Pharmaceutical composition for treating cancer comprising novel compounds for inhibiting prostaglandin e2 receptor and anticancer drug

Abstract

The present invention provides a pharmaceutical composition for cancer treatment comprising a novel compound that inhibits the activity of the prostaglandin E2 receptor and an anticancer agent as active ingredients. The novel compound of the present invention inhibits the activity of the prostaglandin E2 receptor and suppressed tumor growth in colorectal and lung cancer tumor models. Furthermore, it was confirmed that a synergistic effect in anticancer activity occurs when administered in combination with other anticancer agents, such as chemotherapy agents and / or immune checkpoint inhibitors. Therefore, the pharmaceutical composition for cancer treatment comprising the novel compound and the anticancer agent as active ingredients can be usefully employed for the prevention and treatment of cancer.

Description

Technology Field

[0001] The present invention relates to a novel compound having inhibitory activity against prostaglandin E2 receptors. The invention relates to a pharmaceutical composition for treating cancer comprising an anticancer agent as an active ingredient. Background Technology

[0002] Prostaglandins (PGs) are physiologically active substances referred to as prostanoids, along with thromboxanes, and are lipids possessing a prostanate backbone. Prostanoids, such as prostaglandins, are biosynthesized from arachidonic acid released from membrane phospholipids by phospholipase A2. Prostaglandins are classified into groups A through J based on the differences in the oxygen atoms attached to their five-membered rings and the double bonds. Additionally, they are classified into groups 1 through 3 based on the number of double bonds in the prostanate backbone side chains. For example, prostaglandin E (PGE) exists in groups PGE1, PGE2, and PGE3, which differ in the number of double bonds present in the prostanate backbone side chains.

[0003] Prostaglandins are produced from PGG2, which is biosynthesized from arachidonic acid by cyclooxygenase I (COX-I) or cyclooxygenase II (COX-II), to form PGH2; subsequently, due to differences in the cleavage of bonds between oxygen atoms, PGD2, PGE2, and PGF 2αThese are produced. The production reaction of each prostaglandin involves the action of specific enzymes, and these enzymes are known to be tissue-specific. Meanwhile, among prostaglandins, PGE is believed to be responsible for various important biological activities; through its specific receptors, it is involved in vasodilation, hypotension, uterine contractions, as well as the regulation of the immune system. Like other PG receptors, the PGE2 receptor is a 7-times transmembrane G protein conjugated receptor, abbreviated as EP, and the existence of four subtypes (EP1, EP2, EP3, EP4) has been identified. In vivo, regarding each subtype, EP1 [involves] intracellular Ca 2＋ EP2 and EP4 are involved in the increase of cAMP, and EP3 is involved in the decrease of cAMP.

[0004] Meanwhile, cancer is one of the leading causes of death worldwide. Tumors consist not only of abnormally proliferating malignant cancer cells but also a functionally supporting microenvironment. This tumor microenvironment is composed of a complex array of cells, extracellular matrix components, and signaling molecules, established by altered communication between stromal cells and tumor cells. As tumors grow in size, they lead to the production of various factors that can aid tumor growth, such as angiogenic factors (promoting blood vessel growth), or help evade attacks by the host immune response. Under these microenvironments, PGE2 functions as one of these immuno-regulatory factors produced in tumors. PGE2's EP receptors, specifically EP2 and EP4, are abnormally overexpressed in several types of cancer, specifically gastrointestinal (GI) cancer and pancreatic cancer. Furthermore, the overexpression of PGE2 and / or EP2 and / or EP4 is closely correlated with cancers such as esophageal squamous cell carcinoma, lung squamous cell carcinoma, prostate cancer, and head and neck squamous cell carcinoma. In addition, kinetically, PGE2 signaling is known to be involved in communication between tumor cells and stromal cells, thereby creating a microenvironment favorable for tumor growth. Furthermore, tumor cells overexpressing EP2 and / or EP4 have been discovered, and it has been reported that PGE2 signaling can directly induce the proliferation of tumor cells.

[0005] In addition, PGE2 antagonists, such as EP2 and / or EP4 antagonists, have been reported to be effective in chronic inflammatory diseases and in neurodegenerative diseases such as epilepsy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and traumatic brain injury.

[0006] Against this technological backdrop, research on antagonists for prostaglandin E2 receptors that can be utilized in various clinical ways is underway (Korean Patent Publication No. 10-2013-0092579), but the current situation is still insufficient. Prior art literature

[0007] (Patent Document 1) KR 10-2013-0092579 A The problem to be solved

[0008] Accordingly, the inventors completed the present invention by confirming, through research to develop a safe and effective anticancer agent, that a novel compound having inhibitory activity against the prostaglandin E2 receptor exhibits an excellent anticancer effect when used in combination with a chemotherapy agent and / or an immune checkpoint inhibitor. means of solving the problem

[0009] To achieve the above objective, one aspect of the present invention provides a pharmaceutical composition and kit for treating cancer comprising a compound of Formula I, or a solvate, stereoisomer, or pharmaceutically acceptable salt thereof; and an anticancer agent as an active ingredient:

[0010] [Chemical Formula I]

[0011] . Effects of the invention

[0012] The novel compound of the present invention inhibited the activity of the prostaglandin E2 receptor and suppressed tumor growth in colorectal and lung cancer tumor models. Furthermore, it was confirmed that a synergistic effect in anticancer activity occurs when administered in combination with other anticancer agents, such as chemotherapy agents and / or immune checkpoint inhibitors. Therefore, a pharmaceutical composition for cancer treatment comprising the novel compound having inhibitory activity against the prostaglandin E2 receptor and an anticancer agent as active ingredients can be usefully employed for the prevention and treatment of cancer. Brief explanation of the drawing

[0013] Figure 1 is a graph showing the results of observing changes in mouse body weight following the administration of A01 (Example 34b), an anti-PD-1 antibody, or a combination of A01 and an anti-PD-1 antibody in a mouse-derived colorectal carcinoma CT26 animal model. Figure 2 is a graph showing the tumor size measured by administering A01, anti-PD-1 antibody, or a combination of A01 and anti-PD-1 antibody in a mouse-derived colorectal carcinoma CT26 animal model. Figure 3 is a graph showing the results of observing changes in mouse body weight following the administration of A02 (Example 1b), an anti-PD-1 antibody, or a combination of A02 and an anti-PD-1 antibody in a mouse-derived colorectal carcinoma MC38 animal model. Figure 4 is a graph showing the tumor size measured in a mouse-derived colorectal carcinoma MC38 animal model following the administration of A02, anti-PD-1 antibody, or a combination of A02 and anti-PD-1 antibody. Figure 5 is a graph showing the tumor size measured in a mouse-derived lung carcinoma TC1 animal model with the combined administration of Cisplatin, Pemetrexed, and anti-PD-1 antibody or Cisplatin, Pemetrexed, anti-PD-1 antibody, and A01. Specific details for implementing the invention

[0014] Pharmaceutical composition comprising a prostaglandin E2 receptor inhibitor compound and an anticancer agent

[0015] One aspect of the present invention provides a pharmaceutical composition for the prevention or treatment of cancer comprising a prostaglandin E2 receptor inhibitor compound, a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof; and an anticancer agent.

[0016] Prostaglandin E2 receptor inhibitory compounds

[0017] One aspect of the above-mentioned prostaglandin E2 receptor inhibitory compound may be a compound represented by the following chemical formula I, a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof:

[0018] [Chemical Formula I]

[0019]

[0020] In the above chemical formula I,

[0021] Either X or Y is S, and the other is CR 1 And, is a single bond or a double bond, wherein two of them are double bonds;

[0022] R 1 and R 2 is hydrogen, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C8 cycloalkyl and C6-C 10 Selected from the group consisting of aryls, wherein the C1-C6 alkyl and C1-C6 alkoxy groups may each independently be optionally substituted with one or more halogens, hydroxyl, cyano, or amino groups, and the C3-C8 cycloalkyl and C6-C 10 Each aryl can be independently optionally substituted with one or more halogens, hydroxy, cyano, amino, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;

[0023] R 3 silver or

[0024] R 1 It is hydrogen, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C8 cycloalkyl and C6-C 10 Selected from the group consisting of aryls, wherein the C1-C6 alkyl and C1-C6 alkoxy groups may each independently be optionally substituted with one or more halogens, hydroxyl, cyano, or amino groups, and the C3-C8 cycloalkyl and C6-C 10Each aryl can be independently optionally substituted with one or more halogens, hydroxy, cyano, amino, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;

[0025] R 2 and R 3 together with the carbon atoms to which they are bonded Form, to the nitrogen atom is combined, Any one or both of the carbon atoms of may be optionally substituted with a halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 haloalkoxy;

[0026] W is -(CH2) o -, -(CH2) o -C≡C-, -C(O)-, -O-, -S-, -NH- or -N(C1-C6alkyl)-, and the H of the CH2 may optionally be substituted with one or more halogens, hydroxy, cyano, C1-C6alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 haloalkoxy;

[0027] Cy is C6-C 14 Selected from the group consisting of aryl, quaternaryl to quaternaryl, quaternaryl to quaternaryl heterocycloalkyl, C3-C8 cycloalkyl, and C3-C8 cycloalkenyl, and may optionally be substituted with one or more R's;

[0028] R a is hydrogen, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl), -N(C1-C6 alkyl)2, oxo, or -V-Cy2, wherein the C1-C6 alkyl and C1-C6 alkoxy groups may be optionally substituted with one or more halogens, hydroxy, cyano, or amino groups.

[0029] Here, V is absent or -NH-, -NHCH2-, -NHCH3-, -CONH-, -NHCO-, -NHSO2-, -S-, -SO2-, -CH2-, -OCH2- or -O-, and

[0030] Cy2 is C6-C 14 Selected from the group consisting of aryl, quaternaryl to quaternaryl, quaternaryl to quaternaryl heterocycloalkyl, C3-C8 cycloalkyl, and C3-C8 cycloalkenyl, and may be optionally substituted with one or more R'';

[0031] R' is each independently selected from the group consisting of halogen, hydroxy, cyano, amino, oxo, C1-C6 alkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl), and -N(C1-C6 alkyl)2, wherein the C1-C6 alkyl and C1-C6 alkoxy may be optionally substituted with one or more halogens, hydroxy, cyano, or aminos;

[0032] R'' is a halogen, hydroxy, cyano, amino, oxo, C1-C6 alkyl, C1-C6 alkoxy, -S-(C1-C6 alkyl), -SO2-(C1-C6 alkyl), -CO-(C1-C6 alkyl), -C(O)H, -COO-(C1-C6 alkyl), -COOH, -CONH2, -CONH-(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -(CH2) p -NH2, -(CH2) p -NH-(C1-C6alkyl), -(CH2) p -N(C1-C6alkyl)2, -(CH2) p -NH-CO-(C1-C6alkyl), -(CH2) p -NH-COO-(C1-C6alkyl), -(CH2) p -OH, ternary to hyphal heterocycloalkyl, C3-C8 cycloalkyl and -(CH2) pSelected from the group consisting of -(C3-C8 cycloalkyl), wherein the C1-C6 alkyl and C1-C6 alkoxy may be optionally substituted with one or more halogens, hydroxy, cyano, or aminos, and the ternary to hepta heterocycloalkyl and C3-C8 cycloalkyl may be optionally substituted with one or more halogens, hydroxy, cyano, oxo, or aminos;

[0033] R 4 is hydrogen or C1-C6 alkyl;

[0034] R 5 , R 6 and R 7 Each has the following definition

[0035] (i) R 5 and R 6 is H and R 7 This is an absence, or

[0036] (ii) R 5 and R 6 Together -(CH2) q - indicates, R 7 This is an absence, or

[0037] (iii) R 5 is H, and R 6 and R 7 Together -(CH2) r - indicates;

[0038] P is absent or -CH2-, but R 7 If this is absent, then P is also absent;

[0039] R 8 silver and here, Z is -(CH2) s and R 8' is hydrogen, hydroxy, C1-C6 alkyl, or C1-C6 alkoxy;

[0040] l, m, and n are each independently integers from 0 to 2, wherein at least one of m and n is not 0, and P and R 7 In the case of this absence, l is 0 and;

[0041] o and p are each independently integers from 0 to 3;

[0042] q and r are each independently integers of 1 or 2;

[0043] s is an integer from 0 to 3.

[0045] In some embodiments, X is S and Y is CR 1 Or, X is CR 1 And Y is S. In one specific example, The bonds are single or double bonds, two of which are double bonds, so that a five-membered ring containing X and Y forms a thiophenyl ring.

[0046] In some embodiments, R 1 may be hydrogen, halogen, hydroxy, cyano, amino, C1-C3 alkyl, C1-C3 alkoxy, -NH-(C1-C3 alkyl) or -N(C1-C3 alkyl)2, and said C1-C3 alkyl and C1-C3 alkoxy may each be independently optionally substituted with one or more halogens, hydroxy, cyano, or aminos. In one embodiment, R 1 It may be hydrogen, halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or C1-C3 haloalkoxy. In one embodiment, R 1 It can be hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.

[0047] In some embodiments, R 2 may be hydrogen, halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C3-C6 cycloalkyl, or phenyl, and the C1-C3 alkyl and C1-C3 alkoxy may each be independently optionally substituted with one or more halogens, hydroxy, cyano, or aminos. In one embodiment, R 2 may be hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl, cyclobutyl, or phenyl. In one embodiment, R2 It may be hydrogen, fluoro, chloro, bromo, methyl, ethyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, or phenyl, etc.

[0048] In some embodiments, R 3 Is It could be.

[0049] In another embodiment, R 2 and R 3 together with the carbon atoms to which they are bonded It can form a 4H-thieno[3,2-b]pyrrole fusion ring by forming, and in this case to the nitrogen atom can be combined.

[0050] In one specific example, Any one or both of the carbon atoms may be optionally substituted with a halogen, a C1-C3 alkyl, or a C1-C3 haloalkyl. In one embodiment, Any one or both of the carbon atoms of may be optionally substituted with fluoro, chloro, bromo, methyl, ethyl, trifluoromethyl, difluoromethyl, etc. In one embodiment, The carbon atoms of can be arbitrarily substituted with C1-C3 alkyl groups.

[0051] In some embodiments, W is -(CH2) o -, -(CH2) o It may be -C≡C-, -C(O)-, -O-, -NH- or -N(C1-C3alkyl)-, and the H of the CH2 may optionally be substituted with one or more halogens, hydroxyl, C1-C3 alkoxy, or C1-C3 haloalkoxy.

[0052] In one specific example, W is -(CH2) o It may be -, -C(O)-, -O-, -NH-, or -N(C1-C6alkyl)-. In other embodiments, W is -(CH2) o - or -(CH2) o -C≡C- can be

[0053] In one embodiment, the H of CH2 may be optionally substituted with one or more halogens, hydroxyl groups, or C1-C3 alkoxy groups. In one embodiment, the H of CH2 may be optionally substituted with hydroxyl groups, methoxyl groups, ethoxyl groups, trifluoromethoxyl groups, difluoromethoxyl groups, etc. In one embodiment, o may be an integer of 0, 1, or 2. In one embodiment, o may be an integer of 0 or 1.

[0054] In some embodiments, Cy is C6-C 10 It may be a pentagonal to tenagonal heteroaryl comprising 1 to 3 heteroatoms selected from aryl, N, O, and S, or a tetraagonal to tenagonal heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, and S. In one embodiment, Cy is phenyl, naphthyl; a heteroaryl selected from pyrroleyl, furanyl, thiophenyl, pyrazolyl, imidazoleyl, oxazolyl, isoxazolyl, thiazolyl, isothiazoyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridineyl, pyrimidineyl, pyridazineyl, pyrazineyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazoyl, quinolineyl, and isoquinolineyl; Or it may be a heterocycloalkyl selected from azetidine-yl, oxetan-yl, pyrrolidine-yl, tetrahydrofuran-yl, pyrazolidin-yl, imidazolidin-yl, thiazolidin-yl, oxazolidin-yl, isoxazolidin-yl, piperidine-yl, piperazine-yl, and morpholine-yl.

[0055] In one embodiment, Cy may be phenyl, a 5- to 10-membered heteroaryl containing 1 or 2 nitrogen atoms, or a 4- to 7-membered heterocycloalkyl containing 1 or 2 nitrogen atoms. In one embodiment, Cy may be phenyl, pyrroleyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazineyl, pyrazineyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, pyrrolidinyl, piperidinyl, piperazineyl, or morpholine. In one embodiment, Cy may be phenyl, pyrazolyl, pyridinyl, pyrimidinyl, indolyl, or piperazineyl.

[0056] The above Cy may optionally be substituted with one or more R's. In one embodiment, R' may be a halogen, hydroxy, cyano, amino, oxo, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NH-(C1-C3 alkyl) or -N(C1-C3 alkyl)2. In one embodiment, R' may be a halogen, amino, C1-C3 alkyl, or C1-C3 haloalkyl. In one embodiment, R' may be one or more fluoro, chloro, bromo, amino, methylamino, dimethylamino, ethylamino, or diethylamino, etc.

[0057] In some embodiments, R a may be hydrogen, halogen, amino, C1-C3 alkyl, C1-C3 haloalkyl, -NH-(C1-C3 alkyl), or -N(C1-C3 alkyl)2, or -V-Cy2. In one embodiment, R a can be hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or -V-Cy2. In one embodiment, R a may be hydrogen, fluoro, chloro, bromo, methyl, ethyl, trifluoromethyl, difluoromethyl, or -V-Cy2. In one embodiment, R a It can be -V-Cy2.

[0058] In some embodiments, V may be absent or -NH-, -NHCH2-, -NHCH3-, -S-, -SO2-, -CH2-, -OCH2-, or -O-. In one embodiment, V may be absent or -CH2- or -O-. In one embodiment, V may be absent or -CH2-.

[0059] In some embodiments, Cy2 is C6-C 10 It may be selected from the group consisting of 5 to 10-membered heteroaryls comprising 1 to 3 heteroatoms selected from aryl, N, O, and S, 4 to 10-membered heterocycloalkyls comprising 1 to 3 heteroatoms selected from N, O, and S, C3-C8 cycloalkyls, and C3-C8 cycloalkenyls. In one embodiment, Cy2 is phenyl; heteroaryls selected from pyrroleyl, furanyl, thiophenyl, pyrazolyl, imidazoleyl, oxazolyl, isoxazolyl, thiazolyl, isothiazoyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazineyl, pyrazineyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazoyl, quinolineyl, and isoquinolineyl; It may be a heterocycloalkyl selected from azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazineyl, and morpholineyl; cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; or cyclobuteneyl, cyclopenteneyl, cyclohexeneyl, or cyclohepteneyl.

[0060] In one embodiment, Cy2 may be selected from the group consisting of 5 to 10 heteroaryls comprising 1 or 2 heteroatoms selected from phenyl, N or O, 4 or 7 heterocycloalkyls comprising 1 or 2 heteroatoms selected from N or O, C4-C7 cycloalkyls, and C4-C7 cycloalkenyls. In one embodiment, Cy2 may be phenyl, pyrroleyl, furanyl, pyrazolyl, imidazolyl, pyridineyl, pyrimidineyl, pyridazineyl, pyrazineyl, pyrrolidineyl, tetrahydrofuranyl, piperidineyl, piperazineyl, morpholine, cyclopentyl, cyclohexyl, cyclopenteneyl, or cyclohexeneyl. In one embodiment, Cy2 may be phenyl, furanyl, pyrazolyl, pyridinyl, pyrimidinyl, piperidinyl, morpholineyl, cyclohexyl, or cyclohexene.

[0061] The above Cy2 may be optionally substituted with R''. In some embodiments, R'' is a halogen, hydroxy, cyano, amino, oxo, C1-C6 alkyl, C1-C6 alkoxy, -S-(C1-C6 alkyl), -SO2-(C1-C6 alkyl), -COO-(C1-C6 alkyl), -COOH, -CONH2, -(CH2) p -NH2, -(CH2) p -NH-(C1-C6alkyl), -(CH2) p -N(C1-C6alkyl)2, -(CH2) p -NH-COO-(C1-C6alkyl), -(CH2) p ternary to pentary heterocycloalkyl, C3-C5 cycloalkyl, comprising one heteroatom selected from -OH, N, O, and S, and -(CH2) pSelected from the group consisting of -(C3-C5 cycloalkyl), said C1-C6 alkyl and C1-C6 alkoxy may be optionally substituted with one or more halogens, hydroxy, cyano, or aminos, and said ternary to pentary heterocycloalkyl and C3-C5 cycloalkyl may be optionally substituted with one or more halogens, hydroxy, cyano, oxo, or aminos. In one embodiment, said ternary to pentary heterocycloalkyl may be aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, and tetrahydrofuranyl or C3-C5 cycloalkyl. In one embodiment, p may be an integer of 0, 1, or 2. In one embodiment, p may be an integer of 0 or 1.

[0062] In one embodiment, R'' is a halogen, hydroxy, cyano, amino, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -S-(C1-C6 alkyl), -SO2-(C1-C6 alkyl), -COO-(C1-C6 alkyl), -COOH, -CONH2, -(CH2) p -NH2, -(CH2) p -NH-(C1-C6alkyl), -(CH2) p -N(C1-C6alkyl)2, -(CH2) p -NH-COO-(C1-C6alkyl), -(CH2) p -OH; azetidinyl or oxetanyl optionally substituted with a hydroxy or oxo; may be cyclopropyl or cyclopropylmethyl optionally substituted with a hydroxy or oxo.

[0063] In other embodiments, R'' is a halogen, hydroxy, cyano, amino, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -(CH2) p -NH2, -(CH2) p -NH-(C1-C6alkyl), -(CH2) p-N(C1-C6alkyl)2; azetidinyl or oxetaneyl optionally substituted with a hydroxy or oxo; cyclopropyl or cyclopropylmethyl optionally substituted with a hydroxy or oxo.

[0064] In one embodiment, R'' is a halogen, hydroxy, methyl, ethyl, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, trifluoromethyl, difluoromethyl, trifluoroethyl, difluoroethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, cyano, amino, oxo, -S-CH3, -S-CH2CH3, -SO2-CH3, -SO2-CH2CH3, -COOCH3, -COOCH2CH3, -COOCH2CH2CH3, -COOCH(CH3)2, -COOCH2CH(CH3)2, -COOC(CH3)4, -COOH, -CONH2, -CH2NH2, -CH2CH2NH2, -CH2NHCOOCH3, -CH2NHCOOCH2CH3, -CH2NHCOOCH2CH2CH3, It may be -CH2NHCOOCH(CH3)2, -CH2NHCOOCH2CH(CH3)2, -CH2NHCOOC(CH3)3, -CH2OH, -CH2CH2OH, azetidinyl, oxetanyl, cyclopropyl, or cyclobutylmethyl.

[0065] In one specific example, R a is -V-Cy2 and, has a structure selected from the following group, wherein Cy and Cy2 can be arbitrarily substituted with R' and R'', respectively:

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073] and .

[0074] In some embodiments, R4 may be hydrogen or C1-C3 alkyl.

[0075] In some embodiments, R 5 and R 6 is H and R 7 This may be a component, and the structure attached to the amide bond in Chemical Formula I may be the following structure:

[0076] (Here, n and m can be integers of 1 or 2, respectively.)

[0077] In another embodiment, R 5 and R 6 Together -(CH2) q - indicates, R 7 This may be an absence, in which case the structure attached to the amide bond in Formula I may be the following structure:

[0078] (Here, n, m, and q can each be integers of 1 or 2.)

[0079] In another embodiment, R 5 is H, and R 6 and R 7 Together -(CH2) r - can be represented, and in this case, the structure attached to the amide bond in Chemical Formula I may be the following structure:

[0080] (Here, n, m, r, and l can each be integers of 1 or 2.)

[0081] In one embodiment, the structure attached to the amide bond in Formula I comprises an isomer of the said structure, and may be, for example, but not limited to, the following structure:

[0082] or .

[0083] In some embodiments, R 8 silver and here Z is -(CH2) s and R 8' can be a hydroxyl or a C1-C6 alkoxy, and s can be an integer of 0 or 1. In one embodiment, s is 0, and R 8' It can be a hydroxyl group.

[0084] In the present invention, the above chemical formula I may be the following chemical formula IA-1 or IA-2:

[0085] [Chemical Formula IA-1]

[0086]

[0087] [Chemical Formula IA-2]

[0088]

[0089] In the above chemical formulas IA-1 and IA-2,

[0090] R 1 and R 2 is hydrogen, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C8 cycloalkyl and C6-C 10 Selected from the group consisting of aryls, wherein the C1-C6 alkyl and C1-C6 alkoxy groups may each independently be optionally substituted with one or more halogens, hydroxyl, cyano, or amino groups, and the C3-C8 cycloalkyl and C6-C 10 Each aryl can be independently optionally substituted with one or more halogens, hydroxy, cyano, amino, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;

[0091] R 3 silver And;

[0092] W, Cy, Ra, R 4 , R8 , n, m, r, and l are as defined in the above chemical formula I. In chemical formula I, R 1 , R 2 , W, Cy, R a , R 4 , R 8 The specific examples and embodiments described with respect to , n, m, r and l may be applied in the same way to formulas IA-1 and IA-2 as long as they are structurally permissible.

[0093] In some embodiments of chemical formulas IA-1 and IA-2, R 1 is hydrogen, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl) or -N(C1-C6 alkyl)2, and said C1-C6 alkyl and C1-C6 alkoxy may each be independently optionally substituted with one or more halogens, hydroxy, cyano, or aminos. In one embodiment, R 1 It may be hydrogen, halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or C1-C3 haloalkoxy. In one embodiment, R 1 It can be hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl.

[0094] In some embodiments, R 2 may be hydrogen, halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C3-C6 cycloalkyl, or phenyl, and the C1-C3 alkyl and C1-C3 alkoxy may each independently be optionally substituted with one or more halogens, hydroxy, cyano, or aminos. In one embodiment, the C3-C6 cycloalkyl and phenyl may be optionally substituted with one or more halogens, C1-C3 alkyl, or C1-C3 haloalkyl. In one embodiment, R 2 It can be hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl, cyclobutyl, or phenyl.

[0095] In some embodiments, W is -(CH2) o -, -(CH2) o It may be -C≡C-, -C(O)-, -O-, -NH-, or -N(C1-C3alkyl)-. In one embodiment, W is -(CH2) o It may be -, -C(O)-, -O-, -NH-, or -N(C1-C6 alkyl)-. In this case, the H of the CH2 of W may be optionally substituted with one or more halogens, hydroxyl, or C1-C6 alkoxy.

[0096] In some embodiments, Cy is C6-C 10 It may be a 5- to 10-membered heteroaryl comprising 1 to 3 heteroatoms selected from aryl, N, O, and S, or a 4- to 10-membered heterocycloalkyl comprising 1 to 3 heteroatoms selected from N, O, and S. In one embodiment, Cy may be a phenyl, a 5- to 10-membered heteroaryl comprising 1 or 2 nitrogen atoms, or a 4- to 7-membered heterocycloalkyl comprising 1 or 2 nitrogen atoms. For example, Cy may be phenyl, pyrroleyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazineyl, pyrazineyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, pyrrolidinyl, piperidinyl, piperazineyl, or morpholine. In one embodiment, Cy may be phenyl, pyrazolyl, pyridinyl, pyrimidinyl, indolyl, or piperazine. In one embodiment, Cy may be phenyl, pyrazolyl, or piperazine.

[0097] The above Cy may optionally be substituted with one or more R's. In some embodiments, R' may be a halogen, hydroxy, cyano, amino, oxo, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NH-(C1-C3 alkyl), or -N(C1-C3 alkyl)2. In one embodiment, R' may be a halogen, amino, C1-C3 alkyl, or C1-C3 haloalkyl.

[0098] In some embodiments, R a can be hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or -V-Cy2. In one embodiment, R a It can be -V-Cy2.

[0099] In some embodiments, V may be absent or -NH-, -NHCH2-, -NHCH3-, -S-, -SO2-, -CH2-, -OCH2-, or -O-. In one embodiment, V may be absent or -CH2-, or -O-.

[0100] In some embodiments, Cy2 is C6-C 10 It may be selected from the group consisting of 5 to 10 heteroaryls comprising 1 to 3 heteroatoms selected from aryl, N, O and S, 4 to 10 heterocycloalkyls comprising 1 to 3 heteroatoms selected from N, O and S, C3-C8 cycloalkyls and C3-C8 cycloalkenyls. In one embodiment, Cy2 may be selected from the group consisting of 5 to 10 heteroaryls comprising 1 or 2 heteroatoms selected from phenyl, N or O, 4 or 7 heterocycloalkyls comprising 1 or 2 heteroatoms selected from N or O, C4-C7 cycloalkyls and C4-C7 cycloalkenyls.

[0101] In one embodiment, Cy2 may be phenyl, furanyl, pyrazolyl, pyridinyl, pyrimidinyl, piperidinyl, morpholineyl, cyclohexyl, or cyclohexeneyl. In one embodiment, Cy2 may be phenyl, furanyl, pyrazolyl, pyridinyl, morpholineyl, piperidinyl, cyclohexyl, or cyclohexeneyl.

[0102] The above Cy2 may optionally be substituted with one or more R''. In some embodiments, R'' is a halogen, hydroxy, cyano, amino, oxo, C1-C6 alkyl, C1-C6 alkoxy, -S-(C1-C6 alkyl), -SO2-(C1-C6 alkyl), -COO-(C1-C6 alkyl), -COOH, -CONH2, -(CH2) p -NH2, -(CH2) p -NH-(C1-C6alkyl), -(CH2) p -N(C1-C6alkyl)2, -(CH2) p -NH-COO-(C1-C6alkyl), -(CH2) p ternary to pentary heterocycloalkyl, C3-C5 cycloalkyl, comprising one heteroatom selected from -OH, N, O, and S, and -(CH2) p It can be selected from the group consisting of -(C3-C5 cycloalkyl). In this case, the C1-C6 alkyl and C1-C6 alkoxy may be optionally substituted with one or more halogens, hydroxy, cyano, or aminos, and the ternary to pentary heterocycloalkyl and C3-C5 cycloalkyl may be optionally substituted with one or more halogens, hydroxy, cyano, oxo, or aminos.

[0103] In one embodiment, R'' is a halogen, hydroxy, cyano, amino, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -S-(C1-C6 alkyl), -SO2-(C1-C6 alkyl), -COO-(C1-C6 alkyl), -COOH, -CONH2, -(CH2) p -NH2, -(CH2) p -NH-(C1-C6alkyl), -(CH2) p -N(C1-C6alkyl)2, -(CH2) p -NH-COO-(C1-C6alkyl), -(CH2) p-OH; azetidinyl or oxetanyl optionally substituted with a hydroxy or oxo; and cyclopropyl or cyclopropylmethyl optionally substituted with a hydroxy or oxo may be selected from the group consisting of

[0104] In some embodiments, R 4 It can be hydrogen or C1-C3 alkyl.

[0105] In some embodiments, the compound having the formula IA-1 or IA-2 may be represented by the following formula IA-3 or IA-4:

[0106] [Chemical Formula IA-3]

[0107]

[0108] [Chemical Formula IA-4]

[0109]

[0110] In the above chemical formulas IA-3 and IA-4, R 1 , R 2 , R 3 , R 4 and R 8 It is as defined in the above chemical formulas IA-1 and IA-2.

[0112] In the present invention, the compound of formula I may be the following formula IB-1:

[0113] [Chemical Formula IB-1]

[0114]

[0115] In chemical formula IB-1,

[0116] R 1 It is hydrogen, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C8 cycloalkyl and C6-C 10Selected from the group consisting of aryls, wherein the C1-C6 alkyl and C1-C6 alkoxy groups may each independently be optionally substituted with one or more halogens, hydroxyl, cyano, or amino groups, and the C3-C8 cycloalkyl and C6-C 10 Each aryl can be independently optionally substituted with one or more halogens, hydroxy, cyano, amino, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;

[0117] Any one or both of the carbon atoms of may be optionally substituted with a halogen, hydroxy, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 haloalkoxy;

[0118] W, Cy, R a , R 4 , R 5 , R 6 , R 7 , R 8 , P, n, m and l are as defined in the above chemical formula I.

[0119] In chemical formula I, W, Cy, R a , R 4 , R 8 , R 6 , R 7 , R 8 The specific examples and embodiments described with respect to , P, n, m and l can be applied in the same way to the formula IB-1 as long as it is structurally permissible.

[0120] In some embodiments, a compound having the formula IB-1 may be represented by the following formulas IB-2, IB-3, or IB-4:

[0121] [Chemical Formula IB-2]

[0122]

[0123] [Chemical Formula IB-3]

[0124]

[0125] [Chemical Formula IB-4]

[0126]

[0127] In some embodiments of chemical formulas IB-2, IB-3 and IB-4, R 1 is hydrogen, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl) or -N(C1-C6 alkyl)2, and said C1-C6 alkyl and C1-C6 alkoxy may each be independently optionally substituted with one or more halogens, hydroxy, cyano, or aminos. In one embodiment, R 1 It can be hydrogen, halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or C1-C3 haloalkoxy.

[0128] In some embodiments, Any one or both of the carbon atoms may be optionally substituted with a halogen, a C1-C3 alkyl, or a C1-C3 haloalkyl. In one embodiment, Any one or both of the carbon atoms can be optionally substituted with C1-C3 alkyl groups.

[0129] In some embodiments, W is -(CH2) o -, -(CH2) o It may be -C≡C-, -C(O)-, -O-, -NH-, or -N(C1-C3alkyl)-. In one embodiment, W is -(CH2) o - or -(CH2) o -C≡C- may be possible. In this case, the H of the CH2 may be optionally substituted with one or more halogens, hydroxyl groups, or C1-C6 alkoxyl groups.

[0130] In some embodiments, Cy is C6-C 10It may be selected from the group consisting of 5 to 10 heteroaryls comprising 1 to 3 heteroatoms selected from aryl, N, O and S, and 4 to 10 heterocycloalkyls comprising 1 to 3 heteroatoms selected from N, O and S. In one embodiment, Cy may be phenyl, or a 5 to 10 heteroaryl comprising 1 or 2 nitrogen atoms. In one embodiment, Cy may be phenyl, pyrroleyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazineyl, pyrazineyl, indolyl, isoindolyl, benzimidazolyl, or indazolyl. In one embodiment, Cy may be phenyl, pyridinyl, pyrimidinyl, or indolyl.

[0131] The above Cy may optionally be substituted with one or more R's. In some embodiments, R' may be a halogen, hydroxy, cyano, amino, oxo, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NH-(C1-C3 alkyl) or -N(C1-C3 alkyl)2. In one embodiment, R' may be a halogen, amino, C1-C3 alkyl, or C1-C3 haloalkyl.

[0132] In some embodiments, R a may be hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or -V-Cy2. In this case, V may be absent or -NH-, -NHCH2-, -NHCH3-, -S-, -SO2-, -CH2-, -OCH2-, or -O-. In one embodiment, V may be absent or -CH2-, or -O-. In one embodiment, V may be absent or -CH2-.

[0133] In some embodiments, Cy2 is C6-C 10It may be selected from the group consisting of 5 to 10 heteroaryls comprising 1 to 3 heteroatoms selected from aryl, N, O and S, 4 to 10 heterocycloalkyls comprising 1 to 3 heteroatoms selected from N, O and S, C3-C8 cycloalkyls and C3-C8 cycloalkenyls. In one embodiment, Cy2 may be phenyl, or a 5 to 10 heteroaryl comprising 1 or 2 nitrogen atoms. In one embodiment, Cy2 may be phenyl, pyrroleyl, furanyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazineyl, pyrazineyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazineyl, morpholine, cyclopentyl, cyclohexyl, cyclopenteneyl, or cyclohexeneyl. In one embodiment, Cy2 may be phenyl, pyrazolyl, pyridinyl, or pyrimidinyl.

[0134] The above Cy2 may optionally be substituted with one or more R''. In some embodiments, R'' is a halogen, hydroxy, cyano, amino, oxo, C1-C6 alkyl, C1-C6 alkoxy, -S-(C1-C6 alkyl), -SO2-(C1-C6 alkyl), -COO-(C1-C6 alkyl), -COOH, -CONH2, -(CH2) p -NH2, -(CH2) p -NH-(C1-C6alkyl), -(CH2) p -N(C1-C6alkyl)2, -(CH2) p -NH-COO-(C1-C6alkyl), -(CH2) p ternary to pentary heterocycloalkyl, C3-C5 cycloalkyl, comprising one heteroatom selected from -OH, N, O, and S, and -(CH2) pIt may be selected from the group consisting of -(C3-C5 cycloalkyl). The C1-C6 alkyl and C1-C6 alkoxy may be optionally substituted with one or more halogens, hydroxy, cyano, or aminos, and the ternary to pentary heterocycloalkyl and C3-C5 cycloalkyl may be optionally substituted with one or more halogens, hydroxy, cyano, oxo, or aminos.

[0135] In one embodiment, R'' is a halogen, hydroxy, cyano, amino, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -(CH2) p -NH2, -(CH2) p -NH-(C1-C6alkyl), -(CH2) p -N(C1-C6alkyl)2; azetidinyl or oxetanyl optionally substituted with a hydroxy or oxo; and cyclopropyl or cyclopropylmethyl optionally substituted with a hydroxy or oxo may be selected from the group consisting of

[0136] In some embodiments, R 4 It can be hydrogen or C1-C3 alkyl.

[0137] In some embodiments, R 8 silver and here, Z is -(CH2) s and R 8' can be a hydroxyl or a C1-C6 alkoxy. In this case, s can be an integer of 0 or 1.

[0138] In one embodiment, l, m, and n may each be an integer of 1 or 2 independently. In one embodiment, o and p may each be an integer of 0 to 2 independently. In one embodiment, q and r may each be an integer of 1 or 2 independently. In one embodiment, s may be an integer of 0 or 1.

[0139] In some embodiments, the compound of formula IB-1 may be the following formulas IB-5, IB-6, IB-7, or IB-8:

[0140] [Chemical Formula IB-5]

[0141]

[0142] [Chemical Formula IB-6]

[0143]

[0144] [Chemical Formula IB-7]

[0145]

[0146] [Chemical Formula IB-8]

[0147]

[0148] In the above chemical formulas IB-5, IB-6, IB-7, and IB-8, R 1 , W, Cy, R a , R 4 and R 8 It is as defined in chemical formula IB-1.

[0149] In one embodiment, the compound of Formula I of the present invention may be a compound selected from the group consisting of the following compounds:

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172]

[0173]

[0174]

[0175]

[0176]

[0177]

[0178] and .

[0179] In one embodiment, the compound of Formula I of the present invention may be a compound selected from the group consisting of the following compounds:

[0180]

[0181]

[0182] and .

[0183] definition

[0184] All technical and scientific terms used herein have the meanings generally understood by those skilled in the art, and unless otherwise noted, conventional measurement methods, manufacturing methods, conventional ingredients, or substances are used based on prior art such as pharmacology, pharmaceutical manufacturing, mass spectrometry, NMR, HPLC, and biochemistry.

[0185] Unless otherwise specified, in this specification and the appended claims, “or” and “and” mean “and / or.” The terms “comprising” and “comprising” are open-ended and mean that a compound, composition, or method may include additional features or components in addition to the features or components listed.

[0186] In this document, the "*" marked at the connector end of the residue indicates the location where it binds to the rest of the compound.

[0187] In this specification, the term "halogen" may be F, Cl, Br, or I.

[0188] In this specification, the term "alkyl" means a straight-chain or branched hydrocarbon residue that may be substituted or unsubstituted, unless otherwise noted. The alkyl is C1-C 15 Alkyl, C1-C 12 It may be alkyl, C1-C9 alkyl, C1-C6 alkyl, or C1-C3 alkyl. Examples of alkyl may include, without limitation, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 3-methylbut-1-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethyleth-1-yl, n-hexyl, n-heptyl, and n-octyl, and all possible isomers thereof.

[0189] In this specification, the term “alkoxy” indicates a straight-chain or branched hydrocarbon residue connected to oxygen, which may be substituted or unsubstituted unless otherwise noted. The alkoxy may include, without limitation, all possible isomers thereof, such as, for example, methoxy, ethoxy, propoxy, and butoxy, or isopropoxy, isobutoxy, and t-butoxy.

[0190] In this specification, the term "cycloalkyl" refers to a saturated hydrocarbon ring having a specified number of carbon atoms as ring elements (i.e., C3-C8 cycloalkyl refers to a cycloalkyl group having 3, 4, 5, 6, 7, or 8 carbon atoms as ring elements). The cycloalkyl is C3-C 15 Cycloalkyl, C3-C 13 Cycloalkyl, C3-C 11 It may be a cycloalkyl, C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C3-C5 cycloalkyl, and the cycloalkyl having a polycyclic hydrocarbon ring may have two or more cycloalkyls crosslinked or fused.

[0191] In this specification, the term “cycloalkenyl” refers to a non-aromatic unsaturated monocyclic or polycyclic hydrocarbon ring having one or more carbon-carbon double bonds and containing a specified number of carbon atoms. For example, cycloalkenyls include, but are not limited to, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, cyclohex-1,3-diene-1-yl, etc.

[0192] In this specification, the term "hydroxyl" refers to an -OH group.

[0193] In this specification, the term "oxo" refers to a substituent having the structure =O, wherein a double bond exists between the atom and the oxygen atom.

[0194] In this specification, the term “haloalkyl” refers to an alkyl group in which at least one hydrogen atom is replaced by a halogen atom. In some embodiments, one, two, or three hydrogen atoms of the alkyl group may be replaced by halogen atoms. In one embodiment, the hydrogen atoms may be replaced by the same halogen atom (e.g., fluoro) or by a combination of different halogen atoms (e.g., fluoro and chloro).

[0195] In this specification, the term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom is replaced by a halogen atom, and the provisions described for "haloalkyl" also apply to "haloalkoxy".

[0196] In this specification, the term "aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon group. The aryl is characterized by alternating double bonds between adjacent carbon atoms and may include forms in which two or more rings are simply pendent or condensed. The aryl is, for example, a C6-C 14 Aryl, C6-C 10 It may be an aryl, C6-C9 aryl, and may include, for example, phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthraceneyl, or all possible isomers thereof without limitation.

[0197] In this specification, the term "heteroaryl" means a heterocyclic aromatic group comprising at least one heteroatom selected from B, N, O, S, P(=O), Si, and P as a ring-forming atom. The heteroaryl may also include a form in which two or more rings are simply attached (penant) or condensed together.

[0198] In some embodiments, the heteroaryl may comprise one to four heteroatoms selected from N, O, and S, one to three heteroatoms, one or two heteroatoms, or one heteroatom. In one embodiment, the heteroaryl may comprise one to three Ns, one or two Ns, or one N. In some embodiments, the heteroaryl may comprise four to fourteen, five to ten, or five to six ring atoms.

[0199] Examples of monocyclic heteroaryls include, but are not limited to, thiophenyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazoyl, oxazolyl, isooxazolyl, imidazoyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazoyl, pyridinyl, pyridazineyl, pyrimidinyl, pyrazineyl, triazineyl, and similar groups. Examples of bicyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, indazolyl, indolizinyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzopyrazolyl, benzoxazolyl, benzisothiazolyl, benzthiazolyl, benzthiadiazolyl, benztriazolyl, quinolineyl, isoquinolineyl, quinoxalineyl, quinazolinyl, purineyl, phthalazinyl, pteridineyl, furopyridineyl, oxochromene, dioxoisoindoline, imidazopyridineyl, pyrrolopyridineyl, pyrrolopyrimidineyl, pyrazolopyridineyl, and similar groups.

[0200] In this specification, the term “heterocycloalkyl” refers, unless otherwise noted, to a monocyclic or polycyclic saturated or partially unsaturated ring system comprising one or more heteroatoms selected from B, N, O, S, P(=O), Si, and P and having a specified number of ring elements (i.e., ternary to heptary heterocycloalkyl refers to a heterocycloalkyl group having 3, 4, 5, 6, or 7 ring elements including heteroatoms). Polycyclic heterocycloalkyl may have two or more heterocycloalkyls crosslinked or fused together.

[0201] In some embodiments, the heterocycloalkyl may comprise one to four heteroatoms selected from N, O, and S, one to three heteroatoms, one or two heteroatoms, or one heteroatom. In one embodiment, the heterocycloalkyl may comprise one to three Ns, one or two Ns, or one N. In some embodiments, the heterocycloalkyl may comprise three to seven, three to six, four to six, four to ten, or four to fourteen ring atoms.

[0202] For example, the above heterocycloalkyl group is not limited to aziridine, oxiran, azetidine, oxetan, thiethane, pyrrolidine, pyrroline, dihydrofuran, tetrahydrofuran, dihydrothiophene, tetrahydrothiophene, sulfolanyl, dioxolanyl, imidazoline, imidazolidin, pyrazolin, pyrazolidin, thiazolin, thiazolidin, isothiazoline, isothiazolidin, oxazolin, oxazolidin, isoxazolin, isoxazolidin, triazolin, triazolidin, tetrazoline, tetrazolidin, pyran, dihydropyran, tetrahydropyran, thiopyran, tetrahydrothiopyran, Dihydrothiopyranyl, dioxaneyl, tetrahydrotriazineyl, hexahydrotriazineyl, morpholineyl, thiomorpholineyl, piperidineyl, dihydropyridineyl, tetrahydropyridineyl, piperazineyl, tetrahydropyrimidineyl, dihydropyrimidineyl, dihydropyridazineyl, tetrahydropyridazineyl, tetrahydrooxazineyl, hexahydroazepineyl, perhydroazepineyl, perhydrooxepinyl, indolineyl, isoindolineyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzoxazolyl, dihydrobenzothiazoyl, chromanyl, isochromanyl, azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.2.1]heptanyl, 7-azabicyclo[4.1.0]-heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, tropaneyl, 2-oxa-6-azaspiro[3.3]heptanyl, and their N-oxides, sulfones, or sulfoxides.

[0203] In some embodiments, the heterocycloalkyl includes aziridine-yl, oxiran-yl, azetidin-yl, oxetan-yl, pyrrolidine-yl, tetrahydrofuran-yl, pyrazolidin-yl, imidazolidin-yl, thiazolidin-yl, oxazolidin-yl, isoxazolidin-yl, piperidine-yl, piperazine-yl, thiomorpholine-yl, or morpholine-yl.

[0204] In this specification, the term “substituted” refers to a group in which one or more hydrogen atoms are replaced by one or more non-hydrogen groups, provided that the valence requirement is satisfied and a chemically stable compound results from the substitution. Within this specification, unless explicitly stated as “unsubstituted,” all substituents should be interpreted as being capable of being substituted or unsubstituted. In this specification, “arbitrarily substituted” as mentioned without limitation to specific substituents encompasses moiety substituted or unsubstituted with any substituent, such as halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C8 cycloalkyl, C6-C 14 It comprises a moiety substituted with an aryl, a quaternaryl to a quaternaryl, or a quaternaryl to a quaternaryl heterocycloalkyl. In one embodiment, the “optionally substituted” moiety comprises a moiety substituted with a halogen, a hydroxyl, a cyano, an amino, a C1-C6 alkyl, a C1-C6 alkoxy, -NH-(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0205] In this specification, when a combination of substituents is referred to as a single group, e.g., arylalkyl, cycloalkylalkyl, etc., the last mentioned group contains an atom attached to the end of the molecule.

[0206] In this specification, a numerical range indicated by the term "to" refers to a range that includes the values ​​described before and after the term "to" as a lower limit and an upper limit, respectively.

[0207] In this specification, the term “solvate” 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 any solvent that is volatile, non-toxic, and / or suitable for administration to humans.

[0208] In this specification, 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 specifically, may be a diastereomer, enantiomer, or geometric isomer.

[0209] In some embodiments, the compound of the present invention may include one or more asymmetric centers and may be in the form of a racemic mixture, a single enantiomer, a mixture of enantiomers, a single diastereomer, a mixture of diastereomers, etc. In one embodiment, due to the nature or limited rotation of the asymmetric center, the compound of the present invention may exist in the form of an enantiomer or a diastereomer.

[0210] When two or more asymmetric centers are present in the compound of the present invention, various diastereomers and enantiomers of the chemical structure disclosed herein may exist, and pure isomers, separated isomers, partially pure isomers, or racemic mixtures are all intended to fall within the scope of the present invention.

[0211] The purification of the above isomers and the separation of the mixture of isomers can be achieved by standard techniques known in the art. For example, a mixture of diastereomers can be separated into each diastereomer by a chromatographic process or crystallization, and a racemic mixture can be separated into each enantiomer by a chiral phase chromatographic process or splitting.

[0212] In addition, if the compound of the present invention comprises a group capable of tautomerization, all tautomeric forms are included within the scope of the present invention. For example, 2-hydroxypyridine may include 2-pyridone, and all such isomer forms are included in the present invention.

[0213] The “pharmaceuticalally acceptable salt” as used herein may include acid or basic salts of a parent compound, and, without limitation, may include acid or organic acid salts of basic residues such as amines, alkali or organic salts of acid residues such as carboxylic acids, etc.

[0214] For example, a pharmaceutically acceptable salt of the compound of the present invention may be formed from a pharmaceutically acceptable non-toxic base comprising an inorganic base and an organic base. In one embodiment, the pharmaceutically acceptable salt of the present invention comprises an inorganic base addition salt, e.g., a lithium salt, a sodium salt, a potassium salt, a magnesium salt, a calcium salt, an aluminum salt, an ammonium salt, a copper salt, a ferric salt, a ferrous salt, a manganese salt, a zinc salt, etc. In one embodiment, the pharmaceutically acceptable salt of the present invention may comprise a salt derived from an organic base addition salt, such as arginine, betaine salt, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperisin, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, dicyclohexylamine, tris(hydroxymethyl)methylamine, etc.

[0215] In addition, the compound of the present invention may be used in the form of a pharmaceutically acceptable salt derived from an inorganic acid or an organic acid, for example, said salt may be a salt derived from hydrochloric acid, hydrobromide, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvate, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, or toluenesulfonic acid, etc.

[0216] A pharmaceutically acceptable salt of the above compound can be prepared, for example, by dissolving the compound of Formula I in a water-miscible organic solvent, such as acetone, methanol, ethanol, or acetonitrile, adding an excess amount of organic acid or an aqueous solution of an inorganic acid, and then precipitating or crystallizing. Subsequently, the solvent or excess acid can be evaporated from the mixture and dried to obtain an addition salt, or the precipitated salt can be prepared by suction filtration.

[0217] Meanwhile, the acid addition salt form of the present invention can be easily converted into a free base form by treatment with a suitable base, and the base addition salt form can be easily converted into a free acid form by treatment with a suitable acid.

[0218] General method of preparing compounds

[0219] Meanwhile, the above compound can be prepared through chemical modifications well known to a person skilled in the art of organic / medicinal chemistry according to the method typically described below.

[0220] The following general reaction equation is a general example of a representative method for preparing a compound of Formula I. A person skilled in the art would be able to easily prepare the compound of Formula I by appropriately selecting starting materials, reaction temperature, reaction conditions, catalyst, solvent, processing method, etc. suitable for the desired compound, based on the manufacturing method specifically disclosed in the embodiments of the present invention.

[0221] For example, a compound of formula I having a thiophene ring can be prepared according to the following reaction schemes 1 to 5:

[0222] [Reaction Equation 1]

[0223]

[0224]

[0225] [Reaction Equation 2]

[0226]

[0227]

[0228] [Reaction Equation 3]

[0229]

[0230]

[0231] [Reaction Equation 4]

[0232]

[0233]

[0234] [Reaction Equation 5]

[0235]

[0236]

[0237] For example, a compound of formula I having a 4H-thieno[3,2-b]pyrrole fusion ring can be prepared according to the following reaction scheme 6.

[0238] [Reaction Equation 6]

[0239]

[0240]

[0241]

[0242] When preparing compounds according to the above reaction schemes 1 to 6, instead of methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride, suitable amino-cycloalkyl-carboxylate compounds, such as methyl 3-aminocyclobutane-1-carboxylate, methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate, methyl 4-aminobicyclo[1.1.1]octane-1-carboxylate, etc., can be used to prepare compounds in which various ring structures are bonded to the amide bond.

[0243] The above compounds, solvates, stereoisomers, or pharmaceutically acceptable salts thereof of the present invention exhibit a tumor growth inhibitory effect.

[0244] In one embodiment of the present invention, when the compound was administered to mouse-derived colorectal and lung cancer tumor models, tumor growth was inhibited compared to the control group.

[0246] anticancer drugs

[0247] The anticancer agent of the present invention may be selected from the group consisting of chemotherapy agents, targeted anticancer agents, oncolytic viruses, antibody therapeutic agents, cell therapeutic agents, immune checkpoint inhibitors, and combinations thereof.

[0248] In this specification, the term "chemotherapy agent" is also referred to as an antitumor agent or a cytotoxic agent. It is a collective term for drugs that exhibit anticancer activity by acting directly on DNA to block DNA replication, transcription, and translation processes, or by interfering with the synthesis of nucleic acid precursors in metabolic pathways and inhibiting cell division. The aforementioned antitumor agents act on normal cells as well as tumor cells to exhibit cytotoxicity. Chemotherapy agents may be used in maintenance therapy. Furthermore, as used in this specification, the term "maintenance therapy" refers to a treatment method involving the use of drugs to treat cancer following initial anticancer treatment, implemented to prevent or delay the recurrence of cancer.

[0249] Specifically, the chemotherapy agent may be any one selected from the group consisting of an alkylating agent, a microtubule inhibitor, antimetabolite, and a topoisomerase inhibitor. The alkylating agent may be any one selected from the group consisting of mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, thiotepa, altretamine, procarbazine, busulan, streptozotocin, carmustine, lomustine, dacarbazine, cisplatin, carboplatin, and oxaliplatin. The microtubule inhibitor may be any one selected from the group consisting of docetaxel, paclitaxel, velban, oncovin, and navelbine. The anti-metabolite may be any one selected from the group consisting of Fluorouracil, Capecitabine, Cytarabine, Gemcitabine, Fludarabine, Methotrexate, Pemetrexed, and Mercaptopurine. The topoisomerase inhibitor may be any one selected from the group consisting of Hycamtin, Camptosar, Vepesid, Blenoxane, Adriamycin, and Cerubidine.

[0250] In this specification, the term "targeted anticancer agent" refers to a therapeutic agent that specifically kills cancer cells by blocking signals involved in the growth and development of cancer, targeting specific proteins or specific genetic mutations that are abundant only in cancer cells. It is classified into monoclonal antibodies, which react outside the cell, and small molecules, which act inside the cell. Monoclonal antibodies are anticancer agents that block cancer cell-inducing signals transmitted outside the cell and act on initiation signals related to proliferation and death, while small molecules act on complex signal transduction occurring inside the cell.

[0251] Specifically, the target proteins are EGFR, VEGFR, CD20, CD38, RNAK-L, BTK, Bcr-abl, PDGFR / FGFR family, MEK / RAF / KRAS, HER2 / Neu, Ubiquitin, JAK, ALK, PARP, TGFβRI, Proteasome, Bcl-2, C-Met, VR1, VR2, VR3, c-kit, AXL, It could be RET, Braf, DNMT, CDK4 / 6, STING, etc.

[0252] Cetuximab, Trastuzumab, Pertuzumab, Gefitinib, Erlotinib, Osimertinib, Panitumumab, Axitinib, Lenvatinib, Bevacizumab, Ramucirumab, Aflibercept, Rituximab, Obinutuzumab, Daratumumab, Denosumab, Ibrutinib, Dasatinib, Nilotinib, Imatinib, Bosutinib, Galunisertib, Vactosertib, Nintedanib, Sunitinib, Sorafenib, Cabozantinib, Regorafenib, Masitinib, Semaxanib, Tivozanib, Vandetanib, Pazopanib, Trametinib, Dabrafenib, Sotorasib, Afatinib, Lapatinib, Neratinib, Lenalidomide, Ixazomib, Ruxolitinib, Lestaurtinib, Pacritinib, Cobimetinib, Selumetinib, Binimetinib, Alectinib, Crizotinib, Venetoclax, Bemcentinib, Gilteritinib, Selpercatinib, Pralsetinib, Vemurafenib, Olaparib, Talazoparib, Niraparib, It may be one selected from the group consisting of Rucaparib, Azacitidine, Decitabine, Guadecitabine, Abemaciclib, Ribociclib, Palbociclib, CDNs, SB11285 and DMXAA.

[0253] In this specification, the term "Epidermal growth factor receptor (EGFR)" refers to a cell membrane receptor that regulates cell growth, division, survival, and death, and the expression of EGFR is increased in tumor tissues in various cancers. Tumor tissues with increased EGFR are known to have high invasion, metastasis, and resistance to anticancer drugs. An EGFR inhibitor is a substance that inhibits EGFR, and in one embodiment, may be Cetuximab, Trastuzumab, Pertuzumab, Gefitinib, Erlotinib, Osimertinib, or Panitumumab.

[0254] In this specification, the term "Vascular Endothelial Growth Factor Receptor (VEGFR)" refers to a cell membrane receptor of angiogenic factors that induce angiogenesis, and VEGFR inhibitors inhibit said angiogenesis to inhibit tumor growth and metastasis. An example of a VEGF inhibitor or VEGFR inhibitor may be Axitinib, Lenvatinib, Bevacizumab, Ramucirumab, or Aflibercept.

[0255] In this specification, the term "CD20 (B lymphocyte antigen CD20)" refers to a protein expressed on the surface of B cells and is used as a target protein for the treatment of B-cell lymphoma. A CD20 target inhibitor may be Rituximab or Obinutuzumab.

[0256] In this specification, the term "CD38 (Cluster of differentiation 38)" refers to a protein that acts as a signaling pathway receptor in immune cells and regulates cell proliferation and death, and an inhibitor targeting this may be Daratumumab.

[0257] In this specification, the term "RNAK-L (Receptor activator of nuclear factor kappa-B ligand)" refers to a RANK receptor expressed on the surface of osteoclasts, which acts to cause bone destruction when activated by binding to a ligand. RANK-L inhibitors are primarily used in cancer patients suffering from bone metastasis or osteoporosis, and specifically may be Denosumab.

[0258] In this specification, the term "BTK (Bruton's tyrosine kinase)" refers to an enzyme involved in the proliferation of B cells that can develop into blood cancer when overexpressed. One embodiment of a BTK targeted inhibitor may be Ibrutinib.

[0259] In this specification, the term "Bcr-abl" refers to a fusion protein that is highly expressed in patients with chronic myeloid leukemia and is known to induce abnormal proliferation of blood cells. Specifically, inhibitors of said protein may be Dasatinib, Nilotinib, Imatinib, or Bosutinib.

[0260] In this specification, the term "tumor growth factor β receptor (TGFβR)" refers to a cell membrane receptor of tumor growth factor that regulates the growth, migration, differentiation, and death of epithelial cells and hematopoietic cells. Examples of TGFβR target inhibitors include Galunisertib or Vactosertib, but are not limited thereto.

[0261] In this specification, the term "PDGFR (Platelet-derived growth factor)" refers to a cell membrane receptor for PDGF that is frequently expressed in cancer cells and is known to regulate cancer growth, metastasis, and drug resistance by participating in angiogenesis. FGFR (Fibroblast growth factor receptor) is a receptor for fibroblast growth factor (FGF) and regulates various biological processes, including cell growth, differentiation, and migration. The FGFR gene is prone to mutation, and such variants are commonly observed in breast cancer, uterine cancer, ovarian cancer, and cervical cancer. Inhibitors targeting PDGFR or FGFR may be Nintedanib, Sunitinib, Sorafenib, Cabozantinib, Lenvatinib, Regorafenib, Masitinib, Semaxanib, Tivozanib, Vandetanib, Axitinib, or Pazopanib.

[0262] In this specification, the term "MEK / RAF / KRAS" refers to an intracellular signaling mediator involved in cell proliferation, cell cycle regulation, cell survival, angiogenesis, cell migration, etc., which is overactive in cancer cells. Inhibitors targeting MEK / RAF / KRAS may be Trametinib, Dabrafenib, or Sotorasib.

[0263] In this specification, the term "HER-2 / neu (Human epidermal growth factor receptor 2) regulates cell proliferation through the activation of PI3K / AkT. It is known to be overexpressed in metastatic breast cancer and ovarian cancer, etc., and to induce resistance to anticancer drugs. Her2 / neu targeted anticancer drugs may be Trastuzumab, Afatinib, Lapatinib, or Neratinib.

[0264] In this specification, the term "ubiquitin" maintains cellular homeostasis by binding to other proteins and inducing protein degradation by the proteasome, a proteolytic enzyme (Ubiquitin-proteasome system, UPS). Abnormal expression or activity of the UPS is observed in various tumors, and inhibitors of these exhibit anticancer activity. Specifically, inhibitors targeting ubiquitin or the proteasome may be Lenalidomide or Ixazomib.

[0265] In this specification, the term "JAK (Janus kinase)" refers to a upstream protein of STAT, a transcription factor that regulates cell proliferation, cell survival, cell migration, and immune response, and inhibitors of JAK are known to reduce cell proliferation and induce apoptosis by inhibiting the activity of STAT. The JAK target inhibitor may be Ruxolitinib, Lestaurtinib, or Pacritinib.

[0266] In this specification, the term "MAP2K (Mitogen-activated protein kinase kinase)" refers to an intracellular signaling mediator involved in cell proliferation, cell cycle regulation, cell survival, angiogenesis, cell migration, etc., by phosphorylating MAPK, and is overactivated in cancer cells. MAP2K target inhibitors may be Cobimetinib, Selumetinib, Trametinib, or Binimetinib.

[0267] In this specification, the term "ALK (Anaplastic lymphoma kinase)" is a signaling mediator that promotes cell proliferation, cell migration, and angiogenesis, and inhibits apoptosis, and is overactive in various cancer tissues. An ALK targeted inhibitor may be Alectinib or Crizotinib.

[0268] In this specification, the term "Bcl-2" refers to a protein that inhibits cell death and is overexpressed or overactive in various cancer tissues. An inhibitor targeting Bcl-2 may be Venetoclax.

[0269] In this specification, the term "C-Met" refers to a receptor for hepatocyte growth factor (HGF) that activates signaling related to cell growth, formation, motility, survival, and angiogenesis. The C-Met targeted anticancer agent may be Crizotinib or Cabozantinib.

[0270] In this specification, the term "VR (Vanilloid receptor)" is also known as TRPV (Transient receptor potential vanilloid) and exists in the forms VR1, VR2, VR3, VR4, VR5, and VR6. VR is known to regulate the proliferation, death, migration, invasion, and angiogenesis of cancer cells at each stage of cancer progression.

[0271] In this specification, the term "c-kit" is also known as CD117 and induces signal transduction that activates cell survival, proliferation, and differentiation. c-kit is a proto-oncogene, and overexpression or mutation of said gene is associated with the development of cancer.

[0272] In this specification, the term "AXL (Yyrosin-protein kinase receptor UFO)" refers to a tyrosine kinase receptor present on the cell surface that mediates signal transduction involved in cell proliferation and survival. It is known to be involved in anticancer drug resistance in anticancer therapy. One embodiment of an AXL-targeted anticancer drug may be Bemcentinib or Gilteritinib.

[0273] In this specification, the term "RET (Rearragned during transfection)" is As a receptor that mediates signals involved in cell proliferation, apoptosis, and survival, mutations in RET are known to be involved in carcinogenesis. Targeted inhibitors of RET may be, but are not limited to, Selpercatinib or Pralsetinib.

[0274] In this specification, the term "Braf" refers to a MAPK signaling mediator involved in cell proliferation, cell cycle regulation, cell survival, angiogenesis, cell migration, etc., and genetic mutations are observed in cancer cells. An inhibitor targeting Braf may be Vemurafenib.

[0275] In this specification, the term "PARP (Poly[ADP-ribose]polymerase)" refers to a protein that recognizes damaged DNA in the nucleus, becomes activated, and then activates proteins related to DNA repair. PARP targeted inhibitors inhibit the proliferation of cancer cells by inhibiting DNA repair in cancer cells. One embodiment of the PARP targeted inhibitor may be Olaparib, Talazoparib, Niraparib, or Rucaparib.

[0276] In this specification, the term "DNA methyltransferase (DNMT)" refers to an enzyme that attaches a methyl group to a histone protein wrapping DNA, and through this process, gene expression is suppressed. The DMMT target inhibitor exhibits anticancer activity by inhibiting the hypermethylation of tumor suppressor genes and inducing normal expression of tumor suppressor genes. One embodiment of the DNMT target inhibitor may be Azacitidine, Decitabine, or Guadecitabine.

[0277] In this specification, the term "CDK (Cyclin dependent kinase) 4 / 6" refers to a protein that promotes cell growth by regulating the cell cycle and is hyperactive during the development and progression stages of various malignant tumors. CDK4 / 6 targeted inhibitors exhibit anticancer activity by inhibiting the cell cycle of cancer cells, thereby suppressing cell proliferation and inducing apoptosis. CDK4 / 6 targeted inhibitors may be Abemaciclib, Ribociclib, or Palbociclib.

[0278] In this specification, the term "STING (Stimulator of Interferon Genes)" refers to an in vivo sensor that recognizes DNA fragments released from cancer cells and stimulates interferon genes to activate immune cells in the body, such as dendritic cells. The agonist of the STING exhibits an immune-enhancing effect and an anti-angiogenesis effect, and, for example, the STING agonist may be CDNs, SB11285, DMXAA, etc.

[0279] In this specification, the term "oncolytic virus therapeutic agent" refers to a therapeutic agent that kills cancer by inserting a specific gene targeting cancer cells into a proliferative and infective virus. The oncolytic virus therapeutic agent may be Talimogene Laherparepvec.

[0280] In this specification, the term "antibody therapeutic" refers to a therapeutic agent that exhibits an anticancer effect by utilizing an antibody that recognizes a specific protein of a cancer cell as an antigen. Antibody therapeutics may be Cetuximab, Trastuzumab, Emtansine, Rituximab, Ibritumomab, Tositumomab, Brentuximab, Ofatumumab, Obinutuzumab, Necitumumab, Bevacizumab, Ramucirumab, Nivolumab, Pembrolizumab, Atezolizumab, Durvalumab, Ipilimumab, etc.

[0281] In this specification, the term "immunotherapy" refers to a therapeutic agent that exhibits an anticancer effect by activating the body's immune response using immune cells such as dendritic cells, natural killer cells, and T cells. Immunotherapy is used by extracting immune cells from the body, enhancing them, or genetically modifying them, and then re-injecting them into the body. Representative immunotherapys include T cell receptor-modified T cells (TCR-T) and chimeric antigen receptor-modified T cells (CAR-T). Specifically, it may be Tisagenlecleucel or Axicabtagene Ciloleucel, but is not limited thereto.

[0282] In this specification, the term "immune checkpoint inhibitor" refers to a substance that inhibits the activity of immune checkpoint proteins, which inhibit the differentiation, proliferation, and activity of immune cells, and is known to eliminate cancer cells by preventing them from exercising the function of evading the immune system. The immune checkpoint inhibitor may be any one selected from the group consisting of anti-CTLA-4 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-B7-H4 antibody, anti-HVEM antibody, anti-TIM3 antibody, anti-GAL9 antibody, anti-LAG3 antibody, anti-VISTA antibody, anti-KIR antibody, anti-BTLA antibody, and anti-TIGIT antibody. In one embodiment, the immune checkpoint inhibitor may be, but is not limited to, Ipilimumab, Pembrolizumab, Nivolumab, Cemiplimab, Atezolizumab, Avelumab, and Durvalumab.

[0283] In this specification, the term "ADC (Antibody drug conjugate)" refers to a therapeutic agent that exhibits a high anticancer effect through targeted delivery by chemically conjugating an antibody and a cytotoxic drug. It may be Gemtuzumab-Ozogamicin, Brentuximab-Vedotin, Trastuzumab-Emtansine, Inotuzumab-Ozogamicin, and Eribulin-Mesylate, etc.

[0284] The above anticancer agent may comprise one or more anticancer agents. Specifically, the compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof may be used in combination with two anticancer agents. For example, it may be a chemotherapy anticancer agent and a targeted anticancer agent; a chemotherapy anticancer agent and an oncolytic virus; a targeted anticancer agent and an antibody therapeutic agent; a chemotherapy anticancer agent and a cell therapeutic agent; and a chemotherapy anticancer agent and an immune checkpoint inhibitor. Additionally, it may be a targeted anticancer agent and an oncolytic virus; a targeted anticancer agent and an antibody therapeutic agent; a targeted anticancer agent and a cell therapeutic agent; a targeted anticancer agent and an immune checkpoint inhibitor. Additionally, it may be an oncolytic virus and an antibody therapeutic agent; an oncolytic virus and a cell therapeutic agent; and an oncolytic virus and an immune checkpoint inhibitor. Additionally, it may be an antibody therapeutic agent and a cell therapeutic agent; and an antibody therapeutic agent and an immune checkpoint inhibitor.

[0285] The above compounds, solvates, stereoisomers, or pharmaceutically acceptable salts thereof may be used with three anticancer agents. The above two anticancer agents may additionally include different anticancer agents.

[0286] According to one embodiment, the compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof may be used in combination with two or more chemotherapy agents and immune checkpoint inhibitors. For example, the two or more chemotherapy agents may include an alkylating agent and an antimetabolite.

[0287] The above compounds, solvates, stereoisomers, or pharmaceutically acceptable salts thereof may be used with four anticancer agents. The above three anticancer agents may be used with additional different anticancer agents.

[0288] The above compounds, solvates, stereoisomers, or pharmaceutically acceptable salts thereof may be used with five anticancer agents. The above four anticancer agents may be used with additional different anticancer agents.

[0289] The above compounds, solvates, stereoisomers, or pharmaceutically acceptable salts thereof may be used with six anticancer agents.

[0290] The above compounds, solvates, stereoisomers, or pharmaceutically acceptable salts thereof may be used in conjunction with anticancer vaccines.

[0291] In this specification, the term "anticancer vaccine" refers to an active immunotherapy that eliminates cancer cells by strengthening in vivo immune function through the activation of the immune system by administering tumor-specific antigens (TSAs) possessed by cancer cells to cancer patients. Anticancer vaccines include DNA vaccines, peptide vaccines, and cell vaccines depending on the type of antigen and the method of antigen delivery, and currently, cell vaccines and DNA vaccines developed by introducing antigens are being representatively developed.

[0292] The above-mentioned compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof may be used in conjunction with the above-mentioned anticancer agent and anticancer vaccine. Herein, the above-mentioned compound and anticancer agent are the same as those described above.

[0294] Medicinal use, pharmaceutical composition, method of administration

[0295] The above cancers may be, but are not limited to, squamous cell carcinoma, basal cell carcinoma, glioblastoma, bone cancer, gastric cancer, kidney cancer, lung cancer, bladder cancer, prostate cancer, breast cancer, prostate cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, head and neck cancer, renal cell carcinoma, esophageal cancer, pancreatic cancer, brain cancer, gastrointestinal cancer, liver cancer, leukemia, lymphoma, melanoma, multiple myeloma, osteosarcoma, colorectal cancer, cholangiocarcinoma, choriocarcinoma, oral cancer, neuroblastoma, skin cancer, testicular cancer, stromal tumor, germ cell tumor, or thyroid cancer.

[0296] Here, the cancer may be a disease associated with prostaglandin E2 overexpression and / or overexpression of the prostaglandin E2 receptor, which may be caused by the overexpression or overactivation of prostaglandin E2 and / or the prostaglandin E2 receptor.

[0297] In this specification, the terms “preventing” or “prevention” mean 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.

[0298] In this specification, 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 further occurrence of the pathology and / or sign; or improving a disease, e.g., in an individual experiencing or exhibiting a pathology or sign of a disease, condition, or disorder, i.e., reversing the pathology and / or sign, e.g., reducing the severity of the disease.

[0299] According to one embodiment, a compound represented by Formula I, IA-1, IA-2, IA-3, IA-4, IB-1, IB-2, IB-3, IB-4, IB-5, IB-6, IB-7, or IB-8 exhibits effective inhibitory activity against prostaglandin E2 receptors, e.g., EP2 and / or EP4, and a therapeutic effect can be exerted by regulating the activity of prostaglandin E2 through antagonistic action against such prostaglandin E2 receptors.

[0300] According to one experimental example of the present invention, when the compound and the anti-PD-1 antibody were administered in combination to a tumor animal model implanted with a mouse-derived colorectal carcinoma, an enhanced anticancer effect was shown compared to the administration of the compound or the anti-PD-1 antibody alone.

[0301] In addition, according to one experimental example of the present invention, when the compound, a chemotherapy agent, and an anti-PD-1 antibody were administered in combination to a tumor animal model implanted with a mouse-derived lung carcinoma, an enhanced anticancer effect was shown compared to the standard treatment method of administering the chemotherapy agent and the anti-PD-1 antibody in combination.

[0302] Accordingly, a compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof represented by the above formulas I, IA-1, IA-2, IA-3, IA-4, IB-1, IB-2, IB-3, IB-4, IB-5, IB-6, IB-7, or IB-8; and a pharmaceutical composition comprising an anticancer agent as an active ingredient can be used to treat cancer.

[0303] In one embodiment, the pharmaceutical composition may include a conventionally pharmaceutically acceptable carrier, excipient, or additive. The pharmaceutical composition may be formulated according to conventional methods and may 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.

[0304] When the above pharmaceutical composition is prepared in the form of an oral formulation, examples of additives or carriers used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents, etc. When the pharmaceutical composition of the present invention is prepared in the form of an injectable formulation, examples of additives or carriers include water, saline solution, glucose aqueous solution, similar sugar aqueous solution, alcohol, glycol, ether (e.g., polyethylene glycol 400), oil, fatty acid, fatty acid ester, glyceride, surfactant, suspending agent, emulsifier, etc.

[0305] The dosage of the above pharmaceutical composition is an amount effective for the treatment or prevention of an individual or patient, and may be administered orally or parenterally as intended. When administered orally, it may be administered in amounts ranging from 0.01 to 1000 mg per kg of body weight per day based on the active ingredient, more specifically from 0.1 to 300 mg; when administered parenterally, it may be administered in amounts ranging from 0.01 to 100 mg per kg of body weight per day based on the active ingredient, more specifically from 0.1 to 50 mg. The dosage for a specific individual or patient should be determined in light of various relevant factors such as the patient's body weight, age, gender, health status, diet, time of administration, method of administration, and severity of the disease, and it should be understood that it may be appropriately adjusted by a professional; the above dosage is not intended to limit the scope of the present invention in any way. A physician or veterinarian with ordinary skills in the relevant technical field can easily determine and prescribe the required effective amount of the pharmaceutical composition. For example, a physician or veterinarian may start the dosage of the compound of the present invention used in a pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect, and gradually increase the dosage until the desired effect is achieved.

[0306] In one embodiment, the pharmaceutical composition comprises within its scope a pharmaceutical composition comprising, alone or in combination with a pharmaceutical carrier, at least one of the compounds according to one embodiment as an active ingredient in a therapeutically effective amount. The term “therapeutically effective amount” or “effective amount” means an amount sufficient to produce a beneficial or desired clinical result, e.g., an amount sufficient to alleviate, improve, stabilize, reverse, slow, or delay the progression of a disease.

[0307] Optionally, the compound according to one embodiment may be administered alone, simultaneously with, separately from, or sequentially in combination with another anticancer agent.

[0308] Another aspect provides a method for preventing or treating cancer comprising the step of administering to an individual a pharmaceutical composition comprising a compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof represented by the above formulas I, IA-1, IA-2, IA-3, IA-4, IB-1, IB-2, IB-3, IB-4, IB-5, IB-6, IB-7, or IB-8; and an anticancer agent as an active ingredient. Among the terms or elements mentioned in the description of the method, those identical to those already mentioned are as previously described.

[0309] The above administration may be oral or parenteral. When administered orally, it may be administered in amounts of 0.01 to 1000 mg per kg of body weight per day based on the active ingredient, more specifically 0.1 to 300 mg; when administered parenterally, it may be administered in amounts of 0.01 to 100 mg per kg of body weight per day based on the active ingredient, more specifically 0.1 to 50 mg. The dosage for a specific individual or patient must be determined in light of various relevant factors such as the patient's body weight, age, gender, health status, diet, time of administration, method of administration, and severity of the disease, and may be appropriately adjusted by a specialist.

[0310] In this specification, the term "individual" means an object requiring treatment or prevention of a disease, and more specifically, means mammals such as human or non-human primates, mice, dogs, cats, horses, and cattle.

[0311] Another aspect provides the use of a pharmaceutical composition comprising a compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof represented by the above formulas I, IA-1, IA-2, IA-3, IA-4, IB-1, IB-2, IB-3, IB-4, IB-5, IB-6, IB-7, or IB-8 for preventing or treating cancer; and an anticancer agent as an active ingredient. Any terms or elements mentioned in the description of the method or use that are identical to those already mentioned are as previously described.

[0312] Another aspect provides a use of a pharmaceutical composition comprising a compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof represented by the formulas I, IA-1, IA-2, IA-3, IA-4, IB-1, IB-2, IB-3, IB-4, IB-5, IB-6, IB-7, or IB-8, represented by the formulas I, IA-1, IA-2, IA-3, IA-4, IB-5, IB-6, IB-7, or IB-8, for manufacturing a medicine for preventing or treating cancer; and an anticancer agent as an active ingredient. Among the terms or elements mentioned in the description of the method or use, those identical to those already mentioned are as described above.

[0314] Kit

[0315] Another aspect of the present invention provides a kit for the prevention or treatment of cancer comprising the compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof; and an anticancer agent as an active ingredient. Any terms or elements mentioned in the description of the kit that are identical to those already mentioned are as previously described.

[0317] The present invention will be explained in detail below by way of examples. However, the following examples are merely illustrative of the present invention, and the scope of the present invention is not limited by the following examples.

[0318] [Preparation Example]

[0319] Preparation Example 1: Methyl 6-aminospiro[3,3]heptane-2-carboxylate hydrochloride

[0320]

[0321] Methyl 6-((t-butoxycarbonyl)amino)spiro[3.3]heptane-2-carboxylate (10 g, 37.1 mmol) was added to a 4 N HCl (in dioxane) solution and stirred for 15 hours, after which the solution was concentrated under reduced pressure. The resulting crude product was washed with diethyl ether (100 mL) and dried to obtain intermediate A (7.32 g, yield 96%), which is a white solid. 1 H NMR (300 Hz, DMSO-d6) δ 8.09 (bs, 2H), 3.58 (s, 3H), 3.03 (p, J = 8.4 Hz, 1H), 2.43-2.31 (m, 1H), 2.28-1.95 (m, 6H).

[0322] Preparation Example 2: Methyl 2-azido acetate

[0323]

[0324] NaN3 (4.88 g, 75.0 mmol) was added to a solution of methyl 2-bromoacetate (7.65 g, 50.0 mmol) mixed in DMSO (0.5 M) and stirred for 24 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with distilled water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain intermediate B (4.09 g, yield 75%), which is a colorless liquid. 1 ¹H NMR(300MHz, chloroform-d) δ 3.91(s, 2H), 3.83(s, 3H).

[0325] Preparation Example 3: 3-Bromo-2,5-Dimethylthiophene

[0326]

[0327] NBS (17.8 g, 100 mmol) was added to a solution of 2,5-dimethylthiophene (11.2 g, 100 mmol) mixed with acetic acid (0.2 M) and stirred for 15 hours. The reaction mixture was concentrated and diluted with diethyl ether, then washed with distilled water, a sodium bicarbonate solution, and brine. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The crude product was purified by column chromatography to obtain intermediate C (8.80 g, yield 46%), which is a colorless liquid. 1 ¹H NMR(300MHz, chloroform-d) δ 6.60 - 6.56(m, 1H), 2.42(s, 3H), 2.35(s, 3H).

[0328] Preparation Example 4: Methyl 4-bromo-2,5-dimethylthiophene-3-carboxylate

[0329] Step 1: Synthesis of 3,4-Dibromo-2,5-Dimethylthiophene

[0330]

[0331] In a solution of tetrabromothiophene (8.0 g, 20.0 mmol, 1.0 equivalent) mixed in THF (60 mL, 0.3 M) n -BuLi (2.0 M in cyclohexane, 25.0 mL, 50.0 mmol, 2.5 equivalents) was added at -78°C and stirred at -78°C for 1 hour. Iodomethane (3.8 mL, 60.0 mmol, 3.0 equivalents) was added and stirred at room temperature for 20 hours. The reaction mixture was added to saturated NH4Cl and extracted with EtOAc. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The crude product was purified by column chromatography to obtain 3,4-dibromo-2,5-dimethylthiophene (4.9 g, yield 90%).

[0332] Step 2: Synthesis of 4-Bromo-2,5-Dimethylthiophene-3-Carboxylic Acid

[0333]

[0334] In a solution of 3,4-dibromo-2,5-dimethylthiophene (4.9 g, 18.1 mmol, 1.0 equivalent) mixed in THF (60 mL)n -BuLi (2.0 M in cyclohexane, 8.2 mL, 0.9 equivalents) was added at -78°C and stirred at -78°C for 30 minutes. After adding excess dry ice, the mixture was stirred at room temperature for 30 minutes. The reaction mixture was added to 1 N NaOH and extracted with Et2O, and the aqueous layer was acidified with a 1 N HCl solution. The resulting precipitate was removed by filtration, washed with distilled water, and dried to obtain 4-bromo-2,5-dimethylthiophene-3-carboxylic acid (3.3 g, yield 77%).

[0335] Step 3: Synthesis of Methyl 4-Bromo-2,5-Dimethylthiophene-3-Carboxylate

[0336]

[0337] Iodomethane (1.4 mL, 22.4 mmol, 2.0 equivalents) was added to a solution of 4-bromo-2,5-dimethylthiophene-3-carboxylic acid (2.64 g, 11.2 mmol, 1.0 equivalent) and K2CO3 (3.1 g, 22.4 mmol, 2.0 equivalents) mixed in DMF (15 mL), and the mixture was stirred for 12 hours. The reaction mixture was added to distilled water and extracted with DCM. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The crude product was purified by column chromatography to obtain intermediate D (2.55 g, yield 91%).

[0338] Preparation Example 5: 3-fluoro-[1,1'-biphenyl]-4-carboxylic acid

[0339]

[0340] 6.47 g (18.45 mmol, 2.25 equivalents) of 26% Me4N·OH aqueous solution was added to 1.0 g of phenylboronic acid (8.20 mmol, 1.0 equivalents) and 1.80 g of 4-bromo-2-fluorobenzoic acid (8.20 mmol, 1.0 equivalents), and the mixture was stirred at 50°C. 25 mL of distilled water and 25 mg (0.025 w / w) of 5% Pd / C were added under Ar substitution, and the mixture was stirred at 80°C for 1.5 hours. The reaction mixture was cooled to room temperature, and the Pd / C was removed by filtration through Celite. 2.2 mL of 6 M HCl aqueous solution (13.12 mmol, 1.6 equivalents) was added to the reaction mixture to neutralize and crystallize it, after which 10 mL of distilled water was added and the mixture was stirred for 30 minutes. After washing the precipitated crystals with distilled water, the intermediate E (1.5 g, yield 85%) was obtained by drying under reduced pressure. 1 H NMR (500 MHz, Chloroform-d) δ 8.14 (t, J = 7.9 Hz, 1H), 7.65 (d, J = 7.2 Hz, 2H), 7.54-7.49 (m, 3H), 7.48-7.41 (m, 2H). LC / MS(ESI) m / z: 217.2 [M+H] + .

[0341] Preparation Example 6: 2-amino-[1,1'-biphenyl]-4-carbonyl chloride

[0342] Step 1: Synthesis of 2-amino-[1,1'-biphenyl]-4-carboxylic acid

[0343]

[0344] 3-amino-4-bromobenzoic acid (5.0 g, 23.2 mmol), 5% Pd / C (255 mg, 0.45 mmol), K2CO3 (12.8 g, 92.6 mmol), and phenylboronic acid (3.2 g, 25.5 mmol) were added to a sealed tube. Distilled water (46 mL, 0.5 M) was added and stirred at 100°C for 12 hours. The reaction mixture was cooled to room temperature, filtered through a Celite plug, and washed with distilled water (2 × 20 mL). The solution was slowly acidified with a 1 N citric acid solution, and the precipitate was filtered and dried to obtain intermediate F (3.5 g, yield 71%). 1 H NMR (300 MHz, DMSO-d6) δ 12.69 (s, 1H), 7.47 (d, J = 6.5 Hz, 4H), 7.41-7.34 (m, 2H), 7.21 (dd, J = 7.9, 1.6 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 5.04(s, 2H).

[0345] Step 2: Synthesis of 2-amino-[1,1'-biphenyl]-4-carbonyl chloride

[0346]

[0347] Thionyl chloride (3.5 mL, 48.1 mmol) was added to a solution of 2-amino-[1,1'-biphenyl]-4-carboxylic acid (2.5 g, 11.73 mmol) mixed in ethyl acetate (39 mL, 0.3 M) while stirring. The reaction mixture was refluxed and stirred for 4 hours, then cooled to room temperature and concentrated under reduced pressure to obtain intermediate F (2.95 g).

[0348] Preparation Example 7: (2'-methoxy-[1,1'-biphenyl]-4-yl)methanol

[0349] Step 1: Synthesis of Methyl 2'-Methoxy-[1,1'-Biphenyl]-4-Carboxylate

[0350]

[0351] A mixed solution of 4-(methoxycarbonylphenyl)boronic acid (1.08 g, 6 mmol), Na2CO3 (1.91 g, 18 mmol), Pd(OAc)2 (0.269 g, 1.2 mmol), and PPh3 (0.63 g, 2.4 mmol) was added to a stirred solution of 2-bromoanisole (0.75 mL, 6 mmol) in toluene (0.6 M), and the mixture was stirred at 100°C for 6 hours. The reaction mixture was extracted with ethyl acetate (20 mL × 3), the organic layer was washed with a saline solution, dried with Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane:ethyl acetate = 97:3 to 95:5) to obtain methyl 2'-methoxy-[1,1'-biphenyl]-4-carboxylate (507 mg, yield 35%). 1 H NMR (500 MHz, CDCl3) δ 8.08 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.39 - 7.30 (m, 2H), 7.04 (s, 1H), 6.99 (d, J = 8.2 Hz, 1H), 3.93(d, J = 1.9 Hz, 3H), 3.81(s, 3H).

[0352] Step 2: Synthesis of (2'-methoxy-[1,1'-biphenyl]-4-yl)methanol

[0353]

[0354] Methyl 2'-methoxy-[1,1'-biphenyl]-4-carboxylate (507 mg, 2.09 mmol) was dissolved in THF (0.2 M), and LiAlH4 (397 mg, 10.5 mmol) was added and stirred for 3 hours. After cooling the reaction mixture to 0°C, distilled water (1.6 mL) and an aqueous NaOH solution were added, dried with Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane:ethyl acetate = 7:3) to obtain intermediate G (340 mg). 1H NMR (500 MHz, CDCl3) δ 7.55 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 7.9 Hz, 2H), 7.34 (d, J = 7.5 Hz, 2H), 7.05 (s, 1H), 7.01 (d, J = 8.0 Hz, 1H), 4.70(s, 2H), 3.81(s, 3H), 2.23(s, 1H).

[0355] Preparation Example 8: 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

[0356]

[0357] Bis(pinacolato)diborone (1.1 g, 4.4 mmol), KOAc (1.18 g, 12 mmol), and Pd(dppf)Cl2 (146.0 mg, 0.2 mmol) were added to a solution of 3-fluoro-5-bromoaniline (380 mg, 2.0 mmol) mixed in 1,4-dioxane (20.0 mL) under N2 atmosphere, and the mixture was stirred at 90°C for 32 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and washed with EtOAc. The organic layer was concentrated under reduced pressure to obtain intermediate H (1.4 g).

[0358] Preparation Example 9: 2-(3-fluoro-5-(methylthio)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan

[0359] Step 1: Synthesis of (3-bromo-5-fluorophenyl)(methyl)sulfane

[0360]

[0361] N,N A solution of 3,5-difluorobromobenzene (3 g, 15.54 mmol) mixed with dimethylformamide (30 mL) was cooled to 0°C, sodium thiomethoxide solution (7.1 mL, 15.54 mmol) was added, and the mixture was stirred for 30 minutes. The reaction mixture was diluted with distilled water and extracted with hexane, then washed with brine and dried over Na2SO4. The organic layer was concentrated under reduced pressure to obtain (3-bromo-5-fluorophenyl)(methyl)sulfane (2.6 g, yield 75%) as a clear liquid.

[0362] Step 2: Synthesis of 2-(3-fluoro-5-(methylthio)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan

[0363]

[0364] A sealed tube containing (3-bromo-5-fluorophenyl)(methyl)sulfan (1 g, 4.523 mmol), potassium acetate (2.2 g, 22.615 mmol), (pinacolato)diborone (1.7 g, 6.784 mmol), and Pd(dppf)Cl2 (complex with DCM; 369 mg, 0.452 mmol) was replaced under an N2 atmosphere, 1,4-dioxane was added, and the mixture was stirred at 80°C for 12 hours. After cooling the reaction mixture to room temperature, ethyl acetate was added, and the precipitate was removed by Celite filtration. The organic layer was concentrated under reduced pressure, and the crude product was purified by flash column chromatography (0% to 100% concentration hexane / ethyl acetate) to obtain intermediate I (932 mg, yield 70%) as a yellow liquid.

[0365] Preparation Example 10: 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

[0366] Step 1: Synthesis of 3-Bromo-5-Fluorobenzamide

[0367]

[0368] A solution of 3-bromo-5-fluorobenzoic acid (1 g, 4.566 mmol) mixed with thionyl chloride (4 mL) was stirred under reflux conditions for 2 hours. The reaction mixture solution was concentrated under reduced pressure, and 28% ammonia water (1.5 mL) was added and stirred for 12 hours. The reaction mixture was washed three times with distilled water to obtain 3-bromo-5-fluorobenzamide (533 mg, yield 54%) as a white solid. 1 H NMR (300 MHz, Chloroform-d) δ 7.74 - 7.72 (m, 1H), 7.49 - 7.45 (m, 1H), 7.44 - 7.40 (m, 1H), 5.83 (s, 2H).

[0369] Step 2: Synthesis of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

[0370]

[0371] Intermediate J was obtained by reacting 3-bromo-5-fluorobenzamide in the same manner as in Preparation Example 8.

[0372] Preparation Example 11: 3-Methoxy-5-(4,4,5,5-Tetramethyl-1,3,2-Dioxabololan-2-yl)benzamide

[0373]

[0374] Intermediate K was obtained in the same manner as in Preparation Example 10, except that 3-bromo-5-methoxybenzoic acid was used instead of 3-bromo-5-fluorobenzoic acid in Step 1. 1 ¹H NMR(300 MHz, DMSO- d 6) δ 8.03(s, 1H), 7.77(dd, J = 1.6, 0.9 Hz, 1H), 7.53(dd, J = 2.7, 1.6 Hz, 1H), 7.33(s, 1H), 7.27(dd, J = 2.7, 0.9 Hz, 1H), 3.81(s, 3H), 1.16(d, J = 2.6 Hz, 12H).

[0375] Preparation Example 12: tert-butyl(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate

[0376] Step 1: Synthesis of (3-Bromo-5-Methoxyphenyl)Methaneamine

[0377]

[0378] 3-bromo-5-methoxybenzonitrile (1 g, 4.716 mmol) was dissolved in THF (9 mL), and then BH3-THF (1 M in THF, 6 mL, 5.895 mmol) was slowly added at 0°C. The reaction mixture was stirred at 80°C for 16 hours, after which the solvent was concentrated under reduced pressure and acidified by adding 1 N HCl. The reaction mixture was stirred at room temperature for 2 hours, after which EA and distilled water were added to extract the aqueous layer. The aqueous layer was neutralized with 2 N NaOH (pH 10) and then extracted with EA and brine. The organic layer was concentrated under reduced pressure to obtain (3-bromo-5-methoxyphenyl)methaneamine (741 mg, yield 72%). 1¹H NMR(300 MHz, Chloroform- d ) δ 7.08 - 7.03(m, 1H), 6.92(t, J = 2.0 Hz, 1H), 6.83 - 6.79(m, 1H), 3.81(s, 2H), 3.78(s, 3H).

[0379] Step 2: Synthesis of tert-butyl(3-bromo-5-methoxybenzyl)carbamate

[0380]

[0381] (3-bromo-5-methoxyphenyl)methaneamine (741 mg, 3.429 mmol) and Boc2O (749 mg, 3.429 mmol) were dissolved in DCM. TEA (0.53 mL, 3.772 mmol) was added at 0°C and stirred for 16 hours. The DCM was partially concentrated and extracted with EA and brine. The organic layer was dried with MgSO4, concentrated under reduced pressure, and purified using a silica column (EA:hexane=1:3) to obtain tert-butyl(3-bromo-5-methoxybenzyl)carbamate (766 mg, yield 70%). 1 ¹H NMR(300 MHz, Chloroform- d ) δ 7.00(s, 1H), 6.94(t, J = 2.1 Hz, 1H), 6.75(s, 1H), 4.84(s, 1H), 4.25(s, 2H), 3.78(s, 3H), 1.46(s, 9H).

[0382] Step 3: Synthesis of tert-butyl(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate

[0383]

[0384] Intermediate L was obtained by reacting tert-butyl(3-bromo-5-methoxybenzyl)carbamate in the same manner as in Preparation Example 8. 1 ¹H NMR(300 MHz, Chloroform- d) δ 7.30(s, 1H), 7.22(s, 1H), 6.95(s, 1H), 4.79(s, 1H), 4.29(s, 2H), 3.82(s, 3H), 1.46(s, 9H), 1.34(s, 12H).

[0385] Preparation Example 13: 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol

[0386] Step 1: Synthesis of (3-bromo-5-fluorophenyl)methanol

[0387]

[0388] 3-bromo-5-fluorobenzoic acid (657.0 mg, 3.0 mmol) was added to THF (15.0 mL) and cooled to 0°C, and BH3·DMS (5 M, 1.2 mL, 6.0 mmol) was added over 15 minutes and stirred for 12 hours. The reaction mixture was cooled to 0°C and an excess amount of methanol was added. The solution diluted with ethyl acetate was washed with a 1 N aqueous sodium hydroxide solution and brine, dried over Na2SO4, and then concentrated under reduced pressure. The crude product was purified by column chromatography (0 to 30% EtOAc / Hexane) to obtain (3-bromo-5-fluorophenyl)methanol (400 mg, yield 65%). 1 H NMR (300 MHz, CDCl3) δ 7.33 - 7.28 (m, 1H), 7.17 (dt, J = 8.1, 2.1 Hz, 1H), 7.04 (ddd, J = 9.1, 2.4, 1.3 Hz, 1H), 4.69 (s, 2H).

[0389] Step 2: Synthesis of (3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol

[0390]

[0391] Intermediate M was obtained by reacting (3-bromo-5-fluorophenyl)methanol in the same manner as in Preparation Example 8.

[0392] Preparation Example 14: 3-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol

[0393] Step 1: Synthesis of 3-(3-bromo-5-methoxyphenyl)oxetan-3-ol

[0394]

[0395] TMEDA (923 μL, 6.0 mmol) and a solution of 1,3-dibromo-5-methoxybenzene (1.06 g, 4.0 mmol) in THF (0.2 M) mixed with n -BuLi (2.5 M in THF, 2.4 mL, 6.0 mmol) was added at -78°C and stirred for 1 hour. Oxetanone (1.02 mL, 4.8 mmol) was added to the reaction mixture and slowly heated to room temperature. After 4 hours, the resulting mixture was diluted with an aqueous NH4Cl solution (40 mL) and ethyl acetate (40 mL), and the aqueous layer was extracted with ethyl acetate (40 mL). The organic layer was dried with Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane:ethyl acetate = 1:2) to obtain 3-(3-bromo-5-methoxyphenyl)oxetan-3-ol as a colorless oil (443.0 mg as a mixture, approx. 320.0 mg, yield 31%). 1 H NMR (500 MHz, CDCl3) δ 7.34 (s, 1H), 7.07 (d, J = 2.0 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H), 4.86 (d, J = 6.8 Hz, 2H), 4.83 (d, J = 7.0 Hz, 2H), 3.80(s, 4H).

[0396] Step 2: Synthesis of 3-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol

[0397]

[0398] Intermediate N was obtained by reacting 3-(3-bromo-5-methoxyphenyl)oxetan-3-ol in the same manner as in Preparation Example 8. 1 H NMR (500 MHz, CDCl3) δ 7.57(s, 1H), 7.27(d, J = 2.6 Hz, 1H), 7.19(dd, J = 2.6, 1.8 Hz, 1H), 4.94(d, J = 6.9 Hz, 2H), 4.87(d, J = 6.8 Hz, 2H), 3.84(s, 3H), 1.33(s, 12H).

[0399] Preparation Example 15: 1-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine-2-one

[0400] Step 1: Synthesis of 1-(3-methoxyphenyl)azetidine-2-one

[0401]

[0402] In a solution mixed with 1-iodo-3-methoxybenzene (936.1 mg, 4.0 mmol) in toluene (0.8 M), azetidinone (340.0 mg, 4.8 mmol), CuI (38.1 mg, 0.2 mmol), K2CO3 (1.1 g, 8.0 mmol) and N,N'- Dimethylethylenediamine (43 μL, 0.4 mmol) was added and stirred at 140°C for 24 hours. The reaction mixture was cooled to room temperature and diluted with brine (20 mL) and ethyl acetate (20 mL), and the aqueous layer was extracted with ethyl acetate (20 mL). The organic layer was dried with Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane:ethyl acetate = 2:1) to obtain 1-(3-methoxyphenyl)azetidin-2-one (436.0 mg, yield 61%) as a colorless oil (436.0 mg, 61%). 1 H NMR (500 MHz, CDCl3) δ 7.14 (t, J = 8.1 Hz, 1H), 6.92 (s, 1H), 6.78 (dd, J = 8.1, 1.9 Hz, 1H), 6.56 (dd, J = 8.4, 2.5 Hz, 1H), 3.72 (s, 3H), 3.48(t, J = 4.5 Hz, 2H), 2.98(d, J = 4.5 Hz, 2H).

[0403] Step 2: 1-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine-2-one

[0404]

[0405] [Ir(cod)OMe]2 (195.7 mg, 0.295 mmol), 4,4'-di-tert-butyl-2'2-bipyridine (btbpy) (158.5 mg, 0.590 mmol), bis(pinacolato)diborone (1.25 g, 4.90 mmol), and BpinH (42.8 μL, 0.295 mmol) were added to a solution of 1-(3-methoxyphenyl)azetidine-2-one (436.0 mg, 2.46 mmol) in cyclohexane (0.1 M), and the mixture was stirred at 80°C for 24 hours. The reaction mixture was cooled to room temperature and diluted with brine (40 mL) and ethyl acetate (40 mL), after which the aqueous layer was extracted with ethyl acetate (40 mL). The organic layer was dried with Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane:ethyl acetate = 1:1) to obtain intermediate O (405.2 mg, yield 54%) as a yellow solid. 1 H NMR (500 MHz, CDCl3) δ 7.32 (t, J = 2.3 Hz, 1H), 7.05 (d, J = 2.5 Hz, 1H), 7.04 (d, J = 1.9 Hz, 1H), 3.81 (s, 3H), 3.62 (t, J = 4.5 Hz, 2H), 3.07(t, J = 4.5 Hz, 2H).

[0406] Preparation Example 16: tert-butyl (3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate

[0407]

[0408]

[0409] Intermediate P was obtained in the same manner as in Preparation Example 12, except that 3-bromo-5-fluorobenzonitrile was used instead of 3-bromo-5-methoxybenzonitrile in Step 1 of Preparation Example 12.

[0410] Preparation Example 17: tert-butyl 3-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine-1-carboxylate

[0411] Step 1: Synthesis of tert-butyl 3-(3-bromo-5-fluorophenyl)azetidine-1-carboxylate

[0412]

[0413] Tert-butyl 3-(2-((4-methoxyphenyl)sulfonyl)hydrazineylidene)azetidine-1-carboxylate (1.0 g, 2.8 mmol), 3-bromo-5-fluorophenylboronic acid (1.23 g, 5.6 mmol), and cesium carbonate (1.83 g, 5.6 mmol) were added to 1,4-dioxane (10.0 mL, 0.3 M). The tube was sealed and stirred at 110°C for 15 hours. The reaction mixture was cooled to room temperature, quenched with a saturated aqueous solution of NaHCO3 (30 mL), dried with MgSO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography (10-30% EtOAc / hexane) to obtain tert-butyl 3-(3-bromo-5-fluorophenyl)azetidine-1-carboxylate (261 mg, 28%). 1 H NMR (300 MHz, Chloroform-d) δ 7.28 (d, J = 3.8 Hz, 1H), 7.16 (dt, J = 8.1, 2.0 Hz, 1H), 7.00 (dt, J = 9.3, 1.8 Hz, 1H), 4.34 (t, J = 8.7 Hz, 2H), 3.93(dd, J = 8.7, 5.8 Hz, 2H), 3.69(d, J = 14.4 Hz, 1H), 1.49(s, 9H).

[0414] Step 2: Synthesis of tert-butyl 3-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine-1-carboxylate

[0415]

[0416] Intermediate Q was obtained by reacting tert-butyl 3-(3-bromo-5-fluorophenyl)azetidine-1-carboxylate in the same manner as in Preparation Example 8. 1H NMR (300 MHz, Chloroform-d) δ 7.50(s, 1H), 7.39(dd, J = 8.7, 2.2 Hz, 1H), 7.14(dt, J = 9.8, 2.1 Hz, 1H), 4.34(t, J = 8.7 Hz, 2H), 4.00(dd, J = 8.6, 6.0 Hz, 2H), 3.77(ddd, J = 12.8, 7.8, 5.1 Hz, 1H), 1.49(s, 9H), 1.37(s, 12H).

[0417] Preparation Example 18: Methyl 6-(methylamino)spiro[3,3]heptane-2-carboxylate hydrochloride

[0418] Step 1: Synthesis of methyl 6-((tert-butoxycarbonyl)(methyl)amino)spiro[3,3]heptane-2-carboxylate

[0419]

[0420] 60% NaH (60 mg, 1.50 mmol) was added to a stirred solution of methyl 6-((tert-butoxycarbonyl)amino)spiro[3.3]heptane-2-carboxylate (269 mg, 1.0 mmol) in THF (0.1 M) and stirred at 0°C for 15 minutes, and iodomethane (0.2 mL, 3.0 mmol) was added to the reaction mixture and stirred for 20 hours. The reaction mixture was quenched with cold distilled water and extracted with ethyl acetate (20 mL). The organic layer was washed with distilled water and brine, dried with Na2SO4, and then concentrated under reduced pressure to obtain methyl 6-((tert-butoxycarbonyl)(methyl)amino)spiro[3.3]heptane-2-carboxylate (288 mg, crude product) as a yellow liquid. 1 H NMR (400 MHz, chloroform-d) δ 4.6-4.14(m, 1H), 3.69(s, 3H), 3.05(p, J = 8.5 Hz, 1H), 2.39-2.25(m, 1H), 2.2-2.00(m, 1H), 1.47(s, 9H).

[0421] Step 2: Synthesis of Methyl 6-(methylamino)spiro[3,3]heptane-2-carboxylate hydrochloride

[0422]

[0423] A 4 N HCl (in dioxane) solution was added to methyl 6-((tert-butoxycarbonyl)(methyl)amino)spiro[3.3]heptane-2-carboxylate (288 mg, 1.02 mmol) at 0°C and stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure to obtain the hydrochloride (244 mg) of intermediate R as a yellow solid. 1 H NMR (400 MHz, DMSO) δ 9.07 (s, 2H), 3.59 (s, 2H), 3.53-3.39 (m, 1H), 3.22-2.78 (m, 1H), 2.37 (s, 3H), 2.34-2.23 (m, 2H), 2.24-2.01(m, 6H).

[0424] Preparation Example 19: 4-(((tert-butyldimethylsilyl)oxy)methyl)-2,5-dimethylthiophene-3-carboxylic acid

[0425] Step 1: Synthesis of 4-Bromo-2,5-Dimethylthiophene-3-Carbaldehyde

[0426]

[0427] In a solution mixed with 3,4-dibromo-2,5-dimethylthiophene (6.37 g, 23.6 mmol) and TMEDA (3.9 mL, 26 mmol) in THF (0.4 M) n -BuLi (2.5 M in THF, 9.4 mL, 23.6 mmol) was added at -78°C and stirred for 1 hour. After adding DMF to the reaction mixture, the mixture was slowly heated to room temperature and stirred for 15 hours. The reaction mixture was quenched with distilled water (20 mL), acidified with a 1 N HCl solution, and then extracted with ethyl acetate. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure to obtain 4-bromo-2,5-dimethylthiophene-3-carbaldehyde (3.64 g) as an off-white solid. 1 H NMR (300 MHz, CDCl3) δ 10.03(s, 0H), 2.74(s, 1H), 2.38(s, 1H).

[0428] Step 2: Synthesis of (4-bromo-2,5-dimethylthiophene-3-yl)methanol

[0429]

[0430] LiAlH4 (191 mg, 5.02 mmol) was added at 0°C to a solution of 4-bromo-2,5-dimethylthiophene-3-carbaldehyde (1.10 g, 5.02 mmol) in THF (0.2 M) and stirred for 2 hours. The reaction mixture was quenched with EtOAc (1 mL) and ice water (0.3 mL) and stirred for 30 minutes, then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (20% EtOAc in Hexane) to obtain (4-bromo-2,5-dimethylthiophene-3-yl)methanol (754 mg, yield 68%) as a colorless liquid. 1 H NMR (400 MHz, DMSO); δ 4.33(s, 1H), 2.40(s, 3H), 2.36(s, 1H), 2.30(s, 3H).

[0431] Step 3: Synthesis of ((4-bromo-2,5-dimethylthiophene-3-yl)methoxy)(tert-butyl)dimethylsilane

[0432]

[0433] Tert-butyldimethylsilyl chloride (777 mg, 5.16 mmol) and imidazole (439 mg, 6.44 mmol) were added to a mixed solution of (4-bromo-2,5-dimethylthiophene-3-yl)methanol solution (950 mg, 4.30 mmol) in THF (0.2 M, 0°C) and stirred for 24 hours. The reaction mixture was diluted with EtOAc (20 mL) and washed with distilled water (20 mL, twice). The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (5% EtOAc in Hexane) to obtain ((4-bromo-2,5-dimethylthiophene-3-yl)methoxy)(tert-butyl)dimethylsilane (937 mg, yield 65%) as a colorless liquid. 1 H NMR (300 MHz, chloroform-d) δ 4.60(s, 1H), 2.45(s, 2H), 2.35(s, 2H), 1.57(s, 1H), 0.94(s, 4H), 0.12(s, 3H).

[0434] Step 4: Synthesis of 4-(((tert-butyldimethylsilyl)oxy)methyl)-2,5-dimethylthiophene-3-carboxylic acid

[0435]

[0436] In a solution mixed with ((4-bromo-2,5-dimethylthiophene-3-yl)methoxy)(tert-butyl)dimethylsilane (335 g, 1.0 mmol) and TMEDA (165 μL, 1.10 mmol) in THF (0.2 M) n -BuLi (2.5 M in THF, 0.44 mL, 1.10 mmol) was added at -78°C and stirred for 1 hour. The reaction mixture was quenched with CO2 gas at -78°C, then slowly heated to room temperature and stirred for 15 hours. The reaction mixture was quenched with distilled water (20 mL), acidified with a 1 N HCl solution, and then extracted with ethyl acetate. The organic layer was dried with Na2SO4, filtered, and then concentrated under reduced pressure. The crude product was purified by column chromatography (20% EtOAc in Hexane) to obtain intermediate S (300 mg) as a white solid. 1 ¹H NMR(300 MHz, chloroform- d ) δ 4.74(s, 2H), 2.67(s, 3H), 2.38(s, 3H), 0.94(s, 9H), 0.18(s, 6H).

[0437] Preparation Example 20: Methyl 3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylate

[0438] Step 1: Synthesis of Methyl(Z)-2-azido-3-(4-bromothiophene-2-yl)acrylate

[0439]

[0440] 4 M NaOMe (15 mL, 60.0 mmol) was added at -25°C to a solution mixed with 4-bromothiophene-2-carbaldehyde (3.82 g, 20.0 mmol, 1.0 equivalent) and intermediate B (6.91 g, 60.0 mmol, 3.0 equivalent) in MeOH (30 mL), and stirred at 0°C for 2 hours. Ice was added to the reaction mixture, and after washing with distilled water and filtering, the reaction product was dried to obtain methyl(Z)-2-azido-3-(4-bromothiophene-2-yl)acrylate. 1 H NMR (300MHz, chloroform-d) δ 7.37(dd, J = 1.4, 0.7 Hz, 1H), 7.22(dd, J = 1.4, 0.6 Hz, 1H), 7.03(d, J = 0.7 Hz, 1H), 3.90(s, 3H).

[0441] Step 2: Synthesis of Methyl 3-Bromo-4H-Thieno[3,2-b]pyrrole-5-carboxylate

[0442]

[0443] A solution of methyl(Z)-2-azido-3-(4-bromothiophene-2-yl)acrylate (4.79 g, 16.6 mmol, 1.0 equivalent) in o-xylene (60 mL) was stirred at 160°C for 1 hour. The reaction mixture was partially concentrated and filtered, then washed with hexane and dried to obtain intermediate T. 1 H NMR (300 MHz, chloroform-d) δ 9.10 (s, 1H), 7.23 (s, 1H), 7.15 (d, J = 1.9 Hz, 1H), 3.93 (s, 3H).

[0444] Preparation Example 21: Methyl 3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate

[0445] Step 1: Preparation of 4-Bromo-5-methylthiophene-2-carbaldehyde

[0446]

[0447] Bromine (1.7 mL, 33 mmol) was added to a solution of 5-methylthiophene-2-carbaldehyde (2.78 g, 22.0 mmol) mixed in THF (0.5 M) at 0°C and stirred for 25 hours. A 10% aqueous solution of Na2S2O3 (30 mL) and a 10% aqueous solution of NaHCO3 (30 mL) were added to the reaction mixture and extracted with EtOAc (150 mL). The organic phase was dried on the Na2SO4 phase and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain a colorless solid of 4-bromo-5-methylthiophene-2-carbaldehyde (862 mg, yield 16%). 1 ¹H NMR(300MHz, chloroform-d) δ 9.80(s, 1H), 7.62(s, 1H), 2.51(s, 3H).

[0448] Step 2: Preparation of Methyl(Z)-2-azido-3-(4-bromo-5-methylthiophene-2-yl)acrylate

[0449]

[0450] 4 M NaOMe (3 mL, 11.6 mmol) and intermediate B (1.43 g, 12.4 mmol) were added to a 1.5 M MeOH solution mixed with 4-bromo-5-methylthiophene-2-carbaldehyde (850 mg, 4.14 mmol) at -25°C. The reaction mixture was stirred at 0°C for 2 hours, then diluted with EtOAc and washed with a saline solution. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain a yellow solid methyl(Z)-2-azido-3-(4-bromo-5-methylthiophene-2-yl)acrylate (813 mg, yield 65%). 1 ¹H NMR(300MHz, chloroform-d) δ 7.15(s, 1H), 6.99(s, 1H), 3.91(s, 3H), 2.45(s, 3H).

[0451] Step 3: Preparation of methyl 3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate

[0452]

[0453] oMethyl(Z)-2-azido-3-(4-bromo-5-methylthiophene-2-yl)acrylate (795 mg, 2.63 mmol) mixed with 4 mL of xylene was added to xylene (5 mL) over a period of 10 minutes. After refluxing and stirring for 1 hour, the reaction mixture was cooled to room temperature and partially concentrated. The solid was filtered to obtain intermediate U (554 mg, yield 77%), which is an off-white solid. 1 ¹H NMR(300 MHz, chloroform-d) δ 8.99(s, 1H), 7.10(d, J = 1.9 Hz, 1H), 3.93(s, 3H), 2.50(s, 3H).

[0454] Preparation Example 22: Ethyl 3-bromo-6-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate

[0455] Step 1: Synthesis of 1-(3,4-dibromothiophene-2-yl)ethane-1-one

[0456]

[0457] 3,4-dibromothiophene (1.2 g, 5.0 mmol) was added to a solution of AlCl3 (1.33 g, 10.0 mmol, 2.0 equivalents) mixed in DCM (20 mL) at 0°C and stirred for 10 minutes. Acetyl chloride (360 μL, 5.0 mmol, 1.0 equivalent) was added and stirred at 0°C for 3 hours. The reaction mixture was acidified by adding 6 M HCl and extracted with DCM. The organic layer was dried with MgSO4 and then concentrated under reduced pressure to obtain 1-(3,4-dibromothiophene-2-yl)ethane-1-one. 1 H NMR (300 MHz, Chloroform-d) δ 7.63(s, 1H), 2.72(s, 3H).

[0458] Step 2: Synthesis of ethyl 3-bromo-6-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate

[0459]

[0460] A solution of 1-(3,4-dibromothiophene-2-yl)ethane-1-one (1.42 g, 5.0 mmol), ethyl isocyanoacetate (600 μL, 5.5 mmol, 1.1 equivalents), CuI (95 mg, 0.5 mmol, 0.1 equivalents), and Cs2CO3 (3.26 g, 10.0 mmol, 2.0 equivalents) mixed in DMSO (5 mL) was stirred at 50°C for 4 hours. Distilled water was added to the reaction mixture and extracted with DCM. The organic layer was dried with MgSO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography to obtain intermediate V (806 mg, yield 56%). 1 H NMR (300 MHz, Chloroform-d) δ 9.01 (s, 1H), 7.18 (s, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H).

[0461] Preparation Example 23: Methyl 3-bromo-2-chloro-4H-thieno[3,2-b]pyrrole-5-carboxylate

[0462] Step 1: Synthesis of 4-Bromo-5-Chlorothiophen-2-Carvaldehyde

[0463]

[0464] In a solution mixed with 4-bromothiophene-2-carbaldehyde (500 mg, 2.62 mmol, 1.0 equivalent) in DMF (5 mL) N -Chlorosuccinimide (699 mg, 5.24 mmol) was added and stirred at 70°C for 12 hours. Distilled water was added to the reaction mixture, and the solid was filtered, washed with distilled water, and dried to obtain 4-bromo-5-chlorothiophene-2-carbaldehyde (421 mg, yield 70%). 1 H NMR (300 MHz, Chloroform-d) δ 9.76(s, 1H), 7.60(s, 1H).

[0465] Steps 2 and 3: Synthesis of methyl 3-bromo-2-chloro-4H-thieno[3,2-b]pyrrole-5-carboxylate

[0466]

[0467] Intermediate W was obtained by reacting 4-bromo-5-chlorothiophene-2-carbaldehyde in the same manner as in Preparation Example 20. 1 H NMR (300 MHz, Chloroform-d) δ 9.04 (s, 1H), 7.07 (d, J = 1.9 Hz, 1H), 3.92 (s, 3H).

[0468] Preparation Example 24: 4'-(bromomethyl)-3-methoxy-1,1'-biphenyl

[0469] Step 1: Synthesis of (3'-methoxy-[1,1'-biphenyl]-4-yl)methanol

[0470]

[0471] 3-bromoanisole (935 mg, 5 mmol), 4-(hydroxymethyl)phenylboronic acid (912 mg, 6 mmol), Na2CO3 (1.3 g, 12.5 mmol), and Pd(PPh3)4 (289 mg, 0.25 mmol) were dissolved in a mixture of H2O and DME and stirred at 85°C for 24 hours. After cooling the reaction mixture to room temperature, it was filtered with Celite and extracted with EA and brine, and the organic layer was dried with MgSO4. The crude product was purified using a silica gel column (EtOAc:Hexane = 1:2) to obtain (3'-methoxy-[1,1'-biphenyl]-4-yl)methanol (1.00 g, yield 93%) as a yellow oil. 1 ¹H NMR(300 MHz, Chloroform- d ) δ 7.59(d, J = 8.2 Hz, 2H), 7.44(d, J = 8.2 Hz, 2H), 7.36(t, J = 7.9 Hz, 1H), 7.21-7.16(m, 1H), 7.12(t, J = 2.1 Hz, 1H), 6.90(ddd, J = 8.1, 2.6, 0.9 Hz, 1H), 4.75(s, 2H), 3.87(s, 3H).

[0472] Step 2: Synthesis of 4'-(bromomethyl)-3-methoxy-1,1'-biphenyl

[0473]

[0474] (3'-methoxy-[1,1'-biphenyl]-4-yl)methanol (1.00 g, 4.667 mmol) and CBr4 (1.7 g, 5.134 mmol) were dissolved in DCM (16 mL) and stirred at 0°C for 10 minutes. PPh3 (1.35 g, 5.134 mmol) was slowly added and stirred for 40 minutes. The organic layer was concentrated under reduced pressure and purified using a silica gel column (EtOAc:Hexane=1:25) to obtain intermediate X (1.14 g, yield 88%). 1 ¹H NMR(300 MHz, Chloroform- d ) δ 7.57(d, J = 8.3 Hz, 2H), 7.47(d, J = 8.3 Hz, 2H), 7.37(t, J = 7.9 Hz, 1H), 7.20 - 7.15(m, 1H), 7.13 - 7.11(m, 1H), 6.94 - 6.89(m, 1H), 4.56(s, 2H), 3.87(s, 3H).

[0475] Preparation Example 25: 4'-(bromomethyl)-3-fluoro-5-methoxy-1,1'-biphenyl

[0476]

[0477] Intermediate Y was obtained using (4-bromophenyl)methanol and (3-fluoro-5-methoxyphenyl)boronic acid as starting materials in the same manner as in Preparation Example 24. 1 H NMR (300 MHz, Chloroform-d) δ 7.59 - 7.54 (m, 2H), 7.51 - 7.46 (m, 2H), 6.90 (dd, J = 9.2, 2.2 Hz, 2H), 6.64 (dt, J = 10.5, 2.3 Hz, 1H), 4.57(s, 2H), 3.88(s, 3H).

[0478] Preparation Example 26: Methyl(2R,4R,6R)-6-aminospiro[3,3]heptane-2-carboxylate hydrochloride

[0479] Step 1: Synthesis of Methyl 6-(((benzyloxy)carbonyl)amino)spiro[3,3]heptane-2-carboxylate

[0480]

[0481] Intermediate A (3 g, 14.58 mmol) and benzyl chloroformate (3.1 mL, 21.87 mmol) were dissolved in DCM (0.5 M), and DIPEA (7.62 mL, 43.75 mmol) was slowly added at 0°C and stirred at room temperature for 14 hours. The reaction mixture was extracted with an aqueous NH4Cl solution and DCM, after which the organic layer was dried with MgSO4 and concentrated under reduced pressure. The crude product was purified using a silica gel column (EtOAc:Hexane=1:1) to obtain methyl 6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptane-2-carboxylate (4.4 g, yield 99%). 1 H NMR (300 MHz, CDCl3) δ 7.40 - 7.28 (m, 5H), 5.06 (s, 2H), 4.84 (d, J = 8.3 Hz, 1H), 4.11-3.97 (m, 1H), 3.65 (s, 3H), 3.01 (p, J = 8.5) Hz, 1H), 2.50(dt, J = 12.0, 6.6 Hz, 1H), 2.43-2.21(m, 4H), 2.12(ddd, J = 11.7, 8.7, 2.8 Hz, 1H), 1.84(ddd, J = 15.9, 11.3, 8.7 Hz, 2H).

[0482] Step 2: Purification of methyl 6-(((benzyloxy)carbonyl)amino)spiro[3,3]heptane-2-carboxylate

[0483]

[0484] Methyl 6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptane-2-carboxylate (4.34 g) was purified by supercritical fluid chromatography (SFC) under the following conditions, and compounds of methyl(2S, 4S, 6S)-6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptane-2-carboxylate (2.99 g) and methyl(2R, 4R, 6R)-6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptane-2-carboxylate (0.88 g) were each separated as yellow oils.

[0485] Column: Daicel ChiralPak IG mobile phase (250 mm × 4.6 mm, 1 µm)

[0486] Mobile phase: [Hexane / EtOH]; 80 / 20(V / V), 9.4 min(2S, 4S, 6S), 10.7 min(2R, 4R, 6R)

[0487] Step 3: Synthesis of Methyl(2R,4R,6R)-6-aminospiro[3,3]heptane-2-carboxylate hydrochloride

[0488]

[0489] Methyl(2R, 4R, 6R)-6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptane-2-carboxylate (312 mg, 1.03 mmol) was dissolved in MeOH (10.3 mL, 0.1 M), and 10% Pd / C (110 mg, 0.1 equivalent) was added. The reaction mixture was purged under H2 atmosphere and stirred for 16 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure. 1,4-dioxane (10.3 mL, 0.1 M) and 4 N HCl solution (0.8 mL, 3.09 mmol) were added to the concentrated reaction mixture and stirred for an additional 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain intermediate Z (180 mg).

[0490] Preparation Example 27: 4'-(bromomethyl)-3,5-dimethoxy-1,1'-biphenyl

[0491]

[0492] Intermediate AA was obtained using 1-bromo-3,5-dimethoxybenzene and ((4-hydroxy)methylphenyl)boronic acid as starting materials in the same manner as in Preparation Example 24. 1 ¹H NMR(300 MHz, Chloroform- d ) δ 7.55(d, J = 8.3 Hz, 2H), 7.45(d, J = 8.3 Hz, 2H), 6.71(d, J = 2.2 Hz, 2H), 6.48(t, J = 2.2 Hz, 1H), 4.55(s, 2H), 3.85 (s, 6H).

[0493] Preparation Example 28: 4-(2-bromoethyl)-1,1'-biphenyl

[0494] Step 1: Synthesis of 2-([1,1'-biphenyl]-4-yl)ethanol-1-ol

[0495]

[0496] LiAlH in a solution of 2-([1,1'-biphenyl]-4-yl)acetic acid (559 mg, 3 mmol) in THF (7 mL) 4( 1 M in THF, 9.0 mL, 3.0 equivalents) was added at 0°C and stirred at 75°C for 4 hours, after which 1 N NaOH was carefully added and quenched. The reaction mixture was filtered through Celite, the filtrate was poured into distilled water and extracted with EtOAc. The organic layer was dried with MgSO4 and then concentrated under reduced pressure to obtain 2-([1,1'-biphenyl]-4-yl)ethanol-1-ol (522 mg, yield 87%). 1 H NMR (300 MHz, Chloroform-d) δ 7.62-7.52 (m, 2H), 7.49-7.40 (m, 1H), 7.39-7.29 (m, 2H), 3.91 (t, J = 6.5 Hz, 1H), 2.92 (t, J = 6.5 Hz, 1H).

[0497] Step 2: Synthesis of 4-(2-bromoethyl)-1,1'-biphenyl

[0498]

[0499] CBr4 (1.02 g, 3.1 mmol, 1.1 equivalents) was added to a solution of 2-([1,1'-biphenyl]-4-yl)ethanol-1-ol (522 mg, 2.8 mmol, 1.0 equivalents) in DCM (12 mL) at 0°C and stirred for 15 minutes, then PPh3 (813 mg, 3.1 mmol, 1.1 equivalents) was added and stirred for 40 minutes. The precipitated solid was filtered to obtain the intermediate BB (639 mg, yield 87%). 1 ¹H NMR(300 MHz, Chloroform- d ) δ 7.61-7.53(m, 4H), 7.48-7.40(m, 2H), 7.38-7.29(m, 3H), 3.91(t, J = 6.5 Hz, 2H), 2.92(t, J= 6.5 Hz, 2H).

[0500] Preparation Example 29: 4'-(bromomethyl)-3-fluoro-1,1'-biphenyl

[0501] Step 1: Synthesis of (3'-fluoro-[1,1'-biphenyl]-4-yl)methanol

[0502]

[0503] (4-(hydroxymethyl)phenyl)boronic acid (1.04 g, 6.857 mmol), 1-bromo-3-fluorobenzene (1 g, 5.714 mmol), Na2CO3 (1.51 g, 14.285 mmol), and Pd(PPh3)4 (330 mg, 0.286 mmol) were dissolved in DME and H2O (2:1), heated to 85°C, and stirred for 24 hours. The reaction mixture was extracted with EA and distilled water, and the crude product was purified by flash column chromatography to obtain (3'-fluoro-[1,1'-biphenyl]-4-yl)methanol (1.26 g) as a white solid. 1 H NMR (300 MHz, Chloroform-d) δ 7.63-7.56 (m, 2H), 7.50-7.34 (m, 4H), 7.32-7.27 (m, 1H), 7.09-6.99 (m, 1H), 4.76 (s, 2H).

[0504] Step 2: Synthesis of 4'-(bromomethyl)-3-fluoro-1,1'-biphenyl

[0505]

[0506] (3'-fluoro-[1,1'-biphenyl]-4-yl)methanol (304 mg, 1.641 mmol) was dissolved in DCM, PBr3 (0.59 mL, 6.231 mmol) was added at 0°C and stirred for 2 hours, after which an additional 100 μL of PBr3 was added and stirred. After 4 hours, 1 mL of MeOH was added at 0°C, and the organic layer was concentrated under reduced pressure to obtain intermediate CC (1.7 g) as a white solid. 1H NMR (300 MHz, Chloroform-d) δ 7.59-7.53 (m, 2H), 7.51-7.45 (m, 2H), 7.43-7.26 (m, 3H), 7.08-7.02 (m, 1H), 4.55 (s, 2H).

[0507] Preparation Example 30: 2-(4-(bromomethyl)phenyl)pyrimidine

[0508]

[0509] Intermediate DD was obtained in the same manner as in Preparation Example 24, except that 2-bromopyridine was used instead of 3-bromoanisole in Step 1 of Preparation Example 24. 1 H NMR (300 MHz, chloroform-d) δ 8.81 (d, J = 4.9 Hz, 2H), 8.43 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.20 (t, J = 4.8 Hz, 1H), 4.56 (s, 2H).

[0510] Preparation Example 31: 5-(bromomethyl)-2-phenylpyrimidine

[0511] Step 1: Synthesis of (2-phenylpyrimidine-5-yl)methanol

[0512]

[0513] (2-chloropyrimidine-5-yl)methanol (1.156 g, 8 mmol), phenylboronic acid (1.463 g, 12 mmol), Pd(OAc)2 (179 mg, 0.8 mmol), Xphos (381 mg, 0.8 mmol), and Na2CO3 (2.199 g, 20 mmol) were dissolved in dioxane / H2O (4:1, 26 mL), then switched to an Ar atmosphere and stirred at 100°C for 12 hours. The reaction mixture was filtered via Celite and extracted with EA and brine. The organic layer was concentrated under reduced pressure and purified using a silica column (EtOAc:Hexane=1:1) to obtain (2-phenylpyrimidine-5-yl)methanol (661 mg, yield 44%). 1H NMR (300 MHz, Chloroform-d) δ 8.82 (s, 2H), 8.22-8.52 (m, 2H), 7.58-7.47 (m, 3H), 4.78 (s, 2H).

[0514] Step 2: Synthesis of 5-(bromomethyl)-2-phenylpyrimidine

[0515]

[0516] (2-phenylpyrimidine-5-yl)methanol (661 mg, 3.549 mmol) was dissolved in DCM (11 mL), and then CBr4 (1.412 g, 4.258 mmol) and PPh3 (1.116 g, 4.258 mmol) were added over 10 minutes at 0°C and stirred for 40 minutes. The reaction mixture was concentrated under reduced pressure and purified using a silica column (EA:hexane=1:9) to obtain the intermediate EE (762 mg, yield 86%). 1 H NMR (300 MHz, Chloroform-d) δ 8.82 (s, 2H), 8.43-8.46 (m, 2H), 7.49-7.51 (m, 3H), 4.48 (s, 2H).

[0517] Preparation Example 32: (3-bromoprop-1-phosphorus-1-yl)benzene

[0518]

[0519] PBr in a solution of (3-hydroxyprop-1-phosphorus-1-yl)benzene (10.0 g, 75.6 mmol, 9.43 mL, 1.00 equivalent) and DMF (276 mg, 3.78 mmol, 0.05 equivalent) in DCM (100 mL). 3(24.5 g (90.8 mmol, 1.20 equivalents) was added at 0°C and stirred for 1 hour. After cooling the reaction mixture to 0°C, distilled water (50 mL) was added to quench it, and it was extracted with DCM (50 mL twice). The organic layer was washed with an aqueous NaHCO3 solution (100 mL once) and brine (100 mL once), dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ether / ethyl acetate = 50 / 1 to 20 / 1) to obtain the intermediate FF (13.8 g, 70.7 mmol, yield 93.5%) as a colorless oil.

[0520] Preparation Example 33: (4-(pyridine-3-yl)phenyl)methanol

[0521]

[0522] (4-(hydroxymethyl)phenyl)boronic acid (1.154 g, 7.595 mmol), 3-bromopyridine (1 g, 6.329 mmol), Na2CO3 (1.68 g, 15.823 mmol), and Pd(PPh3)4 (366 mg, 0.316 mmol) were dissolved in DME / H2O (2:1) and stirred at 85°C for 12 hours. The reaction mixture was cooled to room temperature and extracted with EA and distilled water. The crude product was purified by flash column chromatography to obtain the intermediate GG (1.34 g) as a yellow solid. 1 H NMR (300 MHz, Chloroform-d) δ 8.82-8.81 (m, 1H), 8.61-8.59 (m, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.61-7.55 (m, 2H), 7.53-7.45 (m, 3H), 4.78(s, 2H).

[0523] Preparation Example 34: (4-(5-fluoropyridine-3-yl)phenyl)methanol

[0524]

[0525] Intermediate HH was obtained using the corresponding starting material in the same manner as in Preparation Example 33. 1H NMR (300 MHz, Chloroform-d) δ 8.63-8.61 (m, 1H), 8.45-8.44 (m, 1H), 7.65-7.45 (m, 5H), 4.78 (s, 2H).

[0526] Preparation Example 35: (4-(5-methoxypyridine-3-yl)phenyl)methanol

[0527]

[0528] Intermediate II was obtained using the corresponding starting material in the same manner as in Preparation Example 33. 1 H NMR (300 MHz, Chloroform-d) δ 8.49-8.48 (m, 1H), 8.30-8.29 (m, 1H), 7.67-7.65 (m, 1H), 7.60-7.50 (m, 4H), 4.79 (s, 2H), 3.99 (s, 3H).

[0529] Preparation Example 36: (4-(1-benzyl-1H-pyrazole-4-yl)phenyl)methanol

[0530]

[0531] (4-bromophenyl)methanol (1.49 g, 8 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.5 g, 12 mmol), Pd(PPh3)2Cl2 (561 mg, 0.8 mmol), and Na2CO3 (2.199 g, 20 mmol) were dissolved in THF / H2O (2:1, 16 mL), and after substitution under an Ar atmosphere, the mixture was stirred at 80°C for 6 hours. The reaction mixture was filtered via Celite, extracted with EA and brine, and dried with MgSO4. The intermediate JJ (948 mg, yield 63%) was obtained by purification using a silica gel column (EA:hexane=1:3). 1 H NMR (300 MHz, Chloroform-d) δ 7.76 (d, J = 0.8 Hz, 1H), 7.62 (d, J = 0.8 Hz, 1H), 7.43-7.50 (m, 2H), 7.31-7.41 (m, 2H), 4.69 (s, 2H), 3.95(s, 3H).

[0532] Preparation Example 37: (1-benzyl-1H-indole-5-yl)methanol

[0533] Step 1: Synthesis of Methyl 1-Benzyl-1H-Indole-5-Carboxylate

[0534]

[0535] To a solution in which methyl 1H-indole-5-carboxylate (2.80 g, 16 mmol) and benzyl bromide (2.1 mL, 17.6 mmol) were mixed in DMF (30 mL), NaH (460 mg, 19.2 mmol) was added gradually at 0°C and stirred at room temperature for 12 hours. The reaction mixture was extracted with EA and brine, and the organic layer was dried with MgSO4 and then concentrated under reduced pressure. The crude product was purified using a silica column (EA:hexane=1:9) to obtain methyl 1-benzyl-1H-indole-5-carboxylate (5.083 g, yield 78%). 1 H NMR (300 MHz, Chloroform-d) δ 8.42 (dd, J = 0.7, 1.7 Hz, 1H), 7.88 (dd, J = 1.7, 8.7 Hz, 1H), 7.25-7.35 (m, 4H), 7.19 (d, J = 3.2 Hz, 1H), 7.06-7.14(m, 2H), 6.65(dd, J = 0.9, 3.3 Hz, 1H), 5.35(s, 2H), 3.93(s, 3H).

[0536] Step 2: Synthesis of (1-benzyl-1H-indole-5-yl)methanol

[0537]

[0538] Methyl 1-benzyl-1H-indole-5-carboxylate (2.0 g, 7.538 mmol) was dissolved in THF (25 mL), LiAlH4 (1 M in THF, 22.6 mL, 22.615 mmol) was added at 0°C and stirred at 75°C for 4 hours. The organic layer was filtered through Celite, concentrated under reduced pressure, and purified by a silica column (EA:hexane=1:2) to obtain the intermediate KK (1.734 g, yield 97%). 1H NMR (300 MHz, Chloroform-d) δ 7.62(m, 1H), 7.22-7.31(m, 4H), 7.18 (dd, J = 1.7, 8.5 Hz, 1H), 7.04-7.11(m, 2H), 6.53(dd, J = 0.8, 3.1 Hz, 1H), 5.31(s, 2H), 4.74(s, 2H).

[0539] Preparation Example 38: (4-(pyridine-2-yl)phenyl)methanol

[0540]

[0541] Intermediate LL was obtained using the corresponding starting material in the same manner as in Preparation Example 33. 1 H NMR (300 MHz, chloroform-d) δ 8.73 (d, J = 4.9 Hz, 1H), 8.01 (d, J = 8.2 Hz, 2H), 7.88-7.73 (m, 2H), 7.49 (d, J = 8.2 Hz, 2H), 7.32-7.30 (m, 1H), 4.77(s, 2H).

[0542] Preparation Example 39: (6-phenylpyridine-3-yl)methanol

[0543]

[0544] Phenylboronic acid (914.5 mg, 7.5 mmol), Pd(OAc)2 (56.1 mg, 0.25 mmol), Xphos (238.4 mg, 0.5 mmol), and Na2CO2 were added to a solution of (6-bromopyridine-3-yl)methanol (940.1 mg, 5.0 mmol) mixed in 1,4-dioxane / H2O (0.25 M). 3( 1.59 g (15.0 mmol) was added and stirred at 100°C. After 18 hours, the reaction mixture was cooled to room temperature and diluted with brine (50 mL) and ethyl acetate (50 mL), and the aqueous layer was extracted with ethyl acetate (30 mL). The organic layer was dried with Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane:ethyl acetate = 3:7) to obtain the intermediate MM (618.6 mg, yield 67%) as a white solid.1 H NMR (500 MHz, CDCl3) δ 8.66 - 8.62 (m, 1H), 7.99 - 7.93 (m, 2H), 7.77 (dd, J = 8.1, 2.2 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.46 (t, J = 7.5) Hz, 2H), 7.43 - 7.36(m, 1H), 4.75(s, 2H).

[0545] Preparation Example 40: (4-pyridine-4-yl)phenyl)methanol

[0546]

[0547] Intermediate NN was obtained using the corresponding starting material in the same manner as in Preparation Example 33. 1 H NMR (300 MHz, Chloroform-d) δ 8.71 - 8.62 (m, 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.60 - 7.55 (m, 2H), 7.51 (d, J = 8.2 Hz, 2H), 4.79 (s, 2H).

[0548] Preparation Example 41: (4-(6-methoxypyridine-2-yl)phenyl)methanol

[0549]

[0550] Intermediate OO was obtained using the corresponding starting material in the same manner as in Preparation Example 39. 1 H NMR (300 MHz, Chloroform-d) δ 8.07 (d, J = 8.3 Hz, 2H), 7.69 - 7.62 (m, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 7.4 Hz, 1H), 6.72 (d, J = 8.2 Hz, 1H), 4.78(s, 2H), 4.06(s, 3H).

[0551] Preparation Example 42: (4-(4-methoxypyridine-2-yl)phenyl)methanol

[0552]

[0553] Intermediate PP was obtained using the corresponding starting material in the same manner as in Preparation Example 33. 1H NMR (300 MHz, Chloroform-d) δ 8.63 (d, J = 6.3 Hz, 1H), 8.02 (d, J = 8.2 Hz, 2H), 7.52 (d, J = 8.2 Hz, 3H), 7.30 (d, J = 2.5 Hz, 1H), 6.97 (dd, J = 6.3, 2.5 Hz, 1H), 4.78(s, 2H), 4.03(s, 3H).

[0554] Preparation Example 43: (6-(3-fluoro-5-methoxyphenyl)pyridine-3-yl)methanol

[0555]

[0556] Intermediate QQ was obtained using the corresponding starting material in the same manner as in Preparation Example 39. 1 H NMR (300 MHz, DMSO-d6) δ 8.63-8.60 (m, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.82 (dd, J = 8.1, 2.0 Hz, 1H), 7.53-7.45 (m, 2H), 6.94-6.86 (m, 1H), 5.39(s, 1H), 4.58(d, J = 5.6 Hz, 2H), 3.86(s, 3H).

[0557] Preparation Example 44: (4-(4-methyl-1H-pyrazole-1-yl)phenyl)methanol

[0558]

[0559] (4-iodophenyl)methanol (234 mg, 1 mmol), 4-methyl-1H-pyrazole (121 µL, 1.5 mmol), Cs2CO3 (651 mg, 2 mmol), and Cu(OAc)2 (18 mg, 0.1 mmol) were dissolved in DMF (5 mL), and the mixture was placed under an Ar atmosphere and stirred at 100°C for 12 hours. The reaction mixture was extracted with EA and brine, the organic layer was dried with MgSO4, and concentrated under reduced pressure. The mixture was purified by silica chromatography (EA:hexane = 1:3) to obtain the intermediate RR (191 mg, mixture). LC / MS(ESI) m / z: 189.1 [M+H].

[0560] Preparation Example 45: (4-(3-methyl-5-(trifluoromethyl)-1H-pyrazole-1-yl)phenyl)methanol

[0561]

[0562] 3-methyl-5-(trifluoromethyl)-1H-pyrazole (353 mg, 2.35 mmol), (4-iodophenyl)methanol (500 mg, 2.136 mmol), K2CO3 (590 mg, 4.272 mmol), CuI (41 mg, 0.214 mmol), N,N Dimethylglycine (44 mg, 0.427 mmol) was dissolved in DMSO and heated to 130°C and stirred for 24 hours. The reaction mixture was cooled to room temperature and extracted with EA and distilled water, after which the crude product was purified by flash column chromatography to obtain the intermediate SS (562 mg, yield 99%) as a clear liquid. 1 H NMR (300 MHz, Chloroform-d) δ 7.54 - 7.40 (m, 4H), 6.46 (s, 1H), 4.78 (d, J = 5.9 Hz, 2H), 2.35 (d, J = 0.7 Hz, 3H), 1.87 (t, J = 5.9 Hz, 1H).

[0563] Preparation Example 46: (5-(3-fluoro-5-methoxyphenyl)pyridine-2-yl)methanol

[0564]

[0565] Intermediate TT was obtained using the corresponding starting material in the same manner as in Preparation Example 39. 1 H NMR (300 MHz, DMSO-d6) δ 8.83 (d, J = 2.1 Hz, 1H), 8.13 (dd, J = 8.2, 2.4 Hz, 1H), 7.55 (d, J = 8.2 Hz, 1H), 7.22 - 7.12 (m, 2H), 6.88 (dt, J = 11.0, 2.2 Hz, 1H), 5.49(t, J = 5.9 Hz, 1H), 4.62(d, J = 5.9 Hz, 2H), 3.85(s, 3H).

[0566] [Example]

[0567] Example 1: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0568] Step 1: Synthesis of [1,1'-biphenyl]-4-yl(2,5-dimethylthiophene-3-yl)methanene

[0569]

[0570] SOCl2 (4.9 g, 41.0 mmol) was added at 0°C to a solution of [1,1'-biphenyl]-4-carboxylic acid (7.8 g, 39.3 mmol) and DMF (approx. 0.1 mL) mixed in PhCl2 (45 mL, 0.8 M), and the reaction mixture was heated to 50°C and stirred for 1 hour. After 1 hour, the mixture was cooled to room temperature, and dimethylthiophene (4.1 mL, 35.7 mmol) was added. The reaction mixture solution was cooled to 0°C, and 1 M TiCl4 solution (35.7 mL, 35.7 mmol) was added. After 1 hour, 1 N HCl solution was added to acidify the reaction mixture, and it was extracted with heptane. The mixed extract was dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to obtain [1,1'-biphenyl]-4-yl(2,5-dimethylthiophene-3-yl)methanene (3.31 g, yield 32%). 1 H NMR (500 MHz, chloroform-d) δ 7.90 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 7.1 Hz, 2H), 7.51 (t, J = 7.5 Hz, 2H), 7.43 (t, J = 7.4 Hz, 1H), 6.85(s, 1H), 2.63(s, 3H), 2.46(s, 3H). LC / MS(ESI) m / z: 293.7 [M+H] + .

[0571] Step 2: Synthesis of [1,1'-biphenyl]-4-yl(4-bromo-2,5-dimethylthiophene-3-yl)methanene

[0572]

[0573] ZnCl2 (46.0 mg, 0.34 mmol) was added to a mixed solution of [1,1'-biphenyl]-4-yl(2,5-dimethylthiophene-3-yl)methanol (3.29 g, 11.25 mol) and PhCl2 (14.1 mL, 0.8 M), and the reaction mixture was cooled to 16°C. Br2 (1.8 g, 22.5 mmol) was added over 30 minutes at 16°C. The reaction mixture was stirred at room temperature for 30 minutes, and the mixture was acidified by adding a 1 N HCl solution. The product was extracted with heptane, and the mixed extract was dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to obtain [1,1'-biphenyl]-4-yl(4-bromo-2,5-dimethylthiophene-3-yl)methanene (2.61 g, yield 63%). 1 H NMR (500 MHz, chloroform-d) δ 7.94 (d, J = 7.5 Hz, 2H), 7.72 (d, J = 7.7 Hz, 2H), 7.67 (d, J = 7.6 Hz, 2H), 7.50 (t, J = 7.3 Hz, 2H), 7.44 (t, J = 7.3 Hz, 1H), 2.42(s, 3H), 2.38(s, 3H). LC / MS(ESI) m / z: 373.3 [M+H] + .

[0574] Step 3: Synthesis of 3-([1,1'-biphenyl]-4-ylmethyl)-4-bromo-2,5-dimethylthiophene

[0575]

[0576] Et3SiH (2.1 g, 17.6 mmol) was added to a mixed solution of [1,1'-biphenyl]-4-yl(4-bromo-2,5-dimethylthiophene-3-yl)methanol (2.61 g, 7.03 mmol) and DCE (14.1 mL, 0.5 M). The reaction mixture was cooled to -8°C, and 1 M TiCl4 solution (7.1 mL, 7.1 mmol) was slowly added. The reaction mixture was stirred at room temperature for 1 hour, after which 1 N HCl solution was added to acidify the mixture. The product was extracted with heptane, dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to obtain 3-([1,1'-biphenyl]-4-ylmethyl)-4-bromo-2,5-dimethylthiophene (1.45 g, yield 58%). 1 H NMR (500 MHz, chloroform-d) δ 7.59 (d, J = 7.6 Hz, 2H), 7.52 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 7.6 Hz, 2H), 7.35 (d, J = 7.3 Hz, 1H), 7.24 (d, J = 7.9 Hz, 2H), 4.00(s, 2H), 2.40(d, J = 4.4 Hz, 6H).

[0577] Step 4: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxylic acid

[0578]

[0579] 3-([1,1'-biphenyl]-4-ylmethyl)-4-bromo-2,5-dimethylthiophene (1.0 g, 2.80 mmol), TMEDA (0.46 mL, 3.08 mmol) and methyl t - In a solution mixed with butyl ether (14 mL, 0.2 M) n -BuLi (1.5 mL, 2.64 mmol) was gradually added at -65℃ and stirred.

[0580] After stirring the mixture for 30 minutes, an excess amount of dry ice was added at -65°C and stirred for 1 hour. The reaction mixture was acidified by adding a 1 N HCl solution, and then extracted with EtOAc and distilled water. The organic layer was dried over Na2SO4, filtered, concentrated, and purified to obtain 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxylic acid (0.46 g, yield 51%). 1 H NMR (500 MHz, DMSO-d6) δ 12.64 (s, 1H), 7.61 (d, J = 7.6Hz, 2H), 7.55-7.52 (m, 2H), 7.44 (t, J = 7.2Hz, 2H), 7.36-7.32 (m, 1H), 7.16-7.12(m, 2H), 4.17(s, 2H), 2.55(s, 3H), 2.31(s, 3H).

[0581] Step 5: Synthesis of Methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate

[0582]

[0583] Intermediate A (70 mg, 0.34 mmol), HATU (0.13 g, 0.34 mmol), and DIPEA (0.16 mL, 0.93 mmol) were added to a solution of 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxylic acid (0.1 g, 0.31 mmol) mixed in DMF (1.1 mL, 0.3 M), and the mixture was stirred at room temperature for 3 hours. After basicizing the reaction mixture by adding 1N NaOH solution, it was extracted with EtOAc and distilled water. The organic layer was dried over Na2SO4, filtered and concentrated, and purified by column chromatography to obtain methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (110 mg, yield 75%). 1H NMR (500 MHz, chloroform-d) δ 7.57 (d, J = 7.6 Hz, 2H), 7.52 (d, J = 7.3 Hz, 2H), 7.46 (t, J = 7.3 Hz, 2H), 7.36 (t , J = 7.2 Hz, 1H), 7.19 (d, J = 7.6 Hz, 2H), 5.39(d, J = 7.1 Hz, 1H), 4.28(m, 1H), 4.00(s, 2H), 3.66(s, 3H), 2.97(p, J = 8.9, 8.4Hz, 1H), 2.46(s, 3H), 2.38(s, 3H), 2.30(dd, J = 14.1, 7.1 Hz, 4H), 2.21-2.14(m, 1H), 1.99(d, J = 19.5 Hz, 1H), 1.53(dt, J = 19.1, 10.0 Hz, 2H). LC / MS(ESI) m / z: 475.2 [M+H] + .

[0584] Step 6: Synthesis of 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0585]

[0586] LiOH·H2O (29 mg, 0.69 mmol) was added to a solution of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxyamido)spiro[3,3]heptane-2-carboxylate (110 mg, 0.23 mmol) mixed in H2O:THF:MeOH (1:1:1) and stirred for 4 hours. After acidifying the reaction mixture by adding a 1 N HCl solution, it was extracted with EtOAc and distilled water. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the compound of Example 1 (86 mg, yield 81%) without purification. 1H NMR (500 MHz, DMSO-d6) δ 12.03 (s, 1H), 8.29 (d, J = 7.4 Hz, 1H), 7.61 (d, J = 7.7 Hz, 2H), 7.51 (d, J = 7.6 Hz, 2H), 7.45 (t, J = 7.4 Hz, 2H), 7.34(t, J = 7.2 Hz, 1H), 7.19(d, J = 7.7 Hz, 2H), 4.16(h, J = 8.3 Hz, 1H), 3.90(s, 2H), 2.91(p, J = 8.3 Hz, 1H), 2.34(s, 3H), 2.32(s, 3H), 2.29-2.13(m, 4H), 2.11-2.06(m, 1H), 2.02(s, 1H), 1.87(s, 1H), 1.85(d, J = 9.6 Hz, 1H). LC / MS(ESI) m / z: 460.01 [M+H] + .

[0587] The compounds of Examples 2 to 5 were prepared using the same method as described in Example 1, except for differences in the manufacturing method described below.

[0588] Example number chemical structure designation Differences in manufacturing methods 2 6-(2,5-dimethyl-4-(4-methylbenzyl)thiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid Use 4-methylbenzoic acid instead of [1,1'-biphenyl]-4-carboxylic acid in Step 1 3 6-(4-([1,1'-biphenyl]-3-ylmethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid Use [1,1'-biphenyl]-3-carboxylic acid instead of [1,1'-biphenyl]-4-carboxylic acid in Step 1 4 6-(4-([1,1'-biphenyl]-2-ylmethyl)-2,5-dimethylthiophene-3-carboxyamido)spiro[3,3]heptane-2-carboxylic acid Use [1,1'-biphenyl]-2-carboxylic acid instead of [1,1'-biphenyl]-4-carboxylic acid in Step 1 5 6-(2,5-dimethyl-4-(4-phenoxybenzyl)thiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid Use 4-phenoxybenzoic acid instead of [1,1'-biphenyl]-4-carboxylic acid in Step 1

[0589] Example number LC / MS(ESI) m / z: [M+H] + NMR 2 398.5 1 H NMR(500 MHz, DMSO-d6) δ 12.01(s, 1H), 8.25(d, J = 7.5 Hz, 1H), 7.02(d, J = 7.7 Hz, 2H), 6.97(d, J = 7.7 Hz, 2H), 4.15(d, J = 7.9 Hz, 1H), 3.80(s, 2H), 2.96-2.88(m, 1H), 2.35(dd, J = 11.1, 6.3 Hz, 1H), 2.29(d, J = 7.1 Hz, 6H), 2.25(s, 1H), 2.23(s, 3H), 2.18(t, J = 9.5 Hz, 2H), 2.12-2.00(m, 2H), 1.93-1.87(m, 1H), 1.86-1.80(m, 1H) 3 460.2 1 H NMR(500 MHz, Chloroform-d) δ 7.57(d, J = 7.1 Hz, 2H), 7.46(t, J = 7.7 Hz, 3H), 7.37(q, J = 7.4 Hz, 3H), 7.09(d, J = 7.1 Hz, 1H), 5.36(d, J = 7.7 Hz, 1H), 4.23(h, J = 7.8 Hz, 1H), 4.03(s, 2H), 2.97(p, J = 8.5 Hz, 1H), 2.44(s, 3H), 2.40(s, 3H), 2.37-2.30(m, 1H), 2.24(dt, J = 17.2, 6.8 Hz, 3H), 2.17-2.11(m, 1H), 1.99-1.93(m, 1H), 1.51-1.43(m, 2H). 4 460.6 1 H NMR(500 MHz, Chloroform-d) δ 7.46(t, J = 7.4 Hz, 2H), 7.39(d, J = 7.4 Hz, 1H), 7.37-7.33(m, 2H), 7.30(d, J = 5.2 Hz, 1H), 7.29-7.25(m, 2H), 6.95(d, J = 7.8 Hz, 1H), 5.34(d, J = 7.5 Hz, 1H), 4.20(h, J = 7.9 Hz, 1H), 3.86(s, 2H), 3.03(p, J = 8.4 Hz, 1H), 2.45(s, 3H), 2.41(dd, J = 7.0, 4.8 Hz, 1H), 2.34-2.26(m, 3H), 2.23(dd, J = 11.7, 8.3 Hz, 1H), 2.14(s, 3H), 2.11-2.05(m, 1H), 1.45(ddd, J = 20.5, 11.3, 8.6 Hz, 2H). 5 476.4 1 H NMR(500 MHz, Chloroform-d) δ 7.36 - 7.32(m, 2H), 7.09(dd, J = 23.6, 8.0 Hz, 3H), 6.99(d, J = 8.5 Hz, 2H), 6.94(d, J = 8.6 Hz, 2H), 5.42(d, J = 7.8 Hz, 1H), 4.30(h, J = 8.0 Hz, 1H), 3.93(s, 2H), 3.05(p, J = 8.5 Hz, 1H), 2.52 - 2.46(m, 1H), 2.45(s, 3H), 2.36(d, J = 4.3 Hz, 6H), 2.27(dd, J = 11.7, 8.2 Hz, 1H), 2.12(ddd, J = 11.6, 8.7, 2.3 Hz, 1H), 1.66 - 1.56(m, 2H).

[0590] Example 6: 6-(4-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0591] Step 1: Synthesis of 2-([1,1'-biphenyl]-4-yl)-1-(2,5-dimethylthiophene-3-yl)ethane-1-one

[0592]

[0593] SOCl2 (6.1 g, 51.3 mmol) was added dropwise at 0°C to a solution of 2-([1,1'-biphenyl]-4-yl)acetic acid (10.4 g, 49.1 mmol) and DMF (approx. 1 mL) mixed in toluene (56 mL, 0.8 M), and the reaction mixture was heated to 50°C for 1 hour. The reaction mixture was cooled to room temperature, dimethylthiophene (5.1 mL, 44.6 mmol) was added, the mixture was cooled to 0°C, and a 1 M TiCl4 solution (45 mL, 44.6 mmol) was added. The reaction mixture was acidified by adding a 1 N HCl solution and extracted with heptane; the mixed extract was dried over Na2SO4, filtered, and concentrated. The crude product was purified by column chromatography to obtain 2-([1,1'-biphenyl]-4-yl)-1-(2,5-dimethylthiophene-3-yl)ethane-1-one (8.8 g, yield 64%). 1 H NMR (500 MHz, chloroform-d) δ 7.60 (t, J = 8.6 Hz, 4H), 7.46 (t, J = 7.5 Hz, 2H), 7.36 (dd, J = 15.0, 7.5 Hz, 3H), 7.14(s, 1H), 4.17(s, 2H), 2.71(s, 3H), 2.46(s, 3H).

[0594] Step 2: Synthesis of 3-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene

[0595]

[0596] 80% hydrazine hydrate (2.0 mL) and KOH (2.5 g, 44.5 mmol) were added to a solution of 2-([1,1'-biphenyl]-4-yl)-1-(2,5-dimethylthiophene-3-yl)ethane-1-one (4.0 g, 13.1 mmol) mixed with diethylene glycol (17.7 mL, 0.7 M). The reaction mixture was refluxed and stirred at 195°C for 6 hours, after which the solution was cooled to room temperature and 18 mL of distilled water was added. Then, 3-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene (1.97 g, yield 52%) was obtained by slowly pouring the solution into 11 mL of 6 N aqueous HCl solution to induce precipitation. 1 H NMR (500 MHz, chloroform-d) δ 7.63 (d, J = 7.1 Hz, 2H), 7.55 (d, J = 6.5 Hz, 2H), 7.47 (t, J = 7.7 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.27 (d, J = 8.1Hz, 2H), 6.55(s, 1H), 2.91-2.87(m, 2H), 2.82-2.77(m, 2H), 2.44(s, 3H), 2.22(s, 3H).

[0597] Step 3: Synthesis of 3-(2-([1,1'-biphenyl]-4-yl)ethyl)-4-bromo-2,5-dimethylthiophene

[0598]

[0599] In an AcOH (4 mL) solution mixed with 3-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene (0.21 g, 0.72 mmol) N Bromosuccinimide (0.13 g, 0.72 mmol) was added. After stirring for 12 hours, the solution was added to an excess of ice water and extracted with DCM. The DCM solution was washed with an aqueous sodium carbonate solution and distilled water. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The remaining solution was purified by column chromatography to obtain 3-(2-([1,1'-biphenyl]-4-yl)ethyl)-4-bromo-2,5-dimethylthiophene (159 mg, yield 60%).1 H NMR (500 MHz, chloroform-d) δ 7.62 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.2 Hz, 2H), 7.47 (t, J = 7.7 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.27 (d, J = 8.1 Hz, 2H), 2.85(p, J = 3.4 Hz, 4H), 2.40(s, 3H), 2.15(s, 3H).

[0600] Step 4: Synthesis of 4-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene-3-carboxylic acid

[0601]

[0602] In a solution mixed with 3-(2-([1,1'-biphenyl]-4-yl)ethyl)-4-bromo-2,5-dimethylthiophene (159 mg, 0.43 mmol), THF (2.2 mL, 0.2 M), and TMEDA (70 μL, 0.47 mmol) n -BuLi (2.5 M in THF, 0.22 mL, 0.56 mmol) was gradually added at -65°C and stirred. After 30 minutes, dry ice was added in excess at -65°C and stirred at room temperature for 1 hour. After acidifying the reaction mixture by adding 1 M HCl solution, it was extracted with EtOAc and distilled water. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain 4-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene-3-carboxylic acid (72 mg, yield 51%). 1 H NMR (500 MHz, DMSO-d6) δ 12.69 (s, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.2 Hz, 2H), 7.46 (t, J = 7.7 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.27(d, J = 8.2 Hz, 2H), 2.96(dd, J = 9.4, 6.5 Hz, 2H), 2.75-2.70(m, 2H), 2.56(s, 3H), 2.15(s, 3H).

[0603] Step 5: Synthesis of Methyl 6-(4-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate

[0604]

[0605] DIPEA (0.11 mL, 0.63 mmol) was added to a solution of 4-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene-3-carboxylic acid (72 mg, 0.21 mmol), intermediate A (47 mg, 0.23 mmol), and HATU (87 mg, 0.23 mmol) mixed in DCM (1.1 mL, 0.2 M), and stirred at room temperature for 3 hours. The reaction mixture was partially concentrated, the organic layer was extracted with 1 N NaOH and ethyl acetate, and the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with brine, dried and concentrated over Na2SO4, and then purified by column chromatography to obtain methyl 6-(4-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (70 mg, yield 70%). 1H NMR (500 MHz, chloroform-d) δ 7.61 (d, J = 7.1 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 7.46 (t, J = 7.7 Hz, 2H), 7.36 (t, J = 7.9 Hz, 1H), 7.20 (d, J = 8.2 Hz, 2H), 5.55 (d, J = 7.7 Hz, 1H), 4.45 (h, J = 7.8 Hz, 1H), 3.69 (s, 3H), 3.05 (p, J = 8.5 Hz, 1H), 2.86 (dd, J = 6.4, 4.0 Hz, 2H), 2.82(dd, J = 9.8, 6.5 Hz, 2H), 2.61(dt, J = 11.8, 5.5 Hz, 1H), 2.48(dd, J = 11.8, 7.1 Hz, 1H), 2.45(s, 3H), 2.37(d, J = 8.4 Hz, 2H), 2.32-2.27(m, 1H), 2.19(s, 3H), 2.16-2.10(m, 1H), 1.92-1.82(m, 2H); LC / MS(ESI) m / z: 488.3 [M+H] + .

[0606] Step 6: Synthesis of 6-(4-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0607]

[0608] LiOH·H2O (18 mg, 0.42 mmol) was added to a solution of methyl 6-(4-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene-3-carboxylamido)spiro[3.3]heptane-2-carboxylate (70 mg, 0.14 mmol) mixed in H2O:THF:MeOH (1:1:1). The reaction mixture was stirred at room temperature for 4 hours, then acidified by adding a 1 N HCl solution and extracted with DCM. The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the compound of Example 6 (46 mg, 69% yield) without purification. 1H NMR (500 MHz, Methanol-d4) δ 8.48 (d, J = 7.2 Hz, 1H), 7.61 (d, J = 7.2 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.43 (t, J = 7.7 Hz, 2H), 7.32 (t, J = 7.4 Hz, 1H), 7.21(d, J = 8.2 Hz, 2H), 4.36(dt, J = 13.2, 6.8 Hz, 1H), 3.04(p , J = 8.5 Hz, 1H), 2.88-2.82(m, 2H), 2.80-2.75(m, 2H), 2.61-2.55(m, 1H), 2.45-2.42(m, 1H), 2.41(s, 3H), 2.41-2.34(m, 2H), 2.29-2.24(m, 1H), 2.22-2.16(m, 1H), 2.11(s, 3H), 2.10-2.01(m, 2H). LC / MS(ESI) m / z: 474.3 [M+H] + .

[0609] Example 7: 6-(4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0610] Step 1: Synthesis of (4-bromo-2,5-dimethylthiophene-3-yl)(3-fluoro-[1,1'-biphenyl]-4-yl)methanene

[0611]

[0612] SOCl2 (0.18 mL, 2.4 mmol) was added at 0°C to a solution in which intermediate E (0.50 g, 2.31 mmol) and DMF (approx. 1 mL) were mixed in toluene (2.6 mL, 0.8 M). The reaction mixture was heated to 50°C and stirred for 1 hour, after which intermediate C (0.40 g, 2.1 mmol) was added. The reaction mixture was cooled to 0°C and TiCl 4(0.23 mL (2.1 mmol) was added. 1 N HCl aqueous solution (10 mL) was added and stirred for 5 minutes, after which the organic layer was extracted and the aqueous layer was washed twice with heptane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to obtain (4-bromo-2,5-dimethylthiophene-3-yl)(3-fluoro-[1,1'-biphenyl]-4-yl)methaneone (200 mg, yield 25%). 1 H NMR (500 MHz, Chloroform-d) δ 7.78 (t, J = 7.8 Hz, 1H), 7.65 (d, J = 7.2 Hz, 2H), 7.53-7.49 (m, 3H), 7.46 (d, J = 7.3 Hz, 1H), 7.36 (d, J = 11.9 Hz, 1H), 2.48(s, 3H), 2.39(s, 3H).

[0613] Step 2: Synthesis of 3-bromo-4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene

[0614]

[0615] Et3SiH (0.18 mL, 1.17 mmol) was added to a solution in which (4-bromo-2,5-dimethylthiophene-3-yl)(3-fluoro-[1,1'-biphenyl]-4-yl)methanol (150 mg, 0.39 mmol) was mixed in DCE (0.9 mL, 0.5 M). The reaction mixture was cooled to -8°C, TiCl4 (43 μL, 0.39 mmol) was slowly added, and the reaction mixture was stirred for 1 hour. After adding 1 N HCl aqueous solution (10 mL) and stirring for 5 minutes, the organic layer was extracted and the aqueous layer was washed twice with heptane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to obtain 3-bromo-4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene (74 mg, yield 53%). 1H NMR (500 MHz, Chloroform-d) δ 7.57 (d, J = 7.1 Hz, 2H), 7.45 (t, J = 7.6 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.30 (d, J = 9.6 Hz, 1H), 7.26 (d, J = 6.1 Hz, 1H), 7.00(t, J = 8.0 Hz, 1H), 4.00(s, 2H), 2.40 (s, 3H), 2.38(s, 3H).

[0616] Step 3: Synthesis of 4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxylic acid

[0617]

[0618] In a THF (1.0 mL, 0.2 M) solution mixed with 3-bromo-4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene (74 mg, 0.20 mmol) and tetramethylenediamine (33 μL, 0.22 mmol) at -65℃ n -BuLi (2.5 M in THF, 0.09 mL, 0.22 mmol) was slowly added and stirred for 45 minutes, and an excess amount of dry ice was added at -65°C. After adding 1 N HCl aqueous solution (2.0 mL) and stirring for 15 minutes, the organic layer was extracted and the aqueous layer was washed twice with EA. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to obtain 4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxylic acid (30 mg, yield 45%). 1 H NMR (500 MHz, Chloroform-d) δ 7.55 (d, J = 7.1 Hz, 2H), 7.44 (t, J = 7.6 Hz, 2H), 7.36 (d, J = 7.3 Hz, 1H), 7.27 (d, J = 9.5 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 6.91(t, J = 8.0 Hz, 1H), 4.24(s, 2H), 2.70(s, 3H), 2.33(s, 3H).

[0619] Step 4: Synthesis of methyl 6-(4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate

[0620]

[0621] DIPEA (0.05 mL, 0.27 mmol) was added at room temperature to a solution mixed with 4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxylic acid (30 mg, 0.09 mmol), intermediate A (21 mg, 0.1 mmol), and HATU (38 mg, 0.1 mmol) in DMF (0.3 mL, 0.3 M) and stirred for 3 hours. The reaction mixture was concentrated and diluted with 1N NaOH aqueous solution and ethyl acetate, and the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 to concentrate, and purified by silica gel column chromatography (n-hexane and ethyl acetate) to obtain methyl 6-(4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (12 mg, yield 30%). 1 H NMR (500 MHz, Chloroform-d) δ 7.57-7.53(m, 2H), 7.46(t, J = 7.6 Hz, 2H), 7.38(t, J = 7.9 Hz, 1H), 7.29(s, 1H), 7.26(s, 1H), 7.08(t, J = 7.8 Hz, 1H), 5.49(d, J = 7.8 Hz, 1H), 4.34(h, J = 8.0 Hz, 1H), 3.98(s, 2H), 3.67(s, 3H), 2.99(p, J = 8.5 Hz, 1H), 2.53-2.47(m, 1H), 2.46(s, 3H), 2.39-2.36(m, 1H), 2.35(s, 3H), 2.33-2.29(m, 2H), 2.21(dd, J = 11.6, 8.4 Hz, 1H), 2.06-2.00(m, 1H), 1.69-1.65(m, 1H), 1.61 (dd, J = 11.6, 8.7 Hz, 1H). LC / MS(ESI) m / z: 492.4 [M+H] +.

[0622] Step 5: Synthesis of 6-(4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0623]

[0624] LiOH·H2O (3.0 mg, 0.06 mmol) was added to a solution of methyl 6-(4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (12 mg, 0.02 mmol) mixed in H2O / THF / MeOH (0.3 M, 0.1 mL) and stirred for 4 hours. The reaction mixture was acidified by adding 1 N aqueous HCl solution and extracted with EA (3×5 mL). The organic layer was dried over MgSO4, filtered, and concentrated, then purified by silica gel column chromatography (n-hexane and ethyl acetate) to obtain the compound of Example 7 (6.0 mg, yield 55%). 1 H NMR (500 MHz, Chloroform-d) δ 7.55 (d, J = 7.2 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.38 (t, J = 7.3 Hz, 1H), 7.27 (d, J = 9.7 Hz, 2H), 7.08 (t, J = 7.8 Hz, 1H), 5.48(d, J = 7.8 Hz, 1H), 4.34(h, J = 8.0 Hz, 1H), 3.98(s, 2H), 3.03(p, J = 8.4 Hz, 1H), 2.50(dt, J = 11.9, 6.3 Hz, 1H), 2.46(s, 3H), 2.41-2.36(m, 2H), 2.35(s, 3H), 2.34(s, 1H), 2.23(dd, J = 11.7, 8.2 Hz, 1H), 2.08(ddd, J = 11.6, 8.6, 2.2 Hz, 1H), 1.64(ddd, J = 20.8, 11.4, 8.5 Hz, 2H). LC / MS(ESI) m / z: 478.2 [M+H] + .

[0625] Example 8: 6-(4-((2-amino-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0626] Step 1: Synthesis of (2-amino-[1,1'-biphenyl]-4-yl)(4-bromo-2,5-dimethylthiophene-3-yl)methanone

[0627]

[0628] Intermediate C (2.5 g, 13.1 mmol) was added to a mixture of AlCl3 (1.74 g, 13.1 mmol) and DCM (42.2 mL, 0.3 M) and stirred for 30 minutes, then intermediate F (2.95 g, 12.7 mmol) was added to the reaction mixture and stirred for 12 hours. The reaction mixture was placed on ice and acidified with a 1 N aqueous citric acid solution, and then extracted twice with DCM. The organic layer was washed with distilled water and brine, dried over MgSO4, concentrated under reduced pressure, and purified by column chromatography to obtain (2-amino-[1,1'-biphenyl]-4-yl)(4-bromo-2,5-dimethylthiophene-3-yl)methanol (960 mg, yield 20%). 1 H NMR (300 MHz, chloroform-d) δ 7.50 (d, J = 4.4 Hz, 4H), 7.44-7.40 (m, 1H), 7.31 (d, J = 1.2 Hz, 1H), 7.26-7.22 (m, 2H), 4.02 (s, 2H), 2.41(s, 3H), 2.37(s, 3H).

[0629] Steps 2 to 5: Synthesis of 6-(4-((2-amino-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0630]

[0631]

[0632] The (2-amino-[1,1'-biphenyl]-4-yl)(4-bromo-2,5-dimethylthiophene-3-yl)methanene obtained in Step 1 above was reacted in the same manner as Steps 2 to 5 of Example 7 to prepare the compound of Example 8. 1H NMR (300 MHz, chloroform-d) δ 7.50-7.33 (m, 5H), 7.08 (d, J = 7.7 Hz, 1H), 6.63 (d, J = 8.7 Hz, 1H), 6.57 (s, 1H), 5.67 (d, J = 8.8 Hz, 1H), 4.27(q, J = 8.0 Hz, 1H), 3.91(s, 2H), 3.08-2.94(m, 1H), 2.46(s, 4H), 2.37(s, 3H), 2.31(d, J = 8.1 Hz, 3H), 2.26-2.17(m, 1H), 2.11-2.01(m, 1H), 1.65-1.50(m, 2H). LC / MS(ESI) m / z: 475.5 [M+H] + .

[0633] Example 9: 6-(2,5-dimethyl-4-(4-morpholinobenzyl)thiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0634] Step 1: Synthesis of (4-bromo-2,5-dimethylthiophene-3-yl)(4-fluorophenyl)methanene

[0635]

[0636] SOCl2 (1.8 mL, 24.6 mmol) was added to a solution of 4-fluorobenzoic acid (3.0 g, 21.3 mmol) and DMF (about 1 mL) mixed in toluene (24 mL, 0.8 M) at 0°C, and then stirred at 50°C for 5 hours. 3-Bromo-2,5-dimethylthiophene (3.7 g, 19.4 mmol) was added at 50°C, followed by the addition of a TiCl4 (2.1 mL, 19.4 mmol) solution. After adding a 1 N HCl aqueous solution (30 mL) and stirring for 5 minutes, the organic layer was extracted and the aqueous layer was washed twice with heptane. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to obtain (4-bromo-2,5-dimethylthiophene-3-yl)(4-fluorophenyl)methane (1.45 g, yield 24%).

[0637] Step 2: Synthesis of (4-bromo-2,5-dimethylthiophene-3-yl)(4-morpholinophenyl)methanene

[0638]

[0639] K2CO3 (0.95 g, 6.5 mmol) was added to a solution of (4-bromo-2,5-dimethylthiophene-3-yl)(4-fluorophenyl)methaneone (1.45 g, 4.62 mmol) and morpholine (1.2 mL, 13.9 mmol) mixed in DMSO:H2O (8 mL, 0.6 M), and then heated to 90°C and stirred for 8 hours. The reaction mixture was diluted with distilled water and extracted twice with DCM. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated to obtain (4-bromo-2,5-dimethylthiophene-3-yl)(4-morphophenolphenyl)methaneone (1.21 g, yield 69%).

[0640] Step 3: Synthesis of 4-(4-((4-bromo-2,5-dimethylthiophene-3-yl)methyl)phenyl)morpholine

[0641]

[0642] Et3SiH (1.80 mL, 11.2 mmol) was added to a TFA (8 mL, 0.4 M) solution mixed with (4-bromo-2,5-dimethylthiophene-3-yl)(4-morpholinophenyl)methanol (1.21 g, 3.2 mmol) at -10°C and stirred for 12 hours at room temperature. The reaction mixture was poured into 10 mL of ice water and extracted with ethyl acetate (3 × 20 mL), then washed with a saturated aqueous NaHCO3 solution (20 mL), distilled water (10 mL), and brine (20 mL) and dried on Na2SO4. After concentrating under reduced pressure, the crude product was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 4-(4-((4-bromo-2,5-dimethylthiophene-3-yl)methyl)phenyl)morpholine (0.62 g, yield 53%). 1 H NMR (300 MHz, Chloroform-d) δ 7.08 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.3 Hz, 2H), 3.91 - 3.84 (m, 6H), 3.17 - 3.11 (m, 4H), 2.38-2.34 (m, 6H).

[0643] Step 4: Synthesis of 2,5-dimethyl-4-(4-morpholinobenzyl)thiophene-3-carboxylic acid

[0644]

[0645] In a solution mixed with 4-(4-((4-bromo-2,5-dimethylthiophene-3-yl)methyl)phenyl)morpholine (0.62 g, 1.69 mmol), TMEDA (48 μL, 1.86 mmol), and THF (8.5 mL, 0.2 M) at -65℃ n -BuLi (2.5 M in THF, 0.73 mL, 1.86 mmol) was slowly added and stirred for 45 minutes. Excess dry ice was added to the reaction mixture at -65°C and stirred at room temperature for 1 hour. A 1 N aqueous citric acid solution (2.0 mL) was added and stirred for 15 minutes to extract the organic layer, and the aqueous layer was washed twice with EA. The organic layer was washed with brine and dried over MgSO4, then filtered and concentrated to obtain 2,5-dimethyl-4-(4-morpholinobenzyl)thiophene-3-carboxylic acid. 1 H NMR (500 MHz, Chloroform-d) δ 7.03 (d, J = 8.6 Hz, 2H), 6.82 (d, J = 8.6 Hz, 2H), 4.14 (d, J = 2.7 Hz, 2H), 3.88 - 3.83 (m, 4H), 3.13 - 3.09(m, 4H), 2.66(s, 3H), 2.32(s, 3H).

[0646] Step 5: Synthesis of Methyl 6-(2,5-dimethyl-4-(4-morpholinobenzyl)thiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate

[0647]

[0648] DIPEA (0.4 mL, 1.98 mmol) was added to a solution mixed with 2,5-dimethyl-4-(4-morpholinobenzyl)thiophene-3-carboxylic acid (220 mg, 0.66 mmol), intermediate A (148 mg, 0.72 mmol), and HATU (273 mg, 0.72 mmol) in DMF (2.2 mL, 0.3 M), and stirred for 3 hours. The reaction mixture was concentrated and diluted with 1N NaOH aqueous solution and ethyl acetate, and the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with brine and dried over MgSO4 to concentrate, then purified by silica gel column chromatography using n-hexane and ethyl acetate to obtain methyl 6-(2,5-dimethyl-4-(4-morpholinobenzyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (157 mg, yield 49%). 1 H NMR (500 MHz, Chloroform-d) δ 7.01 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.7 Hz, 2H), 5.41 (d, J = 7.7 Hz, 1H), 4.27 (h, J = 7.9 Hz, 1H), 3.88 (t, J = 4.8 Hz, 6H), 3.68(s, 3H), 3.14-3.10(m, 4H), 3.00(p, J = 8.5 Hz, 1H), 2.45(s, 4H), 2.34(s, 3H), 2.31(ddd, J = 12.4, 8.6, 4.9 Hz, 3H), 2.21(dd, J = 11.6, 8.4 Hz, 1H), 2.03(ddd, J = 11.6, 8.6, 2.7 Hz, 1H), 1.57(dd, J = 11.1, 8.5 Hz, 1H), 1.50(dd, J = 11.6, 8.6 Hz, 1H).

[0649] Step 6: Synthesis of 6-(2,5-dimethyl-4-(4-morpholinobenzyl)thiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0650]

[0651] LiOH·H2O (40 mg, 0.96 mmol) was added to a solution of methyl 6-(2,5-dimethyl-4-(4-morpholinobenzyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (157 mg, 0.32 mmol) mixed in H2O / THF / MeOH (0.3 M, 1.1 mL) and stirred for 4 hours. The reaction mixture was acidified by adding 1 N aqueous citric acid solution and extracted with EA (3×5 mL). The organic layer was dried over MgSO4, filtered, and concentrated, then purified by silica gel column chromatography (n-hexane and ethyl acetate) to obtain the compound of Example 9 (12 mg, yield 8%). 1 H NMR (500 MHz, Chloroform-d) δ 7.01 (d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.7 Hz, 2H), 5.42 (d, J = 7.7 Hz, 1H), 4.26 (h, J = 7.9 Hz, 1H), 3.88 (t, J = 4.8 Hz, 6H), 3.15-3.10(m, 4H), 3.02(p, J = 8.3 Hz, 1H), 2.45(s, 4H), 2.34(s, 3H), 2.31(dd, J = 11.3, 8.8 Hz, 3H), 2.21(dd, J = 11.7, 8.0 Hz, 1H), 2.11-2.05(m, 1H), 1.57(dd, J = 11.2, 8.3 Hz, 1H), 1.48(dd, J = 11.6, 8.4 Hz, 1H). LC / MS(ESI) m / z: 469.4 [M+H] + .

[0652] Example 10: 6-(4-([1,1'-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0653] Step 1: Synthesis of 4-([1,1'-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carbonitrile

[0654]

[0655] CuCN (0.63 g, 7.0 mmol) was added to a DMF (58 mL, 0.06 M) solution of [1,1'-biphenyl]-4-yl(4-bromo-2,5-dimethylthiophene-3-yl)methanol (1.30 g, 3.5 mmol) obtained in Step 2 of Example 1, and the mixture was stirred at 110°C for 24 hours. The reaction mixture was concentrated and diluted with 1 N HCl aqueous solution and ethyl acetate, after which the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with brine, dried and concentrated over MgSO4, and then purified by silica gel column chromatography (n-hexane and ethyl acetate) to obtain 4-([1,1'-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carbonitrile (610 mg). 1 H NMR (500 MHz, Chloroform-d) δ 7.91 (d, J = 8.2 Hz, 2H), 7.75 (d, J = 8.2 Hz, 2H), 7.67 (d, J = 7.6 Hz, 2H), 7.51 (t, J = 7.6 Hz, 2H), 7.44 (t, J = 7.3 Hz, 1H), 2.67(s, 3H), 2.43(s, 3H).

[0656] Step 2: Synthesis of 4-([1,1'-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carboxylic acid

[0657]

[0658] 4-([1,1'-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carbonitrile (340 mg, 1.07 mmol) was added to a 70% aqueous H2SO4 solution (5.3 mL, 0.2 M) and stirred under reflux at 110°C for 1 hour. The reaction mixture was poured into ice water and extracted three times with DCM. The organic layer was dried and concentrated over MgSO4, and then purified by silica gel column chromatography (DCM and MeOH) to obtain 4-([1,1'-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carboxylic acid (42 mg, yield 12%). 1H NMR (500 MHz, Chloroform-d) δ 7.85 (d, J = 8.4 Hz, 2H), 7.66 - 7.61 (m, 4H), 7.48 (t, J = 7.5 Hz, 2H), 7.42 (t, J = 7.3 Hz, 1H), 2.68 (s, 3H), 2.27(s, 3H).

[0659] Step 3: Synthesis of Methyl 6-(4-([1,1'-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate

[0660]

[0661] DIPEA (0.04 mL, 0.22 mmol) was added to a solution mixed with 4-([1,1'-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carboxylic acid (12 mg, 0.036 mmol), intermediate A (17 mg, 0.08 mmol), and HATU (31 mg, 0.08 mmol) in DMF (0.3 mL, 0.3 M) and stirred for 3 hours. The reaction mixture was concentrated and diluted with 1 N NaOH aqueous solution and ethyl acetate, and the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with brine, dried and concentrated over MgSO4, and then purified by silica gel column chromatography (n-hexane and ethyl acetate) to obtain methyl 6-(4-([1,1'-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (33 mg, yield 55%). 1H NMR (500 MHz, Chloroform-d) δ 7.89 (d, J = 8.4 Hz, 2H), 7.69 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 7.2 Hz, 2H), 7.50 (t, J = 7.5 Hz, 2H), 7.43 (t, J = 7.3 Hz, 1H), 5.97(d, J = 7.3 Hz, 1H), 4.09(dd, J = 16.0, 7.6 Hz, 1H), 3.65(s, 3H), 2.96(p, J = 8.5 Hz, 1H), 2.60(s, 3H), 2.34(s, 4H), 2.26 - 2.17(m, 4H), 2.09 - 2.03(m, 1H), 1.66 - 1.63(m, 1H), 1.60(d, J = 9.0 Hz, 1H). LC / MS(ESI) m / z: 488.4 [M+H] + .

[0662] Step 4: Synthesis of 6-(4-([1,1'-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0663]

[0664] LiOH·H2O (9 mg, 0.21 mmol) was added to a solution of methyl 6-(4-([1,1'-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (33 mg, 0.07 mmol) mixed in H2O / THF / MeOH (0.3 M, 0.2 mL) and stirred for 4 hours. The reaction mixture was acidified by adding a 1 N HCl aqueous solution and extracted with EA (3 × 20 mL). The organic layer was dried over MgSO4, filtered, and concentrated, and then purified by silica gel column chromatography (n-hexane and ethyl acetate) to obtain the compound of Example 10 (20 mg, yield 63%). 1H NMR (500 MHz, Chloroform-d) δ 7.89 (d, J = 8.3 Hz, 2H), 7.69 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 7.3 Hz, 2H), 7.50 (t, J = 7.5 Hz, 2H), 7.43 (t, J = 7.3 Hz, 1H), 6.03(d, J = 7.3 Hz, 1H), 4.10(h, J = 8.1 Hz, 1H), 2.99(p, J = 8.5 Hz, 1H), 2.59(s, 3H), 2.34(s, 4H), 2.23(dt, J = 23.0, 9.6 Hz, 4H), 2.10(t, J = 10.3 Hz, 1H), 1.66 - 1.59(m, 2H). LC / MS(ESI) m / z: 474.4 [M+H]+.

[0665] Example 11: 6-(4-([1,1'-biphenyl]-4-yl(hydroxy)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0666]

[0667] NaBH4 (1.5 mg, 0.04 mmol) and CaCl2 (2.0 mg, 0.02 mmol) were added to a mixture of the compound of Example 10 (10 mg, 0.02 mmol) and ethanol (0.4 mL, 0.05 M) and stirred for 12 hours. After adding distilled water and ethyl acetate, the aqueous layer was extracted with ethyl acetate (10 mL). The organic layer was dried with MgSO4 and concentrated, then purified by silica gel column chromatography (DCM and MeOH) to obtain the compound of Example 11 (4.0 mg, yield 40%). 1H NMR (500 MHz, Methanol-d4) δ 8.42 (t, J = 7.8 Hz, 1H), 7.61 (t, J = 7.0 Hz, 2H), 7.55 (dd, J = 8.3, 6.4 Hz, 2H), 7.44 (t, J = 7.5 Hz, 2H), 7.36 - 7.31(m, 3H), 5.94(d, J = 3.9Hz, 1H), 4.00 - 3.89(m, 1H), 2.90(dq, J = 32.3, 8.5 Hz, 1H), 2.49(d, J = 1.9Hz, 3H), 2.42(d, J = 2.1Hz, 3H), 2.37 - 2.15(m, 4H), 2.14 - 1.94(m, 3H), 1.74(dt, J = 20.8, 10.7Hz, 1H), 1.57 - 1.51(m, 1H). LC / MS(ESI) m / z: 474.3 [M+H] - .

[0668] Example 12: 6-(4-([1,1'-biphenyl]-4-yl(methoxy)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0669] Step 1: Synthesis of [1,1'-biphenyl]-4-yl(4-bromo-2,5-dimethylthiophene-3-yl)methanol

[0670]

[0671] NaBH4 (0.41 g, 10.8 mmol) and CaCl2 (0.60 g, 5.39 mmol) were added to a mixture of [1,1'-biphenyl]-4-yl(4-bromo-2,5-dimethylthiophene-3-yl)methanol (2.0 g, 5.39 mmol) and ethanol (108 mL, 0.05 M) obtained in Step 2 of Example 1, and stirred for 12 hours. After adding distilled water and ethyl acetate, the aqueous layer was extracted with ethyl acetate (50 mL). The organic layer was dried and concentrated with MgSO4, and then purified by silica gel column chromatography (DCM and MeOH) to obtain [1,1'-biphenyl]-4-yl(4-bromo-2,5-dimethylthiophene-3-yl)methanol (1.3 g, yield 62%). 1H NMR (300 MHz, Chloroform-d) δ 7.65 - 7.57 (m, 4H), 7.46 (dd, J = 7.9, 3.8 Hz, 4H), 7.37 (t, J = 7.3 Hz, 1H), 6.13 (dd, J = 10.9, 3.2 Hz, 1H), 2.42 - 2.35(m, 6H).

[0672] Step 2: Synthesis of 3-([1,1'-biphenyl]-4-yl(methoxy)methyl)-4-bromo-2,5-dimethylthiophene

[0673]

[0674] HCl (35% in H2O, 19 mL, 214 mmol) was added to a solution of [1,1'-biphenyl]-4-yl(4-bromo-2,5-dimethylthiophene-3-yl)methanol (900 mg, 2.41 mmol) in methanol (80 mL, 0.03 M) and stirred for 12 hours. The reaction mixture was concentrated, based with an aqueous sodium bicarbonate solution, and extracted with EA. The organic layer was dried and concentrated with MgSO4, then purified by silica gel column chromatography (0-5% MeOH in DCM) to obtain 3-([1,1'-biphenyl]-4-yl(methoxy)methyl)-4-bromo-2,5-dimethylthiophene (680 mg, yield 50%). 1 H NMR (300 MHz, Chloroform-d) δ 7.63-7.54(m, 4H), 7.49-7.41(m, 4H), 7.35(t, J = 7.3 Hz, 1H), 5.68(s, 1H), 3.45(s, 3H), 2.41 - 2.35(m, 6H).

[0675] Step 3: Synthesis of 4-([1,1'-biphenyl]-4-yl(methoxy)methyl)-2,5-dimethylthiophene-3-carboxylic acid

[0676]

[0677] In a solution mixed with 3-([1,1'-biphenyl]-4-yl(methoxy)methyl)-4-bromo-2,5-dimethylthiophene (517 mg, 1.33 mmol), TMEDA (0.22 mL, 1.46 mmol), and Et2O (6.7 mL, 0.2 M). n-BuLi (2.5 M in THF, 0.70 mL, 1.73 mmol) was slowly added at -65°C and stirred for 45 minutes, after which an excess amount of dry ice was added. A 1 N HCl aqueous solution (10 mL) was added and stirred for 15 minutes, after which the organic layer was extracted and the aqueous layer was washed twice with EA. The organic layer was washed with brine and dried with MgSO4, then filtered and concentrated to obtain 4-([1,1'-biphenyl]-4-yl(methoxy)methyl)-2,5-dimethylthiophene-3-carboxylic acid (151 mg, yield 32%). 1 H NMR (300 MHz, DMSO-d6) δ 12.88 (s, 1H), 7.67 - 7.58 (m, 4H), 7.45 (t, J = 7.5 Hz, 2H), 7.36 (d, J = 8.1 Hz, 3H), 6.11 (s, 1H), 3.31 (s, 3H), 2.54(s, 3H), 2.23(s, 3H).

[0678] Step 4: Synthesis of methyl 6-(4-([1,1'-biphenyl]-4-yl(methoxy)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate

[0679]

[0680] DIPEA (0.22 mL, 1.3 mmol) was added to a solution mixed with 4-([1,1'-biphenyl]-4-yl(methoxy)methyl)-2,5-dimethylthiophene-3-carboxylic acid (151 mg, 0.43 mmol), intermediate A (96 mg, 0.47 mmol), and HATU (179 mg, 0.47 mmol) in DMF (1.4 mL, 0.3 M), and stirred for 3 hours. The reaction mixture was concentrated and diluted with 1 N NaOH aqueous solution and ethyl acetate, and the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with brine, dried and concentrated over MgSO4, and then purified by silica gel column chromatography (n-hexane and ethyl acetate) to obtain methyl 6-(4-([1,1'-biphenyl]-4-yl(methoxy)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (138 mg, yield 64%). 1H NMR (300 MHz, Chloroform-d) δ 7.55 (dt, J = 9.7, 7.2 Hz, 4H), 7.45 (t, J = 7.6 Hz, 2H), 7.35 (td, J = 7.6, 3.6 Hz, 3H), 5.63 (s, 1H), 3.97 (h, J = 8.3 Hz, 1H), 3.65 (d, J = 4.9 Hz, 3H), 3.52 (d, J = 0.9 Hz, 3H), 2.95 (dt, J = 15.0, 8.6 Hz, 1H), 2.58 (d, J = 2.6 Hz, 3H), 2.47(s, 3H), 2.44-2.35(m, 1H), 2.29 - 2.11(m, 4H), 2.08-1.91(m, 1H), 1.78-1.65(m, 1H), 1.23-1.10(m, 1H).

[0681] Step 5: Synthesis of 6-(4-([1,1'-biphenyl]-4-yl(methoxy)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0682]

[0683] LiOH·H2O (34 mg, 0.81 mmol) was added to a solution of methyl 6-(4-([1,1'-biphenyl]-4-yl(methoxy)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate (138 mg, 0.27 mmol) mixed in H2O / THF / MeOH (0.3 M, 0.9 mL) and stirred for 12 hours. The reaction mixture was acidified by adding a 1 N HCl aqueous solution and extracted with EA (20 mL × 3). The organic layer was dried, filtered, and concentrated over MgSO4, and purified by silica gel column chromatography (n-hexane and ethyl acetate) to obtain 6-(4-([1,1'-biphenyl]-4-yl(methoxy)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (121 mg, yield 90%). 1H NMR (300 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.41 (d, J = 7.3 Hz, 1H), 7.62 (dd, J = 13.7, 7.8 Hz, 4H), 7.41 (tt, J = 15.5, 7.2 Hz, 5H), 5.51(s, 1H), 4.17(h, J = 8.0 Hz, 1H), 3.30(s, 3H), 2.92(p, J = 8.5 Hz, 1H), 2.45 - 2.30(m, 4H), 2.28 - 2.14(m, 6H), 2.12 - 2.03(m, 2H), 1.91(tt, J = 19.4, 8.9 Hz, 2H). LC / MS(ESI) m / z: 488.3 [M+H] - .

[0684] Example 13: 6-(4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0685] Step 1: Synthesis of 2-([1,1'-biphenyl]-4-ylmethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

[0686]

[0687] A solution containing 4-bromomethyl-biphenyl (600 mg, 2.44 mmol), K2CO3 (1.0 g, 7.28 mmol), (pinacolato)divorone (740 mg, 2.92 mmol) and Pd(PPh3)4 (140 mg, 0.12 mmol) mixed in 1,4-dioxane (12 mL) was stirred at 100°C for 12 hours. After removing the precipitate by Celite filtration with the addition of ethyl acetate (20 mL), the organic layer was concentrated under reduced pressure, and the crude product was purified by flash column chromatography (0 to 100% Hexane / EtOAc) to obtain 2-([1,1'-biphenyl]-4-ylmethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (61 mg, yield 86%) as a white solid. 1H NMR (300 MHz, Chloroform-d) δ 7.60 - 7.54 (m, 2H), 7.49 - 7.45 (m, 2H), 7.44 - 7.37 (m, 2H), 7.33 - 7.29 (m, 1H), 7.27 - 7.24 (m, 2H), 2.34(s, 2H), 1.25(s, 12H).

[0688] Step 2: Synthesis of Methyl 4-([1,1'-Biphenyl]-4-ylmethyl)thiophene-3-carboxylate

[0689]

[0690] Under N2, methyl 3-bromobenzo[b]thiophene-2-carboxylate (300 mg, 1.32 mmol), 2-(biphenyl-4-ylmethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (192 mg, 0.528 mmol), and Pd(PPh3)4 (60 mg) were placed in a flask containing THF (18 mL) and 2 N K2CO3 aqueous solution and stirred at 85°C for 12 hours. After cooling the reaction mixture to room temperature, it was extracted with distilled water and EtOAc. After washing the organic layer with brine, drying and filtering it over MgSO4, concentrating it under reduced pressure, and using silica gel column chromatography, methyl 4-([1,1'-biphenyl]-4-ylmethyl) thiophene-3-carboxylate (306 mg, yield 75%) of a pale yellow oil was obtained. 1 H NMR (400 MHz, chloroform-d) δ 10.07 (s, 1H), 8.12 (d, J = 3.6 Hz, 1H), 7.99 - 7.94 (m, 1H), 7.78 - 7.73 (m, 1H), 7.67 - 7.62 (m, 1H), 7.61 - 7.53 (m, 1H), 7.52 - 7.46 (m, 2H), 7.45 - 7.41 (m, 1H), 7.41 - 7.36 (m, 1H), 7.32 (d, J = 3.7 Hz, 1H), 3.91 - 3.87 (m, 5H).

[0691] Step 3: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid

[0692]

[0693] A 2 N NaOH aqueous solution (0.2 mL) was added to a solution of methyl 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylate (121 mg, 0.39 mmol) mixed in THF (0.18 mL), and the mixture was stirred at 65°C for 12 hours. After cooling the reaction mixture to room temperature, a 2 N HCl aqueous solution was added to adjust the pH to 2, and the mixture was stirred for 2 hours and then extracted with EtOAc. The organic layer was washed with brine, dried and filtered over MgSO4, concentrated under reduced pressure, and purified by column chromatography to obtain 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid (51 mg, yield 42%), which is a white solid. 1 H NMR (500 MHz, chloroform-d) δ 8.28 (d, J = 3.6 Hz, 1H), 7.59-7.57 (m, 2H), 7.54 (d, J = 7.9 Hz, 2H), 7.47-7.44 (m, 2H), 7.33 (s, 1H), 7.32-7.28(m, 2H), 6.83(dd, J = 2.8, 1.7Hz, 1H), 4.31(s, 2H).

[0694] Step 4: Synthesis of Methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate

[0695]

[0696] Intermediate A (20 mg, 0.12 mmol), HATU (36 mg, 0.12 mmol), and DIPEA (0.03 mL, 0.4 mmol) were added to a solution of methyl 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid (30 mg, 0.1 mmol) in DCM (1 mL) and stirred for 12 hours. EtOAc and brine were added to the reaction mixture, the organic layer was dried with MgSO4, and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxyamide)spiro[3.3]heptane-2-carboxylate (26 mg, yield 59%), which is a white solid. 1H NMR (300 MHz, chloroform-d) δ 7.63 (d, J = 3.2 Hz, 1H), 7.61-7.51 (m, 4H), 7.45 (ddd, J = 7.6, 6.8, 1.3 Hz, 2H), 7.38-7.32 (m, 1H), 7.30 (s, 1H), 7.27(s, 1H), 6.97(dt, J = 3.2, 0.9 Hz, 1H), 5.82(d, J = 7.7 Hz, 1H), 4.39-4.27(m, 1H), 4.23(s, 2H), 3.68(s, 3H), 3.02(p, J = 8.4Hz, 1H), 2.54(tt, J = 7.5, 5.2Hz, 1H), 2.46-2.38(m, 1H).

[0697] Step 5: Synthesis of 6-(4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0698]

[0699] A 2 N NaOH aqueous solution was added to a solution of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (20 mg, 0.04 mmol) mixed in THF, and the mixture was stirred at 65°C for 12 hours. After cooling the reaction mixture to room temperature, a 2 N HCl aqueous solution was added to adjust the pH to 2, and the mixture was stirred for 2 hours and then extracted with EtOAc. The organic layer was washed with brine, dried and filtered over MgSO4, concentrated under reduced pressure, and purified by column chromatography to obtain the compound of Example 13 (3.2 mg, yield 19%), which is a white solid. 1H NMR (500 MHz, chloroform-d) δ 7.61 (d, J = 3.2 Hz, 1H), 7.58-7.55 (m, 2H), 7.54-7.50 (m, 2H), 7.45-7.40 (m, 2H), 7.36-7.31 (m, 1H), 7.27 (s, 2H), 6.95 (dt, J = 3.3, 0.9 Hz, 1H), 5.80 (d, J = 7.6 Hz, 1H), 4.33 (h, J = 8.0 Hz, 1H), 4.21 (s, 2H), 3.04 (p, J = 8.5 Hz, 1H), 2.55-2.49(m, 1H), 2.44-2.38(m, 1H), 2.35(dd, J = 8.5, 2.6 Hz, 2H), 2.26(dd, J = 11.8, 8.2Hz, 1H), 2.12-2.08(m, 1H), 1.78-1.71(m, 2H). LC / MS(ESI) m / z: 432.3 [M+H] + .

[0700] Example 14: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2-methylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0701] Step 1: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid

[0702]

[0703] LiOH·H2O (51 mg, 1.20 mmol, 3.0 equivalents) was added to a THF / MeOH / H2O (2 / 1 / 2 mL) solution of methyl 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylate (120 mg, 0.4 mmol) obtained in Step 2 of Example 13, and stirred for 3 hours. The reaction mixture was partially concentrated and acidified with 1 N HCl, after which the aqueous layer was extracted with EtOAc. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (15% EtOAc / hexane) to obtain 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid (101 mg, yield 86%) as a white solid. 1H NMR (400 MHz, Chloroform-d) δ 10.02 (s, 1H), 8.23 ​​(dd, J = 3.1, 1.2 Hz, 1H), 7.60 - 7.52 (m, 6H), 7.44 - 7.40 (m, 1H), 7.35 - 7.28 (m, 2H), 6.82(d, J = 3.3 Hz, 1H), 4.31(s, 2H).

[0704] Step 2: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-2-methylthiophene-3-carboxylic acid

[0705]

[0706] In a solution of methyl 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid (70 mg, 0.12 mmol) in THF (1 mL) cooled to -78℃ n -BuLi (2.5 M in THF, 125 μL, 0.27 mmol) was added and stirred for 30 minutes. Iodomethane (18 μL, 0.31 mmol) was slowly added at -78°C and the mixture was stirred at room temperature for 12 hours. After quenching the reaction mixture with distilled water (15 mL) and EtOAc, it was purified by silica gel column chromatography to obtain 4-([1,1'-biphenyl]-4-ylmethyl)-2-methylthiophene-3-carboxylic acid (32 mg, yield 45%) as a white solid. 1 H NMR (300 MHz, Chloroform-d) δ 7.60 - 7.51 (m, 3H), 7.48 - 7.38 (m, 3H), 7.35 - 7.26 (m, 2H), 7.00 (d, J = 5.4 Hz, 1H), 6.50 (d, J = 1.2 Hz, 1H), 4.24(s, 2H), 2.77(s, 3H).

[0707] Step 3: Synthesis of Methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2-methylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate

[0708]

[0709] 4-(4,6-dimethoxy-[1,3,5]triazine-2-yl)-4-methyl-morpholine-4-nium chloride (DMT-MM) (27 mg, 0.105 mmol) was added to a solution of 4-([1,1'-biphenyl]-4-ylmethyl)-2-methylthiophene-3-carboxylic acid (30 mg, 0.096 mmol) mixed in MeCN (0.6 mL) and stirred for 1 hour. Intermediate A (15 mg, 0.105 mmol) and N-methylpyrrolidone (25.8 μL) were added to the reaction mixture and stirred for 12 hours, after which the reaction was quenched with distilled water and EtOAc. The crude product was purified by column chromatography (hexane:EA (35%)) to obtain methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2-methylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (18 mg, yield 40%). 1 H NMR (500 MHz, Chloroform-d) δ 7.57-7.54 (m, 2H), 7.52-7.49 (m, 2H), 7.43 (dd, J = 8.5, 6.9 Hz, 2H), 7.36-7.32 (m, 1H), 7.25-7.21 (m, 2H), 6.74(s, 1H), 5.46(d, J = 7.7 Hz, 1H), 4.35-4.27(m, 1H), 4.02(s, 2H), 3.65(s, 3H), 2.96(q, J = 8.5 Hz, 1H), 2.50(s, 3H), 2.48-2.44(m, 1H), 2.37-2.33(m, 1H), 2.29(dd, J = 8.5, 4.0 Hz, 2H), 2.20(dd, J = 11.7, 8.4 Hz, 1H), 2.02(ddd, J = 11.6, 8.6, 2.7 Hz, 1H), 1.66-1.61(m, 2H).

[0710] Step 4: Synthesis of 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2-methylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0711]

[0712] LiOH·H2O (2 mg, 3.0 equivalents) was added to a solution of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2-methylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (10 mg) mixed in THF / MeOH / H2O (2 / 1 / 2 mL) and stirred for 3 hours. The mixture was partially concentrated and then acidified with a 1 N HCl aqueous solution. The aqueous layer was extracted with EtOAc, the organic layer was dried over MgSO4, and then concentrated under reduced pressure. The crude product was purified by column chromatography (hexane:EA (60%)) to obtain the compound of Example 14 (2.3 mg, yield 24%). 1 H NMR (500 MHz, Methanol-d4) δ 7.61 - 7.58 (m, 2H), 7.53-7.50 (m, 2H), 7.43 (td, J = 7.9, 2.1 Hz, 2H), 7.32 (td, J = 7.2, 1.4 Hz, 1H), 7.24(t, J = 8.4 Hz, 2H), 6.89(s, 1H), 4.21-4.16(m, 1H), 4.01(s, 2H), 2.96(q, J = 8.5 Hz, 1H), 2.44(s, 3H), 2.43-2.37(m, 1H), 2.35-2.26(m, 3H), 2.16(dd, J = 11.8, 8.4 Hz, 1H), 2.10-2.05(m, 1H), 1.86-1.79(m, 2H). LC / MS(ESI) m / z: 446.58 [M+H] + , 444.42 [M+H] - .

[0713] Example 15: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0714] Step 1: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid

[0715]

[0716] LiOH·H2O (530 mg, 12.645 mmol, 3.0 equivalents) was added to a THF / MeOH / H2O (2 / 1 / 2 mL) solution of methyl 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylate (1.3 g, 4.215 mmol) obtained in Step 2 of Example 13, and stirred for 12 hours. The reaction mixture was partially concentrated, acidified with a 1 N HCl aqueous solution, and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated under reduced pressure, after which the crude product was purified by a silica gel column to obtain 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid (350 mg, yield 28%) as an ivory solid. 1 H NMR (400 MHz, Chloroform-d) δ 8.32-8.28 (m, 1H), 7.64-7.60 (m, 2H), 7.60-7.55 (m, 2H), 7.48-7.43 (m, 2H), 7.37-7.32 (m, 3H), 6.89-6.82(m, 1H), 4.34(s, 2H).

[0717] Step 2: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxylic acid

[0718]

[0719] To a solution of 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid (200 mg, 0.66 mmol) in THF (1 mL), Br2 (0.04 mL, 0.69 mmol) was added at 0°C and stirred for 4 hours. The reaction mixture was acidified with a 1 N HCl aqueous solution, and the aqueous layer was extracted with ether. The organic layer was then washed with distilled water, dried over MgSO4, and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography to obtain 4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxylic acid (132 mg, yield 28%) as a brown solid. 1H NMR (500 MHz, Chloroform-d) δ 8.29(s, 1H), 7.59-7.54(m, 2H), 7.52-7.48(m, 2H), 7.44-7.40(m, 2H), 7.36-7.31(m, 1H), 7.30-7.29(m, 1H), 7.29-7.27(m, 1H), 4.41-4.36(m, 2H).

[0720] Step 3: Synthesis of Methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate

[0721]

[0722] DIPEA (0.070 mL, 0.402 mmol) was added to a mixed solution of 4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxylic acid (50 mg, 0.134 mmol) and HATU (56 mg, 0.147 mmol) in DMF (1 mL), and intermediate A (17 mg, 0.120 mmol) was added to the reaction mixture and stirred for 15 hours. The reaction mixture was diluted with ethyl acetate and washed with distilled water and a saline solution. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (20% ethyl acetate in hexane) to obtain methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (44.9 mg, yield 64%) as an ivory solid. 1H NMR (500 MHz, Chloroform-d) δ 7.56-7.53 (m, 3H), 7.50-7.48 (m, 2H), 7.44-7.39 (m, 2H), 7.35-7.31 (m, 1H), 7.26-7.22 (m, 2H), 5.82-5.76(m, 1H), 4.28-4.23(m, 1H), 4.22(s, 2H), 3.63(s, 3H), 3.02- 2.91(m, 1H), 2.48-2.41(m, 1H), 2.35-2.31(m, 1H), 2.30-2.25(m, 2H), 2.22-2.16(m, 1H), 2.04- 1.96(m, 1H), 1.68-1.59(m, 2H).

[0723] Step 4: Synthesis of 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0724]

[0725] LiOH·H2O (5 mg, 0.114 mmol, 3.0 equivalents) was added to a solution of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (20 mg, 0.038 mmol) in THF / MeOH / H2O (2 / 1 / 2 mL) and stirred for 3 hours. The mixture was partially concentrated and then acidified with 1 N HCl, after which the aqueous layer was extracted with EtOAc. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The crude product was purified using a silica gel column to obtain the compound of Example 15 (15 mg, yield 77%) as an ivory solid. 1H NMR (400 MHz, Chloroform-d) δ 7.58(s, 1H), 7.56-7.52(m, 2H), 7.51-7.47(m, 2H), 7.45-7.40(m, 2H), 7.36-7.30(m, 1H), 7.25-7.21(m, 2H), 5.74-5.68(m, 1H), 4.33-4.26(m, 1H), 4.23(s, 2H), 3.05-2.94(m, 1H), 2.50-2.41(m, 1H), 2.39-2.35(m, 1H), 2.34-2.29(m, 2H), 2.24-2.16(m, 1H), 2.07-1.99(m, 1H), 1.68-1.58(m, 2H). LC / MS(ESI) m / z: 510.51 [M+H] + , 508.35 [MH] - .

[0726] Example 16: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0727] Step 1: Synthesis of Methyl 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxylate

[0728]

[0729] NBS (287 mg, 1.622 mmol) was added in DMF (3 mL) to methyl 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylate (100 mg, 0.324 mmol) obtained in Step 2 of Example 13, and stirred at 80°C for 24 hours. A 10% aqueous sodium bicarbonate solution and EA were added to the reaction mixture, and the organic layer was dried and concentrated over MgSO4 to obtain methyl 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxylate (76 mg, yield 50%) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 7.59 - 7.53 (m, 2H), 7.51 - 7.46 (m, 2H), 7.44 - 7.39 (m, 2H), 7.30 - 7.33 (m, 1H), 7.18 (d, J = 8.2 Hz, 2H), 4.23(s, 2H), 3.76(s, 3H).

[0730] Step 2: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxylic acid

[0731]

[0732] LiOH·H2O (21 mg, 0.489 mmol) was added to a solution of methyl 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxylate (76 mg, 0.163 mmol) in THF / MeOH / H2O (1 / 1 / 1 mL) and stirred for 12 hours. The reaction mixture was partially concentrated, acidified with a 1 N HCl aqueous solution, and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated to obtain 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxylic acid (35.5 mg, yield 47%) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 7.50 - 7.56 (m, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.45 - 7.40 (m, 2H), 7.35 - 7.32 (m, 1H), 7.19 (d, J = 8.2 Hz, 2H), 4.29(s, 2H).

[0733] Step 3: Synthesis of Methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate

[0734]

[0735] After adding DIPEA (0.041 mL, 0.237 mmol) to a mixed solution of 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxylic acid (35.5 mg, 0.079 mmol) and HATU (33 mg, 0.086 mmol) in DMF (1 mL), intermediate A (18 mg, 0.086 mmol) was added and stirred for 15 hours. The reaction mixture was diluted with ethyl acetate and washed with distilled water and a saline solution. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (43.8 mg, yield 92%) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 7.57-7.51 (m, 2H), 7.50-7.40 (m, 4H), 7.37-7.30 (m, 1H), 7.20 (s, 2H), 5.58 (d, J = 7.9 Hz, 1H), 4.32-4.24(m, 1H), 4.11(s, 2H), 3.65(s, 3H), 3.02-2.91(m, 1H), 2.50-2.42(m, 1H), 2.25-2.40(m, 3H), 2.20-2.17(m, 1H), 2.06-1.99(m, 1H), 1.73-1.63(m, 2H).

[0736] Step 4: Synthesis of 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0737]

[0738] LiOH·H2O (9 mg, 0.209 mmol) was added to a solution of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (42 mg, 0.070 mmol) in THF / MeOH / H2O (1 / 1 / 1 mL) and stirred for 12 hours. The reaction mixture was partially concentrated, acidified with a 1 N aqueous HCl solution, and filtered to obtain the compound of Example 16 (4 mg, yield 4%) as a white solid. 1 H NMR (300 MHz, CDCl3) δ 7.56-7.51 (m, 2H), 7.50-7.39 (m, 4H), 7.36-7.33 (m, 1H), 7.21 (d, J = 8.2 Hz, 2H), 5.58 (d, J = 7.7 Hz, 1H), 4.32-4.24(m, 1H), 4.11(s, 2H), 3.06-2.95(m, 1H), 2.51-2.29(m, 4H), 2.25-2.17(m, 1H), 2.14-2.04(m, 1H), 1.77-1.63(m, 2H). LC / MS(ESI) m / z: 590.4 [M+H] + .

[0739] Example 17: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dichlorothiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0740] Step 1: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dichlorothiophene-3-carboxylic acid

[0741]

[0742] NCS (250 mg, 1.869 mmol) was added to 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid (110 mg, 0.374 mmol) obtained in Step 3 of Example 13 in DMF (3.6 mL), heated to 70°C, and stirred for 24 hours. The reaction mixture was quenched with a 10% aqueous sodium bicarbonate solution, extracted with EA and distilled water after 15 minutes, and dried and concentrated over MgSO4 to obtain a crude product (34.4 mg, yield 25%) of 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dichlorothiophene-3-carboxylic acid. 1H NMR (300 MHz, CDCl3) δ 7.58-7.52 (m, 2H), 7.52-7.46 (m, 2H), 7.42 (td, J = 8.2, 1.8 Hz, 3H), 7.36 (s, 1H), 7.23 (d, J = 8.2 Hz, 2H), 4.29(s, 2H).

[0743] Steps 2 and 3: Synthesis of 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dichlorothiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0744]

[0745] The 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dichlorothiophene-3-carboxylic acid obtained in Step 1 above was reacted in the same manner as Steps 3 and 4 of Example 16 to obtain the compound of Example 17. 1 H NMR (300 MHz, CDCl3) δ 7.57-7.51 (m, 2H), 7.50-7.39 (m, 4H), 7.34-7.31 (m, 1H), 7.22 (d, J = 8.2 Hz, 2H), 5.68 (d, J = 7.6 Hz, 1H), 4.33-4.25(m, 1H), 4.11(s, 2H), 3.07-2.95(m, 1H), 2.53-2.30(m, 4H), 2.27-2.03 (m, 2H), 1.75-1.66(m, 2H). LC / MS(ESI) m / z: 500.3[M+H] + .

[0746] Example 18: 6-(3-([1,1'-biphenyl]-4-ylmethyl)thiophene-2-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0747] Step 1: Synthesis of 3-([1,1'-biphenyl]-4-ylmethyl)thiophene-2-carboxylic acid

[0748]

[0749] to thiophene-2-carboxylic acid (200 mg, 1.561 mmol) in THF (15 mL) n-BuLi (10 M in THF, 0.324 mL, 3.434 mmol) was slowly added at -78°C for 0.5 hours, after which 4-(bromomethyl)-1,1'-biphenyl (772 mg, 3.122 mmol) was added. The reaction mixture was stirred for 6 hours, then quenched with 1 N aqueous HCl solution and extracted with EA and distilled water. The organic layer was dried with MgSO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography to obtain 3-([1,1'-biphenyl]-4-ylmethyl)thiophene-2-carboxylic acid as a white solid (28 mg, yield 6%). 1 H NMR (300 MHz, CDCl3) δ 7.60 - 7.55 (m, 2H), 7.55 - 7.48 (m, 3H), 7.45 - 7.40 (m, 2H), 7.35 - 7.28 (m, 3H), 6.93 (d, J = 5.1 Hz, 1H), 4.45(s, 2H).

[0750] Step 2: Synthesis of Methyl 6-(3-([1,1'-biphenyl]-4-ylmethyl)thiophene-2-carboxamido)spiro[3,3]heptane-2-carboxylate

[0751]

[0752] DIPEA (0.046 mL, 0.264 mmol) was added to a mixed solution of 3-([1,1'-biphenyl]-4-ylmethyl)thiophene-2-carboxylic acid (26 mg, 0.088 mmol) and HATU (20 mg, 0.097 mmol) in DCM (1 mL) and stirred for 10 minutes. Intermediate A (20 mg, 0.097 mmol) was added to the reaction mixture and stirred for 15 hours. The reaction mixture was diluted with ethyl acetate and washed with distilled water and a saline solution. The organic layer was dried with Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (20% EtOAc in Hexane) to obtain methyl 6-(3-([1,1'-biphenyl]-4-ylmethyl)thiophene-2-carboxamido)spiro[3.3]heptane-2-carboxylate (32 mg, yield 82%) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.59-7.50 (m, 4H), 7.42 (t, J = 7.3 Hz, 2H), 7.34 (d, J = 7.3 Hz, 1H), 7.32-7.27 (m, 3H), 6.92 (d, J = 5.0 Hz, 1H), 5.84(d, J = 7.5 Hz, 1H), 4.50-4.34(m, 3H), 3.66(s, 3H), 3.07-2.96(m, 1H), 2.59-2.51(m, 1H), 2.46-2.40(m, 1H), 2.35-2.22(m, 3H), 2.14-2.07(m, 1H), 1.87-1.76(m, 2H).

[0753] Step 3: Synthesis of 6-(3-([1,1'-biphenyl]-4-ylmethyl)thiophene-2-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0754]

[0755] LiOH·H2O (9 mg, 0.209 mmol) was added to a solution of methyl 6-(3-([1,1'-biphenyl]-4-ylmethyl)thiophene-2-carboxamido)spiro[3.3]heptane-2-carboxylate (32 mg, 0.072 mmol) in THF / MeOH / H2O (1 / 1 / 1) and stirred for 12 hours. The reaction mixture was partially concentrated, then acidified with a 1 N HCl aqueous solution, and filtered to obtain the compound of Example 18 (30.7 mg, yield 99%) as a pale yellow solid. 1 H NMR (300 MHz, CDCl3) δ 7.59-7.50 (m, 4H), 7.42 (t, J = 7.4 Hz, 2H), 7.34 (d, J = 7.4 Hz, 1H), 7.31-7.26 (m, 3H), 6.92 (d, J = 5.0 Hz, 1H), 5.85(d, J = 7.5 Hz, 1H), 4.47-4.29(m, 3H), 3.11-2.99(m, 1H), 2.60-2.52(m, 1H), 2.46-2.40(m, 1H), 2.38-2.36(m, 2H), 2.30-2.26(m, 1H); 2.18-2.14(m, 1H), 1.87-1.77(m, 2H). LC / MS(ESI) m / z: 432.4 [M+H]+ .

[0756] Example 19: 6-(3-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)thiophene-2-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0757] Steps 1 and 2: Synthesis of Methyl 6-(3-(4-chlorobenzyl)thiophene-2-carboxamido)spiro[3,3]heptane-2-carboxylate

[0758]

[0759] Methyl 6-(3-(4-chlorobenzyl)thiophene-2-carboxamido)spiro[3.3]heptane-2-carboxylate was obtained in the same manner as steps 1 and 2 of Example 18, except that 4-chlorobenzyl bromide was used instead of 4-(bromomethyl)-1,1-biphenyl in step 1 of Example 18. 1 H NMR (300 MHz, chloroform-d) δ 7.25-7.17 (m, 3H), 7.17-7.09 (m, 2H), 6.80 (d, J = 5.0 Hz, 1H), 5.95 (d, J = 7.5 Hz, 1H), 4.42-4.28 (m, 1H), 4.24(s, 2H), 3.64(s, 3H), 3.06-2.95(m, 1H), 2.57-2.49(m, 1H), 2.46-2.36(m, 1H), 2.34-2.22(m, 3H), 2.17-2.07(m, 1H), 1.91-1.80(m, 2H).

[0760] Step 3: Synthesis of methyl 6-(3-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)thiophene-2-carboxamido)spiro[3,3]heptane-2-carboxylate

[0761]

[0762] Methyl 6-(3-(4-chlorobenzyl)thiophene-2-carboxamido)spiro[3,3]heptane-2-carboxylate (286 mg, 0.7 mmol), 3-fluoro-5-methoxyphenylboronic acid (178 mg, 1.05 mmol, 1.5 equivalents), Pd(OAc)2 (16 mg, 0.07 mmol, 0.1 equivalents), XPhos (67 mg, 0.14 mmol, 0.2 equivalents), and K3PO4 (297 mg, 1.4 mmol, 2.0 equivalents) were stirred in 1,4-dioxane / H2O (10 / 1 mL) under microwave irradiation at 100°C for 2 hours. The reaction mixture was poured into distilled water and extracted with DCM. The organic layer was dried with MgSO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography to obtain methyl 6-(3-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)thiophene-2-carboxamido)spiro[3,3]heptane-2-carboxylate. 1 H NMR (300 MHz, chloroform-d) δ 7.47 (d, J = 8.2 Hz, 2H), 7.33-7.27 (m, 2H), 6.93-6.80 (m, 3H), 6.58 (dt, J = 10.5, 2.3 Hz, 1H), 5.89 (d, J = 7.5 Hz, 1H), 4.44-4.35(m, 1H), 4.34(s, 2H), 3.83(s, 3H), 3.65(s, 3H), 3.07-2.96(m, 1H), 2.63-2.49(m, 1H), 2.47-2.24(m, 4H), 2.15-2.07(m, 1H), 1.90-1.79 (m, 2H).

[0763] Step 4: Synthesis of 6-(3-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)thiophene-2-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0764]

[0765] The methyl 6-(3-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)thiophene-2-carboxamido)spiro[3,3]heptane-2-carboxylate obtained in Step 3 above was reacted in the same manner as in Step 3 of Example 18 to obtain the compound of Example 19. 1 H NMR (300 MHz, Methanol-d4) δ 8.15 (d, J = 7.2 Hz, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 5.0 Hz, 1H), 7.26 (d, J = 8.3 Hz, 2H), 6.94 (t, J = 1.9 Hz, 1H), 6.92-6.86(m, 2H), 6.64(dt, J = 10.7, 2.3 Hz, 1H), 4.31-4.23(m, 3H), 3.83(s, 3H), 3.07-2.95(m, 1H), 2.54-2.46(m, 1H), 2.39-2.30(m, 3H), 2.29-2.14(m, 2H), 2.07-1.96(m, 2H). LC / MS(ESI) m / z: 480.4 [M+H] + .

[0766] Example 20: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0767] Step 1: Synthesis of Methyl 4-([1,1'-Biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxylate

[0768]

[0769] In an AcOH solution containing methyl 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylate (200 mg, 0.649 mmol) obtained in Step 2 of Example 13 NBromosuccinimide (NBS, 115 mg, 0.649 mmol) was slowly added at room temperature. After stirring for 15 hours, the reaction mixture was extracted with DCM and washed with an aqueous sodium carbonate solution and distilled water. The organic layer was washed twice again with distilled water and dried with MgSO4, then filtered and concentrated under reduced pressure. The crude product was purified by silica gel (hexane) column chromatography to obtain methyl 4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxylate (150 mg, yield 59%) as a yellow solid. 1 H NMR (300 MHz, Chloroform-d) δ 8.16(s, 1H), 7.64-7.59(m, 2H), 7.57-7.53(m, 2H), 7.49-7.43(m, 2H), 7.39-7.30(m, 3H), 4.42(s, 2H), 3.83(s, 3H).

[0770] Step 2: Synthesis of Methyl 4-([1,1'-Biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxylate

[0771]

[0772] Iodomethane (0.065 mL, 1.548 mmol, 3.0 equivalents) was added to a THF (10 mL) solution mixed with methyl 4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxylate (200 mg, 0.516 mmol) and cooled to -78°C. To the reaction mixture n -BuLi (2M in THF, 0.516 mL, 1.032 mmol) was added and stirred for 4 hours, then slowly heated to room temperature, diluted with ethyl acetate, and washed with distilled water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain a crude product (49 mg) of methyl 4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxylate as a yellow solid. 1H NMR (400 MHz, Chloroform-d) δ 7.99(s, 1H), 7.61-7.59(m, 2H), 7.53-7.51(m, 2H), 7.46-7.44(m, 2H), 7.37-7.33(m, 2H), 7.23-7.22(m, 1H), 4.36(s, 2H), 3.82(s, 3H), 2.46(s, 3H).

[0773] Step 3: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxylic acid

[0774]

[0775] LiOH·H2O (8 mg, 0.186 mmol, 3 equivalents) was added to a mixed solution of methyl 4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxylate (20 mg, 0.062 mmol) in THF / MeOH / H2O (2 / 1 / 2) and stirred for 8 hours. The reaction mixture was partially concentrated and then acidified with an aqueous 1 N HCl solution. The aqueous layer was extracted with EtOAc, the organic layer was dried with MgSO4, and then concentrated under reduced pressure. The crude product was purified by a silica gel column to obtain 4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxylic acid (4.3 mg, yield 22%) as an ivory solid. 1 H NMR (300 MHz, chloroform-d) δ 8.10(s, 1H), 7.59-7.54(m, 2H), 7.50-7.47(m, 2H), 7.45-7.39(m, 2H), 7.36-7.31(m, 1H), 7.22-7.16(m, 2H), 4.34(s, 2H), 2.44(s, 3H).

[0776] Step 4: Synthesis of Methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate

[0777]

[0778] DIPEA (0.013 mL, 0.072 mmol) was added to a mixed solution of 4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxylic acid (7.3 mg, 0.024 mmol) and HATU (10 mg, 0.026 mmol) in DMF and stirred for 10 minutes, after which intermediate A (4 mg, 0.026 mmol) was added and stirred for 15 hours. The reaction mixture was diluted with ethyl acetate and washed with distilled water and brine. The organic layer was dried with Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (20% EtOAc in hexane) to obtain methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (6.9 mg, yield 63%) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 7.58-7.56(m, 2H), 7.52-7.50(m, 2H), 7.47-7.43(m, 2H), 7.41(s, 1H), 7.38-7.33(m, 1H), 7.22-7.17(m, 2H), 5.77-5.71(m, 1H), 4.36-4.28(m, 1H), 4.19(s, 2H), 3.67(s, 3H), 3.04-2.95(m, 1H), 2.52-2.48(m, 1H), 2.46(s, 3H), 2.40-2.34(m, 1H); 2.34-2.27(m, 2H), 2.26-2.18(m, 1H), 2.08-2.00(m, 1H), 1.68-1.63(m, 2H).

[0779] Step 5: Synthesis of 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0780]

[0781] LiOH·H2O (2 mg, 0.044 mmol, 3.0 equivalents) was added to a solution of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate (6.8 mg, 0.015 mmol) in THF / MeOH / H2O (2 / 1 / 2) and stirred for 3 hours. The reaction mixture was partially concentrated and then acidified with a 1 N HCl aqueous solution, after which the aqueous layer was extracted with EtOAc. The organic layer was dried with MgSO4 and then concentrated under reduced pressure. The crude product was purified by a silica gel column to obtain the compound of Example 20 (4.7 mg, yield 70%) as an ivory solid. 1 H NMR (500 MHz, chloroform-d) δ 7.58-7.56 (m, 2H), 7.53-7.50 (m, 2H), 7.47-7.43 (m, 3H), 7.38-7.34 (m, 1H), 7.22-7.17 (m, 2H), 5.76-5.71(m, 1H), 4.31-4.29(m, 1H), 4.19(s, 2H), 3.05-2.98(m, 1H), 2.52-2.49(m, 1H), 2.46(s, 3H), 2.36-2.33(m, 3H), 2.27-2.22(m, 1H), 2.10-2.05(m, 1H), 1.71-1.65(m, 2H). LC / MS(ESI) m / z: 446.11 [M+H] + , 444.28 [MH] - .

[0782] The compounds of Examples 21 and 22 were prepared using the same method as described in Example 20, except for differences in the manufacturing method described below.

[0783] Example number chemical structure designation Differences in manufacturing methods 21 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-phenylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid Suzuki coupling was performed using phenylboronic acid instead of MeI in Step 2. Reaction reagents and conditions: Na2CO3 (4 equivalents) and Pd(PPh3)4 (12 mol%), toluene / H2O (6:1), 90°C, 12 hours. 22 6-(4-(1,1'-biphenyl]-4-ylmethyl)-5-cyclopropylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid Suzuki coupling was performed using cyclopropylboronic acid instead of MeI in Step 2. The reaction reagents and conditions were the same as in Example 21.

[0784] Example number LC / MS(ESI) m / z: [M+H] + NMR 21 n+1=508.5 1 H NMR(300 MHz, DMSO) δ 12.04(s, 1H), 8.39(d, J = 7.4 Hz, 1H), 7.89(s, 1H), 7.62-7.55(m, 2H), 7.51-7.38(m, 8H), 7.35-7.29(m, 1H), 7.02-6.95(m, 2H), 4.23(s, 2H), 4.13-4.05(m, 1H), 2.94-2.83(m, 1H), 2.35-2.25(m, 1H), 2.24-1.96(m, 5H), 1.92-1.81(m, 2H). 22 n+1=472.4 1 H NMR(300 MHz, DMSO-d6) δ 12.05(s, 1H), 8.32(d, J = 7.5 Hz, 1H), 7.64 - 7.58(m, 2H), 7.54(s, 1H), 7.51(d, J = 8.2 Hz, 2H), 7.44(t, J = 7.5 Hz, 2H), 7.36-7.31(m, 1H), 7.22(d, J = 8.2 Hz, 2H), 4.26(s, 2H), 4.21-4.08(m, 1H), 2.97-2.86(m, 1H), 2.40-2.32(m, 1H), 2.26 - 2.02(m, 6H), 1.98 - 1.86(m, 2H), 1.07 - 0.98(m, 2H), 0.63 - 0.57(m, 2H).

[0785] Example 23: 6-(4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0786] Step 1: Synthesis of 3-Bromo-4-(4-chlorobenzyl)-2,5-dimethylthiophene

[0787]

[0788] Intermediate C (1.15 g, 6.0 mmol), MsOH (78 μL, 1.20 mmol), and FeCl3 (194 mg, 1.20 mmol) were added to a solution of (4-chlorophenyl)methanol (427 mg, 3.0 mmol) mixed with DCE (3 mL), and then heated to 55°C and stirred for 12 hours. The reaction mixture was diluted with ethyl acetate and washed with distilled water and a saline solution. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The crude product was purified by column chromatography to obtain bromo-4-(4-chlorobenzyl)-2,5-dimethylthiophene (541 mg, yield 57%) as a white solid. 1 H NMR (300MHz, chloroform-d) δ 7.28-7.20(m, 2H), 7.08(d, J = 8.6 Hz, 2H), 3.91(s, 2H), 2.37(s, 3H), 2.35(s, 3H).

[0789] Step 2: Synthesis of 4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxylic acid

[0790]

[0791] In a solution of 3-bromo-4-(4-chlorobenzyl)-2,5-dimethylthiophene (541 mg, 1.71 mmol) and TMEDA (0.3 mL, 1.88 mmol) mixed in THF (10 mL) n -BuLi (2.5 M in THF, 0.8 mL, 2.0 mmol) was added at -78°C and stirred for 1 hour. The reaction mixture was quenched with CO2 gas at -78°C and left at room temperature for 30 minutes. The reaction mixture was acidified with a 1 N HCl solution, diluted with EtOAc, and washed with distilled water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain 4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxylic acid (450 mg, crude product) as a pale yellow solid. LC / MS(ESI) m / z: 281.26 [M+H] + .

[0792] Step 3: Synthesis of Methyl 6-(4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate

[0793]

[0794] Dipaea (0.8 mL, 4.81 mmol) was added to a solution of 4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxylic acid (450 mg, 1.60 mmol) and HATU (670 mg, 1.76 mmol) mixed in DMF (8 mL) and stirred for 10 minutes, after which intermediate A (330 mg, 1.60 mmol) was added to the reaction mixture and stirred for 15 hours. The reaction mixture was diluted with EtOAc and washed with distilled water and a saline solution. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure. The crude product was purified by column chromatography to obtain methyl 6-(4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (418 mg, yield 56%) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 7.23 (d, J = 8.5 Hz, 2H), 7.04 (d, J = 8.4 Hz, 2H), 5.47 - 5.17 (m, 1H), 4.36 - 4.17 (m, 1H), 3.91 (s, 2H), 3.69 (s, 3H), 3.02 (t, J = 8.5 Hz, 1H), 2.54 - 2.41 (m, 4H), 2.40 - 2.29 (m, 5H), 2.25 (dd, J = 11.7, 8.4 Hz, 1H), 2.13 - 2.01 (m, 1H), 1.68 - 1.52(m, 3H). LC / MS(ESI) m / z: 432.37 [M+H] + .

[0795] Step 4: Synthesis of 6-(4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0796]

[0797] LiOH·H2O (13 mg, 0.3 mmol) was added to a solution mixed with methyl 6-(4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (43 mg, 0.1 mmol) in H2O:THF:MeOH (1:1:1) and stirred for 4 hours. The reaction mixture was partially concentrated under reduced pressure, acidified (pH ~6) by adding 1 N HCl, and then extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the compound of Example 23 (30 mg, yield 71%). 1 H NMR (300 MHz, chloroform-d) δ 7.27-7.18 (m, 2H), 7.04 (d, J = 8.5 Hz, 2H), 5.35 (d, J = 7.9 Hz, 1H), 4.27 (d, J = 7.8 Hz, 1H), 3.91 (s, 2H), 3.06(t, J = 8.5 Hz, 1H), 2.53-2.44(m, 1H), 2.43(s, 3H), 2.41-2.35(m, 2H), 2.35-2.30(m, 1H), 2.33(s, 3H), 2.31-2.21(m, 1H), 2.17-2.06(m, 1H), 1.60 (dt, J = 11.5, 7.7 Hz, 2H). LC / MS(ESI) m / z: 418.23 [M+H] + .

[0798] The compounds of Examples 24 and 25 were prepared using the same method as described in Example 23, except for differences in the manufacturing method described below.

[0799] Example number chemical structure designation Differences in manufacturing methods 24 6-(4-((2'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid Use intermediate G instead of (4-chlorophenyl)methanol in Step 1 25 6-(4-((2'-hydroxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid The methoxy group of the compound in Example 24 was demethylated. Reaction conditions and reagents: BBr3, DCM (0.01M), rt, 1.5h

[0800] Example number LC / MS(ESI) m / z: [M+H] + NMR 24 ES+ 490.12 1 H NMR(500 MHz, CDCl3) δ 7.42(d, J = 8.2 Hz, 2H), 7.29(td, J = 7.8, 1.8 Hz, 1H), 7.25-7.22(m, 3H), 7.09(d, J = 7.9 Hz, 2H), 7.00(td, J = 7.5, 1.1 Hz, 1H), 6.96(d, J = 8.2 Hz, 1H), 5.36(d, J = 7.9 Hz, 1H), 4.23(h, J = 7.9 Hz, 1H), 3.86(d, J = 83.4 Hz, 5H), 2.96(p, J = 8.5 Hz, 1H), 2.42(s, 3H), 2.34(s, 3H), 2.27(dd, J = 8.6, 2.4Hz, 3H), 2.15(dd, J = 11.8, 8.2 Hz, 1H), 1.48(ddd, J = 17.8, 11.4, 8.5 Hz, 2H). 25 ES+ 476.15 1 H NMR(500 MHz, CDCl3) δ 7.38(d, J = 7.8Hz, 2H), 7.24(s, 1H), 7.20(d, J = 7.8 Hz, 3H), 6.99-6.94(m, 2H), 5.41(d, J = 7.8 Hz, 1H), 4.28(d, J = 8.0 Hz, 1H), 3.98(s, 2H), 3.03-2.99(m, 1H), 2.44(s, 3H), 2.36(s, 3H), 2.31(d, J = 8.5 Hz, 2H), 1.56(dt, J = 20.7, 10.1Hz, 8H).

[0801] Example 26: 6-(2,5-dimethyl-4-(4-(pyridine-4-yl)benzyl)thiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0802] Step 1: Synthesis of Methyl 6-(2,5-dimethyl-4-(4-(pyridine-4-yl)benzyl)thiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate

[0803]

[0804] After replacing the solution obtained in Step 3 of Example 23, in which methyl 6-(4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-carboxylate (27 mg, 0.06 mmol), pyridine-4-ylboronic acid (9 mg, 0.075 mmol), and K3PO4 (13 mg, 0.063 mmol) were mixed in 1,4-dioxane:H2O (2:1), under an N2 atmosphere, Pd2(dba)3 (6 mg, 6.2 μmol) and PCy3 (3 mg, 9.4 μmol) were added. After microwave irradiating the reaction mixture at 110°C for 1.5 hours, it was filtered through Celite and concentrated under reduced pressure to obtain methyl 6-(2,5-dimethyl-4-(4-(pyridine-4-yl)benzyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate. LC / MS(ESI) m / z: 476.28 [M+2] + .

[0805] Step 2: Synthesis of 6-(2,5-dimethyl-4-(4-(pyridine-4-yl)benzyl)thiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0806]

[0807] LiOH·H2O (9 mg, 0.18 mmol) was added to a solution of methyl 6-(2,5-dimethyl-4-(4-(pyridine-4-yl)benzyl)thiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate (crude product, 0.06 mmol) mixed in H2O:THF:MeOH (1:1:1) and stirred for 4 hours. The reaction mixture was concentrated under reduced pressure and diluted with distilled water, then acidified with 1 N HCl (pH ~6) and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the compound of Example 26 (12 mg, yield 42%) as a white solid. 1H NMR (300 MHz, methanol-d4) δ 8.92-8.31 (m, 2H), 7.68 (dd, J = 14.7, 7.0 Hz, 4H), 7.25 (d, J = 8.1 Hz, 2H), 4.34-3.95 (m, 1H), 4.00 (s, 2H), 3.07-2.82(m, 1H), 2.38(s, 6H), 2.34-2.19(m, 3H), 2.20-1.93(m, 3H), 1.91-1.60(m, 2H). LC / MS(ESI) m / z: 462.31 [M+2] + .

[0808] Example 27: 6-(2,5-dimethyl-4-(4-(pyridine-3-yl)benzyl)thiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0809]

[0810] The compound of Example 27 as a white solid was obtained by the same method described in Example 26, except that pyridin-3-ylboronic acid was used instead of pyridin-4-ylboronic acid in Step 1 of Example 26. 1 H NMR (500MHz, methanol-d4) δ 8.78 (s, 1H), 8.51 (d, J = 4.2Hz, 1H), 8.08 (d, J = 8.0Hz, 1H), 7.62-7.49 (m, 3H), 7.24 (d, J = 8.2Hz, 2H), 4.26-4.08(m, 1H), 4.00(s, 2H), 3.03-2.87(m, 1H), 2.45-2.37(m, 1H), 2.38(s, 6H), 2.35-2.21(m, 3H), 2.13(dd, J = 8.2 Hz, 1H), 2.10-2.00(m, 1H), 1.79(ddd, J = 24.7, 11.0, 8.9 Hz, 2H). LC / MS(ESI) m / z: 462.24 [M+2] + .

[0811] Example 28: 6-(4-((3',4'-dimethyl-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0812] Step 1: Synthesis of methyl 6-(4-((3',4'-dimethyl-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate

[0813]

[0814] Methyl 6-(4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-carboxylate (50 mg, 0.023 mmol) and 3,4-dimethylphenylboronic acid (4.1 mg, 0.027 mmol) obtained in Step 3 of Example 23 were placed in a sealed tube in 1,4-dioxane (0.2 mL), and distilled water (0.01 mL) and Cs2CO3 (8 mg, 0.046 mmol) were added. After adding Pd(OAc)2 (0.5 mg) and Xphos (13 mg, 0.023 mmol) under N2 atmosphere, the reaction mixture was stirred at 90°C for 15 hours. The reaction mixture was diluted with ethyl acetate, washed with distilled water, dried with Na2SO4, filtered, and concentrated. The crude product was purified using a silica column (6% MeOH in CHCl3) to obtain methyl 6-(4-((3',4'-dimethyl-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (20 mg, mixture). 1 H NMR (500 MHz, Chloroform-d) δ 7.48-7.45(m, 2H), 7.32(d, J = 2.0 Hz, 1H), 7.28(dd, J = 7.8, 2.1 Hz, 1H), 7.19(d, J = 8.1 Hz, 1H), 7.13(d, J = 8.2 Hz, 2H), 5.38(d, J = 7.8 Hz, 1H), 4.24(h, J = 7.9 Hz, 1H), 3.96(s, 2H), 3.63(s, 3H), 2.96-2.90(m, 1H), 2.43(s, 2H), 2.42-2.39(m, 2H), 2.35(s, 3H), 2.32(s, 3H), 2.30(s, 3H), 2.27-2.23(m, 2H), 2.15(dd, J = 11.7, 8.5 Hz, 1H), 1.96(ddd, J = 11.7, 8.6, 2.9 Hz, 1H), 1.49 (ddd, J = 14.9, 11.4, 8.5 Hz, 2H).

[0815] Step 2: Synthesis of 6-(4-((3',4'-dimethyl-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0816]

[0817] LiOH·H2O (4 mg, 0.084 mmol, 3.0 equivalents) was added to a solution of methyl 6-(4-((3',4'-dimethyl-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (20 mg) in THF / MeOH / H2O (2 / 1 / 2) and stirred for 3 hours. The reaction mixture was partially concentrated, then acidified with an aqueous 1 N HCl solution, and the aqueous layer was extracted with EtOAc. The organic layer was dried with MgSO4 and then concentrated under reduced pressure. The crude product was purified by preparative TLC to obtain the compound of Example 28 (3.4 mg, yield 30%). 1 H NMR (500 MHz, chloroform-d) δ 7.49-7.45 (m, 2H), 7.32 (d, J = 2.0 Hz, 1H), 7.28 (dd, J = 7.8, 2.1 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 7.14-7.11(m, 2H), 5.35(d, J = 7.8 Hz, 1H), 4.24(h, J = 8.0 Hz, 1H), 3.96(s, 2H), 2.97(p, J = 8.5 Hz, 1H), 2.43(s, 3H), 2.42-2.36(m, 2H), 2.36(s, 3H), 2.32(s, 3H), 2.30(s, 3H), 2.28(t, J = 4.1 Hz, 2H), 2.17(dd, J = 11.7, 8.3 Hz, 1H), 1.99(ddd, J = 11.6, 8.7, 2.4 Hz, 1H), 1.49(dt, J = 11.7, 9.1 Hz, 2H). LC / MS(ESI) m / z: 488.43 [M+H] + .

[0818] The compounds of Examples 29 to 66 were prepared using the same method as described in Example 28, except for differences in the manufacturing method described below.

[0819] Example number chemical structure designation Differences in manufacturing methods 29 6-(4-((3'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid Use 3-methoxyphenylboronic acid instead of 3,4-dimethylphenylboronic acid in Step 1 30 6-(4-((3'-cyano-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid Use 3-(cyanophenyl)boronic acid instead of 3,4-dimethylphenylboronic acid in Step 1 31 6-(4-((4'-ethyl-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Use 4-ethylphenylboronic acid instead of 3,4-dimethylphenylboronic acid in Step 1 32 6-(2,5-dimethyl-4-((2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Use 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane instead of 3,4-dimethylphenylboronic acid in Step 1 33 6-(4-(4-(furan-3-yl)benzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid Use 3-furylboronic acid instead of 3,4-dimethylphenylboronic acid in Step 1 34 6-(4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid Use 3-fluoro-5-methoxyphenylboronic acid instead of 3,4-dimethylphenylboronic acid in Step 1 35 6-(2,5-dimethyl-4-((4'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)methyl)thiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid Use 4-(methanesulfonyl)phenylboronic acid instead of 3,4-dimethylphenylboronic acid in Step 1 36 6-(4-((4'-(tert-butoxycarbonyl)-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Use 4-tert-butoxycarbonylphenylboronic acid instead of 3,4-dimethylphenylboronic acid in Step 1 37 6-(4-((3'-carboxy-4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Use 4-fluoro-3-methoxycarbonylphenylboronic acid instead of 3,4-dimethylphenylboronic acid in Step 1 38 6-(2,5-dimethyl-4-((2'-methyl-[1,1'-biphenyl]-4-yl)methyl)thiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid Use 2-methylphenylboronic acid instead of 3,4-dimethylphenylboronic acid in Step 1 39 6-(2,5-dimethyl-4-(4-(1-methyl-1H-pyrazole-4-yl)benzyl)thiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid Use 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole instead of 3,4-dimethylphenylboronic acid in Step 1 40 6-(4-((3'-fluoro-4'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid Use (3-fluoro-4-methoxyphenyl)boronic acid instead of 3,4-dimethylphenylboronic acid in Step 1 41 6-(4-((3'-cyano-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid In Step 1, use 3-cyano-5-methoxyphenylboronic acid pinacol ester instead of 3,4-dimethylphenylboronic acid.

[0820] Example number LC / MS(ESI) m / z: [M+H] + NMR 29 - 1 H NMR(500 MHz, Chloroform-d) δ 7.51 - 7.46(m, 2H), 7.34(t, J = 7.9 Hz, 1H), 7.17 - 7.11(m, 3H), 7.08(dd, J = 2.6, 1.6 Hz, 1H), 6.88(ddd, J = 8.2, 2.6, 1.0 Hz, 1H), 5.37(d, J = 7.8 Hz, 1H), 4.29 - 4.21(m, 1H), 3.97(s, 2H), 3.85(s, 3H), 3.01 - 2.94(m, 1H), 2.45 - 2.42(m, 3H), 2.41 - 2.37(m, 1H), 2.36(s, 3H), 2.33 - 2.27(m, 3H), 2.16(dd, J = 11.8, 8.2 Hz, 1H), 2.03 - 1.99(m, 1H), 1.54 - 1.47(m, 2H). 30 [M+H] + : 485.33, [M+H] - : 483.51 1 H NMR(500 MHz, Chloroform-d) δ 7.81(t, J = 1.8 Hz, 1H), 7.76(dt, J = 7.9, 1.5 Hz, 1H), 7.60(dt, J = 7.7, 1.4 Hz, 1H), 7.53(t, J = 7.8 Hz, 1H), 7.47-7.42(m, 2H), 7.20(d, J = 8.1 Hz, 2H), 5.46(d, J = 7.8 Hz, 1H), 4.32-4.24(m, 1H), 3.98(s, 2H), 2.98(p, J = 8.4 Hz, 1H), 2.47-2.42(m, 4H), 2.37-2.32(m, 4H), 2.30(d, J = 8.3 Hz, 2H), 2.18(dd, J = 11.8, 8.1 Hz, 1H), 2.05-2.00(m, 1H), 1.63-1.53(m, 2H). 31 [M+H] + : 488.64, [M+H] - : 486.54 1 H NMR(300 MHz, Chloroform-d) δ 7.49(dd, J = 4.2, 1.9 Hz, 2H), 7.46(d, J = 4.1 Hz, 2H), 7.28(s, 2H), 7.14(d, J = 8.1 Hz, 2H), 5.35(d, J = 7.9 Hz, 1H), 4.32-4.18(m, 1H), 3.97(s, 2H), 2.98(p, J = 8.5 Hz, 1H), 2.69(q, J = 7.6 Hz, 2H), 2.43(s, 3H), 2.39(d, J = 4.8 Hz, 1H), 2.36(s, 3H), 2.29(d, J = 8.4 Hz, 3H), 2.17(dd, J = 11.7, 8.2 Hz, 1H), 2.04-1.95(m, 1H), 1.52-1.44(m, 2H), 1.28(d, J = 7.6 Hz, 3H). 32 [M+H] + : 464.40, [M+H] - : 462.58 1 H NMR(500 MHz, Methanol-d4) δ 7.24(d, J = 8.3 Hz, 2H), 7.00(d, J = 8.1 Hz, 2H), 6.06(tt, J = 3.9, 1.8 Hz, 1H), 4.16-4.06(m, 1H), 3.89(s, 2H), 2.97(p, J = 8.4 Hz, 1H), 2.40-2.37(m, 3H), 2.35(d, J = 5.5 Hz, 6H), 2.31-2.25(m, 2H), 2.24-2.19(m, 3H), 2.18-2.14(m, 1H), 2.09-2.07(m, 1H), 1.81-1.73(m, 4H), 1.69-1.66(m, 2H). 33 [M+H] + : 450.6, [M+H] - : 448.6 1 H NMR(400 MHz, Chloroform-d) δ 7.72-7.66(m, 1H), 7.49-7.43(m, 1H), 7.41-7.34(m, 2H), 7.12-7.04(m, 2H), 6.71-6.63(m, 1H), 5.42-5.32(m, 1H), 4.29-4.18(m, 1H), 3.93(s, 2H), 3.05-2.93(m, 1H), 2.42(s, 3H), 2.43-2.37(m, 1H), 2.34(s, 3H), 2.34-2.25(m, 3H), 2.21-2.12(m, 1H), 2.06-1.96(m, 1H), 1.57-1.48(m, 2H) 34 [M+H] + : 508.42, [M+H] - : 506.53 1 H NMR(500 MHz, Chloroform-d) δ 7.50-7.45(m, 2H), 7.21-7.18(m, 2H), 6.91-6.86(m, 2H), 6.64-6.59(m, 1H), 5.40-5.35(m, 1H), 4.34-4.26(m, 1H), 4.00(s, 2H), 3.87(s, 3H), 3.08-2.97(m, 1H), 2.45(s, 3H), 2.38(s, 3H), 2.36-2.31(m, 3H), 2.23-2.17(m, 1H), 2.08-2.03(m, 1H), 1.57-1.52(m, 3H). 35 [M+H] + : 538.4, [M+H] - : 536.5 1 H NMR(400 MHz, Chloroform-d) δ 8.02-7.96(m, 2H), 7.75-7.69(m, 2H), 7.53-7.49(m, 2H), 7.24-7.19(m, 2H), 5.43-5.38(m, 1H), 4.32-4.21(m, 1H), 3.99(s, 2H), 3.09(s, 3H), 3.02-2.94(m, 1H), 2.48-2.46(m, 1H), 2.43(s, 3H), 2.35(s, 3H), 2.32-2.28(m, 3H), 2.19-2.13(m, 1H), 2.05-1.99(m, 1H), 1.65-1.58(m, 1H), 1.55-1.48(m, 1H). 36 [M+H] + :560.4, [M+H] - : 558.4 1 H NMR(400 MHz, Chloroform-d) δ 8.08-8.01(m, 2H), 7.67-7.60(m, 2H), 7.55-7.51(m, 2H), 7.23-7.17(m, 2H), 5.49-5.43(m, 1H), 4.35-4.22(m, 1H), 4.00(s, 2H), 3.07-2.94(m, 1H), 2.44(s, 3H), 2.43-2.39(m, 1H), 2.37(s, 3H), 2.36-2.29(m, 3H), 2.19-2.15(m, 1H), 2.07-1.99(m, 1H), 1.63(s, 9H), 1.61-1.53(m, 2H). 37 [M+H] + : 522.5, [M+H] - : 520.6 1 H NMR(400 MHz, DMSO-d6) δ 7.96-7.81(m, 2H), 7.58-7.52(m, 1H), 7.47-7.41(m, 2H), 7.18-7.13(m, 1H), 7.13-7.08(m, 2H), 4.11-4.07(m, 1H), 4.04-3.96(m, 1H), 3.89(s, 2H), 3.20-3.16(m, 2H), 2.81-2.73(m, 1H), 2.42(s, 3H), 2.26(s, 3H), 2.22-2.17(m, 2H), 2.05-1.97(m, 2H), 1.86-1.79(m, 1H), 1.66-1.60(m, 1H), 1.54-1.47(m, 1H). 38 [M+H] + : 474.5, [M+H] - : 472.5 1 H NMR(500 MHz, Chloroform-d) δ 7.26-7.23(m, 5H), 7.19-7.14(m, 1H), 7.14-7.11(m, 2H), 5.42-5.36(m, 1H), 4.32-4.24(m, 1H), 3.98(s, 2H), 3.04-2.96(m, 1H), 2.45(s, 3H), 2.43-2.40(m, 1H), 2.36(s, 3H), 2.32-2.29(m, 3H), 2.26(s, 3H), 2.22-2.17(m, 1H), 2.06-2.01(m, 1H), 1.56-1.54(m, 2H). 39 [M+H] + : 464.33, [M+H] - : 462.44 1 H NMR(300 MHz, Chloroform-d) δ 7.72(s, 1H), 7.57(s, 1H), 7.38-7.31(m, 2H), 7.11-7.04(m, 2H), 5.40(d, J = 7.7 Hz, 1H), 4.30-4.17(m, 1H), 3.93(s, 3H), 3.92(s, 2H), 2.97(p, J = 8.4 Hz, 1H), 2.42(s, 4H), 2.34(s, 3H), 2.32-2.23(m, 3H), 2.15(dd, J = 11.7, 8.0 Hz, 1H), 2.03-1.95(m, 1H), 1.57-1.44(m, 2H). 40 [M+H] + : 508.35, [M+H] - : 506.46 1 H NMR(500 MHz, Chloroform-d) δ 7.44-7.40(m, 2H), 7.30-7.27(m, 1H), 7.26-7.23(m, 1H), 7.16-7.10(m, 2H), 7.04-6.99(m, 1H), 5.41-5.39(m, 1H), 4.30-4.22(m, 1H), 3.96(s, 2H), 3.92(s, 3H), 3.04-2.94(m, 1H), 2.42(s, 3H), 2.41-2.38(m, 1H), 2.35(s, 3H), 2.33-2.28(m, 3H), 2.19-2.14(m, 1H), 2.02-1.97(m, 1H), 1.57-1.48(m, 2H). 41 [M+H] + : 515.44, [M+H] - : 513.48 1 H NMR(500 MHz, Chloroform-d) δ 7.47-7.39(m, 3H), 7.28-7.27(m, 1H), 7.20-7.15(m, 2H), 7.11-7.09(m, 1H), 5.43-5.38(m, 1H), 4.31-4.24(m, 1H), 3.98(s, 3H), 3.88(s, 2H), 3.03-2.93(m, 1H), 2.47-2.44(m, 1H), 2.42(s, 3H), 2.34(s, 3H), 2.33-2.28(m, 3H), 2.22-2.15(m, 1H), 2.06-2.00(m, 1H), 1.62-1.53(m, 2H).

[0821] Example number chemical structure designation Differences in manufacturing methods 42 6-(2,5-dimethyl-4-((4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)methyl)thiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid Use 4-(trifluoromethoxy)phenylboronic acid instead of 3,4-dimethylphenylboronic acid in Step 1 43 6-(4-((3'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Use 3-fluorophenylboronic acid instead of 3,4-dimethylphenylboronic acid in Step 1 44 6-(2,5-dimethyl-4-((3'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)thiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid Use 3-(trifluoromethyl)phenylboronic acid instead of 3,4-dimethylphenylboronic acid in Step 1 45 6-(4-((3'-ethoxy-5'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid Use 3-fluoro-5-ethoxyphenylboronic acid instead of 3,4-dimethylphenylboronic acid in Step 1 46 6-(4-((3'-fluoro-5'-isopropoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid Use 3-fluoro-5-isopropoxyphenylboronic acid instead of 3,4-dimethylphenylboronic acid in Step 1 47 6-(4-((2'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid In Step 1, use (2-fluoro-5-methoxyphenyl)boronic acid instead of 3,4-dimethylphenylboronic acid, and use K3PO4 instead of Cs2CO3. 48 6-(4-((5'-fluoro-2'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid In Step 1, use 5-fluoro-2-methoxyphenylboronic acid instead of 3,4-dimethylphenylboronic acid, and use K3PO4 instead of Cs2CO3. 49 6-(4-((2'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid In Step 1, use 2-fluorophenylboronic acid instead of 3,4-dimethylphenylboronic acid, and use K3PO4 instead of Cs2CO3. 50 6-(4-(4-(2-methoxypyridine-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid In Step 1, use (2-methoxypyridine-4-yl)boronic acid instead of 3,4-dimethylphenylboronic acid, and use K3PO4 instead of Cs2CO3. 51 6-(4-((3'-methoxy-5'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid Use (3-methoxy-5-trifluoromethyl)phenylboronic acid instead of 3,4-dimethylphenylboronic acid in Step 1

[0822] Example number LC / MS(ESI) m / z: [M+H] + NMR 42 [M+H] + : 544.33, [M+H] - : 542.44 1 H NMR(400 MHz, Chloroform-d) δ 7.58-7.53(m, 2H), 7.46(s, 2H), 7.29-7.26(m, 2H), 7.21-7.15(m, 2H), 5.43-5.36(m, 1H), 4.31-4.23(m, 1H), 3.97(s, 2H), 3.03-2.95(m, 1H), 2.43(s, 3H), 2.41-2.39(m, 1H), 2.35(s, 3H), 2.34-2.28(m, 4H), 2.20-2.14(m, 1H), 1.60-1.50(m, 2H). 43 478.4 1 H NMR(500 MHz, Chloroform-d) δ 7.49(d, J = 8.1 Hz, 2H), 7.43-7.38(m, 1H), 7.34(d, J = 7.8 Hz, 1H), 7.26(dt, J = 10.2, 1.9 Hz, 1H), 7.19(d, J = 8.1 Hz, 2H), 7.04(td, J = 8.3, 2.2 Hz, 1H), 5.44(d, J = 7.7 Hz, 1H), 4.28(h, J = 8.0 Hz, 1H), 4.00(s, 2H), 3.00(p, J = 8.4 Hz, 1H), 2.47-2.41(m, 4H), 2.37(s, 3H), 2.33(td, J = 7.8, 4.2 Hz, 3H), 2.19(dd, J = 11.7, 8.2 Hz, 1H), 2.03(ddd, J = 11.5, 8.8, 2.1 Hz, 1H), 1.56(ddd, J = 16.2, 11.3, 8.6 Hz, 2H). 44 528.3 1 H NMR(500 MHz, Chloroform-d) δ 7.80(s, 1H), 7.74(d, J = 7.6 Hz, 1H), 7.58(dt, J = 15.3, 7.7 Hz, 2H), 7.51(d, J = 8.1 Hz, 2H), 7.22(d, J = 8.1 Hz, 2H), 5.42(d, J = 7.8 Hz, 1H), 4.30(h, J = 8.0 Hz, 1H), 4.01(s, 2H), 3.00(p, J = 8.5 Hz, 1H), 2.45(s, 4H), 2.38(s, 3H), 2.33(t, J = 7.6 Hz, 3H), 2.20(dd, J = 11.7, 8.2 Hz, 1H), 2.04(q, J = 9.4, 8.7 Hz, 1H), 1.58(ddd, J = 16.6, 11.3, 8.7 Hz, 2H). 45 [M+H] + : 522.19, [M+H] - : 520.36 1 H NMR(300 MHz, Chloroform-d) δ 7.47-7.42(m, 2H), 7.18-7.13(m, 2H), 6.88-6.79(m, 2H), 6.62-6.54(m, 1H), 5.42-5.33(m, 1H), 4.33-4.16(m, 1H), 4.11-4.02(m, 2H), 3.96(s, 2H), 3.04-2.91(m, 1H), 2.45-2.38(m, 4H), 2.35(s, 3H), 2.32-2.26(m, 3H), 2.21-2.14(m, 1H), 2.08-1.99(m, 1H), 1.59-1.47(m, 2H), 1.46-1.40(m, 3H). 46 [M+H] + : 536.30, [M+H] - : 534.47 1 H NMR(400 MHz, Chloroform-d) δ 7.46-7.42(m, 2H), 7.17-7.13(m, 2H), 6.84-6.79(m, 2H), 6.60-6.54(m, 1H), 5.41-5.35(m, 1H), 4.61-4.52(m, 1H), 4.30-4.20(m, 1H), 3.96(s, 2H), 3.04-2.93(m, 1H), 2.45-2.40(m, 4H), 2.35(s, 3H), 2.32-2.28(m, 3H), 2.22-2.15(m, 1H), 2.06-2.00(m, 1H), 1.58-1.48(m, 2H), 1.37-1.34(m, 6H). 47 508.28 1 H NMR(500 MHz, CDCl3) δ 7.46(d, J = 7.7 Hz, 2H), 7.18(d, J = 7.9 Hz, 2H), 7.08(t, J = 9.4 Hz, 1H), 6.92(dd, J = 6.3, 3.2 Hz, 1H), 6.84(dt, J = 9.0, 3.4 Hz, 1H), 5.37(d, J = 7.8 Hz, 1H), 4.27(d, J = 8.0 Hz, 1H), 4.00(s, 2H), 3.84(s, 3H), 3.01(t, J = 8.5 Hz, 1H), 2.45(s, 3H), 2.31(d, J = 8.7 Hz, 3H), 2.18(d, J = 8.5 Hz, 3H), 2.05(t, J = 10.3 Hz, 1H), 1.56-1.51(m, 2H), 1.29(d, J = 15.5 Hz, 3H) 48 509.43 1 H NMR(500 MHz, CDCl3) δ 7.44(d, J = 8.0Hz, 2H), 7.15(d, J = 7.9Hz, 2H), 7.03-6.98(m, 2H), 6.92(dd, J = 9.8, 4.5 Hz, 1H), 5.40(d, J = 7.9 Hz, 1H), 4.29(q, J = 8.1 Hz, 1H), 3.99(s, 2H), 3.80(s, 3H), 3.02(p, J = 8.4 Hz, 1H), 2.46(s, 3H), 2.38(s, 3H), 2.33(d, J = 8.5 Hz, 4H), 2.20(dd, J = 11.9, 8.1 Hz, 2H), 2.12-2.02(m, 2H). 49 478.24 1 H NMR(500 MHz, CDCl3) δ 7.50-7.45(m, 2H), 7.41(td, J = 7.8, 1.8 Hz, 1H), 7.37-7.29(m, 1H), 7.25-7.21(m, 1H), 7.20-7.11(m, 3H), 5.37(d, J = 7.9 Hz, 1H), 4.27(h, J = 8.0 Hz, 1H), 4.00(s, 2H), 3.12-2.91(m, 1H), 2.50-2.40(m, 1H), 2.45(s, 3H), 2.39(s, 3H), 2.34-2.29(m, 3H), 2.24-2.16(m, 1H), 2.08-2.00(m, 1H), 1.58-1.48(m, 2H). 50 491.27 1 H NMR(400 MHz, MeOD) δ 8.16(d, J = 5.5Hz, 1H), 7.63-7.55(m, 2H), 7.25-7.18(m, 3H), 7.02(d, J = 1.5Hz, 1H), 4.14(p, J = 8.1Hz, 1H), 3.99(s, 2H), 3.96(s, 3H), 2.93(p, J = 8.5Hz, 1H), 2.38(s, 7H), 2.34-2.18(m, 3H), 2.18-2.09(m, 1H), 2.08-1.97(m, 1H), 1.84-1.70(m, 2H). 51 [M+H] + : 558.6, [M+H] - : 556.5 1 H NMR(400 MHz, chloroform -d) δ 7.51-7.44(m, 2H), 7.36(s, 1H), 7.23-7.21(m, 1H), 7.19-7.16(m, 2H), 7.10-7.07(m, 1H), 5.44-5.34(m, 1H), 4.34-4.20(m, 1H), 3.98(s, 2H), 3.89(s, 3H), 3.03-2.91(m, 1H), 2.42(s, 3H) ), 2.40-2.38(m, 1H), 2.35(s, 3H), 2.33-2.27(m, 3H), 2.20-2.14(m, 1H), 2.05-1.98(m, 1H), 1.60-1.50(m, 2H).

[0823] Example number chemical structure designation Differences in manufacturing methods 52 6-(4-((3',5'-difluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid In Step 1, use 3,5-difluorophenylboronic acid instead of 3,4-dimethylphenylboronic acid, and use K3PO4 instead of Cs2CO3. 53 6-(4-((3',5'-dimethoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid In Step 1, use 3,5-dimethoxyphenylboronic acid instead of 3,4-dimethylphenylboronic acid, and use K3PO4 instead of Cs2CO3. 54 6-(4-((3'-amino-5'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Use intermediate H instead of 3,4-dimethylphenylboronic acid in Step 1 55 6-(4-((3'-fluoro-5'-(methylthio)-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Use intermediate I instead of 3,4-dimethylphenylboronic acid in step 1 56 6-(4-((3'-fluoro-5'-(methylsulfonyl)-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid After oxidizing the methyl thio group of methyl 6-(4-((3'-fluoro-5'-(methylthio)-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate obtained in Step 1 of Example 55, proceed to Step 2. Oxidation reaction conditions and reagents: Oxone, MeOH / H2O, 0°C to room temperature, 5 hours. 57 6-(4-((3'-carbamoyl-5'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Use intermediate J instead of 3,4-dimethylphenylboronic acid in Step 1 58 6-(4-((3'-carbamoyl-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid Use intermediate K instead of 3,4-dimethylphenylboronic acid in Step 1 59 6-(4-((3'-(((tert-butoxycarbonyl)amino)methyl)-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Use intermediate L instead of 3,4-dimethylphenylboronic acid in Step 1 60 6-(4-((3'-fluoro-5'-(hydroxymethyl)-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Use intermediate M instead of 3,4-dimethylphenylboronic acid in Step 1 61 6-(4-((3'-(3-hydroxyoxetane-3-yl)-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid In Step 1, use intermediate N instead of 3,4-dimethylphenylboronic acid, and use K3PO4 instead of Cs2CO3. 62 6-(4-((3'-methoxy-5'-(2-oxozetidine-1-yl)-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid In Step 1, use intermediate O instead of 3,4-dimethylphenylboronic acid, and use K3PO4 instead of Cs2CO3. 63 (2R, 4R, 6R)-6-(4-((3'-methoxy-5'-(2-oxozetidine-1-yl)-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid In Step 1, intermediate O was used instead of 3,4-dimethylphenylboronic acid, and K3PO4 was used instead of Cs2CO3. Additionally, in Step 1, (2R, 4R, 6R)-methyl 6-(4-4-chlorobenzyl-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-carboxylate obtained by using intermediate Z instead of intermediate A in Step 3 of Example 23 was used. 64 6-(4-((3'-(aminomethyl)-5'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid 6-(4-((3'-(((tert-butoxycarbonyl)amino)methyl)-5'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid was obtained in the same manner as in Example 28, except that intermediate P was used instead of 3,4-dimethylphenylboronic acid in Step 1. Subsequently, Boc deprotection was performed to obtain the hydrochloride salt of the compound of Example 64. Boc deprotection reaction reagents and conditions: 4N HC(in dioxane) solution (1M), DCM, room temperature, 15 hours 65 6-(4-((3'-(azetidine-3-yl)-5'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid The hydrochloride salt of the compound of Example 65 was obtained in the same manner as in Example 64, except that intermediate Q was used instead of 3,4-dimethylphenylboronic acid and K3PO4 was used instead of Cs2CO3 in Step 1. 66 6-(4-((3'-(aminomethyl)-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid The hydrochloride salt of the compound of Example 66 was obtained in the same manner as in Example 64, except that intermediate L was used instead of 3,4-dimethylphenylboronic acid in Step 1.

[0824] Example number LC / MS(ESI) m / z: [M+H] + NMR 52 496.5 1 H NMR(300 MHz, DMSO-d6) δ 12.01(s, 1H), 8.28(d, J = 7.5 Hz, 1H), 7.64-7.56(m, 2H), 7.38(dt, J = 7.6, 2.2 Hz, 2H), 7.23-7.14(m, 3H), 4.18-4.10(m, 1H), 3.90(s, 2H), 2.95-2.84(m, 1H), 2.38-2.27(m, 7H), 2.26-2.13(m, 3H), 2.10-1.98(m, 2H), 1.85(ddd, J = 15.9, 11.0, 8.5 Hz, 2H). 53 520.5 1 H NMR(300 MHz, Methanol-d4) δ 7.44(d, J = 8.2 Hz, 2H), 7.12(d, J = 8.2 Hz, 2H), 6.69(d, J = 2.3 Hz, 2H), 6.45(t, J = 2.2 Hz, 1H), 4.18-4.06(m, 1H), 3.94(s, 2H), 3.81(s, 6H), 2.97-2.88(m, 1H), 2.41-2.33(m, 7H), 2.31-2.17(m, 3H), 2.16-2.10(m, 1H), 2.06-1.98(m, 1H), 1.79-1.71(m, 2H). 54 493.5 1 H NMR(400 MHz, CDCl3) δ 7.44(d, J = 8.1 Hz, 2H), 7.15(d, J = 7.9 Hz, 2H), 6.71-6.60(m, 2H), 6.40(dt, J = 10.3, 2.2 Hz, 1H), 5.33(d, J = 8.0 Hz, 1H), 4.26(h, J = 8.1 Hz, 1H), 3.98(s, 2H), 2.99(p, J = 8.0 Hz, 1H), 2.44(s, 3H), 2.44-2.38(m, 1H), 2.38(s, 3H), 2.37-2.24(m, 3H), 2.17-2.01(m, 2H), 1.55(dd, J = 11.4, 8.3 Hz, 1H), 1.39(dd, J = 11.7, 8.4 Hz, 1H). 55 - 1 H NMR(500 MHz, Chloroform-d) δ 7.49-7.45(m, 2H), 7.20-7.17(m, 3H), 7.03-6.99(m, 1H), 6.94-6.91(m, 1H), 5.44-5.42(m, 1H), 4.33-4.26(m, 1H), 4.00(s, 2H), 3.05-2.97(m, 1H), 2.55-2.53(m, 3H), 2.48-2.46(m, 1H), 2.45(s, 3H), 2.45-2.42(m, 1H), 2.37(s, 3H), 2.35-2.30(m, 3H), 2.23-2.18(m, 1H), 1.61-1.54(m, 2H). 56 [M+H] + :556.28, [M-H] - :554.39 1H NMR (300 MHz, Chloroform-d) δ7.96-7.94 (m, 1H), 7.64-7.63 (m, 1H), 7.54-7.51 (m, 3H), 7.26-7.24 (m, 2H), 6.07-6.05 (m, 1H), 4.32-4.29(m, 1H), 3.51(s, 2H), 3.15(s, 3H), 3.06-3.04(m, 1H), 2.57-2.55(m, 1H), 2.53-2.51(m, 3H), 2.46-2.46(m, 1H), 2.43(s, 3H), 2.38-2.37(m, 3H), 2.22-2.22(m, 1H), 1.70-1.67(m, 2H). 57 521.5 1 H NMR(300 MHz, Methanol-d4) δ8.23(d, J = 7.3 Hz, 1H), 7.95(t, J = 1.5 Hz, 1H), 7.60 - 7.50(m, 4H), 7.20(d, J = 8.2Hz, 2H), 4.18-4.07(m, 1H), 3.97(s, 2H), 2.99-2.88(m, 1H), 2.37(s, 3H), 2.37(s, 3H), 2.36(s, 3H), 2.32 - 2.18(m, 3H), 2.16 - 1.96(m, 3H), 1.84 - 1.70(m, 2H). 58 533.6 1 H NMR(300 MHz, DMSO- d 6) δ 8.28(d, J = 7.5 Hz, 1H), 8.07(s, 1H), 7.69(s, 1H), 7.57(d, J = 8.2 Hz, 2H), 7.42(s, 1H), 7.38(s, 1H), 7.26(s, 1H), 7.19(d, J = 8.2 Hz, 2H), 4.26 - 4.08(m, 1H), 3.90(s, 2H), 3.85(s, 3H), 2.95 - 2.79(m, 1H), 2.31(s, 6H), 2.23 - 2.12(m, 3H), 2.09 - 1.97(m, 2H), 1.94 - 1.78(m, 2H), 1.68 - 1.55(m, 1H). 59 619.5 1 H NMR(300 MHz, Methanol- d 4) δ 7.46(d, J = 8.2 Hz, 2H), 7.13(d, J = 8.2 Hz, 2H), 7.07(s, 1H), 6.97(s, 1H), 6.81(s, 1H), 4.63(s, 1H), 4.25(s, 2H), 4.18 - 4.03(m, 1H), 3.95(s, 2H), 3.83(s, 3H), 3.01 - 2.84(m, 1H), 2.36(s, 6H), 2.32 - 2.17(m, 3H), 2.17 - 2.08(m, 1H), 2.08 - 1.97(m, 1H), 1.82 - 1.68(m, 2H), 1.47(s, 9H). 60 508.08 1 H NMR(400 MHz, CDCl3) δ7.50(d, J = 8.0 Hz, 2H), 7.38(s, 1H), 7.23-7.15(m, 3H), 7.07-7.00(m, 1H), 5.34(d, J = 8.0 Hz, 1H), 4.78(s, 2H), 4.23(h, J = 7.7, 7.2 Hz, 1H), 4.00(s, 2H), 2.95(p, J = 8.0 Hz, 1H), 2.47-2.41(m, 1H), 2.44(s, 3H), 2.39(s, 3H), 2.35-2.25(m, 3H), 2.13-1.97(m, 2H), 1.58(dd, J = 11.6, 7.8 Hz, 1H), 1.36(dd, J = 11.8, 7.9 Hz, 1H). 61 ES+ 562.08 1 H NMR(500 MHz, CDCl3) δ7.48(d, J = 8.0 Hz, 2H), 7.35(s, 1H), 7.16-7.09(m, 3H), 7.02(s, 1H), 5.30(d, J = 8.0 Hz, 1H), 5.05-4.85(m, 4H), 4.19(q, J = 7.8 Hz, 1H), 3.96(s, 2H), 3.86(s, 3H), 2.91(p, J = 8.1 Hz, 1H), 2.40(s, 3H), 2.40-2.35(m, 1H), 2.35(s, 3H), 2.25(dd, J = 13.0, 7.6 Hz, 3H), 2.01(t, J = 8.8 Hz, 2H), 1.54(dd, J = 11.6, 7.7 Hz, 1H), 1.32(dd, J = 12.0, 8.0 Hz, 1H). 62 ES+ 559.32 1 H NMR(500 MHz, CDCl3) δ 7.45(d, J = 7.9 Hz, 2H), 7.15-7.11(m, 3H), 6.86(t, J = 2.1 Hz, 1H), 6.79(t, J = 1.9 Hz, 1H), 5.33(d, J = 7.8 Hz, 1H), 4.22(h, J = 8.0 Hz, 1H), 3.95(s, 2H), 3.84(s, 3H), 3.64(t, J = 4.5 Hz, 2H), 3.10(t, J = 4.5 Hz, 2H), 2.95(p, J = 8.4 Hz, 1H), 2.40(s, 3H), 2.39-2.34(m, 1H), 2.34(s, 3H), 2.30-2.23(m, 3H), 2.11(dd, J = 11.8, 8.0 Hz, 1H), 2.06-1.97(m, 1H), 1.48(ddd, J = 16.7, 11.6, 8.3 Hz, 2H). 63 ES+ 559.32 1 H NMR(500 MHz, CDCl3) δ 7.45(d, J = 7.9 Hz, 2H), 7.15-7.11(m, 3H), 6.86(t, J = 2.1 Hz, 1H), 6.79(t, J = 1.9 Hz, 1H), 5.33(d, J = 7.8 Hz, 1H), 4.22(h, J = 8.0 Hz, 1H), 3.95(s, 2H), 3.84(s, 3H), 3.64(t, J = 4.5 Hz, 2H), 3.10(t, J = 4.5 Hz, 2H), 2.95(p, J = 8.4 Hz, 1H), 2.40(s, 3H), 2.39-2.34(m, 1H), 2.34(s, 3H), 2.30-2.23(m, 3H), 2.11(dd, J = 11.8, 8.0 Hz, 1H), 2.06-1.97(m, 1H), 1.48(ddd, J = 16.7, 11.6, 8.3 Hz, 2H). 64 n+1=507.5 1 H NMR(300 MHz, DMSO-d6) δ8.30(d, J = 7.5 Hz, 1H), 7.65(d, J = 1.5 Hz, 1H), 7.58(d, J = 8.2 Hz, 2H), 7.52-7.47(m, 1H), 7.33-7.29(m, 1H), 7.21(d, J = 8.2 Hz, 2H), 4.22 - 4.06(m, 3H), 3.90(s, 2H), 2.96-2.85(m, 1H), 2.39 - 2.28(m, 7H), 2.27 - 2.10(m, 3H), 2.09 - 2.02(m, 2H), 1.90 - 1.81(m, 2H). 65 533.3 1 H NMR(300 MHz, Methanol-d4) δ7.55(d, J = 8.2 Hz, 2H), 7.46(s, 1H), 7.32(dt, J = 9.9, 2.0 Hz, 1H), 7.23 - 7.15(m, 3H), 4.48 - 4.27(m, 5H), 4.14(p, J = 8.0 Hz, 1H), 3.98(s, 2H), 3.01 - 2.87(m, 1H), 2.38(d, J = 4.4 Hz, 7H), 2.31 - 2.18(m, 3H), 2.17 - 1.99(m, 2H), 1.87 - 1.70(m, 2H). 66 519.5 1 H NMR(300 MHz, DMSO- d 6) δ 8.31(d, J = 7.5 Hz, 1H), 7.54(d, J = 8.0 Hz, 2H), 7.33(s, 1H), 7.19(d, J = 8.0 Hz, 2H), 7.13(s, 1H), 7.07(s, 1H), 4.24 - 4.09(m, 1H), 4.05(s, 2H), 3.89(s, 2H), 3.83(s, 3H), 2.98 - 2.83(m, 1H), 2.31(d, J = 1.4 Hz, 6H), 2.27 - 2.10(m, 4H), 2.10 - 1.97(m, 2H), 1.95 - 1.77(m, 2H).

[0825] Example 67: 6-(4-(4-cyclohexylbenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0826] Step 1: Synthesis of methyl 6-(2,5-dimethyl-4-((2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)thiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate

[0827]

[0828] Methyl 6-(4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (50 mg, 0.11 mmol) and 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (27 mg, 0.13 mmol) obtained in Step 3 of Example 23 were placed in a sealed tube in 1,4-dioxane (1 mL), and H2O (0.05 mL) and Cs2CO3 (40 mg, 0.22 mmol) were added. Pd(OAc)2 (2.5 mg) and Xphos (65 mg, 0.115 mmol) were added under N2 atmosphere, and the mixture was stirred at 90°C for 15 hours. The reaction mixture was diluted with ethyl acetate, washed with distilled water, dried with MgSO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (30% EtOAc in hexane) to obtain methyl 6-(2,5-dimethyl-4-((2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (59 mg, mixture). 1H NMR (400 MHz, Methanol-d4) δ 7.28-7.22 (m, 2H), 7.00 (d, J = 8.3 Hz, 2H), 6.07 (tt, J = 3.9, 1.7 Hz, 1H), 4.13-4.09 (m, 1H), 3.90 (s, 2H), 3.66 (s, 3H), 3.02 (p, J = 8.5 Hz, 1H), 2.50-2.42 (m, 1H), 2.41-2.37 (m, 2H), 2.35 (d, J = 5.5 Hz, 6H), 2.32-2.25 (m, 2H), 2.24-2.13(m, 4H); 2.10-2.05(m, 1H), 1.81-1.75(m, 4H), 1.71-1.67(m, 2H).

[0829] Step 2: Synthesis of Methyl 6-(4-(4-cyclohexylbenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate

[0830]

[0831] 10% Pd / C (2.2 mg) was added to a solution of methyl 6-(2,5-dimethyl-4-((2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (20 mg, 0.042 mmol) mixed in ethyl acetate / methanol (8 / 2, 0.2 mL). The reaction mixture was stirred under hydrogen gas for 24 hours and filtered with Celite using ethyl acetate to obtain methyl 6-(4-(4-cyclohexylbenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (12 mg). 1H NMR (400MHz, Chloroform-d) δ 7.16-7.10(m, 2H), 7.02(s, 2H), 5.32(d, J = 7.9Hz, 1H), 4.31-4.13(m, 1H), 3.91(s, 2H), 3.68(s, 3H), 3.03-2.95(m, 1H), 2.52-2.46(m, 1H), 2.45(s, 3H), 2.40-2.36(m, 1H), 2.35(s, 3H), 2.30-2.26(m, 2H), 2.26-2.23(m, 1H), 2.22-2.16(m, 1H); 2.02-1.96(m, 1H), 1.87-1.83(m, 4H), 1.69-1.65(m, 2H), 1.48-1.43(m, 2H), 1.40-1.32(m, 5H).

[0832] Step 3: Synthesis of 6-(4-(4-cyclohexylbenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0833]

[0834] LiOH·H2O (3 mg, 0.075 mmol, 3.0 equivalents) was added to a solution of methyl 6-(4-(4-cyclohexylbenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (12 mg) in THF / MeOH / H2O (2 / 1 / 2) and stirred for 3 hours. The reaction mixture was partially concentrated, then acidified with a 1 N HCl aqueous solution, and the aqueous layer was extracted with EtOAc. The organic layer was dried with MgSO4 and concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the compound of Example 67 (3.7 mg, yield 32%). 1H NMR (300 MHz, Chloroform-d) δ 7.14-7.08 (m, 2H), 6.99 (d, J = 8.1 Hz, 2H), 5.30 (d, J = 7.8 Hz, 1H), 4.29-4.12 (m, 1H), 3.89 (s, 2H), 3.00(p, J = 8.5 Hz, 1H), 2.52-2.45(m, 1H), 2.42(s, 3H), 2.40-2.35(m, 1H), 2.33(s, 3H), 2.31-2.27(m, 2H), 2.26-2.21(m, 1H), 2.18(dd, J = 10.6, 7.2 Hz, 1H), 2.06-1.96(m, 1H), 1.82(d, J = 8.1 Hz, 3H), 1.74(d, J = 13.0 Hz, 2H), 1.47-1.31(m, 6H), 1.30-1.22(m, 1H). LC / MS(ESI) m / z: 466.43 [M+H] + , 464.54 [M+H] - .

[0835] Example 68: 6-(2,5-dimethyl-4-(4-(piperidine-4-yl)benzyl)thiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0836] Steps 1 to 3: Synthesis of 6-(4-(4-(1-(tert-butoxycarbonyl)piperidine-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0837]

[0838]

[0839] 6-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid was obtained as an ivory solid in the same manner as in Example 67, except that tert-butyl 4-(4-(1-(tert-butoxycarbonyl)piperidine-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid was obtained as an ivory solid. 1H NMR (400 MHz, Chloroform-d) δ 7.13(s, 2H), 7.06-7.01(m, 2H), 5.34-5.29(m, 1H), 4.30-4.20(m, 3H), 3.91(s, 2H), 3.05-2.96(m, 1H), 2.86-2.74(m, 2H), 2.69-2.59(m, 1H), 2.43(s, 3H), 2.41-2.38(m, 1H), 2.35(s, 3H), 2.33-2.27(m, 4H), 2.15-2.09(m, 1H), 1.82-1.76(m, 2H); 1.67-1.54(m, 4H), 1.50(s, 9H).

[0840] Step 4: Synthesis of 6-(2,5-dimethyl-4-(4-(piperidine-4-yl)benzyl)thiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0841]

[0842] A solution of 6-(4-(4-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (14 mg, 0.024 mmol) and 4 N HCl (in dioxane (0.5 mL)) was stirred for 2 hours. The reaction mixture was poured into ether and concentrated under reduced pressure to obtain the hydrochloride (4 mg, 33%) of the compound of Example 68 as an ivory solid. 1 H NMR (500 MHz, Methanol-d4) δ 7.15-7.08(m, 2H), 7.04-6.98(m, 2H), 4.16-4.09(m, 1H), 3.86(s, 2H), 3.49-3.44(m, 2H), 3.16-3.08(m, 2H), 3.03-2.97(m, 1H), 2.86-2.79(m, 1H), 2.41-2.35(m, 2H), 2.33(s, 3H), 2.30(s, 3H), 2.26-2.20(m, 2H), 2.17-2.12(m, 1H), 2.12-2.06(m, 1H), 2.03-1.98(m, 2H), 1.93-1.81(m, 3H), 1.77-1.70(m, 1H). LC / MS(ESI) m / z: 465.7 [MH] - .

[0843] Example 69: 6-(4-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0844]

[0845] The compound of Example 23 (30 mg, 0.069 mmol) and 4-fluoroboronic acid (12 mg, 0.083 mmol) were placed in a sealed tube in 1,4-dioxane (0.2 mL), and H2O (0.01 mL) and Cs2CO3 (45 mg, 0.138 mmol) were added. Pd(OAc)2 (2 mg, 0.007 mmol) and Xphos (33 mg, 0.069 mmol) were added under N2 atmosphere, and the mixture was stirred at 90°C for 12 hours. The reaction mixture was diluted with ethyl acetate, washed with distilled water, dried with Na2SO4, and then filtered and concentrated. The crude product was purified using a silica column (hexane:ethyl acetate = 1:1) to obtain the compound of Example 69 (3 mg, yield 12%) as an ivory solid. 1 H NMR (500 MHz, Chloroform-d) δ 7.55-7.49 (m, 2H), 7.48-7.45 (m, 2H), 7.19-7.17 (m, 2H), 7.17-7.12 (m, 2H), 5.46-5.35 (m, 1H), 4.33-4.25(m, 1H), 3.99(s, 2H), 3.04-2.96(m, 1H), 2.46(s, 3H), 2.44-2.41(m, 0H), 2.38(s, 3H), 2.36 2.30(m, 4H), 2.22-2.15(m, 1H), 2.06-1.98(m, 1H), 1.62-1.49(m, 3H). LC / MS(ESI) m / z: 478.6 [M+H] + , 476.6 [MH] -

[0846] Example 70: 6-(4-((3'-cyano-5'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0847]

[0848] The compound of Example 70 was obtained in the same manner as in Example 69, except that 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile was used instead of 4-fluoroboronic acid in Example 69, and K3PO4 was used instead of Cs2CO3. 1 H NMR (300 MHz, MeOD) δ 8.28 (d, J = 7.5 Hz, 1H), 7.85 (t, J = 1.5 Hz, 1H), 7.73 (ddd, J = 10.1, 2.5, 1.6 Hz, 1H), 7.63-7.54 (m, 2H), 7.52 (ddd, J = 8.1, 2.5, 1.3 Hz, 1H), 7.23 (d, J = 8.2 Hz, 2H), 4.22-4.08 (m, 1H), 3.99 (s, 2H), 2.95 (p, J = 8.4 Hz, 1H), 2.49-2.38(m, 1H), 2.39(s, 3H), 2.37(s, 3H), 2.35 -2.20(m, 3H), 2.19-2.10(m, 1H), 2.09-1.99(m, 1H), 1.87-1.70(m, 2H). LC / MS(ESI) m / z: 503.02 [M+H] + .

[0849] Example 71: 6-(4-((3'-fluoro-5'-hydroxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0850] Step 1: Synthesis of methyl 6-(4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate

[0851]

[0852] Methyl 6-(4-((3'-fluoro-5'-methoxyphenyl)boronic acid)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate was obtained in the same manner as in Step 1 of Example 67, except that (3-fluoro-5-methoxyphenyl)boronic acid was used instead of 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in Step 1 of Example 67. 1H NMR (400 MHz, CDCl3) δ 7.50-7.46 (m, 2H), 7.18 (d, J = 8.2 Hz, 2H), 7.01 (d, J = 5.4 Hz, 1H), 6.89 (q, J = 2.1, 1.7 Hz, 1H), 6.62 (dt, J = 10.5, 2.3 Hz, 1H), 5.39(d, J = 7.8 Hz, 1H), 4.28(q, J = 8.1 Hz, 1H), 3.99(s, 2H), 3.87(s, 3H), 3.66(s, 3H), 3.03-2.95(m, 1H), 2.45(s, 3H), 2.37(s, 3H), 2.30 (dq, J = 8.6, 4.2, 3.4 Hz, 3H), 2.18 (dd, J = 11.7, 8.4 Hz, 1H), 2.02-1.97 (m, 1H), 1.58-1.51 (m, 2H).

[0853] Step 2: Synthesis of 6-(4-((3'-fluoro-5'-hydroxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0854]

[0855] BBr3 (0.7 mL, 0.72 mmol) was added at 0°C to a solution mixed with methyl 6-(4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (94 mg, 0.18 mmol) in DCM (0.1 M) and stirred for 5 hours at room temperature. The reaction mixture was quenched with distilled water and stirred for an additional 15 hours, then extracted with ethyl acetate (20 mL twice) and washed with brine. The organic layer was dried with Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (5% MeOH in DCM) to obtain the compound of Example 71 (22 mg, yield 25%) as an off-white solid. 1 ¹H NMR(500 MHz, CDCl₃) 1 ¹H NMR(400 MHz, Chloroform- d ) δ 7.41(d, J= 7.8 Hz, 2H), 7.14(d, J = 8.0 Hz, 2H), 6.88(t, J = 1.9 Hz, 1H), 6.83-6.75(m, 1H), 6.62-6.54(m, 1H), 5.40-5.26(m, 1H), 4.24(h, J = 8.1 Hz, 1H), 3.98(s, 2H), 3.02(p, J = 7.5 Hz, 1H), 2.49-2.27(m, 3H), 2.41(s, 3H), 2.40(s, 3H), 2.17-2.08(m, 2H), 1.60(dd, J = 12.1, 8.1 Hz, 1H), 1.38-1.22(m, 2H). LC / MS(ESI) m / z: 494.1 [M+H] + .

[0856] Example 72: 6-(4-(4-(2-hydroxypyridine-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0857] Steps 1 and 2: Synthesis of Methyl 6-(4-(4-(2-hydroxypyridine-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate

[0858]

[0859]

[0860] Methyl 6-(4-(4-(2-hydroxypyridine-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate was obtained in the same manner as in Example 71, except that (2-methoxypyridine-4-yl)boronic acid was used instead of (3-fluoro-5-methoxyphenyl)boronic acid in Step 1 of Example 71 and K3PO4 was used instead of Cs2CO3.

[0861] Step 3: Synthesis of 6-(4-(4-(2-hydroxypyridine-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0862]

[0863] A solution mixed with methyl 6-(4-(4-(2-hydroxypyridine-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate in H2O (0.1 M) was stirred for 15 hours. The precipitated solid was filtered and dried to obtain the crude product, which was then purified by column chromatography (15% MeOH in DCM) to obtain the compound of Example 72 as an off-white solid. 1 H NMR (300 MHz, MeOD) δ 8.25 (d, J = 7.4 Hz, 1H), 7.61-7.54 (m, 2H), 7.51 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 8.2 Hz, 2H), 6.78-6.69 (m, 2H), 4.21-4.08(m, 1H), 3.99(s, 2H), 2.96(p, J = 8.4 Hz, 1H), 2.38(s, 6H), 2.32-1.98(m, 6H), 1.76(ddd, J = 17.0, 11.4, 8.6 Hz, 2H); LC / MS(ESI) m / z: 477.16 [M+H] + .

[0864] Example 73: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-N,2,5-trimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0865] Step 1: Synthesis of 3-([1,1'-biphenyl]-4-ylmethyl)-4-bromo-2,5-dimethylthiophene

[0866]

[0867] 3-bromo-2,5-dimethylthiophene (918 mg, 4.80 mmol), FeCl3 (195 mg, 1.20 mmol), and MsOH (78 μL, 1.20 mmol) were added to a solution of [1,1'-biphenyl]-4-ylmethanol (553 mg, 3.0 mmol) in DCE (0.5 M), and the mixture was stirred at 55°C for 10 hours. Ethyl acetate was added to the reaction mixture, and after washing with distilled water and brine, the organic layer was dried with Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane) to obtain 3-([1,1'-biphenyl]-4-ylmethyl)-4-bromo-2,5-dimethylthiophene (466 mg, yield 43%) as a white solid. 1 H NMR (500 MHz, chloroform-d) δ 7.61-7.57(m, 2H), 7.52(m, 2H), 7.44(t, J = 7.7 Hz, 2H), 7.39-7.31(m, 1H), 7.24(d, J = 7.9 Hz, 2H), 4.00(s, 2H), 2.41(s, 3H), 2.40(s, 3H).

[0868] Step 2: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxylic acid

[0869]

[0870] In a mixed solution of 3-([1,1'-biphenyl]-4-ylmethyl)-4-bromo-2,5-dimethylthiophene (169 mg, 0.47 mmol) and TMEDA (78 μL, 0.52 mmol) in THF (0.1 M) at -78°C n-BuLi (0.228 mL, 0.57 mmol) was added and stirred for 1.5 hours. The reaction mixture was quenched with CO2 gas at -78°C and then slowly heated to room temperature over 2 hours. It was acidified with 1 N HCl solution, extracted with ethyl acetate, and washed with water. The organic layer was dried with Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane) to obtain 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxylic acid (56 mg, yield 37%) as a white solid.

[0871] Step 3: Synthesis of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-N,2,5-trimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate

[0872]

[0873] DIPEA (84 μL, 0.48 mmol) was added to a solution of 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxylic acid (52 mg, 0.16 mmol) and HATU (68 mg, 0.18 mmol) in DMF (0.05 M) and stirred for 10 minutes, then intermediate R (39 mg, 0.18 mmol) was added and stirred for 15 hours. The reaction mixture was diluted with ethyl acetate and washed with distilled water and brine. The organic layer was dried with Na2SO4 and concentrated under reduced pressure, then purified by column chromatography (20% EtOAc in hexane) to obtain methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-N,2,5-trimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (47 mg, yield 59%) as a white solid.

[0874] Step 4: Synthesis of 6-(4-([1,1'-biphenyl]-4-ylmethyl)-N,2,5-trimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0875]

[0876] LiOH·H2O (12 mg, 0.3 mmol) was added to a solution of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-N,2,5-trimethylthiophene-3-carboxyamido)spiro[3,3]heptane-2-carboxylate (47 mg, 0.1 mmol) stirred in H2O:THF:MeOH (0.1 M), and the mixture was stirred for 4 hours. The reaction mixture was concentrated under reduced pressure, acidified (pH ~6) with an aqueous 2 N HCl solution, and extracted with ethyl acetate (30 mL twice). The organic layer was dried with Na2SO4 and concentrated under reduced pressure, then purified by column chromatography (70% EtOAc in hexane) to obtain the compound of Example 73 (36 mg, yield 79%) as a white solid. LC / MS(ESI) m / z: 474.25 [M+H] + .

[0877] Example 74: 6-(4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0878] Step 1: Synthesis of Methyl 4-([1,1'-Biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxylate

[0879]

[0880] A solution containing intermediate D (996 mg, 4.0 mmol), 4-phenylphenol (817 mg, 4.8 mmol, 1.2 equivalents), CuBr (115 mg, 0.8 mmol, 0.2 equivalents), and Cs2CO3 (3.9 g, 12.0 mmol, 3.0 equivalents) mixed in pyridine (8 mL) was stirred at 150°C for 1 hour while irradiating with microwaves. The reaction mixture was filtered through Celite, added to distilled water, and extracted with EtOAc; the organic layer was then dried with MgSO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain methyl 4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxylate (550 mg, 40% yield).

[0881] Step 2: Synthesis of 4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxylic acid

[0882]

[0883] LiOH·H2O (340 mg, 8.12 mmol, 5.0 equivalents) was added to a solution of methyl 4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxylate (550 mg, 1.62 mmol) mixed in THF / MeOH / H2O (1:1:1), and the reaction mixture was stirred at 70°C for 12 hours. The reaction mixture was partially concentrated, then acidified with 1 N HCl, and the aqueous layer was extracted with DCM. The organic layer was dried with MgSO4, concentrated under reduced pressure, and purified by column chromatography to obtain 4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxylic acid (100 mg, yield 19%).

[0884] Step 3: Synthesis of Methyl 6-(4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate

[0885]

[0886] DIPEA (80 μL, 0.45 mmol, 1.5 equivalents) was added at 0°C to a solution containing 4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxylic acid (100 mg, 0.3 mmol) and HATU (137 mg, 0.36 mmol, 1.2 equivalents) in DCM (2 mL) and stirred for 15 minutes. A solution containing intermediate A (68 mg, 0.33 mmol, 1.1 equivalents) in DCM (1 mL) was added to the reaction mixture and stirred for 8 hours. The reaction mixture was added to distilled water and extracted with DCM. The organic layer was dried with MgSO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain methyl 6-(4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (50 mg, 34% yield).

[0887] Step 4: Synthesis of 6-(4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0888]

[0889] LiOH·H2O (13 mg, 0.3 mmol, 3.0 equivalents) was added to a solution of methyl 6-(4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (50 mg, 0.5 mmol) mixed in THF / MeOH / H2O (1:1:1) and stirred for 12 hours. The reaction mixture was partially concentrated, then acidified with 1 N HCl and extracted with EtOAc. The organic layer was dried with MgSO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to obtain the compound of Example 74 (22 mg, yield 47%). 1 H NMR (300 MHz, methanol-d4) δ 7.60-7.49 (m, 4H), 7.46-7.34 (m, 2H), 7.34-7.23 (m, 1H), 6.98-6.87 (m, 2H), 4.12-3.96 (m, 1H), 2.96-2.85(m, 1H), 2.52(s, 3H), 2.36-2.28(m, 1H), 2.25-2.18(m, 5H), 2.18-1.95(m, 3H), 1.75-1.65(m, 2H). LC / MS(ESI) m / z: 462.5 [M+H] + .

[0890] Example 75: 6-(4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0891] Step 1: Synthesis of Methyl 4-amino-2,5-dimethylthiophene-3-carboxylate

[0892]

[0893] NH3in H2O (5 mL) was added to a solution containing intermediate D (1.25 g, 5.0 mmol, 1.0 equivalent) and Cu2O (715 mg, 5.0 mmol, 1.0 equivalent) in NMP (10 mL), heated to 100°C, and stirred for 12 hours. The reaction mixture was added to distilled water and extracted with DCM. The organic layer was dried with MgSO4 and then concentrated under reduced pressure. The crude product was purified by column chromatography to obtain methyl 4-amino-2,5-dimethylthiophene-3-carboxylate (182 mg, yield 19%).

[0894] Step 2: Synthesis of Methyl 4-([1,1'-Biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxylate

[0895]

[0896] A solution containing methyl 4-amino-2,5-dimethylthiophene-3-carboxylate (182 mg, 0.98 mmol), 4-bromoviphenyl (274 mg, 1.18 mmol, 1.2 equivalents), Pd(OAc)2 (22 mg, 0.098 mmol, 0.1 equivalents), Xantphos (114 mg, 0.196 mmol, 0.2 equivalents), and Cs2CO3 (639 mg, 1.96 mol, 2.0 equivalents) mixed in toluene (7 mL) was stirred at 110°C for 5 hours. The reaction mixture was added to distilled water and extracted with DCM. The organic layer was dried with MgSO4 and then concentrated under reduced pressure. The crude product was purified by column chromatography to obtain methyl 4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxylate (147 mg, 44% yield).

[0897] Step 3: Synthesis of 4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxylic acid

[0898]

[0899] LiOH·H2O (53 mg, 1.26 mmol, 3.0 equivalents) was added to a solution of methyl 4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxylate (142 mg, 0.42 mmol) mixed in THF / MeOH / H2O (1:1:1), and the mixture was stirred at 70°C for 12 hours. The reaction mixture was partially concentrated and then acidified with 1 N HCl. The precipitated solid was removed by filtration, washed with distilled water, and dried to obtain 4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxylic acid (135 mg, yield 99%).

[0900] Step 4: Synthesis of Methyl 6-(4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate

[0901]

[0902] DIPEA (110 μL, 0.62 mmol, 1.5 equivalents) was added at 0°C to a solution containing 4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxylic acid (135 mg, 0.41 mmol) and HATU (186 mg, 0.49 mmol, 1.2 equivalents) in DCM (2 mL) and stirred for 15 minutes. A solution containing intermediate A (93 mg, 0.45 mmol, 1.1 equivalents) in DCM (1 mL) was added to the reaction mixture and stirred for 12 hours. The reaction mixture was added to distilled water and extracted with DCM. The organic layer was dried with MgSO4 and then concentrated under reduced pressure. The crude product was purified by column chromatography to obtain methyl 6-(4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (126 mg, 65% yield).

[0903] Step 5: Synthesis of 6-(4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0904]

[0905] LiOH·H2O (13 mg, 0.3 mmol, 3.0 equivalents) was added to a solution of methyl 6-(4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate (50 mg, 0.1 mmol) mixed in THF / MeOH / H2O (1:1:1) and stirred for 12 hours. The reaction mixture was partially concentrated, then acidified with 1 N HCl and extracted with EtOAc. The organic layer was dried with MgSO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography to obtain the compound of Example 75 (20 mg, 43% yield). 1 H NMR (300 MHz, Methanol-d4) δ 7.56-7.47 (m, 2H), 7.47-7.30 (m, 4H), 7.28-7.16 (m, 1H), 6.67 (d, J = 8.6 Hz, 2H), 4.16-3.99 (m, 1H), 2.92-2.80(m, 1H), 2.57(s, 3H), 2.35-2.27(m, 1H), 2.23(s, 3H), 2.22-2.11(m, 3H), 2.08-2.02(m, 1H), 1.98-1.90(m, 1H), 1.63-1.54(m, 2H). LC / MS(ESI) m / z: 461.6 [M+1] + .

[0906] Example 76: 6-(4-([1,1'-biphenyl]-4-yl(methyl)amino)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0907] Step 1: Synthesis of methyl 6-(4-([1,1'-biphenyl]-4-yl(methyl)amino)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate

[0908]

[0909] Iodomethane (80 μL, 1.25 mmol, 5.0 equivalents) was added to methyl 6-(4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (120 mg, 0.25 mmol, 1.0 equivalent) and K2CO3 (104 mg, 0.75 mmol, 3.0 equivalents) obtained in Step 4 of Example 75 in DMF (3 mL), and the mixture was stirred at 80°C for 5 days. The reaction mixture was added to distilled water and extracted with DCM. The organic layer was dried with MgSO4 and then concentrated under reduced pressure. The crude product was purified by flash column chromatography to obtain methyl 6-(4-([1,1'-biphenyl]-4-yl(methyl)amino)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (18 mg). 1 H NMR (300 MHz, Chloroform-d) δ 7.58-7.46 (m, 4H), 7.40 (dd, J = 8.4, 6.8 Hz, 2H), 7.32-7.26 (m, 1H), 6.72-6.67 (m, 2H), 4.27-4.19 (m, 1H), 3.60(s, 3H), 3.20(s, 3H), 2.96-2.84(m, 1H), 2.69-2.63(m, 3H), 2.44-2.33(m, 1H), 2.32-2.16(m, 3H), 2.14-2.10(m, 3H), 2.10-2.03(m, 1H), 1.94-1.86(m, 1H), 1.48-1.38(m, 2H).

[0910] Step 2: Synthesis of 6-(4-([1,1'-biphenyl]-4-yl(methyl)amino)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0911]

[0912] LiOH·H2O (5 mg, 0.108 mmol, 3.0 equivalents) was added to a solution of methyl 6-(4-([1,1'-biphenyl]-4-yl(methyl)amino)-2,5-dimethylthiophene-3-carboxyamido)spiro[3.3]heptane-2-carboxylate (18 mg, 0.036 mmol) in THF / MeOH / H2O (3 / 2 / 3 mL) and stirred for 3 hours. The reaction mixture was partially concentrated and then acidified with 1 N HCl. The precipitated solid was filtered, washed with H2O, and dried to obtain the compound of Example 76 (12 mg). 1 H NMR (500 MHz, Methanol-d4) δ 7.76 (d, J = 7.2 Hz, 1H), 7.56-7.51 (m, 2H), 7.47 (d, J = 8.8 Hz, 2H), 7.36 (t, J = 7.8 Hz, 2H), 7.22 (t, J = 7.4 Hz, 1H), 6.69(d, J = 8.7 Hz, 2H), 4.06-4.01(m, 1H), 3.23(s, 3H), 2.88-2.81(m, 1H), 2.48(s, 3H), 2.30(dt, J = 12.1, 6.1 Hz, 1H), 2.21-2.18(m, 2H), 2.18(s, 3H), 2.17-2.12(m, 1H), 2.06-2.02(m, 1H), 1.96-1.90(m, 1H), 1.60-1.54(m, 2H. LC / MS(ESI) m / z: 475.7 [M+H] + .

[0913] Example 77: 6-(2,5-dimethyl-4-((4-phenylpiperazine-1-yl)methyl)thiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0914] Step 1: Synthesis of 4-Bromo-2,5-Dimethylthiophene-3-Carboxylic Acid

[0915]

[0916] LiOH·H2O (1.1 g, 27.1 mmol) was added to a solution containing intermediate D (2.25 g, 9.03 mmol) mixed in H2O / THF / MeOH (0.3 M, 30 mL) and stirred for 12 hours. The reaction mixture was acidified by adding a 1 N HCl solution and extracted with EA (3 × 30 mL). The organic layer was dried over MgSO4, filtered, and concentrated, and then purified by silica gel column chromatography (n-hexane and ethyl acetate) to obtain 4-bromo-2,5-dimethylthiophene-3-carboxylic acid (1.97 g, yield 93%). 1 H NMR (500 MHz, DMSO-d6) δ 13.06 (s, 1H), 2.55 (s, 3H), 2.32 (s, 3H).

[0917] Step 2: Synthesis of (4-bromo-2,5-dimethylthiophene-3-yl)(4-phenylpiperazine-1-yl)methanone

[0918]

[0919] DIPEA (4.3 mL, 25.2 mmol) was added to a solution in which 4-bromo-2,5-dimethylthiophene-3-carboxylic acid (1.97 g, 8.4 mmol), 1-phenylpiperazine (1.4 mL, 9.24 mmol), and HATU (3.5 g, 9.24 mmol) were mixed in DMF (28 mL, 0.3 M) and stirred for 3 hours. The reaction mixture was concentrated and diluted with 1 N NaOH aqueous solution and ethyl acetate, and the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with brine, dried and concentrated over MgSO4, and then purified by silica gel column chromatography (n-hexane and ethyl acetate) to obtain (4-bromo-2,5-dimethylthiophene-3-yl)(4-phenylpiperazine-1-yl)methane (2.92 g, yield 92%). 1H NMR (500 MHz, Chloroform-d) δ 7.34-7.29 (m, 2H), 6.95 (dd, J = 13.9, 7.6 Hz, 3H), 4.07 (dt, J = 13.0, 5.0 Hz, 1H), 3.92 (dt, J = 13.0, 5.3 Hz, 1H), 3.54(ddd, J = 13.0, 6.6, 3.3 Hz, 1H), 3.45(ddd, J = 13.0, 7.2, 3.3 Hz, 1H), 3.29(t, J = 5.2 Hz, 2H), 3.24(ddd, J = 10.7, 7.2, 3.4 Hz, 1H), 3.15-3.09(m, 1H), 2.41(s, 3H), 2.37(s, 3H).

[0920] Step 3: Synthesis of 1-((4-bromo-2,5-dimethylthiophene-3-yl)methyl)-5-phenylpiperazine

[0921]

[0922] BH in a stirred solution of (4-bromo-2,5-dimethylthiophene-3-yl)(4-phenylpiperazine-1-yl)methanone (2.87 g, 7.6 mmol) and THF (19 mL, 0.4 M). 3· Me2S (19.5 mL, 39 mmol) was added and stirred at 40°C for 12 hours. The reaction mixture was cooled to room temperature and extracted with an aqueous solution of NaHCO3 (70 mL) and EA. The organic layer was dried over Na2SO4 and filtered, and the crude product was purified by silica gel column chromatography (ethyl acetate / hexane) to obtain 1-((4-bromo-2,5-dimethylthiophene-3-yl)methyl)-5-phenylpiperazine (1.4 g, yield 51%). 1 H NMR (500 MHz, Chloroform-d) δ 7.30-7.26 (m, 2H), 6.94 (d, J = 7.8 Hz, 2H), 6.87 (t, J = 7.3 Hz, 1H), 3.49 (s, 2H), 3.21-3.16 (m, 4H), 2.67-2.63(m, 4H), 2.46(s, 3H), 2.38(s, 3H).

[0923] Step 4: Synthesis of 2,5-dimethyl-4-((4-phenylpiperazine-1-yl)methyl)thiophene-3-carboxylic acid

[0924]

[0925] In a stirred solution of 1-((4-bromo-2,5-dimethylthiophene-3-yl)methyl)-5-phenylpiperazine (500 mg, 1.37 mmol), tetramethylenediamine (0.23 mL, 1.51 mmol), and THF (7.0 mL, 0.2 M) at -65°C n -BuLi (2.5 M in THF, 0.72 mL, 1.8 mmol) was slowly added and stirred for 1 hour, after which an excess amount of dry ice was added. The mixture was acidified with 1 N HCl and extracted with EtOAc. The organic layer was dried with MgSO4, filtered, and concentrated to obtain 2,5-dimethyl-4-((4-phenylpiperazine-1-yl)methyl)thiophene-3-carboxylic acid (502 mg).

[0926] Step 5: Synthesis of methyl 6-(2,5-dimethyl-4-((4-phenylpiperazine-1-yl)methyl)thiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate

[0927]

[0928] DIPEA (0.80 mL) was added to a solution mixed with 2,5-dimethyl-4-((4-phenylpiperazine-1-yl)methyl)thiophene-3-carboxylic acid (576 mg, 1.52 mmol), intermediate A (0.34 g, 1.67 mmol), and HATU (0.63 g, 1.67 mmol) in DMF (5.1 mL, 0.3 M) and stirred for 3 hours. The reaction mixture was concentrated and diluted with 1 N NaOH aqueous solution and ethyl acetate, and the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with brine, dried and concentrated over MgSO4, and then purified by silica gel chromatography (n-hexane and ethyl acetate) to obtain methyl 6-(2,5-dimethyl-4-((4-phenylpiperazine-1-yl)methyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (102 mg, yield 14%). 1H NMR (500 MHz, Chloroform-d) δ 9.73 (d, J = 7.0 Hz, 1H), 7.32 (t, J = 7.9 Hz, 2H), 6.94 (dd, J = 17.1, 7.9 Hz, 3H), 4.45 (h, J = 8.2, 7.7 Hz, 1H), 3.68(s, 3H), 3.44(s, 2H), 3.23(s, 4H), 3.05(p, J = 8.5 Hz, 1H), 2.72(s, 4H), 2.62(s, 4H), 2.47(dt, J = 12.5, 6.5 Hz, 1H), 2.38(d, J = 7.0 Hz, 5H), 2.31(dd, J = 11.6, 8.5 Hz, 1H), 2.16-2.10(m, 1H), 1.91(dt, J = 23.8, 10.4 Hz, 2H).

[0929] Step 6: Synthesis of 6-(2,5-dimethyl-4-((4-phenylpiperazine-1-yl)methyl)thiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0930]

[0931] LiOH·H2O (43 mg, 1.02 mmol) was added to a solution of methyl 6-(2,5-dimethyl-4-((4-phenylpiperazine-1-yl)methyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (163 mg, 0.34 mmol) mixed in H2O / THF / MeOH (0.3 M, 1.1 mL) and stirred for 12 hours. The reaction mixture was acidified by adding 1 N HCl solution and extracted with EA (20 mL aliquots, three times). The organic layer was dried over MgSO4, filtered, and concentrated, then purified by silica gel column chromatography (n-hexane and ethyl acetate) to obtain the compound of Example 77 (12 mg, yield 8%). 1H NMR (500 MHz, Methanol-d4) δ 7.27 (t, J = 7.8 Hz, 2H), 7.00 (d, J = 8.3 Hz, 2H), 6.88 (t, J = 7.3 Hz, 1H), 4.37 (p, J = 8.2 Hz, 1H), 3.64 (s, 2H), 3.24(s, 4H), 3.01(p, J = 8.4 Hz, 1H), 2.83(s, 4H), 2.59(dt, J = 11.7, 6.6 Hz, 1H), 2.53(s, 3H), 2.41(s, 4H), 2.39-2.31(m, 2H), 2.28-2.23(m, 1H), 2.16(t, J = 10.1 Hz, 1H), 2.04(dt, J = 28.7, 9.7 Hz, 2H). LC / MS(ESI) m / z: 468.3 [M+H] + .

[0932] Example 78: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-N,2,5-trimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0933] Step 1: Synthesis of methyl 6-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate

[0934]

[0935] Dipea (0.5 mL, 3.0 mmol) was added to a solution of intermediate S (300 mg, 1.0 mmol) and HATU (456 mg, 1.20 mmol) in DMF (0.1 M) and stirred for 10 minutes, and intermediate A (169 mg, 1.0 mmol) was added and stirred for 15 hours. The reaction mixture was diluted with ethyl acetate and washed with distilled water (25 mL a time, three times) and brine. The organic layer was dried with Na2SO4, concentrated under reduced pressure, and purified by column chromatography (40% EtOAc in hexane) to obtain methyl 6-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (260 mg, yield 83%) as a yellow liquid. 1H NMR (300 MHz, chloroform-d) δ 7.85 (d, J = 7.6 Hz, 1H), 4.58 (s, 2H), 4.55-4.32 (m, 1H), 3.69 (s, 3H), 3.06 (p, J = 8.6 Hz, 1H), 2.68-2.59(m, 1H), 2.58(s, 3H), 2.52-2.41(m, 1H), 2.41-2.25(m, 6H), 2.20-2.09(m, 1H), 2.04-1.85(m, 2H), 0.94(s, 9H), 0.16(s, 6H).

[0936] Step 2: Synthesis of Methyl 6-(4-(hydroxymethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate

[0937]

[0938] TBAF (0.75 mL, 0.75 mmol) was added to a solution mixed with methyl 6-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,5-methylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (226 mg, 0.50 mmol) in THF (0.1 M), and the mixture was stirred for 15 hours. The reaction mixture was diluted with ethyl acetate and washed with distilled water (25 mL a few times) and saline solution. The organic layer was dried with Na2SO4, concentrated under reduced pressure, and purified by column chromatography (30% EtOAc in hexane) to obtain methyl 6-(4-(hydroxymethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (171 mg) as a yellow liquid. 1 H NMR (300 MHz, chloroform-d) δ 6.49 (d, J = 7.9 Hz, 1H), 4.53-4.37 (m, 3H), 3.69 (s, 3H), 3.05 (q, J = 8.5 Hz, 1H), 2.71-2.58 (m, 1H), 2.54(s, 3H), 2.53-2.44(m, 1H), 2.40(s, 3H), 2.38-2.27(m, 3H), 2.24-2.14(m, 1H), 2.07-1.86(m, 2H).

[0939] Step 3: Synthesis of Methyl 6-(4-(bromomethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate

[0940]

[0941] PBr3 (92 μL, 2.03 mmol) was added at 0°C to a solution of methyl 6-(4-(hydroxymethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (82 mg, 0.24 mmol) stirred in DCM (0.1 M) and stirred for 15 hours. The reaction mixture was diluted with ethyl acetate and washed with a bicarbonate solution and distilled water. The organic layer was dried with Na2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography (25% EtOAc in hexane) to obtain methyl 6-(4-(bromomethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (49 mg, yield 50%) as a white solid. 1 ¹H NMR(300 MHz, chloroform- d ) δ 6.18(d, J = 7.0 Hz, 1H), 4.53(s, 2H), 4.53-4.39(m, 1H), 3.69(s, 3H), 3.05(q, J = 8.5 Hz, 1H), 2.74-2.59(m, 1H), 2.57-2.51(m, 1H), 2.47(s, 3H), 2.42-2.35(m, 1H), 2.38(s, 3H), 2.38-2.28(m, 2H), 2.25-2.15(m, 1H), 2.11-1.91(m, 2H).

[0942] Step 4: Synthesis of methyl 6-(2,5-dimethyl-4-((4-phenyl-1H-pyrazole-1-yl)methyl)thiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylate

[0943]

[0944] NaH (5 mg, 0.12 mmol) was added to a solution of 4-phenyl-1H-pyrazole (12 mg, 0.08 mmol) mixed in DMF (0.1 M) and stirred for 15 minutes. Methyl 6-(4-(bromomethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (32 mg, 0.08 mmol) was added and stirred for 4 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with distilled water (10 mL twice). The organic layer was dried with Na2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography (40% EtOAc in hexane) to obtain methyl 6-(2,5-dimethyl-4-((4-phenyl-1H-pyrazole-1-yl)methyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (16 mg, yield 43%) as a white solid.

[0945] Step 5: Synthesis of 6-(2,5-dimethyl-4-((4-phenyl-1H-pyrazole-1-yl)methyl)thiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0946]

[0947] LiOH·H2O (3 mg, 0.1 mmol) was added to a solution of methyl 6-(2,5-dimethyl-4-((4-phenyl-1H-pyrazole-1-yl)methyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (16 mg, 0.03 mmol) in H2O:THF:MeOH (1:1:1, 0.1 M) and stirred for 15 hours. The reaction mixture was partially concentrated, acidified (pH ~4) with 1 N HCl solution, and extracted with ethyl acetate (10 mL twice). The organic layer was dried with Na2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography (5% MeOH in DCM) to obtain the compound of Example 78 (5 mg, yield 32%) as a white solid. 1H NMR (400 MHz, MeOD) δ 7.85 (s, 1H), 7.81 (s, 1H), 7.57-7.50 (m, 2H), 7.36 (t, J = 7.7 Hz, 2H), 7.26-7.17 (m, 1H), 5.28 (s, 2H), 4.20 (p, J = 8.1 Hz, 1H), 2.91 (p, J = 8.5 Hz, 1H), 2.46 (s, 3H), 2.43-2.32 (m, 1H), 2.40 (s, 3H), 2.31-2.19 (m, 3H), 2.17-2.07(m, 1H), 2.01(ddd, J = 11.4, 8.7, 2.7 Hz, 1H), 1.93-1.80(m, 2H). LC / MS(ESI) m / z: 450.09 [M+H] + .

[0948] Example 79: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0949] Step 1: Synthesis of Methyl 4-([1,1'-biphenyl]-4-ylmethyl)-3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylate

[0950]

[0951] 4-bromomethyl-biphenyl (890 mg, 3.6 mmol, 1.2 equivalents) was added to a mixed solution of intermediate T (780 mg, 3.0 mmol, 1.0 equivalents) and Cs2CO3 (2.44 g, 7.5 mmol, 2.5 equivalents) in DMF (10 mL) and stirred for 12 hours. The reaction mixture was poured into distilled water and extracted with DCM, after which the organic layer was dried with MgSO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography to obtain methyl 4-([1,1'-biphenyl]-4-ylmethyl)-3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylate (940 mg, yield 73%). 1 ¹H NMR(300 MHz, chloroform- d ) δ 7.57-7.48(m, 4H), 7.44-7.37(m, 2H), 7.36-7.29(m, 1H), 7.26(s, 1H), 7.25(s, 1H), 7.11(d, J= 8.1 Hz, 2H), 6.14(s, 2H), 3.82(s, 3H).

[0952] Step 2: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid

[0953]

[0954] LiOH·H2O (277 mg, 6.6 mmol, 3.0 equivalents) was added to a solution of methyl 4-([1,1'-biphenyl]-4-ylmethyl)-3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylate (940 mg, 2.2 mmol) in THF / MeOH / H2O (20 / 10 / 10 mL), and the mixture was stirred at 70°C for 12 hours. The reaction mixture was partially concentrated and then acidified with a 1 N HCl solution. The precipitated solid was filtered, washed with distilled water, and dried to obtain 4-([1,1'-biphenyl]-4-ylmethyl)-3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (815 mg, yield 90%). 1 ¹H NMR(300 MHz, chloroform- d ) δ 7.58-7.36(m, 3H), 7.43-7.36(m, 2H), 7.32(d, J = 6.8 Hz, 2H), 7.11(d, J = 8.1 Hz, 2H), 6.12(s, 2H).

[0955] Step 3: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole

[0956]

[0957] A solution of 4-([1,1'-biphenyl]-4-ylmethyl)-3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (815 mg, 1.97 mmol) and Cu powder (82 mg, 10 wt%) mixed in quinoline (10 mL) was stirred at 140°C for 12 hours. The reaction mixture was cooled, acidified with 6 N HCl solution, and then extracted with Et2O. The organic layer was dried with MgSO4 and concentrated under reduced pressure, and the crude product was purified by flash column chromatography to obtain 4-([1,1'-biphenyl]-4-ylmethyl)-3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole (170 mg, yield 23%).

[0958] Step 4: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid

[0959]

[0960] In a solution mixed with 4-([1,1'-biphenyl]-4-ylmethyl)-3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole (170 mg, 0.46 mmol, 1.0 equivalent) in THF (5 mL) n -BuLi (2.0 M in cyclohexane, 0.3 mL, 1.2 equivalents) was added at -78°C and stirred for 10 minutes. Dry ice was added to the reaction mixture and stirred at room temperature for 1 hour, then acidified with 1 N HCl solution and extracted with EtOAc. The organic layer was dried with MgSO4 and concentrated under reduced pressure, and the crude product was purified by flash column chromatography to obtain 4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid (100 mg, mixture).

[0961] Step 5: Synthesis of Methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxamido)spiro[3,3]heptane-2-carboxylate

[0962]

[0963] DIPEA (80 μL, 0.45 mmol, 1.5 equivalents) was added at 0°C to a mixed solution of 4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid (100 mg, 0.3 mmol) and HATU (137 mg, 0.36 mmol, 1.2 equivalents) in DCM (2 mL), and stirred for 15 minutes. Intermediate A (68 mg, 0.33 mmol, 1.1 equivalents) was added to the reaction mixture, and stirred for 12 hours. The reaction mixture was poured into distilled water and extracted with DCM; the organic layer was dried with MgSO4 and then concentrated under reduced pressure. The crude product was purified by flash column chromatography to obtain methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxamido)spiro[3.3]heptane-2-carboxylate (40 mg, yield 30%). 1 H NMR (300 MHz, chloroform-d) δ 7.56-7.50 (m, 2H), 7.50-7.39 (m, 4H), 7.36-7.29 (m, 1H), 7.11 (d, J = 8.3 Hz, 2H), 7.00 (dd, J = 2.9, 1.3 Hz, 1H), 6.44(d, J = 2.9 Hz, 1H), 5.99(d, J = 7.8 Hz, 1H), 5.60(s, 2H), 4.36-4.28(m, 1H), 3.66(s, 3H), 3.05-2.94(m, 1H), 2.54-2.46(m, 1H), 2.42-2.36(m, 1H), 2.33-2.30(m, 2H), 2.27-2.20(m, 1H), 2.09-2.01(m, 1H), 1.80-1.71(m, 2H).

[0964] Step 6: Synthesis of 6-(4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0965]

[0966] LiOH·H2O (10 mg, 0.24 mmol, 3.0 equivalents) was added to a solution of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxamido)spiro[3.3]heptane-2-carboxylate (40 mg, 0.08 mmol) in THF / MeOH / H2O (1:1:1, 9 mL) and stirred for 12 hours. The reaction mixture was partially concentrated and then acidified with a 1 N HCl solution. The precipitated solid was filtered, washed with distilled water, and dried, and the crude product was purified by flash column chromatography to obtain the compound of Example 79 (15 mg, yield 40%). 1 H NMR (300 MHz, methanol-d4) δ 8.34 (d, J = 7.3 Hz, 1H), 7.58-7.52 (m, 2H), 7.50-7.44 (m, 2H), 7.44-7.35 (m, 3H), 7.33-7.26 (m, 1H), 7.15 (dd, J = 3.0, 1.3 Hz, 1H), 7.02 (d, J = 8.3 Hz, 2H), 6.43 (d, J = 3.0 Hz, 1H), 5.56 (s, 2H), 4.25-4.11 (m, 1H), 3.02-2.90 (m, 1H), 2.46-2.38(m, 1H), 2.35-2.23(m, 3H), 2.22-2.01(m, 2H), 1.91-1.81(m, 2H). LC / MS(ESI) m / z: 471.4 [M+H] + .

[0967] The compounds of Examples 80 to 89 were prepared using the same method as described in Example 79, except for differences in the manufacturing method described below.

[0968] Example number chemical structure designation Differences in manufacturing methods 80 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2-methyl-4H-thieno[3,2-b]pyrrole-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Use intermediate U instead of intermediate T in Step 1 81 6-(4-([1,1'-biphenyl]-4-ylmethyl)-6-methyl-4H-thieno[3,2-b]pyrrole-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Use intermediate V instead of intermediate T in Step 1 82 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2-chloro-4H-thieno[3,2-b]pyrrole-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Use intermediate W instead of intermediate T in Step 1 83 (1R,3R)-3-(4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxamido)cyclobutane-1-carboxylic acid In Step 5, methyl(1R,3R)-3-aminocyclobutane-1-carboxylate hydrochloride of the following structure is used instead of intermediate A: 84 (1S,3S)-3-(4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxamido)cyclobutane-1-carboxylic acid In Step 5, methyl(1S,3S)-3-aminocyclobutane-1-carboxylate hydrochloride of the following structure is used instead of intermediate A: 85 6-(4-((3'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-4H-thieno[3,2-b]pyrrole-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Use intermediate X instead of 4'-bromomethylbiphenyl in Step 1 86 (2R,4R,6R)-6-(4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-4H-thieno[3,2-b]pyrrole-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Use intermediate Y instead of 4'-bromomethylbiphenyl in Step 1, and use intermediate Z instead of intermediate A in Step 5. 87 3-(4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxamido)bicyclo[1.1.1]pentane-1-carboxylic acid In step 5, use methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride of the following structure instead of intermediate A: 88 4-(4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxamido)bicyclo[2.2.2]octane-1-carboxylic acid In step 5, use methyl 4-aminobicyclo[1.1.1]octane-1-carboxylate hydrochloride of the following structure instead of intermediate A: 89 6-(4-((3',5'-dimethoxy-[1,1'-biphenyl]-4-yl)methyl)-4H-thieno[3,2-b]pyrrole-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Use intermediate AA instead of 4'-bromomethylbiphenyl in Step 1

[0969] Example number LC / MS(ESI) m / z: [M+H] + NMR 80 485.26 1 H NMR(400 MHz, Chloroform-d) δ 7.60-7.52(m, 2H), 7.52-7.47(m, 2H), 7.45(t, J = 7.7 Hz, 2H), 7.40-7.32(m, 1H), 7.07(d, J = 8.0 Hz, 2H), 6.92(d, J = 3.0 Hz, 1H), 6.39(d, J = 2.9 Hz, 1H), 5.57(d, J = 7.9 Hz, 1H), 5.42(s, 2H), 4.33(d, J = 8.1 Hz, 1H), 3.03(m, 1H), 2.56(s, 3H), 2.52-2.43(m, 1H), 2.36(d, J = 8.3 Hz, 3H), 2.28-2.16(m, 1H), 2.08(m, 1H), 1.65(d, J = 10.0 Hz, 2H). 81 485.4 1 H NMR(300 MHz, DMSO-d6) δ 12.03(s, 1H), 8.48(d, J = 7.4 Hz, 1H), 7.62-7.55(m, 3H), 7.55-7.50(m, 2H), 7.45-7.40(m, 2H), 7.35-7.30(m, 1H), 7.14(d, J = 8.1 Hz, 2H), 7.05(s, 1H), 5.53(s, 2H), 4.24-4.16(m, 1H), 2.97-2.86(m, 1H), 2.43-2.35(m, 1H), 2.31-2.16(m, 3H), 2.14(s, 3H), 2.11-1.86(m, 4H). 82 505.4 1 H NMR(300 MHz, DMSO-d6) δ 12.03(s, 1H), 8.73(d, J = 7.5 Hz, 1H), 7.65-7.51(m, 4H), 7.45(t, J = 7.6 Hz, 2H), 7.39-7.32(m, 2H), 7.14(d, J = 8.2 Hz, 2H), 6.43(d, J = 3.0 Hz, 1H), 5.33(s, 2H), 4.24-4.14(m, 1H), 2.95-2.83(m, 1H), 2.41-2.31(m, 1H), 2.31-2.14(m, 3H), 2.10-1.93(m, 2H), 1.93-1.77(m, 2H). 83 431.4 1 H NMR(300 MHz, DMSO-d6) δ 8.61(d, J = 7.7 Hz, 1H), 7.63-7.56(m, 3H), 7.53(d, J = 8.2 Hz, 2H), 7.43(t, J = 7.4 Hz, 2H), 7.34(t, J = 5.0 Hz, 2H), 7.15(d, J = 8.2 Hz, 2H), 6.46(d, J = 2.9 Hz, 1H), 5.62(s, 2H), 4.51(h, J = 7.7 Hz, 1H), 2.89-2.78(m, 1H), 2.47-2.36(m, 2H), 2.19(td, J = 12.2, 11.0, 6.0 Hz, 2H). 84 431.1 1 H NMR(300 MHz, DMSO-d6) δ 12.13(s, 1H), 8.61(d, J = 7.7 Hz, 1H), 7.64-7.56(m, 3H), 7.53(d, J = 8.2 Hz, 2H), 7.43(t, J = 7.4 Hz, 2H), 7.37-7.29(m, 2H), 7.15(d, J = 8.2 Hz, 2H), 6.46(d, J = 2.9 Hz, 1H), 5.63(s, 2H), 4.31(h, J = 7.9 Hz, 1H), 2.84-2.69(m, 1H), 2.44(td, J = 8.3, 2.8 Hz, 2H), 2.16(qd, J = 9.5, 2.5 Hz, 2H). 85 [M+1]=501.4 1 H NMR(300 MHz, DMSO-d6) δ 12.03(s, 1H), 8.48(d, J = 7.5 Hz, 1H), 7.57(d, J = 1.3 Hz, 1H), 7.53(d, J = 8.3 Hz, 2H), 7.40-7.27(m, 2H), 7.18-7.05(m, 4H), 6.94-6.82(m, 1H), 6.44(d, J = 2.9 Hz, 1H), 5.61(s, 2H), 4.21(h, J = 8.1 Hz, 1H), 3.79(s, 3H), 2.92(p, J = 8.4 Hz, 1H), 2.46-2.35(m, 1H), 2.30-2.18(m, 3H), 2.13-1.85(m, 4H). 86 519.3 1 H NMR(300 MHz, DMSO-d6) δ 12.03(s, 1H), 8.49(d, J = 7.5 Hz, 1H), 7.57(d, J = 8.4 Hz, 3H), 7.31(dd, J = 2.9, 1.1 Hz, 1H), 7.13(d, J = 8.2 Hz, 2H), 7.02(dt, J = 12.2, 1.9 Hz, 2H), 6.81(dt, J = 10.9, 2.2 Hz, 1H), 6.45(d, J = 2.9 Hz, 1H), 5.62(s, 2H), 4.22(p, J = 8.2 Hz, 1H), 3.81(s, 3H), 2.93(p, J = 8.4 Hz, 1H), 2.40(dt, J = 11.7, 6.5 Hz, 1H), 2.24(dtd, J = 24.3, 13.7, 12.5, 3.8 Hz, 3H), 2.13-2.03(m, 2H), 2.01-1.88(m, 2H). 87 - 1 H NMR(300 MHz, DMSO-d6) δ 12.45(s, 1H), 8.97(s, 1H), 7.58(dd, J = 16.3, 8.0 Hz, 5H), 7.44(t, J = 7.5 Hz, 2H), 7.37-7.31(m, 2H), 7.18(d, J = 8.2 Hz, 2H), 6.46(d, J = 2.9 Hz, 1H), 5.62(s, 2H), 2.28(s, 6H). 88 485.3 1 H NMR(300 MHz, DMSO-d6) δ 12.05(s, 1H), 7.78(s, 1H), 7.63-7.51(m, 5H), 7.44(t, J = 7.4 Hz, 2H), 7.37-7.28(m, 2H), 7.18(d, J = 8.2 Hz, 2H), 6.44(d, J = 2.9 Hz, 1H), 5.60(s, 2H), 1.90(dd, J = 10.7, 4.4 Hz, 6H), 1.77(dd, J = 10.3, 4.5 Hz, 6H). 89 531.5 1 H NMR(300 MHz, DMSO- d 6) δ 12.04(s, 1H), 8.48(d, J = 7.5 Hz, 1H), 7.58(d, J = 1.3 Hz, 1H), 7.52(d, J = 8.2 Hz, 2H), 7.30(dd, J = 3.0, 1.3 Hz, 1H), 7.11(d, J = 8.2 Hz, 2H), 6.70 - 6.69(m, 2H), 6.47(t, J = 2.2 Hz, 1H), 6.44(d, J = 2.9 Hz, 1H), 5.61(s, 2H), 4.34 - 4.09(m, 1H), 3.77(s, 6H), 2.98 - 2.85(m, 1H), 2.45 - 2.35(m, 1H), 2.32 - 2.18(m, 3H), 2.12 - 2.02(m, 2H), 2.01 - 1.86(m, 2H).

[0970] Example 90: 6-(4-(4-(trifluoromethyl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0971] Steps 1 to 3: Synthesis of 3-bromo-4-(4-(trifluoromethyl)benzyl)-4H-thieno[3,2-b]pyrrole

[0972]

[0973]

[0974] 3-bromo-4-(4-(trifluoromethyl)benzyl)-4H-thieno[3,2-b]pyrrole was obtained as a yellow liquid in the same manner as steps 1 to 3 of Example 79, except that 1-bromomethyl-4-(trifluoromethyl)benzene was used instead of 4-bromomethylbiphenyl in step 1 of Example 79. 1 ¹H NMR(300 MHz, chloroform- d ) δ 7.60-7.55(m, 2H), 7.23-7.17(m, 2H), 7.03-6.98(m, 1H), 6.88-6.85(m, 1H), 6.44(d, J = 3.0 Hz, 1H), 5.57(d, J = 9.4 Hz, 2H).

[0975] Step 4: Synthesis of 4-(4-(trifluoromethyl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid

[0976]

[0977] Pd(OAc)2 (3 mol%) and Xantphos (3 mol%) were placed in an oven-dried tube under vacuum and purged with argon three times, after which a mixed solution of formic acid (0.24 mL, 6.258 mmol) and 3-bromo-4-(4-(trifluoromethyl)benzyl)-4H-thieno[3,2-b]pyrrole (322 mg, 0.894 mmol) in DMF (3.0 mL) was added. After adding DCC (37 mg, 0.179 mmol) and Et3N (0.25 mL, 1.788 mmol), the tube was sealed and the mixture was stirred at 100°C for 20 hours. After filtering the reaction mixture and concentrating it under reduced pressure, the crude product was purified by silica gel column chromatography to obtain 4-(4-(trifluoromethyl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid (124 mg, yield 43%) as a white solid. 1H NMR (300 MHz, chloroform-d) δ 8.09 (d, J = 1.3 Hz, 1H), 7.51 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 8.1 Hz, 2H), 6.95 (dd, J = 3.1, 1.3 Hz, 1H), 6.51(d, J = 3.1 Hz, 1H), 5.81(s, 2H).

[0978] Steps 5 and 6: Synthesis of 6-(4-(4-(trifluoromethyl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid

[0979]

[0980] The compound of Example 90 was obtained by reacting 4-(4-(trifluoromethyl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid in the same manner as steps 5 and 6 of Example 79. 1 ¹H NMR(300 MHz, DMSO- d 6) δ 12.0(br s, 1H) 8.42(d, J = 7.5 Hz, 1H), 7.61(d, J = 8.0 Hz, 2H), 7.58(d, J = 1.3 Hz, 1H), 7.30(dd, J = 3.0, 1.3 Hz, 1H), 7.16(d, J = 8.0 Hz, 2H), 6.47(d, J = 3.0 Hz, 1H), 5.68(s, 2H), 4.18-4.04(m, 1H), 2.96-2.85(m, 1H), 2.39-2.00(m, 6H), 1.92-1.85(m, 2H). LC / MS(ESI) m / z: 463.4 [M+H] + .

[0981] Compounds of Examples 91 to 94 were prepared using the same method as described in Example 90, except for differences in the manufacturing method described below.

[0982] Example number chemical structure designation Differences in manufacturing methods 91 6-(4-(2-([1,1'-biphenyl]-4-yl)ethyl)-4H-thieno[3,2-b]pyrrole-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Use intermediate BB instead of 1-(bromomethyl)-4-(trifluoromethyl)benzene in Step 1 92 6-(4-((3'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-4H-thieno[3,2-b]pyrrole-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Use intermediate CC instead of 1-(bromomethyl)-4-(trifluoromethyl)benzene in Step 1 93 6-(4-(4-(pyrimidine-2-yl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid Use intermediate DD instead of 1-(bromomethyl)-4-(trifluoromethyl)benzene in Step 1 94 6-(4-((2-phenylpyrimidine-5-yl)methyl)-4H-thieno[3,2-b]pyrrole-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Use intermediate EE instead of 1-(bromomethyl)-4-(trifluoromethyl)benzene in Step 1

[0983] Example number LC / MS(ESI) m / z: [M+H] + NMR 91 [M+H]+ = 485.4, [M+K] + = 522.4, [M+H+DMSO] + = 563.4 1 H NMR(300 MHz, DMSO-d6) δ 8.69-8.59(m, 1H), 7.74(d, J = 1.2 Hz, 1H), 7.70-7.62(m, 2H), 7.60-7.56(m, 2H), 7.48-7.43(m, 2H), 7.37-7.32(m, 1H), 7.31-7.21(m, 3H), 4.57-4.52(m, 2H), 4.31-4.24(m, 1H), 2.99-2.87(m, 3H), 2.48-2.38(m, 1H), 2.32-2.21(m, 3H), 2.15-1.99(m, 4H). 92 489.4 1 H NMR(300 MHz, DMSO-d6) δ 12.06(s, 1H), 8.48(d, J = 7.5 Hz, 1H), 7.64-7.53(m, 3H), 7.52-7.45(m, 3H), 7.31(dd, J = 3.0, 1.3 Hz, 1H), 7.20-7.14(m, 1H), 7.16-7.11(m, 2H), 6.45(d, J = 2.9 Hz, 1H), 5.62(s, 2H), 4.24-4.16(m, 1H), 2.97-2.86(m, 1H), 2.43-2.35(m, 1H), 2.10-1.90(m, 7H). 93 473.5 1 H NMR(300 MHz, DMSO-d6) δ 12.01(s, 1H), 8.91-8.83(m, 2H), 8.47(d, J = 7.4 Hz, 1H), 8.26(d, J = 7.8 Hz, 2H), 7.57(s, 1H), 7.43-7.40(m, 1H), 7.32(s, 1H), 7.17(d, J = 7.9 Hz, 2H), 6.46(s, 1H), 5.65(s, 2H), 4.22-4.14(m, 1H), 2.96-2.85(m, 1H), 2.42-2.32(m, 1H), 2.29-2.15(m, 3H), 2.12-1.83(m, 4H). 94 473.3 1 H NMR(300 MHz, DMSO- d 6) δ 12.02(s, 1H), 8.53(s, 2H), 8.34 - 8.30(m, 2H), 7.64(s, 1H), 7.54 - 7.48(m, 3H), 7.40 - 7.36(m, 1H), 6.50(d, J = 3.0 Hz, 1H), 5.68(s, 2H), 5.57(d, J = 8.0 Hz, 1H), 4.24 - 4.10(m, 1H), 2.98 - 2.83(m, 1H), 2.42 - 2.32(m, 1H), 2.30 - 2.14(m, 3H), 2.12 - 1.98(m, 2H), 1.96 - 1.83(m, 2H).

[0984] Example 95: 6-(4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2-methyl-4H-thieno[3,2-b]pyrrole-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0985] Steps 1 to 3: Synthesis of 3-bromo-4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2-methyl-4H-thieno[3,2-b]pyrrole

[0986]

[0987]

[0988] 3-bromo-4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)2-methyl-4H-thieno[3,2-b]pyrrole was obtained using intermediates U and Y as starting materials in the same manner as steps 1 to 3 of Example 79. 1 H NMR (400 MHz, CDCl3) δ 7.50(d, J = 8.3 Hz, 2H), 7.18(d, J = 8.1 Hz, 2H), 6.92-6.79(m, 3H), 6.60(td, J = 2.3, 10.5 Hz, 1H), 6.37(d, J = 2.9 Hz, 1H), 5.57(s, 2H), 3.84(s, 3H), 2.44(s, 3H). LC / MS(ESI) m / z: 430.2 [M+1].

[0989] Step 4: Synthesis of methyl 4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2-methyl-4H-thieno[3,2-b]pyrrole-3-carboxylate

[0990]

[0991] Pd(dppf)Cl in a solution mixed with 3-bromo-4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)2-methyl-4H-thieno[3,2-b]pyrrole (410 mg, 953 umol, 1.00 equivalents) in MeOH (4 mL). 2·CH2Cl2 (156 mg, 191 μmol, 0.2 equivalents) and TEA (289 mg, 2.86 mmol, 398 μL, 3.0 equivalents) were added under an N2 atmosphere. The reaction mixture was substituted three times under a CO atmosphere and then stirred at 70°C for 24 hours under CO (50 Psi). After cooling, filtering, and concentrating the reaction mixture, the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 20 / 1) to obtain methyl 4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2-methyl-4H-thieno[3,2-b]pyrrole-3-carboxylate (280 mg, yield 71.7%) as a yellow oil. 1 H NMR (400 MHz, DMSO) δ 7.46 (d, J = 8.40 Hz, 2 H), 7.07 (d, J = 8.40 Hz, 2 H), 6.93-6.82 (m, 3 H), 6.59 (td, J = 2.40, 10.4 Hz, 1 H), 6.40 (d, J = 3.00 Hz, 1 H), 5.64(s, 2 H), 3.84(s, 3 H), 3.76(s, 3 H), 2.69(s, 3 H).

[0992] Step 5: Synthesis of 4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2-methyl-4H-thieno[3,2-b]pyrrole-3-carboxylic acid

[0993]

[0994] LiOH·H2O (1 M, 3.66 mL, 6.00 equivalents) was added to a mixed solution of methyl 4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2-methyl-4H-thieno[3,2-b]pyrrole-3-carboxylate (250 mg, 611 μmol, 1.00 equivalents) in MeOH (1 mL) and THF (1 mL), and the mixture was stirred at 55°C for 24 hours. The reaction mixture was partially concentrated, then acidified (pH=3) with a 1 N HCl solution, and the aqueous layer was extracted with EtOAc (50 mL × 2). The organic layer was washed with brine (50 mL × 1) and dried with Na2SO4, then filtered and concentrated under reduced pressure to obtain 4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2-methyl-4H-thieno[3,2-b]pyrrole-3-carboxylic acid (220 mg, yield 91.1%) as a yellow solid. 1 H NMR (400 MHz, DMSO) δ 13.29-12.68 (m, 1 H), 7.60 (d, J = 8.40 Hz, 2 H), 7.21 (d, J = 3.00 Hz, 1H), 7.09-6.98 (m, 4H), 6.80 (td, J = 2.20, 11.2 Hz, 1H), 6.41(d, J = 3.00 Hz, 1H), 5.66(s, 2H), 3.81(s, 3H), 2.61(s, 3H).

[0995] Steps 6 and 7: Synthesis of 6-(4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2-methyl-4H-thieno[3,2-b]pyrrole-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0996]

[0997]

[0998] The compound of Example 95 was obtained by reacting 4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2-methyl-4H-thieno[3,2-b]pyrrole-3-carboxylic acid in the same manner as steps 5 and 6 of Example 79. 1 H NMR (400 MHz, DMSO) δ 12.26 - 11.69 (m, 1 H), 8.40 (d, J= 7.60 Hz, 1 H), 7.57(d, J = 8.20 Hz, 2 H), 7.19(d, J = 3.00 Hz, 1 H), 7.10(d, J = 8.20 Hz, 2 H), 7.06-6.96(m, 2 H), 6.86-6.77(m, 1 H), 6.35(d, J = 2.80 Hz, 1H), 5.35(s, 2 H), 4.30-4.14(m, 1 H), 3.82(s, 3 H), 2.98-2.83(m, 1 H), 2.42(s, 3 H), 2.39-2.16(m, 4 H), 2.10-1.95(m, 2 H), 1.91-1.77(m, 2 H). LC / MS(ESI) m / z: 533.1 [M+1].

[0999] Example 96: 6-(2-methyl-4-(3-phenylprop-2-phosphor-1-yl)-4H-thieno[3,2-b]pyrrole-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[1000] Step 1: Synthesis of 3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid

[1001]

[1002] LiOH·H2O (1 M, 32.8 mL, 3.00 equivalents) was added to a solution of intermediate U (3.00 g, 10.9 mmol, 1.00 equivalents) mixed in THF (15 mL) and MeOH (15 mL), and the mixture was stirred at 55°C for 2 hours. The reaction mixture was partially concentrated and acidified (pH 3) with a 1 N HCl solution, after which the aqueous layer was extracted with EtOAc (50 mL × 2). The organic layer was filtered and concentrated under r...

Claims

Claim 1 A pharmaceutical composition for the prevention or treatment of cancer associated with prostaglandin E2 overexpression and / or overexpression of a prostaglandin E2 receptor, comprising a compound of Formula I, or a solvate, stereoisomer, or pharmaceutically acceptable salt thereof; and an anticancer agent as an active ingredient, wherein the cancer is selected from the group consisting of squamous cell carcinoma, basal cell carcinoma, glioblastoma, bone cancer, gastric cancer, renal cancer, lung cancer, bladder cancer, prostate cancer, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, head and neck cancer, renal cell carcinoma, esophageal cancer, pancreatic cancer, brain cancer, gastrointestinal cancer, liver cancer, leukemia, lymphoma, melanoma, multiple myeloma, osteosarcoma, colorectal cancer, cholangiocarcinoma, choriocarcinoma, oral cancer, neuroblastoma, skin cancer, testicular cancer, stromal tumor, germ cell tumor, and thyroid cancer: [Formula I] In the above chemical formula I, either X or Y is S, and the other is CR 1 And, is a single bond or a double bond, wherein two of them are double bonds; R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; R 2 is selected from the group consisting of hydrogen, halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C3-C6 cycloalkyl, and phenyl; R 3 silver or; or R 1 is selected from the group consisting of hydrogen, halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; R 2 and R 3 together with the carbon atoms to which they are bonded Form, to the nitrogen atom is combined, Any one or both of the carbon atoms of can be optionally substituted with C1-C6 alkyl groups; and W is -(CH2) o -, -(CH2) o -C≡C-, -C(O)-, -O-, -NH-, or -N(C1-C6alkyl)-, and the H of the CH2 may be optionally substituted with one or more halogens, hydroxyl, or C1-C6 alkoxy; and Cy is C6-C 10 Selected from the group consisting of aryl, 5- to 10-membered heteroaryl, and 4- to 7-membered heterocycloalkyl, and may optionally be substituted with one or more R'; R a is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or -V-Cy2, where V is absent, -CH2-, or -O-, and Cy2 is C6-C 10 Selected from the group consisting of aryl, 5- to 10-membered heteroaryl, 4- to 7-membered heterocycloalkyl, C3-C8 cycloalkyl, and C3-C8 cycloalkenyl, and may optionally be substituted with one or more R''; R' is each independently selected from the group consisting of halogen, amino, C1-C3 alkyl, and C1-C3 haloalkyl; and R'' is halogen, hydroxy, cyano, amino, oxo, C1-C6 alkyl, C1-C6 alkoxy, -S-(C1-C6 alkyl), -SO2-(C1-C6 alkyl), -CO-(C1-C6 alkyl), -C(O)H, -COO-(C1-C6 alkyl), -COOH, -CONH2, -CONH-(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -(CH2) p -NH2, -(CH2) p -NH-(C1-C6alkyl), -(CH2) p -N(C1-C6alkyl)2, -(CH2) p -NH-CO-(C1-C6alkyl), -(CH2) p -NH-COO-(C1-C6alkyl), -(CH2) p -OH, ternary to pentary heterocycloalkyl, C3-C5 cycloalkyl, and -(CH2) p Selected from the group consisting of -(C3-C5 cycloalkyl), wherein the C1-C6 alkyl and C1-C6 alkoxy may be optionally substituted with one or more halogens, hydroxy, cyano, or aminos, and the ternary to pentary heterocycloalkyl and C3-C5 cycloalkyl may be optionally substituted with one or more halogens, hydroxy, cyano, oxo, or aminos; R 4 is hydrogen, or a C1-C6 alkyl;R 8 -C(=O)R 8' and R 8' is a hydroxyl or C1-C6 alkoxy; o is an integer of 1 or 2; and p is an integer of 0, 1, or 2. Claim 2 In paragraph 1, R 1 is hydrogen, a halogen, or a C1-C3 alkyl, and the C1-C3 alkyl may optionally be substituted with one or more halogens; R 2 A pharmaceutical composition for the prevention or treatment of cancer, comprising hydrogen, halogen, C1-C3 haloalkyl, cyclopropyl, cyclobutyl, or phenyl. Claim 3 A pharmaceutical composition for the prevention or treatment of cancer according to claim 1, wherein Cy is phenyl, pyrazolyl, pyridinyl, pyrimidinyl, indolyl, or piperazineyl; and Cy2 is phenyl, furanyl, pyrazolyl, pyridinyl, pyrimidinyl, piperidinyl, morpholineyl, cyclohexyl, or cyclohexeneyl. Claim 4 In paragraph 1, R a is -V-Cy2 and, A pharmaceutical composition for the prevention or treatment of cancer, having a structure selected from the following group, wherein Cy and Cy2 can each be optionally substituted with R' and R'': , , , , , , , , , , , , , , , , , , , , , , , , , , , , and . Claim 5 In paragraph 1, R 8 -C(=O)R 8' and R 8' A pharmaceutical composition for the prevention or treatment of cancer, wherein the hydroxyl group is hydroxyl. Claim 6 In claim 1, the compound has the following chemical formula IA-3: R 1 is hydrogen, halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl or C1-C3 haloalkoxy; R 2 is hydrogen, halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 haloalkoxy, C3-C6 cycloalkyl or phenyl; R 3 silver And;W is -(CH2) o -, -C(O)-, -O-, -NH-, or -N(C1-C6alkyl)-, and the H of the CH2 may optionally be substituted with one or more halogens, hydroxyl, or C1-C6 alkoxy; and Cy is C6-C 10 Selected from the group consisting of aryls, 5 to 10-membered heteroaryls comprising 1 or 2 nitrogen atoms, and 4 to 7-membered heterocycloalkyls comprising 1 or 2 nitrogen atoms, and optionally substituted with one or more R's; R a is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or -V-Cy2, where V is absent or -O-, and Cy2 is C6-C 10 Selected from the group consisting of aryl, pentagonal to tenagonal heteroaryls comprising 1 or 2 heteroatoms selected from N and O, tetraagonal to heptagonal heterocycloalkyls comprising 1 or 2 heteroatoms selected from N and O, C3-C8 cycloalkyls, and C3-C8 cycloalkenyls, and optionally substituted with one or more R''s, wherein R' is a halogen, amino, C1-C3 alkyl, or C1-C3 haloalkyl; and R'' is a halogen, hydroxy, cyano, amino, oxo, C1-C6 alkyl, C1-C6 alkoxy, -S-(C1-C6 alkyl), -SO2-(C1-C6 alkyl), -COO-(C1-C6 alkyl), -COOH, -CONH2, -(CH2) p -NH2, -(CH2) p -NH-(C1-C6alkyl), -(CH2) p -N(C1-C6alkyl)2, -(CH2) p -NH-COO-(C1-C6alkyl), -(CH2) p ternary to pentary heterocycloalkyl, C3-C5 cycloalkyl, comprising one heteroatom selected from -OH, N, O, and S, and -(CH2) p Selected from the group consisting of -(C3-C5 cycloalkyl), wherein the C1-C6 alkyl and C1-C6 alkoxy may be optionally substituted with one or more halogens, hydroxy, cyano, or aminos, and the ternary to pentary heterocycloalkyl and C3-C5 cycloalkyl may be optionally substituted with one or more halogens, hydroxy, cyano, oxo, or aminos; R 4 is hydrogen or C1-C3 alkyl and R 8 -C(=O)R 8' and R 8' A pharmaceutical composition for the prevention or treatment of cancer, wherein is a hydroxyl or C1-C6 alkoxy; o is an integer of 1 or 2; and p is an integer of 0, 1, or 2. Claim 7 In Paragraph 6, R 1 is hydrogen, halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or C1-C3 haloalkoxy; R 2 is hydrogen, a halogen, a C1-C3 alkyl, a C1-C3 haloalkyl, a cyclopropyl, a cyclobutyl, or a phenyl; Cy is phenyl, a 5- to 10-membered heteroaryl containing 1 or 2 nitrogen atoms, or a 4- to 7-membered heterocycloalkyl containing 1 or 2 nitrogen atoms, and may be optionally substituted with one or more R'; R a is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or -V-Cy2, where V is absent or -O-, and Cy2 is selected from the group consisting of phenyl, 5- to 10-membered heteroaryls comprising 1 or 2 heteroatoms selected from N or O, 4- or 7-membered heterocycloalkyls comprising 1 or 2 heteroatoms selected from N or O, C4-C7 cycloalkyls, and C4-C7 cycloalkenyls, and may be optionally substituted with one or more R''s; R' is halogen, amino, C1-C3 alkyl, or C1-C3 haloalkyl; and R'' is halogen, hydroxy, cyano, amino, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -S-(C1-C6 alkyl), -SO2-(C1-C6 alkyl), -COO-(C1-C6 alkyl), -COOH, -CONH2, -(CH2) p -NH2, -(CH2) p -NH-(C1-C6alkyl), -(CH2) p -N(C1-C6alkyl)2, -(CH2) p -NH-COO-(C1-C6alkyl), -(CH2) p A pharmaceutical composition for the prevention or treatment of cancer, selected from the group consisting of -OH; azetidineyl or oxetanyl optionally substituted with a hydroxyl or iodine; and cyclopropyl or cyclopropylmethyl optionally substituted with a hydroxyl or iodine. Claim 8 A pharmaceutical composition for the prevention or treatment of cancer according to claim 7, wherein Cy is phenyl, pyrazolyl, or piperazine; and Cy2 is phenyl, furanyl, pyrazolyl, pyridinyl, morpholineyl, piperidinyl, cyclohexyl, or cyclohexeneyl. Claim 9 A pharmaceutical composition for the prevention or treatment of cancer according to claim 1, wherein the compound is of the following chemical formula IB-5: [Chemical formula IB-5] In the above chemical formula IB-5, R 1 is hydrogen, halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or C1-C3 haloalkoxy; Any one or both of the carbon atoms of can be optionally substituted with C1-C3 alkyl groups; and W is -(CH2) o - or -(CH2) o -C≡C-, and the H of CH2 can be optionally substituted with one or more halogens, hydroxyl groups, or C1-C6 alkoxy groups; and Cy is C6-C 10 Selected from the group consisting of aryls and 5 to 10 heteroaryls comprising 1 or 2 nitrogen atoms, and optionally substituted with one or more R's; R a is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or -V-Cy2, where V is absent or -CH2-, and Cy2 is C6-C 10 Selected from the group consisting of aryls and 5 to 10 heteroaryls comprising 1 or 2 nitrogen atoms, and optionally substituted with one or more R''; R' is a halogen, amino, C1-C3 alkyl or C1-C3 haloalkyl; R'' is selected from halogen, hydroxy, cyano, amino, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy; R 4 is hydrogen or C1-C3 alkyl and R 8 -C(=O)R 8' and R 8' is a hydroxyl or C1-C6 alkoxy; o is an integer of 1 or 2. Claim 10 A pharmaceutical composition for the prevention or treatment of cancer according to claim 9, wherein Cy is selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, and indolyl; and Cy2 is selected from the group consisting of phenyl, pyrazolyl, pyridinyl, and pyrimidinyl. Claim 11 A pharmaceutical composition for the prevention or treatment of cancer according to claim 1, wherein the compound is selected from the group consisting of the following compounds: and . Claim 12 A pharmaceutical composition for the prevention or treatment of cancer according to claim 11, wherein the compound is selected from the group consisting of the following compounds: and . Claim 13 A pharmaceutical composition for the prevention or treatment of cancer associated with prostaglandin E2 overexpression and / or overexpression of a prostaglandin E2 receptor, comprising a compound selected from the group consisting of the following compounds, or a solvate, stereoisomer, or pharmaceutically acceptable salt thereof; and an anticancer agent as an active ingredient, wherein the cancer is selected from the group consisting of squamous cell carcinoma, basal cell carcinoma, glioblastoma, bone cancer, gastric cancer, renal cancer, lung cancer, bladder cancer, prostate cancer, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, head and neck cancer, renal cell carcinoma, esophageal cancer, pancreatic cancer, brain cancer, gastrointestinal cancer, liver cancer, leukemia, lymphoma, melanoma, multiple myeloma, osteosarcoma, colorectal cancer, cholangiocarcinoma, choriocarcinoma, oral cancer, neuroblastoma, skin cancer, testicular cancer, stromal tumor, germ cell tumor, and thyroid cancer: . Claim 14 A pharmaceutical composition for the prevention or treatment of cancer, wherein, in claim 1 or 13, the anticancer agent is any one selected from the group consisting of chemotherapy agents, targeted anticancer agents, oncolytic viruses, antibody therapeutic agents, cell therapeutic agents, and immune checkpoint inhibitors. Claim 15 A pharmaceutical composition for the prevention or treatment of cancer according to claim 14, wherein the chemical anticancer agent is any one selected from the group consisting of an alkylating agent, a microtubule inhibitor, antimetabolite, and a topoisomerase inhibitor. Claim 16 In claim 15, the above chemo-anticancer drugs are mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, thiotepa, altretamine, procarbazine, busulfan, streptozotocin, carmustine, lomustine, dacarbazine, cisplatin, carboplatin, oxaliplatin, docetaxel, Velban, Oncovin, Navelbine, fluorouracil, capecitabine, A pharmaceutical composition for the prevention or treatment of cancer, which is any one selected from the group consisting of cytarabine, gemcitabine, fludarabine, methotrexate, pemetrexed, mercaptopurine, hycamtin, camptosar, bepecid, paclitaxel, blenoxane, adriamycin, and cerubidine. Claim 17 In claim 14, the above-mentioned targeted anticancer agents are EGFR, VEGFR, CD20, CD38, RNAK-L, BTK, Bcr-abl, PDGFR / FGFR series, MEK / RAF / KRAS, HER2 / Neu, ubiquitin, JAK, ALK, PARP, TGFβR, proteasome, Bcl-2, C-Met, VR1, VR2, VR3, c-kit, AXL, A pharmaceutical composition for the prevention or treatment of cancer, which targets any one protein selected from the group consisting of RET, Braf, DNMT, CDK4 / 6 and STING. Claim 18 In claim 17, the above-mentioned targeted anticancer drugs are Cetuximab, Trastuzumab, Pertuzumab, Gefitinib, Erlotinib, Osimertinib, Panitumumab, Axitinib, Lenvatinib, Bevacizumab, Ramucirumab, Aflibercept, Rituximab, Obinutuzumab, Daratumumab, Denosumab, Ibrutinib, Dasatinib, Nilotinib, Imatinib, Bosutinib, Galunisertib, Vactosertib, Nintedanib, Sunitinib, Sorafenib, Cabozantinib, Regorafenib, Masitinib, Semaxanib, Tibozanib, Vandetanib, Pazopanib, Trametinib, Dabrafenib, Sotorasib, Afatinib, Lapatinib, Neratinib, Lenalidomide, Ixazomib, Ruxolitinib, Lestaurtinib, Pacritinib, Cobimetinib, Selumetinib, Binimetinib, Alectinib, Crizotinib, Venetoclax, Bemcentinib, Gliteritinib,A pharmaceutical composition for the prevention or treatment of cancer, which is any one selected from the group consisting of selpercatinib, pralsetinib, vemurafenib, olaparib, talazoparib, niraparib, rucaparib, azacitidine, decitabine, guadesitabine, abemaciclib, ribociclib, palbociclib, CDNs, SB11285, and DMXAA. Claim 19 A pharmaceutical composition for the prevention or treatment of cancer, wherein the anticancer virus in claim 14 is Talimogene Laherparepvec. Claim 20 In claim 14, the above antibody therapeutics are cetuximab, trastuzumab, pertuzumab, panitumumab, emtansine, rituximab, daratumumab, denosumab, ibritumomab, tositumomab, brentuximab, ofatumumab, obinutuzumab, necitumumab, bevacizumab, ramucirumab, nivolumab, pembrolizumab, atezolizumab, A pharmaceutical composition for the prevention or treatment of cancer, which is selected from the group consisting of durvalumab and ipilimumab. Claim 21 A pharmaceutical composition for the prevention or treatment of cancer, wherein the cell therapy agent is any one selected from the group consisting of tisagenlecleucel and axicabtagene ciloleucel. Claim 22 A pharmaceutical composition for the prevention or treatment of cancer according to claim 14, wherein the immune checkpoint inhibitor is any one selected from the group consisting of anti-CTLA-4 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-B7-H4 antibody, anti-HVEM antibody, anti-TIM3 antibody, anti-GAL9 antibody, anti-LAG3 antibody, anti-VISTA antibody, anti-KIR antibody, anti-BTLA antibody, and anti-TIGIT antibody. Claim 23 A pharmaceutical composition for the prevention or treatment of cancer, wherein the immune checkpoint inhibitor in claim 22 is any one selected from the group consisting of ipilimumab, pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, and durvalumab. Claim 24 In claim 14, the above anticancer agent is a pharmaceutical composition for the prevention or treatment of cancer, comprising a chemotherapy agent and an immune checkpoint inhibitor. Claim 25 In claim 24, the above chemical anticancer agent is a pharmaceutical composition for the prevention or treatment of cancer comprising an alkylating agent and an antimetabolite. Claim 26 delete Claim 27 delete Claim 28 delete Claim 29 delete Claim 30 delete Claim 31 delete

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