Cycloalkene derivatives, methods for preparing them, and their applications.

Abstract

Provided are a polycyclic derivative regulator, a preparation method therefor, and an application thereof. In particular, provided are a compound represented by general formula (I'), a preparation method therefor, a pharmaceutical composition comprising the compound, and an application thereof as a regulator in the preparation of a drug for treating metabolic diseases and related diseases; the substituents in general formula (I') are the same as those defined in the description.

Description

Cycloolefin derivative regulator, preparation method and application thereof Technical Field

[0001] The present invention belongs to the field of biomedicine, and specifically relates to a cycloolefin derivative regulator, a preparation method and an application thereof. Background Art

[0002] Diabetes mellitus is a common endocrine and metabolic disease caused by a variety of metabolic disorders, leading to multi-system and multi-organ damage. It has a high incidence rate, with approximately 425 million people suffering from diabetes worldwide. In China, the incidence rate is approximately 10%, of which type 2 diabetes accounts for 90%. The prevalence is still increasing, and the age of onset is becoming younger.

[0003] Currently, there are many types of drugs on the market for the treatment of type 2 diabetes, including insulin, biguanides, glucagon-like peptide 1 (GLP-1) receptor agonists, dipeptidyl peptidase (DPP-IV) inhibitors, sodium-glucose cotransporter 2 (SGLT-2) inhibitors, α-glucosidase inhibitors, etc., among which GLP-1 receptor agonists are the most popular.

[0004] GLP-1 is a peptide hormone secreted by human intestinal L cells. Its receptors are distributed in pancreatic islet cells, various gastrointestinal cells, and neurons in the central and peripheral nervous systems. Activation of the GLP-1 receptor has physiological effects such as promoting insulin secretion, inhibiting glucagon secretion, suppressing appetite, and delaying gastric emptying. Clinical evidence shows that compared with other hypoglycemic drugs, GLP-1 receptor agonists have a better blood sugar-lowering effect and are less likely to cause side effects such as hypoglycemia. In addition, they have additional cardiovascular benefits, can reduce food intake and delay gastric emptying, and are beneficial for weight control.

[0005] Currently available GLP-1 receptor agonists are all peptide drugs, most of which require subcutaneous administration, resulting in poor patient compliance. Furthermore, oral peptides have very low bioavailability. Therefore, there is a significant clinical need for the development of oral small molecule GLP-1 receptor agonists.

[0006] While no small-molecule GLP-1 receptor agonists have been approved, three have entered clinical development, including PF-06882961 and PF-07081532 developed by Pifzer, and TTP273 developed by vTv. All are currently in Phase I / II clinical trials. PF-06882961 has demonstrated significant glucose-lowering and weight-reducing effects in early clinical trials, with a safety profile similar to that of peptide-based GLP-1 receptor agonists. It is expected to provide additional treatment options for patients with diabetes, obesity, and NASH.

[0007] There is a huge clinical need for GLP-1 receptor agonists. Oral small-molecule GLP-1 receptor agonists with lower costs and better compliance have the potential to treat a variety of metabolic diseases and have broad market prospects.

[0008] Summary of the Invention

[0009] The object of the present invention is to provide a compound represented by general formula (IA), its stereoisomers or pharmaceutically acceptable salts thereof:

[0010]

[0011] in:

[0012] L1 is selected from a bond, alkenylene, alkynylene, -(CH2) n1 -、-(CH2) n1 (CR aa R bb ) n2 -、-(CR aa R bb ) n1 O(CH2) n2 -、-(CH2) n1 O(CR aa R bb ) n2 -、-(CR aa R bb ) n1 S(CH2) n2 -、-(CH2) n1 S(CR aa R bb ) n2 -、-(CR aa R bb ) n1 (CH2) n2 NR cc -、-(CH2) n1 NR aa (CR bb R cc )n2 -、-(CH2) n1 C(O)(CR aa R bb ) n2 -、-(CH2) n1 NR aa C(O)(CR aa R bb ) n2 -、-(CH2) n1 P(O)R aa -、-(CH2) n1 S(O) m1 -、-(CH2) n1 S(O) m1 NR aa -、-(CH2) n1 NR aa S(O) m1 -or-(CH2) n1 C(O)NR aa -;

[0013] R aa 、R bb and R cc each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterated alkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0014] Or, R aa 、R bb and R cc Any two of them may be linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0015] L2 is selected from a bond, alkenylene, alkynylene, -(CH2) n3 -、-(CH2) n3 (CR a1 R b1 ) n4 -、-(CR a1 R b1 ) n3 O(CH2) n4 -、-(CH2) n3 O(CR a1 R b1 )n4 -、-(CR a1 R b1 ) n3 S(CH2) n4 -、-(CH2) n3 S(CR a1 R b1 ) n4 -、-(CR a1 R b1 ) n3 (CH2) n4 NR c1 -、-(CH2) n3 NR a1 (CR b1 R c1 ) n4 -、-(CH2) n3 C(O)(CR a1 R b1 ) n4 -、-(CH2) n3 NR a1 C(O)(CR a1 R b1 ) n4 -、-(CH2) n3 P(O)R a1 -、-(CH2) n3 S(O) m2 -、-(CH2) n3 S(O) m2 NR a1 -、-(CH2) n3 NR a1 S(O) m2 -or-(CH2) n3 C(O)NR a1 -;

[0016] R a1 、R b1 and R c1 each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0017] Or, R a1 does not exist;

[0018] Or, R a1 、Rb1 and R c1 Any two of them may be linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0019] L3 is selected from a bond, alkenylene, alkynylene, -(CH2) n5 -、-(CH2) n5 (CR a2 R b2 ) n6 -、-(CR a2 R b2 ) n5 O(CH2) n6 -、-(CH2) n5 O(CR a2 R b2 ) n6 -、-(CR a2 R b2 ) n5 S(CH2) n6 -、-(CH2) n5 S(CR a2 R b2 ) n6 -、-(CR a2 R b2 ) n5 (CH2) n6 NR c2 -、-(CH2) n5 NR a2 (CR b2 R c2 ) n6 -、-(CH2) n5 C(O)(CR a2 R b2 ) n6 -、-(CH2) n5 NR a2 C(O)(CR a2 R b2 ) n6 -、-(CH2) n5 P(O)R a2 -、-(CH) n (CH2) n5 S(O) m3 -、-(CH2) n5 S(O) m3 NR a2 -、-(CH2) n5 NR a2 S(O) m3 -or-(CH2)n5 C(O)NR a2 -;

[0020] R a2 、R b2 and R c2 each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0021] Or, R a2 does not exist;

[0022] Or, R a2 、R b2 and R c2 Any two of them may be linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0023] Ring A is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and the cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted;

[0024] Alternatively, ring A is absent;

[0025] Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and the cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted;

[0026] Alternatively, ring B is absent;

[0027] Ring C is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and the cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted;

[0028] Alternatively, ring C is absent;

[0029] Ring D is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, and the cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted;

[0030] Alternatively, ring D is absent;

[0031] R 1each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterated alkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0032] Or, any two R 1 Linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0033] Or, R 1 Linked to L1 to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted;

[0034] R 2 each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0035] Or, any two R 2 Linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0036] Or, R 2 Linked to L1 to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted;

[0037] Or, R 2 Linked to L2 to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted;

[0038] Or, R 2 With R 3 Linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0039] R 3each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0040] Or, any two R 3 Can be linked to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted;

[0041] Or, R 3 Linked to L2 to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted;

[0042] Or, R 3 Linked to L3 to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted;

[0043] R is each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, carboxyl, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0044] represents a single bond or a double bond;

[0045] x is an integer from 0 to 12;

[0046] y is an integer from 0 to 12;

[0047] z is an integer from 0 to 12;

[0048] m1 to m3 are integers from 0 to 2; and

[0049] n1~n6 are integers of 0~3.

[0050] In certain further preferred embodiments of the present invention, the compound is further represented by general formula (I') or (I"):

[0051]

[0052] R1 , R 2 , R 3 , L1, L2, L3, x, y, z, and ring B are as defined above;

[0053] W is selected from CR m or N;

[0054] W3 is selected from CR m1 R m2 or NR m3 ;

[0055] Ring C is selected from aryl or heteroaryl, preferably phenyl or pyridyl;

[0056] L4 is selected from a bond, -(CH2) n7 -、-(CH2) n7 (CR a3 R b3 ) n8 -、-(CR a3 R b3 ) n7 O(CH2) n8 -、-(CH2) n7 O(CR a3 R b3 ) n8 -、-(CR a3 R b3 ) n7 S(CH2) n8 -、-(CH2) n7 S(CR a3 R b3 ) n8 -、-(CR a3 R b3 ) n7 (CH2) n8 NR c3 -、-(CH2) n7 NR a3 (CR b3 R c3 ) n8 -、-(CH2) n7 C(O)(CR a3 R b3 ) n8 -、-(CH2) n7 NR a3 C(O)(CR a3 R b3 ) n8 -、-(CH2) n7 P(O)R a3 -、-(CH2) n7 S(O)m4 -、-(CH2) n7 S(O) m4 NR a3 -、-(CH2) n7 NR a3 S(O) m4 -or-(CH2) n7 C(O)NR a3 -;

[0057] R a3 、R b3 and R c3 each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and optionally further substituted;

[0058] Or, R a3 、R b3 and R c3 Any two of them may be linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which may be further substituted;

[0059] R 4 each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, carboxyl, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and optionally further substituted;

[0060] R 5 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, which may be further substituted;

[0061] R m 、R m1 、R m2 and R m3 each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and optionally further substituted;

[0062] M1 is O, S, N, C, (CH) n9 、(CH2) n9 O, (CH2) n9 S, (CH2)n9 NH or (CH2) n9 ;

[0063] M2 is O, S, N, C, (CH) n10 、(CH2) n10 O, (CH2) n10 S, (CH2) n10 NH or (CH2) n10 ;

[0064] p is an integer from 0 to 4;

[0065] n7 to n10 are integers from 0 to 3;

[0066] m4 is an integer from 0 to 2.

[0067] In certain further preferred embodiments of the present invention, the compound is further represented by general formula (I'):

[0068]

[0069] is a single bond or a double bond;

[0070] Ring B is selected from cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl may be further substituted; or, Ring B is absent;

[0071] Ring C is selected from aryl or heteroaryl, preferably phenyl or pyridyl;

[0072] L1 is selected from a bond, alkenylene, alkynylene, -(CH2) n1 -、-(CH2) n1 (CR aa R bb ) n2 -、-(CR aa R bb ) n1 O(CH2) n2 -、-(CH2) n1 O(CR aa R bb ) n2 -、-(CR aa R bb ) n1 S(CH2) n2 -、-(CH2) n1 S(CR aa R bb ) n2 -、-(CR aa R bb ) n1 (CH2)n2 NR cc -、-(CH2) n1 NR aa (CR bb R cc ) n2 -、-(CH2) n1 C(O)(CR aa R bb ) n2 -、-(CH2) n1 NR aa C(O)(CR aa R bb ) n2 -、-(CH2) n1 P(O)R aa -、-(CH2) n1 S(O) m1 -、-(CH2) n1 S(O) m1 NR aa -、-(CH2) n1 NR aa S(O) m1 -or-(CH2) n1 C(O)NR aa -;

[0073] R aa 、R bb and R cc each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterated alkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0074] Or, R aa 、R bb and R cc Any two of them may be linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0075] L2 is selected from a bond, alkenylene, alkynylene, -(CH2) n3 -、-(CH2) n3 (CR a1 R b1 ) n4 -、-(CR a1 R b1) n3 O(CH2) n4 -、-(CH2) n3 O(CR a1 R b1 ) n4 -、-(CR a1 R b1 ) n3 S(CH2) n4 -、-(CH2) n3 S(CR a1 R b1 ) n4 -、-(CR a1 R b1 ) n3 (CH2) n4 NR c1 -、-(CH2) n3 NR a1 (CR b1 R c1 ) n4 -、-(CH2) n3 C(O)(CR a1 R b1 ) n4 -、-(CH2) n3 NR a1 C(O)(CR a1 R b1 ) n4 -、-(CH2) n3 P(O)R a1 -、-(CH2) n3 S(O) m2 -、-(CH2) n3 S(O) m2 NR a1 -、-(CH2) n3 NR a1 S(O) m2 -or-(CH2) n3 C(O)NR a1 -;

[0076] R a1 、R b1 and R c1 each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0077] Or, R a1 does not exist;

[0078] Or, R a1 、R b1 and R c1 Any two of them may be linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0079] L3 is selected from a bond, alkenylene, alkynylene, -(CH2) n5 -、-(CH2) n5 (CR a2 R b2 ) n6 -、-(CR a2 R b2 ) n5 O(CH2) n6 -、-(CH2) n5 O(CR a2 R b2 ) n6 -、-(CR a2 R b2 ) n5 S(CH2) n6 -、-(CH2) n5 S(CR a2 R b2 ) n6 -、-(CR a2 R b2 ) n5 (CH2) n6 NR c2 -、-(CH2) n5 NR a2 (CR b2 R c2 ) n6 -、-(CH2) n5 C(O)(CR a2 R b2 ) n6 -、-(CH2) n5 NR a2 C(O)(CR a2 R b2 ) n6 -、-(CH2) n5 P(O)R a2 -、-(CH) n (CH2) n5 S(O) m3 -、-(CH2) n5 S(O)m3 NR a2 -、-(CH2) n5 NR a2 S(O) m3 -or-(CH2) n5 C(O)NR a2 -;

[0080] R a2 、R b2 and R c2 each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0081] Or, R a2 does not exist;

[0082] W is selected from CR m or N;

[0083] R m is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, which may be further substituted;

[0084] L4 is selected from a bond, -(CH2) n7 -、-(CH2) n7 (CR a3 R b3 ) n8 -、-(CR a3 R b3 ) n7 O(CH2) n8 -、-(CH2) n7 O(CR a3 R b3 ) n8 -、-(CR a3 R b3 ) n7 S(CH2) n8 -、-(CH2) n7 S(CR a3 R b3 ) n8 -、-(CR a3 R b3 )n7 (CH2) n8 NR c3 -、-(CH2) n7 NR a3 (CR b3 R c3 ) n8 -、-(CH2) n7 C(O)(CR a3 R b3 ) n8 -、-(CH2) n7 NR a3 C(O)(CR a3 R b3 ) n8 -、-(CH2) n7 P(O)R a3 -、-(CH2) n7 S(O) m4 -、-(CH2) n7 S(O) m4 NR a3 -、-(CH2) n7 NR a3 S(O) m4 -or-(CH2) n7 C(O)NR a3 -;

[0085] R a3 、R b3 and R c3 each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and optionally further substituted;

[0086] Or, R a3 、R b3 and R c3 Any two of them may be linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which may be further substituted;

[0087] R 1 Each is independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterated alkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -(CH2) n1 C(O)R aa or -(CH2) n1 C(O)NR aa R bb, the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may optionally be further substituted;

[0088] Or, any two R 1 Linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0089] Or, R 1 Linked to L1 to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted;

[0090] R 2 each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0091] Or, any two R 2 Linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0092] Or, R 2 Linked to L1 to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted;

[0093] Or, R 2 Linked to L2 to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted;

[0094] Or, R 2 With R 3 Linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, wherein the cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0095] R 3each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, mercapto, oxo, thio, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, wherein the amino, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups may be further substituted;

[0096] Or, any two R 3 Can be linked to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted;

[0097] Or, R 3 Linked to L2 to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted;

[0098] Or, R 3 Linked to L3 to form a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaryl group, wherein the cycloalkyl group, the heterocyclic group, the aryl group and the heteroaryl group may be further substituted;

[0099] R 4 each independently selected from hydrogen, deuterium, halogen, oxo, amino, nitro, hydroxy, carboxyl, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and optionally further substituted;

[0100] R 5 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, which may be further substituted;

[0101] M1 is O, S, N, C, (CH) n9 、(CH2) n9 O, (CH2) n9 S, (CH2) n9 NH or (CH2) n9 ;

[0102] M2 is O, S, N, C, (CH) n10 、(CH2) n10 O, (CH2) n10 S, (CH2) n10 NH or (CH2) n10 ;

[0103] x is an integer from 0 to 12;

[0104] y is an integer from 0 to 12;

[0105] z is an integer from 0 to 12;

[0106] p is an integer from 0 to 4;

[0107] n1 to n6 are integers from 0 to 3; and

[0108] n7 to n10 are integers from 0 to 3;

[0109] m1 to m3 are integers ranging from 0 to 2;

[0110] m4 is an integer from 0 to 2.

[0111] In certain further preferred embodiments of the present invention, the compound is further represented by general formula (I):

[0112]

[0113] R 1 , R 2 , R 3 , L1, L2, L3, x, y, z, and ring B are as defined above;

[0114] L4 is selected from a bond, -(CH2) n7 -、-(CH2) n7 (CR a3 R b3 ) n8 -、-(CR a3 R b3 ) n7 O(CH2) n8 -、-(CH2) n7 O(CR a3 R b3 ) n8 -、-(CR a3 R b3 ) n7 S(CH2) n8 -、-(CH2) n7 S(CR a3 R b3 ) n8 -、-(CR a3 R b3 ) n7 (CH2) n8 NR c3 -、-(CH2) n7 NR a3 (CRb3 R c3 ) n8 -、-(CH2) n7 C(O)(CR a3 R b3 ) n8 -、-(CH2) n7 NR a3 C(O)(CR a3 R b3 ) n8 -、-(CH2) n7 P(O)R a3 -、-(CH2) n7 S(O) m4 -、-(CH2) n7 S(O) m4 NR a3 -、-(CH2) n7 NR a3 S(O) m4 -or-(CH2) n7 C(O)NR a3 -;

[0115] R a3 、R b3 and R c3 each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, carboxyl, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and optionally further substituted;

[0116] Or, R a3 、R b3 and R c3 Any two of them may be linked to form a cycloalkyl, heterocyclyl, aryl or heteroaryl group, which may be further substituted;

[0117] R 4 each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, carboxyl, cyano, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, and optionally further substituted;

[0118] R 5 is selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thio, alkyl, deuterated alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, which may be further substituted;

[0119] M1 is O, S, N, C, (CH) n9 、(CH2) n9 O, (CH2) n9 S, (CH2) n9 NH or (CH2) n9 ;

[0120] M2 is O, S, N, C, (CH) n10 、(CH2) n10 O, (CH2) n10 S, (CH2) n10 NH or (CH2) n10 ;

[0121] p is an integer from 0 to 4;

[0122] n7 to n10 are integers from 0 to 3;

[0123] m4 is an integer from 0 to 2.

[0124] In certain further preferred embodiments of the present invention, in the compounds of the aforementioned general formulas (IA), (I'), (I") and (I):

[0125] Ring B is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl;

[0126] Preferred C 3-8 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0127] More preferably C 5-8 Cycloalkyl, 5-10 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-8 Aryl or 5-10 membered heteroaryl containing 1-3 N, O or S atoms; further preferably 5-10 membered nitrogen-containing heterocyclic group; most preferably piperidinyl or piperazinyl.

[0128] In a further preferred embodiment of the present invention, in the compounds of the aforementioned general formulae (IA), (I'), (I") and (I):

[0129] Ring B is selected from C 3-12 Cycloalkyl, 3-12 membered heterocyclic group, C 6-14 Aryl or 5-14 membered heteroaryl;

[0130] Preferred C 3-8 Cycloalkyl, 4-12 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0131] More preferably C 5-8Cycloalkyl, 5-10 membered heterocyclic group containing 1-3 N, O or S atoms, C 6-8 Aryl or 5-10 membered heteroaryl containing 1-3 N, O or S atoms; further preferably 5-10 membered nitrogen-containing heterocyclic group; most preferably piperidinyl.

[0132] In certain further preferred embodiments of the present invention, the compound is further represented by general formula (II') or (IV):

[0133]

[0134] W is selected from CR m or N;

[0135] W1 is selected from CH or N;

[0136] W2 is selected from CR m5 or N;

[0137] W3 is selected from CR m1 R m2 or NR m3 ;

[0138] R 1 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy or C 1-6 Halogenated alkoxy, preferably hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy or C 1-3 Haloalkoxy, more preferably hydrogen, deuterium, fluorine, chlorine, cyano, -OCD3 or methoxy;

[0139] R 2 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 Halogenated alkoxy, preferably hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy or C 1-3 haloalkoxy, more preferably hydrogen, deuterium, fluorine, chlorine or methyl;

[0140] R 3 are each independently selected from hydrogen, deuterium, fluorine, methyl, deuterated methyl or halomethyl, preferably hydrogen or methyl;

[0141] R m5 Selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy or C 1-6 Halogenated alkoxy, preferably hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy or C 1-3 haloalkoxy, more preferably hydrogen or deuterium;

[0142] R 4 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 haloalkyl, preferably carboxyl;

[0143] R 5 Selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Substituted by one or more substituents in cycloalkyl or 3-8 membered heterocyclic group, preferably C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, optionally further substituted with halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6Halogenated alkyl, C 3-8 substituted by one or more substituents in a cycloalkyl or 3-8 membered heterocyclic group, more preferably

[0144] L1, L2 are each independently selected from a bond or -(CH2) n1 -, preferred key;

[0145] L3 is selected from a bond or -(CH2) n1 -, preferably -CH2-;

[0146] L4 is selected from a bond or -(CH2) n7 -, preferably a bond or -CH2-;

[0147] M1 is N, C or (CH) n9 ;

[0148] M2 is N, C or (CH) n10 ;

[0149] n9 or n10 are each independently an integer from 0 to 2;

[0150] The definitions of x, y, and z are as described above.

[0151] In certain further preferred embodiments of the present invention, the compound is further represented by general formula (II') or (IV):

[0152]

[0153] W1 is selected from CH or N;

[0154] W2 is selected from CR m5 or N;

[0155] R 1 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy or C 1-6 haloalkoxy;

[0156] R 2 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0157] R 3are each independently selected from hydrogen, deuterium, fluorine, methyl, deuterated methyl or halomethyl;

[0158] R m5 Selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy or C 1-6 Halogenated alkoxy, preferably hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy or C 1-3 haloalkoxy, more preferably hydrogen or deuterium;

[0159] R 4 are independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, oxo, C 1-6 Carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 A haloalkyl group or a 5-6 membered heteroaryl group containing 1-4 atoms selected from N, O or S, optionally, the C 1-6 Carboxyl or 5-6 membered heteroaryl containing 1-4 atoms selected from N, O or S, further substituted by one or more atoms selected from oxo, halogen, cyano, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy or C 1-6 Substituted by a haloalkoxy substituent, preferably a carboxyl group or -C(O)OCH3;

[0160] R 5 Selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C1-6 Cyanoalkyl, C 3-8 Substituted by one or more substituents in cycloalkyl or 3-8 membered heterocyclic group, preferably C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, optionally further substituted with halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Cyanoalkyl, C 3-8 substituted by one or more substituents in a cycloalkyl group or a 3-8 membered heterocyclic group;

[0161] L1, L2 are each independently selected from a bond or -(CH2) n1 -, preferred key;

[0162] L3 is selected from a bond or -(CH2) n1 -, preferably -CH2-;

[0163] L4 is selected from a bond or -(CH2) n7 -, preferably a bond or -CH2-;

[0164] M1 is N, NH, O, S, C or (CH) n9 ;

[0165] M2 is N, NH, O, S, C or (CH) n10 ;

[0166] n9 or n10 are each independently an integer from 0 to 2;

[0167] The definitions of x, y, and z are as described above.

[0168] In certain further preferred embodiments of the present invention, the compound is further represented by general formula (II'):

[0169]

[0170] W1 is selected from CH or N;

[0171] W2 is selected from CR m5 or N;

[0172] R 1 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6Haloalkoxy, -C(O)R aa or -C(O)NR aa R bb ;

[0173] R aa and R bb are each independently selected from hydrogen, deuterium, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl;

[0174] R 2 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy or C 1-6 haloalkoxy;

[0175] R 3 are each independently selected from hydrogen, deuterium, fluorine, methyl, deuterated methyl or halomethyl;

[0176] R m5 Selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy or C 1-6 Halogenated alkoxy, preferably hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy or C 1-3 haloalkoxy, more preferably hydrogen or deuterium;

[0177] R 4 are independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, oxo, C 1-6 Carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 haloalkyl or substituted or unsubstituted 5-6 membered heteroaryl, optionally, the C 1-6 The carboxyl group is further substituted by one or more radicals selected from halogen and C1-6 Alkyl is substituted by a substituent, preferably carboxyl or -C(O)OCH3;

[0178] R 5 Selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Cyanoalkyl, C 3-8 Substituted by one or more substituents in cycloalkyl or 3-8 membered heterocyclic group, preferably C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, optionally further substituted with halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Cyanoalkyl, C 3-8 substituted by one or more substituents in a cycloalkyl group or a 3-8 membered heterocyclic group;

[0179] L1, L2 are each independently selected from a bond or -(CH2) n1 -, preferred key;

[0180] L3 is selected from a bond or -(CH2) n1 -, preferably -CH2-;

[0181] L4 is selected from a bond or -(CH2) n7 -, preferably a bond or -CH2-;

[0182] M1 is N, NH, O, S, C or (CH) n9 ;

[0183] M2 is N, NH, O, S, C or (CH) n10 ;

[0184] n9 and n10 are each independently an integer of 0 to 2.

[0185] In certain further preferred embodiments of the present invention, R aa and R bb are each independently selected from hydrogen, deuterium, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Hydroxyalkyl, C 1-3 Alkoxy, C 1-3 Halogenated alkoxy, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 6-10 aryl or 5-6 membered heteroaryl.

[0186] In certain further preferred embodiments of the present invention, the compound is further represented by the following general formula:

[0187]

[0188]

[0189] In certain further preferred embodiments of the present invention, the compound is further represented by general formula (II):

[0190]

[0191] R 1 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0192] Or, any two R 1 Link Form C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl,

[0193] or, R 2 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0194] Or, any two R 2 Link Form C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0195] or, R 3 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0196] or, R 4 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl,

[0197] Or, any two R 4 Link Form C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl,

[0198] or, R 5 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, carboxyl, C 1-6 Alkyl, C 1-6Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl,

[0199] Or, M1 is O, S, N, C, CH or (CH)2;

[0200] Or, M2 is O, S, N, C, CH or (CH)2;

[0201] Or, x is 0, 1, 2, 3, 4 or 5;

[0202] Or, y is 0, 1, 2, 3 or 4;

[0203] or, z is 0, 1, 2, 3 or 4;

[0204] Or, p is 0, 1, 2 or 3.

[0205] In certain further preferred embodiments of the present invention, the compound is further represented by general formula (II):

[0206]

[0207] R 1 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0208] Or, any two R 1 Link Form C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0209] R 2 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0210] Or, any two R2 Link Form C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0211] R 3 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0212] R 4 are each independently selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl,

[0213] Or, any two R 4 Link Form C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, the C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl and 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0214] R 5 Selected from hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxyl, oxo, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, amino, nitro, hydroxy, cyano, oxo, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Cyanoalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 substituted by one or more substituents of aryl and 5-10 membered heteroaryl;

[0215] M1 is O, S, N, NH, C, CH or (CH)2;

[0216] M2 is O, S, N, NH, C, CH or (CH)2;

[0217] x is 0, 1, 2, 3, 4, or 5;

[0218] y is 0, 1, 2, 3, or 4;

[0219] z is 0, 1, 2, 3, or 4;

[0220] p is 0, 1, 2 or 3.

[0221] In certain further preferred embodiments of the present invention, in the above general formulas, R 1 Each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy or C 1-6 Halogenated alkoxy, preferably hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy or C 1-3 The haloalkoxy group is more preferably hydrogen, deuterium, fluorine, chlorine, cyano, -OCD3 or methoxy.

[0222] In certain further preferred embodiments of the present invention, in the above general formulas, R 2 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy or C 1-6 Halogenated alkoxy, preferably hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy or C 1-3 The haloalkoxy group is more preferably hydrogen, deuterium, fluorine, chlorine or methyl.

[0223] In certain further preferred embodiments of the present invention, in the above general formulas, R 3 Each is independently selected from hydrogen, deuterium, fluorine, methyl, deuterated methyl or halomethyl, preferably hydrogen or methyl.

[0224] In certain further preferred embodiments of the present invention, in the above general formulas, R 4 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 Halogenated alkyl, preferably carboxyl.

[0225] In certain further preferred embodiments of the present invention, in the above general formulas, R 4 are independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, oxo, C 1-6 Carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 A haloalkyl group or a 5-6 membered heteroaryl group containing 1-4 atoms selected from N, O or S, optionally, the C 1-6 Carboxyl or 5-6 membered heteroaryl containing 1-4 atoms selected from N, O or S, further substituted by one or more atoms selected from oxo, halogen, cyano, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy or C 1-3 The substituent of the haloalkoxy group is preferably substituted by a carboxyl group or -C(O)OCH3.

[0226] In certain further preferred embodiments of the present invention, in the above general formulas, R 5 Selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 1-6 Cyanoalkyl, C 3-8 Substituted by one or more substituents in cycloalkyl or 3-8 membered heterocyclic group, preferably C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, optionally further substituted with halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Cyanoalkyl, C 3-6 substituted by one or more substituents in a cycloalkyl or 3-6 membered heterocyclic group, more preferably C 3-6 Cycloalkyl or 3-6 membered heterocyclic group containing 1-2 atoms selected from N, O or S, optionally further substituted by halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Cyanoalkyl or C 1-3 is substituted by one or more substituents in the haloalkyl group, and more preferably

[0227] In certain further preferred embodiments of the present invention, in the above general formulas, R 5 Selected from C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Cycloalkyl, 3-8 membered heterocyclic group, C 6-10 Aryl or 5-10 membered heteroaryl, optionally further substituted with halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Hydroxyalkyl, C 1-6 Alkoxy, C 1-6 Halogenated alkoxy, C 3-8 Substituted by one or more substituents in cycloalkyl or 3-8 membered heterocyclic group, preferably C 1-3Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, optionally further substituted with halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 3-6 substituted by one or more substituents in a cycloalkyl or 3-6 membered heterocyclic group, more preferably

[0228] In certain further preferred embodiments of the present invention, in the aforementioned general formulas, M1 is N, C or (CH) n9 .

[0229] In certain further preferred embodiments of the present invention, in the aforementioned general formulas, M2 is N, C or (CH) n10 .

[0230] In certain further preferred embodiments of the present invention, in the aforementioned general formulae, n9 or n10 is independently an integer of 0 to 2.

[0231] In certain further preferred embodiments of the present invention, in the aforementioned general formulas, L1 and L2 are each independently selected from a bond or -(CH2) n1 -, preferred key.

[0232] L3 is selected from a bond or -(CH2) n1 -, preferably -CH2-.

[0233] L4 is selected from a bond or -(CH2) n7 -, preferably a bond or -CH2-.

[0234] In a further preferred embodiment of the present invention, in the above general formulas, R 1 Each is independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, methoxy or -OCD3.

[0235] R 2 are each independently selected from hydrogen, deuterium, fluorine or methyl.

[0236] R 3 are each independently selected from hydrogen or methyl.

[0237] R 4 are each independently selected from hydrogen or carboxyl.

[0238] R 5 Selected from

[0239] R 5 Selected from

[0240] L1 and L2 are each independently a bond; L3 is -CH2-; and L4 is a bond.

[0241] In a further preferred embodiment of the present invention, R 1 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano or methoxy.

[0242] R 2 are each independently selected from hydrogen, deuterium, fluorine or methyl.

[0243] R 3 are each independently selected from hydrogen.

[0244] R 4 are each independently selected from hydrogen or carboxyl.

[0245] R 5 Selected from

[0246] R 5 Selected from

[0247] L1 and L2 are each independently a bond; L3 is -CH2-; and L4 is a bond.

[0248] In a further preferred embodiment of the present invention, the compound is further represented by general formula (III) to (III-3):

[0249]

[0250] R 1 Each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy or C 1-6 haloalkoxy;

[0251] R 2 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy;

[0252] R 3 are each independently selected from hydrogen, deuterium, fluorine, methyl, deuterated methyl or halomethyl;

[0253] R 4 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, carboxyl, C1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 alkyl halide;

[0254] R5 is selected from C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, optionally further substituted by halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 substituted by one or more substituents in a haloalkyl group;

[0255] M1 is O, S, N, C, CH or (CH)2;

[0256] M2 is O, S, N, C, CH or (CH)2;

[0257] n7 is 0, 1, 2, or 3;

[0258] x is 0, 1, 2, 3, 4, or 5;

[0259] y is 0, 1, 2, 3, or 4;

[0260] z is 0, 1, 2, 3, or 4;

[0261] p is 0, 1, 2 or 3.

[0262] In a further preferred embodiment of the present invention, the compound is further represented by general formula (III) to (III-7), wherein:

[0263] R 1 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy or C 1-3 haloalkoxy;

[0264] R 2 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy or C 1-3 haloalkoxy;

[0265] R 3 are each independently selected from hydrogen, deuterium or fluorine;

[0266] R 4Each independently selected from a 5-6 membered heteroaryl group containing 1-4 atoms selected from N, O or S, further substituted by one or more selected from oxo, halogen, cyano, C 1-3 Alkyl and C 1-3 Substituted by a haloalkyl substituent, -(CH2) n COOH or -(CH2) n C(O)OCH3;

[0267] R 5 Selected from C 3-6 Cycloalkyl or 3-6 membered heterocyclic group containing 1-2 atoms selected from N, O or S, optionally further substituted by halogen, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Cyanoalkyl or C 1-3 substituted by one or more substituents in a haloalkyl group;

[0268] M1 and M2 are each independently selected from N, CH or (CH)2;

[0269] n is 0, 1, 2 or 3.

[0270] In certain further preferred embodiments of the present invention, the compound is further represented by general formula (III):

[0271]

[0272] R 1 Each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 Deuterated alkoxy or C 1-6 haloalkoxy;

[0273] R 2 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 1-6 Halogenated alkyl, C 1-6 Alkoxy, C 1-6 haloalkoxy;

[0274] R 3 are each independently selected from hydrogen, deuterium, and fluorine;

[0275] R 4 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, carboxyl, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6alkyl halide;

[0276] R5 is selected from C 3-8 Cycloalkyl or 3-8 membered heterocyclic group, optionally further substituted by halogen, C 1-6 Alkyl, C 1-6 Deuterated alkyl or C 1-6 substituted by one or more substituents in a haloalkyl group;

[0277] M1 is O, S, N, C, CH or (CH)2;

[0278] M2 is O, S, N, C or CH;

[0279] n7 is 0, 1, 2, or 3;

[0280] x is 0, 1, 2, 3, 4, or 5;

[0281] y is 0, 1, 2, 3, or 4;

[0282] z is 0, 1, 2, 3, or 4;

[0283] p is 0, 1, 2 or 3.

[0284] In certain further preferred embodiments of the present invention, for the compounds represented by general formula (III) to (III-7), their stereoisomers or pharmaceutically acceptable salts thereof, wherein:

[0285] In certain embodiments, R 1 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy or C 1-3 Haloalkoxy, preferably hydrogen, deuterium, fluorine, chlorine, cyano, methoxy or -OCD3;

[0286] In certain embodiments, R 2 Each independently selected from preferably hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy or C 1-3 haloalkoxy, preferably hydrogen, deuterium, fluorine or methyl;

[0287] In certain embodiments, R 3 are each independently selected from hydrogen, deuterium, fluorine or methyl, preferably hydrogen or methyl;

[0288] In certain embodiments, R 4are each independently a carboxyl group;

[0289] In certain embodiments, R 5 Each independently selected from

[0290] In some embodiments, x is 0; in some embodiments, x is 1; in some embodiments, x is 2; in some embodiments, x is 3; in some embodiments, x is 4; in some embodiments, x is 5;

[0291] In some embodiments, y is 0; in some embodiments, y is 1; in some embodiments, y is 2; in some embodiments, y is 3;

[0292] In some embodiments, z is 0; in some embodiments, z is 1; in some embodiments, z is 2; in some embodiments, z is 3;

[0293] In some embodiments, n7 is 0; in some embodiments, n7 is 1; in some embodiments, n7 is 2;

[0294] In some embodiments, p is 0; in some embodiments, p is 1; in some embodiments, p is 2; in some embodiments, p is 3.

[0295] In a further preferred embodiment of the present invention, for the compound represented by general formula (III), its stereoisomers or pharmaceutically acceptable salts thereof, wherein:

[0296] R 1 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy or C 1-3 haloalkoxy;

[0297] R 2 Each independently selected from preferably hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy or C 1-3 haloalkoxy;

[0298] R 3 are each independently selected from hydrogen, deuterium or fluorine;

[0299] R 4 It is a carboxyl group.

[0300] In a further preferred embodiment of the present invention, the compound is further represented by the general formula (III'):

[0301]

[0302] R 1 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy or C 1-3 Haloalkoxy, preferably hydrogen, deuterium, fluorine, chlorine, methoxy or -OCD3;

[0303] R 2 Each independently selected from preferably hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy or C 1-3 haloalkoxy, preferably hydrogen, deuterium, fluorine, chlorine or methyl;

[0304] R 3 are each independently selected from hydrogen, deuterium or fluorine, preferably hydrogen;

[0305] M1 is N or CH, preferably N;

[0306] W2 is N or CH, preferably CH;

[0307] x, y and z are each independently 0, 1 or 2;

[0308] R 5 Selected from Preferably

[0309] In a further preferred embodiment of the present invention, the compound is further represented by general formula (V-1) or general formula (V-2):

[0310]

[0311] R 1 are each independently selected from hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy or C 1-3Haloalkoxy, preferably hydrogen, deuterium, fluorine, chlorine, methoxy or -OCD3;

[0312] R 2 Each independently selected from preferably hydrogen, deuterium, fluorine, chlorine, cyano, C 1-3 Alkyl, C 1-3 Deuterated alkyl, C 1-3 Halogenated alkyl, C 1-3 Alkoxy, C 1-3 Deuterated alkoxy or C 1-3 haloalkoxy, preferably hydrogen, deuterium, fluorine, chlorine or methyl;

[0313] R 3 are each independently selected from hydrogen, deuterium or fluorine, preferably hydrogen;

[0314] M1 is N or CH, preferably N;

[0315] W2 is N or CH, preferably CH;

[0316] x, y and z are each independently 0, 1 or 2;

[0317] R 5 Selected from Preferably Further optimization

[0318] In a further preferred embodiment of the present invention, the compound is further represented by general formula (V-3) or general formula (V-4):

[0319]

[0320] In a further preferred embodiment of the present invention, the compound is further represented by formula (V-5) or formula (V-6):

[0321]

[0322] The present invention further relates to a pharmaceutical composition comprising a therapeutically effective dose of any compound of the general formula shown, its stereoisomers or pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable carriers, diluents or excipients.

[0323] The present invention further relates to the use of any compound of the general formula shown, its stereoisomers or pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of GLP-1 receptor agonist drugs.

[0324] The present invention further relates to the use of a compound represented by the general formula, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the preparation of a medicament for treating metabolic-related diseases, wherein the metabolic-related diseases are selected from diabetes, obesity, or non-alcoholic steatohepatitis-related diseases or other related diseases caused by diabetes, obesity, or non-alcoholic steatohepatitis.

[0325] The present invention further relates to a method for using the compound represented by the general formula, its stereoisomers or pharmaceutically acceptable salts, or its pharmaceutical composition in preparing drugs for treating metabolic diseases and related diseases.

[0326] The present invention also relates to a method for treating, preventing and / or treating metabolic-related diseases, which comprises administering to a patient a therapeutically effective dose of a compound represented by the general formula, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0327] The present invention also provides methods of using the compounds or pharmaceutical compositions of the present invention to treat disease conditions, including but not limited to conditions associated with GLP-1 receptor modulators.

[0328] The present invention also relates to a method for treating metabolic disease-related diseases in mammals, comprising administering to the mammal a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivative thereof.

[0329] Detailed Description of the Invention

[0330] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0331] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 8 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and most preferably an alkyl group 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, 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, and various branched-chain isomers thereof. More preferred are lower alkyl groups containing 1 to 6 carbon atoms, non-limiting examples of which 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, and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituent is preferably one or more of the following 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 groups. Methyl, ethyl, isopropyl, tert-butyl, haloalkyl, deuterated alkyl, alkoxy-substituted alkyl and hydroxy-substituted alkyl are preferred.

[0332] The term "alkylene" means that one hydrogen atom of an alkyl group is further substituted, for example: "methylene" refers to -CH2-, "ethylene" refers to -(CH2)2-, "propylene" refers to -(CH2)3-, "butylene" refers to -(CH2)4-, etc.

[0333] The term "alkenylene" refers to an alkenyl group with one hydrogen atom further substituted, for example, "vinylene" refers to -CH2=CH2-, "propenylene" refers to -CH2-=CH2-CH2-, etc. Alkenylene can be substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio. The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, more preferably 3 to 8 carbon atoms, and even more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

[0334] The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, wherein the cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, and more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyls include spirocyclic, fused, and bridged cycloalkyls, preferably cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, and cycloheptyl.

[0335] The term "spiroalkyl" refers to a polycyclic group having a carbon atom (called a spiro atom) shared between 5 to 20 monocyclic rings, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spiroalkyl group is divided into a single spiroalkyl group, a double spiroalkyl group or a multi-spiroalkyl group, preferably a single spiroalkyl group and a double spiroalkyl group. More preferably, it is a 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan single spiroalkyl group. Non-limiting examples of spiroalkyl groups include:

[0336]

[0337] It also includes spirocycloalkyl groups that share a spiro atom with a heterocycloalkyl group. Non-limiting examples include:

[0338]

[0339] 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 adjacent carbon atoms with the other rings in the system, wherein one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic alkyl groups. Non-limiting examples of fused cycloalkyl groups include:

[0340]

[0341] The term "bridged cycloalkyl" refers to a 5-20 membered, all-carbon polycyclic group in which any two rings share two carbon atoms that are not directly connected, which may contain one or more double bonds, but no ring has a completely conjugated π electron system. Preferably, it is 6-14 members, more preferably 7-10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged cycloalkyl groups include:

[0342]

[0343] The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring attached to the parent structure is a cycloalkyl, non-limiting examples of which include indanyl, tetrahydronaphthyl, benzocycloheptanyl, etc. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following 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.

[0344] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent containing 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) m(wherein m is an integer from 0 to 2) heteroatoms, but excluding the ring portion of -OO-, -OS- or -SS-, the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably, it contains 3 to 10 ring atoms; further preferably, it contains 3 to 8 ring atoms; and further preferably, it contains 3 to 6 ring atoms, of which 1 to 2 are heteroatoms selected from nitrogen, oxygen or sulfur. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, azetidinyl, oxetanyl, oxetanyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and pyranyl, etc.; preferably, pyrrolidinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, pyrazolidinyl, morpholinyl, Piperazinyl and pyranyl; more preferably pyrrolidinyl, azetidinyl, oxetanyl, oxahenyl, piperidinyl, Piperazinyl and pyranyl. Polycyclic heterocyclic groups include spirocyclic, fused-ring and bridged heterocyclic groups; wherein the spirocyclic, fused-ring and bridged heterocyclic groups are optionally connected to other groups through single bonds, or further connected to other cycloalkyl, heterocyclic, aryl and heteroaryl groups through any two or more atoms on the ring.

[0345] The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which the monocyclic rings of 5 to 20 members share one atom (called a spiro atom), wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer 0 to 2) heteroatom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but no ring has a completely conjugated π electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of shared spiral atoms between the rings, the spiro heterocyclic group is divided into a monospiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a monospiro heterocyclic group and a dispiro heterocyclic group. It is more preferably 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospiro heterocyclic group. Non-limiting examples of spiro heterocyclic groups include:

[0346]

[0347] The term "fused heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 20 members, wherein each ring in the system shares a pair of adjacent atoms with other rings in the system, one or more rings may contain one or more double bonds, but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m(wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0348]

[0349] The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, which may contain one or more double bonds but no ring has a completely conjugated π electron system, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O) m (wherein m is an integer from 0 to 2) heteroatoms, the remaining ring atoms being carbon. Preferably, it is 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it can be classified as a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic, tricyclic or tetracyclic group, more preferably a bicyclic or tricyclic group. Non-limiting examples of bridged heterocyclic groups include:

[0350]

[0351] The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which include:

[0352]

[0353] The heterocyclyl group may be optionally substituted or unsubstituted. When substituted, 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, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.

[0354] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6- to 10-membered, more preferably 6- to 8-membered, such as phenyl and naphthyl. Phenyl is more preferred. The aryl ring may be fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, wherein the ring attached to the parent structure is the aryl ring, non-limiting examples of which include:

[0355]

[0356] The aryl group may be substituted or unsubstituted. When substituted, 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, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0357] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10-membered, more preferably 5 to 8-membered, and most preferably 5-membered or 6-membered, such as imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, etc., preferably triazolyl, thienyl, imidazolyl, pyrazolyl or pyrimidinyl, thiazolyl; more preferably triazolyl, pyrrolyl, thienyl, thiazolyl and pyrimidinyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, non-limiting examples of which include:

[0358]

[0359] The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, 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, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0360] The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein the definition of alkyl is as described above, preferably an alkyl containing 1 to 8 carbon atoms, more preferably an alkyl containing 1 to 6 carbon atoms, more preferably an alkyl containing 1 to 3 carbon atoms. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy. Alkoxy can be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, sulfhydryl, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0361] "Alkenyl" refers to a chain alkenyl group, also known as an alkene group, preferably an alkenyl group containing 2 to 8 carbon atoms, more preferably an alkenyl group containing 2 to 6 carbon atoms, and most preferably an alkenyl group containing 2 to 3 carbon atoms, such as vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl, etc. The alkenyl group may be further substituted with other related groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate.

[0362] "Alkynyl" refers to (CH≡C-), preferably an alkynyl containing 2 to 8 carbon atoms, more preferably an alkynyl containing 2 to 6 carbon atoms, and most preferably an alkynyl containing 2 to 3 carbon atoms. The alkynyl group may be further substituted with other related groups, such as alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, carboxyl or carboxylate groups.

[0363] The term "alkynylene" refers to an alkynyl group with one hydrogen atom further substituted, for example, "ethynylene" refers to -C≡C-, "propynylene" refers to -C≡C-CH2-, etc. Alkynylenes (containing three or more carbon atoms) may be substituted or unsubstituted. When substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkyloxy, heterocycloalkyloxy, cycloalkylthio, and heterocycloalkylthio.

[0364] "Haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

[0365] "Haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein alkoxy is as defined above.

[0366] "Hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, wherein alkyl is as defined above.

[0367] “C 1-6 "Cyanoalkyl" refers to -C 1-6 Alkyl CN, such as -CH2CN, -CH2CH2CN, etc.

[0368] “C 1-6 "Carboxyl" refers to -C 1-5 AlkylCOOH.

[0369] "Hydroxy" refers to an -OH group.

[0370] "Halogen" refers to fluorine, chlorine, bromine or iodine.

[0371] "Amino" refers to -NH2.

[0372] "Cyano" refers to -CN.

[0373] "Nitro" refers to -NO2.

[0374] "Carboxyl" refers to -C(O)OH.

[0375] "THF" refers to tetrahydrofuran.

[0376] "EtOAc" refers to ethyl acetate.

[0377] "MeOH" refers to methanol.

[0378] "DMF" refers to N,N-dimethylformamide.

[0379] "DIPEA" refers to diisopropylethylamine.

[0380] "TFA" refers to trifluoroacetic acid.

[0381] "MeCN" refers to acetylene glycol.

[0382] "DMA" refers to N,N-dimethylacetamide.

[0383] "Et2O" refers to diethyl ether.

[0384] "DCE" refers to 1,2-dichloroethane.

[0385] "DIPEA" refers to N,N-diisopropylethylamine.

[0386] "NBS" refers to N-bromosuccinimide.

[0387] "NIS" refers to N-iodosuccinimide.

[0388] "Cbz-Cl" refers to benzyl chloroformate.

[0389] "Pd2(dba)3" refers to tris(dibenzylideneacetone)dipalladium.

[0390] "Dppf" refers to 1,1'-bis(diphenylphosphino)ferrocene.

[0391] "HATU" refers to 2-(7-benzotriazole oxide)-N,N,N',N'-tetramethyluronium hexafluorophosphate.

[0392] "KHMDS" refers to potassium hexamethyldisilazide.

[0393] "LiHMDS" refers to lithium bis(trimethylsilylamide).

[0394] "MeLi" refers to methyllithium.

[0395] "n-BuLi" refers to n-butyllithium.

[0396] "NaBH(OAc)3" refers to sodium triacetoxyborohydride.

[0397] Indicates a single bond or a double bond.

[0398] 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, that is, X can be any one or more of A, B, and C.

[0399] The hydrogen atoms described in the present invention can all be replaced by their isotope deuterium, and any hydrogen atom in the example compounds of the present invention can also be replaced by a deuterium atom.

[0400] "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, "a heterocyclic group optionally substituted with an alkyl group" means that the alkyl group may but need not be present, and that the description includes instances where the heterocyclic group is substituted with an alkyl group and instances where the heterocyclic group is not substituted with an alkyl group.

[0401] "Substituted" means that one or more hydrogen atoms, preferably up to 5, more preferably 1 to 3 hydrogen atoms, in a group are replaced independently of one another by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and a person skilled in the art can determine (by experiment or theory) which substitutions are possible or impossible without undue effort. For example, an amino or hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (e.g., olefinic) bond.

[0402] A "pharmaceutical composition" refers to a mixture containing one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, together with other chemical components, as well as other components such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration to an organism, facilitating absorption of the active ingredient and thereby exerting its biological activity.

[0403] "Pharmaceutically acceptable salts" refer to salts of the compounds of the present invention, which are safe and effective when used in mammals and have the desired biological activity. DETAILED DESCRIPTION

[0404] Intermediate Im-1

[0405] Synthesis of ((S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester)

[0406]

[0407] first step

[0408] (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester

[0409] In a 50 mL reaction flask, 3-fluoro-4-(1-((6-(piperidin-4-yl)pyridin-2-yl)oxy)cyclopropyl)benzonitrile (2 g, 10.04 mmol) and KCO (2.78 g, 20.08 mmol) were dissolved in tetrahydrofuran (30 mL). (S)-oxetan-2-ylmethylamine (874 mg, 10.04 mmol) was then added. The reaction mixture was stirred at room temperature for 12 hours. The reaction was stopped and quenched by the addition of water (20 mL). The mixture was extracted with ethyl acetate (15 mL x 2). The combined organic phases were washed with saturated sodium chloride (10 mL), dried over anhydrous sodium sulfate, filtered, and the resulting residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to afford the title product, (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester (2.0 g, yellow solid) in a yield of 74.8%.

[0410] MS m / z(ESI):267.0[M+1].

[0411] Step 2

[0412] (S)-4-Amino-3-((oxetan-2-ylmethyl)amino)benzoic acid methyl ester

[0413] Methyl (S)-4-nitro-3-((oxetan-2-ylmethyl)amino)benzoate (3 g, 11.27 mmol) was dissolved in methanol (30 mL), followed by the addition of 10% Pd / C (300 mg). The mixture was replaced with hydrogen three times and stirred for 3 hours. The reaction mixture was filtered, and the organic phase was dried and spin-dried to afford the title product, methyl (S)-4-amino-3-((oxetan-2-ylmethyl)amino)benzoate (2.6 g, yellow solid) in a 97.7% yield.

[0414] MS m / z(ESI):237.1[M+1].

[0415] Step 3

[0416] (S)-2-(Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid methyl ester

[0417] In a 50 mL reaction flask, (S)-methyl 4-nitro-3-((oxetan-2-ylmethyl)amino)benzoate (2 g, 8.46 mmol) and p-toluenesulfonic acid (86 mg, 499.41 μmol) were dissolved in tetrahydrofuran (100 mL). 2-Chloro-1,1,1-trimethoxyethane (1.3 g, 8.41 mmol) was then added. The reaction mixture was stirred at 60°C for 1 hour. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to afford the title product, (S)-methyl 2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (Im-1) (1.3 g, yellow solid) in a 52.0% yield.

[0418] MS m / z(ESI):295.0[M+1].

[0419] Intermediate Im-2

[0420] Synthesis of ((S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazole[4,5-d]pyridine-5-carboxylic acid methyl ester)

[0421]

[0422] first step

[0423] (S)-5-nitro-6-((oxetan-2-ylmethyl)amino)2-picolinic acid methyl ester

[0424] Starting from methyl 6-chloro-5-nitro-2-picolinate, refer to step 1 of intermediate Im-1 to obtain the title product (S)-5-nitro-6-((oxetan-2-ylmethyl)amino)2-picolinate.

[0425] MS m / z(ESI):268.1[M+1].

[0426] Step 2

[0427] (S)-methyl 5-amino-6-((oxetan-2-ylmethyl)amino)2-picolinate.

[0428] Using (S)-5-nitro-6-((oxetan-2-ylmethyl)amino)2-picolinic acid methyl ester as the starting material, refer to step 2 of intermediate Im-1 to obtain the title product, (S)-5-amino-6-((oxetan-2-ylmethyl)amino)2-picolinic acid methyl ester.

[0429] MS m / z(ESI):238.1[M+1].

[0430] Step 3

[0431] ((S)-2-(Chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazole[4,5-d]pyridine-5-carboxylic acid methyl ester

[0432] At room temperature, (S)-methyl 5-amino-6-((oxetan-2-ylmethyl)amino)-2-picolinate (340 mg, 1.43 mmol) was dissolved in tetrahydrofuran (5 mL), and then a solution of chloroacetic anhydride (257.27 mg, 1.50 mmol) in tetrahydrofuran (5 mL) was added dropwise. The mixture was stirred at room temperature for 30 minutes, then heated to 60°C and reacted for 2 hours. The mixture was cooled to room temperature. LCMS indicated that the reaction was complete. The reaction solution was diluted with ethyl acetate (30 mL), then washed with saturated sodium bicarbonate solution (15 mL × 3), washed with saturated sodium chloride solution (15 mL × 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and spin-dried to give the title product ((S)-2-(chloromethyl)-3-(oxabutan-2-ylmethyl)-3H-imidazole[4,5-d]pyridine-5-carboxylic acid methyl ester (Im-2) (yellow oil, 0.4 g) with a yield of 94.4%. The crude product was used directly in the next step.

[0433] MS m / z(ESI):296.1[M+1].

[0434] Intermediate Im-3

[0435] (S)-2-(Chloromethyl)-1-(oxetan-2-ylmethyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid methyl ester

[0436]

[0437] Using 5-fluoro-6-nitronicotinoic acid methyl ester as starting material, the product (S)-2-(chloromethyl)-1-(oxetan-2-ylmethyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid methyl ester was obtained by referring to the synthesis of intermediate Im-2.

[0438] MS m / z(ESI):296.1[M+1].

[0439] Intermediate Im-4

[0440] Synthesis of Ethyl 2-(Chloromethyl)-1-((1-(Fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0441]

[0442] first step

[0443] Ethyl 1-(fluoromethyl)cyclopropane-1-carboxylate

[0444] Dissolve ethyl 1-(hydroxymethyl)cyclopropanecarboxylate (7 g, 48.55 mmol) in DCM (100 mL) and add DAST (8.61 g, 53.41 mmol) at -78°C. Allow the reaction to warm to room temperature and stir for 16 hours. After completion, add 50 mL of water and extract with dichloromethane (50 mL x 2). Wash with saturated sodium chloride solution (30 mL x 2), dry over anhydrous sodium sulfate, and concentrate to obtain the title product, ethyl 1-(fluoromethyl)cyclopropane-1-carboxylate (6.5 g, yellow oil) in a 91.6% yield.

[0445] 1 H NMR (400MHz, CDCl3): δ4.52(dd,1.5Hz,2H),4.17(q,2H),1.41–1.33(m,2H),1.26(t,3H),1.05–0.95(m,2H).

[0446] Step 2

[0447] 1-(Fluoromethyl)cyclopropylmethanol

[0448] Dissolve ethyl 1-(fluoromethyl)cyclopropane-1-carboxylate (6.5 g, 44.47 mmol) in THF (60 mL) and add LiAlH₄ (2.53 g, 66.71 mmol) in an ice-water bath. Allow the reaction to warm to room temperature and stir for 16 hours. After completion, quench the reaction with 15 g of sodium sulfate decahydrate. Filter and concentrate to obtain the title product, 1-(fluoromethyl)cyclopropylmethanol (3.5 g, yellow oil) in a 75.6% yield.

[0449] 1 H NMR (400MHz, CDCl3): δ4.36 (d, 2H), 3.58 (s, 2H), 0.60 (m, 4H).

[0450] Step 3

[0451] (1-(Fluoromethyl)cyclopropyl)methyl methanesulfonate

[0452] 1-(Fluoromethyl)cyclopropylmethanol (1.3 g, 12.49 mmol) was dissolved in DCM (30 mL). Methanesulfonyl chloride (1.86 g, 16.23 mmol, 1.26 mL) and triethylamine (2.53 g, 24.97 mmol, 3.48 mL) were added dropwise in an ice-water bath. The reaction system was stirred at 20°C. After completion, saturated NaHCO₃ (10 mL) was added dropwise to quench the reaction. The mixture was extracted with dichloromethane (20 mL × 3), washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated to afford crude (1-(fluoromethyl)cyclopropyl)methyl methanesulfonate (2.0 g, light yellow oil) in an 87.0% yield.

[0453] 1 H NMR (400MHz, CDCl3) δ4.32(d,2H),4.19(s,2H),3.05(s,3H),0.81–0.72(m,4H).

[0454] Step 4

[0455] (1-(Fluoromethyl)cyclopropyl)methylamine

[0456] Dissolve (1-(Fluoromethyl)cyclopropyl)methyl methanesulfonate (1.0 g, 5.49 mmol) in NH3 / i-PrOH (10 mL). Heat the reaction system at 60°C in a microwave oven for 6 hours. After completion, concentrate the reaction to afford the title product, (1-(fluoromethyl)cyclopropyl)methanamine (600 mg, yellow oil). The crude product is used directly in the next reaction.

[0457] Step 5

[0458] Ethyl 3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)-4-nitrobenzoate

[0459] Ethyl 3-fluoro-4-nitrobenzoate (1.24 g, 5.82 mmol) was dissolved in DMF (30 mL), and (1-(fluoromethyl)cyclopropyl)methanamine (600 mg, 5.82 mmol) and K2CO3 (1.61 g, 11.64 mmol) were added. The reaction system was stirred at 20°C for four hours. After completion, the reaction was diluted with water (10 mL), extracted with ethyl acetate (20 mL x 2), washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product, ethyl 3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)-4-nitrobenzoate (1.2 g, pale yellow solid), in a yield of 69.6%.

[0460] MS m / z(ESI):297.1[M+1].

[0461] 1 H NMR (400MHz, CDCl3): δ8.22(d,1H),7.56(s,1H),7.25(d,1H),4.41(q,2H),4.30(d,2H),3.42(d,2H),1.41(t,3H),0.76(m,4H).

[0462] Step 6

[0463] Ethyl 4-amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)benzoate

[0464] Ethyl 3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)-4-nitrobenzoate (1.2 g, 4.05 mmol) was dissolved in MeOH (30 mL), and Pd / C (200 mg, 10% purity) was added. The reaction system was purged with hydrogen three times and stirred at 20°C for 2 hours. After completion of the reaction, the mixture was filtered through celite, and the filtrate was concentrated to afford the title product, ethyl 4-amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)benzoate (1.0 g, yellow solid) in a yield of 92.7%.

[0465] MS m / z(ESI):267.1[M+1].

[0466] Step 7

[0467] Ethyl 2-(chloromethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0468] Ethyl 4-amino-3-(((1-(fluoromethyl)cyclopropyl)methyl)amino)benzoate (1.0 g, 3.76 mmol) was dissolved in MeCN (30 mL), and p-toluenesulfonic acid (193.99 mg, 1.13 mmol) and 2-chloro-1,1,1-trimethoxyethane (1.16 g, 7.51 mmol) were added. The reaction system was stirred in an oil bath at 60°C for 4 hours. After completion, the reaction was concentrated to obtain the crude product. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to provide ethyl 2-(chloromethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (700 mg, yellow solid) in a yield of 57.4%.

[0469] MS m / z(ESI):325.1[M+1].

[0470] 1H NMR (400MHz, CDCl3): δ8.21(s,1H),8.04(d,1H),7.81(d,1H),4.97(s,2H),4.47(s,2H),4.44(q,2H),4.03(d,2H),1.43(t,3H),0.92–0.82(m,4H).

[0471] Intermediate Im-5

[0472] Synthesis of Ethyl 2-(Chloromethyl)-3-((1-(Fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate

[0473]

[0474] Using ethyl 6-chloro-5-nitropyridine as starting material, the title product, ethyl 2-(chloromethyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate, was obtained by referring to the synthesis of intermediate Im-4.

[0475] MS m / z(ESI):326.10[M+1].

[0476] Intermediate Im-6

[0477] Methyl 2-(chloromethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylate

[0478]

[0479] Using methyl 5-fluoro-6-nitronicotinate as the starting material, the product methyl 2-(chloromethyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylate was obtained by referring to the synthesis of intermediate Im-4.

[0480] MS m / z(ESI):312.1[M+1].

[0481] Intermediate Im-7

[0482] tert-Butyl-4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate

[0483]

[0484] first step

[0485] tert-Butyl 4-(3-acetyl-2-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0486] Dissolve 1-(3-bromo-2-hydroxyphenyl)ethan-1-one Im-7a (20 g, 0.09 mol), tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (32 g, 0.10 mol), Pd(dppf)Cl2·CH2Cl2 (7.6 g, 9.40 mmol), and anhydrous potassium carbonate (39 g, 0.28 mol) in 250 mL of a 4:1 mixture of dioxane and water. Heat the reaction mixture to 100°C and stir for 8 hours. The reaction was stopped and the reaction solution was cooled to ambient temperature. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluents to give the title product, tert-butyl-4-(3-acetyl-2-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate Im-7b (26 g, colorless oil) in a yield of 88.1%.

[0487] MS m / z(ESI):318.1[M+1].

[0488] Step 2

[0489] tert-Butyl-4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate

[0490] Tert-butyl-4-(3-acetyl-2-hydroxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate Im-7b (26 g, 0.08 mol) and Pd / C (2.6 g, 10% wt.) were dispersed in methanol (300 mL). Hydrogen was introduced three times, and air was expelled. The reaction mixture was stirred for 12 hours. The reaction was terminated, filtered through celite, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product, tert-butyl-4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate Im-7 (25 g, white solid) in a yield of 95.6%.

[0491] MS m / z(ESI):320.1[M+1].

[0492] Example 1

[0493] 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0494]

[0495] first step

[0496] (E)-1-(3-Bromo-2-hydroxy-phenyl)-3-(4-chloro-2-fluoro-phenyl)prop-2-en-1-one

[0497] To a solution of 1-(3-bromo-2-hydroxy-phenyl)ethanone (13 g, 60.45 mmol) and 4-chloro-2-fluoro-benzaldehyde (10.06 g, 63.48 mmol) in ethanol (125 mL) and water (200 mL) was added sodium tetraborate decahydrate (45.97 g, 66.50 mmol), followed by stirring at 90°C for 12 hours, cooling, filtering, washing the filter cake with water, and drying the filter cake to give the title product (E)-1-(3-bromo-2-hydroxy-phenyl)-3-(4-chloro-2-fluoro-phenyl)prop-2-en-1-one (20 g, yellow solid) in a yield of 93.0%.

[0498] MS m / z(ESI):354.9[M+1]

[0499] Step 2

[0500] 8-Bromo-2-(4-chloro-2-fluoro-phenyl)chroman-4-one

[0501] A solution of (E)-1-(3-bromo-2-hydroxy-phenyl)-3-(4-chloro-2-fluoro-phenyl)prop-2-en-1-one (2 g, 5.62 mmol) and concentrated hydrochloric acid (4 mL) in ethanol (10 mL) was stirred at 110°C under microwave conditions for 20 hours, cooled, and dried by spin drying. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to give the title product, 8-bromo-2-(4-chloro-2-fluoro-phenyl)chroman-4-one (1.8 g, yellow solid) in a yield of 90.0%.

[0502] MS m / z(ESI):355.0[M+1]

[0503] Step 3

[0504] 8-Bromo-2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chromane

[0505] To a solution of 8-bromo-2-(4-chloro-2-fluoro-phenyl)chroman-4-one (1.8 g, 5.06 mmol) in tetrahydrofuran (10 mL) was added 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-sulfanyl)ethylamine (10 mL) dropwise, followed by stirring at 70°C for 12 hours, cooling, quenching the reaction with water, and extraction with dichloromethane (50 mL × 3). The organic phase was washed with saturated sodium bicarbonate solution (50 mL × 2) and saturated sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluent to give the title product 8-bromo-2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chroman (400 mg, yellow solid) in a yield of 20.9%.

[0506] MS m / z(ESI):377.0[M+1]

[0507] Step 4

[0508] 4-[2-(4-Chloro-2-fluoro-phenyl)-4,4-difluoro-chroman-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester

[0509] 8-Bromo-2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chromane (400 mg, 1.06 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (360.32 mg, 1.17 mmol), sodium carbonate (280.71 mg, 2.65 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (77.44 mg, 105.94 μmol), 1,4-dioxane (10 A mixture of 4-[2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chroman-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (450 mg, yellow oil) was obtained. The mixture was cooled, water was added, and the mixture was extracted with dichloromethane (10 mL × 2). The organic phase was washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluent to give the title product, 4-[2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chroman-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (450 mg, yellow oil) in a yield of 88.5%.

[0510] MS m / z(ESI):480.1[M+1]

[0511] Step 5

[0512] 4-[2-(4-Chloro-2-fluoro-phenyl)-4,4-difluoro-chroman-8-yl]piperidine-1-carboxylic acid tert-butyl ester

[0513] A mixture of tert-butyl 4-[2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chroman-8-yl]-3,6-dihydro-2H-pyridine-1-carboxylate (450 mg, 937.66 μmol), palladium on carbon (80 mg, 10%), and ethyl acetate (30 mL) was replaced with hydrogen three times and stirred for 5 hours. The mixture was filtered and dried to give the title product, tert-butyl 4-[2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chroman-8-yl]piperidine-1-carboxylate (380 mg, light yellow oil) in a yield of 84.1%.

[0514] MS m / z(ESI):482.2[M+1]

[0515] Step 6

[0516] 4-[2-(4-Chloro-2-fluoro-phenyl)-4-fluoro-2H-chromen-8-yl]piperidine

[0517] A mixture of tert-butyl 4-[2-(4-chloro-2-fluoro-phenyl)-4,4-difluoro-chromen-8-yl]piperidine-1-carboxylate (340 mg, 705.49 μmol) and hexafluoroisopropanol (10 mL) was stirred at 80° C. under microwave conditions for 4 hours, cooled, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluents to give the title product, 4-[2-(4-chloro-2-fluoro-phenyl)-4-fluoro-2H-chromen-8-yl]piperidine (40 mg, colorless oil) in a yield of 15.7%.

[0518] MS m / z(ESI):362.1[M+1]

[0519] Step 7

[0520] 2-[[4-[2-(4-Chloro-2-fluoro-phenyl)-4-fluoro-2H-chromen-8-yl]-1-piperidinyl]methyl]-3-[[1-(fluoromethyl)cyclopropyl]methyl]benzimidazole-5-carboxylic acid methyl ester

[0521] A mixture of 4-[2-(4-chloro-2-fluoro-phenyl)-4-fluoro-2H-chromen-8-yl]piperidine (40 mg, 110.55 μmol), Im-1 (46.68 mg, 143.72 μmol), potassium carbonate (61.03 mg, 442.22 μmol) and acetonitrile (5 mL) was stirred at 50°C for 3 hours, cooled, added with 5 mL of water, extracted with dichloromethane (20 mL×3), and the organic phase was washed with saturated sodium chloride solution. The mixture was washed with 4% paraformaldehyde (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to give the title product, ethyl 2-[[4-[2-(4-chloro-2-fluoro-phenyl)-4-fluoro-2H-chromen-8-yl]-1-piperidinyl]methyl]-3-[[1-(fluoromethyl)cyclopropyl]methyl]benzimidazole-5-carboxylate (30 mg, colorless oil) in a yield of 43.7%.

[0522] MS m / z(ESI):620.2[M+1]

[0523] Step 8

[0524] 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0525] A mixture of methyl 2-[[4-[2-(4-chloro-2-fluoro-phenyl)-4-fluoro-2H-chromen-8-yl]-1-piperidinyl]methyl]-3-[[1-(fluoromethyl)cyclopropyl]methyl]benzimidazole-5-carboxylate (30 mg, 48.38 μmol), lithium hydroxide monohydrate (20 mg, 476.62 μmol), methanol (2 mL), water (2 mL), and tetrahydrofuran (3 mL) was stirred at room temperature. The mixture was stirred for 12 hours, and formic acid was added to adjust the pH to 6. The mixture was dried by spin drying, and the residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluent to give 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (20 mg, white solid) in a yield of 68.2%.

[0526] MS m / z(ESI):606.2[M+1].

[0527] 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was chirally separated to obtain

[0528]

[0529] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (1-A)

[0530] MS m / z(ESI):606.2[M+1].

[0531] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (1-B)

[0532] MS m / z(ESI):606.2[M+1].

[0533] Example 2

[0534] 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0535] Im-1 was replaced with Im-2, and reference was made to Example 1 to obtain 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid.

[0536] MS m / z(ESI):607.2[M+1].

[0537] 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was chirally resolved to obtain

[0538]

[0539] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 2-A)

[0540] MS m / z(ESI):607.2[M+1].

[0541] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 2-B)

[0542] MS m / z(ESI):607.2[M+1].

[0543] Example 3

[0544] 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0545] Im-1 was replaced with Im-4, and reference was made to Example 1 to obtain 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0546] MS m / z(ESI):622.2[M+1].

[0547] 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was chirally separated to obtain

[0548]

[0549] (R)-2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 3-A)

[0550] MS m / z(ESI):622.2[M+1].

[0551] (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 3-B)

[0552] MS m / z(ESI):622.2[M+1].

[0553] Example 4

[0554] 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0555] Im-1 was replaced with Im-5, and reference was made to Example 1 to obtain 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid.

[0556] MS m / z(ESI):623.2[M+1].

[0557] 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was chirally separated to obtain

[0558]

[0559] (R)-2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 4-A)

[0560] MS m / z(ESI):623.2[M+1].

[0561] (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 4-B)

[0562] MS m / z(ESI):623.2[M+1].

[0563] Example 5

[0564] 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0565]

[0566] first step

[0567] (E)-1-(3-Bromo-2-hydroxyphenyl)-3-(2,4-dichlorophenyl)prop-2-en-1-one

[0568] Using 2,4-dichlorobenzaldehyde as raw material, refer to Example 1 in the first step to obtain (E)-1-(3-bromo-2-hydroxyphenyl)-3-(2,4-dichlorophenyl)prop-2-en-1-one

[0569] MS m / z(ESI):371.0[M+1].

[0570] Step 2

[0571] 4-(2-(2,4-Dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidine

[0572] Using (E)-1-(3-bromo-2-hydroxyphenyl)-3-(2,4-dichlorophenyl)prop-2-en-1-one as a raw material, refer to the second to sixth steps of Example 1 to obtain 4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidine

[0573] MS m / z(ESI):378.1[M+1].

[0574] Step 3

[0575] 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0576] Using 4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidine and Im-5 as raw materials, refer to the seventh to eighth steps of Example 1 to obtain 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0577] MS m / z(ESI):639.2[M+1].

[0578] 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was chirally separated to obtain

[0579]

[0580] (R)-2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 5-A)

[0581] MS m / z(ESI):639.2[M+1].

[0582] (S)-2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 5-B)

[0583] MS m / z(ESI):639.2[M+1].

[0584] Example 6

[0585] 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid

[0586] Replace Im-1 with Im-6, and refer to Example 1 to obtain 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid

[0587] MS m / z(ESI):623.2[M+1].

[0588] 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid was chirally separated to obtain

[0589]

[0590] (R)-2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (Example 6-A)

[0591] MS m / z(ESI):623.2[M+1].

[0592] (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (Example 6-B)

[0593] MS m / z(ESI):623.2[M+1].

[0594] Example 7

[0595] 2-((4-(2-(4-Cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0596]

[0597] first step

[0598] (E)-4-(3-(3-Bromo-2-hydroxyphenyl)-3-carbonylprop-1-en-1-yl)-3-fluorobenzonitrile

[0599] Using 3-fluoro-4-formylbenzonitrile as raw material, refer to Example 1 in the first step to obtain (E)-4-(3-(3-bromo-2-hydroxyphenyl)-3-carbonylprop-1-en-1-yl)-3-fluorobenzonitrile

[0600] MS m / z(ESI):346.0[M+1].

[0601] Step 2

[0602] 3-Fluoro-4-(4-fluoro-8-(piperidin-4-yl)-2H-chromen-2-yl)benzonitrile

[0603] Using (E)-1-(3-bromo-2-hydroxyphenyl)-3-(2,4-dichlorophenyl)prop-2-en-1-one as starting material, refer to steps 2 to 6 of Example 1 to obtain 3-fluoro-4-(4-fluoro-8-(piperidin-4-yl)-2H-chromen-2-yl)benzonitrile

[0604] MS m / z(ESI):353.1[M+1].

[0605] Step 3

[0606] 2-((4-(2-(4-Cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0607] Using 3-fluoro-4-(4-fluoro-8-(piperidin-4-yl)-2H-chromen-2-yl)benzonitrile and Im-4 as raw materials, refer to the seventh to eighth steps of Example 1 to obtain 2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0608] MS m / z(ESI):613.2[M+1].

[0609] 2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was chirally separated to obtain

[0610]

[0611] (R)-2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 7-A)

[0612] MS m / z(ESI):613.2[M+1].

[0613] (S)-2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 7-B)

[0614] MS m / z(ESI):613.2[M+1].

[0615] Example 8

[0616] 2-((4-(2-(4-Cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0617] Using 3-fluoro-4-(4-fluoro-8-(piperidin-4-yl)-2H-chromen-2-yl)benzonitrile and Im-1 as raw materials, 2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained with reference to Example 1.

[0618] MS m / z(ESI):597.2[M+1].

[0619] 2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was chirally separated to obtain

[0620]

[0621] 2-((4-((R)-2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 8-A)

[0622] MS m / z(ESI):597.2[M+1].

[0623] 2-((4-((S)-2-(4-Cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 8-B)

[0624] MS m / z(ESI):597.2[M+1].

[0625] Example 9

[0626] 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid

[0627] Using 4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidine and Im-6 as raw materials, refer to Example 1 to obtain 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid

[0628] MS m / z(ESI):639.2[M+1].

[0629] 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid was chirally separated to obtain

[0630]

[0631] (R)-2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (Example 9-A)

[0632] MS m / z(ESI):639.2[M+1].

[0633] (S)-2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (Example 9-B)

[0634] MS m / z(ESI):639.2[M+1].

[0635] Example 10

[0636] 2-((4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0637]

[0638] first step

[0639] (E)-tert-Butyl 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl)-2-hydroxyphenyl)piperidine-1-carboxylate

[0640] Using (E)-1-(3-bromo-2-hydroxy-phenyl)-3-(4-chloro-2-fluoro-phenyl)prop-2-en-1-one as raw material, refer to the fourth step of Example 1, and the fifth step to obtain (E)-4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl)-2-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester

[0641] MS m / z(ESI):460.2[M+1].

[0642] Step 2

[0643] tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate

[0644] To a solution of tert-butyl (E)-4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl)-2-hydroxyphenyl)piperidine-1-carboxylate (1 g, 2.18 mmol) in isopropanol (25 mL) at 50°C was added sodium borohydride (248 mg, 6.54 mmol), followed by stirring at room temperature for 16 hours. The reaction was quenched by adding 10 mL of water and extracted with dichloromethane (50 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluent to give tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate (260 mg, light yellow oil) in a yield of 26.9%.

[0645] MS m / z(ESI):444.2[M+1].

[0646] Step 3

[0647] 2-((4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0648] Using tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate and Im-5 as raw materials, refer to steps 6 to 8 of Example 1 to obtain 2-((4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0649] MS m / z(ESI):605.2[M+1].

[0650] 2-((4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was chirally separated to obtain

[0651]

[0652] (R)-2-((4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 10-A)

[0653] MS m / z(ESI):605.2[M+1].

[0654] (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 10-B)

[0655] MS m / z(ESI):605.2[M+1].

[0656] Example 11

[0657] 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid

[0658] Using 4-[2-(4-chloro-2-fluoro-phenyl)-4-fluoro-2H-chromen-8-yl]piperidine and Im-3 as raw materials, refer to Example 1 to obtain 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid

[0659] MS m / z(ESI):607.2[M+1].

[0660] 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid was chirally separated to obtain

[0661]

[0662] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (Example 11-A)

[0663] MS m / z(ESI):607.2[M+1].

[0664] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (Example 11-B)

[0665] MS m / z(ESI):607.2[M+1].

[0666] Example 12

[0667] 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0668] Using 4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidine and Im-4 as raw materials, refer to Example 1 to obtain 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0669] MS m / z(ESI):638.2[M+1].

[0670] 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was chirally separated to obtain

[0671]

[0672] (R)-2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 12-A)

[0673] MS m / z(ESI):638.2[M+1].

[0674] (S)-2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 12-B)

[0675] MS m / z(ESI):638.2[M+1].

[0676] Example 13

[0677] 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0678] Using 4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidine and Im-2 as raw materials, refer to Example 1 to obtain 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0679] MS m / z(ESI):623.2[M+1].

[0680] 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was chirally separated to obtain

[0681]

[0682] 2-((4-((R)-2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 13-A)

[0683] MS m / z(ESI):623.2[M+1].

[0684] 2-((4-((S)-2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 13-B)

[0685] MS m / z(ESI):623.2[M+1].

[0686] Example 14

[0687] 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0688] Using 4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidine and Im-1 as raw materials, refer to Example 1 to obtain 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxabutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0689] MS m / z(ESI):622.2[M+1].

[0690] 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was chirally separated to obtain

[0691]

[0692] 2-((4-((R)-2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 14-A)

[0693] MS m / z(ESI):622.2[M+1].

[0694] 2-((4-((S)-2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 14-B)

[0695] MS m / z(ESI):622.2[M+1].

[0696] Example 15

[0697] 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid

[0698] Using 4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidine and Im-3 as raw materials, refer to Example 1 to obtain 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid

[0699] MS m / z(ESI):623.2[M+1].

[0700] 2-((4-(2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid was chirally separated to obtain

[0701]

[0702] 2-((4-((R)-2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (Example 15-A)

[0703] MS m / z(ESI):623.2[M+1].

[0704] 2-((4-((S)-2-(2,4-dichlorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (Example 15-B)

[0705] MS m / z(ESI):623.2[M+1].

[0706] Example 16

[0707] 2-((4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0708]

[0709] first step

[0710] tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-4-carbonylchroman-8-yl)piperidine-1-carboxylate

[0711] Using 8-bromo-2-(4-chloro-2-fluorophenyl)chroman-4-one as starting material, refer to the fourth and fifth steps of Example 1 to obtain the product tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-4-carbonylchroman-8-yl)piperidine-1-carboxylate.

[0712] MS m / z(ESI):460.1[M+1].

[0713] Step 2

[0714] tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-2H-chromen-8-yl)piperidine-1-carboxylate

[0715] Dissolve tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-4-carbonylchroman-8-yl)piperidine-1-carboxylate (1 g, 2.17 mmol) in THF (20 mL). Add lithium bis(trimethylsilylamide) (2.4 mL, 2.40 mmol) at -78°C and allow to react for 1 hour. Add a solution of 2-[N,n-bis(trifluoromethanesulfonyl)amino]-5-chloropyridine (0.94 g, 2.4 mmol) in THF (20 mL) at -78°C, slowly warm to room temperature, and stir for 5 hours. Quench the reaction by adding sodium bicarbonate (10 mL), and extract with ethyl acetate (20 mL x 3). Combine the organic phases, wash with saturated sodium chloride solution (20 mL x 2), dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The resulting residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to give tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-2H-chromen-8-yl)piperidine-1-carboxylate (456 mg, yield: 35.5%).

[0716] MS m / z(ESI):592.1[M+1].

[0717] Step 3

[0718] tert-Butyl 4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate

[0719] Dissolve tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-4-(((trifluoromethyl)sulfonyl)oxy)-2H-chromen-8-yl)piperidine-1-carboxylate (0.5 g, 0.84 mmol) in 10 mL of DMA / THF (v:v = 1:3). Add nickel acetate tetrahydrate (24.8 mg, 0.1 mmol), zinc powder (10 mg, 0.16 mmol), 1,5-cyclooctadiene (11 mg, 0.1 mmol), and lithium chloride (53 mg, 1.3 mmol). React at room temperature under nitrogen for 16 hours. Quench the reaction with water (10 mL) and extract with ethyl acetate (20 mL x 3). The combined organic phases are washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the crude product. The resulting residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to give tert-butyl 4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate (241 mg, yield: 60.0%).

[0720] MS m / z(ESI):478.1[M+1].

[0721] Step 4

[0722] 2-((4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0723] Using tert-butyl 4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate and Im-1 as raw materials, the product 2-((4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained from the sixth to eighth steps of Reference Example 1.

[0724] MS m / z(ESI):622.1[M+1].

[0725] 2-((4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxabutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was resolved to obtain the product

[0726]

[0727] 2-((4-((R)-4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 16-A)

[0728] MS m / z(ESI):622.1[M+1].

[0729] 2-((4-((S)-4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 16-B).

[0730] MS m / z(ESI):622.1[M+1].

[0731] Example 17

[0732] 2-((4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0733] Using tert-butyl 4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate and Im-2 as raw materials, refer to steps 6 to 8 of Example 1 to obtain the product 2-((4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid.

[0734] MS m / z(ESI):623.1[M+1].

[0735] 2-((4-(4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxabutane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was resolved to obtain the product

[0736]

[0737] 2-((4-((R)-4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 17-A)

[0738] MS m / z(ESI):623.1[M+1].

[0739] 2-((4-((S)-4-chloro-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 17-B).

[0740] MS m / z(ESI):623.1[M+1].

[0741] Example 18

[0742] 2-((4-(2-(4-chloro-2-fluorophenyl)-4-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0743]

[0744] first step

[0745] (E)-2-Bromo-6-(4-(4-chloro-2-fluorophenyl)-2-hydroxybut-3-en-2-yl)phenol

[0746] (E)-1-(3-bromo-2-hydroxyphenyl)-3-(4-chloro-2-fluorophenyl)prop-2-en-1-one (1 g, 2.81 mmol) was dissolved in 30 mL of THF. Methylmagnesium bromide (7 mL, 7 mmol) was added at 0°C and the mixture was slowly warmed to room temperature with stirring for 3 hours. The reaction was quenched by the addition of ammonium chloride (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phases were washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield the crude product. The resulting residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to yield (E)-2-bromo-6-(4-(4-chloro-2-fluorophenyl)-2-hydroxybut-3-en-2-yl)phenol (831 mg, yield: 79.6%).

[0747] MS m / z(ESI):370.9[M+1].

[0748] Step 2

[0749] 8-Bromo-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromene

[0750] (E)-2-Bromo-6-(4-(4-chloro-2-fluorophenyl)-2-hydroxybut-3-en-2-yl)phenol (0.5 g, 1.34 mmol) was dissolved in 15 mL of nitromethane, and (2,3,4,5-tetrafluorophenyl)boronic acid (52 mg, 0.26 mmol) was added. The mixture was stirred at 60°C for 16 hours. The reaction was quenched by the addition of water (10 mL) and extracted with ethyl acetate (20 mL × 3). The mixture was washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to afford 8-bromo-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromene (326 mg, 68.0% yield).

[0751] MS m / z(ESI):356.9[M+1].

[0752] Step 3

[0753] 2-((4-(2-(4-chloro-2-fluorophenyl)-4-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0754] Using 8-bromo-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromene as the starting material, the fourth, fifth, seventh and eighth steps of Reference Example 1 were used to obtain the product 2-((4-(2-(4-chloro-2-fluorophenyl)-4-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0755] MS m / z(ESI):602.2[M+1].

[0756] 2-((4-(2-(4-chloro-2-fluorophenyl)-4-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxabutane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid is resolved to obtain the product

[0757]

[0758] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 18-A)

[0759] MS m / z(ESI):602.2[M+1].

[0760] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-4-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 18-B).

[0761] MS m / z(ESI):602.2[M+1].

[0762] Example 19

[0763] 2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0764] Using 4-chloro-2-methoxybenzaldehyde as starting material, refer to Example 3 to obtain the product 2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0765] MS m / z(ESI):634.2[M+1].

[0766] 2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was resolved to obtain the product

[0767]

[0768] (R)-2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 19-A)

[0769] MS m / z(ESI):634.2[M+1].

[0770] (S)-2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 19-B).

[0771] MS m / z(ESI):634.2[M+1].

[0772] Example 20

[0773] 2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0774] Using 4-chloro-2-methoxybenzaldehyde as the raw material, refer to Example 4 to obtain the product 2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid.

[0775] MS m / z(ESI):635.2[M+1].

[0776] 2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was resolved to obtain the product

[0777]

[0778] (R)-2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 20-A)

[0779] MS m / z(ESI):635.2[M+1].

[0780] (S)-2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 20-B).

[0781] MS m / z(ESI):635.2[M+1].

[0782] Example 21

[0783] 2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid

[0784] Using 4-chloro-2-methoxybenzaldehyde as raw material, referring to Example 6, the product 2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid was obtained.

[0785] MS m / z(ESI):635.2[M+1].

[0786] 2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid was chirally separated to obtain

[0787]

[0788] (R)-2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (Example 21-A)

[0789] MS m / z(ESI):635.2[M+1].

[0790] (S)-2-((4-(2-(4-chloro-2-methoxyphenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-imidazo[4,5-b]pyridine-6-carboxylic acid (Example 21-B)

[0791] MS m / z(ESI):635.2[M+1].

[0792] Example 22

[0793] 2-((4-(2-(4-Cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0794] Using 3-fluoro-4-(4-fluoro-8-(piperidin-4-yl)-2H-chromen-2-yl)benzonitrile and Im-2 as raw materials, refer to the seventh to eighth steps of Example 1 to obtain the product 2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid.

[0795] MS m / z(ESI):598.2[M+1].

[0796] 2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was chirally separated to obtain

[0797]

[0798] 2-((4-((R)-2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 22-A)

[0799] MS m / z(ESI):598.2[M+1].

[0800] 2-((4-((S)-2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 22-B)

[0801] MS m / z(ESI):598.2[M+1].

[0802] Example 23

[0803] 2-((4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0804] Using 4-chloro-2-(methoxy-d3)benzaldehyde as raw material, referring to Example 2, the product 2-((4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxabutane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained.

[0805] MS m / z(ESI):622.2[M+1].

[0806] 2-((4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was chirally separated to obtain

[0807]

[0808] 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 23-A)

[0809] MS m / z(ESI):622.2[M+1].

[0810] 2-((4-((S)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 23-B)

[0811] MS m / z(ESI):622.2[M+1].

[0812] Example 24

[0813] 2-((4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0814] Using 4-chloro-2-(methoxy-d3)benzaldehyde as raw material, refer to Example 1 to obtain the product 2-((4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxabutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0815] MS m / z(ESI):621.2[M+1].

[0816] 2-((4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was chirally separated to obtain

[0817]

[0818] 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 24-A)

[0819] MS m / z(ESI):621.2[M+1].

[0820] 2-((4-((S)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 24-B)

[0821] MS m / z(ESI):621.2[M+1].

[0822] Example 25

[0823] 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0824]

[0825] first step

[0826] tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-4,4-difluorochroman-8-yl)piperazine-1-carboxylate

[0827] To a mixture of 8-bromo-2-(4-chloro-2-fluorophenyl)-4,4-difluorochromane (1 g, 2.65 mmol), tert-butylpiperazine-1-carboxylate (740 mg, 3.97 mmol), cesium carbonate (2.59 g, 7.95 mmol) and toluene (30 mL) were added tris(dibenzylideneacetone)dipalladium (238 mg, 0.26 mmol) and 4,5-bisdiphenylphosphino-9,9-dimethylxanthene (300 mg, 0.52 mmol). After nitrogen substitution, the mixture was stirred at 80°C for 12 hours. After completion of the reaction, the mixture was cooled and filtered. The filtrate was concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluent to give tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-4,4-difluorochroman-8-yl)piperazine-1-carboxylate (750 mg) in a yield of 58.6%.

[0828] MS m / z(ESI):483.1[M+1].

[0829] Step 2

[0830] 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0831] Using tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-4,4-difluorochromen-8-yl)piperazine-1-carboxylate as starting material, refer to steps 6 to 8 of Example 1 to obtain the product 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0832] MS m / z(ESI):607.1[M+1].

[0833] 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was chirally resolved to obtain

[0834]

[0835] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 25-A)

[0836] MS m / z(ESI):607.1[M+1].

[0837] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 25-B)

[0838] MS m / z(ESI):607.1[M+1].

[0839] Example 26

[0840] 2-((4-(2-(4-chloro-2-fluorophenyl)-2H-benzo[b][1,4]oxazin-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0841]

[0842] first step

[0843] 8-Bromo-2-(4-chloro-2-fluorophenyl)-2H-benzo[b][1,4]oxazine

[0844] 2-Chloro-1-(4-chloro-2-fluorophenyl)ethan-1-one (1 g, 4.83 mmol) and 2-amino-6-bromophenol (908 mg, 4.83 mmol) were dissolved in THF (30 mL). After nitrogen substitution, the mixture was stirred in a microwave oven at 60°C for 2 hours. After completion of the reaction, the mixture was cooled and the filtrate was concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluent to give 8-bromo-2-(4-chloro-2-fluorophenyl)-2H-benzo[b][1,4]oxazine (810 mg) in a yield of 49.2%.

[0845] MS m / z(ESI):340.1[M+1].

[0846] Step 2

[0847] 2-((4-(2-(4-chloro-2-fluorophenyl)-2H-benzo[b][1,4]oxazin-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0848] Using 8-bromo-2-(4-chloro-2-fluorophenyl)-2H-benzo[b][1,4]oxazine as starting material, refer to steps 4 to 8 of Example 1 to obtain the product 2-((4-(2-(4-chloro-2-fluorophenyl)-2H-benzo[b][1,4]oxazin-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxabutane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0849] MS m / z(ESI):589.2[M+1].

[0850] 2-((4-(2-(4-chloro-2-fluorophenyl)-2H-benzo[b][1,4]oxazin-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was chirally resolved to obtain

[0851]

[0852] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-2H-benzo[b][1,4]oxazin-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 26-A)

[0853] MS m / z(ESI):589.2[M+1].

[0854] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-benzo[b][1,4]oxazin-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 26-B)

[0855] MS m / z(ESI):589.2[M+1].

[0856] Example 27

[0857] 2-(((2S)-4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0858] Using 8-bromo-2-(4-chloro-2-fluorophenyl)-4,4-difluorochromene and (S)-2-methylpiperazine-1-carboxylic acid tert-butyl ester as raw materials, reference was made to Example 25 to obtain the product 2-(((2S)-4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxabutane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0859] MS m / z(ESI):621.2[M+1]

[0860] 2-(((2S)-4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was chirally resolved to obtain

[0861]

[0862] 2-(((S)-4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 27-A)

[0863] MS m / z(ESI):621.2[M+1].

[0864] 2-(((S)-4-((S)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)-2-methylpiperazin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 27-B)

[0865] MS m / z(ESI):621.2[M+1].

[0866] Example 28

[0867] 2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0868]

[0869] Using 3-fluoro-4-(4-fluoro-8-(piperidin-4-yl)-2H-chromen-2-yl)benzonitrile and Im-5 as raw materials, refer to the seventh to eighth steps of Example 1 to obtain 2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid.

[0870] MS m / z(ESI):614.2[M+1].

[0871] 2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was chirally separated to obtain

[0872]

[0873] (S)-2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 28-A)

[0874] MS m / z(ESI):614.2[M+1].

[0875] (R)-2-((4-(2-(4-cyano-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 28-B)

[0876] MS m / z(ESI):614.2[M+1].

[0877] Example 29

[0878] 2-((4-(3-(4-chloro-2-fluorophenyl)-4,4-difluorochroman-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0879]

[0880] first step

[0881] (E)-4-Chloro-2-fluoro-1-(2-nitrovinyl)benzene

[0882] 4-Chloro-2-fluorobenzaldehyde (4 g, 25.23 mmol) and nitromethane (14 mL) were dissolved in glacial acetic acid (50 mL). Ammonium acetate (5.83 g, 75.68 mmol) was added and stirred at 110°C for 3 hours. The mixture was cooled and poured into ice water. A solid precipitated and was filtered. The filter cake was purified by silica gel column chromatography using a petroleum ether and ethyl acetate system as eluent to obtain (E)-4-chloro-2-fluoro-1-(2-nitrovinyl)benzene (2.50 g, yield: 49.2%).

[0883] MS m / z(ESI):202.0[M+1].

[0884] Step 2

[0885] 5-Bromo-3-(4-chloro-2-fluorophenyl)chroman-4-one

[0886] To a solution of (E)-4-chloro-2-fluoro-1-(2-nitrovinyl)benzene (451.26 mg, 2.24 mmol), 2-bromo-6-hydroxybenzaldehyde (300 mg, 1.49 mmol), and 4A molecular sieves (400 mg) in dichloromethane (10 mL) was added 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide (37.63 mg, 149.24 μmol), followed by stirring at room temperature for 0.5 hour. 1,4-diazolobicyclo[2.2.2]octane (33.48 mg, 298.48 μmol) was then added dropwise. The mixture was stirred at room temperature under nitrogen for 12 hours, and the mixture was concentrated to dryness under reduced pressure on silica gel. The residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluent to give 5-bromo-3-(4-chloro-2-fluorophenyl)chroman-4-one (90 mg, yield: 16.9%).

[0887] MS m / z(ESI):355.0[M+1].

[0888] Step 3

[0889] 2-((4-(3-(4-chloro-2-fluorophenyl)-4,4-difluorochroman-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0890] Using 5-bromo-3-(4-chloro-2-fluorophenyl)chroman-4-one as the raw material, the product 2-((4-(3-(4-chloro-2-fluorophenyl)-4,4-difluorochroman-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxabutane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained by reference to the third to eighth steps of Example 1.

[0891] MS m / z(ESI):627.2[M+1].

[0892] 2-((4-(3-(4-chloro-2-fluorophenyl)-4,4-difluorochroman-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was chirally resolved to obtain

[0893]

[0894] 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-4,4-difluorochroman-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 29-A)

[0895] MS m / z(ESI):627.2[M+1].

[0896] 2-((4-((R)-3-(4-chloro-2-fluorophenyl)-4,4-difluorochroman-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 29-B)

[0897] MS m / z(ESI):627.2[M+1].

[0898] Example 30

[0899] 2-((4-(3-(4-chloro-2-fluorophenyl)chroman-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0900]

[0901] first step

[0902] 5-Bromo-3-(4-chloro-fluorophenyl)chromane

[0903] To a solution of 5-bromo-3-(4-chloro-2-fluorophenyl)chroman-4-one (500 mg, 1.41 mmol) in trifluoroacetic acid (5 mL) was added triethylsilane (655 mg, 0.9 mL, 5.65 mmol) dropwise, followed by stirring at 60°C for 8 hours, cooling, and quenching the reaction with water. The mixture was extracted with dichloromethane (30 mL × 3), and the organic phase was washed with saturated sodium bicarbonate solution (50 mL × 2) and sodium chloride solution (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent of petroleum ether and ethyl acetate to give 5-bromo-3-(4-chloro-2-fluorophenyl)chroman as a light yellow solid (230 mg, yield: 47.8%).

[0904] MS m / z(ESI):340.9[M+1].

[0905] Step 2

[0906] 2-((4-(3-(4-chloro-2-fluorophenyl)chroman-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0907] Using 5-bromo-3-(4-chloro-2-fluorophenyl)chromane as a raw material, as a raw material, refer to the fourth to eighth steps of Example 1 to obtain 2-((4-(3-(4-chloro-2-fluorophenyl)chromane-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxabutane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0908] MS m / z(ESI):591.2[M+1].

[0909] 2-((4-(3-(4-chloro-2-fluorophenyl)chroman-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was chirally separated to obtain

[0910]

[0911] 2-((4-((S)-3-(4-chloro-2-fluorophenyl)chroman-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 30-A)

[0912] MS m / z(ESI):591.2[M+1].

[0913] 2-((4-((R)-3-(4-chloro-2-fluorophenyl)chroman-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 30-B)

[0914] MS m / z(ESI):591.2[M+1].

[0915] Example 31

[0916] 2-((4-(3-(4-chloro-2-fluorophenyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0917]

[0918] first step

[0919] tert-Butyl 4-(3-hydroxy-2-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0920] 3-Bromo-2-nitrophenol (2 g, 9.17 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylate (2.84 g, 9.17 mmol), sodium carbonate (1.94 g, 18.34 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (335.48 mg, 458.5 μmol) were dissolved in 1,4-dioxane (20 mL) and water (3 mL), and the reaction was stirred at 80 ° C for 6 hours. 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined and washed sequentially with saturated sodium bicarbonate solution (5 mL × 2), saturated ammonium chloride solution (5 mL × 2), and saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent of petroleum ether and ethyl acetate to give the title product, tert-butyl 4-(3-hydroxy-2-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (2.3 g, yellow solid) in a yield of 78.3%.

[0921] MS m / z(ESI):321.1[M+1]

[0922] Step 2

[0923] tert-Butyl 4-(3-(2-(4-chloro-2-fluorophenyl)-2-carbonylethoxy)-2-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate

[0924] Dissolve tert-butyl 4-(3-hydroxy-2-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (2.30 g, 7.18 mmol), 2-chloro-1-(4-chloro-2-fluorophenyl)ethane-1-one (1.49 g, 7.18 mmol), and potassium carbonate (1.98 g, 14.36 mmol) in toluene (20 mL) and stir the reaction at 80 °C for 2 hours. 20 mL of water was added to the reaction solution, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined and washed sequentially with saturated sodium bicarbonate solution (5 mL × 2), saturated ammonium chloride solution (5 mL × 2), and saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent of petroleum ether and ethyl acetate to give the title product, tert-butyl 4-(3-(2-(4-chloro-2-fluorophenyl)-2-carbonylethoxy)-2-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (3.1 g, yellow solid) in a yield of 87.9%.

[0925] MS m / z(ESI):491.1[M+1]

[0926] Step 3

[0927] tert-Butyl 4-(3-(4-chloro-2-fluorophenyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[0928] Dissolve tert-butyl 4-(3-(2-(4-chloro-2-fluorophenyl)-2-carbonylethoxy)-2-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (3.10 g, 6.31 mmol) and paraformaldehyde (1.13 g, 12.62 mmol) in 30 mL of methanol and 10 mL of water, add palladium / carbon (310 mg, 10%), replace the atmosphere with hydrogen three times, and stir the reaction for 12 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography using a petroleum ether and ethyl acetate system as eluent to give the title product, tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.30 g, yellow oil) in a yield of 44.9%.

[0929] MS m / z(ESI):459.1[M+1]

[0930] Step 4

[0931] 2-((4-(3-(4-chloro-2-fluorophenyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0932] Using tert-butyl 4-(3-(4-chloro-2-fluorophenyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)-3,6-dihydropyridine-1(2H)-carboxylate as the raw material, the product 2-((4-(3-(4-chloro-2-fluorophenyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxabutane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained in the fifth to eighth steps of Reference Example 1.

[0933] MS m / z(ESI):606.2[M+1]

[0934] 2-((4-(3-(4-chloro-2-fluorophenyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxabutan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was chirally resolved to obtain

[0935]

[0936] 2-((4-((S)-3-(4-chloro-2-fluorophenyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 31-A)

[0937] MS m / z(ESI):606.2[M+1]

[0938] 2-((4-((R)-3-(4-chloro-2-fluorophenyl)-4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-5-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 31-B)

[0939] MS m / z(ESI):606.2[M+1]

[0940] Example 32

[0941] 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0942]

[0943] first step

[0944] 2-(Chloromethyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester

[0945] Using 6-fluoro-5-nitromethylpyridine acid methyl ester and 2-(1-(aminomethyl)cyclopropyl)acetonitrile as raw materials, referring to the synthesis of Im-2, the product 2-(chloromethyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester was finally obtained.

[0946] MS m / z(ESI):319.0[M+1]

[0947] Step 2: 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0948] Using 2-(chloromethyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester and 4-[2-(4-chloro-2-fluoro-phenyl)-4-fluoro-2H-chromen-8-yl]piperidine as raw materials, the synthesis of the product 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained by reference to the seventh and eighth steps of Example 1.

[0949] MS m / z(ESI):630.2[M+1]

[0950] 2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was chirally resolved to obtain

[0951]

[0952] (R)-2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 32-A)

[0953] MS m / z(ESI):630.2[M+1]

[0954] (S)-2-((4-(2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(cyanomethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 32-B)

[0955] MS m / z(ESI):630.2[M+1]

[0956] Example 33

[0957] 2-((4-(2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0958]

[0959] first step

[0960] (E)-2-Bromo-6-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl)phenol

[0961] (E)-1-(3-Bromo-2-hydroxyphenyl)-3-(4-chloro-2-fluorophenyl)prop-2-en-1-one (500 mg, 1.41 mmol) was dissolved in methanol (15 mL), and sodium borohydride (64 mg, 1.69 mmol) was added. The mixture was stirred at room temperature for 2 hours, and the reaction was quenched by adding water. The mixture was extracted with dichloromethane (30 mL × 3), washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluent to obtain (E)-2-bromo-6-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl)phenol (454 mg, yield: 90.0%).

[0962] MS m / z(ESI):356.9[M+1].

[0963] Step 2

[0964] 8-Bromo-2-(4-chloro-2-fluorophenyl)-2H-chromene

[0965] (E)-2-Bromo-6-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl)phenol (300 mg, 0.84 mmol) was dissolved in dichloromethane (10 mL), and p-toluenesulfonic acid (29 mg, 0.17 mmol) was added. The mixture was stirred at room temperature for 2 hours, and the reaction was quenched by adding water. The mixture was extracted with dichloromethane (30 mL × 3), washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluent to give (8-bromo-2-(4-chloro-2-fluorophenyl)-2H-chromene (200 mg, yield: 70.1%).

[0966] MS m / z(ESI):338.9[M+1].

[0967] Step 3

[0968] 8-Bromo-2-(4-chloro-2-fluorophenyl)chroman-3-ol

[0969] 8-Bromo-2-(4-chloro-2-fluorophenyl)-2H-chromene (200 mg, 0.59 mmol) was dissolved in THF (10 mL), and a THF solution of borane (0.71 mL, 0.71 mmol) was added. The mixture was stirred at 0°C for 1 hour, and 2 mL of water was added, followed by the addition of NaOH (71 mg, 1.77 mmol) and 0.1 mL of hydrogen peroxide solution. The mixture was stirred at 40°C for 2 hours. The reaction was quenched by adding 10 mL of water, extracted with dichloromethane (30 mL × 3), washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with a petroleum ether and ethyl acetate system as eluent to give 8-bromo-2-(4-chloro-2-fluorophenyl)chromen-3-ol (63 mg, yield: 29.8%).

[0970] MS m / z(ESI):356.9[M+1].

[0971] Step 4

[0972] 8-Bromo-2-(4-chloro-2-fluorophenyl)chroman-3-one

[0973] 8-Bromo-2-(4-chloro-2-fluorophenyl)chroman-3-ol (500 mg, 1.40 mmol) was dissolved in DCM (20 mL), and Dess-Martin periodinane (0.71 mL, 1.67 mmol) was added. The mixture was stirred at 0°C for 1 hour. The reaction was quenched by adding 10 mL of water, extracted with dichloromethane (30 mL × 3), washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluent to give 8-bromo-2-(4-chloro-2-fluorophenyl)chroman-3-one (448 mg, yield: 89.9%).

[0974] MS m / z(ESI):354.9[M+1].

[0975] Step 5

[0976] tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-3,3-difluorochroman-8-yl)piperidine-1-carboxylate

[0977] Using 8-bromo-2-(4-chloro-2-fluorophenyl)chroman-3-one as the raw material, the product tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-3,3-difluorochroman-8-yl)piperidine-1-carboxylate was obtained by reference to the third to fifth steps of Example 1.

[0978] MS m / z(ESI):482.2[M+1].

[0979] Step 6

[0980] 4-(2-(4-Chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl)piperidine

[0981] Using tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-3,3-difluorochromene-8-yl)piperidine-1-carboxylate as raw material, the product 4-(2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromene-8-yl)piperidine was obtained in the sixth step of Example 1.

[0982] MS m / z(ESI):362.1[M+1].

[0983] Step 7

[0984] 2-((4-(2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0985] Using 4-(2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl)piperidine as the raw material, the product 2-((4-(2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxabutane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was obtained by reference to the seventh and eighth steps of Example 1.

[0986] MS m / z(ESI):607.1[M+1].

[0987] Chiral separation of 2-((4-(2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0988]

[0989] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 33-A)

[0990] MS m / z(ESI):607.1[M+1].

[0991] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 33-B)

[0992] MS m / z(ESI):607.1[M+1].

[0993] Example 34

[0994] 2-((4-(2-(4-cyano-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0995] Using 4-formyl-3-hydroxybenzonitrile as the starting material, the product 2-((4-(2-(4-cyano-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxabutane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by reference to Example 24.

[0996] MS m / z(ESI):612.2[M+1].

[0997] 2-((4-(2-(4-cyano-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was chirally resolved to obtain

[0998]

[0999] 2-((4-((R)-2-(4-cyano-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 34-A)

[1000] MS m / z(ESI):612.2[M+1].

[1001] 2-((4-((S)-2-(4-cyano-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (Example 34-B)

[1002] MS m / z(ESI):612.2[M+1].

[1003] Example 35

[1004] 2-((4-(2-(4-cyano-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[1005] Using 4-formyl-3-hydroxybenzonitrile as the raw material, refer to Example 20 to obtain the product 2-((4-(2-(4-cyano-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[1006] MS m / z(ESI):629.2[M+1].

[1007] 2-((4-(2-(4-cyano-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid was chirally resolved to obtain

[1008]

[1009] (R)-2-((4-(2-(4-cyano-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 35-A)

[1010] MS m / z(ESI):629.2[M+1].

[1011] (S)-2-((4-(2-(4-cyano-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-((1-(fluoromethyl)cyclopropyl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (Example 35-B)

[1012] MS m / z(ESI):629.2[M+1].

[1013] Example 36

[1014] 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[1015]

[1016] first step

[1017] 1-(4-chloro-2-(methoxy-d3)phenyl)ethan-1-one

[1018] 1-(4-chloro-2-hydroxyphenyl)ethan-1-one 36a (15 g, 87.93 mmol), deuterated iodomethane (16.57 g, 114.31 mmol), and anhydrous potassium carbonate (36.46 g, 0.26 mol) were dispersed in DMF (150 mL). The reaction solution was heated to 50°C and stirred vigorously for 12 hours. The reaction was terminated, filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product, 1-(4-chloro-2-(methoxy-d3)phenyl)ethan-1-one 36b (15 g), in a 90.9% yield.

[1019] MS m / z(ESI):188.1[M+1].

[1020] Step 2

[1021] tert-Butyl-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)-3-hydroxybutyryl)-2-hydroxyphenyl)piperidine-1-carboxylate

[1022] Dissolve tert-butyl-4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate Im-7 (25 g, 79.94 mmol) in tetrahydrofuran (300 mL). Cool the solution in a dry ice / ethanol bath, then slowly add LiHMDS (18.4 mL, 0.184 mol, 1 M in THF) and stir for 30 minutes. Dissolve 1-(4-chloro-2-(methoxy-d3)phenyl)ethan-1-one 36b (15 g, 79.94 mmol) in THF (30 mL) and slowly add this solution dropwise to the reaction mixture. Maintain the dry ice / ethanol bath temperature and stir for 40 minutes. The reaction was stopped and the dry ice / ethanol bath was removed. Saturated ammonium chloride solution was added to the reaction solution to quench the reaction, and the mixture was extracted with ethyl acetate (300 mL×2). The organic phases were combined, washed with saturated sodium chloride (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to give the title product, tert-butyl-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)-3-hydroxybutyryl)-2-hydroxyphenyl)piperidine-1-carboxylate 36c (31 g) in a yield of 76.5%.

[1023] MS m / z(ESI):507.2[M+1].

[1024] Step 3

[1025] tert-Butyl-4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidine-1-carboxylate

[1026] Tert-butyl-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)-3-hydroxybutyryl)-2-hydroxyphenyl)piperidine-1-carboxylate 36c (2.00 g, 4.07 mmol) and BAST (10 mL) were dissolved in DMF (10 mL). Ethanol (20 μL) was then added to the reaction solution and the reaction was stirred for 4 hours. The reaction was stopped and the reaction solution was slowly added to ice water to quench the mixture. The mixture was extracted with ethyl acetate (50 mL×2). The organic phases were combined, washed with water (100 mL), washed with saturated sodium bicarbonate (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluent to give the title product, tert-butyl-4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidine-1-carboxylate 36d (750 mg) in a yield of 38.7%.

[1027] MS m / z(ESI):491.2[M+1].

[1028] Step 4

[1029] 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidine

[1030] Tert-butyl-4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidine-1-carboxylate 36d (750 mg, 1.53 mmol), boron trifluoride etherate (543 mg, 3.83 mmol), and powdered 4 molecular sieves (750 mg) were dispersed in dichloromethane (10 mL) and stirred at 0°C for 3 hours. The reaction was stopped and quenched by adding saturated sodium bicarbonate solution. The mixture was filtered through celite, the filtrate was allowed to stand, the organic layer was separated, the aqueous layer was extracted with dichloromethane (20 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system of dichloromethane and methanol to give the title product 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidine 36e (490 mg) in a yield of 82.1%.

[1031] MS m / z(ESI):391.2[M+1].

[1032] Step 5

[1033] Methyl 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate

[1034] Disperse 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidine 36e (490 mg, 1.25 mmol), methyl (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate Im-2 (371 mg, 1.25 mmol), and anhydrous potassium carbonate (518 mg, 3.75 mmol) in acetonitrile (8 mL). Heat the reaction mixture to 50°C and stir vigorously for 3 hours. The reaction was stopped, and the reaction solution was cooled to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with ethyl acetate as eluent. The purified sample was then subjected to chiral HPLC preparative separation to give the title product, methyl 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 36f (210 mg) in a yield of 26.5%.

[1035] MS m / z(ESI):632.2[M+1].

[1036] Step 6

[1037] 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[1038] Methyl 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 36f (210 mg, 332.19 μmol) and lithium hydroxide (133 mg, 3.32 mmol) were dissolved in 9 mL of a mixed solvent of THF, water, and methanol (4:4:1) and stirred for 3 hours. The reaction was stopped, and formic acid was added to adjust the pH to 6. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give the title product 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 36 (170 mg) in a yield of 82.8%.

[1039] MS m / z(ESI):618.2[M+1].

[1040] 1 H NMR(400MHz,MeOD)δ8.16–7.97(m,2H),7.29(d,J=8.2Hz,1H),7.08–6.98(m,2H),6.94–6.85(m ,2H),6.81(t,J=7.5Hz,1H),6.57(d,J=9.8Hz,1H),5.78(d,J=9.8Hz,1H),5.25(dd,J=7.5,3.0 Hz,1H),4.96(dd,J=14.9,6.7Hz,1H),4.83(dd,J=14.9,3.1Hz,1H),4.66–4.53(m,1H),4.48–4 .35(m,1H),4.25(d,J=14.2Hz,1H),4.16(d,J=14.2Hz,1H),3.25(d,J=11.5Hz,1H),3.12(d,J= 11.5Hz,1H),2.91(s,1H),2.83–2.70(m,1H),2.61–2.41(m,3H),1.85(q, J=3.9Hz,2H),1.78(s,3H),1.68(d,J=3.7Hz,1H),1.59(d,J=14.9Hz,1H).

[1041] Example 37

[1042] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[1043]

[1044] Using tert-butyl 4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate Im-7 and 1-(4-chloro-2-fluorophenyl)ethan-1-one as starting materials, the second to sixth steps of Reference Example 36 were used to obtain 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 37.

[1045] MS m / z(ESI):621.2[M+1].

[1046] Example 38

[1047] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[1048]

[1049] first step

[1050] tert-Butyl-4-(3-(3-(4-chloro-2-fluorophenyl)-3-hydroxybutyryl)-2-hydroxyphenyl)piperidine-1-carboxylate

[1051] Referring to the synthesis method of Example 37, 1-(4-chloro-2-fluorophenyl)ethane-1-one 38a (5 g, 28.97 mmol), Im-7 (9.25 g, 28.97 mmol), LiHMDS (66.6 mL, 66.63 mmol) and THF (100 mL) were added to obtain the title product tert-butyl-4-(3-(3-(4-chloro-2-fluorophenyl)-3-hydroxybutyryl)-2-hydroxyphenyl)piperidine-1-carboxylate 41b (7.60 g) in a yield of 53.3%.

[1052] MS m / z(ESI):492.2[M+1].

[1053] Step 2

[1054] 2-(4-Chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chroman-4-one

[1055] Tert-butyl-4-(3-(3-(4-chloro-2-fluorophenyl)-3-hydroxybutyryl)-2-hydroxyphenyl)piperidine-1-carboxylate 38b (5 g, 10.16 mmol) and p-toluenesulfonic acid (5.25 g, 30.48 mmol) were dissolved in toluene (50 mL). The reaction solution was heated to 100°C and stirred for 5 hours. The reaction was stopped and cooled to room temperature. 2M sodium hydroxide solution was added to quench the reaction. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using dichloromethane and methanol as eluent to afford the title product, 2-(4-chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chroman-4-one 38c (2.36 g) in a 62.1% yield.

[1056] MS m / z(ESI):374.1[M+1].

[1057] Step 3

[1058] 2-(4-Chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chromen-4-ol

[1059] 2-(4-chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chromen-4-one 38c (2 g, 5.35 mmol) was dissolved in methanol (30 mL). Sodium borohydride (396 mg, 10.70 mmol) was slowly added portionwise to the solution under an ice bath. After the addition was complete, the ice bath was removed and the reaction mixture was allowed to warm to ambient temperature for 2 hours. The reaction was stopped and quenched by the addition of saturated ammonium chloride solution. The pH was adjusted to 10 with 1 M sodium hydroxide solution and the mixture was extracted with dichloromethane (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to afford the title product, 2-(4-chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chromen-4-ol 38d (1.88 g) in a 93.5% yield. This compound was used directly in the next reaction without further purification.

[1060] MS m / z(ESI):376.1[M+1].

[1061] Step 4

[1062] 4-(2-(4-Chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidine

[1063] 2-(4-chloro-2-fluorophenyl)-2-methyl-8-(piperidin-4-yl)chromen-4-ol 38d (1.50 g, 3.99 mmol) and p-toluenesulfonic acid (2.06 g, 11.97 mmol) were dissolved in toluene (20 mL). The reaction solution was heated to 100°C and stirred for 30 minutes. The reaction was stopped and cooled to room temperature. 2M sodium hydroxide solution was added to quench the reaction. The organic layer was separated, and the aqueous layer was extracted with dichloromethane (30 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product, 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidine 38e (1.02 g) in a yield of 71.4%. This compound was used directly in the next reaction without further purification.

[1064] MS m / z(ESI):358.1[M+1].

[1065] Step 5

[1066] Methyl 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate

[1067] Referring to the synthesis method of the fifth step of Example 37, 4-(2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidine 38e (500 mg, 1.40 mmol), methyl (S)-2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate Im-2 (413 mg, 1.40 mmol), anhydrous carbonic acid and the like were added. The title product, methyl 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 41f (263 mg), was obtained in a yield of 30.5%.

[1068] MS m / z(ESI):617.2[M+1].

[1069] Step 6

[1070] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[1071] Referring to the synthesis method of the sixth step of Example 37, methyl 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 38f (100 mg, 162 μmol) and lithium hydroxide (39 mg, 1.62 mmol) were added to give the title product 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 38 (76 mg) in a yield of 77.8%.

[1072] MS m / z(ESI):603.2[M+1].

[1073] Example 39

[1074] 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1075]

[1076] Referring to the synthetic method of Example 36, Im-1 was used as the starting material to obtain the title product 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2-methyl-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxabutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[1077] MS m / z(ESI):617.3[M+1].

[1078] Example 40

[1079] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[1080]

[1081] first step

[1082] 4-Chloro-2-fluoro<α-2H>benzaldehyde

[1083] 4-Chloro-2-fluoro-1-iodobenzene (5 g, 19.50 mmol) and toluene (50 mL) were added to a 100 mL flask. Isopropyl magnesium chloride (12.9 mL, 3 M, 38.99 mmol) was added at -30°C, and the reaction mixture was allowed to react at -20°C for 2 h. N,N-dimethylformamide-D7 (3.12 g, 38.99 mmol) was then added to the reaction mixture, and the reaction was continued at 0°C for 1 h. The reaction was terminated and quenched with saturated aqueous ammonium chloride. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The resulting residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to afford the title product, 4-chloro-2-fluoro<α-2H>benzaldehyde 40b (2.7 g), in an 86.79% yield.

[1084] MS m / z(ESI):160.0[M+1].

[1085] Step 2

[1086] tert-Butyl 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl-3-d-3-d-2-hydroxyphenyl)piperidine-1-carboxylate

[1087] 4-Chloro-2-fluoro<α-2H>benzaldehyde 40b (1.5 g, 9.40 mmol), tert-butyl 4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate Im-7 (3.00 g, 9.40 mmol) and tetrahydrofuran (40 mL) were added to a 100 mL flask, and sodium hydride (1.13 g, 28.20 mmol, 60% purity) was added at 0°C, and the reaction solution was reacted at 25°C for 3 h. The reaction was stopped, and the reaction solution was quenched with saturated aqueous ammonium chloride solution, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluent to give the title product, tert-butyl 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 40c (3 g) in a yield of 69.23%.

[1088] MS m / z(ESI):461.1[M+1].

[1089] Step 3

[1090] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[1091] Using tert-butyl 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 40c as starting material, the synthesis method of steps 3 to 6 of Example 36 was used to obtain 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 40.

[1092] MS m / z(ESI):608.1[M+1].

[1093] 1 H NMR(400MHz,DMSO-d6)δ8.10(d,1H),7.97(d,1H),7.54(dd,1H),7.41(t,1H),7.29(dd,1H),7.24–7.15 (m,2H),6.96(t,1H),5.67(d,1H),5.20–5.11(m,1H),4.88–4.79(m,1H),4.74–4.65(m,1H),4.53–4.43 (m,1H),4.41–4.31(m,1H),3.97(d,1H),3.88(d,1H),2.98–2.91(m,1H),2.87–2.79(m,1H),2.75–2.62 (m,2H),2.49–2.41(m,1H),2.25–2.07(m,2H),1.73–1.59(m,2H),1.54–1.41(m,1H),1.37–1.29(m,1H).

[1094] Example 41

[1095] 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[1096]

[1097] first step

[1098] 1-Bromo-4-chloro-2-(methoxy-d3)benzene

[1099] Using 2-bromo-5-chlorophenol 41a as starting material, 1-bromo-4-chloro-2-(methoxy-d3)benzene 41b was obtained by referring to the synthesis method of the first step of Example 36.

[1100] MS m / z(ESI):223.9[M+1].

[1101] Step 2

[1102] 4-Chloro-2-(methoxy-d3)<α-2H>benzaldehyde

[1103] Using 1-bromo-4-chloro-2-(methoxy-d3)benzene 41b as starting material, the synthesis method of the first step of Example 40 was referred to obtain 4-chloro-2-(methoxy-d3)<α-2H>benzaldehyde 41c.

[1104] MS m / z(ESI):175.0[M+1].

[1105] Step 3

[1106] tert-Butyl 4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate

[1107] Using 4-chloro-2-(methoxy-d3)<α-2H>benzaldehyde 41c as starting material, the synthesis method of the second step of reference Example 40 was used to obtain tert-butyl 4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 41d.

[1108] MS m / z(ESI):476.2[M+1].

[1109] Step 4

[1110] 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[1111] Using tert-butyl 4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 41d as raw material, the synthesis method of the third to sixth steps of Example 36 was used to obtain

[1112] 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 41.

[1113] MS m / z(ESI):623.2[M+1].

[1114] 1 H NMR(400MHz,Methanol-d4)δ8.14–8.04(m,2H),7.31(d,1H),7.20–7.13(m,2H),7.05(d,1H),6.96– 6.87(m,2H),5.36(d,1H),5.29–5.24(m,1H),5.03–4.93(m,1H),4.82–4.75(m,1H),4.65–4.55(m,1H ),4.45–4.36(m,1H),4.20(d,1H),4.10(d,1H),3.23–3.15(m,1H),3.09–3.02(m,1H),2.91–2.86(m, 1H),2.81–2.72(m,1H),2.57–2.37(m,3H),1.88–1.78(m,2H),1.71–1.63(m,1H),1.59–1.52(m,1H).

[1115] Example 42

[1116] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[1117]

[1118] first step

[1119] 4-Chloro-2-fluoro<α-2H>benzaldehyde

[1120] 4-Chloro-2-fluoro-1-iodo-benzene 42a (5 g, 19.50 mmol) and toluene (50 mL) were added to a 100 mL flask. Isopropyl magnesium chloride (12.9 mL, 3 M, 38.99 mmol) was added at -30°C, and the reaction mixture was allowed to react at -20°C for 2 h. N,N-dimethylformamide-D7 (3.12 g, 38.99 mmol) was then added to the reaction mixture, and the reaction was continued at 0°C for 1 h. The reaction was terminated and quenched with saturated aqueous ammonium chloride. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The resulting residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to afford the title product, 4-chloro-2-fluoro<α-2H>benzaldehyde 42b (2.7 g), in an 86.79% yield.

[1121] MS m / z(ESI):160.0[M+1].

[1122] Step 2

[1123] tert-Butyl 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl-3-d-3-d-2-hydroxyphenyl)piperidine-1-carboxylate

[1124] 4-Chloro-2-fluoro<α-2H>benzaldehyde 42b (1.5 g, 9.40 mmol), tert-butyl 4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate Im-7 (3.00 g, 9.40 mmol) and tetrahydrofuran (40 mL) were added to a 100 mL flask, and sodium hydride (1.13 g, 28.20 mmol, 60% purity) was added at 0°C, and the reaction solution was reacted at 25°C for 3 h. The reaction was stopped, and the reaction solution was quenched with saturated aqueous ammonium chloride solution, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL×3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluent to give the title product, tert-butyl 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 42c (3 g) in a yield of 69.23%.

[1125] MS m / z(ESI):461.1[M+1].

[1126] Step 3

[1127] tert-Butyl 4-(3-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate

[1128] Tert-butyl 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 42c (3 g, 6.51 mmol) and isopropanol (50 mL) were added to a 250 mL flask, and sodium borohydride (369.33 mg, 9.76 mmol) was added at 0°C. The reaction solution was then reacted at 20°C for 3 hours. The reaction was stopped and quenched with water (10 mL). The mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and dried to give the title product, tert-butyl 4-(3-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 42d (3 g), in a yield of 99.56%.

[1129] MS m / z(ESI):463.1[M+1].

[1130] Step 4

[1131] tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidine-1-carboxylate

[1132] Tert-butyl 4-(3-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 42d (3 g, 6.48 mmol) and N,N-dimethylformamide (30 mL) were added to a 100 mL flask, and p-toluenesulfonic acid (1.67 g, 9.72 mmol) was added at 25°C. The reaction mixture was then reacted at 50°C for 4 hours. The reaction was stopped, and the reaction solution was quenched with water (20 mL), extracted with ethyl acetate (20 mL×3), and the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluent to obtain the title product, tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidine-1-carboxylate 42e (1.7 g), in a yield of 58.96%.

[1133] MS m / z(ESI):445.1[M+1].

[1134] Step 5

[1135] 4-(2-(4-Chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidine

[1136] Tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidine-1-carboxylate 42e (1.7 g, 3.82 mmol) and dichloromethane (25 mL) were added to a 100 mL flask. 4A molecular sieves (1.7 g) and boron trifluoride etherate (1.36 g, 9.55 mmol) were added at 0°C. The reaction mixture was then allowed to react at 0°C for 2 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL), water (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and dried to afford the title product, 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidine 42f (1.3 g), in a yield of 98.67%.

[1137] MS m / z(ESI):345.1[M+1]

[1138] Step 6

[1139] 2-((4-(-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester

[1140] 4-(2-(4-Chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidine 42f (1.3 g, 3.77 mmol) and acetonitrile (15 mL) were added to a 100 mL flask, followed by potassium carbonate (1.04 g, 7.54 mmol) and (S)-methyl 2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate Im2 (1.11 g, 3.77 mmol) at 25°C. The reaction mixture was then stirred at 25°C for 10 hours. The reaction was stopped, and the reaction solution was quenched with aqueous solution (10 mL), extracted with dichloromethane (10 mL×3), and the organic phase was washed with saturated sodium chloride solution (10 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to give the title product, 2-((4-(-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester, 42 g (1.7 g), yield: 74.65%.

[1141] MS m / z(ESI):604.2[M+1]

[1142] Step 7

[1143] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester

[1144] 42 g of methyl 2-((4-(-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate was chirally resolved to obtain

[1145] Methyl 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 42h.

[1146] Split condition: DH 4.6*250

[1147] Hexane:EtOH:MeOH:DEA=70:15:15:0.1%

[1148] F=1mL T=35℃

[1149] Step 8

[1150] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[1151] Methyl 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 42h (100 mg, 165.54 μmol) and methanol (2 mL) were added to a 25 mL flask. Lithium hydroxide (39.64 mg, 1.66 mmol) was dissolved in water (1 mL) and added dropwise to the reaction solution at 25°C. The reaction solution was then reacted at 25°C for 1 hour. The reaction was stopped, and the reaction solution was quenched with formic acid (0.1 mL), added with water (2 mL), and extracted with dichloromethane (2 mL×3). The organic phase was washed with saturated sodium chloride solution (2 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by prep-HPLC to give the title product, 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxabutan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 42 (70 mg), yield: 71.66%.

[1152] MS m / z(ESI):590.2[M+1]

[1153] 1 H NMR(400MHz,DMSO)δ8.08(d,1H),7.96(d,1H),7.52(dd,1H),7.34(t,1H),7.27(dd,1H),7.05(dd,1H),6.98 (dd,1H),6.85(t,1H),6.75(d,1H),5.91(d,1H),5.18–5.11(m,1H),4.87–4.80(m,1H),4.72–4.65(m,1H),4 .53–4.43(m,1H),4.39–4.31(m,1H),3.96(d,1H),3.87(d,1H),3.01–2.90(m,1H),2.89–2.79(m,1H),2.77– 2.61(m,2H),2.48–2.45(m,1H),2.27–2.08(m,2H),1.73–1.61(m,2H),1.54–1.42(m,1H),1.42–1.34(m,1H).

[1154] Example 43

[1155] 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[1156]

[1157] first step

[1158] 1-Bromo-4-chloro-2-(methoxy-d3)benzene

[1159] 2-Bromo-5-chlorophenol 43a (10 g, 48.20 mmol), deuterated iodomethane (10.48 g, 72.30 mmol), and anhydrous potassium carbonate (13.33 g, 96.41 mol) were dispersed in DMF (100 mL). The reaction solution was heated to 50°C and stirred vigorously for 12 hours. The reaction was terminated, filtered through celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product, 1-bromo-4-chloro-2-(methoxy-d3)benzene 43b (10 g), in a 92.5% yield.

[1160] MS m / z(ESI):223.9[M+1].

[1161] Step 2

[1162] 4-Chloro-2-(methoxy-d3)benzaldehyde-d

[1163] 1-Bromo-4-chloro-2-(methoxy-d3)benzene 43b (1.6 g, 7.13 mmol) was dissolved in tetrahydrofuran (30 mL). After purging with nitrogen, n-BuLi (2.5 M, 3.42 mL) was slowly added dropwise at -78°C. After complete addition, stirring was maintained at -78°C for 1 hour, followed by the dropwise addition of N,N-dimethylformamide-d7 (856.71 mg, 10.69 mmol). The reaction system was stirred for 3 hours and allowed to warm to room temperature. Saturated ammonium chloride solution (20 mL) was slowly added dropwise to quench the reaction. The product was then extracted with ethyl acetate (30 mL x 3), washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to afford 4-chloro-2-(methoxy-d3)-benzaldehyde-d43c (1.2 g, 6.87 mmol) as a white solid in a 96.42% yield.

[1164] MS m / z(ESI):175.0[M+1].

[1165] Step 3

[1166] tert-Butyl (E)-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate

[1167] 4-Chloro-2-(methoxy-d3)-benzaldehyde-d43c (700 mg, 4.01 mmol) and tert-butyl-4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate Im-7 (1.28 g, 4.01 mmol) were dissolved in tetrahydrofuran (40 mL). Sodium hydride (481.05 mg, 12.03 mmol, 60% purity) was added portionwise in an ice-water bath. The reaction system was stirred in an ice-water bath for 0.5 hour and then stirred at room temperature (20°C) for 2.5 hours. After completion, water (20 mL) was added dropwise to quench the reaction. The mixture was extracted with ethyl acetate (30 mL x 3), washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography using a system of petroleum ether and ethyl acetate as eluent to give the title product, tert-butyl (E)-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 43d (1.5 g). Yield: 78.6%

[1168] MS m / z(ESI):476.2[M+1].

[1169] Step 4

[1170] tert-Butyl (E)-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)-1-hydroxyallyl-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate

[1171] Tert-butyl (E)-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)acryloyl-3-d-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 43d (1.4 g, 2.94 mmol) was dissolved in tetrahydrofuran (30 mL), and sodium borohydride (333.82 mg, 8.82 mmol) was added thereto in batches at room temperature. The reaction system was stirred at room temperature for 2 hours. After the reaction was completed, water (20 mL) was added dropwise to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL x 3), washed with saturated brine (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the title product tert-butyl

[1172] (E)-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)-1-hydroxyallyl-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 43e (1.4 g).

[1173] MS m / z(ESI):478.2[M+1].

[1174] Step 5

[1175] tert-Butyl 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidine-1-carboxylate

[1176] Tert-butyl (E)-4-(3-(3-(4-chloro-2-(methoxy-d3)phenyl)-1-hydroxyallyl-3-d)-2-hydroxyphenyl)piperidine-1-carboxylate 43e (1.40 g, 2.93 mmol) was dissolved in dichloromethane (20 mL), and p-toluenesulfonic acid (151.62 mg, 880.49 μmol) was added. The reaction system was stirred at room temperature for 3 hours. After the reaction was completed, the solvent was directly concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product, tert-butyl 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidine-1-carboxylate 43f (600 mg, 1.30 mmol) in a yield of 44.4%.

[1177] MS m / z(ESI):460.2[M+1].

[1178] Step 6

[1179] 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidine

[1180] Tert-butyl 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidine-1-carboxylate 43f (260 mg, 565.22 μmol) was dissolved in dichloromethane (10 mL) and 4A was added thereto in an ice-water bath. o The reaction mixture was stirred in an ice-water bath for 1 hour. After completion, a saturated sodium bicarbonate solution (10 mL) was added dropwise to quench the reaction. The mixture was extracted with dichloromethane (20 mL x 3), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain 43 g (200 mg) of crude 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidine.

[1181] MS m / z(ESI):360.2[M+1].

[1182] Step 7

[1183] Methyl 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate

[1184] Dissolve 43 g (200 mg, 555.74 μmol, crude) of 4-(2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidine, (S)-methyl 2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate Im-2 (180.17 mg, 611.31 μmol), and potassium carbonate (230.42 mg, 1.67 mmol) in acetonitrile (10 mL). Stir the reaction system in an oil bath at 60°C for 4 hours. After completion, dilute the reaction solution with water (10 mL), extract with ethyl acetate (20 mL x 3), wash with saturated brine (20 mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate to obtain the crude product. The crude product was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents, and the purified sample was then subjected to chiral HPLC preparative separation to give the title product, methyl 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 43h (100 mg, 161.5 μmol) in a yield of 29.1%.

[1185] MS m / z(ESI):619.2[M+1].

[1186] Step 8

[1187] 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[1188] Methyl 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate 43h (100 mg, 161.5 μmol) and lithium hydroxide (38.8 mg, 1.62 mmol) were dissolved in 9 mL of a mixed solvent of THF, water and methanol (4:4:1) and stirred for 3 hours. The reaction was stopped, and formic acid was added to adjust the pH to 6. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC to give the title product 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 43 (60 mg) in a yield of 61.5%.

[1189] MS m / z(ESI):605.2[M+1].

[1190] 1 H NMR (400MHz, DMSO) δ8.08(d,1H),7.96(d,1H),7.22(d,1H),7.14(d,1H),7.02(d,1H),6.99–6.91( m,2H),6.82(t,1H),6.66(d,1H),5.86(d,1H),5.17–5.11(m,1H),4.86–4.77(m,1H),4.73–4.65(m ,1H),4.51–4.45(m,1H),4.38–4.30(m,1H),3.97–3.84(m,2H),2.98–2.91(m,1H),2.87–2.81(m,1 H),2.76–2.64(m,2H),2.47–2.45(m,1H),2.24–2.09(m,2H),1.70–1.64(m,2H),1.50–1.38(m,2H).

[1191] Example 44

[1192] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[1193]

[1194] first step

[1195] 1-(3-Bromo-2-hydroxyphenyl)-3-(4-chloro-2-fluorophenyl)prop-2-en-1-one-3-d

[1196] 4-Chloro-2-fluoro<α-2H>benzaldehyde 44a and 1-(3-bromo-2-hydroxyphenyl)ethane-1-one were used as starting materials and the synthesis method of the first step of Example 1 was used to obtain 1-(3-bromo-2-hydroxyphenyl)-3-(4-chloro-2-fluorophenyl)prop-2-en-1-one-3-d 44b.

[1197] MS m / z(ESI):355.9[M+1].

[1198] Step 2

[1199] 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[1200] Starting from 1-(3-bromo-2-hydroxyphenyl)-3-(4-chloro-2-fluorophenyl)prop-2-en-1-one-3-d 44b, the synthesis method of Example 33 was used to obtain 2-((4-((S)-2-(4-chloro-2-fluorophenyl)-3-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 44.

[1201] MS m / z(ESI):608.1[M+1].

[1202] Example 45

[1203] 2-((4-((S)-2-(4-chloro-2-(methoxy-d3)phenyl)-3-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[1204]

[1205] first step

[1206] 1-(3-Bromo-2-hydroxyphenyl)-3-(4-chloro-2-(methoxy-d3)phenyl)prop-2-en-1-one-3-d

[1207] Using 4-chloro-2-(methoxy-d3)<α-2H>benzaldehyde 45a and 1-(3-bromo-2-hydroxyphenyl)ethane-1-one as raw materials, the synthesis method of the first step of Example 1 was referred to to obtain 1-(3-bromo-2-hydroxyphenyl)-3-(4-chloro-2-(methoxy-d3)phenyl)prop-2-en-1-one-3-d 45b.

[1208] MS m / z(ESI):371.0[M+1].

[1209] Step 2

[1210] 2-((4-((S)-2-(4-chloro-2-(methoxy-d3)phenyl)-3-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[1211] Using 1-(3-bromo-2-hydroxyphenyl)-3-(4-chloro-2-(methoxy-d3)phenyl)prop-2-en-1-one-3-d 45b as the starting material, the synthesis method of Example 33 was used to obtain 2-((4-((S)-2-(4-chloro-2-(methoxy-d3)phenyl)-3-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 45.

[1212] MS m / z(ESI):623.2[M+1].

[1213] Example 46

[1214] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1215]

[1216] Using intermediate Im1 as the starting material, refer to Example 40 to obtain the product 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[1217] MS m / z(ESI):607.2[M+1].

[1218] Example 47

[1219] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1220]

[1221] Using intermediate Im1 as the starting material, refer to Example 42 to obtain the product 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[1222] MS m / z(ESI):589.2[M+1].

[1223] Example 48

[1224] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[1225] Method 1

[1226] Reference Example 42 was used to obtain the product 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid.

[1227] Method 2

[1228]

[1229] first step

[1230] tert-Butyl 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl)-2-hydroxyphenyl)piperidine-1-carboxylate

[1231] Tert-butyl 4-(3-acetyl-2-hydroxyphenyl)piperidine-1-carboxylate Im7 (20.3 g, 63.56 mmol) and tetrahydrofuran (300 mL) were added to a 1000 mL flask and cooled at 0°C for 10 minutes. Sodium hydride (7.63 g, 190.67 mmol, 60% purity) was then added. 4-Chloro-2-fluorobenzaldehyde 48a (10.08 g, 63.56 mmol) was then dissolved in THF (100 mL) and slowly added dropwise to the reaction mixture via a constant pressure dropping funnel over 20 minutes. After the addition was complete, the temperature was raised to 25°C and allowed to react for 2 hours. The reaction was stopped, and the reaction solution was quenched with saturated aqueous ammonium chloride solution (200 mL). Water (50 mL) was added and the mixture was extracted with ethyl acetate (200 mL×3). The organic phase was washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. Ethyl acetate (60 mL) was added, the mixture was slurried (stirred for 15 minutes), filtered, and the filter cake was washed with petroleum ether (30 mL) and dried to give the title product, tert-butyl 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl)-2-hydroxyphenyl)piperidine-1-carboxylate 48b (15.2 g) in a yield of 52.00%.

[1232] MS m / z(ESI):460.1[M+1].

[1233] Step 2

[1234] tert-Butyl 4-(3-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl)-2-hydroxyphenyl)piperidine-1-carboxylate

[1235] Tert-butyl 4-(3-(3-(4-chloro-2-fluorophenyl)acryloyl)-2-hydroxyphenyl)piperidine-1-carboxylate 48b (25 g, 54.36 mmol) and isopropanol (500 mL) were added to a 1000 mL flask, and sodium borohydride (3.08 g, 81.53 mmol) was added at 0°C. The reaction mixture was then allowed to react at 20°C for 3 hours. The reaction was stopped and quenched with water (100 mL). The mixture was extracted with ethyl acetate (200 mL × 3). The organic phase was washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, and dried to give the title product, tert-butyl 4-(3-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl)-2-hydroxyphenyl)piperidine-1-carboxylate 48c (25 g), in a yield of 99.56%.

[1236] MS m / z(ESI):462.1[M+1].

[1237] Step 3

[1238] tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate

[1239] Tert-butyl 4-(3-(3-(4-chloro-2-fluorophenyl)-1-hydroxyallyl)-2-hydroxyphenyl)piperidine-1-carboxylate 48c (25 g, 54.12 mmol) and N,N-dimethylformamide (300 mL) were added to a 500 mL flask, and p-toluenesulfonic acid (13.98 g, 81.18 mmol) was added at 25°C. The reaction mixture was then reacted at 50°C for 4 hours. The reaction was stopped, and the reaction solution was quenched with water (200 mL), extracted with ethyl acetate (200 mL×3), and the organic phase was washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by silica gel column chromatography with petroleum ether and ethyl acetate as eluent to obtain the title product, tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate 48d (13 g), in a yield of 54.11%.

[1240] MS m / z(ESI):444.1[M+1].

[1241] Step 4

[1242] (R)-tert-Butyl 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate

[1243] Chiral separation of tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate 48d afforded (R)-tert-butyl 4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate 48e.

[1244] Split Condition

[1245] OD-H 4.6*150

[1246] Hexane:IPA:DEA=90:10:0.1%

[1247] F=1mL T=35℃

[1248] MS m / z(ESI):444.1[M+1].

[1249] Step 5

[1250] (R)-4-(2-(4-Chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine

[1251] Tert-butyl (R)-4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate 48e (2.55 g, 5.74 mmol) and dichloromethane (50 mL) were added to a 100 mL flask. 4A molecular sieves (2.55 g) and boron trifluoride etherate (2.04 g, 14.36 mmol) were added at 0°C. The reaction mixture was then allowed to react at 0°C for 2 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL), water (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL x 3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and dried to afford the title product, (R)-4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine 48f (1.97 g, 100% yield).

[1252] MS m / z(ESI):344.1[M+1]

[1253] Step 6

[1254] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester

[1255] (R)-4-(2-(4-Chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine 48f (1.97 g, 5.73 mmol) and acetonitrile (50 mL) were added to a 100 mL flask. Potassium carbonate (1.58 g, 11.46 mmol) and (S)-methyl 2-(chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate Im2 (1.69 g, 5.73 mmol) were then added at 25°C. The reaction mixture was then incubated at 25°C for 10 hours. The reaction was stopped, and the reaction solution was quenched with aqueous solution (20 mL), extracted with dichloromethane (20 mL×3), and the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to give the title product, 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester, 48 g (3.1 g), yield: 89.71%.

[1256] MS m / z(ESI):603.2[M+1]

[1257] Step 7

[1258] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[1259] 48 g (3.1 g, 5.14 mmol) of methyl 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate and methanol (25 mL) were added to a 100 mL flask. Lithium hydroxide (1.23 g, 51.40 mmol) was dissolved in water (10 mL) and added dropwise to the reaction solution at 25°C. The reaction solution was then reacted at 25°C for 1 hour. The reaction was stopped, and the reaction solution was quenched with formic acid (1 mL), added with water (20 mL), and extracted with dichloromethane (20 mL×3). The organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by prep-HPLC to give the title product 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxabutan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid 48 (2.1 g, yield: 69.35%).

[1260] MS m / z(ESI):589.1[M+1]

[1261] 1 H NMR(400MHz,MeOD)δ8.14–8.03(m,2H),7.40(t,1H),7.25(dd,1H),7.15(dd, 1H),7.05(dd,1H),6.92(dd,1H),6.84(t,1H),6.68(dd,1H),6.21(dd,1H),5 .82(dd,1H),5.30–5.24(m,1H),5.03–4.93(m,1H),4.85–4.81(m,1H),4.64– 4.54(m,1H),4.45–4.35(m,1H),4.23(d,1H),4.13(d,1H),3.25–3.18(m,1H), 3.12–3.05(m,1H),2.95-2.85(m,1H),2.83–2.70(m,1H),2.57–2.38(m,3H),1.88–1.78(m,2H),1.78–1.63(m,1H),1.59–1.51(m,1H).

[1262] Example 49

[1263] 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1264]

[1265] Reference Example 41 was used to obtain the product 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-4-fluoro-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[1266] MS m / z(ESI):622.2[M+1].

[1267] Example 50

[1268] 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1269]

[1270] Reference Example 43 gave the product 2-((4-((R)-2-(4-chloro-2-(methoxy-d3)phenyl)-2H-chromen-8-yl-2-d)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[1271] MS m / z(ESI):604.2[M+1].

[1272] Example 51

[1273] 2-((4-((R)-2-(4-cyano-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[1274]

[1275] Using 4-cyano-2-fluorobenzaldehyde and intermediate Im-2 as raw materials, refer to Example 42 to obtain the product 2-((4-((R)-2-(4-cyano-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid.

[1276] MS m / z(ESI):580.2[M+1].

[1277] 1 H NMR(400MHz,MeOD)δ8.13–8.02(m,2H),7.71–7.57(m,2H),7.55–7.49(m,1H),7.15–7.02(m,1H),6.97–6.91(m ,1H),6.92–6.83(m,1H),6.73–6.64(m,1H),6.33–6.25(m,1H),5.89–5.80(m,1H),5.37–5.18(m,1H),5.05–4. 92(m,1H),4.84–4.79(m,1H),4.72–4.58(m,1H),4.52–4.39(m,1H),4.35–4.19(m,2H),3.29–3.25(m,1H),3.2 1–3.12(m,1H),3.02–2.86(m,1H),2.82–2.69(m,1H),2.65–2.42(m,3H),1.98–1.72(m,3H),1.68–1.59(m,1H).

[1278] Example 52

[1279] 2-((4-((R)-2-(4-cyano-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1280]

[1281] Using 4-cyano-2-fluorobenzaldehyde and intermediate Im-1 as raw materials, reference Example 42 was used to obtain the product 2-((4-((R)-2-(4-cyano-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)--1H-benzo[d]imidazole-6-carboxylic acid.

[1282] MS m / z(ESI):579.2[M+1].

[1283] 1H NMR (400MHz, DMSO) δ8.25(d,1H),7.95(dd,1H),7.79(dd,1H),7.70(dd,1H),7.62(d,1H),7.52(t,1H),7. 07(dd,1H),6.99(dd,1H),6.87(t,1H),6.75(dd,1H),6.33(dd,1H),5.93(dd,1H),5.11–5.00(m,1H),4.85 –4.71(m,1H),4.67–4.58(m,1H),4.52–4.44(m,1H),4.42–4.31(m,1H),3.92(d,1H),3.75(d,1H),3.04–2. 92(m,1H),2.83–2.62(m,3H),2.46–2.38(m,1H),2.23–2.02(m,2H),1.73–1.56(m,2H),1.48–1.34(m,2H).

[1284] Example 53

[1285] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1286]

[1287] Using Im-1 as the starting material, refer to Example 48 to obtain the product 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[1288] MS m / z(ESI):588.2[M+1].

[1289] 1H NMR(400MHz,MeOD)δ8.30(s,1H),7.96(dd,1H),7.66(d,1H),7.40(t,1H),7.25(s,1H),7.16(d,1H),7 .04(dd,1H),6.92(dd,1H),6.83(d,1H),6.68(dd,1H),6.23–6.19(m,1H),5.83(dd,1H),5.27–5.20(m ,1H),4.85–4.80(m,1H),4.74–4.62(m,2H),4.48–4.41(m,1H),4.05(d,1H),3.95(d,1H),3.12–3.05( m,1H),2.94–2.77(m,3H),2.55–2.46(m,1H),2.39–2.25(m,2H),1.82–1.73(m,2H),1.66–1.50(m,2H).

[1290] Example 54

[1291] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid methyl ester

[1292]

[1293] Reference Example 48 was used to obtain the product methyl 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate.

[1294] MS m / z(ESI):603.2[M+1].

[1295] Example 55

[1296] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-4H-1,2,4-triazole-3-carbonitrile

[1297]

[1298] first step

[1299] (S)-2-Bromo-4-nitro-5-((oxetan-2-ylmethyl)amino)pyridine 1-oxide

[1300] Using 2-bromo-5-fluoro-4-nitropyridine N-oxide as the raw material, the product (S)-2-bromo-4-nitro-5-((oxetan-2-ylmethyl)amino)pyridine 1-oxide was obtained in the first step with reference to intermediate Im-1.

[1301] MS m / z(ESI):303.9[M+1].

[1302] Step 2

[1303] (S)-6-Bromo-N3-(oxetan-2-ylmethyl)pyridine-3,4-diamine

[1304] At room temperature, ((S)-2-bromo-4-nitro-5-((oxetan-2-ylmethyl)amino)pyridine 1-oxide (1 g, 3.28 mmol) and Zn powder (2.1 g, 32.8 mmol) were dissolved in methanol (25 mL). Acetic acid (985 mg, 16.4 mmol) was then added dropwise. The mixture was heated to 60°C and stirred for 2 hours. The mixture was cooled to room temperature and filtered. The filtrate was adjusted to pH 7 with saturated sodium bicarbonate and extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried to give the title product, (S)-6-bromo-N3-(oxetan-2-ylmethyl)pyridine-3,4-diamine (804 mg), in a 95% yield.

[1305] MS m / z(ESI):258.0[M+1].

[1306] Step 3

[1307] (S)-4-Amino-5-((oxetan-2-ylmethyl)amino)picolinonitrile

[1308] At room temperature, (S)-6-bromo-N3-(oxetan-2-ylmethyl)pyridine-3,4-diamine (500 mg, 1.94 mmol), RuPhos-Pd-G3 (324.5 mg, 0.39 mmol), X-Phos (186 mg, 0.39 mmol), and Zn(CN)2 (458 mg, 3.9 mmol) were dissolved in NMP (15 mL). The atmosphere was replaced with nitrogen three times, and the mixture was heated to 130°C and stirred for 0.5 hours. The mixture was cooled to room temperature and filtered. The filtrate was extracted with ethyl acetate (30 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The resulting residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to give the title product, (S)-4-amino-5-((oxetan-2-ylmethyl)amino)picolinonitrile (345 mg), in an 87.1% yield.

[1309] MS m / z(ESI):205.1[M+1].

[1310] Step 4

[1311] (S)-2-(Chloromethyl)-3-(oxetan-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile

[1312] Using (S)-4-amino-5-((oxetane-2-ylmethyl)amino)picolinonitrile as the raw material, the product (S)-2-(chloromethyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile was obtained in the third step with reference to intermediate Im-2.

[1313] MS m / z(ESI):263.0[M+1].

[1314] Step 5

[1315] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile

[1316] Using (S)-2-(chloromethyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile and (R)-4-(2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidine as raw materials, reference was made to the sixth step of Example 48 to obtain the product 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetane-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile.

[1317] MS m / z(ESI):570.2[M+1].

[1318] Step 6

[1319] Methyl 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidate

[1320] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (500 mg, 0.88 mmol) was dissolved in methanol (15 mL) at room temperature, and sodium methoxide (95 mg, 1.76 mmol) was added, and the mixture was stirred at room temperature for 24 hours. Add 20 mL of water, extract with ethyl acetate (30 mL×3), dry the organic phase over anhydrous sodium sulfate, filter, and spin dry to give the title product, methyl 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetane-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidate (450 mg), yield: 85%.

[1321] MS m / z(ESI):602.2[M+1].

[1322] Step 7

[1323] 5-(2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-4H-1,2,4-triazole-3-carboxamide

[1324] Methyl 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidate (100 mg, 0.17 mmol) and 2-hydrazino-2-oxoacetamide (35 mg, 0.34 mmol) were dissolved in n-butanol (5 mL), DIEA (66 mg, 0.51 mmol) was added, the atmosphere was replaced with nitrogen three times, and the reaction was carried out at 120°C under nitrogen protection for 16 hours. The mixture was cooled to room temperature, 20 mL of water was added, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by silica gel column chromatography with an eluent system of dichloromethane and methanol to give the title product 5-(2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)oxetane-2-yl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-4H-1,2,4-triazole-3-carboxamide (67 mg) in a yield of 60%.

[1325] MS m / z(ESI):655.2[M+1].

[1326] Step 8

[1327] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-4H-1,2,4-triazole-3-carbonitrile

[1328] 5-(2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-4H-1,2,4-triazole-3-carboxamide (50 mg, 0.076 mmol) and DIEA (30 mg, 0.23 mmol) were dissolved in DCM, TFAA (24 mg, 0.11 mmol) was added, and the mixture was stirred at room temperature for 10 minutes. Add 50 mL of water, extract with ethyl acetate (10 mL×3), dry the organic phase over anhydrous sodium sulfate, filter, and spin-dry. Purify the residue by prep-HPLC to give the title product 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxabutane-2-yl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-4H-1,2,4-triazole-3-carbonitrile (12 mg), yield: 25%.

[1329] MS m / z(ESI):637.2[M+1].

[1330] Example 56

[1331] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine

[1332]

[1333] first step

[1334] (Z)-2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-N'-hydroxy-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide

[1335] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carbonitrile (50 mg, 0.088 mmol), DIEA (57 mg, 0.44 mmol) and hydroxylamine hydrochloride (12 mg, 0.18 mmol) were dissolved in ethanol (5 mL) and stirred at 90 ° C for 2 hours. The solid was filtered and dried in spin-drying to give the title product, (Z)-2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-N'-hydroxy-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide (21.2 mg), yield: 40%.

[1336] MS m / z(ESI):603.2[M+1].

[1337] Step 2

[1338] 3-(2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl-3H-imidazo[4,5-c]pyridin-6-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole

[1339] (Z)-2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-N'-hydroxy-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide (50 mg, 0.083 mmol) and trifluoroacetic anhydride TFAA (87 mg, 0.42 mmol) were dissolved in THF (5 mL) and stirred at 60°C for 2 hours. 10 mL of saturated sodium bicarbonate solution was added, and the mixture was extracted with ethyl acetate (10 mL×3). The organic phase was dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The residue was purified by silica gel column chromatography with an eluent system of dichloromethane and methanol to give the title product (3-(2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetane-2-yl)methyl-3H-imidazo[4,5-c]pyridin-6-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (41.3 mg) in a yield of 73%.

[1340] MS m / z(ESI):681.2[M+1].

[1341] Step 3

[1342] 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine

[1343] (3-(2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl-3H-imidazo[4,5-c]pyridin-6-yl)-5-(trifluoromethyl)-1,2,4-oxadiazole (50 mg, 0.073 mmol) and 2 drops of hydrazine hydrate were dissolved in DMF (2 mL) and stirred at room temperature for 2 h. The mixture was filtered. , spin-dried, and the residue was purified by prep-HPLC to give the title product 2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetane-2-yl)methyl)-6-(5-(trifluoromethyl)-4H-1,2,4-triazol-3-yl)-3H-imidazo[4,5-c]pyridine (21 mg) in a yield of 42%.

[1344] MS m / z(ESI):680.2[M+1].

[1345] Example 57

[1346] 3-(2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one

[1347]

[1348] (Z)-2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-N'-hydroxy-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-c]pyridine-6-carboximidamide (50 mg, 0.083 mmol) and CDI (27 mg, 0.166 mmol) were dissolved in DMF (2 mL) and stirred at 80°C for 2 hours. The mixture was filtered, dried in spin-drying, and the residue was purified by prep-HPLC to give the title product, 3-(2-((4-((R)-2-(4-chloro-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)oxetane-2-yl)methyl)-3H-imidazo[4,5-c]pyridin-6-yl)-1,2,4-oxadiazol-5(4H)-one (20.9 mg), yield: 40%.

[1349] MS m / z(ESI):629.2[M+1].

[1350] Example 58

[1351] 2-((4-((R)-2-(4-Carbamoyl-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[1352]

[1353] 2-((4-((R)-2-(4-cyano-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxetan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (100 mg, 172.52 μmol) and ethanol (5 mL) were added to a 25 mL flask. Potassium hydroxide (96.79 mg, 1.73 mmol) dissolved in water (1 mL) was added dropwise to the reaction mixture at 25°C. The reaction mixture was then reacted at 80°C for 2 hours. The reaction was stopped and cooled to 25°C. The reaction solution was quenched with formic acid (0.1 mL), added with water (2 mL), and extracted with dichloromethane (2 mL×3). The organic phase was washed with saturated sodium chloride solution (2 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by prep-HPLC to give the title product, 2-((4-((R)-2-(4-carbamoyl-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-3-(((S)-oxabutan-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (40 mg), in a yield of 38.79%.

[1354] MS m / z(ESI):598.2[M+1]

[1355] Example 59

[1356] 2-((4-((R)-2-(4-Carbamoyl-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1357]

[1358] 2-((4-((R)-2-(4-cyano-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (100 mg, 172.82 μmol) and ethanol (5 mL) were added to a 25 mL flask. Potassium hydroxide (96.96 mg, 1.73 mmol) dissolved in water (1 mL) was added dropwise to the reaction mixture at 25°C. The reaction mixture was then reacted at 80°C for 2 hours. The reaction was stopped and cooled to 25°C. The reaction solution was quenched with formic acid (0.1 mL), added with water (2 mL), and extracted with dichloromethane (2 mL×3). The organic phase was washed with saturated sodium chloride solution (2 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by prep-HPLC to give the title product, 2-((4-((R)-2-(4-carbamoyl-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxabutan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (35 mg), in a yield of 33.94%.

[1359] MS m / z(ESI):597.2[M+1]

[1360] Example 60

[1361] 2-((4-((R)-2-(4-(dimethylcarbamoyl)-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1362]

[1363] first step

[1364] 3-Fluoro-4-formyl-N,N-dimethylbenzamide

[1365] 3-Fluoro-4-formylbenzoic acid (5 g, 29.74 mmol) was dissolved in N,N-dimethylformamide (50 mL). Dimethylamine (1.34 g, 29.74 mmol), HATU (11.30 g, 29.74 mmol), and DIEA (3.84 g, 29.74 mmol) were then added to the reaction. The reaction was stirred at 25°C for 8 hours. The reaction was stopped, water (50 mL) was added, and the mixture was extracted with dichloromethane (30 mL x 3). The organic phase was washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and dried by spin drying. The resulting residue was purified by silica gel column chromatography using petroleum ether and ethyl acetate as eluents to obtain the title product, 3-fluoro-4-formyl-N,N-dimethylbenzamide (4.5 g), in a yield of 77.52%.

[1366] MS m / z(ESI):196.0[M+1].

[1367] Step 2

[1368] 2-((4-((R)-2-(4-(dimethylcarbamoyl)-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1369] Using 3-fluoro-4-formyl-N,N-dimethylbenzamide as the starting material, the target product 2-((4-((R)-2-(4-(dimethylcarbamoyl)-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by referring to Example 48.

[1370] MS m / z(ESI):625.2[M+1].

[1371] Example 61

[1372] 2-((4-((R)-2-(4-(cyclopropylcarbonyl)-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1373]

[1374] first step

[1375] (R)-tert-Butyl 4-(2-(4-(cyclopropylcarbonyl)-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate

[1376] (R)-tert-Butyl 4-(2-(4-cyano-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate (1 g, 2.30 mmol) and tetrahydrofuran (20 mL) were added to a 100 mL flask. Cyclopropylmagnesium bromide (2.3 mL, 1 M, 2.30 mmol) was added at 0°C, and the reaction mixture was reacted at 80°C for 12 hours. The reaction mixture was cooled to 0°C, and then 2N hydrochloric acid (2 mL) was added to the reaction mixture. The reaction mixture was continued at 0°C for 2 hours. The mixture was then neutralized with a saturated sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate (20 mL×3), and the organic phase was washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and spin-dried. The residue was purified by silica gel column chromatography with an eluent system of petroleum ether and ethyl acetate to give the title product, (R)-tert-butyl 4-(2-(4-(cyclopropylcarbonyl)-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylate (0.6 g), in a yield of 54.59%.

[1377] MS m / z(ESI):478.2[M+1]

[1378] Step 2

[1379] 2-((4-((R)-2-(4-(cyclopropylcarbonyl)-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1380] Using (R)-4-(2-(4-(cyclopropylcarbonyl)-2-fluorophenyl)-2H-chromen-8-yl)piperidine-1-carboxylic acid tert-butyl ester as the starting material, the target product 2-((4-((R)-2-(4-(cyclopropylcarbonyl)-2-fluorophenyl)-2H-chromen-8-yl)piperidin-1-yl)methyl)-1-(((S)-oxetan-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid was obtained by reference to the fifth to seventh steps of Example 48.

[1381] MS m / z(ESI):622.2[M+1].

[1382] Biological test evaluation

[1383] The present invention is further described and explained below in conjunction with test examples, but these examples are not intended to limit the scope of the present invention.

[1384] 1. Determination of the ability of the compounds of the present invention to stimulate cAMP production in human GLP1 receptor stably transfected cell lines

[1385] 1. Experimental purpose:

[1386] The purpose of this test is to test the ability of compounds to activate human GLP-1 receptors on cell surfaces. 50 Characterize the compounds' ability to activate the human GLP-1 receptor.

[1387] 2. Experimental reagents and instruments:

[1388] 2.1 Experimental instruments:

[1389] Microplate reader (BioTek Synergy H1);

[1390] Pipette (Eppendorf & Rainin).

[1391] 2.2 Experimental reagents:

[1392] DMEM / F12 medium was purchased from Gibco, catalog number 11330032;

[1393] Casein was purchased from Sigma, product number C3400;

[1394] 384-well plates were purchased from Sigma, catalog number CLS4514;

[1395] IBMX was purchased from Sigma, product number I7018;

[1396] Cisbio cAMP-Gs Dynamic kit was purchased from Cisbio, catalog number 62AM4PEC.

[1397] 3. Experimental methods:

[1398] The frozen human GLP1 receptor stably transfected cell line CHO-K1 / GLP-1R / CRE-luc was taken out from the liquid nitrogen tank, quickly thawed in a 37°C water bath, resuspended with DMEM / F12 medium, washed once after centrifugation, and resuspended with experimental buffer, which is DMEM / F12 medium containing 0.1% casein. The cell density was adjusted with experimental buffer and plated in a 384-well plate at a density of 2500 cells / 5μL / well. Then 2.5μL of IBMX working solution prepared in buffer was added to each well, with a final concentration of IBMX of 0.5mM, and 2.5μL of serially diluted compound samples (starting at 1000nM, 3-fold dilution, 11 concentrations). The mixture was centrifuged at 1000rpm for 1min, shaken for 30 seconds to mix, and incubated at room temperature for 30 minutes. The cAMP-d2 and Anti-cAMP-Eu were detected using the Cisbio cAMP-Gs Dynamic kit. 3+-Cryptate were diluted 20 times with cAMP Lysis & Detection Buffer and mixed well. Add 5 μL of diluted cAMP-d2 solution to each well, and then add 5 μL of diluted Anti-cAMP-Eu3 + The α-Cryptate solution was shaken for 30 seconds to mix thoroughly and incubated at room temperature in the dark for 1 hour. HTRF signals were read using a Biotek Synergy H1 microplate reader with an excitation wavelength of 320 nm and emission wavelengths of 620 nm and 665 nm.

[1399] 4. Experimental data processing method:

[1400] The signal ratio (665 nm / 620 nm * 10,000) was calculated and the signal ratio and sample concentration were nonlinearly fitted using a four-parameter equation in GraphPad Prism 6 to obtain the EC 50 value.

[1401] 5. Experimental results:

[1402] Table 1

[1403] Example EC 50 (nM)10.132-A0.0730.0623-A0.0724-A0.05400.1410.04420.07430.05470.08480.03490.08520.05

[1404] 530.06

[1405] 6. Experimental Conclusion

[1406] The above scheme shows that the compounds of the present invention exhibit good biological activity in the experiment of stimulating human GLP1 receptor stably transfected cell lines to produce cAMP.

[1407] 2. Effects of a single administration of the compound of the present invention on intraperitoneal glucose tolerance in GLP-1R humanized mice

[1408] 1. Purpose of the test:

[1409] The effect of a single administration of the compound of the present invention on blood glucose changes in an intraperitoneal glucose tolerance test (ipGTT) test of GLP-1R humanized C57BL / 6 mice was evaluated.

[1410] 2. Experimental Materials:

[1411] C57BL / 6_hGLP-1R, male, 5-8 weeks old; clean bench; electronic balance; active blood glucose meter; glucose.

[1412] 3 Experimental operation and data processing:

[1413] 3.1. The day before the experiment, animals were randomly divided into groups based on body weight, with 5 animals in each group. All animals were deprived of food overnight and fasted for at least 16 hours until the time of dosing.

[1414] 3.2. Prepare 0.2 g / mL glucose solution using pure water and filter through a 0.22 μm filter membrane for later use.

[1415] 3.3. On the day of testing, the blood glucose level of each animal was measured by tail snip method before administration and recorded as the baseline value;

[1416] Blood glucose test method: Place the mouse in a restrainer, disinfect the tail tip with an alcohol cotton ball, then cut off a small part of the tail tip with scissors. After discarding the first drop of blood, drop the second drop of blood onto the prepared blood glucose test strip to test the blood glucose value;

[1417] 3.4. Administer the drug according to the animal's weight and record the time of administration for each animal. 1 hour after administration, measure the blood glucose level of each animal in turn and record it as the blood glucose level at 0 min.

[1418] 3.5. Immediately administer an intraperitoneal injection of pure water or glucose solution (10 mL / kg, 2 g / kg glucose dose) based on the patient's body weight.

[1419] 3.6. Measure the blood glucose level of each mouse 15, 30, 60, 90, and 120 minutes after the injection of pure water or glucose solution, and record the time and data;

[1420] 3.7. After the test, all animals resumed eating.

[1421] 3.8 Data Processing

[1422] Draw the blood glucose (BG)-time curve and calculate the area under the blood glucose-time curve. The calculation formula is:

[1423] AUC (mmol / L.hr)=(BG0+BG15)×0.25 / 2+(BG15+BG30)×0.25 / 2+(BG30+BG60)×0.5 / 2+(BG60+BG90)×0.5 / 2+(BG90+BG120)×0.5 / 2.

[1424] Note: BG0, BG15, BG30, BG60, BG90 and BG120 represent the blood glucose values ​​before glucose administration (0 min), 15, 30, 60, 90 and 120 min after glucose administration, respectively.

[1425] The blood glucose reduction rate at each time point and AUC was calculated based on the average blood glucose value and blood glucose AUC at each time point. The calculation formula was: blood glucose reduction rate = (blood glucose of the drug group / AUC - blood glucose of the model control group / AUC) / blood glucose of the model control group / AUC × 100%.

[1426] 4 Experimental results:

[1427]

[1428] 5. Experimental Conclusion

[1429] According to the above experimental results, it can be seen that the compounds of the embodiments of the present invention can effectively lower the blood sugar of mice.

[1430] 3. Effects of long-term administration of the compounds of the present invention on body weight and food intake of GLP-1R humanized mice fed a high-fat diet

[1431] 1. Experimental purpose:

[1432] The purpose of this test is to evaluate the effects of long-term administration of compounds on body weight and food intake in GLP-1R humanized C57BL / 6 mice fed a high-fat diet.

[1433] 2. Experimental Reagents and Instruments

[1434] C57BL / 6_hGLP-1R, male, 5-8 weeks old; 60% high-fat diet (HFD); ultra-clean workbench; electronic balance.

[1435] 3. Experimental Methods

[1436] 3.1 On the day of starting high-fat diet, C57BL / 6 mice were randomly divided into two groups according to body weight. The first group consisted of 7 mice, namely Blank group, which was fed with normal control diet. The remaining animals were in the modeling group, which was fed with high-fat diet until the end of the experiment.

[1437] 3.2 At week 8 of HFD feeding, the modeling group animals were randomly divided into groups based on body weight, with 7 animals per group. The first group was the vehicle group (0.5% CMC-Na + 1% Tween 80), which received the vehicle; the remaining groups were the drug-treated groups. The drug-treated group received oral administration of the corresponding compound once daily for 14 days at a dose of 10 mg / kg in a 10 mL / kg volume. The blank group continued to receive a normal diet and did not receive any drug administration.

[1438] 3.3 The day of drug administration is defined as Day 0.

[1439] 3.4 Each time the drug is administered, the animals are weighed and the data are recorded. Oral administration is performed based on body weight, with a dosage volume of 10 mL / kg.

[1440] 3.5 Starting from day 0 of the experiment, the food intake of each group of mice was measured every three days. Specifically, the feed was replaced after each dose and the added and remaining amounts were recorded.

[1441] On Day 14, all mice were euthanized according to grouping order, and their livers were removed and weighed.

[1442] 4. Experimental Data Processing and Statistical Analysis

[1443] The body weight and body weight change rate of the mice after administration were summarized and statistically analyzed. The body weight change rate was calculated as: (BWt - BW0) / BW0 × 100%. BWt represents the body weight of the mouse on experimental day t, and BW0 represents the body weight of the mouse on experimental day 0.

[1444] The food intake was calculated as follows: (added amount (g) - remaining amount (g)) / number of animals in each cage. The cumulative food intake was the sum of the daily food intake of each animal during the administration period.

[1445] Experimental data were analyzed using GraphPad Prism software. Comparisons between two groups were performed using the t-test. Comparisons between three or more groups were performed using one-way ANOVA.

[1446] 5. Experimental Results

[1447]

[1448]

[1449] 6. Experimental Conclusion

[1450] According to the above experimental results, it can be seen that long-term administration of the compounds of the present invention has a good weight-reducing effect on GLP-1R humanized C57BL / 6 mice fed a high-fat diet.

[1451] IV. Pharmacokinetics in SD rats

[1452] 1. Research objectives:

[1453] SD rats were used as test animals to study the pharmacokinetic behavior of the following compound examples in rat plasma after oral administration at a dose of 50 mg / kg.

[1454] 2. Experimental Plan

[1455] 2.1 Investigational Drugs:

[1456] Vehicle formulation: 0.5% CMC-Na (1% Tween 80);

[1457] The embodiment of the present invention is homemade.

[1458] 2.2 Experimental Animals

[1459] There were 3 male SD rats in each group.

[1460] 2.3 Administration:

[1461] Three male SD rats were fasted overnight and administered PO to each group at a dose of 50 mg / kg in a volume of 10 mL / kg.

[1462] 2.4 Sample collection:

[1463] Before and after administration, 0.2 mL of blood was collected from the jugular vein of rats at 0, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours, placed in an EDTA-K2 test tube, and centrifuged at 6000 rpm at 4°C for 6 minutes to separate plasma, which was then stored at -80°C and eaten 4 hours after administration.

[1464] 2.5 Sample processing:

[1465] 1) 40 μL of plasma sample was added to 160 μL of acetonitrile for precipitation, mixed and centrifuged at 3500 × g for 5-20 minutes.

[1466] 2) Take 100 μL of the supernatant solution after treatment and perform LC / MS / MS analysis to determine the concentration of the test compound.

[1467] 2.6 Liquid phase analysis

[1468] Liquid phase conditions: Shimadzu LC-20AD pump

[1469] ●Mass spectrometry conditions: AB Sciex API 4000 mass spectrometer

[1470] ●Chromatographic column: phenomenex Gemiu 5um C18 50×4.6mm

[1471] ●Mobile phase: Liquid A is 0.1% formic acid aqueous solution, Liquid B is methanol

[1472] Flow rate: 1.0 mL / min

[1473] Elution time: 0-4.0 minutes, eluent is as follows:

[1474]

[1475] 3. Test results and analysis

[1476] The main pharmacokinetic parameters were calculated using WinNonlin 8.2.

[1477] 4. Test results

[1478] Compound t max (h)C max (ng / mL)AUC 0-t (ng / mL*h)AUC0-∞(ng / ml*h)t 1 / 2 (h) Example 2-A 2.0715735755358383.1 Example 401.0230310311108312.0 Example 482.0640319084191143.8 Example 521.0939712550125551.6 Example 530.5798021532215562.0

[1479] 5. Experimental conclusion:

[1480] From the results of the rat pharmacokinetic experiment in the table, it can be seen that at a dose of 50 mg / kg, the compounds of the present invention showed good metabolic properties, with exposure AUC and maximum blood concentration C max All performed well.

Claims

DEPCT6728 / 03 / 25671. Compounds having the formula (I'), stereoisomers of such, or pharmaceutically acceptable salts of such: (chemical formula)(I')(symbol) is either a single or double bond; ring B is chosen from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl can be substituted additionally as an alternative; or, ring B is absent; ring C is chosen from aryl or heteroaryl, appropriately phenyl or pyridinyl; L1 is chosen from the group consisting of bonds, alkyneline, alkyneline. ,-(CH2)n1-,-(CH2)n1(CRaaRbb)n2-,-(CRaaRbb)n1O(CH2)n2-,-(CH2)n1O(CRaaRbb)n2-,-(CRaaRbb)n1S(CH2)n2-,-(CH2)n1S(CRaaRbb)n2-,-(CRa aRbb)n1(CH2)n2NRcc-,-(CH2)n1NRaa(CRbbRcc)n2-,-(CH2)n1C(O)(CRaaRbb)n2-,-(CH2)n1NRaaC(O)(CRaaRbb)n2-,-(CH2)n1P(O)Raa-,-(CH2)n1S (O)m1-,-(CH2)n1S(O)m1NRaa-,-(CH2)n1NRaaS(O)m1- and -(CH2)n1C(O)NRaa-;Raa,Rbb, andRcc were each independently selected from a group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, carboxy, alkyl, deuterium-added alkyl, haloalkyl,Hydroxyalkyl, alkoxy, haloalkoxy, deuterium-doped alkoxy, alkenil, alkinil, heterocyclyl alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, where amino, alkyl, deuterium-doped alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenil, alkinil, heterocyclyl alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl each can be substituted optionally; or, any two of Raa, Rbb, and Rcc are crosslinked to form cycloalkyl, heterocyclyl, aryl, or heteroa. aryl, where cycloalkyl, heterocyclyl, aryl and heteroaryl each can be further substituted alternatively; L2 is chosen from the group containing the bond, alkyneline, alkyneline,-(CH2)n3-,-(CH2)n3(CRa1Rb1)n4-,-(CRa1Rb1)n3O(CH2)n4-,-(CH2)n3O(CRa1Rb1)n4-,- (CRa1Rb1)n3S(CH2)n4-,-(CH2)n3S(CRa1Rb1)n4-,-(CRa1Rb1)n3(CH2)n4NRc1-,-(CH2)n3NRa1(CRb1Rc1)n4-,-(CH2)n3C(O)(CRa1Rb1)n4-,-(CH 2)n3NRa1C(O)(CRa1Rb1)n4-,-(CH2)n3P(O)Ra1-,-(CH2)n3S(O)m2-,-(CH2)n3S(O)m2NRa1-,-(CH2)n3NRa1S(O)m2-and-(CH2)n3C(O)NRa1-;Ra1,Each Rb1 and Rc1 was independently selected from a group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, alkyl, deuterium-added alkyl, haloalkyl, hydroxyl alkyl, alkoxy, haloalkoxy, alkenil, alkynil, heterocyclyl alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, where each amino, alkyl, deuterium-added alkyl, haloalkyl, hydroxyl alkyl, alkoxy, haloalkoxy, alkenil, alkynil, heterocyclyl alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl each had three components. It can be further substituted as an alternative; or, Ra1 is absent; or, any two of the elements in Ra1, Rb1, and Rc1 are bonded to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each of the cycloalkyl, heterocyclyl, aryl, and heteroaryl can be further substituted. As an alternative, L3 was selected from the group containing the bonds: alkyneline, alkyneline,-(CH2)n5-,-(CH2)n5(CRa2Rb2)n6-,-(CRa2Rb2)n5O(CH2)n6-,-(CH2)n5O(CRa2Rb2)n6-,-(CRa2Rb2)n5S(CH2)n6-,-(CH2)n5S(CRa2Rb2)n6-,-(CRa2Rb2)n5(CH2)n6NRc2-,-(CH2)n5NRa2(CRb2Rc2)n6-,-(CH2)n5C(O)(CRa2Rb2)n6-,-(CH2)n5NRa2C(O)(CRa2Rb2)n6-,-(CH2)n5P(O)Ra2-,-(CH)n(CH2)n5S(O)m3-,-(CH2)n5S(O)m3NRa2-,-(CH2)n5NRa2S(O)m3- and -(CH2)n5C(O)NRa2-;Ra2,Rb2 and Rc2 were each independently selected from a group consisting of hydrogen, deuterium, and halogen. Amino, nitro, hydroxya, cyano, oxo, thioxo, carboxy, alkyl, deuterium-added alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclyl alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, where amino, alkyl, alkyl Deuterium-doped alkyls, haloalkyls, hydroxylakyls, alkoxy, haloalkoxy, alkenyls, alkinyls, heterocyclic alkyls, cycloalkyls, heterocyclyls, aryls, and heteroaryls can each be optionally substituted; or, Ra2 is absent; W is chosen from CRm or N; Rm is chosen from groups containing hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thioxo, alkyls, deuterium-doped alkyls, haloalkyls, hydroxylakyls, alkoxy, haloalkoxy, alkenyls, alkinyls, heterocyclic alkyls, cycloalkyls, heterocyclyls, aryls, and heteroaryls.Aryl and heteroaryl can be further substituted as an alternative; L4 was chosen from groups containing the bonds -(CH2)n7-,-(CH2)n7(CRa3Rb3)n8-,-(CRa3Rb3)n7O(CH2)n8-,-(CH2)n7O(CRa3Rb3)n8-,-(CRa3Rb3)n7S(CH2)n8-,-(CH2)n7S(CRa3Rb3)n8-,-(CRa3Rb3)n7(CH2)n8NRc3-,-(C H2)n7NRa3(CRb3Rc3)n8-,-(CH2)n7C(O)(CRa3Rb3)n8-,-(CH2)n7NRa3C(O)(CRa3Rb3)n8-,-(CH2)n7P(O)Ra3-,-(CH2)n7S(O)m4-,-(CH2)n7S(O)m4NRa3-,-(CH2)n7NRa3S(O)m4- and -(CH2)n7C(O)NRa3-;Ra3,Rb3 and Rc3 were each independently selected from the group of hydrogen,d Deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thioxo, carboxy, alkyl, deuterium-doped alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclyl alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl can be optionally substituted; or, any two in Ra3, Rb3, and Rc3 bonded to form cycloalkyl, heterocyclyl, aryl, or heteroaryl can be optionally substituted; each R1 is independently selected from the hydrogen-containing groups.Deuterium, halogen, amino, nitro, hydroxy, cyano, alkyl, deuterium-added alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, deuterium-added alkoxy, alkenyl, alkynyl, heterocyclyl alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,-(CH₃⁻) 2)n1C(O)Raa and -(CH2)n1C(O)NRaaRbb, where amino, alkyl, alkyl added deuterium, haloalkyl, hydroxylalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl each can be further substituted. Alternatively, any two of the components in R1 are bonded to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl can be further optionally substituted; or, R1 and L1 are bonded to form a cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl can be further optionally substituted; each R2 is independently selected from a group containing hydrogen, deuterium, halogen, amino,Nitro, hydroxyl, cyano, oxo, thioxo, alkyl, deuterium-doped alkyl, haloalkyl, hydroxyl alkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclyl alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, where amino, alkyl, deuterium-doped alkyl, haloalkyl, hydroxyl alkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclyl alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl each can be optionally substituted; or, any two of any two in R2 are crosslinked. R2 and L1 are bonded to form cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl can be further substituted optionally; or R2 and L1 are bonded to form cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl can be further substituted optionally; or R2 and L2 are bonded to form cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, or heteroaryl,Each aryl and heteroaryl can be substituted optionally; or, R2 and R3 are bonded to form cycloalkyl, heterocyclyl, aryl, or heteroaryl, where each cycloalkyl, heterocyclyl, aryl, and heteroaryl can be substituted optionally; each R3 is independently selected from a group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, thiol, oxo, thioxo, alkyl, deuterium-added alkyl, haloalkyl, hydroxylalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, etc. Heterocyclyl alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, where each deuterium-doped aminoalkyl, alkyl, haloalkyl, hydroxyl alkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclyl alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substitutable; or, any two in R3 are crosslinked to form cycloalkyl, heterocyclyl, aryl or heteroaryl, where each cycloalkyl, heterocyclyl, aryl and heteroaryl are each optionally substitutable; or,R3 and L2 are bonded to form cycloalkyl, heterocyclic, aryl, or heteroaryl, where each cycloalkyl, heterocyclic, aryl, and heteroaryl can be further substituted optionally; or, R3 and L3 are bonded to form cycloalkyl, heterocyclic, aryl, or heteroaryl, where each cycloalkyl, heterocyclic, aryl, and heteroaryl can be further substituted optionally; each R4 is independently selected from a group consisting of hydrogen, deuterium, halogen, oxo, amino, nitro, hydroxyl, C1-6C. Barboxy, cyano, alkyl, deuterium-doped alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclyl alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl can be optionally substituted; R5 is selected from the group containing hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thioxo, alkyl, deuterium-doped alkyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclyl alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl.Additional substitutions are possible as an alternative; M1 is chosen from a group consisting of O, S, N, C, (CH)n9, (CH2)n9O, (CH2)n9S, (CH2)n9NH, and (CH2)n9; M2 is chosen from a group consisting of O, S, N, C, (CH)n10, (CH2)n10O, (CH2)n10S, (CH2)n10NH, and (CH2)n10; x is an integer from 0 to 12; y is an integer from 0 to 12; z is an integer from 0 to 12; p is an integer from 0 to 4; n1~n6 each independently are integers from 0 to 3; n7~n10 each independently are integers from 0 to 3; m1~m3 each independently are integers from 0 to 2; and m4 is an integer from 0 to 3.

22. A compound, a stereoisomer of such and such, or a pharmaceutically acceptable salt of such under claim 1, which is characterized that the compound is also expressed as formula(I):(chemical formula)(I)L4 chosen from groups containing bonds,-(CH2)n7-,-(CH2)n7(CRa3Rb3)n8- ,-(CRa3Rb3)n7O(CH2)n8-,-(CH2)n7O(CRa3Rb3)n8-,-(CRa3Rb3)n7S(CH2)n8-,-(CH2)n7S(CRa3Rb3)n8-,-(CRa3Rb3)n7(CH2)n8NRc3-,-(CH2)n7N Ra3(CRb3Rc3)n8-,-(CH2)n7C(O)(CRa3Rb3)n8-,-(CH2)n7NRa3C(O)(CRa3Rb3)n8-,-(CH2)n7P(O)Ra3-,-(CH2)n7S(O)m4-,-(CH2)n7S(O)m4NRa3-,-(CH2)n7NRa3S(O)m4- and -(CH2)n7C(O)NRa3-; Ra3, Rb3, and Rc3 are each independently selected from groups consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, oxo, thioxo, carboxy, alkyl, deuterium-added alkyl, haloalkyl, hydroxylalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, which can be substituted optionally; or, any two of Ra3, Rb3, and Rc3 are crosslinked to form cycloalkyl, heterocyclyl, aryl, or heteroaryl. Eril can be optionally substituted; each R4 is chosen independently from a group consisting of hydrogen, deuterium, halogen, oxo, amino, nitro, hydroxy, carboxy, cyano, alkyl, deuterium-added alkyl, haloalkyl, hydroxylalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl, heterocyclylalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, which can be optionally substituted; R5 is chosen from a group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, thioxo, alkyl.Deuterium-doped alkyls, haloalkyls, hydroxylalkyls, alkoxy, haloalkoxy, alkenyls, alkinyls, heterocyclylalkyls, cycloalkyls, heterocyclyls, aryls, and heteroaryls can be optionally substituted; M1 is chosen from the group consisting of O, S, N, C, (CH)n9, (CH2)n9O, (CH2)n9S, (CH2)n9NH, and (CH2)n9; M2 is chosen from the group consisting of O, S, N, C, (CH)n10, (CH2)n10O, (CH2)n10S, (CH2)n10NH, and (CH2)n10; p is an integer from 0 to 4; n7~n10, each independently, are integers from 0 to 3; m4 is an integer from 0 to 23. The compounds are Compound, stereoisomer of such thing or pharmaceutically acceptable salt of such thing according to claim 1 or 2, which is characterized that, ring B is selected from a group consisting of C3-12 cycloalkyl, heterocyclyl of 3 to 12 members, C6-14 aryl and heteroaryl of 5 to 14 members; suitable C3-8 cycloalkyl, heterocyclyl of 4 to 12 members, C6-10 aryl and heteroaryl of 5 to 10 members; more suitable C5-8 cycloalkyl, heterocyclyl of 5 to 10 members containing 1 to 3 nitrogen atoms, oxygen atoms, or sulfur atoms.C6-8 aryl and heteroaryl compounds with 5 to 10 members incorporating 1 to 3 nitrogen atoms, oxygen atoms, or sulfur atoms; also suitable piperidinil and piperazinil, and even more suitable than piperidinil 4. Compounds, stereoisomers of such, or pharmaceutically acceptable salts of such as in claim 1, which are characterized by the compound also being expressed as a formula (II'): (chemical formula)(II')W1 is chosen from CH or N;W2 is chosen from CRm5 or N;R1 each is chosen independently from Groups consisting of hydrogen, deuterium, fluorine, chlorine, cyano, C1-6 alkyl, deuterium-doped C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, deuterium-doped C1-6 alkoxy, C1-6 haloalkoxy, -C(O)Raa and -C(O)NRaaRbb;Raa, and Rbb are each independently selected from groups consisting of hydrogen, deuterium, C1-6 alkyl, deuterium-doped C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, heterocyclyl with 3 to 8 members,C6-10 aryls and heteroaryls with 5 to 10 members; R2 each is independently selected from a group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, C1-6 alkyl, C1-6 alkyls added to deuterium, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy; R3 each is independently selected from a group consisting of hydrogen, deuterium, fluorine, methyl, methyl added to deuterium, and halomethyl; Rm5 is selected from a group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, C1-6 alkyl, C1-6 alkyls added to deuterium, and C1-6 haloalkoxy. C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy doped with deuterium, and C1-6 haloalkoxy, suitable for hydrogen, deuterium, fluorine, chlorine, cyano, C1-3 alkyl, C1-3 alkyl doped with deuterium, C1-3 haloalkyl, C1-3 alkoxy, C1-3 alkoxy doped with deuterium, and C1-3 haloalkoxy, suitable for hydrogen, and deuterium; R4 is independently selected from a group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, oxo, C1-6 carboxylate, C1-6 alkyl, C1-6 alkyl doped with deuterium, C1-6 haloalkyl,And heteroeryls with 5 to 6 substituted or unsubstituted members, where C1-6 carboxylic acids are optionally further substituted by one or more substituted groups chosen from halogenated or C1-6 alkyl, suitable carboxylic acids and -C(O)OCH3;R5 are chosen from groups consisting of C1-6 alkyl, deuterium-doped C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxylalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl, heterocyclyls with 3 to 8 members, C6-10 aryl and heteroeryls with 5 to 10 members, which are optionally further substituted by one or more substituted groups. One or more substituents selected from a group consisting of halogenated, C1-6 alkyl, deuterium-doped C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyl alkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 cyanoalkyl, C3-8 cycloalkyl, and 3 to 8-member heterocyclyl, suitable C1-6 alkyl, deuterium-doped C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, and 3 to 8-member heterocyclyl, were optionally further substituted by one or more substituents selected from a group consisting of halogenated, C1-6 alkyl, C1-6 deuterium-doped C1-6 alkyl,C1-6 haloalkyl, C1-6 cyanoalkyl, C3-8 cycloalkyl, and heterocyclyls with 3 to 8 members; L1 and L2 are each chosen independently from the appropriate or -(CH2)n1- bond; L3 is chosen from the appropriate or -(CH2)n1- bond; L4 is chosen from the appropriate or -(CH2)n7- bond; M1 is chosen from the group consisting of N, NH, O, S, C, and (CH)n9; M2 is chosen from the group consisting of N, NH, O, S, C, and (CH)n10; n9 or n10 are each independently an integer from 0 to 25. Compounds, stereoisomers of such, or pharmacologically acceptable salts.

6. Compounds, stereoisomers of such thing or pharmaceutically acceptable salts of such thing as described in claim 3, which are characterized by the fact that the compound is also represented by the formula (II'-a) or (II'-b): (chemical formula)(II'-a) or (chemical formula)(II'-b). Each R1 is independently selected from a group consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C1-6 alkyl, deuterium-added C1-6 alkyl, C1-6 haloalkyl,C1-6 hydroxylakyl, C1-6 alkoxy, C1-6 deuterium-doped alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, heterocyclic groups with 3 to 8 members, C6-10 aryl and heteroaryl groups with 5 to 10 members, optionally substituted by one or more substituents selected from halogenated, amino, nitro, hydroxy, cyano, oxo-containing, C1-6 alkyl, C1-6 deuterium-doped alkyl, C1-6 haloalkyl, C1-6 hydroxylakyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, heterocyclic groups. A 3- to 8 member C3-8 alkyl, a 3- to 8 member heterocyclyl, a 5- to 10 member C6-10 aryl, or a 5- to 10 member heteroyryl; or, any two in R1 are bonded to form a C3-8 cycloalkyl, a 3- to 8 member heterocyclyl, a C6-10 aryl, or a 5- to 10 member heteroyryl, where each of the C3-8 cycloalkyl, 3- to 8 member heterocyclyl, C6-10 aryl, and 5- to 10 member heteroyryl are optionally further substituted by one or more substituents chosen from halogenated, amino, nitro, hydroxyl, cyano, oxo, C1-6 alkyl, deuterium-doped C1-6 alkyl, or C1-6 haloalkyl groups.C1-6 hydroxyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, heterocyclyls with 3 to 8 members, C6-10 aryls and heteroaryls with 5 to 10 members; R2, each independently selected from a group containing hydrogen, deuterium. C1-6 alkyl, halogenated, amino, nitro, hydroxy, cyano, oxo, C1-6 alkyl, deuterium-doped C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, heterocyclyl with 3 to 8 members, C6-10 aryl and heterocyclyl. Aroeryls with 5 to 10 members, which are optionally further substituted by one or more substituents chosen from groups consisting of halogen, amino, nitro, hydroxy, cyano, oxo, C1-6 alkyl, deuterium-doped C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxylalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, heterocyclyls with 3 to 8 members, C6-10 aryls and heteroeryls with 5 to 10 members; or, any two of any two in R2 are bonded to form C3-8 cycloalkyl, heterocyclyls with 3 to 8 members.C6-10 aryls and heteroaryls with 5 to 10 members, which are optionally further substituted by one or more substituents selected from groups consisting of halogen, amino, nitro, hydroxy, cyano, oxo, C1-6 alkyls, C1-6 alkyls with deuterium added, C1-6 haloalkyls, C1-6 hydroxylalkyls, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyls, C2-6 alkinyls, C3-8 cycloalkyls, heterocyclyls with 3 to 8 members, C6-10 aryls and heteroaryls with 5 to 10 members; R3, each independently selected from groups consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C1-6 alkyls, C1-6 alkyls, C1-6 haloalkyls, C2-6 alken ... alkynyls, C3-8 cycloalkyls, heterocyclyls with 3 to 8 members, C6-10 aryls and heteroaryls with 5 to 10 members; R3, each selected independently from groups consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxyl, cyano, oxo, C1-6 alkyls, C1-6 alkyls, C2 Amino, nitro, hydroxy, cyano, carboxy, oxo, C1-6 alkyl, deuterium-doped C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, heterocyclyl with 3 to 8 members, C6-10 aryl and heteroaryl with 5 to 10 members, optionally substituted by one or more substituents selected from halogenated groups, amino, nitro, hydroxy, cyano, oxo, carboxy, C1-6 alkyl, deuterium-doped C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl,C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, heterocyclyl with 3 to 8 members, C6-10 aryl and heteroaryl with 5 to 10 members; R4, each is independently selected from groups containing hydrogen, deuterium, halogen, amino, or nitric acid. C1-6 alkyls, C1-6 alkyls with deuterium doping, C1-6 haloalkyls, C1-6 hydroxyalkyls, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyls, C2-6 alkynyls, C3-8 cycloalkyls, heterocyclyls with 3 to 8 members, C6-10 aryls and heteroarylts. A 5 to 10-membered substituent, which is optionally further substituted by one or more substituents chosen from groups consisting of halogen, amino, nitro, hydroxy, cyano, oxo, carboxy, C1-6 alkyl, deuterium-doped C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, 3 to 8-membered heterocyclyl, C6-10 aryl and 5 to 10-membered heteroaryl; or, any two of any two in R4 are bonded to form a C3-8 cycloalkyl or 3 to 8-membered heterocyclyl.C6-10 aryls and heteroaryls with 5 to 10 members, where C3-8 cycloalkyls, heterocyclyls with 3 to 8 members, C6-10 aryls and heteroaryls with 5 to 10 members are each optionally substituted by one or more substituents selected from groups consisting of halogen, amino, nitro, hydroxy, cyano, oxo, C1-6 alkyls, C1-6 deuterium-doped alkyls, C1-6 haloalkyls, C1-6 hydroxyalkyls, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyls, C2-6 alkinyls, C3-8 cycloalkyls, heterocyclyls with 3 to 8 members, C6-10 aryls and heteroaryls with 5 to 10 members 10 members; R5 is selected from groups consisting of hydrogen, deuterium, halogen, amino, nitro, hydroxy, cyano, carboxy, oxo, C1-6 alkyl, C1-6 alkyl with deuterium added, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, heterocyclyl with 3 to 8 members, C6-10 aryl and heteroaryl with 5 to 10 members, which are optionally further substituted by one or more substituents selected from groups consisting of halogen, amino, nitro, hydroxy, cyano, oxo, carboxy, C1-6 alkyl.C1-6 deuterium-doped alkyls, C1-6 haloalkyls, C1-6 hydroxyalkyls, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 cyanoalkyls, C2-6 alkenyls, C2-6 alkynyls, C3-8 cycloalkyls, heterocyclyls with 3 to 8 members, C6-10 aryls and heteroaryls with 5 to 10 members; M1 is selected from groups containing O, S, N, NH, C, CH and (CH)2; M2 is selected from groups containing O, S, N, NH, C, CH and (CH)2; x is 0, 1, 2, 3, 4 or 5; y is 0, 1, 2, 3 or 4; z is 0, 1, 2, 3 or 4; p is 0, 1, 2, or 3.

7. Compounds, stereoisomers of such or acceptable salts. The pharmaceuticals of any one of the claims 1 through 6 are characterized by the fact that each R1 is independently selected from a group of hydrogen, deuterium, fluorine, chlorine, cyano, C1-6 alkyl, deuterium-doped C1-6 alkyl, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy, suitable hydrogen, deuterium, fluorine, chlorine, cyano, C1-3 alkyl, deuterium-doped C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy, more suitable hydrogen, deuterium, fluorine, chlorine, cyano, C1-3 alkyl, deuterium-doped C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy, more suitable hydrogen, deuterium, fluorine, chlorine, cyano, C1-3 alkyl, C1-3 alkoxy, and C1-3 haloalkoxy, more suitable hydrogen, deuterium, fluorine, chlorine, cyano, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalk ...Cyanos and methoxy; R2 each was independently selected from a group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, C1-6 alkyl, C1-6 alkyl doped deuterium, C1-6 haloalkyl, C1-6 alkoxy, and C1-6 haloalkoxy, suitable hydrogen, deuterium, fluorine, chlorine, cyano, C1-3 alkyl, C1-3 alkyl doped deuterium, C1-3 haloalkyl, C1-3 alkoxy, and C1-3 haloalkoxy, more suitable hydrogen, deuterium, fluorine, chlorine, and methyl; R3 each was independently selected from a group consisting of... R1-6 alkyls, deuterium-doped C1-6 alkyls, and fluorine-doped C1-6 alkyls, suitable for hydrogen; R4 is independently selected from a group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, carboxylic acids, C1-6 alkyls, deuterium-doped C1-6 alkyls, and carboxylic acids; R5 is selected from a group consisting of C1-6 alkyls, deuterium-doped C1-6 alkyls, C1-6 haloalkyls, C1-6 hydroxyalkyls, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyls, heterocyclyls with 3 to 8 members, C6-10 aryls, and heteroaryls with 5 to 10 members.Optionally, further substitution is made by one or more substituents selected from the halogenated, C1-6 alkyl, deuterium-doped C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C3-8 cycloalkyl and 3-8 member heterocyclyl groups, suitable C1-6 alkyl, deuterium-doped C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl and 3-8 member heterocyclyl groups, which are optionally further substituted by one or more substituents selected from the halogenated groups. C1-6 alkyls, deuterium-doped C1-6 alkyls, C1-6 haloalkyls, C3-8 cycloalkyls and heterocyclyls of 3 to 8 members, more suitable (chemical formula) and (chemical formula); L1 and L2 each are independently selected from bonds or -(CH2)n1-, suitable bonds; L3 is selected from bonds or -(CH2)n1-, suitable -CH2-; L4 is selected from bonds or -(CH2)n7-, suitable bonds or -CH2-8. Compounds, stereoisomers of such or pharmaceutically acceptable salts of such under any one of claims 1 to 6, having the characteristic that,Each R1 is independently selected from a group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, C1-6 alkyl, C1-6 alkyl doped deuterium, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkoxy doped deuterium, and C1-6 haloalkoxy, suitable hydrogen, deuterium, fluorine, chlorine, cyano, C1-3 alkyl, C1-3 alkyl doped deuterium, C1-3 haloalkyl, C1-3 alkoxy, C1-3 alkoxy doped deuterium, and C1-3 haloalkoxy, more suitable hydrogen, deuterium, fluorine, chlorine, cyano, -OCD. Each R2 methoxy is independently selected from a group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, C1-6 alkyl, C1-6 alkyl doped with deuterium, C1-6 haloalkyl, C1-6 alkoxy, C1-6 alkoxy doped with deuterium, and C1-6 haloalkoxy, suitable hydrogen, deuterium, fluorine, chlorine, cyano, C1-3 alkyl, C1-3 alkyl doped with deuterium, C1-3 haloalkyl, C1-3 alkoxy, C1-3 alkoxy doped with deuterium, and C1-3 haloalkoxy, more suitable hydrogen, deuterium, fluorine, chlorine, cyano.Each R3 is independently selected from a group consisting of hydrogen, deuterium, and fluorine, suitable for hydrogen; each R4 is independently selected from a group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, oxo, C1-6 carboxylate, C1-6 alkyl, C1-6 alkyl doped deuterium, C1-6 haloalkyl and heteroeryls with 5 to 6 members consisting of 1 to 4 nitrogen atoms, oxygen atoms, or sulfur atoms, where C1-6 carboxylate and heteroeryls with 5 to 6 members consisting of 1 to 4 nitrogen atoms, oxygen atoms, or sulfur atoms. Each was optionally further replaced by one or more substituents selected from groups consisting of oxo, halogen, cyano, deuterium-doped C1-3 alkyls, C1-3 haloalkyls, C1-3 alkoxys, deuterium-doped C1-3 alkoxys, and C1-3 haloalkoxys, suitable carboxyls and -C(O)OCH3;R5; selected from groups consisting of C1-6 alkyls, deuterium-doped C1-6 alkyls, C1-6 haloalkyls, C1-6 hydroxyalkyls, C1-6 alkoxys, C1-6 haloalkoxys, C3-8 cycloalkyls, heterocyclyls with 3 to 8 members, C6-10 aryls and heteroaryls with 5 to 10 members.Optionally, further substitution is possible by one or more substituents selected from halogenated, C1-6 alkyl, deuterium-doped C1-6 alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 cyanoalkyl, C3-8 cycloalkyl, and 3 to 8-membered heterocyclyls; suitable C1-3 alkyl, deuterium-doped C1-3 alkyl, C1-3 haloalkyl, C3-6 cycloalkyl, and 3 to 6-membered heterocyclyls; optionally, further substitution is possible by one or more substituents selected from the assembled group. With halogens, C1-3 alkyls, deuterium-doped C1-3 alkyls, C1-3 haloalkyls, C1-3 cyanoalkyls, C3-6 cycloalkyls, and 3 to 6-membered heterocyclyls, more suitable than C3-6 cycloalkyls, and 3 to 6-membered heterocyclyls containing 1 to 2 nitrogen, oxygen, or sulfur atoms, which are optionally further replaced by one or more substituents chosen from the group consisting of halogens, C1-3 alkyls, deuterium-doped C1-3 alkyls, C1-3 cyanoalkyls, and C1-3 haloalkyls, which are also suitable (chemical formulas),and (chemical formula); L1 and L2 are each chosen independently from the bond or -(CH2)n1-, suitable bond; L3 is chosen from the bond or -(CH2)n1-, suitable bond -CH2-; L4 is chosen from the bond or -(CH2)n7-, suitable bond or -CH2-9. Compounds, stereoisomers of such and such, or pharmaceutically acceptable salts of such according to claims 4, 7 or 8, which are characterized that the compound is also expressed as formula (III)-(III-1): (chemical formula)(chemical formula)(III) or (III-1) where: R5 is chosen from C3-8 cycloalkyl, or heterocyclyl of 3 to 8 members, which are substituted. An optional substituent is selected from a group consisting of halogenated, C1-6 alkyl, deuterium-doped, C1-6 cyanoalkyl, and C1-6 haloalkyl substituents; M1 is selected from a group consisting of O,S,N,C,CH, and (CH)2; M2 is selected from a group consisting of O,S,N,C,CH, and (CH)2; n7 is 0,1,2, or 3; x is 0,1,2,3,4, or 5; y is 0,1,2,3, or 4; z is 0,1,2,3, or 4; p is 0,1,2, or 3.

10. Compounds, stereoisomers of such, or pharmaceutically acceptable salts of such under Claim 4, which are characterized as follows:Each R1 was independently selected from a group consisting of hydrogen, deuterium, fluorine, chlorine, cyanose, C1-3 alkyl, deuterium-added C1-3 alkyl, C1-3 alkoxy, deuterium-added C1-3 alkoxy, and C1-3 haloalkoxy; each R2 was independently selected from a group consisting of hydrogen, deuterium, fluorine, chlorine, cyanose, C1-3 alkyl, deuterium-added C1-3 alkyl, C1-3 alkoxy, deuterium-added C1-3 haloalkyl, C1-3 alkoxy; each R3 was independently selected from... R4 is chosen independently from 5- to 6-membered heteroeryls containing 1 to 4 nitrogen, oxygen, or sulfur atoms, which are optionally replaced by one or more substituents chosen from oxo, halogen, cyano, C1-3 alkyl, and C1-3 haloalkyl, -(CH2)nCOOH and -(CH2)nC(O)OCH3; R5 is chosen from 3- to 6-membered C3-6 cycloalkyl or heterocyclyls containing 1 to 2 nitrogen, oxygen, or sulfur atoms.Substituted additionally as an alternative by one or more substituents selected from groups consisting of halogen, C1-3 alkyl, deuterium-doped C1-3 alkyl, C1-3 cyanoalkyl, and C1-3 haloalkyl; M1 and M2 each selected independently from groups consisting of N, CH, and (CH)2; n is 0, 1, 2, or 311. Compounds, stereoisomers of such, or pharmaceutically acceptable salts of such pursuant to claim 4, which are characterized by the compound also being expressed as formulas (V-1) and (V-2): (chemical formula)(chemical formula)(V-1) or (V-2) where:R1 Each was independently selected from a group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, C1-3 alkyl, C1-3 alkyl doped deuterium, C1-3 haloalkyl, C1-3 alkoxy, C1-3 alkoxy doped deuterium, and C1-3 haloalkoxy, suitable hydrogen, deuterium, fluorine, chlorine, methoxy and -OCD3;R2.And C1-3 haloalkoxy, suitable hydrogen, deuterium, fluorine, chlorine, and methyl; R3 each is chosen independently from the group containing hydrogen, deuterium, and fluorine, suitable hydrogen; M1 is chosen from N or CH, suitable N; W2 is chosen from N or CH, suitable CH; x, y, and z each are independently 0, 1, or 2; R5 is chosen from the group containing (chemical formula), and (chemical formula), suitable (chemical formula).

12. The compounds as shown below, stereoisomers of them or pharmacologically acceptable salts.

13. A pharmaceutical compound consisting of the therapeutic dose of the compound, a stereoisomer of such substance, or a pharmaceutically acceptable salt of such substance as per any of Claims 1 through 12, and one or more pharmaceutically acceptable carriers or inoculants.

14. Use of the compound, a stereoisomer of such substance, or a pharmaceutically acceptable salt of such substance as per any of Claims 1 through 12,or the pharmaceutical components under claim 13 in the preparation of an active drug that is a GLP-115 receptor agonist; the use of the compound, stereoisomer of such, or any of the pharmaceutically acceptable salts of such as under claims 1 through 12, or the pharmaceutical components under claim 13 in the preparation of an active drug for therapeutic metabolic disease; appropriate where the metabolic disease is selected from diabetes, obesity or non-alcoholic inflammatory fatty liver disease or other related diseases arising from diabetes, obesity or non-alcoholic inflammatory fatty liver disease;