Novel Compounds Having Inhibitory Activity Against Prostaglandin E2 Receptor and Use Thereof

Abstract

The present application relates to novel compounds having inhibitory activity against prostaglandin E2 receptors and uses thereof, and provides compounds represented by formula I, solvates, stereoisomers or pharmaceutically acceptable salts thereof, pharmaceutical compositions containing them, and methods of using them.

Description

Technical Field

[0001] The present application relates to a novel compound having inhibitory activity against the prostaglandin E2 receptor, its use, a pharmaceutical composition containing the novel compound, and a method for treating or preventing a disease using the novel compound.

Background Art

[0002] Prostaglandin (PG) is a physiologically active substance known as a prostanoid, like thromboxane, and is a lipid having a prostanoic acid skeleton. Prostanoids, such as prostaglandins, are biosynthesized from arachidonic acid released from membrane phospholipids by the action of phospholipase A2. Prostaglandins are classified into groups A to J based on the type of oxygen atom bonded to the five-membered ring and the type of double bond. In addition, prostaglandins are classified into groups 1 to 3 based on the members of the double bond in the side chain of the prostanoic acid skeleton. For example, prostaglandin E (PGE) includes PGE1, PGE2, and PGE3, which differ from each other in terms of the number of double bonds in the side chain of the prostanoic acid skeleton.

[0003] Regarding prostaglandin, PGH2 is generated from PGG2 biosynthesized from arachidonic acid by the action of cyclooxygenase I (COX-I) or cyclooxygenase II (COX-II), and then PGD2, PGE2, PGF 2αThey are generated based on differences in the cleavage of the bond between oxygen atoms. The production reaction of each prostaglandin is caused by the action of specific enzymes, and these enzymes are known to have tissue specificity. On the other hand, among prostaglandins, PGE plays a role in various important biological activities, and it is considered that, mediated by specific receptors, PEG is involved in immune system regulation, as well as vasodilation, blood pressure reduction, and uterine contraction. The PEG2 receptor is a seven-transmembrane G protein-coupled receptor, and the same is true for other PG receptors. The PEG2 receptor is abbreviated as EP, and it has been revealed that EP has four subtypes (EP1, EP2, EP3, and EP4). Each subtype is involved in various phenomena in vivo. That is, EP1 is involved in the increase in intracellular Ca 2+ concentration, EP2 and EP4 are involved in the increase in cAMP level, and EP3 is involved in the decrease in cAMP level.

[0004] On the other hand, cancer is one of the major causes of death worldwide. A tumor consists of abnormally proliferated malignant cancer cells and a microenvironment that functionally supports them. This tumor microenvironment consists of complex cell lines, extracellular matrix components, and signaling molecules, and is established by changes in communication between stromal cells and tumor cells. As the tumor grows in size, it leads to the production of various factors, such as angiogenic factors (which promote the growth of blood vessels) that can help tumor growth or help avoid attacks by the host immune response. Under this microenvironment, PGE2 functions as an immune regulatory factor produced by the tumor. The EP receptors of PGE2, especially EP2 and EP4, are abnormally overexpressed in several types of cancer, specifically gastrointestinal (GI) cancer and pancreatic cancer. In addition, PGE2 and / or EP2 and / or EP4 are 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, epidemiologically, PGE2 signaling is known to be mainly involved in the communication between tumor cells and stromal cells, creating a favorable microenvironment for tumor growth. It is worth noting that some tumor cells overexpress EP2 and / or EP4, and thereby 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 are effective in neurodegenerative diseases such as epilepsy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and traumatic brain injury.

[0006] Under this technical background, research on antagonists of prostaglandin E2 receptors that can be clinically utilized in various ways is ongoing (Korean Patent Application Publication No. 10-2013-0092579), but it is still incomplete.

[0007] [Disclosure of the Invention] [Technical Problem] In one aspect, there is provided a novel compound having inhibitory activity against prostaglandin E2 receptor, its solvate, stereoisomer or pharmaceutically acceptable salt.

[0008] In another aspect, there is provided a pharmaceutical composition containing the novel compound, its solvate, stereoisomer or pharmaceutically acceptable salt as an active ingredient, or its pharmaceutical use.

[0009] [Solution to the Problem] Each description and embodiment disclosed in the present application can also be mutually applied to the description and embodiment. That is, all combinations of various elements disclosed in the present application fall within the scope of the present application. In addition, it is intended that the scope of the present application is not limited to the specific description described below.

[0010] In one aspect of the present invention, there is provided a compound represented by formula I, its solvate, stereoisomer or pharmaceutically acceptable salt, [Chemical Formula] wherein, one of X and Y is S and the other is CR 1 and [Chemical Formula] is a single bond or a double bond, two of which are double bonds; R 1 and R 2 are selected from the group consisting of 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 aryl, wherein the C1-C6 alkyl and C1-C6 alkoxy may each independently be optionally substituted with one or more halogen, hydroxy, cyano or amino, and the C3-C8 cycloalkyl and C6-C 10 aryl may each independently be optionally substituted with one or more halogen, hydroxy, cyano, amino, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; R 3 is

Chemical formula

Chemical formula

[0011] In some embodiments, X is S and Y is CR 1 or X is CR 1 and Y is S. In one embodiment, [Chemistry] is a single bond or a double bond, two of which are double bonds, whereby the 5-membered ring containing X and Y forms a thiophenyl ring.

[0012] 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, wherein the C1-C3 alkyl and C1-C3 alkoxy may each independently be optionally substituted with one or more halogen, hydroxy, cyano or amino. In one embodiment, R 1 may be hydrogen, halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl or C1-C3 haloalkoxy. In one embodiment, R 1 may be hydrogen, halogen, C1-C3 alkyl or C1-C3 haloalkyl.

[0013] 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, wherein the C1-C3 alkyl and C1-C3 alkoxy may each independently be optionally substituted with one or more halogen, hydroxy, cyano or amino. In one embodiment, R 2 may be hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl, cyclobutyl or phenyl. In one embodiment, R 2 may be hydrogen, fluoro, chloro, bromo, methyl, ethyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl or phenyl, etc.

[0014] In some embodiments, R 3 is [Chemistry] It may be.

[0015] In another embodiment, R 2 and R 3 are, together with the carbon atom to which R 2 and R 3 is attached,

Chemical formula

Chemical formula

Chemical formula

[0016] In one embodiment,

Chemical formula

Chemical formula

Chemical formula

[0017] In some embodiments, W is -(CH2) o -, -(CH2) o -C≡C-, -C(O)-, -O-, -NH- or -N(C1-C3 alkyl)-, and the H of the CH2 may be optionally substituted with one or more halogens, hydroxy, C1-C3 alkoxy or C1-C3 haloalkoxy.

[0018] In one embodiment, W is -(CH2) o -, -C(O)-, -O-, -NH- or -N(C1-C6 alkyl)-. In another embodiment, W is -(CH2) o - or -(CH2) o -C≡C-.

[0019] In one embodiment, the H of the CH2 may be optionally substituted with one or more halogens, hydroxy or C1-C3 alkoxy. In one embodiment, the H of the CH2 may be optionally substituted with hydroxy, methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, 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.

[0020] In some embodiments, Cy is C6-C 10It can be an aryl, a 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S, or a 4- to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S. In one embodiment, Cy can be a heteroaryl selected from phenyl, naphthyl; pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, quinolinyl, and isoquinolinyl; or a heterocycloalkyl selected from azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, and morpholinyl.

[0021] In one embodiment, Cy can 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 can be phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl. In one embodiment, Cy can be phenyl, pyrazolyl, pyridinyl, pyrimidinyl, indolyl, or piperazinyl.

[0022] Cy may be optionally substituted with one or more R'. In one embodiment, R' may be 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 halogen, amino, C1-C3 alkyl or C1-C3 haloalkyl. In one embodiment, R' may be one or more of fluoro, chloro, bromo, amino, methylamino, dimethylamino, ethylamino or diethylamino, etc.

[0023] In one embodiment, 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 may 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 may be -V-Cy2.

[0024] In some embodiments, V is absent or may be -NH-, -NHCH2-, -NHCH3-, -S-, -SO2-, -CH2-, -OCH2- or -O-. In one embodiment, V is absent or may be -CH2- or -O-. In one embodiment, V is absent or may be -CH2-.

[0025] In some embodiments, Cy2 is C6-C 10It may be selected from the group consisting of 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from aryl, N, O and S, 4- to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, C3-C8 cycloalkyl, and C3-C8 cycloalkenyl. In one embodiment, Cy2 is phenyl; heteroaryl selected from pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, quinolinyl and isoquinolinyl; heterocycloalkyl selected from azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl and morpholinyl; cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; or cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl.

[0026] In one embodiment, Cy2 may be selected from the group consisting of phenyl, 5- to 10-membered heteroaryl containing 1 or 2 heteroatoms selected from N or O, 4- or 7-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N or O, C4-C7 cycloalkyl and C4-C7 cycloalkenyl. In one embodiment, Cy2 may be phenyl, pyrrolyl, furanyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholine, cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl. In one embodiment, Cy2 may be phenyl, furanyl, pyrazolyl, pyridinyl, pyrimidinyl, piperidinyl, morpholinyl, cyclohexyl or cyclohexenyl.

[0027] Cy2 may be optionally substituted with R”. In some embodiments, R” is 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-C6 alkyl), -(CH2) p -N(C1-C6 alkyl)2, -(CH2) p -NH-COO-(C1-C6 alkyl), -(CH2) p -OH, 3- to 5-membered heterocycloalkyl containing one heteroatom selected from N, O and S, C3-C5 cycloalkyl, and -(CH2) p - (C3-C5 cycloalkyl), and is selected from the group consisting of, the C1-C6 alkyl and C1-C6 alkoxy may be optionally substituted with one or more halogen, hydroxy, cyano or amino, and the 3- to 5-membered heterocycloalkyl and C3-C5 cycloalkyl may be optionally substituted with one or more halogen, hydroxy, cyano, oxo or amino. In one embodiment, the 3- to 5-membered 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.

[0028] In one embodiment, 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-C6 alkyl), -(CH2) p -N(C1-C6 alkyl)2, -(CH2) p-NH-COO-(C1-C6 alkyl), -(CH2) p -OH; azetidinyl or oxetanyl optionally substituted with hydroxy or oxo; cyclopropyl or cyclopropylmethyl optionally substituted with hydroxy or oxo.

[0029] In another embodiment, R” is halogen, hydroxy, cyano, amino, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -(CH2) p -NH2, -(CH2) p -NH-(C1-C6 alkyl), -(CH2) p -N(C1-C6 alkyl)2; azetidinyl or oxetanyl optionally substituted with hydroxy or oxo; cyclopropyl or cyclopropylmethyl optionally substituted with hydroxy or oxo.

[0030] In one embodiment, R” is 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, -CH2NHCOOCH(CH3)2, -CH2NHCOOCH2CH(CH3)2, -CH2NHCOOC(CH3)3, -CH2OH, -CH2CH2OH, azetidinyl, oxetanyl, cyclopropyl or cyclobutylmethyl.

[0031] In one embodiment, R ais -V-Cy2, [Chemical formula] has a structure selected from the following group, and Cy and Cy2 may each be optionally substituted with R’ and R”: [Chemical formula] In some embodiments, R4 can be hydrogen or C1-C3 alkyl.

[0032] In some embodiments, R 5 and R 6 may be H, R 7 may be absent, and the structure attached to the amide bond of formula I is the following structure: [Chemical formula] may be (wherein n and m can each be an integer of 1 or 2).

[0033] In another embodiment, R 5 and R 6 may together represent -(CH2) q -, R 7 may be absent, and in this case, the structure attached to the amide bond of formula I is the following structure: [Chemical formula] may be (wherein n, m and q can each be an integer of 1 or 2).

[0034] In another embodiment, R 5 may be H, R 6 and R 7 may together represent -(CH2) r -, and in this case, the structure attached to the amide bond of formula I is the following structure: [Chemical formula] may also be (wherein n, m, r and l may each be an integer of 1 or 2).

[0035] In one embodiment, the structure bonded to the amide bond of Formula I includes isomers of the structure and may be, for example, but not limited to, the following structures: [Chemical formula] In some embodiments, R 8 is [Chemical formula] may also be, Z may be -(CH2) s may also be, R 8’ may be hydroxy or C1-C6 alkoxy, and s may be an integer of 0 or 1. In one embodiment, s may be 0 and R 8’ may be hydroxy.

[0036] In another aspect of the present invention, there is provided a compound of Formula IA-1 or IA-2, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof, [Chemical formula] wherein R 1 and R 2 are selected from the group consisting of 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 aryl, wherein the C1-C6 alkyl and C1-C6 alkoxy may each independently be optionally substituted with one or more halogens, hydroxy, cyano or amino, and the C3-C8 cycloalkyl and C6-C 10Aryl may each independently be optionally substituted with one or more halogen, hydroxy, cyano, amino, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy or C1-C6 haloalkoxy; R 3 is

Chemical formula

[0037] In some embodiments of formulas IA-1 and IA-2, R 1 may be hydrogen, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl) or -N(C1-C6 alkyl)2, and the C1-C6 alkyl and C1-C6 alkoxy may each independently be optionally substituted with one or more halogen, hydroxy, cyano or amino. In one embodiment, R 1 may be hydrogen, halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl or C1-C3 haloalkoxy. In one embodiment, R 1 may be hydrogen, halogen, C1-C3 alkyl or C1-C3 haloalkyl.

[0038] In some embodiments, R 2may 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 of halogen, hydroxy, cyano or amino. In one embodiment, the C3-C6 cycloalkyl and phenyl may be optionally substituted with one or more of halogen, C1-C3 alkyl or C1-C3 haloalkyl. In one embodiment, R 2 may be hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl, cyclobutyl or phenyl.

[0039] In some embodiments, W may be -(CH2) o -, -(CH2) o -C≡C-, -C(O)-, -O-, -NH- or -N(C1-C3 alkyl)-. In one embodiment, W may be -(CH2) o -, -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 of halogen, hydroxy or C1-C6 alkoxy.

[0040] In some embodiments, Cy is C6-C 10It may be a 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from aryl, N, O, and S, or a 4- to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S. 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. For example, Cy may be phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl. In one embodiment, Cy may be phenyl, pyrazolyl, pyridinyl, pyrimidinyl, indolyl or piperazinyl. In one embodiment, Cy may be phenyl, pyrazolyl or piperazinyl.

[0041] Said Cy may be optionally substituted with one or more R'. In some embodiments, R' may be 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 halogen, amino, C1-C3 alkyl or C1-C3 haloalkyl.

[0042] In some embodiments, R a may be hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl or -V-Cy2. In one embodiment, R a may be -V-Cy2.

[0043] In some embodiments, V may be absent or may be -NH-, -NHCH2-, -NHCH3-, -S-, -SO2-, -CH2-, -OCH2- or -O-. In one embodiment, V may be absent or may be -CH2- or -O-.

[0044] In some embodiments, Cy2 is C6-C 10 It may be selected from the group consisting of aryl, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O, and S, 4- to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S, C3-C8 cycloalkyl, and C3-C8 cycloalkenyl. In one embodiment, Cy2 may be selected from the group consisting of phenyl, 5- to 10-membered heteroaryl containing 1 or 2 heteroatoms selected from N or O, 4- or 7-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N or O, C4-C7 cycloalkyl, and C4-C7 cycloalkenyl.

[0045] In one embodiment, Cy2 may be phenyl, furanyl, pyrazolyl, pyridinyl, pyrimidinyl, piperidinyl, morpholinyl, cyclohexyl, or cyclohexenyl. In one embodiment, Cy2 may be phenyl, furanyl, pyrazolyl, pyridinyl, morpholinyl, piperidinyl, cyclohexyl, or cyclohexenyl.

[0046] Said Cy2 may be optionally substituted with one or more R”. In some embodiments, R” is 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-C6 alkyl), -(CH2) p -N(C1-C6 alkyl)2, -(CH2) p -NH-COO-(C1-C6 alkyl), -(CH2) p -OH, 3- to 5-membered heterocycloalkyl containing 1 heteroatom selected from N, O, and S, C3-C5 cycloalkyl, and -(CH2) p- It may 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 halogen, hydroxy, cyano or amino, and the 3- to 5-membered heterocycloalkyl and C3-C5 cycloalkyl may be optionally substituted with one or more halogen, hydroxy, cyano, oxo or amino.

[0047] In one embodiment, 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-C6 alkyl), -(CH2) p -N(C1-C6 alkyl)2, -(CH2) p -NH-COO-(C1-C6 alkyl), -(CH2) p -OH; azetidinyl or oxetanyl optionally substituted with hydroxy or oxo; and cyclopropyl or cyclopropylmethyl optionally substituted with hydroxy or oxo, and may be selected from the group consisting of.

[0048] In some embodiments, R 4 may be hydrogen or C1-C3 alkyl.

[0049] In some embodiments, the compound having the above formula IA-1 or IA-2 can be represented by formula IA-3 or IA-4,

Chemical formula

[0050] In another aspect, there is provided a compound of formula IB-1, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof,

Chemical formula

Chemical formula

[0051] W, Cy, R a 、R 4 、R 8 、R 6 、R 7 、R 8The specific examples and embodiments described with respect to P, n, m, r, and l can also be equally applicable to Formula IB-1 as long as the structure permits.

[0052] In some embodiments, a compound having Formula IB-1 can be represented by Formula IB-2, IB-3, or IB-4.

Chemical Formula

[0053] In some embodiments of Formulas IB-2, IB-3, and IB-4, R 1 may be hydrogen, halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl), or -N(C1-C6 alkyl)2, and the C1-C6 alkyl and C1-C6 alkoxy may each independently be optionally substituted with one or more halogens, hydroxy, cyano, or amino. In one embodiment, R 1 may be hydrogen, halogen, hydroxy, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or C1-C3 haloalkoxy.

[0054] In some embodiments,

Chemical Formula

Chemical Formula

[0055] In some embodiments, W is -(CH2) o -, -(CH2) o-C≡C-, -C(O)-, -O-, -NH- or -N(C1-C3 alkyl)-. In one embodiment, W is -(CH2) o - or -(CH2) o -C≡C-. In this case, the H of the CH2 may be optionally substituted with one or more halogens, hydroxy or C1-C6 alkoxy.

[0056] In some embodiments, Cy is C6-C 10 aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, and 4-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S. In one embodiment, Cy may be phenyl, or 5-10 membered heteroaryl containing one or two nitrogen atoms. In one embodiment, Cy may be phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzimidazolyl or indazolyl. In one embodiment, Cy may be phenyl, pyridinyl, pyrimidinyl or indolyl.

[0057] The Cy may be optionally substituted with one or more R'. In some embodiments, R' may be 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 halogen, amino, C1-C3 alkyl or C1-C3 haloalkyl.

[0058] In some embodiments, R aIt can be hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl or -V-Cy2. In this case, V can be absent or -NH-, -NHCH2-, -NHCH3-, -S-, -SO2-, -CH2-, -OCH2- or -O-. In one embodiment, V can be absent or -CH2- or -O-. In one embodiment, V can be absent or -CH2-.

[0059] In some embodiments, Cy2 is C6-C 10 It can be selected from the group consisting of aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, 4-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, C3-C8 cycloalkyl, and C3-C8 cycloalkenyl. In one embodiment, Cy2 can be phenyl or 5-10 membered heteroaryl containing 1 or 2 nitrogen atoms. In one embodiment, Cy2 can be phenyl, pyrrolyl, furanyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholine, cyclopentyl, cyclohexyl, cyclopentenyl or cyclohexenyl. In one embodiment, Cy2 can be phenyl, pyrazolyl, pyridinyl or pyrimidinyl.

[0060] Said Cy2 may be optionally substituted with one or more R”. In some embodiments, R” is 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-C6 alkyl), -(CH2) p -N(C1-C6 alkyl)2, -(CH2) p -NH-COO-(C1-C6 alkyl), -(CH2) p3- to 5-membered heterocycloalkyl containing 1 heteroatom selected from -OH, N, O, and S, C3-C5 cycloalkyl, and -(CH2) p 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 halogen, hydroxy, cyano, or amino, and the 3- to 5-membered heterocycloalkyl and C3-C5 cycloalkyl may be optionally substituted with one or more halogen, hydroxy, cyano, oxo, or amino.

[0061] In one embodiment, R” may be halogen, hydroxy, cyano, amino, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -(CH2) p -NH2, -(CH2) p -NH-(C1-C6 alkyl), -(CH2) p -N(C1-C6 alkyl)2; azetidinyl or oxetanyl optionally substituted with hydroxy or oxo; and cyclopropyl or cyclopropylmethyl optionally substituted with hydroxy or oxo, and may be selected from the group consisting of.

[0062] In some embodiments, R 4 may be hydrogen or C1-C3 alkyl.

[0063] In some embodiments, R 8 may be

Chemical formula

[0064] In one embodiment, l, m, and n can each independently be an integer of 1 or 2. In one embodiment, o and p can each independently be an integer from 0 to 2. In one embodiment, q and r can each independently be an integer of 1 or 2. In one embodiment, s can be an integer of 0 or 1.

[0065] In some embodiments, the compound having the above formula IB-1 can be represented by formula IB-5, IB-6, IB-7, or IB-8,

Chemical formula

[0066] In one embodiment, the compound of formula I of the present invention can be a compound selected from the group consisting of the following compounds.

Chemical formula

[0067] In one embodiment, the compound of formula I of the present invention can be a compound selected from the group consisting of the following compounds.

Chemical formula

[0068] Definition All technical and scientific terms used in this specification have the meanings commonly understood by those skilled in the art, and unless otherwise specified, conventional measurement methods, manufacturing methods, conventional components or substances are used based on conventional techniques, such as pharmacology, pharmaceutical chemistry, mass spectrometry, NMR, HPLC, biochemistry, etc.

[0069] Unless otherwise indicated, in this disclosure and the appended claims, "or" and "and" mean "and / or". The terms "include" and "included" are open-ended and mean that a compound, composition or method may include additional features or components in addition to the recited features or components.

[0070] The " * " shown at the end of the linking group of the residue in this specification indicates the position where the linking group of the residue binds to the rest of the compound.

[0071] In this disclosure, the term "halogen" can be F, Cl, Br or I.

[0072] In this disclosure, unless otherwise specified, the term "alkyl" refers to a straight-chain or branched-chain hydrocarbon residue that may be unsubstituted or substituted. Alkyl can be C1-C 15 alkyl, C1-C 12 alkyl, C1-C9 alkyl, C1-C6 alkyl or C1-C3 alkyl. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, penta-1-yl, penta-2-yl, penta-3-yl, 3-methylbuta-1-yl, 3-methylbuta-2-yl, 2-methylbuta-2-yl, 2,2,2-trimethyletha-1-yl, n-hexyl, n-heptyl and n-octyl, and all possible isomers thereof.

[0073] In the present disclosure, unless otherwise specified, the term "alkoxy" refers to a linear or branched hydrocarbon residue, which may be unsubstituted or substituted, and is linked by oxygen. Alkoxy includes, but is not limited to, methoxy, ethoxy, propoxy, and butoxy, or all possible isomers thereof, such as isopropoxy, isobutoxy, and t-butoxy.

[0074] In the present disclosure, the term "cycloalkyl" refers to a saturated hydrocarbon ring having a specific 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). Cycloalkyl may be C3-C 15 cycloalkyl, C3-C 13 cycloalkyl, C3-C 11 cycloalkyl may be C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C3-C5 cycloalkyl, and cycloalkyl having a polycyclic hydrocarbon ring may have two or more cycloalkyls that are bridged or fused.

[0075] In the present disclosure, the term "cycloalkenyl" refers to a non-aromatic unsaturated monocyclic or polycyclic hydrocarbon ring having at least one carbon-carbon double bond and containing a specific number of carbon atoms. For example, cycloalkenyl includes, but is not limited to, cyclopenta-1-en-1-yl, cyclohexa-1-en-1-yl, cyclohexa-1,3-dien-1-yl, etc.

[0076] In the present disclosure, the term "hydroxyl" refers to an -OH group.

[0077] In the present disclosure, the term "oxo" refers to a substituent having a structure =O with a double bond between an atom and an oxygen atom.

[0078] In the present disclosure, 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 of the hydrogen atoms of the alkyl may be replaced by a halogen atom. In one embodiment, the hydrogen atoms may be replaced by the same halogen atom (e.g., fluoro) or a combination of different halogen atoms (e.g., fluoro and chloro).

[0079] In the present disclosure, the term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom is replaced by a halogen atom, and the description of "haloalkyl" above also applies to "haloalkoxy".

[0080] In the present disclosure, the term "aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon group. Aryl can have alternating (resonating) double bonds between adjacent carbon atoms and can include forms in which two or more rings are simply bonded to each other (side chains) or fused. Aryl can be, for example, C6~C 14 aryl, C6~C 10 aryl or C6-C9 aryl, and can include, without limitation, for example, phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthracenyl, or all possible isomers thereof.

[0081] In the present disclosure, the term "heteroaryl" refers to a heterocyclic aromatic group containing at least one heteroatom selected from B, N, O, S, P(=O), Si, and P as ring-forming atoms. Heteroaryl can also include forms in which two or more rings are simply bonded to each other (side chains) or fused.

[0082] In some embodiments, the heteroaryl can contain 1 to 4 heteroatoms selected from N, O, and S, 1 to 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom. In one embodiment, the heteroaryl can contain 1 to 3 N, 1 or 2 N, or 1 N. In some embodiments, the heteroaryl can contain 4 to 14 ring atoms, 5 to 10 ring atoms, or 5 to 6 ring atoms.

[0083] Examples of monocyclic heteroaryls include, but are not limited to, thiophenyl, furanyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and groups similar thereto. Examples of bicyclic heteroaryls include, but are not limited to, indolyl, isoindolyl, indazolyl, indolizinyl, benzothiophenyl, benzofuranyl, benzimidazolyl, benzpyrazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, purinyl, phthalazinyl, pteridinyl, furopyridinyl, oxochromene, dioxoisoindoline, imidazopyridinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, and groups similar thereto.

[0084] In the present disclosure, unless otherwise specified, the term "heterocycloalkyl" refers to a monocyclic or polycyclic, saturated or partially unsaturated ring system containing at least 1 heteroatom selected from B, N, O, S, P(=O), Si, and P and having a specific number of ring elements (i.e., 3-7 membered heterocycloalkyl refers to a heterocycloalkyl group having 3, 4, 5, 6, or 7 ring elements including heteroatoms). The polycyclic heterocycloalkyl can have two or more heterocycloalkyls that are bridged or fused.

[0085] In some embodiments, the heterocycloalkyl can contain from 1 to 4 heteroatoms selected from N, O, and S, from 1 to 3 heteroatoms, 1 or 2 heteroatoms, or 1 heteroatom. In one embodiment, the heterocycloalkyl can contain from 1 to 3 N, 1 or 2 N, or 1 N. In some embodiments, the heterocycloalkyl can contain from 3 to 7, from 3 to 6, from 4 to 6, from 4 to 10, or from 4 to 14 ring atoms.

[0086] For example, heterocycloalkyl groups include, but are not limited to, aziridinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl, sulfolanyl, dioxolanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, triazolinyl, triazolidinyl, tetrazolinyl, tetrazolidinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrothiopyranyl, dihydrothiopyranyl, dioxanyl, tetrahydrotriazinyl, hexahydrotriazinyl, morpholinyl, thiomorpholinyl, piperidinyl, dihydropyridinyl, tetrahydropyridinyl, piperazinyl, tetrahydropyrimidinyl, dihydropyrimidinyl, dihydropyridazinyl, tetrahydropyridazinyl, tetrahydrooxazinyl, hexahydroazepinyl, perhydroazepinyl, perhydrooxepinyl, indolinyl, isoindolinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, 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, tropanyl, 2-oxa-6-azaspiro[3.3]heptanyl, and their N-oxides, sulfones or sulfoxides.

[0087] In some embodiments, heterocycloalkyl includes aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, thiomorpholinyl or morpholinyl.

[0088] In the present disclosure, the term "substituted" group refers to a group in which one or more hydrogen atoms are replaced by one or more non-hydrogen atom groups, provided that the valence requirements should be satisfied and a chemically stable compound should be produced by the substitution. In the present disclosure, unless explicitly stated as "unsubstituted", all substituents should be construed as being capable of being unsubstituted or substituted. The "optionally substituted" portion described herein includes, without limitation to specific substituents, an unsubstituted portion or a portion substituted with any substituent, for example, 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 aryl, a portion substituted with a 4- to 14-membered heteroaryl or a 4- to 14-membered heterocycloalkyl. In one embodiment, the "optionally substituted" portion includes a portion substituted with halogen, hydroxy, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl) or -N(C1-C6 alkyl)2.

[0089] In the present disclosure, when a combination of substituents is described as, for example, a single group, such as arylalkyl, cycloalkylalkyl, etc., the last-described group contains the atom bonded to the end of the molecule.

[0090] In the present disclosure, the numerical range indicated using the term "to" refers to a range that includes the numerical values described before and after the term "to" as the lower limit and the upper limit, respectively.

[0091] In the present disclosure, the term "solvate" can refer to a compound of the present invention or a salt thereof that contains a theoretical or non-theoretical amount of a solvent bound by non-covalent intermolecular forces. Preferred solvents therefor can be any solvent that is volatile, non-toxic, and / or suitable for administration to humans.

[0092] In the present disclosure, the term "stereoisomer" can refer to compounds of the present invention or salts thereof that have the same chemical formula or molecular formula but are optically or stereochemically different, and specifically can be diastereomers, enantiomers or geometric isomers.

[0093] In some embodiments, the compounds of the present invention can be in the form of a racemate, a single enantiomer, a mixture of enantiomers, a single diastereomer, a mixture of diastereomers, etc., containing one or more asymmetric centers. In some embodiments, due to restricted rotation or the nature of the asymmetric centers, the compounds of the present invention can be in the form of enantiomers or diastereomers.

[0094] When two or more asymmetric centers are present in the compounds herein, several diastereomers and enantiomers having the chemical structures disclosed herein may exist, and pure isomers, separate isomers, partially pure isomers, racemic mixtures, etc. are all intended to fall within the scope of the present invention.

[0095] Purification of isomers and separation of isomer mixtures can be achieved by standard techniques known in the art. For example, a mixture of diastereomers can be separated into the corresponding diastereomers by chromatography processes or crystallization, and a racemate can be separated into the corresponding enantiomers by resolution using a chiral phase or chromatography processes.

[0096] In addition, when the compounds of the present invention contain groups capable of tautomerism, all tautomeric forms are included within the scope of the present invention. For example, 2-hydroxypyridine may include 2-pyridone, and such isomeric forms are all included in the present invention.

[0097] As used herein, "pharmaceutically acceptable salts" can include acidic or basic salts of the parent compound, and examples include, but are not limited to, mineral or organic acid salts of basic residues such as amines, and alkali or organic salts of acidic residues such as carboxylic acids.

[0098] For example, the pharmaceutically acceptable salts of the compounds of the present invention can be formed from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. In one embodiment, the pharmaceutically acceptable salts of the present invention include inorganic base addition salts, such as lithium salts, sodium salts, potassium salts, magnesium salts, calcium salts, aluminum salts, ammonium salts, copper salts, ferric salts, ferrous salts, manganese salts, zinc salts, and the like. In one embodiment, the pharmaceutically acceptable salts of the present invention include organic base addition salts, such as salts derived from arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, dicyclohexylamine, tris(hydroxymethyl)methylamine, and the like.

[0099] In addition, the compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic acids or organic acids. For example, the salts can be salts derived from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, 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, toluenesulfonic acid, and the like.

[0100] Pharmaceutically acceptable salts of the compounds can be prepared, for example, by dissolving a compound of formula I in a water-miscible organic solvent such as acetone, methanol, ethanol, acetonitrile, etc., adding an excess of an organic acid or adding an aqueous acid solution of an inorganic acid, and then precipitating or crystallizing. Subsequently, the solvent or the excess acid can be evaporated from this mixture and then dried to obtain the addition salt, or the precipitated salt can be prepared by suction filtration.

[0101] On the one hand, the acid addition salt form of the present invention can be easily converted to the free base form by treating with a suitable base, and the base addition salt form can be easily converted to the free acid form by treating with a suitable acid.

[0102] General preparation method of compounds On the other hand, the compounds can be prepared via chemical modifications well-known to those skilled in the art of organic chemistry / pharmaceutical chemistry according to the methods typically shown below.

[0103] The following general reaction schemes are general examples of representative preparation methods of the compounds of formula I. Those skilled in the art can easily prepare the compounds of formula I by appropriately selecting starting materials, reaction temperatures, reaction conditions, catalysts, solvents, treatment methods, etc. suitable for the desired compounds based on the preparation methods specifically disclosed in the examples of this specification.

[0104] For example, compounds of formula I having a thiophene ring can be prepared according to the following Reaction Schemes 1-5.

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0105] For example, the compound of formula I having a 4H-thieno[3,2-b]pyrrole fused ring can be prepared according to the following reaction scheme 6. [Chemical formula]

[0106] In the preparation of the compounds according to the above reaction schemes 1 to 6, compounds in which various ring structures are bonded to an amide bond can be prepared by using an appropriate amino-cycloalkyl-carboxylate compound, for example, methyl 3-aminocyclobutane-1-carboxylate, methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate, methyl 4-aminobicyclo[1.1.1]octane-1-carboxylate, etc., instead of methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride.

[0107] Pharmaceutical uses, pharmaceutical compositions, administration methods In another aspect, there is provided a pharmaceutical composition for preventing and / or treating a disease associated with overexpression of prostaglandin E2 and / or overexpression of a prostaglandin E2 receptor, comprising as an active ingredient a compound represented by the above 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, a solvate, stereoisomer or pharmaceutically acceptable salt thereof.

[0108] In the present disclosure, the term "prevent" or "prevention" refers to preventing a disease, for example, preventing a disease, condition or disorder in a subject who may be susceptible to the disease, condition or disorder but has not yet experienced or exhibited the symptoms or signs of the disease.

[0109] In the present disclosure, the term "treat" or "treatment" refers to inhibiting a disease, e.g., inhibiting a disease, condition or disorder in a subject experiencing or presenting a medical condition or symptom of the disease, condition or disorder, i.e., preventing further occurrence of the medical condition and / or symptom, or alleviating a disease, e.g., alleviating a disease, condition or disorder in a subject experiencing or presenting a medical condition or symptom of the disease, condition or disorder, i.e., reversing the medical condition and / or symptom, e.g., reducing the severity of the disease.

[0110] The disease "disease associated with prostaglandin E2 overexpression and / or prostaglandin E2 receptor overexpression" that is prevented or treated by the pharmaceutical composition is a disease closely related to the activity of prostaglandin E2, and can refer to a disease in which an effective therapeutic effect can be achieved through an antagonistic effect on prostaglandin E2 or the prostaglandin E2 receptor. The disease associated with prostaglandin E2 overexpression and / or prostaglandin E2 receptor overexpression can be a disease caused by overexpression or overactivity of prostaglandin E2 and / or the prostaglandin E2 receptor. The disease associated with prostaglandin E2 overexpression and / or prostaglandin E2 receptor overexpression can be, for example, cancer, neurodegenerative disease or inflammatory disease. Cancer can be, for example, 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, but is not limited thereto. The neurodegenerative disease can be epilepsy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis or traumatic brain injury, but is not limited thereto. The inflammatory disease can be edema, allergy, asthma, conjunctivitis, periodontitis, rhinitis, otitis media, pharyngolaryngitis, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, colitis, hemorrhoids, gout, ankylosing spondylitis, rheumatic fever, lupus, fibromyalgia, psoriatic arthritis, osteoarthritis, rheumatoid arthritis, periarthritis of shoulder, tendinitis, tenosynovitis, myositis, hepatitis, cystitis, nephritis, Sjogren's syndrome or multiple sclerosis, but is not limited thereto.

[0111] When used for the treatment of cancer, the compounds of the present invention can be used alone or in combination with other anti-cancer therapies, such as radiotherapy, anti-CTLA4 antibodies (e.g., ipilimumab), anti-PD-L1 antibodies (e.g., atezolizumab, avelumab), anti-PD-1 antibodies (e.g., nivolumab, pembrolizumab) or cytotoxic agents (e.g., alkylating agents such as cisplatin, dacarbazine and chlorambucil; antimetabolites such as methotrexate, fludarabine and gemcitabine; microtubule inhibitors such as vinblastine and paclitaxel; topoisomerase inhibitors such as topotecan and doxorubicin), etc.

[0112] According to one embodiment, the compounds 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 exhibit effective inhibitory activity against prostaglandin E2 receptors, such as EP2 and / or EP4, and as described above, can exert a therapeutic effect by controlling the activity of prostaglandin E2 through antagonism against prostaglandin E2 receptors. Therefore, the compounds 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, their solvates, stereoisomers or pharmaceutically acceptable salts can be used to treat diseases associated with prostaglandin E2 overexpression and / or prostaglandin E2 receptor overexpression.

[0113] In one embodiment, the pharmaceutical composition can include conventional pharmaceutically acceptable carriers, excipients or additives. The pharmaceutical composition can be formulated according to conventional methods and can be prepared in various oral dosage forms, such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions, or parenteral dosage forms, such as intramuscular, intravenous or subcutaneous dosage forms.

[0114] When the pharmaceutical composition is prepared in the form of an oral preparation, 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, and the like. When the pharmaceutical composition of the present invention is prepared in an injectable form, additives or carriers include water, saline, aqueous glucose solutions, similar aqueous sugar solutions, alcohols, glycols, ethers (e.g., polyethylene glycol 400), oils, fatty acids, fatty acid esters, glycerides, surfactants, suspending agents, emulsifiers, and the like.

[0115] The dosage of the pharmaceutical composition is an amount effective for the treatment or prevention of the subject or patient and can be administered orally or parenterally as desired. When administered orally, an amount of 0.01 to 1000 mg per kg of body weight, more specifically 0.1 to 300 mg, based on the active ingredient, is administered daily, or when administered parenterally, an amount of 0.01 to 100 mg per kg of body weight, more specifically 0.1 to 50 mg, based on the active ingredient, is administered daily, and can be administered in divided doses from once to several times. The dosage administered to a particular subject or patient should be determined taking into account several relevant factors, such as the patient's weight, age, gender, health status, diet, administration time, administration method, severity of the disease, etc., and it should be understood that it can be appropriately increased or decreased by an expert. The above dosages are not intended to limit the scope of the present invention in any way. A physician or veterinarian skilled in the art can easily determine and prescribe the required effective amount of the pharmaceutical composition. For example, by a physician or veterinarian, the dosage of the compound of the present invention used in the pharmaceutical composition may start at a level lower than that required to achieve the desired therapeutic effect and may be gradually increased until the desired effect is achieved.

[0116] In one embodiment, the pharmaceutical composition encompasses, within its scope, a pharmaceutical composition comprising, as an active ingredient, at least one of the compounds according to one embodiment in a therapeutically effective amount, alone or in combination with a pharmaceutical carrier. The terms "therapeutically effective amount" or "effective amount" refer to an amount sufficient to produce a beneficial or desired clinical result, for example, an amount sufficient to reduce, alleviate, stabilize, reverse, slow or delay the progression of a disease.

[0117] Optionally, the compound according to one embodiment may be administered alone, in combination with a compound according to another embodiment, or in combination with one or more other therapeutic agents, such as an anticancer agent or other pharmaceutically active substance, and may be administered simultaneously, separately or sequentially. Anticancer agents include, for example, anticancer agents, antiangiogenic agents, anti-inflammatory agents, immunosuppressive agents, etc., and may be, for example, known immune checkpoint inhibitors, such as immune anticancer agents including CTLA-4, PD-1, PD-L1, etc.

[0118] In another aspect, there is provided a method for preventing or treating a disease associated with prostaglandin E2 overexpression and / or prostaglandin E2 receptor overexpression, the method comprising administering to a subject 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, a solvate, stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

[0119] Among the terms or elements described in the description of the method, those that are the same as those already described are as described above.

[0120] Administration can be oral or parenteral. When administered orally, it is administered daily in an amount of 0.01 to 1000 mg, more specifically 0.1 to 300 mg, per kg of body weight based on the active ingredient, or when administered parenterally, it is administered daily in an amount of 0.01 to 100 mg, more specifically 0.1 to 50 mg, per kg of body weight based on the active ingredient, and can be administered in divided doses from once to several times. The dose to be administered to a specific subject or patient should be determined taking into account several relevant factors, such as the patient's weight, age, sex, health status, diet, administration time, administration method, severity of the disease, etc., and can be appropriately increased or decreased by an expert.

[0121] In the present disclosure, the term "subject" refers to a subject in need of treatment or prevention of a disease, and more specifically means a mammal, such as a human or non-human primate, mouse, dog, cat, horse, and cow.

[0122] In another aspect, there is provided a pharmaceutical use of 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, a solvate, stereoisomer or pharmaceutically acceptable salt thereof for the prevention or treatment of a disease associated with prostaglandin E2 overexpression and / or prostaglandin E2 receptor overexpression, or a use of 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, a solvate, stereoisomer or pharmaceutically acceptable salt thereof for the manufacture of a therapeutic agent for a disease associated with prostaglandin E2 overexpression and / or prostaglandin E2 receptor overexpression. Among the terms or elements described in the description of the method or use, those that are the same as those already described are as described above.

[0123] [Advantageous Effects of the Invention] A compound, a solvate, a stereoisomer or a pharmaceutically acceptable salt thereof according to one aspect has effective inhibitory activity against prostaglandin E2 receptors, such as EP2 and / or EP4.

[0124] Thus, a compound, its solvate, stereoisomer or pharmaceutically acceptable salt according to one aspect can be used as an active ingredient of a pharmaceutical composition for the prevention or treatment of diseases associated with prostaglandin E2 overexpression and / or prostaglandin E2 receptor overexpression, such as cancer, neurodegenerative diseases or inflammatory diseases.

[0125] [Mode of the Invention] The present invention will be described in detail below by way of examples. However, the following examples are merely illustrative of the present invention, and the content of the present invention is not limited by the following examples.

[0126] [Preparation Example] Preparation Example 1: Methyl 6-aminospiro[3.3]heptane-2-carboxylate hydrochloride [Chemical Formula]

[0127] Methyl 6-((tert-butoxycarbonyl)amino)spiro[3.3]heptane-2-carboxylate (10 g, 37.1 mmol) was added to a solution of 4N HCl in dioxane, stirred for 15 hours, and then 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%) as 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).

[0128] Preparation Example 2: Methyl 2-azidoacetate [Chemical Formula]

[0129] To a solution of methyl 2-bromoacetate (7.65 g, 50.0 mmol) in DMSO (0.5 M) was added NaN3 (4.88 g, 75.0 mmol), and the mixture was stirred for 24 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with distilled water. The organic layer was dried over Na2SO4 and then concentrated under reduced pressure to give Intermediate B (4.09 g, 75% yield) as a colorless liquid. 1 H NMR (300 MHz, chloroform-d) δ 3.91 (s, 2H), 3.83 (s, 3H).

[0130] Preparation Example 3: 3-Bromo-2,5-dimethylthiophene

Chemical formula

[0131] To a solution of 2,5-dimethylthiophene (11.2 g, 100 mmol) in acetate (0.2 M) was added NBS (17.8 g, 100 mmol), and the mixture was stirred for 15 h. The reaction mixture was concentrated, diluted with diethyl ether, and then washed with distilled water, 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 give Intermediate C (8.80 g, 46% yield) as a colorless liquid. 1 H NMR (300 MHz, chloroform-d) δ 6.60 - 6.56 (m, 1H), 2.42 (s, 3H), 2.35 (s, 3H).

[0132] Preparation Example 4: Methyl 4-bromo-2,5-dimethylthiophene-3-carboxylate Step 1: Synthesis of 3,4-dibromo-2,5-dimethylthiophene

Chemical formula

[0133] Step 2: Synthesis of 4-bromo-2,5-dimethylthiophene-3-carboxylic acid

Chemical formula

[0134] To a solution of 3,4-dibromo-2,5-dimethylthiophene (4.9 g, 18.1 mmol, 1.0 equiv) in THF (60 mL) was added dropwise with n-BuLi (2.0 M in cyclohexane, 8.2 mL, 0.9 equiv) at -78 °C and stirred at -78 °C for 30 min. An excess of dry ice was added, and then the mixture was stirred at ambient temperature for 30 min. The reaction mixture was added to 1N NaOH, extracted with Et2O, and the aqueous layer was acidified with 1N HCl solution. The resulting precipitate was removed by filtration, washed with distilled water, and then dried to give 4-bromo-2,5-dimethylthiophene-3-carboxylic acid (3.3 g, 77% yield).

[0135] Step 3: Synthesis of methyl 4-bromo-2,5-dimethylthiophene-3-carboxylate

Chemical formula

[0136] A solution of 4-bromo-2,5-dimethylthiophene-3-carboxylic acid (2.64 g, 11.2 mmol, 1.0 equiv) and K2CO3 (3.1 g, 22.4 mmol, 2.0 equiv) in DMF (15 mL) was added with iodomethane (1.4 mL, 22.4 mmol, 2.0 equiv) and stirred for 12 h. 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, 91% yield).

[0137] Preparation Example 5: 3-Fluoro-[1,1'-biphenyl]-4-carboxylic acid

Chemical formula

[0138] To 1.0 g of phenylboronic acid (8.20 mmol, 1.0 equiv) and 1.80 g of 4-bromo-2-fluoro-benzoic acid (8.20 mmol, 1.0 equiv), 6.47 g of 26% aqueous Me4N·OH solution (18.45 mmol, 2.25 equiv) was added and stirred at 50 °C. 25 mL of distilled water and 25 mg of 5% Pd / C (0.025 w / w) were added under Ar substitution and stirred at 80 °C for 1.5 h. The reaction mixture was cooled to ambient temperature and Pd / C was removed by filtration through celite. After adding 2.2 mL of 6M aqueous HCl solution (13.12 mmol, 1.6 equiv) to the reaction mixture for neutralization and crystallization, 10 mL of distilled water was added and stirred for 30 min. The precipitated crystals were washed with distilled water and then dried under reduced pressure to obtain Intermediate E (1.5 g, 85% yield). 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] + .

[0139] Preparation Example 6: 2-Amino-[1,1'-biphenyl]-4-carbonyl chloride Step 1: Synthesis of 2-amino-[1,1'-biphenyl]-4-carboxylic acid

Chem.

[0140] 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 the mixture was stirred at 100 °C for 12 h. The reaction mixture was cooled to ambient temperature, filtered through a celite plug and then washed with distilled water (2 × 20 mL). The solution was slowly acidified with 1 N citric acid solution, the precipitate was filtered off and then dried to give Intermediate F (3.5 g, 71% yield). 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).

[0141] Step 2: Synthesis of 2-amino-[1,1'-biphenyl]-4-carbonyl chloride

Chem.

[0142] Thionyl chloride (3.5 mL, 48.1 mmol) was added dropwise with stirring to a solution of 2-amino-[1,1'-biphenyl]-4-carboxylic acid (2.5 g, 11.73 mmol) in ethyl acetate (39 mL, 0.3 M). The reaction mixture was stirred under reflux for 4 h, then cooled to ambient temperature and concentrated under reduced pressure to give Intermediate F (2.95 g).

[0143] Preparation Example 7: (2'-Methoxy-[1,1'-biphenyl]-4-yl)methanol Step 1: Synthesis of methyl 2'-methoxy-[1,1'-biphenyl]-4-carboxylate

Chem.

[0144] A 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) in a stirred solution of 2-bromoanisole (0.75 mL, 6 mmol) in toluene (0.6 M) was stirred at 100 °C for 6 h. The reaction mixture was extracted with ethyl acetate (20 mL × 3), the organic layer was washed with brine solution, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane:ethyl acetate = 97:3 to 95:5) to give methyl 2'-methoxy-[1,1'-biphenyl]-4-carboxylate (507 mg, 35% yield). 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).

[0145] Step 2: Synthesis of (2'-methoxy-[1,1'-biphenyl]-4-yl)methanol

Chemical Structure

[0146] Methyl 2'-methoxy-[1,1'-biphenyl]-4-carboxylate (507 mg, 2.09 mmol) was dissolved in THF (0.2 M), LiAlH4 (397 mg, 10.5 mmol) was added, and the mixture was stirred for 3 h. The reaction mixture was cooled to 0 °C, then distilled water (1.6 mL) and aqueous NaOH were added, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane:ethyl acetate = 7:3) to give intermediate G (340 mg). 11H 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).

[0147] Preparation Example 8: 3-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

Chemical Structure

[0148] To a solution of 3-fluoro-5-bromoaniline (380 mg, 2.0 mmol) in 1,4-dioxane (20.0 mL) were added bis(pinacolato)diboron (1.1 g, 4.4 mmol), KOAc (1.18 g, 12 mmol), and Pd(dppf)Cl2 (146.0 mg, 0.2 mmol) under an N2 atmosphere, and the mixture was stirred at 90 °C for 32 hours. The reaction mixture was cooled to ambient temperature, filtered through celite, and washed with EtOAc. The organic layer was concentrated under reduced pressure to obtain Intermediate H (1.4 g).

[0149] Preparation Example 9: 2-(3-Fluoro-5-(methylthio)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Step 1: Synthesis of (3-bromo-5-fluorophenyl)(methyl)sulfane

Chemical Structure

[0150] A solution of 3,5-difluorobromobenzene (3 g, 15.54 mmol) in N,N-dimethylformamide (30 mL) was cooled to 0 °C, and a sodium thiomethoxide solution (7.1 mL, 15.54 mmol) was added. The mixture was stirred for 30 minutes. The reaction mixture was diluted with distilled water, 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.

[0151] Step 2: Synthesis of 2-(3-fluoro-5-(methylthio)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Chemical formula

[0152] (3-Bromo-5-fluorophenyl)(methyl)sulfane (1 g, 4.523 mmol), potassium acetate (2.2 g, 22.615 mmol), (pinacolato)diboron (1.7 g, 6.784 mmol), and Pd(dppf)Cl2 (complex with DCM; 369 mg, 0.452 mmol) were added to a sealed tube, which was purged under an N2 atmosphere. 1,4-Dioxane was added, and then the mixture was stirred at 80 °C for 12 hours. The reaction mixture was cooled to ambient temperature, then ethyl acetate was added, and the precipitate was removed by filtration through celite. The organic layer was concentrated under reduced pressure, and the crude product was purified by flash column chromatography (hexane / ethyl acetate with a concentration of 0% - 100%) to obtain Intermediate I (932 mg, yield 70%) as a yellow liquid.

[0153] Preparation Example 10: 3-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide Step 1: Synthesis of 3-bromo-5-fluorobenzamide

Chemical formula

[0154] A solution of 3-bromo-5-fluorobenzoic acid (1 g, 4.566 mmol) in thionyl chloride (4 mL) was stirred under reflux conditions for 2 hours. The reaction mixture solution was concentrated under reduced pressure, 28% aqueous ammonia (1.5 mL) was added, and then 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).

[0155] Step 2: Synthesis of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

Chemical formula

[0156] Intermediate J was obtained by reacting 3-bromo-5-fluorobenzamide in the same manner as in Preparation Example 8.

[0157] Preparation Example 11: 3-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

Chemical formula

[0158] 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 H NMR (300 MHz, DMSO-d6) 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).

[0159] Preparation Example 12: tert-Butyl (3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate Step 1: Synthesis of (3-bromo-5-methoxyphenyl)methanamine

Chem.

[0160] 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 h, then the solvent was concentrated under reduced pressure and acidified by the addition of 1N HCl. The reaction mixture was stirred at ambient temperature for 2 h, then EA and distilled water were added, and the aqueous layer was extracted. The aqueous layer was neutralized with 2N NaOH (pH 10), then extracted with EA and brine. The organic layer was concentrated under reduced pressure to give (3-bromo-5-methoxyphenyl)methanamine (741 mg, yield 72%). 1 H NMR (300 MHz, chloroform-d) δ 7.08 - 7.03 (m, 1H), 6.92 (t, J = 2.0Hz, 1H), 6.83 - 6.79 (m, 1H), 3.81 (s, 2H), 3.78 (s, 3H).

[0161] Step 2: Synthesis of tert-butyl (3-bromo-5-methoxybenzyl)carbamate

Chem.

[0162] (3-Bromo-5-methoxyphenyl)methanamine (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 then stirred for 16 hours. The DCM was partially concentrated and extracted with EA and brine. The organic layer was dried over MgSO4 and then concentrated under reduced pressure and purified by silica column (EA:hexane = 1:3) to obtain tert-butyl (3-bromo-5-methoxybenzyl)carbamate (766 mg, yield 70%). 1 H 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).

[0163] Step 3: Synthesis of tert-butyl (3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate

Chem.

[0164] Intermediate L was obtained by reacting tert-butyl (3-bromo-5-methoxybenzyl)carbamate in the same manner as in Preparation Example 8. 1 H 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).

[0165] Preparation Example 13: 3-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol Step 1: Synthesis of (3-bromo-5-fluorophenyl)methanol

Chem.

[0166] 3-Bromo-5-fluorobenzoic acid (657.0 mg, 3.0 mmol) was added to THF (15.0 mL), cooled to 0 °C, and BH3·DMS (5 M, 1.2 mL, 6.0 mmol) was added over 15 minutes, followed by stirring for 12 hours. The reaction mixture was cooled to 0 °C and an excess of methanol was added. The solution diluted with ethyl acetate was washed with 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 - 30% EtOAc / hexane) to give (3-bromo-5-fluorophenyl)methanol (400 mg, 65% yield). 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).

[0167] Step 2: Synthesis of (3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol

Chemical Structure

[0168] Intermediate M was obtained by reacting (3-bromo-5-fluorophenyl)methanol in the same manner as in Preparation Example 8.

[0169] Preparation Example 14: 3-(3-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol Step 1: Synthesis of 3-(3-bromo-5-methoxyphenyl)oxetan-3-ol

Chemical Structure

[0170] To a solution of 1,3-dibromo-5-methoxybenzene (1.06 g, 4.0 mmol) in THF (0.2 M) was added TMEDA (923 μL, 6.0 mmol) and n-BuLi (2.5 M in THF, 2.4 mL, 6.0 mmol) at -78 °C, and the mixture was stirred for 1 hour. To the reaction mixture was added oxetanone (1.02 mL, 4.8 mmol), and the mixture was slowly warmed to ambient temperature. After 4 hours, the resulting mixture was diluted with aqueous NH4Cl (40 mL) and ethyl acetate (40 mL), and the aqueous layer was extracted with ethyl acetate (40 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane:ethyl acetate = 1:2) to give 3-(3-bromo-5-methoxyphenyl)oxetan-3-ol (443.0 mg as a mixture, about 320.0 mg, 31% yield) as a colorless oil. 1 1H NMR (500 MHz, CDCl3) δ 7.34 (s, 1H), 7.07 (d, J = 2.0Hz, 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).

[0171] Step 2: Synthesis of 3-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol

Chemical Structure

[0172] Intermediate N was obtained by reacting 3-(3-bromo-5-methoxyphenyl)oxetan-3-ol in the same manner as in Preparation Example 8. 1 1H 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).

[0173] Preparation Example 15: 1-(3-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidin-2-one Step 1: Synthesis of 1-(3-methoxyphenyl)azetidin-2-one [Chemical Structure]

[0174] To a solution of 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) were added, and the mixture was stirred at 140 °C for 24 hours. The reaction mixture was cooled to ambient temperature, 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 over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane:ethyl acetate = 2:1) to give 1-(3-methoxyphenyl)azetidin-2-one (436.0 mg, 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).

[0175] Step 2: 1-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidin-2-one [Chemical Structure]

[0176] To a solution of 1-(3-methoxyphenyl)azetidin-2-one (436.0 mg, 2.46 mmol) in cyclohexane (0.1 M), [Ir(cod)OMe]2 (195.7 mg, 0.295 mmol), 4,4’-di-tert-butyl-2,2’-bipyridine (dtbpy) (158.5 mg, 0.590 mmol), bis(pinacolato)diboron (1.25 g, 4.90 mmol) and BpinH (42.8 μL, 0.295 mmol) were added, and the mixture was stirred at 80 °C for 24 h. The reaction mixture was cooled to room temperature, diluted with brine (40 mL) and ethyl acetate (40 mL), and then the aqueous layer was extracted with ethyl acetate (40 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane:ethyl acetate = 1:1) to give Intermediate O (405.2 mg, 54% yield) as a yellow solid. 1 1H 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).

[0177] Preparation Example 16: tert-Butyl (3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate

Chemical formula

[0178] 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.

[0179] Preparation Example 17: tert-Butyl 3-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine-1-carboxylate Step 1: Synthesis of tert-butyl 3-(3-bromo-5-fluorophenyl)azetidine-1-carboxylate

Chem.

[0180] tert-Butyl 3-(2-((4-methoxyphenyl)sulfonyl)hydrazinylidene)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 h. The reaction mixture was cooled to ambient temperature, quenched with saturated aqueous NaHCO3 (30 mL), then dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (10 - 30% EtOAc / hexane) to afford 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).

[0181] 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

Chem.

[0182] 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. 11H 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).

[0183] Preparation Example 18: Methyl 6-(methylamino)spiro[3.3]heptane-2-carboxylate hydrochloride Step 1: Synthesis of methyl 6-((tert-butoxycarbonyl)(methyl)amino)spiro[3.3]heptane-2-carboxylate

Chemical Structure

[0184] 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), 60% NaH (60 mg, 1.50 mmol) was added and stirred at 0 °C for 15 minutes. 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 over 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 1H 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).

[0185] Step 2: Synthesis of methyl 6-(methylamino)spiro[3.3]heptane-2-carboxylate hydrochloride

Chemical Structure

[0186] To methyl 6-((tert-butoxycarbonyl)(methyl)amino)spiro[3.3]heptane-2-carboxylate (288 mg, 1.02 mmol), 4N HCl in dioxane was added at 0 °C, and the mixture was stirred at ambient temperature for 15 hours. The reaction mixture was concentrated under reduced pressure to obtain the hydrochloride salt of intermediate R (244 mg) 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).

[0187] Preparation Example 19: 4-(((tert-butyldimethylsilyl)oxy)methyl)-2,5-dimethylthiophene-3-carboxylic acid Step 1: Synthesis of 4-bromo-2,5-dimethylthiophene-3-carbaldehyde

Chemical formula

[0188] To a solution of 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 the mixture was stirred for 1 hour. DMF was added to the reaction mixture, then the mixture was slowly warmed to ambient temperature and stirred for 15 hours. The reaction mixture was quenched with distilled water (20 mL), acidified with 1N HCl solution, and then extracted with ethyl acetate. The organic layer was dried over 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).

[0189] Step 2: Synthesis of (4-bromo-2,5-dimethylthiophen-3-yl)methanol

Chem.

[0190] To a solution of 4-bromo-2,5-dimethylthiophene-3-carbaldehyde (1.10 g, 5.02 mmol) in THF (0.2 M) was added LiAlH4 (191 mg, 5.02 mmol) at 0 °C, and the mixture was stirred for 2 h. The reaction mixture was quenched with EtOAc (1 mL) and ice water (0.3 mL), stirred for 30 min, then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (20% EtOAc in hexane) to give (4-bromo-2,5-dimethylthiophen-3-yl)methanol (754 mg, 68% yield) as a colorless liquid. 1 1H NMR (400 MHz, DMSO); δ 4.33 (s, 1H), 2.40 (s, 3H), 2.36 (s, 1H), 2.30 (s, 3H).

[0191] Step 3: Synthesis of ((4-bromo-2,5-dimethylthiophen-3-yl)methoxy)(tert-butyl)dimethylsilane

Chem.

[0192] To a solution of (4-bromo-2,5-dimethylthiophen-3-yl)methanol (950 mg, 4.30 mmol) in THF (0.2 M, 0 °C) were added tert-butyldimethylsilyl chloride (777 mg, 5.16 mmol) and imidazole (439 mg, 6.44 mmol), and the mixture was stirred for 24 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with distilled water (2 × 20 mL). The organic layer was dried over Na2SO4, filtered, and then concentrated under reduced pressure. The crude product was purified by column chromatography (5% EtOAc in hexane) to give ((4-bromo-2,5-dimethylthiophen-3-yl)methoxy)(tert-butyl)dimethylsilane (937 mg, 65% yield) as a colorless liquid. 11H 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).

[0193] Step 4: Synthesis of 4-(((tert-butyldimethylsilyl)oxy)methyl)-2,5-dimethylthiophene-3-carboxylic acid

Chem.

[0194] To a solution of ((4-bromo-2,5-dimethylthiophen-3-yl)methoxy)(tert-butyl)dimethylsilane (335 g, 1.0 mmol) and TMEDA (165 μL, 1.10 mmol) in THF (0.2 M) was added n-BuLi (2.5 M in THF, 0.44 mL, 1.10 mmol) at -78 °C, and the mixture was stirred for 1 hour. The reaction mixture was quenched with CO2 gas at -78 °C and then slowly warmed to ambient temperature and stirred for 15 hours. The reaction mixture was quenched with distilled water (20 mL), acidified with 1 N HCl solution, and then extracted with ethyl acetate. The organic layer was dried over Na2SO4, filtered, and then concentrated under reduced pressure. The crude product was purified by column chromatography (20% EtOAc in hexane) to give 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).

[0195] Preparation Example 20: Methyl 3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylate Step 1: Synthesis of methyl (Z)-2-azido-3-(4-bromothiophen-2-yl)acrylate

Chem.

[0196] To a solution of 4-bromothiophene-2-carbaldehyde (3.82 g, 20.0 mmol, 1.0 equiv) and Intermediate B (6.91 g, 60.0 mmol, 3.0 equiv) in MeOH (30 mL) was added 4 M NaOMe (15 mL, 60.0 mmol) at -25 °C, and the mixture was stirred at 0 °C for 2 h. Ice was added to the reaction mixture, which was then washed with distilled water, filtered, and the reaction product was dried to obtain methyl (Z)-2-azido-3-(4-bromothiophen-2-yl)acrylate. 1 H NMR (300 MHz, 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).

[0197] Step 2: Synthesis of methyl 3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylate

Chemical Structure

[0198] A solution of methyl (Z)-2-azido-3-(4-bromothiophen-2-yl)acrylate (4.79 g, 16.6 mmol, 1.0 equiv) in o-xylene (60 mL) was stirred at 160 °C for 1 h. The reaction mixture was partially concentrated, 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).

[0199] Preparation Example 21: Methyl 3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate Step 1: Preparation of 4-bromo-5-methylthiophene-2-carbaldehyde

Chemical Structure

[0200] A solution of 5-methylthiophene-2-carbaldehyde (2.78 g, 22.0 mmol) in THF (0.5 M) was added bromine (1.7 mL, 33 mmol) at 0 °C and stirred for 25 h. To the reaction mixture were added 10% aqueous Na2S2O3 solution (30 mL) and 10% aqueous NaHCO3 solution (30 mL), and the mixture was extracted with EtOAc (150 mL). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to give 4-bromo-5-methylthiophene-2-carbaldehyde (862 mg, yield 16%) as a colorless solid. 1 H NMR (300 MHz, chloroform-d) δ 9.80 (s, 1H), 7.62 (s, 1H), 2.51 (s, 3H).

[0201] Step 2: Preparation of methyl (Z)-2-azido-3-(4-bromo-5-methylthiophen-2-yl)acrylate

Chemical Structure

[0202] To a solution of 4-bromo-5-methylthiophene-2-carbaldehyde (850 mg, 4.14 mmol) in MeOH (1.5 M) were added 4 M NaOMe (3 mL, 11.6 mmol) and intermediate B (1.43 g, 12.4 mmol) at -25 °C. The reaction mixture was stirred at 0 °C for 2 h, then diluted with EtOAc and washed with brine solution. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography to give methyl (Z)-2-azido-3-(4-bromo-5-methylthiophen-2-yl)acrylate (813 mg, yield 65%) as a yellow solid. 1 H NMR (300 MHz, chloroform-d) δ 7.15 (s, 1H), 6.99 (s, 1H), 3.91 (s, 3H), 2.45 (s, 3H).

[0203] Step 3: Preparation of methyl 3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate

Chemical Structure

[0204] A solution of methyl (Z)-2-azido-3-(4-bromo-5-methylthiophen-2-yl)acrylate (795 mg, 2.63 mmol) in 4 mL of xylene was added to o-xylene (5 mL) over 10 minutes. After stirring for 1 hour under reflux, the reaction mixture was cooled to ambient temperature and concentrated in part. The solid was filtered to give Intermediate U (554 mg, 77% yield) as an off-white solid. 1 H 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).

[0205] Preparation Example 22: Ethyl 3-bromo-6-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate Step 1: Synthesis of 1-(3,4-dibromothiophen-2-yl)ethan-1-one

Chemical formula

[0206] To a solution of AlCl3 (1.33 g, 10.0 mmol, 2.0 equiv) in DCM (20 mL) was added 3,4-dibromothiophene (1.2 g, 5.0 mmol) at 0 °C, and the mixture was stirred for 10 minutes. Acetyl chloride (360 μL, 5.0 mmol, 1.0 equiv) was added, and the mixture was stirred at 0 °C for 3 hours. The reaction mixture was acidified by the addition of 6 M HCl and extracted with DCM. The organic layer was dried over MgSO4 and then concentrated under reduced pressure to give 1-(3,4-dibromothiophen-2-yl)ethan-1-one. 1 H NMR (300 MHz, chloroform-d) δ 7.63 (s, 1H), 2.72 (s, 3H).

[0207] Step 2: Synthesis of ethyl 3-bromo-6-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate

Chemical formula

[0208] A solution of 1-(3,4-dibromothiophen-2-yl)ethan-1-one (1.42 g, 5.0 mmol), ethyl isocyanoacetate (600 μL, 5.5 mmol, 1.1 equiv), CuI (95 mg, 0.5 mmol, 0.1 equiv) and Cs2CO3 (3.26 g, 10.0 mmol, 2.0 equiv) in DMSO (5 mL) was stirred at 50 °C for 4 h. Distilled water was added to the reaction mixture and it was extracted with DCM. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The crude product was purified by flash column chromatography to give Intermediate V (806 mg, 56% yield). 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).

[0209] Preparation Example 23: Methyl 3-bromo-2-chloro-4H-thieno[3,2-b]pyrrole-5-carboxylate Step 1: Synthesis of 4-bromo-5-chlorothiophene-2-carbaldehyde

Chemical Structure

[0210] To a solution of 4-bromothiophene-2-carbaldehyde (500 mg, 2.62 mmol, 1.0 equiv) in DMF (5 mL) was added N-chlorosuccinimide (699 mg, 5.24 mmol) and the mixture was stirred at 70 °C for 12 h. Distilled water was added to the reaction mixture, the solid was filtered off, then washed with distilled water and dried to give 4-bromo-5-chlorothiophene-2-carbaldehyde (421 mg, 70% yield). 1 H NMR (300 MHz, chloroform-d) δ 9.76 (s, 1H), 7.60 (s, 1H).

[0211] Steps 2 and 3: Synthesis of methyl 3-bromo-2-chloro-4H-thieno[3,2-b]pyrrole-5-carboxylate

Chemical Structure

[0212] The 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).

[0213] Preparation Example 24: 4'-(Bromomethyl)-3-methoxy-1,1'-biphenyl Step 1: Synthesis of (3'-methoxy-[1,1'-biphenyl]-4-yl)methanol

Chemical formula

[0214] 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. The reaction mixture was cooled to ambient temperature, then filtered through celite, extracted with EA and brine, and the organic layer was dried over MgSO4. The crude product was purified by silica gel column (EtOAc:hexane = 1:2) to give (3'-methoxy-[1,1'-biphenyl]-4-yl)methanol (1.00 g, yield 93%) as a yellow oil. 1 H 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).

[0215] Step 2: Synthesis of 4'-(bromomethyl)-3-methoxy-1,1'-biphenyl

Chemical formula

[0216] (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 then 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 by silica gel column (EtOAc:hexane = 1:25) to obtain Intermediate X (1.14 g, yield 88%). 1 H 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).

[0217] Preparation Example 25: 4'-(Bromomethyl)-3-fluoro-5-methoxy-1,1'-biphenyl

Chemical formula

[0218] Intermediate Y was obtained by using (4-bromophenyl)methanol and (3-fluoro-5-methoxyphenyl)boronic acid as starting materials and using the same method 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).

[0219] Preparation Example 26: Methyl (2R,4R,6R)-6-aminospiro[3.3]heptane-2-carboxylate hydrochloride Step 1: Synthesis of methyl 6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptane-2-carboxylate

Chem.

[0220] 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 ambient temperature for 14 h. The reaction mixture was extracted with aqueous NH4Cl solution and DCM, then the organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by silica gel column (EtOAc:hexane = 1:1) to give 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).

[0221] Step 2: Purification of Methyl 6-(((Benzyloxy)Carbonyl)Amino)Spiro[3.3]Heptane-2-Carboxylate

Chem.

[0222] 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 to separate into the 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), respectively, as yellow oils.

[0223] Column: Daicel ChralPak IG Mobile phase (250 mm × 4.6 mm, 1um) Mobile phase: [Hexane / EtOH]; 80 / 20 (V / V), 9.4 minutes for (2S,4S,6S), 10.7 minutes for (2R,4R,6R)

[0224] Step 3: Synthesis of Methyl (2R,4R,6R)-6-Aminospiro[3.3]Heptane-2-Carboxylate Hydrochloride

Chemical formula

[0225] 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 a 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 4N HCl solution (0.8 mL, 3.09 mmol) were added to the concentrated reaction mixture, and it was further stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain Intermediate Z (180 mg).

[0226] Preparation Example 27: 4'-(Bromomethyl)-3,5-dimethoxy-1,1'-biphenyl

Chemical formula

[0227] Intermediate AA was obtained by using 1-bromo-3,5-dimethoxybenzene and ((4-hydroxy)methylphenyl)boronic acid as starting materials and using the same method as in Preparation Example 24. 1 H 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).

[0228] Preparation Example 28: 4-(2-Bromoethyl)-1,1'-biphenyl Step 1: Synthesis of 2-([1,1'-Biphenyl]-4-yl)Ethan-1-ol

Chemical formula

[0229] To a solution of 2-([1,1'-biphenyl]-4-yl)acetic acid (559 mg, 3 mmol) in THF (7 mL), LiAlH4 (1 M in THF, 9.0 mL, 3.0 equivalents) was added at 0 °C, and the mixture was stirred at 75 °C for 4 hours. Then, 1 N NaOH was carefully added to quench the reaction. The reaction mixture was filtered through Celite, and the filtrate was poured into distilled water and extracted with EtOAc. The organic layer was dried over MgSO4 and then concentrated under reduced pressure to obtain 2-([1,1'-biphenyl]-4-yl)ethan-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).

[0230] Step 2: Synthesis of 4-(2-Bromoethyl)-1,1'-Biphenyl

Chemical formula

[0231] To a solution of 2-([1,1'-biphenyl]-4-yl)ethan-1-ol (522 mg, 2.8 mmol, 1.0 eq) in DMC (12 mL) was added CBr4 (1.02 g, 3.1 mmol, 1.1 eq) at 0 °C, and the mixture was stirred for 15 minutes. Then PPh3 (813 mg, 3.1 mmol, 1.1 eq) was added, and the mixture was stirred for 40 minutes. The precipitated solid was filtered to obtain Intermediate BB (639 mg, yield 87%). 1 H 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).

[0232] Preparation Example 29: 4'-(Bromomethyl)-3-fluoro-1,1'-biphenyl Step 1: Synthesis of (3'-Fluoro-[1,1'-Biphenyl]-4-yl)Methanol

Chemical Structure

[0233] (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, 0.268 mmol) were dissolved in DME and H2O (2:1), then 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).

[0234] Step 2: Synthesis of 4'-(Bromomethyl)-3-Fluoro-1,1'-Biphenyl [Chem.]

[0235] (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, stirred for 2 hours, then an additional PBr3 (100 μL) 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. 1 H 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).

[0236] Preparation Example 30: 2-(4-(Bromomethyl)phenyl)pyrimidine [Chem.]

[0237] 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).

[0238] Preparation Example 31: 5-(Bromomethyl)-2-phenylpyrimidine Step 1: Synthesis of (2-Phenylpyrimidin-5-yl)Methanol [Chem.]

[0239] (2-Chloropyrimidin-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), purged under an Ar atmosphere, and then stirred at 100 °C for 12 h. The reaction mixture was filtered through celite and then extracted with EA and brine. The organic layer was concentrated under reduced pressure and purified by silica column (EtOAc:hexane = 1:1) to obtain (2-phenylpyrimidin-5-yl)methanol (661 mg, yield 44%). 1 H 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).

[0240] Step 2: Synthesis of 5-(Bromomethyl)-2-Phenylpyrimidine

Chemical formula

[0241] (2-Phenylpyrimidin-5-yl)methanol (661 mg, 3.549 mmol) was dissolved in DCM (11 mL), and then CBr4 (1.421 g, 4.258 mmol) and PPh3 (1.116 g, 4.258 mmol) were added at 0 °C over 10 min and stirred for 40 min. The reaction mixture was concentrated under reduced pressure and purified by silica column (EA:hexane = 1:9) to obtain 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).

[0242] Preparation Example 32: (3-Bromoprop-1-yn-1-yl)benzene

Chemical formula

[0243] To a solution of (3-hydroxyprop-1-yn-1-yl)benzene (10.0 g, 75.6 mmol, 9.43 mL, 1.00 equiv) and DMF (276 mg, 3.78 mmol, 0.05 equiv) in DCM (100 mL) was added PBr3 (24.5 g, 90.8 mmol, 1.20 equiv) at 0 °C, and the mixture was stirred for 1 h. The reaction mixture was cooled to 0 °C and then quenched by the addition of distilled water (50 mL) and extracted with DCM (2 × 50 mL). The organic layer was washed with aqueous NaHCO3 solution (1 × 100 mL) and brine (1 × 100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ether / ethyl acetate = 50 / 1 - 20 / 1) to give Intermediate FF (13.8 g, 70.7 mmol, 93.5% yield) as a colorless oil.

[0244] Preparation Example 33: (4-(Pyridin-3-yl)phenyl)methanol

Chemical Structure

[0245] (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 then stirred at 85 °C for 12 h. The reaction mixture was cooled to ambient temperature and then extracted with EA and distilled water. The crude product was purified by flash column chromatography to give 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).

[0246] Preparation Example 34: (4-(5-Fluoropyridin-3-yl)phenyl)methanol

Chem.

[0247] Intermediate HH was obtained by using the corresponding starting material in the same manner as in Preparation Example 33. 1 H 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).

[0248] Preparation Example 35: (4-(5-Methoxypyridin-3-yl)phenyl)methanol

Chem.

[0249] Intermediate II was obtained by 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).

[0250] Preparation Example 36: (4-(1-Benzyl-1H-pyrazol-4-yl)phenyl)methanol

Chem.

[0251] (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), purged under an Ar atmosphere and then stirred at 80 °C for 6 h. The reaction mixture was filtered through Celite, then extracted with EA and brine, and dried over MgSO4. Purification by silica gel column (EA: hexane = 1:3) gave intermediate JJ (948 mg, 63% yield). 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).

[0252] Preparation Example 37: (1-Benzyl-1H-indol-5-yl)methanol Step 1: Synthesis of Methyl 1-Benzyl-1H-Indole-5-Carboxylate

Chemical formula

[0253] To a solution of methyl 1H-indole-5-carboxylate (2.80 g, 16 mmol) and benzyl bromide (2.1 mL, 17.6 mmol) in DMF (30 mL), NaH (460 mg, 19.2 mmol) was added portionwise at 0 °C and the mixture was stirred at ambient temperature for 12 h. The reaction mixture was extracted with EA and brine, the organic layer was dried over MgSO4 and then concentrated under reduced pressure. The crude product was purified by silica column (EA: hexane = 1:9) to give methyl 1-benzyl-1H-indole-5-carboxylate (5.083 g, 78% yield). 11H 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).

[0254] Step 2: Synthesis of (1-Benzyl-1H-Indole-5-yl)Methanol

Chem.

[0255] Methyl 1-benzyl-1H-indole-5-carboxylate (2.0 g, 7.538 mmol) was dissolved in THF (25 mL), and LiAlH4 (1 M in THF, 22.6 mL, 22.615 mmol) was added at 0 °C. The mixture was stirred at 75 °C for 4 hours. The organic layer was filtered through celite, concentrated under reduced pressure, and purified by silica column (EA:hexane = 1:2) to obtain Intermediate KK (1.734 g, yield 97%). 1 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).

[0256] Preparation Example 38: (4-(Pyridin-2-yl)phenyl)methanol

Chem.

[0257] Intermediate LL was obtained by using the corresponding starting material in the same manner as in Preparation Example 33. 11H 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).

[0258] Preparation Example 39: (6-Phenylpyridin-3-yl)methanol

Chemical formula

[0259] To a solution of (6-bromopyridin-3-yl)methanol (940.1 mg, 5.0 mmol) in 1,4-dioxane / H2O (0.25 M), 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 Na2CO3 (1.59 g, 15.0 mmol) were added, and the mixture was stirred at 100 °C. After 18 hours, the reaction mixture was cooled to ambient temperature, 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 over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane:ethyl acetate = 3:7) to give Intermediate MM (618.6 mg, 67% yield) as a white solid. 1 1H 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).

[0260] Preparation Example 40: (4-Pyridin-4-yl)phenyl)methanol

Chemical formula

[0261] The intermediate NN was obtained by 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 = 8.2Hz, 2H), 7.60 - 7.55 (m, 2H), 7.51 (d, J = 8.2 Hz, 2H), 4.79 (s, 2H).

[0262] Preparation Example 41: (4-(6-Methoxypyridin-2-yl)phenyl)methanol

Chemical formula

[0263] The intermediate OO was obtained by 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 = 8.2Hz, 1H), 4.78 (s, 2H), 4.06 (s, 3H).

[0264] Preparation Example 42: (4-(4-Methoxypyridin-2-yl)phenyl)methanol

Chemical formula

[0265] The intermediate PP was obtained by using the corresponding starting material in the same manner as in Preparation Example 33. 11H 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).

[0266] Preparation Example 43: (6-(3-Fluoro-5-methoxyphenyl)pyridin-3-yl)methanol

Chemical Structure

[0267] Intermediate QQ was obtained by using the corresponding starting materials in the same manner as in Preparation Example 39. 1 1H 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).

[0268] Preparation Example 44: (4-(4-Methyl-1H-pyrazol-1-yl)phenyl)methanol

Chemical Structure

[0269] (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), then the mixture was purged under an Ar atmosphere and then stirred at 100 °C for 12 h. The reaction mixture was extracted with EA and brine, then the organic layer was dried over MgSO4 and concentrated under reduced pressure. The mixture was purified by silica chromatography (EA:hexane = 1:3) to give intermediate RR (191 mg, mixture). LC / MS (ESI) m / z: 189.1 [M+H].

[0270] Preparation Example 45: (4-(3-Methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol

Chemical Structure

[0271] 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) and N,N-dimethylglycine (44 mg, 0.427 mmol) were dissolved in DMSO, heated to 130 °C and stirred for 24 h. The reaction mixture was cooled to ambient temperature, extracted with EA and distilled water, and then the crude product was purified by flash column chromatography to give 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).

[0272] Preparation Example 46: (5-(3-Fluoro-5-methoxyphenyl)pyridin-2-yl)methanol

Chem.

[0273] The intermediate TT was obtained by using the corresponding starting materials 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).

Example

[0274] Example 1: 6-(4-([1,1'-Biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of [1,1'-Biphenyl]-4-yl(2,5-Dimethylthiophen-3-yl)Methanone

Chem.

[0275] Step 2: Synthesis of [1,1'-Biphenyl]-4-yl(4-Bromo-2,5-Dimethylthiophen-3-yl)Methanone

Chemical formula

[0276] Step 3: Synthesis of 3-([1,1'-Biphenyl]-4-ylmethyl)-4-Bromo-2,5-Dimethylthiophene

Chem.

[0277] Step 4: Synthesis of 4-([1,1'-Biphenyl]-4-ylmethyl)-2,5-Dimethylthiophene-3-Carboxylic Acid

Chem.

[0278] Step 5: Synthesis of Methyl 6-(4-([1,1'-Biphenyl]-4-ylmethyl)-2,5-Dimethylthiophene-3-Carboxamido)Spiro[3.3]Heptane-2-Carboxylate

Chemical formula

[0279] Step 6: Synthesis of 6-(4-([1,1'-Biphenyl]-4-ylmethyl)-2,5-Dimethylthiophene-3-Carboxamido)Spiro[3.3]Heptane-2-Carboxylic Acid

Chem.

[0280] The compounds of Examples 2 to 5 were prepared by the same method as in Example 1, except for the differences in the preparation methods described below.

Table 1

Table 2

[0281] Example 6: 6-(4-(2-([1,1'-Biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of 2-([1,1'-Biphenyl]-4-yl)-1-(2,5-Dimethylthiophen-3-yl)Methan-1-one

Chem.

[0282] Step 2: Synthesis of 3-(2-([1,1'-Biphenyl]-4-yl)Ethyl)-2,5-Dimethylthiophene

Chem.

[0283] Step 3: Synthesis of 3-(2-([1,1'-Biphenyl]-4-yl)Ethyl)-4-Bromo-2,5-Dimethylthiophene

Chemical Structure

[0284] Step 4: Synthesis of 4-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene-3-carboxylic acid

Chemical formula

[0285] 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 [Chemical formula] 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) in DCM (1.1 mL, 0.2 M), DIPEA (0.11 mL, 0.63 mmol) was added and the mixture was stirred at ambient temperature for 3 h. The reaction mixture was partially concentrated and the organic layer was extracted with 1N NaOH and ethyl acetate, and the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, concentrated, and then purified by column chromatography to give methyl 6-(4-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (70 mg, 70% yield). 1 H 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] + .

[0286] 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

Chem.

[0287] Example 7: 6-(4-((3-Fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of (4-bromo-2,5-dimethylthiophen-3-yl)(3-fluoro-[1,1'-biphenyl]-4-yl)methanone

Chem.

[0288] Step 2: Synthesis of 3-bromo-4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene

Chem.

[0289] Step 3: Synthesis of 4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxylic acid

Chemical formula

[0290] 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

Chemical formula

[0291] 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

Chemical Structure

[0292] Example 8: 6-(4-((2-Amino-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of (2-amino-[1,1'-biphenyl]-4-yl)(4-bromo-2,5-dimethylthiophen-3-yl)methanone

Chem.

[0293] Steps 2 - 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

Chem.

[0294] Example 9: 6-(2,5-Dimethyl-4-(4-morpholinobenzyl)thiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of (4-bromo-2,5-dimethylthiophen-3-yl)(4-fluorophenyl)methanone

Chem.

[0295] Step 2: Synthesis of (4-bromo-2,5-dimethylthiophen-3-yl)(4-morpholinophenyl)methanone

Chem.

[0296] Step 3: Synthesis of 4-(4-((4-bromo-2,5-dimethylthiophen-3-yl)methyl)phenyl)morpholine

Chemical formula

[0297] Step 4: Synthesis of 2,5-dimethyl-4-(4-morpholinobenzyl)thiophene-3-carboxylic acid

Chemical formula

[0298] Step 5: Synthesis of Methyl 6-(2,5-dimethyl-4-(4-morpholinobenzyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate

Chemical formula

[0299] Step 6: Synthesis of 6-(2,5-dimethyl-4-(4-morpholinobenzyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

Chemical Structure

[0300] Example 10: 6-(4-([1,1'-Biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of 4-([1,1'-Biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carbonitrile

Chemical Structure

[0301] Step 2: Synthesis of 4-([1,1'-Biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carboxylic acid

Chem.

[0302] Step 3: Synthesis of Methyl 6-(4-([1,1'-Biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate [Chemical formula] To a solution of 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) was added DIPEA (0.04 mL, 0.22 mmol), and the mixture was stirred for 3 hours. The reaction mixture was concentrated, diluted with 1N aqueous NaOH and ethyl acetate, and the aqueous layer was extracted 3 times with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, concentrated, and then purified by silica gel column chromatography (n-hexane and ethyl acetate) to give methyl 6-(4-([1,1'-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (33 mg, yield 55%). 11H 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] +

[0303] Step 4: Synthesis of 6-(4-([1,1'-Biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

Chem.

[0304] Example 11: 6-(4-([1,1'-Biphenyl]-4-yl(hydroxy)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [Chemical formula] To a mixture of the compound of Example 10 (10 mg, 0.02 mmol) and ethanol (0.4 mL, 0.05 M) were added NaBH4 (1.5 mg, 0.04 mmol) and CaCl2 (2.0 mg, 0.02 mmol), and the mixture was stirred for 12 hours. Distilled water and ethyl acetate were added, and then the aqueous layer was extracted with ethyl acetate (10 mL). The organic layer was dried over MgSO4, concentrated, and then purified by silica gel column chromatography (DCM and MeOH) to obtain the compound of Example 11 (4.0 mg, yield 40%). 11H 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 = 3.9 Hz, 1H), 4.00 - 3.89 (m, 1H), 2.90 (dq, J = 32.3, 8.5 Hz, 1H), 2.49 (d, J = 1.9 Hz, 3H), 2.42 (d, J = 2.1 Hz, 3H), 2.37 - 2.15 (m, 4H), 2.14 - 1.94 (m, 3H), 1.74 (dt, J = 20.8, 10.7 Hz, 1H), 1.57 - 1.51 (m, 1H). LC / MS (ESI) m / z: 474.3 [M+H] - .

[0305] Example 12: 6-(4-([1,1'-Biphenyl]-4-yl(methoxy)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of [1,1'-Biphenyl]-4-yl(4-bromo-2,5-dimethylthiophen-3-yl)methanol

Chemical Structure

[0306] Step 2: Synthesis of 3-([1,1'-Biphenyl]-4-yl(methoxy)methyl)-4-bromo-2,5-dimethylthiophene

Chem.

[0307] Step 3: Synthesis of 4-([1,1'-Biphenyl]-4-yl(methoxy)methyl)-2,5-dimethylthiophene-3-carboxylic acid

Chem.

[0308] 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

Chemical formula

[0309] 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

Chemical Structure

[0310] Example 13: 6-(4-([1,1'-Biphenyl]-4-ylmethyl)thiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of 2-([1,1'-Biphenyl]-4-ylmethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Chem.

[0311] A solution of 4-bromomethyl-biphenyl (600 mg, 2.44 mmol), K2CO3 (1.0 g, 7.28 mmol), (pinacolato)diboron (740 mg, 2.92 mmol) and Pd(PPh3)4 (140 mg, 0.12 mmol) in 1,4-dioxane (12 mL) was stirred at 100 °C for 12 h. Ethyl acetate (20 mL) was added, the precipitate was removed by filtration through celite, and then the organic layer was concentrated under reduced pressure. The crude product was purified by flash column chromatography (0 - 100% hexane / EtOAc) to give 2-([1,1'-biphenyl]-4-ylmethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (61 mg, 86% yield) as a white solid. 1 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).

[0312] Step 2: Synthesis of Methyl 4-([1,1'-Biphenyl]-4-ylmethyl)thiophene-3-carboxylate

Chemical formula

[0313] Step 3: Synthesis of 4-([1,1'-Biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid

Chem.

[0314] Step 4: Synthesis of Methyl 6-(4-([1,1'-Biphenyl]-4-ylmethyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate

Chem.

[0315] Step 5: Synthesis of 6-(4-([1,1'-Biphenyl]-4-ylmethyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic Acid

Chemical Structure

[0316] Example 14: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2-methylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of 4-([1,1'-Biphenyl]-4-ylmethyl)thiophene-3-carboxylic Acid

Chemical formula

[0317] Step 2: Synthesis of 4-([1,1'-Biphenyl]-4-ylmethyl)-2-methylthiophene-3-carboxylic Acid

Chemical formula

[0318] Step 3: Synthesis of Methyl 6-(4-([1,1'-Biphenyl]-4-ylmethyl)-2-methylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate

Chemical formula

[0319] Step 4: Synthesis of 6-(4-([1,1'-Biphenyl]-4-ylmethyl)-2-methylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic Acid [Chemical formula] To a solution of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2-methylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (10 mg) in THF / MeOH / H2O (2 / 1 / 2 mL), LiOH·H2O (2 mg, 3.0 equiv) was added and stirred for 3 h. The mixture was partially concentrated and then acidified with 1N aqueous HCl. 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 give the compound of Example 14 (2.3 mg, 24% yield). 11H 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] - .

[0320] Example 15: 6-(4-([1,1'-Biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of 4-([1,1'-Biphenyl]-4-ylmethyl)thiophene-3-carboxylic Acid

Chemical formula

[0321] Step 2: Synthesis of 4-([1,1'-Biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxylic Acid

Chem.

[0322] Step 3: Synthesis of Methyl 6-(4-([1,1'-Biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate

Chem.

[0323] Step 4: Synthesis of 6-(4-([1,1'-Biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic Acid

Chemical Structure

[0324] Example 16: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of Methyl 4-([1,1'-Biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxylate

Chemical Structure

[0325] Step 2: Synthesis of 4-([1,1'-Biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxylic Acid

Chemical Structure

[0326] Step 3: Synthesis of Methyl 6-(4-([1,1'-Biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate

Chem.

[0327] Step 4: Synthesis of 6-(4-([1,1'-Biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic Acid

Chem.

[0328] Example 17: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dichlorothiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of 4-([1,1'-Biphenyl]-4-ylmethyl)-2,5-dichlorothiophene-3-carboxylic acid

Chemical Structure

[0329] 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 [Chemical formula] The compound of Example 17 was obtained by reacting 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dichlorothiophene-3-carboxylic acid obtained in Step 1 above in the same manner as Steps 3 and 4 of Example 16. 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] + .

[0330] Example 18: 6-(3-([1,1'-Biphenyl]-4-ylmethyl)thiophene-2-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of 3-([1,1'-Biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid

Chemical Structure

[0331] Step 2: Synthesis of Methyl 6-(3-([1,1'-Biphenyl]-4-ylmethyl)thiophene-2-carboxamido)spiro[3.3]heptane-2-carboxylate

Chemical Structure

[0332] Step 3: Synthesis of 6-(3-([1,1'-Biphenyl]-4-ylmethyl)thiophene-2-carboxamido)spiro[3.3]heptane-2-carboxylic acid [Chemical Structure] A solution of methyl 6-(3-([1,1'-biphenyl]-4-ylmethyl)thiophene-2-carboxamide)spiro[3.3]heptane-2-carboxylate (32 mg, 0.072 mmol) in THF / MeOH / H2O (1 / 1 / 1) was added with LiOH·H2O (9 mg, 0.209 mmol) and stirred for 12 h. The reaction mixture was partially concentrated, then acidified with 1N aqueous HCl 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] + .

[0333] Example 19: 6-(3-((3'-Fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)thiophene-2-carboxamide)spiro[3.3]heptane-2-carboxylic acid Steps 1 and 2: Synthesis of Methyl 6-(3-(4-chlorobenzyl)thiophene-2-carboxamido)spiro[3.3]heptane-2-carboxylate

Chemical Structure

[0334] 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 [Chemical formula] 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 equiv), Pd(OAc)2 (16 mg, 0.07 mmol, 0.1 equiv), XPhos (67 mg, 0.14 mmol, 0.2 equiv) and K3PO4 (297 mg, 1.4 mmol, 2.0 equiv) were stirred in 1,4-dioxane / H2O (10 / 1 mL) at 100 °C for 2 h under microwave irradiation. The reaction mixture was poured into distilled water and extracted with DCM. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography to give methyl 6-(3-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)thiophene-2-carboxamido)spiro[3.3]heptane-2-carboxylate. 11H 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 = 7.5Hz, 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).

[0335] 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

Chem.

[0336] Example 20: 6-(4-([1,1'-Biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of Methyl 4-([1,1'-Biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxylate

Chem.

[0337] Step 2: Synthesis of Methyl 4-([1,1'-Biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxylate

Chem.

[0338] Step 3: Synthesis of 4-([1,1'-Biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxylic acid

Chemical Structure

[0339] Step 4: Synthesis of Methyl 6-(4-([1,1'-Biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate

Chemical formula

[0340] Step 5: Synthesis of 6-(4-([1,1'-Biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid [Chemical formula] 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), LiOH·H2O (2 mg, 0.044 mmol, 3.0 equiv) was added and stirred for 3 h. The reaction mixture was partially concentrated, then acidified with 1N aqueous HCl, and then 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 to give the compound of Example 20 (4.7 mg, 70% yield) as an off-white solid. 11H 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 [M - H] - .

[0341] The compounds of Examples 21 and 22 were prepared in the same manner as in Example 20, except for the differences in the preparation methods described below.

Table 3

Table 4

[0342] Example 23: 6-(4-(4-Chlorobenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of 3-bromo-4-(4-chlorobenzyl)-2,5-dimethylthiophene

Chemical Structure

[0343] Step 2: Synthesis of 4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxylic acid

Chemical formula

[0344] Step 3: Synthesis of methyl 6-(4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate

Chemical formula

[0345] Step 4: Synthesis of 6-(4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

Chemical Structure

[0346] The compounds of Examples 24 and 25 were prepared in the same manner as in Example 23, except for the difference in the preparation methods described below.

Table 5

Table 6

[0347] Example 26: 6-(2,5-Dimethyl-4-(4-(pyridin-4-yl)benzyl)thiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of methyl 6-(2,5-dimethyl-4-(4-(pyridin-4-yl)benzyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate

Chem.

[0348] Step 2: Synthesis of 6-(2,5-dimethyl-4-(4-(pyridin-4-yl)benzyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

Chem.

[0349] Example 27: 6-(2,5-Dimethyl-4-(4-(pyridin-3-yl)benzyl)thiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid

Chem.

[0350] Example 28: 6-(4-((3’,4’-Dimethyl-[1,1’-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid 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

Chemical formula

[0351] 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 [Chemical formula] To a solution of methyl 6-(4-((3’,4’-dimethyl-[1,1’-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate (20 mg) in THF / MeOH / H2O (2 / 1 / 2), LiOH·H2O (4 mg, 0.084 mmol, 3.0 equiv) was added and stirred for 3 h. The reaction mixture was partially concentrated, then acidified with 1N aqueous HCl, and 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 preparative TLC to give the compound of Example 28 (3.4 mg, 30% yield). 11H 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] + .

[0352] The compounds of Examples 29 to 66 were prepared by the same method as in Example 28, except for the differences in the preparation methods described below. [Table 7] JPEG0007698708000202.jpg226149 JPEG0007698708000203.jpg226149 TIFF0007698708000204.tif60149 [Table 8] TIFF0007698708000206.tif52149 JPEG0007698708000207.jpg226149 TIFF0007698708000208.tif44149 JPEG0007698708000209.jpg226149

Table 9

Table 10

Table 11

Table 12

[0353] Example 67: 6-(4-(4-Cyclohexylbenzyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid 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 [Chemical formula] A solution of methyl 6-(4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxamide)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) in 1,4-dioxane (1 mL) was placed in a sealed tube, 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 a 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, then dried over MgSO4, filtered, and concentrated. The crude product was purified by silica gel column chromatography (30% EtOAc in hexane) to give methyl 6-(2,5-dimethyl-4-((2’,3’,4’,5’-tetrahydro-[1,1’-biphenyl]-4-yl)methyl)thiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate (59 mg, mixture). 11H 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).

[0354] Step 2: Synthesis of methyl 6-(4-(4-cyclohexylbenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate [Chemical formula] To a solution of methyl 6-(2,5-dimethyl-4-((2’,3’,4’,5’-tetrahydro-[1,1’-biphenyl]-4-yl)methyl)thiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate (20 mg, 0.042 mmol) in ethyl acetate / methanol (8 / 2, 0.2 mL) was added 10% Pd / C (2.2 mg). The reaction mixture was stirred under hydrogen gas for 24 h and filtered through celite using ethyl acetate to give methyl 6-(4-(4-cyclohexylbenzyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate (12 mg). 11H NMR (400 MHz, chloroform-d) δ 7.16 - 7.10 (m, 2H), 7.02 (s, 2H), 5.32 (d, J = 7.9 Hz, 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).

[0355] Step 3: Synthesis of 6-(4-(4-cyclohexylbenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid [Chemical formula] 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), LiOH·H2O (3 mg, 0.075 mmol, 3.0 equiv) was added and stirred for 3 h. The reaction mixture was partially concentrated, then acidified with 1N aqueous HCl, and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgSO4 and then concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give the compound of Example 67 (3.7 mg, 32% yield). 11H 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] - .

[0356] Example 68: 6-(2,5-Dimethyl-4-(4-(piperidin-4-yl)benzyl)-thiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Steps 1-3: Synthesis of 6-(4-(4-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

Chemical Structure

[0357] Step 4: Synthesis of 6-(2,5-dimethyl-4-(4-(piperidin-4-yl)benzyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid [Chemical formula] A solution of 6-(4-(4-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid (14 mg, 0.024 mmol) and 4N 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 salt of the compound of Example 68 (4 mg, 33%) as an off-white solid. 11H 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 [M - H] - .

[0358] Example 69: 6-(4-((4’-Fluoro-[1,1’-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid

Chem.

[0359] Example 70: 6-(4-((3’-Cyano-5’-fluoro-[1,1’-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid

Chem.

[0360] Example 71: 6-(4-((3’-Fluoro-5’-hydroxy-[1,1’-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of methyl 6-(4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate [Chemical Structure] Methyl 6-(4-((3’-fluoro-5’-methoxy-[1,1’-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)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. 11H 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).

[0361] Step 2: Synthesis of 6-(4-((3'-fluoro-5'-hydroxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid

Chem.

[0362] Example 72: 6-(4-(4-(2-Hydroxypyridin-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Steps 1 and 2: Synthesis of methyl 6-(4-(4-(2-hydroxypyridin-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate

Chem.

[0363] Step 3: Synthesis of 6-(4-(4-(2-hydroxypyridin-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid

Chem.

[0364] Example 73: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-N,2,5-trimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of 3-([1,1'-biphenyl]-4-ylmethyl)-4-bromo-2,5-dimethylthiophene

Chemical Structure

[0365] Step 2: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxylic acid

Chemical formula

[0366] Step 3: Synthesis of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-N,2,5-trimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate [Chem.] 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), DIPEA (84 μL, 0.48 mmol) was added and stirred for 10 minutes. 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 over Na2SO4, concentrated under reduced pressure, and then purified by column chromatography (20% EtOAc in hexane) to give methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-N,2,5-trimethylthiophene-3-carboxamide) spiro[3.3]heptane-2-carboxylate (47 mg, 59% yield) as a white solid.

[0367] Step 4: Synthesis of 6-(4-([1,1'-biphenyl]-4-ylmethyl)-N,2,5-trimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [Chem.] To a stirred solution of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-N,2,5-trimethylthiophene-3-carboxamide) spiro[3.3]heptane-2-carboxylate (47 mg, 0.1 mmol) in H2O:THF:MeOH (0.1 M), LiOH·H2O (12 mg, 0.3 mmol) was added and stirred for 4 hours. The reaction mixture was partially concentrated under reduced pressure, acidified with 2N aqueous HCl (pH ca. 6), and extracted with ethyl acetate (2 × 30 mL). The organic layer was dried over Na2SO4, concentrated under reduced pressure, and then purified by column chromatography (70% EtOAc in hexane) to give the compound of Example 73 (36 mg, 79% yield) as a white solid. LC / MS (ESI) m / z: 474.25 [M+H] + .

[0368] Example 74: 6-(4-([1,1'-Biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of methyl 4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxylate

Chem.

[0369] Step 2: Synthesis of 4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxylic acid

Chem.

[0370] Step 3: Synthesis of methyl 6-(4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate

Chem.

[0371] Step 4: Synthesis of 6-(4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [Chemical Structure] 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) in THF / MeOH / H2O (1:1:1), LiOH·H2O (13 mg, 0.3 mmol, 3.0 eq) was added and stirred for 12 hours. The reaction mixture was partially concentrated, then acidified with 1N HCl 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 give the compound of Example 74 (22 mg, yield 47%). 11H 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] + .

[0372] Example 75: 6-(4-([1,1'-Biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of methyl 4-amino-2,5-dimethylthiophene-3-carboxylate

Chem.

[0373] Step 2: Synthesis of methyl 4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxylate

Chem.

[0374] Step 3: Synthesis of 4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxylic acid

Chem.

[0375] Step 4: Synthesis of methyl 6-(4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate

Chem.

[0376] Step 5: Synthesis of 6-(4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

Chemical formula

[0377] Example 76: 6-(4-([1,1'-Biphenyl]-4-yl(methyl)amino)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid 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 [Chemical Structure] To a solution of methyl 6-(4-([1,1'-biphenyl]-4-yl(methyl)amino)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate (120 mg, 0.25 mmol, 1.0 equiv) and K2CO3 (104 mg, 0.75 mmol, 3.0 equiv) in DMF (3 mL) was added iodomethane (80 μL, 1.25 mmol, 5.0 equiv), 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 over MgSO4 and then concentrated under reduced pressure. The crude product was purified by flash column chromatography to give methyl 6-(4-([1,1'-biphenyl]-4-yl(methyl)amino)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate (18 mg). 11H 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).

[0378] 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

Chem.

[0379] Example 77: 6-(2,5-Dimethyl-4-((4-phenylpiperazin-1-yl)methyl)thiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of 4-bromo-2,5-dimethylthiophene-3-carboxylic acid

Chemical Structure

[0380] Step 2: Synthesis of (4-bromo-2,5-dimethylthiophen-3-yl)(4-phenylpiperazin-1-yl)methanone

Chem.

[0381] Step 3: Synthesis of 1-((4-bromo-2,5-dimethylthiophen-3-yl)methyl)-5-phenylpiperazine

Chem.

[0382] Step 4: Synthesis of 2,5-dimethyl-4-((4-phenylpiperazin-1-yl)methyl)thiophene-3-carboxylic acid

Chemical formula

[0383] Step 5: Synthesis of methyl 6-(2,5-dimethyl-4-((4-phenylpiperazin-1-yl)methyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate

Chemical formula

[0384] Step 6: Synthesis of 6-(2,5-dimethyl-4-((4-phenylpiperazin-1-yl)methyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

Chemical Structure

[0385] Example 78: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-N,2,5-trimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of methyl 6-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate

Chemical Structure

[0386] Step 2: Synthesis of Methyl 6-(4-(Hydroxymethyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate

Chemical Structure

[0387] Step 3: Synthesis of Methyl 6-(4-(Bromomethyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate [Chemical Structure] To a stirred solution of methyl 6-(4-hydroxymethyl)-2,5-dimethylthiophene-3-carboxamide) spiro[3.3]heptane-2-carboxylate (82 mg, 0.24 mmol) in DCM (0.1 M) was added PBr3 (92 μL, 2.03 mmol) at 0 °C and the mixture was stirred for 15 h. The reaction mixture was diluted with ethyl acetate and washed with bicarbonate solution and distilled water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure and purified by column chromatography (25% EtOAc in hexane) to give methyl 6-(4-(bromomethyl)-2,5-dimethylthiophene-3-carboxamide) spiro[3.3]heptane-2-carboxylate (49 mg, 50% yield) as a white solid. 1 H 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).

[0388] Step 4: Synthesis of Methyl 6-(2,5-Dimethyl-4-((4-phenyl-1H-pyrazol-1-yl)methyl)thiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate

Chem.

[0389] Step 5: Synthesis of 6-(2,5-Dimethyl-4-((4-phenyl-1H-pyrazol-1-yl)methyl)thiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic Acid [Chemical formula] To a solution of methyl 6-(2,5-dimethyl-4-((4-phenyl-1H-pyrazol-1-yl)methyl)thiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate (16 mg, 0.03 mmol) in H2O:THF:MeOH (1:1:1, 0.1 M) was added LiOH·H2O (3 mg, 0.1 mmol), and the mixture was stirred for 15 hours. The reaction mixture was partially concentrated, acidified with 1N HCl solution (pH about 4), and extracted with ethyl acetate (2 × 10 mL). The organic layer was dried over Na2SO4, filtered, concentrated under reduced pressure, and then purified by column chromatography (5% MeOH in DCM) to give the compound of Example 78 (5 mg, yield 32%) as a white solid. 11H 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] + .

[0390] Example 79: 6-(4-([1,1'-Biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of Methyl 4-([1,1'-Biphenyl]-4-ylmethyl)-3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylate

Chemical Structure

[0391] Step 2: Synthesis of 4-([1,1'-Biphenyl]-4-ylmethyl)-3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic Acid

Chem.

[0392] Step 3: Synthesis of 4-([1,1'-Biphenyl]-4-ylmethyl)-3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole

Chem.

[0393] Step 4: Synthesis of 4-([1,1'-Biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic Acid

Chemical Structure

[0394] Step 5: Synthesis of Methyl 6-(4-([1,1'-Biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxamide)spiro[3.3]heptane-2-carboxylate

Chemical Structure

[0395] Step 6: Synthesis of 6-(4-([1,1'-Biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxamide)spiro[3.3]heptane-2-carboxylic Acid

Chemical Structure

[0396] The compounds of Examples 80-89 were prepared in the same manner as in Example 79, except for the differences in the preparation methods described below.

Table 13

Table 14

[0397] Example 90: 6-(4-(4-(Trifluoromethyl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Steps 1 - 3: Synthesis of 3-Bromo-4-(4-(Trifluoromethyl)benzyl)-4H-thieno[3,2-b]pyrrole

Chemical formula

[0398] Step 4: Synthesis of 4-(4-(Trifluoromethyl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic Acid

Chemical formula

[0399] Steps 5 and 6: Synthesis of 6-(4-(4-(Trifluoromethyl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxamide)spiro[3.3]heptane-2-carboxylic Acid

Chemical Structure

[0400] The compounds of Examples 91 to 94 were prepared in the same manner as in Example 90, except for the differences in the preparation methods described below.

Table 15

Table 16

[0401] 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 Steps 1 - 3: Synthesis of 3 - bromo - 4 - ((3’ - fluoro - 5’ - methoxy - [1,1’ - biphenyl] - 4 - yl)methyl) - 2 - methyl - 4H - thieno[3,2 - b]pyrrole

Chemical formula

[0402] 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

Chem.

[0403] 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

Chem.

[0404] 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

Chem.

[0405] Example 96: 6-(2-Methyl-4-(3-phenylprop-2-yn-1-yl)-4H-thieno[3,2-b]pyrrole-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of 3 - bromo - 2 - methyl - 4H - thieno[3,2 - b]pyrrole - 5 - carboxylic acid

Chem.

[0406] Step 2: Synthesis of 3 - bromo - 2 - methyl - 4H - thieno[3,2 - b]pyrrole

Chemical Structure

[0407] Step 3: Synthesis of 3 - bromo - 2 - methyl - 4 - (3 - phenylprop - 2 - yn - 1 - yl) - 4H - thieno[3,2 - b]pyrrole

Chem.

[0408] Steps 4 - 7: Synthesis of 6 - (2 - methyl - 4 - (3 - phenylprop - 2 - yn - 1 - yl) - 4H - thieno[3,2 - b]pyrrole - 3 - carboxamido)spiro[3.3]heptane - 2 - carboxylic acid

Chem.

[0409] The compounds of Examples 97 and 98 were prepared by the same method as in Example 96, except for the differences in the preparation methods described below.

Table 17

Table 18

[0410] Example 99: 6-(4-(4-(Pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of methyl 3 - bromo - 4 - (4 - (pyridin - 3 - yl)benzyl) - 4H - thieno[3,2 - b]pyrrole - 5 - carboxylate

Chemical Structure

[0411] Step 2: Synthesis of 3 - bromo - 4 - (4 - (pyridin - 3 - yl)benzyl) - 4H - thieno[3,2 - b]pyrrole - 5 - carboxylic acid

Chemical Structure

[0412] Step 3: Synthesis of 3 - bromo - 4 - (4 - (pyridin - 3 - yl)benzyl) - 4H - thieno[3,2 - b]pyrrole

Chemical formula

[0413] Step 4: Synthesis of 4 - (4 - (pyridin - 3 - yl)benzyl) - 4H - thieno[3,2 - b]pyrrole - 3 - carboxylic acid [Chemistry] Pd(OAc)2 (3 mol%) and xanthphos (3 mol%) were added to an oven-dried tube under an N2 atmosphere, and the tube was refilled with argon three times. A solution of formic acid (0.4 mL, 10.5966 mmol) and 3-bromo-4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole (559 mg, 1.5138 mmol) in DMF (3.0 mL) was added. DCC (62 mg, 0.3028 mmol) and Et3N (0.42 mL, 3.0276 mmol) were added, then the tube was sealed and the mixture was stirred at 100 °C for 20 h. The reaction mixture was filtered, concentrated under reduced pressure, and then the crude product was purified by silica gel column chromatography to obtain 4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid (crude product).

[0414] Step 5: Synthesis of methyl 6 - (4 - (4 - (pyridin - 3 - yl)benzyl) - 4H - thieno[3,2 - b]pyrrole - 3 - carboxamido)spiro[3.3]heptane - 2 - carboxylate [Chemistry] To a solution of 4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid (512 mg) and HATU (582 mg, 1.531 mmol) in DMF (4 mL), DIPEA (0.8 mL, 4.593 mmol) was added and stirred for 10 min, then intermediate A (315 mg, 1.531 mmol) was added and stirred for 12 h. The reaction mixture was diluted with ethyl acetate and washed with distilled water and brine. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and then the crude product was purified by column chromatography to obtain methyl 6-(4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxamido)spiro[3.3]heptane-2-carboxylate (147 mg, yield 16%). 11H NMR (300 MHz, chloroform-d) δ 8.87 (d, J = 2.1 Hz, 1H), 8.64 (d, J = 5.5 Hz, 1H), 8.46 (d, J = 8.1 Hz, 1H), 7.90 (dd, J = 8.1, 5.5 Hz, 1H), 7.48 (d, J = 8.2 Hz, 2H), 7.36 - 7.32 (m, 1H), 7.27 (s, 1H), 7.24 (s, 1H), 6.98 (dd, J = 3.0, 1.3 Hz, 1H), 6.47 (d, J = 3.0 Hz, 1H), 6.06 (d, J = 7.7 Hz, 1H), 5.71 (d, J = 5.9 Hz, 2H), 4.37 - 4.29 (m, 1H), 3.66 (s, 3H), 3.07 - 2.95 (m, 1H), 2.62 - 2.47 (m, 1H), 2.47 - 2.22 (m, 4H), 2.19 - 2.07 (m, 1H), 1.92 - 1.75 (m, 2H).

[0415] Step 6: Synthesis of 6-(4-(4-(Pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [Chemical Structure] To a solution of methyl 6-(4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxamide)spiro[3.3]heptane-2-carboxylate (147 mg, 0.3027 mmol) in THF / MeOH / H2O (1 / 1 / 1) was added LiOH·H2O (38 mg, 0.9081 mmol), and the mixture was stirred for 12 h. The reaction mixture was partially concentrated, then acidified with 1N HCl solution, and the aqueous layer was extracted with EtOAc. The organic layer was dried over MgSO4 and then concentrated under reduced pressure to give the compound of Example 99 (92 mg, 64% yield). 11H NMR (300 MHz, DMSO-d6) δ 12.04 (s, 1H), 8.83 (s, 1H), 8.54 (d, J = 4.6 Hz, 1H), 8.48 (d, J = 7.5 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.63 - 7.59 (m, 2H), 7.58 (d, J = 1.3 Hz, 1H), 7.46 (t, J = 6.3 Hz, 1H), 7.31 (dd, J = 3.0, 1.3 Hz, 1H), 7.16 (d, J = 8.2 Hz, 2H), 6.45 (d, J = 3.0 Hz, 1H), 5.63 (s, 2H), 4.24 - 4.16 (m, 1H), 2.99 - 2.85 (m, 1H), 2.43 - 2.35 (m, 1H), 2.32 - 1.85 (m, 7H). LC / MS (ESI) m / z: 472.4 [M+H] + .

[0416] The compounds of Examples 100 to 113 were prepared in the same manner as Example 99, except for the differences in the preparation methods described below. [Table 19] TIFF0007698708000299.tif221149 TIFF0007698708000300.tif211149 TIFF0007698708000301.tif68149 [Table 20] TIFF0007698708000303.tif35149 JPEG0007698708000304.jpg226149 TIFF0007698708000305.tif85149 TIFF0007698708000306.tif168149

[0417] [Preparation of Isomers] Example 1a and 1b: (2S,4S,6S)-6-(4-([1,1'-Biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxamide) spiro[3.3]heptane-2-carboxylic acid (1a) and (2R,4R,6R)-6-(4-([1,1'-Biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxamide) spiro[3.3]heptane-2-carboxylic acid (1b) [Chemical Structure] The compound of Example 1 (106 g, 231 mmol, 1.00 equivalent) was purified by supercritical fluid chromatography (SFC) under the following conditions to isolate Example 1a (66.06 g, 143 mmol, yield 61.9%, purity 99.3%) and Example 1b (16.02 g, 34.4 mmol, yield 14.9%, purity 98.6%) as white solids, respectively. Column: DAICEL CHIRALCEL OJ column (250 mm×50 mm, 10 μm) Mobile phase: [Neu-MeOH]; B%: 30% - 30%, 4.6; 1860 minutes. Example 1a: 1 H NMR (400 MHz, DMSO) δ 12.00 (br s, 1H), 8.26 (br d, J = 7.60 Hz, 1H), 7.60 (br d, J = 7.20 Hz, 2H), 7.51 (d, J = 8.40 Hz, 2H), 7.45 (t, J = 7.60 Hz, 2H), 7.37 - 7.31 (m, 1H), 7.18 (d, J = 8.00 Hz, 2H), 4.22 - 4.11 (m, 1H), 3.90 (s, 2H), 2.91 (m, 1H), 2.38 (br s, 1H), 2.33 (br d, J = 7.60 Hz, 6H), 2.29 - 2.14 (m, 3H), 2.12 - 1.98 (m, 2H), 1.94 - 1.80 (m, 2H). LC / MS (ESI) m / z = 460.2 [M+H] + . Example 1b:1 HNMR (400 MHz, DMSO) δ 11.99 (br s, 1H), 8.26 (d, J = 7.60 Hz, 1H), 7.65 - 7.57 (m, 2H), 7.51 (d, J = 8.00 Hz, 2H), 7.45 (t, J = 7.60 Hz, 2H), 7.37 - 7.31 (m, 1H), 7.19 (d, J = 8.00 Hz, 2H), 4.16 (m, 1H), 3.90 (s, 2H), 2.91 (m, 1H), 2.40 - 2.35 (m, 1H), 2.33 (d, J = 7.20 Hz, 6H), 2.29 - 2.14 (m, 3H), 2.12 - 1.99 (m, 2H), 1.93 - 1.80 (m, 2H). LC / MS (ESI) m / z = 460.2 [M+H] + .

[0418] Example 34a and 34b: (2S,4S,6S)-6-(4-((3’-Fluoro-5’-methoxy-[1,1’-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (34a) and (2R,4R,6R)-6-(4-((3’-Fluoro-5’-methoxy-[1,1’-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (34b) Step 1: Separation of Methyl (2S,4S,6S)-6-(4-((3’-Fluoro-5’-methoxy-[1,1’-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate (34a’) and Methyl (2R,4R,6R)-6-(4-((3’-Fluoro-5’-methoxy-[1,1’-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate (34b’)

Chem.

[0419] Step 2a: Preparation of (2S,4S,6S)-6-(4-((3’-Fluoro-5’-methoxy-[1,1’-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid (34a)

Chem.

[0420] Step 2b: Preparation of (2R,4R,6R)-6-(4-((3’-Fluoro-5’-methoxy-[1,1’-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid (34b)

Chem.

[0421] Examples 79a and 79b: (2S,4S,6S)-6-(4-([1,1'-Biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid (79a) and (2R,4R,6R)-6-(4-([1,1'-Biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid (79b)

Chemical formula

[0422] Examples 80a and 80b: (2S,4S,6S)-6-(4-([1,1'-Biphenyl]-4-ylmethyl)-2-methyl-4H-thieno[3,2-b]pyrrole-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid (80a) and (2R,4R,6R)-6-(4-([1,1'-Biphenyl]-4-ylmethyl)-2-methyl-4H-thieno[3,2-b]pyrrole-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid (80b) [Chemical formula] The compound of Example 80 (80.0 g, 165 mmol, 1.00 equivalent) was purified by supercritical fluid chromatography (SFC) under the following conditions to separate the compound of Example 80a (30.0 g, 61.9 mmol, yield 37.5%) and the compound of Example 80b (10.0 g, 20.6 mmol, yield 12.5%) as a white solid and an off-white solid, respectively. Column: DAICEL CHIRALPAK AD column (250 mm × 50 mm, 10um) Mobile phase: [Neu-ETOH]; B%: 40% - 40%, 14.2; 870 minutes Example 80a: 1 H NMR (400 MHz, DMSO) δ 11.74 - 12.27 (m, 1H) 8.43 (d, J = 7.58 Hz, 1H) 7.60 (d, J = 7.58 Hz, 2H) 7.54 (d, J = 8.19 Hz, 2H) 7.45 (t, J = 7.64 Hz, 2H) 7.32 - 7.38 (m, 1H) 7.20 (d, J = 2.81 Hz, 1H) 7.16 (d, J = 8.19 Hz, 2H) 6.36 (d, J = 2.81 Hz, 1H) 5.35 (s, 2H) 4.18 - 4.29 (m, 1H) 2.86 - 2.95 (m, 1H) 2.43 (s, 3H) 2.33 - 2.40 (m, 1H) 2.16 - 2.31 (m, 3H) 1.96 - 2.11 (m, 2H) 1.79 - 1.93 (m, 2H). LC / MS (ESI) m / z = 485.1 [M+H]+ . Example 80b: 1 H NMR (400 MHz, DMSO) δ 11.44 - 12.66 (m, 1H) 8.42 (d, J = 7.58 Hz, 1H) 7.60 (d, J = 7.46 Hz, 2H) 7.54 (d, J = 8.19 Hz, 2H) 7.45 (t, J = 7.64 Hz, 2H) 7.32 - 7.37 (m, 1H) 7.20 (d, J = 2.81 Hz, 1H) 7.13 (d, J = 8.19 Hz, 2H) 6.35 (d, J = 2.93 Hz, 1H) 5.35 (s, 2H) 4.19 - 4.29 (m, 1H) 2.90 (quintet, J = 8.47 Hz, 1H) 2.43 (s, 3H) 2.34 - 2.39 (m, 1H) 2.17 - 2.28 (m, 3H) 1.96 - 2.10 (m, 2H) 1.79 - 1.91 (m, 2H). LC / MS (ESI) m / z = 485.1 [M+H] + .

[0423] [Experimental Example: Evaluation of Inhibitory Activity against EP2 and / or EP4] 1. cAMP Assay for hEP2 HEK293 cells overexpressing hEP2 were cultured in growth medium (GM: MEM (Gibco (trademark), 11095080) / 10% HI FBS (Gibco (trademark), 10082147) / 1% penicillin / streptomycin). Before the experiment, the growth medium was removed and starvation medium (HBSS (Gibco (trademark), 14025076) / 10% GM) was added. Then, the cells were incubated for 4 hours. HEK293 cells with hEP2 were detached from the culture dish with non - enzymatic cell dissociation buffer (Gibco (trademark), 15040066). The cells were resuspended in assay buffer (AB: HBSS, 0.1% BSA stabilizer, 0.5 mM IBMX, 5 mM HEPES). 1,000 cells in 5 μL of AB were seeded per well of a 384-well plate (Corning® 3570). A stock solution of the test compound was prepared in DMSO at a concentration of 1 mM and serially diluted with DMSO to the concentrations required for the inhibition dose-response curve (test concentration range of 10 μM to 0.001 nM). PGE2 (Sigma, P0409, stock solution: 1 μM) was used as an agonist at a final concentration of 400 pM corresponding to EC 50~80 2.5 μL of the diluted compound and 2.5 μL of PGE2 (final concentration 400 pM) were transferred to the assay plate, and then the plate was incubated at room temperature for 12 minutes. 5 μL each of donor (Eu-cAMP tracer) and acceptor (ULight anti-cAMP) were added, and the plate was incubated at room temperature for 1 hour in the dark, and then results were obtained using a Varioskan LUX multimode microplate reader (excitation: 334 nm, emission: 615 and 665 nm). The obtained FRET fluorescence values (665 nm / 615 nm * 10000) were converted and then calculated as the percentage of cAMP relative to the DMSO control value. IC 50 values and curves were generated using GraphPad Prism software using the logarithm (inhibitor) versus the response variable slope (4-parameter), and the median value from multiple experiments was used as the experimental result.

[0424] 2. cAMP assay for hEP4 HEK293 cells overexpressing hEP4 were cultured in growth medium (GM: MEM (Gibco®, 11095080) / 10% HI FBS (Gibco®, 10082147) / 1% penicillin / streptomycin). Prior to the experiment, the growth medium was removed and starvation medium (HBSS (Gibco®, 14025076) / 10% GM) was added. The cells were then incubated for 4 hours. HEK293 cells with hEP4 were detached from the culture dish with non-enzymatic cell dissociation buffer (Gibco®, 15040066). The cells were resuspended in assay buffer (AB: HBSS, 0.1% BSA stabilizer, 0.5 mM IBMX, 5 mM HEPES). 1,000 cells in 5 μL of AB were seeded into each well of a 384-well plate (Corning® 3570). A stock solution of the test compound was prepared at a concentration of 1 mM in DMSO and serially diluted with DMSO to the concentrations required for the inhibition dose-response curve (test concentration range of 10 μM to 0.001 nM). PGE2 (Sigma, P0409, stock solution: 100 μM) was used as an agonist at a final concentration of 20 nM corresponding to EC 50~80 2.5 μL of the diluted compound and 2.5 μL of PGE2 (final concentration 20 nM) were transferred to the assay plate, and then the plate was incubated at room temperature for 18.5 minutes. 5 μL each of donor (Eu-cAMP tracer) and acceptor (ULight anti-cAMP) were added, and the plate was incubated at room temperature for 1 hour in the dark. Then, results were obtained using a Varioskan LUX multimode microplate reader (excitation: 334 nm, emission: 615 and 665 nm). The obtained FRET fluorescence values (665 nm / 615 nm * 10000) were converted and then calculated as the percentage of cAMP compared to the DMSO control value. IC 50 values and curves were generated using GraphPad Prism software using the logarithm (inhibitor) vs. the response variable slope (4-parameter), and the median value from multiple experiments was taken as the experimental result.

[0425] 3. Experimental Results The inhibitory activities of the compounds of Examples 1 to 113 against EP2 and EP4 measured by the above experimental method were evaluated based on the criteria in Table 21 below, and the results are shown in Tables 22 to 25.

Table 21

Table 22

Table 23

Table 24

Table 25

Claims

1. A compound of formula I, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof. 【Chemical 1】 [Wherein, One of X and Y is S, and the other is CR １ and 【Chemical 2】 is a single bond or a double bond, two of which are double bonds; R １ and R ２ are selected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, C １ to C ６ alkyl, C １ to C ６ alkoxy, -NH-(C １ to C ６ alkyl), -N(C １ to C ６ alkyl) ２ , C ３ to C ８ cycloalkyl and C ６ to C １０ aryl, wherein said C １ to C ６ alkyl and C １ to C ６ alkoxy may each independently be optionally substituted with one or more halogen, hydroxy, cyano or amino, and said C ３ to C ８ cycloalkyl and C ６ to C １０ aryl may each independently be optionally substituted with one or more halogen, hydroxy, cyano, amino, oxo, C １ to C ６ alkyl, C １ to C ６ haloalkyl, C １ to C ６ alkoxy or C １ to C ６ haloalkoxy; R ３ is 【Chemical Formula 3】 is; or R １ is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, C １ to C ６ alkyl, C １ to C ６ alkoxy, -NH-(C １ to C ６ alkyl), -N(C １ to C ６ alkyl) ２ ; C ３ to C ８ cycloalkyl and C ６ to C １０ aryl, and the C １ to C ６ alkyl and C １ to C ６ alkoxy may each independently be optionally substituted with one or more halogen, hydroxy, cyano or amino, and the C ３ to C ８ cycloalkyl and C ６ to C １０ aryl may each independently be optionally substituted with one or more halogen, hydroxy, cyano, amino, oxo, C １ to C ６ alkyl, C １ to C ６ haloalkyl, C １ to C ６ alkoxy or C １ to C ６ haloalkoxy; R ２ and R ３ are, together with the carbon atom to which R ２ and R ３ is attached, 【Chemical Formula 4】 is, 【Chemical Formula 5】 is, [Chemical Formula 6] is attached to the nitrogen atom of, 【Chemical Formula 7】 One or both of the carbon atoms are halogen, hydroxy, cyano, C １ to C ６ alkyl, C １ to C ６ alkoxy, C １ to C ６ haloalkyl or C １ to C ６ optionally substituted with haloalkoxy; W is -(CH ２ ), -(CH ｏ ), -(CH ２ ), C(O)-, -O-, -S-, -NH- or -N(C １ -C ６ alkyl)-, and the H of the CH ２ may be optionally substituted with one or more halogen, hydroxy, cyano, C １ -C ６ alkyl, C １ -C ６ alkoxy, C １ -C ６ haloalkyl or C １ -C ６ haloalkoxy; Cy is C ６ to C １４ aryl, 4- to 14-membered heteroaryl, 4- to 14-membered heterocycloalkyl, C ３ to C ８ cycloalkyl and C ３ to C ８ selected from the group consisting of cycloalkenyl, and may be optionally substituted with one or more R'; R ａ is -V-Cy ２ and V is non-existent or is -NH-, -NHCH ２ -, -NHCH ３ -, -CONH-, -NHCO-, -NHSO ２ -, -S-, -SO ２ -, -CH ２ -, -OCH ２ - or -O-; Cy ２ is selected from the group consisting of C ６ to C １４ aryl, 4- to 14-membered heteroaryl, 4- to 14-membered heterocycloalkyl, C ３ to C ８ cycloalkyl and C ３ to C ８ cycloalkenyl, and may be optionally substituted with one or more R″; R' is each independently halogen, hydroxy, cyano, amino, oxo, C １ -C ６ alkyl, C １ -C ６ alkoxy, -NH-(C １ -C ６ alkyl) and -N(C １ -C ６ alkyl) ２ ２ selected from the group consisting of, said C １ -C ６ alkyl and C １ -C ６ alkoxy may be optionally substituted with one or more halogen, hydroxy, cyano or amino; "R” is halogen, hydroxy, cyano, amino, oxo, C １ ~C ６ alkyl, C １ ~C ６ alkoxy, -S-(C １ ~C ６ alkyl), -SO ２ -(C １ ~C ６ alkyl), -CO-(C １ ~C ６ alkyl), -C(O)H, -COO-(C １ ~C ６ alkyl), -COOH, -CONH ２ , -CONH-(C １ ~C ６ alkyl), -CON(C １ ~C ６ alkyl) ２ , -(CH ２ ) ｐ -NH ２ , -(CH ２ ) ｐ -NH-(C １ ~C ６ alkyl), -(CH ２ ) ｐ -N(C １ ~C ６ alkyl) ２ , -(CH ２ ) ｐ -NH-CO-(C １ ~C ６ alkyl), -(CH ２ ) ｐ -NH-COO-(C １ ~C ６ alkyl), -(CH ２ ) ｐ -OH, 3- to 7-membered heterocycloalkyl, C ３ ~C ８ cycloalkyl and -(CH ２ ) ｐ -(C ３ ~C ８ cycloalkyl) selected from the group consisting of, said C １ ~C ６ alkyl and C １ ~C ６ The alkoxy may be optionally substituted with one or more halogens, hydroxy, cyano or amino, and the 3- to 7-membered heterocycloalkyl and C ３ -C ８ The cycloalkyl may be optionally substituted with one or more halogens, hydroxy, cyano, oxo or amino; R ４ is hydrogen or C １ to C ６ alkyl; R ５ , R ６ and R ７ are each defined as follows: (i) R ５ and R ６ are H, and R ７ is absent, or (ii) R ５ and R ６ are represented together as -(CH ２ ) ｑ -, and R ７ is absent or (iii) R ５ is H, and R ６ and R ７ are taken together to represent —(CH ２ ) ｒ —. has; P is non-existent or -CH ２ -, provided that when R ７ is non-existent, P is also non-existent; R ８ is 【Chemical Formula 8】 and Z is -(CH ２ ) ｓ and R ８’ is hydrogen, hydroxy, C １ -C ６ alkyl or C １ -C ６ alkoxy; l, m, and n are each independently an integer from 0 to 2, at least one of m and n is not 0, and when P and R ７ do not exist, l is 0; o and p are each independently an integer from 0 to 3; q and r are each independently an integer of 1 or 2; s is an integer from 0 to 3. ]

2. R １ is hydrogen, halogen, hydroxy, cyano, amino, C １ to C ３ alkyl, C １ to C ３ alkoxy, -NH-(C １ to C ３ alkyl) or -N(C １ to C ３ alkyl); ２ wherein said C １ to C ３ alkyl and C １ to C ３ alkoxy may each independently be optionally substituted with one or more halogen, hydroxy, cyano or amino; R ２ is hydrogen, halogen, hydroxy, C １ -C ３ alkyl, C １ -C ３ alkoxy, C １ -C ３ haloalkyl, C １ -C ３ haloalkoxy, C ３ -C ６ cycloalkyl or phenyl, wherein said C １ -C ３ alkyl and C １ -C ３ alkoxy may each independently be optionally substituted with one or more halogens, hydroxy, cyano or amino, a compound of formula I according to claim 1, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof.

3. Cy is C ６ ~C １０ selected from the group consisting of 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from C, N, O and S, and 4- to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, and may be optionally substituted with one or more R'; Cy ２ is C ６ -C １０ aryl, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, 4- to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, C ３ -C ８ cycloalkyl, and C ３ -C ８ cycloalkenyl, and is optionally substituted with one or more R″; R' is halogen, hydroxy, cyano, amino, oxo, C １ -C ３ -C alkyl, C １ -C ３ -C haloalkyl, C １ -C ３ -C alkoxy, C １ -C ３ -C haloalkoxy, -NH-(C １ -C ３ -C alkyl) or -N(C １ -C ３ -C alkyl) ２ and; "R” is halogen, hydroxy, cyano, amino, oxo, C １ -C ６ alkyl, C １ -C ６ alkoxy, -S-(C １ -C ６ alkyl), -SO ２ -(C １ -C ６ alkyl), -COO-(C １ -C ６ alkyl), -COOH, -CONH ２ , -(CH ２ ) ｐ -NH ２ , -(CH ２ ) ｐ -NH-(C １ -C ６ alkyl), -(CH ２ ) ｐ -N(C １ -C ６ alkyl) ２ , -(CH ２ ) ｐ -NH-COO-(C １ -C ６ alkyl), -(CH ２ ) ｐ -OH, a 3- to 5-membered heterocycloalkyl containing one heteroatom selected from N, O and S, C ３ -C ５ cycloalkyl, and -(CH ２ ) ｐ -(C ３ -C ５ cycloalkyl) selected from the group consisting of, wherein the C １ -C ６ alkyl and C １ -C ６ alkoxy may be optionally substituted with one or more halogens, hydroxy, cyano or amino, and the 3- to 5-membered heterocycloalkyl and C ３ -C ５ cycloalkyl may be optionally substituted with one or more halogens, hydroxy, cyano, oxo or amino. The compound of formula I according to claim 1, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof.

4. Cy is heteroaryl selected from phenyl; pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, quinolinyl and isoquinolinyl; or heterocycloalkyl selected from azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl and morpholinyl; Cy ２ is phenyl; heteroaryl selected from pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, quinolinyl and isoquinolinyl; heterocycloalkyl selected from azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl and morpholinyl; cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; or cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl, a compound of formula I according to claim 3, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof.

5. R ａ is -V-Cy ２ and 【Chemical Formula 9】 has, 【Chemical Formula 10】 a structure selected from, Cy and Cy ２ The compound of formula I according to claim 1, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof, wherein Cy and Cy may each optionally be substituted by R' and R".

6. R ８ is 【Chemical 11】 and Z is -(CH ２ ) ｓ and R8' is hydroxy or C １ -C ６ alkoxy; The compound of formula I according to claim 1, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof, wherein s is an integer of 0 or 1.

7. The compound of formula I according to claim 1, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound has formula IA-1 or IA-2. 【Chemical 12】 [Wherein, R １ and R ２ are selected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, C １ to C ６ alkyl, C １ to C ６ alkoxy, -NH-(C １ to C ６ alkyl), -N(C １ to C ６ alkyl) ２ ; C ３ to C ８ cycloalkyl and C ６ to C １０ aryl, and the C １ to C ６ alkyl and C １ to C ６ alkoxy may each independently be optionally substituted with one or more halogens, hydroxy, cyano or amino; and the C ３ to C ８ cycloalkyl and C ６ to C １０ aryl may each independently be optionally substituted with one or more halogens, hydroxy, cyano, amino, oxo, C １ to C ６ alkyl, C １ to C ６ haloalkyl, C １ to C ６ alkoxy or C １ to C ６ haloalkoxy; R ３ is 【Chemical 13】 is; W, Cy, Ra, R ４ , R ８ , n, m, r and l are as defined in claim 1.

8. R １ is hydrogen, halogen, hydroxy, cyano, amino, C １ to C ６ alkyl, C １ to C ６ alkoxy, -NH-(C １ to C ６ alkyl) or -N(C １ to C ６ alkyl); ２ wherein said C １ to C ６ alkyl and C １ to C ６ alkoxy may each independently be optionally substituted with one or more halogen, hydroxy, cyano or amino; R ２ is hydrogen, halogen, hydroxy, C １ -C ３ alkyl, C １ -C ３ alkoxy, C １ -C ３ haloalkyl, C １ -C ３ haloalkoxy, C ３ -C ６ cycloalkyl or phenyl, and the C １ -C ３ alkyl and C １ -C ３ alkoxy may each independently be optionally substituted with one or more of halogen, hydroxy, cyano or amino; R ３ is 【Chemical 14】 is; W is -(CH ２ ) ｏ -, -C(O)-, -O-, -NH- or -N(C １ ~C ６ alkyl)-, and the H of the CH ２ may be optionally substituted with one or more halogens, hydroxy or C １ ~C ６ alkoxy; Cy is C ６ ~C １０ selected from the group consisting of 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from aryl, N, O, and S, and 4- to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O, and S, and may be optionally substituted with one or more R'; R ａ is -V-Cy ２ wherein V is absent or -NH-, -NHCH ２ -, -NHCH ３ -, -S-, -SO ２ -, -CH ２ -, -OCH ２ - or -O-, and Cy ２ is C ６ ~C １０ aryl, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, 4- to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, C ３ ~C ８ cycloalkyl, and C ３ ~C ８ cycloalkenyl, and is optionally substituted with one or more R"; R' is halogen, hydroxy, cyano, amino, oxo, C １ ~C ３ alkyl, C １ ~C ３ haloalkyl, C １ ~C ３ alkoxy, C １ ~C ３ haloalkoxy, -NH-(C １ ~C ３ alkyl) or -N(C １ ~C ３ alkyl) ２ ; "R” is halogen, hydroxy, cyano, amino, oxo, C １ ~C ６ alkyl, C １ ~C ６ alkoxy, -S-(C １ ~C ６ alkyl), -SO ２ -(C １ ~C ６ alkyl), -COO-(C １ ~C ６ alkyl), -COOH, -CONH ２ , -(CH ２ ) ｐ -NH ２ , -(CH ２ ) ｐ -NH-(C １ ~C ６ alkyl), -(CH ２ ) ｐ -N(C １ ~C ６ alkyl) ２ , -(CH ２ ) ｐ -NH-COO-(C １ ~C ６ alkyl), -(CH ２ ) ｐ -OH, a 3- to 5-membered heterocycloalkyl containing one heteroatom selected from N, O and S, C ３ ~C ５ cycloalkyl, and -(CH ２ ) ｐ -(C ３ ~C ５ cycloalkyl) selected from the group consisting of; wherein the C １ ~C ６ alkyl and C １ ~C ６ alkoxy may be optionally substituted with one or more halogen, hydroxy, cyano or amino; and the 3- to 5-membered heterocycloalkyl and C ３ ~C ５ cycloalkyl may be optionally substituted with one or more halogen, hydroxy, cyano, oxo or amino; R ４ is hydrogen or C １ to C ３ alkyl; R ８ is 【Chemical Formula 15】 wherein Z is -(CH ２ ) ｓ wherein R8' is hydroxy or C １ -C ６ alkoxy; l, m, n and r are each independently an integer of 1 or 2; o and p are each an integer of 0, 1 or 2; The compound of formula I according to claim 7, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof, wherein s is an integer of 0 or 1.

9. R １ is hydrogen, halogen, hydroxy, C １ to C ３ alkyl, C １ to C ３ alkoxy, C １ to C ３ haloalkyl or C １ to C ３ haloalkoxy; R ２ is hydrogen, halogen, C １ to C ３ alkyl, C １ to C ３ haloalkyl, cyclopropyl, cyclobutyl or phenyl; Cy is phenyl, 5- to 10-membered heteroaryl containing one or two nitrogen atoms, or 4- to 7-membered heterocycloalkyl containing one or two nitrogen atoms, optionally substituted with one or more R'; R ａ is -V-Cy ２ where V is absent or -CH ２ - or -O-, and Cy ２ is selected from the group consisting of 5- to 10-membered heteroaryl containing one or two heteroatoms selected from phenyl, N or O, 4- or 7-membered heterocycloalkyl containing one or two heteroatoms selected from N or O, C ４ -C ７ -cycloalkyl, and C ４ -C ７ -cycloalkenyl, and may be optionally substituted with one or more R''; R' is halogen, amino, C １ ~C ３ alkyl or C １ ~C ３ haloalkyl; "R” is halogen, hydroxy, cyano, amino, oxo, C １ ~C ６ alkyl, C １ ~C ６ haloalkyl, C １ ~C ６ alkoxy, C １ ~C ６ haloalkoxy, -S-(C １ ~C ６ alkyl), -SO ２ -(C １ ~C ６ alkyl), -COO-(C １ ~C ６ alkyl), -COOH, -CONH ２ , -(CH ２ ) ｐ -NH ２ , -(CH ２ ) ｐ -NH-(C １ ~C ６ alkyl), -(CH ２ ) ｐ -N(C １ ~C ６ alkyl) ２ , -(CH ２ ) ｐ -NH-COO-(C １ ~C ６ alkyl), -(CH ２ ) ｐ -OH; azetidinyl or oxetanyl optionally substituted with hydroxy or oxo; and cyclopropyl or cyclopropylmethyl optionally substituted with hydroxy or oxo, a compound of formula I according to claim 8, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof.

10. Cy is phenyl, pyrazolyl or piperazinyl; Cy ２ The compound of formula I according to claim 9, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof, wherein Cy is phenyl, furanyl, pyrazolyl, pyridinyl, morpholinyl, piperidinyl, cyclohexyl or cyclohexenyl.

11. The compound of formula I according to claim 7, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof, wherein the compound has formula IA-3 or IA-4. 【Chemical Formula 16】 [wherein, R １ , R ２ , R ３ , R ４ and R ８ are as defined in claim 7.]

12. The compound according to claim 1, wherein the compound has formula IB-1, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof. 【Chemical 17】 [wherein, R １ is selected from the group consisting of hydrogen, halogen, hydroxy, cyano, amino, C １ to C ６ alkyl, C １ to C ６ alkoxy, -NH-(C １ to C ６ alkyl), -N(C １ to C ６ alkyl) ２ , C ３ to C ８ cycloalkyl and C ６ to C １０ aryl, wherein said C １ to C ６ alkyl and C １ to C ６ alkoxy may each independently be optionally substituted with one or more halogen, hydroxy, cyano or amino, and said C ３ to C ８ cycloalkyl and C ６ to C １０ aryl may each independently be optionally substituted with one or more halogen, hydroxy, cyano, amino, oxo, C １ to C ６ alkyl, C １ to C ６ haloalkyl, C １ to C ６ alkoxy or C １ to C ６ haloalkoxy; 【Chemical Formula 18】 One or both of the carbon atoms are halogen, hydroxy, cyano, C １ -C ６ -alkyl, C １ -C ６ -alkoxy, C １ -C ６ -haloalkyl or C １ -C ６ -haloalkoxy, and may be optionally substituted; W, Cy, R ａ , R ４ , R ５ , R ６ , R ７ , R ８ , P, n, m and l are as defined in claim 1.

13. The compound according to claim 12, wherein the compound has formula IB-2, IB-3 or IB-4, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof. 【Chemical 19】 [wherein, R １ is hydrogen, halogen, hydroxy, cyano, amino, C １ to C ６ alkyl, C １ to C ６ alkoxy, -NH-(C １ to C ６ alkyl) or -N(C １ to C ６ alkyl); ２ wherein said C １ to C ６ alkyl and C １ to C ６ alkoxy may each independently be optionally substituted with one or more halogen, hydroxy, cyano or amino; 【Chemical 20】 One or both of the carbon atoms are halogen, C １ -C ３ alkyl or C １ -C ３ optionally substituted with haloalkyl; W is -(CH ２ ) ｏ - or -(CH ２ ) ｏ -C≡C-, and the H of the CH ２ may be optionally substituted with one or more halogens, hydroxy or C １ ~C ６ alkoxy; Cy is C ６ ~C １０ selected from the group consisting of 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from C, N, O and S, and 4- to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, and may be optionally substituted with one or more R'; R ａ is -V-Cy ２ wherein V is absent or is -NH-, -NHCH ２ -, -NHCH ３ -, -S-, -SO ２ -, -CH ２ -, -OCH ２ - or -O-, and Cy ２ is C ６ ~C １０ aryl, 5- to 10-membered heteroaryl containing 1 to 3 heteroatoms selected from N, O and S, 4- to 10-membered heterocycloalkyl containing 1 to 3 heteroatoms selected from N, O and S, C ３ ~C ８ cycloalkyl, and C ３ ~C ８ cycloalkenyl, and is optionally substituted with one or more R''; R' is halogen, hydroxy, cyano, amino, oxo, C １ ~C ３ alkyl, C １ ~C ３ haloalkyl, C １ ~C ３ alkoxy, C １ ~C ３ haloalkoxy, -NH-(C １ ~C ３ alkyl) or -N(C １ ~C ３ alkyl) ２ ; "R” is halogen, hydroxy, cyano, amino, oxo, C １ ~C ６ alkyl, C １ ~C ６ alkoxy, -S-(C １ ~C ６ alkyl), -SO ２ -(C １ ~C ６ alkyl), -COO-(C １ ~C ６ alkyl), -COOH, -CONH ２ , -(CH ２ ) ｐ -NH ２ , -(CH ２ ) ｐ -NH-(C １ ~C ６ alkyl), -(CH ２ ) ｐ -N(C １ ~C ６ alkyl) ２ , -(CH ２ ) ｐ -NH-COO-(C １ ~C ６ alkyl), -(CH ２ ) ｐ -OH, a 3- to 5-membered heterocycloalkyl containing one heteroatom selected from N, O, and S, C ３ ~C ５ cycloalkyl, and -(CH ２ ) ｐ -(C ３ ~C ５ cycloalkyl) selected from the group consisting of; wherein the C １ ~C ６ alkyl and C １ ~C ６ alkoxy may be optionally substituted with one or more halogens, hydroxy, cyano, or amino; and the 3- to 5-membered heterocycloalkyl and C ３ ~C ５ cycloalkyl may be optionally substituted with one or more halogens, hydroxy, cyano, oxo, or amino; R ４ is hydrogen or C １ to C ３ alkyl; R ８ is 【Chemical 21】 and Z is -(CH ２ ) ｓ and R ８ ' is hydroxy or C １ -C ６ alkoxy; l, m, and n are each independently an integer of 1 or 2; o and p are each independently an integer from 0 to 2; q and r are each independently an integer of 1 or 2; s is an integer of 0 or 1. ]

14. R １ is hydrogen, halogen, hydroxy, C １ to C ３ alkyl, C １ to C ３ alkoxy, C １ to C ３ haloalkyl or C １ to C ３ haloalkoxy; 【Chemical 22】 One or both of the carbon atoms are halogen, C １ -C ３ alkyl or C １ -C ３ optionally substituted with haloalkyl; Cy is phenyl or a 5- to 10-membered heteroaryl containing one or two nitrogen atoms; R ａ is -V-Cy ２ where V is absent or -CH ２ -, and Cy ２ is phenyl or 5- to 10-membered heteroaryl containing one or two nitrogen atoms; R' is halogen, amino, C １ ~C ３ alkyl, or C １ ~C ３ haloalkyl; "R” is halogen, hydroxy, cyano, amino, oxo, C １ ~C ６ alkyl, C １ ~C ６ haloalkyl, C １ ~C ６ alkoxy, C １ ~C ６ haloalkoxy, -(CH ２ ) ｐ -NH ２ 、-(CH ２ ) ｐ -NH-(C １ ~C ６ alkyl), -(CH ２ ) ｐ -N(C １ ~C ６ alkyl) ２ ; azetidinyl or oxetanyl optionally substituted with hydroxy or oxo; cyclopropyl or cyclopropylmethyl optionally substituted with hydroxy or oxo, a compound of formula I according to claim 13, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof.

15. Cy is selected from the group consisting of phenyl, pyridinyl, pyrimidinyl and indolyl; Cy ２ The compound of formula I according to claim 14, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof, wherein Cy is selected from the group consisting of phenyl, pyrazolyl, pyridinyl and pyrimidinyl.

16. The compound according to claim 12, wherein the compound has formula IB-5, IB-6, IB-7 or IB-8, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof. 【Chemical 23】 [wherein, R １ , W, Cy, R ａ , R ４ and R ８ are as defined in claim 12.]

17. The following compounds: 【Chemical 24】 【Chem.】 【Chem.】 [Chemical] 【Chem.】 【Chem.】 【Chem.】 【Chem.】 【Chem.】 The compound according to claim 1, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof, selected from the group consisting of.

18. The following compounds: 【Chemical Formula 25】 The compound according to claim 17, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof, selected from the group consisting of.

19. A pharmaceutical composition comprising the compound according to any one of claims 1 to 18, or a solvate, stereoisomer or pharmaceutically acceptable salt thereof, as an active ingredient.

20. Prostaglandin E ２ Overexpression and / or prostaglandin E ２ The pharmaceutical composition according to claim 19, which is for preventing or treating diseases associated with overexpression of the receptor.

21. Prostaglandin E ２ Overexpression and / or prostaglandin E ２ The pharmaceutical composition according to claim 20, wherein the disease associated with overexpression of the receptor is cancer, a neurodegenerative disease or an inflammatory disease.

22. The cancer is selected from the group consisting of squamous cell carcinoma, basal cell carcinoma, glioblastoma, bone cancer, gastric cancer, kidney 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, the pharmaceutical composition according to claim 21.

23. The neurodegenerative disease is selected from the group consisting of epilepsy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and traumatic brain injury, the pharmaceutical composition according to claim 21.

24. The pharmaceutical composition according to claim 21, wherein the inflammatory disease is selected from the group consisting of edema, allergy, asthma, conjunctivitis, periodontitis, rhinitis, otitis media, pharyngolaryngitis, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, colitis, hemorrhoids, gout, ankylosing spondylitis, rheumatic fever, lupus, fibromyalgia, psoriatic arthritis, osteoarthritis, rheumatoid arthritis, periarthritis of shoulder, tendinitis, tenosynovitis, myositis, hepatitis, cystitis, nephritis, Sjogren's syndrome, and multiple sclerosis.

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