PYRIDINE-CONTAINING POLYCYCLIC DERIVATIVE, AND PREPARATION METHOD THEREFOR AND USE THEREOF

TECHNICAL FIELD

The present invention belongs to the field of biomedicine, and specifically relates to a pyridine-containing polycyclic derivative, a preparation method therefor, and the use thereof.

BACKGROUND ART

MK2 (MAPK activated protein kinase 2), as an important downstream molecule of the classical inflammatory signal transduction pathway MAPK, is a protein kinase which regulates the expression of inflammatory factors. After cells undergo inflammatory stimulation, the activated p38 MAPK protein phosphorylates and activates MK2, which leads to phosphorylation of the MK2 substrate TTP and contributes to the mRNA stability of pro-inflammatory cytokines, thus improving the protein expression level of inflammatory cytokines.

MK2 is activated in both a mouse arthritis model and chondrocytes in patients with osteoarthritis. Inhibition of p38-MK2 pathway by either genetic or pharmacological means can inhibit the expression level of inflammatory factors, indicating that MK2 participates in mediating inflammatory regulation of arthritis. p38-MK2 inhibitors are promising in treating patients with rheumatoid arthritis who are relapsed, refractory, and poorly responsive to existing therapies.

At present, only the p38-MK2 inhibitor ATI-450 from Aclaris Therapeutics has entered the phase IIb clinical trial of rheumatoid arthritis in the world. The preliminary clinical trial results have shown that ATI-450 is safe and tolerable in patients with rheumatoid arthritis and has outstanding and lasting efficacy. Other MK2 inhibitors in clinical trials further include CC-99677 from BMS and MMI-0100 from Moerae Matrix, both of which can directly inhibit the activity of MK2 in a mechanism different from that of ATI-450.

Existing published patent applications regarding p38-MK2 (or MK2) inhibitors include: patents from Aclaris Therapeutics (WO-2012078684, WO-2013086208, WO-2014197846, WO-2021022186, WO-2012078687, WO 2012078673, and WO 2012078674); patents from BMS (WO-2020236636, WO-2018170199, WO-2016044463, WO-2018170201, WO-2018170200, WO-2018170203, US 20210198276, US 20210139501, US 20200148701, and US 20200102326); patents from Moerae Matrix (WO-2016112292, WO-2016145234, U.S. Ser. No. 10/336,788, WO-2014040074, WO-2018231722, WO-2012142320, WO-2016033432, WO-2013134636, and WO-2011149964), etc.

P38-MK2 inhibitors as drugs have a good application prospect in the pharmaceutical industry. P38-MK2 inhibitors are provided as a safer and more effective treatment for patients with rheumatoid arthritis who are relapsed, refractory, and poorly responsive to existing therapies. P38-MK2 inhibitors have a broad-spectrum anti-inflammatory effect (TNF/IL-6/IL-1), which can be used to treat a variety of inflammatory diseases and autoimmune diseases in theory. P38-MK2 inhibitors are small molecule inhibitors. Compared with macromolecular drugs such as TNF monoclonal antibodies, such p38-MK2 inhibitors have the advantages of oral convenience, good patient compliance, etc. In addition, no reports regarding toxic and side effects of JAK inhibitors such as infection, tumor, thrombosis and cardiotoxicity have been found in p38-MK2 inhibitors in clinical trials. Therefore, there is a huge clinical need for the development of novel p38-MK2 inhibitors.

SUMMARY OF THE INVENTION

An objective of the present invention is to provide a compound represented by general formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound represented by general formula (I) has a structure as follows:

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wherein:

ring A is selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl;

ring B is selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl;

L₁is selected from a bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, —(CH₂)_n—, —(CH₂)_nC(O)(CR_aaR_bb)_n1—, —(CH₂)_nC(O)NR_cc(CH₂)_n1—, —(CH₂)_n(CR_aaR_bb)_n1—, —(CR_aaR_bb)_nO(CH₂)_n1—, —(CH₂)_nO(CR_aaR_bb)_n1—, —(CR_aaR_bb)_nS(CH₂)_n1—, —(CH₂)_nS(CR_aaR_bb)_n1—, —(CR_aaR_bb)_n(CH₂)_n1NR_cc—, —(CH₂)_nNR_cc(CR_aaR_bb)_n1—, —(CH₂)_nNR_ccC(O)—, —(CH₂)_nP(O)_pR_aa—, —(CH₂)_nS(O)_m—, —(CH₂)_nS(O)_mNR_cc—, and —(CH₂)_nNR_ccS(O)_m—;

R_aa, R_bb, and R_ccare each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, deuteroalkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the amino, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, deuteroalkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be optionally further substituted;

or any two of R_aa, R_bb, and R_ccare connected to form cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl may be optionally further substituted; L₂and L₃are each independently selected from a bond, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, —(CH₂)_n2—, —(CH₂)_n2C(O)(CR_a1R_b1)_n3—, —(CH₂)_n2C(O)NR_c1(CH₂)_n3—, —(CH₂)_n2(CR_a1R_b1)_n3—, —(CR_a1R_b1)_n2O(CH₂)_n3—, —(CH₂)_n2O(CR_a1R_b1)_n3—, —(CR_a1R_b1)_n2S(CH₂)_n3—, —(CH₂)_n2S(CR_a1R_b1)_n3—, —(CR_a1R_b1)_n2(CH₂)_n3NR_c1—, —(CH₂)_n2NR_c1(CR_a1R_b1)_n3—, —(CH₂)_n2NR_c1C(O)—, —(CH₂)_n2P(O)_p1R_a1—, —(CH₂)_n2S(O)_m1—, —(CH₂)_n2S(O)_m1NR_c1—, and —(CH₂)_n2NR_c1S(O)_m1—;

R_a1, R_b1, and R_c1are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, deuteroalkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the amino, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, deuteroalkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be optionally further substituted;

each R^ais independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, deuteroalkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the amino, alkyl, deuteroalkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be optionally further substituted; each R^bis independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, deuteroalkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the amino, alkyl, deuteroalkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be optionally further substituted;

each R^cis independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, deuteroalkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the amino, alkyl, deuteroalkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be optionally further substituted; R^band R^care connected to form cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl may be optionally further substituted; each R^dis independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, bridged cycloalkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, deuteroalkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CR_eeR_ff)_n4C(O)R_gg, —(CR_eeR_ff)_n4NR_hhC(O)R_gg, —(CR_eeR_ff)_n4S(O)₂R_gg, —(CR_eeR_ff)_n4C(O)NR_hhR_gg, or —(CR_eeR_ff)_n4S(O)₂NR_hhR_gg, wherein the amino, alkyl, bridged cycloalkyl, deuteroalkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be optionally further substituted;

R_ee, R_ff, R_gg, and R_hhare each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, carboxyl, C_1-8alkyl, C_1-8deuteroalkyl, C_1-8haloalkyl, C_1-8hydroxyalkyl, C_1-8alkoxy, C_1-8deuteroalkoxy, C_1-8haloalkoxy, C_2-8alkenyl, C_2-8alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl; preferably, R_ee, R_ff, R_gg, and R_hhare each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, or 5- to 10-membered heteroaryl;

or R_eeand R_ffare connected to form cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl may be optionally further substituted;

n4 is 0, 1, 2, 3, or 4;

preferably,

each R^dis independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxy, deuteroalkoxy, haloalkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the amino, alkyl, deuteroalkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl may be optionally further substituted;

or any two adjacent or non-adjacent R^dare connected to form cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl may be optionally further substituted;

or L₃and R^dare connected to form cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl may be optionally further substituted; or R^cand R^dare connected to form cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl may be optionally further substituted;

x is an integer of 0-6;

y is an integer of 0-6;

z is an integer of 0-6;

e is an integer of 0-6;

n is 0, 1, 2, or 3;

n1 is 0, 1, 2, or 3;

n2 is 0, 1, 2, or 3;

n3 is 0, 1, 2, or 3;

m is 0, 1, 2, or 3;

p is 0, 1, 2, or 3;

m1 is 0, 1, 2, or 3; and

p1 is 0, 1, 2, or 3.

In a preferred embodiment of the present invention, the compound is further as represented by general formula (I′-1):

embedded image

wherein:

ring D is selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl;

ring E is heterocyclyl;

ring B is selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl;

X₃is selected from N or CR^b1;

L₁is selected from a bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, —(CH₂)_n—, —(CH₂)_nC(O)(CR_aaR_bb)_n1—, —(CH₂)_nC(O)NR_cc(CH₂)_n1—, —(CH₂)_n(CR_aaR_bb)_n1—, —(CR_aaR_bb)_nO(CH₂)_n1—, —(CH₂)_nO(CR_aaR_bb)_n1—, —(CR_aaR_bb)_nS(CH₂)_n1—, —(CH₂)_nS(CR_aaR_bb)_n1—, —(CR_aaR_bb)_n(CH₂)_n1NR_cc—, —(CH₂)_nNR_cc(CR_aaR_bb)_n1—, —(CH₂)_nNR_ccC(O)—, —(CH₂)_nP(O)_pR_aa—, —(CH₂)_nS(O)_m—, —(CH₂)_nS(O)_mNR_cc—, and —(CH₂)_nNR_ccS(O)_m—;

R_aa, R_bb, and R_ccare each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

L₃is selected from a bond, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, —(CH₂)_n2—, —(CH₂)_n2C(O)(CR_a1R_b1)_n3—, —(CH₂)_n2C(O)NR_c1(CH₂)_n3—, —(CH₂)_n2(CR_a1R_b1)_n3—, —(CR_a1R_b1)_n2O(CH₂)_n3—, —(CH₂)_n2O(CR_a1R_b1)_n3—, —(CR_a1R_b1)_n2S(CH₂)_n3—, —(CH₂)_n2S(CR_a1R_b1)_n3—, —(CR_a1R_b1)_n2(CH₂)_n3NR_c1—, —(CH₂)_n2NR_c1(CR_a1R_b1)_n3—, —(CH₂)_n2NR_c1C(O)—, —(CH₂)_n2P(O)_p1R_a1—, —(CH₂)_n2S(O)_m1—, —(CH₂)_n2S(O)_m1NR_c1—, and —(CH₂)_n2NR_c1S(O)_m—;

R_a1, R_b1, and R_c1are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

each R^ais independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

or any two adjacent or non-adjacent R^aare connected to form C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

or L₁and R^aare connected to form C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

each R^b1or R^b3is independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

each R^c2or R^c3is independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

each R^dis independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6bridged cycloalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, 5- to 14-membered heteroaryl, —(CR_eeR_ff)_n4C(O)R_gg, —(CR_eeR_ff)_n4NR_hhC(O)R_gg, —(CR_eeR_ff)_n4NR_hhOR_gg, —(CR_eeR_ff)_n4S(O)₂R_gg, —(CR_eeR_ff)_n4S(O)R_gg, —(CR_eeR_ff)_n4SR_gg, —(CR_eeR_ff)_n4C(O)NR_hhR_gg, —(CR_eeR_ff)_n4S(O)NR_hhR_gg, —(CR_eeR_ff)_n4SNR_hhR_gg, or —(CR_eeR_ff)_n4S(O)₂NR_hhR_gg, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6bridged cycloalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

R_ee, R_ff, R_gg, and R_hhare each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl; or R_eeand R_ffare connected to form C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

x is an integer of 0-6;

e is an integer of 0-6;

n is 0, 1, 2, or 3;

n1 is 0, 1, 2, or 3;

n2 is 0, 1, 2, or 3;

n3 is 0, 1, 2, or 3;

n4 is 0, 1, 2, 3, or 4;

n6 is 0, 1, 2, 3, or 4;

m is 0, 1, 2, or 3;

p is 0, 1, 2, or 3;

m1 is 0, 1, 2, or 3; and

p1 is 0, 1, 2, or 3.

In a further preferred embodiment of the present invention, ring D as described in the present invention is selected from C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl; preferably, ring D is selected from C_6-10aryl, 5- to 6-membered monocyclic heteroaryl, or 7- to 10-membered bicyclic heteroaryl; and more preferably, ring D is selected from pyrazolyl, thienyl, thiazolyl, oxazolyl, pyrimidinyl, pyridinyl, phenyl,

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In a further preferred embodiment of the present invention, ring E as described in the present invention is 6- to 12-membered heterocyclyl; and preferably, ring E is selected from

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In a preferred embodiment of the present invention, the compound is further as represented by general formula (XIV):

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wherein:

M¹is selected from C, CH, or N, or is absent;

M²is selected from C, CH, or N, or is absent;

M³is selected from C, CH, or N, or is absent;

X₃is selected from N or CR^b1;

ring B is selected from cycloalkyl, heterocyclyl, aryl, or heteroaryl;

L₁is selected from a bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, —(CH₂)_n—, —(CH₂)_nC(O)(CR_aaR_bb)_n1—, —(CH₂)_nC(O)NR_cc(CH₂)_n1—, —(CH₂)_n(CR_aaR_bb)_n1—, —(CR_aaR_bb)_nO(CH₂)_n1—, —(CH₂)_nO(CR_aaR_bb)_n1—, —(CR_aaR_bb)_nS(CH₂)_n1—, —(CH₂)_nS(CR_aaR_bb)_n1—, —(CR_aaR_bb)_n(CH₂)_n1NR_cc—, —(CH₂)_nNR_cc(CR_aaR_bb)_n1—, —(CH₂)_nNR_ccC(O)—, —(CH₂)_nP(O)_pR_aa—, —(CH₂)_nS(O)_m—, —(CH₂)_nS(O)_mNR_cc—, and —(CH₂)_nNR_ccS(O)_m—;

R_aa, R_bb, and R_ccare each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

L₃is selected from a bond, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, —(CH₂)_n2—, —(CH₂)_n2C(O)(CR_a1R_b1)_n3—, —(CH₂)_n2C(O)NR_c1(CH₂)_n3—, —(CH₂)_n2(CR_a1R_b1)_n3—, —(CR_a1R_b1)_n2O(CH₂)_n3—, —(CH₂)_n2O(CR_a1R_b1)_n3—, —(CR_a1R_b1)_n2S(CH₂)_n3—, —(CH₂)_n2S(CR_a1R_b1)_n3—, —(CR_a1R_b1)_n2(CH₂)_n3NR_c1—, —(CH₂)_n2NR_c1(CR_a1R_b1)_n3—, —(CH₂)_n2NR_c1C(O)—, —(CH₂)_n2P(O)_p1R_a1—, —(CH₂)_n2S(O)_m1—, —(CH₂)_n2S(O)_m1NR_c1—, and —(CH₂)_n2NR_c1S(O)_m—;

R_a1, R_b1, and R_c1are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

each R^ais independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

or any two adjacent or non-adjacent R^aare connected to form C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl; or L₁and R^aare connected to form C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

each R^b1or R^b3is independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

each R^c2or R^c3is independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

each R^dis independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6bridged cycloalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, 5- to 14-membered heteroaryl, —(CR_eeR_ff)_n4C(O)R_gg, —(CR_eeR_ff)_n4NR_hhC(O)R_gg, —(CR_eeR_ff)_n4NR_hhOR_gg, —(CR_eeR_ff)_n4S(O)₂R_gg, —(CR_eeR_ff)_n4S(O)R_gg, —(CR_eeR_ff)_n4SR_gg, —(CR_eeR_ff)_n4C(O)NR_hhR_gg, —(CR_eeR_ff)_n4S(O)NR_hhR_gg, —(CR_eeR_ff)_n4SNR_hhR_gg, or —(CR_eeR_ff)_n4S(O)₂NR_hhR_gg, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6bridged cycloalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

R_ee, R_ff, R_gg, and R_hhare each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl; or R_eeand R_ffare connected to form C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

x is an integer of 0-6;

e is an integer of 0-6;

n is 0, 1, 2, or 3;

n1 is 0, 1, 2, or 3;

n2 is 0, 1, 2, or 3;

n3 is 0, 1, 2, or 3;

n4 is 0, 1, 2, 3, or 4;

n6 is 0, 1, 2, 3, or 4;

m is 0, 1, 2, or 3;

p is 0, 1, 2, or 3;

m1 is 0, 1, 2, or 3; and

p1 is 0, 1, 2, or 3.

In a more preferred embodiment of the present invention, ring A as described in the present invention is selected from C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl;

preferably, ring A is selected from 6- to 12-membered bicyclic heterocyclyl, 5- to 6-membered monocyclic heteroaryl, or 7- to 10-membered bicyclic heteroaryl; and

more preferably, ring A is selected from pyrazolyl, thienyl, thiazolyl, oxazolyl, pyrimidinyl, pyridinyl, phenyl, tetrahydroquinolinyl, benzocyclopentyl, pyrrolopyrimidinyl, pyrrolopyridinyl, pyrazolopyridine, or imidazopyridine.

In a more preferred embodiment of the present invention, ring B as described in the present invention is selected from C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl;

preferably, ring B is selected from 3-7-membered monocyclic heterocyclyl, 6- to 12-membered bicyclic heterocyclyl, 5-membered monocyclic heteroaryl, 6-membered monocyclic heteroaryl, or 7- to 14-membered heteroaryl fused ring;

more preferably, ring B is selected from 5-membered monocyclic nitrogen-containing heteroaryl, 6-membered monocyclic nitrogen-containing heteroaryl, 5- to 6-membered heteroaryl fused to 5- to 6-membered cycloalkyl, 5- to 6-membered heteroaryl fused to 5- to 6-membered heteroaryl, or 5- to 6-membered heteroaryl fused to phenyl;

further preferably, ring B is selected from pyrimidine, pyridocyclohexyl, pyridocyclopentyl, pyrrolotriazinyl, pyrrolopyrimidinyl, pyridocyclopentenyl, pyridine, thiazole, pyrazole, pyridopyrrolidone, pyridofuranone, pyridosulfolane,

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and

further more preferably, ring B is selected from thiazolyl, oxazolyl, pyrazolyl, imidazolyl, 1,2,4-thiadiazolyl, 1,3,4-oxadiazolyl, pyrimidinyl, pyridocyclohexyl, pyridocyclopentyl, pyrrolotriazinyl, pyrrolopyrimidinyl, pyridocyclopentenyl, pyridinyl, pyridopyrrolidone, pyridofuranone, or pyridosulfolane.

In a further preferred embodiment of the present invention, L₁described in the present invention is selected from a bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, —(CH₂)_n—, —(CH₂)_nC(O)(CR_aaR_bb)_n1—, —(CH₂)_nC(O)NR_cc(CH₂)_n1—, —(CH₂)_n(CR_aaR_bb)_n1—, —(CR_aaR_bb)_nO(CH₂)_n1—, —(CH₂)_nO(CR_aaR_bb)_n1—, —(CR_aaR_bb)_nS(CH₂)_n1—, —(CH₂)_nS(CR_aaR_bb)_n1—, —(CR_aaR_bb)_n(CH₂)_n1NR_cc—, —(CH₂)_nNR_cc(CR_aaR_bb)_n1—, —(CH₂)_nNR_ccC(O)—, —(CH₂)_nP(O)_pR_aa—, —(CH₂)_nS(O)_m—, —(CH₂)_nS(O)_mNR_cc—, and —(CH₂)_nNR_ccS(O)_m—; preferably, L₁is selected from a bond, substituted or unsubstituted alkenylene, substituted or unsubstituted alkynylene, —(CH₂)_n—, —(CH₂)_nC(O)—, —(CR_aaR_bb)_nO—, —O(CR_aaR_bb)_n1—, —(CR_aaR_bb)_nS—, —S(CR_aaR_bb)_n1—, —(CH₂)_n1NR_cc—, —NR_cc(CR_aaR_bb)_n1—, or —NR_ccC(O)—;

more preferably, L₁is selected from a bond, —CH₂—, —OCH₂—, —OCD₂-, —NH—, —C(O)NH—, —OCH(CH₃)—, —OC(CH₃)₂—, —NH—CH₂—, or

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R_aa, R_bb, and R_ccare each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

preferably, R_aa, R_bb, and R_ccare each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-3alkyl, C_1-3deuteroalkyl, C_1-3haloalkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-3deuteroalkoxy, C_1-3haloalkoxy, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, or 5- to 10-membered heteroaryl, wherein the amino, C_1-3alkyl, C_1-3deuteroalkyl, C_1-3haloalkyl, C_1-3alkoxy, C_1-3haloalkoxy, C_1-3hydroxyalkyl, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, and 5- to 10-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-3alkyl, C_1-3deuteroalkyl, C_1-3haloalkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-3deuteroalkoxy, C_1-3haloalkoxy, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, and 5- to 10-membered heteroaryl;

or any two of R_aa, R_bb, and R_ccare connected to form C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, and C_1-6haloalkoxy; and

preferably, any two of R_aa, R_bb, and R_ccare connected to form C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, or 5- to 10-membered heteroaryl, wherein the C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, and 5- to 10-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-3alkyl, C_1-3deuteroalkyl, C_1-3haloalkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-3deuteroalkoxy, and C_1-3haloalkoxy.

In a further preferred embodiment of the present invention, the compound is further as represented by general formula (XV):

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wherein:

X₁is selected from N or CR^a6;

X₃is selected from N or CR^b1;

each R^a1, R^a2, R^a3, R^a4, or R^a5is independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

or any two adjacent or non-adjacent R^a1, R^a2, R^a3, R^a4, and R^a5are connected to form C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered each heteroaryl;

each R_aaor R_bbis independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

or R_aaand R_bbare connected to form C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

each R^b1, R^b2, or R^b3is independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

or the substituents R^b1and R^b2are connected to form C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

each R^c1, R^c2, or R^c3is independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

or the substituents R^c1and R^c2are connected to form C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

or the substituents R^c1and R^b2are connected to form 3- to 12-membered heterocyclyl or 5- to 14-membered heteroaryl, wherein the 3- to 12-membered heterocyclyl and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

R¹is selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6bridged cycloalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, 5- to 14-membered heteroaryl, —(CR_eeR_ff)_n4C(O)R_gg, —(CR_eeR_ff)_n4NR_hhC(O)R_gg, —(CR_eeR_ff)_n4NR_hhOR_gg, —(CR_eeR_ff)_n4S(O)₂R_gg, —(CR_eeR_ff)_n4S(O)R_gg, —(CR_eeR_ff)_n4SR_gg, —(CR_eeR_ff)_n4C(O)NR_hhR_gg, —(CR_eeR_ff)_n4S(O)NR_hhR_gg, —(CR_eeR_ff)_n4SNR_hhR_gg, or —(CR_eeR_ff)_n4S(O)₂NR_hhR_gg, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6bridged cycloalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl; R_ee, R_ff, R_gg, and R_hhare each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl; or R_eeand R_ffare connected to form C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

each R², R³, or R⁴is independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

or any two adjacent or non-adjacent R¹, R², R³, and R⁴are connected to form C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

- n4 is 0, 1, 2, 3, or 4; and
- the

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is not

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In a further preferred embodiment of the present invention, the compound is further as represented by general formula (XIV-A), (XIV-B), or (XIV-C):

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wherein:

X₁is selected from N or CR^a5;

X₂is selected from N or CR²;

X₃is selected from N or CR^b1;

each R^a1, R^a2, R^a3, R^a4, or R^a5is independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

or any two adjacent or non-adjacent R^a1, R^a2, R^a3, R^a4, and R^a5are connected to form C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered each heteroaryl;

each R_aaor R_bbis independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

or R_aaand R_bbare connected to form C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

each R^b1or R^b3is independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

each R^c2or R^c3is independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

each R_da, R_db, or R′_dais independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

or R_daand R_dbare connected to form C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

each R_dcor R_ddis independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

or R_dcand R_ddare connected to form C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

R¹is selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6bridged cycloalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, 5- to 14-membered heteroaryl, —(CR_eeR_ff)_n4C(O)R_gg, —(CR_eeR_ff)_n4NR_hhC(O)R_gg, —(CR_eeR_ff)_n4NR_hhOR_gg, —(CR_eeR_ff)_n4S(O)₂R_gg, —(CR_eeR_ff)_n4S(O)R_gg, —(CR_eeR_ff)_n4SR_gg, —(CR_eeR_ff)_n4C(O)NR_hhR_gg, —(CR_eeR_ff)_n4S(O)NR_hhR_gg, —(CR_eeR_ff)_n4SNR_hhR_gg, or —(CR_eeR_ff)_n4S(O)₂NR_hhR_gg, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6bridged cycloalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl; R_ee, R_ff, R_gg, and R_hhare each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl; or R_eeand R_ffare connected to form C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

each R², R³, or R⁴is independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

or any two adjacent or non-adjacent R¹, R², R³, and R⁴are connected to form C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

R⁷is selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6bridged cycloalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, 5- to 14-membered heteroaryl, —(CR_eeR_ff)_n4C(O)R_gg, —(CR_eeR_ff)_n4NR_hhC(O)R_gg, —(CR_eeR_ff)_n4NR_hhOR_gg, —(CR_eeR_ff)_n4S(O)₂R_gg, —(CR_eeR_ff)_n4S(O)R_gg, —(CR_eeR_ff)_n4SR_gg, —(CR_eeR_ff)_n4C(O)NR_hhR_gg, —(CR_eeR_ff)_n4S(O)NR_hhR_gg, —(CR_eeR_ff)_n4SNR_hhR_gg, or —(CR_eeR_ff)_n4S(O)₂NR_hhR_gg, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6bridged cycloalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl; R_ee, R_ff, R_gg, and R_hhare each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl;

or R_eeand R_ffare connected to form C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

each R⁶or R⁸is independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

or any two adjacent or non-adjacent R⁶, R⁷, and R⁸are connected to form C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

n4 is 0, 1, 2, 3, or 4;

n5 is 0, 1, or 2;

n5′ is 0, 1, or 2;

n5 and n5′ are not both 0; and

n6 is 0, 1, 2, 3, or 4.

In a further preferred embodiment of the present invention, the compound is further as represented by general formula (I′-1-1), (I′-1-2), (XIV-1), (XIV-2), (XIV-A-1), (XIV-A-2), (XIV-B-1), (XIV-B-2), (XIV-C-1), (XIV-C-2), (XV-1), or (XV-2):

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In a further preferred embodiment of the present invention, each R^adescribed in the present invention is independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl; and

preferably, each R^ais independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-3alkyl, C_1-3deuteroalkyl, C_1-3haloalkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-3deuteroalkoxy, C_1-3haloalkoxy, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, or 5- to 10-membered heteroaryl, wherein the amino, C_1-3alkyl, C_1-3deuteroalkyl, C_1-3haloalkyl, C_1-3alkoxy, C_1-3haloalkoxy, C_1-3hydroxyalkyl, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, and 5- to 10-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-3alkyl, C_1-3deuteroalkyl, C_1-3haloalkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-3deuteroalkoxy, C_1-3haloalkoxy, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, and 5- to 10-membered heteroaryl.

In a further preferred embodiment of the present invention, each R^bdescribed in the present invention is independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl; and

preferably, each R^bis independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-3alkyl, C_1-3deuteroalkyl, C_1-3haloalkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-3deuteroalkoxy, C_1-3haloalkoxy, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, or 5- to 10-membered heteroaryl, wherein the amino, C_1-3alkyl, C_1-3deuteroalkyl, C_1-3haloalkyl, C_1-3alkoxy, C_1-3haloalkoxy, C_1-3hydroxyalkyl, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, and 5- to 10-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-3alkyl, C_1-3deuteroalkyl, C_1-3haloalkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-3deuteroalkoxy, C_1-3haloalkoxy, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, and 5- to 10-membered heteroaryl.

In a further preferred embodiment of the present invention, each R^cdescribed in the present invention is independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

preferably, each R^cis independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-3alkyl, C_1-3deuteroalkyl, C_1-3haloalkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-3deuteroalkoxy, C_1-3haloalkoxy, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, or 5- to 10-membered heteroaryl, wherein the amino, C_1-3alkyl, C_1-3deuteroalkyl, C_1-3haloalkyl, C_1-3alkoxy, C_1-3haloalkoxy, C_1-3hydroxyalkyl, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, and 5- to 10-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-3alkyl, C_1-3deuteroalkyl, C_1-3haloalkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-3deuteroalkoxy, C_1-3haloalkoxy, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, and 5- to 10-membered heteroaryl;

or R^band R^care connected to form C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl.

In a further preferred embodiment of the present invention, each R^ddescribed in the present invention is independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, 5- to 10-membered bridged cycloalkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, 5- to 14-membered heteroaryl, —(CR_eeR_ff)_n4C(O)R_gg, —(CR_eeR_ff)_n4NR_hhC(O)R_gg, —(CR_eeR_ff)_n4S(O)₂R_gg, —(CR_eeR_ff)_n4C(O)NR_hhR_gg, or —(CR_eeR_ff)_n4S(O)₂NR_hhR_gg, wherein the amino, C_1-6alkyl, 5- to 10-membered bridged cycloalkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

R_ee, R_ff, R_gg, and R_hhare each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, carboxyl, C_1-8alkyl, C_1-8deuteroalkyl, C_1-8haloalkyl, C_1-8hydroxyalkyl, C_1-8alkoxy, C_1-8deuteroalkoxy, C_1-8haloalkoxy, C_2-8alkenyl, C_2-8alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl; preferably, R_ee, R_ff, R_gg, and R_hhare each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, or 5- to 10-membered heteroaryl;

or R_eeand R_ffare connected to form cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl; and n4 is 0, 1, 2, 3, or 4.

Preferably,

each R^dis independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl; and

preferably, each R^dis independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-3alkyl, C_1-3deuteroalkyl, C_1-3haloalkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-3deuteroalkoxy, C_1-3haloalkoxy, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, or 5- to 10-membered heteroaryl, wherein the amino, C_1-3alkyl, C_1-3deuteroalkyl, C_1-3haloalkyl, C_1-3alkoxy, C_1-3haloalkoxy, C_1-3hydroxyalkyl, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, and 5- to 10-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-3alkyl, C_1-3deuteroalkyl, C_1-3haloalkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-3deuteroalkoxy, C_1-3haloalkoxy, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, and 5- to 10-membered heteroaryl.

Further preferably, each R^dis independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-3alkyl, C_1-3deuteroalkyl, C_1-3haloalkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-3deuteroalkoxy, C_1-3haloalkoxy, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, 5- to 10-membered heteroaryl, —(CR_eeR_ff)_n4C(O)R_gg, —(CR_eeR_ff)_n4NR_hhC(O)R_gg, —(CR_eeR_ff)_n4S(O)₂R_gg, —(CR_eeR_ff)_n4C(O)NR_hhR_gg, or —(CR_eeR_ff)_n4S(O)₂NR_hhR_gg;

R_ee, R_ff, R_gg, and R_hhare each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, carboxyl, C_1-3alkyl, C_1-3deuteroalkyl, C_1-3haloalkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-3deuteroalkoxy, C_1-3haloalkoxy, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, or 5- to 10-membered heteroaryl; and n4 is 0, 1, 2, 3, or 4.

In a further preferred embodiment of the present invention, R^a1, R^a2, R^a3, R^a4, R^a5, R^b1, R^b2, R^b3, R^c1, R^c2, and R^c3described in the present invention are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-3alkyl, C_1-3deuteroalkyl, C_1-3haloalkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-3deuteroalkoxy, C_1-3haloalkoxy, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, or 5- to 10-membered heteroaryl, wherein the amino, C_1-3alkyl, C_1-3deuteroalkyl, C_1-3haloalkyl, C_1-3alkoxy, C_1-3haloalkoxy, C_1-3hydroxyalkyl, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, and 5- to 10-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-3alkyl, C_1-3deuteroalkyl, C_1-3haloalkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-3deuteroalkoxy, C_1-3haloalkoxy, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, and 5- to 10-membered heteroaryl.

In a further preferred embodiment of the present invention, R_da, R_db, R′_da, R_dc, and R_dddescribed in the present invention are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-3alkyl, C_1-3deuteroalkyl, C_1-3haloalkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-3deuteroalkoxy, C_1-3haloalkoxy, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, or 5- to 10-membered heteroaryl, wherein the amino, C_1-3alkyl, C_1-3deuteroalkyl, C_1-3haloalkyl, C_1-3alkoxy, C_1-3deuteroalkoxy, C_1-3hydroxyalkyl, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, and 5- to 10-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-3alkyl, C_1-3deuteroalkyl, C_1-3haloalkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-3deuteroalkoxy, C_1-3haloalkoxy, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, and 5- to 10-membered heteroaryl.

In a further preferred embodiment of the present invention, R¹and R⁷described in the present invention are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-3alkyl, C_1-3deuteroalkyl, C_1-3haloalkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-3deuteroalkoxy, C_1-3haloalkoxy, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, 5- to 10-membered heteroaryl, —(CR_eeR_ff)_n4C(O)R_gg, —(CR_eeR_ff)_n4NR_hhC(O)R_gg, —(CR_eeR_ff)_n4S(O)₂R_gg, —(CR_eeR_ff)_n4C(O)NR_hhR_gg, or —(CR_eeR_ff)_n4S(O)₂NR_hhR_gg;

In a further preferred embodiment of the present invention, R², R³, R⁴, R⁶, and R⁸described in the present invention are each independently selected from hydrogen, deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-3alkyl, C_1-3deuteroalkyl, C_1-3haloalkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-3deuteroalkoxy, C_1-3haloalkoxy, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, or 5- to 10-membered heteroaryl, wherein the amino, C_1-3alkyl, C_1-3deuteroalkyl, C_1-3haloalkyl, C_1-3alkoxy, C_1-3haloalkoxy, C_1-3hydroxyalkyl, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, and 5- to 10-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-3alkyl, C_1-3deuteroalkyl, C_1-3haloalkyl, C_1-3hydroxyalkyl, C_1-3alkoxy, C_1-3deuteroalkoxy, C_1-3haloalkoxy, C_2-4alkenyl, C_2-4alkynyl, C_3-8cycloalkyl, 3- to 8-membered heterocyclyl, C_6-10aryl, and 5- to 10-membered heteroaryl.

In a further preferred embodiment of the present invention, each R²described in the present invention is selected from halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

preferably, R²is selected from halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, or C_2-6alkynyl; and more preferably, R²is fluorine.

In a further preferred embodiment of the present invention, each R⁶described in the present invention is selected from halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, or 5- to 14-membered heteroaryl, wherein the amino, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6alkoxy, C_1-6haloalkoxy, C_1-6hydroxyalkyl, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl may be optionally further substituted with one or more substituents of deuterium, halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, C_2-6alkynyl, C_3-12cycloalkyl, 3- to 12-membered heterocyclyl, C_6-14aryl, and 5- to 14-membered heteroaryl;

preferably, R⁶is selected from halogen, nitro, hydroxy, mercapto, cyano, amino, oxo, thio, carboxyl, C_1-6alkyl, C_1-6deuteroalkyl, C_1-6haloalkyl, C_1-6hydroxyalkyl, C_1-6alkoxy, C_1-6deuteroalkoxy, C_1-6haloalkoxy, C_2-6alkenyl, or C_2-6alkynyl; and more preferably, R⁶is fluorine.

The present invention provides a compound represented by general formula (M-1) or (M-2), or a stereoisomer or pharmaceutically acceptable salt thereof:

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wherein:

X₄is selected from halogen, preferably chlorine or bromine; and ring D, ring E, M¹, M², M³, n6, L₁, R^a, R^b3, R^c2, R^c3, X₃, and x are as described above.

The present invention further provides a method for preparing the above-mentioned compound of general formula (I′-1) or the stereoisomer and pharmaceutically acceptable salt thereof, comprising the following steps:

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reacting a compound represented by general formula (M-1) to obtain a target compound represented by general formula (I′-1);

wherein

X₄is selected from halogen, preferably chlorine or bromine; and

ring D, ring E, ring B, L₁, L₃, R^a, R^b3, R^c2, R^c3, X₃, R^d, x, and e are as described above.

The present invention further provides a method for preparing the above-mentioned compound of general formula (XIV) or the stereoisomer and pharmaceutically acceptable salt thereof, comprising the following steps:

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reacting a compound represented by general formula (M-2) to obtain a target compound represented by general formula (XIV);

wherein

X₄is selected from halogen, preferably chlorine or bromine; and

M¹, M², M³, L₁, L₃, R^a, R^b3, R^c2, R^c3, X₃, R^d, x, e, and n6 are as described above.

The present invention further provides a method for preparing the above-mentioned compound of general formula (XV) or the stereoisomer and pharmaceutically acceptable salt thereof, comprising the following steps:

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reacting general formula (M-3) with general formula (M-4) to obtain a target compound represented by general formula (XV);

wherein

X₁, X₃, R^a1, R^a2, R^a3, R^a4, R_aa, R_bb, R^b2, R^b3, R^c1, R^c2, R^c3, R¹, R², R³, and R⁴are as described above.

The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of the compound or the stereoisomer or pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients; and furthermore, the weight percentage of the compound or the stereoisomer or pharmaceutically acceptable salt thereof in the composition is 0.1-95%, preferably 0.5-85%, more preferably 1-60%, further preferably 10-50%, further more preferably 15-40%, further more preferably 20-30%, and further more preferably 20-25% (based on the total weight of the pharmaceutical composition).

The present invention further relates to the use of the compound or the stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the preparation of a medicament for the treatment of a p38 kinase-mediated disease.

The present invention further relates to the use of the compound, or the stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the preparation of a medicament for the treatment of autoimmune diseases, metabolic diseases, tumors, etc., wherein the autoimmune diseases are selected from chronic inflammatory diseases, acute inflammatory diseases, autoimmune diseases, atherosclerosis, etc.; the metabolic diseases are selected from diabetes, fibrotic diseases, etc.; and the tumors are selected from leukemia, lymphoma, etc. The present invention further relates to a method for treating or preventing and/or treating autoimmune diseases, metabolic diseases, tumors, etc., comprising administering a therapeutically effective dose of the compound of the present invention, or the stereoisomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof to a patient; wherein the autoimmune diseases are selected from chronic inflammatory diseases, acute inflammatory diseases, autoimmune diseases, atherosclerosis, etc.; the metabolic diseases are selected from diabetes, fibrotic diseases, etc.; and the tumors are selected from leukemia, lymphoma, etc.

The present invention further provides a method for treating a disease condition with the compound or pharmaceutical composition of the present invention. The disease condition includes, but is not limited to, conditions related to p38 kinase-mediated diseases.

DETAILED DESCRIPTION OF THE INVENTION

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The term “alkyl” refers to a saturated aliphatic hydrocarbon group, which is a linear or branched chain group containing 1 to 20 carbon atoms, preferably alkyl containing 1 to 12 carbon atoms, more preferably alkyl containing 1 to 8 carbon atoms, further preferably alkyl containing 1 to 6 carbon atoms, and most preferably alkyl containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 4-heptyl, 1-propylbutyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, their respective branched chain isomers, etc. Lower alkyl groups containing 1 to 6 carbon atoms are more preferred, and non-limiting examples thereof include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, 4-heptyl, 1-propylbutyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, etc. Alkyl may be substituted or unsubstituted, and when it is substituted, the substituents may be at any available point of attachment. The substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate group, and methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuteroalkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred in the present invention.

The term “alkylene” refers to bivalent alkyl formed by further replacing one hydrogen atom of alkyl, wherein the alkyl is as defined above. For example, “methylene” refers to —CH₂—, “ethylene” refers to —(CH₂)₂—, “propylene” refers to —(CH₂)₃—, and “butylene” refers to —(CH₂)₄—, etc. The point of attachment of an alkylene chain to the rest of a molecule and to a group can be via one carbon or any two carbons in the chain. Alkylene may be substituted or unsubstituted, and when it is substituted, the substituents may be at any available point of attachment. The substituents are preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate group, and methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuteroalkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred in the present invention.

The term “alkenyl” refers to alkyl as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, which is a linear or branched group containing 2 to 20 carbon atoms, preferably alkenyl containing 2 to 12 carbon atoms, more preferably alkenyl containing 2 to 8 carbon atoms, further preferably alkenyl containing 2 to 6 carbon atoms, and most preferably alkenyl containing 2 to 4 carbon atoms. Examples are vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, or 3-butenyl, etc. Alkenyl can be substituted or unsubstituted. When it is substituted, the substituent is preferably one or more of groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, or heterocycloalkylthio.

The term “alkenylene” refers to bivalent alkenyl formed by further replacing one hydrogen atom of alkenyl, wherein the alkenyl group is defined as above, for example, vinylidene, propenylidene, and butenylidene. Alkenylene can be substituted or unsubstituted. When it is substituted, the substituent is preferably one or more of groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, or heterocycloalkylthio.

The term “alkynyl” refers to alkyl as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, which is a linear or branched group containing 2 to 20 carbon atoms, preferably alkynyl containing 2 to 12 carbon atoms, more preferably alkynyl containing 2 to 8 carbon atoms, further preferably alkynyl containing 2 to 6 carbon atoms, and most preferably alkynyl containing 2 to 4 carbon atoms. Examples are ethynyl, propynyl, 1-butynyl, 2-butynyl, or 3-butynyl, etc. Alkynyl can be substituted or unsubstituted. When it is substituted, the substituent is preferably one or more of groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, or heterocycloalkylthio.

The term “alkynylene” refers to bivalent alkynyl formed by further replacing one hydrogen atom of alkynyl, wherein the alkynyl is as defined above. Examples are ethynylene, propynylene, butynylene, etc. Alkynylene can be substituted or unsubstituted. When it is substituted, the substituent is preferably one or more of groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, or heterocycloalkylthio.

The term “cycloalkyl” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the cycloalkyl comprises 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and further preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc. Polycyclic cycloalkyl includes spiro, fused and bridged cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl and cycloheptyl.

The term “spirocycloalkyl” refers to a 5- to 20-membered polycyclic group with monocyclic rings sharing one carbon atom (called a spiro atom). It may contain one or more double bonds, but no ring has a completely conjugated n electron system. Preferably, it is 6- to 14-membered and more preferably 7- to 10-membered. According to the number of shared spiro atoms between rings, the spirocycloalkyl is divided into monospirocycloalkyl, bispirocycloalkyl or polyspirocycloalkyl, preferably monospirocycloalkyl and bispirocycloalkyl. More preferably, it is 3-membered/6-membered, 3-membered/5-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl include:

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and also included are spirocycloalkyl in which monospirocycloalkyl and heterocycloalkyl share a spiro atom. Non-limiting examples include:

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The term “fused cycloalkyl” refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares a pair of carbon atoms neighboring another ring in the system, one or more ring of which may contain one or more double bonds, but no ring has a fully conjugated n electron system. Preferably, it is 6- to 14-membered and more preferably 7- to 10-membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, and more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic cycloalkyl. Non-limiting examples of fused cycloalkyl include:

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The term “bridged cycloalkyl” refers to a 5- to 20-membered all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has a fully conjugated n electron system. It is preferably 6- to 14- or 5- to 14-membered and more preferably 7- to 10-membered or 5- to 10-membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl include:

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The cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is cycloalkyl, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl,

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Cycloalkyl may be optionally substituted or unsubstituted, and when it is substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate group.

The term “cycloalkylene” refers to bivalent cycloalkyl formed by further replacing one hydrogen atom of cycloalkyl, wherein the cycloalkylene is optionally substituted or unsubstituted, and the cycloalkyl is defined as above.

The term “heterocyclyl” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which comprises 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, C(O), or S(O)_m(wherein m is an integer of 0 to 2), but excluding ring moieties of —O—O—, —O—S—, or —S—S—, and the remaining ring atoms are carbon. Preferably, it comprises 3 to 12 ring atoms, of which 1-4 are heteroatoms; more preferably, it comprises 3 to 8 ring atoms or 6 to 12 ring atoms; most preferably, it comprises 3 to 6 ring atoms; and further preferably, it is a 3- to 8-membered heterocyclyl containing 1-3 nitrogen atoms, optionally substituted with 1-2 oxygen atoms, sulfur atoms, or oxo, including monocyclic heterocyclyl, spirocyclic heterocyclyl, or fused heterocyclyl.

Non-limiting examples of monocyclic heterocyclyl include oxetanyl, azetidinyl, thietanyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyranyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, azepanyl, 1,4-diazacycloheptyl, pyridonyl, pyranyl, tetrahydrothiopyranyl dioxide group,

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Polycyclic heterocyclyl includes spiro, fused and bridged heterocyclyl; the involved spiro, fused and bridged heterocyclyl are optionally connected to other groups through a single bond, or further fused to other cycloalkyl, heterocyclyl, aryl and heteroaryl through any two or more atoms on the ring.

The term “spiroheterocyclyl” refers to a 5- to 20-membered polycyclic heterocyclic group with monocyclic rings sharing one atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)_m(wherein m is an integer of 0 to 2), and the remaining ring atoms are carbon. Spiroheterocyclyl may contain one or more double bonds, but no ring has a fully conjugated n electron system. Preferably, it is 6- to 14-membered and more preferably 8- to 12-membered. According to the number of shared spiro atoms between rings, the spiro heterocyclyl is divided into monospiroheterocyclyl, bispiroheterocyclyl or polyspiroheterocyclyl, preferably monospiroheterocyclyl and bispiroheterocyclyl. More preferably, it is 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiro heterocyclyl. Non-limiting examples of spiro heterocyclyl include:

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The term “fused heterocyclyl” refers to a 5- to 20-membered polycyclic heterocyclic group with each ring in the system sharing a pair of atoms neighboring other rings in the system, and one or more rings may contain one or more double bonds, but no ring has a fully conjugated n electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)_m(wherein m is an integer of 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered and more preferably 8- to 12-membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, preferably bicyclic or tricyclic, more preferably 4-membered/5-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/6-membered, and 6-membered/7-membered bicyclic fused heterocyclyl. Non-limiting examples of fused heterocyclyl include:

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The term “bridged heterocyclyl” refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected. It may contain one or more double bonds, but no ring has a fully conjugated n electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O)_m(wherein m is an integer of 0 to 2), and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered and more preferably 7- to 10-membered. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, preferably bicyclic, tricyclic or tetracyclic, and more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl include:

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The heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is heterocyclyl, and the non-limiting examples thereof include:

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Heterocyclyl may be optionally substituted or unsubstituted, and when it is substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, or carboxylate group.

The term “heterocyclylalkylene” refers to heterocyclyl connected to alkylene to form “heterocyclyl-alkylene-”, wherein the heterocyclyl or alkyl may be optionally substituted or unsubstituted, and the heterocyclyl and alkylene are as defined above.

The term “heterocyclylene” refers to bivalent heterocyclyl formed by further replacing one hydrogen atom of cycloalkyl, wherein the heterocyclylene may be optionally substituted or unsubstituted, and the heterocyclyl is defined as above.

The term “aryl” refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing an adjacent pair of carbon atoms) group having a conjugated n electron system, preferably 6- to 10-membered aryl, such as phenyl and naphthyl. Phenyl is more preferred. An aryl ring can be fused to heteroaryl, heterocyclyl or cycloalkyl ring, including benzo 5- to 10-membered heteroaryl, benzo 3- to 8-membered cycloalkyl and benzo 3- to 8-membered heteroalkyl, preferably benzo 5- to 6-membered heteroaryl, benzo 3- to 6-membered cycloalkyl and benzo 3- to 6-membered heteroalkyl, wherein the heterocyclyl is heterocyclyl containing 1-3 nitrogen atoms, oxygen atoms, or sulfur atoms; or further including a three-membered nitrogen-containing fused ring containing a benzene ring,

wherein the ring connected to the parent structure is an aryl ring, and the non-limiting examples thereof include:

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Aryl may be substituted or unsubstituted, and when it is substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate group.

The term “arylene” refers to bivalent aryl formed by further replacing one hydrogen atom of cycloalkyl, wherein the arylene is optionally substituted or unsubstituted, and the aryl is defined as above.

The term “heteroaryl” refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl is preferably 5- to 6-membered monocyclic heteroaryl, or 8- to 12-membered bicyclic heteroaryl, e.g., imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, thiadiazolyl, pyrazinyl, etc., preferably pyridinyl, oxadiazolyl, triazolyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyrimidinyl, or thiazolyl; and tetrazolyl, pyridinyl, oxadiazolyl, pyrazolyl, pyrrolyl, thiazolyl, and oxazolyl are more preferred.

Non-limiting examples of bicyclic heteroaryl include:

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The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is heteroaryl ring, and the non-limiting examples thereof include:

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Heteroaryl may be optionally substituted or unsubstituted, and when it is substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate group.

The term “heteroarylene” refers to bivalent heteroaryl formed by further replacing one hydrogen atom of cycloalkyl, wherein the heteroarylene is optionally substituted or unsubstituted, and the heteroaryl is defined as above.

The term “alkoxy” refers to —O-(alkyl) and —O-(unsubstituted cycloalkyl), where the alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutoxy, cyclopentyloxy, and cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted, and when it is substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or carboxylate group.

“Haloalkyl” refers to alkyl substituted with one or more halogens, wherein the alkyl is as defined above. Non-limiting examples of haloalkyl include: trifluoromethyl, —CH₂CF₃,

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“Haloalkoxy” refers to alkoxy substituted with one or more halogens, wherein the alkoxy is as defined above.

“Hydroxyalkyl” refers to alkyl substituted with hydroxy, wherein the alkyl is as defined above.

The term “alkenylcarbonyl” refers to —C(O)-(alkenyl), wherein the alkenyl is as defined above. Non-limiting examples of alkenylcarbonyl include: ethenylcarbonyl, propenylcarbonyl, and butenylcarbonyl. Alkenylcarbonyl can be optionally substituted or unsubstituted. When it is substituted, the substituent is preferably one or more groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl, or a carboxylate group.

“Aminocarbonyl” refers to NH₂—C(O)—.

“Alkylaminocarbonyl” means that one or both of two hydrogens on aminocarbonyl (NH₂—C(O)—) are substituted by alkyl, wherein the alkyl is as described above.

“Alkylamino” means that one or both of two hydrogens on the amino are substituted by alkyl, wherein the alkyl is as described above.

“Alkylcarbonyl” or “acyl” refers to (alkyl)-C(O)—, wherein the alkyl is as described above.

“Hydroxyl” refers to a —OH group.

“Halogen” refers to fluorine, chlorine, bromine, or iodine.

“Amino” refers to —NH₂.

“Cyano” refers to —CN.

“Nitro” refers to —NO₂.

“Carbonyl” refers to —C(O)—.

“Carboxyl” refers to —C(O)OH.

“THF” refers to tetrahydrofuran.

“Ethyl acetate” refers to ethyl acetate.

“MeOH” refers to methanol.

“DMF” refers to N,N-dimethylformamide.

“DIPEA” refers to diisopropylethylamine.

“TFA” refers to trifluoroacetic acid.

“TEA” refers to triethylamine.

“MeCN” refers to acetonitrile.

“DMA” refers to N,N-dimethylacetamide.

“Et₂O” refers to diethyl ether.

“DCM” refers to dichloromethane.

“DMAP” refers to 4-dimethylaminopyridine.

“DCC” refers to dicyclohexylcarbodiimide.

“DCE” refers to 1,2-dichloroethane.

“DIPEA” refers to N,N-diisopropylethylamine.

“NBS” refers to N-bromosuccinimide.

“NIS” refers to N-iodosuccinimide.

“Cbz-Cl” refers to benzyl chloroformate.

“Pd₂(dba)₃” refers to tris(dibenzylideneacetone)dipalladium.

“Dppf” refers to 1,1′-bisdiphenylphosphine ferrocene.

“HATU” refers to 2-(7-oxidobenzotriazole)-N,N,N′,N′-tetramethyluronium hexafluorophosphate.

“KHMDS” refers to potassium hexamethyldisilazide.

“LiHMDS” refers to lithium bis(trimethylsilyl)amide.

“MeLi” refers to methyl lithium.

“n-BuLi” refers to n-butyl lithium.

“NaBH(OAc)₃” refers to sodium triacetoxyborohydride.

Different expressions such as “X is selected from A, B, or C”, “X is selected from A, B, and C”, “X is A, B, or C”, and “X is A, B, and C” all express the same meaning, i.e., X can be any one or more of A, B, and C.

The hydrogen atoms described in the present invention can be replaced by its isotope deuterium, and any hydrogen atom in the example compounds involved in the present invention can also be replaced by deuterium atom.

“Optional” or “optionally” means that the event or circumstance subsequently described may but need not to occur, and the description includes the occasions where the events or circumstances occur or do not occur. For example, “heterocyclic group optionally substituted with alkyl” means the alkyl may but need not be present, the description includes the case where the heterocyclic group is substituted with alkyl and the case where the heterocyclic group is not substituted with alkyl.

“Substituted” refers to one or more hydrogen atoms in the group, preferably at most 5, more preferably 1-3 hydrogen atoms each independently substituted with a corresponding number of substituents. It goes without saying, the substituents may be only in their possible chemical positions, a person skilled in the art can determine the possible or impossible substitutions (by experiment or theory) without paying too much effort. For example, amino having a free hydrogen or a hydroxy group may be unstable when combined the carbon atoms having an unsaturated (e.g., olefinic) bond.

“Pharmaceutical composition” denotes a mixture containing one or more of the compounds as described herein or physiologically/pharmaceutically acceptable salts or prodrug thereof and other chemical components, as well as other components, such as a physiologically/pharmaceutically acceptable carrier and an excipient. The purpose of pharmaceutical compositions is to facilitate administration to living organisms and facilitate the absorption of active ingredients to exert biological activity.

“Pharmaceutically acceptable salt” refers to a salt of the compound of the present invention, which are safe and effective when used in mammals, and have appropriate biological activity.

DETAILED DESCRIPTION OF EMBODIMENTS

The present invention will be further described below with reference to examples, but these examples do not limit the scope of the present invention.

EXAMPLE

The structure of the compound of the present invention was determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shift (6) was given in parts per million (ppm) unit. NMR was determined using Bruker AVANCE-400 nuclear magnetic instrument. The solvents for determination were deuterated dimethyl sulfoxide (DMSO-d6), deuterated methanol (CD₃OD), deuterated chloroform (CDCl₃), or deuterium water (D₂O), and the internal standard was tetramethylsilane (TMS).

Agilent 1200 Infinity Series mass spectrometer was used for Liquid chromatography-mass spectrometry LC-MS determination. HPLC determination used Agilent 1200DAD high-pressure liquid chromatograph instrument (Sunfire C18 150×4.6 mm chromatographic column) and Waters 2695-2996 high-pressure liquid chromatograph instrument (Gimini C18 150×4.6 mm chromatographic column).

Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate was used as a thin layer chromatography silica plate, and the specification used for the TLC was 0.15-0.20 mm, and the specification when separating and purifying a product by thin layer chromatography is 0.4-0.5 mm. For the column chromatography, Yantai Huanghai silica gel of 200-300 mesh silica gel was generally used as a carrier.

The starting materials in the examples of the present invention were known and can be purchased on the market, or can be synthesized using or according to methods known in the art.

Unless otherwise specified, all reactions of the present invention were carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere, the solvent was a dry solvent, and the reaction temperature unit was degrees Celsius.

Eluent systems for silica gel column chromatography and developer systems for thin layer chromatography, which were used for the purification of compounds in the intermediates and examples, included: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, and C: dichloromethane and acetone system, wherein the volume ratio between the solvents could be adjusted depending on the polarity of the compound, or could also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.

Unless otherwise specified, in the examples of the present invention, ratios in mobile phases in HPLC chiral resolution conditions and HPLC chiral analysis conditions were volume ratios.

Intermediate 1
2′,3-Dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one

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Step 1

2′-Chloro-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one a (200 mg, 0.8 mmol, referring to WO 2014197846 A1 for the synthesis method therefor), 2-(chloromethyl)-3,5-difluoro-pyridine (157 mg, 0.96 mmol), potassium carbonate (276 mg, 1.99 mmol), and 18-crown-6 (21 mg, 0.08 mmol) were dissolved in N,N-dimethylformamide (4 mL). The reaction was heated to 60° C. and stirred for 16 hours. Water (20 mL) was added to the reaction liquid, the aqueous phase was extracted with ethyl acetate (20 mL×2), and the organic phases were combined, dried, and concentrated. The residue was subjected to separation by silica gel column chromatography (eluent system A) to obtain the product 2′-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one b (301 mg), yield: 99%.

MS m/z (ESI): 378.1 [M+H]⁺.

Step 2

2′-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one b (301 mg, 0.8 mmol) and N-chlorosuccinimide (117 mg, 0.88 mmol) were dissolved in isopropanol (6 mL), and the reaction was heated to 60° C. and stirred for 16 hours. After cooling to room temperature, the reaction liquid was concentrated, and the residue was subjected to separation by silica gel column chromatography (eluent system A) to obtain the product 2′,3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one intermediate 1 (190 mg), yield: 57.9%.

MS m/z (ESI): 412.1 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (s, 1H), 8.54 (s, 1H), 8.07-8.13 (m, 1H), 7.69 (s, 1H), 6.80 (s, 1H), 5.48 (s, 2H), 1.98 (s, 3H), 1.96 (s, 3H).

Intermediate 2
2-(1H-pyrazol-3-yl)propan-2-ol

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Step 1

Methyl 1H-pyrazole-3-carboxylate (2 g, 15.9 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to 0° C. Methyl magnesium chloride (1 M, 47.58 mL) was dropwise added to the reaction liquid with stirring. After the dropwise addition was completed, the reaction was heated to room temperature and stirred for 2 hours. Ethyl acetate (100 mL) was added to the reaction liquid, and the organic phase was washed with water and saturated ammonium chloride, dried, and concentrated to obtain the product 2-(1H-pyrazol-3-yl)propan-2-ol intermediate 2 (840 mg), yield: 42%.

MS m/z (ESI): 127.1 [M+H]⁺.

¹H NMR (400 MHz, CDCl₃) δ 7.51 (d, 1H), 6.64 (s, 2H), 6.18 (d, 1H), 1.62 (s, 6H).

Intermediate 3
2′,3-Dichloro-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one

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Step 1

a (10 g, 40 mmol) was dissolved in a mixed solution of dichloroethane (600 mL) and isopropanol (400 mL). The reaction liquid was heated to 60° C., N-chlorosuccinamide (6.4 g, 50 mmol) was added to the reaction liquid in portions, and the reaction continued to be stirred at 60° C. for 2 hours. The reaction liquid was concentrated, isopropanol (50 mL) was added to the residue, and the mixed solution was stirred at 60° C. for 1 hour. The mixed solution was cooled and filtered, and the filter cake was washed with isopropanol. The filter cake was dried to obtain the product 2′,3-dichloro-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one intermediate 3 (8.0 g), yield: 71%.

MS m/z (ESI): 285.0 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ 11.61 (s, 1H), 8.52 (s, 1H), 7.64 (s, 1H), 6.17 (d, 1H), 1.97 (s, 3H), 1.86 (s, 3H).

Intermediate 4
1-(Chloromethyl-d2)-2,4-difluorobenzene

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Step 1

Methyl 2,4-difluorobenzoate 4A (0.5 g, 2.90 mmol) was dissolved in tetrahydrofuran (8 mL) and stirred. A solution of lithium aluminum deuteride (122 mg, 2.90 mmol) in tetrahydrofuran (5 mL) was added to the reaction liquid in an ice bath. The reaction was stirred in the ice bath for 1 hour, the reaction liquid was quenched with saturated ammonium chloride, the aqueous phase was extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated sodium chloride, dried, and concentrated, and the residue was subjected to silica gel column chromatography (elution system B) to obtain (2,4-difluorophenyl)methan-d₂-ol 4B (0.4 g), yield: 94%.

MS m/z (ESI): 147.1 [M+H]⁺.

Step 2

(2,4-Difluorophenyl)methan-d₂-ol 4B (400 mg, 2.74 mmol) and N,N-dimethylformamide (0.05 mL) were dissolved in dichloromethane (10 mL) and stirred, and sulfoxide chloride (749 mg, 6.30 mmol) was slowly dropwise added to the reaction liquid in an ice bath. The reaction was transferred to room temperature and stirred for 1 hour. The reaction liquid was concentrated, the residue was diluted with a saturated sodium bicarbonate solution, the aqueous phase was extracted with dichloromethane (20 mL×3), and the organic phases were combined, washed with saturated sodium chloride, dried, and concentrated to obtain 1-(chloromethyl-d2)-2,4-difluorobenzene intermediate 4 (0.42 g).

Intermediate 5
(2-(2-Hydroxypropan-2-yl)thiazol-4-yl)boronic acid

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Step 1

4-Bromothiazol-2-carboxylic acid 5A (1 g, 4.81 mmol) was dissolved in methanol (10 mL), and thionyl chloride (1.72 g, 14.42 mmol) was slowly dropwise added to the reaction liquid at room temperature. After the dropwise addition was completed, the reaction was heated to 50° C. and stirred for 3.5 hours. The reaction was returned to room temperature and directly concentrated, and the residue was subjected to separation by silica gel column chromatography (eluent system A) to obtain the product methyl 4-bromothiazol-2-carboxylate 5B (1.02 g), yield: 95.6%.

MS m/z (ESI): 222.1, 224.1 [M+H]⁺.

Step 2

Methyl 4-bromothiazol-2-carboxylate 5B (970 mg, 4.37 mmol) was dissolved in tetrahydrofuran (30 mL) and cooled to 0° C. Magnesium methyl bromide (3 M, 4.37 mL) was dropwise added to the reaction liquid, and the mixture was returned to room temperature and continued to be stirred for 5 hours. A saturated ammonium chloride (15 mL) solution was added to the reaction liquid, which was extracted with ethyl acetate (15 mL×2), the organic phases were combined, dried, and concentrated, and the residue was subjected to separation by silica gel column chromatography (eluent system A) to obtain the product 2-(4-bromothiazol-2-yl)propan-2-ol 5C (805 mg), yield: 83.0%.

MS m/z (ESI): 222.1, 224.1 [M+H]⁺.

Step 3

2-(4-Bromothiazol-2-yl)propan-2-ol 5C (100 mg, 0.45 mmol), bis(pinacolato)diboron (137.2 mg, 0.54 mmol), tris(dibenzylideneacetone)dipalladium (20.6 mg, 0.02 mmol), 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl (25.8 mg, 0.05 mmol), and potassium acetate (88.4 mg, 0.9 mmol) were dissolved in anhydrous 1,4-dioxane (9 mL), and after displacement with nitrogen for 1 minute, the reaction was heated to 110° C. and stirred for 2 hours. After cooling to room temperature, the reaction liquid was filtered, the filtrate was concentrated, and the residue was subjected to reversed-phase HPLC (formic acid system) to prepare the title product (2-(2-hydroxypropan-2-yl)thiazol-4-yl)boronic acid intermediate 5 (65 mg), yield: 77.2%.

MS m/z (ESI): 188.1 [M+H]⁺.

Intermediate 6
2-(Chloromethyl-d2)-3,5-difluoropyridine

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Step 1

Lithium aluminum deuteride (388 mg, 9.24 mmol) was added to a solution of methyl 3,5-difluoropyridine-2-carboxylate (1.00 g, 5.78 mmol) in tetrahydrofuran (20 mL) in portions in an ice bath. The reaction was stirred at room temperature for 2 hours. The reaction was quenched with ice cubes, and the reaction liquid was filtered. The filtrate was concentrated, and the residue was subjected to separation by silica gel column chromatography (eluent system B) to obtain the product (3,5-difluoropyridin-2-yl)methan-d2-ol 6A (345 mg), yield: 40.6%.

MS m/z (ESI): 148.0 [M+H]⁺.

Step 2

With stirring, thionyl dichloride (839 mg, 7.06 mmol) was dropwise added to a solution of (3,5-difluoropyridin-2-yl)methan-d2-ol 6A (346 mg, 2.35 mmol) in dichloromethane (5 mL) and N,N-dimethylformamide (0.1 mL). The reaction was stirred at room temperature for 3 hours. The reaction liquid was diluted with ethyl acetate (160 mL), and the organic phase was washed with saturated sodium bicarbonate and water. The organic phase was concentrated, and the residue was subjected to separation by silica gel column chromatography (eluent system B) to obtain the product 2-(chloromethyl-d2)-3,5-difluoropyridine intermediate 6 (150 mg), yield: 38.5%.

MS m/z (ESI): 166.0 [M+H]⁺.

Intermediate 7
1-(2-Bromo-5-methyl-4-pyridinyl)-3-chloro-4-hydroxy-6-methyl-pyridin-2-one

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Step 1

2-Bromo-5-methyl-pyridin-4-amine 7A (2.03 g, 10.86 mmol) and 2,2-dimethyl-6-(2-carbonylpropyl)-4H-1,3-dioxin-4-one (2 g, 10.86 mmol) was dissolved in 1,4-dioxane (80 mL) and stirred. The reaction was placed in a reactor preheated to 90° C. and stirred for 3 hours. Concentrated sulfuric acid (1.8 g, 18.35 mmol) was added to the reaction liquid, and stirring was continued for 1 hour. The reaction liquid was cooled, the supernatant was removed, and water was added to the residual oil. The mixture was stirred at room temperature for 30 minutes and filtered to obtain 2′-bromo-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one 7B (1.7 g), yield: 53%.

MS m/z (ESI): 296.1 [M+H]⁺.

Step 3

2′-Bromo-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one 7B (1.7 g, 5.76 mmol) was dissolved in isopropanol (40 mL) and 1,2-dichloroethane (60 mL), heated to 60° C., and stirred. N-Chlorosuccinamide (923 mg, 6.91 mmol) was added to the reaction liquid in portions, and the mixture was stirred for 2 hours. The reaction liquid was concentrated, isopropanol (20 mL) was added to the residue, and the mixture was heated to 60° C. and stirred for 0.5 hours. The reaction liquid was cooled and filtered to obtain 1-(2-bromo-5-methyl-4-pyridinyl)-3-chloro-4-hydroxy-6-methyl-pyridin-2-one intermediate 7 (1.71 g), yield: 90.1%.

MS m/z (ESI): 330.9 [M+H]⁺.

Intermediate 8
2′-Bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one

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Step 1

1-(2-Bromo-5-methyl-4-pyridinyl)-3-chloro-4-hydroxy-6-methyl-pyridin-2-one intermediate 7 (550 g, 1.67 mmol), intermediate 6 (387 mg, 2.34 mmol), potassium carbonate (577 mg, 4.17 mmol), and 18-crown-6 ether (662 mg, 2.50 mmol) were dissolved in N,N-dimethylformamide (25 mL), heated to 70° C., and stirred for 3 hours. Ethyl acetate (50 mL) was added to the reaction liquid, and the organic phase was washed with water and saturated sodium chloride, dried, and concentrated. The residue was purified by silica gel column (elution system A) to obtain 2′-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one intermediate 8 (540 mg), yield: 70.6%.

MS m/z (ESI): 458.0 [M+H]⁺.

Intermediate 9
N-(2-(4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide

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Step 1

In an ice bath, methyl 4-fluoro-1H-pyrazol-3-carboxylate (600 mg, 4.16 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), a solution of methyl magnesium bromide (3 M, 6.9 mL, 20.7 mmol) in tetrahydrofuran was dropwise added to the reaction liquid while stirring, and the reaction was stirred at room temperature for 3 hours. The reaction liquid was poured into a saturated ammonium chloride solution (50 mL), and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with water (50 mL) and a saturated sodium chloride solution (50 mL) in sequence, dried, and concentrated to obtain 2-(4-fluoro-1H-pyrazol-3-yl)propan-2-ol 9A (600 mg), and the product was directly used in the next reaction without purification.

MS m/z (ESI): 145.1 [M+H]⁺.

Step 2

9A (600 mg, 4.17 mmol) was dissolved in acetonitrile (15 mL) and stirred, concentrated sulfuric acid (5 mL) was dropwise added to the reaction liquid at 0° C., and the reaction was heated to room temperature and stirred for 3 hours. The reaction liquid was poured into a saturated sodium bicarbonate solution (100 mL), and the aqueous phase was extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with water (50 mL) and a saturated sodium chloride solution (50 mL) in sequence, dried, and concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain N-(2-(4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide intermediate 9 (510 mg), yield: 86.8%.

MS m/z (ESI): 186.1 [M+H]⁺.

Intermediate 10
2′-Bromo-3-chloro-4-((2,4-difluorophenyl)methoxy-d2)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one

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Step 1

Under nitrogen protection, intermediate 7 (400 mg, 1.21 mmol), potassium carbonate (503 mg, 3.64 mmol), and 18-crown-6 (481 mg, 1.82 mmol) were dissolved in anhydrous N,N-dimethylformamide (6 mL), heated to 75° C., and stirred, and intermediate 4 (300 mg, 1.82 mmol) was dropwise added to the reaction liquid. The reaction was stirred at 75° C. for 1 hour. Water (50 mL) was added to the reaction liquid, and the aqueous phase was extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed with water (50 mL) and a saturated sodium chloride solution (50 mL) in sequence, and dried, the filtrate was concentrated, and the residue was subjected to separation by silica gel column chromatography (elution system B) to obtain 2′-bromo-3-chloro-4-((2,4-difluorophenyl)methoxy-d2)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one intermediate 10 (480 mg), yield: 86.4%.

MS m/z (ESI): 457.0 [M+H]⁺.

Reference Example 1
3-Chloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′-methyl-2H-[1,4′-bipyridin]-2-one

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Step 1

2,2,6-Trimethyl-4H-1,3-dioxin-4-one 1-a (8.16 g, 57.40 mmol) was dissolved in tetrahydrofuran (60 mL) and cooled to −78° C. Lithium bis(trimethylsilyl)amide (1 M, 63 mL) was dropwise added to the reaction liquid, and after the dropwise addition was completed, the reaction was stirred at −78° C. for 1 hour. A solution of cyclopropylformyl chloride (3 g, 28.70 mmol, 2.60 mL) in tetrahydrofuran (10 mL) was dropwise added to the reaction liquid, and the reaction was stirred at −78° C. for 16 hours. In an ice bath, a saturated ammonium chloride solution (30 mL) was added to the reaction liquid to quench the reaction, and the pH was adjusted to weak acidity with diluted hydrochloric acid. The organic phase was separated, and the aqueous phase was extracted with ethyl acetate (30 mL×2). The organic phases were combined, dried, and concentrated. The residue was subjected to separation by silica gel column chromatography (eluent system B) to obtain the product 6-(2-cyclopropyl-2-carbonylethyl)-2,2-dimethyl-4H-1,3-dioxin-4-one 1-b (2.93 g), yield: 48%.

MS m/z (ESI): 211.1 [M+H]⁺.

Step 2

6-(2-Cyclopropyl-2-carbonylethyl)-2,2-dimethyl-4H-1,3-dioxin-4-one1-b (700 mg, 3.33 mmol) and 2-chloro-4-amino-5-methyl pyridine (617 mg, 4.33 mmol) were dissolved in 1,4-dioxane (10 mL), and the reaction was heated to 90° C. and stirred for 3.5 hours. Concentrated sulfuric acid (0.25 mL) was added to the reaction liquid, and the reaction was stirred at 90° C. for 1 hour. Water (10 mL) was added to the reaction liquid, and subjected to separation by preparative reversed-phase HPLC (formic acid system) to obtain the product 2′-chloro-6-cyclopropyl-4-hydroxy-5′-methyl-2H-[1,4′-bipyridin]-2-one 1-c (318 mg), yield: 34.5%.

MS m/z (ESI): 277.1 [M+H]⁺.

Step 3

2′-Chloro-6-cyclopropyl-4-hydroxy-5′-methyl-2H-[1,4′-bipyridin]-2-one 1-c (318 mg, 1.15 mmol), 2-(chloromethyl)-3,5-difluoro-pyridine (226 mg, 1.38 mmol), potassium carbonate (397 mg, 2.87 mmol), and 18-crown-6 (30 mg, 0.11 mmol) were dissolved in N,N-dimethylformamide (5 mL). The reaction was heated to 60° C. and stirred for 3 hours. Water (20 mL) was added to the reaction liquid, and the aqueous phase was extracted with ethyl acetate (20 mL×2). The organic phases were combined, dried, and concentrated. The residue was subjected to separation by silica gel column chromatography (eluent system A) to obtain the product 2′-chloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-5′-methyl-2H-[1,4′-bipyridin]-2-one 1-d (380 mg), yield: 81%.

MS m/z (ESI): 404.1 [M+H]⁺.

Step 4

2′-Chloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-5′-methyl-2H-[1,4′-bipyridin]-2-one 1-d (150 mg, 0.37 mmol), tributyl (1-ethoxyvinyl)stannane (148 mg, 0.41 mmol), and bis(triphenylphosphine)palladium dichloride (26 mg, 0.04 mmol) were dissolved in 1,4-dioxane (3 mL) and displaced with nitrogen for 2 minutes. The reaction was heated to 130° C. by microwave and stirred for 2 hours. The reaction liquid was filtered, and the filtrate was concentrated. The residue was dissolved with tetrahydrofuran (3 mL), and diluted hydrochloric acid (2 M, 1 mL) was dropwise added for a reaction until the raw materials were completely hydrolyzed. A saturated sodium bicarbonate solution was added to the reaction liquid to adjust the pH to weak alkalinity, and the aqueous phase was extracted with ethyl acetate (20 mL×2). The organic phases were combined, dried, and concentrated, and the residue was subjected to separation by silica gel column chromatography (eluent system A) to obtain the product 2′-acetyl-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-5′-methyl-2H-[1,4′-bipyridin]-2-one 1-e (90 mg), yield: 58.9%.

MS m/z (ESI): 412.1 [M+H]⁺.

Step 5

2′-Acetyl-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-5′-methyl-2H-[1,4′-bipyridin]-2-one 1-e (90 mg, 0.22 mmol) and N-chlorosuccinimide (32 mg, 0.24 mmol) were dissolved in isopropanol (2 mL), and the reaction was heated to 60° C. and stirred for 3 hours. The reaction liquid was concentrated, and the residue was subjected to separation by silica gel column chromatography (eluent system B) to obtain the product 2′-acetyl-3-chloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-5′-methyl-2H-[1,4′-bipyridin]-2-one 1-f (90 mg), yield: 92%.

MS m/z (ESI): 446.1 [M+H]⁺.

Step 6

2′-Acetyl-3-chloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-5′-methyl-2H-[1,4′-bipyridin]-2-one 1-f (90 mg, 0.2 mmol) and N,N-dimethylformamide dimethylacetal (72 mg, 0.61 mmol) were dissolved in N,N-dimethylformamide (2 mL), and the reaction was heated to 50° C. and stirred for 16 hours. Water (10 mL) was added to the reaction liquid, the aqueous phase was extracted with ethyl acetate (15 mL×2), the organic phases were combined, dried, and concentrated to obtain the crude product (E)-3-chloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(3-(dimethylamino)acryloyl)-5′-methyl-2H-[1,4′-bipyridin]-2-one 1-g (80 mg), and the product was directly used in the next reaction without purification.

MS m/z (ESI): 501.1 [M+H]⁺.

Step 7

(E)-3-chloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(3-(dimethylamino)acryloyl)-5′-methyl-2H-[1,4′-bipyridin]-2-one 1-g (80 mg, 0.16 mmol), 2-hydroxy-2-methylpropionamidine hydrochloride (33 mg, 0.24 mmol), and potassium carbonate (44 mg, 0.32 mmol) were dissolved in N,N-dimethylformamide (2 mL), and the reaction was heated to 75° C. and stirred for 16 hours. After cooling to room temperature and filtration, the filtrate was subjected to separation by preparative reversed-phase HPLC (formic acid system) to obtain the title product 3-chloro-6-cyclopropyl-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′-methyl-2H-[1,4′-bipyridin]-2-one Reference Example 1 (55 mg), yield: 63.8%.

MS m/z (ESI): 540.1 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ 8.96 (d, 1H), 8.85 (s, 1H), 8.75 (s, 1H), 8.62 (d, 1H), 8.24 (d, 1H), 8.15-8.05 (m, 1H), 6.47 (s, 1H), 5.53 (d, 2H), 5.24 (s, 1H), 2.13 (s, 3H), 1.53 (d, 6H), 1.36-1.23 (m, 1H), 1.02-0.93 (m, 1H), 0.92-0.81 (m, 1H), 0.75-0.63 (m, 2H).

Reference Example 2
3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one

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Step 1

Under nitrogen protection, intermediate 1 (50 mg, 0.12 mmol), intermediate 5 (50.8 mg, 0.17 mmol, purity: 62%), 1,1-bis(diphenylphosphine) 1,1′-bisdiphenylphosphineferrocene palladium dichloride (8.9 mg, 0.01 mmol), and cesium carbonate (79 mg, 0.24 mmol) were dissolved in a mixed solvent of 1,4-dioxane (1 mL) and water (0.3 mL). The reaction was heated to 100° C. and stirred for 3 hours. The reaction liquid was concentrated, and the residue was subjected to separation by silica gel column chromatography (eluent system B) to obtain the title product 3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)thiazol-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one Reference Example 2 (32 mg), yield: 50.8%.

MS m/z (ESI): 519.1 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (s, 1H), 8.61 (d, 1H), 8.18 (s, 1H), 8.15-8.05 (m, 1H), 7.86 (s, 1H), 6.80 (s, 1H), 6.06 (s, 1H), 5.48 (d, 2H), 2.03 (s, 3H), 1.97 (s, 3H), 1.55 (d, 6H).

Example 1
11-Chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azol-12-one

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Step 1

At −50° C., lithium bis(trimethylsilyl)amide (66.1 mL, 1 M in tetrahydrofuran) was dropwise added to a solution of 2,2,6-trimethyl-4H-1,3-dioxy-4-one 1a (9.50 g, 66.8 mmol) in tetrahydrofuran (20 mL). After the reaction was stirred at −50° C. for 1 hour, pent-4-enoyl chloride (4.40 g, 37.11 mmol) was dropwise added to the reaction liquid, and the stirring was continued for 1 hour. The reaction liquid was quenched with formic acid and filtered, the filtrate was concentrated, and the residue was subjected to separation by silica gel column chromatography (eluent system A) to obtain the title product 2,2-dimethyl-6-(2-oxohex-5-en-1-yl)-4H-1,3-dioxy-4-one 1b (3.60 g), yield: 43.3%.

MS m/z (ESI): 225.1 [M+H]⁺.

Step 2

Under nitrogen protection, 1j (1.50 g, 5.89 mmol), tributyl vinyl tin (2.43 g, 7.66 mmol), and 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (431 mg, 0.59 mmol) were dissolved in 1,4-dioxane (15 mL) and sealed in a microwave tube, and the reaction was heated to 100° C. by microwave and stirred for 2 hours. The reaction liquid was concentrated, and the residue was subjected to separation by silica gel column chromatography (eluent system A) to obtain the title product 2-chloro-4-amino-5-vinylpyridine 1k (460 mg), yield: 50.5%.

MS m/z (ESI): 155.0 [M+H]⁺.

Step 3

1b (6.70 g, 29.88 mmol) and 1k (3.08 g, 19.92 mmol) were dissolved in 1,4-dioxane (80 mL), heated to 100° C., and stirred for 1.5 hours. Concentrated sulfuric acid (4.88 g, 49.80 mmol) was slowly dropwise added to the reaction liquid, and the reaction was stirred at 100° C. for 2 hours. The reaction liquid was concentrated, methanol and water were added to the residue, which was filtered, and the filtrate was concentrated and subjected to separation by preparative reversed-phase HPLC (formic acid system) to obtain the title product 6-(but-3-en-1-yl)-2′-chloro-4-hydroxy-5′-vinyl-2H-[1,4′-bipyridin]-2-one 1c (3.80 g), yield: 63.0%.

MS m/z (ESI): 303.1 [M+H]⁺.

Step 4

Under nitrogen protection, 1c (334 mg, 1.11 mmol) and Grubbs second-generation catalyst (93 mg, 0.11 mmol) were dissolved in 1,2-dichloroethane (300 mL), and the reaction was heated to 60° C. and stirred for 2 hours. Methanol (10 mL) was added to the reaction liquid and concentrated, and the residue was subjected to separation by silica gel column chromatography (eluent system A) to obtain the title product (Z)-2-chloro-10-hydroxy-7,8-dihydro-12H-dipyrido[1,2-a:3′,4′-g]azol-12-one 1d (110 mg), yield: 36.0%.

MS m/z (ESI): 275.0 [M+H]⁺.

Step 5

In a hydrogen atmosphere, 1d (300 mg, 0.19 mmol) and platinum dioxide (25 mg, 0.19 mmol) were dissolved in tetrahydrofuran (20 mL), and the reaction was stirred at 25° C. for 3 hours. The reaction liquid was filtered, the filtrate was concentrated, and the residue was subjected to separation by silica gel column chromatography (eluent system A) to obtain the title product 2-chloro-10-hydroxy-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azol-12-one 1e (200 mg), yield: 66.2%.

MS m/z (ESI): 277.1 [M+H]⁺.

Step 6

1e (480 mg, 1.76 mmol) and N-chlorosuccinimide (347 mg, 2.61 mmol) were dissolved in isopropanol (20 mL), and the reaction was heated to 35° C. and stirred for 1 hour. The reaction liquid was concentrated, and the residue was subjected to separation by silica gel column chromatography (eluent system A) to obtain the title product 2,11-dichloro-10-hydroxy-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azol-12-one 1f (200 mg), yield: 64.3%.

MS m/z (ESI): 311.0 [M+H]⁺.

Step 7

1f (168 mg, 0.54 mmol), potassium carbonate (149 mg, 1.08 mmol), and intermediate 6 (119 mg, 0.81 mmol) were dissolved in N,N-dimethylformamide (5 mL), and the reaction was heated to 70° C. and stirred for 16 hours. The reaction liquid was concentrated, and the residue was subjected to separation by preparative reversed-phase HPLC (formic acid system) to obtain the title product 2,11-dichloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azol-12-one 1g (172 mg), yield: 72.4%.

MS m/z (ESI): 40.1 [M+H]⁺.

Step 8

Under nitrogen protection, 1g (150 mg, 0.34 mmol), tributyl(1-ethoxyvinyl)stannane (185 mg, 0.51 mmol) and bis(triphenylphosphine)palladium dichloride (24 mg, 0.03 mmol) were dissolved in a solution of 1,4-dioxane (5 mL), and the reaction was heated to 123° C. by microwave and stirred for 2 hours. The reaction liquid was quenched with diluted hydrochloric acid (0.6 M, 0.5 mL), stirred at room temperature for 30 minutes, and concentrated, and the residue was subjected to separation by preparative reversed-phase HPLC (formic acid system) to obtain the title product 2-acetyl-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azol-12-one 1h (132 mg), yield: 86.5%.

MS m/z (ESI): 448.1 [M+H]⁺.

Step 9

A solution of 1h (160 mg, 0.36 mmol) in N,N-dimethylformamide (2 mL) and 1,1-dimethoxy-N,N-dimethylmethylamine (2 mL) was warmed to 70° C. and stirred for 16 hours. The reaction liquid was concentrated, and the residue was subjected to separation by preparative reversed-phase HPLC (formic acid system) to obtain the title product (Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(dimethylamino)acryloyl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azol-12-one 1i (85 mg), yield: 47.3%.

MS m/z (ESI): 503.2 [M+H]⁺.

Step 10

1i (85 mg, 0.17 mmol), 2-hydroxy-2-methylpropionamidine hydrochloride (70 mg, 0.51 mmol), and potassium carbonate (70 mg, 0.51 mmol) were dissolved in N,N-dimethylformamide (3 mL), and the reaction was heated to 75° C. and stirred for 16 hours. The reaction liquid was cooled to room temperature and filtered, and the filtrate was subjected to separation by preparative reversed-phase HPLC (formic acid system) to obtain the title product 11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azol-12-one 1 (50 mg), yield: 54.6%.

MS m/z (ESI): 542.2 [M+H]+.

¹H NMR (400 MHz, CD₃OD) δ 8.90 (d, 1H), 8.86 (s, 1H), 8.54 (s, 1H), 8.46 (d, 1H), 8.29 (d, 1H), 7.73 (m, 1H), 6.84 (s, 1H), 2.90 (m, 2H), 2.26 (m, 3H), 2.04 (m, 1H), 1.62 (m, 8H).

Resolution of Example 1
(S)-11-Chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azol-12-one and (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azol-12-one

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Example 1 (50 mg, 0.091 mmol) was subjected to chiral resolution (OD column) to obtain 1-1 (20 mg, R.T=3.807 min), yield: 40.0%; 1-2 (20 mg, R.T=7.060 min), yield: 40.0%.

Example 1-1: MS m/z (ESI): 542.2 [M+H]⁺;

¹H NMR (400 MHz, CD₃OD) δ 8.90 (d, 1H), 8.86 (s, 1H), 8.54 (s, 1H), 8.46 (d, 1H), 8.29 (d, 1H), 7.73 (m, 1H), 6.84 (s, 1H), 2.90 (m, 2H), 2.26 (m, 3H), 2.04 (m, 1H), 1.62 (m, 8H).

Example 1-2: MS m/z (ESI): 542.2 [M+H]⁺;

¹H NMR (400 MHz, CD₃OD) δ 8.90 (d, 1H), 8.86 (s, 1H), 8.54 (s, 1H), 8.46 (d, 1H), 8.29 (d, 1H), 7.73 (m, 1H), 6.84 (s, 1H), 2.90 (m, 2H), 2.26 (m, 3H), 2.04 (m, 1H), 1.62 (m, 8H).

HPLC Chiral Resolution Conditions:

Instrument
HPLC (Waters)

Column type
DAICEL CHIPAKPAK ®OD

250 * 20 mm 5.0 μm

Column pressure
800 psi

Mobile phase
Hexane:MeOH (+0.1% DEA) = 70:30

Flow rate
15 mL/min

Detection
UV 214 nm

wavelength

Column
R.T.

temperature

HPLC Chiral Analysis Conditions:

Instrument
HPLC (Waters)

Column type
DAICEL CHIRALCEL OD-H 4.6 mm

I.D × 150 mmL 5.0 μm

Column pressure
45 psi

Mobile phase
Hexane:MeOH (+0.1% DEA) = 70:30

Flow rate
1 mL/min

Detection
UV 214 nm

wavelength

Column
35°C

temperature

Example 2
11-Chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azol-12-one

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Step 1

Under nitrogen protection, 2-bromo-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azol-12-one 2a (50 mg, 0.10 mmol; for the synthesis method therefor, reference could be made to the synthesis of 1g in Example 1), intermediate 2 (20 mg, 0.15 mmol), cesium carbonate (50 mg, 0.15 mmol), and cuprous iodide (10 mg, 0.05 mmol) were dissolved in 1,4-dioxane (3 mL), and the reaction was heated to 100° C. and stirred for 2 hours. The reaction liquid was concentrated, and the residue was subjected to separation by silica gel column chromatography (eluent system A) to obtain 11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azol-12-one 2 (41 mg), yield: 75.0%.

MS m/z (ESI): 530.2 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (m, 2H), 8.52 (d, 1H), 8.10 (m, 1H), 7.70 (s, 1H), 6.80 (s, 1H), 6.56 (d, 1H), 5.13 (s, 1H), 2.85 (m, 2H), 2.09 (m, 3H), 1.90 (m, 1H), 1.47 (m, 8H).

Resolution of Example 2
(S)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azol-12-one and (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azol-12-one

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Example 2 (80 mg, 0.151 mmol) was subjected to chiral resolution (IB column) to obtain 2-1 (35 mg, R.T=3.677 min), yield: 43.7%; 2-2 (30 mg, R.T=6.300 min), yield: 37.5%.

Example 2-1: MS m/z (ESI): 530.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (m, 2H), 8.52 (d, 1H), 8.10 (m, 1H), 7.70 (s, 1H), 6.80 (s, 1H), 6.56 (d, 1H), 5.13 (s, 1H), 2.85 (m, 2H), 2.09 (m, 3H), 1.90 (m, 1H), 1.47 (m, 8H).

Example 2-2: MS m/z (ESI): 530.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (m, 2H), 8.52 (d, 1H), 8.10 (m, 1H), 7.70 (s, 1H), 6.80 (s, 1H), 6.56 (d, 1H), 5.13 (s, 1H), 2.85 (m, 2H), 2.09 (m, 3H), 1.90 (m, 1H), 1.47 (m, 8H).

HPLC Chiral Resolution Conditions:

Instrument
HPLC (Waters)

Column type
DAICEL CHIPAKPAK ® IB

250 * 20 mm 5.0 μm

Column pressure
800 psi

Mobile phase
Hexane:EtOH:MeOH (+0.1% DEA) = 70:15:15

Flow rate
15 mL/min

Detection
UV 214 nm

wavelength

Column
R.T.

temperature

HPLC Chiral Analysis Conditions:

Instrument
HPLC (Waters)

Column type
DAICEL CHIRALCEL IB-H 4.6 mm I.D ×

150 mmL 5.0 μm

Column pressure
45 psi

Mobile phase
Hexane:EtOH:MeOH (+0.1% DEA) = 70:15:15

Flow rate
1 mL/min

Detection
UV 214 nm

wavelength

Column
35° C.

temperature

Example 3
N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3′,4′-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide

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Step 1

Under nitrogen protection, 2a (100 mg, 0.206 mmol), intermediate 9 (52 mg, 0.280 mmol), cuprous iodide (19.64 mg, 0.103 mmol), (1R,2R)—N1,N2-dimethylcyclohexane-1,2-diamine (23.48 mg, 0.165 mmol), and cesium carbonate (100.58 mg, 0.309 mmol) were dissolved in 1,4-dioxane (2 mL), and the reaction liquid was heated to 100° C. and stirred for 0.5 hours. The reaction liquid was filtered and concentrated. The residue was purified by silica gel column chromatography (elution system C) to obtain N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3′,4′-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide 3 (90 mg), yield: 74.1%.

MS m/z (ESI): 589.2 [M+H]⁺.

Resolution of Example 3
(S)—N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3′,4′-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R)—N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3′,4′-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide

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Example 3 (90 mg, 0.152 mmol) was subjected to chiral resolution (OD column) to obtain 3-1 (20.4 mg, R.T=3.403 min), yield: 22.35%; 3-2 (21.9 mg, R.T=4.447 min), yield: 23.56%.

Example 3-1: MS m/z (ESI): 589.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ 8.64-8.51 (m, 3H), 8.15-8.04 (m, 2H), 7.68 (s, 1H), 6.79 (s, 1H), 2.93-2.76 (in, 2H), 2.15-1.89 (m, 4H), 1.79 (s, 3H), 1.57 (d, 6H), 1.53-1.29 (in, 2H).

Example 3-2: MS m/z (ESI): 589.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ 8.64-8.54 (m, 3H), 8.15-8.06 (m, 2H), 7.68 (s, 1H), 6.79 (s, 1H), 2.93-2.76 (in, 2H), 2.16-1.89 (m, 4H), 1.79 (s, 3H), 1.57 (d, 6H), 1.50-1.29 (in, 2H).

HPLC Chiral Resolution Conditions:

Instrument
Waters HPLC

Column type
DAICEL CHIRALCEL ® OD 20 mm I.D ×

250 mm 5.0 μm

Column pressure
900 psi

Mobile phase
Hexane:EtOH (+0.1% DEA) = 70:30

Flow rate
15 mL/min

Detection
254 nm

wavelength

Column
R.T.

temperature

HPLC Chiral Analysis Method:

Instrument
Thermo Ultimate 3000

Column type
DAICEL CHIRALCEL ® OD 4.6 mm I.D ×

150 mm 5.0 μm

Column
55 bar

pressure

Mobile phase
Hexane:EtOH (+0.1% DEA) = 70:30

Flow rate
1 ml/min

Detection
254 nm

wavelength

Column
35° C.

temperature

Example 4
N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3′,4′-g]azocin-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide

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Referring to the synthesis method of Example 1, the target product N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3′,4′-g]azocin-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide 4 was synthesized.

MS m/z (ESI): 583.2 [M+H]⁺;

Resolution of Example 4
(S)—N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3′,4′-g]azocin-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide and (R)—N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3′,4′-g]azocin-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide

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Example 4 (26 mg, 0.047 mmol) was subjected to chiral resolution (IB column) to obtain 4-1 (5 mg, R.T=4.387 min), yield: 19.23%; 4-2 (5 mg, R.T=5.183 min), yield: 19.23%.

Example 4-1: MS m/z (ESI): 583.2 [M+H]⁺;

Example 4-2: MS m/z (ESI): 583.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ 8.94-8.83 (m, 2H), 8.61 (d, 1H), 8.24 (d, 2H), 8.16 (d, 1H), 8.10 (ddd, 1H), 6.81 (s, 1H), 2.98 (dd, 1H), 2.80 (dd, 1H), 2.21-2.05 (m, 3H), 1.95-1.82 (m, 1H), 1.77 (s, 3H), 1.60 (d, 6H), 1.48-1.29 (m, 2H).

HPLC Chiral Resolution Conditions:

Instrument
HPLC (Waters)

Column type
DAICEL CHIPAKPAK ® IB 250 * 20 mm 5.0 μm

Column pressure
800 psi

Mobile phase
Hexane:EtOH:MeOH (+0.1% DEA) = 70:15:15

Flow rate
15 mL/min

Detection
UV 214 nm

wavelength

Column
R.T.

temperature

HPLC Chiral Analysis Conditions:

Instrument
HPLC (Waters)

Column type
DAICEL CHIRALCEL IB-H 4.6 mm I.D ×

150 mmL 5.0 μm

Column pressure
45 psi

Mobile phase
Hexane:EtOH: MeOH (+0.1% DEA) = 70:15:15

Flow rate
1 mL/min

Detection
UV 214 nm

wavelength

Column
35° C.

temperature

Example 5
N-(2-(3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy-d2)-5′,6″-dimethyl-2,2″-dicarbonyl-2H,2″H-[1,2′:4′,1″-terpyridin]-3-yl)propan-2-yl)acetamide

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Step 1

At 0° C., methyl magnesium bromide (3 M, 2.61 mL) was dropwise added to a solution of methyl 2-oxo-1,2-dihydro-3-pyridinecarboxylate 5a (300 mg, 1.96 mmol) in tetrahydrofuran (8 mL), and the reaction was warmed to room temperature and stirred for 1.5 hours. The reaction liquid was cooled to 0° C., and a saturated ammonium chloride solution was dropwise added to the reaction liquid to quench the reaction. The aqueous phase was extracted with ethyl acetate (25 mL×4), the organic phases were combined, dried, and concentrated, and the residue was subjected to separation by silica gel column chromatography (elution system B) to obtain 3-(2-hydroxypropan-2-yl)pyridin-2(1H)-one 5b (173 mg), yield: 57.65%.

MS m/z (ESI): 154.1 [M+H]⁺; Step 2

Concentrated sulfuric acid (960 mg, 9.8 mmol) was dropwise added to a solution of 5b (150 mg, 0.98 mmol) in acetonitrile (2 mL), and the reaction was warmed to room temperature and stirred for 3 hours. At 0° C., a saturated sodium bicarbonate solution was added to the above reaction liquid to adjust pH to weak alkalinity. The reaction liquid was concentrated, and the residue was subjected to separation by silica gel column chromatography (elution system B) to obtain N-(2-(2-carbonyl-1,2-dihydropyridin-3-yl)propan-2-yl)acetamide 5c (168 mg), yield: 88.33%.

MS m/z (ESI): 195.2 [M+H]⁺;

Step 3

Under nitrogen protection, intermediate 8 (60 mg, 0.13 mmol), 5c (33 mg, 0.17 mmol), cuprous iodide (10 mg, 0.05 mmol), and potassium carbonate (18 mg, 0.13 mmol) were dissolved in N,Ndimethylacetamide (1 mL), and the reaction was heated to 120° C. and stirred for 6 hours. A saturated ammonium chloride solution was added to the reaction liquid, the aqueous phase was extracted with ethyl acetate (20 mL×2), the organic phases were combined, dried, and concentrated, and the residue was subjected to preparation by reversed-phase HPLC to obtain N-(2-(3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy-d2)-5′,6″-dimethyl-2,2″-dicarbonyl-2H,2″H-[1,2′:4′,1″-terpyridin]-3-yl)propan-2-yl)acetamide 5 (35 mg), yield: 46.78%.

MS m/z (ESI): 572.2 [M+H]⁺;

Resolution of Example 5
(S)—N-(2-(3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy-d2)-5′,6″-dimethyl-2,2″-dicarbonyl-2H,2″H-[1,2′:4′,1″-terpyridin]-3-yl)propan-2-yl)acetamide and (R)—N-(2-(3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy-d2)-5′,6″-dimethyl-2,2″-dicarbonyl-2H,2″H-[1,2′:4′,1″-terpyridin]-3-yl)propan-2-yl)acetamide

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Example 5 (33 mg, 0.06 mmol) was subjected to chiral resolution (IB column) to obtain the title product 5-1 (11.1 mg, R.T=5.100 min), yield: 33.64%; 5-2 (11 mg, R.T=6.173 min), yield: 33.33%.

Example 5-1, MS m/z (ESI): 572.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (s, 1H), 8.60 (d, 1H), 8.14-8.04 (m, 1H), 7.88-7.80 (m, 2H), 7.75 (s, 1H), 7.39-7.30 (m, 1H), 6.79 (s, 1H), 6.36 (t, 1H), 2.07 (s, 3H), 2.00 (s, 3H), 1.81 (s, 3H), 1.61-1.58 (m, 6H).

Example 5-2, MS m/z (ESI): 572.2 [M+H]⁺;

HPLC Chiral Resolution Conditions:

Instrument
HPLC (Waters)

Column type
DAICEL CHIRALPAK ® IB 270 * 30 mm 10.0 μm

Column pressure
800 psi

Mobile phase
Hexane/EtOH (+0.1% DEA) = 70/30

Flow rate
15 mL/min

Detection
UV 214 nm

wavelength

Column
25° C.

temperature

HPLC Chiral Analysis Method:

Instrument
HPLC (Waters)

Column type
DAICEL CHIRALPAK ® IB N-5 150 * 4.6 mm

5.0 μm

Column pressure
35 bar

Mobile phase
Hexane/EtOH (+0.1% DEA) = 70/30

Flow rate
1 mL/min

Detection
214 nm

wavelength

Column
35° C.

temperature

Example 6
N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d₂)-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3′,4′-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide

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Step 1

Under nitrogen protection, 6a (4 g, 27.3 mmol) was dissolved in anhydrous acetonitrile (60 mL), N-iodosuccinimide (7.37 g, 32.8 mmol) and p-toluenesulfonic acid (235 mg, 1.36 mmol) were added, and the reaction was heated to 80° C. and stirred for 16 hours. The reaction liquid was cooled to room temperature, diluted with ethyl acetate (100 mL), then washed with a saturated sodium sulfite solution (80 mL), water (80 mL), and a saturated sodium chloride solution (80 mL) in sequence, dried, and concentrated, and the residue was purified by silica gel column chromatography (elution system A) to obtain 2-chloro-3-fluoro-5-iodo-pyridin-4-amine 6b (6.5 g), yield: 87.4%.

MS m/z (ESI): 272.9 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (s, 1H), 6.69 (s, 2H).

Step 2

Under nitrogen protection, 6b (4 g, 14.7 mmol) was dissolved in 1,4-dioxane (60 mL), and water (12 mL), potassium vinyltrifluoroborate (2.36 g, 17.6 mmol), 1,1-bis(diphenylphosphine)ferrocene palladium dichloride (533 mg, 0.734 mmol), and sodium carbonate (3.89 g, 36.7 mmol) were added, and the reaction was heated to 80° C. and stirred for 4 hours. The reaction liquid was cooled to room temperature, diluted with ethyl acetate (100 mL), then washed with water (60 mL) and a saturated sodium chloride solution (60 mL) in sequence, dried, filtered, and concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 2-chloro-3-fluoro-5-vinyl-pyridin-4-amine 6c (2.1 g), yield: 82.9%.

MS m/z (ESI): 173.0 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ 7.98 (s, 1H), 6.82 (dd, 1H), 6.62 (s, 2H), 5.78 (dd, 1H), 5.33 (dd, 1H).

Step 3

6c (1 g, 5.79 mmol) was dissolved in 1,4-dioxane (15 mL), 1b (1.30 g, 5.79 mmol) was added, and the reaction was heated to 100° C. and stirred for 2 hours. Concentrated sulfuric acid (1.42 g, 0.772 mL) was added to the reaction liquid, and the reaction continued to be stirred at 100° C. for 0.5 hours. The reaction liquid was cooled to room temperature, diluted with ethyl acetate (50 mL), then washed with water (50 mL) and a saturated sodium chloride solution (50 mL) in sequence, dried, and concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 6-(but-3-en-1-yl)-2′-chloro-3′-fluoro-4-hydroxy-5′-vinyl-2H-[1,4′-bipyridin]-2-one 6d (1.1 g), yield: 59.2%.

MS m/z (ESI): 321.0 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ 11.13 (s, 1H), 8.80 (s, 1H), 6.29-6.22 (m, 1H), 6.08-6.00 (m, 2H), 5.67-5.58 (m, 3H), 4.95-4.89 (m, 2H), 2.19-2.16 (m, 2H), 2.13-2.09 (m, 2H).

Step 4

6d (100 mg, 0.312 mmol) was dissolved in N,N-dimethylformamide (3 mL), intermediate 6 (77 mg, 0.468 mmol), 18-crown-6 (124 mg, 0.468 mmol), and potassium carbonate (129 mg, 0.935 mmol) were added, and the reaction was heated to 75° C. and stirred for 2 hours. The reaction liquid was cooled to room temperature and extracted with ethyl acetate (50 mL), the organic phase was washed with water (30 mL×2) and a saturated sodium chloride solution (30 mL) in sequence, dried, and concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 6-(but-3-en-1-yl)-2′-chloro-4-((3,5-difluoropyridin-2-yl)methoxy-d2)-3′-fluoro-5′-vinyl-2H-[1,4′-bipyridin]-2-one 6e (110 mg), yield: 78.4%.

MS m/z (ESI): 450.1 [M+H]⁺; Step 5

6e (110 mg, 0.245 mmol) and Grubbs second-generation catalyst (21 mg, 0.0245 mmol) were dissolved in 1,2-dichloroethane (80 mL), and the reaction was heated to 40° C. under nitrogen protection and stirred for 1 hour. The reaction liquid was cooled to room temperature and concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain (Z)-2-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-7,8-dihydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one 6f (95 mg), yield: 92.1%.

MS m/z (ESI): 422.1 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ 8.59 (d, 1H), 8.32 (s, 1H), 8.10-8.05 (m, 1H), 6.43 (d, 1H), 6.19 (d, 1H), 6.04 (d, 1H), 6.03-5.98 (m, 1H), 2.72-2.64 (m, 2H), 2.59-2.52 (m, 1H), 2.47-2.41 (m, 1H).

Step 6

6f (95 mg, 0.225 mmol) and platinum dioxide (5 mg, 0.0225 mmol) were dissolved in tetrahydrofuran (3 mL), and the reaction was subjected to displacement with hydrogen 3 times and then stirred at room temperature in a hydrogen atmosphere for 2 hours. The reaction liquid was filtered and concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 2-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one 6g (90 mg), yield: 94.3%.

MS m/z (ESI): 424.1 [M+H]⁺; Step 7

6g (90 mg, 0.212 mmol) and N-chlorosuccinimide (34 mg, 0.255 mmol) were dissolved in 1,2-dichloroethane (9 mL) and isopropanol (3 mL), and the reaction was heated to 60° C. for 2 hours of reaction. The reaction liquid was cooled to room temperature, washed with water (20 mL) and a saturated sodium chloride solution (20 mL) in sequence, dried, and concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 2,11-dichloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one 6h (90 mg), yield: 92.5%.

MS m/z (ESI): 458.0 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ 8.39 (d, 1H), 8.26 (s, 1H), 7.35-7.30 (m, 1H), 6.43 (s, 1H), 2.93-2.88 (m, 1H), 2.80-2.75 (m, 1H), 2.28-2.17 (m, 3H), 2.05-1.95 (m, 1H), 1.62-1.45 (m, 2H).

Step 8

Under nitrogen protection, 6h (100 mg, 0.218 mmol), intermediate 9 (81 mg, 0.436 mmol), cesium carbonate (213 mg, 0.655 mmol), cuprous iodide (62 mg, 0.327 mmol), and trans-N,N-dimethyl-1,2-cyclohexanediamine (31 mg, 0.218 mmol) were dissolved in 1,4-dioxane (2 mL), and the reaction was heated to 100° C. and stirred for 16 hours. The reaction liquid was cooled to room temperature and filtered, the filtrate was diluted with ethyl acetate (50 mL), then washed with water (30 mL) and a saturated sodium chloride solution (30 mL) in sequence, dried, and concentrated, and the residue was purified by reversed-phase column chromatography (eluent system C) to obtain N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d₂)-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3′,4′-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide 6 (40 mg), yield: 30.2%.

MS m/z (ESI): 607.2 [M+H]⁺;

Resolution of Example 6
(R)—N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d₂)-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3′,4′-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide and (S)—N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d₂)-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3′,4′-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide

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Example 6 (40 mg, 0.066 mmol) was subjected to chiral resolution (IB column) to obtain 6-1 (13.2 mg, R.T=4.940 min), yield: 33.0%; 6-2 (15.8 mg, R.T=7.710 min), yield: 21.3%.

Example 6-1: MS m/z (ESI): 607.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (d, 1H), 8.50 (s, 1H), 8.45 (d, 1H), 8.13-8.07 (m, 2H), 6.86 (s, 1H), 3.03-2.98 (m, 1H), 2.86-2.80 (m, 1H), 2.18-1.99 (m, 4H), 1.79 (s, 3H), 1.61-1.50 (m, 7H), 1.40-1.34 (m, 1H).

Example 6-2: MS m/z (ESI): 607.2 [M+H]⁺;

HPLC Chiral Resolution Conditions:

Instrument
Waters HPLC

Column type
DAICEL CHIRALCEL ® IB 20 mm I.D ×

250 mm 5.0 μm

Column pressure
900 psi

Mobile phase
Hexane:EtOH (+0.1% DEA) = 70:30

Flow rate
15 mL/min

Detection
214 nm

wavelength

Column temperature
R.T.

HPLC Chiral Analysis Method:

Instrument
Thermo Ultimate 3000

Column type
DAICEL CHIRALCEL ® IB 4.6 mm I.D ×

150 mm 5.0 μm

Column pressure
55 bar

Mobile phase
Hexane:EtOH (+0.1% DEA) = 70:30

Flow rate
1 mL/min

Detection
214 nm

wavelength

Column
35° C.

temperature

Example 7
N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d₂)-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3′,4′-g]azocin-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide

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Step 1

Under nitrogen protection, 6h (90 mg, 0.196 mmol) was dissolved in 1,4-dioxane (2 mL), tributyl (1-ethoxyvinyl)tin (75 mg, 0.206 mmol) and bis(triphenylphosphine)palladium dichloride (14 mg, 0.019 mmol) were added, and the mixed solution was reacted in a microwave reactor at 125° C. for 2 hours. The reaction liquid was cooled to room temperature, and diluted hydrochloric acid (0.2 M, 1 mL) was added and stirred for 1 hour. The reaction liquid was diluted with ethyl acetate (50 mL), then washed with a saturated sodium bicarbonate solution (30 mL) and a saturated sodium chloride solution (30 mL) in sequence, the organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 2-acetyl-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d₂)-1-fluoro-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3,4′-g]azocin-12-one 7a (90 mg), yield: 98.4%.

MS m/z (ESI): 466.1 [M+H]⁺.

Step 2

Under nitrogen protection, 7a (90 mg, 0.193 mmol) was dissolved in N,N-dimethylformamide (2 mL), N,N-dimethylformamide dimethylacetal (115 mg, 0.966 mmol) was added, and the reaction was heated to 55° C. and stirred for 6 hours. The reaction liquid was cooled to room temperature, then washed with ethyl acetate (50 mL), then washed with water (30 mL×2) and a saturated sodium chloride solution (30 mL) in sequence, dried, and concentrated to obtain 11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d₂)-2-(3-(dimethylamino)acryloyl)-1-fluoro-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one 7b (110 mg), and the product was directly used in the next reaction without purification.

MS m/z (ESI): 521.2 [M+H]⁺.

Step 3

Under nitrogen protection, 7b (110 mg, 0.211 mmol) was dissolved in N,N-dimethylformamide (3 mL), N-(1-amino-1-imino-2-methylpropan-2-yl)acetamide acetate (90 mg, 0.443 mmol; for the preparation method therefor, reference could be made to the document: Chemistry of Heterocyclic Compounds 2020, 56(10), 1329-1334.) and potassium carbonate (146 mg, 1.06 mmol) were added, and the reaction was heated to 75° C. and stirred for 16 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (50 mL), then washed with water (30 mL×2) and a saturated sodium chloride solution (30 mL) in sequence, dried, and concentrated, and the residue was subjected to separation by preparative HPLC (formic acid system) to obtain N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d₂)-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3′,4′-g]azocin-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide 7 (35 mg), yield: 27.6%.

MS m/z (ESI): 601.2 [M+H]⁺;

Resolution of Example 7
(R)—N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d₂)-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3,4′-g]azocin-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide and (S)—N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d₂)-1-fluoro-12-carbonyl-6,7,8,12-tetrahydro-5H-dipyrido[1,2-a:3′,4′-g]azocin-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide

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Example 7 (35 mg, 0.058 mmol) was subjected to chiral resolution (IB column) to obtain 7-1 (10.7 mg, R.T=4.640 min), yield: 30.45%; 7-2 (10.4 mg, R.T=5.473 min), yield: 29.54%.

Example 7-1: MS m/z (ESI): 601.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ 8.92 (d, 1H), 8.77 (s, 1H), 8.60 (d, 1H), 8.22 (s, 1H), 8.10 (ddd, 1H), 7.93 (d, 1H), 6.86 (s, 1H), 3.05 (dd, 1H), 2.84 (dd, 1H), 2.16 (q, 3H), 2.07-1.94 (m, 1H), 1.76 (s, 3H), 1.59 (d, 7H), 1.49-1.35 (m, 1H).

Example 7-2: MS m/z (ESI): 601.2 [M+H]⁺;

HPLC Chiral Resolution Conditions:

Instrument
Waters HPLC

Column type
DAICEL CHIRALCEL ® IB 20 mm I.D ×

250 mm 5.0 μm

Column pressure
900 psi

Mobile phase
Hexane:EtOH:MeOH (+0.1% DEA) = 70:15:15

Flow rate
15 mL/min

Detection
214 nm

wavelength

Column temperature
R.T.

HPLC Chiral Analysis Method:

Instrument
Thermo Ultimate 3000

Column type
DAICEL CHIRALCEL ® IB 4.6 mm I.D ×

150 mm 5.0 μm

Column pressure
55 bar

Mobile phase
Hexane:EtOH:MeOH (+0.1% DEA) = 70:15:15

Flow rate
1 ml/min

Detection
214 nm

wavelength

Column temperature
35° C.

Example 8
11-Chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d₂)-1-fluoro-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-dipyridol[1,2-a;3′,4′-g]azocin-12-one

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Referring to the synthesis method for Example 6, the target product 11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d₂)-1-fluoro-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3,4′-g]azocin-12-one 8 (20 mg) was synthesized, yield: 32.1%.

MS m/z (ESI): 548.2 [M+H]⁺;

Resolution of Example 8
(R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d₂)-1-fluoro-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one and (S)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d₂)-1-fluoro-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one

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Example 8 (20 mg, 0.036 mmol) was subjected to chiral resolution (IB column) to obtain 8-1 (10 mg, R.T=4.923 min), yield: 50.0%; 8-2 (3 mg, R.T=9.473 min), yield: 15%.

Example 8-1: MS m/z (ESI): 548.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (d, 1H), 8.50 (s, 1H), 8.33 (d, 1H), 8.10 (ddd, 1H), 6.86 (s, 1H), 6.57 (d, 1H), 5.11 (s, 1H), 3.01 (dd, 1H), 2.83 (dd, 1H), 2.20-1.97 (m, 4H), 1.55 (d, 1H), 1.46 (d, 6H), 1.41-1.31 (m, 1H).

Example 8-2: MS m/z (ESI): 548.2 [M+H]⁺;

Instrument
Thermo Ultimate 3000

Column type
DAICEL CHIRALCEL ® IB 4.6 mm I.D ×

150 mm 5.0 μm

Column pressure
55 bar

Mobile phase
Hexane:EtOH (+0.1% DEA) = 70:30

Flow rate
1 ml/min

Detection
214 nm

wavelength

Column temperature
35° C.

Example 9
11-Chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d₂)-1-fluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one

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Step 1

Under nitrogen protection, 7b (100 mg, 0.192 mmol) was dissolved in N,N-dimethylformamide (2 mL), 2-hydroxy-2-methylpropionamidine hydrochloride (80 mg, 0.576 mmol), and potassium carbonate (133 mg, 0.960 mmol) were added, and the reaction was heated to 75° C. and stirred for 16 hours. The reaction was cooled to room temperature, diluted with ethyl acetate (50 mL), and then washed with water (30 mL×2) and a saturated sodium chloride solution (30 mL) in sequence, the organic phase was dried and concentrated, and the residue was purified by silica gel column chromatography (elution system B) to obtain 11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d₂)-1-fluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one 9 (50 mg), yield: 46.5%.

MS m/z (ESI): 560.2 [M+H]⁺.

Resolution of Example 9
(R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d₂)-1-fluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′4′-g]azocin-12-one and (S)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d₂)-1-fluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one

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Example 9 (50 mg, 0.089 mmol) was subjected to chiral resolution (IB column) to obtain 9-1 (15.4 mg, R.T=4.973 min), yield: 30.8%; 9-2 (15.8 mg, R.T=8.337 min), yield: 31.6%.

Example 9-1: MS m/z (ESI): 560.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (d, 1H), 8.79 (s, 1H), 8.61 (d, 1H), 8.13-8.08 (m, 1H), 8.03 (d, 1H), 6.87 (s, 1H), 5.09 (s, 1H), 3.09-3.04 (m, 1H), 2.88-2.82 (m, 1H), 2.22-2.11 (m, 3H), 2.06-1.99 (m, 1H), 1.62-1.53 (m, 1H), 1.52 (s, 6H), 1.46-1.39 (m, 1H).

Example 9-2: MS m/z (ESI): 560.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (d, 1H), 8.79 (s, 1H), 8.61 (d, 1H), 8.13-8.08 (m, 1H), 8.03 (d, 1H), 6.87 (s, 1H), 5.09 (s, 1H), 3.09-3.04 (m, 1H), 2.88-2.82 (m, 1H), 2.22-2.13 (m, 3H), 2.06-1.99 (m, 1H), 1.62-1.53 (m, 1H), 1.52 (s, 6H), 1.46-1.39 (m, 1H).

Instrument
Waters HPLC

Column type
DAICEL CHIRALCEL ® IB 20 mm I.D ×

250 mm 5.0 μm

Column pressure
900 psi

Mobile phase
Hexane:MeOH:EtOH (+0.1% DEA) = 70:15:15

Flow rate
15 mL/min

Detection
214 nm

wavelength

Column temperature
R.T.

HPLC Chiral Analysis Method:

Instrument
Thermo Ultimate 3000

Column type
DAICEL CHIRALCEL ® IB 4.6 mm I.D ×

150 mm 5.0 μm

Column pressure
55 bar

Mobile phase
Hexane:MeOH:EtOH (+0.1% DEA) = 70:15:15

Flow rate
1 mL/min

Detection
214 nm

wavelength

Column temperature
35° C.

Example 10
3″,5′-Dichloro-4″-((3,5-difluoropyridin-2-yl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-6″-methyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione

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Step 1

Under nitrogen protection, 2′,3,5′-trichloro-4-hydroxy-6-methyl-2H-[1,4′-bipyridin]-2-one (150 mg, 0.49 mmol; for the synthesis method therefor, reference could be made to the synthesis of intermediate 3), 5b (90 mg, 0.59 mmol), and cesium carbonate (400 mg, 1.23 mmol) were dissolved in dimethyl sulfoxide (2 mL), and the reaction was heated to 120° C. and stirred for 16 hours. The reaction liquid was cooled to room temperature, formic acid was dropwise added to the reaction liquid, the pH was adjusted to weak acidity, the reaction liquid was extracted with a saturated sodium chloride solution and ethyl acetate (25 mL×2), the organic phases were combined, dried, and concentrated, and the residue was subjected to separation by silica gel column chromatography (elution system B) to obtain 3″,5′-dichloro-4″-hydroxy-3-(2-hydroxypropan-2-yl)-6″-methyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione 10a (147 mg), yield: 70.91%.

MS m/z (ESI): 422.1 [M+H]⁺;

Step 2

10a (147 mg, 0.35 mmol), potassium carbonate (96 mg, 0.7 mmol), and 18-crown-6 (138 mg, 0.52 mmol) were dissolved in N,N-dimethylformamide (2 mL), and the reaction was heated to 65° C. and stirred for 10 minutes. Intermediate 6 (75 mg, 0.45 mmol) was dropwise added to the reaction liquid, and the reaction was stirred at 65° C. for 2 hours. A saturated sodium chloride solution was added to the reaction liquid, the aqueous phase was extracted with ethyl acetate (25 mL×2), the organic phases were combined, dried, and concentrated, and the residue was subjected to separation by silica gel column chromatography (elution system B) to obtain 3″,5′-dichloro-4″-((3,5-difluoropyridin-2-yl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-6″-methyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione 10 (127 mg), yield: 66.17%.

MS m/z (ESI): 551.1 [M+H]⁺;

Resolution of Example 10
(S)-3″,5′-dichloro-4″-((3,5-difluoropyridin-2-yl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-6″-methyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione and (R)-3″,5′-dichloro-4″-((3,5-difluoropyridin-2-yl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-6″-methyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione

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Example 10 (127 mg, 0.23 mmol) was subjected to chiral resolution (IB column) to obtain the title product 10-1 (26.2 mg, R.T=5.667 min), yield: 20.63%; 10-2 (22.1 mg, R.T=7.113 min), yield: 17.40%.

Example 10-1, MS m/z (ESI): 551.1 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.60 (d, 1H), 8.16-8.06 (m, 2H), 7.92-7.86 (m, 1H), 7.75-7.68 (m, 1H), 6.83 (s, 1H), 6.45 (t, 1H), 5.21 (s, 1H), 2.03 (s, 3H), 1.47 (d, 6H).

Example 10-2, MS m/z (ESI): 551.1 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.60 (d, 1H), 8.16-8.06 (m, 2H), 7.92-7.86 (m, 1H), 7.75-7.68 (m, 1H), 6.83 (s, 1H), 6.45 (t, 1H), 5.21 (s, 1H), 2.03 (s, 3H), 1.47 (d, 6H).

HPLC Chiral Resolution Conditions:

Instrument
HPLC (Waters)

Column type
DAICEL CHIRALPAK ®IB

270 * 30 mm 10.0 μm

Column pressure
800 psi

Mobile phase
Hexane/EtOH/MeOH (+0.1% DEA) = 70/15/15

Flow rate
15 mL/min

Detection
UV 214 nm

wavelength

Column
25° C.

temperature

HPLC Chiral Analysis Method:

Instrument
HPLC (Waters)

Column type
DAICEL CHIRALPAK ®IB N-5

150 * 4.6 mm 5.0 μm

Column pressure
35 bar

Mobile phase
Hexane/EtOH/MeOH (+0.1% DEA) = 70/15/15

Flow rate
1 mL/min

Detection
214 nm

wavelength

Column
35° C.

temperature

Example 11
3″-Chloro-4″-((3,5-difluoropyridin-2-yl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione

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Step 1

Under nitrogen protection, intermediate 8 (85 mg, 0.19 mmol), 3-(2-hydroxypropan-2-yl)pyridin-2(1H)-one 5b (37 mg, 0.24 mmol), cuprous iodide (18 mg, 0.09 mmol), and potassium carbonate (26 mg, 0.19 mmol) were dissolved in N,N-dimethylacetamide (1.5 mL), and the reaction was heated to 120° C. and stirred for 5 hours. A saturated ammonia chloride solution was added to the reaction liquid, the aqueous phase was extracted with ethyl acetate (20 mL×2), the organic phases were combined, dried, and concentrated, and the residue was subjected to preparation by reversed-phase HPLC to obtain 3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione 11 (23 mg), yield: 23.38%.

MS m/z (ESI): 531.2 [M+H]⁺;

Resolution of Example 11
(S)-3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione and (R)-3″-chloro-4″-((3,5-difluoropyridin-2-yl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione

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Example 11 (23 mg, 0.04 mmol) was subjected to chiral resolution (IB column) to obtain the title product 11-1 (7.4 mg, R.T=4.833 min), yield: 32.17%; 11-2 (8.5 mg, R.T=6.753 min), yield: 36.96%.

Example 11-1, MS m/z (ESI): 531.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (s, 1H), 8.60 (d, 1H), 8.14-8.05 (m, 1H), 7.88-7.82 (m, 1H), 7.78 (s, 1H), 7.72-7.66 (m, 1H), 6.80 (s, 1H), 6.42 (t, 1H), 5.23 (s, 1H), 2.07 (s, 3H), 2.00 (s, 3H), 1.49-1.44 (m, 6H).

Example 11-2, MS m/z (ESI): 531.2 [M+H]⁺;

HPLC Chiral Resolution Conditions:

Instrument
HPLC (Waters)

Column type
DAICEL CHIRALPAK ®IB

270 * 30 mm 10.0 μm

Column pressure
800 psi

Mobile phase
Hexane/EtOH (+0.1% DEA) = 70/30

Flow rate
15 mL/min

Detection
UV 214 nm

wavelength

Column
25° C.

temperature

HPLC Chiral Analysis Method:

Instrument
HPLC (Waters)

Column type
DAICEL CHIRALPAK ® IB N-5

150 * 4.6 mm 5.0 μm

Column pressure
35 bar

Mobile phase
Hexane/EtOH (+0.1% DEA) = 70/30

Flow rate
1 mL/min

Detection
214 nm

wavelength

Column
35° C.

temperature

Example 12
N-(2-(3″,5′-dichloro-4″-((3,5-difluoropyridin-2-yl)methoxy-d2)-6″-methyl-2,2″-dicarbonyl-2H,2″H-[1,2′:4′,1″-terpyridin]-3-yl)propan-2-yl)acetamide

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Step 1

Under nitrogen protection, 2′,3,5′-trichloro-4-hydroxy-6-methyl-2H-[1,4′-bipyridin]-2-one (100 mg, 0.33 mmol), 5c (83 mg, 0.43 mmol), and cesium carbonate (320 mg, 0.98 mmol) were dissolved in dimethyl sulfoxide (2 mL), and the reaction was heated to 120° C. and stirred for 16 hours. A saturated sodium chloride solution was added to the reaction liquid, the pH was adjusted to weak acidity with formic acid, the reaction liquid was extracted with ethyl acetate (25 mL×3), and the organic phases are combined, dried, and concentrated to obtain the crude product N-(2-(3″,5′-dichloro-4″-hydroxy-6″-methyl-2,2″-dicarbonyl-2H,2″H-[1,2′:4′,1″-terpyridin]-3-yl)propan-2-yl)acetamide 12a (100 mg), which was directly used in the next reaction without purification.

MS m/z (ESI): 463.1 [M+H]⁺;

Step 2

12a (27 mg, 0.06 mmol), potassium carbonate (16 mg, 0.12 mmol), and 18-crown-6 (23 mg, 0.09 mmol) were dissolved in N,N-dimethylformamide (1 mL) and stirred at 65° C. for 15 minutes, and intermediate 6 (14 mg, 0.09 mmol) was added to the above reaction liquid and stirred at 65° C. for 1 hour. A saturated sodium chloride solution was added to the reaction liquid, which was extracted with ethyl acetate (25 mL×2), the organic phases were combined, dried, and concentrated, and the residue was subjected to preparation by reversed-phase HPLC to obtain N-(2-(3″,5′-dichloro-4″-((3,5-difluoropyridin-2-yl)methoxy-d2)-6″-methyl-2,2″-dicarbonyl-2H,2″H-[1,2′:4′,1″-terpyridin]-3-yl)propan-2-yl)acetamide 12 (15.8 mg), yield: 45.77%.

MS m/z (ESI): 592.1 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ 8.97 (s, 1H), 8.60 (d, 1H), 8.15-8.06 (m, 2H), 7.92-7.82 (m, 2H), 7.41-7.32 (m, 1H), 6.83 (s, 1H), 6.39 (t, 1H), 2.02 (s, 3H), 1.81 (s, 3H), 1.60 (d, 6H).

Example 13
N-(2-(3″-chloro-4″-((2,4-difluorophenyl)methoxy-d2)-5′,6″-dimethyl-2,2″-dicarbonyl-2H,2″H-[1,2′:4′,1″-terpyridin]-3-yl)propan-2-yl)acetamide

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Step 1

Under nitrogen protection, intermediate 10 (85 mg, 0.19 mmol), N-(2-(2-carbonyl-1,2-dihydropyridin-3-yl)propan-2-yl)acetamide 5c (43 mg, 0.22 mmol), cuprous iodide (18 mg, 0.09 mmol), and potassium carbonate (26 mg, 0.19 mmol) were dissolved in N,N-dimethylacetamide (1.5 mL), and the reaction was heated to 120° C. and stirred for 3 hours. A saturated sodium chloride solution was added to the reaction liquid, which was extracted with ethyl acetate (25 mL×2), the organic phases were combined, dried, and concentrated, and the residue was subjected to preparation by reversed-phase HPLC to obtain N-(2-(3″-chloro-4″-((2,4-difluorophenyl)methoxy-d2)-5′,6″-dimethyl-2,2″-dicarbonyl-2H,2″H-[1,2′:4′,1″-terpyridin]-3-yl)propan-2-yl)acetamide 13 (40 mg), yield: 37.72%.

MS m/z (ESI): 571.2 [M+H]⁺;

Resolution of Example 13
(S)—N-(2-(3″-chloro-4″-((2,4-difluorophenyl)methoxy-d2)-5′,6″-dimethyl-2,2″-dicarbonyl-2H,2″H-[1,2′:4′,1″-terpyridin]-3-yl)propan-2-yl)acetamide and (R)—N-(2-(3″-chloro-4″-((2,4-difluorophenyl)methoxy-d2)-5′,6″-dimethyl-2,2″-dicarbonyl-2H,2″H-[1,2′:4′,1″-terpyridin]-3-yl)propan-2-yl)acetamide

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Example 13 (40 mg, 0.07 mmol) was subjected to chiral resolution (AD column) to obtain the title product 13-1 (14.6 mg, R.T=5.173 min), yield: 36.50%; 13-2 (15.6 mg, R.T=8.937 min), yield: 39.00%.

Example 13-1, MS m/z (ESI): 571.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (s, 1H), 7.88-7.80 (m, 2H), 7.77-7.66 (m, 2H), 7.42-7.31 (m, 2H), 7.25-7.15 (m, 1H), 6.82 (s, 1H), 6.36 (t, 1H), 2.07 (s, 3H), 2.02 (s, 3H), 1.81 (s, 3H), 1.60 (d, 6H).

Example 13-2, MS m/z (ESI): 571.2 [M+H]⁺;

HPLC Chiral Resolution Conditions:

Instrument
HPLC (Waters)

Column type
DAICEL CHIRALPAK ®

AD 250 * 20 mm 5.0 μm

Column pressure
800 psi

Mobile phase
Hexane/EtOH (+0.1% DEA) = 70/30

Flow rate
15 mL/min

Detection
UV 214 nm

wavelength

Column
25° C.

temperature

HPLC Chiral Analysis Method:

Instrument
HPLC (Waters)

Column type
DAICEL CHIRALPAK ®AD

250*4.6 mm 5.0 μm

Column pressure
35 bar

Mobile phase
Hexane/EtOH (+0.1% DEA) = 70/30

Flow rate
1 mL/min

Detection
214 nm

wavelength

Column
35° C.

temperature

Example 14
3″-Chloro-4″-((2,4-difluorophenyl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione

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Step 1

Under nitrogen protection, intermediate 10 (70 mg, 0.15 mmol), 5b (28 mg, 0.18 mmol), cuprous iodide (15 mg, 0.08 mmol), and potassium carbonate (21 mg, 0.15 mmol) were dissolved in N,N-dimethylacetamide (1.5 mL), and the reaction was heated to 120° C. and stirred for 3 hours. A saturated sodium chloride solution was added to the reaction liquid, which was extracted with ethyl acetate (25 mL×2), the organic phases were combined, dried, and concentrated, and the residue was subjected to preparation by reversed-phase HPLC to obtain 3″-chloro-4″-((2,4-difluorophenyl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-5′,6-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione 14 (35 mg), yield: 43.18%.

MS m/z (ESI): 530.2 [M+H]⁺;

Resolution of Example 14
(S)-3″-chloro-4″-((2,4-difluorophenyl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione and (R)-3″-chloro-4″-((2,4-difluorophenyl)methoxy-d2)-3-(2-hydroxypropan-2-yl)-5′,6″-dimethyl-2H,2″H-[1,2′:4′,1″-terpyridine]-2,2″-dione

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Example 14 (35 mg, 0.07 mmol) was subjected to chiral resolution (IB column) to obtain the title product 14-1 (12.2 mg, R.T=5.990 min), yield: 34.86%; 14-2 (11.9 mg, R.T=9.167 min), yield: 34.00%.

Example 14-1, MS m/z (ESI): 530.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (s, 1H), 7.88-7.82 (m, 1H), 7.78 (s, 1H), 7.74-7.65 (m, 2H), 7.43-7.32 (m, 1H), 7.24-7.16 (m, 1H), 6.82 (s, 1H), 6.42 (t, 1H), 5.23 (s, 1H), 2.07 (s, 3H), 2.02 (s, 3H), 1.46 (d, 6H).

Example 14-2, MS m/z (ESI): 530.2 [M+H]⁺;

HPLC Chiral Resolution Conditions:

Instrument
HPLC (Waters)

Column type
DAICEL CHIRALPAK ®IB

270 * 30 mm 10.0 μm

Column pressure
800 psi

Mobile phase
Hexane/EtOH (+0.1% DEA) = 70/30

Flow rate
15 mL/min

Detection
UV 214 nm

wavelength

Column
25° C.

temperature

HPLC Chiral Analysis Method:

Instrument
HPLC (Waters)

Column type
DAICEL CHIRALPAK ® IB N-5

150 * 4.6 mm 5.0 μm

Column pressure
35 bar

Mobile phase
Hexane:EtOH (+0.1% DEA) = 70/30

Flow rate
1 mL/min

Detection
214 nm

wavelength

Column
35° C.

temperature

Example 15
11-Chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-2-carbonylpyridin-1(2H)-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one

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Under nitrogen protection, 2a (100 mg, 0.21 mmol), 5b (41 mg, 0.27 mmol), (15,25)—N1,N2-dimethylcyclohexane-1,2-diamine (31 mg, 0.22 mmol), cuprous iodide (20 mg, 0.1 mmol), and cesium carbonate (134 mg, 0.41 mmol) were dissolved in 1,4-dioxane (1.5 mL), and the reaction was heated to 100° C. and stirred for 1.5 hours. A saturated ammonium chloride solution was added to the reaction liquid, which was extracted with ethyl acetate (25 mL×2), the organic phases were combined, dried, and concentrated, and the residue was subjected to separation by silica gel column chromatography (elution system B) to obtain 11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-2-carbonylpyridin-1(2H)-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one 15 as a white solid (105 mg), yield: 91.38%.

MS m/z (ESI): 557.2 [M+H]⁺;

Resolution of Example 15
(S)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-2-carbonylpyridin-1(2H)-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one and (R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-2-carbonylpyridin-1(2H)-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one

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Example 15 (105 mg, 0.19 mmol) was subjected to chiral resolution (IB column) to obtain the title product 15-1 (36.5 mg, R.T=3.977 min), yield: 34.76%; 15-2 (34.3 mg, R.T=5.027 min), yield: 32.67%.

Example 15-1, MS m/z (ESI): 557.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ 8.75 (s, 1H), 8.60 (d, 1H), 8.13-8.06 (m, 1H), 7.88-7.82 (m, 1H), 7.74-7.67 (m, 2H), 6.80 (s, 1H), 6.42 (t, 1H), 5.21 (s, 1H), 3.02-2.90 (m, 1H), 2.88-2.77 (m, 1H), 2.23-2.04 (m, 3H), 1.95-1.82 (m, 1H), 1.58 (d, 1H), 1.47 (s, 3H), 1.45 (s, 3H), 1.42-1.32 (m, 1H).

Example 15-2, MS m/z (ESI): 557.2 [M+H]⁺;

HPLC Chiral Resolution Conditions:

Instrument
HPLC (Waters)

Column type
DAICEL CHIRALPAK ®IB

270 * 30 mm 10.0 μm

Column pressure
800 psi

Mobile phase
Hexane:EtOH:MeOH (+0.1% DEA) = 70:15:15

Flow rate
15 mL/min

Detection
UV 214 nm

wavelength

Column
25° C.

temperature

HPLC Chiral Analysis Method:

Instrument
HPLC (Waters)

Column type
DAICEL CHIRALPAK ® IB

N-5 150 * 4.6 mm 5.0 μm

Column pressure
35 bar

Mobile phase
Hexane:EtOH:MeOH (+0.1% DEA) = 70:15:15

Flow rate
1 mL/min

Detection
214 nm

wavelength

Column
35° C.

temperature

Example 16
(Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one

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Referring to the synthesis method for Example 1, the target product (Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one 16 was synthesized.

MS m/z (ESI): 540.2 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ 8.99 (d, 1H), 8.80 (s, 1H), 8.66-8.57 (m, 2H), 8.26 (d, 1H), 8.11 (ddd, 1H), 6.81 (s, 1H), 6.53 (dd, 1H), 6.03 (d, 1H), 5.29 (s, 1H), 2.76 (d, 2H), 2.57 (dd, 1H), 2.00 (q, 1H), 1.53 (d, 6H).

Resolution of Example 16
(S,Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one and (R,Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one

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Example 16 (20 mg, 0.037 mmol) was subjected to chiral resolution (OD column) to obtain the title product 16-1 (8 mg, R.T=3.623 min), yield: 40%; 16-2 (6 mg, R.T=7.39 min), yield: 30%.

Example 16-1, MS m/z (ESI): 540.2 [M+H]⁺;

Example 16-2, MS m/z (ESI): 540.2 [M+H]⁺;

HPLC Chiral Resolution Conditions:

Instrument
Waters HPLC

Column type
DAICEL CHIRALCEL ®OD 20 mm

I.D × 250 mm 5.0 μm

Column pressure
900 psi

Mobile phase
Hexane:EtOH:MeOH (+0.1% DEA) = 70:15:15

Flow rate
15 mL/min

Detection
254 nm

wavelength

Column
R.T.

temperature

HPLC Chiral Analysis Method:

Instrument
Thermo Ultimate 3000

Column type
DAICEL CHIRALCEL ®OD 4.6 mm

I.D × 150 mm 5.0 μm

Column
55 bar

pressure

Mobile phase
Hexane:EtOH:MeOH (+0.1% DEA) = 70:15:15

Flow rate
1 mL/min

Detection
254 nm

wavelength

Column
35° C.

temperature

Example 17
(Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one

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Referring to the synthesis method for Example 2, the target product (Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one 17 was synthesized.

MS m/z (ESI): 528.2 [M+H]⁺.

Resolution of Example 17
(S,Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one and (R,Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one

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Example 17 (80 mg, 0.152 mmol) was subjected to chiral resolution (OD column) to obtain the title product 17-1 (36 mg, R.T=3.553 min), yield: 45%; 17-2 (38 mg, R.T=5.693 min), yield: 47.5%.

Example 17-1, MS m/z (ESI): 528.2 [M+H]⁺;

Example 17-2, MS m/z (ESI): 528.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (d, 1H), 8.53 (d, 1H), 8.49 (s, 1H), 8.10 (td, 1H), 7.72 (s, 1H), 6.79 (s, 1H), 6.57 (d, 1H), 6.47-6.39 (m, 1H), 5.99-5.88 (m, 1H), 5.14 (s, 1H), 2.80-2.67 (m, 2H), 2.67-2.52 (m, 2H), 1.47 (d, 6H).

HPLC Chiral Resolution Conditions:

HPLC Chiral Analysis Method:

Instrument
Thermo Ultimate 3000

Column type
DAICEL CHIRALCEL ®OD 4.6 mm

I.D × 150 mm 5.0 μm

Column pressure
55 bar

Mobile phase
Hexane:EtOH:MeOH (+0.1% DEA) = 70:15:15

Flow rate
1 mL/min

Detection
254 nm

wavelength

Column
35° C.

temperature

Example 18
(Z)—N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-8,12-dihydro-7H-dipyrido[1,2-a:3′,4′-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide

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Referring to the synthesis method of Example 3, the target product (Z)—N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-8,12-dihydro-7H-dipyrido[1,2-a:3′,4′-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide 18 was synthesized.

MS m/z (ESI): 587.2 [M+H]⁺.

Resolution of Example 18
(S,Z)—N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-8,12-dihydro-7H-dipyrido[1,2-a:3′,4′-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide and (R,Z)—N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-12-carbonyl-8,12-dihydro-7H-dipyrido[1,2-a:3′,4′-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide

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Example 18 (86 mg, 0.147 mmol) was subjected to chiral resolution (OD column) to obtain the title product 18-1 (32 mg, R.T=3.280 min), yield: 37.2%; 18-2 (32 mg, R.T=4.387 min), yield: 37.2%.

Example 18-1, MS m/z (ESI): 587.2 [M+H]˜

Example 18-2, MS m/z (ESI): 587.2 [M+H]˜

¹H NMR (400 MHz, DMSO-d₆) δ 8.59 (dd, 2H), 8.48 (s, 1H), 8.18-8.02 (m, 2H), 7.71 (s, 1H), 6.78 (s, 1H), 6.44 (d, 1H), 5.99-5.91 (m, 1H), 2.78-2.65 (m, 2H), 2.57 (dd, 2H), 1.79 (s, 3H), 1.58 (d, 6H).

HPLC Chiral Resolution Conditions:

HPLC Chiral Analysis Method:

Example 19
(Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-2-carbonylpyridin-1(2H)-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one

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Referring to the synthesis method of Example 15, the target product (Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-2-carbonylpyridin-1(2H)-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one 19 was synthesized.

MS m/z (ESI): 555.2 [M+H]⁺.

Resolution of Example 19
(S,Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-2-carbonylpyridin-1(2H)-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one and (R,Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-2-(3-(2-hydroxypropan-2-yl)-2-carbonylpyridin-1(2H)-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one

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Example 19 (76 mg, 0.137 mmol) was subjected to chiral resolution (IB column) to obtain the title product 19-1 (33 mg, R.T=5.147 min), yield: 43.4%; 19-2 (27 mg, R.T=7.360 min), yield: 35.5%.

Example 19-1, MS m/z (ESI): 555.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ 8.64 (s, 1H), 8.60 (d, 1H), 8.09 (td, 1H), 7.87 (dd, 1H), 7.78 (s, 1H), 7.70 (dd, 1H), 6.80 (s, 1H), 6.53-6.38 (m, 2H), 6.06-5.94 (m, 1H), 5.20 (s, 1H), 2.78 (d, 2H), 2.59-2.51 (m, 2H), 1.46 (d, 6H).

Example 19-2, MS m/z (ESI): 555.2 [M+H]⁺;

HPLC Chiral Resolution Conditions:

Instrument
HPLC (Waters)

Column type
DAICEL CHIRALPAK ®IB 270 * 30 mm 10.0 μm

Column pressure
800 psi

Mobile phase
Hexane:EtOH:MeOH (+0.1% DEA) = 70:15:15

Flow rate
15 mL/min

Detection
UV 214 nm

wavelength

Column
25° C.

temperature

HPLC Chiral Analysis Method:

Instrument
HPLC (Waters)

Column type
DAICEL CHIRALPAK ® IB N-5

150 * 4.6 mm 5.0 μm

Column pressure
35 bar

Mobile phase
Hexane:EtOH:MeOH (+0.1% DEA) = 70:15:15

Flow rate
1 mL/min

Detection
214 nm

wavelength

Column
35° C.

temperature

Example 56
11-Chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-2-(3-(2-hydroxypropan-2-yl)-2-carbonylpyridin-1(2H)-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one

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Step 1

56a (150 mg, 0.298 mmol; for the preparation method therefor, reference could be made to the synthesis of 6h in Example 6) was dissolved in dimethyl sulfoxide (1.5 mL), 5b (137 mg, 0.895 mmol), cesium carbonate (292 mg, 0.895 mmol), ethyl 2-cyclohexanonecarboxylate (51 mg, 0.298 mmol), and cuprous bromide (64 mg, 0.447 mmol) were added, and the reaction was heated to 80° C. under nitrogen protection and stirred for 16 hours. The reaction liquid was cooled to room temperature and filtered, the filtrate was diluted with ethyl acetate (30 mL), then washed with water (30 mL) and a saturated sodium chloride solution (30 mL) in sequence, dried, and concentrated, and the residue was purified by reversed-phase chromatographic column (eluent system C) to obtain 11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-2-(3-(2-hydroxypropan-2-yl)-2-carbonylpyridin-1(2H)-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one 56 (30 mg), yield: 17.5%.

MS m/z (ESI): 575.1 [M+H]⁺;

Resolution of Example 56
(R)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-2-(3-(2-hydroxypropan-2-yl)-2-carbonylpyridin-1(2H)-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one and (S)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-2-(3-(2-hydroxypropan-2-yl)-2-carbonylpyridin-1(2H)-yl)-5,6,7,8-tetrahydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one

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Example 56 (30 mg, 0.066 mmol) was subjected to chiral resolution (OD column) to obtain 56-1 (13.5 mg, R.T=3.543 min), yield: 45.0%; 56-2 (13.2 mg, R.T=5.707 min), yield: 44.0%.

Example 56-1: M S m/z (ESI): 575.1 [M+H]⁺

¹H NMR (400 M Hz, DMSO-d₆) δ 8.63 (d, 1H), 8.59 (d, 1H), 8.12-8.06 (m, 1H), 7.73 (d, 1H), 7.69-7.65 (m, 1H), 6.87 (s, 1H), 6.48-6.40 (m, 1H), 5.18 (s, 1H), 3.09-3.03 (m, 1H), 2.94-2.83 (m, 1H), 2.22-2.03 (m, 4H), 1.61-1.54 (m, 1H), 1.46-1.34 (m, 7H).

Example 56-2: M S m/z (ESI): 575.1 [M+H]⁺;

HPLC Chiral Resolution Conditions:

Instrument
Waters HPLC

Column type
DAICEL CHIRALCEL ®OD 20 mm

I.D × 250 mm 5.0 μm

Column pressure
900 psi

Mobile phase
Hexane:EtOH (+0.1% DEA) = 70:30

Flow rate
15 mL/min

Detection
214 nm

wavelength

Column temperature
R.T.

HPLC Chiral Analysis Method:

Instrument
Thermo Ultimate 3000

Column type
DAICEL CHIRALCEL ®OD 4.6 mm

I.D × 150 mm 5.0 μm

Column pressure
55 bar

Mobile phase
Hexane:EtOH (+0.1% DEA) = 70:30

Flow rate
1 mL/min

Detection
214 nm

wavelength

Column temperature
35° C.

Example 59
(Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one

embedded image

Referring to the synthesis method for Example 9, the target product (Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one 59 was synthesized.

MS m/z (ESI): 558.1 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (d, 1H), 8.68 (s, 1H), 8.60 (d, 1H), 8.09 (ddd, 1H), 8.03 (d, 1H), 6.87 (s, 1H), 6.56 (d, 1H), 6.09 (ddd, 1H), 5.07 (s, 1H), 2.80 (d, 2H), 2.72-2.52 (m, 2H), 1.59-1.44 (m, 6H).

Example 60
(Z)—N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-12-carbonyl-8,12-dihydro-7H-dipyrido[1,2-a:3′,4′-g]azocin-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide

embedded image

Referring to the synthesis method of Example 7, the target product (Z)—N-(2-(4-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-12-carbonyl-8,12-dihydro-7H-dipyrido[1,2-a:3′,4′-g]azocin-2-yl)pyrimidin-2-yl)propan-2-yl)acetamide 60 was synthesized.

MS m/z (ESI): 599.2 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d₆) δ 8.93 (d, 1H), 8.66 (s, 1H), 8.60 (d, 1H), 8.21 (s, 1H), 8.09 (ddd, 1H), 7.93 (d, 1H), 6.86 (s, 1H), 6.58-6.51 (m, 1H), 6.14-6.02 (m, 1H), 2.87-2.58 (m, 4H), 1.76 (s, 3H), 1.59 (s, 6H).

Example 61
(Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one

embedded image

Referring to the synthesis method for Example 6, the target product (Z)-11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-2-(3-(2-hydroxypropan-2-yl)-1H-pyrazol-1-yl)-7,8-dihydro-12H-dipyrido[1,2-a:3′,4′-g]azocin-12-one 61 was synthesized.

MS m/z (ESI): 546.2 [M+H]⁺;

¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (d, 1H), 8.40 (s, 1H), 8.35 (d, 1H), 8.14-8.06 (m, 1H), 6.86 (s, 1H), 6.59 (d, 1H), 6.50 (d, 1H), 6.08-5.95 (m, 1H), 5.14 (s, 1H), 2.84-2.68 (m, 3H), 2.57-2.52 (m, 1H), 1.46 (d, 6H).

Example 62
(Z)—N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-12-carbonyl-8,12-dihydro-7H-dipyrido[1,2-a:3′,4′-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide

embedded image

Referring to the synthesis method of Example 6, the target product (Z)—N-(2-(1-(11-chloro-10-((3,5-difluoropyridin-2-yl)methoxy-d2)-1-fluoro-12-carbonyl-8,12-dihydro-7H-dipyrido[1,2-a:3′,4′-g]azocin-2-yl)-4-fluoro-1H-pyrazol-3-yl)propan-2-yl)acetamide 62 was synthesized.

MS m/z (ESI): 605.2 [M+H]⁺;

¹H NMR (400 MHz, CDCl₃) δ 8.39 (d, 1H), 8.24 (s, 1H), 8.18 (d, 1H), 7.37-7.29 (m, 1H), 6.57 (s, 1H), 6.46-6.36 (m, 2H), 6.00-5.89 (m, 1H), 2.89-2.78 (m, 1H), 2.76-2.67 (m, 2H), 2.57-2.42 (m, 1H), 2.00 (s, 3H), 1.79 (s, 6H).

Examples could also be obtained by referring to the above synthesis method:

Example
Structure
MS m/z (ESI)

20

embedded image

540.2 [M + H] ⁺

21

embedded image

554.2 [M + H] ⁺

22

embedded image

538.1 [M + H] ⁺

23

embedded image

552.2 [M + H] ⁺

24

embedded image

545.1 [M + H] ⁺

25

embedded image

526.1 [M + H] ⁺

26

embedded image

528.2 [M + H] ⁺

27

embedded image

556.2 [M + H] ⁺

28

embedded image

514.1 [M + H] ⁺

29

embedded image

516.2 [M + H] ⁺

30

embedded image

528.2 [M + H] ⁺

31

embedded image

542.2 [M + H] ⁺

32

embedded image

544.2 [M + H] ⁺

33

embedded image

573.2 [M + H] ⁺

34

embedded image

575.1 [M + H] ⁺

35

embedded image

587.2 [M + H] ⁺

36

embedded image

601.2 [M + H] ⁺

37

embedded image

603.2 [M + H] ⁺

38

embedded image

567.2 [M + H] ⁺

39

embedded image

569.2 [M + H] ⁺

40

embedded image

581.2 [M + H] ⁺

41

embedded image

595.2 [M + H] ⁺

42

embedded image

597.2 [M + H] ⁺

43

embedded image

550.1 [M + H] ⁺

44

embedded image

552.2 [M + H] ⁺

45

embedded image

564.2 [M + H] ⁺

46

embedded image

566.2 [M + H] ⁺

47

embedded image

558.2 [M + H] ⁺

48

embedded image

580.2 [M + H] ⁺

49

embedded image

584.2 [M + H] ⁺

50

embedded image

586.2 [M + H] ⁺

51

embedded image

598.2 [M + H] ⁺

52

embedded image

600.2 [M + H] ⁺

53

embedded image

612.2 [M + H] ⁺

54

embedded image

614.2 [M + H] ⁺

55

embedded image

598.2 [M + H] ⁺

57

embedded image

616.2 [M + H] ⁺

58

embedded image

581.2 [M + H] ⁺

63

embedded image

573.1 [M + H] ⁺

64

embedded image

540.2 [M + H] ⁺

65

embedded image

581.2 [M + H] ⁺

66

embedded image

528.2 [M + H] ⁺

67

embedded image

587.2 [M + H] ⁺

68

embedded image

555.2 [M + H] ⁺

69

embedded image

558.1 [M + H] ⁺

70

embedded image

599.2 [M + H] ⁺

71

embedded image

546.1 [M + H] ⁺

72

embedded image

605.2 [M + H] ⁺

73

embedded image

573.1 [M + H] ⁺

74

embedded image

540.2 [M + H] ⁺

75

embedded image

581.2 [M + H] ⁺

76

embedded image

528.2 [M + H] ⁺

77

embedded image

587.2 [M + H] ⁺

78

embedded image

555.2 [M + H] ⁺

79

embedded image

558.1 [M + H] ⁺

80

embedded image

599.2 [M + H] ⁺

81

embedded image

546.1 [M + H] ⁺

82

embedded image

605.2 [M + H] ⁺

83

embedded image

573.1 [M + H] ⁺

84

embedded image

554.2 [M + H] ⁺

85

embedded image

595.2 [M + H] ⁺

86

embedded image

542.2 [M + H] ⁺

87

embedded image

601.2 [M + H] ⁺

88

embedded image

567.2 [M + H] ⁺

89

embedded image

572.2 [M + H] ⁺

90

embedded image

613.2 [M + H] ⁺

91

embedded image

560.2 [M + H] ⁺

92

embedded image

619.2 [M + H] ⁺

93

embedded image

587.2 [M + H] ⁺

94

embedded image

554.2 [M + H] ⁺

95

embedded image

595.2 [M + H] ⁺

96

embedded image

542.2 [M + H] ⁺

97

embedded image

601.2 [M + H] ⁺

98

embedded image

569.2 [M + H] ⁺

99

embedded image

572.2 [M + H] ⁺

100

embedded image

613.2 [M + H] ⁺

101

embedded image

560.2 [M + H] ⁺

102

embedded image

619.2 [M + H] ⁺

103

embedded image

587.2 [M + H] ⁺

104

embedded image

554.2 [M + H] ⁺

105

embedded image

595.2 [M + H] ⁺

106

embedded image

542.2 [M + H] ⁺

107

embedded image

601.2 [M + H] ⁺

108

embedded image

569.2 [M + H] ⁺

109

embedded image

572.2 [M + H] ⁺

110

embedded image

613.2 [M + H] ⁺

111

embedded image

560.2 [M + H] ⁺

112

embedded image

619.2 [M + H] ⁺

113

embedded image

587.2 [M + H] ⁺

114

embedded image

554.2 [M + H] ⁺

115

embedded image

595.2 [M + H] ⁺

116

embedded image

542.2 [M + H] ⁺

117

embedded image

601.2 [M + H] ⁺

118

embedded image

569.2 [M + H] ⁺

119

embedded image

572.1 [M + H] ⁺

120

embedded image

613.2 [M + H] ⁺

121

embedded image

560.2 [M + H] ⁺

122

embedded image

619.2 [M + H] ⁺

123

embedded image

587.2 [M + H] ⁺

124

embedded image

544.2 [M + H] ⁺

125

embedded image

532.2 [M + H] ⁺

126

embedded image

591.2 [M + H] ⁺

127

embedded image

559.2 [M + H] ⁺

128

embedded image

562.1 [M + H] ⁺

129

embedded image

550.1 [M + H] ⁺

130

embedded image

609.2 [M + H] ⁺

131

embedded image

577.1 [M + H] ⁺

132

embedded image

544.2 [M + H] ⁺

133

embedded image

532.2 [M + H] ⁺

134

embedded image

591.2 [M + H] ⁺

135

embedded image

559.2 [M + H] ⁺

136

embedded image

562.1 [M + H] ⁺

137

embedded image

550.1 [M + H] ⁺

138

embedded image

609.2 [M + H] ⁺

139

embedded image

577.1 [M + H] ⁺

140

embedded image

544.2 [M + H] ⁺

141

embedded image

532.2 [M + H] ⁺

142

embedded image

591.2 [M + H] ⁺

143

embedded image

559.2 [M + H] ⁺

144

embedded image

562.1 [M + H] ⁺

145

embedded image

550.1 [M + H] ⁺

146

embedded image

609.2 [M + H] ⁺

147

embedded image

577.1 [M + H] ⁺

148

embedded image

544.2 [M + H] ⁺

149

embedded image

532.2 [M + H] ⁺

150

embedded image

591.2 [M + H] ⁺

151

embedded image

559.2 [M + H] ⁺

152

embedded image

562.1 [M + H] ⁺

153

embedded image

550.1 [M + H] ⁺

154

embedded image

609.2 [M + H] ⁺

155

embedded image

577.1 [M + H] ⁺

156

embedded image

546.1 [M + H] ⁺

157

embedded image

534.1 [M + H] ⁺

158

embedded image

593.1 [M + H] ⁺

159

embedded image

561.1 [M + H] ⁺

160

embedded image

564.1 [M + H] ⁺

161

embedded image

552.1 [M + H] ⁺

162

embedded image

611.1 [M + H] ⁺

163

embedded image

579.1 [M + H] ⁺

164

embedded image

578.1 [M + H] ⁺

165

embedded image

561.2 [M + H] ⁺

166

embedded image

575.1 [M + H] ⁺

167

embedded image

575.1 [M + H] ⁺

168

embedded image

566.2 [M + H] ⁺

169

embedded image

548.2 [M + H] ⁺

170

embedded image

607.2 [M + H] ⁺

171

embedded image

589.2 [M + H] ⁺

172

embedded image

613.2 [M + H] ⁺

173

embedded image

595.2 [M + H] ⁺

174

embedded image

554.2 [M + H] ⁺

175

embedded image

536.2 [M + H] ⁺

176

embedded image

581.2 [M + H] ⁺

177

embedded image

563.2 [M + H] ⁺

178

embedded image

568.2 [M + H] ⁺

179

embedded image

550.2 [M + H] ⁺

180

embedded image

609.2 [M + H] ⁺

181

embedded image

591.2 [M + H] ⁺

182

embedded image

615.2 [M + H] ⁺

183

embedded image

597.2 [M + H] ⁺

184

embedded image

556.2 [M + H] ⁺

185

embedded image

538.2 [M + H] ⁺

186

embedded image

583.2 [M + H] ⁺

187

embedded image

565.2 [M + H] ⁺

188

embedded image

568.2 [M + H] ⁺

189

embedded image

550.2 [M + H] ⁺

190

embedded image

609.2 [M + H] ⁺

191

embedded image

591.2 [M + H] ⁺

192

embedded image

615.2 [M + H] ⁺

193

embedded image

597.2 [M + H] ⁺

194

embedded image

556.2 [M + H] ⁺

195

embedded image

538.2 [M + H] ⁺

196

embedded image

583.2 [M + H] ⁺

197

embedded image

565.2 [M + H] ⁺

198

embedded image

547.1 [M + H] ⁺

199

embedded image

547.1 [M + H] ⁺

200

embedded image

565.1 [M + H] ⁺

201

embedded image

565.1 [M + H] ⁺

202

embedded image

561.1 [M + H] ⁺

203

embedded image

561.1 [M + H] ⁺

204

embedded image

579.1 [M + H] ⁺

205

embedded image

579.1 [M + H]

206

embedded image

533.1 [M + H] ⁺

207

embedded image

533.1 [M + H] ⁺

208

embedded image

551.1 [M + H] ⁺

209

embedded image

551.1 [M + H] ⁺

210

embedded image

588.2 [M + H] ⁺

211

embedded image

606.1 [M + H] ⁺

212

embedded image

602.2 [M + H] ⁺

213

embedded image

620.2 [M + H] ⁺

214

embedded image

573.1 [M + H] ⁺

215

embedded image

592.1 [M + H] ⁺

TEST AND EVALUATION OF EXAMPLES

The present invention will be further described and explained below in conjunction with test examples, but these examples are not meant to limit the scope of the present invention.

Test Example 1. Determination of Inhibitory Effect of the Compound of the Present Invention on p38α/MK2 Enzyme Activity
1. Experimental Purpose:

The purpose of this test example is to determine the ability of the compound to inhibit p38α/MK2 enzyme activity.

2. Experimental Instruments and Reagents:
2.1 Instruments:

Name of instrument
Manufacturer
Specification and model

EnVision
PerkinElmer
ENVISION 2015

2.2 Reagents:

Reagents and materials
Manufacturer
Item No.

Active p38 alpha Protein
R & D systems
5477-KS-010

Inactive MK2
Thermo
PV3316

ULight-CREBtide
Perkinelmer
TRF0107

ATP Solution
Invitrogen
PV3227

DMSO
Sigma
D2650

HEPES(1M)
Gibco
15630-080

MgCl₂(1M)
Invitrogen
AM9530G

Tween 20
Sigma
P9416

EGTA
Alfa Aesar
J60767

DTT(1M)
Sigma
43816

Europium-anti-phospho-CREB
PerkinElmer
TRF0200

EDTA(0.5M)
Invitrogen
AM9260G

10X LANCE detection buffer
PerkinElmer
CR97-100

384-well plate
Perkinelmer
6007299

96 V-bottom plate (PS)
Axygen
WIPP02280

3. Experimental Method:

Experimental method for determining the p38/MK2 enzyme activity: 0.06 nM p38a (Active p38 alpha Protein), 1.2 nM MK2 (Inactive MK2), and compounds diluted in a certain concentration gradient were incubated in 1× enzyme reaction buffer (50 mM HEPES pH 7.5, 1 mM EGTA, 10 mM MgCl₂, 2 mM DTT, 0.01% Tween-20) for 1 hour. 50 nM ULight-CREBtide and 25 μM ATP (ATP Solution) were added, and the mixture was reacted at room temperature for 1.5 hours. An equal volume of a detection and termination mixed solution (1×LANCE detection buffer containing 20 mM EDTA and 2 nM Europium-anti-phospho-CREB) was added, the mixture was mixed until uniform and centrifuged, a plate sealing film was attached, and a reaction was performed at room temperature for 1 hour. TR-FRET program of the EnVision instrument was used to read the plate, and the fluorescence value of each well was detected at 665 nm/615 nm.

Experimental method for determining the p38 enzyme activity: 3 nM p38a (Active p38 alpha Protein) and compounds diluted in a certain concentration gradient were incubated in 1× enzyme reaction buffer (50 mM HEPES pH 7.5, 1 mM EGTA, 10 mM MgCl₂, 2 mM DTT, 0.01% Tween-20) for 1 hour. 50 nM ULight-MBP and 50 μM ATP (ATP 10 mM Solution) were added, and the mixture was reacted at room temperature for 1.5 hours. An equal volume of a detection and termination mixed solution (1×LANCE detection buffer containing 20 mM EDTA and 2 nM Europium-anti-P-MBP) was added, the mixture was mixed until uniform and centrifuged, a plate sealing film was attached, and a reaction was performed at room temperature for 1 hour. TR-FRET program of the EnVision instrument was used to read the plate, and the fluorescence value of each well was detected at 665 nm/615 nm.

4. Experimental Data Processing Method:

Calculation was performed on the raw data (665 nm/615 nm reading ratio) according to the following formula to obtain the inhibition rate. Inhibition rate %=[(mean value in positive control well−value in sample well)/(mean value in positive control well−mean value in negative control well)]×100, wherein the positive control well was a reaction well without a compound and an enzyme, and the negative control well was a reaction wells without an enzyme.

Log(inhibitor) vs. response−Variable slope (four parameters) in GraphPad Prism 6 was used for fitting equation analysis of the compound concentration and the corresponding inhibition rate, and the curve was fitted to obtain the IC₅₀value of the compound.

The fitting calculation equation was Y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((Log IC₅₀−X)*HillSlope)).

5. Experimental Results:

Example
p38/MK2 IC₅₀(nM)
p38 IC₅₀(nM)
p38/p38/MK2

1-1
0.71
77.4
109

2-1
0.42
/
/

3-1
0.18
/
/

5-1
0.79
525.8
666

6-1
0.10
15.3
153

7-1
0.34
49.1
144

8-1
0.25
/
/

9-1
0.14
22.9
164

10-1
0.13
/
/

11-1
0.28
96.9
346

13-1
0.12
16.5
138

14-1
0.05
5.1
102

15-1
0.2
53.6
268

16-1
0.49
/
/

17-1
0.27
/
/

18-1
0.12
/
/

19-1
0.12
/
/

6. Experimental Conclusion:

The above data show that the compounds of the examples of the present invention have a stronger ability to inhibit p38α/MK2 enzyme activity and also have good selectivity.

Test Example 2. Determination of Inhibitory Effect of the Compound of the Present Invention on p-Hsp27 in U937 Cells
1. Experimental Purpose:

The purpose of this test example is to determine the ability of the compound of the present invention to inhibit p-Hsp27 in U937 cells.

2. Experimental Instruments and Reagents:

Name of instrument
Manufacturer
Specification and model

EnVision
PerkinElmer
ENVISION 2015

2.2 Reagents:

Reagents and materials
Manufacturer
Item No.

U937
ATCC
CRL-1593.2

Phospho-HSP27 (S78/S82)
R & D systems
DYC2314-5

DuoSet IC ELISA

DuoSet ELISA Ancillary Reagent Kit 2
R & D systems
DY008

Phorbol 12-myristate 13-acetate (PMA)
Abcam
Ab120297

Lipopolysaccharides from
Sigma-Aldrich
L4391

Escherichia coli 0111:B4

3. Experimental Method:

U937 cells were treated with 20 ng/ml PMA for differentiation overnight, and after replacement with a fresh culture medium, the U937 cells were rested overnight. After differentiation, the U937 cell were digested and counted, and 25,000 cells per well were seeded in a 96-well plate until the cells adhered to the wall. A compound concentration gradient was prepared, the cells were pretreated with the compound for 1 hour (the highest final concentration of the compound was 1 μM, diluted in 3-fold concentration gradient), and 10 ng/ml LPS (Lipopolysaccharides from Escherichia coli O111:B4) was added for stimulation for 0.5 hours. After the cells were washed with PBS, the cells were lysed with a lysis solution. p-Hsp27 in the cell lysate was detected by using Phospho-HSP27 (S78/S82) DuoSet IC ELISA kit. For specific steps, reference could be made to the standard steps provided by the kit manufacturer.

4. Experimental Data Processing Method:

Calculation of p-Hsp27 inhibition rate: Inhibition rate %=[(mean value of p-Hsp27 in positive control well−mean value of p-Hsp27 in sample well)/(mean value of p-Hsp27 in positive control well−mean value of p-Hsp27 in negative control well)]×100%, wherein the positive control well was a well without a compound (DMSO-treated well), and the negative control well was a well without LPS stimulation.

Dose response curve fitting: Log(inhibitor) vs. response−Variable slope (four parameters) in GraphPad Prism 6 was used for fitting equation analysis of the compound concentration and the corresponding inhibition rate, and the curve was fitted to obtain the IC₅₀value of the compound.

The fitting calculation equation was Y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((Log IC₅₀−X)*HillSlope)).

5. Experimental Results:

U937 cell activity test

Example
p-HSP27 IC₅₀(nM)

1-1
0.17

2-1
0.28

3-1
0.15

4-1
0.35

6-1
0.15

7-1
0.35

8-1
0.22

9-1
0.10

10-1
0.13

11-1
0.10

13-1
0.56

14-1
0.13

15-1
0.32

16-1
0.28

6. Experimental Conclusion:

The above data show that the compounds of the examples of the present invention have a stronger ability to inhibit p-Hsp27 in U937 cells.

Test Example 3. Determination of Inhibitory Effect of the Compound of the Present Invention on the Expression Level of TNF-α in U937 Cells
1. Experimental Purpose:

The purpose of this test example is to determine the ability of the compound of the present invention to inhibit the expression level of TNF-α in U937 cells.

2. Experimental Instruments and Reagents:

Name of instrument
Manufacturer
Specification and model

EnVision
PerkinElmer
2105-0020

2.2 Reagents:

Reagents and materials
Manufacturer
Item No.

U937
ATCC
CRL-1593.2

Human TNF-alpha DuoSet ELISA
R & D systems
DY210

DuoSet ELISA Ancillary Reagent Kit 2
R & D systems
DY008

Phorbol 12-myristate 13-acetate (PMA)
Abcam
Ab120297

Lipopolysaccharides from Escherichia coli
Sigma-Aldrich
L4391

0111:B4

3. Experimental Method:

U937 cells were treated with 20 ng/ml PMA for differentiation overnight, and after replacement with a fresh culture medium, the U937 cells were rested overnight. After differentiation, the U937 cells were digested and counted, and 50,000 cells per well were seeded in a 96-well plate until the cells adhered to the wall. A compound concentration gradient was prepared, the cells were pretreated with the compound for 1 hour (the highest final concentration of the compound was 1 μM, diluted in 3-fold concentration gradient), and 10 ng/ml LPS (Lipopolysaccharides from Escherichia coli O111:B4) was added for stimulation for 4 hours. Thereafter, the culture supernatant was collected by centrifugation and used for subsequent ELISA to detect the concentration of TNF-α in the supernatant. The concentration of TNF-α was detected according to the standard steps provided by the ELISA kit manufacturer.

4. Experimental Data Processing Method:

A standard curve was plotted by a linear regression method from a TNF-α standard, and the concentration of TNF-α in a sample was derived by conversion according to the standard curve.

Calculation of inhibition rate: Inhibition rate %=[(mean value of TNF-α concentration in positive control well−mean value of TNF-α concentration in sample well)/(mean value of TNF-α concentration in positive control well−mean value of TNF-α concentration in negative control well)]×100%, wherein the positive control well was a well without a compound (DMSO-treated well), and the negative control well was a culture medium well.

5. Experimental Results:

U937 cell activity test

Example
TNF-α IC₅₀(nM)

1-1
1.20

2-1
0.33

3-1
0.18

4-1
1.20

6-1
0.16

7-1
0.34

8-1
0.19

9-1
0.12

10-1
0.10

11-1
0.21

13-1
0.51

14-1
0.12

15-1
0.18

16-1
0.85

6. Experimental Conclusion:

The above data show that the compounds of the examples of the present invention have a stronger ability to inhibit the expression level of TNF-α in U937 cells.

Test Example 4. Pharmacokinetic Assay in SD Rats
1. Experimental Purpose:

SD rats were used as test animals to study the pharmacokinetic behavior of the compounds of the present invention in the rat body (plasma) after oral administration at a dose of 5 mg/kg or 2 mg/kg and intravenous administration at a dose of 1 mg/kg.

2. Experimental Scheme
2.1 Test Drugs:

Compounds of the present invention, made in house.

2.2 Test Animals:

3 SD rats/group, male, from Shanghai Jiesijie Experimental Animal Co., Ltd., animal production license number (SCXK (Shanghai) 2013-0006 N0.311620400001794).

2.3 Drug Preparation:

PO, 10% solutol HS15 was dissolved by ultrasound and prepared into a clear solution or homogeneous suspension.

IV, 5% DMSO+10% Solutol HS15+85% PBS was dissolved by ultrasound and prepared into a clear solution.

2.4 Administration Scheme:

3 SD rats/group, male; After fasting overnight, the rats were administered p.o. at a dose of 5 mg/kg or 2 mg/kg with a dosage volume of 10 mL/kg and i.v. at a dose 1 mg/kg with a dosage volume of 5 mL/kg, respectively.

2.5 Sample Collection:

At 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after oral administration in the rats and at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after intravenous administration in the rats, 0.2 mL of blood was collected from the jugular vein, placed in an EDTA-K₂test tube, centrifuged at 4° C. at 6000 rpm for 6 min to separate plasma, which was stored at −80° C.

2.6 Sample Treatment:

- 1) 100 μL of acetonitrile was added to 20 μL of plasma sample for pelleting, and it was mixed and centrifuged at 3500×g for 5-20 min.
- 2) The treated supernatant solution was taken and subjected to LC/MS/MS to analyze the concentrations of the test compounds. LC/MS/MS analysis instrument: AB Sciex API 4000 Qtrap.

2.7 Liquid Phase Analysis:

- Liquid phase conditions: Shimadzu LC-20AD pump
- Chromatographic column: Waters Xbridge C18 5 μm, 4.6×50 mm, mobile phase: liquid A was 0.1% aqueous formic acid solution, and liquid B was methanol
- Flow rate: 1.0 mL/min
- Elution time: 0-4.0 min, the eluent was as follows:

Time/min
Liquid A
Liquid B

0.2
90%
10%

1.2
2%
98%

3.0
2%
98%

3.1
90%
10%

4.0
Stop

3. Test Results and Data Processing:

The main pharmacokinetic parameters were calculated using WinNonlin 6.1.

Pharmacokinetic experiment (PO administration)

Time
Plasma
Area

to
con-
under the

peak
cen-
curve

Mean

Ex-

t_max
tration
AUC_0-∞
Half-
residence

am-
Dose
(ng/
C_max
(ng/
life
time

ple
mg/kg
mL)
(ng/mL)
mL × h)
t_1/2(h)
MRT (h)

6-1
5
1
4177
14213
2.7
2.9

7-1
2
1
2157
7349
1.4
2.5

9-1
5
0.5
3757
22011
2.5
3.8

4. Experimental Conclusion

The pharmacokinetic determination results in the SD rats showed that the compounds of the present invention had better PK properties.

Number	Date	Country	Kind
202210041733.4	Jan 2022	CN	national
202211294865.4	Oct 2022	CN	national
202211474196.9	Nov 2022	CN	national

PYRIDINE-CONTAINING POLYCYCLIC DERIVATIVE, AND PREPARATION METHOD THEREFOR AND USE THEREOF

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