Novel sodium channel modulator

Abstract

Provided is a novel sodium channel modulator, in particular a Nav1.8 channel modulator, the compound having a formula I, a formula II, or a formula III, an isomer, a racemate, or a pharmaceutically acceptable salt or prodrug thereof, where the formula I is as shown in the specification. # imgabs0 #

Description

[0001] This application claims the right of priority from the prior application filed by the applicant:

[0002] filed with the China National Intellectual Property Administration on December 1, 2023, with the patent application number 202311629063.9 and the title "A New Sodium Channel Modulator";

[0003] filed with the China National Intellectual Property Administration on December 22, 2023, with the patent application number 202311779844.6 and the title "A New Sodium Channel Modulator";

[0004] filed with the China National Intellectual Property Administration on April 18, 2024, with the patent application number 202410465333.5 and the title "A New Sodium Channel Modulator";

[0005] filed with the China National Intellectual Property Administration on July 19, 2024, with the patent application number 202410973765.7 and the title "A Novel Sodium Channel Modulator";

[0006] The full text of the said prior application is incorporated into this application by reference. Technical Field

[0007] The present invention relates to a new sodium channel modulator, particularly a Nav1.8 channel modulator. Background Art

[0008] Voltage-gated sodium channels (VGSCs) mediate the selective influx of sodium ions in excitable cells and play an important role in initiating and propagating action potentials. Voltage-gated sodium channels are ubiquitously present in the central and peripheral nervous systems and are also present in skeletal and cardiac muscles.

[0009] Nav’s form a subfamily of the voltage-gated ion channel superfamily and contain nine isoforms, named Nav1.1-Nav1.9. The tissue localization of the nine isoforms varies. Nav1.4 is the main sodium channel in skeletal muscle, and Nav1.5 is the main sodium channel in cardiomyocytes. Nav1.7, 1.8, and 1.9 are mainly localized in the peripheral nervous system, while Nav1.1, 1.2, 1.3, and 1.6 are neuronal channels found in the central and peripheral nervous systems. The nine isoforms have similar functional behaviors but differ in specific aspects of 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 pruritus, and inflammatory pain sensation.

[0011] There is still a need for effective Nav1.8 sodium channel activity inhibitors with selective activity against the Nav1.8 sodium channel. Accordingly, the compounds of the present invention can be used for 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 compounds for treating and preventing diseases, disorders, and conditions involving the Nav1.8 receptor and the Nav1.8 voltage-gated sodium channel as follows.

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

[0014]

[0015] its isomers (stereoisomers), racemates, or pharmaceutically acceptable salts or prodrugs thereof, wherein:

[0016] R 1 and R 2 are each independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, halo C 1-6 alkyl, halo C 1-6 alkoxy, halo C 3-6 cycloalkyl, halo 3-7 membered heterocycloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, halo C 1-6 alkyl, halo C 1-6 alkoxy, halo C 3-6 cycloalkyl, halo 3-7 membered heterocycloalkyl, which may optionally be further substituted by one or more substituents independently selected from hydrogen, hydroxy, C 1-6 alkoxy;

[0017] R 3 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, -S-C 1-6 alkyl, C 3-6 cycloalkyloxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, halo C 3-6 cycloalkyl, halo C 3-6 cycloalkyloxy, halo 3-7 membered heterocycloalkyl;

[0018] R4 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 may optionally be substituted with one or more substituents independently selected from hydrogen, halogen, deuterium, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 alkoxy, -S-C 1-6 alkyl, C 3-6 cycloalkyloxy, halo C 1-6 alkyl, halo C 2-6 alkenyl, halo C 1-6 alkoxy, -S-halo C 1-6 alkyl, deuterated C 1-6 alkoxy, -S-deuterated C 1-6 alkyl, halo C 3-6 cycloalkyl, halo C 3-6 cycloalkyloxy, halo 3-7 membered heterocycloalkyl, -NH halo C 1-6 alkyl, -L 1 -L 2 -OR 7 、-L 1 -(C 2-6 alkenylene)-OR 7 、-L 1 -L 2 -NR 8 R 9 、-CO-NR 8 R 9 、-SO 2 -NR 8 R 9 、-L 1 -L 2 -NHS(O)C 1-6 alkyl, L 1 -L 2 -R 10 ;

[0019] L 1 is selected from a bond, O;

[0020] L 2 is selected from C 1-6 alkylene;

[0021] R 7 is selected from hydrogen, C 1-6 alkyl, halo C 1-6 alkyl;

[0022] R 8 、R9 Independently selected from hydrogen, hydroxyl group, C 1-6 alkyl group, 3- to 7-membered heteroalkyl group;

[0023] R 10 is selected from C 3-6 cycloalkyl group, 3- to 8-membered heteroalkyl group, 5- to 6-membered heteroaryl group, -C(O)O C 1-6 alkyl group, -COOH, -SO 2 C 1-6 alkyl group or -C(O)NR 8 R 9 , wherein the 5- to 6-membered heteroaryl group may optionally be further substituted by one or more substituents selected from hydrogen, halogen, hydroxyl group, C 1-6 alkyl group, halo C 1-6 alkyl group, C 1-6 alkoxy group, halo C 1-6 alkoxy group;

[0024] R 11 is selected from hydrogen, hydroxyl group or C 1-6 alkyl group;

[0025] Further cyclizes with the carbon atom to which they are attached to form a 5- to 10-membered heteroalkyl group (that is, in, R 5 and R 6 cyclize with the carbon atom to which they are attached to form a 5- to 10-membered heteroalkyl group);

[0026] In one embodiment of the present invention, the is selected from wherein, J 1 , J 2 , J 3 , J 4 are independently selected from NH, CO, C 1-6 alkylene group, bond, O or SO 2 ;

[0027] However, J 1 , J 2 , J 3 , J 4 no more than 2 of them are NH, CO, C 1-6 alkylene group, bond, O or SO 2 ;

[0028] J 1 , J 2 , J 3 , J 4 no more than 2 of them are NH, CO, C 1-6 alkylene group, bond, O or SO 2 represents J1 , J 2 , J 3 , J 4 Among them, no more than 2 are NH, and J 1 , J 2 , J 3 , J 4 Among them, no more than 2 are CO, and J 1 , J 2 , J 3 , J 4 Among them, no more than 2 are C 1-6 alkylene, and J 1 , J 2 , J 3 , J 4 Among them, no more than 2 are bonds, and J 1 , J 2 , J 3 , J 4 Among them, no more than 2 are O, and J 1 , J 2 , J 3 , J 4 Among them, no more than 2 are SO 2 .

[0029] In one embodiment of the present invention, J 1 is selected from a bond, C 1-6 alkylene, NH, CO, SO 2 .

[0030] In one embodiment of the present invention, J 2 is selected from a bond, C 1-6 alkylene, CO, NH, O.

[0031] In one embodiment of the present invention, J 3 is selected from a bond, C 1-6 alkylene, CO, NH, O.

[0032] In one embodiment of the present invention, J 4 is selected from a bond, C 1-6 alkylene, NH, CO, O.

[0033] In one embodiment of the present invention, J 1 , J 2 , J 3 , J 4 Among them, no more than 2 are NH, CO, O, bond or C 1-6 alkylene.

[0034] In one embodiment of the present invention, when J 1 is NH, J 2 is CO.

[0035] In one embodiment of the present invention, when J 1 is CO or SO 2 then J 2 is NH.

[0036] In one embodiment of the present invention, is selected from the group consisting of:

[0037]

[0038] According to an embodiment of the present invention, the H on may further be substituted by one or more substituents selected from hydroxy, halogen, deuterium, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 alkylene hydroxy, -C 1-6 alkylene OR 7 、-C 1-6 alkylene NR 8 R 9 、-C 1-6 alkylene CONH 2 、-(NC 1-6 alkyl)CONH 2 、-(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; the C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 alkylene hydroxy, -C 1-6 alkylene OR 7 、-C 1-6 alkylene NR 8 R 9 、-C 1-6 alkylene CONH 2 、-(NC 1-6 alkyl)CONH 2 、-(C=NR 11 )-NR 8 R 9 、-C1-6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3-8 membered heterocycloalkyl, -C 1-6 Alkylene 5-10 membered heteroaryl optionally substituted by one or more substituents independently selected from hydrogen, halogen, hydroxy, amino, C 1-6 Alkyl, halo C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -OR 7 , -NR 8 R 9 ;

[0039] According to an embodiment of the present invention, the (when the structure contains N), the H on NH may optionally be further substituted by one or more selected from hydroxy, halogen, deuterium, C 1-6 Alkyl, halo C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 Alkylene hydroxy, -C 1-6 Alkylene OR 7 , -C 1-6 Alkylene NR 8 R 9 , -C 1-6 Alkylene CONH 2 , -(NC 1-6 Alkyl)CONH 2 , -(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; the C 1-6 Alkyl, halo C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 Alkylene hydroxy, -C 1-6 Alkylene OR 7 , -C 1-6 Alkylene NR 8 R 9 , -C 1-6 Alkylene CONH 2 , -(NC 1-6 Alkyl)CONH 2 , -(C=NR 11 )-NR8 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 optionally substituted by one or more substituents independently selected from hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, halo - C 1-6 alkyl, C 3-8 cycloalkyl, 3 - 8 - membered heterocycloalkyl, 5 - 10 - membered heteroaryl, -OR 7 、 -NR 8 R 9 ;

[0040] In one embodiment of the present invention, the in (when the structure contains N), the H on NH is substituted by the following groups:

[0041] -C 1-6 alkylene NR 8 R 9 、

[0042] wherein, -C 1-6 alkylene NR 8 R 9 is optionally substituted by one or more substituents independently selected from hydrogen, C 1-6 alkyl, -NR 8 R 9 ;

[0043] L 3 is selected from a bond or C 1-6 alkylene;

[0044] A is selected from C 3-8 cycloalkyl;

[0045] C 3-8 cycloalkyl can be a 3 - 8 - membered monocyclic, spiro or bridged cycloalkane;

[0046] R a1 、R a2 are each independently selected from H, C 1-6 alkyl, halo - C 1-6 alkyl or hydroxy - substituted C 1-6 alkyl;

[0047] R a3 、R a4 are each independently selected from H or C 1-6 alkyl;

[0048] L 4 is selected from a bond or C 1-6Alkylene;

[0049] B is selected from 3- to 10-membered N-containing heterocycloalkyl;

[0050] 3- to 10-membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S, 3- to 10-membered N-containing heterocycloalkyl;

[0051] 3- to 10-membered N-containing heterocycloalkyl can be monocyclic, spiro, bridged N-containing heterocycloalkyl;

[0052] R b1 、R b2 are each independently selected from H, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl;

[0053] R b3 is selected from H, C 1-6 alkyl.

[0054] In one embodiment of the present invention, in the when the structure contains N, the H on NH is substituted by the following groups:

[0055] -C 1-6 alkylene NR 8 R 9 、

[0056] wherein, -C 1-6 alkylene NR 8 R 9 is optionally substituted by one or more substituents independently selected from hydrogen, C 1-6 alkyl, -NR 8 R 9 ;

[0057] u, v, r, s, b, p, q, m, n are each independently selected from 0, 1, 2 or 3;

[0058] w is selected from 1 to 6, preferably selected from 1 or 2;

[0059] Preferably, R a3 can form a ring with the carbon atom on ;

[0060] Preferably, the cycloalkyl or N-containing heterocycloalkyl of

[0061] L 3 is selected from a bond or C 1-6 alkylene;

[0062] Ra1 , R a2 are each independently selected from H, C 1-6 alkyl, halo C 1-6 alkyl or hydroxy-substituted C 1-6 alkyl;

[0063] R a3 , R a4 are each independently selected from H or C 1-6 alkyl;

[0064] L 4 is selected from a bond or C 1-6 alkylene;

[0065] R b1 , R b2 are each independently selected from H, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl;

[0066] R b3 is selected from H, C 1-6 alkyl.

[0067] In one embodiment of the present invention, the is substituted with one or more R 56 , where the R 56 is selected from hydrogen, hydroxy, halogen, deuterium, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 alkylene hydroxy, -C 1-6 alkylene OR 7 , -C 1-6 alkylene NR 8 R 9 , -C 1-6 alkylene CONH 2 , -(NC 1-6 alkyl)CONH 2 , -(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; the C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C1-6 Alkylene hydroxy, -C 1-6 Alkylene OR 7 、-C 1-6 Alkylene NR 8 R 9 、-C 1-6 Alkylene CONH 2 、-(NC 1-6 Alkyl)CONH 2 、-(C=NR 11 )-NR 8 R 9 、-C 1-6 Alkylene C 3-8 Cycloalkyl, -C 1-6 Alkylene 3- to 8-membered heterocycloalkyl, -C 1-6 Alkylene 5- to 10-membered heteroaryl optionally substituted by one or more substituents independently selected from hydrogen, halogen, hydroxy, amino, C 1-6 Alkyl, halo C 1-6 Alkyl, C 3-8 Cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -OR 7 、-NR 8 R 9 ; In some embodiments, said R 56 is further selected from R 56N ,R 56N The structure is schematically shown as follows:

[0068]

[0069]

[0070] In some embodiments, in the (when the structure contains N), the H on NH is substituted by R 56N .

[0071] In one embodiment of the present invention, the is selected from the following structures:

[0072]

[0073] Wherein,

[0074] said R 56 is as defined above.

[0075] In one embodiment of the present invention, R 1 、R 2 are each independently selected from C 1-6 Alkyl or halo C 1-6 Alkyl, wherein the "halo C1-6 "Alkyl" may be selected from -CF 3 , -CHF 2 , -CH 2 F, -CH 2 CH 2 F.

[0076] In one embodiment of the present invention, R 1 is selected from -CF 3 .

[0077] In one embodiment of the present invention, R 2 is selected from -CH 3 .

[0078] In one embodiment of the present invention, R 3 is selected from -H, -CH 3 , -OCH 3 , halogen or -CH 2 F.

[0079] In one embodiment of the present invention, R 4 is selected from

[0080] According to the embodiment of the present invention, the compound shown in Formula I is selected from the following Formula I-YG:

[0081]

[0082] In the said Formula I-YG, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 are defined as in Formula I above.

[0083] In one embodiment of the present invention, is selected from the group consisting of:

[0084] The H on the group NH may be further substituted by one or more substituents selected from hydroxyl, halogen, deuterium, C 1-6 alkyl, halo-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 CONH 2 , -(NC 1-6 alkyl)CONH 2 , -(C=NR 11 )-NR 8 R 9 , -C 1-6 alkylene C 3-8 cycloalkyl, -C 1-6 alkylene 3- to 8-membered heterocycloalkyl, -C 1-6 alkylene 5- to 10-membered heteroaryl is substituted by a substituent; said C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -C 1-6 alkylene hydroxy, -C 1-6 alkylene OR 7 , -C 1-6 alkylene NR 8 R 9 , -C 1-6 alkylene CONH 2 , -(NC 1-6 alkyl)CONH 2 , -(C=NR 11 )-NR 8 R 9 , -C 1-6 alkylene C 3-8 cycloalkyl, -C 1-6 alkylene 3- to 8-membered heterocycloalkyl, -C 1-6 alkylene 5- to 10-membered heteroaryl may be optionally substituted by one or more substituents independently selected from hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -OR 7 , -NR 8 R 9 ;

[0085] R 11 is selected from hydrogen, hydroxy or C 1-6 alkyl.

[0086] In one embodiment of the present invention, R 1 is selected from -CF 3 .

[0087] In one embodiment of the present invention, R 2 is selected from -CH 3 .

[0088] In one embodiment of the present invention, formula I preferably has the structure of formula Ia:

[0089]

[0090] Formula Ia is selected from formula Ia-YG:

[0091]

[0092] In the said formula Ia and formula Ia-YG, R 3 、R 4 、R 5 、R 6 are as defined in formula I above.

[0093] In one embodiment of the present invention, R 3 is selected from -H, -CH 3 、-OCH 3 、halogen or -CH 2 F.

[0094] In one embodiment of the present invention, R 4 is selected from

[0095]

[0096] On the other hand, the present invention also provides a compound of structural formula II:

[0097]

[0098] its isomers, racemates, or pharmaceutically acceptable salts or prodrugs,

[0099] According to the embodiment of the present invention, in the said formula II, R 1 、R 2 、R 3 、R 4 、 are as defined above.

[0100] According to the embodiment of the present invention, wherein:

[0101] R 1 、R 2 are each independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, halo C 1-6 alkyl, halo C 1-6 alkoxy, halo C 3-6 cycloalkyl, halo 3-7 membered heterocycloalkyl, C 1-6 alkyl, C1-6 Alkoxy, C 3-6 Cycloalkyl, 3-7 membered hetero cycloalkyl, halo C 1-6 Alkyl, halo C 1-6 Alkoxy, halo C 3-6 Cycloalkyl, halo 3-7 membered hetero cycloalkyl may optionally be further substituted by one or more substituents independently selected from hydrogen, hydroxy, C 1-6 Alkoxy;

[0102] R 3 Selected from hydrogen, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-6 Cycloalkyl, 3-7 membered hetero cycloalkyl, -S-C 1-6 Alkyl, C 3-6 Cycloalkyloxy, halo C 1-6 Alkyl, halo C 1-6 Alkoxy, halo C 3-6 Cycloalkyl, halo C 3-6 Cycloalkyloxy, halo 3-7 membered hetero cycloalkyl;

[0103] R 4 Selected from hydrogen, 6-10 membered aryl, benzo 5-6 membered hetero cycloalkyl, 5-6 membered heteroaryl, 9-10 membered heteroaryl, said 6-10 membered aryl, benzo 5-6 membered hetero cycloalkyl, 5-6 membered heteroaryl, 9-10 membered heteroaryl may optionally be substituted by one or more substituents independently selected from hydrogen, halogen, deuterium, hydroxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-7 membered hetero cycloalkyl, C 1-6 Alkoxy, -S-C 1-6 Alkyl, C 3-6 Cycloalkyloxy, halo C 1-6 Alkyl, halo C 2-6 Alkenyl, halo C 1-6 Alkoxy, -S-halo C 1-6 Alkyl, deuterated C 1-6 Alkoxy, -S-deuterated C 1-6 Alkyl, halo C 3-6 Cycloalkyl, halo C 3-6 Cycloalkyloxy, halo 3-7 membered hetero cycloalkyl, -NH halo C 1-6 Alkyl, -L 1 -L 2 -OR 7 、-L 1 -(C 2-6 Alkenylene)-OR 7 、-L 1 -L 2 -NR 8 R9 、 -CO-NR 8 R 9 、 -SO 2 -NR 8 R 9 、 -L 1 -L 2 -NHS(O)C 1-6 alkyl, L 1 -L 2 -R 10 is substituted by a substituent of;

[0104] L 1 is selected from a bond, O;

[0105] L 2 is selected from C 1-6 alkylene;

[0106] R 7 is selected from hydrogen, C 1-6 alkyl, halo C 1-6 alkyl;

[0107] R 8 、 R 9 are each independently selected from hydrogen, hydroxy, C 1-6 alkyl, 3-7 membered heterocycloalkyl;

[0108] R 10 is selected from C 3-6 cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl, -C(O)O C 1-6 alkyl, -COOH, -SO 2 C 1-6 alkyl or -C(O)NR 8 R 9 , wherein the 5-6 membered heteroaryl may optionally be further substituted by one or more substituents selected from hydrogen, halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy;

[0109] J 1 、 J 2 、 J 3 、 J 4 are each independently selected from NH, CO, C 1-6 alkylene, a bond, O or SO 2 ;

[0110] However, J 1 、 J 2 、 J 3 、 J 4 no more than 2 of them are NH, CO, C1-6 an alkylene group, a bond, O or SO 2 ;

[0111] J 1 , J 2 , J 3 , J 4 , not more than 2 of which are NH, CO, C 1-6 an alkylene group, a bond, O or SO 2 represents J 1 , J 2 , J 3 , J 4 , not more than 2 of which are NH, and J 1 , J 2 , J 3 , J 4 , not more than 2 of which are CO, and J 1 , J 2 , J 3 , J 4 , not more than 2 of which are C 1-6 an alkylene group, and J 1 , J 2 , J 3 , J 4 , not more than 2 of which are bonds, and J 1 , J 2 , J 3 , J 4 , not more than 2 of which are O, and J 1 , J 2 , J 3 , J 4 , not more than 2 of which are SO 2 .

[0112] In some embodiments, Formula II is the isomer represented by Formula II-YG:

[0113]

[0114] wherein R 1 , R 2 , R 3 , R 4 , is defined as in Formula I above.

[0115] In one embodiment of the present invention, the H on may optionally be further substituted by one or more substituents selected from hydroxyl, halogen, deuterium, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heteroalkyl, 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 Alkylene CONH 2 、-(NC 1-6 Alkyl)CONH 2 、-(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 is substituted by the substituent; the 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 Hydroxy、-C 1-6 Alkylene OR 7 、-C 1-6 Alkylene NR 8 R 9 、-C 1-6 Alkylene CONH 2 、-(NC 1-6 Alkyl)CONH 2 、-(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 may be optionally substituted by one or more substituents 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 of the substituents.

[0116] R 8 、R 9 、R 11 have the definitions as described above.

[0117] In one embodiment of the present invention, J 1 is selected from a bond, C 1-6Alkylene, NH, CO, SO 2 。

[0118] In one embodiment of the present invention, J 2 is selected from a bond, C 1-6 alkylene, CO, NH, O.

[0119] In one embodiment of the present invention, J 3 is selected from a bond, C 1-6 alkylene, CO, NH, O.

[0120] In one embodiment of the present invention, J 4 is selected from a bond, C 1-6 alkylene, NH, CO, O.

[0121] In one embodiment of the present invention, J 1 , J 2 , J 3 , J 4 no more than 2 of them are NH, CO, O, a bond or C 1-6 alkylene.

[0122] In one embodiment of the present invention, when J 1 is NH, J 2 is CO.

[0123] In one embodiment of the present invention, when J 1 is CO or SO 2 , J 2 is NH.

[0124] In one embodiment of the present invention, R 1 is selected from -CF 3 .

[0125] In one embodiment of the present invention, R 2 is selected from -CH 3 .

[0126] In one embodiment of the present invention, Formula II is selected from Formula IIa:

[0127]

[0128] Formula IIa is selected from Formula IIa-YG:

[0129]

[0130] In said Formula IIa and Formula IIa-YG, R 3 , R 4 , are as defined above.

[0131] In one embodiment of the present invention, R 3 is selected from -H, -CH 3 , -OCH 3 , halogen or -CH 2 F.

[0132] In one embodiment of the present invention, R 4 is selected from

[0133] In another embodiment of the present invention, is selected from

[0134] In another embodiment of the present invention, the H on the group NH may optionally be further substituted by one or more substituents selected from hydroxyl, halogen, deuterium, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 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 CONH 2 , -(NC 1-6 alkyl)CONH 2 , -(C═NR 11 )-NR 8 R 9 , -C 1-6 alkylene C 3-8 cycloalkyl, -C 1-6 alkylene 3- to 8-membered heterocycloalkyl, -C 1-6 alkylene 5- to 10-membered heteroaryl; the C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 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 CONH 2 , -(NC 1-6 alkyl)CONH 2 , -(C═NR11 )-NR 8 R 9 、-C 1-6 alkylene C 3-8 cycloalkyl, -C 1-6 alkylene 3- to 8-membered heterocycloalkyl, -C 1-6 alkylene 5- to 10-membered heteroaryl optionally substituted by one or more substituents independently selected from hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, halo-C 1-6 alkyl, C 3-8 cycloalkyl, 3- to 8-membered heterocycloalkyl, 5- to 10-membered heteroaryl, -OR 7 、-NR 8 R 9 and is substituted by substituents;

[0135] R 11 is selected from hydrogen, hydroxy or C 1-6 alkyl.

[0136] The present invention also provides a compound of structural formula III:

[0137]

[0138] its isomers, racemates, or pharmaceutically acceptable salts or prodrugs,

[0139] According to an embodiment of the present invention, in formula III, R 1 、R 2 、R 3 、R 5 、R 6 may be selected from those defined above.

[0140] According to an embodiment of the present invention, in formula III,

[0141] R 1 、R 2 are each independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, halo-C 3-6 cycloalkyl, halo-3- to 7-membered heterocycloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3- to 7-membered heterocycloalkyl, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, halo-C 3-6 cycloalkyl, halo-3- to 7-membered heterocycloalkyl may be further substituted by one or more substituents independently selected from hydrogen, hydroxy, C1-6 Substituted by a substituent of an alkoxy group;

[0142] R 3 Selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, -S-C 1-6 alkyl, C 3-6 cycloalkyloxy, halo-C 1-6 alkyl, halo-C 1-6 alkoxy, halo-C 3-6 cycloalkyl, halo-C 3-6 cycloalkyloxy, halo-3-7 membered heterocycloalkyl;

[0143] Further cyclized with the carbon atom to which they are attached to form a 5-10 membered heterocycloalkyl.

[0144] In one embodiment of the present invention, Selected from the group consisting of:

[0145]

[0146] The H of may be further substituted by one or more selected from hydroxyl, halogen, deuterium, C 1-6 alkyl, halo-C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 alkylidene hydroxyl, -C 1-6 alkylidene OR 7 、-C 1-6 alkylidene NR 8 R 9 、-C 1-6 alkylidene CONH 2 、-(NC 1-6 alkyl)CONH 2 、-(C=NR 11 )-NR 8 R 9 、-C 1-6 alkylidene C 3-8 cycloalkyl, -C 1-6 alkylidene 3-8 membered heterocycloalkyl, -C 1-6 alkylidene 5-10 membered heteroaryl; the C 1-6 alkyl, halo-C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6Alkylene hydroxy, -C 1-6 Alkylene OR 7 、-C 1-6 Alkylene NR 8 R 9 、-C 1-6 Alkylene CONH 2 、-(NC 1-6 Alkyl)CONH 2 、-(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 optionally substituted by one or more substituents independently selected from hydrogen, halogen, hydroxy, amino, C 1-6 Alkyl, halo C 1-6 Alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -OR 7 、-NR 8 R 9 ;

[0147] R 12 、R 13 、R 14 、R 15 、R 16 are each independently selected from hydrogen, deuterium, halogen, hydroxy, C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6 Alkoxy, -S-C 1-6 Alkyl, C 3-6 Cycloalkyloxy, halo C 1-6 Alkyl, halo C 2-6 Alkenyl, halo C 1-6 Alkoxy, -S-halo C 1-6 Alkyl, deutero C 1-6 Alkoxy, -S-deutero C 1-6 Alkyl, halo C 3-6 Cycloalkyl, halo C 3-6 Cycloalkyloxy, halo 3-7 membered heterocycloalkyl, -NH halo C 1-6 Alkyl, -L 1 -L 2 -OR 7 、-L 1 -(C 2-6 Alkenylene)-OR 7 、-L 1 -L2 -NR 8 R 9 、 -CO-NR 8 R 9 、 -SO 2 -NR 8 R 9 、 -L 1 -L 2 -NHS(O)C 1-6 alkyl or L 1 -L 2 -R 10 ;

[0148] Preferably, R 12 、 R 13 or R 15 、 R 16 can further cyclize with the carbon atom to which they are attached to form a 5- to 6-membered heteroalkyl ring;

[0149] L 1 is selected from a bond, O;

[0150] L 2 is selected from C 1-6 alkylene;

[0151] R 7 is selected from hydrogen, C 1-6 alkyl, halo C 1-6 alkyl;

[0152] R 8 、 R 9 are each independently selected from hydrogen, hydroxy, C 1-6 alkyl, 3- to 7-membered heteroalkyl;

[0153] R 10 is selected from C 3-6 cycloalkyl, 3- to 8-membered heteroalkyl, 5- to 6-membered heteroaryl, -C(O)O C 1-6 alkyl, -COOH, -SO 2 C 1-6 alkyl or -C(O)NR 8 R 9 , wherein the 5- to 6-membered heteroaryl may optionally be further substituted by one or more substituents selected from hydrogen, halogen, hydroxy, C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkoxy, halo C 1-6 alkoxy;

[0154] R 11 is selected from hydrogen, hydroxy or C 1-6 alkyl;

[0155] In one embodiment of the present invention, R 12 and R 16 are independently selected from hydrogen, deuterium, halogen, C 1-6 alkoxy, -S-C 1-6 alkyl, halo-C 1-6 alkoxy, -S-halo-C 1-6 alkyl, deuterio-C 1-6 alkoxy, -S-deuterio-C 1-6 alkyl, -NR 8 R 9 , -NH-halo-C 1-6 alkyl or -OC 1-6 alkyleneSO 2 C 1-6 alkyl.

[0156] In another embodiment of the present invention, R 13 and R 15 are independently selected from hydrogen or halogen.

[0157] In another embodiment of the present invention, R 12 is independently selected from hydrogen, deuterium, halogen, C 1-6 alkoxy, -S-C 1-6 alkyl, -OC 1-6 alkylene or C 3-6 cycloalkyl.

[0158] The formula III is selected from formula III-YG:

[0159]

[0160] wherein R 1 , R 2 , R 3 , R 5 , R 6 , R 12 , R 13 , R 14 , R 15 , R 16 are as defined in formula III above.

[0161] In another embodiment of the present invention, R 12 and R 16 are independently selected from hydrogen, deuterium, halogen, C 1-6 alkoxy, -S-C 1-6 alkyl, halo-C 1-6 alkoxy, -S-halo-C 1-6 alkyl, deuterio-C 1-6 alkoxy, -S-deuterio-C 1-6 alkyl, -NR 8 R 9, -NH halo C 1-6 alkyl or -OC 1-6 alkylene SO 2 C 1-6 alkyl.

[0162] In another embodiment of the present invention, R 13 , R 15 are independently selected from hydrogen or halogen.

[0163] In another embodiment of the present invention, R 12 is independently selected from hydrogen, deuterium, halogen, C 1-6 alkoxy, -S-C 1-6 alkyl, -OC 1-6 alkylene or C 3-6 cycloalkyl.

[0164] In another embodiment of the present invention, R 12 , R 13 or R 15 , R 16 may further cyclize with the carbon atom to which they are attached to form a 5- to 6-membered heteroalkyl ring.

[0165] In another embodiment of the present invention, the compound of formula III is selected from the compounds of formula IIIa as follows:

[0166]

[0167] The said formula III is selected from formula IIIa-YG:

[0168]

[0169] In the said 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.

[0170] According to an embodiment of the present invention,

[0171] J 1 , J 2 , J 3 , J 4 are independently selected from NH, CO, C 1-6 alkylene, bond, O or SO 2 ;

[0172] However, J 1 , J2 , J 3 , J 4 No more than 2 of them are NH, CO, C 1-6 alkylene, bond, O or SO 2 ;

[0173] In one embodiment of the present invention, The H on can optionally be further substituted by one or more substituents selected from hydroxyl, halogen, deuterium, C 1-6 alkyl, halo 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 CONH 2 , -(NC 1-6 alkyl) CONH 2 , -(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; the C 1-6 alkyl, halo 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 CONH 2 , -(NC 1-6 alkyl) CONH 2 , -(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 can be optionally substituted by one or more independently selected from hydrogen, halogen, hydroxyl, amino, C 1-6 alkyl, halo C1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -OR 7 , -NR 8 R 9 is substituted by a substituent;

[0174] R 11 is selected from hydrogen, hydroxy or C 1-6 alkyl;

[0175] R 1 , R 2 are each independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, halo C 1-6

[0176] alkyl, halo C 1-6 alkoxy, halo C 3-6 cycloalkyl, halo 3-7 membered heterocycloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, halo C 1-6 alkyl, halo C 1-6 alkoxy, halo C 3-6 cycloalkyl, halo 3-7 membered heterocycloalkyl may optionally be further substituted by one or more substituents independently selected from hydrogen, hydroxy, C 1-6 alkoxy;

[0177] R 3 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, -S-C 1-6 alkyl, C 3-6 cycloalkyloxy, halo C 1-6 alkyl, halo C 1-6 alkoxy, halo C 3-6 cycloalkyl, halo C 3-6 cycloalkyloxy, halo 3-7 membered heterocycloalkyl;

[0178] R 12 , R 13 , R 14 , R 15 , R 16 are each independently selected from hydrogen, halogen, deuterium, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, 3-7 membered heterocycloalkyl, C 1-6Alkoxy, -S-C 1-6 Alkyl, C 3-6 Cycloalkyloxy, halo-C 1-6 Alkyl, halo-C 2-6 Alkenyl, halo-C 1-6 Alkoxy, -S-halo-C 1-6 Alkyl, deuterated-C 1-6 Alkoxy, -S-deuterated-C 1-6 Alkyl, halo-C 3-6 Cycloalkyl, halo-C 3-6 Cycloalkyloxy, halo 3-7-membered heterocycloalkyl, -NH halo-C 1-6 Alkyl, -L 1 -L 2 -OR 7 、-L 1 -(C 2-6 Alkenylene)-OR 7 、-L 1 -L 2 -NR 8 R 9 、-CO-NR 8 R 9 、-SO 2 -NR 8 R 9 、-L 1 -L 2 -NHS(O)C 1-6 Alkyl or L 1 -L 2 -R 10 ;

[0179] Preferably, R 12 、R 13 or R 15 、R 16 can further cyclize with the carbon atom to which they are attached to form a 5-6-membered heterocycloalkyl;

[0180] L 1 is selected from a bond, O;

[0181] L 2 is selected from C 1-6 Alkylene;

[0182] R 7 is selected from hydrogen, C 1-6 Alkyl, halo-C 1-6 Alkyl;

[0183] R 8 、R 9 are each independently selected from hydrogen, hydroxy, C 1-6 Alkyl, 3-7-membered heterocycloalkyl;

[0184] R10 Selected from C 3-6 Cycloalkyl, 3- to 8-membered heteroalkyl, 5- to 6-membered heteroaryl, -C(O)O C 1-6 Alkyl, -COOH, -SO 2 C 1-6 Alkyl or -C(O)NR 8 R 9 , wherein the 5- to 6-membered heteroaryl may optionally be further substituted by one or more substituents selected from hydrogen, halogen, hydroxy, C 1-6 Alkyl, halo C 1-6 Alkyl, C 1-6 Alkoxy, halo C 1-6 Alkoxy;

[0185] In another embodiment of the present invention, in one embodiment of the present invention, J 1 Selected from a bond, C 1-6 Alkylene, NH, CO, SO 2 .

[0186] In one embodiment of the present invention, J 2 Selected from a bond, C 1-6 Alkylene, CO, NH, O.

[0187] In one embodiment of the present invention, J 3 Selected from a bond, C 1-6 Alkylene, CO, NH, O.

[0188] In one embodiment of the present invention, J 4 Selected from a bond, C 1-6 Alkylene, NH, CO, O.

[0189] In one embodiment of the present invention, J 1 , J 2 , J 3 , J 4 No more than 2 of them are NH, CO, O, a bond or C 1-6 Alkylene.

[0190] In one embodiment of the present invention, when J 1 is NH, J 2 is CO.

[0191] In one embodiment of the present invention, when J 1 is CO or SO 2 , J 2 is NH.

[0192] In another embodiment of the present invention, Selected from

[0193] In one embodiment of the present invention, the H on the group NH may further be substituted by one or more substituents selected from hydroxy, halogen, deuterium, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 alkylene hydroxy, -C 1-6 alkylene OR 7 、-C 1-6 alkylene NR 8 R 9 、-C 1-6 alkylene CONH 2 、-(NC 1-6 alkyl)CONH 2 、-(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; C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -C 1-6 alkylene hydroxy, -C 1-6 alkylene OR 7 、-C 1-6 alkylene NR 8 R 9 、-C 1-6 alkylene CONH 2 、-(NC 1-6 alkyl)CONH 2 、-(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 may be optionally substituted by one or more substituents independently selected from hydrogen, halogen, hydroxy, amino, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, 5-10 membered heteroaryl, -OR 7 、-NR 8 R9 is substituted by a substituent;

[0194] R 11 is selected from hydrogen, hydroxy or C 1-6 alkyl.

[0195] In one embodiment of the present invention, R 1 is selected from -CF 3 .

[0196] In one embodiment of the present invention, R 2 is selected from -CH 3 .

[0197] In one embodiment of the present invention, the compound of formula III is selected from the compounds of formula IIIb as follows:

[0198]

[0199] Formula IIIb is selected from formula IIIb-YG:

[0200]

[0201] In the said formula IIIb and formula IIIb-YG, R 3 , R 12 , R 13 , R 14 , R 15 , R 16 , are as defined above.

[0202] R 12 , R 13 , R 14 , R 15 , R 16 have the definitions as described in formula IIIa;

[0203] J 1 , J 2 , J 3 , J 4 have the definitions as described in formula IIIa;

[0204] R 3 has the definition as described in formula IIIa.

[0205] According to the compounds shown by the general formulas I, II, III (or the general formulas within their scope) described above, their isomers, racemates, or their pharmaceutically acceptable salts or prodrugs, wherein, the said compounds do not include

[0206] their isomers, racemates, or their pharmaceutically acceptable salts or prodrugs.

[0207] In some embodiments of the present invention, selected from the group consisting of:

[0208] when, the H on the group NH is further selected from H, hydroxyl, halogen, deuterium, C 1-6 alkyl, halo 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)CONH 2 、-(NC 1-6 alkyl)CONH 2 、-(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; the C 1-6 alkyl, halo 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 CONH 2 、-(NC 1-6 alkyl)CONH 2 、-(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 may be optionally substituted by one or more independently selected from hydrogen, halogen, hydroxyl, amino, C 1-6 alkyl, halo C 1-6 alkyl, C 3-8Cycloalkyl, 3- to 8-membered heteroalkyl, 5- to 10-membered heteroaryl, -OR 7 、-NR 8 R 9 and is substituted with a substituent;

[0209] Preferably, it is further substituted with a group represented by the following formula:

[0210] -C 1-6 alkyleneNR 8 R 9 、

[0211] -C 1-6 alkyleneNR 8 R 9 optionally substituted with one or more substituents independently selected from hydrogen, C 1-6 alkyl, -NR 8 R 9 ;

[0212] L 3 is selected from a bond or C 1-6 alkylene;

[0213] A is selected from C 3-8 cycloalkyl;

[0214] C 3-8 The cycloalkyl can be a 3- to 8-membered monocyclic, spiro or bridged cycloalkane;

[0215] R a1 、R a2 are each independently selected from H, C 1-6 alkyl, halo C 1-6 alkyl or hydroxy-substituted C 1-6 alkyl;

[0216] R a3 、R a4 are each independently selected from H or C 1-6 alkyl;

[0217] L 4 is selected from a bond or C 1-6 alkylene;

[0218] B is selected from 3- to 10-membered N-containing heteroalkyl;

[0219] The 3- to 10-membered heteroalkyl is a 3- to 10-membered N-containing heteroalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S;

[0220] The 3- to 10-membered N-containing heteroalkyl can be a monocyclic, spiro or bridged N-containing heteroalkyl;

[0221] R b1 、R b2Independently selected from H, C 1-6 alkyl, halo C 1-6 alkyl, hydroxy-substituted C 1-6 alkyl;

[0222] R b3 Selected from H, C 1-6 alkyl.

[0223] In some embodiments of the present invention, Selected from the group consisting of:

[0224] The H on the group NH is more preferably substituted by a group represented by the following formula:

[0225] -C 1-6 alkylene NR 8 R 9 ,

[0226] wherein, -C 1-6 alkylene NR 8 R 9 Optionally substituted by one or more substituents independently selected from hydrogen, C 1-6 alkyl, -NR 8 R 9 ;

[0227] u, v, r, s, b, p, q, m, n are independently selected from 0, 1, 2 or 3;

[0228] w is selected from 1 to 6, preferably selected from 1 or 2;

[0229] Preferably, R a3 can form a ring with the carbon atom on ;

[0230] Preferably, the cycloalkyl or N-containing heterocycloalkyl of

[0231] L 3 is selected from a bond or C 1-6 alkylene;

[0232] R a1 , R a2 are independently selected from H, C 1-6 alkyl, halo C 1-6 alkyl or hydroxy-substituted C 1-6 alkyl;

[0233] R a3 , R a4 are independently selected from H or C1-6 Alkyl;

[0234] L 4 Selected from a bond or C 1-6 Alkylene;

[0235] R b1 、R b2 Are each independently selected from H, C 1-6 Alkyl, halo C 1-6 Alkyl, hydroxy-substituted C 1-6 Alkyl;

[0236] R b3 Is selected from H, C 1-6 Alkyl.

[0237] For the compounds of Formula I, Formula II, and Formula III described above according to the present invention, their isomers, racemates, or their pharmaceutically acceptable salts or prodrugs, wherein the compounds are selected from:

[0238]

[0239]

[0240]

[0241]

[0242]

[0243] In some embodiments, for the compounds of Formula I, Formula II, and Formula III described above according to the present invention, their isomers, racemates, or their pharmaceutically acceptable salts or prodrugs, wherein the compounds are selected from:

[0244]

[0245]

[0246]

[0247]

[0248] In some embodiments, for the compounds of Formula I, Formula II, and Formula III described above according to the present invention, their isomers, racemates, or their pharmaceutically acceptable salts or prodrugs, wherein the compounds are selected from:

[0249]

[0250]

[0251]

[0252]

[0253]

[0254]

[0255] Term Definition:

[0256] In the present invention, the term "C 1-6 alkyl" refers to a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, neopentyl, pivalyl, or similar groups.

[0257] In the present invention, the term "C 1-6 alkylene" refers to a divalent group formed by removing another hydrogen of C 1-6 alkyl, and may be substituted or unsubstituted. In some embodiments, C 1-4 alkylene, C 2-4 alkylene, and C 1-3 alkylene are preferred. The unsubstituted alkylene includes but is not limited to: methylene, ethylene, propylene, butylene, pentylene, hexylene, and the like.

[0258] In the present invention, the term "C 1-6 alkoxy" refers to a straight-chain or branched-chain alkoxy group having 1 to 6 carbon atoms, including non-limitingly methoxy, ethoxy, propoxy, isopropoxy, and butoxy, etc. Preferably C 1-4 alkoxy.

[0259] In the present invention, the term "C 2-6 alkenyl" refers to a straight-chain or branched-chain alkenyl group having 2 to 6 carbon atoms and containing one double bond, including non-limitingly vinyl, propenyl, butenyl, isobutenyl, pentenyl, and hexenyl, etc.

[0260] 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. C 3-8 cycloalkyl can be a 3- to 8-membered monocyclic, spiro, or bridged cycloalkane.

[0261] 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, C 3-6 cycloalkyl can be a 3- to 6-membered monocyclic, spiro, or bridged cycloalkane, including non-limitingly cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0262] The term "heterocycloalkyl" should be understood as a non-aromatic cyclic group containing heteroatoms, which can be 5- to 10-membered, 3- to 7-membered, 3- to 8-membered, 5- to 6-membered heterocycloalkyl, etc. The heteroatoms in the "heterocycloalkyl" can be one, two or more than two heteroatoms selected from N, O, S. The term "5- to 10-membered heterocycloalkyl" is a 5- to 10-membered (5, 6, 7, 8, 9, 10-membered) heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O, S, and can be monocyclic, spirocyclic, bridged cyclic. Preferably, the 5- to 10-membered heterocyclic group contains one or more groups selected from NH, CO, C 1-6 alkylene, O or SO 2 groups. The term "3- to 8-membered heterocycloalkyl" is a 3- to 8-membered heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O, S, and can be monocyclic, spirocyclic, bridged cyclic, including but not limited to 3- to 7-membered heterocycloalkyl, Exemplarily, the "3- to 7-membered heterocycloalkyl" is a 3- to 7-membered (such as 3, 4, 5, 6, 7-membered) heterocyclic group containing 1, 2 or 3 heteroatoms selected from N, O, S, and can be monocyclic, spirocyclic, bridged cyclic. The term "heterocycloalkyl" includes but is not limited to the following groups:

[0263] Preferably, the heterocycloalkyl is a nitrogen-containing heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O, S.

[0264] In the present invention, the term "halogen" includes fluorine, chlorine, bromine and iodine.

[0265] In the present invention, the term "halogenated" means being substituted by halogen. Halogenated C 1-6 alkyl, halogenated C 2-6 alkenyl, halogenated C 1-6 alkoxy, halogenated C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyloxy, halogenated 3- to 7-membered heterocycloalkyl means that one or more hydrogen atoms in C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, 3- to 7-membered heterocycloalkyl are replaced by halogen groups.

[0266] In the present invention, the term "oxy" is O.

[0267] In the present invention, the term "bond" is -.

[0268] In the present invention, used to depict a chemical bond, and the chemical bond is the point where a moiety or substituent is connected to the core structure or backbone structure.

[0269] In the present invention, the terms "aromatic ring" or "aryl" have the same meaning, preferably "C 6-10 aryl". The term "C 6-10 aryl" or "6-10 membered aryl" refers to an aromatic cyclic group having 6-10 carbon atoms without heteroatoms in the ring, such as phenyl, naphthyl, etc.

[0270] In the present invention, the terms "aromatic heterocycle" or "heteroaryl" have the same meaning, referring to a heteroaromatic group containing one or more 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 3-10 (3, 4, 5, 6, 7, 8, 9, 10) carbon atoms. "Heteroaryl" may 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. Heteroaryl may be optionally substituted or unsubstituted.

[0271] In the present invention, the term "optionally substituted by one or more" or "optionally further substituted by one or more" means that one or more hydrogen atoms on a specific group are substituted by specific substituents. The specific substituents are the substituents described correspondingly in the foregoing, or the substituents appearing in each embodiment. Unless otherwise specified, a substituted group may have a substituent selected from a specific group at any substitutable site of the group, and the substituents may be the same or different at each position. Among them, "more than one" includes two or more, for example, 2, 3, 4, 5, 6.

[0272] In the present invention, the term "1-6" means 1, 2, 3, 4, 5 or 6. Other similar terms each independently have a similar meaning. The term "more than one" means 2-6, such as 2, 3, 4, 5 or 6.

[0273] In the present invention, the term "substituted" should be considered to include multiple degrees of substitution of the indicated substituents. When multiple substituent moieties are disclosed or claimed, the substituted compound may be independently singly or multiply substituted by one or more of the disclosed or claimed substituent moieties. Independently substituted means that (two or more) substituents may be the same or different.

[0274] The compounds of the present invention may contain one or more asymmetric centers, and thus may exist in the form of isomers, racemates, etc., wherein, racemates include racemic bodies 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. Those skilled in the art can understand that the isomers cover optical isomers (or stereoisomers)

[0275] "Stereoisomers" refer to compounds with the same chemical structure but different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereoisomers, conformational isomers (rotational isomers), geometric isomers (cis / trans isomers), atropisomers, and so on.

[0276] "Enantiomers" refer to two isomers of a compound that are non-superimposable but mirror images of each other.

[0277] "Diastereoisomers" refer to stereoisomers that have two or more chiral centers and whose molecules are not mirror images of each other. Diastereoisomers have different physical properties, such as melting point, boiling point, spectroscopic properties, and reactivity. Mixtures of diastereoisomers can be separated by high-resolution analytical operations such as electrophoresis and chromatography, e.g., HPLC.

[0278] Any asymmetric atom (e.g., carbon, etc.) of the compounds of the present invention can exist in racemic or enantiomerically enriched form, e.g., in the (R)-, (S)-, or (R,S)-configurational form. 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.

[0279] The independent synthesis of optical isomers and diastereoisomers or their chromatographic separation can be achieved by appropriate modification of the methods disclosed herein, as known in the art. Their absolute stereochemistry can be determined by X-ray crystallography of the crystalline product or crystalline intermediate, which, if necessary, is derivatized with a reagent containing an asymmetric center of known absolute configuration or sufficiently heavy atoms for absolute assignment.

[0280] If desired, the racemic mixture of the compound can be separated to isolate the individual enantiomers. The separation can be carried out by methods well known in the art, e.g., by coupling the racemic mixture of the compound to an enantiomerically pure compound to form a mixture of diastereoisomers, followed by separation of the individual diastereoisomers by standard methods (e.g., fractional crystallization or chromatography).

[0281] The racemic mixture of the compound can also be directly separated by chromatographic methods using a chiral stationary phase, which is 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 by methods well known in the art.

[0282] The term "prodrug" represents a structure that can be converted in vivo into a compound of formula (I). Such conversion is affected by hydrolysis of the prodrug in the blood or enzymatic conversion in the blood or tissues into the parent structure.

[0283] In the compounds of general formula I, II or III, the atoms may exhibit their natural isotopic abundances, or one or more atoms may be artificially enriched with specific isotopes having the same atomic number but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.

[0284] The present invention is intended to include all suitable isotopic variants of the compounds of structural formula I, II or III. For example, different isotopic forms of hydrogen (H) include protium (1H), deuterium (2H) and tritium (3H).

[0285] 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 similar to those described in the protocols and examples herein, using appropriate isotopically enriched reagents and / or intermediates, without undue experimentation.

[0286] In yet another aspect, the present invention provides a pharmaceutical composition comprising a compound, an isomer, a racemate, or a pharmaceutically acceptable salt or prodrug thereof, as described in any one of the above, and a pharmaceutically acceptable carrier.

[0287] In yet 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 in any one of the above, in the manufacture of a medicament for treating a condition, disorder or disease responsive to inhibition of Nav1.8 channel activity in a mammalian subject 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 a complete and / or partial reduction of channel function, such as a reduction of at least 10%, in some embodiments at least 20%, 30%, 50%, 75%, 95%, 98% and up to and including 100%.

[0288] More specifically, the compounds of the present invention have an IC 50 value or inhibitory activity against the Nav1.8 channel of less than 10 μM, more preferably less than 1 μM, more preferably less than 50 nM, more preferably less than 10 nM.

[0289] In yet 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 in any one of the above, in the manufacture of a medicament for treating, preventing or controlling pain conditions, cough disorders, acute pruritus disorders or chronic pruritus disorders.

[0290] In one embodiment of the present invention, the medical conditions include 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 arrhythmia, or methods for reducing their severity.

[0291] In one embodiment of the present invention, the pain includes neuropathic pain, musculoskeletal pain (preferably osteoarthritis pain), acute pain (preferably acute postoperative pain), postoperative pain or visceral pain.

[0292] In one embodiment of the present invention, the neuropathic pain includes postherpetic neuralgia, small fiber neuropathy, idiopathic small fiber neuropathy or diabetic neuropathy, preferably one or more of diabetic peripheral neuropathy.

[0293] In one embodiment of the present invention, the postoperative pain includes one or more of pain after bunionectomy, abdominoplasty pain or hernia repair pain.

[0294] The present invention also discloses administering one or more additional therapeutic agents to the subject simultaneously, before or after treating with a compound, its isomers, racemates, or its pharmaceutically acceptable salts or pharmaceutical compositions.

[0295] Another aspect of the present invention discloses the compound, its isomers, racemates, or its pharmaceutically acceptable salts or prodrugs as described in any one of the above; the use of the pharmaceutical composition as described in any one of the above as a medicine.

[0296] Beneficial effects

[0297] The present invention provides a Nav1.8 selective inhibitor with a novel structure, excellent pharmacokinetic properties, good pharmacodynamic effects and drug-likeness, which can be used for the treatment, prevention or control of Nav1.8-related pain conditions, cough conditions, acute itching conditions or chronic itching conditions, and has significant clinical application value. Description of the drawings

[0298] Figure 1 Schematic diagram of the voltage stimulation protocol for whole-cell patch clamp recording of TTX-R current in Test Example 2. Detailed implementation manners

[0299] The following further illustrates the present invention with reference to 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 the present invention claimed.

[0300] 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.

[0301] Experimental materials and analytical instruments:

[0302] The thin layer chromatography (TLC) plate is of the HSGF-254 type (thickness 0.15 - 0.2 mm, produced by Yantai Chemical Industry Experiment Factory); the silica gel for column chromatography is commercial silica gel of 200 - 300 mesh produced by Qingdao Ocean Chemical Factory;

[0303] 1 1H-NMR was recorded using a Bruker Avance III-400 nuclear magnetic resonance spectrometer, with tetramethylsilane (TMS) as the internal standard; the chemical shift is (ppm, δ:), and the proton coupling is labeled as singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m);

[0304] Low-resolution mass spectrometry was recorded using an Agilent 6110 mass spectrometer.

[0305] Abbreviations and notes:

[0306] DMF: N,N-dimethylformamide; DMSO: dimethyl sulfoxide; psi: pounds per square inch; DIPEA: N,N-diisopropylethylamine; HATU: 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; CDI: N,N′-carbonyldiimidazole; MTBE: methyl tert-butyl ether; DIBAL-H: diisobutylaluminum hydride; DMAP: 4-dimethylaminopyridine; THF: tetrahydrofuran; DPPF: 1,1-bis(diphenylphosphino)ferrocene; NMI: N-methylimidazole; TCFH: tetramethylchlorourea hexafluorophosphate; HCl: hydrochloric acid; EA: ethyl acetate; TEA: triethanolamine; TMSOTf: trimethylsilyl trifluoromethanesulfonate; LDA: lithium diisopropylamide; i-PrMgBr: isopropylmagnesium chloride; LiCl: lithium chloride.

[0307] Example 1: Preparation of Compound P-1

[0308] The synthetic route of Compound P-1 is as follows:

[0309]

[0310] In this synthetic route, -OTf represents

[0311] Step 1: Preparation of ethyl 2-diazo-3-oxopentanoate

[0312] At 0 °C, ethyl propionylacetate (20.00 g, 138.7 mmol) and triethylamine (15.40 g, 152.6 mmol) were successively added to acetonitrile for activation, and then p-acetamidobenzenesulfonyl azide (34.90 g, 141.5 mmol) was slowly added in batches. The reaction was warmed to room temperature and stirred for 1 hour. After the reaction was completed, it was washed with n-hexane:ethyl ether = 1:1, filtered by suction, and the filtrate was concentrated and mixed with samples, and purified by column chromatography to obtain 20.50 g of ethyl 2-diazo-3-oxo-pentanoate as a yellow oil, with a yield of 86.8%. MS m / z calculated value: 170.06; experimental value: 171.1 [M+H] + 。

[0313] Step 2: Preparation of ethyl 2-diazo-3-(tert-butyldimethylsilyloxy)-pent-3-enoate

[0314] At -25 °C, triethylamine (8.94 g, 88.1 mmol) was added to a dichloromethane solution (200 mL) of ethyl 2-diazo-3-oxo-pentanoate (10.00 g, 58.8 mmol). 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 about 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 and concentrating in vacuo, 15.90 g of crude ethyl 2-diazo-3-(tert-butyldimethylsilyloxy)-pent-3-enoate as a red oil was obtained, with a yield of 95.4%. MS m / z calculated value: 284.15; experimental value: 285.2 [M+H] + 。

[0315] Step 3: Preparation of ethyl 2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxo-hexanoate

[0316] In a -78 °C cryomixer, TiCl was slowly added 4(14.1 g, 74.34 mmol) was added dropwise to a dichloromethane solution (150 mL) of 1,1,1-trifluoropropan-2-one (11.12 g, 99.0 mmol). After the addition was completed, stirring was continued for about 30 minutes, and then ethyl 2-diazo-3-tert-butyldimethylsilyloxy-pent-3-enoate (12.05 g, 49.5 mmol) was added dropwise to the solution. The reaction was allowed to cool to room temperature naturally and was carefully quenched with water. Then, the mixture was extracted with dichloromethane 2 - 3 times (200 mL). After combining the organic phases, the mixture was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. After purification by column chromatography, 8.50 g of ethyl 2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxo-hexanoate as a yellow oil was obtained, with a yield of 61.2%. MS m / z calculated value: 282.08; experimental value: 283.1 [M+H] + 。

[0317] Step 4: Preparation of ethyl 4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0318] Rhodium(II) acetate (0.12 g, 0.2 mmol) was added to a 500 mL two-necked flask. After purging with nitrogen 2 - 3 times, an appropriate amount of toluene solution (50 mL) was added, and the reaction system was stirred under reflux for about 30 minutes. Then, 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 slowly added, and the reaction was continued to be heated under reflux for 1 hour. The reaction was monitored by TLC until completion. After cooling to room temperature, the mixture was concentrated in vacuo to obtain 2.43 g of crude ethyl 4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate as a green oil, with a yield of 54.4%. MS m / z calculated value: 254.07; experimental value: 255.1 [M+H] + 。

[0319] Step 5: Preparation of ethyl 4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyloxy))-4,5-dihydrofuran-2-carboxylate

[0320] At 0 °C, sodium hydride (0.43 g, 10.8 mmol) was added to a dichloromethane solution of ethyl 4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (2.34 g, 9.0 mmol), and the mixture was stirred for 30 minutes while maintaining the temperature. Subsequently, trifluoromethanesulfonic anhydride (2.52 g, 9.0 mmol) was added to the reaction mixture. The reaction was allowed to proceed at room temperature until completion. The reaction was quenched with an ice-water bath, and the reaction system was extracted with dichloromethane solution. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain 3.11 g of crude ethyl 4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyloxy)-4,5-dihydrofuran-2-carboxylate as a yellow oil, with a yield of 88.7%. MS m / z calculated value: 386.02; experimental value: 387.0 [M+H] + 。

[0321] Step 6: Preparation of ethyl 3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate

[0322] Under nitrogen atmosphere, (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 a reaction flask. After purging with nitrogen, 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, and 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 then washed with saturated brine solution and concentrated in vacuo. Purification by column chromatography gave 0.85 g of ethyl 3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate as a transparent oil, with a yield of 43.5%. MS m / z calculated value: 380.10; experimental value: 381.1 [M+H] + 。Step 7: Preparation of ethyl 3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0323] To a high-pressure reactor containing ethyl 3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (0.50 g, 1.3 mmol), ethanol (20 mL), palladium / carbon (10% wt, 0.14 g, 1.3 mmol), and palladium hydroxide / carbon (20% wt, 0.22 g, 1.5 mmol) were added respectively. After degassing the mixture, it was pressurized to 36 psi and reacted overnight at 80 °C. The reaction mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo to obtain 0.48 g of ethyl 3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate as a white powder, with a yield of 95.2%. MS m / z calculated value: 382.12; experimental value: 382.2 [M+H] + .

[0324] Step 8: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

[0325] 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 sodium hydroxide (2 M) and 20 mL of methanol were added, and the mixture was heated to 60 °C and monitored by TLC until the reaction was complete. The reaction system was partitioned between ethyl acetate and 1 M hydrochloric acid, the layers were separated and the organic layer was combined and concentrated in vacuo to obtain 0.09 g of 3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid as a transparent oil, with a yield of 84.4%. MS m / z calculated value: 354.08; experimental value: 355.1 [M+H] + .

[0326] Step 9: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl chloride

[0327] Under ice bath conditions, 3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (0.09 g, 0.2 mmol) was dissolved in dichloromethane solution (20 mL) in a 100 mL flask, a catalytic amount of DMF (3 - 4 drops) was added, and then oxalyl chloride (0.06 g, 0.5 mmol) was 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 TLC until it was complete and concentrated in vacuo to obtain 0.09 g of the crude product as a yellow powder, with a yield of 98.0%. MS m / z calculated value: 372.05; experimental value: 373.1 [M+H]+ 。Step 10: Preparation of 3-(3,4-difluoro-2-methoxy)-4,5-dimethyl-N-(2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0328] Under ice bath 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 respectively added to a 100 mL flask. Subsequently, using a constant pressure dropping funnel, 3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonyl chloride (0.93 g, 0.2 mmol) was slowly added to the mixture. TLC was used to monitor the reaction until completion. The reaction was quenched by adding water, and the layers were separated. 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 obtain 0.28 g of a white solid compound with a yield of 65.4%.

[0329] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.00 (s, 1H), 9.48 (s, 1H), 7.08–7.03 (m, 2H), 6.98 (d, J = 8.1 Hz, 1H), 6.94 (d, J = 2.0 Hz, 1H), 6.74 (m, 1H), 4.82 (d, J = 9.0 Hz, 1H), 3.98 (d, J = 2.0 Hz, 3H), 3.84 (m, 1H), 3.19 (m, 1H), 2.75 (t, J = 7.5 Hz, 2H), 2.37 (m, 2H), 1.41 (s, 3H), 0.93 (d, J = 6.7 Hz, 3H).

[0330] Example 2: Preparation of Compound P-2

[0331]

[0332] This preparation method is similar to that of Example 1, except that: 7-amino-3,4-dihydro-1H-quinolin-2-one in step 10) was replaced with an equimolar amount of 5-aminoisoindolin-1-one to obtain a white solid compound P-2 with a yield of 54.5%.

[0333] 1 H NMR (400 MHz, DMSO-d 6)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).

[0334] Example 3: Preparation of Compound P-3

[0335]

[0336] This 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%.

[0337] 1 H NMR(400MHz,DMSO-d 6 )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).

[0338] Example 4: Preparation of Compound P-4

[0339]

[0340] This 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 7-aminoquinazoline-2,4(1H,3H)-dione to obtain a white solid compound P-4 with a yield of 69.4%.

[0341] 1 H NMR(400MHz,DMSO-d 6)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).

[0342] Example 5: Preparation of Compound P-5

[0343]

[0344] This 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 6-aminosaccharin to obtain white powdery compound P-5 with a yield of 37.8%.

[0345] 1 H NMR(400MHz,DMSO-d 6 )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).

[0346] Example 6: Preparation of Compound P-6

[0347]

[0348] This 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 6-amino-2,3-dihydrophtalazine-1,4-dione to obtain white compound P-6 with a yield of 43.5%.

[0349] 1 H NMR(400MHz,DMSO-d 6)δ 11.90 (d, J = 48.7 Hz, 1H), 7.17 (d, J = 7.4 Hz, 2H), 7.10–6.95 (m, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.51–6.26 (m, 3H), 5.28 (m, 1H), 4.07 (d, J = 11.7 Hz, 1H), 4.03 (d, J = 7.5 Hz, 3H), 3.14 (m, 1H), 1.47 (d, J = 4.7 Hz, 3H), 1.02 (d, J = 6.4 Hz, 3H).

[0350] Example 7: Preparation of Compound P-7

[0351]

[0352] This 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%.

[0353] 1 H NMR (400 MHz, DMSO-d 6 )δ 11.58 (s, 1H), 10.16 (s, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.43 (d, J = 1.9 Hz, 1H), 7.08–7.03 (m, 3H), 4.91 (d, J = 9.0 Hz, 1H), 4.01 (d, J = 2.2 Hz, 3H), 3.90 (m, 1H), 3.22 (m, 1H), 1.44 (s, 3H), 0.98 (d, J = 6.8 Hz, 3H).

[0354] Example 8: Preparation of Compound P-8

[0355] The synthetic route of compound P8 is as follows:

[0356]

[0357] Step 1: Preparation of ethyl 3-(4-fluorobenzofuran-7-yl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate

[0358] (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 successively added to a 250 mL reaction tube. 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 h. TLC monitoring showed that the raw materials had completely reacted. After cooling to room temperature, it 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 a white solid compound with a yield of 85.2%. Calculated MS m / z: 372.09; found: 373.1 [M+H] + 。

[0359] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.07 (d, J = 2.3 Hz, 1H), 7.35 (dd, J = 8.4, 5.3 Hz, 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 = 7.2 Hz, 3H), 0.86 (t, J = 7.1 Hz, 3H).

[0360] Step 2: Preparation of ethyl 3-(4-fluoro-2,3-dihydrobenzofuran-7-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0361] 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 a high-pressure reactor and dissolved in absolute ethanol. Then palladium / carbon (10% wt, 8.62 g, 81.4 mmol) and palladium hydroxide / carbon (20% wt, 5.75 g, 40.5 mmol) were added successively. After gas displacement three times, hydrogen was charged to a pressure of 50 psi. The mixture was heated to 80 °C and stirred for 16 h. After the mixture was cooled to room temperature, the reactor was opened and TLC monitoring showed that the raw materials had completely reacted. It was filtered under reduced pressure through diatomaceous earth filter aid, the filter cake was rinsed with absolute ethanol, and the filtrate was concentrated under reduced pressure to obtain 2.98 g of a white solid compound with a yield of 96.6%. Calculated MS m / z: 376.12; found: 377.1 [M+H] + 。

[0362] Step 3: Preparation of 3-(4-fluoro-2,3-dihydrobenzofuran-7-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

[0363] Dissolve ethyl 3-(4-fluoro-2,3-dihydrobenzofuran-7-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (2.90 g, 7.7 mmol) in methanol (100 mL), add dropwise an aqueous solution (50 mL) of sodium hydroxide (1.85 g, 46.3 mmol), and stir at 60 °C for 8 hours. Monitor the reaction by TLC until the raw materials are completely reacted. Adjust the pH to 1 - 2 with dilute hydrochloric acid, extract the reaction system with ethyl acetate (200 mL) 2 - 3 times. Then wash the combined organic phases with saturated brine (200 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by column chromatography to obtain 2.39 g of a pale yellow oil, with a yield of 89.4%. MS m / z calculated value: 348.09; experimental value: 349.1 [M + H] + 。

[0364] 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

[0365] Add oxalyl chloride (0.14 g, 1.1 mmol) 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 mmol) and DMF (3.5 μL, 0.04 mmol) in dichloromethane (20 mL) under stirring at 0 °C. After the addition, transfer the reaction to room temperature, stir for 1 hour and then concentrate under reduced pressure. Dissolve the obtained product in dichloromethane (20 mL) and add it dropwise via a dropping funnel to a solution of 5-aminoisoisoindolin-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) under stirring at -10 °C. Monitor the reaction by TLC until the raw materials are completely reacted. Dilute the mixture in water (100 mL), separate the layers and further extract the aqueous phase with dichloromethane (50 mL). After collecting the organic phase, wash it twice with saturated brine (50 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 0.19 g of a white solid compound, with a yield of 68.3%.

[0366] 1 H NMR(400MHz,DMSO-d 6)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),3.12(q,J=8.2Hz,2H),2.00(d,J=8.0Hz,1H),1.38(s,3H),0.94(d,J=6.7Hz,3H).

[0367] Example 9: Preparation of Compound P-9

[0368]

[0369] This preparation method is similar to Example 8, except that: 5-aminoisatin-1-one in step 4) is replaced with an equimolar amount of 5-aminoisatin-1,3-dione to obtain a white solid compound P-9 with a yield of 58.5%.

[0370] 1 H NMR(400MHz,DMSO-d 6 )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).

[0371] Example 10: Preparation of Compound P-10

[0372]

[0373] This preparation method is similar to Example 8, except that: 5-aminoisatin-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%.

[0374] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.12–11.09 (m, 1H), 10.98 (d, J = 1.7 Hz, 1H), 9.90 (s, 1H), 7.71 (d, J = 8.6 Hz, 1H), 7.44 (d, J = 1.9 Hz, 1H), 7.02–6.93 (m, 2H), 6.53 (t, J = 8.6 Hz, 1H), 4.84 (d, J = 9.0 Hz, 1H), 4.65–4.52 (m, 2H), 3.72 (dd, J = 12.5, 9.1 Hz, 1H), 3.24 (dd, J = 12.6, 6.7 Hz, 1H), 3.20–3.08 (m, 2H), 1.38 (s, 3H), 0.93 (d, J = 6.7 Hz, 3H).

[0375] Example 11: Preparation of Compound P-11

[0376] The synthetic route of Compound P-11 is as follows:

[0377]

[0378] Step 1: Preparation of Ethyl 3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate

[0379] Add ethyl 4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)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) into a 100 mL reaction tube. Then add potassium phosphate trihydrate (2.00 g, 7.8 mmol) and tetrakis(triphenylphosphine)palladium (0.15 g, 0.1 mmol). After adding the materials, replace the air with argon three times, and then add 30 mL of toluene solution with a syringe. Heat the mixture to 100 °C and react for 5 hours. Monitor the reaction by TLC until the raw materials are completely reacted. After cooling to room temperature, filter the system by suction, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography to obtain 0.76 g of pale yellow oil, with a yield of 77.2%. MS m / z calculated value: 378.11; experimental value: 379.1 [M + H] + .

[0380] Step 2: Preparation of Ethyl 3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0381] 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 to a high-pressure reactor. Then, 50 mL of methanol was added. After replacing the hydrogen three times, the high-pressure reactor was charged with hydrogen again to 50 psi. The high-pressure reactor was heated to 80 °C and reacted for 24 h. TLC was used to monitor the complete reaction of the raw materials. The system was cooled to room temperature, filtered through diatomaceous earth by suction, and the obtained filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain 0.66 g of a pale yellow oil, with a yield of 88.2%. Calculated MS m / z: 380.12; Experimental value: 381.0 [M+H] + 。

[0382] Step 3: Preparation of 3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

[0383] Ethyl 3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-tetrahydrofuran-2-carboxylate (0.65 g, 2.0 mmol) was added to a 100 mL round-bottom flask. Then, 15 mL of methanol and 5 mL of sodium hydroxide solution (2 M) were added successively. The obtained solution was heated to 60 °C and reacted for 3 h. TLC was used to monitor the complete reaction of the raw materials. The mixture was cooled to room temperature, and the pH was adjusted to 4 with dilute hydrochloric acid (2 M). Then, the system was transferred to a separatory funnel with ethyl acetate (500 mL) and washed three times with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.58 g of the target pale yellow oil, with a yield of 79.4%. Calculated MS m / z: 366.11; Experimental value: 367.1 [M+H] + 。

[0384] 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

[0385] 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) were added to a single-necked flask containing 100 mL of DMF solvent. Then, HATU (0.20 g, 1.1 mmol) and DIPEA (0.37 g, 2.2 mmol) were added. After the addition was complete, the reaction was carried out at room temperature for 12 h. TLC was used to monitor the complete reaction of the starting materials. The reaction system was transferred to a separatory funnel with ethyl acetate (500 mL), washed three times with saturated brine (200 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 0.13 g of a off-white solid with a yield of 49.4%.

[0386] 1 H NMR(400MHz,DMSO-d 6 )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).

[0387] Example 12: Preparation of Compound P-12

[0388]

[0389] This preparation method is similar to Example 11, except that 7-aminoquinazoline-2,4(1H,3H)-dione in step 4) was replaced with an equimolar amount of 4-aminophthalimide to obtain Compound P-12 as a white solid with a yield of 58.5%.

[0390] 1 H NMR(400MHz,DMSO-d 6)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).

[0391] Example 13: Preparation of Compound P-13

[0392] The synthetic route of Compound P-13 is as follows:

[0393]

[0394] Step 1: Preparation of Ethyl 3-(4-fluoro-2-nitrophenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate

[0395] Add ethyl 4,5-dimethyl-5-(trifluoromethyl)-3-((trifluoromethylsulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate (0.92 g, 2.5 mmol), tetrakis(triphenylphosphine)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) into a 100 mL reaction tube. After adding the materials, replace the air with nitrogen three times. Add toluene solution (50 mL), and heat the resulting solution to 100 °C and react overnight. Monitor the reaction of the raw materials by TLC until it is complete. After filtration, concentrate the filtrate under reduced pressure. The residue is purified by column chromatography to obtain 0.59 g of a pale yellow oil, with a yield of 65.4%. Calculated MS m / z: 363.07; Experimental value: 364.1 [M+H] + 。

[0396] Step 2: Preparation of 3-(4-fluoro-2-nitrophenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylic acid

[0397] 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 to a 250 mL single-necked round-bottomed flask 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 of the starting materials was monitored by TLC and found to be complete. The system was transferred to a 500 mL beaker, and ethyl acetate (100 mL) was added. The reaction mixture was acidified to pH = 2 with 1 M hydrochloric acid solution. The reaction system was transferred to a separatory funnel, and the organic layer was retained. The organic layer was washed 2-3 times with saturated brine (300 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 0.46 g of a pale yellow oil with a yield of 83.4%. MS m / z calculated value: 349.05; experimental value: 350.1 [M+H] + 。

[0398] Step 3: Preparation of N-(1,3-dioxoisoindol-5-yl)-3-(4-fluoro-2-nitrophenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxamide

[0399] 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) were successively added to a 100 mL round-bottomed flask. The above compounds were dissolved in DMF solvent and stirred overnight at room temperature. After monitoring the reaction to completion by TLC, the reaction system was transferred to a separatory funnel (250 mL), diluted with ethyl acetate (150 mL), washed 2-3 times with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 0.27 g of an off-white solid with a yield of 42.5%. MS m / z calculated value: 493.09; experimental value: 494.1 [M+H] + 。

[0400] Step 4: Preparation of 3-(2-amino-4-fluorophenyl)-N-(1,3-dioxoisoindol-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0401] N-(1,3-dioxoisoindol-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 absolute ethanol (100 mL) were added to a high-pressure reactor. Hydrogen was charged into the reaction system to reach a pressure of 50 psi, and the mixture was heated to 80 °C and reacted for 36 hours. The reaction was monitored by TLC and found to be complete. The mixture was filtered through diatomaceous earth under reduced pressure, and the filter cake was washed with ethanol. 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%.

[0402] 1 H NMR(400MHz,DMSO-d 6 )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).

[0403] Example 14: Preparation of Compound P-14

[0404]

[0405] This preparation method is similar to that of Example 13, except that: 5-aminoisatoindoline-1,3-dione in Step 2 was replaced with 7-aminoquinazoline-2,4(1H,3H)-dione to obtain a white solid compound P-14 with a yield of 38.8%.

[0406] 1 H NMR(400MHz,DMSO-d 6 )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).

[0407] Example 15: Preparation of Compound P-15

[0408] The synthetic route of Compound P-15 is as follows:

[0409]

[0410] Step 1: Preparation of Ethyl 2-diazo-3-oxobutanoate

[0411] 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). p-Acetamidobenzenesulfonyl azide (19.00 g, 79.1 mmol) was added slowly and the reaction mixture was allowed to warm to room temperature and stirred at room temperature for 1 hour. After the reaction mixture was filtered by suction, it was concentrated under reduced pressure and purified by column chromatography to obtain 10.00 g of ethyl 2-diazo-3-oxobutanoate as a pale yellow oil, with a yield of 83.2%. Calculated MS m / z: 156.05; Experimental value: 157.0 [M+H] + 。

[0412] Step 2: Preparation of Ethyl 3-((tert-butyldimethylsilyl)oxy)-2-diazobut-3-enoate

[0413] To a solution of ethyl 2-diazo-3-oxobutanoate (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 added slowly 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 with dichloromethane (200 mL) 2 - 3 times. Then the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 17.04 g of crude ethyl 3-((tert-butyldimethylsilyl)oxy)-2-diazobut-3-enoate, with a yield of 98.2%. Calculated MS m / z: 255.11; Experimental value: 256.1 [M+H] + 。

[0414] Step 3: Preparation of Ethyl 2-diazo-6,6,6-trifluoro-5-hydroxy-5-methyl-3-oxohexanoate

[0415] 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 TiCl was added dropwise 4(19.50 g, 100.2 mmol). The reaction was maintained at -78 °C for 10 minutes, then ethyl 3-tert-butyldimethylsilyloxy-2-diazo-but-3-enoate (17.00 g, 62.9 mmol) was added dropwise. The reaction was maintained at -78 °C for 1 hour, then the reaction was quenched by adding saturated sodium bicarbonate solution and extracted 2-3 times with dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, concentrated in vacuo and purified by column chromatography to give 2.00 g of ethyl 2-diazo-6,6,6-trifluoro-5-hydroxy-5-methyl-3-oxo-hexanoate as a pale yellow liquid, with a yield of 12.6%. MS m / z calculated: 254.05; found: 255.0 [M+H] + 。

[0416] Step 4: Preparation of ethyl 5-methyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0417] Rhodium(II) acetate (0.05 g, 124.4 mmol) was charged into a dried two-necked flask, toluene (40 mL) was added and the solution was stirred at 100 °C for 10 minutes. The solution was briefly removed from the oil bath while a solution of ethyl 2-diazo-6,6,6-trifluoro-5-hydroxy-5-methyl-3-oxo-hexanoate (2.00 g, 7.9 mmol) in toluene (20 mL) was added dropwise, and the reaction was heated under reflux for 1 hour. The reaction mixture was filtered and concentrated in vacuo to give 1.94 g of crude ethyl 5-methyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate, with a yield of 99.5%. MS m / z calculated: 240.06; found: 241.2 [M+H] + 。

[0418] Step 5: Preparation of ethyl 5-methyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate

[0419] At 0 °C, trifluoromethanesulfonic anhydride (2.70 g, 9.6 mmol) was added dropwise to a solution of sodium hydride (60% wt, 0.48 g, 11.9 mmol) in a dichloromethane solution (150 mL) of ethyl 5-methyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (1.92 g, 7.91 mmol), and the reaction mixture was stirred for 2.5 h. Then, the reaction mixture was slowly added dropwise to 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 2.92 g of ethyl 5-methyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate in 98.5% yield. MS m / z calcd: 372.01; found: 373.0 [M+H] + 。

[0420] Step 6: Preparation of ethyl 3-(3,4-difluoro-2-methoxyphenyl)-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate

[0421] To a stirred solution of (3,4-difluoro-2-methoxyphenyl)boronic acid (1.62 g, 8.5 mmol) and ethyl 5-methyl-5-(trifluoromethyl)-3-(((trifluoromethyl)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 min, then tetrakis(triphenylphosphine)palladium (0.45 g, 0.4 mmol) was added and the mixture was heated to 100 °C for 1 h. 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 gave 0.56 g of ethyl 3-(3,4-difluoro-2-methoxyphenyl)-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate as a pale yellow liquid in 35.5% yield. MS m / z calcd: 366.08; found: 367.1 [M+H] + 。

[0422] Step 7: Preparation of ethyl 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0423] Ethyl 3-(3,4-difluoro-2-methoxyphenyl)-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate (0.21 g, 0.6 mmol), palladium / carbon (10% wt, 0.61 g, 5.7 mmol), and palladium hydroxide / carbon (20% wt, 0.48 g, 3.4 mmol) were added anhydrous ethanol (30 mL). The mixture was degassed and stirred under hydrogen (50 psi, 80 °C) for 12 h. The catalyst was removed by filtration, washed with anhydrous ethanol (50 mL) and concentrated in vacuo. 0.21 g of ethyl 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate was obtained as a white solid, with a yield of 99.8%. MS m / z calculated: 368.10; found: 369.1 [M+H] + .

[0424] Step 8: 3-(3,4-Difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

[0425] Ethyl 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (0.21 g, 0.6 mmol) was dissolved in methanol (40 mL): water (20 mL). Sodium hydroxide pellets (0.11 g, 2.9 mmol) were added and the suspension was stirred at 40 °C for 12 h. The filtrate was diluted with 1 M hydrochloric acid to pH = 2, the aqueous layer was extracted with ethyl acetate, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 0.19 g of 3-(3,4-difluoro-2-methoxyphenyl)-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid, with a yield of 98.2%. MS m / z calculated: 340.97; found: 341.1 [M+H] + .

[0426] 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

[0427] At 0 °C, 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), and 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 respectively. The reaction mixture was moved to room temperature, 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, with a yield of 14.4%.

[0428] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.18 (s, 1H), 11.04 (s, 1H), 10.15 (s, 1H), 7.82 (d, J = 8.7 Hz, 1H), 7.78 (d, J = 1.8 Hz, 1H), 7.43–7.38 (m, 1H), 7.20–7.12 (m, 1H), 6.54 (s, 1H), 4.15 (d, J = 18.3 Hz, 1H), 3.90–3.82 (m, 3H), 2.91 (m, 1H), 2.75 (m, 1H), 2.33 (m, 1H), 1.58 (s, 3H).

[0429] Example 16: Preparation of Compound P-16

[0430] The synthetic route of Compound P-16 is as follows:

[0431]

[0432] Step 1: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

[0433] Ethyl 4-(3,4-difluoro-2-methoxyphenyl)-2,3-dimethyl-2-(trifluoromethyl)-3H-furan-5-carboxylate (0.2 g, 0.3 mmol) was added with 10 mL of sodium hydroxide (2 M) and 20 mL of methanol, heated to 60 °C, and monitored by TLC until the reaction was complete. The reaction system was partitioned between ethyl acetate and 1 M hydrochloric acid, and the layers were separated and the organic layer was combined, concentrated under reduced pressure in vacuo to give 0.19 g of 3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid as a transparent oil, with a yield of 78.4%. MS m / z calculated value: 352.07; experimental value: 353.1 [M+H] + 。

[0434] Step 2: Preparation of 3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(1-oxoisoindol-5-yl)-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxamide

[0435] 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), and 5-aminoisatoic anhydride (0.08 g, 0.6 mmol), DIPEA (0.07 g, 2.5 mmol), and HATU (0.21 g, 1.0 mmol) were added respectively. The reaction mixture was allowed to warm to room temperature and reacted for 4 hours, then diluted with ethyl acetate, and subsequently washed with saturated brine. The organic layer was dried, concentrated under reduced pressure, and purified by column chromatography to give 0.15 g of 3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(1-oxoisoindol-5-yl)-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxamide as a white solid, with a yield of 57.7%.

[0436] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.06 (s, 1H), 8.43 (s, 1H), 7.96 (s, 1H), 7.66 (m, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.20–7.10 (m, 2H), 4.30 (s, 2H), 3.81 (d, J = 1.6 Hz, 3H), 3.78 (d, J = 7.2 Hz, 1H), 1.58 (s, 3H), 0.99 (d, J = 7.2 Hz, 3H).

[0437] Example 17: Preparation of Compound P-17

[0438] The synthetic route of Compound P-17 is as follows:

[0439]

[0440]

[0441] Step 1: Preparation of (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one

[0442] Dissolve 2-(3,4-difluoro-2-methoxyphenyl)acetic acid (Intermediate A, 10.00 g, 49.5 mmol) in an acetonitrile solution, and then add CDI (9.22 g, 56.9 mmol). Activate and stir at 40 °C for 15 minutes. Add (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) thereto in sequence, and raise the temperature to 60 °C and continue stirring for 24 hours. Quench the reaction with water, and extract the aqueous phase with MTBE 2 - 3 times. Wash the organic phase with 2 M hydrochloric acid solution (2 × 50 mL), dry over anhydrous sodium sulfate, and concentrate under reduced pressure in vacuo. Purify by column chromatography to obtain 11.5 g of the white solid compound (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one, with a yield of 72.1%. Calculated MS m / z: 322.06; Experimental value: 323.1 [M + H] + 。

[0443] Step 2: Preparation of (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one

[0444] (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one (3.00 g, 9.3 mmol) was added to a high-pressure reactor and dissolved in absolute ethanol. Then palladium / carbon (10% wt, 0.99 g, 9.3 mmol) and palladium hydroxide / carbon (20% wt, 1.57 g, 11.16 mmol) were added successively. After gas displacement three times, hydrogen was charged until the pressure reached 50 psi. The mixture was heated to 80 °C and stirred for 40 hours. After the mixture was cooled to room temperature, the reactor was opened and monitored by TLC until the raw material reaction was complete. The mixture was filtered under reduced pressure with diatomaceous earth filter aid, the filter cake was rinsed with absolute ethanol, and the filtrate was concentrated under reduced pressure to obtain 2.75 g of white solid compound (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one, with a yield of 91.1%. MS m / z calculated value: 324.07; experimental value: 325.08 [M+H] + 。

[0445] Step 3: Preparation of (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-ol

[0446] Under nitrogen protection at -78 °C, DIBAL-H (2.30 g, 16.2 mmol) was slowly added dropwise to a dichloromethane solution containing the compound (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)dihydrofuran-2(3H)-one (2.50 g, 7.7 mmol), and TLC was used to monitor until the reaction was complete. Subsequently, saturated ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate 2-3 times. The combined organic phases were washed with saturated brine and concentrated under reduced pressure to obtain 2.50 g of a crude product mainly composed of the diastereoisomer (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-ol, with a yield of 99.2%. MS m / z calculated value: 326.09; experimental value: 327.1 [M+H] + 。

[0447] Step 4: Preparation of (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl acetate

[0448] Under normal temperature conditions, 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). TLC was used to monitor the reaction until it was complete. After the reaction was completed, saturated sodium bicarbonate solution was added, and the reaction system was extracted with dichloromethane. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 2.77 g of a stereoisomer with (3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-yl acetate as the main diastereomer, with a yield of 98.5%. MS m / z calculated value: 368.10; experimental value: 369.1 [M+H] + Step 5: Preparation of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonitrile

[0449] Under -78 °C conditions, trimethylsilyl cyanide (1.86 g, 18.8 mmol) and boron trifluoride diethyl etherate (3.20 g, 22.5 mmol) were successively added 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). The reaction mixture was stirred for 30 minutes, and then the reaction was transferred to room temperature until the reaction was complete. The reaction was quenched with saturated sodium bicarbonate solution (60 mL), and then the mixture was extracted with dichloromethane. The organic phases were combined and dried, concentrated under reduced pressure, to obtain 2.48 g of a stereoisomer with (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carbonitrile as the main diastereoisomer, with a yield of 98.5%. MS m / z calculated value: 335.09; experimental value: 336.1 [M+H] + .

[0450] Step 6: Preparation of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

[0451] 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), 10 mL of sodium hydroxide (2 M) and 20 mL of methanol were added. The mixture was heated to 60 °C and monitored by TLC until the reaction was complete. The reaction system was partitioned between ethyl acetate and 1 M hydrochloric acid. The layers were separated and the organic layer was combined, concentrated under reduced pressure in vacuo to give 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 transparent oil, with a yield of 95.9%. MS m / z calculated: 354.08; found: 355.1 [M+H] + 。

[0452] 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

[0453] 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). 5-Aminoisoindolin-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 allowed to warm to room temperature and stirred for 4 h. 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 give 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%.

[0454] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.53 (s, 1H), 8.44 (s, 1H), 7.96 (s, 1H), 7.62 (d, J = 1.2 Hz, 2H), 7.25–7.12 (m, 2H), 5.12 (d, J = 10.3 Hz, 1H), 4.34 (s, 2H), 4.29 (dd, J = 10.3, 7.6 Hz, 1H), 3.97 (d, J = 2.0 Hz, 3H), 2.80 (q, J = 7.5 Hz, 1H), 1.62 (s, 3H), 0.79–0.70 (m, 3H).

[0455] Example 18: Preparation of Compound P-18

[0456]

[0457] This preparation method is similar to that of Example 17, except that: 5-aminoisoindol-1-one in Step 7 is replaced with 7-aminoquinazoline-2,4(1H,3H)-dione, to obtain a white solid compound P-18 with a yield of 38.6%.

[0458] 1 H NMR(400MHz,DMSO-d 6 )δ10.23(s,1H),10.11(s,1H),7.23(d,J=1.9Hz,1H),7.21–7.17(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).

[0459] Example 19: Preparation of Compound P-19

[0460]

[0461] This preparation method is similar to that of Example 17, except that: 5-aminoisoindol-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%.

[0462] 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),3.94(dd,J=8.5,2.1Hz,3H),2.78(q,J=7.3Hz,1H),1.60(s,3H),0.72(s,3H).

[0463] Example 20: Preparation of Compound P-20

[0464]

[0465] This preparation method is similar to that of Example 17, except that: 5-Aminoisoindolin-1-one in Step 7 is replaced with 7-Aminoquinazoline-2,4(1H,3H)-dione to obtain a white solid compound P-20 with a yield of 52.4%.

[0466] 1 H 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=21.2,8.2Hz,2H),5.09(d,J=10.3Hz,1H),4.26(dd,J=10.3,7.6Hz,1H),3.94(dd,J=8.5,2.1Hz,3H),2.78(q,J=7.3Hz,1H),1.60(s,3H),0.72(s,3H).

[0467] Example 21: Preparation of Compound P-21

[0468]

[0469] This preparation method is similar to that of Example 17, except that: 5-Aminoisoindolin-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%.

[0470] 1 H NMR(400MHz,DMSO-d 6 )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).

[0471] Example 22: Preparation of Compound P-22

[0472]

[0473] This preparation method is similar to Example 17, except that: 5-aminoisoindol-1-one in step 7 is replaced with 6-aminosaccharin to obtain a white solid compound P-22 with a yield of 54.5%.

[0474] 1 H NMR(400MHz,DMSO-d 6 )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).

[0475] Example 23: Preparation of compound P-23

[0476]

[0477] This preparation method is similar to Example 17, except that: 5-aminoisoindol-1-one in step 7 is replaced with 5-amino-2-methylisoindolin-1-one to obtain a white solid compound P-23 with a yield of 60.5%.

[0478] 1 H NMR(400MHz,DMSO-d 6 )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).

[0479] Example 24: Preparation of compound P-24

[0480]

[0481] This preparation method is similar to Example 17, except that: 5-aminoisatin-1-one in Step 7 is replaced with 6-amino-2H-benzo[b][1,4]oxazin-3(4H)-one to obtain a white solid compound P-24 with a yield of 56.4%.

[0482] 1 H NMR(400MHz,DMSO-d 6 )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).

[0483] Example 25: Preparation of Compound P-25

[0484] The synthetic route of Compound P-25 is as follows:

[0485]

[0486] Step 1: Preparation of ethyl 3-(4-(difluoromethoxy)-3-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate

[0487] 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) into a 100 mL reaction tube. Then add potassium phosphate trihydrate (1.17 g, 4.5 mmol) and tetrakis(triphenylphosphine)palladium (0.17 g, 0.2 mmol). After adding the materials, replace the gas with argon three times, and then add 25 mL of toluene solution with a syringe. Heat the mixture to 100 °C and react for 5 hours. Monitor the reaction of the raw materials by TLC until it is complete. After cooling to room temperature, filter the system by suction, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography to obtain 0.40 g of a white solid product with a yield of 63.4%. Calculated value of MS m / z: 428.11; Experimental value: 429.2 [M+H] + .

[0488] Step 2: Preparation of Ethyl 3-(4-(difluoromethoxy)-3-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0489] 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 to a high-pressure reactor. Then 100 mL of methanol was added. After replacing the hydrogen three times, the high-pressure reactor was charged with hydrogen again to 50 psi. The high-pressure reactor was heated to 80 °C and reacted for 24 h. TLC was used to monitor the complete reaction of the starting materials. The system was cooled to room temperature, filtered through diatomaceous earth by suction, and the obtained filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography to obtain 0.32 g of a white powdery compound with a yield of 80.2%. MS m / z calculated value: 430.12; experimental value: 431.1 [M+H] + 。

[0490] Step 3: Preparation of 3-(4-(difluoromethoxy)-3-fluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

[0491] Ethyl 3-(3-fluoro-2,4-dimethoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-tetrahydrofuran-2-carboxylate (0.32 g, 0.7 mmol) was added to a 100 mL round-bottom flask. Then 30 mL of methanol and 15 mL of sodium hydroxide solution (2 M) were added successively. The obtained solution was heated to 60 °C and reacted for 3 h. TLC was used to monitor the complete reaction of the starting materials. The mixture was cooled to room temperature, adjusted to pH 4 with dilute hydrochloric acid (2 M), and then the system was transferred to a separatory funnel with ethyl acetate (500 mL) and washed three times with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.21 g of a pale yellow oily target product with a yield of 70.3%. MS m / z calculated value: 402.09; experimental value: 403.1 [M+H] + 。

[0492] Step 4: Preparation of 3-(4-(difluoromethoxy)-3-fluoro-2-methoxyphenyl)-4,5-dimethyl-N-(1-oxoisoindolin-5-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0493] To a single-necked flask containing 100 mL of DMF solvent, 5-aminoisatin-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) were added. Then, HATU (0.21 g, 0.4 mmol) and DIPEA (0.14 g, 0.8 mmol) were added. After the addition was completed, the reaction was carried out at room temperature overnight. The reaction of the raw materials was monitored by TLC. The reaction system was transferred to a separatory funnel with ethyl acetate (500 mL) and washed three times with saturated brine (200 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 0.02 g of a off-white solid with a yield of 15.1%.

[0494] 1 H NMR(400MHz,DMSO-d 6 )δ9.52(s,1H),8.49(s,1H),7.44–7.34(m,3H),7.20(t,J=14.7Hz,1H)

[0495] 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).

[0496] Example 26: Preparation of Compound P-26

[0497] The synthetic route of Compound P-26 is as follows:

[0498]

[0499] Step 1: Preparation of ethyl 3-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate

[0500] 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) were added to a 100 mL reaction tube. Then, potassium phosphate trihydrate (1.80 g, 6.6 mmol) and tetrakis(triphenylphosphine)palladium (0.13 g, 0.1 mmol) were added. After the addition was complete, the system was purged with argon three times, and then 25 mL of toluene solution was added via syringe. The temperature was raised to 100 °C and the reaction was carried out for 5 hours. The reaction of the starting materials was monitored by TLC. After cooling to room temperature, the system was filtered by suction, the filtrate was concentrated under reduced pressure, and 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 value: 416.08; experimental value: 417.1 [M+H] + 。

[0501] Step 2: Preparation of ethyl 3-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0502] 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 to a high-pressure reaction kettle. Then, 100 mL of methanol was added. After purging with hydrogen 3 times, the high-pressure reaction kettle was filled with hydrogen again to 50 psi. The high-pressure reaction kettle was heated to 80 °C and the reaction was carried out for 24 h. The reaction of the starting materials was monitored by TLC. The system was cooled to room temperature, filtered by suction through diatomaceous earth, the obtained filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography to obtain 0.27 g of a white powdery compound with a yield of 59.7%. MS m / z calculated value: 418.10; experimental value: 419.1 [M+H] + 。

[0503] Step 3: Preparation of 3-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid

[0504] Ethyl 3-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (0.27 g, 0.6 mmol) was added to a 100 mL round-bottom flask. Then, 30 mL of methanol and 15 mL of sodium hydroxide solution (2 M) were added successively. The resulting solution was heated to 60 °C and reacted for 3 h. TLC was used to monitor the complete reaction of the starting materials. The mixture was cooled to room temperature, and the pH was adjusted to 4 with dilute hydrochloric acid (2 M). Then, the system was transferred to a separatory funnel with ethyl acetate (500 mL) and washed three times with saturated brine (200 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.23 g of a white powdery product with a yield of 94.0%. Calculated MS m / z: 390.07; Experimental value: 391.0 [M+H] + 。

[0505] Step 4: Preparation of 3-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,5-dimethyl-N-(1-oxoisoindolin-5-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0506] 5-Aminoisoindolin-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) were added to a single-necked flask containing 100 mL of DMF solvent. Then, HATU (0.19 g, 0.4 mmol) and DIPEA (0.10 g, 0.6 mmol) were added. After the addition was complete, the reaction was carried out at room temperature overnight. TLC was used to monitor the complete reaction of the starting materials. The reaction system was transferred to a separatory funnel with ethyl acetate (500 mL) and 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 obtain 0.04 g of a white solid with a yield of 30.1%.

[0507] 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.98 (s, 1H), 8.41 (s, 1H), 7.55 (d, J = 1.7 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.26 - 7.19 (m, 3H), 7.18 - 7.10 (m, 1H), 4.93 (d, J = 9.0 Hz, 1H), 4.27 (s, 2H), 4.03 (dd, J = 12.4, 9.0 Hz, 1H), 3.34 - 3.22 (m, 1H), 1.46 (s, 3H), 1.00 (d, J = 6.7 Hz, 3H).

[0508] Example 27: Preparation of Compound P-27

[0509] The synthetic route of compound P-27 is as follows:

[0510]

[0511] 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

[0512] Add 3-(3,4-difluoro-2-methoxyphenyl)-N-(1,3-dioxoisoindolin-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) into a 20 mL microwave reaction tube, and then inject 10 mL of acetone solution. The temperature of the microwave reactor is set at 120 °C and reacted for 1.5 hours. Cool to room temperature, monitor the complete reaction of the raw materials by TLC, and the residue is purified by column chromatography to obtain 0.15 g of white solid product, with a yield of 81.2%. MS m / z calculated value: 542.14; experimental value: 543.2 [M+H] + 。

[0513] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.21 (s, 1H), 7.86 (d, J = 1.7 Hz, 1H), 7.74 (d, J = 8.1 Hz, 1H), 7.59 (dd, J = 8.2, 1.8 Hz, 1H), 7.14 - 6.99 (m, 2H), 4.90 (d, J = 9.0 Hz, 1H), 4.80 (t, J = 5.9 Hz, 1H), 4.00 (d, J = 2.1 Hz, 3H), 3.96 - 3.84 (m, 1H), 3.64 - 3.49 (m, 4H), 3.22 (dd, J = 12.4, 6.6 Hz, 1H), 1.44 (s, 3H), 0.97 (d, J = 6.7 Hz, 3H).

[0514] Example 28: Preparation of compound P-28

[0515]

[0516] This 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 6-aminobenzo[d]isoxazol-3(2H)-one to obtain white powdery compound P-28, with a yield of 56.5%.

[0517] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 9.78 (s, 1H), 7.78 (s, 1H), 7.42 (d, J = 9.0 Hz, 1H), 7.27 (d, J = 9.2 Hz, 1H), 7.07 (d, J = 7.0 Hz, 2H), 7.05 - 7.02 (m, 1H), 4.85 (d, J = 9.0 Hz, 1H), 3.99 (d, J = 2.1 Hz, 3H), 3.88 (d, J = 1.8 Hz, 1H), 3.85 (d, J = 1.7 Hz, 1H), 1.42 (s, 3H), 0.95 (d, J = 6.8 Hz, 3H).

[0518] Example 29: Preparation of Compound P-29

[0519]

[0520] This preparation method is similar to that of Example 17, except that: 5-aminoisoindol-1-one in Step 7 is replaced with 5-amino-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (Intermediate E), to obtain the white solid compound P-29 with a yield of 70.8%.

[0521] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 10.56 (s, 1H), 8.13 (d, J = 1.9 Hz, 1H), 7.85 (t, J = 4.9 Hz, 1H), 7.77 (m, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.20 - 7.12 (m, 2H), 5.10 (d, J = 10.2 Hz, 1H), 4.34 (d, J = 4.9 Hz, 2H), 4.26 (m, 1H), 3.95 (d, J = 2.1 Hz, 3H), 2.78 (q, J = 7.5 Hz, 1H), 1.61 (s, 3H), 0.78 - 0.67 (m, 3H).

[0522] Example 30: Preparation of Compound P-30

[0523]

[0524] The preparation method of this compound is similar to that of Example 17, except that: 5-aminoisoindol-1-one in Step 7 is replaced with an equimolar amount of 5-amino-3,3-dimethylisoindolin-1-one hydrochloride (Intermediate F), to obtain 0.04 g of the white solid compound with a yield of 33.1%.

[0525] 1H NMR (400 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.56 (s, 1H), 7.95 (s, 1H), 7.54 (d, J = 1.9 Hz, 2H), 7.25 - 7.10 (m, 2H), 5.12 (d, J = 10.4 Hz, 1H), 4.26 (dd, J = 10.4, 7.5 Hz, 1H), 3.96 (d, J = 2.2 Hz, 3H), 2.77 (p, J = 7.4 Hz, 1H), 1.60 (s, 3H), 1.39 (d, J = 4.3 Hz, 6H), 0.73 (d, 3H).

[0526] Example 31: Preparation of Compound P-31

[0527]

[0528] The preparation method of this compound is similar to that of Example 17, except that: 5-aminoisatin-1-one in Step 7 is replaced with an equimolar amount of 5-amino-7-fluoro isatin-1-one (Intermediate G), and 0.07 g of the compound as a white solid is obtained, with a yield of 61.8%.

[0529] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 10.89 (s, 1H), 8.20 (d, J = 1.6 Hz, 1H), 7.76 (s, 1H), 7.29 - 7.17 (m, 2H), 7.05 (t, 1H), 5.29 (d, J = 10.3 Hz, 1H), 4.65 (s, 2H), 4.24 (dd, J = 10.3, 7.6 Hz, 1H), 3.98 (s, 3H), 2.79 (m, 1H), 1.68 (s, 3H), 0.76 (d, J = 4.6 Hz, 3H).

[0530] Example 32: Preparation of Compound P-32

[0531]

[0532] In this reaction route, Boc- represents tert-butoxycarbonyl.

[0533] Step 1: Preparation of tert-butyl 4-(5-nitro-1-oxoisoindolin-2-yl)-1H-pyrazole-1-carboxylate

[0534] To a 250 mL round-bottom flask, add methyl 2-(bromomethyl)-4-nitrobenzoate (1.00 g, 3.6 mmol), triethylamine (1.48 g, 14.6 mmol), and methanol (100 mL). After stirring at room temperature, add tert-butyl 4-amino-1H-pyrazole-1-carboxylate (0.80 g, 4.3 mmol) to the resulting solution. Heat the mixture to 70 °C and react for 3 hours. Monitor the reaction by TLC until the raw materials are completely reacted. Then, directly purify the product by column chromatography to obtain 0.73 g of white solid with a yield of 61.3%. Calculated MS m / z: 344.11; Experimental value: 345.1 [M+H] + 。

[0535] Step 2: Preparation of tert-butyl 4-(5-amino-1-oxoisoindolin-2-yl)-1H-pyrazole-1-carboxylate

[0536] To a 250 mL round-bottom flask, add tert-butyl 4-(5-nitro-1-oxoisoindolin-2-yl)-1H-pyrazole-1-carboxylate (0.73 g, 2.8 mmol). Dissolve it in absolute ethanol, add Pd / C (10%, 0.29 g), and finally fill the flask with hydrogen gas. Stir at room temperature for 4 hours. Monitor the reaction by TLC until the raw materials are completely reacted. Filter through diatomaceous earth filter aid under reduced pressure. Wash the filter cake with absolute ethanol. Concentrate the filtrate under reduced pressure to obtain 0.69 g of white solid with a yield of 92.6%. Calculated MS m / z: 314.13; Experimental value: 315.0 [M+H] + 。

[0537] 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

[0538] At room temperature, dissolve (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) in DMF (50 mL). Add tert-butyl 4-(5-amino-1-oxoisoindolin-2-yl)-1H-pyrazole-1-carboxylate (0.08 g, 0.3 mmol), NMI (0.08 g, 1.0 mmol), and TCFH (0.12 g, 0.4 mmol) respectively. Stir for 2 hours. Monitor the reaction by TLC until the raw materials are completely reacted. Dilute the reaction system with ethyl acetate, and then wash it with saturated brine. Dry the organic layer, concentrate it under reduced pressure, and purify it by column chromatography to obtain 0.12 g of white solid with a yield of 65.6%. Calculated MS m / z: 650.21; Experimental value: 651.2 [M+H] + 。

[0539] 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

[0540] 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), stirred for 6 hours, monitored by TLC to ensure complete reaction of the starting material. After suction filtration under reduced pressure, the target product was obtained as a white solid (0.07 g), with a yield of 63.5%.

[0541] 1 H NMR(400MHz,DMSO-d 6 )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).

[0542] Example 33: Preparation of Compound P-33

[0543]

[0544] The preparation method of this compound is similar to that of Example 32, except that: in Step 1, tert-butyl (2-aminoethyl)carbamate (0.70 g, 4.4 mmol) was replaced with an equimolar amount of tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate, and 0.08 g of a white compound was obtained.

[0545] 1 H NMR(400MHz,DMSO-d 6)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).

[0546] Example 34: Preparation of Compound P-34

[0547]

[0548] 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 was replaced with an equimolar amount of tert-butyl 2-aminoethyl(ethyl)carbamate, and 0.10 g of a white compound was obtained.

[0549] 1 H NMR(400MHz,DMSO-d 6 )δ10.95–10.62(m,1H),8.60(d,J=59.7Hz,2H),8.01(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 - 2.91(m,2H),2.04 - 1.96(m,1H),1.60(s,3H),1.18(s,3H),0.78–0.69(m,3H).

[0550] Example 35: Preparation of Compound P-35

[0551]

[0552] The preparation method of this compound is similar to that of Example 32, except that: tert-butyl (2-aminoethyl)carbamate in Step 1 was replaced with an equimolar amount of tert-butyl 3-amino-3-methylazetidine-1-carboxylate, and 0.15 g of a white solid compound was obtained.

[0553] 1 H NMR(400MHz,DMSO-d 6)δ 10.93 - 10.74 (m, 1H), 9.53 (s, 1H), 8.00 (s, 1H), 7.68 (d, J = 6.3 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.19 (dd, J = 20.8, 11.4 Hz, 2H), 5.26 - 5.12 (m, 1H), 4.51 (s, 2H), 4.47 (d, J = 10.3 Hz, 2H), 4.27 (dd, J = 10.4, 7.5 Hz, 1H), 3.95 (d, J = 2.1 Hz, 3H), 3.89 (s, 2H), 2.77 (t, J = 7.4 Hz, 1H), 1.91 (s, 1H), 1.64 (s, 3H), 1.60 (d, 3H), 0.76 - 0.70 (m, 3H).

[0554] Example 36: Preparation of Compound P-36

[0555]

[0556] 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.

[0557] 1 H NMR (400 MHz, DMSO-d 6 )δ 10.73 (s, 1H), 8.46 (s, 2H), 7.97 (s, 1H), 7.62 (d, J = 3.1 Hz, 2H), 7.25 - 7.11 (m, 2H), 5.20 - 5.13 (m, 1H), 4.37 (s, 2H), 4.26 (dd, J = 10.4, 7.5 Hz, 1H), 3.95 (d, J = 2.1 Hz, 3H), 3.26 (ddd, J = 8.3, 4.9, 2.5 Hz, 1H), 2.99 (s, 1H), 2.76 (p, J = 7.5 Hz, 1H), 1.91 (s, 1H), 1.59 (s, 3H), 1.36–1.21 (m, 2H), 0.76–0.69 (m, 3H).

[0558] Example 37: Preparation of Compound P-37

[0559]

[0560] 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.

[0561] 1 H NMR(400MHz, DMSO-d 6 ) δ 10.87 (s, 1H), 9.37 (s, 1H), 8.80 (s, 1H), 8.02 (s, 1H), 7.72 - 7.61 (m, 2H), 7.29 - 7.10 (m, 2H), 5.26 - 5.15 (m, 1H), 4.54 (s, 2H), 4.27 (t, J = 8.9 Hz, 1H), 3.95 (s, 3H), 3.89 - 3.71 (m, 4H), 3.18 (d, J = 54.2 Hz, 2H), 2.76 (td, J = 8.9, 4.5 Hz, 1H), 2.07 (s, 1H), 1.91 (d, J = 2.5 Hz, 2H), 1.60 (s, 3H), 0.84 (d, J = 8.2 Hz, 3H).

[0562] Example 38: Preparation of Compound P-38

[0563]

[0564] The preparation method of this compound is similar to that of Example 32, except that: the tert-butyl (2-aminoethyl)carbamate in Step 1 is replaced with an equimolar amount of tert-butyl (1-(aminomethyl)cyclopropyl)carbamate, and 0.15 g of the compound as a white solid is obtained.

[0565] 1 H NMR(400MHz, DMSO-d 6 ) δ 10.52 (s, 1H), 7.93 (s, 1H), 7.60 (s, 2H), 7.23 - 7.10 (m, 4H), 5.11 (d, J = 10.3 Hz, 1H), 4.54 (s, 2H), 4.27 (dd, J = 10.3, 7.6 Hz, 1H), 3.95 (s, 3H), 3.52 (s, 2H), 2.77 (m, 1H), 1.60 (s, 3H), 0.75 (d, J = 4.6 Hz, 3H), 0.45 - 0.32 (m, 4H).

[0566] Example 39: Preparation of Compound P-39

[0567]

[0568] The preparation method of this compound is similar to that of Example 32, except that: the tert-butyl (2-aminoethyl)carbamate in Step 1 is replaced with an equimolar amount of tert-butyl (2-aminocyclopentyl)carbamate, and 0.13 g of the compound as a white solid is obtained.

[0569] 1 H NMR(400 MHz, DMSO-d 6 ) δ 11.16 (s, 1H), 8.28 (d, J = 1.9 Hz, 1H), 8.13 (s, 2H), 7.92 (dd, J = 8.5, 2.0 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.32 (ddd, J = 8.5, 5.9, 2.0 Hz, 1H), 7.21 - 7.05 (m, 1H). 5.11 (d, J = 10.3 Hz, 1H), 4.54 (s, 2H), 4.27 (dd, J = 10.3, 7.6 Hz, 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 = 4.6 Hz, 3H).

[0570] Example 40: Preparation of Compound P-40

[0571]

[0572] 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-azetidine-1-carboxylate, and 0.11 g of a white solid compound is obtained.

[0573] 1 H NMR(400 MHz, DMSO-d 6 ) δ 10.86 (s, 1H), 8.86 (s, 1H), 8.05 (d, J = 1.6 Hz, 1H), 7.72 - 7.65 (m, 2H), 7.30 - 7.16 (m, 2H), 5.16 (d, J = 10.3 Hz, 1H), 4.58 (s, 2H), 4.28 (dd, J = 10.3, 7.6 Hz, 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 = 4.6 Hz, 3H).

[0574] Example 41: Preparation of Compound P-41

[0575]

[0576] 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-pyrrolidine-1-carboxylate, and 0.15 g of a white solid compound is obtained.

[0577] 1 H NMR(400MHz, DMSO-d 6 ) δ 10.73 (s, 1H), 8.91 (s, 1H), 8.06 (d, J = 1.6 Hz, 1H), 7.73 - 7.65 (m, 2H), 7.30 - 7.16 (m, 2H), 5.16 (d, J = 10.3 Hz, 1H), 4.58 (s, 2H), 4.28 (dd, J = 10.3, 7.6 Hz, 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 = 4.6 Hz, 3H).

[0578] Example 42: Preparation of Compound P-42

[0579]

[0580] 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.

[0581] 1 H NMR(400MHz, DMSO-d 6 ) δ 10.92 (s, 1H), 8.95 (s, 2H), 8.01 (d, J = 1.6 Hz, 1H), 7.73–7.65 (m, 2H), 7.29 - 7.15 (m, 2H), 5.20 (d, J = 10.3 Hz, 1H), 4.61 (s, 2H), 4.25 (dd, J = 10.3, 7.6 Hz, 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 = 4.6 Hz, 3H).

[0582] Example 43: Preparation of Compound P-43

[0583]

[0584] 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.

[0585] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 10.82 (s, 1H), 8.97 (s, 1H), 8.06 (d, J = 1.6 Hz, 1H), 7.78 - 7.69 (m, 2H), 7.34 - 7.28 (m, 2H), 5.19 (d, J = 10.3 Hz, 1H), 4.60 (s, 2H), 4.26 (dd, J = 10.3, 7.6 Hz, 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 = 4.6 Hz, 3H).

[0586] Example 44: Preparation of Compound P-44

[0587]

[0588] 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 methyl(2-(methylamino)ethyl)carbamate, and 0.09 g of the compound as a white solid is obtained.

[0589] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 10.84 (s, 1H), 8.63 (s, 2H), 8.01 (d, J = 1.6 Hz, 1H), 7.69–7.62 (m, 2H), 5.20 (d, J = 10.4 Hz, 1H), 4.47 (s, 2H), 3.95 (d, J = 2.1 Hz, 3H), 3.19 (d, J = 6.1 Hz, 2H), 2.77 (q, J = 7.4 Hz, 1H), 2.56 (t, J = 5.3 Hz, 3H), 2.04 - 1.89 (m, 1H), 1.60 (s, 3H), 1.23 (s, 3H), 0.79 - 0.69 (m, 3H).

[0590] Example 45: Preparation of Compound P-45

[0591]

[0592] 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 N-(3-aminocyclobutyl)carbamate, and 0.03 g of the compound as a white solid is obtained.

[0593] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.15 (s, 1H), 8.28 (d, J = 1.9 Hz, 1H), 8.12 (s, 3H), 7.92 (dd, J = 8.5, 2.0 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.31 (ddd, J = 8.4, 5.9, 1.9 Hz, 1H), 7.18 - 7.11 (m, 1H), 5.25 (d, J = 10.4 Hz, 1H), 4.26 (dd, J = 10.4, 7.5 Hz, 1H), 3.95 (d, J = 2.0 Hz, 4H), 3.46 (t, J = 6.3 Hz, 3H), 3.12 (d, J = 6.3 Hz, 2H), 2.76 (p, J = 7.4 Hz, 1H), 1.60 (s, 3H), 0.86 (m, 1H), 0.75 (m, 3H).

[0594] Example 46: Preparation of Compound P-46

[0595]

[0596] The preparation method of the compound was similar to that of Example 32, except that: tert-Butyl (2-aminoethyl)carbamate in Step 1 was replaced with an equimolar amount of tert-Butyl 3-amino-3-methylpyrrolidine-1-carboxylate to obtain 0.15 g of a white solid compound with a yield of 77.4%.

[0597] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.99–10.72 (m, 1H), 8.02–7.94 (m, 1H), 7.73–7.65 (m, 1H), 7.63–7.57 (m, 1H), 7.26–7.12 (m, 1H), 5.19 (td, J = 9.8, 4.3 Hz, 1H), 4.64–4.49 (m, 2H), 4.26 (dd, J = 10.8, 11.0, 7.8 Hz, 1H), 3.95 (s, 2H), 1.63 (s, 1H), 1.59 (s, 2H), 1.45 (s, 8H), 1.22 (d, J = 4.0 Hz, 3H), 0.76–0.69 (m, 6H).

[0598] Example 47: Preparation of Compound P-47

[0599]

[0600] 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-(2-aminoethyl)-1-azetidinecarboxylate, and 0.08 g of a white solid compound is obtained.

[0601] 1 H NMR(400MHz,DMSO-d 6 )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),2.93-2.67(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).

[0602] Example 48: Preparation of Compound P-48

[0603]

[0604] 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]pentanecarboxylate, and 0.14 g of a white solid compound is obtained.

[0605] 1 H NMR(400MHz,DMSO-d 6 )δ9.68(s,1H),7.87(d,J=8.9Hz,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,3H),2.62–2.59(m,1H),2.07–1.97(m,6H),1.40(s,3H),1.10(d,J=6.6Hz,3H).

[0606] Example 49: Preparation of Compound P-49

[0607]

[0608] Step 1: Preparation of Methyl (R)-2-(2-(3,4-Difluoro-2-methoxyphenyl)acetoxy)-3,3,3-trifluoro-2-methylpropionate

[0609] At 0 °C, 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), and the mixture was stirred at room temperature for 1 hour. After the reaction mixture was concentrated in vacuo, it was added to a solution of methyl (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionate (Intermediate F, 4.40 g, 25.6 mmol) and triethylamine (7.8 mL, 55.9 mmol) in DCM (10 mL), and the mixture was stirred at room temperature overnight until the reaction was complete. The reaction was quenched by adding saturated ammonium chloride solution (50 mL). The aqueous phase was extracted with DCM (150 mL) 2 - 3 times. The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by column chromatography gave 4.30 g of a white solid product with a yield of 41.5%. MS m / z calculated value: 356.07; experimental value: 357.1 [M+H] + .

[0610] Step 2: Preparation of (R)-3-(3,4-Difluoro-2-methoxyphenyl)-4-hydroxy-5-methyl-5-(trifluoromethyl)furan-2(5H)-one

[0611] After dissolving methyl (R)-2-(2-(3,4-difluoro-2-methoxyphenyl)acetoxy)-3,3,3-trifluoro-2-methylpropionate (1.48 g, 4.2 mmol) in THF (20 mL) solution, it was slowly added to a solution of LiHMDS (10 mL, 10.0 mmol) in THF (20 mL) at -78 °C. The reaction mixture was continued to be stirred at -78 °C for 5 h, and TLC was monitored until the reaction was complete. The reaction was quenched by adding 2M HCl. The aqueous phase was extracted with EtOAC (150 mL) 2 - 3 times. The combined organic phases were dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by column chromatography gave 0.80 g of a yellow oily product with a yield of 59.7%. MS m / z calculated value: 324.04; experimental value: 325.0 [M+H] + .

[0612] Step 3: Preparation of (R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)furan-2(5H)-one

[0613] Under nitrogen protection, 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 continuous stirring for 1 hour, the mixture was transferred to room temperature and reacted overnight. The reaction mixture was concentrated in vacuo. Column chromatography purification gave 2.1 g of colorless oil 1,3-dicyclohexyl-2-methylisourea. Subsequently, 1,3-dicyclohexyl-2-methyl-isourea (0.44 g, 1.7 mmol) was dissolved in THF solution, and then slowly added dropwise to a THF solution of methyl (R)-2-(2-(3,4-difluoro-2-methoxyphenyl)acetoxy)-3,3,3-trifluoro-2-methylpropionate (0.28 g, 0.8 mmol). The reaction mixture was heated at 85 °C overnight. After the reaction was completed, the white precipitate in the reaction mixture was filtered. The mother liquor was collected and concentrated in vacuo. Column chromatography purification gave 0.26 g of (R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)furan-2(5H)-one, with a yield of 86.4%. MS m / z calculated value: 338.06; experimental value: 339.1 [M+H] + 。

[0614] The series of reactions from Step 4 to Step 8 in this example was similar to the reaction process of Step 2 to Step 6 in Example 17, except that: the reaction raw material (R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)furan-2(5H)-one in Step 2 of Example 17 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 transparent oily (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4-methoxy-5-methyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid was obtained, with a yield of 95.9%. MS m / z calculated value: 370.08; experimental value: 369.1 [M+H] + 。

[0615] 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

[0616] To a single-necked flask containing 100 mL of DMF solvent, add tert-butyl 3-(5-amino-1-oxoisoindolin-2-yl)azetidine-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). Then add HATU (0.41 g, 1.1 mmol) and DIPEA (0.28 g, 2.2 mmol). After the addition is complete, react at room temperature overnight. Monitor the reaction by TLC until the raw materials are completely reacted. Transfer the reaction system to a separatory funnel with ethyl acetate (500 mL), wash it three times with saturated brine (200 mL), dry it over anhydrous sodium sulfate, concentrate it under reduced pressure, and purify the residue by column chromatography to obtain 0.04 g of a white solid with a yield of 38.7%.

[0617] 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 At room temperature, dissolve 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) in a hydrochloric acid solution in ethyl acetate (20 mL), stir for 6 hours, monitor the reaction by TLC until the raw materials are completely reacted, and obtain 0.03 g of a white solid 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 by suction filtration under reduced pressure, with a yield of 96.5%.

[0618] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.86 (s, 1H), 8.86 (s, 1H), 8.05 (d, J = 1.6 Hz, 1H), 7.72–7.65 (m, 2H), 7.30–7.16 (m, 2H), 5.16 (d, J = 10.3 Hz, 1H), 4.58 (s, 2H), 4.28 (dd, J = 10.3, 7.6 Hz, 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).

[0619] Example 50: Preparation of Compound P-50

[0620]

[0621] Step 1: Preparation of Methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0622] 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). Then, methyl iodide (0.59 g, 4.2 mmol) was 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 naturally, 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 to obtain 0.92 g of crude methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate with a yield of 88.5%. Calculated MS m / z: 368.10; Experimental value: 369.1 [M+H] + 。

[0623] Step 2: Preparation of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0624] 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 7M ammonia in methanol (10 mL). After stirring for 6 h, the reaction was monitored by TLC until completion. The mixture was concentrated in vacuo to obtain 0.47 g of crude (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide with a yield of 92%. Calculated MS m / z: 353.11; Experimental value: 354.1 [M+H] + 。

[0625] Step 3: Preparation of tert-Butyl 3-(6-bromo-1,1-dimethyl-3-oxoisoindolin-2-yl)azetidine-1-carboxylate

[0626] 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 the reaction was carried out at 120 °C for 24 h. After monitoring the reaction by TLC and completion, the system 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. Purification by column chromatography gave 130 mg of tert-butyl 3-(6-bromo-1,1-dimethyl-3-oxoisoindolin-2-yl)azetidine-1-carboxylate with a yield of 26.3%. MS m / z calculated value: 394.09; experimental value: 395.1 [M+H] + 。

[0627] 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

[0628] To a 250 mL three-necked flask, 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), tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.029 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (33 mg, 0.057 mmol), and cesium carbonate (280 mg, 0.86 mmol) were added. After feeding, the system was purged with argon three times, and toluene (100 mL) was added. The reaction was carried out at 100 °C overnight. After monitoring the reaction by TLC and completion, filtration was carried out 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 give 150 mg of a yellow solid with a yield of 79.3%. MS m / z calculated value: 667.67; experimental value: 668.7 [M+H] + 。

[0629] Step 5: Preparation of (2R,3S,4S,5R)-N-(2-(azetidin-3-yl)-3,3-dimethyl-1-oxoisoindolin-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide hydrochloride

[0630] To a 100 mL single-necked flask was added 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), ethyl acetate solution of hydrogen chloride (4 mol / L, 10 mL), and the mixture was stirred at room temperature for 2 h. The reaction was monitored by TLC and was complete. After concentration under reduced pressure, 120 mg of a pale yellow solid was obtained, with a yield of 90.3%.

[0631] 1 H NMR(400MHz,DMSO-d 6 )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,3H),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).

[0632] Example 51: Preparation of Compound P-51

[0633]

[0634] The preparation method of this compound was similar to that of Example 50, except that: 5-bromo-3,3-dimethylisoindolin-1-one in Step 3 was replaced with an equimolar amount of 6'-bromospiro[cyclopropane-1,1'-isoindolin]-3'-one, and 0.08 g of a white solid compound was obtained, with a yield of 36.0%.

[0635] 1 H NMR(400MHz,DMSO-d 6)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=7.4Hz,1H),1.69(t,J=3.8Hz,2H),1.60(s,3H),1.55–1.51(m,2H),0.76–0.70(m,3H).

[0636] Example 52: Preparation of Compound P-52

[0637]

[0638] The preparation method of the compound was similar to that of Example 32, except that: tert-butyl 4-amino-1H-pyrazole-1-carboxylate in Step 1 was replaced with an equimolar amount of tert-butyl 3-amino-3-(fluoromethyl)azetidine-1-carboxylate to obtain 0.16 g of a white solid compound with a yield of 75.0%.

[0639] 1 H NMR(400MHz,DMSO-d 6 )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),4.76(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).

[0640] Example 53: Preparation of Compound P-53

[0641]

[0642] The preparation method of the compound was similar to that of Example 32, except that: tert-butyl 4-amino-1H-pyrazole-1-carboxylate in Step 1 was replaced with an equimolar amount of tert-butyl (2R,3S)-3-amino-2-methylazetidine-1-carboxylate, and 0.18 g of a white solid compound was obtained with a yield of 88.0%.

[0643] 1 H NMR(400MHz,DMSO-d 6 )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).

[0644] Example 54: Preparation of Compound P-54

[0645]

[0646] The preparation method of the compound was similar to that of Example 32, except that: tert-butyl 4-amino-1H-pyrazole-1-carboxylate in Step 1 was replaced with an equimolar amount of tert-butyl (2S,3S)-3-amino-2-methylazetidine-1-carboxylate, and 0.18 g of a white solid compound was obtained with a yield of 85.0%.

[0647] 1 H NMR(400MHz,DMSO-d 6 )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).

[0648] Example 55: Preparation of Compound P-55

[0649]

[0650] The preparation method of the compound was similar to that of Example 32, except that tert-butyl 4-amino-1H-pyrazole-1-carboxylate in Step 1 was replaced with an equimolar amount of tert-butyl (2S,3R)-3-amino-2-methylazetidine-1-carboxylate, and 0.11 g of a white solid compound was obtained with a yield of 60.0%.

[0651] 1 H NMR(400MHz,DMSO-d 6 )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=10.3Hz,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).

[0652] Example 56: Preparation of Compound P-56

[0653]

[0654] The preparation method was similar to that of Example 17, except that 5-aminoisatin in Step 7 was replaced with tert-butyl 3-(5-amino-1,3-dioxoisoindolin-2-yl)azetidine-1-carboxylate, and then deprotection was carried out to obtain 0.06 g of a white solid compound with a yield of 67.2%.

[0655] 1 H NMR(400MHz,DMSO-d 6)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=8.2Hz,1H),4.53(t,J=9.3Hz,2H),4.27(dd,J=10.3,7.5Hz,1H),4.19(t,J=10.0Hz,2H),3.95(d,J=2.0Hz,3H),2.78(q,J=7.5Hz,1H),1.61(s,3H),0.79–0.72(m,3H).

[0656] Example 57: Preparation of Compound P-57

[0657]

[0658] The preparation method of the compound was similar to that of Example 32, except that: tert-butyl (2-aminoethyl)carbamate in Step 1 was replaced with an equimolar amount of tert-butyl 2-amino-5-azaspiro[3.4]octane-5-carboxylate, and 0.12 g of the compound as a white solid was obtained with a yield of 65.0%.

[0659] 1 H NMR(400MHz,DMSO-d 6 )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=10.4,7.5Hz,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).

[0660] Example 58: Preparation of Compound P-58

[0661]

[0662] 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]pent-1-yl)(methyl)carbamate

[0663] Add 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]pent-1-yl)carbamate (200 mg, 0.3 mmol), cesium carbonate (244 mg, 0.75 mmol), and methyl iodide (84 mg, 0.6 mmol) to a 100 mL single-necked flask, and then add DMF (20 mL). Heat the reaction mixture to 100 °C and stir for 12 h. Monitor the reaction by TLC until completion. Transfer the reaction mixture to a separatory funnel with 100 mL of ethyl acetate, wash with saturated brine (100 mL), dry the organic phase over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 95 mg of a yellow solid with a yield of 46.5%. MS m / z: calculated value: 679.26; experimental value: 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]pent-1-yl)-1-oxoisoindolin-5-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide Hydrochloride

[0664] At room temperature, dissolve 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]pent-1-yl)(methyl)carbamate (95 mg, 0.14 mmol) in a hydrochloric acid solution in ethyl acetate (20 mL), stir for 2 h, monitor the reaction by TLC until the starting material is completely reacted, and filter under reduced pressure to obtain 68 mg of a white solid of (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-N-(2-(3-(methylamino)bicyclo[1.1.1]pent-1-yl)-1-oxoisoindolin-5-yl)-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide hydrochloride with a yield of 78.9%.

[0665] 1 1H NMR (400 MHz, DMSO-d 6)δ 10.85–10.68 (m, 1H), 9.83 (s, 2H), 7.97 (s, 1H), 7.66 (d, J = 8.9 Hz, 1H), 7.63–7.56 (m, 1H), 7.21–7.11 (m, 2H), 5.17 (d, J = 9.8 Hz, 1H), 4.46 (s, 2H), 4.27 (t, J = 9.0 Hz, 1H), 3.96 (d, J = 2.4 Hz, 3H), 2.81–2.73 (m, 1H), 2.55 (d, J = 3.2 Hz, 3H), 2.42 (s, 6H), 1.60 (s, 3H), 0.73 (d, J = 7.3 Hz, 3H). Example 59: Preparation of Compound P-59

[0666]

[0667] Step 1: Preparation of tert-butyl (3-(5-nitro-1,3-dioxoisoindolin-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

[0668] 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) to a 100 mL single-necked flask. Heat the mixture to 130 °C and react for 6 h. Monitor the reaction by TLC until completion. Transfer the reaction system to a separatory funnel with 100 mL of ethyl acetate and wash it with saturated brine (100 mL). Dry the organic phase with anhydrous sodium sulfate and concentrate it under reduced pressure. Purify the residue by column chromatography to obtain 180 mg of a yellow solid with a yield of 48%. Calculated MS m / z: 373.13; Experimental value: 374.1 [M+H] + .

[0669] Step 2: Preparation of tert-butyl (3-(5-amino-1,3-dioxoisoindol-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate

[0670] Add tert-butyl (3-(5-nitro-1,3-dioxoisoindolin-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) to a 100 mL single-necked flask. React the mixture at room temperature for 2 h under a hydrogen balloon atmosphere. Monitor the reaction by TLC until completion. Filter the reaction system and concentrate the filtrate under reduced pressure. Purify the residue by column chromatography to obtain 115 mg of tert-butyl (3-(5-amino-1,3-dioxoisoindol-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate with a yield of 70.7%. Calculated MS m / z: 343.15; Experimental value: 344.1 [M+H] + .

[0671] 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-dioxoisoindol-2-yl)bicyclo[1.1.1]pent-1-yl)carbamate

[0672] Add tert-butyl (3-(5-amino-1,3-dioxoisoindol-2-yl)bicyclo[1.1.1]pent-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) to a single-necked flask containing 100 mL of DMF solvent. Then add HATU (0.19 g, 0.4 mmol) and DIPEA (0.10 g, 0.6 mmol). After the addition, react at room temperature overnight. Monitor the reaction by TLC until the raw materials are completely reacted. Transfer the reaction system to a separatory funnel with ethyl acetate (500 mL), wash it three times with saturated brine (200 mL), dry it over anhydrous sodium sulfate, concentrate it under reduced pressure, and purify the residue by column chromatography to obtain 0.11 g of a white solid with a yield of 80%. MS m / z calculated value: 679.23; experimental value: 680.1 [M+H] + 。

[0673] Step 4: Preparation of (2R,3S,4S,5R)-N-(2-(3-Aminobicyclo[1.1.1]pent-1-yl)-1,3-dioxoisoindol-5-yl)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide Hydrochloride

[0674] 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 ethyl acetate solution of hydrogen chloride (4 mol / L, 10 mL) to a 100 mL single-necked flask. Stir the reaction at room temperature for 2 h. Monitor the reaction by TLC until it is complete. Concentrate it under reduced pressure to obtain 90 mg of a pale yellow solid with a yield of 91.0%.

[0675] 1 H NMR(400MHz,DMSO-d 6)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).

[0676] Example 60: Preparation of Compound P-60

[0677]

[0678] The preparation method of the compound was similar to that of Example 32, except that: tert-butyl (2-aminoethyl)carbamate in Step 1 was replaced with an equimolar amount of tert-butyl ((1R,3R)-3-aminocyclobutyl)carbamate, and 0.09 g of the compound as a white solid was obtained with a yield of 77.0%.

[0679] 1 H NMR(400MHz,DMSO-d 6 )δ10.91(d,J=2.5Hz,1H),8.36(s,3H),8.01(d,J=1.8Hz,1H),7.68(dd,J=8.4,1.8Hz,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),2.76(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).

[0680] Example 61: Preparation of Compound P-61

[0681]

[0682] This preparation method is similar to 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, and 0.10 g of a white solid compound is obtained with a yield of 55.5%.

[0683] 1 H NMR(400MHz,DMSO-d 6 )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).

[0684] Example 62: Preparation of Compound P-62

[0685]

[0686] This preparation method is similar to 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, and 0.13 g of a white solid compound is obtained with a yield of 72.5%.

[0687] 1 H NMR(400MHz,DMSO-d 6 )δ10.70(s,1H),8.28(s,3H),7.98(d,J=1.7Hz,1H),7.66–7.52(m,2H),7.23–7.12(m,2H),5.15(d,J=10.6Hz,1H),5.10(d,J=8.8Hz,1H),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).

[0688] Example 63: Preparation of Compound P-63

[0689]

[0690] The preparation method of the compound was similar to that of Example 32, except that tert-butyl 4-amino-1H-pyrazole-1-carboxylate in Step 1 was replaced with 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%.

[0691] 1 H NMR(400MHz,DMSO-d 6 )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,1H),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).

[0692] Example 64: Preparation of Compound P-64

[0693]

[0694] The preparation method of the compound was similar to that of Example 32, except that tert-butyl 4-amino-1H-pyrazole-1-carboxylate in Step 1 was replaced with 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%.

[0695] 1 H NMR(400MHz,DMSO-d 6)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=8.1,5.1,2.4Hz,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).

[0696] Example 65: Preparation of Compound P-65

[0697]

[0698] This preparation method is similar to 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%.

[0699] 1 H NMR(400MHz,DMSO-d 6 )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).

[0700] Example 66: Preparation of Compound P-66

[0701]

[0702] The preparation method of the compound was similar to that of Example 32, except that: tert-butyl (2-aminoethyl)carbamate in Step 1 was replaced with an equimolar amount of tert-butyl ((1R,2S)-2-aminocyclopropyl)carbamate, and 0.13 g of the compound as a white solid was obtained with a yield of 74.0%.

[0703] 1 H NMR(400MHz,DMSO-d 6 )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).

[0704] Example 67: Preparation of Compound P-67

[0705]

[0706] The preparation method of the compound was similar to that of Example 32, except that: tert-butyl (2-aminoethyl)carbamate in Step 1 was replaced with an equimolar amount of tert-butyl 6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate, and 0.16 g of the compound as a white solid was obtained with a yield of 80.0%.

[0707] 1 H NMR(400MHz,DMSO-d 6 )δ10.71(s,1H),9.52(s,1H),9.02(s,1H),7.95(d,J=1.7Hz,1H),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).

[0708] Example 68: Preparation of Compound P-68

[0709]

[0710] This preparation method is similar to Example 32, except that: the tert-butyl 4-amino-1H-pyrazole-1-carboxylate in Step 1 is replaced by tert-butyl (2S,4S)-4-amino-2-(fluoromethyl)pyrrolidine-1-carboxylate, and 0.16 g of a white solid compound is obtained, with a yield of 75.2%.

[0711] 1 H NMR(400MHz,DMSO-d 6 )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).

[0712] Example 69: Preparation of Compound P-69

[0713]

[0714] This preparation method is similar to Example 32, except that: the tert-butyl 4-amino-1H-pyrazole-1-carboxylate in Step 1 is replaced by tert-butyl (2S,4R)-4-amino-2-(hydroxymethyl)pyrrolidine-1-carboxylate, and 0.12 g of a white solid compound is obtained, with a yield of 68.1%.

[0715] 1 H NMR(400MHz,DMSO-d 6)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,2H),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).

[0716] Example 70: Preparation of Compound P-70

[0717]

[0718] The preparation method of the compound was similar to that of Example 32, except that: tert-butyl (2-aminoethyl)carbamate in Step 1 was replaced with an equimolar amount of tert-butyl 4-amino-2-azabicyclo[2.1.1]hexane-2-carboxylate to obtain 0.16 g of a white solid compound with a yield of 80.0%.

[0719] 1 H NMR(400MHz,DMSO-d 6 )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),4.26(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).

[0720] Example 71: Preparation of Compound P-71

[0721]

[0722] This preparation method is similar to Example 32, except that: tert-butyl 4-amino-1H-pyrazole-1-carboxylate in Step 1 is replaced by tert-butyl (S)-3-aminopyrrolidine-1-carboxylate, obtaining 0.05 g of a white solid compound with a yield of 66.5%.

[0723] 1 H NMR(400MHz,DMSO-d 6 )δ10.79(s,1H),9.35(s,2H),7.99(d,J=1.7Hz,1H),7.72–7.60(m,2H),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).

[0724] Example 72: Preparation of Compound P-72

[0725]

[0726] The preparation method of the compound is similar to 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, obtaining 0.08 g of a white solid compound with a yield of 43.0%.

[0727] 1 H NMR(400MHz,DMSO-d 6 )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).

[0728] Example 73: Preparation of Compound P-73

[0729]

[0730] 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, and 0.12 g of the compound as a white solid is obtained, with a yield of 70.4%.

[0731] 1 H 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,1H),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).

[0732] Example 74: Preparation of Compound P-74

[0733]

[0734] Step 1: Preparation of ethyl rac-(4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate

[0735] 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 a solution of toluene (90 mL) and water (10 mL). Potassium phosphate (11.17 g, 52.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.04 g, 2.63 mmol) were added thereto. The mixture was purged with nitrogen three times and stirred at 100 °C for 1 hour. TLC monitoring showed that the raw materials had completely reacted. After cooling to room temperature, water (200 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL × 2). 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 8.6 g of yellow solid compound ethyl rac-(4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)-4,5-dihydrofuran-2-carboxylate, with a yield of 78.0%. Calculated MS m / z: 396.08; Experimental value: 397.1 [M+H] + 。

[0736] Step 2: Preparation of ethyl rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0737] 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). 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 successively to obtain 0.5 g of yellow solid compound ethyl rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate, with a yield of 9.52%. Calculated MS m / z: 398.10; Experimental value: 399.1 [M+H] + 。

[0738] 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

[0739] Dissolve 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) in a solution of tetrahydrofuran (9 mL) and water (3 mL). Add lithium hydroxide monohydrate (2.18 g, 5.19 mmol) thereto and stir at room temperature for 2 hours. Then add water (10 mL) to the reaction solution, adjust the pH value to ~2 with 1 M dilute hydrochloric acid, extract with ethyl acetate (10 mL × 3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain 480 mg of pale yellow solid rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid with a yield of 92%. Calculated MS m / z: 370.07; Experimental value: 371.1 [M+H] + 。

[0740] Step 4: Resolution of chiral isomers

[0741] Dissolve rac-(2R,3S,4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid (480 mg) and perform resolution by SFC column chromatography with the eluent [40% IPA(NH 4 OH 0.2%):60% CO 2 to obtain two single isomers: The first eluted isomer P1 (RT = 2.18 min): 116.48 mg of white solid (2R,3S,4S,5R)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid with a yield of 24.2%. Calculated MS m / z: 370.07; Experimental value: 371.1 [M+H] + 。The second eluted isomer P2 (RT = 2.37 min): 166.73 mg of white solid (2S,3R,4R,5S)-3-(3,4-difluoro-2-(methylthio)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid with a yield of 34.7%. Calculated MS m / z: 370.07; Experimental value: 371.1 [M+H] + 。

[0742] 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

[0743] 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). 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, TLC was used to monitor the complete reaction of the starting materials. 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 0.1 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, with a yield of 90.1%. MS m / z calculated value: 655.21; experimental value: 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

[0744] 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). After stirring for 6 hours, TLC was used to monitor the complete reaction of the starting materials. After suction filtration under reduced pressure, 0.09 g 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 was obtained as a white solid, with a yield of 98.2%.

[0745] 1 H NMR (400 MHz, DMSO-d 6)δ 10.82 (d, J = 7.0 Hz, 1H), 8.97 (s, 2H), 8.05–7.94 (m, 1H), 7.72–7.60 (m, 2H), 7.46 (q, J = 8.9 Hz, 1H), 7.35 (dd, J = 9.0, 4.7 Hz, 1H), 5.25 (d, J = 10.5 Hz, 1H), 5.13 (p, J = 8.2 Hz, 1H), 4.65 (d, J = 7.4 Hz, 2H), 4.50–4.33 (m, 2H), 4.14 (s, 2H), 4.00–3.86 (m, 1H), 2.81 (p, J = 7.5 Hz, 1H), 2.43 (d, J = 2.1 Hz, 3H), 1.61 (s, 3H), 0.73–0.67 (m, 3H).

[0746] Example 75: Preparation of Compound P-75

[0747]

[0748] The preparation method of the compound was similar to that of Example 74, except that: tert-butyl 3-(5-amino-1-isobenzofuran-2-yl)azetidine-1-carboxylate in Step 5 was replaced with an equimolar amount of 5-amino-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide-3,3-D 2 (Intermediate J), and without going through Step 6, 0.18 g of the compound as a white solid was obtained, with a yield of 64.0%.

[0749] 1 H NMR (400 MHz, DMSO-d 6 )δ 10.58 (s, 1H), 8.11 (s, 1H), 7.82 (s, 1H), 7.76 (d, J = 8.5 Hz, 1H), 7.53–7.44 (m, 2H), 7.29 (s, 1H), 5.16 (d, J = 10.4 Hz, 1H), 4.64 (t, J = 9.2 Hz, 1H), 2.85–2.77 (m, 1H), 2.43 (s, 3H), 1.63 (s, 3H), 0.73–0.67 (m, 3H).

[0750] Example 76: Preparation of Compound P-76

[0751]

[0752] 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 with 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%.

[0753] 1 H NMR(400MHz,DMSO-d 6 )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),7.40–7.33(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).

[0754] Example 77: Preparation of Compound P-77

[0755]

[0756] 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 with an equimolar amount of 5-amino-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (Intermediate E), and Step 6 is not required, to obtain 0.06 g of the compound as a white solid, with a yield of 41.6%.

[0757] 1 H NMR(400MHz,DMSO-d 6 )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).

[0758] Example 78: Preparation of Compound P-78

[0759]

[0760] The preparation method of this compound is similar to that of Example 74, except that: in step 1, the reaction raw material (3,4-difluoro-2-(methylthio)phenyl)boronic acid (Intermediate I) is replaced with an equimolar amount of (3,4-difluoro-2-((fluoromethyl)thio)phenyl)boronic acid (commercially available), and in step 5, tert-butyl 3-(5-amino-1-isobenzofuran-2-yl)azetidine-1-carboxylate is replaced with an equimolar amount of 5-amino-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide-3,3-D 2 (Intermediate J). Without going through step 6, 0.05 g of the compound as a white solid was obtained with a yield of 34.9%.

[0761] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.53 (s, 1H), 8.11 (d, J = 1.9 Hz, 1H), 7.85 (s, J = 4.9 Hz, 1H), 7.77 (dd, J = 8.5, 2.0 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.41–7.22 (m, 2H), 5.61–5.54 (m, 1H), 5.48 (d, J = 4.7 Hz, 1H), 5.11 (d, J = 10.3 Hz, 1H), 4.33 (dd, J = 11.4 Hz, 1H), 2.79 (m, 1H), 1.61 (s, 3H), 0.78–0.71 (m, 3H).

[0762] Example 79: Preparation of Compound P-79

[0763]

[0764] The preparation method of this compound is similar to that of Example 74, except that: in step 1, the reaction raw material (3,4-difluoro-2-(methylthio)phenyl)boronic acid (Intermediate I) is replaced with an equimolar amount of (3,4-difluoro-2-((trifluoromethyl)thio)phenyl)boronic acid (commercially available), and in step 5, tert-butyl 3-(5-amino-1-isobenzofuran-2-yl)azetidine-1-carboxylate is replaced with an equimolar amount of 5-amino-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide (Intermediate E). Without going through step 6, 0.07 g of the compound as a white solid was obtained with a yield of 50.3%.

[0765] 1 H NMR (400 MHz, DMSO-d 6)δ 10.50 (s, 1H), 8.08 (d, J = 1.7 Hz, 1H), 7.79 (t, J = 4.6 Hz, 1H), 7.79 (dd, J = 8.1, 1.8 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.60–7.52 (m, 2H), 5.10 (d, J = 10.5 Hz, 1H), 4.35 - 4.30 (dd, J = 10.5, 6.1 Hz, 3H), 2.78 (m, 1H), 1.63 (s, 3H), 0.80 (d, J = 1.8 Hz, 3H).

[0766] Example 80: Preparation of Compound P-80

[0767] The synthetic route of Compound P-80 is as follows:

[0768]

[0769] Step 1: Preparation of Methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0770] 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). Then, methyl iodide (0.59 g, 4.2 mmol) was added dropwise to the solution. After the addition was complete, the temperature was raised to 70 °C. The reaction was monitored by TLC. After naturally 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 obtain 0.92 g of crude methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate with a yield of 88.5%. MS m / z calculated value: 368.10; experimental value: 369.1 [M + H] + 。

[0771] Step 2: Preparation of Methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0772] At 0 °C, boron tribromide (1.87 g, 7.5 mmol) was slowly added dropwise to a solution of methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (0.92 g, 2.5 mmol) in dichloromethane (100 mL). After monitoring the reaction by TLC and completion of the reaction, the reaction system was slowly added dropwise to ice water for quenching, and the pH of the solution was adjusted to 7 - 8 using saturated sodium bicarbonate solution. The layers were separated and the aqueous phase was extracted with dichloromethane (200 mL) 2 - 3 times. After combining the organic phases, they were washed with saturated brine (300 mL) 2 - 3 times, dried over anhydrous sodium sulfate and concentrated in vacuo. After purification by column chromatography, 0.71 g of methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate as a yellow oily liquid was obtained, with a yield of 80.2%. MS m / z calculated value: 354.08; experimental value: 355.1 [M + H] + 。

[0773] 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

[0774] Cesium carbonate (1.95 g, 6.0 mmol) was added to a solution of methyl (2R,3S,4S,5R)-3-(3,4-difluoro-2-hydroxyphenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (0.71 g, 2.0 mmol) in N,N-dimethylformamide (50 mL), and then 2-bromoethyl methyl ether (0.42 g, 3.0 mmol) was added dropwise to the solution. After the addition was complete, the temperature was raised to 100 °C. After monitoring the reaction by TLC and completion of the reaction, it was allowed to cool naturally to room temperature, and then ethyl acetate (200 mL) was added to the reaction system for dilution. It was washed with saturated brine (300 mL) 3 - 5 times, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. After column chromatography, 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 was obtained, with a yield of 65.2%. MS m / z calculated value: 412.13; experimental value: 413.1 [M + H] + 。

[0775] Step 4: Preparation of (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0776] 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 a 7 M ammonia methanol solution (10 mL). After stirring for 6 h, the reaction was monitored by TLC and completed. The reaction mixture was concentrated in vacuo to obtain 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 with a yield of 92.3%. MS m / z calculated value: 397.13; experimental value: 398.1 [M+H] + 。

[0777] 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

[0778] Under nitrogen atmosphere, (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(diphenylphosphino)-9,9-dimethylxanthene (0.14 g, 0.24 mmol), and cesium carbonate (0.78 g, 2.4 mmol) were added to a Schlk tube. After purging the system with nitrogen three times, toluene (50 mL) was added and the reaction mixture was heated to 100 °C and stirred overnight. After the reaction was monitored by TLC and completed, the reaction mixture was cooled to room temperature naturally. Ethyl acetate (200 mL) was added to dilute the reaction mixture, and the mixture was washed with saturated brine (300 mL) 3 - 5 times. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. After column chromatography, 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 was obtained with a yield of 59.1%. MS m / z calculated value: 683.26; experimental value: 684.3 [M+H] + 。

[0779] 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)

[0780] Dissolve 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) in trifluoroacetic acid (10 mL). After monitoring the reaction by TLC and concentrating under vacuum, a white solid, (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), 0.41 g was obtained with a yield of 82.2%. MS m / z calculated value: 584.21; experimental value: 585.2 [M+H] + 。

[0781] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.61 (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 = 7.2 Hz, 1H), 1.61 (s, 3H), 0.75–0.69 (m, 3H).

[0782] Example 81: Preparation of Compound P-81

[0783]

[0784] This preparation method is similar to Example 80, except that: 2-bromoethyl methyl ether in Step 3 was replaced with fluoroiodomethane, and 0.15 g of a white solid compound was obtained with a yield of 72.5%.

[0785] 1 H NMR (400 MHz, DMSO-d 6)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).

[0786] Example 82: Preparation of Compound P-82

[0787]

[0788] The preparation method was similar to that of Example 80, except that: 2-bromoethyl methyl ether in Step 3 was replaced with iodoethane, and trifluoroacetic acid in Step 6 was replaced with hydrochloric acid, to obtain 0.12 g of a white solid compound with a yield of 68.4%.

[0789] 1 H NMR(400MHz,DMSO-d 6 )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).

[0790] Example 83: Preparation of Compound P-53

[0791]

[0792] The preparation method of the compound was similar to that of Example 80, except that: 2-bromoethyl methyl ether in Step 3 was replaced with an equimolar amount of 1-fluoro-2-iodoethane, to obtain 0.18 g of a white solid compound with a yield of 86.0%.

[0793] 1 H NMR(400MHz,DMSO-d 6)δ 10.81 (s, 1H), 9.02 (s, 2H), 8.04 (d, J = 1.6 Hz, 1H), 7.75–7.61 (m, 2H), 7.33–7.12 (m, 2H), 5.21 (d, J = 10.7 Hz, 1H), 5.13 (q, J = 8.2 Hz, 1H), 4.84–4.77 (m, 1H), 4.68 (d, J = 4.6 Hz, 2H), 4.51–4.26 (m, 6H), 4.15 (s, 2H), 2.79 (p, J = 7.4 Hz, 1H), 1.58 (s, 3H), 0.76–0.70 (m, 3H).

[0794] Example 84: Preparation of Compound P-84

[0795]

[0796] The preparation method of the compound was similar to those of Examples 80 and 81, except that: tert-butyl 3-(5-bromo-1-oxoisoindolin-2-yl)azetidine-1-carboxylate in Step 5 was replaced with an equimolar amount of tert-butyl (2S,3S)-3-(5-bromo-1-oxoisoindolin-2-yl)-2-methylazetidine-1-carboxylate, and 0.17 g of the compound as a white solid was obtained, with a yield of 84.0%.

[0797] 1 H NMR (400 MHz, DMSO-d 6 )δ 10.91 (s, 1H), 9.24 (d, J = 40.4 Hz, 2H), 8.03 (d, J = 1.7 Hz, 1H), 7.75–7.68 (m, 1H), 7.65 (d, J = 8.3 Hz, 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 = 10.3 Hz, 1H), 4.94–4.85 (m, 1H), 4.80 (d, J = 17.4 Hz, 1H), 4.75–4.61 (m, 2H), 4.52 (d, J = 15.7 Hz, 1H), 4.34 (dd, J = 10.4, 7.5 Hz, 1H), 4.24 (s, 1H), 2.79 (p, J = 7.4 Hz, 1H), 1.59 (s, 3H), 1.29 (dd, J = 7.1, 3.5 Hz, 3H), 0.74 (d, J = 7.3 Hz, 3H).

[0798] Example 85: Preparation of Compound P-85

[0799]

[0800] 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 with an equimolar amount of tert-butyl 4-(5-bromo-1-isoindolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate, and 0.17 g of the compound as a white solid is obtained, with a yield of 83.0%.

[0801] 1 H NMR(400MHz,DMSO-d 6 )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).

[0802] Example 86: Preparation of Compound P-86

[0803]

[0804] 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 with an equimolar amount of tert-butyl 4-(5-bromo-1-isoindolin-2-yl)-2-azabicyclo[2.1.1]hexane-2-carboxylate, and 0.17 g of the compound as a white solid is obtained, with a yield of 83.0%.

[0805] 1 H NMR(400MHz,DMSO-d 6)δ8.57(s,1H),9.49(s,2H),8.08–8.03(m,1H),7.75(d,J=8.2Hz,1H),7.30(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).

[0806] Example 87: Preparation of Compound P-87

[0807]

[0808] The preparation method of the compound was similar to that of Example 32, except that: tert-butyl (2-aminoethyl)carbamate in Step 1 was replaced with an equimolar amount of tert-butyl ((1R,3R)-3-aminocyclobutyl)(methyl)carbamate, and 0.15 g of the compound as a white solid was obtained with a yield of 83.2%.

[0809] 1 H NMR(400MHz,DMSO-d 6 )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).

[0810] Example 88: Preparation of Compound P-88

[0811]

[0812] This preparation method is similar to Example 80, with the differences being that: 2-bromoethyl methyl ether in Step 3 is replaced with fluoromethane iodide, 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, obtaining 0.11 g of a white solid compound with a yield of 64.4%.

[0813] 1 H NMR(400MHz,DMSO-d 6 )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),5.07(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).

[0814] Example 89: Preparation of Compound P-89

[0815]

[0816] This preparation method is similar to Example 80, with the differences being 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, obtaining 0.13 g of a white solid compound with a yield of 71.6%.

[0817] 1 H NMR(400MHz,DMSO-d 6)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=10.7,7.2Hz,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).

[0818] Example 90: Preparation of Compound P-90

[0819]

[0820] The preparation method of the compound was similar to that of Example 80, except that: tert-butyl 3-(5-bromo-1-oxoisoindolin-2-yl)azetidine-1-carboxylate in Step 5 was replaced with 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 a white solid compound with a yield of 82.4%.

[0821] 1 H NMR(400MHz,DMSO-d 6 )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,1H),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).

[0822] Example 91: Preparation of Compound P-91

[0823]

[0824] 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 with an equimolar amount of tert-butyl (3-(5-bromo-1-oxoisoindolin-2-yl)bicyclo[1.1.1]pentan-1-yl)carbamate, and 0.14 g of the compound as a white solid is obtained with a yield of 77.7%.

[0825] 1 H NMR(400MHz,DMSO-d 6 )δ10.76(s,1H),8.94(s,3H),7.96(d,J=1.7Hz,1H),7.65(dd,J=8.4,1.7Hz,1H),7.58(d,J=8.3Hz,1H),7.33(dd,J=8.4,5.1Hz,2H),5.93–5.86(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).

[0826] Example 92: Preparation of Compound P-92

[0827]

[0828] Steps 1 to 3 are the same as the synthetic route of Example 80.

[0829] 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

[0830] 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) dissolved in methanol (10 mL) was added dropwise to an aqueous solution (5 mL) of sodium hydroxide (0.15 g, 3.7 mmol). The mixture was stirred at 60 °C for 4 h. TLC monitored the complete reaction of the starting materials. The pH was adjusted to 1 - 2 with dilute hydrochloric acid. The reaction system was diluted with ethyl acetate (20 mL) and transferred to a separatory funnel, washed 3 times with saturated brine (200 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain 0.28 g of a pale yellow oil with a yield of 96.6%. MS m / z: calculated value: 398.12; experimental value: 399.1 [M + H] + 。

[0831] Step 5: Preparation of (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-N-(1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide

[0832] 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). 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 h, TLC monitored the complete reaction of the starting materials. 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 white solid (2R,3S,4S,5R)-3-(3,4-difluoro-2-(2-methoxyethoxy)phenyl)-N-(1,1-dioxido-2,3-dihydrobenzo[d]isothiazol-5-yl)-4,5-dimethyl-5-(trifluoromethyl)tetrahydrofuran-2-carboxamide with a yield of 84.7%.

[0833] 1 H NMR (400 MHz, DMSO-d 6)δ10.53(s,1H),8.13(d,J=2.0Hz,1H),7.85(t,J=4.9Hz,1H),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).

[0834] Example 93: Preparation of Compound P-93

[0835]

[0836] The preparation method of the compound was similar to that of Example 92, except that: 2-bromoethyl methyl ether in Step 3 was replaced with an equimolar amount of fluoroiodomethane to obtain 0.18 g of a white solid compound with a yield of 62.3%.

[0837] 1 H NMR(400MHz,DMSO-d 6 )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(dd,J=11.4,6.9Hz,3H),2.79(p,J=7.5Hz,1H),1.61(s,3H),0.78–0.71(m,3H).

[0838] Example 94: Preparation of Compound P-94

[0839]

[0840] The preparation method of the compound was similar to that of Example 92, except that: 5-amino-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide in Step 5 was replaced with an equimolar amount of 5-amino-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide-3,3-D 2 (Intermediate J) to obtain 0.16 g of a white solid compound with a yield of 56.3%.

[0841] 1 H NMR(400MHz, DMSO-d 6 ) δ 10.52(s, 1H), 8.13(d, J=1.9Hz, 1H), 7.81(s, 1H), 7.79(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=4.5Hz, 2H), 3.27(s, 3H), 2.83(t, J=7.3Hz, 1H), 1.62(s, 3H), 0.71(d, J=7.3Hz, 3H).

[0842] Example 95: Preparation of Compound P-95

[0843]

[0844] The preparation method of the compound was similar to that of Example 94, except that 1-bromo-2-methoxyethane in Step 3 was replaced with an equimolar amount of fluoroiodomethane to obtain 0.16 g of a white solid compound with a yield of 53.6%.

[0845] 1 H NMR(400MHz, DMSO-d 6 ) δ 10.50(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).

[0846] Example 96: Preparation of Compound P-96

[0847]

[0848] The preparation method of this compound was similar to that of Example 80, except that tert-butyl 4-amino-1H-pyrazole-1-carboxylate in Step 1 was replaced with an equimolar amount of deuterated iodomethane to obtain 0.05 g of a white solid compound with a yield of 55.6%.

[0849] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 11.95 (s, 1H), 8.91 (d, J = 41.0 Hz, 3H), 7.96 (s, 1H), 7.64 (d, J = 8.5 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.30–7.11 (m, 2H), 5.16 (t, J = 10.8 Hz, 1H), 4.45 (s, 2H), 4.26 (dd, J = 10.4, 7.5 Hz, 1H), 2.77 (t, J = 7.7 Hz, 1H), 2.41 (s, 6H), 1.59 (s, 3H), 0.79–0.67 (m, 3H).

[0850] Example 97: Preparation of Compound P-97

[0851]

[0852] This preparation method is similar to Example 17, except that: 5-aminoisatin-1-one in step 7 of Example 17 is replaced with an equimolar amount of 5-amino-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide-3,3-D 2 , obtaining 0.18 g of a white solid compound with a yield of 67.2%.

[0853] 1 1H NMR (400 MHz, DMSO-d 6 ) δ 10.60 (s, 1H), 8.11 (s, 1H), 7.84 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H), 7.52–7.46 (m, 2H), 7.24 (s, 1H), 5.18 (d, J = 10.4 Hz, 1H), 4.66 (t, J = 9.4 Hz, 1H), 2.80–2.74 (m, 1H), 2.43 (s, 3H), 1.62 (s, 3H), 0.70–0.66 (m, 3H).

[0854] Example 98: Preparation of Compound P-98

[0855]

[0856] This preparation method is similar to Example 49, except that: tert-butyl 3-(5-amino-1-oxoisoindolin-2-yl)azetidine-1-carboxylate in step 9 is replaced with 6-amino-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide-3,3-D 2 (Intermediate J), obtaining 0.12 g of a white solid compound with a yield of 41.4%.

[0857] 1 H NMR(400MHz, DMSO-d 6 ) δ 10.60 (s, 1H), 8.10 (d, J = 1.9 Hz, 1H), 7.83 (s, 1H), 7.73 (dd, J = 8.5, 2.0 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.21 (dd, J = 9.9, 6.4 Hz, 2H), 5.05 (d, J = 11.0 Hz, 1H), 4.12 (ddd, J = 21.1, 10.7, 4.9 Hz, 2H), 3.96 (d, J = 1.8 Hz, 3H), 2.92 (s, 3H), 1.56 (s, 3H).

[0858] Example 99: Preparation of Compound P-99

[0859]

[0860] 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%.

[0861] 1 H NMR(400MHz, DMSO-d 6 ) δ 10.80 (s, 1H), 8.00 (s, 1H), 7.93 (s, 2H), 7.65 (d, J = 3.5 Hz, 2H), 7.26–7.11 (m, 2H), 5.19 (d, J = 10.3 Hz, 1H), 4.47 (s, 2H), 4.26 (t, J = 9.2 Hz, 1H), 3.95 (s, 3H), 3.72 (d, J = 6.6 Hz, 2H), 3.08 (s, 2H), 2.76 (t, J = 7.4 Hz, 1H), 1.60 (s, 3H), 0.73 (d, J = 7.2 Hz, 3H).

[0862] Example 100: Preparation of Compound P-100

[0863]

[0864] This preparation method is similar to that of Example 17, except that: 5-aminoisoindolin-1-one in step 7 is replaced with 6-aminoisoindolin-1-one to obtain 0.14 g of a white solid compound with a yield of 55.6%.

[0865] 1H NMR (400 MHz, DMSO-d 6 ) δ 10.43 (s, 1H), 8.58 (s, 1H), 7.99 (s, 1H), 7.74 (d, J = 8.3 Hz, 1H), 7.51 (d, J = 8.2 Hz, 1H), 7.18 (t, J = 8.9 Hz, 2H), 5.08 (d, J = 10.3 Hz, 1H), 4.31 (s, 2H), 4.30–4.22 (m, 1H), 3.95 (s, 3H), 2.77 (t, J = 7.6 Hz, 1H), 1.61 (s, 3H), 0.80–0.69 (m, 3H).

[0866] Example 101: Preparation of Compound P-101

[0867]

[0868] The preparation method was similar to that of Example 17, except that: 5-aminoisoindol-1-one in Step 7 was replaced with 5-aminobenzo[d]isoxazol-3(2H)-one, and 0.15 g of a white solid compound was obtained with a yield of 60.1%.

[0869] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.60 (s, 1H), 8.30 (s, 1H), 8.04–7.98 (m, 1H), 7.95 (s, 1H), 7.66 (d, J = 9.1 Hz, 1H), 7.17 (d, J = 7.0 Hz, 2H), 5.10 (d, J = 10.3 Hz, 1H), 4.25 (t, J = 9.2 Hz, 1H), 3.95 (d, J = 2.6 Hz, 3H), 2.81–2.74 (m, 1H), 1.61 (s, 3H), 0.74 (d, J = 7.2 Hz, 3H).

[0870] Example 102: Preparation of Compound P-102

[0871]

[0872] The preparation method of the compound was similar to that of Example 17, except that: 5-aminoisoindol-1-one in Step 7 was replaced with an equimolar amount of 4-aminoisoindol-1-one, and 0.16 g of a white solid compound was obtained with a yield of 63.0%.

[0873] 1 H NMR (400 MHz, DMSO-d 6)δ10.04(s,1H),8.55(s,1H),7.76(d,J=7.4Hz,1H),7.53–7.42(m,2H),7.20(t,J=8.1Hz,2H),5.19(d,J=10.4Hz,1H),4.20(s,2H),3.95(d,J=2.7Hz,3H),2.75(q,J=7.4Hz,1H),1.62(s,3H),1.23(s,1H),0.74(d,J=7.3Hz,3H). Example 103: Preparation of Compound P-103

[0874]

[0875] The preparation method of the compound was similar to that of Example 32, except that: tert-butyl 4-amino-1H-pyrazole-1-carboxylate in Step 1 was replaced with 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%.

[0876] 1 H NMR(400MHz,DMSO-d 6 )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,2H),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).

[0877] Example 104: Preparation of Compound P-104

[0878]

[0879] The preparation method of the compound was similar to that of Example 32, except that: tert-butyl 4-amino-1H-pyrazole-1-carboxylate in Step 1 was replaced with an equimolar amount of 2-methoxyethan-1-amine to obtain 0.11 g of a white solid compound with a yield of 78.2%.

[0880] 1 H NMR(400MHz,DMSO-d 6)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).

[0881] Example 105: Preparation of Compound P-105

[0882]

[0883] The preparation method of the compound was similar to that of Example 32, except that: tert-butyl 4-amino-1H-pyrazole-1-carboxylate in Step 1 was replaced with an equimolar amount of cyclopropylamine to obtain 0.02 g of a white solid compound with a yield of 83.0%.

[0884] 1 H NMR(400MHz,DMSO-d 6 )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),3.95(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).

[0885] Example 106: Preparation of Compound P-106

[0886]

[0887] The preparation method of this compound was similar to that of Example 32, except that: tert-butyl 4-amino-1H-pyrazole-1-carboxylate in Step 1) was replaced with an equimolar amount of 2-((tert-butyldimethylsilyl)oxy)ethan-1-amine, and finally the -TBS protecting group was removed to obtain white solid Compound P-106 with a yield of 60.8%.

[0888] 1 H NMR(400MHz,DMSO-d6 )δ10.54 (singlet, 1H), 7.94 (singlet, 1H), 7.61 (doublet, J = 1.2 Hz, 2H), 7.24–7.11 (multiplet, 2H), 5.11 (doublet, J = 10.4 Hz, 1H), 4.83 (triplet, J = 5.3 Hz, 1H), 4.49 (singlet, 2H), 4.27 (doublet of doublets, J = 10.4, 7.5 Hz, 1H), 3.95 (doublet, J = 2.2 Hz, 3H), 3.56 (doublet of triplets, J = 22.1, 5.4 Hz, 4H), 2.77 (sextet, J = 7.4 Hz, 1H), 1.60 (singlet, 3H), 0.77–0.70 (doublet, J = 7.3 Hz, 3H).

[0889] Example 107: Preparation of Compound P-107

[0890]

[0891] The preparation method of this compound is similar to that of Example 32, except that: the tert-butyl 4-amino-1H-pyrazole-1-carboxylate in step 1) is replaced with an equimolar amount of methyl glycinate, and finally ammonolysis gives the white solid compound P-107, with a yield of: 89.2%.

[0892] 1 H NMR (400 MHz, DMSO-d 6 )δ10.53 (singlet, 1H), 7.95 (singlet, 1H), 7.62 (doublet, J = 2.7 Hz, 2H), 7.52 (singlet, 1H), 7.22–7.08 (multiplet, 3H), 5.11 (doublet, J = 10.3 Hz, 1H), 4.45 (singlet, 2H), 4.27 (doublet of doublets, J = 10.3, 7.6 Hz, 1H), 4.08 (singlet, 2H), 3.95 (doublet, J = 2.2 Hz, 3H), 2.76 (quartet, J = 7.6 Hz, 1H), 1.60 (singlet, 3H), 0.73 (doublet, J = 7.3 Hz, 3H).

[0893] Example 108: Preparation of Compound P-108

[0894]

[0895] The preparation method of this compound is similar to that of Example 32, except that: the tert-butyl 4-amino-1H-pyrazole-1-carboxylate in step 1) is replaced with an equimolar amount of 3-aminooxetane, and the white solid compound P-108 is obtained, with a yield of: 70.1%.

[0896] 1 H NMR (400 MHz, DMSO-d 6)δ 10.44 (s, 1H), δ 7.70–7.56 (m, 2H), 7.51 (t, J = 7.7 Hz, 1H), 7.03 (d, J = 86.4 Hz, 2H), 5.17 (t, J = 8.7 Hz, 1H), 4.61 (s, 1H), 4.42 (d, J = 14.9 Hz, 2H), 4.29 (d, J = 12.4 Hz, 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 = 23.5 Hz, 3H), 0.61 (s, 3H).

[0897] Example 109: Preparation of Compound P-109

[0898]

[0899] This preparation method is similar to 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 the white solid compound P-109 with a yield of 70.3%.

[0900] 1 H NMR (400 MHz, DMSO-d 6 )δ 9.77 (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 = 8.9 Hz, 1H), 4.26 (s, 2H), 3.99 (d, J = 2.0 Hz, 3H), 3.95–3.82 (m, 1H), 3.29–3.16 (m, 1H), 1.42 (s, 3H), 0.95 (d, J = 6.7 Hz, 3H).

[0901] Comparative Example 1

[0902]

[0903] Preparation of Intermediate A

[0904] The synthetic route of Intermediate A is as follows:

[0905]

[0906] Step 1: Preparation of Ethyl 2-(3,4-difluoro-2-methoxyphenyl)acetate

[0907] Ethyl 2-bromoacetate (23.12 g, 127.7 mmol), potassium carbonate (44.12 g, 319.2 mmol), tetrakis(triphenylphosphine)palladium(0) (0.26 g, 0.2 mmol) and cuprous oxide (0.46 g, 3.2 mmol) were added to a reaction tube. The tube was purged with nitrogen three times, and then a toluene solution containing (3,4-difluoro-2-methoxyphenyl)boronic acid (20.00 g, 106.4 mmol) was added thereto. The reaction was carried out overnight at 100 °C, and the reaction was monitored by TLC until completion. The reaction was cooled to room temperature, and the reaction mixture was diluted with ethyl acetate solution. It was washed with saturated brine 2-3 times, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 18.49 g of ethyl 2-(3,4-difluoro-2-methoxyphenyl)acetate with a yield of 75.5%. MS m / z calculated value: 230.07; experimental value: 231.1 [M+H] + 。

[0908] Step 2: Preparation of 2-(3,4-difluoro-2-methoxyphenyl)acetic acid

[0909] At room temperature, 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). Subsequently, the temperature was raised to 50 °C and monitored until the reaction was completed. Hydrochloric acid solution (1 M) was added to the reaction mixture to adjust the pH = 2, and it was extracted with ethyl acetate 2-3 times. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 3.54 g of crude product of 2-(3,4-difluoro-2-methoxyphenyl)acetic acid as a white solid with a yield of 99.6%. MS m / z calculated value: 202.04; experimental value: 203.2 [M+H] + 。

[0910] Preparation of Intermediate B

[0911] The synthetic route of Intermediate B is as follows:

[0912]

[0913] Step 1: Preparation of (R)-4,4,4-trifluoro-3-hydroxy-3-methylbutan-2-one

[0914] (R)-3,3,3-Trifluoro-2-hydroxy-2-methylpropanoic acid (50.00 g, 316.3 mmol) and diethyl ether (10 L) were charged into a dry reaction flask under nitrogen atmosphere. Under ice bath condition, methyllithium lithium bromide complex (27.54 g, 253.04 mmol) was slowly added, and then the reaction mixture was stirred overnight at room temperature. The mixture was neutralized by adding citric acid (121.53 g, 632.6 mmol) 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). The distillate was a colorless oil. By adding solid potassium carbonate particles, the product was dried and allowed to stand for 6 hours and then filtered through a glass filter to obtain 32.24 g of colorless oily compound (R)-4,4,4-trifluoro-3-hydroxy-3-methylbutan-2-one, with a yield of 65.3%. MS m / z calculated value: 156.03; experimental value: 157.1 [M + H] + 。

[0915] Preparation of Intermediate C

[0916] The synthetic route of Intermediate C is as follows:

[0917]

[0918] Step 1: Preparation of 1-bromo-4-(difluoromethoxy)-3-fluoro-2-methoxybenzene

[0919] 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 to a 250 mL flask and dissolved in an aqueous DMF solution (DMF:H 2 O = 4:1). The reaction was carried out overnight at 100 °C, and the reaction was monitored by TLC until completion. The mixture was washed with saturated brine 2 - 3 times, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 0.42 g of 1-bromo-4-(difluoromethoxy)-3-fluoro-2-methoxybenzene, with a yield of 34.4%. MS m / z calculated value: 269.95; experimental value: 271.9 [M + H] + 。

[0920] Step 2: Preparation of 2-(4-(difluoromethoxy)-3-fluoro-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0921] DPPF palladium dichloride (0.06 g, 0.1 mmol), potassium acetate (0.45 g, 4.5 mmol) and bis(pinacolato)diboron (0.47 g, 1.8 mmol) were successively added to a 250 mL reaction tube. After purging with nitrogen three times, a solution of 1-bromo-4-(difluoromethoxy)-3-fluoro-2-methoxybenzene (0.42 g, 1.5 mmol) in 1,4-dioxane was added via syringe. The reaction temperature was set at 100 °C and the reaction was carried out overnight. The reaction was monitored by TLC until completion. The reaction mixture was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 0.25 g of the white solid product 2-(4-(difluoromethoxy)-3-fluoro-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, with a yield of 50.8%. MS m / z calculated value: 318.13; experimental value: 317.1 [M+H] + 。

[0922] Preparation of Intermediate D

[0923] The synthetic route of Intermediate D is as follows:

[0924]

[0925] Step 1: Preparation of 1-bromo-4-(difluoromethoxy)-2,3-difluorobenzene

[0926] 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 to a 250 mL flask and dissolved in an aqueous DMF solution (DMF:H 2 O = 4:1). The reaction was carried out at 100 °C overnight. The reaction was monitored by TLC until completion. The reaction mixture was washed with saturated brine 2-3 times, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 0.67 g of 1-bromo-4-(difluoromethoxy)-2,3-difluorobenzene, with a yield of 27.1%. MS m / z calculated value: 257.93; experimental value: 259.4 [M+H] + 。

[0927] Step 2: Preparation of 2-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0928] PdCl₂(DPPF) (0.09 g, 0.1 mmol), potassium acetate (0.74 g, 7.5 mmol) and bis(pinacolato)diboron (0.76 g, 3.0 mmol) were successively added to a 250 mL reaction tube. The tube was purged with nitrogen three times, and then a solution of 1-bromo-4-(difluoromethoxy)-2,3-difluorobenzene (0.65 g, 2.5 mmol) in 1,4-dioxane was added via syringe. The reaction temperature was set at 100 °C and the reaction was carried out overnight. The reaction was monitored by TLC until completion. The reaction mixture was washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure and purified by column chromatography to obtain 0.37 g of the white solid product 2-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, with a yield of 48.2%. MS m / z calculated value: 306.10; experimental value: 305.1 [M+H] + 。

[0929] Preparation of Intermediate E

[0930] The synthetic route of Intermediate E is as follows:

[0931]

[0932] Under ice bath 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 added portionwise slowly. The mixture was allowed to warm to room temperature naturally and monitored by TLC until the reaction was complete. The reaction mixture was poured into ice water to adjust the pH to 7, and the aqueous phase was extracted with ethyl acetate, washed with saturated brine, and purified by column chromatography to obtain 75.5 mg of white solid powder, with a yield of 16.3%. MS m / z calculated value: 184.03; experimental value: 185.11 [M+H] + 。

[0933] Preparation of Intermediate F

[0934] The synthetic route of Intermediate F is as follows:

[0935]

[0936] In this reaction route, PMB- represents p-methoxybenzyl.

[0937] Step 1: Preparation of 5-bromo-2-(4-methoxybenzyl)-3,3-dimethylisoindolin-1-one

[0938] Add 5-bromo-2,3-dihydro-3,3-dimethyl-1H-isoindol-1-one (0.9 g, 3.8 mmol) to a 100 mL round-bottom flask. Then, successively add cesium carbonate (3.7 g, 11.4 mmol), 4-methoxybenzyl chloride (0.88 g, 5.7 mmol), and DMF (30 mL). Heat the resulting solution to 60 °C and react for 3 hours. Monitor the reaction by TLC until the raw materials are completely reacted. Cool the mixture to room temperature, then transfer the system to a separatory funnel with ethyl acetate (500 mL), wash it three times with saturated brine (200 mL), dry it over anhydrous sodium sulfate, and concentrate it under reduced pressure to obtain 1.00 g of a yellow oily product with a yield of 66.7%. MS m / z calculated value: 359.05; experimental value: 359.1 [M+H] + .

[0939] Step 2: Preparation of tert-butyl (2-(4-methoxybenzyl)-3,3-dimethyl-1-oxoisoindolin-5-yl)carbamate

[0940] Add 5-bromo-2-(4-methoxybenzyl)-3,3-dimethylisoindolin-1-one (1.0 g, 2.77 mmol), tert-butoxycarbonylamine (0.49 g, 4.16 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.25 g, 0.28 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.32 g, 0.55 mmol), and cesium carbonate (2.7 g, 8.32 mmol) to a 500 mL three-necked flask. After feeding, displace the air with nitrogen three times, add toluene (200 mL), heat to 100 °C and react overnight. Monitor the reaction by TLC until it is complete, then filter under reduced pressure. Wash the filter cake with ethyl acetate and concentrate the filtrate under reduced pressure. The residue is purified by column chromatography to obtain 0.82 g of a yellow oily compound with a yield of 74.6%. MS m / z calculated value: 396.20; experimental value: 397.1 [M+H] + .

[0941] Step 3: Preparation of tert-butyl (3,3-dimethyl-1-oxoisoindolin-5-yl)carbamate

[0942] Add 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) to a 250 mL round-bottom flask. Under an ice bath, add ammonium cerium(IV) nitrate (3.90 g, 7.08 mmol) to the system in batches. After adding it in batches, raise the temperature of the system to room temperature and react overnight. After monitoring the reaction to completion by TLC, transfer the system to a 1000 mL beaker, add saturated sodium bicarbonate solution (200 mL), filter under reduced pressure. Extract the filtrate with dichloromethane (500 mL) three times. Wash the organic phase with saturated brine (300 mL) three times, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 0.25 g of a yellow crude product with a yield of 50.5%. MS m / z calculated value: 276.15; experimental value: 276.1 [M+H] + 。

[0943] Step 4: Preparation of 5-amino-3,3-dimethylisoindolin-1-one hydrochloride

[0944] Add tert-butyl (3,3-dimethyl-1-oxoisoindolin-5-yl)carbamate (0.25 g, 0.9 mmol) and ethanol solution of hydrogen chloride (20 mL) to a 100 mL round-bottom flask. Stir at room temperature for 2 hours. After monitoring the reaction to completion by TLC, concentrate under reduced pressure. Pulverize and purify the obtained crude product with dichloromethane to obtain 0.15 g of a pale yellow solid compound with a yield of 75.1%. MS m / z calculated value: 176.09; experimental value: 176.1 [M+H] + 。

[0945] Preparation of Intermediate G

[0946] The synthetic route of Intermediate G is as follows:

[0947]

[0948] In this reaction route, -PMB represents p-methoxybenzyl.

[0949] Step 1: Preparation of methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate

[0950] Methyl 4-bromo-2-fluoro-6-methylbenzoate (5.00 g, 20.0 mmol), carbon tetrachloride (200 mL) were added to a 500 mL round-bottom flask. After stirring at room temperature, N-bromophthalimide (4.27 g, 24.0 mmol) and 2,2'-azobis(2-methylpropionitrile) (0.33 g, 2.0 mmol) were added to the resulting solution. The mixture was heated to 80 °C and reacted overnight. After monitoring the complete reaction of the starting materials by TLC, the reaction mixture was washed with saturated sodium sulfite solution and saturated brine, and then purified by column chromatography to obtain 5.00 g of a white solid with a yield of 76.8%. MS m / z calculated value: 323.88; experimental value: 324.9 [M+H] + 。

[0951] Step 2: Preparation of 5-bromo-7-fluoro-2-(4-methoxybenzyl)isoindolin-1-one

[0952] Methyl 4-bromo-2-(bromomethyl)-6-fluorobenzoate (5.00 g, 15.4 mmol) and tetrahydrofuran (200 mL) were added to a 500 mL round-bottom flask. After stirring at room temperature, 4-methoxybenzylamine (3.16 g, 23.1 mmol) was added dropwise to the system. The temperature was raised to 80 °C and the mixture was reacted overnight. After monitoring the complete reaction of the starting materials by TLC, the solvent was directly evaporated under reduced pressure. The resulting yellow powder was triturated with n-hexane to obtain 4.82 g of a pale yellow solid with a yield of 89.4%. MS m / z calculated value: 350.19; experimental value: 351.2 [M+H] + 。

[0953] Step 3: Preparation of tert-butyl (7-fluoro-2-(4-methoxybenzyl)-1-oxoisoindolin-5-yl)carbamate

[0954] 5-Bromo-7-fluoro-2-(4-methoxybenzyl)isoindolin-1-one (1.00 g, 2.8 mmol), tert-butyl carbamate (0.50 g, 4.2 mmol), tris(dibenzylideneacetone)dipalladium(0) (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) were added to a 100 mL Schlenk tube. After the addition was complete, the tube was purged with argon three times. Toluene (200 mL) was added and the mixture was heated to 100 °C and reacted overnight. After monitoring the complete reaction by TLC, the reaction mixture was 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 a yellow oily compound with a yield of 59.6%. MS m / z calculated value: 386.42; experimental value: 387.4 [M+H] + 。

[0955] Step 4: Preparation of tert-butyl (7-fluoro-1-oxoisoindolin-5-yl)carbamate

[0956] To a 250 mL round-bottom flask, add 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). Under an ice bath, cerium ammonium nitrate (2.75 g, 6.8 mmol) was added to the system in batches. After the addition was completed in batches, the system was warmed to room temperature and reacted overnight. After monitoring the reaction to completion by TLC, the system was transferred to a 1000 mL beaker, saturated sodium bicarbonate solution (200 mL) was added, and the mixture was filtered under reduced pressure. 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 obtain 0.33 g of a yellow crude product with a yield of 71.1%. MS m / z calculated value: 266.27; experimental value: 267.2 [M+H] + 。

[0957] Step 5: Preparation of 5-amino-7-fluoroisoindol-1-one

[0958] To a 100 mL round-bottom flask, add tert-butyl (7-fluoro-1-oxoisoindolin-5-yl)carbamate (0.33 g, 1.2 mmol) and ethanol solution of hydrogen chloride (20 mL). Stir at room temperature for 2 hours. After monitoring the reaction to completion by TLC, concentrate under reduced pressure. The obtained crude product was triturated and purified with dichloromethane to obtain 0.27 g of a pale yellow solid compound with a yield of 80.0%. MS m / z calculated value: 166.16; experimental value: 167.1 [M+H] + 。Preparation of Intermediate H

[0959] The synthetic route of Intermediate H is as follows:

[0960]

[0961] Step 1: Preparation of ethyl 2-diazo-3-oxopentanoate

[0962] Dissolve ethyl propionylacetate (28.8 g, 200 mmol) in dichloromethane (250 mL) solution. Replace the gas in the reaction system with nitrogen three times. Cool the reaction solution to 0 °C, add TEA (60.6 g, 600 mmol) to it, stir at 0 °C for 5 minutes, add 4-methylbenzenesulfonyl azide (47.3 g, 240 mmol), and slowly return to room temperature and stir for 6 h. Quench the reaction with water (300 mL), extract with dichloromethane (1000 mL), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 17.3 g of ethyl 2-diazo-3-oxopentanoate as a colorless oily compound with a yield of 51%. MS m / z calculated value: 170.17; experimental value: 171.1 [M+H] + 。

[0963] Step 2: Preparation of Ethyl (Z)-2-diazo-3-((trimethylsilyl)oxy)penta-3-enoate

[0964] Dissolve ethyl 2-diazo-3-oxopentanoate (60.0 g, 353 mmol) in dichloromethane (720 mL), and cool the solution 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, and monitor the reaction completion by TLC. Wash the reaction mixture with saturated sodium bicarbonate solution (1000 mL), separate the organic layer, wash it with water (500 mL), dry over anhydrous sodium sulfate, filter, and concentrate in vacuo to obtain 72 g of crude ethyl (Z)-2-diazo-3-((trimethylsilyl)oxy)penta-3-enoate with a yield of 67%. The product can be directly used in the next step without further purification.

[0965] Step 3: Preparation of Ethyl rac-(4R,5R)-2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxohexanoate

[0966] Cool a solution of trifluoroacetone (47.0 g, 37.5 mL, 416 mmol) in dichloromethane (300 mL) to -78 °C. Add a solution of titanium tetrachloride (78.9 g, 416 mmol) in dichloromethane (340 mL) dropwise to the stirred reaction mixture. Stir the reaction mixture at -78 °C for 10 minutes, and then add a solution of ethyl (Z)-2-diazo-3-((trimethylsilyl)oxy)penta-3-enoate (72.0 g, 297 mmol) in dichloromethane (300 mL) dropwise. Stir the reaction mixture at -78 °C for 2 hours. Add saturated aqueous sodium bicarbonate solution (1000 mL), extract the aqueous phase with dichloromethane (300 mL x 2), separate the organic layer, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 51 g of pale yellow liquid ethyl rac-(4R,5R)-2-diazo-6,6,6-trifluoro-5-hydroxy-4,5-dimethyl-3-oxohexanoate with a yield of 57.6%. Calculated MS m / z: 282.08; Experimental value: 283.1 [M+H] + Step 4: Preparation of Ethyl rac-(4R,5R)-4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate

[0967] Dissolve 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) in toluene (100 mL), and add rhodium(II) acetate dimer (470 mg, 1.06 mmol, 0.015 eq). Stir the reaction mixture at 100 °C for 2 hours. Remove the solvent in the mixture under vacuum to obtain 18.0 g of crude product ethyl rac-(4R,5R)-4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate as a green oil, which is directly used in the next step of the reaction.

[0968] Step 5: Preparation of ethyl rac-(4R,5R)-4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate

[0969] Dissolve crude ethyl rac-(4R,5R)-4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylate (18.0 g, 70.5 mmol) in anhydrous dichloromethane (200 mL) solution. Replace the gas with nitrogen three times. Cool the reaction solution to -78 °C, add diisopropylethylamine (10.9 g, 84.6 mmol) and a solution of trifluoromethanesulfonic anhydride (23.9 g, 84.6 mmol) in anhydrous dichloromethane (50 mL) thereto, and stir at this temperature for 1 hour. Gradually warm the reaction to 0 °C and stir for 0.5 hour. Quench the reaction with saturated sodium bicarbonate solution (100 mL), extract with dichloromethane (150 mL), and combine the organic phases. Wash with saturated brine, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 15 g of ethyl rac-(4R,5R)-4,5-dimethyl-5-(trifluoromethyl)-3-(((trifluoromethyl)sulfonyl)oxy)-4,5-dihydrofuran-2-carboxylate as a colorless oil, with a yield of 54.6%. Calculated MS m / z: 386.03; experimental value: 387.1 [M+H] + 。

[0970] Preparation of Intermediate I

[0971] The synthetic route of Intermediate I is as follows:

[0972]

[0973] Step 1: Preparation of (6-bromo-2,3-difluorophenyl)(methyl)sulfane

[0974] 4-Bromo-1,2-difluorobenzene (20 g, 103.6 mmol) was dissolved in tetrahydrofuran (200 mL) solution, replaced with nitrogen three times, and the reaction solution was cooled to -78 °C. LDA (62 mL, 124 mmol, 2 M) was added and stirred at this temperature for half an hour, and dimethyl disulfide (11.7 g, 124 mmol) was added. The reaction was gradually warmed to room temperature and stirred for 2.5 hours. The reaction was quenched with saturated ammonium chloride solution (400 mL), extracted with ethyl acetate (150 mL × 3), and 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 12 g of a colorless oily compound (6-bromo-2,3-difluorophenyl) (methyl) sulfane with a yield of 46%. MS m / z calculated value: 239.92; experimental value: 238.9 [MH] - .

[0975] Step 2: Preparation of (3,4-difluoro-2-(methylthio)phenyl)boronic acid

[0976] Dissolve (6-bromo-2,3-difluorophenyl)(methyl)sulfane (12g, 50.2mmol) in tetrahydrofuran (120mL) solution, replace with nitrogen three times, cool the reaction solution to 0℃, add i-PrMgBr.LiCl (30.1mL, 60.2mmol, 2M), stir at 0℃ for half an hour, add triisopropyl borate (18.88g, 100.4mmol), stir at 0℃ for 2.5 hours. Quench the reaction with saturated ammonium chloride solution (300mL), extract with ethyl acetate (100mL×3), combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify by column chromatography to obtain 8g of colorless oily compound (3,4-difluoro-2-(methylthio)phenyl)boronic acid, with a yield of 52%. MS m / z calculated value: 204.02; experimental value: 203.0[MH] - .

[0977] Preparation of intermediate J

[0978] The synthetic route of intermediate J is as follows:

[0979]

[0980] Step 1: 5-amino-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide-3,3-d 2 Preparation

[0981] Under an ice bath, lithium aluminum deuteride (0.51 g, 12 mmol) was added portionwise to a solution of 5-aminobenzo[d]isothiazol-3(2H)-one 1,1-dioxide (2 g, 10 mmol) in tetrahydrofuran (30 mL). After stirring for half an hour, the mixture was transferred to room temperature and stirred for another 2 hours. After monitoring the completion of the reaction, the reaction was quenched with a saturated solution of potassium sodium tartrate. The aqueous phase was extracted with ethyl acetate (20 mL×3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain the yellow solid compound 5-amino-2,3-dihydrobenzo[d]isothiazole 1,1-dioxide-3,3-d 2 Approximately 0.98 g, with a yield of 52%. Calculated MS m / z: 186.04; Experimental value: 187.1 [M+H] + .

[0982] Biological part test:

[0983] Test Example 1: Blocking activity of the compound of the present invention against sodium channel 1.8 (Nav1.8)

[0984] 1. Detection method: The whole-cell manual patch clamp technique was used to detect the effect of the compound on the voltage-gated Nav1.8 channel current

[0985] 2. Preparation and analysis of the test compound

[0986] Blank control: An appropriate amount of DMSO was added to the extracellular fluid to obtain an extracellular fluid containing 0.1% DMSO as the blank control working solution

[0987] Test compound: An appropriate amount of the test substance was weighed and dissolved in DMSO to obtain a stock solution of the test compound to be tested. Subsequently, it was further diluted with extracellular fluid to obtain test compound working solutions with different final concentrations such as 10 nM, 50 nM, 0.1 μM, 1 μM, and 10 μM (the DMSO concentration in the working solution did not exceed 0.3%)

[0988] 3. Cell culture

[0989] The CHO cell line stably expressing Nav1.8 was used (gene information: SCN10A, NM_006514; SCN1B, NM_199037; SCN3B, NM_018400). In a cell culture dish, cell culture and passage were carried out using HAM’S / F-12 medium (containing 10% fetal bovine serum, 10 μg / mL Blasticidin, 200 μg / mL Hygromycin B, and 100 μg / mL Zeocin). The temperature of the cell culture incubator was 37°C, and the carbon dioxide concentration was 5%. To maintain the electrophysiological activity of the cells, the cell density in the culture dish should not exceed 80%

[0990] Before patch clamp detection, cells were separated with 0.25%-Trypsin-EDTA, and 6.5×10 3 cells were plated onto cover slips and cultured in 24-well plates (final volume: 500 μL). After adding tetracycline and inducing for 24 - 72 hours, the experiment was detected.

[0991] 4. Electrophysiological experiments

[0992] (1) Liquids used in electrophysiological experiments

[0993] Extracellular fluid: 140 mM NaCl, 3.5 mM KCl, 1 mM MgCl 2 ·6H 2 O, 2 mM CaCl 2 ·2H 2 O, 10 mM D-Glucose, 10 mM HEPES, 1.25 mM NaH 2 PO 4 ·2H 2 O, pH was adjusted to 7.4 with NaOH.

[0994] Intracellular fluid: 50 mM CsCl, 10 mM NaCl, 10 mM HEPES, 60 mM CsF, 20 mM EGTA, pH was adjusted to 7.2 with CsOH.

[0995] (2) Patch clamp detection

[0996] The voltage stimulation protocol for whole-cell patch clamp recording of sodium current was as follows: When a whole-cell seal was formed, the cell voltage was clamped at -120 mV. First, the voltage was stepped from -130 mV to -10 mV in 10 mV increments and maintained for 5 s, then a depolarizing pulse to 0 mV was given to obtain the half-inactivation voltage (Vhalf). The resting state and half-inactivated state of sodium current were detected using a double-pulse mode. First, a first depolarizing pulse (TP1) to 0 mV for 50 ms was given to detect the sodium current in the resting state. Then the voltage was adjusted to Vhalf and maintained for 5 s, then the voltage was restored to -120 mV and maintained for 20 ms, and then a second depolarizing pulse (TP2) to 0 mV for 50 ms was given to detect the sodium current in the half-inactivated state. Finally, the voltage was restored to the clamped voltage of -120 mV. Data was collected every 20 s to observe the effect of the drug on the peak values of sodium current in two different states. The experimental data was collected by an EPC 10 amplifier (HEKA) and stored in the PatchMaster (HEKA) software.

[0997] Patch clamp operation: First, a glass capillary is pulled into a recording electrode using a microelectrode puller. Then, the electrode filled with intracellular solution is inserted into a microelectrode holder. Under an inverted microscope, the microelectrode manipulator is used to immerse the electrode in the extracellular solution and record the electrode resistance (Rpip). Then, the electrode is slowly brought into contact with the cell surface, and negative pressure aspiration is applied to form a GΩ high-resistance seal. At this time, fast capacitance compensation is performed, and negative pressure is continuously applied to rupture the cell membrane to form the whole-cell recording mode. Finally, slow capacitance compensation is carried out and experimental parameters such as series resistance (Rs) are recorded. Leakage compensation is not given.

[0998] When the sodium current in the whole-cell recording is stable, drug administration is started. After each drug concentration acts for 5 min (or until the current is stable), the next concentration is detected. The coverslip with cells is placed in a recording bath under an inverted microscope. The blank control extracellular solution and the working solution of the compound to be tested are perfused through the recording bath from low concentration to high concentration in sequence by gravity perfusion to act on the cells, and at the same time, a peristaltic pump is used for liquid replacement during the recording. The current detected in the extracellular solution without the compound for each cell serves as its own control group. Each concentration is independently repeated and detected at least twice using two cells. All electrophysiological experiments are carried out at room temperature.

[0999] 5. Data analysis

[1000] First, the peak sodium current (Peak current compound ) after the action of each drug concentration and the peak current of the blank control (Peak current control ) are normalized, and then the inhibition rate corresponding to each drug concentration in different states is calculated, that is And the average value of the inhibition rate for each concentration is taken.

[1001] The dose-effect curve is 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, Y represents the Peak-current compound / Peak-current Control value, IC 50 represents the drug concentration that produces a half-inhibitory effect, and HillSlope represents the Hill coefficient.

[1002] The results of the blocking activity of some compounds of the present invention on the Nav1.8 channel are shown in Tables 1 to 5. TP1 is the Resting state (resting state), and TP2 is the Half-inactivated state (semi-inactivated state).

[1003] Table 1 Percentage blockage activities of some compounds of the present invention on Nav1.8 channels at a concentration of 10 μM

[1004]

[1005] Table 2 Percentage blockage activities of some compounds of the present invention on Nav1.8 channels at a concentration of 1 μM

[1006]

[1007] Table 3 Percentage blockage activities of some compounds of the present invention on Nav1.8 channels at a concentration of 100 nM

[1008]

[1009]

[1010] The inhibition rates of P-50, P-51, P-59, P-63, P-68, P-72, P-73, P-94, P-103 on TP1 and TP2 are > 50% at a concentration of 100 nM. Table 4 Percentage blockage activities of some compounds of the present invention on Nav1.8 channels at a concentration of 10 nM

[1011]

[1012] The inhibition rates of 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, P-90 on TP1 and TP2 are > 50% at a concentration of 10 nM.

[1013] Table 5 Activity IC of representative compounds on Nav1.8 channels 50 Value (nM)

[1014]

[1015]

[1016] Test Example 2: Detection of the effect of the test substance on the TTX-R current of acutely isolated rat dorsal root ganglion (DRG) by manual patch clamp technique

[1017] 1) Isolation of DRG neurons

[1018] In this test example, acutely isolated rat DRG neurons were used.

[1019] a. Solution preparation

[1020]

[1021] b. Separation step

[1022] Anesthetize 2 - 3 week - old rats with 0.4 mL / 100 g of 20% urethane, place them in the prone position, disinfect the skin with 75% alcohol, cut the skin at the tail with surgical scissors, fully expose the spine, and remove the muscle tissue on both sides of the spine.

[1023] Remove the spine from the caudal vertebra to the cervical vertebra and place it in a 10 - cm dish containing HBSS on an ice box. Use rat scissors to cut off the upper 1 / 3 of the spinal cord cross - section. After removing the spinal cord, the nerve connecting the DRG can be seen. Under the dissecting microscope, remove the L4 - L6 DRG.

[1024] After removing all DRGs, cut off the nerves connected to the DRGs under the microscope.

[1025] Cut the DRGs with the nerves removed into small pieces and aspirate them into a 15 - mL centrifuge tube, then transfer them to the cell culture room.

[1026] Centrifuge at 1000 r / min for 5 min and discard the supernatant.

[1027] Add 5 mL of digestive solution, place it in an incubator at 37°C with 5% CO 2 for about 20 min, shake it from time to time to resuspend the tissue, pipette the tissue. During the digestion process, the tissue can be seen to be filamentous. After repeating two or three times, the filaments disappear and there are no tissue blocks, indicating that the digestion is complete.

[1028] After the digestion is completed, add 5 mL of complete medium, centrifuge at 1000 r / min for 5 min, and discard the supernatant.

[1029] Add an appropriate amount of complete medium, gently resuspend the cells, and add the cell suspension to the coated PLL cell slides.

[1030] It can be used for patch - clamp experiments after 2 h. At this time, divide the cells into two groups: a blank control group and an INS018_055 5 μM drug - treated group.

[1031] For the INS018_055 5 μM drug - treated group, after the cells adhere to the wall, add 5 μM of the final concentration in the complete medium and incubate for 1 h before using for experimental detection.

[1032] 2) Electrophysiological recording

[1033] a. Liquid used for recording

[1034] Extracellular fluid: DRG - 004 - 1

[1035] 22 mM NaCl, 110 mM Choline - Cl, 0.8 mM MgCl 2 ·6H 2 O, 1.8 mM CaCl 2 ·2H 2 O, 5 mM D - Glucose, 10 mM

[1036] HEPES, 0.1 mM CdCl 2 , pH was adjusted to 7.4 with NaOH.

[1037] Intracellular fluid: DRG - 004 - 2

[1038] 10 mM CsCl, 5 mM NaCl, 10 mM HEPES, 135 mM CsF, 5 mM EGTA, pH was adjusted to 7.2 with CsOH. 2 mM Mg - ATP was added freshly before use.

[1039] The extracellular fluid was stored at 4°C for 2 weeks. After the intracellular fluid was prepared, it was aliquoted into 1 - mL tubes and stored at - 20°C in the refrigerator. Freshly thawed intracellular fluid was used for each experiment.

[1040] All intracellular fluid should be used up within three months, otherwise it should be discarded and re - prepared.

[1041] b. Patch - clamp detection

[1042] The voltage - stimulation protocol for whole - cell patch - clamp recording of TTX - R current is as follows (e.g., Figure 1Schematic illustration: After forming a whole-cell seal, the cell voltage was clamped at -120 mV. First, the voltage was stepped from -130 mV to -10 mV in 10 mV increments and maintained for 5 s, and then a 0 mV depolarizing pulse was applied to obtain the half-inactivation voltage (Vhalf). The resting state and half-inactivated state of the TTX-R current were detected using a double-pulse protocol. First, a first depolarizing pulse (TP1) to 0 mV for 50 ms was given to detect the TTX-R current in the resting state. Then the voltage was adjusted to Vhalf and maintained for 5 s, and then the voltage was restored to -120 mV and maintained for 20 ms to allow the channels that were not bound to the compound and in the inactivated state to recover. Then a second depolarizing pulse (TP2) to 0 mV for 50 ms was given to detect the TTX-R current in the half-inactivated state. Finally, the voltage was restored to the clamped voltage of -120 mV, and data were collected at 20 s intervals to observe the effect of the drug on the peak sodium current in the two different states. The experimental data were collected by an EPC 10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.

[1043] For patch clamp operation, a glass capillary was first pulled into a recording electrode using a microelectrode puller, and then the electrode filled with intracellular solution was inserted into the microelectrode holder. Next, the coverslip with cells was placed in the recording bath under an inverted microscope, and the microelectrode manipulator was used under the inverted microscope to immerse the electrode in the extracellular solution and record the electrode resistance (Rpip). Then the electrode was slowly brought into contact with the cell surface, and negative pressure aspiration was applied to form a GΩ high-resistance seal. At this time, fast capacitance compensation was performed, and negative pressure was continuously applied to rupture the cell membrane to form a whole-cell recording mode. Finally, slow capacitance compensation was performed and experimental parameters such as the series resistance (Rs) were recorded. Leakage compensation was not given.

[1044] Drug administration was started after the current amplitude was stable when the cells were in the control extracellular solution. The current was measured at the next concentration after the current reached equilibrium block at each drug concentration. The blank control extracellular solution and the working solution of the compound to be tested were perfused through the recording bath from low concentration to high concentration in sequence by gravity perfusion to act on the cells, and at the same time, a peristaltic pump was used for liquid replacement during the recording. The current detected in the extracellular solution without the compound for each cell was used as its own control group. Each concentration of the TTX-R current was independently repeated 2 times, and all electrophysiological experiments were carried out at room temperature.

[1045] 3) Data analysis

[1046] First, the peak TTX-R current (Peak current compound ) after the action of each drug concentration and the peak control current (Peak current control)Normalize, and then calculate the inhibition rate corresponding to each drug concentration under different states, that is And calculate the mean (Mean), standard deviation (SD) and standard error (SE) for the inhibition rate of each concentration. The data is expressed as Mean±SE.

[1047] Y = Bottom+(Top - Bottom) / (1 + 10^((LogIC 50 -X)*HillSlope))

[1048] Use the above equation to calculate the IC 50 value of the compound, and perform non-linear fitting on the concentration-effect curve. Among them, IC 50 is the half-inhibitory concentration. The calculation of IC 50 and curve fitting are completed using GraphPad Prism software.

[1049] 4) Test results

[1050] The inhibitory effect of the test substance on the TTX-R current of acutely isolated 2-3 week rat dorsal root ganglion (DRG) neurons (dorsal root ganglion, DRG) was detected by manual patch clamp technique in two independent repeated tests. The test results showed that the compounds of the present invention had good inhibitory effects. Among them, the IC 50 <200 nM for the inhibitory effect of P-40, P-48, P-66, P-81, P-87, P-93, P-95, P-100 on the resting state of rat DRG TTX-R; the IC 50 of the inhibitory effect of P-81 and P-87 on the resting state of rat DRG TTX-R was 200 - 500 nM; the IC 50 >1000 nM for the inhibitory effect of P-100 on the resting state of rat DRG TTX-R.

[1051] Test Example 3: hERG inhibitory activity test:

[1052] 1. Sample preparation

[1053] Preparation of blank control: Take an appropriate amount of DMSO and add it to the extracellular fluid to obtain an extracellular fluid containing 0.3% DMSO as the working solution of the blank control.

[1054] 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 (ensure that the DMSO concentration is 0.3%).

[1055] Preparation of the test substance: Weigh an appropriate amount of the test substance, dissolve it in an appropriate amount of DMSO, and then prepare working solutions of the test substance with concentrations of 30 μM, 10 μM, 3 μM, 1 μM, and 0.3 μM using extracellular fluid, ensuring that the concentration of DMSO in each working solution is 0.3%.

[1056] 2. Cell culture

[1057] Use the HEK-293 cell line stably expressing the hERG potassium channel. The hERG potassium channel cells were purchased from Creacell (product number: A-0320). In cell culture dishes, culture and passage the cells using DMEM medium containing 10% fetal bovine serum and 0.8 mg / mL G418. The temperature of the cell culture incubator is 37 °C, and the carbon dioxide concentration is 5%. To maintain the electrophysiological activity of the cells, the cell density must not exceed 80%.

[1058] Before patch clamp detection, the cells were separated with TrypLE TM Express, and 4 × 10 3 cells were plated onto cover slips and cultured in 24-well plates (final volume: 500 μL). After 18 hours, the test was performed.

[1059] 3. Electrophysiological recording

[1060] Extracellular fluid: K-007-1, 140 mM NaCl, 3.5 mM KCl, 1 mM MgCl 2 ·6H 2 O, 2 mM CaCl 2 ·2H 2 O, 10 mM D-Glucose, 10 mM HEPES, 1.25 mM NaH 2 PO 4 ·2H 2 O, adjusted to pH = 7.4 with NaOH.

[1061] Intracellular fluid: K-002-2, 20 mM KCl, 115 mM K-Aspartic, 1 mM MgCl 2 ·6H 2 O, 5 mM EGTA, 10 mM HEPES, 2 mM Na 2 -ATP, adjusted to pH = 7.2 with KOH.

[1062] Patch clamp assay: The voltage stimulation protocol for whole-cell patch clamp recording of hERG current is as follows: After forming a whole-cell seal, the cell membrane potential is clamped at -80 mV. The holding potential is depolarized from -80 mV to -50 mV for 0.5 s (as a leakage current detection), then stepped to 30 mV for 2.5 s, and then rapidly restored to -50 mV for 4 s to evoke the tail current of the hERG channel. Data is collected every 10 s to observe the effect of the drug on the hERG tail current. A -50 mV stimulation for 0.5 s is used as the leakage current detection. The experimental data is collected by an IPA amplifier (Sutter Instrument) and stored in the SutterPatch (with IgorPro) software.

[1063] For patch clamp operation, a glass capillary is first pulled into a recording electrode using a microelectrode puller, and then the electrode filled with intracellular solution is inserted into the microelectrode holder. Under an inverted microscope, the microelectrode manipulator is used to immerse the electrode in the extracellular solution and record the electrode resistance (Rpip). Then the electrode is slowly brought into contact with the cell surface, and negative pressure is applied to form a GΩ high-resistance seal. At this time, fast capacitance compensation is performed, and negative pressure is continuously applied to break the cell membrane to form a whole-cell recording mode. Finally, slow capacitance compensation is performed and experimental parameters such as the series resistance (Rs) are recorded. Leakage compensation is not given.

[1064] When the hERG current in whole-cell recording is stable, the drug is administered. Each drug concentration acts for 5 min (or until the current is stable), and then the next concentration is tested. Multiple concentrations are tested for each test compound. The coverslip with cells is placed in the recording bath under an inverted microscope. The blank control extracellular solution and the working solution of the test compound are perfused through the recording bath from low concentration to high concentration in sequence by gravity perfusion to act on the cells, and a peristaltic pump is used for liquid exchange during recording. The current detected in the extracellular solution without the compound for each cell is used as its own control group. Each concentration is independently repeated and tested at least three times using at least three cells. All electrophysiological experiments are performed at room temperature.

[1065] 4. Data analysis

[1066] First, the tail current (Peak tail current compound ) after the action of each drug concentration and the blank control tail current (Peak tail current control ) are normalized, and then the inhibition rate corresponding to each drug concentration is calculated and the average value of the inhibition rate for each concentration is calculated.

[1067] The dose-effect curve is fitted using the Hill equation: Y = Bottom + (Top - Bottom) / (1 + 10^((LogIC 50-(X)*Hill Slope)), 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 represents the drug concentration that produces a half-inhibitory effect, and Hill Slope represents the Hill coefficient.

[1068] Table 6 Inhibitory activity of representative compounds against hERG

[1069] Compound Number <![CDATA[hERG, IC 50 > P-19 >10 μM P-20 >30 μM P-29 >30 μM

[1070] The results show that the compounds of the present invention have very weak inhibitory activity against hERG (potassium ion channel) and exhibit high ion channel selectivity.

[1071] Test Example 4: Liver microsome metabolic stability test:

[1072] 1. Sample preparation

[1073] Working solutions of the test compound and the positive control compound: The test compound and the positive control compound (dextromethorphan) were separately dissolved in DMSO to prepare 1 mM intermediate working solutions. Subsequently, the intermediate working solutions were diluted with acetonitrile (ACN) to 200 μM working solutions.

[1074] Phosphate buffer solution: 8.709 g of dipotassium hydrogen phosphate (K 2 HPO 4 ) was dissolved in 950 mL of water, the pH value of the solution was adjusted to 7.4 with hydrochloric acid, and then the volume was made up to 1000 mL with water. After filtration through a 0.22 μm filter membrane, it was stored in a refrigerator at 4 °C for standby.

[1075] Incubation matrix working solution: Liver microsomes of various species (protein concentration 20 mg / mL) were melted in a water bath at 37 °C and then diluted with phosphate buffer solution to obtain liver microsome working solutions with a protein concentration of 0.629 mg / mL.

[1076] NADPH working solution: Prepared into a 5 mM NADPH solution with the above phosphate buffer solution for standby.

[1077] Reaction termination solution: A stock solution of 1 mg / mL terfenadine / tolbutamide was prepared with DMSO, and then diluted with a mixed solution of 50% methanol / 50% acetonitrile to obtain a reaction termination solution containing 5 / 10 ng / mL (terfenadine / tolbutamide) internal standard.

[1078] 2. Incubation and detection

[1079] Add 238.5 μL of liver microsome working solutions of different species into 1.1 mL microtubes, and add 1.5 μL of the test compound working solution or the positive control compound (dextromethorphan) working solution (200 μM) respectively. After mixing, pre-incubate in a 37 °C water bath for 5 min. Add 60 μL of NADPH solution to initiate the reaction. After thorough mixing, at the time points of 0, 5, 15, 30, and 60 minutes after the reaction, transfer 30 μL of the reaction solution to 300 μL of the reaction termination solution respectively. Vortex all the samples vigorously for 1 minute and then centrifuge at 4000 rpm at 4 °C for 15 minutes. Take the supernatant for LC-MS / MS analysis.

[1080] 3. Data analysis

[1081] The slope (ke) was measured by plotting the natural logarithm of the percentage of the remaining compound against time, and the T 1 / 2 and the intrinsic clearance (CL int ) were calculated according to the first-order kinetic formula:

[1082] The calculation formula for the remaining rate of the compound is as follows:

[1083]

[1084] C t = C 0 *e -ke*t

[1085] lnC t = lnC o –ke*t

[1086] According to the above formula, when , the following can be obtained

[1087] The intrinsic clearance CL int (μL / min / mg protein) = 0.693 * 1000 / T 1 / 2 / protein concentration (0.5 mg protein / mL)

[1088] C t = C 0 ×e -ke·t ,

[1089]

[1090] It is assumed that the unbound part (Fu) in the liver microsome mixture is 100%.

[1091]

[1092] The following physiological variables are used for predictive calculations:

[1093]

[1094] The test results of liver microsomal stability are shown in Table 7.

[1095] Table 7 Liver microsomal stability of the compounds of the present invention against Nav1.8 channels

[1096]

[1097]

[1098] The results show that the compounds of the present invention exhibit good metabolic stability in human and rat liver microsomes.

[1099] Test Example 5: Solubility test

[1100] Method for determining solubility in pH 7.4 phosphate buffer: Excess DMSO stock solutions of the test compounds to be measured were separately placed in pH 7.4 phosphate buffer, shaken at 25 °C - 350 rpm for 4 h, sampled, filtered through a 0.22 μm filter membrane, and the concentration of the continued filtrate was measured. The results are shown in the following table:

[1101] Table 8 Solubility of representative compounds

[1102] Compound Number Solubility, μM (pH = 7.4) P-17 1.8 P-35 50.7 P-36 84.8 P-38 125 P-40 145 P-44 300 P-57 137 P-67 30.3 P-70 230 P-74 25.6 P-85 62.9 P-86 254 P-99 116

[1103] The results show that the compounds of the present invention exhibit good solubility.

[1104] Test Example 6: CYP450 enzyme inhibition test

[1105] An in vitro test system was used to evaluate the effects of the test substances on the activities of 5 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A) of cytochrome P450 (CYP) in human liver microsomes. The specific probe substrates of CYP450 isoenzymes were incubated with human liver microsomes and different concentrations of the test substances, respectively. Reduced nicotinamide adenine dinucleotide phosphate (NADPH) was added to initiate the reaction. After the reaction ended, the samples were processed and the metabolites produced by the specific substrates were quantitatively detected by liquid chromatography - tandem mass spectrometry (LC - MS / MS) method to determine the changes in CYP enzyme activity and calculate the IC 50 value to evaluate the inhibitory ability of the test substances on each CYP enzyme subtype.

[1106] Conclusion: The IC of the compounds P-36, P-40, P-44, P-48, P-70, and P-87 of the present invention against 5 isozymes of CYP (CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A) 50 is greater than 10 μM.

[1107] Test Example 7: In Vitro Induction Experiment of Metabolic Enzymes

[1108] 1) Experimental Procedure

[1109] On the first day, after thawing cryopreserved human hepatocytes from a single donor, the cell count and cell viability were determined, and the cell viability needed to be greater than or equal to 80%. The cells were diluted to contain 700,000 - 1,000,000 viable cells per milliliter and seeded onto a cell plate pre-coated with collagen. After incubating for at least 4 hours until the cells adhered, the seeding culture medium was replaced with an incubation culture medium containing 2.0% (v / v) basement matrix gel (sandwich culture method). All incubations were carried out in an incubator at 37 ± 1°C, 5.0% CO 2 and saturated humidity conditions. The cryopreserved human hepatocytes from a single donor were incubated with the control compound and test articles at different concentrations at 37 ± 1°C for 48 - 72 hours or longer, and then an enzyme probe substrate was added for incubation. The generation amount of each substrate metabolite was quantitatively analyzed by liquid chromatography tandem mass spectrometry (LC-MS / MS). A commercial cytotoxicity detection kit was used to detect cell viability. The gene expression level in the cells was evaluated by fluorescence real-time quantitative PCR (the experimental conditions can be adjusted as needed).

[1110] Table 9 CYP Enzyme Inducers in In Vitro Tests

[1111]

[1112]

[1113] Table 10 CYP Enzyme Pointer Substrates and Metabolites in In Vitro Tests

[1114]

[1115] 2) Calculation Method

[1116] a. Enzyme Activity

[1117] The calculation method of the enzyme activity induction multiple and the induction ratio compared with the control compound are as follows:

[1118] Induction multiple = Enzyme activity in the sample treated with the test article (or control compound) / Enzyme activity in the sample treated with the matrix control

[1119] Induction ratio (%) compared with the control compound = (Induction fold of the sample treated with the test article - 1) / (Induction fold of the sample treated with the control compound - 1) × 100

[1120] b. Gene expression

[1121] This project uses the ΔCt relative quantification method to compare the differences in gene expression between different treatment groups, and uses a reference gene to correct the gene expression level of each sample. The Ct value of the target gene minus the Ct value of the reference gene is ΔCt, that is, Ct target gene – Ct reference gene = ΔCt. Subtracting the ΔCt value of the matrix control group from the ΔCt value of the treatment group gives ΔΔCt, that is, ΔCt treatment group – ΔCt matrix control group = ΔΔCt. Finally, statistical analysis is performed by the method of 2 -ΔΔCt to compare the fold change between the treatment group and the matrix control group. The calculation method of the induction ratio of the test article and the control compound is as follows:

[1122] Induction ratio (%) compared with the control compound = (Induction fold of the sample treated with the test article - 1) / (Induction fold of the sample treated with the control compound - 1) × 100

[1123] 3) Conclusion:

[1124] The compounds P-36, P-44, P-48, P-58, and P-74 of the present invention are not regarded as inducers of CYP1A2, CYP2B6, and CYP3A4 in the concentration range of 0.100 to 10.0 μM. P-17 is regarded as an inducer of CYP3A4 at a concentration of 10.0 μM.

[1125] Test Example 8: In vivo pharmacokinetic test in rats:

[1126] This experimental example evaluated the in vivo pharmacokinetics of rats by single intravenous injection.

[1127] 1. Test methods and conditions: Male SD rats were fasted overnight and were respectively given a single intravenous injection of the test compound at 1 mg / kg or 5 mg / Kg; the test compound was orally administered at 30 mg / Kg.

[1128] 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 dosing, placed in a microcentrifuge tube containing EDTA-K2 anticoagulant, centrifuged at 4000 rpm for 5 min at 4 °C, and the supernatant was taken and stored in a refrigerator at -75 °C ± 15 °C.

[1129] 3. Detection information: The drug concentration in plasma at different time points was detected by LC-MS / MS, and the relevant pharmacokinetic parameters were calculated using WinNonlin 8.3.1 software. The results are as follows:

[1130] Table 11 PK Results of Representative Compounds in Rats

[1131]

[1132]

[1133] 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.

[1134] Test Example 9: Mouse Neuropathic Pain Model Induced by Spinal Nerve Ligation (SNL)

[1135] Female SPF-grade C57BL / 6J mice were adaptively raised for one week and then the model was established. The specific establishment method is as follows:

[1136] 1. Spinal Nerve Ligation (SNL) Modeling

[1137] (1) Disinfect surgical instruments;

[1138] (2) The experimental animals were anesthetized with isoflurane through a small animal gas anesthesia machine and placed in the prone position on the operating table. The hair on the lumbar hip bone was shaved and prepared for skin disinfection;

[1139] (3) After disinfection with iodophor, make an opening about 2 cm near the hip bone along the spine, separate the fascia and muscles, and expose the L5 transverse process;

[1140] (4) Carefully bite off the L5 transverse process with forceps to expose the L5 nerve;

[1141] (5) Separate the L5 nerve with a glass microprobe and ligate the nerve with a 5-0 ligature;

[1142] (6) Suture the muscles and skin and disinfect.

[1143] (7) Observe the overall recovery of the mice after the operation, as well as the gait, spontaneous pain, and weight-bearing preference of the mice. Pay attention to whether the back skin of the mice heals well.

[1144] 2. Observation of General Clinical Symptoms

[1145] After modeling, observe the movement of the right hind limb of the mice during movement. The mice with successful modeling showed abnormal gait, manifested as mostly dragging or limping of the right hind limb; spontaneous pain behavior, manifested as licking or stroking the affected limb; weight-bearing preference, manifested as the mice tending to avoid placing weight on the affected hind limb.

[1146] 3. Measurement of Mechanical Pain

[1147] The mechanical withdrawal threshold of mice was detected using the classical up-down test method. The determination of the 50% paw withdrawal threshold refers to the mechanical force at which multiple mechanical stimulations can cause a 50% paw withdrawal response. An acrylic box was placed on a metal screen. After the mice were allowed to acclimate in the acrylic box for 30 minutes, the plantar surface of the hind paw of the mice was vertically stimulated with a Von Frey filament for a duration of ≤4 s. A positive response was considered when the mice showed a paw lift or licking behavior, and a negative response otherwise.

[1148] Stimulation was started with a force of 0.4. If there was no paw withdrawal response, a force of 0.6 above it was selected to stimulate the hind toe; if there was a paw withdrawal response, a force of 0.16 below it was selected, and so on. When there was a different response from the previous one, from a paw withdrawal response to no paw withdrawal response or from no paw withdrawal response to a paw withdrawal response, stimulation was continued sequentially 4 more times, for a total of 6 times, and the determination of the 50% paw withdrawal threshold was completed. If the force required exceeded 2.0 or was lower than 0.02, the threshold on that side was directly recorded as 2.0 or 0.02, with a 30 s interval between each stimulation. In the experiment, the measurement techniques were kept as consistent as possible, such as the direction of the force, the speed of force application, and the degree of filament bending, to maintain the stability of the force and the speed of force withdrawal. In addition, the criteria for judging the mice's responses were kept as consistent as possible. The 50% paw withdrawal threshold was calculated using the formula 50% paw withdrawal threshold = 10log(X) + κδ (where X is the force used in the last stimulation; κ is the coefficient for different stimulation methods, found in the coefficient table; and δ is the average of the adjacent intervals between each stimulation force, here δ = 0.224).

[1149] The 50% paw withdrawal thresholds at 0.5 h, 1 h, 3 h, 6 h, and 8 h were measured and recorded after oral gavage administration.

[1150] 4. Data analysis

[1151] 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). Independent sample t-tests were used for between-group comparisons. p<0.05, p<0.01, and p<0.001 indicated statistically significant differences.

[1152] 5. Conclusion

[1153] The compounds of the present invention, such as the compounds in the examples, have significant analgesic efficacy. 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 efficacy at a dosing dose of 15 mg / kg or 45 mg / kg.

[1154] In the above embodiments, the numbering and the corresponding structural formulas shall prevail, and they are only used to illustrate the technical solutions of the present invention by way of example, rather than to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that: within the scope not departing from the spirit and essence defined by the claims of the present invention, the technical solutions described in the foregoing embodiments may be modified, or some or all of the technical features may be equivalently replaced; and such modifications or replacements are still within the scope defined by 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 1-6 Alkylene, 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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