Bicyclic heteroaryl compounds

Abstract

Novel compounds (e.g., formula I), pharmaceutical compositions, and methods of use for treating various diseases or disorders, such as cancer, are provided herein. TIFF2026520429000231.tif41149

Description

Detailed description of the invention

[0001]

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 503,822, filed on 23 May 2023, the entirety of which is incorporated herein by reference.

[0002]

[0002] In various embodiments, the disclosure generally relates to novel bicyclic heteroaryl compounds, compositions comprising the same, methods for preparing the same, and methods for using the same, for example, to inhibit PARG enzyme activity and / or to treat or prevent proliferative disorders as described herein.

[0003] [background]

[0003] Poly(ADP-ribose) glycohydrolase (PARG) is the main enzyme that catalyzes the degradation of poly(ADP-ribose). PARG is an endoglycohydrolase that degrades PAR, produced by the poly(ADP-ribose) polymerase (PARP) family of proteins, such as PARP1, to coordinate DNA repair. Houl JH et al., Nature Communications, Vol. 10: p. 5654 (2019). PARG expression has been found to be elevated in the majority of human cancers. Ibid. Houl et al. have also shown that PARG inhibition sensitizes cells to radiation-induced DNA damage, suppresses replication fork progression, and impairs cancer cell survival, thus suggesting that PARG inhibition can be used in cancer treatment. Ibid.

[0004]

[0004] Considering the therapeutic potential of PARG inhibitors in cancer treatment, the development of novel PARG inhibitors is needed.

[0005] [Brief Overview]

[0005] In various embodiments, this disclosure is partly based on the discovery of certain novel bicyclic heteroaryl compounds that may be PARG inhibitors and can be used to inhibit PARG enzyme activity in cells (e.g., cancer cells) and / or to treat or prevent proliferative disorders described herein, such as cancer.

[0006]

[0006] In some embodiments, the present disclosure provides compounds of formula I or pharmaceutically acceptable salts thereof: [ka] (wherein the formulas, variable symbols are defined herein). In some embodiments, compounds of formula I may be characterized by having a structure with subformulas selected from formulas I-1, I-2, I-3, I-1a, I-1b, I-1c, I-2a, I-2b, I-3a, I-3b, I-1a-1, I-1a-2, I-2a-1, I-2a-2, I-3a-1, I-3a-2, I-1b-1, I-1b-2, I-2b-1, I-2b-2, I-3b-1, I-3b-2, IA, I-A1, I-A2, IB, IC, or ID as defined herein. In some embodiments, the disclosure also provides compounds selected from Table 1 herein or pharmaceutically acceptable salts thereof.

[0007]

[0007] Some embodiments of the present disclosure relate to pharmaceutical compositions comprising one or more compounds of the present disclosure (for example, compounds of formula I (e.g., formula I-1, I-2, I-3, I-1a, I-1b, I-1c, I-2a, I-2b, I-3a, I-3b, I-1a-1, I-1a-2, I-2a-1, I-2a-2, I-3a-1, I-3a-2, I-1b-1, I-1b-2, I-2b-1, I-2b-2, I-3b-1, I-3b-2, IA, I-A1, I-A2, IB, IC, or ID), any of the compounds listed in Table 1 of this specification, or pharmaceutically acceptable salts thereof) and optionally pharmaceutically acceptable excipients. The pharmaceutical compositions described herein may be formulated for different routes of administration, for example, for oral administration or parenteral injection.

[0008]

[0008] Certain embodiments of the present disclosure relate to methods for treating diseases or disorders in which PARG activity as described herein is involved, such as proliferative disorders. In some embodiments, the method includes administering a therapeutically effective amount of the compounds of the present disclosure (e.g., compounds of formula I (e.g., formula I-1, I-2, I-3, I-1a, I-1b, I-1c, I-2a, I-2b, I-3a, I-3b, I-1a-1, I-1a-2, I-2a-1, I-2a-2, I-3a-1, I-3a-2, I-1b-1, I-1b-2, I-2b-1, I-2b-2, I-3b-1, I-3b-2, IA, I-A1, I-A2, IB, IC, or ID), any of the compounds listed in Table 1 of this specification, or pharmaceutically acceptable salts thereof) or pharmaceutical composition to a subject in need thereof. In some embodiments, the disease or disorder involving PARG activity is cancer.

[0009]

[0009] The administration in the methods herein is not limited to any particular route of administration. For example, in some embodiments, administration may be oral, nasal, transdermal, transpulmonary, inhaled, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, transrectal, intrapleural, intrathecal, or parenteral. In some embodiments, administration is oral. In some embodiments, administration is parenteral injection, for example, intravenous injection.

[0010]

[0010] The compounds of this disclosure may be used as monotherapy or in combination therapy. In some embodiments of the methods described herein, one or more compounds of this disclosure may be administered as the sole active ingredient. In some embodiments, the methods described herein further include the step of administering an additional therapeutic agent described herein, such as an additional anticancer agent.

[0011]

[0011] It should be understood that both the above summary and the following detailed description are illustrative and descriptive, and do not restrict the inventions described herein.

[0012] [Detailed explanation] In various embodiments, novel compounds, pharmaceutical compositions, methods of preparation, and methods of use are provided herein. The compounds of the disclosure are generally PARG inhibitors, which are also useful for treating various diseases or disorders, such as those described herein, such as cancer. Compound Formula I

[0013] In some embodiments, the disclosure provides a compound of Formula I or a pharmaceutically acceptable salt thereof:

Chemical formula

[0014]

[0014] In some embodiments, the compounds of formula I (including any of the applicable subforms described herein) may contain one or more chiral centers and / or axial chirality, and therefore may exist in various stereoisomer forms, for example, as enantiomers and / or diastereomers. In some embodiments, the compounds of formula I may exist, where applicable, in the form of individual enantiomers and / or diastereomers, or in the form of stereoisomer mixtures including racemic mixtures and mixtures containing many of one or more stereoisomers. In some embodiments, where applicable, the compounds of formula I (including any of the applicable subforms described herein) may exist as individual enantiomers that are substantially free of other enantiomers, for example, with an enantiomer excess of more than 60% ("ee"), preferably more than 80%ee, more than 90%ee, more than 95%ee, more than 98%ee, or more than 99%ee. In some embodiments, where applicable, the compound of formula I (including any of the applicable subformulas described herein) may also exist as a mixture of stereoisomers in any proportion, for example, a racemic mixture.

[0015]

[0015] In some embodiments, the compound of formula I (including any of the applicable subformulas described herein) may exist as an isotopically labeled compound, in particular as a deuterated analog in which one or more hydrogen atoms of the compound of formula I are substituted with deuterium atoms in amounts exceeding their natural abundance, for example, as a CD3 analog if the compound has a CH3 group. While we do not wish to be constrained by theory, in certain circumstances, substitution with deuterium may result in a deuterated analog with a superior pharmacokinetic profile. Deuterated analogs may generally be prepared by using commercially available deuterating reagents.

[0016]

[0016] In certain specific cases, it should be apparent to those skilled in the art that the compounds of formula I may exist as a mixture of tautomers. The present disclosure is not limited to any particular tautomer. Rather, the present disclosure encompasses all of such tautomers, whether or not explicitly illustrated or referred to.

[0017]

[0017] J in formula I 1 ~J 8 The combination of ~J is not particularly limited as long as the bicyclic ring containing J~J is a heteroaryl ring. Typically, the 5-membered ring of J, J, J, J, and J in formula I has 1, 2, or 3 ring nitrogen atoms. を含む二環式環がヘテロアリール環である限りは特に限定されない。典型的には、式IにおけるJ 1 、J 2 、J 6 、J 7 、及びJ 8 の5員環は、1、2、又は3個の環窒素原子を有している。

[0018]

[0018] In some preferred embodiments, J is N and J is C. 6 はNであり、J 8 はCである。

[0019]

[0019] In some preferred embodiments, J is N and J is C. 8 はNであり、J 6 はCである。

[0020]

[0020] In some preferred embodiments, both J and J are C. 6 とJ 8 の両方はCである。

[0021]

[0021] In some embodiments, J is N and both J and J are C. 7 はNであり、J 6 とJ 8 の両方はCである。

[0022]

[0022] In some embodiments, J is C. <​​​​​​​​​​​​1 and J 2 The other is defined herein.

[0024]

[0024] In some embodiments, J 1 and J 2 Both are N.

[0025]

[0025] In some embodiments, J 1 is N and J 2 CR 4 And R 4 This is defined herein.

[0026]

[0026] In some embodiments, J 2 is N and J 1 CR 3 And R 3 This is defined herein.

[0027]

[0027] In some embodiments, J 1 CR 3 And J 2 CR 4 And R 3 and R 4 J is defined herein. For example, in some embodiments, 1 and J 2 Both are CH.

[0028]

[0028] Typically, J 3 CR 5 And R 5 This is defined herein.

[0029]

[0029] In some embodiments, J 3 It may also be N.

[0030]

[0030] Typically, J 4 and J 5 Neither of them is N.

[0031]

[0031] In some embodiments, J4 and J 5 One of them is N.

[0032]

[0032] In some embodiments, J 4 CR 6 And R 6 This is defined herein. Typically, R 6 is either hydrogen or F.

[0033]

[0033] In some embodiments, J 5 CR 7 And R 7 This is defined herein. Typically, R 7 It is hydrogen.

[0034]

[0034] In some embodiments, J 4 and J 5 Both are CH.

[0035]

[0035] In some embodiments, J 4 CF is J 5 It is CH.

[0036]

[0036] J 1 CR 3 In this embodiment, R 3 R is typically hydrogen, deuterium, or a halogen. In some preferred embodiments, 3 is hydrogen. However, in some embodiments, R 3 , CN, G 1 OG 1 NHG 1 , NG 1 G 1 C(O)G 1 C(O)NHG 1 , or C(O)NG 1 G 1 It may be G 1 R is defined herein. For example, in some embodiments, 3 , CN, G 1 C(O)G 1 C(O)NHG1 , or C(O)NG 1 G 1 It may be G 1 R is defined herein. In some embodiments, 3 is G 1 It may also be G 1 For each instance, C is replaced by F at will. 1~4 C optionally substituted with alkyl or F 1~4 Heteroalkyl, or C 3~10 A 3-10 membered ring selected from a carbocyclic ring, a 4-10 membered heterocyclic ring, or a 5-10 membered heteroaryl ring, or independently selected from phenyl, wherein the 3-10 membered ring is optionally substituted with a halogen (e.g., F), CN, OH, or F. 1~4 C optionally substituted with alkyl or F 1~4 It is optionally substituted with one to three substituents independently selected from heteroalkyl or 3-4 membered rings, such as cyclopropyl or cyclobutyl. In some embodiments, R 3 is G 1 It may be G 1 C is replaced by F through arbitrary selection. 1~4 C optionally substituted with alkyl or F 1~4 It is heteroalkyl. In some embodiments, R 3 is G 1 It may be G 1 C 3~6 A 3-6 membered ring selected from a carbocyclic ring, a 4-6 membered heterocyclic ring, or a 5- or 6-membered heteroaryl ring, wherein the 3-6 membered ring is optionally substituted with a halogen (e.g., F), CN, OH, or F. 1~4 C optionally substituted with alkyl or F 1~4 The molecule is optionally substituted with one to three substituents independently selected from heteroalkyl or 3-4 membered rings, such as cyclopropyl or cyclobutyl.

[0037]

[0037] J 2 CR 4 In this embodiment, R 4These are typically hydrogen, deuterium, or halogens. For example, in some embodiments, J 2 is CH. In some embodiments, J 2 is CF. In some embodiments, J 2 is C-Cl. However, in some embodiments, R 4 , CN, optionally replaced with C 1~4 Alkyl, optionally substituted C 2~4 Alkenil, C replaced by any choice 2~4 Alkinyl, optionally replaced with C 1~4 It may be a heteroalkyl or optionally substituted 3- to 6-membered ring. For example, in some embodiments, R 4 C is optionally replaced with CN and F. 1~4 C optionally substituted with alkyl or F 1~4 Heteroalkyl, or C 3~6 The ring may be a carbocyclic ring, a 4-6 membered heterocyclic ring, or a 3-6 membered ring selected from 5- or 6-membered heteroaryl rings, where the 3-6 membered ring is optionally substituted with a halogen (e.g., F), CN, OH, or F. 1~4 C optionally substituted with alkyl or F 1~4 It is optionally substituted with one to three substituents independently selected from heteroalkyl or 3-4 membered rings, such as cyclopropyl or cyclobutyl. In some embodiments, R 4 This is C, which has been replaced by an optional substitution. 2~4 It may also be an alkynyl. 4 OG 1 NHG 1 , or NG 1 G 1 It may be G 1 This is defined herein.

[0038]

[0038] In some preferred embodiments, the compound of formula I has the structure according to formula I-1: [ka] (In the formula, L 1 , L 2 , R1 , R 2 , R 5 , J 1 , J 2 , J 4 , and J 5 (This includes any combination of any of the terms described herein).

[0039]

[0039] In some embodiments, J in formula I-1 1 is N, and the compound may have the structure shown in formula I-1a: [ka] (In the formula, L 1 , L 2 , R 1 , R 2 , R 4 , R 5 , J 4 , and J 5 This includes any combination of any of those described herein. In some embodiments of formula I-1a, J 4 and J 5 Both are CH. In some embodiments according to formula I-1a, J 4 CF is J 5 is CH. For example, in some embodiments, the compound of formula I-1a may have the structure of formula I-1a-1 or I-1a-2: [ka] L 1 , L 2 , R 1 , R 2 , R 4 , and R 5 This includes any combination of any of those described herein. In some embodiments, R in formula I-1a-1 or I-1a-2 4 (This is hydrogen or a halogen, for example, hydrogen, F, or Cl).

[0040]

[0040] In some embodiments, J in formula I-1 2is N. For example, in some embodiments, the compound may have the structure of formula I-1b: [ka] (In the formula, L 1 , L 2 , R 1 , R 2 , R 3 , R 5 , J 4 , and J 5 This includes any combination of any of those described herein. In some embodiments of formula I-1b, J 4 and J 5 Both are CH. In some embodiments according to formula I-1b, J 4 CF is J 5 is CH. For example, in some embodiments, the compound of formula I-1b may have the structure of formula I-1b-1 or I-1b-2: [ka] L 1 , L 2 , R 1 , R 2 , and R 5 (This includes any combination of any of the terms described herein).

[0041]

[0041] In some embodiments, J in formula I-1 1 and J 2 Both are N, and the compound may have the structure according to formula I-1c: [ka] (In the formula, L 1 , L 2 , R 1 , R 2 , R 5 , J 4 , and J 5 (This includes any combination of any of those described herein). In some preferred embodiments according to Formula I-1c, J 4 and J5 Both are CH. In some embodiments according to formula I-1c, J 4 CF is J 5 (is CH).

[0042]

[0042] In some preferred embodiments, the compound of formula I has the structure according to formula I-2: [ka] (In the formula, L 1 , L 2 , R 1 , R 2 , R 5 , J 1 , J 2 , J 4 , and J 5 (This includes any combination of any of the terms described herein).

[0043]

[0043] In some embodiments, J in formula I-2 1 is N, and the compound may have the structure shown in formula I-2a: [ka] (In the formula, L 1 , L 2 , R 1 , R 2 , R 4 , R 5 , J 4 , and J 5 (This includes any combination of any of those described herein). In some embodiments of formula I-2a, J 4 and J 5 Both are CH. In some embodiments according to formula I-2a, J 4 CF is J 5 is CH. For example, in some embodiments, the compound of formula I-2a may have the structure of formula I-2a-1 or I-2a-2: [ka] (In the formula, L 1 , L2 , R 1 , R 2 , and R 5 (This includes any combination of any of those described herein). In some embodiments, R in formula I-2a-1 or I-2a-2 4 is hydrogen or halogen, preferably R 4 (wherein it is hydrogen, F, or Cl).

[0044]

[0044] In some embodiments, J in formula I-2 2 is N. For example, in some embodiments, the compound may have the structure of formula I-2b: [ka] (In the formula, L 1 , L 2 , R 1 , R 2 , R 3 , R 5 , J 4 , and J 5 (This includes any combination of any of those described herein). In some embodiments according to Formula I-2b, J 4 and J 5 Both are CH. In some embodiments according to formula I-2b, J 4 CF is J 5 is CH. For example, in some embodiments, the compound of formula I-2b may have the structure of formula I-2b-1 or I-2b-2: [ka] (In the formula, L 1 , L 2 , R 1 , R 2 , and R 5 (This includes any combination of any of the terms described herein).

[0045]

[0045] In some preferred embodiments, the compound of formula I has the structure according to formula I-3: [ka] (In the formula, L 1 , L 2 , R 1 , R 2 , R 5 , J 1 , J 2 , J 4 , and J 5 (This includes any combination of any of the terms described herein).

[0046]

[0046] In some embodiments, J in formula I-3 1 is N, and the compound may have the structure shown in formula I-3a: [ka] (In the formula, L 1 , L 2 , R 1 , R 2 , R 4 , R 5 , J 4 , and J 5 (This includes any combination of any of those described herein). In some embodiments of formula I-3a, J 4 and J 5 Both are CH. In some embodiments according to formula I-3a, J 4 CF is J 5 is CH. For example, in some embodiments, the compound of formula I-3a may have the structure according to formula I-3a-1 or I-3a-2: [ka] (In the formula, L 1 , L 2 , R 1 , R 2 , and R 5 (This includes any combination of any of those described herein). In some embodiments, R in formula I-3a-1 or I-3a-2 4 is hydrogen or halogen, preferably R 4 (wherein it is hydrogen, F, or Cl).

[0047]

[0047] In some embodiments, J in formula I-3 2 is N. For example, in some embodiments, the compound may have a structure according to formula I-3b: [ka] (In the formula, L 1 , L 2 , R 1 , R 2 , R 3 , R 5 , J 4 , and J 5 (This includes any combination of any of those described herein). In some embodiments of formula I-3b, J 4 and J 5 Both are CH. In some embodiments according to formula I-3a, J 4 CF is J 5 is CH. For example, in some embodiments, the compound of formula I-3b may have the structure of formula I-3b-1 or I-3b-2: [ka] (In the formula, L 1 , L 2 , R 1 , R 2 , and R 5 (This includes any combination of any of the terms described herein).

[0048]

[0048] In some embodiments, in formula I (for example, any of the applicable subformulas), L 1 C is a non-existent, arbitrarily replaced C 1~6 Alkylene, optionally replaced with C 2~6 Alkenylene, optionally replaced with C 2~6 Alkynylene is a 3- to 8-membered ring that has been optionally substituted, R 1 This is a 3- to 8-membered ring that has been substituted by choice, for example, a 3- to 6-membered ring that has been substituted by choice. If substituted, the C that has been substituted by choice is 1~6 Alkylene, C2~6 Alkenylene, C 2~6 The alkynylene, 3-8 membered ring, or 3-6 membered ring is preferably optionally substituted with (i) a halogen (e.g., F), (ii) OH, (iii) CN, or (iv) F. 1~4 C optionally substituted with alkyl or (v)F 2~4 Alkenil, (vi) C replaced by F of any choice 2~4 Alkynyl, (vii) each independently, oxy, CN, F, OH, and C substituted with 1 to 3 F as arbitrary choices. 1~2 C is optionally substituted with alkyl or 1 to 3 F atoms. 1~2 A heteroalkyl 3-5 membered ring having 0-3 heteroatoms optionally substituted with 1-3 substituents, e.g., cyclopropyl, and (viii) a C having 1 or 2 heteroatoms independently being N, S, or O. 1~4 A heteroalkyl group in which the S atom may be optionally oxidized, and C may be optionally substituted with F. 1~4 The heteroalkyl group may be substituted with 1 to 3 substituents independently selected from each group.

[0049]

[0049] In some embodiments, in formula I (for example, any of the applicable subformulas), L 1 R is a 3-8 membered ring that is optionally substituted with 0-4 ring heteroatoms independently selected from N, O, and S, and 1 These are optionally substituted 3- to 6-membered non-aromatic rings, such as 3- to 4-membered cycloalkyl or 4- to 5-membered heterocyclic rings. Typically, 3- to 8-membered rings are 5- or 6-membered heteroaryl rings having 1-3 ring heteroatoms.

[0050]

[0050] For example, in some embodiments, in formula I (for example, any of the applicable subformulas), L 1 R may be an optionally substituted five-membered heteroaryl ring, for example, an optionally substituted ring selected from thiazole, oxazole, imidazole, oxadiazole, or thiadiazole. 1is an optionally substituted 3- to 6-membered non-aromatic ring, for example, a 3- to 4-membered cycloalkyl or a 4- to 5-membered heterocyclic ring. In some embodiments, L 1 teeth [ka] In some embodiments, L 1 teeth [ka] The bond point located at the meta position relative to the S atom is R 1 It is connected.

[0051]

[0051] In some embodiments, in formula I (for example, any of the applicable subformulas), L 1 R may be an optionally substituted six-membered heteroaryl ring, for example, an optionally substituted six-membered heteroarylene having one or two ring nitrogens, for example, an optionally substituted pyridylene or optionally substituted pyridadylene, 1 is an optionally substituted 3- to 6-membered non-aromatic ring, for example, a 3- to 4-membered cycloalkyl or a 4- to 5-membered heterocyclic ring. For example, in some embodiments, L 1 teeth [ka] In some embodiments, L 1 teeth [ka] Typically, the bond point located at the meta position relative to the N atom is R 1 It is connected.

[0052]

[0052] In some embodiments, in formula I (for example, any of the applicable subformulas), L 1 L may be optionally substituted phenyl. In some embodiments, L 1 The rings may be optionally substituted 3- to 8-membered carbon rings or heterocyclic rings.

[0053]

[0053] In some embodiments, the inventors of this specification have used R 1 We discovered that having a small 3-4 membered ring structure may be beneficial for inhibiting PARG activity. In some embodiments, in formula I (e.g., any of the applicable subformulas), L 1 This may be any of the ones described herein, R 1 The ring may be a 3-4 membered ring, such as cyclopropyl or cyclobutyl, and this 3-4 membered ring may be optionally substituted. If substituted, the 3-4 membered ring is typically deuterium, F, OH, CN, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl and C 1~4 It is substituted with 1 to 3 substituents independently selected from heteroalkyl groups, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, or C 1~4 The heteroalkyl group is optionally substituted with 1 to 3 substituents independently selected from F and OH. In some preferred embodiments, R 1 This may be optionally substituted cyclopropyl. Preferably, if substituted, the cyclopropyl is optionally substituted with F, OH, CN, or 1 to 3 F atoms. 1~2 It is substituted with 1 to 3 substituents independently selected from the alkyl group, for example, R 1 teeth, [ka] That's fine.

[0054]

[0054] In some preferred embodiments, the compound of formula I may be characterized by having the structure of formula IA: [ka] (In the formula: R 100This can be hydrogen, F, OH, CN, or optionally substituted alkyl, for example, C optionally substituted with deuterium or F. 1~4 Alkyl (e.g., CH3, CD3, CH2F, CHF2, etc.), or optionally substituted heteroalkyl groups, for example, C optionally substituted with deuterium or fluorine. 1~4 It is heteroalkyl; preferably, R 100 This is a methyl group optionally substituted with hydrogen, F, OH, CN, or deuterium or F (e.g., CH3, CD3, CH2F, CHF2, etc.), J 1 , J 2 , J 3 , J 4 , J 5 , J 6 , J 7 , J 8 , L 1 , L 2 , and R 2 This includes any combination of any of those described herein. Typically, in formula IA, L 1 This is an optionally substituted five-membered heteroarylene having 1 to 3 ring heteroatoms independently selected from S, N, and O, for example, an optionally substituted ring selected from thiazole, oxazole, imidazole, oxadiazole, or thiadiazole. In some embodiments, L 1 teeth [ka] In some embodiments, L 1 teeth [ka] The bond point located at the meta position relative to the S atom is bonded to the cyclopropyl ring of formula IA. In some embodiments, in formula IA, L 1 This refers to optionally substituted six-membered heteroarylenes having one or two ring nitrogen atoms, for example, optionally substituted pyridylenes or optionally substituted pyridadiylenes, for example, [ka] It may also be R 100 is F, CN, CH3, CD3, CH2F, or CHF2. In some embodiments of formula IA, R 100 is F. In some embodiments of formula IA, R 100 is CN. In some embodiments of formula IA, R 100 It is CHF2. In some embodiments of formula IA, the bicyclic heteroaryl portion [ka] This may also be a bicyclic heteroaryl moiety defined in formulas I-1, I-2, I-3, I-1a, I-1b, I-1c, I-2a, I-2b, I-3a, I-3b, I-1a-1, I-1a-2, I-2a-1, I-2a-2, I-3a-1, I-3a-2, I-1b-1, I-1b-2, I-2b-1, I-2b-2, I-3b-1, or I-3b-2. For clarity, [ka] In the embodiment referred to as the bicyclic heteroaryl portion defined in formula I-1a-1, [ka] part is, [ka] It has a structure, R 4 and R 5 It should be understood that this is defined herein, including as specifically defined with respect to formula I-1a-1. Similar expressions relating to other formulas herein should be understood in the same way.

[0055]

[0055] In some preferred embodiments, the compound according to formula IA may have the structure of formula I-A1 or I-A2: [ka] (In the formula, J 1 , J 2 , J 3 , J 4 , J 5 , J 6 , J 7 , J 8 , L 2 , and R 2 (This includes any combination of any of those described herein). In some embodiments of formula I-A1 or I-A2, a bicyclic heteroaryl portion [ka] This is a bicyclic heteroaryl moiety defined in formulas I-1, I-2, I-3, I-1a, I-1b, I-1c, I-2a, I-2b, I-3a, I-3b, I-1a-1, I-1a-2, I-2a-1, I-2a-2, I-3a-1, I-3a-2, I-1b-1, I-1b-2, I-2b-1, I-2b-2, I-3b-1, or I-3b-2.

[0056]

[0056] In some embodiments, in formula I (for example, IA), L 1 This is C, which has been replaced by an optional substitution. 1~4 Alkylene, optionally replaced with C 2~4 Alkenylene, or optionally substituted C 2~4 It may also be alkynylene, R 1 is a 3- to 8-membered ring (for example, as described herein) that has been optionally substituted.

[0057]

[0057] In some embodiments, in formula I (for example, any of the applicable subformulas), L 1 This may be a 7-12 member bicyclic ring structure that is absent or optionally substituted; R 1 C is a hydrogen, deuterium, halogen, CN, OH, NH2, or optionally substituted C 1~4 Alkyl, optionally substituted C 2~4 Alkenil, C replaced by any choice 2~4 Alkinyl, optionally replaced with C 1~4It is a heteroalkyl or optionally substituted 3-6 membered ring. If substituted, it is an optionally substituted 7-12 membered bicyclic ring structure, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 1~4 The heteroalkyl or 3-6 membered ring is preferably optionally substituted with (i) a halogen (e.g., F), (ii) OH, (iii) CN, or (iv) F. 1~4 C optionally substituted with alkyl or (v)F 2~4 Alkenil, (vi) C replaced by F of any choice 2~4 Alkynyl, (vii) each independently, oxy, CN, F, OH, and C substituted with 1 to 3 F as arbitrary choices. 1~2 C is optionally substituted with alkyl or 1 to 3 F atoms. 1~2 A heteroalkyl 3-5 membered ring having 0-3 heteroatoms optionally substituted with 1-3 substituents, e.g., cyclopropyl, and (viii) a C having 1 or 2 heteroatoms independently being N, S, or O. 1~4 A heteroalkyl group in which the S atom may be optionally oxidized, and C may be optionally substituted with F. 1~4 The heteroalkyl group may be substituted with 1 to 3 substituents independently selected from each of them. Typically, in such embodiments, L 1 R is an 8-10 member fused bicyclic ring structure that has been optionally substituted, such as a fused bicyclic heterocyclic ring or a heteroaryl ring. 1 These are hydrogen, deuterium, halogen (preferably F or Cl), OH, CN, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, or C 1~4 It is a heteroalkyl group, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, or C 1~4 The heteroalkyl group is optionally substituted with 1 to 3 substituents independently selected from F and OH. In some preferred embodiments, R 1C is optionally substituted with hydrogen, F, OH, CN, or 1 to 3 substituents independently selected from F and OH. 1~4 It is alkyl.

[0058]

[0058] In some embodiments, L 1 This is an optionally substituted 8-10 membered condensed bicyclic ring structure having a first and a second constituent ring, wherein the first constituent ring is a 5-membered heteroaryl ring having 1-3 ring heteroatoms independently selected from N, O, and S, and the second constituent ring is an aryl, heteroaryl, carbocyclic, or heterocyclic ring. In some embodiments, L 1 L is an optionally substituted 8 or 9-membered condensed bicyclic heteroaryl having a first and a second constituent ring, wherein the first constituent ring is a 5-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, O, and S, and the second constituent ring is phenyl, a 5-membered heteroaryl, or a 6-membered heteroaryl. In some embodiments, L 1 This is an optionally substituted 8 or 9-membered condensed bicyclic heterocyclyl ring having a first and a second constituent ring, wherein the first constituent ring is a 5-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, O, and S, and the second constituent ring is a 5- to 6-membered carbocyclic or heterocyclic ring. In some embodiments, the first constituent ring is a thiazole ring, [ka] In some embodiments, the second constituent ring is a 5-membered or 6-membered heteroaryl ring, for example, a pyridine ring, for example, [ka] In some embodiments, the second constituent ring is typically a five- or six-membered heterocycline having one or two ring heteroatoms independently of N, O, and S, where the S atom is optionally oxidized, for example, the second constituent ring is [ka] This may also be the case, and this constituent ring is optionally substituted. In these embodiments, L 1 Typically, this occurs through the ring atoms of the first constituent ring, J 7 It is bonded to R via the ring atom of the second constituent ring. 1 It is coupled to L. For example, in some embodiments, 1 teeth, [ka] It may also be a condensed bicyclic heteroaryl having the structure, where the thiazole ring (the first constituent ring) is connected to a carbon atom via J as shown. 7 It is coupled with R 1 It is bonded to the ring carbon atom of the pyridine ring (the second constituent ring).

[0059]

[0059] L 1 However, in embodiments of the optionally substituted 8-10 membered condensed bicyclic ring structure described herein, R 1 Preferably, hydrogen, deuterium, halogen (preferably F or Cl), OH, CN, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, or C 1~4 It may also be a heteroalkyl, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, or C 1~4 The heteroalkyl group is optionally substituted with 1 to 3 substituents independently selected from F and OH. In some preferred embodiments, R 1 C is optionally substituted with hydrogen, F, OH, CN, or 1 to 3 substituents independently selected from F and OH. 1~4 It is alkyl.

[0060]

[0060] In some more specific embodiments, the compound of formula I may be characterized by having a structure according to formula IB: [ka] (In the formula: Ring B is an optionally substituted 5-membered or 6-membered heterocyclyl or heteroaryl ring having 1 to 3 ring heteroatoms that are independently N, O, or S; R 1 C is a hydrogen, deuterium, halogen, CN, OH, NH2, or optionally substituted C 1~4 Alkyl, optionally substituted C 2~4 Alkenil, C replaced by any choice 2~4 Alkinyl, optionally replaced with C 1~4 A heteroalkyl or optionally substituted 3- to 6-membered ring; J 1 , J 2 , J 3 , J 4 , J 5 , J 6 , J 7 , J 8 , L 2 , and R 2 (This includes any combination of any of those described herein). If substituted, the 5-membered or 6-membered heterocyclyl or heteroaryl ring of ring B is preferably optionally substituted with (i) a halogen (e.g., F), (ii) OH, (iii) CN, or (iv) F. 1~4 C optionally substituted with alkyl or (v)F 2~4 Alkenil, (vi) C replaced by F of any choice 2~4 Alkynyl, (vii) oxo (as far as valence allows), (viii) C having one or two heteroatoms that are independently N, S, or O. 1~4 A heteroalkyl group in which the S atom may be optionally oxidized, and C may be optionally substituted with F. 1~4 Heteroalkyl and (ix) are each independently substituted with oxo, CN, F, OH, and 1 to 3 F atoms as optional substitutions. 1~2 C is optionally substituted with alkyl or 1 to 3 F atoms. 1~2The heteroalkyl ring has 0 to 3 heteroatoms and is substituted with 1 to 3 substituents, independently selected from cyclopropyl, and is substituted with 1 to 3 substituents. In some embodiments, ring B is an optionally substituted 6-membered heteroaryl, for example, an optionally substituted pyridine. For clarity, in formula IB, ring B is R 1 If it is said that ring B is always linked to and therefore substituted, it should be understood that ring B has one or more substituents in the remaining positions. In some embodiments of formula IB, R 1 These are hydrogen, deuterium, halogen (preferably F or Cl), OH, CN, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, or C 1~4 It is a heteroalkyl group, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, or C 1~4 The heteroalkyl group is optionally substituted with 1 to 3 substituents independently selected from F and OH. In some embodiments of formula IB, the bicyclic heteroaryl moiety [ka] This is a bicyclic heteroaryl moiety defined in formulas I-1, I-2, I-3, I-1a, I-1b, I-1c, I-2a, I-2b, I-3a, I-3b, I-1a-1, I-1a-2, I-2a-1, I-2a-2, I-3a-1, I-3a-2, I-1b-1, I-1b-2, I-2b-1, I-2b-2, I-3b-1, or I-3b-2.

[0061]

[0061] In some embodiments, in formula I (for example, any of the applicable subformulas), L 1 It may also be non-existent, that is, R 1 J is a bicyclic heteroaryl 7 It is directly bonded to. For example, in some embodiments, the compound of formula I may be characterized by having a structure according to formula IC: [ka] (In the formula, J 1 , J 2 , J 3 , J 4 , J 5 , J 6 , J 7 , J 8 , R 1 , L 2 , and R 2 (This includes any combination of any of those described herein). Typically, in formula IC, R 1 R is an optionally substituted five-membered heteroaryl having 1 to 3 ring heteroatoms independently selected from S, N, and O, for example, an optionally substituted ring selected from thiazole, oxazole, imidazole, oxadiazole, or thiadiazole. In some embodiments, in formula IC, R 1 This may be an optionally substituted six-membered heteroaryl having one or two ring nitrogens, for example, optionally substituted pyridyl or optionally substituted pyridazyl. If substituted, the optionally substituted five-membered heteroaryl or optionally substituted six-membered heteroaryl is preferably optionally substituted with (i) a halogen (e.g., F), (ii) OH, (iii) CN, or (iv) F. 1~4 C optionally substituted with alkyl or (v)F 2~4 Alkenil, (vi) C replaced by F of any choice 2~4 Alkynyl, (vii) each independently, oxy, CN, F, OH, and C substituted with 1 to 3 F as arbitrary choices. 1~2 C is optionally substituted with alkyl or 1 to 3 F atoms. 1~2 A heteroalkyl 3-5 membered ring having 0-3 heteroatoms optionally substituted with 1-3 substituents, e.g., cyclopropyl, and (viii) a C having 1 or 2 heteroatoms independently being N, S, or O. 1~4 A heteroalkyl group in which the S atom may be optionally oxidized, and C may be optionally substituted with F. 1~4They may be substituted with 1 to 3 substituents independently selected from heteroalkyl groups. For example, in some embodiments, in formula IC, R 1 This may be thiazole, oxazole, imidazole, oxadiazole, or thiadiazole, each of which is C optionally substituted with F. 1~2 Alkyl atoms, such as CF2H, CH3, CF3, etc., are optionally substituted. For example, in some embodiments, in formula IC, R 1 teeth, [ka] It may also be the case that in formula IC, R 1 This is C, which has been replaced by an optional substitution. 1~4 Alkyl, optionally substituted C 2~4 Alkenil, or C substituted by any choice 2~4 It may also be an alkynyl. In some embodiments of formula IC, a bicyclic heteroaryl portion [ka] This is a bicyclic heteroaryl moiety defined in formulas I-1, I-2, I-3, I-1a, I-1b, I-1c, I-2a, I-2b, I-3a, I-3b, I-1a-1, I-1a-2, I-2a-1, I-2a-2, I-3a-1, I-3a-2, I-1b-1, I-1b-2, I-2b-1, I-2b-2, I-3b-1, or I-3b-2.

[0062]

[0062] Exemplary L suitable for formula I (e.g., any of the applicable subformulas) 1 -R 1 This includes one of the groups represented by the specific compounds listed in Table 1 of this specification.

[0063]

[0063] In some specific embodiments, unless otherwise specified or contrary to the context, L in formula I (e.g., any applicable subformula) 1 -R 1 teeth, [ka] It may be, preferably, [ka] That's fine.

[0064]

[0064] In some specific embodiments, unless otherwise specified or contrary to the context, L in formula I (e.g., any of the applicable subformulas) 1 -R 1 teeth, [ka] That's fine.

[0065]

[0065] In some specific embodiments, unless otherwise specified or contrary to the context, L in formula I (e.g., any applicable subformula) 1 -R 1 teeth, [ka] That's fine.

[0066]

[0066] In formula I (for example, any of the applicable subformulas), L 2 These are typically 3- to 5-membered carbon-cyclic or heterocyclic rings that are optionally substituted, such as optionally substituted cyclopropyl rings or condensed or bridged C rings. 4~5 It is a carbocyclic ring. In some embodiments, L 2 The cyclopropyl ring may be optionally substituted. In some embodiments, L 2 This was replaced by F with optional selection. [ka] ,for example [ka] It may also be L2 teeth, [ka] It may also be L 2 This is C, which has been replaced by an optional substitution. 1~4 It may be an alkylene, which is a linear or branched C 1~4 Alkylenes, such as C(CH3)2, may also be used.

[0067]

[0067] Various groups R 2 Suitable for R 2 C is a C atom optionally substituted with hydrogen, F, F. 1~2 C optionally substituted with alkyl (e.g., CH3, CHF2, or CF3), CN, cyclopropyl, or F 2~3 Alkinyl, for example, [ka] That's fine.

[0068]

[0068] Exemplary L suitable for formula I (e.g., any of the applicable subformulas) 2 -R 2 This includes one of the groups represented by the specific compounds listed in Table 1 of this specification.

[0069]

[0069] For example, in some embodiments, unless otherwise specified or contrary to the context, in formula I (e.g., any of the applicable subformulas), L 2 -R 2 teeth, [ka] You can also use these.

[0070]

[0070] In some preferred embodiments, L 2 is a substituted cyclopropylene, and the compound of formula I may be characterized by having the structure of formula ID. [ka] (In the formula: q is either 1 or 2; R 101 is a methyl molecule optionally substituted with F or F; J 1 , J 2 , J 3 , J 4 , J 5 , J 6 , J 7 , J 8 , L 1 , R 1 , and R 2 (R is defined herein). Typically, in such embodiments, R 101 is F. In some embodiments, q is 1. In some embodiments, [ka] Some of them [ka] It may have a stereochemistry selected from. In some embodiments, q is 2. In some embodiments, [ka] Some of them [ka] It may have a structure, typically consisting of two R 101 The base is the same. Typically, in expression ID, R 2 C is a C atom optionally substituted with hydrogen, F, F. 1~2 C optionally substituted with alkyl (e.g., CH3, CH2F, CHF2, or CF3), CN, cyclopropyl, or F 2~3 Alkinyl, for example, [ka] For example, in some embodiments, [ka] Some of them [ka] It may also be a bicyclic heteroaryl portion. In some embodiments of formula ID, the bicyclic heteroaryl portion [ka] This is a bicyclic heteroaryl moiety defined in formulas I-1, I-2, I-3, I-1a, I-1b, I-1c, I-2a, I-2b, I-3a, I-3b, I-1a-1, I-1a-2, I-2a-1, I-2a-2, I-3a-1, I-3a-2, I-1b-1, I-1b-2, I-2b-1, I-2b-2, I-3b-1, or I-3b-2.

[0071]

[0071] In formula I and its subformula, J 3 Typically, CR 5 And R 5 This is defined herein.

[0072]

[0072] In some embodiments, R 5 This may be hydrogen, a halogen, or an OH group.

[0073]

[0073] In some embodiments, R 5 is G 2 It may be G 2 This is a 3- to 14-membered ring, preferably a heteroaryl or heterocyclic ring, which is optionally substituted.

[0074]

[0074] In some embodiments, R 5This may be an optionally substituted 4-12 membered heterocyclic ring having 1-4 ring heteroatoms independently selected from N, O, and S, where the S atom is optionally oxidized. The 4-12 membered heterocyclic ring is typically a monocyclic ring (typically having 4-7 ring members with 1 or 2 ring heteroatoms) or a bicyclic ring (typically having 5-12 ring members with 1-3 ring heteroatoms), which may be a condensed, spiro, or bridging bicyclic ring.

[0075]

[0075] In some embodiments, R 5 The ring may be an optionally substituted 4-7 member heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O, and S, with the S atom optionally oxidized (e.g., S(O), SO2, S(=NH)(=O)), for example, a monocyclic 5- or 6-member heterocyclic ring having one or two ring heteroatoms, such as a pyrrolidine, piperidine, or piperazine ring. When substituted, the 4-7 member heterocyclic ring is typically independently oxo, halogen (e.g., F), OH, CN, G A OG A C(O)G A C(O)NH2, SO2G A P(O)G A G A C(O)NHG A , C(O)NG A G A SO2NHG A S(=NH)(=O)G A , S(=NG A )(=O)G A SO2NG A G A NHC(O)G A , or N(G A )C(O)G A It may be substituted with 1 to 3 substituents, G A For each existence, (i)C 1~4 Alkyl; (ii)C 1~4 (iii) a heteroalkyl group; and a group optionally substituted independently from a 3- to 10-membered ring, or two G AThese atoms bond together with intervening atoms to form optionally substituted 4- to 10-membered heterocyclic rings; If replaced, C 1~4 Alkyl or C 1~4 The heteroalkyl group is preferably (1) a halogen (preferably F), CN, OH, or NH2, and (2) C optionally substituted with F. 1~4 Heteroalkyl; or (3) a 3- to 10-membered ring substituted with 1 to 3 substituents of any choice; If substituted, the 3-10 membered ring or 4-10 membered heterocyclic ring is preferably independently (1) oxo (where applicable), halogen (e.g., F, Cl), CN, OH, or NH2; (2) C optionally substituted with F. 1~4 Alkyl; (3) C optionally substituted with F 1~4 Heteroalkyl; or (4) C optionally substituted with oxo, F, Cl, CN, OH, F 1~4 C optionally substituted with alkyl and F 1~4 It is a 3- to 6-membered ring that is optionally substituted with 1 to 3 substituents independently selected from the heteroalkyl group.

[0076]

[0076] In some more specific embodiments, R 5 It may have the following structure according to F-1, F-2, or F-3: [ka] (In the formula: n is an integer from 0 to 4. (a)R 10 These are independently present in the following categories: oxo, halogen (e.g., F), OH, CN, G A OG A C(O)G A SO2G A P(O)G A G A C(O)NHG A , C(O)NG A G A SO2NHG A S(=NH)(=O)GA , S(=NG A )(=O)G A SO2NG A G A NHC(O)G A , or N(G A )C(O)G A is, or (b) Two R 10 They bond to form an optionally substituted 3-6 membered ring (e.g., cyclopropyl, cyclobutyl, or oxetane ring), and any of the remaining R 10 (a) is also as defined; or (c) A set of R 10 and R 11 They bond to form a 3-6 membered ring which is optionally substituted, and any of the remaining R 10 As defined in (a); R 11 is hydrogen, G A C(O)G A SO2G A C(O)OG A C(O)NHG A , C(O)NG A G A SO2NHG A S(=NH)(=O)G A , S(=NG A )(=O)G A , or SO2NG A G A , or as defined in (c) above; G A For each existence, (i)C 1~4 Alkyl; (ii)C 1~4 (iii) a heteroalkyl group; and a group optionally substituted independently from a 3- to 10-membered ring, or two G A These atoms bond together with intervening atoms to form optionally substituted 4- to 10-membered heterocyclic rings; If replaced, C 1~4 Alkyl or C 1~4The heteroalkyl group is preferably (1) a halogen (preferably F), CN, OH, or NH2, and (2) C optionally substituted with F. 1~4 Heteroalkyl; or (3) a 3- to 10-membered ring substituted with 1 to 3 substituents of any choice; If substituted, the 3-10 membered ring or 4-10 membered heterocyclic ring is preferably independently (1) oxo (where applicable), halogen (e.g., F, Cl), CN, OH, or NH2; (2) C optionally substituted with F. 1~4 Alkyl; (3) C optionally substituted with F 1~4 Heteroalkyl; or (4) C optionally substituted with oxo, F, Cl, CN, OH, F 1~4 C optionally substituted with alkyl and F 1~4 A 3- to 6-membered ring optionally substituted with 1 to 3 substituents independently selected from the heteroalkyl group (substituted with 1 to 3 substituents). To clarify, two R 10 When it is said that two Rs are bonded together to form a ring structure, 10 The carbon atoms may be bonded to the same carbon, two adjacent carbon atoms, or two non-adjacent carbon atoms, and therefore the formed ring may be a spiro ring, a fused ring, or a bridging ring. Similarly, a set of R 10 and R 11 When it is said that R is bonded to form a ring structure, 10 (NR 11 It may be bonded to a carbon atom adjacent to or not adjacent to the nitrogen atom of ), thus forming a fused ring or a bridging ring.

[0077]

[0077] In some embodiments, in F-1, F-2, or F-3, n is 0, 1, or 2; R 10 Each instance is independently either CN or G A And R 11 is hydrogen, G A C(O)G A SO2G A C(O)OG A C(O)NHGA , C(O)NG A G A SO2NHG A S(=NH)(=O)G A , S(=NG A )(=O)G A , or SO2NG A G A G A The terms are defined herein. In some embodiments, G A Each existence is independent: (1) C independently of each other, F, OH, and C substituted with 1 to 3 Fs of any choice. 1~4 Alkoxy, NH(C 1~4 Alkyl), or N(C 1~3 Alkyl)(C 1~3 C(alkyl) which is optionally substituted with 1 to 3 substituents. 1~4 Alkyl; or (2) Preferably, the 3-10 member ring is C 3~6 A 3-6 membered ring selected from cycloalkyl, 4-6 membered heterocyclyl, 5- or 6 membered heteroaryl, or phenyl, wherein the 3-10 membered ring is optionally substituted with oxo, F, Cl, OH, CN, or F. 1~4 C optionally substituted with alkyl or F 1~4 alkoxy, and 3-10 membered rings optionally substituted with 1-3 substituents independently selected from optionally substituted 3-5 membered rings (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.), (C 1~4 Alkylene)-(3-10 member ring), or (C 1~4 Heteroalkylene)-(3-10 member ring) That is the case.

[0078]

[0078] In some embodiments, in F-1, F-2, or F-3, n is 0, 1, or 2; R 10 Each presence independently has C, which is optionally substituted with CN, cyclopropyl, or F. 1~4 C optionally substituted with alkyl (e.g., CH3) or F 1~4 It is a heteroalkyl group (e.g., CH2OCH3), and R11 is hydrogen, G A C(O)G A SO2G A C(O)OG A C(O)NHG A , C(O)NG A G A SO2NHG A S(=NH)(=O)G A , S(=NG A )(=O)G A , or SO2NG A G A G A This is defined herein.

[0079]

[0079] In some embodiments, n is 0 in F-1, F-2, or F-3.

[0080]

[0080] In some embodiments, n is 1 in F-1, F-2, or F-3.

[0081]

[0081] In some embodiments, n is 2 in F-1, F-2, or F-3.

[0082]

[0082] In some embodiments, two R in F-1, F-2, or F-3 10 They bond to form an optionally substituted 3-6 membered ring (e.g., cyclopropyl, cyclobutyl, or oxetane ring), and any of the remaining R 10 Also, independently, C is arbitrarily replaced by F. 1~4 C optionally substituted with alkyl or F 1~4 It is heteroalkyl. For example, in some embodiments, R 5 teeth, [ka] It may have a structure such that m is 0, 1, or 2, and R 10 Each instance is independently replaced by C with arbitrary selection in F. 1~4 C optionally substituted with alkyl or F 1~4It is heteroalkyl, R 11 This is defined herein.

[0083]

[0083] In some embodiments, in F-1, F-2, or F-3, a set of R 10 and R 11 They bond to form a 3-6 membered ring which is optionally substituted, and any of the remaining R 10 Also, independently, C is arbitrarily replaced by F. 1~4 C optionally substituted with alkyl or F 1~4 It is heteroalkyl. For example, in some embodiments, R 5 teeth, [ka] It may have a structure such that m is 0, 1, or 2, and R 10 Each instance is independently replaced by C with arbitrary selection in F. 1~4 C optionally substituted with alkyl or F 1~4 It is heteroalkyl.

[0084]

[0084] In some embodiments, in F-1, F-2, or F-3, R 11 C(O)G A SO2G A C(O)OG A C(O)NHG A , C(O)NG A G A SO2NHG A S(=NH)(=O)G A , S(=NG A )(=O)G A , or SO2NG A G A G A R is defined herein. For example, in some embodiments, 11 C(O)G A SO2G A C(O)OG A C(O)NHG A , C(O)NG A G ASO2NHG A S(=NH)(=O)G A , S(=NG A )(=O)G A , or SO2NG A G A G A (1) Independently for each existence, (1) each independently, C is substituted with F, OH, and 1 to 3 Fs of any choice. 1~4 Alkoxy, NH(C 1~4 Alkyl), or N(C 1~3 Alkyl)(C 1~3 C(alkyl) which is optionally substituted with 1 to 3 substituents. 1~4 Alkyl, or (2)C 3~6 C selected from cycloalkyl, 4-6 membered heterocyclyl, 5- or 6-membered heteroaryl, or phenyl, and optionally substituted with oxo, F, Cl, OH, CN, or F. 1~4 C optionally substituted with alkyl or F 1~4 It is a 3- to 6-membered ring optionally substituted with alkoxys and 1 to 3 substituents independently selected from optionally substituted 3- to 5-membered rings (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.).

[0085]

[0085] In some embodiments, in F-1, F-2, or F-3, R 11 C(O)G A1 C(O)OG A1 SO2G A1 C(O)NHG A1 , or C(O)NG A1 G A1 It may be G A1 Each instance is independently replaced by C with arbitrary selection in F. 1~4 Alkyl, for example, methyl, ethyl, n-propyl, or isopropyl. In some embodiments, in F-1, F-2, or F-3, R 11 C(O)G A2 SO2G A2 C(O)NHG A2 or SO2NHG A2 It may be G A2 C3~6 A 3-6 membered ring selected from cycloalkyl, 4-6 membered heterocyclyl, 5- or 6 membered heteroaryl, or phenyl, wherein the 3-6 membered ring is optionally substituted with oxo, F, Cl, OH, CN, or F. 1~4 C optionally substituted with alkyl or F 1~4 It is optionally substituted with alkoxys and 1 to 3 substituents independently selected from optionally substituted 3- to 5-membered rings (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.). In some embodiments, G A2 C 3~6 This C may be a cycloalkyl, for example, cyclopropyl or cyclobutyl. 3~6 Each cycloalkyl group is optionally substituted with one or two substituents, each independently of F, OH, CN, or CH3. In some embodiments, G A2 This may be a 4-6 membered heterocycline having one or two ring heteroatoms, such as pyrrolidine, piperidine, or piperazine, and each of these 4-6 membered heterocyclines is independently and optionally substituted with one or two substituents that are F, OH, CN, or CH3.

[0086]

[0086] In some specific embodiments, in F-1, F-2, or F-3, R 11 teeth: [ka] You may choose from the following. Typically, in such embodiments, n is 0, 1, or 2, and R 10 Each presence independently has C, which is optionally substituted with CN, cyclopropyl, or F. 1~4 C optionally substituted with alkyl (e.g., CH3) or F 1~4 It is a heteroalkyl group (e.g., CH2OCH3).

[0087]

[0087] In some embodiments, in F-1, F-2, or F-3, R 11 G A It may be G AR is defined herein. For example, in some embodiments, 11 This may be a optionally substituted 5-membered or 6-membered heteroaryl, and this 5-membered or 6-membered heteroaryl is optionally substituted, preferably, if substituted, the 5-membered or 6-membered heteroaryl is optionally substituted with F, Cl, OH, CN, F. 1~4 C optionally substituted with alkyl or F 1~4 It is substituted with an alkoxy and 1 to 3 substituents independently selected from optionally substituted 3- to 5-membered rings (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.). Typically, in such embodiments, n is 0, 1, or 2, and R 10 Each presence independently has C, which is optionally substituted with CN, cyclopropyl, or F. 1~4 C optionally substituted with alkyl (e.g., CH3) or F 1~4 It is a heteroalkyl group (e.g., CH2OCH3). In some embodiments, R 11 Each of these may be an optionally substituted five- or six-membered heteroaryl having two or three heteroatoms, each independently being N, O, or S, for example, an optionally substituted imidazole or thiadiazole. For example, in some embodiments, R 11 teeth, [ka] That's fine.

[0088]

[0088] In some embodiments, R 5 This may be an optionally substituted 5-12 membered, for example, 7-12 membered heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O, and S, with the S atom optionally oxidized, and may be a 7-12 membered bicyclic heterocyclic ring that can be, for example, a spiro, condensed, or bridging bicyclic heterocyclic ring.

[0089]

[0089] In some embodiments, R 5Each of these may be a 7-12 membered spirodicyclic heterocyclic ring having 1-3 ring heteroatoms that are N, O, and S, and the S atom is optionally oxidized. For example, in some embodiments, R 5 This refers to a spironic heterocyclic ring having one ring that is a 4-membered, 5-membered, or 6-membered ring and the other ring that is a 3-membered, 4-membered, or 5-membered ring, for example: [ka] These spironic heterocyclic rings may be, for example, one or more R as defined herein. 10 The group is optionally substituted. In some embodiments, if substituted, the substituents are optionally substituted with halogens (e.g., F), CN, cyclopropyl, and F, respectively. 1~4 C optionally substituted with alkyl (e.g., CH3) or F 1~4 It is a heteroalkyl group (e.g., CH2OCH3).

[0090]

[0090] In some preferred embodiments, R 5 It may have a spirooxetane ring, for example, in some embodiments, R 5 teeth, [ka] It can be represented by the structure, where ring A is a 4- to 8-membered carbocyclic or heterocyclic ring, sharing a single ring carbon atom with the oxetane ring. In some specific embodiments, R 5 teeth, [ka] That's fine.

[0091]

[0091] In some embodiments, R 5 It may also contain a thiethan spirooxide ring, for example, in some embodiments, R 5 teeth, [ka] The structure can be represented as follows: ring A is a 4- to 8-membered carbocyclic or heterocyclic ring, sharing a single ring carbon atom with the thietan oxide ring.

[0092]

[0092] In some embodiments, R 5 Each of these may be a 7-10 membered fused bicyclic heterocyclic ring having 1-3 ring heteroatoms that are N, O, and S, respectively. For example, in some embodiments, R 5 These are biring heterocyclic rings of 4,5-condensed, 4,6-condensed, 4,7-condensed, 5,5-condensed, 5,6-condensed, 5,7-condensed, or 6,6-condensed rings, such as the following: [ka] These biring heterocyclic rings may be, for example, one or more R as defined herein. 10 The group is optionally substituted. In some embodiments, if substituted, the substituents are optionally substituted with halogens (e.g., F), CN, cyclopropyl, and F, respectively. 1~4 C optionally substituted with alkyl (e.g., CH3) or F 1~4 It is a heteroalkyl group (e.g., CH2OCH3).

[0093]

[0093] In some embodiments, R 5 Each of these may be a 7-10 membered bridging bicyclic heterocyclic ring having 1-3 ring heteroatoms that are N, O, and S, for example, a 2,1,1-bridging bicyclic ring, a 2,2,1-bridging bicyclic ring, a 2,2,2-bridging bicyclic ring, a 2,3,1-bridging bicyclic ring, or a 2,4,1-bridging bicyclic ring, for example, R 5 The following are: [ka] You may choose from these, and these complex rings may be, for example, one or more R as defined herein. 10The group is optionally substituted. In some embodiments, if substituted, the substituents are optionally substituted with halogens (e.g., F), CN, cyclopropyl, and F, respectively. 1~4 C optionally substituted with alkyl (e.g., CH3) or F 1~4 It is a heteroalkyl group (e.g., CH2OCH3).

[0094]

[0094] In some embodiments, R 5 The 5-membered or 6-membered heteroaryl having 1 to 3 ring heteroatoms independently selected from N, O, and S, such as imidazole, pyrazole, thiadiazole, etc., which may be optionally substituted. If substituted, the 5-membered or 6-membered heteroaryl is preferably independently a halogen (e.g., F), OH, NH2, CN, G B OG B C(O)G B SO2G B P(O)G B G B C(O)NHG B , C(O)NG B G B SO2NHG B S(=NH)(=O)G B , S(=NG B )(=O)G B SO2NG B G B NHC(O)G B , or N(G B )C(O)G B It is substituted with 1 to 3 substituents, G B For each existence, (i) C is replaced by 1 to 3 Fs of any choice. 1~4 (ii) C optionally substituted with 1 to 3 F 1~4 Heteroalkyl; and (iii) C optionally substituted with oxo, halogen (e.g., F), OH, CN, or F. 1~2 Alkyl and C having one or two heteroatoms that are independently O, N, or S 1~4It is optionally substituted with 1 to 3 substituents independently selected from the heteroalkyl group, and S is optionally oxidized, C 1~4 The heteroalkyl group is optionally substituted with 1 to 3 F atoms, or with 2 G atoms. B However, it is independently selected from 3- to 7-membered rings that bond together with intervening atoms to form optionally substituted 4- to 7-membered heterocyclic rings. For example, in some embodiments, R 5 The compound may be optionally substituted with a 5-membered or 6-membered heteroaryl, for example, a pyrazole. If substituted, the 5-membered or 6-membered heteroaryl is preferably independently (1) a halogen (e.g., F, Cl), CN, OH, or NH2; (2) C optionally substituted with F. 1~4 Alkyl; (3) C optionally substituted with F 1~4 Heteroalkyl; or (4) C optionally substituted with oxo, F, Cl, CN, OH, F 1~4 C optionally substituted with alkyl and F 1~4 A 3-6 membered ring optionally substituted with 1-3 substituents independently selected from the heteroalkyl group. In some embodiments, C 1~4 A heteroalkyl group has one or two heteroatoms that are independently O, N, or S, and the S is optionally oxidized.

[0095]

[0095] In some embodiments, R 5 L 3 -G 2 Even if it is L 3 is O, NH, CO, C(O)NH, C(O)N(C 1~4 Alkyl), SO2, SO2NH, SO2N(C 1~4 C (alkyl), optionally substituted 1~4 Alkylene, optionally replaced with C 2~4 Alkenylene, optionally replaced with C 2~4 Alkynylene, or optionally substituted C 1~4 It is a heteroalkylene, G 2is an optionally substituted 3- to 14-membered ring, for example, any of the monocyclic or bicyclic heterocyclic rings described herein.

[0096]

[0096] In some particular embodiments, R 5 may have a structure according to any of those corresponding to the R 5 groups described in Table 1.

[0097]

[0097] In some embodiments, the present disclosure also provides Embodiments A1-29 listed below: Embodiment A1. A compound of Formula I-A or a pharmaceutically acceptable salt thereof:

Chemical formula

Chemical formula

[0098]

[0098] In some embodiments, the Disclosure also provides embodiments B1-43 listed below: Embodiment B1. Compound of formula ID or a pharmaceutically acceptable salt thereof: [ka] (In the formula: q is either 1 or 2; R 101 is a methyl molecule optionally substituted with F or F; J 1 , J 2 , J 3 , J 4 , J 5 , J 6 , J 7 , J 8 , L 1 , R 1 , and R 2 (as defined herein). Embodiment B2.R 101 A compound of Embodiment B1 or a pharmaceutically acceptable salt thereof, wherein F is present. A compound of Embodiment B1 or 2, or a pharmaceutically acceptable salt thereof, wherein Embodiment B3.q is 1. A compound of Embodiment B1 or 2 or a pharmaceutically acceptable salt thereof, wherein q in Embodiment B4 is 2. Embodiment B5.R 2 is hydrogen, F, C 1~2 alkyl optionally substituted with F (e.g., CH3, CH2F, CHF2, or CF3), CN, cyclopropyl, or C 2~3 alkynyl, for example,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0099]

[0099] In some embodiments, the Disclosure also provides embodiments C1 to C26 listed below: Embodiment C1. Compound of formula IB or a pharmaceutically acceptable salt thereof: [ka] (In the formula: Ring B is an optionally substituted 5-membered or 6-membered heterocyclyl or heteroaryl ring having independently 1 to 3 ring heteroatoms that are N, O, or S; R 1 C is a hydrogen, deuterium, halogen, CN, OH, NH2, or optionally substituted C 1~4 Alkyl, optionally substituted C 1~4 A heteroalkyl or optionally substituted 3- to 6-membered ring; J 1 , J 2 , J 3 , J 4 , J 5 , J 6 , J 7 , J 8 , L 1 , L 2 , and R 2 (as defined herein). Embodiment C2. Ring B is an optionally substituted 6-membered heteroaryl, for example, an optionally substituted pyridine, for example, [ka] but [ka] A compound of Embodiment C1 or a pharmaceutically acceptable salt thereof, which may have the structure of the above. Embodiment C3. Ring B is a six-membered complex ring that has been optionally substituted, for example, [ka] but, [ka] The compound of Embodiment C1 or a pharmaceutically acceptable salt thereof may have the structure of which is optionally substituted. Embodiment C4.R 1 However, hydrogen, deuterium, halogen (preferably F or Cl), OH, CN, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, or C 1~4 It is a heteroalkyl group, C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, or C 1~4 A compound according to any one of Embodiments C1 to C3, or a pharmaceutically acceptable salt thereof, wherein the heteroalkyl group is optionally substituted with 1 to 3 substituents independently selected from F and OH. Embodiment C5. [ka] but [ka] The compound of Embodiment C1 or a pharmaceutically acceptable salt thereof. Embodiment C6.L 2 but [ka] And R 2 However, C is substituted with hydrogen, F, F as an arbitrary choice. 1~2 C optionally substituted with alkyl (e.g., CH3, CH2F, CHF2, or CF3), CN, cyclopropyl, or F 2~3 Alkinyl, for example, [ka] The compound described in any one of Embodiments C1 to C5 or a pharmaceutically acceptable salt thereof. Embodiment C7.L 2 -R 2 but, [ka] The compound of Embodiment C6 or a pharmaceutically acceptable salt thereof. Embodiment C8.J 3 CR 5 And R 5 However, the compound described in any one of Embodiments C1 to C7 as defined herein, or a pharmaceutically acceptable salt thereof. Embodiment C9. [ka] but, [ka] And R 4 However, it is hydrogen or halogen, preferably R 4 The compound or pharmaceutically acceptable salt thereof according to any one of Embodiments C1 to C7, wherein the compound is hydrogen, F, or Cl. Embodiment C10. [ka] but, [ka] The compound described in any one of embodiments C1 to C7 or a pharmaceutically acceptable salt thereof. Embodiment C11. [ka] but, [ka] The compound described in any one of embodiments C1 to C7 or a pharmaceutically acceptable salt thereof. Embodiment C12. [ka] but, [ka] And R 4 However, it is hydrogen or halogen, preferably R 4 The compound or pharmaceutically acceptable salt thereof according to any one of Embodiments C1 to C7, wherein the compound is hydrogen, F, or Cl. Embodiment C13. [ka] but, [ka] The compound described in any one of embodiments C1 to C7 or a pharmaceutically acceptable salt thereof. Embodiment C14. [ka] but, [ka] And R 4 However, it is hydrogen or halogen, preferably R 4 The compound or pharmaceutically acceptable salt thereof according to any one of Embodiments C1 to C7, wherein the compound is hydrogen, F, or Cl. Embodiment C15. [ka] but, [ka] The compound described in any one of embodiments C1 to C7 or a pharmaceutically acceptable salt thereof. Embodiment C16.R 5 The compound according to any one of Embodiments C8 to 15 or a pharmaceutically acceptable salt thereof, wherein the compound is an optionally substituted 4-12 membered heterocyclic ring having 1-4 ring heteroatoms independently selected from N, O, and S, and the S atom is optionally oxidized. Embodiment C17.R 5The compound according to any one of embodiments C8 to 15, or a pharmaceutically acceptable salt thereof, wherein the compound is an optionally substituted monocyclic five-membered or six-membered heterocyclic ring having one or two ring heteroatoms. Embodiment C18.R 5 However, the compound described in any one of Embodiments C8 to 15 or a pharmaceutically acceptable salt thereof having a structure according to F-1, F-2, or F-3 as defined herein. Embodiment C19.R 5 However, it has a structure made of F-1, F-2, or F-3, R 11 but: [ka] Selected from, where n is 0, 1, or 2, R 10 However, C is optionally substituted with CN, cyclopropyl, and F, independently of the others. 1~4 C optionally substituted with alkyl (e.g., CH3) or F 1~4 A compound according to any one of embodiments C8 to 15, or a pharmaceutically acceptable salt thereof, which is a heteroalkyl (e.g., CH2OCH3). Embodiment C20.R 5 However, it has a structure made of F-1, F-2, or F-3, R 11 However, each is an optionally substituted 5-membered or 6-membered heteroaryl having two or three heteroatoms that are N, O, or S, for example, an optionally substituted imidazole or thiadiazole, where n is 0, 1, or 2, and R 10 However, C is optionally substituted with CN, cyclopropyl, and F, independently of the others. 1~4 C optionally substituted with alkyl (e.g., CH3) or F 1~4 A compound according to any one of embodiments C8 to 15, or a pharmaceutically acceptable salt thereof, which is a heteroalkyl (e.g., CH2OCH3). Embodiment C21.R 5However, each is independently a 7-12 membered spirodicyclic heterocyclic ring having 1-3 ring heteroatoms that are N, O, and S, respectively, and the S atom is optionally oxidized, for example: [ka] A compound according to any one of embodiments C8 to 15, or a pharmaceutically acceptable salt thereof, wherein the 7- to 12-membered spirodicyclic heterocyclic ring is optionally substituted with a compound selected from the above. Embodiment C22.R 5 However, each is independently a 7-10 membered fused bicyclic heterocyclic ring having 1-3 ring heteroatoms that are N, O, and S, respectively, and is optionally substituted, for example: [ka] A compound according to any one of embodiments C8 to 15, or a pharmaceutically acceptable salt thereof, wherein the 7-10 membered condensed bicyclic heterocyclic ring is optionally substituted with a compound selected from the above. Embodiment C23.R 5 However, each is independently a 7-10 member bridged bicyclic heterocyclic ring having 1-3 ring heteroatoms that are N, O, and S, respectively, substituted by any choice, for example: [ka] A compound according to any one of embodiments C8 to 15, or a pharmaceutically acceptable salt thereof, wherein a 7-10 member bridged bicyclic heterocyclic ring is optionally substituted. Embodiment C24.R 5 The compound or a pharmaceutically acceptable salt thereof according to any one of Embodiments C8 to 15, wherein the compound is a 5-membered or 6-membered heteroaryl having 1 to 3 ring heteroatoms independently selected from N, O, and S, such as imidazole, pyrazole, or thiadiazole, and this 5-membered or 6-membered heteroaryl is optionally substituted. Embodiment C25.R 5 but [ka] The compound described in any one of embodiments C8 to C15 or a pharmaceutically acceptable salt thereof. Embodiment C26.R 5 However, R in Table 1 5 A compound according to any one of embodiments C8 to C15, or a pharmaceutically acceptable salt thereof, which corresponds to any of the bases.

[0100]

[0100] In some embodiments, the disclosure also provides compounds selected from Table 1 below, their deuterated analogs, their stereoisomers, or pharmaceutically acceptable salts thereof: [Table 1] TIFF2026520429000156.tif206149TIFF2026520429000157.tif177149

[0101]

[0101] In some embodiments, to the extent applicable, the genera of compounds described herein will exclude any specific known single compound prior to this disclosure. In some embodiments, to the extent applicable, any subgenus or species of prior to this disclosure that is within the full scope of the genera of compounds described herein may be excluded from such genera herein.

[0102] Synthesis method

[0102] The compounds of this disclosure can be readily synthesized by those skilled in the art in consideration of this disclosure. Exemplary synthesis is also shown in the Examples section.

[0103]

[0103] As will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent undesirable reactions from occurring in certain functional groups. Suitable protecting groups for various functional groups, as well as suitable conditions for protecting and deprotecting specific functional groups, are well known in the art. For example, numerous protecting groups are described in "Protective Groups in Organic Synthesis," 4th edition, PGMWuts;TW Greene, John Wiley, 2007 and the literature cited therein. The reagents for the reactions described herein are generally known compounds or may be prepared by known procedures or obvious modifications thereof. For example, many of the reagents are available from commercial suppliers, such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA) and Sigma (St. Louis, Missouri, USA). Other preparations may be made by following the procedures described in any of the standard reference texts, such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5 and Supplement (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry (Wiley, 7th edition), and Larock's Comprehensive Organic Transformations (Wiley-VCH, 1999), or any updated editions available at the time of this application, or obvious modifications thereof.

[0104] Pharmaceutical composition

[0104] Certain embodiments relate to pharmaceutical compositions comprising one or more compounds of the present disclosure.

[0105]

[0105] The pharmaceutical composition may optionally contain pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition comprises the compounds of the Disclosure (for example, compounds of formula I (e.g., formula I-1, I-2, I-3, I-1a, I-1b, I-1c, I-2a, I-2b, I-3a, I-3b, I-1a-1, I-1a-2, I-2a-1, I-2a-2, I-3a-1, I-3a-2, I-1b-1, I-1b-2, I-2b-1, I-2b-2, I-3b-1, I-3b-2, IA, I-A1, I-A2, IB, IC, or ID), any of the compounds listed in Table 1 of this specification, or pharmaceutically acceptable salts thereof) and pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients are known in the art. Suitable non-limiting excipients include, for example, encapsulating materials or additives such as antioxidants, binders, buffers, carriers, coatings, colorants, diluents, disintegrants, emulsifiers, bulking agents, fillers, flavoring agents, humectants, lubricants, fragrances, preservatives, propellants, release agents, sterilizers, sweeteners, solubilizers, wetting agents, and mixtures thereof. See also Remington's The Science and Practice of Pharmacy, 21st edition, ARGennaro (Lippincott, Williams & Wilkins, Baltimore, Maryland, 2005; incorporated herein by reference), which discloses a variety of excipients used in the formulation of pharmaceutical compositions and known techniques for preparing them.

[0106]

[0106] The pharmaceutical composition may contain one or more of the compounds of the Disclosure. For example, in some embodiments, the pharmaceutical composition may contain, for example, a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. In any of the embodiments described herein, the pharmaceutical composition may contain a therapeutically effective amount (for example, a therapeutically effective amount for treating cancer as described herein) of any of Examples 1 to 41, or any of the specific compounds disclosed in Table 1 herein, or a compound selected from a pharmaceutically acceptable salt thereof. In some preferred embodiments, the pharmaceutical composition may contain an IC50 of less than 100 nM when measured according to Biological Example 1.50 The value, more preferably, is less than 50 nM for ICs. 50 The compound may be selected from the compounds of Examples 1 to 41 that have a value.

[0107]

[0107] The pharmaceutical compositions described herein may be formulated for delivery via any known delivery route, which are not limited to, oral, nasal, dermal, pulmonary, inhalation, buccal, sublingual, intraperitoneal, subcutaneous, intramuscular, intravenous, rectal, intrapleural, intrathecal, or parenteral administration.

[0108]

[0108] In some embodiments, the pharmaceutical composition may be formulated for oral administration. The oral formulation may be provided as individual units, each containing a predetermined amount of the active compound, for example, as capsules, pills, cachets, lozenges, or tablets; as powders or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. Excipients for preparing compositions for oral administration are known in the art. Non-limiting suitable excipients include, for example, agar, alginic acid, aluminum hydroxide, benzyl alcohol, benzyl benzoate, 1,3-butylene glycol, carbomer, castor oil, cellulose, cellulose acetate, cocoa butter, corn starch, corn oil, cottonseed oil, crospovidone, diglycerides, ethanol, ethylcellulose, ethyl laurate, ethyl oleate, fatty acid esters, gelatin, germ oil, glucose, glycerol, peanut oil, hydroxypropyl methylcellulose, isopropanol, isotonic saline, lactol The ingredients include magnesium hydroxide, magnesium stearate, malt, mannitol, monoglycerides, olive oil, peanut oil, potassium phosphate, potato starch, povidone, propylene glycol, Ringer's solution, safflower oil, sesame oil, sodium carboxymethylcellulose, sodium phosphate, sodium lauryl sulfate, sodium sorbitol, soybean oil, stearic acid, stearyl fumarate, sucrose, surfactants, talc, tragacanth, tetrahydrofurfuryl alcohol, triglycerides, water, and mixtures thereof.

[0109]

[0109] In some embodiments, the pharmaceutical composition is formulated for parenteral administration (e.g., intravenous injection or infusion, subcutaneous or intramuscular injection). Parenteral formulations may be, for example, aqueous solutions, suspensions, or emulsions. Excipients for preparing parenteral formulations are known in the art. Non-limiting suitable excipients include, for example, 1,3-butanediol, castor oil, corn oil, cottonseed oil, dextrose, germ oil, peanut oil, liposomes, oleic acid, olive oil, peanut oil, Ringer's solution, safflower oil, sesame oil, soybean oil, USP or isotonic sodium chloride solution, water, and mixtures thereof.

[0110]

[0110] The compounds of this disclosure may be used alone, in combination with each other, or in combination with one or more additional therapeutic agents, for example, additional anticancer therapeutic agents, such as the chemotherapeutic agents described herein, or the chemotherapeutic agents described in International Publication No. 2023 / 057389, International Publication No. 2021 / 055744, and International Publication No. 2023 / 057394.

[0111]

[0111] When used in combination with one or more additional therapeutic agents, the compounds of the Disclosure or the pharmaceutical compositions herein may be administered to a subject simultaneously or sequentially to such additional therapeutic agents in any order. In some embodiments, a pharmaceutical composition may contain one or more compounds of the Disclosure and one or more additional therapeutic agents in a single composition. In some embodiments, a pharmaceutical composition containing one or more compounds of the Disclosure may be contained in a kit, which also contains individual pharmaceutical compositions containing one or more additional therapeutic agents.

[0112]

[0112] A pharmaceutical composition may contain varying amounts of the compound of the Disclosure depending on various factors, such as the intended use, efficacy, and selectivity of the compound. In some embodiments, the pharmaceutical composition contains a therapeutically effective amount of the compound of the Disclosure. In some embodiments, the pharmaceutical composition contains a therapeutically effective amount of the compound of the Disclosure and a pharmaceutically acceptable excipient. When used herein, the therapeutically effective amount of the compound of the Disclosure is an amount effective to treat the disease or disorder described herein, such as cancer herein, and may depend on the recipient of the treatment, the disorder, condition, or disease being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance rate, and whether or not another drug is administered concurrently.

[0113] Treatment / Usage

[0113] The compounds of this disclosure have a variety of uses. For example, the compounds of this disclosure may be used as therapeutic active substances to treat and / or prevent diseases or disorders in which PARG activity is involved. Accordingly, some embodiments of this disclosure also relate to methods of using one or more compounds of this disclosure or pharmaceutical compositions herein to treat or prevent diseases or disorders in which PARG activity is involved in subjects in which it is needed, for example, to treat cancer in subjects in which it is needed.

[0114]

[0114] In some embodiments, the Disclosure provides a method for inhibiting PARG enzyme activity in cells, comprising the step of contacting cells with an effective amount of a compound of the Disclosure (e.g., a compound of formula I (e.g., formula I-1, I-2, I-3, I-1a, I-1b, I-1c, I-2a, I-2b, I-3a, I-3b, I-1a-1, I-1a-2, I-2a-1, I-2a-2, I-3a-1, I-3a-2, I-1b-1, I-1b-2, I-2b-1, I-2b-2, I-3b-1, I-3b-2, IA, I-A1, I-A2, IB, IC, or ID), any of the compounds listed in Table 1 of this Spec, or a pharmaceutically acceptable salt thereof). In some embodiments, the contact of cells is performed in vitro. In some embodiments, the contact of cells is performed in vivo. In some embodiments, the method selectively inhibits PARG enzyme activity rather than PARP1 or ARH3 enzyme activity.

[0115]

[0115] In some embodiments, the present disclosure provides a method for inhibiting cell proliferation in vitro or in vivo, comprising the step of contacting cells with an effective amount of a compound of the present disclosure (for example, a compound of formula I (e.g., formula I-1, I-2, I-3, I-1a, I-1b, I-1c, I-2a, I-2b, I-3a, I-3b, I-1a-1, I-1a-2, I-2a-1, I-2a-2, I-3a-1, I-3a-2, I-1b-1, I-1b-2, I-2b-1, I-2b-2, I-3b-1, I-3b-2, IA, I-A1, I-A2, IB, IC, or ID), any of the compounds listed in Table 1 of this specification, or a pharmaceutically acceptable salt thereof).

[0116]

[0116] In some embodiments, the Disclosure provides a method for treating a disease or disorder involving PARG activity in a subject in need thereof, comprising the step of administering a therapeutically effective amount of a compound of the Disclosure (e.g., a compound of formula I (e.g., formula I-1, I-2, I-3, I-1a, I-1b, I-1c, I-2a, I-2b, I-3a, I-3b, I-1a-1, I-1a-2, I-2a-1, I-2a-2, I-3a-1, I-3a-2, I-1b-1, I-1b-2, I-2b-1, I-2b-2, I-3b-1, I-3b-2, IA, I-A1, I-A2, IB, IC, or ID), any of the compounds listed in Table 1 herein, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition as defined herein to the subject. In some embodiments, the disease or disorder involving PARG activity is a proliferative disorder as described herein. In some embodiments, the disease or disorder involving PARG activity is a cancer as described herein. In some embodiments, the cancer may be selected from ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, lung cancer (e.g., small cell lung carcinoma (SCLC)), colorectal cancer, melanoma, sarcoma, and gastric cancer.

[0117]

[0117] In some embodiments, the Disclosure provides a method for treating a proliferative disorder in a subject in need thereof, comprising the step of administering a therapeutically effective amount of a compound of the Disclosure (e.g., a compound of formula I (e.g., formula I-1, I-2, I-3, I-1a, I-1b, I-1c, I-2a, I-2b, I-3a, I-3b, I-1a-1, I-1a-2, I-2a-1, I-2a-2, I-3a-1, I-3a-2, I-1b-1, I-1b-2, I-2b-1, I-2b-2, I-3b-1, I-3b-2, IA, I-A1, I-A2, IB, IC, or ID), any of the compounds listed in Table 1 herein, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition as defined herein to the subject. Examples of proliferative conditions include, but are not limited to, malignant neoplasms and tumors, cancer, pre-malignant and malignant cell proliferation including but not limited to leukemia, psoriasis, bone diseases, fibroproliferative disorders (e.g., fibroproliferative disorders of connective tissue), and atherosclerosis. Any type of cell, including but not limited to those of the lungs, colon, breast, ovaries, prostate, liver, pancreas, brain, and skin, may be treated.

[0118]

[0118] Preferably, the proliferative disorder is cancer. Accordingly, in some embodiments, the Disclosure provides a method for treating cancer in a subject in need thereof, comprising the step of administering a therapeutically effective amount of a compound of the Disclosure (e.g., a compound of formula I (e.g., formula I-1, I-2, I-3, I-1a, I-1b, I-1c, I-2a, I-2b, I-3a, I-3b, I-1a-1, I-1a-2, I-2a-1, I-2a-2, I-3a-1, I-3a-2, I-1b-1, I-1b-2, I-2b-1, I-2b-2, I-3b-1, I-3b-2, IA, I-A1, I-A2, IB, IC, or ID), any of the compounds listed in Table 1 herein, or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition as defined herein to the subject. In some embodiments, the cancer may be selected from ovarian cancer, breast cancer, prostate cancer, pancreatic cancer, lung cancer (e.g., small cell lung carcinoma (SCLC)), colorectal cancer, melanoma, sarcoma, and gastric cancer. In certain embodiments, the cancer is human cancer.

[0119]

[0119] The compounds of the Disclosure may be used in the methods herein as monotherapy or in combination therapy. For example, in some embodiments, the compounds of the Disclosure may be used in combination with conventional surgical or radiation therapy or chemotherapeutic agents. In some embodiments, such chemotherapeutic agents include the following antitumor agents (i) antiproliferative agents / antineoplastic agents and combinations thereof, e.g., alkylating agents (e.g., cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulfan, temozolamide, and nitrosourea); antimetabolites (e.g., gemcitabine and antifolic acid agents, e.g., fluoropyrimidines such as 5-fluorouracil and tegafur, larcitrexed) , methotrexate, cytosine arabinoside, and hydroxyurea); antitumor antibiotics (e.g., anthracyclines such as adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mitramycin); antimitotic agents (e.g., vinca alkaloids such as vincristine, vinblastine, vindesine, and vinorelbine, as well as taxoids such as taxol and taxotere, and polokina (ii) Cell division arresting agents, e.g., antiestrogens (e.g., tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene, and iodoxifene), antiandrogens (e.g., bicalutamide, flutamide, nilutamide, and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., (iii) Goserelin, leuprorelin, and buserelin), progestogens (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, borazole, and exemestane), and 5oc-reductase inhibitors, e.g., finasteride; (iii) anti-infiltration agents [e.g., 4-(6-chloro-2,3-methylenedioxyanilino)-7-[2-(4-methylpiperazine-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530;International Publication No. 01 / 94341), c-Src kinase family inhibitors such as N-(2-chloro-6-methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidine-4-ylamino}thiazole-5-carboxamide (dasatinib, BMS-354825; J.Med.Chem., 2004, Vol. 47, pp. 6658-6661) and bosutinib (SKI-606), as well as metalloproteinase inhibitors such as marimastat, uro (iv) Inhibitors of kinase plasminogen activator receptor function or antibodies against heparanase; (iv) Growth factor function inhibitors: For example, such inhibitors include growth factor antibodies and growth factor receptor antibodies (e.g., anti-erbB2 antibody trastuzumab [Herceptin (trademark)], anti-EGFR antibody panitumumab, anti-erbB1 antibody cetuximab [Elbitux, C225], and any growth factor or growth factor receptor antibody disclosed by Stern et al. (Critical reviews in (Oncology / Haematology, 2005, Vol. 54, pp. 11-29) are examples of such inhibitors; other examples of such inhibitors include tyrosine kinase inhibitors, such as epidermal growth factor family inhibitors (e.g., EGFR family tyrosine kinase inhibitors, e.g., N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazoline-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-meth Examples include xiethoxy)quinazoline-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazoline-4-amine (Cl1033); erbB2 tyrosine kinase inhibitors, e.g., lapatinib); hepatocyte growth factor family inhibitors; insulin growth factor family inhibitors; platelet-derived growth factor family inhibitors, e.g., imatinib and / or nilotinib (AMN107);Serine / threonine kinase inhibitors (e.g., Ras / Raf signaling inhibitors, e.g., phenesyltransferase inhibitors, e.g., sorafenib (BAY 43-9006), tipifarnib (R1 15777), and ronafarnib (SCH66336)), MEK and / or AKT kinase-mediated cell signaling inhibitors, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1R kinase inhibitors, IGF receptor (insulin-like growth factor) kinase inhibitors; Aurora kinase inhibitors (e.g., AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 and (v) AX39459), and cyclin-dependent kinase inhibitors, e.g., CDK2 and / or CDK4 inhibitors; (v) angiogenesis inhibitors, e.g., those that inhibit the effects of vascular endothelial growth factor [e.g., anti-vascular endothelial growth factor antibody bevacizumab (Avastin®)], and e.g., VEGF receptor tyrosine kinase inhibitors, e.g., vandetanib (ZD6474), batalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW786034), and 4-(4-fluoro-2-methylindole-5-yloxy)-6-methoxy-7-(3-pyrrolidine-1-ylpropoxy)quinazoline (AZD2171; Example 240 in International Publication No. 00 / 47212), compounds, for example, those disclosed in International Publication No. 97 / 22596, International Publication No. 97 / 30035, International Publication No. 97 / 32856, and International Publication No. 98 / 13354, as well as compounds acting by other mechanisms (e.g.) (i) linamide, integrin AVB3 function inhibitors, and angiostatins); (vi) vascular damage agents, e.g., combretastatin A4, and compounds disclosed in International Publications 99 / 02166, 00 / 40529, 00 / 41669, 01 / 92224, 02 / 04434, and 02 / 08213; (vii) endothelin receptor antagonists, e.g., dibotentan (ZD4054) or atrasentan;(viii) Antisense therapies, e.g., targeted therapies as listed above, e.g., anti-ras antisense ISIS2503; (ix) approaches to replace abnormal genes, e.g., abnormal p53 or abnormal BRCA1 or BRCA2; GDEPT (gene-directed enzyme prodrug therapy) approaches, e.g., those using cytosine deaminase, thymidine kinase, or bacterial nitroreductase; and approaches to improve patient tolerance to chemotherapeutic drugs or radiation therapy, e.g., gene therapy approaches including multidrug resistance gene therapy; and (x) one or more immunotherapy approaches, e.g., ex-vivo and in-vivo approaches to enhance the immunogenicity of patient tumor cells, e.g., transduction using cytokines, e.g., interleukin-2, interleukin-4, or granulocyte-macrophage colony-stimulating factor; approaches to reduce T cell anergy; approaches using genetically modified immune cells, e.g., approaches using dendritic cells genetically modified with cytokines; approaches using tumor cell lines genetically modified with cytokines; and approaches using anti-idiotype antibodies. Other medications that may be used in combination with PARG inhibitors are listed in International Publications 2023 / 057389, 2021 / 055744, and 2023 / 057394.

[0120]

[0120] As understood herein, the term “combination” refers to simultaneous, individual, or sequential administration. In one aspect of the present invention, “combination” refers to simultaneous administration. In another aspect of the present invention, “combination” refers to individual administration. In a further aspect of the present invention, “combination” refers to sequential administration. When administration is sequential or individual, delays in the administration of the second component should not result in the loss of the beneficial effect of the combination.

[0121]

[0121] The dosages and administrations of the methods described herein may be modified and adjusted depending on the recipient of the treatment, the disorder, condition or disease being treated and its severity, the composition containing the compound, the time of administration, the route of administration, the duration of treatment, the potency of the compound, its clearance rate, and whether or not other drugs are being administered concurrently.

[0122] definition

[0122] It is intended that the appropriate valence is maintained for all parts and combinations thereof.

[0123]

[0123] It is also intended to be understood that certain embodiments of the variable symbol portion in this specification may be the same as or different from other particular embodiments having the same identifier.

[0124]

[0124] Suitable groups for the variable symbol in a compound of formula I or its subformula are selected independently, where applicable. Useful groups not limited to the variable symbol in a compound of formula I or its subformula include, where applicable, any of the groups individually or in any combination, as shown in the examples or in the specific compounds listed in Table 1 herein. Furthermore, it should be understood that the definition of the variable symbol in formula I may have the same definition as the variable symbol defined in a subformula of formula I. Similarly, unless otherwise specified or contrary to the context, the definition of a subformula of formula I may have the same definition as the variable symbol defined in relation to formula I or another subformula of formula I.

[0125]

[0125] The embodiments described herein may be combined. Such combinations have been considered and are within the scope of this disclosure. For example, J of formula I 1 , J 2 , J 3 , J 4 , J 5 , J 6 , J 7 , J 8 , L 1 , L 2 , R 1 , and R2 Any one or more of the definitions below, where applicable, 1 , J 2 , J 3 , J 4 , J 5 , J 6 , J 7 , J 8 , L 1 , L 2 , R 1 , and R 2 This may be combined with any one or more of the other definitions, and compounds obtained from such combinations may fall within the scope of this disclosure.

[0126]

[0126] Symbol [ka] When shown perpendicular to (or especially intersecting) the bond, it indicates the point where the shown portion is bonded to the rest of the molecule. For divalent (or polyvalent) structures, the directly bonded group shown in the formula or the appropriate variable symbol indicates the direction of the bond. [ka] It should be noted that this may be shown in the outer divalent (or polyvalent) structure. Unless otherwise specified or clearly contrary to the context, if a directly linked group or variable symbol is not shown with respect to either of the two bond sites in the divalent structure, it should be assumed that bonding to the rest of the molecule is possible in either direction.

[0127]

[0127] Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, CAS edition, Handbook of Chemistry and Physics, 75th edition, inside front cover, and specific functional groups are generally defined as described therein. Furthermore, general principles of organic chemistry, as well as specific functional parts and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th 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, 3rd edition, Cambridge University Press, Cambridge, 1987. This disclosure is not intended to be limited in any way by the exemplary enumeration of substituents described herein.

[0128]

[0128] The compounds described herein may contain one or more chiral centers and therefore may exist in various stereoisomers, for example, 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 stereoisomerized mixtures, including racemic mixtures and mixtures containing many of one or more stereoisomers. The isomers may be isolated from the mixture by methods known to those skilled in the art, including chiral high-performance liquid chromatography (HPLC), chiral supercritical fluid chromatography (SFC), and the formation and crystallization of chiral salts; preferred isomers may be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron Vol. 33: p. 2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions, p. 268 (edited by ELEliel, Univ. of Notre Dame Press, Notre Dame, 1972). This disclosure further encompasses the compounds described herein as individual isomers substantially free from other isomers, or as mixtures of various isomers, including racemic mixtures. Where stereochemistry is specifically described, unless otherwise inconsistent with the context, the compound may primarily exist as the stereoisomer shown in the illustration with respect to its particular chiral center or axial chirality, and may contain other stereoisomers in amounts less than 20% by weight, less than 10% by weight, less than 5% by weight, less than 1% by weight, or undetectable amounts, for example, by HPLC area or SFC area or both. It should be understood that the compound may have an enantiomer excess of more than 60%, more than 80%, more than 90%, more than 95%, more than 98%, or more than 99%.The presence and / or amount of stereoisomers, including those obtained by the use of chiral HPLC or chiral SFC, may be determined by a person skilled in the art in consideration of this disclosure. As will be understood by a person skilled in the art, where “*” is shown in a chemical structure herein, unless particularly inconsistent with the context, it indicates that the corresponding chiral center is either enantiomerically pure or contains a large proportion of either the enantiomerically pure or the configuration as depicted, for example, by HPLC area or SFC area or both, in amounts less than 20% by weight, less than 10% by weight, less than 5% by weight, less than 1% by weight, or in amounts in which other stereoisomers are undetectable. Furthermore, where stereochemistry is not specifically depicted and “*” is not used in a chemical structure, unless particularly inconsistent with the context, it should be understood that such a structure includes the corresponding compound as any stereoisomerized form containing individual isomers substantially free of other isomers, and as a mixture of various isomers, including racemic mixtures.

[0129]

[0129] When a range of values ​​is listed, it is intended to include each value and subranges within that range. For example, "C 1~6 ” is 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

[0130]

[0130] As used herein, the term “compounds of the disclosure” means any of the compounds described herein by formula I (e.g., I-1, I-2, I-3, I-1a, I-1b, I-1c, I-2a, I-2b, I-3a, I-3b, I-1a-1, I-1a-2, I-2a-1, I-2a-2, I-3a-1, I-3a-2, I-1b-1, I-1b-2, I-2b-1, I-2b-2, I-3b-1, I-3b-2, IA, I-A1, I-A2, IB, IC, or ID), any of Examples 1 to 41, or any of the specific compounds disclosed in Table 1 of this specification. This refers to any of these isotopically labeled compounds (e.g., deuterated analogs in which one or more of the hydrogen atoms are replaced by deuterium atoms in amounts exceeding their natural abundance, e.g., CD3 analogs if the compound has a CH3 group), their possible regioisomers, possible geometric isomers, possible stereoisomers (including diastereomers, enantiomers, and racemic mixtures), their tautomers, their conformational isomers, their pharmaceutically acceptable esters, and / or their possible pharmaceutically acceptable salts (e.g., acid adduct salts, e.g., HCl salts, or base adduct salts, e.g., Na salts). In some embodiments, the compounds of the Disclosure may be selected from any of the listed embodiments A1 to 29. In some embodiments, the compounds of the Disclosure may be selected from any of the listed embodiments B1 to 43. In some embodiments, the compounds of the Disclosure may be selected from any of the listed embodiments C1 to 26. Hydrates and solvates of the compounds of the Disclosure are considered to be compositions of the Disclosure in which the compounds are associated with water or a solvent, respectively.

[0131]

[0131] The compounds of this disclosure may exist in an isotope-labeled or isotope-enriched form containing one or more atoms having atomic masses or mass numbers different from those most abundantly found in nature. The isotopes may be radioactive or non-radioactive. The isotopes of atoms, for example, hydrogen, carbon, phosphorus, sulfur, fluorine, chlorine, and iodine, are not limited to these, 2 H, 3 H, 13 C, 14C, 15 N, 18 O, 32 P, 35 S, 18 F, 36 Cl, and 125 There is I. Compounds containing other isotopes of these and / or other atoms are within the scope of the present invention.

[0132]

[0132] When used herein, the phrases “administer” the compound, “administer” the compound, or other variations thereof, mean to provide the compound or a prodrug of the compound to an individual in need of treatment.

[0133]

[0133] As used herein, the term "alkyl" refers to a linear or branched aliphatic saturated hydrocarbon, either by itself or as part of another group. In some embodiments, alkyl consists of 1 to 12 carbon atoms (i.e., C 1~12 It may contain alkyl groups or a specified number of carbon atoms. In one embodiment, the alkyl group is a linear C 1~10 It is an alkyl group. In another embodiment, the alkyl group is a branched chain C 3~10 It is an alkyl group. In another embodiment, the alkyl group is a linear C 1~6 It is an alkyl group. In another embodiment, the alkyl group is a branched chain C 3~6 It is an alkyl group. In another embodiment, the alkyl group is a linear C 1~4 It is an alkyl group. For example, C 1~4 Alkyl groups include methyl, ethyl, propyl (n-propyl), isopropyl, butyl (n-butyl), sec-butyl, tert-butyl, and iso-butyl. As used herein, the term "alkylene," whether used alone or as part of another group, refers to a divalent radical derived from an alkyl group. Examples of non-restrictive linear alkylene groups include -CH2-CH2-CH2-CH2-, -CH2-CH2-CH2-, and -CH2-CH2-.

[0134]

[0134] As used herein, the term “alkenyl” refers to a linear or branched aliphatic hydrocarbon containing one or more carbon-carbon double bonds, for example, one, two, or three, either by itself or as part of another group. In one embodiment, the alkenyl group is C 2~6 It is an alkenyl group. In another embodiment, the alkenyl group is C 2~4 These are alkenyl groups. Non-exclusive exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec-butenyl, pentenyl, and hexenyl.

[0135]

[0135] As used herein, the term "alkynyl" refers to a linear or branched aliphatic hydrocarbon containing one or more, for example, one to three carbon-carbon triple bonds, when used by itself or as part of another group. In one embodiment, the alkynyl has one carbon-carbon triple bond. In one embodiment, the alkynyl group is C 2~6 In another embodiment, the alkynyl group is C 2~4 These are alkynyl groups. Non-exclusive exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.

[0136]

[0136] When used herein, the term "alkoxy" means, when used by itself or as part of another group, the formula OR a1 It refers to the radical of, in the formula, R a1 It is alkyl.

[0137]

[0137] When used herein, the term "cycloalkoxy" means, when used by itself or as part of another group, the formula OR a1 It refers to the radical of, in the formula, R a1 It is a cycloalkyl group.

[0138]

[0138] As used herein, the term “haloalkyl” refers to an alkyl group substituted with one or more fluorine, chlorine, bromine, and / or iodine atoms, either by itself or as part of another group. In preferred embodiments, a haloalkyl group is an alkyl group substituted with one, two, or three fluorine atoms. In one embodiment, the haloalkyl group is C 1~10 It is a haloalkyl group. In one embodiment, the haloalkyl group is C 1~6 It is a haloalkyl group. In one embodiment, the haloalkyl group is C 1~4 It is a haloalkyl group.

[0139]

[0139] As used herein, the term "heteroalkyl," either by itself or in combination with other terms, means, unless otherwise specified, a stable linear or branched alkyl group, for example, having 2 to 14 carbon atoms in the chain, for example, 2 to 10 carbon atoms, one or more of which are S, O 、 It is replaced by a heteroatom selected from P and N, and the nitrogen, phosphine, and sulfur atoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. S, O of the heteroatom 、 P and N may be replaced at any internal position of the heteroalkyl group or at positions where the alkyl group is bonded to the rest of the molecule. When a heteroalkyl group is said to be substituted, the substituents may replace one or more hydrogen atoms bonded to the carbon atom and / or the heteroatom of the heteroalkyl group. In some embodiments, the heteroalkyl group is C 1~4 This refers to a heteroalkyl group, which is a heteroalkyl group as defined herein having 1 to 4 carbon atoms. 1~4Examples of heteroalkyls, but not limited to these, include C4 heteroalkyls, e.g., -CH2-CH2-N(CH3)-CH3; C3 heteroalkyls, e.g., -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-S-CH2-CH3, -CH2-CH2-S(O)-CH3, -CH2-CH2-S(O)2-CH3; C2 heteroalkyls, e.g., -CH2-CH2-OH, -CH2-CH2-NH2, -CH2-NH(CH3), -O-CH2-CH3; and C1 heteroalkyls, e.g., -CH2-OH, -CH2-NH2, -O-CH3. Preferably, C in this specification 1~4 Heteroalkyl (or C 1~4 A heteroalkylene contains one or two heteroatoms, e.g., one oxygen, one nitrogen, two oxygens, two nitrogens, or one oxygen and one nitrogen. Similarly, the term “heteroalkylene” means a divalent radical derived from a heteroalkyl group, either by itself or as part of another substituent, as exemplified by -CH2-CH2-O-CH2-CH2- and -O-CH2-CH2-NH-CH2-. With respect to heteroalkylene groups, the heteroatoms may occupy either or both of the chain ends (e.g., alkylene oxy, alkylenedioxy, alkylene amino, alkylenediamino, etc.). Furthermore, with respect to alkylene and heteroalkylene bonding groups, the orientation of the bonding group is not implied by the direction in which the formula of the bonding group is written. When “heteroalkyl” is mentioned, followed by a specific heteroalkyl group, e.g., -NR'R”” it will be understood that the terms heteroalkyl and -NR'R” are neither redundant nor mutually exclusive. Rather, the specific heteroalkyl group is mentioned for clarity. Therefore, the term "heteroalkyl" refers to a specific heteroalkyl group, e.g., -NR'R ” This specification should not be interpreted as excluding such things.

[0140]

[0140] When used by itself or as part of another group, a "carbocykrill" or "carbocyclic formula" must have at least three carbon atoms, for example, 3 to 10 ring carbon atoms ("C 3~10 The term "carbocyclyl" refers to a radical of a non-aromatic cyclic hydrocarbon group having zero heteroatoms in the non-aromatic ring system. Carbocyclyl groups may be monocyclic ("monocyclic carbocyclyl"), condensed, cross-linked, or spirocyclic systems, such as bicyclic systems ("bicyclic carbocyclyl"), and may be saturated or partially unsaturated. Non-limiting exemplary carbocyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbornyl, decalin, adamantyl, cyclopentenyl, and cyclohexenyl. As used herein, the term "carbocyclylene," whether used by itself or as part of another group, refers to a divalent radical derived from a carbocyclyl group as defined herein.

[0141]

[0141] In some embodiments, the "carbocyryl" is fully saturated and is also called a cycloalkyl. In some embodiments, the cycloalkyl may have 3 to 10 ring carbon atoms ("C 3~10 (Cycloalkyl). In preferred embodiments, the cycloalkyl is a monocyclic ring. As used herein, the term "cycloalkylene," when used by itself or as part of another group, refers to a divalent radical derived from a cycloalkyl group, for example, [ka] This refers to things like that.

[0142]

[0142] Unless otherwise defined or contrary to the context, heteroatoms as used herein refer to atoms selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon.

[0143]

[0143] "Heterocyclyl" or "heterocyclic" means a 3-membered or greater, e.g., 3-14-membered non-aromatic cyclic radical having a ring carbon atom and at least one ring heteroatom, e.g., 1-4 ring heteroatoms, when used by itself or as part of another group, where each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon. In heterocyclyl groups containing one or more nitrogen atoms, the bond site may be a carbon or nitrogen atom, as long as the valence allows. Heterocyclyl groups may be monocyclic ("monocyclic heterocyclyl"), condensed, bridging, or spirocyclic systems, e.g., bicyclic systems ("bicyclic heterocyclyl"), and may be saturated or partially unsaturated. Heterocyclyl bicyclic systems may contain one or more heteroatoms in one or both rings, and the bond site may be located on either ring. As used herein, the term “heterocyclylene” refers to a divalent radical derived from a heterocyclyl group as defined herein, whether used by itself or as part of another group. The heterocyclyl or heterocyclylene may optionally be bonded to the rest of the molecule via carbon or nitrogen atoms.

[0144]

[0144] Exemplary three-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azildinyl, oxyranil, and thiranil. Exemplary four-membered heterocyclyl groups containing one heteroatom include, but are not limited to, azetidinyl, oxetanil, and thietanil. Exemplary five-membered heterocyclyl groups containing one heteroatom include, but are not limited to, tetrahydrofuranil, dihydrofuranil, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary five-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, dioxolanil, oxasulfuranil, disulfuranil, and oxazolidine-2-one. Exemplary five-membered heterocyclyl groups containing three heteroatoms include, but are not limited to, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Examples of six-membered heterocyclyl groups containing one heteroatom include, but are not limited to, piperidinyl, tetrahydropyranil, dihydropyridinyl, and thianyl. Examples of six-membered heterocyclyl groups containing two heteroatoms include, but are not limited to, piperazinyl, morpholinil, dithianyl, and dioxanil. 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 heterocyclic rings) include, but are not limited to, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, and benzoxazolinonyl. Examples of six-membered heterocyclyl groups fused to an aryl ring (also referred to herein as 6,6-bicyclic heterocyclic rings) include, but are not limited to, tetrahydroquinolinyl and tetrahydroisoquinolinyl.

[0145]

[0145] When used by itself or as part of another group, "aryl" refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., one having 6, 10, or 14 pi electrons shared in the cyclic arrangement) that has 6 to 14 ring carbon atoms in the aromatic ring system and no heteroatoms ("C 6~14 In some embodiments, the aryl group has six ring carbon atoms ("C6 aryl"; e.g., phenyl). In some embodiments, the aryl group has ten ring carbon atoms ("C6 aryl"). 10 "Aryl"; for example, naphthyl, e.g., 1-naphthyl and 2-naphthyl). In some embodiments, the aryl group consists of 14 ring carbon atoms ("C"). 14 Having an aryl group (for example, anthracyl). As used herein, the term "arylene," whether used by itself or as part of another group, refers to a divalent radical derived from an aryl group as defined herein.

[0146]

[0146] When used by itself or as part of another group, "aralkyl" refers to an alkyl group that is substituted with one or more aryl groups, preferably one aryl group substituted. Examples of aralkyls include benzyl and phenethyl. When an aralkyl is said to be optionally substituted, either the alkyl or aryl portion of the aralkyl may be optionally substituted.

[0147]

[0147] When used by itself or as part of another group, “heteroaryl” refers to a radical of a 5- to 14-membered monocyclic, bicyclic, or tricyclic 4n+2 aromatic ring system (e.g., one having 6 or 10 pi electrons shared in the cyclic arrangement) having a ring carbon atom and at least one, preferably 1 to 4, ring heteroatoms in the aromatic ring system, where each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5- to 14-membered heteroaryl"). In heteroaryl groups containing one or more nitrogen atoms, the bond site may be on a carbon or nitrogen atom, as long as the valence allows. Heteroaryl bicyclic ring systems may contain one or more heteroatoms in one or both rings. In bicyclic heteroaryl groups that do not contain a heteroatom in one ring (e.g., indolyl, quinolinyl, etc.), the bond site may be on either ring, i.e., either ring containing a heteroatom (e.g., 2-indolyl) or ring not containing a heteroatom (e.g., 5-indolyl). As used herein, the term "heteroarylene," when used by itself or as part of another group, refers to a divalent radical derived from a heteroaryl group as defined herein.

[0148]

[0148] Exemplary five-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyrrolyl, furanyl, and thiophenyl. Exemplary five-membered heteroaryl groups containing two heteroatoms include, but are not limited to, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary five-membered heteroaryl groups containing three heteroatoms include, but are not limited to, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary five-membered heteroaryl groups containing four heteroatoms include, but are not limited to, tetrazolyl. Exemplary six-membered heteroaryl groups containing one heteroatom include, but are not limited to, pyridinyl. Exemplary six-membered heteroaryl groups containing two heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary six-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetradinyl. Examples of seven-membered heteroaryl groups containing one heteroatom include, but are not limited to, azepinyl, oxepinyl, and thiepinyl. Examples of 5,6-bicyclic heteroaryl groups include, but are not limited to, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranil, benzoisofuranil, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolidinyl, and prinyl. Examples of 6,6-bicyclic heteroaryl groups include, but are not limited to, naphthylidinyl, pteridinyl, quinolinyl, isoquinolinyl, cinolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0149]

[0149] When used by itself or as part of another group, “heteroaralkyl” refers to an alkyl group that is substituted with one or more heteroaryl groups, preferably one heteroaryl group. When a heteroaralkyl is said to be optionally substituted, either the alkyl portion or the heteroaryl portion of the heteroaralkyl may be optionally substituted.

[0150]

[0150] In use herein, unless otherwise specified or specifically indicated to the contrary, “ring structure,” “cyclic structure,” or simply “ring,” e.g., “3-10 membered ring structure,” “3-12 membered ring structure,” or “5 or 6 membered ring,” having a specified number of ring members should be understood to encompass any ring structure having a specified number of ring members (e.g., carbocyclic, heterocyclic, aryl, heteroaryl, etc.), and a ring structure is (1) monocyclic or polycyclic (where chemically feasible), e.g., monocyclic ring or bicyclic ring (condensed, spiro, and bridging bicyclic rings) (1) The ring may be a ring system in which two monocyclic rings are linked by a single or double bond; (2) It may be aromatic, partially unsaturated, or fully saturated; in the case of a polycyclic structure, each ring may independently be aromatic, partially unsaturated, or fully saturated; (3) It may contain no heteroatoms (i.e., all ring members are carbon atoms) or it may contain 1 to 4 heteroatoms; or in the case of a polycyclic structure, each ring may independently have no ring heteroatoms or 1 to 4 ring heteroatoms (e.g., O, N, S). Where a ring is said to contain a ring sulfur or nitrogen atom, the sulfur or nitrogen atom may optionally be oxidized. One or more ring carbon atoms in a ring structure may exist as C(=O). A fully saturated ring means a ring in which neither the ring carbon atoms nor any present ring heteroatoms (e.g., nitrogen) form double or triple bonds with any other atoms. The ring structure may optionally be substituted with one or more substituents as described herein. The substituents of the cyclic structure in this specification may also have a cyclic structure, and in some cases, it can be said that two substituents of the cyclic structure are bonded together to form a cyclic structure.

[0151]

[0151] For clarity, as is generally understood in the art, if a structure can be characterized in multiple ways, then the structure can be said to be a suitable definition for the variable symbol, insofar as one such characterization falls within the scope of the definition of the variable symbol as herein. For example, if a monovalent variable symbol is defined as a six-membered ring substituted by any choice, then the variable symbol can be considered, in particular, as a six-membered monocyclic or bicyclic ring substituted with a phenyl group. [ka] (b) The structure of (b) can be considered as a six-membered ring in which two substituents are bonded to form a cyclopropyl ring. [ka] It encompasses the structure of; however, since the connecting ring is not a 6-membered ring under any structural characterization, the variable symbol is [ka] This would mean that it does not include. For further explanation, instead, if the variable symbol is defined as a monoring 6-membered ring with optional substitutions, then the variable symbol is [ka] It does not include, [ka] It encompasses the structure of . If the variable symbol is defined as a six-membered ring optionally substituted with a halogen, then each of these can be considered as an unsubstituted six-membered ring or a six-membered ring substituted with one or two fluorine atoms, so the variable symbol is a structure, for example, [ka] It may include.

[0152]

[0152] As is commonly understood in the art, alkylene, alkenylene, alkynylene, heteroalkylene, carbocyrylene, heterocyclylene, arylene, and heteroarylene refer to the corresponding divalent radicals of alkyl, alkenyl, alkynyl, heteroalkyl, carbocyryl, heterocyclyl, aryl, and heteroaryl groups, respectively.

[0153]

[0153] The terms "optionally substituted" groups, such as optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl groups, refer to the respective unsubstituted or substituted groups. Generally, the term "substituted" means that at least one hydrogen (e.g., carbon or nitrogen atom) present on the group is replaced by an acceptable substituent, such as a substituent that results in a stable compound upon substitution, such as rearrangement, cyclization, disappearance, or other reaction, with a compound that is not spontaneously converted. Unless otherwise indicated, a "substituted" group has substituents at one or more substituted positions on the group, and if more than one position is substituted in any given structure, the substituents may be the same or different at each position. Typically, if substituted, the optionally substituted groups as used herein may be substituted with 1 to 5 substituents. The substituents may, where applicable, be carbon atom substituents, nitrogen atom substituents, oxygen atom substituents, or sulfur atom substituents, each of which may be optionally isotopically labeled or, for example, deuterated. Two of the optionally substituted substituents may bond to form a ring structure, such as an optionally substituted cycloalkyl, heterocyclyl, aryl, or heteroaryl ring. Substitutions may occur on any available carbon, oxygen, or nitrogen atom and can form a spiro ring. Typically, substitutions as used herein do not result in OO, ON, SS, SN (except SO2-N bonds), heteroatom-halogens, or -C(O)-S bonds (except O-SO2-O, O-SO2-N, and N-SO2-N), except for three or more consecutive heteroatoms, however, this may be possible if some of such bonds or linkages are present in a stable aromatic system.

[0154]

[0154] In a broad range of embodiments, the substituents permitted herein include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permitted substituents may be one or more, and may be the same or different, with respect to a suitable organic compound. For the purposes of this disclosure, a heteroatom, for example, nitrogen, may have any permitted substituent of the organic compound described herein that satisfies the valence of the hydrogen substituent and / or the heteroatom. Substituents may be any substituents described herein, such as halogens, hydroxyls, carbonyls (e.g., carboxyls, alkoxycarbonyls, formyls, or acyls), thiocarbonyls (e.g., thioesters, thioacetates, or thioformates), alkoxys, cycloalkoxys, phosphoryls, phosphates, phosphonates, phosphinates, aminos, amides, amidines, imines, cyanos, nitros, azides, sulfhydryls, alkylthios, sulfates, sulfonates, sulfamoyls, sulfonamides, sulfonyls, heterocyclyls, aralkyls, aryls, or heteroaryls, each of which may be substituted as appropriate.

[0155]

[0155] Exemplary substituents include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl, -arylene-alkyl, -alkylene-heteroaryl, -alkenylene-heteroaryl, -alkyline-heteroaryl, -OH, hydroxyalkyl, haloalkyl, -O-alkyl, -O-haloalkyl, -alkylene-O-alkyl, -O-aryl, -O-alkylene-aryl, -O-heteroaryl, -O-alkylene-heteroaryl, -O-cycloalkyl, -O- Terocycloalkyl, acyl, -C(O)-alkyl, -C(O)-haloalkyl, -C(O)-aryl, -C(O)-alkylene-aryl, -C(O)-heteroaryl, -C(O)-alkylene-heteroaryl, -C(O)-cycloalkyl, -C(O)-heterocycloalkyl, halo, -NO2, -CN, -SF5, -C(O)OH, -C(O)O-alkyl, -C(O)O-aryl, -C(O)O-alkylene-aryl, -S(O)-alkyl, -S(O)2-alkyl, -S(O)-haloalkyl, -S(O)2-haloalkyl, -S (O)-aryl, -S(O)2-aryl, -S(O)-heteroaryl, -S(O)2-heteroaryl, -S-alkyl, -S-aryl, -S-heteroaryl, -S-alkylene-aryl, -S-alkylene-heteroaryl, -S(O)2-alkylene-aryl, -S(O)2-alkylene-heteroaryl, -S-cycloalkyl, -S-heterocycloalkyl, -S(O)-cycloalkyl, -S(O)-heterocycloalkyl, -S(O)2-cycloalkyl, -S(O)2-heterocycloalkyl, -S(O)(=NH)-aryl Kill, -S(O)(=NH)-haloalkyl, -S(O)(=NH)-aryl, -S(O)(=NH)-alkylene-aryl, -S(O)(=NH)-heteroaryl, -S(O)(=NH)-alkylene-heteroaryl, -S(O)(=NH)-cycloalkyl, -S(O)(=NH)-heterocycloalkyl, -S(O)(=Nalkyl)-alkyl, -S(O)(=Nalkyl)-haloalkyl, -S(O)(=Nalkyl)-aryl, -S(O)(=Nalkyl)-alkylene-aryl, -S(O)(=Nalkyl)-heteroaryl,-S(O)(=Nalkyl)-alkylene-heteroaryl, -S(O)(=Nalkyl)-cycloalkyl, -S(O)(=Nalkyl)-heterocycloalkyl, cycloalkyl, heterocycloalkyl, -OC(O)-alkyl, -OC(O)-aryl, -OC(O)-cycloalkyl, -C(=N-CN)-NH2, -C(=NH)-NH2, -C(=NH)-NH(alkyl), -N(Y1)(Y2), -alkylene-N(Y 1) There are (Y2), -C(O)N(Y1)(Y2), and -S(O)2N(Y1)(Y2), where Y1 and Y2 may be the same or different, and are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, aryl, -alkylene-aryl, heteroaryl, -alkylene-heteroaryl, cycloalkyl, and heterocycloalkyl. Y1 and Y2 can form heterocyclic rings together with the nitrogen to which they are bonded.

[0156]

[0156] Some examples of preferred substituents, but not limited to these, include (C1-C8) alkyl groups, (C2-C8) alkenyl groups, (C2-C8) alkynyl groups, (C3-C 10)Cycloalkyl groups, halogens (F, Cl, Br or I), halogenated (C1~C8) alkyl groups (e.g., -CF3, but not limited to these), -O-(C1~C8) alkyl groups, -OH, -S-(C1~C8) alkyl groups, -SH, -NH(C1~C8) alkyl groups, -N((C1~C8)alkyl)2 groups, -NH2, -C(O)NH2, -C(O)NH(C1~C8) alkyl groups, -C(O)N((C1~C8)alkyl)2, -NHC(O)H, -NHC(O)(C1~C8) alkyl groups, -NHC(O)(C3~C8) cycloalkyl groups, -N ((C1~C8)alkyl)C(O)H, -N((C1~C8)alkyl)C(O)(C1~C8)alkyl group, -NHC(O)NH2, -NHC(O)NH(C1~C8)alkyl group, -N((C1~C8)alkyl)C(O)NH2 group, -NHC(O)N((C1~C8)alkyl)2 group, -N((C1~C8)alkyl)C(O)N((C1~C8)alkyl)2 group, -N((C1~C8)alkyl)C(O)NH((C1~C8)alkyl), -C(O)H, -C(O)(C1~C8)alkyl group, -CN, -NO2, -S(O)(C1~C8) HCl group, -S(O)2(C1~C8)alkyl group, -S(O)2N((C1~C8)alkyl)2 group, -S(O)2NH(C1~C8)alkyl group, -S(O)2NH(C3~C8)cycloalkyl group, -S(O)2NH2 group, -NHS(O)2(C1~C8)alkyl group, -N((C1~C8)alkyl)S(O)2(C1~C8)alkyl group, -(C1~C8)alkyl-O-(C1~C8)alkyl group, -O-(C1~C8)alkyl-O-(C1~C8)alkyl group, -C(O)OH, -C(O)O(C1~C8)alkyl group, NHOH, NHO (C1~C8) alkyl groups, -O-halogenated (C1~C8) alkyl groups (e.g., -OCF3, but not limited to these), -S(O)2-halogenated (C1~C8) alkyl groups (e.g., -S(O)2CF3, but not limited to these), -S-halogenated (C1~C8) alkyl groups (e.g., -SCF3, but not limited to these), -(C1~C6) heterocyclic groups (e.g., pyrrolidine, tetrahydrofuran, pyran, or morpholine, but not limited to these), -(C1~C6) heteroaryl groups (e.g., tetrazole, imidazole, but not limited to these),These include furan, pyrazine, or pyrazole, -phenyl, -NHC(O)O-(C1~C6)alkyl, -N((C1~C6)alkyl)C(O)O-(C1~C6)alkyl, -C(=NH)-(C1~C6)alkyl, -C(=NOH)-(C1~C6)alkyl, or -C(=NO-(C1~C6)alkyl)-(C1~C6)alkyl.

[0157]

[0157] Exemplary carbon atom substituents include, but are not limited to, deuterium, halogens, -CN, -NO2, -N3, hydroxyl, alkoxy, cycloalkoxy, aryloxy, amino, monoalkylamino, dialkylamino, amide, sulfonamide, thiol, acyl, carboxylic acid, ester, sulfone, sulfoxide, alkyl, haloalkyl, alkenyl, alkynyl, C 3~10 Carbocyclyl, C 6~10 Examples include aryls, 3-10 membered heterocyclines, and 5-10 membered heteroaryls. For example, exemplary carbon atom substituents include F, Cl, -CN, -SO2H, -SO3H, -OH, and -OC. 1~6 Alkyl, -NH2, -N(C 1~6 Alkyl)2,-NH(C 1~6 Alkyl), -SH, -SC 1~6 Alkyl, -C(=O)(C 1~6 Alkyl), -CO2H, -CO2(C 1~6 Alkyl), -OC(=O)(C 1~6 Alkyl), -OCO2(C 1~6 Alkyl), -C(=O)NH2, -C(=O)N(C 1~6 Alkyl)2,-OC(=O)NH(C 1~6 Alkyl), -NHC(=O)(C 1~6 Alkyl), -N(C 1~6 Alkyl)C(=O)(C 1~6 Alkyl), -NHCO2(C 1~6 Alkyl), -NHC(=O)N(C 1~6 Alkyl)2,-NHC(=O)NH(C 1~6 Alkyl), -NHC(=O)NH2, -NHSO2(C 1~6 Alkyl), -SO2N(C1~6 Alkyl)2,-SO2NH(C 1~6 Alkyl), -SO2NH2,-SO2C 1~6 Alkyl, -SO2OC 1~6 Alkyl, -OSO2C 1~6 Alkyl, -SOC 1~6 Alkyl, C 1~6 Alkyl, C 1~6 Haloalkyl, C 2~6 Alkenil, C 2~6 Alkinyl, C 3~10 Carbocyclyl, C 6~10 The substituents may be aryl, 3- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl; or two geminal substituents may be bonded to form =O.

[0158]

[0158] Nitrogen atoms may be substituted or unsubstituted as long as their valence allows, and nitrogen atoms can be primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents, but are not limited to these, include hydrogen, acyl groups, esters, sulfones, sulfoxides, and C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenil, C 2~10 Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C 6~14The rings may consist of an aryl group and a 5- to 14-membered heteroaryl group, or two substituents bonded to the nitrogen atom to form a 3- to 14-membered heterocyclyl or 5- to 14-membered heteroaryl ring, where each alkyl, alkenyl, alkynyl, carbocykryl, heterocyclyl, aryl, and heteroaryl group may be further substituted as defined herein. In certain embodiments, the substituents on the nitrogen atom are nitrogen protecting groups (also known as amino protecting groups). Nitrogen protecting groups are well known in the art, and include those described in detail in Protective Groups in Organic Synthesis, TW Greene and PGMWuts, 3rd edition, John Wiley & Sons, 1999, which are incorporated herein by reference. Examples of nitrogen protecting groups include, but are not limited to, those that form carbamates, such as carbobenzyloxy (Cbz) group, p-methoxybenzylcarbonyl (Moz or MeOZ) group, tert-butyloxycarbonyl (BOC) group, Troc, 9-fluorenylmethyloxycarbonyl (Fmoc) group, etc.; those that form amides, such as acetyl, benzoyl, etc.; those that form benzylamines, such as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, etc.; those that form sulfonamides, such as tosyl, nosyl, etc.; and others, such as p-methoxyphenyl.

[0159]

[0159] Examples of oxygen atom substituents are not limited to these, but include acyl groups, esters, sulfonates, and C 1~10 Alkyl, C 1~10 Haloalkyl, C 2~10 Alkenil, C 2~10 Alkinyl, C 3~10 Carbocyclyl, 3-14 member heterocyclyl, C 6~14There are aryl and 5- to 14-membered heteroaryl groups, each alkyl, alkenyl, alkynyl, carbocyryl, heterocyclyl, aryl, and heteroaryl group may be further substituted as defined herein. In certain embodiments, the oxygen atom substituent present on the oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups are well known in the art, and include those described in detail in Protective Groups in Organic Synthesis, TW Greene and PGMWuts, 3rd edition, John Wiley & Sons, 1999, which are incorporated herein by reference. Examples of oxygen protecting groups include, but are not limited to, those forming alkyl ethers or substituted alkyl ethers, such as methyl, allyl, benzyl, substituted benzyl, such as 4-methoxybenzyl, methoxylmethyl (MOM), benzyloxymethyl (BOM), and 2-methoxyethoxymethyl (MEM); those forming silyl ethers, such as trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), and t-butyldimethylsilyl (TBDMS); those forming acetals or ketals, such as tetrahydropyranyl (THP); those forming esters, such as formates, acetates, chloroacetates, dichloroacetates, trichloroacetates, trifluoroacetates, and methoxyacetates; and those forming carbonates or sulfonates, such as methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

[0160]

[0160] Unless otherwise expressly provided, combinations of substituents and / or variable symbols are acceptable only if such combinations are chemically possible and result in a stable compound. A “stable” compound is one that can be prepared and isolated, and whose structure and properties remain substantially unchanged or can be kept substantially unchanged for a sufficient period of time to enable the compound to be used for the purposes described herein (e.g., therapeutic administration to a subject).

[0161]

[0161] In some embodiments, the "optionally substituted" alkyl, alkylene, heteroalkyl, heteroalkylene, alkenyl, alkynyl, carbocyclic, carbocyclylene, cycloalkyl, cycloalkylene, alkoxy, cycloalkoxy, heterocyclyl, or heterocyclylene in this specification may not be independently substituted with deuterium, F, Cl, -OH, protected hydroxyl, oxo (where applicable), NH2, protected amino, NH(C) 1~4 Alkyl) or its protected derivatives, N(C 1~4 Alkyl((C 1~4 Alkyl), C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 1~4 Alkoxy, C 3~6 Cycloalkyl, C 3~6 The alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxyphenyl, heteroaryl, and heterocyclyl compounds may be substituted with one, two, three, or four substituents independently selected from cycloalkoxy, phenyl, O, S, and N, 5- or 6-membered heteroaryl compounds containing one, two, or three ring heteroatoms independently selected from O, S, and N, each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxyphenyl, heteroaryl, and heterocyclyl compounds may be substituted with deuterium, F, -OH, oxo (where applicable), C 1~4 Alkyl, fluorosubstituted C 1~4 Alkyl (e.g., CF3), C 1~4 Alkoxy and fluorosubstituted C 1~4The alkoxy is optionally substituted with one, two, or three substituents independently selected. In some embodiments, the "optionally substituted" aryl, arylene, heteroaryl, or heteroarylene groups as used herein may not be independently substituted with deuterium, F, Cl, -OH, -CN, NH2, protected amino, or NH(C) 1~4 Alkyl) or its protected derivatives, N(C 1~4 Alkyl((C 1~4 Alkyl), -S(=O)(C 1~4 Alkyl), -SO2(C 1~4 Alkyl), C 1~4 Alkyl, C 2~4 Alkenil, C 2~4 Alkinyl, C 1~4 Alkoxy, C 3~6 Cycloalkyl, C 3~6 The alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, oxo (where applicable), and heterocyclyl may be substituted with one, two, three, or four substituents independently selected from cycloalkoxy, phenyl, O, S, and N, 5- or 6-membered heteroaryls containing one, two, or three ring heteroatoms independently selected from O, S, and N, each alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkoxy, phenyl, heteroaryl, and heterocyclyl may be substituted with deuterium, F, -OH, oxo (where applicable), C 1~4 Alkyl, fluorosubstituted C 1~4 Alkyl, C 1~4 Alkoxy and fluorosubstituted C 1~4 It is optionally substituted with one, two, or three substituents independently selected from the alkoxy.

[0162]

[0162] "Halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iod, -I).

[0163]

[0163] The term "pharmaceutically acceptable salt" refers to a salt that, within the bounds of sound medical judgment, does not exhibit excessive toxicity, irritation, or allergic reactions, is suitable for use in contact with human and lower animal tissues, and has a reasonable benefit-to-risk ratio. pharmaceutically acceptable salts are well known in the art.

[0164]

[0164] The terms “tautomer” or “tautomerous” refer to two or more interconvertible compounds resulting from tautomerization. The exact ratio of tautomers depends on several factors, including, for example, temperature, solvent, and pH. Tautomerization is known to those skilled in the art. Exemplary tautomerizations include tautomerization from keto to enol, amide to imide, lactam to lactim, enamine to imine, and enamine to (different enamine).

[0165]

[0165] The term “subject” (or “patient” as used herein) means, as used herein, an animal, preferably a mammal, most preferably a human being, that is being treated, observed or experimented on.

[0166]

[0166] As used herein, terms such as “to treat,” “to treat,” and “treatment” mean to eliminate, reduce, or improve a disease or condition and / or symptoms associated therewith. Treating a disease or condition does not mean eliminating it, but does not require the complete disappearance of the disease, condition, or symptoms associated therewith. As used herein, terms such as “to treat,” “to treat,” and “treatment” may include “preventive treatment,” which means reducing the probability of recurrence of a disease or condition or a previously controlled disease or condition in subjects who do not have a disease or condition but are at risk of recurring or are highly susceptible to recurrence of a disease or condition. The term “to treat” and its synonyms are intended to mean administering a therapeutically effective amount of the compound described herein to subjects requiring such treatment.

[0167]

[0167] The term “effective dose” refers to the amount of any compound or combination of compounds described herein that is sufficient to produce the intended application, including the prevention or treatment of a disease. The therapeutic effective dose may vary depending on the intended application (in vitro or in vivo), or the subject and disease state being treated (e.g., the subject’s weight, age, and sex), the severity of the disease state, the mode of administration, etc., and can be readily determined by those skilled in the art. The term also applies to the dose that will induce a particular response in target cells and / or tissues. The specific dose will vary depending on the specific compound selected, the dosage to be followed, whether the compound is administered in combination with other compounds, the timing of administration, the tissue to which it is administered, and the physical delivery system through which the compound is delivered.

[0168]

[0168] In this specification, the singular forms "a," "an," and "the" include plural referents unless expressly provided otherwise or unless it is entirely clear from the context that this is not the intended meaning.

[0169]

[0169] When the term “and / or” is used herein in a phrase, for example, “A and / or B,” it is intended to include both A and B; A or B; A (alone); and B (alone). Similarly, when the term “and / or” is used in a phrase, for example, “A, B, and / or C,” it is intended to include the following embodiments, respectively: A, B, and C; A, B, or C; A or C; A or B; B or C; A and C; A and B; B and C; A (alone); B (alone); and C (alone).

[0170]

[0170] Headings and subheadings are used solely for convenience and / or formal compliance and are not intended to limit the scientific and technological subject matter, nor are they to be referenced in connection with the interpretation of the description of the scientific and technological subject matter. Features described under one heading or subheading of the disclosure may be combined in various embodiments with features described under other headings or subheadings. Furthermore, it is not necessarily required that all features under a single heading or subheading be used together in an embodiment.

[0171] [Examples]

[0171] Various starting materials, intermediates, and compounds of the embodiments herein may be isolated and purified, where appropriate, using the prior art, e.g., precipitation, filtration, crystallization, evaporation, distillation, and chromatography. These compounds may be characterized using conventional methods, e.g., by melting point, mass spectrometry, nuclear magnetic resonance, and various other spectroscopic analyses. Abbreviations used in the Examples section should be understood to have their ordinary meanings in the art unless otherwise specifically indicated or obviously contrary to the context. The examples are illustrative and in no way limit the claimed invention.

[0172]

[0172] Exemplary embodiments of the steps for synthesizing the products described herein are described in further detail below.

[0173]

[0173] Intermediate A

[0174]

[0174] 2-(5-(benzylthio)-7-chloropyrazolo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole(A) [ka]

[0175]

[0175] Step 1: 5-bromo-7-chloropyrazolo[1,5-a]pyridine (A-1)

[0176]

[0176] To a solution of 5-bromopyrazolo[1,5-a]pyridine (3 g, 15.2 mmol) in dry THF (70 mL), LiHMDS (1 M in THF solution, 18.3 mL, 18.3 mmol) was added dropwise under N2 at -78°C. After stirring for 2 hours, a solution of C2Cl6 (3.24 g, 13.7 mmol) in dry THF (5 mL) was added dropwise under an N2 atmosphere at -78°C. The reaction mixture was then warmed to room temperature and stirred at room temperature for 6 hours. LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This was purified by silica gel flash column chromatography (eluting with 8% Â in PE) to obtain 5-bromo-7-chloropyrazolo[1,5-a]pyridine (2.7 g). LCMS (ESI, m / z): [M+H] + = 230.9.

[0177]

[0177] Step 2: 5-(benzylthio)-7-chloropyrazolo[1,5-a]pyridine (A-2)

[0178]

[0178] To a solution of 5-bromo-7-chloropyrazolo[1,5-a]pyridine (2.9 g, 12.5 mmol) and phenylmethanethiol (1.87 g, 15.0 mmol) in 1,4-dioxane (100 mL), DIEA (1.62 g, 12.5 mmol, 2.18 mL), xanthophos (1.45 g, 2.51 mmol), and Pd2(dba)3 (1.15 g, 1.25 mmol) were added under N2 conditions. The reaction mixture was degassed and then stirred at 100°C for 3 hours under an N2 atmosphere. LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and extracted with phenylmethane. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (elution with 13% ethyl acetate in PE) to obtain 5-benzylsulfanyl-7-chloropyrazolo[1,5-a]pyridine (700 mg). LCMS (ESI, m / z): [M+H]+ = 274.9.

[0179]

[0179] Step 3: 5-(benzylthio)-7-chloro-3-iodopyrazolo[1,5-a]pyridine (A-3)

[0180]

[0180] To a solution of 5-benzylsulfanyl-7-chloropyrazolo[1,5-a]pyridine (587 mg, 2.14 mmol) in acetonitrile (15 mL), NIS (514.3 mg, 2.29 mmol) was added under N2 at room temperature. The reaction mixture was stirred at room temperature for 1 hour. LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluted with 15% ethyl acetate in PE) to obtain 5-benzylsulfanyl-7-chloro-3-iodopyrazolo[1,5-a]pyridine (788 mg). LC-MS (ESI, m / z): [M+H] + = 400.8.

[0181]

[0181] Step 4: 5-(benzylthio)-7-chloro-3-(trimethylstannyl)pyrazolo[1,5-a]pyridine (A-4)

[0182]

[0182] To a solution of 5-benzylsulfanyl-7-chloro-3-iodopyrazolo[1,5-a]pyridine (600 mg, 1.5 mmol) in 1,4-dioxane (10 mL), trimethyl(trimethylstannyl)stannane (588 mg, 1.8 mmol) and Pd(PPh3)4 (86 mg, 0.075 mmol) were added under N2. The reaction mixture was degassed with N2 and then stirred at 100°C for 1.5 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. LC-MS (ESI, m / z): [M+H] + = 437.0.

[0183]

[0183] Step 5: 2-(5-(benzylthio)-7-chloropyrazolo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole(A)

[0184]

[0184] To a solution of (5-benzylsulfanyl-7-chloropyrazolo[1,5-a]pyridine-3-yl)-trimethyl-stannan (300 mg, 0.69 mmol) in DMF (10 mL), 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (162 mg, 0.75 mmol) and Pd(PPh3)4 (80 mg, 0.068 mmol) were added under N2 conditions. The reaction mixture was degassed and then stirred at 100°C for 5 hours under an N2 atmosphere. LC-MS indicated that the reaction was complete. The reaction mixture was then work-treated with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (elution with 5%-10% ethyl acetate in PE) to obtain 2-(5-(benzylthio)-7-chloropyrazolo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (230 mg). LCMS (ESI, m / z): [M+H] + = 409.1.

[0185]

[0185] Intermediate B

[0186]

[0186] 7-Chloro-N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)pyrazolo[1,5-a]pyridine-5-sulfonamide(B) [ka]

[0187]

[0187] Step 1: 7-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)pyrazolo[1,5-a]pyridine-5-sulfonyl chloride (B-1)

[0188]

[0188] The mixture was stirred at room temperature for 1.5 hours. LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product (420 mg), which was used directly in the next step without further purification. LC-MS (ESI, m / z): [M+H] + = 385.1.

[0189]

[0189] Step 2: 7-Chloro-N-(1-cyanocyclopropyl)-3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)pyrazolo[1,5-a]pyridine-5-sulfonamide (B)

[0190]

[0190] To a solution of 1-aminocyclopropane carbonitride hydrochloride (27.7 mg, 0.234 mmol) in DCM (1 mL), TEA (79 mg, 0.779 mmol, 0.109 mL) was added. After stirring for 5 minutes, 7-chloro-3-[5-(difluoromethyl)-1,3,4-thiadiazole-2-yl]pyrazolo[1,5-a]pyridine-5-sulfonyl chloride (100 mg, 0.260 mmol) in DCM (1 mL) was added under N2 at 0°C. The reaction mixture was stirred at 0°C for 2 hours. LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (elution with 5% MeOH in DCM) to obtain 7-chloro-N-(1-cyanocyclopropyl)-3-[5-(difluoromethyl)-1,3,4-thiadiazole-2-yl]pyrazolo[1,5-a]pyridine-5-sulfonamide (12 mg). LCMS (ESI, m / z): [M+H] + = 431.0.

[0191]

[0191] Intermediate C

[0192]

[0192] 2-bromo-5-(1-fluorocyclopropyl)-1,3,4-thiadiazole (C) [ka]

[0193]

[0193] Step 1: 5-(1-fluorocyclopropyl)-1,3,4-thiadiazole-2-amine(C-1)

[0194]

[0194] To a solution of 1-fluorocyclopropanecarboxylic acid (2 g, 19.2 mmol) in POCl3 (20 mL), aminothiourea (1.75 g, 19.2 mmol) was added under N2. The mixture was stirred at 80°C for 1 hour. LC-MS indicated that the reaction was complete. The reaction mixture was cooled to room temperature, carefully poured into water, and then neutralized to pH 7-8 with saturated NaHCO3 aqueous solution. The resulting mixture was extracted with ELISA. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 5-(1-fluorocyclopropyl)-1,3,4-thiadiazole-2-amine (2.17 g). LC-MS (ESI, m / z): [M+H] + = 160.0.

[0195]

[0195] Step 2: 2-bromo-5-(1-fluorocyclopropyl)-1,3,4-thiadiazole (C)

[0196]

[0196] To a solution of 5-(1-fluorocyclopropyl)-1,3,4-thiadiazole-2-amine (2.17 g, 13.6 mmol) in ACN (50 mL), CuBr2 (4.57 g, 20.5 mmol) and tert-butylnitrite (1.72 g, 16.6 mmol, 1.98 mL) were added under N2 at -20°C. The mixture was stirred at -20°C for 5 hours. LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluted with 13% ethyl acetate in PE) to obtain 2-bromo-5-(1-fluorocyclopropyl)-1,3,4-thiadiazole (1.4 g). LC-MS (ESI, m / z): [M+H] + = 222.8.

[0197]

[0197] Intermediate D

[0198]

[0198] 2-Bromo-4-(difluoromethyl)thiazole (D) [ka]

[0199]

[0199] To a solution of 2-bromothiazole-4-carbaldehyde (2.0 g, 10.4 mmol) in DCM (20 mL), DAST (6.72 g, 41.7 mmol) was added under N2 at 0°C. The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was quenched with saturated NaHCO3 aqueous solution and then extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluted with 5% ethyl acetate in PE) to obtain 2-bromo-4-(difluoromethyl)thiazole (1.5 g). 1 H NMR (400 MHz, DMSO-d6) δ 8.18 (s 1H), 7.07 (t, J = 54.0 Hz, 1H).

[0200]

[0200] Intermediate E

[0201]

[0201] Isopropylpiperazine-1-carboxylate hydrochloride (E) [ka]

[0202]

[0202] Step 1: 1-(tert-butyl)4-isopropylpiperazine-1,4-dicarboxylate (E-1)

[0203]

[0203] To a mixture of tert-butylpiperazine-1-carboxylate (1 g, 5.37 mmol) and TEA (1.63 g, 16.1 mmol, 2.25 mL) in DCM (10 mL), isopropyl carbonochloride (790 mg, 6.44 mmol) was added under N2 at room temperature. The mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was work-treated with water and extracted with DCM. The combined organic layer was washed with aqueous HCl (1 M), then saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain 1-(tert-butyl)4-isopropylpiperazine-1,4-dicarboxylate (1.3 g).

[0204]

[0204] Step 2: Isopropylpiperazine-1-carboxylate hydrochloride (E)

[0205]

[0205] 1-(tert-butyl)4-isopropylpiperazine-1,4-dicarboxylate (1 g, 3.67 mmol) was added to a solution of HCl in a 1,4-dioxane solution (4.0 M, 11 mL). The reaction mixture was stirred at room temperature for 1 hour. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain isopropylpiperazine-1-carboxylate hydrochloride (750 mg), which was used directly in the next step without further purification.

[0206]

[0206] Intermediate F

[0207]

[0207] (1-methylcyclobutyl)(piperazin-1-yl)methanone hydrochloride (F) [ka]

[0208]

[0208] Step 1: tert-butyl 4-(1-methylcyclobutanecarbonyl)piperazine-1-carboxylate (F-1)

[0209]

[0209] In a solution of 1-methylcyclobutanecarboxylic acid (505 mg, 4.42 mmol), tert-butylpiperazine-1-carboxylate (750 mg, 4.03 mmol), and DIPEA (1.56 g, 12.1 mmol, 2.10 mL) in DMF (5 mL), HATU (1.68 g, 4.42 mmol) was added under N2. The reaction mixture was stirred at room temperature for 3 hours. LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluting with 0-30% ethyl acetate in PE) to obtain tert-butyl 4-(1-methylcyclobutanecarbonyl)piperazine-1-carboxylate (0.95 g).

[0210]

[0210] Step 2: (1-methylcyclobutyl)-piperazine-1-yl-methanone hydrochloride (F)

[0211]

[0211] tert-butyl 4-(1-methylcyclobutanecarbonyl)piperazine-1-carboxylate (300 mg, 1.06 mmol) was added to HCl in 1,4-dioxane (4 M, 6 mL) at 0°C. The mixture was warmed to room temperature and stirred under an N2 atmosphere for 3 hours. TLC indicated that the reaction was complete. The reaction mixture was concentrated to obtain (1-methylcyclobutyl)(piperazine-1-yl)methanone hydrochloride (200 mg). LCMS (ESI, m / z): [M+H] + = 183.1.

[0212]

[0212] Intermediate G

[0213]

[0213] 2-methyl-5-(piperazin-1-yl)-1,3,4-thiadiazole hydrochloride (G) [ka]

[0214]

[0214] Step 1: tert-butyl 4-(5-methyl-1,3,4-thiadiazole-2-yl)piperazine-1-carboxylate (G-1)

[0215]

[0215] To a solution of 2-bromo-5-methyl-1,3,4-thiadiazole (500 mg, 2.79 mmol) and DIPEA (256 mg, 5.58 mmol) in 1,4-dioxane (7 mL), tert-butylpiperazine-1-carboxylate (520 mg, 2.79 mmol) was added under N2 at room temperature. The reaction mixture was stirred at 110 °C for 5 hours. LC-MS indicated that the reaction was complete. The reaction mixture was cooled to room temperature, work-treated with water, and then extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluting with 30% ethyl acetate in PE) to obtain tert-butyl 4-(5-methyl-1,3,4-thiadiazole-2-yl)piperazine-1-carboxylate (680 mg). LCMS (ESI, m / z): [M+H] + = 285.4.

[0216]

[0216] Step 2: 2-Methyl-5-piperazine-1-yl-1,3,4-thiadiazole hydrochloride (G)

[0217]

[0217] tert-butyl 4-(5-methyl-1,3,4-thiadiazole-2-yl)piperazine-1-carboxylate (680 mg, 2.39 mmol) was added to a solution of HCl in 1,4-dioxane (4 M, 4 mL). The mixture was stirred at room temperature for 2 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain 2-methyl-5-piperazine-1-yl-1,3,4-thiadiazole hydrochloride (520 mg). LC-MS (ESI, m / z): [M+H] + = 184.26.

[0218]

[0218] Intermediate H

[0219]

[0219] (S)-(3-fluoropyrrolidine-1-yl)(piperazine-1-yl)methanone hydrochloride (H) [ka]

[0220]

[0220] Step 1: tert-butyl(S)-4-(3-fluoropyrrolidine-1-carbonyl)piperazine-1-carboxylate(H-1)

[0221]

[0221] To a solution of tert-butylpiperazine-1-carboxylate (1.92 g, 10.3 mmol) and bis(trichloromethyl) carbonate (1.53 g, 5.17 mmol) in DCM (40 mL), DIEA (4.01 g, 30.9 mmol, 5.40 mL) was added dropwise at 0°C under N2. The mixture was stirred at room temperature under an N2 atmosphere for 3 hours. Then, (S)-3-fluoropyrrolidine (920 mg, 10.3 mmol) was added and stirred for a further 30 minutes. After completion, the reaction mixture was work-treated with water and then extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (0.05% NH4HCO3) to obtain tert-butyl(S)-4-(3-fluoropyrrolidine-1-carbonyl)piperazine-1-carboxylate (800 mg). LCMS (ESI, m / z): [M+H-tBu] + = 246.2.

[0222]

[0222] Step 2: (S)-(3-fluoropyrrolidine-1-yl)(piperazine-1-yl)methanone(H)

[0223]

[0223] To a solution of tert-butyl(S)-4-(3-fluoropyrrolidine-1-carbonyl)piperazine-1-carboxylate (500 mg, 1.66 mmol) in MeOH (5 mL), HCl (4.0 M in 1,4-dioxane, 2.5 mL) was added. The mixture was stirred at room temperature for 3 hours. After completion, the mixture was concentrated under reduced pressure to obtain (S)-(3-fluoropyrrolidine-1-yl)(piperazine-1-yl)methanone hydrochloride (330 mg). LCMS (ESI, m / z): [M+H] + = 202.3.

[0224]

[0224] Intermediate I

[0225]

[0225] 2-methyl-5-(piperazin-1-yl)-1,3,4-oxadiazole hydrochloride (I) [ka]

[0226]

[0226] Step 1: tert-butyl 4-(5-methyl-1,3,4-oxadiazole-2-yl)piperazine-1-carboxylate (I-1)

[0227]

[0227] To a solution of 2-bromo-5-methyl-1,3,4-oxadiazole (500 mg, 3.07 mmol) in 1,4-dioxane (7 mL), tert-butylpiperazine-1-carboxylate (571 mg, 3.07 mmol) and DIEA (786 mg, 6.14 mmol) were added at room temperature. The mixture was stirred at 110 °C for 5 hours under an N2 atmosphere. LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and then extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluting with 30% ethyl acetate in PE) to obtain tert-butyl 4-(5-methyl-1,3,4-oxadiazole-2-yl)piperazine-1-carboxylate (650 mg). LCMS (ESI, m / z): [M+H] + = 269.2.

[0228]

[0228] Step 2: 2-Methyl-5-piperazin-1-yl-1,3,4-oxadiazole(I)

[0229]

[0229] A mixture of tert-butyl 4-(5-methyl-1,3,4-oxadiazole-2-yl)piperazine-1-carboxylate (300 mg, 1.12 mmol) in a solution of HCl (4.0 M in 1,4-dioxane, 4 mL) was stirred at room temperature for 2 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain 2-methyl-5-(piperazine-1-yl)-1,3,4-oxadiazole hydrochloride (230 mg), which was used directly in the next step without further purification. LC-MS (ESI, m / z): [M+H] + = 169.1.

[0230]

[0230] Intermediate J

[0231]

[0231] 5-bromo-3-(difluoromethyl)-1,2,4-thiadiazole (J) [ka]

[0232]

[0232] Step 1: 2,2-difluoroacetoimidamide hydrochloride (J-1)

[0233]

[0233] Trimethylaluminum (10.4 g, 143.8 mmol) was added to a stirred suspension of NH4Cl (8.2 g, 153 mmol) in dry toluene (6 mL) at 0°C under N2 conditions, and the mixture was stirred until foaming ceased. Methyl 2,2-difluoroacetic acid (4.8 g, 43.6 mmol) was then added. The resulting mixture was stirred overnight at 80°C under an N2 atmosphere. After completion, the reaction mixture was cooled to 0°C and quenched by adding methanol dropwise. The resulting mixture was stirred at 0°C for 90 minutes until solids formed. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain 2,2-difluoroacetoimidamide hydrochloride (2.2 g).

[0234]

[0234] Step 2: (E)-N'-chloro-2,2-difluoroacetoimidamide (J-2)

[0235]

[0235] To a solution of 2,2-difluoroacetoimidamide hydrochloride (2.2 g, 16.9 mmol) in water (30 mL), an aqueous solution of NaClO (w / w% = 7.5%, 12 mL) was added. The mixture was stirred at 0°C for 30 minutes. LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and then extracted with RINKAN. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain N'-chloro-2,2-difluoroacetamidine (500 mg). LC-MS (ESI, m / z): [M+H] + = 128.9.

[0236]

[0236] Step 3: 3-(difluoromethyl)-1,2,4-thiadiazole-5-amine (J-3)

[0237]

[0237] A solution of N'-chloro-2,2-difluoroacetamidine (500 mg, 3.9 mmol) in methanol (9 mL) was treated with thiocyanic acid (230 mg, 3.9 mmol) at 0°C for 5 minutes, followed by the addition of ytterbium(III) trifluoromethanesulfonate hydrate (242 mg, 0.39 mmol) in portions under N2 at room temperature for 5 hours. LC-MS confirmed the completion of the reaction. The reaction mixture was work-treated with water and then extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluting with 0-5% MeOH in DCM) to obtain 3-(difluoromethyl)-1,2,4-thiadiazole-5-amine (300 mg). LC-MS (ESI, m / z): [M+H] + = 151.9. 1 H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 2H), 6.78 (t, J = 52 Hz, 1H).

[0238]

[0238] Step 4: 5-bromo-3-(difluoromethyl)-1,2,4-thiadiazole (J)

[0239]

[0239] To a solution of 3-(difluoromethyl)-1,2,4-thiadiazole-5-amine (300 mg, 1.98 mmol) in CH3CN (3 mL), CuBr2 (532 mg, 2.38 mmol), followed by tert-butylnitrite (266 mg, 2.58 mmol) was added at room temperature. The reaction mixture was stirred at 45°C for 4 hours. LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and then extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluting with 0-10% ethyl acetate in PE) to obtain 5-bromo-3-(difluoromethyl)-1,2,4-thiadiazole (100 mg). LC-MS (ESI, m / z): [M+H] + = 214.8.

[0240]

[0240] Intermediate K

[0241]

[0241] [(3S)-3-hydroxypyrrolidine-1-yl]-piperazine-1-yl-methanone(K) [ka]

[0242]

[0242] Step 1: tert-butyl 4-[(3S)-3-hydroxypyrrolidine-1-carbonyl]piperazine-1-carboxylate (K-1)

[0243]

[0243] To a solution of tert-butylpiperazine-1-carboxylate (1.92 g, 10.3 mmol) and bis(trichloromethyl) carbonate (1.53 g, 5.17 mmol) in DCM (40 mL), DIEA (4.01 g, 31.0 mmol) was added dropwise at 0°C under N2. The reaction mixture was warmed to room temperature and stirred for 3 hours. TLC showed that all starting materials had been consumed. (3S)-pyrrolidine-3-ol (900 mg, 10.3 mmol) was added to the mixture at 0°C under N2. The reaction mixture was stirred at room temperature for 30 minutes. LC-MS showed that the reaction was complete. The reaction mixture was work-treated with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (0.05% NH4HCO3) to obtain tert-butyl 4-[(3S)-3-hydroxypyrrolidine-1-carbonyl]piperazine-1-carboxylate (800 mg). LCMS (ESI, m / z): [M+H] + = 300.3.

[0244]

[0244] Step 2: [(3S)-3-hydroxypyrrolidine-1-yl]-piperazine-1-yl-methanone (K)

[0245]

[0245] To a solution of tert-butyl 4-[(3S)-3-hydroxypyrrolidine-1-carbonyl]piperazine-1-carboxylate (500 mg, 1.67 mmol) in MeOH (5 mL), HCl (4.0 M in 1,4-dioxane, 1.25 ml, 5.0 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. LC-MS indicated that all of the starting material had been consumed. The reaction mixture was concentrated under reduced pressure to obtain (S)-(3-hydroxypyrrolidine-1-yl)(piperazine-1-yl)methanone hydrochloride (400 mg). LC-MS (ESI, m / z): [M+H] + = 200.3.

[0246]

[0246] Intermediate L

[0247]

[0247] 2-bromo-4H-pyrano[3,4-d]thiazole-7(6H)-one(L) [ka]

[0248]

[0248] Step 1: 2-amino-4H-pyrano[3,4-d]thiazole-7(6H)-one(L-1)

[0249]

[0249] 3-hydroxy-2H-pyran-5-one (5 g, 43.8 mmol) and anhydrous sodium acetate (5.4 g, 65.8 mmol) were suspended in acetic acid (50 mL) with stirring. Br2 (7 g, 43.8 mmol) was added dropwise under N2 at room temperature. The reaction mixture was stirred at room temperature for 2 hours, then thiourea (3.34 g, 43.8 mmol) was added under N2. After heating at 100°C for 16 hours, the reaction mixture was cooled and concentrated under reduced pressure. The residue was made into a slurry with water, and then with heated phenylethylamine. After drying in vacuum, 2-amino-4H-pyrano[3,4-d]thiazole-7-one (5.5 g) was obtained. LCMS (ESI, m / z): [M+H] + = 171.1.

[0250]

[0250] Step 2: 2-bromo-4H-pyrano[3,4-d]thiazole-7(6H)-one(L)

[0251]

[0251] To a solution of 2-amino-4H-pyrano[3,4-d]thiazole-7-one (5 g, 29.3 mmol) in ACN (50 mL), tert-butylnitrite (6.06 g, 58.8 mmol) was added dropwise at 0°C, followed by the addition of CuBr2 (13.1 g, 58.7 mmol). The mixture was stirred under N2 at 80°C for 16 hours. The reaction mixture was work-treated with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluted with 25% ethyl acetate in PE) to obtain 2-bromo-4H-pyrano[3,4-d]thiazole-7-one (2.3 g). LCMS (ESI, m / z): [M+H] + = 233.9.

[0252]

[0252] Intermediate M

[0253]

[0253] 1-(5-bromo-1,3,4-thiadiazole-2-yl)cyclobutan-1-ol (M) [ka]

[0254]

[0254] Step 1: 1-(5-amino-1,3,4-thiadiazole-2-yl)cyclobutanol (M-1)

[0255]

[0255] To a solution of 1-hydroxycyclobutancarboxylic acid (1.00 g, 8.61 mmol) in phosphoryl trichloride (5.30 mL), aminothiourea (785 mg, 8.61 mmol) was added under N2 conditions. The mixture was stirred at 80°C for 1 hour under an N2 atmosphere. After completion, the reaction mixture was quenched by carefully adding it to water, and then neutralized to pH 8-9 with saturated NaHCO3 aqueous solution. The resulting mixture was extracted with toluene. The combined organic layers were washed with saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 1-(5-amino-1,3,4-thiadiazole-2-yl)cyclobutanol (796 mg). LCMS (ESI, m / z): [M+H]+ = 172.1.

[0256]

[0256] Step 2: 1-(5-bromo-1,3,4-thiadiazole-2-yl)cyclobutanol (M)

[0257]

[0257] A mixture of tert-butylnitrite (2.53 g, 24.5 mmol) and CuBr2 (4.11 g, 18.4 mmol) in MeCN (84 mL) was mixed with 1-(5-amino-1,3,4-thiadiazole-2-yl)cyclobutanol (2.10 g, 12.3 mmol). The mixture was stirred at 80°C for 1 hour. After completion, the reaction mixture was work-treated with saturated aqueous NH4Cl solution and then extracted with DCM. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluted with 20% ethyl acetate in PE) to obtain 1-(5-bromo-1,3,4-thiadiazole-2-yl)cyclobutanol (183 mg). LCMS (ESI, m / z): [M+H] + = 235.0.

[0258]

[0258] Intermediate N

[0259]

[0259] 1-(5-bromo-1,3,4-thiadiazole-2-yl)cyclopropane-1-carbonitrile (N) [ka]

[0260]

[0260] Step 1: 1-(5-amino-1,3,4-thiadiazole-2-yl)cyclopropane-1-carbonitrile (N-1)

[0261]

[0261] To a solution of 1-cyanocyclopropanecarboxylic acid (10 g, 90.0 mmol) in POCl3 (100 mL), aminothiourea (8.20 g, 90.0 mmol) was added under N2 conditions. The mixture was stirred at 80°C for 30 minutes under an N2 atmosphere. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM and then neutralized to pH 8-9 with saturated NaHCO3 aqueous solution. The resulting mixture was then extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 1-(5-amino-1,3,4-thiadiazole-2-yl)cyclopropanecarbonitrile (3.4 g). LC-MS (ESI, m / z): [M+H] + = 167.1.

[0262]

[0262] Step 2: 1-(5-bromo-1,3,4-thiadiazole-2-yl)cyclopropane-1-carbonitrile (N)

[0263]

[0263] To a solution of 1-(5-amino-1,3,4-thiadiazole-2-yl)cyclopropanecarbonitrile (3.84 g, 23.1 mmol) in ACN (200 mL), tert-butylnitrite (2.91 g, 28.2 mmol) and CuBr2 (7.74 g, 34.7 mmol) were added under N2. The mixture was stirred under an N2 atmosphere at -20°C for 5 hours. LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluted with 9% ethyl acetate in PE) to obtain 1-(5-bromo-1,3,4-thiadiazole-2-yl)cyclopropanecarbonitrile (1.2 g). LC-MS (ESI, m / z): [M+H] + = 300.0.

[0264]

[0264] Intermediate O

[0265]

[0265] 1-(1H-pyrazole-4-yl)cyclopropane-1-carbonitrili (O) [ka]

[0266]

[0266] Step 1: 1-Tetrahydropyran-2-ylpyrazole-4-carbaldehyde (O-1)

[0267]

[0267] A mixture of 1H-pyrazole-4-carbaldehyde (2 g, 20.8 mmol) in THF (60 mL) was mixed with 3,4-dihydro-2H-pyran (3.50 g, 41.6 mmol) and 4-methylbenzenesulfonic acid (358 mg, 2.08 mmol). The mixture was stirred at 60°C for 2 hours. After completion, the reaction mixture was work-treated with water and then extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluting with 50% ethyl acetate in PE) to obtain 1-tetrahydropyran-2-ylpyrazole-4-carbaldehyde (3.27 g). LCMS (ESI, m / z): [M+H] + = 181.2.

[0268]

[0268] Step 2: 2-(1-tetrahydropyran-2-ylpyrazole-3-yl)acetonitrile (O-2)

[0269]

[0269] To a solution of TosMIC (3.64 g, 18.6 mmol) in 1,2-dimethoxyethane (22.6 mL), a solution of KOtBu (1 M in THF, 35.5 mL, 35.5 mmol) was added dropwise under N2 at -50°C. The mixture was stirred at -50°C for 20 minutes. Then, a solution of 1-tetrahydropyran-2-ylpyrazole-3-carbaldehyde (3.2 g, 17.8 mmol) in 1,2-dimethoxyethane (22.6 mL) was added dropwise. The reaction mixture was stirred under an N2 atmosphere at -50°C for 30 minutes. After completion, MeOH (22.6 mL) was added to the reaction mixture, and then stirred at 80°C for 1 hour. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residues were work-treated with water and then acidified with AcOH to pH=5-6. The resulting mixture was extracted by DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluting with 33% Â in PE) to obtain 2-(1-tetrahydropyran-2-ylpyrazole-3-yl)acetonitrile (2.1 g). LCMS (ESI, m / z): [M+H] + = 108.2.

[0270]

[0270] Step 3: 1-(1-tetrahydropyran-2-ylpyrazole-4-yl)cyclopropanecarbonitric (O-3)

[0271]

[0271] To a solution of diisopropylamine (2.97 g, 29.3 mmol) in THF (34 mL), n-BuLi (1.6 M in hexane, 16.7 mL, 26.7 mmol) was added dropwise under N2 at -30°C. The mixture was stirred at room temperature for 1 hour. Then, 2-(1-tetrahydropyran-2-ylpyrazole-4-yl)acetonitrile (1.70 g, 8.89 mmol) in THF (8.5 mL) was added to the mixture under N2 at 0°C. The mixture was stirred at room temperature for 1 hour. Then, BrCH2CH2Br (5.12 g, 26.7 mmol) was added at 0°C. The reaction mixture was stirred further under an N2 atmosphere at 0°C for another 1 hour. After completion, the reaction mixture was quenched with saturated NH4Cl aqueous solution and then extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (elution with 33% ethyl acetate in PE) to obtain 1-(1-tetrahydropyran-2-ylpyrazole-4-yl)cyclopropanecarbonitrile (1.0 g). LCMS (ESI, m / z): [M+H-THP] + = 134.2.

[0272]

[0272] Step 4: 1-(1H-pyrazole-4-yl)cyclopropanecarbonitric (O)

[0273]

[0273] To a solution of 1-(1-tetrahydropyran-2-ylpyrazole-4-yl)cyclopropane carbonitride (900 mg, 4.14 mmol) in 1,4-dioxane (10 mL), HCl (4 M in 1,4-dioxane, 3.1 mL, 12.4 mmol) was added dropwise. The mixture was stirred at room temperature for 1 hour. After completion, the reaction mixture was filtered to obtain a filtrate, which was further washed with a mixture of PE and HCl (10:1). The solid was placed in a saturated sodium bicarbonate aqueous solution and then extracted with DCM. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated to obtain 1-(1H-pyrazole-4-yl)cyclopropane carbonitride (506 mg). LCMS (ESI, m / z): [M+H] + = 134.1.

[0274]

[0274] Intermediate P

[0275]

[0275] 5-Chloro-1-iodoimidazo[1,5-a]pyridine-7-sulfonyl chloride (P) [ka]

[0276]

[0276] Step 1: (4-bromo-6-chloropyridine-2-yl)methanamine (P-1)

[0277]

[0277] To a solution of 4-bromo-6-chloropyridine-2-carbonitrile (6 g, 27.6 mmol) in DCM (100 mL), DIBAL-H (1.0 mol / L in n-hexane, 82.8 mL, 82.8 mmol) was added dropwise under N2 at 0°C. The reaction solution was stirred at 0°C for 2 hours. LC-MS indicated that the reaction was complete. The mixture was work-treated with saturated aqueous ammonium chloride solution and then extracted with RINKAN. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product, which was used directly in the next step without further purification. LC-MS (ESI, m / z): [M+H] + = 221.0.

[0278]

[0278] Step 2: N-((4-bromo-6-chloropyridine-2-yl)methyl)formamide (P-2)

[0279]

[0279] To a solution of (4-bromo-6-chloro-2-pyridyl)methanamine (6 g, 27.1 mmol) in formic acid (80 mL), acetic anhydride (16 mL) was added under N2 conditions. The reaction mixture was stirred at 80°C for 16 hours. LC-MS indicated that the reaction was complete. The mixture was concentrated to obtain the crude product, which was used directly in the next step without further purification. LC-MS (ESI, m / z): [M+H] + = 249.0.

[0280]

[0280] Step 3: 7-bromo-5-chloroimidazo[1,5-a]pyridine (P-3)

[0281]

[0281] To a solution of N-[(4-bromo-6-chloro-2-pyridyl)methyl]formamide (7.1 g, 28.5 mmol) in toluene (60 mL), POCl3 (6 mL) was added under N2. The reaction solution was stirred at 80°C for 3 hours. LC-MS indicated that the reaction was complete. The mixture was concentrated and work-treated with water. The solution was neutralized to pH=8 with saturated NaHCO3 aqueous solution and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by silica gel flash column chromatography (elution with 10% ethyl acetate in PE) to obtain 7-bromo-5-chloroimidazo[1,5-a]pyridine (4.35 g). LC-MS (ESI, m / z): [M+H] + = 233.1.

[0282]

[0282] Step 4: 7-benzylsulfanyl-5-chloroimidazo[1,5-a]pyridine (P-4)

[0283]

[0283] To a solution of 7-bromo-5-chloroimidazo[1,5-a]pyridine (4.35 g, 18.8 mmol) in 1,4-dioxane (60 mL), phenylmethanethiol (1.87 g, 15.0 mmol), DIEA (2.43 g, 18.8 mmol), xanthophos (2.17 g, 3.76 mmol), and Pd2(dba)3 (593 mg, 0.648 mmol) were added under N2 conditions. The reaction solution was degassed and then stirred at 80°C for 3 hours under an N2 atmosphere, and LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and then extracted with RINKAN. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by silica gel flash column chromatography (elution with 25% ethyl acetate in PE) to obtain 7-benzylsulfanyl-5-chloroimidazo[1,5-a]pyridine (3.7 g). LCMS (ESI, m / z): [M+H]+ = 275.1.

[0284]

[0284] Step 5: 7-(benzylthio)-5-chloro-1-iodoimidazo[1,5-a]pyridine (P-5)

[0285]

[0285] To a solution of 7-benzylsulfanyl-5-chloroimidazo[1,5-a]pyridine (1.5 g, 5.46 mmol) in THF (20 mL), NIS (1.84 g, 8.19 mmol) was added under N2 at 0°C. The reaction mixture was stirred at 0°C for 2 hours. LC-MS indicated that the reaction was complete. The reaction was work-treated with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel flash column chromatography (elution with 25% ethyl acetate in PE) to obtain 7-benzylsulfanyl-5-chloro-1-iodoimidazo[1,5-a]pyridine (1.66 g). LC-MS (ESI, m / z): [M+H] + = 401.0.

[0286]

[0286] Step 6: 5-Chloro-1-iodoimidazo[1,5-a]pyridine-7-sulfonyl chloride (P)

[0287]

[0287] To a solution of 7-benzylsulfanyl-5-chloro-1-iodoimidazo[1,5-a]pyridine (1.66 g, 4.14 mmol) in dichloromethane, acetic acid (9.5 mL), water (3.0 mL), and NCS (1.66 g, 12.4 mmol) were added gradually at 0°C. The mixture was stirred at 25°C for 2 hours. LC-MS indicated that the reaction was complete. The reaction was quenched with water and extracted with DCM. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel flash column chromatography (eluted with 10% ethyl acetate in PE) to obtain 5-chloro-1-iodoimidazo[1,5-a]pyridine-7-sulfonyl chloride (950 mg). LC-MS (ESI, m / z): [M+H] + = 376.9.

[0288]

[0288] Intermediate Q

[0289]

[0289] 2-(6-(benzylthio)-4-chloro-1H-indazole-1-yl)-5-(difluoromethyl)-1,3,4-thiadiazole(Q) [ka]

[0290]

[0290] Step 1: 6-(benzylthio)-4-chloro-1H-indazole (Q-1)

[0291]

[0291] A mixture of 6-bromo-4-chloro-1H-indazole (5.0 g, 21.6 mmol), phenylmethanethiol (8.05 g, 64.8 mmol), and DIEA (8.38 g, 64.8 mmol) in 1,4-dioxane (50 ml) was mixed with xanthophos (1.25 g, 2.16 mmol) and Pd2(dba)3·CHCl3 (1.12 g, 1.08 mmol) under N2 conditions. The mixture was degassed and stirred at 100°C for 3 hours under an N2 atmosphere. TLC showed that all of the starting material had been consumed. The reaction mixture was work-treated with water and then extracted with phenylethylamine. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (elution with 10% Â in PE) to obtain the product 6-benzylsulfanyl-4-chloro-1H-indazole (5.5 g). LCMS (ESI, m / z): [M+H] + = 275.1.

[0292]

[0292]

[0293]

[0293] Step 2: 2-(6-(benzylthio)-4-chloro-1H-indazole-1-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (Q)

[0294]

[0294] A mixture of 6-benzylsulfanyl-4-chloro-1H-indazole (3.3 g, 12.0 mmol) and 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (3.87 g, 18.0 mmol) in DMF (50 ml) was mixed with Cs2CO3 (5.87 g, 18.0 mmol). The mixture was stirred at 60°C for 2 hours under an N2 atmosphere. After completion, the mixture was work-treated with water and then extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluted with 1% ethyl acetate in PE) to obtain 2-(6-benzylsulfanyl-4-chloro-indazole-1-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (4.0 g). LCMS (ESI, m / z): [M+H] + = 409.2. Example 1 3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-methylcyclopropyl)-7-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyrazolo[1,5-a]pyridine-5-sulfonamide(1) [ka]

[0295]

[0295] Step 1: 7-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)pyrazolo[1,5-a]pyridine-5-sulfonyl chloride (1-1)

[0296]

[0296] To a suspension of 2-(5-benzylsulfanyl-7-chloropyrazolo[1,5-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (375 mg, 0.917 mmol), acetic acid (0.34 mL), and water (0.23 mL) in acetonitrile (9.2 mL), 1,3-dichloro-5,5-dimethylimidazolidin-2,4-dione (271 mg, 1.38 mmol) was gradually added under N2 at 0°C. The resulting mixture was stirred at 0°C for 2 hours. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated to obtain the crude product, which was used directly in the next step without further purification. LC-MS (ESI, m / z): [M+H] + = 384.9.

[0297]

[0297] Step 2: 7-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyridine-5-sulfonamide(1-2)

[0298]

[0298] To a suspension of 1-methylcyclopropan-1-amine hydrochloride (195.8 mg, 1.82 mmol), TEA (462 mg, 4.57 mmol, 0.64 mL), and DMAP (11.1 mg, 0.091 mmol) in DCM (5 mL), 7-chloro-3-[5-(difluoromethyl)-1,3,4-thiadiazole-2-yl]pyrazolo[1,5-a]pyridine-5-sulfonyl chloride (352 mg, 0.914 mmol) was added under N2 at 0°C. The resulting mixture was stirred overnight at room temperature. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (elution with 30% ethyl acetate in PE) to obtain 7-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyridine-5-sulfonamide (90 mg). LCMS (ESI, m / z): [M+H] + = 420.2.

[0299]

[0299] Step 3: 3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-methylcyclopropyl)-7-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyrazolo[1,5-a]pyridine-5-sulfonamide(1)

[0300]

[0300] A mixture of 2-oxa-7-azaspiro[3.5]nonanehemishalate (54.5 mg, 0.317 mmol) and 7-chloro-3-[5-(difluoromethyl)-1,3,4-thiadiazole-2-yl]-N-(1-methylcyclopropyl)-pyrazolo[1,5-a]pyridine-5-sulfonamide (90 mg, 0.215 mmol) in DMF (8 mL) was mixed with TEA (173 mg, 1.71 mmol, 0.24 mL) under N2 conditions. The reaction mixture was stirred at 100 °C for 16 hours. LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (elution with 5% MeOH in DCM) to obtain the product, which was further purified by preparative HPLC (0.05% NH4HCO3) to obtain 3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-methylcyclopropyl)-7-(2-oxa-7-azaspiro[3.5]nonane-7-yl)pyrazolo[1,5-a]pyridine-5-sulfonamide. LCMS (ESI, m / z): [M+H] + = 511.2. 1 H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.45 (s, 1H), 8.39 (s, 1H), 7.66 (t, J = 52.0 Hz, 1H), 6.82 (s, 1H), 4.43 (s, 4H), 3.47-3.40 (m, 4H), 2.09-2.02 (m, 4H), 1.13 (s, 3H), 0.74-0.67 (m, 2H), 0.49-0.42 (m, 2H).

[0301]

[0301] Examples 2 to 24 were prepared in a manner similar to that used to synthesize the compounds of the examples using appropriate intermediates, in accordance with the general procedure of this specification relating to Example 1. Starting materials were prepared as described in the section on intermediates, or were commercially available, or were prepared from commercially available reagents using conventional reactions well known in the art. [Table 2] TIFF2026520429000186.tif216149TIFF2026520429000187.tif191149TIFF2026520429000188.tif202149TIFF2026520429000189.tif201149TIFF2026520429000190.tif143149TIFF2026520429000191.tif145149TIFF2026520429000192.tif217149TIFF2026520429000193.tif149149Example 25 3-(3-(difluoromethyl)-1,2,4-thiadiazole-5-yl)-N-(1-methylcyclopropyl)-7-(2-oxa-7-azaspiro[3.5]nonanane-7-yl)pyrazolo[1,5-a]pyridine-5-sulfonamide(25) [ka]

[0302]

[0302] Step 1: 7-Chloro-3-iodopyrazolo[1,5-a]pyridine-5-sulfonyl chloride (25-1)

[0303]

[0303] To a solution of 5-benzylsulfanyl-7-chloro-3-iodopyrazolo[1,5-a]pyridine (A-3, 403 mg, 1.01 mmol), formic acid (1.5 mL), and water (0.7 mL) in DCM (12 mL), NCS (537 mg, 4.02 mmol) was added at 0°C. The reaction mixture was stirred at room temperature for 1 hour. LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and then extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was used directly in the next step without further purification.

[0304]

[0304] Step 2: 7-Chloro-3-iodo-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyridine-5-sulfonamide(25-2)

[0305]

[0305] To a solution of 1-methylcyclopropane-1-amine hydrochloride (102 mg, 0.95 mmol) in pyridine (6 mL), 7-chloro-3-iodo-pyrazolo[1,5-a]pyridine-5-sulfonyl chloride (360 mg, 0.95 mmol) was added under N2 at 0°C. The mixture was stirred at room temperature for 30 minutes. LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and then extracted with ethyl acetate. The combined organic layers were washed with water and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluted with 20% ethyl acetate in PE) to obtain 7-chloro-3-iodo-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyridine-5-sulfonamide (290 mg). LC-MS (ESI, m / z): [M+H] + = 411.9.

[0306]

[0306] Step 3: 3-Iodo-N-(1-methylcyclopropyl)-7-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyrazolo[1,5-a]pyridine-5-sulfonamide(25-3)

[0307]

[0307] A mixture of 7-chloro-3-iodo-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyridine-5-sulfonamide (482 mg, 0.70 mmol) and 2-oxa-7-azaspiro[3.5]nonanehemiooxalate (269 mg, 1.72 mmol) in DMF (5.0 mL) was to be mixed with TEA (712 mg, 7.0 mmol) under N2. The mixture was stirred at 100 °C for 5 hours. LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and extracted with siRNA. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (elution with 50% ethyl acetate in PE) to obtain 3-iodo-N-(1-methylcyclopropyl)-7-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyrazolo[1,5-a]pyridine-5-sulfonamide (123 mg). LCMS (ESI, m / z): [M+H] + = 503.1.

[0308]

[0308] Step 4: N-(1-methylcyclopropyl)-7-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-3

[0309]

[0309] (Trimethylstannyl)pyrazolo[1,5-a]pyridine-5-sulfonamide(25-4)

[0310]

[0310] To a solution of 3-iodo-N-(1-methylcyclopropyl)-7-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyrazolo[1,5-a]pyridine-5-sulfonamide (100 mg, 0.20 mmol) in 1,4-dioxane (1 mL), trimethyl(trimethylstannyl)stannane (78 mg, 0.24 mmol) and Pd(PPh3)4 (23 mg, 0.02 mmol) were added under N2. The reaction mixture was degassed and then stirred at 100°C for 1.5 hours under an N2 atmosphere. After completion, the reaction mixture was work-treated with water and then extracted with siRNA. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product, which was used in the next step without further purification. LCMS (ESI, m / z): [M+H] + = 539.1.

[0311]

[0311] Step 5: 3-(3-(difluoromethyl)-1,2,4-thiadiazole-5-yl)-N-(1-methylcyclopropyl)-7-(2-oxa-7-azaspiro[3.5]nonan-7-yl)pyrazolo[1,5-a]pyridine-5-sulfonamide(25)

[0312]

[0312] To a solution of N-(1-methylcyclopropyl)-7-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-3-(trimethylstannyl)pyrazolo[1,5-a]pyridine-5-sulfonamide (60 mg, 0.11 mmol) in 1,4-dioxane (40 mL), 5-bromo-3-(difluoromethyl)-1,2,4-thiadiazole (48 mg, 0.22 mmol) and Pd(PPh3)4 (13 mg, 0.01 mmol) were added under N2. The mixture was degassed and then stirred at 100°C for 5 hours under an N2 atmosphere. LCMS indicated that the reaction was complete. The reaction mixture was work-treated with water and then extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (0.1% FA) to obtain 3-(3-(difluoromethyl)-1,2,4-thiadiazole-5-yl)-N-(1-methylcyclopropyl)-7-(2-oxa-7-azaspiro[3.5]nonanane-7-yl)pyrazolo[1,5-a]pyridine-5-sulfonamide. LCMS (ESI, m / z): [M+H] + = 509.2. 1 H NMR (400 MHz, DMSO-d6) δ 9.06 (s, 1H), 8.48 (s, 1H), 8.29 (s, 1H), 7.30 (t, J = 54 Hz, 1H), 6.84 (s, 1H), 4.42 (s, 4H) 3.45-3.39 (m, 4H), 2.08-2.01 (m, 4H), 1.13 (s, 3H), 0.75-0.68 (m, 2H), 0.49-0.42 (m, 2H). Example 26 1-[5-(difluoromethyl)-1,3,4-thiadiazole-2-yl]-N-(1-ethinylcyclopropyl)-4-[4-[(3S)-3-hydroxypyrrolidine-1-carbonyl]piperazine-1-yl]indazole-6-sulfonamide(26) [ka]

[0313]

[0313] Step 1: 4-Chloro-1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-1H-indazole-6-sulfonyl chloride (26-1)

[0314]

[0314] To a solution of 2-(6-benzylsulfanyl-4-chloroindazole-1-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (2 g, 4.89 mmol) in MeCN (20 mL), AcOH (0.42 mL) and water (0.26 mL) were added. 1,3-dichloro-5,5-dimethylhydantoin (1.45 g, 7.36 mmol) was added gradually under N2 conditions at 0°C. The reaction mixture was stirred at 0°C for 2 hours. After completion, the reaction mixture was concentrated to obtain the crude product, which was used directly in the next step without further purification. LCMS (ESI, m / z): [M+H] + = 385.3.

[0315]

[0315] Step 2: 4-Chloro-1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-ethinylcyclopropyl)-1H-indazole-6-sulfonamide(26-2)

[0316]

[0316] To a solution of 1-ethinylcyclopropane-1-amine hydrochloride (610 mg, 5.19 mmol) in pyridine (20 mL), 4-chloro-1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-1H-indazole-6-sulfonyl chloride (2.0 g, 5.19 mmol) was gradually added at room temperature under N2. The resulting mixture was stirred at room temperature for 12 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (elution with 35% ethyl acetate in PE) to obtain 4-chloro-1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-ethinylcyclopropyl)-1H-indazole-6-sulfonamide (1.1 g). LCMS (ESI, m / z): [M+H] + = 430.3.

[0317]

[0317] Step 3: 1-[5-(difluoromethyl)-1,3,4-thiadiazole-2-yl]-N-(1-ethinylcyclopropyl)-4-[4-[(3S)-3-hydroxypyrrolidine-1-carbonyl]piperazine-1-yl]indazole-6-sulfonamide(26)

[0318]

[0318] A solution of 4-chloro-1-[5-(difluoromethyl)-1,3,4-thiadiazole-2-yl]-N-(1-ethinylcyclopropyl)indazole-6-sulfonamide (100 mg, 0.233 mmol), [(3S)-3-hydroxypyrrolidine-1-yl]-piperazine-1-yl-methanone (69.5 mg, 0.349 mmol), and t-BuONa (44.7 mg, 0.465 mmol) was added to 1,4-dioxane (5 mL) under N2 conditions, to which Pd-PEPPSI-IPent catalyst (36.8 mg, 0.047 mmol) was added. The mixture was degassed and then stirred at 100°C for 2 hours. The reaction mixture was work-treated with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (elution with 10% MeOH in DCM) to obtain the product, which was further purified by preparative HPLC (0.1% FA) to obtain 1-[5-(difluoromethyl)-1,3,4-thiadiazole-2-yl]-N-(1-ethynylcyclopropyl)-4-[4-[(3S)-3-hydroxypyrrolidine-1-carbonyl]piperazine-1-yl]indazole-6-sulfonamide. LCMS (ESI, m / z): [M+H] + = 593.3. 1H NMR (400 MHz, DMSO-d6) δ 8.87 (s, 1H), 8.71 (br s, 1H), 8.43 (s, 1H), 7.54 (t, J= 52.0 Hz, 1H), 7.15 (s, 1H), 4.84 (br s, 1H), 4.18-4.12 (m, 1H), 3.50-3.29 (m, 8H), 3.28-3.24 (m, 3H), 3.10-3.04 (m, 1H), 2.60 (s, 1H), 1.82-1.66 (m, 2H), 1.13-1.08 (m, 2H), 0.95-0.90 (m, 2H).

[0319]

[0319] Examples 27-33 were prepared in a manner similar to that used to synthesize the compounds of the examples using appropriate intermediates, following the general procedure described herein relating to Example 26. Starting materials were prepared as described in the section on intermediates, or were commercially available, or were prepared from commercially available reagents using conventional reactions well known in the art. [Table 3] TIFF2026520429000197.tif201149TIFF2026520429000198.tif132149Example 34 1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-methylcyclopropyl)-5-(2-oxa-7-azaspiro[3.5]nonane-7-yl)imidazo[1,5-a]pyridine-7-sulfonamide(34) [ka]

[0320]

[0320] Step 1: 5-Chloro-1-iodo-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-7-sulfonamide(34-1)

[0321]

[0321] To a solution of 1-methylcyclopropane-1-amine hydrochloride (306 mg, 3.28 mmol) in pyridine (3 mL), 5-chloro-1-iodo-imidazo[1,5-a]pyridine-7-sulfonyl chloride (950 mg, 2.52 mmol) was added under N2 at room temperature. The mixture was stirred at room temperature for 1 hour. LC-MS indicated that the reaction was complete. The reaction was work-treated with water and extracted by DCM. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel flash column chromatography (elution with 30% ethyl acetate in PE) to obtain 5-chloro-1-iodo-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-7-sulfonamide (637 mg). LC-MS (ESI, m / z): [M+H] + = 412.0.

[0322]

[0322] Step 2: 5-Chloro-N-(1-methylcyclopropyl)-1-(trimethylstannyl)imidazo[1,5-a]pyridine-7-sulfonamide(34-2)

[0323]

[0323] To a solution of 5-chloro-1-iodo-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-7-sulfonamide (637 mg, 1.55 mmol) in 1,4-dioxane (10 mL), trimethyl(trimethylstannyl)stannane (761 mg, 2.32 mmol) and Pd(PPh3)4 (179 mg, 0.155 mmol) were added under argon. The mixture was degassed and stirred at 100°C for 2 hours under an argon atmosphere. LC-MS indicated that the reaction was complete. The resulting mixture was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without purification. LC-MS (ESI, m / z): [M+H] + = 450.1

[0324]

[0324] Step 3: 5-Chloro-1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-7-sulfonamide(34-3)

[0325]

[0325] To a solution of 5-chloro-N-(1-methylcyclopropyl)-1-trimethylstannyl-imidazo[1,5-a]pyridine-7-sulfonamide (800 mg, 1.78 mmol) in DMF (10 mL), 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (374 mg, 1.74 mmol) and Pd(PPh3)4 (155 mg, 0.133 mmol) were added under argon. The mixture was degassed and then stirred at 90°C for 2 hours under an argon atmosphere. LCMS showed that the desired product was detected. Water was added to the mixture, and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel flash column chromatography (elution with 50% ethyl acetate in PE) to obtain 5-chloro-1-[5-(difluoromethyl)-1,3,4-thiadiazole-2-yl]-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-7-sulfonamide (178 mg). LCMS (ESI, m / z): [M+H] + = 420.1.

[0326]

[0326] Step 4: 1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-methylcyclopropyl)-5-(2-oxa-7-azaspiro[3.5]nonanane-7-yl)imidazo[1,5-a]pyridine-7-sulfonamide(34)

[0327]

[0327] To a solution of 5-chloro-1-[5-(difluoromethyl)-1,3,4-thiadiazole-2-yl]-N-(1-methylcyclopropyl)imidazo[1,5-a]pyridine-7-sulfonamide (170 mg, 0.405 mmol) in DMAc (4 mL), 2-oxa-7-azaspiro[3.5]nonane (103 mg, 0.81 mmol) and DIPEA (157 mg, 1.21 mmol) were added under argon. The reaction mixture was stirred under microwave and argon atmosphere at 120 °C for 2 hours. LC-MS indicated that the reaction was complete. Water was added, and the resulting mixture was extracted with RINKAN. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (0.1% FA) to obtain 1-[5-(difluoromethyl)-1,3,4-thiadiazole-2-yl]-N-(1-methylcyclopropyl)-5-(2-oxa-7-azaspiro[3.5]nonanane-7-yl)imidazo[1,5-a]pyridine-7-sulfonamide. LCMS (ESI, m / z): [M+H] + = 511.2. 1 HNMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 8.33 (d, J = 1.6 Hz, 1H), 8.30 (br s, 1H), 7.57 (t, J = 53.6 Hz, 1H), 6.59 (d, J = 1.6 Hz, 1H), 4.35 (s, 4H), 3.06-3.03 (m, 4H), 2.03-2.00 (m, 4H), 1.06 (s, 3H), 0.65-0.62 (m, 2H), 0.39-0.36 (m, 2H). Example 35 1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-(difluoromethyl)cyclopropyl)-5-(2-oxa-7-azaspiro[3.5]nonane-7-yl)imidazo[1,5-a]pyridine-7-sulfonamide(35) [ka]

[0328]

[0328] Step 1: 5-Chloro-N-(1-(difluoromethyl)cyclopropyl)-1-iodoimidazo[1,5-a]pyridine-7-sulfonamide(35-1)

[0329]

[0329] To a solution of 1-(difluoromethyl)cyclopropan-1-amine hydrochloride (267 mg, 1.86 mmol) in pyridine (6 mL), 5-chloro-1-iodoimidazo[1,5-a]pyridine-7-sulfonyl chloride (550 mg, 1.46 mmol) was added under N2 at room temperature. The mixture was stirred at room temperature for 30 minutes. LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and extracted with DCM. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (elution with 50% ethyl acetate in PE) to obtain 5-chloro-N-[1-(difluoromethyl)cyclopropyl]-1-iodoimidazo[1,5-a]pyridine-7-sulfonamide (400 mg). LC-MS (ESI, m / z): [M+H] + = 448.0.

[0330]

[0330] Step 2: 5-Chloro-N-(1-(difluoromethyl)cyclopropyl)-1-(trimethylstannyl)imidazo[1,5-a]pyridine-7-sulfonamide(35-2)

[0331]

[0331] To a solution of 5-chloro-N-[1-(difluoromethyl)cyclopropyl]-1-iodoimidazo[1,5-a]pyridine-7-sulfonamide (400 mg, 0.894 mmol) in 1,4-dioxane (10 mL), trimethyl(trimethylstannyl)stannane (439 mg, 1.34 mmol) and Pd(PPh3)4 (103 mg, 0.089 mmol) were added under N2. The mixture was degassed and then stirred at 100°C for 2 hours under an N2 atmosphere. LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and extracted with DCM. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without purification. LC-MS (ESI, m / z): [M+H] + = 484.1.

[0332]

[0332] Step 3: 5-Chloro-1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-(difluoromethyl)cyclopropyl)imidazo[1,5-a]pyridine-7-sulfonamide(35-3)

[0333]

[0333] To a solution of 5-chloro-N-[1-(difluoromethyl)cyclopropyl]-1-trimethylstannyl-imidazo[1,5-a]pyridine-7-sulfonamide (600 mg, 1.24 mmol) in DMF (6 mL), 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (231 mg, 1.07 mmol) and Pd(PPh3)4 (96 mg, 0.083 mmol) were added under N2 conditions. The mixture was degassed and then stirred at 100°C for 3 hours under an N2 atmosphere. LC-MS indicated that the reaction was complete. The reaction products were work-treated with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (elution with 50% ethyl acetate in PE) to obtain 5-chloro-N-[1-(difluoromethyl)-cyclopropyl]-1-[5-(difluoromethyl)-1,3,4-thiadiazole-2-yl]imidazo[1,5-a]pyridine-7-sulfonamide (300 mg). LCMS (ESI, m / z): [M+H] + = 456.1.

[0334]

[0334] Step 4: 1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-(difluoromethyl)cyclopropyl)-5-(2-oxa-7-azaspiro[3.5]nonanane-7-yl)imidazo[1,5-a]pyridine-7-sulfonamide(35)

[0335]

[0335] To a solution of 2-oxa-7-azaspiro[3.5]nonane (34 mg, 0.267 mmol) and DIEA (85 mg, 0.658 mmol) in DMAc (5 mL), 5-chloro-N-[1-(difluoromethyl)-cyclopropyl]-1-[5-(difluoromethyl)-1,3,4-thiadiazole-2-yl]imidazo[1,5-a]pyridine-7-sulfonamide (100 mg, 0.219 mmol) was added under N2. The mixture was stirred under microwave at 120°C for 1 hour. LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (0.1% FA) to obtain 1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-(difluoromethyl)cyclopropyl)-5-(2-oxa-7-azaspiro[3.5]nonane-7-yl)imidazo[1,5-a]pyridine-7-sulfonamide. LCMS (ESI, m / z): [M+H] + = 547.2. 1 HNMR (400 MHz, DMSO-d6) δ 9.10 (br s, 1H), 8.64 (s, 1H), 8.37 (s, 1H), 7.64 (t, J = 53.2 Hz, 1H), 6.66 (s, 1H), 5.78 (t, J = 56.0 Hz, 1H), 4.43 (s, 4H), 3.15-3.08 (m, 4H), 2.13-2.06 (m, 4H), 0.99-0.90 (m, 4H). Example 36 N-(1-cyanocyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-5-(2-oxa-7-azaspiro[3.5]nonanane-7-yl)imidazo[1,5-a]pyridine-7-sulfonamide(36) [ka]

[0336]

[0336] Step 1: 5-Chloro-N-(1-cyanocyclopropyl)-1-(trimethylstannyl)imidazo[1,5-a]pyridine-7-sulfonamide(36-1)

[0337]

[0337] To a solution of 1-amino-1-cyclopropane carbonitride hydrochloride (57.2 mg, 0.482 mmol) in pyridine (1 mL), 5-chloro-1-iodoimidazo[1,5-a]pyridine-7-sulfonyl chloride (140 mg, 0.371 mmol) was added under N2 at room temperature. The mixture was stirred at room temperature for 1 hour. LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and extracted by DCM. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluted with 30% ethyl acetate in PE) to obtain 5-chloro-N-(1-cyanocyclopropyl)-1-iodoimidazo[1,5-a]pyridine-7-sulfonamide (120 mg). LC-MS (ESI, m / z): [M+H] + = 423.0.

[0338]

[0338] Step 2: 5-Chloro-N-(1-cyanocyclopropyl)-1-(trimethylstannyl)imidazo[1,5-a]pyridine-7-sulfonamide(36-2)

[0339]

[0339] To a solution of 5-chloro-N-(1-cyanocyclopropyl)-1-iodoimidazo[1,5-a]pyridine-7-sulfonamide (100 mg, 0.237 mmol) in 1,4-dioxane (3 mL), trimethyl(trimethylstannyl)stannane (117 mg, 0.356 mmol) and Pd(PPh3)4 (28 mg, 0.024 mmol) were added under N2 conditions. The reaction mixture was degassed and then stirred at 100°C for 2 hours under an N2 atmosphere. LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and extracted by DCM. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without purification. LC-MS (ESI, m / z): [M+H] + = 459.1.

[0340]

[0340] Step 3: 5-Chloro-N-(1-cyanocyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)imidazo[1,5-a]pyridine-7-sulfonamide(36-3)

[0341]

[0341] To a solution of 5-chloro-N-(1-cyanocyclopropyl)-1-(trimethylstannyl)imidazo[1,5-a]pyridine-7-sulfonamide (200 mg, 0.435 mmol) in DMF (3 mL), 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (70 mg, 0.326 mmol) and Pd(PPh3)4 (25 mg, 0.0217 mmol) were added under N2 conditions. The reaction mixture was degassed and then stirred at 100°C for 3 hours under an N2 atmosphere. LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (elution with 50% ethyl acetate in PE) to obtain 5-chloro-N-(1-cyanocyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)imidazo[1,5-a]pyridine-7-sulfonamide (60 mg). LCMS (ESI, m / z): [M+H] + = 431.0.

[0342]

[0342] Step 4: N-(1-cyanocyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-5-(2-oxa-7-azaspiro[3.5]nonanane-7-yl)imidazo[1,5-a]pyridine-7-sulfonamide(36)

[0343]

[0343] To a solution of 5-chloro-N-(1-cyanocyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)imidazo[1,5-a]pyridine-7-sulfonamide (60 mg, 0.139 mmol) in DMAc (2 mL), 2-oxa-7-azaspiro[3.5]nonane (23 mg, 0.263 mol) and DIPEA (54 mg, 0.417 mmol) were added under N2. The reaction mixture was stirred under microwave at 120°C for 1 hour. LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (0.1% FA) to obtain N-(1-cyanocyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-5-(2-oxa-7-azaspiro[3.5]nonanane-7-yl)imidazo[1,5-a]pyridine-7-sulfonamide. LCMS (ESI, m / z): [M+H] + = 522.3. 1 HNMR (400 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.48 (s, 1H), 7.65 (t, J = 52.0 Hz, 1H), 6.67 (s, 1H), 4.43 (s, 4H), 3.17-3.11 (m, 4H), 2.13-2.06 (m, 4H), 1.51-1.44 (m, 2H), 1.41-1.33 (m, 2H). Example 37 3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-(difluoromethyl)cyclopropyl)-8-(2-oxa-7-azaspiro[3.5]nonane-7-yl)imidazo[1,2-a]pyridine-6-sulfonamide(37) [ka]

[0344]

[0344] Step 1: Ethyl 6-bromo-8-chloroimidazo[1,2-a]pyridine-3-carboxylate (37-1)

[0345]

[0345] A solution of 5-bromo-3-chloropyridine-2-amine (20 g, 96 mmol) and ethyl 2-chloro-3-oxopropanoate (16 g, 106 mmol) in EtOH (300 mL) was stirred at 80°C for 3 hours under N2. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (elution with 0%~10% MeOH in DCM) to obtain the product. The product was slurryed with ethyl acetate to obtain ethyl 6-bromo-8-chloroimidazo[1,2-a]pyridine-3-carboxylate (12 g). LCMS (ESI, m / z): [M+H] + = 302.9.

[0346]

[0346] Step 2: Ethyl 6-(benzylthio)-8-chloroimidazo[1,2-a]pyridine-3-carboxylate (37-2)

[0347]

[0347] To a solution of ethyl 6-bromo-8-chloroimidazo[1,2-a]pyridine-3-carboxylate (8.5 g, 26.0 mmol) in 1,4-dioxane (150 mL), phenylmethanethiol (3.3 g, 27 mmol), xanthophos (3.0 g, 5.2 mmol), DIEA (10 g, 78 mmol), and Pd2(dba)3.CHCl3 (2.7 g, 2.6 mmol) were added under N2. The mixture was degassed with N2 and then stirred at 90°C for 3 hours. After completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (elution at 0%~30% ethyl in PE) to obtain ethyl 6-(benzylthio)-8-chloroimidazo[1,2-a]pyridine-3-carboxylate (7.6 g). LCMS (ESI, m / z): [M+H] + = 347.2.

[0348]

[0348] Step 3: 6-(benzylthio)-8-chloroimidazo[1,2-a]pyridine-3-carbohydrazide(37-3)

[0349]

[0349] A solution of ethyl 6-(benzylthio)-8-chloroimidazo[1,2-a]pyridine-3-carboxylate (7.6 g, 20 mmol) and hydrazine hydrate (80% in water, 25.5 g, 408 mmol) in EtOH (100 mL) was stirred at 60°C under N2 for 2 hours. After completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was made into a slurry with diethyl ether and filtered to obtain 6-(benzylthio)-8-chloroimidazo[1,2-a]pyridine-3-carbohradazide (6.7 g). LCMS (ESI, m / z): [M+H] + = 333.1.

[0350]

[0350] Step 4: 6-(benzylthio)-8-chloro-N'-(2,2-difluoroacetyl)imidazo[1,2-a]pyridine-3-carbohydrazide(37-4)

[0351]

[0351] In a solution of 6-(benzylthio)-8-chloroimidazo[1,2-a]pyridine-3-carbozide (6.7 g, 19 mmol) and TEA (2.5 g, 25 mmol) in DCM (100 mL), 2,2-anhydrous difluoroacetic acid (4.0 g, 23 mmol) was added under N2 at 0°C. The mixture was warmed to room temperature and stirred for 2 hours. After completion, the reaction mixture was work-treated with water, extracted with DCM, and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was made into a slurry with ethyl acetate and filtered to obtain 6-(benzylthio)-8-chloro-N'-(2,2-difluoroacetyl)imidazo[1,2-a]pyridine-3-carbozide (4.5 g). LCMS (ESI, m / z): [M+H] + = 411.1.

[0352]

[0352] Step 5: 2-(6-(benzylthio)-8-chloroimidazo[1,2-a]pyridine-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole(37-5)

[0353]

[0353] A solution of 6-(benzylthio)-8-chloro-N'-(2,2-difluoroacetyl)imidazo[1,2-a]pyridine-3-carbohydrazide (5 g, 11 mmol) and Lawson's reagent (5.5 g, 14 mmol) in THF (80 mL) was stirred at 70°C for 2 hours under N2. After completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (elution at 0%~50% ethyl acetate in PE) to obtain 2-(6-(benzylthio)-8-chloroimidazo[1,2-a]pyridine-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (4.3 g). LCMS (ESI, m / z): [M+H] + = 409.0.

[0354]

[0354] Step 6: 8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)imidazo[1,2-a]pyridine-6-sulfonyl chloride (37-6)

[0355]

[0355] To a solution of 2-(6-(benzylthio)-8-chloroimidazo[1,2-a]pyridine-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (500 mg, 1 mmol) in water (2 mL) and AcOH (6 mL), NCS (607 mg, 5 mmol) was added under N2. The mixture was stirred at room temperature for 2 hours. After completion, the reaction mixture was work-treated with water and extracted by DCM. The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): [M+H] + = 384.9.

[0356]

[0356] Step: 7: 8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-(difluoromethyl)cyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide(37-7)

[0357]

[0357] 1-(difluoromethyl)cyclopropan-1-amine hydrochloride (142 mg, 0.99 mmol), pyridine (524 mg, 7 mmol), 4A molecular sieve, and DCM (6 mL) were added to a round-bottom flask under N2 conditions. A solution of 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)imidazo[1,2-a]pyridine-6-sulfonyl chloride (300 mg, 0.79 mmol) in DCM (2 mL) was added dropwise at room temperature. The mixture was stirred at room temperature for 16 hours. After completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluting with 0% to 50% ethyl acetate in petroleum ether) to obtain 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-(difluoromethyl)cyclopropyl)-imidazo[1,2-a]pyridine-6-sulfonamide (170 mg). LCMS (ESI, m / z): [M+H] + = 456.0.

[0358]

[0358] Step 8: 3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-(difluoromethyl)cyclopropyl)-8-(2-oxa-7-azaspiro[3.5]nonan-7-yl)imidazo[1,2-a]pyridine-6-sulfonamide(37)

[0359]

[0359] To a solution of 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-(difluoromethyl)cyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (130 mg, 0.26 mmol) in 1,4-dioxane (4 mL), 2-oxa-7-azaspiro[3.5]nonane (67 mg, 0.53 mmol), Pd-PEPPSI-IPentCl catalyst (44 mg, 0.045 mmol), and Cs2CO3 (259 mg, 0.79 mmol) were added under N2. The mixture was degassed with N2 and then stirred at 105°C for 3 hours. After completion, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (elution with 0%-15% MeOH in DCM) to obtain the crude product, which was further purified by preparative HPLC (0.1% NH4HCO3) to obtain 3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-(difluoromethyl)cyclopropyl)-8-(2-oxa-7-azaspiro[3.5]nonane-7-yl)imidazo[1,2-a]pyridine-6-sulfonamide. LCMS (ESI, m / z): [M+H] + = 547.1. 1 H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 9.10 (s, 1H), 8.60 (s, 1H), 7.70 (t, J = 53.2 Hz, 1H), 6.99 (s, 1H), 5.78 (t, J = 55.6 H, 1H), 4.41 (s, 4H), 3.57-3.53 (m, 4H), 2.02-1.97 (m, 4H), 0.99-0.92 (m, 4H). 19 F NMR (400 MHz, DMSO-d6) δ -109.15, -120.30 Example 38 8-(4-acetylpiperazine-1-yl)-3-(5-(1-cyanocyclopropyl)-1,3,4-thiadiazole-2-yl)-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide(38) [ka]

[0360]

[0360] Step 1: 6-(benzylthio)-8-chloroimidazo[1,2-a]pyridine (38-1)

[0361]

[0361] To a solution of 6-bromo-8-chloroimidazo[1,2-a]pyridine (5.00 g, 21.6 mmol) in 1,4-dioxane (50 ml), phenylmethanethiol (2.95 g, 23.8 mmol), DIEA (8.38 g, 64.8 mmol), xanthophos (1.25 g, 2.16 mmol), and Pd2(dba)3·CHCl3 (1.12 g, 1.08 mmol) were added under N2 atmosphere. The mixture was degassed and then stirred at 100°C for 3 hours under an N2 atmosphere. The reaction mixture was work-treated with water and then extracted with phenylmethane. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluted with 100% dichloromethane) to obtain 6-(benzylthio)-8-chloroimidazo[1,2-a]pyridine (5.9 g). LCMS (ESI, m / z): [M+H] + = 275.1.

[0362]

[0362] Step 2: 6-(benzylthio)-8-chloro-3-iodoimidazo[1,2-a]pyridine(38-2)

[0363]

[0363] To a solution of 6-benzylsulfanyl-8-chloroimidazo[1,2-a]pyridine (5.0 g, 18.2 mmol) in ACN (50 mL), NIS (4.50 g, 20.0 mmol) was added at 0°C. The mixture was warmed to room temperature and stirred for 16 hours. After completion, the reaction mixture was work-treated with water and then extracted with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluted with 15% ethyl acetate in PE) to obtain 6-(benzylthio)-8-chloro-3-iodoimidazo[1,2-a]pyridine (7.26 g). LCMS (ESI, m / z): [M+H] + = 401.0.

[0364]

[0364] Step 3: 6-(benzylthio)-8-chloro-3-(tributylstannyl)imidazo[1,2-a]pyridine(38-3)

[0365]

[0365] To a solution of 6-benzylsulfanyl-8-chloro-3-iodoimidazo[1,2-a]pyridine (2.0 g, 4.99 mmol) in anhydrous THF (40 mL), i-PrMgCl.LiCl (1.3 M in THF, 4.2 mL, 5.49 mmol) was added dropwise under Ar at -20°C. The mixture was stirred at -20°C for 15 minutes. Then tributylchlorostannane (1.79 g, 5.49 mmol) was added dropwise at -20°C. The resulting mixture was warmed to room temperature and stirred under an N2 atmosphere for 1 hour. TLC indicated that the reaction was complete. The reaction mixture was quenched with saturated ammonium chloride aqueous solution and then extracted with RINKAN. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product, which was used directly in the next step without further purification. LCMS (ESI, m / z): [M+H] + = 563.1.

[0366]

[0366] Step 4: 1-(5-(6-(benzylthio)-8-chloroimidazo[1,2-a]pyridine-3-yl)-1,3,4-thiadiazole-2-yl)cyclopropane-1-carbonitrile(38-4)

[0367]

[0367] To a solution of 6-(benzylthio)-8-chloro-3-(tributylstannyl)imidazo[1,2-a]pyridine (1.8 g, 3.19 mmol) in DMF (100 mL), 1-(5-bromo-1,3,4-thiadiazole-2-yl)cyclopropanecarbonitride (881 mg, 3.83 mmol) and Pd(PPh3)4 (369 mg, 0.319 mmol) were added under N2. The mixture was degassed and then stirred under N2 at 100°C for 16 hours, and LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and then extracted with RINKAN. The combined organic layers were washed with saturated brine, dried over anhydrous sodium Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (elution with 80% ethyl acetate in PE) to obtain 1-(5-(6-benzylsulfanyl-8-chloroimidazo[1,2-a]pyridine-3-yl)-1,3,4-thiadiazole-2-yl)cyclopropanecarbonitride (1.2 g). LCMS (ESI, m / z): [M+H] + = 424.2.

[0368]

[0368] Step 5: 8-Chloro-3-(5-(1-cyanocyclopropyl)-1,3,4-thiadiazole-2-yl)imidazo[1,2-a]pyridine-6-sulfonyl chloride (38-5)

[0369]

[0369] To a solution of 1-[5-(6-benzylsulfanyl-8-chloroimidazo[1,2-a]pyridine-3-yl)-1,3,4-thiadiazole-2-yl]cyclopropanecarbonitride (900 mg, 2.12 mmol) in formic acid (3.2 mL), water (1.5 mL), and DCM (5 mL), 1-chloropyrrolidine-2,5-dione (850 mg, 6.37 mmol) was added under N2 at 0°C. The mixture was warmed to room temperature and stirred under an N2 atmosphere for 1 hour. LCMS indicated that the reaction was complete. The reaction mixture was work-treated with water and then extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (elution with 50% ethyl acetate in PE) to obtain 8-chloro-3-[5-(1-cyanocyclopropyl)-1,3,4-thiadiazole-2-yl]imidazo[1,2-a]pyridine-6-sulfonyl chloride (320 mg). LCMS (ESI, m / z): [M+H] + = 400.0.

[0370]

[0370] Step 6: 8-Chloro-3-(5-(1-cyanocyclopropyl)-1,3,4-thiadiazole-2-yl)-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide(38-6)

[0371]

[0371] To a solution of 1-methylcyclopropanamine hydrochloride (103 mg, 0.959 mmol) in pyridine (4 mL), 8-chloro-3-[5-(1-cyanocyclopropyl)-1,3,4-thiadiazole-2-yl]imidazo[1,2-a]pyridine-6-sulfonyl chloride (320 mg, 0.799 mmol) was added under N2 at room temperature. The mixture was stirred at room temperature for 1 hour. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluted with 80% ethyl acetate in PE) to obtain 8-chloro-3-[5-(1-cyanocyclopropyl)-1,3,4-thiadiazole-2-yl]-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (200 mg). LCMS (ESI, m / z): [M+H] + = 435.1.

[0372]

[0372] Step 7: 8-(4-acetylpiperazine-1-yl)-3-(5-(1-cyanocyclopropyl)-1,3,4-thiadiazole-2-yl)-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide(38)

[0373]

[0373] To a solution of 8-chloro-3-[5-(1-cyanocyclopropyl)-1,3,4-thiadiazole-2-yl]-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide (150 mg, 0.345 mmol) in 1,4-dioxane (20 mL), 1-piperazine-1-ylethanone (133 mg, 1.03 mmol), Cs2CO3 (225 mg, 0.689 mmol), and Pd-PEPPSI-IHept-Cl catalyst (67.0 mg, 0.069 mmol) were added under N2. The reaction mixture was degassed and then stirred under N2 at 95°C for 1.5 hours. LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and then extracted with ELISA. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (elution with 5% MeOH in DCM), and further purified by preparative HPLC (0.05% NH4HCO3) to obtain 8-(4-acetylpiperazin-1-yl)-3-[5-(1-cyanocyclopropyl)-1,3,4-thiadiazole-2-yl]-N-(1-methylcyclopropyl)imidazo[1,2-a]pyridine-6-sulfonamide. LCMS (ESI, m / z): [M+H] + = 527.3. 1 HNMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.50 (s, 1H), 8.37 (s, 1H), 6.96 (s, 1H), 3.73-3.54 (m, 8H), 2.22-2.15 (m, 2H), 2.08 (s, 3H), 2.01-1.94 (m, 2H), 1.13 (s, 3H), 0.73-0.67 (m, 2H), 0.47-0.40 (m, 2H). Example 39 3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-(difluoromethyl)cyclopropyl)-8-(2-oxa-7-azaspiro[3.5]nonane-7-yl)imidazo[1,5-a]pyridine-6-sulfonamide(39) [ka]

[0374]

[0374] Step 1: (5-bromo-3-chloropyridine-2-yl)methanamine (39-1)

[0375]

[0375] To a stirred solution of 5-bromo-3-chloropyridine-2-carbonitrile (1 g, 4.6 mmol) in dry DCM (10 mL), DIBAL-H (1 mol / L in DCM, 14 mL, 14 mmol) was added dropwise under N2 at -78°C. The resulting mixture was stirred at -78°C for 1 hour. After completion, the reaction mixture was quenched by adding ice water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluting with 0-10% MeOH in DCM) to obtain (5-bromo-3-chloropyridine-2-yl)methaneamine (500 mg). LCMS (ESI, m / z): [M+H] + = 220.9.

[0376]

[0376] Step 2: Ethyl 2-(((5-bromo-3-chloropyridine-2-yl)methyl)amino)-2-oxoacetate(39-2)

[0377]

[0377] To a solution of (5-bromo-3-chloropyridine-2-yl)methaneamine (100 mg, 0.45 mmol) and TEA (91.4 mg, 0.93 mmol) in DCM (2 ml), ethyl 2-chloro-2-oxoacetate (62 mg, 0.45 mmol) was added under N2 at 0°C. The resulting mixture was stirred at 0°C for 4 hours. After completion, the reaction mixture was work-treated with water and extracted with DCM. The combined organic layer was washed with saturated brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): [M+H] + = 321.1.

[0378]

[0378] Step 3: Ethyl 6-bromo-8-chloroimidazo[1,5-a]pyridine-3-carboxylate (39-3)

[0379]

[0379] Ethyl 2-(((5-bromo-3-chloropyridine-2-yl)methyl)amino)-2-oxoacetate (100 mg, 0.31 mmol) and phosphate chloride (1 mL) were added to a vial under N2 conditions. The resulting mixture was stirred at 110°C for 8 hours. After completion, the reaction mixture was quenched by carefully adding water and then extracted with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and then concentrated under reduced pressure. The residue was purified by preparative TLC (PE:Â=1:1) to obtain ethyl 6-bromo-8-chloroimidazo[1,5-a]pyridine-3-carboxylate (80 mg). LCMS (ESI, m / z): [M+H] + = 302.5.

[0380]

[0380] Step 4: Ethyl 6-(benzylthio)-8-chloroimidazo[1,5-a]pyridine-3-carboxylate (39-4)

[0381]

[0381] To a solution of ethyl 6-bromo-8-chloroimidazo[1,5-a]pyridine-3-carboxylate (3.78 g, 12.5 mmol) in 1,4-dioxane (50 ml), xanthophos (1.44 g, 2.5 mmol), Pd2(dba)3.CHCl3 (1.29 g, 1.2 mmol), and DIEA (3.22 g, 24.9 mmol) were added under N2. The resulting mixture was degassed with N2 and then stirred at 85°C for 2 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (elution with 30% ethyl phenylethylamine in PE) to obtain ethyl 6-(benzylsulfanyl)-8-chloroimidazo[1,5-a]pyridine-3-carboxylate (3 g). LCMS (ESI, m / z): [M+H] + = 347.1.

[0382]

[0382] Step 5: 6-(benzylthio)-8-chloroimidazo[1,5-a]pyridine-3-carbohydrazide (39-5)

[0383]

[0383] Ethyl 6-(benzylsulfanyl)-8-chloroimidazo[1,5-a]pyridine-3-carboxylate (3 g, 8.7 mmol), hydrazine hydrate (80% in H2O, 8 mL, 132 mmol), and EtOH (30 mL) were added to a round-bottom flask under N2 conditions. The resulting mixture was stirred at 50°C for 2 hours. After completion, the precipitate was collected by filtration and washed with EtOH to obtain 6-(benzylsulfanyl)-8-chloroimidazo[1,5-a]pyridine-3-carbohazide (2.5 g). LCMS (ESI, m / z): [M+H] + = 333.1.

[0384]

[0384] Step 6: 6-(benzylthio)-8-chloro-N'-(2,2-difluoroacetyl)imidazo[1,5-a]pyridine-3-carbohydrazide(39-6)

[0385]

[0385] In a round-bottom flask, 25 ml of THF contained 2 g of 6-(benzylsulfanyl)-8-chloroimidazo[1,5-a]pyridine-3-carbozide and 1.6 g of DIEA (12 mmol). The resulting mixture was cooled to 0°C. Then, 1.2 g of 2,2-difluoroacetic anhydride (6.9 mmol) was added dropwise under N2 at 0°C. The resulting mixture was stirred at 0°C for 4 hours. After completion, the reaction mixture was work-treated with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by scrubbing with ethyl ether to obtain 1 g of 6-(benzylsulfanyl)-8-chloro-N'-(2,2-difluoroacetyl)imidazo[1,5-a]pyridine-3-carbozide. LCMS (ESI, m / z): [M+H] + = 411.1.

[0386]

[0386] Step 7: 2-(6-(benzylthio)-8-chloroimidazo[1,5-a]pyridine-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (39-7)

[0387]

[0387] 6-(benzylsulfanyl)-8-chloro-N'-(2,2-difluoroacetyl)imidazo[1,5-a]pyridine-3-carbohydrazide (1 g, 2.4 mmol), Lawson's reagent (1.3 g, 3.2 mmol), and THF (10 mL) were added to a round-bottom flask under N2 conditions. The resulting mixture was stirred at 70°C for 4 hours. After completion, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (elution with 10% ethyl acetate in PE) to obtain 2-(6-(benzylthio)-8-chloroimidazo[1,5-a]pyridine-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (560 mg). LCMS (ESI, m / z): [M+H] + = 409.0.

[0388]

[0388] Step 8: 8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)imidazo[1,5-a]pyridine-6-sulfonyl chloride (39-8)

[0389]

[0389] To a solution of 2-(6-(benzylthio)-8-chloroimidazo[1,5-a]pyridine-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (500 mg, 1.2 mmol) in water (2 mL) and AcOH (6 mL), NCS (653 mg, 4.9 mmol) was gradually added at room temperature. The resulting mixture was stirred at room temperature for 3 hours. After completion, the reaction mixture was work-treated with water and extracted with DCM. The combined organic layers were washed with saturated brine and dried over anhydrous MgSO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): [M+H] + = 385.2.

[0390]

[0390] Step 9: 8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-(difluoromethyl)cyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide(39-9)

[0391]

[0391] 1-(difluoromethyl)cyclopropan-1-amine hydrochloride (187 mg, 1.3 mmol), pyridine (308 mg, 3.9 mmol), 4A molecular sieve, and DCM (10 mL) were added to a round-bottom flask. The mixture was stirred for 20 minutes, and then 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)imidazo[1,5-a]pyridine-6-sulfonyl chloride (500 mg, 1.3 mmol) was added under N2 at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (elution with 10% ethyl acetate in PE) to obtain 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-(difluoromethyl)cyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (200 mg). LCMS (ESI, m / z): [M+H] + = 455.9.

[0392]

[0392] Step 10: 8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-(difluoromethyl)cyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide(39)

[0393]

[0393] A solution of 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-(difluoromethyl)cyclopropyl)imidazo[1,5-a]pyridine-6-sulfonamide (130 mg, 0.285 mmol), 2-oxa-7-azaspiro[3.5]nonane (181 mg, 1.42 mmol), Pd-PEPPSI-IPentCl catalyst (49 mg, 0.05 mmol), and Cs2CO3 (215 mg, 0.66 mmol) in 1,4-dioxane (4 mL) was degassed with N2, and then stirred at 105°C for 16 hours under an N2 atmosphere. After completion, the mixture was cooled to room temperature, post-treated with water, and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (PE:Â=1:2) to obtain the product, which was further purified by preparative HPLC (0.1% FA) to obtain 3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-(difluoromethyl)cyclopropyl)-8-(2-oxa-7-azaspiro[3.5]nonane-7-yl)imidazo[1,5-a]pyridine-6-sulfonamide. LCMS (ESI, m / z): [M+H] + = 547.3. 1 H NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 9.13 (s, 1H), 7.96 (s, 1H), 7.68 (t, J =53 Hz, 1H), 6.68 (s, 1H), 5.79 (t, J = 56 Hz ,1H), 4.41 (s, 4H), 3.25-3.21 (m, 4H), 2.08-2.04 (m, 4H), 0.98-0.94 (m, 4H). 19 F NMR (400 MHz, DMSO-d6) δ -109.31, -120.27. Example 40 3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-(difluoromethyl)cyclopropyl)-8-(2-oxa-7-azaspiro[3.5]nonanane-7-yl)-[1,2,4]triazolo[4,3-a]pyridine-6-sulfonamide(40) [ka]

[0394]

[0394] Step 1: 5-Bromo-3-chloro-2-hydrazinylpyridine (40-1)

[0395]

[0395] 5-bromo-3-chloro-2-fluoropyridine (19 g, 90 mmol), hydrazine hydrate (98%, 19 mL, 383 mmol), and EtOH (200 mL) were added under N2 conditions to a round-bottom flask equipped with a reflux condenser. The resulting mixture was stirred under reflux for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to obtain the crude product. The crude product was slurryed with water at 25°C for 30 minutes, then filtered and dried under vacuum to obtain 5-bromo-3-chloro-2-hydrazinylpyridine (19.3 g). LCMS (ESI, m / z): [M+H] + = 221.9.

[0396]

[0396] Step 2: Ethyl 6-bromo-8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (40-2)

[0397]

[0397] 5-bromo-3-chloro-2-hydrazinylpyridine (14 g, 62 mmol), ethyl 2-oxoacetate (7.6 g, 74 mmol), and MeOH (160 mL) were added under N2 conditions to an oven-dried round-bottom flask. The resulting mixture was stirred at 60°C for 2 hours. The reaction mixture was then cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in DCM (160 mL) and phenyl-λ was added. 3-Iodanediyl diacetate (26 g, 81 mmol) was added gradually at 0°C. After addition, the mixture was warmed to room temperature and stirred for 16 hours. Upon completion of the reaction, the resulting mixture was concentrated under reduced pressure. The residue was purified by C18 silica gel reverse-phase flash column chromatography (eluting with 0%~50% MeCN in water (0.05% NH4HCO3)) to obtain ethyl 6-bromo-8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (16.2 g). LCMS (ESI, m / z): [M+H] + = 304.0.

[0398]

[0398] Step 3: Ethyl 6-(benzylthio)-8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate(40-3)

[0399]

[0399] Ethyl 6-bromo-8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (11 g, 37 mmol), phenylmethanethiol (3.6 g, 29 mmol), Pd2(dba)3.CHCl3 (3.8 g, 3.7 mmol), xanthophos (4.3 g, 7.4 mmol), DIEA (14.3 g, 110 mmol), and 1,4-dioxane (400 mL) were added under N2 conditions. The reaction mixture was degassed with N2 and then stirred at 90°C for 3 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was post-treated with water and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to dryness under reduced pressure. The residue was purified by C18 silica gel reverse-phase flash column chromatography (eluting with 0%-50% MeCN in water (0.05% NH4HCO3)) to obtain ethyl 6-(benzylthio)-8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (11 g). LCMS (ESI, m / z): [M+H] + = 348.0.

[0400]

[0400] Step 4: 6-(benzylthio)-8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-carbohydrazide(40-4)

[0401]

[0401] Ethyl 6-(benzylthio)-8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (8.0 g, 22 mmol), EtOH (80 mL), and hydrazine hydrate (98%, 4.6 g, 90 mmol) were added to a round-bottom flask under N2 at room temperature. The resulting mixture was stirred at 30°C for 1 hour. The mixture was cooled to room temperature. The precipitate was collected by filtration and washed with EtOH. The resulting solid was dried under vacuum to obtain 6-(benzylthio)-8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-carbohydrazide (7.0 g). The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): [M+H] + = 334.1.

[0402]

[0402] Step 5: 6-(benzylthio)-8-chloro-N'-(2,2-difluoroacetyl)-[1,2,4]triazolo[4,3-a]pyridine-3-carbohydrazide(40-5)

[0403]

[0403] 6-(benzylthio)-8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-carbohydrazide (6.5 g, 18 mmol), THF (70 mL), DIEA (4.6 g, 36 mmol), and 2,2-anhydrous difluoroacetic acid (3.7 g, 21 mmol) were added to a flask under N2 at 0°C. The resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and work-up with water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel reverse-phase flash column chromatography (eluting with 30%-50% MeCN in water (0.05% NH4HCO3)) to obtain 6-(benzylthio)-8-chloro-N'-(2,2-difluoroacetyl)-[1,2,4]triazolo[4,3-a]pyridine-3-carbohradazide (7.0 g). LCMS (ESI, m / z): [M+H] + = 412.1.

[0404]

[0404] Step 6: 2-(6-(benzylthio)-8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole(40-6)

[0405]

[0405] 6-(benzylthio)-8-chloro-N'-(2,2-difluoroacetyl)-[1,2,4]triazolo[4,3-a]pyridine-3-carbohydrazide (4.2 g, 10 mmol), 1,4-dioxane (80 mL), and 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (6.1 g, 15 mmol) were added to a round-bottom flask at room temperature under N2. The resulting mixture was stirred under reflux under an N2 atmosphere for 16 hours. The reaction mixture was cooled to room temperature, work-treated with water, and extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (elution at 20% EA in PE) to obtain 2-(6-(benzylthio)-8-chloro-[1,2,4]triazolo[4,3-a]pyridine-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (4.0 g). LCMS (ESI, m / z): [M+H] + = 410.1.

[0406]

[0406] Step 7: 8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-6-sulfonyl chloride (40-7)

[0407]

[0407] To a mixture of 2-(6-(benzylthio)-8-chloro-[1,2,4]triazolo[4,3-a]pyridin-3-yl)-5-(difluoromethyl)-1,3,4-thiadiazole (1.4 g, 3.4 mmol) in AcOH (7.4 mL) and H2O (2.8 mL), NCS (1.8 g, 14 mmol) was gradually added at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was work-treated with water and then extracted with phenylethylamine. The combined organic layers were washed with saturated brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to obtain 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-sulfonyl chloride (1.3 g). The crude product was used directly in the next step without further purification. LCMS (ESI, m / z): [M+H] + = 386.0.

[0408]

[0408] Step 8: 8-Chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-(difluoromethyl)cyclopropyl)-[1,2,4]triazolo[4,3-a]pyridine-6-sulfonamide(40-8)

[0409]

[0409] In a stirred solution of 1-(difluoromethyl)cyclopropan-1-amine hydrochloride (775 mg, 5.18 mmol) and TEA (788 mg, 7.78 mmol) in DCM (20 mL), 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-[1,2,4]triazolo[4,3-a]pyridine-6-sulfonyl chloride (1.0 g, 2.6 mmol) was gradually added at room temperature under N2. The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was work-treated with water and then extracted with ethylethanol. The combined organic layers were washed with saturated brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by C18 silica gel reverse-phase flash column chromatography (eluting with 30%-50% MeCN in water (0.05% NH4HCO3)) to obtain 8-chloro-3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-(difluoromethyl)cyclopropyl)-[1,2,4]triazolo[4,3-a]pyridine-6-sulfonamide (790 mg). LCMS (ESI, m / z): [M+H] + = 457.1.

[0410]

[0410] Step 9: 3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-(difluoromethyl)cyclopropyl)-8-(2-oxa-7-azaspiro[3.5]nonanane-7-yl)-[1,2,4]triazolo[4,3-a]pyridine-6-sulfonamide(40)

[0411]

[0411] 8-chloro-3-[5-(difluoromethyl)-1,3,4-thiadiazole-2-yl]-N-[1-(difluoromethyl)cyclopropyl]-[1,2,4]triazolo[4,3-a]pyridine-6-sulfonamide (150 mg, 0.328 mmol), 2-oxa-7-azaspiro[3.5]nonane (208 mg, 1.64 mmol), Cs2CO3 (321 mg, 0.985 mmol), 1,4-dioxane (1.5 mL), and Pd-PEPPSI-IPentCl catalyst (55 mg, 0.057 mmol) were added to a vial under N2 conditions. The resulting mixture was degassed with N2 and then stirred at 105°C for 1.5 hours. The reaction mixture was cooled to room temperature and post-treated with water at room temperature. The resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by achiral HPLC eluting with ACN:MeOH=80:20 (1% in MeOH, 2M NH3 aqueous solution) to obtain 3-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-N-(1-(difluoromethyl)cyclopropyl)-8-(2-oxa-7-azaspiro[3.5]nonanane-7-yl)-[1,2,4]triazolo[4,3-a]pyridine-6-sulfonamide. LCMS (ESI, m / z): [M+H] + = 548.2. 1 H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 9.20 (s, 1H), 7.74 (t, J = 53.2 Hz, 1H), 6.90 (s, 1H), 5.79 (t, J = 56.0 Hz, 1H), 4.41 (s, 4H), 3.73-3.68 (m, 4H), 2.03-1.99 (m, 4H), 0.98-0.94 (m, 4H). 19 F NMR (400 MHz, DMSO-d6) δ -109.74, -120.58. Example 41 N-(1-cyanocyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-6-fluoro-5-(2-oxa-7-azaspiro[3.5]nonanane-7-yl)imidazo[1,5-a]pyridine-7-sulfonamide(41) [ka]

[0412]

[0412] Step 1: 5-Fluoro-4-iodopyridine-2-carbonitrile (41-1)

[0413]

[0413] To a solution of 5-fluoropyridine-2-carbonitride (18.5 g, 152 mmol) in dry THF (200 mL), TMPMgCl.LiCl (1.0 M in THF, 228 mL, 228 mmol) was added dropwise under N2 at -30°C. The mixture was stirred at -30°C for 1 hour. Then, iodine solution (46.2 g, 182 mmol) in dry THF (150 mL) was added under N2 at -30°C. The mixture was warmed to room temperature and stirred at room temperature for 1 hour. LC-MS indicated that the reaction was complete. The reaction mixture was quenched with saturated NH4Cl aqueous solution and then extracted with Â. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (elution with 7% ethyl acetate in PE) to obtain 5-fluoro-4-iodopyridine-2-carbonitrile (26 g). LCMS (ESI, m / z): [M+H] + = 249.0.

[0414]

[0414] Step 2: 5-Fluoro-4-iodo-1-oxide-pyridine-1-ium-2-carbonitrile (41-2)

[0415]

[0415] To a solution of 5-fluoro-4-iodopyridine-2-carbonitrile (26 g, 104.8 mmol) in TFA (200 mL), H2O2 (30% in water, 160 mL) was added dropwise at 0°C. The mixture was stirred at 80°C for 4 hours. After completion, the reaction mixture was quenched with saturated Na2SO3 aqueous solution and then extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluted with 17% ethyl acetate in PE) to obtain 5-fluoro-4-iodo-1-oxidepyridine-1-ium-2-carbonitrile (10 g). LCMS (ESI, m / z): [M+H] + = 265.0.

[0416]

[0416] Step 3: 6-Chloro-5-fluoro-4-iodopyridine-2-carbonitrili (41-3)

[0417]

[0417] A solution of 5-fluoro-4-iodo-1-oxide-pyridine-1-ium-2-carbonitrile (10 g, 37.9 mmol) in POCl3 (50 mL) was stirred at 70°C for 1 hour under N2. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to remove most of the POCl3. The residue was then work-treated with water and extracted with siRNA. The combined organic layers were washed with saturated sodium bicarbonate aqueous solution and saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by silica gel flash column chromatography (eluted with 5% siRNA in PE) to obtain 6-chloro-5-fluoro-4-iodo-pyridine-2-carbonitrile (4.5 g). LC-MS (ESI, m / z): [M+H] + = 282.9.

[0418]

[0418] Step 4: (6-chloro-5-fluoro-4-iodo-2-pyridyl)methanamine (41-4)

[0419]

[0419] To a solution of 6-chloro-5-fluoro-4-iodopyridine-2-carbonitrile (4.2 g, 14.9 mmol) in DCM (100 mL), DIBAL-H (1.0 M in hexane, 74.5 mL, 74.5 mmol) was added dropwise under N2 at 0°C. The mixture was stirred under an N2 atmosphere at 0°C for 1 hour. LC-MS indicated that the reaction was complete. The reaction mixture was quenched with saturated NH4Cl aqueous solution and then extracted with siRNA. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product, which was used directly in the next step without further purification. LC-MS (ESI, m / z): [M+H] + = 287.0.

[0420]

[0420] Step 5: N-[(6-chloro-5-fluoro-4-iodo-2-pyridyl)methyl]formamide (41-5)

[0421]

[0421] To a solution of (6-chloro-5-fluoro-4-iodo-2-pyridyl)methanamine (3.5 g, 12.2 mmol) in formic acid (40 mL), acetic anhydride (8 mL) was added under N2 conditions. The mixture was stirred at 80°C for 4 hours under an N2 atmosphere. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. LC-MS (ESI, m / z): [M+H] + = 315.0.

[0422]

[0422] Step 6: 5-chloro-6-fluoro-7-iodoimidazo[1,5-a]pyridine(41-6)

[0423]

[0423] To a solution of N-[(6-chloro-5-fluoro-4-iodo-2-pyridyl)methyl]formamide (3.2 g, 10.2 mmol) in toluene (20 mL), POCl3 (2 mL) was added under N2. The reaction solution was stirred at 80°C for 4 hours under an N2 atmosphere. LC-MS indicated that the reaction was complete. The reaction mixture was concentrated under reduced pressure. The residue was adjusted to pH=8 with saturated sodium bicarbonate aqueous solution and then extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluted with 20% ethyl acetate in PE) to obtain 5-chloro-6-fluoro-7-iodoimidazo[1,5-a]pyridine (2.47 g). LC-MS (ESI, m / z): [M+H] + = 297.0.

[0424]

[0424] Step 7: 7-benzylsulfanyl-5-chloro-6-fluoroimidazo[1,5-a]pyridine (41-7)

[0425]

[0425] To a solution of 5-chloro-6-fluoro-7-iodoimidazo[1,5-a]pyridine (2.47 g, 8.3 mmol) in 1,4-dioxane (40 mL), phenylmethanethiol (1.09 g, 8.75 mmol), DIEA (1.08 g, 8.33 mmol), xanthophos (964 mg, 1.67 mmol), and Pd2(dba)3 (763 mg, 0.83 mmol) were added under N2. The reaction mixture was degassed and then stirred at 80°C under N2 for 3 hours. LCMS indicated that the reaction was complete. The reaction mixture was work-treated with water and then extracted with siRNA. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (elution with 20% ethyl acetate in PE) to obtain 7-benzylsulfanyl-5-chloro-6-fluoroimidazo[1,5-a]pyridine (1.8 g). LCMS (ESI, m / z): [M+H] + = 293.1.

[0426]

[0426] Step 8: 7-benzylsulfanyl-5-chloro-6-fluoro-1-iodoimidazo[1,5-a]pyridine (41-8)

[0427]

[0427] To a solution of 7-benzylsulfanyl-5-chloro-6-fluoroimidazo[1,5-a]pyridine (900 mg, 3.07 mmol) in THF (20 mL), 1-iodopyrrolidine-2,5-dione (830 mg, 3.69 mmol) was added at 0°C. The mixture was stirred at 0°C for 2 hours. LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and then extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by silica gel flash column chromatography (eluted with 10% ethyl acetate in PE) to obtain 7-benzylsulfanyl-5-chloro-6-fluoro-1-iodoimidazo[1,5-a]pyridine (900 mg). LC-MS (ESI, m / z): [M+H] + = 419.0.

[0428]

[0428] Step 9: 5-Chloro-6-fluoro-1-iodoimidazo[1,5-a]pyridine-7-sulfonyl chloride (41-9)

[0429]

[0429] To a solution of 7-benzylsulfanyl-5-chloro-6-fluoro-1-iodoimidazo[1,5-a]pyridine (800 mg, 1.91 mmol) in formic acid (3 mL), water (0.3 mL), and DCM (10 mL), 1-chloropyrrolidine-2,5-dione (765 mg, 5.73 mmol) was added under N2 at 0°C. The mixture was warmed to room temperature and stirred for 1 hour. LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and then extracted with DCM. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (elution with 30% ethyl acetate in PE) to obtain 5-chloro-6-fluoro-1-iodoimidazo[1,5-a]pyridine-7-sulfonyl chloride (500 mg). LCMS (ESI, m / z): [M+H] + = 395.0.

[0430]

[0430] Step 10: 5-Chloro-N-(1-cyanocyclopropyl)-6-fluoro-1-iodoimidazo[1,5-a]pyridine-7-sulfonamide(41-10)

[0431]

[0431] To a solution of 1-aminocyclopropane carbonitride hydrochloride (180 mg, 1.52 mmol) in pyridine (7 mL), 5-chloro-6-fluoro-1-iodo-imidazo[1,5-a]pyridine-7-sulfonyl chloride (500 mg, 1.27 mmol) was added under N2 at room temperature. The mixture was stirred at room temperature for 1 hour. LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and then extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (eluting with 60% ethyl acetate in PE) to obtain 5-chloro-N-(1-cyanocyclopropyl)-6-fluoro-1-iodo-imidazo[1,5-a]pyridine-7-sulfonamide (500 mg). LCMS (ESI, m / z): [M+H] + = 441.0.

[0432]

[0432] Step 11: 5-Chloro-N-(1-cyanocyclopropyl)-6-fluoro-1-(trimethylstannyl)imidazo[1,5-a]pyridine-7-sulfonamide(41-11)

[0433]

[0433] To a solution of 5-chloro-N-(1-cyanocyclopropyl)-6-fluoro-1-iodoimidazo[1,5-a]pyridine-7-sulfonamide (500 mg, 1.13 mmol) in 1,4-dioxane (5 mL), trimethyl(trimethylstannyl)stannane (744 mg, 2.27 mmol) and Pd(PPh3)4 (131.1 mg, 0.113 mmol) were added under N2. The mixture was degassed and then stirred at 100°C for 7 hours under an N2 atmosphere. After completion, the reaction mixture was concentrated under reduced pressure to obtain the crude product, which was used directly in the next step without further purification. LCMS (ESI, m / z): [M+H] + = 479.1.

[0434]

[0434] Step 12: 5-Chloro-N-(1-cyanocyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-6-fluoroimidazo[1,5-a]pyridine-7-sulfonamide(41-12)

[0435]

[0435] To a solution of 5-chloro-N-(1-cyanocyclopropyl)-6-fluoro-1-trimethylstannyl-imidazo[1,5-a]pyridine-7-sulfonamide (500 mg, 1.05 mmol) in DMF (7 mL), 2-bromo-5-(difluoromethyl)-1,3,4-thiadiazole (270 mg, 1.26 mmol) and Pd(PPh3)4 (121 mg, 0.105 mmol) were added under N2 conditions. The reaction mixture was degassed and then stirred at 100°C for 7 hours under an N2 atmosphere. LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and then extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (elution with 50% ethyl acetate in PE) to obtain 5-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazole-2-yl]-6-fluoroimidazo[1,5-a]pyridine-7-sulfonamide (280 mg). LCMS (ESI, m / z): [M+H] + = 449.1.

[0436]

[0436] Step 13: N-(1-cyanocyclopropyl)-1-(5-(difluoromethyl)-1,3,4-thiadiazole-2-yl)-6-fluoro-5-(2-oxa-7-azaspiro[3.5]nonan-7-yl)imidazo[1,5-a]pyridine-7-sulfonamide(41)

[0437]

[0437] To a solution of 5-chloro-N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazole-2-yl]-6-fluoroimidazo[1,5-a]pyridine-7-sulfonamide (100 mg, 0.223 mmol) in N,N-dimethylacetamide (3 mL), 2-oxa-7-azaspiro[3.5]nonanehemiooxalate (76.5 mg, 0.445 mmol) was added under N2. The mixture was stirred under microwave and N2 atmosphere at 120 °C for 5 hours. LC-MS indicated that the reaction was complete. The reaction mixture was work-treated with water and then extracted with RINKAN. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (0.1% FA) to obtain N-(1-cyanocyclopropyl)-1-[5-(difluoromethyl)-1,3,4-thiadiazole-2-yl]-6-fluoro-5-(2-oxa-7-azaspiro[3.5]nonanane-7-yl)imidazo[1,5-a]pyridine-7-sulfonamide. LCMS (ESI, m / z): [M+H] + = 540.2. 1 HNMR (400 MHz, DMSO-d6) δ 9.77 (br s, 1H), 8.69 (s, 1H), 8.54 (d, J = 6.0 Hz, 1H), 7.65 (t, J = 53.2 Hz, 1H), 4.43 (s, 4H), 3.22 (m, 4H), 2.06 (s, 4H), 1.51-1.45 (m, 2H), 1.40-1.33 (m, 2H). Biological Example 1 PARG Biochemical Enzyme Assay

[0438]

[0438] BL21(DE3) competent cells were transformed using TEV-His8-PolyADP-ribose polymerase 1 (379-1014) (PARP1) and N-his8-TEV-hPARG (389-976), followed by growth at 37°C for 1 hour and plating on kanamycin-resistant agar plates. Single colonies were then inoculated into 1 ml of Luria broth and grown in a 1 liter scale at 37°C for 3 hours. Expression was induced in BL21(DE3) Escherichia coli (E. coli) via 0.2 mM IPTG at 16°C for 20 hours. Purification was then performed using nickel column size exclusion chromatography and HPLC analysis.

[0439]

[0439] For substrate preparation, 2 mM nicked DNA and 2 μM PARP1 protein were mixed at 25°C for 10 minutes. Then, 10 μM biotin-NAD+ and 100 μM NAD+ were added and incubated at 30°C for 60 minutes to obtain PAR-modified PARP1 substrate.

[0440]

[0440] For the screening of compounds, the compounds were serially diluted to three times the final concentration in assay buffer containing 1% DMSO (Tris pH 7.5 50 mM, KCl 50 mM, Tween-20 0.01%, BSA 0.1 mg / ml, EDTA 3 mM, EGTA 0.4 mM, DTT 1 mM). The highest concentration of 1.5 μM was used for the 10-point dose-response curve using a 1:3 dilution curve. A 2.5-fold PARG (active concentration 156.25 pM, final concentration 62.5 pM) was prepared in assay buffer, and 4 μl was added to a 384-well assay plate containing 2 μl of the serially diluted compound. The plate was then centrifuged for 10 seconds and incubated at 23°C for 60 minutes. Next, 4 μl of 2.5-fold biotin-PAR-conjugated PARP1 (active concentration 12.5 nM, final concentration 5 nM) was added to the plate and incubated at 23°C for 10 minutes. 4 μl of 100 μl of detection reagent containing 0.44 μg / ml streptavidin-europium cryptotate and 4 μg / ml anti-6His-XL665 monoclonal antibody was added to the plate and incubated at 23°C for 60 minutes. Homogeneous time-resolved fluorescence (HTRF) signals were then measured using a hypothetical plate reader, with excitation wavelength 337 nm and emission wavelengths 615 nm and 665 nm. Normalized inhibition percentages were then calculated using the following formula: Normalized Inhibition % = (Compound Signal - Minimum Signal) / (Maximum Signal - Minimum Signal) * 100%, where the maximum signal was the substrate-only well and the minimum signal was the enzyme and substrate well. IC 50 The inhibition percentage and the logarithm of the compound concentration were calculated by fitting them to a nonlinear regression (log(inhibitor) vs. response - variable slope (4 parameters)) using GraphPad 9.4.1.

[0441]

[0441] Regarding biochemical activity, the parentheses indicate: A < 100 nM; 100 nM <B<500nM;C> It shows 500 nM. [Table 4] Biological Example 2 Cell viability assay

[0442]

[0442] Kuramochi cells were seeded at a density of 1000 cells per well in a 384-well white sterile clear-bottom plate using a multi-drip liquid dispenser and incubated at 37°C for 24 hours in a 5% CO2 humidified environment. After 24 hours, the compound was added using an iDOT HT liquid handler, starting with the highest dose of 10 μM at a 1:3 dilution, to create a 9-point dose-response curve, which was incubated at 37°C in a 5% CO2 humidified environment for 5 days. After 5 days and on day 0, the plates were incubated at room temperature for 30 minutes, followed by the addition of 30 μl of CellTiter-Glo reagent. The plates were then mixed in an orbital shaker for 10 minutes, followed by incubation at room temperature for 20 minutes. Luminescence was then read using an Envision plate reader. Next, the growth inhibition percentage was calculated using the following formula: Normalized growth inhibition percentage = 100 - (compound signal - T0) / (maximum signal - T0) * 100%, where the maximum signal refers to cells treated with DMSO alone and T0 refers to the viability measurement on day 0. Then, growth inhibition 50 was calculated using the following formula: Y = bottom + (top - bottom) / (1 + 10^((LogIC50 - X) * slope)).

[0443]

[0443] Regarding cell activity, the parentheses indicate: A<1uM; 1uM <B<5uM;C> It shows 5 μM. [Table 5]

[0444]

[0444] The Summary and Abstract sections describe, but may not include, one or more exemplary embodiments of the Invention as considered by the inventors, and are therefore not intended to limit the scope of the Invention and the appended claims.

[0445]

[0445] The present invention has been described above using functional configuration blocks that exemplify the realization of specific functions and their relationships. The boundaries of these functional configuration blocks are arbitrarily defined herein for the sake of explanation. Alternative boundaries can be defined as long as the specific functions and their relationships are properly realized.

[0446]

[0446] With respect to the aspects of the present invention described as categories, all individual types can be considered individually as distinct aspects of the present invention. Where an aspect of the present invention is described as "containing" a feature, the embodiment may also be considered to "consist of" or "substantially consist of" the feature.

[0447]

[0447] The above description of specific embodiments will fully illuminate the general nature of the invention, and those skilled in the art can readily modify and / or adapt such specific embodiments to various applications by applying knowledge within the scope of the art without excessive experimentation and without departing from the general concept of the invention. Accordingly, such adaptations and modifications are intended to be within the scope of the meaning of the disclosed embodiments and their equivalents, based on the teachings and guidance presented herein. The terms and expressions used herein are for illustrative purposes only, not limiting purposes, and as a result, it should be understood that the terms and expressions used herein should be judged by those skilled in the art in consideration of the teachings and guidance.

[0448]

[0448] The breadth and scope of the present invention should not be limited by any of the exemplary embodiments described above.

[0449]

[0449] All of the various aspects, embodiments, and options described herein can be combined in any and all variations.

[0450]

[0450] All publications, patents, and patent applications described herein are incorporated by reference to the same extent as each individual publication, patent, or patent application is specifically indicated to be incorporated by reference. In the event of any conflict between the meaning or definition of any term in this document and any meaning or definition of the same term in any document incorporated by reference, the meaning or definition assigned to the term in this document shall prevail.

Claims

1. Compounds of formula I or pharmaceutically acceptable salts thereof 【Chemistry 1】 (In the formula: J １ CR ３ , NR ３ , O, S, or N; J ２ CR ４ , NR ４ , O, S, or N; J ３ CR ５ or N; J ４ is either CR ６ or N; J ５ CR ７ or N; J ６ is C or N; J ７ is C or N; J ８ is C or N; However, J １ ~J ８ The bicyclic ring containing is a heteroaryl ring, preferably J １ J ２ J ６ J ７ , and J ８ The ring has one, two, or three ring nitrogen atoms; L １ C is a non-existent, arbitrarily replaced C １～６ Alkylene, optionally replaced with C ２～６ Alkenylene, optionally substituted with C ２～６ Alkynylene is a 3- to 8-membered ring that is optionally substituted, R １ is a 3- to 8-membered ring that has been optionally substituted; or L １ R is a 7-12 membered bicyclic ring structure that is absent or optionally substituted; １ These are hydrogen, deuterium, halogens, CN, OH, and NH. ２ , C replaced by arbitrary selection １～４ Alkyl, optionally substituted C ２～４ Alkenyl, C substituted by choice ２～４ Alkinyl, optionally replaced with C １～４ A heteroalkyl or optionally substituted 3- to 6-membered ring; L ２ C is replaced by an optional substitution. １～４ Alkylene or optionally substituted 3- to 5-membered carboncyclic or heterocyclic rings, R ２ C is a hydrogen, deuterium, halogen, CN, OH, or optionally substituted C １～４ Alkyl, optionally substituted C ２～４ Alkenyl, or C as optionally substituted. ２～４ Alkynyl, or optionally substituted 3- to 5-membered carbon-cyclic or heterocyclic rings, R ３ hydrogen, deuterium, halogen, CN, G １ OG １ NHG １ NG １ G １ C(O)G １ C(O)NHG １ , or C(O)NG １ G １ And; R ４ This includes hydrogen, deuterium, halogens, CN, and optionally substituted C. １～４ Alkyl, optionally substituted C ２～４ Alkenyl, C substituted by choice ２～４ Alkinyl, optionally replaced with C １～４ Heteroalkyl, OG １ NHG １ NG １ G １ , or a 3- to 6-membered ring that has been optionally substituted; G １ Each instance independently contains hydrogen, or C which is optionally substituted. １～４ Alkyl, optionally substituted C ２～４ Alkenyl, C substituted by choice ２～４ Alkinyl, optionally replaced with C １～４ A heteroalkyl or optionally substituted 3- to 10-membered ring; or two G １ Both of them bond together with the nitrogen atom to which they are bonded, forming an optionally substituted 4- to 10-membered heterocyclic ring; R ５ Hydrogen, halogen, CN, OH, G ２ , or L ３ -G ２ And L ３ are O, NH, CO, C(O)NH, C(O)N(C １～４ Alkyl), SO ２ SO ２ NH, SO ２ N(C) １～４ C (alkyl), optionally substituted １～４ Alkylene, optionally replaced with C ２～４ Alkenylene, optionally substituted with C ２～４ Alkynylene, or optionally substituted C １～４ It is a heteroalkylene, G ２ These are 3- to 14-membered rings that have been optionally substituted; R ６ and R ７ Each of these is independently substituted with hydrogen, deuterium, halogen, CN, or optionally substituted C １～４ (It is alkyl.)

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized by having a structure according to formula I-1. 【Chemistry 2】

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized by having a structure according to formula I-2. 【Transformation 3】

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, characterized by having a structure according to formula I-3. 【Chemistry 4】

5. J １ A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein is N.

6. J １ CR ３ A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein the compound is preferably CH.

7. J ２ A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is N.

8. J ２ is CR ４ and preferably, R ４ is hydrogen or halogen, and preferably, R ４ is hydrogen, F, or Cl, the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

9. J ４ The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein the compound is CH or CF.

10. J ５ A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein the compound is CH.

11. J ４ and J ５ A compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein both are CH.

12. L １ is an optionally substituted 5-membered heteroarylene having 1 to 3 ring heteroatoms independently selected from S, N, and O, for example, an optionally substituted ring selected from thiazole, oxazole, imidazole, oxadiazole, or thiadiazole, or L １ is an optionally substituted 6-membered heteroarylene having 1 or 2 ring nitrogens, for example, optionally substituted pyridylene or optionally substituted pyridazylene, the compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

13. L １ but, 【Transformation 5】 And the bond point located at the meta position relative to the S atom is R １ A compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, which is bonded to a compound according to any one of claims 1 to 11.

14. L １ but, 【Transformation 6】 The compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

15. R １ However, deuterium, F, OH, CN, C １～４ Alkyl, C ２～４ Alkenil, C ２～４ Alkinyl and C １～４ A 3-4 membered ring optionally substituted with 1-3 substituents independently selected from the heteroalkyl group, and the C １～４ Alkyl, C ２～４ Alkenil, C ２～４ Alkinyl, or C １～４ The compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein the heteroalkyl group is optionally substituted with one to three substituents independently selected from F and OH.

16. R １ However, it is a cyclopropyl that is optionally substituted, and preferably, if substituted, the cyclopropyl is optionally substituted with F, OH, CN, or 1 to 3 F atoms. １～２ It is substituted with 1 to 3 substituents independently selected from alkyl groups, for example, R １ but, 【Transformation 7】 The compound according to any one of claims 1 to 15 or a pharmaceutically acceptable salt thereof.

17. L １ The compound according to any one of claims 1 to 14 or a pharmaceutically acceptable salt thereof, wherein the compound is an optionally substituted 8- to 10-membered condensed bicyclic ring structure having a first constituent ring and a second constituent ring, the first constituent ring being a 5-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, O, and S, and the second constituent ring being an aryl, heteroaryl, carbocyclic, or heterocyclic ring.

18. L １ The compound according to claim 17 or a pharmaceutically acceptable salt thereof, wherein the first constituent ring is an optionally substituted 8 or 9-membered condensed bicyclic heteroaryl having a first constituent ring and a second constituent ring, the first constituent ring being a 5-membered heteroaryl ring having 1 to 3 ring heteroatoms independently selected from N, O, and S, and the second constituent ring being phenyl, a 5-membered heteroaryl, or a 6-membered heteroaryl.

19. L １ However, through the ring atoms of the first constituent ring, J ７ It is bonded, and via the ring atoms of the second constituent ring, R １ A compound according to claim 17 or 18, or a pharmaceutically acceptable salt thereof, bonded to a compound.

20. The first constituent ring is a thiazole ring, 【Transformation 8】 The compound according to any one of claims 17 to 19 or a pharmaceutically acceptable salt thereof.

21. The second constituent ring is a 5-membered or 6-membered heteroaryl, for example, L １ but 【Chemistry 9】 (R １ The compound according to any one of claims 17 to 20 or a pharmaceutically acceptable salt thereof, wherein the (is illustrated to show the direction of bonding).

22. R １ However, hydrogen, deuterium, halogen (preferably F or Cl), OH, CN, C １～４ Alkyl, C ２～４ Alkenil, C ２～４ Alkinyl, or C １～４ It is a heteroalkyl, and the C １～４ Alkyl, C ２～４ Alkenil, C ２～４ Alkinyl, or C １～４ The compound according to any one of claims 17 to 21 or a pharmaceutically acceptable salt thereof, wherein the heteroalkyl group is optionally substituted with one to three substituents independently selected from F and OH.

23. L １ -R １ A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following. 【Chemistry 10】

24. L １ -R １ A compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following. 【Chemistry 11】

25. R ５ The compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, wherein the compound is an optionally substituted 4- to 12-membered heterocyclic ring having 1 to 4 ring heteroatoms independently selected from N, O, and S, and the S atom is optionally oxidized.

26. R ５ The compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, wherein the compound is an optionally substituted 4- to 7-membered heterocyclic ring having 1 to 3 ring heteroatoms independently selected from N, O, and S, and the S atom is optionally oxidized.

27. R ５ The compound according to claim 26 or a pharmaceutically acceptable salt thereof, selected from the following: 【Chemistry 12】 (In the formula: n is an integer from 0 to 4, (a) R １０ These are independently present in the form of oxo, halogen (e.g., F), OH, CN, and G. Ａ OG Ａ C(O)G Ａ SO ２ G Ａ P(O)G Ａ G Ａ C(O)NHG Ａ C(O)NG Ａ G Ａ SO ２ NHG Ａ , S(=NH)(=O)G Ａ , S(=N-G Ａ ) (=O)G Ａ SO ２ NG Ａ G Ａ NHC(O)G Ａ , or N(G Ａ ) C(O)G Ａ is, or (b) Two R １０ They bond to form optionally substituted 3- to 6-membered rings (e.g., cyclopropyl, cyclobutyl, or oxetane rings), and any remaining R １０ (a) is also defined as; or (c) A set of R １０ and R １１ They bond to form a 3- to 6-membered ring with optional substitutions, and any remaining R １０ As defined in (a); R １１ is hydrogen, G Ａ C(O)G Ａ SO ２ G Ａ C(O)OG Ａ C(O)NHG Ａ C(O)NG Ａ G Ａ SO ２ NHG Ａ , S(=NH)(=O)G Ａ , S(=N-G Ａ ) (=O)G Ａ , or SO ２ NG Ａ G Ａ , or as defined in (c) above; G Ａ For each existence, (i) C １～４ Alkyl; (ii) C １～４ Heteroalkyl groups; and (iii) optionally substituted groups independently selected from 3- to 10-membered rings, or two G groups. Ａ These atoms bond together with intervening atoms to form optionally substituted 4- to 10-membered heterocyclic rings; If replaced, the C １～４ Alkyl or C １～４ The heteroalkyl groups are preferably, independently of each other, (1) halogen (preferably F), CN, OH, or NH ２ (2) C which has been arbitrarily replaced in F １～４ Heteroalkyl; or (3) a 3- to 10-membered ring optionally substituted with 1 to 3 substituents; If substituted, the 3-10 membered ring or the 4-10 membered heterocyclic ring is preferably independently (1) an oxo (where applicable), a halogen (e.g., F, Cl), CN, OH, or NH ２ (2) C replaced by arbitrary selection in F １～４ Alkyl; (3) C optionally substituted with F １～４ Heteroalkyl; or (4) C optionally substituted with oxo, F, Cl, CN, OH, or F １～４ A 3-6 membered ring optionally substituted with 1-3 substituents independently selected from alkyl groups, and C optionally substituted with F. １～４ (It is a heteroalkyl group, substituted with 1 to 3 substituents.)

28. The compound according to claim 27 or a pharmaceutically acceptable salt thereof, wherein n is 0.

29. G Ａ However, each entity exists independently: (1) C independently of F, OH, and C substituted with 1 to 3 Fs of any choice. １～４ Alkoxy, NH(C) １～４ Alkyl), or N(C) １～３ (Alkyl) (C １～３ C(alkyl) which is optionally substituted with 1 to 3 substituents. １～４ Alkyl; or (2) Preferably, the 3 to 10 member ring is C ３～６ A 3-6 membered ring selected from cycloalkyl, 4-6 membered heterocyclyl, 5- or 6 membered heteroaryl, or phenyl, wherein the 3-10 membered ring is optionally substituted with oxo, F, Cl, OH, CN, or F. １～４ C optionally substituted with alkyl or F １～４ A 3-10 membered ring, (C) optionally substituted with alkoxys and 1-3 substituents independently selected from optionally substituted 3-5 membered rings (e.g., cyclopropyl, cyclobutyl, azetidinyl, oxetanyl, etc.). １～４ Alkylene)-(3-10 membered ring), or (C) １～４ Heteroalkylene (3-10 membered ring) The compound according to claim 27 or 28, or a pharmaceutically acceptable salt thereof.

30. R １１ However, C(O)G Ａ SO ２ G Ａ C(O)OG Ａ C(O)NHG Ａ C(O)NG Ａ G Ａ SO ２ NHG Ａ , S(=NH)(=O)G Ａ , S(=N-G Ａ ) (=O)G Ａ , or SO ２ NG Ａ G Ａ The compound according to any one of claims 27 to 29 or a pharmaceutically acceptable salt thereof.

31. R １１ but: 【Chemistry 13】 A compound according to claim 30 or a pharmaceutically acceptable salt thereof, selected from the above.

32. R １１ G Ａ And preferably, G Ａ The compound according to any one of claims 27 to 29 or a pharmaceutically acceptable salt thereof, wherein the compound is a five-membered or six-membered heteroaryl that is optionally substituted.

33. R １１ but, 【Chemistry 14】 The compound according to claim 32 or a pharmaceutically acceptable salt thereof.

34. R ５ The compound according to any one of claims 1 to 25 or a pharmaceutically acceptable salt thereof, wherein the compound is an optionally substituted 7-12 membered heterocyclic ring having 1-3 ring heteroatoms independently selected from N, O, and S, and the S atom is optionally oxidized.

35. R ５ It contains a spirooxetane ring, for example, R ５ but, 【Chemistry 15】 The compound according to claim 34 or a pharmaceutically acceptable salt thereof, which can be represented by the structure, wherein ring A is a 4- to 8-membered carbocyclic or heterocyclic ring and shares a single ring carbon atom with the oxetane ring.

36. R ５ but: 【Chemistry 16】 A compound according to claim 35 or a pharmaceutically acceptable salt thereof, selected from the above.

37. R ５ However, if optionally substituted, the five-membered or six-membered heteroaryl, for example, pyrazole, is substituted, then preferably independently, (1) a halogen (e.g., F, Cl), CN, OH, or NH ２ (2) C replaced by arbitrary selection in F １～４ Alkyl; (3) C optionally substituted with F １～４ Heteroalkyl; or (4) C optionally substituted with oxo, F, Cl, CN, OH, or F １～４ C optionally substituted with alkyl and F １～４ A compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, which is a 3- to 6-membered ring optionally substituted with 1 to 3 substituents independently selected from a heteroalkyl group, and which is substituted with 1 to 3 substituents.

38. L ２ but 【Chemistry 17】 And, those that have been arbitrarily replaced by F, for example, [Chemistry 18] The compound according to any one of claims 1 to 37 or a pharmaceutically acceptable salt thereof.

39. R ２ However, C is substituted with hydrogen, F, F at will. １～２ Alkyl (e.g., CH ３ ,CH ２ F, CHF ２ , or CF ３ ), C optionally substituted with CN, cyclopropyl, or F ２～３ Alkinyl, for example, 【Chemistry 19】 The compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof.

40. Where applicable, a compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, characterized by having the structure of formula I-A. 【Chemistry 20】 (In the formula: R １００ This can be hydrogen, F, OH, CN, or optionally substituted alkyl, for example, C optionally substituted with deuterium or F. １～４ Alkyl (e.g., CH ３ CD ３ ,CH ２ F, CHF ２ (etc.), or optionally substituted heteroalkyls, for example, C optionally substituted with deuterium or F. １～４ (It is heteroalkyl.)

41. A compound according to claim 40 or a pharmaceutically acceptable salt thereof, as defined in any of embodiments A2 to 29 of this specification.

42. Where applicable, a compound according to any one of claims 1 to 38 or a pharmaceutically acceptable salt thereof, characterized by having a structure according to formula I-D: 【Chemistry 21】 (In the formula: q is either 1 or 2; R １０１ (where is a methyl atom optionally substituted with F or F).

43. A compound according to claim 42, or a pharmaceutically acceptable salt thereof, as defined in any of embodiments B2 to 43 of this specification.

44. Where applicable, a compound according to any one of claims 1 to 38, or a pharmaceutically acceptable salt thereof, characterized by having a structure according to formula I-D. 【Chemistry 22】 (In the formula: Ring B is an optionally substituted five-membered or six-membered heterocyclyl or heteroaryl ring having one to three ring heteroatoms that are independently N, O, or S; R １ These are hydrogen, deuterium, halogens, CN, OH, and NH. ２ , C replaced by arbitrary selection １～４ Alkyl, optionally substituted C １～４ (A heteroalkyl group, or a 3- to 6-membered ring optionally substituted.)

45. A compound according to claim 44 or a pharmaceutically acceptable salt thereof, as defined in any of embodiments C2 to C26 of this specification.

46. A compound selected from Table 1 or Examples 1 to 41, or a pharmaceutically acceptable salt thereof.

47. A pharmaceutical composition comprising a compound according to any one of claims 1 to 46 or a pharmaceutically acceptable salt thereof.

48. A method for treating a disease or disorder involving PARG activity, comprising the step of administering an effective amount of a compound according to any one of claims 1 to 46 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 47.

49. The method according to claim 48, wherein the disease or disorder is cancer.

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