Activators of pyruvate kinase isoform m2 and methods for treating neurodegenerative disease

Abstract

Provided for are activators of pyruvate kinase isoform M2 (PKM2), pharmaceutical compositions thereof, and related methods of treating neurologic and neurodegenerative disease as well as well as other PKM2-associated disorders.

Description

ACTIVATORS OF PYRUVATE KINASE ISOFORM M2 AND METHODS FORTREATING NEURODEGENERATIVE DISEASECROSS REFERENCE TO RELATED APPLICATION

[0001] This international patent application claims priority to United States provisional patent Application No. 63 / 645,090, filed May 9, 2024, which is hereby incorporated by reference in its entirety.TECHNICAL FIELD

[0002] Provided for are activators of pyruvate kinase isoform M2 (PKM2), pharmaceutical compositions thereof, and related methods of treating neurologic and neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS), as well as other PKM2-associated disorders.BACKGROUND

[0003] Pyruvate Kinase Isoform M2 (PKM2) activation has been implicated in the treatment of neurologic diseases. Among potentially relevant mechanisms of action, PKM2 activators may limit the activation of reactive astrocytes which are believed to be relevant to the development and progression of neurologic and neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS).

[0004] Astrocytes support synaptic communication and are associated with plasticity and repair. Insult or injury is known to cause astrogliosis, i.e., an increase in the number of astrocytes. Astrogliosis has been observed in the neurodegenerative diseases multiple sclerosis (MS) and ALS. During the pro-inflammatory response, such as in MS and ALS, astrocytes are activated to a reactive state characterized by hypertrophy of processes and upregulation of glial fibrillary acidic protein (GFAP). GFAP is a protein primarily expressed in astrocytes whose increased expression is indicative of activation of reactive astrocytes during neurodegenerati on .

[0005] It is believed that reactive astrocytes consume primarily glycolytic energy, implicating the rate-limiting glycolytic enzyme pyruvate kinase (PK). The Ml and M2 isoforms of PK (i.e., PKM1 and PKM2), show differential expression in the brain tissues, with PKM1 being preferentially expressed in neurons and PKM2 being preferentially expressed in astrocytes. PKM2 expression has been correlated with astrogliosis. In addition, PKM2 has been characterized as a functional driver of anabolic processes in numerous cell types, through the diversion of glycolytic intermediates into macromolecule synthesis. Moreover, PKM2 existsin an equilibrium of constitutively active tetramers, and dimers with lower catalytic activity, a process which is allosterically and pharmacologically regulated. The dimeric form of PKM2 can translocate to the nucleus, where it influences gene regulation via its protein kinase activity and protein-protein interactions, while the tetrameric form of PKM2 is localized to the cytoplasm. Evidence suggests that monomeric / dimeric PKM2 can enter the nucleus and upregulate transcription of pro-inflammatory factors, which further promotes activation of reactive astrocytes.

[0006] As PKM2 expression is high in epithelial cells of the choroid plexus, the association of PKM2-driven metabolism and ATP provision to the elaboration of cerebrospinal fluid (CSF) is considered important. CSF provides an important vehicle for the elimination of central nervous system (CNS) waste including neurotoxic agents and excess fluid. In multiple CNS conditions in which brain fluid homeostasis is imbalanced and cerebral edema results, including traumatic encephalopathies, brain tumors, stroke, traumatic head injury or other causes of subdural, epidural or intracerebral hematoma, infections, high altitude and other metabolic imbalances, increased intracranial pressure results in brain ischemia, tentorial herniation and other secondary pathologies. Activation of PKM2 in the choroid plexus which elaborates CSF together with astrocytes which control brain fluid homeostatic balance is believed to be a mechanism to control intracranial pressure and enhance elimination of neurotoxic agents and excess fluid.

[0007] Dual central and peripheral activation of PKM2 has been shown experimentally to have discrete anti-inflammatory properties in Thl7 cell-dependent models, as well as the potential to divert metabolism away from the production of potentially neurotoxic intermediates in neurodegenerative diseases, including excitatory amino acids glycine, serine, and D-aspartate, as well as ceramides important in neurodegenerative conditions and epilepsy. PKM2 activation may also enhance alternate sources of ATP to glial cells, and through both glycolysis and the lactate shunt, indirectly to neurons. Neurodegeneration and neuroinflammation are understood to combine in a reciprocal negative interaction to accelerate several chronic conditions. Employing PKM2 central activation to both individually mitigate neurodegeneration and neuroinflammation, and thereby prevent negative disease synergy, is a novel and unique facet of PKM2 central pharmacology.

[0008] Small molecule activators of PKM2 have been developed, which stabilize the tetrameric form of PKM2, thereby limiting PKM2-associated metabolism and nuclear localization. These PKM2 activators were shown to be effective in a mouse model of intracerebral hemorrhage (ICH), leading to increased glial PKM2 expression, reduced PKM2nuclear translocation, attenuation of astrocyte activation, and improved functional recovery. Furthermore, bioinformatic analyses of mouse brains following treatment with PKM2 activators revealed downregulation of differentially expressed genes (DEGs) associated with autophagy and metabolic processes. However, such small molecules may have limited brain penetrance and insufficient efficacy for the treatment of neurologic and neurodegenerative disorders. As such, improved PKM2 activators are crucial to developing more effective treatments.

[0009] As such, provided for herein are PKM2 activator compounds, and compositions and methods utilizing these compounds. The PKM2 activators may have improved brain penetrance, activity against astrogliosis or astrocyte activation / reactivity, favorable pharmacokinetics, and / or activity against the development / progression of neurologic and neurodegenerative diseases. Also provided for are PKM2 activator compounds, compositions, and methods for treatment of peripheral PKM2-associated diseases having pathology outside the CNS.SUMMARY

[0010] Provided for are PKM2 activators, including 1 -benzoylpiperidine PKM2 activators, having CNS and / or peripheral activity for the treatment of PKM2-associated diseases. The PKM2 activators may be compounds according to, for example, Formulae I- VI as described herein, including pharmaceutically acceptable salts thereof.

[0011] Also provided for are pharmaceutical compositions comprising one or more PKM2 activators as described herein, and a pharmaceutically-acceptable carrier. The PKM2 activator compounds and pharmaceutical compositions may be administered to a human or mammalian subject or patient in a pharmaceutically effective amount to obtain a benefit in the subject or patient. The pharmaceutical compositions may be formulated for administration as, for example, an oral dosage form, nasal dosage form, or parenteral dosage form, among others. The pharmaceutical compositions may be formulated as a unit dosage comprising, for example, between 1 - 1000 mg of PKM2 activator, or more.

[0012] Also provided for are methods for treating diseases or disorders associated with PKM2, i.e., diseases or disorders for which a meaningful patient benefit may be obtained by administering a PKM2 activator to a patient in need thereof. In some embodiments, provided for are methods for treating CNS diseases, such as neurological or neurodegenerative diseases, by administering a therapeutically effective amount of a PKM2 activator to a patient in need thereof. In some embodiments, the CNS disease is a neurodegenerative diseaseselected from alpha-synucleinopathies, multiple sclerosis (MS) amyotrophic lateral sclerosis (ALS), Parkinson’s disease, Huntington’s disease, stroke, Alzheimer’s disease, neuroinflammation, and Lewy body dementia.

[0013] In some embodiments, provided for are methods for treating peripheral diseases, such as a fibrotic disorders, inflammatory disorders, autoimmune disorders, and skin disorders, by administering a therapeutically effective amount of a PKM2 activator to a patient in need thereof. In some embodiments, the fibrotic disorder is selected from arthritis, arthrofibrosis, cystic fibrosis, fibrotic eye diseases, fibrotic kidney diseases, idiopathic pulmonary fibrosis, scleroderma, hypertrophic cardiomyopathy, myocarditis, systemic sclerosis, atrial / ventricular fibrillation, liver cirrhosis, dilated cardiomyopathy, fibrothorax, bridging fibrosis of the liver, glial scar, arterial stiffness, Crohn’s disease, Dupuytren’s contracture, keloid fibrosis, lipedema, mediastinal fibrosis, myelofibrosis, myofibrosis, Peyronie’s disease, nephrogenic systemic fibrosis, progressive massive fibrosis of the lungs, retroperitoneal fibrosis, adhesive capsulitis, acute myocardial infarction, and other fibrotic diseases. In further embodiments, the peripheral disease is an eye disease selected from age-related macular degeneration and retinitis pigmentosa. In further embodiments, the peripheral disease is non-ketotic hyperglycinemia.BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Aspects and advantages of the present disclosure will become apparent from the following exemplary embodiments taken in conjunction with the accompanying drawings, of which:

[0015] FIG. 1 : Mean plasma and brain concentration of Cpd. 3 after PO Dosing at 50.0 mg / kg in mice.

[0016] FIGs. 2A, 2B, 2C, 2D-1, 2D-2: Evaluation in experimental autoimmune encephalomyelitis (EAE) model. FIG. 2A - Overview of in vivo study using Cpd. 3 at lOOmpk and 300mpk. Four groups of 12 mice (Naive vehicle, EAE model, lOOmpk treatment and 300mpk treatment) were dosed via bi-daily oral gavage for a total of 4 weeks. FIG. 2B - Clinical score results are shown. Clinical score was assessed using limp tail and hindlimb paralysis measures. Two-way ANOVA with Dunnett’s multiple comparison test, compared to Naive vehicle: *p<0.05, **p<0.01, ***p<0.001; n=12 mice. FIG. 2C - Body weight change results are shown. Two-way ANOVA with Dunnett’s multiple comparison test, compared to Naive vehicle: *p<0.05, **p<0.01, ***p<0.001; n=12 mice. FIG. 2D-1 - Formalin-fixed cervical spinal cord sections stained with GFAP. FIG 2D-2 - Quantitative morphometry ofGFAP IHC staining. Two-way ANOVA with Dunnett’s multiple comparison test, compared to EAE model group: *p<0.05, **p<0.01, ***p<0.001; n=12 mice.DETAILED DESCRIPTION

[0017] In some aspects, the present invention provides for activators of pyruvate kinase isoform M2 (PKM2), pharmaceutical compositions thereof, and related methods of treating neurologic and neurodegenerative disease as well as other central nervous system disorders. In some aspects, the present invention provides for improved 1 -benzoylpiperidine PKM2 activator compounds for the treatment of neurological and neurodegenerative diseases. Existing 1 -benzoylpiperidine PKM2 activator compounds are unable to effectively cross the blood-brain barrier to exhibit pharmacological activity in tissues involved with neurological and neurodegenerative diseases, rendering them ineffective therefor. For example, WO 2014 / 139144 Al, published September 18, 2024, and WO 2014 / 139325, published September 18, 2014, teach that the piperidine moiety of the 1 -benzoylpiperidine PKM2 activator contains a hydrophilic substituent such as hydroxyl (-OH), carboxylic acid (- COOH), aldehyde (-CHO), ester (-CO2-), certain amines, or phosphate (-OP(=O)(OH)2).

[0018] It has been discovered that by eliminating hydrophilic substituents to the piperidine moiety, both favorable membrane permeability and PKM2 activation potency can be obtained. As such, embodiments herein provided for improved 1 -benzoylpiperidine PKM2 activator compounds, and pharmaceutical compositions thereof, for the treatment of neurological and neurodegenerative diseases.

[0019] More generally, the PKM2 activators herein may The PKM2-associated disorders may include any disorder for which administration of a PKM2 activator provides a beneficial effect in a patient in need thereof. The PKM2-associated disorders may be CNS-associated neurological or neurodegenerative diseases. The PKM2-associated disorders may be peripheral diseases having non-CNS symptoms or effects. The peripheral diseases may have a CNS component. The PKM2-associated disorders may be treated or a patient benefit may be obtained by administering an effective amount of a compound according to the following Formulae I, II, Ila, III, IV, V, and VI.

[0020] In some embodiments, provided for are compounds according to Formula I:including pharmaceutically acceptable salts thereof, whereinR1is -H, halogen, C1-C3 alkyl, saturated or unsaturated, or C1-C3 haloalkyl, saturated or unsaturated, andR2is C1-C8 alkyl, saturated or unsaturated, C3-C6 cycloalkyl, saturated or unsaturated, phenyl, or C5-C6 heteroaryl, said C3-C6 cycloalkyl, phenyl, and C5-C6 heteroaryl optionally connected through C1-C3 alkylene, saturated or unsaturated, said C1-C8 alkyl, C3-C6 cycloalkyl, phenyl, and C1-C3 alkylene unsubstituted, monosubstituted, or polysubstituted with R6; or R1and R2together form C3-C5 cycloalkyl, saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted with R6;R3and R4are independently in each case and at each occurrence selected from the group consisting of halogen, C1-C6 alkyl, saturated or unsaturated, and C1-C6 haloalkyl, saturated or unsaturated; n is an integer ranging from 0 to 4; m is an integer ranging from 0 to 4;L is -X-NR5-SO2-Y- or -X-SO2-NR5-Y-;X and Y are independently absent to form a single bond or X and Y are independently selected from methylene and ethylene;R5is -H or C1-C3 alkyl;A is C6-C14 heterocycle, unsubstituted, monosubstituted, or polysubstituted with R6and / or C1-C6 heteroalkyl, saturated or unsaturated;R6is independently at each occurrence selected from the group consisting of halogen, C1-C6 alkyl, saturated or unsaturated, C1-C6 haloalkyl, saturated or unsaturated, and C3-C5 cycloalkyl, saturated or unsaturated, said C3-C5 cycloalkyl unsubstituted, monosubstituted, or polysubstituted with halogen or C1-C3 haloalkyl.

[0021] In an alternative embodiment of Formula I, said C3-C6 cycloalkyl, phenyl, and C5-C6 heteroaryl optionally connected through -O-. In a further alternative embodiment of Formula I, said C3-C6 cycloalkyl, phenyl, and C5-C6 heteroaryl connected through -O-. In a further alternative embodiment of Formula I, R2 is phenyl connected through -O-, wherein said phenyl is unsubstituted, monosubstituted, or polysubstituted with R6.

[0022] In some embodiments, neither R1nor R2comprise a hydrophilic substituent containing oxygen or amine. In some embodiments, neither R1nor R2comprise -OH, - CH2OH, -CHO, -CO2H, -NH2, -N(H)(CI-6alkyl), -N(CI-6alkyl)2, -CO2-C1-6 alkyl, - OP(=O)(OH)2, or -OCO2-CH2-OP(=O)(OH)2. Preferably, R1and R2independently comprise non-hydrophilic (i.e., lipophilic) substituents including -H, halogen, alkyl, phenyl, heteroaryl, and cycloalkyl, optionally substituted with alkyl, halogen (such as fluorine), or haloalkyl.

[0023] In some embodiments, R1is -H or -F. In some embodiments, R1is -F. In some embodiments, R1is -H. In further embodiments, R1is -H or -Cl. In further embodiments, R1is -H or -Br. In further embodiments, R1is methyl. In further embodiments, R1is trifluoromethyl (-CF3), difluoromethyl (-CF2H), or fluoromethyl (-CH2F).

[0024] In some embodiments, R2is cyclopropyl or cyclobutyl optionally connected through C1-C3 alkylene. In some embodiments, said cyclopropyl or cyclobutyl of R2is monosubstituted, di substituted, or tri substituted with methyl and / or -F. In alternative embodiments, said cyclopropyl or cyclobutyl of R2is monosubstituted, di substituted, or tri substituted with fluoromethyl, difluoromethyl, or trifluoromethyl. In various embodiments, said C1-C3 alkylene is monosubstituted or disubstituted with -F and / or methyl.

[0025] In further embodiments, R2is C1-C6 alkyl. In some embodiments, said C1-C6 alkyl includes a tertiary or quaternary carbon atom, optionally wherein said tertiary or quaternary carbon atom is bonded to at least one halogen. In alternative embodiments, said tertiary or quaternary carbon atom are bonded to one or more deuterium atoms or deuterated alkyl groups (such as -CD3). Alternatively, in various embodiments, any -H atom or atoms present in the compound may be substituted with deuterium. In some embodiments, said C1-C6 alkyl includes an isopropyl group optionally connected to the piperidine group through C1-C3 alkylene. In some embodiments, said C1-C6 alkyl includes a tert-butyl group optionally connected to the piperidine group through C1-C2 alkylene. In various embodiments, said Ci- C3 alkylene and C1-C2 alkylene are monosubstituted or disubstituted with -F and / or methyl.

[0026] In further embodiments, R2is phenyl optionally connected through C1-C3 alkylene. In some embodiments, said phenyl of R2is monosubstituted or disubstituted with -F and / or Ci haloalkyl (including trifluoromethyl, difluoromethyl, and / or fluoromethyl). In alternative embodiments of Formulae I, II, III, and IV (not described in these Formulae), R2is phenoxy connected to piperidine through its oxy group (i.e., -O-phenyl), or R2is -O-heteroaryl such as -O-Cs-Ceheteroaryl, said phenyl and heteroaryl unsubstituted, monosubstituted, or polysubstituted with R6.

[0027] In further embodiments, R2is Cs-Ce heteroaryl optionally connected through C1-C3 alkylene. In some embodiments, said C5 heteroaryl is furan, oxazole, isoxazole, 1,3,4,- oxadiazole, thiophene, thiazole, 1,3,4-thiadiazole, or imidazole. In some embodiments, said Ce heteroaryl is pyridine, pyrimidine, pyrazine, pyridazine, 1,2,4-triazine, or 1,3,5-triazine. In some embodiments, said C5 or Ce heteroaryl is monosubstituted, di substituted, or tri substituted with -F and / or Ci haloalkyl (including trifluoromethyl, difluoromethyl, and / or fluoromethyl). In some embodiments, R2is pyridine monosubstituted or disubstituted with -F and / or Ci haloalkyl.

[0028] In further embodiments, R1and R2combine to form a spiro group on the piperidine to which they are attached. In some embodiments, the spiro group is C3-C5 cycloalkyl, saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted with R6. In some embodiments, the spiro group is cyclopropyl, cyclobutyl, or cyclopentyl. In some embodiments, the spiro group is cyclopentyl. In various embodiments, the spiro group is monosubstituted, di substituted, or tri substituted with -F and / or Ci haloalkyl. In alternative embodiments, R1or R2combine with one of R3to form a fused C3-C6 cycloalkyl, saturated or unsaturated, or fused C5-C6 heteroaryl, each unsubstituted, monosubstituted, or polysubstituted with R6.

[0029] In some embodiments, n is 0, meaning that no R3substituent is present on the piperidine ring of Formula I. In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, R3, if present, is independently selected from methyl, -F, and Ci haloalkyl. In further embodiments R3, if present, is independently selected from ethyl and C2 haloalkyl. In some embodiments, m is 0, meaning that no R4substituent is present on the phenyl ring of Formula I. In some embodiments, m is 0, 1, 2, 3, or 4. In some embodiments, R4, if present, is independently selected from methyl, -F, and Ci haloalkyl. In further embodiments R4, if present, is independently selected from ethyl and C2 haloalkyl. In alternative embodiments, R4is deuterium present at one, two, three, or four positions of the phenyl ring (i.e., m is 1, 2, 3, or 4).

[0030] In some embodiments, X and Y are absent to form single bonds and L comprises - NR5-SO2- or -SO2-NR5-. In some embodiments, X and Y are absent to form single bonds and L comprises -NR5-SO2-, with R5being methyl or -H. In some embodiments, one of X and Y are methylene or ethylene and the other of X and Y is absent to form a single bond. In some embodiments, one of X and Y is methylene or ethylene and the other of X and Y is independently methylene or ethylene. In additional embodiments, the methylene and ethylene of X and / or Y are optionally monosubstituted or polysubstituted with R6.

[0031] In various embodiments, A is Ce-Cu heterocycle, including Ce-Cu heterocycloalkyl, saturated or unsaturated, and Ce-Cu heteroaryl. In some embodiments, the Ce-Cu heterocycle is monocyclic, fused bicyclic, or fused tricyclic. In an embodiment, A is Ce-Cu heteroaryl. In an embodiment, the Ce-Cu heteroaryl is a fused bicyclic. In an embodiment, A is a C9-C10 heteroaryl. In an embodiment, the C9-C10 heteroaryl is a fused bicyclic selected from:wherein RNis -H or C1-C3 alkyl, and wherein said C9-C10 heteroaryl is unsubstituted, monosubstituted, or disubstituted with R6and / or C1-C6 heteroalkyl, saturated or unsaturated.

[0032] In further embodiments, provided for are compounds according to Formula II:Formula II including pharmaceutically acceptable salts thereof, whereinR1is -H, halogen, C1-C3 alkyl, saturated or unsaturated, or C1-C3 haloalkyl, saturated or unsaturated, andR2is C1-C8 alkyl, saturated or unsaturated, C3-C6 cycloalkyl, saturated or unsaturated, phenyl, or C5-C6 heteroaryl, said C3-C6 cycloalkyl, phenyl, and C5-C6 heteroaryl optionally connected through C1-C3 alkylene, saturated or unsaturated, said C1-C8 alkyl, C3-C6 cycloalkyl, phenyl, and C1-C3 alkylene unsubstituted, monosubstituted, or polysubstituted with R6; or R1and R2together form C3-C5 cycloalkyl, saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted with R6;L is -X-NR5-SO2-Y- or -X-SO2-NR5-Y-;X and Y are independently absent to form a single bond or X and Y are independently selected from methylene and ethylene;R5is -H or C1-C3 alkyl;A is C6-C14 heterocycle, unsubstituted, monosubstituted, or polysubstituted with R6and / or C1-C6 heteroalkyl, saturated or unsaturated;R6is independently at each occurrence selected from the group consisting of halogen, C1-C6 alkyl, saturated or unsaturated, C1-C6 haloalkyl, saturated or unsaturated, and C3-C5cycloalkyl, saturated or unsaturated, said C3-C5 cycloalkyl unsubstituted, monosubstituted, or polysubstituted with halogen or C1-C3 haloalkyl.

[0033] In further embodiments, provided for are compounds according to Formula III:Formula III including pharmaceutically acceptable salts thereof, where one of the dashed bonds to Z or T represents a single bond and the other represents a double bond, wherein:R1is -H, halogen, C1-C3 alkyl, saturated or unsaturated, or C1-C3 haloalkyl, saturated or unsaturated, andR2is C1-C8 alkyl, saturated or unsaturated, C3-C6 cycloalkyl, saturated or unsaturated, phenyl, or C5-C6 heteroaryl, said C3-C6 cycloalkyl, phenyl, and C5-C6 heteroaryl optionally connected through C1-C3 alkylene, saturated or unsaturated, said C1-C8 alkyl, C3-C6 cycloalkyl, phenyl, and C1-C3 alkylene unsubstituted, monosubstituted, or polysubstituted with R6; or R1and R2together form C3-C5 cycloalkyl, saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted with R6;R5is, independently at each occurrence, -H or C1-C3 alkyl;Q is independently, at each occurrence, N, CH, or C(R6); wherein one of Z and T to which a double bond is connected is N, CH, or C(R6); wherein the other of Z and T to which a single bond is connected is CH=CH, C(R6)=CH, C(R6)=C(R6), N=CH, N=C(R6), S, O, N(R5), CH2, CH-R6, or C(R6)2; andR6is independently at each occurrence selected from the group consisting of halogen, C1-C6 alkyl, saturated or unsaturated, C1-C6 haloalkyl, saturated or unsaturated, and C3-C5 cycloalkyl, saturated or unsaturated, said C3-C5 cycloalkyl unsubstituted, monosubstituted, or polysubstituted with halogen or C1-C3 haloalkyl.

[0034] In some embodiments, the ring including Z and T is a 5-membered ring. In some embodiments, one of Z or T of said 5-membered ring is S, O, N(R5), CH2, CH-R6, or C(R6)2, and the other of Z or T of said 5-membered ring is N, CH, or C(R6), where said S, O, N, or C atom constitutes an atom of the 5-membered ring. In some embodiments, the ring including Z and T is a 6-membered ring. In some embodiments, one of Z or T is CH=CH, where the carbon atoms constitute part of the 6-membered ring. In some embodiments, one of Z or T isC(R6)=CH, which can be present in the ring in either orientation (i.e., C(R6)=CH orientation or CH=C(R6) orientation). In some embodiments, one of Z or T is C(R6)=C(R6), where the carbon atoms constitute part of the 6-membered ring. In some embodiments, one of Z or T is N=CH, which can be present in the ring in either orientation (i.e., N=CH orientation or CH=N orientation).

[0035] In further embodiments, provided for are compounds according to Formulae Ill-i or Ill-iiwith their variables defined as in Formula III. In embodiments of Formula Ill-i, Z is N, CH, or C(R6), and T is CH=CH, C(R6)=CH, C(R6)=C(R6), N=CH, N=C(R6), S, O, N(R5), CH2, CH-R6, or C(R6)2. In embodiments of Formula Ill-ii, Z is CH=CH, C(R6)=CH, C(R6)=C(R6), N=CH, N=C(R6), S, O, N(R5), CH2, CH-R6, or C(R6)2, and T is N, CH, or C(R6).

[0036] In further embodiments, provided for are compounds according to Formula IV:Formula IV including pharmaceutically acceptable salts thereof, wherein:R1is -H, halogen, C1-C3 alkyl, saturated or unsaturated, or C1-C3 haloalkyl, saturated or unsaturated, andR2is C1-C8 alkyl, saturated or unsaturated, C3-C6 cycloalkyl, saturated or unsaturated, phenyl, or C5-C6 heteroaryl, said C3-C6 cycloalkyl, phenyl, and C5-C6 heteroaryl optionally connected through C1-C3 alkylene, saturated or unsaturated, said C1-C8 alkyl, C3-C6 cycloalkyl, phenyl, and C1-C3 alkylene unsubstituted, monosubstituted, or polysubstituted with R6; or R1and R2together form C3-C5 cycloalkyl, saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted with R6; andR6is independently at each occurrence selected from the group consisting of halogen, C1-C6 alkyl, saturated or unsaturated, C1-C6 haloalkyl, saturated or unsaturated, and C3-C5cycloalkyl, saturated or unsaturated, said C3-C5 cycloalkyl unsubstituted, monosubstituted, or polysubstituted with halogen or C1-C3 haloalkyl.

[0037] In further embodiments, provided for are compounds according to Formula V:Formula V including pharmaceutically acceptable salts thereof, where one of the dashed bonds to Z or T represents a single bond and the other represents a double bond, wherein:R5is, independently at each occurrence, -H or C1-C3 alkyl;Q is independently, at each occurrence, N, CH, or C(R6); wherein one of Z and T to which a double bond is connected is N, CH, or C(R6); wherein the other of Z and T to which a single bond is connected is CH=CH, C(R6)=CH, C(R6)=C(R6), N=CH, N=C(R6), S, O, N(R5), CH2, CH-R6, or C(R6)2; andR6is independently at each occurrence selected from the group consisting of halogen, C1-C6 alkyl, saturated or unsaturated, C1-C6 haloalkyl, saturated or unsaturated, and C3-C5 cycloalkyl, saturated or unsaturated, said C3-C5 cycloalkyl unsubstituted, monosubstituted, or polysubstituted with halogen or C1-C3 haloalkyl.

[0038] In some embodiments, the ring including Z and T is a 5-membered ring. In some embodiments, one of Z or T of said 5-membered ring is S, O, N(R5), CH2, CH-R6, or C(R6)2, and the other of Z or T of said 5-membered ring is N, CH, or C(R6), where said S, O, N, or C atom constitutes an atom of the 5-membered ring. In some embodiments, the ring including Z and T is a 6-membered ring. In some embodiments, one of Z or T is CH=CH, where the carbon atoms constitute part of the 6-membered ring. In some embodiments, one of Z or T is C(R6)=CH, which can be present in the ring in either orientation (i.e., C(R6)=CH orientation or CH=C(R6) orientation). In some embodiments, one of Z or T is C(R6)=C(R6), where the carbon atoms constitute part of the 6-membered ring. In some embodiments, one of Z or T is N=CH, which can be present in the ring in either orientation (i.e., N=CH orientation or CH=N orientation).

[0039] In further embodiments, provided for are compounds according to Formulae V-i or V- iiormu a including pharmaceutically acceptable salts thereof, whereinQ is, at each occurrence, independently N, C-H, or C-R6;R5is -H or C1-C3 alkyl; andR6is independently at each occurrence selected from the group consisting of halogen, C1-C6 alkyl, saturated or unsaturated, C1-C6 haloalkyl, saturated or unsaturated, and C3-C5 cycloalkyl, saturated or unsaturated, said C3-C5 cycloalkyl unsubstituted, monosubstituted, or polysubstituted with halogen or C1-C3 haloalkyl.

[0041] In an embodiment of Formula V, the PKM2 activator is a compound having a formula according to Formula Vl-i:Formula Vl-i including pharmaceutically acceptable salts thereof, wherein: q is an integer ranging from 0 to 4; andR6is independently at each occurrence selected from the group consisting of halogen, C1-C6 alkyl, saturated or unsaturated, C1-C6 haloalkyl, saturated or unsaturated, and C3-C5 cycloalkyl, saturated or unsaturated, said C3-C5 cycloalkyl unsubstituted, monosubstituted, or polysubstituted with halogen or C1-C3 haloalkyl.

[0042] In an embodiment, the PKM2 activator is a compound selected from the group consisting of the compounds of Table A:Table A: Exemplary PKM2 activators

[0043] As used herein, the substituents or variables R1, R2, R3, R4, R5, R6, L, A, X, Y, Q, T, Z, n, m, and p as used in Formulae I, II, III, IV, V, and VI may analogously apply to any of Formulae I, II, III, IV, V, and VI in various additional embodiments. The terms “Formulae I - VI” or “Formula I - Formula VI” or the like represent a grouping of Formulae I, II, III, IV, V, and VI. Moreover, the term “PKM2 activator(s)” and like terms are intended to include the definitions of any of Formulae I - VI, as well as other PKM2 activators described herein. In aspects of the disclosure, provided for are PKM2 activator compounds according to any of Formulae I - VI, pharmaceutical compositions comprising a PKM2 activator and a pharmaceutically acceptable carrier, and methods of treating neurological and / or neurodegenerative diseases comprising administering a PKM2 activator to a subject in need thereof. Also provided for are uses of PKM2 activator compounds in uses of manufacturing a medicament for the treatment of neurological and / or neurodegenerative diseases. Also provided for are uses of PKM2 activator compounds in methods of treating neurological and / or neurodegenerative diseases. Also provided for are uses of PKM2 activator compounds in methods of treating peripheral diseases having pathology outside the CNS. In general, peripheral diseases have non-CNS pathology, but may further involve or implicate a CNS orneurologic component. In some cases, the peripheral disease involves a CNS or neurologic component. In some cases, the peripheral disease does not involve a CNS or neurologic component. In various embodiments, the PKM2 activator compounds may be useful in either or both peripheral and / or CNS-associated indications or diseases.

[0044] In some embodiments, provided for herein are methods for treating CNS-associated diseases by administering to a patient or subject in need thereof an effective amount of a PKM2 activator. In some embodiments, the CNS-associated diseases are neurodegenerative or neurologic disorders / diseases. In some embodiments, the neurodegenerative or neurological disease is selected from alpha-synucleinopathies, multiple sclerosis (MS) amyotrophic lateral sclerosis (ALS), Parkinson’s disease, Huntington’s disease, stroke, Alzheimer’s disease, neuroinflammation diseases, and Lewy body dementia.

[0045] In further embodiments, provided for herein are methods for treating peripheral diseases by administering to a patient or subject in need thereof an effective amount of a PKM2 activator.

[0046] In an embodiment, the peripheral disease is Guillain Barre syndrome.

[0047] In an embodiment, the peripheral disease is a fibrotic disease. Fibrotic diseases involve fibrosis, which results in excessive buildup of fibrous connective tissue such as collagen. PKM2 has been implicated in fibrosis development and progression. See, e.g., Satyanarayana, G. et al., “Pyruvate kinase M2 regulates fibrosis development and progression by controlling glycine auxotrophy in myofibroblasts,” Theranostics, 11(19) pp. 9331-9341 (2021). Fibrosis may also occur in CNS-associated diseases, for example as a result of injury. Exemplary diseases associated with fibrosis and for which a PKM2 activator may be administered include arthritis, arthrofibrosis, cystic fibrosis, fibrotic eye diseases, fibrotic kidney diseases, idiopathic pulmonary fibrosis, scleroderma, hypertrophic cardiomyopathy, myocarditis, systemic sclerosis, atrial / ventricular fibrillation, liver cirrhosis, dilated cardiomyopathy, fibrothorax, bridging fibrosis of the liver, glial scar, arterial stiffness, Crohn’s disease, Dupuytren’s contracture, keloid fibrosis, lipedema, mediastinal fibrosis, myelofibrosis, myofibrosis, Peyronie’s disease, nephrogenic systemic fibrosis, progressive massive fibrosis of the lungs, retroperitoneal fibrosis, adhesive capsulitis, acute myocardial infarction, and other fibrotic diseases.

[0048] In further embodiments, the peripheral disease is an inflammatory disease. In some embodiments, the inflammatory disease is dermatitis, atopic dermatitis, inflammatory bowel disease, rheumatoid arthritis, psoriasis.

[0049] In further embodiments, the peripheral disease is an eye disease. In some embodiments, the eye disease is age-related macular degeneration or retinitis pigmentosa.

[0050] In a further embodiment, the peripheral disease is non-ketotic hyperglycinemia (NKH). In a further embodiment, the peripheral disease is obesity, weight gain, anorexia, hyperlipidemia, or Prader-Willi Syndrome.

[0051] In a further embodiment, the peripheral disease is a cancer. In some embodiments the cancer is selected from the group consisting of: Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Adenocarcinoma, Adrenocortical Carcinoma, AIDS-Related Lymphoma, AIDS-Related Malignancies, Anal Cancer, Bile Duct Cancer, Bladder Cancer, Bone Cancer, Brain Stem Glioma, Brain Tumor, Breast Cancer, Bronchial Adenomas, Bronchial Carcinoid, Carcinoid Tumor, Central Nervous System Lymphoma, Cerebellar Astrocytoma, Cervical Cancer, Clear Cell Sarcoma, Colon Cancer, Colorectal Cancer, Cutaneous T-Cell Lymphoma, Endometrial Cancer, Ependymoma, Esophageal Cancer, Ewing's Sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Gallbladder Cancer, Gastric Cancer, Gastrointestinal Carcinoid Tumor, Genitourinary Cancer, Gestational Trophoblastic Tumor, Hairy Cell Leukemia, Head and Neck Cancer, Hepatocellular Cancer, Hodgkin's Lymphoma, Hypopharyngeal Cancer, Hypothalamic Glioma, Intraocular Melanoma, Islet Cell Carcinoma, Kaposi's Sarcoma, Kidney Cancer, Laryngeal Cancer, Lip and Oral Cavity Cancer, Liver Cancer, Lymphocytic Leukemia, Lymphoma, Male Breast Cancer, Malignant Glioma, Malignant Thymoma, Medulloblastoma, Melanoma, Merkel Cell Carcinoma, Mesothelioma, Multiple Endocrine Neoplasia Syndrome, Multiple Myeloma, Mycosis Fungoides, Myelodysplastic Syndrome, Myelogenous Leukemia, Myeloid Leukemia, Nasal Sinus Cancer, Nasopharyngeal Cancer, Nephroblastoma, Neuroblastoma, Non-Hodgkin's Lymphoma, Non-small cell lung cancer, Oropharyngeal Cancer, Osteosarcoma, Ovarian Epithelial Cancer, Ovarian Germ Cell Tumor, Pancreatic Cancer, Parathyroid Cancer, Penile Cancer, Pharangeal Cancer, Pheochromocytoma, Pituitary Tumor, Plasma Cell Neoplasm, Pleuropulmonary Blastoma, Primitive Neuroectodermal Tumors, Prostate Cancer, Rectal Cancer, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Sezary Syndrome, Skin Cancer, Small Cell Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Neck Cancer, Supratentorial Primitive Neuroectodermal Tumor, Testicular Cancer, Thymoma, Thyroid Cancer, Transitional Cell Cancer, Trophoblastic Tumor, Urethral Cancer, Uterine Sarcoma, Vaginal Cancer, and Vulvar Cancer.

[0052] In further embodiments, the peripheral disease is a blood disease or disorder. In an embodiment, the blood disease or disorder is selected from anemia, thalassemia, spherocytosis, elliptocytosis, abetalipoproteinemia, paroxysmal nocturnal hemoglobinuria, hereditary red blood cell disorder, erythrocyte membranopathy, myelodysplastic syndrome, and others. In embodiments, the anemia is sickle cell anemia, non- spherocytic hemolytic anemia, hemolytic anemia (hereditary or acquired), or other anemias. In an embodiment, the thalassemia is selected from non-transfusion-dependent alpha-thalassemia and non- transfusion-dependent beta-thalassemia. In an embodiment, the thalassemia is selected from transfusion-dependent alpha-thalassemia and transfusion-dependent beta thalassemia.

[0053] Various particular embodiments are described herein to exemplify aspects of the invention. These embodiments are not to be construed as limiting upon the disclosure. Rather, exemplified aspects from particular embodiments may be present in additional embodiments which incorporate aspects of various (i.e., one or more) particular embodiments. As such, the terms “in an embodiment,” “in some embodiments,” “in alternative embodiments,” and “in one embodiment,” among others, may precede particular embodiments of which the exemplified aspects are described, and such exemplified aspects are expressly contemplated as being a part of various additional embodiments.

[0054] In various embodiments, a range of atoms is provided by the notation “Cx-Cy” or like notations. In the case of groups which contain only carbon atoms (saturated with -H or other substituents, or containing one or more unsaturations), this notation describes a range of total constituent carbon atoms in the group which are contemplated, in the integer range from X to Y. For example, the range “ C1-C6 alkyl” or like terms denote an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms in the linear or branched chain. If the group is mono-, di-, tri-, or polysubstituted, the substitution groups are not included in the specified range. Likewise, in other groups specifying particular substituents, such as “haloalkyl,” the one or more halogen substituents (e.g., -F, -Cl, or -Br) are not included in the range Cx-Cy. In the case of a group containing heteroatoms (e.g., C1-C6 heteroalkyl), this notation likewise refers to the total number of atoms in the linear or branched chain, including the heteroatoms. In the context of cyclic groups (e.g., cycloalkyl, heterocycloalkyl, aryl, and heteroaryl), the range specifies the number of atoms constituting the ring(s). In general, where a range is given in a particular embodiment, alternative embodiments separate from the particular embodiment having one, two, or three atoms outside the range, on either or both sides of the range, are contemplated.

[0055] In various embodiments, specified groups are “optionally substituted” or “unsubstituted,” “monosubstituted,” “di substituted,” or “polysubstituted.” These terms mayprecede a listing of substituents which may generally replace one or more hydrogen atoms on the specified group. If no listing follows, these terms may more generally refer to any viable substituent to the specified group in view of the disclosure. Where a group is “polysubstituted,” there are generally two, three, four, five, or six substituents present which may be the same or different. In some embodiments, “polysubstituted” means there are two, three, or four substituents present which may be the same or different (i.e., di substituted, tri substituted, or tetrasubstituted).

[0056] The term “alkyl, saturated or unsaturated” as used herein encompasses aliphatic linear or branched hydrocarbon groups which are saturated (i.e., coordinatively saturated) or unsaturated (i.e., containing one or more double or triple bonds). The term “alkyl, saturated or unsaturated” generally encompasses unsaturated “alkenyl” groups having at least one double bond (such as one or two double bonds) and unsaturated “alkynyl” groups having at least one triple bond (such as one or two triple bonds).

[0057] In various embodiments, a substituent or structural element is “optional” or said element is “optionally” present. It is expressly intended that embodiments with and without said “optional” element(s) are contemplated. For example, where a substituent is X optionally substituted with Y, it is intended that the embodiments of “wherein X is substituted with Y,” and “wherein X is not substituted with Y” are contemplated.

[0058] The term “alkylene, saturated or unsaturated” as used herein encompasses a linear or branched hydrocarbon having two monovalent radicals derived from the removal of two hydrogen atoms. In many cases, the “alkylene, saturated or unsaturated” is a linking group between two functional groups of the compounds herein. Non-limiting examples of “alkylene, saturated or unsaturated” include methylene (-CH2-), 1,2-ethylene (-CH2-CH2-), 1,3-propylene (-CH2-CH2-CH2-), 1,4-butylene (-CH2-CH2-CH2-CH2-), 1,5-propylene (-CH2- CH2-CH2-CH2-CH2-), and 1,6-hexylene (-CH2-CH2-CH2-CH2-CH2-CH2-) including unsaturated variants thereof. “Alkylene” may be linear as in the preceding examples, or may be branched (e.g.,The term “alkylene, saturated or unsaturated” generally encompasses unsaturated “alkenylene” groups having at least one double bond (such as one or two double bonds) and unsaturated “alkynylene” groups having at least one triple bond (such as one or two triple bonds).

[0059] The term “cycloalkyl, saturated or unsaturated” as used herein encompasses groups having one or more hydrocarbon rings. Where the group has more than one hydrocarbonrings, they rings may be “fused” (i.e., they may share two adjacent atoms), “bridged” (i.e., they may share two non-adjacent atoms), or “spiro” (i.e., they may share one atom). Nonlimiting examples of saturated cycloalkyl rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. Additional non-limiting examples include bridged groups such as adamantyl, nonbomane (nonbomyl), bornane (bomanyl), and bicyclo[2.2.2]octanyl. The term “cycloalkyl, saturated or unsaturated” generally encompasses unsaturated “cycloalkenyl” groups having at least one double bond (such as one or two double bonds) and unsaturated “cycloalkynyl” groups having at least one triple bond (preferably one or two triple bonds).

[0060] The term “aryl” encompasses aromatic structures comprised of one or more rings. As would be appreciated by a person of ordinary skill in the art, aromatic structures generally follow HiickeTs rule and / or meet other well-accepted defining criteria for aromaticity. “Aryl” includes monocyclic groups such as phenyl or others, and polycyclic groups such as naphthalene or others.

[0061] Various groups referenced in the disclosure may include “heteroatoms,” including but not limited to “heteroalkyl,” “heterocycloalkyl,” “heteroaryl,” “heteroalkylene,” “alkoxy,” and, as appropriate, unsaturated or saturated analogues thereof. The term “heteroatom” generally encompasses the atoms oxygen (O), nitrogen (N), and sulfur (S). In some cases where feasible, the term “heteroatom” may further include phosphorous (P) and silicon (Si). Where a group includes “one or more heteroatoms” or “one or more ring heteroatoms,” it may generally comprise one, two, three, four, or five heteroatoms. In some embodiments, the group includes one N atom, one O atom, or one S atom. In some embodiments, the group includes one or more N atoms, one or more S atoms, and / or one or more O atoms. In some embodiments, the group includes two N atoms, two O atoms, two S atoms, one N atom and one S atom, one N atom and one O atom, or one S atom and one O atom. In yet further embodiments, the group includes one or more P atoms or one or more Si atoms, or one P atom or one Si atom.

[0062] The term “heteroalkyl, saturated or unsaturated” as used herein encompasses aliphatic linear or branched hydrocarbon groups which are saturated or unsaturated, and which contain one or more heteroatoms in the linear or branched group replacing one or more carbon atoms thereof. The term “heteroalkyl, saturated or unsaturated” generally encompasses unsaturated “heteroalkenyl” groups having at least one double bond (such as one or two double bonds) and unsaturated “heteroalkynyl” groups having at least one triple bond (such as one or two triple bonds).

[0063] The term “alkoxy” means a group containing an -O- or -OH moiety. Unless otherwise specified, the “alkoxy” may be saturated or may contain one or more unsaturations. An “alkoxy” group may, in addition to an -O- or -OH moiety, further comprise a carbonyl moiety to form, e.g., ester, carbonate, or carboxylic acid / carb oxy late.

[0064] The term “heterocycle, saturated or unsaturated” as used herein is a generic term including “heterocycloalkyl” and / or “heteroaryl” which are further defined below.

[0065] The term “heterocycloalkyl, saturated or unsaturated” as used herein encompasses groups having one or more hydrocarbon rings which contain one or more ring heteroatoms replacing one or more carbon atoms thereof. Where the group has more than one hydrocarbon rings, with at least one ring containing a ring heteroatom, they rings may be “fused” (i.e., they may share two adjacent atoms), “bridged” (i.e., they may share two non-adjacent atoms), or “spiro” (i.e., they may share one atom). The term “heterocycloalkyl, saturated or unsaturated” generally encompasses unsaturated “heterocycloalkenyl” groups having at least one double bond (such as one or two double bonds) and unsaturated “heterocycloalkynyl” groups having at least one triple bond (preferably one or two triple bonds). Generally, “heterocycloalkyl, saturated or unsaturated” may comprise one or more nitrogen, oxygen, or sulfur atoms in the ring(s) thereof.

[0066] The term “heteroaryl” encompasses aromatic structures comprised of one or more rings which contain one or more ring heteroatoms. “Heteroaryl” includes monocyclic groups such as phenyl or others, and polycyclic groups such as naphthalene or others. Generally, “heteroaryl” ring(s) comprises one or more nitrogen, oxygen, and / or sulfur as a ring member of the aromatic system.

[0067] The compounds described herein may contain one or more chiral centers, and may therefore include optical isomers, i.e. enantiomers, and diastereomers. The compounds may be obtained as racemic mixtures or enantiomerically pure R and S stereoisomers and pharmaceutically acceptable salts thereof. Cis and trans isomers of alkenes and imines or other double-bonded species are also contemplated. Certain stereoisomers may be obtained by standard techniques known in the art such as asymmetric synthesis, diastereomeric recrystallization, kinetic resolution, chromatographic or other separation techniques, etc. Chromatographic techniques may include column chromatography, thin-layer chromatography, and high-performance liquid chromatography (HPLC), and may incorporate chiral columns which generally have a chiral stationary phase. Chromatographic and other separation techniques are well-known in the art and standard procedures may be followed to obtain enantiomerically-pure or diastereomerically-pure compounds.

[0068] Pharmaceutically-acceptable salts of compounds of the present teachings can be formed using organic and inorganic bases, or organic and inorganic acids. Both mono and polyanionic salts are contemplated, depending on the number of charges available on the compound. Suitable salts formed with bases include metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts; ammonia salts and organic amine salts, such as those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine (e.g., ethyl -tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-, di-, or trihydroxy lower alkylamine (e.g., mono-, di- or triethanolamine). Specific non-limiting examples of inorganic bases include NaHCCb, Na2CO3, KHCO3, K2CO3, CsCO3, LiOH, NaOH, KOH, NaH2PO4, Na2HPO4, and Na3PO4. Internal salts also can be formed. Similarly, when a compound disclosed herein contains a basic moiety, salts can be formed using organic and inorganic acids. For example, salts can be formed from the following acids: acetic, trifluoroacetic, propionic, lactic, benzenesulfonic, benzoic, camphorsulfonic, citric, tartaric, succinic, di chloroacetic, ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, napthalenesulfonic, nitric, oxalic, pamoic, pantothenic, phosphoric, phthalic, propionic, succinic, sulfuric, tartaric, toluenesulfonic, and camphorsulfonic as well as other known pharmaceutically acceptable acids.

[0069] In each of the embodiments disclosed herein, the compositions and methods may be utilized with or on a subject in need of such treatment, which may also be referred to as “in need thereof,” means that the subject has been identified as having a need for the particular method or treatment, as may be determined by a medical professional or where otherwise indicated.

[0070] As used herein, the term “therapeutic” means an agent utilized to treat, combat, ameliorate, or prevent, or any combination thereof, an unwanted condition, disorder or disease of a subject or patient.

[0071] As used herein, the term “patient” and “subject” are interchangeable and may be taken to mean any living organism, which may be treated with compounds of the present invention. As such, the terms “patient” and “subject” may include, but are not limited to, any nonhuman mammal, primate or human. In some embodiments, the “patient” or “subject” is an adult, child, infant, or fetus. In some embodiments, the “patient” or “subject” is a human. In some embodiments, the “patient” or “subject” is a mammal, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, primates, or humans.

[0072] The terms “therapeutically effective amount” or “therapeutic dose” as used herein are interchangeable and may refer to the amount of an active agent or pharmaceutical compound (i.e., a PKM2 activator according to Formulae I - VI) or composition thereof which is sufficient to elicit a desirable or beneficial result in a patient or subject. The result may be clinical, or any other biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinical professional. A clinical, biological or medical response may include, for example, one or more of the following: (1) preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display pathology or symptoms of the disease, condition or disorder, (2) inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptoms of the disease, condition or disorder or arresting further development of the pathology and / or symptoms of the disease, condition or disorder, (3) ameliorating a disease, condition or disorder in an individual that is experiencing or exhibiting the pathology or symptoms of the disease, condition or disorder or reversing the pathology and / or symptoms experience or exhibited by the individual, and / or (4) effecting any beneficial or desirable biological response in a patient.

[0073] In the context of neurologic or neurodegenerative disorders, diseases, conditions, or symptoms (whether general or ascribable to a particular disorder), the beneficial or desirable results provided by a therapeutically effective amount or dose of the PKM2 activator herein may include, but are not limited to, improvements in cognitive function, memory, mood, motor skills, locomotion, pain, sensation, hypersensitivity, vision changes, hearing changes, sleep, speech, swallowing, seizures, consciousness, life expectancy, and others as monitored or otherwise determined by medical or research professionals.

[0074] The terms “treat,” “treated,” or “treating” may be taken to mean prophylaxis of a specific disorder, disease or condition, alleviation of the symptoms associated with a specific disorder, disease or condition and / or prevention of the symptoms associated with a specific disorder, disease or condition. In some embodiments, the term refers to slowing the progression of the disorder, disease or condition or alleviating the symptoms associated with the specific disorder, disease or condition. In some embodiments, the term refers to alleviating the symptoms a disease or condition. In some embodiments, the term refers to restoring function which was impaired or lost due to a specific disorder, disorder or condition.

[0075] The PKM2 activators herein are generally “brain penetrant” meaning that at least some administered compound crosses the blood-brain barrier. In general cases, the term “brain penetrant” means that a partition percentage of the compound between the brain and the plasma, as evaluated in human subjects or suitable research models such as mouse, rat, dog, or primate, is at least about 10% as measured by Cmax and / or AUC parameters (meaning that the Cmax and / or AUC value of the brain is at least about 10% of that of plasma). In other cases, the partition percentage is at least about 20%, 30%, 40%, 50%, 60%, or 70%. In general, a person skilled in the art using sound medical judgement would appreciate whether a PKM2 activator is appreciably brain penetrant to provide a meaningful patient benefit.

[0076] Another aspect of the disclosure is a pharmaceutical composition comprising a compound of Formula I - Formula VI with a pharmaceutically acceptable adjuvant, carrier, or diluent. Further aspects of the disclosure are method for treating a neurologic or neurodegenerative disorder in a subject in need thereof by administration of a prodrug compound according to Formula I - Formula VI. The administration route may be oral, or may be intravenous or other parenteral route, or any other appropriate route.

[0077] Compounds are generally given as pharmaceutical compositions comprised of a therapeutically effective amount of one or more of a compound of Formula I - Formula VI or pharmaceutically acceptable salt(s) thereof, and a pharmaceutically acceptable carrier, further optionally containing conventional excipients. A therapeutically effective amount is the amount needed to provide a meaningful or desirable patient benefit or result as determined by practitioners in that art. Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles. Compositions encompass all common solid and liquid forms including capsules, tablets, lozenges, and powders as well as liquid suspensions, syrups, elixirs, and solutions. Solid compositions may by formed in timed or sustained released formulations. Compositions are made using common formulation techniques and conventional excipients (such as binding and wetting agents) and / or vehicles (such as water and alcohols).

[0078] The disclosure and methods encompass all conventional modes of administration including oral, parenteral, intranasal, sublingual, topical, and transdermal methods. Typically, the daily dose may be 0.01-100 mg / kg body weight daily. Generally, more compound is required orally and less parenterally. The specific dosing regime, however, should be determined by a physician using sound medical judgement.

[0079] Among other routes of administration, the standard routes of administration described by the FDA are contemplated herein (FDA Routes of Administration; retrieved from the official FDA website.) These routes include auricular (otic), buccal, conjunctival, cutaneous,dental, electro-osmosis, endocervical, endosinusial, endotracheal, enteral, epidural, extra amniotic, extracorporeal, hemodialysis, infiltration, interstitial, intra-abdominal, intra- amniotic, intra-arterial, intra-articular, intrabiliary, intrabronchial, intrabursal, intracardiac, intracartilaginous, intracaudal, intracavemous, intracavitary, intracerebral, intracisternal, intracorneal, intracoronal, dental, intracoronary, intracorporus cavemosum, intradermal, intradiscal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralesional, intraluminal, intralymphatic, intramedullary, intrameningeal, intramuscular, intraocular, intraovarian, intrapericardial, intraperitoneal, intrapleural, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratendinous, intratesticular, intrathecal, intrathoracic, intratubular, intratumor, intratympanic, intrauterine, intravascular, intravenous, intravenous bolus, intravenous drip, intraventricular, intravesical, intravitreal, iontophoresis, irrigation, laryngeal, nasal, nasogastric, not applicable, occlusive dressing technique, ophthalmic, oral, oropharyngeal, parenteral, percutaneous, periarticular, peridural, perineural, periodontal, rectal, respiratory (inhalation), retrobulbar, soft tissue, subarachnoid, subconjunctival, subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transplacental, transtracheal, transtympanic, ureteral, urethral, and / or vaginal.

[0080] In some embodiments, the route of administration for compounds of Formulae I- VI may be oral. In some embodiments, the route of administration may be intravenous or other parenteral. In other embodiments, the administration route may be intranasal or inhalant.

[0081] The formulator will understand that excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient. An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizing system or coating.

[0082] Pharmaceutical compositions may comprise one or more pharmaceutically acceptable carriers, excipients, or diluents. Examples of such carriers are well known to those skilled in the art and can be prepared in accordance with acceptable pharmaceutical procedures, such as, for example, those described in Remington's Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985), the entire disclosure of which is incorporated by reference herein for all purposes. As used herein, “pharmaceutically acceptable” refers to a substance that is acceptable for use in pharmaceutical applications from a toxicological perspective and does not adversely interact with the active ingredient. Accordingly, pharmaceutically acceptable carriers are those that are compatible with the otheringredients in the formulation and are biologically acceptable. Supplementary active ingredients can also be incorporated into the pharmaceutical compositions.

[0083] While oral is preferred in some embodiments, compounds of the present teachings can be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances which can also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents, or encapsulating materials. Oral formulations containing a compound disclosed herein can comprise any conventionally used oral form, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. In powders, the carrier can be a finely divided solid, which is an admixture with a finely divided compound. In tablets, a compound disclosed herein can be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets can contain up to 99% of the compound.

[0084] Capsules can contain mixtures of one or more compound(s) disclosed herein with inert filler(s) and / or diluent(s) such as pharmaceutically acceptable starches (e.g., com, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses (e.g., crystalline and microcrystalline celluloses), flours, gelatins, gums, and the like.

[0085] Useful tablet formulations can be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including, but not limited to, magnesium stearate, stearic acid, sodium lauryl sulfate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidine, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, low melting waxes, ion exchange resins, benzyl alcohol, eucalyptol, gelatin, limonene, mannitol, menthol, menthone, menthyl acetate, sucralose, and vanillin. Surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, pol oxamer 188, benzalkonium chloride, calcium stearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidal silicon dioxide, phosphates, sodium dodecyl sulfate, magnesium aluminum silicate, and triethanolamine. Oral formulations herein can utilize standard delay or time-release formulations to alter the absorption of the compound(s). The oral formulation canalso consist of administering a compound disclosed herein in water or fruit juice, containing appropriate solubilizers or emulsifiers as needed.

[0086] Liquid carriers can be used in preparing solutions for oral or parenteral administration (such as intravenous, intramuscular, or other injections), including suspensions, emulsions, syrups, elixirs, and additionally for inhaled delivery. A compound of the present teachings can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a mixture of both, saline, or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers, and osmo-regulators. Examples of liquid carriers for oral and parenteral administration include, but are not limited to, water (particularly containing additives as described herein, e.g., cellulose derivatives such as a sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives, and oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration, the carrier can be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration. The liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellants.

[0087] Liquid pharmaceutical compositions, which are sterile solutions or suspensions, can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile injectable solutions can also be administered intravenously. Compositions for oral administration can be in either liquid or solid form.

[0088] Preferably the pharmaceutical composition is in unit dosage form, for example, as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the pharmaceutical composition can be further sub-divided to contain appropriate quantities of the compound. The unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. Alternatively, the unit dosage form can be a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form. Such doses can be administered in any manner useful in directing the compound(s) to the recipient's bloodstream, including orally, via implants, parenterally (including intravenous, intraperitoneal and subcutaneous injections), rectally, vaginally, and transdermally.

[0089] When administered for the treatment or inhibition of a particular disease state or disorder, it is understood that an effective dosage can vary depending upon the particularcompound utilized, the pharmaceutical composition formulated, the mode of administration, and severity of the condition being treated, as well as the various physical factors related to the individual being treated. In therapeutic applications, a compound of the present teachings can be provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. The dosage to be used in the treatment of a specific individual typically must be subjectively determined by the attending physician. The variables involved include the specific condition and its state as well as the size, age and response pattern of the patient.

[0090] In some embodiments, the effective dose of the PKM2 activator is a dose ranging from about 1 mg to about 1000 mg. In some embodiments, the dose ranges from about 10 mg to about 500 mg. In some embodiments, the dose is about 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg, or multiples or divisions thereof ranging from about 1 mg to about 1500 mg. In some embodiments, the dosage is administered to the patient once daily, twice daily, thrice daily, once every other day, once every two days, once weekly, or biweekly, where the dosage and interval are selected based upon the patient characteristics and treatment benefit as would be appreciated by one skilled in the art.

[0091] In some cases it may be desirable to administer a compound directly to the airways of the patient, using devices such as, but not limited to, metered dose inhalers, breath-operated inhalers, multidose dry-powder inhalers, pumps, squeeze-actuated nebulized spray dispensers, aerosol dispensers, and aerosol nebulizers. For administration by intranasal or intrabronchial inhalation, the compounds of the present teachings can be formulated into a liquid composition, a solid composition, or an aerosol composition. The liquid composition can include, by way of illustration, one or more compounds of the present teachings dissolved, partially dissolved, or suspended in one or more pharmaceutically acceptable solvents and can be administered by, for example, a pump or a squeeze-actuated nebulized spray dispenser. The solvents can be, for example, isotonic saline or bacteriostatic water. The solid composition can be, by way of illustration, a powder preparation including one or more compounds of the present teachings intermixed with lactose or other inert powders that are acceptable for intrabronchial use, and can be administered by, for example, an aerosol dispenser or a device that breaks or punctures a capsule encasing the solid composition and delivers the solid composition for inhalation. The aerosol composition can include, by way of illustration, one or more compounds of the present teachings, propellants, surfactants, and co-solvents, and can be administered by, for example,a metered device. The propellants can be a chlorofluorocarbon (CFC), a hydrofluoroalkane (HF A), or other propellants that are physiologically and environmentally acceptable.

[0092] Compounds described herein can be administered parenterally or intraperitoneally. Solutions or suspensions of these compounds or a pharmaceutically acceptable salts, hydrates, or esters thereof can be prepared in water suitably mixed with a surfactant such as hydroxylpropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations typically contain a preservative to inhibit the growth of microorganisms.

[0093] The pharmaceutical forms suitable for injection can include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In some embodiments, the form can sterile and its viscosity permits it to flow through a syringe. The form preferably is stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.EXAMPLESTable 1 : AbbreviationsCompound Synthesis and CharacterizationScheme 1Example 1. Synthesis of A-(4-(4-fluoro-4-isobutylpiperidine-l- carbonyl)phenyl)benzo[J]thiazole-4-sulfonamide (Cpd. 3) (N232660-168 & N232660-170) and potassium (benzo[J|thiazol-4-ylsulfonyl)(4-(4-fluoro-4-isobutylpiperidine-l- carbonyl)phenyl)amide (Potassium salt of Cpd. 3) (N232659-157).Step 1. Synthesis of tert-butyl 4-hydroxy-4-isobutylpiperidine-l-carboxylate (N232660- 158).

[0094] A solution of CeCL (200 g, 811 mmol) in anhydrous THF (1500 mL) was stirred at 0 °C for 2 hrs, then isobutylmagnesium bromide (450 mL, 900 mmol, 2 M in Et2O) was added and the mixture was stirred for another 3 hrs at 0 °C. After that, tert-butyl 4-oxopiperidine-l- carboxylate (100 g, 502 mmol) in anhydrous THF (500 mL) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 hr, quenched with 20% AcOH aqueous solution and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 5% EtOAc in PE) to afford the title compound (100 g, 389 mmol, 77.5% yield) as a colorless oil. LC-MS m / e\ 258 (MH+).Step 2. Synthesis of tert-butyl 4-fluoro-4-isobutylpiperidine-l-carboxylate and tert-butyl 4-isobutyl-3,6-dihydropyridine-l(2ZZ)-carboxylate (N232660-165).

[0095] To a solution of tert-butyl 4-hydroxy-4-isobutylpiperidine-l-carboxylate (100 g, 389 mmol) in anhydrous DCM (1500 mL) was added DAST (94.0 g, 583 mmol) at -78 °C dropwise. After addition, the reaction mixture was stirred at this temperature for 2 hr, quenched with sat. NaHCCh solution and the aqueous layer was extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to afford the crude title compound (100 g, 386 mmol, 99.5% yield) as a yellow oil, which was used directly in the next step without further purification. LC-MS m / e: 204 (MH+-56).Step 3. Synthesis of tert-butyl 4-fluoro-4-isobutylpiperidine-l-carboxylate (N232660-166).

[0096] To a solution of crude tert-butyl 4-fluoro-4-isobutylpiperidine-l-carboxylate and tert-butyl 4-isobutyl-3,6-dihydropyridine-l(2rt)-carboxylate (100 g, 386 mmol) in DCM (1500 mL) was added m-CPBA (63.6 g, 313 mmol, 85%) at 0 °C and stirred at room temperature for 2 hrs. The reaction mixture was cooled to 0 °C and quenched with sat. NaHCCh solution. The aqueous layer was extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 3% EtOAc in PE) to afford the title compound (50.0 g, 193 mmol, 50.0 % yield) as a yellow oil. LC-MS m / e'. 204 (MH+-56).Step 4. Synthesis of 4-fluoro-4-isobutylpiperidine hydrochloride (N232660-167).

[0097] A solution of tert-butyl 4-fluoro-4-isobutylpiperidine-l-carboxylate (50.0 g, 193 mmol) in HC1 solution (200 mL, 4 M in EtOAc) was stirred at room temperature for 2 hrs. Then the mixture was concentrated to afford the title compound (36.8 g, 188 mmol, 97.4 % yield). LC- MS m e. 160 (MH+).Step 5. Synthesis of 4-(benzylthio)benzo [J] thiazole (N222302-231).

[0098] A solution of 4-bromobenzo[d]thiazole (50.0 g, 233 mmol), benzyl mercaptan (145 g, 1167 mmol), Xantphos (13.5 g, 23 mmol), Pd2(dba)a (10.7 g, 11.7 mmol) and EhN (130 mL, 934 mmol) in dioxane (1000 mL) was stirred at 100 °C under N2 atmosphere overnight. The mixture was cooled to room temperature and most of the solvent removed. The residue was filtered and concentrated to dryness as a yellow oil. Then the oil was treated with a mixture solution (400 mL, PE: EtOAc = 10: 1). The precipitate was formed and filtered. The filter cake was washed with PE (100 mL x 2) and dried under vacuum at 50 °C to afford tittle compound (50 g, 194 mmol, 83.2%) as a yellow solid. LC-MS m e. 258 (MH+).Step 6. Synthesis of benzo[J]thiazole-4-sulfonyl chloride (N222302-232).

[0099] To a solution of 4-(benzylthio)benzo[d]thiazole (50 g, 194 mmol) in CHCL (500 mL) and 10% HC1 solution (500 mL) was added 10% NaClO solution (1000 mL) at 0-5 °C dropwise. After addition, the mixture was stirred at 0 °C for 30 mins. The resulting mixture was separated. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under vacuum at 30 °C to afford crude tittle compound (60 g, 257 mmol, 132% yield), which was used directly in the next step without further purification. LC-MS m e. 215 (M-C1+NH4+). (checked by adding NH4OH).Step 7. Synthesis of 4-(benzo[J]thiazole-4-sulfonaniido)benzoic acid (N222302-238).

[0100] To a solution of crude benzo[d]thiazole-4-sulfonyl chloride (60 g, 257 mmol) and pyridine (46.0 g, 582 mmol) in THF (500 mL) was added 4-aminobenzoic acid (21.3 g, 155mmol). The reaction mixture was stirred at room temperature for 1 hr. Then the mixturewas concentrated to dryness at 50 °C. The residue was treated with EtOH (300 mL) and stirred for 1 hr. The precipitate was filtered and the cake was washed with EtOH (50 mL x 2). The solid was dried under vacuum at 60 °C for 3 hrs to afford tittle compound (33.2 g, 98.7 mmol, 38.4% yield) as a pink solid. LC-MS m / c. 335 (MH+).Step 8. Synthesis of 7V-(4-(4-fluoro-4-isobutylpiperidine-l- carbonyl)phenyl)benzo[J]thiazole-4-sulfonamide (Cpd. 3) (N232660-168 & N232660- 170).

[0101] To a solution of 4-(benzo[d]thiazole-4-sulfonamido) benzoic acid (16.8 g, 50.2 mmol) in DMAc (200 mL) was added CDI (8.96 g, 55.2 mmol) at 0 °C and stirred at room temperature for 1 hr, then 4-fluoro-4-isobutylpiperidine hydrochloride (9.81 g, 50.2 mmol) was added. The resulting mixture was stirred at room temperature for 12 hrs, quenched with water and extracted with EtOAc three times. The combined organic layers were washed with brine and dried over anhydrous NaiSCU, filtered and concentrated. The residue was purified by reverse-phase chromatography (20%-95% MeCN in H2O with 0.1% formic acid) to afford the title compound (10 g, 21.0 mmol, 41.9% yield) as a white solid. ’H NMR (400 MHz, DMSO- d6) 5 10.77 (s, 1H), 9.65 (s, 1H), 8.50 (d, J= 8.0 Hz, 1H), 8.12 (d, J= 8.0 Hz, 1H), 7.64 (t, J= 8.0 Hz, 1H), 7.21 - 7.19 (m, 2H), 7.13 - 7.11 (m, 2H), 4.25 - 4.16 (m, 1H), 3.50 - 3.46 (m, 1H), 3.10 - 3.05 (m, 2H), 1.83 - 1.44 (m, 7H), 0.89 (d, J= 8.0 Hz, 6H). LC-MS m e. 476 (MH+).Step 9. Synthesis of potassium (benzo[J]thiazol-4-ylsulfonyl)(4-(4-fluoro-4- isobutylpiperidine-l-carbonyl)phenyl)amide (Potassium salt of Cpd. 3) (N232659-157)

[0102] A cooled KOH solution (75.69 mL, 37.845 mmol, 0.5 M in water, 0.9 eq.) was added to 7V-(4-(4-fluoro-4-isobutylpiperidine-l-carbonyl)phenyl)benzo[J]thiazole-4- sulfonamide (20 g, 42.1 mmol) dropwise at 0 °C. After addition, the mixture was stirred at 0 °C for 30 mins. The resulting solution was lyophilized to afford the title compound (21 g, 40.88 mmol, 97.2% yield) as a white solid. ‘HNMR (400 MHz, DMSO-d6 ) δ 9.40 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.96 (d, J= 8.0 Hz, 1H), 7.46 (t, J= 4.0 Hz, 1H), 6.97 (d, J = 8.0 Hz, 2H), 6.77 (d, J= 8.0 Hz, 2H), 3.90 - 3.84 (m, 2H), 3.08 - 3.04 (m, 2H), 1.83 - 1.75 (m, 3H), 1.53 - 1.45 (m, 4H), 0.89 (d, J= 4.0 Hz, 6H). LC-MS m e. 476 (MH+).Example 2. Synthesis of 7V-(4-(4-fluoro-4-isobutylpiperidine-l-carbonyl)phenyl-2, 3,5,6- 6L)benzo[J]thiazole-4-sulfonamide (Cpd. 18) (N233307-058) and 7V-(4-(4- neopentylpiperidine-l-carbonyl)phenyl-2,3,5,6-6L)benzo[J]thiazole-4-sulfonamide (Cpd. 19) (N233307-060).Step 1. Synthesis of 4-(benzo[J]thiazole-4-sulfonamido)benzoic-2,3,5,6-J. / acid (N233307- 056).

[0103] To a solution of benzo[d]thiazole-4-sulfonyl chloride (1.32 g, 5.65 mmol) in anhydrous THF (10 mL) were added 4-aminobenzoic-2,3,5,6-t4 acid (400 mg, 2.83 mmol) and pyridine (0.688 mL, 8.50 mmol. The mixture was stirred at room temperature for 2 hrs, concentrated and triturated with water. The solid was collected, washed with EtOH and dried under vacuum to afford the title compound (400 mg, 1.18 mmol, 41.7% yield) as a red solid. LC-MS: m / e 339 (MH+).Step 2. Synthesis of 7V-(4-(4-fluoro-4-isobutylpiperidine-l-carbonyl)phenyl-2, 3,5,6- <Z. / )benzo[J|thiazole-4-sulfonaniide (Cpd. 18) (N233307-058).

[0104] To a solution of 4-(benzo[d]thiazole-4-sulfonamido)benzoic-2,3,5,6-t4 acid (150 mg, 0.443 mmol) in DMF (3 mL) were added EhN (0.185 mL, 1.33 mmol), HATU (253 mg, 0.665 mmol) and 4-fluoro-4-isobutylpiperidine (106 mg, 0.665 mmol). The reaction mixture was stirred at room temperature for 1 hr, poured into water and extracted with DCM three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by pre-HPLC (YMC- Actus Triart C18 250*21mm, 5 ~ 95% MeCN in H2O with 0.1% formic acid) to afford the title compound (41.5 mg, 0.087 mmol, 19.5% yield) as a white solid.1HNMR (400 MHz, DMSO- <76) 8 10.79 (s, 1H), 9.64 (s, 1H), 8.49 (d, J= 8.0 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.64 (t, J= 8.0 Hz, 1H), 4.13 - 3.54 (m, 2H), 3.08 - 2.97 (m, 2H), 1.81 - 1.78 (m, 3H), 1.52 - 1.50 (m, 1H), 1.50 - 1.44 (m, 3H), 0.89 (d, J= 8.0 Hz, 6H). LC-MS: m / e 480 (MH+).Step 3. Synthesis of 7V-(4-(4-neopentylpiperidine-l-carbonyl)phenyl-2, 3,5,6-<<L)benzo[< / ]thiazole-4-sulfonaniide (Cpd. 19) (N233307-060).

[0105] To a solution of 4-(benzo[<7]thiazole-4-sulfonamido)benzoic-2,3,5,6-64 acid (150 mg, 0.443 mmol) in DMF (3 mL) were added EhN (0.185 mL, 1.33 mmol), HATU (253mg, 0.665 mmol), followed by adding 4-neopentylpiperidine (69 mg, 0.443 mmol). The reaction mixture was stirred at room temperature for 1 hr, poured into water and extracted with DCM three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by Prep-HPLC (YMC- Actus Triart C18 250*21mm, 5 ~ 95% MeCN in H2O with 0.1% formic acid) to afford the title compound (183 mg, 0.385 mmol, 86.9% yield) as a white solid.

[0106] 1HNMR (400 MHz, DMSO) 5 10.75 (s, 1H), 9.65 (s, 1H), 8.50 (d, J = 8.0 Hz ,1H), 8.11 (d, J= 8.0 Hz, 1H), 7.64 (t, J= 4.0 Hz, 1H), 4.27 - 3.47 (m, 2H), 2.91 - 2.68 (m, 2H), 1.62 - 1.51 (m, 3H), 1.10 - 1.03 (m, 4H), 0.87 (s, 9H). LC-MS: m / e 476 (MH+).Scheme 2Example 3. Synthesis of 7V-(4-(4-hydroxy-4-isobutylpiperidine-l- carbonyl)phenyl)quinoxaline-5-sulfonamide (Cpd. 160) (N-232660-160).

[0107] The following compound (Cpd. 160) described in WO 2014 / 139144, containing a hydrophilic -OH moiety on piperidine, was prepared as follows (see also, generic Scheme 2 above for like compounds) as a representative comparison to the compounds of the present disclosure, which lack such a hydrophilic moiety.Step 1. Synthesis of 4-(quinoxaline-5-sulfonamido)benzoic acid (N232660-157).

[0108] To a solution of quinoxaline-5-sulfonyl chloride (30 g, 131 mmol) and pyridine (42.4 mL, 524 mmol) in THF (500 mL) was added 4-aminobenzoic acid (17.9 g, 131 mmol) and stirred at room temperature for 3 hrs. Then the mixture was concentrated to dryness at 50 °C. The residue was treated with EtOH (150 mL) and stirred for 1 hr. The precipitate was collected by filtration and the cake was washed with EtOH. The solid was dried under vacuum at 60 °C for 3 hrs to afford tittle compound (40 g, 121 mmol, 92.6% yield). LC-MS m / e\ 330 (MH+).Step 2. Synthesis of 4-isobutylpiperidin-4-ol (N232660-159).

[0109] A solution of / c / 7-butyl 4-hydroxy-4-isobutylpiperidine-l -carboxylate (22.0 g, 85.5 mmol) in HC1 solution (100 mL, 4 M in EtOAc) was stirred at room temperature for 2 hrs. Then the mixture was concentrated to afford the title compound (13.1 g, 82.7 mmol, 96.7 % yield). LC-MS m / c. 158 (MH+).Step 3. Synthesis of 7V-(4-(4-hydroxy-4-isobutylpiperidine-l- carbonyl)phenyl)quinoxaline-5-sulfonamide(Cpd. 160) (N232660-160).

[0110] To a solution of 4-(quinoxaline-5-sulfonamido)benzoic acid (32.67 g, 99.2 mmol) in DMAc (200 mL) was added CDI (16.1 g, 99.2 mmol) at 0 °C and stirred at room temperature for 1 hr, then 4-isobutylpiperidin-4-ol (13 g, 82.7 mmol) was added. The resulting mixture was stirred at room temperature for 12 hrs, quenched with water and extracted with EtOAc three times. The combined organic layers were washed with brine and dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by reverse-phase chromatography (SilaSep™ C18 silica flash cartridge, 20%-95% MeCN in H2O with 0.1% formic acid) to afford the title compound (30 g, 64.0 mmol, 77.4% yield) as a white solid.1HNMR (400 MHz, DMSO-t / d) 5 10.63 (s, 1H), 9.14 - 9.10 (m, 2H), 8.51 - 8.50 (m, 1H), 8.49 - 8.48 (m, 1H), 7.98 (t, J= 8.0 Hz, 1H), 7.16 - 7.09 (m, 4H), 4.15 - 4.01 (m, 2H), 3.18 - 3.03 (m, 3H), 1.80 - 1.73 (m, 1H), 1.46 - 1.25 (m, 6H), 0.88 (d, J= 8.0 Hz, 6H). LC-MS m / c. 469 (MH+).Scheme 3Example 4. Synthesis of 7V-(4-(4-(2-fluorophenoxy)piperidine-l- carbonyl)phenyl)benzo[J|thiazole-4-sulfonamide (Cpd. 1) (N222310-356) and potassium 7V-(4-(4-(2-fluorophenoxy)piperidine-l-carbonyl)phenyl)benzo[J]thiazole-4-sulfonamide (Step 1. Synthesis of tert-butyl 4-(2-fluorophenoxy)piperidine-l-carboxylate (N222310- 343).

[0111] To a solution of tert-butyl 4-hydroxypiperidine-l -carboxylate (40 g, 199 mmol), 2-fluorophenol (22.3 g, 199 mmol) and PPFh (78.19 g, 298 mmol) in THF (500 mL) was added DIAD (60.3 g, 298 mmol) at 0 °C under N2 atmosphere. The resulting mixture was stirred at 25 °C for 3 hrs under N2 atmosphere, concentrated to dryness and purified by silica gel column chromatography (gradient: 100% PE to 10% EtOAc in PE) to afford the title compound (29.5 g, 99.9 mmol, 50.3% yield) as an off-white solid. 'H NMR (400 MHz, DMSO- d6) 5 7.16-7.29 (m, 2H), 7.12 (t, J = 8.0 Hz, 1H), 6.87-6.95 (m, 1H), 4.65 - 4.41 (m, 1H), 3.73 - 3.60 (m, 2H), 3.25 - 3.10 (m, 2H), 1.85-1.95 (m, 2H), 1.48 - 1.58 (m, 2H), 1.41 (s, 9H).Step 2. Synthesis of 4-(2-fluorophenoxy)piperidine hydrochloride (N222310-344).

[0112] A mixture of tert-butyl 4-(2-fluorophenoxy)piperidine-l -carboxylate (29.5 g, 99.9 mmol) in HC1 solution (300 mL, 600 mmol, 2 M in EtOAc) was stirred at 25 °C for Ihr under N2 atmosphere. Then the mixture was concentrated to dryness. The residue was triturated with MTBE. The solid was collected by filtration. The filter cake was dried under vacuum to afford the title compound (21.0 g, 90.7 mmol, 90.8% yield) as an off-white solid, which was used directly in the next step without further purification.Step 3. Synthesis of 7V-(4-(4-(2-fluorophenoxy)piperidine-l- carbonyl)phenyl)benzo[J]thiazole-4-sulfonaniide (Cpd. 1) (N222310-356).

[0113] To a solution of 4-(benzo[d]thiazole-4-sulfonamido)benzoic acid (30 g, 89.7 mmol) in DMAc (150 mL) was added CDI (16.0 g, 98.7 mmol) at 25 °C and stirred at 25 °C for 2 hrs under N2 atmosphere. Then 4-(2-fluorophenoxy)piperidine hydrochloride (21.0 g,90.8 mmol) was added to the mixture and stirred at 25 °C for 18 hrs under N2 atmosphere. Water was added dropwise into the resulting mixture and stirred for 2 hrs at 25 °C. The solid was collected by filtration, dried under vacuum and recrystallized with a mixture of H2O and MeCN (3 / 7 in v / v) to afford the title compound (33 g, 64.5 mmol, 71.9% yield) as an off-white solid. ‘HNMR (400 MHz, DMSO-d6 ) δ 10.72 (s, 1H), 9.61 (s, 1H), 8.44 (d, J= 8.0 Hz, 1H), 8.09 (d, J= 8.0 Hz, 1H), 7.62 (t, J = 8.0 Hz, 1H), 7.25 - 7.16 (m, 4H), 7.12 - 7.05 (m, 3H), 6.97 - 6.95 (m, 1H), 4.61 - 4.58 (m, 1H), 3.81 - 3.58 (m, 2H), 3.27 - 3.25 (m, 2H), 1.91 - 1.84 (m, 2H), 1.61 - 1.56 (m, 2H). LC-MS m / e: 512 (MH+)Step 4. Synthesis of potassium (benzo [ J]thiazol-4-ylsulfonyl)(4-(4-(2- fluorophenoxy)piperidine-l-carbonyl)phenyl)amide (Potassium salt of Cpd. 1) (N222310- 370).

[0114] A cooled KOH solution (1.760 mL, 0.880 mmol, 0.5 M in water, 0.9 eq.) was added to a suspension of A-(4-(4-(2-fluorophenoxy)piperidine-l- carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide (500 mg, 0.977 mmol) in water (10 mL) dropwise at 0 °C. After addition, the mixture was stirred at 0 °C for 30 mins. The resulting solution was lyophilized to afford the title compound (521 mg, 0.948 mmol, 97.0% yield) as a white solid. ’H NMR (400 MHz, DMSO-d6 ) δ 9.41 (s, 1H), 8.23 - 8.17 (m, 1H), 8.05 - 7.97 (m, 1H), 7.53 - 7.44 (m, 1H), 7.28 - 7.18 (m, 2H), 7.10 (t, J = 8.0 Hz, 1H), 7.02 - 6.93 (m, 3H), 6.92 - 6.79 (m, 2H), 4.60 - 4.57(m, 1H), 3.75-3.73 (m, 2H), 3.30 - 3.26 (m, 2H), 1.89 - 1.60 (m, 2H), 1.58 - 1.53 (m, 2H). LC-MS m / e: 512 (MH+).Example 5. Synthesis of 7V-(4-(4-(2,4-difluorophenoxy)piperidine-l- carbonyl)phenyl)benzo[J]thiazole-4-sulfonamide (Cpd. 4) (N222310-358).N222310-358Synthesis of 7V-(4-(4-(2,4-difluorophenoxy)piperidine-l- carbonyl)phenyl)benzo[J]thiazole-4-sulfonamide (Cpd. 4) (N222310-358).

[0115] To a solution of 4-(benzo[d]thiazole-4-sulfonamido)benzoic acid (45 g, 135 mmol) in DMAc (225 mL) was added CDI (26.2 g, 162 mmol) at 25°C and stirred at 25 °C for 2 hrs under N2 atmosphere. Then 4-(2,4-difluorophenoxy)piperidine (28.7 g, 135 mmol) was added to the mixture and stirred for further 18 hrs at 25 °C under N2 atmosphere. Water wasadded dropwise into the mixture and the resulting mixture was stirred for 2 hrs at 25 °C. The solid was collected by filtration, dried under vacuum and recrystallized from a mixture of H2O and MeCN (3 / 7 in v / v) to afford the title compound (32 g, 62.6 mmol, 46.5% yield) as an off- white solid. ’H NMR (400 MHz, DMSO-T / 6) 5 10.78 (s, 1H), 9.66 (s, 1H), 8.50 (Dd, J = 8.0, 4.0 Hz, 1H), 8.12 (d, J= 8.0 Hz, 1H), 7.65 (t, J= 8.0 Hz, 1H), 7.30 - 7.27 (m, 4H), 7.26 - 7.01 (m, 2H), 6.99 - 6.97 (m, 1H), 4.54 - 4.51(m, 1H), 3.94 - 3.63 (m, 2H), 3.28 - 3.21 (m, 2H), 1.88 (m, 2H), 1.70 - 1.58 (m, 2H). LC-MS m / e: 530 (MH+).Scheme 4Example 6. Synthesis of 7V-(4-(4-fluoro-4-((l-methylcyclopropyl)methyl)piperidine-l- carbonyl)phenyl)benzo[J|thiazole-4-sulfonamide (Cpd. 9) (N222299-437).N222299-435 N222299-437Step 1. Synthesis of benzyl 4-hydroxy-4-(2-methylallyl)piperidine-l-carboxylate (N222299-414).

[0116] To a suspension of 3-bromo-2-methylprop-l-ene (10.4 g, 77.2 mmol) and benzyl 4-oxopiperidine-l -carboxylate (7.20 g, 30.9 mmol) in THF (100 mL) and sat. NH4CI solution (500 mL) was added Zn dust (4.04 g, 61.7 mmol) portion-wise at 10 °C under N2 atmosphere. After addition, the reaction mixture was stirred at room temperature overnight under N2 atmosphere, diluted with water and acidified with 10% AcOH solution to pH ~ 6. Theresulting mixture was extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 20% EtOAc in PE) to afford the title compound (7.90 g, 27.3 mmol, 88.5% yield) as a white solid. LC-MS m / e'. 290 (MH+).Step 2. Synthesis of benzyl 4-hydroxy-4-((l-methylcyclopropyl)methyl)piperidine-l- carboxylate (N222299-415).

[0117] To a solution of diethylzinc (5.18 mL, 5.18 mmol, IM in hexane) in DCM (5 mL) was added TFA (0.265 mL, 3.47 mmol) in 0.5 mL DCM dropwise at 0 °C and stirred for 15 mins. Then diiodomethane (926 mg, 3.46 mmol) in 0.50 mL DCM was added to the mixture and stirred for further 15 mins at 0 °C before adding benzyl 4-hydroxy-4-(2- methylallyl)piperidine-l -carboxylate (500 mg, 1.73 mmol) in 1 mL DCM. After that, the reaction mixture was stirred at 25 °C for 18 hrs. The resulting mixture was poured into icewater and the aqueous layer was extracted with DCM three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 10% EtOAc in PE) to afford the title compound (440 mg, 1.45 mmol, 83.9% yield) as a yellow oil. LC-MS m e. 304 (MH+).Step 3. Synthesis of 4-((l-methylcyclopropyl)methyl)piperidin-4-ol (N222299-434).

[0118] To a solution of benzyl 4-hydroxy-4-((l-methylcyclopropyl)methyl)piperidine- 1-carboxylate (500 mg, 1.65 mmol) in MeOH (5 mL) was added ammonium formate (1.04 g, 16.5 mmol) and Pd on activated carbon (10%) (wetted with ca. 55% water) (100 mg) and stirred at 60 °C for 2 hrs. The resulting mixture was cooled to room temperature, filtered through a pad of Celite and the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure to afford the title compound (270 mg, 1.60 mmol, 96.8% yield) as a white solid. LC-MS m e. 170 (MH+).Step 4. Synthesis of 7V-(4-(4-hydroxy-4-((l-methylcyclopropyl)methyl)piperidine-l- carbonyl)phenyl)benzo[J]thiazole-4-sulfonaniide (N222299-435).

[0119] To a solution of 4-((l-methylcyclopropyl)methyl)piperidin-4-ol (270 mg, 1.60 mmol) and 4-(benzo[d]thiazole-4-sulfonamido)benzoic acid (267 mg, 0.798 mmol) in DMF (5 mL) were added EhN (1.11 mL, 7.98 mmol) and HATU (727 mg, 1.91 mmol). The reaction mixture was stirred at room temperature for 10 mins, poured into ice water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel columnchromatography (gradient: 100% DCM to 10% MeOH in DCM) to afford the title compound (210 mg, 0.433 mmol, 54.3% yield) as a yellow oil. LC-MS m / c. 486 (MH+).Step 5. Synthesis of 7V-(4-(4-fluoro-4-((l-methylcyclopropyl)methyl)piperidine-l- carbonyl)phenyl)benzo[J|thiazole-4-sulfonamide (Cpd. 9) (N222299-437).

[0120] To a solution of A-(4-(4-hydroxy-4-((l-methylcyclopropyl)methyl)piperidine- l-carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide (210 mg, 0.433 mmol) in DCM (5 mL) was added DAST (209 mg, 1.30 mmol) at -78 °C and stirred at room temperature for 2 hrs. The reaction mixture was poured into cooled sat. NaHCCh solution and extracted with DCM three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18 250*21mm, 5 ~ 95% MeCN in H2O with 0.1% formic acid) to afford the title compound (6.8 mg, 0.014 mmol, 3.23% yield) as a white solid.1HNMR (400 MHz, DMSO- <76) 8 10.78 (s, 1H), 9.64 (s, 1H), 8.49 (d, J= 8.0 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.64 (t, J= 8.0 Hz, 1H), 7.18 (m, 2H), 7.10 (m, 2H), 4.37 - 3.63 (m, 2H), 3.19 - 2.91 (m, 2H), 1.91 - 1.69 (m, 2H), 1.67 - 1.49 (m, 4H), 1.05 (d, J= 1.6 Hz, 3H), 0.35 - 0.19 (m, 4H). LC-MS m e. 488 (MH+).Scheme 5Example 7. Synthesis of (l?)-7V-(4-(4-((2,2-difluoro-l-methylcyclopropyl)methyl)-4- fluoropiperidine-l-carbonyl)phenyl)benzo[J|thiazole-4-sulfonamide (Cpd. 11) (N222299- 495-P1) and (5)-7V-(4-(4-((2,2-difluoro-l-methylcyclopropyl)methyl)-4-fluoropiperidine-Step 1. Synthesis of benzyl 4-((2,2-difluoro-l-methylcyclopropyl)methyl)-4- hydroxypiperidine-l-carboxylate (N222299-423).

[0121] A solution of benzyl 4-hydroxy-4-(2-methylallyl)piperidine-l -carboxylate (3.00 g, 10.4 mmol), trimethyl(trifluoromethyl)silane (4.42 g, 31.1 mmol) and Nal (3.11 g, 20.7 mmol) in THF (15 mL) was stirred in a sealed tube at 80 °C for 18 hrs under N2 atmosphere. The reaction mixture was cooled to room temperature, pour into water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 10% EtOAc in PE) to afford the title compound (2.8 g, 8.25 mmol, 79.6% yield) as a yellow oil. ’H NMR (400 MHz, DMSO) 5 7.38 - 7.26 (m, 5H), 5.05 (s, 2H), 3.59 -3 .27 (m, 2H), 3.26 - 3.17 (m, 3H), 1.82 - 1.53 (m, 6H), 1.31 - 1.25 (m, 1H), 1.20 (s, 3H), 1.18 - 1.14 (m, 1H).

[0122] Step 2. Synthesis of benzyl 4-((2,2-difluoro-l-methylcyclopropyl)methyl)-4- fluoropiperidine-l-carboxylate (N222299-427).

[0123] To a solution of benzyl 4-((2,2-difluoro-l-methylcyclopropyl)methyl)-4- hydroxypiperidine-1 -carboxylate (3.5 g, 10.3 mmol) in DCM (50 mL) was added DAST (8.32 g, 51.5 mmol) dropwise at 0 °C under N2 atmosphere and stirred at room temperature for 2 hrs. The resulting mixture was quenched with sat. NaHCCh solution and the aqueous layer was extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 10% EtOAc in PE) to afford the title compound (600 mg, 1.76 mmol, 17.1% yield) as a yellow oil. LC-MS m / c. 342(MH+).Step 3. Synthesis of 4-((2,2-difluoro-l-methylcyclopropyl)methyl)-4-fluoropiperidine (N222299-429).

[0124] To a solution of benzyl 4-((2,2-difluoro-l-methylcyclopropyl)methyl)-4- fhioropiperidine-l -carboxylate (600 mg, 1.76 mmol) in MeCN (10 mL) were added Nal (1.32g, 8.80 mmol) and TMSC1 (956 mg, 8.80 mmol) and stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure to afford the crude title compound (600 mg) as a yellow solid, which was used in the next step without further purification. LC- MS m e. 208(MH+), 188(MH+-20).Step 4. Synthesis of 7V-(4-(4-((2,2-difluoro-l-methylcyclopropyl)methyl)-4- fluoropiperidine-l-carbonyl)phenyl)benzo[J]thiazole-4-sulfonaniide (N222299-432).

[0125] To a solution of 4-((2,2-difluoro-l-methylcyclopropyl)methyl)-4-fluoropiperidine (600 mg, crude) and 4-(benzo[d]thiazole-4-sulfonamido)benzoic acid (588 mg, 1.76 mmol) in acetonitrile (20 mL) were added 1 -methylimidazole (435 mg, 5.29 mmol) and TCFH (740 mg, 2.64 mmol) and stirred at room temperature for 10 mins. The reaction mixture was poured into water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by reverse-phase chromatography (YMC-Actus Triart C18 250*21mm, 5 ~ 95% MeCN in H2O with 0.1% formic acid) to afford the title compound (290 mg, 0.554 mmol, 31.5% yield) as a white solid.XH NMR (400 MHz, DMSO-d6 ) δ 10.78 (s, 1H), 9.54 (s, 1H), 8.86 - 8.60 (m, 1H), 8.36 (d, J= 8.0 Hz, 1H), 8.03 (d, J= 8.0 Hz, 1H), 7.56 (t, J= 8.0 Hz, 1H), 7.11 -7.09 (m, 2H), 6.97 - 6.95 (m, 2H), 4.17 - 3.33 (m, 2H), 3.11 - 2.95 (m, 2H), 1.84 - 1.61 (m, 5H), 1.37 - 1.32 (m, 1H), 1.32-1.23 (m, 2H), 1.23-1.19 (m, 3H). LC- MS m / e-. 524(MH+).Step 5. Synthesis of (7?)-A-(4-(4-((2,2-difluoro-l-methylcyclopropyl)methyl)-4- fluoropiperidine-l-carbonyl)phenyl)benzo[J|thiazole-4-sulfonamide (Cpd. 11) and (N222299-495-P1) (3)-7V-(4-(4-((2,2-difluoro-l-methylcyclopropyl)methyl)-4- fluoropiperidine-l-carbonyl)phenyl)benzo[J|thiazole-4-sulfonaniide (Cpd. 12) (N222299- 495-P2).

[0126] The A-(4-(4-((2,2-difluoro- 1 -methylcyclopropyl)methyl)-4-fluoropiperidine- 1 - carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide (280 mg, 0.535 mmol) was purified by Chiral SFC (ChiralPak C-IG, 250x30mm I.D., 5pm, 0-50% MeOH in CO2 for 30 mins) to afford (A)-A-(4-(4-((2,2-difluoro- 1 -methylcyclopropyl)methyl)-4-fluoropiperidine- 1 - carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide (Cpd. 11) (N222299-495-P1) (106.1 mg, 0.203 mmol, 37.9% yield, Rt=3.656 min) as a white solid and (5)-A-(4-(4-((2,2-difluoro-l- methylcyclopropyl)methyl)-4-fluoropiperidine-l-carbonyl)phenyl)benzo[J]thiazole-4- sulfonamide (Cpd. 12) (N222299-495-P2) (115.2 mg, 0.220 mmol, 41.1% yield, Rt=6.378 min) as a white solid.Cpd. 11, N222299-495-P1:

[0127] ’H NMR (400 MHz, DMSO-d6 ) δ 10.77 (s, 1H), 9.65 (s, 1H), 8.49 (d, J = 8.0 Hz, 1H), 8.11 (d, .7= 8.0 Hz, 1H), 7.65 (t, J = 8.0 Hz, 1H), 7.20 - 7.18 (m, 2H), 7.11 - 7.09 (m, 2H), 4.34 - 3.34 (m, 2H), 3.17 - 2.85 (m, 2H), 1.91 - 1.53 (m, 6H), 1.38 - 1.22 (m, 2H), 1.23- 1.19 (m, 3H). LC-MS m e. 524(MH+).Cpd. 12, N222299-495-P2:

[0128] ’H NMR (400 MHz, DMSO-d6 ) δ 10.77 (s, 1H), 9.65 (s, 1H), 8.50 (d, J = 8.0 Hz, 1H), 8.11 (d, J= 8.0 Hz, 1H), 7.64 (t, J= 8.0 Hz, 1H), 7.19 (m, 2H), 7.11 (m, 2H), 4.41 -3.41 (m, 2H), 3.18 - 2.88 (m, 2H), 1.88 - 1.54 (m, 6H), 1.38 - 1.23 (m, 2H), 1.19 (s, 3H). LC- MS m / e: 524(MH+).Scheme 6Example 8. Synthesis of 7V-(4-(4-fluoro-4-(4-fluorobenzyl)piperidine-l- carbonyl)phenyl)benzo[J]thiazole-4-sulfonamide (Cpd. 5) (N232817-060).Step 1. Synthesis of tert-butyl 4-(4-fluorobenzylidene)piperidine-l-carboxylate (N232817- 018).

[0129] To a solution of diethyl (4-fluorobenzyl)phosphonate (2.00 g, 8.12 mmol) in THF (30 mL) was added t-BuOK (1.26 g, 11.2 mmol) at 0 °C under N2 atmosphere. The mixture was stirred at 0 °C for 30 mins. Then tert-butyl 4-oxopiperidine-l -carboxylate (1.58 g, 7.93 mmol) in THF (5 mL) was added to the mixture at 0 °C. The resulting mixture was stirred at room temperature for 30 mins, quenched with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 20% EtOAc in PE) to afford the title compound (1.80 g, 76.1% yield) as a white solid. LC-MS m / e'. 292.1 (MH+).Step 2. Synthesis of tert-butyl 2-(4-fluorophenyl)-l-oxa-6-azaspiro[2.5]octane-6- carboxylate (N232817-040).

[0130] To a solution of tert-butyl 4-(4-fluorobenzylidene)piperidine-l -carboxylate (1.80 g, 6.18 mmol) in DCM (80 mL) was added m-CPBA (1.97 g, 8.03 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 hrs, poured into sat. NaHCCh solution and the aqueous layer was extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 20% EtOAc in PE) to afford the title compound (1.70 g, 89.5% yield) as a yellow oil. LC-MS m / e'. 252.1 (MH+-56).Step 3: Synthesis of tert-butyl 4-(4-fluorobenzyl)-4-hydroxypiperidine-l-carboxylate (N232817-057).

[0131] To a solution of tert-butyl 2-(4-fluorophenyl)-l-oxa-6-azaspiro[2.5]octane-6- carboxylate (1.70 g, 5.53 mmol) in MeOH (25 mL) was added Pd on activated carbon (10%) (wetted with ca. 55% water) (800 mg) and stirred at room temperature under 15 psi of EE for 1 hr. The resulting mixture was filtered through a pad of Celite and the filter cake was washed with MeOH. The filtrate was concentrated to afford the title compound (1.50 g, 87.7% yield) as a green oil. LC-MS m e. 210.0 (MH+-100).Step 4: Synthesis of tert-butyl 4-fluoro-4-(4-fluorobenzyl)piperidine-l-carboxylate (N232817-058).

[0132] To a solution of tert-butyl 4-(4-fluorobenzyl)-4-hydroxypiperidine-l- carboxylate (1.50 g, 4.85 mmol) in DCM (25 mL) was added DAST (1.56 g, 9.70 mmol) at 0 °C under N2 atmosphere. The reaction mixture was stirred at room temperature for 1 hr, poured into sat. NaHCCh solution and the aqueous layer was extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 20% EtOAc in PE) to afford the title compound (800 mg, 53.0% yield) as a green oil. LC-MS m e. 256.0 (MH+-56).Step 5: Synthesis of 4-fluoro-4-(4-fluorobenzyl)piperidine (N232817-059).

[0133] To a solution of tert-butyl 4-fhioro-4-(4-fluorobenzyl)piperidine-l -carboxylate (800 mg, 2.57 mmol) in EtOAc (15 mL) were added HC1 solution (10 mL, 40 mmol, 4 M in EtOAc) at 0 °C under N2 atmosphere. The reaction mixture was concentrated to dryness under reduced pressure to afford the title compound (500 mg, 92.1% yield) as a white solid, which was used directly without further purification.Step 6: Synthesis of 7V-(4-(4-fluoro-4-(4-fluorobenzyl)piperidine-l- carbonyl)phenyl)benzo[J]thiazole-4-sulfonaniide (Cpd. 5) (N232817-060).

[0134] To a solution of 4-fluoro-4-(4-fluorobenzyl)piperidine (150 mg, 0.710 mmol) in MeCN (20 mL) were added 4-(benzo[d]thiazole-4-sulfonamido)benzoic acid (237 mg, 0.710 mmol), TCFH (356 mg, 1.42 mmol) and NMI (175 mg, 2.13 mmol). The reaction mixture was stirred at room temperature for 1 hr, poured into water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18 250*21mm, 5 ~ 95% MeCN in H2O with 0.1% FA) to afford the title compound (110.2 mg, 29.4% yield) as a white solid. ’H NMR (400 MHz, DMSO-d6 ) δ 10.77 (s, 1H), 9.65 (s, 1H),8.49 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.25 - 7.15 (m, 4H), 7.15-7.10 (m, 4H), 4.41 - 3.86 (m, 1H), 3.49-3.45 (m, 1H), 3.13 - 2.94 (m, 2H), 2.91-2.50 (m, 2H), 1.73 - 1.47 (m, 4H). LC-MS m / e: 528.3 (MH+).Scheme 7Example 9. Synthesis of 7V-(4-(4-fluoro-4-(2-fluoro-2-methylpropyl)piperidine- 1 - carbonyl)phenyl)benzo[J]thiazole-4-sulfonamide (Cpd. 13) (N232817-182).Step 1. Synthesis of benzyl 4-(2-ethoxy-2-oxoethyl)-4-hydroxypiperidine-l-carboxylate (N233128-005).

[0135] To a solution of EtOAc (7.93 g, 90.0 mmol) in THF (100 mL) was added LDA (51.4 mL, 102.8 mmol, 2.0 M in THF) at - 60 °C under N2. The mixture was stirred at - 60 °C for 30 mins. Then benzyl 4-oxopiperidine-l -carboxylate (20.0 g, 85.7 mmol) in THF (20 mL) was added to the mixture at - 60 °C. The resulting mixture was stirred at room temperature for 2 hrs, quenched with sat. NH4CI solution and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 10% EtOAc in PE) to afford the title compound (22.0 g, 79.9% yield) as a white solid. LC- MS m / e-. 322 (MH+).Step 2. Synthesis of benzyl 4-((benzyloxy)methoxy)-4-(2-ethoxy-2-oxoethyl)piperidine-l- carboxylate (N222299-451).

[0136] To a solution of benzyl 4-(2-ethoxy-2-oxoethyl)-4-hydroxypiperidine-l- carboxylate (5.00 g, 15.6 mmol) in DCE (80 mL) were added BOMC1 (4.87 g, 31.2 mmol) and EtaN (3.15 g, 31.2 mmol) and stirred at 80 °C for 18 hrs. Then the resulting mixture was cooled to room temperature, poured into water and the aqueous layer was extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 3% EtOAc in PE) to afford the title compound (4.50 g, 65.2% yield) as a yellow oil. LC-MS m e. 442 (MH+).Step 3. Synthesis of benzyl 4-((benzyloxy)methoxy)-4-(2-hydroxy-2- methylpropyl)piperidine-l-carboxylate (N232817-153).

[0137] To a solution of benzyl 4-((benzyloxy)methoxy)-4-(2-ethoxy-2- oxoethyl)piperidine-l -carboxylate (2.20 g, 4.97 mmol) in THF (25 mL) was added MeMgBr (2.8 mmol, 8.4 mmol, 3.0 M in Et2O) at 0 °C under N2 atmosphere and stirred at room temperature for 3 hr. The resulting mixture was poured into sat. NH4CI solution and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to afford the title compound (1.50 g, 70.6% yield) as a green oil, which was used directly in the next step without further purification.Step 4. Synthesis of benzyl 4-((benzyloxy)methoxy)-4-(2-fluoro-2- methylpropyl)piperidine-l-carboxylate (N232817-154).

[0138] To a solution of benzyl 4-((benzyloxy)methoxy)-4-(2-hydroxy-2- methylpropyl)piperidine-l -carboxylate (900 mg, 2.11 mmol) in DCM (25 mL) was added DAST (680 mg, 4.22 mmol) at 0 °C under N2 atmosphere. The resulting mixture was stirred at room temperature for 2 hrs, poured into sat. NaHCCf solution at 0 °C and the aqueous layerwas extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 5% EtOAc in PE) to afford the title compound (500 mg, 55.2% yield) as a green oil. LC-MS m / e'. 430.2 (MH+).Step 5. Synthesis of benzyl 4-(2-fluoro-2-methylpropyl)-4-hydroxypiperidine-l- carboxylate (N232817-178).

[0139] To a solution of benzyl 4-((benzyloxy)methoxy)-4-(2-fluoro-2- methylpropyl)piperidine-l -carboxylate (500 mg, 1.16 mmol) in EtOAc (25 mL) was added HC1 solution (8 mmol, 2.0 mL, 4.0 M in EtOAc) at 0 °C under N2 atmosphere. The resulting mixture was poured into sat. NaHCCf solution at 0 °C and the aqueous layer was extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 50% EtOAc in PE) to afford the title compound (300 mg, 83.6% yield) as a green oil. LC-MS m e. 310.2 (MH+).Step 6: Synthesis of benzyl 4-fluoro-4-(2-fluoro-2-methylpropyl)piperidine-l-carboxylate (N232817-179).

[0140] To a solution of benzyl 4-(2-fluoro-2-methylpropyl)-4-hydroxypiperidine-l- carboxylate (300 mg, 0.970 mmol) in DCM (20 mL) was added DAST (313 mg, 1.94 mmol) at 0 °C under N2 atmosphere. The resulting mixture was stirred at room temperature for 2 hrs, poured into sat. NaHCCf solution at 0 °C and the aqueous layer was extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 30% EtOAc in PE) to afford the title compound (120 mg, 39.7% yield) as a colorless oil. LC-MS m e. 312.2 (MH+), 292.1 (MH+-20).Step 7: Synthesis of 4-fluoro-4-(2-fluoro-2-methylpropyl)piperidine (N232817-180).

[0141] To a solution of benzyl 4-fluoro-4-(2-fluoro-2-methylpropyl)piperidine-l- carboxylate (120 mg, 0.385 mmol) in MeCN (20 mL) were added TMSC1 (209 mg, 1.93 mmol), Nal (289 mg, 1.93 mmol) at 0 °C under N2 atmosphere. The reaction mixture was stirred at room temperature for 3 hrs, filtered through a pad of Celite and the filtrate was concentrated to afford the crude title compound (60.0 mg, 87.9% yield) as a brown solid, which was used in the next step without further purification. LC-MS m / e'. 178.1 (MH+).Step 8. Synthesis of A-(4-(4-fluoro-4-(2-fluoro-2-methylpropyl)piperidine-l- carbonyl)phenyl)benzo[J]thiazole-4-sulfonaniide (Cpd. 13) (N232817-182).

[0142] To a solution of 4-fluoro-4-(2-fluoro-2-methylpropyl)piperidine (60 mg, 0.339 mmol) in MeCN (20 mL) were added 4-(benzo[d]thiazole-4-sulfonamido)benzoic acid (113 mg, 0.339 mmol), TCFH (170 mg, 0.687 mmol) and NMI (83.5 mg, 1.02 mmol). The resulting mixture was stirred at room temperature for 1 hr, quenched with water and extracted with EtO Ac three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (YMC- Actus Triart C18 250*21mm, 5 ~ 95% MeCN in H2O with 0.1% FA) to afford the title compound (64.2 mg, 64.1% yield) as a white solid.

[0143] Tf NMR (400 MHz, DMSO-d6 ) δ 10.76 (s, 1H), 9.65 (s, 1H), 8.50 (d, J = 8.0 Hz, 1H), 8.11 (d, J= 8.0 Hz, 1H), 7.64 (t, J= 8.0 Hz, 1H), 7.19 (d, J= 8.0 Hz, 2H), 7.11 (d, J = 8.0 Hz, 2H), 4.39 - 3.92 (m, 1H), 3.36 - 3.32 (m, 1H), 3.14 - 2.97 (m, 2H), 2.04-1.98 (m, 2H), 1.92-1.89 (m, 2H), 1.73 - 1.57 (m, 2H), 1.37 (d, J= 21.5 Hz, 6H). LC-MS m / e: 494.1 (MH+).Scheme 8Example 10. Synthesis of 7V-(4-(4-fluoro-4-(3-methylcyclobutyl)piperidine-l- carbonyl)phenyl)benzo[J|thiazole-4-sulfonamide (Cpd. 16) (N232838-142).Step 1. Synthesis of 3-carboxy-2-(pyridin-l-ium-l-yl)propanoate (N232838-123).

[0144] A solution of maleic acid (10.0 g, 86.1 mmol) and pyridine (6.97 mL, 86.1 mmol) in water (60 mL) was stirred at 90 °C for 2 hrs. After a crystalline solid appeared in reaction mixture, AcOH (5.92 mL, 103 mmol) was added. The solution was kept in suspension with stirring at the same temperature for 24 hrs. The crude reaction mixture was cooled down to room temperature, filtered, washed with small amount of MeOH and EtOAc. The resulting white solid was dried under reduced pressure by rotary evaporator and high vacuum to afford the title compound (9.50 g, 48.7 mmol, 56.5% yield). The product was used for the next step without further purification. ’H NMR (400 MHz, D2O) 3 8.85 (d, J= 4.0 Hz, 2H), 8.51 (t, J = 8.0 Hz, 1H), 8.01 (t, J= 8.0 Hz, 2H), 5.62 - 5.58 (m, 1H), 3.52 - 3.46 (m, 1H), 3.35 - 3.28 (m, 1H). LC-MS m / e: 196 (MH+).Step 2. Synthesis of l-(l,4-diethoxy-l,4-dioxobutan-2-yl)pyridin-l-ium ethyl sulfate (N232838-124).

[0145] A solution of 3 -carboxy -2-(pyridin-l-ium-l-yl)propanoate (9.50 g, 48.7 mmol) in EtOH (150 mL) with concentrated H2SO4 (5.21 mL, 97.3 mmol) was stirred at 90 °C for 18 hrs. Upon completion, the solvent was evaporated under reduced pressure. The concentrated crude mixture was diluted in di chloromethane and water. The aqueous layer was extracted with DCM 10 times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford the title compound (7.10 g, 18.8 mmol, 57.8% yield) as a white solid. LC-MS m / e: 252 (M+).Step 3. Synthesis of l-(l,4-diethoxy-l,4-dioxobutan-2-yl)-4-(3-methylcyclobutyl)pyridin- 1-ium (N232838-125).

[0146] To a stirred solution of l-(l,4-di ethoxy- l,4-dioxobutan-2-yl)pyri din- 1-iumethyl sulfate (6.80 g, 26.9 mmol) in DCE and H2O (20 mL, 1 / 1 in v / v) were added 3- methylcyclobutane-1 -carboxylic acid (6.15 g, 53.9 mmol), ammonium persulfate (12.3 g, 53.9 mmol) and silver nitrate (920 mg, 5.39 mmol). The biphasic mixture was stirred at 50 °C for 2 hrs. The reaction was monitored by LCMS. Upon completion, the reaction was diluted with DCM (5 mL). The aqueous layer was extracted with DCM three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, concentrated under reduced pressure to afford the title compound (6.0 g 18.7 mmol, 69.5% yield). The crude material was used in the next step without further purification. LC-MS m / e: 320 (M+).Step 4. Synthesis of 4-(3-methylcyclobutyl)pyridine (N232838-126).

[0147] To a stirred solution of l-(l,4-di ethoxy- l,4-dioxobutan-2-yl)-4-(3- methylcyclobutyl)pyridin-l-ium (6.0 g, 18.7 mmol) in DCM (60 mL) was added DBU (8.55 g, 56.2 mmol). The resulting mixture was stirred at room temperature for 1 hr. Upon completion, the reaction was diluted with DCM and washed with saturated NaHCCf solution twice. The organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 70% EtOAc in PE) to afford the title compound (1.30 g, 8.83 mmol, 47.1% yield) as colorless oil. LC-MS m e. 148 (MH+).Step 5. Synthesis of l-benzyl-4-(3-methylcyclobutyl)pyridin-l-ium bromide (N232838- 127).

[0148] To a solution of 4-(3-methylcyclobutyl)pyridine (1.30 g, 8.83 mmol) in MeCN (20 mL) was added benzyl bromide (2.27 g, 13.2 mmol) and the resulting mixture was stirred at 60 °C for 2 hrs. Upon completion, the reaction mixture was cooled to room temperature, concentrated under reduce pressure and recrystallized with petroleum ether to remove excess benzyl bromide. Then the residue was concentrated under vacuum to afford the title compound (2 g, 8.39 mmol, 95.0% yield) as yellow oil. LC-MS m e. 238 (M+).Step 6. Synthesis of l-benzyl-4-(3-methylcyclobutyl)-l,2,3,6-tetrahydropyridine (N232838-128).

[0149] To a solution of l-benzyl-4-(3-methylcyclobutyl)pyridin-l-ium bromide (2.0 g, 8.39 mmol) in EtOH (30 mL) was added NaBEL (960 mg, 25.2 mmol) at 0 °C and the resulting mixture was stirred at room temperature for 2 hrs. Upon completion, the reaction mixture was concentrated and diluted with EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 40% EtOAc in PE) to afford the title compound (1.0 g, 4.14 mmol, 49.3% yield) as a colorless oil.1HNMR (400 MHz, CDCh) d 7.42 - 7.18 (m, 5H),5.37 - 5.28 (m, 1H), 3.57 (s, 2H), 2.99 - 2.96 (m, 5H), 2.56- 2.51 (m, 5H), 1.68-1.67 (m, 1H), 1.45 - 1.43(m, 1H), 1.14 - 0.98 (m, 3H). LC-MS m / e: 242 (MH+).Step 7. Synthesis of l-benzyl-4-(3-methylcyclobutyl)piperidin-4-ol (N232838-135).

[0150] To a solution of l-benzyl-4-(3-methylcyclobutyl)-l,2,3,6-tetrahydropyridine (550 mg, 2.28 mmol) in DCM (1 mL) and i-PrOH (9 mL) was added Mn(dpm)a (138 mg, 0.228 mmol). The resulting mixture was cooled to 0 °C under O2 atmosphere and then phenylsilane (740 mg, 6.84 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 2 hrs, quenched with saturated NaHCCh solution and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 80% EtOAc in PE) to afford the title compound (400 mg, 1.54 mmol, 67.7% yield) as a colorless oil. LC-MS m / e\ 260 (MH+).Step 8. Synthesis of l-benzyl-4-fluoro-4-(3-methylcyclobutyl)piperidine (N232838-136).

[0151] To a solution of l-benzyl-4-(3-methylcyclobutyl)piperidin-4-ol (400 mg, 1.54 mmol) in DCM (6 mL) was added DAST (746 mg, 4.63 mmol) at 0 °C and stirred at 0 °C for 2 hrs. Upon completion, the reaction mixture was poured into ice saturated NaHCCh solution and the aqueous layer was extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 60% EtOAc in PE) to afford the title compound (150 mg, 0.574 mmol, 37.2% yield) as a colorless oil. LC- MS m e. 262 (MH+).Step 9. Synthesis of benzyl 4-fluoro-4-(3-methylcyclobutyl)piperidine-l-carboxylate (N232838-139).

[0152] To a solution of l-benzyl-4-fluoro-4-(3-methylcyclobutyl)piperidine (100 mg, 0.383 mmol) in DCE (5 mL) was added CbzCl (326 mg, 1.91 mmol) and the resulting mixture was stirred overnight at 80 °C. Upon completion, the reaction mixture was diluted with DCM, washed with brine, then dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 40% EtOAc in PE) to afford the title compound (60 mg, 0.196 mmol, 51.3% yield) as a colorless oil. LC-MS m e. 306 (MH+).Step 10. Synthesis of 4-fluoro-4-(3-methylcyclobutyl)piperidine (N232838-141).

[0153] To a solution of benzyl 4-fluoro-4-(3-methylcyclobutyl)piperidine-l- carboxylate (60 mg, 0.196 mmol) in MeCN (5 mL) were added TMSC1 (107 mg, 0.982 mmol) and Nal (147 mg, 0.982 mmol) and the resulting mixture was stirred at rt for 2 hrs. Uponcompletion, the reaction mixture was concentrated under vacuum to afford the title compound (50 mg, crude), which was used directly int the next step without further purification. LC-MS m / e: 172 (MH+).Step 11. Synthesis of 7V-(4-(4-fluoro-4-(3-methylcyclobutyl)piperidine-l- carbonyl)phenyl)benzo[J]thiazole-4-sulfonamide (Cpd. 16) (N232838-142).

[0154] To a solution of 4-(benzo[d]thiazole-4-sulfonamido)benzoic acid (40.0 mg, 0.120 mmol) and 4-fhioro-4-(3-methylcyclobutyl)piperidine (30.8 mg, 0.180 mmol) in DMAc (5 mL) were added 1 -methylimidazole (29.5 mg, 0.359 mmol) and TCFH (40.3 mg, 0.144 mmol) and stirred at room temperature for 1 hr. After the reaction was completed, it was diluted with EtOAc and washed with brine, dried over anhydrous NaiSCU, filtered and the filtrate was concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18 250*21mm, 50 ~ 95% MeCN in H2O with 0.1% formic acid, a gradient elution) to afford the title compound (12 mg, 0.025 mmol, 20.5% yield) as a white solid.XH NMR (400 MHz, DMSO-t / 6) 3 10.75 (s, 1H), 9.65 (s, 1H), 8.49 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.64 (t, J= 8.0 Hz, 1H), 7.19 - 7.10 (m, 4H), 4.42 - 3.82 (m, 1H), 3.75 - 3.35 (m, 1H), 3.18 - 2.80 (m, 2H), 2.25 - 1.92 (m, 4H), 1.70 - 1.30 (m, 6H), 1.12 - 0.91 (m, 3H). LC-MS m / e: 488 (MH+).Scheme 9Example 11. Synthesis of \-(4-(4-neopentylpiperidine-l- carbonyl)phenyl)benzo[J|thiazole-4-sulfonamide (Cpd. 7) (N232660-256) and potassium (benzo[J]thiazol-4-ylsulfonyl)(4-(4-neopentylpiperidine-l-carbonyl)phenyl)amide (Potassium salt of Cpd. 7) (N232660-257).Step 1. Synthesis of tert-butyl 4-neopentyl-3,6-dihydropyridine-l(2 / T)-carboxylate (N232660-253).

[0155] A suspension of tert-butyl 4-(((trifluoromethyl)sulfonyl)oxy)-3,6- dihydropyridine-l(2J7)-carboxylate (23.0 g, 69.4 mmol), neopentylboronic acid (16.1 g, 139 mmol), tricyclohexylphosphane (5.84 g, 20.8 mmol), Pd(OAc)2 (4.68 g, 20.8 mmol) andKaPCU (44.2 g, 208 mmol) in toluene (300 mL) and H2O (30 mL) was stirred at 110 °C for 16 hrs under N2 atmosphere. The resulting mixture was cooled to room temperature, diluted with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 3% EtOAc in PE) to afford the title compound (10.0 g, 39.5 mmol, 56.9% yield) as a light yellow oil.1HNMR (400 MHz, DMSO-d6 ) δ 5.34 (s, 1H), 3.79 (s, 2H), 3.35 (t, J= 5.2 Hz, 2H), 2.04 (s, 2H), 1.88 (s, 2H), 1.40 (d, J= 0.7 Hz, 9H), 0.88 (d, J= 0.4 Hz, 9H).Step 2. Synthesis of tert-butyl 4-neopentylpiperidine-l-carboxylate (N232660-254).

[0156] To a solution of tert-butyl 4-neopentyl-3,6-dihydropyridine-l(2J7)-carboxylate (10.0 g, 39.5 mmol) in MeOH (200 mL) was added Pd(OH)2 on activated carbon (20%) (wetted with ca. 55% water) (2.69 g) and stirred at room temperature under 15 psi of H2 for 16 hrs. The resulting mixture was filtered through a pad of Celite and the filter cake was washed with MeOH. The filtrate was concentrated to afford the title compound (9.00 g, 35.1 mmol, 88.9% yield) as a colorless oil. LC-MS m / e'. 200 (MH+-56).Step 3. Synthesis of 4-neopentylpiperidine hydrochloride (N232660-255).

[0157] A solution of / c / 7-butyl 4-neopentylpiperidine- 1 -carboxylate (8.00 g, 31.3 mmol) in HC1 solution (50 mL, 4 M in EtOAc) was stirred at room temperature for 2 hrs. Then the mixture was concentrated to afford the title compound (5.55 g, 29.0 mmol, 92.6 % yield). LC-MS m / e-. 156 (MH+).Step 4. Synthesis of 7V-(4-(4-neopentylpiperidine-l-carbonyl)phenyl)benzo[J]thiazole-4- sulfonamide (Cpd. 7) (N232660-256).

[0158] To a solution of 4-(benzo[d]thiazole-4-sulfonamido) benzoic acid (1.94 g, 5.80 mmol) in DMAc (20 mL) was added CDI (1.04 g, 6.44 mmol) at 0 °C and stirred at room temperature for 1 hr, then 4-neopentylpiperidine hydrochloride (1.23 g, 6.44 mmol) was added. The resulting mixture was stirred at room temperature for 12 hrs, quenched with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography (gradient: 100% DCM to 15% MeOH in DCM) to afford the title compound (2.1 g, 4.46 mmol, 76.8% yield, -90% purity) as a light-yellow solid. 200 mg pure title compound (white solid) was obtained after prep-HPLC (YMC-Actus Triart C18 250*21mm, 5 - 95% MeCN in H2O with 0.1% formic acid) from 500 mg impure title compound. ‘HNMR (400 MHz, DMSO-d6 ) δ 10.74 (s, 1H), 9.65 (s, 1H), 8.49 (d, J= 8.0 Hz, 1H), 8.10 (d, J= 8.0 Hz, 1H), 7.64 (t, J = 8.0 Hz, 1H), 7.21 - 7.01 (m, 4H), 4.25 (m, 1H), 3.65 - 3.33 (m, 1H), 3.04 - 2.62 (m, 2H), 1.76 - 1.45 (m, 3H), 1.13 - 0.97 (m, 4H), 0.87 (s, 9H). LC-MS m / e'. 472 (MH+).Step 5. Synthesis of potassium (benzo[J]thiazol-4-ylsulfonyl)(4-(4-neopentylpiperidine-l- carbonyl)phenyl)amide (Potassium salt of Cpd. 7) (N232660-257).

[0159] A cold KOH solution (0.382 mL, 0.191 mmol, 0.5 M in water, 0.9 e.q.) was added to A-(4-(4-neopentylpiperidine- 1 -carbonyl)phenyl)benzo[ d]thiazole-4-sulfonamide (100 mg, 0.212 mmol) dropwise at 0 °C. After addition, the mixture was stirred at 0 °C for 30 mins. The resulting solution was lyophilized to afford the title compound (103 mg, 0.202 mmol, 93.6% yield) as a white solid. ’H NMR (400 MHz, DMSO-d6 ) δ 9.42 (s, 1H), 8.20 (d, J= 8.0 Hz, 1H), 7.96 (d, J= 8.0 Hz, 1H), 7.47 (t, J= 8.0 Hz, 1H), 6.94 (d, J= 8.0 Hz, 2H), 6.78 (d, J = 8.0 Hz, 2H), 3.95 (m, 2H), 2.81 (m, 2H), 1.67 - 1.48 (m, 3H), 1.12 - 0.99 (m, 4H), 0.87 (s, 9H). LC-MS m e. 472 (MH+).Scheme 10Example 12. Synthesis of 7V-(4-(4-fluoro-4-neopentylpiperidine-l- carbonyl)phenyl)benzo[J|thiazole-4-sulfonamide (Cpd. 14) (N232659-168).Step 4N232659-168Step 1. Synthesis of tert-butyl 3-bromo-4-fluoro-4-neopentylpiperidine-l-carboxylate (N232659-165).

[0160] To a solution of tert-butyl 4-neopentyl-3,6-dihydropyridine-l(2J7)-carboxylate (2.00 g, 7.9 mmol) and triethylamine trihydrofluoride (3.82 g, 23.7 mmol) in DCM (50 mL) was added NBS (1.69 g, 9.47 mmol) at 0 °C and stirred at room temperature for 2 hrs. The mixture was quenched with sat. NaHCCh solution and the aqueous layer was extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 9% EtOAc in PE) to afford the tittle compound (1.40 g, 3.97 mmol, 50.4% yield) as a yellow oil. LC-MS: m / e 276, 278(MH+-56-20).Step 2. Synthesis of tert-butyl 4-fluoro-4-neopentylpiperidine-l-carboxylate (N232659- 166).

[0161] To a solution of tert-butyl 3-bromo-4-fluoro-4-neopentylpiperidine-l- carboxylate (1.4 g, 3.97 mmol) and EhN (1.66 mL, 11.9 mmol) in MeOH (20 mL) was added Pd on activated carbon (5%) (wetted with ca. 55% water (200 mg) and stirred with H2 balloon at room temperature for 2 hrs. The mixture was filtered through a pad of Celite and washedwith MeOH. The filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 7% EtOAc in PE) to afford the tittle compound (1.00 g, 3.66 mmol, 92.0% yield) as a colorless oil. LC-MS: m / c. 218 (MEE-56).Step 3. Synthesis of 4-fluoro-4-neopentylpiperidine hydrochloride (N232659-167).

[0162] A solution of tert-butyl 4-fluoro-4-neopentylpiperidine-l -carboxylate (150 mg, 0.549 mmol) in HC1 solution (5 mL, 20 mmol, 4M in EtOAc) was stirred at room temperature for 30 mins. The mixture was concentrated to afford the crude tittle compound (150 mg) as a yellow oil as a hydrochloride salt, which was used directly in the next step without further purification. LC-MS m e. 154 (MH+-20).Step 4. Synthesis of 7V-(4-(4-fluoro-4-neopentylpiperidine-l- carbonyl)phenyl)benzo[J]thiazole-4-sulfonamide (Cpd. 14) (N232659-168).

[0163] A solution of CDI (140 mg, 0.866 mmol) and 4-(benzo[d]thiazole-4- sulfonamido)benzoic acid (289 mg, 0.866 mmol) in DMAc (8 mL) was stirred at room temperature for 1 hr, then crude 4-fluoro-4-neopentylpiperidine hydrochloride (150 mg, 0.866 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for 2 hrs, diluted with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18 250*21mm, 5 ~ 95% MeCN in H2O with 0.1% formic acid) to afford the title compound (90 mg, 0.184 mmol, 21.2% yield) as a white solid. 'HNMR (400 MHz, DMSO-d6 ) δ 10.79 (s, 1H), 9.64 (s, 1H), 8.49 (d, J= 8.0 Hz, 1H), 8.10 (d, J= 8.0 Hz, 1H), 7.64 (t, J= 8.0 Hz, 1H), 7.19 - 7.17 (m, 2H), 7.10 - 7.08 (m, 2H), 4.39 - 3.39 (m, 2H), 3.16 - 2.81 (m, 2H), 1.94 - 1.73 (m, 2H), 1.69 - 1.49 (m, 4H), 0.97 (s, 9H). LC-MS m e. 490.4 (MH+).Scheme 11Example 13. Synthesis of A-(4-(4-fluoro-4-(2-(methyl-< / 5)propyl-2,3,3,3-^)piperidine-l- carbonyl)phenyl)benzo[J]thiazole-4-sulfonamide (Cpd. 17) (N232659-199).Step 1. Synthesis of tert-butyl 4-(l-hydroxy-2-(methyl-< / 3)propyl-2,3,3,3-<<M-3,6- dihydropyridine-l(2ZT)-carboxylate (N232659-192 & 193).

[0164] Introduce 292 mg of magnesium (12 mmol) into a dry, 2-necked, round bottom flask together with iodine (0.35 g, 1.39 mmol). Keep the system under N2 atmosphere cooled in an ice bath. Dry diethyl ether (40 mL) was added to the reaction flask. 2-bromopropane- 1,1,1,2,3,3,3-t / / (10 g, 69.4 mmol) was added to the mixture slowly at room temperature for 30 mins. The mixture was heated to reflux for 15 mins then cooled the reaction flask to room temperature and stirred for 2 hrs to afford (propan-2-yl-t / 7)magnesium bromide solution. To a solution of tert-butyl 4-formyl-3,6-dihydropyridine-l(2J7)-carboxylate (5.4 g, 25.6 mmol) in THF (40 mL) was added (propan-2-yl-t / 7)magnesium bromide solution (40 mL) at 0 °C and stirred at 0 °C for 4 hrs. The resulting mixture was quenched with sat. NH4CI solution and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 9% EtOAc in PE) to afford the title compound (1.90 g, 7.24 mmol, 28.3% yield) as a colorless oil. LC-MS m / e'. 189 (MH+-56-18).Step 2. Synthesis of tert-butyl 4-(l-acetoxy-2-(methyl-< / 3)propyl-2,3,3,3-<<M-3,6- dihydropyridine-l(2ZT)-carboxylate (N232659-194).

[0165] A solution of tert-butyl 4-(l-hydroxy-2-(methyl-t / 5)propyl-2,3,3,3-t4)-3,6- dihydropyridine-l(2J7)-carboxylate (1.9 g, 7.24 mmol), AC2O (2.22 g, 21.7 mmol) and DMAP (0.09 g, 0.724 mmol) in pyridine (1.15 g, 14.5 mmol) was stirred at room temperature overnight. The mixture was diluted with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 2% EtOAc in PE) to afford the title compound (1.30 g, 5.29 mmol, 73.1% yield) as a colorless oil. LC-MS: m / e 189 (MH+-56-AcO).Step 3. Synthesis of tert-butyl 4-(2-(methyl-< / 3)propyl-2,3,3,3-6L)-3,6-dihydropyridine-1 ( 2 / / )-ca rboxy late (N232659-195).

[0166] A suspension of tert-butyl 4-(l -acetoxy -2-(methyl-t / 3)propyl-2, 3 ,3 ,3-<4)-3 ,6- dihydropyridine-l(2rt)-carboxylate (1.30 g, 5.29 mmol), Pd(PPha)4 (3.05 g, 2.64 mmol), HCOONH4 (1.00 g, 15.9 mmol) and n-BuaP (1.07 g, 5.29 mmol) in THF (20 mL) was stirred at 70 °C under N2 atmosphere overnight. The mixture was cooled to room temperature and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 1% EtOAc in PE) to afford tittle compound (1.00 g, 4.06 mmol, 76.8% yield) as a colorless oil. LC-MS m / c. 191 (MH+).Step 4. Synthesis of tert-butyl 3-bromo-4-fluoro-4-(2-(methyl-< / 3)propyl-2, 3,3,3- J. / )piperidine-l-carboxylate (N232659-196).

[0167] To a solution of tert-butyl 4-(2-(methyl-t / 3)propyl-2,3,3,3-t4)-3,6- dihydropyridine-l(2rt)-carboxylate (1.00 g, 4.06 mmol) and triethylamine trihydrofluoride (1.96 g, 12.2 mmol) in DCM (20 mL) was added NBS (870 mg, 4.87 mmol) and stirred at room temperature overnight. The reaction mixture was quenched with sat. NaHCCh solution and the aqueous layer was extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 4% EtOAc in PE) to afford tittle compound (500 mg, 1.45 mmol, 35.7% yield) as a colorless oil. LC-MS m / e'. 269, 271 (MH+-56-20).Step 5. Synthesis of tert-butyl 4-fluoro-4-(2-(methyl-< / 3)propyl-2,3,3,3-6L)piperidine-l- carboxylate (N232659-197).

[0168] A solution of tert-butyl 3-bromo-4-fluoro-4-(2-(methyl-t / 3)propyl-2, 3,3,3- t / fipiperidine- l -carboxylate (500 mg, 1.45 mmol), AIBN (238 mg, 1.45 mmol) and n-BuaSnH (421 mg, 1.45 mmol) in toluene (15 mL) was stirred at 100°C for 2 hrs. The mixture was cooled to room temperature and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 3% EtOAc in PE) to afford tittle compound (180 mg, 0.676 mmol, 46.7% yield) as a colorless oil. LC-MS m e. 211 (MH+-56).Step 6. Synthesis of 4-fluoro-4-(2-(methyl-< / 3)propyl-2,3,3,3-6L)piperidine hydrochloride (N232659-198).

[0169] A solution of tert-butyl 4-fluoro-4-(2-(methyl-t / 3)propyl-2,3,3,3-t4)piperidine- 1-carboxylate (180 mg, 0.676 mmol) in HC1 solution (2 mL, 8 mmol, 4M in dioxane) was stirred at room temperature for 30 mins. The mixture was concentrated to give crude tittle compound (180 mg, 1.08 mmol, 100% yield) as a yellow oil as a hydrochloride salt, which was used directly in the next step without further purification. LC-MS: m / e 167(MH+).Step 7. 7V-(4-(4-fluoro-4-(2-(methyl-J3)propyl-2,3,3,3-6L)piperidine-l- carbonyl)phenyl)benzo[J]thiazole-4-sulfonamide (Cpd. 17, N232659-199).

[0170] A solution of CDI (116 mg, 0.714 mmol) and 4-(benzo[d]thiazole-4- sulfonamido)benzoic acid (240 mg, 0.718 mmol) in DMAc (2 mL) was stirred at room temperature for 2 hrs, then crude 4-fluoro-4-(2-(methyl-t / ?)propyl-2,3,3,3-t / 7)piperidine hydrochloride (180 mg, 1.08 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 2 hrs, diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18 250*21mm, 5 ~ 95% MeCN in H2O with 0.1% formic acid) to afford tittle compound (70 mg, 0.145 mmol, 13.4% yield) as a white solid.1HNMR (400 MHz, DMSO-d6 ) δ 10.76 (s, 1H), 9.65 (s, 1H), 8.50 (d, J= 8.0 Hz, 1H), 8.11 (d, J= 8.0 Hz, 1H), 7.64 (t, J= 8.0 Hz, 1H), 7.19 - 7.17 (m, 2H), 7.11 - 7.09 (m, 2H), 4.23 - 3.75 (m, 1H), 3.40 - 3.33 (m, 1H), 3.22 - 2.88 (m, 2H), 1.96 - 1.65 (m, 2H), 1.65 - 1.45 (m, 3H), 1.50-1.44 (m, 1H). LC-MS m e. 483 (MH+).Scheme 12Example 14. Synthesis of 7V-(4-(4-isobutylpiperidine-l- carbonyl)phenyl)benzo[d]thiazole-4-sulfonamide (Cpd. 6) (N232817-098).N232817-094 N232817-098Step 1: Synthesis of 4-isobutylpiperidine (N232817-094).

[0171] To a solution of 4-isobutylpyridine (300 mg, 2.22 mmol) in HCI solution (25 mL, 50 mmol, 2 M in MeOH) was added PtO2 (25 mg, 0.11 mmol) and stirred under 15 psi of H2 at room temperature for 16 hrs. The resulting mixture was filtered through a pad of Celite and the filter cake was washed with MeOH. The filtrate was concentrated to afford the title compound (300 mg, 95.7% yield) as a yellow oil. LC-MS m / e\ 142.2 (MH+).Step 2: Synthesis of 7V-(4-(4-isobutylpiperidine-l-carbonyl)phenyl)benzo[J]thiazole-4- sulfonamide (Cpd. 6) (N232817-098).

[0172] To a solution of 4-isobutylpiperidine (150 mg, 1.06 mmol) in MeCN (20 mL) were added 4-(benzo[d]thiazole-4-sulfonamido)benzoic acid (354 mg, 1.06 mmol), TCFH (531 mg, 2.12 mmol) and NMI (261 mg, 3.18mmol). The reaction mixture was stirred at room temperature for 1 hr, poured into water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18 250*21mm, 5 ~ 95% MeCN in H2O with 0.1% formic acid) to afford the title compound (75.2 mg, 15.5% yield) as a white solid. ‘H NMR (400 MHz, DMSO-d6 ) δ 10.73 (s, 1H), 9.65 (s, 1H), 8.49 (d, J= 8.0 Hz, 1H), 8.10 (d, J= 8.0 Hz, 1H), 7.64 (t, J= 8.0 Hz, 1H), 7.15 -7.13 (m, 2H), 7.10 - 7.08 (m, 2H), 4.60 - 4.09 (m, 1H), 3.56 - 3.38 (m, 1H), 3.00 - 2.62 (m, 2H), 1.70 - 1.45 (m, 4H), 1.06 - 1.04 (m, 2H), 1.03 - 0.95 (m, 2H), 0.83 (d, J= 8.0 Hz, 6H). LC-MS m / e: 458.1 (MH+).Scheme 13Example 15 Synthesis of 7V-(4-(4-(l,l-difluoro-2-methylpropyl)piperidine-l- carbonyl)phenyl)benzo[J|thiazole-4-sulfonamide (Cpd. 15) (N222310-392).N222310-390 N222310-392Step 1. Synthesis of 2-methyl-l-(pyridin-4-yl)propan-l-ol (N222310-386).

[0173] To a solution of isonicotinaldehyde (15 g, 140 mmol) in THF (150 mL) was added isopropylmagnesium chloride (105 mL, 210 mmol, 2 M in EfeO) at 0 °C. The resulting mixture was stirred at 20 °C for 3 hrs under N2 atmosphere, quenched with sat. NH4CI solution,the aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 8% EtOAc in PE) to afford the title compound (3.2 g, 21.2 mmol, 15.1% yield) as a light-yellow solid. LC-MS m / e'. 152 (MH+).Step 2. Synthesis of 2-methyl-l-(pyridin-4-yl) propan-l-one (N222310-387).

[0174] To a solution of 2-methyl-l-(pyridin-4-yl) propan- l-ol (3.2 g, 21.2 mmol) in DCE (40 mL) was added activated Mn02 (18.4 g, 212 mmol) at 25 °C and stirred at 80 °C for 18 hrs. The resulting mixture was cooled to room temperature, filtered through a pad of Celite and the filter cake was washed with DCE. The combined filtrate was concentrated to afford the title compound (3.00 g, 20.1 mmol, 95.0% yield) as a light-yellow solid. LC-MS m / e'. 150 (MH+).Step 3. Synthesis of 4-(l,l-difluoro-2-methylpropyl) pyridine (N222310-388).

[0175] To a solution of 2-methyl-l-(pyridin-4-yl) propan-l-one (272 mg, 1.82 mmol) in DCM (5 mL) were added tri ethylamine trihydrofluoride (882 mg, 5.47 mmol), XtalFluor-E (626 mg, 2.73 mmol) and EhN (368 mg, 3.64 mmol) at 0 °C. The mixture was stirred at 25 °C for 2 hrs under N2 atmosphere. Then the resulting mixture was diluted with DCM and washed with sat. NaHCCf solution. The aqueous layer was extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by reverse phase column chromatography to afford the title compound (90 mg, 0.526 mmol, 28.8% yield) as light-yellow solid. LC-MS m / e'. 172 (MH+).Step 4. Synthesis of 4-(l,l-difluoro-2-methylpropyl)piperidine (N222310-390).

[0176] To a solution of 4-(l,l-difluoro-2-methylpropyl) pyridine (90 mg, 0.526 mmol) in EtOH (10 mL) and cone. HC1 (1 mL) was added PtCL (36 mg) at 25 °C and stirred under 15 psi of H2 at 25°C for 2 hrs. The resulting mixture was filtered through a pad of Celite and the filter cake was washed with EtOH. The filtrate was concentrated to afford the title compound (84 mg, 0.474 mmol, 90.2% yield) as light-yellow solid. LC-MS m e. 178 (MH+).Step 5. Synthesis of 7V-(4-(4-(l,l-difluoro-2-methylpropyl)piperidine-l- carbonyl)phenyl)benzo[J]thiazole-4-sulfonaniide (Cpd. 15) (N222310-392).

[0177] To a solution of 4-(benzo[d]thiazole-4-sulfonamido)benzoic acid (150 mg, 0.449 mmol) in DMF (5 mL) were added HATU (256 mg, 0.673 mmol) and DIEA (174 mg, 1.35 mmol) and stirred for 10 mins. Then 4-(l,l-difluoro-2-methylpropyl)piperidine (80 mg, 0.449 mmol) was added and the reaction mixture was stirred at 25 °C for 2 hrs under N2atmosphere. The resulting mixture was poured into water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18 250*21mm, 5 ~ 95% MeCN in H2O with 0.1% formic acid) to afford the title compound (35 mg, 0.071 mmol, 15.8% yield) as a white solid. ’H NMR (400 MHz, DMSO- d6) 6 10.76 (s, 1H), 9.65 (s, 1H), 8.50 (d, J= 8.0 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.64 (t, J= 8.0 Hz, 1H), 7.18 - 7.16 (m, 2H), 7.12 - 7.10 (m, 2H), 4.47- 3.40 (m, 2H), 2.74 (m, 2H), 2.26 -2.05 (m, 2H), 1.75 - 1.70 (m, 2H), 1.22 (m, 2H), 0.94 (d, J = 4.0 Hz, 6H). LC-MS m / e: 494 (MH+).Scheme 14Example 16. Synthesis of \-(4-(4-(2.2-bis(melhyl-t / ?) propyl-3,3,3- ds) piperidine-1- carbonyl) phenyl) benzo[J|thiazole-4-sulfonamide (Cpd. 20) (N222307-468).N222302-471 N222307-468Step 1. Synthesis of 2-(methyl-< / 5)-l-(pyridin-4-yl)propan-l-one-3,3,3-< / 5 (N222307-476).

[0178] To a solution of l-(pyridin-4-yl)ethan-l-one (4.0 mL, 33.0 mmol) in toluene (50 mL) were added KOH (18.5 g, 330 mmol) and 18-Crown-6 (90 mg, 0.340 mmol) at 25 °C. Then CD3I (14.4 g, 99.1 mmol) was added at 0 °C under N2 atmosphere and the mixture was stirred at 25 °C for 4.5 hrs. The resulting mixture was concentrated under vacuum. Andpurified by silica gel column chromatography (gradient: 100% PE to 50% EtOAc in PE) to afford the title compound (1.2 g, 7.73 mmol, 23.5% yield) as a yellow oil. LC-MS m / e: 156(MH+).Step 2. Synthesis of 2,2-bis(methyl-< / 3)-l-(pyridin-4-yl) propan-l-one-3,3,3-^3 (N2 22302- 469).

[0179] To a solution of l-(pyridin-4-yl) propan-l-one-3,3,3-6?3 (2.6 g, 18.8 mmol) in anhydrous THF (100 mL) was added NaH (3.76 g, 94.2 mmol, 60% in mineral oil) portionwise at 0 °C under N2 atmosphere. The reaction mixture was stirred at 0 °C for 1 hr. After that, CD3I (13.7 g, 94.2 mmol) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 hr, quenched with sat. NH4CI solution and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 20% EtOAc in PE) to afford the title compound (2.1 g, 70% purity, 8.5 mmol, 45.2% yield) as a colorless oil. LC-MS m / e: 173(MH+).Step 3. Synthesis of 4-(2,2-bis(methyl-< / 3) propyl-3,3,3-^3)pyridine (N222302-470).

[0180] To a solution of 2,2-bis(methyl-t / 3)-l-(pyridin-4-yl) propan-l-one-3,3,3-6?3 (550 mg, 70% purity, 2.24 mmol) in ethylene glycol (5 mL) were added N2H4H2O (336 mg, 6.72 mmol, 80% purity) and KOH (251 mg, 4.48 mmol). After addition, the reaction mixture was stirred at 80 °C for 2 hrs and 180 °C for 5 hrs. The resulting mixture was cooled to room temperature, diluted with water and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 10% EtOAc in PE) to afford the title compound (250 mg, 1.58 mmol, 70.5% yield) as a yellow oil. LC-MS m / e: 159 (MH+).Step 4. Synthesis of 4-(2,2-bis(methyl-< / 3) propyl-3,3,3- ds) piperidine (N222302-471).

[0181] To a solution of 4-(2,2-bis(methyl-6?3) propyl-3,3,3- ds) pyridine (250 mg, 1.58 mmol) in EtOH (5 mL) and HC1 solution (5 mL, 6 M in water) was added PtO2 (50 mg). The reaction mixture was purged with H2 balloon for three times and stirred under H2 balloon at room temperature for 16 hrs. The resulting mixture was filtered through a pad of Celite and washed with EtOH. The filtrate was concentrated to afford the title compound (320 mg, 1.58 mmol, 100 % crude yield) as a white solid. LC-MS m / e: 165 (MH+).Step 5. Synthesis of N-(4-(4-(2,2-bis(methyl- < / 3)propyl-3,3,3- <fc)piperidine-l-car bonyl)phenyl)benzo[d]thiazole-4-sulfonamide (Cpd. 20) (N222307-468).

[0182] To a solution of 4-(benzo[d]thiazole-4-sulfonamido) benzoic acid (200 mg, 0.6mmol) in DMF (5 mL) were added HATU (273 mg, 0.72 mmol), EhN (0.34 mL, 2.4 mmol) and 4-(2,2-bis(methyl-6?3) propyl-3,3,3- di) piperidine (197 mg, 1.2 mmol) successively at 25 °C. The mixture was stirred at 25 °C for 1 hr and purified by prep-HPLC (YMC-Actus Triart C18 250*21mm, 5 ~ 95% MeCN in H2O with 0.1% formic acid) to afford the title compound (67.3 mg, 0.140 mmol, 23.4% yield) as a white solid. ’H NMR (400 MHz, DMSO4) 8 10.70 (s, 1H), 9.64 (s, 1H), 8.49 (d, J = 8.0 Hz, 1H), 8.10 (d, J= 8.0 Hz, 1H), 7.63 (t, J= 8.0 Hz, 1H), 7.15 - 7.08 (m, 4H), 4.50 - 4.25 (m, 2H), 3.0 - 2.81 (m, 2H), 1.73 - 1.45 (m, 3H), 1.12 - 0.95 (m, 4H). LC-MS m / e: 481 (MH+).Scheme 15Example 17. Synthesis of 7V-(4-(4-(2-cyclopropylpropan-2-yl)piperidine-l- carbonyl)phenyl)benzo[J|thiazole-4-sulfonamide (Cpd. 10) (N232850-171).Step 1. Synthesis of tert-butyl 4-(2-methylbut-3-en-2-yl) piperidine-l-carboxylate (N232850-130).

[0183] To a suspension of methyltriphenylphosphonium bromide (2.44 g, 6.84 mmol) in THF (30 mL) was added t-BuOK (770 mg, 6.84 mmol) at 0 °C and stirred at 0 °C for 30 mins. Then tert-butyl 4-(2-methyl-l-oxopropan-2-yl) piperidine-l-carboxylate (1.10 g, 4.56 mmol) was added at 0 °C. The resulting mixture was stirred at room temperature overnight, quenched with sat. NH4CI solution at 0 °C and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PEto 20% EtOAc in PE) to afford the title compound (880 mg, 3.68 mmol, 80.7 % yield) as a yellow oil. LC-MS m / e: 198 (MH+-56).Step 2. Synthesis of 4-(2-methylbut-3-en-2-yl) piperidine (N232850-138).

[0184] A solution of tert-butyl 4-(2-methylbut-3-en-2-yl) piperidine- 1 -carboxylate (880 mg, 3.68 mmol) in HC1 solution (20 mL, 80 mmol, 4 M in dioxane) was stirred at room temperature for 2 hrs. The mixture was concentrated to afford the title compound (528 mg, 3.43 mmol, 93.0 % yield) as a yellow oil, which was used directly without further purification. LC-MS m / e'. 154 (MH+).Step 3. Synthesis of (4-(2-methylbut-3-en-2-yl)piperidin-l-yl)(4-nitrophenyl)methanone (N232850-161).

[0185] To a solution of 4-(2-methylbut-3-en-2-yl) piperidine (250 mg, 1.63 mmol) and 4-nitrobenzoyl chloride (303 mg, 1.63 mmol) in DCM (lO mL) was added DIEA (422 mg, 3.27 mmol) at 0 °C. The mixture was stirred at room temperature overnight, diluted with water and the aqueous layer was extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 50% EtOAc in PE) to afford the title compound (400 mg, 1.32 mmol, 81.1% yield) as a yellow solid. LC-MS m / e'. 303 (MH+).Step 4. Synthesis of (4-(2-cyclopropylpropan-2-yl)piperidin-l-yl)(4- nitrophenyl)methanone (N232850-162).

[0186] To a solution of diiodomethane (1.68 g, 6.27 mmol) in DCM (10 mL).was added diethylzinc (6.27 mL, 6.27 mmol, 1 M in hexane) at 0 °C under N2 atmosphere. The mixture was stirred at 0 °C for 30 mins. Then (4-(2-methylbut-3-en-2-yl)piperidin-l-yl)(4- nitrophenyl)methanone (380 mg, 1.26 mmol) in DCM (1 mL) was added at 0 °C. The resulting mixture was warm to room temperature, stirred overnight and quenched with sat. NH4CI solution slowly at 0 °C. The aqueous layer was extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 50% EtOAc in PE) to afford the title compound (280 mg, crude, -10% purity) as a yellow solid. LC-MS m e. 317 (MH+).Step 5. Synthesis of (4-aminophenyl)(4-(2-cyclopropylpropan-2-yl)piperidin-l- yl)methanone (N232850-169).

[0187] To a solution of (4-(2-cyclopropylpropan-2-yl)piperidin-l-yl)(4- nitrophenyl)methanone (100 mg, 0.316 mmol) in MeOH (10 mL) was added Pd on activatedcarbon (10%) (wetted with ca. 55% water) (30 mg) and stirred under 15 psi of H2 at room temperature for 2 hrs. The resulting mixture was filtered through a pad of Celite and the filter cake was washed with MeOH. The filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 80% EtOAc in PE) to afford the title compound (55 mg, 0.192 mmol, 60.8% yield) as a light brown solid. LC-MS m / e-. 287 (MH+).Step 6. Synthesis of \-(4-(4-(2-cyclopropylpropan-2-yl)piperidine-l- carbonyl)phenyl)benzo[J|thiazole-4-sulfonamide (Cpd. 10) (N232850-171).

[0188] To a solution of benzo[d]thiazole-4-sulfonyl chloride (67 mg, 0.289 mmol) and((4-aminophenyl)(4-(2-cyclopropylpropan-2-yl)piperidin-l-yl)methanone (55 mg, 0.192 mmol) in THF (3 mL) was added pyridine (152 mg, 1.92 mmol) and stirred at room temperature for 2 hrs. The reaction mixture was quenched with water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep-HPLC (YMC-Actus Triart C18 250*21mm, 5 ~ 95% MeCN in H2O with 0.1% formic acid) to afford the title compound (22 mg, 0.044 mmol, 24.2% yield) as a white solid. ’H NMR (400 MHz, DMSO-d6 ) δ 10.80 (s, 1H), 9.64 (s, 1H), 8.49 (d, J= 8.0 Hz, 1H), 8.10 (d, J= 8.0 Hz, 1H), 7.64 (t, J= 8.0 Hz, 1H), 7.16 - 7.14 (m, 2H), 7.10 - 7.08 (m, , 2H), 4.67 - 4.07 (m, 1H), 3.81 - 3.45 (m, 1H), 3.04 - 2.63 (m, 2H), 1.79 - 1.56 (m, 2H), 1.39 - 1.27 (m, 1H), 1.19 - 1.00 (m, 2H), 0.62 (s, 6H), 0.60 - 0.55 (m, 1H), 0.28 - 0.18 (m, 2H), 0.14 - 0.08 (m, 2H). LC-MS m e. 484 (MH+).Scheme 16Example 18. Synthesis of 7V-(4-(2-(trifluoromethyl)-8-azaspiro[4.5]decane-8- carbonyl)phenyl)benzo[J|thiazole-4-sulfonamide (Cpd. 8) (N232661-226).Step 1. Synthesis of tert-butyl 2-hydroxy-2-(trifluoromethyl)-8-azaspiro[4.5]decane-8- carboxylate (N232661-220).

[0189] To a solution of tert-butyl 2-oxo-8-azaspiro[4.5]decane-8-carboxylate (1 g, 3.95 mmol) and TMSCF3 (2.25 g, 15.8 mmol) in THF (20 mL) was added TBAF (0.5 mL, 0.5 mmol, IM in THF) at 0 °C and stirred at 20 °C for 18 hrs under N2 atmosphere. The resulting mixture was partitioned between water and EtOAc, the aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 18% EtOAc in PE) to afford the title compound (1.2 g, 3.71 mmol, 94.0% yield) as a yellow oil. LC-MS m / c. 268 (MH+-56).Step 2. Synthesis of tert-butyl 2-(((methylthio)carbonothioyl)oxy)-2-(trifluoromethyl)-8- azaspiro[4.5]decane-8-carboxylate (N232661-221).

[0190] To a solution of tert-butyl 2-hydroxy-2-(trifluoromethyl)-8- azaspiro[4.5]decane-8-carboxylate (1.10 g, 3.40 mmol) in THF (20 mL) was added NaH (0.272 g, 6.80 mmol, 60% dispersion in mineral oil) portion-wise at 0 °C followed by adding CS2 (9 mL), and CH3I (9 mL, 110 mmol) at 0 °C. After addition, the mixture was stirred at 20 °C for 1 hr. The resulting mixture was partitioned between water rand EtOAc, the aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 10% EtOAc in PE) to afford the title compound (1.40 g, 3.38 mmol, 99.3% yield) as a yellow oil. LC-MS m e. 314 (MH+-100).Step 3. Synthesis of tert-butyl 2-(trifluoromethyl)-8-azaspiro[4.5]decane-8-carboxylate (N232661-223).

[0191] To a solution of tert-butyl 2-(((methylthio)carbonothioyl)oxy)-2- (trifluoromethyl)-8-azaspiro[4.5]decane-8-carboxylate (1.40 g, 3.61 mmol) and AIBN (122mg, 0.743 mmol) in toluene (20 mL) was added BuaSnH (6.49 g, 22.3 mmol) at 20 °C. The mixture was stirred at 80 °C for 2 hrs under N2 atmosphere, cooled to room temperature, poured into sat. KF solution and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 5% EtOAc in PE) to afford the title compound (0.564 g, 1.83 mmol, 49.4% yield) as a yellow oil. LC-MS m / e'. 252 (MH+-56).Step 4. Synthesis of 2-(trifluoromethyl)-8-azaspiro[4.5]decane (N232661-225).

[0192] A solution of tert-butyl 2-(trifluoromethyl)-8-azaspiro[4.5]decane-8- carboxylate (300 mg, 0.976 mmol) in HC1 solution (3 mL, 12 mmol, 4 M in EtOAc) was stirred at room temperature for 1 hr. The resulting mixture was concentrated under vacuum to afford the title compound (200 mg, 0.965 mmol, 98.8% yield) as a HC1 salt. The crude product was used directly in the next step without further purification. LC-MS m / e'. 208(MH+).Step 5. Synthesis of 7V-(4-(2-(trifluoromethyl)-8-azaspiro[4.5]decane-8- carbonyl)phenyl)benzo[J]thiazole-4-sulfonamide (Cpd. 8) (N232661-226).

[0193] To a solution of 4-(benzo[d]thiazole-4-sulfonamido) benzoic acid (150 mg, 0.449 mmol) in DMAc (3 mL) was added CDI (108 mg, 0.666 mmol) at 25 °C and stirred for 1 hr at 25 °C. Then 2-(trifluoromethyl)-8-azaspiro[4.5]decane (93.0 mg, 0.449 mmol) was added and stirred at 25°C for further 18 hrs. The resulting mixture was poured into water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by prep- HPLC (YMC-Actus Triart C18 250*21mm, 5 ~ 95% MeCN in H2O with 0.1% formic acid) to afford the title compound (44.3 mg, 0.094 mmol, 21.1% yield) as white solid.1HNMR (400 MHz, DMSO-d6 ) δ 10.74 (s, 1H), 9.64 (s, 1H), 8.49 (d, J = 8.0 Hz, 1H), 8.10 (d, J = 8.0 Hz, 1H), 7.64 (t, J= 8.0 Hz, 1H), 7.16 - 7.14 (m, 2H), 7.11 - 7.08 (m, 2H), 3.60 - 3.35 (m, 2H), 3.28 - 3.06 (m, 2H), 2.97 - 2.83 (m, 1H), 1.95 - 1.79 (m, 2H), 1.70 - 1.30 (m, 8H). LC-MS m e. 524(MH+).Scheme 17Example 19. Synthesis of 4-(benzo[d]thiazole-4-sulfonamido)-N-((3-fluoro-2- (trifluoromethyl)pyridin-4-yl)methyl)-N-methylbenzamide (Cpd. 2) (N222298-371).Step 1. Synthesis of 3-fluoro-N-methyl-2-(trifluoromethyl)isonicotinamide (N222298- 365).

[0194] To a solution of 3-fluoro-2-(trifluoromethyl)isonicotinic acid (50.0 g, 239 mmol) in DCM (350 mL) and DMF (0.35 g, 4.78 mmol) was added (COC1)2 (49.5 g, 251 mmol) dropwise at 0 °C. After addition, the reaction mixture was stirred at 25 °C for 2 hrs and concentrated to dryness. The residue was dissolved in DCM (350 mL) and added DIEA (92.5 g, 717 mmol) dropwise at 0 °C, then methanamine hydrochloride (20.2 g, 299 mmol) was added. The resulting mixture was stirred at 25 °C for 30 mins, poured into ice water, the aqueous layer was extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient: 100% PE to 50% EtOAc in PE) to afford the title compound (45.0 g, 202 mmol, 84.7% yield) as a yellow solid. LC-MS m / e\ 223 (MH+).Step 2. Synthesis of l-(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)-N-methylmethanamine (N222298-367).

[0195] To a solution of 3-fluoro-N-methyl-2-(trifluoromethyl) isonicotinamide (45.0 g,202 mmol) in THF (200 mL) was added BH3(3.04 L, 3.04 mol, 1 M in THF) at 20 °C and stirred at 70 °C for 48 hrs. After cooling, HC1 (3.0 L, 1 M in water) was added dropwise to the reaction mixture at 0 °C and stirred at room temperature for 1 hr. Then sat. Na2CO3solution was added to the resulting mixture, adjusted pH to 8~9 and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient, EtOAc: PE=1 : 1 to DCM: MeOH=10: l) to afford the title compound (20.0 g, 96.1 mmol, 47.4% yield) as a yellow oil. ’H NMR (400 MHz, DMSO-d6 ) δ 8.55 (d, J= 4.0 Hz, 1H), 7.88 - 7.85 (m, 1H), 3.82 (s, 2H), 3.42 -3 .33 (m, 1H), 2.30 (s, 3H). LC-MS m / e: 209 (MH+).Step 3. Synthesis of 4-(benzo[J]thiazole-4-sulfonaniido)-A-((3-fluoro-2- (trifluoromethyl)pyridin-4-yl)methyl)-7V-methylbenzamide (Cpd. 2) (N222298-371).

[0196] To a solution of l-(3-fluoro-2-(trifluoromethyl)pyridin-4-yl)-7V-methylmethanamine (23.8 g, 114 mmol), 4-(benzo[d]thiazole-4-sulfonamido)benzoic acid (35.0 g, 104 mmol) and EhN (12.6 g, 125 mmol) in DMF (100 mL) was added HATU (47.4 g, 125 mmol) in portions. After addition, the reaction mixture was stirred at 20 °C for 30 mins, poured into ice water and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel column chromatography (gradient, 100% DCM to 10% MeOH in DCM) and then recrystallized with EtOAc to afford the title compound (32.0 g, 61.0 mmol, 58.6% yield) as a white solid. U NMR (400 MHz, DMSO-d6 ) δ 10.81 (s, 1H), 9.65 (s, 1H), 8.52 - 8.48 (m, 2H), 8.12 (d, J = 8.0 Hz, 1H), 7.66 -7 .62 (m, 2H), 7.40 - 7.32 (m, 2H), 7.15 - 7.13 (m, 2H), 4.73 (s, 2H), 2.90 (s, 3H). LC-MS m / e: 525 (MH+).Example 20: Biochemical AssaysBiochemical AC 50 Protocol

[0197] Compounds herein were evaluated by a PKM2 activation assay. Reagent concentrations are shown in Table 2 below.Table 2: PKM2 AC50 reagent concentrations.

[0198] Compounds were added to a 384-well plate (Corning 3640) using an Echo liquid handler. The top concentration tested was 30 pM and diluted by a factor of 1 / 3 with 11 concentrations tested for each compound. All reagents were mixed except for ADP and added to the wells. The plate was incubated for 1 hour at room temperature, and the assay was initiated with ADP. The final reaction volume was 50 pL and the final DMSO concentration was 1%. The NADH absorbance was measured at 340 nm for 30 minutes at room temperature. Initial rates were determined from the first 10 minutes of the kinetic read. Initial rates were determined from the first 10 minutes of the read, converted to umol / sec / g, and normalized to 10 uM an internal control (mitapivat). The data was fit with a 4-parameter dose response fit. AC 50 ais reported for this assay.A549 Cell-based Viability Assay Protocol (IC50)

[0199] A luminescence assay (CellTiter-Glo 2.0 Assay from Promega) was used to assess the effect of our compounds on the viability of A549 cells that were cultured under low serine media conditions. For routine culture, A549 cells were grown in 10cm dish in a humidified incubator (37 °C, 5% CO2) with RPMI 1640 + 2mM glutamine+ 10% heat- inactivated FBS+ 1% penicillin / streptomycin and passaged twice per week at 80-90% confluence. For passaging cells, the cell monolayer was washed one time with 10ml DPBS (without calcium and magnesium), and then 3ml of 0.25% Trypsin-EDTA was added for 5min (dish was kept in the incubator) which was neutralized with 6ml of growth medium. Cells were harvested and diluted to 2xl04cells / ml for dispensing lOOul / well into 96-well black-wall, clear flat bottom plates (2,000 cells / well).

[0200] After overnight incubation, the cells were first washed one time with 200ul / well of the assay medium (Basal Medium Eagle+ 10% dialyzed FBS+ 2mM glutamine+ 1% penicillin / streptomycin+ L-alanine / L-proline / L-asparagine / L-aspartic acid / L-glutamic acid 100uM / each+ 150uM L-Glycine+ 4.5 g / L glucose final concentration) and then lOOul of assay medium was added to the wells. Compounds were dosed using D300e Tecan instrument, starting from luM top concentration and generating a 10-point dose response with 4-fold dilution. All wells were normalized to 0.1% DMSO final concentration and DMSO controls were included in each plate. After a 72-hour incubation in a humidified incubator (37 °C, 5% CO2), CTG assay was performed according to manufacturer: the plate was kept at room temperature for 30min, lOOul of CTG reagent was added per well, shaking for 2min at 800rpm, kept in the dark at room temperature for another lOmin, and endpoint luminescence measurement was acquired on a BioTek Synergy Neo2 plate reader. Each time that this assay was performed there was an extra plate (TOh time point), that was read at the time of dosingcompounds, and the luminescence signal at 72hours was divided by the signal at TOh time point (autoscale was chosen for TO and the same gain was used for the other plates). IC50 values were determined from a 4-parameter logistic fit of compound concentration-response curves.Table 3: Reagent information for PKM2 cell viability assayA549 cell-based LDH-coupled PKM2 activity assay protocol (AC50)

[0201] PKM2 activity was assessed with an LDH-coupled assay. For routine culture, A549 cells were grown in 10cm dish in a humidified incubator (37 °C, 5% CO2) with RPMI 1640 + 2mM glutamine+ 10% heat-inactivated FBS+ 1% penicillin / streptomycin and passaged twice per week at 80-90% confluence. For passaging cells, the cell monolayer was washed one time with 10ml DPBS (without calcium and magnesium), and then 3ml of 0.25% Trypsin- EDTA was added for 5 minutes (dish was kept in the incubator) which was neutralized with 6ml of growth medium. Cells were harvested and diluted to 20xl04cells / ml for dispensing lOOul / well into 96-well clear-wall, clear flat bottom plates (20,000 cells / well). After overnight incubation, the media was aspirated and lOOul of pre-warmed media containing RPMI 1640 without phenol red, 10% FBS, and 2mM glutamine was added to the wells. Compounds were dosed using D300e Tecan instrument, starting from lOuM top concentration and generating a 10-point dose response with 3-fold dilution. DMSO controls and reference compound controls (reference compound at lOuM) were included in each plate. After a one-hour treatment, cells were washed one time with ice-cold PBS (200 ul / well), lysed with 100 ul / well of Triton X-100 lysis buffer on ice for 15min, and shaken for 5min. During that period, a PK assay mastermixwas prepared (Table 4) and 170ul / well was added to a new 96-well clear flat bottom plate, in which lOul of the cell lysate was added. The plate was incubated at room temperature for lOmin and 20ul / well of ADP solution (7mM stock ADP solution, final concentration in reaction was 0.7mM) was added to initiate the reaction. The absorbance was monitored at 340nm for 30min, reading every 30sec. Protein concentrations were determined by using BCA protein assay kit and following manufacturer’s instructions. Initial rates were determined from the first 10 minutes of the read, converted to umol / sec / g, and normalized to 10 uM an internal control (mitapivat). The data was fit with a 4-parameter dose response fit. AC50 is reported for this assay.Table 4: PK assay mastermixTable 5: Reagent information for PKM2 activity assayOligomerization Assay Protocol

[0202] Compounds herein were evaluated by a PKM2 oligomerization assay. Reagent concentrations are shown in Table 6 below.Table 6: PKM2 oligomerization reagent concentrations.

[0203] The PKM2 enzyme was diluted the into the assay buffer, the final concentrations are noted in the table above. The diluted enzyme stock was transferred to a 96- well plate (transferred 99 pL). The PKM2 activators were added to each well (1 pL of a 1 mM stock in DMSO). The final DMSO concentration was 1%. The plate was incubated at room temperature overnight. The samples were run on an Agilent 1260 HPLC equipped with a Bio SEC-3 HPLC column (300 x 7.8 mm, 3 pm particle size and 300 A pore size) and a UV and fluorescence detector. PKM2 oligomers were separated on the SEC column, and tryptophan fluorescence (absorbance 295 nm, emission 350 nm) was used to detect PKM2. The percent tetramer was calculated by determining the area of the tetramer peak, divided by the total area corresponding to tetrameric, dimeric and monomeric form of PKM2.Biochemical Data Summary

[0204] PKM2 activation was investigated by the biochemical and oligomerization assays, the results for which are depicted in Table 7 below. PKM2 Biochemical AC50 legend: + (AC50 > 0.075 pM); ++ (0.075 pM > AC50 > 0.055 pM); +++ (AC50 < 0.055 pM). PKM2 A549 Cell-Based IC50 legend: + (IC50 > 0.03 pM); ++ (0.03 pM > IC50 > 0.015 pM); +++ (IC50 < 0.015 pM). PKM2 A549 Cell-Based LDH-Coupled AC50 legend: + (AC50 > 0.5 pM); ++ (0.5 pM > AC50 > 0.3 pM); +++ (IC50 < 0.3 pM). Oligomerization assay (reported as PKM2 tetramer formation percentage) legend: + (PKM2 Tetramer % < 60% or undetectable); ++ (60% < PKM2 Tetramer % < 70%); +++ (PKM2 Tetramer % > 70%).Table 7: AC50 and oligomerization assay results.Example 22: Pharmacokinetic Studies

[0205] A pharmacokinetic study was performed using male C57BL / 6J mice (7-9 weeks of age, overnight fasted) to investigate the brain and plasma concentrations of compounds herein. Animals were dosed orally by gavage using the vehicles described in Table 8. Plasma and brain concentrations of the compound were monitored and select derived pharmacokinetic (PK) parameters are shown in Table 9 below.Table 8: Pharmacokinetic study vehicles by compound.Table 9: Select derived PK parameters

[0206] From these PK results, it was observed that all compounds were detected in the brain, with the exception of control compound 160 having a hydrophilic -OH group on its piperidine moiety. Compound 160 concentration in the brain was BLQ (below the lower limit of quantitation (LLOQ)). FIG. 1 depicts an exemplary plot of plasma concentration in the plasma vs. brain at 1 and 3 hours post-administration. As shown by these results, several compounds exhibited excellent brain penetration indicating applicability to neurological and neurodegenerative diseases, as well as other central nervous system and / or PKM2-associated diseases.Example 23: Compound evaluation in MOG35-55 induced EAE in C57BL / 6j mice

[0207] Experimental autoimmune encephalomyelitis (EAE) is a CD4+T cell-mediated autoimmune disease characterized by perivascular CD4+T cell and mononuclear cell inflammation and subsequent primary demyelination of axonal tracks in the central nervous system (CNS), leading to progressive hind-limb paralysis. For the description of the EAE model, please see Angiari et al. “Pharmacological Activation of Pyruvate Kinase M2 Inhibits CD4+ T Cell Pathogenicity and Suppresses Autoimmunity” Cell Metabolism 2020, 31, 391- 405.

[0208] The objective of this study was to evaluate the efficacy of test compound on MOG33-55 induced EAE in female C57BL / 6j mice.

[0209] Experimental autoimmune encephalomyelitis (EAE) is a CD4+T cell-mediated autoimmune disease characterized by perivascular CD4+T cell and mononuclear cell inflammation and subsequent primary demyelination of axonal tracks in the central nervous system (CNS), leading to progressive hind-limb paralysis.Materials and MethodsConsumables and Equipment

[0210] The following listing of consumables and equipment were utilized:Experimental autoimmune encephalomyelitis (EAE) is a CD4+T cell-mediated autoimmune diseaseSyringe: Shanghai Misawa Medical Industry Co., Ltd; CFDSM Certified No. (2011)3151258Ultra-Fine needle syringe: 0.5ml, 29G; BD, USA; REF#320312Balance: QUINTIX2102-1CN; SAIDUOLISISonicator: IKA, ULTRA-TURRAXCentrifuge: Eppendorf 5810Vortex Genius 3: IKA®, DN-201Dispersing machine (IKA, ULTRA-TURRAX)18 G needle and 25 G needleReagentsTable 10: Reagent listingFormulation PreparationPreparation of Complete Freund’s adjuvant (CFA)

[0211] Accurately weighed out 65.38 mg of Mycobacterium Tuberculosis H37Ra (Purity>100%) into a vial, and then added 8.173 ml of incomplete Freund’s adjuvant (IF A), vortex to get a final concentration solution of M. tuberculosis was 8mg / ml.Preparation of MOG33-35

[0212] Accurately weighed out 20mg of MOG35-55 (Purity>95.6%) a vial, and then added 6.37ml of saline, vortex to get a final concentration solution of MOG35-55 was 3mg / ml.Preparation of Emulsion of MOG35-55

[0213] Mixed 6.37ml CFA with 6.37ml MOG35-55 solution in 20ml glass vial. Repeatedly drawing up and expelling the mixture using a 25-G needle attached to a 10-ml syringe, dispersed on ice on a dispersing machine for lOmin on ice, sonicate on ice for 20 sec x 3 times with 3 sec interval on a sonicator.Preparation of PTX

[0214] 2hrs and 48hrs after MOG35 -55 emulsion injection, animals in model groups received an i.p. injection of PTX at a volume of lOOpl (200ng / per animal, PTX stock solution: 2mg / ml in sterile PBS).Preparation of FTY720

[0215] FTY720: dosing level, 1 mg / kg; concentration, 0.1 mg / mL; dosing volume, 10 mL / kg.

[0216] Accurately weighed out Img of FTY720, and added into 10 ml of dd water, vertex to mix well. Final concentration was O. lmg / ml. Formulations were freshly prepared daily.Preparation of Cpd. 3

[0217] Cpd. 3: MW 475.60, FW 513.70, Purity 99.89%

[0218] Cpd. 3: dosing level, 100 mg / kg; concentration, 10 mg / mL; dosing volume, 10 mL / kg. Accurately weighed out 70 mg of Cpd. 3, and added into 6.47 ml of PEG300, stirred 20 minutes at 1700 rpm at 37°C on a Magnetic Stirrer to get the final formulation (clear solution). Final concentration was 10 mg / ml. Formulations were freshly prepared and dosed within four hours after formulation are prepared.

[0219] Cpd. 3: dosing level, 300 mg / kg; concentration, 30 mg / mL; dosing volume, 10 mL / kg. Accurately weighed out 210 mg of Cpd. 3, and added into 6.47 ml of PEG300, stirred20 minutes at 1700 rpm at 37°C on a Magnetic Stirrer to get the final formulation (clear solution). Final concentration was 30 mg / ml. Formulations were freshly prepared and dosed within four hours after formulation are prepared.Animals

[0220] C57BL / 6j mice (female, 9-10 weeks old) were purchased from GEMPHARMATECH. All the in vivo experimental procedures were approved by the institutional animal care and use committee (IACUC) at HDB. All euthanasia was performed using carbon dioxide inhalation and all efforts were made to minimize animal suffering. The AUF number for this study at HDB is 131.Results

[0221] The compounds herein are brain penetrant PKM2 activators with enhanced pharmacokinetic (PK) properties, leading to sufficient brain exposure to activate PKM2, while maintaining good safety profiles in rodents. This opens avenues for new neurodegenerative indications characterized by astrocyte reactivity. In MS, a demyelinating autoimmune neurodegenerative condition affecting the brain and spinal cord, reactive astrocytes are thought to contribute to neuronal damage via impaired glutamate uptake, evidenced by increased glutamate levels in postmortem patient tissue analysis.

[0222] The PKM2 activator compounds have been tested in a mouse model of MS, the experimental autoimmune encephalomyelitis (EAE) model. Exemplary results for Cpd. 3 are presented herein. This model was developed by immunizing female C57 / BL6 mice against myelin-derived antigen (MOG35-55). Injection of MOG35-55 peptide with Complete Freund’s Adjuvant (CFA) and pertussis toxin (PTx) on a defined schedule led to a characteristic T cell-mediated autoimmune disease with key pathologic features such as neuroinflammation and white matter demyelination. Cpd. 3 was administered via bi-daily gavage between 9 and 10 weeks of age, for a total of 31 days. Body weight and clinical score were measured daily (FIG. 2A). Treatment with lead PKM2 activator significantly improved clinical score, in a dose-dependent manner (FIG. 2B). Treatment was well tolerated in mice, as highlighted by comparable improvements in the body weights of treatment and vehicle groups (FIG. 2C). After treatment for 31 days, mice were euthanized for tissue extraction. Spinal cord sections from these mice were prepared and stained for GFAP. Compared to naive mice, EAE mice showed extensive astrogliosis, while mice treated with PKM2 activator showed a significant dose-dependent decrease in GFAP-positive area (FIG. 2D-1, FIG. 2D-2).

[0223] These results provide an indication that the brain penetrant PKM2 activators herein are effective for neurologic / neurodegenerative and other CNS diseases associated with PKM2 activity, such as multiple sclerosis and amyotrophic lateral sclerosis.Example 24: hTDP43 ANLS Mouse Model Study

[0224] An 8-week bi-daily oral gavage dosing of the PKM2 activators at lOOmpk in the hTDP43 ANLS mouse model is performed. This treatment is prophylactic, starting treatment on the same day as low doxycycline (Low Dox) diet. Clinical assessments are performed three times per week. To further investigate PKM2’s role in astrogliosis, GFAP in the brain and spinal cords of these mice is stained for. In addition, we request tissue collection for drug exposure and exploratory biomarker analysis is performed in accordance with Table 11 below.Table 11. Description of prophylactic study with PKM2 activator at 300mpk compared to vehicle, in the hTDP43 ANLS mouse model.

[0225] Throughout this application, various publications are referenced by author name and date, or by patent number or patent publication number. The disclosures of these publications are hereby incorporated in their entireties by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the dateof the invention described and claimed herein. However, the citation of a reference herein should not be construed as an acknowledgement that such reference is prior art to the present invention.

[0226] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, numerous equivalents to the specific procedures described herein. Such equivalents are considered to be within the scope of this invention and are covered by the following claims. For example, pharmaceutically acceptable salts other than those specifically disclosed in the description and Examples herein can be employed. Furthermore, it is intended that specific items within lists of items, or subset groups of items within larger groups of items, can be combined with other specific items, subset groups of items or larger groups of items whether or not there is a specific disclosure herein identifying such a combination.

Claims

CLAIMSWhat is claimed is:

1. A compound according to Formula II:Formula II including pharmaceutically acceptable salts thereof, whereinR1is -H, halogen, C1-C3 alkyl, saturated or unsaturated, or C1-C3 haloalkyl, saturated or unsaturated, andR2is C1-C8 alkyl, saturated or unsaturated, C3-C6 cycloalkyl, saturated or unsaturated, phenyl, or C5-C6 heteroaryl, said C3-C6 cycloalkyl, phenyl, and C5-C6 heteroaryl optionally connected through C1-C3 alkylene, saturated or unsaturated, said C1-C8 alkyl, C3-C6 cycloalkyl, phenyl, and C1-C3 alkylene unsubstituted, monosubstituted, or polysubstituted with R6; or R1and R2together form C3-C5 cycloalkyl, saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted with R6;L is -X-NR5-SO2-Y- or -X-SO2-NR5-Y-;X and Y are independently absent to form a single bond or X and Y are independently selected from methylene and ethylene;R5is -H or C1-C3 alkyl;A is C6-C14 heterocycle, unsubstituted, monosubstituted, or polysubstituted with R6and / or C1-C6 heteroalkyl, saturated or unsaturated;R6is independently at each occurrence selected from the group consisting of halogen, C1-C6 alkyl, saturated or unsaturated, C1-C6 haloalkyl, saturated or unsaturated, and C3-C5 cycloalkyl, saturated or unsaturated, said C3-C5 cycloalkyl unsubstituted, monosubstituted, or polysubstituted with halogen or C1-C3 haloalkyl.

2. A compound according to claim 1, wherein R1is -H.

3. A compound according to claim 1, wherein R1is -F.

4. A compound according to claim 1, wherein R1is methyl.

5. A compound according to claim 1, wherein R1is trifluoromethyl (-CF3), difluoromethyl (-CF2H), or fluoromethyl (-CH2F).

6. A compound according to any one of claim 1 to 5, wherein R2is cyclopropyl or cyclobutyl optionally connected through C1-C3 alkylene, said cyclopropyl or cyclobutyl unsubstituted, monosubstituted, or polysubstituted with methyl and / or -F.

7. A compound according to any one of claims 1 to 5, wherein R2is C1-C6 alkyl, optionally comprising a tertiary or quaternary carbon atom.

8. A compound according to claim 7, wherein said tertiary or quaternary carbon atoms respectively comprise isopropyl or tert-butyl groups, optionally fully or partially deuterated.

9. A compound according to any one of claims 1 to 5, wherein R2is phenyl, optionally connected through C1-C3 alkylene, said phenyl unsubstituted, monosubstituted, or polysubstituted with -F and / or Ci haloalkyl.

10. A compound according to any one of claims 1 to 5, wherein R2is C5-C6 heteroaryl, optionally connected through C1-C3 alkylene, said C5-C6 heteroaryl unsubstituted, monosubstituted, or polysubstituted with -F and / or Ci haloalkyl.

11. A compound according to claim 1, wherein R1and R2together form a spiro C3-C5 cycloalkyl, unsubstituted, monosubstituted, or polysubstituted with -F and / or Ci haloalkyl.

12. A compound according to any one of claims 1 to 11, wherein X and Y are absent to form single bonds and L comprises -NR5-SO2- or -SO2-NR5-, optionally wherein R5is -H.

13. A compound according to any one of claims 1 to 12, wherein A is C9-C10 heteroaryl.

14. A compound according to claim 13, wherein said C9-C10 heteroaryl is a fused bicyclic selected from:wherein RNis -H or C1-C3 alkyl, and wherein said C9-C10 heteroaryl is unsubstituted, monosubstituted, or di substituted with R6.

15. A compound according to any one of claims 1 to 14, wherein A isA compound according to any one of claims 1 to 15, wherein17. A compound or pharmaceutically acceptable salt thereof, selected from the group consisting of:Formula III including pharmaceutically acceptable salts thereof, where one of the dashed bonds to Z or T represents a single bond and the other represents a double bond, wherein:R1is -H, halogen, C1-C3 alkyl, saturated or unsaturated, or C1-C3 haloalkyl, saturated or unsaturated, andR2is C1-C8 alkyl, saturated or unsaturated, C3-C6 cycloalkyl, saturated or unsaturated, phenyl, or C5-C6 heteroaryl, said C3-C6 cycloalkyl, phenyl, and C5-C6 heteroaryl optionally connected through C1-C3 alkylene, saturated or unsaturated, said C1-C8 alkyl, C3-C6 cycloalkyl, phenyl, and C1-C3 alkylene unsubstituted, monosubstituted, or polysubstituted with R6; or R1and R2together form C3-C5 cycloalkyl, saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted with R6;R5is, independently at each occurrence, -H or C1-C3 alkyl;Q is independently, at each occurrence, N, CH, or C(R6); wherein one of Z and T to which a double bond is connected is N, CH, or C(R6); wherein the other of Z and T to which a single bond is connected is CH=CH, C(R6)=CH, C(R6)=C(R6), N=CH, N=C(R6), S, O, N(R5), CH2, CH-R6, or C(R6)2; andR6is independently at each occurrence selected from the group consisting of halogen, C1-C6 alkyl, saturated or unsaturated, C1-C6 haloalkyl, saturated or unsaturated, and C3-C5 cycloalkyl, saturated or unsaturated, said C3-C5 cycloalkyl unsubstituted, monosubstituted, or polysubstituted with halogen or C1-C3 haloalkyl.

19. A compound according to claim 18, according to Formula Ill-ii :Formula Ill-ii.

20. A compound according to claim 19, wherein the ring comprising T and Z is a 5- membered ring, wherein Z is S, O, N(R5), CH2, CH-R6, or C(R6)2, and wherein T is N, CH, or C(R6).

21. A compound according to claim 20, wherein T is N and Z is S.

22. A compound according to any one of claims 18 to 21, wherein Q is, at each occurrence, CH.

23. A compound according to Formula IVFormula IV including pharmaceutically acceptable salts thereof, wherein:R1is -H, halogen, C1-C3 alkyl, saturated or unsaturated, or C1-C3 haloalkyl, saturated or unsaturated, andR2is C1-C8 alkyl, saturated or unsaturated, C3-C6 cycloalkyl, saturated or unsaturated, phenyl, or C5-C6 heteroaryl, said C3-C6 cycloalkyl, phenyl, and C5-C6 heteroaryl optionally connected through C1-C3 alkylene, saturated or unsaturated, said C1-C8 alkyl, C3-C6 cycloalkyl, phenyl, and C1-C3 alkylene unsubstituted, monosubstituted, or polysubstituted with R6; or R1and R2together form C3-C5 cycloalkyl, saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted with R6; andR6is independently at each occurrence selected from the group consisting of halogen, C1-C6 alkyl, saturated or unsaturated, C1-C6 haloalkyl, saturated or unsaturated, and C3-C5 cycloalkyl, saturated or unsaturated, said C3-C5 cycloalkyl unsubstituted, monosubstituted, or polysubstituted with halogen or C1-C3 haloalkyl.

24. A compound according to any one of claims 18 to 23, wherein R1is -H.

25. A compound according to any one of claims 18 to 23, wherein R1is -F.

26. A compound according to any one of claims 18 to 23, wherein R1is methyl.

27. A compound according to any one of claims 18 to 23, wherein R1is trifluoromethyl (-CF3), difluoromethyl (-CF2H), or fluoromethyl (-CH2F).

28. A compound according to any one of claims 18 to 27, wherein R2is cyclopropyl or cyclobutyl optionally connected through C1-C3 alkylene, said cyclopropyl or cyclobutyl unsubstituted, monosubstituted, or polysubstituted with methyl and / or -F.

29. A compound according to any one of claims 18 to 27, wherein R2is C1-C6 alkyl, optionally comprising a tertiary or quaternary carbon atom.

30. A compound according to claim 29, wherein said tertiary or quaternary carbon atoms respectively comprise isopropyl or tert-butyl groups, optionally fully or partially deuterated.

31. A compound according to any one of claims 18 to 27, wherein R2is phenyl, optionally connected through C1-C3 alkylene, said phenyl unsubstituted, monosubstituted, or polysubstituted with -F and / or Ci haloalkyl.

32. A compound according to any one of claims 18 to 27, wherein R2is C5-C6 heteroaryl, optionally connected through C1-C3 alkylene, said C5-C6 heteroaryl unsubstituted, monosubstituted, or polysubstituted with -F and / or Ci haloalkyl.

33. A compound according to any one of claims 18 to 23, wherein R1and R2together form a spiro C3-C5 cycloalkyl, unsubstituted, monosubstituted, or polysubstituted with -F and / or Ci haloalkyl.

34. A PKM2 activator compound having the following structure:, including pharmaceutically acceptable salts thereof.

35. A PKM2 activator compound having the following structure:, including pharmaceutically acceptable salts thereof.

36. A PKM2 activator compound having the following structure:, including pharmaceutically acceptable salts thereof.

37. A method of treating a neurological or neurodegenerative disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 36.

38. The method of claim 37, wherein the neurological or neurodegenerative disorder is selected from alpha-synucleinopathies, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson’s disease, Huntington’s disease, stroke, Alzheimer’s disease, neuroinflammation, and Lewy body dementia.

39. The method of claim 38, wherein the neurological or neurodegenerative disorder is multiple sclerosis (MS).

40. The method of claim 38, wherein the neurological or neurodegenerative disorder is amyotrophic lateral sclerosis (ALS).

41. A method of treating a CNS disorder associated with PKM2 in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 36.

42. The method of any one of claims 37 to 41, wherein the therapeutically-effective amount is a dosage ranging from about 1 mg to about 1000 mg.

43. The method of claim 42, wherein the dose is administered once daily, twice daily, thrice daily, once every other day, once every two days, once weekly, or twice weekly.

44. A pharmaceutical composition comprising one or more PKM2 activator compounds according to any one of claims 1 to 36, and a pharmaceutically acceptable carrier.

45. A pharmaceutical composition according to claim 44, wherein the composition is formulated as a unit dosage containing from about 1 mg to about 1000 mg of PKM2 activator compound.

46. A method for treating amyotrophic lateral sclerosis, comprising administering to a subject in need thereof a pharmaceutically acceptable amount of a brain penetrant PKM2 activator or a pharmaceutical composition thereof.

47. The method of claim 46, wherein the brain penetrant PKM2 activator is a compound according to Formula II:Formula II including pharmaceutically acceptable salts thereof, whereinR1is -H, halogen, C1-C3 alkyl, saturated or unsaturated, or C1-C3 haloalkyl, saturated or unsaturated, andR2is C1-C8 alkyl, saturated or unsaturated, C3-C6 cycloalkyl, saturated or unsaturated, phenyl, or C5-C6 heteroaryl, said C3-C6 cycloalkyl, phenyl, and C5-C6 heteroaryl optionally connected through C1-C3 alkylene, saturated or unsaturated, said C1-C8 alkyl, C3-C6 cycloalkyl, phenyl, and C1-C3 alkylene unsubstituted, monosubstituted, or polysubstituted with R6; or R1and R2together form C3-C5 cycloalkyl, saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted with R6;L is -X-NR5-SO2-Y- or -X-SO2-NR5-Y-;X and Y are independently absent to form a single bond or X and Y are independently selected from methylene and ethylene;R5is -H or C1-C3 alkyl;A is C6-C14 heterocycle, unsubstituted, monosubstituted, or polysubstituted with R6and / or C1-C6 heteroalkyl, saturated or unsaturated;R6is independently at each occurrence selected from the group consisting of halogen, C1-C6 alkyl, saturated or unsaturated, C1-C6 haloalkyl, saturated or unsaturated, and C3-C5 cycloalkyl, saturated or unsaturated, said C3-C5 cycloalkyl unsubstituted, monosubstituted, or polysubstituted with halogen or C1-C3 haloalkyl.

48. The method of claim 46, wherein the brain penetrant PKM2 activator is a compound according to Formula III:Formula III including pharmaceutically acceptable salts thereof, where one of the dashed bonds to Z or T represents a single bond and the other represents a double bond, wherein:R1is -H, halogen, C1-C3 alkyl, saturated or unsaturated, or C1-C3 haloalkyl, saturated or unsaturated, andR2is C1-C8 alkyl, saturated or unsaturated, C3-C6 cycloalkyl, saturated or unsaturated, phenyl, or C5-C6 heteroaryl, said C3-C6 cycloalkyl, phenyl, and C5-C6 heteroaryl optionally connected through C1-C3 alkylene, saturated or unsaturated, said C1-C8 alkyl, C3-C6 cycloalkyl, phenyl, and C1-C3 alkylene unsubstituted, monosubstituted, or polysubstituted with R6; or R1and R2together form C3-C5 cycloalkyl, saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted with R6;R5is, independently at each occurrence, -H or C1-C3 alkyl;Q is independently, at each occurrence, N, CH, or C(R6); wherein one of Z and T to which a double bond is connected is N, CH, or C(R6);wherein the other of Z and T to which a single bond is connected is CH=CH, C(R6)=CH, C(R6)=C(R6), N=CH, N=C(R6), S, O, N(R5), CH2, CH-R6, or C(R6)2; andR6is independently at each occurrence selected from the group consisting of halogen, C1-C6 alkyl, saturated or unsaturated, C1-C6 haloalkyl, saturated or unsaturated, and C3-C5 cycloalkyl, saturated or unsaturated, said C3-C5 cycloalkyl unsubstituted, monosubstituted, or polysubstituted with halogen or C1-C3 haloalkyl.

49. The method of claim 46, wherein the brain penetrant PKM2 activator is a compound according to Formula IV:Formula IV including pharmaceutically acceptable salts thereof, wherein:R1is -H, halogen, C1-C3 alkyl, saturated or unsaturated, or C1-C3 haloalkyl, saturated or unsaturated, andR2is C1-C8 alkyl, saturated or unsaturated, C3-C6 cycloalkyl, saturated or unsaturated, phenyl, or C5-C6 heteroaryl, said C3-C6 cycloalkyl, phenyl, and C5-C6 heteroaryl optionally connected through C1-C3 alkylene, saturated or unsaturated, said C1-C8 alkyl, C3-C6 cycloalkyl, phenyl, and C1-C3 alkylene unsubstituted, monosubstituted, or polysubstituted with R6; or R1and R2together form C3-C5 cycloalkyl, saturated or unsaturated, unsubstituted, monosubstituted, or polysubstituted with R6; andR6is independently at each occurrence selected from the group consisting of halogen, C1-C6 alkyl, saturated or unsaturated, C1-C6 haloalkyl, saturated or unsaturated, and C3-C5 cycloalkyl, saturated or unsaturated, said C3-C5 cycloalkyl unsubstituted, monosubstituted, or polysubstituted with halogen or C1-C3 haloalkyl.

50. The method of claim 46, wherein the brain penetrant PKM2 activator is selected from the group consisting of:

51. The method of claim 46, wherein the brain penetrant PKM2 activator is, including pharmaceutically acceptable salts thereof.

52. The method of claim 46, wherein the brain penetrant PKM2 activator is, including pharmaceutically acceptable salts thereof.

53. The method of claim 46, wherein the brain penetrant PKM2 activator is, including pharmaceutically acceptable salts thereof.

54. The method of any one of claims 46 to 53, wherein the brain penetrant PKM2 activator, pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof is administered in a dose from about 1 mg to about 1000 mg.

55. The method of any one of claims 46 to 54, wherein the brain penetrant PKM2 activator, pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof is administered once daily, twice daily, every other day, every third day, every fourth day, every fifth day, every sixth day, weekly, biweekly, or monthly.

56. A compound according to Formula V:Formula V including pharmaceutically acceptable salts thereof, where one of the dashed bonds to Z or T represents a single bond and the other represents a double bond, wherein:R5is, independently at each occurrence, -H or C1-C3 alkyl;Q is independently, at each occurrence, N, CH, or C(R6); wherein one of Z and T to which a double bond is connected is N, CH, or C(R6); wherein the other of Z and T to which a single bond is connected is CH=CH, C(R6)=CH, C(R6)=C(R6), N=CH, N=C(R6), S, O, N(R5), CH2, CH-R6, or C(R6)2; andR6is independently at each occurrence selected from the group consisting of halogen, C1-C6 alkyl, saturated or unsaturated, C1-C6 haloalkyl, saturated or unsaturated, and C3-C5 cycloalkyl, saturated or unsaturated, said C3-C5 cycloalkyl unsubstituted, monosubstituted, or polysubstituted with halogen or C1-C3 haloalkyl.

57. A compound according to claim 56, having a structure according to Formula V-iiwith their variables defined as in Formula V.

58. A compound according to claim 57, wherein Z is CH=CH, C(R6)=CH, C(R6)=C(R6), N=CH, N=C(R6), S, O, N(R5), CH2, CH-R6, or C(R6)2, and T is N, CH, or C(R6).

59. A compound according to claim 58, wherein Z is S and T is N.

60. A compound according to Formula VI:Formula VI including pharmaceutically acceptable salts thereof, wherein Q is, at each occurrence, independently N, C-H, or C-R6;R5is -H or C1-C3 alkyl; andR6is independently at each occurrence selected from the group consisting of halogen, C1-C6 alkyl, saturated or unsaturated, C1-C6 haloalkyl, saturated or unsaturated, and C3-C5 cycloalkyl, saturated or unsaturated, said C3-C5 cycloalkyl unsubstituted, monosubstituted, or polysubstituted with halogen or C1-C3 haloalkyl.

61. A compound according to F ormula Vl-i :Formula Vl-i including pharmaceutically acceptable salts thereof, wherein: q is an integer ranging from 0 to 4; andR6is independently at each occurrence selected from the group consisting of halogen, C1-C6 alkyl, saturated or unsaturated, C1-C6 haloalkyl, saturated or unsaturated, and C3-C5 cycloalkyl, saturated or unsaturated, said C3-C5 cycloalkyl unsubstituted, monosubstituted, or polysubstituted with halogen or C1-C3 haloalkyl.

62. A method of treating a neurological or neurodegenerative disorder in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 56 to 61.

63. The method of claim 62, wherein the neurological or neurodegenerative disorder is selected from alpha-synucleinopathies, multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), Parkinson’s disease, Huntington’s disease, stroke, Alzheimer’s disease, neuroinflammation, and Lewy body dementia.

64. The method of claim 63, wherein the neurological or neurodegenerative disorder is multiple sclerosis (MS).

65. The method of claim 63, wherein the neurological or neurodegenerative disorder is amyotrophic lateral sclerosis (ALS).

66. A method of treating a CNS disorder associated with PKM2 in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 56 to 61.

67. The method of any one of claims 62 to 66, wherein the therapeutically-effective amount is a dosage ranging from about 1 mg to about 1000 mg.

68. The method of claim 67, wherein the dose is administered once daily, twice daily, thrice daily, once every other day, once every two days, once weekly, or twice weekly.

69. A pharmaceutical composition comprising one or more PKM2 activator compounds according to any one of claims 56 to 61, and a pharmaceutically acceptable carrier.

70. A pharmaceutical composition according to claim 69, wherein the composition is formulated as a unit dosage containing from about 1 mg to about 1000 mg of PKM2 activator compound.

71. A method of treating a peripheral disease associated with PKM2 in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound according to any one of claims 1 to 36 or 56 to 61.

72. The method of claim 71, wherein the peripheral disease is selected from a fibrotic disorder, an inflammatory disorder, an autoimmune disorder, and a skin disorder.

73. The method of claim 72, wherein the peripheral disease is a fibrotic disorder.

74. The method of claim 73, wherein the fibrotic disorder is selected from the group consisting of include arthritis, arthrofibrosis, cystic fibrosis, fibrotic eye diseases, fibrotic kidney diseases, idiopathic pulmonary fibrosis, scleroderma, hypertrophic cardiomyopathy, myocarditis, systemic sclerosis, atrial / ventricular fibrillation, liver cirrhosis, dilated cardiomyopathy, fibrothorax, bridging fibrosis of the liver, glial scar, arterial stiffness, Crohn’s disease, Dupuytren’s contracture, keloid fibrosis, lipedema, mediastinal fibrosis, myelofibrosis, myofibrosis, Peyronie’s disease, nephrogenic systemic fibrosis, progressive massive fibrosis of the lungs, retroperitoneal fibrosis, adhesive capsulitis, acute myocardial infarction, and other fibrotic diseases.

75. The method of claim 71, wherein the peripheral disease is non-ketotic hyperglycinemia.

76. The method of claim 71, wherein the peripheral disease is an eye disease.

77. The method of claim 76, wherein the eye disease is age-related macular degeneration or retinitis pigmentosa.

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