GLP-1 receptor agonist and uses thereof

Abstract

The present invention relates to a novel GLP-1 receptor agonist and uses thereof, and provides a pharmaceutical composition for the prevention or treatment of obesity, diabetes, or various metabolic diseases related thereto, comprising a GLP-1 receptor agonist compound in a therapeutically effective amount.

Description

GLP-1 receptor agonists and their uses

[0001] The present invention relates to a novel GLP-1 receptor agonist and its use, and provides a pharmaceutical composition for the prevention or treatment of various diseases related thereto, including obesity and diabetes, such as obesity, diabetes, or related metabolic diseases, comprising a therapeutically effective amount of a GLP-1 receptor agonist compound.

[0002] Diabetes is a metabolic disease characterized by the loss of blood glucose regulation due to abnormal insulin secretion or relative insulin deficiency resulting from insulin resistance. Incretins are hormones secreted by the digestive system that increase insulin secretion while nutrients are absorbed within the intestinal tract. Glucagon-like peptide-1 (GLP-1) is one of the incretin hormones secreted in the small intestine. GLP-1 acts on the pancreas to increase insulin secretion and decreases glucagon secretion, thereby exhibiting a blood glucose-lowering effect. It also delays the passage of food through the stomach and acts on the brain to suppress appetite, contributing to blood glucose regulation in a complex manner and aiding in weight loss.

[0003] Currently, GLP-1 receptor agonists approved in the United States for the treatment of type 2 diabetes include exenatide, liraglutide, lixisenatide, albiglutide, and dulaglutide, which can be classified as protein drugs.

[0004] The inventors have completed the present invention by developing a novel GLP-1 receptor agonist compound that exhibits excellent effects as a GLP-1 receptor agonist.

[0005] [Prior Art Literature]

[0006] [Patent Literature]

[0007] (Patent Document 1) WO2018109607

[0008] (Patent Document 2) WO2021160127

[0009] (Patent Document 3) WO2024107781

[0010] [Non-patent literature]

[0011] (Non-patent literature 1) Diabetes Spectr. 2017 Aug; 30(3): 202-210.

[0012] One aspect is to provide a novel GLP-1 receptor agonist compound that exhibits excellent efficacy as a GLP-1 receptor agonist.

[0013] Another aspect is to provide a pharmaceutical composition comprising the above-mentioned GLP-1 receptor agonist compound and a pharmaceutically acceptable excipient.

[0014] Another aspect is to provide a use for the prevention or treatment of various diseases related thereto, such as obesity, diabetes, or related metabolic diseases, using a GLP-1 receptor agonist compound or a pharmaceutical composition containing the same.

[0015] Another aspect is to provide a method for preventing or treating various diseases related thereto, such as obesity, diabetes, or related metabolic diseases, using a GLP-1 receptor agonist compound or a pharmaceutical composition containing the same.

[0016] Other objects and advantages of this application will become more apparent from the following detailed description together with the appended claims. Content not described in this specification is omitted, as it can be sufficiently recognized and inferred by those skilled in the art within the field of this application or a similar field.

[0017] One aspect provides a compound selected from the compound of Formula 1 below, its optical isomers, diastereomers, solvates, hydrates, and pharmaceutically acceptable salts thereof:

[0018] [Chemical Formula 1]

[0019]

[0020] In the above chemical formula 1,

[0021] Rings A, B, and C are each independently C 3-12 Cycloalkyl, C 6-12 Aril, C 3-12 Heteroaryl and C 3-12 It is any one selected from heterocyclils, and

[0022] The above C 3-12 Cycloalkyl, C 6-12 Aril, C 3-12 Heteroaryl or C 3-12 Each heterocyclic can be monocyclic, bicyclic, or polycyclic, and

[0023] Here, C 3-12 Cycloalkyl, C 6-12 Aril, C 3-12 Heteroaryl or C 3-12 Heterocyclile is R 3 Substituted or unsubstituted with 1 to 5 substituents each independently selected from, and

[0024] Here, C 3-12 Cycloalkyl or C 3-12 Heterocycliles are saturated or partially saturated;

[0025] L 1 , L 2 , L 3 and L 4 does not exist or each independently C 1-3 Alkylene, -O-, -NH-, -N(C 1-3 Alkyl)-, -NH(C 1-3 Alkyl)-, -O(C 1-3Alkyl)-, -S-, -SO-, -SO2-, -SO2NH-, -C(O)-, -C(H)=, -CF2-, -CHF-, C 2-4 Alkenylene, C 2-4 alkynylene, C 1-6 Aryllene, C 5-10 Heteroarylene, C 3-8 Cycloalkylene, C 3-8 Heterocycloalkylene, or direct bonding;

[0026] X, Y, and Z are each independently N, CH, or CR 4 This or,

[0027] X is CH, Y is S, and Z is a single bond;

[0028] R 1 is -Y1-Y2, and

[0029] Y1 is directly coupled, C 1-6 alkyl , C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 alkynylene, C 1-6 Aryllene, C 5-10 Heteroarylene, C 3-8 Cycloalkylene, or C 3-8 It is a heterocycloalkylene, and

[0030] Y2 is C 1-6 Alkyl, C 1-6 Alkoxy , C 3-8 Cycloalkyl, C 6-10 Aril, C 1-6 Heteroalkyl, C 3-8 Heterocycloalkyl, or C 0-8 It is heteroaryl, and

[0031] Here, each Y1 and Y2 is independently R 3 Substituted or unsubstituted with 1 to 5 substituents selected from;

[0032] R 2 is hydrogen, -COOH, CN, or a carboxyl surrogate;

[0033] R3 and R 4 are independently hydrogen, deuterium, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, oxo(=O), thiol, C 1-6 Alkylthio, C 1-6 Alkylsulfonyl, Halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, cyano, amino, C 1-6 Alkylamino, C 1-6 haloalkylamino, di(C 1-3 Alkyl)amino, carbonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkoxycarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, di(C 1-6 Alkyl)aminocarbonyl, carboxyl, hydroxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Hydroxyalkylamino, (C 1-3 Alkoxy)C 1-3 Alkyl, (C 1-3 Alkoxy)C 1-3 Alkoxy, (C 1-3 Alkoxy)C 1-3 Alkylamino, C 1-6 Aminoalkyl, C 1-6 Aminoalkoxy, C 1-6 Aminoalkylamino, C 6-10 Aril, C 1-8 Heteroaryl, C 1-8 Heteroaryloxy, C 1-8 Heteroarylamino, C 3-8 Heterocyclil, C 3-8 Heterocyclyloxy, C 3-8 Heterocyclylamino, C 3-10 Heterocyclyloxyalkoxy or C 3-10 It is a heterocyclyloxyalkylamino, and

[0034] Here, C 1-6 Alkyl, C1-6 Alkoxy, C 3-8 Cycloalkyl, C 6-10 Aril, C 1-8 Heteroaryl or C 3-8 Heterocycliles, each independently

[0035] C 1-3 Alkyl, C 3-6 Cycloalkyl, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 1-3 Alkoxy, hydroxy, halogen, cyano, C 1-3 Hydroxyalkyl, (C 1-3 Alkoxy)C 1-3 Alkyl and C 1-3 Substituted or unsubstituted with 1 to 3 substituents selected from aminoalkyl;

[0036] It represents a single bond or a double bond.

[0037] Another aspect provides a pharmaceutical composition comprising the above-mentioned GLP-1 receptor agonist compound and a pharmaceutically acceptable excipient.

[0038] Another aspect provides a use for the prevention or treatment of various diseases related thereto, such as obesity, diabetes, or related metabolic diseases, using a GLP-1 receptor agonist compound or a pharmaceutical composition containing the same.

[0039] Another aspect provides a method for preventing or treating various related diseases, such as obesity, diabetes, or related metabolic diseases, using a GLP-1 receptor agonist compound or a pharmaceutical composition containing the same.

[0040] A compound according to one aspect exhibits activity as a novel GLP-1 receptor agonist and can be used for the prevention or treatment of various related diseases, such as obesity, diabetes, or related metabolic diseases.

[0041] The present invention will be described in more detail below. Unless otherwise defined, all technical terms used in the present invention are used in the sense generally understood by those skilled in the art in the relevant field of the present invention. Furthermore, while preferred methods or samples are described herein, similar or equivalents are also included within the scope of the present invention.

[0042] One aspect provides a compound selected from the compound of Formula 1 below, its optical isomers, diastereomers, solvates, hydrates, and pharmaceutically acceptable salts thereof:

[0043] [Chemical Formula 1]

[0044]

[0045] In the above chemical formula 1,

[0046] Rings A, B, and C are each independently C 3-12 Cycloalkyl, C 6-12 Aril, C 3-12 Heteroaryl and C 3-12 It is any one selected from heterocyclils, and

[0047] The above C 3-12 Cycloalkyl, C 6-12 Aril, C 3-12 Heteroaryl or C 3-12 Each heterocyclic can be monocyclic, bicyclic, or polycyclic, and

[0048] Here, C 3-12 Cycloalkyl, C 6-12 Aril, C 3-12 Heteroaryl or C 3-12 Heterocyclile is R 3 Substituted or unsubstituted with 1 to 5 substituents each independently selected from, and

[0049] Here, C 3-12 Cycloalkyl or C 3-12 Heterocycliles are saturated or partially saturated;

[0050] L1 , L 2 , L 3 and L 4 does not exist or each independently C 1-3 Alkylene, -O-, -NH-, -N(C 1-3 Alkyl)-, -NH(C 1-3 Alkyl)-, -O(C 1-3 Alkyl)-, -S-, -SO-, -SO2-, -SO2NH-, -C(O)-, -C(H)=, -CF2-, -CHF-, C 2-4 Alkenylene, C 2-4 alkynylene, C 1-6 Aryllene, C 5-10 Heteroarylene, C 3-8 Cycloalkylene, C 3-8 Heterocycloalkylene, or direct bonding;

[0051] X, Y, and Z are each independently N, CH, or CR 4 This or,

[0052] X is CH, Y is S, and Z is a single bond;

[0053] R 1 is -Y1-Y2, and

[0054] Y1 is directly coupled, C 1-6 alkyl , C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 alkynylene, C 1-6 Aryllene, C 5-10 Heteroarylene, C 3-8 Cycloalkylene, or C 3-8 It is a heterocycloalkylene, and

[0055] Y2 is C 1-6 Alkyl, C 1-6 Alkoxy , C 3-8 Cycloalkyl, C 6-10 Aril, C 1-6 Heteroalkyl, C 3-8 Heterocycloalkyl, or C 0-8 It is heteroaryl, and

[0056] Here, each Y1 and Y2 is independently R 3 Substituted or unsubstituted with 1 to 5 substituents selected from;

[0057] R 2 is hydrogen, -COOH, CN, or a carboxyl surrogate;

[0058] R 3 and R 4 are independently hydrogen, deuterium, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, oxo(=O), thiol, C 1-6 Alkylthio, C 1-6 Alkylsulfonyl, Halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, cyano, amino, C 1-6 Alkylamino, C 1-6 haloalkylamino, di(C 1-3 Alkyl)amino, carbonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkoxycarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, di(C 1-6 Alkyl)aminocarbonyl, carboxyl, hydroxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Hydroxyalkylamino, (C 1-3 Alkoxy)C 1-3 Alkyl, (C 1-3 Alkoxy)C 1-3 Alkoxy, (C 1-3 Alkoxy)C 1-3 Alkylamino, C 1-6 Aminoalkyl, C 1-6 Aminoalkoxy, C 1-6 Aminoalkylamino, C 6-10 Aril, C 1-8 Heteroaryl, C 1-8 Heteroaryloxy, C 1-8 Heteroarylamino, C3-8 Heterocyclil, C 3-8 Heterocyclyloxy, C 3-8 Heterocyclylamino, C 3-10 Heterocyclyloxyalkoxy or C 3-10 It is a heterocyclyloxyalkylamino, and

[0059] Here, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 6-10 Aril, C 1-8 Heteroaryl or C 3-8 Heterocycliles, each independently

[0060] C 1-3 Alkyl, C 3-6 Cycloalkyl, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 1-3 Alkoxy, hydroxy, halogen, cyano, C 1-3 Hydroxyalkyl, (C 1-3 Alkoxy)C 1-3 Alkyl and C 1-3 Substituted or unsubstituted with 1 to 3 substituents selected from aminoalkyl;

[0061] It represents a single bond or a double bond.

[0062] In one implementation example,

[0063] -L 1 -L 2 - is any one selected from the group consisting of -CH2-, -O-, -S-, -CH2O-, -OCH2-, CH2S-, -SCH2-, -OC(H,Me)-, -NH-, -N(Me)-, -N(Et)-, -NHCH2-, -N(Me)CH2-, and -SO2NH-;

[0064] L 3 -O-, NH-, -C(O)-, -CH2-, -C(H)=, -CF2-, -SO2-, -N(Me)-, direct bonding, and It is any one selected from the group consisting of;

[0065] L 4 It can be any one selected from the group consisting of -CH2-, -C(O)-, -CH2O-, and -OCH2-.

[0066] In one implementation example,

[0067] R 1 is substituted or unsubstituted C 1-12 Alkyl, substituted, or unsubstituted C 6-16 Arylalkylene, substituted or unsubstituted C 1-12 Heteroalkyl, substituted or unsubstituted C 0-12 Heteroarylalkylene, substituted or unsubstituted C 3-12 Cycloalkyl, or substituted or unsubstituted C 4-12 Cycloalkylalkylene, substituted or unsubstituted C 3-12 Heterocycloalkyl, or substituted or unsubstituted C 4-12 It can be a heterocycloalkylene.

[0068] In one implementation example,

[0069] R 1 is substituted or unsubstituted C 1-12 Alkyl, substituted, or unsubstituted C 7-12 Arylalkylene, substituted or unsubstituted C 1-6 Heteroalkyl, substituted or unsubstituted C 6-12 Heteroarylalkylene, substituted or unsubstituted C 3-12 Cycloalkyl, or substituted or unsubstituted C 4-12 Cycloalkylalkylene, substituted or unsubstituted C 3-12 Heterocycloalkyl, or substituted or unsubstituted C 4-12 It may be a compound that is a heterocycloalkylene.

[0070] In one implementation example,

[0071] R 1 is -Y1-Y2, and

[0072] Y1 is directly connected or C 1-6 It is an alkylene, and

[0073] Y2 is C 1-6 Alkyl, C 1-6 Alkoxy , C 3-8 Cycloalkyl, C 6-10 Aril, C 1-6 Heteroalkyl, C 3-8 Heterocycloalkyl, or C 0-8 It is heteroaryl, and

[0074] Here, each Y1 and Y2 is independently R 3 It may be substituted or unsubstituted with 1 to 5 substituents selected from.

[0075] In one implementation example,

[0076] R 1 is -Y1-Y2, and

[0077] Y1 is C 1-3 It is an alkylene or a direct bond,

[0078] Y2 is C 1-6 Alkyl, C 1-6 Alkoxy, , , , , , , , , , , , , , , , , , , , , , , , , , , and It is one of the selected from among, and

[0079] Here, each Y1 and Y2 is independently C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6Alkinyl, C 1-6 Alkoxy, oxo(=O), thiol, C 1-6 Alkylthio, C 1-6 Alkylsulfonyl, Halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, cyano, amino, C 1-6 Alkylamino, C 1-6 haloalkylamino, di(C 1-3 Alkyl)amino, carbonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkoxycarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, di(C 1-3 Alkyl)aminocarbonyl, hydroxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Hydroxyalkylamino, (C 1-3 Alkoxy)C 1-3 Alkyl, (C 1-3 Alkoxy)C 1-3 Alkoxy, (C 1-3 Alkoxy)C 1-3 Alkylamino, C 1-6 Aminoalkyl, C 1-6 Aminoalkoxy, C 1-6 Aminoalkylamino, C 6-8 Aryl, and C 3-8 It may be substituted or unsubstituted with 1 to 3 substituents selected from heteroaryls.

[0080] In one implementation example,

[0081] The above carboxyl group substitutes are -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, , , , , , , tetrazolyl, and -COO-R aIt is one of the selected from among, and

[0082] Here -COO-R a is (isobutyryloxy)methyl ester, (pivaloyloxy)methyl ester, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, or other biodegradable ester groups;

[0083] R 5 is hydrogen or C 1-6 It can be an alkyl.

[0084] In one implementation example,

[0085] Rings A, B, and C are each independently C 3-12 Cycloalkyl, C 6-12 Aril, C 0-12 Heteroaryl and C 3-12 It can be heterocyclil.

[0086] In one implementation example,

[0087] Ring A is or And,

[0088] T 1 , T 2 , T 3 , T 4 , and T 5 Each is independently selected from N, NH, CH, and CH2; T 1 , T 2 , T 3 , T 4 , and T 5 Among them, those that are N or NH are 3 or fewer, and

[0089] S 1 and S 2 Each is independently selected from O, S, N, NH, CH, and CH2, and

[0090] n can be an integer from 0 to 5.

[0091] In one implementation example,

[0092] Ring A can be phenyl, benzofuran, or pyridine.

[0093] In one implementation example,

[0094] Ring B is And,

[0095] Q 1 , Q 2 , Q 3 , and Q 4 Wow, U 1 , U 2 , U 3 , and U 4 -C(H)=, -O-, -S-, -S(O)2-, -C(O)-, -N-, -N=, -N(R 7 )-, -C-, -C(R 7 )=, or -C(R 7 )(R 8 )- and;

[0096] R 7 and R 8 Each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, oxo(=O), thiol, C 1-6 Alkylthio, C 1-6 Alkylsulfonyl, Halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, cyano, amino, C 1-6 Alkylamino, C 1-6 haloalkylamino, di(C 1-3 Alkyl)amino, carbonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkoxycarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, di(C 1-3 Alkyl)aminocarbonyl, hydroxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Hydroxyalkylamino, (C 1-3 Alkoxy)C 1-3 Alkyl, (C 1-3 Alkoxy)C 1-3 Alkoxy, (C1-3 Alkoxy)C 1-3 Alkylamino, C 1-6 Aminoalkyl, C 1-6 Aminoalkoxy, C 1-6 Aminoalkylamino, C 6-8 Aril, C 3-8 Heteroaryl, C 3-8 Heteroaryloxy, C 3-8 Heteroarylamino, C 3-8 Heterocyclil, C 3-8 Heterocyclyloxy, C 3-8 Heterocyclylamino, C 3-8 Heterocyclyloxyalkoxy or C 3-8 It can be a heterocyclyloxyalkylamino.

[0097] In one implementation example,

[0098] Ring B is , , , , , , , , , , , , , , , , , , , , , , , , , , , , and It is one of the selected ones, and

[0099] represents a single bond or a double bond,

[0100] R 9 is hydrogen or C 1-3 It is alkyl, and

[0101] The above ring B is R 3 It may be substituted or unsubstituted with at least one substituent independently selected from each.

[0102] In one embodiment, the ring B is R 3 It may be substituted or unsubstituted with 1 to 3, or 1 to 2, substituents each independently selected from.

[0103] In one implementation example, ring B is U 1 , U 2 , and U 3 It can be a compound where any two are -N= or -NH- and the other is C(H)=.

[0104] In one embodiment, ring B may be a fused pyrimidine heterocycle. For example, ring B may be a heterocycle in which thiophene, cyclopentane, furan, thiazole, imidazole, pyrrole, or pyrazole are each fused with pyrimidine. For example, ring B is thieno[3,2-d]pyrimidine, thieno[2,3-d]pyrimidine, 6,7-dihydro-5H-cyclopenta[d]pyrimidine, cyclopenta[d]pyrimidine, furo[3,4-d]pyrimidine, furo[3,2-d]pyrimidine, 5,7-dihydrofuro[3,4-d]pyrimidine, thiazolo[5,4-d]pyrimidine, 9H-purine, purine, pyrrolo[2,3-d]pyrimidine, 7H-pyrrolo[2,3-d]pyrimidine, 5H-pyrrolo[3,2-d]pyrimidine, pyrrolo[3,2-d]pyrimidine, or It may be pyrazolo[1,5-a]pyrimidine.

[0105] In one implementation example,

[0106] Ring C is And,

[0107] Here, W or Q is N, CH, or C;

[0108] When W or Q is N, adjacent represents a single bond;

[0109] When W or Q is CH, adjacent represents a single bond;

[0110] When W or Q is C, adjacent It represents a double bond or;

[0111] Or when W or Q is C, adjacent represents a single bond, where L3 or L4 connected to W or Q is -C(H)=;

[0112] n can be an integer from 0 to 5.

[0113] In one embodiment, ring C may be an aromatic or non-aromatic monocyclic compound. For example, ring C may be a monocyclic nitrogen heterocyclic compound and may be a saturated or partially saturated compound. In another example, ring C is C 6-12 It can be an aryl, for example, phenyl. For example, ring C can be piperidine, piperazine, 5,6-dihydropyridine, pyridine, or phenyl.

[0114] In one embodiment, the ring C is R 3 It may be substituted or unsubstituted with 1 to 3, or 1 to 2, substituents each independently selected from.

[0115] In one implementation example,

[0116] The substituted Y1 or substituted Y2 is as follows R 6 It is substituted or unsubstituted with 1 to 3 substituents independently selected from each, and

[0117] R 6 C 1-6 Alkyl, C 3-8Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Alkoxy, hydroxy, halogen, amino, C 1-6 Alkylamino, C 1-6 haloalkylamino, di(C 1-3 Alkyl)amino, cyano, C 1-6 Hydroxyalkyl, (C 1-3 Alkoxy)C 1-3 Alkyl, C 1-6 Aminoalkyl, C 3-8 Heterocyclil, C 6-10 Aryl, and C 1-8 It can be any one selected from heteroaryls.

[0118] In one implementation example,

[0119] Rings A, B, and C are each independently C 6-12 Aryl, Monocyclic C 3-12 Heteroaryl, bicyclic C 3-12 Heteroaryl, and saturated or partially saturated C 3-12 It is any one selected from heterocyclils, and

[0120] At this time, rings A, B, and C are C 1-3 Alkyl, halogen, and C 1-3 Substituted or unsubstituted with 1 to 3 substituents selected from haloalkyls;

[0121] L 1 is C 1-3 Alkylene, -O-, or -S- and;

[0122] L 2 is C 1-3 It is an alkylene, -O-, or direct bond;

[0123] L 3 is -O- or direct bonding;

[0124] L 4 is C 1-3 It is an alkylene;

[0125] X, Y, and Z are each independently N, CH, or CR 10This or,

[0126] X is CH, Y is S, and Z is a single bond, or

[0127] X and Z are CH, and Y is CR 15 And;

[0128] R 1 is -Y1-Y2, and

[0129] Y1 is directly connected or C 1-6 It is an alkylene, and

[0130] Y2 is C 1-6 Alkyl, C 1-6 Alkoxy , C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, or C 0-8 It is heteroaryl, and

[0131] Here, each Y1 and Y2 is independently C 1-3 Alkyl, halogen, and C 1-3 Substituted or unsubstituted with 1 to 3 substituents selected from haloalkyls;

[0132] R 2 is hydrogen, -COOH, CN, or a carboxyl surrogate;

[0133] R 10 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, Halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, cyano, amino, C 1-6 Alkyl carbonyl, carboxyl, (C 1-3 Alkoxy)C 1-3 Alkoxy, (C 3-6 cycloalkyl)C 1-3 Alkyl, (C 3-6 cycloalkyl)C 1-3 Alkoxy, or C 3-8 It is a heterocyclil;

[0134] R 15 is a carboxyl group;

[0135] It can represent a single bond or a double bond.

[0136] In one implementation example,

[0137] Ring A is or And,

[0138] T 10 , T 20 , T 30 , T 40 , and T 50 are all CH or,

[0139] T 10 , T 20 , T 30 , T 40 , and T 50 One of them is N, and the rest are CH,

[0140] S 10 and S 20 One of them is O, S, or N, and the rest are CH;

[0141] Ring B is And,

[0142] Q 10 , Q 20 , Q 30 , and Q 40 Wow, U 10 , U 20 , U 30 , and U 40 -C(H)=, -O-, -S-, -N-, -N=, -N(R 12 )-, -C-, -C(R 12 )=, or -C(R 12 )(R 13 )- and;

[0143] Ring C is And,

[0144] Here, W is N, CH, or C, and Q is N or,

[0145] W and Q are both C;

[0146] R 11 C each independently 1-3 Alkyl, halogen, and C 1-3 Selected from haloalkyls;

[0147] R 12 and R 13 Each independently consists of hydrogen or C 1-3 It is alkyl;

[0148] m can be an integer from 0 to 3.

[0149] In one implementation example, L 1 is C 1-3 It can be alkylene, -O-, or -S-.

[0150] In one implementation example, L 2 is C 1-3 It can be an alkylene, -O-, or direct bond.

[0151] In one implementation example, L 3 It can be -O- or a direct bond.

[0152] In one implementation example, L 4 is C 1-3 It can be an alkylene.

[0153] In one implementation example,

[0154] L 1 is methylene, -O-, or -S-;

[0155] L 2 is methylene, -O-, or a direct bond;

[0156] L 3 is -O- or direct bonding;

[0157] L 4 is methylene;

[0158] X is N or CH, Y is CH, and Z is CH or CR 14 This or,

[0159] X is CH, Y is S, and Z is a single bond, or

[0160] X and Z are CH, and Y is CR 16 And;

[0161] R 1 is -Y1-Y2, and

[0162] Y1 is methylene, ethylene, or directly bonded, and

[0163] Y2 is C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 It is a cycloalkyl, oxetane, tetrahydrofuran, thiazole, or imidazole, and

[0164] Each Y2 is C 1-3 Alkyl, halogen, and C 1-3 Substituted or unsubstituted with 1 to 3 substituents independently selected from haloalkyls;

[0165] R 2 is hydrogen, -COOH, CN, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -CONHSO2H, CONHSO2(C 1-3 alkyl), , tetrazolyl, and -COO-R a It is one of the selected from among, and

[0166] Here -COO-R a is (isobutyryloxy)methyl ester, (pivaloyloxy)methyl ester, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, or other biodegradable ester groups;

[0167] R 14 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, Halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, carboxyl, (C 1-3 Alkoxy)C 1-3 Alkoxy, or -OC 1-3 Alkyl-C 3-6It is cycloalkyl;

[0168] R 16 It can be a carboxyl group.

[0169] In one embodiment, Y1 may be methylene (-CH2-), ethylene (-CH2-CH2-), or a direct bond.

[0170] In one implementation example, Y2 is C 1-3 Alkyl, halogen, and C 1-3 C substituted with or unsubstituted by 1 to 3 substituents each independently selected from haloalkyls 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 It may be cycloalkyl, oxetane, tetrahydrofuran, thiazole, or imidazole, for example, methyl, methoxy, (fluoromethyl)cyclopropyl, (dimethyl)tetrahydrofuran, thiazole, or (ethyl)imidazole.

[0171] In one implementation example, R 4 and R 14 Each may be independently selected from F, Cl, Br, I, methoxy(-OCH3), ethoxy(-OCH2CH3), methoxyethoxy(-OCH2CH2-OCH3), isopropoxy(-OCH(CH3)2), cyclopropoxy(-O-cyclopropyl), and cyclopropylmethoxy((-OCH2-cyclopropyl).

[0172] The number of carbon atoms of each substituent mentioned herein may be in the range of 0 to 20, for example, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 3 to 10, 3 to 8, or 2 to 6. For example, the substituent is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, oxo(=O), thiol, C 1-6 Alkylthio, C 1-6 Alkylsulfonyl, Halogen, C 1-6 Haloalkyl, C 1-6Haloalkoxy, C 3-8 Cycloalkyl, cyano, amino, C 1-6 Alkylamino, C 1-6 Haloalkylamino, C 2-8 Dialkylamino, di(C 1-4 Alkyl)amino, carbonyl (C=O), C 1-6 Alkyl carbonyl, C 1-6 Alkoxycarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, C 3-8 Dialkylaminocarbonyl, di(C 1-4 Alkyl)aminocarbonyl, hydroxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Hydroxyalkylamino, C 2-6 Alkoxyalkyl, (C 1-3 Alkoxy)C 1-3 Alkyl, C 2-6 Alkoxyalkoxy, (C 1-3 Alkoxy)C 1-3 Alkoxy, C 2-6 Alkoxyalkylamino, (C 1-3 Alkoxy)C 1-3 Alkylamino, C 1-6 Aminoalkyl, C 1-6 Aminoalkoxy, C 1-6 Aminoalkylamino, C 6-8 Aril, C 3-8 Heteroaryl, C 1-8 Heteroaryloxy, C 1-8 Heteroarylamino, C 3-8 Heterocyclil, C 3-8 Heterocyclyloxy, C 3-8 Heterocyclylamino, C 3-10 Heterocyclyloxyalkoxy or C 3-10 It may be a heterocyclyloxyalkylamino.

[0173] In one embodiment, the compound may be a compound selected from the following compounds, their optical isomers, diastereomers, solvates, hydrates, and pharmaceutically acceptable salts thereof:

[0174] 1) (S)-2-((4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0175] 2) (S)-2-((4-((2-((4-cyano-2-fluorobenzyl)oxy)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0176] 3) (S)-2-((4-((2-((4-ethinyl-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0177] 4) (S)-2-((4-((2-((4-cyclopropyl-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0178] 5) 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0179] 6) 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0180] 7) 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-3-(((S)-oxetane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid;

[0181] 8) (S)-2-((4-((2-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0182] 9) 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[2,3-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0183] 10) 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-((S)-4,4-dimethyltetrahydrofuran-3-yl)-4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0184] 11) 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-fluoro-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0185] 12) 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0186] 13) 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-fluoro-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0187] 14) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0188] 15) 2-(((2S,4S)-4-((2-((4-chloro-2-cyanofenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0189] 16) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0190] 17) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-fluoro-1-(thiazole-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0191] 18) 2-(((2S,4S)-4-((2-(((4-chlorobenzofuran-7-yl)oxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0192] 19) 2-(((2S,4S)-4-((2-(((4-chlorobenzofuran-7-yl)oxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0193] 20) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-(2-methoxyethoxy)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0194] 21) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid;

[0195] 22) 2-(((2S,4S)-4-((2-((4-chloro-2-methoxyphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0196] 23) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-isopropoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0197] 24) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-5-carboxylic acid;

[0198] 25) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-methyl-1H-benzo[d]imidazole-6-carboxylic acid;

[0199] 26) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-cyclopropoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0200] 27) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-(cyclopropylmethoxy)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0201] 28) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[2,3-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0202] 29) 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0203] 30) 2-(((2S,4S)-4-((2-((2-chloro-4-methylphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0204] 31) 2-(((2S,4S)-4-((2-((4-chloro-2-cyanofenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-(difluoromethoxy)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0205] 32) 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-(difluoromethoxy)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0206] 33) 2-(((2S,4S)-4-((2-((2-cyano-4-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0207] 34) 2-(((2S,4S)-4-((2-((4-bromo-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0208] 35) 4-ethoxy-2-(((2S,4S)-2-methyl-4-((2-((perfluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0209] 36) 2-(((2S,4S)-4-((2-((2,4-difluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0210] 37) 4-ethoxy-2-(((2S,4S)-4-((2-((4-ethinyl-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0211] 38) 2-(((2S,4S)-4-((2-((2,4-dimethylphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0212] 39) 4-ethoxy-2-(((2S,4S)-4-((2-((4-fluoro-2-methoxyphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0213] 40) 4-ethoxy-2-(((2S,4S)-4-((2-((2-fluoro-4-(trifluoromethyl)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0214] 41) 4-ethoxy-2-(((2S,4S)-2-methyl-4-((2-((4-(trifluoromethyl)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0215] 42) 4-ethoxy-2-(((2S,4S)-4-((2-((2-fluoro-4-methylphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0216] 43) 4-ethoxy-2-(((2S,4S)-2-methyl-4-((2-((4-(trifluoromethoxy)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0217] 44) 2-(((2S,4S)-4-((2-((4-chlorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0218] 45) 2-(((2S,4S)-4-((2-((4-(1H-1,2,4-triazole-1-yl)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0219] 46) 2-(((2S,4S)-4-((2-((2,5-difluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0220] 47) 2-(((2S,4S)-4-((2-((4-cyano-2-(trifluoromethyl)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0221] 48) 2-(((2S,4S)-4-((2-((4-(1H-imidazole-1-yl)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0222] 49) 4-ethoxy-2-(((2S,4S)-4-((2-((2-methoxy-4-(trifluoromethyl)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0223] 50) 2-(((2S,4S)-4-((2-((4-bromo-3-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0224] 51) 4-ethoxy-2-(((2S,4S)-4-((2-((4-fluoro-2-methylphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0225] 52) 2-(((2S,4S)-4-((2-((4-bromo-2,6-difluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0226] 53) 2-(((2S,4S)-4-((2-((2-cyano-4-methylphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0227] 54) 2-(((2S,4S)-4-((2-((4-chloro-2-(trifluoromethyl)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0228] 55) 2-(((2S,4S)-4-((2-((4-chloro-3,5-difluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0229] 56) 2-(((2S,4S)-4-((2-((4-cyanofenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0230] 57) (S)-2-((4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0231] 58) 2-(((2S,4S)-4-((2-((3,5-dimethylphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0232] 59) 4-ethoxy-2-(((2S,4S)-2-methyl-4-((2-((2,4,6-trichlorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0233] 60) 2-(((2S,4S)-4-((2-((3,4-dichlorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0234] 61) 2-(((2S,4S)-4-((2-((4-chloro-3,5-dimethylphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0235] 62) 2-(((2S,4S)-4-((2-((4-chloro-2,6-difluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0236] 63) 4-ethoxy-2-(((2S,4S)-2-methyl-4-((2-((3,4,5-trifluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0237] 64) 2-(((2S,4S)-4-((2-((4-chloro-3-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0238] 65) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0239] 66) 5-chloro-2-((4-(((2S,4S)-1-((4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-6-(1H-tetrazole-5-yl)-1H-benzo[d]imidazole-2-yl)methyl)-2-methylpiperidine-4-yl)oxy)thieno[3,2-d]pyrimidine-2-yl)methoxy)benzonitrile;

[0240] 67) (isobutyryloxy)methyl 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate;

[0241] 68) (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate;

[0242] 69) (pivaloyloxy)methyl 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate;

[0243] 70) (isobutyryloxy)methyl 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate;

[0244] 71) (pivaloyloxy)methyl 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate;

[0245] 72) (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate;

[0246] 73) (S)-2-((4-((2-((4-chlorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0247] 74) (S)-2-((4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0248] 75) (S)-2-((4-((2-((2-methoxy-4-(trifluoromethyl)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0249] 76) (S)-2-((4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0250] 77) 4-fluoro-2-(((2S,4S)-4-((2-(((4-fluorobenzofuran-7-yl)oxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0251] 78) 2-(((2S,4S)-4-((2-(((4-cyanobenzofuran-7-yl)oxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0252] 79) 2-(((2S,4S)-4-((2-(((4-cyano-2-fluorobenzofuran-7-yl)oxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0253] 80) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0254] 81) 2-(((2S,4S)-4-((2-((4-acetyl-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0255] 82) 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[2,3-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0256] 83) 2-(((2S,4S)-4-((2-((4-chloro-2-cyanofenoxy)methyl)thieno[2,3-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0257] 84) 2-(((2S,4S)-4-((2-((4-cyano-2-methoxyphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0258] 85) 2-(((2S,4S)-4-((2-((4-chloro-2-cyanofenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0259] 86) (S)-2-((4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0260] 87) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile;

[0261] 88) (S)-2-((4-((2-(((4-cyano-2-fluorophenyl)thio)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0262] 89) 2-(((2S,4S)-4-((2-((2-fluoro-4-(oxetane-3-yl)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0263] 90) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-((1-ethyl-1H-imidazole-5-yl)methyl)-4-methoxy-1H-benzo[d]imidazole-6-carboxylic acid;

[0264] 91) (S)-2-(4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-fluorobenzyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0265] 92) (S)-2-(4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2,5-difluorobenzyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0266] 93) (S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0267] 94) 2-(((S)-4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0268] 95) 2-(((S)-4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-6-methyl-3,6-dihydropyridine-1(2H)-yl)methyl)-4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0269] 96) 2-(((S)-4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methyl-3,6-dihydropyridine-1(2H)-yl)methyl)-4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0270] 97) 2-(((2S)-4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperidine-1-yl)methyl)-4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0271] 98) (S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[3,2-d]pyrimidine-2-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0272] 99) (S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[3,2-d]pyrimidine-2-yl)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0273] 100) 2-(((S)-4-(4-((4-chlorobenzofuran-7-yl)methoxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0274] 101) 2-(((S)-4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0275] 102) 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0276] 103) 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0277] 104) 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-N-(3-methyl-1H-indazole-5-yl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxamide;

[0278] 105) 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-5-carboxylic acid;

[0279] 106) (S)-2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-methyl-1H-benzo[d]imidazole-6-carboxylic acid;

[0280] 107) 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-(cyclopropylmethoxy)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0281] 108) 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-cyclopropoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0282] 109) 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[3,2-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0283] 110) 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)-7-methylthieno[3,2-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0284] 111) 2-(((S)-4-(4-((2-fluoro-4-(oxetane-3-yl)benzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0285] 112) (S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0286] 113) (S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-5,7-dihydrofuro[3,4-d]pyrimidine-2-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0287] 114) 2-(((S)-4-(6-((4-chloro-2-fluorobenzyl)oxy)-9-methyl-9H-purine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0288] 115) 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)furo[3,2-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0289] 116) 2-(((S)-4-(7-((4-chloro-2-fluorobenzyl)oxy)thiazolo[5,4-d]pyrimidine-5-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0290] 117) 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0291] 118) 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0292] 119) 2-(((S)-4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0293] 120) 2-(((S)-4-(4-((4-cyano-2-fluorobenzyl)oxy)-6-methylthieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0294] 121) 2-(((S)-4-(4-((4-cyano-2-fluorobenzyl)oxy)-5,6-dimethylthieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0295] 122) (S)-2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)thieno[3,2-d]pyrimidine-4-yl)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0296] 123) (S)-2-((4-(2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0297] 124) 2-(((S)-4-(2-((4-chloro-2-fluorobenzyl)oxy)-7-methylthieno[3,2-d]pyrimidine-4-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0298] 125) (S)-2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0299] 126) 2-(((S)-4-(5-((4-chloro-2-fluorobenzyl)oxy)pyrazolo[1,5-a]pyrimidine-7-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0300] 127) (S)-2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)thieno[3,2-d]pyrimidine-7-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0301] 128) (S)-2-((4-(2-(4-cyano-2-fluorophenoxy)thieno[3,2-d]pyrimidine-7-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0302] 129) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)-7-methylthieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0303] 130) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)-6-methylthieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0304] 131) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)-6-methylthieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0305] 132) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)-6-methylthieno[2,3-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0306] 133) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)-5-methylthieno[2,3-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0307] 134) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)-5,6-dimethylthieno[2,3-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0308] 135) 2-(((2S,4S)-4-((2-((4-chloro-2-cyanofenoxy)methyl)-5,6-dimethylthieno[2,3-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0309] 136) 2-(((2S,4S)-4-((5-((4-cyano-2-fluorophenoxy)methyl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidine-7-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0310] 137) 2-(((2S,4S)-4-((2-(((5-chloro-3-fluoropyridine-2-yl)oxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0311] 138) 2-(((2S,4S)-4-((2-(((5-cyanopyridine-2-yl)oxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0312] 139) 2-(((2S,4S)-4-((2-(((5-chloropyridine-2-yl)oxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0313] 140) (S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)benzyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0314] 141) (S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)benzyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0315] 142) (S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-fluorobenzyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid;

[0316] 143) (S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-3-fluorobenzyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; and

[0317] 144) (S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2,5-difluorobenzyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.

[0318] As used herein, the term "direct bond" refers to a case where one atom is directly connected to another atom through a single bond. That is, it includes cases where the atom is directly attached to a carbon of a ring or a heteroatom without the intervention of other atoms or functional groups.

[0319] The terms “halogen” and “halo” as used in this specification are used interchangeably and represent fluoro (F), chloro (Cl), bromo (Br), and iodine (I).

[0320] As used herein, the term "alkyl" refers to a straight-chain or branched hydrocarbon residue that may be substituted or unsubstituted unless otherwise noted. For example, alkyl groups may include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, or t-butyl.

[0321] As used herein, the term "cycloalkyl" refers to a saturated or partially saturated (i.e., cycloalkenyl) or polycyclic hydrocarbon ring that may be substituted or unsubstituted, unless otherwise noted. For example, the cycloalkyl group may include, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

[0322] As used herein, the term “heterocycloalkyl” refers to a cyclic alkyl that may be substituted or unsubstituted and comprises one or more heteroatoms selected from N, O, and S, unless otherwise noted. For example, the heterocycloalkyl group may include, but is not limited to, oxetanyl, azetidinyl, piperidinyl, piperazinyl, tetrahydrofuranyl, tetrahydropyranyl, or 2-pyrrolidonyl, morpholinyl, or pyrrolidinyl.

[0323] The term "haloalkyl" as used in this specification indicates, unless otherwise noted, that it includes monohaloalkyl and polyhaloalkyl groups that may be substituted or unsubstituted. For example, haloalkyls may include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, trifluoromethylethyl, or pentafluoroethyl.

[0324] Unless otherwise noted, the term "hydroxyalkyl" as used in this specification refers to an alkyl group in which one or more hydrogen atoms of the alkyl group are replaced by hydroxyl groups.

[0325] The term "alkoxy" as used herein indicates, unless otherwise noted, a straight-chain or branched hydrocarbon residue connected to oxygen, which may be substituted or unsubstituted. For example, alkoxy may include, but is not limited to, methoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy, or t-butoxy.

[0326] As used herein, the term “cycloalkoxy” refers, unless otherwise noted, to an ether structure in which a saturating or partially saturated (i.e., cycloalkenyl) cyclic or polycyclic hydrocarbon ring is connected to an oxygen atom, which may be substituted or unsubstituted. For example, the cycloalkoxy group may include, but is not limited to, cyclopropoxy (i.e., -O-cyclopropyl), cyclobutoxy (i.e., -O-cyclobutyl), cyclopentyloxy (i.e., -O-cyclopentyl), etc.

[0327] Unless otherwise noted, the term "alkoxyalkyl" as used in this specification refers to an alkyl group in which one or more hydrogen atoms of the alkyl group are replaced by an alkoxy group. For example, alkoxyalkyls may include, but are not limited to, methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, methoxypropyl, ethoxypropyl, or isopropoxymethyl.

[0328] Unless otherwise noted, the term "aminoalkyl" as used in this specification refers to an alkyl group in which one or more hydrogen atoms of the alkyl group are replaced by an amino group. For example, aminoalkyl may include, but is not limited to, aminomethyl (-CH2NH2), aminoethyl (-CH2CH2NH2), amino-1-methyl-ethyl (-CH(CH3)CH2NH2), aminopropyl (-CH2CH2CH2NH2), 2-aminobutyl (-CH2CH2CH(CH3)NH2), or 2-aminopentyl (CH2CH2CH(CH2CH3)NH2).

[0329] Unless otherwise noted, the term "alkoxyalkoxy" as used in this specification refers to a structure in which another alkoxy group is substituted for the alkyl portion of an alkoxy group. For example, alkoxyalkoxy may include, but is not limited to, methoxymethoxy (-OCH2OCH3), ethoxymethoxy (-OCH2CH2OCH3), methoxyethoxy (-OCH(OCH3)CH3), ethoxyethoxy (-OCH2CH2OCH2CH3), methoxypropoxy (-OCH2CH2CH2OCH3), or ethoxypropoxy (-OCH2CH2OCH2CH2CH3).

[0330] Unless otherwise noted, the term "alkylthio" as used in this specification refers to a structure in which a thio group (-S-) is bonded to an alkyl group. For example, alkylthios may include, but are not limited to, methylthio (-S-CH3), ethylthio (-S-CH2CH3), propylthio (-S-CH2CH2CH3), etc.

[0331] Unless otherwise noted, the term "alkoxyalkylamino" as used in this specification refers to a structure in which an amino group (-NH2) is bonded to an alkyl group in which one or more hydrogen atoms of the alkyl group are substituted with an alkoxy group. For example, alkoxyalkylamino may include, but is not limited to, methoxymethylamino (-NH-CH2OCH3), ethoxyethylamino (-NH-CH2CH2OCH2CH3), methoxypropylamino (-NH-CH2CH2CH2OCH3), etc.

[0332] As used herein, the term "aryl" refers to an aromatic group that may be substituted or unsubstituted unless otherwise noted, e.g., C3-C 10 It may include aryls, C3-C8 aryls, or C3-C6 aryls, etc., and double bonds alternate (resonate) between adjacent carbon atoms or suitable heteroatoms, and include monocyclic, bicyclic, or polycyclic. For example, it may include phenyl, biphenyl, naphthyl, toluyl, or naphthalenyl, etc., but is not limited thereto.

[0333] As used herein, the term “heteroaryl” may mean a monocyclic, bicyclic, or polycyclic aromatic group that may be substituted or unsubstituted, comprising one or more heteroatoms selected from N, O, and S, unless otherwise noted. For example, monocyclic heteroaryls may include, but are not limited to, pyridinyl, imidazolyl, thiazolyl, oxazolyl, thiophenyl, furanyl, pyrrolyl, isoxazolyl, pyrazolyl, triazolyl, thiadiazolyl, tetrazolyl, oxadiazolyl, pyridazinyl, pyrimidinyl, or pyrazinyl. For example, bicyclic heteroaryls may include, but are not limited to, indolyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, thienopyrimidinyl, thienopyridinyl, quinolinyl, isoquinolinyl, purinyl, or furopyridinyl.

[0334] Unless otherwise noted, the term “carbocyclil” as used herein refers to a substituent comprising carbon ring atoms having the structure of a saturated carbocyclil (i.e., “cycloalkyl”), a partially saturated carbocyclil (i.e., “cycloalkenyl”), or a completely unsaturated carbocyclil (i.e., “aryl”). The carbocyclil may have a single ring (monocyclic), bicyclic, or polycyclic ring structure. In this specification, the carbocyclil may comprise, for example, 3 to 14, or for example, 3 to 8, carbon ring atoms and may be saturated, unsaturated, or aromatic. Herein, ring atoms are atoms that are bonded together to form a ring or rings of the carbocyclil substituent. For example, saturated carbocyclil groups may include, but are not limited to, cyclopropyl, cyclopentyl, and cyclohexyl. For example, unsaturated carbocyclils may include three or fewer double bonds. For example, the aromatic carbocyclil group may be phenyl. Additionally, the term carbocyclil may include condensation combinations of carbocyclil groups, and may include, for example, naphthyl, phenanthril, indanyl, or indenyl, but is not limited thereto.

[0335] Unless otherwise noted, the term “heterocyclil” as used herein refers to a substituent comprising at least one heteroatom ring atom having a structure of a saturated heterocyclil (i.e., “heterocycloalkyl”), a partially saturated heterocyclil (i.e., “heterocycloalkenyl”), or a completely unsaturated heterocyclil (i.e., “heteroaryl”). The heterocyclil may have a single ring (monocyclic), bicyclic, or polycyclic ring structure. In this specification, the heterocyclil may comprise, for example, a total of 3 to 14 ring atoms, or for example, a total of 3 to 8 ring atoms, and may be saturated, unsaturated, or aromatic. Here, the ring atom is an atom that is bonded together to form a ring or rings of the heterocyclil substituent. For example, at least one of the ring atoms is nitrogen, oxygen, or sulfur, and the remaining ring atoms are independently selected from the group consisting of carbon, nitrogen, oxygen, and sulfur. For example, four or fewer ring atoms of the heterocyclile may be heteroatoms such as N, O, and S, for example, may include a total of 3 to 14 ring atoms, or for example, a total of 5 to 7 ring atoms, and may be saturated, unsaturated, or aromatic. For example, the heterocyclile may include furanyl, thiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, oxetanyl, dioxolanyl, oxazolyl, tyzolyl, imidazolyl, imidazolidinyl, imidazolidinyl, pyrazolyl, pyrazolidinyl, pyrazolidinyl, isoxazolyl, isothizolyl, oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl, pyridinyl, piperidinyl, dioxanyl, morpholino, dithianyl, thiomorpholino, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, sulfolanyl, triazinyl, azefinil, oxazefinil, thiazefinil, diazefinil, or thiazolidinyl, etc. However, it is not limited to this.In addition, the term heterocyclil may include a condensed heterocyclil group, and may include, for example, benzimidazolinyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl, oxazolopyridinyl, quinolinyl, quinazolinyl, quinoxazolinyl, dihydroquinazolinyl, benzothiazolyl, phthalimido, benzofuranyl, benzodiazepinyl, indolyl, or isoindolyl, but is not limited thereto.

[0336] Unless otherwise noted, the term "alkylene" as used herein comprises a straight-chain or branched divalent hydrocarbon group having 1 to 15 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 6 carbon atoms, and even more preferably 1 to 4 carbon atoms. Examples may include, but are not limited to, methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, or hexamethylene.

[0337] As used in this specification, the terms "alkylene," "alkenylene," "alkynylene," "arylene," "heteroarylene," "cycloalkylene," and "heterocycloalkylene" each represent a divalent group having two bonding positions in an alkyl, alkenyl, alkynylene, aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group. For example, unless otherwise noted, the term "alkenylene" as used in this specification comprises a straight-chain or branched divalent hydrocarbon group having 2 to 15 carbon atoms, preferably 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and even more preferably 2 to 4 carbon atoms, having one or more double bonds at any position. Examples may include, but are not limited to, vinylene, propenylene, butenylene, or pentenylene.

[0338] As used herein, the term "carboxyl surrogate" refers to a substitute compound or structure used in place of a carboxyl group (-COOH). By being used in place of a carboxyl group, it may be used to modify chemical properties, facilitate synthesis pathways, or increase reaction efficiency. For example, a carboxyl surrogate may be a carboxylic acid derivative such as an amide (-CONH2), an ester (-COOR), or a derivative thereof. In addition, for example, carboxyl surrogates include -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, , , , , , , tetrazolyl, and -COO-R a (Here -COO-R a It may be any one selected from (isobutyryloxy)methyl ester, (pivaloyloxy)methyl ester, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, or other biodegradable ester groups.

[0339] Unless otherwise noted, the term "alkyl carbonyl" as used herein refers to a group (e.g., of the -CO-R form) in which the "alkyl" is bonded to a carbonyl group (-CO-). For example, alkyl carbonyls include C1 alkyl carbonyls such as an acetyl group (-COCH3).

[0340] Unless otherwise noted, the term "alkylamino" as used in this specification refers to a group in which "alkyl" is substituted with one hydrogen atom bonded to the nitrogen atom of the amino group (-NH2) (e.g., -NH-R form) or two hydrogen atoms (e.g., -N(R)(R') form).

[0341] As used in this specification, the term "partially saturated" indicates that it includes at least one saturated site, i.e., at least one single bond.

[0342] As used herein, the term "stereoisomer" may mean a compound of the present invention or a salt thereof having the same chemical formula or molecular formula but differing optically or stereochemically, and includes optical isomers or diastereomers.

[0343] The term "optical isomer" as used in this specification refers to two stereoisomers of a compound that are mirror images of each other and do not overlap.

[0344] The term "diastereoisomer" as used in this specification refers to a stereoisomer having two or more chiral centers, the molecules of which are not mirror images of each other.

[0345] The compounds of the present invention may contain asymmetric or chiral centers and thus may exist in different stereoisomer forms. All stereoisomer forms of the compounds of the present invention, such as diastereomers, optical isomers, and racemic mixtures, are considered to constitute part of the present invention. A 50:50 mixture of optical isomers is called a racemic mixture or racemic mixture.

[0346] As used herein, the term “solvent” may mean a compound of the present invention or a salt thereof comprising stoichiometric or non-stoichiometric amounts of solvent bound by non-covalent intermolecular forces. Preferred solvents thereof may be volatile, non-toxic, and / or suitable for administration to humans. The “solvent” may comprise a molecular complex comprising said compound and one or more pharmaceutically acceptable solvent molecules, e.g., ethanol.

[0347] As used in this specification, the term "hydrate" refers to a complex in which the solvent molecule is water.

[0348] As used herein, the term "pharmaceuticalally acceptable salt" refers to a pharmaceutically acceptable organic or inorganic salt and may be prepared by any suitable method useful to those skilled in the art. For example, if the compound of the present invention is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method useful to those skilled in the art, for example, by treating said organic base with an inorganic acid or an organic acid.

[0349] According to another embodiment of the present invention, a pharmaceutical composition for the prevention or treatment of various diseases related thereto, including obesity and diabetes, is provided, comprising a therapeutically effective amount of the compound described above.

[0350] Another aspect provides a pharmaceutical composition comprising the above-mentioned GLP-1 receptor agonist compound, its optical isomer, diastereomer, solvate, hydrate, or pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.

[0351] In one embodiment, the pharmaceutical composition may contain a therapeutically effective amount of a compound selected from the compound of Formula 1, its optical isomers, diastereomers, solvates, hydrates, and pharmaceutically acceptable salts thereof.

[0352] As used herein, the term "therapeutic effective amount" refers to an amount of the compound of the present invention that treats or prevents a specific disease, condition, or disorder, alleviates, improves, or eliminates one or more symptoms of a specific disease, condition, or disorder, or prevents or delays the onset of one or more symptoms of a specific disease, condition, or disorder.

[0353] A physician with ordinary knowledge in the relevant technical field can easily determine and prescribe an effective required dose of the pharmaceutical composition. For example, the pharmaceutical composition may contain the compound in an amount of 0.0001 mg to 10 g, but is not limited thereto.

[0354] In one embodiment, the pharmaceutical composition may further include pharmaceutically acceptable additives in addition to the active ingredient. The additives may include, for example, diluents, disintegrants, binders, lubricants, surfactants, suspending agents, or emulsifiers, but are not limited thereto.

[0355] The pharmaceutical composition of the present invention can be formulated according to conventional methods and can be prepared in various forms of oral administration such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions, or forms of parenteral administration such as intramuscular, intravenous, or subcutaneous administration.

[0356] Another aspect provides a GLP-1 receptor agonist compound for use in the treatment of metabolic diseases or a pharmaceutical composition containing the same.

[0357] Another aspect provides a GLP-1 receptor agonist compound or a pharmaceutical composition containing the same for manufacturing a medicine for treating metabolic diseases.

[0358] Another aspect provides a use for the prevention or treatment of various diseases related thereto, such as obesity, diabetes, or related metabolic diseases, using a GLP-1 receptor agonist compound or a pharmaceutical composition containing the same.

[0359] Another aspect provides a method for preventing or treating various related diseases, such as obesity, diabetes, or related metabolic diseases, using a GLP-1 receptor agonist compound or a pharmaceutical composition containing the same.

[0360] The compounds of the present disclosure exhibit sufficient activity as GLP-1 receptor agonists and simultaneously possess excellent pharmacokinetic properties, tolerability, and compliance.

[0361] In one embodiment, a compound selected from the compound of Formula 1, its optical isomers, diastereomers, solvates, hydrates, and pharmaceutically acceptable salts thereof, or a pharmaceutical composition comprising these as active ingredients may be administered to a subject suffering from GLP-1 receptor dysregulation, e.g., obesity, diabetes, and various related diseases, such as obesity, diabetes, or related metabolic diseases.

[0362] As used herein, the terms “treating” or “treating” mean inhibiting a disease, e.g., in an individual experiencing or exhibiting a pathology or sign of a disease, condition, or disorder, i.e., preventing or reversing the further occurrence of the pathology and / or sign, or improving a disease, e.g., reducing the severity of the disease.

[0363] As used herein, the terms “preventing” or “prevention” refer to preventing a disease, for example, preventing a disease, condition, or disorder in an individual who may have a predisposition to a disease, condition, or disorder but has not yet experienced or exhibited the pathology or signs of the disease.

[0364] As used herein, the terms “object” or “individual” may be vertebrates such as mammals, fish, birds, reptiles, or amphibians. For example, said object may be a human, a non-human primate, a horse, a pig, a rabbit, a dog, a sheep, a goat, a cow, a cat, a guinea pig, or a rodent.

[0365] As used herein, the terms “administering” and “administering” refer to any method of providing a subject with the compound disclosed herein or a composition containing the same.

[0366] The dosage, frequency, or method of administration of the compound or pharmaceutical composition according to one embodiment may vary depending on the subject being treated, the severity of the disease or condition, the rate of administration, and the judgment of the prescribing physician. For example, the dosage for a person with a typical body weight of 70 kg may be administered in an amount of 0.0001 mg to 10 g per day, for example, 1 mg to 1 g. The frequency of administration may be one to several times, for example, 1 to 4 times, or on an on / off schedule, and the method of administration may be oral or parenteral. For example, the compound or pharmaceutical composition according to one embodiment may be administered orally or parenterally in an amount ranging from 0.1 to 100 mg / kg (body weight).

[0367] The physician may start at a level lower than that required to achieve the target therapeutic effect and gradually increase the dose of the compound or pharmaceutical composition of the present invention administered to the subject until the intended effect is achieved.

[0368] According to another embodiment of the present invention, a kit is provided comprising as active ingredients a compound of Formula 1, an optical isomer, a diastereomer, a solvate, a hydrate, and pharmaceutically acceptable salts thereof.

[0369] In one embodiment, the compound, composition, and kit of the present invention may be administered individually or sequentially, either alone or simultaneously with at least one other therapeutic agent.

[0370] In the context of the present invention, the singular form of a word may include the plural unless the context explicitly indicates otherwise, and vice versa.

[0371] The numerical values ​​described in this specification are deemed to include the meaning of "about" unless explicitly stated. The term "about" as used in this specification indicates within 5% of a predetermined value or range, preferably within 1% to 2%.

[0372] A numerical range indicated by the term "to" as used in this specification refers to a range that includes the values ​​described before and after the term "to" as a lower limit and an upper limit, respectively.

[0373] Expressions such as "have," "may have," "include," or "may include" as used in this specification refer to the existence of the relevant feature (e.g., a numerical value or a component, etc.) and do not exclude the existence of additional features.

[0374] Even if exemplary methods or materials are described herein, other similar or equivalents also fall within the scope of the invention. The contents of all publications cited by reference in this specification are incorporated herein by reference in their entirety.

[0375] A compound according to one embodiment of the present invention may be prepared according to the method described in the following examples, but is not limited thereto. A person skilled in the art of organic compounds will understand that specific reaction pathways, reaction conditions, reaction amounts, etc., can be appropriately controlled to prepare a desired compound.

[0376]

[0377] The present invention will be explained in more detail below through the following examples and experimental examples. However, these examples and experimental examples are intended only to aid in understanding the present invention and do not limit the scope of the present invention in any way.

[0378]

[0379] <Synthesized Example 1>

[0380] Example 1: (S)-2-((4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0381]

[0382] Step 1. Preparation of 4-chloro-2-(chloromethyl)thieno[3,2-d]pyrimidine

[0383]

[0384] 2-(chloromethyl)-3H-thieno[3,2-d]pyrimidine-4-one (300 mg, 1.47 mmol) was dissolved in phosphoryl chloride (1.39 mL, 14.65 mmol) and cooled to 0°C. Then, pyridine (0.75 mL, 0.73 mmol) was slowly added dropwise, and the reaction mixture was stirred at 110°C for 2 hours. After the reaction was complete, the product was slowly poured into ice water and stirred for 30 minutes. The resulting solid was collected by filtration, washed with water, and dried to obtain the title compound (280.5 mg, 87.4%).

[0385] Step 2. Preparation of t-butyl 4-((2-(chloromethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-carboxylate

[0386]

[0387] t-butyl 4-hydroxypiperidin-1-carboxylate (56 mg, 0.27 mmol) was dissolved in anhydrous tetrahydrofuran (1 mL) and cooled to 0°C. Sodium hydride (14 mg, 0.34 mmol) was added, and the mixture was stirred under nitrogen for 10 minutes. Then, 4-chloro-2-(chloromethyl)thieno[3,2-d]pyrimidine (50 mg, 0.23 mmol) synthesized in [Step 1] above was added, and the mixture was stirred at 25°C for 12 hours. Water was added to the reaction product and stirred at room temperature for 30 minutes. After extraction with ethyl acetate, the separated organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated. The title compound (71.4 mg, 81.5%) was obtained by purification using silica gel column chromatography.

[0388] Step 3. Preparation of t-butyl 4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-carboxylate

[0389]

[0390] t-butyl 4-((2-(chloromethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-carboxylate (71 mg, 0.19 mmol), 3-fluoro-4-hydroxy-benzonitrile (29 mg, 0.21 mmol), and potassium carbonate (39 mg, 0.28 mmol) synthesized in [Step 2] above were dissolved in acetnitrile (1 mL) and stirred at 60°C for 16 hours. After cooling the reaction product to room temperature, water was added and extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate and concentrated by filtration. Purification by silica gel column chromatography yielded the title compound (61.6 mg, 68.4%).

[0391] Step 4. Preparation of 3-fluoro-4-[(4-(piperidine-4-yloxy)thieno[3,2-d]pyrimidine-2-yl)methoxy]benzonitrile hydrochloride

[0392]

[0393] The t-butyl 4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-carboxylate (61.6 mg, 0.13 mmol) synthesized in [Step 3] above was dissolved in dichloromethane (1 mL), and then 4N hydrochloric acid 1,4-dioxane solution was slowly added and stirred at room temperature for 1 hour. The reaction product was used without further purification after removing the solvent.

[0394] Step 5. Preparation of methyl (S)-2-((4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0395]

[0396] 3-fluoro-4-[(4-(piperidin-4-yloxy)thieno[3,2-d]pyrimidin-2-yl)methoxy]benzonitrile hydrochloride (53 mg, 0.13 mmol) synthesized in [Step 4] above was dissolved in N,N-dimethylformamide (1 mL) and cooled to 0°C. Then, methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (37 mg, 0.13 mmol) and triethylamine (0.35 mL, 2.52 mmol) were added, and the mixture was stirred at 50°C for 19 hours. Water was added to the reaction product, and it was extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated. The title compound (80 mg, 98.8%) was obtained by purification using silica gel column chromatography.

[0397] Step 6. Preparation of (S)-2-((4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0398]

[0399] Methyl (S)-2-((4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (80 mg, 0.125 mmol) synthesized in [Step 5] above was dissolved in 1,4-dioxane (2 mL) and cooled to 0°C, after which sodium hydroxide (20.5 mg, 0.50 mmol) dissolved in water (1 mL) was added. The temperature was gradually raised to room temperature and the reaction mixture was stirred for 18 hours. The reaction product was acidified by slowly adding 1N hydrochloric acid dropwise and extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated. The title compound (40 mg, 51.1%) was obtained by purification using silica gel column chromatography.

[0400] Example 2: (S)-2-((4-((2-((4-cyano-2-fluorobenzyl)oxy)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0401]

[0402] The same reaction up to [Step 6] was carried out using 2,4-dichlorothieno[3,2-d]pyrimidine instead of 4-chloro-2-(chloromethyl)thieno[3,2-d]pyrimidine in [Step 2] of <Synthetic Example 1> to obtain the title compound (23.7 mg, 29.2%).

[0403]

[0404] <Intermediate Synthesis Example 1>

[0405]

[0406] Step 1. Preparation of 4-Bromo-2-Fluorphenyl Acetate

[0407]

[0408] 4-bromo-2-fluorophenyl (2 g, 10.26 mmol) and acetic anhydride (3.03 mL, 30.79 mmol) were added to pyridine (8 mL) and stirred at 100°C for 6 hours. After cooling to room temperature, the reaction product was acidified by slowly adding 3N hydrochloric acid dropwise and extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (2.1 g, 87.8%).

[0409] Step 2. Preparation of 2-fluoro-4-((trimethylsilyl)ethynyl)phenyl acetate

[0410]

[0411] 4-bromo-2-fluorophenyl acetate (1.1 g, 4.72 mmol), tetrakis(triphenylphosphine)palladium (0) (169 mg, 0.24 mmol), cuprous iodide (45 mg, 0.24 mmol), triethylamine (9.97 mL, 70.80 mmol), triphenylphosphine (61.9 mg, 0.24 mmol), and ethinyltrimethylsilane (1.35 mL, 9.44 mmol) synthesized in [Step 1] above were added and refluxed at 110°C for 17 hours. After cooling to room temperature, the reaction product was acidified by slowly adding 3N hydrochloric acid dropwise and extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated. Purified by silica gel column chromatography, the title compound (1.06 g, 89.7%) was obtained.

[0412] Step 3. Preparation of 4-ethynyl-2-fluorophenol

[0413]

[0414] 2-fluoro-4-((trimethylsilyl)ethynyl)phenyl acetate (1.06 g, 4.23 mmol) synthesized in [Step 2] above was mixed with 1 M tetrahydrofuran solution of tetrabutylammonium fluoride (6.35 mL, 6.35 mmol) and stirred at room temperature for 1 hour. Water was added to the reaction product and extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated. The result was purified by silica gel column chromatography to obtain the title compound (364 mg, 63.2%).

[0415] Example 3: (S)-2-((4-((2-((4-ethinyl-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0416]

[0417] The same reaction up to [Step 6] was carried out using 4-ethynyl-2-fluorophenol synthesized in <Intermediate Synthesis Example 1> instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3] of <Synthesis Example 1> to obtain the title compound (77 mg, 25.0%).

[0418]

[0419] <Intermediate Synthesis Example 2>

[0420]

[0421] Step 1. Preparation of 4-Bromo-2-Fluorphenyl Acetate

[0422]

[0423] The same reaction as [Step 1] of <Intermediate Synthesis Example 1> was carried out to obtain the title compound (2.1 g, 87.8%).

[0424] Step 2. Preparation of 4-cyclopropyl-2-fluorophenyl acetate

[0425]

[0426] 4-bromo-2-fluorophenyl acetate (1 g, 4.29 mmol), cyclopropylboronic acid (1.1 g, 12.87 mmol), tris(dibenzylideneacetone)dipalladium (0) (393 mg, 0.43 mmol), sodium carbonate (1.4 g, 12.87 mmol), and esphos (360 mg, 0.86 mmol) synthesized in [Step 1] above were added to toluene (10 mL) and refluxed at 100°C for 24 hours. After cooling to room temperature, the reaction product was neutralized by slowly adding 3N hydrochloric acid dropwise and extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated. Purified by silica gel column chromatography, the title compound (721 mg, 86.5%) was obtained.

[0427] Step 3. Preparation of 4-cyclopropyl-2-fluorophenol

[0428]

[0429] The 4-cyclopropyl-2-fluorophenyl acetate (721 mg, 3.71 mmol) synthesized in [Step 2] above was dissolved in methanol (7.21 mL), potassium carbonate (2 g, 14.85 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction product was concentrated, acidified by slowly adding 1N hydrochloric acid dropwise, and extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (506 mg, 89.6%).

[0430] Example 4: (S)-2-((4-((2-((4-cyclopropyl-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0431]

[0432] The same reaction up to [Step 6] was carried out using 4-cyclopropyl-2-fluorophenol synthesized in <Intermediate Synthesis Example 2> instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3] of <Synthesis Example 1> to obtain the title compound (100 mg, 29.3%).

[0433] Example 5: 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0434]

[0435] The same reaction up to [Step 6] was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1> to obtain the title compound (9.8 mg, 43.0%).

[0436]

[0437] <Intermediate Synthesis Example 3>

[0438]

[0439] Step 1. Preparation of methyl(S)-3-fluoro-4-nitro-5-((oxetane-2-ylmethyl)amino)benzoate

[0440]

[0441] Methyl 3,5-difluoro-4-nitrobenzoate (3 g, 13.54 mmol), (S)-oxetane-2-ylmethanamine (1.58 g, 17.60 mmol), and potassium carbonate (3.76 g, 27.08 mmol) were added to acetonitrile (30 mL) and stirred at 70°C for 15 hours. After cooling the reaction product to room temperature, water was added and extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated. Purified by silica gel column chromatography, the title compound (2.6 g, 67.6%) was obtained.

[0442] Step 2. Preparation of methyl (S)-4-amino-3-fluoro-5-((oxetane-2-ylmethyl)amino)benzoate

[0443]

[0444] Methyl (S)-3-fluoro-4-nitro-5-((oxetane-2-ylmethyl)amino)benzoate (2.6 g, 9.15 mmol) synthesized in [Step 1] above was dissolved in methanol (26 mL), and 10% palladium / carbon (260 mg, 0.24 mmol) was added under nitrogen gas. After hydrogen gas substitution, the mixture was stirred at room temperature for 1 hour. The reaction product was filtered using Celite, and the filtrate was concentrated and used without further purification. (2.26 g, 97.17%)

[0445] Step 3. Preparation of Methyl (S)-4-(2-chloroacetamido)-3-fluoro-5-((oxetane-2-ylmethyl)amino)benzoate

[0446]

[0447] (S)-4-amino-3-fluoro-5-((oxetane-2-ylmethyl)amino)benzoate (100 mg, 0.39 mmol) synthesized in [Step 2] above was added to tetrahydrofuran (1 mL) and cooled to 0°C, after which chloroacetic anhydride (76.3 mg, 0.43 mmol) was added. This mixture was stirred at room temperature for 3 hours. The reaction product was concentrated and purified by silica gel column chromatography to obtain the title compound (94.5 mg, 72.65%).

[0448] Step 4. Preparation of Methyl (S)-2-(chloromethyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0449]

[0450] Methyl (S)-4-(2-chloroacetamido)-3-fluoro-5-((oxetane-2-ylmethyl)amino)benzoate (20 mg, 0.06 mmol) synthesized in [Step 2] above was added to acetic acid (0.5 mL) and toluene (0.5 mL) and stirred at 110°C for 14 hours. The reaction product was cooled to room temperature, concentrated, and purified by silica gel column chromatography to obtain the title compound (18 mg, 95.18%).

[0451] Example 6: 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0452]

[0453] The same reaction up to [Step 4] was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthesizing Example 1>, and the same reaction up to [Step 6] was carried out using methyl (S)-2-(chloromethyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate synthesized in <Intermediate Synthesis Example 3> instead of methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate in [Step 5] to obtain the title compound (7.5 mg, 76.6%).

[0454] Example 7: 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-3-(((S)-oxetane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid

[0455]

[0456] The same reaction up to [Step 4] was carried out using t-butyl (2S, 4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 6] was carried out using methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate instead of methyl (S)-2-(chloromethyl)-3-(oxetane-2-ylmethyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (WO2022184849) in [Step 5] to obtain the title compound (6.4 mg, 40.9%).

[0457] Example 8: (S)-2-((4-((2-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0458]

[0459] The same reaction was carried out up to [Step 5] using 2,4-dichlorothieno[2,3-d]pyrimidine instead of 4-chloro-2-(chloromethyl)thieno[3,2-d]pyrimidine in [Step 2] of <Synthetic Example 1>, and the same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (62 mg, 60.4%).

[0460] Example 9: 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[2,3-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0461]

[0462] The same reaction up to [Step 5] was carried out using 4-chloro-2-(chloromethyl)thieno[3,2-d]pyrimidine instead of 4-chloro-2-(chloromethyl)thieno[2,3-d]pyrimidine and t-butyl (2S,4S)-4-hydroxy-2-methylpiperidine-1-carboxylate instead of t-butyl 4-hydroxypiperidine-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (25.9 mg, 58.8%).

[0463] Example 10: 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-((S)-4,4-dimethyltetrahydrofuran-3-yl)-4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0464]

[0465] The same reaction up to [Step 4] was performed using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidine-1-carboxylate instead of t-butyl 4-hydroxypiperidine-1-carboxylate in [Step 2] of <Synthetic Example 1>.

[0466] The same reaction was performed using methyl (S)-2-(chloromethyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-4-fluoro-1H-benzo[d]imidazole-6-carboxylate, which was prepared using (S)-4,4-dimethyltetrahydrofuran-3-amine hydrochloride (WO2022225941), instead of (S)-oxetane-2-ylmethanamine in [Step 1] of <Intermediate Synthesis Example 3>, instead of (S)-2-(chloromethyl)-1-(4,4-dimethyltetrahydrofuran-3-yl)-4-fluoro-1H-benzo[d]imidazole-6-carboxylate.

[0467] The same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] of <Synthetic Example 1> to obtain the title compound (25.9 mg, 58.8%).

[0468]

[0469] <Intermediate Synthesis Example 4>

[0470]

[0471] Step 1. Preparation of methyl 3-fluoro-5-(((1-(hydroxymethyl)cyclopropyl)methyl)amino)-4-nitrobenzoate

[0472]

[0473] Methyl 3,5-difluoro-4-nitrobenzoate (1.1 g, 4.97 mmol), (1-(aminomethyl)cyclopropyl)methanol (0.57 g, 5.46 mmol), and N,N-diisopropylamine (1.75 mL, 9.93 mmol) were added to tetrahydrofuran (10 mL) and stirred at room temperature for 15 hours. Water was added to the reaction product and extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated. Purified by silica gel column chromatography, the title compound (1.16 g, 78.3%) was obtained.

[0474] Step 2. Preparation of methyl 4-amino-3-fluoro-5-(((1-(hydroxymethyl)cyclopropyl)methyl)amino)benzoate

[0475]

[0476] The same reaction was carried out using the methyl 3-fluoro-5-(((1-(hydroxymethyl)cyclopropyl)methyl)amino)-4-nitrobenzoate synthesized in [Step 1] above instead of the (S)-3-fluoro-4-nitro-5-((oxetane-2-ylmethyl)amino)benzoate in [Step 2] of <Intermediate Synthesis Example 3> to obtain the title compound (919 mg, 88.1%).

[0477] Step 3. Preparation of methyl 4-(2-chloroacetamido)-3-fluoro-5-(((1-(hydroxymethyl)cyclopropyl)methyl)amino)benzoate

[0478]

[0479] The same reaction was carried out using the methyl 4-amino-3-fluoro-5-(((1-(hydroxymethyl)cyclopropyl)methyl)amino)benzoate synthesized in [Step 2] above instead of the (S)-4-amino-3-fluoro-5-(((1-(hydroxymethyl)cyclopropyl)methyl)amino)benzoate in [Step 3] of <Intermediate Synthesis Example 3> to obtain the title compound (868 mg, 82.5%).

[0480] Step 4. Preparation of methyl 2-(chloromethyl)-4-fluoro-1-((1-(hydroxymethyl)cyclopropyl)methyl)-1H-benzo[d]imidazo-6-carboxylate

[0481]

[0482] The same reaction was carried out using the methyl 4-(2-chloroacetamido)-3-fluoro-5-(((1-(hydroxymethyl)cyclopropyl)methyl)amino)benzoate synthesized in [Step 3] above instead of the methyl (S)-4-(2-chloroacetamido)-3-fluoro-5-(((1-(hydroxymethyl)cyclopropyl)methyl)amino)benzoate in [Step 4] of <Intermediate Synthesis Example 3> to obtain the title compound (560 mg, 68.1%).

[0483] Step 5. Preparation of methyl 2-(chloromethyl)-4-fluoro-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0484]

[0485] Methyl 2-(chloromethyl)-4-fluoro-1-((1-(hydroxymethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate (320 mg, 0.98 mmol) synthesized in [Step 4] above was dissolved in dichloromethane (9 mL), cooled to 0°C, and then (diethylamino)surfer trifluoride (0.17 mL, 1.18 mmol) was added and the mixture was stirred at 0°C for 2 hours. The reaction mixture was concentrated and purified by silica gel column chromatography to obtain the title compound (209 mg, 64.9%).

[0486] Example 11: 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-fluoro-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0487]

[0488] The same reaction was performed using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidine-1-carboxylate instead of t-butyl 4-hydroxypiperidine-1-carboxylate in [Step 2] of <Synthetic Example 1>.

[0489] [Step 6] was performed with the compound obtained by carrying out the same reaction using methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, triethylamine, N,N-dimethylformamide synthesized in the above <Intermediate Synthesis Example 4> instead of methyl (S)-2-(chloromethyl)-4-fluoro-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, 1,4-dioxane.

[0490] The same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] of <Synthetic Example 1> to obtain the title compound (25.9 mg, 58.8%).

[0491]

[0492] <Intermediate Synthesis Example 5>

[0493]

[0494] Step 1. Preparation of Methyl 3-Fluoro-5-Methoxy-4-Nitrobenzoate

[0495]

[0496] Methyl 3,5-difluoro-4-nitrobenzoate (2 g, 9.21 mmol) was dissolved in methanol (25 mL), and 25% sodium methoxide (2.2 mL, 9.67 mmol) dissolved in methanol was added. The mixture was stirred at 65°C for 3 hours, and then 0.2 mL of sodium methoxide was added and stirred for 16 hours. The reaction mixture was cooled to room temperature, water was added, and the mixture was stirred for 1 hour. The resulting solid product was filtered under reduced pressure and washed with water and hexane. The filtered solid was dried in an oven at 50°C to obtain the title compound (1.8 g, 85.3%).

[0497] Step 2. Preparation of Methyl (S)-3-methoxy-4-nitro-5-((oxetane-2-ylmethyl)amino)benzoate

[0498]

[0499] The title compound (1.11 g, 85.9%) was obtained by carrying out the same reaction as in [Step 1] of <Intermediate Synthesis Example 3>, except that the methyl 3,5-difluoro-4-nitrobenzoate synthesized above was used instead of methyl 3,5-methoxy-4-nitrobenzoate.

[0500] Step 3. Preparation of methyl (S)-4-amino-3-methoxy-5-((oxetane-2-ylamine)amino)benzoate

[0501]

[0502] The title compound (997 mg, 99%) was obtained by carrying out the same reaction except that the methyl (S)-3-methoxy-4-nitro-5-((oxetane-2-ylmethyl)amino)benzoate synthesized above was used instead of the methyl (S)-3-fluoro-4-nitro-5-((oxetane-2-ylmethyl)amino)benzoate in [Step 2] of <Intermediate Synthesis Example 3>.

[0503] Step 4. Preparation of Methyl (S)-2-(chloromethyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0504]

[0505] Methyl (S)-4-amino-3-methoxy-5-((oxetane-2-ylamine)amino)benzoate (1 g, 3.76 mmol) synthesized in [Step 3] above was added to tetrahydrofuran (1 mL) and cooled to 0°C, after which chloroacetic anhydride (675.8 mg, 3.76 mmol) was added. This mixture was stirred at room temperature for 3 hours and then stirred at 70°C for 16 hours. The reaction product was cooled to room temperature, concentrated, and purified by silica gel column chromatography to obtain the title compound (917 mg, 75.2%).

[0506] Example 12: 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0507]

[0508] The same reaction up to [Step 4] of <Synthetic Example 1> was performed using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidine-1-carboxylate instead of t-butyl 4-hydroxypiperidine-1-carboxylate in [Step 2] of <Synthetic Example 1>.

[0509] [Step 6] was performed with the compound obtained by carrying out the same reaction using methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in the above <Intermediate Synthesis Example 5> instead of methyl (S)-2-(chloromethyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, 1,4-dioxane.

[0510] The same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] of <Synthetic Example 1> to obtain the title compound (25.9 mg, 58.8%).

[0511] Example 13: 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-fluoro-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0512]

[0513] The same reaction up to [Step 4] of <Synthetic Example 1> was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidine-1-carboxylate instead of t-butyl 4-hydroxypiperidine-1-carboxylate in [Step 2] of <Synthetic Example 1>.

[0514] [Step 6] was performed using the compound obtained by performing the same reaction up to [Step 4] using methyl 2-(chloromethyl)-7-fluoro-3-(2-methoxyethyl)benzimidazole-5-carboxylate, which is the intermediate obtained by using 2-methoxyethanolamine instead of (S)-oxetane-2-ylmethanamine in [Step 1] of <Intermediate Synthesis Example 3>, and by performing the same reaction in [Step 5] of <Synthesis Example 1> using N,N-diisopropylamine and 1,4-dioxane instead of triethylamine and N,N-dimethylformamide.

[0515] The same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] of <Synthetic Example 1> to obtain the title compound (16.3 mg, 46.3%).

[0516] Example 14: 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0517]

[0518] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-chloro-2-fluoro-phenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0519] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 5> above, instead of methyl (S)-2-(chloromethyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane, and the same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (59 mg, 51.3%).

[0520] Example 15: 2-(((2S,4S)-4-((2-((4-chloro-2-cyanofenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0521]

[0522] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 5-chloro-2-hydroxy-benzonitrile instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0523] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 5> above, instead of methyl (S)-2-(chloromethyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane, and the same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (24.7 mg, 46.7%).

[0524]

[0525] <Intermediate Synthesis Example 6>

[0526]

[0527] Step 1. Preparation of 3,5-Difluoro-4-Nitrobenzonitrile

[0528]

[0529] 5-Bromo-1,3-difluoro-2-nitrobenzene (8 g, 33.6 mmol) and copper cyanide (3.9 g, 43.7 mmol) were dissolved in methylpyrrolidone (36.4 mL) and then 160°C under nitrogen gas oThe mixture was stirred at C for 19 hours. The reaction product was added to ice water and filtered using Celite, after which the filtrate was concentrated and extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated. The title compound (2.75 g, 44.4%) was obtained by purification using silica gel column chromatography.

[0530] Step 2. Preparation of 3-fluoro-5-hydroxy-4-nitrobenzonitrile

[0531]

[0532] 3,5-difluoro-4-nitrobenzonitrile (24 g, 128.3 mmol) and calcium carbonate (35.6 g, 256.5 mmol) synthesized in [Step 1] above were dissolved in water (135 mL) and dimethyl sulfoxide (322.5 mL), and then 70°C under nitrogen gas o Stirred at C for 7 hours. After cooling in ice water, acidified by adding 12N hydrochloric acid dropwise. Extracted with ethyl acetate, dried with anhydrous magnesium sulfate, and concentrated by filtration. Purified by silica gel column chromatography and recrystallized with hexane to obtain the title compound (20.6 g, 88.0%).

[0533] Step 3. Preparation of 3-fluoro-5-hydroxy-4-nitrobenzoic acid

[0534]

[0535] After dissolving the 3-fluoro-5-hydroxy-4-nitrobenzonitrile (20.6 g, 112.8 mmol) synthesized in [Step 2] above in a 60% aqueous sulfuric acid solution (82.2 mL), 150 oRefluxed at C for 16 hours. After cooling to room temperature, the reaction product was slowly added to ice water and stirred at room temperature for 2 hours. The resulting solid was filtered, and the filtrate was extracted with ethyl acetate, dried with anhydrous sodium sulfate, and concentrated by filtration. The filtered solid and the concentrated filtrate were recrystallized with hexane to obtain the title compound (21.7 g, 95.6%).

[0536] Step 4. Preparation of Ethyl 3-Ethoxy-5-Fluoro-4-Nitrobenzoate

[0537]

[0538] 3-fluoro-5-hydroxy-4-nitrobenzoic acid (21.6 g, 107.3 mmol), calcium carbonate (35.6 g, 256.5 mmol), and diethyl sulfate (50.6 g, 321.8 mmol) synthesized in [Step 3] above were dissolved in dimethyl sulfoxide (215.7 mL), and then 25 under nitrogen gas o It was stirred at C for 23 hours. After extraction with ethyl acetate, it was dried with anhydrous sodium sulfate, filtered, and concentrated. It was purified by silica gel column chromatography to obtain the title compound (21.2 g, 76.8%).

[0539] Step 5. Preparation of ethyl(S)-3-ethoxy-4-nitro-5-((oxetane-2-ylmethyl)amino)benzoate

[0540]

[0541] Ethyl 3-ethoxy-5-fluoro-4-nitrobenzoate (20.9 g, 81.1 mmol), cesium carbonate (40.0 g, 121.6 mmol), and (S)-oxetane-2-ylmethanamine (9.5 g, 105.4 mmol) synthesized in [Step 4] above were dissolved in acetonitrile (208.6 mL) and stirred at 70°C for 24 hours. After cooling to room temperature, the mixture was extracted with ethyl acetate, dried with anhydrous magnesium sulfate, and concentrated by filtration. The solution was purified by silica gel column chromatography to obtain the title compound (13.2 g, 50.1%).

[0542] Step 6. Preparation of ethyl(S)-4-amino-3-ethoxy-5-((oxetane-2-ylmethyl)amino)benzoate

[0543]

[0544] Ethyl(S)-3-ethoxy-4-nitro-5-((oxetane-2-ylmethyl)amino)benzoate (13.2 g, 40.6 mmol) synthesized in [Step 5] above was dissolved in ethanol (130 mL) and ethyl acetate (130 mL), and 10% palladium / carbon (1.4 g, 1.34 mmol) was added under nitrogen gas. After hydrogen gas substitution, the mixture was stirred at room temperature for 66 hours. The reaction product was filtered using Celite, and the filtrate was concentrated and used without further purification. (12.0 g, 100%)

[0545] Step 7. Preparation of Ethyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0546]

[0547] Ethyl(S)-4-amino-3-ethoxy-5-((oxetane-2-ylmethyl)amino)benzoate (12.2 g, 41.5 mmol), 2-chloro-1,1,1-trimethoxyethane (7.3 g, 45.7 mmol), and p-toluenesulfonic acid (798.2 mg, 4.15 mmol) synthesized in [Step 6] above were added to acetonitrile (122 mL) and stirred at 70°C for 2 hours. After cooling to room temperature, the reaction product was concentrated. The title compound (10.7 g, 73.0%) was obtained by recrystallization with ethyl acetate and hexane.

[0548] Example 16: 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0549]

[0550] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-chloro-2-fluoro-phenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0551] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane, and the same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (35 mg, 45.5%).

[0552] Example 17: 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-fluoro-1-(thiazole-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0553]

[0554] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>. The same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-chloro-2-fluorophenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0555] Using the intermediate methyl 2-(chloromethyl)-7-fluoro-3-(thiazole-5-ylmethyl)benzimidazole-5-carboxylate, obtained by carrying out the same reaction up to [Step 4] in [Step 1] of <Intermediate Synthesis Example 3> using thiazole-5-ylmethanamine hydrochloride, triethylamine, and N,N-dimethylformamide instead of (S)-oxetane-2-ylmethanamine, potassium carbonate, and acetonitrile, and using the compound obtained by carrying out the same reaction in [Step 5] of <Synthesis Example 1> using N,N-diisopropylethylamine, 1,4-dioxane, and 2-((4-chloro-2-fluoro-phenoxy)methyl)-4-(((2S,4S)-2-methyl-4-piperidyl)oxy)thieno[3,2-d]pyrimidine hydrochloride instead of triethylamine and N,N-dimethylformamide. [Step 6] was executed.

[0556] The same reaction was carried out using triazabicyclodecene, acetonitrile, and water instead of sodium hydroxide and 1,4-dioxane in [Step 6] of <Synthetic Example 1> to obtain the title compound (5 mg, 14.3%).

[0557] Example 18: 2-(((2S,4S)-4-((2-(((4-chlorobenzofuran-7-yl)oxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0558]

[0559] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-chlorobenzofuran-7-ol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0560] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 5> above, instead of methyl (S)-2-(chloromethyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane, and in [Step 6], the same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane to obtain the title compound (40.6 mg, 28.3%).

[0561] Example 19: 2-(((2S,4S)-4-((2-(((4-chlorobenzofuran-7-yl)oxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0562]

[0563] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-chlorobenzofuran-7-ol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0564] The same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in the above <Intermediate Synthesis Example 6> instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane in [Step 5] of <Synthesis Example 1>, and the same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (34 mg, 24.9%).

[0565] Example 20: 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-(2-methoxyethoxy)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0566]

[0567] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-chloro-2-fluoro-phenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0568] The same reaction was carried out using methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, triethylamine, and N,N-dimethylformamide instead of methyl (S)-2-(chloromethyl)-1-(2-methoxyethoxy)-3-[[(2S)-oxetane-2-yl]methyl]benzimidazole-5-carboxylate, N,N-diisopropylamine, and 1,4-dioxane in [Step 5] of <Synthesizing Example 1>, and the same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (29 mg, 36.6%).

[0569]

[0570] <Intermediate Synthesis Example 7>

[0571]

[0572] Step 1. Preparation of (S)-Oxetane-2-Carbaldehyde

[0573]

[0574] [(2S)-oxetane-2-yl]methanol (350 mg, 3.97 mmol) was added to dichloromethane (7 mL) and cooled to 0°C, then Desmartin reagent was added and stirred at room temperature for 15 hours. The reaction product was filtered, the filtrate was concentrated, and then added to a 50% hexane / ethyl acetate solution and stirred. After stirring, the mixture was filtered again and the filtrate was concentrated to obtain the title compound (342 mg, 100%) without further purification.

[0575] Step 2. Preparation of methyl 5-((t-butoxycarbonyl)amino)-4-nitrothiophene-2-carboxylate

[0576]

[0577] Methyl 5-amino-4-nitro-thiophene-2-carboxylate (1 g, 4.70 mmol), di-t-butyl dicarbonate (2.07 g, 9.40 mmol), and N,N-diisopropylethylamine (1.22 g, 9.40 mmol) were dissolved in tetrahydrofuran (10 mL) and stirred at 60°C for 19 hours. After cooling the reaction product to room temperature, water was added and extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated. Purified by silica gel column chromatography, the title compound (790 mg, 55.6%) was obtained.

[0578] Step 3. Preparation of Methyl 4-amino-5-((t-butoxycarbonyl)amino)thiophene-2-carboxylate

[0579]

[0580] Methyl 5-((t-butoxycarbonyl)amino)-4-nitrothiophene-2-carboxylate (790 mg, 2.61 mmol) synthesized in [Step 2] above was added to methanol (15 mL) and water (5 mL), iron (811 mg, 13.07 mmol) and ammonium chloride (282 mg, 5.23 mmol) were added, and the mixture was stirred at 40°C for 22 hours. The reaction product was cooled to room temperature and filtered to concentrate the methanol. The separated organic layer was extracted with dichloromethane, dried with anhydrous sodium sulfate, filtered, and concentrated. The title compound (535 mg, 75.2%) was obtained by purification using silica gel column chromatography.

[0581] Step 4. Preparation of methyl(S)-5-((t-butoxycarbonyl)amino)-4-((oxetane-2-ylmethyl)amino)thiophene-2-carboxylate

[0582]

[0583] Methyl 4-amino-5-((t-butoxycarbonyl)amino)thiophene-2-carboxylate (535 mg, 1.96 mmol) synthesized in [Step 3] above was added to dichloromethane (26 mL), (S)-oxetane-2-carbaldehydride (338 mg, 3.92 mmol) synthesized in [Step 1] above and acetic acid (20 μL) were added, and the mixture was stirred at room temperature for 20 minutes. Sodium triacetoxyborohydride (916 mg, 4.32 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction product, and it was extracted with dichloromethane. The separated organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated. The title compound (83 mg, 12.3%) was obtained by purification using silica gel column chromatography.

[0584] Step 5. Preparation of Methyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-thieno[2,3-d]imidazole-5-carboxylate

[0585]

[0586] Methyl(S)-5-((t-butoxycarbonyl)amino)-4-((oxetane-2-ylmethyl)amino)thiophene-2-carboxylate (83 mg, 0.24 mmol) synthesized in [Step 4] above was added to tetrahydrofuran (1.66 mL), 2-chloro-1,1,1-trimethoxyethane (77 mg, 0.48 mmol) and p-toluenesulfonic acid monohydrate (2.3 mg, 0.012 mmol) were added, and the mixture was stirred at 70°C for 4 hours. The reaction product was cooled to room temperature, concentrated, and purified by silica gel column chromatography to obtain the title compound (46 mg, 63.1%).

[0587] Example 21: 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid

[0588]

[0589] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-chloro-2-fluoro-phenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0590] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using methyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, triethylamine, and N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 7> above, and in [Step 6], the same reaction was carried out using lithium hydroxide, tetrahydrofuran, methanol, and water instead of sodium hydroxide and 1,4-dioxane to obtain the title compound (7.3 mg, 22.1%).

[0591] Example 22: 2-(((2S,4S)-4-((2-((4-chloro-2-methoxyphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0592]

[0593] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-chloro-2-methoxy-phenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0594] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane, and the same reaction was carried out using lithium hydroxide, tetrahydrofuran, methanol, and water instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (40.5 mg, 35.6%).

[0595] Example 23: 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-isopropoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0596]

[0597] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-chloro-2-fluoro-phenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0598] The same reaction was carried out using isopropyl 2-(chloromethyl)-7-isopropoxy-3-[[(2S)-oxetane-2-yl]methyl]benzimidazole-5-carboxylate, N,N-diisopropylamine, and 1,4-dioxane instead of methyl (S)-2-(chloromethyl)-1-(oxetane-2-yl]methyl)-1H-benzo[d]imidazole-6-carboxylate, triethylamine, and N,N-dimethylformamide in [Step 5] of <Synthesizing Example 1>, and the same reaction was carried out using lithium hydroxide, tetrahydrofuran, and water instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (9.3 mg, 19.7%).

[0599] Example 24: 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-5-carboxylic acid

[0600]

[0601] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-chloro-2-fluoro-phenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0602] The same reaction was carried out using methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, triethylamine, and N,N-dimethylformamide instead of methyl (S)-2-(chloromethyl)-1-[[(2S)-oxetane-2-yl]methyl]benzimidazole-5-carboxylate, N,N-diisopropylamine, and 1,4-dioxane instead of sodium hydroxide and 1,4-dioxane in [Step 5], and the title compound (36.2 mg, 35.2%) was obtained by carrying out the same reaction using lithium hydroxide, tetrahydrofuran, methanol, and water instead of sodium hydroxide and 1,4-dioxane in [Step 6].

[0603] Example 25: 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-methyl-1H-benzo[d]imidazole-6-carboxylic acid

[0604]

[0605] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-chloro-2-fluoro-phenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0606] The same reaction was carried out using ethyl 2-(chloromethyl)-7-ethoxy-3-methyl-benzimidazole-5-carboxylate, N,N-diisopropylamine, and 1,4-dioxane instead of methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, triethylamine, and N,N-dimethylformamide in [Step 5] of <Synthesizing Example 1>, and the same reaction was carried out using lithium hydroxide, tetrahydrofuran, methanol, and water instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (58.1 mg, 46.3%).

[0607] Example 26: 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-cyclopropoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0608]

[0609] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-chloro-2-fluoro-phenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0610] The same reaction was carried out using methyl(S)-2-(chloromethyl)-4-cyclopropoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane instead of methyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane in [Step 5] of <Synthesizing Example 1>, and the same reaction was carried out using lithium hydroxide, tetrahydrofuran, methanol, and water instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (56.8 mg, 54.2%).

[0611] Example 27: 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-(cyclopropylmethoxy)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0612]

[0613] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-chloro-2-fluoro-phenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0614] The same reaction was carried out using methyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane instead of methyl(S)-2-(chloromethyl)-4-(cyclopropylmethoxy)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane instead of sodium hydroxide and 1,4-dioxane in [Step 5], and the title compound (70.4 mg, 59.6%) was obtained by carrying out the same reaction in [Step 6] using lithium hydroxide, tetrahydrofuran, methanol, and water instead of sodium hydroxide and 1,4-dioxane.

[0615] Example 28: 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[2,3-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0616]

[0617] In [Step 2] of <Synthetic Example 1>, 4-chloro-2-(chloromethyl)thieno[3,2-d]pyrimidine was used instead of 4-chloro-2-(chloromethyl)thieno[2,3-d]pyrimidine, and t-butyl (2S,4S)-4-hydroxy-2-methylpiperidine-1-carboxylate was used instead of t-butyl 4-hydroxypiperidine-1-carboxylate, and the same reaction was carried out using 4-chloro-2-fluorophenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0618] In [Step 4] of <Synthesizing Example 1>, the same reaction was carried out using trifluoroacetic acid instead of 4N hydrochloric acid-1,4-dioxane solution, and after neutralization by adding an aqueous sodium bicarbonate solution dropwise, the mixture was extracted with dichloromethane and methanol in a 5:1 solvent ratio. The organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain an intermediate.

[0619] In [Step 5], the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylethylamine, acetonitrile.

[0620] In [Step 6] of <Synthesizing Example 1>, the same reaction was carried out using lithium hydroxide monohydrate, methanol, water, and tetrahydrofuran instead of sodium hydroxide and 1,4-dioxane, and then the residue obtained by neutralizing with 5% citric acid was purified by silica gel chromatography to obtain the title compound (117.9 mg, 66.5%).

[0621] Example 29. 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0622]

[0623] The same reaction up to [Step 4] was performed using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidine-1-carboxylate instead of t-butyl 4-hydroxypiperidine-1-carboxylate in [Step 2] of <Synthetic Example 1>.

[0624] The same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in the above <Intermediate Synthesis Example 6> instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane in [Step 5] of <Synthesis Example 1>, and the same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (137 mg, 72.7%).

[0625] Example 30. 2-(((2S,4S)-4-((2-((2-chloro-4-methylphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0626]

[0627] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 2-chloro-4-methylphenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0628] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane, and the same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (129.2 mg, 79.7%).

[0629] Example 31. 2-(((2S,4S)-4-((2-((4-chloro-2-cyanofenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-(difluoromethoxy)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0630]

[0631] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 5-chloro-2-hydroxy-benzonitrile instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0632] The same reaction was carried out using methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, triethylamine, and N,N-dimethylformamide instead of methyl (S)-2-(chloromethyl)-1-(oxetane-2-yl]methyl]benzimidazole-5-carboxylate, N,N-diisopropylamine, and methanol in [Step 5] of <Synthesizing Example 1>, and the same reaction was carried out using triazabicyclodecene, acetonitrile, and water instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (24.9 mg, 14.9%).

[0633] Example 32. 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-(difluoromethoxy)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0634]

[0635] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidine-1-carboxylate instead of t-butyl 4-hydroxypiperidine-1-carboxylate in [Step 2] of <Synthetic Example 1>.

[0636] The same reaction was carried out using methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, triethylamine, and N,N-dimethylformamide instead of methyl (S)-2-(chloromethyl)-1-(oxetane-2-yl]methyl]benzimidazole-5-carboxylate, N,N-diisopropylamine, and methanol in [Step 5] of <Synthesizing Example 1>, and the same reaction was carried out using triazabicyclodecene, acetonitrile, and water instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (87 mg, 71.1%).

[0637] Example 33. 2-(((2S,4S)-4-((2-((2-cyano-4-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0638]

[0639] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 5-fluoro-2-hydroxy-benzonitrile instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0640] The same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in the above <Intermediate Synthesis Example 6>, N,N-diisopropylamine, and methanol instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and methanol instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (174 mg, 75.9%).

[0641] Example 34. 2-(((2S,4S)-4-((2-((4-bromo-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0642]

[0643] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-bromo-2-fluorophenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0644] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane, and the same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (122.3 mg, 80.0%).

[0645] Example 35. 4-ethoxy-2-(((2S,4S)-2-methyl-4-((2-((perfluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0646]

[0647] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 2,3,4,5,6-pentafluorophenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0648] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane, and the same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (132.3 mg, 85.3%).

[0649] Example 36. 2-(((2S,4S)-4-((2-((2,4-difluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0650]

[0651] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 2,4-difluorophenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0652] The same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in the above <Intermediate Synthesis Example 6>, N,N-diisopropylamine, and methanol instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and methanol instead of sodium hydroxide and 1,4-dioxane in [Step 6], and the title compound (205 mg, 87.0%) was obtained.

[0653] Example 37. 4-ethoxy-2-(((2S,4S)-4-((2-((4-ethinyl-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0654]

[0655] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-ethynyl-2-fluorophenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0656] The same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in the above <Intermediate Synthesis Example 6>, N,N-diisopropylamine, and methanol instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and methanol instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (48 mg, 41.0%).

[0657] Example 38. 2-(((2S,4S)-4-((2-((2,4-dimethylphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0658]

[0659] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 2,4-dimethylphenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0660] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and acetonitrile, and in [Step 6], the same reaction was carried out using lithium hydroxide monohydrate, methanol, water, and tetrahydrofuran instead of sodium hydroxide and 1,4-dioxane to obtain the title compound (88.4 mg, 51.2%).

[0661] Example 39. 4-ethoxy-2-(((2S,4S)-4-((2-((4-fluoro-2-methoxyphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0662]

[0663] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-fluoro-2-methoxyphenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0664] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and acetonitrile, and in [Step 6], the same reaction was carried out using lithium hydroxide monohydrate, methanol, water, and tetrahydrofuran instead of sodium hydroxide and 1,4-dioxane to obtain the title compound (101.4 mg, 48.7%).

[0665] Example 40. 4-ethoxy-2-(((2S,4S)-4-((2-((2-fluoro-4-(trifluoromethyl)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0666]

[0667] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 2-fluoro-4-trifluoromethylphenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0668] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane, and the same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (86.4 mg, 57.2%).

[0669] Example 41. 4-ethoxy-2-(((2S,4S)-2-methyl-4-((2-((4-(trifluoromethyl)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0670]

[0671] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-(trifluoromethyl)phenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0672] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane, and the same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (151.8 mg, 73.2%).

[0673] Example 42. 4-ethoxy-2-(((2S,4S)-4-((2-((2-fluoro-4-methylphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0674]

[0675] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 2-fluoro-4-methylphenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0676] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and acetonitrile, and in [Step 6], the same reaction was carried out using lithium hydroxide monohydrate, methanol, water, and tetrahydrofuran instead of sodium hydroxide and 1,4-dioxane to obtain the title compound (113.2 mg, 62.1%).

[0677] Example 43. 4-ethoxy-2-(((2S,4S)-2-methyl-4-((2-((4-(trifluoromethoxy)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0678]

[0679] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-(trifluoromethoxy)phenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0680] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, N,N-diisopropylamine, and methanol instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and methanol, and in [Step 6], the same reaction was carried out using lithium hydroxide monohydrate, methanol, water, and tetrahydrofuran instead of sodium hydroxide and 1,4-dioxane to obtain the title compound (86.2 mg, 62.7%).

[0681] Example 44. 2-(((2S,4S)-4-((2-((4-chlorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0682]

[0683] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-chlorophenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0684] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane, and the same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (156.6 mg, 76.9%).

[0685] Example 45. 2-(((2S,4S)-4-((2-((4-(1H-1,2,4-triazole-1-yl)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0686]

[0687] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-(1H-1,2,4-triazole-1-yl)phenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0688] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, N,N-diisopropylamine, and methanol instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and methanol, and in [Step 6], the same reaction was carried out using lithium hydroxide monohydrate, methanol, water, and tetrahydrofuran instead of sodium hydroxide and 1,4-dioxane to obtain the title compound (70 mg, 34.5%).

[0689] Example 46. 2-(((2S,4S)-4-((2-((2,5-difluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0690]

[0691] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 2,5-difluorophenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0692] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane, and the same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (111.6 mg, 54.0%).

[0693] Example 47. 2-(((2S,4S)-4-((2-((4-cyano-2-(trifluoromethyl)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0694]

[0695] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-hydroxy-3-(trifluoromethyl)benzonitrile instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0696] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane, and the same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (110.6 mg, 68.4%).

[0697] Example 48. 2-(((2S,4S)-4-((2-((4-(1H-imidazole-1-yl)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0698]

[0699] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-(1H-imidazole-1-yl)phenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0700] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and acetonitrile, and in [Step 6], the same reaction was carried out using lithium hydroxide monohydrate, methanol, water, and tetrahydrofuran instead of sodium hydroxide and 1,4-dioxane to obtain the title compound (66.1 mg, 57.2%).

[0701] Example 49. 4-ethoxy-2-(((2S,4S)-4-((2-((2-methoxy-4-(trifluoromethyl)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0702]

[0703] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 2-methoxy-4-(trifluoromethyl)phenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0704] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and acetonitrile, and in [Step 6], the same reaction was carried out using lithium hydroxide monohydrate, methanol, water, and tetrahydrofuran instead of sodium hydroxide and 1,4-dioxane to obtain the title compound (98.5 mg, 47.8%).

[0705] Example 50. 2-(((2S,4S)-4-((2-((4-bromo-3-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0706]

[0707] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-bromo-3-fluorophenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0708] The same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in the above <Intermediate Synthesis Example 6> instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane in [Step 5] of <Synthesis Example 1>, and the same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (162 mg, 88.0%).

[0709] Example 51. 4-ethoxy-2-(((2S,4S)-4-((2-((4-fluoro-2-methylphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0710]

[0711] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-fluoro-2-methylphenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0712] The same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in the above <Intermediate Synthesis Example 6> instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane in [Step 5] of <Synthesis Example 1>, and the same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (113 mg, 80.7%).

[0713] Example 52. 2-(((2S,4S)-4-((2-((4-bromo-2,6-difluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0714]

[0715] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-bromo-2,6-difluorophenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0716] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane, and the same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (130.2 mg, 81.9%).

[0717] Example 53. 2-(((2S,4S)-4-((2-((2-cyano-4-methylphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0718]

[0719] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 2-hydroxy-5-methylbenzonitrile instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0720] The same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in the above <Intermediate Synthesis Example 6>, N,N-diisopropylamine, and methanol instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and methanol instead of sodium hydroxide and 1,4-dioxane in [Step 6], and the title compound (151 mg, 65.3%) was obtained.

[0721] Example 54. 2-(((2S,4S)-4-((2-((4-chloro-2-(trifluoromethyl)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0722]

[0723] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-chloro-2-(trifluoromethyl)phenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0724] The same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in the above <Intermediate Synthesis Example 6>, N,N-diisopropylamine, and methanol instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and methanol instead of sodium hydroxide and 1,4-dioxane in [Step 6], and the title compound (172 mg, 71.6%) was obtained.

[0725] Example 55. 2-(((2S,4S)-4-((2-((4-chloro-3,5-difluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0726]

[0727] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-chloro-3,5-difluorophenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0728] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane, and the same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (109.4 mg, 82.2%).

[0729] Example 56. 2-(((2S,4S)-4-((2-((4-cyanofenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0730]

[0731] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-hydroxybenzonitrile instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0732] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane, and the same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (111.5 mg, 72.2%).

[0733] Example 57. (S)-2-((4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0734]

[0735] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-chloro2-fluorophenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0736] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane, and the same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (144.8 mg, 95.1%).

[0737] Example 58. 2-(((2S,4S)-4-((2-((3,5-dimethylphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0738]

[0739] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 3,5-dimethylphenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0740] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane, and the same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (147.5 mg, 85.9%).

[0741] Example 59. 4-ethoxy-2-(((2S,4S)-2-methyl-4-((2-((2,4,6-trichlorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0742]

[0743] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 2,4,6-trichlorophenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0744] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane, and the same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (117.4 mg, 77.9%).

[0745] Example 60. 2-(((2S,4S)-4-((2-((3,4-dichlorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0746]

[0747] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 3,4-dichlorophenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0748] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane, and the same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (107.6 mg, 81.9%).

[0749] Example 61. 2-(((2S,4S)-4-((2-((4-chloro-3,5-dimethylphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0750]

[0751] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-chloro-3,5-dimethylphenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0752] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and acetonitrile, and in [Step 6], the same reaction was carried out using lithium hydroxide monohydrate, methanol, water, and tetrahydrofuran instead of sodium hydroxide and 1,4-dioxane to obtain the title compound (131.2 mg, 77.1%).

[0753] Example 62. 2-(((2S,4S)-4-((2-((4-chloro-2,6-difluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0754]

[0755] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-chloro-2,6-difluorophenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0756] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane, and the same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (109.2 mg, 82.6%).

[0757] Example 63. 4-ethoxy-2-(((2S,4S)-2-methyl-4-((2-((3,4,5-trifluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0758]

[0759] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 3,4,5-trifluorophenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0760] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane, and the same reaction was carried out using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (89.4 mg, 79.1%).

[0761] Example 64. 2-(((2S,4S)-4-((2-((4-chloro-3-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0762]

[0763] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-chloro-3-fluorophenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0764] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, N,N-diisopropylamine, and methanol instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and methanol, and in [Step 6], the same reaction was carried out using lithium hydroxide monohydrate, methanol, water, and tetrahydrofuran instead of sodium hydroxide and 1,4-dioxane to obtain the title compound (141 mg, 74.0%).

[0765] Example 65. 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0766]

[0767] The same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and the same reaction up to [Step 4] of <Synthetic Example 1> was carried out using 4-chloro-3-fluorophenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0768] The same reaction was carried out in [Step 5] of <Synthesizing Example 1> using N,N-diisopropylamine and methanol instead of methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, triethylamine, and N,N-dimethylformamide, and the same reaction was carried out in [Step 6] using lithium hydroxide monohydrate, methanol, water, and tetrahydrofuran instead of sodium hydroxide and 1,4-dioxane to obtain the title compound (242 mg, 85.8%).

[0769] Example 66. 5-chloro-2-((4-(((2S,4S)-1-((4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-6-(1H-tetrazole-5-yl)-1H-benzo[d]imidazole-2-yl)methyl)-2-methylpiperidine-4-yl)oxy)thieno[3,2-d]pyrimidine-2-yl)methoxy)benzonitrile

[0770]

[0771] 2-(((2S,4S)-4-((2-((4-chloro-2-cyanofenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (50 mg, 0.067 mmol), sodium azide (43.7 mg, 0.673 mmol), and triethylamine hydrochloride (92.6 mg, 0.673 mmol) synthesized in Example 85 were added to N,N-dimethylformamide (1 mL) and stirred at 100°C for 16 hours. The reaction product was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate and concentrated by filtration. Purification by silica gel column chromatography yielded the title compound (20.2 mg, 41.7%).

[0772] Example 67. (Isobutyryloxy)methyl 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0773]

[0774] 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (35 mg, 0.051 mmol), chloromethyl isobutyrate (35.5 mg, 0.25 mmol), and potassium carbonate (21.2 mg, 0.15 mmol) of Example 29 were dissolved in N,N-dimethylformamide (1 mL) and stirred at room temperature for 17 hours. Water was added to the reaction product and stirred at room temperature for 1 hour. The solid produced was filtered and dried to obtain the title compound (24.1 mg, 60.1%).

[0775] Example 68. (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0776]

[0777] In Example 67, 4-chloromethyl-5-methyl-1,3-dioxol-2-one was used instead of chloromethyl isobutyrate and dimethylacetamide was used instead of N,N-dimethylformamide to dissolve the mixture, and the mixture was stirred at room temperature for 17 hours. Water was added to the reaction product and stirred at room temperature for 1 hour. The resulting solid was filtered and dried to obtain the title compound (27 mg, 66.3%).

[0778] Example 69. (Pivaloyloxy)methyl 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0779]

[0780] In Example 67, chloromethyl 2,2-dimethylpropanoate was used instead of chloromethyl isobutyrate and dissolved, then stirred at room temperature for 17 hours. Water was added to the reaction product and extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate and concentrated by filtration. Water was added to the concentrated reaction product and stirred at room temperature for 1 hour. The resulting solid was filtered and dried to obtain the title compound (20.9 mg, 59.7%).

[0781] Example 70. (Isobutyryloxy)methyl 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0782]

[0783] 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (80 mg, 0.115 mmol) synthesized in Example 16 was dissolved in N,N-dimethylformamide (1 mL), chloromethyl 2-methylpropanoate (48 mg, 0.344 mmol) and potassium carbonate (48 mg, 0.344 mmol) were added, and the mixture was stirred at 50°C for 16 hours. After cooling to room temperature, water was added to the reaction product and extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate and concentrated by filtration. The title compound (38.8 mg, 42.4%) was obtained by purification using silica gel column chromatography.

[0784] Example 71. (Pivaloyloxy)methyl 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0785]

[0786] The same reaction was carried out using chloromethyl 2,2-dimethylpropanoate instead of chloromethyl 2-methylpropanoate in the synthesis method of Example 70 to obtain the title compound (50.8 mg, 54.6%).

[0787] Example 72. (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate

[0788]

[0789] The same reaction was carried out using 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one instead of chloromethyl 2-methylpropanoate in the synthesis method of Example 70 to obtain the title compound (38.5 mg, 33.2%).

[0790]

[0791] <Synthesized Example 2>

[0792] Example 73: (S)-2-((4-((2-((4-chlorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0793]

[0794] Step 1. Preparation of 2-(chloromethyl)-4-(piperidine-4-yloxy)thieno[3,2-d]pyrimidine hydrochloride

[0795]

[0796] 5 mL of 4N hydrochloric acid-1,4-dioxane solution was slowly added to t-butyl 4-((2-(chloromethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-carboxylate (500 mg, 1.30 mmol) and stirred at room temperature for 1 hour. After removing the solvent, the reaction product was used without further purification. (417 mg, 99.9%)

[0797] Step 2. Preparation of methyl (S)-2-((4-((2-(chloromethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0798]

[0799] The 2-(chloromethyl)-4-(piperidin-4-yloxy)thieno[3,2-d]pyrimidine hydrochloride (417 mg, 1.30 mmol) synthesized in [Step 1] above was dissolved in N,N-dimethylformamide (4.17 mL) and cooled to 0°C. Methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (307 mg, 1.04 mmol) and triethylamine (3.65 mL, 26.04 mmol) were added, and the mixture was stirred at 0°C for 12 hours. Water was added to the reaction product, and it was extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated. The title compound (133 mg, 18.8%) was obtained by purification using silica gel column chromatography.

[0800] Step 3. Preparation of methyl (S)-2-((4-((2-((4-chlorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0801]

[0802] Methyl (S)-2-((4-((2-(chloromethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (15 mg, 0.03 mmol), 4-chlorophenol (4.27 mg, 0.03 mmol), and potassium carbonate (5.77 mg, 0.04 mmol) synthesized in [Step 2] above were added to acetonitrile (0.5 mL) and stirred at 60°C for 22 hours. After cooling the reaction product to room temperature, water was added and extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated. Purified by silica gel column chromatography, the title compound (12 mg, 68.4%) was obtained.

[0803] Step 4. Preparation of (S)-2-((4-((2-((4-chlorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0804]

[0805] Methyl (S)-2-((4-((2-((4-chlorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (12 mg, 0.019 mmol) synthesized in [Step 3] above was dissolved in 1,4-dioxane (0.4 mL) and water (0.2 mL), cooled to 0°C, and then sodium hydroxide (3.1 mg, 0.08 mmol) dissolved in water (0.2 mL) was added. The temperature was slowly raised to room temperature and the reaction mixture was stirred for 23 hours. The reaction product was acidified by slowly adding 1N hydrochloric acid dropwise and extracted with dichloromethane. The separated organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated. The title compound (5.3 mg, 45.2%) was obtained by purification using silica gel column chromatography.

[0806] Example 74: (S)-2-((4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0807]

[0808] The same reaction was carried out up to [Step 4] using 4-chloro-2-fluorophenol instead of 4-chlorophenol in [Step 3] of <Synthesizing Example 2> to obtain the title compound (24.2 mg, 37.0%).

[0809] Example 75: (S)-2-((4-((2-((2-methoxy-4-(trifluoromethyl)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0810]

[0811] The same reaction was carried out up to [Step 4] using 2-methoxy-4-(trifluoromethyl)phenol instead of 4-chlorophenol in [Step 3] of <Synthetic Example 2> to obtain the title compound (21.7 mg, 65.8%).

[0812] Example 76: (S)-2-((4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0813]

[0814] The same reaction was carried out using 2,4-dichlorothieno[2,3-d]pyrimidine instead of 4-chloro-2-(chloromethyl)thieno[3,2-d]pyrimidine in [Step 2] of <Synthetic Example 1>, and using triazabicyclodecene and acetonitrile instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (62 mg, 60.4%).

[0815]

[0816] <Intermediate Synthesis Example 8>

[0817]

[0818] Step 1. Preparation of 2-(2,2-diethoxyethoxy)-4-fluoro-1-methoxybenzene

[0819]

[0820] 6-fluoro-2-methoxyphenol (1 g, 6.90 mmol), 2-bromo-1,1-diethoxyethane (1.82 g, 8.96 mmol), potassium carbonate (1.92 g, 13.79 mmol), and potassium iodide (114.46 mg, 0.69 mmol) were dissolved in N,N-dimethylformamide (10 mL) and refluxed at 90°C for 17 hours. After cooling the reaction product to room temperature, water was added and extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (1.5 g, 84.2%).

[0821] Step 2. Preparation of 4-fluoro-7-methoxybenzofuran

[0822]

[0823] Polyphosphate (1 g, 3.87 mmol) was added to chlorobenzene (15 mL) and heated to 80°C. Then, 2-(2,2-diethoxyethoxy)-4-fluoro-1-methoxybenzene (1 g, 3.87 mmol) synthesized in [Step 1] above was dissolved in chlorobenzene (10 mL) and slowly added. The mixture was refluxed at 120°C for 1 hour, and after cooling the reaction product to room temperature, the chlorobenzene was concentrated. Water was added to the concentrated reaction product and extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated. Purified by silica gel column chromatography, the title compound (650 mg, 32.6%) was obtained.

[0824] Step 3. Preparation of 4-fluorobenzofuran-7-ol

[0825]

[0826] 4-fluoro-7-methoxybenzofuran (821 mg, 4.94 mmol) synthesized in [Step 2] above was dissolved in dichloromethane (49.4 mL) and cooled to 0°C under nitrogen gas. Boron tribromide (0.71 mL, 7.41 mmol) was slowly added and stirred at 0°C for 17 hours. Ice water was added to the reaction product and stirred for 30 minutes, after which it was extracted with dichloromethane. The separated organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (583 mg, 77.6%).

[0827] Example 77: 4-fluoro-2-(((2S,4S)-4-((2-(((4-fluorobenzofuran-7-yl)oxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0828]

[0829] In [Step 1] of <Synthesizing Example 2>, use t-butyl (2S,4S)-4-((2-(chloromethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-carboxylate instead of t-butyl 4-((2-(chloromethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-carboxylate, and in [Step 2], use the methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate synthesized in <Intermediate Synthesis Example 3> instead of methyl (S)-2-(chloromethyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, and [step The same reaction up to [Step 4] was carried out using 4-fluorobenzofuran-7-ol synthesized in <Intermediate Synthesis Example 6> instead of 4-chlorophenol in [3] to obtain the title compound (7.5 mg, 41.3%).

[0830]

[0831] <Intermediate Synthesis Example 9>

[0832]

[0833] Step 1. Preparation of 4-Bromo-2-(2,2-diethoxyethoxy)-1-methoxybenzene

[0834]

[0835] The title compound (7.46 g, 94.9%) was obtained by using 5-bromo-2-methoxyphenol instead of 6-fluoro-2-methoxyphenol in [Step 1] of <Intermediate Synthesis Example 8>.

[0836] Step 2. Preparation of 4-Bromo-7-Methoxybenzofuran

[0837]

[0838] The title compound (2.15 g, 59.3%) was obtained by using 4-bromo-2-(2,2-diethoxyethoxy)-1-methoxybenzene synthesized in [Step 1] above instead of 2-(2,2-diethoxyethoxy)-4-fluoro-1-methoxybenzene in [Step 2] of <Intermediate Synthesis Example 8>.

[0839] Step 3. Preparation of 7-Methoxybenzofuran-4-Carbonitrile

[0840]

[0841] 4-bromo-7-methoxybenzofuran (2.15 g, 9.47 mmol), zinc cyanide (1.13 g, 9.47 mmol), and tetrakis(triphenylphosphine)palladium (0) (1.09 g, 0.95 mmol) synthesized in [Step 2] above were added to N,N-dimethylformamide (10 mL) and refluxed at 100°C for 12 hours. After cooling the reaction product to room temperature, water was added and extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate and concentrated by filtration. Purified by silica gel column chromatography, the title compound (955 mg, 58.2%) was obtained.

[0842] Step 4. Preparation of 7-Hydroxybenzofuran-4-Carbonitrile

[0843]

[0844] In [Step 3] of <Intermediate Synthesis Example 8>, 7-methoxybenzofuran-4-carbonitrile was used instead of 4-fluoro-7-methoxybenzofuran to obtain the title compound (97.1 mg, 80.7%).

[0845] Example 78: 2-(((2S,4S)-4-((2-(((4-cyanobenzofuran-7-yl)oxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0846]

[0847] In [Step 1] of <Synthetic Example 2>, use t-butyl (2S,4S)-4-((2-(chloromethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-carboxylate instead of t-butyl 4-((2-(chloromethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-carboxylate instead of methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate instead of methyl (S)-2-(chloromethyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, and in [Step 3], use <intermediate> instead of 4-chlorophenol Using 7-hydroxybenzofuran-4-carbonitrile synthesized in Synthesis Example 9, the same reaction up to [Step 4] was carried out to obtain the title compound (30 mg, 30.6%).

[0848] Example 79: 2-(((2S,4S)-4-((2-(((4-cyano-2-fluorobenzofuran-7-yl)oxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0849]

[0850] 7-methoxybenzofuran-4-carbonitrile (250 mg, 1.44 mmol) synthesized in [Step 3] of <Intermediate Synthesis Example 9> was dissolved in tetrahydrofuran (5 mL) and cooled to -70°C under nitrogen gas. 2.5 M n-butyllithium solution (1.2 mL, 2.89 mmol) dissolved in hexane was slowly added and stirred at -70°C for 1.5 hours. N-fluorobenzenesulfonimide (185 mg, 2.89 mmol) dissolved in tetrahydrofuran (1 mL) was slowly added and the mixture was stirred at room temperature for 15 hours. An aqueous ammonium chloride solution was added to the reaction product and extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated. 2-fluoro-7-methoxybenzofuran-4-carbonitrile (93 mg, 33.7%) was obtained by purification using silica gel column chromatography.

[0851] 2-fluoro-7-hydroxybenzofuran-4-carbonitrile was synthesized by carrying out the reaction [Step 4] of <Intermediate Synthesis Example 9>, and the title compound (4.3 mg, 23.08%) was obtained by carrying out the same reaction as in Example 18.

[0852] Example 80: 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0853]

[0854] In [Step 1] of <Synthesizing Example 2>, use t-butyl (2S,4S)-4-((2-(chloromethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-carboxylate instead of t-butyl 4-((2-(chloromethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-carboxylate, and in [Step 2], use the methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate synthesized in <Intermediate Synthesis Example 3> instead of methyl (S)-2-(chloromethyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, and [step The same reaction up to [Step 4] was carried out using 4-chloro-2-fluorophenol instead of 4-chlorophenol in [Step 3] to obtain the title compound (31 mg, 62.3%).

[0855] Example 81: 2-(((2S,4S)-4-((2-((4-acetyl-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0856]

[0857] In [Step 1] of <Synthesizing Example 2>, use t-butyl (2S, 4S)-4-((2-(chloromethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-carboxylate instead of t-butyl 4-((2-(chloromethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-carboxylate, and in [Step 2], use the methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate synthesized in <Intermediate Synthesis Example 3> instead of methyl (S)-2-(chloromethyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, and [step The same reaction up to [Step 4] was carried out using 1-(4-hydroxyphenyl)ethane-1-one instead of 4-chlorophenol in [Step 3] to obtain the title compound (17 mg, 43.8%).

[0858] Example 82: 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[2,3-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0859]

[0860] The same reaction up to [Step 4] was carried out using 4-chloro-2-(chloromethyl)thieno[3,2-d]pyrimidine instead of 4-chloro-2-(chloromethyl)thieno[2,3-d]pyrimidine in [Step 2] of <Synthetic Example 1>, and t-butyl (2S,4S)-4-hydroxy-2-methylpiperidine-1-carboxylate instead of t-butyl 4-hydroxypiperidine-1-carboxylate.

[0861] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out at 80°C using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and acetonitrile, and in [Step 6], the same reaction was carried out using triazabicyclodecene, acetonitrile, and water instead of sodium hydroxide and 1,4-dioxane to obtain the title compound (63 mg, 40.3%).

[0862] Example 83: 2-(((2S,4S)-4-((2-((4-chloro-2-cyanofenoxy)methyl)thieno[2,3-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0863]

[0864] In [Step 2] of <Synthetic Example 1>, 4-chloro-2-(chloromethyl)thieno[3,2-d]pyrimidine was used instead of 4-chloro-2-(chloromethyl)thieno[2,3-d]pyrimidine, and t-butyl (2S,4S)-4-hydroxy-2-methylpiperidine-1-carboxylate was used instead of t-butyl 4-hydroxypiperidine-1-carboxylate, and the same reaction was carried out up to [Step 4] using 5-chloro-2-hydroxybenzonitrile instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0865] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out at 80°C using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and acetonitrile, and in [Step 6], the same reaction was carried out using triazabicyclodecene, acetonitrile, and water instead of sodium hydroxide and 1,4-dioxane to obtain the title compound (41.4 mg, 27.5%).

[0866] Example 84: 2-(((2S,4S)-4-((2-((4-cyano-2-methoxyphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0867]

[0868] The same reaction was carried out up to [Step 4] using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and 4-hydroxy-3-methoxybenzonitrile instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0869] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out at 50°C using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, N,N-diisopropylamine, and methanol instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and methanol, and in [Step 6], the same reaction was carried out using triazabicyclodecene, acetonitrile, and water instead of sodium hydroxide and 1,4-dioxane to obtain the title compound (42.6 mg, 60.7%).

[0870] Example 85: 2-(((2S,4S)-4-((2-((4-chloro-2-cyanofenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0871]

[0872] In [Step 2] of <Synthetic Example 1>, t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate was used instead of t-butyl 4-hydroxypiperidin-1-carboxylate, and in [Step 3], 5-chloro-2-hydroxybenzonitrile was used instead of 3-fluoro-4-hydroxy-benzonitrile, and the same reaction was carried out up to [Step 4].

[0873] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out at 70°C using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and acetonitrile, and in [Step 6], the same reaction was carried out using triazabicyclodecene, acetonitrile, and water instead of sodium hydroxide and 1,4-dioxane to obtain the title compound (98 mg, 37.4%).

[0874] Example 86: (S)-2-((4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0875]

[0876] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out at 70°C using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and acetonitrile, and in [Step 6], the same reaction was carried out using triazabicyclodecene, acetonitrile, and water instead of sodium hydroxide and 1,4-dioxane to obtain the title compound (56.9 mg, 37.1%).

[0877] Example 87: 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile

[0878]

[0879] The same reaction was carried out up to [Step 4] using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and 4-chloro-2-fluorophenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0880] The title compound (247 mg, 74.4%) was obtained by carrying out the same reaction at 70°C using the intermediate (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, triethylamine, N,N-dimethylformamide synthesized without performing [Step 3] in the above <Intermediate Synthesis Example 6>, instead of methyl (S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carbonitrile, N,N-diisopropylamine, acetonitrile, which was synthesized without performing [Step 3] in <Intermediate Synthesis Example 6> above.

[0881] Example 88: (S)-2-((4-((2-(((4-cyano-2-fluorophenyl)thio)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0882]

[0883] The same reaction was carried out up to [Step 4] using 3-fluoro-4-mercaptobenzonitrile instead of 4-chlorophenol in [Step 3] of <Synthetic Example 2> to obtain the title compound (6.2 mg, 18.2%).

[0884]

[0885] <Intermediate Synthesis Example 10>

[0886]

[0887] Step 1. Preparation of 1-(benzyloxy)-4-bromo-2-fluorobenzene

[0888]

[0889] 4-bromo-2-fluorophenol (1 g, 5.13 mmol), potassium carbonate (855 mg, 6.16 mmol), and benzyl bromide (985 mg, 5.64 mmol) were dissolved in N,N-dimethylformamide (10 mL) and stirred at room temperature for 16 hours. After the reaction was complete, water was added and the mixture was extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate and concentrated by vacuum filtration. The solution was purified by silica gel column chromatography to obtain the title compound (1.44 g, 99.8%).

[0890] Step 2. Preparation of 3-(4-(benzyloxy)-3-fluorophenyl)oxetan-3-ol

[0891]

[0892] 1-(benzyloxy)-4-bromo-2-fluorobenzene (1 g, 3.56 mmol) synthesized in [Step 1] above was dissolved in anhydrous tetrahydrofuran (2 mL) and cooled to -70°C under nitrogen gas. 2.5 M n-butyllithium solution (1.7 mL, 4.27 mmol) dissolved in hexane was slowly added and stirred at -70°C for 1 hour. Oxetan-3-one (262 mg, 3.56 mmol) dissolved in tetrahydrofuran (0.5 mL) was slowly added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction product, and it was extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated. The title compound (927 mg, 95.0%) was obtained by purification using silica gel column chromatography.

[0893] Step 3. Preparation of O-(3-(4-(benzyloxy)-3-fluorophenyl)oxetane-3-yl)S-methyl carbonodithioate

[0894]

[0895] 3-(4-(benzyloxy)-3-fluorophenyl)oxetan-3-ol (827 mg, 3.02 mmol) synthesized in [Step 2] above was dissolved in anhydrous tetrahydrofuran (8.27 mL) and cooled to 0°C under nitrogen gas. Sodium hydride (241 mg, 6.03 mmol) was slowly added and stirred at room temperature for 2 hours. The mixture was cooled to 0°C, carbon disulfide (230 mg, 3.02 mmol) and methyl iodide (429 mg, 3.02 mmol) were slowly added, and the mixture was stirred at 0°C for 30 minutes. After the reaction was complete, ammonium chloride was added and extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated for use without further purification.

[0896] Step 4. Preparation of 3-(4-(benzyloxy)-3-fluorophenyl)oxetane

[0897]

[0898] O-(3-(4-(benzyloxy)-3-fluorophenyl)oxetane-3-yl)S-methyl carbonodithioate (1 g, 3.01 mmol) synthesized in [Step 3] above was dissolved in toluene (5 mL), and azobisisobutyronitrile (50 mg, 0.301 mmol) and tributyltin hydride (1.8 g, 6.02 mmol) were added and stirred at 125°C for 30 minutes. The reaction product was cooled to room temperature, potassium fluoride aqueous solution (10 mL) was added, stirred for 2 hours, and then extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate and concentrated by filtration. Purification by silica gel column chromatography yielded the title compound (580 mg, 81.9%).

[0899] Step 5. Preparation of 2-fluoro-4-(oxetane-3-yl)phenol

[0900]

[0901] 3-(4-(benzyloxy)-3-fluorophenyl)oxetane (480 mg, 1.86 mmol) synthesized in [Step 4] above was dissolved in ethanol (4.8 mL), and after nitrogen gas substitution, 10% palladium / carbon (198 mg, 0.186 mmol) was added. After hydrogen gas substitution, the mixture was stirred at 40°C for 18 hours. After cooling the reaction product to room temperature, it was filtered using Celite, and the filtrate was concentrated and used without further purification.

[0902] Example 89: 2-(((2S,4S)-4-((2-((2-fluoro-4-(oxetane-3-yl)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0903]

[0904] In [Step 1] of <Synthesis Example 2>, instead of t-butyl 4-((2-(chloromethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-carboxylate, use t-butyl (2S,4S)-4-((2-(chloromethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-carboxylate; in [Step 2], instead of methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, use the methyl (S)-2-(chloromethyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate synthesized in <Intermediate Synthesis Example 5>; [Step In [Step 3], 2-fluoro-4-(oxetane-3-yl)phenol synthesized in <Intermediate Synthesis Example 10> was used instead of 4-chlorophenol, and the same reaction was carried out using triazabicyclodecene, acetonitrile, and water instead of sodium hydroxide and 1,4-dioxane in [Step 4] to obtain the title compound (25 mg, 44.4%).

[0905] Example 90: 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-((1-ethyl-1H-imidazole-5-yl)methyl)-4-methoxy-1H-benzo[d]imidazole-6-carboxylic acid

[0906]

[0907] The same reaction was carried out up to [Step 4] using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthetic Example 1>, and 4-chloro-2-fluorophenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[0908] The intermediate 2-((4-chloro-2-fluorophenoxy)methyl)-4-(((2S,4S)-2-methylpiperidine-4-yl)oxy)thieno[3,2-d]pyrimidine (86.76 mg, 0.21 mmol) obtained by carrying out up to [Step 4], the intermediate 4-(2-chloroacetamido)-3-(((1-ethyl-1H-imidazole-5-yl)methyl)amino)-5-methoxybenzoic acid (90 mg, 0.24 mmol) prepared by using (1-ethyl-1H-imidazole-5-yl)methaneamine instead of (S)-oxetane-2-ylmethaneamine in [Step 2] of <Intermediate Synthesis Example 5> and carrying out only the room temperature reaction of [Step 4], potassium carbonate (98.48 mg, 0.71 mmol) N,N-dimethylformamide (1 It was added to mL) and stirred at room temperature for 15 hours. Water was added to the reaction product and extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate and concentrated by filtration. It was purified by silica gel column chromatography to obtain the title compound (82 mg, 46.13%).

[0909] To the methyl 4-(2-((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidin-1-yl)acetamido)-3-(((1-ethyl-1H-imidazole-5-yl)methyl)amino)-5-methoxybenzoate (91 mg, 0.12 mmol) synthesized above, toluene (1 mL) and acetic acid (0.1 mL) were added and stirred at 110°C for 15 hours. The reaction product was poured into water and extracted with ethyl acetate. The separated organic layer was washed with an aqueous sodium bicarbonate solution and brine, dried with anhydrous sodium sulfate, filtered, and concentrated. Purified by silica gel column chromatography, the title compound (71.3 mg, 80.28%) was obtained.

[0910] In [Step 6] of <Synthetic Example 1>, the same reaction was carried out using lithium hydroxide monohydrate, methanol, water, and tetrahydrofuran instead of sodium hydroxide and 1,4-dioxane, and then the residue obtained by neutralizing with 1N hydrochloric acid dropwise was purified by silica gel chromatography to obtain the title compound (25.5 mg, 37.14%).

[0911]

[0912] <Synthesized Example 3>

[0913] Example 91: (S)-2-(4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-fluorobenzyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0914]

[0915] Step 1. Preparation of methyl 2-(4-((2-(chloromethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-fluorophenyl)acetate

[0916]

[0917] 4-chloro-2-(chloromethyl)thieno[3,2-d]pyrimidine (500 mg, 2.28 mmol), methyl 2-(2-fluoro-4-hydroxyphenyl)acetate (531 mg, 2.74 mmol), and cesium carbonate (901 mg, 2.74 mmol) were dissolved in acetonitrile (5 mL) and stirred at 25°C for 4 hours. Water was added to the reaction product and extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated. Purified by silica gel column chromatography, the title compound (397 mg, 47.4%) was obtained.

[0918] Step 2. Preparation of methyl 2-(4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-fluorophenyl)acetate

[0919]

[0920] Methyl 2-(4-((2-(chloromethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-fluorophenyl)acetate (397 mg, 1.08 mmol), 3-fluoro-4-hydroxy-benzonitrile (167 mg, 1.19 mmol), and potassium carbonate (226 mg, 1.62 mmol) synthesized in [Step 1] above were dissolved in acetonitrile (4 mL) and stirred at 60°C for 16 hours. After cooling the reaction product to room temperature, water was added and extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate and concentrated by filtration. Purification by silica gel column chromatography yielded the title compound (452 ​​mg, 89.3%).

[0921] Step 3. Preparation of 2-(4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-fluorophenyl)acetic acid

[0922]

[0923] Methyl 2-(4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-fluorophenyl)acetate (452 ​​mg, 0.97 mmol) synthesized in [Step 2] above was dissolved in acetonitrile (4.52 mL), and then sodium hydroxide (119 mg, 2.90 mmol) dissolved in water (2.26 mL) was added. The reaction mixture was stirred at 25°C for 16 hours. The reaction product was acidified by slowly adding 1N hydrochloric acid dropwise and extracted with a solvent of dichloromethane:methanol = 5:1. The separated organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (287 mg, 65.5%).

[0924] Step 4. Preparation of methyl (S)-4-(2-(4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-fluorophenyl)acetamido)-3-((oxetane-2-ylmethyl)amino)benzoate

[0925]

[0926] A 50 wt.% ethyl acetate solution (604.19 mg, 0.95 mmol) of 2-(4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-fluorophenyl)acetic acid (287 mg, 0.63 mmol), methyl (S)-4-amino-3-((oxetane-2-ylmethyl)amino)benzoate, N,N-diisopropylethylamine, and propanephosphonic anhydride synthesized in [Step 3] above was dissolved in tetrahydrofuran (2.87 mL) and stirred at 25°C for 15 hours. The reaction product was concentrated and purified by silica gel column chromatography to obtain the title compound (330 mg, 77.6%).

[0927] Step 5. Preparation of methyl (S)-2-(4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-fluorobenzyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0928]

[0929] The methyl (S)-4-(2-(4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-fluorophenyl)acetamido)-3-((oxetane-2-ylmethyl)amino)benzoate (330 mg, 0.49 mmol) synthesized in [Step 4] above was dissolved in toluene (3 mL) and acetic acid (0.3 mL) and refluxed at 110°C for 4 hours. The reaction product was cooled to room temperature, concentrated, and purified by silica gel column chromatography to obtain the title compound (295 mg, 91.9%).

[0930] Step 6. Preparation of (S)-2-(4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-fluorobenzyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0931]

[0932] The methyl (S)-2-(4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-fluorobenzyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (100 mg, 0.15 mmol) synthesized in [Step 5] above was dissolved in acetonitrile (1 mL) and water (0.2 mL), and then triazabicyclodecene (43.46 mg, 0.31 mmol) was added. This mixture was stirred at room temperature for 16 hours. The reaction product was acidified by slowly adding 1N hydrochloric acid dropwise and extracted with dichloromethane solvent. The separated organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated. The title compound (32 mg, 32.7%) was obtained by purification using silica gel column chromatography.

[0933]

[0934] <Synthesized Example 4>

[0935] Example 92: (S)-2-(4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2,5-difluorobenzyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0936]

[0937] Step 1. Preparation of 1-(benzyloxy)-4-bromo-2,5-difluorobenzene

[0938]

[0939] 4-bromo-2,5-difluorophenol (2 g, 9.09 mmol) and cesium carbonate (4.2 g, 12.73 mmol) were dissolved in N,N-dimethylformamide (20 mL) and stirred at 25°C for 15 minutes. (Bromomethyl)benzene (1.08 mL, 9.09 mmol) was added and stirred at 25°C for 1 hour. Ice water was added to the reaction product and stirred for 1 hour; the resulting solid was filtered and dried, and used without further purification.

[0940] Step 2. Preparation of 1-allyl-4-(benzyloxy)-2,5-difluorobenzene

[0941]

[0942] 1-(benzyloxy)-4-bromo-2,5-difluorobenzene (2.8 g, 9.36 mmol), allyl tributylstantanane (3.83 g, 11.23 mmol), and tetrakis(triphenylphosphine)palladium (0) (1.08 g, 0.94 mmol) synthesized in [Step 1] above were added to N,N-dimethylformamide (28 mL), and after nitrogen substitution, the reaction mixture was refluxed at 110°C for 12 hours. After cooling the reaction product to room temperature, water was added and extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate and concentrated by filtration. Purification by silica gel column chromatography yielded the title compound (2.3 g, 94.4%).

[0943] Step 3. Preparation of 2-(4-(benzyloxy)-2,5-difluorophenyl)acetic acid

[0944]

[0945] 1-allyl-4-(benzyloxy)-2,5-difluorobenzene (2.3 g, 8.84 mmol) synthesized in [Step 2] above was added to acetonitrile (0.5 mL), dichloromethane (0.5 mL), and water (1 mL), and cooled to 0°C. Ruthenium chloride hydrate (366 mg, 1.77 mmol) and sodium periodate (9.55 g, 44.18 mmol) were slowly added, and the mixture was stirred at 25°C for 2 hours. The reaction product was filtered using Celite, and the filtrate was extracted with dichloromethane. The separated organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the title compound (600 mg, 24.4%).

[0946] Step 4. Preparation of methyl(S)-4-(2-(4-(benzyloxy)-2,5-difluorophenyl)acetamido)-3-fluoro-5-((oxetane-2-ylmethyl)amino)benzoate

[0947]

[0948] The title compound (297 mg, 53.5%) was obtained by using 2-(4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-fluorophenyl)acetic acid (287 mg, 0.63 mmol) synthesized in [Step 3] above instead of 2-(4-((benzyloxy)-2,5-difluorophenyl)acetic acid (300 mg, 1.08 mmol) in [Step 4] of <Synthesis Example 3>.

[0949] Step 5. Preparation of Methyl (S)-2-(4-(benzyloxy)-2,5-difluorobenzyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0950]

[0951] In [Step 5] of <Synthetic Example 3>, the title compound (178 mg, 62.1%) was obtained using methyl (S)-4-(2-(4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-fluorophenyl)acetamido)-3-((oxetane-2-ylmethyl)amino)benzoate instead of methyl (S)-4-(2-(4-(benzyloxy)-2,5-difluorophenyl)acetamido)-3-fluoro-5-((oxetane-2-ylmethyl)amino)benzoate.

[0952] Step 6. Preparation of Methyl (S)-2-(2,5-difluoro-4-hydroxybenzyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0953]

[0954] Methyl (S)-2-(4-(benzyloxy)-2,5-difluorobenzyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (150 mg, 0.30 mmol) synthesized in [Step 5] above was dissolved in methanol (1.5 mL), and after nitrogen substitution, 10% palladium / carbon (50 mg, 0.16 mmol) was added. After hydrogen substitution, the mixture was stirred at room temperature for 1 hour. The reaction product was filtered using Celite, and the filtrate was concentrated and used without further purification.

[0955] Step 7. Preparation of methyl (S)-2-(4-((2-(chloromethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2,5-difluorobenzyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0956]

[0957] The title compound (70 mg, 43.4%) was obtained by using methyl (S)-2-(2,5-difluoro-4-hydroxybenzyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate instead of methyl 2-(2-fluoro-4-hydroxyphenyl)acetate in [Step 1] of <Synthesizing Example 3>.

[0958] Step 8. Preparation of methyl (S)-2-(4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2,5-difluorobenzyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[0959]

[0960] In [Step 3] of <Synthetic Example 2>, methyl (S)-2-((4-((2-(chloromethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidin-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate was used instead of methyl (S)-2-(4-((2-(chloromethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2,5-difluorobenzyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate and 3-fluoro-4-hydroxy-benzonitrile was used instead of 4-chlorophenol to obtain the title compound (51 mg, 62.2%).

[0961] Step 9. Preparation of (S)-2-(4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2,5-difluorobenzyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0962]

[0963] The title compound (22 mg, 41.4%) was obtained using methyl (S)-2-(4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-fluorobenzyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate instead of methyl (S)-2-(4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2,5-difluorobenzyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate.

[0964] [Table 1]

[0965]

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989]

[0990]

[0991]

[0992]

[0993]

[0994]

[0995]

[0996]

[0997] <Synthesized Example 5>

[0998] Example 93: (S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[0999]

[1000] Step 1. Preparation of 4-(((2-chlorothieno[2,3-d]pyrimidine-4-yl)oxy)methyl)-3-fluorobenzonitrile

[1001]

[1002] The same reaction was carried out using 3-fluoro-4-(hydroxymethyl)benzonitrile (243 mg, 1.56 mmol) instead of t-butyl 4-hydroxypiperidin-1-carboxylate and 2,4-dichlorothieno[2,3-d]pyrimidine (300 mg, 1.42 mmol) instead of 4-chloro-2-(chloromethyl)thieno[3,2-d]pyrimidine to obtain the title compound (280 mg, 61.7%).

[1003] Step 2. Preparation of t-butyl 4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[1004]

[1005] 4-(((2-chlorothieno[2,3-d]pyrimidine-4-yl)oxy)methyl)-3-fluorobenzonitrile (280 mg, 0.88 mmol), t-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (303.9 mg, 0.96 mmol), and potassium carbonate (243.3 mg, 1.75 mmol) synthesized in [Step 1] above were added to 1,4-dioxane (3 mL) and water (0.6 mL); after nitrogen gas evacuation for 10 minutes, 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (67.5 mg, 0.09 mmol) was added, and the mixture was heated at 100°C for 16 hours. The reaction product was refluxed. After cooling the reaction product to room temperature, water was added and extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate and concentrated by vacuum filtration. The title compound (256.4 mg, 62.8%) was obtained by purification by silica gel column chromatography.

[1006] Step 3. Preparation of 3-fluoro-4-(((2-(1,2,3,6-tetrahydropyridine-4-yl)thieno[2,3-d]pyrimidine-4-yl)oxy)methyl)benzonitrile

[1007]

[1008] t-butyl 4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (100 mg, 0.21 mmol) synthesized in [Step 2] above was dissolved in dichloromethane (2 mL), then trifluoroacetic acid (0.33 mL, 4.29 mmol) was slowly added at 0°C, and the mixture was stirred at room temperature for 1 hour. The reaction product was used without further purification after removing the solvent.

[1009] Step 4. Preparation of methyl (S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[1010]

[1011] 3-fluoro-4-(((2-(1,2,3,6-tetrahydropyridine-4-yl)thieno[2,3-d]pyrimidine-4-yl)oxy)methyl)benzonitrile (78 mg, 0.21 mmol) synthesized in [Step 3] above was dissolved in 1,4-dioxane and cooled to 0°C. Then, methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (62.8 mg, 0.21 mmol) and N,N-diisopropylethylamine (0.19 mL, 1.06 mmol) were added, and the mixture was stirred at 50°C for 16 hours. Water was added to the reaction product, and it was extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated. The title compound (80 mg, 98.8%) was obtained by purification using silica gel column chromatography.

[1012] Step 5. Preparation of (S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1013]

[1014] Methyl (S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (80 mg, 0.13 mmol) synthesized in [Step 4] above was dissolved in acetonitrile (2 mL) and water (0.4 mL), and then triazabicyclodecene (36.4 mg, 0.26 mmol) was added. This mixture was stirred at room temperature for 16 hours. The reaction product was acidified by slowly adding 1N hydrochloric acid dropwise and extracted with a solvent of dichloromethane:methanol = 5:1. The separated organic layer was dried with anhydrous sodium sulfate and concentrated by filtration. The title compound (37.7 mg, 48.2%) was obtained by purification using silica gel column chromatography.

[1015] Example 94: 2-(((S)-4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1016]

[1017] 4-(((2-chlorothieno[2,3-d]pyrimidine-4-yl)oxy)methyl)-3-fluorobenzonitrile (50 mg, 0.16 mmol) and t-butyl(S)-2-methylpiperazine-1-carboxylate (35.2 mg, 0.17 mmol) synthesized in [Step 1] of <Synthesis Example 5> were dissolved in 1,4-dioxane, N,N-diisopropylethylamine (0.06 mL, 0.31 mmol) was added, and the mixture was stirred at 110°C for 16 hours. After the reaction was finished, the mixture was cooled to room temperature, water was added to the reaction product, and it was extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate, filtered, and concentrated. The title compound (72 mg, 95.2%) was obtained by purification using silica gel column chromatography.

[1018] Except for [Step 2], the same reaction was carried out up to Step 5 of <Synthetic Example 5> to obtain the title compound (38 mg, 67%).

[1019] Example 95: 2-(((S)-4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-6-methyl-3,6-dihydropyridine-1(2H)-yl)methyl)-4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1020]

[1021] In [Step 2] of <Synthesizing Example 5>, t-butyl (S)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate is used instead of t-butyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate is used instead of methyl (S)-2-(chloromethyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate in the reaction up to [Step 4] After separating isomers using prep HPLC under the conditions below, the same reaction was carried out up to [Step 5] to obtain the title compound (16.7 mg, 45.3%).

[1022] Column: Daicel CHIRALPAK IM 30 mm IDx 250 mm L

[1023] Flow rate: 10 mL / min

[1024] Wavelength: 254 nm

[1025] Elution solvent: Ethanol:n-hexane = 300:700 (v / v)

[1026]

[1027] Example 96: 2-(((S)-4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methyl-3,6-dihydropyridine-1(2H)-yl)methyl)-4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1028]

[1029] In [Step 2] of <Synthesizing Example 5>, the reaction up to [Step 4] was performed using t-butyl (S)-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate instead of t-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate and methyl (S)-2-(chloromethyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate instead of methyl (S)-2-(chloromethyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate. After separating the isomers using prep HPLC under the same conditions as in Example 95 above, the same reaction was carried out up to [Step 5] to obtain the title compound (7.4 mg, 38.8%).

[1030] Example 97: 2-(((2S)-4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperidine-1-yl)methyl)-4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1031]

[1032] The intermediate t-butyl (S)-4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methyl-3,6-dihydropyridine-1(2H)-carboxylate (69 mg, 0.14 mmol) synthesized up to Step 2 of Example 96 was placed in ethanol (2 mL) and ethyl acetate (2 mL), and palladium / carbon (400 mg, 0.08 mmol) was added under nitrogen. After hydrogen gas substitution, the mixture was stirred at room temperature for 16 hours, acetic acid (0.1 mL) was added to the reaction mixture, and the mixture was stirred at 50°C for 16 hours. The reaction product was filtered with Celite and washed with ethyl acetate; the filtrate was concentrated and purified by silica gel column chromatography to obtain the title compound (27 mg, 38.8%).

[1033] Use the t-butyl (2S)-4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperidine-1-carboxylate synthesized above instead of t-butyl 4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-carboxylate in [Step 4] of <Synthesis Example 1>, and use methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate instead of The same reaction up to [step 5] was carried out using methyl(S)-2-(chloromethyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate to obtain the title compound (3.5 mg, 59.6%).

[1034] Example 98: (S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[3,2-d]pyrimidine-2-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1035]

[1036] The same reaction was carried out using 2,4-dichlorothieno[3,2-d]pyrimidine instead of 4-chloro-2-(chloromethyl)thieno[3,2-d]pyrimidine in [Step 2] of <Synthetic Example 1>, and using sodium hydroxide and 1,4-dioxane instead of triazabicyclodecene and acetonitrile in [Step 6] of <Synthetic Example 5> to obtain the title compound (35.9 mg, 36.7%).

[1037] Example 99: (S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[3,2-d]pyrimidine-2-yl)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1038]

[1039] t-butyl 4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (600 mg, 1.29 mmol) synthesized in [Step 2] of <Synthesis Example 5> was dissolved in methanol (6.5 mL), and after nitrogen gas substitution, 10% palladium / carbon (548 mg, 0.51 mmol) was added. After hydrogen gas substitution, the mixture was stirred at room temperature for 1 hour. The reaction product was filtered using Celite, and the filtrate was concentrated and used without further purification.

[1040] The t-butyl 4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)piperidine-1-carboxylate produced here was used instead of t-butyl 4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate in [Step 3] of <Synthesizing Example 5>, and the same reaction was carried out using sodium hydroxide and 1,4-dioxane instead of triazabicyclodecene and acetonitrile in [Step 5] to obtain the title compound (59.7 mg, 33%).

[1041] Example 100: 2-(((S)-4-(4-((4-chlorobenzofuran-7-yl)methoxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1042]

[1043] The same reaction was carried out using (4-chlorobenzofuran-7-yl)methanol (CN116574092) instead of 3-fluoro-4-(hydroxymethyl)benzonitrile in [Step 1] of <Synthesizing Example 5>, and the reaction was carried out at 100°C using N,N-dimethylformamide instead of 1,4-dioxane in [Step 2] of Example 94. In [Step 3] of <Synthesizing Example 5>, a 4N hydrochloric acid 1,4-dioxane solution was used instead of trifluoroacetic acid, and in [Step 4], the methyl (S)-2-(chloromethyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate synthesized in <Intermediate Synthesizing Example 5> was used instead of methyl (S)-2-(chloromethyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate was used instead of methyl (S)-2-(chloromethyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, and the same reaction up to [Step 5] was carried out to obtain the title compound (22.2 mg, 14.3%).

[1044] Example 101: 2-(((S)-4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1045]

[1046] The intermediate t-butyl (S)-4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-carboxylate obtained by reacting up to [Step 2] of Example 94 was used.

[1047] <Synthetic Example 5> In [Step 3], a 4N hydrochloric acid 1,4-dioxane solution was used instead of trifluoroacetic acid, and in [Step 4], the methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate synthesized in <Intermediate Synthetic Example 5> was used instead of methyl (S)-2-(chloromethyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate was used instead of methyl (S)-2-(chloromethyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, and the same reaction up to [Step 5] was carried out to obtain the title compound (40.4 mg, 28.5%).

[1048] Example 102: 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1049]

[1050] In [Step 1] of <Synthesizing Example 5>, the same reaction was carried out at 0°C using (4-chloro-2-fluorophenyl)methanol instead of 3-fluoro-4-(hydroxymethyl)benzonitrile, and in [Step 2] of Example 94, the same reaction was carried out at 60°C using N,N-dimethylformamide instead of 1,4-dioxane.

[1051] In [Step 3], a 4N hydrochloric acid 1,4-dioxane solution was used instead of trifluoroacetic acid, and in [Step 4], the methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate synthesized in <Intermediate Synthesis Example 5> was used instead of methyl (S)-2-(chloromethyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, and the same reaction up to [Step 5] of <Synthesis Example 5> was carried out to obtain the title compound (3 mg, 2.7%).

[1052] Example 103: 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1053]

[1054] In [Step 1] of <Synthesizing Example 5>, the same reaction was carried out at 0°C using (4-chloro-2-fluorophenyl)methanol instead of 3-fluoro-4-(hydroxymethyl)benzonitrile, and in [Step 2] of Example 94, the same reaction was carried out at 60°C using N,N-dimethylformamide instead of 1,4-dioxane.

[1055] In [Step 3], a 4N hydrochloric acid 1,4-dioxane solution was used instead of trifluoroacetic acid, and in [Step 4], ethyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate synthesized in <Intermediate Synthesis Example 6> was used instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, and the same reaction up to [Step 5] of <Synthesis Example 5> was carried out to obtain the title compound (24.7 mg, 29.3%).

[1056] Example 104: 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-N-(3-methyl-1H-indazole-5-yl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxamide

[1057]

[1058] 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid (10 mg, 0.015 mmol), N-hydroxybenzotriazole (3.04 mg, 0.022 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (4.35 mg, 0.022 mmol) synthesized in Example 103 above were dissolved in N,N-dimethylformamide (1 mL) and stirred at room temperature for 30 minutes. N,N-diisopropylethylamine (0.0065 mL, 0.037 mmol) and 3-methyl-1H-indazole-5-amine (2.65 mg, 0.018 mmol) were added to the reaction mixture and stirred at room temperature for 21 hours. Water was added to the reaction product to extract it with ethyl acetate, and the separated organic layer was dried with anhydrous sodium sulfate and filtered to concentrate. The title compound (3.7 mg, 31.1%) was obtained by purification using silica gel column chromatography.

[1059] Example 105: 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-5-carboxylic acid

[1060]

[1061] In [Step 1] of <Synthesizing Example 5>, the same reaction was carried out at 0°C using (4-chloro-2-fluorophenyl)methanol instead of 3-fluoro-4-(hydroxymethyl)benzonitrile, and in [Step 2] of Example 94, the same reaction was carried out at 60°C using N,N-dimethylformamide instead of 1,4-dioxane.

[1062] In [Step 3], p-toluenesulfonic acid monohydrate was used instead of trifluoroacetic acid, and it was obtained by neutralizing with an aqueous sodium bicarbonate solution and extracting with ethyl acetate. In [Step 4], the same reaction was carried out at 80°C using methyl 2-(chloromethyl)-1-(((2S)-oxetane-2-yl)methyl)benzimidazole-5-carboxylate, an intermediate prepared in <Intermediate Synthesis Example 3> using methyl 4-fluoro-3-nitrobenzoate instead of methyl 3,5-difluoro-4-nitrobenzoate in [Step 1], using acetonitrile instead of 1,4-dioxane, instead of methyl (S)-2-(chloromethyl)-1-(((2S)-oxetane-2-yl)methyl)benzimidazole-5-carboxylate.

[1063] In [Step 5], the same reaction was carried out using lithium hydroxide monohydrate (23.1 mg, 0.52 mmol) and tetrahydrofuran (0.7 mL), water (0.7 mL), and methanol (0.7 mL) instead of triazabicyclodecene and acetonitrile to obtain the title compound (8.3 mg, 5.0%).

[1064] Example 106: (S)-2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-methyl-1H-benzo[d]imidazole-6-carboxylic acid

[1065]

[1066] In [Step 1] of <Synthesizing Example 5>, the same reaction was carried out at 0°C using (4-chloro-2-fluorophenyl)methanol instead of 3-fluoro-4-(hydroxymethyl)benzonitrile, and in [Step 2] of Example 94, the same reaction was carried out at 60°C using N,N-dimethylformamide instead of 1,4-dioxane.

[1067] In [Step 3], p-toluenesulfonic acid monohydrate was used instead of trifluoroacetic acid, and it was obtained by neutralizing with an aqueous sodium bicarbonate solution and extracting with ethyl acetate. In [Step 4], the same reaction was carried out at 80°C using ethyl 2-(chloromethyl)-7-ethoxy-3-methyl-benzimidazole-5-carboxylate, an intermediate prepared in <Intermediate Synthesis Example 3> using ethyl 3-ethoxy-5-fluoro-4-nitrobenzoate instead of methyl 3,5-difluoro-4-nitrobenzoate in [Step 1], and acetonitrile instead of 1,4-dioxane. [Step 5] was performed in the same manner as in Example 105 to obtain the title compound (24 mg, 15.6%).

[1068] Example 107: 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-(cyclopropylmethoxy)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1069]

[1070] The intermediate 4-((4-chloro-2-fluoro-phenyl)methoxy)-2-((3S)-3-methylpiperazine-1-yl)thieno[2,3-d]pyrimidine obtained by performing the same reaction up to [Step 3] of Example 105 above, and the intermediate cyclopropylmethyl 3-(cyclopropylmethoxy)-5-fluoro-4-nitrobenzoate prepared by using cyclopropylmethyl 3-(cyclopropylmethoxy)-5-fluoro-4-nitrobenzoate instead of methyl 3,5-difluoro-4-nitrobenzoate in [Step 1] of <Intermediate Synthesis Example 3> instead of methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate in [Step 4]. The same reaction was carried out at 80°C using 2-(chloromethyl)-7-(chloropropylmethoxy)-3-(((2S)-oxetane-2-yl)methyl)benzimidazole-5-carboxylate and acetonitrile instead of 1,4-dioxane. [Step 5] was carried out in the same manner as in Example 105 to obtain the title compound (15.7 mg, 25.5%).

[1071] Example 108: 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-cyclopropoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1072]

[1073] The intermediate 4-((4-chloro-2-fluoro-phenyl)methoxy)-2-((3S)-3-methylpiperazine-1-yl)thieno[2,3-d]pyrimidine obtained by performing the same reaction up to [Step 3] of Example 105 above, and the intermediate methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate in [Step 4], prepared by using methyl 3-(cyclopropoxy)-5-fluoro-4-nitrobenzoate instead of methyl 3,5-difluoro-4-nitrobenzoate in [Step 1] of <Intermediate Synthesis Example 3>, methyl The same reaction was carried out at 80°C using 2-(chloromethyl)-7-(cyclopropoxy)-3-(((2S)-oxetane-2-yl)methyl)benzimidazole-5-carboxylate and acetonitrile instead of 1,4-dioxane. [Step 5] was carried out in the same manner as in Example 105 to obtain the title compound (5.4 mg, 8.9%).

[1074] Example 109: 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[3,2-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1075]

[1076] In [Step 1] of <Synthesizing Example 5>, potassium carbonate (1.99 g, 14.34 mmol) and N,N-dimethylformamide (10 mL) were added and the reaction was carried out at room temperature using (4-chloro-2-fluorophenyl)methanol (939.7 mg, 5.73 mmol) instead of 3-fluoro-4-(hydroxymethyl)benzonitrile and 2,4-dichlorothieno[3,2-d]pyrimidine (1 g, 4.78 mmol) instead of 2,4-dichlorothieno[2,3-d]pyrimidine. After the reaction was finished, water was poured over the resulting solid, which was then filtered, washed with water, and dried to obtain 2-chloro-4-((4-chloro-2-fluorobenzyl)oxy)thieno[3,2-d]pyrimidine (1.27 g, 80.9%). In [Step 2] of Example 94, the same reaction was carried out at 60°C using N,N-dimethylformamide instead of 1,4-dioxane.

[1077] In [Step 4], the same reaction was carried out at 80°C using the intermediate ethyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate made in <Intermediate Synthesis Example 6> instead of methyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, and using acetonitrile instead of 1,4-dioxane.

[1078] [Step 5] was performed in the same manner as in Example 105, and the title compound (42.6 mg, 66.7%) was obtained by adding 5% citric acid dropwise to neutralize it, filtering the resulting solid, and purifying it by silica gel chromatography.

[1079] Example 110: 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)-7-methylthieno[3,2-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1080]

[1081] In [Step 1] of Example 109, the same reaction was carried out using 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine instead of 2,4-dichlorothieno[2,3-d]pyrimidine, and in [Step 2] of Example 94, the same reaction was carried out at 60°C using N,N-dimethylformamide instead of 1,4-dioxane.

[1082] In [Step 4], the same reaction was carried out at 80°C using the intermediate ethyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate made in <Intermediate Synthesis Example 6> instead of methyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, and using acetonitrile instead of 1,4-dioxane.

[1083] [Step 5] was performed in the same manner as in Example 105, and the title compound (75.9 mg, 49.7%) was obtained by adding 5% citric acid dropwise to neutralize it, filtering the resulting solid, and purifying it by silica gel chromatography.

[1084] Example 111: 2-(((S)-4-(4-((2-fluoro-4-(oxetane-3-yl)benzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1085]

[1086] The same reaction was carried out using the intermediate (2-fluoro-4-(oxetane-3-yl)phenyl)methanol, which was prepared by using 4-bromo-2-fluorobenzyl alcohol instead of 3-fluoro-4-(hydroxymethyl)benzonitrile in [Step 1] of <Synthesizing Example 5> and 4-bromo-2-fluorophenol in <Intermediate Synthesis Example 10>.

[1087] [Step 2] uses (S)-t-butyl 3-methylpiperazine-1-carboxylate (215.9 mg, 1.08 mmol) and methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (250 mg, 0.77 mmol) synthesized in <Intermediate Synthesis Example 5>, instead of 3-fluoro-4-(((2-(1,2,3,6-tetrahydropyridine-4-yl)thieno[2,3-d]pyrimidine-4-yl)oxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate and methyl (S)-2-(chloromethyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, which were synthesized in <Intermediate Synthesis Example 5>, in place of methyl (S)-2-(chloromethyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate. The same reaction was carried out at 110°C to obtain methyl 2-(((S)-4-(t-butoxycarbonyl)-2-methylpiperazine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate (308.2 mg, 81.9%), and the next step was carried out in the same manner as [Step 3] of <Synthesizing Example 5> to obtain the intermediate methyl 4-methoxy-2-(((S)-2-methylpiperazine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate.

[1088] [Step 4] involved carrying out the same reaction at 80°C using the intermediate obtained in [Step 1], 2-chloro-4-((2-fluoro-4-(oxetane-3-yl)phenyl)methoxy)thieno[2,3-d]pyrimidine, and the intermediate obtained in [Step 3], 4-methoxy-2-(((S)-2-methylpiperazine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate, but using acetonitrile instead of 1,4-dioxane in [Step 4] of <Synthesization Example 5>.

[1089] [Step 5] was performed in the same manner as in Example 105, and the title compound (38.4 mg, 49.6%) was obtained by adding 5% citric acid dropwise to neutralize it, filtering the resulting solid, and purifying it by silica gel chromatography.

[1090] Example 112: (S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1091]

[1092] In [Step 1] of <Synthesizing Example 5>, 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine was used instead of 2,4-dichlorothieno[2,3-d]pyrimidine, and the same reaction was carried out up to [Step 5] to obtain the title compound (14 mg, 15.9%).

[1093] Example 113: (S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-5,7-dihydrofuro[3,4-d]pyrimidine-2-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1094]

[1095] In [Step 1] of <Synthesizing Example 5>, 2,4-dichloro-5,7-dihydropuro[3,4-d]pyrimidine was used instead of 2,4-dichlorothieno[2,3-d]pyrimidine, and the same reaction was carried out up to [Step 5] to obtain the title compound (7.1 mg, 7.3%).

[1096] Example 114: 2-(((S)-4-(6-((4-chloro-2-fluorobenzyl)oxy)-9-methyl-9H-purine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1097]

[1098] In [Step 1] of <Synthesizing Example 5>, the reaction was carried out using 4-chloro-2-fluorobenzyl alcohol instead of 3-fluoro-4-(hydroxymethyl)benzonitrile, 2,6-dichloro-9-methylpurine instead of 2,4-dichlorothieno[2,3-d]pyrimidine, and potassium carbonate and N,N-dimethylformamide instead of sodium hydride and tetrahydrofuran. [Step 2] was carried out at 80°C using N,N-dimethylformamide instead of 1,4-dioxane in [Step 2] of Example 94.

[1099] [Step 3] was obtained by performing the same procedure as [Step 3] of <Synthesis Example 5> and then neutralizing with an aqueous sodium bicarbonate solution, and in [Step 4], ethyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate synthesized in <Intermediate Synthesis Example 6> was used instead of methyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate. [Step 5] was performed the same procedure as in Example 105, and the title compound (115 mg, 59.0%) was obtained by adding 5% citric acid dropwise to neutralize the mixture, filtering the resulting solid, and purifying it by silica gel chromatography.

[1100] Example 115: 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)furo[3,2-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1101]

[1102] In [Step 1] of Example 114 above, 2,4-dichloropuro[3,2-d]pyrimidine was used instead of 2,6-dichloro-9-methylpurine, and the same procedure was performed up to [Step 6] to obtain the title compound (8 mg, 9.5%).

[1103] Example 116: 2-(((S)-4-(7-((4-chloro-2-fluorobenzyl)oxy)thiazolo[5,4-d]pyrimidine-5-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1104]

[1105] In [Step 1] of Example 114 above, [5,2-d]pyrimidine was used as 5,7-dichlorothiazol instead of 2,6-dichloro-9-methylpurine, and the same procedure was performed up to [Step 6] to obtain the title compound (3.2 mg, 1.8%).

[1106] Example 117: 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1107]

[1108] In [Step 1] of Example 114 above, 2,4-dichloro-7-methyl-pyrrolo[2,3-d]pyrimidine was used instead of 2,6-dichloro-9-methylpurine, and the procedure was carried out in the same manner up to [Step 6] to obtain the title compound (25.8 mg, 26.7%).

[1109] Example 118: 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1110]

[1111] In [Step 1] of Example 114 above, 2,4-dichloro-5-methyl-pyrrolo[3,2-d]pyrimidine was used instead of 2,6-dichloro-9-methylpurine, and the procedure was carried out in the same way up to [Step 6] to obtain the title compound (134.1 mg, 40.4%).

[1112] Example 119: 2-(((S)-4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1113]

[1114] In [Step 2] of Example 94, the same reaction was carried out at 60°C using N,N-dimethylformamide instead of 1,4-dioxane to obtain the intermediate t-butyl (S)-4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-carboxylate.

[1115] In [Step 4], ethyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate synthesized in <Intermediate Synthesis Example 6> was used instead of methyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, and the same reaction was carried out up to [Step 5] to obtain the title compound (48.2 mg, 25.9%).

[1116] Example 120: 2-(((S)-4-(4-((4-cyano-2-fluorobenzyl)oxy)-6-methylthieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1117]

[1118] In [Step 1] of Example 109, the same reaction was carried out using 3-fluoro-4-(hydroxymethyl)benzonitrile instead of 4-chloro-2-fluorobenzyl alcohol and 2,4-dichloro-6-methylthieno[2,3-d]pyrimidine instead of 2,4-dichlorothieno[3,2-d]pyrimidine, and in [Step 2] of Example 94, the same reaction was carried out at 60°C using N,N-dimethylformamide instead of 1,4-dioxane.

[1119] In [Step 4], the same reaction was carried out at 80°C using the intermediate ethyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate prepared in <Intermediate Synthesis Example 6> instead of methyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, and using acetonitrile instead of 1,4-dioxane, and the same reaction was carried out up to [Step 5] to obtain the title compound (21.6 mg, 31.3%).

[1120] Example 121: 2-(((S)-4-(4-((4-cyano-2-fluorobenzyl)oxy)-5,6-dimethylthieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1121]

[1122] In [Step 1] of Example 109, the same reaction was carried out using 4-chloro-2-fluorobenzyl alcohol instead of 3-fluoro-4-(hydroxymethyl)benzonitrile and 2,4-dichloro-5,6-dimethylthieno[2,3-d]pyrimidine instead of 2,4-dichlorothieno[3,2-d]pyrimidine, and in [Step 2] of Example 94, the same reaction was carried out at 60°C using N,N-dimethylformamide instead of 1,4-dioxane.

[1123] In [Step 4], the same reaction was carried out at 80°C using the intermediate ethyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate prepared in <Intermediate Synthesis Example 6> instead of methyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, and acetonitrile instead of 1,4-dioxane.

[1124] [Step 5] was performed in the same manner as in Example 105, and the title compound (18.3 mg, 14%) was obtained by adding 5% citric acid dropwise to neutralize it, filtering the resulting solid, and purifying it by silica gel chromatography.

[1125]

[1126] <Synthesized Example 6>

[1127] Example 122: (S)-2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)thieno[3,2-d]pyrimidine-4-yl)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1128]

[1129] Step 1. Preparation of t-butyl 4-(2-chlorothieno[3,2-d]pyrimidine-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[1130]

[1131] The same reaction was carried out using 2,4-dichlorothieno[3,2-d]pyrimidine (500 mg, 2.44 mmol) instead of 4-(((2-chlorothieno[2,3-d]pyrimidine-4-yl)oxy)methyl)-3-fluorobenzonitrile in [Step 2] of <Synthesizing Example 5> to obtain the title compound (621.9 mg, 72.5%).

[1132] Step 2. Preparation of t-butyl 4-(2-((4-cyano-2-fluorobenzyl)oxy)thieno[3,2-d]pyrimidine-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[1133]

[1134] t-butyl 4-(2-chlorothieno[3,2-d]pyrimidine-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (1.9 g, 4.50 mmol), 4-cyano-2-fluorobenzyl alcohol (1.01 g, 6.48 mmol), t-butyl exphos (473 mg, 1.08 mmol), and cesium carbonate (4.44 g, 13.5 mmol) synthesized in [Step 1] above were dissolved in toluene (18 mL), and nitrogen gas was applied for 10 minutes. Palladium acetate (124 mg, 0.54 mmol) was added to the mixture, and the mixture was stirred under closed conditions at 100°C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, water was added, and the solution was extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate and concentrated by vacuum filtration. The title compound (1.6 g, 63.5%) was obtained by purification using silica gel column chromatography.

[1135] Step 3. Preparation of t-butyl 4-(2-((4-cyano-2-fluorobenzyl)oxy)thieno[3,2-d]pyrimidine-4-yl)piperidine-1-carboxylate

[1136]

[1137] The t-butyl 4-(2-((4-cyano-2-fluorobenzyl)oxy)thieno[3,2-d]pyrimidine-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate (400 mg, 0.86 mmol) synthesized in [Step 2] above was dissolved in methanol (4.3 mL), and after nitrogen gas substitution, 10% palladium / carbon (365 mg, 0.34 mmol) was added. After hydrogen gas substitution, the mixture was stirred at 40°C for 16 hours. The reaction product was filtered using Celite, the filtrate was concentrated, and the solution was purified by silica gel column chromatography to obtain the title compound (88.3 mg, 21.98%).

[1138] Step 4. Preparation of 3-fluoro-4-(((4-(piperidine-4-yl)thieno[3,2-d]pyrimidine-2-yl)oxy)methyl)benzonitrile

[1139]

[1140] The same reaction was performed using the t-butyl 4-(2-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate synthesized above instead of the t-butyl 4-(2-((4-cyano-2-fluorobenzyl)oxy)thieno[3,2-d]pyrimidine-4-yl)piperidine-1-carboxylate in [Step 3] of <Synthesis Example 5> to obtain the title compound (69.4 mg, 100%).

[1141] Step 5. Preparation of methyl (S)-2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)thieno[3,2-d]pyrimidine-4-yl)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[1142]

[1143] 3-fluoro-4-(((4-(piperidin-4-yl)thieno[3,2-d]pyrimidine-2-yl)oxy)methyl)benzonitrile (69 mg, 0.19 mmol) and potassium carbonate (105 mg, 0.75 mmol) synthesized in [Step 4] above were dissolved in acetonitrile (1 mL) and cooled to 0°C. Methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate (72 mg, 0.25 mmol) and potassium iodide (6.3 mg, 0.04 mmol) were added to the mixture and stirred at room temperature for 4 hours. After the reaction was complete, the mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate and concentrated by vacuum filtration. The title compound (84.7 mg, 71.7%) was obtained by purification using silica gel column chromatography.

[1144] Step 6. Preparation of (S)-2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)thieno[3,2-d]pyrimidine-4-yl)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1145]

[1146] In [Step 5] of <Synthesizing Example 5>, the same reaction was performed using methyl (S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, sodium hydroxide, and 1,4-dioxane instead of methyl (S)-2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)thieno[3,2-d]pyrimidine-4-yl)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, sodium hydroxide, and 1,4-dioxane. The title compound (43.9 mg, 53%) was obtained.

[1147] Example 123: (S)-2-((4-(2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1148]

[1149] The same reaction was carried out using 4-chloro-2-(chloromethyl)thieno[3,2-d]pyrimidine instead of 4-(((2-chlorothieno[2,3-d]pyrimidine-4-yl)oxy)methyl)-3-fluorobenzonitrile in [Step 2] of <Synthetic Example 5>, and t-butyl 4-((2-(chloromethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-carboxylate instead of t-butyl 4-(2-(chloromethyl)thieno[3,2-d]pyrimidine-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate in [Step 3] of <Synthetic Example 1> to obtain the title compound (12.8 mg, 72.7%).

[1150] Example 124: 2-(((S)-4-(2-((4-chloro-2-fluorobenzyl)oxy)-7-methylthieno[3,2-d]pyrimidine-4-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1151]

[1152] In [Step 1], 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine (300 mg, 1.60 mmol) and t-butyl(S)-2-methylpiperazine-1-carboxylate (319.03 mg, 1.56 mmol) were dissolved in dichloromethane (3 mL) and cooled to 0°C, after which triethylamine (398.9 mg, 0.55 mL, 3.90 mmol) was slowly added. The mixture was stirred at room temperature for 16 hours. After the reaction was complete, water was poured into the mixture and extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate and concentrated by vacuum filtration. The title compound (498 mg, 99.9%) was obtained by purification using silica gel column chromatography.

[1153] The same reaction was carried out using t-butyl (S)-4-(2-chloro-7-methylthieno[3,2-d]pyrimidine-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate and (4-chloro-2-fluorobenzyl alcohol) synthesized in [Step 1] above, instead of t-butyl (S)-4-(2-chloro-7-methylthieno[3,2-d]pyrimidine-4-yl)-2-methylpiperazine-1-carboxylate and (4-chloro-2-fluorophenyl)methanol, as synthesized in [Step 1] above, in [Step 2] of <Synthesis Example 6>.

[1154] [Step 3] was reacted identically to [Step 3] of <Synthesizing Example 5> using t-butyl (S)-4-(2-((4-chloro-2-fluorobenzyl)oxy)-7-methylthieno[3,2-d]pyrimidine-4-yl)-2-methylpiperazine-1-carboxylate instead of t-butyl 4-(4-((4-cyano-2-fluorobenzyl)oxy)-7-methylthieno[3,2-d]pyrimidine-4-yl)-2-methylpiperazine-1-carboxylate, and in [Step 4] the intermediate prepared in <Intermediate Synthesis Example 6> instead of methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate. The same reaction was carried out at 80°C using ethyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate and acetonitrile instead of 1,4-dioxane.

[1155] [Step 5] was performed in the same manner as in Example 105, and the solid obtained after neutralizing by adding 5% citric acid dropwise was filtered to obtain the title compound (12 mg, 18.4%).

[1156] Example 125: (S)-2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1157]

[1158] The same reaction up to [Step 5] was carried out to obtain the title compound (25 mg, 42%), except that 2,4-dichlorothieno[3,2-d]pyrimidine was used instead of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine in [Step 1] of <Synthesizing Example 6>.

[1159] Example 126: 2-(((S)-4-(5-((4-chloro-2-fluorobenzyl)oxy)pyrazolo[1,5-a]pyrimidine-7-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1160]

[1161] In [Step 1] of Example 124, the same reaction was carried out at 80°C using 5,7-dichloropyrazolo[1,5-a]pyrimidine and isopropyl alcohol instead of 2,4-dichloro-7-methylthieno[3,2-d]pyrimidine and dichloromethane.

[1162] [Step 2] carried out the same reaction at 80°C using t-butyl (S)-4-(5-chloropyrazolo[1,5-a]pyrimidine-7-yl)-2-methylpiperazine-1-carboxylate and (4-chloro-2-fluorophenyl)methanol, N,N-dimethylformamide instead of 3-fluoro-4-(hydroxymethyl)benzonitrile, 2,4-dichlorothieno[2,3-d]pyrimidine, and tetrahydrofuran in [Step 1] of <Synthesizing Example 5>.

[1163] [Step 3] was reacted identically to [Step 3] of <Synthesization Example 5> using the t-butyl (S)-4-(5-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate synthesized above, and in [Step 4] using the intermediate made in <Intermediate Synthesis Example 6> instead of methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate. The same reaction was carried out at 80°C using ethyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate and acetonitrile instead of 1,4-dioxane.

[1164] [Step 5] was performed in the same manner as in Example 105, and the solid obtained after neutralizing by adding 5% citric acid dropwise was filtered to obtain the title compound (79 mg, 65.8%).

[1165]

[1166] <Intermediate Synthesis Example 11>

[1167]

[1168] Step 1. Preparation of t-butyl 4-(2-chlorothieno[3,2-d]pyrimidine-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate

[1169]

[1170] 7-bromo-2-chlorothieno[3,2-d]pyrimidine (600 mg, 2.40 mmol) was dissolved in 1,4-dioxane (14.4 mL), 2N sodium carbonate (772 mg, 7.21 mmol), and t-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (759 mg, 2.40 mmol) were added, and nitrogen gas was replaced for 10 minutes. Bis(triphenylphosphine)palladium(II) dichloride (172 mg, 0.24 mmol) and t-butyl exphos (105 mg, 0.24 mmol) were added to the mixture, and the mixture was stirred at 95°C for 63 hours with the lid closed. After the reaction was complete, the mixture was cooled to room temperature, water was poured in, and it was extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate and concentrated by vacuum filtration. The title compound (343 mg, 40.5%) was obtained by purification using silica gel column chromatography.

[1171] Example 127: (S)-2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)thieno[3,2-d]pyrimidine-7-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1172]

[1173] In [Step 2] of <Synthetic Example 8>, t-butyl 4-(2-chlorothieno[3,2-d]pyrimidine-4-yl)-3,6-dihydropyridine-1(2H)-carboxylate was used instead of t-butyl 4-(2-chlorothieno[3,2-d]pyrimidine-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate, and the same reaction up to [Step 6] was carried out excluding the reaction in [Step 3] to obtain the title compound (19.5 mg, 53.9%).

[1174] Example 128: (S)-2-((4-(2-(4-cyano-2-fluorophenoxy)thieno[3,2-d]pyrimidine-7-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1175]

[1176] In [Step 3] of <Synthetic Example 1>, t-butyl 4-((2-(chloromethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidin-1-carboxylate was used instead of t-butyl 4-(2-chlorothieno[3,2-d]pyrimidine-7-yl)-3,6-dihydropyridine-1(2H)-carboxylate and reacted at 80°C, and the same reaction up to [Step 6] was carried out excluding the reaction in [Step 3] to obtain the title compound (2.9 mg, 19.8%).

[1177] [Table 2]

[1178]

[1179]

[1180]

[1181]

[1182]

[1183]

[1184]

[1185]

[1186]

[1187]

[1188]

[1189]

[1190]

[1191]

[1192] <Intermediate Synthesis Example 12>

[1193]

[1194] Step 1. Preparation of 2-(chloromethyl)-7-methylthieno[3,2-d]pyrimidine-4-ol

[1195]

[1196] Methyl 3-amino-4-methyl-thiophene-2-carboxylate (5.0 g, 28.6 mmol) was dissolved in a 4N hydrochloric acid 1,4-dioxane solution, and 2-chloroacetonitrile (2.4 mL, 37.2 mmol) was added, followed by stirring at room temperature (25℃) for 18 hours. The solvent of the reaction mixture was concentrated, and after adding water, the mixture was alkalized to a pH of approximately 8 using a sodium bicarbonate solution. The resulting solid was collected by filtration, washed with water, and dried to obtain the title compound (5.97 g, 97.2%).

[1197] Step 2. Preparation of 4-chloro-2-(chloromethyl)-7-methylthieno[3,2-d]pyrimidine

[1198]

[1199] 2-(chloromethyl)-7-methylthieno[3,2-d]pyrimidin-4-ol (500 mg, 2.33 mmol) synthesized in Step 1 above was dissolved in phosphoryl chloride (5 mL) and stirred at 90°C for 16 hours. The reaction mixture was slowly poured into ice water and stirred for 1 hour, after which the resulting solid was filtered and collected, washed with water, and dried to obtain the title compound (502 mg, 92.5%).

[1200] Example 129: 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)-7-methylthieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1201]

[1202] In [Step 1] of <Synthesizing Example 1>, 2-(chloromethyl)-7-methylthieno[3,2-d]pyrimidin-4-ol synthesized in <Intermediate Synthesis Example 12> was used instead of 2-(chloromethyl)-3H-thieno[3,2-d]pyrimidin-4-one, and in [Step 2], t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate was used instead of t-butyl 4-hydroxypiperidin-1-carboxylate, and the same reaction was performed up to [Step 4] of <Synthesizing Example 1> using 4-chloro-2-fluoro-phenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3].

[1203] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out at 50°C using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and methanol, and in [Step 6], the same reaction was carried out using lithium hydroxide, tetrahydrofuran, methanol, and water instead of sodium hydroxide and 1,4-dioxane to obtain the title compound (232 mg, 60.7%).

[1204] Example 130: 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)-6-methylthieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1205]

[1206] In [Step 1] of <Synthetic Example 1>, 2-(chloromethyl)-6-methyl-thieno[3,2-d]pyrimidin-4-ol synthesized using methyl 3-amino-5-methyl-thiophene-2-carboxylate instead of 2-(chloromethyl)-3H-thieno[3,2-d]pyrimidin-4-one was used, and in [Step 2], t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate was used instead of t-butyl 4-hydroxypiperidin-1-carboxylate, and in [Step 3], 4-chloro-2-fluorophenol was used instead of 3-fluoro-4-hydroxy-benzonitrile, and <Synthetic Example 1> The same reaction was executed up to [Step 4].

[1207] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out at 50°C using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and methanol, and in [Step 6], the same reaction was carried out using lithium hydroxide, tetrahydrofuran, methanol, and water instead of sodium hydroxide and 1,4-dioxane to obtain the title compound (57.7 mg, 52.8%).

[1208] Example 131: 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)-6-methylthieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1209]

[1210] In [Step 1] of <Synthetic Example 1>, use 2-(chloromethyl)-6-methyl-thieno[3,2-d]pyrimidin-4-ol synthesized using methyl 3-amino-5-methyl-thiophene-2-carboxylate instead of 2-(chloromethyl)-3H-thieno[3,2-d]pyrimidin-4-one, in [Step 1] of <Synthetic Example 1>, perform the same reaction using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate, and in [Step 3], use 4-chloro-2-fluoro-phenol instead of 3-fluoro-4-hydroxy-benzonitrile, in <Synthetic Example 1> [Step The same reaction was performed up to 4.

[1211] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out at 50°C using methyl (S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 5> above, instead of methyl (S)-2-(chloromethyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and methanol, and in [Step 6], the same reaction was carried out using lithium hydroxide, tetrahydrofuran, methanol, and water instead of sodium hydroxide and 1,4-dioxane to obtain the title compound (73.6 mg, 45.1%).

[1212] Example 132: 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)-6-methylthieno[2,3-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1213]

[1214] In [Step 1] of <Synthetic Example 1>, 2-(chloromethyl)-6-methyl-thieno[2,3-d]pyrimidine-4-ol synthesized using methyl 2-amino-5-methyl-thiophene-3-carboxylate instead of methyl 3-amino-4-methyl-thiophene-2-carboxylate from <Intermediate Synthesis Example 12> was used instead of 2-(chloromethyl)-3H-thieno[3,2-d]pyrimidine-4-ol; in [Step 2], the same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate; and in [Step 3], 4-chloro-2-fluorophenol was used instead of 3-fluoro-4-hydroxy-benzonitrile from <Synthetic Example 1> The same reaction was executed up to [Step 4].

[1215] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out at 50°C using ethyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, and methanol, instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and methanol, and in [Step 6], the same reaction was carried out using lithium hydroxide, tetrahydrofuran, methanol, and water instead of sodium hydroxide and 1,4-dioxane, to obtain the title compound (10 mg, 49.5%).

[1216] Example 133: 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)-5-methylthieno[2,3-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1217]

[1218] In [Step 1] of <Synthetic Example 1>, use 2-(chloromethyl)-5-methyl-thieno[2,3-d]pyrimidin-4-ol synthesized using methyl 2-amino-4-methyl-thiophene-3-carboxylate instead of 2-(chloromethyl)-3H-thieno[3,2-d]pyrimidin-4-one, in [Step 1] of <Synthetic Example 1>, perform the same reaction using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate, and in [Step 3], use 4-chloro-2-fluoro-phenol instead of 3-fluoro-4-hydroxy-benzonitrile, in <Synthetic Example 1> [Step The same reaction was performed up to 4.

[1219] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out at 50°C using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and methanol, and in [Step 6], the same reaction was carried out using lithium hydroxide, tetrahydrofuran, methanol, and water instead of sodium hydroxide and 1,4-dioxane to obtain the title compound (106 mg, 68.9%).

[1220] Example 134: 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)-5,6-dimethylthieno[2,3-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1221]

[1222] In [Step 1] of <Synthesis Example 1>, 2-(chloromethyl)-5,6-dimethyl-thieno[2,3-d]pyrimidine-4-ol synthesized using ethyl 2-amino-4,5-dimethyl-thiophene-3-carboxylate instead of methyl 3-amino-4-methyl-thiophene-2-carboxylate in <Intermediate Synthesis Example 12> was used; the same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2], and using 4-chloro-2-fluorophenol instead of 3-fluoro-4-hydroxy-benzonitrile in [Step 3] <Synthesis Example 1> The same reaction was carried out up to [Step 4].

[1223] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out at 50°C using ethyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, and methanol, instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and methanol, and in [Step 6], the same reaction was carried out using lithium hydroxide, tetrahydrofuran, methanol, and water instead of sodium hydroxide and 1,4-dioxane, to obtain the title compound (100 mg, 68.8%).

[1224] Example 135: 2-(((2S,4S)-4-((2-((4-chloro-2-cyanofenoxy)methyl)-5,6-dimethylthieno[2,3-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1225]

[1226] In [Step 1] of <Synthesis Example 1>, 2-(chloromethyl)-5,6-dimethyl-thieno[2,3-d]pyrimidine-4-ol synthesized using ethyl 2-amino-4,5-dimethyl-thiophene-3-carboxylate instead of methyl 3-amino-4-methyl-thiophene-2-carboxylate in <Intermediate Synthesis Example 12> was used instead of 2-(chloromethyl)-5,6-dimethyl-thieno[2,3-d]pyrimidine-4-ol, and in [Step 2], the same reaction was carried out using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate, and in [Step 3], 3-fluoro-4-hydroxy-benzonitrile instead The same reaction was carried out up to <Synthetic Example 1> [Step 4] using 5-chloro-2-hydroxybenzonitrile.

[1227] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out at 70°C using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and acetonitrile, and in [Step 6], the same reaction was carried out using lithium hydroxide, tetrahydrofuran, methanol, and water instead of sodium hydroxide and 1,4-dioxane, to obtain the title compound (95.6 mg, 54.4%).

[1228] Example 136: 2-(((2S,4S)-4-((5-((4-cyano-2-fluorophenoxy)methyl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidine-7-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1229]

[1230] In [Step 1] of <Synthetic Example 1>, 7-chloro-5-(chloromethyl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidine was used instead of 2-(chloromethyl)-3H-thieno[3,2-d]pyrimidine-4-one, and in [Step 2], t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate was used instead of t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate, and the same reaction was carried out at 50°C, and the same reaction was carried out up to [Step 4] of <Synthetic Example 1>.

[1231] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out at 50°C using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, N,N-diisopropylamine, and methanol instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and methanol, and in [Step 6], the same reaction was carried out using triazabicyclodecene, acetonitrile, and water instead of sodium hydroxide and 1,4-dioxane to obtain the title compound (12 mg, 29.1%).

[1232]

[1233] <Intermediate Synthesis Example 13>

[1234]

[1235] Step 1. Preparation of t-butyl(2S,4S)-4-((2-(acetoxymethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-carboxylate

[1236]

[1237] t-butyl(2S,4S)-4-[2-(chloromethyl)thieno[3,2-d]pyrimidine-4-yl]oxy-2-methyl-piperidin-1-carboxylate (300 mg, 0.75 mmol), synthesized using t-butyl (2S,4S)-4-hydroxy-2-methylpiperidin-1-carboxylate instead of t-butyl 4-hydroxypiperidin-1-carboxylate in [Step 2] of <Synthesis Example 1>, was added to N,N-dimethylformamide (3 mL), sodium acetate (505 mg, 6.03 mmol) was added, and the mixture was stirred at 80°C for 3 hours. After the reaction was finished, the mixture was cooled to room temperature, water was poured in, and the mixture was extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate, filtered under reduced pressure, and concentrated for use without further purification.

[1238] Step 2. Preparation of t-butyl(2S,4S)-4-((2-(hydroxymethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-carboxylate

[1239]

[1240] The t-butyl(2S,4S)-4-((2-(acetoxymethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidin-1-carboxylate synthesized in [Step 1] of <Intermediate Synthesis Example 13> was dissolved in tetrahydrofuran (3 mL) and methanol (3 mL) and cooled to 0°C. 1.2 M aqueous sodium hydroxide solution (0.6 mL) was slowly added dropwise and stirred for 30 minutes. After the reaction was complete, water was poured in and extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate, filtered under reduced pressure, and concentrated to obtain the title compound (226 mg, 79.0%).

[1241] Example 137: 2-(((2S,4S)-4-((2-(((5-chloro-3-fluoropyridine-2-yl)oxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1242]

[1243] In [Step 3] of <Synthesizing Example 1>, t-butyl 4-((2-(chloromethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-carboxylate, 3-fluoro-4-hydroxy-benzonitrile, potassium carbonate, and acetnitrile were replaced with t-butyl(2S,4S)-4-((2-(hydroxymethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-carboxylate, 5-chloro-2,3-difluoropyridine, sodium hydride, and anhydrous tetrahydrofuran synthesized in <Intermediate Synthesizing Example 13>, and the reaction was carried out at 50°C, and the same reaction was performed up to [Step 4] of <Synthesizing Example 1>.

[1244] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out at 60°C using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and 1,4-dioxane, and the same reaction was carried out using lithium hydroxide, tetrahydrofuran, methanol, and water instead of sodium hydroxide and 1,4-dioxane in [Step 6] to obtain the title compound (21.9 mg, 45.3%).

[1245] Example 138: 2-(((2S,4S)-4-((2-(((5-cyanopyridine-2-yl)oxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1246]

[1247] In [Step 3] of <Synthesizing Example 1>, t-butyl 4-((2-(chloromethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidin-1-carboxylate, 3-fluoro-4-hydroxy-benzonitrile, potassium carbonate, and acetnitrile were replaced with t-butyl(2S,4S)-4-((2-(hydroxymethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidin-1-carboxylate, 6-fluoronicotinonitrile, sodium hydride, and anhydrous tetrahydrofuran synthesized in <Intermediate Synthesizing Example 13>, and the reaction was carried out at 50°C, and the same reaction was performed up to [Step 4] of <Synthesizing Example 1>.

[1248] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out at 50°C using ethyl(S)-2-(chloromethyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, N,N-diisopropylamine, and methanol instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and methanol, and in [Step 6], the same reaction was carried out using triazabicyclodecene, acetonitrile, and water instead of sodium hydroxide and 1,4-dioxane to obtain the title compound (102 mg, 51.8%).

[1249] Example 139: 2-(((2S,4S)-4-((2-(((5-chloropyridine-2-yl)oxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1250]

[1251] In [Step 3] of <Synthetic Example 1>, t-butyl 4-((2-(chloromethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-carboxylate, 3-fluoro-4-hydroxy-benzonitrile, potassium carbonate, and acetnitrile were replaced with t-butyl(2S,4S)-4-((2-(hydroxymethyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-carboxylate, 5-chloro-2-fluoropyridine, sodium hydride, and anhydrous tetrahydrofuran synthesized in <Intermediate Synthetic Example 13>, and the reaction was carried out at 50°C, and the same reaction was performed up to [Step 4] of <Synthetic Example 1>.

[1252] In [Step 5] of <Synthesizing Example 1>, the same reaction was carried out at 50°C using ethyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-dimethylformamide synthesized in <Intermediate Synthesis Example 6> above, and methanol, instead of methyl(S)-2-(chloromethyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate, N,N-diisopropylamine, and methanol, and in [Step 6], the same reaction was carried out using lithium hydroxide, tetrahydrofuran, methanol, and water instead of sodium hydroxide and 1,4-dioxane, to obtain the title compound (61.3 mg, 58.4%).

[1253]

[1254] <Synthesized Example 7>

[1255] Example 140: (S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)benzyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1256]

[1257] Step 1: Preparation of methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate

[1258]

[1259] Methyl 2-(4-bromophenyl)acetate (1 g, 4.28 mmol), potassium acetate (1.26 g, 12.84 mmol), and bis(pinacolato)diborone (1.19 g, 4.71 mmol) were added to 1,4-dioxane (10 mL), and after nitrogen gas evacuation for 10 minutes, a complex of 1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (174.7 mg, 0.21 mmol) was added, and the mixture was refluxed at 85°C for 16 hours. After cooling the reaction product to room temperature, water was added and extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate and concentrated by vacuum filtration. Purification by silica gel column chromatography yielded the title compound (696.2 mg, 58.9%).

[1260] Step 2: Preparation of methyl 2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)phenyl)acetate

[1261]

[1262] 2-chloro-4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine (200 mg, 0.61 mmol), synthesized by carrying out the same reaction at 0°C using (4-chloro-2-fluorophenyl)methanol instead of 3-fluoro-4-(hydroxymethyl)benzonitrile in [Step 1] of <Synthesis Example 5>, methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (201.3 mg, 0.73 mmol), synthesized in [Step 1] above, and potassium carbonate (168.8 mg, 1.22 mmol) were added to 1,4-dioxane (3 mL) and water (0.6 mL), and after nitrogen gas evacuation for 10 minutes, 1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (46.8 mg, 0.06 mmol) was added, and the mixture was refluxed at 100°C for 16 hours. After cooling the reaction product to room temperature, water was added and extracted with ethyl acetate. The separated organic layer was dried with anhydrous sodium sulfate and concentrated by vacuum filtration. Purification by silica gel column chromatography yielded the title compound (189 mg, 70.24%).

[1263] Step 3: Preparation of 2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)phenyl)acetic acid

[1264]

[1265] Methyl 2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)phenyl)acetate (100 mg, 0.226 mmol) synthesized in [Step 2] above was dissolved in ethanol (1 ml) and tetrahydrofuran (1 mL), and then sodium hydroxide (27.9 mg, 0.677 mmol) dissolved in water (0.5 mL) was added. The reaction mixture was stirred at 25°C for 1 hour. The reaction product was acidified by slowly adding 1N hydrochloric acid dropwise, and the resulting mixture was filtered to obtain the title compound (93.8 mg, 96.9%).

[1266] Step 4: Preparation of ethyl(S)-4-(2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)phenyl)acetamido)-3-ethoxy-5-((oxetane-2-ylmethyl)amino)benzoate

[1267]

[1268] 2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)phenyl)acetic acid (43 mg, 0.100 mmol) synthesized in [Step 3] above, ethyl(S)-4-amino-3-ethoxy-5-((oxetane-2-ylmethyl)amino)benzoate (32.5 mg, 0.110 mmol), N,N-diisopropylethylamine (39.3 mg, 0.301 mmol), and TBTU (39.4 mg, 0.120 mmol) synthesized in [Step 6] of <Intermediate Synthesis Example 6> were dissolved in N,N-dimethylformamide (1 mL) and stirred at 50°C for 19 hours. After cooling the reaction product to room temperature, water was added and the resulting solid was filtered. The title compound (21 mg, 29.7%) was obtained by purification using silica gel column chromatography.

[1269] Step 5: Preparation of ethyl(S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)benzyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylate

[1270]

[1271] Ethyl(S)-4-(2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)phenyl)acetamido)-3-ethoxy-5-((oxetane-2-ylmethyl)amino)benzoate (21 mg, 0.030 mmol) synthesized in [Step 4] above was added to acetic acid (0.2 mL) and stirred at 55°C for 13 hours. The reaction product was cooled to room temperature, concentrated, and purified by silica gel column chromatography to obtain the title compound (20 mg, 97.7%).

[1272] Step 6: Preparation of (S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)benzyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1273]

[1274] The compound (20 mg, 0.029 mmol) synthesized in [Step 5] above was dissolved in tetrahydrofuran (0.3 mL) and methanol (0.3 mL) and cooled to 0°C, after which lithium hydroxide (2.6 mg, 0.058 mmol) was dissolved in water (0.3 mL) and added. The temperature was gradually raised to 50°C and the reaction mixture was stirred for 3 hours. A 5% aqueous citric acid solution was slowly added dropwise to the reaction product, and the resulting solid was purified by silica gel column chromatography to obtain the title compound (4.4 mg, 21.2%).

[1275] Example 141: (S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)benzyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1276]

[1277] In [Step 4] of <Synthetic Example 7>, methyl(S)-4-amino-3-methoxy-5-((oxetane-2-ylmethyl)amino)benzoate was used instead of ethyl(S)-4-amino-3-ethoxy-5-((oxetane-2-ylmethyl)amino)benzoate, and the same reaction was carried out to obtain the title compound (6.1 mg, 17.9%).

[1278] Example 142: (S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-fluorobenzyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1279]

[1280] In [Step 2] of <Synthetic Example 7>, methyl 2-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate was used instead of methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate, and the same reaction was carried out to obtain the title compound (21 mg, 18.9%).

[1281] Example 143: (S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-3-fluorobenzyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1282]

[1283] In [Step 2] of <Synthetic Example 7>, methyl 2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate was used instead of methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate, and the same reaction was carried out to obtain the title compound (7.9 mg, 5.0%).

[1284] Example 144: (S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2,5-difluorobenzyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid

[1285]

[1286] In [Step 2] of <Synthetic Example 7>, ethyl 2-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate was used instead of methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate, and the same reaction was carried out to obtain the title compound (22 mg, 22.7%).

[1287] [Table 3]

[1288]

[1289]

[1290]

[1291]

[1292]

[1293]

[1294] Experimental Example 1: cAMP assay in GLP-1R / CHO cells

[1295] To evaluate GLP-1R activation by the compounds of the present disclosure, the increase in cAMP was measured and quantified in CHO cells stably expressing GLP-1R.

[1296] GLP-1R-expressing CHO cells were cultured in αMEM supplemented with 10% dialyzed FBS, 1 mg / mL G418, 10 nM MTX, and 1% penicillin-streptomycin. They were cultured in flat, clear-bottomed white plates (Corning 384-well) at a density of 2.0 x 10⁶ per well. 3Cells were inoculated at a certain density and cultured for 20 to 24 hours. For analysis, GLP-1 and each compound were diluted using stimulation buffer containing 0.5 mM IBMX, an additional PDE4 inhibitor. Serial dilutions were performed in 3-fold increments to generate 11 dosing points for each compound. The concentration ranges used are as follows:

[1297] GLP-1: 4000~0.07 nM

[1298] Compound A and Compound B: 10,000 ~ 1.69 pM

[1299] Examples Compounds 1–144: 10,000,000 ~ 169.35 nM (*variable)

[1300] Compounds A and B were included in the analysis to verify the stability of the operation.

[1301] After removing the medium, the diluted sample was treated for 15 minutes. Subsequently, a cAMP detection buffer containing the Eu-cAMP tracer and ULight-anti-cAMP was added, and the plate was incubated in the dark for 1 hour. Time-resolved fluorescence was measured at 620 / 665 nm using a microplate reader. The efficacy of the test compound for cAMP production was evaluated using the fluorescence intensity at 665 nm. Finally, EC was calculated using a GraphPad Prism V10 with a log (agent) versus response – variable slope (4 parameters) model. 50 The values ​​were analyzed.

[1302] The results of Experiment Example 1 are shown in [Table 4] below.

[1303] EC 50 The value was indicated as A if it was less than 100 nM, B if it was 100 nM or more and less than 500 nM, C if it was 500 nM or more and less than 1 μM, and D if it was 1 μM or more.

[1304] [Table 4]

[1305]

[1306]

[1307]

[1308]

[1309] The present invention has been described above with reference to specific embodiments. Those skilled in the art will understand that the present invention may be embodied in modified forms without departing from the essential characteristics of the invention. Therefore, the disclosed embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the invention is defined by the claims, not by the foregoing description, and all variations within the scope of the claims should be interpreted as being included in the invention.

[1310] A compound according to one aspect exhibits activity as a novel GLP-1 receptor agonist and can be used for the prevention or treatment of various related diseases, such as obesity, diabetes, or related metabolic diseases.

Claims

1. A compound selected from the compound of Formula 1 below, its optical isomers, diastereomers, solvates, hydrates, and pharmaceutically acceptable salts thereof: [Chemical Formula 1] In the above chemical formula 1, Rings A, B, and C are each independently C 3-12 Cycloalkyl, C 6-12 Aril, C 3-12 Heteroaryl and C 3-12 It is any one selected from heterocyclils, and The above C 3-12 Cycloalkyl, C 6-12 Aril, C 3-12 Heteroaryl or C 3-12 Each heterocyclic can be monocyclic, bicyclic, or polycyclic, and Here, C 3-12 Cycloalkyl, C 6-12 Aril, C 3-12 Heteroaryl or C 3-12 Heterocyclile is R 3 Substituted or unsubstituted with 1 to 5 substituents each independently selected from, and Here, C 3-12 Cycloalkyl or C 3-12 Heterocycliles are saturated or partially saturated; L 1 , L 2 , L 3 and L 4 does not exist or each independently C 1-3 Alkylene, -O-, -NH-, -N(C 1-3 Alkyl)-, -NH(C 1-3 Alkyl)-, -O(C 1-3 Alkyl)-, -S-, -SO-, -SO2-, -SO2NH-, -C(O)-, -C(H)=, -CF2-, -CHF-, C 2-4 Alkenylene, C 2-4 alkynylene, C 1-6 Aryllene, C 5-10 Heteroarylene, C 3-8 Cycloalkylene, C 3-8 Heterocycloalkylene, or direct bonding; X, Y, and Z are each independently N, CH, or CR 4 This or, X is CH, Y is S, and Z is a single bond; R 1 is -Y1-Y2, and Y1 is directly coupled, C 1-6 alkyl , C 1-6 Alkylene, C 2-6 Alkenylene, C 2-6 alkynylene, C 1-6 Aryllene, C 5-10 Heteroarylene, C 3-8 Cycloalkylene, or C 3-8 It is a heterocycloalkylene, and Y2 is C 1-6 Alkyl, C 1-6 Alkoxy , C 3-8 Cycloalkyl, C 6-10 Aril, C 1-6 Heteroalkyl, C 3-8 Heterocycloalkyl, or C 0-8 It is heteroaryl, and Here, each Y1 and Y2 is independently R 3 Substituted or unsubstituted with 1 to 5 substituents selected from; R 2 is hydrogen, -COOH, CN, or a carboxyl surrogate; R 3 and R 4 are independently hydrogen, deuterium, and C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, oxo(=O), thiol, C 1-6 Alkylthio, C 1-6 Alkylsulfonyl, Halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, Cyano, Amino, C 1-6 Alkylamino, C 1-6 haloalkylamino, di(C 1-3 Alkyl)amino, carbonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkoxycarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, di(C 1-6 Alkyl)aminocarbonyl, carboxyl, hydroxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Hydroxyalkylamino, (C 1-3 Alkoxy)C 1-3 Alkyl, (C 1-3 Alkoxy)C 1-3 Alkoxy, (C 1-3 Alkoxy)C 1-3 Alkylamino, C 1-6 Aminoalkyl, C 1-6 Aminoalkoxy, C 1-6 Aminoalkylamino, C 6-10 Aril, C 1-8 Heteroaryl, C 1-8 Heteroaryloxy, C 1-8 Heteroarylamino, C 3-8 Heterocyclil, C 3-8 Heterocyclyloxy, C 3-8 Heterocyclylamino, C 3-10 Heterocyclyloxyalkoxy or C 3-10 It is a heterocyclyloxyalkylamino, and Here, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, C 6-10 Aril, C 1-8 Heteroaryl or C 3-8 Heterocycliles, each independently C 1-3 Alkyl, C 3-6 Cycloalkyl, C 1-3 Haloalkyl, C 1-3 Haloalkoxy, C 1-3 Alkoxy, hydroxy, halogen, cyano, C 1-3 Hydroxyalkyl, (C 1-3 Alkoxy)C 1-3 Alkyl and C 1-3 Substituted or unsubstituted with 1 to 3 substituents selected from aminoalkyl; It represents a single bond or a double bond.

2. In Claim 1, -L 1 -L 2 - is any one selected from the group consisting of -CH2-, -O-, -S-, -CH2O-, -OCH2-, -CH2S-, -SCH2-, -OC(H,Me)-, -NH-, -N(Me)-, -N(Et)-, -NHCH2-, -N(Me)CH2-, and -SO2NH-; L 3 -O-, NH-, -C(O)-, -CH2-, -C(H)=, -CF2-, -SO2-, -N(Me)-, direct bonding, and It is any one selected from the group consisting of; L 4 is a compound selected from the group consisting of -CH2-, -C(O)-, -CH2O-, and -OCH2-.

3. In Claim 1, R 1 is -Y1-Y2, and Y1 is directly connected or C 1-6 It is an alkylene, and Y2 is C 1-6 Alkyl, C 1-6 Alkoxy , C 3-8 Cycloalkyl, C 6-10 Aril, C 1-6 Heteroalkyl, C 3-8 Heterocycloalkyl, or C 0-8 It is heteroaryl, and Here, each Y1 and Y2 is independently R 3 A compound that is substituted or unsubstituted with 1 to 5 substituents selected from.

4. In Claim 1, R 1 is -Y1-Y2, and Y1 is C 1-3 It is an alkylene or a direct bond, Y2 is C 1-6 Alkyl, C 1-6 Alkoxy, , , , , , , , , , , , , , , , , , , , , , , , , , , and It is one of the selected from among, and Here, each Y1 and Y2 is independently C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, oxo(=O), thiol, C 1-6 Alkylthio, C 1-6 Alkylsulfonyl, Halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, cyano, amino, C 1-6 Alkylamino, C 1-6 haloalkylamino, di(C 1-3 Alkyl)amino, carbonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkoxycarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, di(C 1-3 Alkyl)aminocarbonyl, hydroxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Hydroxyalkylamino, (C 1-3 Alkoxy)C 1-3 Alkyl, (C 1-3 Alkoxy)C 1-3 Alkoxy, (C 1-3 Alkoxy)C 1-3 Alkylamino, C 1-6 Aminoalkyl, C 1-6 Aminoalkoxy, C 1-6 Aminoalkylamino, C 6-8 Aryl, and C 3-8 A compound that is substituted or unsubstituted with 1 to 3 substituents selected from heteroaryls.

5. In Claim 1, The above carboxyl group substitutes are -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -PO3H2, -PO(Me)(OH), -SO3H, -SO2NH2, -SO2NHMe, -B(OH)2, , , , , , , tetrazolyl, and -COO-R a It is one of the selected from among, and Here -COO-R a is (isobutyryloxy)methyl ester, (pivaloyloxy)methyl ester, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, or other biodegradable ester groups; R 5 is hydrogen or C 1-6 Alkyl compound.

6. In Claim 1, Ring A is or And, T 1 , T 2 , T 3 , T 4 , and T 5 Each is independently selected from N, NH, CH, and CH2; T 1 , T 2 , T 3 , T 4 , and T 5 Among them, those that are N or NH are 3 or fewer, and S 1 and S 2 Each is independently selected from O, S, N, NH, CH, and CH2, and n is a compound in which n is an integer from 0 to 5.

7. Ring B is And, Q 1 , Q 2 , Q 3 , and Q 4 Wow, U 1 , U 2 , U 3 , and U 4 -C(H)=, -O-, -S-, -S(O)2-, -C(O)-, -N-, -N=, -N(R 7 )-, -C-, -C(R 7 )=, or -C(R 7 )(R 8 )- and; R 7 and R 8 Each independently hydrogen, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, oxo(=O), thiol, C 1-6 Alkylthio, C 1-6 Alkylsulfonyl, Halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, cyano, amino, C 1-6 Alkylamino, C 1-6 haloalkylamino, di(C 1-3 Alkyl)amino, carbonyl, C 1-6 Alkyl carbonyl, C 1-6 Alkoxycarbonyl, aminocarbonyl, C 1-6 Alkylaminocarbonyl, di(C 1-3 Alkyl)aminocarbonyl, hydroxy, C 1-6 Hydroxyalkyl, C 1-6 Hydroxyalkoxy, C 1-6 Hydroxyalkylamino, (C 1-3 Alkoxy)C 1-3 Alkyl, (C 1-3 Alkoxy)C 1-3 Alkoxy, (C 1-3 Alkoxy)C 1-3 Alkylamino, C 1-6 Aminoalkyl, C 1-6 Aminoalkoxy, C 1-6 Aminoalkylamino, C 6-8 Aril, C 3-8 Heteroaryl, C 3-8 Heteroaryloxy, C 3-8 Heteroarylamino, C 3-8 Heterocyclil, C 3-8 Heterocyclyloxy, C 3-8 Heterocyclylamino, C 3-8 Heterocyclyloxyalkoxy or C 3-8 A heterocyclyloxyalkylamino compound.

8. In Claim 7, Ring B is , , , , , , , , , , , , , , , , , , , , , , , , , , , , and It is one of the selected ones, and represents a single bond or a double bond, R 9 is hydrogen or C 1-3 It is alkyl, and The above ring B is R 3 A compound that is substituted or unsubstituted with at least one substituent independently selected from each of the following.

9. In Claim 1, Ring C is And, Here, W or Q is N, CH, or C; When W or Q is N, adjacent represents a single bond; When W or Q is CH, adjacent represents a single bond; When W or Q is C, adjacent represents a double bond; or When W or Q is C, adjacent represents a single bond, where either L3 or L4 connected to W or Q is -C(H)=; n is a compound in which n is an integer from 0 to 5.

10. In Claim 1, the substituted Y1 or substituted Y2 is the following R 6 It is substituted or unsubstituted with 1 to 3 substituents independently selected from each, and R 6 C 1-6 Alkyl, C 3-8 Cycloalkyl, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 1-6 Alkoxy, hydroxy, halogen, amino, C 1-6 Alkylamino, C 1-6 haloalkylamino, di(C 1-3 Alkyl)amino, cyano, C 1-6 Hydroxyalkyl, (C 1-3 Alkoxy)C 1-3 Alkyl, C 1-6 Aminoalkyl, C 3-8 Heterocyclil, C 6-10 Aryl, and C 1-8 A compound selected from heteroaryls.

11. In Claim 1, Rings A, B, and C are each independently C 6-12 Aryl, Monocyclic C 3-12 Heteroaryl, bicyclic C 3-12 Heteroaryl, and saturated or partially saturated C 3-12 It is any one selected from heterocyclils, and At this time, rings A, B, and C are C 1-3 Alkyl, halogen, and C 1-3 Substituted or unsubstituted with 1 to 3 substituents selected from haloalkyls; L 1 is C 1-3 Alkylene, -O-, or -S- and; L 2 is C 1-3 It is an alkylene, -O-, or direct bond; L 3 is -O- or direct bonding; L 4 is C 1-3 It is an alkylene; X, Y, and Z are each independently N, CH, or CR 10 This or, X is CH, Y is S, and Z is a single bond, or X and Z are CH, and Y is CR 15 And; R 1 is -Y1-Y2, and Y1 is directly connected or C 1-6 It is an alkylene, and Y2 is C 1-6 Alkyl, C 1-6 Alkoxy , C 3-8 Cycloalkyl, C 3-8 Heterocycloalkyl, or C 0-8 It is heteroaryl, and Here, each Y1 and Y2 is independently C 1-3 Alkyl, halogen, and C 1-3 Substituted or unsubstituted with 1 to 3 substituents selected from haloalkyls; R 2 is hydrogen, -COOH, CN, or a carboxyl surrogate; R 10 C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkinyl, C 1-6 Alkoxy, Halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-8 Cycloalkyl, C 3-8 Cycloalkoxy, Cyano, Amino, C 1-6 Alkyl carbonyl, carboxyl, (C 1-3 Alkoxy)C 1-3 Alkoxy, (C 3-6 cycloalkyl)C 1-3 Alkyl, (C 3-6 cycloalkyl)C 1-3 Alkoxy, or C 3-8 It is a heterocyclil; R 15 is a carboxyl group; A compound that exhibits a single or double bond.

12. In Claim 1, Ring A is or And, T 10 , T 20 , T 30 , T 40 , and T 50 are all CH or, T 10 , T 20 , T 30 , T 40 , and T 50 One of them is N, and the rest are CH, S 10 and S 20 One of them is O, S, or N, and the rest are CH; Ring B is And, Q 10 , Q 20 , Q 30 , and Q 40 Wow, U 10 , U 20 , U 30 , and U 40 -C(H)=, -O-, -S-, -N-, -N=, -N(R 12 )-, -C-, -C(R 12 )=, or -C(R 12 )(R 13 )- and; Ring C is And, Here, W is N, CH, or C, and Q is N or, W and Q are both C; R 11 C each independently 1-3 Alkyl, halogen, and C 1-3 Selected from haloalkyls; R 12 and R 13 Each independently consists of hydrogen or C 1-3 It is alkyl; m is a compound that is an integer from 0 to 3.

13. In Claim 1, L 1 is methylene, -O-, or -S-; L 2 is methylene, -O-, or a direct bond; L 3 is -O- or direct bonding; L 4 is methylene; X is N or CH, Y is CH, and Z is CH or CR 14 This or, X is CH, Y is S, and Z is a single bond, or X and Z are CH, and Y is CR 16 And; R 1 is -Y1-Y2, and Y1 is methylene, ethylene, or directly bonded, and Y2 is C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 It is a cycloalkyl, oxetane, tetrahydrofuran, thiazole, or imidazole, and Each Y2 is C 1-3 Alkyl, halogen, and C 1-3 Substituted or unsubstituted with 1 to 3 substituents independently selected from haloalkyls; R 2 is hydrogen, -COOH, CN, -COCF3, -C(OH)CF3, -CONHCN, -CONHOH, CONHOMe, -CONHSO2N(Me)2, -CONHSO2H, CONHSO2(C 1-3 alkyl), , tetrazolyl, and -COO-R a It is one of the selected from among, and Here -COO-R a is (isobutyryloxy)methyl ester, (pivaloyloxy)methyl ester, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester, or other biodegradable ester groups; R 14 is hydrogen, C 1-6 Alkyl, C 1-6 Alkoxy, Halogen, C 1-6 Haloalkyl, C 1-6 Haloalkoxy, C 3-6 Cycloalkyl, -OC 3-6 Cycloalkyl, carboxyl, (C 1-3 Alkoxy)C 1-3 Alkoxy, or -OC 1-3 Alkyl-C 3-6 It is cycloalkyl; R 16 is a carboxyl compound.

14. The compound of claim 1, wherein the compound is any one selected from the group consisting of the following compounds, their optical isomers, diastereomers, solvates, hydrates, and pharmaceutically acceptable salts thereof: 1) (S)-2-((4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 2) (S)-2-((4-((2-((4-cyano-2-fluorobenzyl)oxy)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 3) (S)-2-((4-((2-((4-ethinyl-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 4) (S)-2-((4-((2-((4-cyclopropyl-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 5) 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 6) 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 7) 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-3-(((S)-oxetane-2-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid; 8) (S)-2-((4-((2-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 9) 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[2,3-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 10) 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-((S)-4,4-dimethyltetrahydrofuran-3-yl)-4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 11) 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-fluoro-1-((1-(fluoromethyl)cyclopropyl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 12) 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 13) 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-fluoro-1-(2-methoxyethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 14) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 15) 2-(((2S,4S)-4-((2-((4-chloro-2-cyanofenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 16) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 17) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-fluoro-1-(thiazole-5-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 18) 2-(((2S,4S)-4-((2-(((4-chlorobenzofuran-7-yl)oxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 19) 2-(((2S,4S)-4-((2-(((4-chlorobenzofuran-7-yl)oxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 20) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-(2-methoxyethoxy)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 21) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-thieno[2,3-d]imidazole-5-carboxylic acid; 22) 2-(((2S,4S)-4-((2-((4-chloro-2-methoxyphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 23) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-isopropoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 24) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-5-carboxylic acid; 25) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-methyl-1H-benzo[d]imidazole-6-carboxylic acid; 26) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-cyclopropoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 27) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-(cyclopropylmethoxy)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 28) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[2,3-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 29) 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 30) 2-(((2S,4S)-4-((2-((2-chloro-4-methylphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 31) 2-(((2S,4S)-4-((2-((4-chloro-2-cyanofenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-(difluoromethoxy)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 32) 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-(difluoromethoxy)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 33) 2-(((2S,4S)-4-((2-((2-cyano-4-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 34) 2-(((2S,4S)-4-((2-((4-bromo-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 35) 4-ethoxy-2-(((2S,4S)-2-methyl-4-((2-((perfluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 36) 2-(((2S,4S)-4-((2-((2,4-difluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 37) 4-ethoxy-2-(((2S,4S)-4-((2-((4-ethinyl-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 38) 2-(((2S,4S)-4-((2-((2,4-dimethylphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 39) 4-ethoxy-2-(((2S,4S)-4-((2-((4-fluoro-2-methoxyphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 40) 4-ethoxy-2-(((2S,4S)-4-((2-((2-fluoro-4-(trifluoromethyl)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 41) 4-ethoxy-2-(((2S,4S)-2-methyl-4-((2-((4-(trifluoromethyl)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 42) 4-ethoxy-2-(((2S,4S)-4-((2-((2-fluoro-4-methylphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 43) 4-ethoxy-2-(((2S,4S)-2-methyl-4-((2-((4-(trifluoromethoxy)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 44) 2-(((2S,4S)-4-((2-((4-chlorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 45) 2-(((2S,4S)-4-((2-((4-(1H-1,2,4-triazole-1-yl)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 46) 2-(((2S,4S)-4-((2-((2,5-difluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 47) 2-(((2S,4S)-4-((2-((4-cyano-2-(trifluoromethyl)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 48) 2-(((2S,4S)-4-((2-((4-(1H-imidazole-1-yl)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 49) 4-ethoxy-2-(((2S,4S)-4-((2-((2-methoxy-4-(trifluoromethyl)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 50) 2-(((2S,4S)-4-((2-((4-bromo-3-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 51) 4-ethoxy-2-(((2S,4S)-4-((2-((4-fluoro-2-methylphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 52) 2-(((2S,4S)-4-((2-((4-bromo-2,6-difluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 53) 2-(((2S,4S)-4-((2-((2-cyano-4-methylphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 54) 2-(((2S,4S)-4-((2-((4-chloro-2-(trifluoromethyl)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 55) 2-(((2S,4S)-4-((2-((4-chloro-3,5-difluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 56) 2-(((2S,4S)-4-((2-((4-cyanofenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 57) (S)-2-((4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 58) 2-(((2S,4S)-4-((2-((3,5-dimethylphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 59) 4-ethoxy-2-(((2S,4S)-2-methyl-4-((2-((2,4,6-trichlorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 60) 2-(((2S,4S)-4-((2-((3,4-dichlorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 61) 2-(((2S,4S)-4-((2-((4-chloro-3,5-dimethylphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 62) 2-(((2S,4S)-4-((2-((4-chloro-2,6-difluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 63) 4-ethoxy-2-(((2S,4S)-2-methyl-4-((2-((3,4,5-trifluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 64) 2-(((2S,4S)-4-((2-((4-chloro-3-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 65) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 66) 5-chloro-2-((4-(((2S,4S)-1-((4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-6-(1H-tetrazole-5-yl)-1H-benzo[d]imidazole-2-yl)methyl)-2-methylpiperidine-4-yl)oxy)thieno[3,2-d]pyrimidine-2-yl)methoxy)benzonitrile; 67) (isobutyryloxy)methyl 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate; 68) (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate; 69) (pivaloyloxy)methyl 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate; 70) (isobutyryloxy)methyl 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate; 71) (pivaloyloxy)methyl 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate; 72) (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylate; 73) (S)-2-((4-((2-((4-chlorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 74) (S)-2-((4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 75) (S)-2-((4-((2-((2-methoxy-4-(trifluoromethyl)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 76) (S)-2-((4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[2,3-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 77) 4-fluoro-2-(((2S,4S)-4-((2-(((4-fluorobenzofuran-7-yl)oxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 78) 2-(((2S,4S)-4-((2-(((4-cyanobenzofuran-7-yl)oxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 79) 2-(((2S,4S)-4-((2-(((4-cyano-2-fluorobenzofuran-7-yl)oxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 80) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 81) 2-(((2S,4S)-4-((2-((4-acetyl-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 82) 2-(((2S,4S)-4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[2,3-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 83) 2-(((2S,4S)-4-((2-((4-chloro-2-cyanofenoxy)methyl)thieno[2,3-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 84) 2-(((2S,4S)-4-((2-((4-cyano-2-methoxyphenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 85) 2-(((2S,4S)-4-((2-((4-chloro-2-cyanofenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 86) (S)-2-((4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 87) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile; 88) (S)-2-((4-((2-(((4-cyano-2-fluorophenyl)thio)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 89) 2-(((2S,4S)-4-((2-((2-fluoro-4-(oxetane-3-yl)phenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 90) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-1-((1-ethyl-1H-imidazole-5-yl)methyl)-4-methoxy-1H-benzo[d]imidazole-6-carboxylic acid; 91) (S)-2-(4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-fluorobenzyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 92) (S)-2-(4-((2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2,5-difluorobenzyl)-4-fluoro-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 93) (S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 94) 2-(((S)-4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 95) 2-(((S)-4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-6-methyl-3,6-dihydropyridine-1(2H)-yl)methyl)-4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 96) 2-(((S)-4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methyl-3,6-dihydropyridine-1(2H)-yl)methyl)-4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 97) 2-(((2S)-4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperidine-1-yl)methyl)-4-fluoro-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 98) (S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[3,2-d]pyrimidine-2-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 99) (S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[3,2-d]pyrimidine-2-yl)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 100) 2-(((S)-4-(4-((4-chlorobenzofuran-7-yl)methoxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 101) 2-(((S)-4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 102) 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 103) 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 104) 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-N-(3-methyl-1H-indazole-5-yl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxamide; 105) 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-5-carboxylic acid; 106) (S)-2-((4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-methyl-1H-benzo[d]imidazole-6-carboxylic acid; 107) 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-(cyclopropylmethoxy)-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 108) 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-cyclopropoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 109) 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[3,2-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 110) 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)-7-methylthieno[3,2-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 111) 2-(((S)-4-(4-((2-fluoro-4-(oxetane-3-yl)benzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 112) (S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 113) (S)-2-((4-(4-((4-cyano-2-fluorobenzyl)oxy)-5,7-dihydrofuro[3,4-d]pyrimidine-2-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 114) 2-(((S)-4-(6-((4-chloro-2-fluorobenzyl)oxy)-9-methyl-9H-purine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 115) 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)furo[3,2-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 116) 2-(((S)-4-(7-((4-chloro-2-fluorobenzyl)oxy)thiazolo[5,4-d]pyrimidine-5-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 117) 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)-7-methyl-7H-pyrrolo[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 118) 2-(((S)-4-(4-((4-chloro-2-fluorobenzyl)oxy)-5-methyl-5H-pyrrolo[3,2-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 119) 2-(((S)-4-(4-((4-cyano-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 120) 2-(((S)-4-(4-((4-cyano-2-fluorobenzyl)oxy)-6-methylthieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 121) 2-(((S)-4-(4-((4-cyano-2-fluorobenzyl)oxy)-5,6-dimethylthieno[2,3-d]pyrimidine-2-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 122) (S)-2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)thieno[3,2-d]pyrimidine-4-yl)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 123) (S)-2-((4-(2-((4-cyano-2-fluorophenoxy)methyl)thieno[3,2-d]pyrimidine-4-yl)piperidine-1-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 124) 2-(((S)-4-(2-((4-chloro-2-fluorobenzyl)oxy)-7-methylthieno[3,2-d]pyrimidine-4-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 125) (S)-2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 126) 2-(((S)-4-(5-((4-chloro-2-fluorobenzyl)oxy)pyrazolo[1,5-a]pyrimidine-7-yl)-2-methylpiperazine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 127) (S)-2-((4-(2-((4-cyano-2-fluorobenzyl)oxy)thieno[3,2-d]pyrimidine-7-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 128) (S)-2-((4-(2-(4-cyano-2-fluorophenoxy)thieno[3,2-d]pyrimidine-7-yl)-3,6-dihydropyridine-1(2H)-yl)methyl)-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 129) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)-7-methylthieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 130) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)-6-methylthieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 131) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)-6-methylthieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-methoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 132) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)-6-methylthieno[2,3-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 133) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)-5-methylthieno[2,3-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 134) 2-(((2S,4S)-4-((2-((4-chloro-2-fluorophenoxy)methyl)-5,6-dimethylthieno[2,3-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 135) 2-(((2S,4S)-4-((2-((4-chloro-2-cyanofenoxy)methyl)-5,6-dimethylthieno[2,3-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 136) 2-(((2S,4S)-4-((5-((4-cyano-2-fluorophenoxy)methyl)-1-methyl-1H-pyrazolo[4,3-d]pyrimidine-7-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 137) 2-(((2S,4S)-4-((2-(((5-chloro-3-fluoropyridine-2-yl)oxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 138) 2-(((2S,4S)-4-((2-(((5-cyanopyridine-2-yl)oxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 139) 2-(((2S,4S)-4-((2-(((5-chloropyridine-2-yl)oxy)methyl)thieno[3,2-d]pyrimidine-4-yl)oxy)-2-methylpiperidine-1-yl)methyl)-4-ethoxy-1-(((S)-oxetane-2-yl)methyl)-1H-benzo[d]imidazole-6-carboxylic acid; 140) (S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)benzyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 141) (S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)benzyl)-4-methoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 142) (S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2-fluorobenzyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; 143) (S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-3-fluorobenzyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid; and 144) (S)-2-(4-(4-((4-chloro-2-fluorobenzyl)oxy)thieno[2,3-d]pyrimidine-2-yl)-2,5-difluorobenzyl)-4-ethoxy-1-(oxetane-2-ylmethyl)-1H-benzo[d]imidazole-6-carboxylic acid.

15. A pharmaceutical composition comprising a compound of any one of claims 1 to 14, an optical isomer, a diastereomer, a solvate, a hydrate, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

16. A compound of any one of claims 1 to 14 or a pharmaceutical composition of claim 15 for use in the treatment of metabolic diseases.

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