-2-yl)azetidine 22.1 (0.4 g, 1.83 mmol) in DCM (4 mL) was added DIPEA (0.8 mL, 4.58 mmol) followed by di-tert-butyl dicarbonate (0.51 g, 2.2 mmol) at 0 °C. The entire reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with water (10 mL) and extracted with DCM (2 × 15 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude compound. This was then purified by CombiFlash column to give tert-butyl 3-(5-bromothiophen-2-yl)azetidine-1-carboxylate as an off-white solid (0.45 g, 77%). 1 H NMR (400MHz, DMSO-d6): δ 7.09(d,J=4.0Hz,1H),6.91(s,1H),4.35-4.15(m,2H),4.06-3.94(m,1H),3.86-3.72(m,2H),1.39(s,9H).

[0466] Synthesis of tert-butyl 3-(5-((4-methoxybenzyl)thio)thiophen-2-yl)azetidine-1-carboxylate 22.3: Buchwald Coupling: Method I: To a stirred solution of tert-butyl 3-(5-bromothiophen-2-yl)azetidine-1-carboxylate (200 mg, 3.60 mmol) 22.2 and (4-methoxyphenyl)methanethiol (0.5 mL, 3.60 mmol) in toluene (8 mL) was added DIPEA (2 mL, 10.81 mmol), and the solution was degassed with argon. Xantphos (36 mg, 0.06 mmol) was added thereto, followed by Pd2(dba)2 (58 mg, 0.06 mmol) under an inert atmosphere. The mixture was heated at 80 °C and maintained for 12 h. The reaction mixture was cooled and filtered through a bed of Celite. It was then concentrated under reduced pressure to give the crude compound. This was purified by Combiflash chromatography using 10% ethyl acetate-hexane to give tert-butyl 3-(5-((4-methoxybenzyl)thio)thiophen-2-yl)azetidine-1-carboxylate as a pale yellow oil (0.21 mg, 85% yield). 1 H NMR (400MHz, DMSO-d6): δ 7.11(d,J=12.0Hz,2H),6.94-6.80(m,4H),4.33-4.13(m,2H),4.10-3.90(m,3H),3.89-3.61(m,5H),1.39(s,9H).

[0467] Synthesis of tert-butyl 3-(5-(chlorosulfonyl)thiophen-2-yl)azetidine-1-carboxylate 22.4: The sulfonyl chloride 22.4 was synthesized from intermediate 22.3 according to the procedure described in Method T. The crude sulfonyl chloride was used immediately in the subsequent step without further purification.

[0468] Synthesis of tert-butyl 3-(5-(N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)sulfamoyl)thiophen-2-yl)azetidine-1-carboxylate 21.5: Intermediate 22.5 was synthesized from sulfonyl chloride 22.4 using 2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine hydrochloride according to the protocol described in Method O at 60° C. The compound was purified by column chromatography on silica gel using 35% ethyl acetate in hexane, and the pure compound, tert-butyl 3-(5-(N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)sulfamoyl)thiophen-2-yl)azetidine-1-carboxylate, was isolated as a bright yellow gum (150 mg, 45% yield). 1 H NMR (400 MHz, chloroform-d): δ 7.31 (d, J = 12.8 Hz, 1H), 7.28-7.16 (m, 2H), 7.00 (t, J = 8.4 Hz, 2H), 6.78 (d, J = 3.7 Hz, 1H), 5.37 (d, J = 9.0 Hz, 1H), 5.01-4.92 (m, 1H), 4.43-4.22 (m, 2H), 3.91-3.75 (m, 3H), 1.46 (s, 9H).

[0469] Synthesis of tert-butyl 3-(5-(N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)sulfamoyl)thiophen-2-yl)azetidine-1-carboxylate 22.6: Ethylation of intermediate 22.6 was preformed at 60 °C using CsCO according to the protocol described in Method D. Crude tert-butyl 3-(5-(N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)sulfamoyl)thiophen-2-yl)azetidine-1-carboxylate (50 mg) was used in the subsequent step reaction.

[0470] Synthesis of 5-(azetidin-3-yl)-N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide hydrochloride salt (Example 47): To a stirred solution of compound tert-butyl 3-(5-(N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)sulfamoyl)thiophen-2-yl)azetidine-1-carboxylate in 1,4-dioxane (2 mL), HCl (4 M in dioxane) (0.5 mL) was added at 0° C., followed by stirring at ambient temperature for 18 hours. The volatiles were evaporated under reduced pressure. The crude compound was purified by reverse phase preparative HPLC purification to give pure 5-(azetidin-3-yl)-N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiophene-2-sulfonamide hydrochloride salt (25 mg, 40% yield) as a white solid. LCMS: m / z found 423.1 [M+H] + , room temperature = 2.56 min (Method 9) [Waters Xbridge C18 column (3.5 μm, 50 × 3 mm)]; 1 H NMR (400MHz, methanol-d4):δ 8.63-8.43(m,1H),7.59(dd,J=3.9,9.4Hz,1H),7.41(q,J=8.0Hz,2H),7.22-7.05(m,3H),5.87-5.74(m,1H),4.72-4.62(m, 1H),4.51-4.35(m,1H),4.36-4.18(m,2H),4.12-3.99(m,1H),3.45-3.31(m,1H),3.31-3.19(m,1H),1.06(q,J=6.8Hz,3H).

[0471] Examples 48 to 50 [ka] Synthesis of methyl 4-((4-methoxybenzyl)thio)thiazole-2-carboxylate 23.2: Intermediate 23.2 was synthesized from 4-bromothiazole-2-carboxylate 23.1 using (4-methoxyphenyl)methanethiol following a similar method as described in Method I. The crude product was purified by column chromatography on silica gel using 20% ​​ethyl acetate in hexanes, and methyl 4-((4-methoxybenzyl)-thio)thiazole-2-carboxylate (1.1 g, 82% yield) was isolated as a brown sticky gum. 1 H NMR (400MHz, DMSO-d6): δ 7.83(s,1H),7.26(d,J=8.4Hz,2H),6.86(d,J=8.4Hz,2H),4.28(s,2H),3.91(s,3H),3.71(s,3H).

[0472] Synthesis of methyl 4-(chlorosulfonyl)thiazole-2-carboxylate 23.3: The sulfonyl chloride 23.3 was synthesized from intermediate 32 according to the procedure described in Method T. The crude sulfonyl chloride was used immediately in the subsequent step without further purification.

[0473] Synthesis of methyl 4-(N-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)sulfamoyl)thiazole-2-carboxylate 23.4: Intermediate 23.4 was synthesized from sulfonyl chloride 23.3 using 2,2,2-trifluoro-1-(4-fluorophenyl)ethan-1-amine hydrochloride according to the protocol described in Method O at 60° C. The compound was purified by column chromatography on silica gel using 35% ethyl acetate in hexanes, and the desired compound, methyl 4-(N-2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)sulfamoyl)thiazole-2-carboxylate, was isolated as a brown gum (220 mg, 33% yield). 1 H NMR (400MHz, DMSO-d6): δ 9.86-9.74(m,1H),8.54(s,1H),7.62-7.29(m,2H),7.19-6.99(m,2H),5.45-5.23(m,1H),3.90(s,3H).

[0474] Synthesis of methyl 4-(N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)sulfamoyl)thiazole-2-carboxylate (Example 48): Ethylation of intermediate 23.4 was preformed at 60° C. according to the protocol described in Method D. The crude product was purified by column chromatography on silica gel using 30% ethyl acetate in hexanes, and the desired compound, 4-(N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)sulfamoyl)thiazole-2-carboxylate, was isolated as a white solid (280 mg, 52% yield, 94.88% purity). LCMS: m / z found 427.0 [M+H] + , room temperature = 3 minutes (Method 9) [Waters Xbridge C18 column (3.5 μm, 50 × 3 mm))]. 1 H NMR(400MHz,DMSO-d6):δ 8.81(s,1H),7.54(dd,J=5.2,8.6Hz,2H),7.21(t,J=8.7Hz,2H),5.92(q,J=8.7Hz,1H),3.97(s,3H),3.40-3.31(m,2H),0.93(t,J=7.0Hz,3H).

[0475] 4-(N-Ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)sulfamoyl)thiazole-2-carboxamide (Example 49): To a 50 mL seal-capped vial was added freshly prepared NH in MeOH (0.2 mL), to which compound 4-(N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)sulfamoyl)thiazole-2-carboxylate (50 mg, 0.12 mmol) was added at ambient temperature, and then heated at 60° C. for 2 hours. Water (10 mL) was added to the reaction mass, which was then extracted with DCM (3×10 mL). The combined organic layers were all dried over anhydrous MgSO, filtered, and concentrated under reduced pressure to give the crude compound. This was purified by column chromatography on silica gel using 30% EA in hexane to give pure methyl 4-(N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)sulfamoyl)thiazole-2-sulfonamide (20 mg, 48% yield, 98.41% yield) as a white solid. LCMS: m / z found 412.0 [M+H] + , room temperature = 3 min (Method 9) [Waters Xbridge C18 column (3.5 μm, 50 × 3 mm)]; 1 H NMR(400MHz,DMSO-d6):δ 8.69(s,1H),8.26(s,1H),8.10(s,1H),7.47(dd,J=5.3,8.6Hz,2H),7.18(t,J =8.8Hz,2H),5.90(q,J=8.7Hz,1H),3.55-3.27(m,2H),0.98(t,J=7.0Hz,3H).

[0476] Example 50 2-Cyano-N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiazole-4-sulfonamide: To a stirred solution of methyl 4-(N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)sulfamoyl)thiazole-2-carboxamide (40 mg, 0.09 mmol) in pyridine (1 mL) was added trifluoroacetic anhydride (0.05 mL, 0.38 mmol) at −10° C. and stirred for 1 h. Water (10 mL) was added to the reaction, followed by extraction with EA (2×15 mL). The combined organic portion was dried over anhydrous MgSO and concentrated under reduced pressure to give the crude compound. This was purified by column chromatography on silica gel using 20% ​​EA in hexane to give 2-cyano-N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)thiazole-4-sulfonamide (18 mg, 48% yield, 97.52% yield) as a pale yellow sticky gum. LCMS: m / z found 392.0 [M+H] + , room temperature = 3.03 min (Method 9) [Waters Xbridge C18 column (3.5 μm, 50 × 3 mm)]. 1 H NMR(400MHz,DMSO-d6)δ 8.87(s,1H),7.45-7.37(m,2H),7.23(t,J=8.6Hz,2H),5.92(q,J=8.9Hz,1H),3.50-3.32(m,2H),1.00(t,J=6.9Hz,3H).

[0477] Example 51, Example 52 and Example 53 5-(N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)sulfamoyl)nicotinamide (Example 51), (S)-5-(N-ethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)e...

Claims

1. Formula (I): 【Chemistry 1】 (In the formula, R １ is C １～６ Alkyl, C ３～６ Cycloalkyl and C ３～６ Cycloalkyl-C １～６ alkyl-, and R １ is substituted with at least one fluorine, and optionally R １ wherein one or more H is replaced by D; R ２ H, D, C １～６ Alkyl and C １～６ haloalkyl; or R １ and R ２ are, together with the carbon atom to which they are attached, C substituted with at least one fluorine ３～６ forming a cycloalkyl, R ３ is C １～６ Alkyl and C １～６ haloalkyl, and optionally R ３ wherein one or more H is replaced by D; L is a bond and C １～３ alkylene; Ring A is C ３～６ Cycloalkyl, 4- to 7-membered heterocyclyl, 5- to 12-membered heteroaryl and C ６～１０ aryl, and ring A is selected from one or more R ４ and optionally substituted by Each R ４ -Halo, -CN, -NO ２ , =O,C １～６ Alkyl, C １～６ Haloalkyl, 2-8 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 are independently selected from Said C １～６ Alkyl, 2-8 membered heteroalkyl, C ２～６ Alkenyl and C ２～６ Alkynyl is one or more R ７ and optionally substituted by R ５ and R ６ is H, C １～６ Alkyl, C １～６ Haloalkyl and Q １ are each independently selected from Said C １～６ Alkyl is one or more R ８ and optionally substituted by Each R ７ and R ８ is 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 are independently selected from Each Q １ and Q ２ is C ３～６ independently selected from cycloalkyl, 4- to 7-membered heterocyclyl, phenyl, and 5- or 6-membered heteroaryl; Said C ３～６ Cycloalkyl, 4- to 7-membered heterocyclyl, phenyl, and 5- or 6-membered heteroaryl may be one or more R ９ and optionally substituted by Each R ９ is halo, =O, -CN, -NO ２ , C １～４ Alkyl, C １～４ Haloalkyl, -OR ９Ａ , -S(O) ２ R ９Ａ , -NR ９Ａ R ９Ｂ , -C(O)R ９Ａ , -OC(O)R ９Ａ , -C(O)OR ９Ａ , -NR ９Ｂ C(O)R ９Ａ , —C(O)NR ９Ａ R ９Ｂ , -NR ９Ｂ C(O)OR ９Ａ , —OC(O)NR ９Ａ R ９Ｂ , -NR ９Ｂ SO ２ R ９Ａ and -SO ２ NR ９Ａ R ９Ｂ are independently selected from Said C １～４ Alkyl is halo, -CN, -OR ９Ｃ , -NR ９Ｃ R ９Ｄ and -SO ２ R ９Ｃ and optionally substituted by one or two substituents selected from Ring B is phenyl or 5- or 6-membered heteroaryl, and Ring B contains one or more R １０ and optionally substituted by Each R １０ -Halo, -CN, -NO ２ , =O,C １～６ Alkyl, C １～６ Haloalkyl, 2-8 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 are independently selected from Said C １～６ Alkyl, 2-8 membered heteroalkyl, C ２～６ Alkenyl and C ２～６ Alkynyl is one or more R １１ and optionally substituted by Each R １１ is halo, -CN, -OR １１Ａ , -NR １１Ａ R １１Ｂ and -SO ２ R １１Ａ are independently selected from R ７Ａ , R ７Ｂ , R ９Ａ , R ９Ｂ , R ９Ｃ , R ９Ｄ , R １０Ａ , R １０Ｂ , R １１Ａ and R １１Ｂ In each occurrence, H, C １～４ Alkyl and C １～４ haloalkyl; Any —NR in the substituent ５ R ６ , -NR ７Ａ R ７Ｂ , -NR ９Ａ R ９Ｂ , -NR ９Ｃ R ９Ｄ , -NR １０Ａ R １０Ｂ and -NR １１Ａ R １１Ｂ can form a 4- to 6-membered heterocyclyl, said 4- to 6-membered heterocyclyl being selected from halo, ═O, C １～４ Alkyl and C １～４ optionally substituted by one or more substituents selected from haloalkyl; each x is independently 0, 1, or 2; however, (i) Group 【Chemistry 2】 but, 【Transformation 3】 and R ４１ is H, -CH ３ , -CF ３ or cyclopropyl, R ４２ is -NHC(O)R ６ and (ii) Compounds A and B: 【Chemistry 4】 be excluded (Subject to the following conditions) or a pharmaceutically acceptable salt thereof.

2. Ring A is a monocyclic 6-membered heteroaryl or a 9-membered fused bicyclic heteroaryl, and Ring A has 1 to 4 ring nitrogen atoms. Ring A is a 6-membered monocyclic .... Ring A has 1 to 4 ring nitrogen atoms. Ring A has 1 or more R ４ 2. The compound of claim 1, optionally substituted with:

3. Ring A is a monocyclic 6-membered heteroaryl, wherein Ring A has 1, 2, or 3 ring nitrogen atoms, and Ring A is a 6-membered monocyclic heteroaryl, wherein Ring A has 1, 2, or 3 ring nitrogen atoms, and wherein Ring A has one or more R ４ 2. The compound of claim 1, optionally substituted with:

4. Ring A is thienyl, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, tetrahydropyranyl, 【Transformation 5】 and ring A is selected from one or more R ４ 2. The compound of claim 1, optionally substituted with:

5. Ring A is 【Transformation 6】 and ring A is selected from one or more R ４ 2. The compound of claim 1, optionally substituted with:

6. Ring A is 【Transformation 7】 and ring A is selected from one or more R ４ 2. The compound of claim 1, optionally substituted with:

7. Ring A is 【Transformation 8】 2. The compound of claim 1 selected from:

8. Each R ４ -Halo, -CN, -NO ２ , C １～６ Alkyl, C １～６ haloalkyl, 2-8 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 The compound of any one of claims 1 to 7, independently selected from:

9. Each R ４ is halo (e.g., fluoro or chloro), —CN, C １～３ Alkyl, —OC １～３ Alkyl, —C(O)C １～３ Alkyl, —C(O)NH ２ , -C(O)NH(C １～３ alkyl) and —C(O)N(C １～３ alkyl) ２ are independently selected from Optionally, each R ４ The compound of any one of claims 1 to 7, wherein is independently selected from fluoro and -CN.

10. Ring A is 【Chemistry 9】 2. The compound of claim 1 selected from:

11. Formula (III): 【Chemistry 10】 (In the formula, Each R ４ａ -Halo, -CN, -NO ２ , C １～６ Alkyl, C １～６ Haloalkyl, 2-8 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 are independently selected from Said C １～６ Alkyl, C １～６ Heteroalkyl, C ２～６ Alkenyl and C ２～６ Alkynyl is one or more R ７ and a is an integer from 0 to 3. or a pharmaceutically acceptable salt thereof.

12. Formula (XI): 【Chemistry 11】 (In the formula, Each R ４ａ -Halo, -CN, -NO ２ , C １～６ Alkyl, C １～６ Haloalkyl, 2-8 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 are independently selected from Said C １～６ Alkyl, 2-8 membered heteroalkyl, C ２～６ Alkenyl and C ２～６ Alkynyl is one or more R ７ and a is an integer from 0 to 4. or a pharmaceutically acceptable salt thereof.

13. Formula (XIII): 【Chemistry 12】 (In the formula, Each R ４ａ -Halo, -CN, -NO ２ , C １～６ Alkyl, C １～６ Haloalkyl, 2-8 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 are independently selected from Said C １～６ Alkyl, 2-8 membered heteroalkyl, C ２～６ Alkenyl and C ２～６ Alkynyl is one or more R ７ and a is an integer from 0 to 3. or a pharmaceutically acceptable salt thereof.

14. Formula (XV): 【Chemistry 13】 (In the formula, Each R ４ａ -Halo, -CN, -NO ２ , C １～６ Alkyl, C １～６ Haloalkyl, 2-8 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 are independently selected from Said C １～６ Alkyl, 2-8 membered heteroalkyl, C ２～６ Alkenyl and C ２～６ Alkynyl is one or more R ７ and optionally substituted by a is an integer from 0 to 3. or a pharmaceutically acceptable salt thereof.

15. Formula (XXI): 【Chemistry 14】 (In the formula, X ３ is N or CR ４ａ and R ４ａ -Halo, -CN, -NO ２ , C １～６ Alkyl, C １～６ Haloalkyl, 2-8 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 is selected from Said C １～６ Alkyl, 2-8 membered heteroalkyl, C ２～６ Alkenyl and C ２～６ Alkynyl is one or more R ７ (optionally replaced by or a pharmaceutically acceptable salt thereof.

16. Each R ４ａ is halo (e.g., fluoro or chloro), —CN, C １～３ Alkyl, —OC １～３ Alkyl, —C(O)C １～３ Alkyl, —C(O)NH ２ , -C(O)NH(C １～３ alkyl) and —C(O)N(C １～３ alkyl) ２ are independently selected from Optionally, each R ４ The compound of any one of claims 11 to 15, wherein is independently selected from fluoro and -CN.

17. formula: 【Chemistry 15】 The basis of 【Chemistry 16】 16. The compound of claim 15, selected from:

18. Ring B is one or more R １０ 2. The compound of claim 1, wherein the phenyl is optionally substituted by:

19. Ring B is 【Chemistry 17】 2. The compound of claim 1 selected from:

20. Ring B is [Chemistry 18] 2. The compound of claim 1, wherein:

21. Each R １０ Ha, Halo, C １～３ Alkyl, C １～３ Haloalkyl, —OC １～３ Alkyl and —OC １～３ 2. The compound of claim 1, wherein the aryl group is independently selected from haloalkyl.

22. Ring B is 【Chemistry 19】 2. The compound of claim 1 selected from:

23. Ring B is 【Chemistry 20】 2. The compound of claim 1 selected from:

24. The compound of claim 1, wherein Ring B is 4-fluorophenyl.

25. L is a bond and —CH ２ The compound of claim 1, wherein the compound is selected from:

26. The compound of claim 1 , wherein L is a bond.

27. R ３ is methyl, -CD ３ 2. The compound of claim 1, wherein the aryl group is selected from the group consisting of ethyl, 2-fluoroethyl, and 2-fluoroethyl.

28. R ３ The compound of claim 1 , wherein is selected from methyl and ethyl.

29. R １ is C １～６ Alkyl and C ３～６ cycloalkyl; R １ is substituted with at least one fluorine.

30. R １ is CH ２ F, -CHF ２ and -CF ３ 2. The compound of claim 1 selected from:

31. R １ is -CF ３ 2. The compound of claim 1, wherein:

32. R ２ is selected from H and methyl.

33. R ２ The compound of claim 1 , wherein

34. formula: 【Chemistry 21】 The basis of 【Chemistry 22】 2. The compound of claim 1, wherein:

35. formula: 【Chemistry 23】 The basis of 【Chemistry 24】 2. The compound of claim 1, wherein:

36. A compound selected from Compound List 1 of the present specification or a pharmaceutically acceptable salt thereof.

37. 10. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, except that compounds A and B are not excluded, and a pharmaceutically acceptable excipient.

38. 10. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, except that compounds A and B are not excluded, for use as a pharmaceutical.

39. 10. A compound of claim 1, or a pharmaceutically acceptable salt thereof, except that compounds A and B are not excluded, for use in the treatment of a disease or medical disorder mediated by Cav2.

3.

40. A method for 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 claim 1 or a pharmaceutically acceptable salt thereof, except that compounds A and B are not excluded.

41. 10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, except that compounds A and B are not excluded, for use in the treatment of a disease or medical disorder selected from neurodegenerative diseases, neurodevelopmental disorders, epilepsy, endocrine disorders, cerebral vasospasm, and pain.

42. 10. A compound of claim 1 or a pharmaceutically acceptable salt thereof, except that compounds A and B are not excluded, for use in the neuroprotective treatment of neurodegenerative diseases.

43. 10. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, except that compounds A and B are not excluded, for use in the treatment of Parkinson's disease.

44. 10. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, except that compounds A and B are not excluded, for use in preventing or inhibiting degeneration of dopaminergic neurons in a subject with Parkinson's disease.

45. It is intended for use in the prevention or treatment of epilepsy, Optionally, the epilepsy is drug-resistant epilepsy. The compound of claim 1 or a pharmaceutically acceptable salt thereof, except that compounds A and B are not excluded.

46. For use in the prevention or treatment of developmental and epileptic encephalopathies, Optionally, the developmental and epileptic encephalopathy is a monogenic developmental and epileptic encephalopathy (e.g., CACNA1E hyperactivity (DEE69), CDKL5 deficiency (DEE2), Dravet syndrome (DEE6A), DEE9 (caused by mutations in the PCDH19 gene), DEE11 (SCN2A hyperactivity), DEE13, DEE19, DEE43, DEE45, DEE59, DEE74, DEE78, DEE79, or DEE92), except that compounds A and B are not excluded. The compound of claim 1 or a pharmaceutically acceptable salt thereof, except that compounds A and B are not excluded.

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