KCC2 potentiators and uses thereof

Abstract

The present disclosure provides compounds, compositions, and methods for treating or preventing neurological disorders in a patient. The disclosed methods include administration to a subject suffering from a neurological disorder of a compound disclosed herein.

Description

[0001] KCC2 POTENTIATORS AND USES THEREOF

[0002] Background

[0003] Potassium chloride cotransporter-2 (KCC2) has been linked to neurological disorder, psychiatric disorders, and central nervous system injuries, and has been linked to neurological functions such as sensory, motor, cognitive, and / or developmental functions in the affected individual. These disorders often result in profound and irreversible neurological effects that pose severe challenges to an afflicted patient’s everyday life. Few therapeutics have been studied or utilized to treat these neurological disorders, which causes severe challenges and suffering for these patients. Additionally, the few that have been studied or utilized are not adequately sufficient to reduce the individual’s suffering or improve recovery from these neurological disorders. Accordingly, there is a need for novel therapeutic agents for the treatment of neurological disorders.

[0004] Summary of the Disclosure

[0005] The present disclosure provides compounds, compositions, and methods for treating or preventing neurological disorders in a patient. The disclosed methods include administration to a subject suffering from a neurological disorder of a compound disclosed herein. The disclosure further provides pharmaceutical compositions containing one of the compounds described herein. The disclosure further provides compounds and pharmaceutical compositions for use as a medicament. The disclosure further provides compounds and pharmaceutical compositions for use in the treatment or prevention of neurological disorders.

[0006] In the first aspect, the disclosure provides a compound of the formula (I):

[0007] Formula I, or a pharmaceutically acceptable salt thereof, wherein

[0008] R1is H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, SR6, N(R5)2, OR5, S(O)R14, SO2R14, or S(N)R14;

[0009] R4is H, halogen, optionally substituted C1-6 alkyl, optionally substituted cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, OR5, SR6, N(R5)2, S(O)R14, SO2R14, or S(N)R14, or R3and R4, together with the atoms to which each is attached, join to form a 5- to 7- membered aromatic or nonaromatic carbocycle or heterocycle;

[0010] R2and R3are each, independently, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, optionally substituted C5-C12 heteroaryl, optionally substituted C3-C12 heterocycle, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky ny I, optionally substituted C3-C12 cycloalkyl, optionally substituted C7-C14 arylalkyl, (CH2)POZ, C(O)Z, C(O)OZ, C(O)NZ2, OR5, N(R5)2, SR6, S(O)R14, SO2R14, or S(N)R14, or R2and R3, together with the atoms to which each is attached, join to form a 5- to 7- membered aromatic or non-aromatic carbocycle or heterocycle;

[0011] R1ais H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, SR6, N(R5)2, OR5, S(O)R14, SO2R14, or S(N)R14;

[0012] R2ais H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, optionally substituted C5-C12 heteroaryl, optionally substituted C3-C12 heterocycle, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky ny I, optionally substituted C3-C12 cycloalkyl, optionally substituted C7-C14 arylalkyl, (CH2)POZ, C(O)Z, C(O)OZ, C(O)NZ2, OR5, N(R5)2, SR6, S(O)R14, SO2R14, or S(N)R14, or R1aand R2a, together with the atoms to which each is attached, join to form a 5- to 7- membered aromatic or non-aromatic carbocycle or heterocycle;

[0013] R3ais H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, optionally substituted C5-C12 heteroaryl, optionally substituted C3-C12 heterocycle, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky ny I, optionally substituted C3-C12 cycloalkyl, optionally substituted C7-C14 arylalkyl, (CH2)POZ, C(O)Z, C(O)OZ, C(O)NZ2, OR5, N(R5)2, SR6, S(O)R14, SO2R14, or S(N)R14;

[0014] R4ais H, halogen, optionally substituted C1-6 alkyl, optionally substituted cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, OR5, SR6, N(R5)2, S(O)R14, SO2R14, or S(N)R14, or R3aand R4a, together with the atoms to which each is attached, join to form a 5- to 7- membered aromatic or non- aromatic carbocycle or heterocycle; , wherein A is optionally substituted with Ci-Ce alkyl, C5-C12 aryl, C3-C12 cycloalkyl, C5-C12 heteroaryl, or C3-C12 heterocycle, optionally wherein the C5-C12 aryl, C3-C12 cycloalkyl, C5-C12 heteroaryl, or C3-C12 heterocycle is joined to A through one or more carbon atoms; n is 0, 1 , 2, or 3; m is 0, 1 , 2, or 3; each p is, independently, 1 , 2, or 3; each R5is, independently, H, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, or optionally substituted C3-C12 cycloalkyl, and each R6is, independently, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci- Ce heteroalkyl, optionally substituted C3-Ce heterocycle, optionally substituted C3-Ce cycloalkyl, optionally substituted C5-C12 aryl, or optionally substituted C5-C12 heteroaryl; each R14is independently, H, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-Ce heterocycle, optionally substituted C3-Ce cycloalkyl, optionally substituted C5-C12 aryl, or optionally substituted C5-C12 heteroaryl; and each Z is, independently, H, or optionally substituted C1-6 alkyl.

[0015] In some embodiments, In some embodiments,

[0016] In some embodiments,

[0017] In some embodiments, ci

[0018] In some embodiments, O is fr N^CI .

[0019] 1

[0020] In some embodiments, O is N .

[0021] In some embodiments, R1, R2, R3and R4are not all H.

[0022] In some embodiments, R1a, R2a, R3a, and R4aare not all H.

[0023] In some embodiments, R1is a halogen, e.g., Cl or F.

[0024] In some embodiments, R1is Cl, and R4is not H.

[0025] In some embodiments, R1is Cl.

[0026] In some embodiments, R1ais a halogen, e.g., Cl or F.

[0027] In some embodiments, R1ais Cl, and R4is not H.

[0028] In some embodiments, R1is an optionally substituted Ci-Ce alkyl, e.g., CH3, CH2CH3, CF3, CHF2,

[0029] In some embodiments, R1is Me. In some embodiments, R1is CF3. In some embodiments, R1is ,

[0030] In some embodiments, R1ais an optionally substituted Ci-Ce alkyl, e.g., CH3, CH2CH3, CF3, CHF2,

[0031] In some embodiments, R1is Me, and R4is not H.

[0032] In some embodiments, R1is optionally substituted C3-C12 cycloalkyl, e.g., , In some embodiments,

[0033] In some embodiments,

[0034] In some embodiments, R1is optionally substituted C3-C12 heterocycle, e.g., ° , or ,

[0035] In some embodiments, R1is CF3.

[0036] In some embodiments, ,

[0037] In some embodiments, R1is SO2R14, e.g., SO2CH3, SO2CH2CH3, or SO2(CH)(CH3)2.

[0038] In some embodiments, R1is SO2CH2CH3.

[0039] In some embodiments, R1is S(O)R14, e.g., S(O)CH3, S(O)CH2CH3, or S(O)(CH)(CH3)2.

[0040] In some embodiments, R1S(O)CH2CH3.

[0041] In some embodiments, R1is S(N)R14, e.g., S(N)CH3, S(N)CH2CH3, or S(O)(CH)(CH3)2.

[0042] In some embodiments, R4is a halogen e.g., Cl or F.

[0043] In some embodiments, R4is Cl, and R1is not H.

[0044] In some embodiments, R4is an optionally substituted Ci-Ce alkyl, e.g., CH3, CH2CH3, CF3, CHF2,

[0045] In some embodiments, R4is Me.

[0046] In some embodiments, R4is Et. In some embodiments, R4ais an optionally substituted Ci-Ce alkyl, e.g., CH3, CH2CH3, CF3, CHF2,

[0047] In some embodiments, R4is Me, and R1is not H.

[0048] In some embodiments, R4is optionally substituted carbocycle, e.g., ,

[0049] In some embodiments, R4is optionally substituted C3-C12 heterocycle, e.g., , or

[0050] In some embodiments, R4is CF3.

[0051] In some embodiments, R4is SR6, e.g., SF5, SCH3, or SCF3.

[0052] In some embodiments, R4is N(R5)2, e.g., NH2, NHCH3, or N(CH3)2.

[0053] In some embodiments, R4is OR5, e.g., OCH3, OCF3, or OCHF2.

[0054] In some embodiments, R4is OCH3.

[0055] In some embodiments, R4is SO2R14, e.g., SO2CH3, SO2CH2CH3, or SO2(CH)(CH3)2.

[0056] In some embodiments, R4is S(O)R14, e.g., S(O)CH3, S(O)CH2CH3, or S(O)(CH)(CH3)2.

[0057] In some embodiments, R4is S(N)R14, e.g., S(N)CH3, S(N)CH2CH3, or S(O)(CH)(CH3)2.

[0058] In some embodiments, R2is H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, optionally substituted C5-C12 heteroaryl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C7-C14 arylalkyl, (CH2)POZ, C(O)Z, C(O)OZ, C(O)NZ2, OR5, N(R5)2, SR6, S(O)R14, SO2R14, or S(N)R14, or R2and R3together with the atoms to which each is attached, join to form a 5- to 6-membered aromatic or nonaromatic carbocycle or heterocycle.

[0059] In some embodiments, R2is CF3.

[0060] In some embodiments,

[0061] In some embodiments, R2is OMe.

[0062] In some embodiments, R2is a halogen, e.g., Cl or F.

[0063] In some embodiments, R2is Cl, and R1is not H.

[0064] In some embodiments, R2is Cl, and R4is not H.

[0065] In some embodiments, R2is OR5, e.g., OCH3.

[0066] In some embodiments, R2is N(R5)2, e.g., NH2.

[0067] In some embodiments, R2is SO2R14, e.g., SO2CH3, SO2CH2CH3, or SO2(CH)(CH3)2. In some embodiments, R2is S(O)R14, e.g., S(O)CH3, S(O)CH2CH3, or S(O)(CH)(CH3)2.

[0068] In some embodiments, R2is S(N)R14, e.g., S(N)CH3, S(N)CH2CH3, or S(O)(CH)(CH3)2.

[0069] In some embodiments, R3is halogen, optionally substituted Ci-Ce alkyl, optionally substituted C5- C12 aryl, optionally substituted C5-C12 heteroaryl, optionally substituted C3-C12 heterocycle, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky ny I, optionally substituted C3-C12 cycloalkyl, optionally substituted C7-C14 arylalkyl, (CH2)POZ, C(O)Z, C(O)OZ, C(O)NZ2, OR5, N(R5)2, SR6, S(O)R14, SO2R14, or S(N)R14.

[0070] In some embodiments, R3is halogen.

[0071] In some embodiments, R3is Cl.

[0072] In some embodiments, R3is F.

[0073] In some embodiments, R3is an optionally substituted Ci-Ce alkyl, e.g., CH3, CH2CH3, CF3, CHF2, ,

[0074] In some embodiments of any of the aspects described herein, R5is Ci-Ce alkyl, C5-C12 aryl, C5-C12 heteroaryl or C3-C12 heterocycle.

[0075] In some embodiments of any of the aspects described herein, R6is halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C6 heterocycle, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C12 aryl, or optionally substituted C5-C12 heteroaryl.

[0076] In some embodiments of any of the aspects described herein, SR6is SF5. In some embodiments, R6is an optionally substituted Ci-Ce alkyl, e.g., CH3, CH2CH3, CF3, CHF2, some embodiments, R6is optionally substituted carbocycle, e.g.,

[0077] In some embodiments, R6is CF3.

[0078] In some embodiments, R14is an optionally substituted Ci-Ce alkyl, e.g., CH3, CH2CH3, CF3, CHF2,

[0079] In some embodiments, R14is optionally substituted cycloalkyl, e.g.,

[0080] In some embodiments, R14is optionally substituted C3-C12 heterocycle, e.g., , or

[0081] In some embodiments, R14is an optionally substituted Ci-Ce heteroalkyl, e.g., OCH3, OCH2CH3, OCF3, OCHF2, or OCH2CF3.

[0082] In some embodiments, R14is optionally substituted C3-C12 heterocycle, e.g.,

[0083] In some embodiments, n is 0, 1 , 2, or 3.

[0084] In some embodiments, m is 0, 1 , 2, or 3.

[0085] In some embodiments, each p is, independently, 1 , 2, or 3.

[0086] In some embodiments,

[0087] In some embodiments,

[0088] In some embodiments,

[0089] In some embodiments,

[0090] In some embodiments, the compound is a compound of formula (l-A): or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, the compound is a compound of the formula (l-B): or a pharmaceutically acceptable salt thereof.

[0092] In some embodiments, the compound is a compound of formula (l-C): or a pharmaceutically acceptable salt thereof, wherein

[0093] R8, R9, R10and R11are each, independently, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky ny I, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, optionally substituted C7- C14 arylalkyl, (CH2)POZ, C(O)Z, C(O)OZ, C(O)NZ2, OR5, or N(R5)2.

[0094] In some embodiments, the compound is a compound of formula (l-D): or a pharmaceutically acceptable salt thereof, wherein

[0095] R8, R9, R10, and R11are each, independently, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky ny I, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, optionally substituted C7- C14 arylalkyl, (CH2)POZ, C(O)Z, C(O)OZ, C(O)NZ2, OR5, SR6, or N(R5)2.

[0096] In some embodiments, the compound is a compound of formula (l-T): or a pharmaceutically acceptable salt thereof, wherein

[0097] R8, R9, R10and R11are each, independently, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky ny I, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, optionally substituted C7- C14 arylalkyl, (CH2)POZ, C(O)Z, C(O)OZ, C(O)NZ2, OR5, or N(R5)2.

[0098] In some embodiments of any of the aspects described herein, R8is H, halogen, optionally substituted Ci-Ce alkyl, or optionally substituted C3-C6 cycloalkyl.

[0099] In some embodiments of any of the aspects described herein, R9is H, halogen, optionally substituted Ci-Ce alkyl, or optionally substituted C3-C6 cycloalkyl. In some embodiments of any of the aspects described herein, R10is H, halogen, optionally substituted Ci-Ce alkyl, or optionally substituted C3-C6 cycloalkyl.

[0100] In some embodiments of any of the aspects described herein, R11is H, halogen, optionally substituted Ci-Ce alkyl, or optionally substituted C3-C6 cycloalkyl.

[0101] In some embodiments, the compound is a compound of formula (l-E): or a pharmaceutically acceptable salt thereof.

[0102] In some embodiments, the compound is a compound of the formula (l-F): or a pharmaceutically acceptable salt thereof.

[0103] In some embodiments, the compound is a compound of the formula (l-G): or a pharmaceutically acceptable salt thereof.

[0104] In some embodiments, the compound is a compound of the formula (l-H): or a pharmaceutically acceptable salt thereof.

[0105] In some embodiments, the compound is a compound of the formula (l-J): or a pharmaceutically acceptable salt thereof.

[0106] In some embodiments, the compound is a compound of formula (l-K): or a pharmaceutically acceptable salt In some embodiments, the compound is a compound of formula (l-L): or a pharmaceutically acceptable salt thereof.

[0107] In some embodiments, the compound is a compound of formula (l-M): or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments, the compound is a compound of formula (l-N): or a pharmaceutically acceptable salt thereof.

[0109] In some embodiments, the compound is a compound of formula (1-0): or a pharmaceutically acceptable salt thereof.

[0110] In some embodiments, the compound is a compound of formula (l-P): or a pharmaceutically acceptable salt thereof.

[0111] In some embodiments, the compound is a compound of formula (l-Q): or a pharmaceutically acceptable salt thereof.

[0112] In some embodiments, the compound is a compound of formula (l-R): or a pharmaceutically acceptable salt thereof.

[0113] In some embodiments, the compound is a compound of formula (l-S): or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure provides a compound of Table 1 or a pharmaceutically acceptable salt thereof.

[0114] Table 1

[0115]

[0116] In some embodiments, the compound is one the compounds of Table 1 , or a pharmaceutically acceptable salt. In another aspect, the disclosure provides a compound of the Formula (II): or a pharmaceutically acceptable salt thereof, wherein

[0117] R1is H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, SR6, N(R5)2, OR5, S(O)R14, SO2R14, or S(N)R14; R4is H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, OR5, SR6, N(R5)2, S(O)R14, SO2R14, or S(N)R14, or R3and R4, together with the atoms to which each is attached, join to form a 5- to 6-membered aromatic or nonaromatic carbocycle or heterocycle;

[0118] R2, R3are each, independently, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, optionally substituted C5-C12 heteroaryl, optionally substituted C3-C12 heterocycle, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky ny I, optionally substituted C3-C12 cycloalkyl, optionally substituted C7-C14 arylalkyl, (CH2)POZ, C(O)Z, C(O)OZ, C(O)NZ2, OR5, N(R5)2, SR6, S(O)R14, SO2R14, or S(N)R14, or R2and R3together with the atoms to which each is attached, join to form a 5- to 6-membered aromatic or non-aromatic carbocycle or heterocycle; wherein A is optionally substituted with

[0119] Ci-Ce alkyl, C5-C12 aryl, C3-C12 cycloalkyl, C5-C12 heteroaryl, or C3-C12 heterocycle, optionally wherein the C5-C12 aryl, C3-C12 cycloalkyl, C5-C12 heteroaryl, or C3-C12 heterocycle is joined to A through one or more carbon atoms; n is 0, 1 , 2, or 3; m is 0, 1 , 2, or 3; each p is, independently, 1 , 2, or 3; each R5is H, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, or optionally substituted C3-C12 cycloalkyl, each R6is H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-Ce heterocycle, optionally substituted C3-Ce cycloalkyl, optionally substituted C5- C12 aryl, or optionally substituted C5-C12 heteroaryl, each R14is independently, H, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C6 heterocycle, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C12 aryl, or optionally substituted C5-C12 heteroaryl; each Z is, independently, H, or optionally substituted Ci-Ce alkyl; wherein Ra’ is H, OH, optionally substituted

[0120] Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky nyl, optionally substituted C3-C12 cycloalkyl, or optionally substituted Ce-Ci4 aryl; and Rais CH2NH or C(Rd)2O, wherein each Rdis independently H, Ci-Cs alkyl, Ci-Cs cycloalkyl, Ci-Cs aryl, or Ci-Cs heteroaryl; Rbis H, OH, optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky nyl, optionally substituted Ci-Cs alkoxy, optionally substituted C3-C12 cycloalkyl, optionally substituted Ce-Ci4 aryl, or N(Re)2, each Rcis, independently, H, Ci-Cs alkyl, or C6-C14 aryl, and each Reis independently H or Ci-Cs alkyl.

[0121] In some embodiments, R1, R2, R3and R4are not all H. In some embodiments,

[0122] In some embodiments,

[0123] In some embodiments,

[0124] In some embodiments,

[0125] In some embodiments, R12is C(O)Ra’ ,

[0126] In some embodiments, In some embodiments, Ra’ is optionally substituted Ci-Ca

[0127] In some embodiments, Ra’ is CH2CH3, CH(CH3)2, C(CH3)

[0128] In some embodiments, Rais CH2NH.

[0129] In some embodiments, Rais C(Rd)2O.

[0130] In some embodiments, Rd is CH2O or CH(CH3)O.

[0131] In some embodiments, Rais CH2O or CH(CH3)O.

[0132] In some embodiments, Rbis optionally substituted Ci-Cs alkyl

[0133] In some embodiments, Rbis (CH2)5CH3, CH3, C(CH3)3, or CH(CH3)2.

[0134] In some embodiments, Rbis carboxyl substituted Ci-Cs alkyl. In some embodiments, Rbis (CH2)4COOH, CH2COOH, (CH2)2COOH, (CH2)3COOH,

[0135] In some embodiments, Rbis optionally substituted Ci-C3alkoxy.

[0136] In some embodiments,

[0137] In some embodiments, RbN(Re)2, wherein each Reis independently H or Ci-C3alkyl.

[0138] In some embodiments, Rbis NHCH2CH3.

[0139] In some embodiments, each Rcis, independently, H or C(CH3)3.

[0140] In some embodiments, the compound of formula II has the structure: pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula II has the structure:

[0141] In another aspect, the present disclosure provides a compound of Table 2 or a pharmaceutically acceptable salt thereof.

[0142]

[0143]

[0144] In another aspect, the disclosure provides a pharmaceutical composition including a compound described herein (e.g., any one of the compounds of formulas (I), (l-A), (l-B), (l-C), (l-D), (l-E), (l-F), (l-G), (l-H), (l-J), (l-K), (l-L), (l-M) , (l-N) , (l-O), (l-P), (l-R), (l-S), (l-T), and (II), Table 1 and Table 2) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0145] In another aspect, the disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament, wherein formula (I) is: Formula I, or a pharmaceutically acceptable salt thereof, wherein

[0146] R1is H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, SR6, N(R5)2, OR5, S(O)R14, SO2R14, or S(N)R14; R4is H, halogen, optionally substituted C1-6 alkyl, optionally substituted cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, OR5, SR6, N(R5)2, S(O)R14, SO2R14, or S(N)R14, or R3and R4, together with the atoms to which each is attached, join to form a 5- to 7- membered aromatic or nonaromatic carbocycle or heterocycle; R2and R3are each, independently, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, optionally substituted C5-C12 heteroaryl, optionally substituted C3-C12 heterocycle, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky ny I, optionally substituted C3-C12 cycloalkyl, optionally substituted C7-C14 arylalkyl, (CH2)POZ, C(O)Z, C(O)OZ, C(O)NZ2, OR5, N(R5)2, SR6, S(O)R14, SO2R14, or S(N)R14, or R2and R3, together with the atoms to which each is attached, join to form a 5- to 7- membered aromatic or non-aromatic carbocycle or heterocycle; , wherein A is optionally substituted with Ci-Ce alkyl, C5-C12 aryl, C3-C12 cycloalkyl, C5-C12 heteroaryl, or C3-C12 heterocycle, optionally wherein the C5-C12 aryl, C3-C12 cycloalkyl, C5-C12 heteroaryl, or C3-C12 heterocycle is joined to A through one or more carbon atoms; n is 0, 1 , 2, or 3; m is 0, 1 , 2, or 3; each p is, independently, 1 , 2, or 3; each R5is, independently, H, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, or optionally substituted C3-C12 cycloalkyl, and each R6is, independently, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci- Ce heteroalkyl, optionally substituted C3-C6 heterocycle, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C12 aryl, or optionally substituted C5-C12 heteroaryl; each R14is independently, H, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C6 heterocycle, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C12 aryl, or optionally substituted C5-C12 heteroaryl; and each Z is, independently, H, or optionally substituted C1-6 alkyl.

[0147] In some embodiments of Formula (I), if R1is Me or Cl, then R4is not H; if R4is Me or Cl, then R1is not H; and / or if R2is Me or Cl, then R1and R4are both not H.

[0148] In some embodiments of Formula (I), R2is H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, optionally substituted C5-C12 heteroaryl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky ny I, optionally substituted C3-C12 cycloalkyl, optionally substituted C7-14 arylalkyl, (CH2)POZ, C(O)Z, C(O)OZ, C(O)NZ2, OR5, N(R5)2, SR5a, S(O)R14, SO2R14, or S(N)R14;

[0149] In another aspect, the disclosure provides a compound described herein (e.g., any one of the compounds of Formulas (I), (l-A), (l-B), (l-C), (l-D), (l-E), (l-F), (l-G), (l-H), (l-J), (l-K), (l-L), (l-M), (l-N), (I- O), (l-F*). (I-R), (l-S), (l-T), and (II), Table 1 and Table 2), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition including said compound or salt thereof and a pharmaceutically acceptable excipient, for use as a medicament.

[0150] In another aspect, the disclosure provides a method for treating or preventing a neurological disorder, which includes administering to a subject in need thereof a therapeutically effective amount of a compound described herein (e.g., any one of the compounds of formulas (I), (l-A), (l-B), (l-C), (l-D), (l-E), (l-F), (l-G), (l-H), (l-J), (l-K), (l-L), (l-M), (l-N), (l-O), (l-P), (l-R), (l-S), (l-T), and (II), Table 1 and Table 2) or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure provides a method for treating a neurological disorder, which includes administering to a subject in need thereof a therapeutically effective amount of a compound described herein (e.g., any one of the compounds of formulas (l-A), (l-B), (l-C), (l-D), (l-E), (l-F), (l-G), (l-H), (l-J), (l-K), (l-L), (l-M), (l-N), (1-0), (l-P), (l-R), (l-S), (l-T), and (II), Table 1 and Table 2) or a pharmaceutically acceptable salt thereof. In some embodiments, the disclosure provides a method for preventing a neurological disorder, which includes administering to a subject in need thereof a therapeutically effective amount of a compound described herein (e.g., any one of the compounds of formulas (l-A), (l-B), (l-C), (l-D), (l-E), (l-F), (l-G), (l-H), (l-J), (l-K), (l-L), (l-M), (l-N), (l-O), (l-P), (l-R), (l-S), (l-T), and (II), Table 1 and Table 2) or a pharmaceutically acceptable salt thereof.

[0151] In some embodiments, the neurological disorder is a neurotraumatic disorder, a neurodevelopmental disorder, or an affective disorder.

[0152] In some embodiments, the neurological disorder is a neurotraumatic disorder, e.g., spinal cord injury, traumatic brain injury, stroke, peripheral nerve injury, multiple sclerosis, ischemia, amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease, myelopathy, hypoxic-ischemic encephalopathy, tumor-associated epilepsy, spasticity, neurological pain, neurotraumatic injury, neurogenerative disease, or peripheral neuropathy.

[0153] In some embodiments, the neurological pain is a neuropathic pain, inflammation, inflammatory pain, arthritic pain, diabetic pain, or neuralgia.

[0154] In some embodiments, the neurological disorder is epilepsy.

[0155] In some embodiments, the epilepsy is focal epilepsy, temporal lobe epilepsy, refractory epilepsy, generalized epilepsy, developmental and epileptic encephalopathy (DEE), epilepsy of infancy with migrating focal seizures (EIMFS), absence epilepsy, Lennox-Gastaut syndrome, neurotrauma associated epilepsy (ischemia, stroke, traumatic brain injury), status epilepticus, tumor associated epilepsy, hypoxic- ischemic encephalopathy, or sudden unexpected death in epilepsy.

[0156] In some embodiments, the neurodevelopmental disorder is autism spectrum disorder, Rett Syndrome, Tuberous Sclerosis Complex (TSC), Fragile X syndrome, Angelman syndrome, Down syndrome, Dravet syndrome, CKDL5 Deficiency syndrome, SYNGAP1 haploinsufficiency, cerebral palsy, or Huntington's disease.

[0157] In some embodiments, the neurotraumatic injury or neurogenerative disease is traumatic brain injury, stroke, multiple sclerosis, Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease, Alzheimer's disease, spasticity, or spinal cord injury.

[0158] In some embodiments, the affective disorder is schizophrenia, bipolar disorder, general anxiety disorder, social anxiety disorder, and major depressive disorder.

[0159] Definitions

[0160] To facilitate the understanding of the present disclosure, a number of terms are defined below. Terms defined herein have meanings as commonly understood by a person of ordinary skill in the areas relevant to the disclosure. Terms such as "a," "an," and "the" are not intended to refer to only a singular entity but include the general class of which a specific example may be used for illustration. The terminology herein is used to describe specific embodiments of the disclosure, but their usage does not limit the disclosure, except as outlined in the claims.

[0161] As used herein, the term “about” is used to indicate that a value includes the standard deviation of error for the method being employed to determine the value. In certain embodiments, the term “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of a stated value, unless otherwise stated or otherwise evident from the context (e.g., where such number would exceed 100% of a possible value).

[0162] As used herein, any values provided in a range of values include both the upper and lower bounds, and any values contained within the upper and lower bounds.

[0163] As used herein, the terms “administer” and “administering” are used to indicate the process of providing a therapeutic, pharmaceutical, housing compartment, medication, or the like thereof to a subject. In some embodiments, a pharmaceutical is provided via oral administration.

[0164] As used herein, the term “chloride transporter activity” refers to the transport of chloride, or any surrogate ion, across the plasma membrane. Such transport activity may be measured by direct or indirect means using various methods known in the art, examples of which are described herein.

[0165] As used herein, the term “KCC2 activity” refers to any detectable phenotype associated with KCC2. In an embodiment, KCC2 activity includes, but is not limited to potassium transport, chloride transport, or transport of any surrogate ion which may, for example, be determined by assessing levels (either directly or indirectly) of potassium, chloride, and / or surrogate ion inside and / or outside the cell using, for example, reversal potential measurements with patch clamping methods, chloride / potassium sensitive dyes (see for example Haugland, R. P., Handbook of Fluorescent Probes and Research Products, ninth ed., 2002, Molecular Probes, Inc., Eugene, Oreg., USA) electrodes, etc. In addition, KCC2 activity may also affect the neural cell's anion reversal potential (Eanion). The anion reversal potential may be determined, for example, by using gramicidin-perforated patch clamp recording. In an embodiment, KCC2 activity also includes KCC2-mediated synaptic and / or neurite changes.

[0166] As used herein, the terms “improve” and “improving,” in reference to recovery from a disease or condition, e.g., a neurological disorder, refer to an enhancement of recovery in one or more parameters measuring or quantifying the severity of the neurological disorder relative to the recovery in these parameters in or prior to treatment with the compounds or compositions described herein. Alternatively, improvement may be measured with respect to a reference subject having the same diagnosis as the subject but that did not receive treatment with a compound or composition of the disclosure. For neurological disorders, such parameters may include motor and sensory function in a subject. Methods for assessing motor and sensory function in a subject suffering from a neurological disorder are known in the art and are further described herein.

[0167] As used herein, the term “level” refers to a change in the measure of a compound, metabolite, or protein activity (e.g., Chloride transporter activity, or KCC2 activity), or property thereof, as compared to a reference. The reference can be any useful reference, as defined herein. By a “decreased level” or an “increased level” of a compound or enzyme activity is meant a decrease or increase in level, as compared to a reference (e.g., a decrease or an increase by about 5%, about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, about 100%, about 150%, about 200%, about 300%, about 400%, about 500%, or more; a decrease or an increase of more than about 10%, about 15%, about 20%, about 50%, about 75%, about 100%, or about 200%, as compared to a reference; a decrease or an increase by about 0.01 -fold, about 0.01-fold, about 0.02-fold, about 0.1-fold, about 0.3-fold, about 0.5-fold, about 0.8-fold, about 0.9-fold, or less; or an increase by more than about 1.1-fold, about 1.2-fold, about 1.3-fold, about 1.4-fold, about 1.5-fold, about 1.8-fold, about 2.0-fold, about 3.0-fold, about 3.5-fold, about 4.5- fold, about 5.0-fold, about 10-fold, about 15-fold, about 20-fold, about 30-fold, about 40-fold, about 50- fold, about 100-fold, or more). A level of a compound may be expressed in mass / vol (e.g., g / dl, mg / ml, pg / ml, ng / ml), concentration or molarity (e.g., M, mM, pM, nM, pM), or percentage relative to total compound in a sample, or by any other suitable units of measure as described by the disclosure. For example, “increasing levels of KCC2 activity” may be considered a subset of the phrase “potentiating KCC2 activity,” when describing an increase in activity of the potassium chloride cotransporter-2, KCC2, in comparison to a reference level.

[0168] As used herein, the term “neurological disorder” refers to any damage or dysfunction of one or more nerves in a subject. A neurological disorder may include any damage or dysfunction that prevents and / or inhibits one or more electrical and / or chemical transmissions of a sensory and / or motor function signal. A neurological disorder may include any damage or dysfunction that results in a transmission of one or more electrical and / or chemical transmissions of a nerve cell uncontrollably by the subject. A neurological disorder may include damage or dysfunction of one or more nerves located within the central nervous system and / or peripheral nervous system of a subject. A neurological disorder may include damage or dysfunction of a somatic, autonomic, and / or enteric nervous system of a subject. A neurological disorder may include damage or dysfunction of an afferent and / or efferent nervous system of a subject. A neurological disorder may include damage or dysfunction of a sympathetic and / or parasympathetic nervous system of a subject. A neurological disorder may include damage of dysfunction of one or more cranial nerves (e.g., the olfactory nerve, optic nerve, oculomotor nerve, trochlear nerve, trigeminal nerve, abducens nerve, facial nerve, vestibulocochlear nerve, glossopharyngeal nerve, vagus nerve, accessory nerve, and / or hypoglossal nerve) of a subject. A neurological disorder may be a neurodevelopmental disorder, which may include neuropathic pain, inflammation, inflammatory pain, arthritic pain, diabetic pain, or neuralgia. A neurological disorder may be a neurotraumatic disorder, which may include a spinal cord injury, traumatic brain injury, stroke, peripheral nerve injury, multiple sclerosis, ischemia, amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease, myelopathy, hypoxic- ischemic encephalopathy, tumor-associated epilepsy, spasticity, or peripheral neuropathy. A neurological disorder may be epilepsy which may include refractory epilepsy, neurotrauma associated epilepsy (ischemia, stroke, traumatic brain injury), status epilepticus, tumor associated epilepsy and hypoxic- ischemic encephalopathy. A neurological disorder may be a neurodevelopmental disorder, which may include an autism spectrum disorder, Rett syndrome, Tuberous Sclerosis Complex (TSC), Fragile X syndrome, Angelman syndrome, cerebral palsy, Down syndrome, Dravet syndrome, epilepsy (e.g., focal epilepsy, temporal lobe epilepsy, generalized epilepsy, developmental and epileptic encephalopathy (DEE), epilepsy of infancy with migrating focal seizures (EIMFS), absence epilepsy, Lennox -Gastaut syndrome, neurotrauma associated epilepsy (ischemia, stroke, traumatic brain injury), status epilepticus, tumor associated epilepsy, or hypoxic-ischemic encephalopathy), or sudden unexpected death in epilepsy. A neurological disorder may include an affective disorder, which may include schizophrenia, bipolar-disorder, anxiety disorder, major depressive disorder, and the like thereof.

[0169] As used herein, the term “pharmaceutical composition” refers to an active compound, formulated together with one or more pharmaceutically acceptable excipients. In some embodiments, a compound of the disclosure is present in unit dose amount appropriate for administration in a therapeutic regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to a relevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions) or tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, or pastes for application to the tongue.

[0170] The term “pharmaceutically acceptable excipient,” as used herein, refers to any inactive ingredient (for example, a vehicle capable of suspending or dissolving the active compound) having the properties of being nontoxic and non-inflammatory in a subject. Typical excipients include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes, emollients, emulsifiers, diluents, film formers or coatings, flavors, fragrances, glidants, lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, or waters of hydration. Excipients include, but are not limited to: butylated optionally substituted hydroxytoluene (e.g., BHT), calcium carbonate, calcium phosphate dibasic, calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxypropyl cellulose, optionally substituted hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch, stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol. Those of ordinary skill in the art are familiar with a variety of agents and materials useful as excipients.

[0171] As used herein, the term “pharmaceutically acceptable salt” represents those salts of the compounds described that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008 . These salts may be acid addition salts involving inorganic or organic acids. The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting the free base group with a suitable acid . Methods for preparation of the appropriate salts are well-established in the art.

[0172] The phrase “potentiating KCC2 activity,” as used herein, refers to increasing or decreasing the level or activity of the potassium chloride cotransporter-2, KCC2. KCC2 activity may be determined using methods known in the art, e.g., immunoprecipitation, western blot, qPCR, live cell immunolabeling of cell surface expression as described in Medina et al. eNeuro, 2017, 4, 1-19, or immunohistochemistry in primary cultures.

[0173] The term “subject,” as used herein, can be a human, non-human primate, or other mammal, such as but not limited to dog, cat, horse, cow, pig, goat, monkey, rat, mouse, and sheep. In preferred embodiments, the subject is a human. As used herein, the term “therapeutically effective amount” refers to an amount sufficient to effect beneficial or desired results, such as clinical results, and, as such, a “therapeutically effective amount” depends upon the context in which it is being applied. For example, in the context of administering a compound disclosed herein (e.g., a compounds of any one of formulas (I), (l-A), (l-B), (l-C), (l-D), (l-E), (I- F), (l-G), (l-H), (l-J), (l-K), (l-L), (l-M), (l-N), (l-O), (l-P), (l-R), (l-S), (l-T), and (II), and other compounds disclosed herein) to treat a neurological disorder, a therapeutically effective amount of a compound is, for example, an amount sufficient to reverse alleviate the neurological disorder.

[0174] As used herein, the terms “treat” and “treating” refer to a therapeutic treatment of a neurological disorder in a subject. The effect of treatment can include reversing, alleviating, reducing severity of, inhibiting the progression of, reducing the likelihood of recurrence of the neurological disorder or one or more symptoms or manifestations of the neurological disorder, stabilizing (i.e., not worsening) the state of the neurological disorder as compared to the state and / or the condition of the disease or disorder in the absence of the therapeutic treatment.

[0175] Chemical Terms

[0176] The terminology employed herein is for the purpose of describing particular embodiments and is not intended to be limiting.

[0177] For any of the following chemical definitions, a number following an atomic symbol indicates that total number of atoms of that element that are present in a particular chemical moiety. As will be understood, other atoms, such as H atoms, or substituent groups, as described herein, may be present, as necessary, to satisfy the valences of the atoms. For example, an unsubstituted C2 alkyl group has the formula -CH2CH3. When used with the groups defined herein, a reference to the number of carbon atoms includes the divalent carbon in acetal and ketal groups but does not include the carbonyl carbon in acyl, ester, carbonate, or carbamate groups. A reference to the number of oxygen, nitrogen, or sulfur atoms in a heteroaryl group only includes those atoms that form a part of a heterocyclic ring.

[0178] Those skilled in the art will appreciate that certain compounds described herein can exist in one or more different isomeric (e.g., stereoisomers, geometric isomers, atropisomers, tautomers) or isotopic (e.g., in which one or more atoms has been substituted with a different isotope of the atom, such as hydrogen substituted for deuterium) forms. Unless otherwise indicated or clear from context, a depicted structure can be understood to represent any such isomeric or isotopic form, individually or in combination.

[0179] Compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present disclosure that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present disclosure. Cis and trans geometric isomers of the compounds of the present disclosure are described and may be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, one or more compounds depicted herein may exist in different tautomeric forms. As will be clear from context, unless explicitly excluded, references to such compounds encompass all such tautomeric forms. In some embodiments, tautomeric forms result from the swapping of a single bond with an adjacent double bond and the concomitant migration of a proton. In certain embodiments, a tautomeric form may be a prototropic tautomer, which is an isomeric protonation states having the same empirical formula and total charge as a reference form. Examples of moieties with prototropic tautomeric forms are ketone — enol pairs, amide — imidic acid pairs, lactam — lactim pairs, amide — imidic acid pairs, enamine — imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, such as, 1 H- and 3H-imidazole, 1 H-, 2H- and 4H-1 ,2,4-triazole, 1 H- and 2H-isoindole, and 1 H- and 2H-pyrazole. In some embodiments, tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution. In certain embodiments, tautomeric forms result from acetal interconversion.

[0180] In any of the aspects described herein, a compound of Formulas (I), (l-A), (l-B), (l-C), (l-D), (l-E), (l-F), (l-G), (l-H), (l-J), (l-K), (l-L), (l-M), (l-N) , (l-O), (l-P), (l-R), (l-S), (l-T), and (II), Table 1 and Table 2, may exist in multiple tautomeric forms, tautomerizing between keto- and enol forms. As an example,

[0181] Compound 1 may exist in one of the following tautomeric forms:

[0182] Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,32P,33P,35S,18F,36CI,123l and125L Isotopically-labeled compounds (e.g., those labeled with3H and14C) can be useful in compound or substrate tissue distribution assays. Tritiated (i.e. , .sup.3H) and carbon-14 (i.e.,14C)) isotopes can be useful for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e.,2H or D) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements). In some embodiments, one or more hydrogen atoms are replaced by2H, D, or3H, or one or more carbon atoms are replaced by13C- or14C-enriched carbon. Positron emitting isotopes such as15O,13N,11C, and18F are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Preparations of isotopically labelled compounds are known to those of skill in the art. For example, isotopically labeled compounds can generally be prepared by following procedures analogous to those disclosed for compounds of the present invention described herein, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. As is known in the art, many chemical entities can adopt a variety of different solid forms such as, for example, amorphous forms or crystalline forms (e.g., polymorphs, hydrates, solvate). In some embodiments, compounds of the present invention may be utilized in any such form, including in any solid form. In some embodiments, compounds described or depicted herein may be provided or utilized in hydrate or solvate form.

[0183] At various places in the present specification, substituents of compounds of the present disclosure are disclosed in groups or in ranges. It is specifically intended that the present disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the term “Ci-Ce alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and Ce alkyl. Furthermore, where a compound includes a plurality of positions at which substituents are disclosed in groups or in ranges, unless otherwise indicated, the present disclosure is intended to cover individual compounds and groups of compounds (e.g., genera and subgenera) containing each and every individual subcombination of members at each position.

[0184] The term “alkyl,” as used herein, refers to a branched or straight-chain monovalent saturated aliphatic radical containing only C and H when unsubstituted. The monovalency of an alkyl group does not include the optional substituents on the alkyl group. For example, if an alkyl group is attached to a compound, monovalency of the alkyl group refers to its attachment to the compound and does not include any additional substituents that may be present on the alkyl group. In some embodiments, the alkyl group may contain, e.g., 1-20, 1-18, 1-16, 1-14, 1-12, 1-10, 1-8, 1-6, 1-4, or 1-2 carbon atoms (e.g., C1-C20, C1- Cis, C1-C16, C1-C14, C1-C12, C1-C10, Ci-Cs, Ci-Ce, C1-C4, or C1-C2). Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl, and tert-butyl.

[0185] The term “aryl,” as used herein, refers to any monocyclic or fused ring bicyclic or multicyclic system containing only carbon atoms in the ring(s), which has the characteristics of aromaticity in terms of electron distribution throughout the ring system, e.g., phenyl, naphthyl, or phenanthryl. An aryl group may have, e.g., six to sixteen carbons or six to fourteen carbons (e.g., six carbons, ten carbons, thirteen carbons, fourteen carbons, or sixteen carbons).

[0186] The term “arylalkyl,” as used herein, represents an alkyl group substituted with an aryl group. Unsubstituted arylalkyl groups contain from 7 to 30 carbons (e.g., from 7 to 16 or from 7 to 20 carbons, such as Ci-Ce alkyl Ce-C-io aryl, C1-C10 alkyl Ce-C-io aryl, or C1-C20 alkyl Ce-C-io aryl), such as, benzyl and phenethyl. In some embodiments, the alkyl and the aryl each are further substituted with 1 , 2, 3, or 4 substituent groups, valency permitting, as defined herein for the respective groups.

[0187] The term “carbocycle,” as used herein, refers to a monovalent, saturated (“cycloalkyl”) or unsaturated, non-aromatic cyclic group containing only C and H when unsubstituted. A carbocycle may have, e.g., three to twenty carbons (e.g., a C3-C7, C3-C8, C3-C9, C3-C10, C3-C11, C3-C12, C3-C14, C3-C16, C3-C18, or C3-C20 carbocycle).

[0188] The term “cycloalkyl,” as used herein, refers to a monovalent, saturated cyclic group containing only C and H when unsubstituted. A cycloalkyl may have, e.g., three to twenty carbons (e.g., a C3-C7, C3-C8, C3-C9, C3-C10, C3-C11, C3-C12, C3-C14, C3-C16, C3-C18, or C3-C20 cycloalkyl). Cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term “cycloalkyl” also includes cyclic groups having a bridged multicyclic structure in which one or more carbons bridges two non-adjacent members of a monocyclic ring, e.g., bicyclo[2.2.1]heptyl and adamantyl. The term “cycloalkyl” also includes bicyclic, tricyclic, and tetracyclic fused ring structures, e.g., decalin and spiro- cyclic compounds.

[0189] The term “halo,” as used herein, refers to a fluorine (fluoro), chlorine (chloro), bromine (bromo), or iodine (iodo) radical.

[0190] The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl group can be further substituted with 1 , 2, 3, or 4 substituent groups as described herein for alkyl groups. Examples of heteroalkyl groups are an “alkoxy” which, as used herein, refers alkyl-O- (e.g., methoxy and ethoxy). A heteroalkylene is a divalent heteroalkyl group.

[0191] The term “heteroaryl,” as used herein, refers to an aromatic mono- or polycyclic radical of 5 to 12 atoms having at least one aromatic ring containing 1 , 2, or 3 ring atoms selected from nitrogen, oxygen, and sulfur, with the remaining ring atoms being carbon. One or two ring carbon atoms of the heteroaryl group may be replaced with a carbonyl group. Examples of heteroaryl groups are pyridyl, pyrazoyl, benzooxazolyl, benzoimidazolyl, benzothiazolyl, imidazolyl, oxaxolyl, and thiazolyl. A “heteroarylene” is a divalent heteroaryl group.

[0192] The term “heterocycle,” as used herein, represents a monocyclic or fused ring bicyclic or multicyclic system having at least one heteroatom as a ring atom. For example, a heterocycle ring may have, e.g., one to fifteen carbons ring atoms (e.g., a C1-C2, C1-C3, C1-C4, C1-C5, Ci-Ce, C1-C7, Ci-Ca, C1- C9, C1-C10, C1-C11 , C1-C12, C1-C13, C1-C14, or C1-C15 heterocycle) and one or more (e.g., one, two, three, four, or five) ring heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur. Heterocycle groups may or may not include a ring that is aromatic. An aromatic heterocycle group is referred to as a “heteroaryl” group. In preferred embodiments of the disclosure, a heterocycle group is a 3- to 8-membered ring, a 3- to 6-membered ring, a 4- to 6-membered ring, a 6- to 10-membered ring, a 6- to 12-membered ring, a 5-membered ring, or a 6-membered ring. Exemplary 5-membered heterocycle groups may have zero to two double bonds, and exemplary 6-membered heterocycle groups may have zero to three double bonds. Exemplary 5-membered groups include, for example, optionally substituted pyrrole, optionally substituted pyrazole, optionally substituted isoxazole, optionally substituted pyrrolidine, optionally substituted imidazole, optionally substituted thiazole, optionally substituted thiophene, optionally substituted thiolane, optionally substituted furan, optionally substituted tetra hydrofuran, optionally substituted diazole, optionally substituted triazole, optionally substituted tetrazole, optionally substituted oxazole, optionally substituted 1 ,3,4-oxadiazole, optionally substituted 1 ,3,4-thiadiazole, optionally substituted 1 ,2,3,4-oxatriazole, and optionally substituted 1 ,2,3,4-thiatriazole. Exemplary 6- membered heterocycle groups include, for example, optionally substituted pyridine, optionally substituted piperidine, optionally substituted piperazine, optionally substituted pyrimidine, optionally substituted pyrazine, optionally substituted pyridazine, optionally substituted triazine, optionally substituted 2 / 7-pyran, optionally substituted 4 / 7-pyran, and optionally substituted tetrahydropyran. Exemplary 7-membered heterocycle groups include optionally substituted azepine, optionally substituted 1 ,4-diazepine, optionally substituted thiepine, and optionally substituted 1 ,4-thiazepine.

[0193] The phrase “optionally substituted X,” as used herein, is intended to be equivalent to “X, in which X is optionally substituted” (e.g., “alkyl, in which said alkyl is optionally substituted”). It is not intended to mean that the feature “X” (e.g. alkyl) per se is optional. The term “optionally substituted,” as used herein, refers to having 0, 1 , or more substituents (e.g., 0-25, 0-20, 0-10, or 0-5 substituents). In some embodiments, the term “optionally substituted” as used herein refers to having 0 substituents, i.e. , wherein the feature “X” is not substituted. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent, e.g., any of the substituents or groups described herein. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. For example, in the term “optionally substituted Ci-Ce alkyl-C2-Cg heteroaryl,” the alkyl portion, the heteroaryl portion, or both, may be optionally substituted. Combinations of substituents envisioned by the present disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0194] The term “oxo,” as used herein, represents an =0 group.

[0195] The term “thiol,” as used herein, represents an -SH group.

[0196] Alkyl, carbocycle, cycloalkyl, aryl, and heterocycle groups may be substituted with carbocycle (e.g., cycloalkyl); aryl; heterocycle; halo; ORa’, in which Ra’ is H, alkyl, alkenyl, alkynyl, carbocycle (e.g., cycloalkyl), aryl, or heterocycle; SRa, in which Rais as defined herein; CN; NO2; N3; NRbRc, in which each of Rband Rcis, independently, H, alkyl, alkenyl, alkynyl, carbocycle (e.g., cycloalkyl), aryl, or heterocycle; SO2Rd, in which Rdis H, alkyl or aryl; SO2NReRf, in which each of Reand Rfis, independently, H, alkyl, or aryl; SOR9, in which R9is H, alkyl, or aryl; or P(O)(ORh)2,in which each Rhis, independently, H or alkyl. Aryl, carbocycle (e.g., cycloalkyl), heteroaryl, and heterocycle groups may also be substituted with alkyl, alkenyl, or alkynyl. Alkyl, alkylene, alkenyl, alkynyl, carbocycle (e.g., cycloalkyl), and heterocycle groups may also be substituted with oxo or =NRf, in which is H or alkyl. In some embodiments, a substituent is further substituted as described herein. For example, a Ci alkyl group, i.e., methyl, may be substituted with oxo to form a formyl group and further substituted with -OH or -NRbRcto form a carboxyl group or an amido group.

[0197] Heteroaryl, alkenyl, alkynyl and arylalkyl groups may be substituted with carbocycle (e.g., cycloalkyl); aryl; heterocycle; halo; ORa’, in which Ra’ is H, alkyl, alkenyl, alkynyl, carbocycle (e.g., cycloalkyl), aryl, or heterocycle; SRa’, in which Ra’ is as defined herein; CN; NO2; N3; NRb’Rc’, in which each of Rb’ and Rc’ is, independently, H, alkyl, alkenyl, alkynyl, carbocycle (e.g., cycloalkyl), aryl, or heterocycle; SO2Rd’, in which Rd’ is H, alkyl or aryl; SO2NRe’Rf’, in which each of Re’ and Rf’ is, independently, H, alkyl, or aryl; SORg’, in which Rg’ is H, alkyl, or aryl; or P(O)(ORh’)2,in which each Rh is, independently, H or alkyl. Aryl, carbocycle (e.g., cycloalkyl), heteroaryl, and heterocycle groups may also be substituted with alkyl, alkenyl, or alkynyl. Alkyl, alkylene, alkenyl, alkynyl, carbocycle (e.g., cycloalkyl), and heterocycle groups may also be substituted with oxo or =NRj’, in which Rj’ is H or alkyl. In some embodiments, a substituent is further substituted as described herein. For example, a C1 alkyl group, i.e., methyl, may be substituted with oxo to form a formyl group and further substituted with OH or NRb’Rc’ to form a carboxyl group or an amido group. For the avoidance of doubt, any and all disclosures of methods of treatment or prevention provided herein should also be read as disclosing the compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the described methods of treatment or prevention.

[0198] Detailed Description

[0199] Described herein are compounds, compositions, and methods for treating neurological disorders, e.g., neurotraumatic disorders, neurodevelopmental disorders, or affective disorders, in a subject. Without wishing to be bound by theory, the compounds described herein may function as KCC2 potentiators. The compounds described herein are useful for treating neurological disorders, e.g., neurotraumatic disorders, neurodevelopmental disorders, or affective disorders.

[0200] Compounds

[0201] The present disclosure provides compounds and compositions that can be administered to a subject (e.g., a human) in order to treat a neurological disorder (e.g., a neurotraumatic disorder, a neurodevelopmental disorder, or an affective disorder).

[0202] In one aspect, the present disclosure provides a compound of formula (I):

[0203] Formula I, or a pharmaceutically acceptable salt thereof, wherein

[0204] R1is H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, SR6, N(R5)2,OR5, S(O)R14, SO2R14, or S(N)R14;

[0205] R4is H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, OR5, SR6, N(R5)2, S(O)R14, SO2R14, or S(N)R14, or R3and R4, together with the atoms to which each is attached, join to form a 5- to 6-membered aromatic or nonaromatic carbocycle or heterocycle;

[0206] R2and R3are each, independently, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, optionally substituted C5-C12 heteroaryl, optionally substituted C3-C12 heterocycle, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky ny I, optionally substituted C3-C12 cycloalkyl, optionally substituted C7-C14 arylalkyl, (CH2)POZ, C(O)Z, C(O)OZ, C(O)NZ2, OR5, N(R5)2, SR6, S(O)R14, SO2R14, or S(N)R14, or R2and R3together with the atoms to which each is attached, join to form a 5- to 6-membered aromatic or non-aromatic carbocycle or heterocycle; with Ci-Ce alkyl, C5-C12 aryl, C3-C12 cycloalkyl, C5-C12 heteroaryl, or C3-C12 heterocycle, optionally wherein the C5-C12 aryl, C3-C12 cycloalkyl, C5-C12 heteroaryl, or C3-C12 heterocycle is joined to A through one or more carbon atoms; n is 0, 1 , 2, or 3; m is 0, 1 , 2, or 3; each p is, independently, 1 , 2, or 3; each R5is, independently, H, optionally substituted O-Ce alkyl, optionally substituted C5-C12 aryl, or optionally substituted C3-C12 cycloalkyl; each R6is, independently, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-

[0207] Ce heteroalkyl, optionally substituted C3-C6 heterocycle, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C12 aryl, or optionally substituted C5-C12 heteroaryl; each R14is independently, H, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C6 heterocycle, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C12 aryl, or optionally substituted C5-C12 heteroaryl; and each Z is, independently, H, or optionally substituted O-Ce alkyl.

[0208] In some embodiments, R1, R2, R3and R4are not all H.

[0209] In some embodiments,

[0210] In some embodiments,

[0211] In some embodiments,

[0212] In some embodiments,

[0213] In some embodiments,

[0214] In some embodiments,

[0215] In some embodiments, R1is a halogen, e.g., Cl or F.

[0216] In some embodiments, R1is I, and R4is not H. In some embodiments, R1is an optionally substituted Ci-Ce alkyl, e.g., CH3, CH2CH3, CF3, CHF2,

[0217] In some embodiments, R1is Me, and R4is not H.

[0218] In some embodiments, R1is optionally substituted cycloalkyl, e.g.,

[0219] In some embodiments, R1is optionally substituted C3-C12 heterocycle, e.g., or

[0220] In some embodiments, R1is CF3.

[0221] In some embodiments, R4is a halogen e.g., Cl or F.

[0222] In some embodiments, R4is Cl, and R1is not H.

[0223] In some embodiments, R4is an optionally substituted Ci-Ce alkyl, e.g., CH3, CH2CH3, CF3, CHF2,

[0224] In some embodiments, R4is Me, and R1is not H.

[0225] In some embodiments, R4is optionally substituted carbocycle, e.g.,

[0226] In some embodiments, R4is optionally substituted C3-C12 heterocycle, e.g.,

[0227] In some embodiments, R4is CF3.

[0228] In some embodiments, R4is SR6, e.g., SF5, SCH3, or SCF3. some embodiments, R4is N(R5)2, e.g., NH2, NHCH3, or NfCHsk.

[0229] In some embodiments, R4is OR5, e.g., OCH3, OCF3, or OCHF2.

[0230] In some embodiments, R4is SO2R14, e.g., SO2CH3, SO2CH2CH3, or SO2(CH)(CH3)2.

[0231] In some embodiments, R4is S(O)R14, e.g., S(O)CH3, S(O)CH2CH3, or S(O)(CH)(CH3)2.

[0232] In some embodiments, R4is S(N)R14, e.g., S(N)CH3, S(N)CH2CH3, or S(O)(CH)(CH3)2.

[0233] In some embodiments, R2is a halogen, e.g., Cl or F.

[0234] In some embodiments, R2is Cl, and R1is not H.

[0235] In some embodiments, R2is Cl, and R4is not H.

[0236] In some embodiments, R2is OR5, e.g., OCH3.

[0237] In some embodiments, R2is N(R5)2, e.g., NH2.

[0238] In some embodiments, R2is SO2R14, e.g., SO2CH3, SO2CH2CH3, or SO2(CH)(CH3)2.

[0239] In some embodiments, R2is S(O)R14, e.g., S(O)CH3, S(O)CH2CH3, or S(O)(CH)(CH3)2.

[0240] In some embodiments, R2is S(N)R14, e.g., S(N)CH3, S(N)CH2CH3, or S(O)(CH)(CH3)2.

[0241] In some embodiments, R3is an optionally substituted Ci-Ce alkyl, e.g., CH3, CH2CH3, CF3, CHF2,

[0242] In some embodiments, R2is Me, and R1is not H.

[0243] In some embodiments, R2is Me, and R4is not H. ,

[0244] In some embodiments,

[0245] In some embodiments,

[0246] In some embodiments,

[0247] In some embodiments of any of the aspects described herein, R5is Ci-Ce alkyl, C5- C12 aryl, C5- C12 heteroaryl or C3-C12 heterocycle.

[0248] In some embodiments of any of the aspects described herein, R6is halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C6 heterocycle, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C12 aryl, or optionally substituted C5-C12 heteroaryl. In some embodiments of any of the aspects described herein, SR6is SF5.

[0249] In some embodiments, R6is an optionally substituted Ci-Ce alkyl, e.g., CH3, CH2CH3, CF3, CHF2, some embodiments, R6is optionally substituted carbocycle, e.g.,

[0250] In some embodiments, R6is CF3.

[0251] In some embodiments, R14is an optionally substituted Ci-Ce alkyl, e.g., CH3, CH2CH3, CF3, CHF2,

[0252] In some embodiments, R14is optionally substituted cycloalkyl, e.g.,

[0253] In some embodiments, R14is optionally substituted C3-C12 heterocycle, e.g., , or

[0254] In some embodiments, R14is an optionally substituted Ci-Ce heteroalkyl, e.g., OCH3, OCH2CH3, OCF3, OCHF2, or OCH2CF3.

[0255] In some embodiments, R14is optionally substituted C3-C12 heterocycle, e.g.,

[0256] In some embodiments, n is 0, 1 , 2, or 3.

[0257] In some embodiments, m is 0, 1 , 2, or 3.

[0258] In some embodiments, each p is, independently, 1 , 2, or 3.

[0259] In some embodiments, the compound is a compound of formula (l-A): or a pharmaceutically acceptable salt thereof.

[0260] In some embodiments, the compound is a compound of the formula (l-B): or a pharmaceutically acceptable salt thereof.

[0261] In some embodiments, the compound is a compound of formula (l-C): or a pharmaceutically acceptable salt thereof, wherein

[0262] R8, R9, R10and R11are each, independently, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky ny I, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, optionally substituted C7- C14 arylalkyl, (CH2)POZ, C(O)Z, C(O)OZ, C(O)NZ2, OR5, or N(R5)2.

[0263] In some embodiments of any of the aspects described herein, R8is H, halogen, optionally substituted Ci-Ce alkyl, or optionally substituted C3-C6 cycloalkyl.

[0264] In some embodiments of any of the aspects described herein, R9is H, halogen, optionally substituted Ci-Ce alkyl, or optionally substituted C3-C6 cycloalkyl.

[0265] In some embodiments of any of the aspects described herein, R10is H, halogen, optionally substituted Ci-Ce alkyl, or optionally substituted C3-C6 cycloalkyl.

[0266] In some embodiments of any of the aspects described herein, R11is H, halogen, optionally substituted Ci-Ce alkyl, or optionally substituted C3-C6 cycloalkyl.

[0267] In some embodiments, the compound is a compound of formula (l-D): or a pharmaceutically acceptable salt thereof, wherein

[0268] R8, R9, R10, and R11are each, independently, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky ny I, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, optionally substituted C7- C14 arylalkyl, (CH2)POZ, C(O)Z, C(O)OZ, C(O)NZ2, OR5, SR6, or N(R5)2.

[0269] In some embodiments, the compound is a compound of formula (l-E): or a pharmaceutically acceptable salt thereof.

[0270] In some embodiments, the compound is a compound of the formula (l-F): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of the formula (l-G): or a pharmaceutically acceptable salt thereof.

[0271] In some embodiments, the compound is a compound of the formula (l-H): or a pharmaceutically acceptable salt thereof.

[0272] In some embodiments, the compound is a compound of the formula (l-J): or a pharmaceutically acceptable salt thereof.

[0273] In some embodiments, the compound is a compound of formula (l-K): or a pharmaceutically acceptable salt thereof.

[0274] In some embodiments, the compound is a compound of formula (l-L): or a pharmaceutically acceptable salt thereof.

[0275] In some embodiments, the compound is a compound of formula (l-M): or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is a compound of formula (l-N): or a pharmaceutically acceptable salt thereof.

[0276] In some embodiments, the compound is a compound of formula (l-O): or a pharmaceutically acceptable salt thereof.

[0277] In some embodiments, the compound is a compound of formula (l-P): or a pharmaceutically acceptable salt thereof.

[0278] In some embodiments, the compound is a compound of formula (l-Q): or a pharmaceutically acceptable salt thereof.

[0279] In some embodiments, the compound is a compound of formula (l-R): or a pharmaceutically acceptable salt thereof.

[0280] In some embodiments, the compound is a compound of formula (l-S): or a pharmaceutically acceptable salt thereof.

[0281] Exemplary compounds are provided in Table 1.

[0282] In another aspect, the present disclosure provides a compound of Table 1 or a pharmaceutically acceptable salt thereof.

[0283] In another aspect, the present disclosure provides a compound of Formula (II): or a pharmaceutically acceptable salt thereof, wherein

[0284] R1is H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, SR6, N(R5)2, OR5, S(O)R14, SO2R14, or S(N)R14;

[0285] R4is H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, OR5, SR6, N(R5)2, S(O)R14, SO2R14, or S(N)R14, or R3and R4, together with the atoms to which each is attached, join to form a 5- to 6-membered aromatic or nonaromatic carbocycle or heterocycle;

[0286] R2, R3are each, independently, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, optionally substituted C5-C12 heteroaryl, optionally substituted C3-C12 heterocycle, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky ny I, optionally substituted C3-C12 cycloalkyl, optionally substituted C7-C14 arylalkyl, (CH2)POZ, C(O)Z, C(O)OZ, C(O)NZ2, OR5, N(R5)2, SR6, S(O)R14, SO2R14, or S(N)R14, or R2and R3together with the atoms to which each is attached, join to form a 5- to 6-membered aromatic or non-aromatic carbocycle or heterocycle; , wherein A is optionally substituted with

[0287] Ci-Ce alkyl, C5-C12 aryl, C3-C12 cycloalkyl, C5-C12 heteroaryl, or C3-C12 heterocycle, optionally wherein the C5-C12 aryl, C3-C12 cycloalkyl, C5-C12 heteroaryl, or C3-C12 heterocycle is joined to A through one or more carbon atoms; n is 0, 1 , 2, or 3; m is 0, 1 , 2, or 3; each p is, independently, 1 , 2, or 3; each R5is, independently, H, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, or optionally substituted C3-C12 cycloalkyl, each R6is, independently, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C6 heterocycle, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C12 aryl, or optionally substituted C5-C12 heteroaryl, each R14is independently, H, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C6 heterocycle, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C12 aryl, or optionally substituted C5-C12 heteroaryl; each Z is, independently, H, or optionally substituted Ci-Ce alkyl; wherein Ra’ is H, OH, optionally substituted

[0288] Ci-Ca alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky nyl, optionally substituted C3-C12 cycloalkyl, or optionally substituted Ce-Ci4 aryl; and Rais CH2NH or C(Rd)2O, wherein each Rdis independently H, Ci-Cs alkyl, Ci-Cs cycloalkyl, Ci-Cs aryl, or Ci-Cs heteroaryl; Rbis H, OH, optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky nyl, optionally substituted Ci-Cs alkoxy, optionally substituted C3-C12 cycloalkyl, optionally substituted Ce-Ci4 aryl, or N(Re)2, each Rcis, independently H, Ci-Cs alkyl, or C6-C14 aryl, and each Reis independently H or Ci-Cs alkyl.

[0289] In some embodiments, R1, R2, R3and R4are not simultaneously H.

[0290] In some embodiments,

[0291] In some embodiments,

[0292] In some embodiments,

[0293] In some embodiments,

[0294] In some embodiments, R12is C(O)Ra’

[0295] In some embodiments,

[0296] In some embodiments,

[0297] In some embodiments, Ra’ is optionally substituted Ci-Cs alkyl

[0298] In some embodiments, Rais CH2NH. In some embodiments, Rais C(Rd)2O.

[0299] In some embodiments, Rd is CH2O or CH(CH3)O.

[0300] In some embodiments, Rais CH2O or CH(CH3)O.

[0301] In some embodiments, Rbis optionally substituted Ci-C3alkyl.

[0302] In some embodiments, Rbis (CH2)sCH3, CH3, C(CH3)3, or CH(CH3)2.

[0303] In some embodiments, Rbis carboxyl substituted Ci-C3alkyl.

[0304] In some embodiments, Rbis (CH2)4COOH, CH2COOH, (CH2)2COOH, (CH2)3COOH,

[0305] In some embodiments, Rbis optionally substituted Ci-C3alkoxy.

[0306] In some embodiments,

[0307] In some embodiments, each Reis independently H or Ci-C3alkyl.

[0308] In some embodiments, Rbis NHCH2CH3.

[0309] In some embodiments, each Rcis independently, H or C(CH3)3.

[0310] In some embodiments, the compound of formula II has the structure: thereof.

[0311] In some embodiments, the compound of formula II has the structure: salt thereof. Pharmaceutical compositions

[0312] A pharmaceutical composition of the disclosure contains one or more of the compounds disclosed herein (e.g., one or more of the compounds of any one of Formulas (I), (l-A), (l-B), (l-C), (l-D), (l-E), (l-F), (l-G), (l-H), (l-J), (l-K), (l-L), (l-M), (l-N), (l-O), (l-P), (l-R), (l-S), (l-T), and (II), and other compounds disclosed herein) as the therapeutic compound. In addition to a therapeutically effective amount of the compound, the pharmaceutical compositions also contain a pharmaceutically acceptable excipient, which can be formulated by methods known to those skilled in the art. The compounds disclosed herein (e.g., the compounds of Formulas (I), (l-A), (l-B), (l-C), (l-D), (l-E), (l-F), (l-G), (l-H), (l-J), (I-K), (l-L), (l-M), (l-N), (1-0), (l-P), (l-R), (l-S), (l-T), and (II), and other compounds disclosed herein) may also be administered with or without other therapeutics for a particular condition, formulated in the same composition or different compositions for administration via the same or different routes.

[0313] The compounds disclosed herein (e.g., the compounds of Formulas (I), (l-A), (l-B), (l-C), (l-D), (I- E), (l-F), (l-G) , (l-H) , (l-J), (l-K), (l-L), (l-M), (l-N), (1-0), (l-P), (l-R), (l-S), (l-T), and (II), and the compounds of Table 1 and Table 2) may be used in the form of free base, or in the form of salts or solvates. All forms are within the scope of the disclosure.

[0314] Routes of administration of the pharmaceutical compositions (or the compounds of the composition) include oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intra-arterial, intracranial, subcutaneous, intracerebroventricular, intraorbital, intraventricular, intrathecal (intraspinal), intraperitoneal, intranasal, inhalation, and topical administration.

[0315] Neurological disorders

[0316] Neurological disorders are disorders that affect the brain, as well as nerves throughout the body and also the spinal cord. Common symptoms of neurological disorders include numbness, tingling, muscle weakness, loss of muscle tone, loss of sensation, disruption or loss of autonomic function, numbness, bowel, or bladder incontinence, paralysis, confusion, pain, altered levels of consciousness, mood disorders, and sexual dysfunction. Certain primary symptoms, such as impaired movement and sensation, can further lead to secondary symptoms including muscle atrophy, loss of voluntary motor control and spasticity at sites of the body innervated by the neurological disorder, pressure (e.g., bed) sores, infections, and respiratory problems. Furthermore, cell death at the neurological disorder may continue long after the initial insult that precipitated the neurological disorder as a result of stress and inflammatory signaling that leads to further ischemia, inflammation, swelling, and disruption of synaptic signaling. Neurological disorder may result in total loss of motor and sensory function distal to the neurological disorder, or incomplete, resulting in partial loss of motor and sensory function.

[0317] Neurological disorders may present as various distinct conditions, depending on the site and severity of the condition. For example, peripheral neurological disorder results from damage to peripheral nerves that extend to the extremities of an individual, leading to numbness and / or loss of sensory function. Proximal neurological disorder results from damage to peripheral and / or central nerves, leading to muscle weakness in the upper part of the legs, buttocks, and / or hips in a subject. Autonomic neurological disorder results from damage and / or dysfunction of autonomic nerves that least to reduced and / or uncontrolled body homeostasis of an individual. Focal neurological disorder and / or polyneurological disorder results from damage to one nerve and / or a plurality of nerves, respectively. Central cord syndrome frequently results from damage to the cervical spinal cord, resulting in weakness in the upper extremities with relative sparing of function in the legs and spared sensation in sacral dermatomes (e.g., urinary sphincter, anal sphincter, and genitalia).

[0318] Neurological disorders include, but are not limited to neurotraumatic disorders such as spinal cord injury (SCI), traumatic brain injury (TBI), stroke (e.g., hemorrhagic or ischemic stroke), peripheral nerve injury (PNI), myelopathy, hypoxic-ischemic encephalopathy, tumor-associated epilepsy, spasticity, multiple sclerosis, ischemia, amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), Alzheimer’s disease (AD), and peripheral neuropathy (PN); neurodevelopmental disorders such as autism, Rett syndrome, Fragile X syndrome, Angelman syndrome, cerebral palsy, Down syndrome, pain (neuropathic pain, chronic pain, or inflammatory pain), Dravet syndrome, epilepsy (e.g., focal epilepsy, temporal lobe epilepsy, refractory epilepsy, generalized epilepsy, developmental and epileptic encephalopathy (DEE), epilepsy of infancy with migrating focal seizures (EIMFS), absence epilepsy, Lennox-Gastaut syndrome, neurotrauma associated epilepsy, status epilepticus, tumor associated epilepsy, hypoxic-ischemic encephalopathy and sudden unexpected death in epilepsy); and affective disorders, such as schizophrenia, bipolar disorder, anxiety disorder, and major depressive disorder (MDD).

[0319] Neurotraumatic disorders are disorders of the nervous system that result from neurological trauma, such as, e.g., traumatic brain injury (TBI), spinal cord injury (SCI), peripheral nerve injury (PNI), peripheral neuropathy (PN), stroke, ischemia, hypoxic-ischemic encephalopathy, tumor-associated epilepsy, and spasticity. In the U.S., roughly 1.7 million people are estimated to suffer TBI every year from causes such as falls, motor vehicle-related incidents, sports injuries, and violence, roughly 52,000 of which succumb to such injuries. Survivors of neurological trauma often face prolonged or indefinite disability.

[0320] TBI (also known as intracranial injury) usually results from an external force suddenly impacting the head of an individual, with the severity of the from mild (e.g., concussion) to severe (e.g., penetrating injury, coma-inducing injury). Sequalae of TBI often includes loss of consciousness, physical, cognitive, social, emotional, and behavioral impairments, but can also be fatal.

[0321] A SCI (spinal cord injury) refers to any insult to the any region of the spinal cord, e.g., the cervical vertebrae, the thoracic vertebrae, the lumbar vertebrae, the sacral vertebrae, the sacrum, or the coccyx, that causes a negative effect on the function of the spinal cord, e.g., reduce mobility of feeling in limbs. The severity of a spinal cord injury is measured in levels of the injury’s outcome, e.g., ranging from no effect on mobility, e.g., retained walking capacity, to paraplegia (e.g., paralysis of legs and lower region of body), and tetraplegia (e.g., loss of muscle strength in all four extremities).

[0322] PNI (peripheral nerve injury) refers to any disorder resulting from a nerve injury caused by a traumatic event. Peripheral nerve injury is generally divided into three distinct events, namely, (1) Wallerian degeneration; (2) axon regeneration / growth; and (3) nerve innervation. Types of PNI include, from least severe to most severe: neurapraxia (axon remains intact, but myelin is damaged), axonotmesis (disruption ofthe axon with maintenance of the epineurium), and neurotmesis (loss of axon continuity / axon transection).

[0323] Stroke is a condition which occurs when the blood supply to a part of the brain is interrupted (i.e. , ischemic stroke) by obstruction of a blood vessel by a blood clot, an embolism, systemic hypoperfusion, or cerebral venous sinus thrombosis or when a blood vessel in the brain bursts and releases blood into the spaces surrounding the brain cells (i.e., hemorrhagic stroke) as a result of an intracerebral or a subarachnoid hemorrhage. Stroke poses a substantial public burden as nearly 77.2 million people experienced an ischemic stroke, and 29.1 million people experienced a hemorrhagic stroke in 2019. Depending on the area of the brain affected by the stroke, the symptoms of a stroke may include numbness or weakness, especially on one side of the body corresponding to the contralateral side of the stroke, muscle flaccidity or spasticity, confusion, trouble understanding or producing speech, impaired vision in both eyes, impaired mobility, dizziness, severe headache, or loss of balance or coordination. Neurological trauma may also result from progressive neurodegenerative disorders that result in damage to neural tissue of the CNS. Non-limiting examples of neurodegenerative disorders contemplated for treatment using the presently disclosed compositions and methods include, but are not limited to, Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease (PD), Alzheimer's Disease (AD), and peripheral neuropathy (PN).

[0324] Neurodevelopmental disorders refer to neurological disorders resulting from abnormal development of the nervous system and are characterized by abnormal brain function, including, but not limited to, impairments in emotional regulation, learning and memory, impulse control, and cognition. This class of neurological disorders is characterized by diverse etiologies that may account for the multeity of symptoms and their degree of severity. Generally, neurodevelopmental disorders are caused by disruptions the neurotypical developmental trajectory of the nervous system, which can produce pathological anatomical architecture and connectivity in the nervous system. Causes of neurodevelopmental disorders may include genetic and metabolic diseases, social isolation, inflammatory and autoimmune disorders, infectious diseases, malnutrition, physical trauma, as well as environmental factors. The present disclosure contemplates treatment of neurodevelopmental disorders such as, e.g., autism spectrum disorders, Rett syndrome, Fragile X syndrome, Angelman syndrome, cerebral palsy, Down syndrome, pain (e.g., neuropathic pain, chronic pain, or inflammatory pain), Dravet syndrome, epilepsy (e.g., epilepsy related to one or more KCC2 mutations or epilepsy of infancy with migrating focal seizures (EIMFS) or temporal lobe epilepsy), and sudden unexpected death in epilepsy by administering a composition of the disclosure to the afflicted subject, thereby treating the subject.

[0325] Affective disorders (also known as mood disorders) are a class of neurological conditions characterized by dysregulation of normal affect and mood. Disorders of affect may feature mania or hypomania (e.g., schizophrenia and bipolar disorder), depressed mood (e.g., schizophrenia, bipolar disorder, and MDD), and moods that cycle between mania and depression (e.g., bipolar disorder). Affective disorders that may be treated using the disclosed methods and compositions include schizophrenia, bipolar disorder, and MDD.

[0326] Schizophrenia is a psychiatric disease characterized by recurrent psychosis. Symptoms of schizophrenia may include (1) positive symptoms related to hallucinations and reality distortion; (2) disorganized symptoms characterized by attentional impairment and thought disorder; and (3) negative symptoms such as apathy, anhedonia, avolition and loss of verbal fluency. Dysfunction of the limbic- cortical system may be implicated in all three types of symptoms. Causes of schizophrenia have been attributed to biological sex, genetic mutations, environmental factors, malnutrition during pregnancy, and age of parents, among other factors. Several hypotheses exist as to the etiology of schizophrenia, one being the glutamate hypothesis in which reduced glutamatergic drive to potentiatory interneurons is thought to result in reduced cortical inhibition and altered cortical network dynamics that lead to presentation of clinical symptoms.

[0327] Bipolar disorder is an affective disorder that features recurrent bouts of depression and mania (i.e. , abnormally elevated mood) spanning from days to weeks each . Causes of bipolar disorder may be manifold, but genetic and environmental factors have been implicated . Generally, two types of bipolar disorder exist, namely, bipolar I disorder, in which there has been at least one manic episode with or without depressive episodes, and bipolar II disorder, in which there has been at least one hypomanic episode and one major depressive episode.

[0328] MDD is a neurological disorder that is often characterized by the patient having at least two weeks of sustained low mood, low self-esteem, loss of interest in routine activities, hyperalgesia, and low psychomotor activity. Depression in MDD may last for periods of time (weeks, days, months, or years) separated by years or may be continuous. MDD may pose a substantial risk to the afflicted patient as the patient may be at a substantially higher risk for suicide. Etiological causes of the disorder have been attributed to substance abuse, other medical conditions (e.g., neurological disorders, metabolic disorders, gastrointestinal disorders, endocrine disorders, cardiovascular disease, pulmonary disease, cancer, and autoimmune disease), and genetic and environmental factors.

[0329] A neurological disorder may also be caused by infection, ischemia, and tumors. Owing to the physiological barriers to regeneration in the central nervous system (CNS), neurological disorders have been a notoriously difficult condition to treat, with most treatments being palliative and rehabilitative. Most treatments involve imposing limitations to movement, maintenance of proper blood pressure by frequent repositioning of the subject, and physical and occupation therapy.

[0330] Methods of treating a neurological disorder

[0331] The compounds disclosed herein (e.g., the compounds of Formulas(l), (l-A), (l-B), (l-C), (l-D), (I- E), (l-F), (l-G), (l-H), (l-J), (l-K), (l-L), (l-M), (l-N), (l-O), (l-P), (l-R), (l-S), (l-T), and (II), and other compounds disclosed herein) are, in general, suitable for use in preventing or treating a neurological disorder.

[0332] The compounds disclosed herein (e.g., the compounds of Formulas (I), (l-A), (l-B), (l-C), (l-D), (I- E), (l-F), (l-G), (l-H), (l-J), (l-K), (l-L), (l-M), (l-N), (1-0), (l-P), (l-R), (l-S), (l-T), and (II), and other compounds disclosed herein) are, in general, suitable for use in treating a neurological disorder, e.g., a neurotraumatic, neurodevelopmental, and / or affective disorder, or complications resulting therefrom. Nonlimiting examples of neurotraumatic disorders include spinal cord injury (SCI), traumatic brain injury (TBI), stroke (e.g., hemorrhagic or ischemic stroke), peripheral nerve injury (PNI), multiple sclerosis (MS), ischemia, amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), Alzheimer’s disease (AD), peripheral neuropathy (PN), hypoxic-ischemic encephalopathy, tumor-associated epilepsy, and spasticity. Neurodevelopmental disorders may include, but are not limited to autism, Rett syndrome, Fragile X syndrome, Angelman syndrome, cerebral palsy, Down syndrome, pain (e.g., neuropathic pain, chronic pain, or inflammatory pain), Dravet syndrome, epilepsy (e.g., epilepsy related to one or more KCC2 mutations or epilepsy of infancy with migrating focal seizures (EIMFS) or temporal lobe epilepsy), and sudden unexpected death in epilepsy. Non-limiting examples of affective disorders include schizophrenia, bipolar disorder, anxiety disorder, and major depressive disorder (MDD).

[0333] TBI (also known as intracranial injury) usually results from an external force suddenly impacting the head of an individual, with the severity of the from mild (e.g., concussion) to severe (e.g., penetrating injury, coma-inducing injury). Sequalae of TBI often includes loss of consciousness, physical, cognitive, social, emotional, and behavioral impairments, but can also be fatal.

[0334] SCI refers to any insult to any region of the spinal cord, e.g., the cervical vertebrae, the thoracic vertebrae, the lumbar vertebrae, the sacral vertebrae, the sacrum, or the coccyx, that causes a negative effect on the function of the spinal cord, e.g., reduce mobility of feeling in limbs. The severity of a spinal cord injury is measured in levels of the injury’s outcome, e.g., ranging from no effect on mobility, e.g., retained walking capacity, to paraplegia (e.g., paralysis of legs and lower region of body), and tetraplegia (e.g., loss of muscle strength in all four extremities).

[0335] PNI refers to any disorder resulting from a nerve injury caused by a traumatic event. Peripheral nerve injury is generally divided into three distinct events, namely, (1) Wallerian degeneration; (2) axon regeneration / growth; and (3) nerve innervation. Types of PNI include, from least severe to most severe: neurapraxia (axon remains intact, but myelin is damaged), axonotmesis (disruption of the axon with maintenance of the epineurium), and neurotmesis (loss of axon continuity / axon transection).

[0336] Stroke is a condition which occurs when the blood supply to a part of the brain is interrupted (i.e. , ischemic stroke) by obstruction of a blood vessel by a blood clot, an embolism, systemic hypoperfusion, or cerebral venous sinus thrombosis or when a blood vessel in the brain bursts and releases blood into the spaces surrounding the brain cells (i.e., hemorrhagic stroke) as a result of an intracerebral or a subarachnoid hemorrhage. Depending on the area of the brain affected by the stroke, the symptoms of a stroke may include numbness or weakness, especially on one side of the body corresponding to the contralateral side of the stroke, muscle flaccidity or spasticity, confusion, trouble understanding or producing speech, impaired vision in both eyes, impaired mobility, dizziness, severe headache, or loss of balance or coordination.

[0337] Neurological trauma may also result from progressive neurodegenerative disorders that results in damage to neural tissues of the CNS. Non-limiting examples of neurodegenerative disorders contemplated for treatment using the presently disclosed compositions and methods include, but are not limited to, Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease (PD), Alzheimer's Disease (AD), and peripheral neuropathy (PN).

[0338] Neurodevelopmental disorders refer to neurological disorders resulting from abnormal development of the nervous system and are characterized by abnormal brain function, including, but not limited to, impairments in emotional regulation, learning and memory, impulse control, and cognition. This class of neurological disorders is characterized by diverse etiologies that may account for the multeity of symptoms and their degree of severity. Generally, neurodevelopmental disorders are caused by disruptions of the neurotypical developmental trajectory of the nervous system, which can produce pathological anatomical architecture and connectivity in the nervous system. The causes of neurodevelopmental disorders may include genetic and metabolic diseases, social isolation, inflammatory and autoimmune disorders, infectious diseases, malnutrition, physical trauma, as well as environmental factors. The present disclosure contemplates treatment of neurodevelopmental disorders such as, e.g., autism spectrum disorders, Rett syndrome, Fragile X syndrome, Angelman syndrome, cerebral palsy, Down syndrome, pain (e.g., neuropathic pain, chronic pain, or inflammatory pain), Dravet syndrome, epilepsy (e.g., epilepsy related to one or more KCC2 mutations or epilepsy of infancy with migrating focal seizures (EIMFS) or temporal lobe epilepsy), and sudden unexpected death in epilepsy by administering a composition of the disclosure to the afflicted subject, thereby treating the subject.

[0339] Affective disorders (also known as mood disorders) are a class of neurological conditions characterized by dysregulation of normal affect and mood. Disorders of affect may feature mania or hypomania (e.g., schizophrenia and bipolar disorder), depressed mood (e.g., schizophrenia, bipolar disorder, and MDD), and moods that cycle between mania and depression (e.g., bipolar disorder). Affective disorders that may be treated using the disclosed methods and compositions include schizophrenia, bipolar disorder, and MDD.

[0340] Schizophrenia is a psychiatric disease characterized by recurrent psychosis. Symptoms of schizophrenia may include (1) positive symptoms related to hallucinations and reality distortion; (2) disorganized symptoms characterized by attentional impairment and thought disorder; and (3) negative symptoms such as apathy, anhedonia, avolition and loss of verbal fluency. Dysfunction of the limbic- cortical system may be implicated in all three types of symptoms.

[0341] Bipolar disorder is an affective disorder that features recurrent bouts of depression and mania (i.e. , abnormally elevated mood) spanning from days to weeks each. Causes of bipolar disorder may be manifold, but genetic and environmental factors have been implicated. Generally, two types of bipolar disorder exist, namely, bipolar I disorder, in which there has been at least one manic episode with or without depressive episodes, and bipolar II disorder, in which there has been at least one hypomanic episode and one major depressive episode.

[0342] MDD is a neurological disorder that is often characterized by the patient having at least two weeks of sustained low mood, low self-esteem, loss of interest in routine activities, hyperalgesia, and low psychomotor activity. Depression in MDD may last for periods of time (weeks, days, months, or years) separated by years or may be continuous. MDD may pose a substantial risk to the afflicted patient as the patient may be at a substantially higher risk for suicide.

[0343] The dosage of the pharmaceutical compositions of the disclosure depends on factors including, but are not limited to, the route of administration, the severity of the condition to be treated, and physical characteristics, e.g., age, weight, and general health, of the subject. Typically, the amount of a compound disclosed herein (e.g., a compound of any one of Formulas (I), (l-A), (l-B), (l-C), (l-D), (l-E), (l-F), (l-G), (I- H), (l-J), (l-K), (l-L), (l-M), (l-N), (l-O), (l-P), (l-R), (l-S), (l-T), and (II), and other compounds disclosed herein) contained within a single dose may be an amount that effectively imparts the desired therapeutic effect without inducing significant toxicity. The dosage may be adapted by the clinician in accordance with conventional factors such as the extent of the disease and different parameters of the subject .

[0344] Pharmaceutical compositions of the disclosure that contain a compound disclosed herein (e.g., a compound of any one of Formulas (I), (l-A), (l-B), (l-C), (l-D), (l-E), (l-F), (l-G), (l-H), (l-J), (l-K), (l-L), (l-M), (l-N), (l-O), (l-P), (l-R), (l-S), (l-T), and (II), and other compounds disclosed herein may be administered to a subject in need thereof one or more times (e.g., 10 times or more) daily, or as medically necessary. The timing between administrations may decrease as the medical condition improves or increase as the health of the subject declines.

[0345] The compounds of the disclosure, or pharmaceutical compositions of the disclosure that contain a compound disclosed herein (e.g., a compound of any one of Formulas (I), (l-A), (l-B), (l-C), (l-D), (l-E), (l-F), (l-G), (l-H), (l-J), (l-K), (l-L), (l-M), (l-N), (l-O), (l-P), (l-R), (l-S), (l-T), and (II), and other compounds disclosed herein,) may be administered to a subject in need thereof one time daily or twice daily. Thus, the compounds and pharmaceutical compositions may be administered QD or BID.

[0346] The following examples are merely illustrative and should not be construed as limiting the scope of this disclosure in any way as many variations and equivalents will become apparent to those skilled in the art upon reading the present disclosure. The contents of all references, patents, and patent applications cited throughout this application are expressly incorporated herein by reference.

[0347] Examples

[0348] The following examples are put forth so as to provide those of ordinary skill in the art with a description of how the compositions and methods described herein may be used, made, and evaluated, and are intended to be purely exemplary of the disclosure and are not intended to limit the scope of what the inventors regard as their disclosure.

[0349] Example 1 : Synthesis of Compound 18

[0350] Step 1 : 2-(((4-methyl-2-(trifluoromethyl)pyridin-3-yl)methyl)thio)-5,7-dihydrofuro[3,4-d]pyrimidin- 4(3H)-one

[0351] To a stirred solution of 3-(chloromethyl)-4-methyl-2-(trifluoromethyl)pyridine (250 mg, 1.2 mmol, 1 equiv) and 2-mercapto-5,7-dihydrofuro[3,4-c / |pyrimidin-4(3 / 7)-one [CAS No: 1936243-76-3] (203 mg, 1.2 mmol, 1 equiv) in DMF (4 mL) was added DIEA (463 mg, 3.6 mmol, 3 equiv) dropwise at rt. The mixture was stirred at rt for 1 h, then quenched with saturated NH4CI and concentrated under reduced pressure. The residue was purified by reversed-phase chromatography [column, C18 silica gel; mobile phase, H2O in MeCN, 10% to 70% gradient in 16 min) to afford the product (136.8 mg, 33%) as a solid. LCMS (ESI) calcd. for C14H12F3N3O2S, 343.06; Found 344.00 [M+H]+;1H NMR (400 MHz, DMSO-cfe) 6 13.03 (s, 1 H), 8.55 - 8.56 (m, 1 H), 7.64 - 7.64 (m, 1 H), 4.86 - 4.88 (m, 4H), 4.56 - 4.61 (m, 2H), 2.48- 2.51 (m, 2H);19F-NMR (376 MHz, DMSO-cfe) 6 -61 .6.

[0352] Example 2: Synthesis of Compound 19

[0353] Step 1 : 2-chloro-4-((4-methoxybenzyl)oxy)-5,6-dihydrofuro[2,3-d]pyrimidine

[0354] To a stirred solution of (4-methoxyphenyl)methanol (173.6 mg, 1.26 mmol) in DMF (4 mL) were added NaH (50.3 mg, 1.26 mmol) and 2,4-dichloro-5 / 7,6 / 7-furo[2,3-c / |pyrimidine [CAS No: 1823731 -18-5] (200 mg, 1 .05 mmol) at 0 °C over 10 mins. The mixture was allowed to war to rt and stirred for 1 h. The reaction mixture was poured onto cooled H2O (50 mL) and NH4CI saturated aqueous solution (100 mL), then extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by silica gel column eluting with EtOAc I petroleum ether (Gradent:30%) to give the product (150 mg, 49%) as a solid. LC / MS: MS (ESI) calcd. for C14H13CIN2O3: 292.06; Found: 293.90 [M+H]+.

[0355] Step 2: 4-((4-methoxybenzyl)oxy)-2-((4-methoxybenzyl)thio)-5,6-dihydrofuro[2,3-d]pyrimidine

[0356] To a stirred solution of 2-chloro-4-((4-methoxybenzyl)oxy)-5,6-dihydrofuro[2,3-d]pyrimidine (150 mg, 0.51 mmol) in dioxane (3 mL) were added t-Bubrettphos Pd G3 (43.8 mg, 0.05 mmol), t-BuBrettPhos (49.8 mg, 0.10 mmol), Cs2CO3 (0.33 g, 1.02 mmol) and (4-methoxyphenyl)methanethiol (395 mg, 2.56 mmol) at 0 °C over 10 mins, then the mixture was heated to 90 °C and stirred for 2 h. The reaction mixture was poured onto cooled H2O (50 mL) and NH4CI saturated aqueous solution (100 mL), then extracted with EtOAc (2 x 100 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by silica gel column eluting with EtOAc / petroleum ether (Gradent:30%) to give the product (120 mg, 57%) as a solid. LC / MS: MS (ESI) calcd. for C22H22N2O4S: 410.13; Found: 411.05 [M+H]+.

[0357] Step 3: 2-mercapto-5,6-dihydrofuro[2,3-d]pyrimidin-4-ol

[0358] To a stirred solution of 4-((4-methoxybenzyl)oxy)-2-((4-methoxybenzyl)thio)-5,6-dihydrofuro[2,3- d]pyrimidine (110 mg, 0.29 mmol) in TFA (1 .6 mL) was added methanesulfonic acid (0.4 mL) at 0 °C. The mixture was allowed to warm to rt and stirred for 2 h, then poured onto cooled H2O (10 mL). A 2N sodium hydroxide aqueous solution was added thereto at ice cooling temperature, and the emerging precipitate was filtered, to give the product (30 mg, 60%) as a solid. LC / MS: MS (ESI) calcd. for C6H6N2O2S: 170.01 ; Found: 170.95 [M+H]+.

[0359] Step 4: 2-(((4-methyl-2-(trifluoromethyl)pyridin-3-yl)methyl)thio)-5,6-dihydrofuro[2,3-d]pyrimidin- 4(3H)-one

[0360] To a 30 mL round-bottom flask equipped with a stirring bar were added 2-mercapto-5,6- dihydrofuro[2,3-d]pyrimidin-4-ol (80 mg, 0.47 mmol) in DMF (1 mL), followed by addition of 3- (chloromethyl)-4-methyl-2-(trifluoromethyl)pyridine (108 mg, 0.52 mmol) and DIEA (182 mg, 1.41 mmol). The resulting solution was stirred at rt for 2 h, then saturated aqueous NH4CI added, and the emerging precipitate was collected by filtration and the filter cake was washed with MeCN (10 mL). The solid was purified by reverse-phase HPLC [conditions: column, C18 silica gel; mobile phase, MeCN in H2O (0.05 % NH4HCO3), 2% to 50% gradient in 15 min] to give the product (23.5 mg, 14.5% yield) as a solid. LC / MS: MS (ESI) calcd. for C14H12F3N3O2S, 343.06; Found 344.15 [M+H]+;1HNMR (400 MHz, DMSO-cfe) 6 8.51 - 8.52 (m, 1 H), 7.60 - 7.61 (m, 1 H), 4.48 - 4.51 (m, 4H), 2.85 - 2.90 (m, 2H), 2.46 - 2.51 (m, 3H);19FNMR (376 MHz, DMSO-cfe) 6 -61 .5. Example 3: Synthesis of Compound 9

[0361] Step 1 : 2-mercapto-6,7-dihydrofuro[3,2-d]pyrimidin-4(3H)-one

[0362] To a mixture of methyl 3-oxooxolane-2-carboxylate (500 mg, 3.47 mmol, 1 equiv) in MeCN (5 mL) under an atmosphere of N2 was added thiourea (317 mg, 4.16 mmol, 1 .2 equiv) and DBU (792 mg, 5.2 mmol, 1 .5 equiv). The mixture was heated to 85°C and stirred overnight, then concentrated under reduced pressure. The crude residue was recrystallized from EtOAc and MeCN, then dried under reduced pressure to obtain the product as a solid. LC / MS (ESI) calcd. for C6H6N2O2S: 170.01 ; Found 169.05 [M+H]-.

[0363] Step 2: 2-(((4-methoxy-2-methylpyridin-3-yl)methyl)thio)-6,7-dihydrofuro[3,2-d]pyrimidin-4(3H)-one

[0364] To a mixture of 3-(chloromethyl)-4-methoxy-2-methylpyridine (200 mg, 1.17 mmol, 1 equiv) in DMF (2 mL) was added 2-sulfanyl-3 / 7,6 / 7,7 / 7-furo[3,2-c / |pyrimidin-4-one (258 mg, 1 .5 mmol, 1 .3 equiv) and DIEA (603 mg, 4.67 mmol, 4 equiv). The mixture was stirred at rt for 40 min, then purified by reversed-phase chromatography [column, C18 silica gel; mobile phase, MeCN in H2O (10mmol / L NH4HCO3), 10% to 50% gradient in 10 min] and by prep-HPLC [column: XBridge Shield RP 18 OBD Column, 19*250 mm, 5pm; Mobile Phase A: H2O (10mmol / L NH4HCO3), Mobile Phase B: MeCN; Flow rate: 25 mL / min mL / min; Gradient: 15% B to 30% B in 7min] to give the product (25.4 mg, 7%) as a solid. LC / MS: mass calcd for C14H15N3O3S: 305.80; Found, 306.05 [M+H]+;1H NMR (300 MHz, DMSO-cfe) 5 12.60 - 12.80 (br. s, 1 H), 8.28 (m, 1 H), 6.93 (m, 1 H), 4.44 - 4.56 (m, 2H), 4.36 (s, 2H), 3.86 (s, 3H), 3.10 - 3017 (m, 2H), 2.50 - 2.51 (s, 3H).

[0365] Example 4: Synthesis of Compound 11

[0366] Step 1 : 2-[({4-M ethy I -2-[1 -(trifluoromethyl)cyclopropyl]pyridin-3-yl}methyl)sulfanyl]-3H,5H,7H- furo[3,4-d]pyrimidin-4-one; trifluoroacetic acid salt

[0367] To a mixture of 3-(chloromethyl)-4-methyl-2-[1-(trifluoromethyl)cyclopropyl]pyridine (300 mg, 1.2 mmol) and 2-sulfanyl-3 / 7,5 / 7,7 / 7-furo[3,4-c / |pyrimidin-4-one (286 mg, 1.7 mmol) in DMF (5 mL) was added DIEA (465 mg, 3.6 mmol). The mixture was stirred at rt for 2 h, then purified by reversed-phase column chromatography [conditions: column, C18 silica gel; mobile phase, ACN in H2O (0.05 % TFA), 5 to 50% gradient in 20 min] to give the product (178.6 mg, 29%) as a solid. LC / MS: mass calcd for C17H16F3N3O2S: 383.09; Found, 384.20[M+H]+;1H NMR (300 MHz, DMSO-cfe) 6 8.46 - 8.48 (m, 1 H), 7.38 - 7.40 (m, 1 H), 4.87 (s, 4H), 4.74 (s 2H), 2.42 (s, 3H), 1 .42 - 1 .55 (m, 2H), 1.21 - 1 .35 (m, 2 H);19FNMR (282 MHz, DMSO-cfe) 5 -67.1 , -74.9. Example 5: Synthesis of Compound 8

[0368] Step 1 : [2-(Methoxymethyl)-4-methylpyridin-3-yl]methanol

[0369] To a stirred mixture of ethyl 2-(methoxymethyl)-4-methylpyridine-3-carboxylate (400 mg, 1.9 mmol) in THF (5 mL) at 0°C was added LiAIH4 (145 mg, 3.8 mmol). The mixture was warmed to rt and stirred for 1 h, then quenched with ice / H2O (20 mL), filtered, and the filter cake was washed with H2O. The filtrate was extracted with EtOAc (50 mL x 3), and the combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was recrystallized (EtOAc / petroleum ether) to give the product (280 mg, 87%) as an oil. LC / MS: MS (ESI) calcd. for C9Hi3NO2: 167.09; Found: 168.15 [M+H]+.

[0370] Step 2: 3-(Chloromethyl)-2-(methoxymethyl)-4-methylpyridine

[0371] To a mixture of [2-(methoxymethyl)-4-methylpyridin-3-yl]methanol (280 mg, 1.7 mmol) in DCM (6 mL) at 0°C was added thionyl chloride (498 mg, 4.2 mmol). The mixture was warmed to rt and stirred for 1 h, then concentrated under reduced pressure to give the product (240 mg) as a solid.

[0372] Step 3: 2-({[2-(Methoxymethyl)-4-methylpyridin-3-yl]methyl}sulfanyl)-3H,5H,7H-furo[3,4- d]pyrimidin-4-one; trifluoroacetic acid salt

[0373] To a stirred mixture of 3-(chloromethyl)-2-(methoxymethyl)-4-methylpyridine (240 mg, 1.3 mmol) and 2-sulfanyl-3 / 7,5 / 7,7 / 7-furo[3,4-c / |pyrimidin-4-one (308 mg, 1.8 mmol) in DMF (4 mL) at rt was added DIEA (501 mg, 3.9 mmol). The mixture was stirred at rt for 0.5 h, then purified by reversed-phase column chromatography [conditions: column, C18 silica gel; mobile phase, H2O (0.05% TFA) in ACN, 10% to 50% gradient in 20 min] to give the product (142.8 mg) as a solid. LC / MS: MS (ESI) calcd. for C15H17N3O3S: 319.10; Found: 320.25 [M+H]+;1H-NMR (400 MHz, DMSO-cfe) 5 13.03 (s, 1 H), 8.44 - 8.46 (m, 1 H), 7.51 - 7.53 (m, 1 H), 4.87 - 5.00 (m, 4H), 4.85 - 4.86 (m, 2H), 4.54 - 4.59 (m, 2H), 3.36 - 3.38 (m, 3H), 2.58 - 2.64 (m, 3H);19F-NMR (376 MHz, DMSO-cfe) 5 -74.3.

[0374] Example 6: Synthesis of Compound 16

[0375] Step 1 : (2-(Ethylsulfonyl)-4-methylpyridin-3-yl) methanol

[0376] To a stirred mixture of (2-(ethylthio)-4-methylpyridin-3-yl) methanol (200 mg, 1.09 mmol) in DCM (3 mL) at 0°C was added m-CPBA (756 mg, 4.37 mmol). The resulting mixture was warmed to rt and stirred for 2 h, then filtered, and the filter cake was washed with DCM (3 x 3 mL). The filtrate was concentrated under reduced pressure and the residue was purified by reverse phase column chromatography [eluent: ACN and H2O (0.05% TFA)] to give the product (150 mg, 73%) as an oil. LCMS (ESI) m / z calcd. For C9H13NO3S, 215.08; found 216.08 [M+H]+.

[0377] Step 2: 3-(Chloromethyl)-2-(ethylsulfonyl)-4-methylpyridine

[0378] To a mixture of (2-(ethylsulfonyl)-4-methylpyridin-3-yl) methanol (150 mg, 0.69 mmol) in DCM (3 mL) at 0°C was added SOCI2 (207 mg, 1 .74 mmol). The resulting mixture was warmed to rt and stirred for 0.5 h, then concentrated under reduced pressure to give the product (100 mg, 53%) as an oil, which was used in the next step without further purification. LCMS (ESI) m / z calcd. for C9H12CINO2S, 233.03; found 234.03 [M+H]+.

[0379] Step 3: 2-(((2-(Ethylsulfonyl)-4-methylpyridin-3-yl) methyl) thio)-5,7-dihydrofuro[3,4-d] pyrimidin- 4(3H)-one

[0380] To a stirred mixture of 3-(chloromethyl)-2-(ethylsulfonyl)-4-methylpyridine (100 mg, 0.42 mmol) in DMF (2 mL) at rt was added 2-mercapto-5,7-dihydrofuro[3,4-c / | pyrimidin-4(3 / 7)-one (109 mg, 0.64 mmol), DIEA (167 mg, 1 .28 mmol). The mixture was stirred at rt for 0.5 h, then purified by reverse phase column chromatography [ACN and H2O (0.05% TFA)] to give the product (48.7 mg, 30%) as a solid. LCMS (ESI) m / z calcd. for C15H17N3O4S2, 367.07; found 368.05 [M+H]+;1H NMR (400 MHz, DMSO-cfe) 5 12.89 (br. s, 1 H), 8.43 - 8.63 (m, 1 H), 7.68 - 7.81 (m, 1 H), 4.82 - 4.98 (m, 6H), 3.62 - 3.81 (m, 2H), 2.41 - 2 49 (m, 3H), 1.25 (s, 3H);19F-NMR (376 MHz, DMSO-cfe) 5 -73.5.

[0381] Example 7: Synthesis of Compound 15

[0382] Step 1 : (2-(Ethylsulfinyl)-4-methylpyridin-3-yl) methanol

[0383] To a stirred mixture of (2-(ethylthio)-4-methylpyridin-3-yl) methanol (450 mg, 2.45 mmol) in ACN (5 mL) at 0°C and H2O (0.5 mL) was added NaCIO (370 mg, 4.91 mmol). The mixture was warmed to rt and stirred for 0.5 h, then ice-cold H2O added, and the mixture was purified by reverse-phase column chromatography [ACN and H2O (0.05% TFA)] to give the product (210 mg, 45%) as an oil. LCMS (ESI) calcd. m / z for C9H13NO2S, 199.07; found 200.07 [M+H]+.

[0384] Step 2: (2-(Ethylsulfinyl)-4-methylpyridin-3-yl) methyl methanesulfonate

[0385] To a mixture of (2-(ethylsulfinyl)-4-methylpyridin-3-yl) methanol (150 mg, 0.75 mmol) in DCM (3 mL) at 0°C was added TEA (228 mg, 2.26 mmol), MS2O (196 mg, 1 .14 mmol). The mixture was warmed to rt and stirred for 0.5 h, then concentrated under reduced pressure to afford the product (110 mg, 48%) as an oil, which was used in the next step without further purification. LCMS (ESI) m / z calcd. for C10H15NO4S2, 277.04; found 278.04 [M+H]+. Step 3: 2-(((2-(Ethylsulfinyl)-4-methylpyridin-3-yl) methyl) thio)-5,7-dihydrofuro[3,4-d] pyrimidin- 4(3H)-one

[0386] To a mixture of (2-(ethylsulfinyl)-4-methylpyridin-3-yl) methyl methanesulfonate (110 mg, 0.39 mmol) in DMF (2 mL) at rt was added 2-mercapto-5,7-dihydrofuro[3,4-c / | pyrimidin-4(3 / 7)-one (100 mg, 0.59 mmol), DIEA (128.5 mg, 0.98 mmol). The mixture was warmed to rt and stirred for 0.5 h, then purified by reverse-phase column chromatography [ACN and H2O (0.05% TFA)] to give the product (24.5 mg, 17%) as a solid. LCMS (ESI) m / z calcd. for C15H17N3O2S2, 351.07; found 352.10 [M+H]+;1H NMR (400 MHz, DMSO-cfe) 5 8.43 - 8.53 (m, 1 H), 7.38 - 7.48 (m, 1 H), 4.82 - 4.98 (m, 4H), 4.72 - 4.81 (m, 1 H), 3.01 - 3.11 (m, 2H), 2.45 - 2 49 (m, 3H), 1.15 (s, 3H);19F-NMR (376 MHz, DMSO-cfe) 5 -75.0.

[0387] Example 8: Synthesis of Compound 20

[0388] Step 1 : Ethyl 2-(methylsulfanyl)-4-(trifluoromethyl)pyridine-3-carboxylate

[0389] A stirred mixture of 2-(methylsulfanyl)-4-(trifluoromethyl)pyridine-3-carboxylic acid (300 mg, 1.3 mmol), Etl (296 mg, 1 .9 mmol) and K2CO3 (612 mg, 4.4 mmol) in DMF (3 mL) was stirred at 60 °C for 30 min, then extracted with EtOAc (3 x 500 mL). The combined organic layers were washed with H2O (3 x 10 mL), dried over anhydrous Na2SO and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase flash chromatography [conditions: column, C18 silica gel; mobile phase, ACN in H2O (0.1 % TFA), 10% to 80% gradient] to give the product (250 mg) as an oil.

[0390] Step 2: [2-(methylsulfanyl)-4-(trifluoromethyl)pyridin-3-yl]methanol

[0391] A stirred mixture of ethyl 2-(methylsulfanyl)-4-(trifluoromethyl)pyridine-3-carboxylate (250 mg, 0.94 mmol)and DIBAL, 25% in toluene (4.72 mmol) in THF (3 mL) was stirred at rt for 1 h. The mixture was cooled to 0 °C and ice / H2O was added, then purified by reversed-phase flash chromatography [conditions: column, C18 silica gel; mobile phase, ACN in H2O (0.1 % TFA), 10% to 80% gradient] to give the product (200 mg) as an oil. Step 3: 3-(Chloromethyl)-2-(methylsulfanyl)-4-(trifluoromethyl)pyridine

[0392] A stirred mixture of (2-(methylthio)-4-(trifluoromethyl)pyridin-3-yl)methanol (200 mg, 0.9 mmol)and thionyl chloride (267 mg, 2.24 mmol) in DCM (2 mL) was stirred at rt for 0.5 h, then concentrated under reduced pressure. The crude product mixture was used in the next step directly without further purification.

[0393] Step 4: 2-(((2-(methylthio)-4-(trifluoromethyl)pyridin-3-yl)methyl)thio)-3,5,6,7-tetrahydro-4H- cyclopenta[d]pyrimidin-4-one

[0394] A stirred mixture of 3-(chloromethyl)-2-(methylsulfanyl)-4-(trifluoromethyl)pyridine (150 mg, 0.62 mmol), 2-sulfanyl-3 / 7,5 / 7,6 / 7,7 / 7-cyclopenta[d]pyrimidin-4-one (104 mg, 0.62 mmol) and DIPEA (240 mg, 1 .9 mmol) in DMF (2 mL) was stirred at rt temperature for 0.5 h, then purified by reversed-phase column chromatography [conditions: column, C18 silica gel; mobile phase, ACN in H2O (0.1 % TFA), 10% to 80% gradient] to give the product (80.6 mg) as a solid. LC / MS: m / z MS (ESI) calcd. For C15H14F3N3OS2: 373.05. Found: 373.95 [M+H]+.

[0395] Example 9: Synthesis of Compound 12

[0396] Step 1 : Methyl 2-(ethylsulfanyl)-4-methylpyridine-3-carboxylate

[0397] To a stirred mixture of methyl 2-chloro-4-methylpyridine-3-carboxylate (1 .0 g, 5.4 mmol) in 1 ,4- dioxane (10 mL) under an atmosphere of N2 was added ABuBrettPhos Pd G3 (0.69 g, 0.81 mmol), t- BuBrettPhos (0.52 g, 1 .04 mmol) and ethanethiol (1 .67 g, 26.9 mmol). The mixture was heated to 80 °C and was stirred for 2 h, then purified by reversed-phase colum chromatography [conditions: column, C18 silica gel; mobile phase, ACN in H2O (0.1 % TFA), 10% to 80% gradient in 20 min] to give the product (500 mg, 40%) as an oil. LC / MS: mass calcd for C10H13NO2S: 211.07, found: 212.00 [M+H]+.

[0398] Step 2: [2-(ethylsulfanyl)-4-methylpyridin-3-yl]methanol

[0399] A mixture of methyl 2-(ethylsulfanyl)-4-methylpyridine-3-carboxylate (450 mg, 2.13 mmol) and LiAIFL (121 mg, 3.2 mmol) in THF (3 mL) was stirred rt for 1 h. The mixture was quenched with ice / FLO and the resulting mixture was extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography [conditions: column, C18 silica gel; mobile phase, ACN in H2O (0.1 % TFA), 10% to 80% gradient in 20 min] to give the product (250 mg). Step 3: 3-(chloromethyl)-2-(ethylsulfanyl)-4-methylpyridine

[0400] To a stirred mixture of [2-(ethylsulfanyl)-4-methylpyridin-3-yl]methanol (250 mg, 1.36 mmol) in DMF (2 mL) at 0 °C was added SOCh (405mg, 3.4 mmol).The reaction was stirred for 1 h, then concentrated under reduced pressure to give the product (150 mg, 49%) as a solid.

[0401] Step 4: 2-({[2-(ethylsulfanyl)-4-methylpyridin-3-yl]methyl}sulfanyl)-3H,5H,7H-furo[3,4-d]pyrimidin- 4-one

[0402] Undertaken in a manner similar to Step 4, Example 8 and purified by reversed-phase column chromatography [conditions: column, C18 silica gel; mobile phase, ACN in H2O (0.05% TFA), 10% to 80% gradient in 25 min] to give the product (93.5 mg, 36%) as a solid. LC / MS: MS (ESI) calcd. for C15H17N3O2S2: 335.08; Found: 336.00 [M+H]+;1H-NMR (400 MHz, DMSO-cfe) 6 12.95 (s, 1 H), 8.25 (m, 1 H), 7.03 (m, 1 H), 4.87 (s, 4H), 4.43 (s, 2H), 3.18 (m, 2H), 2.34 (s, 3H), 1.29 (m, 3H);19F-NMR (376 MHz, DMSO) 5 -75.2.

[0403] Example 10: Synthesis of Compound 21

[0404] Step 1 : Ethyl 2-cyclobutyl-4-methylnicotinate

[0405] To a stirred mixture of ethyl 2-bromo-4-methylnicotinate (300 mg, 1.23 mmol), Pd(OAc)2 (27 mg, 0.12 mmol) and S-phos (50 mg, 0.12 mmol) in THF (3 mL) under an atmosphere of N2 was added cyclobutylzinc(ll) iodide (2.5 mL, 1 mmol / mL, 2.5 mmol). The mixture was heated to 80 °C and stirred for 1 h, then the mixture was purified by silica gel column chromatography to give the product (210 mg, 77%) as an oil. LCMS (ESI) m / z calcd. for C13H14NO2, 219.13, found 220.20 [M+H]+.

[0406] Step 2: (2-Cyclobutyl-4-methylpyridin-3-yl)methanol

[0407] A stirred mixture ethyl 2-cyclobutyl-4-methylnicotinate (210 mg, 0.96 mmol) in THF (3 mL) at 0 °C was added DIBAL-H (3.26 mmol). The mixture was warmed to rt and stirred for 1 h, then quenched by the addition of ice / H2<D at 0 °C, and the mixture was filtered. The filter cake was washed with EtOAc (3 x 40 mL) and the filtrate was concentrated under reduced pressure to give the product (130 mg, 76%) as a solid. LCMS (ESI) m / z calcd. for C11H15NO, 177.12, found 178.05 [M+H]+. Step 3: 3-(chloromethyl)-2-cyclobutyl-4-methylpyridine

[0408] To a stirred mixture of (2-cyclobutyl-4-methylpyridin-3-yl)methanol (130 mg, 0.73 mmol) in DCM (3 mL) at 0 °C was added SOCh (354 mg, 2.98 mmol). The mixture was warmed to rt and stirred for 2 h, then concentrated under reduced pressure to give the product (120 mg, 84%) as a solid.

[0409] Step 4: 2-{[(2-cyclobutyl-4-methylpyridin-3-yl)methyl]sulfanyl}-3H,5H,6H,7H- cyclopenta[d]pyrimidin-4-one

[0410] Undertaken in a manner similar to Step 4, Example 8 and purified by reversed-phase column chromatography [conditions: C18 silica gel; mobile phase, H2O in ACN, 10% to 70% gradient in 16 min] to give the product (102.5 mg, 37%) as a white solid. LCMS (ESI) m / z calcd. for C15H20N2O2S3, 327.14, found 328.10 [M+H]+;1H NMR (400 MHz, DMSO-cfe) 5 8.46 - 8.48 (m, 1 H), 7.43 - 7.47 (m, 1 H), 4.46 - 4.52 (m, 2H), 4.10 - 4.12 (m, 1 H), 2.78 - 2.81 (m, 2H), 2.63 - 2.67 (m, 2H), 2.59 - 2.62 (m, 3H), 2.42 - 2.45 (m, 2H) , 2.26 - 2.33 (m, 2H) , 1 .94 - 1 .98 (m, 3H) , 1.81 - 1 .86 (m, 1 H);19F-NMR (376 MHz, DMSO-cfe) 6 -74.3.

[0411] Example 11 : Synthesis of Compound 14

[0412] 2-({[4-ethyl-2-(trifluoromethyl)pyridin-3-yl]methyl}sulfanyl)-3H,5H,7H-furo[3,4-d]pyrimidin-4-one; trifluoroacetic acid

[0413] Prepared in a manner similar to Example 10 to give the product (20.8 mg, 13%) as a solid. LC / MS: mass calcd for C15H14F3N3O2S: 357.08, found: 358.05 [M+H]+;1H NMR (300 MHz, DMSO-cfe) 5 13.01 (s, 1 H), 8.60 - 8.61 (m, 1 H), 7.65 - 7.67 (m, 1 H), 4.86 - 4.87 (m, 4H), 4.60 (s, 2H), 2.78 - 2.84 (m, 2H), 1 .21 - 1 .25 (m, 3H);19F-NMR (376 MHz, DMSO-cfe) 5 -61 .5. Example 12: Synthesis of Compound 2

[0414] Step 1 : Methyl 4-cyclopropyl-2-(trifluoromethyl)pyridine-3-carboxylate

[0415] To a stirred mixture of methyl 4-chloro-2-(trifluoromethyl)pyridine-3-carboxylate (250 mg, 1.04 mmol) and cyclopropylboronic acid (179 mg, 2.09 mmol) in 1 ,4-dioxane / H2O (5:1) under an atmosphere of N2 was added Pd(OAc)2 (23 mg, 0.10 mmol), di(1-adamantyl)-A / -butylphosphine (935mg, 2.61 mmol) and CS2CO3 (68 mg, 0.21 mmol). The mixture was heated to 100 °C and stirred for 2 h, then diluted with H2O and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with NH4CI (100 mL), dried over anhydrous Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent, EtOAc / petroleum ether, 35:65) to give the product (210 mg, 82%) as an oil. MS (ESI) m / z calcd. For C11H10F3NO2, 245.07; found 246.00 [M+H]+.

[0416] Step 2: [4-cyclopropyl-2-(trifluoromethyl)pyridine-3-yl]methanol

[0417] A stirred mixture methyl 4-cyclopropyl-2-(trifluoromethyl)pyridine-3-carboxylate (210 mg, 0.86 mmol) in THF (2 mL) at 0 °C was added DIBAL-H (2.57 mL, 2.57 mmol) dropwise. The mixture was warmed to rt and stirred for 2 h, then quenched with H2O at 0 °C and filtered. The filter cake was washed with MeOH (10 mL) and the filtrate was concentrated under reduced pressure to give the crude product, which was used in the next step without further purification.

[0418] Step 3: 3-(Chloromethyl)-2-(methylsulfanyl)-4-(trifluoromethyl)pyridine

[0419] A stirred mixture [4-cyclopropyl-2-(trifluoromethyl)58yridine-3-yl]methanol (140 mg) in DCM (2 mL) at 0 °C was added thionyl chloride (194 mg, 1 .63 mmol) dropwise. The mixture was warmed to rt and stirred for 2 h, then concentrated under reduced pressure to give the crude product, which was used in the next step without further purification.

[0420] Step 4: 2-({[4-Cyclopropyl-2-(trifluoromethyl)pyridine-3-yl]methyl}sulfanyl)-3H,5H,7H-furo[3,4- d]pyrimidin-4-one trifluoroacetic acid salt

[0421] Undertaken in a manner similar to Step 4, Example 8 and purified by reversed-phase prep- HPLC[conditions: Xbridge Prep Shield RP18 5pm OBD 30*150mm; Mobile Phase A: H2O (0.1% TFA), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 26 % B to 46 % B in 10 min] to give the product (41.1 mg, 13% yield) as a solid. LC / MS: mass calcd for C16H14F3N3O2S: 369.08; found: 370.00 [M+H]+;1H NMR (400 MHz, DMSO-cfe) 5 13.00 (s, 1H), 8.52 - 8.53 (m, 1 H), 7.30 - 7.31 (m, 1 H), 4.75 - 4.86 (m, 6H), 2.16 - 2.18 (m, 1 H), 1.11 - 1.13 (m, 2H), 0.90 - 0.91 (m, 2H);19F-NMR (376 MHz, DMSO- cfe) 6 -61 .6, -62.0. Example 13: Synthesis of Compound 17

[0422] Step 1 : Ethyl 2-(isopropylthio)-4-methylnicotinate

[0423] To a stirred mixture of ethyl 2-bromo-4-methylnicotinate (1.0 g, 4.1 mmol) in 1 ,4-dioxane (10 mL) under an atmosphere of N2 was added propane-2-thiol (1.27 g, 20.5 mmol), t-BuBrettPhos Pd G3 (421 mg, 0.49 mmol), t-BuBrettphos (398 mg, 0.82 mmol), CS2CO3 (2.68 g, 8.23 mmol). The mixture was heated to 95 °C and stirred for 1 h, then cooled to 0°C and quenched by the addition of H2O. Ater workup the residue was purified by reverse-phase column chromatography [ACN and H2O (0.05% TFA)] to give the product (700 mg, 71) as an oil. LCMS (ESI) m / z calcd. For C12H17NO2S, 239.10; found 240.10 [M+H]+.

[0424] Step 2: (2-(lsopropylthio)-4-methylpyridin-3-yl) methanol

[0425] To a stirred mixture of ethyl 2-(isopropylthio)-4-methylnicotinate (700 mg, 2.92 mmol) in THF (7 mL) at 0°C was added LiAIF (166 mg, 4.39 mmol). The mixture was warmed to rt and was stirred for 0.5 h, then cooled to 0 °C and quenched with cold H2O, filtered, and the filter cake was washed with ACN (3 x 3 mL). The filtrate was concentrated under reduced pressure to give the product (500 mg, 86% yield) as an oil. LCMS (ESI) m / z calcd. For C10H15NOS, 197.09; found 198.09 [M+H]+.

[0426] Step 3: 3-(Chloromethyl)-2-(isopropylthio)-4-methylpyridine

[0427] To a mixture of (2-(isopropylthio)-4-methylpyridin-3-yl) methanol (500 mg, 2.53 mmol) in DCM (5 mL) at 0°C was added SOCI2 (749 mg, 6.1 mmol). The mixture was warmed to rt and stirred for 0.5 h, then concentrated under reduced pressure to give the product (310 mg, 56%) as an oil, which was used in the next step without further purification. LCMS (ESI) m / z calcd. for C10H14CINS, 215.04; found 216.04 [M+H]+.

[0428] Step 4: 2-(((2-(lsopropylthio)-4-methylpyridin-3-yl) methyl) thio)-5,7-dihydrofuro[3,4-d] pyrimidin- 4(3H)-one

[0429] To a mixture of 3-(chloromethyl)-2-(isopropylthio)-4-methylpyridine (120 mg, 0.55 mmol) in DMF (2 mL) at rt was added 2-mercapto-5,7-dihydrofuro[3,4-c / | pyrimidin-4(3 / 7)-one (189 mg, 1.11 mmol), DIEA (217 mg, 1 .67 mmol). The resulting solution was stirred at rt for 0.5 h, then purified by reverse-phase column chromatography [eluent: ACN and H2O (0.05% TFA)] to give the product (61 .4 mg, 32%) as a solid. LCMS (ESI) m / z calcd. for C16H19N3O2S2, 349.09; found 350.05 [M+H]+;1H NMR (400 MHz, DMSO- cfe) 6 12.95 (br. s, 1 H), 8.14 - 8.34 (m, 1 H), 6.91 - 7.11 (m, 1 H), 4.74 - 4.97 (m, 4H), 4.33 - 4.53 (m, 2H), 3.91 - 4.11 (m, 1 H), 2.22 - 2.42 (m, 3H), 1.32 - 1.52 (m, 3H);19F-NMR (376 MHz, DMSO-cfe) 6 -74.9. Example 14: Synthesis of 6-[(5-fluoro-2,4-dimethyl-3-pyridyl)methylthio]-1-oxa-5,7-diaza-4-indanol

[0430] (C

[0431] Step 1 : Synthesis of 5-fluoro-2,4-dimethyl-3-nitropyridine

[0432] A mixture of 2,4-dibromo-5-fluoro-3-nitropyridine (5 g, 16.673 mmol, 1 equiv), trimethyl-

[0433] 1 ,3,5,2,4,6-trioxatriborinane (12.56 g, 50.019 mmol, 3 equiv, 50%), Pd(dppf)CI2CH2CI2(680.80 mg, 0.834 mmol, 0.05 equiv) and Cs2CO3 (16.30 g, 50.028 mmol, 3.00 equiv) in 1 ,4-Dioxane (40 mL) and H2O (10 mL) was stirred at 100°C for 5h under nitrogen atmosphere. The resulting mixture was diluted with water (100 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4:1) to afford 5-fluoro-2,4-dimethyl-3-nitropyridine (2.4 g, 84.60% yield) as a colorless oil. MS (ESI) calcd. For C7H7FN2O2: 170.05 m / z, found 171.04 [M+H]+.

[0434] Step 2: Synthesis of 5-fluoro-2,4-dimethylpyridin-3-amine

[0435] A solution of 5-fluoro-2,4-dimethyl-3-nitropyridine (2.1 g, 12.343 mmol, 1 equiv) in DMF (10 mL) was treated with 4-(py ridi n-4-y I) py ridi ne (192.78 mg, 1 .234 mmol, 0.10 equiv) at 0°C for 5 min followed by the addition of B2(OH)4 (3.54 g, 39.487 mmol, 3.20 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for 1 h. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in 5-fluoro-2,4- dimethylpyridin-3-amine (1.3 g, 75.15% yield) as a light yellow solid. MS (ESI) calcd. For C7H9FN2:140.07 m / z, found 141.05 [M+H]+.

[0436] Step 3: Synthesis of 5-fluoro-3-iodo-2,4-dimethylpyridine

[0437] To a stirred mixture of 5-fluoro-2,4-dimethylpyridin-3-amine (1.3 g, 9.275 mmol, 1 equiv), 1 ,2- diiodoethane (5.23 g, 18.550 mmol, 2 equiv) and disodium sulfanesulfite pentahydrate (4.60 g, 18.550 mmol, 2 equiv) in MeCN (15 mL) was added KNO3 (18.39 mg, 0.177 mmol, 2.5 equiv) in portions at 0°C under air atmosphere. The resulting mixture was stirred at 85°C for 12h. The reaction was poured into sat. sodium hyposulfite (aq.) (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine (2x100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 :1) to afford 5-fluoro-3-iodo-2,4- dimethylpyridine (260 mg, 11 .17%yield) as a brown solid. MS (ESI) calcd. for C?H7lFN:391 .04 m / z, found 392.01 [M+H]+.

[0438] Step 4: Synthesis of 3-ethenyl-5-fluoro-2,4-dimethylpyridine

[0439] A mixture of 5-fluoro-3-iodo-2,4-dimethylpyridine (240 mg, 0.956 mmol, 1 equiv), 2-ethenyl- 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (294.49 mg, 1.912 mmol, 2 equiv), Pd(dppf)Cl2 (78.07 mg, 0.096 mmol, 0.1 equiv) and K3PO4 (608.78 mg, 2.868 mmol, 3 equiv) in 1 ,4-Dioxane (2 mL) and H2O (0.4 mL) was stirred at 100 °C for 2h under nitrogen atmosphere. The resulting mixture was diluted with H2O (20 mL). The resulting mixture was extracted with EtOAc (3 x 20mL). The combined organic layers were washed with EtOAc (2 x 20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 :1) to afford 3-ethenyl-5-fluoro-2,4-dimethylpyridine (100 mg, 69.19%yield) as a white solid. MS (ESI) calcd. for C9HioFN: 151.08 m / z, found 152.07 [M+H]+.

[0440] Step 5: Synthesis of 5-fluoro-2,4-dimethylpyridine-3-carbaldehyde

[0441] To a stirred mixture of 3-ethenyl-5-fluoro-2,4-dimethylpyridine (90 mg, 0.595 mmol, 1 equiv) and Potassium osmate(VI) dihydrate (10.97 mg, 0.030 mmol, 0.05 equiv) in MeCN (2 mL) was added NalO4 (254.66 mg, 1 .191 mmol, 2.00 equiv) (in 2 mL H2O) dropwise at room temperature under air atmosphere. The resulting mixture was stirred at room temperature for 30 min under air atmosphere. The resulting mixture was extracted with EtOAc (3 x 5 mL). The combined organic layers were washed with brine (2 x10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 :5) to afford 5-fluoro-2,4-dimethylpyridine-3-carbaldehyde (40 mg, 43.87%yield) as a white solid. MS (ESI) calcd. for CsHsFNO: 153.06 m / z, found 154.07 [M+H]+.

[0442] Step 6: Synthesis of (5-fluoro-2,4-dimethylpyridin-3-yl)methanol

[0443] A solution of 5-fluoro-2,4-dimethylpyridine-3-carbaldehyde (40 mg, 0.261 mmol, 1 equiv) and NaBH4 (19.76 mg, 0.522 mmol, 2 equiv) in THF (3 mL) was stirred at room temperature for 1 h under air atmosphere. The reaction was poured into water at room temperature. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE I EA (1 :10) to afford (5-fluoro-2,4-dimethylpyridin-3-yl)methanol (45 mg, 80% purity) as a white solid. MS (ESI) calcd. for CsHioFNO: 155.07 m / z, found 156.07 [M+H]+.

[0444] Step 7: Synthesis of 3-(chloromethyl)-5-fluoro-2,4-dimethylpyridine

[0445] To a stirred solution of (5-fluoro-2,4-dimethylpyridin-3-yl)methanol (40 mg, 0.258 mmol, 1 equiv) in DCM (2 mL) was added SOCI2 (61 .33 mg, 0.516 mmol, 2 equiv) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 h under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure to afford 3-(chloromethyl)-5-fluoro-2,4- dimethylpyridine (30 mg) as a light yellow solid. The crude product was used in the next step directly without further purification. MS (ESI) calcd. for CsHgClFN: 173.04 m / z, found 174.04 [M+H]+. Step 8: Synthesis of 6-[(5-fluoro-2,4-dimethyl-3-pyridyl)methylthio]-1-oxa-5,7-diaza-4-indanol

[0446] A mixture of 3-(chloromethyl)-5-fluoro-2,4-dimethylpyridine (30 mg, 0.173 mmol, 1 equiv), 2- sulfanyl-3H,5H,6H-furo[2,3-d]pyrimidin-4-one (58.81 mg, 0.346 mmol, 2 equiv) and DIEA (55.83 mg, 0.432 mmol, 2.5 equiv) in DMF (1 mL) was stirred at room temperature for 10 min under air atmosphere. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The mixture was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.05% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. After lyophilization, it provided 6-[(5-fluoro-2,4-dimethyl-3-pyridyl)methylthio]-1-oxa-5,7-diaza-4-indanol, as a trifluoroacetate salt (20.2 mg, 27.74%yield) as a white solid. LC / MS: MS (ESI) calcd. for C14H14FN3O2S: 307.08 m / z, found 308.05 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 5 12.67 (s, 1 H), 8.34 (s, 1 H), 4.63 (t, J = 8.8 Hz, 2H), 4.45 (s, 2H), 2.96 (t, J = 7.6, 9.2 Hz, 2H), 2.54 (s, 3H), 2.31 (s, 3H).19F-NMR (376 MHz, DMSO) 5 (ppm): -74.689. -134.302.

[0447] Example 15: Synthesis of 6-[(5-chloro-2,4-dimethyl-3-pyridyl)methylthio]-1-oxa-5,7-diaza-4-indanol

[0448] (

[0449] Step 1 : Synthesis of 5-chloro-2,4-dimethylpyridine-3-carbonitrile

[0450] Into a 30mL vial were added 2,5-dichloro-4-methylpyridine-3-carbonitrile (900 mg, 4.812 mmol, 1 equiv), Pd(dppf)Cl2 (352.12 mg, 0.481 mmol, 0.1 equiv), CS2CO3 (3135.89 mg, 9.624 mmol, 2 equiv), Dioxane (10 mL) and H2O (1 mL) at room temperature under N2. The resulting mixture was stirred at 100°C for additional 1 h. The reaction was monitored by LCMS. The resulting mixture was extracted with EA (2 x 200mL). The combined organic layers were washed with water (1x200 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (0.05% TFA) to afford 5-chloro-2,4- dimethylpyridine-3-carbonitrile (260 mg, 32.43%yield, 95% purity) as a colorless oil. LC / MS: MS (ESI) calcd. for C8H7CIN2: 166.03, Found: 167.10 [M+H]+.

[0451] Step 2: Synthesis of 5-chloro-2,4-dimethylpyridine-3-carbaldehyde

[0452] To a stirred solution of 5-chloro-2,4-dimethylpyridine-3-carbonitrile (150 mg, 0.900 mmol, 1 equiv) in DCM (2 mL) was added DIBAL-H (153.65 mg, 1.080 mmol, 1.2 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for additional 1 h. The reaction was monitored by LCMS. The reaction was quenched with ice water at room temperature. The resulting mixture was filtered; the filter cake was washed with water (2 x 2 mL). The filtrate was concentrated under reduced pressure. The crude product was purified by reverse phase flash with the following conditions (0.05% TFA) to afford 5-chloro- 2,4-dimethylpyridine-3-carbaldehyde (70 mg, 45.84% yield, 95% purity) as a colorless oil. LC / MS: MS (ESI) calcd. for CaHaCINO: 169.03, Found: 171.10 [M+H]+.

[0453] Step 3: Synthesis of (5-chloro-2,4-dimethylpyridin-3-yl)methanol

[0454] To a stirred solution of 5-chloro-2,4-dimethylpyridine-3-carbaldehyde (50 mg, 0.295 mmol, 1 equiv) in THF (2 mL) was added NaBH4 (22.30 mg, 0.590 mmol, 2 equiv) in portions at 0°C. The resulting mixture was stirred at room temperature for additional 1 h. The reaction was monitored by LCMS.The reaction was quenched with ice water at room temperature. The resulting mixture was filtered; the filter cake was washed with water (2 x 3 mL). The filtrate was concentrated under reduced pressure to afford (5-chloro-2,4-dimethylpyridin-3-yl)methanol (40 mg) as a colorless oil. LC / MS: MS (ESI) calcd. for CaHioCINO: 171.05, Found: 172.05 [M+H]+.

[0455] Step 4: Synthesis of 5-chloro-3-(chloromethyl)-2,4-dimethylpyridine

[0456] To a stirred solution of (5-chloro-2,4-dimethylpyridin-3-yl)methanol (40 mg, 0.233 mmol, 1 equiv) in DCM (1 mL) was added SOCh (83.18 mg, 0.699 mmol, 3 equiv) dropwise at 0°C.The resulting mixture was stirred at room temperature for additional 1 h. The reaction was monitored by TLC. The resulting mixture was concentrated under reduced pressure to afford 5-chloro-3-(chloromethyl)-2,4- dimethylpyridine (30 mg) as a yellow oil. The crude product was used in the next step directly without further purification.

[0457] Step 5: Synthesis of 6-[(5-chloro-2,4-dimethyl-3-pyridyl)methylthio]-1-oxa-5,7-diaza-4-indanol

[0458] To a stirred solution of 5-chloro-3-(chloromethyl)-2,4-dimethylpyridine (30 mg, 0.158 mmol, 1 equiv) and 2-sulfanyl-3H,5H,6H-furo[2,3-d]pyrimidin-4-one (29.55 mg, 0.174 mmol, 1.1 equiv) in DMF (1 mL) was added DIEA (61 .20 mg, 0.474 mmol, 3 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for additional 1 h. The reaction was monitored by LCMS. The residue was purified by reverse phase flash with the following conditions (0.05% TFA) to afford 6-[(5-chloro-2,4-dimethyl-3- pyridyl)methylthio]-1-oxa-5,7-diaza-4-indanol (10.7 mg, 20.94%yield, 97.0%purity) as a white solid. LC / MS: MS (ESI) calcd. for C14H14CIN3O2S: 323.05. Found: 324.00 [M+H] +.1H NMR (300 MHz, DMSO- d6) 5 (ppm): 8.39 (s, 1 H), 4.58 - 4.64 (m, 2H), 4.46 (s, 2H), 2.82 - 3.01 (m, 2H), 2.54 (s, 3H), 2.41 (s, 3H). Example 16: Synthesis of 6-[(6-difluoromethoxy-2,4-dimethyl-3-pyridyl)methylthio]-1-oxa-5,7- diaza-4-indanol (Compound 22)

[0459] Step 1 : Synthesis of 5-bromo-4,6-dimethylpyridin-2-ol

[0460] To a solution of 3-bromo-6-chloro-2,4-dimethylpyridine (2 g, 9.071 mmol) in 25 ml of t-BuOH was added KOH (1 .53 g, 27.213 mmol) at room temperature. The resulting mixture was stirred at 130°C for 2h. The reaction progress was monitored by LCMS. The reaction was quenched with sat. NH4CI aqueous solution. The resulting mixture was extracted with EA. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1 :1) to afford 5-bromo-4,6-dimethylpyridin-2-ol (1 g, 54.56% yield) as a white solid. LC / MS: MS (ESI) calcd. for C7H8BrNO, 200.98 m / z, found 202.05, 204.05 [M+H]+, [M+H+2]+.

[0461] Step 2: Synthesis of 3-bromo-6-(difluoromethoxy)-2,4-dimethylpyridine

[0462] To a solution of 5-bromo-4,6-dimethylpyridin-2-ol (500 mg, 2.475 mmol) in 6 ml of ACN was added difluoro(sulfo)acetic acid (616.95 mg, 3.465 mmol), Na2COs (52.46 mg, 0.495 mmol) at 0°C. The resulting mixture was stirred at 30°C for 3 h. The reaction progress was monitored by LCMS. The reaction was quenched with H2O. The resulting mixture was extracted with DCM. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 3-bromo-6-(difluoromethoxy)-2,4- dimethylpyridine (400 mg, 64.13% yield) as a yellow oil. LC / MS: MS (ESI) calcd. for CsHsB^NO, 250.98 m / z, found 252.05, 254.05 [M+H]+, [M+H+2]+.

[0463] Step 3: Synthesis of 6-(difluoromethoxy)-3-ethenyl-2,4-dimethylpyridine

[0464] To a solution of 3-bromo-6-(difluoromethoxy)-2,4-dimethylpyridine (350 mg, 1.389 mmol) in the mixture of solvent 4 ml of Dioxane and 0.5 ml of H2O was added 2-ethenyl-4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane (427.73 mg, 2.778 mmol), K3PO4 (479.77 mg, 3.473 mmol), Pd(dppf)Cl2 (355.56 mg, 0.486 mmol). The resulting mixture was stirred at 100°C for 1 h under N2. The reaction progress was monitored by LCMS. The reaction was quenched with H2O. The resulting mixture was extracted with DCM. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 6-(difluoromethoxy)-3- ethenyl-2,4-dimethylpyridine (270 mg, 97.61 % yield) as a yellow oil. LC / MS: MS (ESI) calcd. for C10H11F2NO, 199.08 m / z, found 200.10 [M+H]+.

[0465] Step 4: Synthesis of 6-(difluoromethoxy)-2,4-dimethylpyridine-3-carbaldehyde

[0466] To a solution of 6-(difluoromethoxy)-3-ethenyl-2,4-dimethylpyridine (270 mg, 1.355 mmol) in 5 ml of ACN was added Potassium osmate(VI) dihydrate (24.97 mg, 0.068 mmol), followed by addition of NalO4 (579.82 mg, 2.710 mmol) in 5 ml of H2O dropwise, the mixture was allowed to warm to r.t and stirred for 1 h. The reaction progress was monitored by LCMS. The reaction was quenched with H2O. The resulting mixture was extracted with DCM. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford 6-(difluoromethoxy)-2,4-dimethylpyridine-3-carbaldehyde (180 mg, 66.01 % yield) as a white solid. LC / MS: MS (ESI) calcd. for C9H9F2NO2, 201.06 m / z, found 202.00 [M+H]+.

[0467] Step 5: Synthesis of [6-(difluoromethoxy)-2,4-dimethylpyridin-3-yl] methanol

[0468] To a solution of 6-(difluoromethoxy)-2,4-dimethylpyridine-3-carbaldehyde (180 mg, 0.895 mmol) in 2 ml of THF was added NaBF (40.62 mg, 1 .074 mmol) at 0°C. The resulting mixture was stirred at r.t for 0.5 h. The reaction progress was monitored by LCMS. The reaction was quenched by the addition of H2O at 0°C. The resulting mixture was extracted with DCM. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford [6-(difluoromethoxy)-2,4-dimethylpyridin-3-yl] methanol (120 mg, 66.01 % yield) as a white oil. LC / MS: MS (ESI) calcd. for C9H11F2NO2, 203.08 m / z, found 204.10 [M+H]+.

[0469] Step 6: Synthesis of 3-(chloromethyl)-6-(difluoromethoxy)-2,4-dimethylpyridine

[0470] To a solution of [6-(difluoromethoxy)-2,4-dimethylpyridin-3-yl] methanol (120 mg, 0.591 mmol) in 2 ml of DCM was added SOCI2 (175.64 mg, 1 .478 mmol) at 0°C. The resulting mixture was stirred at r.t for 0.5 h. The reaction progress was monitored by LCMS. The mixture was concentrated under reduced pressure to afford crude compound 3-(chloromethyl)-6-(difluoromethoxy)-2,4-dimethylpyridine (100 mg) as a yellow oil. The crude product was used in the next step directly without further purification. LC / MS: MS (ESI) calcd. for C9H10CIF2NO, 221 .04 m / z, found 222.00 [M+H]+.

[0471] Step 7: Synthesis of 6-[(6-difluoromethoxy-2,4-dimethyl-3-pyridyl)methylthio]-1-oxa-5,7-diaza-4- indanol

[0472] To a solution of 3-(chloromethyl)-6-(difluoromethoxy)-2,4-dimethylpyridine (100 mg, 0.451 mmol) in 2 ml of DMF was added 2-sulfanyl-3H,5H,6H-furo[2,3-d] pyrimidin-4-one (153.58 mg, 0.902 mmol), DIEA (174.95 mg, 1 .353 mmol) at room temperature. The resulting solution was stirred at r.t for 0.5 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The mixture was further purified by reverse phase column eluted with ACN and H2O (0.05% TFA), after concentrated to afford 6-[(6-difluoromethoxy-2,4-dimethyl-3-pyridyl)methylthio]-1-oxa-5,7-diaza-4-indanol as a trifluoroacetate salt (67.8 mg, 32.01 % yield) as a white solid. LC / MS: MS (ESI) calcd. for C15H15F2N3O3S, 355.08 m / z, found 356.00 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 (ppm): 12.46 (s, 1 H), 7.30 - 7.90 (m, 1 H), 6.82 (s, 1 H), 4.53 - 4.71 (m, 2H), 4.35 (s, 2H), 2.81 - 3.01 (m, 2H), 2.48 (s, 3H), 2.38 (s, 3H).19F-NMR (376 MHz, DMSO) 6 (ppm): -74.89, -86.88.

[0473] Example 17: Synthesis of 6-[(6-methoxy-2,4-dimethyl-3-pyridyl)methylthio]-1-oxa-5,7-diaza-4- indanol (Compound 23)

[0474] Step 1 : Synthesis of 3-ethenyl-6-methoxy-2,4-dimethylpyridine

[0475] To a solution of 3-bromo-6-methoxy-2,4-dimethylpyridine (700 mg, 3.240 mmol) in the mixture solvent of 8 ml of dioxane and 2 ml of H2O was added 2-ethenyl-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (997.92 mg, 6.480 mmol), K3PO4 (1119.31 mg, 8.100 mmol), Pd(dppf)CI2(355.56 mg, 0.486 mmol). The resulting mixture was stirred at 100°C for 1 h under N2. The reaction progress was monitored by LCMS. The reaction was quenched with H2O. The resulting mixture was extracted with DCM. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was further purified by reverse phase column eluted with ACN and H2O (0.05% TFA) to afford 3-ethenyl-6-methoxy- 2,4-dimethylpyridine (350 mg, 66.19%yield) as a white oil. LC / MS: MS (ESI) calcd. for C10H13NO, 163.10 m / z, found 164.10 [M+H]+.

[0476] Step 2: Synthesis of 6-methoxy-2,4-dimethylpyridine-3-carbaldehyde

[0477] To a solution of 3-ethenyl-6-methoxy-2,4-dimethylpyridine (350 mg, 2.144 mmol) in 8 ml ofACN was added Potassium osmate(VI) dihydrate (39.50 mg, 0.107 mmol), follow by addition of NalO4 (917.31 mg, 4.288 mmol) in 8 ml of H2O dropwise, the mixture was allowed to warm to r.t and stirred for 30 mins. The mixture was further purified by reverse phase column eluted with ACN and H2O (0.05% NH4HCO3), after concentrated to afford 6-methoxy-2,4-dimethylpyridine-3-carbaldehyde (175 mg, 49.40% yield) as a white oil. LC / MS: MS (ESI) calcd. for C9H11NO2, 165.08 m / z, found 166.00 [M+H]+.

[0478] Step 3: Synthesis of (6-methoxy-2,4-dimethylpyridin-3-yl) methanol

[0479] To a solution of 6-methoxy-2,4-dimethylpyridine-3-carbaldehyde (175 mg, 1.059 mmol) in 3 ml of THF was added NaBH4 (48.09 mg, 1 .271 mmol) at 0°C. The resulting mixture was stirred at r.t for 0.5 h. The reaction progress was monitored by LCMS. The reaction was quenched by the addition of H2O at 0°C. The resulting mixture was extracted with DCM. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford (6-methoxy-2,4-dimethylpyridin-3-yl) methanol (100 mg, 56.45% yield) as a white oil. LC / MS: MS (ESI) calcd. for C9H13NO2, 167.09 m / z, found 198.10 [M+H]+.

[0480] Step 4: Synthesis of 3-(chloromethyl)-6-methoxy-2,4-dimethylpyridine

[0481] To a solution of (6-methoxy-2,4-dimethylpyridin-3-yl) methanol (100 mg, 0.598 mmol) in 2 ml of DCM was added SOCI2 (177.86 mg, 1 .495 mmol) at 0°C. The resulting mixture was stirred at r.t for 0.5 h. The reaction progress was monitored by LCMS. The mixture was concentrated under reduced pressure to afford crude compound 3-(chloromethyl)-6-methoxy-2,4-dimethylpyridine (90 mg) as a yellow oil. The crude product was used in the next step directly without further purification. MS (ESI) calcd. for C9H12CINO, 185.06 m / z, found 186.00 [M+H]+.

[0482] Step 5: Synthesis of 6-[(6-methoxy-2,4-dimethyl-3-pyridyl)methylthio]-1-oxa-5,7-diaza-4-indanol

[0483] To a solution of 3-(chloromethyl)-6-methoxy-2,4-dimethylpyridine (90 mg, 0.485 mmol) in 2 ml of DMF was added 2-sulfanyl-3H,5H,6H-furo[2,3-d] pyrimidin-4-one (123.76 mg, 0.728 mmol), DIEA (187.97 mg, 1 .455 mmol) at room temperature. The resulting solution was stirred at r.t for 0.5 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The mixture was further purified by reverse phase column eluted with ACN and H2O (0.05% NH4HCO3), after concentrated to afford 2-{[(6-methoxy-2,4-dimethylpyridin-3-yl) methyl] sulfanyl}-3H,5H,6H-furo[2,3-d] pyrimidin-4-one (11.4 mg, 7.36% yield) as a white solid. LC / MS: MS (ESI) calcd. for C15H17N3O3S, 319.10 m / z, found 320.05 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 (ppm): 6.53 (s, 1 H), 4.51 - 4.68 (m, 2H), 4.35 (s, 2H), 3.78 (s, 3H), 2.82 - 3.01 (m, 2H), 2.45 (s, 3H), 2.30 (s, 3H).

[0484] Example 18: Synthesis of 6-[(2,4-dimethyl-3-pyridyl)methylthio]-1-oxa-5,7-diaza-4-indanol

[0485] (Compound 24)

[0486] Step 1 : Synthesis of 3-(chloromethyl)-2,4-dimethylpyridine

[0487] To a solution of (2,4-dimethylpyridin-3-yl) methanol (70 mg, 0.510 mmol) in 1 ml of DCM was added SOCI2 (151 .75 mg, 1 .275 mmol) at 0°C. The resulting mixture was stirred at r.t for 0.5 h. The reaction progress was monitored by LCMS. The mixture was concentrated under reduced pressure to afford crude compound 3-(chloromethyl)-2,4-dimethylpyridine (60 mg) as a yellow oil. The crude product was used in the next step directly without further purification. MS (ESI) calcd. for CsHioCIN, 155.05 m / z, found 156.05 [M+H]+. Step 2: Synthesis of 6-[(2,4-dimethyl-3-pyridyl)methylthio]-1-oxa-5,7-diaza-4-indanol

[0488] To a solution of 3-(chloromethyl)-2,4-dimethylpyridine (60 mg, 0.386 mmol) in 2 ml of DMF was added 2-sulfanyl-5H,6H-furo[2,3-d] pyrimidin-4-ol (98.42 mg, 0.579 mmol), DIEA (149.49 mg, 1.158 mmol) at rt. The resulting solution was stirred at rt for 0.5 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The mixture was further purified by reverse phase column eluted with ACN and H2O (0.05% NH4HCO3), after concentrated to afford 6-[(2,4-dimethyl-3- pyridyl)methylthio]-1-oxa-5,7-diaza-4-indanol (31 .1 mg, 27.88% yield) as a white solid. LC / MS: MS (ESI) calcd. for C14H15N3O2S, 289.09 m / z, found 290.10 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 (ppm): 12.44 (s, 1 H), 8.11 - 8.31 (m, 1 H), 7.01 - 7.18 (m, 1 H), 4.52 - 4.68 (m, 2H), 4.36 (s, 2H), 2.85 - 2.99 (m, 2H), 2.53 (s, 3H), 2.36 (s, 3H).

[0489] Example 19: Synthesis of 6-[(6-methoxy-3-pyridyl)methylthio]-1-oxa-5,7-diaza-4-indanol

[0490] (Compound 25)

[0491] Step 1 : Synthesis of 5-(chloromethyl)-2-methoxypyridine

[0492] To a stirred solution of (6-methoxypyridin-3-yl)methanol (150 mg, 1.078 mmol, 1 equiv) in DCM (2 mL) was added SOCI2 (384.70 mg, 3.234 mmol, 3 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for additional 1 h. The reaction was monitored by TLC. The resulting mixture was concentrated under reduced pressure to afford 5-(chloromethyl)-2-methoxypyridine (130 mg) as a yellow oil.

[0493] Step 2: Synthesis of 6-[(6-methoxy-3-pyridyl)methylthio]-1-oxa-5,7-diaza-4-indanol

[0494] To a stirred solution of 5-(chloromethyl)-2-methoxypyridine (80 mg, 0.508 mmol, 1 equiv) and 2- sulfanyl-3H,5H,6H-furo[2,3-d]pyrimidin-4-one (129.59 mg, 0.762 mmol, 1.5 equiv) in DMF (2 mL) was added DIEA (196.82 mg, 1 .524 mmol, 3 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for additional 1 h. The reaction was monitored by LCMS. The crude product was purified by reverse phase flash (0.05% TFA) to afford 6-[(6-methoxy-3-pyridyl)methylthio]-1-oxa-5,7- diaza-4-indanol as a trifluoroacetate salt (37.7 mg, 18.32%yield, 98.0%purity) as a white solid. LC / MS: MS (ESI) calcd. for C13H13N3O3S: 291.33. Found: 292.05 [M+H]+.1H NMR (300 MHz, DMSO-d6) 6 (ppm): 8.18 - 8.25 (m, 1 H), 7.70 - 7.80 (m, 1 H), 6.74 - 6.85 (m, 1 H), 4.55 -4.65 (m, 2H), 4.29 (s, 2H), 3.81 (s, 3H). 2.85 - 2.99 (m, 2H).19F-NMR (282 MHz, DMSO) 5 (ppm): -74.30. Example 20: Synthesis of 6-{[2-(1-methoxycyclopropyl)-4-methyl-3-pyridyl]methylthio}-1-oxa-5,7- diaza-4-indanol (Compound 26)

[0495] Step 1 : Synthesis of 1-(3-bromo-4-methylpyridin-2-yl)ethanone

[0496] To a solution of 3-bromo-4-methylpyridine-2-carbonitrile (1 .9 g, 9.643 mmol) in THF (30 mL) was added Methyl magnesium bromide, 3 M solution in diethyl ether (3.45 g, 28.929 mmol) dropwise at -40 °C, after stirring for 1 h under nitrogen atmosphere. The reaction was monitored by LCMS. After completion of reaction, the reaction was quenched with HCI (9 mL) and stirred for 1 h at -40 °C. The resulting mixture was extracted with EA ( 100 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was re-crystallized from PE:EA (20:1) to afford 1-(3-bromo-4-methylpyridin- 2-yl)ethanone (1 .3 g) as a white solid. LC / MS: MS (ESI) calcd. For CsH8BrNO:212.98. Found: 213.95 [M+H]+.

[0497] Step 2: Synthesis of 3-bromo-4-methyl-2-{1-[(trimethylsilyl)oxy]ethenyl}pyridine

[0498] To a stirred solution of 1-(3-bromo-4-methylpyridin-2-yl)ethanone (800 mg, 3.737 mmol) in DCM (10 mL) was added TEA (1134.55 mg, 11.211 mmol), TMSOTf (1245.90 mg, 5.606 mmol) at 0 °C. The reaction was stirred for 2 h. The reaction was monitored by LCMS. After completion of reaction, the reaction was quenched with water. The resulting mixture was extracted with DCM (30 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude was washed with PE. This resulted in 3- bromo-4-methyl-2-{1-[(trimethylsilyl)oxy]ethenyl}pyridine (750 mg) as a yellow solid. LC / MS: MS (ESI) calcd. For CnHieBrNOSi: 285.02. Found: 286.15 [M+H]+.

[0499] Step 3: Synthesis of 3-bromo-4-methyl-2-{1-[(trimethylsilyl)oxy]cyclopropyl}pyridine

[0500] To a stirred solution of 3-bromo-4-methyl-2-{1-[(trimethylsilyl)oxy]ethenyl}pyridine (750 mg, 2.620 mmol) in DCM (10 mL) was added diiodomethane (1052.65 mg, 3.930 mmol) , Diethylzinc (488.62 mg, 3.956 mmol) at 0°C . The reaction was stirred for 24 h. The reaction was monitored by LCMS. After completion of reaction, the reaction was quenched with water. The resulting mixture was extracted with DCM (50 mL x 2). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, water (0.05% TFA) in ACN, 10% to 50% gradient in 10 min; detector, UV 254 nm. After concentrated, this resulted in 3-bromo-4-methyl-2-{1-[(trimethylsilyl)oxy]cyclopropyl}pyridine (500 mg) as a yellow solid. LC / MS: MS (ESI) calcd. For Ci2Hi8BrNOSi: 299.03. Found:301.85 [M+H]+.

[0501] Step 4: Synthesis of 1-(3-bromo-4-methylpyridin-2-yl)cyclopropan-1-ol

[0502] To a stirred solution of 3-bromo-4-methyl-2-{1 -[(trimethylsilyl) oxy]cyclopropyl}pyridine (550 mg, 1.832 mmol) in THF (7 mL) was added TBAF (718.39 mg, 2.748 mmol) at 0 °C. The reaction was stirred for 1 h. After completion of reaction, the reaction was quenched with water. The resulting mixture was extracted with EA (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA (1 :1) to afford 1 -(3-bromo-4- methylpyridin-2-yl)cyclopropan-1-ol (410 mg) as a white solid. LC / MS: MS (ESI) calcd. For C17H18N4O2S: 226.99. Found: 229.85 [M+H]+.

[0503] Step 5: Synthesis of 3-bromo-2-(1-methoxycyclopropyl)-4-methylpyridine

[0504] To a stirred solution of 1-(3-bromo-4-methylpyridin-2-yl)cyclopropan-1-ol (430 mg, 1.885 mmol) in THF (9 mL) was added NaH (135.73 mg, 5.655 mmol) , methyl iodide (802.76 mg, 5.655 mmol) at 0 °C. The reaction was stirred for 1 h. The reaction was monitored by LCMS. After completion of reaction, the reaction was quenched with water. The resulting mixture was extracted with EA (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA (1 :1) to afford 3-bromo-2-(1-methoxycyclopropyl)-4-methylpyridine (410 mg) as a white solid. LC / MS: MS (ESI) calcd. For CioHi2BrNO: 241 .01 . Found: 243.90 [M+H]+.

[0505] Step 6: Synthesis of 3-ethenyl-2-(1-methoxycyclopropyl)-4-methylpyridine

[0506] To a solution of 3-bromo-2-(1-methoxycyclopropyl)-4-methylpyridine (400 mg, 1.652 mmol) and 2-ethenyl-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (508.91 mg, 3.304 mmol) in dioxane (6 mL) and H2O (1.5 mL) were added Pd(dppf)CI2(181.33 mg, 0.248 mmol) and K2CO3 (570.82 mg, 4.130 mmol), the reaction mixture was stirred at 100 °C for 2 h under N2atmosphere. The reaction was monitored by LCMS. After completion of reaction, the reaction was quenched with water. The resulting mixture was extracted with EA (100 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA (3:1) to afford 3-ethenyl-2-(1- methoxycyclopropyl)-4-methylpyridine (240 mg,) as a yellow oil. LC / MS: MS (ESI) calcd. For Ci2Hi5NO: 189.12. Found:190.05 [M+H]+.

[0507] Step 7: Synthesis of 2-(1-methoxycyclopropyl)-4-methylpyridine-3-carbaldehyde

[0508] To a stirred solution of 3-ethenyl-2-(1-methoxycyclopropyl)-4-methylpyridine (220 mg, 1.162 mmol) in CH3CN (4 mL) was added potassium osmate(VI) dihydrate (21.41 mg, 0.058 mmol) under nitrogen atmosphere, followed by the addition of NalO4 (621 .58 mg, 2.905 mmol) in H2O (6 mL) dropwise / in portions at 0 °C. The reaction was stirred for 1 h. The reaction was monitored by LCMS. After completion of reaction, the reaction was quenched with water. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, water (0.05% NH4HCO3) in ACN, 10% to 50% gradient in 10 min; detector, UV 254 nm. After concentrated, it was afforded 2-(1-methoxycyclopropyl)-4-methylpyridine-3-carbaldehyde (130 mg) as a white solid. LC / MS: MS (ESI) calcd. For C11H13NO2: 191.09. Found:192.10 [M+H]+.

[0509] Step 8: Synthesis of (2-(1-methoxycyclopropyl)-4-methylpyridin-3-yl)methanol

[0510] To a stirred solution of 2-(1-methoxycyclopropyl)-4-methylpyridine-3-carbaldehyde (130 mg, 0.680 mmol) in THF (3 mL) was added NaBF (30.86 mg, 0.816 mmol) at 0 °C . The reaction was stirred for 1 h. The reaction was monitored by LCMS. After completion of reaction, the reaction was quenched with NH4CI. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, water (0.05% NH4HCO3) in ACN, 10% to 50% gradient in 10 min; detector, UV 254 nm. After concentrated, to afford (2-(1-methoxycyclopropyl)-4- methylpyridin-3-yl)methanol (100 mg) as a white solid. LC / MS: MS (ESI) calcd. For C11H15NO2: 193.11 . Found:194.00 [M+H]+.

[0511] Step 9: Synthesis of 3-(chloromethyl)-2-(1-methoxycyclopropyl)-4-methylpyridine

[0512] To a stirred solution of [2-(1-methoxycyclopropyl)-4-methylpyridin-3-yl]methanol (80 mg, 0.414 mmol) in DCM (3 mL) was added SOCI2 (123.12 mg, 1 .035 mmol) at 0 °C. The reaction was stirred for 1 h. The reaction was monitored by TLC. After completion of reaction, the resulting mixture was concentrated under reduced pressure. This resulted in 3-(chloromethyl)-2-(1-methoxycyclopropyl)-4- methylpyridine (85 mg) as a yellow solid, which was used directly in the next step.

[0513] Step 10: Synthesis of 6-{[2-(1-methoxycyclopropyl)-4-methyl-3-pyridyl]methylthio}-1-oxa-5,7-diaza- 4-indanol

[0514] To a stirred solution of 3-(chloromethyl)-2-(1-methoxycyclopropyl)-4-methylpyridine (85 mg, 0.402 mmol) and 2-sulfanyl-3H,5H,6H-furo[2,3-d]pyrimidin-4-one (136.67 mg, 0.804 mmol) in DMF (3 mL) was added DIEA (155.69 mg, 1 .206 mmol) at 25 °C. The reaction was stirred for 1 h. The reaction was monitored by LCMS. After completion of reaction, the reaction was quenched with water. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, water (0.05% TFA) in ACN, 10% to 50% gradient in 15 min; detector, UV 254 nm. After lyophilized, to afford 6-{[2-(1-methoxycyclopropyl)-4-methyl-3-pyridyl]methylthio}-1-oxa-5,7- diaza-4-indanol as a trifluoroacetate salt (45.0 mg) as a white solid. LC / MS: MS (ESI) calcd. For C17H19N3O3S: 345.11. Found: 346.20 [M+H]+.1H-NMR (400 MHz, DMSO) 5 (ppm): 8.37 - 8.39 (m, 1 H), 7.39 - 7.41 (m, 1 H), 4.72 - 4.74 (m, 2H), 4.59 - 4.64 (m, 2H), 3.05 (s, 3H), 2.92 - 2.97 (m, 2H), 2.43 - 2.45 (m, 3H), 1 .13 - 1 .19 (m, 4H).19F-NMR (376 MHz, DMSO) 5 (ppm): -74.69. Example 21 : Synthesis of 6-{[2-(1-methoxy-1-methylethyl)-4-methyl-3-pyridyl]methylthio}-1-oxa-

[0515] 5,7-diaza-4-indanol (Compound 27)

[0516] Step 1 : Synthesis of 1-(3-bromo-4-methylpyridin-2-yl) ethan-1-one

[0517] To a solution of 3-bromo-4-methylpicolinonitrile (1 .9 g, 9.64 mmol) in THF (38 ml) was added Methylmagnesium bromide, 3 M solution in diethyl ether (3.45 g, 28.92 mmol) dropwise at -20°C, the resulting mixture was stirred at 0 °C for 1 h. Then, to the above mixture was added 2M HCI (10 ml) at - 40°C. The resulting mixture was stirred at -40 °C for 0.5h. The reaction progress was monitored by LCMS. The reaction was quenched by the addition of H2O at 0°C. The resulting mixture was extracted with EA. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford 1 -(3-bromo-4- methylpyridin-2-yl) ethan-1-one (1 g, 48% yield) as a white solid. MS (ESI) calcd. For CaHaBrNO, 212.98 m / z, found 214.05, 216.05 [M+H]+, [M+H+2]+.

[0518] Step 2: Synthesis of 2-(3-bromo-4-methylpyridin-2-yl) propan-2-ol

[0519] To a solution of 1-(3-bromo-4-methylpyridin-2-yl) ethan-1-one (450 mg, 2.10 mmol) in THF (5 ml) was added Methylmagnesium bromide, 3 M solution in diethyl ether (501 .3 mg, 4.20 mmol), the resulting mixture was stirred at rt for 1 h. The reaction progress was monitored by LCMS. The reaction was quenched by the addition of H2O at 0°C. The resulting mixture was extracted with DCM. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford 2-(3-bromo-4- methylpyridin-2-yl) propan-2-ol (410 mg, 84% yield) as a yellow oil. The crude product was used in the next step directly without further purification. MS (ESI) calcd. For CgH^BrNO, 229.01 m / z, found 230.00, 232.00 [M+H]+, [M+H+2]+.

[0520] Step 3: Synthesis of 3-bromo-2-(2-methoxypropan-2-yl)-4-methylpyridine

[0521] To a solution of 2-(3-bromo-4-methylpyridin-2-yl) propan-2-ol (390 mg, 1.69 mmol) in 4 ml of THF was added NaH (122 g, 5.08mmol). The resulting mixture was stirred at 0°C for 20 mins. Then, to the above mixture was added methyl iodide (721 .7 mg, 5.08 mmol) at 0°C. The resulting mixture was stirred at rt for 0.5h. The reaction progress was monitored by LCMS. The reaction was quenched by the addition of H2O at 0°C. The resulting mixture was extracted with DCM. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford 3-bromo-2-(2-methoxypropan-2-yl)-4-methylpyridine (380 mg, 91 % yield) as a white solid. MS (ESI) calcd. for CioHi4BrNO, 243.03 m / z, found 244.00, 246.00 [M+H]+, [M+H+2]+

[0522] Step 4: Synthesis of 2-(2-methoxypropan-2-yl)-4-methyl-3-vinylpyridine

[0523] To a solution 3-bromo-2-(2-methoxypropan-2-yl)-4-methylpyridine (300 mg, 1.22 mmol) in the mixture solvent of 2.8 ml of dioxane and 0.8 ml of H2O was added 4,4,5,5-tetramethyl-2-vinyl-1 ,3,2- dioxaborolane (378.5 mg, 2.45 mmol), K2CO3 (424.5 mg, 3.07 mmol), Pd(dppf)Cl2 (134.8 mg, 0.18 mmol). The resulting mixture was stirred at 100°C for 2 h under N2. The reaction progress was monitored by LCMS. The reaction was quenched by the addition of H2O at 0°C. The resulting mixture was extracted with DCM. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford 2-(2- methoxypropan-2-yl)-4-methyl-3-vinylpyridine (240 mg, 91 % yield) as a yellow oil. MS (ESI) calcd. for C12H7NO, 191.13 m / z, found 192.10 [M+H]+.

[0524] Step 5: Synthesis of 2-(2-methoxypropan-2-yl)-4-methylpyridine-3-carbaldehyde

[0525] To a solution of 3-ethenyl-2-(2-methoxypropan-2-yl)-4-methylpyridine (210 mg, 1.098 mmol) in ACN (7 mL) was added Potassium osmate(VI) dihydrate (20.23 mg, 0.055 mmol, 0.05 equiv), follow by addition of NalO4 (469.66 mg, 2.196 mmol) dissolved in H2O (7 mL) dropwise, the mixture was allowed to warm to rt and stirred for 30 mins. The mixture was further purified by reverse phase column eluted with ACN and H2O (0.05% TFA), after concentrated to afford 2-(2-methoxypropan-2-yl)-4-methylpyridine- 3-carbaldehyde (150 mg, 92% yield) as a yellow oil. MS (ESI) calcd. for C11H15NO2, 193.11 m / z, found 194.05 [M+H]+.

[0526] Step 6: Synthesis of (2-(2-methoxypropan-2-yl)-4-methylpyridin-3-yl) methanol

[0527] To a solution of 2-(2-methoxypropan-2-yl)-4-methylpyridine-3-carbaldehyde (150 mg, 0.77 mmol) in 2 ml of THF was added NaBH4 (188 mg, 1 .20 mmol) at 0°C. The resulting mixture was stirred at rt for 0.5 h. The reaction progress was monitored by LCMS. The reaction was quenched by the addition of H2O at 0°C. The resulting mixture was extracted with DCM. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford (2-(2-methoxypropan-2-yl)-4-methylpyridin-3-yl) methanol (100 mg, 65% yield) as a yellow oil. MS (ESI) calcd. for C11H17NO2, 195.13 m / z, found 196.10 [M+H]+.

[0528] Step 7: Synthesis of 3-(chloromethyl)-2-(2-methoxypropan-2-yl)-4-methylpyridine

[0529] To a solution of (2-(2-methoxypropan-2-yl)-4-methylpyridin-3-yl) methanol (100 mg, 0.51 mmol) in 2 ml of DCM was added SOCI2 (152.3 mg, 1 .28 mmol) at 0°C. The resulting mixture was stirred at r.t for 0.5 h. The reaction progress was monitored by LCMS. The mixture was concentrated under reduced pressure to afford crude compound 3-(chloromethyl)-2-(2-methoxypropan-2-yl)-4-methylpyridine (90 mg, 82 % yield) as a yellow oil. The crude product was used in the next step directly without further purification. MS (ESI) calcd. for CnHieCINO, 213.09 m / z, found 214.00 [M+H]+.

[0530] Step 8: Synthesis of 6-{[2-(1-methoxy-1-methylethyl)-4-methyl-3-pyridyl]methylthio}-1-oxa-5,7- diaza-4-indanol

[0531] To a solution of 3-(chloromethyl)-2-(2-methoxypropan-2-yl)-4-methylpyridine (90 mg, 0.42 mmol) in 2 ml of DMF was added 2-mercapto-5,6-dihydrofuro[2,3-d] pyrimidin-4(3H)-one (107.5 mg, 0.63 mmol), DIEA (163.2 mg, 1 .26 mmol) at rt. The resulting solution was stirred at rt for 0.5 h. The reaction progress was monitored by LCMS, and it showed the reaction was completed. The mixture was further purified by reverse phase column eluted with ACN and H2O (0.05% TFA), after concentrated to afford 6-{[2-(1 - methoxy-1-methylethyl)-4-methyl-3-pyridyl]methylthio}-1-oxa-5,7-diaza-4-indanol as a trifluoroacetate salt (89.7 mg, 46% yield) as a White solid. MS (ESI) calcd. for C17H21N3O3S, 347.13 m / z, found 348.05 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 (ppm): 8.35 - 8.38 (m, 1 H), 7.29 - 7.30 (m, 1 H), 4.83 (s, 2H), 4.58 - 4.64 (m, 2H), 2.91 - 3.04 (m, 5H), 2.41 (s, 3H), 1 .49 - 1 .64 (m, 6H).19F-NMR (282 MHz, DMSO) 5 (ppm): -74.89.

[0532] Example 22: Synthesis of {3-[(4-hydroxy-1-oxa-5,7-diaza-6-indanylthio)methyl]-4-methyl-2- pyridyljacetonitrile (Compound 28)

[0533] Step 1 : Synthesis of (2-bromo-4-methylpyridin-3-yl)methanol

[0534] To a stirred solution of methyl 2-bromo-4-methylpyridine-3-carboxylate (2 g, 8.693 mmol) in THF (25 mL) was added DIBAL-H (3.09 g, 21 .732 mmol) at 0 °C. The reaction was stirred for 1 h. The reaction was monitored by LCMS and TLC. After completion of reaction, the reaction was quenched with ice water. The resulting mixture was filtered; the filter cake was washed with water. The filtrate was concentrated under reduced pressure. The crude product was re-crystallized from PE and EA (1 :1) to afford (2-bromo-4-methylpyridin-3-yl)methanol (1 .4 g) as a yellow oil. LC / MS: MS (ESI) calcd. For C HsBrNO: 200.98. Found: 201.90 [M+H]+.

[0535] Step 2: Synthesis of [4-methyl-2-(1 ,2-oxazol-4-yl)pyridin-3-yl]methanol

[0536] A solution of (2-bromo-4-methylpyridin-3-yl)methanol (1 g, 4.949 mmol), 4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)-1 ,2-oxazole (1930.50 mg, 9.898 mmol), Pd(dtbpf)Cl2 (322.57 mg, 0.495 mmol), K3PO4 (2626.38 mg, 12.372 mmol) in THF (15 mL) and H2O (5 mL) was stirred at 50 °C for 1 h under N2. The reaction was monitored by LCMS. After completion of reaction, the reaction was quenched with water. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, water (0.05% NH4HCO3) in ACN, 10% to 50% gradient in 10 min; detector, UV 254 nm. After concentrated, it affords [4-methyl-2-(1 ,2-oxazol-4-yl)pyridin-3-yl]methanol (810 mg, 86.05%yield, 83%purity) as a yellow oil. LC / MS: MS (ESI) calcd. For C10H10N2O2: 190.07. Found:191.00 [M+H]+.

[0537] Step 3: Synthesis of 2-[3-(hydroxymethyl)-4-methylpyridin-2-yl]acetonitrile

[0538] To a stirred solution of [4-methyl-2-(1 ,2-oxazol-4-yl)pyridin-3-yl]methanol (760 mg, 3.996 mmol) in DMSO (10 mL) was added KF (928.56 mg, 15.984 mmol) in H2O (10 mL) at 25 °C. The reaction was stirred at 140 °C for 0.5 h. The reaction was monitored by LCMS and TLC. The reaction was quenched by the addition of water at 0 °C. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, water (0.05% NH4HCO3) in ACN, 10% to 50% gradient in 10 min; detector, UV 254 nm. After concentrated, it provided 2-[3-(hydroxymethyl)-4- methylpyridin-2-yl]acetonitrile (600 mg) as a colorless oil. LC / MS: MS (ESI) calcd. For C9H10N2O: 162.08. Found:163.30 [M+H]+.

[0539] Step 4: Synthesis of 2-[3-(chloromethyl)-4-methylpyridin-2-yl]acetonitrile

[0540] To a stirred solution of 2-[3-(hydroxymethyl)-4-methylpyridin-2-yl]acetonitrile (150 mg, 0.925 mmol,) in DCM (5 mL) was added SOCI2 (275.04 mg, 2.313 mmol) dropwise at 0 °C. The reaction was stirred for 0.5 h at room temperature. The reaction was monitored by TLC. After completion of reaction, the resulting mixture was concentrated under reduced pressure to afford 2-[3-(chloromethyl)-4- methylpyridin-2-yl]acetonitrile (120 mg) as a yellow solid.

[0541] Step 5: Synthesis of {3-[(4-hydroxy-1-oxa-5,7-diaza-6-indanylthio)methyl]-4-methyl-2- pyridyljacetonitrile

[0542] To a stirred solution of 2-[3-(chloromethyl)-4-methylpyridin-2-yl]acetonitrile (120 mg, 0.664 mmol) and 2-sulfanyl-3H,5H,6H-furo[2,3-d]pyrimidin-4-one (226.12 mg, 1.328 mmol) in DMF (5 mL) was added DIEA (257.58 mg, 1 .992 mmol) at 25 °C. The reaction was stirred for 1 h. The reaction was monitored by LCMS. After completion of reaction, the reaction was quenched with water. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, water (0.05% NH4HCO3) in ACN, 10% to 50% gradient in 15 min; detector, UV 254 nm. After lyophilized, it provided {3-[(4-hydroxy-1-oxa-5,7-diaza-6-indanylthio)methyl]-4-methyl-2- pyridyl}acetonitrile(54.3 mg) as a white solid. LC / MS: MS (ESI) calcd. For C15H14N4O2S: 314.08. Found: 315.15 [M+H]+.1H-NMR (400 MHz, DMSO) 5 (ppm): 12.54 (s, 1 H), 8.35 - 8.36 (m, 1 H), 7.25 - 121 (m, 1 H), 4.59 - 4.63 (m, 2H), 4.41 - 4.42 (m, 4H), 2.91 - 2.96 (m, 2H), 2.36 - 2.40 (m, 3H). Example 23: Synthesis of 1-{3-[(4-hydroxy-1-oxa-5,7-diaza-6-indanylthio)methyl]-4-methyl-2- pyridyljcyclopropanecarbonitrile (Compound 29)

[0543] Step 1 : Synthesis of 2-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-4-methylpyridin-2-yl)acetonitrile

[0544] To a stirred solution of 2-[3-(hydroxymethyl)-4-methylpyridin-2-yl]acetonitrile (700 mg, 4.316 mmol) in DCM (8 mL) was added imidazole (734.55 mg, 10.790 mmol) and TBSCI (975.73 mg, 6.474 mmol) at 0 °C. The reaction was stirred for 1 h. The reaction was monitored by LCMS. After completion of reaction, the reaction was quenched with water (NH4CI aq). The resulting mixture was extracted with EA (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE: EA (3:1) to afford 2-(3-{[(tert-butyldimethylsilyl)oxy]methyl}- 4-methylpyridin-2-yl)acetonitrile (670 mg) as a white solid. LC / MS: MS (ESI) calcd. For Ci5H24N2OSi:276.17. Found: 277.30 [M+H]+.

[0545] Step 2: Synthesis of 1-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-4-methylpyridin-2-yl)cyclopropane- 1 -carbonitrile

[0546] To a stirred solution of 2-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-4-methylpyridin-2-yl)acetonitrile (300 mg, 1.085 mmol) and dioxo(trifluoromethyl)-lambda4-sulfanuide; ethenyldiphenylsulfanium (451.06 mg, 1 .302 mmol) in DMSO (5 mL) was added DBU (495.62 mg, 3.255 mmol) in portions at 0 °C. The reaction was stirred for 1 h at 25 °C. The reaction was monitored by LCMS. After completion of reaction, the reaction was quenched with water (1 mL) at 0 °C. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, water (0.05% TFA) in ACN, 30% to 90% gradient in 20 min; detector, UV 254 nm. After concentrated, it provided 1 -(3-{[(tert- butyldimethylsilyl)oxy]methyl}-4-methylpyridin-2-yl)cyclopropane-1 -carbonitrile (190 mg) as a white solid. LC / MS: MS (ESI) calcd. For C b slWSi: 302.18. Found: 303.15 [M+H]+.

[0547] Step 3: Synthesis of 1-[3-(hydroxymethyl)-4-methylpyridin-2-yl]cyclopropane-1 -carbonitrile

[0548] To a stirred solution of 1-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-4-methylpyridin-2- yl)cyclopropane-1 -carbonitrile (160 mg, 0.529 mmol) in THF (5 mL) was added Tetra-n-butylammonium fluoride (1 .0M in THF) (207.45 mg, 0.794 mmol) at 0 °C. The reaction was stirred for 1 h. The reaction was monitored by LCMS and TLC. After completion of reaction, the reaction was quenched with water. The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 1 -[3-(hydroxymethyl)-4-methylpyridin-2-yl]cyclopropane-1 -carbonitrile (120 mg) as a colorless oil. LC / MS: MS (ESI) calcd. For C11H12N2O: 188.09. Found: 189.20 [M+H]+.

[0549] Step 4: Synthesis of 1-[3-(chloromethyl)-4-methylpyridin-2-yl]cyclopropane-1 -carbonitrile

[0550] To a stirred solution of 1 -[3-(hydroxymethyl)-4-methylpyridin-2-yl]cyclopropane-1 -carbonitrile (110 mg, 0.584 mmol) in DCM (4 mL) was added SOCI2 (173.80 mg, 1.460 mmol) dropwise at 0 °C. The reaction was stirred at 25 °C for 1 h. The reaction was monitored by TLC. After completion of reaction, the resulting mixture was concentrated under reduced pressure to afford 1 -[3-(chloromethyl)-4- methylpyridin-2-yl]cyclopropane-1-carbonitrile (130 mg) as a yellow solid.

[0551] Step 5: Synthesis of 1-{3-[(4-hydroxy-1-oxa-5,7-diaza-6-indanylthio)methyl]-4-methyl-2- pyridyljcyclopropanecarbonitrile

[0552] To a stirred solution of 1 -[3-(chloromethyl)-4-methylpyridin-2-yl]cyclopropane-1 -carbonitrile (110 mg, 0.532 mmol) and 2-sulfanyl-3H,5H,6H-furo[2,3-d]pyrimidin-4-one (181.17 mg, 1.064 mmol) in DMF (3 mL) was added DIEA (206.37 mg, 1 .596 mmol) at 25 °C. The reaction was stirred for 1 h. The reaction was monitored by LCMS. After completion of reaction, the reaction was quenched with water. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, water (0.05% NH4HCO3) in ACN, 10% to 50% gradient in 10 min; detector, UV 254 nm. After lyophilized, it provided 1-{3-[(4-hydroxy-1-oxa-5,7-diaza-6- indanylthio)methyl]-4-methyl-2-pyridyl}cyclopropanecarbonitrile (43.3 mg) as a white solid. LC / MS: MS (ESI) calcd. For C17H16N4O2S: 340.10. Found: 341.20 [M+H]+.1H-NMR (400 MHz, DMSO) 5 (ppm): 8.30 - 8.32 (m, 1 H), 7.29 - 7.30 (m, 1 H), 4.62 - 4.82 (m, 2H), 4.48 - 4.52 (m, 2H), 2.85 - 2.89 (m, 2H), 2.39 - 2.45 (m, 3H), 1 .73 - 1 .75 (m, 2H), 1 .56 - 1 .58 (m, 2H).

[0553] Example 24: Synthesis of 2-{3-[(4-hydroxy-1-oxa-5,7-diaza-6-indanylthio)methyl]-4-methyl-2- pyridyl}-2-methylpropiononitril

[0554] Step 1 : Synthesis of 2-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-4-methylpyridin-2-yl)-2- methylpropanenitrile

[0555] To a solution of 2-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-4-methylpyridin-2-yl)acetonitrile (300 mg, 1 .085 mmol) in DMF (6 mL) was added NaH (57.29 mg, 2.387 mmol) at 0 °C for 10 mins under nitrogen atmosphere, followed by the addition of Ch3l (385.07 mg, 2.712 mmol) dropwise / in portions at 0 °C. The resulting mixture was stirred for 1 h. The reaction was monitored by LCMS and TLC. After completion of reaction, the reaction was quenched with water(NH4CI). The resulting mixture was extracted with EA (100 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA (1 :1) to afford 2-(3-{[(tert- butyldimethylsilyl)oxy]methyl}-4-methylpyridin-2-yl)-2-methylpropanenitrile (210 mg) as a white solid. LC / MS: MS (ESI) calcd. For Ci7H28N2OSi:304.20. Found: 305.25 [M+H]+.

[0556] Step 2: Synthesis of 2-[3-(hydroxymethyl)-4-methylpyridin-2-yl]-2-methylpropanenitrile

[0557] To a stirred solution of 2-(3-{[(tert-butyldimethylsilyl)oxy]methyl}-4-methylpyridin-2-yl)-2- methylpropanenitrile (210 mg, 0.690 mmol) in THF (5 mL) was added TBAF (270.48 mg, 1.035 mmol) at 0 °C. The reaction was stirred for 1 h. The reaction was monitored by LCMS. After completion of reaction, the reaction was quenched with water. The resulting mixture was extracted with EA (50 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 2-[3-(hydroxymethyl)-4- methylpyridin-2-yl]-2-methylpropanenitrile (120 mg) as a yellow oil. LC / MS: MS (ESI) calcd. For CIIHI4N2O: 190.11. Found: 191.10 [M+H]+.

[0558] Step 3: Synthesis of 2-[3-(chloromethyl)-4-methylpyridin-2-yl]-2-methylpropanenitrile

[0559] To a stirred solution of 2-[3-(hydroxymethyl)-4-methylpyridin-2-yl]-2-methylpropanenitrile (120 mg, 0.631 mmol, 1 equiv) in DCM (3 mL) was added SOCI2 (187.59 mg, 1.578 mmol, 2.5 equiv) at 0 °C. The reaction was stirred for 1 h. The reaction was monitored by TLC. After completion of reaction, the resulting mixture was concentrated under reduced pressure. This resulted in 2-[3-(chloromethyl)-4- methylpyridin-2-yl]-2-methylpropanenitrile (130 mg) as a yellow solid.

[0560] Step 4: Synthesis of 2-{3-[(4-hydroxy-1-oxa-5,7-diaza-6-indanylthio)methyl]-4-methyl-2-pyridyl}-2- methylpropiononitrile

[0561] To a stirred solution of 2-[3-(chloromethyl)-4-methylpyridin-2-yl]-2-methylpropanenitrile (130 mg, 0.623 mmol) and 2-sulfanyl-3H,5H,6H-furo[2,3-d]pyrimidin-4-one (212.03 mg, 1.246 mmol) in DMF (3 mL) was added DIEA (241 .54 mg, 1 .869 mmol) at 25 °C. The reaction was stirred for 1 h. The reaction was monitored by LCMS. After completion of reaction, the reaction was quenched with water. The crude product (88mg) was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5pm; Mobile Phase A: Water (1 Ommol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 5% B to 35% B in 10min; Wave Length: 254nm / 220nm nm; RT1 (min): 10.92. After lyophilized, it afford 2-{3-[(4-hydroxy-1-oxa-5,7-diaza-6-indanylthio)methyl]-4- methyl-2-pyridyl}-2-methylpropiononitrile (13.3 mg) as a white solid. LC / MS: MS (ESI) calcd. For Ci7Hi8N4O2S: 342.12. Found: 343.25 [M+H]+.1H-NMR (400 MHz, DMSO) 5 (ppm): 8.35 - 8.36 (m, 1 H), 7.28 - 7.30 (m, 1 H), 4.62 - 4.82 (m, 2H), 4.42 - 4.46 (m, 2H), 2.80 - 2.85 (m, 2H), 2.39 - 2.45 (m, 3H), 1.75 - 1.77 (m, 6H). Example 25: Synthesis of 2-(((4-cyclopropyl-2-methylpyridin-3-yl)methyl)thio)-5,6-dihydrofuro[2,3- d]pyrimidin-4-ol (Comp

[0562] Step 1 : Synthesis of methyl 4-cyclopropyl-2-methylnicotinate

[0563] To a stirred solution of methyl 4-chloro-2-methylpyridine-3-carboxylate (3 g, 16.163 mmol) and cyclopropylboronic acid (2.08 g, 24.245 mmol) in dioxane (30 mL) and H2O (6 mL) were added Pd(OAc)2 (0.54 g, 2.424 mmol), CS2CO3 (13.17 g, 40.407 mmol) and di(1-adamantyl)-N-butylphosphine (1.16 g, 3.233 mmol) at rt. The resulting mixture was stirred at 100°C for 2 h under N2 atmosphere. The reaction was monitored by LCMS. After completion of reaction, the reaction was poured into water. The resulting mixture was extracted with EA (200 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE:EA (3:1) to afford methyl 4-cyclopropyl-2-methylnicotinate (2.91 g, 62.8% yield) as a yellow oil. LC / MS: MS (ESI) calcd. For C11H13NO2: 191 .09. Found: 192.10 [M+H]+.

[0564] Step 2: Synthesis of (4-cyclopropyl-2-methylpyridin-3-yl)methanol

[0565] To a stirred solution of methyl 4-cyclopropyl-2-methylnicotinate (2.91 g, 15.217 mmol) in THF (10 mL) was added DIBAL-H (20% in hexanes) (38.04 mL, 38.043 mmol) dropwise at 0°C. The resulting mixture was stirred for 1 h under N2 atmosphere. The reaction was monitored by LCMS. After completion of the reaction, the reaction mixture was poured into ice water (80 mL). The resulting mixture was filtered, the filter cake was washed with water (20 mL). The filtrate was concentrated under reduced pressure. This resulted in (4-cyclopropyl-2-methylpyridin-3-yl)methanol (2.24 g crude) as a yellow solid. For C10H13NO: 163.10. Found: 164.20 [M+H]+.

[0566] Step 3: Synthesis of 3-(chloromethyl)-4-cyclopropyl-2-methylpyridine

[0567] To a stirred solution of (4-cyclopropyl-2-methylpyridin-3-yl)methanol (2.24 g, 13.724 mmol, 1 equiv) in DCM (20 mL) was added SOCI2 (4.08 g, 34.310 mmol) at 0°C. The reaction was stirred for 1 h. The reaction was monitored by TLC. After completion of reaction, the mixture was concentrated under reduced pressure. This resulted in 3-(chloromethyl)-4-cyclopropyl-2-methylpyridine (2.3 g) as a hydrochloric acid salt and as a yellow solid.

[0568] Step 4: Synthesis of 2-(((4-cyclopropyl-2-methylpyridin-3-yl)methyl)thio)-5,6-dihydrofuro[2,3- d]pyrimidin-4-ol

[0569] To a stirred solution of 3-(chloromethyl)-4-cyclopropyl-2-methylpyridine (2.2 g, 12.111 mmol) and 2-mercapto-5,6-dihydrofuro[2,3-d]pyrimidin-4-ol (2.06 g, 12.111 mmol) in DMF (25 mL) was added DIEA (6.26 g, 48.444 mmol) at O°C. The reaction was stirred for 1 h. The reaction was monitored by LCMS. After completion of reaction, the crude was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, water (0.05% TFA) in ACN, 10% to 50% gradient in 25 min; detector, UV 254 nm. After lyophilization, it provided 2-(((4-cyclopropyl-2- methylpyridin-3-yl)methyl)thio)-5,6-dihydrofuro[2,3-d]pyrimidin-4-ol (2.1890 g, 42.09% yield, 99.9% purity) as a trifluoroacetate salt and a white solid. LC / MS: MS (ESI) calcd. For C16H17N3O2S: 315.10. Found: 316.10 [M+H]+.1H-NMR (400 MHz, DMSO) 5 (ppm): 12.65 (s, 1 H), 8.48 - 8.49 (m, 1 H), 7.21 - 7.23 (m, 1 H), 4.58 - 4.67 (m, 4H), 2.91 - 2.96 (m, 2H), 2.74 (s, 3H), 2.28 - 2.31 (m, 1 H), 1 .23 - 1 .28 (m, 2H), 1 .02 - 1.07 (m, 2H).

[0570] Example 26: In Vitro Chlomeleon Assay

[0571] A study was conducted to determine the Chlomeleon EC50 in NG-108 cells for compounds of Table 1. The tetrahydrofuran-containing compounds, Compounds 2, 12, 17-24 and 26-31 , were surprisingly potent. Experimental Methods:

[0572] A fluorometric assay in NG-108 cells using the Cl-sensitive indicator Chlomeleon assay was performed as previously described (“Gagnon et al. Nature Medicine, 2013, 19, 1524-1528). The results of the study are provided in Table 3a.

[0573] Table 3a

[0574] “+” indicates potentiation effect of > 1 pM;

[0575] “++” indicates potentiation effect of 1 to 0.1 pM;

[0576] “+++” indicates potentiation effect of < 0.1 pM, Example 26: In Vitro CYP3A4 inhibition of Compounds 2, and 18-19.

[0577] Multiple studies were conducted to determine the CYP3A4 inhibition of Compounds 2, and 18-19 in human liver microsomes. Potent CYP3A4 inhibitors are a considerable safety issue (IC50 values ranged from 0.2 - 5 pM including high binding to microsomal protein which may further underestimate their potency to inhibit CYP3A4). CYP3A4 is the key enzyme mediating the metabolism of the majority of marketed drugs in liver and intestine. Therefore, a high risk of drug-drug interactions cannot be ruled out according to current FDA guidelines which poses a particular challenge for chronic neurological disorders since intense co-medication is often required (e.g. the use of midazolam in epilepsy). Compounds 2, 18 and 19 had CYP3A4 IC50 values mostly greater than 50 pM. Therefore, these compounds are not potent CYP3A4 inhibitors.

[0578] Experimental methods:

[0579] 1 pL of multiple concentrations of test compound or positive control compound was transferred to the “Compound Plate.” The concentrations of test compounds or positive control compounds were 0, 0.2, 1 , 2, 10, 50, 200, 2000 and 10000 pM.

[0580] The master solution was prepared according to Table 3, and pre-warmed in the water bath at 37 °C for 5 minutes. 179 pL of master solutions were transferred to “Incubation Plate”. In the mixed system, the final concentrations of test compound and positive control compound were 0, 0.001 , 0.005, 0.01 , 0.05, 0.25, 1 , 10 & 50 pM. All experiments were performed in duplicate.

[0581] Table 3. Preparation of Master Solution

[0582] Stock Final

[0583] Reagent Volume

[0584] Concentration Concentration

[0585] MgCh solution 50 mM 20 pL 5 mM

[0586] Phosphate buffer 200 mM 100 pL 100 mM

[0587] Ultra-pure H2O - 56 pL

[0588] Human liver microsomes 20 mg / mL 2 pL 0.2 mg / mL

[0589] Substrate 1 mM 1 pL 5 pM

[0590] The reaction was started with the addition of 20 pL of 10 mM NADPH solution at the final concentration of 1 mM and carried out at 37 °C. The reaction was stopped by the addition of 2 volumes of cold methanol with IS (100 nM alprazolam, 200 nM imipramine, 200 nM labetalol and 2 pM ketoprofen) to the “Incubation Plate” at the designated time points (5 minutes for midazolam mediated CYP3A4). The “Incubation Plate” was centrifuged at 3,220 g for 60 minutes to precipitate protein. An aliquot of 100 pL of the supernatant was diluted by 100 pL ultra-pure H2O, and the mixture was used for LC-MS / MS analysis. All data analysis calculations were carried out using Microsoft Excel. The formation of metabolites was analyzed by using LC-MS / MS. A decrease in the formation of the metabolites in peak area to vehicle control was used to calculate an IC50 value (test compound concentration which produces 50% inhibition) by using Excel XLfit. The results of the study are provided in Table 4. Table 4

[0591] Enumerated Embodiments

[0592] E1 . A compound of formula (I):

[0593] Formula I, or a pharmaceutically acceptable salt thereof, wherein

[0594] R1is H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, SR6, N(R5)2, OR5, S(O)R14, SO2R14, or S(N)R14;

[0595] R4is H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, OR5, SR6, N(R5)2, S(O)R14, SO2R14, or S(N)R14, or R3and R4, together with the atoms to which each is attached, join to form a 5- to 6-membered aromatic or nonaromatic carbocycle or heterocycle; R2, R3are each, independently, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, optionally substituted C5-C12 heteroaryl, optionally substituted C3-C12 heterocycle, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky ny I, optionally substituted C3-C12 cycloalkyl, optionally substituted C7-C14 arylalkyl, (CH2)POZ, C(O)Z, C(O)OZ, C(O)NZ2, OR5, N(R5)2, SR6, S(O)R14, SO2R14, or S(N)R14, or R2and R3together with the atoms to which each is attached, join to form a 5- to 6-membered aromatic or non-aromatic carbocycle or heterocycle; with Ci-Ce alkyl, C5-C12 aryl, C3-C12 cycloalkyl, C5-C12 heteroaryl, or C3-C12 heterocycle, optionally wherein the C5-C12 aryl, C3-C12 cycloalkyl, C5-C12 heteroaryl, or C3-C12 heterocycle is joined to A through one or more carbon atoms; n is 0, 1 , 2, or 3; m is 0, 1 , 2, or 3; each p is, independently, 1 , 2, or 3; each R5is, independently, H, optionally substituted O-Ce alkyl, optionally substituted C5-C12 aryl, or optionally substituted C3-C12 cycloalkyl, each R6is, independently, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci- Ce heteroalkyl, optionally substituted C3-C6 heterocycle, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C12 aryl, or optionally substituted C5-C12 heteroaryl, each R14is independently, H, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C6 heterocycle, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C12 aryl, or optionally substituted C5-C12 heteroaryl; each Z is, independently, H, or optionally substituted Ci-Ce alkyl.

[0596] E2. A compound of formula (II): or a pharmaceutically acceptable salt thereof, wherein

[0597] R1is H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, SR6, N(R5)2, OR5, S(O)R14, SO2R14, or S(N)R14;

[0598] R4is H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, OR5, SR6, N(R5)2, S(O)R14, SO2R14, or S(N)R14, or R3and R4, together with the atoms to which each is attached, join to form a 5- to 6-membered aromatic or non- aromatic carbocycle or heterocycle;

[0599] R2, R3are each, independently, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, optionally substituted C5-C12 heteroaryl, optionally substituted C3-C12 heterocycle, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky ny I, optionally substituted C3-C12 cycloalkyl, optionally substituted C7-C14 arylalkyl, (CH2)POZ, C(O)Z, C(O)OZ, C(O)NZ2, OR5, N(R5)2, SR6, S(O)R14, SO2R14, or S(N)R14; or R2and R3together with the atoms to which each is attached, join to form a 5- to 6-membered aromatic or non-aromatic carbocycle or heterocycle; , wherein A is optionally substituted with

[0600] C1-C6 alkyl, C5-C12 aryl, C3-C12 cycloalkyl, C5-C12 heteroaryl, or C3-C12 heterocycle, optionally wherein the C5-C12 aryl, C3-C12 cycloalkyl, C5-C12 heteroaryl, or C3-C12 heterocycle is joined to A through one or more carbon atoms; n is 0, 1 , 2, or 3; m is 0, 1 , 2, or 3; each p is, independently, 1 , 2, or 3; each R5is, independently, H, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, or optionally substituted C3-C12 cycloalkyl; each R6is, independently, H, halogen, optionally substituted C1-6 alkyl, optionally substituted C5-12 aryl, or optionally substituted C3-C12 cycloalkyl; each R14is independently, H, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C6 heterocycle, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C12 aryl, or optionally substituted C5-C12 heteroaryl; each Z is, independently, H, or optionally substituted C1-6 alkyl; wherein Ra’ is H, OH, optionally substituted

[0601] Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky nyl, optionally substituted C3-C12 cycloalkyl, or optionally substituted Ce-Ci4 aryl; and Rais CH2NH or C(Rd)2O, wherein each Rdis independently H, Ci-Cs alkyl, Ci-Cs cycloalkyl, Ci-Cs aryl, or Ci-Cs heteroaryl; Rbis H, OH, optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky nyl, optionally substituted Ci-Cs alkoxy, optionally substituted C3-C12 cycloalkyl, optionally substituted Ce-Ci4 aryl, or N(Re)2, each Rcis H, Ci-Cs alkyl, or C6-C14 aryl and wherein each Reis independently H or Ci-Cs alkyl.

[0602] E3. The compound of embodiment 1 or 2, wherein R1, R2, R3and R4are not all H.

[0603] R4

[0604] E4. The compound of embodiment 1 , 2, or 3, wherein ® is .

[0605] E5. The compound of embodiment 1 , 3, or 4, wherein the compound is a compound of formula (I- or a pharmaceutically acceptable salt thereof.

[0606] E6. The compound of embodiment 1 , 3, or 4, wherein the compound is a compound of formula (I-

[0607] C): or a pharmaceutically acceptable salt thereof, wherein

[0608] R8, R9, R10and R11are each, independently, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky ny I, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, optionally substituted C7- C14 arylalkyl, (CH2)POZ, C(O)Z, C(O)OZ, C(O)NZ2, OR5, or N(R5)2.

[0609] E7. The compound of embodiment 1 , 3, or 4, wherein the compound is a compound of formula (I- D): or a pharmaceutically acceptable salt thereof, wherein

[0610] R8, R9, R10, and R11are each, independently, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky ny I, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, optionally substituted C7- C14 arylalkyl, (CH2)POZ, C(O)Z, C(O)OZ, C(O)NZ2, OR5, SR6, or N(R5)2.

[0611] E8. The compound of embodiment 1 , 2, or 3, wherein

[0612] E9. The compound of embodiment 1 , 3, or 8, wherein the compound is a compound of the formula (l-B): or a pharmaceutically acceptable salt thereof.

[0613] E10. The compound of embodiment 1 , 3, or 8, wherein the compound is a compound of formula or a pharmaceutically acceptable salt thereof, wherein

[0614] R8, R9, R10and R11are each, independently, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky ny I, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, optionally substituted C7- C14 arylalkyl, (CH2)POZ, C(O)Z, C(O)OZ, C(O)NZ2, OR5, or N(R5)2.

[0615] E11. The compound of embodiment 6, 7, or 10, wherein R8is H, halogen, optionally substituted

[0616] Ci-Ce alkyl, or optionally substituted C3-C6 cycloalkyl.

[0617] E12. The compound of embodiment 6, 7, or 10, wherein R9is H, halogen, optionally substituted

[0618] Ci-Ce alkyl, or optionally substituted C3-C6 cycloalkyl.

[0619] E13. The compound of embodiment 6, 7, or 10, wherein R10is H, halogen, optionally substituted

[0620] Ci-Ce alkyl, or optionally substituted C3-C6 cycloalkyl.

[0621] E14. The compound of embodiment 6, 7, or 10, wherein R11is H, halogen, optionally substituted Ci-Ce alkyl, or optionally substituted C3-C6 cycloalkyl.

[0622] E15. The compound of any one of embodiments 1 -14, wherein

[0623] E16. The compound of any one of embodiments 1 -14, wherein

[0624] E19. The compound of embodiment 1 , 3-5, or 16, wherein the compound is a compound of formula (l-E): or a pharmaceutically acceptable salt thereof.

[0625] E20. The compound of embodiment 1 , 3-5, or 15, wherein the compound is a compound of the formula (l-F): or a pharmaceutically acceptable salt thereof.

[0626] E21. The compound of embodiment 1 , 3-5, or 15, wherein the compound is a compound of the formula (l-G): or a pharmaceutically acceptable salt E22. The compound of embodiment 1 , 3-5, or 18, wherein the compound is a compound of formula (l-L): or a pharmaceutically acceptable salt thereof.

[0627] E23. The compound of embodiment 1 , 3-5, or 18, wherein the compound is a compound of formula (l-O): or a pharmaceutically acceptable salt thereof.

[0628] E24. The compound of embodiment 1 , 3-5, or 17, wherein the compound is a compound of formula (l-M): or a pharmaceutically acceptable salt thereof.

[0629] E25. The compound of embodiment 1 , 3-5, or 17, wherein the compound is a compound of formula (l-N): or a pharmaceutically acceptable salt thereof.

[0630] E26. The compound of embodiment 1 , 3, 8-9, or 16, wherein the compound is a compound of the formula (l-H): or a pharmaceutically acceptable salt thereof.

[0631] E27. The compound of embodiment 1 , 3, 8-9, or 15, wherein the compound is a compound of the formula (l-J): or a pharmaceutically acceptable salt thereof.

[0632] E28. The compound of embodiment 1 , 3, 8-9, or 15, wherein the compound is a compound of formula (l-K): or a pharmaceutically acceptable salt thereof.

[0633] E29. The compound of embodiment 1 , 3, 8-9, or 18, wherein the compound is a compound of formula (l-P): or a pharmaceutically acceptable salt thereof.

[0634] E30. The compound of embodiment 1 , 3, 8-9, or 17, wherein the compound is a compound of formula (l-Q): or a pharmaceutically acceptable salt thereof.

[0635] E31 . The compound of embodiment 1 , 3, 8-9, or 17, wherein the compound is a compound of formula (l-R): or a pharmaceutically acceptable salt thereof.

[0636] E32. The compound of embodiment 1 , 3, 8-9, or 18, wherein the compound is a compound of formula (l-S): or a pharmaceutically acceptable salt thereof.

[0637] E33. The compound of embodiment 1 -5, or 15-18, E34. The compound of embodiment 1-5, or 15-18, wherein ci

[0638] E35. The compound of embodiment 1-5, or 15-18, wherein

[0639] E36. The compound of embodiment 1-5, or 15-18, wherein

[0640] E37. The compound of embodiment 1 -34, wherein R1is halo.

[0641] E38. The compound of embodiment 1 -34, wherein R1is Cl, and R4is not H.

[0642] E39. The compound of embodiment 1 -32 or 35-36, wherein R1is methyl.

[0643] E40. The compound of embodiment 1-32 or 35-36, wherein R1is methyl and R4is not H.

[0644] E41 . The compound of embodiment 1-32, 34, or 36, wherein R4is methyl.

[0645] E42. The compound of embodiment 1-32, 34, or 36, wherein R4is Me, and R1is not H.

[0646] E43. The compound of embodiment 1 -6, or 8-32, wherein R2is Me.

[0647] E44. The compound of embodiment 1-6, or 8-32, wherein R2is Me, and R1is not H.

[0648] E45. The compound of embodiment 1-6, or 8-32, wherein R2is Me, and R4is not H.

[0649] E46. The compound of embodiment 1 -32, wherein R1is ethyl.

[0650] E47. The compound of embodiment 1-32, wherein R4is ethyl.

[0651] E48. The compound of embodiment 1 -32, wherein R1is OMe.

[0652] E49. The compound of embodiment 1-6, or 8-32, wherein R2is OMe.

[0653] E50. The compound of embodiment 1-32, wherein R3is OMe.

[0654] E51 . The compound of embodiment 1-32, wherein R4is OMe.

[0655] E52. The compound of embodiment 1-32, wherein R1is NH2.

[0656] E53. The compound of embodiment 1-6, or 8-32, wherein R2is NH2.

[0657] E54. The compound of embodiment 1-6, or 8-32, wherein R2is halo.

[0658] E55. The compound of embodiment 1-6, or 8-32, wherein R2is Cl, and R1is not H.

[0659] E56. The compound of embodiment 1-6, or 8-32, wherein R2is Cl, and R4is not H.

[0660] E57. The compound of embodiment 1-32, wherein R3is NH2.

[0661] E58. The compound of embodiment 1-32, wherein R4is NH2.

[0662] E59. The compound of embodiment 1-32, wherein R1is NHMe.

[0663] E60. The compound of embodiment 1-32, wherein R4is NHMe.

[0664] E61. The compound of embodiment 1-32, wherein R1is NMe2.

[0665] E62. The compound of embodiment 1-32, wherein R4is NMe2.

[0666] E63. The compound of embodiment 1-32, wherein R1is CF3.

[0667] E64. The compound of embodiment 1-32, wherein R4is CF3.

[0668] E65. The compound of embodiment 1-32, wherein R1is OCF3.

[0669] E66. The compound of embodiment 1-32, wherein R4is OCF3.

[0670] E67. The compound of embodiment 1-32, wherein R1is CHF2.

[0671] E68. The compound of embodiment 1-32, wherein R4is CHF2.

[0672] E69. The compound of embodiment 1-32, wherein R1is OCHF2. E70. The compound of embodiment 1-32, wherein R4is OCHF2.

[0673] E71 . The compound of embodiment 1-32, wherein R1is SMe.

[0674] E72. The compound of embodiment 1-32, wherein R4is SMe.

[0675] E73. The compound of embodiment 1-32, wherein R1is SCF3.

[0676] E74. The compound of embodiment 1-32, wherein R4is SCF3.

[0677] E75. The compound of embodiment 1-32, wherein R1is SF5.

[0678] E76. The compound of embodiment 1 -32, wherein R4is SF5.

[0679] E77. The compound of embodiment 1 -32, wherein R1is CH2CF3.

[0680] E78. The compound of embodiment 1 -32, wherein R4is CH2CF3.

[0681] E79. The compound of embodiment 1 -32, wherein R4is halo.

[0682] E80. The compound of embodiment 1 -32, wherein R4is Cl, and R1is not H.

[0683] E81. The compound of embodiment 1 -32, wherein R1

[0684] E82. The compound of embodiment 1 -32, wherein

[0685] E83. The compound of embodiment 1 -34, wherein R1

[0686] E84. The compound of embodiment 1 -34, wherein

[0687] E85. The compound of embodiment 1 -32, wherein R1

[0688] E86. The compound of embodiment 1 -32, wherein

[0689] E87. The compound of embodiment 1 -32, wherein R1

[0690] E88. The compound of embodiment 1 -32, wherein

[0691] E89. The compound of embodiment 1 -32, wherein R3is halo.

[0692] E90. The compound of embodiment 1 -32, wherein R1

[0693] E91. The compound of embodiment 1 -32, wherein R1

[0694] E92. The compound of embodiment 1 -32, wherein R1

[0695] E93. The compound of embodiment 1 -32, wherein R1

[0696] E94. The compound of embodiment 1 -32, wherein R1is SCH2CH3.

[0697] E95. The compound of embodiment 1 -32, wherein R1 0,

[0698] E96. The compound of embodiment 1 -32, wherein R1is

[0699] E97. The compound of embodiment 1 -32, wherein R1

[0700] E98. The compound of embodiment 1 -32, wherein R1

[0701] E99. The compound of embodiment 1 -32, wherein R1is SO2CH3 or SO2CH2CH3.

[0702] E100. The compound of embodiment 1 -32, wherein

[0703] E101 . The compound of embodiment 1 -32, wherein

[0704] E102. The compound of embodiment 1 -32, wherein

[0705] E103. The compound of embodiment 1-32, wherein

[0706] E104. The compound of embodiment 1 -32, wherein R4is SCH2CH3.

[0707] E105. The compound of embodiment 1 -32, wherein

[0708] E106. The compound of embodiment 1-32, wherein

[0709] E107. The compound of embodiment 1 -32, wherein

[0710] E108. The compound of embodiment 1 -32, wherein R4is SO2CH3

[0711]

[0712] E110. The compound of embodiment 2-4, 8, or 15-18, wherein

[0713] E111 . The compound of embodiment 2-4, 8, or 15-18, wherein Rbis optionally substituted Ci-Cs alkyl.

[0714] E112. The compound of embodiment 2-4, 8, or 15-18, wherein Rbis (CH2)5CH3, CH3, C(CH3)3, or CH(CH3)2. E113. The compound of embodiment 2-4, 8, or 15-18, wherein Rbis carboxyl substituted Ci-Ca alkyl.

[0715] E114. The compound of embodiment 2-4, 8, or 15-18, wherein Rbis (CH2)4COOH, CH2COOH,

[0716] E115. The compound of embodiment 2-4, 8, or 15-18, wherein Rbis optionally substituted Ci-C3alkoxy.

[0717] E116. The compound of embodiment 2-4, 8, or 15-18, wherein Rbis OCH2CH3or

[0718] E117. The compound of embodiment 2-4, 8, or 15-18, wherein Rbis N(Re)2, wherein each Reis independently H or Ci-C3alkyl.

[0719] E118. The compound of embodiment 2-4, 8, or 15-18, wherein Rbis NHCH2CH3. E119. The compound of embodiment 2-4, 8, or 15-18, wherein Rais CH2NH. E120. The compound of embodiment 2-4, 8, or 15-18, wherein Rais C(Rd)2O. E121 . The compound of embodiment 2-4, 8, or 15-18, wherein R12is C(O)Ra’. E122. The compound of embodiment 2-4, 8, or 15-18, wherein Ra’ is optionally substituted Ci-C3alkyl.

[0720] E123. The compound of embodiment 2-4, 8, or 15-18, wherein Ra’ is CH2CH3, CH(CH3)2, , , ,

[0721] E125. The compound of embodiment 2-4, 8, or 15-18, wherein each Rcis independently H or C(CH3)3.

[0722] E126. The compound of embodiment 2-4, 8, or 15-18, wherein Rd is CH2O, or CH(CH3)O.

[0723] E127. The compound of embodiment 2-4, or 15-18, wherein the compound of formula II has the structure:

[0724]

[0725] 5 thereof.

[0726] E128. The compound of embodiment 2-4, wherein the compound of formula II has the structure:

[0727] salt thereof.

[0728] E129. The compound of embodiment 2-4, wherein the compound of formula II has the structure:

[0729]

[0730] E130. A pharmaceutical composition including a compound of any one of embodiments 1 -129 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0731] E131. A compound of any one of embodiments 1-129, or a pharmaceutical composition of embodiment 130, for use as a medicament.

[0732] E132. A method for treating a neurological disorder, including administering to a subject in need thereof a therapeutically effective amount of a compound of any one of embodiments 1-129 or a pharmaceutically acceptable salt thereof.

[0733] E133. The method of embodiment 132, wherein the neurological disorder is a neurotraumatic disorder, a neurodevelopmental disorder, or an affective disorder.

[0734] E134. The method of embodiment 132, wherein the neurological disorder is a neurotraumatic disorder. E135. The method of embodiment 133, wherein the neurotraumatic disorder is spinal cord injury, traumatic brain injury, stroke, peripheral nerve injury, multiple sclerosis, ischemia, amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease, myelopathy, hypoxic-ischemic encephalopathy, epilepsy, tumor-associated epilepsy, spasticity, or peripheral neuropathy.

[0735] E136. The method of embodiment 132, wherein the neurological disorder is a neurodevelopmental disorder.

[0736] E137. The method of embodiment 136, wherein the neurodevelopmental disorder is an autism spectrum disorder, Tuberous Sclerosis Complex (TSC), Rett syndrome, Fragile X syndrome, Angelman syndrome, cerebral palsy, Down syndrome, pain, Dravet syndrome, epilepsy, or sudden unexpected death in epilepsy.

[0737] E138. The method of embodiment 132, wherein the neurological disorder is an affective disorder.

[0738] E139. The method of embodiment 138, wherein the affective disorder is disorder is schizophrenia, bipolar disorder, anxiety disorder, or major depressive disorder.

[0739] EMO. The method of embodiment 137, wherein the epilepsy is refractory epilepsy, neurotrauma associated epilepsy (ischemia, stroke, traumatic brain injury), status epilepticus, tumor associated epilepsy or hypoxic-ischemic encephalopathy.

[0740] Other Embodiments

[0741] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the disclosure and including such departures from the invention that come within known or customary practice within the art to which the disclosure pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims. Other embodiments are within the claims.

Claims

What is claimed:CLAIMS1 . A compound having the structure of:Formula I, or a pharmaceutically acceptable salt thereof, whereinR1is H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, SR6, N(R5)2, OR5, S(O)R14, SO2R14, or S(N)R14;R4is H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, OR5, SR6, N(R5)2, S(O)R14, SO2R14, or S(N)R14, or R3and R4, together with the atoms to which each is attached, join to form a 5- to 6-membered aromatic or nonaromatic carbocycle or heterocycle;R2, R3are each, independently, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, optionally substituted C5-C12 heteroaryl, optionally substituted C3-C12 heterocycle, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky ny I, optionally substituted C3-C12 cycloalkyl, optionally substituted C7-14 arylalkyl, (CH2)POZ, C(O)Z, C(O)OZ, C(O)NZ2, OR5, N(R5)2, SR6, S(O)R14, SO2R14, or S(N)R14, or R2and R3together with the atoms to which each is attached, join to form a 5- to 6-membered aromatic or non-aromatic carbocycle or heterocycle;A is optionally substituted with Ci-Ce alkyl, C5-C12 aryl, C3-C12 cycloalkyl, C5-C12 heteroaryl, or C3- C12 heterocycle, optionally wherein the C5-C12 aryl, C3-C12 cycloalkyl, C5-C12 heteroaryl, or C3-C12 heterocycle is joined to A through one or more carbon atoms; n is 0, 1 , 2, or 3; m is 0, 1 , 2, or 3; each p is, independently, 1 , 2, or 3; each R5is, independently H, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, or optionally substituted C3-C12 cycloalkyl; each R6is, independently H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci- Ce heteroalkyl, optionally substituted C3-Ce heterocycle, optionally substituted C3-Ce cycloalkyl, optionally substituted C5-C12 aryl, or optionally substituted C5-C12 heteroaryl,each R14is independently, H, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C6 heterocycle, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C12 aryl, or optionally substituted C5-C12 heteroaryl; and each Z is, independently, H or optionally substituted Ci-Ce alkyl.

2. The compound of claim 1 , wherein the compound of formula I has the structure:

4. The compound of claim 1 , wherein the compound of formula I has the structure:or a pharmaceutically acceptable salt thereof, whereinR8, R9, R10and R11are each, independently, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky ny I, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, optionally substituted C7- C14 arylalkyl, (CH2)POZ, C(O)Z, C(O)OZ, C(O)NZ2, OR5, or N(R5)2.

5. The compound of claim 1 , wherein the compound is a compound of formula (l-T):or a pharmaceutically acceptable salt thereof, whereinR8, R9, R10and R11are each, independently, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky ny I, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, optionally substituted C7- C14 arylalkyl, (CH2)POZ, C(O)Z, C(O)OZ, C(O)NZ2, OR5, or N(R5)2.

6. A compound of Formula (II):or a pharmaceutically acceptable salt thereof, whereinR1is H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, SR6, N(R5)2, OR5, S(O)R14, SO2R14, or S(N)R14;R4is H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, OR5, SR6, N(R5)2, S(O)R14, SO2R14, or S(N)R14; or R3and R4, together with the atoms to which each is attached, join to form a 5- to 6-membered aromatic or nonaromatic carbocycle or heterocycle;R2, R3are each, independently, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, optionally substituted C5-C12 heteroaryl, optionally substituted C3-C12 heterocycle, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky ny I, optionally substituted C3-C12 cycloalkyl, optionally substituted C7-C14 arylalkyl, (CH2)POZ, C(O)Z, C(O)OZ, C(O)NZ2, OR5, N(R5)2, SR6, S(O)R14, SO2R14, or S(N)R14, or R2and R3together with the atoms to which each is attached, join to form a 5- to 6-membered aromatic or non-aromatic carbocycle or heterocycle;A is optionally substituted with Ci-Ce alkyl, C5-C12 aryl, C3-C12 cycloalkyl, C5-C12 heteroaryl, or C3- C12 heterocycle, optionally wherein the C5-C12 aryl, C3-C12 cycloalkyl, C5-C12 heteroaryl, or C3-C12 heterocycle is joined to A through one or more carbon atoms; n is 0, 1 , 2, or 3; m is 0, 1 , 2, or 3; each p is, independently, 1 , 2, or 3; each R5is, each, independently, H, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, or optionally substituted C3-C12 cycloalkyl; each R6is, each, independently, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C6 heterocycle, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C12 aryl, or optionally substituted C5-C12 heteroaryl, each R14is independently, H, optionally substituted Ci-Ce alkyl, optionally substituted Ci-Ce heteroalkyl, optionally substituted C3-C6 heterocycle, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C12 aryl, or optionally substituted C5-C12 heteroaryl; each Z is, independently, H or optionally substituted C1-6 alkyl;wherein Ra’ is H, OH, optionally substitutedCi-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky nyl, optionally substituted C3-C12 cycloalkyl, or optionally substituted Ce-Ci4 aryl; and Rais CH2NH or C(Rd)20, wherein each Rdis independently H, Ci-Cs alkyl, Ci-Cs cycloalkyl, Ci-Cs aryl, or Ci-Cs heteroaryl; Rbis H, OH, optionally substituted Ci-Cs alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky nyl, optionally substituted Ci-Cs alkoxy, optionally substituted C3-C12 cycloalkyl, optionally substituted Ce-Ci4 aryl, or N(Re)2, each Rcis, independently, H, Ci-Cs alkyl, or C6-C14 aryl, and each Reis independently H or Ci-Cs alkyl.

7. The compound of any one of claims 1 -6, wherein R1, R2, R3and R4are not all H.R48. The compound of any one of claims 1 , and 6-7, wherein9. The compound of any one of claims 1 , and 6-7, wherein10. The compound of any one of claims 1 -9, wherein, wherein A is optionally substituted with Ci-Ce alkyl, C5-C12 aryl,C3-C12 cycloalkyl, C5-C12 heteroaryl, or C3-C12 heterocycle, optionally wherein the C5-C12 aryl, C3-C12 cycloalkyl, C5-C12 heteroaryl, or C3-C12 heterocycle is joined to A through one or more carbon atoms.

12. The compound of any one of claims 1-9, wherein14. The compound of any one of claims 1-9, wherein15. The compound of claim 1 , wherein the compound of formula I has the structure:or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 , wherein the compound of formula I has the structure:

17. The compound of any one of claims 1 -3 and 6, whereinR2and R3are each, independently, H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, optionally substituted C5-C12 heteroaryl, optionally substituted C3-C12 heterocycle, OR5, N(R5)2, SR6, S(O)R14, SO2R14, or S(N)R14, andR4is H, halogen, optionally substituted Ci-Ce alkyl, CF3, OR5, N(R5)2, SR6S(O)R14, SO2R14, or S(N)R14.

18. The compound of any one of claims 1-3 and 6, wherein R2is H, halogen, optionally substituted Ci-Ce alkyl, optionally substituted C5-C12 aryl, optionally substituted C5-C12 heteroaryl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alky ny I, optionally substituted C3-C12 cycloalkyl, optionally substituted C7-C14 arylalkyl, (CH2)POZ, C(O)Z, C(O)OZ, C(O)NZ2, OR5, N(R5)2, SR6, S(O)R14, SO2R14, or S(N)R14, or R2and R3together with the atoms to which each is attached, join to form a 5- to 6-membered aromatic or non-aromatic carbocycle or heterocycle.

19. The compound of any one of claims 1-16, wherein R1is halogen.

20. The compound of any one of claims 1-16, wherein R1is Cl.

21. The compound of any one of claims 1-16, wherein if R1is Cl, then R4is not H.

22. The compound of any one of claims 1-16, wherein R1is optionally substituted Ci-Ce alkyl.

23. The compound of any one of claims 1-16, wherein R1is methyl, ethyl, propyl, CH2F, CHF2,24. The compound of any one of claims 1-16, wherein if R1is Me, then R4is not H.

25. The compound of any one of claims 1-16, wherein R1is optionally substituted C3-C12 cycloalkyl.

26. The compound of any one of claims 1-16, wherein R1is27. The compound of any one of claims 1-16, wherein R1is optionally substituted C3-C12 heterocycle.

28. The compound of any one of claims 1-16, wherein R1is29. The compound of any one of claims 1-16, wherein R1is SR6.

30. The compound of any one of claims 1-16, wherein R1is SF5, SCH3, SCH2CH3, or SCF3.31 . The compound of any one of claims 1-16, wherein R1is S(O)R14.

32. The compound of any one of claims 1-16, wherein R1is33. The compound of any one of claims 1-16, wherein R1is SO2R14.

34. The compound of any one of claims 1-16, wherein R1is35. The compound of any one of claims 1-16, wherein R1is OR5.

36. The compound of any one of claims 1-16, wherein R1is OCH3, OCH2CH3,37. The compound of any one of claims 1-36, wherein R4is halogen.

38. The compound of any one of claims 1-36, wherein R4is Cl.

39. The compound of any one of claims 1-36, wherein if R4is Cl, then R1is not H.

40. The compound of any one of claims 1-36, wherein R4is optionally substituted Ci-Ce alkyl.

41. The compound of any one of claims 1-36, wherein R4is methyl, ethyl, propyl, CH2F, CHF2, orCF3.

42. The compound of any one of claims 1-36, wherein if R4is Me, then R1is not H.

43. The compound of any one of claims 1-36, wherein R4is optionally substituted carbocycle.

44. The compound of any one of claims 1-36, wherein R4is45. The compound of any one of claims 1-36, wherein R4is SR6.

46. The compound of any one of claims 1-36, wherein R4is SF5, SCH3, SCH2CH3, or SCF3.

47. The compound of any one of claims 1-36, wherein R4is OR5.

48. The compound of any one of claims 1-36, wherein R4is OCH3, OCH2CH3, or OCHF2.

49. The compound of any one of claims 1-16, wherein if R2is Me, then R1is not H.

50. The compound of any one of claims 1-16, wherein if R2is Me, then R4is not H.

51. The compound of any one of claims 1-16, wherein if R2is Cl, then R1is not H.

52. The compound of any one of claims 1-16, wherein if R2is Cl, then R4is not H.

53. The compound of claim 1 or 6, wherein54. The compound of claim 1 , wherein the compound has the structure of any of compounds 1-31 in Table 1 .

55. The compound of any one of claims 6-14, wherein56. The compound of any one of claims 6-14, wherein Rbis optionally substituted Ci-Ca alkyl.

57. The compound of any one of claims 6-14, wherein Rbis (CH2)5CH3, CH3, C(CH3)3, orCH(CH3)2.

58. The compound of any one of claims 6-14, wherein Rbis carboxyl substituted Ci-Cs alkyl.

59. The compound of any one of claims 6-14, wherein Rbis (CH2)4COOH, CH2COOH,60. The compound of any one of claims 6-14, wherein Rbis optionally substituted Ci-Cs alkoxy.61 . The compound of any one62. The compound of any one of claims 6-14, wherein Rbis N(Re)2, wherein each Reis independently H or Ci-Cs alkyl.

63. The compound of any one of claims 6-14, wherein Rbis NHCH2CH3.

64. The compound of any one of claims 6-14, wherein Rais CH2NH.

65. The compound of any one of claims 6-14, wherein Rais C(Rd)2O.

66. The compound of claim 65, wherein Rdis CH2O, or CH(CH3)O.

67. The compound of any one of claims 6-14, wherein R12is C(O)Ra’.

68. The compound of claim 67, wherein Ra’ is optionally substituted Ci-Cs alkyl.

69. The compound of claim 67, wherein Ra’ is CH2CH3, CH(CH3)2, C(CH3)3, CH2N(CH3)2,70. The compound of any one of claims 6-14, wherein71. The compound of claim 70, wherein each Rcis independently H or C(CH3)3.

72. The compound of any one of claims 70-71 , wherein Rais CH2NH.

73. The compound of any one of claims 70-71 , wherein Rais C(Rd)2<D.

74. The compound of claim 73, wherein Rd is CH2O, or CH(CH3)O.

75. The compound of claim 2, wherein the compound of formula II has the structure:or pharmaceutically acceptable salt thereof.

76. The compound of claim 2, wherein the compound has the structure:salt thereof.

77. The compound of claim 2, wherein the compound has the structure of any of compounds 129- 162 in Table 2.

78. A pharmaceutical composition comprising a compound of any one of claims 1 to 77 and a pharmaceutically acceptable excipient.

79. A compound of any one of claims 1 -77, or a pharmaceutical claim of 78, for use as a medicament.

80. A method of treating or preventing pain, in particular neuropathic pain, inflammation, inflammatory pain, arthritic pain, diabetic pain, or neuralgia in a subject in need thereof, the method including administering to the subject an effective amount of a compound of any one of claims 1 to 78, or a pharmaceutical composition of claim 79.81 . A method of treating epilepsy in a subject in need thereof, the method including administering to the subject an effective amount of a compound of any one of claims 1 to 78, or a pharmaceutical composition of claim 79.

82. The method of claim 81 , wherein the epilepsy is focal epilepsy, temporal lobe epilepsy, refractory epilepsy, generalized epilepsy, developmental and epileptic encephalopathy (DEE), epilepsy of infancy with migrating focal seizures (EIMFS), absence epilepsy, Lennox-Gastaut syndrome, neurotrauma associated epilepsy, status epilepticus, tumor associated epilepsy, hypoxic-ischemic encephalopathy or sudden unexpected death in epilepsy.

83. A method of treating neurodevelopmental disorder in a subject in need thereof, the method including administering to the subject an effective amount of a compound of any one of claims 1 to 78, or a pharmaceutical composition of claim 79.

84. The method of claim 83, wherein the neurodevelopmental disorder is autism spectrum disorder, Rett Syndrome, Tuberous Sclerosis Complex (TSC), Fragile X syndrome, Angelman syndrome, Down syndrome, Dravet syndrome, CKDL5 Deficiency syndrome, SYNGAP1 haploinsufficiency, cerebral palsy, or Huntington's disease.

85. A method of treating neurotraumatic injury or neurogenerative disease in a subject in need thereof, the method including administering to the subject an effective amount of a compound of any one of claims 1 to 78, or a pharmaceutical composition of claim 79.

86. The method of claim 85, wherein the neurotraumatic injury or neurogenerative disease is traumatic brain injury, stroke, multiple sclerosis, Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease, Alzheimer's disease, spasticity, or spinal cord injury.

87. A method of treating affective disorders in a subject in need thereof, the method including administering to the subject an effective amount of a compound of any one of claims 1 to 78, or a pharmaceutical composition of claim 79.

88. The method of claim 87, wherein the affective disorder is schizophrenia, bipolar disorder, general anxiety disorder, social anxiety disorder, or major depressive disorder.

89. A method for potentiating KCC2 activity, clustering, dimerization or membrane expression in a cell or subject, the method comprising contacting the cell with, or administering to the subject, an effective amount of a compound of any one of claims 1 to 78, or a pharmaceutical composition of claim 79.

90. A method for increasing Cl efflux or potentiating KCC2 activity in a cell or subject, the method comprising contacting the cell with, or administering to the subject, an effective amount of a compound of any one of claims 1 to 78, or a pharmaceutical composition of claim 79.

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