Novel sodium channel modulator

Abstract

Provided is a novel sodium channel modulator, in particular a Nav1.8 channel modulator, said compound being a compound of formula I, formula II, or formula III, an isomer thereof, a racemate thereof, or a pharmaceutically acceptable salt or prodrug thereof, wherein formula I is as shown.

Description

A new sodium channel modulator

[0001] This application requires the applicant to:

[0002] The priority benefit of the prior application, patent application number 202311629063.9, filed with the State Intellectual Property Office of China on December 1, 2023, entitled “A New Sodium Channel Modulator”;

[0003] Priority benefit of the prior application, patent application number 202311779844.6, filed with the State Intellectual Property Office of China on December 22, 2023, entitled “A New Sodium Channel Modulator”;

[0004] The priority benefit of the prior application, patent application number 202410465333.5, filed with the State Intellectual Property Office of China on April 18, 2024, entitled “A New Sodium Channel Modulator”;

[0005] Priority benefit of the prior application, patent application number 202410973765.7, filed with the State Intellectual Property Office of China on July 19, 2024, entitled “A Novel Sodium Channel Modulator”;

[0006] The entire contents of said prior application are incorporated into the present application by reference. Technical Field

[0007] The present invention relates to a novel sodium channel regulator, in particular to a Nav1.8 channel regulator. Background Art

[0008] Voltage-gated sodium channels (VGSCs) mediate the selective influx of sodium ions into excitable cells and play an important role in the initiation and propagation of action potentials. Voltage-gated sodium channels are ubiquitous in the central and peripheral nervous systems, as well as in skeletal and cardiac muscles.

[0009] Nav's form a subfamily of the voltage-gated ion channel superfamily and comprise nine isoforms, designated Nav1.1-Nav1.9. The tissue localization of each of the nine isoforms varies. Nav1.4 is the predominant sodium channel in skeletal muscle, and Nav1.5 is the predominant sodium channel in cardiac myocytes. Nav's 1.7, 1.8, and 1.9 are primarily localized in the peripheral nervous system, while Nav's 1.1, 1.2, 1.3, and 1.6 are neural channels found in both the central and peripheral nervous systems. The nine isoforms exhibit similar functional behaviors but differ in specific aspects of their voltage-dependence and kinetic behavior.

[0010] The Nav1.8 voltage-gated sodium channel is thought to play a role in various diseases, including neuropathic pain, chronic itch, and inflammatory pain sensation.

[0011] There is still a need for effective inhibitors of Nav1.8 sodium channel activity that have selective activity against the Nav1.8 sodium channel. Therefore, the compounds of the present invention are useful in treating and preventing diseases, disorders and conditions involving the Nav1.8 receptor and the Nav1.8 voltage-gated sodium channel. Summary of the Invention

[0012] The present invention provides the following compounds for use in the treatment and prevention of diseases, disorders and conditions involving the Nav1.8 receptor and the Nav1.8 voltage-gated sodium ion channel.

[0013] In one aspect, the present application provides a compound of structural formula I:

[0014] Its isomers (stereoisomers), racemates, or pharmaceutically acceptable salts or prodrugs, wherein:

[0015] R1, R2 are independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, halogenated 3-7 membered heterocycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, halogenated 3-7 membered heterocycloalkyl may be further substituted by one or more substituted cycloalkyl groups independently selected from hydrogen, hydroxy, C 1-6 Substitution of alkoxy groups;

[0016] R3 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, -SC 1-6 Alkyl, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyloxy, halogenated 3-7 membered heterocycloalkyl;

[0017] R4 is selected from hydrogen, 6-10 membered aryl, benzo 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 9-10 membered heteroaryl, and the 6-10 membered aryl, benzo 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 9-10 membered heteroaryl can be optionally replaced by one or more independently selected from hydrogen, halogen, deuterium, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, halogenated C 2-6 Alkenyl, halogenated C 1-6 Alkoxy, -S-halogenated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, -S-deuterated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyloxy, halogenated 3-7 membered heterocycloalkyl, -NHhalogenated C 1-6 Alkyl, -L1-L2-OR 7 、-L1-(C 2-6 alkenylene)-OR 7 、-L1-L2-NR 8 R 9 、-CO-NR 8 R 9 、-SO2-NR 8 R 9 、-L1-L2-NHS(O)C 1-6 Alkyl, L1-L2-R 10 Substituents substituted;

[0018] L1 is selected from a bond, O;

[0019] L2 is selected from C 1-6 alkylene;

[0020] R 7 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 alkyl;

[0021] R 8 、R 9 are independently selected from hydrogen, hydroxyl, C 1-6 Alkyl, 3-7 membered heterocycloalkyl;

[0022] R 10 Selected from C 3-6 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, -C(O)OC 1-6Alkyl, -COOH, -SO2C 1-6 Alkyl or -C(O)NR 8 R 9 , wherein the 5-6 membered heteroaryl group may be further substituted by one or more selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Substitution of alkoxy groups;

[0023] R 11 Selected from hydrogen, hydroxyl or C 1-6 alkyl;

[0024] Further cyclize with the carbon atom to which they are connected to form a 5-10 membered heterocycloalkyl group (i.e. In the present invention, R5 and R6 are cyclized with the carbon atoms to which they are attached to form a 5-10 membered heterocycloalkyl group);

[0025] In one embodiment of the present invention, the Selected from Wherein, J1, J2, J3, and J4 are independently selected from NH, CO, C 1-6 Alkylene, bond, O or SO2;

[0026] However, no more than two of J1, J2, J3, and J4 are NH, CO, or C 1-6 Alkylene, bond, O or SO2;

[0027] No more than two of J1, J2, J3, and J4 are NH, CO, or C 1-6 Alkylene, bond, O or SO2 means that no more than two of J1, J2, J3, and J4 are NH, and no more than two of J1, J2, J3, and J4 are CO, and no more than two of J1, J2, J3, and J4 are C 1-6 Alkylene, and no more than two of J1, J2, J3, and J4 are bonds, and no more than two of J1, J2, J3, and J4 are O, and no more than two of J1, J2, J3, and J4 are SO2.

[0028] In one embodiment of the present invention, J1 is selected from a bond, C 1-6 Alkylene, NH, CO, SO2.

[0029] In one embodiment of the present invention, J2 is selected from a bond, C 1-6 Alkylene, CO, NH, O.

[0030] In one embodiment of the present invention, J3 is selected from a bond, C 1-6 Alkylene, CO, NH, O.

[0031] In one embodiment of the present invention, J4 is selected from a bond, C 1-6 Alkylene, NH, CO, O.

[0032] In one embodiment of the present invention, no more than two of J1, J2, J3, and J4 are NH, CO, O, a bond, or C 1-6 Alkylene.

[0033] In one embodiment of the present invention, when J1 is NH, J2 is CO.

[0034] In one embodiment of the present invention, when J1 is CO or SO2, J2 is NH.

[0035] In one embodiment of the present invention, Select from the group consisting of:

[0036] According to an embodiment of the present invention, the The H on the alkyl group may be further replaced by one or more alkyl groups selected from hydroxyl, halogen, deuterium, C 1- 6 alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 Alkylene hydroxyl, -C 1-6 Alkylene OR 7 、-C 1-6 Alkylene NR 8 R 9 、-C 1-6 AlkyleneCONH2, -(NC 1-6 alkyl)CONH2, -(C=NR 11 )-NR 8 R 9 、-C 1-6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6 Alkylene 5-10 membered heteroaryl substituents substituted; said C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3- 8-membered cycloalkyl, 3-8-membered heterocycloalkyl, 5-10-membered heteroaryl, -C 1-6 Alkylene hydroxyl, -C 1-6 Alkylene OR 7 、-C 1-6 Alkylene NR 8 R 9 、-C1-6 AlkyleneCONH2, -(NC 1-6 alkyl)CONH2, -(C=NR 11 )-NR 8 R 9 、-C 1-6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6 Alkylene 5-10 membered heteroaryl groups may be optionally substituted by one or more independently selected from hydrogen, halogen, hydroxy, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -OR 7 、-NR 8 R 9 Substituents substituted;

[0037] According to an embodiment of the present invention, the In the case of a structure containing N, the H on the NH can be further replaced by one or more selected from hydroxyl, halogen, deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 Alkylene hydroxyl, -C 1-6 Alkylene OR 7 、-C 1-6 Alkylene NR 8 R 9 、-C 1-6 AlkyleneCONH2, -(NC 1-6 alkyl)CONH2, -(C=NR 11 )-NR 8 R 9 、-C 1-6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6 Alkylene 5-10 membered heteroaryl substituents substituted; said C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 Alkylene hydroxyl, -C 1-6 Alkylene OR 7 、-C 1-6 Alkylene NR 8 R 9 、-C 1-6 AlkyleneCONH2, -(NC1-6 alkyl)CONH2, -(C=NR 11 )-NR 8 R 9 、-C 1-6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6 Alkylene 5-10 membered heteroaryl groups may be optionally substituted by one or more independently selected from hydrogen, halogen, hydroxy, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -OR 7 、-NR 8 R 9 Substituents substituted;

[0038] In one embodiment of the present invention, the In the case of (when the structure contains N), the H on NH is replaced by the following groups:

[0039] -C 1-6 Alkylene NR 8 R 9 、

[0040] Among them, -C 1-6 Alkylene NR 8 R 9 Optionally, one or more independently selected from hydrogen, C 1-6 Alkyl, -NR 8 R 9 Substituents substituted;

[0041] L3 is selected from a bond or C 1-6 alkylene;

[0042] A is selected from C 3-8 Cycloalkyl;

[0043] C 3-8 Cycloalkyl can be a 3-8 membered monocyclic, spirocyclic, or bridged cycloalkane;

[0044] R a1 、R a2 are independently selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl or hydroxy substituted C 1-6 alkyl;

[0045] R a3 、R a4 are independently selected from H or C 1-6 alkyl;

[0046] L4 is selected from a bond or C 1-6 alkylene;

[0047] B is selected from 3-10 membered N-containing heterocyclic alkyl;

[0048] 3-10 membered heterocycloalkyl; 3-10 membered N-containing heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0049] The 3-10 membered N-containing heterocycloalkyl group may be a monocyclic, spirocyclic, or bridged ring N-containing heterocycloalkyl group;

[0050] R b1 、R b2 are independently selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 alkyl;

[0051] R b3 Selected from H, C 1-6 alkyl.

[0052] In one embodiment of the present invention, the In the case of (when the structure contains N), the H on NH is replaced by the following groups:

[0053] -C 1-6 Alkylene NR 8 R 9 、

[0054] Among them, -C 1-6 Alkylene NR 8 R 9 Optionally, one or more independently selected from hydrogen, C 1-6 Alkyl, -NR 8 R 9 Substituents substituted;

[0055] u, v, r, s, b, p, q, m, and n are each independently selected from 0, 1, 2, or 3;

[0056] w is selected from 1 to 6, preferably 1 or 2;

[0057] Preferably, R a3 Can be used with The carbon atoms on the ring form a ring;

[0058] Preferably, The cycloalkyl or N-containing heterocycloalkyl is a 3-8 membered ring;

[0059] L3 is selected from a bond or C 1-6 alkylene;

[0060] R a1 、R a2 are independently selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl or hydroxy substituted C 1-6 alkyl;

[0061] R a3 、R a4 are independently selected from H or C 1-6 alkyl;

[0062] L4 is selected from a bond or C 1-6 alkylene;

[0063] R b1 、R b2 are independently selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 alkyl;

[0064] R b3 Selected from H, C 1-6 alkyl.

[0065] In one embodiment of the present invention, the By one or more R 56 Substituted, the R 56 Selected from hydrogen, hydroxyl, halogen, deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 Alkylene hydroxyl, -C 1-6 Alkylene OR 7 、-C 1-6 Alkylene NR 8 R 9 、-C 1-6 AlkyleneCONH2, -(NC 1-6 alkyl)CONH2, -(C=NR 11 )-NR 8 R 9 、-C 1-6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6 Alkylene 5-10 membered heteroaryl substituents substituted; said C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 Alkylene hydroxyl, -C1-6 Alkylene OR 7 、-C 1-6 Alkylene NR 8 R 9 、-C 1-6 AlkyleneCONH2, -(NC 1-6 alkyl)CONH2, -(C=NR 11 )-NR 8 R 9 、-C 1-6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6 Alkylene 5-10 membered heteroaryl groups may be optionally substituted by one or more independently selected from hydrogen, halogen, hydroxy, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -OR 7 、-NR 8 R 9 In some embodiments, the R 56 Further selected from R 56N , R 56N The structure is shown below:

[0066] In some embodiments, the In the case of nitrogen, the H on NH is replaced by R 56N replace.

[0067] In one embodiment of the present invention, the Selected from the following structures:

[0068] Among them, the R 56 As defined above.

[0069] In one embodiment of the present invention, R1 and R2 are independently selected from C 1-6 Alkyl or halogenated C 1-6 Alkyl, wherein the "halogenated C 1- 6-alkyl" can be selected from -CF3, -CHF2, -CH2F, -CH2 CH2F.

[0070] In one embodiment of the present invention, R1 is selected from -CF3.

[0071] In one embodiment of the present invention, R2 is selected from -CH3.

[0072] In one embodiment of the present invention, R3 is selected from -H, -CH3, -OCH3, halogen or -CH2F.

[0073] In one embodiment of the present invention, R4 is selected from

[0074] According to an embodiment of the present invention, the compound represented by formula I is selected from the following formula I-YG:

[0075] In the formula I-YG, R 1 、R 2 、R 3 、R 4 、R 5 、R 6 As defined above for Formula I.

[0076] In one embodiment of the present invention, Select from the group consisting of: The H on the group NH can be further replaced by one or more selected from hydroxyl, halogen, deuterium, C 1- 6 alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 Alkylene hydroxyl, -C 1-6 Alkylene OR 7 、-C 1-6 Alkylene NR 8 R 9 、-C 1-6 AlkyleneCONH2, -(NC 1-6 alkyl)CONH2, -(C=NR 11 )-NR 8 R 9 、-C 1-6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6 Alkylene 5-10 membered heteroaryl substituents substituted; said C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3- 8-membered cycloalkyl, 3-8-membered heterocycloalkyl, 5-10-membered heteroaryl, -C 1-6 Alkylene hydroxyl, -C 1-6 Alkylene OR 7 、-C 1-6 Alkylene NR 8 R 9 、-C1-6 AlkyleneCONH2, -(NC 1-6 alkyl)CONH2, -(C=NR 11 )-NR 8 R 9 、-C 1-6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6 Alkylene 5-10 membered heteroaryl groups may be optionally substituted by one or more independently selected from hydrogen, halogen, hydroxy, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -OR 7 、-NR 8 R 9 Substituents substituted;

[0077] R 11 Selected from hydrogen, hydroxyl or C 1-6 alkyl.

[0078] In one embodiment of the present invention, R1 is selected from -CF3.

[0079] In one embodiment of the present invention, R2 is selected from -CH3.

[0080] In one embodiment of the present invention, Formula I preferably has the structure of the following Formula Ia:

[0081] Formula Ia is selected from Formula Ia-YG:

[0082] In the formula Ia and formula Ia-YG, R 3 、R 4 、R 5 、R 6 As defined above for Formula I.

[0083] In one embodiment of the present invention, R3 is selected from -H, -CH3, -OCH3, halogen or -CH2F.

[0084] In one embodiment of the present invention, R4 is selected from

[0085] On the other hand, the present invention also provides a compound of structural formula II:

[0086] its isomers, racemates, or pharmaceutically acceptable salts or prodrugs,

[0087] According to an embodiment of the present invention, in the formula II, R 1 、R 2 、R 3 、R 4 、 As defined above.

[0088] According to an embodiment of the present invention, wherein:

[0089] R1, R2 are independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, halogenated 3-7 membered heterocycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, halogenated 3-7 membered heterocycloalkyl may be further substituted by one or more substituted cycloalkyl groups independently selected from hydrogen, hydroxy, C 1-6 Substitution of alkoxy groups;

[0090] R3 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, -SC 1-6 Alkyl, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyloxy, halogenated 3-7 membered heterocycloalkyl;

[0091] R4 is selected from hydrogen, 6-10 membered aryl, benzo 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 9-10 membered heteroaryl, and the 6-10 membered aryl, benzo 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 9-10 membered heteroaryl can be optionally replaced by one or more independently selected from hydrogen, halogen, deuterium, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, halogenated C2-6 Alkenyl, halogenated C 1-6 Alkoxy, -S-halogenated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, -S-deuterated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyloxy, halogenated 3-7 membered heterocycloalkyl, -NHhalogenated C 1-6 Alkyl, -L1-L2-OR 7 、-L1-(C 2-6 alkenylene)-OR 7 、-L1-L2-NR 8 R 9 、-CO-NR 8 R 9 、-SO2-NR 8 R 9 、-L1-L2-NHS(O)C 1-6 Alkyl, L1-L2-R 10 Substituents substituted;

[0092] L1 is selected from a bond, O;

[0093] L2 is selected from C 1-6 alkylene;

[0094] R 7 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 alkyl;

[0095] R 8 、R 9 are independently selected from hydrogen, hydroxyl, C 1-6 Alkyl, 3-7 membered heterocycloalkyl;

[0096] R 10 Selected from C 3-6 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, -C(O)OC 1-6 Alkyl, -COOH, -SO2C 1-6 Alkyl or -C(O)NR 8 R 9 , wherein the 5-6 membered heteroaryl group may be further substituted by one or more selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Substitution of alkoxy groups;

[0097] J1, J2, J3, and J4 are independently selected from NH, CO, C 1-6 Alkylene, bond, O or SO2;

[0098] However, no more than two of J1, J2, J3, and J4 are NH, CO, or C 1-6 Alkylene, bond, O or SO2;

[0099] No more than two of J1, J2, J3, and J4 are NH, CO, or C 1-6 Alkylene, bond, O or SO2 means that no more than two of J1, J2, J3, and J4 are NH, and no more than two of J1, J2, J3, and J4 are CO, and no more than two of J1, J2, J3, and J4 are C 1-6 Alkylene, and no more than two of J1, J2, J3, and J4 are bonds, and no more than two of J1, J2, J3, and J4 are O, and no more than two of J1, J2, J3, and J4 are SO2.

[0100] In some embodiments, the formula II is an isomer represented by formula II-YG:

[0101] Among them, R 1 、R 2 、R 3 、R 4 、 As defined above in Formula I.

[0102] In one embodiment of the present invention, The H on the alkyl group may be further replaced by one or more alkyl groups selected from hydroxyl, halogen, deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 Alkylene hydroxyl, -C 1-6 Alkylene OR 7 、-C 1-6 Alkylene NR 8 R 9 、-C 1-6 AlkyleneCONH2, -(NC 1-6 alkyl)CONH2, -(C=NR 11 )-NR 8 R 9 、-C 1-6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6 Alkylene 5-10 membered heteroaryl substituents substituted; said C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 Alkylene hydroxyl, -C 1-6 Alkylene OR 7 、-C 1-6 Alkylene NR 8 R 9 、-C 1-6 AlkyleneCONH2, -(NC 1-6 alkyl)CONH2, -(C=NR 11 )-NR 8 R 9 、-C 1-6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6 Alkylene 5-10 membered heteroaryl groups may be optionally substituted by one or more independently selected from hydrogen, halogen, hydroxy, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -OR 7 、-NR 8 R 9 substituted by a substituent.

[0103] R 8 、R 9 、R 11 Having the definitions as above.

[0104] In one embodiment of the present invention, J1 is selected from a bond, C 1-6 Alkylene, NH, CO, SO2.

[0105] In one embodiment of the present invention, J2 is selected from a bond, C 1-6 Alkylene, CO, NH, O.

[0106] In one embodiment of the present invention, J3 is selected from a bond, C 1-6 Alkylene, CO, NH, O.

[0107] In one embodiment of the present invention, J4 is selected from a bond, C 1-6 Alkylene, NH, CO, O.

[0108] In one embodiment of the present invention, no more than two of J1, J2, J3, and J4 are NH, CO, O, a bond, or C 1-6 Alkylene.

[0109] In one embodiment of the present invention, when J1 is NH, J2 is CO.

[0110] In one embodiment of the present invention, when J1 is CO or SO2, J2 is NH.

[0111] In one embodiment of the present invention, R1 is selected from -CF3.

[0112] In one embodiment of the present invention, R2 is selected from -CH3.

[0113] In one embodiment of the present invention, Formula II is selected from Formula IIa:

[0114] Formula IIa is selected from Formula IIa-YG:

[0115] In the formula IIa and formula IIa-YG, R 3 、R 4 、 As defined above.

[0116] In one embodiment of the present invention, R3 is selected from -H, -CH3, -OCH3, halogen or -CH2F.

[0117] In one embodiment of the present invention, R4 is selected from

[0118] In another embodiment of the present invention, Selected from

[0119] In another embodiment of the present invention, The H on the group NH can be further replaced by one or more selected from hydroxyl, halogen, deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 Alkylene hydroxyl, -C 1- 6 alkylene OR 7 、-C 1-6 Alkylene NR 8 R 9 、-C 1-6 AlkyleneCONH2, -(NC 1-6 alkyl)CONH2, -(C=NR 11 )-NR 8 R 9 、-C 1-6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6Alkylene 5-10 membered heteroaryl substituents substituted; said C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 Alkylene hydroxyl, -C 1-6 Alkylene OR 7 、-C 1-6 Alkylene NR 8 R 9 、-C 1-6 AlkyleneCONH2, -(NC 1-6 alkyl)CONH2, -(C=NR 11 )-NR 8 R 9 、-C 1-6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6 Alkylene 5-10 membered heteroaryl groups may be optionally substituted by one or more independently selected from hydrogen, halogen, hydroxy, amino, C 1- 6 alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -OR 7 、-NR 8 R 9 Substituents substituted;

[0120] R 11 Selected from hydrogen, hydroxyl or C 1-6 alkyl.

[0121] The present invention also provides a compound of structural formula III:

[0122] its isomers, racemates, or pharmaceutically acceptable salts or prodrugs,

[0123] According to an embodiment of the present invention, in the formula III, R 1 、R 2 、R 3 、R 5 、R 6 Can be selected from the previous definitions.

[0124] According to an embodiment of the present invention, in the formula III,

[0125] R1, R2 are independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, halogenated C 1-6 Alkyl, halogenated C1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, halogenated 3-7 membered heterocycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, halogenated 3-7 membered heterocycloalkyl may be further substituted by one or more substituted cycloalkyl groups independently selected from hydrogen, hydroxy, C 1-6 Substitution of alkoxy groups;

[0126] R3 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, -SC 1-6 Alkyl, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyloxy, halogenated 3-7 membered heterocycloalkyl;

[0127] The carbon atoms to which they are attached are further cyclized to form a 5-10 membered heterocycloalkyl group.

[0128] In one embodiment of the present invention, Select from the group consisting of:

[0129] H can be further replaced by one or more selected from hydroxyl, halogen, deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 Alkylene hydroxyl, -C 1-6 Alkylene OR 7 、-C 1-6 Alkylene NR 8 R 9 、-C 1-6 AlkyleneCONH2, -(NC 1-6 alkyl)CONH2, -(C=NR 11 )-NR 8 R 9 、-C 1-6 Alkylene C 3-8 Cycloalkyl, -C1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6 Alkylene 5-10 membered heteroaryl substituents substituted; said C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 Alkylene hydroxyl, -C 1-6 Alkylene OR 7 、-C 1-6 Alkylene NR 8 R 9 、-C 1-6 AlkyleneCONH2, -(NC 1-6 alkyl)CONH2, -(C=NR 11 )-NR 8 R 9 、-C 1-6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6 Alkylene 5-10 membered heteroaryl groups may be optionally substituted by one or more independently selected from hydrogen, halogen, hydroxy, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -OR 7 、-NR 8 R 9 Substituents substituted;

[0130] R 12 、R 13 、R 14 、R 15 、R 16 are independently selected from hydrogen, deuterium, halogen, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, halogenated C 2-6 Alkenyl, halogenated C 1-6 Alkoxy, -S-halogenated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, -S-deuterated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyloxy, halogenated 3-7 membered heterocycloalkyl, -NHhalogenated C 1-6Alkyl, -L1-L2-OR 7 、-L1-(C 2-6 alkenylene)-OR 7 、-L1-L2-NR 8 R 9 、-CO-NR 8 R 9 、-SO2-NR 8 R 9 、-L1-L2-NHS(O)C 1-6 Alkyl or L1-L2-R 10 ;

[0131] Preferably, R 12 、R 13 or R 15 、R 16 They can be further cyclized with the carbon atoms to which they are attached to form 5-6 membered heterocycloalkyl groups;

[0132] L1 is selected from a bond, O;

[0133] L2 is selected from C 1-6 alkylene;

[0134] R 7 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 alkyl;

[0135] R 8 、R 9 are independently selected from hydrogen, hydroxyl, C 1-6 Alkyl, 3-7 membered heterocycloalkyl;

[0136] R 10 Selected from C 3-6 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, -C(O)OC 1-6 Alkyl, -COOH, -SO2C 1-6 Alkyl or -C(O)NR 8 R 9 , wherein the 5-6 membered heteroaryl group may be further substituted by one or more selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Substitution of alkoxy groups;

[0137] R 11 Selected from hydrogen, hydroxyl or C 1-6 alkyl;

[0138] In one embodiment of the present invention, R 12 、R 16independently selected from hydrogen, deuterium, halogen, C 1-6 Alkoxy, -SC 1-6 Alkyl, halogenated C 1-6 Alkoxy, -S-halogenated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, -S-deuterated C 1-6 Alkyl, -NR 8 R 9 、-NH halide C 1-6 Alkyl or -OC 1-6 Alkylene SO2C 1-6 alkyl.

[0139] In another embodiment of the present invention, R 13 、R 15 are independently selected from hydrogen or halogen.

[0140] In another embodiment of the present invention, R 12 independently selected from hydrogen, deuterium, halogen, C 1-6 Alkoxy, -SC 1-6 Alkyl, -OC 1-6 Alkylene or C 3-6 Cycloalkyl.

[0141] The formula III is selected from the formula III-YG:

[0142] Among them, R 1 、R 2 、R 3 、R 5 、R 6 、R 12 、R 13 、R 14 、R 15 、R 16 As defined above for Formula III.

[0143] In another embodiment of the present invention, R 12 、R 16 independently selected from hydrogen, deuterium, halogen, C 1-6 Alkoxy, -SC 1-6 Alkyl, halogenated C 1-6 Alkoxy, -S-halogenated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, -S-deuterated C 1-6 Alkyl, -NR 8 R 9 、-NH halide C 1-6 Alkyl or -OC 1-6 Alkylene SO2C 1-6 alkyl.

[0144] In another embodiment of the present invention, R 13 、R 15 are independently selected from hydrogen or halogen.

[0145] In another embodiment of the present invention, R 12 independently selected from hydrogen, deuterium, halogen, C 1-6 Alkoxy, -SC 1-6 Alkyl, -OC 1-6 Alkylene or C 3-6 Cycloalkyl.

[0146] In another embodiment of the present invention, R 12 、R 13 or R 15 、R 16 The carbon atoms to which they are attached may be further cyclized to form a 5-6 membered heterocycloalkyl group.

[0147] In another embodiment of the present invention, the compound of formula III is selected from the following compounds of formula IIIa:

[0148] The formula III is selected from the formula IIIa-YG:

[0149] In the formula IIIa and formula IIIa-YG, R 1 、R 2 、R 3 、R 12 、R 13 、R 14 、R 15 、R 16 、 As defined above.

[0150] According to an embodiment of the present invention,

[0151] J1, J2, J3, and J4 are independently selected from NH, CO, C 1-6 Alkylene, bond, O or SO2;

[0152] However, no more than two of J1, J2, J3, and J4 are NH, CO, or C 1-6 Alkylene, bond, O or SO2;

[0153] In one embodiment of the present invention, The H on the alkyl group may be further replaced by one or more alkyl groups selected from hydroxyl, halogen, deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6Alkylene hydroxyl, -C 1-6 Alkylene OR 7 、-C 1-6 Alkylene NR 8 R 9 、-C 1-6 AlkyleneCONH2, -(NC 1-6 alkyl)CONH2, -(C=NR 11 )-NR 8 R 9 、-C 1-6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6 Alkylene 5-10 membered heteroaryl substituents substituted; said C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3- 8-membered cycloalkyl, 3-8-membered heterocycloalkyl, 5-10-membered heteroaryl, -C 1-6 Alkylene hydroxyl, -C 1-6 Alkylene OR 7 、-C 1-6 Alkylene NR 8 R 9 、-C 1-6 AlkyleneCONH2, -(NC 1-6 alkyl)CONH2, -(C=NR 11 )-NR 8 R 9 、-C 1-6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6 Alkylene 5-10 membered heteroaryl groups may be optionally substituted by one or more independently selected from hydrogen, halogen, hydroxy, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -OR 7 、-NR 8 R 9 Substituents substituted;

[0154] R 11 Selected from hydrogen, hydroxyl or C 1-6 alkyl;

[0155] R1, R2 are independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6Alkoxy, halogenated C 3-6 Cycloalkyl, halogenated 3-7 membered heterocycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, halogenated 3-7 membered heterocycloalkyl may be further substituted by one or more substituted cycloalkyl groups independently selected from hydrogen, hydroxy, C 1-6 Substitution of alkoxy groups;

[0156] R3 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, -SC 1-6 Alkyl, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyloxy, halogenated 3-7 membered heterocycloalkyl;

[0157] R 12 、R 13 、R 14 、R 15 、R 16 are independently selected from hydrogen, halogen, deuterium, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, halogenated C 2-6 Alkenyl, halogenated C 1-6 Alkoxy, -S-halogenated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, -S-deuterated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyloxy, halogenated 3-7 membered heterocycloalkyl, -NHhalogenated C 1-6 Alkyl, -L1-L2-OR 7 、-L1-(C 2-6 alkenylene)-OR 7 、-L1-L2-NR 8 R 9 、-CO-NR 8 R9 、-SO2-NR 8 R 9 、-L1-L2-NHS(O)C 1-6 Alkyl or L1-L2-R 10 ;

[0158] Preferably, R 12 、R 13 or R 15 、R 16 They can be further cyclized with the carbon atoms to which they are attached to form 5-6 membered heterocycloalkyl groups;

[0159] L1 is selected from a bond, O;

[0160] L2 is selected from C 1-6 alkylene;

[0161] R 7 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 alkyl;

[0162] R 8 、R 9 are independently selected from hydrogen, hydroxyl, C 1-6 Alkyl, 3-7 membered heterocycloalkyl;

[0163] R 10 Selected from C 3-6 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, -C(O)OC 1-6 Alkyl, -COOH, -SO2C 1-6 Alkyl or -C(O)NR 8 R 9 , wherein the 5-6 membered heteroaryl group may be further substituted by one or more selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Substitution of alkoxy groups;

[0164] In another embodiment of the present invention, in one embodiment of the present invention, J1 is selected from the group consisting of a bond, C 1-6 Alkylene, NH, CO, SO2.

[0165] In one embodiment of the present invention, J2 is selected from a bond, C 1-6 Alkylene, CO, NH, O.

[0166] In one embodiment of the present invention, J3 is selected from a bond, C 1-6 Alkylene, CO, NH, O.

[0167] In one embodiment of the present invention, J4 is selected from a bond, C 1-6 Alkylene, NH, CO, O.

[0168] In one embodiment of the present invention, no more than two of J1, J2, J3, and J4 are NH, CO, O, a bond, or C 1-6 Alkylene.

[0169] In one embodiment of the present invention, when J1 is NH, J2 is CO.

[0170] In one embodiment of the present invention, when J1 is CO or SO2, J2 is NH.

[0171] In another embodiment of the present invention, Selected from

[0172] In one embodiment of the present invention, The H on the group NH can be further replaced by one or more selected from hydroxyl, halogen, deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 Alkylene hydroxyl, -C 1- 6 alkylene OR 7 、-C 1-6 Alkylene NR 8 R 9 、-C 1-6 AlkyleneCONH2, -(NC 1-6 alkyl)CONH2, -(C=NR 11 )-NR 8 R 9 、-C 1-6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6 Alkylene 5-10 membered heteroaryl substituents substituted; C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 Alkylene hydroxyl, -C 1-6 Alkylene OR 7 、-C 1-6 Alkylene NR 8 R 9 、-C 1-6 AlkyleneCONH2, -(NC 1-6alkyl)CONH2, -(C=NR 11 )-NR 8 R 9 、-C 1-6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6 Alkylene 5-10 membered heteroaryl groups may be optionally substituted by one or more independently selected from hydrogen, halogen, hydroxy, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -OR 7 、-NR 8 R 9 Substituents substituted;

[0173] R 11 Selected from hydrogen, hydroxyl or C 1-6 alkyl.

[0174] In one embodiment of the present invention, R1 is selected from -CF3.

[0175] In one embodiment of the present invention, R2 is selected from -CH3.

[0176] In one embodiment of the present invention, the compound of formula III is selected from the following compounds of formula IIIb:

[0177] Formula IIIb is selected from Formula IIIb-YG:

[0178] In the formula IIIb and formula IIIb-YG, R 3 、R 12 、R 13 、R 14 、R 15 、R 16 、 As defined above.

[0179] R 12 、R 13 、R 14 、R 15 、R 16 Having the definition as described in formula IIIa;

[0180] J1, J2, J3, and J4 are as defined in Formula IIIa;

[0181] R3 has the same definition as described for formula IIIa.

[0182] According to the above-mentioned general formula I, II, III (or the general formula within the scope thereof), the compound, its isomer, racemate, or its pharmaceutically acceptable salt or prodrug, wherein the compound does not contain Its isomers, racemates, or pharmaceutically acceptable salts or prodrugs.

[0183] In some embodiments of the present invention, Select from the group consisting of: When the H on the group NH is further selected from H, hydroxyl, halogen, deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 Alkylene hydroxyl, -C 1-6 Alkylene OR 7 、-C 1-6 Alkylene NR 8 R 9 、-(C 1-6 Alkylene)CONH2, -(NC 1-6 alkyl)CONH2, -(C=NR 11 )-NR 8 R 9 、-C 1-6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6 Alkylene 5-10 membered heteroaryl substituents substituted; said C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 Alkylene hydroxyl, -C 1-6 Alkylene OR 7 、-C 1-6 Alkylene NR 8 R 9 、-C 1-6 AlkyleneCONH2, -(NC 1-6 alkyl)CONH2, -(C=NR 11 )-NR 8 R 9 、-C 1-6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6 Alkylene 5-10 membered heteroaryl groups may be optionally substituted by one or more independently selected from hydrogen, halogen, hydroxy, amino, C1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -OR 7 、-NR 8 R 9 Substituents substituted;

[0184] Preferably, it is further substituted by a group represented by the following formula:

[0185] -C 1-6 Alkylene NR 8 R 9 、

[0186] -C 1-6 Alkylene NR 8 R 9 Optionally, one or more independently selected from hydrogen, C 1-6 Alkyl, -NR 8 R 9 Substituents substituted;

[0187] L3 is selected from a bond or C 1-6 alkylene;

[0188] A is selected from C 3-8 Cycloalkyl;

[0189] C 3-8 Cycloalkyl can be a 3-8 membered monocyclic, spirocyclic, or bridged cycloalkane;

[0190] R a1 、R a2 are independently selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl or hydroxy substituted C 1-6 alkyl;

[0191] R a3 、R a4 are independently selected from H or C 1-6 alkyl;

[0192] L4 is selected from a bond or C 1-6 alkylene;

[0193] B is selected from 3-10 membered N-containing heterocyclic alkyl;

[0194] 3-10 membered heterocycloalkyl; 3-10 membered N-containing heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O and S;

[0195] The 3-10 membered N-containing heterocycloalkyl group may be a monocyclic, spirocyclic, or bridged ring N-containing heterocycloalkyl group;

[0196] Rb1 、R b2 are independently selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 alkyl;

[0197] R b3 Selected from H, C 1-6 alkyl.

[0198] In some embodiments of the present invention, Select from the group consisting of:

[0199] The H on the NH group is more preferably substituted with a group represented by the following formula:

[0200] -C 1-6 Alkylene NR 8 R 9 、

[0201] Among them, -C 1-6 Alkylene NR 8 R 9 Optionally, one or more independently selected from hydrogen, C 1-6 Alkyl, -NR 8 R 9 Substituents substituted;

[0202] u, v, r, s, b, p, q, m, and n are each independently selected from 0, 1, 2, or 3;

[0203] w is selected from 1 to 6, preferably 1 or 2;

[0204] Preferably, R a3 Can be used with The carbon atoms on the ring form a ring;

[0205] Preferably, The cycloalkyl or N-containing heterocycloalkyl is a 3-8 membered ring;

[0206] L3 is selected from a bond or C 1-6 alkylene;

[0207] R a1 、R a2 are independently selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl or hydroxy substituted C 1-6 alkyl;

[0208] R a3 、Ra4 are independently selected from H or C 1-6 alkyl;

[0209] L4 is selected from a bond or C 1-6 alkylene;

[0210] R b1 、R b2 are independently selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 alkyl;

[0211] R b3 Selected from H, C 1-6 alkyl.

[0212] According to the aforementioned compounds of formula I, formula II, formula III, their isomers, racemates, or pharmaceutically acceptable salts or prodrugs, the compounds are selected from:

[0213] In some embodiments, according to the aforementioned compounds of Formula I, Formula II, Formula III, their isomers, racemates, or pharmaceutically acceptable salts or prodrugs, the compounds are selected from:

[0214] In some embodiments, according to the aforementioned compounds of Formula I, Formula II, Formula III, their isomers, racemates, or pharmaceutically acceptable salts or prodrugs, the compounds are selected from:

[0215] Definition of terms:

[0216] In the present invention, the term "C 1-6 The term "alkyl" refers to a straight or branched chain alkyl group containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, tert-pentyl, or the like.

[0217] In the present invention, the term "C 1-6 "Alkylene" refers to the removal of C 1-6In some embodiments, C 1-4 Alkylene, C 2-4 Alkylene and C 1-3 Alkylene is preferred. Unsubstituted alkylene includes, but is not limited to, methylene, ethylene, propylene, butylene, pentylene, hexylene, and the like.

[0218] In the present invention, the term "C 1-6 "Alkoxy" refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, including but not limited to methoxy, ethoxy, propoxy, isopropoxy and butoxy. Preferably, C 1-4 Alkoxy.

[0219] In the present invention, the term "C 2-6 The term "alkenyl" refers to a straight or branched alkenyl group having 2 to 6 carbon atoms and containing one double bond, including but not limited to ethenyl, propenyl, butenyl, isobutenyl, pentenyl and hexenyl.

[0220] In the present invention, the term "C 3-8 "Cycloalkyl" refers to a cyclic alkyl group having 3 to 8 carbon atoms in the ring. 3-8 The cycloalkyl group can be a 3-8 membered monocyclic ring, a spirocyclic ring, or a bridged cycloalkane.

[0221] In the present invention, the term "C 3-6 "Cycloalkyl" refers to a cyclic alkyl group having 3 to 6 carbon atoms in the ring. 3-6 The cycloalkyl group may be a 3-6 membered monocyclic, spirocyclic, or bridged cycloalkane, including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, wait.

[0222] The term "heterocycloalkyl" should be understood as a non-aromatic cyclic group containing heteroatoms, which can be a 5-10-membered, 3-7-membered, 3-8-membered, 5-6-membered heterocycloalkyl group, etc. The heteroatoms in the "heterocycloalkyl" can be one, two or more heteroatoms selected from N, O, and S. The term "5-10-membered heterocycloalkyl" is a 5-10-membered (5, 6, 7, 8, 9, 10-membered) heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O, and S, which can be a monocyclic, spirocyclic, or bridged ring. Preferably, the 5-10-membered heterocyclic group contains one or more heteroatoms selected from NH, CO, C 1-6 The term "3-8 membered heterocycloalkyl" refers to a 3-8 membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O and S, which may be a monocyclic, spirocyclic or bridged ring, including but not limited to 3-7 membered heterocycloalkyl, Exemplarily, "3-7 membered heterocycloalkyl" is a 3-7 membered (e.g., 3, 4, 5, 6, 7 membered) heterocyclic group containing 1, 2, or 3 heteroatoms selected from N, O, and S, which may be a monocyclic, spirocyclic, or bridged ring. The term "heterocycloalkyl" includes, but is not limited to, the following groups:

[0223] Preferably, the heterocycloalkyl group is an N-containing heterocycloalkyl group containing 1, 2 or 3 heteroatoms selected from N, O and S.

[0224] In the present invention, the term "halogen" includes fluorine, chlorine, bromine and iodine.

[0225] In the present invention, the term "halogenated" refers to substitution with halogen. 1-6 Alkyl, halogenated C 2-6 Alkenyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyloxy and halogenated 3-7 membered heterocycloalkyl refer to C 1-6 Alkyl, C 2-6 Alkenyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, C 3-6 One or more hydrogen atoms in the cycloalkyloxy group and the 3- to 7-membered heterocycloalkyl group are replaced by a halogen group.

[0226] In the present invention, the term "oxy group" is O.

[0227] In the present invention, the term "bond" is -.

[0228] In the present invention, Used to depict chemical bonds, which are the points where a moiety or substituent is attached to a core or backbone structure.

[0229] In the present invention, the term "aromatic ring" or "aryl group" has the same meaning, preferably "C 6-10 Aryl". The term "C 6-10 "Aryl" or "6-10 membered aryl" refers to an aromatic ring group having 6 to 10 carbon atoms and containing no heteroatoms in the ring, such as phenyl, naphthyl, etc.

[0230] In the present invention, the term "aromatic heterocycle" or "heteroaryl" has the same meaning and refers to a heteroaromatic group containing one to multiple heteroatoms. For example, "heteroaryl" refers to an aromatic heterocycle containing 1 to 4 (1, 2, 3, 4) heteroatoms selected from oxygen, sulfur and nitrogen and 3 to 10 (3, 4, 5, 6, 7, 8, 9, 10) carbon atoms. "Heteroaryl" can be selected from 5-10 membered, 5-6 membered, 9-10 membered heteroaryl. Non-limiting examples include: furyl, thienyl, pyridyl, pyrazolyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, etc. The heteroaryl group can be optionally substituted or unsubstituted.

[0231] In the present invention, the term "optionally substituted with one or more" or "optionally further substituted with one or more" means that one or more hydrogen atoms on a specific group are replaced by a specific substituent. The specific substituent is the substituent described above or the substituent appearing in the examples. Unless otherwise specified, a substituted group may have a substituent selected from the specific group at any substitutable position of the group, and the substituent may be the same or different at each position. Here, "plurality" includes two or more, for example, 2, 3, 4, 5, or 6.

[0232] In the present invention, the term "1-6" refers to 1, 2, 3, 4, 5 or 6. Other similar terms independently have similar meanings. The term "plurality" refers to 2-6, such as 2, 3, 4, 5 or 6.

[0233] In the present invention, the term "substituted" should be considered to include multiple degrees of substitution of the substituent indicated. When multiple substituent moieties are disclosed or claimed, the substituted compound can be independently substituted with one or more of the disclosed or claimed substituent moieties, either singly or multiply. Independently substituted means that the (two or more) substituents can be the same or different.

[0234] The compounds of the present invention may contain one or more asymmetric centers and thus may exist as isomers, racemates, etc., wherein racemates include racemates and racemic mixtures; isomers include single enantiomers, diastereomeric mixtures, and single diastereomers. The present invention is intended to include all such isomeric forms of the compounds of Formula I, II, or III. It will be understood by those skilled in the art that the isomers encompass optical isomers (or stereoisomers).

[0235] "Stereoisomers" are compounds that have identical chemical constitutions but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric (cis / trans) isomers, atropisomers, and the like.

[0236] "Enantiomers" refer to two non-superimposable isomers of a compound that are mirror images of each other.

[0237] "Diastereoisomers" refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of one another. Diastereoisomers have different physical properties, such as melting points, boiling points, spectral properties, and reactivities. Diastereomeric mixtures can be separated by high-resolution analytical procedures such as electrophoresis and chromatography, for example, HPLC.

[0238] Any asymmetric atom (e.g., carbon, etc.) of the compounds of the present invention may exist in a racemic or enantiomerically enriched form, such as in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 0% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in terms of the (R)- or (S)-configuration.

[0239] The independent syntheses of optical isomers and diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by X-ray crystallography of crystalline products or crystalline intermediates which, if necessary, are derivatized with reagents containing asymmetric centers of known absolute configuration or sufficiently heavy atoms to allow absolute assignment.

[0240] If desired, a racemic mixture of a compound can be separated to isolate the individual enantiomers. Separation can be performed by methods well known in the art, for example, by coupling the racemic mixture of the compound to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods (e.g., fractional crystallization or chromatography).

[0241] Racemic mixtures of the compounds can also be separated directly by chromatographic methods using chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of the compound can be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration using methods well known in the art.

[0242] The term "prodrug" refers to a structure that can be converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissues.

[0243] In the compounds of Formula I, II or III, the atoms may exhibit their natural isotopic abundance, or one or more atoms may be artificially enriched with a particular isotope having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.

[0244] The present invention is intended to include all suitable isotopic variations of the compounds of formula I, II or III. For example, different isotopic forms of hydrogen (H) include protium (1H), deuterium (2H) and tritium (3H).

[0245] Isotopically enriched compounds within structural formula I, II or III can be prepared by conventional techniques well known to those skilled in the art or by methods analogous to those described in the schemes and examples herein using appropriate isotopically enriched reagents and / or intermediates without undue experimentation.

[0246] In another aspect, the present invention provides a pharmaceutical composition comprising any one of the above-mentioned compounds, its isomers, racemates, or pharmaceutically acceptable salts or prodrugs, and a pharmaceutically acceptable carrier.

[0247] In another aspect, the present invention also discloses the use of a compound, an isomer, a racemate, or a pharmaceutically acceptable salt or prodrug thereof as described above, and a pharmaceutical composition for the preparation of a medicament for treating a disorder, condition or disease responsive to inhibition of Nav1.8 channel activity in a mammal in need thereof. The ability of the compounds of the present invention to block, partially block, interfere with, reduce or decrease the activity or expression of Nav1.8 in a subject, "inhibition" encompasses complete and / or partial reduction of channel function, for example, a reduction of at least 10%, in some embodiments a reduction of at least 20%, 30%, 50%, 75%, 95%, 98% and up to and including 100%.

[0248] More specifically, the IC activity of the compounds of the present invention on Nav1.8 channels is 50 The inhibitory value or inhibitory activity is less than 10 μM, more preferably less than 1 μM, more preferably less than 50 nM, and more preferably less than 10 nM.

[0249] In another aspect, the present invention also discloses the use of any of the above-mentioned compounds, their isomers, racemates, or pharmaceutically acceptable salts or prodrugs, and pharmaceutical compositions in the preparation of drugs for treating, preventing or controlling pain conditions, cough conditions, acute itching conditions or chronic itching conditions.

[0250] In one embodiment of the invention, the condition comprises chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough or cardiac arrhythmia, or a method of reducing the severity thereof.

[0251] In one embodiment of the invention, the pain comprises neuropathic pain, musculoskeletal pain (preferably osteoarthritis pain), acute pain (preferably acute postoperative pain), postoperative pain or visceral pain.

[0252] In one embodiment of the present invention, the neuropathic pain comprises one or more of postherpetic neuralgia, small fiber neuropathy, idiopathic small fiber neuropathy or diabetic neuropathy, preferably diabetic peripheral neuropathy.

[0253] In one embodiment of the invention, the postoperative pain comprises one or more of bunionectomy pain, abdominoplasty pain, or herniorrhaphy pain.

[0254] The present invention also discloses treating the subject by administering one or more additional therapeutic agents simultaneously with, before, or after treatment with the compound, its isomers, racemates, or pharmaceutically acceptable salts or pharmaceutical compositions thereof.

[0255] In another aspect, the present invention discloses any one of the above compounds, its isomers, racemates, or pharmaceutically acceptable salts or prodrugs; and use of any one of the above pharmaceutical compositions as a drug. Beneficial effects

[0256] The present invention provides a Nav1.8 selective inhibitor with novel structure, excellent pharmacokinetic properties, good efficacy and drugability, which can be used to treat, prevent or control Nav1.8-related pain symptoms, cough symptoms, acute itching symptoms or chronic itching symptoms, and has significant clinical application value. DETAILED DESCRIPTION

[0257] The present invention will be further described below with reference to the examples. It should be noted that the following examples are provided for illustrative purposes only and do not constitute a limitation on the scope of protection claimed in the present invention.

[0258] Unless otherwise specified, the raw materials, reagents, methods, etc. used in the examples are conventional raw materials, reagents, methods in the art, and the experimental materials and reagents used can be obtained from commercial channels.

[0259] Experimental materials and analytical instruments:

[0260] The thin layer chromatography (TLC) plate model was HSGF-254 (thickness 0.15-0.2 mm, produced by Yantai Chemical Experimental Plant); the column chromatography silica gel was 200-300 mesh commercial silica gel produced by Qingdao Ocean Chemical Plant;

[0261] 1H-NMR spectra were recorded using a Bruker Avance III-400 NMR spectrometer with tetramethylsilane (TMS) as the internal standard; chemical shifts are in ppm, δ:, and proton coupling is labeled as singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m).

[0262] Low-resolution mass spectra were recorded using an Agilent 6110 mass spectrometer.

[0263] Abbreviations and notes:

[0264] DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; psi: pounds per square inch; DIPEA: N,N-diisopropylethylamine; HATU: 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate; CDI: N,N'-carbonyldiimidazole; MTBE: tert-butyl methyl ether; DIBAL-H: diisobutylaluminum hydride; DMAP: 4-dimethylaminopyridine; THF: tetrahydrofuran; DPPF: 1,1-bis(diphenylphosphino)ferrocene; NMI: N-methylimidazole; TCFH: tetramethylchlorouronium hexafluorophosphate; HCl: hydrochloric acid; EA: ethyl acetate; TEA: triethanolamine; TMSOTf: trimethylsilyl trifluoromethanesulfonate; LDA: lithium diisopropylamide; i-PrMgBr: isopropylmagnesium chloride; LiCl: lithium chloride.

[0265] Example 1: Preparation of Compound P-1

[0266] The synthetic route of compound P-1 is as follows:

[0267] In this synthetic route, -OTf represents

[0268] Step 1: Preparation of ethyl 2-diazo-3-oxo-pentanoate

[0269] At 0°C, ethyl propionyl acetate (20.00 g, 138.7 mmol) and triethylamine (15.40 g, 152.6 mmol) were added sequentially to acetonitrile for activation. Then, 4-acetamidobenzenesulfonyl azide (34.90 g, 141.5 mmol) was slowly added portionwise. The reaction was warmed to room temperature and stirred for 1 hour. After completion, the reaction was washed with n-hexane:diethyl ether (1:1 ratio). The filtrate was filtered, concentrated, and purified by column chromatography to yield 20.50 g of ethyl 2-diazo-3-oxo-pentanoate as a yellow oil in an 86.8% yield. MS m / z calculated: 170.06; found: 171.1 [M+H] + .

[0270] Step 2: Preparation of 2-diazo-3-tert-butyldimethylsilyloxy-pent-3-enoic acid ethyl ester

[0271] Triethylamine (8.94 g, 88.1 mmol) was added to a solution of ethyl 2-diazo-3-oxopentanoate (10.00 g, 58.8 mmol) in dichloromethane (200 mL) at -25°C. After stirring for 15 minutes, tert-butyldimethylsilyl trifluoromethanesulfonate (18.62 g, 70.5 mmol) was added dropwise, and the mixture was stirred at -25°C for approximately 30 minutes. The reaction mixture was diluted with saturated sodium bicarbonate, the layers were separated, and the organic phase was washed 2-3 times with saturated brine (400 mL). After drying over anhydrous sodium sulfate, the mixture was concentrated in vacuo to afford 15.90 g of crude ethyl 2-diazo-3-tert-butyldimethylsilyloxypent-3-enoate as a red oil in a 95.4% yield. MS m / z calculated: 284.15; found: 285.2 [M+H] + .

[0272] Step 3: Preparation of ethyl 2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxo-hexanoate

[0273] TiCl4 (14.1 g, 74.34 mmol) was slowly added dropwise to a dichloromethane solution (150 mL) of 1,1,1-trifluoropropan-2-one (11.12 g, 99.0 mmol) in a -78°C stirred well. After the addition was complete, stirring was continued for approximately 30 minutes, followed by the dropwise addition of ethyl 2-diazo-3-tert-butyldimethylsilyloxypent-3-enoate (12.05 g, 49.5 mmol). The mixture was allowed to cool to room temperature and carefully quenched with water. The mixture was then extracted with dichloromethane 2-3 times (200 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by column chromatography afforded 8.50 g of ethyl 2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxo-hexanoate as a yellow oil in a 61.2% yield. MS m / z calculated: 282.08; found: 283.1 [M+H] + .

[0274] Step 4: Preparation of ethyl 4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0275] Rhodium(II) acetate (0.12 g, 0.2 mmol) was added to a 500 mL two-necked flask. After nitrogen displacement 2-3 times, an appropriate amount of toluene solution (50 mL) was added and the reaction system was stirred at reflux for approximately 30 minutes. A toluene solution of ethyl 2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxo-hexanoate (5.00 g, 17.7 mmol) was then slowly added and the reaction was continued under reflux for 1 hour. The reaction was monitored by a flow cytometer until completion. After cooling to room temperature, the mixture was concentrated in vacuo to afford 2.43 g of crude ethyl 4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate as a green oil in a 54.4% yield. MS m / z calculated: 254.07; found: 255.1 [M+H] + .

[0276] Step 5: Preparation of ethyl 4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl))sulfonyloxy)-4,5-dihydrofuran-2-carboxylate

[0277] To a solution of ethyl 4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (2.34 g, 9.0 mmol) in dichloromethane at 0°C, sodium hydride (0.43 g, 10.8 mmol) was added and stirred at the same temperature for 30 minutes. Trifluoromethylsulfonyl trifluoromethanesulfonate (2.52 g, 9.0 mmol) was then added to the reaction mixture. The mixture was brought to room temperature until the reaction was complete. The reaction was quenched in an ice-water bath and extracted with dichloromethane. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 3.11 g of crude ethyl 4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl))sulfonyloxy)-4,5-dihydrofuran-2-carboxylate as a yellow oil in an 88.7% yield. MS m / z calculated: 386.02; found: 387.0 [M+H] + .

[0278] Step 6: Preparation of ethyl 3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate

[0279] Under nitrogen, (3,4-difluoro-2-methoxyphenyl)boronic acid (1.12 g, 5.7 mmol), potassium phosphate trihydrate (4.13 g, 15.5 mmol), and tetrakis(triphenylphosphine)palladium (0.30 g, 0.2 mmol) were added to the reaction flask. After nitrogen replacement, a toluene solution of ethyl 4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl))sulfonyloxy)-4,5-dihydrofuran-2-carboxylate (2.0 g, 5.2 mmol) was slowly added. The reaction was heated at 100°C for 2 hours. The reaction was monitored until completion, diluted with water, and the aqueous layer was extracted with ethyl acetate (2 × 100 mL). The organic phase was washed with saturated brine and concentrated in vacuo. Purification by column chromatography afforded 0.85 g of ethyl 3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate as a clear oil in a 43.5% yield. MS m / z calculated: 380.10; found: 381.1 [M+H] + .

[0280] Step 7: Preparation of ethyl 3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0281] To an autoclave containing ethyl 3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (0.50 g, 1.3 mmol) was added ethanol (20 mL), palladium on carbon (10% wt, 0.14 g, 1.3 mmol), and palladium hydroxide on carbon (20% wt, 0.22 g, 1.5 mmol). The mixture was degassed, pressurized to 36 psi, and reacted at 80°C overnight. The reaction mixture was filtered through celite, and the filtrate was concentrated in vacuo to afford ethyl 3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate as a white powder (0.48 g, 95.2% yield). MS m / z calculated: 382.12; found: 382.2 [M+H] + .

[0282] Step 8: Preparation of 3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

[0283] To ethyl 3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (0.12 g, 0.3 mmol), 10 mL of 2 M sodium hydroxide and 20 mL of methanol were added. The reaction was heated to 60°C and monitored with a microplate reader until completion. The reaction was partitioned between ethyl acetate and 1 M hydrochloric acid. The layers were separated, combined, and concentrated in vacuo to afford 0.09 g of 3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid as a clear oil in an 84.4% yield. MS m / z calculated: 354.08; found: 355.1 [M+H] + .

[0284] Step 9: Preparation of 3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-yl chloride

[0285] In a 100 mL flask, 3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (0.09 g, 0.2 mmol) was dissolved in 20 mL of dichloromethane. A catalytic amount of DMF (3-4 drops) was added dropwise. Oxalyl chloride (0.06 g, 0.5 mmol) was then slowly added dropwise to the reaction system. After the addition was complete, the ice bath was removed and the reaction was allowed to warm to room temperature. The reaction was monitored by a microplate reader until completion. The product was then concentrated in vacuo to afford 0.09 g of the crude product as a yellow powder in a 98.0% yield. MS m / z calculated: 372.05; found: 373.1 [M+H]. + Step 10: Preparation of 3-(3,4-difluoro-2-methoxy)-4,5-dimethyl-nitrogen-(2-oxy-1,2,3,4-tetrahydroquinolin-7-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0286] Under ice-cooling conditions, 7-amino-3,4-dihydro-1H-quinolin-2-one (0.05 g, 0.3 mmol), triethylamine (0.04 g, 0.3 mmol), and a catalytic amount of DMF (3-4 drops) were added to a 100 mL flask. Subsequently, 3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-yl chloride (0.93 g, 0.2 mmol) was slowly added to the mixture using a constant pressure dropping funnel. The reaction was monitored by a microplate reader until completion. Water was added to quench the reaction. The layers were separated, and the aqueous phase was further extracted with dichloromethane (100 mL). The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography to afford 0.28 g of the compound as a white solid in a 65.4% yield.

[0287] 1H NMR (400MHz, DMSO-d6) δ10.00(s,1H),9.48(s,1H),7.08–7.03(m,2H),6.98(d,J=8.1Hz,1H),6.94(d,J=2.0Hz,1H),6.74(m,1H),4.82(d ,J=9.0Hz,1H),3.98(d,J=2.0Hz,3H),3.84(m,1H),3.19(m,1H),2.75(t,J=7.5Hz,2H),2.37(m,2H),1.41(s,3H),0.93(d,J=6.7Hz,3H).

[0288] Example 2: Preparation of Compound P-2

[0289] The preparation method is similar to that of Example 1, except that 7-amino-3,4-dihydro-1H-quinolin-2-one in step 10) is replaced with an equimolar amount of 5-aminoisoindole-1-one to obtain a white solid compound P-2 with a yield of 54.5%.

[0290] 1 H NMR (400MHz, DMSO-d6) δ9.87(s,1H),8.39(s,1H),7.61(s,1H),7.50(d,J=8.4Hz,1H),7.25(d,J=8.4Hz,1H),7.12–6.99(m,2H),4.88 (d,J=9.0Hz,1H),4.26(s,2H),3.98(d,J=2.0Hz,3H),3.85(d,J=10.1Hz,1H),3.28–3.15(m,1H),1.42(s,3H),0.95(d,J=6.4Hz,3H).

[0291] Example 3: Preparation of Compound P-3

[0292] The preparation method is similar to that of Example 1, except that 7-amino-3,4-dihydro-1H-quinolin-2-one in step 10) is replaced with an equimolar amount of 5-aminoisoindoline-1,3-dione to obtain a white solid compound P-3 with a yield of 68.5%.

[0293] 1H NMR (400MHz, DMSO-d6) δ11.23(s,1H),10.22(s,1H),7.81(d,J=1.8Hz,1H),7.70(d,J=8.2Hz,1H),7.59(d,J=8.7Hz,1H),7.13– 6.94(m,2H),4.90(d,J=9.0Hz,1H),4.00(d,J=2.1Hz,3H),3.93–3.79(m,1H),3.23(m,1H),1.44(s,3H),0.97(d,J=6.7Hz,3H).

[0294] Example 4: Preparation of Compound P-4

[0295] The preparation method is similar to that of Example 1, except that the 7-amino-3,4-dihydro-1H-quinolin-2-one in step 10) is replaced with an equimolar amount of 7-aminoquinazoline-2,4(1H,3H)-dione to obtain a white solid compound P-4 with a yield of 69.4%.

[0296] 1 H NMR (400MHz, DMSO-d6) δ11.12(s,1H),10.99(d,J=1.8Hz,1H),9.99(s,1H),7.72(d,J=8.6Hz,1H),7.40(d,J=1.9Hz,1H),7.06(s,1H),7.04(d ,J=2.6Hz,1H),6.97(m,1H),4.88(d,J=9.0Hz,1H),3.99(d,J=2.1Hz,3H),3.87–3.82(m,1H),3.21(m,1H),1.42(s,3H),0.95(d,J=6.8Hz,3H).

[0297] Example 5: Preparation of Compound P-5

[0298] The preparation method is similar to that of Example 1, except that 7-amino-3,4-dihydro-1H-quinolin-2-one in step 10) is replaced with an equal molar amount of 6-aminosaccharin to obtain a white powdery compound P-5 with a yield of 37.8%.

[0299] 1H NMR (400MHz, DMSO-d6) δ10.10(s,1H),7.95(s,1H),7.74(d,J=1.8Hz,1H),7.55(d,J=8.2Hz,1H),7.41(m,1H),7.13–7.06(m,1H),7 .05–6.99(m,1H),4.87(d,J=9.0Hz,1H),3.99(d,J=2.1Hz,3H),3.93–3.87(m,1H),3.23(m,1H),1.43(s,3H),0.95(d,J=6.7Hz,3H).

[0300] Example 6: Preparation of Compound P-6

[0301] The preparation method is similar to that of Example 1, except that 7-amino-3,4-dihydro-1H-quinolin-2-one in step 10) is replaced with an equal molar amount of 6-amino-2,3-dihydrophthalazine-1,4-dione to obtain a white compound P-6 with a yield of 43.5%.

[0302] 1 H NMR (400MHz, DMSO-d6) δ11.90(d,J=48.7Hz,1H),7.17(d,J=7.4Hz,2H),7.10–6.95(m,1H),6.89(d,J=8.3Hz,1H),6.51–6.26( m,3H),5.28(m,1H),4.07(d,J=11.7Hz,1H),4.03(d,J=7.5Hz,3H),3.14(m,1H),1.47(d,J=4.7Hz,3H),1.02(d,J=6.4Hz,3H).

[0303] Example 7: Preparation of Compound P-7

[0304] The preparation method is similar to that of Example 1, except that 7-amino-3,4-dihydro-1H-quinolin-2-one in step 10) is replaced with an equimolar amount of 4-aminoisatoic anhydride to obtain a white solid compound P-7 with a yield of 52.6%.

[0305] 1H NMR (400MHz, DMSO-d6) δ11.58(s,1H),10.16(s,1H),7.78(d,J=8.7Hz,1H),7.43(d,J=1.9Hz,1H),7.08–7.03(m, 3H), 4.91 (d, J = 9.0Hz, 1H), 4.01 (d, J = 2.2Hz, 3H), 3.90 (m, 1H), 3.22 (m, 1H), 1.44 (s, 3H), 0.98 (d, J = 6.8Hz, 3H).

[0306] Example 8: Preparation of Compound P-8

[0307] The synthetic route of compound P8 is as follows:

[0308] Step 1: Preparation of ethyl 3-(4-fluorobenzofuran-7-yl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate

[0309] To a 250 mL reaction tube, (4-fluorobenzofuran-7-yl)boronic acid (1.98 g, 11.2 mmol), potassium phosphate trihydrate (8.00 g, 30.4 mmol), and tetrakis(triphenylphosphine)palladium (1.73 g, 1.5 mmol) were added sequentially. The reaction was degassed, and then a toluene solution of ethyl 2,3-dimethyl-2-(trifluoromethyl)-4-(trifluoromethylsulfonyloxy)-3H-furan-5-carboxylate (3.87 g, 10 mmol) was added under a nitrogen atmosphere. After further degassing, the reaction was heated at 100°C for 2 hours. The reaction was monitored for complete reaction by spotting. After cooling to room temperature, the mixture was diluted with ethyl acetate (500 mL) and washed three times with saturated brine (200 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 3.55 g of the compound as a white solid with a yield of 85.2%. MS m / z calculated: 372.09; found: 373.1 [M+H] + .

[0310] 1 H NMR(400MHz, DMSO-d6)δ8.07(d,J=2.3Hz,1H),7.35(dd,J=8.4,5.3Hz,1H),7.16–7.12(m,1H),7.12–7 .10(m,1H),4.01–3.95(m,2H),2.76(s,1H),1.53(s,3H),0.97(d,J=7.2Hz,3H),0.86(t,J=7.1Hz,3H).

[0311] Step 2: Preparation of ethyl 3-(4-fluoro-2,3-dihydrobenzofuran-7-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0312] Ethyl 3-(4-fluorobenzofuran-7-yl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (3.00 g, 8.2 mmol) was added to an autoclave and dissolved in anhydrous ethanol. Palladium on carbon (10% wt, 8.62 g, 81.4 mmol) and palladium hydroxide on carbon (20% wt, 5.75 g, 40.5 mmol) were then added sequentially. After three gas replacements, hydrogen was introduced to a pressure of 50 psi. The mixture was heated to 80°C and stirred for 16 hours. After the mixture cooled to room temperature, the autoclave was opened and the reaction was monitored for complete reaction using a platen. The reaction mixture was filtered under reduced pressure through diatomaceous earth, the filter cake was rinsed with anhydrous ethanol, and the filtrate was concentrated under reduced pressure to yield 2.98 g of the compound as a white solid in a 96.6% yield. MS m / z calculated: 376.12; found: 377.1 [M+H] + .

[0313] Step 3: Preparation of 3-(4-fluoro-2,3-dihydrobenzofuran-7-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

[0314] Ethyl 3-(4-fluoro-2,3-dihydrobenzofuran-7-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (2.90 g, 7.7 mmol) was dissolved in methanol (100 mL). A solution of sodium hydroxide (1.85 g, 46.3 mmol) in water (50 mL) was added dropwise and stirred at 60°C for 8 hours. The reaction was monitored for completion by a microplate reader. The pH was adjusted to 1-2 with dilute hydrochloric acid. The reaction system was extracted two to three times with ethyl acetate (200 mL). The combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield 2.39 g of a light yellow oil in 89.4% yield. MS m / z calculated: 348.09; found: 349.1 [M+H] + .

[0315] Step 4: Preparation of 3-(4-fluoro-2,3-dihydrobenzofuran-7-yl)-4,5-dimethyl-N-(1-oxoisoindolin-5-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0316] To a solution of 3-(4-fluoro-2,3-dihydrobenzofuran-7-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (0.20 g, 0.5 mmmol) and DMF (3.5 μL, 0.04 mmol) in dichloromethane (20 mL) stirred at 0 ° C. was added oxalyl chloride (0.14 g, 1.1 mmol). After the addition was complete, the reaction was moved to room temperature, stirred for 1 hour, and concentrated under reduced pressure. The resulting product was dissolved in dichloromethane (20 mL) and added to a solution of 5-aminoisoindolin-1-one (0.08 g, 0.5 mmol), DMF (3.5 μL, 0.04 mmol) and triethylamine (0.08 g, 0.9 mmol) in dichloromethane (30 mL) stirred at -10 ° C. via a dropping funnel. The reaction of the starting material was monitored for complete reaction. The mixture was diluted with water (100 mL), the layers separated, and the aqueous phase was further extracted with dichloromethane (50 mL). The organic phase was collected, washed twice with saturated brine (50 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 0.19 g of the compound as a white solid in a yield of 68.3%.

[0317] 1 H NMR (400MHz, DMSO-d6) δ9.79 (s, 1H), 8.36 (s, 1H), 7.63 (s, 1H), 7.50 (d, J = 8. 2Hz,1H),7.25(d,J=7.7Hz,1H),7.05–7.00(m,1H),6.54(s,1H),4.84(d,J=9 .0Hz,1H),4.57(dd,J=21.3,9.1Hz,2H),4.26(s,2H),3.76–3.66(m,1H),3.1 2(q,J=8.2Hz,2H),2.00(d,J=8.0Hz,1H),1.38(s,3H),0.94(d,J=6.7Hz,3H).

[0318] Example 9: Preparation of Compound P-9

[0319] The preparation method is similar to that of Example 8, except that 5-aminoisoindolin-1-one in step 4) is replaced with an equal molar amount of 5-aminoisoindolin-1,3-dione to obtain a white solid compound P-9 with a yield of 58.5%.

[0320] 1H NMR (400MHz, DMSO-d6) δ11.20(s,1H),10.13(s,1H),7.80(d,J=1.8Hz,1H),7.68(d,J= 8.1Hz, 1H), 7.56 (dd, J=8.2, 1.9Hz, 1H), 7.02 (dd, J=8.7, 5.6Hz, 1H), 6.52 (t, J=8.6Hz, 1H),4.84(d,J=9.1Hz,1H),4.58(td,J=9.8,7.8Hz,2H),3.75(dd,J=12.4,9.1Hz,1H),3 .25(dd,J=12.5,6.7Hz,1H),3.11(q,J=8.9Hz,2H),1.39(s,3H),0.94(d,J=6.7Hz,3H).

[0321] Example 10: Preparation of Compound P-10

[0322] The preparation method is similar to that of Example 8, except that 5-aminoisoindolin-1-one in step 4) is replaced with an equimolar amount of 7-aminoquinazoline-2,4(1H,3H)-dione to obtain a white solid compound P-10 with a yield of 69.4%.

[0323] 1 H NMR(400MHz,DMSO-d6)δ11.12–11.09(m,1H),10.98(d,J=1.7Hz,1H),9.90(s,1H) ,7.71(d,J=8.6Hz,1H),7.44(d,J=1.9Hz,1H),7.02–6.93(m,2H),6.53(t,J=8.6H z,1H),4.84(d,J=9.0Hz,1H),4.65–4.52(m,2H),3.72(dd,J=12.5,9.1Hz,1H),3. 24(dd,J=12.6,6.7Hz,1H),3.20–3.08(m,2H),1.38(s,3H),0.93(d,J=6.7Hz,3H).

[0324] Example 11: Preparation of Compound P-11

[0325] The synthetic route of compound P-11 is as follows:

[0326] Step 1: Preparation of ethyl 3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate

[0327] To a 100 mL reaction tube, ethyl 4,5-dimethyl-5-(trifluoromethyl)-3-((trifluoromethanesulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate (1.00 g, 2.6 mmol) and 2-(3-fluoro-2,4-dimethoxyphenyl)-4,4,5-5-tetramethyl-1,3,2-dioxaborolane (0.55 g, 2.8 mmol) were added, followed by potassium phosphate trihydrate (2.00 g, 7.8 mmol) and tetrakistriphenylphosphine palladium (0.15 g, 0.1 mmol). After the addition was complete, the atmosphere was replaced with argon three times, and then 30 mL of toluene solution was added via syringe. The temperature was raised to 100°C and the reaction was allowed to proceed for 5 hours. The reaction was monitored by a plate-triggering assay for complete reaction. After cooling to room temperature, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to yield 0.76 g of a light yellow oil in a 77.2% yield. MS m / z calculated: 378.11; found: 379.1 [M+H] + .

[0328] Step 2: Preparation of ethyl 3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0329] To an autoclave, ethyl 3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (0.76 g, 2.0 mmol), palladium / carbon (2.02 g), and palladium hydroxide / carbon (1.60 g) were added. Then, 50 mL of methanol was added. The atmosphere was replaced with hydrogen three times, and the autoclave was refilled with hydrogen to 50 psi. The autoclave was heated to 80°C for 24 h. The reaction was monitored for complete reaction by a plate-drip. The system was cooled to room temperature, filtered through celite, and the resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to yield 0.66 g of a light yellow oil in 88.2% yield. MS m / z calculated: 380.12; found: 381.0 [M+H] + .

[0330] Step 3: Preparation of 3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

[0331] To a 100 mL round-bottom flask was added ethyl 3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-tetrahydrofuran-2-carboxylate (0.65 g, 2.0 mmol). Then, 15 mL of methanol and 5 mL of 2 M sodium hydroxide solution were added sequentially. The resulting solution was heated to 60°C for 3 h. The reaction was monitored for complete reaction by a microplate reader. The mixture was cooled to room temperature and adjusted to pH 4 with dilute hydrochloric acid (2 M). The mixture was then transferred to a separatory funnel with ethyl acetate (500 mL), washed three times with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 0.58 g of the desired product as a pale yellow oil in a 79.4% yield. MS m / z calculated: 366.11; found: 367.1 [M+H] + .

[0332] Step 4: Preparation of N-(2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0333] To a single-necked flask containing 100 mL of DMF solvent was added 7-aminoquinazoline-2,4(1H,3H)-dione (0.09 g, 0.6 mmol) and 3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (0.20 g, 0.5 mmol). HATU (0.20 g, 1.1 mmol) and DIPEA (0.37 g, 2.2 mmol) were then added. The mixture was allowed to react at room temperature for 12 h. The reaction was monitored for complete reaction by a microplate reader. The reaction mixture was transferred to a separatory funnel with ethyl acetate (500 mL), washed three times with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield 0.13 g of an off-white solid in a 49.4% yield.

[0334] 1 H NMR (400MHz, DMSO-d6) δ13.82(s,1H),12.34(s,1H),8.79(dd,J=4.4,1.4Hz,1H),8.56(dd,J=8.4,1.4Hz,1H),7.54(dd,J=8.4,4.4Hz,1H),6.98– 6.85(m,2H),4.69(d,J=9.4Hz,1H),3.91(d,J=1.7Hz,3H),3.89–3.85(m, 1H),3.83(s,3H),3.08–2.93(m,1H),1.38(s,3H),0.94(d,J=6.7Hz,3H).

[0335] Example 12: Preparation of Compound P-12

[0336] The preparation method is similar to that of Example 11, except that 7-aminoquinazoline-2,4(1H,3H)-dione in step 4) is replaced with an equimolar amount of 4-aminophthalimide to obtain compound P-12 as a white solid with a yield of 58.5%.

[0337] 1 H NMR (400MHz, DMSO-d6) δ13.84(s,1H),12.36(s,1H),8.78(dd,J=4.4,1.4Hz,1H),8.55(dd,J=8.5,1.4Hz,1H),7.53(dd,J=8.4,4.4Hz,1H),6.97–6. 83(m,2H),4.69(d,J=9.4Hz,1H),3.91(d,J=1.7Hz,3H),3.87(d,J=7.0Hz ,1H),3.83(s,3H),3.04–2.92(m,1H),1.38(s,3H),0.94(d,J=6.7Hz,3H).

[0338] Example 13: Preparation of Compound P-13

[0339] The synthetic route of compound P-13 is as follows:

[0340] Step 1: Preparation of ethyl 3-(4-fluoro-2-nitrophenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate

[0341] To a 100 mL reaction tube, add ethyl 4,5-dimethyl-5-(trifluoromethyl)-3-((trifluoromethanesulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate (0.92 g, 2.5 mmol), tetrakistriphenylphosphine palladium (0.01 g, 0.1 mmol), potassium phosphate trihydrate (1.94 g, 7.3 mmol), and (4-fluoro-2-nitrophenyl)-boronic acid pinacol ester (0.69 g, 2.7 mmol). After completion of the addition, the atmosphere was purged with nitrogen three times. Toluene solution (50 mL) was added, and the resulting solution was heated to 100°C and reacted overnight. The reaction was monitored by a plate-triggering assay. The filtrate was filtered and concentrated under reduced pressure. The residue was purified by column chromatography to afford 0.59 g of a light yellow oil in a 65.4% yield. MS m / z calculated: 363.07; found: 364.1 [M+H] + .

[0342] Step 2: Preparation of 3-(4-fluoro-2-nitrophenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylic acid

[0343] To a 250 mL single-necked round-bottom flask, ethyl 3-(4-fluoro-2-nitrophenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (0.58 g, 1.6 mmol) and methanol (100 mL) were added and stirred at room temperature. NaOH (2 M, 50 mL) was added to the mixture and stirred at room temperature for 2 h. The reaction was monitored by a plate to complete the reaction. The mixture was transferred to a 500 mL beaker and ethyl acetate (100 mL) was added. The reaction was acidified to pH 2 with 1 M hydrochloric acid solution and transferred to a separatory funnel. The organic layer was retained and washed 2-3 times with saturated brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to afford 0.46 g of a light yellow oil in an 83.4% yield. MS m / z calculated: 349.05; found: 350.1 [M+H] + .

[0344] Step 3: Preparation of N-(1,3-dioxoindole-5-yl)-3-(4-fluoro-2-nitrophenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxamide

[0345] To a 100 mL round-bottom flask were added 3-(4-fluoro-2-nitrophenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylic acid (0.47 g, 1.3 mmol), 5-aminoisoindoline-1,3-dione (0.26 g, 1.6 mmol), DIPEA (0.52 g, 4.0 mmol), and HATU (1.00 g, 2.7 mmol). The above compounds were dissolved in DMF and stirred at room temperature overnight. After completion of the reaction, the reaction mixture was transferred to a 250 mL separatory funnel, diluted with ethyl acetate (150 mL), washed 2-3 times with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield 0.27 g of an off-white solid in a 42.5% yield. MS m / z calculated: 493.09; found: 494.1 [M+H] + .

[0346] Step 4: Preparation of 3-(2-amino-4-fluorophenyl)-nitrogen-(1,3-dioxoisoindole-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0347] To a high-pressure reactor were added N-(1,3-dioxoindole-5-yl)-3-(4-fluoro-2-nitrophenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxamide (0.28 g, 0.6 mmol), palladium / carbon (0.61 g, 0.6 mmol), palladium hydroxide / carbon (0.95 g, 0.7 mmol), and anhydrous ethanol (100 mL). The reaction system was filled with hydrogen to a pressure of 50 psi, heated to 80 ° C, and reacted for 36 hours. The reaction was monitored by spot plate to complete the reaction. The product was filtered under reduced pressure through diatomaceous earth, the filter cake was rinsed with ethanol, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 0.13 g of a white solid compound with a yield of 48.7%.

[0348] 1 H NMR (400MHz, DMSO-d6) δ11.19(s,1H),9.93(s,1H),7.72(s,1H),7.65(d,J=8.1Hz,1H),7.49(d,J=8.2Hz,1H),6.97(t,J=7.9Hz,1H), 6.26–6.11(m,2H),5.63(s,1H),4.95(d,J=8.7Hz,1H),3.78(t,J=10.5Hz,1H),3.13–3.03(m,2H),1.46(s,3H),0.91(d,J=6.6Hz,3H).

[0349] Example 14: Preparation of Compound P-14

[0350] The preparation method is similar to that of Example 13, except that 5-aminoisoindoline-1,3-dione in step 2 is replaced with 7-aminoquinazoline-2,4(1H,3H)-dione to obtain a white solid compound P-14 with a yield of 38.8%.

[0351] 1 H NMR (400MHz, DMSO-d6) δ11.03(d,J=48.8Hz,2H),9.70(s,1H),7.70(d,J=8.6Hz,1H),7.39(s,1H),7.02–6.82(m,2H),6.23( d,J=12.1Hz,2H),5.60(s,1H),4.96(d,J=8.6Hz,1H),3.78(t,J=10.5Hz,1H),3.13(s,2H),1.47(s,3H),1.00–0.84(d,3H).

[0352] Example 15: Preparation of Compound P-15

[0353] The synthetic route of compound P-15 is as follows:

[0354] Step 1: Preparation of ethyl 2-diazo-3-oxo-butyrate

[0355] To a solution of ethyl acetoacetate (10.00 g, 64.1 mmol) in acetonitrile (250 mL) stirred at 0°C was added triethylamine (8.60 g, 85.0 mmol). 4-Acetamidobenzenesulfonyl azide (19.00 g, 79.1 mmol) was slowly added and the reaction mixture was brought to room temperature and stirred at room temperature for 1 hour. The reaction mixture was filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 10.00 g of ethyl 2-diazo-3-oxo-butyrate as a pale yellow oil in an 83.2% yield. MS m / z calculated: 156.05; found: 157.0 [M+H] + .

[0356] Step 2: Preparation of 3-tert-butyldimethylsilyloxy-2-diazo-but-3-enoic acid ethyl ester

[0357] To a solution of ethyl 2-diazo-3-oxo-butyrate (10.00 g, 64.1 mmol) in dichloromethane (250 mL) stirred at 0°C was added triethylamine (16.32 g, 161.1 mmol). Tert-butyldimethylsilyl trifluoromethanesulfonate (19.00 g, 71.9 mmol) was slowly added and the reaction mixture was stirred at 0°C for 30 minutes. The reaction was quenched with saturated sodium bicarbonate solution (200 mL). The organic layer was separated and the aqueous phase was extracted 2-3 times with dichloromethane (200 mL). The organic layers were then combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 17.04 g of crude ethyl 3-tert-butyldimethylsilyloxy-2-diazo-but-3-enoate with a yield of 98.2%. MS m / z calculated value: 255.11; found value: 256.1 [M+H] + .

[0358] Step 3: Preparation of ethyl 2-diazo-6,6,6-trifluoro-5-hydroxy-5-methyl-3-oxo-hexanoate

[0359] A solution of 1,1,1-trifluoropropan-2-one (14.00 g, 124.9 mmol) in dichloromethane (250 mL) was stirred at -78 ° C and TiCl4 (19.50 g, 100.2 mmol) was added dropwise. The reaction was maintained at -78 ° C for 10 minutes, and then 3-tert-butyldimethylsilyloxy-2-diazo-but-3-enoic acid ethyl ester (17.00 g, 62.9 mmol) was added dropwise. The reaction was maintained at -78 ° C for 1 hour, and then saturated sodium bicarbonate solution was added to quench the reaction and extracted with dichloromethane 2-3 times. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by column chromatography to obtain 2.00 g of 2-diazo-6,6,6-trifluoro-5-hydroxy-5-methyl-3-oxo-hexanoic acid ethyl ester as a light yellow liquid with a yield of 12.6%. MS m / z calculated: 254.05; found: 255.0 [M+H] + .

[0360] Step 4: Preparation of ethyl 5-methyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0361] Rhodium (II) acetate (0.05 g, 124.4 mmol) was loaded into a dried double-necked flask, toluene (40 mL) was added and the solution was stirred at 100 ° C for 10 minutes. The solution was briefly extracted from the oil bath while adding a solution of 2-diazo-6,6,6-trifluoro-5-hydroxy-5-methyl-3-oxo-hexanoic acid ethyl ester (2.00 g, 7.9 mmol) in toluene (20 mL) dropwise and heated under reflux for 1 hour. The reaction mixture was filtered and concentrated in vacuo to obtain 5-methyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid ethyl ester crude product 1.94 g in a yield of 99.5%. MS m / z calculated value: 240.06; Found: 241.2 [M+H] + .

[0362] Step 5: Preparation of ethyl 5-methyl-5-(trifluoromethyl)-3-(((trifluoromethane)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate

[0363] At 0 ° C, to a solution of 5-methyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid ethyl ester (1.92 g, 7.91 mmol) in dichloromethane (150 mL) was slowly added sodium hydride (60% wt, 0.48 g, 11.9 mmol) dropwise added trifluoromethanesulfonic anhydride (2.70 g, 9.6 mmol) and stirred for 2.5 hours, and then the reaction mixture was slowly dropped into ice water (150 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×30 mL). The combined organic extracts were dried, filtered and concentrated in vacuo to give 5-methyl-5-(trifluoromethyl)-3-(((trifluoromethane)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylic acid ethyl ester 2.92 g with a yield of 98.5%. MS m / z calculated value: 372.01; found value: 373.0 [M+H] + .

[0364] Step 6: Preparation of ethyl 3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate

[0365] To a stirred solution of (3,4-difluoro-2-methoxy-phenyl)boronic acid (1.62 g, 8.5 mmol) and ethyl 5-methyl-5-(trifluoromethyl)-3-(((trifluoromethane)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate (2.94 g, 7.8 mmol) in toluene (60 mL) was added potassium phosphate trihydrate (6.20 g, 23.3 mmol). The mixture was degassed with nitrogen for 20 minutes, followed by the addition of palladium tetrakistriphenylphosphine (0.45 g, 0.4 mmol) and then heated to 100 ° C for 1 hour. The mixture was filtered through celite, the filtrate was diluted with water (50 mL) and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried, and concentrated under reduced pressure. Purification by column chromatography afforded 0.56 g of ethyl 3-(3,4-difluoro-2-methoxyphenyl)-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate as a pale yellow liquid in a 35.5% yield. MS m / z calculated: 366.08; found: 367.1 [M+H] + .

[0366] Step 7: Preparation of ethyl 3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0367] To 3-(3,4-difluoro-2-methoxy-phenyl)-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylic acid ethyl ester (0.21g, 0.6mmol), palladium on carbon (10% wt, 0.61g, 5.7mmol) and palladium hydroxide on carbon (20% wt, 0.48g, 3.4mmol) was added anhydrous ethanol (30mL). The mixture was degassed and stirred under hydrogen conditions (50psi, 80°C) for 12 hours. The catalyst was removed by filtration, washed with anhydrous ethanol (50mL) and concentrated in vacuo. 3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid ethyl ester 0.21g was obtained as a white solid with a yield of 99.8%. MS m / z calculated value: 368.10; Found: 369.1[M+H] + .

[0368] Step 8: 3-(3,4-Difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

[0369] Ethyl 3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (0.21 g, 0.6 mmol) was dissolved in methanol (40 mL) and water (20 mL). Sodium hydroxide pellets (0.11 g, 2.9 mmol) were added and the suspension was stirred at 40°C for 12 hours. The filtrate was diluted with 1M hydrochloric acid to pH 2, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to afford 0.19 g of 3-(3,4-difluoro-2-methoxy-phenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid in a 98.2% yield. MS m / z calculated: 340.97; found: 341.1 [M+H] + .

[0370] Step 9: 3-(3,4-difluoro-2-methoxyphenyl)-N-(2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0371] 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (0.19 g, 0.6 mmol) was dissolved in DMF (30 mL) at 0°C. 7-aminoquinazoline-2,4-dione (0.20 g, 1.1 mmol), DIPEA (0.29 g, 2.2 mmol), and HATU (0.32 g, 0.8 mmol) were added. The reaction mixture was brought to room temperature and diluted with ethyl acetate after 4 hours and washed with saturated brine. The organic layer was dried, concentrated under reduced pressure, and purified by column chromatography to obtain 0.04 g of 3-(3,4-difluoro-2-methoxyphenyl)-N-(2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide as a white solid in a yield of 14.4%.

[0372] 1 H NMR (400MHz, DMSO-d6) δ11.18(s,1H),11.04(s,1H),10.15(s,1H),7.82(d,J=8.7Hz,1H),7.78(d,J=1.8Hz,1H),7.43–7.38(m,1H ),7.20–7.12(m,1H),6.54(s,1H),4.15(d,J=18.3Hz,1H),3.90–3.82(m,3H),2.91(m,1H),2.75(m,1H),2.33(m,1H),1.58(s,3H).

[0373] Example 16: Preparation of Compound P-16

[0374] The synthetic route of compound P-16 is as follows:

[0375] Step 1: Preparation of 3-(3,4-difluoro-2-methoxy-phenyl)-4,5-dimethyl-5(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

[0376] To ethyl 4-(3,4-difluoro-2-methoxyphenyl)-2,3-dimethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate (0.2 g, 0.3 mmol), 10 mL of 2 M sodium hydroxide and 20 mL of methanol were added. The reaction was heated to 60°C and monitored with a microplate reader until completion. The reaction was partitioned between ethyl acetate and 1 M hydrochloric acid. The layers were separated, combined, and concentrated in vacuo to afford 0.19 g of 3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid as a clear oil in a 78.4% yield. MS m / z calculated: 352.07; found: 353.1 [M+H]+ .

[0377] Step 2: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-nitrogen-(1-oxoisoindol-5-yl)-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxamide

[0378] At 0°C, 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (0.19 g, 0.5 mmol) was dissolved in DMF (30 mL). 5-aminoisoindol-1-one (0.08 g, 0.6 mmol), DIPEA (0.07 g, 2.5 mmol), and HATU (0.21 g, 1.0 mmol) were added. The reaction mixture was brought to room temperature and allowed to react for 4 hours. The reaction system was then diluted with ethyl acetate and washed with saturated brine. The organic layer was dried, concentrated under reduced pressure, and purified by column chromatography to obtain 0.15 g of 3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-nitrogen-(1-oxoisoindol-5-yl)-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxamide as a white solid in a yield of 57.7%.

[0379] 1 H NMR(400MHz,DMSO-d6)δ10.06(s,1H),8.43(s,1H),7.96(s,1H),7.66(m,1H),7.57(d,J=8.3Hz,1H),7.20– 7.10(m,2H),4.30(s,2H),3.81(d,J=1.6Hz,3H),3.78(d,J=7.2Hz,1H),1.58(s,3H),0.99(d,J=7.2Hz,3H).

[0380] Example 17: Preparation of Compound P-17

[0381] The synthetic route of compound P-17 is as follows:

[0382] Step 1: Preparation of (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one

[0383] 2-(3,4-Difluoro-2-methoxyphenyl)acetic acid (Intermediate A, 10.00 g, 49.5 mmol) was dissolved in acetonitrile, followed by the addition of CDI (9.22 g, 56.9 mmol). The mixture was stirred at 40°C for 15 minutes. (R)-4,4,4-Trifluoro-3-hydroxy-3-methylbutan-2-one (Intermediate B, 7.72 g, 59.4 mmol) and potassium carbonate (8.46 g, 61.9 mmol) were added sequentially, and the temperature was raised to 60°C and stirred for 24 hours. The reaction was quenched with water, and the aqueous phase was extracted 2-3 times with MTBE. The organic phase was washed with 2M hydrochloric acid (2 × 50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography yielded 11.5 g of (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one as a white solid in a 72.1% yield. MS m / z calculated: 322.06; found: 323.1 [M+H] + .

[0384] Step 2: Preparation of (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one

[0385] To an autoclave, add (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one (3.00 g, 9.3 mmol) and dissolve in anhydrous ethanol. Then, add palladium on carbon (10% wt, 0.99 g, 9.3 mmol) and palladium hydroxide on carbon (20% wt, 1.57 g, 11.16 mmol) in that order. After three gas replacements, introduce hydrogen to a pressure of 50 psi. Heat to 80°C and stir for 40 hours. After cooling the mixture to room temperature, open the autoclave and monitor the complete reaction of the starting materials using TLC. The mixture was filtered through diatomaceous earth under reduced pressure, and the filter cake was rinsed with anhydrous ethanol. The filtrate was concentrated under reduced pressure to give 2.75 g of (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one as a white solid, with a yield of 91.1%. MS m / z calculated: 324.07; found: 325.08 [M+H] + .

[0386] Step 3: Preparation of (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-ol

[0387] Under nitrogen at -78°C, DIBAL-H (2.30 g, 16.2 mmol) was slowly added dropwise to a dichloromethane solution containing (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one (2.50 g, 7.7 mmol). The reaction was monitored by a microplate reader until completion. The reaction was then quenched by the addition of saturated ammonium chloride solution. The reaction mixture was extracted two to three times with ethyl acetate. The combined organic phases were washed with saturated brine and concentrated under reduced pressure to yield 2.50 g of a crude product, with (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-ol as the major diastereomer, in a yield of 99.2%. MS m / z calculated: 326.09; found: 327.1 [M+H] + .

[0388] Step 4: Preparation of (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl acetate

[0389] At room temperature, acetic anhydride (4.69 g, 46.2 mmol) was added to a mixed solution of (3S,4S,5R)-3-(3-fluoro-4-hydroxy-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-ol (2.50 g, 7.7 mmol) and DMAP (1.40 g, 11.6 mmol). The reaction was monitored with a microplate reader until completion. After completion, saturated sodium bicarbonate solution was added, and the reaction system was extracted with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to yield 2.77 g of the stereoisomer, with (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl acetate as the major diastereomer, in a yield of 98.5%. MS m / z calculated: 368.10; found: 369.1 [M+H] + .

[0390] Step 5: Preparation of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonitrile

[0391] Trimethylsilyl cyanide (1.86 g, 18.8 mmol) and boron trifluoride etherate (3.20 g, 22.5 mmol) were added sequentially to a dichloromethane solution of (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl acetate (2.77 g, 7.5 mmol) at -78 °C. The reaction mixture was stirred for 30 minutes and then brought to room temperature until the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution (60 mL), and the mixture was extracted with dichloromethane. The organic compounds were combined, dried, and concentrated under reduced pressure to afford 2.48 g of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonitrile as the major diastereomer in a 98.5% yield. MS m / z calculated: 335.09; found: 336.1 [M+H] + .

[0392] Step 6: Preparation of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

[0393] To (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonitrile (2.00 g, 5.9 mmol) was added 10 mL of 2 M sodium hydroxide and 20 mL of methanol. The reaction was heated to 60°C and monitored with a microplate reader until completion. The reaction was partitioned between ethyl acetate and 1 M hydrochloric acid. The layers were separated, combined, and concentrated in vacuo to afford 2.02 g of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid as a clear oil in a 95.9% yield. MS m / z calculated: 354.08; found: 355.1 [M+H] + .

[0394] Step 7: Preparation of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(1-oxoisoindolin-5-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0395] At 0°C, (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (0.20 g, 0.5 mmol) was dissolved in DMF (30 mL), and 5-aminoisoindole-1-one (0.08 g, 0.6 mmol), DIPEA (0.08 g, 2.5 mmol) and HATU (0.21 g, 1.0 mmol) were added respectively. The reaction mixture was brought to room temperature and reacted for 4 hours. The reaction system was diluted with ethyl acetate and then washed with saturated brine. The organic layer was dried, concentrated under reduced pressure, and purified by column chromatography to obtain 0.16 g of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(1-oxoisoindolin-5-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide as a white solid with a yield of 57.8%.

[0396] 1 H NMR (400MHz, DMSO-d6) δ10.53(s,1H),8.44(s,1H),7.96(s,1H),7.62(d,J=1.2Hz,2H),7.25–7.12(m,2H),5.12(d,J=10.3Hz, 1H), 4.34 (s, 2H), 4.29 (dd, J=10.3, 7.6Hz, 1H), 3.97 (d, J=2.0Hz, 3H), 2.80 (q, J=7.5Hz, 1H), 1.62 (s, 3H), 0.79–0.70 (m, 3H).

[0397] Example 18: Preparation of Compound P-18

[0398] The preparation method is similar to that of Example 17, except that 5-aminoisoindole-1-one in step 7 is replaced by 7-aminoquinazoline-2,4(1H,3H)-dione to obtain a white solid compound P-18 with a yield of 38.6%.

[0399] 1H NMR (400MHz, DMSO-d6) δ10.23 (s, 1H), 10.11 (s, 1H), 7.23 (d, J = 1.9Hz, 1H), 7.2 1–7.17(m,1H),7.16–7.13(m,1H),7.13–7.05(m,2H),5.06(d,J=10.4Hz,1H),4 .25(dd,J=10.4,7.6Hz,1H),3.97(d,J=2.1Hz,3H),2.81(t,J=8.6,6.5Hz,2H), 2.79–2.72(m,1H),2.42(t,J=8.5,6.5Hz,2H),1.60(s,3H),0.80–0.71(m,3H).

[0400] Example 19: Preparation of Compound P-19

[0401] The preparation method is similar to that of Example 17, except that 5-aminoisoindole-1-one in step 7 is replaced with 5-aminoisoindoline-1,3-dione to obtain a white solid compound P-19 with a yield of 58.5%.

[0402] 1 H NMR (400MHz, DMSO-d6) δ11.23(s,1H),10.22(s,1H),7.81(d,J=1.7Hz,1H),7.70(d,J=8.2Hz,1H),7.62–7.52(m,1H),7.08(d,J=7.6Hz,1H),4.90(d ,J=9.0Hz,1H),5.09(d,J=10.3Hz,1H),4.26(dd,J=10.3,7.6Hz,1H),3.9 4(dd,J=8.5,2.1Hz,3H),2.78(q,J=7.3Hz,1H),1.60(s,3H),0.72(s,3H).

[0403] Example 20: Preparation of Compound P-20

[0404] The preparation method is similar to that of Example 17, except that 5-aminoisoindole-1-one in step 7 is replaced by 7-aminoquinazoline-2,4(1H,3H)-dione to obtain a white solid compound P-20 with a yield of 52.4%.

[0405] 1H NMR (400MHz, DMSO-d6) δ11.19–11.02(m,2H),10.63(s,1H),7.81(d,J=8.6Hz,1H),7.68(d,J=1.9Hz,1H),7.29(dd,J=8.7,1.9Hz,1H),7.15(dt,J=2 1.2,8.2Hz,2H),5.09(d,J=10.3Hz,1H),4.26(dd,J=10.3,7.6Hz,1H),3.9 4(dd,J=8.5,2.1Hz,3H),2.78(q,J=7.3Hz,1H),1.60(s,3H),0.72(s,3H).

[0406] Example 21: Preparation of Compound P-21

[0407] The preparation method is similar to that of Example 17, except that 5-aminoisoindole-1-one in step 7 is replaced with 7-amino-2H-benzo[d][1,3]oxazine-2,4(1H)-dione to obtain a white solid compound P-21 with a yield of 48.7%.

[0408] 1 H NMR (400MHz, DMSO-d6) δ11.70(s,1H),10.75(s,1H),7.87(d,J=8.7Hz,1H),7.70(d,J=1.9Hz,1H),7.37(dd,J=8.7,1.9Hz,1H),7.20–7. 10(m,2H),5.11(d,J=10.2Hz,1H),4.31–4.21(m,1H),3.97(d,J=2.1Hz,3H),2.79(t,J=7.5Hz,1H),1.61(s,3H),0.75(d,J=7.3Hz,3H).

[0409] Example 22: Preparation of Compound P-22

[0410] The preparation method is similar to that of Example 17, except that 5-aminoisoindole-1-one in step 7 is replaced with 6-aminosaccharin to obtain a white solid compound P-22 with a yield of 54.5%.

[0411] 1H NMR (400MHz, DMSO-d6) δ10.10(s,1H),7.74(d,J=1.7Hz,1H),7.55(d,J=8.2Hz,1H),7.41(dd,J=8.2,1.8Hz,1H),7.22(s,1H),7.12–6.99( m,2H),4.87(d,J=9.0Hz,1H),3.99(d,J=2.1Hz,3H),3.92–3.84(m,1H),3.22(dq,J=13.2,6.7Hz,1H),1.42(s,3H),0.95(d,J=6.7Hz,3H).

[0412] Example 23: Preparation of Compound P-23

[0413] The preparation method is similar to that of Example 17, except that 5-aminoisoindole-1-one in step 7 is replaced with 5-amino-2-methylisoindolin-1-one to obtain white solid compound P-23 with a yield of 60.5%.

[0414] 1 H NMR (400MHz, DMSO-d6) δ10.55(s,1H),7.97(d,J=1.6Hz,1H),7.63–7.58(m,2H),7.26–7.11(m,2H),5.12(d,J=10.3Hz,1H),4.42 (s,2H),4.28(dd,J=10.4,7.6Hz,1H),3.97(d,J=2.1Hz,3H),3.05(s,3H),2.79(p,J=7.4Hz,1H),1.62(s,3H),0.78–0.72(m,3H).

[0415] Example 24: Preparation of Compound P-24

[0416] The preparation method is similar to that of Example 17, except that 5-aminoisoindole-1-one in step 7 is replaced by 6-amino-2H-benzo[b][1,4]oxazine-3(4H)-one to obtain white solid compound P-24 with a yield of 56.4%.

[0417] 1H NMR (400MHz, DMSO-d6) δ10.72(s,1H),10.22(s,1H),7.35–7.30(m,1H),7.15(dt,J=22.8,7.7Hz,2H),7.06(d,J=8.7Hz,1H),6.87(d,J=8. 7Hz,1H),5.02(d,J=10.4Hz,1H),4.51(s,2H),4.22(t,J=9.0Hz,1H),3.94(s,3H),2.79–2.70(m,1H),1.58(s,3H),0.71(d,J=7.3Hz,3H).

[0418] Example 25: Preparation of Compound P-25

[0419] The synthetic route of compound P-25 is as follows:

[0420] Step 1: Preparation of ethyl 3-(4-(difluoromethoxy)-3-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate

[0421] To a 100 mL reaction tube, add ethyl 4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate (0.75 g, 2.1 mmol) and 2-(4-(difluoromethoxy)-3-fluoro-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate C, 0.40 g, 1.5 mmol). Then, add potassium phosphate trihydrate (1.17 g, 4.5 mmol) and tetrakistriphenylphosphine palladium (0.17 g, 0.2 mmol). After the addition is complete, the atmosphere is replaced with argon three times, and then 25 mL of toluene solution is added via syringe. The temperature is raised to 100°C and the reaction is allowed to proceed for 5 hours. The reaction was complete after monitoring with a plate. After cooling to room temperature, the system was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain 0.40 g of a white solid product with a yield of 63.4%. MS m / z calculated: 428.11; found: 429.2 [M+H] + .

[0422] Step 2: Preparation of ethyl 3-(4-(difluoromethoxy)-3-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0423] To an autoclave, ethyl 3-(4-(difluoromethoxy)-3-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (0.40 g, 0.9 mmol), palladium / carbon (0.99 g), and palladium hydroxide / carbon (0.65 g) were added. Then, 100 mL of methanol was added. After three hydrogen replacements, the autoclave was refilled with hydrogen to 50 psi. The autoclave was heated to 80°C for 24 h. The reaction was monitored for complete reaction by a plate-drip. The system was cooled to room temperature, filtered through celite, and the resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to yield 0.32 g of the compound as a white powder in an 80.2% yield. MS m / z calculated: 430.12; found: 431.1 [M+H] + .

[0424] Step 3: Preparation of 3-(4-(difluoromethoxy)-3-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

[0425] To a 100 mL round-bottom flask was added ethyl 3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-tetrahydrofuran-2-carboxylate (0.32 g, 0.7 mmol). Then, 30 mL of methanol and 15 mL of 2 M sodium hydroxide solution were added sequentially. The resulting solution was heated to 60°C for 3 h. A RT-PCR plate was used to monitor the reaction until the starting material was complete. The mixture was cooled to room temperature and adjusted to pH 4 with dilute hydrochloric acid (2 M). The mixture was then transferred to a separatory funnel with ethyl acetate (500 mL), washed three times with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 0.21 g of the desired product as a pale yellow oil in a 70.3% yield. MS m / z calculated: 402.09; found: 403.1 [M+H] + .

[0426] Step 4: Preparation of 3-(4-(difluoromethoxy)-3-fluoro-2-methoxyphenyl)-4,5-dimethyl-N-(1-oxoisoindolin-5-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0427] To a single-necked flask containing 100 mL of DMF solvent was added 5-aminoisoindole-1-one (0.04 g, 0.3 mmol) and 3-(4-(difluoromethoxy)-3-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (0.10 g, 0.2 mmol). HATU (0.21 g, 0.4 mmol) and DIPEA (0.14 g, 0.8 mmol) were then added. The mixture was allowed to react overnight at room temperature. The reaction was monitored for complete reaction by a microplate reader. The reaction mixture was transferred to a separatory funnel with ethyl acetate (500 mL), washed three times with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield 0.02 g of an off-white solid in a 15.1% yield.

[0428] 1 H NMR(400MHz, DMSO-d6)δ9.52(s,1H),8.49(s,1H),7.44–7.34(m,3H),7.20(t,J=14.7Hz,1H)7.16–7.11(m,1H),7.03–6.99(m ,1H),4.96(d,J=9.1Hz,1H),3.98(d,J=1.9Hz,3H),3.96–3.80(m,3H),3.28–3.16(m,1H),1.44(s,3H),0.97(d,J=6.7Hz,3H).

[0429] Example 26: Preparation of Compound P-26

[0430] The synthetic route of compound P-26 is as follows:

[0431] Step 1: Preparation of ethyl 3-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate

[0432] To a 100 mL reaction tube, add ethyl 4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate (0.87 g, 2.2 mmol) and 2-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate D, 0.76 g, 2.4 mmol). Then, add potassium phosphate trihydrate (1.80 g, 6.6 mmol) and tetrakistriphenylphosphine palladium (0.13 g, 0.1 mmol). After the addition is complete, replace the atmosphere with argon three times, and then add 25 mL of toluene solution via syringe. Heat to 100°C and react for 5 hours. The reaction of the starting material was monitored for completion by spot monitoring. After cooling to room temperature, the system was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain 0.45 g of a white solid product with a yield of 48.0%. MS m / z calculated: 416.08; found: 417.1 [M+H] + .

[0433] Step 2: Preparation of ethyl 3-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0434] To an autoclave, ethyl 3-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (0.45 g, 1.1 mmol), palladium / carbon (1.15 g), and palladium hydroxide / carbon (0.9 g) were added. Then, 100 mL of methanol was added. After three hydrogen replacements, the autoclave was refilled with hydrogen to 50 psi. The autoclave was heated to 80°C for 24 h. The reaction was monitored for complete reaction by a plate-drip. The system was cooled to room temperature, filtered through celite, and the resulting filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to yield 0.27 g of the compound as a white powder in a 59.7% yield. MS m / z calculated: 418.10; found: 419.1 [M+H] + .

[0435] Step 3: Preparation of 3-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

[0436] To a 100 mL round-bottom flask was added ethyl 3-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (0.27 g, 0.6 mmol). Then, 30 mL of methanol and 15 mL of 2 M sodium hydroxide solution were added sequentially. The resulting solution was heated to 60°C and reacted for 3 h. A plate was used to monitor the complete reaction of the starting material. The mixture was cooled to room temperature and adjusted to pH 4 with dilute hydrochloric acid (2 M). The mixture was then transferred to a separatory funnel with ethyl acetate (500 mL), washed three times with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.23 g of the product as a white powder with a yield of 94.0%. MS m / z calculated: 390.07; found: 391.0 [M+H] + .

[0437] Step 4: Preparation of 3-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,5-dimethyl-N-(1-oxoisoindolin-5-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0438] To a single-necked flask containing 100 mL of DMF solvent was added 5-aminoisoindole-1-one (0.04 g, 0.2 mmol) and 3-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (0.10 g, 0.2 mmol). HATU (0.19 g, 0.4 mmol) and DIPEA (0.10 g, 0.6 mmol) were then added. The mixture was allowed to react overnight at room temperature. The reaction was monitored for complete reaction by a microplate reader. The reaction mixture was transferred to a separatory funnel with ethyl acetate (500 mL), washed three times with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield 0.04 g of a white solid in a 30.1% yield.

[0439] 1 H NMR (400MHz, DMSO-d6) δ9.98(s,1H),8.41(s,1H),7.55(d,J=1.7Hz,1H),7.51(d,J=8.2Hz,1H),7.26-7.19(m,3H),7.18-7.10( m,1H),4.93(d,J=9.0Hz,1H),4.27(s,2H),4.03(dd,J=12.4,9.0Hz,1H),3.34-3.22(m,1H),1.46(s,3H),1.00(d,J=6.7Hz,3H).

[0440] Example 27: Preparation of Compound P-27

[0441] The synthetic route of compound P-27 is as follows:

[0442] Step 1: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-N-(2-(2-hydroxyethyl)-1,3-dioxoisoindolin-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0443] To a 20 mL microwave reaction tube, 3-(3,4-difluoro-2-methoxyphenyl)-N-(1,3-dihydroisoindolin-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (Compound P-3, 0.17 g, 0.3 mmol), 2-bromoethanol (0.11 g, 0.7 mmol), and potassium carbonate (0.12 g, 0.7 mmol) were added, followed by injection of 10 mL of acetone solution. The microwave reactor was set to 120°C and reacted for 1.5 hours. After cooling to room temperature, the reaction was monitored for complete reaction. The residue was purified by column chromatography to afford 0.15 g of a white solid product in an 81.2% yield. MS m / z calculated: 542.14; found: 543.2 [M+H] + .

[0444] 1 H NMR (400MHz, DMSO-d6) δ10.21(s,1H),7.86(d,J=1.7Hz,1H),7.74(d,J=8.1 Hz,1H),7.59(dd,J=8.2,1.8Hz,1H),7.14-6.99(m,2H),4.90(d,J=9.0Hz,1H ),4.80(t,J=5.9Hz,1H),4.00(d,J=2.1Hz,3H),3.96-3.84(m,1H),3.64-3. 49(m,4H),3.22(dd,J=12.4,6.6Hz,1H),1.44(s,3H),0.97(d,J=6.7Hz,3H).

[0445] Example 28: Preparation of Compound P-28

[0446] The preparation method is similar to that of Example 1, except that 7-amino-3,4-dihydro-1H-quinolin-2-one in step 10 is replaced with an equal molar amount of 6-aminobenzo[d]isoxazol-3(2H)-one to obtain white powder compound P-28 with a yield of 56.5%.

[0447] 1H NMR (400MHz, DMSO-d6) δ9.78(s,1H),7.78(s,1H),7.42(d,J=9.0Hz,1H),7.27(d,J=9.2Hz,1H),7.07(d,J=7.0Hz,2H),7.05-7.02(m ,1H),4.85(d,J=9.0Hz,1H),3.99(d,J=2.1Hz,3H),3.88(d,J=1.8Hz,1H),3.85(d,J=1.7Hz,1H),1.42(s,3H),0.95(d,J=6.8Hz,3H).

[0448] Example 29: Preparation of Compound P-29

[0449] This preparation method is similar to that of Example 17, except that 5-aminoisoindole-1-one in step 7 is replaced by 5-amino-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (Intermediate E) to obtain white solid compound P-29 with a yield of 70.8%.

[0450] 1 H NMR (400MHz, DMSO-d6) δ10.56(s,1H),8.13(d,J=1.9Hz,1H),7.85(t,J=4.9Hz,1H),7.77(m,1H),7.51(d,J=8.4Hz,1H),7.20-7.12(m,2H) ,5.10(d,J=10.2Hz,1H),4.34(d,J=4.9Hz,2H),4.26(m,1H),3.95(d,J=2.1Hz,3H),2.78(q,J=7.5Hz,1H),1.61(s,3H),0.78-0.67(m,3H).

[0451] Example 30: Preparation of Compound P-30

[0452] The preparation method of this compound is similar to that of Example 17, except that 5-aminoisoindole-1-one in step 7 is replaced by an equimolar amount of 5-amino-3,3-dimethylisoindolin-1-one hydrochloride (Intermediate F) to obtain 0.04 g of the compound as a white solid with a yield of 33.1%.

[0453] 1H NMR (400MHz, DMSO-d6) δ10.55(s,1H),8.56(s,1H),7.95(s,1H),7.54(d,J=1.9Hz,2H),7.25-7.10(m,2H),5.12(d,J=10.4Hz,1 H), 4.26 (dd, J = 10.4, 7.5Hz, 1H), 3.96 (d, J = 2.2Hz, 3H), 2.77 (p, J = 7.4Hz, 1H), 1.60 (s, 3H), 1.39 (d, J = 4.3Hz, 6H), 0.73 (d, 3H).

[0454] Example 31: Preparation of Compound P-31

[0455] The preparation method of this compound is similar to that of Example 17, except that 5-aminoisoindole-1-one in step 7 is replaced by an equimolar amount of 5-amino-7-fluoroisoindole-1-one (intermediate G) to obtain 0.07 g of the compound as a white solid with a yield of 61.8%.

[0456] 1 H NMR (400MHz, DMSO-d6) δ10.89(s,1H),8.20(d,J=1.6Hz,1H),7.76(s,1H),7.29-7.17(m,2H),7.05(t,1H),5.29(d,J= 10.3Hz,1H),4.65(s,2H),4.24(dd,J=10.3,7.6Hz,1H),3.98(s,3H),2.79(m,1H),1.68(s,3H),0.76(d,J=4.6Hz,3H).

[0457] Example 32: Preparation of Compound P-32

[0458] In this reaction scheme, Boc- represents tert-butyloxycarbonyl.

[0459] Step 1: Preparation of tert-butyl 4-(5-nitro-1-oxoisoindolin-2-yl)-1H-pyrazole-1-carboxylate

[0460] To a 250 mL round-bottom flask, methyl 2-(bromomethyl)-4-nitrobenzoate (1.00 g, 3.6 mmol), triethylamine (1.48 g, 14.6 mmol), and methanol (100 mL) were added. After stirring at room temperature, tert-butyl 4-amino-1H-pyrazole-1-carboxylate (0.80 g, 4.3 mmol) was added to the resulting solution. The reaction was heated to 70°C for 3 hours. The reaction was monitored by a microplate reader to ensure complete reaction. The product was directly purified by column chromatography to afford 0.73 g of a white solid in a 61.3% yield. MS m / z calculated: 344.11; found: 345.1 [M+H] + .

[0461] Step 2: Preparation of tert-butyl 4-(5-amino-1-oxoisoindolin-2-yl)-1H-pyrazole-1-carboxylate

[0462] To a 250 mL round-bottom flask, tert-butyl 4-(5-nitro-1-oxoisoindolin-2-yl)-1H-pyrazole-1-carboxylate (0.73 g, 2.8 mmol) was added and dissolved in anhydrous ethanol. Pd / C (10%, 0.29 g) was added, and the flask was filled with hydrogen. Stirring was continued at room temperature for 4 hours. A plate was used to monitor the reaction. The mixture was filtered under reduced pressure through diatomaceous earth, and the filter cake was rinsed with anhydrous ethanol. The filtrate was concentrated under reduced pressure to yield 0.69 g of a white solid, with a yield of 92.6%. MS m / z calculated: 314.13; found: 315.0 [M+H] + .

[0463] Step 3: Preparation of tert-butyl 4-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-1-oxoisoindolin-2-yl)-1H-pyrazole-1-carboxylate

[0464] At room temperature, (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (0.10 g, 0.3 mmol) was dissolved in DMF (50 mL). 4-(5-amino-1-oxoisoindolin-2-yl)-1H-pyrazole-1-carboxylic acid tert-butyl ester (0.08 g, 0.3 mmol), NMI (0.08 g, 1.0 mmol), and TCFH (0.12 g, 0.4 mmol) were added. After stirring for 2 hours, the reaction was monitored for complete reaction. The reaction system was diluted with ethyl acetate and then washed with saturated brine. The organic layer was dried, concentrated under reduced pressure, and purified by column chromatography to obtain 0.12 g of a white solid in a 65.6% yield. MS m / z calculated: 650.21; found: 651.2 [M+H] + .

[0465] Step 4: Preparation of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(1-oxo-2-(1H-pyrazol-4-yl)isoindolin-5-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide hydrochloride

[0466] At room temperature, 0.12 g of tert-butyl 4-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-1-oxoisoindolin-2-yl)-1H-pyrazole-1-carboxylate was dissolved in HCl-EA solution (10 mL) and stirred for 6 hours. The reaction was completed by a plate-triggering. After vacuum filtration, the target product was obtained as a white solid (0.07 g) with a yield of 63.5%.

[0467] 1 H NMR (400MHz, DMSO-d6) δ10.54(s,1H),8.61(s,1H),8.41(s,1H),7.94(s,1H),7.66(m,2H),7.58(d,J=1.2Hz,2H),7.27-7.19(m,2H),5 .15(d,J=10.3Hz,1H),4.26(m,1H),4.10(dd,J=10.3,7.6Hz,1H),3.99(d,J=2.0Hz,3H),2.80–2.74(m,1H),1.60(s,3H),0.74(d,3H).

[0468] Example 33: Preparation of Compound P-33

[0469] The preparation method of this compound is similar to that of Example 32, except that tert-butyl (2-aminoethyl)carbamate (0.70 g, 4.4 mmol) in step 1 is replaced by an equimolar amount of tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate to obtain 0.08 g of a white compound.

[0470] 1H NMR (400MHz, DMSO-d6) δ10.53(s,1H),7.96(s,1H),7.62(d,J=1.2Hz,2H),7.24-7.16(m,2H),5.12(d,J=10.3Hz,1H),4.34(s,2H),4. 29(dd,J=10.3,7.6Hz,1H),4.14(m,1H),3.97(d,J=2.0Hz,3H),3.34(m,4H),2.84-2.76(m,1H),1.84(m,4H)1.62(s,3H),0.75(d,3H).

[0471] Example 34: Preparation of Compound P-34

[0472] The preparation method of this compound is similar to that of Example 32, except that tert-butyl (2-aminoethyl)carbamate (0.70 g, 4.4 mmol) in step 1 is replaced by an equimolar amount of tert-butyl 2-aminoethyl (ethyl)carbamate to obtain 0.10 g of a white compound.

[0473] 1 H NMR(400MHz,DMSO-d6)δ10.95–10.62(m,1H),8.60(d,J=59.7Hz,2H),8.0 1(s,1H),7.65(s,2H),7.30-7.09(m,2H),5.24-5.11(m,1H),4.48(s,2H), 4.31-4.21(m,1H),3.95(s,3H),3.79(s,2H),3.22-3.17(m,2H),3.04-2.9 1(m,2H),2.04-1.96(m,1H),1.60(s,3H),1.18(s,3H),0.78–0.69(m,3H).

[0474] Example 35: Preparation of Compound P-35

[0475] The preparation method of this compound is similar to that of Example 32, except that tert-butyl (2-aminoethyl)carbamate in step 1 is replaced by an equimolar amount of tert-butyl 3-amino-3-methylazetidine-1-carboxylate to obtain 0.15 g of the compound as a white solid.

[0476] 1H NMR (400MHz, DMSO-d6) δ10.93-10.74(m,1H),9.53(s,1H),8.00(s,1H),7.68(d,J=6.3H z,1H),7.62(d,J=8.4Hz,1H),7.19(dd,J=20.8,11.4Hz,2H),5.26-5.12(m,1H),4.51(s, 2H),4.47(d,J=10.3Hz,2H),4.27(dd,J=10.4,7.5Hz,1H),3.95(d,J=2.1Hz,3H),3.89( s,2H),2.77(t,J=7.4Hz,1H),1.91(s,1H),1.64(s,3H),1.60(d,3H),0.76-0.70(m,3H).

[0477] Example 36: Preparation of Compound P-36

[0478] The preparation method of this compound is similar to that of Example 32, except that tert-butyl (2-aminoethyl)carbamate in step 1 is replaced with an equimolar amount of tert-butyl (2-aminocyclopropyl)carbamate to obtain 0.07 g of the compound as a white solid.

[0479] 1 H NMR (400MHz, DMSO-d6) δ10.73(s,1H),8.46(s,2H),7.97(s,1H),7.62(d,J=3.1Hz ,2H),7.25-7.11(m,2H),5.20-5.13(m,1H),4.37(s,2H),4.26(dd,J=10.4,7.5Hz ,1H),3.95(d,J=2.1Hz,3H),3.26(ddd,J=8.3,4.9,2.5Hz,1H),2.99(s,1H),2.76 (p,J=7.5Hz,1H),1.91(s,1H),1.59(s,3H),1.36–1.21(m,2H),0.76–0.69(m,3H).

[0480] Example 37: Preparation of Compound P-37

[0481] The preparation method of this compound is similar to that of Example 32, except that tert-butyl (2-aminoethyl)carbamate in step 1 is replaced with an equimolar amount of tert-butyl 2-(aminomethyl)pyrrolidine-1-carboxylate to obtain 0.08 g of the compound as a white solid.

[0482] 1H NMR(400MHz,DMSO-d6)δ10.87(s,1H),9.37(s,1H),8.80(s,1H),8.02(s,1H),7.7 2-7.61(m,2H),7.29-7.10(m,2H),5.26-5.15(m,1H),4.54(s,2H),4.27(t,J=8.9H z,1H),3.95(s,3H),3.89-3.71(m,4H),3.18(d,J=54.2Hz,2H),2.76(td,J=8.9,4 .5Hz,1H),2.07(s,1H),1.91(d,J=2.5Hz,2H),1.60(s,3H),0.84(d,J=8.2Hz,3H).

[0483] Example 38: Preparation of Compound P-38

[0484] The preparation method of this compound is similar to that of Example 32, except that tert-butyl (2-aminoethyl)carbamate in step 1 is replaced with an equal molar amount of tert-butyl (1-(aminomethyl)cyclopropyl)carbamate to obtain 0.15 g of the compound as a white solid.

[0485] 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),7.93(s,1H),7.60(s,2H),7.23-7.10(m,4H),5.11(d,J=10.3Hz,1H),4.54(s,2H),4 .27(dd,J=10.3,7.6Hz,1H),3.95(s,3H),3.52(s,2H),2.77(m,1H),1.60(s,3H),0.75(d,J=4.6Hz,3H),0.45-0.32(m,4H).

[0486] Example 39: Preparation of Compound P-39

[0487] The preparation method of this compound is similar to that of Example 32, except that: (2-aminoethyl)carbamic acid tert-butyl ester in step 1 is replaced by an equimolar amount of (2-aminocyclopentyl)carbamic acid tert-butyl ester to obtain 0.13 g of the compound as a white solid.

[0488] 1H NMR (400MHz, DMSO-d6) δ11.16(s,1H),8.28(d,J=1.9Hz,1H),8.13(s,2H),7.92(dd,J=8. 5,2.0Hz,1H),7.59(d,J=8.4Hz,1H),7.32(ddd,J=8.5,5.9,2.0Hz,1H),7.21-7.05(m,1H ).5.11(d,J=10.3Hz,1H),4.54(s,2H),4.27(dd,J=10.3,7.6Hz,1H),3.95(s,3H),3.56( m,1H),3.26(m,1H),2.77(m,1H),1.90-1.71(m,6H),1.60(s,3H),0.75(d,J=4.6Hz,3H).

[0489] Example 40: Preparation of Compound P-40

[0490] The preparation method of this compound is similar to that of Example 32, except that tert-butyl (2-aminoethyl)carbamate in step 1 is replaced by an equimolar amount of tert-butyl 3-aminoazetidine-1-carboxylate to obtain 0.11 g of the compound as a white solid.

[0491] 1 H NMR (400MHz, DMSO-d6) δ10.86(s,1H),8.86(s,1H),8.05(d,J=1.6Hz,1H),7.72-7.65(m,2H),7.30-7.16(m,2H),5.16(d,J=10.3Hz,1H), 4.58(s,2H),4.28(dd,J=10.3,7.6Hz,1H),4.13(s,1H),3.98(s,3H),3.90-3.62(m,4H),2.79(m,1H),1.65(s,3H),0.76(d,J=4.6Hz,3H).

[0492] Example 41: Preparation of Compound P-41

[0493] The preparation method of this compound is similar to that of Example 32, except that tert-butyl (2-aminoethyl)carbamate in step 1 is replaced with an equimolar amount of tert-butyl 3-aminopyrrolidine-1-carboxylate to obtain 0.15 g of the compound as a white solid.

[0494] 1H NMR (400MHz, DMSO-d6) δ10.73(s,1H),8.91(s,1H),8.06(d,J=1.6Hz,1H),7.73-7.65(m,2H),7.30-7.16(m,2H),5.16(d,J=10.3Hz,1H),4.58(s,2 H),4.28(dd,J=10.3,7.6Hz,1H),4.05(m,1H),3.98(s,3H),3.15-2.93(m ,4H),2.79(m,1H),1.83-1.75(m,2H),1.65(s,3H),0.76(d,J=4.6Hz,3H).

[0495] Example 42: Preparation of Compound P-42

[0496] The preparation method of this compound is similar to that of Example 32, except that tert-butyl (2-aminoethyl)carbamate in step 1 is replaced with an equimolar amount of di-tert-butyl 2-(aminomethyl)piperazine-1,4-dicarboxylate to obtain 0.07 g of the compound as a white solid.

[0497] 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),8.95(s,2H),8.01(d,J=1.6Hz,1H),7.73–7.65(m,2H),7.29-7.15(m,2H),5.20(d,J=10.3Hz,1H),4. 61(s,2H),4.25(dd,J=10.3,7.6Hz,1H),3.98(s,3H),3.15-3.3(m,3H),2.79(m,1H),2.70-2.61(m,4H),1.65(s,3H),0.76(d,J=4.6Hz,3H).

[0498] Example 43: Preparation of Compound P-43

[0499] The preparation method of this compound is similar to that of Example 32, except that tert-butyl (2-aminoethyl)carbamate in step 1 is replaced with an equimolar amount of tert-butyl 2-(aminomethyl)azetidine-1-carboxylate to obtain 0.15 g of the compound as a white solid.

[0500] 1H NMR(400MHz, DMSO-d6)δ10.82(s,1H),8.97(s,1H),8.06(d,J=1.6Hz,1H), 7.78-7.69(m,2H),7.34-7.28(m,2H),5.19(d,J=10.3Hz,1H),4.60(s,2H), 4.26(dd,J=10.3,7.6Hz,1H),3.95(s,3H),3.40-3.35(m,3H),2.79(m,1H) ,2.73-2.69(m,2H),1.65-1.59(m,2H),1.65(s,3H),0.76(d,J=4.6Hz,3H).

[0501] Example 44: Preparation of Compound P-44

[0502] The preparation method of this compound is similar to that of Example 32, except that tert-butyl (2-aminoethyl)carbamate in step 1 is replaced with an equal molar amount of tert-butyl methyl (2-(methylamino)ethyl)carbamate to obtain 0.09 g of the compound as a white solid.

[0503] 1 H NMR (400MHz, DMSO-d6) δ10.84(s,1H),8.63(s,2H),8.01(d,J=1.6Hz,1H),7.69–7.62(m,2H),5.20(d,J=10.4Hz,1H),4.47(s,2H),3.95(d,J=2 .1Hz,3H),3.19(d,J=6.1Hz,2H),2.77(q,J=7.4Hz,1H),2.56(t,J=5.3H z,3H),2.04-1.89(m,1H),1.60(s,3H),1.23(s,3H),0.79-0.69(m,3H).

[0504] Example 45: Preparation of Compound P-45

[0505] The preparation method of this compound is similar to that of Example 32, except that tert-butyl (2-aminoethyl)carbamate in step 1 is replaced by an equimolar amount of tert-butyl N-(3-aminocyclobutyl)carbamate to obtain 0.03 g of the compound as a white solid.

[0506] 1H NMR (400MHz, DMSO-d6) δ11.15(s,1H),8.28(d,J=1.9Hz,1H),8.12(s,3H),7.92(dd,J=8.5, 2.0Hz,1H),7.58(d,J=8.4Hz,1H),7.31(ddd,J=8.4,5.9,1.9Hz,1H),7.18-7.11(m,1H),5. 25(d,J=10.4Hz,1H),4.26(dd,J=10.4,7.5Hz,1H),3.95(d,J=2.0Hz,4H),3.46(t,J=6.3Hz ,3H),3.12(d,J=6.3Hz,2H),2.76(p,J=7.4Hz,1H),1.60(s,3H),0.86(m,1H),0.75(m,3H).

[0507] Example 46: Preparation of Compound P-46

[0508] The preparation method of the compound is similar to that of Example 32, except that tert-butyl (2-aminoethyl)carbamate in step 1 is replaced by an equimolar amount of tert-butyl 3-amino-3-methylpyrrolidine-1-carboxylate to obtain 0.15 g of the compound as a white solid with a yield of 77.4%.

[0509] 1 H NMR(400MHz,DMSO-d6)δ10.99–10.72(m,1H),8.02–7.94(m,1H),7.73–7.6 5(m,1H),7.63–7.57(m,1H),7.26–7.12(m,1H),5.19(td,J=9.8,4.3Hz,1H) ,4.64–4.49(m,2H),4.26(dd,J=10.8,11.0,7.8Hz,1H),3.95(s,2H),1.63( s,1H),1.59(s,2H),1.45(s,8H),1.22(d,J=4.0Hz,3H),0.76–0.69(m,6H).

[0510] Example 47: Preparation of Compound P-47

[0511] The preparation method of this compound is similar to that of Example 32, except that tert-butyl (2-aminoethyl)carbamate in step 1 is replaced by an equimolar amount of tert-butyl 3-(2-aminoethyl)-1-azetidinecarboxylate to obtain 0.08 g of the compound as a white solid.

[0512] 1H NMR (400MHz, DMSO-d6) δ10.90-10.84(m,1H),8.06(s,1H),8.02-7.98(m,1H),7.67(dd,J=8. 0,5.8Hz,1H),7.60(dd,J=8.3,3.6Hz,1H),7.26(t,J=7.6Hz,1H),7.21-7.11(m,1H),5.21(d, J=10.4Hz,1H),4.56-4.37(m,2H),4.26(dd,J=10.4,7.4Hz,1H),3.98-3.88(m,4H),2.93-2.6 7(m,3H),2.06-1.95(m,1H),1.86-1.64(m,2H),1.59(s,3H),1.23(s,1H),0.78-0.69(m,3H).

[0513] Example 48: Preparation of Compound P-48

[0514] The preparation method of this compound is similar to that of Example 32, except that tert-butyl (2-aminoethyl)carbamate in step 1 is replaced with an equimolar amount of tert-butyl 3-aminobicyclo[1.1.1]pentylcarboxylate to obtain 0.14 g of the compound as a white solid.

[0515] 1 H NMR (400MHz, DMSO-d6) δ9.68 (s, 1H), 7.87 (d, J = 8.9 Hz, 1H), 7.60 (dd, J = 8.9, 2.3Hz,2H),7.54(dt,J=2.1,1.0Hz,1H),7.27(d,J=9.0Hz,1H),7.13(dd,J=9 .0,0.6Hz,2H),4.75–4.73(m,1H),4.57(s,2H),3.96–3.92(m,1H),3.87(s,3 H),2.62–2.59(m,1H),2.07–1.97(m,6H),1.40(s,3H),1.10(d,J=6.6Hz,3H).

[0516] Example 49: Preparation of Compound P-49

[0517] Step 1: Preparation of (R)-methyl 2-(2-(3,4-difluoro-2-methoxyphenyl)acetoxy)-3,3,3-trifluoro-2-methylpropanoate

[0518] Oxalyl chloride (6.00 mL, 68.8 mmol) was added dropwise to a solution of 2-(3,4-difluoro-2-methoxyphenyl)acetic acid (Intermediate A, 6.00 g, 29.9 mmol) and DMF (100.0 μL, 1.3 mmol) in DCM (100 mL) at 0°C and stirred at room temperature for 1 hour. The reaction was concentrated in vacuo, and then a solution of (R)-methyl 3,3,3-trifluoro-2-hydroxy-2-methylpropanoate (Intermediate F, 4.40 g, 25.6 mmol) and triethylamine (7.8 mL, 55.9 mmol) in DCM (10 mL) was added. The mixture was stirred at room temperature overnight until the reaction was complete. The reaction was quenched by the addition of saturated ammonium chloride solution (50 mL). The aqueous phase was extracted with DCM (150 mL) two to three times. The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo. Column chromatography purification afforded 4.30 g of a white solid product with a yield of 41.5%. MS m / z calculated: 356.07; found: 357.1 [M+H] + .

[0519] Step 2: Preparation of (R)-3-(3,4-difluoro-2-methoxyphenyl)-4-hydroxy-5-methyl-5-(trifluoromethyl)furan-2(5H)-one

[0520] Methyl (R)-2-(2-(3,4-difluoro-2-methoxyphenyl)acetoxy)-3,3,3-trifluoro-2-methylpropanoate (1.48 g, 4.2 mmol) was dissolved in THF (20 mL) and slowly added to a solution of LiHMDS (10 mL, 10.0 mmol) in THF (20 mL) at -78°C. The reaction mixture was stirred at -78°C for 5 h with a plate monitor until the reaction was complete. 2M HCl was added to quench the reaction, and the aqueous phase was extracted 2-3 times with EtOAc (150 mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated in vacuo. Purification by column chromatography afforded 0.80 g of the product as a yellow oil in a 59.7% yield. MS m / z calculated: 324.04; found: 325.0 [M+H] + .

[0521] Step 3: Preparation of (R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)furan-2(5H)-one

[0522] Under nitrogen, methanol (4 mL, 68.5 mmol) was added dropwise to a mixture of DCC (2.71 g, 13.1 mmol) and CuCl (0.04 g, 0.4 mmol) at 0°C. After stirring for 1 hour, the mixture was allowed to react at room temperature overnight. The reaction mixture was concentrated in vacuo. Column chromatography afforded 2.1 g of 1,3-dicyclohexyl-2-methylisourea as a colorless oil. Subsequently, 1,3-dicyclohexyl-2-methylisourea (0.44 g, 1.7 mmol) was dissolved in THF and slowly added dropwise to a THF solution of methyl (R)-2-(2-(3,4-difluoro-2-methoxyphenyl)acetoxy)-3,3,3-trifluoro-2-methylpropanoate (0.28 g, 0.8 mmol). The reaction mixture was heated at 85°C overnight. After completion of the reaction, the white precipitate was filtered. The mother liquor was collected and concentrated in vacuo. Column chromatography purification afforded 0.26 g of (R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)furan-2(5H)-one in an 86.4% yield. MS m / z calculated: 338.06; found: 339.1 [M+H] + .

[0523] The series of reactions from Steps 4 to 8 in this example were similar to the reactions from Steps 2 to 6 in Example 17, except that the starting material in Step 2 of Example 17, (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one, was replaced with an equimolar amount of (R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)furan-2(5H)-one. After a series of reactions, 2.02 g of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid was obtained as a transparent oil in a 95.9% yield. MS m / z calculated: 370.08; found: 369.1 [M+H] + .

[0524] Step 9: Preparation of tert-butyl (2-(5-((2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-1-oxoisoindolin-2-yl)ethyl)azetidine-1-carboxylate

[0525] To a single-necked flask containing 100 mL of DMF solvent was added tert-butyl 3-(5-amino-1-oxoisoindolin-2-yl)azetidin-1-carboxylate (178 mg, 0.59 mmol) and 3-(4-(difluoromethoxy)-2,3-difluorophenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (0.20 g, 0.5 mmol). HATU (0.41 g, 1.1 mmol) and DIPEA (0.28 g, 2.2 mmol) were then added. The mixture was allowed to react overnight at room temperature. The reaction was monitored for complete reaction by a microplate reader. The reaction mixture was transferred to a separatory funnel with ethyl acetate (500 mL), washed three times with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to yield 0.04 g of a white solid in a 38.7% yield.

[0526] Step 10: Preparation of (2R,3R,4S,5R)-N-(2-(3-azetidinyl)-1-oxoisoindolin-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide hydrochloride

[0527] At room temperature, tert-butyl (2-(5-((2R,3R,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-1-oxoisoindolin-2-yl)ethyl)azetidine-1-carboxylate (0.08 g, 0.12 mmol) was dissolved in a solution of hydrochloric acid in ethyl acetate (20 mL) and stirred for 6 hours. The reaction was monitored by plate counting until completion. After reduced pressure filtration, 0.03 g of (2R,3R,4S,5R)-N-(2-(3-azetidinyl)-1-oxoisoindolin-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide hydrochloride was obtained as a white solid in a yield of 96.5%.

[0528] 1 H NMR (400MHz, DMSO-d6) δ10.86(s,1H),8.86(s,1H),8.05(d,J=1.6Hz,1H),7.72–7.65(m,2H),7.30–7.16(m,2H),5.16(d,J=10.3Hz, 1H), 4.58 (s, 2H), 4.28 (dd, J = 10.3, 7.6Hz, 1H), 4.13 (s, 1H), 3.98 (s, 3H), 3.90-3.62 (m, 4H), 3.41 (s, 3H), 2.79 (m, 1H), 1.65 (s, 3H).

[0529] Example 50: Preparation of Compound P-50

[0530] Step 1: Preparation of methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0531] Potassium carbonate (1.16 g, 8.5 mmol) was added to a solution of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1.0 g, 2.8 mmol) in N,N-dimethylformamide (50 mL). Methyl iodide (0.59 g, 4.2 mmol) was then added dropwise to the solution. After the addition was complete, the temperature was raised to 70°C. The reaction was monitored by TLC until completion. After cooling to room temperature, the reaction system was diluted with ethyl acetate (200 mL) and washed 3-5 times with saturated brine (300 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield 0.92 g of crude methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate in an 88.5% yield. MS m / z calculated: 368.10; found: 369.1 [M+H] + .

[0532] Step 2: Preparation of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0533] Methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (0.53 g, 1.3 mmol) was dissolved in 7 M ammonia in methanol (10 mL). After stirring for 6 h, the reaction was monitored by TLC for completion. The product was concentrated in vacuo to afford 0.47 g of crude (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide in a 92% yield. MS m / z calculated: 353.11; found: 354.1 [M+H] + .

[0534] Step 3: Preparation of tert-butyl 3-(6-bromo-1,1-dimethyl-3-oxoisoindolin-2-yl)azetidine-1-carboxylate

[0535] 5-Bromo-3,3-dimethylisoindolin-1-one (0.30 g, 1.25 mmol), tert-butyl 3-iodoazetidine-1-carboxylate (0.39 g, 1.37 mmol), and cesium carbonate (1.0 g, 3.07 mmol) were dissolved in DMF and heated to 120°C for 24 h. The reaction was monitored by TLC until completion. The solution was transferred to a separatory funnel with 100 mL of ethyl acetate and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 130 mg of tert-butyl 3-(6-bromo-1,1-dimethyl-3-oxoisoindolin-2-yl)azetidine-1-carboxylate in a yield of 26.3%. MS m / z calculated: 394.09; found: 395.1 [M+H] + .

[0536] Step 4: Preparation of tert-butyl 3-(6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-1,1-dimethyl-3-oxoisoindol-2-yl)azetidine-1-carboxylate

[0537] To a 250 mL three-necked flask were added tert-butyl 3-(6-bromo-1,1-dimethyl-3-oxoisoindolin-2-yl)azetidine-1-carboxylate (105 mg, 0.28 mmol), (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (130 mg, 0.34 mmol), trisdibenzylideneacetone dipalladium (27 mg, 0. The mixture was prepared by adding 1,4-diphenylphosphino-9,9-dimethylxanthene (33 mg, 0.029 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (33 mg, 0.057 mmol), and cesium carbonate (280 mg, 0.86 mmol). After the addition was complete, the atmosphere was replaced with argon three times, and toluene (100 mL) was added. The temperature was raised to 100°C and the reaction was allowed to proceed overnight. After TLC monitoring, the reaction was completed and filtered under reduced pressure. The filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain 150 mg of a yellow solid in a yield of 79.3%. MS m / z calculated: 667.67; found: 668.7 [M+H] + .

[0538] Step 5: Preparation of (2R,3S,4S,5R)-N-(2-(aza-3-yl)-3,3-dimethyl-1-oxoisoindolin-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide hydrochloride

[0539] To a 100 mL single-necked flask, add tert-butyl 3-(6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-1,1-dimethyl-3-oxoisoindol-2-yl)azetidine-1-carboxylate (150 mg, 0.22 mmol) and a solution of hydrogen chloride in ethyl acetate (4 mol / L, 10 mL). Stir at room temperature for 2 h. The reaction was complete, as monitored by TLC. The solution was concentrated under reduced pressure to give 120 mg of a light yellow solid in a 90.3% yield.

[0540] 1 H NMR(400MHz,DMSO-d6)δ11.17(s,1H),9.74(s,1H),9.40(s,1H),8.14(s,1H),7.78( t,J=6.8Hz,2H),7.31(dd,J=9.2,6.5Hz,1H),7.15(q,J=8.9Hz,1H),5.66–5.61(m,1H ),5.29(d,J=10.5Hz,1H),4.53–4.47(m,2H),4.32–4.23(m,3H),3.96(d,J=2.1Hz,3 H), 2.77 (p, J = 7.5Hz, 1H), 1.61 (s, 3H), 1.51 (d, J = 5.2Hz, 6H), 0.73 (d, J = 7.3Hz, 3H).

[0541] Example 51: Preparation of Compound P-51

[0542] The preparation method of this compound is similar to that of Example 50, except that 5-bromo-3,3-dimethylisoindolin-1-one in step 3 is replaced by an equimolar amount of 6'-bromospiro[cyclopropane-1,1'-isoindolin]-3'-one to obtain 0.08 g of the compound as a white solid with a yield of 36.0%.

[0543] 1H NMR (400MHz, DMSO-d6) δ10.44(s,1H),7.78(t,J=6.8Hz,2H),7.66(t,J=1.2Hz,1H ),7.53(d,J=1.7Hz,2H),7.22–7.08(m,2H),5.36–5.27(m,1H),5.10(d,J=10.4Hz ,1H),4.31–4.19(m,3H),3.95(d,J=2.1Hz,3H),3.92–3.86(m,2H),2.76(p,J=7.4 Hz,1H),1.69(t,J=3.8Hz,2H),1.60(s,3H),1.55–1.51(m,2H),0.76–0.70(m,3H).

[0544] Example 52: Preparation of Compound P-52

[0545] The preparation method of the compound is similar to that of Example 32, except that tert-butyl 4-amino-1H-pyrazole-1-carboxylate in step 1 is replaced by an equimolar amount of tert-butyl 3-amino-3-(fluoromethyl)azetidine-1-carboxylate to obtain 0.16 g of the compound as a white solid with a yield of 75.0%.

[0546] 1 H NMR(400MHz,DMSO-d6)δ10.71(s,1H),9.27(s,1H),9.12(s,1H),8.01(s,1H),7. 66(d,J=2.1Hz,2H),7.21–7.11(m,2H),5.14(d,J=10.3Hz,1H),4.88(s,1H),4.7 6(s,1H),4.56(s,2H),4.50(s,2H),4.27(dd,J=10.4,7.5Hz,1H),4.15(s,2H),3 .95(d,J=2.1Hz,3H),2.77(p,J=7.6Hz,1H),1.60(s,3H),0.73(d,J=7.4Hz,4H).

[0547] Example 53: Preparation of Compound P-53

[0548] The preparation method of the compound is similar to that of Example 32, except that tert-butyl 4-amino-1H-pyrazole-1-carboxylate in step 1 is replaced by an equimolar amount of tert-butyl (2R,3S)-3-amino-2-methylazetidine-1-carboxylate to obtain 0.18 g of the compound as a white solid with a yield of 88.0%.

[0549] 1 H NMR (400MHz, DMSO-d6) δ10.72(s,1H),8.88(s,2H),8.02(s,1H),7.65(s,2H),7.22–7.11(m,2H),5.16(d,J=10.4Hz,1H),4.82–4.72(m,2H) ),4.63(s,2H),4.31–4.22(m,2H),3.95(d,J=2.1Hz,4H),2.77(t,J=7.4Hz,1H),1.60(s,3H),1.47(d,J=6.1Hz,3H),0.74(d,J=7.3Hz,3H).

[0550] Example 54: Preparation of Compound P-54

[0551] The preparation method of the compound is similar to that of Example 32, except that tert-butyl 4-amino-1H-pyrazole-1-carboxylate in step 1 is replaced by an equimolar amount of tert-butyl (2S,3S)-3-amino-2-methylazetidine-1-carboxylate to obtain 0.18 g of the compound as a white solid with a yield of 85.0%.

[0552] 1 H NMR (400MHz, DMSO-d6) δ10.80(s,1H),9.09(s,2H),8.03(s,1H),7.72–7.62(m,2H),7.22(d,J= 6.5Hz,1H),7.20–7.09(m,1H),5.18(d,J=10.4Hz,1H),4.87(td,J=14.0,7.4Hz,1H),4.77(d,J =17.6Hz,1H),4.72–4.60(m,2H),4.56–4.47(m,1H),4.26(dd,J=10.5,7.4Hz,2H),3.95(d,J=2 .1Hz,3H),2.76(p,J=7.4Hz,1H),1.60(s,3H),1.30(dd,J=7.1,3.5Hz,3H),0.76–0.70(m,3H).

[0553] Example 55: Preparation of Compound P-55

[0554] The preparation method of the compound is similar to that of Example 32, except that tert-butyl 4-amino-1H-pyrazole-1-carboxylate in step 1 is replaced by an equimolar amount of tert-butyl (2S,3R)-3-amino-2-methylazetidine-1-carboxylate to obtain 0.11 g of the compound as a white solid with a yield of 60.0%.

[0555] 1 H NMR (400MHz, DMSO-d6) δ10.91(s,1H),9.14(s,2H),8.03(s,1H),7.69(d,J=8.4Hz,1H ),7.64(d,J=8.3Hz,1H),7.26(t,J=7.7Hz,1H),7.15(q,J=8.9Hz,1H),5.22(d,J=10.3 Hz,1H),4.78(dd,J=19.0,10.8Hz,2H),4.64(s,2H),4.29–4.18(m,2H),3.96–3.91(m, 4H), 2.76 (p, J = 7.5Hz, 1H), 1.59 (s, 3H), 1.48 (d, J = 6.1Hz, 3H), 0.73 (d, J = 7.3Hz, 3H).

[0556] Example 56: Preparation of Compound P-56

[0557] The preparation method is similar to that of Example 17, except that 5-aminoisoindole-1-one in step 7 is replaced by tert-butyl 3-(5-amino-1,3-dioxoisoindolin-2-yl)azetidine-1-carboxylate, followed by deprotection to obtain 0.06 g of a white solid compound with a yield of 67.2%.

[0558] 1 H NMR (400MHz, DMSO-d6) δ11.23 (s, 1H), 9.12 (d, J = 59.5Hz, 2H), 8.29 (d, J = 1.8Hz, 1H),8.08–7.80(m,2H),7.35–7.11(m,2H),5.26(d,J=10.3Hz,1H),5.08(t,J=8.2 Hz,1H),4.53(t,J=9.3Hz,2H),4.27(dd,J=10.3,7.5Hz,1H),4.19(t,J=10.0Hz,2 H),3.95(d,J=2.0Hz,3H),2.78(q,J=7.5Hz,1H),1.61(s,3H),0.79–0.72(m,3H).

[0559] Example 57: Preparation of Compound P-57

[0560] The preparation method of the compound is similar to that of Example 32, except that tert-butyl (2-aminoethyl)carbamate in step 1 is replaced by an equimolar amount of tert-butyl 2-amino-5-azaspiro[3.4]octane-5-carboxylate to obtain 0.12 g of the compound as a white solid with a yield of 65.0%.

[0561] 1 H NMR(400MHz,DMSO-d6)δ10.72(s,1H),9.35(s,2H),8.04–7.96(m,1H),7.69–7.57(m,2H),7.24– 7.12(m,2H),5.16(d,J=10.4Hz,1H),5.00(p,J=8.9Hz,1H),4.56(s,2H),4.27(dd,J=10.4,7.5H z,1H),3.95(d,J=2.1Hz,3H),3.22(t,J=6.8Hz,2H),2.77(p,J=7.4Hz,1H),2.67(t,J=7.8Hz,4H ), 2.01 (dd, J=8.3, 6.5Hz, 2H), 1.89 (dp, J=14.6, 7.3Hz, 2H), 1.60 (s, 3H), 0.73 (d, J=7.3Hz, 3H).

[0562] Example 58: Preparation of Compound P-58

[0563] Step 1: Preparation of tert-butyl (3-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-1-oxoisoindolin-2-yl)bicyclo[1.1.1]pentan-1-yl)(methyl)carbamate

[0564] To a 100 mL single-necked flask was added tert-butyl (3-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-1-oxoisoindolin-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (200 mg, 0.3 mmol), cesium carbonate (244 mg, 0.75 mmol), and iodomethane (84 mg, 0.6 mmol), followed by DMF (20 mL). The reaction was heated to 100°C for 12 h. TLC was used to monitor the reaction until completion. The solution was transferred to a separatory funnel with 100 mL of ethyl acetate and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography afforded 95 mg of a yellow solid with a yield of 46.5%. MS m / z: Calculated: 679.26; Found: 680.30 [M+H] + Step 2: Preparation of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(2-(3-(methylamino)bicyclo[1.1.1]pentan-1-yl)-1-oxoisoindolin-5-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide hydrochloride

[0565] At room temperature, tert-butyl (3-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-1-oxoisoindolin-2-yl)bicyclo[1.1.1]pentan-1-yl)(methyl)carbamate (95 mg, 0.14 mmol) was dissolved in a solution of hydrochloric acid in ethyl acetate (20 mL). The mixture was stirred for 2 hours, and the reaction of the raw materials was monitored by plate counting. After vacuum filtration, 68 mg of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(2-(3-(methylamino)bicyclo[1.1.1]pentan-1-yl)-1-oxoisoindolin-5-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide hydrochloride as a white solid was obtained with a yield of 78.9%.

[0566] 1H NMR(400MHz,DMSO-d6)δ10.85–10.68(m,1H),9.83(s,2H),7.97(s,1H),7.6 6(d,J=8.9Hz,1H),7.63–7.56(m,1H),7.21–7.11(m,2H),5.17(d,J=9.8Hz,1 H),4.46(s,2H),4.27(t,J=9.0Hz,1H),3.96(d,J=2.4Hz,3H),2.81–2.73(m, 1H), 2.55 (d, J = 3.2Hz, 3H), 2.42 (s, 6H), 1.60 (s, 3H), 0.73 (d, J = 7.3Hz, 3H).

[0567] Example 59: Preparation of Compound P-59

[0568] Step 1: Preparation of tert-butyl (3-(5-nitro-1,3-diketoisoindolin-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

[0569] To a 100 mL single-necked flask, add 5-nitroisobenzofuran-1,3-dione (200 mg, 1.03 mmol), tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate (250 mg, 1.24 mmol), and DMF (20 mL). The reaction was heated to 130°C for 6 h. TLC monitored the reaction completion. The solution was transferred to a separatory funnel with 100 mL of ethyl acetate and washed with saturated brine (100 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography afforded 180 mg of a yellow solid in a 48% yield. MS m / z calculated: 373.13; found: 374.1 [M+H] + .

[0570] Step 2: Preparation of tert-butyl (3-(5-amino-1,3-dioxoisoindole-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

[0571] To a 100 mL single-necked flask, tert-butyl (3-(5-nitro-1,3-diketoisoindolin-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (180 mg, 0.48 mmol), methanol (10 mL), and palladium / carbon catalyst (20 mg, 10% wt) were added. The reaction was allowed to proceed at room temperature for 2 h under a hydrogen balloon atmosphere. TLC monitored the reaction completion. The system was filtered, and the filtrate was concentrated under reduced pressure and purified by column chromatography to yield 115 mg of tert-butyl (3-(5-amino-1,3-dioxoisoiindol-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate in a 70.7% yield. MS m / z calculated: 343.15; found: 344.1 [M+H]+ .

[0572] Step 3: Preparation of tert-butyl (3-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-1,3-dioxindol-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

[0573] To a single-necked flask containing 100 mL of DMF solvent was added tert-butyl (3-(5-amino-1,3-dioxoisoindole-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate (82 mg, 0.24 mmol) and 3-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (0.10 g, 0.2 mmol). HATU (0.19 g, 0.4 mmol) and DIPEA (0.10 g, 0.6 mmol) were then added. The mixture was allowed to react at room temperature overnight. The reaction was monitored for complete reaction by a microplate reader. The reaction mixture was transferred to a separatory funnel with ethyl acetate (500 mL), washed three times with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to afford 0.11 g of a white solid in 80% yield. MS m / z calculated: 679.23; found: 680.1 [M+H] + .

[0574] Step 4: Preparation of (2R,3S,4S,5R)-N-(2-(3-aminobicyclo[1.1.1]pentan-1-yl)-1,3-dioxoisoindole-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide hydrochloride

[0575] To a 100 mL single-necked flask, add tert-butyl 3-(6-((2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-1,1-dimethyl-3-oxoisoindol-2-yl)azetidine-1-carboxylate (110 mg, 0.16 mmol) and a solution of hydrogen chloride in ethyl acetate (4 mol / L, 10 mL). Stir at room temperature for 2 h. The reaction was complete, as monitored by TLC. The solution was concentrated under reduced pressure to give 90 mg of a light yellow solid in a 91.0% yield.

[0576] 1H NMR (400MHz, DMSO-d6) δ11.11(s,1H),8.99(s,3H),8.22(d,J=1.8Hz,1H),8.01( dd,J=8.3,1.9Hz,1H),7.81(d,J=8.2Hz,1H),7.25(t,J=7.6Hz,1H),7.16(td,J= 9.4,7.5Hz,1H),5.21(d,J=10.3Hz,1H),4.27(dd,J=10.3,7.5Hz,1H),3.95(d,J =2.1Hz,3H),2.77(p,J=7.5Hz,1H),2.54(s,6H),1.61(s,3H),0.75–0.70(m,3H).

[0577] Example 60: Preparation of Compound P-60

[0578] The preparation method of the compound is similar to that of Example 32, except that the (2-aminoethyl)carbamic acid tert-butyl ester in step 1 is replaced by an equimolar amount of ((1R,3R)-3-aminocyclobutyl)carbamic acid tert-butyl ester to obtain 0.09 g of the compound as a white solid with a yield of 77.0%.

[0579] 1 H NMR (400MHz, DMSO-d6) δ10.91(d,J=2.5Hz,1H),8.36(s,3H),8.01(d,J=1.8Hz,1H),7.68(dd,J=8.4,1.8H z,1H),7.59(d,J=8.3Hz,1H),7.26(t,J=7.4Hz,1H),7.15(td,J=9.5,7.6Hz,1H),5.22(d,J=10.4Hz,1H), 5.14(p,J=8.3Hz,1H),4.57(s,2H),4.26(dd,J=10.5,7.5Hz,1H),3.95(d,J=2.2Hz,3H),3.74(s,1H),2.7 6(p,J=7.4Hz,2H),2.68(s,1H),2.39(ddd,J=14.6,10.3,3.2Hz,2H),1.59(s,3H),0.73(d,J=7.4Hz,3H).

[0580] Example 61: Preparation of Compound P-61

[0581] The preparation method is similar to that of Example 32, except that tert-butyl 4-amino-1H-pyrazole-1-carboxylate in step 1 is replaced with tert-butyl ((1S,3S)-3-aminocyclobutyl)carbamate to obtain 0.10 g of a white solid compound with a yield of 55.5%.

[0582] 1 H NMR (400MHz, DMSO-d6) δ10.86(s,1H),8.33(d,J=5.1Hz,3H),8.03(d,J=1.7Hz,1H ),7.78–7.54(m,2H),7.39–7.07(m,2H),5.21(d,J=10.4Hz,1H),4.59(d,J=8.9Hz ,1H),4.56(s,2H),4.27(dd,J=10.4,7.5Hz,1H),3.96(d,J=2.1Hz,3H),3.50(d,J =7.0Hz,1H),2.77(p,J=7.5Hz,1H),1.91(s,4H),1.60(s,3H),0.78–0.69(m,3H).

[0583] Example 62: Preparation of Compound P-62

[0584] The preparation method is similar to that of Example 32, except that tert-butyl 4-amino-1H-pyrazole-1-carboxylate in step 1 is replaced with tert-butyl (1R,3R)-3-amino-1-methylcyclobutylcarbamate to obtain 0.13 g of a white solid compound with a yield of 72.5%.

[0585] 1 H NMR (400MHz, DMSO-d6) δ10.70 (s, 1H), 8.28 (s, 3H), 7.98 (d, J = 1.7Hz, 1H), 7.6 6–7.52(m,2H),7.23–7.12(m,2H),5.15(d,J=10.6Hz,1H),5.10(d,J=8.8Hz,1 H),4.57(s,2H),4.27(dd,J=10.4,7.6Hz,1H),3.95(d,J=2.1Hz,3H),2.77(t, J=7.4Hz,1H),2.60-2.45(m,4H),1.60(s,3H),1.46(s,3H),0.76–0.71(m,3H).

[0586] Example 63: Preparation of Compound P-63

[0587] The preparation method of the compound is similar to that of Example 32, except that tert-butyl 4-amino-1H-pyrazole-1-carboxylate in step 1 is replaced by an equimolar amount of tert-butyl (2-aminocyclobutyl)carbamate to obtain 0.09 g of the compound as a white solid with a yield of 51.0%.

[0588] 1 H NMR (400MHz, DMSO-d6) δ10.92(s,1H),8.32(s,3H),8.01(d,J=1.8Hz,1H),7.68(dd,J=8.4,1. 8Hz,1H),7.58(d,J=8.3Hz,1H),7.25(t,J=7.4Hz,1H),7.20–7.10(m,1H),5.25(d,J=10.4Hz,1 H),5.12(q,J=8.2Hz,1H),4.56(s,2H),4.25(dd,J=10.5,7.5Hz,1H),3.97(d,J=2.2Hz,3H),3. 76(s,1H),2.81–2.72(m,3H),2.41(tt,J=8.7,4.4Hz,2H),1.62(s,3H),0.76(d,J=7.4Hz,3H).

[0589] Example 64: Preparation of Compound P-64

[0590] The preparation method of the compound is similar to that of Example 32, except that tert-butyl 4-amino-1H-pyrazole-1-carboxylate in step 1 is replaced by an equimolar amount of tert-butyl (1S,2S)-2-aminocyclopropylcarbamate to obtain 0.11 g of the compound as a white solid with a yield of 63.0%.

[0591] 1 H NMR (400MHz, DMSO-d6) δ10.90(s,1H),8.60(s,3H),7.97(d,J=1.6Hz,1H),7.67(dd,J= 8.3,1.8Hz,1H),7.60(d,J=8.3Hz,1H),7.26(td,J=6.5,3.1Hz,1H),7.18–7.09(m,1H) ,5.21(d,J=10.4Hz,1H),4.37(s,2H),3.94(d,J=2.1Hz,3H),3.28(dd,J=8.1,5.1,2.4 Hz,1H),2.76(q,J=7.4Hz,1H),1.59(s,3H),1.24(q,J=2.1Hz,2H),0.75–0.69(m,3H).

[0592] Example 65: Preparation of Compound P-65

[0593] The preparation method is similar to that of Example 32, except that tert-butyl 4-amino-1H-pyrazole-1-carboxylate in step 1 is replaced with tert-butyl N-[(1R,2R)-2-aminocyclopropyl]carbamate to obtain 0.13 g of a white solid compound with a yield of 75.2%.

[0594] 1 H NMR (400MHz, DMSO-d6) δ10.88(s,1H),8.60(d,J=4.3Hz,3H),7.99(d,J=1.7Hz,1H),7.73–7. 57(m,2H),7.33–7.11(m,2H),5.23(d,J=10.4Hz,1H),4.39(s,2H),4.28(dd,J=10.4,7.5Hz, 1H),3.96(d,J=2.1Hz,3H),3.30(ddd,J=8.2,5.0,2.4Hz,1H),3.00(s,1H),2.78(q,J=7.5Hz ,1H),2.70(s,2H),1.61(s,3H),1.38(dddd,J=33.5,8.7,6.9,5.0Hz,2H),0.78–0.68(m,3H).

[0595] Example 66: Preparation of Compound P-66

[0596] The preparation method of the compound is similar to that of Example 32, except that: (2-aminoethyl)carbamic acid tert-butyl ester in step 1 is replaced by an equimolar amount of ((1R,2S)-2-aminocyclopropyl)carbamic acid tert-butyl ester to obtain 0.13 g of the compound as a white solid with a yield of 74.0%.

[0597] 1H NMR (400MHz, DMSO-d6) δ10.83(s,1H),8.21(s,3H),7.96(d,J=1.8Hz,1H),7.71(d,J=8 .5Hz,1H),7.64(d,J=8.3Hz,1H),7.23(s,1H),7.20–7.11(m,1H),5.20(d,J=10.4Hz,1H ),4.47(s,2H),4.26(dd,J=10.4,7.5Hz,1H),3.95(d,J=2.1Hz,3H),2.98–2.92(m,1H), 2.91(s,1H),2.77(q,J=7.6Hz,1H),1.59(s,3H),1.33–1.17(m,2H),0.76–0.69(m,3H).

[0598] Example 67: Preparation of Compound P-67

[0599] The preparation method of the compound is similar to that of Example 32, except that tert-butyl (2-aminoethyl)carbamate in step 1 is replaced by an equimolar amount of tert-butyl 6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate to obtain 0.16 g of the compound as a white solid with a yield of 80.0%.

[0600] 1 H NMR (400MHz, DMSO-d6) δ10.71(s,1H),9.52(s,1H),9.02(s,1H),7.95(d,J=1.7Hz,1 H),7.66–7.56(m,2H),7.25–7.10(m,2H),5.16(d,J=10.4Hz,1H),4.37(s,2H),4.26( dd,J=10.3,7.4Hz,1H),3.95(d,J=2.1Hz,3H),3.43(dt,J=14.4,7.3Hz,4H),3.01(t, J=2.6Hz,1H),2.81–2.71(m,1H),2.31–2.21(m,2H),1.59(s,3H),0.76–0.69(m,3H).

[0601] Example 68: Preparation of Compound P-68

[0602] The preparation method is similar to that of Example 32, except that tert-butyl 4-amino-1H-pyrazole-1-carboxylate in step 1 is replaced with tert-butyl (2S,4S)-4-amino-2-(fluoromethyl)pyrrolidine-1-carboxylate to obtain 0.16 g of a white solid compound with a yield of 75.2%.

[0603] 1 H NMR(400MHz,DMSO-d6)δ10.89(s,1H),10.09(s,1H),9.60(s,1H),8.00(d,J=1.6Hz,1H), 7.78–7.58(m,2H),7.32–7.08(m,2H),5.22(d,J=10.4Hz,1H),4.93–4.61(m,3H),4.57(d ,J=11.3Hz,2H),4.27(dd,J=10.4,7.5Hz,1H),3.96(d,J=2.2Hz,3H),3.61–3.39(m,3H), 2.77(p,J=7.5Hz,1H), 2.33(ddd,J=13.8,8.5,5.5Hz,1H), 2.10(dt,J=13.7,8.2Hz,1H).

[0604] Example 69: Preparation of Compound P-69

[0605] The preparation method is similar to that of Example 32, except that tert-butyl 4-amino-1H-pyrazole-1-carboxylate in step 1 is replaced with tert-butyl (2S,4R)-4-amino-2-(hydroxymethyl)pyrrolidine-1-carboxylate to obtain 0.12 g of a white solid compound with a yield of 68.1%.

[0606] 1 H NMR (400MHz, DMSO-d6) δ10.83(s,1H),9.69(s,1H),8.94(s,1H),8.00(s,1H),7.65(q,J=8.3Hz,2H),7.20(dt ,J=23.9,9.0Hz,2H),5.47(t,J=5.1Hz,1H),5.19(d,J=10.2Hz,1H),4.86(t,J=7.0Hz,1H),4.55(d,J=5.8Hz,2 H),4.26(dd,J=10.3,7.5Hz,1H),3.95(d,J=2.1Hz,3H),3.89(d,J=8.2Hz,1H),3.73–3.44(m,3H),2.77(t,J=7 .5Hz,1H),2.25(dt,J=13.9,7.4Hz,1H),2.05(ddd,J=22.6,15.6,8.0Hz,1H),1.60(s,3H),0.77–0.70(m,3H).

[0607] Example 70: Preparation of Compound P-70

[0608] The preparation method of the compound is similar to that of Example 32, except that tert-butyl (2-aminoethyl)carbamate in step 1 is replaced by an equimolar amount of tert-butyl 4-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate to obtain 0.16 g of the compound as a white solid with a yield of 80.0%.

[0609] 1 H NMR (400MHz, DMSO-d6) δ10.88(s,1H),9.49(s,2H),7.98(d,J=1.8Hz,1H),7.69(dd,J=8.3,1.8Hz,1H) ,7.61(d,J=8.3Hz,1H),7.34–7.21(m,1H),7.20–7.09(m,1H),5.20(d,J=10.4Hz,1H),4.56(s,2H),4.2 6(dd,J=10.4,7.5Hz,1H),4.17(d,J=2.5Hz,1H),3.95(d,J=2.1Hz,3H),3.49(t,J=5.0Hz,2H),2.76(p ,J=7.4Hz,1H),2.36(d,J=5.3Hz,2H),2.03(dd,J=5.4,2.1Hz,2H),1.59(s,3H),0.73(d,J=7.2Hz,3H).

[0610] Example 71: Preparation of Compound P-71

[0611] The preparation method is similar to that of Example 32, except that 4-amino-1H-pyrazole-1-carboxylic acid tert-butyl ester in step 1 is replaced with (S)-3-aminopyrrolidine-1-carboxylic acid tert-butyl ester to obtain 0.05 g of a white solid compound with a yield of 66.5%.

[0612] 1H NMR (400MHz, DMSO-d6) δ10.79(s,1H),9.35(s,2H),7.99(d,J=1.7Hz,1H),7.72–7.60(m,2 H),7.30–7.09(m,2H),5.19(d,J=11.9Hz,1H),4.82(p,J=7.6Hz,1H),4.53(d,J=4.1Hz,2H) ,4.27(dd,J=10.4,7.5Hz,1H),3.95(d,J=2.2Hz,3H),3.41(td,J=8.7,7.7,3.8Hz,2H),3. 35–3.14(m,2H),2.76(p,J=7.5Hz,1H),2.28–2.09(m,2H),1.60(s,3H),0.79–0.70(m,3H).

[0613] Example 72: Preparation of Compound P-72

[0614] The preparation method of the compound is similar to that of Example 32, except that tert-butyl 4-amino-1H-pyrazole-1-carboxylate in step 1 is replaced by an equimolar amount of tert-butyl 4-amino-2-azabicyclo[2.2.1]heptane-2-carboxylate to obtain 0.08 g of the compound as a white solid with a yield of 43.0%.

[0615] 1 H NMR (400MHz, DMSO-d6) δ10.77(s,1H),7.97(s,1H),7.63(d,J=20.1Hz,2H),7.17(d,J=19.6Hz,2H),5.17(d,J=10.4Hz,1H),4.58( s,2H),4.26(s,1H),4.01(s,1H),3.95(s,3H),3.58(d,J=10.4Hz,1H),2.76(s,1H),2.35–1.85(m,8H),1.59(s,3H),0.73(s,3H).

[0616] Example 73: Preparation of Compound P-73

[0617] The preparation method of this compound is similar to that of Example 32, except that tert-butyl (2-aminoethyl)carbamate in step 1 is replaced by an equimolar amount of tert-butyl (1S,2S,4R)-2-amino-7-azabicyclo[2.2.1]heptane-7-carboxylate to obtain 0.12 g of the compound as a white solid with a yield of 70.4%.

[0618] 1H NMR(400MHz,Chloroform-d)δ8.54(s,1H),8.06(s,1H),7.88(m,2H),7.77(d,J=7.4Hz,1H),7 .30(d,J=7.1Hz,1H),7.15–7.07(m,1H),6.91(td,J=9.2,7.4Hz,1H),5.03(d,J=10.9Hz,1H), 4.70(s,1H),4.45–4.24(m,4H),4.17–4.05(m,1H),4.00(d,J=2.6Hz,3H),2.75(p,J=7.6Hz,1 H),2.35–2.19(m,1H),1.91–1.81(m,1H),1.71–1.67(m,4H),1.62(s,3H),0.86–0.77(m,3H).

[0619] Example 74: Preparation of Compound P-74

[0620] Step 1: Preparation of rac-(4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylic acid ethyl ester

[0621] Ethyl rac-(4R,5R)-4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate (Intermediate H, 10.2 g, 26.3 mmol) and (3,4-difluoro-2-(methylthio)phenyl)boronic acid (Intermediate I, 8 g, 39.4 mmol) were dissolved in toluene (90 mL) and water (10 mL) solution, potassium phosphate (11.17 g, 52.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.04 g, 2.63 mmol) were added thereto, nitrogen was replaced three times, and the mixture was stirred at 100°C for 1 hour. TLC confirmed the complete reaction of the starting material. After cooling to room temperature, the reaction mixture was added with water (200 mL) and extracted with ethyl acetate (100 mL x 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to yield 8.6 g of rac-(4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylic acid ethyl ester, a yellow solid, in a yield of 78.0%. MS m / z calculated: 396.08; found: 397.1 [M+H] + .

[0622] Step 2: Preparation of rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid ethyl ester

[0623] Ethyl rac-(4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (5 g, 12.6 mmol) was dissolved in methanol (50 mL), and magnesium chips (1.53 mL, 63 mmol) and 1,2-dibromoethane (2.37 g, 12.6 mmol) were added thereto. The mixture was stirred at 70 ° C for 3 days, filtered, and the filter cake was washed with methanol. The filtrate was concentrated under reduced pressure and purified by column chromatography and HPLC to obtain 0.5 g of ethyl rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate as a yellow solid compound with a yield of 9.52%. MS m / z calculated: 398.10; found: 399.1 [M+H] + .

[0624] Step 3: Preparation of rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

[0625] Ethyl rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (500 mg, 1.30 mmol) was dissolved in a solution of tetrahydrofuran (9 mL) and water (3 mL), and lithium hydroxide monohydrate (2.18 g, 5.19 mmol) was added thereto. After stirring at room temperature for 2 hours, water (10 mL) was added to the reaction solution, and the pH value was adjusted to ~2 with 1 M dilute hydrochloric acid. The solution was extracted with ethyl acetate (10 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 480 mg of rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid as a light yellow solid with a yield of 92%. MS m / z calculated: 370.07; found: 371.1 [M+H] + .

[0626] Step 4: Separation of chiral isomers

[0627] rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (480 mg) was separated by SFC column chromatography using an eluent of 40% IPA (0.2% NH4OH):60% CO2 to afford two single isomers. The first eluting isomer, P1 (RT = 2.18 min), was a white solid (116.48 mg of (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid) in a 24.2% yield. MS m / z Calcd: 370.07; Found: 371.1 [M+H] + Second eluting isomer P2 (RT = 2.37 min): 166.73 mg of (2S,3R,4R,5S)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid as a white solid, 34.7% yield. MS m / z calculated: 370.07; found: 371.1 [M+H] + .

[0628] Step 5: Preparation of tert-butyl 3-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-1-oxoisoindolin-2-yl)azetidine-1-carboxylate

[0629] At room temperature, (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (0.06 g, 0.16 mmol) was dissolved in DMF (50 mL), and tert-butyl 3-(5-amino-1-isoindolin-2-yl)azetidine-1-carboxylate (0.06 g, 0.19 mmol), NMI (0.05 g, 0.56 mmol) and TCFH (0.12 g, 0.4 mmol) were added respectively. After stirring for 2 hours, the reaction of the raw materials was completed by monitoring with a plate. The reaction system was diluted with ethyl acetate and then washed with saturated brine. The organic layer was dried, concentrated under reduced pressure, and purified by column chromatography to afford 0.1 g of tert-butyl 3-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-1-oxoisoindolin-2-yl)azetidine-1-carboxylate as a white solid in a 90.1% yield. MS m / z calculated: 655.21; found: 656.2 [M+H] +Step 6: Preparation of (2R,3S,4S,5R)-N-(2-(azetidin-3-yl)-1-oxoisoindolin-5-yl)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0630] At room temperature, tert-butyl 3-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-1-oxoisoindolin-2-yl)azetidine-1-carboxylate (0.1 g, 0.15 mmol) was dissolved in HCl-EA solution (20 mL) and stirred for 6 h. The reaction was monitored by plate counting to ensure that the raw material reaction was complete. After vacuum filtration, 0.09 g of (2R,3S,4S,5R)-N-(2-(azetidine-3-yl)-1-oxoisoindolin-5-yl)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide was obtained as a white solid with a yield of 98.2%.

[0631] 1 H NMR(400MHz,DMSO-d6)δ10.82(d,J=7.0Hz,1H),8.97(s,2H),8.05–7.94(m,1H),7.72–7 .60(m,2H),7.46(q,J=8.9Hz,1H),7.35(dd,J=9.0,4.7Hz,1H),5.25(d,J=10.5Hz,1H), 5.13(p,J=8.2Hz,1H),4.65(d,J=7.4Hz,2H),4.50–4.33(m,2H),4.14(s,2H),4.00–3.8 6(m,1H),2.81(p,J=7.5Hz,1H),2.43(d,J=2.1Hz,3H),1.61(s,3H),0.73–0.67(m,3H).

[0632] Example 75: Preparation of Compound P-75

[0633] The preparation method of the compound is similar to that of Example 74, except that tert-butyl 3-(5-amino-1-isoindolin-2-yl)azetidine-1-carboxylate in step 5 is replaced by an equimolar amount of 5-amino-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide-3,3-D2 (intermediate J), ​​and step 6 is omitted to obtain 0.18 g of the compound as a white solid with a yield of 64.0%.

[0634] 1H NMR (400MHz, DMSO-d6) δ10.58(s,1H),8.11(s,1H),7.82(s,1H),7.76(d,J=8.5Hz,1H),7.53–7.44(m,2H),7.29(s, 1H), 5.16 (d, J = 10.4Hz, 1H), 4.64 (t, J = 9.2Hz, 1H), 2.85–2.77 (m, 1H), 2.43 (s, 3H), 1.63 (s, 3H), 0.73–0.67 (m, 3H).

[0635] Example 76: Preparation of Compound P-76

[0636] The preparation method of this compound is similar to that of Example 74, except that tert-butyl 3-(5-amino-1-isoindolin-2-yl)azetidine-1-carboxylate in step 5 is replaced by an equimolar amount of tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate to obtain 0.05 g of the compound as a white solid with a yield of 60.4%.

[0637] 1 H NMR (400MHz, DMSO-d6) δ10.86 (s, 1H), 8.97 (s, 3H), 7.95 (d, J = 1.7Hz, 1H), 7. 66(dd,J=8.3,1.8Hz,1H),7.58(d,J=8.3Hz,1H),7.52–7.42(m,1H),7.40–7.3 3(m,1H),5.27(d,J=10.5Hz,1H),4.64(dd,J=10.6,7.5Hz,1H),2.93–2.74(m ,1H),2.43(s,3H),2.41(s,6H),1.91(s,1H),1.61(s,3H),0.76–0.64(m,3H).

[0638] Example 77: Preparation of Compound P-77

[0639] The preparation method of this compound is similar to that of Example 74, except that tert-butyl 3-(5-amino-1-isoindolin-2-yl)azetidine-1-carboxylate in Step 5 is replaced by an equimolar amount of 5-amino-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (Intermediate E), and Step 6 is omitted to obtain 0.06 g of the compound as a white solid with a yield of 41.6%.

[0640] 1H NMR (400MHz, DMSO-d6) δ10.55(s,1H),8.09(s,1H),7.80(s,1H),7.75(d,J=8.3Hz,1H),7.55–7.46(m,2H),7.28(s,1H),5.15(d ,J=10.2Hz,1H),4.60(t,J=9.2Hz,1H),4.33(d,J=6.1Hz,2H),2.83–2.75(m,1H),2.40(s,3H),1.61(s,3H),0.77–0.70(m,3H).

[0641] Example 78: Preparation of Compound P-78

[0642] The preparation method of this compound is similar to that of Example 74, except that: the reaction raw material in step 1 (3,4-difluoro-2-(methylthio)phenyl)boric acid (intermediate I) is replaced by an equal molar amount of (3,4-difluoro-2-((fluoromethyl)thio)phenyl)boric acid (commercially available), and the 3-(5-amino-1-isoindolin-2-yl)azetidine-1-carboxylic acid tert-butyl ester in step 5 is replaced by an equal molar amount of 5-amino-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide-3,3-D2 (intermediate J), ​​and step 6 is omitted to obtain 0.05 g of the compound as a white solid with a yield of 34.9%.

[0643] 1 H NMR (400MHz, DMSO-d6) δ10.53(s,1H),8.11(d,J=1.9Hz,1H),7.85(s,J=4.9Hz,1H),7.77(dd,J=8.5,2.0Hz,1H),7.50(d,J=8.4Hz,1H),7.41–7.2 2(m,2H),5.61–5.54(m,1H),5.48(d,J=4.7Hz,1H),5.11(d,J=10.3Hz,1H ), 4.33(dd,J=11.4Hz,1H),2.79(m,1H),1.61(s,3H),0.78–0.71(m,3H).

[0644] Example 79: Preparation of Compound P-79

[0645] The preparation method of this compound is similar to that of Example 74, except that: the reaction raw material in step 1 (3,4-difluoro-2-(methylthio)phenyl)boric acid (Intermediate I) is replaced by an equal molar amount of (3,4-difluoro-2-((trifluoromethyl)thio)phenyl)boric acid (commercially available), and tert-butyl 3-(5-amino-1-isoindolin-2-yl)azetidine-1-carboxylate in step 5 is replaced by an equal molar amount of 5-amino-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (Intermediate E), and step 6 is omitted to obtain 0.07 g of the compound as a white solid with a yield of 50.3%.

[0646] 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),8.08(d,J=1.7Hz,1H),7.79(t,J=4.6Hz,1H),7.79(dd,J=8.1,1.8Hz,1H),7.63(d,J=8.3Hz,1 H),7.60–7.52(m,2H),5.10(d,J=10.5Hz,1H),4.35-4.30(dd,J=10.5,6.1Hz,3H),2.78(m,1H),1.63(s,3H),0.80(d,J=1.8Hz,3H).

[0647] Example 80: Preparation of Compound P-80

[0648] The synthetic route of compound P-80 is as follows:

[0649] Step 1: Preparation of methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0650] Potassium carbonate (1.16 g, 8.5 mmol) was added to a solution of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (1.00 g, 2.8 mmol) in N,N-dimethylformamide (50 mL). Methyl iodide (0.59 g, 4.2 mmol) was then added dropwise to the solution. After the addition was complete, the temperature was raised to 70°C. The reaction was monitored by TLC until completion. After cooling to room temperature, the reaction system was diluted with ethyl acetate (200 mL) and washed 3-5 times with saturated brine (300 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to yield 0.92 g of crude methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate in an 88.5% yield. MS m / z calculated: 368.10; found: 369.1 [M+H] + .

[0651] Step 2: Preparation of methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0652] Boron tribromide (1.87 g, 7.5 mmol) was slowly added dropwise to a solution of (2R, 3S, 4S, 5R) -3- (3, 4-difluoro-2-methoxyphenyl) -4, 5-dimethyl -5- (trifluoromethyl) tetrahydrofuran-2-carboxylic acid methyl ester (0.92 g, 2.5 mmol) in dichloromethane (100 mL) at 0 ° C. After the reaction was completed as monitored by TLC, the reaction system was slowly dropped into ice water to quench the reaction, and the solution pH was adjusted to 50 with saturated sodium bicarbonate solution. Adjust the temperature to 7-8, separate the layers, and extract the aqueous phase 2-3 times with dichloromethane (200 mL). Combine the organic phases and wash them 2-3 times with saturated brine (300 mL). Dry over anhydrous sodium sulfate, concentrate in vacuo, and purify by column chromatography to obtain 0.71 g of (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid methyl ester as a yellow oil in an 80.2% yield. MS m / z calculated: 354.08; found: 355.1 [M+H] + .

[0653] Step 3: Preparation of methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0654] Cesium carbonate (1.95 g, 6.0 mmol) was added to a solution of (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid methyl ester (0.71 g, 2.0 mmol) in N,N-dimethylformamide (50 mL). 2-Bromoethyl methyl ether (0.42 g, 3.0 mmol) was then added dropwise to the solution. After the addition was complete, the temperature was raised to 100°C. The reaction was monitored for completion by TLC. After cooling to room temperature, the reaction system was diluted with ethyl acetate (200 mL) and washed 3-5 times with saturated brine (300 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography afforded 0.53 g of methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate as a pale yellow oily liquid in a 65.2% yield. MS m / z calculated: 412.13; found: 413.1 [M+H] + .

[0655] Step 4: Preparation of (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0656] Methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (0.53 g, 1.3 mmol) was dissolved in 7 M ammonia in methanol (10 mL). After stirring for 6 h, the reaction was monitored by TLC for completion and concentrated in vacuo to afford 0.47 g of crude (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide in a 92.3% yield. MS m / z calculated: 397.13; found: 398.1 [M+H] + .

[0657] Step 5: Preparation of tert-butyl 3-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-1-oxoisoindolin-2-yl)azetidine-1-carboxylate

[0658] Under nitrogen conditions, (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (0.47 g, 1.2 mmol), tert-butyl 3-(5-bromo-1-oxoisoindolin-2-yl)azetidine-1-carboxylate (0.51 g, 1.4 mmol), tris(dibenzylideneacetone)dipalladium (0.11 g, 0.12 mmol), 4,5-bis(diphenylphosphine-9,9-dimethylxanthene) (0.14 g, 0.24 mmol), and cesium carbonate (0.78 g, 2.4 mmol) were added to the Schlk tube. The nitrogen atmosphere was replaced with three Toluene (50 mL) was added to the system, and the temperature was raised to 100°C and allowed to react overnight. After completion of the reaction, the mixture was cooled to room temperature. Ethyl acetate (200 mL) was added to the reaction system for dilution, and the mixture was washed 3-5 times with saturated brine (300 mL). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Column chromatography afforded 0.48 g of tert-butyl 3-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-1-oxoisoindolin-2-yl)azetidine-1-carboxylate as a white oil in a 59.1% yield. MS m / z calculated: 683.26; found: 684.3 [M+H] + .

[0659] Step 6: Preparation of (2R,3S,4S,5R)-N-(2-(azetidin-3-yl)-1-oxoisoindolin-5-yl)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (trifluoroacetate)

[0660] tert-Butyl 3-(5-((2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamido)-1-oxoisoindolin-2-yl)azetidine-1-carboxylate (0.48 g, 0.71 mmol) was dissolved in trifluoroacetic acid (10 mL). After completion of the reaction monitored by TLC, the solution was concentrated in vacuo to give 0.41 g of (2R,3S,4S,5R)-N-(2-(azetidin-3-yl)-1-oxoisoindolin-5-yl)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide (trifluoroacetate) as a white solid with a yield of 82.2%. MS m / z calculated: 584.21; found: 585.2 [M+H] + .

[0661] 1 H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.78(s,2H),8.04(s,1H),7.72–7.58(m,2H),7.25–7.13(m,2H),5.20–5.07(m,2H) ,4.67(s,2H),4.45–4.13(m,7H),3.68–3.57(m,2H),3.30(s,3H),2.86(p,J=7.2Hz,1H),1.61(s,3H),0.75–0.69(m,3H).

[0662] Example 81: Preparation of Compound P-81

[0663] The preparation method is similar to that of Example 80, except that 2-bromoethyl methyl ether in step 3 is replaced by iodomethane to obtain 0.15 g of a white solid compound with a yield of 72.5%.

[0664] 1 H NMR(400MHz, DMSO-d6)δ10.59(s,1H),8.75(s,2H),8.03(d,J=1.6Hz,1H),7.76–7.53(m,2H),7.42–7.19(m,2H),5.96–5.87(m,1H),5.80– 5.73(m,1H),5.20–5.07(m,2H),4.66(s,2H),4.47–4.31(m,3H),4.17(d,J=8.8Hz,2H),2.87–2.77(m,1H),1.60(s,3H),0.80–0.71(m,3H).

[0665] Example 82: Preparation of Compound P-82

[0666] This preparation method is similar to that of Example 80, except that 2-bromoethyl methyl ether in step 3 is replaced by iodoethane, and trifluoroacetic acid in step 6 is replaced by hydrochloric acid to obtain 0.12 g of a white solid compound with a yield of 68.4%.

[0667] 1H NMR (400MHz, DMSO-d6) δ10.85(s,1H),8.75(s,2H),7.97(s,1H),7.74–7.55(m,2H),7.29–7.08(m,2H),5.18(d,J=10.3Hz,1H),4. 61(s,2H),4.34–4.04(m,7H),2.74(t,J=7.4Hz,1H),2.43(q,J=7.1Hz,1H),1.60(s,3H),1.36(t,J=7.0Hz,3H),0.79–0.70(m,3H).

[0668] Example 83: Preparation of Compound P-53

[0669] The preparation method of the compound is similar to that of Example 80, except that the 2-bromoethyl methyl ether in step 3 is replaced by an equal molar amount of 1-fluoro-2-iodoethane to obtain 0.18 g of the compound as a white solid with a yield of 86.0%.

[0670] 1 H NMR (400MHz, DMSO-d6) δ10.81(s,1H),9.02(s,2H),8.04(d,J=1.6Hz,1H),7.75–7.61(m,2H),7.33–7.12(m,2H),5.21(d,J=10.7Hz,1H),5.13(q ,J=8.2Hz,1H),4.84–4.77(m,1H),4.68(d,J=4.6Hz,2H),4.51–4.26(m, 6H), 4.15 (s, 2H), 2.79 (p, J = 7.4Hz, 1H), 1.58 (s, 3H), 0.76–0.70 (m, 3H).

[0671] Example 84: Preparation of Compound P-84

[0672] The preparation method of the compound is similar to that of Examples 80 and 81, except that tert-butyl 3-(5-bromo-1-oxoisoindolin-2-yl)azetidine-1-carboxylate in step 5 is replaced by an equimolar amount of tert-butyl (2S,3S)-3-(5-bromo-1-oxoisoindolin-2-yl)-2-methylazetidine-1-carboxylate to obtain 0.17 g of the compound as a white solid with a yield of 84.0%.

[0673] 1H NMR (400MHz, DMSO-d6) δ10.91(s,1H),9.24(d,J=40.4Hz,2H),8.03(d,J=1.7Hz,1H),7.75–7.68(m,1H),7.65( d,J=8.3Hz,1H),7.46–7.36(m,1H),7.35–7.27(m,1H),5.93–5.86(m,1H),5.80–5.73(m,1H),5.25(d,J=10.3Hz ,1H),4.94–4.85(m,1H),4.80(d,J=17.4Hz,1H),4.75–4.61(m,2H),4.52(d,J=15.7Hz,1H),4.34(dd,J=10.4,7 .5Hz,1H),4.24(s,1H),2.79(p,J=7.4Hz,1H),1.59(s,3H),1.29(dd,J=7.1,3.5Hz,3H),0.74(d,J=7.3Hz,3H).

[0674] Example 85: Preparation of Compound P-85

[0675] The preparation method of the compound is similar to that of Examples 80 and 81, except that tert-butyl 3-(5-bromo-1-oxoisoindolin-2-yl)azetidine-1-carboxylate in step 5 is replaced by an equimolar amount of tert-butyl 4-(5-bromo-1-isoindolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate to obtain 0.17 g of the compound as a white solid with a yield of 83.0%.

[0676] 1 H NMR(400MHz,DMSO-d6)δ10.50(s,1H),9.42(s,2H),7.92(s,1H),7.66–7.56(m,2H),7.35 (q,J=9.0Hz,1H),7.28–7.20(m,1H),5.90(q,J=2.6Hz,1H),5.80–5.73(m,1H),5.12(d,J= 10.3Hz,1H),4.53(s,2H),4.34(dd,J=10.3,7.6Hz,1H),4.22(s,1H),3.52(s,2H),2.80(p ,J=7.5Hz,1H),2.27(d,J=4.0Hz,2H),1.88–1.82(m,2H),1.59(s,3H),0.78–0.71(m,3H).

[0677] Example 86: Preparation of Compound P-86

[0678] The preparation method of the compound is similar to that of Example 80, except that tert-butyl 3-(5-bromo-1-oxoisoindolin-2-yl)azetidine-1-carboxylate in step 5 is replaced by an equimolar amount of tert-butyl 4-(5-bromo-1-isoindolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate to obtain 0.17 g of the compound as a white solid with a yield of 83.0%.

[0679] 1 H NMR(400MHz,DMSO-d6)δ8.57(s,1H),9.49(s,2H),8.08–8.03(m,1H),7.75(d,J=8.2Hz,1H),7.3 0(dd,J=8.3,1.9Hz,1H),7.17–7.09(m,1H),6.99–6.88(m,1H),5.02(d,J=11.5Hz,1H),4.39(t, J=2.1Hz,1H),4.35(s,2H),4.32–4.24(m,2H),4.24–4.16(m,1H),3.68–3.53(m,4H),3.27(s,3H ),2.86(p,J=7.6Hz,1H),2.31–2.26(m,2H),2.09–1.99(m,2H),1.70(s,3H),0.81–0.76(m,3H).

[0680] Example 87: Preparation of Compound P-87

[0681] The preparation method of the compound is similar to that of Example 32, except that: (2-aminoethyl)carbamic acid tert-butyl ester in step 1 is replaced by an equimolar amount of ((1R,3R)-3-aminocyclobutyl)(methyl)carbamic acid tert-butyl ester to obtain 0.15 g of the compound as a white solid with a yield of 83.2%.

[0682] 1H NMR(400MHz,DMSO-d6)δ10.61(s,1H),8.87(s,2H),7.99(s,1H),7.61(s,2H),7.17( dd,J=8.5,4.7Hz,2H),5.12(d,J=10.2Hz,1H),5.07(t,J=8.2Hz,1H),4.58(s,2H),4. 27(dd,J=10.4,7.6Hz,1H),3.95(d,J=2.1Hz,3H),3.69(s,1H),2.82–2.74(m,1H),2. 74–2.64(m,2H),2.54(s,3H),2.46–2.40(m,2H),1.60(s,3H),0.74(d,J=7.3Hz,3H).

[0683] Example 88: Preparation of Compound P-88

[0684] This preparation method is similar to that of Example 80, except that: 2-bromoethyl methyl ether in step 3 is replaced by iodomethane, tert-butyl 3-(5-bromo-1-oxoisoindolin-2-yl)azetidine-1-carboxylate in step 5 is replaced by tert-butyl ((1R,3R)-3-(5-bromo-1-oxoisoindolin-2-yl)cyclobutyl)(methyl)carbamate, and trifluoroacetic acid in step 6 is replaced by hydrochloric acid to obtain 0.11 g of a white solid compound with a yield of 64.4%.

[0685] 1 H NMR(400MHz,DMSO-d6)δ10.73(s,1H),9.18(s,2H),8.00(s,1H),7.72–7.58(m,2H) ,7.37–7.26(m,2H),5.84(ddd,J=53.4,8.2,2.5Hz,2H),5.21(d,J=10.4Hz,1H),5.0 7(p,J=8.2Hz,1H),4.58(s,2H),4.35(dd,J=10.3,7.7Hz,1H),3.71(s,1H),3.32(s ,3H),2.81(t,J=7.5Hz,1H),2.76-2.67(m,4H),1.60(s,3H),0.76(d,J=7.4Hz,3H).

[0686] Example 89: Preparation of Compound P-89

[0687] This preparation method is similar to that of Example 80, except that tert-butyl 3-(5-bromo-1-oxoisoindolin-2-yl)azetidine-1-carboxylate in step 5 is replaced with tert-butyl ((1R,3R)-3-(5-bromo-1-oxoisoindolin-2-yl)cyclobutyl)(methyl)carbamate, and trifluoroacetic acid in step 6 is replaced with hydrochloric acid to obtain 0.13 g of a white solid compound with a yield of 71.6%.

[0688] 1 H NMR(400MHz,DMSO-d6)δ10.75(s,1H),9.30–9.13(m,2H),8.01(s,1H),7.80–7.54(m,2H),7.21(dt,J =47.9,8.4Hz,2H),5.20(d,J=10.8Hz,1H),5.07(p,J=8.1Hz,1H),4.59(s,2H),4.37(dd,J=10.7,7.2 Hz,1H),4.24(ddt,J=33.8,10.9,5.4Hz,2H),3.71(s,1H),3.64(dt,J=6.0,3.2Hz,2H),3.34(s,3H), 3.31(s,3H),2.85(p,J=7.4Hz,1H),2.72(dt,J=15.7,8.3Hz,4H),1.61(s,3H),0.72(d,J=7.3Hz,3H).

[0689] Example 90: Preparation of Compound P-90

[0690] The preparation method of the compound is similar to that of Example 80, except that tert-butyl 3-(5-bromo-1-oxoisoindolin-2-yl)azetidine-1-carboxylate in step 5 is replaced by an equimolar amount of tert-butyl (3-(5-bromo-1-oxoisoindolin-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate to obtain 0.15 g of the compound as a white solid with a yield of 82.4%.

[0691] 1H NMR (400MHz, DMSO-d6) δ10.72 (s, 1H), 8.90 (s, 3H), 7.96 (d, J = 1.7Hz, 1H), 7.66 (dd ,J=8.4,1.8Hz,1H),7.58(d,J=8.3Hz,1H),7.26–7.10(m,2H),5.17(d,J=10.8Hz,1 H),4.44(s,2H),4.35(dd,J=10.8,7.1Hz,1H),4.31–4.16(m,2H),3.69–3.56(m,2H ),3.29(s,3H),2.84(p,J=7.3Hz,1H),2.41(s,6H),1.60(s,3H),0.74–0.67(m,3H).

[0692] Example 91: Preparation of Compound P-91

[0693] The preparation method of the compound is similar to that of Examples 80 and 81, except that tert-butyl 3-(5-bromo-1-oxoisoindolin-2-yl)azetidine-1-carboxylate in step 5 is replaced by an equimolar amount of tert-butyl (3-(5-bromo-1-oxoisoindolin-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate to obtain 0.14 g of the compound as a white solid with a yield of 77.7%.

[0694] 1 H NMR (400MHz, DMSO-d6) δ10.76(s,1H),8.94(s,3H),7.96(d,J=1.7Hz,1H),7.65(d d,J=8.4,1.7Hz,1H),7.58(d,J=8.3Hz,1H),7.33(dd,J=8.4,5.1Hz,2H),5.93–5.8 6(m,1H),5.80–5.73(m,1H),5.20(d,J=10.4Hz,1H),4.44(s,2H),4.34(dd,J=10. 4,7.5Hz,1H),2.79(p,J=7.4Hz,1H),2.41(s,6H),1.59(s,3H),0.77–0.71(m,3H).

[0695] Example 92: Preparation of Compound P-92

[0696] Step 1 to step 3 are the same as the synthetic route of Example 80.

[0697] Step 4: Preparation of (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

[0698] Methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (0.30 g, 0.73 mmol) was dissolved in methanol (10 mL). A 5 mL solution of sodium hydroxide (0.15 g, 3.7 mmol) was added dropwise, and the mixture was stirred at 60°C for 4 hours. TLC confirmed the completion of the reaction. The pH was adjusted to 1-2 with dilute hydrochloric acid. The reaction mixture was diluted with ethyl acetate (20 mL) and transferred to a separatory funnel. The mixture was washed three times with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to afford 0.28 g of a light yellow oil in a 96.6% yield. MS m / z: Calcd: 398.12; Found: 399.1 [M+H] + .

[0699] Step 5: Preparation of (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-N-(1,1-dioxo-2,3-dihydrobenzo[d]isothiazol-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0700] At room temperature, (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (0.15 g, 0.37 mmol) was dissolved in acetonitrile (10 mL), and 5-amino-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (Intermediate J, 0.08 g, 0.45 mmol), NMI (0.11 g, 1.0 mmol) and TCFH (0.26 g, 0.9 mmol) were added respectively. After stirring for 2 hours, the reaction of the raw materials was completed by spotting the plate monitoring. The reaction system was diluted with ethyl acetate and then washed with saturated brine. The organic layer was dried, concentrated under reduced pressure, and purified by column chromatography to obtain 0.18 g of a white solid (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-N-(1,1-dioxo-2,3-dihydrobenzo[d]isothiazol-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide with a yield of 84.7%.

[0701] 1H NMR (400MHz, DMSO-d6) δ10.53(s,1H),8.13(d,J=2.0Hz,1H),7.85(t,J=4.9Hz,1 H),7.78(dd,J=8.4,2.0Hz,1H),7.51(d,J=8.4Hz,1H),7.17(d,J=6.7Hz,2H),5. 11(d,J=10.7Hz,1H),4.35(dd,J=9.5,6.1Hz,3H),4.31–4.13(m,2H),3.61(q,J= 4.5Hz,2H),3.27(s,3H),2.83(t,J=7.3Hz,1H),1.61(s,3H),0.74–0.67(m,3H).

[0702] Example 93: Preparation of Compound P-93

[0703] The preparation method of the compound is similar to that of Example 92, except that the 2-bromoethyl methyl ether in step 3 is replaced by an equimolar amount of iodomethane to obtain 0.18 g of the compound as a white solid with a yield of 62.3%.

[0704] 1 H NMR (400MHz, DMSO-d6) δ10.51(s,1H),8.11(d,J=1.9Hz,1H),7.85(t,J=4.9Hz ,1H),7.77(dd,J=8.5,2.0Hz,1H),7.50(d,J=8.4Hz,1H),7.41–7.22(m,2H),5 .93–5.86(m,1H),5.76(dt,J=5.3,2.6Hz,1H),5.11(d,J=10.3Hz,1H),4.33(d d,J=11.4,6.9Hz,3H),2.79(p,J=7.5Hz,1H),1.61(s,3H),0.78–0.71(m,3H).

[0705] Example 94: Preparation of Compound P-94

[0706] The preparation method of the compound is similar to that of Example 92, except that the 5-amino-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide in step 5 is replaced by an equimolar amount of 5-amino-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide-3,3-D2 (intermediate J) to obtain 0.16 g of the compound as a white solid with a yield of 56.3%.

[0707] 1H NMR(400MHz,DMSO-d6)δ10.52(s,1H),8.13(d,J=1.9Hz,1H),7.81(s,1H),7.7 9(dd,J=8.6,1.9Hz,1H),7.50(d,J=8.4Hz,1H),7.21–7.13(m,2H),5.11(d,J= 10.7Hz,1H),4.35(dd,J=10.8,7.2Hz,1H),4.32–4.14(m,2H),3.65(q,J=4.5H z,2H),3.27(s,3H),2.83(t,J=7.3Hz,1H),1.62(s,3H),0.71(d,J=7.3Hz,3H).

[0708] Example 95: Preparation of Compound P-95

[0709] The preparation method of the compound is similar to that of Example 94, except that 1-bromo-2-methoxyethane in step 3 is replaced by an equimolar amount of fluoroiodomethane to obtain 0.16 g of the compound as a white solid with a yield of 53.6%.

[0710] 1 H NMR (400MHz, DMSO-d6) δ10.50(s,1H),8.13–8.08(m,1H),7.82(s,1H),7.77(dd,J=8.3,1.8Hz,1H),7.50(d,J=8.4Hz,1H),7.40–7.22(m,2H),5. 93–5.86(m,1H),5.79–5.72(m,1H),5.11(d,J=10.3Hz,1H),4.33(dd,J= 10.3,7.6Hz,1H),2.79(p,J=7.4Hz,1H),1.61(s,3H),0.78–0.71(m,3H).

[0711] Example 96: Preparation of Compound P-96

[0712] The preparation method of this compound is similar to that of Example 80, except that tert-butyl 4-amino-1H-pyrazole-1-carboxylate in step 1 is replaced with an equimolar amount of deuterated iodomethane to obtain 0.05 g of the compound as a white solid with a yield of 55.6%.

[0713] 1H NMR (400MHz, DMSO-d6) δ11.95(s,1H),8.91(d,J=41.0Hz,3H),7.96(s,1H),7.64(d,J=8.5Hz,1H),7.59(d,J=8.4Hz,1H),7.30–7.11(m,2H ),5.16(t,J=10.8Hz,1H),4.45(s,2H),4.26(dd,J=10.4,7.5Hz,1H),2.77(t,J=7.7Hz,1H),2.41(s,6H),1.59(s,3H),0.79–0.67(m,3H).

[0714] Example 97: Preparation of Compound P-97

[0715] This preparation method is similar to that of Example 17, except that the 5-aminoisoindole-1-one in Step 7 of Example 17 is replaced by an equimolar amount of 5-amino-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide-3,3-D2 to obtain 0.18 g of a white solid compound with a yield of 67.2%.

[0716] 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),8.11(s,1H),7.84(s,1H),7.74(d,J=8.5Hz,1H),7.52–7.46(m,2H),7.24(s, 1H),5.18(d,J=10.4Hz,1H),4.66(t,J=9.4Hz,1H),2.80–2.74(m,1H),2.43(s,3H),1.62(s,3H),0.70–0.66(m,3H).

[0717] Example 98: Preparation of Compound P-98

[0718] The preparation method is similar to that of Example 49, except that tert-butyl 3-(5-amino-1-oxoisoindolin-2-yl)azetidin-1-carboxylate in Step 9 is replaced by 6-amino-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide-3,3-D2 (Intermediate J) to obtain 0.12 g of a white solid compound with a yield of 41.4%.

[0719] 1H NMR (400MHz, DMSO-d6) δ10.60(s,1H),8.10(d,J=1.9Hz,1H),7.83(s,1H),7.73(dd,J=8.5,2.0Hz,1H),7.50(d,J=8.4Hz,1H),7.21( dd,J=9.9,6.4Hz,2H),5.05(d,J=11.0Hz,1H),4.12(ddd,J=21.1,10.7,4.9Hz,2H),3.96(d,J=1.8Hz,3H),2.92(s,3H),1.56(s,3H).

[0720] Example 99: Preparation of Compound P-99

[0721] The preparation method of this compound is similar to that of Example 32, except that tert-butyl 4-amino-1H-pyrazole-1-carboxylate in step 1) is replaced with an equimolar amount of tert-butyl (2-aminoethyl)carbamate, and finally the -Boc protecting group is removed to obtain a white solid compound with a yield of 98.2%.

[0722] 1 H NMR (400MHz, DMSO-d6) δ10.80(s,1H),8.00(s,1H),7.93(s,2H),7.65(d,J=3.5Hz,2H),7.26–7.11(m,2H),5.19(d,J=10.3Hz,1H),4.47( s,2H),4.26(t,J=9.2Hz,1H),3.95(s,3H),3.72(d,J=6.6Hz,2H),3.08(s,2H),2.76(t,J=7.4Hz,1H),1.60(s,3H),0.73(d,J=7.2Hz,3H).

[0723] Example 100: Preparation of Compound P-100

[0724] The preparation method is similar to that of Example 17, except that 5-aminoisoindole-1-one in step 7 is replaced by 6-aminoisoindolin-1-one to obtain 0.14 g of a white solid compound with a yield of 55.6%.

[0725] 1H NMR (400MHz, DMSO-d6) δ10.43(s,1H),8.58(s,1H),7.99(s,1H),7.74(d,J=8.3Hz,1H),7.51(d,J=8.2Hz,1H),7.18(t,J=8.9Hz, 2H),5.08(d,J=10.3Hz,1H),4.31(s,2H),4.30–4.22(m,1H),3.95(s,3H),2.77(t,J=7.6Hz,1H),1.61(s,3H),0.80–0.69(m,3H).

[0726] Example 101: Preparation of Compound P-101

[0727] The preparation method is similar to that of Example 17, except that 5-aminoisoindole-1-one in step 7 is replaced by 5-aminobenzo[d]isoxazol-3(2H)-one to obtain 0.15 g of a white solid compound with a yield of 60.1%.

[0728] 1 H NMR (400MHz, DMSO-d6) δ10.60(s,1H),8.30(s,1H),8.04–7.98(m,1H),7.95(s,1H),7.66(d,J=9.1Hz,1H),7.17(d,J=7.0Hz,2H ),5.10(d,J=10.3Hz,1H),4.25(t,J=9.2Hz,1H),3.95(d,J=2.6Hz,3H),2.81–2.74(m,1H),1.61(s,3H),0.74(d,J=7.2Hz,3H).

[0729] Example 102: Preparation of Compound P-102

[0730] The preparation method of the compound was similar to that of Example 17, except that 5-aminoisoindole-1-one in step 7 was replaced with an equal molar amount of 4-aminoisoindole-1-one to obtain 0.16 g of the compound as a white solid with a yield of 63.0%.

[0731] 1H NMR (400 MHz, DMSO-d6) δ 10.04 (s, 1H), 8.55 (s, 1H), 7.76 (d, J = 7.4 Hz, 1H), 7.53–7.42 (m, 2H), 7.20 (t, J = 8.1 Hz, 2H), 5.19 (d, J = 10.4 Hz, 1H), 4.20 (s, 2H), 3.95 (d, J = 2.7 Hz, 3H), 2.75 (q, J = 7.4 Hz, 1H), 1.62 (s, 3H), 1.23 (s, 1H), 0.74 (d, J = 7.3 Hz, 3H). Example 103: Preparation of Compound P-103

[0732] The preparation method of the compound is similar to that of Example 32, except that tert-butyl 4-amino-1H-pyrazole-1-carboxylate in step 1 is replaced by an equimolar amount of tert-butyl (2-aminopropyl)carbamate to obtain 0.10 g of a white solid compound with a yield of 60.2%.

[0733] 1 H NMR(400MHz,DMSO-d6)δ10.90(d,J=8.6Hz,1H),8.04–7.93(m,4H),7.75–7.68(m,1H), 7.68–7.58(m,1H),7.27(t,J=7.5Hz,1H),7.21–7.09(m,1H),5.22(d,J=10.4Hz,1H),4 .51–4.32(m,3H),4.26(dd,J=10.2,7.8Hz,1H),3.95(d,J=2.1Hz,3H),3.20–2.94(m,2 H),2.76(p,J=7.4Hz,1H),1.60(s,3H),1.26(dd,J=6.9,2.3Hz,3H),0.80–0.70(m,3H).

[0734] Example 104: Preparation of Compound P-104

[0735] The preparation method of the compound is similar to that of Example 32, except that tert-butyl 4-amino-1H-pyrazole-1-carboxylate in step 1 is replaced by an equimolar amount of 2-methoxyethane-1-amine to obtain 0.11 g of the white solid compound with a yield of 78.2%.

[0736] 1H NMR (400MHz, DMSO-d6) δ10.53(s,1H),7.94(t,J=1.2Hz,1H),7.61(d,J=1.1Hz ,2H),7.24–7.08(m,2H),5.11(d,J=10.3Hz,1H),4.46(s,2H),4.27(dd,J=10.3 ,7.6Hz,1H),3.95(d,J=2.1Hz,3H),3.64(t,J=5.4Hz,2H),3.53(dd,J=10.1,4 .7Hz,2H),3.25(s,3H),2.76(q,J=7.5Hz,1H),1.60(s,3H),0.77–0.69(m,3H).

[0737] Example 105: Preparation of Compound P-105

[0738] The preparation method of the compound is similar to that of Example 32, except that tert-butyl 4-amino-1H-pyrazole-1-carboxylate in step 1 is replaced by an equimolar amount of cyclopropylamine to obtain 0.02 g of a white solid compound with a yield of 83.0%.

[0739] 1 H NMR (400MHz, DMSO-d6) δ10.52(s,1H),7.91(s,1H),7.63–7.56(m,2H),7.23–7.11(m,2H),5.10(d,J=10.3Hz,1H),4.34(s,2H),3.9 5(d,J=2.1Hz,3H),2.93–2.85(m,1H),2.76(q,J=7.5Hz,1H),1.60(s,3H),0.86–0.82(m,1H),0.82–0.76(m,4H),0.76–0.70(m,3H).

[0740] Example 106: Preparation of Compound P-106

[0741] The preparation method of this compound is similar to that of Example 32, except that tert-butyl 4-amino-1H-pyrazole-1-carboxylate in step 1) is replaced with an equimolar amount of 2-((tert-butyldimethylsilyl)oxy)ethan-1-amine, and finally the -TBS protecting group is removed to obtain a white solid compound P-106 with a yield of 60.8%.

[0742] 1H NMR (400MHz, DMSO-d6) δ10.54(s,1H),7.94(s,1H),7.61(d,J=1.2Hz,2H), 7.24–7.11(m,2H),5.11(d,J=10.4Hz,1H),4.83(t,J=5.3Hz,1H),4.49(s,2 H),4.27(dd,J=10.4,7.5Hz,1H),3.95(d,J=2.2Hz,3H),3.56(dt,J=22.1,5 .4Hz,4H),2.77(p,J=7.4Hz,1H),1.60(s,3H),0.77–0.70(d,J=7.3Hz,3H).

[0743] Example 107: Preparation of Compound P-107

[0744] The preparation method of this compound is similar to that of Example 32, except that tert-butyl 4-amino-1H-pyrazole-1-carboxylate in step 1) is replaced with an equimolar amount of glycine methyl ester, and finally aminolysis is performed to obtain a white solid compound P-107 with a yield of 89.2%.

[0745] 1 H NMR (400MHz, DMSO-d6) δ10.53(s,1H),7.95(s,1H),7.62(d,J=2.7Hz,2H),7.52(s,1H),7.22–7.08(m,3H),5.11(d,J=10.3Hz,1H),4.4 5(s,2H),4.27(dd,J=10.3,7.6Hz,1H),4.08(s,2H),3.95(d,J=2.2Hz,3H),2.76(q,J=7.6Hz,1H),1.60(s,3H),0.73(d,J=7.3Hz,3H).

[0746] Example 108: Preparation of Compound P-108

[0747] The preparation method of this compound is similar to that of Example 32, except that tert-butyl 4-amino-1H-pyrazole-1-carboxylate in step 1) is replaced with an equimolar amount of 3-aminooxetane to obtain a white solid compound P-108 with a yield of 70.1%.

[0748] 1H NMR (400MHz, DMSO-d6) δ10.44(s,1H), δ7.70–7.56(m,2H),7.51(t,J=7.7Hz,1H),7.03(d,J=86.4Hz,2H),5.17(t,J=8.7Hz,1H),4.61(s,1H),4.42(d ,J=14.9Hz,2H),4.29(d,J=12.4Hz,1H),4.15–3.96(m,2H),3.85(s,3H),3 .73–3.43(m,2H),2.70–2.53(m,1H),1.44(d,J=23.5Hz,3H),0.61(s,3H).

[0749] Example 109: Preparation of Compound P-109

[0750] The preparation method is similar to that of Example 1, except that 7-amino-3,4-dihydro-1H-quinolin-2-one in step 10) is replaced with an equal molar amount of 5-aminoisoindole-1-one to obtain white solid compound P-109 with a yield of 70.3%.

[0751] 1 H NMR (400MHz, DMSO-d6) δ9.77(s,1H),8.52(s,1H),7.68–7.62(m,1H),7.44–7.34(m,2H),7.13–6.97(m,2H),4.85(d,J=8 .9Hz,1H),4.26(s,2H),3.99(d,J=2.0Hz,3H),3.95–3.82(m,1H),3.29–3.16(m,1H),1.42(s,3H),0.95(d,J=6.7Hz,3H).

[0752] Comparative Example 1

[0753] Preparation of intermediate A

[0754] The synthetic route of intermediate A is as follows:

[0755] Step 1: Preparation of ethyl 2-(3,4-difluoro-2-methoxyphenyl)acetate

[0756] Ethyl 2-bromoacetate (23.12 g, 127.7 mmol), potassium carbonate (44.12 g, 319.2 mmol), tetrakistriphenylphosphine palladium (0.26 g, 0.2 mmol), and cuprous oxide (0.46 g, 3.2 mmol) were added to a reaction tube. The atmosphere was purged with nitrogen three times, followed by the addition of a toluene solution containing (3,4-difluoro-2-methoxyphenyl)boronic acid (20.00 g, 106.4 mmol). The reaction was allowed to proceed overnight at 100°C, with a microplate reader monitoring the reaction for completion. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The product was washed two to three times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to yield 18.49 g of ethyl 2-(3,4-difluoro-2-methoxyphenyl)acetate in a 75.5% yield. MS m / z calculated: 230.07; found: 231.1 [M+H] + .

[0757] Step 2: Preparation of 2-(3,4-difluoro-2-methoxyphenyl)acetic acid

[0758] Lithium aluminum hydride (2.08 g, 52.2 mmol) was added to a solution of ethyl 2-(3,4-difluoro-2-methoxyphenyl)acetate (4.00 g, 17.4 mmol) in THF (50 mL) at room temperature. The temperature was then raised to 50°C and the reaction monitored until completion. Hydrochloric acid (1 M) was added to the reaction mixture to adjust the pH to 2. The mixture was extracted with ethyl acetate 2-3 times. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 3.54 g of crude 2-(3,4-difluoro-2-methoxyphenyl)acetic acid as a white solid in a 99.6% yield. MS m / z calculated: 202.04; found: 203.2 [M+H] + .

[0759] Preparation of intermediate B

[0760] The synthetic route of intermediate B is as follows:

[0761] Step 1: Preparation of (R)-4,4,4-trifluoro-3-hydroxy-3-methylbutan-2-one

[0762] (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid (50.00 g, 316.3 mmol) and diethyl ether (10 L) were placed in a dry, nitrogen-filled reaction flask. Methyllithium bromide complex (27.54 g, 253.04 mmol) was slowly added under an ice bath, and the reaction mixture was stirred overnight at room temperature. Citric acid (121.53 g, 632.6 mmol) was added to neutralize the mixture and stirred for 30 minutes. The aqueous phase was separated and extracted with diethyl ether 2-3 times. The combined organic phases were distilled under reduced pressure (200 mbar, 70°C) to a colorless oil. Solid potassium carbonate pellets were added, the product was dried, allowed to stand for 6 hours, and then filtered through a glass filter to obtain 32.24 g of (R)-4,4,4-trifluoro-3-hydroxy-3-methylbutan-2-one as a colorless oil with a yield of 65.3%. MS m / z calculated: 156.03; found: 157.1 [M+H] + .

[0763] Preparation of intermediate C

[0764] The synthetic route of intermediate C is as follows:

[0765] Step 1: Preparation of 1-bromo-4-(difluoromethoxy)-3-fluoro-2-methoxybenzene

[0766] To a 250 mL flask, 4-bromo-2-fluoro-3-methoxyphenol (1.00 g, 4.5 mmol), potassium carbonate (2.5 g, 18.0 mmol), and sodium 2-chloro-2,2-difluoroacetate (2.06 g, 13.5 mmol) were added and dissolved in DMF (DMF:H₂O = 4:1). The mixture was reacted overnight at 100°C, monitored for completion by a microplate reader. The product was washed 2-3 times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to afford 0.42 g of 1-bromo-4-(difluoromethoxy)-3-fluoro-2-methoxybenzene in a 34.4% yield. MS m / z calculated: 269.95; found: 271.9 [M+H] + .

[0767] Step 2: Preparation of 2-(4-(difluoromethoxy)-3-fluoro-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0768] DPPF palladium dichloride (0.06 g, 0.1 mmol), potassium acetate (0.45 g, 4.5 mmol), and pinacol diboron (0.47 g, 1.8 mmol) were added sequentially to a 250 mL reaction tube. The atmosphere was purged with nitrogen three times, followed by the addition of a solution of 1-bromo-4-(difluoromethoxy)-3-fluoro-2-methoxybenzene (0.42 g, 1.5 mmol) in 1,4-dioxane vial. The reaction was set to 100°C and allowed to react overnight, monitored by a microplate reader until completion. The product was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to yield 0.25 g of 2-(4-(difluoromethoxy)-3-fluoro-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a white solid in a 50.8% yield. MS m / z calculated: 318.13; found: 317.1 [M+H] + .

[0769] Preparation of intermediate D

[0770] The synthetic route of intermediate D is as follows:

[0771] Step 1: Preparation of 1-bromo-4-(difluoromethoxy)-2,3-difluorobenzene

[0772] To a 250 mL flask, 4-bromo-2,3-difluorophenol (2.00 g, 9.5 mmol), potassium carbonate (4.30 g, 30.4 mmol), and sodium 2-chloro-2,2-difluoroacetate (2.92 g, 19.0 mmol) were added and dissolved in DMF (DMF:H₂O = 4:1). The mixture was reacted overnight at 100°C, monitored for completion by a microplate reader. The product was washed 2-3 times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to afford 0.67 g of 1-bromo-4-(difluoromethoxy)-2,3-difluorobenzene in a 27.1% yield. MS m / z calculated: 257.93; found: 259.4 [M+H] + .

[0773] Step 2: Preparation of 2-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0774] DPPF palladium dichloride (0.09 g, 0.1 mmol), potassium acetate (0.74 g, 7.5 mmol), and pinacol diboron (0.76 g, 3.0 mmol) were added sequentially to a 250 mL reaction tube. The atmosphere was purged with nitrogen three times, followed by the addition of a solution of 1-bromo-4-(difluoromethoxy)-2,3-difluorobenzene (0.65 g, 2.5 mmol) in 1,4-dioxane vial. The reaction was set to 100°C and allowed to react overnight, monitored by a microplate reader until completion. The product was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to afford 0.37 g of 2-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane as a white solid in a 48.2% yield. MS m / z calculated: 306.10; found: 305.1 [M+H] + .

[0775] Preparation of intermediate E

[0776] The synthetic route of intermediate E is as follows:

[0777] Under ice-cooling conditions, 6-aminosaccharin (0.50 g, 2.5 mmol) and 7 mL of concentrated hydrochloric acid solution (40 mL) were added to a 100 mL round-bottom flask. After stirring for 10-20 minutes, zinc powder (1.35 g, 20.4 mmol) was slowly added portionwise. The reaction mixture was allowed to warm to room temperature and monitored with a microplate reader until completion. The reaction solution was poured into ice water to adjust the pH to 7. The aqueous phase was extracted with ethyl acetate, washed with saturated brine, and purified by column chromatography to obtain 75.5 mg of a white solid powder in a 16.3% yield. MS m / z calculated: 184.03; found: 185.11 [M+H] + .

[0778] Preparation of intermediate F

[0779] The synthetic route of intermediate F is as follows:

[0780] In this reaction scheme, PMB- represents p-methoxybenzyl.

[0781] Step 1: Preparation of 5-bromo-2-(4-methoxybenzyl)-3,3-dimethylisoindolin-1-one

[0782] To a 100 mL round-bottom flask was added 5-bromo-2,3-dihydro-3,3-dimethyl-1H-isoindol-1-one (0.9 g, 3.8 mmol). Cesium carbonate (3.7 g, 11.4 mmol), p-methoxybenzyl chloride (0.88 g, 5.7 mmol), and DMF (30 mL) were then added sequentially. The resulting solution was heated to 60°C for 3 hours. A RT-PCR plate was used to monitor the reaction completion. The mixture was cooled to room temperature and then transferred to a separatory funnel with ethyl acetate (500 mL). The mixture was washed three times with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 1.00 g of the product as a yellow oil in a 66.7% yield. MS m / z calculated: 359.05; found: 359.1 [M+H] + .

[0783] Step 2: Preparation of tert-butyl (2-(4-methoxybenzyl)-3,3-dimethyl-1-oxoisoindolin-5-yl)carbamate

[0784] To a 500 mL three-necked flask were added 5-bromo-2-(4-methoxybenzyl)-3,3-dimethylisoindolin-1-one (1.0 g, 2.77 mmol), tert-butyloxycarbonylamine (0.49 g, 4.16 mmol), trisdibenzylideneacetone dipalladium (0.25 g, 0.28 mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (0.32 g, 0.55 mmol), and cesium carbonate (2.7 g, 8.32 mmol). After the addition was complete, the atmosphere was replaced with nitrogen three times, toluene (200 mL) was added, the temperature was raised to 100 ° C, and the reaction was allowed to proceed overnight. After the reaction was complete, the reaction was monitored by plate spotting and filtered under reduced pressure. The filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain 0.82 g of a yellow oily compound with a yield of 74.6%. MS m / z calculated: 396.20; found: 397.1 [M+H] + .

[0785] Step 3: Preparation of tert-butyl (3,3-dimethyl-1-oxoisoindolin-5-yl)carbamate

[0786] To a 250 mL round-bottom flask, tert-butyl (2-(4-methoxybenzyl)-3,3-dimethyl-1-oxoisoindolin-5-yl)carbamate (700 mg, 1.77 mmol), acetonitrile (50 mL), and water (25 mL) were added portionwise under an ice bath. Ceric ammonium nitrate (3.90 g, 7.08 mmol) was added portionwise. After completion of the addition, the mixture was warmed to room temperature and allowed to react overnight. After completion of the reaction, the mixture was transferred to a 1000 mL beaker and saturated sodium bicarbonate solution (200 mL) was added. The mixture was filtered under reduced pressure and the filtrate was extracted three times with dichloromethane (500 mL). The organic phase was washed three times with saturated brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 0.25 g of a crude yellow product in a 50.5% yield. MS m / z calculated: 276.15; found: 276.1 [M+H] + .

[0787] Step 4: Preparation of 5-amino-3,3-dimethylisoindolin-1-one hydrochloride

[0788] To a 100 mL round-bottom flask, tert-butyl (3,3-dimethyl-1-oxoisoindolin-5-yl)carbamate (0.25 g, 0.9 mmol) and a 20 mL solution of hydrogen chloride in ethanol were added. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was monitored by a microplate reader and concentrated under reduced pressure. The crude product was purified by slurrying with dichloromethane to afford 0.15 g of a pale yellow solid compound in a 75.1% yield. MS m / z calculated: 176.09; found: 176.1 [M+H] + .

[0789] Preparation of intermediate G

[0790] The synthetic route of intermediate G is as follows:

[0791] In this reaction scheme, -PMB represents p-methoxybenzyl.

[0792] Step 1: Preparation of methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate

[0793] To a 500 mL round-bottom flask, methyl 4-bromo-2-fluoro-6-methylbenzoate (5.00 g, 20.0 mmol) and carbon tetrachloride (200 mL) were added. After stirring at room temperature, bromophthalimide (4.27 g, 24.0 mmol) and azobisisobutyronitrile (0.33 g, 2.0 mmol) were added to the resulting solution. The mixture was heated to 80°C and reacted overnight. The reaction was monitored by a microplate reader until the reaction was complete. After washing with saturated sodium sulfite solution and saturated brine, the mixture was purified by column chromatography to obtain 5.00 g of a white solid in a 76.8% yield. MS m / z calculated: 323.88; found: 324.9 [M+H]. + .

[0794] Step 2: Preparation of 5-bromo-7-fluoro-2-(4-methoxybenzyl)isoindol-1-one

[0795] To a 500 mL round-bottom flask, methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate (5.00 g, 15.4 mmol) and tetrahydrofuran (200 mL) were added. After stirring at room temperature, p-methoxybenzylamine (3.16 g, 23.1 mmol) was added dropwise. The temperature was raised to 80°C and the reaction was allowed to proceed overnight. The reaction was monitored by a plate-drip monitor to confirm complete reaction. The solvent was then directly evaporated to obtain a yellow powder. After slurrying with n-hexane, 4.82 g of a pale yellow solid was obtained, with a yield of 89.4%. MS m / z calculated: 350.19; found: 351.2 [M+H] + .

[0796] Step 3: Preparation of tert-butyl (7-fluoro-2-(4-methoxybenzyl)-1-oxoisoindolin-5-yl)carbamate:

[0797] To a 100 mL Shrek tube, add 5-bromo-7-fluoro-2-(4-methoxybenzyl)isoindol-1-one (1.00 g, 2.8 mmol), tert-butyl carbamate (0.50 g, 4.2 mmol), trisdibenzylideneacetone dipalladium (0.30 g, 0.28 mmol), 4,5-bis(diphenylphosphino-9,9-dimethylxanthene) (0.34 g, 0.6 mmol), and cesium carbonate (1.40 g, 4.2 mmol). After the addition, the atmosphere was replaced with argon three times. Toluene (200 mL) was added, and the temperature was raised to 100°C and allowed to react overnight. After the reaction was complete, the reaction was monitored by a plate and filtered under reduced pressure. The filter cake was washed with ethyl acetate, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography to obtain 0.66 g of the compound as a yellow oil in a 59.6% yield. MS m / z calculated: 386.42; found: 387.4 [M+H] + .

[0798] Step 4: Preparation of tert-butyl (7-fluoro-1-oxoisoindolin-5-yl)carbamate

[0799] To a 250 mL round-bottom flask, tert-butyl (7-fluoro-2-(4-methoxybenzyl)-1-oxoisoindolin-5-yl)carbamate (0.66 g, 1.7 mmol), acetonitrile (50 mL), and water (25 mL) were added portionwise under an ice bath. Ceric ammonium nitrate (2.75 g, 6.8 mmol) was added portionwise. After completion of the addition, the mixture was warmed to room temperature and allowed to react overnight. After completion of the reaction, the mixture was transferred to a 1000 mL beaker and saturated sodium bicarbonate solution (200 mL) was added. The mixture was filtered under reduced pressure and the filtrate was extracted three times with dichloromethane (500 mL). The organic phase was washed three times with saturated brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield 0.33 g of a crude yellow product in a 71.1% yield. MS m / z calculated: 266.27; found: 267.2 [M+H] + .

[0800] Step 5: Preparation of 5-amino-7-fluoroisoindolin-1-one: To a 100 mL round-bottom flask, tert-butyl (7-fluoro-1-oxoisoindolin-5-yl)carbamate (0.33 g, 1.2 mmol) and a 20 mL solution of hydrogen chloride in ethanol were added. The mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction was monitored by a plate-trace monitor and concentrated under reduced pressure. The crude product was purified by slurrying with dichloromethane to afford 0.27 g of a pale yellow solid compound in an 80.0% yield. MS m / z calculated: 166.16; found: 167.1 [M+H]. + Preparation of Intermediate H

[0801] The synthetic route of intermediate H is as follows:

[0802] Step 1: Preparation of ethyl 2-diazo-3-oxopentanoate

[0803] Ethyl propionyl acetate (28.8 g, 200 mmol) was dissolved in dichloromethane (250 mL) and the atmosphere was replaced with nitrogen three times. The reaction solution was cooled to 0°C and TEA (60.6 g, 600 mmol) was added. The mixture was stirred at 0°C for 5 minutes. 4-Methylbenzenesulfonyl azide (47.3 g, 240 mmol) was then added and the mixture was slowly returned to room temperature and stirred for 6 hours. The reaction was quenched with water (300 mL) and dichloromethane (1000 mL). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography yielded 17.3 g of ethyl 2-diazo-3-oxopentanoate as a colorless oil in a 51% yield. MS m / z calculated: 170.17; found: 171.1 [M+H] + .

[0804] Step 2: Preparation of ethyl (Z)-2-diazo-3-((trimethylsilyl)oxy)pent-3-enoate

[0805] Dissolve ethyl 2-diazo-3-oxopentanoate (60.0 g, 353 mmol) in dichloromethane (720 mL) and cool to -10°C-0°C. Add TEA (57.0 g, 79.4 mL, 564 mmol) and slowly add trimethylsilyl trifluoromethanesulfonate (TMSOTf) (102.0 g, 82.8 mL, 458 mmol). Stir the reaction mixture at 0°C for 60 minutes. The reaction is nearly complete as determined by TLC. Wash the reaction mixture with saturated sodium bicarbonate (1000 mL). The organic layer is separated, washed with water (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 72 g of crude ethyl (Z)-2-diazo-3-(trimethylsilyl)oxy)pent-3-enoate in a 67% yield. The crude product was used directly in the next step without further purification.

[0806] Step 3: Preparation of rac-(4R,5R)-2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxohexanoic acid ethyl ester

[0807] A solution of trifluoroacetone (47.0 g, 37.5 mL, 416 mmol) in dichloromethane (300 mL) was cooled to -78°C. A solution of titanium tetrachloride (78.9 g, 416 mmol) in dichloromethane (340 mL) was added dropwise to the stirred reaction mixture. The reaction mixture was stirred at -78°C for 10 minutes, followed by the dropwise addition of a solution of ethyl (Z)-2-diazo-3-((trimethylsilyl)oxy)pent-3-enoate (72.0 g, 297 mmol) in dichloromethane (300 mL). The reaction mixture was stirred at -78°C for 2 hours. Saturated aqueous sodium bicarbonate (1000 mL) was added, and the aqueous phase was extracted with dichloromethane (300 mL x 2). The organic layer was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 51 g of rac-(4R,5R)-2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxohexanoic acid ethyl ester, a pale yellow liquid, in a yield of 57.6%. MS m / z calculated: 282.08; found: 283.1 [M+H] + .

[0808] Step 4: Preparation of rac-(4R,5R)-4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid ethyl ester

[0809] Ethyl rac-(4R,5R)-2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxohexanoate (20.0 g, 70.9 mmol, 1.00 eq) was dissolved in toluene (100 mL) and dimeric rhodium acetate (470 mg, 1.06 mmol, 0.015 eq) was added. The reaction mixture was stirred at 100°C for 2 hours. The solvent was removed under vacuum to yield 18.0 g of crude green oily product, ethyl rac-(4R,5R)-4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate, which was used directly in the next reaction.

[0810] Step 5: Preparation of rac-(4R,5R)-4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylic acid ethyl ester

[0811] Ethyl rac-(4R,5R)-4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (18.0 g crude product, 70.5 mmol) was dissolved in anhydrous dichloromethane (200 mL) and the atmosphere was replaced with nitrogen three times. The reaction solution was cooled to -78°C and a solution of diisopropylethylamine (10.9 g, 84.6 mmol) and trifluoromethanesulfonic anhydride (23.9 g, 84.6 mmol) in anhydrous dichloromethane (50 mL) was added. The mixture was stirred at this temperature for 1 hour. The reaction mixture was gradually warmed to 0°C and stirred for 0.5 hours. The reaction was quenched with saturated sodium bicarbonate solution (100 mL) and extracted with dichloromethane (150 mL). The organic phases were combined. The residue was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 15 g of rac-(4R,5R)-4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylic acid ethyl ester as a colorless oil in a 54.6% yield. MS m / z calculated: 386.03; found: 387.1 [M+H] + .

[0812] Preparation of intermediate I

[0813] The synthetic route of intermediate I is as follows:

[0814] Step 1: Preparation of (6-bromo-2,3-difluorophenyl)(methyl)sulfane

[0815] 4-Bromo-1,2-difluorobenzene (20 g, 103.6 mmol) was dissolved in tetrahydrofuran (200 mL) and the atmosphere was replaced with nitrogen three times. The reaction solution was cooled to -78°C and LDA (62 mL, 124 mmol, 2 M) was added. The mixture was stirred at this temperature for half an hour. Dimethyl disulfide (11.7 g, 124 mmol) was then added. The reaction mixture was gradually warmed to room temperature and stirred for 2.5 hours. The reaction was quenched with saturated ammonium chloride solution (400 mL) and extracted with ethyl acetate (150 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification by column chromatography afforded 12 g of (6-bromo-2,3-difluorophenyl)(methyl)sulfane as a colorless oil in a 46% yield. MS m / z calculated: 239.92; found: 238.9 [MH] - .

[0816] Step 2: Preparation of (3,4-difluoro-2-(methylthio)phenyl)boronic acid

[0817] (6-Bromo-2,3-difluorophenyl)(methyl)sulfane (12 g, 50.2 mmol) was dissolved in tetrahydrofuran (120 mL) and the atmosphere was replaced with nitrogen three times. The reaction solution was cooled to 0°C and i-PrMgBr.LiCl (30.1 mL, 60.2 mmol, 2 M) was added. The mixture was stirred at 0°C for half an hour. Triisopropyl borate (18.88 g, 100.4 mmol) was added and stirred at 0°C for 2.5 hours. The reaction was quenched with saturated ammonium chloride solution (300 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 8 g of (3,4-difluoro-2-(methylthio)phenyl)boronic acid as a colorless oil in a 52% yield. MS m / z calculated: 204.02; found: 203.0 [MH] - .

[0818] Preparation of intermediate J

[0819] The synthetic route of intermediate J is as follows:

[0820] Step 1: Preparation of 5-amino-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide-3,3-d2

[0821] To a solution of 5-aminobenzo[d]isothiazol-3(2H)-one 1,1-dioxide (2 g, 10 mmol) in tetrahydrofuran (30 mL) was added portionwise lithium aluminum hydride (0.51 g, 12 mmol) under ice. The mixture was stirred for half an hour, then brought to room temperature and stirred for an additional 2 hours. The reaction was monitored for completion and quenched with saturated sodium potassium tartrate solution. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to afford approximately 0.98 g of 5-amino-2,3-dihydrobenzo[d]isothiazol-1,1-dioxide-3,3-d2 as a yellow solid in a 52% yield. MS m / z calculated: 186.04; found: 187.1 [M+H] + .

[0822] Biological part of the test:

[0823] Test Example 1: Blocking activity of the compound of the present invention on sodium ion channel 1.8 (Nav1.8)

[0824] 1. Detection method: Whole-cell manual patch clamp technique to detect the effect of compounds on voltage-gated Nav1.8 channel current

[0825] 2. Preparation and Analysis of Test Compounds

[0826] Blank control: Take an appropriate amount of DMSO and add it to the extracellular solution to obtain an extracellular solution containing 0.1% DMSO as the blank control working solution.

[0827] Test compound: Weigh an appropriate amount of the test substance and dissolve it with DMSO to obtain a stock solution of the test compound, which is then further diluted with extracellular fluid to working solutions of the test compound with different final concentrations such as 10nM, 50nM, 0.1μM, 1μM and 10μM (the DMSO concentration in the working solution does not exceed 0.3%).

[0828] 3. Cell Culture

[0829] CHO cell lines stably expressing Nav1.8 (gene information: SCN10A, NM_006514; SCN1B, NM_199037; SCN3B, NM_018400) were cultured and passaged in HAM'S / F-12 medium (supplemented with 10% fetal bovine serum, 10 μg / mL blasticidin, 200 μg / mL hygromycin B, and 100 μg / mL zeocin) in a 37°C incubator with 5% carbon dioxide. To maintain electrophysiological activity, the cell density in the culture dish should not exceed 80%.

[0830] Before the patch clamp test, cells were detached with 0.25% trypsin-EDTA and 6.5 × 10 3 Cells were plated on coverslips and cultured in 24-well plates (final volume: 500 μL). After induction with tetracycline for 24-72 hours, the assay was performed.

[0831] 4. Electrophysiological Experiments

[0832] (1) Fluids used in electrophysiological experiments

[0833] Extracellular solution: 140 mM NaCl, 3.5 mM KCl, 1 mM MgCl2·6H2O, 2 mM CaCl2·2H2O, 10 mM D-Glucose, 10 mM HEPES, 1.25 mM NaH2PO4·2H2O, pH adjusted to 7.4 with NaOH.

[0834] Intracellular solution: 50 mM CsCl, 10 mM NaCl, 10 mM HEPES, 60 mM CsF, 20 mM EGTA, pH adjusted to 7.2 with CsOH.

[0835] (2) Patch clamp assay

[0836] The voltage stimulation protocol for whole-cell patch-clamp recording of sodium currents was as follows: After whole-cell seal formation, the cell was voltage-clamped at -120 mV. The voltage was first stepped from -130 mV to -10 mV in 10 mV steps and held for 5 seconds. A depolarizing pulse of 0 mV was then applied to obtain the half-inactivation voltage (Vhalf). The resting and half-inactivated states of sodium current were monitored using a double-pulse protocol. The first depolarizing pulse (TP1) was applied to 0 mV for 50 ms to measure the resting sodium current. The voltage was then adjusted to Vhalf and held for 5 seconds. The voltage was then returned to -120 mV and held for 20 ms. A second depolarizing pulse (TP2) was applied to 0 mV for 50 ms to measure the half-inactivated sodium current. Finally, the voltage was returned to the holding voltage of -120 mV. Data were collected repeatedly every 20 seconds to observe the effects of drugs on the peak sodium currents in the two different states. The experimental data were collected by EPC 10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.

[0837] The patch clamp procedure begins by pulling a recording electrode from a glass capillary using a microelectrode puller. The electrode, filled with intracellular fluid, is then placed in a microelectrode holder. Under an inverted microscope, the microelectrode manipulator is used to immerse the electrode in extracellular fluid and record the electrode resistance (Rpip). The electrode is then slowly brought into contact with the cell surface, and negative pressure is applied to create a high-resistance GΩ seal. Fast capacitance compensation is then performed, and negative pressure is continued to rupture the cell membrane, establishing whole-cell recording mode. Finally, slow capacitance compensation is performed, and experimental parameters such as series resistance (Rs) are recorded. No leakage compensation is performed.

[0838] When the sodium current recorded in the whole cell is stable, the drug is administered. Each drug concentration is allowed to act for 5 minutes (or the current is stable) before the next concentration is detected. The coverslip with cells is placed in a recording bath under an inverted microscope. The blank control external solution and the working solution of the compound to be tested are administered by gravity perfusion from low concentration to high concentration through the recording bath to act on the cells. At the same time, a peristaltic pump is used for liquid replacement during the recording. The current detected in the external solution without compound for each cell serves as its own control group. At least two cells are used for each concentration and the test is repeated twice independently. All electrophysiological experiments are performed at room temperature.

[0839] 5. Data Analysis

[0840] First, the peak sodium current after each drug concentration is compound ) and blank control current peak value (Peak current control ) normalized, and then calculated the inhibition rate corresponding to each drug concentration under different conditions, that is, The inhibition rate at each concentration was averaged.

[0841] The dose-effect curve was fitted using the Hill equation: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope)), where Bottom and Top represent the minimum and maximum values ​​of inhibition, respectively, X represents the logarithm of the compound concentration, and Y represents the Peak-current compound / Peak-current Control Value, IC 50 It represents the drug concentration that produces half-maximal inhibition effect, and HillSlope represents the Hill coefficient.

[0842] The blocking activity results of some compounds of the present invention on Nav1.8 channels are shown in Tables 1 to 5. TP1 represents the resting state, and TP2 represents the half-inactivated state.

[0843] Table 1 The percentage blocking activity of some compounds of the present invention on Nav1.8 channels at a concentration of 10 μM

[0844] Table 2 Percentage blocking activity of some compounds of the present invention on Nav1.8 channels at a concentration of 1 μM

[0845] Table 3 Percent blocking activity of some compounds of the present invention on Nav1.8 channels at a concentration of 100 nM

[0846] The inhibition rates of P-50, P-51, P-59, P-63, P-68, P-72, P-73, P-94 and P-103 on TP1 and TP2 at a concentration of 100 nM were greater than 50%. Table 4 The percentage blocking activity of some compounds of the present invention on Nav1.8 channels at a concentration of 10 nM

[0847] P-52, P-53, P-54, P-55, P-56, P-57, P-60, P-61, P-62, P-64, P-65, P-66, P-68, P-71, P-74, P-76, P-77, P-82, P-83, P-85, P-86, P-88, P-89, and P-90 have an inhibition rate of >50% on TP1 and TP2 at a concentration of 10 nM.

[0848] Table 5 IC values ​​of representative compounds for Nav1.8 channels 50 Value (nM)

[0849] Test Example 2: Manual patch clamp technique to detect the effect of the test substance on TTX-R currents in acutely isolated rat dorsal root ganglia (DRG)

[0850] 1) DRG neuron isolation

[0851] In this test example, acutely isolated rat DRG neurons were used.

[0852] a. Solution preparation

[0853] b. Separation step

[0854] 2-3 week old rats were anesthetized with 0.4 mL / 100 g of 20% urethane and placed in a prone position. The skin was disinfected with 75% alcohol. The skin was cut open from the tail with surgical scissors to fully expose the spine, and the muscle tissue on both sides of the spine was removed.

[0855] The spine was removed from the coccyx to the cervical vertebrae and placed in a 10 cm dish filled with HBSS on an ice box. The upper 1 / 3 of the spinal cross section was cut with rat scissors. After removing the spinal cord, the nerves connected to the DRG were visible. L4 to L6 DRGs were removed under a dissecting microscope.

[0856] After all DRGs were removed, the nerves connected to the DRGs were cut off under a microscope.

[0857] The DRG with the nerves removed was cut into small pieces and transferred into a 15 mL centrifuge tube and then transferred into the cell compartment.

[0858] Centrifuge at 1000 r / min for 5 min and discard the supernatant.

[0859] Add 5 mL of digestion solution and place in an incubator at 37°C and 5% CO2. Digest for about 20 minutes. Shake the tissue from time to time to resuspend it. Use a pipette to blow the tissue. During the digestion process, the tissue can be seen to become filamentous. After repeating two or three times, the filaments disappear and there are no tissue blocks, indicating that the digestion is complete.

[0860] After digestion, add 5 mL of complete medium, centrifuge at 1000 rpm for 5 min, and discard the supernatant.

[0861] Add an appropriate amount of complete culture medium, gently resuspend the cells, and add the cell suspension to the coated PLL cell slide.

[0862] After 2 hours, the cells can be used for patch clamp experiments. At this point, the cells are divided into two groups: a blank control group and a 5μM INS018_055 treatment group. After the cells in the 5μM INS018_055 treatment group have attached, they are added to the complete culture medium at a final concentration of 5μM and incubated for 1 hour before being used for experimental detection.

[0863] 2) Electrophysiological recording

[0864] a. Record the liquid used

[0865] Extracellular fluid: DRG-004-1

[0866] 22mM NaCl, 110mM Choline-Cl, 0.8mM MgCl2·6H2O, 1.8mM CaCl2·2H2O, 5mM D-Glucose, 10mM HEPES, 0.1mM CdCl2, NaOH adjust pH=7.4.

[0867] Intracellular fluid: DRG-004-2

[0868] 10 mM CsCl, 5 mM NaCl, 10 mM HEPES, 135 mM CsF, 5 mM EGTA, adjust pH to 7.2 with CsOH. 2 mM Mg-ATP was added immediately upon use.

[0869] The extracellular solution was stored at 4°C for 2 weeks. After the intracellular solution was prepared, it was aliquoted into 1 mL tubes and stored frozen at -20°C. Freshly thawed intracellular solution was used daily for testing. All intracellular solution should be used within 3 months, otherwise it should be discarded and reconstituted.

[0870] b. Patch clamp assay

[0871] The voltage stimulation protocol for whole-cell patch-clamp recordings of TTX-R currents was as follows: After whole-cell patch clamping, the cell was voltage-clamped at -120 mV. The voltage was first stepped from -130 mV to -10 mV in 10 mV steps and held for 5 s, followed by a 0 mV depolarizing pulse to obtain the half-inactivation voltage (Vhalf). The resting and half-inactivated states of TTX-R currents were measured using a double-pulse protocol. A first depolarizing pulse (TP1) was applied to 0 mV for 50 ms to measure the resting TTX-R current. The voltage was then adjusted to Vhalf and held for 5 s, followed by a return to -120 mV for 20 ms to allow unbound, inactivated channels to recover. A second depolarizing pulse (TP2) was applied to 0 mV for 50 ms to measure the half-inactivated TTX-R current. Finally, the holding voltage was restored to -120 mV, and data were repeatedly collected at 20-second intervals to observe the effects of the drugs on the peak sodium currents in the two different states. The experimental data were acquired by an EPC 10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.

[0872] The patch clamp procedure begins by pulling a glass capillary into a recording electrode using a microelectrode puller. The electrode, filled with intracellular fluid, is then placed in a microelectrode holder. The coverslip containing the cells is then placed in the recording bath under an inverted microscope. Under the microscope, the microelectrode manipulator is used to immerse the electrode in the extracellular fluid and record the electrode resistance (Rpip). The electrode is then slowly brought into contact with the cell surface, and negative pressure is applied to create a GΩ high-resistance seal. Fast capacitance compensation is then performed, and negative pressure is continued to rupture the cell membrane, establishing whole-cell recording mode. Finally, slow capacitance compensation is performed, and experimental parameters such as series resistance (Rs) are recorded. No leakage compensation is performed.

[0873] Drug administration was initiated after the current amplitude stabilized in the control extracellular solution. The next drug concentration was measured after the current reached equilibrium at each drug concentration. Blank control solution and test compound working solutions were administered by gravity perfusion, flowing from low to high concentrations through the recording bath, where they acted on the cells. A peristaltic pump was used to replace the fluid during recording. The current measured in each cell in the compound-free extracellular solution served as its own control. TTX-R currents were measured in duplicate for each concentration. All electrophysiological experiments were performed at room temperature.

[0874] 3) Data Analysis

[0875] First, the peak current of TTX-R after each drug concentration was calculated. compound ) and peak current control ) normalized, and then calculated the inhibition rate corresponding to each drug concentration under different conditions, that is, The mean (Mean), standard deviation (SD) and standard error (SE) of the inhibition rate at each concentration were calculated, and the data were expressed as Mean ± SE. Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope))

[0876] Calculate the IC of the compound using the above equation 50 The concentration-effect curve was fitted nonlinearly, where IC 50 IC is the half inhibitory concentration. 50 Calculations and curve fitting were performed using GraphPad Prism software.

[0877] 4) Test results

[0878] Manual patch clamp technique was used to detect the inhibitory effect of the test substances on TTX-R currents in acutely isolated 2-3 week old rat dorsal root ganglion (DRG) neurons in two independent repeated experiments. The test results showed that the compounds of the present invention had a good inhibitory effect. Among them, the inhibitory effects of P-40, P-48, P-66, P-81, P-87, P-93, P-95, and P-100 on the resting state of rat DRG TTX-R were IC 50 <200nM; IC values ​​of P-81 and P-87 for the inhibitory effects on resting rat DRG TTX-R 50 The inhibitory effect of P-100 on the resting state of rat DRG TTX-R is 200~500nM; IC 50 >1000nM.

[0879] Test Example 3: hERG inhibitory activity test:

[0880] 1. Sample Preparation

[0881] Preparation of blank control substance: Take an appropriate amount of DMSO and add it to the extracellular solution to obtain an extracellular solution containing 0.3% DMSO as the blank control substance working solution.

[0882] Preparation of positive control: Weigh an appropriate amount of Cisapride, dissolve it with an appropriate amount of dimethyl sulfoxide (DMSO), and then dilute it with extracellular fluid to prepare working solutions with concentrations of 1000 nM, 100 nM, 10 nM, 1 nM and 0.1 nM (make sure the DMSO concentration is 0.3%).

[0883] Preparation of test substances: Weigh an appropriate mass of the test substance, dissolve it with an appropriate amount of DMSO, and then use extracellular fluid to prepare working solutions of the test substance with concentrations of 30 μM, 10 μM, 3 μM, 1 μM, and 0.3 μM, ensuring that the DMSO concentration in each working solution is 0.3%.

[0884] 2. Cell Culture

[0885] HEK-293 cells stably expressing the hERG potassium channel were used. hERG potassium channel cells were purchased from Creacell (Cat. No. A-0320). Cells were cultured and passaged in DMEM supplemented with 10% fetal bovine serum and 0.8 mg / mL G418 in a cell culture dish in an incubator at 37°C and 5% CO2. To maintain electrophysiological activity, the cell density must not exceed 80%.

[0886] Before patch clamp testing, cells were stained with TrypLE TM Express separation, 4×103 The cells were plated on coverslips and cultured in 24-well plates (final volume: 500 μL). After 18 hours, the assay was performed.

[0887] 3. Electrophysiological Recording

[0888] Extracellular solution: K-007-1, 140 mM NaCl, 3.5 mM KCl, 1 mM MgCl2·6H2O, 2 mM CaCl2·2H2O, 10 mM D-Glucose, 10 mM HEPES, 1.25 mM NaH2PO4·2H2O, NaOH adjusted to pH = 7.4.

[0889] Intracellular solution: K-002-2, 20 mM KCl, 115 mM K-Aspartic, 1 mM MgCl2·6H2O, 5 mM EGTA, 10 mM HEPES, 2 mM Na2-ATP, pH adjusted to 7.2 with KOH.

[0890] Patch clamp detection: The voltage stimulation scheme for whole-cell patch clamp recording of hERG current is as follows: After the whole-cell seal is formed, the cell membrane voltage is clamped at -80mV. The clamping voltage is depolarized from -80mV to -50mV for 0.5s (as a leakage current detection), then stepped to 30mV for 2.5s, and then quickly restored to -50mV for 4s to stimulate the tail current of the hERG channel. Data is collected repeatedly every 10s to observe the effect of drugs on the hERG tail current. A 0.5s stimulation of -50mV is used as a leakage current detection. The experimental data are collected by an IPA amplifier (Sutter Instrument) and stored in SutterPatch (with Igor Pro) software.

[0891] The patch clamp procedure begins by pulling a recording electrode from a glass capillary using a microelectrode puller. The electrode, filled with intracellular fluid, is then placed in a microelectrode holder. Under an inverted microscope, the microelectrode manipulator is used to immerse the electrode in extracellular fluid and record the electrode resistance (Rpip). The electrode is then slowly brought into contact with the cell surface, and negative pressure is applied to create a high-resistance GΩ seal. Fast capacitance compensation is then performed, and negative pressure is continued to rupture the cell membrane, establishing whole-cell recording mode. Finally, slow capacitance compensation is performed, and experimental parameters such as series resistance (Rs) are recorded. No leakage compensation is performed.

[0892] When the hERG current recorded by the whole cell is stable, the drug is administered. After each drug concentration is applied for 5 minutes (or the current is stable), the next concentration is detected. Multiple concentrations are detected for each test compound. The coverslip with cells is placed in a recording bath under an inverted microscope. The blank control external solution and the working solution of the test compound are flowed through the recording bath from low concentration to high concentration by gravity perfusion to act on the cells. A peristaltic pump is used for liquid exchange during recording. The current detected in the external solution without compound for each cell serves as its own control group. At least three cells are used for each concentration and the test is repeated three times independently. All electrophysiological experiments are performed at room temperature.

[0893] 4. Data Analysis

[0894] First, the peak tail current after each drug concentration is compound ) and blank control tail current (Peak tail current control ) normalized, and then calculated the inhibition rate corresponding to each drug concentration The average inhibition rate was calculated for each concentration.

[0895] The dose-effect curve was fitted using the Hill equation: Y = Bottom + (Top-Bottom) / (1 + 10^((LogIC 50 =X)*HillSlope)), where Bottom and Top represent the minimum and maximum values ​​of inhibition, respectively; X represents the logarithm of the compound concentration; and Y represents the Peak tail current. compound / Peak tail current Control Value, IC 50 It represents the drug concentration that produces half-maximal inhibition effect, and HillSlope represents the Hill coefficient.

[0896] Table 6 Inhibitory activity of representative compounds on hERG

[0897] The results showed that the compound of the present invention had very weak inhibitory activity on hERG (potassium ion channel) and exhibited high ion channel selectivity.

[0898] Test Example 4: Liver microsome metabolic stability test:

[0899] 1. Sample Preparation

[0900] Working solutions of test compounds and positive control compounds: The test compounds and positive control compound (dextromethorphan) were dissolved in DMSO to prepare 1 mM intermediate working solutions, which were then diluted with acetonitrile (ACN) to 200 μM working solutions.

[0901] Phosphate buffer: Dissolve 8.709g of potassium dihydrogen phosphate (K2HPO4) in 950mL of water. Adjust the pH of the solution to 7.4 with hydrochloric acid, then add water to 1000mL. Filter through a 0.22μm filter and store in a refrigerator at 4°C until needed.

[0902] Incubation matrix working solution: After various types of liver microsomes (protein concentration 20 mg / mL) were melted in a 37°C water bath, they were diluted with phosphate buffer solution to obtain liver microsome working solution with a protein concentration of 0.629 mg / mL.

[0903] NADPH working solution: Use the above phosphate buffer to prepare a 5mM NADPH solution for later use.

[0904] Reaction stop solution: Prepare a 1 mg / mL stock solution of terfenadine / tolbutamide in DMSO, and then dilute it with a mixture of 50% methanol / 50% acetonitrile to a reaction stop solution containing 5 / 10 ng / mL (terfenadine / tolbutamide) as internal standard.

[0905] 2. Incubation and Detection

[0906] 238.5 μL of liver microsome working solution from different species was added to a 1.1 mL microtube. 1.5 μL of the test compound working solution or the positive control compound (dextromethorphan) working solution (200 μM) was added to each tube. Mix thoroughly and pre-incubate in a 37°C waterbath for 5 minutes. The reaction was initiated by adding 60 μL of NADPH solution. After thorough mixing, 30 μL of the reaction solution was pipetted into 300 μL of the reaction stop solution at 0, 5, 15, 30, and 60 minutes after the reaction. Samples at all time points were vortexed vigorously for 1 minute and centrifuged at 4000 rpm for 15 minutes at 4°C. The supernatant was analyzed by LC-MS / MS.

[0907] 3. Data Analysis

[0908] The slope (ke) was measured by plotting the natural logarithm of the percentage of the remaining compound against time, and T was calculated according to the first-order kinetic formula. 1 / 2 and intrinsic clearance (CL int ):

[0909] The compound residual rate is calculated as follows: C t =C0*e -ke*t lnC t =lnC o –ke*t

[0910] According to the above formula, when When

[0911] Intrinsic clearance CL int (μL / min / mg protein)=0.693*1000 / T 1 / 2 / Protein concentration (0.5mg protein / mL)

[0912] The unbound fraction (Fu) in the liver microsomal mixture was assumed to be 100%.

[0913] The following physiological variables were used for prediction calculations:

[0914] The results of the liver microsome stability test are shown in Table 7.

[0915] Table 7 The stability of the compounds of the present invention on the liver microsomes of Nav1.8 channel

[0916] The results showed that the compound of the present invention exhibited good metabolic stability in human and rat liver microsomes.

[0917] Test Example 5: Solubility Test

[0918] Solubility determination in pH 7.4 phosphate buffer: Excess DMSO stock solution of the test compound was placed in pH 7.4 phosphate buffer, shaken at 25°C and 350 rpm for 4 hours, then sampled and filtered through a 0.22 μm filter. The filtrate was then used to determine the concentration. The results are shown in the following table:

[0919] Table 8 Solubility of representative compounds

[0920] The results showed that the compound of the present invention exhibited good solubility.

[0921] Test Example 6: CYP450 enzyme inhibition test

[0922] An in vitro test system was used to evaluate the effects of the test substances on the activities of five isoenzymes of cytochrome P450 (CYP) in human liver microsomes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A). Specific probe substrates for the CYP450 isoenzymes were incubated with human liver microsomes and varying concentrations of the test substances. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction, the samples were processed and the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography-tandem mass spectrometry (LC-MS / MS). Changes in CYP enzyme activity were measured, and the IC values ​​were calculated. 50 The inhibitory ability of the test substance on each CYP enzyme subtype was evaluated.

[0923] Conclusion: The IC values ​​of compounds P-36, P-40, P-44, P-48, P-70 and P-87 on five CYP isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A) are 50 All were greater than 10μM.

[0924] Test Example 7: In vitro induction experiment of metabolic enzymes

[0925] 1) Experimental steps

[0926] On the first day, cryopreserved human hepatocytes from a single donor were revived and their cell count and viability were determined. Cell viability was required to be ≥80%. Cells were diluted to contain 700,000 to 1,000,000 viable cells per ml and seeded onto pre-collagenized cell plates. The cells were incubated for at least 4 hours. Once adherent, the seeding medium was replaced with 2.0% (v / v) basement matrix gel (sandwich culture). All incubations were performed in an incubator at 37±1°C, 5.0% CO2, and saturated humidity. Cryopreserved human hepatocytes from a single donor were incubated with control compounds and test articles at varying concentrations at 37±1°C for 48–72 hours or longer, followed by incubation with enzyme probe substrates. Liquid chromatography-tandem mass spectrometry (LC-MS / MS) was used to quantify the production of metabolites from each substrate. Cell viability was assessed using a commercially available cytotoxicity assay kit. Gene expression levels were assessed using real-time quantitative PCR (experimental conditions can be adjusted as needed).

[0927] Table 9 CYP enzyme inducers tested in vitro

[0928] Table 10 CYP enzyme indicator substrates and metabolites in in vitro assays

[0929] 2) Calculation method

[0930] a. Enzyme activity

[0931] The calculation method of enzyme activity induction fold and the calculation method of induction ratio with control compound are as follows:

[0932] Induction fold = enzyme activity in samples treated with the test article (or control compound) / enzyme activity in samples treated with the matrix control

[0933] Induction ratio of the control compound (%) = (induction fold of the sample treated with the test compound - 1) / (induction fold of the sample treated with the control compound - 1) × 100

[0934] b. Gene expression

[0935] This project uses the ΔCt relative quantitative method to compare the differences in gene expression between different treatment groups, and uses the internal reference gene to correct the gene expression level of each sample. The Ct value of the target gene minus the Ct value of the internal reference gene is ΔCt, that is, Ct target gene - Ct internal reference gene = ΔCt. The ΔCt value of the matrix control group is subtracted from the ΔCt value of the treatment group to obtain ΔΔCt, that is, ΔCt treatment group - ΔCt matrix control group = ΔΔCt. Finally, 2 -ΔΔCt Statistical analysis was performed using the PCR method to compare the fold changes between the treated groups and the matrix control group. The induction ratio of the test article to the control compound was calculated as follows:

[0936] Induction ratio of the control compound (%) = (induction fold of the sample treated with the test compound - 1) / (induction fold of the sample treated with the control compound - 1) × 100

[0937] 3) Conclusion:

[0938] Compounds P-36, P-44, P-48, P-58, and P-74 of the present invention were not considered inducers of CYP1A2, CYP2B6, and CYP3A4 at concentrations ranging from 0.100 to 10.0 μM. P-17 was considered an inducer of CYP3A4 at a concentration of 10.0 μM.

[0939] Test Example 8: Pharmacokinetic test in rats:

[0940] In this study, the pharmacokinetics of the drug were evaluated in rats via a single intravenous injection.

[0941] 1. Test methods and conditions: Male SD rats were fasted overnight and given a single intravenous dose of 1 mg / kg or 5 mg / kg of the test compound; and 30 mg / kg of the test compound was given orally.

[0942] 2. Sampling information: Whole blood was collected at 0.083, 0.25, 0.5, 1.0, 2.0, 4.0, 7.0 and 24 h after administration, respectively. The blood was placed in a microcentrifuge tube containing EDTA-K2 anticoagulant and centrifuged at 4°C and 4000 rpm for 5 min. The supernatant was collected and stored in a refrigerator at -75°C ± 15°C.

[0943] 3. Test information: Plasma drug concentrations at different time points were measured using LC-MS / MS, and relevant pharmacokinetic parameters were calculated using WinNonlin 8.3.1 software. The results are as follows:

[0944] Table 11 PK results of representative compounds in rats

[0945] The results showed that the compounds P-36, P-44, P-48, P-58, P-87, P-88, P-91 and P-95 of the present invention exhibited excellent oral pharmacokinetic properties in rats.

[0946] Test Example 9: Spinal Nerve Ligation (SNL)-induced Neuropathic Pain Model in Mice

[0947] The model was established after one week of adaptive breeding of female SPF-grade C57BL / 6J mice. The specific establishment method is as follows:

[0948] 1. Spinal Nerve Ligation (SNL) Model

[0949] (1) Sterilization of surgical instruments;

[0950] (2) The experimental animals were anesthetized with isoflurane using a small animal gas anesthesia machine and placed in a prone position on the operating table. The hair at the lumbar spine and hip bones were trimmed and the skin was disinfected.

[0951] (3) After disinfection with iodine, a 2-cm incision is made along the spine near the hip bone, the fascia and muscles are separated, and the L5 transverse process is exposed;

[0952] (4) Use forceps to carefully bite off the L5 transverse process and expose the L5 nerve;

[0953] (5) The L5 nerve was separated by a glass needle and ligated using a 5-0 ligature;

[0954] (6) Suture the muscles and skin and disinfect.

[0955] (7) After surgery, observe the overall recovery of the mice, as well as their gait, spontaneous pain, and weight-bearing preference, and pay attention to whether the skin on the back of the mice has healed well.

[0956] 2. Observation of general clinical symptoms

[0957] After modeling, the activity of the right hind limb of the mice was observed during movement. The mice with successful modeling had abnormal gait, manifested as dragging or lameness of the right hind limb; spontaneous pain behavior, manifested as licking or stroking the affected limb; weight-bearing preference, manifested as the mice tended to avoid placing weight on the affected hind limb.

[0958] 3. Mechanical Pain Measurement

[0959] The mechanical withdrawal threshold (MPT) of mice was measured using the classic up-down test. The 50% paw withdrawal threshold (50% PTT) is determined by the mechanical force required to elicit a 50% paw withdrawal response after repeated mechanical stimulation. After the mice were acclimated to the Plexiglas box for 30 minutes, Von Frey fibers were used to vertically stimulate the mid-plantar aspect of the hind limb for ≤4 seconds. A positive response was considered if the mouse lifted its paw or licked its paw; a negative response was considered otherwise.

[0960] Start with a force of 0.4. If there is no withdrawal, stimulate the hind toe at a force above 0.6. If there is a withdrawal, stimulate the hind toe at a force below 0.16, and so on. Continue stimulating four times in sequence until a different response occurs, from withdrawal to no withdrawal, or from no withdrawal to withdrawal, for a total of six times, to determine the 50% withdrawal threshold. If the force required exceeds 2.0 or is less than 0.02, the threshold for that side will be recorded as 2.0 or 0.02. Leave 30 seconds between each stimulation. Maintain consistent measurement techniques throughout the experiment, such as force direction, force application speed, fiber bending degree, force stability, and force removal speed. Additionally, ensure consistent criteria for judging the mouse's response. The 50% paw withdrawal threshold was calculated using the formula 50% paw withdrawal threshold = 10log(X) + κδ (X is the intensity of the final stimulus used; κ is the coefficient of different stimulus methods, which can be found in the coefficient table; δ refers to the average of the adjacent intervals of each stimulus intensity, here δ = 0.224).

[0961] The 50% paw withdrawal threshold was measured and recorded at 0.5 h, 1 h, 3 h, 6 h, and 8 h after oral administration.

[0962] 4. Data Analysis

[0963] All experimental data were analyzed using GraphPad Prism 9 and IBM SPSS Statistics 19 software. The data were expressed as mean ± standard deviation (x ± s). The independent sample t test was used for comparison between groups. P < 0.05, p < 0.01, and p < 0.001 indicated statistically significant differences.

[0964] 5. Conclusion

[0965] The compounds of the present invention, such as the example compounds, have significant analgesic effects. Among them, compounds P-36, P-44, P-45, P-48, P-58, P-60, P-75, P-87, P-88, P-91, P-92, P-93, P-95, and P-97 all have significant analgesic effects at a dosage of 15 mg / kg or 45 mg / kg.

[0966] The above embodiments are based on the numbers and corresponding structural formulas and are only used to illustrate the technical solutions of the present invention, not to limit them. Although the present invention has been described in detail with reference to the above embodiments, it should be understood by those skilled in the art that the technical solutions described in the above embodiments may be modified, or some or all of the technical features therein may be replaced with equivalents, without departing from the spirit and essence of the claims of the present invention; and such modifications or replacements are still within the scope of the claims of the present invention.

Claims

1. Compounds of formula I: Its isomers, racemates, or pharmaceutically acceptable salts or prodrugs, wherein: R1, R2 are independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, halogenated 3-7 membered heterocycloalkyl, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, halogenated 3-7 membered heterocycloalkyl may be further substituted by one or more independently selected from hydrogen, hydroxyl, C 1-6 Substitution of alkoxy groups; R3 is selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, -SC 1-6 Alkyl, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, halogenated C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyloxy, halogenated 3-7 membered heterocycloalkyl; R4 is selected from hydrogen, 6-10 membered aryl, benzo 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 9-10 membered heteroaryl, wherein the 6-10 membered aryl, benzo 5-6 membered heterocycloalkyl, 5-6 membered heteroaryl, 9-10 membered heteroaryl can be optionally replaced by one or more independently selected from hydrogen, halogen, deuterium, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, halogenated C 2-6 Alkenyl, halogenated C 1-6 Alkoxy, -S-halogenated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, -S-deuterated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyloxy, halogenated 3-7 membered heterocycloalkyl, -NHhalogenated C 1-6 Alkyl, -L1-L2-OR 7 、-L1-(C 2-6 Alkenylene)-OR 7 、-L1-L2-NR 8 R 9 、-CO-NR 8 R 9 、-SO2-NR 8 R 9 、-L1-L2-NHS(O)C 1-6 Alkyl, L1-L2-R 10 Substituents are substituted; L1 is selected from a bond, O; L2 is selected from C 1-6 Alkylene; R 7 Selected from hydrogen, C 1-6 Alkyl, halogenated C 1-6 alkyl; R 8 , R 9 are independently selected from hydrogen, hydroxyl, C 1-6 Alkyl, 3-7 membered heterocycloalkyl; R 10 Selected from C 3-6 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, -C(O)OC 1-6 Alkyl, -COOH, -SO2C 1-6 Alkyl or -C(O)NR 8 R 9 , wherein the 5-6 membered heteroaryl group may be further substituted by one or more selected from hydrogen, halogen, hydroxyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, halogenated C 1-6 Substitution of alkoxy groups; Further cyclize with the carbon atom to which they are attached to form a 5-10 membered heterocycloalkyl group (i.e. In the formula (a), R5 and R6 are cyclized with the carbon atoms to which they are attached to form a 5-10 membered heterocycloalkyl); Preferably, the Selected from Wherein, J1, J2, J3, and J4 are independently selected from NH, CO, C 1- 6Alkylene, bond, O or SO2; However, no more than two of J1, J2, J3, and J4 are NH, CO, or C 1-6 Alkylene, bond, O or SO2; No more than two of J1, J2, J3, and J4 are NH, CO, or C 1-6 Alkylene, bond, O or SO2 means that no more than 2 of J1, J2, J3, and J4 are NH, and no more than 2 of J1, J2, J3, and J4 are CO, and no more than 2 of J1, J2, J3, and J4 are C 1-6 Alkylene, and no more than 2 of J1, J2, J3, and J4 are bonds, and no more than 2 of J1, J2, J3, and J4 are O, and no more than 2 of J1, J2, J3, and J4 are SO2; Preferably, J1 is selected from a bond, C 1-6 Alkylene, NH, CO, SO2; Preferably, J2 is selected from a bond, C 1-6 Alkylene, CO, NH, O; Preferably, J3 is selected from a bond, C 1-6 Alkylene, CO, NH, O; Preferably, J4 is selected from a bond, C 1-6 Alkylene, NH, CO, O; Preferably, no more than 2 of J1, J2, J3, and J4 are NH, CO, O, a bond, or C 1-6 Alkylene; Preferably, when J1 is NH, J2 is CO; Preferably, when J1 is CO or SO2, J2 is NH; The H on the molecule may be further replaced by one or more selected from hydroxyl, halogen, deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 Alkylene hydroxyl, -C 1-6 Alkylene OR 7 , -C 1-6 Alkylene NR 8 R 9 、-(C 1-6 Alkylene)CONH2, -(NC 1-6 alkyl)CONH2, -(C=NR 11 )-NR 8 R 9 , -C 1-6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6 Alkylene 5-10 membered heteroaryl substituents substituted; said C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 Alkylene hydroxyl, -C 1-6 Alkylene OR 7 , -C 1-6 Alkylene NR 8 R 9 , -C 1-6 AlkyleneCONH2, -(NC 1-6 alkyl)CONH2, -(C=NR 11 )-NR 8 R 9 , -C 1-6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6 The 5-10 membered alkylene heteroaryl group may be optionally substituted by one or more independently selected from hydrogen, halogen, hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -OR 7 、-NR 8 R 9 Substituents are substituted; R 11 Selected from hydrogen, hydroxyl or C 1-6 alkyl; Preferably, R1 and R2 are independently selected from C 1-6 Alkyl or halogenated C 1-6 Alkyl, wherein the "halogenated C 1-6 "Alkyl" may be selected from -CF3, -CHF2, -CH2F, -CH2CH2F; Preferably, R1 is selected from -CF3; Preferably, R2 is selected from -CH3; Preferably, R3 is selected from -H, -CH3, -OCH3, halogen or -CH2F; Preferably, R4 is selected from Preferably, the isomer is the isomer represented by formula I-YG:

2. The compound according to claim 1, its isomer, racemate, or pharmaceutically acceptable salt or prodrug thereof, wherein: Formula I preferably has the structure of Formula Ia below: The formula Ia is selected from the formula Ia-YG:

3. The compound according to claim 1 or 2, its isomer, racemate, or pharmaceutically acceptable salt or prodrug thereof, wherein: Formula I has the following structural formula II: In the formula II, R 1 , R 2 , R 3 , R 4 , As defined in claim 1; Preferably, the formula II is an isomer shown in formula II-YG: Preferably, The H on the molecule may be further replaced by one or more selected from hydroxyl, halogen, deuterium, C 1-6 Alkyl, halogenated C 1- 6 alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 Alkylene hydroxyl, -C 1-6 Alkylene OR 7 , -C 1-6 Alkylene NR 8 R 9 、-(C 1-6 Alkylene)CONH2, -(NC 1-6 alkyl)CONH2 or -(C=NR 11 )-NR 8 R 9 , -C 1-6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6 Alkylene 5-10 membered heteroaryl substituents substituted; said C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 Alkylene hydroxyl, -C 1-6 Alkylene OR 7 , -C 1-6 Alkylene NR 8 R 9 , -C 1-6 AlkyleneCONH2, -(NC 1-6 alkyl)CONH2, -(C=NR 11 )-NR 8 R 9 , -C 1-6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6 The 5-10 membered alkylene heteroaryl group may be optionally substituted by one or more independently selected from hydrogen, halogen, hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -OR 7 、-NR 8 R 9 Substituents are substituted; R 8 , R 9 , R 11 Having the definition as claimed in claim 1.

4. The compound according to any one of claims 1 to 3, its isomer, racemate, or pharmaceutically acceptable salt or prodrug thereof, wherein: Preferably, J1 is selected from a bond, C 1-6 Alkylene, NH, CO, SO2; Preferably, J2 is selected from a bond, C 1-6 Alkylene, CO, NH, O; Preferably, J3 is selected from a bond, C 1-6 Alkylene, CO, NH, O; Preferably, J4 is selected from a bond, C 1-6 Alkylene, NH, CO, O; However, no more than two of J1, J2, J3, and J4 are NH, CO, O, bond, or C 1-6 Alkylene; Preferably, when J1 is NH, J2 is CO; Preferably, when J1 is CO or SO2, J2 is NH; Preferably, R1 is selected from -CF3; Preferably, R2 is selected from -CH3; Preferably, the compound of formula II is selected from the following compounds of formula IIa: Formula IIa is selected from Formula IIa-YG: Preferably, Selected from Preferably, By one or more R 56 Substitution, the R 56 Selected from hydrogen, hydroxyl, halogen, deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 Alkylene hydroxyl, -C 1-6 Alkylene OR 7 , -C 1-6 Alkylene NR 8 R 9 , -C 1-6 AlkyleneCONH2, -(NC 1-6 alkyl)CONH2, -(C=NR 11 )-NR 8 R 9 , -C 1-6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6 Alkylene 5-10 membered heteroaryl substituents substituted; said C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 Alkylene hydroxyl, -C 1-6 Alkylene OR 7 , -C 1-6 Alkylene NR 8 R 9 , -C 1-6 AlkyleneCONH2, -(NC 1-6 alkyl)CONH2, -(C=NR 11 )-NR 8 R 9 , -C 1- 6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6 The 5-10 membered alkylene heteroaryl group may be optionally substituted by one or more independently selected from hydrogen, halogen, hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -OR 7 、-NR 8 R 9 Substituents are substituted; Preferably, the R 56 Further selected from R 56N , R 56N The structure is shown below: Preferably, the In the case of a structure containing N, the H on NH is replaced by R 56N replace; Preferably, the Selected from the following structures:

5. The compound according to any one of claims 1 to 4, its isomer, racemate, or pharmaceutically acceptable salt or prodrug thereof, wherein: Formula I has the structure of Formula III: Wherein: R1, R2, R3, R5, R6 have the definitions as in claim 1; R 12 , R 13 , R 14 , R 15 , R 16 are independently selected from hydrogen, halogen, deuterium, hydroxyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 Alkoxy, -SC 1-6 Alkyl, C 3-6 Cycloalkyloxy, halogenated C 1-6 Alkyl, halogenated C 2-6 Alkenyl, halogenated C 1-6 Alkoxy, -S-halogenated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, -S-deuterated C 1-6 Alkyl, halogenated C 3-6 Cycloalkyl, halogenated C 3-6 Cycloalkyloxy, halogenated 3-7 membered heterocycloalkyl, -NHhalogenated C 1-6 Alkyl, -L1-L2-OR 7 、-L1-(C 2-6 (Alkenylene)-OR 7 、-L1-L2-NR 8 R 9 、-CO-NR 8 R 9 、-SO2-NR 8 R 9 、-L1-L2-NHS(O)C 1-6 Alkyl or L1-L2-R 10 ; Preferably, R 12 , R 13 or R 15 , R 16 They can be further cyclized with the carbon atoms to which they are attached to form 5-6 membered heterocycloalkyl groups; L1, L2, R 7 , R 8 , R 9 , R 10 Having the definition as claimed in claim 1; Preferably, the formula III is selected from formula III-YG: Preferably, R 12 , R 16 independently selected from hydrogen, deuterium, halogen, C 1-6 Alkoxy, -SC 1-6 Alkyl, halogenated C 1-6 Alkoxy, -S-halogenated C 1-6 Alkyl, deuterated C 1-6 Alkoxy, -S-deuterated C 1-6 Alkyl, -NR 8 R 9 、-NH halide C 1-6 Alkyl or -OC 1-6 Alkylene SO2C 1-6 alkyl; Preferably, R 13 , R 15 are independently selected from hydrogen or halogen; Preferably, R 12 independently selected from hydrogen, deuterium, halogen, C 1-6 Alkoxy, -SC 1-6 Alkyl, -OC 1-6 Alkylene or C 3-6 Cycloalkyl; Preferably, R 12 , R 13 or R 15 , R 16 They can be further cyclized with the carbon atoms to which they are attached to form 5-6 membered heterocycloalkyl groups; Preferably, the compound of formula III is selected from the following formula IIIa: Formula IIIa is selected from Formula IIIa-YG: Among them, R 1 , R 2 , R 3 , R 12 , R 13 , R 14 , R 15 , R 16 , As defined in formula III; Preferably, the compound of formula III is selected from the following formula IIIb: Formula IIIb is selected from Formula IIIb-YG: In the formula IIIb and formula IIIb-YG, R 3 , R 12 , R 13 , R 14 , R 15 , R 16 , As defined in formula III.

6. The compound according to any one of claims 1 to 5, its isomer, racemate, or pharmaceutically acceptable salt or prodrug thereof, wherein: Preferably, the compound does not contain Its isomers, racemates, or pharmaceutically acceptable salts or prodrugs; Preferably, Select from the group consisting of: The H on the group NH is further selected from H, hydroxyl, halogen, deuterium, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 Alkylene hydroxyl, -C 1-6 Alkylene OR 7 , -C 1-6 Alkylene NR 8 R 9 、-(C 1-6 Alkylene)CONH2, -(NC 1-6 alkyl)CONH2, -(C=NR 11 )-NR 8 R 9 , -C 1-6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6 Alkylene 5-10 membered heteroaryl substituents substituted; said C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 Alkylene hydroxyl, -C 1-6 Alkylene OR 7 , -C 1-6 Alkylene NR 8 R 9 , -C 1-6 AlkyleneCONH2, -(NC 1-6 alkyl)CONH2, -(C=NR 11 )-NR 8 R 9 , -C 1-6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6 The 5-10 membered alkylene heteroaryl group may be optionally substituted by one or more independently selected from hydrogen, halogen, hydroxyl, amino, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -OR 7 、-NR 8 R 9 Substituents are substituted; Preferably, the H on the NH group is further substituted by a group represented by the following formula: -C 1-6 Alkylene NR 8 R 9 , -C 1-6 Alkylene NR 8 R 9 Optionally, one or more independently selected from hydrogen, C 1-6 Alkyl, -NR 8 R 9 Substituents are substituted; L3 is selected from a bond or C 1-6 Alkylene; A is selected from C 3-8 Cycloalkyl; C 3-8 The cycloalkyl group can be a 3-8 membered monocyclic ring, a spirocyclic ring, or a bridged cycloalkane; R a1 , R a2 are independently selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl or hydroxy substituted C 1-6 alkyl; R a3 , R a4 are independently selected from H or C 1-6 alkyl; L4 is selected from a bond or C 1-6 Alkylene; B is selected from 3-8 membered N-containing heterocyclic alkyl; 3-8 membered heterocycloalkyl; 3-8 membered N-containing heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O and S; The 3-8 membered N-containing heterocyclic alkyl group may be a monocyclic, spirocyclic, or bridged ring N-containing heterocyclic alkyl group; R b1 , R b2 are independently selected from H, C 1-6 Alkyl, halogenated C 1-6 Alkyl, hydroxy substituted C 1-6 alkyl; R b3 Selected from H, C 1-6 alkyl; Preferably, the H on the NH group is more preferably substituted by a group represented by the following formula: -C 1-6 Alkylene NR 8 R 9 , Among them, -C 1-6 Alkylene NR 8 R 9 Optionally, one or more independently selected from hydrogen, C 1-6 Alkyl, -NR 8 R 9 Substituents are substituted; u, v, r, s, b, p, q, m, and n are independently selected from 0, 1, 2, or 3; w is selected from 1 to 6, preferably 1 or 2; Preferably, R a3 Can be used with The carbon atoms on the ring form a ring; Preferably, The cycloalkyl or N-containing heterocycloalkyl is a 3-8 membered ring.

7. The compound according to claim 1, its isomer, racemate, or pharmaceutically acceptable salt or prodrug thereof, wherein the compound is selected from:

8. A pharmaceutical composition comprising the compound according to any one of claims 1 to 7, its isomer, racemate, or pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier.

9. Use of the compound according to any one of claims 1 to 7, its isomer, racemate, or pharmaceutically acceptable salt or prodrug thereof, or the pharmaceutical composition according to claim 8 as a drug, preferably, the use is for the preparation of a drug for treating a disorder, condition or disease responsive to inhibition of Nav1.8 channel activity in a mammal in need thereof.

10. Use of the compound according to any one of claims 1 to 7, its isomer, racemate, or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 8 in the preparation of a medicament for treating, preventing or controlling pain conditions, cough conditions, acute pruritus conditions or chronic pruritus conditions; Preferably, the condition comprises chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence, pathological cough or cardiac arrhythmia or a method of reducing the severity thereof; Preferably, the pain comprises neuropathic pain, musculoskeletal pain (preferably osteoarthritis pain), acute pain (preferably acute postoperative pain), postoperative pain or visceral pain; Preferably, the neuropathic pain comprises one or more of postherpetic neuralgia, small fiber neuropathy, idiopathic small fiber neuropathy or diabetic neuropathy, preferably diabetic peripheral neuropathy; Preferably, the postoperative pain includes one or more of bunionectomy pain, abdominoplasty pain, or hernia repair pain; Preferably, the subject is treated with one or more additional therapeutic agents simultaneously, prior to or after treatment with the compound, its isomer, racemate, or pharmaceutically acceptable salt or pharmaceutical composition thereof.

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