Preparation method for cbl-b regulator, and use

Abstract

The present invention provides a novel small molecule compound which has E3 ubiquitin ligase inhibitory activity, and relates to the compound as shown in formula (II), a stereoisomer, a tautomer, an isotope derivative or a pharmaceutically acceptable salt thereof, a preparation method therefor, and a use of the compound, belonging to the field of pharmaceutical chemistry.

Description

Preparation method and use of CBL-B regulator Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to a new class of small molecule compounds with E3 ubiquitin ligase inhibitory activity, a preparation method thereof, and uses of such compounds. Background Art

[0002] The ubiquitin-proteasome system (UPS) is the primary pathway for intracellular protein degradation, involved in the degradation of over 80% of proteins. Protein synthesis and degradation are crucial for cell cycle regulation, cell proliferation, apoptosis, and many other cellular processes. E3 ubiquitin ligases are crucial components of the UPS, determining substrate recognition specificity. Dysregulation of E3 ubiquitin ligases can cause a variety of diseases, including cancer and neurodegeneration. Modulating and intervening in E3 ubiquitin ligases holds promise as a new avenue for treating cancer and related diseases.

[0003] E3 ubiquitin ligases play a decisive role in the type of protein ubiquitination and degradation. Among them, Cbl-b is an important RING-type E3 ubiquitin ligase. In recent years, increasing evidence has shown that Cbl-b plays an important role in T cell regulation and tumor immunity. Targeted therapy for Cbl-b may become a key strategy for curing cancer. Currently, there are no drugs targeting Cbl-b on the market. Cbl-b inhibitors developed by Nurix Pharmaceuticals Research and Development in San Francisco, USA, have entered clinical trials. Its applied patents WO2020210508, WO2020264398, WO2021021761, WO2021061853, and WO2020236654 disclose a series of Cbl-b small molecule inhibitors.

[0004] The present invention provides a new class of Cbl-b small molecule inhibitors. Compared with other known compounds, the compounds of the present invention have better anticancer activity and lower toxicity.

[0005] Summary of the Invention

[0006] The first aspect of the present invention relates to a compound represented by formula (II), its stereoisomers, tautomers, isotopic derivatives or pharmaceutically acceptable salts thereof,

[0007] Among them, W 0 CR 0 or N, R 0 is -H or -halogen, preferably R 0 is -H or F, more preferably R 0 is -H;

[0008] R 2 -halogen, -CN, -C 2-5 Alkynyl or -C 1-3 Alkyl, wherein the -C 1-3 The alkyl group is optionally substituted with one or more halogens as allowed by valence;

[0009] L 1 For-(CR 12 R 13 ) m -or-(CR 12 R 13 ) m -NR 11 -(CR 12 R 13 ) m -, R 11 -H or -C 1-3 alkyl,

[0010] R 12 and R 13 Each independently represents -H, -OH, -C 1-3 Alkyl, -C 1-3 Alkylene-OH, m is each independently 0, 1, 2, 3 or 4;

[0011] Ring B is a 5-7 membered aromatic ring, a 5-7 membered heterocyclic ring or an 8-12 membered fused heterobicyclic ring;

[0012] R 10 are each independently -halogen, -C 1-6 Alkyl, -NH-C 1-6 Alkyl, -OC 1-6 Alkyl, -C 1-3 Alkyl-OC 1-3 Alkyl, -SO2-C 1- 3 alkyl, -OH, oxo (=O), -C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, the -C 1-6 Alkyl and -C 1-3 The alkyl group is optionally substituted with one or more halogen groups as allowed by the valence, and p is 0, 1, 2 or 3;

[0013] L 2 for

[0014] R 3 and R 4 Each is independently -H, -CN, -C 1-3 Alkylene-CN, -halogen, -C 1-3Alkyl or -OC 1-3 alkyl;

[0015] R 9 is -H or -CN;

[0016] R 5 -H, -C 1-3 Alkyl, wherein the -C 1-3 The alkyl group is optionally substituted with one or more halogens or D as allowed by valence;

[0017] Ring A is -C 3-6 Cycloalkyl or 4-12 membered heterocycloalkyl;

[0018] T2 is each independently -OH, -halogen, -C 1-6 Alkyl, -CONR a R b 、-OC 1-6 Alkyl, -C 1-6 Alkylene -OH, -CN, -C 1- 6-alkylene-CN, -C 1-3 Alkylene-OC 1-3 Alkyl, the -C 1-6 Alkyl, -C 1-6 Alkylene-, -C 1-3 Alkylene- or -C 1-3 The alkyl group is optionally substituted with one or more halogens within the allowed range of valence, wherein R a 、R b are each independently -H or -C 1-6 Alkyl, or T2 is -C 1-4 Alkylene-, n is 0, 1, 2, 3 or 4.

[0019] In some embodiments of the present invention, R 2 -F, -Cl, -Br, -CN, -C 2-3 Alkynyl or -C 1-3 Alkyl, the -C 1-3 The alkyl group is optionally substituted with one or more F groups as allowed by the valence; in some embodiments of the present invention, R 2 is -Cl, -Br, -C≡CH, -CN, -CF3, -CH2F or -CF2H, preferably, R 2 It is -CF3 or -CF2H.

[0020] In some embodiments of the present invention, R 11 is -H or -Me, preferably R 11 is -H;

[0021] In some embodiments of the present invention, R 12 and R 13 Each independently represents -H, -OH, -Me, -CH2-OH, preferably R 12 and R 13 Both H or R 12 and R 13 One of them is H, and the other is -OH, -Me or -CH2-OH.

[0022] In some embodiments of the present invention, L 1 For the bond, -(CH2) m -、-CH(C 1-3 Alkyl)-, -(CH2) m NH-, -NH(CH2) m -、-NHCH(C 1-3 alkyl)-, -CH2NHCH2-, -NHCH2CH(OH)-, -NHCH(CH2OH)-, m is 1 or 2.

[0023] In some embodiments of the present invention, L 1 It is a bond, -CH2-, -CH(Me)-, -CH2NH-, -NHCH2-, -NHCH(Me)-, -CH2NHCH2-, -NHCH2CH(OH)-, -NHCH(CH2OH)-.

[0024] In some embodiments of the present invention, R 10 Each independently represents -F, -C 1-3 Alkyl, -NH-C 1-3 Alkyl, -OC 1-3 Alkyl, -C 1-3 Alkyl-OC 1-3 Alkyl, -SO2-C 1-3 Alkyl, -OH, oxo (=O), -C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, the -C 1-3 The alkyl group may be optionally substituted with one or more F groups as allowed by valence.

[0025] In some embodiments of the present invention, R 10Each is independently -F, -Me, -Et, -CHMe2, -CH2CH2CH3, -NH-Me, -NH-Et, -OMe, -OEt, -CH2OMe, -SO2Me, -SO2Et, -OH, =O, -cyclopropyl, -O-cyclopropyl, -CHF2, -CH2F, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CF2CH3, -CF2CHF2, -CF2CH2F, -CH2CF2CF3, -OCH2CHF2, -OCHF2 or -OCH2CF3.

[0026] In some embodiments of the present invention, L 2 for

[0027] In some embodiments of the present invention, R 3 and R 4 Each is independently -H, -C 1-3 Alkyl or -OC 1-3 Alkyl, preferably, R 3 and R 4 Each is independently -H, -Me or -O-Me.

[0028] In some embodiments of the present invention, R 5 is -H, -Me, -Et, -CD3, or one or more F-substituted methyl or ethyl groups within the allowed range of valence, preferably R 5 is -H, -Me, -Et, -CHF2, -CF3 or -CD3, more preferably, R 5 For-Me.

[0029] In some embodiments of the invention, Ring A is or a 4-6 membered heterocycloalkyl group, wherein the heterocycloalkyl group has 1 or 2 heteroatoms, and the heteroatoms are N or O.

[0030] In some embodiments of the invention, Ring A is

[0031] In some embodiments of the present invention, T2 is independently -OH, -F, -C 1-4 Alkyl, -CONR a R b 、-OC 1-3 Alkyl, -C 1-3 Alkylene -OH, -CN, -C 1-3 Alkylene CN, -C optionally substituted with one or more F as allowed by the valence 1-3 Alkyl, -C 1-3 Alkylene-OC 1-3Alkyl, the R a 、R b are each independently -H or -C 1-3 Alkyl, or T2 is -C 1-2 Alkylene-.

[0032] In some embodiments of the present invention, T2 is each independently -OH, -F, -Me, -Et, -CONH2, -O-Me, -CH2-OH, -CN, -CH2CN, -CH2F, -C2H4OMe or -CH2- connected to two carbon atoms on the A ring.

[0033] In some embodiments of the present invention, for Preferably More preferably

[0034] In some embodiments of the present invention, Ring B is a benzene ring, a 6-membered heterocycle or a 9-10-membered fused heterobicyclic ring, and the number of heteroatoms in the heterocycle or fused heterobicyclic ring is 1, 2, 3 or 4.

[0035] In some embodiments of the invention, Ring B is Among them, M 1 、M 2 、M 3 、M 4 are each independently N, CH or C as allowed by valence, and M 1 、M 2 Not N at the same time.

[0036] In some embodiments of the invention, Ring B is

[0037] In some embodiments of the invention, Ring B is Among them, Z 1 、Z 2 、Z 3 、Z 4 or Z 5 are each independently C, CH or N as allowed by valence, preferably Z 1 、Z 2 、Z 3 、Z 4 or Z 5 One or two of them are N, and the rest are C or CH.

[0038] In some embodiments of the invention, Ring B is

[0039] In some embodiments of the present invention, the compound represented by formula (II) has the following structure:

[0040] W 1 is CH2 or O, R 10 -C 1-6 Alkyl or -C 3-6 Cycloalkyl, the -C 1-6 The alkyl group is optionally substituted with one or more halogens as allowed by the valence; preferably R 10 -C 1-3 Alkyl, -C 3-6 Cycloalkyl, the -C 1-3 The alkyl group is optionally substituted with one or more F groups as allowed by the valence; more preferably, R 10 It is -cyclopropyl, -Et, -CH2CF3, -CHMe2, -CH2CF2CF3.

[0041] In some embodiments of the present invention, the compound represented by formula (II) has the following structure:

[0042] W 1 CH2 or O, E 1 、E 2 Each independently is N or CR 10 And E 1 、E 2 Not all N at the same time;

[0043] R 10 -H, -halogen, -C 1-3 Alkyl, -NH-C 1-3 Alkyl, -OC 1-3 Alkyl, -C 1-3 Alkyl-OC 1-3 Alkyl, -SO2-C 1-3 Alkyl, -C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, the -C 1-3 The alkyl group is optionally substituted with one or more halogens as allowed by the valence; preferably -H, -F, -C 1-3 Alkyl, -NH-C 1-3 Alkyl, -OC 1-3 Alkyl, -C 1-3 Alkyl-OC 1-3 Alkyl, -SO2-C 1-3 Alkyl, -OC 3-6 Cycloalkyl, the -C 1-3Alkyl is optionally substituted with one or more F as allowed by the valence; more preferably -H, -F, -OEt, -NHEt, -OCH2CHF2, -OCHF2, -OCH2CF3, -O-cyclopropyl, -OMe, -OEt, -CH2OMe or -SO2Et.

[0044] In some embodiments of the present invention, the compound represented by formula (II) has the following structure:

[0045] Z 1 is N or CH,

[0046] R 2 is -CF3 or -CF2H,

[0047] Ring A, T2, n, L 1 As described in Formula II.

[0048] In some embodiments, L 1 -(CH2) m -、-CH(C 1-3 Alkyl)-, -(CH2) m NH-, -NH(CH2) m -、-NHCH(C 1-3 alkyl)-, -CH2NHCH2-, -NHCH2CH(OH)-, -NHCH(CH2OH)-, m is 1 or 2; preferably L 1 It is -CH2-, -CH(Me)-, -CH2NH-, -NHCH2-, -NHCH(Me)-, -CH2NHCH2-, -NHCH2CH(OH)-, -NHCH(CH2OH)-.

[0049] In some embodiments of the invention, Ring A is or a 4-6 membered heterocycloalkyl group, wherein the heteroatom of the heterocycloalkyl group is 1 or 2, and the heteroatom is N or O, preferably ring A is

[0050] In some embodiments of the present invention, T2 is each independently -OH, -F, -Me, -Et, -CONH2, -O-Me, -CH2-OH, -CN, -CH2CN, -CH2F, -C2H4OMe.

[0051] In some embodiments, Ring A is a 6-membered heterocyclic ring, and the heteroatom of the heterocycloalkyl group is N or O.

[0052] In some embodiments, n is 1, 2, or 3.

[0053] In some embodiments, for T2 is -C 1-3 Alkyl; preferably, for

[0054] In some embodiments of the present invention, the compound represented by formula (II) has the following structure:

[0055] Where X is CX 0 or N; X 0 is -H or -halogen;

[0056] m is 0, 1, 2, 3 or 4;

[0057] R 1 for

[0058] Y is -C 1-3 Alkyl or -C 3-6 Cycloalkyl, wherein the -C 1-3 The alkyl group is optionally substituted with one or more halogens as allowed by valence;

[0059] X 1 For CX 2 or N; X 2 is -H or -halogen;

[0060] Y 1 For CY 2 or N; Y 2 -H, -halogen, -C 1-3 Alkylamino, -C 1-3 Alkyloxy, -C 1-3 Cycloalkyloxy, the -C 1- 3-alkylamino or -C 1-3 The alkyloxy group is optionally substituted with one or more halogen or cycloalkyl groups as allowed by valence;

[0061] where X 1 and Y 1 Not all N at the same time;

[0062] R 3 and R 4 are independently -H, -CN, halogen, -C 1-3 Alkyl or -C 1-3 alkoxy;

[0063] R 5 -H, -C 1-3 Alkyl, wherein the -C 1-3The alkyl group is optionally substituted with one or more halogens as allowed by valence;

[0064] R 9 is -H or -CN;

[0065] R 2 -halogen, -CN, -C 2-5 Alkynyl or -C 1-3 Alkyl, wherein the -C 1-3 The alkyl group is optionally substituted with one or more halogens as allowed by valence;

[0066] R 6 -NR 7 R 8 or Where A is -C 3-6 Cycloalkyl or 4-12 membered heterocycloalkyl, T2 is -C 1-4 Alkyl, aminocarbonyl (the amino group is -NH2, mono-C 1-3 Alkylamino or di-C 1-3 Alkylamino), or T2 is -C 1-4 Alkylene-, n is any integer from 0 to 12;

[0067] R 7 and R 8 are independently hydrogen, -C 1-3 Alkyl or -C 3-6 Cycloalkyl, wherein the -C 3-6 The cycloalkyl group is optionally substituted with one or more T3 groups as allowed by the valence, wherein the T3 group is -C 1-3 alkyl.

[0068] In some embodiments of the present invention, the compound represented by formula (II) has the following structure:

[0069] Where X is CX 0 or N; X 0 is -H or -halogen;

[0070] R1 is

[0071] Y is -C 1-3 Alkyl or -C 3-6 Cycloalkyl, wherein the -C 1-3 The alkyl group is optionally substituted with one or more halogens as allowed by valence;

[0072] X 1 For CX 2 or N; X 2is -H or -halogen;

[0073] Y 1 For CY 2 or N; Y 2 -H, halogen, -C 1-3 Alkylamino, -C 1-3 Alkyloxy, the -C 1-3 Alkyl or -C 1-3 Alkylamino or -C 1-3 The alkyloxy group is optionally substituted with one or more halogen or cycloalkyl groups as allowed by valence;

[0074] where X 1 and Y 1 Not all N at the same time;

[0075] R 3 and R 4 are independently -H, -CN, halogen, -C 1-3 Alkyl or -C 1-3 alkoxy;

[0076] R 5 -H or -C 1-3 alkyl;

[0077] R 9 is -H or -CN;

[0078] R 2 Halogen, -CN, -C 2-5 Alkynyl or -C 1-3 Alkyl, wherein the -C 1-3 The alkyl group is optionally substituted with one or more halogens as allowed by valence;

[0079] R 6 -NR 7 R 8 or Where A is -C 3-6 Cycloalkyl or 4-12 membered heterocycloalkyl, T2 is -C 1-4 Alkyl, aminocarbonyl (the amino group is -NH2, mono-C 1-3 Alkylamino or di-C 1-3 Alkylamino), or T2 is C connected to two carbon atoms on the A ring 1-4 Alkylene, n is any integer from 0 to 12;

[0080] R 7 and R 8 are independently hydrogen, -C 1-3 Alkyl or -C 3-6 Cycloalkyl, wherein the -C 3-6The cycloalkyl group is optionally substituted with one or more T3 groups as allowed by the valence, wherein the T3 group is -C 1-3 alkyl.

[0081] In some embodiments of the present invention, X is CX 0 or N, X 0 Preferably, X is -H or -F.

[0082] In some embodiments of the present invention, R 1 for Y is -C 1-3 Alkyl or -C 3-5 Cycloalkyl; preferably, the -C 1-3 The alkyl group is optionally substituted with one or more F groups as allowed by valence; more preferably, Y is methyl, ethyl, -CH2CF3, isopropyl or cyclopropyl.

[0083] In some embodiments of the present invention, R 1 for Preferably, X 1 CH, CF or N, Y 1 For CY 2 ; or X 1 CH or CF, Y 1 is N.

[0084] In some embodiments of the present invention, R 1 for

[0085] In some embodiments of the present invention, R 1 for

[0086] In some embodiments of the present invention, R 1 for

[0087] In some embodiments of the present invention, Y 2 -H, -F, -C 1-3 Alkylamino, -C 1-3 Alkyloxy; preferably, the -C 1- 3-alkylamino or -C 1-3 The alkyloxy group is optionally substituted with one or more F or cyclopropane groups as allowed by the valence; more preferably, Y 2 is -H, -F, -OCH3, -OCH2CH3, -NHCH2CH3, -OCH2CHF2, -OCHF2, -OCH2CF3 or

[0088] In some embodiments of the present invention, R2 Halogen, -CN, -C 2-3 Alkynyl or -C 1-3 Alkyl; preferably, the -C 1-3 The alkyl group is optionally substituted with one or more F groups as allowed by the valence; more preferably, R 2 It is -Br, -Cl, -C≡CH, -CN, -CF3 or -CF2H.

[0089] In some embodiments of the present invention, R 6 -NR 7 R 8 , R 7 and R 8 One of them is H and the other is -C 3-6 Cycloalkyl, wherein the -C 3-6 The cycloalkyl group is optionally substituted with one or more T3 groups as allowed by the valence, wherein T3 is -C 1-3 Alkyl, for example, T3 is methyl, ethyl, n-propyl or isopropyl; preferably, R 7 and R 8 One of them is H and the other is -C substituted by methyl 3-6 Cycloalkyl; more preferably, R 7 and R 8 One of them is H and the other is a cyclobutyl group substituted with a methyl group.

[0090] In some embodiments of the present invention, R 6 for Wherein A is a 4-6 membered heterocycloalkyl group or C 4-6 Cycloalkyl, preferably the 4-6 membered heterocycloalkyl contains 1 or 2 heteroatoms on the heterocycle, wherein the heteroatoms are N or O, more preferably A is azacyclopentyl, azacyclohexyl, morpholinyl, cyclobutane, cyclopentane or cyclohexane; n is 0, 1 or 2, preferably 0 or 1; T2 is -C 1-4 Alkyl or single C 1-3 Alkylamino or T2 is a methylene group attached to two carbon atoms on the A ring, preferably a methyl group or -C(=O)NH2.

[0091] In some preferred embodiments of the present invention, R 6 for

[0092] In some preferred embodiments of the present invention, R 6 for

[0093] In some embodiments of the present invention, R 3 and R 4are independently -H or -C 1-3 Alkyl; preferably, R 3 and R 4 are independently -H or -CH3; more preferably, R 3 and R 4 One of them is -H and the other is -CH3.

[0094] In some embodiments of the present invention, R 5 -C 1-3 Alkyl, preferably -CH3.

[0095] In some embodiments of the present invention, the compound of the first aspect of the present invention is selected from the following compounds:

[0096] In some embodiments of the present invention, the compound of the first aspect of the present invention is selected from the following compounds:

[0097] Another aspect of the present invention provides a method for preparing the compound of the first aspect of the present invention, wherein the method comprises the steps of Scheme 1, Scheme 2, Scheme 3, Scheme 4, Scheme 5, Scheme 6, Scheme 7 or Scheme 8, wherein Scheme 1: when R 1 for X 1 CH, Y 1 For CY 2 , R 5 When it is methyl,

[0098] Option 2: When R 1 for X 1 CH, Y 1 For CY 2 , R 5 When it is methyl,

[0099] Option 3:

[0100] Option 4: When R 1 for X 1 N, Y 1 For CY 2 , R 5 When it is methyl,

[0101] Option 5: When R 1 for hour,

[0102] Solution 6: When X is N,

[0103] Option 7: When R 1 for hour,

[0104] Option 8: When R 1 for hour,

[0105] Wherein each group is as described in the first aspect of the present invention.

[0106] Another aspect of the present invention provides a pharmaceutical composition comprising at least one compound according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable carriers and / or additives.

[0107] Another aspect of the present invention provides use of the compound or pharmaceutically acceptable salt thereof according to the first aspect of the present invention or the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating cancer.

[0108] In some embodiments of the present invention, the cancer comprises gastric cancer.

[0109] Another aspect of the present invention provides use of the compound or pharmaceutically acceptable salt thereof or the pharmaceutical composition of the first aspect of the present invention as a Cbl-b inhibitor.

[0110] Another aspect of the present invention provides a method for treating cancer, comprising: administering a therapeutically effective amount of a Cbl-b inhibitor to an individual suffering from cancer, wherein the Cbl-b inhibitor is the compound according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to the present invention.

[0111] Another aspect of the present invention provides a method for regulating immune cell activity, comprising contacting the immune cell with a therapeutically effective amount of a Cbl-b inhibitor to regulate the immune cell activity, wherein the Cbl-b inhibitor is the compound according to the first aspect of the present invention or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of the present invention.

[0112] The pharmaceutically acceptable salts of the present invention can be prepared by reacting with corresponding organic or inorganic acids in an organic solvent.

[0113] The compounds of the present invention can exist as optically pure enantiomers, pure diastereomers, mixtures of enantiomers, mixtures of diastereomers, racemic mixtures of enantiomers, racemates or mixtures of racemates. All possible isomers, stereoisomers and mixtures thereof of the compounds of the first aspect of the present invention are also within the scope of the present invention. Metabolites of the compounds of the first aspect of the present invention and isotopic derivatives of the compounds of the first aspect of the present invention are also within the scope of the present invention. For example, the compounds of the present invention The range includes mixtures thereof, mixtures of diastereomers, racemic mixtures of enantiomers, racemates or mixtures of racemates.

[0114] The optically pure enantiomers and pure diastereomers of the present invention can be obtained by chiral resolution or chiral synthesis. For example, the chiral centers of compound 12 are introduced by synthesis using commercially available chiral raw materials.

[0115] In some embodiments of the present invention, the compound or pharmaceutically acceptable salt thereof according to the first aspect of the present invention may be an isotopic derivative (eg, a deuterated compound).

[0116] In some embodiments of the present invention, the compound or pharmaceutically acceptable salt thereof according to the first aspect of the present invention may be a metabolite thereof.

[0117] The pharmaceutical composition provided by the present invention can be prepared in any form, such as granules, powders, tablets, coated tablets, capsules, pills, syrups, drops, solutions, suspensions and emulsions, or sustained-release preparations of the active ingredients.

[0118] The pharmaceutical compositions of the present invention may further include one or more pharmaceutically acceptable carriers, which are suitably formulated for ease of administration. For example, pharmaceutically or physiologically acceptable carriers may include saline, autoclaved water, Ringer's solution, buffered saline, glucose, maltodextrin, glycerol, ethanol, and mixtures thereof. The pharmaceutical compositions of the present invention may also include pharmaceutically acceptable additives, such as diluents, lubricants, binders, glidants, disintegrants, sweeteners, flavoring agents, wetting agents, dispersants, surfactants, solvents, coating agents, foaming agents, or fragrances.

[0119] The pharmaceutical composition of the present invention can be administered by various routes according to conventional methods, including oral, intravenous, intraarterial, intraperitoneal, intrathoracic, transdermal, nasal, inhalation, rectal, ocular and subcutaneous administration.

[0120] Pharmacological experiments have shown that the compounds or pharmaceutical compositions provided by the present invention can be used to treat cancer, including but not limited to gastric cancer. DETAILED DESCRIPTION

[0121] Unless otherwise indicated, conventional methods within the technical scope of the art, such as mass spectrometry, NMR and pharmacological methods, are adopted. Unless specifically defined, the terms used herein in the relevant descriptions of analytical chemistry, organic synthesis chemistry and medicine and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, preparation and delivery, and in the treatment of patients. For example, the instructions for use of the manufacturer's test kit can be utilized, or reaction and purification can be implemented according to a manner well known in the art or the description of the present invention. Conventionally, the above-mentioned techniques and methods can be implemented according to conventional methods well known in the art, based on the description of a plurality of summaries and more specific documents cited and discussed in this specification.

[0122] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0123] The term "optionally" includes both "optional" and "not optional". For example, "optionally substituted methyl" means "unsubstituted methyl" or "substituted methyl".

[0124] The term "substituted" refers to the replacement of one or more hydrogen atoms on a designated atom or group with a selected group, provided that the normal valence of the designated atom is not exceeded. When the substituent is oxo or keto (i.e., =O), then two hydrogen atoms on the atom are replaced. Substitution with one or more substituents, as allowed by the valence range, refers to replacement with as many substituents as allowed by the valence range.

[0125] Refers to the presence or absence of a key, e.g. Refers to a single key or double bond

[0126] The terms "Cbl-b" and "CBL-B" have the same meaning and refer to Cbl-b proteins. The term also includes naturally occurring Cbl-b variants, including splice variants or allelic variants. The term also includes non-naturally occurring Cbl-b variants, such as recombinant Cbl-b proteins or truncated variants thereof, which generally retain the binding ability of naturally occurring Cbl-b or naturally occurring Cbl-b variants (e.g., the ability to bind to an E2 enzyme).

[0127] The term "alkyl," by itself or as part of another substituent, refers to a radical having the specified number of carbon atoms (ie, C 1-10Meaning a saturated aliphatic hydrocarbon group of one to ten carbon atoms, which is an uncyclized straight or branched carbon chain (or carbon), or a combination thereof, examples of saturated hydrocarbon groups include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, (for example) n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like homologues and isomers. Preferably, the alkyl group contains 1 to 12 (for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms, more preferably, the alkyl group contains 1 to 6 carbon atoms, and further preferably, the alkyl group contains 1 to 3 carbon atoms. For example, C 1-3 Alkyl refers to methyl, ethyl, n-propyl and isopropyl.

[0128] The term "-C 1-n "Alkylene-" refers to a group consisting of -C 1-n The residue resulting from the removal of one hydrogen atom from an alkyl group is a straight or branched chain group containing 1 to n carbon atoms, preferably containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (i.e., -C 1-12 Alkylene-), more preferably an alkylene group containing 1 to 6 carbon atoms (i.e. -C 1-6 Alkylene-). For example, -C 1-3 Alkylene includes -CH2-, -CH2-CH2-, -CH(CH3)-, -CH2-CH2-CH2-, -C(CH3)2-, -CH(CH2CH3)-, -CH(CH3)-CH2-, -CH2-CH(CH3)-, etc. Alkylene can be substituted or unsubstituted, and when substituted, it can be substituted at any available point of attachment.

[0129] An alkoxy group is an alkyl group attached to the rest of the molecule via an oxygen linker (—O—).

[0130] The term "alkynyl" refers to a straight or branched hydrocarbon group containing one or more triple bonds as allowed by valence and having the specified number of carbon atoms. For example, "C 2-5 "Alkynyl" refers to an alkynyl group containing 2 to 5 carbon atoms. Alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and the like.

[0131] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 (e.g., 3, 4, 5, 6, 7, and 8) carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc.; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls.

[0132] The term "heterocycloalkyl" refers to a cycloalkyl group containing at least one ring heteroatom (e.g., a nitrogen atom, an oxygen atom, or a sulfur atom). In some embodiments of the present invention, the heterocyclyl group is a 4-12 membered heterocyclyl group. In some embodiments of the present invention, the heterocyclyl group is a 4-6 membered heterocyclyl group, such as furanyl, imidazolidinyl, imidazolinyl, imidazolyl, isoquinolinyl, thiazolyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, oxazolidinyl, oxazolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl 5(4H)-onyl, piperazinyl, piperidinyl, piperidonyl , 4-piperidonyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, tetrahydrofuranyl, tetrazolyl, thienyl, tetrahydrothiophene, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, oxetanyl, oxolanyl, oxhexanyl, azetidinyl, azepanyl, azahexanyl.

[0133] The term "fused heterobicyclic" refers to a bicyclic fused cycloalkyl group having a fused heteroaryl group. The term "fused cycloalkyl" refers to a polycyclic ring system that shares two adjacent carbon atoms between the rings, which is a monocyclic cycloalkyl fused to one or more monocyclic cycloalkyl groups, as allowed by valence, or a monocyclic cycloalkyl fused to one or more heterocyclyl, aryl, or heteroaryl groups, wherein the point of attachment is on the monocyclic cycloalkyl group, which may contain one or more double bonds within the ring, as allowed by valence, and has 5 to 20 (e.g., 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) ring atoms (i.e., a 5- to 20-membered fused cycloalkyl group).

[0134]

[0046] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom.

[0135] The term "isotopic derivative" refers to a derivative of a compound in which one or more atoms, as far as valence permits, are replaced by an isotope thereof (an atom having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number prevalent in nature). Examples of isotopes include, but are not limited to, isotopes of hydrogen (e.g. 2 H. 3 H), carbon isotopes (e.g. 11 C. 13 C and 14 C), isotopes of fluorine (e.g. 18 F), nitrogen isotopes (e.g.13 N and 15 N), oxygen isotopes (e.g. 15 O. 17 O and 18 O).

[0136] The terms "pharmaceutically acceptable salts" and "pharmaceutically acceptable salts" have the same meaning and refer to salts of the active compounds prepared with relatively nontoxic acids or bases, depending on the specific substituents found on the compounds described herein. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base (either neat or in a suitable inert solvent). Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid (either neat or in a suitable inert solvent). Examples of pharmaceutically acceptable acid addition salts can be found, for example, in Berge et al., "Pharmaceutical Salts", Journal of Pharmaceutical Science, 1977, 66, 1-19. Certain specific compounds of the present invention contain both basic and acidic functional groups, which allow the compounds to be converted into either base or acid addition salts.

[0137] "Pharmaceutically acceptable carriers and / or additives" refer to substances that facilitate administration of the compound to an individual and its absorption by the individual and can be included in the compositions of the present invention without causing significant adverse toxic effects to the patient. Such formulations can be sterilized and, if desired, can be mixed with adjuvants that do not adversely react with the compounds of the present invention, such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for affecting osmotic pressure, buffers, coloring and / or aromatic substances, etc. Those skilled in the art will recognize that pharmaceutical carriers and / or diluents are useful in the present invention.

[0138] The comparative compound NX-1607 described in the present invention has a CAS number of 2573775-59-2 and can be prepared with reference to WO2020264398A1.

[0139] The term "treating" refers to any marker of successful treatment or improvement of an injury, disease, pathology, or condition, including any objective or subjective parameter, such as alleviation of symptoms; remission; reduction or rendering the injury, pathology, or condition more tolerable to the patient; slowing the rate of degeneration or decline; rendering the degenerative endpoint less debilitating; and improvement of the patient's physical or mental well-being. Treatment or improvement of symptoms can be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, and / or psychiatric evaluation. The term "treating" and variations thereof may include preventing an injury, pathology, condition, or disease. In embodiments, treatment is prophylaxis. In embodiments, treatment does not include prophylaxis.

[0140] As used herein, "treatment" (and as is known in the art) also broadly includes any method that can achieve a beneficial or desired result (including a clinical result) in an individual's condition. Favorable or desired clinical results can include, but are not limited to, alleviation or improvement of one or more symptoms or symptoms, reduction in the extent of the disease, stabilization of the disease state (i.e., not worsening), prevention of disease transmission or spread, delay or slowing of disease progression, improvement or palliation of the disease state, reduction of disease recurrence, and remission, whether partial or complete and whether detectable or undetectable. In other words, "treatment" as used herein includes any cure, improvement, or prevention of a disease. Treatment can prevent the disease from occurring; inhibit the spread of the disease; alleviate the symptoms of the disease; completely or partially remove the underlying cause of the disease; shorten the duration of the disease; or a combination of these events.

[0141] As used herein, "treatment" includes preventative treatment. Treatment methods include administering to an individual a therapeutically effective amount of a compound described herein. The administration step may include a single administration or may include a series of administrations. The length of the treatment period depends on a variety of factors, such as the severity of the condition, the patient's age, the concentration of the compound, the activity of the composition used for treatment, and combinations thereof. It should also be understood that the effective amount of the agent used for treatment or prevention may increase or decrease over the course of a particular treatment or prevention regimen. Changes in dosage can be obtained and become apparent through standard diagnostic assays known in the art. In some instances, long-term administration may be required. For example, the composition is administered to an individual in an amount and for a duration sufficient to treat the patient.

[0142] The term "prevent" refers to reducing the occurrence of symptoms of a disease in a patient. As described above, prevention can be complete (no detectable symptoms) or partial, such that fewer symptoms are observed than would occur without treatment. In embodiments, prevention refers to slowing the progression of a disease, disorder, or condition, or inhibiting its progression to a harmful or otherwise undesirable state.

[0143] "Patient" or "individual in need thereof" refers to a living organism suffering from or susceptible to a disease or condition that can be treated by administering a pharmaceutical composition as provided herein. Non-limiting examples include humans, other mammals, cattle, rats, mice, dogs, monkeys, goats, sheep, cows, deer, and other non-mammalian animals. In some embodiments, the patient is a human.

[0144] An "effective amount" is an amount that is sufficient to achieve the specified purpose of the compound (e.g., to achieve the effect of its administration, treat a disease, reduce enzyme activity, increase enzyme activity, reduce a signaling pathway, or alleviate one or more symptoms of a disease or condition) relative to the absence of the compound. An example of an "effective amount" is an amount that is sufficient to promote the treatment, prevention, or alleviation of one or more symptoms of a disease, also referred to as a "therapeutically effective amount." "Alleviation" of one or more symptoms (and grammatical equivalents of this phrase) means reducing the severity or frequency of the symptoms, or eliminating the symptoms. A "prophylactically effective amount" of a drug is an amount that, when administered to an individual, has the expected prophylactic effect, such as preventing or delaying the onset (or recurrence) of an injury, disease, pathology, or condition, or reducing the likelihood of the onset (or recurrence) of an injury, disease, pathology, or condition or its symptoms. A complete prophylactic effect does not necessarily occur by administering one dose, and may only occur after administering a series of doses. Therefore, a prophylactically effective amount may be administered over the course of one or more administrations. As used herein, an "activity-reducing amount" refers to the amount of antagonist required to reduce enzyme activity relative to the absence of the antagonist. As used herein, "functionally disruptive amount" refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of an antagonist. The exact amount will depend on the purpose of the treatment and will be determined by those skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (Volumes 1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). The therapeutically effective amount can be determined by measuring the relevant physiological effects and can be adjusted in conjunction with the individual's dosage regimen and diagnostic analysis of the condition.

[0145] As used herein, the term "administration" means oral administration, administration as a suppository, topical contact, intravenous, parenteral, intraperitoneal, intramuscular, intralesional, intrathecal, intracranial, intranasal or subcutaneous administration, or implanting a sustained-release device, such as a micro-osmotic pump, to an individual. Administered by any route, including parenteral and transmucosal (e.g., oral, sublingual, palate, gum, nose, vagina, rectum or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial. Other modes of delivery include, but are not limited to, the use of liposome formulations, intravenous infusions, transdermal patches, etc. "Combined administration" means administering a composition described herein while, just before, or just after administering one or more additional therapies (e.g., anticancer agents, chemotherapy, or treatment of neurodegenerative diseases). The compounds of the present invention can be administered alone or can be administered in combination to a patient. Combined administration is intended to include administering compounds individually or in combination) more than one compound or agent) simultaneously or sequentially. Thus, the formulations may also be combined with other active substances, if desired (e.g., to reduce metabolic degradation). The compositions of the present invention may be delivered transdermally via a topical route and may be formulated as applicators, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, coatings, powders, and aerosols. Oral formulations include tablets, pills, powders, dragees, capsules, liquids, lozenges, cachets, gels, syrups, slurries, suspensions, and the like, suitable for ingestion by the patient. Solid form formulations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. Liquid form formulations include solutions, suspensions, and emulsions, such as aqueous solutions or water / propylene glycol solutions.

[0146] The present invention is further described by way of the following examples, which are illustrative and do not limit the present invention in any way. Any modifications or variations that are readily accomplished by one of ordinary skill in the art will fall within the scope of the present invention.

[0147] Unless otherwise specified, the raw materials and reagents used in the examples of the present invention are commercially available.

[0148] The abbreviations used in the present invention have the conventional meanings in the art. For example, the following abbreviations have the following meanings:

[0149] Preparation method of compound

[0150] Example 1: Synthesis of Compound 1

[0151] Synthesis of 1-(3-bromo-4-fluorophenyl)-3-methylcyclobutane-1-carbonitrile 1b

[0152] (3-Bromo-4-fluorophenyl)acetonitrile 1a (6.0 g, 28 mmol) and 1,3-dibromo-2-methylpropane (9.0 g, 42 mmol) were dissolved in anhydrous THF (100 mL). NaH (3.3 g, 84 mmol) was added under ice-cooling conditions and stirred at room temperature for 2 hours. The mixture was quenched with saturated aqueous NH4Cl solution and extracted with EA. The organic phase was dried, filtered, and the filtrate was concentrated and flash purified (PE:EA = 30:1) to afford compound 1b (5.0 g).

[0153] LCMS (ESI-MS) m / z: 269.30 [M+H] + .

[0154] Synthesis of methyl 1-(3-bromo-4-fluorophenyl)-3-methylcyclobutane-1-carboxylate 1c

[0155] Compound 1b (5.0 g, 19 mmol) was dissolved in MeOH, and thionyl chloride (11 g, 93 mmol) was added dropwise in an ice bath. After addition, the mixture was stirred at room temperature for 14 hours. The crude product, compound 1c, was obtained by concentration and used directly in the next reaction.

[0156] LCMS (ESI-MS) m / z: 302.10 [M+H] + .

[0157] Synthesis of 1-(3-bromo-4-fluorophenyl)-3-methylcyclobutane-1-carbohydrazide 1d

[0158] Compound 1c (3.0 g, 9.9 mmol) and hydrazine hydrate (5.0 mL) were dissolved in EtOH and stirred at room temperature for 12 hours. The reaction was concentrated to obtain crude compound 1d, which was used directly in the next reaction.

[0159] LCMS (ESI-MS) m / z: 300.10 [M+H] + .

[0160] Synthesis of 2-[1-(3-bromo-4-fluorophenyl)-3-methylcyclobutane-1-carbonyl]-N-methylhydrazine-1-thioamide 1e

[0161] A THF solution of compound 1d (3.0 g, 9.9 mmol) and methyl isothiocyanate (3.1 g, 30 mmol) was stirred at 80° C. for 2 h. The reaction solution was concentrated and flash purified (PE:EA=5:1) to give compound 1e (2.0 g).

[0162] LCMS (ESI-MS) m / z: 373.10 [M+H] + .

[0163] Synthesis of 5-[1-(3-bromo-4-fluorophenyl)-3-methylcyclobutyl]-4-methyl-4H-1,2,4-triazole-3-thiol 1f

[0164] A solution of compound 1e (400 mg, 1.1 mmol) and 1.0 M aqueous NaOH (5.0 mL) in EtOH (2.0 mL) was stirred at 120°C for 2 hours. The reaction solution was concentrated, cooled, neutralized with dilute hydrochloric acid, extracted with DCM, and the organic phase was dried and concentrated to obtain crude compound 1f, which was used directly in the next reaction.

[0165] LCMS (ESI-MS) m / z: 358.10 [M+H] + .

[0166] Synthesis of 1 g of 3-[1-(3-bromo-4-fluorophenyl)-3-methylcyclobutyl]-4-methyl-4H-1,2,4-triazole.

[0167] Compound 1f (290 mg, 0.8 mmol) was dissolved in DCM (10 mL), and AcOH (2.0 mL) and H2O2 (1.0 mL) were added. The mixture was stirred at room temperature for 4 h, quenched with water, extracted with DCM, and the organic phase was dried and concentrated to obtain crude compound 1g, which was used directly in the next reaction.

[0168] LCMS (ESI-MS) m / z: 326.10 [M+H] + .

[0169] Synthesis of (S)-2-(2-fluoro-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindol-1-one 1.

[0170] Compound 1g (180 mg, 0.55 mmol), (S)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindole-1-one 1h (170 mg, 0.55 mmol), Pd(OAc)2 (25 mg, 0.11 mmol), Xantphos (63 mg, 0.11 mmol) and Cs2CO3 (540 mg, 1.7 mmol) were dispersed in anhydrous dioxane, stirred at 120°C for 2 hours under nitrogen protection, filtered, and the filtrate was purified by Prep-HPLC to obtain compound 1 (15 mg).

[0171] LCMS (ESI-MS) m / z: 556.40 [M+H] + .

[0172] 1H NMR(400MHz,DMSO-d6)δ8.28(s,1H),7.95(s,1H),7.92(s,1H),7.78-7.76 (dd,J=8Hz,1H),7.39–7.31(m,1H),7.26–7.21(m,1H),5.11(d,J=8Hz,2H), 3.64(s,3H),3.22(s,2H),2.87–2.77(m,2H),2.75–2.62(m,2H),2.55(m,2 H),1.93(m,2H),1.67–1.51(m,4H),1.45(m,2H),1.05(m,3H),0.80(m,3H).

[0173] Example 2: Synthesis of Compound 2

[0174] Synthesis of methyl 4-bromo-1-toluenesulfonyl-1H-indole-6-carboxylate g2

[0175] Methyl 4-bromo-1H-indole-6-carboxylate g1 (5.0 g, 20 mmol) was dissolved in DMF (50 mL) and NaH (60%, 940 mg, 24 mmol) was added. After stirring at room temperature for 1 hour, p-toluenesulfonyl chloride (4.5 g, 24 mmol) was added and stirred at room temperature for 2 hours. After completion of the reaction, the mixture was quenched with saturated aqueous NH4Cl solution and extracted with EA. The organic phase was dried, concentrated, and flash purified (EA / PE = 30%) to afford compound g2 (5.8 g).

[0176] LCMS (ESI-MS) m / z: 408.10 [M+H] + .

[0177] Synthesis of (4-bromo-1-toluenesulfonyl-1H-indol-6-yl)methanol g3

[0178] Take a single-necked flask and add compound g2 (5.8 g, 14 mmol) and anhydrous THF (60 mL) in sequence. At -50°C, under nitrogen protection, add 1.0 M DIBAL-H cyclohexane solution (40 mL, 40 mmol) dropwise. Slowly warm to room temperature and stir for 3 hours. After LCMS detection, the reaction is complete. At 0°C, quench with 1.0 M HCl aqueous solution, adjust the pH to 6-7, extract with DCM three times, dry the organic phase with magnesium sulfate, filter, concentrate, and flash purify to obtain compound g3 (4.8 g).

[0179] LCMS (ESI-MS) m / z: 362.1 [M+H] + .

[0180] Synthesis of (4-bromo-1-toluenesulfonyl-1H-indol-6-yl)methyl 4-methylbenzenesulfonate g4

[0181] Take a single-necked flask and add compound g3 (4.8 g, 13 mmol), THF (130 mL), TsCl (7.2 g, 38 mmol), and KOH (7.1 g, 130 mmol) in sequence. Stir at room temperature overnight and detect by LCMS. After the reaction is complete, filter and wash with THF. The filtrate is concentrated and purified by Flash (EA / PE = 0-30%) to give compound g4 (3.8 g).

[0182] LCMS (ESI-MS) m / z: 556.01 [M+Na] + .

[0183] Synthesis of 2-(4-bromo-1-toluenesulfonyl-1H-indol-6-yl)acetonitrile g5

[0184] In a single-necked flask, compound g4 (4.5 g, 16 mmol) and THF (26 mL) were added, followed by TMSCN (2.1 g) and a 1.0 M TBAF solution in THF (21 mL). The mixture was reacted at 35°C under nitrogen for 6 hours. LCMS confirmed the reaction was complete. The mixture was cooled to room temperature, and EA and water were added. The organic phase was dried, concentrated, and flash purified (EA / PE: 0-23%) to afford compound g5 (2.4 g).

[0185] LCMS (ESI-MS) m / z: 389.1 [M+H] + .

[0186] Synthesis of methyl 2-(4-bromo-1-toluenesulfonyl-1H-indol-6-yl)acetate g6

[0187] Take a single-necked flask and add compound g5 (1.0 g, 2.6 mmol), MeOH (12 mL) and TMSCl (2.0 mL, 15 mmol) in sequence. Stir at 65 ° C for 12 hours. After LCMS detection, the reaction is complete. Water is added and extracted with EA. The mixture is washed once with saturated NaHCO3 aqueous solution and saturated NaCl aqueous solution. The organic phase is dried, concentrated, and flash purified (EA / PE = 0-60%) to give compound g6 (900 mg).

[0188] LCMS (ESI-MS) m / z: 422.1 [M+H] + .

[0189] Synthesis of methyl 1-(4-bromo-1-toluenesulfonyl-1H-indol-6-yl)-3-methylcyclobutane-1-carboxylate 2a

[0190] To a three-necked flask, add NaH (60%, 170 mg, 4.3 mmol) and anhydrous DMF (9.0 mL). Under nitrogen at 0°C, add a solution of compound g6 (900 mg, 2.1 mmol) and 1,3-dibromo-2-methylpropane (460 mg, 2.1 mmol) in anhydrous DMF (2.0 mL) dropwise. Stir at room temperature overnight. LCMS confirms the completion of the reaction. The product is quenched with saturated aqueous NH4Cl solution and extracted with EA. The organic phase is dried, concentrated, and flash purified (EA / PE = 0-80%) to afford compound 2a (920 mg).

[0191] LCMS (ESI-MS) m / z: 476.2 [M+H] + .

[0192] Synthesis of 1-(4-bromo-1-toluenesulfonyl-1H-indol-6-yl)-3-methylcyclobutane-1-carboxylic acid hydrazide 2b

[0193] Compound 2a (920 mg, 1.9 mmol) was dissolved in EtOH / THF (6.0 mL / 6.0 mL) and 80% hydrazine hydrate (10 mL) was added. The mixture was stirred at 85°C for 24 hours. LCMS confirmed the completion of the reaction. The mixture was concentrated and flash purified (MeOH / DCM = 0-12%) to afford compound 2b (830 mg).

[0194] LCMS (ESI-MS) m / z: 476.2 [M+H] + .

[0195] Synthesis of 5-(1-(4-bromo-1-tosyl-1H-indol-6-yl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol 2c

[0196] Compound 2b (830 mg, 1.8 mmol) was dissolved in EtOH (12 mL) and methyl isothiocyanate (140 mg, 1.9 mmol) was added. After stirring at 80°C for 2 hours, 1.0 M aqueous NaHCO₃ (5.3 mL) was added to the reaction mixture. Stirring was continued at 80°C for 3 hours. LCMS monitoring indicated a good reaction. The mixture was cooled, and saturated aqueous NaCl (10 mL) was added. The mixture was extracted three times with DCM. The organic phase was concentrated to afford crude product 2c, which was used directly in the next step.

[0197] LCMS (ESI-MS) m / z: 531.2 [M+H] + .

[0198] Synthesis of 4-bromo-6-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-1-toluenesulfonyl-1H-indole

[0199] Compound 2c (1.8 mmol) was dissolved in DCM (10 mL) and AcOH (210 mg) and 30% H₂O₂ (990 mg) were added. The mixture was stirred at room temperature for 2 hours. LCMS confirmed the reaction was complete. An aqueous sodium sulfite solution (1.5 eq.) was added to quench the reaction until the starch potassium iodide test paper did not turn blue. The organic phase was separated and washed with a saturated aqueous NaCl solution. The organic phase was dried, filtered, concentrated, and flash purified ((25% EtOH / EA) / PE = 0-40%) to afford compound 2d (560 mg).

[0200] LCMS (ESI-MS) m / z: 499.2 [M+H] + .

[0201] Synthesis of (S)-2-(6-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-1-tosyl-1H-indol-4-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindol-1-one 2e

[0202] To a sealed tube, compound 2d (300 mg, 0.60 mmol), 1h (210 mg, 0.66 mmol), Pd(OAc)2 (27 mg, 0.12 mmol), Xantphos (69 mg, 0.12 mmol), Cs2CO3 (390 mg, 1.2 mmol), and dioxane (8.0 mL) were added sequentially. Under nitrogen, the tube was sealed and stirred at 100°C for 3 hours. LCMS analysis was performed. After completion of the reaction, the mixture was cooled, filtered through celite, and washed with dioxane. The filtrate was concentrated and flash purified ((25% EtOH / EA) / PE = 0-40%, MeOH / DCM = 0-12%) to afford compound 2e (140 mg).

[0203] LCMS (ESI-MS) m / z: 499.2 [M+H] + .

[0204] Synthesis of (S)-2-(6-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-1H-indol-4-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindol-1-one 2

[0205] Compound 2f (70 mg, 0.095 mmol) was dissolved in MeOH (2.0 mL), and K2CO3 (80 mg, 0.58 mmol) was added. The mixture was stirred at 50°C for 4 hours. After completion of the reaction by LCMS, the mixture was filtered and the filtrate was concentrated. The mixture was purified by preparative thin layer chromatography (MeOH / DCM = 10%) to give compound 2 (17 mg).

[0206] LCMS (ESI-MS) m / z: 577.4 [M+H] + .

[0207] 1 H NMR(400MHz,Methanol-d4)δ8.35(s,1H),8.27(s,1H),8.13(s,1H),7.51(s,1H),7.2 8(s,1H),7.23-7.22(d,J=8Hz,1H),6.40(d,J=8Hz,1H),5.18(s,2H),3.71(s,2H),3. 24-3.21(s,3H),3.12-3.10(m,1H),2.87-2.73(m,4H),2.55-2.53(m,2H),2.31-2.26 (m,1H),1.99-1.98(m,1H),1.68-1.47(m,5H),1.09-1.06(m,3H),0.87-0.80(m,3H).

[0208] Example 3: Synthesis of Compound 3

[0209] Synthesis of methyl 1-(2-chloropyridin-4-yl)-3-methylcyclobutane-1-carboxylate 3b

[0210] Methyl 2-(2-chloropyridin-4-yl)acetate 3a (3.5 g, 19 mmol) was dissolved in DMF (50 mL) and cooled to 0°C in an ice bath. NaH (60%, 1.7 g, 42 mmol) was added portionwise and stirred at 0°C for 1 hour. 1,3-Dibromo-2-methylpropane (4.1 g, 19 mmol) was added dropwise. The mixture was stirred at room temperature for 16 hours and analyzed by LCMS. The reaction was complete and quenched with saturated aqueous NH4Cl solution. Water (150 mL) was added and the mixture was extracted twice with EA (80 mL). The organic phases were combined and washed sequentially with water (80 mL) and saturated aqueous NaCl solution (80 mL), dried over anhydrous Na2SO4, filtered, concentrated, and flash purified (EA / PE = 0-30%) to afford compound 3b (2.5 g).

[0211] LCMS (ESI-MS) m / z: 240 (M+H + ).

[0212] Synthesis of 1-(2-ethoxypyridin-4-yl)-3-methylcyclobutane-1-carboxylic acid 3c

[0213] Compound 3b (3.3 g, 14 mmol) was dissolved in EtOH (10 mL), and a solution of sodium ethoxide in EtOH (24 mL, 69 mmol) was added. The mixture was heated to 100°C in a microwave oven and stirred for 16 hours. The mixture was analyzed by LCMS. After completion of the reaction, water (60 mL) was added to the reaction solution, and the pH was adjusted to 5-6 with 1.0 M aqueous HCl. The solution was extracted twice with EA (100 mL). The organic phases were combined and washed sequentially with water (80 mL) and saturated aqueous NaCl (80 mL), dried over anhydrous NaSO, filtered, and concentrated to afford compound 3c (1.8 g).

[0214] LCMS (ESI-MS) m / z: 236 (M+H + ).

[0215] Synthesis of tert-butyl 2-[1-(2-ethoxypyridin-4-yl)-3-methylcyclobutane-1-carbonyl]hydrazine-1-carboxylate 3d

[0216] Compound 3c (1.8 g, 7.7 mmol) was dissolved in DMF (30 mL), and Et3N (2.3 g, 23 mmol) and HATU (4.4 g, 12 mmol) were added. After stirring at room temperature for 30 min, tert-butyl hydrazinoate (1.2 g, 9.2 mmol) was added. The mixture was stirred at room temperature for 16 hours and analyzed by LCMS. Upon completion of the reaction, the reaction mixture was poured into ice water (100 mL) and extracted twice with EA (80 mL). The organic phases were combined and washed sequentially with water (80 mL) and saturated aqueous NaCl solution (80 mL), dried over anhydrous Na2SO4, filtered, concentrated, and flash purified (EA / PE = 0-30%) to afford compound 3d (1.9 g).

[0217] LCMS (ESI-MS) m / z: 350 (M+H + ).

[0218] Synthesis of 1-(2-ethoxypyridin-4-yl)-3-methylcyclobutane-1-carboxylic acid hydrazide 3e

[0219] Compound 3d (1.9 g, 5.4 mmol) was dissolved in DCM (20 mL), and TFA (20 mL) was added. The mixture was stirred at room temperature for 3 hours and analyzed by LCMS. The reaction was essentially complete, and the reaction mixture was poured into ice water (60 mL). The pH was adjusted to 7-8 with saturated aqueous NaHCO₃ solution, and extracted three times with DCM (80 mL). The organic phases were combined, washed sequentially with water (80 mL) and saturated aqueous NaCl solution (80 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to afford compound 3e (1.3 g).

[0220] LCMS (ESI-MS) m / z: 250 (M+H + ).

[0221] Synthesis of 5-[1-(2-ethoxypyridin-4-yl)-3-methylcyclobutyl]-4-methyl-4H-1,2,4-triazole-3-thiol 3f

[0222] Compound 3e (1.3 g, 5.2 mmol) was dissolved in THF (30 mL), and methyl isothiocyanate (1.1 g, 16 mmol) was added. The reaction mixture was stirred at 70°C for 3 hours. After cooling to room temperature, 20 mL of an aqueous solution of KOH (1.5 g, 15 mmol) was added. After the addition, the reaction mixture was stirred at 70°C for 3 hours and analyzed by LCMS. After the reaction was complete, water (100 mL) was added to the reaction mixture, and the aqueous phase was adjusted to pH 5-6 with 1.0 M aqueous HCl. The mixture was extracted twice with EA (80 mL). The organic phases were combined, washed sequentially with water (80 mL) and saturated aqueous NaCl (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford compound 3f (1.5 g).

[0223] LCMS (ESI-MS) m / z: 305 (M+H + ).

[0224] Synthesis of 3g of 2-ethoxy-4-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]pyridine

[0225] Compound 3f (1.5 g, 4.9 mmol) was dissolved in DCM (30 mL), and H₂O₂ (5.6 g, 49 mmol) and acetic acid (2.9 g, 49 mmol) were added. The mixture was stirred at room temperature for 3 hours and analyzed by LCMS. The reaction was essentially complete, and the reaction solution was poured into ice water (60 mL). The pH was adjusted to 7-8 with saturated aqueous NaHCO₃. The mixture was extracted three times with DCM (80 mL). The organic phases were combined, washed sequentially with water (80 mL) and saturated aqueous NaCl (80 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to afford compound 3g (1.3 g).

[0226] LCMS (ESI-MS) m / z: 273 (M+H + ).

[0227] Synthesis of 2-ethoxy-4-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]-1-oxo-pyridine 3h

[0228] Compound 3g (1.2 g, 4.4 mmol) was dissolved in AcOH (15 mL), and H2O2 (4.3 g, 44 mmol) was added. The mixture was stirred at 90°C for 6 hours and analyzed by LCMS. The reaction was essentially complete, and the mixture was quenched with Na2SO3 solution, concentrated under reduced pressure, and flash purified (MeOH / DCM = 0-10%) to afford compound 3h (610 mg).

[0229] LCMS (ESI-MS) m / z: 289 (M+H + ).

[0230] Synthesis of 2-chloro-6-ethoxy-4-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]pyridine 3i

[0231] Compound 3h (350 mg, 1.2 mmol) was dissolved in phosphorus oxychloride (6.0 mL), and the reaction mixture was stirred at 110°C for 3 hours and analyzed by LCMS. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The pH was adjusted to 7-8 with saturated aqueous NaHCO₃ solution, and the mixture was extracted twice with DCM (60 mL). The organic phases were combined, washed sequentially with water (60 mL) and saturated aqueous NaCl solution (60 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated to afford compound 3i (150 mg).

[0232] LCMS (ESI-MS) m / z: 289 (M+H + ).

[0233] Synthesis of (S)-2-(6-ethoxy-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-6-(3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindol-1-one 3

[0234] Compound 3i (150 mg, 0.49 mmol), 1h (150 mg, 0.49 mmol), Xantphos (57 mg, 0.098 mmol), Cs2CO3 (480 mg, 1.5 mmol), and dioxane (5.0 mL) were added to a reaction flask. After evacuating the flask and replacing it with nitrogen, Pd(OAc)2 (11 mg, 0.049 mmol) was added. After evacuating the flask again and replacing it with nitrogen, the reaction was continued in an oil bath at 105°C for 5 hours. LCMS confirmed the reaction was complete. The reaction solution was cooled to room temperature, water (80 mL) was added, and the mixture was extracted twice with EA (50 mL). The organic phases were combined, washed with saturated aqueous NaCl (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give the crude product. Prep-HPLC yielded compound 3 (46 mg).

[0235] LCMS (ESI-MS) m / z: 583 (M+H + ).

[0236] 1 H NMR(400MHz,DMSO-d6)δ8.32(s,1H),8.01(s,1H),7.94(s,1H),7.91(s,1H ),6.53(s,1H),5.17(s,2H),4.37-4.28(m,2H),3.62(s,3H),3.24(s,2H), 2.86-2.75(m,2H),2.67(m,4H),2.54(m,2H),1.68-1.52(m,5H),1.47(t,J =12.0Hz,2H),1.37-1.32(m,3H),1.10-1.03(m,3H),0.79(d,J=5.8Hz,3H).

[0237] Example 4: Synthesis of Compound 4

[0238] Synthesis of methyl 5-cyano-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate 4b

[0239] Methyl 2-bromo-5-cyanobenzoate 4a (15 g, 63 mmol) was dissolved in dioxane (300 mL), and Bin2P (21 g, 81 mmol), Pd(dppf)Cl2 (3.7 g, 5.0 mmol), and potassium acetate (12 g, 30 mmol) were added. The atmosphere was replaced with nitrogen, and the mixture was stirred at 100°C for 2 hours. The mixture was cooled, filtered through celite, and the filtrate was concentrated and flash purified (EA / PE = 30%) to afford compound 4b (12 g).

[0240] LCMS (ESI-MS) m / z: 288.2 (M+H + ).

[0241] Synthesis of 4-(Benzyloxy)-2,6-dichloropyridine H2

[0242] Bian alcohol (9.8 g, 91 mmol) was dissolved in THF (130 mL). NaH (60%, 3.7 g, 91 mmol) was added at 0°C under nitrogen. After stirring at 0°C for 30 minutes, a solution of 2,6-dichloro-4-nitropyridine m4 (16 g, 83 mmol) in THF (30 mL) was added dropwise at 0°C. The mixture was slowly warmed to room temperature and stirred for 2 hours. LCMS confirmed the completion of the reaction. The product was quenched with 1.0 M aqueous HCl at 0°C, the pH was adjusted to 6-7, and the product was extracted three times with EA. The organic phase was dried over magnesium sulfate, filtered, concentrated, and flash purified (EA / PE = 25%) to afford compound h2 (11 g).

[0243] LCMS (ESI-MS) m / z: 254.1 (M+H + ).

[0244] Synthesis of methyl 2-(4-(benzyloxy)-6-chloropyridin-2-yl)-5-cyanobenzoate 4c

[0245] To a single-necked flask, add compound h2 (6.6 g, 26 mmol), dioxane / H2O (120 mL / 30 mL), 4b (7.5 g, 26 mmol), Pd(PPh3)4 (2.4 g, 2.1 mmol), and K3PO4 (11 g, 53 mmol). Stir at 100°C for 3 hours under nitrogen, cool, and separate. Add EA to the organic phase and wash once with saturated aqueous NaCl. Dry, concentrate, and flash-purify (EA / PE = 0-38%) to afford compound 4c (3.7 g).

[0246] LCMS (ESI-MS) m / z: 379.2 (M+H + ).

[0247] Synthesis of methyl 2-(4-(benzyloxy)-6-((tert-butoxycarbonyl)(ethyl)amino)pyridin-2-yl)-5-cyanobenzoate 4d

[0248] To a sealed tube, compound 4c (3.7 g, 9.8 mmol), tert-butyl ethylcarbamate (2.3 g, 16 mmol), Pd(OAc)2 (440 mg, 2.0 mmol), Xantphos (1.7 g, 2.9 mmol), Cs2CO3 (6.4 g, 20 mmol), and dioxane (30 mL) were added sequentially under nitrogen atmosphere and sealed. Stir at 100°C for 3 hours. The reaction was complete after LCMS analysis. Cool to room temperature, filter through celite, add water, and extract with EA. The organic phase was dried, concentrated, and flash purified (EA / PE = 0-35%) to afford compound 4d (1.5 g).

[0249] LCMS (ESI-MS) m / z: 488.4 (M+H + ).

[0250] Synthesis of tert-butyl (4-(benzyloxy)-6-(4-cyano-2-(hydrazinecarbonyl)phenyl)pyridin-2-yl)(ethyl)carbamate 4e

[0251] To a single-necked flask, compound 4d (1.5 g, 3.1 mmol), EtOH (14 mL), and 80% hydrazine hydrate (3.5 mL) were added sequentially. Stir at 80°C for 2 hours. LCMS analysis indicated that the starting material remained, but impurities had appeared, prompting prompt discontinuation. The reaction mixture was concentrated and flash purified (EA / PE = 0-35%, MeOH / DCM = 0-12%) to afford compound 4e (890 mg).

[0252] LCMS (ESI-MS) m / z: 488.4 (M+H + ).

[0253] Synthesis of tert-Butyl (4-(benzyloxy)-6-(4-cyano-2-(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-2-yl)(ethyl)carbamate 4f

[0254] Compound 4e (890 mg, 1.8 mmol) was dissolved in EtOH (8.0 mL) and methyl isothiocyanate (270 mg, 3.7 mmol) was added. After stirring at 80°C for 2 hours, 1.0 M aqueous NaHCO₃ (5.5 mL) was added to the reaction mixture. Stirring was continued at 80°C for 3 hours. LCMS monitoring indicated a good reaction. The mixture was cooled, and 10 mL of saturated aqueous NaCl was added. The mixture was extracted three times with DCM. The organic phase was concentrated to afford crude product 4f, which was used directly in the next step.

[0255] LCMS (ESI-MS) m / z: 543.4 (M+H + ).

[0256] Synthesis of 4 g of tert-butyl (4-(benzyloxy)-6-(4-cyano-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-2-yl)(ethyl)carbamate

[0257] Compound 4f (1.8 mmol) was dissolved in DCM (20 mL) and added with AcOH (220 mg, 3.7 mmol) and 30% H₂O₂ (1.0 g, 9.2 mmol). The mixture was stirred at room temperature for 2-3 hours. LCMS confirmed the reaction was complete and quenched with aqueous sodium sulfite (1.5 eq.) until the color did not turn blue on starch potassium iodide paper. The organic phase was separated and washed with saturated aqueous NaCl. The organic phase was dried, filtered, concentrated, and flash purified ((25% EtOH / EA) / PE = 0-40%) to afford compound 4g (580 mg).

[0258] LCMS (ESI-MS) m / z: 511.4 (M+H + ).

[0259] Synthesis of tert-butyl (6-(4-cyano-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-4-hydroxypyridin-2-yl)(ethyl)carbamate 4h

[0260] To a single-necked flask, compound 4g (580 mg, 1.1 mmol) and MeOH / THF (20 mL / 20 mL) were added sequentially. Pd(OH)2 (55% wet, 70 mg) was added under nitrogen, and the atmosphere was replaced with H2. The mixture was stirred at room temperature for 18 hours. Upon completion, the reaction was monitored by LCMS. The mixture was filtered through Celite, washed with MeOH, and the filtrate was concentrated to afford crude compound 4h (510 mg).

[0261] LCMS (ESI-MS) m / z: 421.3 (M+H + ).

[0262] Synthesis of 2-((tert-Butoxycarbonyl)(ethyl)amino)-6-(4-cyano-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-4-yl trifluoromethanesulfonate 4i

[0263] Compound 4h (300 mg, 0.60 mmol) was dissolved in DCM (20 mL). DIEA (0.78 mL, 4.6 mmol) and trifluoromethanesulfonic anhydride (390 mg, 1.4 mmol) in DCM (0.50 mL) were added at 0°C. Stirring was performed at 0-25°C for 2 hours under nitrogen. LCMS confirmed the reaction was complete. The mixture was diluted with DCM, and the organic phase was washed once with water, dried, concentrated, and flash purified ((25% EtOH / EA) / PE = 0-40%, MeOH / DCM = 0-10%) to afford compound 4i (260 mg).

[0264] LCMS (ESI-MS) m / z: 553.3 (M+H + ).

[0265] Synthesis of tert-butyl (S)-(6-(4-cyano-2-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-4-(6-((3-methylpiperidin-1-yl)methyl)-1-oxo-4-(trifluoromethyl)isoindol-2-yl)pyridin-2-yl)(ethyl)carbamate 4k

[0266] Take a sealed tube and add compound 4i (260 mg, 0.47 mmol), 1h (150 mg, 0.47 mmol), Pd(OAc)2 (21 mg, 0.094 mmol), Xantphos (82 mg, 0.14 mmol), Cs2CO3 (310 mg, 0.94 mmol), and dioxane (6.0 mL) in sequence. Protect with nitrogen, seal the tube and stir at 100°C for 3 hours. Detect by LCMS. After the reaction is complete, cool, filter through celite, wash with dioxane, concentrate the filtrate, and purify by flash chromatography ((25% EtOH / EA) / PE = 0-40%, MeOH / DCM = 0-13%) to give compound 4j (120 mg).

[0267] LCMS (ESI-MS) m / z: 715.5 (M+H + ).

[0268] Synthesis of (S)-4-(6-(ethylamino)-4-(6-((3-methylpiperidin-1-yl)methyl)-1-oxo-4-(trifluoromethyl)isoindol-2-yl)pyridin-2-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)benzonitrile 4

[0269] Compound 4j (120 mg, 0.17 mmol) was dissolved in TFA / DCM (1:2, 3.0 mL) and stirred at room temperature overnight. The mixture was concentrated below 40°C. The mixture was diluted with DCM at 0°C and the pH was adjusted to 7-8 with saturated aqueous NaHCO₃. The organic phase was washed once with cold water. The organic phase was dried over anhydrous Na₂SO₄, filtered, concentrated, and purified by silica gel thin-layer chromatography (MeOH / DCM = 10%) to afford compound 4 (26 mg).

[0270] LCMS (ESI-MS) m / z: 615.4 (M+H + ).

[0271] 1 H NMR(400MHz, DMSO-d6)δ8.46(s,1H),8.13(dd,J=8.1,1.8Hz,1H),8.05–7.99(m,2H ),7.96(s,1H),7.93(s,1H),7.15(s,1H),7.06(s,1H),6.62(br,1H),5.05(s,2H),3 .63(s,2H),3.27(s,3H),2.95–2.85(m,2H),2.75–2.64(m,2H),1.97–1.89(m,1H),1 .68–1.53(m,4H),1.52–1.42(m,1H),1.21(m,1H),0.99(m,3H),0.80(d,J=6Hz,3H).

[0272] Example 5: Synthesis of Compound 5

[0273] Synthesis of 3-bromo-5-(bromomethyl)-2-chloropyridine e2

[0274] To a single-necked flask, 3-bromo-2-chloro-5-methylpyridine e1 (5.0 g, 24 mmol), NBS (4.3 g, 24 mmol), BOP (580 mg, 2.4 mmol), and DCE (30 mL) were added sequentially and stirred at 90°C for 3 hours. The mixture was extracted with EA, and the organic phase was concentrated and flash purified (DCM / MeOH = 5%) to afford compound e2 (5.3 g).

[0275] LCMS (ESI-MS) m / z: 285.90 (M+H + ).

[0276] Synthesis of 2-(5-bromo-6-chloropyridin-3-yl)acetonitrile e3

[0277] Take a single-necked flask and add compound e2 (5.0 g, 18 mmol), acetonitrile (5.0 mL), LiOH (490 mg, 21 mmol), and H2O (380 mg, 21 mmol) in sequence. Trimethylsilyl cyanide (2.1 g, 21 mmol) was added dropwise under ice bath. The reaction was allowed to proceed for 3 hours. After LCMS detection, the reaction was completed. Water was added, the mixture was extracted with EA, dried, filtered, concentrated, and flash purified to obtain compound e3 (2.3 g).

[0278] LCMS (ESI-MS) m / z: 231.0 (M+H + ).

[0279] Synthesis of 1-(5-bromo-6-chloropyridin-3-yl)-3-methylcyclobutane-1-carbonitrile 5a

[0280] In a single-necked flask, compound e3 (2.0 g, 8.7 mmol), DMF (20 mL), and 1,3-dibromo-2-methylpropane (1.9 g, 8.7 mmol) were added sequentially. Sodium methoxide (1.1 g, 21 mmol) was added under ice-cooling. The mixture was allowed to react for 3 hours. LCMS analysis was performed. The remaining starting material was supplemented with an equal amount of the reagent. After completion of the reaction, water was added, the mixture was extracted with EA, dried, filtered, concentrated, and flash purified to afford compound 5a (1.0 g).

[0281] LCMS (ESI-MS) m / z: 285.0 (M+H + ).

[0282] Synthesis of 1-(5-bromo-6-chloropyridin-3-yl)-3-methylcyclobutane-1-carboxylic acid 5b

[0283] Compound 5a (4.5 g, 16 mmol) and 18 M aqueous sulfuric acid solution (10 mL) were added sequentially to a single-necked bottle and stirred at 100°C for 2 hours. After completion of the reaction by LCMS, the mixture was concentrated to give compound 5b (4.6 g).

[0284] LCMS (ESI-MS) m / z: 304.0 (M+H + ).

[0285] Synthesis of 1-(5-bromo-6-hydroxypyridin-3-yl)-3-methylcyclobutane-1-carboxylic acid 5c

[0286] Compound 5b (4.5 g, 15 mmol) was added to a single-necked flask, followed by potassium tert-butoxide (8.0 g, 71 mmol) in isoamyl alcohol (30 mL). The mixture was stirred at 100°C for 8 h. After LCMS analysis, the reaction was complete. Water was added and the mixture was extracted with EA. The product was in the aqueous phase. The aqueous phase was concentrated to give crude product 5c, which was used directly in the next step.

[0287] LCMS (ESI-MS) m / z: 286.1 (M+H + ).

[0288] Synthesis of 1-(5-bromo-6-hydroxypyridin-3-yl)-3-methylcyclobutane-1-carboxylic acid methyl ester 5d

[0289] In a single-necked flask, compound 5c (4.0 g, 14 mmol) and MeOH (30 mL) were added in sequence, followed by 18 M aqueous sulfuric acid solution (2.0 mL). The mixture was stirred at 70°C for 3 h. After completion of the reaction, the pH was adjusted to 8 with NaHCO3 and extracted with EA to give compound 5d (3.0 g).

[0290] LCMS (ESI-MS) m / z: 300.0 (M+H + ).

[0291] Synthesis of methyl 1-(5-bromo-1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)-3-methylcyclobutane-1-carboxylate 5e

[0292] To a single-necked flask, compound 5d (1.0 g, 3.3 mmol) was added sequentially. Cyclopropylboronic acid (1.1 g, 13 mmol), copper acetate (1.5 g, 8.0 mmol), 2,2-bipyridine (1.3 g, 8.0 mmol), and sodium carbonate (1.8 g, 17 mmol) were added to DCE (20 mL). The mixture was heated open at 90°C for 3 hours. LCMS analysis indicated that the reaction was complete, extracted with DCM, and flash purified to afford compound 5e (300 mg).

[0293] LCMS (ESI-MS) m / z: 340.0 (M+H + ).

[0294] Synthesis of 1-(5-bromo-1-cyclopropyl-6-oxo-1,6-dihydropyridin-3-yl)-3-methylcyclobutane-1-carboxylic acid hydrazide 5f

[0295] In a single-necked bottle, compound 5e (300 g, 0.88 mmol) and hydrazine hydrate (0.20 mL) were added in sequence to EtOH (1.0 mL). The mixture was stirred at 50°C for 1 hour. After LCMS detection, the reaction was completed. The mixture was extracted with DCM and purified by Flash to obtain compound 5f (120 mg).

[0296] LCMS (ESI-MS) m / z: 340.0 (M+H + ).

[0297] Synthesis of 5g of 3-bromo-1-cyclopropyl-5-(3-methyl-1-(4-methyl-5-sulfoxy-4,5-dihydro-3H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2(1H)one

[0298] Take a single-necked bottle and add compound 5f (300 mg, 0.88 mmol) in sequence. Add methyl isothiocyanate (86 mg) to THF (2.0 mL) and stir at room temperature for 1 hour. LCMS detection shows that the reaction is complete. Add saturated NaHCO3 aqueous solution (2.0 mL) and stir at 80°C for 4 hours. LCMS detection shows that the reaction is complete. Extract with EA and flash purify to obtain compound 5g (130 mg).

[0299] LCMS (ESI-MS) m / z: 395.2 (M+H + ).

[0300] Synthesis of 3-bromo-1-cyclopropyl-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2(1H)-one 5h

[0301] To a single-necked flask, compound 5g (130 mg, 0.33 mmol) was added, followed by acetic acid (0.20 mL) and 30% H2O2 (0.40 mL) in DCM (1.0 mL). The mixture was stirred at room temperature for 10 minutes. After completion of the reaction by LCMS, the mixture was quenched with aqueous sodium sulfite solution, extracted with DCM, and the organic phase was concentrated to give compound 5h (100 mg).

[0302] LCMS (ESI-MS) m / z: 363.2 (M+H + ).

[0303] Synthesis of (S)-2-(1-cyclopropyl-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindol-1-one 5

[0304] To a single-necked flask, compound 5h (120 mg, 0.33 mmol), 1h (100 mg, 0.33 mmol), Pd(OAc)2 (22 mg, 0.099 mmol), Xantphos (38 mg, 0.066 mmol), Cs2CO3 (210 mg, 0.66 mmol), and dioxane (1.0 mL) were added in sequence. The mixture was protected by nitrogen and sealed. The mixture was stirred at 100°C for 1 hour. The reaction was detected by LCMS. After completion of the reaction, the mixture was filtered and the filtrate was purified by Prep-HPLC to obtain compound 5 (55 mg).

[0305] LCMS (ESI-MS) m / z: 595.5 (M+H + ).

[0306] 1 H NMR(400MHz,Methanol-d4)δ8.59(s,1H),8.21(s,1H),8.15(s,1H),7.81(s,1H),7.69(s,1H),5.19(s,2H),4.52(s,2H),3.54(s,3H),3.47(m,1H),3 .41(m,2H),2.93(m,1H),2.93-2.86(m,2H),2.66(m,2H),2.58-2.50(m,2H ),1.86(m,6H),1.23-1.17(m,2H),1.15(m,3H),1.02(m,1H),0.99(m,3H).

[0307] Example 6: Synthesis of Compound 6

[0308] Synthesis of 2-methylpropan-2-yl(2-((1-(5-bromo-6-chloropyridin-3-yl)-3-methylcyclobutyl)carbonyl)diazoyl)carboxylate 6a

[0309] 5b (1.3 g, 6.2 mmol), tert-butylhydrazinecarboxylate (0.83 g, 6.3 mmol), HATU (1.6 g, 4.2 mmol), and TEA (0.84 g, 8.4 mmol) were dissolved in DMF and stirred at room temperature for 2 hours. The mixture was quenched with water and extracted with EA. The organic phase was dried, concentrated, and flash purified to afford 6a (1.2 g).

[0310] LCMS (ESI-MS) m / z: 420.20 (M+H + ).

[0311] Synthesis of 1-(5-bromo-6-chloropyridin-3-yl)-3-methylcyclobutane-1-carbohydrazide 6b

[0312] 6a (1.2 g, 2.8 mmol) was dissolved in DCM (20 mL), and TFA (10 mL) was added, stirred at room temperature for 2 hours, and concentrated to obtain crude product 6b, which was used directly in the next reaction.

[0313] LCMS (ESI-MS) m / z: 320.1 (M+H + ).

[0314] Synthesis of (1-(5-bromo-6-chloropyridin-3-yl)-3-methylcyclobutyl)(2-((methylamino)thiolidenemethyl)ethanoyl)methanone 6c

[0315] Disperse 6b (1.0 g, 3.1 mmol), methyl isothiocyanate (0.68 g, 9.4 mmol) and TEA (1.6 g, 16 mmol) in THF, stir at 80 °C for 2 h, and concentrate to obtain crude product 6c, which was used directly in the next reaction.

[0316] LCMS (ESI-MS) m / z: 393.10 (M+H + ).

[0317] Synthesis of 5-[1-(5-bromo-6-chloropyridin-3-yl)-3-methylcyclobutyl]-4-methyl-4H-1,2,4-triazole-3-thiol 6d

[0318] 6c (450 mg, 1.1 mmol) and 1.0 M aqueous NaOH solution (50 mL) were dissolved in EtOH (50 mL) and stirred at 100°C for 3 hours. The mixture was neutralized with dilute hydrochloric acid and extracted with EA. The organic phase was washed with water, dried, and concentrated to give crude product 6d, which was used directly in the next reaction.

[0319] LCMS (ESI-MS) m / z: 375.10 (M+H + ).

[0320] Synthesis of 3-bromo-2-chloro-5-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]pyridine 6e

[0321] 6d (400 mg, 1.0 mmol) was dissolved in DCM (30 mL), and AcOH (3.0 mL) and H2O2 (1.0 mL) were added. The mixture was stirred at room temperature for 4 h, neutralized with saturated aqueous NaHCO3 solution, extracted with DCM, and the organic phase was dried and concentrated to give crude product 6e, which was used directly in the next reaction.

[0322] LCMS (ESI-MS) m / z: 343.1 (M+H + ).

[0323] Synthesis of 3-bromo-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2(1H)-one 6f

[0324] Compound 6e (340 mg, 0.99 mmol) and potassium tert-butoxide (1.2 g, 9.9 mmol) were dissolved in tert-butanol and stirred at 120°C for 2 hours. The reaction solution was concentrated and purified by Prep-HPLC to give compound 6f (130 mg).

[0325] LCMS (ESI-MS) m / z: 323.10 (M+H + ).

[0326] Synthesis of 6g of 3-bromo-1-ethyl-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2(1H)-one

[0327] 6f (130 mg, 0.4 mmol), iodoethane (130 mg, 0.8 mmol) and Cs2CO3 (390 mg, 1.2 mmol) were dissolved in DMF, stirred at room temperature for 2 hours, filtered, and the filtrate was purified by Prep-HPLC to obtain compound 6g (100 mg).

[0328] LCMS (ESI-MS) m / z: 351.20 (M+H + ).

[0329] Synthesis of (S)-2-(1-ethyl-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)-6-(3-methylpiperidin-1-yl)methyl)-4-trifluoromethylisoindolin-1-one 6

[0330] 6g (80 mg, 0.23 mmol), 1h (86 mg, 0.27 mmol), Pd(OAc)2 (10 mg, 0.046 mmol), Xantphos (53 mg, 0.092 mmol), and Cs2CO3 (150 mg, 0.46 mmol) were dissolved in dioxane, stirred at 110°C for 2 hours, and filtered. The filtrate was concentrated and purified by Prep-HPLC to give compound 6 (56 mg).

[0331] LCMS (ESI-MS) m / z: 583.40 (M+H + ).

[0332] 1H NMR(400MHz,DMSO-d6)δ8.47(s,1H),8.20(s,1H),8.16(s,1H),8.04(s,1H),7.49(s,1H),5.17(s,2H),4.49(s,2H),4.05-4.0(m,2H),3.38(s ,3H),3.24(m,1H),3.03(m,1H),2.78(m,3H),2.54-2.56(m,2H),2.43- 1.95(m,2H),1.86-1.53(m,5H),1.28(m,3H),1.06(m,3H),0.86(m,3H).

[0333] Example 7: Synthesis of Compound 7

[0334] Synthesis of methyl 2-(3-fluoro-5-nitrophenyl)acetate 7b

[0335] A solution of 3-fluoro-5-nitrophenylacetic acid 7a (5.0 g, 25 mmol) and thionyl chloride (10 g, 84 mmol) in MeOH (50 mL) was heated under reflux for 6 hours, cooled to room temperature, diluted with H2O (300 mL), extracted with EA (300 mL), and the organic phase was washed with water (200 mL) twice, dried over anhydrous Na2SO4, filtered, and concentrated to give compound 7b (4.8 g).

[0336] LCMS (ESI-MS) m / z: 214.1 (M+H + ).

[0337] Synthesis of methyl 1-(3-fluoro-5-nitrophenyl)-3-methylcyclobutane-1-carboxylate 7c

[0338] Compound 7b (4.8 g, 23 mmol) was dissolved in DMF (50 mL) and cooled to 0-5°C in an ice bath. NaH (60%, 1.9 g, 48 mmol) was added portionwise. After stirring in an ice bath for 1 hour, 1,3-dibromo-2-methylpropane (5.5 g, 26 mmol) was added. The mixture was stirred at room temperature for 16 hours, diluted with H2O (300 mL), extracted with EA (300 mL), and the organic phase was washed three times with water (200 mL), dried over anhydrous Na2SO4, filtered, concentrated, and flash purified (PE / EA = 0-10%) to afford compound 7c (2.6 g).

[0339] LCMS (ESI-MS) m / z: 268.2 (M+H + ).

[0340] Synthesis of 1-(3-Fluoro-5-nitrophenyl)-3-methylcyclobutane-1-carbohydrazide 7d

[0341] A solution of compound 7c (4.8 g, 23 mmol) and hydrazine hydrate (5.0 g, 100 mmol) in EtOH (30 mL) was heated to 70° C. and stirred for 2 hours, concentrated, and flash purified (PE / EA=0-100%) to give compound 7d (700 mg).

[0342] LCMS (ESI-MS) m / z: 268.2 (M+H + ).

[0343] Synthesis of 2-(1-(3-fluoro-5-nitrophenyl)-3-methylcyclobutane-1-carbonyl)-N-methylhydrazine-1-carbothioamide 7e

[0344] A solution of compound 7d (700 mg, 2.6 mmol) and methyl isothiocyanate (200 mg, 2.7 mmol) in THF (10 mL) was heated to 70° C. and stirred for 2 hours. The mixture was cooled to room temperature to obtain a solution of crude product 7e, which was used directly in the next step.

[0345] LCMS (ESI-MS) m / z: 341.2 (M+H + ).

[0346] Synthesis of 5-(1-(3-fluoro-5-nitrophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol 7f

[0347] To a solution of compound 7e (890 mg, 2.6 mmol) in THF (10 mL) was added an aqueous solution of NaOH (400 mg, 10 mmol) (10 mL), and the mixture was stirred at room temperature for 1 hour. The pH was adjusted to <8.0 with 1.0 M aqueous HCl solution, and the mixture was extracted with EA (50 mL). The organic phase was washed with water (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give compound 7f (400 mg).

[0348] LCMS (ESI-MS) m / z: 323.2 (M+H + ).

[0349] Synthesis of 7g of 3-(1-(3-fluoro-5-nitrophenyl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole

[0350] To a solution of compound 7f (400 mg, 1.2 mmol) in DCM (10 mL) were added AcOH (10 mL) and H2O2 (2.0 mL), stirred at room temperature for 16 h, diluted with DCM (30 mL), washed with water (20 mL) twice, dried over anhydrous Na2SO4, filtered, and concentrated to give compound 7g (350 mg).

[0351] LCMS (ESI-MS) m / z: 291.2 (M+H + ).

[0352] Synthesis of 3-fluoro-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)aniline 7h

[0353] To a solution of compound 7g (350 mg, 1.2 mmol) in MeOH (20 mL) was added Pd / C (100 mg) and H2 was replaced three times. The mixture was stirred at room temperature for 3 hours, filtered, and concentrated to give compound 7h (300 mg).

[0354] LCMS (ESI-MS) m / z: 261.2 (M+H + ).

[0355] Synthesis of methyl 5-bromo-2-methyl-3-(trifluoromethyl)benzoate 7j

[0356] To a solution of 2-methyl-3-trifluoromethyl-benzoic acid methyl ester 7i (5.0 g, 23 mmol) in AcOH (30 mL) were added 70% aqueous nitric acid (10 mL) and Br2 (5.0 g, 32 mmol), and then 2.5 M aqueous silver nitrate (13 mL, 33 mmol) was slowly added dropwise to the reaction. The mixture was stirred at room temperature for 16 h, poured into ice water, diluted with 1.0 M aqueous NaOH (100 mL), extracted with EA (50 mL) three times, and the organic phases were combined, washed three times with saturated aqueous NaHCO3 (50 mL), washed three times with saturated aqueous Na2CO3 (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated to give compound 7j (5.0 g).

[0357] Synthesis of methyl 5-bromo-2-(bromomethyl)-3-(trifluoromethyl)benzoate 7k

[0358] Under nitrogen, a solution of compound 7j (5.0 g, 17 mmol), NBS (9.0 g, 51 mmol) and BPO (2.0 g, 8.3 mmol) in CCl4 (30 mL) was heated to 80°C and stirred for 24 h, filtered, diluted with DCM (200 mL), washed with water (100 mL) three times, dried over anhydrous Na2SO4, filtered, concentrated, and flash purified (PE / EA = 0-15%) to give compound 7k (3.0 g).

[0359] LCMS (ESI-MS) m / z: 375.0 (M+H + ).

[0360] Synthesis of 6-bromo-2-(3-fluoro-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-4-(trifluoromethyl)isoindol-1-one 7l

[0361] To a solution of compounds 7h (300 mg, 1.2 mmol) and 7k (800 mg, 2.1 mmol) in acetonitrile (10 mL) was added an aqueous solution (5.0 mL) of silver nitrate (300 mg, 1.8 mmol) under ice bath. The mixture was stirred at room temperature overnight, diluted with DCM (100 mL), washed with water (100 mL) twice, dried over anhydrous Na2SO4, filtered, concentrated, and flash purified (DCM / MEOH = 0-10%) to give compound 7l (200 mg).

[0362] LCMS (ESI-MS) m / z: 525.2 (M+H + ).

[0363] Synthesis of 2-(3-fluoro-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-4-(trifluoromethyl)-6-vinylisoindol-1-one 7m

[0364] Under nitrogen, a solution of compound 7l (200 mg, 0.38 mmol), vinylboronic acid pinacol ester (100 mg, 0.65 mmol), K3PO4 (100 mg, 0.47 mmol) and Pd(dppf)Cl2 (50 mg, 0.070 mmol) in dioxane (10 mL) was heated to 100°C and stirred for 3 hours. The mixture was cooled to room temperature, filtered, concentrated, and flash purified (DCM / MeOH = 0-10%) to give compound 7m (100 mg).

[0365] LCMS (ESI-MS) m / z: 471.3 (M+H + ).

[0366] Synthesis of 2-(3-fluoro-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-oxo-7-(trifluoromethyl)isoindoline-5-carbaldehyde 7n

[0367] Compound 7m (100 mg, 0.21 mmol) was dissolved in dioxane (2.0 mL) and water (0.50 mL). Potassium osmate (1.0 mg, 3.0 umol) was added under ice bath and stirring was continued for 2 hours. Sodium periodate (100 mg, 0.47 mmol) was added and stirred at room temperature for 16 hours. The mixture was diluted with 10 mL of water and extracted three times with DCM (5.0 mL). The mixture was dried over anhydrous Na2SO4, filtered, concentrated, and flash purified (DCM / MeOH = 0-10%) to give compound 7n (80 mg).

[0368] LCMS (ESI-MS) m / z: 473.3 (M+H + ).

[0369] Synthesis of (S)-2-(3-fluoro-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindol-1-one 7

[0370] To a DCM solution (10 mL) of compound 7n (80 mg, 0.17 mmol) and (S)-3-methylpiperidine (40 mg, 0.40 mmol) was added sodium triacetoxyborohydride (200 mg, 0.94 mmol), stirred at room temperature for 16 hours, concentrated, and purified by Prep-HPLC to give compound 7 (23 mg).

[0371] LCMS (ESI-MS) m / z: 556.4 (M+H + ).

[0372] 1 H NMR (400MHz, DMSO-d6) δ8.34(s,1H),7.93(s,2H),7.70–7.58(m,2H),6.80(d,J=12Hz,1H),5.17(s,2H),3.63(s,2H),3.24(s,3H),3.17– 3.02(m,2H),2.68(m,2H),2.54(m,1H),2.41–2.18(m,3H),1.96–1.88(m,1H),1.69–1.53(m,4H),1.47(m,1H),1.09(m,3H),0.80(m,3H).

[0373] Example 8: Synthesis of Compound 8

[0374] Synthesis of methyl 2-(2,6-dichloropyridin-4-yl)acetate d2

[0375] Dissolve 2,6-dichloro-4-methylpyridine d1 (5.0 g, 31 mmol) in THF (120 mL). Add LDA (2.0 M, 31 mL, 62 mmol) dropwise slowly at -78°C under nitrogen. Stir at this temperature for 30 minutes. Add a solution of dimethyl carbonate (6.7 g, 74 mmol) in THF (15 mL). After addition, slowly warm the mixture to 0°C. Stir at 0°C for 2 hours. Wash the mixture sequentially with saturated aqueous NaHCO3 and saturated NaCl solution. The organic phase is dried, concentrated, and flash purified (EA / PE = 0-6%) to yield compound d2 (4.7 g).

[0376] LCMS (ESI-MS) m / z: 220.0 (M+H + ).

[0377] Synthesis of methyl 1-(2,6-dichloropyridin-4-yl)-3-methylcyclobutane-1-carboxylate 8a

[0378] NaH (60%, 1.7 g, 43 mmol) was dissolved in DMF (8.0 mL). Under nitrogen, a solution of compound d2 (4.7 g, 21 mmol) and 1,3-dibromo-2-methylpropane (4.6 g, 21 mmol) in DMF (2.0 mL) was slowly added dropwise at 0°C. The mixture was stirred overnight at room temperature. The mixture was cooled to 0°C, quenched with aqueous NH4Cl (30 mL), and extracted twice with EA. The organic phase was dried, concentrated, and flash purified (EA / PE = 0-6%) to afford compound 8a (2.1 g).

[0379] LCMS (ESI-MS) m / z: 274.1 (M+H + ).

[0380] Synthesis of methyl 1-(2-chloro-6-(2,2-difluoroethoxy)pyridin-4-yl)-3-methylcyclobutane-1-carboxylate 8b

[0381] To a sealed tube, compound 8a (1.8 g, 6.6 mmol), 2,2-difluoroethanol (540 mg, 6.6 mmol), Pd(OAc)2 (220 mg, 0.99 mmol), Xantphos (760 mg, 1.3 mmol), K3PO4 (2.8 g, 13 mmol), and dioxane (30 mL) were added sequentially. Under nitrogen, the tube was sealed and stirred at 100°C for 40 minutes. The reaction was complete after LCMS analysis. The mixture was cooled to room temperature, filtered through celite, and washed with dioxane. The filtrate was concentrated and purified by flash chromatography (EA / PE = 0-25%) to afford compound 8b (1.3 g).

[0382] LCMS (ESI-MS) m / z: 320.2 (M+H + ).

[0383] Synthesis of 1-(2-chloro-6-(2,2-difluoroethoxy)pyridin-4-yl)-3-methylcyclobutane-1-carboxylic acid hydrazide 8c

[0384] Compound 8b (1.3 g, 4.1 mmol) was dissolved in EtOH / THF (6.0 mL / 5.0 mL), and hydrazine hydrate (80%, 8.0 mL) was added. The mixture was stirred at 85°C for 4 hours. The reaction solution was concentrated and flash purified (25% EtOH / EA) / PE = 0-38%) to give compound 8c (750 mg).

[0385] LCMS (ESI-MS) m / z: 320.2 (M+H + ).

[0386] Synthesis of 5-(1-(2-chloro-6-(2,2-difluoroethoxy)pyridin-4-yl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol 8d

[0387] Crude compound 8c (750 mg, 2.4 mmol) was dissolved in EtOH (6.0 mL) and methyl isothiocyanate (190 mg, 2.6 mmol) was added. After stirring at 80°C for 2 hours, 1.0 M aqueous NaHCO₃ (7.0 mL) was added. Stir at 80°C for 3 hours, monitoring by LCMS. If the reaction was satisfactory, the mixture was cooled, and 10 mL of saturated aqueous NaCl solution was added. The mixture was extracted three times with DCM. The organic phase was concentrated to afford crude compound 8d, which was used directly in the next step.

[0388] LCMS (ESI-MS) m / z: 375.1 (M+H + ).

[0389] Synthesis of 2-chloro-6-(2,2-difluoroethoxy)-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine 8e

[0390] Crude compound 8d (2.4 mmol) was dissolved in DCM (10 mL), and AcOH (280 mg, 4.7 mmol) and 30% H₂O₂ (1.3 g, 12 mmol) were added. The mixture was stirred at room temperature for 2-3 hours. LCMS confirmed the reaction was complete, and aqueous sodium sulfite (1.5 eq.) was added to quench the reaction until the color did not turn blue on starch potassium iodide paper. The organic phase was separated and washed with saturated aqueous NaCl. The organic phase was dried, filtered, concentrated, and flash purified (MeOH / DCM = 0-6%) to afford compound 8e (520 mg).

[0391] LCMS (ESI-MS) m / z: 343.2 (M+H + ).

[0392] Synthesis of (S)-2-(6-(2,2-difluoroethoxy)-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindol-1-one 8

[0393] To a sealed tube, compound 8e (230 mg, 0.67 mmol), 1h (230 mg, 0.74 mmol), Pd(OAc)2 (30 mg, 0.13 mmol), Xantphos (75 mg, 0.13 mmol), Cs2CO3 (440 mg, 1.5 mmol), and dioxane (8.0 mL) were added sequentially. The mixture was sealed under nitrogen and stirred at 100°C for 3 hours. The reaction was monitored by LCMS. After completion, the mixture was cooled, filtered through celite, and washed with dioxane. The filtrate was concentrated and purified by flash chromatography (25% EtOH / EA) / PE = 0-40%, MeOH / DCM = 0-13%) to afford the desired product (175 mg) with 87% purity. 75 mg of the product was then purified by Prep-HPLC (10% MeOH / DCM) to afford compound 8 (15 mg).

[0394] LCMS (ESI-MS) m / z: 619.4 (M+H + ).

[0395] 1 H NMR(400MHz,DMSO-d6)δ8.32(s,1H),8.06(s,1H),7.95-7.91(m,2H),6.69( s,1H),6.63-6.32(m,1H),5.22(s,2H),4.66-4.57(m,2H),3.63(s,2H),3.25 -3.22(m,5H),2.82-2.78(m,2H),2.73-2.64(m, 2H),2.58-2.55(m,2H),1.95-1.90(m,1H),1.65-1.57(m,4H),1.50-1.41(m,1H),1.08-1.06(m,3H),0.80(m,3H).

[0396] Example 9: Synthesis of Compound 9

[0397] Synthesis of 2-bromo-6-fluoroisonicotinic acid 9b

[0398] To a single-necked flask, add 2-bromo-6-fluoro-4-methylpyridine 9a (5.0 g, 26 mmol) in sequence. Add sulfuric acid (38 mL) under an ice bath, and then add chromium trioxide (7.9 g, 79 mmol) in batches. Stir to room temperature and allow to react overnight. Upon completion of the reaction by LCMS, pour the reaction solution onto ice to precipitate a solid, which was then dried to afford compound 9b (4.1 g).

[0399] LCMS (ESI-MS) m / z: 220.0 (M+H + ).

[0400] Synthesis of 2-bromo-6-fluoroisonicotinyl chloride 9c

[0401] In a single-necked flask, compound 9b (3.6 g, 16 mmol) was added in sequence. DCM (30 mL) and thionyl chloride (2.7 mL, 32 mmol) were added under ice bath, and DMF (0.40 mL) was added dropwise. The mixture was stirred at room temperature for 10 minutes and concentrated to obtain compound 9c, which was used directly in the next reaction.

[0402] Synthesis of 2-(2-bromo-6-fluoropyridin-4-yl)acetic acid 9d

[0403] Compound 9c was dissolved in THF / acetonitrile (18 mL / 18 mL) and TMSCHN2 (25 mL, 49 mmol) was added under ice-cooling within 3 minutes. After the reaction was completed, the mixture was flash purified to obtain compound 9d (3.5 g).

[0404] Synthesis of 2-(2-bromo-6-fluoropyridin-4-yl)acetic acid 9e

[0405] Compound 9d was dissolved in dioxane / H2O (15 mL / 15 mL), and silver acetate (0.80 g) was added. The mixture was heated at 100°C under sunlight for 1 hour. After completion of the reaction, the mixture was extracted with EA and purified by flash chromatography to obtain compound 9e (1.8 g).

[0406] LCMS (ESI-MS) m / z: 234.2 (M+H + ).

[0407] Synthesis of methyl 2-(2-bromo-6-fluoropyridin-4-yl)acetate 9f

[0408] To a single-necked flask, compound 9e (3.4 g, 15 mmol), MeOH (6.0 mL), and sulfuric acid (2.0 mL) were added sequentially. The mixture was stirred at 60°C for 1 hour. The reaction was complete by LCMS. The product was concentrated, the pH was adjusted to 6 with NaHCO₃, and the mixture was extracted with EA. The mixture was dried, filtered, concentrated, and flash purified (PE:EA = 10:1) to afford compound 9f (2.7 g).

[0409] LCMS (ESI-MS) m / z: 248.0 (M+H + ).

[0410] Synthesis of 9g of 2-(2-bromo-6-hydroxypyridin-4-yl)acetic acid

[0411] In a single-necked flask, compound 9f (1.4 g, 5.7 mmol) and 2.0 M aqueous NaOH (28 mL) were added sequentially and stirred at 100°C for 2 hours. The reaction mixture was concentrated to obtain crude compound 9g, which was used directly in the next reaction.

[0412] Synthesis of methyl 2-(2-bromo-6-hydroxypyridin-4-yl)acetate 9h

[0413] The crude compound 9g, MeOH (15mL), 18M aqueous sulfuric acid solution (2.0mL), were heated at 60°C for 1 hour. After completion of the reaction, LCMS was performed. The pH was adjusted to 8 with NaHCO3 under ice bath. The product was extracted with EA, and the organic phase was directly concentrated and purified by flash chromatography (PE:EA=3:1) to give compound 9h (1.1g).

[0414] LCMS (ESI-MS) m / z: 246.0 (M+H + ).

[0415] Synthesis of methyl 2-(2-bromo-6-(difluoromethoxy)pyridin-4-yl)acetate 9i

[0416] To a single-necked flask, compound 9h (1.1 g, 4.5 mmol) was added to acetonitrile (14 mL) in sequence. 2-Fluorosulfonyldifluoroacetic acid (1.2 g, 6.7 mmol) and NaH (270 mg, 6.7 mmol) were then added under ice-cooling. Stir at room temperature for 1 hour, and analyze by LCMS. Upon completion of the reaction, the product was quenched with saturated aqueous NH4Cl solution under ice-cooling, extracted with EA, washed with water, then washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, filtered, concentrated, and purified by flash chromatography to afford compound 9i (660 mg).

[0417] LCMS (ESI-MS) m / z: 296.0 (M+H + ).

[0418] Synthesis of methyl 1-(2-bromo-6-(difluoromethoxy)pyridin-4-yl)-3-methylcyclobutane-1-carboxylate 9j

[0419] In a single-necked flask, compound 9i (600 mg, 2.0 mmol), DMF (20 mL), and 1,3-dibromo-2-methylpropane (660 mg, 3.0 mmol) were added in sequence. K3PO4 (1.3 g, 6.1 mmol) was added, the tube was sealed, and the mixture was stirred at 100°C for 20 min. The mixture was poured into saturated aqueous NH4Cl solution under an ice bath, extracted with EA, and flash purified (PE:EA=20:1) to give compound 9j (500 mg).

[0420] LCMS (ESI-MS) m / z: 350.0 (M+H + ).

[0421] Synthesis of 1-(2-bromo-6-(difluoromethoxy)pyridin-4-yl)-3-methylcyclobutane-1-carboxylic acid hydrazide 9k

[0422] In a single-necked bottle, compound 9j (500 g, 1.4 mmol) and hydrazine hydrate (1.0 mL) were added to EtOH (5.0 mL) in sequence and stirred at 50°C for 2 hours. After LCMS detection, the reaction was completed, extracted with DCM, and purified by Flash to obtain compound 9k (280 mg).

[0423] LCMS (ESI-MS) m / z: 350.1 (M+H + ).

[0424] Synthesis of 5-(1-(2-bromo-6-(difluoromethoxy)pyridin-4-yl)-3-methylcyclobutyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione 9l

[0425] Compound 9k (280 mg, 0.80 mmol), THF (2.0 mL), and methyl isothiocyanate (120 mg, 1.6 mmol) were added sequentially to a single-necked flask, stirred at room temperature for 1 hour, and monitored by LCMS. The reaction was complete to obtain a reaction solution of compound 9l.

[0426] Synthesis of 5-(1-(2-bromo-6-difluoromethoxy)pyridin-4-yl)-3-methylcyclobutyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione 9m

[0427] The reaction mixture of compound 91 was directly added to a saturated aqueous NaHCO3 solution (2.0 mL), stirred at 80°C for 4 hours, and the reaction was complete after LCMS analysis. The mixture was extracted with EA and purified by Flash chromatography to obtain compound 9m (130 mg).

[0428] LCMS (ESI-MS) m / z: 405.1 (M+H + ).

[0429] Synthesis of 2-bromo-6-(difluoromethoxy)-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine 9n

[0430] To a single-necked flask, compound 9m (80 mg, 0.20 mmol), DCM (1.0 mL), AcOH (4 drops), and 30% H2O2 (8 drops) were added sequentially. Stir at room temperature for 10 minutes and analyze by LCMS. Upon completion of the reaction, the mixture was quenched with aqueous sodium sulfite solution, extracted with DCM, and the organic phase was concentrated to afford compound 9n (73 mg).

[0431] LCMS (ESI-MS) m / z: 373.2 (M+H + ).

[0432] Synthesis of (S)-2-(6-(difluoromethoxy)-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4(trifluoromethyl)isoindol-1-one 9

[0433] To a single-necked flask, compound 9n (73 mg, 0.20 mmol), 1h (49 mg, 0.16 mmol), Pd(OAc)2 (13 mg, 0.059 mmol), Xantphos (22 mg, 0.040 mmol), Cs2CO3 (130 mg, 0.40 mmol), and dioxane (1.0 mL) were added sequentially. Under nitrogen protection, the tube was sealed and heated at 100°C for 1 hour. LCMS analysis was performed. Upon completion, the filtrate provided compound 9 (25 mg).

[0434] LCMS (ESI-MS) m / z: 605.4 (M+H + ).

[0435] 1 H NMR(400MHz,DMSO-d6)δ9.74(br,1H),8.46(s,1H),8.22(s,1H),8.17(s,1H),7.87(m,2H),6.98(s,1H),5.23(s,2H),4.50(s,2H),3.35 (m,1H),3.26(s,3H),3.11(m,1H),2.89–2.80(m,2H),2.59(d,J=7.6Hz,4H),2.29(m,1H),1.87–1.57(m,5H),1.08(m,3H),0.86(m,3H).

[0436] Example 10: Synthesis of Compound 10

[0437] Synthesis of methyl 1-(2-bromo-6-fluoropyridin-4-yl)-3-methylcyclobutane-1-carboxylate 10a

[0438] To a single-necked flask, compound 9f (900 mg, 3.6 mmol), DMF (10 mL), 1,3-dibromo-2-methylpropane (1.2 g, 5.5 mmol), and K₃PO₄ (3.6 g, 11 mmol) were added sequentially. The mixture was sealed and stirred at 100°C for 20 minutes. The product was poured into saturated aqueous NH₄Cl solution under an ice bath, extracted with EA, and flash purified (PE:EA = 20:1) to afford compound 10a (1.0 g).

[0439] LCMS (ESI-MS) m / z: 302.1 (M+H + ).

[0440] Synthesis of (2-bromo-6-fluoropyridin-4-yl)-3-methylcyclobutane-1-carboxylic acid 10b

[0441] Compound 10a (1.0 g, 3.3 mmol) and MeOH (10 mL) were added sequentially to a single-necked flask. Aqueous NaOH solution (2.0 M, 3.3 mL) was added and stirred at room temperature for 1 hour. After LCMS detection, the reaction was completed. The pH was adjusted to 6 with 1.0 M HCl aqueous solution, and the product was extracted with EA and purified by Flash to give compound 10b (600 mg).

[0442] LCMS (ESI-MS) m / z: 287.1 (M+H + ).

[0443] Synthesis of tert-butyl (1-(2-bromo-6-fluoropyridin-4-yl)-3-methylcyclobutane-1-carbonyl)hydrazine-1-carboxylate 10c

[0444] To a single-necked flask, compound 10b (600 mg, 2.1 mmol) and DMF (5.0 mL) were added sequentially, followed by 1-tert-butyloxycarbonyl-1-methylhydrazine (330 mg, 2.5 mmol), HATU (1.2 g, 3.1 mmol), and Et3N (630 mg, 6.3 mmol). The mixture was stirred at room temperature for 2 hours and analyzed by LCMS. After completion of the reaction, the mixture was extracted with EA, and the organic phase was washed with water and saturated aqueous NaCl solution. Flash purification (PE:EA = 10:1) afforded compound 10c (600 mg).

[0445] LCMS (ESI-MS) m / z: 402.2 (M+H + ).

[0446] Synthesis of (2-bromo-6-fluoropyridin-4-yl)-3-methylcyclobutane-1-carboxylic acid hydrazide 10d

[0447] Compound 10c (580 mg, 1.4 mmol) and HCl / MeOH (8.0 mL) were added sequentially to a single-necked bottle, stirred at room temperature for 6 hours, and the reaction was complete after LCMS analysis. The mixture was concentrated to afford compound 10d (490 mg).

[0448] LCMS (ESI-MS) m / z: 302.1 (M+H + ).

[0449] Synthesis of 2-(1-(2-bromo-6-fluoropyridin-4-yl)-3-methylcyclobutane-1-carbonyl)-N-methylhydrazine-1-carbothioamide 10e

[0450] In a single-necked flask, compound 10d (440 mg, 1.4 mmol), methyl isothiocyanate (210 mg, 2.9 mmol), and Et3N (360 mg, 3.6 mmol) were added in sequence and stirred at room temperature for 10 minutes. After LCMS analysis, the reaction was complete to obtain reaction solution 10e, which was used directly in the next step.

[0451] LCMS (ESI-MS) m / z: 375.1 (M+H + ).

[0452] Synthesis of 5-(1-(2-bromo-6-fluoropyridin-4-yl)-3-methylcyclobutyl)-4-methyl-2,4-dihydro-3H-1,2,4-triazole-3-thione 10f

[0453] In a single-necked flask, compound 10e (540 mg, 1.4 mmol), NaHCO3 (1.2 g, 14 mmol), and H2O (12 mL) were added in sequence and stirred at 80°C for 3 hours. After the reaction was completed, the mixture was extracted with EA, and the organic phase was washed with water and saturated aqueous NaCl solution. Flash purification (PE:EA=5:1) gave compound 10f (340 mg).

[0454] LCMS (ESI-MS) m / z: 375.1 (M+H + ).

[0455] Synthesis of 10g of 2-bromo-6-fluoro-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine

[0456] To a single-necked flask, compound 10f (340 mg, 0.95 mmol), DCM (8.0 mL), acetic acid (0.50 mL), and 30% H2O2 (0.50 mL) were added sequentially. The mixture was stirred at room temperature for 10 minutes. After completion of the reaction, the mixture was quenched with aqueous sodium sulfite solution, extracted with EA, and the organic phase was washed with water and saturated aqueous NaCl solution and concentrated to give compound 10g (300 mg).

[0457] LCMS (ESI-MS) m / z: 325.1 (M+H + ).

[0458] Synthesis of (S)-2-(6-fluoro-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindol-1-one 10h

[0459] To a single-necked flask, compound 10g (300 mg, 0.92 mmol), 1h (290 mg, 0.92 mmol), Pd(OAc)2 (62 mg, 0.28 mmol), Xantphos (110 mg, 0.18 mmol), Cs2CO3 (600 mg, 1.8 mmol), and dioxane (5.0 mL) were added in sequence. The mixture was protected by nitrogen and sealed with a tube. The mixture was stirred at 100°C for 1 hour. After LCMS detection, the reaction was completed and the filtrate was flash purified to obtain compound 10h (260 mg).

[0460] LCMS (ESI-MS) m / z: 557.1 (M+H + ).

[0461] Synthesis of (S)-2-(6-(ethylamino)-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindol-1-one 10

[0462] To a single-necked flask, compound 10h (30 mg, 0.054 mmol), ethylamine hydrochloride (80 mg, 0.98 mmol), Et3N (0.20 mL), and DMF (0.50 mL) were added sequentially. The mixture was sealed and stirred at 120°C for 3 hours, followed by LCMS analysis. Upon completion of the reaction, Prep-HPLC purification afforded compound 10 (8.0 mg).

[0463] LCMS (ESI-MS) m / z: 582.4 (M+H + ).

[0464] 1H NMR(400MHz,DMSO-d6)δ8.45(s,1H),8.18(m,2H),7.62(s,1H),6.39(s,1H),5.27(s,2H),4.50(s,2H),3.35(m,2 H),3.27(s,3H),3.05(m,2H),2.87-2.75(m,2H),2.57(m,4H),2.28(m,2H),1.84-1.58(m,5H),1.09-0.86(m,9H).

[0465] Example 11: Synthesis of Compound 11

[0466] Synthesis of (S)-2-(4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-6-(2,2,2-trifluoroethoxy)pyridin-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one 11

[0467] The preparation method refers to compound 10, replacing the ethylamino group with a trifluoroethoxy group to obtain compound 11.

[0468] LCMS (ESI-MS) m / z: 637.40 (M+H + ).

[0469] 1 H NMR(400MHz,DMSO-d6)δ8.39(s,1H),8.22(s,1H),7.93(m,2H),6.76(s,1H),5.23 -5.19(s,2H),5.08-5.02(m,2H),3.62(s,2H),3.25(m,1H),3.22(s,3H),3.11-3.0 6(m,1H),2.83(m,1H),2.68(m,2H),2.56(m,2H),2.27-2.22(m,1H),1.94-1.88(m ,1H),1.65-1.56(m,4H),1.50-1.40(m,1H),1.09-1.06(m,3H),0.88-0.79(m,3H).

[0470] Example 12: Synthesis of Compound 12

[0471] Synthesis of 6-fluoro-3-iodo-2-methylbenzoic acid 12b

[0472] 6-Fluoro-2-methylbenzoic acid 12a (5.0 g, 32 mmol) was added to 18 M aqueous sulfuric acid (30 mL) under an ice bath. NIS (7.2 g, 32 mmol) was added at the same temperature and stirred at room temperature for 6 hours. The reaction mixture was quenched by pouring into ice water. The organic phase was extracted with EA, washed with water, dried, and concentrated to afford crude product 12b, which was used directly in the next reaction.

[0473] LCMS (ESI-MS) m / z: 473.3 (M+H + ).

[0474] Synthesis of ethyl 6-fluoro-3-iodo-2-methylbenzoate 12c

[0475] 12b (5.0 g, 18 mmol) was dissolved in acetonitrile, and Cs2CO3 (17 g, 53 mmol) and iodoethane (5.5 g, 36 mmol) were added. The mixture was stirred at 80°C for 2 h. The mixture was filtered, the filtrate was concentrated, and flash purified (PE:EA = 10:1) to give compound 12c (6.2 g).

[0476] LCMS (ESI-MS) m / z: 309 (M+H + ).

[0477] Synthesis of 6-fluoro-2-methyl-3-(trifluoromethyl)benzoic acid ethyl ester 12d

[0478] 12c (2.0 g, 7.6 mmol), methyl difluoro(fluorosulfonyl)acetate (2.9 g, 15 mmol) and CuI (1.4 g, 7.6 mmol) were dissolved in DMF and stirred at 100°C under nitrogen for 8 hours. The mixture was filtered and the filtrate was poured into water. The organic phase was extracted with EA, dried, concentrated, and flash purified (PE:EA=15:1) to give compound 12d (1.5 g).

[0479] LCMS (ESI-MS) m / z: 251.10 (M+H + ).

[0480] Synthesis of ethyl 3-bromo-2-fluoro-6-methyl-5-(trifluoromethyl)benzoate 12e

[0481] Compound 12d (2.0 g, 8.0 mmol) was dissolved in concentrated sulfuric acid, and NBS (2.1 g, 12 mmol) was added under ice-cooling. Stirring was continued at room temperature for 3 hours. The mixture was poured into ice-water and extracted with EA. The organic phase was washed with water, dried, concentrated, and flash purified (PE:EA = 5:1) to afford compound 12e (2.0 g).

[0482] LCMS (ESI-MS) m / z: 329.10 (M+H+ ).

[0483] Synthesis of ethyl 3-bromo-6-(bromomethyl)-2-fluoro-5-(trifluoromethyl)benzoate 12f

[0484] 12e (2.0 g, 6.0 mmol), NBS (1.6 g, 9.1 mmol) and AIBN (0.20 g, 1.2 mmol) were dissolved in DCE, and the mixture was stirred at 90 °C for 2 h, cooled, washed with saturated aqueous NaHCO3 solution, extracted with DCM, and the organic phase was dried, concentrated, and flash purified (PE:EA = 20:1) to give compound 12f (2.4 g).

[0485] LCMS (ESI-MS) m / z: 409.0 (M+H + ).

[0486] Synthesis of 12g of 6-bromo-7-fluoro-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one

[0487] 12f (2.5 g, 6.1 mmol) was dissolved in 7.0 M ammonia in MeOH (100 mL), stirred at room temperature for 4 h, and concentrated to afford a crude product (12 g), which was used directly in the next reaction.

[0488] LCMS (ESI-MS) m / z: 298.0 (M+H + ).

[0489] Synthesis of 6-vinyl-7-fluoro-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 12h

[0490] 12h (900 mg, 3.0 mmol), potassium vinyl trifluoroborate (800 mg, 6.0 mmol), Pd(dppf)Cl2 (440 mg, 0.60 mmol), K3PO4 (1.9 g, 9.0 mmol), and water (0.50 mL) were dissolved in dioxane and stirred at 90°C under nitrogen for 1 hour. The mixture was cooled, concentrated, and flash purified to afford compound 12h (600 mg).

[0491] LCMS (ESI-MS) m / z: 246.10 (M+H + ).

[0492] Synthesis of 4-fluoro-3-oxo-7-(trifluoromethyl)-2,3-dihydro-1H-isoindole-5-carbaldehyde 12i

[0493] 12i (600 mg, 2.5 mmol), sodium periodate (1.6 g, 7.3 mmol), and potassium osmate (7.0 mg, 0.024 mmol) were dissolved in dioxane (100 mL) and water (50 mL) and stirred at room temperature for 3 hours. The mixture was quenched with water and extracted with EA. The organic phase was washed with water, dried, and concentrated to afford compound 12i (500 mg).

[0494] LCMS (ESI-MS) m / z: 248.10 (M+H + ).

[0495] Synthesis of 7-fluoro-6-(hydroxymethyl)-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 12j

[0496] 12i (500 mg, 2.0 mmol) was dissolved in DCM (100 mL) and AcOH (50 mL), and sodium acetate borohydride (850 mg, 4.0 mmol) was added at room temperature. The mixture was stirred at room temperature for 2 hours, quenched with water, neutralized with saturated aqueous NaHCO3, extracted with DCM, and the organic phase was washed with water, dried, concentrated, and purified by Flash chromatography (DCM:MeOH = 20:1) to afford 12j (260 mg).

[0497] LCMS (ESI-MS) m / z: 250.10 (M+H + ).

[0498] Synthesis of 6-(chloromethyl)-7-fluoro-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 12k

[0499] 12j (260 mg, 1.0 mmol) was dissolved in DCM, and thionyl chloride (1.2 g, 10 mmol) was added, followed by stirring at 90°C for 4 hours. The reaction solution was concentrated to obtain crude product 12k, which was used directly in the next reaction.

[0500] Synthesis of 7-fluoro-6-{[(3S)-3-methylhexahydropyridin-1-yl]methyl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 12l

[0501] 12k (260 mg, 0.97 mmol), (3S)-3-methylpiperidine (190 mg, 1.9 mmol), potassium carbonate (400 mg, 2.9 mmol) and sodium iodide (140 mg, 0.97 mmol) were dissolved in DMF and stirred at room temperature for 3 hours. The mixture was quenched with water and extracted with EA. The organic phase was washed with water, dried, concentrated, and flash purified (DCM:MeOH = 10:1) to give compound 12l (300 mg).

[0502] LCMS (ESI-MS) m / z: 331.2 (M+H + ).

[0503] Synthesis of 7-fluoro-2-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl-6-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one 12

[0504] 12l (260 mg, 0.78 mmol), 3-[(1S,3S)-1-(3-bromophenyl)-3-methylcyclobutyl]-4-methyl-4H-1,2,4-triazole 12m (290 mg, 0.94 mmol), Pd(OAc)2 (35 mg, 0.15 mmol), Xantphos (180 mg, 0.31 mmol) and Cs2CO3 (510 mg, 1.6 mmol) were dissolved in dioxane and stirred at 110°C for 4 hours under nitrogen protection. The mixture was filtered and the filtrate was concentrated. The reaction mixture was flash purified (DCM:MeOH=10:1) to give compound 12 (70 mg).

[0505] LCMS (ESI-MS) m / z: 556.40 (M+H + ).

[0506] 1 H NMR(400MHz,DMSO-d6)δ8.22(s,1H),7.97–7.93(m,2H),7.57–7.53(m,1H),7.37(m,1H),7.07(m,1H),5.15(s,2H ),3.57(s,2H),3.14(s,3H),2.79(m,5H),2.48(m,3H),1.88(m,1H),1.63–1.31(m,6H),1.02(m,3H),0.75(m,3H).

[0507] Example 13: Synthesis of Compound 13

[0508] 6-(Hydroxymethyl)-4-(trimethylsilyl)ethynyl)isoindol-1-one 13b

[0509] 4-Bromo-6-hydroxymethylisoindol-1-one 13a (1.5 g, 6.2 mmol) and ethynyltrimethylsilane (6.1 g, 62 mmol) were dissolved in dioxane (30 mL). Pd(PPh3)4 (1.4 g, 1.2 mmol), CuI (470 mg, 2.5 mmol) and Et3N (1.3 g, 12 mmol) were added to the solution in sequence. The reaction solution was replaced with nitrogen three times and microwaved at 110 ° C for 3 hours under nitrogen protection. After cooling, the reaction solution was flash purified to obtain compound 13b (500 mg).

[0510] LCMS (ESI-MS) m / z: 260 (M+H + ).

[0511] 6-(Chloromethyl)-4-(trimethylsilyl)ethynyl)isoindol-1-one 13c

[0512] Compound 13b (500 mg, 1.9 mmol) was dissolved in thionyl chloride (30 mL), and the reaction mixture was stirred at reflux for 1 hour. After the reaction was completed, the reaction mixture was concentrated, and DCM (30 mL) was added and concentrated to give compound 13c (300 mg).

[0513] LCMS (ESI-MS) m / z: 278 (M+H + ).

[0514] (S)-4-Ethynyl-6-((3-methylpiperidin-1-yl)methyl)isoindol-1-one 13d

[0515] Compound 13c (300 mg, 1.1 mmol) and (3S)-3-methylpiperidine (120 mg, 1.2 mmol) were dissolved in acetonitrile (20 mL). Potassium iodide (180 mg, 1.1 mmol) and potassium carbonate (450 mg, 3.2 mmol) were added. The reaction mixture was refluxed for 3 hours and then concentrated. Ice water (20 mL) was added and the mixture was extracted with EA (50 mL). The organic phase was dried, concentrated, and flash purified to afford compound 13d (190 mg).

[0516] LCMS (ESI-MS) m / z: 269 (M+H + ).

[0517] 4-Ethynyl-2-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((S)-3-methylpiperidin-1-yl)methyl)isoindol-1-one 13

[0518] Compound 13d (190 mg, 0.71 mmol) and compound 12m (260 mg, 0.85 mmol) were dissolved in dioxane (6.0 mL). Pd(OAc)2 (16 mg, 0.070 mmol), Xantphos (81 mg, 0.14 mmol), and Cs2CO3 (460 mg, 1.4 mmol) were added. The reaction mixture was purged with nitrogen three times and stirred at 110°C for 3 hours. After the reaction was complete, the mixture was filtered while hot and the residue was washed with DCM (20 mL). The resulting organic phase was flash purified and then purified by HPLC to yield compound 13 (8.0 mg).

[0519] LCMS (ESI-MS) m / z: 494.40 (M+H + ).

[0520] 1 H NMR(400MHz,DMSO-d6)δ8.28(s,1H),8.04(s,1H),7.73–7.61(m,3H),7.40(m,1H),7.07(m,1H),5.01(s,2H),4.63(s ,1H),3.52(s,2H),3.20(s,3H),2.84(m,1H),2.68(m,3H),2.53(m,4H),1.68–1.47(m,6H),1.07(m,3H),0.79(m,3H).

[0521] Example 14: Synthesis of Compound 14

[0522] Synthesis of methyl 3-methyl-4-(trifluoromethyl)pyridine-2-carboxylate 14a

[0523] To a solution of methyl 3-methyl-2-pyridinecarboxylate f1 (5.0 g, 33 mmol) in DCE (250 mL) were added zinc trifluoromethanesulfinate (22 g, 66 mmol) and H2O (75 mL). Tert-butyl peroxide (8.9 g, 99 mmol) was slowly added dropwise under ice bath conditions. The atmosphere was replaced with nitrogen and stirred at 50°C for 4 hours. LCMS monitoring showed that the raw material reaction was complete. Water was added, washed with saturated aqueous Na2CO3 solution, extracted with DCM, washed with saturated aqueous NaCl solution, dried over anhydrous Na2SO4, concentrated, and purified by Flash to obtain compound 14a (2.3 g).

[0524] LCMS (ESI-MS) m / z: 220.1 (M+H + ).

[0525] 1H NMR (400MHz, Chloroform-d) δ8.66 (d, J = 5.0 Hz, 1H), 7.63 (d, J = 5.0 Hz, 1H), 4.00 (s, 3H), 2.61 (q, J = 1.7 Hz, 3H).

[0526] Synthesis of 2-(methoxycarbonyl)-3-methyl-4-(trifluoromethyl)pyridine-1-oxide 14b

[0527] To 14a (1.9 g, 8.6 mmol) in AcOH (20 mL) was added H2O2 (4.0 mL), the atmosphere was replaced with nitrogen, and the mixture was stirred at 90°C for 8 hours. After cooling to room temperature, the reaction mixture was poured into ice water, washed with saturated aqueous Na2S2O3, extracted with EA, washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, concentrated, and flash purified (EA / PE = 0-50%) to afford compound 14b (2.1 g).

[0528] LCMS (ESI-MS) m / z: 236.1 (M+H + ).

[0529] 1 H NMR (400MHz, Chloroform-d) δ8.15(d,J=6.8Hz,1H),7.52(d,J=6.7Hz,1H),4.04(d,J=1.0Hz,3H),2.37(t,J=1.5Hz,3H).

[0530] Synthesis of methyl 6-chloro-3-methyl-4-(trifluoromethyl)pyridine-2-carboxylate 14c

[0531] 14b (2.0 g, 8.5 mmol) was dissolved in DCE (30 mL), and Pcl3 (4.0 mL) was added. The mixture was stirred at 90°C under nitrogen for 8 hours. LCMS confirmed the reaction was complete. The reaction mixture was poured into ice water, extracted with DCM, washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, concentrated, and purified by flash chromatography (EA / PE = 0-50%) to afford compound 14c (1.3 g).

[0532] LCMS (ESI-MS) m / z: 254.0 (M+H + ).

[0533] 1 H NMR (400MHz, Chloroform-d) δ7.67 (s, 1H), 3.99 (s, 3H), 2.57 (d, J = 1.6Hz, 3H).

[0534] Synthesis of methyl 3-(bromomethyl)-6-chloro-4-(trifluoromethyl)pyridine-2-carboxylate 14d

[0535] 14c (1.3 g, 5.1 mmol) was dissolved in DCE (30 mL), and NBS (2.7 g, 15 mmol) and BPO (510 mg, 2.1 mmol) were added. The mixture was stirred at 90°C under nitrogen for 8 hours. LCMS confirmed the reaction was complete. The product was filtered, concentrated, and flash purified (25% EtOH / EA / PE = 0-40%) to afford compound 14d (1.6 g).

[0536] LCMS (ESI-MS) m / z: 334.0 (M+H + ).

[0537] Synthesis of 2-chloro-4-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-7-one 14e

[0538] Dissolve 14d (1.6 g, 4.8 mmol) in MeOH (20 mL), add ammonia in MeOH (5.0 mL), and stir under nitrogen at room temperature for 6 hours. LCMS analysis indicates the reaction is complete. The reaction solution is concentrated and flash purified (EA / PE = 0-50%) to afford compound 14e (1.1 g).

[0539] LCMS (ESI-MS) m / z: 237.0 (M+H + ).

[0540] Synthesis of 4-(Trifluoromethyl)-2-vinyl-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-7-one 14f

[0541] 14e (1.1 g, 4.6 mmol) was dissolved in dioxane (20 mL), and potassium vinyl trifluoroborate (1.2 g, 9.2 mmol), Pd(dppf)Cl2 (370 mg, 0.50 mmol), K3PO4 (1.9 g, 9.2 mmol), and H2O (4.0 mL) were added under nitrogen and stirred at 90°C for 1 hour. LCMS confirmed the reaction was complete. The reaction solution was poured into water, extracted with EA, washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, concentrated, and purified by flash chromatography to afford compound 14f (770 mg).

[0542] LCMS (ESI-MS) m / z: 229.1 (M+H + ).

[0543] Synthesis of 14 g of 2-methylprop-2-yl 7-oxyylidene-4-(trifluoromethyl)-2-vinyl-6,7-dihydro-5H-pyrrolo[4,3-b]pyridine-6-carboxylate

[0544] 14f (1.5 g, 6.5 mmol) was dissolved in THF (20 mL), and (BOC)2O (2.8 g, 13 mmol), DIEA (1.6 g, 13 mmol), and DMAP (790 mg, 6.5 mmol) were added under nitrogen and stirred at room temperature for 1 hour. LCMS confirmed the reaction was complete. The reaction solution was concentrated and flash purified to afford compound 14g (1.7 g).

[0545] LCMS (ESI-MS) m / z: 229.1 (M-99).

[0546] Synthesis of 2-methylprop-2-yl-2-formyl-7-oxyylidene-4-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[4,3-b]pyridine-6-carboxylate

[0547] Dissolve 14g (660mg, 2.0mmol) in dioxane (20mL), add H2O (20mL) and NMO (350mg, 3.0mmol), and under nitrogen, add potassium osmate (7.3mg, 0.020mmol) in an ice bath. Stir for 1 hour, then add sodium periodate (860mg, 4.0mmol), return to room temperature, and stir for 2 hours. LCMS analysis indicates the reaction is complete. Add saturated aqueous NaHCO3 solution, extract with EA, wash with saturated aqueous NaCl solution, dry over anhydrous Na2SO4, concentrate, and purify by flash chromatography to obtain compound 14h (600mg).

[0548] LCMS (ESI-MS) m / z: 231.1 (M-99).

[0549] Synthesis of 2-{[(3S)-3-methylhexahydropyridin-1-yl]methyl}-7-oxylidene-4-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[4,3-b]pyridine-6-carboxylic acid 2-methylprop-2-yl ester 14i

[0550] 14h (600 mg, 1.8 mmol) was dissolved in DCM (30 mL), and (3S)-3-methylpiperidine (220 mg, 2.2 mmol) was added. The mixture was stirred under nitrogen atmosphere on ice for 1 hour, followed by the addition of sodium triacetoxyborohydride (1.1 g, 5.4 mmol). The mixture was stirred for 8 hours. LCMS analysis indicated the reaction was complete. A saturated aqueous NaHCO₃ solution was added, and the mixture was extracted with DCM. The mixture was washed with a saturated aqueous NaCl solution, dried over anhydrous Na₂SO₄, concentrated, and purified by flash chromatography to afford compound 14i (330 mg).

[0551] LCMS (ESI-MS) m / z: 414.3 (M+H + ).

[0552] Synthesis of 2-{[(3S)-3-methylhexahydropyridin-1-yl]methyl}-4-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-7-one 14j

[0553] 14i (330 mg, 0.72 mmol) was dissolved in DCM (5.0 mL) and TFA (2.0 mL) was added. The mixture was stirred at room temperature under nitrogen atmosphere for 2 hours. LCMS analysis indicated the reaction was complete. The reaction solution was concentrated to afford compound 14j (160 mg).

[0554] LCMS (ESI-MS) m / z: 314.2 (M+H + ).

[0555] Synthesis of 6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl-2-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 14

[0556] 14j (160 mg, 0.51 mmol) was dissolved in dioxane (5.0 mL), and 12m (160 mg, 0.51 mmol), Pd2(dba)3 (64 mg, 0.07 mmol), Xantphos (87 mg, 0.15 mmol), and Cs2CO3 (330 mg, 1.0 mmol) were added. The mixture was stirred at 105°C for 1 hour under nitrogen atmosphere. LCMS confirmed the reaction was complete. The reaction solution was poured into water, extracted with EA, washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, concentrated, and purified by Prep-HPLC to obtain compound 14 (26 mg).

[0557] LCMS (ESI-MS) m / z: 539.4 (M+H + ).

[0558] 1 H NMR(400MHz,DMSO-d6)δ8.78(br,1H),8.27(s,1H),8.06(s,1H),7.80(m,1H),7.51(m,1H), 7.27(m,1H),5.31(s,2H),4.67(s,2H),3.58-3.19(m,5H),3.04-2.86(m,3 H),2.75(s,1H),2.59(m,3H),2.01-1.69(m,5H),1.10(m,3H),0.88(m,3H).

[0559] Example 15: Synthesis of Compound 15

[0560] Synthesis of 2-{[(1S,4R)-2-azabicyclo[2.2.1]hept-2-yl]methyl}-7-oxylidene-4-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[4,3-b]pyridine-6-carboxylic acid 2-methylprop-2-yl ester 15a

[0561] 14h (280 mg, 0.84 mmol) was dissolved in DCM (20 mL), and (1R,4S)-3-azabicyclo[2.2.1]heptane (91 mg, 0.93 mmol) was added. The mixture was stirred under nitrogen atmosphere on ice for 1 hour, followed by sodium acetate borohydride (530 mg, 2.5 mmol) and stirring for 2 hours. LCMS analysis indicated the reaction was complete. Saturated aqueous NaHCO₃ was added, and the mixture was extracted with DCM, washed with saturated aqueous NaCl, dried over anhydrous Na₂SO₄, concentrated, and purified by flash chromatography to afford compound 15a (180 mg).

[0562] LCMS (ESI-MS) m / z: 412.3 (M+H + ).

[0563] Synthesis of 2-{[(1S,4R)-2-azabicyclo[2.2.1]hept-2-yl]methyl}-4-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-7-one 15b

[0564] 15a (180 mg, 0.43 mmol) was dissolved in DCM (5.0 mL), and TFA (2.0 mL) was added. The mixture was stirred at room temperature under nitrogen for 2 hours. LCMS analysis indicated the reaction was complete. The reaction solution was concentrated to afford compound 15b (80 mg).

[0565] LCMS (ESI-MS) m / z: 312.2 (M+H + ).

[0566] Synthesis of 2-(((1S,4R)-2-azabicyclo[2.2.1]hept-2-yl)methyl)-6-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-4-(trifluoromethyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 15

[0567] 15b (80 mg, 0.26 mmol) was dissolved in dioxane (2.0 mL), and 12m (92 mg, 0.30 mmol), Pd2(dba)3 (36 mg, 0.040 mmol), Xantphos (45 mg, 0.080 mmol), and K3PO4 (10 mg, 0.52 mmol) were added. The mixture was stirred at 105°C for 1 hour under nitrogen. LCMS confirmed the reaction was complete. The reaction solution was poured into water, extracted with EA, washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, concentrated, and purified by Prep-HPLC to yield compound 15 (2.5 mg).

[0568] LCMS (ESI-MS) m / z: 537.4 (M+H + ).

[0569] 1 H NMR(400MHz,DMSO-d6)δ8.35(s,1H),8.18(s,1H),7.99(m,1H),7.75(m,1H),7.48(m,1H),7.23(m,1H),5.28(s,2H),4.79(s,2H), 3.22(s,3H),3.10(m,1H),2.87(m,3H),2.72-2.53(m,4H),2.14(m,1H),1.92(m,1H),1.77-1.58(m,4H),1.43(m,1H),1.08(m,3H).

[0570] Example 16: Synthesis of Compound 16

[0571] Synthesis of 4-bromo-6-(chloromethyl)-2,3-dihydro-1H-isoindol-1-one 16a

[0572] 13a (300 mg, 1.2 mmol) was dissolved in DCM (50 mL), and thionyl chloride (730 mg, 6.2 mmol) was added. The mixture was stirred at 70°C for 2 hours and concentrated to afford crude product 16a, which was used directly in the next reaction.

[0573] Synthesis of 4-bromo-6-(((3S)-3-methylpiperidin-1-yl)methyl)-2,3-dihydro-1H-isoindol-1-one 16b

[0574] 16a (280 mg, 1.1 mmol), (3S)-3-methylpiperidine (160 mg, 1.6 mmol), potassium carbonate (300 mg, 2.1 mmol), and sodium iodide (10 mg, 0.060 mmol) were dissolved in DMF and stirred at room temperature for 4 hours. The mixture was quenched with water and extracted with EA. The organic phase was washed with water, dried, concentrated, and flash purified (DCM:MeOH = 10:1) to afford 16b (300 mg).

[0575] LCMS (ESI-MS) m / z: 325 (M+H + ).

[0576] Synthesis of 4-bromo-2-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((S)-3-methylpiperidin-1-yl)methyl)isoindol-1-one 16

[0577] 16b (100 mg, 0.30 mmol), 12m (95 mg, 0.30 mmol), Pd(OAc)2 (13 mg, 0.060 mmol), Xantphos (70 mg, 0.12 mmol), and Cs2CO3 (200 mg, 0.60 mmol) were dissolved in dioxane and stirred at 110°C under nitrogen for 2 hours. The mixture was filtered, the filtrate was concentrated, and purified by Prep-HPLC to afford compound 16 (39 mg).

[0578] LCMS (ESI-MS) m / z: 549 (M+H + ).

[0579] 1 H NMR(400MHz,DMSO-d6)δ8.27(s,1H),8.01(s,1H),7.77(s,1H),7.68(m,2H),7.41(m,1H), 7.08(m,1H),4.93(s,2H),3.54(s,2H),3.19(s,3H),2.84(m,2H),2.69(m,3H) ,2.53(m,3H),1.93–1.82(m,1H),1.68–1.40(m,5H),1.07(m,3H),0.79(m,3H).

[0580] Example 17: Synthesis of Compound 17

[0581] Synthesis of 2-methylpropan-2-yl 2-(((1S,4R)-2-azabicyclo[2.2.1]hept-2-yl)methyl)-7-oxylidene-4-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[4,3-b]pyridine-6-carboxylate 17a

[0582] 14h (230 mg, 0.69 mmol) was dissolved in DCM (20 mL), and 3-aza-6-oxabicyclo[2.2.1]heptane (100 mg, 1.0 mmol) was added. The mixture was stirred under nitrogen atmosphere on ice for 1 hour, followed by sodium acetate borohydride (440 mg, 2.1 mmol) and stirring for 2 hours. LCMS analysis indicated the reaction was complete. Saturated aqueous NaHCO₃ was added, and the mixture was extracted with DCM, washed with saturated aqueous NaCl, dried over anhydrous Na₂SO₄, concentrated, and purified by flash chromatography to afford compound 17j (130 mg).

[0583] LCMS (ESI-MS) m / z: 414.3 (M+H + ).

[0584] Synthesis of 4-(trifluoromethyl)-2-(2-aza-5-oxabicyclo[2.2.1]hept-2-ylmethyl)-6,7-dihydro-5H-pyrrolo[4,3-b]pyridin-7-one 17b

[0585] 17a (130 mg, 0.31 mmol) was dissolved in DCM (5.0 mL), and TFA (2.0 mL) was added. The mixture was stirred at room temperature under nitrogen for 2 hours. LCMS analysis indicated the reaction was complete. The reaction solution was concentrated to afford compound 17b (70 mg).

[0586] LCMS (ESI-MS) m / z: 314.2 (M+H + ).

[0587] Synthesis of 2-((2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)-6-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-4-(trifluoromethyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one 17

[0588] 17b (70 mg, 0.22 mmol) was dissolved in dioxane (2.0 mL), and 12m (82 mg, 0.26 mmol), Pd2(dba)3 (30 mg, 0.033 mmol), Xantphos (38 mg, 0.066 mmol), and K3PO4 (93 mg, 0.44 mmol) were added. The mixture was stirred at 105°C for 1 hour under nitrogen atmosphere. LCMS confirmed the reaction was complete. The reaction solution was poured into water, extracted with EA, washed with saturated aqueous NaCl, dried over anhydrous Na2SO4, concentrated, and purified by HPLC to afford compound 17 (24 mg).

[0589] LCMS (ESI-MS) m / z: 539.4 (M+H + ).

[0590] 1 H NMR (400MHz, DMSO-d6) δ8.68(s,1H),8.21(s,1H),8.03(t,J=2.0Hz,1H),7.79(dd,J=8.1,2. 1Hz,1H),7.51(t,J=8.0Hz,1H),7.27(dd,J=7.3,1.7Hz,1H),5.31(s,2H),4.92(s,1H),4.84 (s,1H),4.71(s,1H),4.55(s,1H),4.28(s,4H),3.78(dd,J=9.9,2.0Hz,1H),3.30(s,3H),2. 90(dd,J=5.1,2.4Hz,2H),2.67-2.53(m,3H),2.10(d,J=11.5Hz,1H),1.10(d,J=5.7Hz,3H).

[0591] Example 18: Synthesis of Compound 18

[0592] Synthesis of 4-chloro-2-(3-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl-6-(((S)-3-methylpiperidin-1-yl)methyl)isoindol-1-one 18

[0593] Compound 16 (15 mg, 0.027 mmol) and cuprous chloride (5.5 mg, 0.054 mmol) were dissolved in DMSO (2.0 mL) and stirred in a microwave oven at 120°C for 3 hours under nitrogen protection. The mixture was filtered, the filtrate was concentrated, and Prep-HPLC purification was performed to obtain compound 18 (6.5 mg).

[0594] LCMS (ESI-MS) m / z: 505 (M+H +).

[0595] 1 H NMR (400MHz, DMSO-d6) δ8.43(s,1H),7.96(s,1H),7.92(s,1H),7.74(dd,J=7.9,1.9Hz,1H),7.44(t,J=7.9Hz,1H),7.29-7.01(m,2H),5.09(s,2H) ,4.41(s,2H),3.42-3.25(m,4H),3.22(s,3H),2.86(s,3H),2.53(d,J=6. 5Hz,3H),1.87-1.58(m,4H),1.07(d,J=4.7Hz,3H),0.86(d,J=6.6Hz,3H).

[0596] Example 19: Synthesis of Compound 19

[0597] Synthesis of tert-butyl 2-(2-(4-methoxybenzyl)-3-oxo-7-(trifluoromethyl)isoindolin-5-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate 19b

[0598] 6-Bromo-2-(4-methoxybenzyl)-4-(trifluoromethyl)isoindol-1-one 19a (1.6 g, 4.0 mmol), tert-butyl 2,3-dihydro-1H-pyrrole-1-carboxylate (0.88 g, 5.2 mmol), palladium acetate (90 mg, 0.40 mmol), Xantphos (460 mg, 0.80 mmol), and cesium carbonate (3.9 g, 12 mmol) were dissolved in anhydrous dioxane (30 mL). The reaction solution was stirred at 100°C under nitrogen for 5 hours. The reaction solution was cooled to room temperature, poured into ice water, and extracted with ethyl acetate. The organic phase was dried, filtered, and the filtrate was concentrated and flash purified (EA / PE = 0-50%) to obtain compound 19b (0.72 g).

[0599] LCMS (ESI-MS) m / z: 489.30 [M+H] + .

[0600] Synthesis of tert-butyl 2-(2-(4-methoxybenzyl)-3-oxo-7-(trifluoromethyl)isoindolin-5-yl)pyrrolidine-1-carboxylate 19c

[0601] 19b (0.72 g, 1.48 mmol) was dissolved in THF, and Pd / C (10%, 0.30 g) was added. The reaction solution was stirred at room temperature for 16 hours. The reaction solution was filtered, the filtrate was concentrated, and flash purified (EA / PE = 0-50%) to give compound 19c (0.67 g).

[0602] LCMS (ESI-MS) m / z: 491.30 [M+H] + .

[0603] Synthesis of tert-butyl 2-(3-oxo-7-(trifluoromethyl)isoindolin-5-yl)pyrrolidine-1-carboxylate 19d

[0604] 19c (0.65 g, 1.3 mmol) was dissolved in acetonitrile / water (10 mL / 5.0 mL). The reaction mixture was stirred at room temperature for 5 hours, poured into ice water, and extracted with ethyl acetate. The organic phase was dried, filtered, and the filtrate was concentrated and flash purified (EA / PE = 0-60%) to give compound 19d (0.22 g).

[0605] LCMS(ESI-MS)m / z:315.20[M-56+H] + .

[0606] Synthesis of tert-butyl 2-(2-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-3-oxo-7-(trifluoromethyl)isoindol-5-yl)pyrrolidine-1-carboxylate 19e

[0607] 19d (0.22 g, 0.60 mmol), 12m (0.22 g, 0.72 mmol), palladium acetate (21 mg, 0.060 mmol), Xantphos (69 mg, 0.12 mmol), and cesium carbonate (590 mg, 1.8 mmol) were dissolved in anhydrous dioxane (30 mL). The reaction solution was stirred at 100°C under nitrogen for 5 hours. The reaction solution was cooled to room temperature, poured into ice water, and extracted with ethyl acetate. The organic phase was dried, filtered, and the filtrate was concentrated and flash purified (MeOH / DCM = 0-10%) to obtain compound 19e (0.32 g).

[0608] LCMS (ESI-MS) m / z: 596.4 [M+H] + .

[0609] Synthesis of 2-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(pyrrolidin-2-yl)-4-(trifluoromethyl)isoindol-1-one 19

[0610] 19e (320 mg, 0.54 mmol) was dissolved in HCl / MeOH (8.0 mL, 4 M, 32 mmol) and the reaction solution was stirred at room temperature for 5 hours. The reaction solution was evaporated to dryness and the residue was neutralized with saturated sodium bicarbonate to pH 7-8. The mixture was extracted with dichloromethane, and the organic phase was dried and concentrated to give a crude compound (230 mg). 100 mg of the crude product was separated by Prep-HPLC to obtain the trifluoroacetate salt of compound 19 (27 mg).

[0611] LCMS (ESI-MS) m / z: 496.40 [M+H] + .

[0612] 1 H NMR(400MHz,DMSO-d6)δ9.65(s,1H),9.01(s,1H),8.47(s,1H),8.19(s,1H), 8.13(s,1H),7.99(s,1H),7.79–7.68(m,1H),7.45(t,J=8.0Hz,1H),7.18(d, J=7.8Hz,1H),5.25(s,2H),4.80(s,1H),3.44–3.34(m,3H),3.24(s,3H),2.9 9–2.79(m,2H),2.58–2.54(m,3H),2.20–1.99(m,3H),1.08(d,J=4.9Hz,3H).

[0613] Example 20: Synthesis of Compound 20

[0614] Synthesis of 2-(3-((1S,3S)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(1-methylpyrrolidin-2-yl)-4-(trifluoromethyl)isoindolin-1-one 20

[0615] Compound 19 (130 mg, 0.26 mmol), aqueous formaldehyde solution (2.0 mL, 37%, 24 mmol), and palladium on carbon (10%, 100 mg) were dissolved in anhydrous methanol (10 mL). The reaction mixture was stirred under a hydrogen atmosphere for 16 hours. The reaction mixture was cooled to room temperature, poured into ice water, and extracted with ethyl acetate. The organic phase was dried, filtered, and the filtrate was concentrated. The crude product was purified by Prep-HPLC to afford compound 20 (25 mg).

[0616] LCMS (ESI-MS) m / z: 510.40 [M+H] + .

[0617] 1H NMR (400MHz, DMSO-d6) δ8.27(s,1H),8.02(t,J=2.0Hz,1H),7.98(s,1H),7.92(s,1H),7.70–7.64(m,1H),7.42(t,J=8.0Hz,1H),7.14–7.08(m,1 H),5.17(s,2H),3.36(t,J=8.3Hz,2H),3.20–3.17(m,4H),2.87–2.82(m ,2H),2.58–2.50(m,2H),2.35–2.18(m,2H),2.10(s,3H),1.90–1.85(m, 1H),1.83–1.70(m,1H),1.61–1.50(m,1H),1.07(d,J=5.0Hz,3H).

[0618] Example 21: Synthesis of Compound 21

[0619] Synthesis of tert-butyl 2-methyl-6-oxopiperidine-1-carboxylate 21b

[0620] Compound 21a (1.0 g, 8.8 mmol), (Boc)2O (3.8 g, 18 mmol), and DMAP (1.1 g, 8.8 mmol) were dissolved in THF (100 mL), and the mixture was stirred at 80°C for 10 hours. The mixture was quenched with saturated NaHCO3 and extracted with DCM. The organic phase was dried, filtered, and the filtrate was concentrated and flash purified (DCM:MeOH = 10:1) to give compound 21b (1.0 g).

[0621] MS (ESI) m / z: 449.40 [2M+Na] + .

[0622] Synthesis of tert-butyl 2-methyl-6-[(trifluoromethylsulfonyl)oxy]-3,4-dihydropyridine-1(2H)-carboxylate 21c

[0623] A THF solution of 21b (1.0 g, 4.7 mmol) was added dropwise to LDA (2.0 N, 4.7 mL, 9.3 mmol) at -78°C. After stirring at -78°C for 2 hours, a THF solution of 1,1,1-trifluoro-N-phenyl-N-trifluoromethanesulfonylmethanesulfonamide (2.5 g, 7.0 mmol) was added dropwise. The mixture was slowly warmed to room temperature and stirred for another 2 hours. The reaction mixture was quenched by addition of saturated ammonium chloride solution and extracted with ethyl acetate. The organic phase was dried, concentrated, and flash purified (PE:EA = 10:1) to afford compound 21c (1.5 g).

[0624] MS (ESI) m / z: 290.10 [M-55]+ .

[0625] Synthesis of tert-butyl 6-(6-methyl-1,4,5,6-tetrahydropyridin-2-yl)-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 21d

[0626] 21c (600 mg, 1.7 mmol), 6-boronic acid 4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one (570 mg, 1.7 mmol), Pd(dppf)Cl2 (120 mg, 0.17 mmol), potassium carbonate (470 mg, 3.4 mmol), and 1 drop of water were dissolved in dioxane. The mixture was stirred at 110°C for 2 hours. The product was concentrated and flash purified (PE:EA = 1:1) to afford compound 21d (370 mg).

[0627] MS (ESI) m / z: 341.20 [M-55] + .

[0628] Synthesis of 6-(6-methyl-1,4,5,6-tetrahydropyridin-2-yl)-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 21e

[0629] 21d (370 mg, 0.93 mmol) was dissolved in DCM (10 mL), trifluoroacetic acid (10 mL) was added, and the mixture was stirred at room temperature for 2 hours and concentrated to give crude product 21e (300 mg).

[0630] MS (ESI) m / z: 297.20 [M+H] + .

[0631] Synthesis of 6-(6-methylpiperidin-2-yl)-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 21f

[0632] 21e (250 mg, 0.84 mmol) and Pd / C (10%, 20 mg) were dispersed in methanol. The reaction mixture was stirred under hydrogen for 2 hours. Filtered and concentrated. The crude product 21f (240 mg) was used directly in the next step.

[0633] MS (ESI) m / z: 299.20 [M+H] + .

[0634] Synthesis of 21 g of 6-(1,6-dimethylpiperidin-2-yl)-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one.

[0635] 21f (180 mg, 0.6 mmol) was dissolved in methanol (20 mL), and aqueous formaldehyde solution (1.0 mL) was added, followed by sodium cyanoborohydride (74 mg, 1.2 mmol). The mixture was stirred at room temperature for 2 hours, quenched with water, extracted with DCM, and the organic phase was dried, concentrated, and purified by Flash chromatography (DCM:MeOH=10:1) to give 21g (70 mg).

[0636] MS (ESI) m / z: 313.20 [M+H] + .

[0637] Synthesis of compound 21.

[0638] 21g (70mg, 0.22mmol), 12m (75mg, 0.24mmol), Pd(OAc)2 (9.8mg, 0.044mmol), Xantphos (51mg, 0.088mmol) and cesium carbonate (140mg, 0.44mmol) were dispersed in dioxane, and the mixture was stirred at 110°C under nitrogen for 2 hours, filtered, concentrated, and the crude product was purified by Prep-HPLC to obtain compound 21 (30mg).

[0639] MS (ESI) m / z: 538.40 [M+H] + .

[0640] 1 H NMR(400MHz,DMSO-d6)δ8.27(s,1H),8.01(t,J=2.0Hz,1H),7.97(s,1H),7.89(s,1H),7.68–7 .63(m,1H),7.42(t,J=8.0Hz,1H),7.13–7.08(m,1H),5.17(s,2H),3.23(d,J=8.8Hz,1H),3.20 (s,3H),2.84(d,J=3.3Hz,2H),2.54(d,J=6.6Hz,2H),2.11(d,J=6.8Hz,1H),1.91(s,3H),1.6 7(t,J=10.8Hz,3H),1.39(q,J=10.3,8.8Hz,4H),1.12(d,J=6.0Hz,3H),1.07(d,J=5.2Hz,3H).

[0641] Example 22

[0642] Synthesis of methyl 1-(3-bromophenyl)-3-methylcyclobutane-1-carboxylate 22b

[0643] Compound 22a (5.0 g, 22 mmol) and 1,3-dibromo-2-methylpropane (4.7 g, 22 mmol) were dissolved in anhydrous DMF (50 mL). NaH (2.0 g, 44 mmol) was added under ice-cooling conditions, and the mixture was stirred at room temperature for 2 hours. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phase was dried, filtered, and the filtrate was concentrated and purified by flash chromatography (PE:EA = 30:1) to afford compound 22b (4.0 g).

[0644] LCMS (ESI-MS) m / z: 283.30 [M+H] + .

[0645] Synthesis of 1-(3-bromophenyl)-3-methylcyclobutane-1-carbohydrazide 22c

[0646] Dissolve 22b (4.0 g, 14 mmol) and hydrazine hydrate (6.0 mL) in ethanol. React at 80°C for 16 hours, then concentrate. Quench with water and extract with DCM. Concentrate the reaction mixture, and use the crude product directly in the next reaction.

[0647] LCMS (ESI-MS) m / z: 283.04 [M+H] + .

[0648] Synthesis of 3-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-(3,4-dimethoxybenzyl)-4H-1,2,4-triazole 22d

[0649] 22c (3.2 g, 11 mmol) was dissolved in acetonitrile, and DMFDMA (2.7 g, 23 mmol) and DMBNH2 (2.8 g, 17 mmol) were added. The mixture was stirred at 50°C for 1 hour. Acetic acid (5.0 mL) was added, and the mixture was poured into a sealed container and heated at 120°C for 5 hours. The mixture was cooled, quenched with water, extracted with EA, concentrated, and purified by flash chromatography to afford compound 22d (2.0 g).

[0650] LCMS (ESI-MS) m / z: 442.10 [M+H] + .

[0651] Synthesis of 3-(1-(3-bromophenyl)-3-methylcyclobutyl)-4H-1,2,4-triazole 22e

[0652] 22d (2.0 g, 4.5 mmol) was dissolved in DCM, TFA (8.0 mL) was added under ice bath, and the mixture was stirred at room temperature for 2 h. The mixture was concentrated and neutralized by adding sodium bicarbonate. The mixture was extracted with DCM, and the organic phase was concentrated to obtain crude compound 22e which was directly used in the next step.

[0653] LCMS (ESI-MS) m / z: 292.10 [M+H] + .

[0654] Synthesis of 4-(bromodifluoromethyl)-3-(1-(3-bromophenyl)-3-methylcyclobutyl)-4H-1,2,4-triazole 22f

[0655] 22e (1.3 g, 4.5 mmol) was dissolved in THF (20 mL), and NaH (350 mg, 8.9 mmol) was added, followed by stirring at room temperature for 0.5 h. CBr2F2 (1.2 g, 8.9 mmol) was then added, and the mixture was stirred at room temperature for 2 h. The mixture was quenched with ammonium chloride and extracted with dichloromethane. The organic phase was dried, concentrated, and purified by flash chromatography to afford compound 22f (1.0 g).

[0656] LCMS (ESI-MS) m / z: 421.50 [M+H] + .

[0657] Synthesis of 22g of 3-(1-(3-bromophenyl)-3-methylcyclobutyl)-4-(trifluoromethyl)-4H-1,2,4-triazole

[0658] Dissolve 22f (1.0 g, 2.4 mmol) in THF (10 mL) and add silver tetrafluoroborate (0.93 g, 4.7 mmol) in an ice-water bath. Stir at 70°C for two hours. Cool to 0°C and quench with aqueous sodium bicarbonate. Extract with EA. The organic phase is dried, concentrated, and purified by flash chromatography to afford compound 22g (300 mg).

[0659] LCMS (ESI-MS) m / z: 360.10 [M+H] + .

[0660] Synthesis of 4-(difluoromethyl)-2-(3-(3-methyl-1-(4-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((S)-3-methylpiperidin-1-yl)methyl)isoindol-1-one 22.

[0661] 22g (150mg, 0.42mmol), 6-{[(3R)-3-methylpiperidin-1-yl]methyl}-4-(difluoromethyl)-2,3-dihydro-1H-isoindol-1-one 22h (120mg, 0.42mmol), Pd(OAc)2 (25mg, 0.11mmol), Xantphos (63mg, 0.11mmol) and cesium carbonate (540mg, 1.7mmol) were dispersed in anhydrous dioxane, and the mixture was stirred at 120°C under nitrogen protection for 2 hours, filtered, and the filtrate was purified by Prep-HPLC to obtain compound 22 (70mg).

[0662] LCMS (ESI-MS) m / z: 574.2 [M+H] +

[0663] 1 H NMR (400MHz, DMSO-d6) δ9.17(s,1H),8.13(s,1H),7.98–7.86(m,3H),7.46–7.27(m,3H),5.18(s,2H),4.47(s,2H),3.31(dd,J=3 8.6,11.9Hz,2H),2.91–2.71(m,3H),2.59(q,J=9.2,8.8Hz,3H),1.90–1.50(m,5H),1.07(d,J=6.4Hz,4H),0.86(d,J=6.5Hz,3H).

[0664] Example 23: Synthesis of Compound 23

[0665] Synthesis of tert-butyl 6-(((1-methylcyclobutyl)amino)methyl)-1-oxo-4-(trifluoromethyl)isoindoline-2-carboxylate 23c

[0666] Dissolve 23a (400 mg, 1.2 mmol) and 23b (210 mg, 2.4 mmol) in DCM (50 mL). Add sodium triacetoxyborohydride (510 mg, 2.4 mmol) under ice-cooling conditions. Add one drop of acetic acid, and stir at room temperature overnight. Quench with saturated sodium bicarbonate, extract with DCM, dry the organic phase, and purify by flash chromatography (PE:EA = 3:1) to afford compound 23c (300 mg).

[0667] LCMS (ESI-MS) m / z: 399.30 [M+H] + .

[0668] Synthesis of 6-(((1-methylcyclobutyl)amino)methyl)-4-(trifluoromethyl)isoindolin-1-one 23d

[0669] 23c (300 mg, 0.75 mmol) and TFA (2.0 mL) were dissolved in DCM. The mixture was reacted at room temperature for 2 hours and concentrated. The mixture was neutralized with saturated sodium bicarbonate and extracted with DCM. The reaction mixture was concentrated and the crude product was used directly in the next reaction.

[0670] LCMS (ESI-MS) m / z: 299.04 [M+H] +

[0671] Synthesis of 2-(3-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)phenyl)-6-(((1-methylcyclobutyl)amino)methyl)-4-(trifluoromethyl)isoindolin-1-one 23

[0672] 23d (200 mg, 0.76 mmol), 12m (210 mg, 0.76 mmol), Pd(OAc)2 (25 mg, 0.11 mmol), Xantphos (63 mg, 0.11 mmol) and cesium carbonate (540 mg, 1.7 mmol) were dispersed in anhydrous dioxane. The mixture was stirred at 120°C under nitrogen for 2 hours, filtered, and the filtrate was purified by Prep-HPLC to give compound 23 (100 mg).

[0673] LCMS (ESI-MS) m / z: 524.6 [M+H] +

[0674] 1 H NMR (400MHz, DMSO-d6) δ9.14(s,1H),8.42(s,1H),8.24(d,J=22.1Hz,2H),7.96(t,J= 2.0Hz,1H),7.76(dd,J=8.1,2.1Hz,1H),7.45(t,J=8.0Hz,1H),7.23–7.16(m,1H),5.2 6(s,2H),4.36–4.27(m,2H),3.24(d,J=2.1Hz,3H),2.92–2.81(m,2H),2.55(d,J=7.4 Hz,3H),2.43(d,J=9.1Hz,2H),1.97–1.77(m,4H),1.55(s,3H),1.08(d,J=5.4Hz,3H).

[0675] Example 24: Synthesis of Compound 24

[0676] Synthesis of 3-bromo-5-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]pyridin-2(1H)-one 24a

[0677] 3-Bromo-5-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]pyridin-2(1H)-one 24a (100 mg, 0.31 mmol), iodomethane (88 mg, 0.61 mmol), and cesium carbonate (400 mg, 1.2 mmol) were dissolved in anhydrous acetonitrile (50 mL). The mixture was stirred at 80°C for 2 hours. The mixture was filtered, the filtrate was concentrated, and flash purified (DCM:MeOH = 10:1) to give compound 24b (40 mg).

[0678] LCMS (ESI-MS) m / z: 337.10 [M+H] + .

[0679] Synthesis of (S)-2-(1-methyl-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one 24

[0680] 24b (40 mg, 0.12 mmol), 6-{[(3R)-3-methylpiperidin-1-yl]methyl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one (36 mg, 0.12 mmol), Pd(OAc)2 (6 mg, 0.024 mmol), Xantphos (27 mg, 0.048 mmol) and cesium carbonate (78 mg, 0.24 mmol) were dispersed in anhydrous dioxane. The mixture was stirred at 120°C under nitrogen protection for 2 hours, filtered, and the filtrate was purified by Prep-HPLC to obtain compound 24 (22 mg).

[0681] LCMS (ESI-MS) m / z: 569.40 [M+H] +

[0682] 1 H NMR (400MHz, DMSO-d6) δ8.45(s,1H),8.20(s,1H),8.15(s,1H),8.03(d,J=2.6 Hz,1H),7.50(d,J=2.6Hz,1H),5.15(s,2H),4.49(s,2H),3.56(s,3H),3.37(s ,3H),2.85–2.71(m,3H),2.60–2.52(m,2H),2.42(t,J=10.2Hz,2H),2.18(t,J =9.7Hz,1H),1.86–1.54(m,6H),1.06(d,J=6.4Hz,3H),0.86(d,J=6.4Hz,3H).

[0683] Example 25: Synthesis of Compound 25

[0684] Synthesis of 1-(2,6-dichloropyridin-4-yl)-3-methylcyclobutane-1-carboxylic acid 25a

[0685] Dissolve 8a (5.0 g, 18 mmol) in methanol (50 mL) and THF (50 mL). Add 10 mL of aqueous sodium hydroxide (1.4 g, 36 mmol) in an ice bath. Stir the mixture at room temperature for 2 hours. Concentrate, neutralize with dilute hydrochloric acid to pH 6-7, extract with EA, dry the organic phase, filter, and concentrate the filtrate for the next step.

[0686] LCMS (ESI-MS) m / z: 260.30 [M+H] + .

[0687] Synthesis of tert-butyl 2-(1-(2,6-dichloropyridin-4-yl)-3-methylcyclobutane-1-carbonyl)hydrazine-1-carboxylate 25b

[0688] Compound 25a (4.7 g, 18 mmol) and Boc-hydrazine (4.7 g, 36 mmol) were dissolved in DMF (50 mL). HATU (13 g, 36 mmol) and TEA (5.4 g, 54 mmol) were added and the mixture was allowed to react at room temperature for 16 hours. The mixture was then concentrated. The reaction mixture was quenched with water and extracted with DCM. The reaction mixture was concentrated and flash purified (PE:EA = 2:1) to afford compound 25b (3.0 g).

[0689] LCMS (ESI-MS) m / z: 374.04 [M+H] + .

[0690] Synthesis of 1-(2,6-dichloropyridin-4-yl)-3-methylcyclobutane-1-carboxylic acid hydrazide 25c

[0691] 25b (3.0 g, 8.3 mmol) was dissolved in DCM, TFA (9.5 g, 83 mmol) was added and stirred at room temperature for 2 h, concentrated, quenched with saturated aqueous sodium bicarbonate solution, extracted with DCM, concentrated, and directly used in the next step.

[0692] LCMS (ESI-MS) m / z: 274.10 [M+H] + .

[0693] Synthesis of 5-(1-(2,6-dichloropyridin-4-yl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol 25d

[0694] A THF solution of 25c (2.3 g, 8.3 mmol) and methyl isothiocyanate (2.1 g, 24 mmol) was stirred at 80°C for 2 hours. The mixture was concentrated, and ethanol (50 mL) and water (10 mL) were added, followed by sodium bicarbonate (1.4 g, 0.16 mmol). The mixture was stirred at 80°C for 6 hours, concentrated, and water was added. The mixture was extracted with DCM, and the organic phase was concentrated and flash purified to give compound 25d (1.0 g).

[0695] LCMS (ESI-MS) m / z: 329.10 [M+H] + .

[0696] Synthesis of 2,6-dichloro-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine 25e

[0697] 25d (330 mg, 1 mmol) was dissolved in DCM (10 mL), and acetic acid (2.0 mL) and hydrogen peroxide (1.0 mL) were added. The mixture was stirred at room temperature for 4 hours, quenched with water, extracted with DCM, and the organic phase was dried and concentrated. The crude compound 25e was used for the next reaction.

[0698] LCMS (ESI-MS) m / z: 297.50 [M+H] + .

[0699] Synthesis of 2-chloro-6-cyclopropyloxy-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine 25f.

[0700] 25e (300 mg, 1.0 mmol) was dissolved in toluene (5.0 mL), and cyclopropanol (1.0 mL) and cesium fluoride (460 mg, 3.0 mmol) were added. The mixture was reacted under microwave at 120°C for 3 h, concentrated, and flash purified (DCM:MeOH=1:50) to give the product 25f (100 mg).

[0701] LCMS (ESI-MS) m / z: 319.10 [M+H] + .

[0702] Synthesis of (S)-2-(6-cyclopropyloxy-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindol-1-one 25.

[0703] 25f (100 mg, 0.32 mmol), 1h (110 mg, 0.32 mmol), Pd(OAc)2 (25 mg, 0.11 mmol), Xantphos (63 mg, 0.11 mmol) and cesium carbonate (540 mg, 1.7 mmol) were dispersed in anhydrous dioxane. The mixture was stirred at 120 °C under nitrogen for 2 h, filtered, and the filtrate was purified by Prep-HPLC to give compound 25 (20 mg).

[0704] LCMS (ESI-MS) m / z: 595.0 [M+H] +

[0705] 1 H NMR (400MHz, DMSO-d6) δ8.48(s,1H),8.21(d,J=10.1Hz,2H),8.02(d,J=1.3Hz,1H),6.58(d,J= 1.3Hz,1H),5.24(d,J=5.0Hz,2H),4.51(s,2H),4.22(dd,J=6.2,3.7Hz,1H),3.35(d,J=11.9Hz, 1H),3.26(d,J=13.2Hz,3H),3.11(t,J=9.3Hz,1H),3.00(s,1H),2.83(s,2H),2.57(d,J=8.0Hz,2H),2.24(t,J=9.9Hz,1H), 1.98(q,J=7.2Hz,1H),1.85–1.58(m,5H),1.09(t,J=6.4Hz,3H),0.87(d,J=6.5Hz,3H),0.79(d,J=6.5Hz,2H),0.71(s,2H).

[0706] Example 26: Synthesis of Compound 26

[0707] Synthesis of [1-(2,6-dichloropyridin-4-yl)-3-methylcyclobutyl]{2-[(methylamino)thiolidenemethyl]ethazine}methanone 26a

[0708] Dissolve 25a (4.9 g, 19 mmol) and (ethylamino)(methylamino)thiophene (2.4 g, 23 mmol) in DMF, add HATU (7.2 g, 19 mmol), and add N,N-diisopropylethylamine (9.9 mL, 57 mmol) under ice-cooling. Stir at room temperature overnight. The mixture is washed with saturated brine and extracted four times with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is used directly in the next reaction.

[0709] LCMS (ESI-MS) m / z: 347.10 [M+H] + .

[0710] Synthesis of 5-[1-(2,6-dichloropyridin-4-yl)-3-methylcyclobutyl]-4-methyl-1,2,4-triazacyclopentane-3-thiophenol 26b

[0711] Dissolve 26a (6.5 g, 19 mmol) in ethanol (90 mL), add sodium bicarbonate (3.4 g, 40 mmol) and water (50 mL), and heat to 80°C in an oil bath for two hours. The mixture is concentrated, washed with saturated brine, and extracted with ethyl acetate. The organic phase is dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product is used directly in the next reaction.

[0712] LCMS (ESI-MS) m / z: 329.10 [M+H] + .

[0713] Synthesis of 2,6-dichloro-4-[3-methyl-1-(4-methyl-1,2,4-triazacyclopentan-3-yl)cyclobutyl]pyridine 26c.

[0714] 26b (6.0 g, 18 mmol) was dissolved in DCM (40 mL), acetic acid (2.0 mL) was added, and 30% hydrogen peroxide (10 mL) was added in an ice bath. The mixture was stirred at room temperature overnight, quenched with saturated sodium sulfite solution, neutralized with sodium carbonate, and extracted with DCM. The organic phase was dried, concentrated, and flash purified (DCM:MeOH = 98:2) to give compound 26c (4.6 g).

[0715] LCMS (ESI-MS) m / z: 297.10 [M+H] + .

[0716] Synthesis of 2-chloro-6-methoxy-4-[3-methyl-1-(4-methyl-1,2,4-triazacyclopentan-3-yl)cyclobutyl]pyridine 26d.

[0717] 26c (0.30 g, 1.0 mmol) was dissolved in tetrahydrofuran (10 mL), and a methanol solution of sodium methoxide (5.4 M, 0.50 mL) was added dropwise in an ice bath. The mixture was stirred at room temperature overnight, quenched with water, and extracted with ethyl acetate. The organic phase was dried and concentrated, and the crude product was purified by flash chromatography (DCM:MeOH=97:3) to give compound 26d (0.27 g).

[0718] LCMS (ESI-MS) m / z: 293.20 [M+H] +

[0719] Synthesis of 6-{[(3S)-3-methylhexahydropyridin-1-yl]methyl}-2-{6-methoxy-4-[3-methyl-1-(4-methyl-1,2,4-triazacyclopentan-3-yl)cyclobutyl]pyridin-2-yl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 26.

[0720] 26d (270 mg, 0.93 mmol), 1h (290 mg, 0.93 mmol), Pd(OAc)2 (34 mg, 0.15 mmol), Xantphos (170 mg, 0.30 mmol) and Cs2CO3 (0.90 g, 2.8 mmol) were added to anhydrous dioxane, and the mixture was stirred at 100°C under nitrogen protection in a stuffy tank for 4 hours, filtered through celite, and the filtrate was concentrated and purified by Prep-HPLC to give compound 26 (270 mg).

[0721] LCMS (ESI-MS) m / z: 569.40 [M+H] +

[0722] 1 H NMR(400MHz,DMSO-d6)δ8.58(d,J=11.6Hz,1H),8.22(d,J=6.1Hz,2H),8.00(s,1H) ,6.70(s,1H),5.29(s,2H),4.53(s,2H),3.93(d,J=4.7Hz,3H),3.37(d,J=12.1Hz,1 H),3.31–3.20(m,4H),3.15–2.99(m,1H),2.84(d,J=3.6Hz,2H),2.58(d,J=6.3Hz,3 H),2.44–2.17(m,1H),1.89–1.57(m,4H),1.13–0.99(m,4H),0.88(d,J=6.5Hz,3H).

[0723] Example 27: Synthesis of Compound 27

[0724] Synthesis of 3-bromo-1-trifluoroethyl-5-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]pyridin-2(1H)-one 27b

[0725] 3-Bromo-5-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]pyridin-2(1H)-one 27a (100 mg, 0.31 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (140 mg, 0.61 mmol), and cesium carbonate (400 mg, 1.2 mmol) were dissolved in anhydrous acetonitrile (50 mL), and the mixture was stirred at 80°C for 2 hours. The mixture was filtered, and the filtrate was concentrated and flash purified (DCM:MeOH = 10:1) to give compound 27b (60 mg).

[0726] LCMS (ESI-MS) m / z: 405.20 [M+H] + .

[0727] Synthesis of (S)-2-(5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridin-3-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one 27

[0728] 27b (60 mg, 0.15 mmol), 6-{[(3R)-3-methylpiperidin-1-yl]methyl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one (47 mg, 0.15 mmol), Pd(OAc)2 (6.0 mg, 0.024 mmol), Xantphos (27 mg, 0.048 mmol) and cesium carbonate (78 mg, 0.24 mmol) were dispersed in anhydrous dioxane. The mixture was stirred at 120°C under nitrogen protection for 2 hours, filtered, and the filtrate was purified by preparative HPLC to give compound 27 (22 mg).

[0729] LCMS (ESI-MS) m / z: 637.40 [M+H] +

[0730] 1H NMR(400MHz,DMSO-d6)δ8.42(s,1H),8.22(s,1H),8.16(s,1H),8.01(s,1H),7.61(d, J=2.5Hz,1H),5.16(s,2H),4.98(q,J=8.8Hz,2H),4.50(s,2H),3.36(s,3H),3.26(d,J =11.7Hz,1H),3.08(d,J=9.6Hz,1H),2.87–2.53(m,3H),2.45(s,2H),2.33–2.35(m,2H ),2.16(t,J=9.6Hz,1H),1.86–1.53(m,6H),0.91–0.92(m,1H),0.86(d,J=6.5Hz,3H).

[0731] Example 28: Synthesis of Compound 28

[0732] Synthesis of 3-[1-(3-bromo-4-fluorophenyl)-3-methylcyclobutyl]-4-methyl-4H-1,2,4-triazole 28b

[0733] 3-Bromo-5-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]pyridin-2(1H)-one 28a (100 mg, 0.31 mmol) was dissolved in acetonitrile (4.0 mL), and cesium carbonate (300 mg, 0.93 mmol) and isopropyl iodide (110 mg, 0.62 mmol) were added. The mixture was stirred at 80°C for 1 hour, quenched with water, and extracted with dichloromethane / methanol. The organic phase was dried, filtered, and the filtrate was concentrated. The crude product was flash purified (DCM:MeOH = 15:1) to give compound 28b (40 mg).

[0734] LCMS (ESI-MS) m / z: 365.20[M+H]+.

[0735] 1 H NMR (400MHz, DMSO-d6) δ8.30(s,1H),7.75(d,J=2.4Hz,1H),7.49(d,J=2.4Hz,1H),5.06(m,1H),3.31(s ,3H),2.80(m,2H),2.44–2.34(m,2H),2.16–2.31(m,1H),1.36(d,J=6.4Hz,6H),1.05(d,J=6.4Hz,3H).

[0736] Synthesis of (R)-2-(1-isopropyl-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindol-1-one 28

[0737] 28b (33 mg, 0.090 mmol), 1h (28 mg, 0.09 mmol), Pd(OAc)2 (4.0 mg, 0.018 mmol), Xantphos (21 mg, 0.036 mmol) and cesium carbonate (59 mg, 0.18 mmol) were dispersed in anhydrous dioxane. The mixture was stirred at 110°C under nitrogen protection for 2 hours, filtered, and the filtrate was purified by Prep-HPLC to give compound 28 (20 mg).

[0738] LCMS (ESI-MS) m / z: 597.40 [M+H] +

[0739] 1 H NMR (400MHz, DMSO-d6) δ8.51 (s, 1H), 8.22 (s, 1H), 8.17 (s, 1H), 7.83 (d, J = 2.4Hz, 1H), 7. 51(d,J=2.4Hz,1H),5.18(s,2H),4.51(s,1H),3.40(s,3H),3.28(d,J=11.6Hz,2H),3.06( d,J=9.6Hz,1H),2.86(m,3H),2.57(d,J=6.4Hz,2H),2.47–2.40(m,2H),2.33–2.22(m,1H ),1.85–1.60(m,5H),1.41(d,J=6.8Hz,6H),1.08(d,J=6.0Hz,3H),0.87(d,J=6.4Hz,3H).

[0740] Example 29: Synthesis of Compound 29

[0741] Synthesis of 2-methylpropan-2-yl(2-{[1-(5-bromo-6-chloropyridin-3-yl)-3-methylcyclobutyl]carbonyl}diazoyl)carboxylate 29a: 5b (1.3 g, 6.2 mmol), tert-butylhydrazinecarboxylate (0.83 g, 6.3 mmol), HATU (1.6 g, 4.2 mmol), and TEA (0.84 g, 8.4 mmol) were dissolved in DMF. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was dried, concentrated, and flash purified to afford compound 29a (1.2 g).

[0742] LCMS (ESI-MS) m / z: 420.10 [M+H] + .

[0743] Synthesis of 1-(5-bromo-6-chloropyridin-3-yl)-3-methylcyclobutane-1-carbohydrazide 29b.

[0744] 29a (1.2 g, 2.8 mmol) was dissolved in DCM (20 mL), and TFA (10 mL) was added. The mixture was stirred at room temperature for 2 hours, concentrated, and the crude product 29b was used directly in the next reaction.

[0745] LCMS (ESI-MS) m / z: 320.10 [M+H] + .

[0746] Synthesis of [1-(5-bromo-6-chloropyridin-3-yl)-3-methylcyclobutyl]{2-[(methylamino)sulfanylidenemethyl]ethazine}methanone 29c

[0747] 29b (1.0 g, 3.1 mmol), methane isothiocyanate (0.68 g, 9.4 mmol) and TEA (1.6 g, 16 mmol) were dispersed in THF. The mixture was stirred at 80°C for 2 hours and concentrated. The crude product 29c was used directly in the next reaction.

[0748] LCMS (ESI-MS) m / z: 393.10 [M+H] + .

[0749] Synthesis of 5-[1-(5-bromo-6-chloropyridin-3-yl)-3-methylcyclobutyl]-4-methyl-4H-1,2,4-triazole-3-thiol 29d.

[0750] 29c (450 mg, 1.2 mmol) and NaOH (1 N, 50 mL) were dissolved in ethanol (50 mL), and the mixture was stirred at 100°C for 3 hours. The mixture was neutralized with dilute hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with water, dried, and concentrated. The crude product 29d was used directly in the next reaction.

[0751] LCMS (ESI-MS) m / z: 375.10 [M+H] + .

[0752] Synthesis of 3-bromo-2-chloro-5-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]pyridine 29e.

[0753] 29d (400 mg, 1.0 mmol) was dissolved in DCM (30 mL), and acetic acid (3.0 mL) and hydrogen peroxide (1.0 mL) were added. The mixture was stirred at room temperature for 4 hours, neutralized with saturated NaHCO3 solution, extracted with DCM, and the organic phase was dried and concentrated. The crude product 29e was used directly in the next reaction.

[0754] LCMS (ESI-MS) m / z: 343.10 [M+H] + .

[0755] Synthesis of 3-bromo-5-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]pyridin-2(1H)-one 29f

[0756] Compound 29e (340 mg, 0.99 mmol) and potassium tert-butoxide (1.2 g, 9.9 mmol) were dissolved in tert-butanol, and the mixture was stirred at 120°C for 2 hours. The mixture was concentrated and the crude product was purified by Prep-HPLC to give compound 29f (130 mg).

[0757] LCMS (ESI-MS) m / z: 323.10 [M+H] + .

[0758] Synthesis of 29g of 3-bromo-1-cyclopropyl-5-[3-methyl-1-(4-methyl-1,2,4-triazacyclopentan-3-yl)cyclobutyl]-1,2-dihydropyridin-2-one

[0759] 29f (170 mg, 0.51 mmol), cyclopropylboronic acid (90 mg, 1.1 mmol), copper acetate (96 mg, 0.53 mmol), 2,2-bipyridine (84 mg, 0.54 mmol), and sodium carbonate (120 mg, 1.1 mmol) were dissolved in 1,2-dichloroethane (20 mL), opened, stirred in an oil bath at 70 ° C for 5 hours, quenched with water, extracted with dichloromethane 4 times, dried over anhydrous sodium sulfate, filtered, and flash purified (DCM:MeOH=95:5) to give compound 29g (110 mg).

[0760] LCMS (ESI-MS) m / z: 363.20 [M+H] + .

[0761] Synthesis of 2-{1-cyclopropyl-5-[3-methyl-1-(4-methyl-1,2,4-triazacyclopentan-3-yl)cyclobutyl]-2-oxypyridin-3-yl}-6-{[(3S)-3-methylhexahydropyridin-1-yl]methyl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 29

[0762] 29g (110 mg, 0.29 mmol), 1h (86 mg, 0.27 mmol), Pd(OAc)2 (22 mg, 0.10 mmol), Xantphos (120 mg, 0.20 mmol), and cesium carbonate (490 mg, 1.5 mmol) were dissolved in dioxane. The mixture was stirred at 100°C in a sealed container under nitrogen for 4 hours and filtered through Celite. The filtrate was concentrated, and the crude product was purified by Prep-HPLC to obtain compound 29 (88 mg).

[0763] LCMS (ESI-MS) m / z: 595.40 [M+H] + .

[0764] 1 H NMR (400MHz, DMSO-d6) δ8.61(s,1H),8.19(d,J=16.5Hz,2H),7.67(d,J=2.6Hz,1H),7. 54(d,J=2.6Hz,1H),5.17(s,2H),4.50(s,2H),3.42(s,3H),3.27(d,J=11.1Hz,1H),3. 08–2.96(m,1H),2.90–2.72(m,3H),2.56(d,J=13.4Hz,1H),2.48-2.37(m,2H),1.89-1 .55(m,4H),1.23(s,2H),1.14-1.00(m,6H),0.99–0.91(m,2H),0.87(d,J=6.5Hz,3H).

[0765] Example 30: Synthesis of Compound 30

[0766] Synthesis of 1-(5-bromo-6-oxo-1,6-dihydropyridin-3-yl-5-bromo-6-chloropyridin-3-yl)-3-methylcyclobutane-1-formyl-N-ethylhydrazine-1-thioamide 30a

[0767] 5b (500 mg, 1.6 mmol), N-ethylhydrazine carbosulfamide (200 mg, 1.6 mmol), HATU (630 mg, 1.6 mmol), and DIPEA (420 mg, 3.3 mmol) were dissolved in DMF (80 mL), and the mixture was stirred at room temperature for 2 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with water, dried, filtered, concentrated, and flash purified (DCM:MeOH = 15:1) to obtain compound 30a (500 mg).

[0768] LCMS (ESI-MS) m / z: 407.10 [M+H] + .

[0769] Synthesis of 5-[1-(5-bromo-6-chloropyridin-3-yl)-3-methylcyclobutyl]-4-ethyl-4H-1,2,4-triazole-3-thiol 30b

[0770] 30a (500 mg, 1.2 mmol) was dispersed in NaOH (1N, 50 mL) and ethanol (50 mL). The mixture was stirred at 70°C for 4 hours, cooled, neutralized with dilute hydrochloric acid, extracted with ethyl acetate, and the organic phase was dried and concentrated to give crude product 30b (450 mg).

[0771] LCMS (ESI-MS) m / z: 389.10 [M+H] +

[0772] Synthesis of 3-bromo-2-chloro-5-[1-(4-ethyl-4H-1,2,4-triazol-3-yl)-3-methylcyclobutyl]pyridine 30c

[0773] 30b (450 mg, 1.2 mmol) was dissolved in DCM, and acetic acid (4.0 mL) and hydrogen peroxide (2.0 mL) were added under ice-cooling. The mixture was stirred at room temperature for 5 hours, neutralized with saturated sodium bicarbonate, extracted with DCM, and the organic phase was washed with water, dried, and concentrated. The crude product 30c (400 mg) was used directly in the next reaction.

[0774] LCMS (ESI-MS) m / z: 357.10 [M+H] +

[0775] Synthesis of 3-bromo-5-[1-(4-ethyl-4H-1,2,4-triazol-3-yl)-3-methylcyclobutyl]pyridin-2(1H)-one 30d

[0776] 30c (400 mg, 1.1 mmol) and potassium tert-butoxide (1.3 g, 1.1 mmol) were dissolved in tert-butanol (20 mL). The mixture was stirred at 120° C. for 4 h, cooled, concentrated, and flash purified (DCM:MeOH=8:1) to give 30d (200 mg).

[0777] LCMS (ESI-MS) m / z: 337.10 [M+H] +

[0778] Synthesis of 3-bromo-1-ethyl-5-[1-(4-ethyl-4H-1,2,4-triazol-3-yl)-3-methylcyclobutyl]pyridin-2(1H)-one 30e

[0779] 30d (200 mg, 0.6 mmol), iodoethane (190 mg, 1.2 mmol), and cesium carbonate (590 mg, 1.8 mmol) were dissolved in anhydrous acetonitrile (50 mL), and the mixture was stirred at 80°C for 2 hours. The mixture was filtered, the filtrate was concentrated, and flash purified (DCM:MeOH = 10:1) to give compound 30e (150 mg).

[0780] LCMS (ESI-MS) m / z: 365.20 [M+H] +

[0781] Synthesis of compound 30

[0782] 30e (150 mg, 0.41 mmol), 6-{[(3R)-3-methylpiperidin-1-yl]methyl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one (130 mg, 0.41 mmol), Pd(OAc)2 (18 mg, 0.08 mmol), Xantphos (95 mg, 0.16 mmol) and cesium carbonate (270 mg, 0.82 mmol) were dispersed in anhydrous dioxane, and the mixture was stirred at 120°C under nitrogen for 2 hours, filtered, and the filtrate was purified by preparative HPLC to give compound 30 (53 mg).

[0783] LCMS (ESI-MS) m / z: 597.50 [M+H] +

[0784] 1 H NMR(400MHz,DMSO-d6)δ8.42(s,1H),8.00(d,J=2.7Hz,1H),7.91(s,1H),7.87(s,1H),7.45 (d,J=2.6Hz,1H),5.08(s,2H),4.05(q,J=7.0Hz,2H),3.68(q,J=7.1Hz,3H),3.62(s,3H),2. 80–2.62(m,5H),2.41(t,J=10.2Hz,1H),1.90(t,J=10.8Hz,1H),1.59(q,J=13.7,11.8Hz,4 H),1.46(t,J=11.9Hz,1H),1.26(t,J=7.1Hz,3H),1.11–1.04(m,6H),0.79(d,J=5.8Hz,3H).

[0785] Example 31: Synthesis of Compound 31

[0786] Synthesis of 3-bromo-1-ethyl-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2(1H)-one 31b

[0787] 3-Bromo-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2(1H)-one 31a (200 mg, 0.60 mmol), iodoethane (190 mg, 1.2 mmol), and cesium carbonate (590 mg, 1.8 mmol) were dissolved in anhydrous acetonitrile (50 mL), and the mixture was stirred at 80°C for 2 hours. The mixture was filtered, the filtrate was concentrated, and the crude product was flash purified (DCM:MeOH = 10:1) to give compound 31b (150 mg).

[0788] LCMS (ESI-MS) m / z: 351.10 [M+H] + .

[0789] Synthesis of (S)-2-(1-ethyl-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one 31c

[0790] Compound 31b (150 mg, 0.41 mmol), 6-{[(3R)-3-methylpiperidin-1-yl]methyl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one (130 mg, 0.41 mmol), Pd(OAc)2 (18 mg, 0.080 mmol), Xantphos (95 mg, 0.16 mmol) and cesium carbonate (270 mg, 0.82 mmol) were dispersed in anhydrous 1,4-dioxane, and the mixture was stirred at 120 °C for 2 h under nitrogen protection, filtered, and the filtrate was purified by preparative HPLC to give compound 31c (53 mg).

[0791] LCMS (ESI-MS) m / z: 583.40 [M+H] + .

[0792] Synthesis of 2-{1-ethyl-5-[(1S,3R)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]-2-oxopyridin-3-yl}-6-{[(3S)-3-methylhexahydropyridin-1-yl]methyl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 31

[0793] Compound 31c (1.4 g, 2.4 mmol) was prepared by chiral separation (chiral column: IH 4.6*100 mm 5 μm, mobile phase: MeOH [0.2% NH 3 (7 M in MeOH)]) to give compound 31 (600 mg, 1.0 mmol).

[0794] LCMS (ESI-MS) m / z: 583.4 0 [M+H] + .

[0795] 1 H NMR (400MHz, DMSO-d6) δ8.30(s,1H),7.97(d,J=2.7Hz,1H),7.92(s,1H),7.88(s,1H),7.50(d,J=2.6Hz,1H),5.09(s,2H),4.04(q,J=7.0Hz,2H),3 .62(s,2H),3.34(s,3H),2.81–2.61(m,4H),2.56–2.50(m,1H),2.41(t,J =10.3Hz,2H),1.92(d,J=11.7Hz,1H),1.59(dt,J=15.3,9.0Hz,4H),1.46 (t,J=12.2Hz,1H),1.27(t,J=7.1Hz,3H),1.06(d,J=6.4Hz,3H),0.85(s,1H),0.79(d,J=5.9Hz,3H).

[0796] Example 32: Synthesis of Compound 32

[0797] Synthesis of 1-(2,6-dichloropyridin-4-yl)-3-methylenecyclobutane-1-carbonitrile 32b

[0798] To a 250 ml three-necked flask, compound 32a (7.2 g, 39 mmol), THF (80 mL), and 3-methylenecyclobutane-1-carbonitrile (3.7 g, 39 mmol) were added. The mixture was cooled to below -60°C with dry ice-ethanol, and a THF solution of LiHMDS (43 mL, 43 mmol) was added portionwise. The temperature was maintained for 2 hours. LCMS monitoring showed that the reaction of the raw materials was complete. Water was added under ice bath conditions to quench the reaction. The mixture was extracted with EA, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and purified with a flash column to obtain the target compound 32b (4.8 g).

[0799] LCMS (ESI-MS) m / z: 239.00 [M+H] + .

[0800] Synthesis of 1-(2,6-dichloropyridin-4-yl)-3-methylenecyclobutane-1-carboxylic acid 32c

[0801] Compound 32b (6.0 g, 25 mmol), dioxane (75 mL), and 1.0 M NaOH (75 mL) were added to a 500 mL round-bottom flask and heated under reflux at 100°C for 6 h. LCMS monitoring showed that the reaction of the starting material was complete. The pH was adjusted to acidic with 3.0 M HCl, extracted with EA, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and purified on a flash column to obtain the target compound 32c (5.4 g).

[0802] LCMS (ESI-MS) m / z: 258.00 [M+H] + .

[0803] Synthesis of 2-(1-(2,6-dichloropyridin-4-yl)-3-methylenecyclobutane-1-carbonyl)-N-methylhydrazine-1-thiocarboamide 32d

[0804] To a 250 mL round-bottom flask, compound 32c (5.4 g, 21 mmol), DMF (50 mL), N-methylhydrazine methylsulfamide (2.6 g, 25 mmol), DIEA (5.4 g, 42 mmol), and HATU (9.5 g, 25 mmol) were added. The mixture was protected by nitrogen and reacted at room temperature for 2 hours. After LCMS monitoring, the reaction of the raw materials was completed. Water was added, and the mixture was extracted with EA. The mixture was washed with saturated NaCl water, dried over anhydrous sodium sulfate, and purified on a flash column to obtain the target compound 32d (7.1 g).

[0805] LCMS (ESI-MS) m / z: 345.10 [M+H] + .

[0806] Synthesis of 5-(1-(2,6-dichloropyridin-4-yl)-3-methylenecyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol 32e

[0807] Compound 32d (5.5 g, 16 mmol) and 1.0 M NaOH aqueous solution (200 mL) were added to a 500 mL round-bottom flask under nitrogen protection. The reaction was allowed to proceed at room temperature for 8 h. LCMS monitoring showed that the reaction of the starting material was complete. The pH was adjusted to acidic with 3.0 M HCl, extracted with EA, washed with saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified with a flash column to obtain the target compound 32e (3.1 g).

[0808] LCMS (ESI-MS) m / z: 327.10 [M+H] + .

[0809] Synthesis of 2,6-dichloro-4-(1-(4-methyl-4H-1,2,4-triazol-3-yl)-3-methylenecyclobutyl)pyridine 32f

[0810] To a 100 mL three-necked flask, compound 32e (2.3 g, 7.0 mmol), THF (20 mL), H2O (20 mL), and NaNO2 (2.4 g, 35 mmol) were added. Under nitrogen protection, an aqueous HNO3 solution (35 mL, 1.0 M) was slowly added dropwise while stirring in an ice bath. The reaction was kept in an ice bath for 2 hours. LCMS monitoring showed that the raw material reaction was complete. Water was added and the pH was adjusted to neutral with a saturated NaHCO3 aqueous solution. The product was extracted with DCM, washed with a saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and purified with a flash column to obtain the target compound 32f (1.7 g).

[0811] LCMS (ESI-MS) m / z: 295.10 [M+H] + .

[0812] Synthesis of 32g of 3-(2,6-dichloropyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutane-1-one

[0813] To a 100 mL round-bottom flask, compound 32f (600 mg, 2.0 mmol), acetonitrile (40 mL), and H2O (20 mL) were added. NMO (360 mg, 3.1 mmol) and K2OsO4 (15 mg, 0.040 mmol) were added while stirring on an ice bath. After stirring at the same temperature for 1 hour, NaIO4 (870 mg, 4.1 mmol) was added and the reaction was continued for 4 hours. LCMS monitoring showed that the starting material had reacted completely. Saturated aqueous NaHSO3 solution was added, and the mixture was extracted with DCM, washed with saturated aqueous NaCl solution, dried over anhydrous sodium sulfate, and purified on a flash column to obtain the target compound 32g (310 mg).

[0814] LCMS (ESI-MS) m / z: 297.10 [M+H] + .

[0815] Synthesis of 3-(2,6-dichloropyridin-4-yl)-3-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutane-1-ol

[0816] Compound 32g (310 mg, 1.0 mmol), MeOH (10 mL), and NaBH4 (120 mg, 3.1 mmol) were added to a 50 mL round-bottom flask and stirred at room temperature for 1 hour. After LCMS monitoring, the reaction of the starting material was complete. Water was added, and the mixture was extracted with DCM. The mixture was washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and the solvent was dried to obtain compound 32h (300 mg).

[0817] LCMS (ESI-MS) m / z: 299.10 [M+H] + .

[0818] Synthesis of 2,6-dichloro-4-(3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine 32i

[0819] Compound 32h (310 mg, 1.0 mmol), THF (20 mL), NaH (120 mg, 3.1 mmol), and iodomethane (440 mg, 3.1 mmol) were added to a 100 mL round-bottom flask and stirred at room temperature for 2 hours. After LCMS monitoring, the reaction of the starting material was complete. Water was added, and the mixture was extracted with EA, washed with saturated NaCl solution, dried over anhydrous sodium sulfate, and prepared by HPLC to obtain the target compound 32i (76 mg).

[0820] LCMS (ESI-MS) m / z: 313.10 [M+H] + .

[0821] Synthesis of 2-chloro-6-(cyclopentyloxy)-4-(3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine 32j

[0822] Take 15 mL of sealed tube, add compound 32i (80 mg, 0.25 mmol), cyclopentanol (4.0 mL), NaH (24 mg, 0.60 mmol), protect with nitrogen, react at 80 ° C for 4 hours, monitor by LCMS, the reaction of raw materials was complete, directly freeze-dried the solvent, and purified by flash column to obtain the target compound 32j (47 mg).

[0823] LCMS (ESI-MS) m / z: 363.20 [M+H] + .

[0824] Synthesis of tert-butyl ((2-(6-(cyclopentyloxy)-4-(3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-3-oxo-7-(trifluoromethyl)isoindolin-5-yl)methyl)(1-methylcyclobutyl)carbamate 32k

[0825] A 15 mL sealed tube was added, and compound 32j (47 mg, 0.13 mmol), dioxane (3.0 mL), Pd2(dba)3 (18 mg, 0.020 mmol), Xantphos (15 mg, 0.026 mmol), tert-butyl (1-methylcyclobutyl)(3-oxo-7-(trifluoromethyl)isoindolin-5-yl)methyl)carbamate (52 mg, 0.13 mmol), and K3PO4 (55 mg, 0.26 mmol) were added. The mixture was protected by nitrogen and heated at 105°C for 2 hours. After LCMS monitoring, the reaction of the raw material was complete. The reaction was filtered and the solvent was dried. The reaction was prepared by HPLC to obtain the target compound 32k (75 mg).

[0826] LCMS (ESI-MS) m / z: 725.50 [M+H] + .

[0827] Synthesis of 2-(6-(cyclopentyloxy)-4-(3-methoxy-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-6-(((1-methylcyclobutyl)amino)methyl)-4-(trifluoromethyl)isoindol-1-one 32

[0828] Compound 32k (75 mg, 0.10 mmol), DCM (4.0 mL), and TFA (2.0 mL) were added to a 25 mL round-bottom flask and stirred at room temperature for 3 hours. After LCMS monitoring, the reaction of the starting material was complete. The solvent was dried and the mixture was prepared by HPLC to obtain the target compound 32 (16 mg).

[0829] LCMS (ESI-MS) m / z: 625.40 [M+H] + .

[0830] 1 H NMR(400MHz, DMSO-d6)δ8.36(s,1H),8.03(d,J=9.7Hz,2H),7.94(s,1H),6.53(s,1H),5.35–5.28(m,1H),5.19(s,2H),4.10(t,J=7.3Hz,1H), 3.81(s,2H),3.26(s,3H),3.17(s,3H),3.09–2.98(m,2H),2.86–2.77( m,2H),1.99(dd,J=12.1,7.7Hz,4H),1.88–1.51(m,11H),1.23(s,3H).

[0831] Example 33: Synthesis of Compound 33

[0832] Synthesis of methyl (2,6-dichloropyridin-4-yl)acetate 33b

[0833] 2,6-Dichloro-4-methylpyridine 33a (4.1 g, 25 mmol) was dissolved in anhydrous THF (100 mL). Under nitrogen protection, 25 mL of lithium diisopropylamide (50 mmol, 2.0 mol / L) was added in a dry ice bath at -70°C. The mixture was stirred in a dry ice bath for 0.5 hours. Dimethyl carbonate (5.3 mL, 63 mmol) was then added, and the reaction mixture was moved to an ice bath at 0°C and stirred for one hour. The reaction mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic phase was dried, filtered, and the filtrate was concentrated. The crude product was flash purified (PE:EA = 95:5) to afford compound 33b (4.9 g).

[0834] LCMS (ESI-MS) m / z: 220.00 [M+H] + .

[0835] Synthesis of methyl 1-(2,6-dichloropyridin-4-yl)-3-methylcyclobutane-1-carboxylate 33c

[0836] Compound 33b (4.9 g, 22 mmol) was dissolved in 25 mL of DMF, and 1,3-dibromo-2-methylpropane (5.3 mL, 44 mmol) was added dropwise. After the addition was complete, potassium phosphate (9.3 g, 44 mmol) was added. The mixture was reacted in an oil bath at 100°C for three hours. After cooling to room temperature, the mixture was extracted with ethyl acetate and washed with saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was flash purified (PE:EA = 95:5) to afford compound 33c (4.9 g).

[0837] LCMS (ESI-MS) m / z: 274.10 [M+H] + .

[0838] Synthesis of 1-(2,6-dichloropyridin-4-yl)-3-methylcyclobutane-1-carboxylic acid 33d

[0839] Compound 33c (4.9 g, 18 mmol) was dissolved in 10 mL of methanol, and lithium hydroxide (0.85 g, 36 mmol) was added. The mixture was stirred at room temperature for 12 hours. Dilute hydrochloric acid (1.0 mol / L) was added under ice-cooling to adjust the pH to between 3 and 4. The mixture was extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was used directly in the next reaction.

[0840] LCMS (ESI-MS) m / z: 260.00 [M+H] + .

[0841] Synthesis of [1-(2,6-dichloropyridin-4-yl)-3-methylcyclobutyl]{2-[(methylamino)sulfanylidenemethyl]ethazine}methanone 33e

[0842] Compound 33d (4.9 g, 19 mmol) and (ethylamino)(methylamino)thiomethanone (2.4 g, 23 mmol) were dissolved in DMF, and HATU (7.2 g, 19 mmol) was added. N,N-diisopropylethylamine (9.9 mL, 57 mmol) was added under ice-cooling, and the mixture was stirred at room temperature overnight. The mixture was washed with saturated brine and extracted four times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was used directly in the next reaction.

[0843] LCMS (ESI-MS) m / z: 347.10 [M+H] + .

[0844] Synthesis of 5-[1-(2,6-dichloropyridin-4-yl)-3-methylcyclobutyl]-4-methyl-1,2,4-triazacyclopentane-3-thiophenol 33f

[0845] Compound 33e (6.5 g, 19 mmol) was dissolved in ethanol (90 mL), and sodium bicarbonate (3.4 g, 40 mmol) and water (50 mL) were added. The mixture was heated to 80°C in an oil bath for two hours. The mixture was concentrated, washed with saturated brine, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was used directly in the next reaction.

[0846] LCMS (ESI-MS) m / z: 329.10 [M+H] + .

[0847] Synthesis of 33 g of 2,6-dichloro-4-[3-methyl-1-(4-methyl-1,2,4-triazacyclopentyl-3-yl)cyclobutyl]pyridine

[0848] Compound 33f (6.0 g, 18 mmol) was dissolved in DCM (40 mL), and acetic acid (2.0 mL) was added. 30% hydrogen peroxide (10 mL) was added in an ice bath. The mixture was stirred at room temperature overnight, quenched with saturated sodium sulfite solution, neutralized with sodium carbonate, and extracted with DCM. The organic phase was dried and concentrated, and the crude product was flash purified (DCM:MeOH = 98:2) to afford compound 33g (4.6 g).

[0849] LCMS (ESI-MS) m / z: 297.10 [M+H] + .

[0850] Synthesis of 2-chloro-6-methoxy-4-[3-methyl-1-(4-methyl-1,2,4-triazacyclopentan-3-yl)cyclobutyl]pyridine 33h

[0851] Compound 33g (0.30 g, 1.0 mmol) was dissolved in 10 mL of tetrahydrofuran, and a methanol solution of sodium methoxide (0.50 mL, 5.4 mol / L) was added dropwise in an ice bath. The mixture was stirred at room temperature overnight, quenched with water, and extracted with ethyl acetate. The organic phase was dried and concentrated, and the crude product was purified by flash chromatography (DCM:MeOH=97:3) to give compound 33h (0.27 g).

[0852] LCMS (ESI-MS) m / z: 293.20 [M+H] + .

[0853] Synthesis of 6-{[(3S)-3-methylhexahydropyridin-1-yl]methyl}-2-{6-methoxy-4-[3-methyl-1-(4-methyl-1,2,4-triazacyclopentan-3-yl)cyclobutyl]pyridin-2-yl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 33j

[0854] Compound 33h (270 mg, 0.93 mmol), compound 33i (290 mg, 0.93 mmol), Pd(OAc)2 (34 mg, 0.15 mmol), Xantphos (170 mg, 0.30 mmol) and Cs2CO3 (0.90 g, 2.8 mmol) were added to anhydrous 1,4-dioxane, and the mixture was stirred at 100°C under nitrogen protection in a stuffy pot for 4 hours, filtered through celite, and the filtrate was concentrated and purified by preparative HPLC to obtain compound 33j (270 mg, 0.47 mmol).

[0855] LCMS (ESI-MS) m / z: 569.40 [M+H] + .

[0856] Synthesis of 6-{[(3S)-3-methylhexahydropyridin-1-yl]methyl}-2-{6-methoxy-4-[(1R,3R)-3-methyl-1-(4-methyl-1,2,4-triazacyclopentan-3-yl)cyclobutyl]pyridin-2-yl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 33

[0857] Compound 33j (270 mg, 0.47 mmol) was purified by chiral-preparative HPLC (chiral column: AD-H 4.6*100 mm 5 μm mobile phase IPA [0.5% NH 3 (7 M in MeOH)]) to give compound 33 (70 mg, 0.12 mmol).

[0858] LCMS (ESI-MS) m / z: 569.40 [M+H] + .

[0859] 1 H NMR (400MHz, DMSO-d6) δ8.34 (s, 1H), 8.04 (d, J = 1.3Hz, 1H), 7.97 (s, 1H), 7.9 3(s,1H),6.58(d,J=1.3Hz,1H),5.22(s,2H),3.91(s,3H),3.65(s,2H),3.22( s,3H),2.85–2.78(m,2H),2.71(m,2H),2.61-2.54(m,3H),1.94(s,1H),1.72- 1.55(m,4H),1.54–1.41(m,1H),1.09(d,J=5.2Hz,3H),0.82(d,J=6.1Hz,4H).

[0860] Example 34: Synthesis of Compound 34

[0861] Synthesis of 3-bromo-1-trifluoroethyl-5-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]pyridin-2(1H)-one 34b

[0862] 3-Bromo-5-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]pyridin-2(1H)-one 34a (100 mg, 0.31 mmol), 2,2,2-trifluoroethyl trifluoromethanesulfonate (140 mg, 0.61 mmol), and cesium carbonate (400 mg, 1.2 mmol) were dissolved in anhydrous acetonitrile (50 mL), and the mixture was stirred at 80°C for 2 hours. The mixture was filtered, the filtrate was concentrated, and the crude product was flash purified (DCM:MeOH = 10:1) to give compound 34b (60 mg).

[0863] LCMS (ESI-MS) m / z: 405.10 [M+H] + .

[0864] Synthesis of (S)-2-(5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridin-3-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one 34c

[0865] Compound 34b (60 mg, 0.15 mmol), 6-{[(3R)-3-methylpiperidin-1-yl]methyl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one (47 mg, 0.15 mmol), Pd(OAc)2 (6.0 mg, 0.024 mmol), Xantphos (27 mg, 0.048 mmol) and cesium carbonate (78 mg, 0.24 mmol) were dispersed in anhydrous 1,4-dioxane. The mixture was stirred at 120°C under nitrogen protection for 2 hours, filtered, and the filtrate was purified by preparative HPLC to obtain compound 34c (22 mg).

[0866] LCMS (ESI-MS) m / z: 637.40 [M+H] + .

[0867] Synthesis of 6-{[(3S)-3-methylhexahydropyridin-1-yl]methyl}-2-{5-[(1S,3R)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]-2-oxo-1-(2,2,2-trifluoroethyl)pyridin-3-yl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 34

[0868] Compound 34c (2.1 g, 3.3 mmol) was prepared by chiral separation (chiral column: IH 4.6*100 mm 5 μm, mobile phase: MeOH [0.2% NH 3 (7.0 M in MeOH)]) to give compound 34 (1.2 g, 1.8 mmol).

[0869] LCMS (ESI-MS) m / z: 637.5 0 [M+H] + .

[0870] 1 H NMR (400MHz, Methanol-d4) δ8.34(s,1H),8.03(s,1H),7.96(s,1H),7.91(d,J=2.6Hz,1H),7.73(d,J=2.5Hz,1H),5.12(s,2H),4.94(d,J=8.7Hz,2 H),3.70(s,2H),3.48(d,J=1.3Hz,3H),2.92–2.77(m,4H),2.63(dt,J=14 .3,7.3Hz,1H),2.53(t,J=10.5Hz,2H),2.00(t,J=11.4Hz,1H),1.77–1.52 (m,5H),1.15(d,J=6.4Hz,3H),0.91(d,J=9.3Hz,1H),0.86(d,J=5.7Hz,3H).

[0871] Example 35: Synthesis of Compound 35

[0872] Synthesis of methyl 2-(2,6-dichloropyridin-4-yl)acetate 35b

[0873] Compound 35a (16 g, 100 mmol) was dissolved in THF (400 mL), and 2.0 M LDA (100 mL, 200 mL) was added dropwise at -78°C under nitrogen. Stirring was continued at this temperature for 30 minutes, followed by the dropwise addition of a solution of dimethyl carbonate (18 g, 200 mmol) in THF (72 mL). The mixture was stirred at -78°C for 1 hour, then raised to 0°C and stirred for 2 hours. After completion of the reaction, the mixture was quenched with ammonium chloride solution, extracted with ethyl acetate, concentrated under reduced pressure, and purified by silica gel column (0-5% EA / PE) to give compound 35b (4.5 g).

[0874] LCMS (ESI-MS) m / z: 220.00 [M+H] + .

[0875] Synthesis of methyl 1-(2,6-dichloropyridin-4-yl)-3-methylcyclobutane-1-carboxylate 35c

[0876] Compound 35b (4.5 g, 21 mmol), 1,3-dibromo-2-methylpropane (8.3 g, 41 mmol), and potassium phosphate (8.5 g, 41 mmol) were dissolved in DMF (20 mL) and stirred at 100°C for 6 hours. After the reaction was complete, the mixture was quenched with water, extracted with ethyl acetate, concentrated under reduced pressure, and purified on a silica gel column (0-5% EA / PE) to give compound 35c (2.5 g).

[0877] LCMS (ESI-MS) m / z: 274.10 [M+H] + .

[0878] Synthesis of 1-(2,6-dichloropyridin-4-yl)-3-methylcyclobutane-1-carboxylic acid 35d

[0879] Compound 35c (2.5 g, 9.1 mmol) and lithium hydroxide (0.79 g, 27 mmol) were dissolved in methanol (11 mL) and water (11 mL) and stirred at room temperature overnight. After the reaction was complete, the pH was adjusted to 3-4 with 1.0 M hydrochloric acid solution, followed by extraction with DCM, drying, filtration, and concentration under reduced pressure to afford crude compound 35d (2.4 g).

[0880] LCMS (ESI-MS) m / z: 260.10 [M+H] + .

[0881] Synthesis of 2-(1-(2,6-dichloropyridin-4-yl)-3-methylcyclobutane-1-carbonyl)hydrazine-1-carbothioamide 35e

[0882] Compound 35d (2.4 g, 9.1 mmol), thiosemicarbazide (1.2 g, 14 mmol), HATU (5.2 g, 14 mmol), and DIPEA (3.5 g, 27 mmol) were dissolved in DMF (12 mL) under nitrogen and stirred overnight at room temperature. After the reaction was complete, the mixture was extracted with DCM, dried, filtered, and concentrated under reduced pressure to afford crude compound 35e (4.5 g).

[0883] LCMS (ESI-MS) m / z: 333.10 [M+H] + .

[0884] Synthesis of 5-(1-(2,6-dichloropyridin-4-yl)-3-methylcyclobutyl)-4H-1,2,4-triazole-3-thiol 35f

[0885] Crude compound 35e (4.5 g) and sodium bicarbonate (2.9 g, 34 mmol) were dissolved in ethanol (11 mL) and water (11 mL) and stirred at 70° C. for 8 hours. After the reaction was completed, the mixture was extracted with DCM, dried, filtered, and concentrated under reduced pressure to obtain crude compound 35f (3.3 g).

[0886] LCMS (ESI-MS) m / z: 315.10 [M+H] + .

[0887] Synthesis of 35 g of 2,6-dichloro-4-(3-methyl-1-(4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine

[0888] Compound 35f (3.2 g), acetic acid (10 mL), DCM (10 mL), and 30% hydrogen peroxide solution (2.5 mL) were added sequentially to a reaction flask and stirred at room temperature overnight. After completion of the reaction, saturated sodium sulfite was added and stirred for 1 hour. The pH was then adjusted to 7-8 with 10% sodium hydroxide solution, extracted with DCM, dried, filtered, concentrated under reduced pressure, and purified on a silica gel column (0-30% EA / PE) to afford compound 35g (700 mg).

[0889] LCMS (ESI-MS) m / z: 283.10 [M+H] + .

[0890] Synthesis of 2-chloro-6-ethoxy-4-(3-methyl-1-(4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine 35h

[0891] Compound 35g (600 mg, 2.1 mmol) and sodium ethoxide (580 mg, 8.5 mmol) were dissolved in ethanol (18 mL). The reaction solution was stirred at 80°C for 60 hours. After completion of the reaction, the mixture was cooled to room temperature. The ethanol was removed under reduced pressure, and the concentrated solid was dissolved in dichloromethane and methanol (10:1). The solution was filtered to obtain crude compound 35h (530 mg).

[0892] LCMS (ESI-MS) m / z: 293.20 [M+H] + .

[0893] Synthesis of 2-chloro-4-(1-(4-(difluoromethyl)-4H-1,2,4-triazol-3-yl)-3-methylcyclobutyl)-6-ethoxypyridine 35i

[0894] Compound 35h (200 mg, 0.68 mmol), sodium chlorodifluoroacetate (160 mg, 1.0 mmol), and cesium carbonate (340 mg, 1.0 mmol) were dissolved in DMF (4 mL) under nitrogen, and the reaction solution was stirred at 80°C for 8 hours. After the reaction was complete, the mixture was extracted with ethyl acetate, and the organic phase was washed with water, dried, filtered, and concentrated under reduced pressure to give crude compound 35i (210 mg).

[0895] LCMS (ESI-MS) m / z: 343.20 [M+H] + .

[0896] Synthesis of (S)-2-(4-(1-(4-(difluoromethyl)-4H-1,2,4-triazol-3-yl)-3-methylcyclobutyl)-6-ethoxypyridin-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one 35

[0897] Compound 35i (100 mg, 0.29 mmol), compound 35j (150 mg, 0.48 mmol), palladium acetate (13 mg, 0.060 mmol), Xantphos (51 mg, 0.090 mmol), and cesium carbonate (290 mg, 0.88 mmol) were dissolved in 1,4-dioxane (4.0 mL) and stirred at 120°C under nitrogen for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, concentrated under reduced pressure, filtered, and purified by prep-HPLC to obtain compound 35 (40 mg).

[0898] LCMS (ESI-MS) m / z: 619.50 [M+H] + .

[0899] 1H NMR(400MHz,DMSO-d6)δ8.96(s,1H),7.98(d,J=1.4Hz,1H),7.94(s,1H),7.90(s,1H),6.61(d,J=1.3Hz,1H),5 .17(d,J=6.5Hz,2H),4.34(qd,J=7.0,2.2Hz,2H),3.62(s,2H),3.08(t,J=8.5Hz,1H),2.82(d,J=3.9Hz,1H),2. 69(t,J=8.9Hz,2H),2.56(d,J=6.8Hz,2H),2.34–2.25(m,1H),1.91(t,J=10.9Hz,1H),1.69–1.53(m,4H),1.47( t,J=12.1Hz,1H),1.35(td,J=7.1,0.9Hz,3H),1.21(s,1H),1.07(dd,J=7.5,5.3Hz,3H),0.80(d,J=6.0Hz,3H).

[0900] Example 36: Synthesis of Compound 36

[0901] Synthesis of 8-bromo-6-(bromomethyl)quinoline 36b

[0902] Compound 36a (10 g, 45 mmol), NBS (12 g, 68 mmol), and AIBN (0.74 g, 4.5 mmol) were dissolved in chlorobenzene (30 mL) and reacted in an oil bath at 70°C for 4 h. After the reaction was complete, water was added, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by flash column chromatography (DCM / MeOH, 0-5%) to afford compound 36b (12 g).

[0903] LCMS (ESI-MS) m / z: 302.00 [M+H] + .

[0904] Synthesis of (8-bromoquinolin-6-yl)acetonitrile 36c

[0905] Compound 36b (12 g, 40 mmol), lithium hydroxide (1.9 g, 80 mmol), and TMSCN (8.0 g, 80 mmol) were dissolved in acetonitrile (30 mL) and reacted at room temperature for 4 hours. After the reaction was complete, the mixture was filtered, concentrated, and purified on a flash column (PE / EA, 0-30%) to obtain compound 36c (1.9 g).

[0906] LCMS (ESI-MS) m / z: 249.10 [M+H] +

[0907] Synthesis of 1-(8-bromoquinolin-6-yl)-3-methylcyclobutane-1-carbonitrile 36d

[0908] Compound 36c (1.9 g, 7.7 mmol), 1,3-dibromo-2-methylpropane (3.3 g, 15 mmol), and potassium phosphate (3.3 g, 15 mmol) were dissolved in DMF (12 mL) and heated in an oil bath at 100°C for 4 h. After the reaction was complete, water was added, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The mixture was then purified by flash column chromatography (PE / EA, 0-20%) to afford compound 36d (840 mg).

[0909] LCMS (ESI-MS) m / z: 303.10 [M+H] + .

[0910] Synthesis of 1-(8-bromoquinolin-6-yl)-3-methylcyclobutane-1-carboxylic acid 36e

[0911] Compound 36d (840 mg, 2.8 mmol) was dissolved in concentrated hydrochloric acid (4.0 mL) and heated in an oil bath at 100°C for 2 h. After the reaction was complete, the mixture was adjusted to a weakly acidic state by adding saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified on a flash column (DCM / MeOH, 0-5%) to afford compound 36e (450 mg).

[0912] LCMS (ESI-MS) m / z: 322.10 [M+H] + .

[0913] Synthesis of [1-(8-bromoquinolin-6-yl)-3-methylcyclobutyl]{2-[(methylamino)thioxomethyl]diazaalkyl}methanone 36f

[0914] Compound 36e (450 mg, 1.4 mmol), (diazanyl)(methylamino)thiomethanone (220 mg, 2.1 mmol), DIEA (540 mg, 4.2 mmol), and HATU (580 mg, 1.5 mmol) were dissolved in DMF (8.0 mL) and reacted at room temperature for 2 h. After the reaction was complete, water was added, the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated to afford crude compound 36f.

[0915] LCMS (ESI-MS) m / z: 409.20 [M+H] + .

[0916] Synthesis of 36 g of 5-[1-(8-bromoquinolin-6-yl)-3-methylcyclobutyl]-4-methyl-4H,3H,5H-1,2,4-triazole-3-thione

[0917] Compound 36f (450 mg, 1.1 mmol) was dissolved in THF (2.0 mL), and 1.0 M aqueous sodium hydroxide solution (3.0 mL) was added. The mixture was reacted in an oil bath at 100°C for 4 h. After the reaction was complete, the pH was adjusted to a weakly acidic state with dilute hydrochloric acid. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield crude compound 36g.

[0918] LCMS (ESI-MS) m / z: 391.10 [M+H] + .

[0919] Synthesis of 8-bromo-6-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]quinoline 36h

[0920] Compound 36g (220 mg, 0.56 mmol) and sodium nitrite (390 mg, 5.6 mmol) were dissolved in ethyl acetate (2.0 mL). Dilute nitric acid (3.0 mL) was added and the mixture was allowed to react in an ice-water bath for 2 h. After the reaction was complete, saturated sodium bicarbonate solution was added to neutralize the mixture. The mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and purified on a flash column (DCM / MeOH, 0-10%) to afford compound 36h (150 mg).

[0921] LCMS (ESI-MS) m / z: 359.20 [M+H] + .

[0922] Synthesis of 6-{[(3S)-3-methylhexahydropyridin-1-yl]methyl}-2-{6-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]quinolin-8-yl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 36

[0923] Compound 36h (80 mg, 0.23 mmol), compound 6-{[(3S)-3-methylhexahydropyridin-1-yl]methyl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one (110 mg, 0.35 mmol), palladium acetate (10 mg, 0.050 mmol), Xantphos (53 mg, 0.090 mmol), and cesium carbonate (230 mg, 0.69 mmol) were dissolved in dioxane (5.0 mL) and placed in an oil bath at 110° C. under an inert atmosphere for 4 h. After the reaction was complete, water was added, extracted with dichloromethane, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 36 (34 mg) from the liquid phase.

[0924] LCMS (ESI-MS) m / z: 589.50 [M+H] + .

[0925] 1 H NMR (400MHz, DMSO-d6) δ8.86(td,J=4.5,1.7Hz,1H),8.49(td,J=8.2,1.8Hz,1H),8.31(s,1H),8.14(d,J=2.2Hz,1H),7.99(s,1H),7.92(s,1H),7 .78(d,J=2.1Hz,1H),7.60(ddd,J=8.4,6.5,4.2Hz,1H),5.32(s,2H),3. 66(s,2H),3.26(d,J=13.1Hz,3H),3.04–2.88(m,2H),2.78–2.54(m,4H), 2.38(d,J=6.8Hz,1H),1.98–1.86(m,1H),1.68–1.41(m,5H),1.09(d,J=5.3Hz,3H),0.80(d,J=5.9Hz,4H).

[0926] Example 37: Synthesis of Compound 37

[0927] Synthesis of 3-bromo-5-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]-1-(2,2,3,3,3-pentafluoropropyl)-1,2-dihydropyridin-2-one 37b

[0928] 3-Bromo-5-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]pyridin-2(1H)-one 36a (50 mg, 0.14 mmol), 2,2,3,3,3-pentafluoropropyl trifluoromethanesulfonate (79 mg, 0.28 mmol), and cesium carbonate (140 mg, 0.42 mmol) were dissolved in anhydrous acetonitrile (50 mL), and the mixture was stirred at 100°C for 2 hours. The mixture was filtered, the filtrate was concentrated, and the crude product was flash purified (DCM:MeOH = 10:1) to give compound 36b (40 mg).

[0929] LCMS (ESI-MS) m / z: 457.20 [M+H] + .

[0930] Synthesis of 6-{[(3S)-3-methylhexahydropyridin-1-yl]methyl}-2-{5-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]-2-oxo-1-(2,2,3,3,3-pentafluoropropyl)pyridin-3-yl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 37

[0931] Compound 36b (40 mg, 0.080 mmol), 6-{[(3R)-3-methylpiperidin-1-yl]methyl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one (27 mg, 0.080 mmol), Pd(OAc)2 (3.6 mg, 0.016 mmol), Xantphos (18 mg, 0.032 mmol) and cesium carbonate (52 mg, 0.16 mmol) were dispersed in anhydrous 1,4-dioxane. The mixture was stirred at 120°C under nitrogen protection for 2 hours, filtered, and the filtrate was purified by preparative HPLC to obtain compound 36 (4.7 mg).

[0932] LCMS (ESI-MS) m / z: 687.50 [M+H] + .

[0933] 1 H NMR(400MHz, Methanol-d4)δ8.35(s,1H),8.05(s,1H),7.98(s,1H),7.88(d,J=2.6Hz,1H),7 .75(d,J=2.6Hz,1H),5.12(d,J=1.6Hz,2H),5.01(t,J=15.2Hz,2H),3.78(s,2H),3.49(s,2H) ,2.87(d,J=10.5Hz,4H),2.63(dd,J=15.2,7.7Hz,1H),2.54(t,J=10.2Hz,2H),2.10(t,J=11. 5Hz,1H),1.85–1.57(m,6H),1.15(d,J=6.4Hz,3H),0.96–0.93(m,1H),0.88(d,J=6.3Hz,3H).

[0934] Example 38: Synthesis of Compound 38

[0935] Synthesis of 2-{6-[(2,2-difluoroethyl)oxy]-4-[3-methyl-1-(4-methyl-1,2,4-triazacyclopentan-3-yl)cyclobutyl]pyridin-2-yl}-6-{[(3S)-3-methylhexahydropyridin-1-yl]methyl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 38c

[0936] Compound 38a (2.6 g, 8.2 mmol) and 2-chloro-6-[(2,2-difluoroethyl)oxy]-4-[3-methyl-1-(4-methyl-1,2,4-triazacyclopentan-3-yl)cyclobutyl]pyridine 38b (2.9 g, 8.6 mmol) were dissolved in 1,4-dioxane (40 mL). Palladium acetate (0.27 g, 1.2 mmol), Xantphos (0.94 g, 1.6 mmol), and Cs2CO3 (6.7 g, 20 mmol) were added. The mixture was sealed under nitrogen and reacted at 110°C for 6 h. The reaction was complete and the sample was then removed. The product was filtered through Celite and dried. The residue was purified by silica gel flash chromatography (DCM:MeOH = 9:1) and then by HPLC to obtain compound 38c (2.4 g, 3.9 mmol).

[0937] LCMS (ESI-MS) m / z: 619.50 [M+H] + .

[0938] Synthesis of 2-{6-[(2,2-difluoroethyl)oxy]-4-[(1S,3R)-3-methyl-1-(4-methyl-1,2,4-triazacyclopentan-3-yl)cyclobutyl]pyridin-2-yl}-6-{[(3S)-3-methylhexahydropyridin-1-yl]methyl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 38

[0939] Compound 38c (2.4 g, 3.9 mmol) was purified by chiral-preparative HPLC: chiral column: 0.46 cm ID×15 cm L, mobile phase: MeOH / DEA=100 / 0.1 (V / V) to obtain compound 38 (1.5 g, 2.4 mmol).

[0940] LCMS (ESI-MS) m / z: 619.50 [M+H] + .

[0941] 1H NMR (400MHz, DMSO-d6) δ8.35(s,1H),8.08(d,J=1.2Hz,1H),7.96(s,1H),7.94(s,1H),6.72( d,J=1.4Hz,1H),6.49(tt,J=54.3,3.3Hz,1H),5.23(s,2H),4.63(td,J=15.0,3.5Hz,2H),3. 64(s,2H),3.23(s,3H),2.90-2.76(m,2H),2.75-2.65(m,2H),2.57(d,J=6.9Hz,3H),1.97–1 .87(m,1H),1.70–1.53(m,4H),1.53-1.40(m,1H),1.15–1.03(m,3H),0.81(d,J=5.8Hz,4H).

[0942] Example 39: Synthesis of Compound 39

[0943] Synthesis of methyl 4-bromo-1-toluenesulfonyl-1H-indole-6-carboxylate 39b

[0944] Compound 39a (5.0 g, 20 mmol) was dissolved in DMF (50 mL), and NaH (940 mg, 60%, 24 mmol) was added. The mixture was stirred at room temperature for 1 hour, followed by the addition of p-toluenesulfonyl chloride (4.5 g, 24 mmol). The mixture was stirred at room temperature for 2 hours. After TLC monitoring, the reaction was quenched with saturated aqueous ammonium chloride and extracted with EA. The organic phase was dried and concentrated, and the residue was purified on silica gel (EA / PE = 30%) to obtain compound 39b (5.8 g).

[0945] LCMS (ESI-MS) m / z: 408.10 [M+H] + .

[0946] Synthesis of (4-bromo-1-tosyl-1H-indol-6-yl)methanol 39c

[0947] Compound 39b (5.8 g, 14 mmol) and anhydrous THF (60 mL) were added sequentially to a single-necked flask. At -50°C, under nitrogen, DIBAL-H (40 mL, 1.0 M hexane solution, 40 mmol) was added dropwise. The temperature was slowly warmed to room temperature and stirred for 3 hours. LCMS confirmed the completion of the reaction, yielding the title compound. The reaction was quenched with dilute hydrochloric acid (1.0 M) at 0°C, and the pH was monitored until it reached 6-7. The product was extracted three times with DCM. The organic phase was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by Flash chromatography to afford compound 39c (4.8 g).

[0948] LCMS (ESI-MS) m / z: 362.10 [M-17] + .

[0949] Synthesis of (4-bromo-1-toluenesulfonyl-1H-indol-6-yl)methyl-4-methylbenzenesulfonate 39d

[0950] To a single-necked flask, compound 39c (4.8 g, 13 mmol), THF (130 mL), TsCl (7.2 g, 38 mmol), and KOH (7.1 g, 130 mmol) were added sequentially. The mixture was allowed to react at room temperature overnight. LCMS was used to monitor the reaction. Upon completion, the mixture was filtered, washed with THF, and the filtrate was concentrated. The residue was purified on flash silica gel (EA / PE = 0-30%) to afford compound 39d (3.8 g).

[0951] LCMS (ESI-MS) m / z: 556.00 [M+Na] + .

[0952] Synthesis of 2-(4-bromo-1-toluenesulfonyl-1H-indol-6-yl)acetonitrile 39e

[0953] To a single-necked flask, compound 39d (4.5 g, 16 mmol) and THF (26 mL) were added sequentially, followed by TMSCN (2.1 g) and TBAF (1.0 M in THF, 21 mL). The mixture was reacted at 35°C under nitrogen for 6 hours. LCMS confirmed the reaction was complete. The mixture was cooled to room temperature, and EA and water were added. The layers were separated, and the organic phase was concentrated. The residue was purified by flash chromatography (EA / PE = 0-23%) to afford compound 39e (2.4 g).

[0954] LCMS (ESI-MS) m / z: 389.10 [M+H] + .

[0955] Synthesis of methyl 2-(4-bromo-1-toluenesulfonyl-1H-indol-6-yl)acetate 39f

[0956] To a single-necked flask, compound 39e (1.0 g, 2.6 mmol) and methanol (12 mL) were added followed by TMSCl (2.0 mL, 15 mmol). The mixture was heated at 65°C for 12 h. After completion of the reaction, LCMS was performed. Water was added, and the mixture was extracted with EA. The mixture was washed once with a saturated aqueous NaHCO3 solution and once with brine. The organic phase was dried and concentrated, and the residue was purified by Flash chromatography (EA / PE = 0-60%) to give compound 39f (900 mg).

[0957] LCMS (ESI-MS) m / z: 424.10 [M+H] + .

[0958] Synthesis of methyl 1-(4-bromo-1-toluenesulfonyl-1H-indol-6-yl)-3-methylcyclobutane-1-carboxylate 39h

[0959] To a three-necked flask, NaH (170 mg, 60%, 4.3 mmol) and anhydrous DMF (9.0 mL) were added. Under nitrogen, 39f (900 mg, 2.1 mmol) and 39g (460 mg, 2.1 mmol) in anhydrous DMF (2.0 mL) were added dropwise at 0°C and stirred overnight at room temperature. LCMS analysis indicated that the reaction was complete and quenched with saturated aqueous ammonium chloride. The organic phase was extracted with EA, dried, and concentrated. The residue was purified on silica gel (EA / PE = 0-80%) to afford compound 39h (920 mg).

[0960] LCMS (ESI-MS) m / z: 478.10 [M+H] + .

[0961] Synthesis of 1-(4-bromo-1-toluenesulfonyl-1H-indol-6-yl)-3-methylcyclobutane-1-carboxylic acid hydrazide 39i

[0962] Compound 39h (920 mg, 1.9 mmol) was dissolved in EtOH / THF (6.0 mL / 6.0 mL) and hydrazine hydrate (80%) (10 mL) was added. The mixture was heated at 85°C for 24 hours and sent to LCMS for detection. After completion of the reaction, the mixture was concentrated and the residue was purified with silica gel (MeOH / DCM = 0-12%) to obtain compound 39i (830 mg).

[0963] LCMS (ESI-MS) m / z: 476.20 [M+H] + .

[0964] Synthesis of 5-(1-(4-bromo-1-tosyl-1H-indol-6-yl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol 39k

[0965] Compound 39i (830 mg, 1.8 mmol) was dissolved in ethanol (12 mL), and methyl isothiocyanate 39j (140 mg, 1.9 mmol) was added. The mixture was stirred at 80°C for 2 hours. NaHCO₃ (1.0 M in H₂O, 5.3 mL) was added to the reaction solution, and stirring was continued at 80°C for 3 hours. LCMS monitoring indicated a good reaction. The mixture was cooled, and 10 mL of brine was added. The mixture was then extracted three times with DCM. The organic phase was concentrated to afford crude product 39k, which was used directly in the next step.

[0966] LCMS (ESI-MS) m / z: 531.20 [M+H] + .

[0967] Synthesis of 4-bromo-6-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-1-toluenesulfonyl-1H-indole 391

[0968] Compound 39k (1.8 mmol) was dissolved in DCM (10 mL) and HOAc (210 mg) and H₂O₂ (30%, 990 mg) were added. The mixture was allowed to react at room temperature for 2 hours. After LCMS analysis, the reaction was quenched by adding an aqueous sodium sulfite solution (1.5 eq.) until the color did not turn blue on starch potassium iodide paper. The organic phase was separated and washed with brine. The organic phase was dried, filtered, and concentrated. The residue was purified on silica gel flash chromatography (0-40% (25% EtOH / EA) / PE) to afford compound 39l (560 mg).

[0969] LCMS (ESI-MS) m / z: 501.20 [M+H] + .

[0970] Synthesis of (S)-2-(6-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-1-tosyl-1H-indol-4-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(difluoromethyl)isoindol-1-one 39n

[0971] A sealed tube was taken and compound 39l (300 mg, 0.60 mmol), 39m (210 mg, 0.66 mmol), Pd(OAc)2 (27 mg, 0.12 mmol), Xantphos (69 mg, 0.12 mmol), Cs2CO3 (390 mg, 1.2 mmol), and dioxane (8.0 mL) were added in sequence under N2 protection. The reaction was heated at 100°C for 3 hours and detected by LCMS. After the reaction was completed, the product was cooled and filtered through celite, washed with 1,4-dioxane, and the filtrate was concentrated. The residue was purified by silica gel flash chromatography (0-40% (25% EtOH / EA) / PE, MeOH / DCM = 0-12%) to give compound 39n (140 mg).

[0972] LCMS (ESI-MS) m / z: 713.80 [M+H] + .

[0973] Synthesis of 4-(difluoromethyl)-6-{[(3S)-3-methylhexahydropyridin-1-yl]methyl}-2-{6-[(1S,3R)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]-1H-indol-4-yl}-2,3-dihydro-1H-isoindol-1-one 39

[0974] Compound 39n (70 mg, 0.095 mmol) was dissolved in MeOH (2.0 mL), and potassium carbonate (80 mg, 0.58 mmol) was added. The mixture was stirred at 50°C for 4 hours and sent to LCMS for detection. After the reaction was completed, the mixture was filtered, the filtrate was concentrated, and purified by preparative thin layer chromatography (MeOH / DCM = 10%) to give compound 39 (5.9 mg).

[0975] LCMS (ESI-MS) m / z: 559.50 [M+H] + .

[0976] 1 H NMR (400MHz, DMSO-d6) δ11.17(s,1H),8.26(s,1H),7.84(s,1H),7.75(s,1H),7.38(d,J=17.8Hz,1H), 7.25(d,J=12.2Hz,2H),7.11(d,J=12.0Hz,1H),6.38(s,1H),5.12(s,2H),3.61(s,2H),3.25(s,2H),3 .21(s,2H),2.88(s,1H),2.72(s,2H),2.56(d,J=11.3Hz,2H),2.28(d,J=11.6Hz,1H),2.02–1.87(m,2H),1.62(d,J=11.7Hz,2H),1.22(s,3H),1.09(t,J=6.2Hz,3H),0.81(d,J=5.9Hz,3H). Example 40: Synthesis of Compound 40

[0977] Synthesis of methyl 4-bromo-1-(4-toluene-1-sulfonyl)-1H-indazole-6-carboxylate 40b

[0978] Compound 40a (9.0 g, 35 mmol) was dissolved in THF (100 mL), and NaH (1.7 g, 60%, 42 mmol) was added at 0°C. After stirring for 1 hour, TsCl (8.0 g, 42 mmol) was added. The reaction mixture was stirred at room temperature overnight, quenched by adding saturated ammonium chloride solution, and extracted twice with ethyl acetate. The organic phase was dried and concentrated to obtain the crude product. The residue was purified on silica gel (EA / PE = 0-20%) to obtain compound 40b (14 mg).

[0979] LCMS (ESI-MS) m / z: 410.00 [M+H] + .

[0980] Synthesis of [4-bromo-1-(4-toluene-1-sulfonyl)-1H-indazol-6-yl]methanol 40c

[0981] Compound 40b (14 g, 34 mmol) was dissolved in THF (150 mL). DIBAL-H (51 mL, 2.0 M solution in hexane, 100 mmol) was added under nitrogen at -50°C. The temperature was slowly raised to room temperature and stirred for 3 hours. After completion of the reaction, the mixture was quenched with dilute hydrochloric acid (1.0 M), and the pH was monitored at 6-7. The mixture was extracted three times with dichloromethane. The organic phase was dried and concentrated to give the crude product. The residue was purified on silica gel (EA / PE = 0-25%) to give compound 40c (12 g).

[0982] LCMS (ESI-MS) m / z: 382.00 [M+H] + .

[0983] Synthesis of (4-bromo-1-toluenesulfonyl-1H-indazol-6-yl)methyl-4-methylbenzenesulfonate 40d

[0984] Compound 40c (12 g, 32 mmol) was dissolved in THF (300 mL), and TsCl (18 g, 95 mmol) and KOH (18 g, 320 mmol) were added. The mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was filtered and washed with THF. The filtrate was concentrated and the residue was purified with silica gel (EA / PE = 0-30%) to obtain compound 40d (16 g).

[0985] LCMS (ESI-MS) m / z: 536.00 [M+H] + .

[0986] Synthesis of [4-bromo-1-(4-toluene-1-sulfonyl)-1H-indazol-6-yl]acetonitrile 40e

[0987] Compound 40d (16 g, 30 mmol) was dissolved in CH3CN (100 mL), and TMSCN (5.9 g, 60 mmol) and LiOH (2.2 g, 90 mmol) were added at 0°C, and the mixture was stirred at 0°C for 3 hours. After the reaction was complete, water (200 mL) was added, and the mixture was extracted three times with ethyl acetate (200 mL). The organic phase was dried and concentrated, and the residue was purified with silica gel (EA / PE = 0-25%) to give compound 40e (7.5 g).

[0988] LCMS (ESI-MS) m / z: 391.00 [M+H] + .

[0989] Synthesis of Methyl (4-Bromo-1H-indazol-6-yl) Acetate 40f

[0990] Compound 40e (7.5 g, 19 mmol) was dissolved in methanol (40 mL), and thionyl chloride (23 g, 190 mmol) was added dropwise under ice-cooling. After completion of the addition, the temperature was raised to 65°C and stirred for 8 hours. After cooling and drying, ethyl acetate and saturated NaHCO₃ solution were added to the residue, and the liquids were separated by extraction. The organic phase was washed with saturated brine, dried, and concentrated. The residue was purified on silica gel (EA / PE = 0-30%) to obtain compound 40f (4.5 g).

[0991] LCMS (ESI-MS) m / z: 270.00 [M+H] + .

[0992] Synthesis of 40 g of methyl [4-bromo-1-(4-toluene-1-sulfonyl)-1H-indazol-6-yl] acetate

[0993] Compound 40f (4.5 g, 17 mmol) was dissolved in DMF (20 mL). TsCl (4.8 g, 25 mmol) and potassium carbonate (4.6 g, 33 mmol) were added under ice-cooling. The mixture was stirred overnight at room temperature and analyzed by LCMS. The reaction was complete. The reaction solution was poured into water and extracted twice with dichloromethane. The organic phase was dried and spin-dried. The residue was purified on silica gel flash chromatography (EA / PE = 0-20%) to obtain compound 40g (4.0 g).

[0994] LCMS (ESI-MS) m / z: 424.00 [M+H] + .

[0995] Synthesis of methyl 1-(4-bromo-1-toluenesulfonyl-1H-indazol-6-yl)-3-methylcyclobutane-1-carboxylate

[0996] To a single-necked flask, NaH (760 mg, 60%, 19 mmol) and DMF (6.0 mL) were added. A solution of 40 g (4.0 g, 9.5 mmol) and 1,3-dibromo-2-methylpropane (3.1 g, 14 mmol) in DMF (10 mL) was then added at 0°C, and the mixture was stirred at 0°C for 2 hours. The mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EA. The organic phase was dried and spin-dried, and the residue was purified on silica gel flash chromatography (EA / PE = 0-25%) to afford compound 40h (1.7 g).

[0997] LCMS (ESI-MS) m / z: 478.00 [M+H] + .

[0998] Synthesis of 1-(4-bromo-1H-indazol-6-yl)-3-methylcyclobutane-1-carbohydrazide 40i

[0999] Compound 40h (1.3 g, 2.7 mmol) was dissolved in EtOH / THF (10 mL / 10 mL), hydrazine hydrate (12 mL) was added, and the mixture was stirred at 80°C for 8 hours. After cooling, the mixture was spin-dried and the residue was purified by silica gel flash chromatography (0-10% MeOH / DCM) to give compound 40i (650 mg).

[1000] LCMS (ESI-MS) m / z: 324.00 [M+H] + .

[1001] Synthesis of 5-[1-(4-bromo-1H-indazol-6-yl)-3-methylcyclobutyl]-4-methyl-4H-1,2,4-triazole-3-thiol 40j

[1002] Compound 40i (650 mg, 2.0 mmol) was dissolved in ethanol (10 mL), and methyl isothiocyanate (180 mg, 2.4 mmol) was added. The mixture was reacted at 80°C for 2 hours. NaHCO₃ (1.0 M in H₂O, 6.0 mL) was added to the reaction solution, and the reaction was continued at 80°C for 2 hours. The mixture was analyzed by LCMS. Upon completion of the reaction, water (10 mL) was added, and the mixture was extracted three times with dichloromethane. The organic phase was dried, filtered, and concentrated to afford crude product 40j, which was used directly in the next step.

[1003] LCMS (ESI-MS) m / z: 379.00 [M+H] +

[1004] Synthesis of 4-bromo-6-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]-1H-indazole 40k

[1005] Compound 40j (2.0 mmol) was dissolved in dichloromethane (10 mL), and HOAc (360 mg) and H₂O₂ (30%, 1.0 mL) were added. The mixture was allowed to react at room temperature for 1 hour. After LCMS analysis, an aqueous sodium sulfite solution (1.5 eq) was added to quench the reaction. The organic phase was separated and washed with brine. The organic phase was dried, filtered, and concentrated. The residue was purified on silica gel flash chromatography (0-10% MeOH / DCM) to afford compound 40k (300 mg).

[1006] LCMS (ESI-MS) m / z: 347.00 [M+H] + .

[1007] Synthesis of 6-{[(3S)-3-methylhexahydropyridin-1-yl]methyl}-2-{6-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]-1H-indol-4-yl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 40

[1008] Take a sealed tube and add compound 40k (100 mg, 0.29 mmol), 40l (90 mg, 0.29 mmol), Pd(OAc)2 (7.0 mg, 0.030 mmol), Xantphos (35 mg, 0.060 mmol), Cs2CO3 (190 mg, 0.58 mmol), dioxane (6.0 mL) in sequence under N2 protection. Seal the tube and heat at 120°C for 3 hours. Send to LCMS for detection. After the reaction is complete, cool and filter on celite, wash with 1,4-dioxane, and concentrate the filtrate. The residue is purified by silica gel flash chromatography (MeOH / DCM = 0-10%) to give the crude product, which is further purified by pre-HPLC to give compound 40 (3.7 mg).

[1009] LCMS (ESI-MS) m / z: 578.50 [M+H] + .

[1010] 1H NMR(400MHz, Methanol-d4)δ8.34(d,J=27.0Hz,1H),8.19–8.08(m,2H),8.03(s,1H),7.53(d,J=84.4Hz, 1H),7.24(dd,J=48.4,1.3Hz,1H),5.27(s,2H),3.88(s,2H),3.35(d,J=5.1Hz,3H),3.25–3.14(m,1H),3 .09–2.89(m,4H),2.67(dq,J=11.0,8.6Hz,2H),2.52–2.38(m,1H),2.20(t,J=11.6Hz,1H),1.91(t,J=10 .9Hz,1H),1.81–1.56(m,4H),1.17(d,J=6.0Hz,3H),0.98(dd,J=12.5,4.1Hz,1H),0.90(d,J=6.4Hz,3H).

[1011] Example 41: Synthesis of Compound 41

[1012] Synthesis of methyl 2-(2-chloro-6-methylpyridin-4-yl)acetate 41b

[1013] Compound 41a (5.0 g, 35 mmol) was dissolved in THF (120 mL). LDA (31 mL, 2.0 M, 62 mmol) was slowly added dropwise at -78°C under nitrogen and stirred at this temperature for 30 minutes. A solution of dimethyl carbonate (6.7 g, 74 mmol) in THF (15 mL) was added. After the addition was complete, the temperature was slowly raised to 0°C and stirred at this temperature for 2 hours. The mixture was washed sequentially with saturated sodium bicarbonate solution and brine. The organic phase was dried and concentrated, and the residue was purified using silica gel (EA / PE = 0-6%) to afford compound 41b (4.0 g).

[1014] LCMS (ESI-MS) m / z: 200.00 [M+H] + .

[1015] Synthesis of methyl 1-(2-chloro-6-methylpyridin-4-yl)-3-methylcyclobutane-1-carboxylate 41c

[1016] Sodium hydroxide (1.7 g, 60%, 43 mmol) was dissolved in DMF (8.0 mL). At 0°C, under nitrogen, a solution of compound 41b (4.3 g, 21 mmol) and 1,3-dibromo-2-methylpropane (4.6 g, 21 mmol) in DMF (2.0 mL) was slowly added dropwise. The mixture was stirred at room temperature overnight. The mixture was cooled to 0°C, quenched with aqueous ammonium chloride (30 mL), and extracted twice with ethyl acetate. The organic phase was dried and concentrated, and the residue was purified on silica gel (EA / PE = 0-6%) to afford compound 41c (2.8 g).

[1017] LCMS (ESI-MS) m / z: 254.10 [M+H] + .

[1018] Synthesis of methyl 1-(2-(bromomethyl)-6-chloropyridin-4-yl)-3-methylcyclobutane-1-carboxylate 41d

[1019] In a single-necked flask, compound 41c (2.0 g, 7.9 mmol) and DCE (20 mL) were added, followed by NBS (1.4 g, 7.9 mmol) and BPO (380 mg, 1.6 mmol), respectively. The mixture was heated at 90°C for 2 hours. LCMS analysis indicated the near disappearance of the starting material, yielding the title compound and a compound lacking two bromine residues. The product was quenched with saturated aqueous NaHCO₃ (20 mL) and extracted with DCM (20 mL x 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated. The residue was purified on silica gel flash chromatography (EA / PE = 0-25%) to afford compound 41d (1.0 g).

[1020] LCMS (ESI-MS) m / z: 332.20 [M+H] + .

[1021] Synthesis of methyl 1-(2-chloro-6-(methoxymethyl)pyridin-4-yl)-3-methylcyclobutane-1-carboxylate 41e

[1022] In a single-necked flask, compound 41d (1.0 g, 3.0 mmol) dissolved in DMF (10 mL) was added, followed by methanol (96 mg, 3.0 mmol) and NaH (180 mg, 4.5 mmol) under ice-bath. The reaction was stirred for 30 min and LCMS analysis confirmed the formation of target compound 41e. The reaction system was directly used for the next step.

[1023] LCMS (ESI-MS) m / z: 284.20 [M+H] + .

[1024] Synthesis of 1-(2-chloro-6-(methoxymethyl)pyridin-4-yl)-3-methylcyclobutane-1-carboxylic acid 41f

[1025] 2.0 N NaOH (2.0 mL) was added to the reaction system to hydrolyze the ester group. The reaction was stirred at room temperature for 1 hour. LCMS confirmed the completion of the reaction to yield the title compound. The pH was adjusted to 6 with 2.0 N HCl, followed by extraction with EA (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified on silica gel flash chromatography (EA / PE = 0-25%) to afford compound 41f (500 mg).

[1026] LCMS (ESI-MS) m / z: 270.21 [M+H] + .

[1027] Synthesis of 41 g of 2-(1-(2-chloro-6-(methoxymethyl)pyridin-4-yl)-3-methylcyclobutane-1-carbonyl)-N-methylhydrazine-1-methylsulfamide

[1028] To a single-necked flask, compound 41f (500 mg, 1.9 mmol) dissolved in DMF (4.0 mL) was added sequentially, followed by hydrazine (290 mg, 2.8 mmol) and DIPEA (360 mg, 2.8 mmol). HATU (1.1 g, 2.8 mmol) was then added portionwise under ice-cooling. The reaction was stirred for 30 minutes. LCMS confirmed the formation of the title compound, followed by extraction with EA (20 mL x 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified on silica gel flash chromatography (EA / PE = 0-25%) to afford compound 41g (450 mg).

[1029] LCMS (ESI-MS) m / z: 357.20 [M+H] + .

[1030] Synthesis of 5-(1-(2-chloro-6-(methoxymethyl)pyridin-4-yl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol 41h

[1031] In a single-necked flask, compound 41g (400 mg, 1.1 mmol) dissolved in ethanol (4.0 mL) was added, followed by aqueous NaHCO₃ (5.0 mL). The mixture was heated at 90°C for 2 hours. The mixture was spin-dried, added with water (20 mL), and extracted with EA (20 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified on silica gel flash chromatography (EA / PE = 0-25%) to afford compound 41h (400 mg).

[1032] LCMS (ESI-MS) m / z: 339.20 [M+H] + .

[1033] Synthesis of 2-chloro-6-(methoxymethyl)-4-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine 41i

[1034] Compound 41h (400 mg, 1.2 mmol) was dissolved in DCM (10 mL), and acetic acid (280 mg, 4.7 mmol) and H₂O₂ (30%, 1.3 g, 12 mmol) were added. The mixture was allowed to react at room temperature for 2-3 hours. After LCMS analysis, the reaction was quenched by adding an aqueous solution of sodium sulfite (1.5 eq.) until the color did not turn blue on starch potassium iodide paper. The organic phase was separated and washed with brine. The organic phase was dried, filtered, and concentrated. The residue was purified on silica gel flash chromatography (0-6% MeOH / DCM) to afford compound 41i (180 mg).

[1035] LCMS (ESI-MS) m / z: 307.60 [M+H] + .

[1036] Synthesis of 2-(6-(methoxymethyl)-4-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-6-(((S)-3-methylpiperidin-1-yl)methyl)-4-trifluoromethylisoindol-1-one 41

[1037] To a sealed tube were added compound 41i (90 mg, 0.29 mmol), 41j (72 mg, 0.29 mmol), Pd3(dba)2 (79 mg, 0.087 mmol), Xantphos (34 mg, 0.058 mmol), Cs2CO3 (190 mg, 0.58 mmol), and dioxane (2.0 mL) in this order. The mixture was sealed and heated at 100°C for 2 h under N2 protection. The mixture was sent for LCMS detection. After completion of the reaction, the mixture was cooled and filtered through celite, washed with 1,4-dioxane, and the filtrate was concentrated. The residue was purified by silica gel flash chromatography (0-40% (25% EtOH / EA) / PE, MeOH / DCM = 0-13%) to give the desired product (45 mg) with 87% purity. 45 mg of the product was further purified by pre-HPLC (10% MeOH / DCM) to give compound 41 (10 mg, cis monomer).

[1038] LCMS (ESI-MS) m / z: 583.50 [M+H] + .

[1039] 1 H NMR(400MHz, Methanol-d4)δ8.62(d,J=1.6Hz,1H),8.35(s,1H),8.08(s,1H),7.99( d,J=1.4Hz,1H),7.19–7.14(m,1H),5.33–5.24(m,2H),4.54(s,2H),3.75(s,2H),3.4 6(s,3H),3.34(s,3H),2.99–2.83(m,4H),2.77–2.63(m,3H),2.08(t,J=11.4Hz,1H) ,1.79–1.60(m,5H),1.18(d,J=6.2Hz,3H),1.01–0.92(m,1H),0.88(d,J=6.3Hz,3H).

[1040] Example 42: Synthesis of Compound 42

[1041] Synthesis of [(trideuterated methyl) nitrogen ylidene] methylthione 42b

[1042] Deuterated methylamine hydrochloride (500 mg, 7.1 mmol) was dissolved in anhydrous DCM (15 mL). CsCO (4.6 g, 14 mmol) and DIEA (1.8 g, 14 mmol) were added, and compound 42a (980 mg, 8.5 mmol, in 10 mL DCM) was slowly added dropwise. The mixture was stirred at 20°C for 10 hours. After the reaction, the mixture was directly dried and used in the next step.

[1043] Synthesis of methyl 1-(2-chloro-6-(2,2-difluoroethoxy)pyridin-4-yl)-3-methylcyclobutane-1-carboxylate 42d

[1044] To a sealed tube, compound 42c (2.6 g, 9.5 mmol), 2,2-difluoroethan-1-ol (430 mg, 5.2 mmol), Pd(OAc)2 (320 mg, 1.4 mmol), Xantphos (1.1 g, 1.9 mmol), K3PO4 (4.0 g, 19 mmol), and dioxane (40 mL) were added sequentially. The mixture was sealed under nitrogen and incubated at 100°C for 40 minutes. LCMS confirmed the reaction was complete. The mixture was cooled to room temperature, filtered through celite, washed with dioxane, and the filtrate was concentrated. The residue was purified on silica gel flash chromatography (EA / PE = 0-25%) to afford compound 42d (1.6 g).

[1045] LCMS (ESI-MS) m / z: 320.2 [M+H] + .

[1046] Synthesis of 1-(2-chloro-6-(2,2-difluoroethoxy)pyridin-4-yl)-3-methylcyclobutane-1-carboxylic acid hydrazide 42e

[1047] Compound 42d (1.4 g, 4.4 mmol) was dissolved in EtOH / THF (6.0 mL / 5.0 mL), and hydrazine hydrate (80%, 8.0 mL) was added. The mixture was stirred at 85°C for 4 hours. The reaction mixture was concentrated. The residue was purified by silica gel flash chromatography (0-38% (25% EtOH / EA) / PE) to afford compound 42e (1.4 g).

[1048] LCMS (ESI-MS) m / z: 320.2 [M+H] + .

[1049] Synthesis of 5-(1-(2-chloro-6-(2,2-difluoroethoxy)pyridin-4-yl)-3-methylcyclobutyl)-4-trideuteriomethyl-4H-1,2,4-triazole-3-thiol 42f

[1050] Compound 42e (750 mg, 2.4 mmol) was dissolved in EtOH (6.0 mL), and methyl isothiocyanate (190 mg, 2.6 mmol) was added. The mixture was stirred at 80°C for 2 hours. Solid NaHCO3 powder (2.0 g, 24 mmol) was added to the reaction solution, and stirring was continued at 80°C for 3 hours. LCMS monitoring indicated a good reaction. The mixture was cooled, and 10 mL of brine was added. The mixture was extracted three times with DCM, and the organic phase was concentrated to obtain crude compound 42f (500 mg).

[1051] LCMS (ESI-MS) m / z: 378.2 [M+H] + .

[1052] Synthesis of 42 g of 2-chloro-6-(2,2-difluoroethoxy)-4-(3-methyl-1-(4-trideuteriomethyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridine

[1053] Crude compound 42f (500 mg, 1.3 mmol) was dissolved in DCM (10 mL), and acetic acid (280 mg, 4.7 mmol) and H₂O₂ (30%, 1.3 g, 12 mmol) were added. The mixture was allowed to react at room temperature for 2-3 hours. After LCMS analysis, the reaction was quenched by adding an aqueous solution of sodium sulfite (1.5 eq.) until the starch potassium iodide test paper turned blue. The organic phase was separated and washed with brine. The organic phase was dried, filtered, and concentrated. The residue was purified by silica gel flash chromatography (0-6% MeOH / DCM) to afford compound 42g (300 mg).

[1054] LCMS (ESI-MS) m / z: 346.3 [M+H] + .

[1055] Synthesis of (S)-2-(6-(2,2-difluoroethoxy)-4-(3-methyl-1-(4-trideuteriomethyl-4H-1,2,4-triazol-3-yl)cyclobutyl)pyridin-2-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindol-1-one 42

[1056] Take a sealed tube and add compound 42g (150 mg, 0.43 mmol), 42h (150 mg, 0.48 mmol), Pd(OAc)2 (20 mg, 0.087 mmol), Xantphos (50 mg, 0.087 mmol), Cs2CO3 (290 mg, 0.87 mmol), dioxane (3.0 mL) in sequence under N2 protection. The tube was sealed and heated at 100°C for 3 hours. LCMS detection showed that the reaction was complete. The product was cooled and filtered through celite, washed with 1,4-dioxane, and the filtrate was concentrated. The residue was purified by silica gel flash chromatography (0-40% (25% EtOH / EA) / PE, MeOH / DCM = 0-13%) to give the crude compound (130 mg). Pre-HPLC purification was continued to give compound 42 (39 mg).

[1057] LCMS (ESI-MS) m / z: 622.6 [M+H] + .

[1058] 1H NMR(400MHz,DMSO-d6)δ8.34–8.41(m,1H),8.08–8.13(m,1H),7.93–7.98(m,2H),6.59–6 .72(m,1H),6.34–6.64(m,1H),5.24(s,2H),4.58–4.68(m,2H),3.65(s,2H),3.08–3.13( m,1H),2.84–2.85(m,2H),2.67–2.72(m,2H),2.55–2.58(m,2H),2.23–2.28(m,1H),1.94 (s,1H),1.54–1.70(m,4H),1.44–1.52(m,1H),1.08–1.11(m,3H),0.82(d,J=8.0Hz,3H).

[1059] Example 43: Synthesis of Compound 43

[1060] Synthesis of 4-bromo-6-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]-1H-indole 43b

[1061] Compound 43a (70 mg, 0.14 mmol) was dissolved in MeOH (2.0 mL), and potassium carbonate (120 mg, 0.84 mmol) was added. The mixture was stirred at 50°C for 4 hours. After completion of the reaction by LCMS, the mixture was filtered and the filtrate was concentrated. The mixture was purified by preparative thin layer chromatography (MeOH / DCM = 10%) to give compound 43b (40 mg).

[1062] LCMS (ESI-MS) m / z: 346.20 [M+H] + .

[1063] Synthesis of 4-bromo-1-ethyl-6-[3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl]-1H-indole 43c

[1064] Compound 43b (40 mg, 0.12 mmol) was dissolved in THF (1.0 mL), and NaH (16 mg, 60%, 0.58 mmol) was added. The mixture was stirred at room temperature for 1 hour, and then iodoethane (13 mg, 0.12 mmol) was added. The reaction was allowed to react at room temperature for 2 hours and monitored by TLC. After the reaction was complete, the mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EA. The organic phase was dried and concentrated, and the residue was purified by silica gel (EA / PE = 30%) to give compound 43c (38 mg).

[1065] LCMS (ESI-MS) m / z: 374.40 [M+H] + .

[1066] Synthesis of 4-(difluoromethyl)-2-{1-ethyl-6-[(1S,3R)-3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]indol-4-yl}-6-{[(3S)-3-methylhexahydropyridin-1-yl]methyl}-2,3-dihydro-1H-isoindol-1-one 43

[1067] Take a sealed tube and add compound 43c (38 mg, 0.10 mmol), 43d (25 mg, 0.10 mmol), Pd(OAc)2 (3.9 mg, 0.020 mmol), Xantphos (9.8 mg, 0.020 mmol), K2CO3 (59 mg, 0.51 mmol), dioxane (1.0 mL) in sequence under N2 protection. Seal the tube and heat at 100°C for 3 hours. Send to LCMS for detection. After the reaction is complete, cool and filter on celite, wash with 1,4-dioxane, concentrate the filtrate, and purify the residue by silica gel flash chromatography (MeOH / DCM = 0-12%) to obtain compound 43 (5.2 mg).

[1068] LCMS (ESI-MS) m / z: 587.60 [M+H] + .

[1069] 1H NMR (400MHz, DMSO-d6) δ8.28(d,J=31.8Hz,1H),7.82(s,1H),7.75(s,1H),7.46(s,1H),7.41(d,J=3.2Hz,1H), 7.28–7.10(m,2H),6.37(d,J=2.7Hz,1H),5.09(s,1H),4.27–4.17(m,2H),3.60(s,2H),3.23(s,2H),2.95(s,2H ),2.72(t,J=10.7Hz,2H),2.54(d,J=6.4Hz,2H),2.33(d,J=9.7Hz,1H),2.02–1.85(m,2H),1.66–1.54(m,3H),1 .45(d,J=15.2Hz,2H),1.34(t,J=7.2Hz,3H),1.22(s,3H),1.08(d,J=4.8Hz,2H),0.82(dd,J=16.9,6.2Hz,3H).

[1070] Example 44: Synthesis of Compound 44

[1071] Synthesis of methyl 4-bromo-3-fluoro-1H-indole-6-carboxylate 44b

[1072] In a single-necked flask, compound 44a (15 g, 59 mmol) was dissolved in acetonitrile (200 mL). AcOH (7.1 g, 120 mmol) was added at room temperature, and then Selecflour (23 g, 65 mmol) was added portionwise. The mixture was stirred at room temperature overnight. The reaction was completed by LCMS. Water (200 mL) was added, and the mixture was extracted with EA (200 mL*2). The organic phases were combined, dried, and concentrated. The residue was purified with silica gel (EA / PE = 30%) to obtain compound 44b (2.5 g).

[1073] LCMS (ESI-MS) m / z: 272.10 [M+H] + .

[1074] Synthesis of methyl 4-bromo-3-fluoro-1-toluenesulfonyl-1H-indole-6-carboxylate 44c

[1075] Compound 44b (5.0 g, 18 mmol) was dissolved in DMF (50 mL), and NaH (940 mg, 60%, 24 mmol) was added. The mixture was stirred at room temperature for 1 hour, followed by the addition of p-toluenesulfonyl chloride (4.5 g, 24 mmol). The mixture was stirred at room temperature for 2 hours. After TLC monitoring, the reaction was quenched with saturated aqueous ammonium chloride and extracted with EA. The organic phase was dried and concentrated, and the residue was purified on silica gel (EA / PE = 30%) to obtain compound 44c (8.0 g).

[1076] LCMS (ESI-MS) m / z: 425.90 [M+H] + .

[1077] Synthesis of (4-bromo-3-fluoro-1-tosyl-1H-indol-6-yl)methanol 44d

[1078] Compound 44c (7.6 g, 18 mmol) and anhydrous THF (60 mL) were added sequentially to a single-necked flask. DIBAL-H (36 mL, 1.5 M hexane solution, 54 mmol) was added dropwise at -50°C under nitrogen. The temperature was slowly warmed to room temperature and stirred for 3 hours. The reaction was monitored by LCMS. Upon completion, the title compound was generated. The product was quenched with dilute hydrochloric acid (1 M) at 0°C, with the pH monitored at 6-7. The product was extracted three times with DCM. The organic phase was dried over magnesium sulfate, filtered, and concentrated. The residue was purified by Flash chromatography to yield compound 44d (5.7 g).

[1079] LCMS (ESI-MS) m / z: 398.10 [M+H] + .

[1080] Synthesis of (4-bromo-3-fluoro-1-toluenesulfonyl-1H-indol-6-yl)methyl-4-methylbenzenesulfonate 44e

[1081] To a single-necked flask, compound 44d (5.7 g, 14 mmol), THF (130 mL), TsCl (8.2 g, 43 mmol), and KOH (8.0 g, 140 mmol) were added sequentially. The mixture was allowed to react at room temperature overnight. LCMS was used to monitor the reaction. Upon completion, the mixture was filtered, washed with THF, and the filtrate was concentrated. The residue was purified on flash silica gel (EA / PE = 0-30%) to afford compound 44e (5.0 g).

[1082] LCMS (ESI-MS) m / z: 574.20 [M+Na] + .

[1083] Synthesis of 2-(4-bromo-3-fluoro-1-toluenesulfonyl-1H-indol-6-yl)acetonitrile 44f

[1084] To a single-necked flask, compound 44e (5.0 g, 9.1 mmol), ACN (50 mL), TMSCN (1.8 g, 18 mmol), and LiOH (650 mg, 27 mL) were added sequentially. The mixture was stirred at room temperature for 2 hours, and the reaction was monitored by LCMS. Upon completion of the reaction, EA and water were added. The layers were separated, and the organic phase was concentrated. The residue was slurried with EA to afford compound 44f (2.7 g).

[1085] LCMS (ESI-MS) m / z: 429.10 [M+Na] + .

[1086] Synthesis of 44 g of methyl 2-(4-bromo-3-fluoro-1-toluenesulfonyl-1H-indol-6-yl)acetate

[1087] To a single-necked flask, compound 44f (2.7 g, 6.7 mmol) and methanol (25 mL) were added followed by SOCl2 (5.0 mL, 15 mmol). The mixture was heated at 60°C for 2 h. After completion of the reaction, the mixture was spin-dried and water was added. The mixture was extracted with EA and washed once with saturated NaHCO3 aqueous solution and brine. The organic phase was dried and concentrated to give a crude product of compound 44g (2.7 g).

[1088] LCMS (ESI-MS) m / z: 462.20 [M+Na] + .

[1089] Synthesis of methyl 1-(4-bromo-3-fluoro-1-toluenesulfonyl-1H-indol-6-yl)-3-methylcyclobutane-1-carboxylate 44h

[1090] In a three-necked flask, compound 44g (1.7 g, 3.9 mmol) and dibromoacetate (1.2 g, 5.8 mmol) in anhydrous DMF (10 mL) were added with cesium carbonate (2.5 g, 7.7 mmol) and stirred at room temperature overnight. LCMS analysis confirmed the completion of the reaction. The product was quenched with saturated aqueous ammonium chloride and extracted with EA. The organic phase was dried and concentrated, and the residue was purified on silica gel (EA / PE = 0-80%) to afford compound 44h (1.0 g).

[1091] LCMS (ESI-MS) m / z: 494.10 [M+H] + .

[1092] Synthesis of 1-(4-bromo-3-fluoro-1-toluenesulfonyl-1H-indol-6-yl)-3-methylcyclobutane-1-carboxylic acid hydrazide 44i

[1093] Compound 44h (1.0 g, 2.0 mmol) was dissolved in EtOH / THF (6.0 mL / 6.0 mL) and hydrazine hydrate (80%, 6.0 mL) was added. The mixture was heated at 85°C for 2 hours and sent to LCMS for detection. After completion of the reaction, the mixture was concentrated and the residue was purified by silica gel (MeOH / DCM = 0-12%) to obtain compound 44i (600 mg).

[1094] LCMS (ESI-MS) m / z: 494.20 [M+H] + .

[1095] Synthesis of 5-(1-(4-bromo-3-fluoro-1-tosyl-1H-indol-6-yl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol 44k

[1096] Compound 44i (600 mg, 1.2 mmol) was dissolved in ethanol (12 mL), and methyl isothiocyanate 44j (140 mg, 1.9 mmol) was added. The mixture was stirred at 80°C for 2 hours. NaHCO (1.0 M in H2O, 5.3 mL) was added to the reaction solution, and stirring was continued at 80°C for 3 hours. LCMS monitoring indicated a good reaction. The mixture was cooled, and 10 mL of brine was added. The mixture was then extracted three times with DCM. The organic phase was concentrated to afford crude product 44k, which was used directly in the next step.

[1097] LCMS (ESI-MS) m / z: 551.10 [M+H] + .

[1098] Synthesis of 4-bromo-3-fluoro-6-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-1-toluenesulfonyl-1H-indole 441

[1099] Compound 44k (500 mg, 0.93 mmol) was dissolved in DCM (10 mL) and HOAc (210 mg) and H₂O₂ (30%, 990 mg) were added. The mixture was allowed to react at room temperature for 2 hours. After LCMS analysis, the reaction was quenched by adding an aqueous sodium sulfite solution (1.5 eq.) until the starch potassium iodide test paper did not turn blue. The organic phase was separated and washed with brine. The organic phase was dried, filtered, and concentrated. The residue was purified on silica gel flash chromatography (0-40% (25% EtOH / EA) / PE) to afford compound 44l (170 mg).

[1100] LCMS (ESI-MS) m / z: 519.20 [M+H] + .

[1101] Synthesis of (S)-2-(3-fluoro-6-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-1-tosyl-1H-indol-4-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindol-1-one 44n

[1102] A sealed tube was taken and compound 44l (170 mg, 0.33 mmol), 44m (64 mg, 0.26 mmol), Pd2(dba)3 (91 mg, 0.099 mmol), Xantphos (38 mg, 0.066 mmol), K3PO4 (140 mg, 0.66 mmol), and dioxane (4.0 mL) were added in sequence under N2 protection. The reaction was heated at 100°C for 3 hours and sent to LCMS for detection. After the reaction was completed, the product was cooled and filtered through celite, washed with 1,4-dioxane, and the filtrate was concentrated. The residue was purified by silica gel flash chromatography (0-40% (25% EtOH / EA) / PE, MeOH / DCM = 0-12%) to obtain compound 44n (150 mg).

[1103] LCMS (ESI-MS) m / z: 749.50 [M+H] + .

[1104] Synthesis of (S)-2-(3-fluoro-6-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-1H-indol-4-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindol-1-one 44

[1105] Compound 44n (150 mg, 0.20 mmol) was dissolved in MeOH (2.0 mL), and potassium carbonate (80 mg, 0.58 mmol) was added. The mixture was stirred at 50°C for 4 hours and sent to LCMS for detection. After the reaction was completed, the mixture was filtered, the filtrate was concentrated, and purified by preparative thin layer chromatography (MeOH / DCM = 10%) to give compound 44 (10 mg).

[1106] LCMS (ESI-MS) m / z: 595.50 [M+H] + .

[1107] 1 H NMR(400MHz,Methanol-d4)δ8.36(s,1H),8.08(s,1H),8.00(s,1H),7.34–7.25(m,1H),7 .13(d,J=2.7Hz,1H),7.11(d,J=1.4Hz,1H),5.10(d,J=6.8Hz,1H),4.72(t,J=1.7Hz,1H), 4.64(s,1H),3.75(s,2H),3.58(s,3H),3.16–3.07(m,1H),2.89(d,J=9.9Hz,3H),2.05(t, J=11.3Hz,1H),1.76(s,3H),1.75–1.55(m,6H),1.01–0.90(m,2H),0.88(d,J=5.9Hz,3H).

[1108] Example 45: Synthesis of Compound 45

[1109] Synthesis of methyl 4-bromo-1H-benzo[d]imidazole-6-carboxylate 45b

[1110] Compound 45a (20 g, 82 mmol) was dissolved in THF, and triethoxymethane (27 mL, 160 mmol) and p-toluenesulfonic acid (1.6 g, 8.2 mmol) were added sequentially. The reaction was allowed to react overnight at rt. LCMS showed the product as the primary product. The reaction solution was evaporated to dryness under reduced pressure, slurried with EA, filtered, and the filter cake was washed with EA. The filtrate was then dried to give compound 45b (22 g).

[1111] LCMS (ESI-MS) m / z: 255.10 [M+H] + .

[1112] Synthesis of methyl 4-bromo-1-(4-methoxybenzyl)-1H-benzo[d]imidazole-6-carboxylate 45c

[1113] Compound 45b (10 g, 40 mmol) was dissolved in DMF (100 mL), cooled to 0°C, and NaH (2.1 g, 52 mmol, 60 wt%) was added. The mixture was stirred for 0.5 hours, and then PMBCl (7.0 mL, 52 mmol) was added. The temperature was slowly raised to room temperature and the reaction was allowed to proceed overnight. LCMS showed the product as the primary product. The reaction solution was quenched with aq. NH4Cl and extracted three times with EA. The combined organic phases were washed three times with brine, dried under reduced pressure, and subjected to FCC (PE / EA 9:1 to 6:4) to afford compound 45c (18 g).

[1114] LCMS (ESI-MS) m / z: 375.20 [M+H] + .

[1115] Synthesis of (4-bromo-1-(4-methoxybenzyl)-1H-benzo[d]imidazol-6-yl)methanol 45d

[1116] Compound 45c (10 g, 27 mmol) was dissolved in THF (200 mL), cooled to -78°C, and DIBAL-H (80 mL, 1.0 M, 80 mmol) was added dropwise. The reaction was incubated for 2 h, then slowly raised to room temperature and allowed to react overnight. LCMS showed the product as the primary product. The reaction solution was quenched with MeOH and further quenched with aq. potassium sodium tartrate and stirred for 2 h. After the reaction solution clarified, it was extracted three times with EA. The organic phase was dried under reduced pressure and subjected to FCC (PE / EA 1:1 to 0:1) to afford compound 45d (7.2 g).

[1117] LCMS (ESI-MS) m / z: 347.20 [M+H] + .

[1118] Synthesis of 4-bromo-6-(chloromethyl)-1-(4-methoxybenzyl)-1H-benzo[d]imidazole 45e

[1119] Compound 45d (7.2 g, 21 mmol) was dissolved in DCM (50 mL), and DIEA (7.2 mL, 41 mmol) and TsCl (5.9 g, 31 mmol) were added sequentially. The reaction was allowed to react at rt overnight. LCMS showed the product as the primary product. The reaction solution was evaporated to dryness under reduced pressure and subjected to FCC (PE / EA 9:1 to 5:5) to afford compound 45e (3.8 g).

[1120] LCMS (ESI-MS) m / z: 365.10 [M+H] + .

[1121] Synthesis of 2-(4-bromo-1-(4-methoxybenzyl)-1H-benzo[d]imidazol-6-yl)acetonitrile 45f

[1122] Compound 45e (3.8 g, 10 mmol) was dissolved in ACN (40 mL), and TMSCN (2.6 mL, 21 mmol) and LiOH (750 mg, 31 mmol) were added sequentially. The temperature was raised to 50°C and the reaction was allowed to react for 4 hours. LCMS showed the product as the primary product. The reaction solution was quenched with aq. NaHCO3 and extracted three times with EA. The organic phase was dried under reduced pressure and subjected to FCC (PE / EA 9:1 to 5:5) to afford compound 45f (2.1 g).

[1123] LCMS (ESI-MS) m / z: 356.20 [M+H] + .

[1124] Synthesis of 45 g of 1-(4-bromo-1-(4-methoxybenzyl)-1H-benzo[d]imidazol-6-yl)-3-methylcyclobutane-1-carbonitrile

[1125] Compound 45f (2.4 g, 6.7 mmol) was dissolved in DMF (40 mL), and 1,3-dibromo-2-methylpropane (1.6 mL, 14 mmol) and MeONa (2.2 g, 40 mmol) were added sequentially. The reaction was allowed to react at rt overnight. LCMS showed the product as the primary product. The reaction solution was quenched with aq. NaHCO3 and extracted three times with EA. The organic phase was evaporated to dryness under reduced pressure and flash purified (PE / EA 8:2 to 6:4) to obtain compound 45g (1.3 g).

[1126] LCMS (ESI-MS) m / z: 410.20 [M+H] + .

[1127] Synthesis of 1-(4-bromo-1-(4-methoxybenzyl)-1H-benzo[d]imidazol-6-yl)-3-methylcyclobutane-1-carboxylic acid 45h

[1128] Compound 45g (2.6 g, 6.3 mmol) was dissolved in EtOH / H₂O (30 mL / 10 mL), and NaOH (1.0 g, 25 mmol) was added. The reaction mixture was heated to 90°C for 16 h. LCMS indicated the product as the primary product. The EtOH was removed by vortexing the reaction mixture under reduced pressure. Concentrated HCl was added dropwise under ice to pH = 2, and the mixture was lyophilized and subjected to FCC (DCM / MeOH 99:1 to 90:10) to afford compound 45h (2.1 g).

[1129] LCMS (ESI-MS) m / z: 429.20 [M+H] + .

[1130] Synthesis of 2-(1-(4-bromo-1-(4-methoxybenzyl)-1H-benzo[d]imidazol-6-yl)-3-methylcyclobutane-1-carbonyl)-N-methylhydrazine-1-methylsulfamide 45i

[1131] Compound 45h (2.7 g, 6.3 mmol) was dissolved in DMF (30 mL), and N-methylhydrazine methylsulfamide (1.0 g, 9.5 mmol), HATU (2.9 g, 7.6 mmol), and DIEA (2.8 mL, 15.8 mmol) were added sequentially. The reaction was allowed to proceed overnight at rt. LCMS showed the product as the primary product. The reaction solution was quenched with aqueous NaHCO3 solution, and the precipitated solid was filtered under reduced pressure. The filter cake was washed with EA to obtain crude compound 45i, which was used directly in the next step.

[1132] LCMS (ESI-MS) m / z: 516.30 [M+H] + .

[1133] Synthesis of 5-(1-(4-bromo-1-(4-methoxybenzyl)-1H-benzo[d]imidazol-6-yl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol 45j

[1134] Crude compound 45i (6.3 mmol) was dissolved in EtOH / H₂O (50 mL / 25 mL), and NaHCO₃ (1.1 g, 13 mmol) was added. The temperature was raised to 80°C and the reaction was allowed to react for 3 h. LCMS indicated the product as the primary product. The reaction solution was decompressed and the EtOH was removed by vortexing. The product was extracted three times with DCM. The organic phase was dried, filtered, and the filtrate was vortexed to dryness to afford crude compound 45j, which was used directly in the next step.

[1135] LCMS (ESI-MS) m / z: 498.30 [M+H] + .

[1136] Synthesis of 4-bromo-1-(4-methoxybenzyl)-6-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-1H-benzo[d]imidazole 45k

[1137] Crude compound 45j (6.6 mmol) was dissolved in DCM (30 mL), and HOAc (750 μL, 13 mmol) was added. The mixture was cooled to 0°C, and H₂O₂ (3.7 mL, 33 mmol, 30%) was added dropwise. The reaction was allowed to react at rt overnight. LCMS indicated the product as the primary product. The reaction was quenched with aq. Na₂SO₃ and neutralized with aq. NaHCO₃. The product was extracted with DCM, and the organic phase was dried under reduced pressure and flash purified (DCM / MeOH 98:2) to afford compound 45k (2.3 g).

[1138] LCMS (ESI-MS) m / z: 466.3 [M+H] + .

[1139] Synthesis of (S)-2-(1-(4-methoxybenzyl)-6-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-1H-benzo[d]imidazol-4-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindol-1-one 45l

[1140] Compound 45k (470 mg, 1.0 mmol), a lactam compound (310 mg, 1.0 mmol), Pd(OAc)2 (34 mg, 0.15 mmol), Xantphos (120 mg, 0.20 mmol), Cs2CO3 (820 mg, 2.5 mmol), and dioxane (10 mL) were placed in a microwave tube, sealed with Ar, and microwaved at 120°C for 4 hours. LCMS indicated the formation of the product. The reaction solution was diluted with EA, filtered through Celite, and dried under reduced pressure. The residue was then flash purified (DCM / MeOH 100:0 to 95:5) to afford compound 45l (340 mg).

[1141] LCMS (ESI-MS) m / z: 698.6 [M+H] + .

[1142] Synthesis of (S)-2-(6-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-1H-benzo[d]imidazol-4-yl)-6-((3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindol-1-one 45

[1143] Compound 451 (170 mg, 0.24 mmol) was dissolved in CH3CN / H2O (4.0 mL / 2.0 mL), and ACN (380 mg, 0.72 mmol) was added. The mixture was allowed to react overnight at rt. LCMS indicated the formation of the product. The reaction solution was directly subjected to RP-HPLC and lyophilized to afford compound 45 (15 mg).

[1144] LCMS (ESI-MS) m / z: 578.5 [M+H] + .

[1145] 1H NMR(400MHz,DMSO-d6)δ12.62(brs,1H),8.29-8.22(m,2H),8.01(s,1H),7. 93(s,1H),7.80(s,1H),7.39(s,1H),5.62(s,2H),3.67(s,2H),3.23(s,3H), 2.88–2.89(m,2H),2.76–2.70(m,2H),2.60–2.56(m,2H),2.37–2.27(m,1H), 1.97–1.91(m,1H),1.68–1.44(m,5H),1.12–1.09(m,3H),0.91–0.81(m,4H).

[1146] Example 46: Synthesis of Compound 46

[1147] Synthesis of 3-bromo-5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one 46b

[1148] Compound 46a (550 mg, 1.7 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (590 mg, 2.5 mmol) were dissolved in acetonitrile (20 mL), and Cs2CO3 (1100 mg, 3.4 mmol) was added. The reaction solution was heated to 80°C and stirred for 4 hours. After the reaction was complete, the reaction solution was cooled and diluted with water (30 mL), and extracted with ethyl acetate (50×2 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and dried to give a crude product, which was purified by silica gel (EA / PE=0-50%) to give compound 46b (370 g).

[1149] LCMS (ESI-MS) m / z: 405.20 [M+H] + .

[1150] Synthesis of 2-methylpropan-2-yl-6-{[(2R)-2-methyl-1,4-oxazin-4-yl]methyl}-1-oxo-4-(trifluoromethyl)-2,3-dihydro-1H-isoindole-2-carboxylate 46e

[1151] Compounds 46c (300 mg, 0.91 mmol) and 46d (6.5 mg, 2.7 mmol) were dissolved in THF (10 mL). Sodium acetate borohydride (580 mg, 2.7 mmol) was added at 0°C, and the reaction mixture was allowed to react at 15°C for 2 hours. After the reaction was complete, sodium bicarbonate was added to neutralize the mixture until it became slightly acidic. The mixture was then extracted with dichloromethane (30 × 3 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spun down to obtain the crude product. The crude product was purified on silica gel (DCM:MEOH = 20:1) to obtain compound 46e (210 mg).

[1152] LCMS (ESI-MS) m / z: 415.40 [M+H] + .

[1153] Synthesis of 6-{[(2R)-2-methyl-1,4-oxazin-4-yl]methyl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 46f

[1154] Compound 46e (210 mg, 0.51 mmol) was dissolved in CH2Cl2 (4.0 mL), and TFA (1.0 mL, 13 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was spin-dried, and dichloromethane (30 mL) was added. The mixture was washed with saturated sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain compound 46f (160 mg).

[1155] LCMS (ESI-MS) m / z: 315.30 [M+H] + .

[1156] Synthesis of 6-{[(2R)-2-methyl-1,4-oxazin-4-yl]methyl}-2-{5-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]-2-oxo-1-(2,2,2-trifluoroethyl)pyridin-3-yl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 46

[1157] Compounds 46f (120 mg, 0.38 mmol) and 46b (150 mg, 0.38 mmol) were mixed in a microwave tube containing dioxane (10 mL). Pd(OAc)2 (17 mg, 0.076 mmol), Xantphos (88 mg, 0.15 mmol), and Cs2CO3 (250 mg, 0.76 mmol) were added sequentially. The mixture was purged with nitrogen for a short time, then sealed and reacted in a microwave reactor at 120°C for 2 hours. After cooling, the reaction solution was filtered and the residue washed with 50 mL of a mixed solvent (CH2Cl2:MeOH = 10:1). The organic phase was directly added with silica gel and purified by column chromatography (eluent: CH2Cl2:MeOH = 15:1) to obtain the crude product. This was then used to prepare compound 46f (60 mg).

[1158] LCMS (ESI-MS) m / z: 639.50 [M+H] + .

[1159] 1 H NMR (400MHz, Methanol-d4) δ8.39 (d, J = 34.6Hz, 1H), 8.05 (s, 1H), 8.01–7.88 (m, 2H), 7.68 (dd, J = 34. 1,2.5Hz,1H),5.12(s,2H),4.99–4.91(m,2H),3.83(ddd,J=11.6,3.5,1.5Hz,1H),3.73(s,2H),3.71 –3.61(m,2H),3.50(d,J=12.0Hz,3H),3.17–2.82(m,2H),2.81–2.58(m,3H),2.53(td,J=9.5,2.5Hz, 2H), 2.28–2.21(m,1H),1.93(dd,J=11.3,10.0Hz,1H),1.16(t,J=6.2Hz,3H),1.10(d,J=6.3Hz,3H).

[1160] Example 47: Synthesis of Compound 47

[1161] Synthesis of 2-(1-(2,2-difluoroethyl)-5-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-oxo-1,2-dihydropyridin-3-yl)-6-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindol-1-one 47

[1162] Compound 47a was purified by chiral-preparative HPLC: chiral column: IH 4.6*100mm 5μm; mobile phase, MeOH [0.2% NH3 (7M in MeOH)] to give compound 47.

[1163] LCMS (ESI-MS) m / z: 619.30 [M+H] + .

[1164] 1 H NMR(400MHz,Methanol-d4)δ8.34(s,1H),8.02(s,1H),7.96(s,1H),7.92-7.91(d, 1H),7.73-7.72(d,1H),6.25-6.23(m,1H),5.11(s,2H),4.58-4.50(m,2H),3.68(s ,2H),3.48(s,3H),2.90-2.79(m,4H),2.67-2.60(m,1H),2.54-2.52(m,2H),2.01- 1.98(m,1H),1.74-1.65(m,4H),1.62(s,1H),1.15-1.13(d,3H),0.87-0.85(m,4H).

[1165] Example 48: Synthesis of Compound 48

[1166] Synthesis of tert-butyl (S)-6-((3-methoxypiperidin-1-yl)methyl)-1-oxo-4-(trifluoromethyl)isoindoline-2-carboxylate 48b

[1167] Compound 48a (500 mg, 1.5 mmol) and (3S)-3-methoxypiperidine (530 mg, 4.6 mmol) were dissolved in DCE (10 mL) and allowed to react at rt for 1 h. NaBH(OAc)3 (1.3 g, 6.1 mmol) was then added and allowed to react overnight at rt. LCMS indicated completion of the reaction. The reaction was quenched with aqueous NaHCO3 (15 mL) and extracted with DCM (15 mL x 3). The organic phases were combined, dried, and spin-dried. The residue was flash purified using PE / (EA:EtOH 4:1) = 9:1-6:4 as the eluent to afford compound 48b (650 mg).

[1168] LCMS (ESI-MS) m / z: 429.40 [M+H] + .

[1169] Synthesis of (S)-6-((3-methoxypiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindol-1-one 48c

[1170] Compound 48b (650 mg, 1.5 mmol) was dissolved in dichloromethane (5.0 mL), cooled to 0°C, and a solution of hydrogen chloride in EA (2.0 M, 5.0 mL, 10 mmol) was added dropwise. The reaction was allowed to react at rt overnight. LCMS indicated the product as the primary product. The reaction was quenched with aqueous NaHCO₃ (15 mL) and extracted three times with DCM / MeOH (10:1, 15 mL). The organic phases were combined, dried, and spin-dried. The residue was flash purified using DCM / MeOH (99:1) as the eluent to afford compound 48c (460 mg).

[1171] LCMS (ESI-MS) m / z: 329.30 [M+H] + .

[1172] Synthesis of (S)-6-((3-methoxypiperidin-1-yl)methyl)-2-(5-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydropyridin-3-yl)-4-(trifluoromethyl)isoindol-1-one 48

[1173] Compound 48c (460 mg, 1.4 mmol), a lactam compound (570 mg, 1.4 mmol), Pd(OAc)2 (47 mg, 0.21 mmol), Xantphos (160 mg, 0.28 mmol), Cs2CO3 (1.1 g, 3.5 mmol), and dioxane (10 mL) were placed in a microwave tube, sealed with Ar, and microwaved at 120°C for 4 hours. LCMS showed the product as the primary product. The reaction solution was diluted with EA, filtered through Celite, and dried under reduced pressure. The crude product was then subjected to RP-HPLC and lyophilized to afford compound 48 (200 mg).

[1174] LCMS (ESI-MS) m / z: 653.50 [M+H] + .

[1175] 1H NMR(400MHz,DMSO-d6)δ8.35(s,1H),7.97–7.96(m,2H),7.91(s,1H),7.65–7.64(m,1H), 5.11(s,2H),5.02–4.96(m,2H),3.73–3.65(m,2H),3.35(s,3H),3.26–3.22(m,1H),3.20( s,3H),3.09–3.04(m,1H),2.87–2.72(m,3H),2.58–2.55(m,1H),2.48–2.43(m,1H),2.19– 2.14(m,1H),2.03–1.87(m,3H),1.67–1.62(m,1H),1.45–1.36(m,1H),1.15–1.07(m,4H).

[1176] Example 49: Synthesis of Compound 49

[1177] Synthesis of 6-(chloromethyl)-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 49b

[1178] In a single-necked flask, compound 49a (380 mg, 1.6 mmol) was added to DCM (4.0 mL), and thionyl chloride (4.0 mL, 3.2 mmol) was added under ice bath. The mixture was heated at 80°C for one hour. The reaction was completed after LCMS detection. The mixture was directly spin-dried and used for the next step.

[1179] LCMS (ESI-MS) m / z: 250.10 [M+H] + .

[1180] Synthesis of 6-[(3-hydroxy-3-methylζ-1-yl)methyl]-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 49c

[1181] Compound 49b (370 mg, 1.5 mmol) was added with acetonitrile (5.0 mL), followed by potassium iodide (250 mg, 1.5 mmol) and potassium carbonate (620 mg, 4.5 mmol). The mixture was heated at 80°C for 2 hours and monitored by LCMS. After completion of the reaction, the mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EA. The organic phase was dried and concentrated, and the residue was purified with silica gel (EA / PE = 30%) to obtain compound 49c (60 mg).

[1182] LCMS (ESI-MS) m / z: 301.10 [M+H] + .

[1183] Synthesis of 6-[(3-hydroxy-3-methylζ-1-yl)methyl]-2-{6-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl]imidazo[1,2-a]pyridin-8-yl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 49

[1184] A sealed tube was removed and compound 49c (50 mg, 0.17 mmol), compound 49d (50 mg, 0.17 mmol), Pd(OAc)2 (11 mg, 0.050 mmol), Xantphos (19 mg, 0.033 mmol), and Cs2CO3 (110 mg, 0.33 mmol) were added. The mixture was then added to dioxane (1.0 mL). The atmosphere was replaced with N2 for 1 minute and the mixture was heated in an oil bath at 105°C for 2 hours. The mixture was then spin-dried to dryness, and 4.0 mL of dichloromethane was added. The mixture was sonicated and filtered through a pad of Celite. The filtrate was spin-dried to dryness to obtain the crude product (100 mg), which was then purified by preparative HPLC to obtain compound 49 (20 mg).

[1185] LCMS (ESI-MS) m / z: 566.50 [M+H] + .

[1186] 1 H NMR (400MHz, Methanol-d4) δ8.78(d,J=1.7Hz,1H),8.34(s,1H),8.06(s,1H),7.99(d,J=1.3Hz ,1H),7.95(s,1H),7.62(d,J=1.3Hz,1H),7.44(d,J=1.7Hz,1H),5.36(s,2H),3.90(s,2H),3.46 (d,J=5.8Hz,3H),3.38(d,J=1.9Hz,2H),3.17(d,J=7.8Hz,2H),3.04–2.96(m,2H),2.76–2.70( m,1H),2.63(d,J=10.5Hz,1H),2.44(d,J=9.9Hz,1H),1.48(s,3H),1.18(dd,J=6.3,4.9Hz,3H).

[1187] Example 50: Synthesis of Compound 50

[1188] Synthesis of 2-methylpropan-2-yl [(3-chloro-5-methylpyridin-2-yl){[(2-methylpropan-2-yl)oxy]carbonyl}amino]methane ester 50b

[1189] Compound 50a (100 g, 700 mmol) was weighed and dissolved in DCM (200 mL) in an eggplant flask. (Boc)2O (340 g, 1500 mmol) and DMAP (8.6 g, 70 mmol) were added sequentially and stirred at room temperature overnight. LCMS monitored the reaction for completion. The product was then washed with water, separated, extracted, and the organic phase collected and dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated to yield the crude product. Wet-loaded and flash column purified (PE:EA = 0-5%) afforded compound 50b (220 g, 630 mmol).

[1190] LCMS (ESI-MS) m / z: 343.20 [M+H] + .

[1191] Synthesis of 2-methylpropan-2-yl {[3-chloro-5-(dibromomethyl)pyridin-2-yl]{[(2-methylpropan-2-yl)oxy]carbonyl}amino}methane ester 50c

[1192] Compound 50b (53 g, 150 mmol) and NBS (55 g, 310 mmol) were weighed and dissolved in DCE (300 mL) in an eggplant flask. AIBN (2.5 g, 15 mmol) was added in an ice bath and the mixture was allowed to react in an oil bath at 80°C for 3 h. LCMS monitored the reaction completion. The reaction solution was cooled and slowly poured into 800 mL of aqueous sodium bicarbonate solution. The mixture was allowed to stand for separation. The organic phase was collected, washed with saturated brine, extracted, and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to obtain the crude product. The crude product was used directly in the next step to obtain compound 50c (79 g, 160 mmol).

[1193] LCMS (ESI-MS) m / z: 499.10 [M+H] + .

[1194] Synthesis of 2-methylpropan-2-yl {[5-(bromomethyl)-3-chloropyridin-2-yl]{[(2-methylpropan-2-yl)oxy]carbonyl}amino}methane ester 50d

[1195] Compound 50c (93 g, 190 mmol) and diethyl phosphonate (13 g, 93 mmol) were weighed and dissolved in THF (500 mL) in an eggplant-shaped flask. DIEA (48 g, 370 mmol) was then added. The reaction mixture immediately turned black and stirred at room temperature for 2 h. LCMS monitored the reaction for completion. The reaction mixture was concentrated in vacuo and slowly poured into water. Extraction was performed with ethyl acetate. The mixture was allowed to stand for separation. The organic phase was collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and slurried with 300 mL of a mixed solvent (PE / EA = 3 / 1). The filter cake was collected and concentrated in vacuo. The filtrate was then spin-dried and dissolved in a small amount of DCM. The mixture was then directly wet-applied and purified using a flash column (PE:EA = 0-10%) to afford compound 50d (72 g).

[1196] LCMS (ESI-MS) m / z: 421.10 [M+H] + .

[1197] Synthesis of 2-methylpropan-2-yl {[3-chloro-5-(cyanomethyl)pyridin-2-yl]{[(2-methylpropan-2-yl)oxy]carbonyl}amino}methane ester 50e

[1198] Compound 50d (40 g, 95 mmol) and trimethylsilyl cyanide (19 g, 190 mmol) were weighed and dissolved in ACN (200 mL) in an eggplant-shaped flask. TBAF (190 mL, 190 mmol) was added and stirred at room temperature for 2 h. The reaction was monitored for completion by LCMS. After completion, 1.0 M sodium hydroxide solution (95 mL) was slowly added, stirred for 30 min, and concentrated at 30°C. The mixture was then dissolved in EA and slowly poured into water for washing. The organic phase was separated, washed with saturated brine, extracted, and separated. The EA phase was collected and concentrated under vacuum. The crude product was slurried with PE (300 mL) and EA (100 mL), filtered, and the filter cake was concentrated under vacuum. The filtrate was then concentrated under vacuum, and an appropriate amount of DCM was added to the sample. Flash purification (PE / (EA / EtOH=1 / 3)=0-30%) was performed. The combined slurries were combined to yield compound 50e (32 g, 86 mmol).

[1199] LCMS (ESI-MS) m / z: 368.20 [M+H] + .

[1200] Synthesis of 2-methylpropan-2-yl {[3-chloro-5-(1-cyano-3-methylcyclobutyl)pyridin-2-yl]{[(2-methylpropan-2-yl)oxy]carbonyl}amino}methane ester 50f

[1201] Compound 50e (36 g, 97 mmol) and 1,3-dibromo-2-methylpropane (25 g, 120 mmol) were weighed into an eggplant flask and dissolved in DMF (170 mL). K₃PO₄ (41 g, 190 mmol) was added and the mixture was reacted in an oil bath at 100°C for 30 min (the reaction mixture was then placed in a pot after the oil bath reached 100°C). LCMS monitored the reaction for completion. The mixture was cooled to room temperature and slowly poured into water. Extraction with ethyl acetate was performed and the layers separated. The organic phase was collected and washed with saturated brine. The ethyl acetate phase was dried over anhydrous sodium sulfate and filtered. The filter cake was washed 2-3 times with ethyl acetate. The filtrate was collected and concentrated in vacuo. The mixture was dissolved in a small amount of DCM, wet loaded, and flash purified (PE:EA = 0-14%, 330 g) to obtain compound 50f (31 g, 74 mmol).

[1202] LCMS (ESI-MS) m / z: 422.20 [M+H] + .

[1203] Synthesis of 50g of 1-(6-amino-5-chloropyridin-3-yl)-3-methylcyclobutane-1-carboxylic acid

[1204] 50f (64 g, 150 mmol) was weighed into an eggplant-shaped flask and concentrated hydrochloric acid (36%-38%, 100 mL) was added. The mixture was reacted in an oil bath at 100°C for 4 h. LCMS monitored the reaction for completion. After completion, the reaction solution was directly concentrated in vacuo. Water was removed from the reaction solution using dioxane (20 mL x 3). The solution was concentrated to afford compound 50g (50 g, 150 mmol).

[1205] LCMS (ESI-MS) m / z: 241.20 [M+H] + .

[1206] Synthesis of 1-(8-chloroimidazo[3,2-a]pyridin-6-yl)-3-methylcyclobutane-1-carboxylic acid 50h

[1207] 2-Bromo-1,1-diethoxyethane (60 g, 300 mmol) was dissolved in dioxane (200 mL) and H₂O (90 mL) in an eggplant flask. Concentrated hydrochloric acid (36%-38%, 5.6 mL, 4.0 mmol) was then added dropwise. The mixture was reacted in an oil bath at 100°C for 1.5 h (the solution became clear), and then cooled in an ice bath. Compound 50 g (37 g, 150 mmol) was dissolved in dioxane (200 mL) and H₂O (90 mL) in an eggplant flask. The solution was slowly added dropwise to the ice bath reaction solution. After the addition was complete, the mixture was reacted in an oil bath at 100°C for 1.5 h. LCMS confirmed the reaction was complete. The mixture was cooled to room temperature and concentrated in vacuo to precipitate a solid. The solid was filtered. The filtrate was concentrated, lyophilized, and then dissolved in methanol. 5 eq of sodium bicarbonate was added to adjust the pH to neutral, and the mixture was filtered. The filter cake was washed two to three times with methanol, and the filtrate was collected and concentrated in vacuo. The filter cake was concentrated in vacuo, flash purified (DCM:MeOH=0-11%), and then concentrated in vacuo. The filtrate was concentrated and mixed with silica gel (40 g) and flash purified (DCM:MeOH=0-3%). The product was collected, concentrated in vacuo, and combined with the product purified from the filter cake to give compound 50h (40 g, 150 mmol).

[1208] LCMS (ESI-MS) m / z: 265.10 [M+H] + .

[1209] Synthesis of methyl 1-(8-chloroimidazo[3,2-a]pyridin-6-yl)-3-methylcyclobutane-1-carboxylate 50i

[1210] Compound 50h (1.0 g, 3.8 mmol) was weighed into an eggplant flask and MeOH (20 mL) was added. Chloranesulfinyl chloride (2.7 g, 23 mmol) was slowly added under ice-cooling, and the mixture was stirred in an oil bath at 70°C for 1.5 h. The reaction was complete as monitored by LCMS. After completion, the mixture was concentrated in vacuo and dissolved in DCM. Saturated aqueous sodium bicarbonate was added to adjust the pH to neutral (weakly basic). Extraction and separation were performed. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was dissolved in DCM and flash purified (DCM:MeOH = 0-5%) to afford compound 50i (270 mg, 0.97 mmol).

[1211] LCMS (ESI-MS) m / z: 279.20 [M+H] + .

[1212] Synthesis of 1-(8-chloroimidazo[3,2-a]pyridin-6-yl)-3-methylcyclobutane-1-carboxylic acid hydrazide 50j

[1213] Compound 50i (270 mg, 0.97 mmol) was weighed and dissolved in ethanol (5.0 mL) in an eggplant-shaped flask. Diazene dihydrogen hydrate (0.47 mL, 9.7 mmol) was added and the reaction was stirred in an oil bath at 80°C for 2.0 h. 30 eq of hydrazine hydrate was added and the reaction continued for 4 h. LCMS confirmed the completion of the reaction. The reaction solution was cooled to room temperature and concentrated in vacuo. A small amount of water was added, and the mixture was extracted with dichloromethane and separated. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was dissolved in dichloromethane, mixed with silica gel (1.5 g), and dried under vacuum. The mixture was then purified by flash chromatography (DCM:MeOH = 0-7%) to afford compound 50j (180 mg, 0.65 mmol).

[1214] LCMS (ESI-MS) m / z: 279.20 [M+H] + .

[1215] Synthesis of 5-[1-(8-chloroimidazo[3,2-a]pyridin-6-yl)-3-methylcyclobutyl]-4-methyl-1,2,4-triazacyclopentane-3-thiophenol 50k

[1216] Compound 50j (23 g, 81 mmol) and methyl isothiocyanate (7.1 g, 97 mmol) were weighed and dissolved in ethanol (20 mL) in an eggplant-shaped flask. The mixture was stirred in an oil bath at 80°C for 1 hour. A plate reader and LCMS confirmed the complete reaction (the solution turned turbid from clear). Sodium bicarbonate (34 g, 400 mmol) was then weighed and dissolved in water. The mixture was then added to the reaction mixture and stirred in an oil bath at 80°C for another 2.0 hours. LCMS confirmed the complete reaction. After the reaction was completed, the mixture was cooled to 40°C and concentrated in vacuo to remove most of the ethanol. The mixture was then slurried with water and dichloromethane, filtered, and the filter cake was collected and dried to yield a pale yellow solid. The filtrate was washed with DCM, extracted, and separated. The organic phase was collected and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The concentrated filtrate was dissolved in DCM and mixed with silica gel (15 g). Flash purification (DCM:MeOH = 0-2%) was performed to yield compound 50k (5.4 g, 49 mmol).

[1217] LCMS (ESI-MS) m / z: 334.20 [M+H] + .

[1218] Synthesis of 8-chloro-6-[3-methyl-1-(4-methyl-1,2,4-triazacyclopentan-3-yl)cyclobutyl]imidazo[3,2-a]pyridine 501

[1219] Compound 50k (16 g, 49 mmol) was weighed into an eggplant-shaped flask and EA (300 mL) was added. The reaction mixture became turbid. Sodium nitrite (17 g, 250 mmol) and nitric acid (190 mL, 190 mmol) were slowly added in an ice bath. The mixture was allowed to react at room temperature for 30 min. When the reaction mixture became clear, LCMS monitoring indicated completion of the reaction. After completion, the reaction mixture was allowed to stand, separated, and the EA phase was separated. After confirming the absence of product by a plate, the aqueous phase was collected and the pH was adjusted to alkaline by adding 6 eq of sodium bicarbonate. The mixture was then extracted with DCM and separated. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and spin-dried to obtain compound 50l (12 g, 40 mmol).

[1220] LCMS (ESI-MS) m / z: 302.20 [M+H] + .

[1221] Synthesis of 8-chloro-6-[(1s,3s)-3-methyl-1-(4-methyl-1,2,4-triazacyclopentan-3-yl)cyclobutyl]imidazo[3,2-a]pyridine 50m

[1222] The crude compound 501 (6.9 g) was purified by chiral-preparative HPLC: chiral column: AY-H 4.6*100 mm 5 μm; mobile phase, IPA [0.5% NH 3 (7.0 M in MeOH)] to give compound 50m (3.1 g).

[1223] Synthesis of 2-(6-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)imidazo[1,2-a]pyridin-8-yl)-6-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindol-1-one 50

[1224] A sealed tube was removed and compound 50m (300 mg, 0.99 mmol), compound 50n (280 mg, 0.60 mmol), Pd(OAc)2 (67 mg, 0.30 mmol), Xantphos (110 mg, 0.20 mmol), and Cs2CO3 (650 mg, 2.0 mmol) were added. The mixture was then added to dioxane (10 mL). The atmosphere was replaced with nitrogen for 1 minute and the mixture was heated in an oil bath at 105°C for 2 hours. The mixture was then spin-dried to dryness, and 4.0 mL of dichloromethane was added. The mixture was sonicated and filtered through a pad of celite. The filtrate was spin-dried to dryness, yielding 300 mg of the crude product, which was then purified by preparative HPLC to afford compound 50 (108 mg).

[1225] LCMS (ESI-MS) m / z: 578.50 [M+H] + .

[1226] 1H NMR (400MHz, DMSO-d6) δ8.79(d,J=1.8Hz,1H),8.33(s,1H),8.02(d,J=1.2Hz,1H),7.98(s,1H),7.92( s,1H),7.62(d,J=1.2Hz,1H),7.54(d,J=1.7Hz,1H),5.62(s,2H),3.63(s,2H),3.31(s,3H),2.85(dd, J=9.8,6.1Hz,2H),2.69(t,J=10.3Hz,2H),2.55(q,J=10.3,8.9Hz,3H),1.90(t,J=11.0Hz,1H),1.66– 1.53(m,4H),1.47(t,J=12.2Hz,1H),1.08(d,J=5.9Hz,3H),0.89–0.82(m,1H),0.79(d,J=5.8Hz,3H).

[1227] Example 51: Synthesis of Compound 51

[1228] Synthesis of 2-methylprop-2-yl 6-{[(3S)-3-(hydroxymethyl)piperidin-1-yl]methyl}-1-oxylidene-4-(trifluoromethyl)-2,3-dihydro-1H-isoindole-2-carboxylate 51b

[1229] Compound 51a (200 mg, 0.61 mmol), [(3S)-hexahydropyridin-3-yl]methanol (210 mg, 1.8 mmol), and sodium triacetoxyborohydride (380 mg, 1.8 mmol) were dissolved in THF (10 mL). Acetic acid (0.36 mg, 0.0060 mmol) was added dropwise and stirred at room temperature overnight. LCMS confirmed the reaction was complete. The mixture was quenched with saturated sodium bicarbonate solution (20 mL), extracted with EA (20 mL × 3), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and spin-dried. The organic phase was dried and concentrated, and the residue was purified using silica gel flash chromatography (PE: (4 / 5 EA + 1 / 5 EtOH) = 6:4) to afford compound 51b (200 mg, 0.47 mmol).

[1230] LCMS (ESI-MS) m / z: 429.40 [M+H] + .

[1231] Synthesis of [(3S)-1-{[3-oxoylidene-7-(trifluoromethyl)-2,3-dihydro-1H-isoindol-5-yl]methyl}hexahydropyridin-3-yl]methyl acetate 51c

[1232] Compound 51b (200 mg, 0.47 mmol) was dissolved in ethyl acetate (2.0 mL), and a solution of hydrogen chloride in ethyl acetate (0.58 mL, 2.3 mmol) was added. The mixture was stirred at room temperature overnight. LCMS confirmed the reaction was complete. The mixture was quenched with saturated sodium bicarbonate solution (20 mL), extracted with EA (20 mL × 3), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified using silica gel flash chromatography (PE:(1 / 4 EtOH + 3 / 4 THF + 5‰ NH3H2O) = 8:2) to afford compound 51c (130 mg, 0.36 mmol).

[1233] LCMS (ESI-MS) m / z: 371.40 [M+H] + .

[1234] Synthesis of [(3S)-1-[(2-{5-[3-methyl-1-(4-methyl-1,2,4-triazacyclopentan-3-yl)cyclobutyl]-2-oxyylidene-1-(2,2,2-trifluoroethyl)pyridin-3-yl}-3-oxyylidene-7-(trifluoromethyl)-2,3-dihydro-1H-isoindol-5-yl)methyl]hexahydropyridin-3-yl]methyl acetate 51e

[1235] Compound 51c (130 mg, 0.36 mmol) and compound 51d (140 mg, 0.36 mmol) were dissolved in 1,4-dioxane (7.0 mL). Palladium acetate (16 mg, 0.071 mmol), Xantphos (82 mg, 0.14 mmol), and Cs2CO3 (350 mg, 1.1 mmol) were added. The mixture was microwaved at 110°C for 2 h under nitrogen protection. LCMS confirmed the reaction was complete. The product was filtered through Celite and dried by spin drying. The residue was purified on silica gel flash chromatography (DCM:MeOH = 95:5) to afford compound 51e (190 mg, 0.27 mmol).

[1236] LCMS (ESI-MS) m / z: 695.50 [M+H] + .

[1237] Synthesis of 6-{[(3S)-3-(hydroxymethyl)hexahydropyridin-1-yl]methyl}-2-{5-[3-methyl-1-(4-methyl-1,2,4-triazacyclopentan-3-yl)cyclobutyl]-2-oxylidene-1-(2,2,2-trifluoroethyl)pyridin-3-yl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 51

[1238] Compound 51e (190 mg, 0.23 mmol) was dissolved in methanol (3.0 mL), and water (3.0 mL) and potassium carbonate (180 mg, 1.3 mmol) were added. The mixture was stirred at room temperature for one hour. LCMS confirmed the reaction was complete. The mixture was extracted with EA (20 mL × 3), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was lyophilized by HPLC to yield compound 51 (67 mg, 0.10 mmol).

[1239] LCMS (ESI-MS) m / z: 653.50 [M+H] + .

[1240] 1 H NMR (400MHz, DMSO-d6) δ8.33(s,1H),7.94(d,J=3.2Hz,2H),7.89(s,1H),7.64(d,J=2.5 Hz,1H),5.09(s,2H),5.02-4.91(m,2H),4.38(t,J=5.3Hz,1H),3.69–3.57(m,2H) ,3.37(s,1H),3.34(s,2H),3.29-3.22(m,1H),3.17–3.02(m,1H),2.80(d,J=10.4H z,1H),2.77–2.65(m,3H),2.47–2.41(m,2H),2.33–2.11(m,1H),2.01–1.89(m,1H) ,1.72-1.53(m,4H),1.44(d,J=10.8Hz,1H),1.11-1.03(m,3H),0.93–0.80(m,1H).

[1241] Example 52: Synthesis of Compound 52

[1242] Synthesis of 6-(hydroxymethyl)-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 52b

[1243] Compound 52a (380 mg, 1.4 mmol) was dissolved in CH3OH (10 mL), and NaBH4 (160 mg, 4.2 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with saturated ammonium chloride solution (15 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered, and dried to give the crude product. The crude product was purified using silica gel (EA / PE = 0-20%) to give compound 52b (180 mg).

[1244] LCMS (ESI-MS) m / z: 232.00 [M+H] + .

[1245] Synthesis of 6-(chloromethyl)-4-(trifluoromethyl)isoindol-1-one 52c

[1246] Compound 52b (180 mg, 0.78 mmol) was dissolved in CH2Cl2 (10 mL), and thionyl chloride (1.0 g, 7.8 mmol) was added at 0°C. The reaction mixture was heated to 45°C and stirred for 2 hours. After the reaction was complete, the reaction solution was dried by vortexing, and the residue was added with CH2Cl2 (20 mL) and dried again by vortexing to obtain compound 52c (190 mg).

[1247] LCMS (ESI-MS) m / z: 250.00 [M+H] + .

[1248] Synthesis of (R)-6-((2-methylmorpholino)methyl)-4-(trifluoromethyl)isoindol-1-one 52d

[1249] Compound 52c (500 mg, 2.0 mmol) and (R)-2-methylmorpholine (410 mg, 4.0 mmol) were dissolved in CH3CN (12 mL). KI (330 mg, 2.0 mmol) and K2CO3 (830 mg, 6.0 mmol) were added, and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was spin-dried, diluted with water, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to obtain the crude product. The crude product was purified on silica gel (DCM / MeOH = 20:1) to obtain compound 52d (260 mg).

[1250] LCMS (ESI-MS) m / z: 315.30 [M+H] + .

[1251] Synthesis of (R)-2-(6-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)imidazo[1,2-a]pyridin-8-yl)-6-(2-methylmorpholinyl)methyl)-4-(trifluoromethyl)isoindol-1-one 52

[1252] Compound 52d (38 mg, 0.12 mmol), 52e (41 mg, 0.14 mmol), Pd(OAc)2 (9.2 mg, 0.041 mmol), Xantphos (16 mg, 0.027 mmol), and Cs2CO3 (89 mg, 0.27 mmol) were mixed in dioxane (3.0 mL), purged with nitrogen briefly, and heated to 105°C in a sealed tube for 2 hours. The reaction mixture was transferred to a single-necked flask, dried by spin-drying, and 10 mL of dichloromethane was added. The mixture was then sonicated briefly, filtered, and the residue was washed with dichloromethane (5.0 mL). The organic phase was then spin-dried to obtain the crude product. The crude product was directly subjected to pre-HPLC to yield compound 52 (10 mg).

[1253] LCMS (ESI-MS) m / z: 580.50 [M+H] + .

[1254] 1H NMR (400MHz, Methanol-d4) δ8.77(d,J=1.8Hz,1H),8.34(s,1H),8.09(d,J=1.4Hz,1H),7.97(dd,J=9 .9,1.4Hz,2H),7.62(dd,J=4.7,1.3Hz,1H),7.39(dd,J=38.2,1.7Hz,1H),5.45–5.20(m,2H),3.89–3. 77(m,1H),3.76–3.57(m,4H),3.45(d,J=5.8Hz,3H),3.06–2.91(m,2H),2.83–2.53(m,5H),2.22(td,J =11.5,3.4Hz,1H),1.91(dd,J=11.3,10.0Hz,1H),1.18(dd,J=6.4,5.0Hz,3H),1.11(d,J=6.3Hz,3H).

[1255] Example 53: Synthesis of Compound 53

[1256] Synthesis of 6-(hydroxymethyl)-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 53b

[1257] Compound 53a (6.8 g, 25 mmol) was dissolved in anhydrous methanol (70 mL). NaBH₄ (1.9 g, 50 mmol) was added portionwise under an ice bath, with vigorous bubbling. After completion of the addition, the mixture was allowed to warm to room temperature and stirred for 1 hour. LCMS confirmed complete reaction. The solution was quenched with saturated ammonium chloride, concentrated, extracted with EA, washed with saturated NaCl, dried over anhydrous sodium sulfate, and spin-dried. The mixture was then passed through a column (SiO₂, DCM:MeOH = 1:0 to 20:1) to yield compound 53b (3.4 g, 15 mmol).

[1258] LCMS (ESI-MS) m / z: 232.20 [M+H] + .

[1259] Synthesis of 6-(chloromethyl)-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 53c

[1260] Compound 53b (1.0 g, 4.3 mmol) was added to a 50 mL single-necked flask. DCM (10 mL) was added, and the substrate partially dissolved. SOCl2 (0.94 mL, 13 mmol) was then added dropwise. The substrate bubbled slightly and dissolved, becoming clear. The reaction mixture was stirred in an oil bath at 50°C for 1 hour. LCMS confirmed complete reaction. The solution was then spin-dried to dryness, and DCM was added and spin-dried again. This process was repeated three times to remove as much residual SOCl2 as possible. The crude product was used directly in the next reaction, yielding crude compound 53c (1.0 g, 4.0 mmol).

[1261] LCMS (ESI-MS) m / z: 250.10 [M+H] + .

[1262] Synthesis of 6-{[(methylcyclopropyl)amino]methyl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 53d

[1263] Compound 53c (500 mg, 2.0 mmol) was dissolved in acetonitrile (10 mL), and potassium carbonate (830 mg, 6.0 mmol), KI (330 mg, 2.0 mmol), and 1-methylcyclopropyl-1-amine hydrochloride (430 mg, 4.0 mmol) were added. The mixture was stirred at room temperature overnight. LCMS confirmed the complete reaction of the starting material. The reaction mixture was briefly filtered, and the filter cake was washed once with acetonitrile. The filtrates were combined and concentrated to dryness, diluted with water, and extracted with EA. The organic phases were combined, dried over anhydrous Na2SO4 solid powder, filtered, dried, and the mixture was passed through a column (SiO2, DCM:MeOH = 1:0 to 20:1) to obtain analogous compound 53d (300 mg, 1.1 mmol).

[1264] LCMS (ESI-MS) m / z: 285.20 [M+H] + .

[1265] Synthesis of 2-methylpropan-2-yl [(methylcyclopropyl){[3-oxyylidene-7-(trifluoromethyl)-2,3-dihydro-1H-isoindol-5-yl]methyl}amino]methane ester 53e

[1266] Compound 53d (300 mg, 1.1 mmol) was dissolved in DCM (3.0 mL), and (Boc)2O (250 mg, 1.2 mmol) and TEA (0.22 mL, 1.6 mmol) were added. The reaction solution was stirred at room temperature for 3 hours. LCMS showed that the starting material had reacted completely. The reaction solution was directly concentrated and passed through a forward phase column (PE:EA = 1:0 to 1:1) to obtain compound 53e (300 mg, 0.73 mmol).

[1267] LCMS (ESI-MS) m / z: 385.30 [M+H] + .

[1268] Synthesis of 2-methylpropan-2-yl [(methylcyclopropyl)[(2-{6-[3-methyl-1-(4-methyl-1,2,4-triazacyclopentyl-3-yl)cyclobutyl]imidazo[1,2-a]pyridin-8-yl}-3-oxyylidene-7-(trifluoromethyl)-2,3-dihydro-1H-isoindol-5-yl)methyl]amino]methane ester 53f

[1269] Compound 53e (120 mg, 0.21 mmol) was dissolved in dioxane (2.0 mL), and 8-chloro-6-[3-methyl-1-(4-methyl-1,2,4-triazacyclopentan-3-yl)cyclobutyl]imidazo[3,2-a]pyridine (63 mg, 0.21 mmol), Pd(OAc)2 (14 mg, 0.062 mmol), Xantphos (24 mg, 0.042 mmol) and Cs2CO3 (140 mg, 0.42 mmol) were added. The reaction system was purged with nitrogen three times and stirred in an oil bath at 105°C for 3 hours. LCMS showed no starting material remaining. The reaction solution was directly filtered, and the filter cake was washed three times with (MeOH:DCM=10:1) solution (5.0 mL). The filtrates were combined, dried, and the mixture was passed through a column (DCM:MeOH=1:0 to 20:1) to give compound 53f (130 mg, 0.40 mmol).

[1270] LCMS (ESI-MS) m / z: 650.50 [M+H] + .

[1271] Synthesis of 6-{[(methylcyclopropyl)amino]methyl}-2-{6-[3-methyl-1-(4-methyl-1,2,4-triazacyclopentyl-3-yl)cyclobutyl]imidazo[1,2-a]pyridin-8-yl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 53

[1272] Compound 53f (110 mg, 0.17 mmol) was dissolved in DCM (3.0 mL), and TFA (1.0 mL) was added, followed by stirring at room temperature overnight. LCMS confirmed complete reaction, and the reaction mixture was directly dried and dissolved in methanol. Solid sodium bicarbonate powder was added to make the solution alkaline, and the sodium bicarbonate powder was removed by filtration. The filter cake was washed twice with methanol, and the filtrates were combined and concentrated to near dryness. Compound 53 (20 mg, 0.036 mmol) was obtained by prep-HPLC (FA system) purification.

[1273] LCMS (ESI-MS) m / z: 550.50 [M+H] + .

[1274] 1 H NMR(400MHz,CD3OD)δ9.19–9.22(m,1H),8.99–9.03(m,1H),8.31–8.37(m,2 H),8.27(s,1H),8.11–8.13(m,1H),7.89–7.96(m,1H),5.36(s,2H),4.61(s, 2H),3.58–3.60(m,3H),3.24–3.29(m,2H),3.08–3.09(m,2H),2.71–2.76(m ,2H),2.54–2.56(m,1H),1.62(s,3H),1.17–1.21(m,3H),0.86–0.90(m,2H).

[1275] Example 54: Synthesis of Compound 54

[1276] Synthesis of 2-methylprop-2-yl 6-{[(methylcyclobutyl)amino]methyl}-1-oxylidene-4-(trifluoromethyl)-2,3-dihydro-1H-isoindole-2-carboxylate 54b

[1277] Compound 54a (500 mg, 1.5 mmol), 1-methyl-1-cyclobutanamine hydrochloride (550 mg, 4.6 mmol), and N,N-diisopropylethylamine (0.77 mL, 4.4 mmol) were dissolved in THF (10 mL) and stirred for 3 min. Sodium triacetoxyborohydride (960 mg, 4.6 mmol) was added and stirred at room temperature overnight. LCMS confirmed the reaction was complete. The mixture was quenched with saturated sodium bicarbonate solution (20 mL), extracted with EA (20 mL × 3), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and spin-dried. The organic phase was dried and concentrated, and the residue was purified using silica gel flash chromatography (PE: (4 / 5 EA + 1 / 5 EtOH) = 8:2) to afford compound 54b (570 mg, 1.4 mmol).

[1278] LCMS (ESI-MS) m / z: 399.30 [M+H] + .

[1279] Synthesis of 6-{[(methylcyclobutyl)amino]methyl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 54c

[1280] Compound 54b (570 mg, 1.4 mmol) was dissolved in dichloromethane (10 mL), and a solution of hydrogen chloride in ethyl acetate (1.8 mL, 7.2 mmol) was added. The mixture was stirred at room temperature overnight. The next day, a sample was sent for LCMS and the reaction was complete. The mixture was quenched with saturated sodium bicarbonate solution (20 mL), extracted with dichloromethane (20 mL × 3), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and dried. The residue was purified using silica gel flash chromatography (PE:(1 / 4 EtOH + 3 / 4 THF + 5‰ NH3H2O) = 7:3) to obtain compound 54c (390 mg, 1.3 mmol).

[1281] LCMS (ESI-MS) m / z: 299.30 [M+H] + .

[1282] Synthesis of 2-methylpropan-2-yl [(methylcyclobutyl){[3-oxyylidene-7-(trifluoromethyl)-2,3-dihydro-1H-isoindol-5-yl]methyl}amino]methane ester 54d

[1283] Compound 54c (390 mg, 1.3 mmol), di-tert-butyl dicarbonate (0.33 mL, 1.4 mmol), and triethylamine (0.27 mL, 1.9 mmol) were dissolved in dichloromethane (3.0 mL) and stirred at room temperature overnight. LCMS indicated the reaction was complete. The product was quenched with saturated sodium bicarbonate solution (20 mL), extracted with DCM (20 mL × 3), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified using silica gel flash chromatography (PE:(1 / 4 EtOH + 3 / 4 THF + 5‰ NH3H2O) = 7:3) to afford compound 54d (380 mg, 0.96 mmol).

[1284] LCMS(ESI-MS)m / z:343.30[M+H-56] + .

[1285] Synthesis of 2-methylpropan-2-yl [(methylcyclobutyl)[(2-{6-[3-methyl-1-(4-methyl-1,2,4-triazacyclopentyl-3-yl)cyclobutyl]imidazo[3,2-a]pyridin-8-yl}-3-oxylidene-7-(trifluoromethyl)-2,3-dihydro-1H-isoindol-5-yl)methyl]amino]methane ester 54f

[1286] Compound 54d (110 mg, 0.28 mmol) and 8-chloro-6-[3-methyl-1-(4-methyl-1,2,4-triazacyclopentan-3-yl)cyclobutyl]imidazo[3,2-a]pyridine 54e (83 mg, 0.28 mmol) were dissolved in 1,4-dioxane (7.0 mL). Palladium acetate (12 mg, 0.055 mmol), Xantphos (64 mg, 0.11 mmol), and Cs2CO3 (270 mg, 0.83 mmol) were added. The mixture was microwaved at 110°C for 2 h under nitrogen protection. LCMS indicated that the reaction was complete. The product was filtered through celite and dried by spin drying. The residue was purified on silica gel flash chromatography (DCM:MeOH = 95:5) to afford compound 54f (100 mg, 0.16 mmol).

[1287] LCMS (ESI-MS) m / z: 664.60 [M+H] + .

[1288] Synthesis of 6-{[(methylcyclobutyl)amino]methyl}-2-{6-[3-methyl-1-(4-methyl-1,2,4-triazacyclopentyl-3-yl)cyclobutyl]imidazo[3,2-a]pyridin-8-yl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 54

[1289] Compound 54f (100 mg, 0.16 mmol) was dissolved in dichloromethane (3.0 mL) and stirred in an ice bath for 2 min. Trifluoroacetic acid (0.50 mL, 6.5 mmol) was then slowly added and stirred at room temperature for one hour. The reaction was complete by LCMS. The product was quenched with saturated sodium bicarbonate solution (20 mL), extracted with dichloromethane (20 mL × 3), washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was lyophilized by HPLC to yield compound 54 (31 mg, 0.055 mmol).

[1290] LCMS (ESI-MS) m / z: 564.50 [M+H] + .

[1291] 1H NMR(400MHz,DMSO-d6)δ8.82(d,J=1.7Hz,1H),8.34(s,1H),8.12(s,1H),8.07(s,1H), 8.05-8.01(m,1H),7.65-7.61(m,1H),7.54(d,J=1.6Hz,1H),5.64(s,2H),3.90(s,2H),3.34(d,J=9.1Hz,3H),2.91-2.81(m,2H) ,2.68-2.52(m,2H),2.41–2.26(m,1H),2.10-2.00(m,2H),1.79–1.62(m,4H),1.28(s,3H),1.24–1.21(m,1H),1.15-1.05(m,3H).

[1292] Example 55: Synthesis of Compound 55

[1293] Synthesis of 5-bromo-7-(bromomethyl)[1,2,4]triazolo[1,5-a]pyridine 55b

[1294] Compound 55a (2.8 g, 13 mmol) was dissolved in carbon tetrachloride (50 mL), and BPO (320 mg, 1.3 mmol) and NBS (2.8 g, 16 mmol) were added. The reaction solution was stirred at 80°C for 8 hours. Saturated sodium bicarbonate solution was added to the reaction solution, and the mixture was extracted twice with dichloromethane. The organic phase was dried and concentrated to give a crude product. The residue was purified with silica gel (EA / PE = 0-20%) to give compound 55b (1.9 g).

[1295] LCMS (ESI-MS) m / z: 292.00 [M+H] + .

[1296] Synthesis of (5-bromo[1,2,4]triazolo[1,5-a]pyridin-7-yl)acetonitrile 55c

[1297] Compound 55b (1.9 g, 6.6 mmol) was dissolved in CH3CN (40 mL), and TMSCN (1.3 g, 13 mmol) and LiOH (480 mg, 20 mmol) were added at 0°C, and stirred at 0°C for 3 hours. After the reaction was complete, water (50 mL) was added, and the mixture was extracted three times with ethyl acetate (60 mL). The organic phase was dried and concentrated, and the residue was purified on silica gel (EA / PE = 0-25%) to give compound 55c (1.2 g).

[1298] LCMS (ESI-MS) m / z: 238.00 [M+H] + .

[1299] Synthesis of Methyl Acetate (5-Bromo[1,2,4]triazolo[1,5-a]pyridin-7-yl) 55d

[1300] Compound 55c (1.2 g, 5.0 mmol) was dissolved in methanol (15 mL), and thionyl chloride (6 g, 50 mmol) was added dropwise under ice-cooling. After completion of the addition, the temperature was raised to 65°C and stirred for 8 hours. After cooling, the mixture was spin-dried. Ethyl acetate and saturated NaHCO₃ solution were added to the residue, and the layers were separated by extraction. The organic phase was washed with saturated brine, dried, and concentrated. The residue was purified on silica gel (EA / PE = 0-20%) to obtain compound 55d (1.0 g).

[1301] LCMS (ESI-MS) m / z: 271.00 [M+H] + .

[1302] Synthesis of methyl 1-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-methylcyclobutane-1-carboxylate 55e

[1303] To a single-necked flask, NaH (300 mg, 60%, 7.4 mmol) and DMF (3.0 mL) were added. Compound 55d (1.0 g, 3.7 mmol) and 1,3-dibromo-2-methylpropane (1.2 g, 5.6 mmol) in DMF (10 mL) were then added at 0°C and stirred at 0°C for 2 hours. The mixture was quenched with saturated aqueous ammonium chloride solution and extracted with EA. The organic phase was dried and spin-dried, and the residue was purified on silica gel flash chromatography (EA / PE = 0-25%) to afford compound 55e (400 mg).

[1304] LCMS (ESI-MS) m / z: 325.00 [M+H] + .

[1305] Synthesis of 1-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-methylcyclobutane-1-carboxylic acid 55f

[1306] Compound 55e (340 mg, 1.0 mmol) was dissolved in a mixture of THF (10 mL) and H₂O (5.0 mL). LiOH (130 mg, 3.1 mmol) was added at 0°C, and the reaction mixture was stirred at 0°C for 4 hours. LCMS confirmed complete reaction. Water (20 mL) was added to the reaction mixture, and acetic acid was added dropwise until the solution became weakly acidic. The mixture was extracted with dichloromethane (30 × 3 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered to dryness to afford compound 55f (320 mg).

[1307] LCMS (ESI-MS) m / z: 311.00 [M+H] + .

[1308] Synthesis of 55 g of [1-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-methylcyclobutyl]{2-[(methylamino)sulfoxymethyl]diazepinyl}methanone

[1309] Compound 55f (280 mg, 0.90 mmol) and N-methylhydrazinecarbosulfamide (190 mg, 1.8 mmol) were dissolved in DMF (8.0 mL). HATU (690 mg, 1.8 mmol) and DIPEA (290 mg, 2.3 mmol) were added, and the reaction mixture was stirred at room temperature overnight. LCMS confirmed complete reaction. The reaction mixture was poured into water (30 mL) and extracted with dichloromethane (40 × 3 mL). The combined organic phases were washed with saturated ammonium chloride solution and brine, dried over anhydrous sodium sulfate, and filtered to dryness to obtain the crude product. The crude product was purified on silica gel flash chromatography (0-10% MeOH / DCM) to afford compound 55g (330 mg).

[1310] LCMS (ESI-MS) m / z: 397.20 [M+H] + .

[1311] Synthesis of 5-[1-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-7-yl)-3-methylcyclobutyl]-4-methyl-1,2,4-triazole-3-thiol 55h

[1312] Compound 55g (310 mg, 0.78 mmol) was dissolved in a mixture of EtOH (10 mL) and H₂O (4.0 mL). NaHCO₃ (200 mg, 2.3 mmol) was added, and the reaction mixture was heated to 80°C for 8 hours. LCMS analysis confirmed complete reaction. The reaction mixture was diluted with water (20 mL) and extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and spun down to obtain crude product 55h, which was used directly in the next step without purification.

[1313] LCMS (ESI-MS) m / z: 380.00 [M+H] + .

[1314] Synthesis of 5-bromo-7-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl][1,2,4]triazolo[1,5-a]pyridine 55i

[1315] Compound 55h (0.79 mmol) was dissolved in dichloromethane (15 mL), and HOAc (440 mg) and H₂O₂ (30%, 0.9 mL) were added. The mixture was allowed to react at room temperature for 1 hour. LCMS confirmed the completion of the reaction. An aqueous solution of sodium sulfite (1.5 eq) was added to quench the reaction. The organic phase was separated and washed with brine. The organic phase was dried, filtered, and concentrated. The residue was purified on silica gel flash chromatography (0-10% MeOH / DCM) to afford compound 55i (160 mg).

[1316] LCMS (ESI-MS) m / z: 348.00 [M+H] + .

[1317] Synthesis of 6-{[(3S)-3-methylhexahydropyridin-1-yl]methyl}-2-{7-[3-methyl-1-(4-methyl-1,2,4-triazol-3-yl)cyclobutyl][1,2,4]triazolo[1,5-a]pyridin-5-yl}-4-(trifluoromethyl)-2,3-dihydro-1H-isoindol-1-one 55k

[1318] Take a sealed tube and add compound 55i (160 mg, 0.51 mmol), 55j (180 mg, 0.51 mmol), Pd(OAc)2 (23 mg, 0.10 mmol), Xantphos (59 mg, 0.10 mmol), Cs2CO3 (330 mg, 1.0 mmol), Dioxane (8.0 mL) in sequence under N2 protection. Seal the tube and heat at 115°C for 2 hours. Send to LCMS for detection. After the reaction is complete, cool and filter on celite. Wash the residue with 1,4-dioxane. Concentrate the filtrate and purify the residue by silica gel flash chromatography (MeOH / DCM = 0-10%) to give the crude product, which is then purified by pre-HPLC to give compound 55k (25 mg).

[1319] LCMS (ESI-MS) m / z: 579.50 [M+H] + .

[1320] Synthesis of 2-(7-((1S,3R)-3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-6-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindolin-1-one 55

[1321] Compound 55k was subjected to chiral resolution to give compound 55 (23 mg).

[1322] LCMS (ESI-MS) m / z: 579.50 [M+H] + .

[1323] 1H NMR(400MHz,Methanol-d4)δ8.48(s,1H),8.37(s,1H),8.12(s,1H),8.04(s,1H),7 .96(d,J=1.9Hz,1H),7.32(d,J=1.8Hz,1H),5.67–5.23(m,2H),3.72(s,2H),3.42( s,3H),3.11–2.97(m,2H),2.92–2.61(m,5H),2.01(td,J=11.4,3.1Hz,1H),1.80–1 .54(m,5H),1.29(dd,J=7.9,2.1Hz,1H),1.18(d,J=6.0Hz,3H),0.99–0.81(m,3H).

[1324] Example 56: Synthesis of Compound 56

[1325] Synthesis of Isothiocyanomethane-d3 56b

[1326] In a single-necked flask, compound 56a (280 mg, 4.0 mmol) was added to DCM (9.0 mL), followed by N,N-diisopropylethylamine (1000 mg, 8.0 mmol) and cesium carbonate (2600 mg, 8.0 mmol). Carbon dichlorosulfide (550 mg, 4.8 mmol) was dissolved in DCM (9.0 mL). The reaction solution was slowly added dropwise to the above reaction solution at room temperature, followed by stirring at room temperature overnight. The mixture was filtered, the filtrate was spin-dried, and used directly in the next reaction.

[1327] Synthesis of N-(methyl-d3)-2-(3-methyl-1-(8-methylimidazo[1,2-a]pyridin-6-yl)cyclobutane-1-carbonyl)hydrazine-1-methylsulfamide 56d

[1328] In a single-necked flask, compound 56c (560 mg, 2.0 mmol) dissolved in ethanol (8.0 mL) was added, followed by compound 56b (300 mg, 4.0 mmol), and the mixture was heated at 80°C for 10 minutes. LCMS was used to check the reaction completion, and the reaction solution was used for the next step.

[1329] LCMS (ESI-MS) m / z: 355.30 [M+H] + .

[1330] Synthesis of 5-(1-(8-chloroimidazo[1,2-a]pyridin-6-yl)-3-methylcyclobutyl)-4-(methyl-d3)-4H-1,2,4-triazole-3-thiol 56e

[1331] In a single-necked flask, compound 56d (560 mg, 2.0 mmol) was dissolved in ethanol (10 mL). Sodium bicarbonate (340 mg, 4.0 mmol) was added and the mixture was heated at 80°C for 10 minutes. The reaction was complete after LCMS analysis. The mixture was spin-dried and saturated aqueous ammonium chloride (30 mL) and ethyl acetate (30 mL) were added. The layers were separated, and the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. Flash purification was performed using a DCM:MeOH ratio of 20:1 to afford the title compound 56e (350 mg).

[1332] LCMS (ESI-MS) m / z: 336.60 [M+H] + .

[1333] Synthesis of 8-chloro-6-(3-methyl-1-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)cyclobutyl)imidazo[1,2-a]pyridine 56f

[1334] In a single-necked flask, compound 56e (350 mg, 1.0 mmol) dissolved in DCM (8.0 mL) was added. Acetic acid (0.50 mL, 8.9 mmol) and hydrogen peroxide (0.50 mL, 1.2 mmol) were added at room temperature and stirred for 10 minutes. The reaction was complete by LCMS. Solid sodium sulfite was added until starch-iodine paper no longer showed blue, followed by solid sodium bicarbonate until the pH was approximately 8. The solution was directly wet-coated and passed through a flash column with DCM:MeOH = 20:1 to obtain the target compound 56f (170 mg).

[1335] LCMS (ESI-MS) m / z: 305.20 [M+H] + .

[1336] Synthesis of 2-(6-((1S,3R)-3-methyl-1-(4-(methyl-d3)-4H-1,2,4-triazol-3-yl)cyclobutyl)imidazo[1,2-a]pyridin-8-yl)-6-(((S)-3-methylpiperidin-1-yl)methyl)-4-(trifluoromethyl)isoindol-1-one 56

[1337] A sealed tube was removed and compound 56f (170 mg, 0.56 mmol), compound 56g (160 mg, 0.50 mmol), Pd(OAc)2 (38 mg, 0.17 mmol), Xantphos (65 mg, 0.11 mmol), and Cs2CO3 (360 mg, 1.1 mmol) were added to dioxane (6.0 mL). The atmosphere was replaced with nitrogen for 1 minute and the mixture was heated in an oil bath at 105°C for 2 hours. The mixture was then spin-dried to dryness, and 10 mL of dichloromethane was added. The mixture was sonicated and filtered through a pad of Celite. The filtrate was spin-dried to dryness, and 100 mg of the crude product was purified by preparative HPLC to afford compound 56 (11 mg).

[1338] LCMS (ESI-MS) m / z: 581.50 [M+H] + .

[1339] 1H NMR (400MHz, Methanol-d4) δ8.78(d,J=1.8Hz,1H),8.34(s,1H),8.07(d,J=1.4Hz,1H),7.99(d,J=1 .4Hz,2H),7.62(d,J=1.3Hz,1H),7.44(d,J=1.7Hz,1H),5.36(d,J=1.6Hz,2H),3.71(s,2H),3.05–2 .94(m,2H),2.83(dd,J=18.0,9.1Hz,2H),2.76–2.70(m,1H),2.67–2.60(m,2H),2.05–1.97(m,1H), 1.76–1.66(m,4H),1.64–1.55(m,1H),1.17(d,J=6.4Hz,3H),0.96–0.89(m,1H),0.89–0.85(m,3H).

[1340] Example 57: Synthesis of Compound 57

[1341] Synthesis of methyl 8-bromoquinoxaline-6-carboxylate 57b

[1342] Compound 57a (9.3 g, 38 mmol) was dissolved in EtOH (250 mL), and 1,4-dioxane-2,3-diol (4.5 g, 37 mmol) was added. The mixture was allowed to react at rt overnight. LCMS indicated the product as the primary product. The reaction mixture was filtered, and the filter cake was washed with EtOH (50 mL). The filter cake was dried under vacuum to afford compound 57b (8.8 g).

[1343] LCMS (ESI-MS) m / z: 267.10 [M+H] + .

[1344] Synthesis of (8-bromoquinoxalin-6-yl)methanol 57c

[1345] Compound 57b (8.0 g, 30 mmol) was dispersed in THF (240 mL), cooled to <-70°C, and DIBAL-H (90 mL, 90 mmol) was added dropwise. The reaction was incubated for 2 h, then slowly warmed to room temperature and allowed to react overnight. LCMS indicated the product as the primary product. The reaction was cooled to <5°C and quenched with MeOH (5.0 mL). Aq. potassium sodium tartrate (200 mL) was then added to further quench the reaction. The mixture was stirred at room temperature until clear. The mixture was then extracted with EA (200 mL x 3). The organic phase was dried, filtered, and spin-dried. The residue was flash purified using DCM / EA (9:1 to 6:4) as eluent to afford compound 57c (5.3 g).

[1346] LCMS (ESI-MS) m / z: 239.10 [M+H] + .

[1347] Synthesis of 5-bromo-7-(chloromethyl)quinoxaline 57d

[1348] Compound 57c (4.8 g, 20 mmol) was dispersed in dichloromethane (80 mL), and DIEA (7.0 mL, 40 mmol) and TsCl (5.7 g, 30 mmol) were added sequentially. The mixture was allowed to react at rt overnight. LCMS showed the product as the primary product. The reaction solution was directly spin-dried and flash purified (PE / EA 9:1 to 8:2) to afford compound 57d (3.2 g).

[1349] LCMS (ESI-MS) m / z: 257.00 [M+H] + .

[1350] Synthesis of 2-(8-bromoquinoxalin-6-yl)acetonitrile 57e

[1351] Compound 57d (1.8 g, 7.0 mmol) was dissolved in ACN (30 mL), and TMSCN (2.6 mL, 21 mmol), LiOH (0.17 g, 7.0 mmol), and potassium iodide (0.12 g, 0.70 mmol) were added sequentially. The mixture was reacted at 40°C for 16 h. LCMS indicated the formation of the product. The reaction was quenched with aq. NaHCO₃ (30 mL) and extracted with EA (30 mL x 3). The organic phases were combined, dried, and spin-dried. The residue was flash purified using DCM / EA (1:0 to 95:5) as eluent to afford compound 57e (690 mg).

[1352] LCMS (ESI-MS) m / z: 248.00 [M+H] + .

[1353] Synthesis of 1-(8-bromoquinoxaline-6-yl)-3-methylcyclobutane-1-carbonitrile 57f

[1354] Compound 57e (590 mg, 2.4 mmol) was dissolved in DMF (12 mL), and 1,3-dibromo-2-methylpropane (1.0 g, 4.8 mmol) and MeONa (770 mg, 14 mmol) were added sequentially. The reaction was allowed to react at rt overnight. LCMS indicated the product as the primary product. The reaction was quenched with aqueous NaHCO₃ (20 mL) and extracted with EA (20 mL x 3). The organic phases were combined, washed with brine (20 mL x 3), dried, and spin-dried. The residue was flash purified (PE / EA 9:1 to 6:4) to afford compound 57f (380 mg).

[1355] LCMS (ESI-MS) m / z: 302.20 [M+H] + .

[1356] Synthesis of 57 g of 1-(8-bromoquinoxaline-6-yl)-3-methylcyclobutane-1-carboxylic acid

[1357] Compound 57f (280 mg, 0.93 mmol) was dissolved in EtOH / H₂O (9.0 mL / 3.0 mL), and NaOH (150 mg, 3.7 mmol) was added. The reaction mixture was heated to 90°C for 16 h. LCMS indicated the product as the primary product. The EtOH was removed by vortexing the reaction mixture under reduced pressure, and concentrated HCl was added dropwise under ice to pH 2. The mixture was lyophilized and flash purified (DCM / MeOH 1:0 to 99:1) to afford compound 57g (240 mg).

[1358] LCMS (ESI-MS) m / z: 321.10 [M+H] + .

[1359] Synthesis of 2-(1-(8-bromoquinoxaline-6-yl)-3-methylcyclobutane-1-carbonyl)-N-methylhydrazine-1-thiocarboamide 57h

[1360] Compound 57g (330 mg, 1.0 mmol) was dissolved in DMF (3.0 mL), and N-methylhydrazine methylsulfamide (160 mg, 1.5 mmol), HATU (470 mg, 1.2 mmol), and DIEA (450 μL, 2.6 mmol) were added sequentially. The reaction was allowed to react at rt overnight. LCMS showed the product as the primary product. The reaction was quenched with aqueous NaHCO₃ (10 mL) and extracted with EA (10 mL x 3). The combined organic phases were washed with brine (10 mL x 3), dried, filtered, and spin-dried to obtain crude compound 57h, which was used directly in the next step.

[1361] LCMS (ESI-MS) m / z: 408.20 [M+H] + .

[1362] Synthesis of 5-(1-(8-bromoquinoxalin-6-yl)-3-methylcyclobutyl)-4-methyl-4H-1,2,4-triazole-3-thiol 57i

[1363] Compound 57h (420 mg, 1.0 mmol) was dissolved in EtOH / H₂O (3.0 mL / 1.5 mL), and NaHCO₃ (170 mg, 2.0 mmol) was added. The mixture was heated to 80°C and allowed to react for 3 h. LCMS indicated the product as the primary product. The EtOH was removed by vortexing the reaction mixture under reduced pressure, and the mixture was extracted with DCM / MeOH (9:1, 10 mL x 3). The organic phase was dried, filtered, and the filtrate was evaporated to dryness to afford crude compound 57i, which was used directly in the next step.

[1364] LCMS (ESI-MS) m / z: 390.10 [M+H] + .

[1365] Synthesis of 5-bromo-7-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)quinoxaline 57j

[1366] Compound 57i (crude, 1.0 mmol) was dissolved in DCM (4.0 mL), and HOAc (120 μL, 2.1 mmol) was added. The mixture was cooled to 0°C, and H₂O₂ (580 μL, 5.1 mmol, 30%) was added dropwise. The reaction was allowed to react at rt for 2 h. LCMS indicated the product as the primary product. The reaction was quenched with aq. Na₂SO₃ (inspected with starch potassium iodide paper), and the reaction mixture was neutralized with aq. NaHCO₃ (10 mL). The reaction mixture was extracted with DCM / MeOH (9:1, 10 mL x 3). The organic phases were combined, dried, filtered, and spin-dried to dryness. The residue was subjected to FCC (DCM / MeOH 99:1) to afford compound 57j (330 mg).

[1367] LCMS (ESI-MS) m / z: 358.20 [M+H] + .

[1368] Synthesis of (S)-4-(difluoromethyl)-2-(7-(3-methyl-1-(4-methyl-4H-1,2,4-triazol-3-yl)cyclobutyl)quinoxalin-5-yl)-6-((3-methylpiperidin...

Claims

1. A compound represented by formula (II), its stereoisomers, tautomers, isotopic derivatives or pharmaceutically acceptable salts thereof, It is characterized in that W 0 CR 0 or N, R 0 is -H or -halogen, preferably R 0 is -H or -F, more preferably R 0 is -H; R 2 -halogen, -CN, -C 2-5 Alkynyl or -C 1-3 Alkyl, wherein the -C 1-3 The alkyl group is optionally substituted with one or more halogens as allowed by the valency; L 1 For-(CR 12 R 13 ) m -or-(CR 12 R 13 ) m -NR 11 -(CR 12 R 13 ) m -, R 11 -H or -C 1-3 alkyl, R 12 and R 13 are independently -H, -OH, -C 1-3 Alkyl, -C 1-3 Alkylene-OH, m is each independently 0, 1, 2, 3 or 4; Ring B is a 5-7 membered aromatic ring, a 5-7 membered heterocyclic ring or an 8-12 membered fused heterobicyclic ring; R 10 are each independently -halogen, -C 1-6 Alkyl, -NH-C 1-6 Alkyl, -OC 1-6 Alkyl, -C 1-3 Alkyl-OC 1-3 Alkyl, -SO2-C 1-3 Alkyl, -OH, oxo, -C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, the -C 1-6 Alkyl and -C 1-3 The alkyl group is optionally substituted with one or more halogen groups as allowed by the valence, and p is 0, 1, 2 or 3; L 2 for R 3 and R 4 are independently -H, -CN, -C 1-3 Alkylene-CN, -halogen, -C 1-3 Alkyl or -OC 1-3 alkyl; R 9 is -H or -CN; R 5 -H, -C 1-3 Alkyl, wherein the -C 1-3 The alkyl group is optionally substituted with one or more halogens or D as allowed by the valence; Ring A is -C 3-6 Cycloalkyl or 4-12 membered heterocycloalkyl; T2 is each independently -OH, -halogen, -C 1-6 Alkyl, -CONR a R b 、-OC 1-6 Alkyl, -C 1-6 Alkylene -OH, -CN, -C 1-6 Alkylene -CN, -C 1-3 Alkylene-OC 1-3 Alkyl, the -C 1-6 Alkyl, -C 1-6 Alkylene-, -C 1-3 Alkylene- or -C 1-3 The alkyl group is optionally substituted with one or more halogen groups within the range allowed by the valence, and the R a , R b Each is independently -H or -C 1-6 Alkyl, or T2 is -C 1-4 Alkylene-, n is 0, 1, 2, 3 or 4.

2. The compound according to claim 1, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that: R 2 -F, -Cl, -Br, -CN, -C 2-3 Alkynyl or -C 1-3 Alkyl, the -C 1-3 The alkyl group is optionally substituted with one or more F groups within the range allowed by the valence; preferably, R 2 is -Cl, -Br, -C≡CH, -CN, -CF3, -CH2F or -CF2H; more preferably, R 2 It is -CF3 or -CF2H.

3. The compound according to claim 1 or 2, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that: R 11 is -H or -Me, preferably R 11 is -H; and / or R 12 and R 13 Each independently represents -H, -OH, -Me, -CH2-OH, preferably R 12 and R 13 Both H or R 12 and R 13 One of them is -H and the other is -OH, -Me or -CH2-OH.

4. The compound according to any one of claims 1 to 3, its stereoisomers, tautomers, isotopic derivatives or pharmaceutically acceptable salts thereof, characterized in that: L 1 is a bond, -(CH2) m -、-CH(C 1-3 Alkyl)-, -(CH2) m NH-, -NH(CH2) m -、-NHCH(C 1-3 alkyl)-, -CH2NHCH2-, -NHCH2CH(OH)-, -NHCH(CH2OH)-, m is 1 or 2; Preferably, L 1 It is a bond, -CH2-, -CH(Me)-, -CH2NH-, -NHCH2-, -NHCH(Me)-, -CH2NHCH2-, -NHCH2CH(OH)-, -NHCH(CH2OH)-.

5. The compound according to any one of claims 1 to 4, its stereoisomers, tautomers, isotopic derivatives or pharmaceutically acceptable salts thereof, characterized in that: R 10 Each independently is -F, -C 1-3 Alkyl, -NH-C 1-3 Alkyl, -OC 1-3 Alkyl, -C 1-3 Alkyl-OC 1-3 Alkyl, -SO2-C 1-3 Alkyl, -OH, oxo, -C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, the -C 1-3 Alkyl or -OC 1-3 The alkyl group is optionally substituted with one or more F groups as allowed by valency; Preferably, R 10 Each is independently -F, -Me, -Et, -CHMe2, -CH2CH2CH3, -NH-Me, -NH-Et, -OMe, -OEt, -CH2OMe, -SO2Me, -SO2Et, -OH, =O, -cyclopropyl, -O-cyclopropyl, -CHF2, -CH2F, -CF3, -CH2CH2F, -CH2CHF2, -CH2CF3, -CF2CH3, -CF2CHF2, -CF2CH2F, -CH2CF2CF 3、 -OCH2CHF2, -OCHF2 or -OCH2CF3.

6. The compound according to any one of claims 1 to 5, its stereoisomers, tautomers, isotopic derivatives or pharmaceutically acceptable salts thereof, characterized in that: L 2 for Preferably, R 3 and R 4 Each is independently -H, -C 1-3 Alkyl or -OC 1-3 More preferably, R 3 and R 4 Each is independently -H, -Me or -O-Me.

7. The compound according to any one of claims 1 to 6, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that: R 5 is -H, -Me, -Et, -CD3, or one or more F-substituted methyl or ethyl groups within the range allowed by the valence, preferably R 5 is -H, -Me, -Et, -CHF2, -CF3 or -CD3, more preferably, R 5 For-Me.

8. The compound according to any one of claims 1 to 7, its stereoisomers, tautomers, isotopic derivatives or pharmaceutically acceptable salts thereof, characterized in that: Ring A is or a 4-6 membered heterocycloalkyl group, wherein the heterocycloalkyl group has 1 or 2 heteroatoms, wherein the heteroatoms are N or O; Preferably, ring A is 9. The compound according to any one of claims 1 to 8, its stereoisomers, tautomers, isotopic derivatives or pharmaceutically acceptable salts thereof, characterized in that: T2 is each independently -OH, -F, -C 1-4 Alkyl, -CONR a R b 、-OC 1-3 Alkyl, -C 1-3 Alkylene -OH, -CN, -C 1-3 Alkylene -CN, -C optionally substituted with one or more F as allowed by the valence 1-3 Alkyl, -C 1-3 Alkylene-OC 1-3 Alkyl, the R a , R b Each is independently -H or -C 1-3 Alkyl, or T2 is -C 1-2 Alkylene-; Preferably, T2 is each independently -OH, -F, -Me, -Et, -CONH2, -O-Me, -CH2-OH, -CN, -CH2CN, -CH2F, -C2H4OMe or -CH2- connected to two carbons on the A ring.

10. The compound according to any one of claims 1 to 9, its stereoisomers, tautomers, isotopic derivatives or pharmaceutically acceptable salts thereof, characterized in that: for Preferably More preferably 11. The compound according to any one of claims 1 to 10, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that: Ring B is a benzene ring, a 6-membered heterocyclic ring or a 9-10-membered fused heterobicyclic ring, wherein the number of heteroatoms in the heterocyclic ring or the fused heterobicyclic ring is 1, 2, 3 or 4.

12. The compound according to any one of claims 1 to 11, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that: Ring B is Among them, M 1 、M 2 、M 3 、M 4 are each independently N, CH or C as allowed by the valence, and M 1 、M 2 Not all are N; Preferably, ring B is 13. The compound according to any one of claims 1 to 11, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that: Ring B is Among them, Z 1 , Z 2 , Z 3 , Z 4 or Z 5 Each independently is C, CH or N as allowed by valence, preferably Z 1 , Z 2 , Z 3 , Z 4 or Z 5 One or two of them are N, and the rest are C or CH; More preferably, ring B is 14. The compound according to claim 1, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (II) has the following structure: W 1 is CH2 or O, R 10 For -C 1-6 Alkyl or -C 3-6 Cycloalkyl, the -C 1-6 The alkyl group is optionally substituted with one or more halogen groups as allowed by the valence; preferably R 10 For -C 1-3 Alkyl, -C 3-6 Cycloalkyl, the -C 1-3 The alkyl group is optionally substituted with one or more F groups within the range allowed by the valence; more preferably, R 10 It is -cyclopropyl, -Et, -CH2CF3, -CHMe2, -CH2CF2CF3.

15. The compound according to claim 1, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (II) has the following structure: W 1 CH2 or O, E 1 、E 2 Each independently is N or CR 10 And E 1 、E 2 Not all are N; R 10 -H, -halogen, -C 1-3 Alkyl, -NH-C 1-3 Alkyl, -OC 1-3 Alkyl, -C 1-3 Alkyl-OC 1-3 Alkyl, -SO2-C 1-3 Alkyl, -C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, the -C 1-3 The alkyl group is optionally substituted with one or more halogens within the range allowed by the valence; preferably -H, -F, -C 1-3 Alkyl, -NH-C 1-3 Alkyl, -OC 1-3 Alkyl, -C 1-3 Alkyl-OC 1-3 Alkyl, -SO2-C 1-3 Alkyl, -OC 3-6 Cycloalkyl, the -C 1-3 The alkyl group is optionally substituted with one or more F groups as allowed by the valence; more preferably -H, -F, -OEt, -NHEt, -OCH2CHF2, -OCHF2, -OCH2CF3, -O-cyclopropyl, -OMe, -OEt, -CH2OMe or -SO2Et.

16. The compound according to claim 1, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (II) has the following structure: Z 1 is N or CH, R 2 is -CF3 or -CF2H, Ring A, T2, n, L 1 As described in claim 1.

17. The compound according to claim 16, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that: L 1 -(CH2) m -、-CH(C 1-3 Alkyl)-, -(CH2) m NH-, -NH(CH2) m -、-NHCH(C 1-3 alkyl)-, -CH2NHCH2-, -NHCH2CH(OH)-, -NHCH(CH2OH)-, m is 1 or 2; preferably, L 1 It is -CH2-, -CH(Me)-, -CH2NH-, -NHCH2-, -NHCH(Me)-, -CH2NHCH2-, -NHCH2CH(OH)-, -NHCH(CH2OH)-.

18. The compound according to claim 16 or 17, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that: Ring A is or a 4-6 membered heterocycloalkyl group, wherein the heteroatom of the heterocycloalkyl group is 1 or 2, wherein the heteroatom is N or O, and preferably ring A is and / or T2 is each independently -OH, -F, -Me, -Et, -CONH2, -O-Me, -CH2-OH, -CN, -CH2CN, -CH2F, -C2H4OMe; and / or n is 1, 2 or 3.

19. The compound according to any one of claims 16 to 18, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that: Ring A is a 6-membered heterocycloalkyl group, wherein the heteroatom of the heterocycloalkyl group is N or O; Preferably, for T2 is -C 1-3 Alkyl; More preferably, for 20. The compound according to claim 1, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (II) has the following structure: Where X is CX 0 or N;X 0 is -H or -halogen; m is 0, 1, 2, 3 or 4; R 1 for Y is -C 1-3 Alkyl or -C 3-6 Cycloalkyl, wherein the -C 1-3 The alkyl group is optionally substituted with one or more halogens as allowed by the valency; X 1 For CX 2 or N;X 2 is -H or -halogen; Y 1 For CY 2 or N; Y 2 -H, -halogen, -C 1-3 Alkylamino, -C 1-3 Alkyloxy, -C 1-3 Cycloalkyloxy, the -C 1-3 Alkylamino or -C 1-3 The alkyloxy group is optionally substituted with one or more halogen or cycloalkyl groups as allowed by valency; Where X 1 and Y 1 Not all are N; R 3 and R 4 are independently -H, -CN, halogen, -C 1-3 Alkyl or -C 1-3 Alkoxy; R 5 -H, -C 1-3 Alkyl, wherein the -C 1-3 The alkyl group is optionally substituted with one or more halogens as allowed by the valency; R 9 is -H or -CN; R 2 -halogen, -CN, -C 2-5 Alkynyl or -C 1-3 Alkyl, wherein the -C 1-3 The alkyl group is optionally substituted with one or more halogens as allowed by the valency; R 6 For-NR 7 R 8 or Where A is -C 3-6 Cycloalkyl or 4-12 membered heterocycloalkyl, T2 is -C 1-4 alkyl aminocarbonyl (the amino group is -NH2, mono-C 1-3 Alkylamino or di-C 1-3 alkylamino), or T2 is -C 1-4 Alkylene-, n is any integer from 0 to 12; R 7 and R 8 -H, -C 1-3 Alkyl or -C 3-6 Cycloalkyl, wherein the -C 3-6 The cycloalkyl group is optionally substituted with one or more T3 groups as allowed by the valence, wherein the T3 group is -C 1-3 alkyl.

21. The compound according to claim 1, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that: The compound represented by formula (II) has the following structure: Where X is CX 0 or N;X 0 is -H or -halogen; R 1 for Y is -C 1-3 Alkyl or -C 3-6 Cycloalkyl, wherein the -C 1-3 The alkyl group is optionally substituted with one or more halogens as allowed by the valency; X 1 For CX 2 or N;X 2 is -H or -halogen; Y 1 For CY 2 or N; Y 2 -H, -halogen, -C 1-3 Alkylamino, -C 1-3 Alkyloxy, the -C 1-3 Alkylamino or -C 1-3 The alkyloxy group is optionally substituted with one or more halogen or cycloalkyl groups as allowed by valency; Where X 1 and Y 1 Not all are N; R 3 and R 4 are independently -H, -CN, -halogen, -C 1-3 Alkyl or -C 1-3 Alkoxy; R 5 -H or -C 1-3 alkyl; R 9 is -H or -CN; R 2 Halogen, -CN, -C 2-5 Alkynyl or -C 1-3 Alkyl, wherein the -C 1-3 The alkyl group is optionally replaced by one or more valence Multiple halogen substitution within the permitted range; R 6 For-NR 7 R 8 or Where A is -C 3-6 Cycloalkyl or 4-12 membered heterocycloalkyl, T2 is -C 1-4 Alkyl, aminocarbonyl (the amino group is -NH2, mono-C 1-3 Alkylamino or di-C 1-3 alkylamino), or T2 is -C 1-4 Alkylene-, n is any integer from 0 to 12; R 7 and R 8 -H, -C 1-3 Alkyl or -C 3-6 Cycloalkyl, wherein the -C 3-6 The cycloalkyl group is optionally substituted with one or more T3 groups as allowed by the valence, wherein the T3 group is -C 1-3 alkyl.

22. The compound according to claim 20 or 21, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that: X is CX 0 or N, X 0 Preferably, X is -H or -F.

23. The compound according to any one of claims 20 to 22, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that: R 1 for Y is -C 1-3 Alkyl or -C 3-5 Cycloalkyl; preferably, the -C 1-3 The alkyl group is optionally substituted with one or more F as allowed by the valence; more preferably, Y is methyl, ethyl, -CH2CF3, isopropyl or cyclopropyl.

24. The compound according to any one of claims 20 to 22, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that: R 1 for Preferably, X 1 CH, CF or N, Y 1 For CY 2 ; or X 1 CH or CF, Y 1 is N.

25. The compound according to any one of claims 20 to 22, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that: R 1 for 26. The compound according to claim 25, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that: Y 2 -H, -F, -C 1-3 Alkylamino, -C 1-3 Alkyloxy; preferably, the -C 1-3 Alkylamino or -C 1-3 The alkyloxy group is optionally substituted with one or more F or cyclopropane groups within the range allowed by the valence; more preferably, Y 2 is -H, -F, -OCH3, -OCH2CH3, -NHCH2CH3, -OCH2CHF2, -OCHF2, -OCH2CF3 or 27. The compound according to any one of claims 20 to 26, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that: R 2 -halogen, -CN, -C 2-3 Alkynyl or -C 1-3 Alkyl; preferably, the -C 1-3 The alkyl group is optionally substituted with one or more F groups within the range allowed by the valence; more preferably, R 2 It is -Br, -Cl, -C≡CH, -CN, -CF3 or -CF2H.

28. The compound according to any one of claims 20 to 27, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that: R 6 For-NR 7 R 8 , R 7 and R 8 One of them is -H and the other is -C 3-6 Cycloalkyl, wherein the -C 3-6 The cycloalkyl group is optionally substituted with one or more T3 groups as allowed by the valence, wherein T3 is -C 1-3 Alkyl; preferably, R 7 and R 8 One of them is -H and the other is -C substituted with methyl 3-6 More preferably, R 7 and R 8 One of them is -H and the other is a cyclobutyl group substituted with a methyl group.

29. The compound according to any one of claims 20 to 27, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that: R 6 for Wherein ring A is a 4-6 membered heterocycloalkyl or -C 4-6 Cycloalkyl, preferably, the 4-6 membered heterocycloalkyl contains 1 or 2 heteroatoms, the heteroatoms are N or O, more preferably, ring A is azacyclopentyl, azacyclohexyl, morpholinyl, cyclobutane, cyclopentane or cyclohexane; n is 0, 1 or 2, preferably 0 or 1; T2 is -C 1-4 Alkyl or mono-C 1-3 Alkylamino or T2 is a methylene group attached to two carbon atoms on ring A, preferably a methyl group or -C(=O)NH2.

30. The compound according to claim 28 or 29, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that: R 6 for Preferably, R 6 for 31. The compound according to any one of claims 19 to 30, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that: R 3 and R 4 are independently -H or -C 1-3 Alkyl; preferably, R 3 and R 4 are independently -H or -CH3; more preferably, R 3 and R 4 One of them is -H and the other is -CH3.

32. The compound according to any one of claims 20 to 31, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that: R 5 For -C 1-3 Alkyl, preferably -CH3.

33. The compound according to any one of claims 1 to 32, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that: A compound selected from the group consisting of:

34. The compound according to any one of claims 1 to 32, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, characterized in that: A compound selected from the group consisting of:

35. A method for preparing a compound according to any one of claims 1 to 34, its stereoisomers, tautomers, isotopic derivatives or pharmaceutically acceptable salts thereof, characterized in that: Contains the steps of Plan 1, Plan 2, Plan 3, Plan 4, Plan 5, Plan 6, Plan 7 or Plan 8, Option 1: When R 1 for X 1 CH, Y 1 For CY 2 , R 5 When it is methyl, Option 2: When R 1 for X 1 CH, Y 1 For CY 2 , R 5 When it is methyl, Option 3: Option 4: When R 1 for X 1 N, Y 1 For CY 2 , R 5 When it is methyl, Option 5: When R 1 for hour, Solution 6: When X is N, Option 7: When R 1 for hour, Option 8: When R 1 for hour, The groups are as described above.

36. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 34, its stereoisomers, tautomers, isotopic derivatives or pharmaceutically acceptable salts thereof, and optionally one or more pharmaceutically acceptable carriers and / or additives.

37. Use of the compound according to any one of claims 1 to 34, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 36 in the preparation of a medicament for preventing or treating cancer, preferably, the cancer includes gastric cancer.

38. Use of the compound according to any one of claims 1 to 34, its stereoisomer, tautomer, isotopic derivative or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 36 as a Cbl-b inhibitor.

39. A method for treating cancer, the method comprising: administering a therapeutically effective amount of a Cbl-b inhibitor to an individual suffering from cancer, wherein the Cbl-b inhibitor is a compound according to any one of claims 1 to 34, a stereoisomer, a tautomer, an isotopic derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 36.

40. A method for regulating immune cell activity, the method comprising: contacting the immune cell with a therapeutically effective amount of a Cbl-b inhibitor to regulate the activity of the immune cell, wherein the Cbl-b inhibitor is a compound according to any one of claims 1 to 34, a stereoisomer, a tautomer, an isotopic derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 36.

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