Compounds, pharmaceutical composition, methods for treating or preventing pain, treating epilepsy, treating neurodevelopmental disorders, treating neurotraumatic injuries, and treating affective disorders in a subject, and methods for potentiating KCC2 activity and increasing CL efflux.

Description

"Compounds, pharmaceutical composition, methods for treating or preventing pain, treating epilepsy, treating neurodevelopmental disorders, treating neurotraumatic injuries, and treating affective disorders in a subject, and methods for enhancing the activity of KCC2." "And to increase the outflow of CL" Priority

[0001] This Application claims the benefit of U.S. Provisional Application No. 63 / 457,326 filed April 5, 2023. The entire contents of those applications are incorporated herein by reference in their entirety. Fundamentals of the Invention

[0002] Potassium chloride cotransporter-2 (KCC2) has been associated with neurological disorders, psychiatric disorders, and central nervous system lesions, 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 serious challenges to the daily life of an afflicted patient. Few therapeutic products have been studied or used to treat these neurological disorders, causing serious challenges and suffering for these patients. Additionally, the few that have been studied or used are not adequately sufficient to reduce the individual's suffering or improve recovery from these neurological disorders. Consequently, there is a need for new therapeutic agents for the treatment of neurological disorders. Summary of the Disclosure

[0003] This disclosure provides compounds, compositions, and methods for treating or preventing neurological disorders in a patient. The Petition 870250110266, dated 01 / 12 / 2025, pp. 242 / 473 2 / 214 disclosed methods include administering a compound disclosed in this document to a subject suffering from a neurological disorder. The disclosure further provides pharmaceutical compositions containing one of the compounds described in this document. The disclosure further provides compounds and pharmaceutical compositions for use as a medicine. The disclosure further provides compounds and pharmaceutical compositions for use in the treatment or prevention of neurological disorders.

[0004] In the first aspect, the disclosure provides a compound of formula (I): the Formula I, or a pharmaceutically acceptable salt thereof, wherein: R1 is H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, SR5a, N(R5)2, OR5, S(O)R14, SO2R14 or S(N)R14, R4e H, halogen, optionally substituted C1-6 alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, OR5, SR5a, N(R5)2, S(O)R14, SO2R14, or S(N)R14, or R3e R4, together with the atoms to which each is attached, join to form a 5- to 7-membered aromatic or non-aromatic carbocycle or heterocycle; R2 is H, halogen, optionally substituted C1-C6 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, SR5a, S(O)R14, SO2R14 or S(N)R14; R3 is H, halogen, optionally substituted C1-C6 alkyl, C5-C12 Petition 870250110266, dated 01 / 12 / 2025, pp. 243 / 473 3 / 214 optionally substituted aryl, optionally substituted C5-C12 heteroaryl, optionally substituted C3C12 heterocycle, 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, SR5a, S(O)R14, SO2R14 or S(N)R14; or R2 and R3, together with the atoms to which each is attached, combine to form a 7-membered aromatic or non-aromatic carbocycle or heterocycle; or where A is optionally replaced with 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 R5 is, independently, H, optionally substituted C1-C6 alkyl, optionally substituted C5-C12 aryl or optionally substituted C3-C12 cycloalkyl, and each R5a is, independently, H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 heterocyclo, optionally substituted C3-C6, optionally substituted C5-C12 aryl or optionally substituted C5-C12 heteroaryl; Each R6 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, C(O)R7, C(O)OR7, SO2R7 or optionally substituted C3-C6 heterocycle; Petition 870250110266, dated 01 / 12 / 2025, pp. 244 / 473 4 / 214 each R7 is, independently, C1-C6 alkyl; Each R13 is independently H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl; Each R14 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 heterocyclo, 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; where R1, R2, R3 and R4 are not all H; where R1 is Me or Cl, then R4 is not H; where R4 is Me or Cl, then R1 is not H; and where R2 is Me or Cl, then both R1 and R4 are not H.

[0005] In some embodiments, R1 is a halogen, for example, Cl or F.

[0006] In some embodiments, R1 is an optionally substituted C1-C6 alkyl, for example, CH3, CH2CH3, CF3, CHF2, CH2CF3 or

[0007] In some embodiments, R1 is optionally substituted C3-C12 cycloalkyl cf^, for example, ,\ / , or

[0008] In some embodiments, R1 is an optionally substituted C3-C12 heterocycle, for example, θ sJ or s

[0009] In some modes, R1 is CF3.

[0010] In some disciplines, R1 is SR5a, for example, SF5, SCH3, SCH2CH3, or SCF3.

[0011] In some forms, R1 is N(R5)2, for example, NH2, Petition 870250110266, dated 01 / 12 / 2025, pp. 245 / 473 5 / 214 NHCH3 or N(CH3)2.

[0012] In some forms, R1 is OR5, for example, OCH3, OCF3 or OCHF2.

[0013] In some embodiments, R1 is SO2R14, for example, SO2CH3, SO2CH2CH3 or SO2(CH)(CH3)2.

[0014] In some modalities, R1 is S(O)R14, for example, S(O)CH3, S(O)CH2CH3 or S(O)(CH)(CH3)2.

[0015] In some modalities, R1 is S(N)R14, for example, S(N)CH3, S(N)CH2CH3 or S(O)(CH)(CH3)2.

[0016] In some embodiments, R4 is a halogen, for example, Cl or F.

[0017] In some embodiments, R4 is an optionally substituted C1-C6 alkyl, for example, CH3, CH2CH3, CF3, CHF2, CH2CF3 or

[0018] In some embodiments, R4 is optionally replaced by the carbocycle xc\Xx x / x^, for example ,X / , 0^ or XX .

[0019] In some embodiments, R4 is an optionally substituted C3-C12 heterocycle, for example, 0· s ous

[0020] In some modes, R4 is CF3.

[0021] In some modalities, R4 is SR5a, for example, SF5, SCH3 or SCF3.

[0022] In some embodiments, R4 is N(R5)2, for example, NH2, NHCH3 or N(CH3)2.

[0023] In some modalities, R4 is OR5, for example, OCH3, OCF3 or OCHF2.

[0024] In some forms, R4 is SO2R14, for example, Petition 870250110266, dated 01 / 12 / 2025, pp. 246 / 473 6 / 214 SO2CH3, SO2CH2CH3 or SO2(CH)(CH3)2.

[0025] In some modalities, R4 is S(O)R14, for example, S(O)CH3, S(O)CH2CH3 or S(O)(CH)(CH3)2.

[0026] In some modalities, R4 is S(N)R14, for example, S(N)CH3, S(N)CH2CH3 or S(O)(CH)(CH3)2.

[0027] In some embodiments, R2 is a halogen, for example, Cl or F.

[0028] In some forms, R2 is OR5, for example, OCH3.

[0029] In some forms, R2 is N(R5)2, for example, NH2.

[0030] In some forms, R2 is SO2R14, for example, SO2CH3, SO2CH2CH3 or SO2(CH)(CH3)2.

[0031] In some modes, R2 is S(O)R14, for example, S(O)CH3, S(O)CH2CH3 or S(O)(CH)(CH3)2.

[0032] In some modalities, R2 is S(N)R14, for example, S(N)CH3, S(N)CH2CH3 or S(O)(CH)(CH3)2.

[0033] In some embodiments, R3 is an optionally substituted C1-C6 alkyl, for example, CH3, CH2CH3, CF3, CHF2, CH2CF3 or

[0034] In some embodiments, R3 is SO2R14, for example, SO2CH3, SO2CH2CH3 or SO2(CH)(CH3)2.

[0035] In some modalities, R3 is S(O)R14, for example, S(O)CH3, S(O)CH2CH3 or S(O)(CH)(CH3)2.

[0036] In some modalities, R3 is S(N)R14, for example, S(N)CH3, S(N)CH2CH3 or S(O)(CH)(CH3)2.

[0037] In some modalities, it is Λί Ζχ / ^NR6 Petition 870250110266, dated 01 / 12 / 2025, pp. 247 / 473 7 / 214

[0038] In some embodiments of any of the aspects described in this document, R5 is C1-C6 alkyl, C5-C12 aryl, C5-C12 heteroaryl or C3C12 heterocycle.

[0039] In some embodiments of any of the aspects described in this document, R5a is halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 heterocyclo, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C12 aryl or optionally substituted C5-C12 heteroaryl.

[0040] In some embodiments of any of the aspects described in this document, SR5aé SF5.

[0041] In some embodiments, R5a is an optionally substituted C1-C6 alkyl, for example, CH3, CH2CH3, CF3, CHF2, CH2CF3 or

[0042] In some forms, R5aé carbociclo is optionally replaced, for example, .

[0043] In some modalities, R5aé CF3.

[0044] In some embodiments, R14 is an optionally substituted C1-C6 alkyl, for example, CH3, CH2CH3, CF3, CHF2, CH2CF3 or

[0045] In some embodiments, R14 is optionally substituted C3-C12 cycloalkyl, for example,

[0046] In some embodiments, R14 is an optionally substituted C3-C12 heterocycle, for example, the ous

[0047] In some embodiments, R14 is an optionally substituted C1-C6 heteroalkyl, for example, OCH3, OCH2CH3, OCF3, OCHF2 or OCH2CF3. Petition 870250110266, dated 01 / 12 / 2025, pp. 248 / 473 8 / 214

[0048] In some embodiments, R14 is optionally substituted for C3-C12 cycloalkyl, for example, .

[0049] In some embodiments, R14 is an optionally substituted C3-C12 heterocycle, for example, oCT.

[0050] In some embodiments of any of the aspects described in this document, R6 is H, optionally substituted C1-C6 alkyl, optionally substituted C3C6 cycloalkyl, C(O)R15, C(O)OR15, SO2R15 or C3-C6 heterocycle.

[0051] In some embodiments of any of the aspects described in this document, R6 is methyl.

[0052] In some embodiments of any of the aspects described in this document, R6 is CD3.

[0053] In some embodiments of any of the aspects described in this document, R6 is oxetan-3-yl.

[0054] In some forms, n is 0, 1, 2 or 3.

[0055] In some forms, m is 0, 1, 2 or 3.

[0056] In some forms, each p is independently 1, or 3.

[0057] In some modalities,

[0058] In some modalities,

[0059] In some modalities,

[0060] In some modalities,

[0061] In some modalities,

[0062] In some modalities, Petition 870250110266, dated 01 / 12 / 2025, pp. 249 / 473 9 / 214

[0063] In some modalities,

[0064] In some modalities, 'nr13n =o

[0065] In some embodiments, the compound is a compound of formula (IA): (IA), or a pharmaceutically acceptable salt thereof. In one embodiment, R1 is ethyl, and R4 is H. For example, the compound is , or a pharmaceutically acceptable salt thereof. In one embodiment, R1 is CF3 and R4O is methyl. In one embodiment, the compound is N CF·-' , or a pharmaceutically acceptable salt thereof.

[0066] In some embodiments, the compound is a compound of formula (IB): (IB), or a pharmaceutically acceptable salt thereof. In one embodiment, A is In one form, the compound is or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, the compound is a compound of the formula (IC): (IC), or a pharmaceutically acceptable salt thereof. In a Petition 870250110266, dated 01 / 12 / 2025, pp. 250 / 473 10 / 214 modality, A is In one form, the compound is or a pharmaceutically acceptable salt thereof. In one embodiment, A is In one form, the compound is or a pharmaceutically acceptable salt thereof.

[0068] In some embodiments, the compound is a compound of the formula (ID): (ID), or a pharmaceutically acceptable salt thereof. In one embodiment, A is In one form, the compound is or a pharmaceutically acceptable salt thereof.

[0069] In some embodiments, the compound is a compound of the formula (IE): (IE), or a pharmaceutically acceptable salt thereof. In one embodiment, A is In one form, the compound is or a pharmaceutically acceptable salt thereof.

[0070] In some embodiments, the compound is a compound of formula (IF): (IF) Petition 870250110266, dated 01 / 12 / 2025, pp. 251 / 473 11 / 214 or a pharmaceutically acceptable salt thereof, where: R8, R9, R10, and R11 are each independently H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C5-C12 aryl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, 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.

[0071] In some embodiments of any of the aspects described in this document, R8 is H, halogen, optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl.

[0072] In some embodiments of any of the aspects described in this document, R9 is H, halogen, optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl.

[0073] In some embodiments of any of the aspects described in this document, R10 is H, halogen, optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl.

[0074] In some embodiments of any of the aspects described in this document, R11 is H, halogen, optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl.

[0075] In some embodiments, the compound is a compound of formula (IG): the R11(IG) or a pharmaceutically acceptable salt thereof, where R8, R9, R10 and R11 are each independently H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C5-C12 aryl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl. Petition 870250110266, dated 01 / 12 / 2025, pp. 252 / 473 12 / 214 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.

[0076] In some embodiments, the compound is a compound of formula (IH): (IH), or a pharmaceutically acceptable salt thereof. In one embodiment, R1 is methyl and R4 is methyl. In one embodiment, the compound is the or a pharmaceutically acceptable salt thereof.

[0077] In some embodiments, the compound is a compound of formula (IJ): (IJ), or a pharmaceutically acceptable salt thereof.

[0078] In another aspect, the present disclosure provides a compound of Table 1 or a pharmaceutically acceptable salt of the same. Table 1 Compound No. Structure 1 O Cl ΗΝ'γΛ 2 ω\ * Á 3 O cd3hn |FA ^n^cd3 Petition 870250110266, dated 01 / 12 / 2025, p. 253 / 473 13 / 214 Compound No. Structure 4 0 i hlV> ^Ν*ΌΙ 5 0 Cl HN |Γ^\ ÔTsAn 6 o ci HN |1—\ Ή^ΌΜθ 7 Ο ή^όοο3 8 Λο OCD'Υ 1 ΗΝ ιΓ^> Ή^ΌΜβ 10 Ο Ί Ηχ\θ> (Xs Ν Ν OMe 11 Ο Ή^ΌΜβ 12 Ο OMe ΗΝ |1—\ ^rr^ci 13 |Τ \Η ο rj^Y^'S'X^N'^ / 14 Ο OMe ΗΝ^γΎ ÓCsAn? Petition 870250110266, dated 01 / 12 / 2025, p. 254 / 473 14 / 214 Compound No. Structure 15 or Ome HN | ÔTsAn 17 OF ò?sA 18 O i HN il^A ÔCsAn 19 o 1 HN il—\ CCsA 20 °íf CO JHZ 21 o ci HN |1—\ ÓCsA 22 O ^IST'-'''' 23 O\ f HN | HlV> EYES N ^N^CI Petition 870250110266, dated 01 / 12 / 2025, p. 255 / 473 15 / 214 N.° do Composto Estrutura 26 oy HN |TA (λ sA 27 O Ύ HN |Γ^1> 28 o HN |TY> 29 o Cl FIN'y^'A rY^Y^S^N^ 30 o NH2HN |ТА ÒTsAn 31 O rY^Y^S^N^ 32 0 nh2hn il—\ (X sAn n't 33 o 1 jÔO rj^í^S^ N ^IFSOI 34 oi H1V> ^N^NHz 35 o F HN ||--\ ÒTsAnnX^\7 36 o F ΗN'ygg iY^Y^sY^ny~y ^n^nh2 Petition 870250110266, de 01 / 12 / 2025, pág. 256 / 473 16 / 214 N.° do Composto Estrutura 37 0 NH2 38 o NH2 HN'>Sr^\ 39 o nh2hn |FA -4-- / ^ι / ηη2 40 b· k o 41 fí' μ co t· 42 o '''O HN'ιι^Α rj^Y^S^N -4- / ^ν^νη2 43 o HN li—\ 0Γ'Λν ν'λ- / 45 o NH2 HN'^U'A ^isr 46 ω / °-t> 48 o ^isr 49 o HN ιΓ^> [YX-^S^N -4- / ^ν^νη2 Petition 870250110266, de 01 / 12 / 2025, pág. 257 / 473 17 / 214 N.° do Composto Estrutura 50 o HN ii—5 52 O HN iP> rj / ^rx^'S'x^N'^ 53 0 HN iGl N 54 O hn^StA. xx JL-y Y^Ps NN 55 o HN il—\ ck^K^s JLy SN 56 o HN il—\ xU JU / N 57 O HN lEÁ HjN^tr 58 o HN ii— 60 o ХНХ|Γ^ F^rr 62 0 63 o ^i\r Petition 870250110266, de 01 / 12 / 2025, pág. 258 / 473 18 / 214 No. of Compound Structure 64 or HN iTX N 67 O HN ll— C^Y^S^N 68 ο HN ιθ ppA, 70 Ο '''Ο ΗΝ |ΤΝ 71 Ο OCD3ην |1^\ ^N^OCDs 72 ο ocd3 ΗΝ'ΥγΆ ÒT sAn 73 Ο ι HN ηΛ rj^Y^S^N '^''2 ^i\tOcd3 74 o OCD3HN |l--\ rj^Y^S^N \ OMe 75 O OMe ΗΝ^^γΎ rj^Y^S^N '^''2 ^n^ocd3 76 or OCF3 ΗΝ^γΎ Y^Y^'S'X^N'^ / ? ^N^OCF3 77 0 ocf3HN |l—\ AQsAn N^ Petition 870250110266, 01 / 12 / 2025, pág. 259 / 473 19 / 214 No. do Compound Structure 78 oi HN iO ^n^ocf3 79 o ochf2 ΗΝ'^γγ ^n^ochf2 80 o OCHF2HN |Γ^\ ÓCsA 81 O 1 ΗΝ>ιΓΥ> ^n^ochf2 82 o SMe HN |T—\ S^SMe 83 O 1 HN iTY* ^N^SMe 84 O SCF3HN |ΓΝ lY^Y^S^N 'J'-^n^scf3 85 o SCF3HN |T^\ rj^Y^S^N^ ^IST' 86 O 1 jôo ^N^SCFg 87 OY jôo ÔCS N 88 o Y HN^Y^K (λ sAn Petition 870250110266, 01 / 12 / 2025, pág. 260 / 473 20 / 214 N.° do Compound Structure 89 o 1 HN ll—5 ÍK Ν'ν-γ 90 O 0 Y aYo (Xs N úo 91 ω o(^>—C: 92 O i Ηόθ (js N Vo 93 o cf3hn iFX ^N^CF3 cf3 93 \ η η>η>η O i HN iO ΑγΧ^Ν''^' ^n^cf3 96 0 CHF2hn |Γ\ <N^'CHF2 97 0 chf2hn [LX 98 O 1 HN ^n^chf2 99 o sf5 ΗΝ'Υγγ rpYY^S^N ^N^SFg Petition 870250110266, of 01 / 12 / 2025, p. 261 / 473 21 / 214 No. of Compound Structure 100 CO 101 CO m 102 o / \ ω O CO 103 oi \ ω 7° 104 0 I HN ιϊ^\ ^nA^cf3 105 OT \ )-Q= HN ||—\ U^NHMe 109 O NHMe HN |l--\ ll^Y^S^N 110 O 1 HN |ϊ—SU^NHMe Petition 870250110266, of 01 / 12 / 2025, p. 262 / 473 22 / 214 No. of Compound Structure 111 o NMe2HN |úA 112 Ο NMe2 ÍA sAn 113 O 1 HN ΐΤΛ ^hT^NMea 116 “& d HN ιΦ) ^tfOCFj 121 O HN ιΐ—5 ^n^ochf2 122 o HN ιΦ) ^n^sf5 123 0 HN ιΐ— Petition 870250110266, of 01 / 12 / 2025, p. 263 / 473 23 / 214 No. of Compound Structure 124 o HN iO ^n^scf3 125 o HN iO ^n^schf2 126 o HN iT7> ^'ΐΨ'ΝΗΜβ 127 O HN iO ^N^NMe2 173 R ω ω _ 177 o 1 k| / XF3 178 OH SMe N |Ί--\ 1 ____ 179 o OH HN^S^A ÒCsAXN^- Petition 870250110266, of 01 / 12 / 2025, p. 264 / 473 24 / 214 N.° do Compound Structure 180 OH .OMe A. r joo N 181 OH OMe Ν^ϊ--K ^N^^CHFz 182 O cf3hn |ΓΛ ^hr'SMe OEt N*|G\ 1 UL / Ap N 186 OH OMe N |ϊ^\ ÚGfj 187 I OH ? íôo ÔC 188 o 1 HN U^N^CFa 189 O \ “ ω Z )=O Petition 870250110266, of 01 / 12 / 2025, p. 265 / 473 25 / 214 No. of Compound Structure 190 o I HN ΙΪ—5 IL .CF3 193 0 HN |1—\ 194 O | ΗΝ-^γ-Α 195 0 γ7 ΗΝ^γ^Χ 196 O . hIjOs γνγ*''··5'Α:'Ν'Λ''~ / 'Γ·Γ 'SMe 199 OI HN'TrAzN— ν,-κο·· 201 °sz? CO O=( )z ϊύ CO ~^z 202 y^r Ccn ω ú~\- z / 0 203 0 I HN^Y^X ts Petition 870250110266, of 01 / 12 / 2025, p. 266 / 473 26 / 214 Compound No. Structure 205 0 1 HfV> A 208 0 1 HN ιΓ^> 211 Λ ° ^0 HN |ΤΑ ^N^CFs 212 O d3cl JL I HÍD ÔCS N 213 0 S HN |t--- ^N^CF3 214 0 1 HN |l—\ ÀF 215 0 i Hóo 216 o I ΗΝ^ιρ^Χ 217 0 I HN iT^ ^n^nC\--f F Petition 870250110266, dated 01 / 12 / 2025, pp. 267 / 473 27 / 214 Compound No. Structure 218 °=0: Z—\ O Λ 1 <n ( o 219 ω ω _ 220 0 1 HN |1—I ^n^cf3

[0079] In some embodiments, the compound is one of the compounds 1-43, 45-60, 62-64, 67-69, 70-113 and 115-128 of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 1 of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 2 of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 171 of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 4 of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 5 of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 67 of Table 1, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is compound 95 of Table 1, or a pharmaceutically acceptable salt thereof.

[0080] In another aspect, the disclosure provides a compound of Formula (II): or a pharmaceutically acceptable salt thereof, in which Petition 870250110266, dated 01 / 12 / 2025, pp. 268 / 473 28 / 214 R1 is H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, SR5a, N(R5)2, OR5, S(O)R14, SO2R14 or S(N)R14; R4 is H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, OR5, SR5a, N(R5)2, S(O)R14, SO2R14, or S(N)R14 or R3 and 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; R2 and R3 are, each independently, H, halogen, optionally substituted C1-C6 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 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, SR5a, S(O)R14, SO2R14, or S(N)R14, or R2 and R3 together with the atoms to which each is attached, combine to form a 5- to 6-membered aromatic or non-aromatic carbocycle or heterocycle; or wherein A is optionally replaced by C1C6 alkyl, C5-C12 aryl, C3-C12 cycloalkyl, C5-C12 heteroaryl or C3-C12 heterocycle, optionally wherein 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 R5 is H, optionally substituted C1-C6 alkyl, C5-C12 aryl Petition 870250110266, dated 01 / 12 / 2025, pp. 269 / 473 29 / 214 optionally substituted or optionally substituted C3-C12 cycloalkyl, each R5a is H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 heterocycle, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C12 aryl or optionally substituted C5-C12 heteroaryl, each R6 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, C(O)R7, C(O)OR7, SO2R7 or optionally substituted C3-C6 heterocycle; each R7 is independently C1-C6 alkyl; Each R13 is independently H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl; Each R14 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 heterocyclo, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C12 aryl, or optionally substituted C5-C12 heteroaryl; Each Z is independently either H or C1-C6 alkyl optionally substituted and 0% / orc, 1 R12 is C(O)Ra', ^RW or A·Rb, where Ra' is H, OH, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2C8 alkynyl, optionally substituted C3-C12 cycloalkyl or optionally substituted C6-C14 aryl; and Ra is CH2NH or C(Rd)2O, wherein each Rd independently is H, C1-C8 alkyl, C1-C8 cycloalkyl, C1-C8 aryl or C1-C8 heteroaryl; Rbé H, OH, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C12 cycloalkyl, optionally substituted C6-C14 aryl or N(Re)2, each Rcé independently, H, C1-C8 alkyl or C6-C14 aryl, and each Reé Petition 870250110266, dated 01 / 12 / 2025, pp. 270 / 473 30 / 214 regardless of whether R1, R2, R3 and R4 are all H or C1-C8 alkyl, where R1, R2, R3 and R4 are not all H.

[0081] In some modalities, R1 is Cl and R4 is not H.

[0082] In some modalities, R1 is Me and R4 is not H.

[0083] In some forms, R4 is Cl and R1 is not H.

[0084] In some modalities, R4 is Me and R1 is not H.

[0085] In some forms, R2 is Cl and R1 is not H.

[0086] In some forms, R2 is Cl and R4 is not H.

[0087] In some modalities, R2 is Me and R1 is not H.

[0088] In some modalities, R2 is Me and R4 is not H.

[0089] In some embodiments, R2 is H, halogen, optionally substituted C1-C6 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, SR5a, S(O)R14, SO2R14, or S(N)R14, or R2 and R3 together with the atoms to which each is attached, combine to form a 5- to 6-membered aromatic or non-aromatic carbocycle or heterocycle.

[0090] In some modes, R12 is C(O)Ra' ov'X ,ORCy Λ □ ^Ra\

[0091] In some modes, R12 is orc.

[0092] In some modes, R12 is . RaRb.

[0093] In some embodiments, Ra' is optionally C1-C8 alkyl substituted.

[0094] In some forms, 1 Ox C(CH3)3, CH2N(CH3)2, k , I Ra' is CH2CH3, CH(CH3)2, , XX or Petition 870250110266, dated 01 / 12 / 2025, pp. 271 / 473 31 / 214 HO

[0095] In some forms, Raé CH2NH.

[0096] In some modalities, Raé C(Rd)2O.

[0097] In some forms, Rd is CH2O or CH(CH3)O.

[0098] In some forms, Raé CH2O or CH(CH3)O.

[0099] In some embodiments, Rb is optionally C1-C8 alkyl substituted.

[0100] In some forms, Rbé (CH2>CH3, CH3, C(CH3)3 or CH(CH3)2.

[0101] In some embodiments, Rbé C1-C8 alkyl substituted by carboxyl.

[0102] In some embodiments, Rbé (CH2)4COOH, CH2COOH, (CH2)2COOH, (CH2)3COOH, CH(CH3)(CH2)3COOH, C(CH3)2(CH2)3COOH or nh2

[0103] In some forms, Rbé C1-C8 alkoxy is optionally replaced.

[0104] In some forms, Rbé OCH2CH3 or

[0105] In some embodiments, Rb-N(Re)2, wherein each Re is independently H or C1-C8 alkyl.

[0106] In some forms, Rbé NHCH2CH3.

[0107] In some forms, each Rcé, independently, H or C(CH3)3.

[0108] In some embodiments, the compound of formula II has the structure: Petition 870250110266, dated 01 / 12 / 2025, pp. 272 / 473 32 / 214

[0109] In some embodiments, the compound of formula II has the structure: Petition 870250110266, dated 01 / 12 / 2025, pp. 273 / 473 33 / 214

[0110] In another aspect, the present disclosure provides a compound from Table 2 or a pharmaceutically acceptable salt thereof. Table 2 Compound No. Structure 129 °VU ° OH LAO NH2 Ν<:Κγ''\ 130 O >^O <o NHZ N |ΓΑ 131 O ho^Ao ° ko 132 O A t zK o'- ° e 133 o nj / Petição 870250110266, de 01 / 12 / 2025, pág. 274 / 473 34 / 214 N.° do Composto Estrutura 134 OH o N lTÃ> 135 \ d A / Vz )=O 136 0 OH JU.JÒO s N 137 A p-' Yes; o=< ω r A 138 o HO^^O 0 TO JUST Γ| SN 139 OH O OA——Αθ A^JÒO s N ^N^CI 140 O Ã ζ 141 OH OO^—^O ^O i ÓO rj^T^S^N^7 ^N^CI Petition 870250110266, dated 01 / 12 / 2025, p. 275 / 473 35 / 214 Compound No. Structure 142 or 143 °ΥΊ ° OH<AO ^0 i ϊΛγ> 144 O i kjO 145 O ΗΟγ° or I^JÓO < SN 146 OH O<o i^jÔO oSs N 147 ..fA o 148 OH O 1 aX> rj^Y^S^N''^ 149 fi °K ΖΛ λ— w -b Petition 870250110266, dated 01 / 12 / 2025, p. 276 / 473 36 / 214 No. of Compound Structure 150 or R ? 2-yr d 151 A o=( wi B o 152 A i B o 153 °ΎΑ ° OH AAO i ÓO ips / ^SN <'Ι\Γ''γ7 154 ° OH SN ^hT'NHz 155 OB ζ )v“ d 156 •BO Petition 870250110266, dated 01 / 12 / 2025, p. 277 / 473 37 / 214 Compound No. Structure O OH L Ό 157 ^O nh2 7 ιΓΛ Ii ί 'X' JL H___ / N / ^ H d. o OH L Ό 158 ^O çf3 7 ArX ll Ί JL II / HN 0 OH 1 Ό 159 ^O 7 ιΓΛ Τι Ί ''X JL JJ__ / HJNO^ / \ o OH L o 160 ^o 7n II η 'X' N IL. -AN 'Cl O OH L Ό ^O 161 7 |ΤΛ ll Ί 'X' JL II / H o OH L o X 162 7 iTU íl Ί 'X' A Αν N se AN

[0111] In another aspect, the disclosure provides a pharmaceutical composition including a compound described in this document (for example, any of the compounds in Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), Petition 870250110266, dated 01 / 12 / 2025, pp. 278 / 473 38 / 214 (IG), (IH), (IJ) and (II), Table 1 and Table 2) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

[0112] 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: in what R1 is H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-12 heterocycle, CF3, SR5a, N(R5)2, OR5, S(O)R14, SO2R14 or S(N)R14; R4e H, halogen, optionally substituted C1-6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, CF3, OR5, SR5a, N(R5)2, S(O)R14, SO2R14, or S(N)R14, or R3e R4, together with the atoms to which each is attached, join to form a 5- to 7-membered aromatic or non-aromatic carbocycle or heterocycle; R2 is H, halogen, optionally substituted C1-C6 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 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, SR5a, S(O)R14, SO2R14 or S(N)R14; R3 is H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C5-C12 aryl, optionally substituted C5-C12 heteroaryl, optionally substituted C3C12 heterocycle, optionally substituted C2-C8 alkenyl Petition 870250110266, dated 01 / 12 / 2025, pages 279 / 473 39 / 214 substituted, 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, SR5a, S(O)R14, SO2R14 or S(N)R14; or R2 and R3, together with the atoms to which each is attached, combine to form a 5- to 7-membered aromatic or non-aromatic carbocycle or heterocycle; and NR6 or , , where A is optionally replaced by 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 R5 is, independently, H, optionally substituted C1-C6 alkyl, optionally substituted C5-C12 aryl or optionally substituted C3-C12 cycloalkyl and each R5a is, independently, H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 heterocyclo, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C12 aryl or optionally substituted C5-C12 heteroaryl; Each R6 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, C(O)R7, C(O)OR7, SO2R7 or optionally substituted C3-C6 heterocycle; each R7 is independently C1-C6 alkyl; Petition 870250110266, dated 01 / 12 / 2025, pages 280 / 473 40 / 214 each R13 is, independently, H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl; Each R14 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 heterocyclo, 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; where R1, R2, R3 and R4 are not all H.

[0113] In some embodiments of Formula (I), if R1 is Me or Cl, then R4 is not H; if R4 is Me or Cl, then R1 is not H; and / or if R2 is Me or Cl, then both R1 and R4 are not H.

[0114] In some embodiments of Formula (I), R2 is H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C5-C12 aryl, optionally substituted C5C12 heteroaryl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, 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;

[0115] In another aspect, the disclosure provides a compound described in this document (for example, any of the compounds in Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (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.

[0116] In another aspect, the disclosure provides a method for treating or preventing a neurological disorder, which includes administering to a subject in need a therapeutically effective amount of a compound described in this document (for example, any of the compounds Petition 870250110266, dated 01 / 12 / 2025, pp. 281 / 473 41 / 214 of formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (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 a therapeutically effective amount of a compound described herein (for example, any of the compounds in formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II), Table 1 and Table 2) or a pharmaceutically acceptable salt thereof.

[0117] In some forms, the neurological disorder is a neurotraumatic disorder, a neurodevelopmental disorder, or an affective disorder.

[0118] In some modalities, the neurological disorder is a neurotraumatic disorder, for example, 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, neurodegenerative disease, or peripheral neuropathy.

[0119] In some modalities, neurological pain is neuropathic pain, inflammation, inflammatory pain, arthritic pain, diabetic pain, or neuralgia.

[0120] In some forms, the neurological disorder is epilepsy.

[0121] In some forms, epilepsy is refractory epilepsy, epilepsy associated with neurotrauma (ischemia, stroke, traumatic brain injury), status epilepticus, tumor-associated epilepsy, and hypoxic-ischemic encephalopathy.

[0122] In some forms, the neurodevelopmental disorder is autism spectrum disorder, Rett syndrome, Petition 870250110266, dated 01 / 12 / 2025, pp. 282 / 473 42 / 214 Tuberous sclerosis complex (TSC), Fragile X syndrome, Angelman syndrome, Down syndrome, Dravet syndrome, CKDL5 deficiency syndrome, SYNGAP1, cerebral palsy and Huntington's disease.

[0123] In some modalities, neurotraumatic injury or neurodegenerative disease is traumatic brain injury, stroke, multiple sclerosis, amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alzheimer's disease, spasticity, and spinal cord injury.

[0124] In some forms, affective disorder is schizophrenia, bipolar disorder, generalized anxiety disorder, social anxiety disorder, and major depressive disorder. Definitions

[0125] To facilitate understanding of this disclosure, a number of terms are defined below. The terms defined in this document have meanings as generally understood by a person skilled in the art in the areas relevant to this disclosure. Terms such as a, an, and the are not intended to refer only to a singular entity, but include the general class of which a specific example may be used for illustration. The terminology is used in this document to describe specific embodiments of the disclosure, but its use does not limit the disclosure, except as described in the claims.

[0126] As used in this document, the term approximately 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 approximately 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 any direction (greater or less than) of a stated value, unless stated otherwise or otherwise evident from the context (e.g., when such a number exceeds 100% of Petition 870250110266, dated 01 / 12 / 2025, pages 283 / 473 43 / 214 (a possible value).

[0127] Those skilled in the art will appreciate that certain compounds described in this document may exist in one or more different isomeric (e.g., stereoisomers, geometric isomers, atropisomers, tautomers) or isotopic (e.g., where one or more atoms have been replaced by a different isotope of the atom, such as hydrogen replaced by deuterium) forms. Unless otherwise indicated or clear from the context, a represented structure may be understood as representing any isomeric or isotopic form, individually or in combination.

[0128] The compounds described in this document may be asymmetric (e.g., with one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are targeted unless otherwise indicated. The compounds of this disclosure containing asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. Methods for preparing optically active forms from optically inactive 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 may also be present in the compounds described in this document, and all such stable isomers are contemplated in this disclosure. Cis and trans geometric isomers of the compounds of this disclosure are described and may be isolated as a mixture of isomers or as separate isomeric forms.

[0129] In some embodiments, one or more compounds represented in this document may exist in different tautomeric forms. As will be clear from the context, unless explicitly excluded, references to such compounds encompass all such forms. Petition 870250110266, dated 01 / 12 / 2025, pp. 284 / 473 44 / 214 tautomeric forms. In some embodiments, tautomeric forms result from the exchange of a single bond for 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 state with the same empirical formula and total charge as the reference form. Examples of fractions 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 in which a proton can occupy two or more positions of a heterocyclic system, such as 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole, and 1H- and 2H-pyrazole. In some embodiments, the tautomeric forms may be in equilibrium or sterically linked to a form by appropriate substitution. In certain embodiments, the tautomeric forms result from acetal interconversion.

[0130] Unless otherwise indicated, structures depicted in this document are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. Exemplary isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 32P, 33P, 35S, 18F, 36Cl, 123I, and 125I. Isotopically labeled compounds (e.g., those labeled with 3H and 14C) may be useful in compound or substrate tissue distribution assays. Tritiated isotopes (i.e., .sup.3H) and carbon-14 (i.e., 14C) may be useful because of their ease of preparation and detectability.Furthermore, substitution with heavier isotopes, such as deuterium (i.e., 2H or D), can provide certain therapeutic advantages resulting from greater metabolic stability (e.g., longer in vivo half-life or reduced dosage requirements). Petition 870250110266, dated 01 / 12 / 2025, pp. 285 / 473 45 / 214 In some embodiments, one or more hydrogen atoms are replaced by 2H, D, or 3H, or one or more carbon atoms are replaced by carbon enriched with 13C or 14C. Positron-emitting isotopes, such as 15O, 13N, 11C, and 18F, are useful for positron emission tomography (PET) studies to examine substrate receptor occupancy. Preparations of isotopically labeled compounds are known to those skilled in the art. For example, isotopically labeled compounds can generally be prepared following procedures analogous to those disclosed for the compounds of the present invention described herein, replacing an isotopically labeled reagent with a non-isotopically labeled reagent.

[0131] 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, solvates). In some embodiments, the compounds of the present invention can be used in any of these forms, including in any solid form. In some embodiments, the compounds described or represented in this document can be supplied or used in the form of a hydrate or solvate.

[0132] In several places in this descriptive report, the substituents of compounds in this disclosure are disclosed in groups or in bands. It is specifically intended that this disclosure include any and all individual subcombinations of the members of these groups and bands. For example, the term C1-C6 alkyl is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and C6 alkyl. Furthermore, where a compound includes a plurality of positions in which the substituents are disclosed in groups or in bands, unless otherwise indicated, this disclosure is intended to cover individual compounds and groups of compounds (e.g., genera and subgenera) containing any and all Petition 870250110266, dated 01 / 12 / 2025, pp. 286 / 473 46 / 214 individual subcombination of members in each position.

[0133] The term optionally substituted X (e.g., optionally substituted alkyl) is intended to be equivalent to X, wherein X is optionally substituted (e.g., alkyl, wherein said alkyl is optionally substituted). It is not intended to mean that the feature X (e.g., alkyl) per se is optional. As described in this document, certain compounds of interest may contain one or more optionally substituted moieties. In general, the substituted term, whether preceded by the term optionally or not, means that one or more hydrogens of the designated moiety are replaced by a suitable substituent, for example, any of the substituents or groups described in this document.Unless otherwise indicated, an optionally substituted group may have a suitable substituent at each substituteable position of the group, and where more than one position in any given structure may be substituted by more than one substituent selected from a specified group, the substituent may be the same or different at each position. For example, in the optionally substituted C1-C6 alkyl-C2C9 heteroaryl term, the alkyl moiety, the heteroaryl moiety, or both, may be optionally substituted. The substituent combinations provided for in this disclosure are preferably those that result in the formation of stable or chemically viable compounds. The term stable, as used herein, refers to compounds that are not substantially altered when subjected to conditions that permit their production, detection and, in certain embodiments, their recovery, purification and use for one or more of the purposes disclosed herein.

[0134] As used in this document, any values ​​given in a range of values ​​include the upper and lower limits and any values ​​contained within the upper and lower limits.

[0135] As used in this document, the terms, administer Petition 870250110266, dated 01 / 12 / 2025, pp. 287 / 473 47 / 214 and administration are used to indicate the process of providing a therapeutic, pharmaceutical, accommodation, medication or similar treatment to a subject. In some modalities, a pharmaceutical treatment is provided through oral administration.

[0136] As used in this document, the terms "improve" and "improving," in reference to recovery from a disease or condition, for example, a neurological disorder, refer to an enhancement of recovery in one or more parameters by measuring or quantifying the severity of the neurological disorder relative to recovery in these parameters on or before treatment with the compounds or compositions described in this document. Alternatively, improvement may be measured relative to a reference subject with the same diagnosis as the subject but who has not received 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 in this document.

[0137] As used in this document, 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 a 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, baths (aqueous or non-aqueous solutions or suspensions) or tablets, for example, those Petition 870250110266, dated 01 / 12 / 2025, pp. 288 / 473 48 / 214 designed for buccal, sublingual and systemic absorption, boluses, powders, granules or pastes for application to the tongue.

[0138] The term pharmaceutically acceptable excipient, as used in this document, refers to any inactive ingredient (e.g., a vehicle capable of suspending or dissolving the active compound) with the properties of being non-toxic and non-inflammatory in a subject. Typical excipients include, for example: anti-adherents, antioxidants, binders, coatings, compression aids, disintegrants, colorants, emollients, emulsifiers, diluents, film formers or coatings, flavors, fragrances, glidants, lubricants, preservatives, printing inks, sorbents, suspending or dispersing agents, sweeteners, or hydration waters.Excipients include, but are not limited to: optionally substituted butylated hydroxytoluene (e.g., BHT), calcium carbonate, dibasic calcium phosphate, calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, optionally substituted hydroxypropylcellulose, optionally substituted hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C and Xylitol. Those skilled in the art are familiar with a variety of useful agents and materials as excipients.

[0139] As used in this document, the term pharmaceutically acceptable salt represents those salts of the compounds described that are, within the scope of good medical judgment, suitable for use in contact with human and animal tissues without toxicity, irritation, or adverse reaction. Petition 870250110266, dated 01 / 12 / 2025, pp. 289 / 473 49 / 214 inappropriate allergic reactions and the like, and are proportionate to 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. PH Stahl and CG Wermuth), Wiley-VCH, 2008. These salts may be acid addition salts involving inorganic or organic acids. The salts may be prepared in situ during the final isolation and purification of the compounds described in this document or separately by reaction of a free base group with a suitable acid. The methods for preparing the appropriate salts are well established in the art.

[0140] The term subject, as used in this document, may 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 forms, the subject is a human.

[0141] As used in this document, the term therapeutically effective amount refers to an amount sufficient to effect beneficial or desired results, such as clinical outcomes, and as such, a therapeutically effective amount depends on the context in which it is being applied. For example, in the context of administering a compound disclosed in this document (e.g., a compound of any of the formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ) and (II) and other compounds disclosed in this document) to treat a neurological disorder, a therapeutically effective amount of a compound is, for example, an amount sufficient to reverse the neurological disorder.

[0142] As used in this document, the terms treat and treating refer to a therapeutic treatment of a neurological disorder in a subject. The effect of the treatment may include reversing, alleviating, reducing the severity, inhibiting the progression, or reducing the likelihood of recurrence of the disorder. Petition 870250110266, dated 01 / 12 / 2025, pp. 290 / 473 50 / 214 neurological or one or more symptoms or manifestations of the neurological disorder, stabilize (i.e., not worsen) the state of the neurological disorder compared to the state and / or condition of the disease or disorder in the absence of therapeutic treatment.

[0143] The term alkyl, as used in this document, refers to a monovalent saturated aliphatic radical with a linear or branched chain containing only C and H when unsubstituted. The monovalence of an alkyl group does not include optional substituents on the alkyl group. For example, if an alkyl group is attached to a compound, the monovalence 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, for example, 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-C18, C1-C16, C1-C14, C1-C12, C1-C10, C1-C8, C1-C6, C1-C4 or C1-C2). Examples include, but are not limited to, methyl, ethyl, isobutyl, sec-butyl and tert-butyl.

[0144] The term aryl, as used in this document, refers to any monocyclic or bicyclic or multicyclic fused ring system containing only carbon atoms in the rings, which has the characteristics of aromaticity in terms of electron distribution throughout the ring system, for example, phenyl, naphthyl or phenanthryl. An aryl group may have, for example, six to sixteen carbons or six to fourteen carbons (e.g., six carbons, ten carbons, thirteen carbons, fourteen carbons or sixteen carbons).

[0145] The term arylalkyl, as used in this document, represents an alkyl group substituted by an aryl group. Unsubstituted arylalkyl groups contain from 7 to 30 carbons (for example, from 7 to 16 or from 7 to 20 carbons, such as C1-C6 alkyl C6-C10 aryl, C1-C10 alkyl C6-C10 aryl or C1-C20 alkyl C6-C10 aryl), such as benzyl and phenethyl. In some embodiments, alkyl and aryl may each be further substituted by 1, 2, 3 or 4 groups Petition 870250110266, dated 01 / 12 / 2025, pp. 291 / 473 51 / 214 substitutes, if valence permits, as defined in this document for the respective groups.

[0146] The term carbocycle, as used in this document, refers to a monovalent, non-aromatic cyclic group, saturated (cycloalkyl) or unsaturated containing only C and H when not substituted. A carbocycle may have, for example, from 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).

[0147] The term cycloalkyl, as used in this document, refers to a monovalent saturated cyclic group containing only C and H when unsubstituted. A cycloalkyl may have, for example, from 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 with a multicyclic bridging structure in which one or more carbons link 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, for example, decalin and spirocyclic compounds.

[0148] The term halo, as used in this document, refers to a fluorine (fluoro), chlorine (chlorine), bromine (bromine) or iodine (iodine) radical.

[0149] The term heterocycle, as used in this document, represents a bicyclic or multicyclic system of a monocyclic or fused ring with at least one heteroatom as a ring atom. For example, a heterocyclic ring may have, for example, from one to fifteen carbon atoms (e.g., a C1-C2, C1-C3, C1-C4, C1-C5, C1-C6, C1-C7, C1-C8, 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. The groups Petition 870250110266, dated 01 / 12 / 2025, pp. 292 / 473 52 / 214 heterocycles 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 from zero to two double bonds, and exemplary 6-membered heterocycle groups may have from zero to three double bonds.Exemplary groups of 5 members 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 tetrahydrofuran, 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.Examples of 6-membered heterocyclic 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 2H-pyran, optionally substituted 4H-pyran, and optionally substituted tetrahydropyran. Examples of 7-membered heterocyclic groups include optionally substituted azepine, optionally substituted 1,4-diazepine, optionally substituted thiepine, and optionally substituted 1,4-thiazepine.

[0150] As used in this document, the term disturbance Petition 870250110266, dated 01 / 12 / 2025, pp. 293 / 473 53 / 214 neurological 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 the uncontrollable transmission of one or more electrical and / or chemical transmissions of a nerve cell 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 can include damage to or dysfunction of a subject's sympathetic and / or parasympathetic nervous system. A neurological disorder can include damage to or 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) in a subject. A neurological disorder can be a neurodevelopmental disorder, which may include neuropathic pain, inflammation, inflammatory pain, arthritic pain, diabetic pain, or neuralgia.A neurological disorder can be a neurotraumatic disorder, which may include 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 can be epilepsy, which may include refractory epilepsy, neurotrauma-associated epilepsy (ischemia, stroke, traumatic brain injury), status epilepticus, tumor-associated epilepsy, and encephalopathy. Petition 870250110266, dated 01 / 12 / 2025, pp. 294 / 473 54 / 214 hypoxic-ischemic. 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., temporal lobe epilepsy), 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 similar disorders.

[0151] The phrase "potentiate KCC2 activity," as used in this document, refers to increasing or decreasing the level or activity of potassium chloride cotransporter-2, KCC2. KCC2 activity can be determined using methods known in the art, for example, immunoprecipitation, Western blot, qPCR, live cell immunostaining of cell surface expression, as described in Medina et al. eNeuro, 2017, 4, 1-19, or immunohistochemistry in primary cultures.

[0152] The phrase increased Cl efflux, as used in this document, refers to an increase in the level of Cl efflux. Cl efflux can be determined using methods known in the art, for example, fluorometric assessment in NG-108 cells using the Cl-sensitive indicator Chlomeleon described in Gagnon et al. Nature Medicine, 2013, 19, 1524-1528, or measuring the GABAa receptor reversal potential in ex vivo neuronal slices, or Rhubidium flux in xenopus oocytes.

[0153] The phrase X optionally substituted, as used in this document, is intended to be equivalent to X, where X is optionally substituted (e.g., alkyl, where 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 in this document, refers to having 0, 1 or more substituents (e.g., 0-25, Petition 870250110266, dated 01 / 12 / 2025, pp. 295 / 473 55 / 214 0-20, 0-10, or 0-5 substitutes). In some embodiments, the term optionally substituted, as used in this document, refers to having 0 substitutes, that is, where feature X is not substituted.

[0154] Alkyl, carbocycle, cycloalkyl, aryl and heterocycle groups may be replaced by carbocycle (e.g., cycloalkyl); aryl; heterocycle; halo; ORa', where Ra' is H, alkyl, alkenyl, alkynyl, carbocycle (e.g., cycloalkyl), aryl or heterocycle; SRa', where Ra' is as defined in this document; CN; NO2; N3; NRb'Rc', where each of Rb' and Rc' is independently H, alkyl, alkenyl, alkynyl, carbocycle (e.g., cycloalkyl), aryl or heterocycle; SO2Rd', where Rd' is H, alkyl or aryl; SO2NRe'Rf', where each of Re' and Rf' is independently H, alkyl or aryl; SORg', where Rg' is H, alkyl or aryl; or P(O)(ORh')2, where each of Rh is independently H or alkyl. The aryl, carbocyclic (e.g., cycloalkyl), heteroaryl, and heterocyclic groups can also be substituted with alkyl, alkenyl, or alkynyl.Alkyl, alkylene, alkenyl, alkynyl, carbocyclic (e.g., cycloalkyl), and heterocyclic groups can also be substituted with oxo or =NRj', where Rj' is H or alkyl. In some embodiments, a substituent is further substituted as described in this document. For example, a C1 alkyl group, i.e., methyl, can 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.

[0155] The heteroaryl, alkenyl, alkynyl and arylalkyl groups may be replaced by carbocycle (e.g., cycloalkyl); aryl; heterocycle; halo; ORa', where Ra' is H, alkyl, alkenyl, alkynyl, carbocycle (e.g., cycloalkyl), aryl or heterocycle; SRa', where Ra' is as defined in this document; CN; NO2; N3; NRb'Rc', where each of Rb' and Rc' is independently H, alkyl, alkenyl, alkynyl, carbocycle (e.g., cycloalkyl), aryl or heterocycle; SO2Rd', where Rd' is H, alkyl or aryl; SO2NRe'Rf', where each of Re' and Rf' is, Petition 870250110266, dated 01 / 12 / 2025, pp. 296 / 473 56 / 214 independently, H, alkyl or aryl; SORg', where Rg' is H, alkyl or aryl; or P(O)(ORh')2, where each Rh is independently H or alkyl. Aryl, carbocyclo (e.g., cycloalkyl), heteroaryl and heterocycle groups may also be substituted by alkyl, alkenyl or alkynyl. Alkyl, alkylene, alkenyl, alkynyl, carbocyclo (e.g., cycloalkyl) and heterocycle groups may also be substituted by oxo or =NRj', where Rj' is H or alkyl. In some embodiments, a substituent is further substituted as described in this document. For example, a C1 alkyl group, i.e., methyl, may be substituted by oxo to form a formyl group and further substituted by OH or NRb'Rc' to form a carboxyl group or an amido group.

[0156] For the avoidance of doubt, any and all disclosure of treatment or prevention methods provided in this document should also be read as disclosure of the compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising them, for use in the described treatment or prevention methods. Detailed Description

[0157] Compounds, compositions, and methods for treating neurological disorders, such as neurotraumatic disorders, neurodevelopmental disorders, or affective disorders, are described in this document. Without wishing to be limited by theory, the compounds described in this document may function as KCC2 potentiators. The compounds described in this document are useful for treating neurological disorders, such as neurotraumatic disorders, neurodevelopmental disorders, or affective disorders. Compounds

[0158] This 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 Petition 870250110266, dated 01 / 12 / 2025, pp. 297 / 473 57 / 214 neurodevelopmental disorder or an affective disorder).

[0159] In one aspect, the present disclosure provides a compound of formula (I): Formula I, or a pharmaceutically acceptable salt thereof, wherein R1 is H, halogen, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, CF3, SR5a, N(R5)2, OR5, S(O)R14, SO2R14 or S(N)R14; R4e H, halogen, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, CF3, OR5, SR5a, N(R5)2, S(O)R14, SO2R14, or S(N)R14, or R3e 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; R2 is H, halogen, optionally substituted C1-C6 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, SR5a, S(O)R14, SO2R14 or S(N)R14; R3 is H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C5-C12 aryl, optionally substituted C5-C12 heteroaryl, optionally substituted C3-C12 heterocyclo, 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, SR5a, S(O)R14, SO2R14 or Petition 870250110266, dated 01 / 12 / 2025, pp. 298 / 473 58 / 214 S(N)R14; or R2 and R3, together with the atoms to which each is attached, combine to form a 5- to 6-membered aromatic or non-aromatic carbocycle or heterocycle; X / ^NR6 / -x^-NR6 Vm-0 Vm-NR6k Jnouk Jn, wherein A is optionally replaced by 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 R5 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C5-C12 aryl or optionally substituted C3-C12 cycloalkyl; each R5a is, independently, H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 heterocyclo, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C12 aryl or optionally substituted C5-C12 heteroaryl; Each R6 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, C(O)R7, C(O)OR7, SO2R7 or optionally substituted C3-C6 heterocycle; each R7 is C1-C6 alkyl; Each R13 is independently H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl; each R14 is independently H, C1-C6 alkyl optionally Petition 870250110266, dated 01 / 12 / 2025, pp. 299 / 473 59 / 214 substituted, optionally substituted C1-C6 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-C6 alkyl.

[0160] In some forms of formula (I), if R1 is Me or Cl, then R4 is not H.

[0161] In some forms of formula (I), if R4 is Me or Cl, then R1 is not H.

[0162] In some forms of formula (I), if R2 is Me or Cl, then R1 and R4 are both not H.

[0163] In some forms of formula (I), R1, R2, R3 and R4 are not all H.

[0164] In some embodiments of formula (I), if R1 is Me or Cl, then R4 is not H; if R4 is Me or Cl, then R1 is not H; if R2 is Me or Cl, then R1 and R4 are both not H; and R1, R2, R3 and R4 are not all H.

[0165] In one aspect, the present disclosure provides a compound of formula (I): Formula I, or a pharmaceutically acceptable salt thereof, wherein R1 is H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, SR5a, N(R5)2, OR5, S(O)R14, SO2R14 or S(N)R14; R4e H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, OR5, SR5a, N(R5)2, S(O)R14, SO2R14, or S(N)R14, or R3e R4, Petition 870250110266, dated 01 / 12 / 2025, pp. 300 / 473 60 / 214 together with the atoms to which each is bonded, combine to form a 5- to 6-membered aromatic or non-aromatic carbocycle or heterocycle; R2 is H, halogen, optionally substituted C1-C6 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, SR5a, S(O)R14, SO2R14 or S(N)R14; R3 is H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C5-C12 aryl, optionally substituted C5-C12 heteroaryl, optionally substituted C3-C12 heterocyclo, 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, SR5a, S(O)R14, SO2R14 or S(N)R14; or R2 and R3, together with the atoms to which each is attached, combine to form a 5- to 6-membered aromatic or non-aromatic carbocycle or heterocycle; or wherein A is optionally replaced by C1C6 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 R5 is, Petition 870250110266, dated 01 / 12 / 2025, pp. 301 / 473 61 / 214 independently, H, optionally substituted C1-C6 alkyl, optionally substituted C5-C12 aryl or optionally substituted C3-C12 cycloalkyl; each R5a is, independently, H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 heterocyclo, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C12 aryl or optionally substituted C5-C12 heteroaryl; Each R6 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, C(O)R7, C(O)OR7, SO2R7 or optionally substituted C3-C6 heterocycle; each R7 is C1-C6 alkyl; Each R13 is independently H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl; Each R14 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 heterocyclo, 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-C6 alkyl; where R1 is Me or Cl, then R4 is not H; where R4 is Me or Cl, then R1 is not H; where R2 is Me or Cl, then R1 and R4 are both not H; and where R1, R2, R3 and R4 are not all H.

[0166] In some embodiments, R1 is a halogen, for example, Cl or F.

[0167] In some embodiments, R1 is an optionally substituted C1-C6 alkyl, for example, CH3, CH2CH3, CF3, CHF2, CH2CF3 or Petition 870250110266, dated 01 / 12 / 2025, pp. 302 / 473 62 / 214

[0168] In some embodiments, R1 is optionally substituted C3-C12 cycloalkyl, for example,

[0169] In some embodiments, R1 is an optionally substituted C3-C12 heterocycle, for example, 0· or s·

[0170] In some modes, R1 is CF3.

[0171] In some disciplines, R1 is SR5a, for example, SF5, SCH3, or SCF3.

[0172] In some embodiments, R1 is N(R5)2, for example, NH2, NHCH3 or N(CH3)2.

[0173] In some forms, R1 is OR5, for example, OCH3, OCF3, or OCHF2.

[0174] In some embodiments, R1 is SO2R14, for example, SO2CH3, SO2CH2CH3 or SO2(CH)(CH3)2.

[0175] In some modalities, R1 is S(O)R14, for example, S(O)CH3, S(O)CH2CH3 or S(O)(CH)(CH3)2.

[0176] In some modalities, R1 is S(N)R14, for example, S(N)CH3, S(N)CH2CH3 or S(O)(CH)(CH3)2.

[0177] In some embodiments, R4 is a halogen, for example, Cl or F.

[0178] In some embodiments, R4 is an optionally substituted C1-C6 alkyl, for example, CH3, CH2CH3, CF3, CHF2, CH2CF3 or

[0179] In some forms, R4é is optionally replaced by a carbon cycle, for example, Petition 870250110266, dated 01 / 12 / 2025, pp. 303 / 473 63 / 214

[0180] In some embodiments, R4 is an optionally substituted C3-C12 heterocycle, for example, or sC / .

[0181] In some modes, R4 is CF3.

[0182] In some modalities, R4 is SR5a, for example, SF5, SCH3 or SCF3.

[0183] In some embodiments, R4 is N(R5)2, for example, NH2, NHCH3 or N(CH3)2.

[0184] In some modalities, R4 is OR5, for example, OCH3, OCF3 or OCHF2.

[0185] In some forms, R4 is SO2R14, for example, SO2CH3, SO2CH2CH3 or SO2(CH)(CH3)2.

[0186] In some modalities, R4 is S(O)R14, for example, S(O)CH3, S(O)CH2CH3 or S(O)(CH)(CH3)2.

[0187] In some modalities, R4 is S(N)R14, for example, S(N)CH3, S(N)CH2CH3 or S(O)(CH)(CH3)2.

[0188] In some embodiments, R2 is a halogen, for example, Cl or F.

[0189] In some forms, R2 is OR5, for example, OCH3.

[0190] In some forms, R2 is N(R5)2, for example, NH2.

[0191] In some embodiments, R2 is SO2R14, for example, SO2CH3, SO2CH2CH3 or SO2(CH)(CH3)2.

[0192] In some modalities, R2 is S(O)R14, for example, S(O)CH3, S(O)CH2CH3 or S(O)(CH)(CH3)2.

[0193] In some modalities, R2 is S(N)R14, for example, S(N)CH3, S(N)CH2CH3 or S(O)(CH)(CH3)2.

[0194] In some embodiments, R3 is an optionally substituted C1-C6 alkyl, for example, CH3, CH2CH3, CF3, CHF2, CH2CF3 or Petition 870250110266, dated 01 / 12 / 2025, pp. 304 / 473 64 / 214

[0195] In some embodiments, R3 is SO2R14, for example, SO2CH3, SO2CH2CH3 or SO2(CH)(CH3)2.

[0196] In some modalities, R3 is S(O)R14, for example, S(O)CH3, S(O)CH2CH3 or S(O)(CH)(CH3)2.

[0197] In some modalities, R3 is S(N)R14, for example, S(N)CH3, S(N)CH2CH3 or S(O)(CH)(CH3)2.

[0198] In some modalities,

[0199] In some modalities,

[0200] In some modalities,

[0201] In some modalities,

[0202] In some modalities,

[0203] In some modalities,

[0204] In some modalities,

[0205] In some embodiments of any of the aspects described in this document, R5 is C1-C6 alkyl, C5-C12 aryl, C5-C12 heteroaryl or C3C12 heterocycle.

[0206] In some embodiments of any of the aspects described in this document, R5a is halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 heterocyclo, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C12 aryl or optionally substituted C5-C12 heteroaryl.

[0207] In some modalities of any of the aspects Petition 870250110266, dated 01 / 12 / 2025, pp. 305 / 473 65 / 214 described in this document, SR5aé SF5.

[0208] In some embodiments, R5a is an optionally substituted C1-C6 alkyl, for example, CH3, CH2CH3, CF3, CHF2, CH2CF3 or

[0209] In some forms, R5aé carbociclo is optionally replaced, for example, .

[0210] In some modalities, R5aé CF3.

[0211] In some embodiments of any of the aspects described in this document, R6 is H, optionally substituted C1-C6 alkyl, optionally substituted C3C6 cycloalkyl, C(O)R15, C(O)OR15, SO2R15 or C3-C6 heterocycle.

[0212] In some embodiments of any of the aspects described in this document, R6 is methyl.

[0213] In some modalities of any of the aspects described in this document, R6 is CD3.

[0214] In some embodiments of any of the aspects described in this document, R6 is oxetan-3-yl.

[0215] In some embodiments, R14 is an optionally substituted C1-6 alkyl, for example, CH3, CH2CH3, CF3, CHF2, CH2CF3 or

[0216] In some embodiments, R14 is optionally substituted for C3-C12 cycloalkyl, for example, .

[0217] In some embodiments, R14 is an optionally substituted C3-C12 heterocycle, for example, , or ZZZ .

[0218] In some embodiments, R14 is an optionally substituted C1-6 heteroalkyl, for example, OCH3, OCH2CH3, OCF3, OCHF2 or Petition 870250110266, dated 01 / 12 / 2025, pp. 306 / 473 66 / 214 OCH2CF3.

[0219] In some embodiments, R14 is optionally substituted C3-C12 cycloalkyl, for example, V.

[0220] In some embodiments, R14 is an optionally substituted C3-C12 heterocycle, for example, .

[0221] In some forms, n is 0, 1, 2 or 3.

[0222] In some forms, m is 0, 1, 2 or 3.

[0223] In some forms, p is 1, 2 or 3.

[0224] In some embodiments, the compound is a compound of formula (IA): R1(IA)

[0225] In some embodiments, the compound is a compound of formula (IB): •Cl (IB), or a pharmaceutically acceptable salt thereof.

[0226] In some embodiments, the compound is a compound of the formula (IC): or a pharmaceutically acceptable salt thereof.

[0227] In some embodiments, the compound is a compound of the formula (ID): Petition 870250110266, dated 01 / 12 / 2025, pp. 307 / 473 67 / 214 or a pharmaceutically acceptable salt thereof.

[0228] In some embodiments, the compound is a compound of the formula (IE): the ISN (IE), or a pharmaceutically acceptable salt thereof.

[0229] In some embodiments, the compound is a compound of formula (IH): (IH), or a pharmaceutically acceptable salt thereof.

[0230] In some embodiments, the compound is a compound of formula (IJ): (IJ), or a pharmaceutically acceptable salt thereof.

[0231] In some embodiments, the compound is a compound of formula (IF): (IF) or a pharmaceutically acceptable salt thereof, wherein R8, R9, R10, and R11 are each independently H, halogen, C1-C6 optionally substituted alkyl, C5-C12 optionally substituted aryl, C2C8 optionally substituted alkenyl, C2-C8 optionally substituted alkynyl, C3-C12 optionally substituted cycloalkyl, C3-C12 optionally substituted heterocycle, C7-C14 optionally substituted arylalkyl, (CH2)pOZ, C(O)Z, Petition 870250110266, dated 01 / 12 / 2025, pp. 308 / 473 68 / 214 C(O)OZ, C(O)NZ2, OR5or N(R5)2.

[0232] In some embodiments of any of the aspects described in this document, R8 is H, halogen, optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl.

[0233] In some embodiments of any of the aspects described in this document, R9 is H, halogen, optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl.

[0234] In some embodiments of any of the aspects described in this document, R10 is H, halogen, optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl.

[0235] In some embodiments of any of the aspects described in this document, R11 is H, halogen, optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl.

[0236] In some embodiments, the compound is a compound with the formula (IG): the R11(IG) or a pharmaceutically acceptable salt thereof, where R8, R9, R10 and R11 are each independently H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C5-C12 aryl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, 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, SR5a or N(R5)2.

[0237] Exemplary compounds are provided in Table 1.

[0238] In another aspect, the present disclosure provides a compound from Table 1 or a pharmaceutically acceptable salt thereof. Petition 870250110266, dated 01 / 12 / 2025, pp. 309 / 473 69 / 214

[0239] In another aspect, the present disclosure provides a compound of Formula (II): or a pharmaceutically acceptable salt thereof, in which R1 is H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, SR5a, N(R5)2, OR5, S(O)R14, SO2R14 or S(N)R14; R4e H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, OR5, SR5a, N(R5)2, S(O)R14, SO2R14, or S(N)R14, or R3e 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; R2 and R3 are, each independently, H, halogen, optionally substituted C1-C6 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 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, SR5a, S(O)R14, SO2R14, or S(N)R14, or R2 and R3, together with the atoms to which each is attached, combine to form a 5- to 6-membered aromatic or non-aromatic carbocycle or heterocycle; L / ^NR6Z / ^NR6 J ())m J (})m VYr„o Ym-„nr6„ λ - xk xx ~ 'tin ou1, where A is optionally replaced by C1C6 alkyl, C5-C12 aryl, C3-C12 cycloalkyl, C5-C12 heteroaryl or C3-C12 heterocycle, Petition 870250110266, dated 01 / 12 / 2025, pp. 310 / 473 70 / 214 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 R5 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C5-C12 aryl or optionally substituted C3-C12 cycloalkyl, each R5a is independently H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 heterocycle, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C12 aryl or optionally substituted C5-C12 heteroaryl, each R6 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, C(O)R7, C(O)OR7, SO2R7 or optionally substituted C3-C6 heterocycle; each R7 is C1-C6 alkyl; Each R13 is independently H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl; Each R14 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 heterocyclo, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C12 aryl, or optionally substituted C5-C12 heteroaryl; Each Z is independently H or C1-C6 alkyl optionally substituted and °, 0 to / 0RC R12é C(O)Ra', QRCouRa Rb, where Ra' is H, OH, C1-C8 optionally substituted alkyl, C2-C8 optionally substituted alkenyl Petition 870250110266, dated 01 / 12 / 2025, pp. 311 / 473 71 / 214 substituted, optionally substituted C2-C8 alkynyl, optionally substituted C3-C12 cycloalkyl or optionally substituted C6-C14 aryl; and Raé CH2NH or C(Rd)2O, wherein each Rd independently is H, C1-C8 alkyl, C1-C8 cycloalkyl, C1-C8 aryl or C1-C8 heteroaryl; Rd independently is H, OH, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C12 cycloalkyl, optionally substituted C6-C14 aryl or N(Re)2, each Rd independently is H, C1-C8 alkyl or C6-C14 aryl, and each Reé independently H or C1-C8 alkyl e where R1, R2, R3 and R4 are not simultaneously H.

[0240] In some modalities, R12 is C(O)Ra'

[0241] In some modalities, R12 is

[0242] In some modalities, R12 is

[0243] In some embodiments, Ra' is optionally C1-C8 alkyl substituted.

[0244] In some forms, Ra' is CH2CH3, CH(CH3)2, CH2N(CH3)2, or C(CH3)3, HO

[0245] In some forms, Raé CH2NH.

[0246] In some modalities, Raé C(Rd)2O.

[0247] In some forms, Rd is CH2O or CH(CH3)O.

[0248] In some forms, Raé CH2O or CH(CH3)O.

[0249] In some embodiments, Rbé C1-C8 alkyl optionally Petition 870250110266, dated 01 / 12 / 2025, pp. 312 / 473 72 / 214 replaced.

[0250] In some forms, Rbé (CH2)5CH3, CH3, C(CH3)3 or CH(CH3)2.

[0251] In some embodiments, Rbé C1-C8 alkyl substituted by carboxyl.

[0252] In some embodiments, Rbé (CH2)4COOH, CH2COOH, (CH2)2COOH, (CH2)3COOH, CH(CH3)(CH2)3COOH, C(CH3)2(CH2)3COOH or nh2

[0253] In some forms, Rbé C1-C8 alkoxy is optionally replaced.

[0254] In some forms, Rbé OCH2CH3 or

[0255] In some embodiments, RbN(Re)2, wherein each Re is independently H or C1-C8 alkyl.

[0256] In some forms, Rbé NHCH2CH3.

[0257] In some forms, each Rcé independently, H or C(CH3)3.

[0258] In some embodiments, the compound of formula II has the structure: Petition 870250110266, dated 01 / 12 / 2025, pp. 313 / 473 73 / 214

[0259] In some embodiments, the compound of formula II has the structure:

[0260] In another aspect, the present disclosure provides a compound from Table 2 or a pharmaceutically acceptable salt thereof. Petition 870250110266, dated 01 / 12 / 2025, pp. 314 / 473 74 / 214

[0261] Exemplary compounds are provided in Table 2. Pharmaceutical compositions

[0262] A pharmaceutical composition of the disclosure contains one or more of the compounds disclosed in this document (for example, one or more of the compounds of any of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II) and other compounds disclosed in this document) as the therapeutic compound. In addition to a therapeutically effective amount of the compound, the pharmaceutical compositions also contain a pharmaceutically acceptable excipient, which may be formulated by methods known to those skilled in the art. The compounds disclosed in this document (for example, the compounds of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II) and other compounds disclosed in this document) may also be administered with or without other therapies for a particular condition, formulated in the same composition or different compositions for administration via the same or different routes.

[0263] The compounds disclosed in this document (for example, the compounds of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II) and the compounds of Table 1 and Table 2) may be used in free base form or in the form of salts or solvates. All forms are within the scope of disclosure.

[0264] Routes of administration of pharmaceutical compositions (or compounds of the composition) include oral, sublingual, buccal, transdermal, intradermal, intramuscular, parenteral, intravenous, intraarterial, intracranial, subcutaneous, intracerebroventricular, intraorbital, intraventricular, intrathecal (intraspinal), intraperitoneal, intranasal, inhalation and topical administration. Neurological disorders

[0265] Neurological disorders are disorders that affect the Petition 870250110266, dated 01 / 12 / 2025, pp. 315 / 473 75 / 214 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 in body sites innervated by the neurological disorder, pressure sores (e.g., bedridden), infections, and respiratory problems.Furthermore, cell death in neurological disorders can continue long after the initial insult that precipitated the neurological disorder as a result of stress and inflammatory signaling leading to further ischemia, inflammation, swelling, and disruption of synaptic signaling. The neurological disorder may result in total loss of motor and sensory function distal to the neurological disorder, or incomplete loss, resulting in partial loss of motor and sensory function.

[0266] Neurological disorders can present as several distinct conditions, depending on the location and severity of the condition. For example, peripheral neurological disorder results from damage to peripheral nerves extending to an individual's extremities, 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 legs, buttocks, and / or hips in a subject. Autonomic neurological disorder results from damage to and / or dysfunction of the autonomic nerves that lessen and / or disrupt an individual's body homeostasis. Focal neurological disorder and / or polyneurological disorder result from damage to one nerve and / or a plurality of nerves, respectively. Central cord syndrome usually results from damage to the spinal cord. Petition 870250110266, dated 01 / 12 / 2025, pp. 316 / 473 76 / 214 cervical spinal cord injury, resulting in weakness in the upper extremities with relatively spared function in the legs and spared sensation in the sacral dermatomes (e.g., urinary sphincter, anal sphincter, and genitalia).

[0267] 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., temporal lobe epilepsy, refractory epilepsy, neurotrauma-associated epilepsy, status epilepsy, 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).

[0268] Neurotraumatic disorders are disorders of the nervous system that result from neurological trauma, such as, for example, TBI, SCI, PNI, PN, stroke, ischemia, hypoxic-ischemic encephalopathy, tumor-associated epilepsy, and spasticity. In the US, it is estimated that about 1.7 million people suffer TBI each year from causes such as falls, motor vehicle-related incidents, sports injuries, and violence, of which about 52,000 succumb to such injuries. Survivors of neurological trauma often face prolonged or indefinite disability.

[0269] TBI (also known as intracranial lesion) Petition 870250110266, dated 01 / 12 / 2025, pp. 317 / 473 77 / 214 usually results from an external force that suddenly strikes an individual's head, with severity ranging from mild (e.g., concussion) to severe (e.g., penetrating injury, coma-inducing injury). Sequelae of TBI generally include loss of consciousness, physical, cognitive, social, emotional, and behavioral impairments, but can also be fatal.

[0270] A spinal cord injury (SCI) refers to any injury to any region of the spinal cord, for example, the cervical vertebrae, the thoracic vertebrae, the lumbar vertebrae, the sacral vertebrae, the sacrum or the coccyx, which causes a negative effect on spinal cord function, for example, reduced mobility and sensation in the limbs. The severity of a spinal cord injury is measured in levels of the injury outcome, for example, ranging from no effect on mobility, for example, retained walking ability, to paraplegia (e.g., paralysis of the legs and lower body region) and tetraplegia (e.g., loss of muscle strength in all four extremities).

[0271] Peripheral nerve injury (PNI) refers to any disorder resulting from nerve damage 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 (the axon remains intact, but the myelin is damaged), axonotmesis (axon rupture with maintenance of the epineurium), and neurotmesis (loss of axon continuity / axon transection).

[0272] A stroke is a condition that occurs when the blood supply to a part of the brain is interrupted (i.e., ischemic stroke) by blockage 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 Petition 870250110266, dated 01 / 12 / 2025, pp. 318 / 473 78 / 214 releases blood into the spaces around brain cells (i.e., hemorrhagic stroke) as a result of an intracerebral or subarachnoid hemorrhage. Stroke represents a substantial public burden, as nearly 77.2 million people suffered an ischemic stroke and 29.1 million people suffered a hemorrhagic stroke in 2019. Depending on the area of ​​the brain affected by the stroke, stroke symptoms 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, difficulty understanding or producing speech, impaired vision in both eyes, impaired mobility, dizziness, severe headache, or loss of balance or coordination.

[0273] Neurological trauma can also result from progressive neurodegenerative disorders that result in damage to the neural tissue of the CNS. Non-limiting examples of neurodegenerative disorders contemplated for treatment using currently 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).

[0274] 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, deficits in emotional regulation, learning and memory, impulse control, and cognition. This class of neurological disorders is characterized by diverse etiologies that can explain the multiplicity of symptoms and their degree of severity. Generally, neurodevelopmental disorders are caused by disruptions in 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 Petition 870250110266, dated 01 / 12 / 2025, pp. 319 / 473 79 / 214 includes genetic and metabolic diseases, social isolation, inflammatory and autoimmune disorders, infectious diseases, malnutrition, physical trauma, as well as environmental factors. This disclosure contemplates the treatment of neurodevelopmental disorders, such as, for example, 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 childhood epilepsy with focal migratory seizures (CFI) 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.

[0275] Affective disorders (also known as mood disorders) are a class of neurological conditions characterized by dysregulation of normal affect and mood. Affective disorders may present with mania or hypomania (e.g., schizophrenia and bipolar disorder), depressed mood (e.g., schizophrenia, bipolar disorder, and MDD), and moods that alternate between mania and depression (e.g., bipolar disorder). Affective disorders that can be treated using the disclosed methods and compositions include schizophrenia, bipolar disorder, and MDD.

[0276] Schizophrenia is a psychiatric illness characterized by recurrent psychosis. Symptoms of schizophrenia may include (1) positive symptoms related to hallucinations and distortion of reality; (2) disorganized symptoms characterized by impaired attention 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. The causes of schizophrenia have been attributed to biological sex, genetic mutations, environmental factors, Petition 870250110266, dated 01 / 12 / 2025, pp. 320 / 473 80 / 214 Malnutrition during pregnancy and parental age, among other factors. There are several hypotheses regarding the etiology of schizophrenia, one of which is the glutamate hypothesis, which believes that a reduction in glutamatergic impulses to potentiating interneurons results in reduced cortical inhibition and altered cortical network dynamics, leading to the presentation of clinical symptoms.

[0277] Bipolar disorder is an affective disorder characterized by recurrent episodes of depression and mania (i.e., abnormally elevated mood) that extend from days to weeks each. The causes of bipolar disorder can be multiple, but genetic and environmental factors have been implicated. Generally, there are two types of bipolar disorder, 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.

[0278] 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 can last for periods of time (weeks, days, months, or years) separated by years or can be continuous. MDD can pose a substantial risk to the afflicted patient, as the patient may be at a substantially higher risk of suicide. The 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 diseases, pulmonary diseases, cancer, and autoimmune diseases), and genetic and environmental factors.

[0279] A neurological disorder can also be caused by infection, ischemia, and tumors. Due to physiological barriers to regeneration in the central nervous system (CNS), neurological disorders have been a Petition 870250110266, dated 01 / 12 / 2025, pp. 321 / 473 81 / 214 is a notoriously difficult condition to treat, with most treatments being palliative and rehabilitative. Most treatments involve imposing movement limitations, maintaining adequate blood pressure through frequent repositioning of the subject, and physical and occupational therapy. Treatment methods for a neurological disorder

[0280] The compounds disclosed in this document (for example, the compounds of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ) and (II) and other compounds disclosed in this document) are generally suitable for use in the prevention or treatment of a neurological disorder. The compounds disclosed in this document (for example, the compounds of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ) and (II) and other compounds disclosed in this document) are generally suitable for use in the prevention of a neurological disorder. The compounds disclosed in this document (for example, the compounds of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ) and (II) and other compounds disclosed in this document) are generally suitable for use in the treatment of a neurological disorder.

[0281] The compounds disclosed in this document (for example, compounds of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II) and other compounds disclosed in this document) are, in general, suitable for use in the treatment of a neurological disorder, for example, a neurotraumatic, neurodevelopmental and / or affective disorder or complications resulting therefrom. Non-limiting 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), Petition 870250110266, dated 01 / 12 / 2025, pp. 322 / 473 82 / 214 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 childhood epilepsy with focal migratory seizures (CFI) 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).

[0282] The compounds disclosed in this document (for example, compounds of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II) and other compounds disclosed in this document) are generally suitable for use in the prevention of a neurological disorder, for example, a neurotraumatic, neurodevelopmental and / or affective disorder or complications resulting therefrom. Non-limiting 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 childhood epilepsy with focal migratory seizures (CFI) or temporal lobe epilepsy), and... Petition 870250110266, dated 01 / 12 / 2025, pp. 323 / 473 83 / 214 sudden unexpected death in epilepsy. Non-limiting examples of affective disorders include schizophrenia, bipolar disorder, anxiety disorder, and major depressive disorder (MDD).

[0283] The dosage of the pharmaceutical compositions disclosed herein depends on factors including, but not limited to, the route of administration, the severity of the condition being treated, and physical characteristics, for example, age, weight, and general health, of the subject. Typically, the amount of a compound disclosed herein (for example, a compound of any of the Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II) and other compounds disclosed herein) contained in a single dose may be an amount that effectively conveys the desired therapeutic effect without inducing significant toxicity. The dosage may be adapted by the physician according to conventional factors such as the extent of the disease and different parameters of the subject.

[0284] The pharmaceutical compositions of the disclosure containing a compound disclosed in this document (for example, a compound of any of the Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ), (II) and other compounds disclosed in this document) may be administered to a subject in need one or more times (for example, 10 times or more) daily or as clinically necessary. The time between administrations may decrease as the medical condition improves or increase as the subject's health declines.

[0285] Disclosure compounds, or disclosure pharmaceutical compositions containing a compound disclosed in this document (for example, a compound of any of Formulas (I), (IA), (IB), (IC), (ID), (IE), (IF), (IG), (IH), (IJ) and (II) and other compounds disclosed in this document, such as compound 2 or compound 13 disclosed in this document), may be administered to a subject in need once a day. Petition 870250110266, dated 01 / 12 / 2025, pp. 324 / 473 84 / 214 a day or twice a day. Thus, pharmaceutical compounds and compositions can be administered QD or BID.

[0286] 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 after reading this disclosure. The content of all references, patents and patent applications cited throughout this application are expressly incorporated herein by reference. Examples

[0287] The following examples are presented so as to provide those skilled in the art with a description of how the compositions and methods described in this document may be used, made and evaluated, and are intended to be purely illustrative of the disclosure and are not intended to limit the scope of what the inventors consider to be their disclosure. Example 1: Synthesis of Compound 1 qC, 2 h Step 1 DIBAL. THF PCI3, DCM °C, 2 h Step 2 DIEA, DMF °C, 2 h Step 3 Step 1: (2,4-dichloropyridin-3-yl)methanol

[0288] A solution of methyl 2,4-dichloropyridine-3-carboxylate (1.4 g, 6.795 mmol, 1 equiv) in THF (15 mL) was prepared, followed by the dropwise addition of DIBAL-H (9.1 mL, 13.650 mmol, 2.01 equiv) at 25 °C. TLC (PE / EA = 3:1, Rf = 0.3) showed that the starting material was completely consumed. The resulting mixture was extracted with EA (3 x 50 mL). The combined organic layers were washed with NH4Cl (50 mL) and dried with anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluted with EA / PE (0-50%) to Petition 870250110266, dated 01 / 12 / 2025, pp. 325 / 473 85 / 214 provide (2,4-dichloropyridin-3-yl)methanol (900 mg, 70.68% yield) as a white solid. Step 2: 2,4-dichloro-3-(chloromethyl)pyridine

[0289] A solution of (2,4-dichloropyridine-3-yl)methanol (800 mg, 4.494 mmol, 1 equiv) in DCM (1 mL) under a nitrogen atmosphere, followed by the dropwise addition of SOCl2 (925.70 mg, 6.741 mmol, 1.5 equiv) at 0 °C. The resulting mixture was then stirred at room temperature for 2 h. The resulting crude product mixture (700 mg) was used directly in the next step without further purification. TLC (PE / EA = 3:1, Rf = 0.3) showed that the starting material was completely consumed. Step 3: 2-{[(2,4-dichloropyridin-3-yl)methyl]sulfanyl}-3H,5H,6H,7Hcyclopenta[d]pyrimidin-4-one (Compound 1)

[0290] To a solution of 2,4-dichloro-3(chloromethyl)pyridine hydrochloride salt (700 mg, 3.005 mmol, 1 equiv) in 10 mL of DMF were added 2-mercapto-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one (605.5 mg, 1.2 eq DEAd DIEA (1162.3 mg, 9.015 mmol, 3 equiv) and stirred for 2 h at 40 °C. The reaction was suppressed with NH4Cl at room temperature. The resulting mixture was extracted with EA (3 x 20 mL). The combined organic layers were washed with NH4Cl (30 mL), dried with anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase flash chromatography with The following conditions were used: column, C18 silica gel; mobile phase, water (0.05% NH4HCO3) in ACN, gradient from 5% to 45% in 10 min; detector, UV 254 nm to provide 2-{[(2,4-dichloropyridin-3-yl)methyl]sulfanyl}-3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one (100 mg, 10.12%) as a white solid.LC / MS: calculated mass for Ci3HiiCi2N3OS: 327.00, obtained: 327.90[M+H]+1H NMR (300 MHz, DMSO) δ (ppm): 8.30 - 8.38 (m, 1H), 7.63 - 7.70 (m, 1H), 4.62 (s, 2H), 2.68 - 2.80 (m, 2H), 2.52 - 2.63 (m, 2H), 1.88 - 2.00 (m, 2H). Petition 870250110266, dated 01 / 12 / 2025, pp. 326 / 473 86 / 214 Example 2: Synthesis of Compound 5 DIBAL. THF °C, 2 h Step 1 SOCI2, DCM °C, 2 h Stage 2 DIEA, DMF °C, 2 h Step 3 Step 1: (4-chloro-2-methylpyridin-3-yl)methanol

[0291] To a solution of ethyl 4-chloro-2-methylpyridine-3-carboxylate (1 g, 5.009 mmol, 1 equiv) in 10 mL of THF, 10 mL of DIBAL-H (1.5 M in hexane) were added dropwise under an ice bath. The resulting mixture was stirred at 25 °C for 1 h. TLC showed that the starting material was completely consumed. The reaction was suppressed with H2O, extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with saturated aqueous NaCl solution, dried with Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography, eluted with EA:PE (1:1) to provide (4-chloro-2-methylpyridin-3-yl)methanol (600 mg, 76.00%) as a white solid. Step 2: 4-chloro-3-(chloromethyl)-2-methylpyridine

[0292] To a solution of (4-chloro-2-methylpyridin-3-yl)methanol (697 mg, 4.4 mmol, 1 equiv) in DCM (8 mL) was added dropwise SOCl2 (1320.94 mg, 11.105 mmol, 2.5 equiv) at 0 °C. The resulting mixture was stirred at 0 °C for 30 min. TLC showed that the starting material was completely consumed. The reaction was concentrated under reduced pressure to give 4-chloro-3-(chloromethyl)-2-methylpyridine (600 mg, 76.74% yield) as a white solid. Step 3: 2-(((4-chloro-2-methylpyridin-3-yl)methyl)thio)-3,5,6,7-tetrahydro-4Hcyclopenta[d]pyrimidin-4-one

[0293] A solution of 2-sulfanyl-3H,5H,6H,7Hcyclopenta[d]pyrimidin-4-one (600 mg, 3.567 mmol, 1 equiv) and 4-chloro-3(chloromethyl)-2-methylpyridine (753.52 mg, 4.280 mmol, 1.2 equiv) in DMF (10 mL) Petition 870250110266, dated 01 / 12 / 2025, pp. 327 / 473 87 / 214 was dropwise added to DEAd DIEA (1.38 g, 10.701 mmol, 3 equiv). The resulting mixture was stirred at 40 °C for 30 min. The reaction was suppressed by the addition of saturated aqueous NH4Cl solution (100 ml) at 25 °C. The aqueous layer was extracted with EtOAc (3 x 100 ml) dried with anhydrous sodium sulfate. The crude product was purified by reverse-phase flash (0.05% NH4HCO3) to provide 2-(((4-chloro-2-methylpyridin-3-yl)methyl)thio)-3,5,6,7-tetrahydro-4Hcyclopenta[d]pyrimidin-4-one (190 mg, 17.06%) as a white solid. LC / MS: calculated mass for Ci4Hi4CIN3OS: 307.1, obtained: 308.05 [M+H]+.1H NMR (300 MHz, DMSO-d6) δ (ppm): 12.51 (s, 1H) 8.26 - 8.38 (m, 1H), 7.39 - 7.49 (m, 1H), 7.53 - 7.64 (m, 2H), 2.71 - 2.89 (m, 2H), 2.58 - 2.71 (m, 5H), 7.00 - 7.15 (m, 1H),1.91 - 2.11 (m, 2H). Example 3: Synthesis of Compound 2 DIBAL. THFeC. 2 h Step 1 SOCl2. DCM °C. 2 h Step 2 DIEA, DMF 'C, 2 h Step 3 Step 1: (2,4-dimethylpyridin-3-yl)methanol

[0294] To a solution of ethyl 2,4-dimethylnicotinate (1 g, 5.580 mmol) in THF (10 mL) was added DIBAL (7.44 mL, 11.160 mmol) at 0 °C over 15 min, the reaction mixture was stirred at rt for 1 h. The progress of the reaction was monitored by LCMS and showed that the reaction was complete. The reaction was suppressed by the addition of ice-cold water at 0 °C. The resulting mixture was filtered; the filter mass was washed with EA (3 x 50 mL). The filtrate was concentrated under reduced pressure to provide (2,4-dimethylpyridin-3-yl)methanol (700 mg, 91.45% yield) as a yellow solid. MS (ESI) calculated for C8H11NO, 137.08 m / z, yielded 138.05 [M+H]+. Step 2: 3-(chloromethyl)-2,4-dimethylpyridine

[0295] To a solution of (2,4-dimethylpyridin-3-yl)methanol (500 mg, 3.645 mmol) in DCM (10 mL) was added SOCl2 (1083.96 mg, 9.113 mmol) Petition 870250110266, dated 01 / 12 / 2025, pp. 328 / 473 88 / 214 at 0 °C for 1 h. The progress of the reaction was monitored by TLC and showed that the reaction was complete. The filtrate was concentrated under reduced pressure to provide 3-(chloromethyl)-2,4-dimethylpyridine (300 mg, 52.89% yield) as a yellow solid. Step 3: 2-(((2,4-dimethylpyridin-3-yl)methyl)thio)-3,5,6,7-tetrahydro-4Hcyclopenta[d]pyrimidin-4-one (Compound 2)

[0296] To a 25 mL round-bottom flask fitted with a stir bar, 3-(chloromethyl)-2,4-dimethylpyridine (200 mg, 1.285 mmol) was added in 20 mL of DMF, followed by the addition of 2-mercapto-3,5,6,7tetrahydro-4H-cyclopenta[d]pyrimidin-4-one (237.78 mg, 1.413 mmol) and DEAd DIEA (498.29 mg, 3.855 mmol) at 0 °C. The resulting solution was stirred at 50 °C for 2 h. The reaction mixture was concentrated directly under reduced pressure to obtain a brown oil. The brown oil was purified by reversed-phase column chemistry to provide 2-(((2,4-dimethylpyridin-3-yl)methyl)thio)-3,5,6,7-tetrahydro4H-cyclopenta[d]pyrimidin-4-one (100.0 mg, 20.95% yield) as a whitish solid. Calculated MS (ESI) For C15H17N3OS, 287.11 m / z, 288.10 [M+H]+.1H was obtained. NMR (300 MHz, DMSO-de) δ (ppm): 12.60 (s, 1H), 8.16 - 8.33 (m, 1H), 7.00 - 7.15 (m, 1H), 4.44 (s, 2H), 2.70 - 2.85 (m, 2H), 2.58 - 2.69 (m, 2H), 2.53 - 2.57 (m, 3H), 2.35 (s, 3H), 1.85 - 2.05 (m, 2H). Example 4: Synthesis of Compound 9 Step 1: Methyl 2-methoxy-4-methylnicotinate

[0297] To a solution of methyl 4-chloro-2-methylnicotinate (650 Petition 870250110266, dated 01 / 12 / 2025, pp. 329 / 473 89 / 214 mg, 5.405 mmol) in MeOH (20 mL) was added to MeONa (729.729 mg, 13.513 mmol) at 50 °C for 1 h. The progress of the reaction was monitored by TLC and showed that the reaction was complete. The reaction was suppressed by the addition of ice-cold water at 0 °C. The resulting mixture was filtered; the filter mass was washed with EA (3 x 60 mL). The filtrate was concentrated under reduced pressure. Methyl 2-methoxy-4-methylnicotinate (200 mg, 28.77% yield) was provided as a yellow solid. Step 2: (2-methoxy-4-methylpyridin-3-yl)methanol

[0298] To a solution of 2-methoxy-4-methylnicotinate methyl (200 mg, 2.106 mmol) in THF (4 mL) was added DIBAL (4.2 mL, 4.216 mmol) at 0 °C for 1 h. The progress of the reaction was monitored by TLC and showed that the reaction was complete. The reaction was suppressed by the addition of ice-cold water at 0 °C. The resulting mixture was filtered, the filter mass was washed with EA (3 x 60 mL). The filtrate was concentrated under reduced pressure. (2-methoxy-4-methylpyridin-3-yl)methanol (140 mg, 83.106% yield) was provided as a yellow solid. Step 3: 3-(chloromethyl)-2-methoxy-4-methylpyridine

[0299] To a solution of (2-methoxy-4-methylpyridin-3-yl)methanol (140 mg, 0.916 mmol) in DCM (3 mL) was added SOCl2 (327 mg, 2.748 mmol) at 0 °C for 1 h. The progress of the reaction was monitored by TLC and showed that the reaction was complete. The filtrate was concentrated under reduced pressure. It was to provide 3-(chloromethyl)-2-methoxy-4-methylpyridine (110 mg, 70.22% yield) as a yellow solid. Step 4: 2-(((2-methoxy-4-methylpyridin-3-yl)methyl)thio)-3,5,6,7-tetrahydro-4Hcyclopenta[d]pyrimidin-4-one (Compound 9)

[0300] To a 100 mL round-bottom flask fitted with a stirring bar, 3-(chloromethyl)-4-methoxy-2-methylpyridine (110 mg, 0.643 mmol) was added in 5 mL of DMF, followed by the addition of 2-mercapto-3,5,6,7 Petition 870250110266, dated 01 / 12 / 2025, pp. 330 / 473 90 / 214 tetrahydro-4H-cyclopenta[d]pyrimidin-4-one (130 mg, 0.772 mmol) from DEAd DIEA (271 mg, 2.106 mmol) at 0 °C. The resulting solution was stirred at 50 °C for 2 h. The reaction mixture was concentrated directly under reduced pressure to obtain a brown oil. The brown oil was purified by reversed-phase column to to provide 2-(((2-methoxy-4-methylpyridin-3-yl)methyl)thio)-3,5,6,7-tetrahydro-4Hcyclopenta[d]pyrimidin-4-one (37.9 mg, 17.81%) as a whitish solid. Calculated MS (ESI) For C15H17N3O2S, 303.10 m / z, 304.05 [M+H]+ was obtained. Example 5: Synthesis of Compound 4 ohA> IOII HsX^7DIBALTHFijAV'OH SOCI2, DCM AG0 DIEA.DMF( Step 1: (2-chloro-4-methylpyridin-3-yl)methanol

[0301] To a solution of ethyl 2-chloro-4-methylnicotinate (2 g, 10.050 mmol) in THF (20 mL) was added DIBAL (15 mL, 22.320 mmol) at 0 °C, the reaction mixture was stirred at rt for 1 h. The progress of the reaction was monitored by TLC and showed that the reaction was complete. The reaction was suppressed by the addition of ice-cold water under an ice bath. The resulting mixture was filtered; the filter mass was washed with EA (3 x 40 mL). The filtrate was concentrated under reduced pressure to provide (2-chloro-4-methylpyridin-3-yl)methanol (1.3 g, 82.39% yield) as a yellow solid. Calculated MS (ESI) For CyHsClNO, 157.03 m / z, 158.00 [M+H]+ was obtained. Step 2: 2-chloro-3-(chloromethyl)-4-methylpyridine

[0302] To a solution of (2-chloro-4-methylpyridin-3-yl)methanol (1.3 g, 8.39 mmol) in DCM (10 mL) was added SOCl2 (1083.96 mg, 9.113 mmol) at 0 °C. The progress of the reaction was monitored by TLC and showed that the reaction was complete. The filtrate was concentrated under reduced pressure to provide 2-chloro-3-(chloromethyl)-4-methylpyridine (1.1 g, 74.9% yield) as a yellow solid. Petition 870250110266, dated 01 / 12 / 2025, pp. 331 / 473 91 / 214 Step 3: 2-(((2-chloro-4-methylpyridin-3-yl)methyl)thio)-3,5,6,7-tetrahydro-4Hcyclopenta[d]pyrimidin-4-one (Compound 4)

[0303] To a 100 mL round-bottom flask fitted with a stirring bar, 2-chloro-3-(chloromethyl)-4-methylpyridine (1100 mg, 6.285 mmol) and 2-mercapto-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4one (1037 mg, 6.285 mmol) were added in 20 mL of DMF, followed by additional DEAf DIEA (900 mg, 6.97 mmol) at 0 °C. The resulting solution was stirred at 40 °C for 2 h. The reaction mixture was concentrated directly under reduced pressure to obtain a brown oil. The brown oil was purified by reversed-phase column (0.05% NH4HCO3) to provide 2-(((2-chloro-4-methylpyridin-3-yl)methyl)thio)-3,5,6,7tetrahydro-4H-cyclopenta[d]pyrimidin-4-one (502.1 mg, 26.25% yield) as a whitish solid. Example 6: Synthesis of Compound 13 Step 1: Methyl 4-methoxy-2-methylnicotinate

[0304] To a solution of methyl 4-chloro-2-methylnicotinate (1 g, 5.405 mmol) in MeOH (20 mL) was added MeONa (729.729 mg, 13.513 mmol) at 40 °C for 1 h. The progress of the reaction was monitored by TLC and showed that the reaction was complete. The reaction was suppressed by the addition of ice-cold water under an ice bath. The resulting predicate solid was filtered, the filter mass was washed with EA (3 x 50 mL). The filtrate was concentrated under reduced pressure to provide methyl 4-methoxy-2-methylnicotinate (800 mg, 81.31% yield) as a yellow solid. Petition 870250110266, dated 01 / 12 / 2025, pp. 332 / 473 92 / 214 Step 2: (4-methoxy-2-methylpyridin-3-yl)methanol

[0305] To a solution of methyl 4-methoxy-2-methylnicotinate (800 g, 4.395 mmol) in THF (10 mL) was added DIBAL (7.44 mL, 11.160 mmol) at 0 °C for 1 h. The progress of the reaction was monitored by TLC and showed that the reaction was complete. The reaction was suppressed by the addition of ice-cold water at 0 °C. The resulting mixture was filtered; the filter mass was washed with EA (3 x 40 mL). The filtrate was concentrated under reduced pressure. It was to provide (4-methoxy-2-methylpyridin-3-yl)methanol (650 mg, 96.66% yield) as a yellow solid. Step 3: 2-chloro-3-(chloromethyl)-4-methylpyridine

[0306] To a solution of (2-chloro-4-methylpyridin-3-yl)methanol (650 mg, 4.248 mmol) in DCM (10 mL) was added SOCl2 (700 mg, 5.932 mmol) at 0 °C for 1 h. The progress of the reaction was monitored by TLC and showed that the reaction was complete. The filtrate was concentrated under reduced pressure to provide 2-chloro-3-(chloromethyl)-4-methylpyridine (350 mg, 48.18% yield) as a yellow solid. Step 4: 2-(((4-methoxy-2-methylpyridin-3-yl)methyl)thio)-3,5,6,7-tetrahydro-4Hcyclopenta[d]pyrimidin-4-one (Compound 13)

[0307] To a 100 mL round-bottom flask fitted with a stir bar, 3-(chloromethyl)-4-methoxy-2-methylpyridine (350 mg, 2.046 mmol) was added in 5 mL of DMF, followed by the addition of 2-mercapto-3,5,6,7tetrahydro-4H-cyclopenta[d]pyrimidin-4-one (360 mg, 2.106 mmol) and DEAd DIEA (1086 mg, 8.42 mmol) at 0 °C. The resulting solution was stirred at 50 °C for 2 h. The reaction mixture was concentrated directly under reduced pressure to obtain a brown oil. The brown oil was purified by reversed-phase column chromatography (0.05% NH4HCO3) to provide 2-(((4-methoxy-2-methylpyridin-3-yl)methyl)thio)3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one (57.9 mg, 7.9%) as a whitish solid. MS (ESI) calculated for C15H17N3O2S, 303.10 m / z, Petition 870250110266, dated 01 / 12 / 2025, pp. 333 / 473 93 / 214 yielded 304.05 [M+H]+. Example 7: Synthesis of Compound 61 the Stage 2 Stage N Step 1: (4-methylpyridin-3-yl)methanol

[0308] A solution of methyl 4-methylpyridine-3-carboxylate (500 mg, 3.308 mmol) in THF (4 mL) was cooled to 0 °C. Then, DIBAL-H (1.17 g, 8.270 mmol, 1.0 M in hexane) was added dropwise to the above solution. The resulting reaction mixture was stirred at room temperature for 2 h. After completion of this reaction, the reaction was suppressed with ice-cold water (500 mL). The resulting mixture was filtered, and the filter mass was washed with EA / MeOH (1:1, V / V). The filtrate was concentrated under reduced pressure, yielding the crude product of (4-methylpyridin-3-yl)methanol (360 mg) as a whitish solid, which was used directly without any purification. MS (ESI) calculated For C7H9NO, 123.07 m / z, 124.16 [M+H]+ was obtained. Step 2: 3-(chloromethyl)-4-methylpyridine

[0309] To a solution of (4-methylpyridin-3-yl)methanol (360 mg, 2.923 mmol, 1 equiv) in DCM (8 mL) was added SOCl2 (869.34 mg, 7.308 mmol, 2.5 equiv) dropwise at 0 °C. The resulting solution was stirred at room temperature for 2 h. After completion of this reaction, the resulting mixture was concentrated to dryness under reduced pressure to yield the crude product 3(chloromethyl)-4-methylpyridine (270 mg) as a white solid, which was used directly without any purification. Step 3: 2-{[(4-methylpyridin-3-yl)methyl]sulfanyl}-3H,5H,6H,7Hcyclopenta[d]pyrimidin-4-one (Compound 61)

[0310] To a solution of 3-(chloromethyl)-4-methylpyridine (200 mg, Petition 870250110266, dated 01 / 12 / 2025, pp. 334 / 473 94 / 214 1,412 mmol, 1 equiv) and 2-sulfanyl-3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one (285.10 mg, 1.694 mmol, 1.2 equiv) in DMF (4 mL) were added DIEA (547.66 mg, 4.236 mmol, 3 equiv). The resulting solution was stirred at room temperature for 2 h. After the reaction was complete, the product was precipitated by the addition of NH4Cl. The precipitated solids were collected by filtration and washed with ACN (10 mL). The residue was purified by reversed-phase flash chromatography under the following conditions: column, silica gel C18; mobile phase, ACN in water (0.05% TFA), gradient from 2% to 50% in 15 min; A UV detector at 254 nm yielded 2-{[(4-methylpyridin-3-yl)methyl]sulfanyl}3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one; trifluoroacetic acid (194.5 mg, 34.48% yield) as a white solid. The calculated MS (ESI) for C14H15N3OS was 273.09 m / z, yielding 274.10 [M+H]+. Example 8: Synthesis of Compound 114 L JL / o DIBAL-H, THF ifjfOHSOCI2, DCMCl DIEA·DMF HjJ JL 0°C, 1h rt, 2h ' rt, 2hNEStep 1 Step 2 Step 3 1 A. N Step 1: (2-methylpyridin-3-yl)methanol

[0311] Methyl 2-methylpyridine-3-carboxylate (500 mg, 3.308 mmol) was dissolved in THF (4 mL) to obtain a clear solution. After cooling to 0 °C, DIBAL-H (1176.05 mg, 8.270 mmol, 1.0 M in hexane) was added dropwise to the above solution. The resulting reaction mixture was stirred at room temperature for 2 h. After completion of this reaction, the reaction was suppressed with ice-cold water (500 mL). The resulting mixture was filtered, and the filter mass was washed with EA / MeOH (1:1, V / V). The filtrate was concentrated under reduced pressure, yielding the crude product (2-methylpyridin-3yl)methanol (450 mg) as a whitish solid, which was used directly without any purification. MS (ESI) calculated For C7H9NO, 123.07 m / z, 124.15 [M+H]+ was obtained. Petition 870250110266, dated 01 / 12 / 2025, pages 335 / 473 95 / 214 Step 2: 3-(chloromethyl)-2-methylpyridine

[0312] To a solution of (2-methylpyridin-3-yl)methanol (450 mg, 3.654 mmol, 1 equiv) in DCM (10 mL) was added SOCl2 (1.09 g, 9.163 mmol, 2.5 equiv) dropwise at 0 °C. The resulting solution was stirred at room temperature for 2 h. After completion of this reaction, the resulting mixture was concentrated to dryness under reduced pressure to yield the crude product 3-(chloromethyl)-2-methylpyridine (380 mg) as a white solid, which was used directly without any purification. Step 3: 2-{[(2-methylpyridin-3-yl)methyl]sulfanyl}-3H,5H,6H,7Hcyclopenta[d]pyrimidin-4-one (Compound 114)

[0313] To a solution of 3-(chloromethyl)-2-methylpyridine (200 mg, 1.412 mmol, 1 equiv) and 2-sulfanyl-3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one (285.10 mg, 1.694 mmol, 1.2 equiv) in DMF (4 mL) were added DIEA (547.66 mg, 4.236 mmol, 3 equiv). The resulting solution was stirred at room temperature for 2 h. After the reaction was complete, the product was precipitated by the addition of NH4Cl. The precipitated solids were collected by filtration and washed with ACN (10 mL). The residue was purified by reversed-phase flash chromatography under the following conditions: column, C18 silica gel; Mobile phase, ACN in water (0.05% TFA), gradient from 2% to 50% in 15 min; detector, UV 254 nm to provide 2-{[(2-methylpyridin-3-yl)methyl]sulfanyl}-3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one; trifluoroacetic acid (188.7 mg, 34.03% yield) as a white solid. Calculated MS (ESI) For C14H15N3OS, 273.09 m / z, 274.20 [M+H]+ was obtained. Example 9: Synthesis of Compound 179 o _ / Jl XXL~Selectride'THF SN Stage step 1 H Step 1: 2-methyl-3-[({4-oxo-3H,5H,6H,7H-cyclopenta[d]pyrimidin-2yl}sulfanyl)methyl]-1H-pyridin-4-one (Compound 179)

[0314] A solution of 2-{[(4-methoxy-2-methylpyridin-3- Petition 870250110266, dated 01 / 12 / 2025, pp. 336 / 473 96 / 214 yl)methyl]sulfanil}-3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one (300 mg, 0.989 mmol, 1 equiv) in THF (3 mL) were added to L-selectride (4.94 mL, 4.945 mmol, 5 equiv). After stirring at 80 °C for 2 h under a nitrogen atmosphere, the desired product can be detected by LCMS. The crude product was purified by Prep-HPLC under the following conditions (Column: Xbridge Prep OBD C18 column, 30*150 mm, 5μm; Mobile phase A: Water (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 5% B to 21% B in 7 min; Wavelength: 254 nm / 220 nm; RT1(min): 6.18) to provide 2-methyl-3-[({4-oxo3H,5H,6H,7H-cyclopenta[d]pyrimidin-2-yl}sulfanyl)methyl]-1H-pyridin-4-one (82.4 mg, 28.73% yield) as a white solid. LC / MS: calculated mass for C14H15N3O2S: 289.09, obtained: 290.15 [M+H]+.1H NMR (300 MHz, DMSO) δ (ppm): 7.56 - 7.59 (m, 1H), 6.09 - 6.13 (m, 1H), 4.44 4.49 (m, 2H), 2.71 - 2.76 (m, 2H), 2.57 - 2.65 (m, 2H), 2.37 (s, 3H), 1.62 1.64 (m, 2H). Example 10: Synthesis of Compound 178 NaSHMe.DMF DiBAI-H,THF SOCI2,DCM SMe HN' rt, 1 h Step 1 O°Cr.t.. 1h Step 2 DIEA, DMF 0°C-rt. 1 h Step 3 rt. 2h Step 4 Step 1: 2-methyl-4-(methylsulfanyl)pyridine-3-carboxylate

[0315] To a solution of methyl 4-chloro-2-methylpyridine-3-carboxylate (1 g, 5.388 mmol, 1 equiv) in dry DMF (20 mL) at rt was added NaSH (302.03 mg, 5.388 mmol, 1 equiv). It was stirred at rt for 1 h. After addition, the resulting mixture was concentrated under reduced pressure. This resulted in methyl 2-methyl-4-(methylsulfanyl)pyridine-3-carboxylate (800 mg, 75.28%) as a brown solid. Step 2: [2-methyl-4-(methylsulfanyl)pyridin-3-yl]methanol

[0316] To a solution of 2-methyl-4-(methylsulfanyl)pyridine-3 Petition 870250110266, dated 01 / 12 / 2025, pp. 337 / 473 97 / 214 Methyl carboxylate (750 mg, 3.802 mmol, 1 equiv) in dry THF (7 mL) at 0 °C was slowly added to DIBAl-H (1.62 g, 11.406 mmol, 3 equiv). After the addition, the mixture was stirred at room temperature for 2 hours and suppressed with NH4Cl (aq. 2 mL). Filtered and concentrated, it yielded the crude compound (220 mg). The residue / crude product was purified by reverse-phase flash under the following conditions (MeCN / Water (0.05% NH4HCO3)) to give [2-methyl-4-(methylsulfanyl)iridine-3-yl]methanol (500 mg, 77.70%) as a white solid. Step 3: 3-(chloromethyl)-2-methyl-4-(methylsulfanyl)pyridine

[0317] To a solution of [2-methyl-4-(methylsulfanyl)pyridine-3yl]methanol (450 mg, 2.659 mmol, 1 equiv) in dry DCM (5 mL) at 0 °C, SOCl2 (948.92 mg, 7.977 mmol, 3 equiv) was slowly added. It was stirred at rt for 1 h. After addition, the resulting mixture was concentrated under reduced pressure. This resulted in 3-(chloromethyl)-2-methyl-4-(methylsulfanyl)pyridine (420 mg, 84.16%) as a brown solid. Step 4: 2-({[2-methyl-4-(methylsulfanyl)pyridin-3-yl]methyl}sulfanyl)3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one (Compound 178)

[0318] To a stirred solution of 3-(chloromethyl)-2-methyl-4(methylsulfanyl)pyridine (200 mg, 1.066 mmol, 1 equiv) in anhydrous DMF (4 mL) was added DIEA (550.90 mg, 4.264 mmol, 4 equiv) at rt and stirred for 1 h. The progress of the reaction was monitored by LC / MS. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to yield the crude product. The residual crude product was purified by reverse-phase flash under the following conditions (5%-30% MeCN / Water (0.05% NH4HCO3)) to provide 2-({[2-methyl-4-(methylsulfanyl)iridine-3yl]methyl}sulfanyl)-3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one (184.5 mg, 52.44%) as a white solid. Calculated MS (ESI) For C15H17N3OS2, 319.44 m / z, 320.10 [M+H]+ was obtained. Petition 870250110266, dated 01 / 12 / 2025, pp. 338 / 473 98 / 214 Example 11: Synthesis of Compound 185 OEt O DIBAL-H, THF rt, 2h Step 1 OEt SOCI2, DCM rt, 2h Step 2 DIEA, DMF rt. 2h Step 3 Step 1: (4-ethoxy-2-methylpyridin-3-yl)methanol

[0319] A solution of methyl 4-ethoxy-2-methylpyridine-3-carboxylate (700 mg, 3.586 mmol, 1 equiv) in THF (7 mL) was added dropwise to DIBAL (10.76 mL, 10.758 mmol, 3 equiv) at 0 °C. The resulting mixture was stirred at room temperature for 2 h. The desired product could be detected by LC / MS. The reaction was suppressed with water at 0 °C. The resulting mixture was filtered; the filter mass was washed with MeOH (20 mL). The filtrate was concentrated under reduced pressure. Then concentrated to provide the crude product, which was used in the next step directly without further purification. LC / MS: calculated mass for C9H13NO2: 167.09, obtained: 168.15 [M+H]+. Step 2: 3-(chloromethyl)-4-ethoxy-2-methylpyridine

[0320] To a stirred solution of (4-ethoxy-2-methylpyridin-3-yl)methanol (480 mg, 2.871 mmol, 1 equiv) in DCM (5 mL) was added SOCl2 (853.74 mg, 7.178 mmol, 2.5 equiv) dropwise at 0 °C. After stirring at room temperature for 2 h, the desired product could be detected by LC / MS. The resulting mixture was concentrated under reduced pressure. After further concentration to provide the crude product, it was used directly in the next step without further purification. LC / MS: calculated mass for C9H12ClNO: 185.06, obtained: 186.00 [M+H]+ Step 3: 2-{[(4-ethoxy-2-methylpyridin-3-yl)methyl]sulfanyl}-3H,5H,6H,7Hcyclopenta[d]pyrimidin-4-one (Compound 185)

[0321] A solution of 3-(chloromethyl)-4-ethoxy-2-methylpyridine (390 mg, 2.101 mmol, 1 equiv) and 2-sulfanyl-3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one Petition 870250110266, dated 01 / 12 / 2025, pp. 339 / 473 99 / 214 (424.04 mg, 2.521 mmol, 1.2 equiv) in DMF (5 mL) were added to DIEA (814.54 mg, 6.303 mmol, 3 equiv), the reaction mixture was stirred at 25 °C for 2 h. LCMS showed that the reaction was complete. The crude product was purified by Prep-HPLC under the following conditions (Column: Xselect CSH C18 OBD column, 30 * 150 mm, 5μm; Mobile phase A: Water (0.1% FA), Mobile phase B: MEOH; Flow rate: 60 mL / min mL / min; Gradient: 3% B to 23% B in 7 min; Wavelength: 254nm / 220nm nm; RT1(min): 5.4) to provide 2-{[(4-ethoxy-2-methylpyridin-3-yl)methyl]sulfanyl}-3H,5H,6H,7H-cyclopenta[d]pyrimidin4-one; formic acid (147.2 mg, 18.82% yield) as a white solid. LC / MS: calculated mass for C16H19N3O2S: 317.12, obtained: 318.05 [M+H]+. 1H NMR (300 MHz, DMSO) δ (ppm): 8.24 - 8.26 (m, 1H), 6.94 - 6.96 (m, 1H), 4.43 (s, 2H), 4.11 - 4.18 (m, 2H), 2.76 - 2.81 (m, 2H), 2.62 - 2.64 (m, 2H), 2.52 (s, 3H), 1.95 - 2.00 (m, 2H), 1.30 - 1.35 (m, 3H). Example 12: Synthesis of Compound 171 HCI Step 1: 2-{[(2,4-Dimethylpyridin-3-yl)methyl]sulfanyl}-3 H,5 H,7 H -thieno[3,4d]pyrimidin-4-one

[0322] To a mixture of 3-(chloromethyl)-2,4-dimethylpyridine (200 mg, 1.29 mmol, 1 equiv) in DMF (2 mL) was added 2-sulfanyl-3H,5H,7H-thieno[3,4o]pyrimidin-4-one [CAS No: 5750-52-7] (311 mg, 1.67 mmol, 1.3 equiv) and DIEA (664 mg, 5.14 mmol, 4 equiv). The mixture was purified by prep-HPLC [Column: Xselect CSH C18 OBD column, 30*150 mm, 5μm; Mobile phase A: Water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 3% B to 18% B in 10 min] to generate the product (111.7 mg, 28%) as a solid. LC / MS: calculated mass for C14H15N3OS2: 305.07; Obtained: 306.00 [M+H]+; Petition 870250110266, dated 01 / 12 / 2025, pages 340 / 473 100 / 2141H RMN (300 MHz, DMSO-d6) δ 12.95 (br. S, 1H), 8.25 (m, 1H), 7.08 - 7.12 (m, 1H), 4.46 (s, 2H), 4.15 - 4.18 (m, 2H), 3.85 - 3.95 (m, 2H), 2.54 (s, 3H), 2.36 (s, 3H). Example 13: Síntese do Composto 95 ο Etapa 1:2-(((4-metil-2-(trifluorometil)piridina-3-il)metil)tio)-3,5,6,7-tetrahydro-4H-cyclopenta[d]pirimidin-4-ona

[0323] To a mixture of 3-(chloromethyl)-4-methyl-2-(trifluoromethyl)pyridine (1.2 g, 5.7 mmol) and 2-sulfanyl-3H,5H,6H,7Hcyclopenta[d]pyrimidin-4-one (1.44 g, 8.6 mmol) in DMF (12 mL) at rt was added DIEA (2.22 g, 17.1 mmol). The mixture was stirred at rt for 1 h, then purified by reversed-phase column chromatography [conditions: column, Cis silica gel; mobile phase, MeCN in H2O (10 mmol / L NH4HCO3), gradient from 30% to 40% in 10 min] to yield the product (1.05 g, 53%) as a solid. LCMS(ESI) m / z calculated for C15H14F3N3OS, 341.08; 342.05 [M+H]+;1H NMR (300 MHz, DMSO-d6) δ 8.53 (m, 1H), 7.61 (m, 1H), 4.59 (s, 2H), 2.70 - 2.89 (m, 2H), 2.59 - 2.69 (m, 2H), 2.46 (s, 3H), 1.91 - 2.11 (m, 2H). Example 14: Synthesis of Compound 186 Step 1: Methyl 4-methoxy-2-(trifluoromethyl)pyridine-3-carboxylate

[0324] A mixture of 2-bromo-4-methoxypyridine-3-carboxylate of Petition 870250110266, dated 01 / 12 / 2025, pp. 341 / 473 101 / 214 methyl (1.0 g, 4.1 mmol) and copper(I) iodide (1.55 g, 8.1 mmol), methyl 2,2-difluoro-2-sulfoacetate (1.56 g, 8.1 mmol) in DMF (15 mL) at 0 °C under a N2 atmosphere was added methyl 2,2-difluoro-2-sulfoacetate (1.56 g, 8.1 mmol). The mixture was heated to 90 °C and stirred for 1 h, then extracted with EtOAc (100 mL x 3). The combined organic layers were dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography [eluent: EtOAc / petroleum ether (0:1 to 1:1)] to yield the product (800 mg, 83%) as a solid. Calculated MS (ESI) for C9H8F3NO3: 235.16; obtained: 236.15 [M+H]+. Step 2: [4-Methoxy-2-(trifluoromethyl)pyridin-3-yl]methanol

[0325] A mixture of methyl 4-methoxy-2-(trifluoromethyl)pyridine-3-carboxylate (600 mg, 2.5 mmol) in THF (20 mL) at 0 °C under a N2 atmosphere was added to DIBAL-H (7.7 mmol). The mixture was heated to rt and stirred for 1 h, then cooled to 0 °C and suppressed with H2O at 0 °C, filtered, and the filter mass was washed with MeOH (50 mL). The filtrate was concentrated under reduced pressure to yield the product (300 mg). LC / MS: 466.05 [M+H]+ Step 3: 3-(chloromethyl)-4-methoxy-2-(trifluoromethyl)pyridine

[0326] To a mixture of [4-methoxy-2-(trifluoromethyl)iridine-3yl]methanol (300 mg, 1.5 mmol) in DCM (10 mL) at 0 °C was added SOCl2 (861 mg, 7.2 mmol). The mixture was heated to rt and stirred for 0.5 h, then concentrated under vacuum to give the product (300 mg). Step 4: 2-({[4-Methoxy-2-(trifluoromethyl)pyridin-3-yl]methyl}sulfanyl)3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one

[0327] To a mixture of 3-(chloromethyl)-4-methoxy-2-(trifluoromethyl)pyridine (300 mg, 1.33 mmol) and 2-sulfanyl-3H,5H,6H,7Hcyclopenta[d]pyrimidin-4-one (268 mg, 1.6 mmol) in DMF (5 mL) at rt was added DIEA (601 mg, 4.7 mmol). The mixture was stirred at rt for 2 h, then purified by reversed-phase column chromatography [conditions: column, Petition 870250110266, dated 01 / 12 / 2025, pages 342 / 473 102 / 214 silica gel C18; mobile phase, ACN in H2O (0.05% NH4HCO3), gradient from 10% to 50% in 10 min] to generate the product (186 mg, 38%) as a solid. LC / MS: 358.10 [M+H]+;1H NMR (300 MHz, DMSO-d6) δ 8.50 - 8.60 (m, 1H), 7.35 - 7.49 (m, 1H), 4.54 (s, 2H), 3.90 - 4.06 (m, 3H), 2.75 - 2.86 (m, 2H), 2.55 - 2.70 (m, 2H), 1.89 - 2.08 (m, 2H); 19F-NMR (282 MHz, DMSO-d6) δ -61.8. Example 15: Synthesis of Compound 178 Step 1: 2-methyl-4-(methylsulfanyl)pyridine-3-carboxylate

[0328] To a mixture of methyl 4-chloro-2-methylpyridine-3-carboxylate (1.0 g, 5.4 mmol, 1 equiv) in dry DMF (20 mL) at room temperature was added CHsSna (302 mg, 5.4 mmol, 1 equiv). The mixture was stirred at room temperature for 1 h, then saturated aqueous NH4Cl (100 mL) was added and the mixture was extracted with EtOAc (50 mL x 3). The combined organic layers were concentrated under reduced pressure and the residue was purified by silica gel column chromatography eluting with EtOAc / petroleum ether to yield the product (800 mg, 75%) as a solid. LC / MS: calculated mass for C9H11NO2S: 197.05; obtained: 198.10[M+H]+. Step 2: 2-Methyl-4-(methylsulfanyl)pyridin-3-yl]methanol

[0329] To a mixture of methyl 2-methyl-4-(methylsulfanyl)pyridine-3-carboxylate (750 mg, 3.8 mmol, 1 equiv) in dry THF (7 mL) at 0 °C, DIBAL-H (1.62 g, 11.4 mmol, 3 equiv) was slowly added. After the addition, the mixture was heated to rt and stirred for 2 h, then quenched with cooled H2O (50 mL). The mixture was filtered, the filtrate was concentrated, and the crude residue was purified by reverse-phase chromatography [eluting with MeCN / H2O (0.05% of Petition 870250110266, dated 01 / 12 / 2025, pages 343 / 473 103 / 214 NH4HCO3)] to generate the product (500 mg, 77%) as a solid. LC / MS: calculated mass for C8H11NOS: 169.06; obtained: 170.10 [M+H]+. Step 3: 2-methyl-4-(methylsulfanyl)pyridine-3-carboxylate methyl

[0330] To a mixture of [2-methyl-4-(methylsulfanyl)pyridine-3yl]methanol (450 mg, 2.659 mmol, 1 equiv) in dry DCM (5 mL) at 0 °C, SOCl2 (948.92 mg, 7.977 mmol, 3 equiv) was slowly added. The mixture was stirred at rt for 1 h, then concentrated under reduced pressure to generate the product (420 mg, 84%) as a solid. Step 4: 2-({[2-Methyl-4-(methylsulfanyl)pyridin-3-yl]methyl}sulfanyl)3 H,5 H,6 H,7 H -cyclopenta[ d]pyrimidin-4-one

[0331] To a stirred mixture of 3-(chloromethyl)-2-methyl-4(methylsulfanyl)pyridine (200 mg, 1.07 mmol, 1 equiv) in anhydrous DMF (4 mL) at rt was added DIEA (551 mg, 4.26 mmol, 4 equiv). The mixture was stirred at rt for 1 h, then concentrated under reduced pressure and purified by reversed-phase chromatography [5%-30% MeCN / H2O (0.05% NH4HCO3)] to yield the product (184.5 mg, 52%) as a solid. LCMS (ESI) calculated For C15H17N3OS2, 319.44; 320.10 [M+H]+ was obtained; 1H-NMR (400 MHz, DMSO-d6) δ 8.25 (m, 1H), 7.16 (m, 1H), 4.49 (s, 2H), 2.79 - 2.74 (m, 2H), 2.63 - 2.59 (m, 2H), 2.02 - 1.96 (m, 2H). Example 16: Synthesis of Compound 213 Step 1: methyl 4-ethyl-2-(trifluoromethyl)pyridine-3-carboxylate

[0332] A mixture of methyl 4-chloro-2-(trifluoromethyl)pyridine-3-carboxylate (336 mg, 1.4 mmol), bromo(ethyl)zinc (734 mg, 4.2 mmol), Pd(Oac)2 (31.5 mg, 0.14 mmol) and QPHOS (199 mg, 0.28 mmol) in THF (2 mL) under a N2 atmosphere was stirred at rt for 3 h. After the reaction was complete, the mixture was quenched with ice-cold H2O and extracted with EtOAc (100 mL x 3). The Petition 870250110266, dated 01 / 12 / 2025, pages 344 / 473 104 / 214 combined organic layers were washed with brine, dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase chromatography [C18 silica gel; mobile phase, H2O (0.05% NH4HCO3) in MeCN, gradient from 10% to 50% in 20 min] to yield the product (265 mg, 81%) as an oil. LC / MS: Calculated MS (ESI) For C10H10F3NO2: 233.07; Obtained: 234.15 [M+H]+. Step 2: [4-Ethyl-2-(trifluoromethyl)pyridin-3-yl]methanol

[0333] To a stirred solution of methyl 4-ethyl-2-(trifluoromethyl)pyridine-3-carboxylate (265 mg, 1.14 mmol) in THF (4 mL) was added DIBALH (404 mg, 2.84 mmol) at 0 °C. The mixture was heated to rt and stirred for 1 h. After completion, the reaction was suppressed with ice H2O, filtered, and the filter mass was washed with H2O. The filtrate was concentrated under reduced pressure to yield the product (170 mg, 73%) as a solid. Calculated MS (ESI) For C9H10F3NO: 205.07 m / z; 206.00 [M+H]+ was obtained. Step 3: 3-(Chloromethyl)-4-ethyl-2-(trifluoromethyl)

[0334] To a stirred mixture of [4-ethyl-2-(trifluoromethyl)iridine-3yl]methanol (170 mg, 0.83 mmol, 1 equiv) in DCM (3 mL) was added SOCl2 (246 mg, 2.07 mmol, 2.5 equiv) at 0 °C. The mixture was stirred for 1 h, then concentrated under reduced pressure to generate the pyridine product (200 mg, presumed 100%) as a solid. Step 4: 2-({[4-Ethyl-2-(trifluoromethyl)pyridin-3-yl]methyl}sulfanyl)3 H,5 H,6 H,7 H -cyclopenta[d]pyrimidin-4-one

[0335] To a stirred mixture of 3-(chloromethyl)-4-ethyl-2-(trifluoromethyl)pyridine (180 mg, 0.81 mmol) and 2-sulfanyl-3H,5H,6H,7Hcyclopenta[d]pyrimidin-4-one (135 mg, 0.81 mmol) in DMF (3 mL) was added DIEA (312 mg, 2.42 mmol). The mixture was stirred at rt for 1 h, then purified by reversed-phase chromatography [column, silica gel C18; mobile phase, H2O (0.05% TFA) in MeCN, gradient from 10% to 70% in 20 min] to generate the product (104,5 Petition 870250110266, dated 01 / 12 / 2025, pages 345 / 473 105 / 214 mg, 36%) as a solid. LC / MS: MS (ESI) calculated For C16H16F3N3OS: 355.10; Obtained: 356.20 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ 12.67 (s, 1H), 8.59 - 8.60 (m, 1H), 7.64 - 7.66 (m, 1H), 4.58 - 4.60 (m, 2H), 2.79 - 2.84 (m, 4H), 2.61 - 2.64 (m, 2H), 1.95 - 2.02 (m, 2H), 1.21 - 1.25 (m, 3H);19F-NMR (376 MHz, DMSO-d5) δ -61.5. Example 17: Synthesis of Composto 15 OMe HN HS N DIEA, DMF Step 1: 2-{[(2-fluoro-4-methoxypyridin-3-yl)methyl]sulfanyl}-3 H,5 H,6 H,7 H cyclopenta[ d]pyrimidin-4-one

[0336] To a stirred mixture of 3-(chloromethyl)-2-fluoro-4-methoxypyridine [CAS No: 451459-10-2] (250 mg, 1.42 mmol) and 2-sulfanyl3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one (199 mg, 1.19 mmol) in DMF (4 mL) was added DIEA (613 mg, 4.75 mmol) dropwise at rt. The resulting mixture was stirred at rt for 2 h, then purified by reversed-phase chromatography [column, silica gel C18; mobile phase, H2O (0.05% NH4HCO3) in MeCN, gradient from 10% to 50% in 25 min] to yield the product (97 mg, 26%) as a solid. LC / MS: MS (ESI) calculated For C14H14FN3O2S: 307.08; Obtained: 308.05 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ 11.43 (s, 1H), 8.08 - 8.10 (m, 1H), 7.09 - 7.10 (m, 1H), 3.96 4.35 (m, 2H), 3.92 - 3.94 (m, 3H), 2.74 - 2.78 (m, 2H), 2.66 - 2.68 (m, 2H), 1.94 2.00 (m, 2H);19F-NMR (376 MHz, DMSO-d6) δ -73.1, -74.4. Example 18: Synthesis of Compound 180 uc Br OI K+Γ -U / IqZ NICI2-dme,lr[dFCF3ppy]2bpyPF6,dtbbpy,K2HPO4 1,41,4-dioxane / DMA), blue LED blue h DIBAI-H.THF °C - rt, 2 h <N· SOCI2, DCM DIEA, DMF °Cr.t., 2h Petition 870250110266, dated 01 / 12 / 2025, pp. 346 / 473 106 / 214 Step 1: Ethyl 4-(methoxymethyl)-2-methylpyridine-3-carboxylate

[0337] 4,4'-di-tert-butyl-2,2'-bipyridine (16.5 mg, 0.06 mmol) and NiCl2*dme (13.5 mg, 0.06 mmol) were weighed into a long, thin (~20 mL) oven-dried 20 mL glass vial. Approximately 1.5 mL of dry, degassed THF was added and the mixture was briefly heated until a pale green solution was obtained. The solvent was then removed under vacuum to yield a pale green bound nickel complex. Next, ethyl 4-bromo-2-methylpyridine-3-carboxylate (300 mg, 1.23 mmol), potassium trifluoro(methoxymethyl)boranuide (224 mg, 1.48 mmol), Ir[dFCF3ppy]2(bpy)*PF6 (49.6 mg, 0.05 mmol), and K2HPO4 (642 mg, 3.7 mmol) were added sequentially. The tube was then sealed and subsequently purged and evacuated four times. Dioxane / DMA (5:1) (12 mL) was then added under an inert atmosphere.The resulting mixture was stirred for 24 hours approximately 4 cm away from two 26 W fluorescent lamps while a fan was blown through the reaction setup to maintain an ambient temperature of 24 °C. The crude mixture was filtered through a Celite cylindrical buffer and rinsed with DCM and EtOAc (10-20 mL). The resulting solution was concentrated and the residue was purified by column chromatography on silica gel, eluting with EtOAc and hexanes, to yield the product (260 mg, 94%) as an oil. LCMS (ESI) calculated for C11H15NO3, 209.11; 210.10 [M+H]+ was obtained. Step 2: [4-(Methoxymethyl)-2-methylpyridin-3-yl]methanol

[0338] To a mixture of ethyl 4-(methoxymethyl)-2-methylpyridine-3-carboxylate (260 mg, 1.24 mmol) in THF (5 mL) at 0 °C, DIBAL-H, 1.0 M in hexane (3.11 mL, 3.11 mmol) was added dropwise. The resulting mixture was heated to rt and stirred for 2 h, then suppressed with ice-cold H2O (20 mL). The resulting mixture was filtered, and the filter mass was washed with EtOAc / MeOH (1:1). The filtrate was concentrated under reduced pressure to generate the Petition 870250110266, dated 01 / 12 / 2025, pages 347 / 473 107 / 214 crude product (240 mg, assumed 100%) as a solid, which was used directly without any purification. LCMS (ESI) calculated for C9H13NO2, 167.09; 168.25 [M+H]+ was obtained. Step 3: 3-(Chloromethyl)-4-(methoxymethyl)-2-methylpyridine

[0339] To a solution of [4-(methoxymethyl)-2-methylpyridin-3-yl]methanol (240 mg, 1.44 mmol) in DCM (5 mL) was added SOCl2 (0.26 mL, 3.59 mmol) dropwise at 0 °C. The resulting solution was stirred at rt for 2 h, then concentrated to dryness under reduced pressure to yield the crude product (260 mg, 97%) as a solid, which was used directly without any purification. Step 4: 2-({[4-(Methoxymethyl)-2-methylpyridin-3-yl]methyl}sulfanyl)-3H,5H,6H,7Hcyclopenta[d]pyrimidin-4-one

[0340] To a mixture of 3-(chloromethyl)-4-(methoxymethyl)-2-methylpyridine (260 mg, 1.4 mmol) in DMF (5 mL) at room temperature, 2-sulfanyl-3H,5H,6H,7Hcyclopenta[d]pyrimidin-4-one (236 mg, 1.4 mmol) and DIEA (453 mg, 3.5 mmol) were added. The resulting mixture was stirred at room temperature for 2 h, then concentrated, and the crude product was purified by reversed-phase chromatography [Column: Xselect CSH C18 OBD column, 30*150 mm, 5μη; Mobile phase A: H2O (0.05% TFA), Mobile phase B: MeCN; Flow rate: 60 mL / min mL / min; Gradient: 3% B to 22% B in 10 min] to generate the product (85.7 mg, 19%) as a solid. Calculated LCMS (ESI) For C16H19N3O2S: 317.12; 318.10 [M+H]+ was obtained; 1H-NMR (400 MHz, DMSO-ds) δ 12.65 (s,1H), 8.59 - 8.57 (m, 1H), 7.62 (m, 1H), 4.77 (s, 2H), 4.52 (s, 2H), 3.41 (s, 3H), 2.78 - 2.76 (m, 2H), 2.62 - 2.59 (m, 2H), 2.02 - 1.94 (m, 2H); 19F-NMR (376 MHz, DMSO-d6) δ -74.1. Example 19: Synthesis of Compound 182 Petition 870250110266, dated 01 / 12 / 2025, pages 348 / 473 108 / 214 Step 1: Ethyl 2-(methylsulfanyl)-4-(trifluoromethyl)pyridine-3-carboxylate

[0341] A stirred mixture of 2-(methylsulfanyl)-4-(trifluoromethyl)pyridine-3-carboxylic acid (300 mg, 1.3 mmol), EtI (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 with anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reversed-phase flash chromatography [conditions: column, silica gel C18; mobile phase, ACN in H2O (0.1% TFA), gradient from 10% to 80%] to yield the product (250 mg) as an oil. Step 2: [2-(methylsulfanyl)-4-(trifluoromethyl)pyridin-3-yl]methanol

[0342] 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, silica gel C18; mobile phase, ACN in H2O (0.1% TFA), gradient from 10% to 80%] to generate the product (200 mg) as an oil. Step 3: 3-(Chloromethyl)-2-(methylsulfanyl)-4-(trifluoromethyl)pyridine

[0343] A stirred mixture of (2-(methylthio)-4-(trifluoromethyl)iridine-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 directly in the next step without further purification. Step 4: 2-(((2-(methylthio)-4-(trifluoromethyl)pyridin-3-yl)methyl)thio)-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one

[0344] A stirred mixture of 3-(chloromethyl)-2-(methylsulfanyl)-4(trifluoromethyl)pyridine (150 mg, 0.62 mmol), 2-sulfanyl-3 H , 5 H , 6 H , 7 H Petition 870250110266, dated 01 / 12 / 2025, pp. 349 / 473 Cyclopenta[d]pyrimidin-4-one (104 mg, 0.62 mmol) and DIPEA (240 mg, 1.9 mmol) in DMF (2 mL) was stirred at room temperature for 0.5 h, then purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, ACN in H2O (0.1% TFA), gradient from 10% to 80%] to yield the product (80.6 mg) as a solid. LC / MS: m / z MS (ESI) calculated. For C15H14F3N3OS2: 373.05. A value of 373.95 [M+H]+ was obtained. Example 20: Synthesis of Compound 181 Step 1: methyl 2-(difluoromethyl)-4-methoxypyridine-3-carboxylate

[0345] To a stirred mixture of methyl 2-bromo-4-methoxypyridine-3-carboxylate (300 mg, 1.22 mmol) in toluene (5 mL) at rt under a N2 atmosphere was added {2-[2-(diphenylphosphanyl)phenoxy]phenyl}diphenylphosphane (131 mg, 0.24 mmol), Pd(dba)2 (707 mg, 1.2 mmol) and SIPr(Ag)CF2H (660 mg, 1.83 mmol). The resulting mixture was heated to 80 °C and stirred for 8 hours at 80 °C, then cooled and purified by reversed-phase flash chromatography [conditions: column, silica gel C18; Mobile phase, ACN in water (0.1% FA), gradient from 10% to 50% in 10 min] to generate the product (230 mg, 87%) as an oil. LC / MS: MS (ESI) calculated For C9H9F2NO3: 217.06; Obtained: 218.00 [M+H]+. Step 2: [2-(difluoromethyl)-4-methoxypyridin-3-yl]methanol

[0346] Performed similarly to Example 19, Step 2 to generate the product (170 mg). LC / MS: MS (ESI) calculated For C8H9F2NO2: 189.06. Obtained: 190.00 [M+H]+. Step 3: 3-(Chloromethyl)-2-(difluoromethyl)-4-methoxypyridine

[0347] To a stirred mixture of [2-(difluoromethyl)-4-methoxypyridin3-yl]methanol (170 mg, 0.9 mmol) in DCM (3 mL) at 0 °C was added SOCl2 Petition 870250110266, dated 01 / 12 / 2025, pages 350 / 473 110 / 214 (267 mg, 2.25 mmol) dropwise. The mixture was heated to rt and stirred for 2 h, then concentrated under reduced pressure to yield the product (200 mg, 100% assumed) as an oil, which was used in the next step without further purification. LC / MS: MS (ESI) calculated For CsH8ClF2NO: 207.02; Obtained: 208.00 [M+H]+. Step 4: 2-({[2-(Difluoromethyl)-4-methoxypyridin-3-yl]methyl}sulfanyl)3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one

[0348] To a stirred mixture of 3-(chloromethyl)-2-(difluoromethyl)-4-methoxypyridine (200 mg, 0.96 mmol) and 2-sulfanyl-3H,5H,6H,7H cyclopenta[d]pyrimidin-4-one (162 mg, 0.96 mmol) in DMF (3 mL) at rt was added DIPEA (249 mg, 1.92 mmol). After completion of the reaction, the mixture was extracted with EtOAc (3 x 20 mL) and the combined organic layers were washed with brine (3 x 50 mL), dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reversed-phase column chromatography [conditions: column, silica gel C18; Mobile phase, ACN in H2O (10 mmol / L NH4HCO3), gradient from 20% to 40% in 10 min] to generate the product (80.7 mg, 23%) as a solid. LC / MS: MS (ESI) calculated For C15H15F2N3O2S: 339.08; Obtained: 340.00 [M+H]+; 1H-NMR (300 MHz, DMSO-d6) δ 13.40 (br.S, 1H), 8.70 - 8.40 (m, 2H), 7.65 - 7.36 (m, 1H), 7.36 - 7.15 (m, 1H), 4.70 - 4.30 (m, 2H), 4.10 - 3.90 (m, 3H), 2.86 - 2.78 (s, 2H), 2.68 - 2.58 (m, 2H), 2.10 - 1.90 (m, 2H);19F-NMR (282 MHz, DMSO-d6) δ -113.6. Example 21: Synthesis of Compound 211HO^ zk λ NaH.DMF _ DIBAL, THFS0CI21DCM I °C~rt. |í 0eOrt. Γ jT ” IjV^01DIEA, DMF ^Γ3 N CF3^n' CF3^N^CFaN CF3 TFA salt Step 1: methyl 4-cyclopropoxy-2-(trifluoromethyl)pyridine-3-carboxylate

[0349] A stirred mixture of cyclopropanol (182 mg, 3.1 mmol) in DMF (5 mL) at 0 °C was treated with NaH (70 mg, 2.9 mmol), heated to rt and Petition 870250110266, dated 01 / 12 / 2025, pp. 351 / 473 111 / 214 stirred for 0.5 h, then methyl 4-chloro-2-(trifluoromethyl)pyridine-3-carboxylate (500 mg, 2.1 mmol) was added in portions. The mixture was stirred at rt for 1 h, then quenched with H2O and purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, H2O (0.05% NH4HCO3) in ACN, gradient from 10% to 50%] to yield the product (287 mg, 52%) as an oil. LCMS (ESI) m / z calculated For CõH7BrN2O, 261.06; 262.15 [M+H]+ was obtained. Step 2: [4-Cyclopropoxy-2-(trifluoromethyl)pyridin-3-yl]methanol

[0350] To a stirred mixture of methyl 4-cyclopropoxy-2(trifluoromethyl)pyridine-3-carboxylate (230 mg, 0.88 mmol) in THF (3 mL) at 0 °C was added DIBAL-H (313 mg, 2.2 mmol). The mixture was heated to rt and stirred for 1 h, suppressed with ice / H2O (50 mL), filtered, and the filter mass was washed with H2O (5 mL). The filtrate was concentrated under reduced pressure to yield the product (190 mg, 88%) as a solid. LCMS (ESI) m / z calculated For C10H10F3NO2, 233.07; 233.95 [M+H]+ was obtained. Step 3: 3-(Chloromethyl)-4-cyclopropoxy-2-(trifluoromethyl)pyridine

[0351] To a stirred mixture of [4-cyclopropoxy-2(trifluoromethyl)iridine-3-yl]methanol (190 mg, 0.82 mmol) in DCM (3 mL) at 0 °C was added SOCl2 (242 mg, 2.0 mmol). The mixture was heated to rt and stirred for 1 h, then concentrated under reduced pressure to generate the product (220 mg) as a solid. Step 4: 2-({[4-Cyclopropoxy-2-(trifluoromethyl)pyridin-3-yl]methyl}sulfanyl)3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one; trifluoroacetic acid salt

[0352] Performed similarly to Step 4, Example 19 and purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, H2O (0.05% TFA) in ACN, gradient from 10% to 50% in 30 min] to yield the product (84 mg, 20%) as a solid. LC / MS: MS (ESI) m / z calculated For C19H17F6N3O4S: 383.09; Obtained: 384.20 [M+H]+; 1H Petition 870250110266, dated 01 / 12 / 2025, pp. 352 / 473 112 / 214 NMR (400 MHz, DMSO-d6) δ 12.56 (s, 1H), 8.58 - 8.60 (m, 1H), 7.64 - 7.65 (m, 1H), 4.48 - 4.50 (m, 2H), 4.15 - 4.18 (m, 1H), 2.67 - 2.80 (m, 2H), 2.60 - 2.63 (m, 2H), 1.94 - 2.08 (m, 2H), 0.80 - 0.89 (m, 2H), 0.69 - 0.76 (m, 2H);19F-NMR (376 MHz, DMSO-d6) δ -61.7, -73.5. Example 22: Synthesis of Compound 70 O HCI Step 1: 3-(chloromethyl)-2,4-dimethoxypyridine

[0353] A mixture of (2,4-dimethoxypyridin-3-yl)methanol (1.2 g, 7.1 mmol) in DCM (15 mL) at 0 °C was added dropwise to SOCl2 (2.11 g, 17.7 mmol). The mixture was heated to rt and stirred for 30 min, then concentrated under reduced pressure to generate the product (presumed quantitative yield) which was used in the next step without further purification. LC / MS (ESI) m / z calculated for C8H10ClNO2: 187.04; Obtained: 186.15 [M+H]-. Step 2: 2-{[(2,4-dimethoxypyridin-3-yl)methyl]sulfanyl}-3 H,5 H,6 H,7 H cyclopenta[ d]pyrimidin-4-one

[0354] To a mixture of 3-(chloromethyl)-2,4-dimethoxypyridine (200 mg, 1.1 mmol) in DMF (2 mL) at rt were added 2-sulfanyl-3H,5H,6H,7H cyclopenta[d]pyrimidin-4-one (233 mg, 1.4 mmol) and DIEA (551 mg, 4.3 mmol). The mixture was stirred for 40 min, then purified by HPLC under the following conditions (Column: Xselect CSH C18 OBD column, 30*150 mm, 5μm; Mobile phase A: Water (0.1% FA), Mobile phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 19% B to 49% B in 7 min) to yield the product (113 mg, 32%) as a solid. LC / MS mass m / z calculated for C15H17N3O3S, 319.10 m / z; Obtained 320.00 [M+H]+;1H NMR (300 MHz, DMSO-d6) δ 12.30 - 12.50 (s, 1H), 8.04 - 8.10 (s, 1H), 6.70 - 6.83 (s, 1H), 4.30 (s, 2H), 3.72 - 3.95 (s, 6H), 2.70 - 2.80 (m, 2H), 2.51 - 2.62 (m, 2H), 1.89 - 2.00 (m, 2H). Petition 870250110266, dated 01 / 12 / 2025, pp. 353 / 473 113 / 214 Example 23: Synthesis of Compound 173 Step 1: methyl 4-methyl-2-(trifluoromethyl)pyridine-3-carboxylate

[0355] To a stirred mixture of methyl 4-chloro-2-(trifluoromethyl)pyridine-3-carboxylate (2.5 g, 10.4 mmol) and trimethyl-1,3,5,2,4,6-trioxatriborinane (2.62 g, 20.9 mmol) in DMF (30 mL) at rt under a N2 atmosphere, K2CO3 (4.33 g, 31.3 mmol) and Pd(PPh3)4 (1.21 g, 1.04 mmol) was added. The mixture was heated to 120 °C and stirred for 2 h, then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield the product (1.7 g, 74%) as a solid. LCMS (ESI) m / z calculated For C9H8F3NO2, 219.05; 220.00 [M+H]+ was obtained. Step 2: [4-Methyl-2-(trifluoromethyl)pyridin-3-yl]methanol

[0356] To a stirred mixture of methyl 4-methyl-2-(trifluoromethyl)pyridine-3-carboxylate (800 mg, 3.7 mmol) in THF (8 mL) at 0 °C was added DIBAL-H (11.0 mmol). The mixture was heated to rt and stirred for 1 h, then cooled to 0 °C and H2O added. The resulting mixture was filtered and the filter mass was washed with EtOAc (3 x 40 mL). The filtrate was concentrated under reduced pressure to yield the product (680 mg, 97%) as an oil. LCMS (ESI) m / z calculated For C8H8F3NO, 191.06; 192.00 [M+H]+ was obtained. Step 3: 3-(Chloromethyl)-4-methyl-2-(trifluoromethyl)pyridine

[0357] To a stirred mixture of [4-methyl-2-(trifluoromethyl)iridine-3yl]methanol (600 mg, 3.14 mmol) in DCM (8 mL) at 0 °C was added SOCl2 (1120 mg, 9.4 mmol). The mixture was stirred at rt for 2 h, then concentrated under reduced pressure to yield the product (620 mg, 94%) as a solid. LCMS Petition 870250110266, dated 01 / 12 / 2025, pp. 354 / 473 114 / 214 (ESI) m / z calculated for CsH8ClF3N, 209.02, obteve-se 210.10 [M+H]+. Etapa 4: 2-({[4-methyl-2-(trifluoromethyl)pyridine-3-yl]methyl}sulfanyl)-3H,5H,7Hthieno[3,4-d]pyrimidin-4-one

[0358] To a stirred mixture of 3-(chloromethyl)-4-methyl-2-(trifluoromethyl)pyridine (250 mg, 1.19 mmol) and 2-sulfanyl-3H,5H,7H-thieno[3,4d]pyrimidin-4-one [CAS No. 5750-52-7] (222 mg, 1.19 mmol) in DMF (4 mL) at rt, DIPEA (462 mg, 3.6 mmol) was added dropwise. The mixture was stirred at rt for 2 h, then quenched with saturated aqueous NH4Cl and concentrated under reduced pressure. The crude residue was purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, H2O in ACN, gradient from 10% to 70%] to yield the product (196 mg, 43%) as a solid. LCMS (ESI) m / z calculated for C14H12F3N3OS2, 359.04; obtained 360.00 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 13.00 (s, 1H), 8.54 - 8.56 (m, 1H), 7.63 - 7.65 (m, 1H), 4.56 - 4.60 (m, 2H), 4.16 - 4.17 (m, 2H), 3.90 - 3.95 (m, 2H), 2.48 - 2.57 (m, 3H);19F-NMR (376 MHz, DMSO-d6) δ -61.6. Step 1: Methyl 4-methyl-2-(3,3,3-trifluoroprop-1-en-2-yl)pyridine-3-carboxylate

[0359] To a stirred mixture of methyl 2-bromo-4-methylpyridine-3-carboxylate (1.0 g, 4.4 mmol) and 4,4,6-Trimethyl-2-[1-(trifluoromethyl)ethenyl]1,3,2-dioxaborinane [CAS No. 1011460-68-6] in 1,4-dioxane / H2O (5 / 1) under a N2 atmosphere, Pd(dppf)Cl2.DCM (0.53 g, 0.65 mmol) and K2CO3 (1.80 g, 13.0 mmol) were added. The mixture was heated to 100 °C and stirred for 2 h, then Petition 870250110266, dated 01 / 12 / 2025, pages 355 / 473 115 / 214 cooled, aqueous NH4Cl (80 mL) was added and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine, dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, ACN in H2O (0.05% NH4HCO3), gradient from 5% to 70% in 15 min] to yield the product (810 mg, 68%) as a solid. LCMS (ESI) m / z calculated For C12H12F3NO2, 259.08; 260.10 [M+H]+ was obtained. Step 2: Ethyl 4-methyl-2-[1-(trifluoromethyl)cyclopropyl]pyridine-3-carboxylate

[0360] To a stirred mixture of methyl 4-methyl-2-(3,3,3-trifluoroprop-1-en2-yl)pyridine-3-carboxylate (810 mg, 3.3 mmol) and methyldiphenylsulfonium tetrafluoroborate (1142 mg, 4.0 mmol) in THF (10 mL) at -78 °C under a N2 atmosphere, LiHMDS, 1.0 M in THF (9.9 mL, 9.9 mmol) was added. The mixture was stirred at -78 °C for 3 h, then suppressed with aqueous NH4Cl (50 mL) and extracted with EtOAc (80 mL x 3). The combined organic layers were washed with brine, dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, ACN in water (0.05% TFA), gradient from 5% to 70% in 15 min] to yield the product (360 mg, 37%) as an oil. LCMS (ESI) m / z calculated. For C13H14F3NO2, 273.10; 274.00 [M+H]+ was obtained. Step 3: {4-Methyl-2-[1-(trifluoromethyl)cyclopropyl]pyridin-3-yl}methanol

[0361] To a stirred mixture of ethyl 4-methyl-2-[1-(trifluoromethyl)cyclopropyl]pyridine-3-carboxylate (360 mg, 1.3 mmol) in THF (5 mL) at 0 °C, DIBAL, 1.0 M in hexanes (3.9 mL, 3.9 mmol) was added dropwise. The mixture was heated to rt and stirred for 2 h, then smothered with H2O at 0 °C, filtered, and the filter mass was washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure to yield the crude product, which was used Petition 870250110266, dated 01 / 12 / 2025, pp. 356 / 473 116 / 214 directly to the next stage without further purification. Step 4: 5-(chloromethyl)-1-ethyl-4-[1-(trifluoromethyl)cyclopropyl]pyridine

[0362] To a stirred mixture of {4-methyl-2-[1(trifluoromethyl)cyclopropyl]iridine-3-yl}methanol (240 mg, 1.0 mmol) in DCM (4 mL) at 0 °C, thionyl chloride (308 mg, 2.6 mmol) was added dropwise. The mixture was heated to rt and stirred for 2 h, then concentrated under reduced pressure to provide the crude product, which was used directly in the next step without further purification. Step 5: 2-[({3-Ethyl-5-[1-(trifluoromethyl)cyclopropyl]pyridine-4-yl}methyl)sulfanyl]-3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one; trifluoroacetic acid salt

[0363] Performed similarly to Step 4, Example 19 and purified by reverse-phase prep-HPLC [conditions: Column: Xselect CSH C18 OBD column, 30*150 mm, 5μm; Mobile phase A: H2O (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 9% B to 39% B B in 7 min) to generate the product (27.5 mg, 19%) as a solid. LC / MS: calculated mass for C18H18F3N3OS: 381.11; obtained: 382.05[M+H]+;1H NMR (300 MHz, DMSO- d6) δ 8.46 - 8.48 (m, 1H), 7.40 - 7.47 (m, 1H), 4.73 (s, 2H), 2.76 2.91 (m, 2H), 2.59 - 2.64 (m, 2H), 2.42 (s, 3H), 1.93 - 2.03 (m, 2H), 1.42 - 1.58 (m, 2H), 1.21 - 1.35 (m, 2H);19F-NMR (376 MHz, DMSO-d6) δ -67.1, -75.0. Example 25: Synthesis of Compound 192 (AAoJ Pd(OAc);, Xanthos, CssCOs. dioxane LiALH4,THF „ Aw'OHSOCI„ PCM . «A'''01______________ ÚAr » «TC·21' ύΆ '''θ''1ÚA OC-rt DIEA.DMF ύΆ / \ III I HCI Step 1: Ethyl 2-(dimethylamino)-4-methylpyridine-3-carboxylate

[0364] A mixture of ethyl 2-bromo-6-methylbenzoate (1.0 g, 4.1 mmol), dimethylamine hydrochloride (0.50 g, 6.2 mmol), Pd(Oac)2 (0.14 g, 0.62 mmol), xanthos (0.60 g, 1.0 mmol) and Cs2CO3 (4.02 g, 12.3 mmol) in 1,4-dioxane (10 mL) under a N2 atmosphere was stirred at 95 °C overnight. A Petition 870250110266, dated 01 / 12 / 2025, pp. 357 / 473 The 117 / 214 mixture was purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, ACN in water (0.1% TFA), gradient from 10% to 80% in 20 min] to generate the product (550 mg, 61%) as an oil. Step 2: [2-(Dimethylamino)-4-methylpyridin-3-yl]methanol

[0365] A stirred mixture of ethyl 2-(dimethylamino)-4-methylpyridine-3-carboxylate (500 mg, 2.4 mmol) and LiAlH4 (136 mg, 3.6 mmol) in THF (5 mL) was stirred at rt for 30 min. After processing, the product was used directly in the next step without further purification. Step 3: 3-(Chloromethyl)-N,N,4-trimethylpyridin-2-amine

[0366] A stirred mixture of [2-(dimethylamino)-4-methylpyridin-3yl]methanol (270 mg, 1.6 mmol) and SOCl2 (483 mg, 4.1 mmol) in DCM (2 mL) was stirred at rt for 30 min, the concentrate under reduced pressure to generate the product, which was used in the next step without further purification. Step 4: 2-({[2-(Dimethylamino)-4-methylpyridin-3-yl]methyl}sulfanyl)3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one

[0367] Performed similarly to Step 4, Example 19 and purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, ACN in H2O (10 mmol / L NH4HCO3), gradient from 10% to 70% in 20 min] to generate the product (8.3 mg, 3%) as a solid. LC / MS: MS (ESI) calculated For C16H20N4OS: 316.14. Obtained: 317.05 [M+H]+. Example 26: Synthesis of Compound 188 Step 1: Ethyl 6-chloro-4-methyl-2-(trifluoromethyl)pyridine-3-carboxylate

[0368] A stirred mixture of 2-bromo-6-chloro-4-methylpyridine-3 Petition 870250110266, dated 01 / 12 / 2025, pp. 358 / 473 Ethyl carboxylate (300 mg, 1.1 mmol), methyl 2,2-difluoro-2-sulfoacetate (1.03 g, 5.4 mmol) and CuI (102 mg, 0.54 mmol) in MPN (6 mL) under a N2 atmosphere was stirred at rt for 1 h, then diluted with H2O (50 mL) and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography [conditions: column, Cis silica gel; mobile phase, MeOH in water (10 mmol / L NH4HCO3), gradient from 10% to 50% in 10 min] to yield the product (110 mg, 35%) as an oil. LC / MS: m / z mass calculated for C10H9CIF3NO2, 267.03; 268.10 [M+H]+ was obtained. Step 2: Ethyl 4,6-dimethyl-2-(trifluoromethyl)pyridine-3-carboxylate

[0369] To a stirred mixture of ethyl 6-chloro-4-methyl-2-(trifluoromethyl)pyridine-3-carboxylate (110 mg, 0.41 mmol) and trimethyl-1,3,5,2,4,6-trioxatriborinane (206 mg, 1.64 mmol) in DMF (2 mL) at room temperature under a N2 atmosphere, Pd(dppf)Cl2 (30 mg, 0.041 mmol) and K2CO3 (170 mg, 1.2 mmol) were added. The mixture was heated to 95 °C and stirred for 1 h, then diluted with H2O (20 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase column chromatography [conditions: column, silica gel C1s; mobile phase, MeCN in H2O (10 mmol / L NH4HCO3), gradient from 10% to 50% in 10 min] to generate the product (30 mg, 29%) as an oil. LC / MS: m / z mass calculated for C11H12F3NO2, 247.08, yielded 248.00 [M+H]+ Step 3: [4,6-Dimethyl-2-(trifluoromethyl)pyridin-3-yl]methanol

[0370] A stirred mixture of ethyl 4,6-dimethyl-2-(trifluoromethyl)pyridine-3-carboxylate (30 mg, 0.121 mmol, 1 equiv) in THF (1 mL) at 0 °C was treated with DIBAL, 1M toluene (0.18 mL, 0.18 mmol). The mixture was heated to rt and stirred for 1 h, then suppressed by the addition of H2O / ice (50 mL) at 0 °C. Petition 870250110266, dated 01 / 12 / 2025, pp. 359 / 473 119 / 214 and filtered. The filter mass was washed with H2O (3 x 10 mL) and the filtrate was concentrated under reduced pressure to generate the product (20 mg, 80%) as an oil, which was used in the next step without further purification. LC / MS: m / z mass calculated for C9H10F3NO, 205.07; 206.05 [M+H]+ was obtained. Step 4: 3-(Chloromethyl)-4,6-dimethyl-2-(trifluoromethyl)pyridine

[0371] To a stirred mixture of [4,6-dimethyl-2(trifluoromethyl)pyridine-3-yl]methanol (20 mg, 0.097 mmol) in DCM (0.5 mL) at rt, thionyl chloride (23 mg, 0.19 mmol) was added dropwise. The resulting mixture was stirred at rt for 1 h, then concentrated under reduced pressure to yield the product (16 mg, 73%) as an oil, which was used in the next step without further purification. Step 5: 2-(((4,6-dimethyl-2-(trifluoromethyl)pyridin-3-yl)methyl)thio)-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one

[0372] Performed similarly to Step 4, Example 19 and purified by reversed-phase column chromatography [conditions: column, Cis silica gel; mobile phase, MeCN in water (10 mmol / L NH4HCO3), gradient from 25% to 40% in 10 min] to generate the product (1.9 mg, 7%) as a solid. LCMS(ESI) m / z calculated For C16H16F3N3OS, 355.10; 356.05 [M+H] was obtained; 1H NMR (300 MHz, DMSO-d6) δ 7.44 (s, 1H), 4.40 (s, 2H), 2.61 - 2.43 (m, 12H); 19F-NMR (376 MHz, DMSO-d6) δ -61.2. Example 27: Synthesis of Compound 194rt'0.5 hNγΛΓ·ι·Ό.5 h Step 1: Ethyl 2-cyclobutyl-4-methylnicotinate

[0373] 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, Petition 870250110266, dated 01 / 12 / 2025, pages 360 / 473 120 / 214 Cyclobutylzinc(II) iodide (2.5 mL, 1 mmol / mL, 2.5 mmol) was added to 0.12 mmol in THF (3 mL) under a N2 atmosphere. The mixture was heated to 80 °C and stirred for 1 h, then purified by silica gel column chromatography to yield the product (210 mg, 77%) as an oil. LCMS (ESI) m / z calculated for C13H14NO2, 219.13, yielded 220.20. [M+H]+. Step 2: (2-Cyclobutyl-4-methylpyridin-3-yl)methanol

[0374] A stirred mixture of ethyl 2-cyclobutyl-4-methylnicotinate (210 mg, 0.96 mmol) in THF (3 mL) at 0 °C was added to DIBAL-H (3.26 mmol). The mixture was heated to rt and stirred for 1 h, then suppressed by the addition of ice / H2O at 0 °C, and the mixture was filtered. The filter mass was washed with EtOAc (3 x 40 mL) and the filtrate was concentrated under reduced pressure to yield the product (130 mg, 76%) as a solid. LCMS (ESI) m / z calculated For C11H15NO, 177.12, 178.05 [M+H]+ was obtained. Step 3: 3-(chloromethyl)-2-cyclobutyl-4-methylpyridine

[0375] To a stirred mixture of (2-cyclobutyl-4-methylpyridin-3yl)methanol (130 mg, 0.73 mmol) in DCM (3 mL) at 0 °C was added SOCl2 (354 mg, 2.98 mmol). The mixture was heated to rt and stirred for 2 h, then concentrated under reduced pressure to generate the product (120 mg, 84%) as a solid. Step 4: 2-{[(2-cyclobutyl-4-methylpyridin-3-yl)methyl]sulfanyl}-3H,5H,6H,7H cyclopenta[d]pyrimidin-4-one

[0376] Performed similarly to Step 4, Example 19 and purified by reversed-phase column chromatography [conditions: silica gel C18; mobile phase, H2O in ACN, gradient from 10% to 70% in 16 min] to yield the product (102.5 mg, 37%) as a white solid. LCMS (ESI) m / z calculated For C15H20N2O2S3, 327.14, 328.10 [M+H]+ was obtained; 1H NMR (400 MHz, DMSO-d6) δ 8.46 - 8.48 (m, 1H), 7.43 - 7.47 (m, 1H), 4.46 - 4.52 Petition 870250110266, dated 01 / 12 / 2025, pages 361 / 473 121 / 214 Pd(dtbpf)CI2, Cs2CO3, dioxane / H2O 95°c, 0.5 h (m, 2H), 4.10 - 4.12 (m, 1H), 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, 1H); 19F-RMN (376 MHz, DMSO- d 6) δ -74.3. Exemplo 28: Compound summary 193 Pd / C, MeOH <10.5 h DIBAL, THF SOCI2, PCM DIEA, DMF _ rt,0.5 h It,0.5 h ''Ν<γ'\Γ·*·.0.5 h Etapa 1: 2-(cyclopent-1-en-1-yl)-4-ethyl methylnicotinate

[0377] A stirred mixture of ethyl 2-bromo-4-methylnicotinate (500 mg, 2.05 mmol), Pd(dtbpf)Cl2 (150 mg, 0.20 mmol), CS2CO3 (1.6 g, 5.14 mmol), 2-(cyclopent-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (598 mg, 3.08 mmol) in 1,4-dioxane (4 mL) and H2O (1 mL) under a N2 atmosphere was heated to 95 °C and stirred for 0.5 h. H2O was added and, after processing, the mixture was purified by reversed-phase column chromatography on silica gel [ACN eluent and H2O (0.05% TFA)] to yield the product (450 mg, 94%) as a solid. LCMS (ESI) m / z calculated For C14H17NO2, 231.3; 232.13 [M+H]+ was obtained. Step 2: Ethyl 2-cyclopentyl-4-methylnicotinate

[0378] A stirred mixture of ethyl 2-(cyclopent-1-en-1-yl)-4-methylnicotinate (450 mg, 1.94 mmol) in MeOH (4 mL) was added to 10% Pd / C (759 mg, 0.38 mmol). The resulting mixture was stirred at rt for 0.5 h under an H2 atmosphere, then filtered, and the filter mass was washed with MeOH (3 x 3 mL). The filtrate was concentrated under reduced pressure to yield the product (400 mg, 88%) as an oil. The crude product was used in the next step without further purification. LCMS (ESI) m / z calculated For C14H19NO2, 233.14; Petition 870250110266, dated 01 / 12 / 2025, pp. 362 / 473 122 / 214 yielded 234.14 [M+H]+. Step 3: (2-Cyclopentyl-4-methylpyridin-3-yl)methanol

[0379] To a stirred mixture of ethyl 2-cyclopentyl-4-methylnicotinate (400 mg, 1.71 mmol) in THF (4 mL) at 0 °C was added DIBAL, 1.0 M (5.15 mL, 5.15 mmol). The resulting solution was heated to rt and stirred for 0.5 h, then H2O was added and the mixture was filtered, and the filter mass was washed with ACN (3 x 3 mL). The filtrate was concentrated under reduced pressure to provide the crude product (350 mg, 88%) as an oil, which was used in the next step without further purification. LCMS (ESI) m / z calculated For C12H17NO, 191.13; 192.13 [M+H]+ was obtained. Step 4: 3-(chloromethyl)-2-cyclopentyl-4-methylpyridine

[0380] To a stirred mixture of (2-cyclopentyl-4-methylpyridin-3yl)methanol (350 mg, 1.83 mmol) in DCM (4 mL) at 0 °C was added SOCl2 (545 mg, 4.58 mmol). The mixture was heated to rt and stirred for 0.5 h, then concentrated under reduced pressure to yield the product (300 mg, 78%) as an oil. The crude product was used in the next step without further purification. LCMS (ESI) m / z calculated For Ci2Hi6CIN, 209.10; obtained, 210.09 [M+H]+. Step 5: 2-(((2-cyclopentyl-4-methylpyridin-3-yl)methyl)thio)-3,5,6,7-tetrahydro4H-cyclopenta[dJpyrimidin-4-one

[0381] Performed similarly to Step 4, Example 20 and purified by reversed-phase column chromatography [ACN and H2O (0.05% TFA)] to generate the product (269.6 mg, 55%) as a solid. LCMS (ESI) m / z calculated For C19H23N3OS, 341.16, obtained 342.10 [M+H]+;1H NMR (400 MHz, DMSO- d 6) δ 12.68 (br. S, 1H), 8.32 - 8.61 (m, 1H), 7.34 - 7.61 (m, 1H), 4.55 - 4.68 (m, 2H), 3.42 - 3.81 (m, 1H), 2.80 - 2.96 (m, 2H), 2.58 - 2.68 (m, 2H), 2.56 (s, 3H), 1.92 - 2.13 (m, 4H), 1.74 - 1.88 (m, 4H), 1.53 - 1.73 (m, 2H);19F-NMR (376 MHz, DMSO-d 6) δ -74.4. Petition 870250110266, dated 01 / 12 / 2025, pages 363 / 473 123 / 214 Example 29: Synthesis of Compound 195 AN ^^^,0^,5h?V __LAH.THF . °™? DIEA.DMF, SA ÇA *0.5 h ÇA *0.5 hΓ·ιΌ,5 h 'Άf-2=o FF 2-(((4-cyclobutyl-2-methylpyridin-3-yl)methyl)thio)-3,5,6,7-tetrahydro-4Hcyclopenta[d]pyrimidin-4-one

[0382] Prepared similarly to Example 27 to generate the product (112.1 mg, 60%) as a solid. LCMS (ESI) m / z calculated For C18H21N3OS, 327.14; obtained 328.05 [M+H]+;1H NMR (400 MHz, DMSOd6) δ 12.63 (br. S, 1H), 8.46 - 8.71 (m, 1H), 7.62 - 7.81 (m, 1H), 4.45 - 4.63 (m, 2H), 3.88 - 4.11 (m, 1H), 2.78 - 2.91 (m, 2H), 2.73 (s, 3H), 2.56 - 2.65 (m, 2H), 2.32 - 2.44 (m, 2H), 2.11 - 2.29 (m, 2H), 1.91 - 2.10 (m, 3H), 1.71 - 1.89 (m, 1H);19F-NMR (376 MHz, DMSO-d6) δ -74.0. Example 30: Synthesis of Compound 177 Step 1: Tert-Butyl 2-({[4-methyl-2-(trifluoromethyl)iridin-3yl]methyl}sulfanyl)-4-oxo-3H,5H,7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate TFA salt

[0383] Performed similarly to Step 4, Example 20 and purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, ACN in H2O (10 mmol / L NH4HCO3), gradient from 10% to 50% in 10 min] to generate the product (200 mg, 35%) as a solid. Step 2: 2-({[4-Methyl-2-(trifluoromethyl)iridin-3-yl]methyl}sulfanyl)3H,5H,6H,7H-pyrrolo[3,4-d]pyrimidin-4-one

[0384] A stirred mixture of tert-butyl 2-({[4-methyl-2(trifluoromethyl)iridine-3-yl]methyl}sulfanyl)-4-oxo-3H,5H,7H-pyrrolo[3,4-d]pyrimidine-6-carboxylate (200 mg, 0.45 mmol) in DCM (10 mL) at 0 °C was added dropwise to TFA (3 mL). The mixture was heated to rt and stirred for 1 h, then purified. Petition 870250110266, dated 01 / 12 / 2025, pp. 364 / 473 124 / 214 by reversed-phase column chromatography [conditions: Column: Xselect CSH Fluoro Pheny, 19*250 mm, 5μm; Mobile phase A: Water (0.05% TFA), Mobile phase B: ACN; Flow rate: 25 mL / min mL / min; Gradient: 5% B to 30% B in 7 min] to generate the product (82.3 mg, 52%) as a solid. LC / MS: MS (ESI) calculated C19H21F3N4O3S, 442.13, obtained 443.00 [M+H]+;1H NMR (300 MHz, DMSO-d6) δ 10.10 (br. S, 1H), 8.70 - 8.50 (m, 1H), 7.80 - 7.60 (s, 1H), 4.80 - 4.60 (s, 2H), 4.50 - 4.30 (m,4H), 2.51 - 2.49 (m, 3H);19F-NMR (282 MHz, DMSO-d6) δ -61.6, -73.7. Example 31: Synthesis of Compound 12 Step 1: 2-{[(2-chloro-4-methoxypyridin-3-yl)methyl]sulfanyl}-3H,5H,6H,7H cyclopenta[d]pyrimidin-4-one

[0385] A mixture of 2-chloro-3-(chloromethyl)-4-methoxypyridine (320 mg, 1.84 mmol) and 2-sulfanyl-3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one (372 mg, 2.21 mmol) in DMF (3 mL) at 0 °C was added dropwise to DIEA (952 mg, 7.37 mmol). The mixture was heated to rt and stirred for 2 h, then purified by reversed-phase column chromatography to yield the product (269.8 mg, 45%) as a solid. LC / MS: MS (ESI) calculated For C14H14ClN3O2S: 323.05; Obtained: 324.10 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 11.60 - 12.80 (s, 1H), 8.15 - 8.40 (m, 1H), 7.05 - 7.25 (m, 1H), 4.35 - 4.60 (m, 2H), 3.77 - 4.08 (m, 3H), 2.70 - 2.98 (m, 2H), 2.55 - 2.65 (m, 2H),1.80 - 2.15 (m, 2H). Example 32: Synthesis of Compound 183 Petition 870250110266, dated 01 / 12 / 2025, pages 365 / 473 125 / 214 Step 1: 2-({[2-(ethylsulfanyl)-4-methylpyridin-3-yl]methyl}sulfanyl)-3H,5H,6H,7H cyclopenta[d]pyrimidin-4-one

[0386] To a stirred mixture of 3-(chloromethyl)-2-(ethylsulfanyl)-4-methylpyridine (150 mg, 0.74 mmol) and 2-sulfanyl-3H,5H,6H,7Hcyclopenta[d]pyrimidin-4-one (187 mg, 1.12 mmol) in DMF (3 mL) at rt was added DIEA (288 mg, 2.23 mmol). The mixture was stirred for 1 h, then purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, H2O (0.05% TFA) in ACN, gradient from 10% to 70% in 20 min] to yield the product (47.1 mg, 18%) as a solid. LC / MS: MS (ESI) calculated For C16H19N3OS2: 333.10; Obtained: 334.05 [M+H]+; 1HRMN (400 MHz, DMSO-d6) δ 12.52 (s, 1H), 8.25 (m, 1H), 7.05 (m, 1H), 4.45 (m, 2H), 3.15 (m, 2H), 2.78 (m, 2H), 2.63 (m, 2H), 2.37 (s, 3H), 1.97 (m, 2H), 1.25 (m, 3H);19FRMN (376 MHz, DMSO-d6) δ -74.7. Example 33: Synthesis of Compound 205 PMBSH, t-BuBrettPhos Pd G3, t-BuBrettphos, Cs2CO3, dioxane; SOCI2, DCM rt, 2 heC, 2h DIBAL-H, THF rt, 2 h TFA / MSA(3 / 1) 40°C, 0.5 h Step 1: Ethyl 2-{[(4-methoxyphenyl)methyl]sulfanyl}-4-methylpyridine-3-carboxylate

[0387] A mixture of ethyl 2-bromo-4-methylpyridine-3-carboxylate (2.0 g, 8.2 mmol), (4-methoxyphenyl)methanethiol (6.32 g, 41.0 mmol), tBuBrettPhos Pd G3 (1.05 g, 1.2 mmol), t-BuBrettphos (0.79 g, 1.6 mmol), Cs2CO3 (5.34 g, 16.4 mmol) in 1,4-dioxane (20 mL) under a N2 atmosphere was heated to 90 °C and stirred for 2 h. The mixture was purified by reversed-phase column chromatography [conditions: column, silica gel C18; Mobile phase, ACN in H2O (10 mmol / L of NH4HCO3), gradient from 10% to 70% in 20 min] to generate the product (1.8 g) as an oil. Petition 870250110266, dated 01 / 12 / 2025, pp. 366 / 473 126 / 214 Step 2: Ethyl 4-methyl-2-sulfanypyridine-3-carboxylate

[0388] A mixture of ethyl 2-{[(4-methoxyphenyl)methyl]sulfanyl}-4-methylpyridine-3-carboxylate (1.8 g, 5.7 mmol) in MeSOaH (5 mL) and TFA (15 mL) was stirred at 40 °C for 30 min. The mixture was diluted with H2O, neutralized to pH 7 with saturated NaHCO3, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, ACN in H2O (10 mmol / L NH4HCO3), gradient from 10% to 70% in 20 min] to yield the product as a solid. Step 3: 2-(cyclopropylsulfanyl)-4-methylpyridine-3-carboxylate methyl

[0389] A mixture of ethyl 4-methyl-2-sulfanylpyridine-3-carboxylate (250 mg, 1.27 mmol) and bromocyclopropane (306 mg, 2.5 mmol), Cs2CO3 (1.03 g, 3.2 mmol2) in DMSO was stirred at 150 °C for 2 h. The mixture was purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, ACN in H2O (0.1% TFA), gradient from 10% to 80% in 20 min] to yield the product (40 mg, 13%) as a solid. Step 4: [2-(Cyclopropylsulfanyl)-4-methylpyridin-3-yl]methanol

[0390] To a mixture of 2-(cyclopropylsulfanyl)-4-methylpyridine-3-carboxylate (40 mg, 0.18 mmol) in THF at rt was added DIBAL-H (0.54 mmol). The mixture was stirred at rt for 30 min, then purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, ACN in H2O (0.1% TFA), gradient from 10% to 80% in 20 min] to generate the product (32 mg, 85%) as a solid. Step 5: 3-(chloromethyl)-2-(cyclopropylthio)-4-methylpyridine

[0391] A mixture of [2-(cyclopropylsulfanyl)-4-methylpyridin-3yl]methanol (32 mg, 0.16 mmol) and SOCl2 (48 mg, 0.41 mmol) in DCM was stirred at rt for 2 h, then concentrated under vacuum and the product used directly in the next step. Petition 870250110266, dated 01 / 12 / 2025, pages 367 / 473 127 / 214 Step 6: 2-({[2-(Cyclopropylsulfanyl)-4-methylpyridin-3-yl]methyl}sulfanyl) H,5 H,6 H,7 H -cyclopenta[d]pyrimidin-4-one

[0392] A mixture of 3-(chloromethyl)-2-(cyclopropylsulfanyl)-4-methylpyridine (35 mg, 0.16 mmol) and 2-sulfanyl-3H,5H,6H,7H-cyclopenta[d]pyrimidin4-one (41 mg, 0.25 mmol), DIEA (63 mg, 0.49 mmol) in DMF (2 mL) was stirred at rt for 2 h. The mixture was purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, ACN in H2O (0.05% TFA), gradient from 10% to 80% in 20 min] to yield the product (17.6 mg, 30%) as a solid. LC / MS: MS (ESI) calculated For C17H19N3OS2: 345.10; Obtained: 346.05 [M+H]+; 1HRMN (300 MHz, DMSO-d6) δ 8.30 (m, 1H), 7.04 (m, 1H), 4.40 (m, 2H), 2.78 (m, 2H), 2.61 (m, 2H), 2.45 (m, 1H), 2.37 (s, 3H), 1.99 (m, 2H), 1.08 (m, 2H), 0.60 (m, 2H);19FRMN (282 MHz, DMSO-d6) δ -74.9. Example 34: Synthesis of Compound 203HX? U.. IHl? ιΓλ _ (i)3A,NHc-i,Pyridine JL_ / I II (2) lr(ppy)2(dtbbpy)PFe,NiBr2(dtbbpy), j 9 I I l| 1 rpV'O'''·' quinuclidina DMA.t-BuOMe , lí]'0'*'' PIBAL-H.THF _ SOCI2, DCM rj-Av^ci X^Br 420 W LED azul .r.t., 12h O’C-rt. 0,5 h ^ΝΧη 0eC~rt.0,5 h X^X^ DIEA, DMF, rt, 0 5 h ^Sk--. Vs ksVs Etapa 1: 4-metil-2-(piridina-3-il)nicotinato de etila

[0393] É feita referência a Dong, Z., MacMillan, D.W.C. Metallaphotoredox-enabled deoxygenative arylation of alcohols. Nature 2021, 598, 451-456.

[0394] To a mixture of pyridine-3-ol (516 mg, 5.73 mmol) in tBuOMe (57 mL) under an N2 atmosphere was added pyridine (414 mg, 5.24 mmol), NHC (2.07 g, 5.2 mmol). The resulting mixture was stirred at 0 °C for 0.5 h, then added to a solution of ethyl 2-bromo-4-methylnicotinate (800 mg, 3.27 mmol) in DMA (57 mL) under an N2 atmosphere was added Tr(ppy)2(dtbbpy) PF6 (899 mg, 0.98 mmol), NiBr2(dtbbpy) (481 mg, 0.98 mmol), quinuclidine (364 mg, 3.27 mmol). The resulting mixture was stirred at rt for 12 h irradiated with a 420 W blue LED. The mixture was filtered through a buffer. Petition 870250110266, dated 01 / 12 / 2025, pages 368 / 473 128 / 214 cylindrical Celite and rinsed with EtOAc (100 mL), the filtrate was concentrated under reduced pressure and the residue was purified by reversed-phase column chromatography to yield the product (320 mg, 41%) as an oil. LCMS (ESI) m / z calculated For C12H15NO2S, 237.08; 238.00 [M+H]+ was obtained. Step 2: (4-Methyl-2-(pyridin-3-yl)pyridin-3-yl)methanol

[0395] To a mixture of ethyl 4-methyl-2-(pyridine-3-yl)nicotinate (320 mg, 1.35 mmol) in THF (1 mL) at 0 °C was added DIBAL-H, 1M (4.05 mL, 4.05 mmol). The resulting solution was heated to rt and stirred for 0.5 h, then filtered, and the filter mass was washed with ACN (3 x 3 mL). The filtrate was concentrated under reduced pressure to yield the product (150 mg, 56%) as an oil. The crude product was used in the next step without further purification. LCMS (ESI) m / z calculated For C10H13NOS, 195.07; 196.07 [M+H]+ was obtained. Step 3: 3-(Chloromethyl)-4-methyl-2-(pyridin-3-yl)pyridine

[0396] To a mixture of (4-methyl-2-(pyridine-3-yl)pyridine-3yl)methanol (150 mg, 0.76 mmol) in DCM (2 mL) at 0 °C was added SOCl2 (228.8 mg, 1.92 mmol). The mixture was heated to rt and stirred for 0.5 h, then concentrated under reduced pressure to yield the product (110 mg, 67%) as an oil. The crude product was used in the next step without further purification. LCMS (ESI) m / z calculated For C10H12CINS, 213.04; 214.04 [M+H]+ was obtained. Step 4: 2-(((4-Methyl-2-(pyridin-3-yl)pyridin-3-yl)methyl)thio)-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one

[0397] To a mixture of 3-(chloromethyl)-4-methyl-2-(pyridine-3yl)pyridine (110 mg, 0.51 mmol) in DMF (4 mL) at rt was added 2-mercapto-3,5,6,7-tetrahydro-4H-cyclopenta[o]pyrimidin-4-one (173 mg, 1.03 mmol), DIEA (201 mg, 1.54 mmol). The mixture was stirred at rt for 0.5 h, then purified by reversed-phase column chromatography [conditions: ACN and H2O (0.05% TFA)] to yield the product (42 mg, 23%) as a solid. LCMS (ESI) m / z calculated For C17H19N3OS2, 345.10, 346.10 [M+H]+;1H NMR (400 Petition 870250110266, dated 01 / 12 / 2025, pages 369 / 473 129 / 214 MHz, DMSO-d6) δ 12.61 (br. S, 1H), 8.24 - 8.34 (m, 1H), 6.91 - 7.11 (m, 1H), 5.82 - 6.06 (m, 2H), 5.22 - 5.38 (m, 1H), 4.95 - 5.12 (m, 1H), 4.36 - 4.58 (m, 2H), 3.81 - 4.01 (m, 2H), 2.76 - 2.92 (m, 2H), 2.56 - 2.75 (m, 2H), 2.48 (s, 3H), 1.81 - 2.11 (m, 2H);19FRMN (376 MHz, DMSO- d6) δ -73.5. Example 35: Synthesis of Compound 94 Step 1: 2-({[4-methyl-2-(methylsulfanyl)pyridin-3-yl]methyl}sulfanyl)3 H,5 H,6 H,7 H -cyclopenta[ d]pyrimidin-4-one

[0398] A mixture of 3-(chloromethyl)-4-methyl-2(methylsulfanyl)pyridine [CAS No. 198401-80-8] (130 mg, 0.69 mmol), 2-sulfanyl3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one (174 mg, 1.04 mmol) and DIEA (268 mg, 2.08 mmol) in DMF (1 mL) was stirred at rt for 0.5 h, then purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, ACN in H2O (0.1% TFA), gradient from 10% to 80% in 30 min] to yield the product (101.2 mg) as a solid. LC / MS: MS (ESI) calculated For C15H14F3N3OS: 341.08; Obtained: 342.15 [M+H]+;1H NMR (400 MHz, DMSOd6) δ 12.70 (br. S, 1H), 8.67 (m, 1H), 7.62 (m, 1H), 4.76 (m, 2H), 2.80 (m, 2H), 2.60 - 2.66 (m, 5H), 2.00 (m, 2H);19FRMN (376 MHz, DMSO-d6) δ -60.1, -74.6. Example 36: Synthesis of Compound 78 Petition 870250110266, dated 01 / 12 / 2025, pages 370 / 473 130 / 214 Step 1: methyl 4-methyl-2-(trifluoromethoxy)pyridine-3-carboxylate

[0399] To a mixture of methyl 2-hydroxy-4-methylpyridine-3-carboxylate (1.7 g, 10.2 mmol) in nitromethane (20 mL) at rt, 1(trifluoromethyl)-1-lambda-3,2-benziodaoxol-3-one (3.21 g, 10.2 mmol) was added in portions. The mixture was heated to 100 °C and stirred for 16 h, then cooled to rt, filtered, and the filter mass was washed with EtOAc (2 x 10 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EtOAc / petroleum ether eluent; 1:1) to yield the product (400 mg, 16%) as a solid. LCMS (ESI) m / z calculated for C9H8F3NO3, 235.05; 236.00 [M+H]+ was obtained. Step 2: [4-methyl-2-(trifluoromethoxy)pyridin-3-yl]methanol

[0400] To a mixture of methyl 4-methyl-2-(trifluoromethoxy)pyridine-3-carboxylate (400 mg, 1.7 mmol) in THF (10 mL) at 0 °C under a N2 atmosphere, LAH (129 mg, 3.4 mmol) was added in portions. The resulting mixture was stirred for 10 min at 0 °C, then quenched with MeOH and concentrated under vacuum. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether eluent; 1:1) to yield the product (180 mg, 51%) as a solid. LCMS (ESI) m / z calculated for C8H8F3NO2, 207.05; 208.05 [M+H]+ was obtained. Step 3: 3-(Chloromethyl)-4-methyl-2-(trifluoromethoxy)pyridine

[0401] To a mixture of [4-methyl-2-(trifluoromethoxy)pyridine-3yl]methanol (180 mg, 0.87 mmol) in DCM (5 mL) at rt, SOCl2 (516 mg, 4.4 mmol) was added dropwise. The resulting mixture was stirred at rt for 2 h, then concentrated under vacuum to yield the product (100 mg, 51%) as a solid. Step 4: 2-({[4-Methyl-2-(trifluoromethoxy)pyridin-3-yl]methyl}sulfanyl)3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one; trifluoroacetic acid salt

[0402] A mixture of 3-(chloromethyl)-4-methyl-2(trifluoromethoxy)pyridine (100 mg, 0.44 mmol) and 2-sulfanyl-3H,5H,6H,7H Petition 870250110266, dated 01 / 12 / 2025, pages 371 / 473 131 / 214 cyclopenta[d]pyrimidin-4-one (89 mg, 0.53 mmol) in DMSO (2 mL) in rt DIEA (343 mg, 2.66 mmol) was added dropwise. The mixture was stirred at rt for 2 h, then purified by Prep-HPLC [conditions: Column: Xselect CSH C18 OBD column, 30*150 mm, 5μm; Mobile phase A: H2O (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min mL / min] to yield the product (39.5 mg, 18%) as a solid. LCMS (ESI) m / z calculated For C17H15F6N3O4S, 357.08; obtained 358.00 [M+H]+;1H NMR (300 MHz, DMSO-d6) δ 12.61 (br. S, 1H), 8.14 (d, J = 5.1 Hz, 1H), 7.30 (d, J = 5.1 Hz, 1H), 4.47 (s, 2H), 2.77 (t, J = 7.8 Hz, 2H), 2.59 (t, J = 6.6 Hz, 2H), 2.48 (s, 3H), 1.92 - 2.02 (m, 2H);19FRMN (282 MHz, DMSO-d6) δ -54.4, -73.4. Example 37: Synthesis of Compound 187 III Io OH O __ •''''Ό Ο o'^' ΗΝ'ΤΓ^Χ II IPr, K2CO3, DMF T ]í DIBAL-H, THF T _ SOCb, DCM I DIEA, DMF I f |l / ΓΧ ° 80 °C, 2 h Q0 / ” (1 °Hr.t.,2hN Step 1: methyl 4-isopropoxy-2-methylpyridine-3-carboxylate

[0403] A mixture of methyl 4-hydroxy-2-methylpyridine-3-carboxylate (1.0 g, 6.0 mmol), 2-iodopropane (1.02 g, 6.0 mmol) and K2CO3 (1.65 g, 12.0 mmol) in DMF (20 mL) was heated to 80 °C and stirred for 2 h. The mixture was neutralized to pH 7 with saturated NH4Cl and extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1 x 30 mL), dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reversed-phase column chromatography [conditions: column, silica gel C18; Mobile phase, MeCN in H2O (10 mmol / L NH4HCO3), gradient from 10% to 50% in 10 min] to generate the product (175 mg) as a solid. LCMS (ESI) m / z calculated for C11H15NO3, 209.11; 210.15 [M+H]+ was obtained. Step 2: (4-Isopropoxy-2-methylpyridin-3-yl)methanol

[0404] DIBAL-H was added to a mixture of methyl 4-isopropoxy-2-methylpyridine-3-carboxylate (175 mg, 0.84 mmol) in THF (7 mL) at 0 °C. Petition 870250110266, dated 01 / 12 / 2025, pages 372 / 473 132 / 214 (2.51 mmol) dropwise. The mixture was suppressed by the addition of H2O (50 mL) at 0 °C, then filtered and the filter mass was washed with MeOH (3 x 20 mL). The filtrate was concentrated under reduced pressure to yield the product (130 mg), which was used in the next step without further purification. LC / MS: MS (ESI) calculated For C10H15NO2: 181.11; Obtained: 182.15 [M+H]+. Step 3

[0405] To a mixture of (4-isopropoxy-2-methylpyridin-3-yl)methanol (130 mg, 0.72 mmol) in DCM (4.3 mL) at rt was added SOCl2 (213 mg, 1.79 mmol). The mixture was stirred at rt for 0.5 h, then concentrated under reduced pressure to yield the product (160 mg) which was used directly in the next step. Step 4: 2-{[(4-Isopropoxy-2-methylpyridin-3-yl)methyl]sulfanyl}-3H,5H,6H,7H cyclopenta[d]pyrimidin-4-one

[0406] A mixture of 3-(chloromethyl)-4-isopropoxy-2-methylpyridine (160 mg, 0.8 mmol), 2-sulfanyl-3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one (175 mg, 1.04 mmol) and DIEA (414 mg, 3.2 mmol) in DMF (2 mL) was stirred at rt for 1 h, then purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, MeCN in H2O (10 mmol / L NH4HCO3), gradient from 10% to 50% in 10 min] to yield the product (101.5 mg, 37%) as a solid. LC / MS: calculated mass for C17H21N3O2S: 331.14; obtained 332.15 [M+H]+;1H NMR (300 MHz, DMSO-d6) δ 12.40 (br. S, 1H), 8.20 (s, 1H), 6.95 (s, 1H), 4.69 - 4.85 (m,1H), 4.35 - 4.45 (s, 2H), 2.78 - 2.88 (m, 2H), 2.58 2.78 (m, 2H), 2.40 - 2.58 (m, 3H), 1.85 - 2.05 (m, 2H), 1.20-1.35 (m, 6H). Example 38: Synthesis of Compound 34 THE Step 1: 3-(chloromethyl)-4-methylpyridin-2-amine

[0407] To a stirred mixture of (2-amino-4-methylpyridin-3 Petition 870250110266, dated 01 / 12 / 2025, pages 373 / 473 133 / 214 yl)methanol [CAS No 179554-99-5] (170 mg, 1.23 mmol) in DCM (2 mL) at 0 °C was added dropwise to SOCl2 (365 mg, 3.1 mmol). The mixture was heated to rt and stirred for 2 h, then concentrated under reduced pressure to yield the product (120 mg) which was used in the next step without further purification. LC / MS: calculated mass for C7HgClN2: 156.05; obtained: 157.00 [M+H]+. Step 2: 2-{[(2-amino-4-methylpyridin-3-yl)methyl]sulfanyl}-3 H,5 H,6 H,7 H cyclopenta[ d]pyrimidin-4-one

[0408] A stirred mixture of 3-(chloromethyl)-4-methylpyridin-2-amine (120 mg, 0.77 mmol) and 2-sulfanyl-3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one (154 mg, 0.92 mmol) in DMF (5 mL) at rt was column chromatography [conditions: column, silica gel C18; mobile phase, ACN in water (0.05% NH4HCO3), gradient from 5% to 50% in 15 min, then conditions: column, silica gel C18; mobile phase, ACN in H2O (0.05% FA), gradient from 0% to 50% in 20 min] to generate the product (54.9 mg, 24%) as a solid. LC / MS: calculated mass for C14H16N4OS: 288.10; obtained: 289.10 [M+H]+;1H NMR (300 MHz, DMSO- d6) δ 8.27 (s, 1H), 7.73 (m, 1H), 6.45 (m, 1H), 4.35 (s, 2H), 2.70 2.83 (m, 2H), 2.58 - 2.68 (m, 2H), 2.25 (s, 3H), 1.90 - 2.10 (m, 2H). Example 39: Synthesis of Compound 42 THE Step 1: (2-Amino-4-methoxypyridin-3-yl)methanol

[0409] To a stirred mixture of methyl 2-amino-4-methoxypyridine-3-carboxylate [CAS No. 2065249-96-7] (500 mg, 2.75 mmol) in THF (10 mL) at 0 °C, DIBAL-H (8.24 mmol) was added dropwise. The mixture was heated to rt and stirred for 1 h, then suppressed by the addition of H2O / ice. The resulting mixture was filtered and the filter mass was washed with MeOH (2 x 20 mL). The filtrate was concentrated under reduced pressure to yield the product (340 mg, 80%) as a solid. LC / MS: calculated mass for C7H10N2O2: 154.07; Petition 870250110266, dated 01 / 12 / 2025, pages 374 / 473 134 / 214 yielded: 155.05 [M+H]+. Step 2: 3-(Chloromethyl)-4-methoxypyridin-2-amine

[0410] To a mixture of (2-amino-4-methoxypyridin-3-yl)methanol (300 mg, 1.95 mmol) in DCM (5 mL) at 0 °C, SOCl2 (694 mg, 5.8 mmol) was added dropwise. The mixture was heated to rt and stirred for 1 h, then concentrated under reduced pressure to yield the product (260 mg, 77%). The crude product was used in the next step without further purification. Step 3: 2-{[(2-amino-4-methoxypyridin-3-yl)methyl]sulfanyl}-3H,5H,6H,7H cyclopenta[d]pyrimidin-4-one

[0411] To a stirred mixture of 3-(chloromethyl)-4-methoxypyridin-2-amine (260 mg, 1.5 mmol) and 2-sulfanyl-3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one (329 mg, 1.96 mmol) in DMF (3 mL) at 0 °C, DIEA (778 mg, 6.0 mmol) was added dropwise. The mixture was heated to rt and stirred for 2 h, then purified by Prep-HPLC [conditions (Column: Xbridge Prep OBD C18 column, 30*150 mm, 5μm; Mobile phase A: H2O (10 mmol / L NH4HCO3 + 0.05% NH3H2O), Mobile phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 3% B to 20% B in 7 min] to yield the product (54.7 mg, 11%) as a solid. LC / MS: calculated mass for C14H16N4O2S: 304.10; obtained: 305.05 [M+H]+; 1H NMR (300 MHz, DMSO- d6) δ 8.05 - 8.28 (m, 1H), 7.70 - 7.95 (m, 1H), 6.30 - 6.40 (m, 1H), 5.85 - 6.29 (m, 2H), 4.20 - 4.35 (m, 2H), 3.80 - 3.85 (m, 3H), 2.75 - 2.85 (m, 2H), 2.55 - 2.68 (m, 2H),1.80 - 2.12 (m, 2H). Example 40: Synthesis of Compound 089 Step 1: Ethyl 2-cyclopropyl-4-methylnicotinate

[0412] To a mixture of ethyl 2-bromo-4-methylnicotinate (2.0 g, 8.2 mmol) in toluene / H2O (5 / 1) under a N2 atmosphere was added cyclopropylboronic acid (1.06 g, 12.3 mmol), tricyclohexylphosphane (0.69 g, 2.5 mmol), Petition 870250110266, dated 01 / 12 / 2025, pages 375 / 473 135 / 214 K3PO4 (5.22 g, 24.6 mmol) and Pd(Oac)2 (0.28 g, 1.2 mmol). The mixture was heated to 100 °C and stirred for 2 h, then extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with NH4HCO3 (100 mL), dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, ACN in H2O (0.05% TFA), gradient from 5% to 40% in 10 min] to yield the product (600 mg, 35%) as an oil. Step 2: (2-Cyclopropyl-4-methylpyridin-3-yl)methanol

[0413] To a stirred mixture of ethyl 2-cyclopropyl-4-methylnicotinate (600 mg, 2.9 mmol) in THF (5 mL) at 0 °C, DIBAl-H (8.8 mmol) was added dropwise. The mixture was heated to rt and stirred for 2 h, then cooled to 0 °C and suppressed with H2O, filtered, and the filter mass was washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure to yield the product (240 mg), which was used in the next step without further purification. LC / MS: calculated mass for C10H13NO: 163.10; obtained: 164.15 [M+H]+ Step 3: 3-(chloromethyl)-2-cyclopropyl-4-methylpyridine

[0414] To a mixture of (2-cyclopropyl-4-methylpyridin-3-yl)methanol (240 mg, 1.5 mmol) in DCM (2.5 mL) at 0 °C, SOCl2 (437 mg, 3.7 mmol) was added dropwise. The mixture was heated to rt and stirred for 2 h, then concentrated under reduced pressure to generate the product, which was used in the next step without further purification. Step 4: 2-{[(2-Cyclopropyl-4-methylpyridin-3-yl)methyl]sulfanyl}-3H,5H,6H,7H cyclopenta[d]pyrimidin-4-one

[0415] To a mixture of 3-(chloromethyl)-2-cyclopropyl-4-methylpyridine (200 mg, 1.1 mmol) and 2-sulfanyl-3H,5H,6H,7H-cyclopenta[o]pyrimidin-4-one (222 mg, 1.3 mmol) in DMF (5 mL) at rt was added DIEA (426 mg, 3.3 mmol). The mixture was stirred at rt for 2 h, then purified by Prep-HPLC [Column conditions: Xbridge Prep OBD C18 column, 30*150 mm, 5μm; Mobile phase A: H2O] Petition 870250110266, dated 01 / 12 / 2025, pages 376 / 473 136 / 214 (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 20% B to 40% B in 7 min] to generate (100 mg, 28%) as a solid. LC / MS: calculated mass for C17H19N3OS: 313.12; obtained: 314.15 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.18 - 8.19 (m, 1H), 6.99 - 7.01 (m, 1H), 4.60 (s, 2H), 2.72 - 2.84 (m, 2H), 2.56 - 2.65 (m, 2H), 2.35 (s, 3H), 2.21 2.30 (m, 1H), 1.91 - 2.04 (m, 2H), 0.89 - 0.98 (m, 4H). Example 41: Synthesis of Compound 88 Step 1: methyl 4-cyclopropyl-2-methylpyridine-3-carboxylate

[0416] Performed similarly to Example 40, Step 1 and purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, ACN in H2O (0.05% TFA), gradient from 5% to 40% in 10 min] to generate the product (730 mg, 35%) as an oil. LC / MS: calculated mass for C11H13NO2: 191.09; obtained: 192.10 [M+H]+. Step 2: (4-Cyclopropyl-2-methylpyridin-3-yl)methanol

[0417] Performed similarly to Example 40, Step 2 and used in the next step after concentration and as a crude product (390 mg). Step 3: 3-(Chloromethyl)-4-cyclopropyl-2-methylpyridine

[0418] Performed similarly to Example 40, Step 3 and used in the next step after concentration and as a crude product (270 mg). LC / MS: calculated mass for CwH12ClN: 181.07; obtained: 182.05 [M+H]+ Step 4: 2-{[(4-Cyclopropyl-2-methylpyridin-3-yl)methyl]sulfanyl}-3H,5H,6H,7H cyclopenta[d]pyrimidin-4-one

[0419] Performed similarly to Example 40, Step 4. Purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, ACN in H2O (0.05% NH4HCO3), 2% gradient] Petition 870250110266, dated 01 / 12 / 2025, pages 377 / 473 137 / 214 to 50% in 15 min] and purification by Prep-HPLC [conditions Column: Xbridge Shield RP 18 OBD column, 19*250 mm, 5μm; Mobile phase A: H2O (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25 mL / min mL / min; Gradient: 19% B to 49% B in 7 min] to generate the product (103 mg, 22%) as a solid. LC / MS: calculated mass for C17H19N3OS: 313.02; obtained: 314.15 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.21 - 8.22 (m, 1H), 6.77 - 6.78 (m, 1H), 4.59 (s, 2H), 2.72 - 2.80 (m, 2H), 2.58 - 2.62 (m, 2H), 2.56 (s, 3H), 2.02 2.17 (m, 1H), 1.90 - 2.00 (m, 2H), 1.00 - 1.09 (m, 2H), 0.70 - 0.79 (m, 2H). Example 42: Synthesis of Compound 087 Step 1: methyl 2,4-dicyclopropylpyridine-3-carboxylate

[0420] To a mixture of methyl 2,4-dichloropyridine-3-carboxylate (1.0 g, 4.9 mmol) in toluene / H2O (5 / 1) under a N2 atmosphere, cyclopropylboronic acid (1.25 g, 14.6 mmol), tricyclohexylphosphane (0.82 g, 2.9 mmol), K3PO4 (6.18 g, 29.1 mmol), and Pd(Oac)2 (0.33 g, 1.5 mmol) was added. The mixture was heated to 120 °C and stirred for 2 h, then extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with NH4HCO3 (100 mL), dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, ACN in H2O (0.05% NH4HCO3), gradient from 5% to 40% in 10 min] to generate the product (540 mg, 47%) as an oil. LC / MS: calculated mass for C13H15NO2: 217.11; obtained: 218.10 [M+H]+. Step 2: (2,4-Dicyclopropylpyridin-3-yl)methanol

[0421] To a mixture of methyl 2,4-dicyclopropylpyridine-3-carboxylate (540 mg, 2.5 mmol) in THF (5 mL) at 0 °C, DIBAL-H (7.46 mL, 7.46 mmol) was added dropwise. The mixture was heated to rt and stirred for 2 h, then Petition 870250110266, dated 01 / 12 / 2025, pages 378 / 473 138 / 214 cooled to 0 °C, suppressed with H2O, filtered, and the filter mass was washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure to yield the product (320 mg), which was used in the next step without further purification. LC / MS: calculated mass for C12H15NO: 189.12; obtained: 190.15 [M+H]+. Step 3: 3-(Chloromethyl)-2,4-dicyclopropylpyridine

[0422] To a mixture of (2,4-dicyclopropylpyridin-3-yl)methanol (320 mg, 1.7 mmol) in DCM (3 mL) at 0 °C, SOCl2 (570 mg, 4.2 mmol) was added dropwise. The mixture was heated to rt and stirred for 2 h, then concentrated under reduced pressure to yield the product (280 mg), which was used in the next step without further purification. LC / MS: calculated mass for Ci2Hi4CIN: 207.08; obtained: 208.10 [M+H]+. Step 4: 2-{[(2,4-Dicyclopropylpyridin-3-yl)methyl]sulfanyl}-3H,5H,6H,7H cyclopenta[d]pyrimidin-4-one

[0423] A mixture of 3-(chloromethyl)-2,4-dicyclopropylpyridine (280 mg, 1.4 mmol) and 2-sulfanyl-3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one (272 mg, 1.6 mmol) in DMF (5 mL) at rt was added DIEA (522 mg, 4.0 mmol). The mixture was stirred at rt for 2 h, then purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, ACN in H2O (0.05% NH4HCO3), gradient from 2% to 50% in 15 min] and purification by Prep-HPLC [conditions: Column: Xbridge Shield RP 18 OBD column, 19*250 mm, 5μm; Mobile phase A: H2O (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25 mL / min mL / min; Gradient: 29% of B to 59% of B in 7 min] to generate the product (80.7 mg, 17%) as a solid.LC / MS: calculated mass for C19H21N3OS: 339.14; obteve-se: 340.15 [M+H]+;1H NMR (300 MHz, DMSO-d6) δ 8.18 - 8.20 (m, 1H), 6.72 - 6.74 (m, 1H), 4.78 (s, 2H), 2.70 - 2.84 (m, 2H), 2.58 - 2.69 (m, 2H), 2.20 - 2.35 (m, 1H), 2.06 - 2.21 (m, 1H), 1.91 - 2.04 (m, 2H), 1.00 -1.15 (m, 2H), 0.83 0.98 (m, 4H), 0.62 - 0.81 (m, 2H). Petition 870250110266, 01 / 12 / 2025, pág. 379 / 473 139 / 214 Example 43: Compound synthesis 184 oo O ^0 0 -Ο -Ο ΗΝ'^ν^Χ IPrZnBr.THF.PdtOAc),, Q-Pho» ||jq / DIBAL-H.THFSOCI2·DCM» DIEA, DMF xk JL / ^N^-Br 8O'C,1h ψγrt| 1 h^n'U'' 0.5 h *1 hCX / ” Step 1: 2-isopropyl-4-methoxipyridine-3-carboxylate methyl

[0424] To a mixture of methyl 2-bromo-4-methoxypyridine-3-carboxylate (500 mg, 2.0 mmol), Pd(Oac)2 (45 mg, 0.2 mmol) and 1,2,3,4,5-pentaphenyl-T(di-tert-butylphosphine) (288 mg, 0.4 mmol) in THF (10 mL) at room temperature under a N2 atmosphere, bromo(propan-2-yl)zinc (4.1 mmol) was added. The resulting mixture was heated to 80 °C and stirred for 1 h, then cooled and suppressed by the addition of H2O and extracted with EtOAc (50 mL x 3). The combined organic layers were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: EtOAc / petroleum ether, 0:1 to 1:1) to generate the product (350 mg, 82%) as a solid. LCMS (ESI) calculated for C11H15NO3: 209.11; yielded: 210.20 [M+H]+. Step 2: methyl 2-isopropyl-4-methoxypyridine-3-carboxylate

[0425] Performed similarly to Example 27, Step 2 to generate the product (300 mg), which was used directly in the following step. Calculated LCMS (ESI) For C10H15NO2: 181.11; yielded: 182.15 [M+H]+ Step 3: 3-(Chloromethyl)-2-isopropyl-4-methoxypyridine hydrochloride

[0426] Performed similarly to Example 27, Step 3 to generate the product (280 mg), which was used directly in the following step. Step 4: 2-{[(2-Isopropyl-4-methoxypyridin-3-yl)methyl]sulfanyl}-3H,5H,6H,7H cyclopenta[d]pyrimidin-4-one

[0427] Performed similarly to Example 27, Step 4 and purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, ACN in H2O (0.05% NH4HCO3), gradient from 10% to 50% in 10 min] to yield the product (110.8 mg, 28%) as a solid. LCMS Petition 870250110266, dated 01 / 12 / 2025, pages 380 / 473 140 / 214 (ESI) calculated For C17H21N3O2S: 331.43; obtained: 358.10 [M+H]+; 1H-NMR (300 MHz, DMSO-d6) δ 8.30 - 8.50 (m, 1H), 6.80 - 7.05 (m, 1H), 4.44 (s, 2H), 3.86 (s, 3H), 3.40 - 3.45 (m, 1H), 2.55 - 2.65 (m, 2H), 1.89 - 2.08 (m, 2H), 1.10 - 1.22 (m, 6H). Example 44: Synthesis of Compound 215 O Step 1: 2-[(2,2-difluorocyclopropyl)sulfanyl]-4-methylpyridine-3-carboxylate

[0428] To a mixture of methyl 4-methyl-2-sulfanylpyridine-3-carboxylate (200 mg, 1.1 mmol) and 2,2-difluorocyclopropyl 4-methylbenzenesulfonate [CAS No. 1536473-24-1] (406 mg, 1.6 mmol) in DMF (3 mL) was added Cs2CO3 (711 mg, 2.2 mmol). The mixture was heated to 60 °C and stirred for 2 h, then purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, ACN in H2O (0.05% TFA), gradient from 5% to 70% in 15 min] to yield the product (140 mg, 49%) as an oil. LCMS (ESI) m / z calculated For C12H13F2NO2S, 273.06; 198.00 [M+H]+ was obtained Step 2: (2-((2,2-Difluorocyclopropyl)thio)-4-methylpyridin-3-yl)methanol

[0429] To a mixture of 2-((2,2-difluorocyclopropyl)thio)-4-methylnicotinate ethyl (140 mg, 0.51 mmol) in THF (1 mL) at 0 °C under a N2 atmosphere, DIBAL-H (1.25 mmol, 1.25 mL) was slowly added in portions. The mixture was gradually heated to rt and stirred at rt for 2 h, then suppressed by the addition of cooled H2O, filtered, and the filter mass was washed with cold MeOH. The filtrate was concentrated under reduced pressure to yield the product (90 mg, 76%) as an oil. Step 3: 3-(Chloromethyl)-2-[(2,2-difluorocyclopropyl)sulfanyl]-4-methylpyridine

[0430] A mixture of {2-[(2,2-difluorocyclopropyl)sulfanyl]-4 Petition 870250110266, dated 01 / 12 / 2025, pp. 381 / 473 141 / 214 methylpyridin-3-yl}methanol (90 mg, 0.39 mmol) in DCM (3 mL) at 0 °C was added thionyl chloride (308 mg, 2.6 mmol) dropwise. After stirring, the mixture was heated to rt and stirred for 2 h, then concentrated under reduced pressure to yield the product (70 mg), which was used in the next step without further purification. Step 4: 2-[({2-[(2,2-Difluorocyclopropyl)sulfanyl]-4-methylpyridin-3yl}methyl)sulfanyl]-3 H,5 H,6 H,7 H -cyclopenta[d]pyrimidin-4-one

[0431] A mixture of 3-(chloromethyl)-2-[(2,2-difluorocyclopropyl)sulfanyl]-4-methylpyridine (70 mg, 0.28 mmol) and 2-sulfanyl3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one (56 mg, 0.34 mmol) in DMF (2 mL) at rt was added DIEA (108 mg, 0.84 mmol). The mixture was stirred at rt for 2 h, then purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, ACN in H2O (0.05% NH4HCO3), gradient from 5% to 70% in 20 min]. The crude product (15 mg) was purified by Prep-HPLC [conditions (Column: Xbridge Prep C18 OBD column, 19*250 mm, 5 μm; Mobile phase A: H2O (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 25 mL / min mL / min; Gradient: 20% B to 55% B in 10 min] to yield the product (4.6 mg, 4%) as a solid. LC / MS: calculated mass for C17H17F2N3OS2: 381.08.; the result was: 382.00 [M+H]+; 1H NMR (400 MHz, DMSO-ds) δ 12.38 (s, 1H), 7.90 - 8.09 (m, 1H), 6.70 - 6.85 (m, 1H), 4.60 - 4.85 (m, 2H), 4.32 - 4.53 (m, 1H), 2.75 - 2.87 (m, 2H), 2.58 - 2.66 (m, 2H), 2.40 - 2.50 (m, 4H), 2.30 - 2.39 (m, 1H), 1.90 - 2.05 (m, 2H);19FRMN (376 MHz, DMSO-d6) δ -130.0 (d), -141.8 (d). Example 45: Synthesis of Compound 219 NBS, PPh3, DCM 0°Ca rt,2h SOCI2, DCM Cart, 2 h DIEA, DMF CH3SNa, DMF °C, 16 h 'SN S. Petition 870250110266, dated 01 / 12 / 2025, pp. 382 / 473 142 / 214 Step 1: 2-(Bromomethyl)-3-{[(tert-butyldimethylsilyl)oxy]methyl}-4-methylpyridine

[0432] To a stirred mixture of (3-{[(tert-butyldimethylsilyl)oxy]methyl}4-methylpyridin-2-yl)methanol (300 mg, 1.12 mmol) and NBS (299 mg, 1.68 mmol) in DCM (3 mL) at 0 °C under a N2 atmosphere, PPh3 (353 mg, 1.35 mmol) was added. The mixture was heated to rt and stirred for 2 h, then H2O was added and the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: EtOAc / petroleum ether (1:2)] to yield the product (290 mg, 78%) as an oil. LCMS (ESI) m / z calculated For C14H24BrNOSi, 329.08, 331.09; 330.05, 332.05 [M+H]+ was obtained. Step 2: {4-methyl-2-[(methylsulfanyl)methyl]iridin-3-yl}methanol

[0433] To a stirred mixture of 2-(bromomethyl)-3-{[(tert-butyldimethylsilyl)oxy]methyl}-4-methylpyridine (280 mg, 0.85 mmol) in DMF (3 mL) at rt under a N2 atmosphere, sodium thiomethoxide solution (2.54 mmol) was added. The mixture was heated to 80 °C and stirred for 16 h, then cooled to rt and suppressed by the addition of H2O (20 mL) and neutralized to pH 8 with saturated NH4Cl (aq.). The mixture was extracted with EtOAc (3 x 25 mL) and the combined organic layers were washed with brine (10 mL), dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography [eluent EtOAc / petroleum ether) (5:1)] to yield the product (140 mg, 90%) as an oil. LCMS (ESI) m / z calculated For CiõH27NOSSí, 297.16; 298.15 [M+H]+ was obtained. Step 3: 3-(Chloromethyl)-4-methyl-2-[(methylsulfanyl)methyl]pyridine

[0434] To a mixture of {4-methyl-2-[(methylsulfanyl)methyl]iridine-3yl}methanol (130 mg, 0.71 mmol) in DCM (1 mL) at 0 °C was added thionyl chloride (168 mg, 1.42 mmol). The mixture was heated to rt and stirred for 1 h, then concentrated under reduced pressure to yield the product (120 mg) as an oil. The crude product was used in the next step without further purification. LCMS Petition 870250110266, dated 01 / 12 / 2025, pages 383 / 473 143 / 214 (ESI) m / z calculated For C9H12CINS, 201.04; 202.00 [M+H]+ was obtained. Step 4: 2-[({4-Methyl-2-[(methylsulfanyl)methyl]iridin-3-yl}methyl)sulfanyl] H,5 H,6 H,7 H -cyclopenta[d]pyrimidin-4-one

[0435] Performed similarly to Step 4, Example 19 and purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, MeCN in H2O (0.1% TFA), gradient from 10% to 50% in 10 min] to yield the product (68.5 mg, 31%) as a solid. LC / MS: calculated mass for C16H19N3OS2: 333.10; obtained: 334.05[M+H]+;1H NMR (400 MHz, DMSO- d6) δ 12.61 (s, 1H), 8.32 (d, J = 5.0 Hz, 1H), 7.27 (d, J = 5.0 Hz, 1H), 4.60 (s, 2H), 3.97 (s, 2H), 2.80 (t, J = 7.2 Hz, 2H), 2.61 (t, J = 7.2 Hz, 2H), 2.41 (s, 3H), 2.05 (s, 3H), 2.03 - 1.92 (m, 2H); 19F-NMR (376 MHz, DMSOd6) δ -73.9. Example 46: Synthesis of Compound 217 Pd(OAc)2, Xantphos, Cs2CO3rDIBAL-H,THF SOCIa, DCM DIEA, DMF IL Step 1: 2-(3,3-Difluoroazetidin-1-yl)-4-methylpyridine-3-carboxylate

[0436] To a mixture of methyl 2-bromo-4-methylpyridine-3-carboxylate (300 mg, 1.3 mmol) and 3,3-difluoroazetidine hydrochloride (202 mg, 1.6 mmol) in 1,4-dioxane (10 mL) at room temperature under a N2 atmosphere, Pd(Oac)2 (29 mg, 0.13 mmol) and XantPhos (75 mg, 0.13 mmol) were added. The mixture was heated to 100 °C and stirred for 1 h, then cooled, filtered, and the filter mass was washed with DCM (3 x 10 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [EtOAc / petroleum ether ether (1:3) eluent] to yield the product (212 mg, 67%) as an oil. LCMS (ESI) m / z calculated For C12H14F2N2O2, 256.10; 257.10 [M+H]+ was obtained. Step 2: [2-(3,3-difluoroazetidin-1-yl)-4-methylpyridin-3-yl]methanol

[0437] A mixture of 2-(3,3-difluoroazetidin-1-yl)-4-methylpyridine Petition 870250110266, dated 01 / 12 / 2025, pp. 384 / 473 144 / 214 Ethyl 3-carboxylate (270 mg, 1.05 mmol) in DCM (5 mL) at 0 °C under a N2 atmosphere was added to DIBAL-H, 1.0 M in DCM (2.63 mL, 2.63 mmol). The mixture was heated to rt and stirred for 1 h, then diluted with H2O (10 mL), filtered, and the filter mass was washed with EtOAc (3 x 10 mL). The filtrate was concentrated under reduced pressure to yield the product (170 mg, 75%) as a solid. LCMS (ESI) m / z calculated For C10H12F2N2O, 214.09; 215.15 [M+H]+ was obtained. Step 3: 3-(Chloromethyl)-2-(3,3-difluoroazetidin-1-yl)-4-methylpyridine

[0438] To a mixture of [2-(3,3-difluoroazetidin-1-yl)-4-methylpyridin-3-yl]methanol (80 mg, 0.37 mmol) in DCM (2 mL) at rt, thionyl chloride (111 mg, 0.93 mmol) was added. The mixture was stirred at rt for 1 h, then concentrated under reduced pressure to generate the product, which was used in the next step without further purification. Step 4: 2-({[2-(3,3-difluoroazetidin-1-yl)-4-methylpyridin-3-yl]methyl}sulfanyl)3 H,5 H,6 H,7 H -cyclopenta[d]pyrimidin-4-one

[0439] A mixture of 2-sulfanyl-3H,5H,6H,7Hcyclopenta[d]pyrimidin-4-one (50 mg, 0.3 mmol) and 3-(chloromethyl)-2-(3,3-difluoroazetidin-1-yl)-4-methylpyridine (70 mg, 0.3 mmol) in DMF (2 mL) at rt was added DIEA (116 mg, 0.9 mmol). The mixture was stirred at rt for 1 h, then diluted with MeCN (5 mL). The precipitated solids were collected by filtration and washed with MeCN (3 x 5 mL) to yield the product (91 mg, 83%) as a solid. LC / MS: calculated mass for C17H18F2N4OS: 364.12; obtained: 365.10 [M+H]+;1H NMR (300 MHz, DMSO-d6) δ 12.59 (br. S, 1H), 8.02 (d, J = 5.0 Hz, 1H), 6.81 (d, J = 5.0 Hz, 1H), 4.51 (d, J = 12.8 Hz, 3H), 4.45 (s, 1H), 4.34 (s, 2H), 2.79 (t, J = 7.6 Hz, 2H), 2.61 (t, J = 7.6 Hz, 2H), 2.34 (s, 3H), 2.03 -1.93 (m, 2H);19F-NMR (376 MHz, DMSO-d6) δ -98.2. Example 47: Synthesis of Compound 216 Onl'x / IQ A>An^Pd(OAc)2, Xantphos, Cl2C0,ÃrQ· ζΛΒΓdox-no DIBAL-H.THF ||^^°ΗSOCI2, DCM O'Cart, 1 h Petition 870250110266, dated 01 / 12 / 2025, pages 385 / 473 145 / 214 Step 1: Ethyl 2-(pyridin-1-yl)-4-methylpyridine-3-carboxylate

[0440] Performed similarly to Example 46, Step 1 and purified by silica gel column chromatography [EtOAc eluent / petroleum ether (1:1)] to generate the product (200 mg) as an oil. LC / MS: MS (ESI) calculated For C12H16N2O2: 220.12; Obtained: 221.10 [M+H]+. Step 2: [2-(Azetidin-1-yl)-4-methylpyridin-3-yl]methanol

[0441] Performed similarly to Example 46, Step 2. After concentration of the filtrate, the crude product was recrystallized from EtOAc / petroleum ether (1:3) to generate the product (100 mg) as a solid. LC / MS: MS (ESI) calculated For C10H14N2O: 178.11; Obtained: 179.30 [M+H]+. Step 3: 2-(Azetidin-1-yl)-3-(chloromethyl)-4-methylpyridine

[0442] To a mixture of [2-(pyridine-1-yl)-4-methylpyridin-3-yl]methanol (100 mg, 0.56 mmol) in DCM (5 mL) at 0 °C was added thionyl chloride (166 mg, 1.4 mmol). The mixture was heated to rt and stirred for 1 h, then concentrated under reduced pressure to yield the product (130 mg) as a solid. Used directly in the next step. Step 4: 2-({[2-(Azetidin-1-yl)-4-methylpyridin-3-yl]methyl}sulfanyl)-3 H,5 H,6 H,7 H cyclopenta[d]pyrimidin-4-one; trifluoroacetic acid salt

[0443] To a mixture of 2-(iridine-1-yl)-3-(chloromethyl)-4-methylpyridine (100 mg, 0.5 mmol) and 2-sulfanyl-3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one (85 mg, 0.5 mmol) in DMF (3 mL) at rt was added DIEA (197 mg, 1.5 mmol). The mixture was stirred at rt for 0.5 h, then purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, H2O (0.05% TFA) in ACN, gradient from 10% to 50% in 20 min] to yield the product (30 mg) as a solid. LC / MS: MS (ESI) calculated For C17H20N4OS.C2HF3O2: 328.14; Obtained: 329.20 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 7.92 - 7.93 (m, 1H), 6.59 - 6.60 (m, 1H), 4.30 - 4.31 (m, 2H), 3.33 - 4.08 (m, 4H), 2.75 - 2.79 (m, 2H), 2.61 - 2.67 (m, 2H), 2.27 - 2.32 (m, 3H), 2.19 - 2.25 (m, Petition 870250110266, dated 01 / 12 / 2025, pages 386 / 473 146 / 214 2H), 1.96 - 2.00 (m, 2H). 19F-NMR (376 MHz, DMSO-d6) δ -73.4. Example 48: Synthesis of Compound 104 Step 1: 3-{[( Tert-butyldimethylsilyl)oxy]methyl}-4-methyl-2-(2,2,2trifluoroethyl)pyridine

[0444] To a mixture of 2-(bromomethyl)-3-{[(tert-butyldimethylsilyl)oxy]methyl}-4-methylpyridine (300 mg, 0.91 mmol) and [5,5'-bis(trifluoromethyl)-2,2'-bipyridine-n1,n1']bis[3,5-difluoro-2-[5(trifluoromethyl)-2-pyridinyl-n]phenyl-c]iridium(III) hexafluorophosphate (52 mg, 0.045 mmol) in acetonitrile (5 mL) at rt under a N2 atmosphere, (trifluoromethyl)bis(2,4,6-trimethylphenyl)sulfanium trifluoromethanesulfonate (887 mg, 1.82 mmol) and Na2CO3 (385 mg, 3.63 mmol) were added. The mixture was stirred at rt for 12 h under LED irradiation. The mixture was concentrated under reduced pressure, then H2O (20 mL) was added and extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (20 mL), dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [eluent: EtOAc / petroleum ether (1:2)] to yield the product (100 mg) as an oil. Step 2: [4-Methyl-2-(2,2,2-trifluoroethyl)iridin-3-yl]methanol

[0445] To a mixture of 3-{[(tert-butyldimethylsilyl)oxy]methyl}-4-methyl2-(2,2,2-trifluoroethyl)pyridine (100 mg, 0.31 mmol) in DCM (1 mL) at 0 °C was added TBAF, 1M in THF (0.3 mL, 0.3 mmol). The mixture was heated to rt and stirred for 1 h, then concentrated under reduced pressure and the residue was purified by silica gel column chromatography [eluent: EtOAc / petroleum ether (5:1)] to yield the product (60 mg) as an oil. Petition 870250110266, dated 01 / 12 / 2025, pp. 387 / 473 147 / 214 Step 3: 3-(Chloromethyl)-4-methyl-2-(2,2,2-trifluoroethyl)pyridine

[0446] To a mixture of [4-methyl-2-(2,2,2-trifluoroethyl)iridine-3yl]methanol (60 mg, 0.29 mmol) in DCM (1 mL) at 0 °C under an N2 atmosphere, thionyl chloride (69 mg, 0.58 mmol) was added. The mixture was heated to rt and stirred for 1 h, then concentrated under reduced pressure to yield the product (60 mg). Step 4: 2-({[4-Methyl-2-(2,2,2-trifluoroethyl)iridin-3-yl]methyl}sulfanyl) 3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one; trifluoroacetic acid salt

[0447] To a mixture of 2-sulfanyl-3H,5H,6H,7H cyclopenta[d]pyrimidin-4-one (45 mg, 0.27 mmol) and DIEA (104 mg, 0.8 mmol) in DMF (1 mL) at 0 °C was added 3-(chloromethyl)-4-methyl-2-(2,2,2-trifluoroethyl)pyridine (60 mg, 0.27 mmol). The mixture was heated to rt and stirred for 1 h, then purified by reversed-phase column chromatography. [Conditions: column, silica gel C18; mobile phase, MeCN in H2O (0.1% TFA), gradient from 20% to 45% in 20 min] to generate the product (53 mg) as a solid. LC / MS: MS (ESI) calculated For C16H16F3N3OS: 355.10; Obtained: 356.15 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ 8.40 (m, 1H), 7.33 (m, 1H), 4.59 (s, 2H), 4.08 (m, 2H), 2.79 (m, 2H), 2.62 (m, 2H), 2.49 (s, 3H), 1.98 (m, 2H);19FRMN (376 MHz, DMSO-d6) δ -62.0, -74.9. Example 49: Synthesis of Compound 83 Step 1: 4-Methyl-2-(methylsulfanyl)pyridine-3-carboxylic acid

[0448] A mixture of methyl 2-chloro-4-methylpyridine-3-carboxylate (300 mg, 1.62 mmol) and (methylsulfanyl)sodium (283 mg, 4.0 mmol) in THF (5 mL) was stirred at 80 °C for 1 h under a N2 atmosphere. The mixture was extracted with EtOAc. Petition 870250110266, dated 01 / 12 / 2025, pages 388 / 473 148 / 214 (3 x 500 mL) and the combined organic layers were washed with H2O (3 x 10 mL), dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, ACN in H2O (0.1% TFA), gradient from 10% to 80% in 30 min] to yield the product (200 mg) as an oil. Step 2: methyl 4-methyl-2-(methylsulfanyl)pyridine-3-carboxylate

[0449] A mixture of 4-methyl-2-(methylsulfanyl)pyridine-3-carboxylic acid (200 mg, 1.09 mmol), MeI (232 mg, 1.64 mmol) and K2CO3 (452 ​​mg, 3.28 mmol) in DMF (2 mL) was stirred at 60 °C for 0.5 h. The mixture was extracted with EtOAc (3 x 500 mL) and the combined organic layers were washed with H2O (3 x 10 mL), dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, ACN in H2O (0.1% TFA), gradient from 10% to 80% in 30 min] to yield the product (150 mg) as an oil. Step 3: [4-methyl-2-(methylsulfanyl)iridin-3-yl]methanol

[0450] A mixture of methyl 4-methyl-2-(methylsulfanyl)pyridine-3-carboxylate (150 mg, 0.76 mmol) and DIBAL-H, 25% in toluene (4.56 mmol) in THF (2 mL) was stirred at rt for 0.5 h under an air atmosphere. The mixture was cooled to 0 °C and suppressed with H2O / ice and filtered. The filtrate was concentrated under reduced pressure to yield the product (120 mg). Step 4

[0451] A mixture of [4-methyl-2-(methylsulfanyl)iridine-3-yl]methanol (120 mg, 0.71 mmol) and thionyl chloride (210 mg, 1.77 mmol) in DCM (2 mL) was stirred at rt for 0.5 h, then concentrated under reduced pressure to generate the product (100 mg). Step 5: 2-({[4-Methyl-2-(methylsulfanyl)pyridin-3-yl]methyl}sulfanyl)3 H,5 H,6 H,7 H -cyclopenta[ d]pyrimidin-4-one

[0452] A mixture of 3-(chloromethyl)-4-methyl-2-(methylsulfanyl)pyridine Petition 870250110266, dated 01 / 12 / 2025, pages 389 / 473 149 / 214 (100 mg, 0.53 mmol), 2-sulfanyl-3H,5H,6HJH-cyclopenta[d]pyrimidin-4-one (89 mg, 0.53 mmol) and DIEA (206 mg, 1.6 mmol) in DMF (1 mL) was stirred at rt for 0.5 h, then purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, ACN in H2O (0.1% TFA), gradient from 10% to 80% in 30 min] to yield the product (82 mg) as a solid. LC / MS: MS (ESI) calculated For C15H17N3OS2: 319.08; Obtained: 320.20 [M+H]+; 1H-NMR (400 MHz, DMSOd6) δ 8.27 (m, 1H), 7.02 (m, 1H), 4.47 (s, 2H), 2.79 (m, 2H), 2.63 (m, 2H), 2.20 (s, 3H), 1.99 (m, 2H);19F-NMR (376 MHz, DMSO-ds) δ -74.7. Example 50: Synthesis of Compound 30 Step 1: 3-(chloromethyl)-2-methylpyridin-4-amine

[0453] To a mixture of (4-amino-2-methylpyridin-3-yl)methanol [CAS No 1807169-23-8] (180 mg, 1.3 mmol) in DCM (2 mL) at 0 °C, SOCl2 (464 mg, 3.9 mmol) was added dropwise. The mixture was heated to rt and stirred for 1 h, then concentrated under reduced pressure to yield the product (120 mg, 58%). Step 2: 2 -{[(4-amino-2-methylpyridin-3-yl)methyl]sulfanyl}-3 H,5 H,6 H,7 H cyclopenta[ d]pyrimidin-4-one

[0454] To a mixture of 3-(chloromethyl)-2-methylpyridin-4-amine (180 mg, 1.15 mmol) and 2-sulfanyl-3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one (212 mg, 1.26 mmol) in DMF (2 mL) at 0 °C, DIEA (594 mg, 4.6 mmol) was added dropwise. The mixture was heated to rt and stirred for 2 h, then purified by Prep-HPLC [conditions: Column: Xbridge Prep OBD C18 column, 30*150 mm, 5μm; Mobile phase A: H2O (10 mmol / L NH4HCO3), Mobile phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 5% B to 23% B in 8 min] to generate the product (45.7 mg, 13%) as a solid. LC / MS: calculated mass for C14H16N4OS: 288.10; obtained: 289.15 [M+H]+;1H NMR (300 MHz, DMSO- d6) δ 7.70 - 7.88 (m, 1H), 6.30 - 6.68 (m, 3H), 4.25 - 4.40 (m, 2H), 2.70 - 2.88 (m, 2H), 2.58 - 2.68 (m, 2H), 2.35 - 2.45 (m, Petition 870250110266, dated 01 / 12 / 2025, pages 390 / 473 150 / 214 3H), 1.91 - 2.08 (m, 2H), 1.60 - 1.70 (m, 1H). Example 51: Synthesis of Compound 14 Step 1: methyl 2-ethyl-4-methoxypyridine-3-carboxylate

[0455] Performed similarly to Example 27, Step 1 to generate the product (350 mg, 69%) as an oil. LC / MS: calculated mass for C10H13NO3: 195.09; obtained: 196.05 [M+H]+. Step 2: (2-Ethyl-4-methoxypyridin-3-yl)methanol

[0456] Performed similarly to Example 27, Step 2 to generate the product (230 mg, 75%) as a solid. LC / MS: calculated mass for C9H13NO2: 167.09; obtained: 168.20 [M+H]+. Step 3: 3-(Chloromethyl)-2-ethyl-4-methoxypyridine

[0457] Performed in a similar manner to Example 27, Step 3 to generate the product (180 mg, 70%). Step 4: 2-{[(2-Ethyl-4-methoxypyridin-3-yl)methyl]sulfanyl}-3H,5H,6H,7H cyclopenta[d]pyrimidin-4-one

[0458] Performed similarly to Example 27, Step 4 to generate the product (179 mg, 57%) as a solid. LC / MS: calculated mass for C16H19N3O2S: 317.12; obtained: 318.05 [M+H]+; 1H NMR (300 MHz, DMSO- d6) δ 8.30 - 8.35 (m, 1H), 6.90 - 6.99 (m, 1H), 4.40 - 4.48 (m, 2H), 3.85 - 3.93 (m, 3H), 2.70 - 2.93 (m, 4H), 2.55 - 2.65 (m, 2H), 1.90 - 2.05 (m, 2H), 1.10 - 1.29 (m, 3H). Example 52: Synthesis of Compound 85 SOCI2, DCM (bpy)Cu(SCF3), Dioxane / ACN (4:1 110 °C, During the night Petition 870250110266, dated 01 / 12 / 2025, pages 391 / 473 151 / 214 Step 1: Ethyl 2-methyl-4-[(trifluoromethyl)sulfanyl]pyridine-3-carboxylate

[0459] A mixture of ethyl 4-bromo-2-methylpyridine-3-carboxylate (800 mg, 3.3 mmol) and (bpy)Cu(SCF3) (1.37 g, 4.3 mmol) in 1,4-dioxane (2 mL) at room temperature was added. ACN (0.5 mL) under a N2 atmosphere was heated to 110 °C and stirred overnight. H2O (5 mL) was added and the mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were dried with anhydrous Na2SO4, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: EtOAc / petroleum ether (1:24)] to yield the product (450 mg, 41%) as an oil. LC / MS: MS (ESI) calculated For C10H10F3NO2S: 265.04; Obtained: 266.00 [M+H]+. Step 2: {2-methyl-4-[(trifluoromethyl)sulfanyl]iridin-3-yl}methanol

[0460] To a mixture of ethyl 2-methyl-4-[(trifluoromethyl)sulfanyl]pyridine-3-carboxylate (400 mg, 1.5 mmol) in THF (5 mL) at 0 °C under a N2 atmosphere, DIBAL-H (3.8 mmol) was added in portions. The mixture was heated to rt and stirred for 2 h, then suppressed by the addition of H2O / ice (10 mL), filtered, and the filter mass was washed with EtOAc / MeOH (1:1) (2 x 10 mL). The filtrate was concentrated under reduced pressure to yield the product (288 mg, 85%) as an oil. LC / MS: MS (ESI) calculated For C8H8F3NOS: 223.03; Obtained: 224.00 [M+H]+ Step 3: 3-(Chloromethyl)-2-methyl-4-[(trifluoromethyl)sulfanyl]pyridine

[0461] To a mixture of {2-methyl-4-[(trifluoromethyl)sulfanyl]iridine-3yl}methanol (288 mg, 1.3 mmol) in DCM (3 mL) at 0 °C, SOCl2 (383 mg, 3.2 mmol) was added dropwise. The mixture was heated to rt and stirred for 2 h, then concentrated under reduced pressure to yield the product (275 mg, 88%) as an oil. LC / MS: MS (ESI) calculated For Ce^ClFaNS: 240.99; Obtained: 242.00 [M+H]+ Step 4: 2-[({2-methyl-4-[(trifluoromethyl)sulfanyl]iridin-3-yl}methyl)sulfanyl]3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one; trifluoroacetic acid salt

[0462] To a mixture of 3-(chloromethyl)-2-methyl-4-Petition 870250110266, dated 01 / 12 / 2025, page 392 / 473 152 / 214 [(trifluoromethyl)sulfanyl]pyridine (250 mg, 1.0 mmol) and 2-sulfanyl-3H,5H,6H,7H cyclopenta[d]pyrimidin-4-one (174 mg, 1.0 mmol) in DMF (3 mL) at rt was added DIEA (534 mg, 4.1 mmol). The mixture was extracted with EtOAc (3 x 20 mL) and the combined organic layers were washed with brine (3 x 50 mL), dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by reversed-phase column chromatography [conditions: column, silica gel C18; mobile phase, ACN in H2O (0.1% TFA), gradient from 20% to 40% in 10 min] to yield the product (38.6 mg, 7%) as a solid. LC / MS: MS (ESI) calculated For C15H15F2N3O2S: 373.05; Obtained: 374.10 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ 12.80 - 12.40 (s, 1H), 8.60 8.35 (m, 1H), 7.70 - 7.45 (m, 1H), 4.85 - 4.60 (m, 2H), 2.85 - 2.78(m,2H), 2.75 - 2.65 (s, 3H), 2.60 - 2.55 (s, 3H), 2.15 - 1.80 (m, 2H); 19F-NMR (376 MHz, DMSO-d6) δ -40.1, -73.5. Example 53: Synthesis of Compound 72 DIBAL, THF ^Bubrettphos Pd G3, ''Bubrettphos, CD3OD, Cs2CO3, dioxane_______ 100 °C, 2h THE Step 1: 4-(2H3) methoxy-2-methylpyridine-3-carboxylate

[0463] A mixture of methyl 4-chloro-2-methylpyridine-3-carboxylate (1.0 g, 5.4 mmol), t-BuBrettPhos Palladacycle Gen. 3 (460 mg, 0.54 mmol) and di-tert-butyl({3,6-dimethoxy-2-[2,4,6-tris(propan-2-yl)phenyl]phenyl})phosphane (130 mg, 0.27 mmol) in 1,4-dioxane (10 mL) at rt under a N2 atmosphere was added dropwise to CD3OD (971 mg, 26.9 mmol). The mixture was heated to 100 °C and stirred for 1 h, then purified by reversed-phase column chromatography (0.05% NH4HCO3) to yield the product (300 mg, 30%) as a solid. LC / MS: calculated mass for C9H11NO3: 184.09; obtained: 185.15 [M+H]+. Petition 870250110266, dated 01 / 12 / 2025, pp. 393 / 473 153 / 214 Step 2: [4-(2H3)methoxy-2-methylpyridin-3-yl]methanol

[0464] To a mixture of methyl 4-(2H3)methoxy-2-methylpyridine-3-carboxylate (300 mg, 1.6 mmol) in THF (3 mL) at 0 °C, DIBAL-H (4.9 mmol) was added dropwise. The mixture was heated to rt and stirred for 1 h, then H2O / ice was added, filtered, and the filter mass was washed with MeOH (2 x 10 mL). The filtrate was concentrated under reduced pressure to yield the product (250 mg, 98%) as a solid. LC / MS: calculated mass for C8H11NO2: 156.10; obtained: 157.15 [M+H]+. Step 3: 3-(Chloromethyl)-4-(2H3)methoxy-2-methylpyridine

[0465] To a mixture of [4-(2H3)methoxy-2-methylpyridin-3-yl]methanol (260 mg, 1.7 mmol) in DCM (3 mL) at 0 °C, SOCl2 (594 mg, 5.0 mmol) was added dropwise. The mixture was heated to rt and stirred for 1 h, then concentrated under reduced pressure to yield the product (245 mg, 84%). Step 4: 2-({[4-(2H3)methoxy-2-methylpyridin-3-yl]methyl}sulfanyl)-3H,5H,6H,7H cyclopenta[d]pyrimidin-4-one

[0466] To a mixture of 3-(chloromethyl)-4-(2H3)methoxy-2-methylpyridine (245 mg, 1.4 mmol) and 2-sulfanyl-3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one (306 mg, 1.8 mmol) in DMF (2.5 mL) at 0 °C, DIEA (725 cmg, 5.6 mmol) was added dropwise. The mixture was heated to rt and stirred for 2 h, then purified by reversed-phase column chromatography (0.05% TFA) to yield the product (141 mg, 31%) as a solid. LC / MS: calculated mass for C15H14D3N3O2S: 306.12; obtained: 307.15 [M+H]+;1H NMR (300 MHz, DMSO-ds) δ 8.50 - 8.80 (m, 1H), 7.40 - 7.60 (m, 1H), 4.35 - 4.55 (m, 2H), 2.71 - 2.88 (m, 5H), 2.55 - 2.68 (m, 2H), 1.91 - 2.08 (m, 2H);19F-NMR (282 MHz, DMSO-d6) δ -73.7. Example 54: Synthesis of Compound 220s X h2n nh2 MeOH N*XF360°C, 3 h TEA, Dioxane 50°C, 16 h Petition 870250110266, dated 01 / 12 / 2025, pp. 394 / 473 154 / 214 Step 1: {[4-Methyl-2-(trifluoromethyl)iridin-3-yl]methyl}sulfanylmethanimidamide

[0467] A mixture of 3-(chloromethyl)-4-methyl-2-(trifluoromethyl)pyridine (200 mg, 0.95 mmol) and thiourea (87 mg, 1.14 mmol) was stirred in MeOH (10 mL) at rt for 2 h, then concentrated in vacuo to generate the product (80 mg, 11%) as a solid. LCMS (ESI) m / z calculated For C9H10F3N3S, 249.05; 249.95 [M+H]+ was obtained. Step 2: 3-({[4-Methyl-2-(trifluoromethyl)iridin-3-yl]methyl}sulfanyl)-2,4diazabicyclo[4.2.0]octa-1(6),2-dien-5-one

[0468] To a mixture of {[4-methyl-2-(trifluoromethyl)iridine-3yl]methyl}sulfanylmethanimidamide (80 mg, 0.32 mmol) in DMF (3 mL) at 0 °C was added 2-chloro-2-cyclopropylideneacetate methyl (47 mg, 0.32 mmol) and Et3N (97 mg, 0.96 mmol). The mixture was stirred at rt for 15 min, then purified by reversed-phase column chromatography [28% to 32% ACN in H2O(NH4HCO3) gradient] to yield the product (12.5 mg, 11%) as a solid. LCMS (ESI) m / z calculated For C14H12F3N3OS, 327.07; obtained 328.15 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 12.59 (s, 1H), 8.54 (s, 1H), 7.64 (s, 1H), 4.56 (s, 2H), 3.05 - 3.13 (m, 2H), 2.80 - 2.89 (m, 2H), 2.51 (s, 3H). Example 55: Synthesis of Compound 81 Step 1: 3-Bromo-2-(difluoromethoxy)-4-methylpyridine

[0469] To a mixture of 3-bromo-4-methylpyridin-2-ol (3.0 g, 16.0 mmol) and difluoro(sulfo)acetic acid (3.41 g, 19.2 mmol) in MeCN (30 mL) was added Na2SO4 (2.72 g, 19.2 mmol). The mixture was stirred at rt for 16 h, Petition 870250110266, dated 01 / 12 / 2025, pages 395 / 473 155 / 214 then diluted with H2O (40 mL) and extracted with DCM (3 x 40 mL). The combed organic layers were concentrated under reduced pressure and the residue was purified by silica-gel column chromatography [eluent EtOAc / petroleum ether (1:3)] to yield the product (3.0 g, 77%) as an oil. LCMS (ESI) m / z calculated for C?H6BrF2NO, 236.03; obtained, 237.85 [M+H]+. Step 2: 2-(difluoromethoxy)-4-methylpyridine-3-carboxylate

[0470] To a mixture of 3-bromo-2-(difluoromethoxy)-4-methylpyridine (3.0 g, 12.6 mmol) in MeOH (20 mL) was added TEA (3.83 g, 37.8 mmol) and Pd(dppf)Cl2 (0.92 g, 1.26 mmol). The resulting mixture was heated to 130 °C and stirred for 16 h under a CO₂ atmosphere (10 atm). The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography [eluent: EtOAc / petroleum ether (3:1)] to yield the product (2.0 g, 70%) as an oil. LCMS (ESI) m / z calculated for C₉H₉F₂NO₃, 217.06; obtained, 218.00 [M+H]⁺. Step 3: [2-(Difluoromethoxy)-4-methylpyridin-3-yl]methanol

[0471] To a mixture of methyl 2-(difluoromethoxy)-4-methylpyridine-3-carboxylate (1.0 g, 4.6 mmol) in THF (15 mL) at 0 °C h under a N2 atmosphere, LAH (0.52 g, 13.8 mmol) was added. The resulting mixture was stirred at 0 °C for 1 h, then diluted with H2O (0.52 g), 15% NaOH (0.52 g), and H2O (1.56 g). The product was extracted with EtOAc (3 x 40 mL) and the combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: EtOAc / petroleum ether (1:1)] to generate the product (800 mg, 90%) as an oil. LCMS (ESI) m / z calculated for C8H9F2NO2, 189.06; obtained, 190.00 [M+H]+. Step 4: 3-(Chloromethyl)-2-(difluoromethoxy)-4-methylpyridine

[0472] To a mixture of [2-(difluoromethoxy)-4-methylpyridin-3yl]methanol (300 mg, 1.6 mmol) in DCM (20 mL) at 0 °C was added SOCl2 (565 mg, 4.8 mmol) and DMF (11.6 mg, 0.16 mmol). The mixture was heated to rt and stirred. Petition 870250110266, dated 01 / 12 / 2025, pp. 396 / 473 156 / 214 for 1 h, then concentrated under reduced pressure to generate the product (300 mg, 91%) as an oil. The crude product was used in the next step without further purification. LCMS (ESI) m / z calculated for C8H8ClF2NO, 207.03; obtained, 208.00 [M+H]+. Step 5: 2-({[2-(Difluoromethoxy)-4-methylpyridin-3-yl]methyl}sulfanyl)3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one; trifluoroacetic acid salt

[0473] To a mixture of 3-(chloromethyl)-2-(difluoromethoxy)-4-methylpyridine (300 mg, 1.5 mmol) and 2-sulfanyl-3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one (291 mg, 1.7 mmol) in DMF (10 mL) was added DIEA (1.12 g, 8.7 mmol). The mixture was stirred at rt for 2 h, then H2O was added and the mixture was extracted with EtOAc (40 mL x 3). The combined organic layers were washed with brine (60 mL x 3) and the combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (PE / EA = 3 / 1 Rf = 0.4) to provide the crude product (140 mg). The crude product (140 mg) was purified by preparative HPLC [Column: Xselect CSH C18 OBD column, 30*150 mm, 5μm; Mobile phase A: Water (0.05% TFA), Mobile phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 32% B to 62% B in 7 min] to yield the product (25.4 mg, 3%) as a solid.LCMS (ESI) m / z calculated for C17H16F5N3O4S, 339.06; obtained, 340.00 [M+H]+;1H NMR (300 MHz, DMSO-ds) δ 12.59 (br s, 1H), 8.05 (d, J = 5.1 Hz, 1H), 7.47 - 7.96 (m, 1H), 7.15 (d, J = 5.1 Hz, 1H), 4.43 (s, 2H), 2.72 - 2.80 (m, 2H), 2.50 - 2.67 (m, 2H), 2.45 (s, 3H), 1.91 - 2.07 (m, 2H). Example 56: Synthesis of Compound 214 Petition 870250110266, dated 01 / 12 / 2025, pp. 397 / 473 157 / 214 Step 1: 3-Bromo-4-methylpyridine-2-thiol

[0474] To a mixture of 3-bromo-2-fluoro-4-methylpyridine (4.0 g, 21.1 mmol) in DMF (10 mL) at rt under a N2 atmosphere, NaSH (1.87 g, 25.3 mmol) was added in portions. The resulting mixture was heated to 100 °C and stirred for 2 h, then cooled to rt and poured into cooled H2O. The emerging precipitate was collected by filtration and the filter mass was washed with cooled H2O (100 mL) and MeCN (3 x 10 mL) to yield the product (2.8 g, 65%) as a solid. LCMS (ESI) m / z calculated for CeHeBrNS, 202.94; obtained, 204.09 [M+H]+. Step 2: 3-Bromo-2-(cyclopropylsulfanyl)-4-methylpyridine

[0475] A mixture of 3-bromo-4-methylpyridine-2-thiol (3.2 g, 15.7 mmol), cyclopropylboronic acid (2.15 g, 25.1 mmol), Cu(OAc)2 (2.85 g, 15.7 mmol), 2,2'-bipyridine (2.45 g, 15.7 mmol) and Cs2CO3 (5.11 g, 15.7 mmol) in DCE (6 mL) was stirred at 70 °C for 2 h under air. The mixture was filtered and the filter mass was washed with DCM (3 x 20 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography [eluent: EtOAc / petroleum ether (1:1)] to yield the product (1.7 g, 44%) as an oil. LCMS (ESI) m / z calculated for CgHwBrNS, 242.97; obtained, 244.21 [M+H]+ Step 3: 3-Bromo-2-[(1-fluorocyclopropyl)sulfanyl]-4-methylpyridine

[0476] To a mixture of 3-bromo-2-(cyclopropylsulfanyl)-4-methylpyridine (1.7 g, 7.0 mmol) and 1-(chloromethyl)-4-fluoro-1,4-diazabicyclo[2.2.2]octane-1,4-di-io[Selectfluor] ditetrafluoroborate (3.70 g, 10.44 mmol) in MeCN (4 mL) at 0 °C under a N2 atmosphere, Et3N (1.06 g, 10.44 mmol) was added in portions. The mixture was stirred at 0 °C for 1 h, then filtered, and the filter mass was washed with DCM (3 x 10 mL). The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography [eluent: EtOAc / petroleum ether (1:1)] to yield the product (360 mg, 19%) as an oil. LCMS (ESI) m / z calculated for CgHgBrFNS, 260.96; obtained, 262.17 Petition 870250110266, dated 01 / 12 / 2025, pages 398 / 473 158 / 214 [M+H]+. Step 4: 2-[(1-Fluorocyclopropyl)sulfanyl]-4-methylpyridine-3-carbaldehyde

[0477] To a mixture of 3-bromo-2-[(1-fluorocyclopropyl)sulfanyl]-4-methylpyridine (210 mg, 0.80 mmol) in THF (4 mL) at -78 °C under a N2 atmosphere, nBuLi, 1.6 M in n-hexane (0.55 mL, 0.88 mmol) was added. The mixture was stirred at -78 °C for 30 min, then ethyl formate (593 mg, 8.0 mmol) was added in portions at -78 °C. The mixture was stirred at -78 °C for 1 h, then suppressed with NH4Cl sat. (aq.) at 0 °C and extracted with DCM (3 x 50 mL). The combined organic layers were washed with H2O (3 x 50 mL), dried with anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography [eluent: EtOAc / petroleum ether (1:1)] to yield the product (135 mg, 80%) as a solid. LCMS (ESI) m / z calculated for C10H10FNOS, 211.05; 212.10 [M+H]+ was obtained. Step 5: {2-[(1-Fluorocyclopropyl)sulfanyl]-4-methylpyridin-3-yl}methanol

[0478] To a mixture of 2-[(1-fluorocyclopropyl)sulfanyl]-4-methylpyridine-3-carbaldehyde (120 mg, 0.57 mmol) in MeOH (2 mL) at 0 °C under a N2 atmosphere, NaBH4 (43 mg, 1.14 mmol) was added in portions. The mixture was heated to reflux and stirred for 2 h, then cooled to 0 °C and suppressed with NH4Cl sat. (aq.). The mixture was filtered and the filter mass was washed with MeCN (3 x 10 mL). The filtrate was concentrated under reduced pressure to yield the product (140 mg) as a solid. LCMS (ESI) m / z calculated for C10H12FNOS, 213.06; obtained, 214.07 [M+H]+. Step 6: {2-[(1-fluorocyclopropyl)sulfanyl]-4-methylpyridin-3-yl}methyl methanesulfonate

[0479] To a mixture of {2-[(1-fluorocyclopropyl)sulfanyl]-4-methylpyridin-3-yl}methanol (130 mg, 0.61 mmol) in DCM (3 mL) at rt under a N2 atmosphere, methanesulfonate (159 mg, 0.92 mmol) and EtaN (123 mg, 1.22 mmol) were added in portions. The mixture was stirred at rt Petition 870250110266, dated 01 / 12 / 2025, pages 399 / 473 159 / 214 for 1 h, then cooled to 0 °C, suppressed with saturated NH4Cl (aq.) and extracted with DCM (2 x 50 mL). The combined organic layers were washed with H2O (2 x 50 mL), dried with anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure to yield the product (150 mg) as a solid. LCMS (ESI) m / z calculated for C11H14FNO3S2, 291.04; 292.10 [M+H]+ was obtained. Step 7: 2-[({2-[(1-Fluorocyclopropyl)sulfanyl]-4-methylpyridin-3yl}methyl)sulfanyl]-3H,5H,6H,7H-cyclopenta[d]pyrimidin-4-one

[0480] To a mixture of 2-sulfanyl-3H,5H,6H,7H cyclopenta[d]pyrimidin-4-one (95 mg, 0.57 mmol) and DIEA (332 mg, 2.58 mmol) in DMF (5 mL) at rt, {2-[(1-fluorocyclopropyl)sulfanyl]-4-methylpyridin-3-yl}methyl methanesulfonate (150 mg, 0.52 mmol) was added in portions. The mixture was stirred at rt for 1 h, then filtered, and the filter mass was washed with EtOAc (3 x 5 mL). The filtrate was concentrated under reduced pressure, and the residue was purified by reversed-phase column chromatography [conditions: column, silica gel C18; Mobile phase, H2O (TFA) in MeCN, gradient from 25% to 50% in 10 min] to generate the product (135 mg, 72%) as a solid.LCMS (ESI) m / z calculated for C17H18FN3OS2, 363.09; was obtained, 364.10 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 8.36 (d, J = 4.8 Hz, 1H), 7.15 (d, J = 4.8 Hz, 1H), 4.42 (s, 2H), 2.80 - 2.76 (m, 2H), 2.62 - 2.58 (m, 2H), 2.58 - 2.49 (m, 3H), 2.01 - 1.95 (m, 2H), 1.61 - 1.54 (m, 2H), 1.23 - 1.21 (m, 2H);19F NMR (376 MHz, DMSO-d6) δ -73.5, -153.8. Example 57: Clomeleon In Vitro Assay

[0481] A study was conducted to determine the Clomeleon EC50 in NG-108 cells using compounds from Table 1. Comparing the meta and para positions of nitrogen with respect to sulfur, meta N-pyridine, Compound 2, showed equal potency to para N-pyridine, Compound 168. When nitrogen is in the meta position with respect to sulfur, the ortho-methyl compounds, Compounds 61 and 114, showed less potency than the ortho-dimethyl compound. Petition 870250110266, dated 01 / 12 / 2025, pp. 400 / 473 160 / 214 Compound 2. Replacing the methyl group with a chlorine group reveals that the chlorine at position 6, Compound 5, is less potent than its regioisomer, Compound 4, where the chlorine is at position 2. Experimental Methods

[0482] A fluorometric assay in NG-108 cells using the Clomeleon Cl-sensitive indicator assay was performed as previously described (Gagnon et al. Nature Medicine, 2013, 19, 1524-1528). The results of the study are provided in Table 3. Table 3 Clomeleon Compound No. EC50 (nM) 1 0 Cl HN^Sr-^\ +++ 2 0 HN li—5 +++ - / W\ I φχ +++ 5 o Cl ΗΚΙ'^ΎΥ ij'^Y^'S'^N ^'Ιψ''' ++ 9 ο +++ 12 ο OMe HN'^Y'A +++ Petition 870250110266, dated 01 / 12 / 2025, pages 401 / 473 161 / 214 No. of Compound Clomeleon EC50 (nM) 13 or OMe HN |TN +++ 14 or OMe HN |F^> +++ 15 0 OMe HN |T—\ +++ 34 0 i hiV> ^N^NHa + 42 o ^o HN l^N^42 ^Y^+S iT~N cm Ά JEy Yl^Y^s N ^KT' + 61 0 HN |Γ—\ ^l\T ++ 70 ο ^O ΗΝ^γγΑ lY^Y^S^JS -^-7 +++ 72 0 OCD3 Η^Ν'^'^Κ +++ Petition 870250110266, dated 01 / 12 / 2025, p. 402 / 473 162 / 214 N.° of Compound Clomeleon EC50 (nM) 78 o 1 HN |ΤΛ +++ Η -1 N'TlCFa 81 O 1 HN ll—\ +++ H .1 ^n^ochf2 83 O 1 HN iT^\ +++ rf + SNN H3 SMe 8 |T—\ +++ H 89 o 1 HN^Ti—\ itj| y +++ [1 ή >—7 94 0 cf3hn |U\ +++ [IJ| N'^- 95 o 1 HN lT^\ +++ H ^N\2F3 114 o HN lT^\ ++ |l N^ Petition 870250110266, dated 01 / 12 / 2025, p. 403 / 473 163 / 214 No. of Compound Clomeleon EC50 (nM) 167 0 Cl HN' n^\ +++ íl x 168 0 HN' Sn +++ [| N^í 169 0 Cl HN' s^ +++ [| N^ ΌΙ 171 o HN' ll ''s +++ íl N'x<^' 173 O HN' jT )s +++ (1 ^i\r ''CFg 178 OH SMe N nT +++ 181 OH OMe N +++ Q jC Al^' 'CHF2 182 O cf+3 HN+Ι +Ι Petition 870250110266, of 01 / 12 / 2025, p. 404 / 473 164 / 214 N.° of Compound Clomeleon EC50 (nM) 183 0 ά s +++ 184 OH OMe òc -------N +++ 185 OH OEt ÔC xÃÒO SN +++ ο·Ύ case ++ U 1 X^N^''7 188 O +++ jfjT ''MC'' 'CF3 190 0 ΓΥ HN ιΓ^> <CF3 +++ 191 o fj FaC'^N'' HxV) +++ Petition 870250110266, of 01 / 12 / 2025, p. 405 / 473 165 / 214 N.° of Compound Clomeleon EC50 (nM) 192 ο HN jO +++ N'x^ / 1 193 0 HN' íi / x A Av fSN ++ N 194 o HN' AA / +++ í| Axs->xn'^ / N 195 o HN' ιΓλ +++ íl Ί |l \ 203 o HN jO +++ Vs 205 o HN iT> Π / ^N^·7 +++ xs À 211 o HN'A-'X ++ íl Petition 870250110266, of 01 / 12 / 2025, p. 406 / 473 166 / 214 Clomeleon Compound No. EC50 (nM) 213 ON HN |Γ\ +++ ^rr^cF3 220 OI 1 ΪΪ +++ + indicates potentiation effect > 1 μM; ++ indicates a potentiation effect of 1 to 0.1 μM; +++ indicates a potentiation effect < 0.1 μM. Example 58: In vitro inhibition of CYP3A4 by Compounds 1, 2, 4, 5, 13, 34, 61, 87-89, 95, 114, 163-170, 173, 183 and 190

[0483] A study was conducted to determine the CYP3A4 inhibition of Compounds 1, 2, 4, 5, 13, 34, 61, 87-89, 95, 114, 163-170, 173, 183 and 190 in human liver microsomes.

[0484] Multiple studies were conducted to determine the CYP3A4 inhibition of Compounds 1, 2, 4, 5, 13, 34, 61, 87-89, 95, 114, 163-170, 173, 183, and 190 in human liver microsomes. Compounds 163 and 165-170 showed considerable safety signaling, as these compounds were potent inhibitors of CYP3A4 (IC50 values ​​ranged from 0.2 to 5 μM, including high microsomal protein binding, which may further underestimate their potency to inhibit CYP3A4). CYP3A4 is the key enzyme that mediates the metabolism of most marketed drugs in the liver and intestine. Therefore, a high risk of drug interactions cannot be ruled out according to current FDA guidelines, which presents a particular challenge for chronic neurological disorders, since intensive comedication is often necessary (e.g., the use of midazolam in epilepsy). Conversely, when nitrogen was moved to the Petition 870250110266, dated 01 / 12 / 2025, pages 407 / 473 167 / 214 meta position relative to sulfur, Compounds 1, 2, 4, 5, and 164 had CYP3A4 IC50 values ​​mostly greater than 50 μM. Compound 2 had a surprisingly higher CYP3A4 IC50 value than Compound 61. Compounds 13, 34, 87-89, 95, and 183 had CYP3A4 IC50 values ​​mostly greater than 50 μM. Experimental methods

[0485] 1 μL of multiple concentrations of the 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 μM.

[0486] The main solution was prepared according to Table 4 and preheated in a water bath at 37 °C for 5 minutes. 179 μL of main solutions were transferred to an incubation plate. In the mixed system, the final concentrations of the test compound and the positive control compound were 0, 0.001, 0.005, 0.01, 0.05, 0.25, 1, 10, and 50 μL. All experiments were performed in duplicate. Table 4. Preparation of the Master Solution Reagent Stock Concentration Volume Final Concentration MgCl2 Solution 50 mM 20 pL 5 mM Phosphate Buffer 200 mM 100 pL 100 mM Ultrapure H2O - 56 pL - Human Liver Microsomes 20 mg / mL 2 pL 0.2 mg / mL Substrate 1 mM 1 pL 5 pM

[0487] The reaction was initiated by adding 20 μL of 10 mM NADPH solution to a final concentration of 1 mM and carried out at 37 °C. The reaction was stopped by adding 2 volumes of cold methanol with IS (100 nM alprazolam, 200 nM imipramine, 200 nM labetalol, and 2 μM 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 the protein. A 100 μL aliquot of Petition 870250110266, dated 01 / 12 / 2025, pp. 408 / 473 The 168 / 214 supernatant was diluted with 100 μL of ultrapure H2O, and the mixture was used for LC-MS / MS analysis. All data analysis calculations were performed using Microsoft Excel. Metabolite formation was analyzed using LC-MS / MS. A decrease in metabolite formation in the peak area for the vehicle control was used to calculate an IC50 value (concentration of the test compound that produces 50% inhibition) using Excel Xlfit. The results of the study are presented in Table 5. Table 5 Compound No. CYP3A4 (M) IC50 (μM) Compound 1 0 Cl HN'jr-'X (Y-aP 16 Compound 5 0 Cl HN |U\ >50 Compound 4 0 1 <v>>50 Compound 2 0 >50 Compound 163 O Cl hn^S 4.7 Compound 164 0 Cl HN |] rjAy^s^N·^ 49.4 Compound 165 0 N HN Ύ nA Petition 870250110266, dated 01 / 12 / 2025, p. 409 / 473 169 / 214 CYP3A4 Compound No. (M) IC50 (µΜ) Compound 166 O 0.56 Compound 167 0 ci HN |1—\ 0.2 Compound 168 0 ApsA / O 0.7 Compound 169 0 ci HN |18 O—\ 0.5 Compound 61 0 1 HfY> N 7.24 Compound 114 0 HN ιΓΑ Ά / ^Ι'Γ''· >50 Compound 13 0 OMe HN |ΓΛ ijPXXS'X^N'^7 >50 Compound HN 34 / N > TA 0 Petition 870250110266, dated 01 / 12 / 2025, p. 410 / 473 170 / 214 CYP3A4 Compound No. (M) IC50 (μΜ) Compound 87 0 ÇAo >50 Compound 88 0 >50 Compound 89 0 . hxV> Ή'η—7 >50 Compound 95 0 íi ίΓ sn kN^CF3 >50 Compound 173 O 1 H / v> 40.4 Compound 183 0 i HN ii—5 ^isr^S >50 Compound 190 CF— O 2 ^H Example 59. In vivo Pharmacokinetics of Two Compounds 2, 4, 5, 13, 61, 114, 163, 164, 167, 168, 169, 209, and 210

[0488] A study was conducted to determine the pharmacokinetics Petition 870250110266, dated 01 / 12 / 2025, pp. 411 / 473 Compounds 2, 4, 5, 13, 61, 114, 163, 164, 167, 168, 169, 200, and 210 were cleared in vivo in male Sprague Dawley rats. Compounds 2, 4, and 5 had surprisingly lower clearance than compounds 167 and 168. Compound 2 had surprisingly lower clearance than compound 210, making it more likely to be effective at a lower dose in humans with the option of QD or BID administration. Compound 2 had surprisingly lower clearance than compounds 61 and 114, making it more likely to be effective at a lower dose in humans with the option of QD or BID administration. Compounds 167 and 169 had surprisingly lower clearance than compounds 163 and 164, making them more likely to be effective at a lower dose in humans with the option of QD or BID administration.Compound 13 had a surprisingly lower clearance than compounds 169 and 202, making them more likely to be effective at a lower dose dosage in humans with the option of QD or BID administration. Experimental protocols

[0489] 1 mg / mL of the test compound was formulated as an IV solution in 10% NMP, 60% PEG400, and 30% water. Formulations were prepared on the day of dosing and stored at room temperature prior to administration. 10 μL aliquots were removed and stored in a freezer to maintain a temperature of -80 °C. Dose samples were diluted and analyzed against the plasma standard curve. Male Sprague-Dawley rats, 68 weeks old, had free access to food and water. Three rats per compound were administered 1 mg / kg to 1 mL / kg IV. After IV administration, blood samples (0.1-0.2 mL) were serially collected from the jugular vein 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours post-dose. Blood samples were collected in tubes containing K2EDTA as an anticoagulant. Plasma samples were prepared Petition 870250110266, dated 01 / 12 / 2025, pages 412 / 473 172 / 214 by centrifugation and distributed into 1.5 mL matrix tubes. Samples were stored in a freezer to maintain a temperature equal to or less than -80 °C before analysis. Residual blood cells were discarded. The plasma concentration of each test compound was determined respectively by protein precipitation and liquid chromatography with mass spectrometry detection (LC-MS / MS). Calibration standards were prepared on the spot in male SD rat plasma using each test compound.

[0490] The analysis was performed on batches containing all IV samples, calibration standards at eight concentration levels, and quality control (QC) samples at four concentration levels in duplicate. The analytical run acceptance criterion for calibration standards and QC samples was that at least 80% of the calculated concentrations back to calibration standards and at least 2 / 3 of the QC samples (at least 50% at each concentration level) were within ±20% of the nominal value.

[0491] Parameters were estimated using Phoenix pharmacokinetic software (WinNonlin) using a non-compartmental approach consistent with the IV route of administration. All parameters were generated for the individual plasma concentrations of each test compound and nominal dose levels. Parameters were estimated using sampling times relative to the start of each dose administration (within an acceptable tolerance limit). Observed in vivo clearance was reported in mL / min / kg. The observed clearance results from the study are provided in Table 6, reported as a fold change relative to the in vivo clearance of its comparator. Table 6 Compound Comparator Fold Change relative to comparator Compound 5 0 Cl HN |ΓΑ AρΑΛ / Compound 167 0 ci hn'yA 1.8x reduction Petition 870250110266, dated 01 / 12 / 2025, pages 413 / 473 173 / 214 Compound Comparator Fold Change relative to comparator Compound 4 0 I HN y K Compound 167 0 XXÓO [ls NN^\ 4.5x Reduction Compound 2 OH 1 £jO ifX''5 Compound 168 0 1.6x Reduction Compound 2 OH 1 JOO íúS5 n Compound 210 O zuA 12x Reduction Compound 2 OH 1 JOO íúS5 Compound 114 0 HíV> γίϊγζΧ-8'Λ'N·>^ / 4x Reduction Compound 2 OH 1 IÍjO oS5 N Compound 61 0 (Y,* / 6x Reduction Compound 167 0 ci HN |1—\ N^x Compound 163 OH ci N<|| ΝχΤχ. 22.8x reduction Compound 169 0 Cl HN |ΓΆ NY^ci Compound 164 0 ci HN |1 íj^i^S^N^ ^N^CI 1.6x reduction Compound 13 0 OMe HN | <a composto 209 oh ome n^|| ócsanj^ redução de 52x petição 870250110266, 01 12 2025, pág. 414 473 174 214 e1. um composto fórmula (i): ο fórmula i, ou um sal farmaceuticamente aceitável do mesmo, em que r1é, independentemente, h, halogênio, c1-c6 alquil opcionalmente substituído, cicloalquil heterociclo cf3, sr5a, nr5ou or5, r4é, c1-6 r3e r4, juntamente com os átomos a cada está ligado, se juntam para formar carbociclo aromático não 5 6 membros; r2, r3são, um, c5-c12 aril heteroaril c3-c12 c2-c8 alquenil alquinil c7-14 arilalquil (ch2)noz, c(o)z, c(o)oz, c(o)nz2, nr5, sr5aou r2e r3juntamente 415 175 nr6 a é substituído por alquil, aril, cicloalquil, heterociclo, o juntado através mais carbono; n 0, 1,2 3; m r5é, r5aé, r6é, c3-c6 c(o)r7, so2r7ou c3c6 substituído; r7é, alquil; e z é, h e2. r1é 416 176 n(r5)2, s(o)r14, so2r14ou s(n)r14; r4é so2r14, s(n)r14, r2é c2c8 c7-c14 (ch2)poz, r3é c3c12 :6^\anr6)m ]| ò )m \rs^jrnr® , c1c6 417 177 p heteroalquil c(o)r15, c(o)or15, so2r15ou r15é, r13é, r14é, me cl, então r4não h; r1não r1e ambos, são r1, todos 418 178 e3. c3-12 carbono 7 r3, 419 179 :6 x ~-nr6)m () cic6 1, 2 c(o)or7, 420 180 e4. 421 181 i6 xz^-nr6)m r7é 422 182 e5. (ii): (ii), c3-12cicloalquil sr5, 423 183 sr5ou °. á _orc r12é c(o)ra', orcou^ rarb, ra' oh, c1-c8 c6-c14 raé ch2nh c(rd)2o, rdé independentemente c1c8 heteroaril; rbé 424 184 alcóxi n(re)2, rcé reé e6. 425 185 c5-12 r15é 426 186 o, orcou e7. o composto, acordo qualquer uma das modalidades 5, (i-a): r4 r® r2n hn r1 (i-a), mesmo; e8. r4 r3a. ua ό ,s="NR13" in '0 t] 'nr' nr6ou nr6, c1petição 427 187 c6 e9. (i-b): (i-b) to e10. 1 428 188 e11. e12. (i-c): a-uo® (i-c) '____ £sznrel^nr6 j0. jq xteδ. * x n- t π; e13. (i-c) 429 189 e14. (i-d): (i-d) ò)m e15. 430 190 e16. (i-e): 0 (i-e) e17. (i-e). e18. 431 191 (i-h): (i-h), e19. (i-j): (i-j), carbono. e20. (i-f): r9o s (i-f) 432 192 r7, r8, r9e r10são, c2-8 -(ch2)noz, -c(o)z, -c(o)nz2, or5ou nr5; e21. r2^n^r1(i-f) r9, r10e r11são, n(r5)2; e22. (i-g): (i-g) 433 193 or5ou e23. r11(i-g) e24. deacordo> from 1 to 16 and from 17 to 20, where * is ; E25. The compound, according to any of the embodiments from 1 to 6, in which R2 is halo; E26. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, wherein R1 is halo; E27. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, in which R1 is methyl; E28. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, in which R4 is methyl; E29. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, wherein R1 is ethyl; E30. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, wherein R4 is ethyl; Petition 870250110266, dated 01 / 12 / 2025, pp. 434 / 473 194 / 214 E31. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, in which R1 is OMe; E32. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, in which R2 is OMe; E33. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, in which R3 is OMe; E34. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, in which R4 is OMe; E35. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, in which R1 is NH2; E36. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, in which R2 is NH2; E37. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, in which R3 is NH2; E38. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, in which R4 is NH2; E39. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, wherein R1 is NHMe; E40. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, in which R4 is NHMe; E41. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, in which R1 is NMe2; E42. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, in which R4 is NMe2; E43. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, in which R1 is CF3; E44. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, in which R4 is CF3; Petition 870250110266, dated 01 / 12 / 2025, pp. 435 / 473 195 / 214 E45. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, in which R1 is OCF3; E46. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, in which R4 is OCF3; E47. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, in which R1 is CHF2; E48. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, in which R4 is CHF2; E49. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, in which R1 is OCHF2; 50. The compound, according to any of the embodiments from 8 to 24, in which R4 is OCHF2; E51. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, in which R1 is SMe; E52. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, in which R4 is SMe; E53. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, in which R1 is SCF3; E54. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, in which R4 is SCF3; E55. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, wherein R1 is SF5; E56. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, in which R4 is SF5; E57. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, in which R1 is CH2CF3; E58. The compound, according to any of the embodiments from 1 to 8 and from 18 to 24, in which R4 is CH2CF3; Petition 870250110266, dated 01 / 12 / 2025, pp. 436 / 473 196 / 214 of 1 of 1 of 1 of 1 of 1 of 1 of 1 of 1 of 1 of 1 of 1 E59. The compound, according to 18 to 24, where R4 is halo; E60. The compound, according to 18 to 24, where R1 is E61. The compound, according to 18 to 24, in which R4 is E62. The compound, according to 18 to 24, where R1 is E63. The compound, according to 18 to 24, in which R4 is; E64. The compound, according to with with with with from 18 to 24, where R1 is ; E65. The compound, according to 18 to 24, where R4 is oG; E66. The compound, according to 18 to 24, where R3 is halo; E67. The compound, according to 18 to 24, where R1 is E68. The compound, according to 18 to 24, where R1 is E69. The compound, according to 18 to 24, where R1 is M; E70. The compound, according to any of the modalities any any any any any any any any one one one one one one one one one one of the modalities of the modalities of the modalities of the modalities of the modalities of the modalities of the modalities of the modalities of the modalities of the modalities of any of the modalities Petition 870250110266, dated 01 / 12 / 2025, pp. 437 / 473 197 / 214 from 18 to 24, where R1 is ; E71. The compound, according to any of the embodiments from 1 to 24, in which R1 is SCH2CH3; E72. The compound, according to any of the modalities S' from 1 to 18 to 24, where R1 is E73. The compound, according to any of the modalities from 1 to 18 to 24, where R1 is E74. The compound, according to any of the modalities O' from 1 to 18 to 24, where R1 is E75. The compound, according to any of the embodiments from 2 to 6 of 1 to 21, wherein R1 is SO2CH3 or SO2CH2CH3; E76. The compound, according to any of the modalities from 1 to 18 to 24, in which R4 is E77. The compound, according to any of the modalities from 1 to 18 to 24, in which R4 is E78. The compound, according to any of the modalities from 1 to 18 to 24, where R4 is θ--- / ; E79. The compound, according to any of the forms from 1 to 18 to 24, where R4 is ; E80. The compound, according to 18 to 24, where R4 is SCH2CH3; any of the options E81. The compound, according to any of the modalities Petition 870250110266, dated 01 / 12 / 2025, pp. 438 / 473 198 / 214 .S' from 1 to 8 from 18 to 24, where R4 is E82. The compound, according to any of the modalities from 2 to 6 of 16 to 22, in which R4 is E83. The compound, according to any of the modalities O' from 1 to 8 and from 18 to 24, where R4 is from 2 to 6 E84. The compound, according to 16 to 22, where R4 is SO2CH3; any of the options E85. The compound, according to any of the embodiments of 1 Jc a 6, de 8 a 16, de 19 a 22 e de 24 a 84, in which E86. The compound, according to any of the embodiments from 1 to 6, from 8 to 16, from 19 to 22 and from 24 to 83, in which Xs E87. The compound, according to any of the modalities s. from 1 to 6, from 8 to 16, from 19 to 22 and from 24 to 83, where E88. The compound, according to any of the modalities from 1 to 6, from 8 to 16, from 19 to 22 and from 24 to 83, in which E89. The compound, according to any of the modalities ,s=o from 1 to 6, from 8 to 16, from 19 to 22 and from 24 to 83, in which E90. The compound, according to any of the embodiments from 1 to 6, from 8 to 16, from 19 to 22 and from 24 to 83, in which Y|)m ,S=NR13''o J E91. The compound, according to any of the modalities Petition 870250110266, dated 01 / 12 / 2025, pp. 439 / 473 199 / 214 from 1 to 6, from 8 to 16, from 19 to 22 and from 24 to 83, where )m 'NR13 E90. The compound, according to any of the modalities from 1 to 6, from 8 to 16, from 19 to 22 and from 24 to 83, in which structure: J o E92. A compound of the oo the the Petition 870250110266, dated 01 / 12 / 2025, pp. 440 / 473 200 / 214 Petition 870250110266, dated 01 / 12 / 2025, pp. 441 / 473 201 / 214 Petition 870250110266, dated 01 / 12 / 2025, pp. 442 / 473 202 / 214 E93. A compound with the following structure: oo o Petition 870250110266, dated 01 / 12 / 2025, pp. 443 / 473 203 / 214 Petition 870250110266, dated 01 / 12 / 2025, pp. 444 / 473 204 / 214 Petition 870250110266, dated 01 / 12 / 2025, pp. 445 / 473 205 / 214 Petition 870250110266, dated 01 / 12 / 2025, pp. 446 / 473 206 / 214 OH Petition 870250110266, dated 01 / 12 / 2025, pp. 447 / 473 207 / 214 or a pharmaceutically acceptable salt thereof; E94. The compound, according to any of the embodiments of oa 5, and of 21 to 89, in which R12eRt>; E95. The compound, according to any of the embodiments from 4 to 5 and from 21 to 89, in which Rbé Ci-Cs alkyl is optionally substituted; E96. The compound, according to embodiment 95, in which Rbé (CH2)5CH3, CH3, C(CH3)3 or CH(CH3)2; E97. The compound, according to any of the embodiments from 4 to 5 and from 23 to 94, in which Rbé Ci-Cs alkyl is substituted by carboxyl; E98. The compound, according to embodiment 97, in which Rbé (CH2)4COOH, CH2COOH, (CH2)2COOH, (CH2)3COOH, CH(CH3)(CH2)3COOH, C(CH3)2(CH2)3COOH or ^^X; E99. The compound, according to any of the embodiments from 5 to 6 and from 23 to 94, in which Rbé C1-C8 alkoxy is optionally substituted; E100. The compound, according to embodiment 98, in which Rbé Petition 870250110266, dated 01 / 12 / 2025, pp. 448 / 473 208 / 214 OCH2CH3 or E101. The compound, according to any of the embodiments from 5 to 6 and from 23 to 94, wherein Rbé N(Re)2, wherein each Re is independently H or C1-C8 alkyl; E102. The compound, according to any of the embodiments from 5 to 6 and from 23 to 94, in which Rbé NHCH2CH3; E103. The compound, according to any of the embodiments from 5 to 6 and from 23 to 94, in which Raé CH2NH; E104. The compound, according to any of the modalities from 5 to 6 and from 23 to 94, in which Raé C(Rd)2O; E105. The compound, according to any of the embodiments from 5 to 6 and from 23 to 94, in which R12 is C(O)Ra'; E106. The compound, according to the 5-6 modality, in which Ra' is optionally substituted C1-C8 alkyl; E107. The compound, according to modality 106, in which Ra' is CH(CH3)2, C(CH3)3, CH2N(CH3)2, CH2CH3, or E108. The compound, according to any of the modalities from 5 to 6 and from 23 to 94, where R12 is OR°; E109. The compound, according to embodiment 107, in which each R is independently H or C(CH3)3; E110. The compound, according to embodiment 103, where Rd is CH2O or CH(CH3)O; Petition 870250110266, dated 01 / 12 / 2025, pp. 449 / 473 209 / 214 E111. The compound, according to the embodiment of 1 to 7, 10 to 13 and 16 to 22, where R1 is methyl and R4 is not H; E112. The compound, according to the modalities 1 to 7 and 16 to 22, in which R1 is Cl and R4 is not H; E113. The compound, according to the modalities of 1 to 7 and 16 to 22, in which R4 is Me and R1 is not H; E114. The compound, according to the modalities 1 to 7 and 16 to 22, in which R4 is Cl and R1 is not H; E115. The compound, according to embodiments 1 to 7 and 16 to 22, in which R2 is halo and R4 is not H; E116. The compound, according to embodiments 1 to 7 and 16 to 22, in which R2 is halo and R1 is not H; E117. The compound, according to embodiments 1 to 7 and 16 to 22, wherein R2 is H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C5-C12 aryl, optionally substituted C5-C12 heteroaryl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3C12 cycloalkyl, optionally substituted C7-C14 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, or R2 and R3 together with the atoms to which each is attached, combine to form a 5- to 6-membered aromatic or non-aromatic carbocycle or heterocycle; E118. The compound, according to embodiment 5 or 6, in which the compound of formula II has the structure: Petition 870250110266, dated 01 / 12 / 2025, pp. 450 / 473 210 / 214 a pharmaceutically acceptable salt thereof; E119. The compound, according to embodiment 5 or 6, in which the compound of formula II has the structure: or a pharmaceutically acceptable salt thereof; E120. A compound with the following structure: Petition 870250110266, dated 01 / 12 / 2025, pp. 451 / 473 211 / 214 Petition 870250110266, dated 01 / 12 / 2025, pp. 452 / 473 212 / 214 or a pharmaceutically acceptable salt thereof; E121. A pharmaceutical composition including a compound, according to any of the embodiments from 1 to 120, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient; E122. A method for treating a neurological disorder, including administering to a subject in need a therapeutically effective amount of a compound conforming to any of the embodiments from 1 to 120 or a pharmaceutically acceptable salt thereof; E123. The method, according to modality 122, in which the neurological disorder is a neurotraumatic disorder, a disorder of Petition 870250110266, dated 01 / 12 / 2025, pp. 453 / 473 213 / 214 neurodevelopment or an affective disorder; E124. The method, according to modality 122, in which the neurological disorder is a neurotraumatic disorder; E125. The method, according to modality 124, in which the neurotraumatic disorder is selected from the group consisting of 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, and peripheral neuropathy; E126. The method, according to modality 122, in which the neurological disorder is a neurodevelopmental disorder; E127. The method, according to modality 126, in which the neurodevelopmental disorder is selected from among an autism spectrum disorder, tuberous sclerosis complex (TSC), Rett syndrome, fragile X syndrome, Angelman syndrome, cerebral palsy, Down syndrome, pain, Dravet syndrome, epilepsy, and sudden unexpected death in epilepsy; E128. The method, according to modality 121, in which the neurological disorder is an affective disorder; E129. The method, according to modality 128, in which the affective disorder is schizophrenia, bipolar disorder, anxiety disorder, or major depressive disorder; and E130. The method, according to modality 128, in which the epilepsy is refractory epilepsy, epilepsy associated with neurotrauma (ischemia, stroke, traumatic brain injury), status epilepticus, tumor-associated epilepsy, and hypoxic-ischemic encephalopathy. Other modalities

[0493] Although the invention has been described in connection with Petition 870250110266, dated 01 / 12 / 2025, pages 454 / 473 214 / 214 specific embodiments thereof, it will be understood that it is also subject to further modifications, and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such deviations from the invention that fall within the known or customary practice of the art to which the invention belongs and that can be applied to the essential features set forth above in this document, and follows within the scope of the claims. Other embodiments are within the claims. < / v>

Claims

1. COMPOUND characterized by having the structure of: Formula I, or a pharmaceutically acceptable salt thereof, wherein R1 is H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-12 cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, SR5a, N(R5)2, OR5, S(O)R14, SO2R14 or S(N)R14; R4 is H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, OR5, SR5a, N(R5)2, S(O)R14, SO2R14 or S(N)R14, or R3 and 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;R2 is H, halogen, optionally substituted C1-C6 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 C7-14 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;R3 is H, halogen, optionally substituted C1-C6 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 alkynyl, 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 or R2 and R3, together with the atoms to which each is attached, combine to form an aromatic or non-aromatic carbocycle or heterocycle of 5 to 6 Petition 870250110266, dated 01 / 12 / 2025, page. 456 / 473 2 / 17 members; NR6 Ò)m NR6 or wherein A is optionally replaced by 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 R5 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C5-C12 aryl, or optionally substituted C3-C12 cycloalkyl; each R5a is independently H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 heterocycle, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C12 aryl, or optionally substituted C5-C12 heteroaryl; each R6 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, C(O)R15, C(O)OR15, SO2R15, or optionally substituted C3-C6 heterocycle; each R15 is independently C1-C6 alkyl. Each R13 is independently H, optionally substituted C1-C6 alkyl, or optionally substituted C3-C6 cycloalkyl;each R14 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 heterocyclo, 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-C6 alkyl; where if R1 is Me or Cl, then R4 is not H; where if R4 is Me or Cl, then R1 is not H; where if R2 is Me or Cl, then R1 and R4 are both not H; and where R1, R2, R3 and R4 are not all H.

2. COMPOUND, according to claim 1, characterized in that the compound of formula I has the structure: R2 × N' r1 (IA), or a pharmaceutically acceptable salt thereof.

3. COMPOUND, according to claim 1, characterized in that the compound of formula I has the structure: (IH), R2n (IK) or a pharmaceutically acceptable salt thereof.

4. COMPOUND of Formula (II): (II), or a pharmaceutically acceptable salt thereof characterized in that R1 is H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, SR5a, N(R5)2, OR5, S(O)R14, SO2R14 or S(N)R14; R4 is H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 heterocycle, CF3, OR5, SR5a, N(R5)2, S(O)R14, SO2R14 or S(N)R14; or R3 and R4, together with the atoms to which each is attached, combine to form a 5- to 6-membered aromatic or non-aromatic carbocycle or heterocycle;R2, R3 are each independently H, halogen, optionally substituted C1-C6 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 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, SR5a, S(O)R14, SO2R14 or S(N)R14 or R2 and R3, together with the atoms to which each is attached, combine to form a 5- to 6-membered aromatic or non-aromatic carbocycle or heterocycle; or wherein A is optionally replaced by C1-C6 alkyl, C5-C12 aryl, C3-C12 cycloalkyl, C5-C12 heteroaryl or C3-C12 heterocycle, optionally wherein 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 R5 is independently optionally substituted H, C1-C6 alkyl, optionally substituted C5-C12 aryl or optionally substituted C3-C12 cycloalkyl, each R5a is independently optionally substituted H, halogen, C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 heterocycle, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C12 aryl or optionally substituted C5-C12 heteroaryl, each R6 is independently optionally substituted H, C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, C(O)R7, C(O)OR7, SO2R7 or optionally substituted C3-C6 heterocycle; Each R7 is independently C1-C6 alkyl; each R13 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl;Each R14 is independently optionally substituted H, C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 heterocyclo, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C12 aryl, or optionally substituted C5-C12 heteroaryl; each Z is independently optionally substituted H or C1-6 alkyl and o. ~ / 0RC HM < Λ R12 is C(O)Ra', o»· or^»· , wherein Ra' is optionally substituted H, OH, C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C12 cycloalkyl, or optionally substituted C6-C14 aryl; and Ra is CH2NH or C(Rd)2O, where each Rd is independently H, C1-C8 alkyl, C1-C8 cycloalkyl, C1-C8 aryl, or C1-C8 heteroaryl;Rb is H, OH, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C3-C12 cycloalkyl, optionally substituted C6-C14 aryl or N(Re)2, each Rc is independently H, C1-C8 alkyl or C6-C14 aryl and each Re is independently H or C1-C8 alkyl; wherein R1, R2, R3 and R4 are not all H. Petition 870250110266, dated 12 / 01 / 2025, p. 460 / 473 6 / 17; 5. COMPOUND, according to any one of claims 1-4, characterized in that R2 is H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C5-C12 aryl, optionally substituted C5-C12 heteroaryl, OR5, N(R5)2, SR5a, S(O)R14, SO2R14 or S(N)R14; R3 is H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C5-C12 aryl, optionally substituted C5-C12 heteroaryl, OR5, N(R5)2, SR5a, S(O)R14, SO2R14 or S(N)R14 and R4 is H, halogen, optionally substituted C1-C6 alkyl, CF3, OR5, N(R5)2, SR5a, S(O)R14, SO2R14 or S(N)R14.

6. COMPOUND, according to claim 1 or 4, characterized by í / / / ^z—nr6 ifx ΊΟ'ι Ίθ)πι JÍ ())m %A <nr6 vw _ yVnr6 _ Λ , é e V , ~)n ,\ Dn ou On , em que A e opcionalmente substituído por C1-C6 alquil, C5-C12 aril, C3-C12 cicloalquil, C5-C12 heteroaril ou C3-C12 heterociclo, opcionalmente em que o C5-C12 aril, C3-C12 cicloalquil, C5-C12 heteroaril ou C3-C12 heterociclo e juntado a A atraves de um ou mais átomos de carbono.

7. COMPOUND, according to any one of claims 1-6, characterized in that R1 is a halogen.

8. COMPOUND, according to any one of claims 1-6, characterized in that R1 is Cl.

9. COMPOUND, according to any one of claims 1-6, characterized in that R1 is optionally C1-C6 alkyl substituted.

10. COMPOUND, according to any one of claims 1-6, characterized in that R1 is methyl, ethyl, propyl, CH2F, CHF2 or CF3.

11. COMPOUND, according to any one of claims 1-6, characterized in that R1 is optionally substituted C3-C12cycloalkyl. Petition 870250110266, dated 12 / 01 / 2025, pp. 461 / 473 7 / 17 12. COMPOUND, according to any one of claims 1-6, characterized in that R1 is .

13. COMPOUND, according to any one of claims 1-6, characterized in that R1 is an optionally substituted C3-C12 heterocycle.

14. COMPOUND, according to any one of claims 1-6, characterized in that R1 is ° sJ or s 15. COMPOUND, according to any one of claims 1-6, characterized in that R1 is SR5a.

16. COMPOUND, according to any one of claims 1-6, characterized in that R1 is SF5, SCH3, SCH2CH3 or SCF3.

17. COMPOUND, according to any one of claims 1-6, characterized in that R1 is OR5.

18. COMPOUND, according to any one of claims 1-6, characterized in that R1 is OCH3, OCH2CH3 or OCHF2.

19. COMPOUND, according to any one of claims 1-18, characterized in that R4 is a halogen.

20. COMPOUND, according to any one of claims 1-6, characterized in that R4 is Cl.

21. COMPOUND, according to any one of claims 1-18, characterized in that R4 is optionally C1-C6 alkyl substituted.

22. COMPOUND, according to any one of claims 1-18, characterized in that R4 is methyl, ethyl, propyl, CH2F, CHF2 or CF3.

23. COMPOUND, according to any one of claims 1-18, characterized in that R4 is SR5a.

24. COMPOUND, according to any one of claims 1-18, characterized by R4 being SF5, SCH3, SCH2CH3 or SCF3.

25. COMPOUND, according to any of the claims Petition 870250110266, dated 12 / 01 / 2025, pp. 462 / 473 8 / 17 1-18, characterized by R4ser OR5.

26. COMPOUND, according to any one of claims 1-18, characterized by R4 being OCH3, OCH2CH3 or OCHF2.

27. COMPOUND, according to claim 1, characterized in that the compound of formula I has the structure: (IB) (IC), (ID) or (IE) or a pharmaceutically acceptable salt thereof.

28. COMPOUND, according to claim 1, characterized in that the compound of formula I has the structure: RR R9 O R10 R4 (IG), or a pharmaceutically acceptable salt thereof, wherein R8, R9, R10 and R11 are each independently H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C5-C12 aryl, optionally substituted C2C8 alkenyl, optionally substituted C2-C8 alkynyl, 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.

29. COMPOUND, according to claim 1, characterized in that the compound of formula I has the structure: or Petition 870250110266, dated 01 / 12 / 2025, p. 463 / 473 9 / 17 or a pharmaceutically acceptable salt thereof.

30. COMPOUND, according to claim 1, characterized in that the compound has the structure of any of the compounds in Table 1, for example, where the compound has the structure of compound 1, compound 2, compound 4, compound 5, compound 67, compound 95 or compound 171 in Table 1.

31. COMPOUND, according to any one of claims 4-26, characterized by R12 being y Ra Rt>.

32. COMPOUND, according to any one of claims 4-26, characterized in that Rb is optionally C1-C8 alkyl substituted.

33. COMPOUND, according to any one of claims 4-26, characterized in that Rb is (CH2)5CH3, CH3, C(CH3)3 or CH(CH3)2.

34. COMPOUND, according to any one of claims 2-4, characterized in that Rb is C1-C8 alkyl substituted by carboxyl.

35. COMPOUND, according to any one of claims 4-26, characterized in that Rb is (CH2)4COOH, CH2COOH, (CH2)2COOH, (CH2)3COOH, CH(CH3)(CH2)3COOH, C(CH3)2(CH2)3COOH or 36. COMPOUND, according to any one of claims 4-26, characterized in that Rb is optionally substituted for C1-C8 alkoxy.

37. COMPOUND, according to any of the claims o—|— O XV / 4-26, characterized by Rb being OCH2CH3 or .

38. COMPOUND, according to any of the claims in Petition 870250110266, dated 12 / 01 / 2025, pp. 464 / 473 10 / 17 4-26, characterized in that Rb is N(Re)2, where each Re is independently H or C1-C8 alkyl.

39. COMPOUND, according to any one of claims 4-26, characterized in that Rb is NHCH2CH3.

40. COMPOUND, according to any one of claims 4-26, characterized in that Ra is CH2NH.

41. COMPOUND, according to any one of claims 4-26, characterized in that Ra is C(Rd)2O.

42. COMPOUND, according to any one of claims 4-26, characterized in that Rd is CH2O or CH(CH3)O.

43. COMPOUND, according to any one of claims 4-26, characterized in that R12 is C(O)Ra'.

44. COMPOUND, according to any one of claims 4-26, characterized in that Ra' is optionally C1-C8 alkyl substituted.

45. COMPOUND, according to any of the claims 46. ​​COMPOUND, according to any of the claims in 4-26, characterized in that R12 is 0R= .

47. COMPOUND, according to claim 46, characterized in that Rc is independently H or C(CH3)3.

48. COMPOUND, according to any one of claims 46-47, characterized in that Ra is CH2NH.

49. COMPOUND, according to any one of claims 46-48, characterized in that Ra is C(Rd)2O. Petition 870250110266, dated 12 / 01 / 2025, pp. 465 / 473 11 / 17 50. COMPOUND, according to claim 49, characterized in that Rd is CH2O or CH(CH3)O.

51. COMPOUND, according to any one of claims 1-4 and 31-50, characterized in that R1 is methyl and R4 is not H.

52. COMPOUND, according to any one of claims 1-4 and 31-50, characterized in that R1 is Cl and R4 is not H.

53. COMPOUND, according to any one of claims 1-4 and 31-50, characterized in that R4 is Me and R1 is not H.

54. COMPOUND, according to any one of claims 1-4 and 31-50, characterized in that R4 is Cl and R1 is not H.

55. COMPOUND, according to any one of claims 1-4 and 31-50, characterized in that R2 is halo and R4 is not halo.

56. COMPOUND, according to any one of claims 1-4 and 31-50, characterized in that R2 is halo and R1 is not H.

57. COMPOUND, according to any one of claims 1-4 and 31-50, characterized in that R2 is H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C5-C12 aryl, optionally substituted C5-C12 heteroaryl, optionally substituted C2C8 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, SR5a, S(O)R14, SO2R14 or S(N)R14 or R2 and R3 together with the atoms to which each is attached, combine to form a 5- to 6-membered aromatic or non-aromatic carbocycle or heterocycle.

58. COMPOUND, according to claim 4, characterized in that the compound of formula II has the structure: Petition 870250110266, dated 01 / 12 / 2025, p. 466 / 473 12 / 17 or a pharmaceutically acceptable salt thereof.

59. COMPOUND, according to claim 4, characterized Petition 870250110266, dated 01 / 12 / 2025, p. 467 / 473 13 / 17 or or a pharmaceutically acceptable salt thereof.

60. COMPOUND, according to claim 4, characterized in that the compound has the structure of any one of compounds 129-162 in Table 2.

61. COMPOUND of formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament, characterized in that formula (I) is: Formula I, wherein R1 is H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-12 heterocycle, CF3, SR5a, N(R5)2, OR5, S(O)R14, SO2R14 or S(N)R14; R4 is H, halogen, optionally substituted C1-C6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycle, CF3, OR5, SR5a, N(R5)2, S(O)R14, SO2R14 or S(N)R14 or R3 and R4, together with the atoms to which each is attached, combine to form a 5- to 7-membered aromatic or non-aromatic carbocycle or heterocycle;R2 is H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C5-C12 aryl, optionally substituted C5-C12 heteroaryl, optionally substituted C3C12 heterocycle, 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, SR5a, S(O)R14, SO2R14 or S(N)R14; R3 is H, halogen, optionally substituted C1-C6 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 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, SR5a, S(O)R14, SO2R14 or S(N)R14;or R2 and 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; / x / ~NR8 / x / ^NR8 1 J ())m Ά1-0 or , where A is optionally replaced by C1-C6 alkyl, C5-C12 aryl, C3-C12 cycloalkyl, C5-C12 heteroaryl or C3-C12 heterocycle, optionally where 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 R5 is independently optionally substituted H, C1-C6 alkyl, optionally substituted C5-C12 aryl, or optionally substituted C3-C12 cycloalkyl; and each R5a is independently optionally substituted H, halogen, C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 heterocycle, optionally substituted C3-C6 cycloalkyl, optionally substituted C5-C12 aryl, or optionally substituted C5-C12 heteroaryl; each R6 is independently optionally substituted H, C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, C(O)R7, C(O)OR7, SO2R7, or optionally substituted C3-C6 heterocycle. Each R7 is independently C1-C6 alkyl; each R13 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl;each R14 is independently H, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted C3-C6 heterocyclo, 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; where R1, R2, R3 and R4 are not all H.

62. PHARMACEUTICAL COMPOSITION characterized by comprising a compound as defined in any one of claims 1 to 60 and a pharmaceutically acceptable excipient.

63. COMPOUND, according to any one of claims 1 to 60, or pharmaceutical composition, according to claim 61, characterized in that it is for use as a medicament.

64. METHOD OF TREATING OR PREVENTING PAIN, particularly neuropathic pain, inflammation, inflammatory pain, arthritic pain, diabetic pain or neuralgia in a subject in need, the method characterized by including administering to the subject an effective amount of a compound as defined in any of claims 1 to 61 or of a pharmaceutical composition as defined in claim 62.

65. A METHOD FOR TREATING EPILEPSY in a subject in need, the method characterized by including administering to the subject an effective amount of a compound as defined in any one of claims 1 to 61 or of a pharmaceutical composition as defined in claim 62.

66. METHOD, according to claim 65, characterized in that the epilepsy is temporal lobe epilepsy, refractory epilepsy, neurotrauma-associated epilepsy, status epilepsy, tumor-associated epilepsy, hypoxic-ischemic encephalopathy, or sudden unexpected death in epilepsy.

67. A METHOD FOR TREATING NEURODEVELOPMENTAL DISORDERS in a subject in need, the method characterized by including administering to the subject an effective amount of a compound as defined in any one of claims 1 to 61 or of a pharmaceutical composition as defined in claim 62.

68. METHOD, according to claim 67, characterized in that the neurodevelopmental disorder is autism spectrum disorder, Rett syndrome, tuberous sclerosis complex, fragile X syndrome, Angelman syndrome, Down syndrome, Dravet syndrome, CKDL5 deficiency syndrome, SYNGAP1, cerebral palsy or Huntington's disease.

69. A METHOD FOR TREATING NEUROTRAUMATIC INJURY or neurodegenerative disease in a subject in need, the method characterized by including administering to the subject an effective amount of a compound as defined in any one of claims 1 to 61 or of a pharmaceutical composition as defined in claim 62.

70. METHOD, according to claim 69, characterized by the neurotraumatic injury or neurodegenerative disease being brain injury Petition 870250110266, dated 12 / 01 / 2025, page 471 / 473 17 / 17 traumatic, stroke, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, spasticity or spinal cord injury.

71. A METHOD FOR TREATING AFFECTIVE DISORDERS IN A SUBJECT in need, the method characterized by including administering to the subject an effective amount of a compound as defined in any one of claims 1 to 61 or of a pharmaceutical composition as defined in claim 62.

72. METHOD, according to claim 71, characterized in that the affective disorder is schizophrenia, bipolar disorder, generalized anxiety disorder, social anxiety disorder, or major depressive disorder.

73. METHOD FOR ENHANCED KCC2 ACTIVITY, clustering, dimerization or membrane expression in a cell or subject, the method characterized by comprising contacting the cell with, or administering to the subject, an effective amount of a compound as defined in any one of claims 1 to 61 or of a pharmaceutical composition as defined in claim 62.

74. METHOD FOR INCREASING CL EFFLUX or potentiating KCC2 activity in a cell or subject, wherein the method is characterized by comprising contacting the cell with, or administering to the subject, an effective amount of a compound as defined in any one of claims 1 to 61 or of a pharmaceutical composition as defined in claim 62.