Compounds and methods of use thereof

Abstract

We provide condensed heteroaryl compounds and compositions useful for preventing and / or treating diseases or conditions associated with abnormal function of voltage-gated sodium ion channels, such as abnormal delayed / persistent sodium currents. [Solution] In one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided. TIFF2026062794000384.tif2550 The invention also provides methods for treating diseases or conditions associated with abnormal function of sodium ion channels, including Dravet syndrome or epilepsy.

Description

[Technical Field]

[0001] Cross-references to related applications This application claims priority and benefits of U.S. Provisional Patent Application No. 62 / 427,044, filed November 28, 2016, U.S. Provisional Patent Application No. 62 / 458,306, filed February 13, 2017, and U.S. Provisional Patent Application No. 62 / 552,073, filed August 30, 2017, each of which is incorporated herein by reference as a whole. [Background technology]

[0002] Sodium ion (Na+) channels primarily open transiently and are rapidly inactivated, thereby generating a fast Na+ current and initiating an action potential. Delayed or sustained sodium currents (INaL) are the sustained components of the fast Na+ current in myocardium and neurons. Numerous common neurological and cardiac diseases are associated with an increase in abnormal INaL, which contributes to the pathogenesis of both electrical dysfunction and systolic dysfunction in mammals (see, e.g., Pharmacol.Ther. (2008) 119:326-339). Therefore, pharmaceutical compounds that selectively modulate sodium channel activity, for example, abnormal INaL, are useful in treating such conditions. [Prior art documents] [Non-patent literature]

[0003] [Non-Patent Document 1] Pharmacol.Ther.(2008)119:326-339 [Overview of the project] [Means for solving the problem]

[0004] This specification describes compounds and compositions of fused heteroaryls useful for preventing and / or treating a disease, disorder or condition, such as a disease, disorder or condition associated with abnormal function of a sodium ion channel, such as an abnormal late sodium current (INaL). In one aspect, the present disclosure provides a compound of formula (I): [Chemical Formula] characterized by a compound of or a pharmaceutically acceptable salt thereof, wherein each of X, Y, and Z is independently N or CR 2 and at least one of X, Y, and Z is independently N; A is aryl or heteroaryl (e.g., monocyclic 6-membered aryl or heteroaryl), each of which is optionally substituted by one or more R 3 ; R 2 is hydrogen, alkyl, or halo; R 1 is hydrogen, alkyl, alkenyl, alkynyl, -OR b , carbocyclyl, heterocyclyl, aryl, heteroaryl, wherein alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are optionally substituted by one or more R 4 ; each R 3 is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, -OR c , -N(R d )2, -C(O)R c , -C(O)OR c , or -C(O)N(R d )2, wherein alkyl, carbocyclyl, and heterocyclyl are optionally substituted by one or more R 5 ; each of R 4 and R 5 is independently alkyl, carb ocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, -OR c , -C(O)N(R d )2, -SO2R c , -SO2ORc , -SO2N(R d )2, -NR d C(O)(R c ), or -N(R d )2, and in this case, alkyl, carbocyryl, heterocyclyl, aryl, and heteroaryl are 1 or more R 7 Optionally substituted by; each R b is hydrogen; each R c R is independently hydrogen, alkyl, carbocyryl, heterocyclyl, aryl, or heteroaryl, where alkyl, aryl, and heteroaryl are 1 or more R 6 Optionally substituted by; each R d These are independently hydrogen or alkyl, in which case each alkyl has 1 or more R 6 Optionally substituted by; each R 6 R is independently alkyl, carbocyryl, heterocyclyl, halo, cyano, nitro, or -OH; and each R 7 These are independently alkyl, halo, or oxo. In one aspect, the present disclosure provides a method for treating a neurological or psychiatric disorder, the method comprising formula (I): [ka] This includes administering a compound or a pharmaceutically acceptable salt thereof. During the ceremony, Each of X, Y, and Z is independently N or CR 2 And in that case, at least one of X, Y, and Z is independently N; A is an aryl or heteroaryl ring, each of which has any one or more R 3 Replaced by; R 1 is hydrogen, alkyl, alkenyl, alkynyl, -OR b , carbocyclyl, heterocyclyl, aryl, or heteroaryl, in which case alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may optionally contain one or more R 4Replaced by; R 2 is hydrogen, alkyl, or halo; Each R 3 These are independently alkyl, carbocyrill, heterocyclyl, halo, cyano, nitro, -OR c , -N(R d )2, -C(O)R c , -C(O)OR c , or -C(O)N(R d )2, in which case alkyl, carbocykyl and heterocyclyl are optionally 1 or more R 5 Replaced by; R 4 and R 5 Each of these can independently be alkyl, carbocyryl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, -OR c ,-C(O)N(R d )2, -SO2R c , -SO2OR c , -SO2N(R d )2, -NR d C(O)(R c ), or -N(R d )2, in which case alkyl, carbocykyl, heterocyclyl, aryl, and heteroaryl are optionally 1 or more R 7 Replaced by; Each R b is hydrogen; Each R c R is independently hydrogen, alkyl, aryl, or heteroaryl, where alkyl, aryl, or heteroaryl can optionally contain one or more R 6 Replaced by; R d Each is independently hydrogen or alkyl, and each alkyl can optionally contain one or more R 6 Replaced by; Each R 6 is independently alkyl, carbocyryl, heterocyclyl, halo, cyano, nitro, or -OH; and Each R 7 These are independently alkyl, halo, or oxo.

[0005] In another aspect, the present disclosure provides a method for treating a neurological or psychiatric disorder, the method being applied to a subject requiring the use of formula (I-2): [ka] This includes administering a compound or a pharmaceutically acceptable salt thereof. During the ceremony, X, Y, and Z are independently N or CR 2 And in that case, at least one of X, Y, and Z is independently N; A is an aryl or heteroaryl ring, each of which has any one or more R 3 Replaced by; R 1 is hydrogen, alkyl, alkenyl, alkynyl, -OR b , -N(R d )2, a carbocyclyl, heterocyclyl, aryl, or heteroaryl, in which case alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl may optionally contain one or more R 4 Replaced by; R 2 is hydrogen, alkyl, halo, N(R) d )2, -C(O)OR c , -NR d C(O)(R c ), or -C(O)N(R d )2 、 In this case, the alkyl group may optionally be substituted with -OH or -O-alkyl groups; Each R 3 These are independently alkyl, carbocykyl, heterocyclyl, halo, cyano, nitro, -OR c , -N(R d )2, -C(O)R c , -C(O)OR c , or -C(O)N(R d )2 、 In this case, alkyl, carbocyryl, and heterocyclyl may optionally have 1 or more R 5 Replaced by; R4 and R 5 Each of which is independently alkyl, carbocyclic, heterocyclic, aryl, heteroaryl, halo, cyano, nitro, -OR c , -C(O)N(R d )2, -SO2R c , -SO2OR c , -SO2N(R d )2, -NR d C(O)(R c ), or -N(R d )2, wherein alkyl, carbocyclic, heterocyclic, aryl, and heteroaryl are optionally substituted by one or more R 7 ; Each R b is hydrogen, alkyl, heteroaryl, or aryl, wherein alkyl or aryl is optionally substituted by one or more halogens; Each R c is independently hydrogen, alkyl, aryl, or heteroaryl, wherein alkyl, aryl, or heteroaryl is optionally substituted by one or more R 6 ; R d is independently hydrogen or alkyl, wherein each alkyl is optionally substituted by one or more R 6 ; wherein two R d can together with the nitrogen atom to which they are attached form a heterocycle; Each R 6 is independently alkyl, carbocyclic, heterocyclic, halo, cyano, nitro, or -OH; and Each R 7 is independently alkyl, halo, or oxo.

[0006] In some embodiments, the neuropathy is epilepsy.

[0007] In some embodiments, the neuropathy is epileptic encephalopathy.

[0008] In some embodiments, epileptic encephalopathy includes Dravet syndrome, infantile seizures, or Lennox-Gastaut syndrome.

[0009] In some embodiments, X is N, and Y and Z are independently CR. 2 That is the case.

[0010] In some embodiments, Y is N, and each of X and Z is independently CR 2 That is .

[0011] In some embodiments, Z is N, and X and Y are independently CR 2 That is the case.

[0012] In some embodiments, R 2 It is hydrogen.

[0013] In some embodiments, A is 1 to 3 R 3 This is an arrow that is replaced by [another arrow].

[0014] In some embodiments, A is phenyl.

[0015] In some embodiments, A is 1 to 3 R 3 It is a heteroaryl that is substituted by [the specified agent].

[0016] In some embodiments, A is pyridyl.

[0017] Some implementation methods, each R 3 These are independently alkyl, halo, cyano, carbocyric, or -OR c That is the case.

[0018] In some embodiments, R 3 is alkyl or -OR c That is the case.

[0019] In some embodiments, R 1 It is an alkyl or carbocyric.

[0020] In some embodiments, R 1 is a substituted alkyl group.

[0021] In some embodiments, R 1 This is a halo, heterocyclyl, or alkyl group substituted with -OH.

[0022] In some embodiments, R 1 It is -CF3.

[0023] In some embodiments, the compound is [ka] [ka] [ka] Alternatively, a selection of pharmaceutically acceptable salts thereof is used.

[0024] In some embodiments, the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] Alternatively, a selection of pharmaceutically acceptable salts thereof is used.

[0025] In another embodiment, this disclosure is formula (III): [ka] Provides compounds or pharmaceutically acceptable salts thereof, During the ceremony, R 1 is hydrogen, C1 alkyl, C 1-6 Haloalkyl, or C 3-8 It is a carbocyclyl, in which case C1 alkyl, C 1-6 Haloalkyl, or C 3-8 Carbocyclyl can optionally have one or more halos, a 3- to 8-membered heterocyclyl ring, or -OR. c Replaced by; R 3 is C 1-6 Alkyl, halo, cyano, nitro, C 3-8 Carbocyclyl, heterocyclyl with 3-8 membered rings, -OR 7 , -N(R d )2, -C(O)R c , -C(O)OR c , or -C(O)N(R d )2 、 At that time, C 1-6 Alkyl, C 3-8 Carbocyclyls, or heterocyclyls with a 3- to 8-membered ring, may optionally contain one or more R 5 Replaced by; R 4is C 1-6 Alkyl, halo, cyano, nitro, C 3-8 Carbocyclyl, heterocyclyl with 3-8 membered rings, -OR c , -N(R d )2, -C(O)R c , -C(O)OR c , or -C(O)N(R d )2 、 At that time, C 1-6 Alkyl, C 3-8 Carbocyclyls, or heterocyclyls with a 3- to 8-membered ring, may optionally contain one or more R 5 Replaced by; m is either 1 or 2; Each R 5 These are independently Halo, Cyano, Nitro, and C 1-6 Alkyl, C 3-8 Carbocyclyl, heterocyclyl with 3-8 membered rings, -OR c ,-C(O)N(R d )2, -SO2R c , -SO2OR c , -SO2N(R d )2, -NR d C(O)(R c ), or -N(R d )2; Each R c These are independently hydrogen or C 1-6 It is an alkyl group, and in this case, each C 1-6 Alkyl can optionally have 1 or more R 6 Replaced by; Each R d These are independently hydrogen or C 1-6 It is alkyl; Each R 6 These are independently halogen, cyano, and C 3-8 Carbocyclyl, or a heterocyclyl with a 3- to 8-membered ring; in this case, C 3-8 Carbocyclyl may optionally be substituted with one or more halogens or cyanosides; R 7 C 1-6 Alkyl or C 3-8 It is carbocyclyl, and in that case, C 1-6 Alkyl or C 3-8Carbocyclyl optionally has a R value of 1 or higher. 6 Replaced by; At that time, the compounds were as follows: [ka] [ka] Or not one of those pharmaceutically acceptable salts.

[0026] In some embodiments, R 1 -OR is optional c C replaced by 1-6 C substituted with a haloalkyl or optionally one or two halogens 3-4 It is carbocyclyl.

[0027] In some embodiments, R 1 It is either CF3 or CHF2.

[0028] In some embodiments, R 3 は-OR 7 That is the case.

[0029] In some embodiments, R 7 C is optionally substituted with 1, 2, or 3 substituents selected from halogens or cyano compounds. 1-6 C optionally substituted with 1, 2, or 3 substituents selected from alkyl, halogen, or cyano 3-8 C substituted with carbocyclyl 1-6 C optionally substituted with one, two, or three substituents selected from alkyl, halogen, or cyano compounds. 3-8 It is carbocyclyl.

[0030] In some embodiments, R 7 C is optionally substituted with 1, 2, or 3 halogens. 1-6 It is alkyl.

[0031] In some embodiments, R 3It is -OCF3 or -O-CH2CF3.

[0032] In some embodiments, R 4 C is independent 1-6 Alkyl, -OR c , or halogen.

[0033] In some embodiments, R 4 It is methyl or fluoride.

[0034] In some embodiments, m is 1.

[0035] In some embodiments, the compound is [ka] [ka] Alternatively, a selection of pharmaceutically acceptable salts thereof is used.

[0036] In another aspect, this disclosure is formula (IIIa): [ka] Provides compounds or pharmaceutically acceptable salts thereof, During the ceremony, R 1 C1 alkyl, C 1-6 Haloalkyl, or C 3-8 It is a carbocyclyl, in which case C1 alkyl, C 1-6 Haloalkyl, or C 3-8 Carbocyclyl can optionally have one or more halos, a 3- to 8-membered heterocyclyl ring, or -OR. c Replaced by; R 4 is C 1-6 Alkyl, halo, cyano, nitro, C 3-8 Carbocyclyl, heterocyclyl with 3-8 membered rings, -OR c , -N(R d )2, -C(O)R c , -C(O)OR c, or -C(O)N(R d )2 、 At that time, C 1-6 Alkyl, C 3-8 Carbocyclyls, or heterocyclyls with a 3- to 8-membered ring, may optionally contain one or more R 5 Replaced by; m is either 1 or 2; Each R 5 These are independently Halo, Cyano, Nitro, and C 1-6 Alkyl, C 3-8 Carbocyclyl, heterocyclyl with 3-8 membered rings, -OR c ,-C(O)N(R d )2, -SO2R c , -SO2OR c , -SO2N(R d )2, -NR d C(O)(R c ), or -N(R d )2; Each R c These are independently hydrogen or C 1-6 It is an alkyl group, and in this case, each C 1-6 Alkyl can optionally have 1 or more R 6 Replaced by; Each R d These are independently hydrogen or C 1-6 It is alkyl; Each R 6 These are independently halogen, cyano, and C 3-8 Carbocyclyl, or a heterocyclyl with a 3- to 8-membered ring; in this case, C 3-8 Carbocyclyl may optionally be substituted with one or more halogens or cyanosides; R 7 C 1-6 Alkyl or C 3-8 It is carbocyclyl, and in that case, C 1-6 Alkyl or C 3-8 Carbocyclyl optionally has a R value of 1 or higher. 6 Replaced by; The compounds are as follows: [ka] Or not one of those salts that is pharmaceutically acceptable.

[0037] In some embodiments, R 1 -OR is optional c C replaced by 1-6 C substituted with a haloalkyl or optionally one or two halogens 3-4 It is carbocyclyl.

[0038] In some embodiments, R 1 It is either CF3 or CHF2.

[0039] In some embodiments, R 7 C is optionally substituted with 1, 2, or 3 substituents selected from halogens or cyano compounds. 1-6 C optionally substituted with 1, 2, or 3 substituents selected from alkyl, halogen, or cyano 3-8 C substituted with carbocyclyl 1-6 C optionally substituted with one, two, or three substituents selected from alkyl, halogen, or cyano compounds. 3-8 It is carbocyclyl.

[0040] In some embodiments, R 7 C is optionally substituted with 1, 2, or 3 halogens. 1-6 It is alkyl.

[0041] In some embodiments, -OR 7 It is -OCF3 or -O-CH2CF3.

[0042] In some embodiments, R 4 C is independent 1-6 Alkyl, -OR c , or halogen.

[0043] In some embodiments, R 4 It is methyl or fluoride.

[0044] In some embodiments, m is 1.

[0045] In some embodiments, the compound is [ka] [ka] Alternatively, a selection of pharmaceutically acceptable salts thereof is used.

[0046] In another aspect, this disclosure relates to formula (IV): [ka] Provides compounds or pharmaceutically acceptable salts thereof, During the ceremony, R 1 is hydrogen, C1 alkyl, C 1-6 Haloalkyl, or C 3-8 It is a carbocyclyl, in which case C1 alkyl, C 1-6 Haloalkyl, or C 3-8 Carbocyclyls are halos (1 or more), heterocyclyls (3-8 membered rings), or -OR. c It can be optionally replaced by; R 2 Hydrogen and C are independent of each other. 1-6 Alkyl or halo; R 3 is C 1-6 Alkyl, halo, cyano, nitro, C 3-8 Carbocyclyl, heterocyclyl with 3-8 membered rings, -OR 7 , -N(R d )2, -C(O)R c , -C(O)OR c , or -C(O)N(R d )2, and in that case, C 1-6 Alkyl, C 3-8 Carbocyclyls, or heterocyclyls with a 3- to 8-membered ring, have one or more R 5 It can be optionally replaced by; R 4 is C 1-6 Alkyl, halo, cyano, nitro, C 3-8 Carbocyclyl, heterocyclyl with 3-8 membered rings, -OR c, -N(R d )2, -C(O)R c , -C(O)OR c , or -C(O)N(R d )2, and in that case, C 1-6 Alkyl, C 3-8 Carbocyclyls, or heterocyclyls with a 3- to 8-membered ring, have one or more R 5 It can be optionally replaced by; m is either 1 or 2; Each R 5 These are independently Halo, Cyano, Nitro, and C 1-6 Alkyl, C 3-8 Carbocyclyl, heterocyclyl with 3-8 membered rings, -OR c ,-C(O)N(R d )2, -SO2R c , -SO2OR c , -SO2N(R d )2, -NR d C(O)(R c ), or -N(R d )2; Each R c These are independently hydrogen or C 1-6 It is an alkyl group, and in this case, each C 1-6 Alkyl is R1 or higher 6 It can be optionally replaced by; Each R d These are independently hydrogen or C 1-6 It is alkyl; Each R 6 These are independently halogen, cyano, and C 3-8 Carbocyclyl, or a heterocyclyl with a 3- to 8-membered ring; in this case, C 3-8 Carbocyclyl is optionally substituted with one or more halogens or cyanosides; and R 7 is C 1-6 Alkyl or C 3-8 It is carbocyclyl, and in that case, C 1-6 Alkyl or C 3-8 Carbocyclyl has an R value of 1 or higher. 6 It can be optionally replaced by [this].

[0047] In some embodiments, R 1is -OR c C optionally replaced by 1-6 C optionally substituted with a haloalkyl or one or two halogens 3-4 It is carbocyclyl.

[0048] In some embodiments, R 1 It is either CF3 or CHF2.

[0049] In some embodiments, R 2 It is hydrogen.

[0050] In some embodiments, R 3 は-OR 7 That is the case.

[0051] In some embodiments, R 7 C is optionally substituted with 1, 2, or 3 substituents selected from halogens or cyano compounds. 1-6 C optionally substituted with 1, 2, or 3 substituents selected from alkyl, halogen, or cyano 3-8 C substituted with carbocyclyl 1-6 C optionally substituted with one, two, or three substituents selected from alkyl, halogen, or cyano compounds. 3-8 It is carbocyclyl.

[0052] In some embodiments, R 7 C is optionally substituted with 1, 2, or 3 halogens. 1-6 It is alkyl.

[0053] In some embodiments, R 3 It is -OCF3 or -O-CH2CF3.

[0054] In some embodiments, R 4 C is independent 1-6 Alkyl, -OR c , or halogen.

[0055] In some embodiments, R 4It is methyl or fluoride.

[0056] In some embodiments, m is 1.

[0057] In some embodiments, the compound is [ka] [ka] Alternatively, a selection of pharmaceutically acceptable salts thereof is used.

[0058] In another aspect, this disclosure is formula (IVa): [ka] Provides compounds or pharmaceutically acceptable salts thereof, During the ceremony, R 1 is hydrogen, C1 alkyl, C 1-6 Haloalkyl, or C 3-8 It is a carbocyclyl, in which case C1 alkyl, C 1-6 Haloalkyl, or C 3-8 Carbocyclyls are halos (1 or more), heterocyclyls (3-8 membered rings), or -OR. c It can be optionally replaced by; R 2 Hydrogen and C are independent of each other. 1-6 Alkyl or halo; R 4 is C 1-6 Alkyl, halo, cyano, nitro, C 3-8 Carbocyclyl, heterocyclyl with 3-8 membered rings, -OR c , -N(R d )2, -C(O)R c , -C(O)OR c ,Ma taha-C(O)N(R d )2, and in that case, C 1-6 Alkyl, C 3-8 Carbocyclyls, or heterocyclyls with a 3- to 8-membered ring, have one or more R 5It can be optionally replaced by; m is either 1 or 2; Each R 5 These are independently Halo, Cyano, Nitro, and C 1-6 Alkyl, C 3-8 Carbocyclyl, heterocyclyl with 3-8 membered rings, -OR c ,-C(O)N(R d )2, -SO2R c , -SO2OR c , -SO2N(R d )2, -NR d C(O)(R c ), or -N(R d )2; Each R c These are independently hydrogen or C 1-6 It is an alkyl group, and in this case, each C 1-6 Alkyl is R1 or higher 6 It can be optionally replaced by; Each R d These are independently hydrogen or C 1-6 It is alkyl; Each R 6 These are independently halogen, cyano, and C 3-8 Carbocyclyl, or a heterocyclyl with a 3- to 8-membered ring; in this case, C 3-8 Carbocyclyl is optionally substituted with one or more halogens or cyanosides; and R 7 is C 1-6 Alkyl or C 3-8 It is carbocyclyl, and in that case, C 1-6 Alkyl or C 3-8 Carbocyclyl has an R value of 1 or higher. 6 It can be optionally replaced by [this].

[0059] In some embodiments, R 1 is -OR c C optionally replaced by 1-6 C optionally substituted with a haloalkyl or one or two halogens 3-4 It is carbocyclyl.

[0060] In some embodiments, R 1It is either CF3 or CHF2.

[0061] In some embodiments, R 2 It is hydrogen.

[0062] In some embodiments, R 7 C is optionally substituted with 1, 2, or 3 substituents selected from halogens or cyano compounds. 1-6 C optionally substituted with 1, 2, or 3 substituents selected from alkyl, halogen, or cyano 3-8 C substituted with carbocyclyl 1-6 C optionally substituted with one, two, or three substituents selected from alkyl, halogen, or cyano compounds. 3-8 It is carbocyclyl.

[0063] In some embodiments, R 7 C is optionally substituted with 1, 2, or 3 halogens. 1-6 It is alkyl.

[0064] In some embodiments, -OR 7 It is -OCF3 or -O-CH2CF3.

[0065] In some embodiments, R 4 C is independent 1-6 Alkyl, -OR c , or halogen.

[0066] In some embodiments, R 4 It is methyl or fluoride.

[0067] In some embodiments, m is 1.

[0068] In some embodiments, the compound is [ka] Alternatively, a selection of pharmaceutically acceptable salts thereof is used.

[0069] In another aspect, this disclosure is formula (IVb): [ka] Provides compounds or pharmaceutically acceptable salts thereof, During the ceremony, R 1 is hydrogen, C1 alkyl, C 1-6 Haloalkyl, or C 3-8 It is a carbocyclyl, in which case C1 alkyl, C 1-6 Haloalkyl, or C 3-8 Carbocyclyls are halos (1 or more), heterocyclyls (3-8 membered rings), or -OR. c Optionally replaced by;R 2 Hydrogen and C are independent of each other. 1-6 Alkyl or halo; R 4 R is 1 or greater 5 C optionally replaced by 1-6 It is alkyl; Each R 5 These are independently Halo, Cyano, Nitro, and C 1-6 Alkyl, C 3-8 Carbocyclyl, heterocyclyl with 3-8 membered rings, -OR c ,-C(O)N(R d )2, -SO2R c , -SO2OR c , -SO2N(R d )2, -NR d C(O)(R c ), or -N(R d )2; Each R c These are independently hydrogen or C 1-6 It is an alkyl group, and in this case, each C 1-6 Alkyl is R1 or higher 6 It can be optionally replaced by; Each R d These are independently hydrogen or C 1-6 It is alkyl; Each R 6 These are independently halogen, cyano, and C 3-8 Carbocyclyl, or a heterocyclyl with a 3- to 8-membered ring; in this case, C3-8 Carbocyclyl is optionally substituted with one or more halogens or cyanosides; and R 7 is C 1-6 Alkyl or C 3-8 It is carbocyclyl, and in that case, C 1-6 Alkyl or C 3-8 Carbocyclyl has an R value of 1 or higher. 6 It can be optionally replaced by [this].

[0070] In some embodiments, R 1 is -OR c C optionally replaced by 1-6 C optionally substituted with a haloalkyl or one or two halogens 3-4 It is carbocyclyl.

[0071] In some embodiments, R 1 It is either CF3 or CHF2.

[0072] In some embodiments, R 2 It is hydrogen.

[0073] In some embodiments, R 7 C is optionally substituted with 1, 2, or 3 substituents selected from halogens or cyano compounds. 1-6 C optionally substituted with 1, 2, or 3 substituents selected from alkyl, halogen, or cyano 3-8 C substituted with carbocyclyl 1-6 C optionally substituted with one, two, or three substituents selected from alkyl, halogen, or cyano compounds. 3-8 It is carbocyclyl.

[0074] In some embodiments, R 7 C is optionally substituted with 1, 2, or 3 halogens. 1-6 It is alkyl.

[0075] In some embodiments, -OR 7 It is -OCF3 or -O-CH2CF3.

[0076] In some embodiments, R 4 It is methyl.

[0077] In some embodiments, the compound is [ka] Alternatively, a selection of pharmaceutically acceptable salts thereof is used.

[0078] In another aspect, this disclosure is formula (V): [ka] Provides compounds or pharmaceutically acceptable salts thereof, During the ceremony, R 1 is hydrogen, C1 alkyl, C 1-6 Haloalkyl, or C 3-8 It is a carbocyclyl, in which case C1 alkyl, C 1-6 Haloalkyl, or C 3-8 Carbocyclyls are halos (1 or more), heterocyclyls (3-8 membered rings), or -OR. c It can be optionally replaced by; R 2 Hydrogen and C are independent of each other. 1-6 Alkyl or halo; R 3 is C 1-6 Alkyl, halo, cyano, nitro, C 3-8 Carbocyclyl, heterocyclyl with 3-8 membered rings, -OR 7 , -N(R d )2, -C(O)R c , -C(O)OR c , or -C(O)N(R d )2, and in that case, C 1-6 Alkyl, C 3-8 Carbocyclyls, or heterocyclyls with a 3- to 8-membered ring, have one or more R 5 It can be optionally replaced by; R 4 is C 1-6 Alkyl, halo, cyano, nitro, C 3-8Carbocyclyl, heterocyclyl with 3-8 membered rings, -OR c , -N(R d )2, -C(O)R c , -C(O)OR c , or -C(O)N(R d )2, and in that case, C 1-6 Alkyl, C 3-8 Carbocyclyls, or heterocyclyls with a 3- to 8-membered ring, have one or more R 5 It can be optionally replaced by; m is either 1 or 2; Each R 5 These are independently Halo, Cyano, Nitro, and C 1-6 Alkyl, C 3-8 Carbocyclyl, heterocyclyl with 3-8 membered rings, -OR c ,-C(O)N(R d )2, -SO2R c , -SO2OR c , -SO2N(R d )2, -NR d C(O)(R c ), or -N(R d )2; Each R c These are independently hydrogen or C 1-6 It is an alkyl group, and in this case, each C 1-6 Alkyl is R1 or higher 6 It can be optionally replaced by; Each R d These are independently hydrogen or C 1-6 It is alkyl; Each R 6 These are independently halogen, cyano, and C 3-8 Carbocyclyl, or a 3-8 membered ring hete It is rocyclyl; in that case, C 3-8 Carbocyclyl is optionally substituted with one or more halogens or cyanosides; and R 7 is C 1-6 Alkyl or C 3-8 It is carbocyclyl, and in that case, C 1-6 Alkyl or C 3-8 Carbocyclyl has an R value of 1 or higher. 6 It can be optionally replaced by [this].

[0079] In some embodiments, R 1 is -OR c C optionally replaced by 1-6 C optionally substituted with a haloalkyl or one or two halogens 3-4 It is carbocyclyl.

[0080] In some embodiments, R 1 It is either CF3 or CHF2.

[0081] In some embodiments, R 2 It is hydrogen.

[0082] In some embodiments, R 3 は-OR 7 That is the case.

[0083] In some embodiments, R 7 C is optionally substituted with 1, 2, or 3 substituents selected from halogens or cyano compounds. 1-6 C optionally substituted with 1, 2, or 3 substituents selected from alkyl, halogen, or cyano 3-8 C substituted with carbocyclyl 1-6 C optionally substituted with one, two, or three substituents selected from alkyl, halogen, or cyano compounds. 3-8 It is carbocyclyl.

[0084] In some embodiments, R 7 C is optionally substituted with 1, 2, or 3 halogens. 1-6 It is alkyl.

[0085] In some embodiments, R 3 It is -OCF3 or -O-CH2CF3.

[0086] In some embodiments, R 4 C is independent 1-6 Alkyl, -OR c , or halogen.

[0087] In some embodiments, R 4 It is methyl.

[0088] In some embodiments, R 4 It is a fluoride.

[0089] In some embodiments, m is 1.

[0090] In some embodiments, the compound is [ka] [ka] Alternatively, a selection of pharmaceutically acceptable salts thereof is used.

[0091] In another aspect, this disclosure is formula (Va): [ka] Provides compounds or pharmaceutically acceptable salts thereof, During the ceremony, R 1 is hydrogen, C1 alkyl, C 1-6 Haloalkyl, or C 3-8 It is a carbocyclyl, in which case C1 alkyl, C 1-6 Haloalkyl, or C 3-8 Carbocyclyls are halos (1 or more), heterocyclyls (3-8 membered rings), or -OR. c It can be optionally replaced by; R 2 Hydrogen and C are independent of each other. 1-6 Alkyl or halo; R 4 is C 1-6 Alkyl, halo, cyano, nitro, C 3-8 Carbocyclyl, heterocyclyl with 3-8 membered rings, -OR c , -N(R d )2, -C(O)R c , -C(O)OR c , or -C(O)N(R d)2, and in that case, C 1-6 Alkyl, C 3-8 Carbocyclyls, or heterocyclyls with a 3- to 8-membered ring, have one or more R 5 It can be optionally replaced by; m is either 1 or 2; Each R 5 These are independently Halo, Cyano, Nitro, and C 1-6 Alkyl, C 3-8 Carbocyclyl, heterocyclyl with 3-8 membered rings, -OR c ,-C(O)N(R d )2, -SO2R c , -SO2OR c , -SO2N(R d )2, -NR d C(O)(R c ), or -N(R d )2; Each R c These are independently hydrogen or C 1-6 It is an alkyl group, and in this case, each C 1-6 Alkyl is R1 or higher 6 It can be optionally replaced by; Each R d These are independently hydrogen or C 1-6 It is alkyl; Each R 6 These are independently halogen, cyano, and C 3-8 Carbocyclyl, or a heterocyclyl with a 3- to 8-membered ring; in this case, C 3-8 Carbocyclyl contains one or more halogens or cyanoacrylates. Therefore, it is arbitrarily substituted; and R 7 is C 1-6 Alkyl or C 3-8 It is carbocyclyl, and in that case, C 1-6 Alkyl or C 3-8 Carbocyclyl has an R value of 1 or higher. 6 It can be optionally replaced by [this].

[0092] In some embodiments, R 1 is -OR c C optionally replaced by 1-6C optionally substituted with a haloalkyl or one or two halogens 3-4 It is carbocyclyl.

[0093] In some embodiments, R 1 It is either CF3 or CHF2.

[0094] In some embodiments, R 2 It is hydrogen.

[0095] In some embodiments, R 7 C is optionally substituted with 1, 2, or 3 substituents selected from halogens or cyano compounds. 1-6 C optionally substituted with 1, 2, or 3 substituents selected from alkyl, halogen, or cyano 3-8 C substituted with carbocyclyl 1-6 C optionally substituted with one, two, or three substituents selected from alkyl, halogen, or cyano compounds. 3-8 It is carbocyclyl.

[0096] In some embodiments, R 7 C is optionally substituted with 1, 2, or 3 halogens. 1-6 It is alkyl.

[0097] In some embodiments, -OR 7 It is -OCF3 or -O-CH2CF3.

[0098] In some embodiments, R 4 C is independent 1-6 Alkyl, -OR c , or halogen.

[0099] In some embodiments, R 4 It is methyl.

[0100] In some embodiments, R 4 It is a fluoride.

[0101] In some embodiments, m is 1.

[0102] In some embodiments, the compound is [ka] [ka] Alternatively, a selection of pharmaceutically acceptable salts thereof is used.

[0103] In another aspect, this disclosure is formula (Vb): [ka] Provides compounds or pharmaceutically acceptable salts thereof, During the ceremony, R 1 is hydrogen, C1 alkyl, C 1-6 Haloalkyl, or C 3-8 It is a carbocyclyl, in which case C1 alkyl, C 1-6 Haloalkyl, or C 3-8 Carbocyclyls are halos (1 or more), heterocyclyls (3-8 membered rings), or -OR. c It can be optionally replaced by; R 2 Hydrogen and C are independent of each other. 1-6 Alkyl or halo; R 4 It is a halogen; Each R 5 These are independently Halo, Cyano, Nitro, and C 1-6 Alkyl, C 3-8 Carbocyclyl, heterocyclyl with 3-8 membered rings, -OR c ,-C(O)N(R d )2, -SO2R c , -SO2OR c , -SO2N(R d )2, -NR d C(O)(R c ), or -N(R d )2; Each R c These are independently hydrogen or C 1-6It is an alkyl group, and in this case, each C 1-6 Alkyl is R1 or higher 6 It can be optionally replaced by; Each R d These are independently hydrogen or C 1-6 It is alkyl; Each R 6 These are independently halogen, cyano, and C 3-8 Carbocyclyl, or a heterocyclyl with a 3- to 8-membered ring; in this case, C 3-8 Carbocyclyl is optionally substituted with one or more halogens or cyanosides; and R 7 is C 1-6 Alkyl or C 3-8 It is carbocyclyl, and in that case, C 1-6 Alkyl or C 3-8 Carbocyclyl has an R value of 1 or higher. 6 It can be optionally replaced by [this].

[0104] In some embodiments, R 1 is -OR c C optionally replaced by 1-6 C optionally substituted with a haloalkyl or one or two halogens 3-4 It is carbocyclyl.

[0105] In some embodiments, R 1 It is either CF3 or CHF2.

[0106] In some embodiments, R 2 It is hydrogen.

[0107] In some embodiments, R 7 C is optionally substituted with 1, 2, or 3 substituents selected from halogens or cyano compounds. 1-6 C optionally substituted with 1, 2, or 3 substituents selected from alkyl, halogen, or cyano 3-8 Carbocycline C replaced by Lu 1-6C optionally substituted with one, two, or three substituents selected from alkyl, halogen, or cyano compounds. 3-8 It is carbocyclyl.

[0108] In some embodiments, R 7 C is optionally substituted with 1, 2, or 3 halogens. 1-6 It is alkyl.

[0109] In some embodiments, -OR 7 It is -OCF3 or -O-CH2CF3.

[0110] In some embodiments, R 4 It is a fluoride.

[0111] In some embodiments, the compound is [ka] [ka] Alternatively, a selection of pharmaceutically acceptable salts thereof is used.

[0112] In another aspect, this disclosure is formula (VI): [ka] Provides compounds or pharmaceutically acceptable salts thereof, During the ceremony, R 1 is hydrogen, C1 alkyl, C 1-6 Haloalkyl, or C 3-8 It is a carbocyclyl, in which case C1 alkyl, C 1-6 Haloalkyl, or C 3-8 Carbocyclyls are halos (1 or more), heterocyclyls (3-8 membered rings), or -OR. c It can be optionally replaced by; R 2 Hydrogen and C are independent of each other. 1-6 Alkyl or halo; R 3 is C1-6 Alkyl, halo, cyano, nitro, C 3-8 Carbocyclyl, heterocyclyl with 3-8 membered rings, -OR 7 , -N(R d )2, -C(O)R c , -C(O)OR c , or -C(O)N(R d )2, and in that case, C 1-6 Alkyl, C 3-8 Carbocyclyls, or heterocyclyls with a 3- to 8-membered ring, have one or more R 5 It can be optionally replaced by; R 4 is C 1-6 Alkyl, halo, cyano, nitro, C 3-8 Carbocyclyl, heterocyclyl with 3-8 membered rings, -OR c , -N(R d )2, -C(O)R c , -C(O)OR c , or -C(O)N(R d )2, and in that case, C 1-6 Alkyl, C 3-8 Carbocyclyls, or heterocyclyls with a 3- to 8-membered ring, have one or more R 5 It can be optionally replaced by; m is 0, 1, or 2; Each R 5 These are independently Halo, Cyano, Nitro, and C 1-6 Alkyl, C 3-8 Carbocyclyl, heterocyclyl with 3-8 membered rings, -OR c ,-C(O)N(R d )2, -SO2R c , -SO2OR c , -SO2N(R d )2, -NR d C(O)(R c ), or -N(R d )2; Each R c These are independently hydrogen or C 1-6 It is an alkyl group, and in this case, each C 1-6 Alkyl is 1 The above R 6 It can be optionally replaced by; Each R dThese are independently hydrogen or C 1-6 It is alkyl; Each R 6 These are independently halogen, cyano, and C 3-8 Carbocyclyl, or a heterocyclyl with a 3- to 8-membered ring; in this case, C 3-8 Carbocyclyl is optionally substituted with one or more halogens or cyanosides; and R 7 is C 1-6 Alkyl or C 3-8 It is carbocyclyl, and in that case, C 1-6 Alkyl or C 3-8 Carbocyclyl has an R value of 1 or higher. 6 It can be optionally replaced by [this].

[0113] In some embodiments, R 1 is -OR c C optionally replaced by 1-6 C optionally substituted with a haloalkyl or one or two halogens 3-4 It is carbocyclyl.

[0114] In some embodiments, R 1 It is either CF3 or CHF2.

[0115] In some embodiments, R 2 It is hydrogen.

[0116] In some embodiments, R 3 は-OR 7 That is the case.

[0117] In some embodiments, R 7 C is optionally substituted with 1, 2, or 3 substituents selected from halogens or cyano compounds. 1-6 C optionally substituted with 1, 2, or 3 substituents selected from alkyl, halogen, or cyano 3-8 C substituted with carbocyclyl 1-6 C optionally substituted with one, two, or three substituents selected from alkyl, halogen, or cyano compounds. 3-8It is carbocyclyl.

[0118] In some embodiments, R 7 C is optionally substituted with 1, 2, or 3 halogens. 1-6 It is alkyl.

[0119] In some embodiments, R 3 It is -OCF3 or -O-CH2CF3.

[0120] In some embodiments, R 4 C is independent 1-6 Alkyl, -OR c , or halogen.

[0121] In some embodiments, R 4 It is methyl or fluoride.

[0122] In some embodiments, m is 1 or 2.

[0123] In some embodiments, m is 1.

[0124] In some embodiments, the compound is [ka] Or a pharmaceutically acceptable salt thereof.

[0125] In another aspect, this disclosure is formula (VIa): [ka] Provides compounds or pharmaceutically acceptable salts thereof, During the ceremony, R 1 is hydrogen, C1 alkyl, C 1-6 Haloalkyl, or C 3-8 It is a carbocyclyl, in which case C1 alkyl, C 1-6 Haloalkyl, or C 3-8 Carbocyclyls are halos (1 or more), heterocyclyls (3-8 membered rings), or -OR.c It can be optionally replaced by; R 2 Hydrogen and C are independent of each other. 1-6 Alkyl or halo; R 4 is C 1-6 Alkyl, halo, cyano, nitro, C 3-8 Carbocyclyl, heterocyclyl with 3-8 membered rings, -OR c , -N(R d )2, -C(O)R c , -C(O)OR c , or -C(O)N(R d )2, and in that case, C 1-6 Alkyl, C 3-8 Carbocyclyls, or heterocyclyls with a 3- to 8-membered ring, have one or more R 5 It can be optionally replaced by; m is either 1 or 2; Each R 5 These are independently Halo, Cyano, Nitro, and C 1-6 Alkyl, C 3-8 Carbocyclyl, heterocyclyl with 3-8 membered rings, -OR c ,-C(O)N(R d )2, -SO2R c , -SO2OR c , -SO2N(R d )2, -NR d C(O)(R c ), or -N(R d )2; Each R c These are independently hydrogen or C 1-6 It is an alkyl group, and in this case, each C 1-6 Alkyl is R1 or higher 6 It can be optionally replaced by; Each R d These are independently hydrogen or C 1-6 It is alkyl; Each R 6 These are independently halogen, cyano, and C 3-8 Carbocyclyl, or a heterocyclyl with a 3- to 8-membered ring; in this case, C 3-8 Carbocyclyl is optionally substituted with one or more halogens or cyanosides; and R7 is C 1-6 Alkyl or C 3-8 It is carbocyclyl, and in that case, C 1-6 Alkyl or C 3-8 Carbocyclyl has an R value of 1 or higher. 6 It can be optionally replaced by [this].

[0126] In some embodiments, R 1 is -OR c C optionally replaced by 1-6 C optionally substituted with a haloalkyl or one or two halogens 3-4 It is carbocyclyl.

[0127] In some embodiments, R 1 It is either CF3 or CHF2.

[0128] In some embodiments, R 2 It is hydrogen.

[0129] In some embodiments, R 7 C is optionally substituted with 1, 2, or 3 substituents selected from halogens or cyano compounds. 1-6 C optionally substituted with 1, 2, or 3 substituents selected from alkyl, halogen, or cyano 3-8 C substituted with carbocyclyl 1-6 C optionally substituted with one, two, or three substituents selected from alkyl, halogen, or cyano compounds. 3-8 It is carbocyclyl.

[0130] In some embodiments, R 7 C is optionally substituted with 1, 2, or 3 halogens. 1-6 It is alkyl.

[0131] In some embodiments, -OR 7 It is -OCF3 or -O-CH2CF3.

[0132] In some embodiments, R 4C is independent 1-6 Alkyl, -OR c , or halogen.

[0133] In some embodiments, R 4 It is methyl or fluoride.

[0134] In some embodiments, m is 1 or 2.

[0135] In some embodiments, m is 1.

[0136] In some embodiments, the compound is [ka] Or a pharmaceutically acceptable salt thereof.

[0137] In another aspect, this disclosure is formula (VII): [ka] Provides compounds or pharmaceutically acceptable salts thereof, During the ceremony, R 1 is hydrogen, C1 alkyl, C 1-6 Haloalkyl, C 3-8 Carbocyclyl, phenyl, O-phenyl, in which case C1 alkyl, C 1-6 Haloalkyl, C 3-8 Carbocyclyl, phenyl, or O-phenyl are halos, heterocyclyls with 3-8 membered rings, or -OR c It can be optionally replaced by; R 2 Hydrogen and C are independent of each other. 1-6 Alkyl or halo; R 3 is C 1-6 Alkyl, halo, cyano, nitro, C 3-8 Carbocyclyl, heterocyclyl with 3-8 membered rings, -OR 7 , -N(R d )2, -C(O)R c , -C(O)OR c, or -C(O)N(R d )2, and in that case, C 1-6 Alkyl, C 3-8 Carbocyclyls, or heterocyclyls with a 3- to 8-membered ring, have one or more R 5 It can be optionally replaced by; R 4 is C 1-6 Alkyl, halo, cyano, nitro, C 3-8 Carbocyclyl, heterocyclyl with 3-8 membered rings, -OR c , -N(R d )2, -C(O)R c , -C(O)OR c , or -C(O)N(R d )2, and in that case, C 1-6 Alkyl, C 3-8 Carbocyclyls, or heterocyclyls with a 3- to 8-membered ring, have one or more R 5 It can be optionally replaced by; m is 0, 1, or 2; Each R 5 These are independently Halo, Cyano, Nitro, and C 1-6 Alkyl, C 3-8 Carbocyclyl, heterocyclyl with 3-8 membered rings, -OR c ,-C(O)N(R d )2, -SO2R c , -SO2OR c , -SO2N(R d )2, -NR d C(O)(R c ), or -N(R d )2; Each R c These are independently hydrogen or C 1-6 It is an alkyl group, and in this case, each C 1-6 Alkyl is 1 The above R 6 It can be optionally replaced by; Each R d These are independently hydrogen or C 1-6 It is alkyl; Each R 6 These are independently halogen, cyano, and C 3-8 Carbocyclyl, or a heterocyclyl with a 3- to 8-membered ring; in this case, C 3-8Carbocyclyl is optionally substituted with one or more halogens or cyanosides; and R 7 is C 1-6 Alkyl or C 3-8 It is carbocyclyl, and in that case, C 1-6 Alkyl or C 3-8 Carbocyclyl has an R value of 1 or higher. 6 It can be optionally replaced by [this].

[0138] In some embodiments, R 1 is hydrogen, C1 alkyl, C 1-6 Haloalkyl, or C 3-8 It is a carbocyclyl, in which case C1 alkyl, C 1-6 Haloalkyl, or C 3-8 Carbocyclyls are halos (1 or more), heterocyclyls (3-8 membered rings), or -OR. c It can be optionally replaced by [this].

[0139] In some embodiments, R 1 It is either CF3 or CHF2.

[0140] In some embodiments, R 2 It is hydrogen.

[0141] In some embodiments, R 3 は-OR 7 That is the case.

[0142] In some embodiments, R 7 C is optionally substituted with 1, 2, or 3 substituents selected from halogens or cyano compounds. 1-6 C optionally substituted with 1, 2, or 3 substituents selected from alkyl, halogen, or cyano 3-8 C substituted with carbocyclyl 1-6 C optionally substituted with one, two, or three substituents selected from alkyl, halogen, or cyano compounds. 3-8 It is carbocyclyl.

[0143] In some embodiments, R7 C is optionally substituted with 1, 2, or 3 halogens. 1-6 It is alkyl.

[0144] In some embodiments, R 3 It is -OCF3 or -O-CH2CF3.

[0145] In some embodiments, R 4 C is independent 1-6 Alkyl, -OR c , or halogen.

[0146] In some embodiments, R 4 It is methyl or fluoride.

[0147] In some embodiments, m is 1 or 2.

[0148] In some embodiments, m is 1.

[0149] In some embodiments, the compound is [ka] [ka] Alternatively, a selection of pharmaceutically acceptable salts thereof is used.

[0150] In some embodiments, the compound is [ka] [ka] Alternatively, a selection of pharmaceutically acceptable salts thereof is used.

[0151] In another aspect, this disclosure is formula (VIIa): [ka] Provides compounds or pharmaceutically acceptable salts thereof, During the ceremony, R 1 is hydrogen, C1 alkyl, C 1-6 Haloalkyl, or C 3-8 It is a carbocyclyl, in which case C1 alkyl, C 1-6 Haloalkyl, or C 3-8 Carbocyclyls are halos (1 or more), heterocyclyls (3-8 membered rings), or -OR. c It can be optionally replaced by; R 2 Hydrogen and C are independent of each other. 1-6 Alkyl or halo; R 4 is C 1-6 Alkyl, halo, cyano, nitro, C 3-8 Carbocyclyl, heterocyclyl with 3-8 membered rings, -OR c , -N(R d )2, -C(O)R c , -C(O)OR c , or -C(O)N(R d )2, and in that case, C 1-6 Alkyl, C 3-8 Carbocyclyls, or heterocyclyls with a 3- to 8-membered ring, have one or more R 5 It can be optionally replaced by; m is 0, 1, or 2; Each R 5 These are independently Halo, Cyano, Nitro, and C 1-6 Alkyl, C 3-8 Carbocyclyl, heterocyclyl with 3-8 membered rings, -OR c ,-C(O)N(R d )2, -SO2R c , -SO2OR c , -SO2N(R d )2, -NR d C(O)(R c ), or -N(R d )2; Each R c These are independently hydrogen or C 1-6 It is an alkyl group, and in this case, each C 1-6 Alkyl is R1 or higher 6 It can be optionally replaced by; Each R d is independently hydrogen or C 1-6 alkyl; Each R 6 is independently halogen, cyano, C 3-8 carbocyclic, or 3- to 8-membered heterocyclic; wherein the C 3-8 carbocyclic is optionally substituted by one or more halogens or cyano; and R 7 is C 1-6 alkyl or C 3-8 carbocyclic, wherein the C 1-6 alkyl or C 3-8 carbocyclic is optionally substituted by one or more R 6 .

[0152] In some embodiments, R 1 is C c haloalkyl optionally substituted by -OR 1-6 or C 3-4 carbocyclic optionally substituted by one or two halogens.

[0153] In some embodiments, R 1 is CF3 or CHF2.

[0154] In some embodiments, R 2 is hydrogen.

[0155] In some embodiments, R 7 is C 1-6 alkyl optionally substituted by one, two, or three substituents selected from halogen or cyano; C 3-8 alkyl substituted by C 1-6 carbocyclic optionally substituted by one, two, or three substituents selected from halogen or cyano; or C 3-8 carbocyclic optionally substituted by one, two, or three substituents selected from halogen or cyano.

[0156] In some embodiments, R7 C is optionally substituted with 1, 2, or 3 halogens. 1-6 It is alkyl.

[0157] In some embodiments, -OR 7 It is -OCF3 or -O-CH2CF3.

[0158] In some embodiments, R 4 C is independent 1-6 Alkyl, -OR c , or halogen.

[0159] In some embodiments, R 4 It is methyl or fluoride.

[0160] In some embodiments, m is 1 or 2.

[0161] In some embodiments, m is 1.

[0162] In some embodiments, the compound is [ka] [ka] Alternatively, a selection of pharmaceutically acceptable salts thereof is used.

[0163] In some embodiments, the compound is [ka] [ka] Alternatively, a selection of pharmaceutically acceptable salts thereof is used.

[0164] In another aspect, this disclosure is formula (VIIb): [ka] Provides compounds or pharmaceutically acceptable salts thereof, During the ceremony, R 1 is hydrogen, C1 alkyl, C 1-6 Haloalkyl, or C 3-8 It is a carbocyclyl, in which case C1 alkyl, C 1-6 Haloalkyl, or C 3-8 Carbocyclyls are halos (1 or more), heterocyclyls (3-8 membered rings), or -OR. c It can be optionally replaced by; R 2 Hydrogen and C are independent of each other. 1-6 Alkyl or halo; R 4 It is a halogen; Each R 5 These are independently Halo, Cyano, Nitro, and C 1-6 Alkyl, C 3-8 Carbocyclyl, heterocyclyl with 3-8 membered rings, -OR c ,-C(O)N(R d )2, -SO2R c , -SO2OR c , -SO2N(R d )2, -NR d C(O)(R c ), or -N(R d )2; Each R c These are independently hydrogen or C 1-6 It is an alkyl group, and in this case, each C 1-6 Alkyl is R1 or higher 6 It can be optionally replaced by; Each R d These are independently hydrogen or C 1-6 It is alkyl; Each R 6 These are independently halogen, cyano, and C 3-8 Carbocyclyl, or a heterocyclyl with a 3- to 8-membered ring; in this case, C 3-8 Carbocyclyl is optionally substituted with one or more halogens or cyanosides; and R 7 is C 1-6 Alkyl or C 3-8 It is carbocyclyl, and in that case, C 1-6Alkyl or C 3-8 Carbocyclyl has an R value of 1 or higher. 6 It can be optionally replaced by [this].

[0165] In some embodiments, R 1 is -OR c C optionally replaced by 1-6 C optionally substituted with a haloalkyl or one or two halogens 3-4 It is carbocyclyl.

[0166] In some embodiments, R 1 It is either CF3 or CHF2.

[0167] In some embodiments, R 2 It is hydrogen.

[0168] In some embodiments, R 7 C is optionally substituted with 1, 2, or 3 substituents selected from halogens or cyano compounds. 1-6 Alkyl; halogen or cyano C optionally substituted with one of the selected substituents 1, 2, or 3 3-8 C substituted with carbocyclyl 1-6 C optionally substituted with one, two, or three substituents selected from alkyl, halogen, or cyano compounds. 3-8 It is carbocyclyl.

[0169] In some embodiments, R 7 C is optionally substituted with 1, 2, or 3 halogens. 1-6 It is alkyl.

[0170] In some embodiments, -OR 7 It is -OCF3 or -O-CH2CF3.

[0171] In some embodiments, R 4 It is a fluoride.

[0172] In some embodiments, the compound is [Chemical formula] [Chemical formula] or is selected from pharmaceutically acceptable salts thereof.

[0173] In another aspect, the present disclosure provides a compound of formula (VIII): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, C1 alkyl, C 1-6 haloalkyl, or C 3-8 carbocyclic, where C1 alkyl, C 1-6 haloalkyl, or C 3-8 carbocyclic is optionally substituted by one or more halos, a 3- to 8-membered heterocyclic ring, or -OR c ; R 4 is C 1-6 alkyl, -OR c or halogen; m is 0, 1, or 2; each R c is independently hydrogen or C 1-6 alkyl, where each C 1-6 alkyl is optionally substituted by one or more R 6 ; each R 6 is independently halogen, cyano, C 3-8 carbocyclic, or a 3- to 8-membered heterocyclic ring; where C 3-8 carbocyclic is optionally substituted by one or more halogens or cyanos; and R 7 is C 1-6 alkyl or C 3-8 carbocyclic, where C 1-6 alkyl or C 3-8 carbocyclic is optionally substituted by one or more R 6It can be optionally replaced by [this].

[0174] In some embodiments, R 1 is -OR c C optionally replaced by 1-6 C optionally substituted with a haloalkyl or one or two halogens 3-4 It is carbocyclyl.

[0175] In some embodiments, R 1 It is either CF3 or CHF2.

[0176] In some embodiments, R 7 C is optionally substituted with 1, 2, or 3 substituents selected from halogens or cyano compounds. 1-6 C optionally substituted with 1, 2, or 3 substituents selected from alkyl, halogen, or cyano 3-8 C substituted with carbocyclyl 1-6 Alkyl; or selected from halogen or cyano. C optionally substituted with substituents 1, 2, or 3 3-8 It is carbocyclyl.

[0177] In some embodiments, R 7 C is optionally substituted with 1, 2, or 3 halogens. 1-6 It is alkyl.

[0178] In some embodiments, -OR 7 It is -OCF3 or -O-CH2CF3.

[0179] In some embodiments, R 4 It is a fluoride.

[0180] In some embodiments, R 4 It is methyl.

[0181] In some embodiments, m is 0.

[0182] In some embodiments, m is 1.

[0183] In some embodiments, the compound is [ka] Alternatively, a selection of pharmaceutically acceptable salts thereof is used.

[0184] In another aspect, this disclosure is formula (IX): [ka] Provides compounds or pharmaceutically acceptable salts thereof, During the ceremony, X, Y, and Z: one of them is N, and the other two are CR 2 And, R 1 is hydrogen, C1 alkyl, C 1-6 Haloalkyl, or C 3-8 It is a carbocyclyl, in which case C1 alkyl, C 1-6 Haloalkyl, or C 3-8 Carbocyclyls are halos (1 or more), heterocyclyls (3-8 membered rings), or -OR. c It can be optionally replaced by; R 2 One of them is hydrogen, and the other is R 2 is C 1-6 Alkyl, halogen, -C(O)O(R) c ), -C(O)N(R d )2, -NR d C(O)(R c ), or -N(R d ) Selected from 2; in that case, C 1-6 Alkyl is -O(R d ) can be optionally replaced by; Each R d These are independently hydrogen or C 1-6 It is alkyl; R 4 is C 1-6 Alkyl, -OR c , or halogen; m is 0, 1, or 2; Each Rc These are independently hydrogen or C 1-6 It is an alkyl group, and in this case, each C 1-6 Alkyl is R1 or higher 6 It can be optionally replaced by; Each R 6 These are independently halogen, cyano, and C 3-8 Carbocyclyl, or a heterocyclyl with a 3- to 8-membered ring; in this case, C 3-8 Carbocyclyl contains one or more halogens or cyanoacrylates. Therefore, it is arbitrarily substituted; and R 7 is C 1-6 Alkyl or C 3-8 It is carbocyclyl, and in that case, C 1-6 Alkyl or C 3-8 Carbocyclyl has an R value of 1 or higher. 6 It can be optionally replaced by [this].

[0185] In some embodiments, X is N, and Y and Z are CR. 2 That is the case.

[0186] In some embodiments, Y is N, and X and Z are CR 2 That is the case.

[0187] In some embodiments, R 1 is -OR c C optionally replaced by 1-6 C optionally substituted with a haloalkyl or one or two halogens 3-4 It is carbocyclyl.

[0188] In some embodiments, R 1 It is either CF3 or CHF2.

[0189] In some embodiments, R 7 C is optionally substituted with 1, 2, or 3 substituents selected from halogens or cyano compounds. 1-6 C optionally substituted with 1, 2, or 3 substituents selected from alkyl, halogen, or cyano 3-8C substituted with carbocyclyl 1-6 C optionally substituted with one, two, or three substituents selected from alkyl, halogen, or cyano compounds. 3-8 It is carbocyclyl.

[0190] In some embodiments, R 7 C is optionally substituted with 1, 2, or 3 halogens. 1-6 It is alkyl.

[0191] In some embodiments, -OR 7 It is -OCF3 or -O-CH2CF3.

[0192] In some embodiments, R 4 It is a fluoride.

[0193] In some embodiments, R 4 It is methyl.

[0194] In some embodiments, m is 0.

[0195] In some embodiments, m is 1.

[0196] In some embodiments, the compound is [ka] [ka] Alternatively, a selection of pharmaceutically acceptable salts thereof is used.

[0197] In another aspect, this disclosure is: [ka] [ka] [ka] [ka] [ka] [ka] [ka] The present invention provides compounds selected from or pharmaceutically acceptable salts thereof.

[0198] In another embodiment, the disclosure provides a pharmaceutical composition comprising a disclosed compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0199] In another aspect, the disclosure provides a method for treating a neurological or psychiatric disorder, the method comprising administering to a subject in need thereof a compound disclosed or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable pharmaceutically composition disclosed.

[0200] Other purposes and advantages will become apparent to those skilled in the art from consideration of the subsequent embodiments, examples, and claims for carrying out the invention. [Modes for carrying out the invention]

[0201] As generally described herein, the present invention provides compounds and compositions useful for preventing and / or treating diseases, disorders or conditions described herein, such as diseases, disorders or conditions related to abnormal function of sodium ion channels, such as abnormal delayed sodium current (INaL). Examples of diseases, disorders or conditions include epilepsy or epileptic syndromes.

[0202] definition chemical definition Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are from the CAS version, Handbook of Chemistry and Physics, 75.th Identification is made according to the periodic table of elements on the inside cover of the ed., and specific functional groups are generally defined as described herein. Furthermore, general principles of organic chemistry, as well as specific functional parts and reactivity, are referenced in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd This information is found in Edition, Cambridge University Press, Cambridge, 1987.

[0203] The compounds described herein may contain one or more chiral centers and therefore may exist in various isomeric forms, such as enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers or geometric isomers, or in the form of a racemic mixture and a mixture of stereoisomers including a mixture concentrated with one or more stereoisomers. The isomers may be isolated from the mixture by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers may be prepared by asymmetric synthesis. For example, Jacques, et al. See also Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, et al., Tetrahedron, 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p.268 (ELEliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present invention further encompasses the compounds described herein as individual isomers substantially free of other isomers, and instead as mixtures of various isomers.

[0204] As used herein, a pure enantiomerized compound is substantially free of other enantiomers or stereoisomers of the compound (i.e., enantiomerized). In other words, the "S" form of a compound is substantially free of the "R" form of the compound, and therefore is enantiomerized in the "R" form. The term "pure as an enantiomer" or "pure enantiomer" means that the compound contains more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight of enantiomers. In certain embodiments, the weight is based on the total weight of all enantiomers or stereoisomers of the compound.

[0205] In the compositions provided herein, a pure compound may exist as an enantiomer together with other active or inactive components. For example, a pharmaceutical composition containing a pure R-compound as an enantiomer may include, for example, about 90% excipients and about 10% of the pure R-compound as an enantiomer. In certain embodiments, the pure R-compound as an enantiomer in such a composition may include, for example, at least about 95% by weight of the R-compound and at most about 5% by weight of the S-compound by the total weight of the compound. For example, a pharmaceutical composition containing a pure S-compound as an enantiomer may include, for example, about 90% excipients and about 10% of the pure S-compound as an enantiomer. In certain embodiments, the pure S-compound as an enantiomer in such a composition may include, for example, at least about 95% by weight of the S-compound and at most about 5% by weight of the R-compound by the total weight of the compound. In certain embodiments, the active ingredient may be formulated with little to no excipients or carriers.

[0206] The compounds described herein may also include one or more isotopic substitutions. For example, H is 1 H, 2 H (D or deuterium) and 3 It may be any isotopic form containing H (T or tritium); C is 12 C, 13 C and 14 It may also be an isotopic form containing C; O is 16 O and 18 This could be an isotopic form containing O; and so on.

[0207] The following terms are intended to have the meanings presented herein and are useful for understanding the description and intended scope of the invention. When describing the invention, which may include compounds, compositions containing such compounds, and methods of using such compounds or compositions, the following terms, if present, have the meanings below unless otherwise specified. Where described herein, any of the parts defined below may be substituted by various substituents, and each definition is intended to include such substituted parts within its scope as set forth below. Unless otherwise specified, the terms “place” have the meanings below. "Interchangeable" should be defined as set forth below. It should be further understood that the terms "base" and "radical" can be considered interchangeable when used herein. The articles "a" and "an" may be used herein to refer to one or more (i.e., at least one) grammatical objects of the articles. For example, "analog" means one analogue or more than one analogue.

[0208] When a range of values ​​is listed, it is intended to include each value and subrange within that range. For example, "C 1-6 "Alkyl" refers to C1, C2, C3, C4, C5, C6, C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 It is intended to include alkyl groups.

[0209] As used herein, “alkyl” refers to, for example, a radical of a linear or branched saturated hydrocarbon group having 1 to 20 carbon atoms (“C 1-20 ("alkyl"). In some embodiments, the alkyl group has 1 to 10 carbon atoms ("C").1-10 ("alkyl"). In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C"). 1-9 ("alkyl"). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C"). 1-8 ("alkyl"). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C"). 1-7 ("alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C"). 1-6 ("alkyl"). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C"). 1-5 ("alkyl"). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C"). 1-4 (alkyl). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1-3 ("alkyl"). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C"). 1-2 ("Alkyl"). In some embodiments, the alkyl group has one carbon atom ("C1 alkyl"). 1-6 Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, and hexyl.

[0210] As used herein, “alkenyl” refers to a radical of a linear or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) ("C 2-20 ("Alkenyl"). In certain embodiments, the alkenyl does not contain a triple bond. In some embodiments, the alkenyl group has 2 to 10 carbon atoms ("C"). 2-10 Alkenil) In some embodiments The alkenyl group has 2 to 9 carbon atoms ("C 2-9 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 8 carbon atoms ("C"). 2-8 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 7 carbon atoms ("C"). 2-7("Alkenyl"). In some embodiments, the alkenyl group has 2 to 6 carbon atoms ("C"). 2-6 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 5 carbon atoms ("C"). 2-5 ("Alkenyl"). In some embodiments, the alkenyl group has 2 to 4 carbon atoms ("C"). 2-4 ("Alkenyl"). In some embodiments, the alkenyl group has 2-3 carbon atoms ("C"). 2-3 "Alkenyl"). In some embodiments, the alkenyl group has two carbon atoms ("C2 alkenyl"). One or more carbon-carbon double bonds can be internal (e.g., 2-butenyl) or terminal (e.g., 1-butenyl). C 2-4 Examples of alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), and butadienyl (C4). 2-6 Examples of alkenyl groups include the aforementioned C 2-4 Examples include alkenyl groups, as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), etc. Additional examples of alkenyl groups include heptenyl (C7), octenyl (C8), octatrienyl (C8), etc.

[0211] As used herein, “alkynyl” refers to a radical of a linear or branched hydrocarbon group having 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) ("C 2-20 ("Alkynyl"). In certain embodiments, the alkynyl does not contain a double bond. In some embodiments, the alkynyl group has 2 to 10 carbon atoms ("C"). 2-10 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 9 carbon atoms ("C"). 2-9 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 8 carbon atoms ("C"). 2-8 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 7 carbon atoms ("C").2-7 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 6 carbon atoms ("C"). 2-6 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 5 carbon atoms ("C"). 2-5 ("Alkynyl"). In some embodiments, the alkynyl group has 2 to 4 carbon atoms ("C"). 2-4 In some embodiments, the alkynyl group has 2-3 carbon atoms ("C"). 2-3 "Alkynyl"). In some embodiments, the alkynyl group has two carbon atoms ("C2 alkynyl"). One or more carbon-carbon triple bonds can be internal (e.g., 2-butynyl) or terminal (e.g., 1-butynyl). C 2-4 Examples of alkynyl groups include, but are not limited to, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), and 2-butynyl (C4). 2-6 Examples of alkenyl groups include the aforementioned C 2-4 Examples include alkynyl groups, as well as pentynyl (C5), hexynyl (C6), etc. Examples of additional alkynyl groups include heptynyl (C7), octinyl (C8), etc.

[0212] As used herein, “alkylene,” “alkenylene,” and “alkynylene” refer to the divalent radicals of an alkyl group, an alkenyl group, and an alkynyl group, respectively. Where a range or number of carbon atoms is provided for a particular “alkylene,” “alkenylene,” or “alkynylene” group, it is understood that the range or number refers to the range or number of carbon atoms in the divalent chain of straight carbon atoms. The “alkylene,” “alkenylene,” and “alkynylene” groups may be substituted with one or more substituents as described herein, or they may be unsubstituted.

[0213] As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10 and 14π electrons shared in a cyclic configuration) having 6 to 14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6-14 In some embodiments, the aryl group has 6 ring carbon atoms ("C6 aryl"; for example, phenyl). In some embodiments, the aryl group has 10 ring carbon atoms ("C6 aryl"). 10 "Aryl"; for example, naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group has 14 ring carbon atoms ("C"). 14 "Aryl" (for example, anthracyl). "Aryl" also includes ring systems in which an aryl ring, as defined above, is fused with one or more carbocyrillic or heterocyclyl groups, where the radical or attachment site is on the aryl ring, and in such cases the number of carbon atoms continues to indicate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, those derived from acetantrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluorantene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indan, indene, naphthalene, octacene, octafen, octaene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiaden, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. In particular, aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl.

[0214] As used herein, “heteroaryl” refers to a radical of a 5- to 10-membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10π electrons shared in a cyclic configuration) having a ring carbon atom and 1-4 ring heteroatoms provided in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 10-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the attachment site can be a carbon or nitrogen atom as the valency allows. Heteroaryl bicyclic ring systems can contain one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems in which a heteroaryl ring as defined above is condensed to one or more carbocykyl or heterocyclyl groups, where the attachment site is on the heteroaryl ring, and in such cases the number of ring members continues to indicate the number of ring members in the heteroaryl ring system. "Hyperaryl" also includes ring systems in which a heteroaryl ring, as defined above, is fused with one or more aryl groups, where the attachment site is on either the aryl ring or the heteroaryl ring, and in such cases the number of ring members indicates the number of ring members in the fused (aryl / heteroaryl) ring system. In bicyclic heteroaryl groups in which one of the rings does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, etc.), the attachment site can be on either ring, i.e., the ring carrying the heteroatom (e.g., 2-indolyl) or the ring not containing a heteroatom (e.g., 5-indolyl).

[0215] In some embodiments, the heteroaryl group is a 5-10 membered aromatic ring system having a ring carbon atom provided in an aromatic ring system and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl ring"). In some embodiments, the heteroaryl group is a 5-8 membered aromatic ring system having a ring carbon atom provided in an aromatic ring system and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl ring"). In some embodiments, the heteroaryl group is a 5-6 membered aromatic ring system having a ring carbon atom provided in an aromatic ring system and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl ring"). In some embodiments, the 5-6 membered heteroaryl ring has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl ring has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl ring has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0216] Examples of five-membered heteroaryl rings containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Examples of five-membered heteroaryl rings containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Examples of five-membered heteroaryl rings containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Examples of five-membered heteroaryl rings containing four heteroatoms include, but are not limited to, tetrazolyl. Examples of six-membered heteroaryl rings containing one heteroatom include, but are not limited to, pyridinyl. Examples of six-membered heteroaryl rings containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Examples of six-membered heteroaryl rings containing three or four heteroatoms include, but are not limited to, triazinyl and tetradinyl, respectively. Examples of seven-membered heteroaryl rings containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryl rings include, but are not limited to, indolyl and isoindolyl. Indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranil, benzoisofuranil, benzimimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl Examples include lyl, benzthiadiazolyl, indolidinyl, and prinyl. 6,6-bicyclic Examples of heteroaryl groups in the formula include, but are not limited to, naphthilidinyl, pteridinyl, quinolinyl, isoquinolinyl, synnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0217] Typical examples of heteroaryls include: [ka] These are listed, where each Z is a carbonyl, N, or NR compound. 65Selected from O and S; R 65 These are independently hydrogen, C1-C8 alkyl, and C3-C 10 Carbocyclyl, a heterocyclyl with a 4-10 membered ring, C6-C 10 These are aryls and heteroaryls with 5-10 member rings.

[0218] As used herein, "carbocykryl" or "carbocyclic" refers to a non-aromatic ring system with 3 to 10 ring carbon atoms ("C"). 3-10 This refers to a radical of a non-aromatic cyclic hydrocarbon group having a carbocyclyl (C) and zero heteroatoms. In some embodiments, the carbocyclyl group has 3 to 8 ring carbon atoms (C). 3-8 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C"). 3-6 Carbocyclyl). In some embodiments, the carbocyclyl group has 3 to 6 ring carbon atoms ("C"). 3-6 (Carbocyclyl). In some embodiments, the carbocyclyl group has 5 to 10 ring carbon atoms ("C"). 5-10 Carbocyclyl). Example C 3-6 Examples of carbocyclyl groups include, but are not limited to, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), and cyclohexadienyl (C6). 3-8 The carbocyryl group is not limited to the aforementioned C 3-6 Examples include the carbocyclyl group, as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), etc. 3-10 The carbocyryl group is not limited to the aforementioned C 3-8 Carbocyclyl group and cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C9) 10 ), cyclodecenyl (C 10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C9) 10 ), spiro[4.5]decanil(C 10 Examples include the above. As illustrated by the examples above, in certain embodiments, the carbocyclyl group may be monocyclic ("monocyclic carbocyclyl") or contain a condensed, bridged, or spiro-ring system such as a bicyclic ("bicyclic carbocyclyl"), and may be saturated or partially unsaturated. "Carbocyclyl" also includes ring systems in which the carbocyclyl ring as defined above is condensed with one or more aryl or heteroaryl groups, where the attachment site is on the carbocyclyl ring, and in such examples, carbon The prime number continues to indicate the number of carbon atoms in the carbocyclyl ring system.

[0219] When the term "cycloalkyl" is used herein, for example, in this specification, C 3-8 Cycloalkyl or C 3-6 A cycloalkyl group refers to a monocyclic saturated or partially unsaturated hydrocarbon ring system having 3 to 8 or 3 to 6 carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclohexyl, cyclohexenyl, cyclopentyl, cyclopentenyl, cyclobutyl, and cyclopropyl.

[0220] As used herein, “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 10-membered non-aromatic ring system having a ring carbon atom and 1- to 4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3- to 10-membered heterocyclyl”). In heterocyclyl groups containing one or more nitrogen atoms, the attachment site can be a carbon or nitrogen atom, as the valency allows. Heterocyclyl groups can be monocyclic (“monocyclic heterocyclyl”) or bicyclic (“bicyclic heterocyclyl”), and can be condensed, bridged, or spirocyclic ring systems, and can be saturated or partially unsaturated. A heterocyclyl bicyclic ring system can contain one or more heteroatoms in one or both rings. "Heterocyclyl" also includes a ring system in which a heterocyclyl ring as defined above is fused with one or more carbocyclyl groups in a ring system in which the heterocyclyl ring as defined above is fused with one or more aryl groups or heteroaryl groups, where the attachment site is on the heterocyclyl ring, and in such cases the number of ring members continues to represent the number of ring members in the heterocyclyl ring system.

[0221] In some embodiments, the heterocyclyl group is a 5-10 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10 membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-8 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, the heterocyclyl group is a 5-6 membered non-aromatic ring system having a ring carbon atom and 1-4 ring heteroatoms, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclil ring has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclil ring has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0222] Examples of three-membered heterocyclyl rings containing one heteroatom include, but are not limited to, azilidinyl, oxyranil, and thiorenyl. Examples of four-membered heterocyclyl rings containing one heteroatom include, but are not limited to, azetidinyl, oxetanil, and thietanil. Examples of five-membered heterocyclyl rings containing one heteroatom include, but are not limited to, tetrahydrofuranil, dihydrofuranil, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-di Examples include: 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanil, oxasulfuranil, disulfuranil, and oxazolidine-2-one. 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinil, oxadiazolinil, and thiadiazolinil. 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinil, tetrahydropyranil, dihydropyridinil, and thianil. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, triazinyl. Examples of seven-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azepanyl, oxepanyl, and thiepanyl. Examples of eight-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azocanyl, oxecanyl, and thiocanyl. Examples of five-membered heterocyclyl groups fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocycles) include, but are not limited to, Examples include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, and benzoxazolinonyl. Examples of 6-membered heterocyclyl groups (also called 6,6-bicyclic heterocycles in this specification) that are fused to an aryl ring include, without limitation, tetra Examples include tetrahydroquinolinyl and tetrahydroisoquinolinyl.

[0223] When used herein, "hetero" in describing a compound or a group present in a compound means that one or more carbon atoms in the compound or group are replaced by a heteroatom of nitrogen, oxygen, or sulfur. Hetero may apply to any of the above-described hydrocarbyl groups having 1 to 5 and particularly 1 to 3 heteroatoms, e.g., alkyl, e.g., heteroalkyl; carbocykryl, e.g., heterocyclyl; aryl, e.g., heteroaryl.

[0224] As used herein, "cyano" refers to -CN.

[0225] As used herein, "halo" or "halogen" refers to fluoro(F), chloro(Cl), bromo(Br), and iod(I). In certain embodiments, the halo group is either fluoro or chloro.

[0226] As used herein, "haloalkyl" refers to an alkyl group substituted with one or more halogen atoms.

[0227] As used herein, "nitro" refers to -NO2.

[0228] As used herein, "oxo" refers to -C=O.

[0229] In general, the term “substituted” means, whether preceded by the term “optionally,” that at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) is replaced by an acceptable substituent, such as a substituent that, upon substitution, produces a stable compound, such as a compound that does not spontaneously undergo transformation by recombination, cyclization, elimination, or other reactions. Unless otherwise specified, a “substituted” group has substituents at one or more substituted positions on the group, and if more than one position is substituted in a given structure, the substituents are either identical or different at each position.

[0230] As used herein, “counterion” or “anion counterion” is a negatively charged group associated with a cationic quaternary amino group in order to maintain electrical neutrality. Examples of counterions include halogen compound ions (e.g., F - Cl - , Br - , I - ), NO3 - ClO4 - , OH - H2PO4 - HSO4 - SO4 -2 Examples include sulfonate ions (for example, methanesulfonic acid, trifluoromethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, 10-camphorsulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1-sulfonic acid-5-sulfonic acid, ethane-1-sulfonic acid-2-sulfonic acid, etc.) and carboxylate ions (for example, acetic acid, ethaneic acid, propanoic acid, benzoic acid, glyceric acid, lactic acid, tartaric acid, glycolic acid, etc.).

[0231] Nitrogen atoms can be substituted or unsubstituted as their valency allows, including primary, secondary, tertiary, and quaternary nitrogen atoms. Examples of substituents on nitrogen atoms include hydrogen, -OH, and -OR. aa , -N(R cc )2, -CN, -C(=O)R aa -C(=O)N(R cc )2, -CO2R aa , -SO2R aa -C(=NR bb )R aa -C(=NR cc )OR aa -C(=NR cc )N(R cc )2, -SO2N(R cc )2, -SO2R cc , -SO2OR cc -SOR aa -C(=S)N(R cc )2, -C(=O)SR cc -C(=S)SR cc -P(=O)2R aa-P(=O)(R aa )2, -P(=O)2N(R cc )2, -P(=O)(NR cc )2, C 1-10 Alkyl, C 1-10 Perhaloalkyl, C 2-10 Alkenil, C 2-10 Alkinyl, C 3-10 Carbocyclyl, heterocyclyl with a 3-14 membered ring, C 6-14 Examples include, but are not limited to, aryls and heteroaryls of 5-14 member rings, or two Rs linked to a nitrogen atom. cc The groups bond to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, in which each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl independently has 0, 1, 2, 3, 4, or 5 R groups. dd Substituted by the group, R aa , R bb , R cc and R dd This is as defined above.

[0232] These and other exemplary substituents are described in further detail in the modes, examples, and claims for carrying out the invention. The present invention is not intended to be limited in any way to the above-mentioned list of exemplary substituents.

[0233] Other definitions As used herein, the term “pharmaceutically acceptable salt” refers to salts that, within the bounds of sound medical judgment, are suitable for use in contact with human and lower animal tissues without causing excessive toxicity, irritation, allergic reactions, etc., and that have a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences (1977) 66:1-19. Examples of pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipine, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphor sulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanate, glycerophosphate, gluconate, hemisulfate, heptanate, hexanoate, hydroiodide, and 2-hydroxyethanesulfonic acid. Examples of pharmaceutically acceptable salts derived from suitable bases include alkali metal salts, alkaline earth metal salts, ammonium salts, and N. + (C 1-4Examples include alkyl(4) salts. Typical alkali metal salts or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, etc. Further pharmaceutically acceptable salts include, as appropriate, non-toxic ammonium, quaternary ammonium, and, for example, halogen compounds, hydroxides, etc. Examples of amine cations formed using counterions such as rubonic acid, sulfuric acid, phosphoric acid, nitric acid, lower alkyl sulfonic acid, and aryl sulfonic acid include amine cations.

[0234] As used herein, the “subject” to which administration is intended includes, but is not limited to, human (i.e., male or female of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young adults, middle-aged adults, or elderly adults) and / or non-human animals, e.g., primates (e.g., cynomolgus macaques, rhesus macaques), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In certain embodiments, the subject is human. In certain embodiments, the subject is a non-human animal. The terms “human,” “patient,” and “subject” are used interchangeably herein.

[0235] Diseases, disorders, and conditions are used interchangeably in this specification.

[0236] As used herein, and unless otherwise specified, the terms “to treat,” “to treat,” and “treatment” refer to actions that occur while an object is suffering from a specified disease, disorder, or condition and that reduce the severity of the disease, disorder, or condition, or slow or reduce the progression of the disease, disorder, or condition ("therapeutic measures"), and also refer to actions that occur before an object begins to suffer from a specified disease, disorder, or condition ("preventive measures").

[0237] As used herein, the “effective amount” of a compound refers to an amount sufficient to elicit a desired biological response. As will be readily apparent to those skilled in the art, the effective amount of a compound in the present invention may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the method of administration, and the age, health, and condition of the subject. The effective amount encompasses both therapeutic and prophylactic treatments.

[0238] As used herein, and unless otherwise specified, “therapeutic amount” of a compound means an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize as much of one or more symptoms associated with the disease, disorder, or condition. A therapeutic amount of a compound means the amount of the therapeutic agent, alone or in combination with other therapeutic agents, that provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term “therapeutic amount” may include an amount that improves the overall treatment, an amount that reduces or avoids the symptoms or causes of the disease or condition, or an amount that enhances the therapeutic effectiveness of other therapeutic agents.

[0239] compound In one embodiment, the present invention is based on formula (II): [ka] Characterized by a compound or a pharmaceutically acceptable salt thereof, where each of X, Y, and Z is independently N or CR. 2 And in this case, at least one of X, Y, and Z is independently N; A is one or more R 3 An aryl or heteroaryl (for example, a monocyclic 6-membered aryl or heteroaryl) that can be optionally substituted by; R 1 is hydrogen, C1 alkyl, haloalkyl, or carbocyclyl, where each alkyl and carbocyclyl is halo, heterocyclyl, or -OR c Optionally replaced by;R 2 R is hydrogen, alkyl, or halo; each R 3 These are independently alkyl, halo, cyano, nitro, carbocyryl, heterocyclyl, and -ORc , -N(R d )2, -C(O)R c , -C(O) Ure c , or -C(O)N(R d )2, and in this case, alkyl, carbocyryl, and heterocyclyl have 1 or more R 5 Optionally substituted by; each R 5 These are independently halo, cyano, nitro, alkyl, carbocyrill, heterocyclyl, and -OR c ,-C(O)N(R d )2, -SO2R c , -SO2OR c , -SO2N(R d )2, -NR d C(O)(R c ), or -N(R d )2; each R c Each of the elements is independently a hydrogen atom, an alkyl group, a carbocykyl group, or a heterocycline group, where each alkyl group, carbocykyl group, or heterocycline group has one or more R groups. 6 Optionally substituted by; each R d R is independently hydrogen or alkyl; and each R 6 These are independently halo, carbocyclyl, or heterocyclyl.

[0240] In some embodiments, X is N. In some embodiments, X is N and Y is CR 2 In some embodiments, X is N and Z is CR. 2 In some embodiments, X is N, and Y and Z are independently CR. 2 In some embodiments, R 2 It is hydrogen.

[0241] In some embodiments, Y is N. In some embodiments, Y is N and X is CR 2 In some embodiments, Y is N and Z is CR. 2 In some embodiments, Y is N, and each of X and Z is independently CR. 2 In some embodiments, R2 It is hydrogen.

[0242] In some embodiments, Z is N. In some embodiments, Z is N and X is CR 2 In some embodiments, Z is N and Y is CR. 2 In some embodiments, Z is N, and X and Y are independently CR. 2 In some embodiments, R 2 It is hydrogen.

[0243] In some embodiments, A is an aryl (e.g., phenyl). In some embodiments, A is a heteroaryl. In some embodiments, A is a six-membered heteroaryl ring. In some embodiments, A is a nitrogen-containing heteroaryl (e.g., pyridyl).

[0244] In some embodiments, R 1 It is hydrogen.

[0245] In some embodiments, R 1 is a C1 alkyl, haloalkyl, or carbocyric. In some embodiments, R 1 is a haloalkyl, for example, a C1-C3 haloalkyl. In some embodiments, R 1 is a C1-C3 haloalkyl, for example, a C1-C3 fluoroalkyl. In some embodiments, R 1 is -CF3, -CHF2, -CH2CF3, or CF2CF3. In some embodiments, R 1 It is -CF3.

[0246] In some embodiments, R 1 is heterocyclyl or -OR c It is a C1 alkyl substituted with R. In some embodiments, 1 is heterocyclyl or -OR c It is -CH2- substituted by. In some embodiments, R 1is an oxygen-containing heterocycline or a -CH2- substituted with -OH. In some embodiments, R 1 This is tetrahydrofuranyl (e.g., 1-tetrahydrofuranyl or 2-tetrahydrofuranyl), tetrahydropyranyl (e.g., 1-tetrahydropyranyl, 2-tetrahydropyranyl, or 3-tetrahydropyranyl), or -CH2- substituted with -OH.

[0247] In some embodiments, R 1 is a halo and -OR c It is a C1 alkyl substituted with R. In some embodiments, 1 -CF2(OR c ) is. In some embodiments, R c The group is an alkyl group (for example, CH3 or -CH2- substituted with a carbocyacrylic group (for example, isopropanyl)).

[0248] In some embodiments, R 1 is carbocyclyl. In some embodiments, R 1 is cyclopropyl or cyclobutyl. In some embodiments, R 1 is cyclopropyl or cyclobutyl substituted with 1-3 halo groups (e.g., 1-3 fluoro). In some embodiments, R 1 It is difluorocyclopropyl or difluorocyclobutyl.

[0249] Some implementation methods, each R 3 These are independently alkyl, halo, cyano, carbocyryl, heterocyclyl, or -OR c In some embodiments, R 3 is alkyl (for example, C1-C4 alkyl). In some embodiments, R 3 is a C1-C4 alkyl group. In some embodiments, R 3 is methyl, ethyl, or isopropyl. In some embodiments, R 3 is R 5(For example, alkyl (e.g., methyl), halo (e.g., fluoro), cyano, carbocyryl, or -OR) c It is a C1-C4 alkyl group substituted with (for example, -OH or -OCH3). In some embodiments, R 3 is -CF3, -C(CH3)2OH, -C(CH3)2OCH3, or CH2OCHF2. In some embodiments, R 3 It is -CF3.

[0250] In some embodiments, R 3 This is a halo (for example, fluoro or chloro).

[0251] In some embodiments, R 3 It is cyano.

[0252] In some embodiments, R 3 is carbocyclyl. In some embodiments, R 3 This is either an unsubstituted carbocyclyl (e.g., unsubstituted cyclopropyl or unsubstituted cyclobutyl) or a substituted carbocyclyl (e.g., substituted with cyano or halo).

[0253] In some embodiments, R 3 is a heterocycline. In some embodiments, R 3 is an oxygen-containing heterocycline. In some embodiments, R 3 It is oxetanyl.

[0254] In some embodiments, R 3 は-OR c In some embodiments, R 3 は-OR c And in that case, R c is alkyl. In some embodiments, R 3 is -OCF3, -OCH3, -OCH(CH3)(CF3), -OCH2CH2, -OCH(CH3)2, or -OCH2CF3. In some embodiments, R 3 は-OR c And in that case, Rc For example, R is 1 or greater. 6 It is a carbocyclyl optionally substituted with R. In some embodiments, R 3 This is a carbocyclyl (e.g., cyclopropyl or cyclobutyl) optionally substituted with a halo (e.g., fluoro) or cyano.

[0255] In another embodiment, formula (III-2) is provided: [ka] A compound of or a pharmaceutically acceptable salt thereof, wherein one of X and Y is N, and the other of X and Y is CR. 2 And A is 1 or more R 3 aryl or heteroaryl (e.g., monocyclic 6-membered aryl or heteroaryl) optionally substituted by; R 1 is hydrogen, C1 alkyl, haloalkyl, or carbocyclyl, where each alkyl and carbocyclyl is halo, heterocyclyl, or -OR c Optionally replaced by;R 2 R is hydrogen, alkyl, or halo; each R 3 They are independent and -OR c , -N(R d )2, -C(O)R c , -C(O)OR c , or -C(O)N(R d )2, and in this case alkyl, carbocykyl, and heterocyclyl are halo, cyano, nitro, alkyl, carbocykyl, heterocyclyl, -OR c ,-C(O)N(R d )2, -SO2R c , -SO2OR c , -SO2N(R d )2, -NR d C(O)(R c ), or -N(R d ) Optionally substituted by 2; each R cThese are independently hydrogen or alkyl, in which case each alkyl has 1 or more R 6 Optionally substituted by; each R d R is independently hydrogen or alkyl; each R 6 These are independently halo, carbocyclyl, or heterocyclyl.

[0256] In some embodiments, X is N. In some embodiments, X is N and Y is CR 2 In some embodiments, R 2 It is hydrogen.

[0257] In some embodiments, X is CR 2 In some embodiments, X is CR 2 And Y is N. In some embodiments, R 2 It is hydrogen.

[0258] In some embodiments, A is an aryl (e.g., phenyl). In some embodiments, A is a heteroaryl. In some embodiments, A is a six-membered heteroaryl ring. In some embodiments, A is a nitrogen-containing heteroaryl (e.g., pyridyl).

[0259] In some embodiments, R 1 It is hydrogen.

[0260] In some embodiments, R 1 is a C1 alkyl, haloalkyl, or carbocyric. In some embodiments, R 1 is a haloalkyl, for example, a C1-C3 haloalkyl. In some embodiments, R 1 is a C1-C3 haloalkyl, for example, a C1-C3 fluoroalkyl. In some embodiments, R 1 is -CF3, -CHF2, -CH2CF3, or CF2CF3. In some embodiments, R 1 It is -CF3.

[0261] In some embodiments, R 1is heterocyclyl or -OR c It is a C1 alkyl substituted with R. In some embodiments, 1 is heterocyclyl or -OR c It is -CH2- substituted by. In some embodiments, R 1 is an oxygen-containing heterocycline or a -CH2- substituted with -OH. In some embodiments, R 1 This is tetrahydrofuranyl (e.g., 1-tetrahydrofuranyl or 2-tetrahydrofuranyl), tetrahydropyranyl (e.g., 1-tetrahydropyranyl, 2-tetrahydropyranyl, or 3-tetrahydropyranyl), or -CH2- substituted with -OH.

[0262] In some embodiments, R 1 is a halo and -OR c It is a C1 alkyl substituted with R. In some embodiments, 1 -CF2(OR c ) is. In some embodiments, R c is an alkyl group (for example, CH3 or -CH2- substituted with a carbocyacrylic (for example, isopropanyl)). In some embodiments, R 1 is carbocyclyl. In some embodiments, R 1 is cyclopropyl or cyclobutyl. In some embodiments, R 1 is cyclopropyl or cyclobutyl substituted with 1-3 halo groups (e.g., 1-3 fluoro). In some embodiments, R 1 It is difluorocyclopropyl or difluorocyclobutyl.

[0263] In some embodiments, R 3 is a heterocycline. In some embodiments, R 3 is an oxygen-containing heterocycline. In some embodiments, R 3 It is oxetanyl.

[0264] Some implementation methods, each R 3These are independently alkyl, halo, cyano, carbocyryl, heterocyclyl, or -OR c In some embodiments, R 3 is alkyl (for example) , C1-C4 alkyl). In some embodiments, R 3 is a C1-C4 alkyl group. In some embodiments, R 3 is methyl. In some embodiments, R 3 is a substituted C1 alkyl (for example, where the C1 alkyl is alkyl (e.g., methyl), halo (e.g., fluoro), cyano, carbocykyl, or -OR). c (For example, it is replaced by -OCH3). In some embodiments, R 3 It is -CF3.

[0265] In some embodiments, R 3 This is a halo (for example, fluoro or chloro).

[0266] In some embodiments, R 3 It is cyano.

[0267] In some embodiments, R 3 is carbocyclyl. In some embodiments, R 3 This is either an unsubstituted carbocyclyl (e.g., unsubstituted cyclopropyl) or a substituted carbocyclyl (e.g., substituted with cyano or halo).

[0268] In some embodiments, R 3 is a heterocycline. In some embodiments, R 3 is an oxygen-containing heterocycline. In some embodiments, R 3 is oxetanyl. In some embodiments, R 3 は-OR c In some embodiments, R 3 は-OR c And in that case, R c is alkyl. In some embodiments, R 3These are -OCF3, -OCH3, -OCH(CH3)(CF3), or -OCH2CF3.

[0269] In some embodiments, the compound of formula (II) or (III) is [ka] [ka] [ka] Or not those salts that are pharmaceutically acceptable.

[0270] In another embodiment, the formula provided is (IV-2): [ka] A compound of or a pharmaceutically acceptable salt thereof, where A is 1 or more R 3 aryl or heteroaryl (e.g., monocyclic 6-membered aryl or heteroaryl) optionally substituted by; R 1 is hydrogen, alkyl, or carbocyrill, where each alkyl and carbocyrill is a halo, heterocyclyl, or -OR. c Optionally substituted by; each R 3 These are independently alkyl, halo, cyano, nitro, carbocyryl, heterocyclyl, and -OR c , -N(R d )2, -C(O)R c , -C(O)OR c , or -C(O)N(R d )2, and in this case alkyl, carbocykrill and heterocyclyl are halo, cyano, nitro, alkyl, carbocykrill, heterocyclyl, carbocykrill, heterocyclyl, -OR c ,-C(O)N(R d )2, -SO2R c , -SO2OR c , -SO2N(R d )2, -NR dC(O)(R c ), or -N(R d ) Optionally substituted by 2; each R c R is independently hydrogen or alkyl, in which case alkyl is 1 or more R 6 Optionally substituted by; each R d These are independently hydrogen or alkyl, in which case each alkyl has 1 or more R 6 It is optionally replaced by; and each R 6 These are independently alkyl, carbocykryl, heterocyclyl, halo, cyano, nitro, or -OH.

[0271] In some embodiments, A is an aryl (e.g., phenyl). In some embodiments, A is a heteroaryl. In some embodiments, A is a six-membered heteroaryl ring. In some embodiments, A is a nitrogen-containing heteroaryl (e.g., pyridyl).

[0272] In some embodiments, R 1 is a haloalkyl, for example, a C1-C3 haloalkyl. In some embodiments, R 1 is a C1-C3 haloalkyl, for example, a C1-C3 fluoroalkyl. In some embodiments, R 1 It is -CHF2.

[0273] Some implementation methods, each R 3 These are independently alkyl, halo, or -OR c In some embodiments, R 3 is alkyl (for example, C1-C4 alkyl). In some embodiments, R 3 is a C1-C4 alkyl group. In some embodiments, R 3 is methyl or isopropanyl. In some embodiments, R 3 is a substituted C1-C4 alkyl (for example, in which case the C1-C4 alkyl is -OR c (For example, it is replaced by -OCH3). In some embodiments, R 3 This is a halo (for example, fluoro or chloro).

[0274] In some embodiments, R 3 This is a halo (for example, a fluoro).

[0275] In some embodiments, R 3 は-OR c In some embodiments, R 3 は-OR c And in that case, R c is alkyl. In some embodiments, R 3 is -OCF3, -OCH3, or -OCH2CF3. In some embodiments, R 3 It is -OCF3.

[0276] In some embodiments, the compound of formula (IV) is [ka] Or not those salts that are pharmaceutically acceptable.

[0277] In another embodiment, the formula provided is (V-2): [ka] A compound of or a pharmaceutically acceptable salt thereof, where A is 1 or more R 3 aryl or heteroaryl (e.g., monocyclic 6-membered aryl or heteroaryl) optionally substituted by; R 1 is hydrogen, C1 alkyl, haloalkyl, or carbocyclyl, where each alkyl and carbocyclyl is halo, heterocyclyl, or -OR c Optionally substituted by; each R 3 These are independently alkyl, halo, cyano, nitro, carbocyryl, heterocyclyl, and -OR c , -N(R d )2, -C(O)R c , -C(O)OR c , or -C(O)N(R d)2, and in this case alkyl, carbocykyl, and heterocyclyl are halo, cyano, nitro, alkyl, carbocykyl, heterocyclyl, -OR c ,-C(O)N(R d )2, -SO2R c , -SO2OR c , -SO2N(R d )2, -NR d C(O)(R c ), or -N(R d ) Optionally substituted by 2; each R c R is hydrogen or alkyl, in which case the alkyl is 1 or more R 6 Optionally substituted by; each R d These are independently hydrogen or alkyl, in which case each alkyl has 1 or more R 6 It is optionally replaced by; and each R 6 These are independently alkyl, carbocykryl, heterocyclyl, halo, cyano, nitro, or -OH.

[0278] In some embodiments, A is an aryl (e.g., phenyl). In some embodiments, A is a heteroaryl. In some embodiments, A is a six-membered heteroaryl ring. In some embodiments, A is a nitrogen-containing heteroaryl (e.g., pyridyl).

[0279] In some embodiments, R 1 is a C1 alkyl, haloalkyl, or carbocyric. In some embodiments, R 1 is a haloalkyl, for example, a C1-C3 haloalkyl. In some embodiments, R 1 is a C1-C3 haloalkyl, for example, a C1-C3 fluoroalkyl. In some embodiments, R 1 is -CF3, -CHF2, -CH2CF3, or CF2CF3. In some embodiments, R 1 It is -CF3.

[0280] In some embodiments, R 1 It is a C1 alkyl group, in which case the alkyl group is heterocyclyl or -ORc It is replaced by R 1 is heterocyclyl or -OR c It is -CH2- substituted by. In some embodiments, R 1 is an oxygen-containing heterocycline or a -CH2- substituted with -OH. In some embodiments, R 1 It is a tetrahydrofuranyl (e.g., 1-tetrahydrofuranyl or 2-tetrahydrofuranyl) or a -CH2- substituted with an -OH group.

[0281] In some embodiments, R 1 is carbocyclyl. In some embodiments, R 1 is cyclopropyl or cyclobutyl. In some embodiments, R 1 is cyclopropyl or cyclobutyl, for example, substituted cyclopropyl or substituted cyclobutyl. In some embodiments, R 1 is cyclopropyl or cyclobutyl substituted with 1-3 halo groups (e.g., 1-3 fluoro). In some embodiments, R 1 It is difluorocyclopropyl or difluorocyclobutyl.

[0282] Some implementation methods, each R 3 These are independently alkyl, halo, cyano, carbocyryl, heterocyclyl, or -OR c In some embodiments, R 3 is alkyl (for example, C1-C4 alkyl). In some embodiments, R 3 is a C1-C4 alkyl group. In some embodiments, R 3 is methyl. In some embodiments, R 3 is a substituted C1 alkyl (for example, where the C1 alkyl is alkyl (e.g., methyl), halo (e.g., fluoro), cyano, carbocykyl, or -OR). c (For example, replaced by -OCH3). In some embodiments, R 3 It is -CF3.

[0283] In some embodiments, R 3 is a halo (for example, fluoro). In some embodiments, R 3 It is cyano.

[0284] In some embodiments, R 3 is carbocyclyl. In some embodiments, R 3 This is either an unsubstituted carbocyclyl (e.g., unsubstituted cyclopropyl) or a substituted carbocyclyl (e.g., substituted with cyano or halo).

[0285] In some embodiments, R 3 は-OR c In some embodiments, R 3 は-OR c And in that case, R c is an alkyl group (for example, a substituted alkyl group or an unsubstituted alkyl group). In some embodiments, R 3 These are -OCF3, -OCH3, -OCH(CH3)(CF3), or -OCH2CF3.

[0286] In some embodiments, the compound of formula (V) is [ka] [ka] Or not those salts that are pharmaceutically acceptable.

[0287] In another embodiment, the formula provided is (V-3): [ka] A compound of or a pharmaceutically acceptable salt thereof, in which R 1 is hydrogen, C1 alkyl, haloalkyl, or carbocyclyl, where each alkyl and carbocyclyl is halo, heterocyclyl, or -OR c Optionally replaced by;R 3is alkyl, carbocyric, or -OR c and; each R 3a These are independently alkyl, halo, cyano, nitro, carbocyryl, heterocyclyl, and -OR c , -N(R d )2, -C(O)R c , -C(O)OR c , or -C(O)N(R d )2, and in this case alkyl, carbocykyl, and heterocyclyl are halo, cyano, nitro, alkyl, carbocykyl, heterocyclyl, -OR c ,-C(O)N(R d )2, -SO2R c , -SO2OR c , -SO2N(R d )2, -NR d C(O)(R c ), or -N(R d ) Optionally substituted by 2; each R c R is hydrogen or alkyl, in which case the alkyl is 1 or more R 6 Optionally substituted by; each R d These are independently hydrogen or alkyl, in which case each alkyl has 1 or more R 6 It is optionally replaced by; and each R 6 These are independently alkyl, carbocykryl, heterocyclyl, halo, cyano, nitro, or -OH.

[0288] In some embodiments, R 1 is a C1 alkyl, haloalkyl, or carbocyric. In some embodiments, R 1 is a haloalkyl, for example, a C1-C3 haloalkyl. In some embodiments, R 1 is a C1-C3 haloalkyl, for example, a C1-C3 fluoroalkyl. In some embodiments, R 1 is -CF3, -CHF2, -CH2CF3, or CF2CF3. In some embodiments, R 1 It is -CF3.

[0289] In some embodiments, R 1It is a C1 alkyl group, in which case the alkyl group is heterocyclyl or -OR c It is replaced by R 1 is heterocyclyl or -OR c It is -CH2- substituted by. In some embodiments, R 1 is an oxygen-containing heterocycline or a -CH2- substituted with -OH. In some embodiments, R 1 It is a tetrahydrofuranyl (e.g., 1-tetrahydrofuranyl or 2-tetrahydrofuranyl) or a -CH2- substituted with an -OH group.

[0290] In some embodiments, R 1 is carbocyclyl. In some embodiments, R 1 is cyclopropyl or cyclobutyl. In some embodiments, R 1 is cyclopropyl or cyclobutyl, for example, substituted cyclopropyl or substituted cyclobutyl. In some embodiments, R 1 is cyclopropyl or cyclobutyl substituted with 1-3 halo groups (e.g., 1-3 fluoro). In some embodiments, R 1 It is difluorocyclopropyl or difluorocyclobutyl.

[0291] In some embodiments, R 3 These are independently alkyl, carbocyric, or -OR c In some embodiments, R 3 is alkyl (for example, C1-C4 alkyl). In some embodiments, R 3 R is an unsubstituted alkyl (e.g., an unsubstituted C1-C4 alkyl) or a substituted alkyl (e.g., a substituted C1-C4 alkyl). In some embodiments, R 3 is a substituted C1 alkyl (for example, where the C1 alkyl is alkyl (e.g., methyl), halo (e.g., fluoro), cyano, carbocykyl, or -OR). c(For example, replaced by -OCH3). In some embodiments, R 3 It is -CF3.

[0292] In some embodiments, R 3 は-OR c In some embodiments, R 3 は-OR c And in that case, R c is an alkyl group (for example, a substituted alkyl group or an unsubstituted alkyl group). In some embodiments, R 3 These are -OCF3, -OCH3, -OCH(CH3)(CF3), or -OCH2CF3.

[0293] Some implementation methods, each R 3a These are independently alkyl, halo, cyano, carbocyryl, heterocyclyl, or -OR c In some embodiments, R 3a is alkyl (for example) For example, C1-C4 alkyl. In some embodiments, R 3a is either an unsubstituted alkyl (e.g., an unsubstituted C1-C4 alkyl) or a substituted alkyl (e.g., a substituted C1-C4 alkyl).

[0294] In some embodiments, R 3a is a halo (for example, fluoro). In some embodiments, R 3a It is cyano.

[0295] In some embodiments, R 3a is carbocyclyl. In some embodiments, R 3a This can be an unsubstituted carbocyclyl (e.g., unsubstituted cyclopropyl) or a substituted carbocyclyl (e.g., substituted with cyano or halo).

[0296] In some embodiments, the compound (Va) is [ka] [ka] Or not those salts that are pharmaceutically acceptable.

[0297] In another embodiment, the formula provided is (V-4): [ka] A compound of or a pharmaceutically acceptable salt thereof, where A is one or more R 3 aryl or heteroaryl (e.g., monocyclic 6-membered ring aryl or heteroaryl) optionally substituted by; each R 3 These are independently alkyl, halo, cyano, nitro, carbocyryl, heterocyclyl, and -OR c , -N(R d )2, -C(O)R c , -C(O)OR c , or -C(O)N(R d )2, and in this case alkyl, carbocykyl, and heterocyclyl are halo, cyano, nitro, alkyl, carbocykyl, heterocyclyl, -OR c ,-C(O)N(R d )2, -SO2R c , -SO2OR c , -SO2N(R d )2, -NR d C(O)(R c ), or -N(R d ) Optionally substituted by 2; each R c R is hydrogen or alkyl, in which case the alkyl is 1 or more R 6 Optionally substituted by; each R d These are independently hydrogen or alkyl, in which case each alkyl has 1 or more R 6 It is optionally replaced by; and each R 6 These are independently alkyl, carbocykryl, heterocyclyl, halo, cyano, nitro, or -OH.

[0298] In some embodiments, A is an aryl (e.g., phenyl). In some embodiments, A is a heteroaryl. In some embodiments, A is a six-membered heteroaryl ring. In some embodiments, A is a nitrogen-containing heteroaryl (e.g., pyridyl).

[0299] Some implementation methods, each R 3 These are independently alkyl, halo, cyano, carbocyryl, heterocyclyl, or -OR c In some embodiments, R 3 is alkyl (for example, C1-C4 alkyl). In some embodiments, R 3 R is an unsubstituted alkyl (e.g., an unsubstituted C1-C4 alkyl) or a substituted alkyl (e.g., a substituted C1-C4 alkyl). In some embodiments, R 3 is methyl. In some embodiments, R 3 is a substituted C1 alkyl (for example, where the C1 alkyl is alkyl (e.g., methyl), halo (e.g., fluoro), cyano, carbocykyl, or -OR). c (For example, replaced by -OCH3). In some embodiments, R 3 It is -CF3.

[0300] In some embodiments, R 3 is a halo (for example, fluoro). In some embodiments, R 3 It is cyano.

[0301] In some embodiments, R 3 is carbocyclyl. In some embodiments, R 3 This is either an unsubstituted carbocyclyl (e.g., unsubstituted cyclopropyl) or a substituted carbocyclyl (e.g., substituted with cyano or halo).

[0302] In some embodiments, R 3 は-OR c In some embodiments, R 3 は-OR cAnd in that case, R c is an alkyl group (for example, a substituted alkyl group or an unsubstituted alkyl group). In some embodiments, R 3 These are -OCF3, -OCH3, -OCH(CH3)(CF3), or -OCH2CF3.

[0303] In some embodiments, the compound (Vb) is [ka] Or not those salts that are pharmaceutically acceptable.

[0304] In another embodiment, the formula provided is (VI-2) [ka] A compound of or a pharmaceutically acceptable salt thereof, where A is one or more R 3 aryl or heteroaryl (e.g., monocyclic 6-membered aryl or heteroaryl) optionally substituted by; R 1 is hydrogen, C1 alkyl, haloalkyl, or carbocyclyl, where each alkyl and carbocyclyl is halo, heterocyclyl, or -OR c Optionally substituted by; each R 3 These are independently alkyl, halo, cyano, nitro, carbocyryl, heterocyclyl, and -OR c , -N(R d )2, -C(O)R c , -C(O)OR c , or -C(O)N(R d )2, and in this case alkyl, carbocykyl, and heterocyclyl are halo, cyano, nitro, alkyl, carbocykyl, heterocyclyl, -OR c ,-C(O)N(R d )2, -SO2R c , -SO2OR c , -SO2N( R d )2, -NR d C(O)(R c ), or -N(Rd ) Optionally substituted by 2; each R c R is hydrogen or alkyl, in which case the alkyl is 1 or more R 6 Optionally substituted by; each R d These are independently hydrogen or alkyl, in which case each alkyl has 1 or more R 6 It is optionally replaced by; and each R 6 These are independently alkyl, carbocykyl heterocyclyl, halo, cyano, nitro, or -OH.

[0305] In some embodiments, A is an aryl (for example, phenyl).

[0306] In some embodiments, R 1 It is hydrogen or a haloalkyl group.

[0307] In some embodiments, R 1 It is hydrogen.

[0308] In some embodiments, R 1 is a haloalkyl, for example, a C1-C3 haloalkyl. In some embodiments, R 1 is a C1-C3 haloalkyl, for example, a C1-C3 fluoroalkyl. In some embodiments, R 1 It is -CF3.

[0309] Some implementation methods, each R 3 -OR is independent c In some embodiments, R 3 は-OR c And in that case, R c is an alkyl group (for example, a substituted alkyl group or an unsubstituted alkyl group). In some embodiments, R 3 It is -OCF3.

[0310] In any and all embodiments, in some embodiments, the compounds of formulas (II), (III), (IV), (V), (Va), (Vb), and (VI) are [ka] [ka] [ka] [ka] Alternatively, a selection of pharmaceutically acceptable salts thereof is used.

[0311] Treatment methods This specification describes compounds, compositions thereof, and uses thereof for treating diseases, disorders, or conditions related to abnormal function of sodium ion channels, such as abnormal delayed sodium (INaL) currents. In some embodiments, the compounds provided by the present invention are effective in treating epilepsy or epileptic syndromes, neurodevelopmental disorders, pain, or neuromuscular diseases. The compounds of the present invention may also modulate all sodium ion channels, or just one or more sodium ion channels, for example, Na V It may be specific to 1.1, 1.2, 1.5, 1.6, 1.7, 1.8, and / or 1.9.

[0312] In typical embodiments, the present invention is intended to encompass the compounds disclosed herein, and pharmaceutically acceptable salts, pharmaceutically acceptable esters, tautomers, polymorphs, and prodrugs of such compounds. In some embodiments, the present invention includes the compounds described herein, for example, the compounds of formula (I); for example, pharmaceutically acceptable addition salts, pharmaceutically acceptable esters, hydrates, tautomer forms, polymorphs, enantiomers, mixtures of enantiomers, stereoisomers, or mixtures of stereoisomers (as pure or racemic mixtures or as non-racemic mixtures) of the compounds of formula (I) named herein.

[0313] Epilepsy and epileptic syndromes The compounds described herein are useful in the treatment of epilepsy and epileptic syndromes. Epilepsy is a disorder of the central nervous system (CNS) in which the activity of nerve cells in the brain is disrupted, causing seizures or periods of abnormal behavior, agitation, and sometimes loss of consciousness. Seizure symptoms can vary greatly, from a simple blank expression lasting a few seconds to repeated convulsions of the limbs during a seizure.

[0314] Epilepsy can involve generalized seizures or partial or focal seizures. All areas of the brain are involved in generalized seizures. A person experiencing a generalized seizure may cry out, make noises, become rigid for a few seconds to a minute, followed by rhythmic movements of the limbs. The eyes are generally open, and the person may appear not breathing, and may even be pale. Consciousness gradually returns, and the person may be confused for several minutes to several hours. There are six main types of generalized seizures: tonic-clonic seizures, tonic seizures, clonic seizures, myoclonic seizures, absence seizures, and nonatonic seizures. In partial or focal seizures, only a part of the brain is involved, and therefore only a part of the body is affected. Symptoms can vary depending on the part of the brain with abnormal electrical activity.

[0315] Epilepsy as described herein includes generalized seizures, partial seizures, complex partial seizures, tonic-clonic seizures, clonic seizures, tonic seizures, refractory seizures, status epilepticus, absence seizures, and fever. This includes sexual seizures or temporal lobe epilepsy.

[0316] The compounds described herein may also be useful in the treatment of epileptic syndromes. Severe syndromes with diffuse brain dysfunction caused at least partially by certain forms of epilepsy are also called epileptic encephalopathy. These are associated with frequent seizures and severe cognitive impairment that are resistant to treatment, such as West syndrome.

[0317] In some embodiments, epileptic syndromes include epileptic encephalopathy, such as Dravet syndrome, Angelman syndrome, CDKL5 disorder, frontal lobe epilepsy, infantile seizures, West's syndrome, childhood myoclonic epilepsy, Landau-Kleffner syndrome, Lennox-Gastaut syndrome, Ohtahara syndrome, PCDH19 epilepsy, or Glut1 deficiency.

[0318] In some embodiments, epilepsy or epileptic syndrome is hereditary epilepsy or hereditary epileptic syndrome. In some embodiments, epilepsy or epileptic syndrome includes epileptic encephalopathy, epileptic encephalopathy associated with mutations in SCN1A, SCN2A, SCN8A, infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with mutation in SCN1A, generalized epilepsy with febrile seizures, generalized tonic-clonic seizures, infantile convulsions, intractable childhood epilepsy with benign familial neonatal-infant seizures, SCN2A type epileptic encephalopathy, focal epilepsy with mutation in SCN3A, cryptogenic childhood partial epilepsy with mutation in SCN3A, SCN8A type epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migratory partial seizures in infants, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 type epileptic encephalopathy, or KCNT1 type epileptic encephalopathy.

[0319] In some embodiments, the methods described herein further involve administering a compound described herein (for example, a compound of formula (I)) prior to the administration of epilepsy or epileptic syndromes (epileptic encephalopathy, epileptic encephalopathy associated with mutations in SCN1A, SCN2A, SCN8A, infantile epileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1A mutation, generalized epilepsy with febrile seizures, generalized tonic-clonic seizures, infantile convulsions, benign familial neonatal infantile seizures) This includes identifying subjects with refractory childhood epilepsy, SCN2A epileptic encephalopathy, focal epilepsy with SCN3A mutation, cryptogenic childhood partial epilepsy with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migratory partial seizures in infants, autosomal dominant nocturnal frontal lobe epilepsy, sudden expected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy.

[0320] In one embodiment, the present invention relates to epilepsy or epileptic syndromes (epileptic encephalopathy, epileptic encephalopathy associated with mutations in SCN1A, SCN2A, SCN8A, infant epileptic encephalopathy, Dravet syndrome, Dravet syndrome with mutation in SCN1A, generalized epilepsy with febrile seizures, generalized tonic-clonic seizures, infantile convulsions, benign familial neonatal infantile seizures with refractory childhood epilepsy, SCN2A type epileptic encephalopathy, SCN3A sudden A method for treating focal epilepsy with mutation, cryptogenic partial epilepsy in children with SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussen encephalitis, malignant migratory partial seizures in infants, autosomal dominant nocturnal frontal lobe epilepsy, sudden unexpected death in epilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epileptic encephalopathy, provided to a patient requiring the treatment with formula (I): [ka] A method comprising administering a compound or a pharmaceutically acceptable salt thereof, In the formula, each of X, Y, and Z is independently N or CR 2 In this case, at least one of X, Y, and Z is independently N; A is an aryl or heteroaryl (for example, a monocyclic 6-membered aryl or heteroaryl), each of which has one or more R 3 Optionally replaced by;R 2 R is hydrogen, alkyl, or halo; 1 is hydrogen, alkyl, alkenyl, alkynyl, -OR b , carbocyclyl, heterocyclyl, aryl, heteroaryl, in which case alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are 1 or more R 4 Optionally substituted by; each R 3 These are independently alkyl, carbocyrill, heterocyclyl, halo, cyano, nitro, -OR c , -N(R d )2, -C(O)R c , -C(O)OR c , or -C(O)N(R d )2, and in this case, alkyl, carbocyryl, and heterocyclyl have 1 or more R 5 Optionally replaced by;R 4 and R 5 Each of these can independently be alkyl, carbocyryl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, -OR c ,-C(O)N(R d )2, -SO2R c , -SO2OR c , -SO2N(R d )2, -NR d C(O)(R c ), or -N(R d )2, and in this case, alkyl, carbocyryl, heterocyclyl, aryl, and heteroaryl are 1 or more R 7 Optionally substituted by; each R b is hydrogen; each R cR is independently hydrogen, alkyl, carbocyryl, heterocyclyl, aryl, or heteroaryl, where alkyl, aryl, and heteroaryl are 1 or more R 6 Optionally substituted by; each R d These are independently hydrogen or alkyl, in which case each alkyl has 1 or more R 6 Optionally substituted by; each R 6 R is independently alkyl, carbocyryl, heterocyclyl, halo, cyano, nitro, or -OH; and each R 7 These are independently alkyl, halo, or oxo.

[0321] The compounds of the present invention (for example, the compounds of formula (I)) may also be used to treat epileptic encephalopathy, in which case the target is ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1, KCNMA1, KCNQ2, One or more of the following have mutations: KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX.

[0322] In some embodiments, the methods described herein further involve administering ALDH7A1, ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, prior to administration of the compounds described herein (for example, the compounds of formula (I)). This includes identifying subjects that have mutations in one or more of the following: HCN1, IER3IP1, KCNA2, KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX.

[0323] Neurodevelopmental disorders The compounds described herein may be useful in the treatment of neurodevelopmental disorders. In some embodiments, the neurodevelopmental disorders include autism, autism with epilepsy, tuberous sclerosis, Fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 deficiency syndrome, Prader-Willi syndrome, palatocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or neurodevelopmental disorders with epilepsy. In some embodiments, the methods described herein further include identifying a subject having a neurodevelopmental disorder (e.g., autism, autism with epilepsy, tuberous sclerosis, Fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 deficiency syndrome, Prader-Willi syndrome, palatocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or neurodevelopmental disorders with epilepsy) prior to administration of the compounds described herein (compounds of formula (I)).

[0324] In one embodiment, the present invention relates to a method for treating neurodevelopmental disorders (for example, autism, autism with epilepsy, tuberous sclerosis, Fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3 deficiency syndrome, Prader-Willi syndrome, palatocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or neurodevelopmental disorders with epilepsy) to a person requiring the treatment, using formula (I): [ka] A method comprising administering a compound or a pharmaceutically acceptable salt thereof, In the formula, each of X, Y, and Z is independently N or CR 2 In this case, at least one of X, Y, and Z is independently N; A is an aryl or heteroaryl (for example, a monocyclic 6-membered aryl or heteroaryl), each of which has one or more R 3 Optionally replaced by;R 2 R is hydrogen, alkyl, or halo; 1is hydrogen, alkyl, alkenyl, alkynyl, -OR b , carbocyclyl, heterocyclyl, aryl, heteroaryl, in which case alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are 1 or more R 4 Optionally substituted by; each R 3 These are independently alkyl, carbocyrill, heterocyclyl, halo, cyano, nitro, -OR c , -N(R d )2, -C(O)R c , -C(O)OR c , or -C(O)N(R d )2, and in this case, alkyl, carbocyryl, and heterocyclyl have 1 or more R 5 Optionally replaced by;R 4 and R 5 Each of these can independently be alkyl, carbocyryl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, -OR c ,-C(O)N(R d )2, -SO2R c , -SO2OR c , -SO2N(R d )2, -NR d C(O)(R c ), or -N(R d )2, and in this case, alkyl, carbocyryl, heterocyclyl, aryl, and heteroaryl are 1 or more R 7 By choice Replaced; each R b is hydrogen; each R c R is independently hydrogen, alkyl, carbocyryl, heterocyclyl, aryl, or heteroaryl, where alkyl, aryl, and heteroaryl are 1 or more R 6 Optionally substituted by; each R d These are independently hydrogen or alkyl, in which case each alkyl has 1 or more R 6 Optionally substituted by; each R 6 R is independently alkyl, carbocyryl, heterocyclyl, halo, cyano, nitro, or -OH; and each R 7These are independently alkyl, halo, or oxo.

[0325] pain The compounds described herein may be useful in treating pain. In some embodiments, pain includes neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, cerebellar ataxia, or related headache disorders. In some embodiments, the methods described herein further include identifying a subject having pain (e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, cerebellar ataxia, or related headache disorder) prior to administration of the compounds described herein (e.g., the compounds of formula (I)).

[0326] In one embodiment, the present invention relates to a method for treating pain (for example, neuropathic pain, trigeminal neuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine, familial hemiplegic migraine type 3, cluster headache, trigeminal neuralgia, cerebellar ataxia, or related headache disorders) to a person requiring the treatment of the same, using formula (I): [ka] A method comprising administering a compound or a pharmaceutically acceptable salt thereof, In the formula, each of X, Y, and Z is independently N or CR 2 In this case, at least one of X, Y, and Z is independently N; A is an aryl or heteroaryl (for example, a monocyclic 6-membered aryl or heteroaryl), each of which has one or more R 3 Optionally replaced by;R 2 R is hydrogen, alkyl, or halo; 1 is hydrogen, alkyl, alkenyl, alkynyl, -OR b, carbocyclyl, heterocyclyl, aryl, heteroaryl, in which case alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are 1 or more R 4 Optionally substituted by; each R 3 These are independently alkyl, carbocyrill, heterocyclyl, halo, cyano, nitro, -OR c , -N(R d )2, -C(O)R c , -C(O)OR c , or -C(O)N(R d )2, and in this case, alkyl, carbocyryl, and heterocyclyl have 1 or more R 5 Optionally replaced by;R 4 and R 5 Each of these can independently be alkyl, carbocyryl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, -OR c ,-C(O)N(R d )2, -SO2R c , -SO2OR c , -SO2N(R d )2, -NR d C(O)(R c ), or -N(R d )2, and in this case, alkyl, carbocyryl, heterocyclyl, aryl, and heteroaryl are 1 or more R 7 Optionally substituted by; each R b is hydrogen; each R c R is independently hydrogen, alkyl, carbocyryl, heterocyclyl, aryl, or heteroaryl, where alkyl, aryl, and heteroaryl are 1 or more R 6 Optionally substituted by; each R d These are independently hydrogen or alkyl, in which case each alkyl has 1 or more R 6 Optionally substituted by; each R 6 R is independently alkyl, carbocyryl, heterocyclyl, halo, cyano, nitro, or -OH; and each R 7 These are independently alkyl, halo, or oxo.

[0327] Neuromuscular diseases The compounds described herein may be useful in the treatment of neuromuscular diseases. In some embodiments, neuromuscular diseases include amyotrophic lateral sclerosis, multiple sclerosis, myotonia, congenital paramyotonia, potassium-exacerbated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or pharyngospasm with SCN4A mutations. In some embodiments, the methods described herein further include identifying subjects with neuromuscular diseases (e.g., amyotrophic lateral sclerosis, multiple sclerosis, myotonia, congenital paramyotonia, potassium-exacerbated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or pharyngospasm with SCN4A mutations) prior to administration of the compounds described herein (e.g., compounds of formula (I)).

[0328] In one embodiment, the present invention relates to a method for treating neuromuscular diseases (e.g., amyotrophic lateral sclerosis, multiple sclerosis, myotonia, congenital paramyotonia, potassium-exacerbated myotonia, periodic paralysis, hyperkalemic periodic paralysis, hypokalemic periodic paralysis, or pharyngospasm associated with SCN4A mutation), wherein the subject requiring the treatment is given formula (I): [ka] A method comprising administering a compound or a pharmaceutically acceptable salt thereof, In the formula, each of X, Y, and Z is independently N or CR 2 In this case, at least one of X, Y, and Z is independently N; A is an aryl or heteroaryl (for example, a monocyclic 6-membered aryl or heteroaryl), each of which has one or more R 3 Optionally replaced by;R 2 R is hydrogen, alkyl, or halo; 1 is hydrogen, alkyl, alkenyl, alkynyl, -OR b, carbocyclyl, heterocyclyl, aryl, heteroaryl, in which case alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl are 1 or more R 4 Optionally substituted by; each R 3 These are independently alkyl, carbocyrill, heterocyclyl, halo, cyano, nitro, -OR c , -N(R d )2, -C(O)R c , -C(O)OR c , or -C(O)N(R d )2, and in this case, alkyl, carbocyryl, and heterocyclyl have 1 or more R 5 Optionally replaced by;R 4 and R 5 Each of these can independently be alkyl, carbocyryl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, -OR c ,-C(O)N(R d )2, -SO2R c , -SO2OR c , -SO2N(R d )2, -NR d C(O)(R c ), or -N(R d )2, and in this case, alkyl, carbocyryl, heterocyclyl, aryl, and heteroaryl are 1 or more R 7 Optionally substituted by; each R b is hydrogen; each R c R is independently hydrogen, alkyl, carbocyryl, heterocyclyl, aryl, or heteroaryl, where alkyl, aryl, and heteroaryl are 1 or more R 6 Optionally substituted by; each R d These are independently hydrogen or alkyl, in which case each alkyl has 1 or more R 6 Optionally substituted by; each R 6 R is independently alkyl, carbocyryl, heterocyclyl, halo, cyano, nitro, or -OH; and each R 7 These are independently alkyl, halo, or oxo.

[0329] Other disabilities In some embodiments, the compounds of the present invention (for example, compounds of formula (I)) may have suitable pharmacokinetic properties so that they may be active with respect to the central nervous system and / or peripheral nervous system. In some embodiments, the compounds provided herein are, for example, These compounds are used to treat atrial and ventricular arrhythmias, including atrial fibrillation; Prinzmetal (variant) angina; stable angina; unstable angina; ischemic and reperfusion injuries of the heart, kidneys, liver, and brain; exercise-induced angina; congestive heart diseases, including pulmonary hypertension, diastolic and systolic dysfunction; and cardiovascular diseases such as myocardial infarction. In some embodiments, the compounds provided herein may be used to treat neuromuscular disorders that cause itching, seizures, or paralysis; or to treat diabetes or decreased insulin sensitivity and diabetes-related conditions, such as diabetic peripheral neuropathy.

[0330] In any and all embodiments, in some embodiments, the compound of formula (I) is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0331] In some embodiments, the compound of formula (I) is [ka] [ka] [ka] [ka] [ka] [ka] [ka] Alternatively, a pharmaceutically acceptable salt thereof is selected.

[0332] Pharmaceutical composition and route of administration The compounds provided according to the present invention are typically administered in the form of pharmaceutical compositions. Accordingly, the present invention provides pharmaceutical compositions comprising, as active ingredients, one or more of the described compounds or pharmaceutically acceptable salts or esters thereof, and a carrier comprising one or more pharmaceutically acceptable excipients, an inert solid diluent and filler, a diluent comprising a sterile aqueous solution and various organic solvents, a permeation enhancer, a solubilizer and an auxiliary agent. The pharmaceutical compositions may be administered alone or in combination with other therapeutic agents. Such compositions are prepared by methods well known in the pharmaceutical art (e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th. Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd. Ed. (GS Banke)). (See r & CTRhodes, Eds.)

[0333] The pharmaceutical composition may be administered in single or multiple doses by any of the permitted methods of administering active substances having similar utility as described in the patents and patent applications incorporated by reference, including via the rectal, buccal, nasal, and transdermal routes, including intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, as an inhalant, or via impregnated or coated devices such as stents or cylindrical polymers inserted into arteries.

[0334] One method of administration is parenteral, particularly by injection. Forms in which the novel compositions of the present invention may be incorporated for injection include aqueous or oily suspensions or emulsions, sterile aqueous solutions, and similar pharmaceutical solvents, containing sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixir, mannitol, or dextrose. Aqueous solutions in physiological saline are also used for injection for convenience, but are not preferred in the context of the present invention. Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, etc. (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. Adequate fluidity can be maintained, for example, by the use of a coating such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial activity can be achieved by various antimicrobial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, etc.

[0335] Sterile injectable solutions are prepared by incorporating the required amount of the compound according to the present invention into a suitable solvent, along with various other components as listed above, as needed, and then sterilizing by filtration. Generally, dispersions are prepared by incorporating various sterilized active ingredients into a sterile solvent containing a basic dispersion medium and other necessary components derived from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, preferred methods of preparation are vacuum drying and freeze-drying, from which powders of the active ingredient plus additional desired components are obtained from the solution that has been previously sterile filtered.

[0336] Oral administration is another route for administering the compounds according to the present invention. Administration may be via capsules or enteric-coated tablets, etc. In preparing a pharmaceutical composition comprising at least one compound described herein, the active ingredient is usually diluted with an excipient and / or encapsulated in a carrier which may be in the form of a capsule, sachet, paper or other container. If the excipient serves as a diluent, it may be in the form of a solid, semi-solid or liquid substance (as described above) that acts as a solvent, carrier or medium for the active ingredient. Thus, the composition may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, sprays (as solid or in a liquid medium), for example, ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injection solutions, and sterile packaged powders.

[0337] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, fine crystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulation may further contain lubricants such as talc, magnesium stearate, and mineral oil; humectants; emulsifiers and suspending agents; preservatives such as methyl and propyl hydroxybenzoic acid; and sweeteners and flavorings.

[0338] The compositions of the present invention can be formulated using procedures known in the art to provide rapid, sustained, or delayed release of the active ingredient after administration to a patient. A controlled-release drug delivery system for oral administration comprises an osmotic pump system and a dissolution system containing a polymer-coated reservoir or a drug-polymer matrix formulation. Examples of controlled-release systems are given in U.S. Patents 3,845,770; 4,326,525; 4,902,514 and 5,616,345. Another formulation for use in the method of the present invention employs a transdermal delivery device ("patch"). Such a transdermal patch may provide continuous or discontinuous exudation of the compound of the present invention in a controlled amount. The construction and use of transdermal patches for the delivery of pharmaceuticals are well known in the art. See, for example, U.S. Patents 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsed, or on-demand delivery of pharmaceutical agents.

[0339] The compositions are preferably formulated in unit dosage forms. The term “unit dosage form” refers to a physically distinct unit suitable as a unit dose for human subjects and other mammals, each unit containing a predetermined amount of the active substance calculated to produce the desired therapeutic effect in conjunction with a suitable pharmaceutical excipient (e.g., tablet, capsule, ampoule). The compounds are generally administered in pharmaceutically effective amounts. Preferably, for oral administration, each dose unit contains 1 mg to 2 g of the compound described herein, and for parenteral administration, preferably 0.1 to 700 mg of the compound described herein. However, it will be understood that the actual amount of compound administered is usually determined by the physician in terms of relevant circumstances, including the condition being treated, the route of administration chosen, the actual compound administered and its associated activity, the age, weight, and response of the individual patient, and the severity of the patient’s symptoms.

[0340] For example, in preparing a solid composition such as a tablet, the most important active ingredients are mixed with pharmaceutical excipients to form a solid pre-formulation containing a homogeneous mixture of the compounds of the present invention. When these pre-formulation compositions are referred to as homogeneous, it means that the active ingredients are uniformly dispersed throughout the composition so that the composition can be easily further divided into uniformly effective unit dosage forms, such as tablets, pills, and capsules.

[0341] The tablets or pills of the present invention may be coated or otherwise formulated to provide a dosage form that offers the benefit of long-lasting action or protection from the acidic conditions of the stomach. For example, the tablets or pills may contain an internally administered component and an externally administered component, with the latter enclosing the former. The two components can be separated by an enteric coating that helps resist disintegration in the stomach and allows the internal component to enter the duodenum intact or to be delayed in release. Various substances can be used for such enteric coatings or coatings, and such substances include numerous polymer acids and mixtures of polymer acids with substances such as shellac, cetyl alcohol, and cellulose acetate.

[0342] Compositions for inhalation or inhalation include solutions and suspensions in pharmaceutically acceptable aqueous solvents or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. Preferably, compositions are administered orally or nasally for topical or systemic effects. Compositions in preferably pharmaceutically acceptable solvents may be atomized using an inert gas. Atomized solutions may be inhaled directly from a spray device, or the spray device may be connected to a face mask tent or intermittent positive airway pressure (CPAP) respirator. Compositions in solution, suspension, or powder form may be administered preferably orally or nasally from a device for delivering formulations in an appropriate manner.

[0343] Combination therapy The compounds or compositions described herein (for example, those used to modulate sodium ion channels, e.g., delayed sodium (INaL) currents) may be administered in combination with other agents or treatments. Subjects receiving the compounds disclosed herein may have diseases, disorders, conditions, or symptoms thereof that would benefit from treatment with other agents or treatments. These diseases or conditions may relate to epilepsy or epileptic syndromes, neurodevelopmental disorders, pain, or neuromuscular disorders.

[0344] Antiepileptic drugs Antiepileptic drugs include brivalacetam, carbamazepine, clobazam, clonazepam, diazepam, divalproex, eslicarzepine, ethosuximide, ezogavine, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, lorazepam, oxcarbazepine, palmpanel, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, tigabin, topiramate, valproic acid, vigabatrin, and zonisamide.

[0345] Combination therapy with cardiovascular drugs Cardiovascular diseases or conditions that may benefit from combination therapy with other therapeutic agents of the sodium channel blocker of the present invention include, but are not limited to, stable angina, unstable angina (UA), exercise-induced angina, variant angina, arrhythmias, intermittent claudication, myocardial infarction including non-STE myocardial infarction (NSTEMI), pulmonary hypertension including pulmonary arterial hypertension, congestive (or chronic) heart failure and heart failure with diastolic heart failure and preserved ejection fraction (diastolic dysfunction), heart failure including acute heart failure, or recurrent ischemia.

[0346] Suitable therapeutic agents for treating cardiovascular diseases or conditions include anti-anginal agents, heart failure agents, antithrombotic agents, antiarrhythmic agents, antihypertensive agents, and lipid-lowering agents.

[0347] The co-administration of the sodium channel blocker of this invention with therapeutic agents suitable for treating cardiovascular conditions allows for enhancement of the standard treatment currently accepted by the patient.

[0348] Antiangin medication Antianginal drugs include beta-blockers, calcium channel blockers, and nitrates. Beta-blockers reduce the oxygen demand of the heart by reducing its workload, leading to a decrease in heart rate and reduced violent contractions. Examples of beta-blockers include acebutolol (Sectral), atenolol (Tenormin), betaxolol (Kerlone), bisoprolol / hydrochlorothiazide (Ziac), bisoprolol (Zebeta), carteolol (Cartrol), esmolol (Brevibloc), labetalol (Normodyne, Trendate), metoprolol (Lopressor, Toprol XL), nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), and timolol (Blocadren).

[0349] Nitrates dilate arteries and veins, thereby increasing coronary blood flow and lowering blood pressure. Examples of nitrates include nitroglycerin, nitrate patches, isosorbide dinitrate, and isosorbide-5-mononitolate.

[0350] Calcium channel blockers disrupt the normal influx of calcium into heart and blood vessel cells, thereby relaxing blood vessels and increasing the supply of blood and oxygen to the heart. Examples of calcium channel blockers include amlodipine (Norvasc, Lotrel), bepridil (Vascor), diltiazem (Cardizem, Tiazac), and felodipine (Ple). Examples include ndil, nifedipine (Adalat, Procardia), nimodipine (Nimotop), nisoldipine (Sular), verapamil (Calan, Isoptin, Verelan), and nicardipine.

[0351] Heart failure medication The agents used to treat heart failure include diuretics, ACE inhibitors, vasodilators, and cardiac glycosides. Diuretics remove excess fluid from tissues and circulation, thereby alleviating many of the symptoms of heart failure. Examples of diuretics include hydrochlorothiazide, metrasone (Zaroxolyn), furosemide (Lasix), bumetanide (Bumex), spironolactone (Aldactone), and eplerenone (Inspra).

[0352] Angiotensin-converting enzyme (ACE) inhibitors reduce the workload on the heart by dilating blood vessels and reducing resistance to blood flow. Examples of ACE inhibitors include benazepril (Lotensin), captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril), lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), ramipril (Altace), and trandolapril (Mavik).

[0353] Vasodilators reduce pressure in blood vessels by relaxing and dilating them. Examples of vasodilators include hydralazine, diazoxide, prazosin, clonidine, and methyldopa. ACE inhibitors, nitrates, potassium channel activators, and calcium channel blockers also act as vasodilators.

[0354] Cardiac glycosides are compounds that enhance the contractile force of the heart. These compounds strengthen the heart's pumping ability and improve irregular heart rate. Examples of cardiac glycosides include digitalis, digoxin, and digitoxin.

[0355] Antithrombotic agents Antithrombotic agents inhibit the blood's ability to coagulate. There are three main types of antithrombotic agents: platelet inhibitors, anticoagulants, and thrombolytic agents.

[0356] Platelet inhibitors inhibit the coagulation activity of platelets, thereby reducing coagulation in arteries. Examples of platelet inhibitors include acetylsalicylic acid (aspirin), ticlopidine, clopidogrel (Plavix), dipyridamole, cilostazol, persantinsulfinpyrazone, dipyridamole, indomethacin, and glycoprotein IIb / IIIa inhibitors, such as absiximab, tyrofiban, and eptifivatide (Integrerin). Beta-blockers and calcium channel blockers also have platelet inhibitory effects.

[0357] Anticoagulants prevent blood clots from growing larger and inhibit the formation of new blood clots. Examples of anticoagulants include bivalirudine (Angiomax), warfarin (Coumadin), unfractionated heparin, low molecular weight heparin, danaparoid, repirudine, and argatroban.

[0358] Thrombolytic agents work by breaking down existing blood clots. Examples of thrombolytic agents include streptokinase, urokinase and tenecteplase (TNK), and tissue plasminogen activator (t-PA).

[0359] Antiarrhythmic drugs Antiarrhythmic drugs are used to treat disorders of heart rate and heart rhythm. Examples of antiarrhythmic drugs include amiodarone, dronedarone, quinidine, procainamide, lidocaine, and propafenone. Cardiac glycosides and beta-blockers are also used as antiarrhythmic drugs.

[0360] Given the recently discovered synergistic effects of sodium channel blockers, lanolazine, amioarone, and dronedarone, the combination of amiodarone and dronedarone is of particular interest.

[0361] Antihypertensive drugs Antihypertensive drugs are used to treat hypertension, a condition in which blood pressure is consistently higher than normal. Hypertension is associated with numerous aspects of cardiovascular disease, including congestive heart failure, atherosclerosis, and presumptive blood clots. Examples of antihypertensive drugs include alpha-1-adrenergic agonists, such as prazosin (Minipress), doxazosin mesylate (Cardura), prazosin hydrochloride (Minipress), prazosin, polythiazide (Minizide), and tetrazosin hydrochloride (Hytrin); beta-adrenergic agonists, such as propranolol (Inderal), nadolol (Corgard), timolol (Blocadren), and metoprolol (L opressor), and pindolol (Visken); central alpha-adrenergic receptor agonists, e.g., clonidine hydrochloride (Catapres), clonidine hydrochloride and chlorthalidone (Clorpres, Combipres), guanabenz acetate (Wytensin), guanfacine hydrochloride (Tenex), methyldopa (Aldomet), methyldopa and chlorothiazide (Aldoclor), methyldopa and hydrochlorothiazide (Aldoril); concomitant alpha / beta-adrenergic agonists, e.g., labetalol (Normodyne, Trendate), carvedilol (Coreg); adrenergic neuron blockers, e.g., guanethidine (ismelin), reserpine (Serpasil); central nervous system acting antihypertensives, e.g., clonidine (Catapres), methyldopa (Aldomet), guanabenz (Wytensin); anti-angiotensin II Drugs; ACE inhibitors, e.g., perindopril (Aceon), captopril (Capoten), enalapril (Vasotec), lisinopril (Prinivil, Zestril); angiotensin-II receptor antagonists, e.g., candesartan (Atacand), eprosartan (Teveten), irbesartan (Avapro), losartan (Cozaar), telmisartan (Micardis), valsartan (Diovan);Examples of calcium channel blockers include verapamil (Calan, Isoptin), diltiazem (Cardizem), and nifedipine (Adalat, Procardia); diuretics; direct vasodilators, such as nitroprusside (Nipride), diazoxide (Hyperstat IV), hydralazine (Apresoline), minoxidil (Loniten), and verapamil; and potassium channel activators, such as apricarim, bimacamim, chromacamim, emacalim, nicorandil, and pinacidil.

[0362] Lipid-lowering drugs Lipid-lowering agents are used to reduce the amount of cholesterol and fatty sugars present in the blood. Examples of lipid-lowering agents include bezafibrate (Bezalip), ciprofibrate (Modalim), and statins such as atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor, Altocor), mevastatin, pitavastatin (Livalo, Pitava), pravastatin (Lipostat), rosuvastatin (Crestor), and simvastatin (Zocor).

[0363] In this invention, patients presenting with acute coronary disease events are, for example, patients with metabolic diseases, lung diseases, peripheral diseases, etc. Patients often suffer from secondary conditions such as one or more vascular or gastrointestinal disorders. Such patients may benefit from combination therapy, including administering lanolazine in combination with at least one other therapeutic agent.

[0364] Combination therapy for lung diseases Lung disease refers to a disease or condition affecting the lungs. Examples of lung disease include, but are not limited to, asthma, chronic obstructive pulmonary disease (COPD), bronchitis, and emphysema.

[0365] Examples of therapeutic agents used to treat lung diseases include bronchodilators, including beta-2 agonists and anticholinergics, corticosteroids, and electrolyte replacement agents. Specific examples of therapeutic agents used to treat lung diseases include epinephrine, terbutaline (Brethaire, Bricanyl), albuterol (Proventil), salmeterol (Serevent, Serevent Diskus), theophylline, ipratropium bromide (Atrovent), tiotropium (Spiriva), methylprednisolone (Solu-Medrol, Medrol), magnesium, and potassium.

[0366] Combination therapy for metabolic diseases Examples of metabolic disorders include, but are not limited to, diabetes mellitus including type 1 and type 2 diabetes, metabolic syndrome, dyslipidemia, obesity, impaired glucose tolerance, hypertension, elevated serum cholesterol, and elevated triglycerides.

[0367] Examples of therapeutic agents used to treat metabolic disorders include antihypertensives and lipid-lowering agents, as described in the "Combination Therapy of Cardiovascular Agents" section above. Additional therapeutic agents used to treat metabolic disorders include insulin, sulfonylurea, biguanides, alpha-glucosidase inhibitors, and incretin mimetic drugs.

[0368] Combination therapy for peripheral vascular disease Peripheral vascular disease is a disease of the blood vessels (arteries and veins) located outside the heart and brain, including, for example, peripheral artery disease (PAD), which occurs when the arteries supplying blood to the internal organs, arms, and legs are completely or partially blocked as a result of atherosclerosis.

[0369] Combination therapy for gastrointestinal diseases Digestive disorders refer to diseases and conditions related to the digestive tract. Examples of digestive disorders include gastroesophageal reflux disease (GERD), inflammatory bowel disease (IBD), gastroenteritis, gastritis and peptic ulcers, and pancreatitis.

[0370] Examples of therapeutic agents used to treat gastrointestinal disorders include, for example, proton pump inhibitors such as pantoprazole (Protonix), lansoprazole (Prevacid), esomeprazole (Nexium), omeprazole (Prilosec), and rabeprazole; H2 blockers such as, for example, cimetidine (Tagamet), ranitidine (Zantac), famotidine (Pepcid), and nizatidine (Axid); prostaglandins such as, for example, misoprostol (Cytotec); sucralfate; and antacids.

[0371] Combination therapy with antibiotics, analgesics, antidepressants, and anti-anxiety medications. Patients presenting with acute coronary events may benefit from the administration of one or more therapeutic agents, including antibiotics, analgesics, antidepressants, and anxiolytics, in combination with lanolazine.

[0372] antibiotics Antibiotics are therapeutic agents that kill or stop the growth of microorganisms, including both bacteria and fungi. Examples of antibiotics include penicillin (amoxicillin), cephalosporins such as cefazolin, cefuroxime, cefadroxil (Duricef), cephalexin (Keflex), cephaladine (Velosef), cefaclor (Ceclor), cefuroxime axtel (Ceftin), cefprodil (Cefzil), loracalbef (Lorabid), cefixime (Suprax), cefpodoxime proxetil (Vantin), ceftibuten (Cedax), cefdinir (Omnicef), ceftriaxone (Rocephin), carbapenems, and mo Examples include beta-lactam antibiotics, including nobactam; tetracyclines, such as tetracycline; macrolide antibiotics, such as erythromycin; aminoglycosides, such as gentamicin, tobramycin, and amikacin; quinolones, such as ciprofloxacin; cyclic peptides, such as vancomycin, streptogramin, and polymyxin; lincosamides, such as clindamycin; oxazolidinones, such as linezolid; and sulfonamide antibiotics, such as sulfisoxazole.

[0373] Pain relievers Analgesics are therapeutic agents used to relieve pain. Examples of analgesics include opiates and morphine-like drugs such as fentanyl and morphine; paracetamol; NSAIDs; and COX-2 inhibitors. V Given the ability of the sodium channel blockers of the present invention to treat neuropathic pain through inhibition of sodium channels 1.7 and 1.8, concomitant use with analgesics is particularly envisioned. See U.S. Patent Application Publication 20090203707.

[0374] Antidepressants and anti-anxiety drugs Antidepressants and anxiolytics include substances used to treat anxiety and depression, as well as those used as sedatives and tranquilizers. Examples of antidepressants and anxiolytics include benzodiazepines such as diazepam, lorazepam, and midasola; barbiturates; glutethimide; chloral hydrate; meprobamate; sertraline (Zoloft, Lustral, Apo-Sertral, Asentra, Gladem, Serlift, Stimuloton); escitalopram (Lexapro, Cipralex); fluoxetine (Prozac, Sarafem, Fluctin, Fontex, Prodep, Fludep, Lovan); and venlafaxine (Effexor Examples include XR, Efexor; citalopram (Celexa, Cipramil, Talohexane); paroxetine (Paxil, Seroxat, Aropax); trazodone (Desyrel); amitriptyline (Elavil); and bupropion (Wellbutrin, Zyban).

[0375] Accordingly, one aspect of the present invention provides a composition comprising the sodium channel blocker of the present invention and at least one therapeutic agent. In an alternative embodiment, the composition comprises the sodium channel blocker of the present invention and at least two therapeutic agents. In a further alternative embodiment, the composition comprises the sodium channel blocker of the present invention and at least three therapeutic agents, the sodium channel blocker of the present invention and at least four therapeutic agents, or the sodium channel blocker of the present invention and at least five therapeutic agents.

[0376] Methods of combination therapy include simultaneous administration of a single formulation containing the sodium channel blocker of the present invention and one or more therapeutic agents; essentially simultaneous administration of one or more formulations containing the sodium channel blocker of the present invention and one or more therapeutic agents; and any order in which the sodium channel blocker of the present invention and one or more therapeutic agents are administered. This includes continuous administration, preferably including a period in which the sodium channel blocker of the present invention and the therapeutic agent (single) or therapeutic agent (multiple) exert their therapeutic effects simultaneously. [Examples]

[0377] The following examples are provided to allow for a more complete understanding of the inventions described herein. The synthetic and biological examples described in this application are presented to illustrate the compounds, pharmaceutical compositions and methods provided herein and should not be construed as limiting their scope in any way.

[0378] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Given typical or preferred operating conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.), it will be understood that other operating conditions may also be used unless otherwise specified. Optimal reaction conditions may vary depending on the specific reactants or solvents used, but such conditions can be determined by those skilled in the art through normal optimization.

[0379] Furthermore, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. Suitable selection of protecting groups for specific functional groups, as well as suitable conditions for protection and deprotection, are well known in the art. For example, numerous protecting groups and their introduction and deprotection are described in TW Greene and PGMWuts, *Protecting Groups in Organic Synthesis*, Second Edition, Wiley, New York, 1991, and the references cited therein.

[0380] The compounds provided herein may be isolated and purified by known standard procedures. Such procedures include recrystallization, filtration, flash chromatography, powdering, high-pressure liquid chromatography (HPLC), or supercritical liquid chromatography (SFC). Note that flash chromatography may be performed manually or via an automated system. The compounds provided herein may also be characterized by known standard procedures, such as nuclear magnetic resonance spectroscopy (NMR) or liquid chromatography-mass spectroscopy (LCMS). Chemical shifts in NMR are reported in parts per million (ppm) and are produced using methods well known to those skilled in the art.

[0381] Examples of common methods for analytical LCMS include Method A (Xtimate C 18 (2.1 mm × 30 mm, 3 μm); A = H2O (0.04% TFA) and B = CH3CN (0.02% TFA); 50°C; 1.2 mL / min; 10-80% B over 0.9 minutes, then 80% B for 0.6 minutes); Method B (Chromolith Flash RP-18 with end cap C 18 (2mm x 25mm); A = H2O (0.04% TFA) and B = CH3CN (0.02% TFA); 50℃; 1.5 mL / min; 5-95% B over 0.7 minutes, then 95% B for 0.4 minutes); and Method C (Xtimate C 18 (2.1 mm × 30 mm, 3 μm); A = H2O (0.04% TFA) and B = CH3CN (0.02% TFA); 50°C; 0.8 mL / min; 10-80% B over 6 minutes, followed by 80% B for 0.5 minutes).

[0382] List of abbreviations NIS:N-iodosuccinimide DMF: N,N-dimethylformamide THF: Tetrahydrofuran MeOH: methanol DCM: Dichloromethane LiHMDS: Lithium bis(trimethylsilyl)amide EtOH: Ethanol Et3N: Trimethylamine Pd(dppf)Cl2: Dichloride [1,1'-Bis(diphenylphosphin)ferro [Cen] Palladium (II) MeI: Methyl iodide Et3SiH: Triethylsilane DBU:1,8-Diazabicyclo(5.4.0)undeca-7-en Acn: Acetate TMSCF3: Trifluoromethyltrimethylsilane TBAB: Tetrabutylammonium bromide Pd(t-Bu3P)2: Bis(tri-tert-butylphosphine)palladium(0)DAST: Diethylaminosulfur trifluoride DIPEA: N,N-diisopropylethylamine HATU: Hexafluorophosphate 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide Pd(dba)3: Tris(dibenzylideneacetone)dipalladium(0) XPhos:2-Dicyclohexylphosphino-2',4',6'-Triisopropylbiphenyl

[0383] Example 1: Synthesis of Compound 1 [ka] A mixture of A-1 (100.00 mg, 449.32 μmol), 4-(trifluoromethyl)phenylboronic acid (102.41 mg, 539.18 μmol), K2CO3 (124.20 mg, 898.64 μmol), and Pd(dppf)Cl2.CH2Cl2 (55.04 mg, 67.40 μmol) in dioxane (6 mL) and water (600 μL) was heated to 90°C under N2 and stirred for 16 hours. The reaction mixture was diluted with HCl (10 mL), filtered, concentrated to obtain the residue, and purified by preparative TLC (silica gel, PE:HCl = 2:1) to obtain compound 1 (26.00 mg) as a solid.1 1H NMR: (400MHz, CDCl3)δ H =8.37(d,1H),8.14(d,2H),7.85(d,2H),7.79(d,1H). LCMS using Method A:R t =1.16 min, MS ESI C 13 H7F6N4[M+H] + Calculated value: 333.05; Measured value: 333.1.

[0384] Example 2: Synthesis of Compound 2 [ka] A mixture of A-1 (100.00 mg, 449.32 μmol), 3-methyl-4-(trifluoromethoxy)-phenylboronic acid (118.59 mg, 539.18 μmol), Pd(dppf)Cl2.CH2Cl2 (55.04 mg, 67.40 μmol), and K2CO3 (124.20 mg, 898.64 μmol) in dioxane (6 mL) and water (600 μL) was heated to 90°C under N2 and stirred for 16 hours. The reaction mixture was diluted with HCl (10 mL), filtered, and concentrated to obtain the residue, which was purified by preparative HPLC (Kromasil (150 mm × 25 mm, 10 μm) A=H2O (0.05% NH4OH) and B=CH3CN; 50-80% B over 8 minutes) to obtain compound 2 (26.80 mg) as a solid. 1 1H NMR (400 MHz, CDCl3) δ H =8.31(d,1H),7.95-7.85(m,2H),7.74(d,1H),7.41(d,1H)2.45(s,3H). LCMS R using Method A t =1.22 min, MS ESI C 14 H9F6N4O[M+H] + Calculated value: 363.06; Measured value: 363.1.

[0385] Example 3: Synthesis of Compound 3 [ka] A mixture of A-1 (100.00 mg, 449.32 μmol), [2-methyl-4-(trifluoromethyl)phenyl]boronic acid (109.97 mg, 539.18 μmol), Pd(pddf)Cl2.CH2Cl2 (55.04 mg, 67.40 μmol), and K2CO3 (124.20 mg, 898.63 μmol) in dioxane (6 mL) and water (600 μL) was heated to 90°C under N2 and stirred for 16 hours. The reaction mixture was diluted with HCl (10 mL), filtered, and concentrated to obtain the residue, which was purified by preparative TLC (silica gel, PE:HCl = 2:1) to obtain compound 3 as a solid. 1 1H NMR (400 MHz, CDCl3) δ H =8.34(d,1H),7.65-7.58(m,3H),7.47(d,1H),2.53(s,3H). LCMS R using Method A t =1.18 min, MS ESI C 14 H9F6N4[M+H] + Calculated value: 347.1; Measured value: 347.1.

[0386] Example 4: Synthesis of Compound 4 [ka] Under N2 conditions, a mixture of A-1 (100.00 mg, 449.32 μmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5-(trifluoromethyl)benzonitrile (160.18 mg, 539.18 μmol), K3PO4 (190.75 mg, 898.64 μmol), and Pd(t-Bu3P)2 (22.96 mg, 44.93 μmol) in a 20 mL sealed tube with dioxane (10 mL) and H2O (900 μL) was stirred at 80°C for 16 hours. The mixture was cooled to room temperature, concentrated, and purified by preparative TLC (silica gel, DCM:EtAOAc=5:1) to obtain compound 4 as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.48(d,1H),8.20(s,1H),8.13-8.03(m,2H),7.78(d,1H). LCMS R using Method A.t =1.08 min, MS ESI C 14 H6F6N5[M+H] + Calculated value: 358.0; Measured value: 357.9.

[0387] Example 5: Synthesis of Compound 5 [ka] Under N2 conditions, a mixture of A-1 (80.00 mg, 359.45 μmol), 2-methoxy-4-(trifluoromethoxy)phenylboronic acid (84.81 mg, 359.45 μmol), Pd(dppf)Cl2.CH2Cl2 (29.35 mg, 35.95 μmol), and Cs2CO3 (234.23 mg, 718.90 μmol) in a 10 mL sealed tube with dioxane (5 mL) and water (500 μL) was stirred at 85°C for 16 hours. The reaction mixture was cooled to room temperature, concentrated, and purified by preparative TLC (silica gel, PE:EtAOAc=2:1) ​​to obtain compound 5 as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.20(d,1H),7.82(d,1H),7.80(d,1H),7.04(d,1H),6.91(s,1H),3.94(s,3H). LCMS R using Method A t =1.18 min, MS ESI C 14 H9F6N4O2[M+H] + Calculated value: 379.0; Measured value: 379.1.

[0388] Example 6: Synthesis of Compound 6 [ka] Synthesis of A-4: To a solution of A-2 (100.00 mg, 691.75 μmol) in toluene (10 mL), 3,3,3-trifluoropropanoyl chloride (121.61 mg, 830.10 μmol) was added, and the mixture was stirred at 110°C for 6 hours. The reaction mixture was concentrated, and AcOH (10 mL) was added to the residue. The resulting mixture was stirred in a microwave reactor at 120°C for 1 hour. The mixture was concentrated, diluted with H2O (10 mL), basicized to approximately pH 9 with solid NaHCO3, and extracted with ethyl acetate (30 mL twice). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by flash chromatography on silica gel (ethyl acetate in PE = 25%~33%~50%~66%) to obtain A-4 as a solid. LCMS R using Method B t =0.66 min, MS ESI C7H5ClF3N4[M+H] + Calculated value: 237.0; Measured value: 237.0.

[0389] Synthesis of Compound 6: A mixture of A-4 (100.00 mg, 422.69 μmol), 4-(trifluoromethoxy)phenylboronic acid (104.45 mg, 507.23 μmol), Pd(dppf)Cl2.CH2Cl2 (34.52 mg, 42.27 μmol), and K2CO3 (116.84 mg, 845.38 μmol) in dioxane (10 mL) and H2O (1 mL) was stirred at 90°C for 4 hours. The mixture was diluted with HCl (20 mL), filtered through silica gel, eluted with HCl (30 mL x 2), and then concentrated to obtain the residue, which was purified by preparative TLC (silica gel, PE:EtAOAc = 2:1) to obtain Compound 6 (17.30 mg) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.26(d,1H),8.08-8.02(m,2H),7.63(d,1H),7.43(d,2H),4.27-4.16(m,2H). LCMS R using Method A t =1.14 min, MS ESI C 14 H9F6N4O[M+H] +Calculated value: 363.0; Measured value: 362.9.

[0390] Example 7: Synthesis of Compound 7 [ka] Synthesis of A-6: 2,2,2-trifluoroethanol (4.86 mL, 67.55 mmol) was added dropwise to a mixture of NaH (2.70 g, 67.55 mmol, 60% purity) in DMF (50 mL) at 10°C, and the mixture was stirred for 1 hour. Then, A-5 (10.00 g, 51.96 mmol) was added all at once, and the reaction mixture was stirred at 30°C for 16 hours. The reaction mixture was stopped with saturated NH4Cl (250 mL), extracted with ethyl acetate (100 mL x 3), the combined organic phase was washed with brine (200 mL), dried over Na2SO4, filtered, and concentrated. The resulting residue was purified by flash chromatography on silica gel (ethyl acetate = 0%~5% in PE) to obtain A-6 (11.00 g) as oil. 1 1H NMR (400MHz, CDCl3)δ H =8.20(d,1H),7.73(dd,1H),6.80(d,1H),4.73(q,2H).

[0391] Synthesis of A-7: A mixture of A-6 (2.00 g, 7.81 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (4.96 g, 19.52 mmol), Pd(dppf)Cl2.CH2Cl2 (637.95 mg, 781.00 μmol), and KOAc (1.92 g, 19.52 mmol) was stirred at 90°C for 12 hours. The mixture was concentrated, and the residue was purified by flash chromatography on silica gel (SiO in PE = 0%~10%) to obtain A-7 (1.90 g, 6.27 mmol) as oil. 1 1H NMR (400MHz, CDCl3)δ H =8.51(d,1H),7.99(dd,1H),6.83(d,1H),4.79(q,2H),1.34(s,12H).

[0392] Synthesis of Compound 7: In a microwave reactor, a mixture of A-4 (100.00 mg, 422.69 μmol), A-7 (128.11 mg, 422.69 μmol), Cs2CO3 (275.44 mg, 845.38 μmol), and Pd(dppf)Cl2.CH2Cl2 (34.52 mg, 42.27 μmol) in H2O (500 μL) and dioxane (5 mL) was stirred at 90°C for 3 hours, and the desired product was observed by LC-MS at that time. The mixture was diluted with HCl (10 mL), filtered through silica gel, and eluted with EtOAC (10 mL × 2). The filtrate was concentrated, and the residue was purified by preparative TLC (silica gel, HCl:DCM = 1:2) to obtain Compound 7 (42.10 mg) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.78(d,1H),8.33(dd,2.4,1H),8.26(d,1H),7.61(d,1H),7.08(d,1H),4.27,4.88(q,2H),4.21(q,2H). LCMS R using Method A t =1.10 min, MS ESI C 14 H 10 F6N5O[M+H] + Calculated value: 378.1; Measured value: 377.9.

[0393] Example 8: Synthesis of Compound 8 [ka] Synthesis of A-9: A mixture of A-2 (200.00 mg, 1.38 mmol) and cyclopropane carbonyl chloride (150.54 μL, 1.66 mmol) in toluene (10 mL) was stirred at 100 °C for 12 hours. This mixture was concentrated, and AcOH (10 mL) was added to the residue. The mixture was stirred in a microwave reactor at 120 °C for 0.5 hours, then concentrated, diluted with H2O (10 mL), basicized to approximately pH 9 with solid NaHCO3, extracted with ELISA (30 mL × 2), washed the combined organic phase with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain crude A-9 (170.00 mg). LCMS R using Method B t =0.64 min, MS ESI C8H8ClN4[M+H] + Calculated value: 194.9; Measured value: 195.0.

[0394] Synthesis of compound 8: A mixture of A-9 (150.00 mg, 770.73 μmol), A-7 (233.59 mg, 770.73 μmol), Cs2CO3 (502.24 mg, 1.54 mmol), and Pd(dppf)Cl2.CH2Cl2 (62.94 mg, 77.07 μmol) in H2O (500 μL) and dioxane (5 mL) was stirred at 90°C for 12 hours. After cooling to room temperature, the mixture was diluted with RINKAN (10 mL), filtered through silica gel, eluted with RINKAN (10 mL x 2), filtered, concentrated to obtain the residue, and purified by preparative HPLC (Kromasil (150 mm x 25 mm, 10 μm); A=H2O (0.05% NH4OH) and B=CH3CN; 30-60% B over 8 minutes) to obtain compound 8 (11.90 mg) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.77(d,1H),8.04(dd,1H),8.15(d,1H),7.47(d,1H),7.06(d1H),4.87(q,2H),2.65-2.53(m,1H),1.50-1.39(m,2H),1.29-1.22(m,2H). LCMS R using Method A t =1.10 min, MS ESI C 15 H 13F3N5O[M+H] + Calculated value: 336.1; Measured value: 336.1.

[0395] Example 9: Synthesis of Compound 9 [ka] Synthesis of A-10: A mixture of A-2 (200.00 mg, 1.38 mmol) and 2,2,3,3,3-pentafluoropropanoyl (327.03 μL, 1.66 mmol) in toluene (10 mL) was stirred at 100 °C for 16 hours. The mixture was concentrated, diluted with H2O (10 mL), basicized to approximately pH 9 with solid NaHCO3, extracted with RINKAN (30 mL x 2), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain A-10 as a solid. LCMS R using Method B t =0.76 min, MS ESI C7H3ClF5N4[M+H] + Calculated value: 273.0; Measured value: 272.9.

[0396] Synthesis of compound 9: A mixture of A-10 (130.00 mg, 476.96 μmol), A-7 (173.47 mg, 572.35 μmol), Cs2CO3 (310.81 mg, 953.92 μmol), and Pd(dppf)Cl2.CH2Cl2 (38.95 mg, 47.70 μmol) in dioxane (10 mL) and H2O (1 mL) was stirred at 90°C for 16 hours. The mixture was diluted with HCl (10 mL), filtered through silica gel, and eluted with HCl (10 mL x 2). The filtrate was concentrated, and the residue was purified by preparative HPLC (Kromasil (150 mm × 25 mm, 10 μm); A=H2O (0.05% NH4OH) and B=CH3CN; 45-75% B over 8 minutes) to obtain compound 9 (14.70 mg, 35.37 μmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H=8.80(d,1H),8.36(d,1H),8.36(d,1H),7.76(d,1H),7.09(d,1H),4.88(q,2H). LCMS R using Method A t =1.18 min, MS ESI C 14 H8F8N5O[M+H] + Calculated value: 414.1; Measured value: 414.0.

[0397] Example 10: Synthesis of Compound 10 [ka] Synthesis of A-11: In a mixture of A-2 (100.0 mg, 691.75 μmol) and PYBOP (539.97 mg, 1.04 mmol) in DCM (10.00 mL), 2-tetrahydrofuran-3-ylacetic acid (90.02 mg, 691.75 μmol) and DIPEA (362.44 μL, 2.08 mmol) were added, and the mixture was stirred at 25°C for 1 hour. The mixture was concentrated to obtain crude A-11 (800.00 mg), which was further purified. I used it as is. Using Method B, LCMS R t =0.18 min, MS ESI C 10 H 14 ClN4O2[M+H] + Calculated value: 257.1; Measured value: 257.0.

[0398] Synthesis of A-12: A mixture of A-11 (800.00 mg, 3.12 mmol, 1.00 equivalent) in AcOH (5 mL) was stirred in a microwave reactor at 120°C for 0.75 hours. The mixture was concentrated, diluted with H2O (10 mL), basicized to approximately pH 9 with solid NaHCO3, extracted with siRNA (30 mL x 2), washed the combined organic phase with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. This was purified by flash chromatography on silica gel (MeOH = 0%~3%~5% in DCM) to obtain A-12 (180.00 mg) as oil. LCMS R using Method B t =0.68 min, MS ESI C 10 H12 ClN4O[M+H] + Calculated value: 239.1; Measured value: 239.0.

[0399] Synthesis of Compound 10: A mixture of A-12 (180.00 mg, 754.18 μmol), [4-(trifluoromethoxy)phenyl]boronic acid (186.37 mg, 905.02 μmol), Pd(dppf)Cl2.CH2Cl2 (61.59 mg, 75.42 μmol), and Cs2CO3 (491.45 mg, 1.51 mmol) in dioxane (5 mL) and H2O (500 μL) was stirred at 90°C for 16 hours. The mixture was concentrated, and the residue was purified by preparative TLC (silica gel, DCM:Â=3:2) to obtain Compound 10 (15.20 mg) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.19(d,1H),8.04(d,2H),7.55(d,1H),7.42(br d,2H),4.06-3.93(m,2H),3.83(q,1H),3.69(dd,1H),3.37(d,2H),3.11-2.96(m,1H),2.25-2.12(m,1H),1.91-1.76(m,1H). LCMS using Method A. R t =1.10 min, MS ESI C 17 H 16 F3N4O2[M+H] + Calculated value: 365.1; Measured value: 365.3.

[0400] Example 11: Synthesis of Compound 11 [ka] Synthesis of A-13: A mixture of A-2 (83.00 mg, 574.16 μmol) and 2-tetrahydrofuran-2-ylacetic acid (74.72 mg, 574.16 μmol) in DCM (10 mL) was mixed with PYBOP (448.18 mg, 861.23 μmol) and DIPEA (601.66 μL, 3.44 mmol), and the mixture was stirred at 25°C for 16 hours. The mixture was concentrated to obtain A-13, which was used in the next step without further purification. LCMS R using Method B t =0.25 min, MS ESI C 10 H 14 Cl N4O2[M+H] + Calculated value: 257.1; Measured value: 256.9.

[0401] Synthesis of A-14: A mixture of A-13 (800.00 mg, 3.12 mmol, 1.00 equivalent) in AcOH (6 mL) was stirred in a microwave reactor at 130°C for 1 hour. The mixture was concentrated, diluted with H2O (10 mL), basicized to approximately pH 9 with solid NaHCO3, extracted with siRNA (30 mL x 2), washed the combined organic phase with brine (10 mL), dried over Na2SO4, filtered, concentrated to obtain the residue, and purified by flash chromatography on silica gel (MeOH = 0%~3%~5% in DCM) to obtain A-14 (100.00 mg) as oil. LCMS R using Method B t =0.66 min, MS ESI C 10 H 12 ClN4O[M+H] + Calculated value: 239.1; Measured value: 239.0.

[0402] Synthesis of compound 11: A mixture of A-14 (100.00 mg, 418.99 μmol), 4-(trifluoromethoxy)phenylboronic acid (103.54 mg, 502.79 μmol), Pd(dppf)Cl2.CH2Cl2 (34.22 mg, 41.90 μmol), and Cs2CO3 (273.03 mg, 837.98 μmol) in dioxane (5 mL) and H2O (500 μL) was stirred at 90°C for 12 hours. The mixture was diluted with HCl (10 mL) and filtered through silica gel. The filtrate was concentrated, and the residue was purified by preparative HPLC (Kromasil (150 mm × 25 mm, 10 μm); A=H2O (0.05% NH4OH) and B=CH3CN; 35-65% B over 8 minutes) to obtain compound 11 (24.30 mg, 66.70 μmol) as a solid. 1 1H NMR (4 00MHz, CDCl3)δ H =8.18(d,1H),8.04(d,2H),7.53(d,1H),7.41(d,2H),4.61(quint,1H),4.02-3.90(m,1H),3.85-3.74(m,1H),3.60(dd,1H),3.42(dd,1H),2.20-2.08(m,1H),2.06-1.91(m,2H),1.89-1.77(m1H). LCMS R using Method A t =1.11 min, MS ESI C 17 H 16 F3N4O2[M+H] + Calculated value: 365.1; Measured value: 365.0.

[0403] Example 12: Synthesis of Compound 12 [ka] A mixture of A-1 (100.00 mg, 449.32 μmol), 4-(1-cyanocyclopropyl)-phenylboronic acid (84.02 mg, 449.32 μmol), Pd(t-Bu3P)2 (45.92 mg, 89.86 μmol), and K3PO4 (190.75 mg, 898.64 μmol) in dioxane (8 mL) and H2O (900 μL) was stirred at 80°C for 16 hours under nitrogen. The mixture was concentrated, and the residue was purified by preparative TLC (silica gel, DCM:HCl=2:1) ​​to obtain compound 12 (73.82 mg, 224.19 μmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.32(d,1H),8.03(d,2H),7.77(d,1H),7.50(d,2H),1.91-1.85(m,2H),1.55-1.50(m,2H). LCMS R using Method A t =1.09 min, MS ESI C 16 H 11 F3N5[ M+H] + Calculated value: 330.1; Measured value: 330.1.

[0404] Example 13: Synthesis of Compound 13 [ka] Synthesis of A-15: A mixture of A-2 (400.00 mg, 2.77 mmol) and 3,3-difluorocyclobutanecarboxylic acid (414.70 mg, 3.05 mmol) in DCM (30 mL) was mixed with PYBOP (2.16 g, 4.16 mmol) and DIPEA (1.45 mL, 8.31 mmol), and the mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated, diluted with NH₄Cl (30 mL), and extracted with HCl (40 mL × 2). The combined organic phase was washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated to obtain crude A-15 (2.45 g) as an oil. LCMS R using Method B t =0.40 min, MS ESI C9H 10 ClF2N4O[M+H] +Calculated value: 263.0; Measured value: 262.9.

[0405] Synthesis of A-16: A solution of A-15 (2.45 g, 9.33 mmol) in AcOH (5 mL) was sealed in a microwave reactor and heated at 120 °C for 1 hour. After cooling to room temperature, the reaction mixture was concentrated, diluted with saturated NaHCO3 (50 mL), and extracted with DCM (50 mL x 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the residue, which was purified by flash chromatography on silica gel (silica gel, PE:siRNA = 5:1~1:1~1:2) to obtain A-16 (500.00 mg, 2.04 mmol) as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H =8.45(d,1H),7.50(d,1H),3.98-3.87(m,1H),3.23-3.12(m,4H).

[0406] Synthesis of compound 13: A mixture of A-16 (100.00 mg, 408.78 μmol), [2-methoxy-4-(trifluoromethoxy)phenyl]boronic acid (96.45 mg, 408.78 μmol), Pd(t-Bu3P)2 (41.78 mg, 81.76 μmol), and K3PO4 (173.54 mg, 817.56 μmol) in dioxane (4 mL) and H2O (400 μL) was stirred at 90°C for 16 hours under N2. The mixture was cooled to room temperature, diluted with HCl (20 mL), filtered through silica gel, eluted with HCl (10 mL), concentrated to obtain the residue, and purified by preparative HPLC (Kromasil (150 mm × 25 mm, 10 μm); A=H2O (0.05% NH4OH) and B=CH3CN; 46-76% B over 10 minutes) to obtain compound 13 (100.70 mg, 246.83 μmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.07(d,1H),7.71(d,1H),7.58(d,1 H), 7.05-6.98 (m, 1H), 6.91 (s, 1H), 4.07-3.96 (m, 1H), 3.93 (s, 3H), 3.40-3.25 (m, 2H), 3.22-3.09 (m, 2H). LCMS R using Method A. t =1.17 min, MS ESI C 17 H 14 F5N4O2[M+H] + Calculated value: 401.1; Measured value: 401.0.

[0407] Example 14: Synthesis of Compound 14 [ka] A mixture of A-16 (100.00 mg, 408.78 μmol), 4-(trifluoromethoxy)phenylboronic acid (84.18 mg, 408.78 μmol), K3PO4 (173.54 mg, 817.56 μmol), and Pd(t-Bu3P)2 (41.78 mg, 81.76 μmol) in dioxane (8 mL) and H2O (800 μL) was stirred at 90°C for 16 hours under N2. The mixture was cooled to room temperature, concentrated, and the residue was subjected to preparative HPLC (Xtimate C). 18 (150 mm × 25 mm, 5 μm); A = H2O (0.05% NH4OH) and B = CH3CN; purified over 10 minutes by 44-74% B) to obtain compound 14 (78.40 mg, 207.43 μmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.21(d,1H),8.04(d,2H),7.58(d,1H),7.42(d,2H),4.07(d5-term,1H),3.43-3.29(m,2H),3.25-3.14(m,2H). LCMS R using Method A t =1.17 min, MS ESI C 16 H 12 F5N4O[M+H] + Calculated value: 371.1; Measured value: 370.9.

[0408] Example 15: Synthesis of Compound 15 [ka] Synthesis of A-17: A mixture of A-2 (400.00 mg, 2.77 mmol) and 2,2-difluorocyclopropanecarboxylic acid (371.55 mg, 3.04 mmol) in DCM (30 mL) is mixed with PYBOP (2.16 g, 4.15 mmol) and DIPEA (1 Add 0.45 mL (8.30 mmol) and stir the mixture at 25°C for 2 hours. The reaction mixture was concentrated, diluted with NH4Cl (50 mL), extracted with HCl (50 mL x 2), washed with brine (20 mL), dried over Na2SO4, filtered, concentrated to obtain A-17 (crudely purified, 3.43 g) as oil. LCMS R using Method B t =0.18 min, MS ESI C8H8ClF2N4O[M+H] + Calculated value: 249.0; Measured value: 248.9.

[0409] Synthesis of A-18: A solution of A-17 (3.30 g, 13.27 mmol) in AcOH (5 mL) was sealed in a microwave reactor and heated at 120 °C for 1.5 hours. After cooling to room temperature, the reaction mixture was concentrated, diluted with saturated NaHCO3 (50 mL), and extracted with DCM (50 mL x 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain the residue, which was purified by flash chromatography on silica gel (PE:siRNA = 5:1 to 1:1) to obtain A-18 (300.00 mg, 1.30 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.09(d,1H),7.15(d,1H),3.24(ddd,1H),2.66-2.55(m,1H),2.22-2.02(m,1H).

[0410] Synthesis of Compound 15: A mixture of 2-methoxy-4-(trifluoromethoxy)phenylboronic acid (102.32 mg, 433.65 μmol), A-18 (100.00 mg, 433.65 μmol), Pd(t-Bu3P)2 (44.32 mg, 86.73 μmol), and K3PO4 (184.10 mg, 867.30 μmol) in dioxane (8 mL) and H2O (800 μL) was stirred at 90°C for 16 hours under N2. The mixture was cooled to room temperature, diluted with HCl (20 mL), filtered through silica gel, and eluted with HCl (10 mL). The filtrate was concentrated to obtain the residue, which was then subjected to preparative HPLC (Xtimate C). 18 (150 mm × 25 mm, 5 μm); A = H2O (0.05% NH4OH) and B = CH3CN; purified over 10 minutes by 42-72% B) to obtain compound 15 (38.20 mg, 96.35 μmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.07(d,1H),7.77(d,1H),7.60(d,1H),7.05-6.99(m,1H),6.92-6.89(m,1H),3.93(s,3H),3.36-3.24(m,1H),2.69-2.58(m,1H),2.20-2.08(m,1H). LCMS R using Method A t =1.16 min, MS ESI C 16 H 12 F5N4O2[M+H] + Calculated value: 387.1; Measured value: 387.0.

[0411] Example 16: Synthesis of Compound 16 [ka] Synthesis of A-19: 2,2-difluoroacetic acid (2,2-difluoroacetyl) (662.43 mg, 3.81 mmol) was slowly added to a suspension of A-2 (500.00 mg, 3.46 mmol) in toluene (10 mL). The reaction mixture was stirred at 110 °C for 16 hours. The reaction mixture was concentrated and diluted with saturated NaHCO3 (30 mL), and the product was extracted with ELISA (20 mL x 2). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain A-19 (600.00 mg, 2.91 mmol) as a solid. LC-MS R using Method B t =0.33 min, MS ESI C6H4ClF2N4[M+H] + Calculated value: 205.0; Measured value: 204.9.

[0412] Synthesis of Compound 16: A mixture of A-19 (100.00 mg, 488.85 μmol), [2-methoxy-4-(trifluoromethoxy)phenyl]boronic acid (115.35 mg, 488.85 μmol), Pd(t-Bu3P)2 (49.97 mg, 97.77 μmol), and K3PO4 (207.54 mg, 977.71 μmol) in H2O (1 mL) and dioxane (5 mL) was stirred at 90°C for 16 hours under N2. The mixture was cooled to room temperature, diluted with HCl (40 mL), filtered through silica gel, and eluted with HCl (10 mL). The filtrate was concentrated to obtain the residue, which was then subjected to preparative HPLC (Xtimate C). 18 (150 mm × 25 mm, 5 μm); A = H2O (0.05% NH4OH) and B = CH3CN; purified over 10 minutes by 39-69% B) to obtain compound 16 (61.10 mg, 166.81 μmol) as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H =8.52(d,1H),7.92-7.53(m,3H),7.30-7.27(m,1H),7.21-7.14(m,1H),3.91(s,3H). LCMS R using Method A t =1.14 min, MS ESI C 14 H 10 F5N4O2[M+H]+ Calculated value: 361.1; Measured value: 360.9.

[0413] Example 17: Synthesis of Compound 17 [ka] A mixture of A-1 (150.00 mg, 673.98 μmol), [3-(trifluoromethoxy)phenyl]-boronic acid (166.55 mg, 808.78 μmol), Cs2CO3 (439.19 mg, 1.35 mmol), and Pd(dppf)Cl2.CH2Cl2 (82.56 mg, 101.10 μmol) in dioxane (3 mL) and H2O (300 μL) was stirred at 90°C for 16 hours under N2. The mixture was cooled to room temperature, diluted with HCl (30 mL), filtered through silica gel, and eluted with HCl (10 mL). The filtrate was concentrated, and the residue was subjected to preparative HPLC (Xtimate C). 18 (150 mm × 25 mm, 5 μm); A = H2O (0.05% NH4OH) and B = CH3CN; purified over 10 minutes by 46-76% B) to obtain compound 17 (50.28 mg, 142.96 μmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.36(d,1H),7.97(d,1H),7.88(s,1H),7.77(d,1H),7.65(t,1H),7.50-7.45(m,1H). LCMS R using Method A t =1.19 min, MS ESI C 13 H7F6N4O[M+H] + Calculated value: 349.0; Measured value: 348.9.

[0414] Example 18: Synthesis of Compound 18 [ka] A mixture of A-1 (150.00 mg, 673.98 μmol), [2-fluoro-5-(trifluoromethoxy)phenyl]boronic acid (150.92 mg, 673.98 μmol), and Cs2CO3 (439.19 mg, 1.35 mmol) in dioxane (3 mL) and H2O (300 μL) was prepared by adding Pd(dppf)Cl2.CH2Cl2 (82.56 mg, 101.10 μmol) and stirring at 90°C for 16 hours under N2. After cooling to room temperature, the mixture was concentrated to obtain the residue, which was purified by preparative TLC (silica gel, Â:PE = 1:2) to obtain compound 18 (22.78 mg, 62.21 μmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.34(d,1H),7.85-7.79(m,2H),7.50-7.43(m,1H),7.37-7.31(t,1H). LCMS R using Method A t =1.19 min, MS ESI C 13 H6F7N4O[M+H] + Calculated value: 367.0; Measured value: 367.2.

[0415] Example 19: Synthesis of Compound 19 [ka] A mixture of A-1 (150.00 mg, 673.98 μmol), [2-fluoro-3-(trifluoromethoxy)phenyl]boronic acid (181.10 mg, 808.78 μmol), Cs2CO3 (439.19 mg, 1.35 mmol), and Pd(dppf)Cl2.CH2Cl2 (82.56 mg, 101.10 μmol) in dioxane (3 mL) and H2O (300 μL) was stirred at 90°C for 16 hours under a nitrogen atmosphere. The mixture was diluted with HCl (15 mL), filtered through silica gel, and eluted with HCl (15 mL x 3). The filtrate was concentrated to obtain the residue, which was purified by preparative TLC (silica gel, HCl:PE = 1:2) and powdered with n-hexane (2 mL) to obtain compound 19 (21.69 mg, 57.90 μmol) as a solid. 11H NMR (400MHz, CDCl3)δ H =8.35(d,1H),7.94-7.85(m,1H),7.79(dd,1H),7.58(t,1H),7.45-7.39(m,1H). LCMS R using Method A t =1.18 min, MS ESI C 13 H6F7N4O[M+H] + Calculated value: 367.0; Measured value: 366.9.

[0416] Example 20: Synthesis of Compound 20 [ka] Synthesis of A-20: A solution of A-2 (2.00 g, 13.84 mmol), 2-benzyloxyacetic acid (2.30 g, 13.84 mmol, 1.98 mL), and PYBOP (10.80 g, 20.76 mmol) in DCM (100 mL) was prepared, to which DIPEA (7.25 mL, 41.52 mmol) was added, and the mixture was stirred at 25°C for 16 hours. The reaction mixture was concentrated, diluted with NH4Cl (20 mL), extracted with ELISA (30 mL x 2), washed with brine (15 mL), dried over Na2SO4, filtered, concentrated, and crude A-20 (13.00 g) was obtained as oil. LCMS R using Method B t =0.67 min, MS ESI C 13 H 14 ClN4O2[M+H] + Calculated value: 293.1; Measured value: 293.0.

[0417] Synthesis of A-21: A mixture of A-20 (10.00 g, 34.16 mmol) in AcOH (50 mL) was stirred at 120°C for 16 hours. After cooling to room temperature, the reaction mixture was concentrated, diluted with saturated NaHCO3 (50 mL), extracted with dimethyl phosphate (80 mL x 2), washed with brine (20 mL), dried over Na2SO4, filtered, concentrated to obtain the residue, which was purified by flash chromatography on silica gel (PE:dimethyl = 1:1~1:2) to obtain A-21 (1.80 g, 5.71 mmol) as a solid. LCMS R using Method At =0.98 min, MS ESI C 13 H 12 ClN4O[M+H] + Calculated value: 275.1; Measured value: 274.9.

[0418] Synthesis of A-22: A mixture of A-21 (1.80 g, 6.55 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (1.48 g, 7.20 mmol), Cs2CO3 (4.27 g, 13.10 mmol), and Pd(dppf)Cl2.CH2Cl2 (802.64 mg, 982.50 μmol) in dioxane (30 mL) and H2O (3 mL) was stirred at 90 °C for 16 hours. The mixture was cooled to room temperature, diluted with HCl (30 mL), filtered through silica gel, and eluted with HCl (10 mL). The filtrate was concentrated to obtain the residue, which was purified by flash chromatography on silica gel (PE:HCl = 2:1 to 1:1) to obtain A-22 (1.30 g, 2.88 mmol) as a solid. LCMS R using Method B t =0.88 min, MS ESI C 20 H 16 F3N4O2[M+H] + Calculated value: 401.1; Measured value: 401.1.

[0419] Synthesis of A-23: A-22 (1.20g, 3.5g) in HBr / AcOH (10mL). A mixture of 00 mmol (1.00 equivalent) was stirred at 80°C for 16 hours under N2. After cooling to room temperature, the mixture was concentrated, diluted with H2O (30 mL), extracted with siRNA (40 mL x 2), the combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain solid A-23 (800.00 mg). LCMS R was performed using Method B. t =0.83 min, MS ESI C 13 H8BrF3N4O[M+H+2] + Calculated value: 375.0; Measured value: 375.0.

[0420] Synthesis of A-24: PPh3 (773.74 mg, 2.95 mmol) was added to a mixture of A-23 (1.10 g, 2.95 mmol) in toluene (20 mL). The reaction mixture was stirred at 110 °C for 16 hours. The reaction mixture was cooled, diluted with PE (20 mL), filtered, and dried to obtain A-24 (800.00 mg) as a solid.

[0421] Synthesis of A-25: To a mixture of A-24 (700.00 mg, 1.10 mmol) in THF (10 mL), n-BuLi (2.5 M, 528.00 μL) was added under N2 at 0°C, and the reaction mixture was stirred at 0°C for 30 minutes. Then, oxetane-3-one (198.17 mg, 2.75 mmol) was added, and the reaction mixture was stirred at 20°C for 16 hours. The reaction was stopped with saturated NH4Cl (10 mL), extracted with siRNA (10 mL x 3), the combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the residue, which was purified by flash chromatography on silica gel (siRNA = 30%~50%~80% in PE) to obtain A-25 (120.00 mg) as a solid. LCMS R using Method B t =0.82 min, MS ESI C 16 H 12 F3N4O2[M+H] + Calculated value: 349.1; Measured value: 349.1.

[0422] Synthesis of compound 20: A-25(1) in methoxy (10 mL) under N2 conditions A mixture of 20.00 mg (344.55 μmol) and wet Pd / C (50.00 mg) was degassed and repacked with H2. The reaction mixture was stirred at 20°C for 2 hours under H2 (15 psi). The reaction mixture was diluted with à (20 mL), filtered through a Celite pad, eluted with à (20 mL), concentrated to obtain the residue, and then subjected to preparative HPLC (Xtimate C). 18(150 mm × 25 mm, 5 μm); A = H2O (0.05% NH4OH) and B = CH3CN; purified over 10 minutes with 27-57% B) to obtain compound 20 (42.00 mg, 118.71 μmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.19(d,1H),8.04(d,2H),7.55(d,1H),7.42(d,2H),4.97(t,2H),4.66(t,2H),3.80-3.70(m,1H),3.69-3.62(m,2H). LCMS R using Method B t =0.76 min, MS ESI C 16 H 14 F3N4O2[M+H] + Calculated value: 351.1; Measured value: 351.1.

[0423] Example 21: Synthesis of Compound 21 [ka] A mixture of A-21 (100.00 mg, 249.78 μmol) in TFA (3 mL) was stirred at 80°C for 16 hours. After cooling to room temperature, the mixture was concentrated to obtain the residue, which was then subjected to preparative HPLC (Xtimate C). 18 (150mm x 25mm, 5μm); A = H2O (0.05% NH4OH) and B = CH3CN; 22-52% B over 10 minutes) The compound 21 (30.59 mg, 96.14 μmol) was purified by [method] to obtain the compound 21 as a solid (30.59 mg, 96.14 μmol). 1 1H NMR (400MHz, CDCl3)δ H =8.23(d,1H),8.05(d,2H),7.60(d,1H),7.42(d,2H),5.34(d,2H),2.76(t,1H). LCMS R using Method A t =0.99 min, MS ESI C 13 H 10 F3N4O2[M+H] + Calculated value: 311.1; Measured value: 310.9.

[0424] Example 22: Synthesis of Compound 22 [ka] Synthesis of A-27: LiAlH4 (1.39 g, 36.72 mmol) was added to a mixture of A-26 (3.00 g, 12.24 mmol) in THF (40 mL) under N2 conditions at -40°C, and the mixture was stirred at -40°C for 2 hours. H2O (1.76 g) was added dropwise to the mixture at -40°C, and the mixture was stirred at 0°C for 0.5 hours, then at 50°C for 0.5 hours. The mixture was then filtered through Celite, eluted with THF (100 mL × 2), concentrated, dissolved in siRNA (200 mL), washed with water (30 mL × 2) and brine (50 mL), dried over Na2SO4, filtered, concentrated to obtain A-27 (2.50 g, 11.52 mmol) as oil. 1 1H NMR (400MHz DMSO-d6)δ H =7.49(d,1H),7.06(s,1H),6.84(d,1H),5.29(t,1H),4.47(d,2H),3.83(s,3H).

[0425] Synthesis of A-28: A mixture of A-27 (2.50 g, 11.52 mmol) in SOCl2 (15 mL) was stirred at 70°C for 2 hours. The mixture was concentrated, and the residue was diluted with dimethyl phosphate (150 mL). The organic phase was washed with water (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain A-28 (2.60 g, 11.04 mmol) as oil. 1 1H NMR (400MHz DMSO-d6)δ H =7.57(d,1H),7.20(d,1H),6.97(dd,1H),4.74(s,2H),3.86(s,3H).

[0426] Synthesis of A-29: A mixture of A-28 (2.60 g, 11.04 mmol) in CH3CN (30 mL) was mixed with TMSCN (2.08 mL, 16.56 mmol) and TBAF (1 M, 16.56 mL), and the mixture was stirred at 25°C for 36 hours. The mixture was diluted with H2O (50 mL), extracted with Depositphotos (100 mL x 2), washed with water (30 mL x 2) and brine (50 mL), dried on Na2SO4, filtered, and concentrated to obtain the residue, which was purified by flash chromatography on silica gel ( Depositphotos = 5%~10%~15% in PE) to obtain A-29 (2.15 g, 9.51 mmol) as oil. 1 1H NMR (400MHz, CDCl3)δ H =7.54(d,1H),6.87(d,1H),6.81(dd,1H),3.93(s,3H),3.74(s,2H).

[0427] Synthesis of A-30: A mixture of A-29 (2.0 g, 8.85 mmol), TBAB (114.08 mg, 353.87 μmol), and KOH (4.96 g, 88.47 mmol) in toluene (40 mL) and H2O (4 mL) was prepared. 1,2-dibromoethane (1.33 mL, 17.69 mmol) was added at 100°C, and the mixture was stirred at 100°C for 1 hour. The mixture was diluted with HCl (150 mL), then washed with water (30 mL x 2) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain the residue. This residue was purified by flash chromatography on silica gel (HCl in PE = 5%~10%) to obtain A-30 (1.72 g) as a solid. 1 1H NMR (400MHz CDCl3)δ H =7.49(d,1H),6.93(d,1H),6.67(dd,1H),3.93(s,3H),1.79-1.72(m,2H),1.45-1.38(m,2H).

[0428] Synthesis of A-31: A mixture of A-30 (500 mg, 1.98 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (1.51 g, 5.94 mmol), Pd(dppf)Cl2.CH2Cl2 (242.54 mg, 297.00 μmol), and KOAc (388.63 mg, 3.96 mmol) in dioxane (25 mL) was stirred at 85 °C for 12 hours under N2. After cooling to room temperature, the mixture was concentrated, diluted with H2O (30 mL), and extracted with  (100 mL x 2). The combined organic phases were washed with water (20 mL x 2) and brine (20 mL), dried on Na2SO4, filtered, and concentrated to obtain the residue, which was purified by flash chromatography on silica gel (EtOAC = 1%~5%~10% in PE) to obtain oil A-31 (510.00 mg). 1 1H NMR (400MHz CDCl3)δ H =7.64(d,1H),6.87(d,1H),6.73(dd,1H),3.87(s,3H),1.78-1.72(m,2H),1.47-1.41(m,2H),1.35(s,12H)

[0429] Synthesis of compound 22: In a 20 mL sealed tube under N2 conditions, a mixture of A-31 (403.27 mg, 1.35 mmol), A-1 (150.00 mg, 673.98 μmol), Pd(t-Bu3P)2 (51.67 mg, 101.10 μmol), and K3PO4 (286.13 mg, 1.35 mmol) in dioxane (10 mL) and H2O (1.35 mL) was stirred at 80°C for 16 hours. After cooling to room temperature, the mixture was concentrated, diluted with H2O (20 mL), and extracted with RINKAN (50 mL x 2). The combined organic phases were washed with water (20 mL x 2) and brine (20 mL), dried on Na2SO4, filtered, and concentrated to obtain the residue, which was purified by preparative TLC (silica gel, siRNA:DCM = 1:2) to obtain compound 22 (147.51 mg) as a solid. 1 1H NMR (400MHz, CDCl3)δ H=8.18(d,1H),7.83(d,1H),7.74(d,1H),7.16(s,1H),6.89(d,1H),3.97(s,3H),1.90-1.81(m,2H),1.56-1.49(m,2H). LCMS R using Method A t =1.11 min, MS ESI C 17 H 13 F3N5O[M+H] + Calculated value: 360.1; Measured value: 360.0.

[0430] Example 23: Synthesis of Compound 23 [ka] Synthesis of A-33: A mixture of A-32 (1.25 g, 4.83 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (3.68 g, 14.48 mmol), Pd(dppf)Cl2.CH2Cl2 (394.13 mg, 482.63 μmol), and KOAc (947.30 mg, 9.65 mmol) in dioxane (30 mL) was stirred at 90 °C for 16 hours. After cooling to room temperature, the mixture was diluted with ELISA (50 mL), filtered through silica gel, concentrated to obtain the residue, and purified by flash chromatography on silica gel (ELISA in PE = 0%~1%) to obtain A-32 (1.29 g) as oil. 1 1H NMR (400MHz CDCl3)δ H =7.78(dd,1H),7.01(d,1H),6.93(d,1H),1.37(s,12H)

[0431] Synthesis of Compound 23: A mixture of A-33 (275.04 mg, 898.64 μmol), A-1 (100.00 mg, 449.32 μmol), Pd(t-Bu3P)2 (45.92 mg, 89.86 μmol), and K3PO4 (190.75 mg, 898.64 μmol) in dioxane (8 mL) and H2O (1 mL) was stirred at 80°C for 16 hours. After cooling to room temperature, the mixture was concentrated to obtain the residue, which was then subjected to preparative HPLC (Xtimate C). 18 (150 mm × 25 mm, 5 μm); A = H2O (0.05% NH4OH) and B = CH3CN; purified over 10 minutes by 45-75% B) to obtain compound 23 (107.00 mg) as a solid. 1 1H NMR (400MHz DMSO-d6)δ H =8.73(d,1H),8.02-7.96(m,2H),7.72(br d,1H),7.53(br d,1H). LCMS R using Method A t =1.197 min, MS ESI C 13 H6F7N4O[M+H] + Calculated value: 367.0; Measured value: 366.9.

[0432] Example 24: Synthesis of Compound 24 [ka] Synthesis of A-35: A mixture of cyclopropylboronic acid (1.94 g, 22.58 mmol), A-34 (3.07 mL, 22.58 mmol), Pd(OAc)2 (506.84 mg, 2.26 mmol), Cs2CO3 (14.71 g, 45.16 mmol), and P(Cy)3 (1.82 mL, 5.65 mmol) in H2O (8 mL) and toluene (80 mL) was stirred at 80°C for 16 hours under N2. After cooling to room temperature, the mixture was washed with water (20 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain the residue, which was purified by flash chromatography on silica gel (dimethyl in PE = 0%~1%~2%) to obtain A-35 (2.70 g, 14.78 mmol) as oil. 11H NMR (400MHz, CDCl3)δ H =7.22(d,1H),6.68(d,1H),6.59(dd,1H),3.90(s,3H),1.93-1.84(m,1H),1.02-0.94(m,2H),0.72-0.66(m,2H).

[0433] Synthesis of A-36: A-35 (2.29 g, 9.03 mmol), A-1 (550.00 mg, 3.01 mmol), KOAc (679.42 mg, 6.92 mmol), and Pd (in dioxane (25 mL)) t A mixture of Bu3P)2 (153.89 mg, 301.00 μmol) and A-36 was stirred at 85°C for 12 hours under N2. The mixture was concentrated, diluted with H2O (30 mL), and extracted with RINKAN (50 mL x 2). The combined organic phases were washed with water (20 mL x 2) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the residue, which was purified by flash chromatography on silica gel (RINKAN in PE = 0%~1%~2%) to obtain A-36 (350.00 mg) as a solid. 1 1H NMR (400MHz CDCl3)δ H =7.58(d,1H),6.67-6.58(m,2H),3.83(s,3H),1.96-1.84(m,1H),1.34(s,12H),1.02-0.94(m,2H),0.78-0.70(m,2H).

[0434] Synthesis of Compound 24: In a 20 mL sealed tube under N2 conditions, a mixture of A-36 (310.42 mg, 1.13 mmol), A-1 (140.00 mg, 629.04 μmol), Pd(t-Bu3P)2 (48.22 mg, 94.36 μmol), and K3PO4 (267.05 mg, 1.26 mmol) in dioxane (10 mL) and H2O (1.35 mL) was stirred at 80°C for 12 hours. The mixture was concentrated, diluted with H2O (20 mL), and extracted with SiO4 (50 mL x 2). The combined organic phase was washed with water (20 mL x 2) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the residue, which was purified by preparative TLC (silica gel, SiO4:DCM = 1:3) to obtain Compound 24 (42.91 mg) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.13(d,1H),7.85(d,1H),7.66(d,1H),6.85-6.76(m,2H),3.91(s,3H),2.04-1.93(m,1H),1.14-1.04(m,2H),0.85-0.77(m,2H). LCMS R using Method A t =1.21 min, MS ESI C 16 H 14 F3N4O[M+H] + Calculated value: 335.1; Measured value: 334.9.

[0435] Example 25: Synthesis of Compound 25 [ka] Synthesis of A-38: MeMgBr (3M, 26.20mL, 6.00 equivalents) was added dropwise to a mixture of A-37 (2.14mL, 13.10 mmol) in THF (80mL) at -30°C. The reaction mixture was warmed to room temperature and stirred at 25°C for 16 hours. The reaction was stopped with saturated NH4Cl (200mL), extracted with siRNA (200mL x 2), and the combined organic layer was washed with H2O (200mL x 2) and brine (100mL). The mixture was dried over Na2SO4, filtered, and concentrated to obtain A-38 (crudely purified, 2.80g) as oil. 1 1H NMR (400MHz DMSO-d6)δH =7.50-7.44(m,2H),7.44-7.38(m,2H),5.10(s,1H),1.40(s,6H).

[0436] Synthesis of A-39: To a mixture of A-38 (2.80 g, 13.02 mmol) in THF (30 mL), NaH (1.04 g, 26.04 mmol, 60% purity) and CH3I (1.62 mL, 26.04 mmol) were added at 0°C, and the mixture was stirred at 25°C for 16 hours. The reaction of the mixture was stopped with a saturated solution of NH4Cl (50 mL), extracted with siRNA (100 mL x 2), washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain A-39 (2.70 g, 11.78 mmol) as oil. 1 1H NMR (400MHz CDCl3)δ H =7.47(d,2H),7.29(d,2H),3.07(s,3H),1.51(s,6H).

[0437] Synthesis of A-40: A mixture of A-39 (1.30 g, 5.67 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (4.32 g, 17.01 mmol), Pd(dppf)Cl2.CH2Cl2 (695.06 mg, 850.50 μmol), and KOAc (1.11 g, 11.34 mmol) in dioxane (70 mL) was stirred at 90 °C for 16 hours. After cooling to room temperature, the mixture was diluted with ELISA (100 mL), filtered through silica gel, and eluted with ELISA (100 mL x 2). The filtrate was concentrated to obtain the residue, which was purified by flash chromatography (PE) on silica gel to obtain A-40 (950.00 mg, 3.44 mmol) as a solid. 1 1H NMR (400MHz CDCl3)δ H =7.81(d,2H),7.43(d,2H),3.08(s,3H),1.53(s,6H),1.35(s,12H).

[0438] Synthesis of Compound 25: A mixture of A-40 (372.28 mg, 1.35 mmol), A-1 (150.00 mg, 673.98 μmol), Pd(t-Bu3P)2 (34.44 mg, 67.40 μmol), and K3PO4 (286.13 mg, 1.35 mmol) in dioxane (10 mL) and H2O (1 mL) was stirred at 80°C for 16 hours. After cooling to room temperature, the mixture was concentrated to obtain the residue, which was then subjected to preparative TLC (silica gel, PE: EtOAc=2:1) ​​and preparative HPLC (Xtimate C 18 (150 mm × 25 mm, 5 μm); A = H2O (0.05% NH4OH) and B = CH3CN; purified over 10 minutes by 55-85% B) to obtain compound 25 (23.00 mg) as a solid. 1 1H NMR (400MHz, CDCl3 + D2O)δ H =8.30(d,1H),8.01(d,2H),7.79(d,1H),7.63(d,2H),3.14(s,3H),1.59(s,6H). LCMS R using Method A t =1.14 min, MS ESI C 16 H 16 F3N4O[M+H] + Calculated value: 337.1; Measured value: 336.9.

[0439] Example 26: Synthesis of Compound 26 [ka] Synthesis of A-42: To a solution of 2,2,2-trifluoroethanol (522.51 μL, 7.26 mmol), NaH (290.40 mg, 7.26 mmol, 60% purity) in DMF (20 mL) was slowly added at 0°C, and the mixture was stirred at 0°C for 30 minutes. Then, A-40 (1.00 g, 4.84 mmol) was added to the mixture, and the mixture was stirred at 20°C for 16 hours. The reaction was stopped with a saturated solution of NH4Cl (30 mL), and extracted with siRNA (50 mL x 2). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain the residue, which was purified by flash chromatography on silica gel (siRNA = 0%~1% in PE) to obtain A-42 (900 mg) as oil. LCMS R using Method B t =0.89 min, MS ESI C8H8BrF3NO[M+H+2] + Calculated value: 272.0; Measured value: 271.9.

[0440] Synthesis of A-43: A mixture of A-42 (900 mg, 3.33 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (1.27 g, 5.00 mmol), KOAc (654.15 mg, 6.67 mmol), and Pd(dppf)Cl2.CH2Cl2 (544.33 mg, 666.54 μmol) in dioxane (20 mL) was stirred at 90 °C for 16 hours. After cooling to room temperature, the mixture was diluted with H2O (20 mL x 3) and extracted with ELISA (50 mL x 2). The combined organic phases were washed with brine (50 mL), dried on Na2SO4, filtered, and concentrated to obtain the residue, which was purified by flash chromatography on silica gel (dimethyl in PE = 0%~1%) to obtain oil A-43 (600 mg, 1.52 mmol). 1 1H NMR (400MHz, CDCl3)δ H =8.44(s,1H),6.65(s,1H),4.78(q,2H),2.48(s,3H),1.34(s,12H). LCMS R using Method B t =0.98 min, MS ESI C14 H 20 BF3NO3[M+H] + Calculation for Value: 318.1; Measured value: 318.4.

[0441] Synthesis of Compound 26: A mixture of A-43 (320.59 mg, 1.01 mmol), A-1 (150.00 mg, 673.98 μmol), Pd(t-Bu3P)2 (51.67 mg, 101.10 μmol), and K3PO4 (286.13 mg, 1.35 mmol) in dioxane (8 mL) and H2O (1 mL) was stirred at 80°C for 16 hours. After cooling to room temperature, the mixture was concentrated and purified by preparative TLC (silica gel, Â:DCM=1:3) and preparative HPLC (Kromasil (150 mm × 25 mm, 10 μm); A=H2O (0.05% NH4OH) and B=CH3CN; 50-60% B over 8 minutes) to obtain Compound 26 (24.13 mg, 63.43 μmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.36-8.30(m,2H),7.51(d,1H),6.92(s,1H),4.85(q,2H),2.53(s,3H). LCMS R using Method B t =0.84 min, MS ESI C 14 H 10 F6N5O[M+H] + Calculated value: 378.1; Measured value: 378.1.

[0442] Example 27: Synthesis of Compound 27 [ka] Synthesis of A-45: 2,2,2-trifluoroethanol (731.52 μL, 10.16 mmol) was added to a mixture of NaH (387.20 mg, 9.68 mmol, 60% purity) in DMF (20 mL) at 0°C under N2 conditions, and the mixture was stirred at 0°C for 0.5 hours. Then, 3-bromo-6-chloro-2-methylpyridine (1.00 g, 4.84 mmol) was added, and the mixture was stirred at 25°C for 16 hours. The reaction of the mixture was stopped with NH4Cl (80 mL), and extracted with ELISA (40 mL x 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain the residue, which was purified by flash chromatography (PE) on silica gel to obtain A-45 (500.00 mg, 1.85 mmol) as oil. 1 1H NMR (400MHz, CDCl3)δ H =7.70(d,1H),6.60(d,1H),4.74(q,2H),2.55(s,3H).

[0443] Synthesis of A-46: In dioxane (5 mL), A-45 (200.00 mg, 740.60 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (564.20 mg, 2.22 mmol), and Pd(dppf)Cl2.CH2Cl2(60.4 A mixture of 8 mg (74.06 μmol) and KOAc (145.36 mg, 1.48 mmol) was stirred at 90°C for 16 hours under N2. The mixture was cooled to room temperature, diluted with HCl (10 mL), filtered through silica gel, eluted with HCl (10 mL), and the filtrate was concentrated to obtain the residue, which was purified by flash chromatography on silica gel (HCl = 50:1 in PE) to obtain A-46 (200.00 mg) as oil. 1 1H NMR (400MHz CDCl3)δ H =7.97(d,1H),6.64(d,1H),4.80(q,2H),2.65(s,3H),1.34(s,12H).

[0444] Synthesis of Compound 27: A mixture of A-46 (170.98 mg, 539.18 μmol), A-1 (100.00 mg, 449.32 μmol), K3PO4 (190.75 mg, 898.64 μmol), and Pd(t-Bu3P)2 (45.92 mg, 89.86 μmol) in dioxane (6 mL) and H2O (1 mL) was stirred at 90°C for 16 hours. The mixture was cooled to room temperature, diluted with SiO2 (20 mL), filtered, and concentrated to obtain the residue, which was then subjected to preparative HPLC (Xtimate C). 18 (150 mm × 25 mm, 5 μm); A = H2O (0.05% NH4OH) and B = CH3CN; purified over 10 minutes by 46-76% B) to obtain compound 27 (53.15 mg, 138.45 μmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.31(d,1H),7.81(d,1H),7.47(d,1H),6.90(d,1H),4.87(q,2H),2.64(s,3H). LCMS R using method C. t =3.42 min, MS ESI C 14 H 10 F6N5O[M+H] + Calculated value: 378.1; Measured value: 377.9.

[0445] Example 28: Synthesis of Compound 28 [ka] Synthesis of A-48: Under N2 conditions at 0°C, 2,2,2-trifluoroethanol (732.02 μL, 10.17 mmol) was added to a mixture of NaH (387.47 mg, 9.69 mmol, 60% purity) in DMF (20 mL), and the mixture was stirred at 0°C for 0.5 hours. Then A-47 (1.00 g, 4.84 mmol) was added, and the yellow mixture was stirred at 25°C for 16 hours. The reaction of the mixture was stopped with NH4Cl (80 mL), and extracted with siRNA (50 mL x 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, concentrated to obtain the residue, and flash chromatographed on silica gel. The oil was refined using a roughing agent (PE) to obtain A-48 (480.00 mg). 1 H NMR (400 MHz, CDCl3) δ H =8.02(d,1H),7.57(d,1H),4.73(q,2H),2.23(s,3H).

[0446] Synthesis of A-49: A mixture of A-48 (200.00 mg, 740.60 μmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (564.20 mg, 2.22 mmol), Pd(dppf)Cl2.CH2Cl2 (60.48 mg, 74.06 μmol), and KOAc (72.68 mg, 740.60 μmol) in dioxane (5 mL) was stirred at 90 °C for 16 hours under N2. The mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), filtered through silica gel, eluted with ethyl acetate (10 mL), concentrated to obtain the residue, which was purified by flash chromatography on silica gel (PE:ethyl = 50:1) to obtain A-49 (180.00 mg) as oil. Using Method B, LCMS R t =1.00 min, MS ESI C 14 H 20 BF3NO3[M+H] + Calculated value: 318.1; Measured value: 318.1.

[0447] Synthesis of Compound 28: A mixture of A-49 (170.98 mg, 539.18 μmol), A-1 (100.00 mg, 449.32 μmol), K3PO4 (190.75 mg, 898.64 μmol), and Pd(t-Bu3P)2 (45.92 mg, 89.86 μmol) in dioxane (6 mL) and H2O (1 mL) was stirred at 90°C for 16 hours under N2. The mixture was cooled to room temperature, diluted with SiO2 (20 mL), filtered, and concentrated to obtain the residue, which was then subjected to preparative HPLC (Xtimate C). 18(150 mm × 25 mm, 5 μm); A = H2O (0.05% NH4OH) and B = CH3CN; purified over 10 minutes by 46-76% B) to obtain compound 28 (31.40 mg) as a solid. 1 1H NMR (400MHz CDCl3)δ H =8.62(s,1H),8.32(d,1H),8.16(s,1H),7.74(d,1H),4.88(q,2H),2.39(s,3H). LCMS R using method C. t =3.52 min, MS ESI C 14 H 10 F6N5O[M+H] + Calculated value: 378.1; Measured value: 377.9.

[0448] Example 29: Synthesis of Compound 29 [ka] Synthesis of A-50: NaH (415.71 mg, 10.40 mmol, 60% purity) was added at 0°C to a mixture of 1,1,1-trifluoropropan-2-ol (1.19 g, 10.40 mmol, 941.53 μL) in DMF (20 mL). The reaction mixture was then heated at 0°C. The mixture was stirred for 15 minutes, then A-5 (1.00 g, 5.20 mmol, 1.0 equivalent) was added at 0°C. The reaction mixture was warmed to 25°C and stirred for 16 hours. The reaction of the mixture was stopped with saturated NH4Cl (100 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with H2O (100 mL) and brine (100 mL), dried on Na2SO4, filtered, and concentrated to obtain the residue, which was purified by flash chromatography on silica gel (ethyl acetate in PE = 0%~1%) to obtain A-50 (1.00 g, 3.67 mmol) as oil. LCMS R using Method B t =0.94 min, MS ESI C8H8BrF3NO[M+H] + Calculated value: 270.0; Measured value: 269.9.

[0449] Synthesis of A-51: A mixture of A-50 (500.00 mg, 1.85 mmol) in dioxane (10 mL), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (1.41 g, 5.55 mmol), Pd(dppf)Cl2.CH2Cl2 (151.08 mg, 185.00 μmol), and KOAc (363.12 mg, 3.70 mmol) was stirred at 90°C for 16 hours. After cooling to room temperature, the mixture was concentrated to obtain the residue, which was purified by flash chromatography on silica gel (ethyl acetate = 0%~1%) to obtain A-51 (400.00 mg) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.51(d,1H),7.98(dd,1H),6.79(d,1H),5.87(td,1H),1.49(d,3H),1.34(s,12H).

[0450] Synthesis of Compound 29: A mixture of A-51 (320.59 mg, 1.01 mmol), A-1 (150.00 mg, 673.98 μmol), Pd(t-Bu3P)2 (34.44 mg, 67.40 μmol), and K3PO4 (286.13 mg, 1.35 mmol) in dioxane (10 mL) and H2O (1 mL) was stirred at 90°C for 16 hours. After cooling to room temperature, the mixture was concentrated to obtain the residue, which was then subjected to preparative HPLC (Xtimate C). 18 (150 mm × 25 mm, 5 μm); A = H2O (0.05% NH4OH) and B = CH3CN; purified over 10 minutes by 45-75% B) to obtain compound 29 (72.61 mg, 192.48 μmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.79(d,1H),8.34(dt,2H),7.74(d,1H),7.03(d,1H),5.90(td,1H),1.56(d,3H). LCMS R using Method A t =1.21 min, MS ESI C 14 H 10 F6N5O[M+H] +Calculated value: 378.1; Measured value: 377.9.

[0451] Example 30: Synthesis of Compound 30 [ka] In dioxane (3 mL) and H2O (1 mL), A-1 (150.00 mg, 673.98 μmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (204.27 mg, 673.98 μmol), and K3PO4 (286.13 mg, 1.35 mmol) The mixture with Pd(t-Bu3P)2 (34.44 mg, 67.40 μmol) was stirred in a microwave reactor at 90°C for 45 minutes. After cooling to room temperature, the mixture was diluted with HCl (10 mL), filtered through Celite, and eluted with HCl (10 mL x 3). The combined organic phase was washed with brine (10 mL), dried on Na2SO4, filtered, and concentrated to obtain the residue, which was purified by flash chromatography on silica gel (HCl = 20%~40%~60% in DCM), and powdered from i-Pr2O (3 mL) to obtain compound 30 (33.50 mg) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.80(d,1H),8.40-8.31(m,2H),7.75(d,1H),7.09(d,1H),4.88(q,2H). LCMS R using Method B t =0.84 min, MS ESI C 13 H8F6N5O[M+H] + Calculated value: 364.1; Measured value: 364.0.

[0452] Example 31: Synthesis of Compound 31 [ka] A mixture of A-1 (150.00 mg, 673.98 μmol), [3-fluoro-4-(trifluoromethoxy)phenyl]boronic acid (181.10 mg, 808.78 μmol), Pd(dppf)Cl2.CH2Cl2 (82.56 mg, 101.10 μmol), and Cs2CO3 (439.19 mg, 1.35 mmol) in dioxane (3 mL) and H2O (300 μL) was stirred at 90°C for 16 hours. The mixture was cooled to room temperature, diluted with HCl (30 mL), filtered through silica gel, and eluted with HCl (10 mL). The filtrate was concentrated to obtain the residue, which was then subjected to preparative HPLC (Xtimate C). 18 (150 mm × 25 mm, 5 μm); A = H2O (0.05% NH4OH) and B = CH3CN; purified over 10 minutes by 46-76% B) to obtain compound 31 (35.50 mg) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.37(d,1H),7.93(dd,1H),7.87-7.82(m,1H),7.74(d,1H),7.54(t,1H). LCMS R using Method A t =1.21 min, MS ESI C 13 H6F7N4O[M+H] + Calculated value: 367.0; Measured value: 366.9.

[0453] Example 32: Synthesis of Compound 32 [ka] Synthesis of A-52: Under N2 conditions, a mixture of [2-chloro-5-(trifluoromethoxy)phenyl]boronic acid (4.81 g, 20.00 mmol), NiI2 (312.53 mg, 1.00 mmol), and (1R,2R)-2-aminocyclohexanol (115.18 mg, 1.00 mmol) was prepared in i-PrOH (20 mL). NaHMDS (1 M, 20.00 mL) was added, and the mixture was stirred at 25°C for 10 minutes. A solution of 3-iodooxetane (1.84 g, 10.00 mmol) in i-PrOH (1 mL) was added, and the mixture was stirred at 80°C for 40 minutes under microwave conditions. After cooling to room temperature, the reaction of the mixture was stopped with a saturated solution of NH4Cl (30 mL), and the mixture was extracted with ELISA (50 mL x 2). The combined organic phases were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by flash chromatography on silica gel (Â in PE = 0%~2.5%~5%) to obtain A-52 (820.00 mg) as oil. 1 1H NMR (400MHz, CDCl3)δ H =7.39(d,1H),7.29(d,1H),7.11(dd,1H),5.13-5.06(m,2H),4.84-4.77(m,2H),4.67-4.57(m,1H).

[0454] Synthesis of A-53: A mixture of A-52 (800.00 mg, 3.17 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (2.41 g, 9.51 mmol), Pd2(dba)3 (290.28 mg, 317.00 μmol), XPhos (377.80 mg, 792.50 μmol), and KOAc (622.21 mg, 6.34 mmol) in dioxane (30 mL) was stirred at 90°C for 16 hours under N2. After cooling to room temperature, the mixture was concentrated to obtain the residue, which was dissolved in H2O (30 mL) and extracted with ELISA (50 mL x 2). The combined organic phases were washed with water (20 mL x 2) and brine (20 mL), dried on Na2SO4, filtered, and the residue was purified by flash chromatography on silica gel (Â in PE = 0%~2%~3%) to obtain A-53 (500 mg, crudely purified) as oil. The crude product was used directly in the next step without further purification.

[0455] Synthesis of Compound 32: In a 20 mL sealed tube under N2 conditions, a mixture of A-53 (500.00 mg, 1.45 mmol), A-1 (70.00 mg, 314.52 μmol), Pd(t-Bu3P)2 (24.11 mg, 47.18 μmol), and K3PO4 (133.53 mg, 629.04 μmol) in dioxane (6 mL) and H2O (600 μL) was stirred at 80°C for 12 hours. After cooling to room temperature, the mixture was concentrated, the residue was diluted with H2O (20 mL), and extracted with SiO2 (30 mL x 2). The combined organic phase was washed with water (15 mL x 2) and brine (20 mL), dried over Na2SO4, filtered, and... The compound 32 (25.11 mg) was purified by preparative TLC (silica gel, dimethyl:PE = 1:1) to obtain the solid. 1 1H NMR (400MHz, CDCl3)δ H=8.36(d,1H),7.68(d,1H),7.55(d,1H),7.43(d,1H),7.35(dd,1H),5.00-4.94(m,2H),4.72-4.66(m,2H),4.65-4.56(m,1H). LCMS R using Method A t =1.14 min, MS ESI C 16 H 11 F6N4O2[M+H] + Calculated value: 405.1; Measured value: 405.2.

[0456] Example 33: Synthesis of Compound 33 [ka] Synthesis of A-54: A mixture of A-2 (3.00 g, 20.75 mmol) and 2-chloro-2,2-difluoroacetic acid (2-chloro-2,2-difluoroacetyl) (5.55 g, 22.83 mmol) in toluene (30 mL) was stirred at 110 °C for 3 hours. The mixture was concentrated, dissolved in saturated NaHCO3 (50 mL), and extracted with ethyl acetate (150 mL x 2). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to obtain A-54 (3.60 g, 15.06 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.22(d,1H), 7.35(d,1H). LCMS R using Method B. t =0.69 min, MS ESI C6H3Cl2F2N4[M+H] + Calculated value: 239.0; Measured value: 238.9.

[0457] Synthesis of A-55: A mixture of A-54 (400.00 mg, 1.67 mmol), [2-methoxy-4-(trifluoromethoxy)phenyl]boronic acid (394.04 mg, 1.67 mmol), Pd(t-Bu3P)2 (128.02 mg, 250.50 μmol), and K3PO4 (708.98 mg, 3.34 mmol) in dioxane (14 mL) and H2O (2 mL) was stirred at 80°C for 16 hours under N2. After cooling to room temperature, the mixture was concentrated, diluted with H2O (50 mL), and extracted with ELISA (100 mL x 2). The combined organic phases were washed with water (30 mL x 2) and brine (50 mL), dried on Na2SO4, filtered, concentrated, and the crude product was purified by flash chromatography on silica gel (siRNA in PE = 20%~40%~60%) to obtain A-55 (400.00 mg) as a solid. 1 1H NMR (400MHz CDCl3)δ H =8.19(d,1H),7.87-7.78(m,2H),7.04(d,1H),6.92(s,1H),3.95(s,3H).

[0458] Synthesis of compound 33: A mixture of A-55 (120.00 mg, 304.04 μmol) in MeOH (3 mL) and CH3CN (4 mL) is mixed with AgOTf (390.61 mg, 1.52 mmol) was added, and the mixture was stirred at 95°C for 120 hours. The mixture was then diluted with H2O (20 mL) and extracted with siRNA (50 mL x 2). The combined organic phase was washed with water (20 mL x 2), dried on Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative TLC (silica gel, siRNA:PE = 1:2), powdered from i-pr2O (1 mL), and dried to obtain compound 33 (18.04 mg) as a solid. 1 1H NMR (400MHz CDCl3)δ H =8.14(d,1H),7.80(d,1H),7.73(d,1H),7.03(d,1H),6.90(s,1H),3.93(s,3H),3.90(s,3H). LCMS using Method A. R t=1.16 min, MS ESI C 15 H 12 F5N4O3[M+H] + Calculated value: 391.1; Measured value: 391.0.

[0459] Example 34: Synthesis of Compound 34 [ka] AgOTf (390.61 mg, 1.52 mmol) was added to a mixture of A-55 (120.00 mg, 304.04 μmol) and cyclopropyl methanol (1.93 mL, 24.32 mmol) in CH3CN (4 mL), and the mixture was stirred at 95°C for 120 hours. The mixture was then diluted with H2O (20 mL) and extracted with siRNA (50 mL × 2). The combined organic phase was washed with water (20 mL × 2), dried over Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by preparative TLC (silica gel, siRNA:PE=1:2) and preparative HPLC (Kromasil (150 mm × 25 mm, 10 μm); A=H2O (0.05% NH4OH) and B=CH3CN; 48-78% B over 8 minutes) to obtain compound 34 (3.52 mg) as a solid. 1 1H NMR (400MHz DMSO-d6)δ H =8.51(d,1H),7.84(d,1H),7.71(d,1H),7.29(s,1H),7.19(d,1H),3.97(d,2H),3.91(s,3H),1.21-1.12(m,1H),0.59-0.52(m,2H),0.36-0.29(m,2H). LCMS R using Method A t =1.24 min, MS ESI C 18 H 16 F5N4O3[M+H] + Calculated value: 431.1; Measured value: 430.9.

[0460] Example 35: Synthesis of Compound 35 [ka] A mixture of A-1 (1.00 g, 4.49 mmol), [2-chloro-5-(trifluoromethoxy)phenyl]-boronic acid (1.19 g, 4.94 mmol), Pd(t-Bu3P)2 (344.44 mg, 673.50 μmol), and K3PO4 (1.91 g, 8.98 mmol) in dioxane (30 mL) and H2O (4 mL) was prepared under N2 conditions. The mixture was stirred at 0°C for 16 hours. The mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with brine (50 mL), dried on Na2SO4, filtered, concentrated, and purified by flash chromatography on silica gel (ethyl acetate in PE = 5%~10%~15%) to obtain a non-pure product. This product was powdered from PE (10 mL), dried, and obtained compound 35 (1.09 g) as a solid. 1 1H NMR (400MHz CDCl3)δ H =8.32(d,1H),7.67(d,1H),7.63(d,1H),7.53(d,1H),7.41(dd,1H). LCMS R using Method A t =1.19 min, MS ESI C 13 H6ClF6N4O[M+H] + Calculated value: 383.0; Measured value: 382.8.

[0461] Example 36: Synthesis of Compound 36 [ka] A mixture of compound 35 (50.00 mg, 130.67 μmol), 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (49.21 mg, 392.01 μmol), K2CO3 (27.09 mg, 196.01 μmol), and Pd(PPh3)4 (15.10 mg, 13.07 μmol) in dioxane (3 mL) was stirred at 110 °C for 16 hours. The mixture was cooled to room temperature, diluted with HCl (10 mL), filtered through silica gel, eluted with HCl (5 mL), concentrated, and subjected to preparative HPLC (Xtimate C). 18(150 mm × 25 mm, 5 μm); A = H2O (0.05% NH4OH) and B = CH3CN; purified over 10 minutes by 45-75% B) to obtain compound 36 (33.50 mg) as a solid. 1 1H NMR (400MHz CDCl3)δ H =8.34(d,1H),7.48(d,1H),7.44(d,1H),7.37-7.30(m,2H),2.48(s,3H). LCMS R using Method A. t =1.19 min, MS ESI C 14 H9F6N4O[M+H] + Calculated value: 363.1; Measured value: 362.8.

[0462] Example 37: Synthesis of Compound 37 [ka] Synthesis of A-56: NaH (540.00 mg, 13.50 mmol, 60% purity) was gradually added to a solution of 2,2,2-trifluoroethanol (971.22 μL, 13.49 mmol) in DMF (20 mL) at 0°C, and the mixture was stirred at 0°C for 30 minutes. Then 3-bromo-6-chloro-2-methoxypyridine (700.00 mg, 3.15 mmol) was added, and the mixture was stirred at 35°C for 16 hours. The reaction of the mixture was then stopped with a saturated solution of NH4Cl (60 mL), and extracted with  (50 mL x 2). The combined organic phase was washed with brine (30 mL), dried on Na2SO4, filtered, concentrated, and the residue was purified by flash chromatography (PE) on silica gel to obtain A-56 (600.00 mg) as oil. 1 1H NMR (400MHz CDCl3)δ H =7.73(d,1H),6.38(d,1H),4.73(q,2H),3.99(s,3H).

[0463] Synthesis of A-57: A mixture of A-56 (500.00 mg, 1.75 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (1.33 g, 5.25 mmol), Pd(dppf)Cl2.CH2Cl2 (285.82 mg, 350.00 μmol), and KOAc (343.49 mg, 3.50 mmol) in dioxane (10 mL) was stirred at 90°C for 16 hours. The mixture was then concentrated, and the residue was purified by flash chromatography on silica gel (Â in PE = 0%~2%) to obtain A-57 as a solid. 1 1H NMR (400MHz, CDCl3)δ H =7.97(d,1H),6.41(d,1H),4.82-4.73(m,2H),3.95(s,3H),1.34(s,12H).

[0464] Synthesis of Compound 37: A mixture of A-57 (299.35 mg, 898.64 μmol), A-1 (100.00 mg, 449.32 μmol), K3PO4 (190.75 mg, 898.64 μmol), and Pd(t-Bu3P)2 (45.92 mg, 89.86 μmol) in dioxane (10 mL) and H2O (900 μL) was stirred at 80°C for 16 hours. The mixture was then concentrated and purified by preparative HPLC (Kromasil (150 mm × 25 mm, 10 μm); A=H2O (0.05% NH4OH) and B=CH3CN; 53-63% B over 8 minutes) to obtain Compound 37 (53.76 mg) as a solid. 1 1H NMR (400MHz CDCl3)δ H =8.27-8.18(m,2H),8.01(d,1H),6.68(d,1H),4.85(q,2H),4.08(s,3H). LCMS R using Method B t =0.91 min, MS ESI C 14 H 10 F6N5O2[M+H] + Calculated value: 394.1; Measured value: 394.1.

[0465] Example 38: Synthesis of Compound 38 [ka] Synthesis of A-58: To a mixture of A-24 (500.00 mg, 786.89 μmol) in THF (10 mL), n-BuLi (2.5 M, 377.71 μL) was added at 0°C under N2. The reaction mixture was stirred at 0°C for 30 minutes, then tetrahydropyran-3-one (196.96 mg, 1.97 mmol) was added. The mixture was stirred at 20°C for 16 hours. The reaction of the mixture was stopped with NH4Cl (50 mL), and extracted with  (50 mL × 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and the residue was purified by flash chromatography on silica gel (Â:PE = 2:1) to obtain A-58 (100.00 mg) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.20(dd,1H),8.08-8.04(m,2H),7.54(dd,1H),7.42(d,2H),6.74(d,1H),5.02(s ,1H),4.35(s,1H),3.95-3.83(m,2H),3.33(t,1H),2.70(t,1H),1.97-1.86(m,2H).

[0466] Synthesis of Compound 38: A mixture of A-58 (100.00 mg, 265.72 μmol) and Pd / C (80.00 mg) in à (20 mL) under N2 was degassed and refilled with H2. The mixture was stirred at 25°C for 2 hours under an H2 balloon (15 psi). The mixture was diluted with à (10 mL), filtered through silica gel, eluted with à (5 mL), concentrated, and the residue was subjected to preparative HPLC (Xtimate C). 18 (150 mm × 25 mm, 5 μm); A = H2O (0.05% NH4OH) and B = CH3CN; purified over 10 minutes by 40-70% B) to obtain compound 38 (42.50 mg, 110.71 μmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H=8.21-8.16(m,1H),8.06-8.02(m,2H),7.56-7.50(m,1H),7.42(d,2H),3.97(dd,1H),3.87(td,1H),3.52-3.42(m,1H),3.40-3.27(m,1H),3.20(d,2H),2.41(tdd,1H),1.99-1.89(m,1H),1.74-1.59(m,2H),1.49-1.37(m,1H). LCMS R using Method A t =1.12 min, MS ESI C 18 H 18 F3N4O2[M+H] + Calculated value: 379.1; Measured value: 378.9.

[0467] Example 39: Synthesis of Compound 39 [ka] Synthesis of A-59: To a mixture of A-24 (500.00 mg, 786.89 μmol) in THF (10 mL), n-BuLi (2.5 M, 377.71 μL) was added at 0°C under N2. The reaction mixture was stirred at 0°C for 30 minutes, then tetrahydropyran-4-one (180.70 μL, 1.97 mmol) was added. The mixture was stirred at 20°C for 16 hours. The reaction of the mixture was stopped with saturated NH4Cl (30 mL), extracted with siRNA (30 mL × 2), washed with brine (15 mL), dried over Na2SO4, filtered, concentrated to obtain the residue, and purified by flash chromatography (siRNA) on silica gel to obtain A-59 (100.00 mg) as a solid. LCMS R using Method B t =0.82 min, MS ESI C 18 H 16 F3N4O2[M+H] + Calculated value: 377.1; Measured value: 377.0.

[0468] Synthesis of Compound 39: A mixture of A-59 (100.00 mg, 265.72 μmol, 1.00 equivalent) and Pd / C (50.00 mg) in à (20.00 mL) under N2 was degassed and refilled with H2. The mixture was stirred at 25°C for 2 hours under an H2 balloon (15 psi). The mixture was diluted with à (10 mL), filtered through silica gel, eluted with à (5 mL), concentrated to obtain the residue, and purified by flash chromatography (Ã) and preparative TLC (silica gel, Ã) to obtain Compound 39 (7.80 mg) as a solid. 1 H NMR (400 MHz, CDCl3) δ H =8.19(d,1H),8.04(d,2H),7.54(d,1H),7.42(br d,2H),3.99(dd,2H),3.47-3.37(m,2H),3.25(d,2H),2.43-2.29(m,1H),1.73(br d,2H),1.58-1.49(m,2H). LCMS R using Method A t =1.12 min, MS ESI C 18 H 18 F3N4O2[M+H] + Calculated value: 379.1; Measured value: 378.9.

[0469] Example 40: Synthesis of Compound 40 [ka] Compound 35 (500.00 mg, 1.31 mmol) and Zn(CN)2 (461.46 mg, 3.93 mmol) were analyzed in a 20 mL sealed tube under N2 conditions using DMF (20 mL). A mixture of Zn (8.57 mg, 131.00 μmol) and Pd(t-Bu3P)2 (133.90 mg, 262.00 μmol) was stirred at 110°C for 36 hours. The mixture was diluted with H2O (50 mL) and extracted with RINKAN (100 mL x 2). The combined organic phase was washed with water (40 mL x 2) and brine (50 mL), dried over Na2SO4, filtered, and concentrated to obtain the residue, which was then subjected to preparative HPLC (Xtimate C).18 (150 mm × 25 mm, 5 μm); A = H2O (0.05% NH4OH) and B = CH3CN; purified by 40-70% B) over 10 minutes to obtain compound 40 (24.90 mg) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.46(d,1H),8.00(d,1H),7.77(d,1H),7.71(s,1H),7.59-7.55(m,1H). LCMS R using Method A t =1.25 min, MS ESI C 14 H6F6N5O[M+H] + Calculated value: 373.0; Measured value: 374.0.

[0470] Example 41: Synthesis of Compound 41 [ka] Synthesis of A-60: A mixture of A-54 (1.00 g, 4.18 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (1.03 g, 5.02 mmol), Pd(t-Bu3P)2 (213.62 mg, 418.00 μmol), and K3PO4 (1.77 g, 8.36 mmol) in dioxane (20 mL) and H2O (2 mL) was stirred at 80°C for 16 hours. The mixture was then concentrated to obtain the residue, which was purified by flash chromatography on silica gel (siRNA in PE = 10%~50%~100%) to obtain A-59 (1.20 g, 2.52 mmol) as a solid. 1 1H NMR (400MHz CDCl3)δ H =8.33(d,1H),8.10(d,2H),7.78(d,1H),7.44(d,2H). LCMS R using Method B t =0.88 min, MS ESI C 13 H7ClF5N4O[M+H] + Calculated value: 365.0; Measured value: 365.0.

[0471] Synthesis of Compound 41: AgOTf (176.15 mg, 685.55 μmol) was added to a mixture of A-59 (50.00 mg, 137.11 μmol) in MeOH (1 mL) and CH3CN (1 mL), and the mixture was stirred at 95°C for 60 hours. The mixture was then diluted with H2O (20 mL) and extracted with HCl (30 mL × 2). The combined organic phase was washed with water (10 mL × 2) and brine (20 mL), dried on Na2SO4, filtered, and concentrated to obtain the residue, which was purified by preparative TLC (silica gel, HCl:PE = 1:1) to obtain Compound 41 (6.42 mg) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.28(d,1H),8.08(d,2H),7.69(d,1H),7.42(d,2H),3.93(s,3H). LCMS R using Method A t =1.14 min, MS ESI C 14 H 10 F5N4O2[M+H] + Calculated value: 361.1; Measured value: 360.9.

[0472] Example 42: Synthesis of Compounds 42 and 43 [ka] A mixture of 2-tetrahydropyran-2-ylacetic acid (498.65 mg, 3.46 mmol) and (6-chloropyridazine-3-yl)hydrazine (500 mg, 3.46 mmol) in DCM (20 mL) was mixed with PyBOP (2.70 g, 5.19 mmol) and DIPEA (1.81 mL, 10.38 mmol). The mixture was stirred at 25°C for 16 hours. The reaction product was diluted with saturated NH4Cl (20 mL), and the mixture was extracted with DCM (20 mL x 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product (2800 mg, 7.83 mmol, crudely purified) as a solid. Chromatography was performed for 1.5 minutes using LCMS R. t =0.67 min, 5~95AB, 75.67% purity, MS ESI C 11 H 16ClN4O2[M+H] + Calculated value: 271.1; Measured value: 271.0.

[0473] A mixture of N'-(6-chloropyridazine-3-yl)-2-tetrahydropyran-2-yl-acetohydrazide (2.80 g, 10.34 mmol) in acetic acid (8 mL) was stirred at 120 °C for 16 hours. After cooling to room temperature, the mixture was concentrated, the residue was diluted with ethyl acetate (20 mL), neutralized to pH=9 with saturated NaHCO3, and extracted with ethyl acetate (20 mL x 2). The combined organic phase was then washed with brine (15 mL), dried over Na2SO4, and concentrated to obtain the crude product. The crude product was purified by flash chromatography on silica gel (ethyl acetate in PE = 50%~70%~100%) to obtain the product (420 mg) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.05(d,1H),7.08(d,1H),4.02-3.90(m,2H),3.48-3.39(m,2H),3.30 -3.22(m,1H),1.91-1.81(m,1H),1.77-1.71(m,1H),1.64-1.42(m,4H).

[0474] A mixture of 6-chloro-3-(tetrahydropyran-2-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazine (420 mg, 1.66 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (410.72 mg, 1.99 mmol), Pd(t-Bu3P)2 (169.88 mg, 0.33 mmol), and K3PO4 (705.71 mg, 3.32 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was stirred at 80°C for 16 hours under N2. After cooling to room temperature, the mixture was concentrated, the residue was diluted with NH4Cl (20 mL), and extracted with ELISA (20 mL x 2). The combined organic phase was then washed with brine (15 mL), dried over Na2SO4, and concentrated. Crude product was obtained. The crude product was purified by flash chromatography with silica gel (siRNA in PE = 70% to 100%) to obtain a non-pure product. The non-pure product was then powdered with i-Pr2O (10 mL) to obtain the solid product (440 mg, 70% yield). 1 1H NMR (400MHz, CDCl3)δ H =8.17(d,1H),8.05(d,2H),7.52(d,1H),7.41(d,2H),4.10-3.93(m,2H),3.61-3.52(m,1H),3 .51-3.42(m,1H),3.40-3.31(m,1H),1.93-1.83(m,1H),1.80-1.72(m,1H),1.58-1.44(m,4H).

[0475] The product was separated by SFC (C2 (250mm × 30mm, 10μm); A=CO2 and B=EtOH (0.1%NH3H2O); 38℃; 60mL / min; 20%B; run for 10 minutes; 12 injections, peak 1 Rt=7.2 min, peak 2 Rt=8.8 min) and obtained as a solid: 3-[[(2R)-tetrahydropyran-2-yl]methyl]-6-[4-(trifluoromethoxy)phenyl]-[1,2,4] The product of triazolo[4,3-b]pyridazine (133.87 mg) (peak 1 in SFC, Rt = 6.26 min) and the solid 3-[[(2S)-tetrahydropyran-2-yl]methyl]-6-[4-(trifluoromethoxy)phenyl]-[1,2,4]triazolo[4,3-b]pyridazine (135.71 mg, 0.37 mmol (peak 2 in SFC: Rt = 6.93 min)) were obtained. Note: Enantiomers were assigned randomly. Compound 42: 1 1H NMR (400MHz, DMSO-d6+D2O)δ H =8.37(d,1H),8.22(d,2H),7.89(d,1H),7.58(d,2H),3.96-3.86(m,1H),3.82-3.73(m,1H),3.40-3.23(m,3H),1.80-1.64(m,2H),1.51-1.31(m,4H). LCMS R by 2 minutes chromatography. t=1.29 min, 10~80 AB, 100% purity, MS ESI C 18 H 18 F3N4O2[M+H] + Calculated value: 379.1; Measured value: 379.0. Compound 43: 1 1H NMR (400MHz, DMSO-d6+D2O)δ H =8.26(d,1H),8.16(d,2H),7.84(d,1H),7.58-7.47(m,2H),3.95-3.85(m,1H) ,3.79-3.68(m,1H),3.39-3.22(m,3H),1.76-1.61(m,2H),1.45-1.28(m,4H). LCMS R by chromatography for 2 minutes t =1.29 min, 10~80 AB, 100% purity, MS ESI C 18 H 18 F3N4O2[M+H] + Calculated value: 379.1; Measured value: 379.0.

[0476] Example 43: Synthesis of compounds 44, 45, and 46 [ka] A mixture of A-18 (100.00 mg, 433.65 μmol), [4-(trifluoromethoxy)-phenyl]boronic acid (98.23 mg, 477.02 μmol), Pd(t-Bu3P)2 (22.16 mg, 43.37 μmol), and K3PO4 (184.10 mg, 867.30 μmol) in dioxane (2 mL) and H2O (200 μL) was stirred at 85°C for 16 hours. The mixture was diluted with HCl (10 mL), filtered through silica gel, eluted with HCl (10 mL), concentrated to obtain the residue, and purified by preparative HPLC (Xbridge (150 mm × 25 mm, 5 μm); A=H2O (0.05% NH4HCO3) and B=CH3CN; 5-65% B over 10 minutes) to obtain compound 44 (25.89 mg, 72.67 μmol) as a solid. 1 1H NMR (400MHz, MeOD-d4)δ H=8.31(d,1H),8.29-8.22(m,2H),7.98(d,1H),7.51(d,2H),3.62-3.46(m,1H),2.58-2.41(m,1H),2.37-2.25(m,1H). LCMS R using Method A t =1.13 min, MS ESI C 15 H 10 F5N4O[M+H] + Calculated value: 357.1; measured value: 356.9. Compound 44 was purified by SFC (Chiralcel AD (250 mm × 30 mm, 5 μm); A = CO2 and B = EtOH (0.1% NH3H2O); 38°C; 50 mL / min; 15% B over 10 minutes; multiple injections) to obtain enantiomer 1, randomly assigned as compound 45 (Rt = 7.0 min), and enantiomer 2, randomly assigned as compound 46 (Rt = 8.2 min). Compound 45 (120.64 mg) 1 ¹H NMR (400MHz, CDCl3) δ = 8.21 (d,1H), 8.07 (d,2H), 7.59 (d,1H), 7.43 (d,2H), 3.39-3.29 (m,1H), 2.71-2.60 (m,1H), 2.23-2.13 (m,1H). LCMS R using Method A. t =1.22 min, MS ESI C 15 H 10 F5N4O[M+H] + Calculated value: 357.1; Measured value: 357.0. Compound 46 (130.7 mg) 1 ¹H NMR (400MHz, CDCl3) δ = 8.21 (d,1H), 8.07 (d,2H), 7.59 (d,1H), 7.43 (d,2H), 3.40-3.28 (m,1H), 2.71-2.61 (m,1H), 2.24-2.13 (m,1H). LCMS R using Method A. t =1.22 min, MS ESI C 15 H 10 F5N4O[M+H] + Calculated value: 357.1; Measured value: 357.0.

[0477] Example 44: Synthesis of Compound 47 [ka] Synthesis of A-64: A mixture of A-63 (10.00 g, 67.12 mmol) in EtOH (80 mL) was stirred at 80°C for 16 hours under N2. The mixture was concentrated to obtain the crude product, which was then powdered with H2O (20 mL) to obtain A-64 (1.60 g, 11.07 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.10-8.01(m,2H),6.03(br s,1H),3.85(br s,2H).

[0478] Synthesis of A-65: A mixture of A-64 (1.99 g, 11.42 mmol) in toluene (20 mL) was stirred at 120°C for 72 hours. The mixture was diluted with H2O (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain the residue, which was purified by flash chromatography on silica gel (ethyl acetate:PE = 5:1 to 1:1) to obtain A-65 (600.00 mg) as a solid. LCMS R using Method B t =0.19 min, MS ESI C6H4ClF2N4[M+H] + Calculated value: 205.0; Measured value: 204.8.

[0479] Synthesis of Compound 47: A mixture of A-65 (50.00 mg, 244.43 μmol), [4-(trifluoromethoxy)phenyl]boronic acid (50.33 mg, 244.43 μmol), K3PO4 (103.77 mg, 488.85 μmol), and Pd(t-Bu3P)2 (24.98 mg, 48.89 μmol) in dioxane (2 mL) and H2O (200 μL) was heated to 85°C under N2 and stirred for 16 hours. After cooling, the mixture was diluted with HCl (10 mL), filtered through a Celite pad, and eluted with HCl (10 mL). The filtrate was concentrated and the residue was subjected to preparative HPLC (Xtimate C). 18(150 mm × 25 mm, 5 μm); A = H2O (0.05% NH4OH) and B = CH3CN; purified over 10 minutes by 42-72% B) to obtain compound 47 (3.04 mg, 9.21 μmol) as a solid. 1 1H NMR (400MHz DMSO-d6)δ H =9.69(s,1H),9.23(s,1H),8.25(d,2H),7.85(t,1H),7.56(d,2H). LCMS R using Method B t =0.82 min, MS ESI C 13 H8F5N4O[M+H] + Calculated value: 331.1, measured value: 330.9.

[0480] Example 45: Synthesis of Compound 48 [ka] A mixture of A-65 (100.00 mg, 488.85 μmol, 1.00 equivalent), [2-methoxy-4-(trifluoromethoxy)phenyl]boronic acid (115.35 mg, 488.85 μmol), K3PO4 (207.54 mg, 977.70 μmol), and Pd(t-Bu3P)2 (49.97 mg, 97.77 μmol) in dioxane (3 mL) and H2O (300 μL) was heated to 85°C under N2 and stirred for 16 hours. The reaction mixture was diluted with HCl (10 mL), filtered through a Celite pad, and eluted with HCl (10 mL). The filtrate was concentrated, and the residue was purified by preparative TLC (silica gel, PE:HCl = 1:1) to obtain compound 48 (13.14 mg, 36.48 μmol) as a solid. 1 1H NMR (400MHz MeOD-d4)δ H =9.54(d,1H),9.18(d,1H),8.33(d,1H),7.60(t,1H),7.15-7.07(m,2H),4.04(s,3H). LCMS R using Method A t =1.16 min, MS ESI C 14 H 10 F5N4O2[M+H] + Calculated value: 361.1; Measured value: 360.9.

[0481] Example 46: Synthesis of Compound 49 [ka] A mixture of A-65 (50.00 mg, 244.42 μmol), [2-methyl-4-(trifluoromethoxy)phenyl]boronic acid (59.14 mg, 268.86 μmol), K3PO4 (103.77 mg, 488.84 μmol), and Pd(t-Bu3P)2 (24.98 mg, 48.88 μmol) in dioxane (2 mL) and H2O (200 μL) was stirred at 80°C for 16 hours under N2. The mixture was diluted with HCl (5 mL), filtered through silica gel, and eluted with HCl (10 mL). The filtrate was concentrated to obtain the residue, which was then subjected to preparative HPLC (Xtimate C). 18 (150 mm × 25 mm, 5 μm); A = H2O (0.05% NH4OH) and B = CH3CN; purified by 40-70% B) over 10 minutes to obtain compound 49 (7.26 mg) as a solid. 1 1H NMR (400MHz, MeOD-d4)δ H =9.52(d,1H),8.62(d,1H),7.70-7.43(m,2H),7.32-7.22(m,2H),2.44(s,3H). LCMS R using Method A t =1.27 min, MS ESI C 14 H 10 F5N4O[M+H] + Calculated value: 345.1; Measured value: 344.9.

[0482] Example 47: Synthesis of Compound 50 [ka] A mixture of A-65 (50.00 mg, 244.42 μmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (81.49 mg, 268.86 μmol), K3PO4 (103.77 mg, 488.84 μmol), and Pd(t-Bu3P)2 (24.98 mg, 48.88 μmol) in dioxane (2 mL) and H2O (200 μL) was stirred at 80°C for 16 hours under N2. The mixture was diluted with HCl (5 mL), filtered through silica gel, and eluted with HCl (5 mL). The filtrate was concentrated to obtain the residue, which was then subjected to preparative HPLC (Xtimate C). 18 (150 mm × 25 mm, 5 μm); A = H2O (0.05% NH4OH) and B = CH3CN; purified over 10 minutes with 35-65% B) to obtain compound 50 (18.08 mg) as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H =9.69(s,1H),9.23(s,1H),8.93(d,1H),8.51(dd,1H),7.82(t,1H),7.20(d,1H),5.09(q,2H). LCMS R using Method A t =1.20 minutes, MS ESI C 13 H9F5N5O[M+H] + Calculated value: 346.1; Measured value: 345.9.

[0483] Example 48: Synthesis of Compound 51 [ka] A mixture of A-65 (100.00 mg, 488.83 μmol), 2-[4-(1-methoxy-1-methyl-ethyl)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (148.51 mg, 537.71 μmol), Pd2(dba)3 (67.14 mg, 73.32 μmol), XPhos (81.56 mg, 171.09 μmol), and Cs2CO3 (318.54 mg, 977.66 μmol) in dioxane (3 mL) and H2O (300 μL) was stirred at 85°C for 16 hours. The mixture was diluted with toluene (10 mL), filtered through silica gel, eluted with toluene (20 mL), concentrated to obtain the residue, and purified by preparative HPLC (Xbridge (150 mm × 25 mm, 5 μm); A=H2O (0.05% NH4HCO3) and B=CH3CN; 27-57% B over 10 minutes) to obtain compound 51 (43.81 mg) as a solid. 1 1H NMR (400MHz, MeOD-d4)δ H =9.53(d,1H),8.88(d,1H),8.08(d,2H),7.73-7.46(m,3H),3.12(s,3H),1.57(s,6H). LCMS R using Method A t =1.16 min, MS ESI C 16 H 17 F2N4O[M+H] + Calculated value for this: 319. 1; Measured value: 318.9.

[0484] Example 49: Synthesis of Compound 52 [ka] A mixture of A-65 (50.00 mg, 244.42 μmol), 2-[2-fluoro-4-(trifluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (74.81 mg, 244.42 μmol), K3PO4 (103.77 mg, 488.84 μmol), and Pd(t-Bu3P)2 (24.98 mg, 48.88 μmol) in H2O (200 μL) and dioxane (2 mL) was stirred at 80°C for 16 hours under N2. The mixture was diluted with HCl (20 mL), filtered through silica gel, and eluted with HCl (10 mL). The filtrate was concentrated to obtain the residue, which was then subjected to preparative HPLC (Xtimate C). 18 (150 mm × 25 mm, 5 μm); A = H2O (0.05% NH4OH) and B = CH3CN; purified by 40-70% B) over 10 minutes to obtain compound 52 (6.68 mg) as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H =9.72(d,1H),8.96(d,1H),8.17(t,1H),7.87(t,1H),7.64(dd,1H),7.47(d,1H). LCMS R using Method A t =1.28 min, MS ESI C 13 H7F6N4O[M+H] + Calculated value: 349.0; Measured value: 348.9.

[0485] Example 50: Synthesis of Compound 54 [ka] Synthesis of A-69: A mixture of A-68 (1.00 g, 5.29 mmol) and TFAA (1.11 g, 5.29 mmol, 735.80 μL) in toluene (20 mL) was stirred at 110 °C for 16 hours. After cooling to room temperature, the mixture was diluted with H₂O (10 mL) and extracted with ELISA (30 mL x 2). The combined organic phase was washed with brine (15 mL), dried over Na₂SO₄, filtered, and concentrated to obtain A-69 (1.30 g, 4.56 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H=8.87-8.56(m,1H),8.41(s,2H).

[0486] Synthesis of A-70: A mixture of A-69 (300.00 mg, 1.05 mmol) and PPA (6.00 g) was stirred at 165°C for 4 hours. The mixture was then diluted with H2O (20 mL), basicized to approximately pH 9 with Na2CO3 (solids), and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with water (20 mL x 2) and brine (20 mL), dried on Na2SO4, filtered, and concentrated to obtain the residue. This residue was purified by flash chromatography on silica gel (ethyl acetate in PE = 10%~15%) to obtain A-70 (190.00 mg, 630.75 μmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =9.07(d,1H), 8.99(d,1H). LCMS R using Method B. t =0.681 min, MS ESI C6H3BrF3N4[M+H] + Calculated value: 266.9; Measured value: 266.8.

[0487] Synthesis of Compound 54: A mixture of A-70 (100.00 mg, 374.52 μmol), [4-(trifluoromethoxy)phenyl]boronic acid (115.69 mg, 561.78 μmol), Pd(t-Bu3P)2 (28.71 mg, 56.18 μmol), and K3PO4 (159.00 mg, 749.04 μmol) in dioxane (5 mL) and H2O (1 mL) was stirred at 80°C for 16 hours under N2. The mixture was then concentrated to obtain the residue, which was purified by preparative TLC (silica gel, PE:HCl = 2:1) to obtain Compound 54 (7.92 mg) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =9.20(d,1H),9.03(d,1H),7.67(m,2H),7.46(d,2H). LCMS R using Method A t =1.29 min, MS ESI C 13 H7F6N4O[M+H] + Calculated value: 349.0; Measured value: 348.9.

[0488] Example 51: Synthesis of Compound 55 [ka] Synthesis of A-71: A mixture of A-68 (500.00 mg, 2.65 mmol) in CH(OEt)3 (882.54 μL, 5.30 mmol) was stirred at 120°C for 16 hours. The mixture was diluted with EtOH (5 mL), the resulting solid was collected by filtration, washed with EtOH (5 mL x 3), and dried in an oven to obtain A-71 (400.00 mg, 1.99 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.81(s,1H),8.68(d,1H),8.62(d,1H). LCMS R using Method B t =0.15 min, MS ESI C5H4BrN4[M+H+2] + Calculated value: 201.0; Measured value: 200.9.

[0489] Synthesis of compound 55: A mixture of A-71 (150.00 mg, 753.73 μmol), [4-(trifluoromethoxy)phenyl]boronic acid (232.82 mg, 1.13 mmol), Pd(t-Bu3P)2 (57.78 mg, 113.06 μmol), and K3PO4 (319.99 mg, 1.51 mmol) in dioxane (7 mL) and H2O (2 mL) was stirred at 80°C for 16 hours under N2. The mixture was concentrated to obtain a residue, which was purified by flash chromatography on silica gel (siRNA = 20%~60%~100% in PE) and preparative HPLC (Kromasil (150mm × 25mm, 10μm); A=H2O (0.05%NH4OH) and B=CH3CN; 25~55% B over 8 minutes) to obtain compound 55 (17.21mg, 60.66μm) as a solid. We obtained (ol). 1 1H NMR (400MHz CDCl3)δ H=9.08(d,1H),9.01(d,1H),8.58(s,1H),7.69-7.63(m,2H),7.43(d,2H). LCMS R using Method A t =1.10 min, MS ESI C 12 H8F3N4O[M+H] + Calculated value: 281.1; Measured value: 280.9.

[0490] Example 52: Synthesis of Compound 56 [ka] Synthesis of A-72: A mixture of A-64 (1 g, 6.92 mmol) and TFAA (1.06 mL, 7.61 mmol) in toluene (20 mL) was stirred at 110 °C for 72 hours. The mixture was cooled to room temperature, concentrated, and the residue was basicized to pH 7-8 with saturated NaHCO3. The mixture was extracted with siRNA (20 mL x 2), the combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. This was purified by flash chromatography on silica gel (MeOH = 0%-5%-10% in DCM) to obtain A-72 (150 mg) as a solid. LCMS R using Method B t =0.41 min, MS ESI C6H3ClF3N4[M+H] + Calculated value: 223.0; Measured value: 222.8.

[0491] Synthesis of compound 56: A mixture of A-72 (100 mg, 449.33 μmol), [4-(trifluoromethoxy)phenyl]boronic acid (111.03 mg, 539.19 μmol), Pd(t-Bu3P)2 (34.44 mg, 67.40 μmol), and K3PO4 (190.76 mg, 898.65 μmol) in dioxane (3 mL) and H2O (0.3 mL) was stirred at 80°C for 16 hours. The mixture was cooled to room temperature, diluted with HCl (5 mL), filtered through silica gel, eluted with HCl (10 mL), and the filtrate was concentrated to obtain the crude product. This was purified by preparative HPLC (Waters Xbridge (150 mm × 25 mm, 5 μm); A=H2O (10 mM NH4HCO3) and B=CH3CN; 50-80% B over 10 minutes) to obtain compound 54 (16.13 mg) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =9.60(s,1H),8.42(s,1H),8.04(d,2H),7.41(d,2H). LCMS R using Method A t =1.16 min, MS ESI C 13 H7F6N4O[M+H] + Calculated value: 349.0; Measured value: 348.7.

[0492] Example 53: Synthesis of Compound 57 [ka] Synthesis of A-73: NaH (1.22 g, 30.60 mmol, 60% purity) was added to a solution of 2-(4-bromophenyl)acetonitrile (2.00 g, 10.20 mmol) in THF (20 mL) at 0°C. The mixture was stirred at 0°C for 30 minutes, and then MeI (4.34 g, 30.60 mmol, 1.90 mL, 3.00 equivalents) was added to the mixture. The mixture was stirred at 15°C for 16 hours. The reaction of the mixture was stopped with saturated NH4Cl (50 mL), and extracted with siRNA (50 mL x 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by flash chromatography on silica gel (PE:siRNA = 20:1 to 10:1) to obtain A-73 (400.00 mg) as oil. 1 1H NMR (400MHz, CDCl3)δ H =7.53(d,2H),7.36(d,2H),1.72(s,6H).

[0493] Synthesis of A-74: A mixture of A-73 (400 mg, 1.78 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (543.92 mg, 2.14 mmol), KOAc (525.54 mg, 5.35 mmol), and Pd(dppf)Cl2.CH2Cl2 (218.65 mg, 267.74 μmol) in dioxane (10 mL) was stirred at 90 °C for 16 hours. The mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), filtered through silica gel, eluted with ethyl acetate (10 mL), concentrated to obtain the crude product, which was purified by flash chromatography on silica gel (PE:ethyl = 50:1~20:1~15:1) to obtain A-74 (360 mg) as a solid. 1 1H NMR (400MHz CDCl3)δ H =7.84(d,2H),7.49(d,2H),1.74(s,6H),1.36(s,12H).

[0494] Synthesis of compound 57: A mixture of A-74 (0.1 g, 488.84 μmol), A-70 (159.07 mg, 586.61 μmol), Pd(t-Bu3P)2 (49.96 mg, 97.77 μmol), and K3PO4 (207.53 mg, 977.68 μmol) in dioxane (3 mL) and H2O (0.3 mL) was stirred at 80 °C for 16 hours. The mixture was cooled to room temperature, diluted with HCl (5 mL), filtered through silica gel, eluted with HCl (10 mL), and concentrated to obtain the crude product. The crude product was purified by preparative HPLC (Waters Xbridge (150 mm × 25 mm, 5 μm); A=H2O (10 mM NH4HCO3) and B=CH3CN; 23-53% B over 10 minutes) to obtain compound 57 (15.48 mg) as a solid. 1 1H NMR (400MHz, MeOD-d4)δ H =9.53(d,1H),8.92(d,1H),8.15(d,2H),7.73-7.45(m,3H),1.78(s,6H). LCMS R using Method A t =1.02 min, MS ESI C 16 H 14 F2N5[M+H] + to The calculated value is 314.1; the measured value is 313.9.

[0495] Example 54: Synthesis of Compound 58 [ka] Synthesis of A-75: A mixture of 2-bromo-5-(2,2,2-trifluoroethoxy)pyridine (2 g, 7.81 mmol), Pd(dppf)Cl2.CH2Cl2 (637.95 mg, 781.19 μmol), and Et3N (2.37 g, 23.44 mmol, 3.26 mL) was degassed and repacked with CO. The reaction mixture was stirred at 80°C for 16 hours under CO (50 psi), at which point the desired product was observed by LC-MS. The reaction mixture was diluted with Depositphotos (20 mL), filtered through a Celite pad, eluted with Depositphotos (20 mL), and concentrated. The residue was purified by flash chromatography on silica gel (PE / Depositphotos = 5 / 1 to 2 / 1 to 1 / 1) to obtain A-75 (1.5 g) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.48(d,1H),8.16(d,1H),7.34(dd,1H),4.55-4.38(m,4H),1.45(t,3H).

[0496] Synthesis of A-76: Under N2 conditions, n-BuLi (2.5M, 1.61mL) was added dropwise to a solution of [methoxy(methyl)phosphoryl]oxymethane (548.66 mg, 4.42 mmol, 472.99 μL) in THF (15 mL) at -70°C, and the reaction mixture was stirred at -70°C for 30 minutes. A-75 (500 mg, 2.01 mmol) was added, and the reaction mixture was stirred at -70°C for 1.5 minutes. The reaction was stopped with saturated NH4Cl (20 mL), and extracted with siRNA (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain the residue, which was purified by flash chromatography on silica gel (PE / siRNA = 5 / 1~2 / 1~1 / 1) to obtain A-76 (500 mg, 1.53 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.42(d,1H),8.13(d,1H),7.35(dd,1H),4.50(q,2H),3.99(d,2H),3.81(s,3H),3.78(s,3H).

[0497] Synthesis of A-77: t-BuOK (205.32 mg, 1.83 mmol) was added to a solution of A-76 (460.52 mg, 1.41 mmol) and 2-ethyl oxoethyl acetate (574.75 mg, 2.81 mmol) in THF (10 mL) at 0°C. The reaction mixture was heated at 15°C for 16 minutes. The mixture was stirred for a specified time. The reaction was stopped with saturated NH4Cl (20 mL), extracted with ethyl acetate (20 mL x 3), washed the combined organic phase with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (PE / ethyl acetate = 5 / 1 to 2 / 1) to obtain solid A-77 (350 mg). LCMS R was performed using method B. t =0.84 min, MS ESI C 13 H 13 F3NO4[M+H] + Calculated value: 304.1; Measured value: 304.0.

[0498] Synthesis of A-78: A mixture of A-77 (350 mg, 1.15 mmol, 1 equivalent) and Pd / C (100 mg) in N2 was degassed and repacked with H2 (15 psi). The reaction mixture was stirred at 15°C for 2 hours under H2 (15 psi). The reaction mixture was diluted with  (20 mL), filtered through a Celite pad, and eluted with  (10 mL). The filtrate was concentrated to obtain A-78 (300 mg) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.29(t,1H),7.31(d,2H),4.85-4.76(m,1H),4.42(q,2H),4.13(q,2H) ,2.58-2.36(m,2H),2.25-2.13(m,1H),2.01-1.90(m,1H),1.26(t,3H).

[0499] Synthesis of A-79: Dess-Martin (621.17 mg, 1.46 mmol) was added to a solution of A-78 (300 mg, 976.36 μmol, 1 equivalent) in DCM (10 mL). The reaction mixture was stirred at 15°C for 2 hours. The reaction mixture was treated with saturated Na2SO3 (10 mL) and extracted with DCM (20 mL x 3). The combined organic phase was washed with saturated NaHCO3 (10 mL), dried over Na2SO4, filtered, concentrated, and the residue was purified by flash chromatography on silica gel (PE / siRNA = 20 / 1 to 10 / 1 to 5 / 1) to obtain A-79 (230 mg) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.40(d,1H),8.08(d,1H),7.34(dd,1H),4.49(q,2H),4.16(q,2H),3.52(t,2H),2.75(t,2H),1.27(t,3H).

[0500] Synthesis of A-80: A mixture of A-79 (230 mg, 753.48 μmol) and NH2NH2.H2O (188.60 mg, 3.77 mmol) in EtOH (5 mL) was heated to 90°C and stirred for 2 hours. After cooling, the reaction mixture was concentrated, the residue was treated with H2O (10 mL), and the mixture was extracted with RINKAN (10 mL x 3). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain A-80 (200 mg) as a solid. LC-MS R using Method B t =0.68 min, MS ESI C 11 H 11 F3N3O2[M+H] + Calculated value: 274.1; Measured value: 273.9.

[0501] Synthesis of A-81: NaOH (87.84 mg, 2.20 mmol) was added to a mixture of A-80 (150 mg, 549.03 μmol) and sodium 3-nitrobenzenesulfonate (247.23 mg, 1.10 mmol) in H2O (10 mL). The reaction mixture was stirred at 100 °C for 16 hours. After cooling, the reaction mixture was adjusted to pH=8 with a 1 M HCl solution, and then the mixture was extracted with ELISA (20 mL x 3). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain A-81 (80 mg) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =11.29(s,1H),8.42-8.35(m,2H),8.13(d,1H),7.37(dd,1H),7.08(d,1H),4.48(q,2H).

[0502] Synthesis of A-82: A mixture of A-81 (80 mg, 294.99 μmol) in POCl3 (1 mL) was heated to 100°C and stirred for 16 hours. After cooling, the reaction mixture was concentrated, the residue was dissolved in DCM (10 mL), and treated with saturated NaHCO3 to pH=8. The mixture was extracted with DCM (10 mL x 3), the combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain A-82 (70 mg, 241.68 μmol) as a solid. LCMS R was performed using Method B. t =0.79 min, MS ESI C 11 H8ClF3N3O[M+H] + Calculated value: 290.0; Measured value: 289.9.

[0503] Synthesis of A-83: Hydrazine (87.41 μL, 2.42 mmol) was added to a solution of A-82 (70 mg, 241.68 μmol) in EtOH (5 mL). The reaction mixture was stirred at 90°C for 16 hours. After cooling, the reaction mixture was concentrated to obtain crude A-83 (70 mg) as a solid. LC-MS R using Method B t =0.64 min, MS ESI C 11 H 11 F3N5O[M+H]+ Calculated value: 286.1; Measured value: 285.9.

[0504] Synthesis of compound 58: TFAA (34.87 μL, 250.68 μmol) was added to a mixture of A-83 (65 mg, 227.89 μmol) in toluene (5 mL). The reaction mixture was stirred at 110 °C for 16 hours. After cooling, the reaction mixture was concentrated, and the residue was purified by preparative HPLC (Phenomenex Gemini (150 mm × 25 mm, 10 μm); A=H₂O (0.05% NH₄OH) and B=CH₃CN); 45-70% B over 9 minutes) to obtain compound 58 (36.03 mg) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.54-8.48(m,2H),8.45(d,1H),8.30(d,1H),7.47(dd,1H),4.53(q,2H). LCMS R using Method B t =0.82 min, MS ESI C 13 H8F6N5O[M+H] + Calculated value: 364.1; Measured value: 364.0.

[0505] Example 55: Synthesis of Compound 59 [ka] Synthesis of A-84: A mixture of A-1 (200 mg, 0.90 mmol), (4-hydroxyphenyl)boronic acid (185.92 mg, 1.35 mmol), Pd(t-Bu3P)2 (68.88 mg, 0.13 mmol), and K3PO4 (381.02 mg, 1.8 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was stirred at 80 °C for 16 hours under N2. After cooling to room temperature, the mixture was concentrated into a residue, diluted with H2O (30 mL), and extracted with siRNA (50 mL x 5). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by flash chromatography on silica gel (siRNA = 20%~60%~100%) to obtain A-84 (200 mg) as a solid.1 1H NMR (400MHz, DMSO-d6)δ H =10.26(s,1H),8.59(d,1H),8.15(d,1H),8.01(d,2H),6.98(d,2H). LCMS R using Method B t =0.72 min, MS ESI C 12 H8F3N4O[M+H] + Calculated value: 281.1; Measured value: 280.9.

[0506] Synthesis of Compound 59: In THF (2 mL), a mixture of A-84 (40 mg, 0.14 mmol), 3,3-difluorocyclobutanol (18.52 mg, 0.17 mmol), and Ph3P (74.89 mg, 0.29 mmol) was added to a mixture of these at 60°C under N2 conditions. The mixture was stirred at 60°C for 16 hours. After cooling to room temperature, the mixture was concentrated to obtain the crude product, which was then subjected to preparative TLC (silica gel, DCM) and preparative HPLC (Phenomenex Gemini (250 mm × 50 m)). The compound 59 (7.80 mg, 20.8 μmol) was obtained as a solid by purifying it with A=H2O(0.05%NH4OH) and B=CH3CN over 8 minutes to obtain 58-68% B). 1 1H NMR (400MHz, CDCl3)δ H =8.26(d,1H),8.01(d,2H),7.74(d,1H),6.99(d,2H),4.81-4.70(m,1H),3.23-3.10(m,2H),2.90-2.75(m,2H). LCMS R using Method A t =1.29 min, MS ESI C 16 H 12 F5N4O[M+H] + Calculated value: 371.1; Measured value: 371.0.

[0507] Example 56: Synthesis of Compound 60 [ka] Synthesis of A-85: To a toluene (30 mL) solution of 2-(4-bromophenyl)acetonitrile (5000 mg, 25.5 mmol) and TBAB (328.88 mg, 1.02 mmol), KOH (7155.43 mg, 127.52 mmol) (75% in water) was added, followed by the addition of 1,3-dibromopropane (10298.41 mg, 51.01 mmol). The mixture was stirred at 100°C for 2 hours. The mixture was then poured into water (50 mL) and extracted with  (100 mL x 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. This was purified by flash chromatography on silica gel (DCM in PE = 20%~40%~60%) to obtain the solid, which was A-85 (1600 mg). 1 1H NMR (400MHz, DMSO-d6)δ H =7.64(d,2H),7.43(d,2H),2.78-2.70(m,2H),2.64-2.56(m,2H),2.27(m,1H),2.05-1.95(m,1H).

[0508] Synthesis of A-86: A mixture of A-85 (1600 mg, 6.78 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (5162.48 mg, 20.33 mmol), KOAc (1330.09 mg, 13.55 mmol), and Pd(dppf)Cl2.CH2Cl2 (829.44 mg, 1.02 mmol) in 1,4-dioxane (20 mL) was stirred at 90°C for 16 hours. After cooling to room temperature, the mixture was filtered through a Celite pad, extracted with ethyl acetate (50 mL x 2), concentrated to obtain the residue, and purified by flash chromatography on silica gel (ethyl acetate in PE = 5%~15%~60%). The impure product was powdered from i-Pr2O (20 mL) and dried in an oven to obtain A-86 (1250 mg, 4.41 mmol) as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H=7.85(d,2H),7.43(d,2H),2.90-2.78(m,2H),2.70-2.59(m,2H),2.45(m,1H),2.09(m,1H),1.36(s,12H).

[0509] Synthesis of compound 60: A mixture of A-86 (152.68 mg, 0.54 mmol), A-1 (100 mg, 0.45 mmol), K3PO4 (181.52 mg, 0.90 mmol), and Pd(t-Bu3P)2 (45.92 mg, 0.09 mmol) in 1,4-dioxane (7 mL) and water (1 mL) was stirred at 90°C for 16 hours. After cooling to room temperature, the mixture was concentrated and purified by preparative TLC (silica gel, PE:siRNA = 1:1) to obtain the crude product, which was powdered from i-Pr2O (10 mL) and dried in an oven to obtain compound 60 (58.8 mg, 0.17 mmol) as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H =8.33(d,1H),8.08(d,2H),7.79(d,1H),7.66(d,2H),2.97-2.86(m,2H),2.74-2.65(m,2H),2.58-2.45(m,1H),2.23-2.10(m,1H). LCMS R using Method A t =1.29 min, MS ESI C 17 H 13 F3N5[M+H] + Calculated value: 344.1; Measured value: 343.9.

[0510] Example 57: Synthesis of Compound 61 [ka] Synthesis of A-87: A mixture of A-2 (300 mg, 2.08 mmol) and 1-fluorocyclopropanecarboxylic acid (237.59 mg, 2.28 mmol) in DCM (5 mL) was mixed with PyBOP (1618.71 mg, 3.11 mmol) and DIPEA (803.13 mg, 6.23 mmol), and the mixture was stirred at 15°C for 16 hours. The reaction mixture was concentrated, diluted with NH4Cl (50 mL), and extracted with RINKAN (50 mL x 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product of A-87 (2000 mg, 8.68 mmol) as an oil, which was used in the next step without further purification.

[0511] Synthesis of A-88: ​​A solution of A-87 (2 g, 8.67 mmol) in acetic acid (10 mL) was sealed and heated in a microwave reactor at 120 °C for 1.5 hours. After cooling to room temperature, the reaction mixture was concentrated, then diluted with saturated NaHCO3 (50 mL), and extracted with DCM (50 mL x 2). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by flash chromatography on silica gel (PE:siRNA = 5:1 to 1:1) to obtain A-88 (250 mg, 1.18 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.12(d,1H),7.21(d,1H),1.75-1.66(m,2H),1.53-1.46(m,2H).

[0512] Synthesis of compound 61: A- in 1,4-dioxane (3 mL) and water (0.3 mL) A mixture of 88 (100 mg, 0.47 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (106.54 mg, 0.5200 mmol), Pd(t-BuP3)2 (36.05 mg, 0.07 mmol), and K3PO4 (129.82 mg, 0.9400 mmol) was stirred at 85°C for 16 hours. The mixture was cooled to room temperature, diluted with RINKAN (5 mL), filtered through silica gel, eluted with RINKAN (10 mL), and concentrated to obtain the crude product. This was purified by preparative HPLC (Phenomenex Gemini (250 mm × 50 mm, 10 μm); A=H2O (0.05% NH4OH) and B=CH3CN; 50-80% B over 8 minutes) to obtain compound 61 (36.2 mg, 0.11 mmol) as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H =8.57(d,1H),8.26(d,2H),8.09(d,1H),7.63(d,2H),1.76-1.62(m,2H),1.51-1.45(m,2H). LCMS R using Method A t =1.23 min, MS ESI C 15 H 11 F4N4O[M+H] + Calculated value: 339.1; Measured value: 338.9.

[0513] Example 58: Synthesis of Compound 62 [ka] To a solution of A-72 (200 mg, 0.90 mmol) in 1,4-dioxane (2 mL) and water (0.20 mL), [4-(trifluoromethyl)phenyl]boronic acid (204.81 mg, 1.08 mmol), Pd(t-Bu3P)2 (68.89 mg, 0.13 mmol), and K3PO4 (381.56 mg, 1.8 mmol) were added. The resulting mixture was stirred at 85°C for 16 hours under N2. The reaction mixture was cooled to room temperature, filtered through Celite, and the filtrate was concentrated to obtain the crude product, which was purified by preparative HPLC (Phenomenex Gemini (250 mm × 50 mm, 10 μm); A=H2O (0.05% NH4OH) and B=CH3CN; 50-80% B over 8 minutes) to obtain compound 62 (38.43 mg, 0.12 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =9.64(s,1H),8.49(s,1H),8.13(d,2H),7.83(d,2H). LCMS R using Method A t =1.22 min, MS ESI C 13 H7F6N4[M+H] + Calculated value: 333.0; Measured value: 332.9.

[0514] Example 59: Synthesis of Compound 63 [ka] To a solution of A-72 (150 mg, 0.6700 mmol) in 1,4-dioxane (3 mL) and water (0.30 mL), [2-methyl-4-(trifluoromethoxy)phenyl]boronic acid (177.89 mg, 0.81 mmol), Pd(t-Bu3P)2 (51.67 mg, 0.10 mmol), and K3PO4 (286.17 mg, 1.35 mmol) were added. The resulting mixture was stirred at 85°C for 16 hours under N2. The reaction mixture was cooled to room temperature, filtered through Celite, concentrated, and purified by preparative HPLC (Phenomenex Gemini (250 mm × 50 mm, 10 μm); A=H2O (0.05% NH4OH) and B=CH3CN; 50-80% B over 8 minutes) to obtain compound 63 (21.69 mg, 0.06 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =9.60(s,1H),8.18(s,1H),7.48(d,1H),7.25-7.19(m,2H),2.44(s,3H). LCMS using Method A R t =1.26 min, MS ESI C 14 H9F6N4O[M+H] + Calculated value: 363.1; Measured value: 363.0.

[0515] Example 60: Synthesis of Compound 64 [ka] A mixture of A-72 (200 mg, 0.90 mmol), A-31 (349.5 mg, 1.17 mmol), Pd(t-Bu3P)2 (68.88 mg, 0.13 mmol), and K3PO4 (340 mg, 1.6 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was stirred at 70°C for 16 hours under N2S. After cooling to room temperature, the mixture was diluted with H2O (30 mL) and extracted with siRNA (50 mL x 2). The combined organic phase was washed with water (20 mL x 2) and brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. The crude product was purified by preparative TLC (silica gel, DCM:MeOH = 100:1), powdered from CH3CN (0.5 mL), and dried in an oven to obtain compound 64 (9.24 mg, 0.03 mmol) as a solid. 1 H NMR (400 MHz, CDCl3) δ H =9.56(s,1H),9.01(s,1H),8.23(d,1H),7.14(s,1H),6.92(dd,1H),4.04(s,3H),1.87-1.81(m,2H),1.54-1.49(m,2H). LCMS R using Method A t =1.16 min, MS ESI C 17 H 13 F3N5O[M+H] + Calculated value: 360.1; Measured value: 360.0.

[0516] Example 61: Synthesis of Compound 65 [ka] Synthesis of A-89: Pd(t-Bu3P)2 (68.88 mg, 0.13 mmol) and K3PO4 (381.02 mg) in 1,4-dioxane (10 mL) and water (2 mL) A mixture of (1.8 mmol), A-1 (200 mg, 0.90 mmol), and (6-fluoro-3-pyridyl)boronic acid (189.94 mg, 1.35 mmol) was stirred at 80°C for 16 hours under N2. After cooling to room temperature, the mixture was concentrated, diluted with H2O (30 mL), and extracted with siRNA (100 mL x 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by flash chromatography on silica gel (siRNA in PE = 20%~60%~100%) to obtain A-89 (140 mg, 0.49 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.87(d,1H),8.53(ddd,1H),8.39(d,1H),7.77(d,1H),7.20(dd,1H).

[0517] Synthesis of Compound 65: NaH (14 mg, 0.35 mmol) was added to a mixture of 3,3-difluorocyclobutanol (28 mg, 0.26 mmol) in THF (5 mL), and the mixture was stirred at 0°C for 10 minutes. A-89 (50 mg, 0.18 mmol) was added to the mixture, and the mixture was stirred at 20°C for 2 hours. The reaction of the mixture was stopped with saturated NH4Cl (10 mL), and extracted with RINKAN (30 mL x 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by preparative TLC (silica gel, PE:RINKAN = 1:3) to obtain Compound 65 (54.57 mg, 0.15 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.79(d,1H),8.36-8.28(m,2H),7.74(d,1H),6.97(d,1H),5.30-5.19(m,1H),3.25-3.12(m,2H),2.86-2.70(m,2H). LCMS R using Method A t =1.21 min, MS ESI C 15 H 11 F5N5O[M+H] + Calculated value: 372.1; Measured value: 372.0.

[0518] Example 62: Synthesis of Compound 66 [ka] Synthesis of A-90: A mixture of A-64 (5 g, 34.59 mmol) and 2,2,2-trifluoroacetaldehyde (5.65 g, 43.23 mmol) in ethanol (25 mL) was stirred at 90°C for 16 hours. After cooling to room temperature, the mixture was concentrated, powdered with n-hexane (20 mL), and dried to obtain A-90 (7500 mg, 33.34 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.50(br s,1H),8.49(d,1H),8.15(d,1H),7.16-7.11(m,1H).

[0519] Synthesis of A-91: A mixture of A-90 (7500 mg, 33.4 mmol) in DMF (30 mL) was mixed with a solution of NBS (6241.93 mg, 35.07 mmol) in DMF (30 mL). The mixture was stirred at 20°C for 1 hour. The mixture was then dissolved in H2O (200 mL). The solution was diluted and extracted with n-hexane (200 mL x 3). The combined organic phase was washed with water (50 mL x 2) and brine (50 mL), dried over Na2SO4, filtered, and concentrated to obtain A-91 (9500 mg, 31.31 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.60(br s,1H),8.47(d,1H),8.21(d,1H).

[0520] Synthesis of A-72: Et3N (6.32 g, 62.61 mmol) was added to a mixture of A-91 (9.5 g, 31.3 mmol) in toluene (20 mL). The mixture was stirred at 20°C for 2 hours. The mixture was diluted with H2O (50 mL) and extracted with siRNA (100 mL x 2). The combined organic phase was washed with water (20 mL x 2) and brine (20 mL), dried on Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by flash chromatography on silica gel (siRNA in PE = 0%~5%~10%) to obtain A-72 (4100 mg, 17.03 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =9.38(d,1H), 8.25(s,1H). LCMS R using Method B. t =0.35 min, MS ESI C6H3ClF3N4[M+H] + Calculated value: 223.0; Measured value: 222.8.

[0521] Synthesis of compound 66: A mixture of A-72 (100 mg, 0.45 mmol), 2-[2-(methoxymethyl)-4-(trifluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (179.07 mg, 0.54 mmol), Pd(dppf)Cl2.CH2Cl2 (55.04 mg, 0.07 mmol), and Cs2CO3 (292.95 mg, 0.90 mmol) in 1,4-dioxane (3 mL) and water (0.50 mL) was stirred at 80°C for 16 hours. The mixture was cooled to room temperature, diluted with toluene (5 mL), filtered through silica gel, eluted with toluene (5 mL), and concentrated to obtain the crude product. This was purified by preparative HPLC (Xbridge (150 mm × 25 mm, 5 μm); A = H2O (0.05% NH4HCO3) and B = CH3CN; 42-72% B over 10 minutes) to obtain compound 66 (85.78 mg, 0.22 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H=9.59(d,1H),8.68(s,1H),7.75(d,1H),7.45(s,1H),7.37(d,1H),4.47(s,2H),3.46(s,3H). LCMS R using Method A t =1.24 min, MS ESI C 15 H 11 F6N4O2[M+H] + Calculated value: 393.1; Measured value: 393.0.

[0522] Example 63: Synthesis of Compound 67 [ka] A mixture of 1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]cyclopropanecarbonitric (199.54 mg, 0.74 mmol), A-72 (150 mg, 0.67 mmol), Pd(dppf)Cl2.CH2Cl2 (82.56 mg, 0.10 mmol), and Cs2CO3 (439.43 mg, 1.35 mmol) in 1,4-dioxane (2 mL) and water (0.20 mL) was prepared in 8 The mixture was stirred at 0°C for 16 hours. The mixture was cooled to room temperature, diluted with toluene (5 mL), filtered through silica gel, eluted with toluene (5 mL), concentrated to obtain the crude product, which was purified by flash chromatography on silica gel (PE:toluene = 5:1 to 1:1) to obtain compound 67 (77.03 mg, 0.24 mmol) as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H =9.76(d,1H),9.01(s,1H),8.20(d,2H),7.49(d,2H),1.86-1.82(m,2H),1.63-1.59(m,2H). LCMS R using Method A t =1.11 min, MS ESI C 16 H 11 F3N5[M+H] + Calculated value: 330.1; Measured value: 329.9.

[0523] Example 64: Synthesis of Compound 68 [ka] Synthesis of A-92: NaH (2.94g, 73.5g) in THF (50mL) To a 6 mmol suspension, 2,2,2-trifluoroethanol (7.36 g, 73.56 mmol) was slowly added at 20°C, and the mixture was stirred for 1 hour. Then, 5-chloro-2,3-difluoropyridine (10 g, 66.88 mmol) was added, and the mixture was stirred for a further 4 hours at 20°C. The reaction of the mixture was stopped with saturated NH4Cl (50 mL), and extracted with siRNA (100 mL x 2). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to obtain A-92 (15000 mg, 65.34 mmol) as oil. 1 1H NMR (400MHz, CDCl3)δ H =7.83(d,1H),7.38(dd,1H),4.73(q,2H).

[0524] Synthesis of A-93: A mixture of A-92 (8 g, 34.85 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (26.55 g, 104.55 mmol), K3PO4 (14.79 g, 69.7 mmol), SPhos (4.29 g, 10.45 mmol), and Pd(OAc)2 (782.4 mg, 3.48 mmol) in 1,4-dioxane (250 mL) was stirred at 85°C for 16 hours. After cooling to room temperature, the mixture was filtered through Celite and eluted with ELISA (50 mL x 2). The filtrate was concentrated, diluted with alkyl hydroxide (200 mL), washed with water (100 mL x 2) and brine (100 mL), dried on Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by flash chromatography on silica gel (alkyl hydroxide in PE = 0%~10%~40%) to obtain A-93 (3 g, 4.6021 mmol) as oil. 1 1H NMR (400MHz, CDCl3)δ H =8.26(d,1H),7.72(dd,1 H), 4.87 (q, 2H), 1.35 (s, 12H). LCMS R using Method B. t =0.94 min, MS ESI C 13 H 17 BF4NO3[M+H] + Calculated value: 322.1; Measured value: 322.3.

[0525] Synthesis of compound 68: A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (163.24 mg, 0.51 mmol), A-65 (80 mg, 0.39 mmol), Pd(dppf)Cl2.CH2Cl2 (39.97 mg, 0.08 mmol), and Cs2CO3 (254.83 mg, 0.78 mmol) in 1,4-dioxane (3 mL) and water (0.50 mL) was stirred at 85°C for 16 hours. After cooling to room temperature, the mixture was filtered through silica gel and eluted with Â(20 mL × 2). The filtrate was concentrated, diluted with toluene (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by preparative TLC (PE:toluene = 1:1) to obtain compound 68 (29.36 mg, 0.0798 mmol) as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H =9.69(s,1H),9.29(s,1H),8.78(d,1H),8.53(dd,1H),7.81(t,1H),5.19(q,2H). LCMS R using Method A t =1.12 min, MS ESI C 13 H8F6N5O[M+H] + Calculated value: 364.1; Measured value: 363.9.

[0526] Example 65: Synthesis of Compound 69 [ka] Synthesis of A-94: The mixture of 2-bromo-1-chloro-4-(trifluoromethoxy)benzene (5.00 g, 18.15 mmol), Pd(dppf)Cl2.CH2Cl2 (1.48 g, 1.82 mmol), and Et3N (7.55 mL, 54.45 mmol) in EtOH (30.00 mL) was degassed and repacked with CO. The reaction mixture was stirred at 80°C for 16 hours under CO (50 psi). The reaction mixture was diluted with EtOH (20 mL), filtered through Celite, concentrated, and flash chromatographed on silica gel (PE). The oil was purified by toluene (0%-5%) to obtain A-94 (2.40 g, 8.93 mmol) as an oil. 1 1H NMR (400MHz, CDCl3)δ H =7.66-7.59(m,1H),7.42(d,1H),7.24-7.19(m,1H),4.36(q,2H),1.35(t,3H).

[0527] Synthesis of A-95: LiAlH4 (406.67 mg, 10.72 mmol) was slowly added to a solution of A-94 (2.40 g, 8.93 mmol) in THF (30 mL) at -40°C. The reaction was stirred at -40°C for 1 hour. The reaction was stopped with saturated NH4Cl (0.4 mL), diluted with siRNA (30 mL), and the resulting solid was filtered through Celite and eluted with siRNA (30 mL). The filtrate was concentrated and purified by flash chromatography on silica gel (siRNA = 0%~10%~20% in PE) to obtain A-95 (1.50 g, 6.62 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =7.45-7.42(m,1H),7.38(d,1H),7.13-7.08(m,1H),4.80(d,2H),2.04(t,1H).

[0528] Synthesis of A-96: NaH (317.76 mg, 7.94 mmol, 60% purity) was slowly added at 0°C to a solution of A-96 (1.50 g, 6.62 mmol, 1.00 equivalent) in THF (20 mL). The mixture was stirred at 0°C for 30 minutes, then MeI (1.24 mL, 19.86 mmol) was added, and the reaction was stirred at 20°C for 16 hours. The reaction of the reaction mixture was stopped with saturated NH4Cl (50 mL), and extracted with Depositphotos (50 mL x 3). The combined organic phase was washed with brine (50 mL), dried on Na2SO4, filtered, concentrated, and the residue was purified by flash chromatography on silica gel ( Depositphotos = 0%~5%~10% in PE) to obtain A-96 (1.40 g, 5.82 mmol) as oil. 1 1H NMR (400MHz CDCl3)δ H =7.43-7.32(m,2H),7.09(dd,1H),4.54(s,2H),3.50(s,3H).

[0529] Synthesis of A-97: In 6 mL of dioxane, a mixture of A-96 (400.00 mg, 1.66 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (505.85 mg, 1.99 mmol), KOAc (325.82 mg, 3.32 mmol), X-Phos (197.84 mg, 415.00 μmol), and Pd2(dba)3 (152.01 mg, 166.00 μmol) was stirred at 80°C for 16 hours under N2. The mixture was cooled to room temperature, concentrated, and the residue was purified by flash chromatography (PE:Â=1:0~50:1) using silica gel to obtain oil A-97 (300.00 mg, 903.29 μmol). LCMS R was then performed using Method B. t =0.99 min, MS ESI C 15 H 21 Calculated value for BF3O4[M+H]+: 333.1; Measured value: 332.7.

[0530] Synthesis of compound 69: A mixture of A-97 (298.46 mg, 898.64 μmol), A-1 (100.00 mg, 449.32 μmol), Pd(t-Bu3P)2 (45.92 mg, 89.86 μmol), and K3PO4 (190.75 mg, 898.64 μmol) was stirred at 80°C for 16 hours under N2. The mixture was cooled to room temperature, diluted with HCl (10 mL), filtered through Celite, eluted with HCl (5 mL), and concentrated to obtain the crude product. This was purified by preparative HPLC (Kromasil (150 mm × 25 mm, 10 μm); A=H2O (0.05% NH4OH) and B=CH3CN; 53-63% B over 8 minutes) to obtain compound 69 (32.30 mg, 81.58 μmol) as a solid. 1 1H NMR (400MHz CDCl3) δ H =8.32(d,1H),7.65-7.55(m,3H),7.35(d,1H),4.65(s,2H),3.37(s,3H). LCMS R using Method B t =0.87 min, MS ESI C 15 H 11 F6N4O2[M+H] + Calculated value: 393.1; Measured value: 392. 9.

[0531] Example 66: Synthesis of Compound 70 [ka] A mixture of [2-methoxy-4-(trifluoromethoxy)phenyl]boronic acid (127.22 mg, 0.54 mmol), A-72 (100 mg, 0.45 mmol), Pd(dppf)Cl2.CH2Cl2 (73.39 mg, 0.09 mmol), and Cs2CO3 (292.77 mg, 0.90 mmol) in 1,4-dioxane (3 mL) and water (0.50 mL) was stirred at 90°C for 16 hours under N2. After cooling to room temperature, the mixture was filtered through silica gel and eluted with Â(20 mL × 2). The filtrate was concentrated, diluted with RINKAN (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. This was purified by preparative HPLC (Phenomenex Gemini (250 mm x 50 mm, 10 μm); A=H2O (0.05% NH4OH) and B=CH3CN; 63-73% B over 8 minutes) to obtain compound 70 (5.62 mg) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =9.57(d,1H),8.98(s,1H),8.28(d,1H),7.05(d,1H),6.92(s,1H),4.01(s,3H). LCMS R using Method A t =1.24 min, MS ESI C 14 H9F6N4O2[M+H] + Calculated value: 379.1; Measured value: 378.9.

[0532] Example 67: Synthesis of Compound 71 [ka] A mixture of A-86 (152.68 mg, 0.54 mmol), A-72 (100 mg, 0.45 mmol), Pd(dppf)Cl2.DCM (73.39 mg, 0.09 mmol), and Cs2CO3 (292.77 mg, 0.90 mmol) in 1,4-dioxane (3 mL) and water (0.50 mL) was stirred at 90°C for 16 hours. After cooling to room temperature, the mixture was filtered through silica gel and eluted with Â(20 mL × 2). The filtrate was concentrated, diluted with ₹ (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried over Na₂SO₄, filtered, and concentrated to obtain the crude product, which was then subjected to preparative HPLC (Phenomenex Gemini (250 mm x 50 mm, 10 μm); A=H₂O (0.05% NH₄OH) and B=CH₃CN; over 8 minutes, 55°C~ The compound was purified using 65% B) to obtain compound 71 (29.77 mg, 0.09 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =9.61(d,1H),8.44(s,1H),8.03(d,2H),7.62(d,2H),2.96-2.86(m,2H),2.74-2.64(m,2H),2.57-2.43(m,1H),2.22-2.09(m,1H). LCMS R using Method A t =1.12 min, MS ESI C 17 H 13 F3N5[M+H] + Calculated value: 344.1; Measured value: 344.0.

[0533] Example 68: Synthesis of Compound 72 [ka] A mixture of 2-[2-fluoro-4-(trifluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (165.02 mg, 0.5400 mmol), A-72 (100 mg, 0.45 mmol), Pd(dppf)Cl2.DCM (73.39 mg, 0.09 mmol), and Cs2CO3 (292.77 mg, 0.90 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) was stirred at 90°C for 16 hours. After cooling to room temperature, the mixture was filtered through silica gel and eluted with ethyl acetate (20 mL x 2). The organic phase was concentrated, diluted with SiO2 (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. This was purified by preparative HPLC (Phenomenex Gemini (250 mm x 50 mm, 10 μm); A=H2O (0.05% NH4OH) and B=CH3CN; 61-71% B over 8 minutes) to obtain compound 72 (36.18 mg, 0.10 mmol) as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H =9.81(d,1H),8.90(s,1H),8.15(t,1H),7.65(d,1H),7.47(d,1H). LCMS R using Method A t =1.23 min, MS ESI C 13 H6F7N4O[M+H] + Calculated value: 367.0; Measured value: 366.9.

[0534] Example 69: Synthesis of Compound 73 [ka] A-72 (100 mg, 0.45 mmol), [2-methyl-4-(trifluoromethyl)phenyl]boronic acid (109.97 mg, 0.54 mmol), and Pd(dppf)Cl2.DCM (73.39) in 1,4-dioxane (3 mL) and water (0.5 mL). A mixture of (mg, 0.09 mmol) and Cs2CO3 (292.77 mg, 0.90 mmol) was stirred at 90°C for 16 hours. After cooling to room temperature, the mixture was filtered through silica gel and eluted with siRNA (20 mL × 2). The filtrate was concentrated, diluted with siRNA (30 mL), washed with water (10 mL × 2) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by preparative HPLC (Phenomenex Gemini (250 mm × 50 mm, 10 μm); A=H2O (0.05% NH4OH) and B=CH3CN; 63-73% B over 8 minutes) to obtain compound 73 (69.69 mg, 0.20 mmol) as an oil. 1 1H NMR (400MHz, CDCl3)δ H =9.61(d,1H),8.21(s,1H),7.65-7.55(m,3H),2.49(s,3H). LCMS R using Method A t =1.19 min, MS ESI C 14 H9F6N4[M+H] + Calculated value: 347.1; Measured value: 346.9.

[0535] Example 70: Synthesis of Compound 74 [ka] A mixture of A-72 (100 mg, 0.45 mmol), (4-ethoxyphenyl)boronic acid (89.49 mg, 0.54 mmol), Pd(dppf)Cl2.DCM (73.39 mg, 0.09 mmol), and Cs2CO3 (146.39 mg, 0.45 mmol) in 1,4-dioxane (3 mL) and water (0.50 mL) was stirred at 90°C for 16 hours. After cooling to room temperature, the mixture was filtered through silica gel and eluted with RINKAN (20 mL x 2). The filtrate was concentrated, diluted with RINKAN (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. This crude product was purified by preparative HPLC (Phenomenex Gemini (250 mm x 50 mm, 10 μm); A=H2O (0.05% NH4OH) and B=CH3CN; 58-68% B over 8 minutes) to obtain compound 74 (31.15 mg, 0.10 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =9.56(d,1H),8.33(s,1H),7.92(d,2H),7.05(d,2H),4.13(q,2H),1.48(t,3H). LCMS R using Method A t =1.13 min, MS ESI C 14 H 12 F3N4O[M+H] + Calculated value: 309.1; Measured value: 308.9.

[0536] Example 71: Synthesis of Compound 75 [ka] Synthesis of A-98: 2-methylpropanoyl chloride (810.77 mg, 7.61 mmol) was added to a mixture of A-64 (1 g, 6.92 mmol) and Et3N (1.91 mL, 13.84 mmol) in DCM (20 mL). The reaction mixture was stirred at 20°C for 16 hours. Saturated NaHCO3 3The reaction of the reaction mixture was stopped with (50 mL) and extracted with DCM (30 mL x 3). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain A-98 (1500 mg, 7.0 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.12(d,1H),7.91(d,1H),7.47(s,1H),6.78(s,1H),2.56-2.47(m,1H),1.25(d,6H).

[0537] Synthesis of A-99: A mixture of A-98 (500 mg, 2.33 mmol), [4-(trifluoromethoxy)-phenyl]boronic acid (527.66 mg, 2.56 mmol), Pd(dppf)Cl2.CH2Cl2 (190.23 mg, 0.23 mmol), and Cs2CO3 (1.52 g, 4.66 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was stirred at 90°C for 16 hours under N2. After cooling, the reaction mixture was diluted with  (20 mL), filtered through a Celite pad, eluted with  (10 mL), concentrated to obtain the residue, and purified by flash chromatography on silica gel ( in PE = 0%~20%~40%) to obtain A-99 (250 mg, 0.73 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.53(d,1H),8.20(d,1H),7.92(d,2H),7.58(d,1H),7.31(d,2H),6.87(d,1H),2.60-2.53(m,1H),1.28(d,6H).

[0538] Synthesis of compound 75: A mixture of A-99 (150 mg, 0.44 mmol) in acetic acid (3 mL) was stirred at 120°C for 16 hours. After cooling, the reaction mixture was concentrated, diluted with saturated NaHCO3 (30 mL), and extracted with siRNA (30 mL x 2). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by flash chromatography on silica gel (siRNA = 0%~20%~40% in PE) to obtain compound 75 (90.4 mg, 0.27 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =9.42(d,1H),8.14(d,1H),8.00(d,2H),7.38(d,2H),3.49(spt,1H),1.61(d,6H). LCMS R using Method A t =1.15 min, MS ESI C 15 H 14 F3N4O[M+H] + Calculated value: 323.1; Measured value: 322.9.

[0539] Example 72: Synthesis of Compound 76 [ka] A mixture of A-72 (100 mg, 0.45 mmol), [2-fluoro-4-(trifluoromethyl)phenyl]boronic acid (112.11 mg, 0.54 mmol), Pd(dppf)Cl2.CH2Cl2 (73.39 mg, 0.09 mmol), and Cs2CO3 (292.77 mg, 0.90 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) was stirred at 90°C for 16 hours under N2. After cooling to room temperature, the mixture was filtered through silica gel and eluted with Â(20 mL × 2). The filtrate was concentrated, diluted with siRNA (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried over Na₂SO₄, filtered, and concentrated to obtain the crude product. This crude product was purified by preparative HPLC (Phenomenex Gemini (250 mm x 50 mm, 10 μm); A=H₂O (0.05% NH₄OH) and B=CH₃CN; 58-68% over 8 minutes) to obtain compound 76 (22.67 mg, 0.06 mmol) as a solid. 1 H NMR (400 MHz, CDCl3) δ H =9.63(d,1H),8.80(s,1H),8.45(t,1H),7.65(d,1H),7.55(d,1H). LCMS R using Method A t =1.18 min, MS ESI C 13 H6F7N4[M+H] + Calculated value: 351.0, measured value: 350.9.

[0540] Example 73: Synthesis of Compound 77 [ka] A mixture of A-72 (100 mg, 0.45 mmol), (4-isopropoxyphenyl)boronic acid (105.15 mg, 0.58 mmol), Pd(dppf)Cl2.CH2Cl2 (73.39 mg, 0.09 mmol), and Cs2CO3 (292.77 mg, 0.90 mmol) in 1,4-dioxane (3 mL) and water (0.50 mL) was stirred at 90°C for 16 hours under N2. After cooling to room temperature, the mixture was filtered through silica gel and eluted with Â(20 mL × 2). The filtrate was concentrated, diluted with siRNA (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried over Na₂SO₄, filtered, and concentrated to obtain the crude product. This crude product was purified by preparative HPLC (Phenomenex Gemini (250 mm x 50 mm, 10 μm); A=H₂O (0.05% NH₄OH) and B=CH₃CN; 63-73% B over 8 minutes) to obtain compound 77 (23.16 mg, 0.07 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =9.56(d,1H),8.32(s,1H),7.91(d,2H),7.04(d,2H),4.66(quint,1H),1.40(d,6H). LCMS R using Method A t =1.17 min, MS ESI C 15 H 14 F3N4O[ M+H] + Calculated value: 323.1; Measured value: 322.9.

[0541] Example 74: Synthesis of Compound 78 [ka] A mixture of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (173.12 mg, 0.54 mmol), A-72 (100 mg, 0.45 mmol), Pd(dppf)Cl2.CH2Cl2 (73.39 mg, 0.09 mmol), and Cs2CO3 (292.77 mg, 0.90 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) was stirred at 90°C for 16 hours under N2. After cooling to room temperature, the mixture was filtered through silica gel and eluted with Â(20 mL × 2). The filtrate was concentrated, diluted with RINKAN (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product. This crude product was purified by preparative HPLC (Phenomenex Gemini (250 mm x 50 mm, 10 μm); A=H2O (0.05% NH4OH) and B=CH3CN; 58-68% B over 8 minutes) to obtain compound 78 (45.53 mg, 0.12 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =9.60(d,1H),8.54(d,1H),8.41(s,1H),8.09(dd,1H),4.94(q,2H). LCMS R using Method A t =1.16 min, MS ESI C 13 H7F7N5O[M+H] + Calculated value: 382.0; Measured value: 381.

[0542] Example 75: Synthesis of Compound 79 [ka] A mixture of A-72 (100 mg, 0.45 mmol), [3-fluoro-4-(trifluoromethoxy)phenyl]boronic acid (120.73 mg, 0.54 mmol), Pd(dppf)Cl2.DCM (73.39 mg, 0.09 mmol), and Cs2CO3 (292.77 mg, 0.90 mmol) in 1,4-dioxane (3 mL) and water (0.5 mL) was stirred at 90°C for 16 hours. After cooling to room temperature, the mixture was filtered through silica gel and eluted with  (20 mL × 2). The filtrate was concentrated, diluted with  (30 mL), washed with water (10 mL × 2) and brine (10 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product, which was then subjected to preparative HPLC (Phenomenex Gemini (250 mm × 50 mm, 10 μm); A=H2O(0.05 The compound 79 (27.15 mg, 0.07 mmol) was purified as a solid by 60-70% B) over 8 minutes using %NH4OH and B=CH3CN. 1 1H NMR (400MHz, CDCl3)δ H =9.60(d,1H),8.43(s,1H),7.92(dd,1H),7.79(td,1H),7.53-7.47(m,1H). LCMS R using Method A t =1.20 min, MS ESI C 13 H6F7N4O[M+H] + Calculated value: 367.0; Measured value: 366.9.

[0543] Example 76: Synthesis of Compound 80 [ka] Synthesis of A-100: To a mixture of A-64 (500 mg, 3.46 mmol) and Et3N (0.96 mL, 6.92 mmol) in DCM (10 mL), cyclopropanecarbonyl chloride (433.85 mg, 4.15 mmol) was added dropwise. The reaction mixture was stirred at 20°C for 2 hours. The reaction mixture was stopped with saturated NaHCO3 (50 mL) and extracted with DCM (30 mL x 3). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, concentrated, and the residue was purified by flash chromatography on silica gel (ethyl acetate in PE = 0%~20%~50%) to obtain A-100 (500 mg, 2.35 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.12(s,1H),7.94(s,1H),7.59(s,1H),6.81(s,1H),1.56-1.48(m,1H),1.10-1.05(m,2H),0.95-0.88(m,2H).

[0544] Synthesis of A-101: SOCl2 (0.36 mL, 4.94 mmol) was added to a mixture of N'-(5-chloropyrazine-2-yl)cyclopropane-carbozide (350 mg, 1.65 mmol) in MeCN (10 mL). The reaction mixture was stirred at 90°C for 1 hour. After cooling, the reaction mixture was concentrated, and the resulting mixture was treated with saturated NaHCO3 (20 mL) and extracted with siRNA (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to provide the residue, which was purified by flash chromatography on silica gel (siRNA = 0%~20%~50% in PE) to obtain A-101 (130 mg, 0.67 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =9.14(d,1H),8.10(d,1H),2.10-2.02(m,1H),1.35-1.26(m,4H).

[0545] Synthesis of compound 80: A-101 (130 mg, 0.67 mmol) and [4-(trifluoromethoxy)phenyl] in 1,4-dioxane (3 mL) and water (0.3 mL) A mixture of boronic acid (165.07 mg, 0.8 mmol), Cs2CO3 (435.25 mg, 1.34 mmol), and Pd(dppf)Cl2.CH2Cl2 (81.82 mg, 0.1 mmol) was stirred at 90°C for 16 hours under N2. The mixture was cooled to room temperature, diluted with RINKAN (20 mL), filtered through silica gel, and eluted with RINKAN (20 mL). The filtrate was concentrated to obtain the crude product, which was purified by preparative HPLC (Xbridge (150 mm × 25 mm, 5 μm); A=H2O (0.05% NH4HCO3) and B=CH3CN; 40-70% B over 10 minutes) to obtain compound 80 (74.19 mg, 0.23 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =9.38(d,1H),8.31(d,1H),8.03(d,2H),7.38(d,2H),2.19-2.11(m,1H),1.38-1.27(m,4H). LCMS R using Method A t =1.12 minutes, ESI C 15 H 12 F3N4O[M+H] + Calculated value: 321.1; Measured value: 320.9.

[0546] Example 77: Synthesis of Compound 81 [ka] Synthesis of A-102: A mixture of A-72 (300 mg, 1.35 mmol), (4-hydroxyphenyl)boronic acid (241.7 mg, 1.75 mmol), Pd(dppf)Cl2.CH2Cl2 (220.16 mg, 0.27 mmol), and Cs2CO3 (878.32 mg, 2.7 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was stirred at 90°C for 16 hours. After cooling to room temperature, the mixture was filtered through silica gel and eluted with Â(20 mL × 2). The filtrate was concentrated, diluted with toluene (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried on Na2SO4, filtered, and concentrated to obtain the crude product. This was purified by flash chromatography on silica gel (toluene in PE = 0-30%-100%) to obtain A-102 (180 mg, 0.59 mmol) as a solid. LCMS R using Method B t =0.69 min, MS ESI C 12 H8F3N4O[M+H] + Calculated value: 281.1; Measured value: 280.9.

[0547] Synthesis of Compound 81: DEAD (190.43 mg, 1.09 mmol) was added at 0°C to a mixture of A-102 (180 mg, 0.61 mmol), 3,3-difluorocyclobutanol (98.5 mg, 0.91 mmol), and PPh3 (286.81 mg, 1.09 mmol) in THF (3 mL). The mixture was heated and then stirred at 70°C for 16 hours. After cooling to room temperature, the mixture was concentrated to obtain the crude product, which was purified by preparative TLC (silica gel, PE:Â=3:1) and preparative HPLC (Phenomenex Gemini (250 mm × 50 mm, 10 μm); A=H2O (0.05% NH4OH) and B=CH3CN; 48-78% B over 8 minutes) to obtain Compound 81 (5.08 mg, 0.01 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H=9.57(d,1H),8.34(s,1H),7.93(d,2H),6.97(d,2H),4.83-4.65(m,1H),3.23-3.06(m,2H),2.91-2.75(m,2H). LCMS R using Method A t =1.19 min, MS ESI C 16 H 12 F5N4O[M+H] + Calculated value: 371.1; Measured value: 371.0.

[0548] Example 78: Synthesis of Compound 82 [ka] Synthesis of A-103: A mixture of A-64 (500 mg, 3.46 mmol), 3,3-difluorocyclobutanecarboxylic acid (517.81 mg, 3.8 mmol), and PyBOP (2.7 g, 5.19 mmol) in DCM (30 mL) was mixed with DIPEA (1.21 mL, 6.92 mmol). The reaction mixture was stirred at 20 °C for 16 hours. The reaction was stopped with saturated NH4Cl (50 mL), and the reaction product was extracted with DCM (50 mL x 3). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by flash chromatography on silica gel (ethyl acetate = 20%~50%) to obtain A-103 (600 mg, 1.64 mmol) as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H =10.10(s,1H),9.12(s,1H),8.19(d,1H),7.83(d,1H),3.03-2.95(m,1H),2.84-2.66(m,4H).

[0549] Synthesis of A-104: A mixture of A-103 (250 mg, 0.95 mmol), [4-(trifluoromethoxy)-phenyl]boronic acid (294.03 mg, 1.43 mmol), Pd(dppf)Cl2.CH2Cl2 (194.33 mg, 0.24 mmol), and Cs2CO3 (620.24 mg, 1.9 mmol) in 1,4-dioxane (3 mL) and water (0.3 mL) was stirred at 90°C for 16 hours under N2. The mixture was cooled to room temperature, diluted with  (30 mL), filtered through silica gel, and eluted with  (30 mL). The filtrate was concentrated to obtain the crude product, which was purified by flash chromatography on silica gel ( = 20%~50% in PE) to obtain A-104 (150 mg, 0.39 mmol) as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H =10.12(s,1H),9.12(s,1H),8.70(d,1H),8.11-8.06(m,3H),7.44(d,2H),3.08-2.99(m,1H),2.84-2.73(m,4H).

[0550] Synthesis of Compound 82: A mixture of A-104 (150 mg, 0.39 mmol) in acetic acid (2 mL) was stirred in a microwave reactor at 120 °C for 1.5 hours. The mixture was cooled to room temperature, concentrated, and the residue was neutralized to pH=7-8 with 1N NaHCO3 and extracted with RINKAN (20 mL x 2). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, and the filtrate was concentrated to obtain the crude product, which was purified by preparative HPLC (Xbridge (150 mm x 25 mm, 5 μm); A=H2O (0.05% NH4HCO3) and B=CH3CN; 38-78% B over 10 minutes) to obtain Compound 82 (44.06 mg, 0.12 mmol) as a solid. 1 1H NMR (400MHz, DMSO-d6)δ H =9.46(d,1H),8.97(s,1H),8.22(d,2H),7.52(d,2H),4.16-4.03(m ,1H),3.33-3.07(m,4H). LCMS R using Method At =1.17 min, MS ESI C 16 H 12 F5N4O[M+H] + Calculated value: 371.1; Measured value: 371.0.

[0551] Example 79: Synthesis of Compound 83 [ka] A mixture of A-16 (100 mg, 0.41 mmol), 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine (196.88 mg, 0.61 mmol), Pd(dppf)Cl2.CH2Cl2 (83.46 mg, 0.1 mmol), and Cs2CO3 (266.36 mg, 0.82 mmol) in 1,4-dioxane (3 mL) was stirred at 80°C for 16 hours under N2. The mixture was cooled to room temperature, diluted with Â(30 mL), filtered through silica gel, and eluted with Â(30 mL). The filtrate was concentrated to obtain the crude product, which was then subjected to preparative HPLC (Xtimate C). 18 (150 mm × 25 mm, 5 μm); A = H2O (0.05% NH4HCO3) and B = CH3CN; purified over 9.5 minutes with 40-65% B) to obtain compound 83 (61.78 mg, 0.15 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =8.53(d,1H),8.24(d,1H),8.11(dd,1H),7.55(d,1H),4.95(q,2H),4.14-3.98(m,1H),3.42-3.15(m,4H). LCMS R using Method A t =1.16 min, MS ESI C 16 H 12 F6N5O[M+H] + Calculated value: 404.1; Measured value: 404.0.

[0552] Example 80: Synthesis of Compound 84 [ka] Synthesis of A-105: 5-bromo-2,3-difluoropyridine (2g, 10.31 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (3.4g, 13.4 mmol), and Pd(dppf)Cl2 in 1,4-dioxane (100 mL). A mixture of .CH2Cl2 (1.26 g, 1.55 mmol) and KOAc (2.02 g, 20.62 mmol) was stirred at 90°C for 16 hours. After cooling to room temperature, the mixture was filtered through silica gel and eluted with Depositphotos (50 mL x 2). The mixture was concentrated, diluted with Depositphotos (150 mL), washed with water (100 mL x 2) and brine (80 mL), dried over Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by flash chromatography on silica gel ( Depositphotos = 0%~10% in PE) to obtain A-105 (2200 mg, 2.32 mmol) as a solid. LCMS R using Method B t =0.88 min B, MS ESI C 11 H 15 BF2NO2[M+H+2] + Calculated value: 242.1; Measured value: 242.0.

[0553] Synthesis of A-106: A mixture of A-105 (324.91 mg, 1.35 mmol), A-72 (200 mg, 0.90 mmol), Pd(t-Bu3P)2 (91.85 mg, 0.18 mmol), and K3PO4 (381.56 mg, 1.8 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was stirred at 80°C for 16 hours under N2. After cooling to room temperature, the mixture was concentrated to obtain the crude product, which was purified by flash chromatography on silica gel (Â in PE = 0-30%) to obtain A-106 (100 mg, 0.32 mmol) as a solid. 1 1H NMR (400MHz CDCl3)δ H =9.62(d,1H),8.58(s,1H),8.48(s,1H),8.31-8.24(m,1H). LCMS R using Method B.t =0.74 min, MS ESI C 11 H5F5N5[M+H] + Calculated value: 302.0; Measured value: 301.8.

[0554] Synthesis of Compound 84: t-BuOK (35.35 mg, 0.32 mmol) was added at 0°C to a mixture of A-106 (50 mg, 0.16 mmol) and 3,3-difluorocyclobutanol (34.06 mg, 0.32 mmol) in 1,4-dioxane (2 mL). The mixture was stirred at 20°C for 2 hours. The mixture was concentrated to obtain the crude product, which was purified by preparative HPLC (Phenomenex Gemini (250 mm × 50 mm, 10 μm); A=H2O (0.05% NH4OH) and B=CH3CN; 50-80% B over 8 minutes) to obtain Compound 84 (13.63 mg, 0.04 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H =9.59(d,1H),8.51(d,1H),8.39(s,1H),8.03(dd,1H),5.33-5.23(m,1H),3.27-3.14(m,2H),2.93-2.79(m,2H). Using Method A, LCMS R t =1.18 min, MS ESI C 15 H 10 F6N5O[M+H] + Calculated value: 390.1; Measured value: 390.0.

[0555] Example 81: Synthesis of Compound 85 [ka] In 1,4-dioxane (3 mL) and water (0.50 mL), A-67 (99.02 mg, 0.48 mmol), A-93 (202.05 mg, 0.63 mmol), K3PO4 (205.54 mg, 0.97 mmol), and Pd(t-Bu3P)2 (37.11 mL) were found in the following concentrations: The mixture with (g, 0.07 mmol) was stirred at 80°C for 16 hours. After cooling to room temperature, the mixture was concentrated to obtain the crude product, which was purified by preparative HPLC (Phenomenex Gemini (250 mm × 50 mm, 10 μm); A=H2O (0.05% NH4OH) and B=CH3CN; 40-70% B over 8 minutes) to obtain compound 85 (108.7 mg, 0.30 mmol) as a solid. 1 1H NMR (400MHz DMSO-d6)δ H =8.86(d,1H),8.67(d,1H),8.56(dd,1H),8.21(d,1H),7.83(t,1H),5.22(q,2H). LCMS R using Method A t =1.14 min, MS ESI C 13 H8F6N5O[M+H] + Calculated value: 364.1; Measured value: 364.0.

[0556] Example 82: Synthesis of Compound 86 [ka] Synthesis of A-107: A mixture of A-72 (200 mg, 0.90 mmol), (6-fluoro-3-pyridyl)boronic acid (151.95 mg, 1.08 mmol), Pd(dppf)Cl2.CH2Cl2 (146.77 mg, 0.18 mmol), and Cs2CO3 (585.55 mg, 1.8 mmol) in 1,4-dioxane (15 mL) and water (3 mL) was stirred at 90°C for 16 hours. The mixture was filtered through silica gel and eluted with Â(20 mL × 2). The filtrate was concentrated, diluted with HCl (30 mL), washed with water (10 mL x 2) and brine (10 mL), dried on Na2SO4, filtered, and concentrated to obtain the crude product. This was purified by flash chromatography on silica gel (HCl in PE = 0-30-50%) to obtain A-107 (140 mg, 0.40 mmol) as a solid. 1 1H NMR (400MHz, CDCl3)δ H=9.62(d,1H),8.84(d,1H),8.47-8.40(m,2H),7.15(dd,1H). LCMS R using Method B. t =0.69 min, MS ESI C 11 H6F4N5[M+H] + Calculated valu...

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[Claim 1] A disease related to abnormal function of sodium ion channels.

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