A compound having prostaglandin e2 receptor inhibitory activity and use thereof

Abstract

The present application relates to a kind of new compound with prostaglandin E2 receptor inhibitory activity and its application, provide a kind of compound as shown in formula I and its solvate, stereoisomer or pharmaceutically acceptable salt, the pharmaceutical composition comprising it and the method using it.

Description

Technical Field

[0001] This invention relates to a novel compound having prostaglandin E2 receptor inhibitory activity, its applications, pharmaceutical compositions comprising the compound, and methods of using the compound to treat or prevent diseases. Background Technology

[0002] Prostaglandins (PGs), like thromboxanes, are physiologically active substances known as prostaglandins and are lipids with a prostaglandin backbone. Under the action of phospholipase A2, arachidonic acid is released from cell membrane phospholipids to biosynthesize prostaglandins such as PGs. Based on the type of oxygen atoms and double bonds attached to their five-membered rings, prostaglandins are classified into groups A to J. Furthermore, based on the number of double bonds on the side chains of the prostaglandin backbone, prostaglandins are classified into groups 1 to 3. For example, prostaglandin E (PGE) includes PGE1, PGE2, and PGE3, which differ from each other in the number of double bonds on their prostaglandin backbone side chains.

[0003] Regarding prostaglandins, PGG2 is biosynthesized from arachidonic acid under the action of cyclooxygenase I (COX-I) or cyclooxygenase II (COX-II), and then PGH2 is generated from PGG2. Subsequently, based on the difference in the breaking of interatomic bonds, PGD2, PGE2, and PGF are generated. 2α The production of each prostaglandin occurs under the action of specific enzymes, which are known to be tissue-specific. Among prostaglandins, PGE2 is generally considered to play a role in various important biological activities, and through specific receptors, it participates in the regulation of the immune system, as well as vasodilation, blood pressure reduction, and uterine contractions. Like other PG receptors, the PGE2 receptor is a seven-transmembrane G protein-coupled receptor. The abbreviation for PGE2 receptor is EP, and four subtypes of EP have been identified (EP1, EP2, EP3, and EP4). Each subtype is involved in various phenomena in the body. That is, EP1 participates in intracellular calcium metabolism. 2+ With increasing concentration, EP2 and EP4 contribute to increasing cAMP levels, while EP3 contributes to decreasing cAMP levels.

[0004] On the other hand, cancer is one of the leading causes of death worldwide. Tumors consist of abnormally proliferating malignant cancer cells and a functionally supporting microenvironment. The tumor microenvironment is composed of a complex set of cellular, extracellular matrix components, and signaling molecules, established by altering the information exchange between stromal cells and tumor cells. As tumor volume increases, it leads to the production of various factors, such as angiogenic factors (promoting blood vessel growth), which can aid tumor growth or help evade the host's immune response. Within this microenvironment, PGE2 functions as an immunomodulatory factor produced within the tumor. The EP receptors of PGE2, particularly EP2 and EP4, are abnormally overexpressed in several types of cancer, especially gastrointestinal (GI) cancers and pancreatic cancer. Furthermore, overexpression of PGE2 and / or EP2 and / or EP4 is closely associated with cancers such as esophageal squamous cell carcinoma, lung squamous cell carcinoma, prostate cancer, and head and neck squamous cell carcinoma. Moreover, it is well known that, from an epidemiological perspective, PGE2 signaling is primarily involved in the information exchange between tumor cells and stromal cells, creating a microenvironment favorable for tumor growth. It is worth noting that some tumor cells overexpress EP2 and / or EP4, thereby PGE2 signaling can directly induce tumor cell proliferation.

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

[0006] Against this technological backdrop, a study on a prostaglandin E2 receptor antagonist that can be used clinically in various ways is underway (Korean Patent Application Publication No. 10-2013-0092579), but is still incomplete. Summary of the Invention

[0007] Technical issues

[0008] On the one hand, a novel compound, its solvate, stereoisomer, or pharmaceutically acceptable salt that exhibits inhibitory activity against prostaglandin E2 receptors is provided.

[0009] On the other hand, a pharmaceutical composition comprising the said compound, its solvate, stereoisomer, or pharmaceutically acceptable salt as an active ingredient, or its pharmaceutical application, is provided.

[0010] Solution to the problem

[0011] Each description and embodiment disclosed in this invention is also applicable to every other description and embodiment. That is, all combinations of the various elements disclosed in this invention fall within the scope of this invention. Furthermore, the scope of this invention is not intended to be limited to the specific descriptions below.

[0012] In one aspect of the invention, a compound, its solvate, stereoisomer, or pharmaceutically acceptable salt as shown in Formula I is provided:

[0013] [Formula I]

[0014]

[0015] in,

[0016] One of X and Y is S, and the other is CR. 1 ,and It can be a single bond or a double bond, including two double bonds;

[0017] R 1 and R 2 Choose from hydrogen, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C8 cycloalkyl, and C6-C 10 The group consisting of aryl groups, wherein the C1-C6 alkyl and C1-C6 alkoxy groups may each be independently and optionally substituted with one or more halogens, hydroxyl groups, cyano groups, or amino groups, and the C3-C8 cycloalkyl and C6-C... 10 The aryl group may be independently and optionally substituted by one or more halogens, hydroxyl groups, cyano groups, amino groups, oxo groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, or C1-C6 haloalkoxy groups; and

[0018] R 3 for or

[0019] R 1 Choose from hydrogen, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C8 cycloalkyl, and C6-C 10 The group consisting of aryl groups, wherein the C1-C6 alkyl and C1-C6 alkoxy groups may each be independently and optionally substituted with one or more halogens, hydroxyl groups, cyano groups, or amino groups, and the C3-C8 cycloalkyl and C6-C... 10 The aryl group may be independently and optionally substituted by one or more halogens, hydroxyl groups, cyano groups, amino groups, oxo groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, or C1-C6 haloalkoxy groups; and

[0020] R 2 and R 3 Together with the carbon atoms they are attached to form in, and The nitrogen atoms on it are connected, and One or two carbon atoms may optionally be substituted with halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl or C1-C6 haloalkoxy;

[0021] W stands for -(CH2) o -、-(CH2) o -C≡C-, -C(O)-, -O-, -S-, -NH- or -N(C1-C6 alkyl)-, wherein the H in the CH2 may optionally be substituted by one or more halogens, hydroxyl groups, cyano groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, C1-C6 haloalkyl groups or C1-C6 haloalkoxy groups;

[0022] Cy selects C6-C freely. 14 The group consisting of aryl, 4- to 14-membered heteroaryl, 4- to 14-membered heterocyclic alkyl, C3-C8 cycloalkyl and C3-C8 cycloalkenyl, and optionally substituted by one or more R';

[0023] R a The radical is hydrogen, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl), -N(C1-C6 alkyl)2, oxo, or -V-Cy2, wherein the C1-C6 alkyl and C1-C6 alkoxy may optionally be substituted with one or more halogens, hydroxyl groups, cyano groups, or amino groups.

[0024] Where V represents the absence of -NH-, -NHCH2-, -NHCH3-, -CONH-, -NHCO-, -NHSO2-, -S-, -SO2-, -CH2-, -OCH2-, or -O-.

[0025] Cy2 is selected from C6-C 14 Aryl, 4- to 14-membered heteroaryl, 4- to 14-membered heterocyclic alkyl, C3-C8 cycloalkyl and C3-C8 cycloalkenyl, and optionally substituted with one or more R”;

[0026] R' is independently selected from the group consisting of halogen, hydroxyl, cyano, amino, oxo, C1-C6 alkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl) and -N(C1-C6 alkyl)2, wherein the C1-C6 alkyl and C1-C6 alkoxy may optionally be substituted with one or more halogens, hydroxyl, cyano or amino groups.

[0027] R is selected from halogen, hydroxyl, cyano, amino, oxo, C1-C6 alkyl, C1-C6 alkoxy, -S-(C1-C6 alkyl), -SO2-(C1-C6 alkyl), -CO-(C1-C6 alkyl), -C(O)H, -COO-(C1-C6 alkyl), -COOH, -CONH2, -CONH-(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -(CH2). p -NH2、-(CH2) p -NH-(C1-C6 alkyl), -(CH2) p -N(C1-C6 alkyl)2, -(CH2) p -NH-CO-(C1-C6 alkyl), -(CH2) p -NH-COO-(C1-C6 alkyl), -(CH2) p -OH, 3- to 7-membered heterocyclic alkyl groups, C3-C8 cycloalkyl groups, and -(CH2) p The group consisting of -(C3-C8 cycloalkyl), wherein the C1-C6 alkyl and C1-C6 alkoxy groups may optionally be substituted with one or more halogens, hydroxyl groups, cyano groups or amino groups, and the 3 to 7-membered heterocyclic alkyl groups and C3-C8 cycloalkyl groups may optionally be substituted with one or more halogens, hydroxyl groups, cyano groups, oxo groups or amino groups.

[0028] R 4 It is hydrogen or C1-C6 alkyl;

[0029] R 5 R 6 and R 7 Each is defined as follows:

[0030] (i)R 5 and R 6 Let H be the number of 'R', and R be the number of 'R'. 7 It does not exist.

[0031] (ii)R 5 and R 6 Together for -(CH2) q -, and R 7 It does not exist, or

[0032] (iii)R 5 Let H be the number of 'R', and R be the number of 'R'. 6 and R 7 Together for -(CH2) r -;and

[0033] P is non-existent or -CH2-, if R 7 If P does not exist, then P also does not exist;

[0034] R 8for Where Z stands for -(CH2). s And R 8 'is hydrogen, hydroxyl, C1-C6 alkyl, or C1-C6 alkoxy;

[0035] l, m, and n are each independent integers from 0 to 2, where at least one of m and n is not 0, if P and R 7 If it does not exist, then l is 0;

[0036] o and p are each an independent integer from 0 to 3;

[0037] q and r are each an independent integer of 1 or 2; and

[0038] s is an integer from 0 to 3.

[0039] In some implementations, X is S and Y is CR 1 , or X is CR 1 And Y is S. In one implementation scheme, It consists of single or double bonds, with two double bonds, which cause the 5-membered ring containing X and Y to form a thiophene ring.

[0040] In some implementation schemes, R 1 It can be hydrogen, halogen, hydroxyl, cyano, amino, C1-C3 alkyl, C1-C3 alkoxy, -NH-(C1-C3 alkyl)2, wherein the C1-C3 alkyl and C1-C3 alkoxy can each be independently and optionally substituted with one or more halogens, hydroxyl groups, cyano groups, or amino groups. In one embodiment, R 1 It can be hydrogen, halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or C1-C3 haloalkoxy. In one embodiment, R 1 It can be hydrogen, halogen, C1-C3 alkyl or C1-C3 haloalkyl.

[0041] In some implementation schemes, R 2 It can be hydrogen, halogen, hydroxyl, 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 groups can each be optionally and independently substituted with one or more halogens, hydroxyl groups, cyano groups, or amino groups. In one embodiment, R 2 It can be hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl, cyclobutyl, or phenyl. In one embodiment, R... 2 It can be hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, or phenyl, etc.

[0042] In some implementation schemes, R 3 Can be

[0043] In another implementation, R 2 and R 3 They can form together with the carbon atoms they are attached to. This results in the formation of a 4H-thiopheno[3,2-b]pyrrole fused ring, in which case... Can be with The nitrogen atoms are connected.

[0044] In one implementation scheme, One or two carbon atoms may optionally be substituted with a halogen, a C1-C3 alkyl group, or a C1-C3 haloalkyl group. In one embodiment, One or two carbon atoms may optionally be substituted with fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, difluoromethyl, etc. In one embodiment, One or two carbon atoms may optionally be substituted with C1-C3 alkyl groups.

[0045] In some implementations, W can be -(CH2). o -、-(CH2) o -C≡C-, -C(O)-, -O-, -NH- or -N(C1-C3 alkyl)-, wherein the H in the CH2 may optionally be substituted with one or more halogens, hydroxyl groups, C1-C3 alkoxy groups or C1-C3 haloalkoxy groups.

[0046] In one implementation, W can be -(CH2). o -, -C(O)-, -O-, -NH-, or -N(C1-C6 alkyl)-. In another embodiment, W may be -(CH2). o -or-(CH2) o -C≡C-.

[0047] In one embodiment, the H in the CH2 may optionally be substituted with one or more halogens, hydroxyl groups, or C1-C3 alkoxy groups. In one embodiment, the H in the CH2 may optionally be substituted with hydroxyl, 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.

[0048] In some implementations, Cy can be C6-C 10The aryl group, comprising 1 to 3 5- to 10-membered heteroaryl groups selected from N, O, and S heteroatoms, or comprising 1 to 3 4- to 10-membered heterocyclic alkyl groups selected from N, O, and S heteroatoms. In one embodiment, Cy may be phenyl, naphthyl; a heteroaryl group selected from pyrroloyl, furanyl, thiopheneyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, quinolinyl, and isoquinolinyl; or a heterocyclic alkyl group selected from azacyclic butyl, oxacyclic butyl, pyrroloyl, tetrahydrofuranyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, piperidinyl, piperazinyl, and morpholinyl.

[0049] In one embodiment, Cy may be phenyl, a 5- to 10-membered heteroaryl group containing one or two nitrogen atoms, or a 4- to 7-membered heterocyclic alkyl group containing one or two nitrogen atoms. In one embodiment, Cy may be phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, benzimidazolyl, indolyl, pyrrolylalkyl, piperidinyl, piperazinyl, or morpholinyl. In one embodiment, Cy may be phenyl, pyrazolyl, pyridinyl, pyrimidinyl, indolyl, or piperazinyl.

[0050] The Cy may optionally be substituted with one or more R's. In one embodiment, R' may be a halogen, hydroxyl, cyano, amino, oxo, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NH-(C1-C3 alkyl) or -N(C1-C3 alkyl)2. In one embodiment, R' may be a halogen, amino, C1-C3 alkyl or C1-C3 haloalkyl. In one embodiment, R' may be one or more fluorine, chlorine, bromine, amino, methylamino, dimethylamino, ethylamino or diethylamino, etc.

[0051] In some implementation schemes, R a It can 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 It can be hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or -V-Cy2. In one embodiment, R... a It can be hydrogen, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, difluoromethyl, or -V-Cy2. In one embodiment, R a It can be -V-Cy2.

[0052] In some embodiments, V may be absent or -NH-, -NHCH2-, -NHCH3-, -S-, -SO2-, -CH2-, -OCH2-, or -O-. In one embodiment, V may be absent or -CH2- or -O-. In another embodiment, V may be absent or -CH2-.

[0053] In some implementations, Cy2 can be optionally free of C6-C. 10 The group consisting of aryl, 5- to 10-membered heteroaryl groups comprising 1 to 3 heteroatoms selected from N, O and S, 4- to 10-membered heterocyclic alkyl groups comprising 1 to 3 heteroatoms selected from N, O and S, C3-C8 cycloalkyl groups and C3-C8 cycloalkenyl groups. In one embodiment, Cy2 may be phenyl; a heteroaryl group selected from pyrroloyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, quinolinyl, and isoquinolinyl; a heterocyclic alkyl group selected from aziridine, oxaziridine, pyrroloyl, tetrahydrofuranyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, piperidinyl, piperazinyl, and morpholinyl; cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; or cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl.

[0054] In one embodiment, Cy2 may be selected from the group consisting of phenyl, 5- to 10-membered heteroaryl groups comprising one or two heteroatoms selected from N or O, 4- to 7-membered heterocyclic alkyl groups comprising one or two heteroatoms selected from N or O, C4-C7 cycloalkyl groups, and C4-C7 cycloalkenyl groups. In one embodiment, Cy2 may be phenyl, pyrrolyl, furanyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolylalkyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, cyclopentyl, cyclohexyl, cyclopentenyl, or cyclohexenyl. In one embodiment, Cy2 may be phenyl, furanyl, pyrazolyl, pyridinyl, pyrimidinyl, piperidinyl, morpholinyl, cyclohexyl, or cyclohexenyl.

[0055] The Cy2 may optionally be substituted with R”. In some embodiments, R” is selected from halogen, hydroxyl, 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 heterocyclic alkyl groups containing one heteroatom selected from N, O, and S, C3-C5 cycloalkyl groups, and -(CH2). p The group consisting of (C3-C5 cycloalkyl), wherein the C1-C6 alkyl and C1-C6 alkoxy groups may optionally be substituted with one or more halogens, hydroxyl groups, cyano groups, or amino groups, and the 3- to 5-membered heterocyclic alkyl and C3-C5 cycloalkyl groups may optionally be substituted with one or more halogens, hydroxyl groups, cyano groups, oxo groups, or amino groups. In one embodiment, the 3- to 5-membered heterocyclic alkyl group may be aziridinyl, ethylene oxide, aziridine, oxadiidine, 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.

[0056] In one embodiment, R” can be halogen, hydroxyl, 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; a nitrogen-containing butylene or oxobutylene optionally substituted with a hydroxyl group or an oxoyl group; a cyclopropyl or cyclopropylmethyl optionally substituted with a hydroxyl group or an oxoyl group.

[0057] In another embodiment, R” can be halogen, hydroxyl, cyano, amino, oxo, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or -(CH2). p -NH2、-(CH2) p -NH-(C1-C6 alkyl), -(CH2) p -N(C1-C6 alkyl)2; a nitrogen-containing alkyl or oxo-containing alkyl optionally substituted with hydroxyl or oxo; a cyclopropyl or cyclopropylmethyl optionally substituted with hydroxyl or oxo.

[0058] In one embodiment, R” can be halogen, hydroxyl, 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、azacyclobutane、oxacyclobutane、cyclopropyl or cyclobutylmethyl.

[0059] In one implementation scheme, R a It is -V-Cy2, and It has a structure selected from the group below, wherein Cy and Cy2 can be optionally replaced by R' and R” respectively:

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068] In some implementation schemes, R 4 It can be hydrogen or C1-C3 alkyl.

[0069] In some implementation schemes, R 5 and R 6 It can be H, R 7 The structure that does not exist and is connected to the amide bond in Formula I can be the following:

[0070] (Where, n and m can be integers of 1 or 2, respectively.)

[0071] In another implementation, R 5 and R 6 They can be represented together as -(CH2). q -, and R 7 It can be that the amide bond is not present. In this case, the structure connected to the amide bond in Formula I can be as follows:

[0072] (Where, n, m, and q can be integers of 1 or 2.)

[0073] In another implementation, R 5 It can be H, and R 6 and R 7 They can be represented together as -(CH2). r In this case, the structure connected to the amide bond in Formula I can be as follows:

[0074] (Where n, m, r, and l can be integers of 1 or 2.)

[0075] In one embodiment, the structure linked to the amide bond in Formula I includes an isomer of that structure, for example, but not limited to the following structures:

[0076]

[0077] In some implementation schemes, R 8 Can be Where Z can be -(CH2). s And R 8 'Can be hydroxyl or C1-C6 alkoxy, and s can be an integer of 0 or 1. In one embodiment, s can be 0, and R 8 'Can be hydroxyl.'

[0078] In another aspect of the invention, a compound of formula IA-1 or IA-2, or a solvate, stereoisomer, or pharmaceutically acceptable salt thereof, is provided:

[0079] [Formula IA-1]

[0080]

[0081] [Formula IA-2]

[0082]

[0083] in,

[0084] R 1 and R2 Choose from hydrogen, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C8 cycloalkyl, and C6-C 10 The group consisting of aryl groups, wherein the C1-C6 alkyl and C1-C6 alkoxy groups may each be independently and optionally substituted with one or more halogens, hydroxyl groups, cyano groups, or amino groups, and the C3-C8 cycloalkyl and C6-C... 10 The aryl group may be independently and optionally substituted by one or more halogens, hydroxyl groups, cyano groups, amino groups, oxo groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, or C1-C6 haloalkoxy groups;

[0085] R 3 for and

[0086] W, Cy, Ra, R 4 R 8 , n, m, r and l are as defined in Equation I above. Regarding R in Equation I... 1 R 2 W, Cy, R a R 4 R 8 The specific embodiments and implementations described by , n, m, r and l are also applicable to formulas IA-1 and IA-2, provided they are structurally acceptable.

[0087] In some implementations of formulas IA-1 and IA-2, R 1 It can be hydrogen, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl)2, wherein the C1-C6 alkyl and C1-C6 alkoxy can each be independently and optionally substituted with one or more halogens, hydroxyl groups, cyano groups, or amino groups. In one embodiment, R 1 It can be hydrogen, halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, or C1-C3 haloalkoxy. In one embodiment, R 1 It can be hydrogen, halogen, C1-C3 alkyl or C1-C3 haloalkyl.

[0088] In some implementation schemes, R 2It can be hydrogen, halogen, hydroxyl, 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 groups can each be optionally substituted independently with one or more halogens, hydroxyl groups, cyano groups, or amino groups. In one embodiment, the C3-C6 cycloalkyl and phenyl groups can be optionally substituted with one or more halogens, C1-C3 alkyl groups, or C1-C3 haloalkyl groups. In one embodiment, R... 2 It can be hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl, cyclobutyl or phenyl.

[0089] In some implementations, W can 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 in CH2 described in W may optionally be substituted with one or more halogens, hydroxyl groups, or C1-C6 alkoxy groups.

[0090] In some implementations, Cy can be C6-C 10 The aryl group, a 5- to 10-membered heteroaryl group comprising 1 to 3 heteroatoms selected from N, O, and S, or a 4- to 10-membered heterocyclic alkyl group comprising 1 to 3 heteroatoms selected from N, O, and S. In one embodiment, Cy may be phenyl, a 5- to 10-membered heteroaryl group comprising 1 or 2 nitrogen atoms, or a 4- to 7-membered heterocyclic alkyl group comprising 1 or 2 nitrogen atoms. For example, Cy may be phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, indolyl, isoindolyl, benzimidazolyl, indolyl, pyrrolylalkyl, 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.

[0091] The Cy may optionally be substituted with one or more R's. In some embodiments, R' may be a halogen, hydroxyl, cyano, amino, oxo, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NH-(C1-C3 alkyl) or -N(C1-C3 alkyl)2. In one embodiment, R' may be a halogen, amino, C1-C3 alkyl or C1-C3 haloalkyl.

[0092] In some implementation schemes, R aIt can be hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, or -V-Cy2. In one embodiment, R... a It can be -V-Cy2.

[0093] In some embodiments, V may be absent or -NH-, -NHCH2-, -NHCH3-, -S-, -SO2-, -CH2-, -OCH2-, or -O-. In a particular embodiment, V may be absent or -CH2- or -O-.

[0094] In some implementations, Cy2 can be optionally free of C6-C. 10 The group consisting of aryl, 5- to 10-membered heteroaryl groups comprising 1 to 3 heteroatoms selected from N, O, and S, 4- to 10-membered heterocyclic alkyl groups comprising 1 to 3 heteroatoms selected from N, O, and S, C3-C8 cycloalkyl groups, and C3-C8 cycloalkenyl groups. In one embodiment, Cy2 may be selected from the group consisting of phenyl, 5- to 10-membered heteroaryl groups comprising 1 or 2 heteroatoms selected from N or O, 4- to 7-membered heterocyclic alkyl groups comprising 1 or 2 heteroatoms selected from N or O, C4-C7 cycloalkyl groups, and C4-C7 cycloalkenyl groups.

[0095] In one embodiment, Cy2 may be phenyl, furanyl, pyrazolyl, pyridyl, pyrimidinyl, piperidinyl, morpholinyl, cyclohexyl, or cyclohexenyl.

[0096] The Cy2 may optionally be substituted with one or more R”. In some embodiments, R” may be selected from halogen, hydroxyl, 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 heterocyclic alkyl groups containing one heteroatom selected from N, O, and S, C3-C5 cycloalkyl groups, and -(CH2). p The group consisting of -(C3-C5 cycloalkyl). In this case, the C1-C6 alkyl and C1-C6 alkoxy groups may optionally be substituted with one or more halogens, hydroxyl groups, cyano groups or amino groups, and the 3 to 5-membered heterocyclic alkyl and C3-C5 cycloalkyl groups may optionally be substituted with one or more halogens, hydroxyl groups, cyano groups, oxo groups or amino groups.

[0097] In one embodiment, R” can be selected from halogen, hydroxyl, 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; a nitrogen-containing butylene or oxobutylene optionally substituted with a hydroxyl or oxo group; and a cyclopropyl or cyclopropylmethyl optionally substituted with a hydroxyl or oxo group.

[0098] In some implementation schemes, R 4 It can be hydrogen or C1-C3 alkyl.

[0099] In some embodiments, compounds having the above formula IA-1 or IA-2 may be represented by formula IA-3 or IA-4.

[0100] [Formula IA-3]

[0101]

[0102] [Formula IA-4]

[0103]

[0104] Among them, R 1 R 2 R 3 R 4 and R 8 As defined in equations IA-1 and IA-2 above.

[0105] In another aspect, a compound of formula IB-1 or a solvate, stereoisomer, or pharmaceutically acceptable salt thereof is provided:

[0106] [Formula IB-1]

[0107]

[0108] in,

[0109] R 1Choose from hydrogen, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C8 cycloalkyl, and C6-C 10 The group consisting of aryl groups, wherein the C1-C6 alkyl and C1-C6 alkoxy groups may each be independently and optionally substituted with one or more halogens, hydroxyl groups, cyano groups, or amino groups, and the C3-C8 cycloalkyl and C6-C... 10 The aryl group may be independently and optionally substituted by one or more halogens, hydroxyl groups, cyano groups, amino groups, oxo groups, C1-C6 alkyl groups, C1-C6 haloalkyl groups, C1-C6 alkoxy groups, or C1-C6 haloalkoxy groups;

[0110] One or two carbon atoms may optionally be substituted with a halogen, hydroxyl, cyano, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, or C1-C6 haloalkoxy; and

[0111] W, Cy, R a R 4 R 5 R 6 R 7 R 8 P, n, m and l are as defined in Equation I above.

[0112] Regarding W, Cy, and R in Equation I a R 4 R 8 R 6 R 7 R 8 The specific embodiments and implementations described in P, n, m and l are also applicable to formula IB-1, provided they are structurally acceptable.

[0113] In some embodiments, compounds having formula IB-1 may be represented by formula IB-2, IB-3, or IB-4:

[0114] [Formula IB-2]

[0115]

[0116] [Formula IB-3]

[0117]

[0118] [Formula IB-4]

[0119]

[0120] In some implementations of formulas IB-2, IB-3, and IB-4, R1 It can be hydrogen, halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl)2, wherein the C1-C6 alkyl and C1-C6 alkoxy can each be independently and optionally substituted with one or more halogens, hydroxyl groups, cyano groups, or amino groups. In one embodiment, R 1 It can be hydrogen, halogen, hydroxyl, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl or C1-C3 haloalkoxy.

[0121] In some implementation schemes, One or two carbon atoms may optionally be substituted with a halogen, a C1-C3 alkyl group, or a C1-C3 haloalkyl group. In one embodiment, One or two carbon atoms may optionally be replaced by C1-C3 alkyl groups.

[0122] In some implementations, W can be -(CH2). o -、-(CH2) o -C≡C-, -C(O)-, -O-, -NH-, or -N(C1-C3 alkyl)-. In one embodiment, W may be -(CH2). o -or-(CH2) o -C≡C-. In this case, the H in the CH2 may optionally be replaced by one or more halogens, hydroxyl groups, or C1-C6 alkoxy groups.

[0123] In some implementations, Cy can be optionally free of C6-C. 10 The group consisting of aryl, 5- to 10-membered heteroaryl groups comprising 1 to 3 heteroatoms selected from N, O, and S, and 4- to 10-membered heterocyclic alkyl groups comprising 1 to 3 heteroatoms selected from N, O, and S. In one embodiment, Cy may be phenyl, or a 5- to 10-membered heteroaryl group comprising 1 or 2 nitrogen atoms. In one embodiment, Cy may be phenyl, pyrrolyl, pyrazolyl, imidazoleyl, pyridyl, pyrimidinyl, pyridazinyl, indoleyl, isoindoleyl, benzimidazolyl, or indazoleyl. In one embodiment, Cy may be phenyl, pyridyl, pyrimidinyl, or indoleyl.

[0124] The Cy may optionally be substituted with one or more R's. In some embodiments, R' may be a halogen, hydroxyl, cyano, amino, oxo, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, -NH-(C1-C3 alkyl) or -N(C1-C3 alkyl)2. In one embodiment, R' may be a halogen, amino, C1-C3 alkyl or C1-C3 haloalkyl.

[0125] In some implementation schemes, Ra It 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-.

[0126] In some implementations, Cy2 can be optionally free of C6-C. 10 The group consisting of aryl, 5- to 10-membered heteroaryl groups comprising 1 to 3 heteroatoms selected from N, O, and S, 4- to 10-membered heterocyclic alkyl groups comprising 1 to 3 heteroatoms selected from N, O, and S, C3-C8 cycloalkyl groups, and C3-C8 cycloalkenyl groups. In one embodiment, Cy2 may be phenyl, or a 5- to 10-membered heteroaryl group comprising 1 or 2 nitrogen atoms. In one embodiment, Cy2 may be phenyl, pyrrolyl, furanyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrrolylalkyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, cyclopentyl, cyclohexyl, cyclopentenyl, or cyclohexenyl. In one embodiment, Cy2 may be phenyl, pyrazolyl, pyridinyl, or pyrimidinyl.

[0127] The Cy2 may optionally be substituted with one or more R”. In some embodiments, R” may be selected from halogen, hydroxyl, 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 heterocyclic alkyl groups containing one heteroatom selected from N, O, and S, C3-C5 cycloalkyl groups, and -(CH2). p The group consisting of (C3-C5 cycloalkyl). The C1-C6 alkyl and C1-C6 alkoxy groups may optionally be substituted with one or more halogens, hydroxyl groups, cyano groups or amino groups, and the 3 to 5-membered heterocyclic alkyl and C3-C5 cycloalkyl groups may optionally be substituted with one or more halogens, hydroxyl groups, cyano groups, oxo groups or amino groups.

[0128] In one embodiment, R” can be selected from halogen, hydroxyl, 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; a nitrogen-containing alkyl or oxo-containing alkyl optionally substituted with hydroxyl or oxo; and a cyclopropyl or cyclopropylmethyl optionally substituted with hydroxyl or oxo.

[0129] In some implementation schemes, R 4 It can be hydrogen or C1-C3 alkyl.

[0130] In some implementation schemes, R 8 Can be Where Z can be -(CH2). s And R 8 'Can be hydroxyl or C1-C6 alkoxy. In this case, s can be an integer of 0 or 1.

[0131] In one implementation, l, m, and n can each be an integer of 1 or 2 independently. In one implementation, o and p can each be an integer from 0 to 2 independently. In one implementation, q and r can each be an integer of 1 or 2 independently. In one implementation, s can be an integer of 0 or 1.

[0132] In some embodiments, compounds having the above formula IB-1 may be represented by formulas IB-5, IB-6, IB-7, or IB-8:

[0133] [Formula IB-5]

[0134]

[0135] [Formula IB-6]

[0136]

[0137] [Formula IB-7]

[0138]

[0139] [Formula IB-8]

[0140]

[0141] Among them, R 1 W, Cy, R a R 4 and R 8 As defined in equation IB-1.

[0142] In one embodiment, the compound of formula I described in this invention may be selected from the group consisting of:

[0143]

[0144]

[0145]

[0146]

[0147]

[0148]

[0149]

[0150]

[0151]

[0152]

[0153]

[0154]

[0155]

[0156]

[0157]

[0158]

[0159]

[0160]

[0161]

[0162]

[0163]

[0164]

[0165]

[0166]

[0167]

[0168]

[0169]

[0170]

[0171]

[0172] In one embodiment, the compound of formula I described in this invention may be selected from the group consisting of:

[0173]

[0174] definition

[0175] All technical and scientific terms used herein have the meanings commonly understood by one of ordinary skill in the art. Unless otherwise stated, conventional measurement methods, preparation methods, and conventional components or substances are based on conventional techniques such as pharmacology, pharmaceutical chemistry, mass spectrometry, NMR, HPLC, and biochemistry.

[0176] Unless otherwise stated, in this invention and the appended claims, "or" and "and" mean "and / or". The terms "comprising" and "including" are open-ended, meaning that a compound, composition, or method may include additional features or ingredients in addition to those listed.

[0177] In this article, the asterisk (*) at the end of the linker group indicates the position where it binds to the rest of the compound.

[0178] In this invention, the term "halogen" may be F, Cl, Br or I.

[0179] In this invention, unless otherwise stated, the term "alkyl" refers to a straight-chain or branched hydrocarbon group, which may be unsubstituted or substituted. Alkyl groups may be C1-C2. 15 Alkyl, C1-C 12 Alkyl, C1-C9 alkyl, C1-C6 alkyl, or C1-C3 alkyl. Examples of alkyl groups may include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 3-methylbut-1-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethylethyl-1-yl, n-hexyl, n-heptyl, and n-octyl, and all their possible isomers.

[0180] In this invention, unless otherwise stated, the term "alkoxy" refers to a straight-chain or branched hydrocarbon group, which may be unsubstituted or substituted, and is linked by an oxygen group. Alkoxy groups may include, but are not limited to, methoxy, ethoxy, propoxy, and butoxy, or all possible isomers thereof, such as isopropoxy, isobutoxy, and tert-butoxy.

[0181] In this invention, the term "cycloalkyl" refers to a saturated hydrocarbon ring having a specific number of carbon atoms as the ring element (i.e., C3-C8 cycloalkyl refers to a cycloalkyl group having 3, 4, 5, 6, 7, or 8 carbon atoms as the ring element). The cycloalkyl group can be C3-C8. 15 cycloalkyl, C3-C 13 cycloalkyl, C3-C 11 Cycloalkyl, C3-C8 cycloalkyl, C3-C6 cycloalkyl or C3-C5 cycloalkyl, and cycloalkyl having a polycyclic hydrocarbon ring may have two or more bridged or fused cycloalkyl groups.

[0182] In this invention, 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 cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, cyclohex-1,3-dien-1-yl, etc., but is not limited thereto.

[0183] In this invention, the term "hydroxyl group" refers to the -OH group.

[0184] In this invention, the term "oxo" refers to a substituent having a =O structure, wherein a double bond exists between the atom and the oxygen atom.

[0185] In this invention, the term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom is replaced by a halogen atom. In some embodiments, one, two, or three hydrogen atoms in the alkyl group may be replaced by a halogen atom. In one embodiment, the hydrogen atoms may be replaced by the same halogen atom (e.g., fluorine) or by a combination of different halogen atoms (e.g., fluorine and chlorine).

[0186] In this invention, the term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom is replaced by a halogen atom, and the above description of "haloalkyl" also applies to "haloalkoxy".

[0187] In this invention, the term "aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon group. The aryl group has alternating (resonant) double bonds between adjacent carbon atoms, and may also include forms in which two or more rings are simply connected (dangling) or fused together. The aryl group can be, for example, C6-C. 14 Aryl, C6-C 10Aryl or C6-C9 aryl, and may include, but is not limited to, phenyl, biphenyl, naphthyl, toluyl, naphthyl, anthracene, or all possible isomers thereof.

[0188] In this invention, the term "heteroaryl" refers to a heterocyclic aryl group containing at least one heteroatom selected from B, N, O, S, P (=O), Si, and P as a cyclic atom. Heteroaryl groups may also include forms in which two or more rings are simply connected (dangling) or fused together.

[0189] In some embodiments, the heteroaryl group may contain 1 to 4, 1 to 3, 1 or 2, or 1 heteroatom selected from N, O, and S. In one embodiment, the heteroaryl group may contain 1 to 3 N atoms, 1 or 2 N atoms, or 1 N atom. In some embodiments, the heteroaryl group may contain 4 to 14, 5 to 10, or 5 to 6 cyclic atoms.

[0190] Examples of monocyclic heteroaryl groups may include, but are not limited to, thienyl, furanyl, pyrroleyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazoleyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and similar groups. Examples of bicyclic heteroaryl groups may include, but are not limited to, indolyl, isoindolyl, indazole, indolazinyl, benzothiophene, benzofuranyl, benzimidazolyl, benzopyrazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, benzothiadiazolyl, benzotriazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, purinyl, phthalazinyl, pteridine, furanpyridyl, oxochromenyl, dioxoisoindolyl, imidazopyridyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrazolopyridyl and similar groups.

[0191] In this invention, unless otherwise stated, the term "heterocyclic alkyl" refers to a monocyclic or polycyclic, saturated or partially unsaturated ring system containing at least one heteroatom selected from B, N, O, S, P (=O), Si, and P and having a specified number of ring elements (i.e., 3- to 7-membered heterocyclic alkyl refers to a heterocyclic alkyl having 3, 4, 5, 6, or 7 ring elements, including heteroatoms). Polycyclic heterocyclic alkyl may have two or more bridged or fused heterocyclic alkyl groups.

[0192] In some embodiments, the heterocyclic alkyl group may contain 1 to 4, 1 to 3, 1 or 2, or 1 heteroatom selected from N, O, and S. In one embodiment, the heterocyclic alkyl group may contain 1 to 3 N, 1 or 2 N, or 1 N. In some embodiments, the heterocyclic alkyl group may contain 3 to 7, 3 to 6, 4 to 6, 4 to 10, or 4 to 14 ring atoms.

[0193] For example, heterocyclic alkyl groups include aziridinyl, ethylene oxide, aziridine, oxacyclobutane, thioheterobutyl, pyrrolyl, pyrrolinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl, sulfolane, dioxacyclopentyl, imidazolinyl, imidazolinyl, pyrazolinyl, pyrazolinyl, thiazolinyl, thiazolinyl, isothiazolinyl, isothiazolinyl, oxazolinyl, oxazolinyl, isoxazolinyl, triazolinyl, triazolinyl, tetraazolinyl, tetraazolinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, thiaranyl, tetrahydrothiaranyl, dioxacycloalkyl, tetrahydrotriazinyl, hexahydrotriazinyl, morpholinyl, thiomorpholinyl, piperidinyl, dihydropyridinyl, tetrahydro Pyridyl, piperazinyl, tetrahydropyrimidinyl, dihydropyrimidinyl, dihydropyridazinyl, tetrahydropyridazinyl, tetrahydrooxazinyl, hexahydroazapyrrolyl, perhydroazapyrrolyl, perhydrooxazinyl, indololinyl, isoindololinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, benzodihydropyranyl, benzodihydroisopyranyl, azabicyclo[2.2.1]heptyl, 3-azabicyclo[3.2.1]heptyl, 7-azabicyclo[4.1.0]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl, tropyl, 2-oxa-6-azaspiro[3.3]heptyl and their N-oxides, sulfones or sulfoxides, but not limited thereto.

[0194] In some embodiments, heterocyclic alkyl groups include aziridinyl, ethylene oxide, aziridine, oxadiazinyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolyl, imidazoalkyl, thiazoalkyl, oxazolyl, isoxazolyl, piperidinyl, piperazinyl, thiomorpholinyl, or morpholinyl.

[0195] In this invention, the term "substituted" group refers to a group in which one or more hydrogen atoms are replaced by one or more non-hydrogen groups, provided that the valence requirement is met and the substitution produces a chemically stable compound. In this invention, unless explicitly stated as "unsubstituted," all substituents are to be interpreted as capable of being unsubstituted or substituted. Without limiting specific substituents, the term "optionally substituted" as used herein includes portions that are unsubstituted or substituted by any substituent, such as those substituted by halogens, hydroxyl groups, cyano groups, amino groups, C1-C6 alkyl groups, C1-C6 alkoxy groups, -NH-(C1-C6 alkyl), -N(C1-C6 alkyl)2, C3-C8 cycloalkyl groups, C6-C6 cycloalkyl groups, etc. 14 The portion substituted with aryl, 4- to 14-membered heteroaryl, or 4- to 14-membered heterocyclic alkyl. In one embodiment, the "optionally substituted" portion includes the portion substituted with halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, -NH-(C1-C6 alkyl), or -N(C1-C6 alkyl)2.

[0196] In this invention, when the combination of substituents mentioned is a single group, such as arylalkyl, cycloalkylalkyl, etc., the last mentioned group contains an atom attached to the end of the molecule.

[0197] In this invention, the numerical range referred to by the term "to" refers to the range including the values ​​described before and after the term "to" as the lower limit and upper limit, respectively.

[0198] In this invention, the term "solvent" can refer to the compound of the invention or its salts comprising stoichiometric or non-stoichiometric amounts of a solvent bound by non-covalent intermolecular forces. Therefore, preferred solvents can be any volatile, non-toxic, and / or suitable for human administration.

[0199] In this invention, the term "stereoisomer" can refer to a compound or salt thereof of the present invention having the same chemical formula or molecular formula but different optically or stereoscopically, specifically, it can be a diastereomer, enantiomer or geometric isomer.

[0200] In some embodiments, the compounds of the present invention may be in the form of racemic mixtures, single enantiomers, mixtures of enantiomers, single diastereomers, mixtures of diastereomers, etc., containing one or more asymmetric centers. In one embodiment, due to the finite rotation or nature of the asymmetric centers, the compounds of the present invention may be in the form of enantiomers or diastereomers.

[0201] When the compounds of the present invention contain two or more asymmetric centers, the chemical structures disclosed herein may contain several diastereomers and enantiomers, and pure isomers, isolated isomers, partially pure isomers, racemic mixtures, etc., may all fall within the scope of the present invention.

[0202] Purification of isomers and separation of mixtures of isomers can be achieved using standard techniques known in the art. For example, mixtures of diastereomers can be separated into their respective diastereomers by chromatography or crystallization, and racemic mixtures can be separated into their respective enantiomers by resolution or chromatography on a chiral phase.

[0203] Furthermore, when the compounds of the present invention contain tautomerizing groups, all tautomers are included within the scope of the present invention. For example, 2-hydroxypyridine can include 2-pyridone, and all such isomers are included in the present invention.

[0204] As used herein, "pharmaceutically acceptable salt" may include, but is not limited to, acid salts or base salts of parent compounds, inorganic acid salts or organic acid salts of basic residues such as amines, or base salts or organic salts of acidic residues such as carboxylic acids.

[0205] For example, pharmaceutically acceptable salts of the compounds of the present invention can be formed from pharmaceutically acceptable non-toxic bases, including inorganic and organic bases. In one embodiment, the pharmaceutically acceptable salts of the present invention include inorganic base addition salts, such as lithium, sodium, potassium, magnesium, calcium, aluminum, ammonium, copper, iron, ferrous, manganese, zinc, etc. In one embodiment, the pharmaceutically acceptable salts of the present invention may 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, glucosamine, glucosamine, histidine, isopropylamine, lysine, meglumine, morpholine, piperazine, piperidine, polyamine resins, procaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, dicyclohexylamine, and tri(hydroxymethyl)methylamine, etc.

[0206] Furthermore, the compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids, for example, 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, etc.

[0207] Pharmaceutically acceptable salts of compounds can be prepared, for example, by dissolving a compound of formula I in a water-soluble organic solvent, such as acetone, methanol, ethanol, acetonitrile, etc., and adding an excess of organic acid or an acidic aqueous solution containing an inorganic acid, followed by precipitation or crystallization. Subsequently, after evaporating the solvent or excess acid from the mixture, the salt can be prepared by drying to obtain an addition salt or by precipitating the salt through vacuum filtration.

[0208] On the other hand, the acid addition salt form of the present invention can be easily converted into a free base form by treatment with a suitable alkali, and the base addition salt form can be easily converted into a free acid form by treatment with a suitable acid.

[0209] Conventional preparation methods of compounds

[0210] On the other hand, the compound can be prepared by chemical modifications well known to those skilled in the art of organic / pharmaceutical chemistry, as exemplified by the following methods.

[0211] The following conventional reaction scheme is a general description of a representative preparation method for compounds of Formula I. Those skilled in the art will be able to easily prepare compounds of Formula I by selecting suitable starting materials, reaction temperatures, reaction conditions, catalysts, solvents, processing methods, etc., based on the preparation methods specifically disclosed in the examples herein.

[0212] For example, compounds of formula I having a thiophene ring can be prepared according to the following reaction schemes 1 to 5:

[0213] [Reaction Scheme 1]

[0214]

[0215] [Reaction Scheme 2]

[0216]

[0217]

[0218] [Reaction Scheme 3]

[0219]

[0220]

[0221] [Reaction Scheme 4]

[0222]

[0223]

[0224] [Reaction Scheme 5]

[0225]

[0226]

[0227] For example, compounds of formula I having a fused 4H-thiopheno[3,2-b]pyrrole ring can be prepared according to the following reaction scheme 6:

[0228] [Reaction Scheme 6]

[0229]

[0230]

[0231]

[0232] When preparing compounds according to reaction schemes 1 to 6 above, suitable amino-cycloalkyl-carboxylic acid esters, such as methyl 3-aminocyclobutane-1-carboxylate, methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate, methyl 4-aminobicyclo[1.1.1]octane-1-carboxylate, etc., can be used instead of methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride to prepare compounds in which various cyclic structures are bonded to amide bonds.

[0233] Pharmaceutical applications, pharmaceutical compositions, and methods of administration

[0234] On the other hand, a pharmaceutical composition is provided for the prevention or treatment of diseases associated with prostaglandin E2 overexpression and / or prostaglandin E2 receptor overexpression, comprising a compound, its solvate, stereoisomer, or pharmaceutically acceptable salt as shown in 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 above as an active ingredient.

[0235] In this invention, the term "prevention" refers to the prevention of disease, such as the prevention of disease, symptom or disorder in a subject who may be susceptible to the disease, symptom or disorder but has not yet experienced or exhibited the pathology or signs of the disease.

[0236] In this invention, the term "treatment" refers to suppressing a disease, for example, suppressing the disease, condition, or disorder in a subject who experiences or exhibits the pathology or signs of a disease, symptom, or disorder, i.e., preventing the further development of the pathology and / or signs, or improving the disease, for example, improving the disease, symptom, or disorder in a subject who experiences or exhibits the pathology or signs of a disease, symptom, or disorder, i.e., reversing the pathology and / or signs, for example, reducing the severity of the disease.

[0237] The term "diseases associated with prostaglandin E2 overexpression and / or prostaglandin E2 receptor overexpression" refers to the diseases that the pharmaceutical composition aims to prevent or treat. These diseases are closely related to the activity of prostaglandin E2 and can refer to diseases for which effective therapeutic effects can be achieved through antagonism of prostaglandin E2 or its receptor. The diseases associated with prostaglandin E2 overexpression and / or prostaglandin E2 receptor overexpression can be diseases caused by the overexpression or overactivation of prostaglandin E2 and / or its receptor. These diseases can include, for example, cancer, neurodegenerative diseases, or inflammatory diseases. The cancers mentioned may include, for example, squamous cell carcinoma, basal cell carcinoma, glioma, 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, bile duct cancer, choriocarcinoma, oral cancer, neuroblastoma, skin cancer, testicular cancer, stromal tumor, germ cell tumor, or thyroid cancer, but are not limited thereto. The neurodegenerative diseases mentioned may include epilepsy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), or traumatic brain injury, but are not limited thereto. The inflammatory diseases mentioned may include edema, allergies, asthma, conjunctivitis, periodontitis, rhinitis, otitis media, pharyngitis, tonsillitis, pneumonia, gastric ulcer, gastritis, Crohn's disease, colitis, hemorrhoids, gout, ankylosing spondylitis, rheumatic fever, lupus, fibromyalgia, psoriatic arthritis, osteoarthritis, rheumatoid arthritis, frozen shoulder, tendinitis, tenosynovitis, myositis, hepatitis, cystitis, nephritis, Sjögren's syndrome, or multiple sclerosis, but are not limited to these.

[0238] When used to treat cancer, the compounds of the present invention can be used alone or in combination with other anticancer 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; antimicrotubule agents such as vincristine and paclitaxel; topoisomerase inhibitors such as topotecan and doxorubicin).

[0239] In one embodiment, compounds such as those of 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 potent inhibitory activity against prostaglandin E2 receptors such as EP2 and / or EP4, and exert therapeutic effects by modulating prostaglandin E2 activity through the antagonistic effect on prostaglandin E2 receptors as described above. Therefore, compounds such as those of 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 may be used to treat diseases associated with prostaglandin E2 overexpression and / or prostaglandin E2 receptor overexpression.

[0240] In one embodiment, the pharmaceutical composition may comprise conventional, pharmaceutically acceptable carriers, excipients, or additives. The pharmaceutical composition may be formulated using conventional methods and can be produced in various oral dosage forms, such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions, or parenteral dosage forms, such as intramuscular, intravenous, or subcutaneous injections.

[0241] When the pharmaceutical composition is formulated into an oral dosage form, examples of additives or carriers used may include cellulose, calcium silicate, corn starch, lactose, sucrose, glucose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents, etc. When the pharmaceutical composition of the present invention is formulated into an injectable dosage form, additives or carriers may include water, physiological saline, aqueous glucose solution, similar aqueous sugar solution, alcohol, glycol, ether (e.g., polyethylene glycol 400), oil, fatty acids, fatty acid esters, glycerides, surfactants, suspending agents, emulsifiers, etc.

[0242] The dosage of the pharmaceutical composition is an effective amount for treatment or prevention in a subject or patient, and may be administered orally or parenterally as needed. When administered orally, the dosage is 0.01 to 1000 mg per kg body weight daily, more specifically, 0.1 to 300 mg per kg body weight, based on the active ingredient, administered in one to several divided doses. When administered parenterally, the dosage is 0.01 to 100 mg per kg body weight daily, more specifically, 0.1 to 50 mg per kg body weight, based on the active ingredient. The dosage for a specific subject or patient should be determined based on several relevant factors, including weight, age, sex, patient's health condition, diet, time of administration, route of administration, and severity of disease. It should be understood that the dosage may be appropriately increased or decreased by an expert. The above dosages are not intended to limit the scope of the invention in any way. A physician or veterinarian of ordinary skill in the art can readily determine and prescribe the required effective amount of the pharmaceutical composition. For example, the dosage of the compound of the invention used in a pharmaceutical composition prescribed by a physician or veterinarian may begin below the level required to achieve the desired therapeutic effect and may be gradually increased until the desired effect is achieved.

[0243] In one embodiment, the pharmaceutical composition within its scope includes a pharmaceutical composition comprising, alone, a therapeutically effective amount of at least one compound according to a certain embodiment as an active ingredient, or comprising a combination of the compound and a drug carrier. The terms "therapeutically effective amount" or "effective amount" refer to an amount sufficient to produce a beneficial or desired clinical outcome, such as an amount sufficient to alleviate, improve, stabilize, reverse, slow, or delay the progression of a disease.

[0244] Optionally, the compound according to one embodiment may be administered alone, in combination with a compound according to another embodiment, or simultaneously, separately, or sequentially in combination with one or more other therapeutic agents, such as anticancer agents or other pharmaceutically active substances. The anticancer agents include, for example, anticancer agents, anti-angiogenic agents, anti-inflammatory agents, immunosuppressants, etc., and may be, for example, immunoanticancer agents, including known immune checkpoint inhibitors such as CTLA-4, PD-1, PD-L1, etc.

[0245] In another aspect, a method is provided for the prevention or treatment of diseases associated with prostaglandin E2 overexpression and / or prostaglandin E2 receptor overexpression, comprising administering to a subject a compound, solvate thereof, stereoisomer thereof, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a compound as shown in 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.

[0246] In the description of the method, the terms or elements that are the same as those already mentioned are as described above.

[0247] The administration may be oral or parenteral. When administered orally, the dose is 0.01 to 1000 mg per kg of body weight daily, more specifically, 0.1 to 300 mg per kg of body weight, divided into one or more doses based on the active ingredient. When administered parenterally, the dose is 0.01 to 100 mg per kg of body weight daily, more specifically, 0.1 to 50 mg per kg of body weight, based on the active ingredient. The dosage for a specific subject or patient should be determined based on several relevant factors, including weight, age, sex, patient's health status, diet, time of administration, route of administration, and severity of disease, and may be appropriately increased or decreased by a specialist physician.

[0248] In this invention, the term "subject" refers to a subject who needs treatment or prevention of a disease, and more specifically to mammals such as humans or non-human primates, mice, dogs, cats, horses, and cattle.

[0249] In another aspect, a compound, its solvate, stereoisomer, or pharmaceutically acceptable salt as shown in 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, is provided for pharmaceutical use in the prevention or treatment of diseases associated with prostaglandin E2 overexpression and / or prostaglandin E2 receptor overexpression; or the use of a compound, its solvate, stereoisomer, or pharmaceutically acceptable salt as shown in 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, in the preparation of a therapeutic agent for diseases associated with prostaglandin E2 overexpression and / or prostaglandin E2 receptor overexpression. Among the terms or elements mentioned in the description of the method or application, those identical to those already mentioned are those described above.

[0250] Invention Effects

[0251] According to one aspect, the compound, its solvate, stereoisomer, or pharmaceutically acceptable salt has potent inhibitory activity against prostaglandin E2 receptors such as EP2 and / or EP4.

[0252] Therefore, according to one aspect, the said compound, its solvates, stereoisomers, or pharmaceutically acceptable salts can be used as active ingredients in pharmaceutical compositions 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. Detailed Implementation

[0253] The present invention will be described in detail below through embodiments. However, the following embodiments are for illustrative purposes only, and the content of the present invention is not limited to the following embodiments.

[0254] [Preparation Example]

[0255] Preparation Example 1: Methyl 6-aminospiro[3.3]heptane-2-carboxylic acid hydrochloride

[0256]

[0257] Methyl 6-((tert-butoxycarbonyl)amino)spiro[3.3]heptane-2-carboxylic acid (10 g, 37.1 mmol) was added to a 4N HCl solution of dioxane and stirred for 15 hours, then concentrated under reduced pressure. The crude product was washed with ether (100 mL) and dried to give intermediate A (7.32 g, 96% yield), a white solid. 1 H NMR (300Hz, DMSO-d6) δ8.09 (bs, 2H), 3.58 (s, 3H), 3.03 (p, J = 8.4Hz, 1H), 2.43-2.31 (m, 1H), 2.28-1.95 (m, 6H).

[0258] Preparation Example 2: Methyl 2-azidoacetate

[0259]

[0260] NaN3 (4.88 g, 75.0 mmol) was added to a DMSO (0.5 M) solution of methyl 2-bromoacetate (7.65 g, 50.0 mmol), and the mixture was stirred for 24 hours. The reaction solution was diluted with EtOAc (100 mL) and washed with distilled water. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to give intermediate B (4.09 g, 75% yield), a colorless liquid. 1 H NMR (300MHz, chloroform-d) δ3.91 (s, 2H), 3.83 (s, 3H).

[0261] Preparation Example 3: 3-Bromo-2,5-Dimethylthiophene

[0262]

[0263] NBS (17.8 g, 100 mmol) was added to a 0.2 M acetic acid solution of 11.2 g (100 mmol) of 2,5-dimethylthiophene and stirred for 15 hours. 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 sodium sulfate 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(300MHz,chloroform-d)δ6.60-6.56(m,1H),2.42(s,3H),2.35(s,3H).

[0264] Preparation Example 4: Methyl 4-bromo-2,5-dimethylthiophene-3-carboxylic acid

[0265] Step 1: Synthesis of 3,4-dibromo-2,5-dimethylthiophene

[0266]

[0267] At -78°C, n-BuLi (25.0 mL, 50.0 mmol, 2.5 equivalences in 2.0 M cyclohexane solution, 8.0 g, 20.0 mmol, 1.0 equivalences) in THF (60 mL, 0.3 M) was added, and the mixture was stirred at -78°C for 1 hour. Iodomethane (3.8 mL, 60.0 mmol, 3.0 equivalences) was added, and the mixture was stirred at room temperature for 20 hours. The reaction mixture was then extracted with EtOAc in saturated ammonium chloride solution. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The crude product was purified by column chromatography to give 3,4-dibromo-2,5-dimethylthiophene (4.9 g, 90% yield).

[0268] Step 2: Synthesis of 4-bromo-2,5-dimethylthiophene-3-carboxylic acid

[0269]

[0270] At -78 °C, n-BuLi (2.0 M cyclohexane solution, 8.2 mL, 0.9 equivalent) was added to a THF (60 mL) solution of 3,4-dibromo-2,5-dimethylthiophene (4.9 g, 18.1 mmol, 1.0 equivalent) and stirred at -78 °C for 30 min. Excess dry ice was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was added to 1 N NaOH and extracted with Et₂O. The aqueous layer was acidified with 1 N HCl solution. The precipitate was removed by filtration, washed with distilled water, and dried to give 4-bromo-2,5-dimethylthiophene-3-carboxylic acid (3.3 g, 77% yield).

[0271] Step 3: Synthesis of methyl 4-bromo-2,5-dimethylthiophene-3-carboxylic acid ester

[0272]

[0273] Iodomethane (1.4 mL, 22.4 mmol, 2.0 equivalent) was added to a DMF (15 mL) solution of 4-bromo-2,5-dimethylthiophene-3-carboxylic acid (2.64 g, 11.2 mmol, 1.0 equivalent) and K₂CO₃ (3.1 g, 22.4 mmol, 2.0 equivalent), and the mixture was stirred for 12 hours. The reaction solution was added to distilled water and extracted with DCM. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The crude product was purified by column chromatography to give intermediate D (2.55 g, 91% yield).

[0274] Preparation Example 5: 3-Fluoro-[1,1'-Biphenyl]-4-carboxylic acid

[0275]

[0276] To 1.0 g phenylboronic acid (8.20 mmol, 1.0 equivalent) and 1.80 g 4-bromo-2-fluorobenzoic acid (8.20 mmol, 1.0 equivalent), 6.47 g of 26% Me₄N·OH aqueous solution (18.45 mmol, 2.25 equivalent) was added, and the mixture was stirred at 50 °C. Under Ar-substitution conditions, 25 mL of distilled water and 25 mg of 5% Pd / C (0.025 w / w) were added, and the mixture was stirred at 80 °C for 1.5 h. The reaction solution was cooled to room temperature, and Pd / C was removed by diatomaceous earth filtration. 2.2 mL of 6M HCl aqueous solution (13.12 mmol, 1.6 equivalent) was added to the reaction solution. After neutralization and crystallization, 10 mL of distilled water was added, and the mixture was stirred for 30 min. The precipitated crystals were washed with distilled water and then dried under reduced pressure to give intermediate E (1.5 g, 85% yield). 1 H NMR (500MHz, Chloroform-d) δ8.14 (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] + .

[0277] Preparation Example 6: 2-Amino-[1,1'-biphenyl]-4-formyl chloride

[0278] Step 1: Synthesis of 2-amino-[1,1'-biphenyl]-4-carboxylic acid

[0279]

[0280] 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 hours. The reaction solution was cooled to room temperature, filtered through a diatomaceous earth stopper, 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 (300MHz, DMSO-d6) δ12.69(s,1H),7.47(d,J=6.5Hz,4H),7.41-7.34(m,2H),7.21(dd,J=7.9,1.6Hz,1H),7.08(d,J=7.8Hz,1H),5.04(s,2H).

[0281] Step 2: Synthesis of 2-amino-[1,1'-biphenyl]-4-formyl chloride

[0282]

[0283] Thionyl chloride (3.5 mL, 48.1 mmol) was added to a solution of 2-amino-[1,1'-biphenyl]-4-carboxylic acid (2.5 g, 11.73 mmol) in ethyl acetate (39 mL, 0.3 M) with stirring. The reaction mixture was stirred under reflux for 4 hours, then cooled to room temperature and concentrated under reduced pressure to give intermediate F (2.95 g).

[0284] Preparation Example 7: (2'-methoxy-[1,1'-biphenyl]-4-yl)methanol

[0285] Step 1: Synthesis of methyl 2'-methoxy-[1,1'-biphenyl]-4-carboxylic acid

[0286]

[0287] 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 2-bromoanisole (0.75 mL, 6 mmol) in toluene (0.6 M) was stirred at 100 °C for 6 hours. The reaction mixture was extracted with ethyl acetate (20 mL × 3), the organic layer was washed with brine, dried over sodium sulfate, 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-carboxylic acid (507 mg, yield 35%). 1H NMR(500MHz, CDCl3)δ8.08(d,J=8.4Hz,2H),7.61(d,J=8.4Hz,2H),7.39-7.30( m, 2H), 7.04 (s, 1H), 6.99 (d, J = 8.2Hz, 1H), 3.93 (d, J = 1.9Hz, 3H), 3.81 (s, 3H).

[0288] Step 2: Synthesis of (2'-methoxy-[1,1'-biphenyl]-4-yl)methanol

[0289]

[0290] Methyl 2'-methoxy-[1,1'-biphenyl]-4-carboxylic acid (507 mg, 2.09 mmol) was dissolved in THF (0.2 M), and LiAlH4 (397 mg, 10.5 mmol) was added. The mixture was stirred for 3 hours. The reaction solution was cooled to 0 °C, and then distilled water (1.6 mL) and NaOH aqueous solution were added. The solution was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane:ethyl acetate = 7:3) to give intermediate G (340 mg). 1 H NMR (500MHz, CDCl3) δ7.55(d,J=8.1Hz,2H),7.41(d,J=7.9Hz,2H),7.34(d,J=7.5H z, 2H), 7.05 (s, 1H), 7.01 (d, J = 8.0Hz, 1H), 4.70 (s, 2H), 3.81 (s, 3H), 2.23 (s, 1H).

[0291] Preparation Example 8: 3-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)aniline

[0292]

[0293] Under a nitrogen atmosphere, bis(pinacol)diboron (1.1 g, 4.4 mmol), KOAc (1.18 g, 12 mmol), and Pd(dppf)Cl2 (146.0 mg, 0.2 mmol) were added to a dioxane (20.0 mL) solution of 3-fluoro-5-bromoaniline (380 mg, 2.0 mmol) and stirred at 90 °C for 32 hours. The reaction solution was cooled to room temperature, filtered through diatomaceous earth, and washed with EtOAc. The organic layer was concentrated under reduced pressure to give intermediate H (1.4 g).

[0294] Preparation Example 9: 2-(3-fluoro-5-(methylthio)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane

[0295] Step 1: Synthesis of (3-bromo-5-fluorophenyl)(methyl)thion

[0296]

[0297] A solution of 3,5-difluorobromobenzene (3 g, 15.54 mmol) in N,N-dimethylformamide (30 mL) was cooled to 0 °C, and sodium methanethiol solution (7.1 mL, 15.54 mmol) was added. The mixture was stirred for 30 minutes. The reaction solution was diluted with distilled water, extracted with hexane, washed with brine, and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to give (3-bromo-5-fluorophenyl)(methyl)thione (2.6 g, 75% yield) as a clear liquid.

[0298] Step 2: Synthesis of 2-(3-fluoro-5-(methylthio)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxane-pentaborane become

[0299]

[0300] Under a nitrogen atmosphere, a sealed tube containing (3-bromo-5-fluorophenyl)(methyl)thione (1 g, 4.523 mmol), potassium acetate (2.2 g, 22.615 mmol), (pinacol)diboron (1.7 g, 6.784 mmol), and Pd(dppf)Cl2 (forming a complex with DCM; 369 mg, 0.452 mmol) was purged. Dioxane was added, and the mixture was stirred at 80 °C for 12 hours. The reaction solution was cooled to room temperature, and ethyl acetate was added. The precipitate was removed by diatomaceous earth filtration. The organic layer was concentrated under reduced pressure, and the crude product was purified by rapid column chromatography (hexane / ethyl acetate, concentration 0% to 100%) to give intermediate I (932 mg, yield 70%) as a yellow liquid.

[0301] Preparation Example 10: 3-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzamide

[0302] Step 1: Synthesis of 3-bromo-5-fluorobenzamide

[0303]

[0304] A solution of 3-bromo-5-fluorobenzoic acid (1 g, 4.566 mmol) in thionyl chloride (4 mL) was stirred under reflux for 2 hours. The reaction solution was concentrated under reduced pressure, and 1.5 mL of 28% ammonia solution was added, followed by stirring for 12 hours. The reaction solution was washed three times with distilled water to give 3-bromo-5-fluorobenzamide (533 mg, yield 54%) as a white solid. 1 H NMR (300MHz, Chloroform-d) δ7.74-7.72(m,1H),7.49-7.45(m,1H),7.44-7.40(m,1H),5.83(s,2H).

[0305] Step 2: Synthesis of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzamide

[0306]

[0307] 3-Bromo-5-fluorobenzamide was reacted using the same method as in Preparation Example 8 to give intermediate J.

[0308] Preparation Example 11: 3-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzamide

[0309]

[0310] Except that 3-bromo-5-fluorobenzoic acid in step 1 was replaced with 3-bromo-5-methoxybenzoic acid, intermediate K was obtained using the same method as in Preparation Example 10. 1 H NMR (300MHz, DMSO-d6) δ8.03(s,1H),7.77(dd,J=1.6,0.9Hz,1H),7.53(dd,J=2.7,1.6 Hz, 1H), 7.33 (s, 1H), 7.27 (dd, J = 2.7, 0.9Hz, 1H), 3.81 (s, 3H), 1.16 (d, J = 2.6Hz, 12H).

[0311] Preparation Example 12: (3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzyl)tert-butyl carbamate

[0312] Step 1: Synthesis of (3-bromo-5-methoxyphenyl)methylamine

[0313]

[0314] 3-Bromo-5-methoxybenzonitrile (1 g, 4.716 mmol) was dissolved in THF (9 mL), and then BH3-THF (1 M THF solution, 6 mL, 5.895 mmol) was slowly added at 0 °C. The reaction mixture was stirred at 80 °C for 16 hours, then the solvent was concentrated under reduced pressure and acidified with 1 N HCl. The reaction mixture was stirred at room temperature for 2 hours, and then EA and distilled water were added to extract the aqueous layer. The aqueous layer was neutralized with 2 N NaOH (pH = 10) and then extracted with EA and brine. The organic layer was concentrated under reduced pressure to give (3-bromo-5-methoxyphenyl)methylamine (741 mg, yield 72%). 1 H NMR (300MHz, Chloroform-d) δ7.08-7.03 (m, 1H), 6.92 (t, J = 2.0Hz, 1H), 6.83-6.79 (m, 1H), 3.81 (s, 2H), 3.78 (s, 3H).

[0315] Step 2: Synthesis of tert-butyl (3-bromo-5-methoxybenzyl)carbamate

[0316]

[0317] (3-Bromo-5-methoxyphenyl)methylamine (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 the mixture was stirred for 16 hours. The DCM was partially concentrated and extracted with ethyl acetate and brine. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (EA:hexane = 1:3) to give tert-butyl (3-bromo-5-methoxybenzyl)carbamate (766 mg, 70% yield). 1 H NMR (300MHz, Chloroform-d) δ7.00 (s, 1H), 6.94 (t, J = 2.1Hz, 1H), 6.75 (s, 1H), 4.84 (s, 1H), 4.25 (s, 2H), 3.78 (s, 3H), 1.46 (s, 9H).

[0318] Step 3: (3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)benzyl)amino Synthesis of tert-butyl formate

[0319]

[0320] (3-Bromo-5-methoxybenzyl)carbamate tert-butyl ester was reacted using the same method as in Preparation Example 8 to give intermediate L. 1 HNMR(300MHz,Chloroform-d)δ7.30(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).

[0321] Preparation Example 13: 3-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl)methanol

[0322] Step 1: Synthesis of (3-bromo-5-fluorophenyl)methanol

[0323]

[0324] 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 excess methanol was added. The above solution, diluted with ethyl acetate, was washed with 1 N sodium hydroxide aqueous solution and brine, dried over sodium sulfate, and then concentrated under reduced pressure. The crude product was purified by column chromatography (0 to 30% ethyl acetate / hexane) to give (3-bromo-5-fluorophenyl)methanol (400 mg, 65% yield). 1 H NMR (300MHz, CDCl3) δ7.33-7.28 (m, 1H), 7.17 (dt, J = 8.1, 2.1Hz, 1H), 7.04 (ddd, J = 9.1, 2.4, 1.3Hz, 1H), 4.69 (s, 2H).

[0325] Step 2: Synthesis of (3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl)methanol become

[0326]

[0327] (3-bromo-5-fluorophenyl)methanol was reacted using the same method as in Preparation Example 8 to give intermediate M.

[0328] Preparation Example 14: 3-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl)oxacyclobut-3-ol

[0329] Step 1: Synthesis of 3-(3-bromo-5-methoxyphenyl)oxetane-3-ol

[0330]

[0331] At -78°C, TMEDA (923 μL, 6.0 mmol) and n-BuLi (2.4 mL, 6.0 mmol) in a 0.2 M THF solution of 1,3-dibromo-5-methoxyphenyl (1.06 g, 4.0 mmol) were added, and the mixture was stirred for 1 hour. Oxybutanone (1.02 mL, 4.8 mmol) was added to the reaction mixture, and the temperature was slowly raised to room temperature. After 4 hours, the resulting reaction mixture was diluted with 40 mL of ammonium chloride aqueous solution and 40 mL of ethyl acetate. The aqueous layer was extracted with 40 mL of ethyl acetate. The organic layer was dried over sodium sulfate 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)oxybutan-3-ol (443.0 mg of mixture, approximately 320.0 mg, yield 31%), as a colorless oil. 1H NMR (500MHz, CDCl3) δ7.34 (s, 1H), 7.07 (d, J = 2.0Hz, 1H), 7.00 (d, J = 2.0Hz, 1H), 4.86 (d, J = 6.8Hz, 2H), 4.83 (d, J = 7.0Hz, 2H), 3.80 (s, 4H).

[0332] Step 2: 3-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl)oxy Synthesis of heterocyclic but-3-ol

[0333]

[0334] 3-(3-bromo-5-methoxyphenyl)oxetane-3-ol was reacted using the same method as in Preparation Example 8 to give intermediate N. 1 HNMR (500MHz, CDCl3) δ7.57(s,1H),7.27(d,J=2.6Hz,1H),7.19(dd,J=2.6,1.8H z, 1H), 4.94 (d, J = 6.9Hz, 2H), 4.87 (d, J = 6.8Hz, 2H), 3.84 (s, 3H), 1.33 (s, 12H).

[0335] Preparation Example 15: 1-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl)azacyclobut-2-one

[0336] Step 1: Synthesis of 1-(3-methoxyphenyl)azacyclobut-2-one

[0337]

[0338] To a 0.8 M toluene solution of 1-iodo-3-methoxybenzene (936.1 mg, 4.0 mmol), azacyclobutanone (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 room temperature and diluted with brine (20 mL) and ethyl acetate (20 mL). The aqueous layer was extracted with ethyl acetate (20 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane:ethyl acetate = 2:1) to give 1-(3-methoxyphenyl)azacyclobutanone-2-one (436.0 mg, yield 61%) as a colorless oil (436.0 mg, 61%). 1H NMR(500MHz, CDCl3)δ7.14(t,J=8.1Hz,1H),6.92(s,1H),6.78(dd,J=8.1,1.9Hz,1H), 6.56 (dd, J=8.4, 2.5Hz, 1H), 3.72 (s, 3H), 3.48 (t, J=4.5Hz, 2H), 2.98 (d, J=4.5Hz, 2H).

[0339] Step 2: 1-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaneborane-2-yl)phenyl)nitrogen Heterocyclic 2-one

[0340]

[0341] To a cyclohexane (0.1 M) solution of 1-(3-methoxyphenyl)azacyclobut-2-one (436.0 mg, 2.46 mmol), [Ir(cod)OMe]2 (195.7 mg, 0.295 mmol), 4,4'-di-tert-butyl-2'-bipyridine (dtbpy) (158.5 mg, 0.590 mmol), bis(pinacol)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 hours. The reaction mixture was cooled to room temperature, diluted with brine (40 mL) and ethyl acetate (40 mL), and the aqueous layer was extracted with ethyl acetate (40 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane:ethyl acetate = 1:1) to obtain intermediate O (405.2 mg, yield 54%), which was a yellow solid. 1 H NMR (500MHz, CDCl3) δ7.32 (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).

[0342] Preparation Example 16: (3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzyl)tert-butyl carbamate

[0343]

[0344]

[0345] Except that 3-bromo-5-methoxybenzonitrile in step 1 of Preparation Example 12 was replaced with 3-bromo-5-fluorobenzonitrile, intermediate P was obtained using the same method as in Preparation Example 12.

[0346] Preparation Example 17: tert-butyl 3-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl)azacyclobutane-1-carboxylate

[0347] Step 1: Synthesis of tert-butyl 3-(3-bromo-5-fluorophenyl)azacyclobutane-1-carboxylate

[0348]

[0349] 3-(2-((4-methoxyphenyl)sulfonyl)hydrazine)azacyclobutane-1-carboxylic acid tert-butyl ester (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 dioxane (10.0 mL, 0.3 M). The tube was sealed and stirred at 110 °C for 15 hours. The reaction mixture was cooled to room temperature, quenched with saturated sodium bicarbonate aqueous solution (30 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by rapid column chromatography (10 to 30% ethyl acetate / hexane) to give 3-(3-bromo-5-fluorophenyl)azacyclobutane-1-carboxylic acid tert-butyl ester (261 mg, 28%). 1 HNMR(300MHz,Chloroform-d)δ7.28(d,J=3.8Hz,1H),7.16(dt,J=8.1,2.0Hz,1H),7.00(dt,J=9.3, 1.8Hz, 1H), 4.34 (t, J = 8.7Hz, 2H), 3.93 (dd, J = 8.7, 5.8Hz, 2H), 3.69 (d, J = 14.4Hz, 1H), 1.49 (s, 9H).

[0350] Step 2: 3-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)phenyl)azo-heterocyclic ring Synthesis of tert-butyl butane-1-carboxylate

[0351]

[0352] 3-(3-bromo-5-fluorophenyl)azacyclobutane-1-carboxylic acid tert-butyl ester was reacted using the same method as in Preparation Example 8 to give intermediate Q. 1 H NMR(300MHz,Chloroform-d)δ7.50(s,1H),7.39(dd,J=8.7,2.2Hz,1H),7.14(dt,J=9.8,2.1Hz,1H),4.34(t ,J=8.7Hz,2H),4.00(dd,J=8.6,6.0Hz,2H),3.77(ddd,J=12.8,7.8,5.1Hz,1H),1.49(s,9H),1.37(s,12H).

[0353] Preparation Example 18: Methyl 6-(methylamino)spiro[3.3]heptane-2-carboxylic acid hydrochloride

[0354] Step 1: Synthesis of methyl 6-((tert-butoxycarbonyl)(methyl)amino)spiro[3.3]heptane-2-carboxylic acid

[0355]

[0356] 60% NaH (60 mg, 1.50 mmol) was added to a THF (0.1 M) stirred solution of methyl 6-((tert-butoxycarbonyl)(methyl)amino)spiro[3.3]heptane-2-carboxylate (269 mg, 1.0 mmol). The mixture was stirred at 0 °C for 15 minutes. Iodomethane (0.2 mL, 3.0 mmol) was then added to the reaction solution, and the mixture was stirred for 20 hours. The reaction solution 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 sodium sulfate, and then concentrated under reduced pressure to obtain methyl 6-((tert-butoxycarbonyl)(methyl)amino)spiro[3.3]heptane-2-carboxylate (288 mg, crude product), which was a yellow liquid. 1 H NMR (400MHz, chloroform-d) δ4.6-4.14(m,1H),3.69(s,3H),3.05(p,J=8.5Hz,1H),2.39-2.25(m,1H),2.2-2.00(m,1H),1.47(s,9H).

[0357] Step 2: Synthesis of methyl 6-(methylamino)spiro[3.3]heptane-2-carboxylic acid hydrochloride

[0358]

[0359] At 0 °C, 4N HCl dioxane solution was added to methyl 6-((tert-butoxycarbonyl)(methyl)amino)spiro[3.3]heptane-2-carboxylate (288 mg, 1.02 mmol), and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of intermediate R (244 mg), which was a yellow solid. 1 H NMR (400MHz, DMSO) δ9.07(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).

[0360] Preparation Example 19: 4-(((tert-butyldimethylsilyl)oxy)methyl)-2,5-dimethylthiophene-3-carboxylic acid

[0361] Step 1: Synthesis of 4-bromo-2,5-dimethylthiophene-3-carboxaldehyde

[0362]

[0363] At -78°C, n-BuLi (2.5M THF solution, 9.4mL, 23.6mmol) was added to a THF (0.4M) solution of 3,4-dibromo-2,5-dimethylthiophene (6.37g, 23.6mmol) and TMEDA (3.9mL, 26mmol), and the mixture was stirred for 1 hour. DMF was added to the reaction mixture, and the mixture was then slowly heated to room temperature and stirred for 15 hours. The reaction mixture was quenched with distilled water (20mL), acidified with 1N HCl solution, and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to give 4-bromo-2,5-dimethylthiophene-3-carboxaldehyde (3.64g), a grayish-white solid. 1 H NMR (300MHz, CDCl3) δ10.03(s,0H),2.74(s,1H),2.38(s,1H).

[0364] Step 2: Synthesis of (4-bromo-2,5-dimethylthiophene-3-yl)methanol

[0365]

[0366] At 0 °C, LiAlH4 (191 mg, 5.02 mmol) was added to a THF (0.2 M) solution of 4-bromo-2,5-dimethylthiophene-3-carboxaldehyde (1.10 g, 5.02 mmol), and the mixture was stirred for 2 hours. The reaction solution was quenched with EtOAc (1 mL) and ice water (0.3 mL), stirred for 30 minutes, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (20% EtOAc in hexane solution) to obtain (4-bromo-2,5-dimethylthiophene-3-yl)methanol (754 mg, yield 68%), as a colorless liquid. 1 H NMR (400MHz, DMSO); δ4.33(s,1H),2.40(s,3H),2.36(s,1H),2.30(s,3H).

[0367] Step 3: Synthesis of ((4-bromo-2,5-dimethylthiophen-3-yl)methoxy)(tert-butyl)dimethylsilane

[0368]

[0369] To a solution of (4-bromo-2,5-dimethylthiophene-3-yl)methanol (950 mg, 4.30 mmol) in THF (0.2 M, 0 °C), tert-butyldimethylchlorosilane (777 mg, 5.16 mmol) and imidazole (439 mg, 6.44 mmol) were added, and the mixture was stirred for 24 hours. The reaction solution was diluted with EtOAc (20 mL) and washed with distilled water (2 × 20 mL). The organic layer was dried over sodium sulfate, 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-dimethylthiophene-3-yl)methoxy)(tert-butyl)dimethylsilane (937 mg, yield 65%) as a colorless liquid. 1 H NMR (300MHz, chloroform-d) δ4.60(s,1H),2.45(s,2H),2.35(s,2H),1.57(s,1H),0.94(s,4H),0.12(s,3H).

[0370] Step 4: Synthesis of 4-(((tert-butyldimethylsilyl)oxy)methyl)-2,5-dimethylthiophene-3-carboxylic acid

[0371]

[0372] At -78°C, n-BuLi (0.44 mL, 1.10 mmol in 2.5 M THF solution) was added to a solution of ((4-bromo-2,5-dimethylthiophene-3-yl)methoxy)(tert-butyl)dimethylsilane (335 g, 1.0 mmol) and TMEDA (165 μL, 1.10 mmol) in THF (0.2 M), and the mixture was stirred for 1 hour. The reaction mixture was quenched with CO2 gas at -78°C, then slowly heated to room temperature and stirred for 15 hours. The reaction mixture was quenched with distilled water (20 mL), acidified with 1 N HCl solution, and then extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The crude product was purified by column chromatography (20% ethyl acetate in hexane solution) to give intermediate S (300 mg) as a white solid. 1 H NMR(300MHz,chloroform-d)δ4.74(s,2H),2.67(s,3H),2.38(s,3H),0.94(s,9H),0.18(s,6H).

[0373] Preparation Example 20: Methyl 3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid

[0374] Step 1: Synthesis of (Z)-2-azido-3-(4-bromothiophene-2-yl)methyl acrylate

[0375]

[0376] At -25°C, 4M NaOMe (15 mL, 60.0 mmol) was added to a MeOH (30 mL) solution of 4-bromothiophene-2-carboxaldehyde (3.82 g, 20.0 mmol, 1.0 equivalent) and intermediate B (6.91 g, 60.0 mmol, 3.0 equivalent), and the mixture was stirred at 0°C for 2 hours. Ice was added to the reaction mixture, and the solution was washed with distilled water, filtered, and then dried to give (Z)-2-azido-3-(4-bromothiophene-2-yl)methyl acrylate. 1 H NMR (300MHz, chloroform-d) δ7.37 (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).

[0377] Step 2: Synthesis of methyl 3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid

[0378]

[0379] A solution of (Z)-2-azido-3-(4-bromothiophene-2-yl)methyl acrylate (4.79 g, 16.6 mmol, 1.0 equivalent) in o-xylene (60 mL) was stirred at 160 °C for 1 hour. The reaction solution was partially concentrated, filtered, washed with hexane, and dried to give intermediate T. 1 H NMR (300MHz, chloroform-d) δ9.10 (s, 1H), 7.23 (s, 1H), 7.15 (d, J = 1.9Hz, 1H), 3.93 (s, 3H).

[0380] Preparation Example 21: Methyl 3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid ester

[0381] Step 1: Preparation of 4-bromo-5-methylthiophene-2-carboxaldehyde

[0382]

[0383] Bromine (1.7 mL, 33 mmol) was added to a THF (0.5 M) solution of 2.78 g (22.0 mmol) of 5-methylthiophene-2-carboxaldehyde at 0 °C, and the mixture was stirred for 25 hours. 30 mL of 10% Na₂S₂O₃ aqueous solution and 30 mL of 10% NaHCO₃ aqueous solution were added to the reaction mixture, and the mixture was extracted with EtOAc (150 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give 4-bromo-5-methylthiophene-2-carboxaldehyde (862 mg, yield 16%) as a colorless solid. ¹H NMR (300 MHz, chloroform-d) δ 9.80 (s, 1H), 7.62 (s, 1H), 2.51 (s, 3H).

[0384] Step 2: Preparation of (Z)-2-azido-3-(4-bromo-5-methylthiophen-2-yl)methyl acrylate

[0385]

[0386] At -25°C, 4M NaOMe (3 mL, 11.6 mmol) and intermediate B (1.43 g, 12.4 mmol) were added to a MeOH (1.5 M) solution of 4-bromo-5-methylthiophene-2-carboxaldehyde (850 mg, 4.14 mmol). The reaction mixture was stirred at 0°C for 2 hours, then diluted with EtOAc and washed with a saline solution. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give (Z)-2-azido-3-(4-bromo-5-methylthiophene-2-yl)methyl acrylate (813 mg, yield 65%) as a yellow solid. ¹H NMR (300 MHz, chloroform-d) δ 7.15 (s, 1H), 6.99 (s, 1H), 3.91 (s, 3H), 2.45 (s, 3H).

[0387] Step 3: Preparation of methyl 3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid

[0388]

[0389] A 4 mL xylene solution of (Z)-2-azido-3-(4-bromo-5-methylthiophene-2-yl)acrylate (795 mg, 2.63 mmol) was added to 5 mL of o-xylene over 10 minutes. After stirring under reflux for 1 hour, the reaction mixture was cooled to room temperature and partially concentrated. The solid was filtered to give intermediate U (554 mg, 77% yield), a grayish-white solid. 1 H NMR (300MHz, chloroform-d) δ8.99 (s, 1H), 7.10 (d, J = 1.9Hz, 1H), 3.93 (s, 3H), 2.50 (s, 3H).

[0390] Preparation Example 22: Ethyl 3-bromo-6-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid

[0391] Step 1: Synthesis of 1-(3,4-dibromothiophene-2-yl)ethyl-1-one

[0392]

[0393] At 0 °C, 3,4-dibromothiophene (1.2 g, 5.0 mmol) was added to a 20 mL solution of AlCl3 (1.33 g, 10.0 mmol, 2.0 equivalents) in DCM, and the mixture was stirred for 10 minutes. Acetyl chloride (360 μL, 5.0 mmol, 1.0 equivalents) was then added, and the mixture was stirred at 0 °C for 3 hours. The reaction mixture was acidified with 6 M HCl and extracted with DCM. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to give 1-(3,4-dibromothiophene-2-yl)ethyl-1-one. 1 H NMR (300MHz, Chloroform-d) δ7.63 (s, 1H), 2.72 (s, 3H).

[0394] Step 2: Synthesis of ethyl 3-bromo-6-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate

[0395]

[0396] A solution of 1-(3,4-dibromothiophene-2-yl)ethyl-1-one (1.42 g, 5.0 mmol), ethyl isocyanate (600 μL, 5.5 mmol, 1.1 equivalent), CuI (95 mg, 0.5 mmol, 0.1 equivalent), and Cs₂CO₃ (3.26 g, 10.0 mmol, 2.0 equivalent) in DMSO (5 mL) was stirred at 50 °C for 4 hours. Distilled water was added to the reaction mixture, and the mixture was extracted with DCM. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The crude product was purified by rapid column chromatography to give intermediate V (806 mg, yield 56%). 1 H NMR (300MHz, Chloroform-d) δ9.01 (s, 1H), 7.18 (s, 1H), 4.40 (q, J = 7.1Hz, 2H), 1.41 (t, J = 7.1Hz, 3H).

[0397] Preparation Example 23: Methyl 3-bromo-2-chloro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid

[0398] Step 1: Synthesis of 4-bromo-5-chlorothiophene-2-carboxaldehyde

[0399]

[0400] N-chlorosuccinimide (699 mg, 5.24 mmol) was added to a DMF (5 mL) solution of 4-bromothiophene-2-carboxaldehyde (500 mg, 2.62 mmol, 1.0 equivalent), and the mixture was stirred at 70 °C for 12 hours. Distilled water was added to the reaction solution, the solid was filtered off, washed with distilled water, and dried to give 4-bromo-5-chlorothiophene-2-carboxaldehyde (421 mg, 70% yield). 1 H NMR (300MHz, Chloroform-d) δ9.76 (s, 1H), 7.60 (s, 1H).

[0401] Steps 2 and 3: Synthesis of methyl 3-bromo-2-chloro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid

[0402]

[0403] 4-Bromo-5-chlorothiophene-2-carboxaldehyde was reacted using the same method as in Preparation Example 20 to give intermediate W. ¹H NMR (300 MHz, Chloroform-d) δ 9.04 (s, ¹H), 7.07 (d, J = 1.9 Hz, ¹H), 3.92 (s, ³H).

[0404] Preparation Example 24: 4'-(bromomethyl)-3-methoxy-1,1'-biphenyl

[0405] Step 1: Synthesis of (3'-methoxy-[1,1'-biphenyl]-4-yl)methanol

[0406]

[0407] 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 room temperature, filtered through diatomaceous earth, and extracted with EA and brine. The organic layer was dried over magnesium sulfate. The crude product was purified by silica gel column chromatography (EtOAc:hexane = 1:2) to give (3'-methoxy-[1,1'-biphenyl]-4-yl)methanol (1.00 g, 93% yield), as a yellow oil. 1 H NMR(300MHz,Chloroform-d)δ7.59(d,J=8.2Hz,2H),7.44(d,J=8.2Hz,2H),7.36(t,J=7.9Hz,1H),7. 21-7.16(m,1H),7.12(t,J=2.1Hz,1H),6.90(ddd,J=8.1,2.6,0.9Hz,1H),4.75(s,2H),3.87(s,3H).

[0408] Step 2: Synthesis of 4'-(bromomethyl)-3-methoxy-1,1'-biphenyl

[0409]

[0410] (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 the mixture was stirred at 0 °C for 10 min. PPh3 (1.35 g, 5.134 mmol) was slowly added, and the mixture was stirred for 40 min. The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (EtOAc:hexane = 1:25) to give intermediate X (1.14 g, 88% yield). 1 H NMR(300MHz,Chloroform-d)δ7.57(d,J=8.3Hz,2H),7.47(d,J=8.3Hz,2H),7.37(t,J=7.9H z,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).

[0411] Preparation Example 25: 4'-(bromomethyl)-3-fluoro-5-methoxy-1,1'-biphenyl

[0412]

[0413] Intermediate Y was obtained using (4-bromophenyl)methanol and (3-fluoro-5-methoxyphenyl)boronic acid as starting materials, following the same method as in Preparation Example 24. 1 H NMR (300MHz, Chloroform-d) δ7.59-7.54(m,2H),7.51-7.46(m,2H),6.90(dd,J=9.2,2.2Hz,2H),6.64(dt,J=10.5,2.3Hz,1H),4.57(s,2H),3.88(s,3H).

[0414] Preparation Example 26: (2R,4R,6R)-6-aminospiro[3.3]heptane-2-carboxylic acid methyl ester hydrochloride

[0415] Step 1: Synthesis of methyl 6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptane-2-carboxylic acid

[0416]

[0417] 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, with stirring at room temperature for 14 hours. The reaction mixture was extracted with ammonium chloride aqueous solution and DCM, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc:hexane = 1:1) to give methyl 6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptane-2-carboxylic acid (4.4 g, 99% yield). 1 H NMR (300MHz, CDCl3) δ7.40-7.28(m,5H),5.06(s,2H),4.84(d,J=8.3Hz,1H),4.11-3.97(m,1H),3.65(s,3H),3.01(p,J=8.5Hz, 1H), 2.50 (dt, J=12.0, 6.6Hz, 1H), 2.43-2.21 (m, 4H), 2.12 (ddd, J=11.7, 8.7, 2.8Hz, 1H), 1.84 (ddd, J=15.9, 11.3, 8.7Hz, 2H).

[0418] Step 2: Purification of methyl 6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptane-2-carboxylic acid

[0419]

[0420] 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, separating compounds (2S,4S,6S)-6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptane-2-carboxylate (2.99 g) and (2R,4R,6R)-6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptane-2-carboxylate (0.88 g), which were yellow oily substances.

[0421] Chromatographic column: Daicel ChiralPak IG mobile phase (250 mm × 4.6 mm, 1 μm)

[0422] Mobile phase: [hexane / ethanol]; 80 / 20 (V / V), 9.4 min (2S, 4S, 6S), 10.7 min (2R, 4R, 6R)

[0423] Step 3: Synthesis of (2R,4R,6R)-6-aminospiro[3.3]heptane-2-carboxylic acid methyl ester hydrochloride

[0424]

[0425] Methyl (2R,4R,6R)-6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptane-2-carboxylic acid (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 solution was purged and stirred under H2 atmosphere for 16 hours. The reaction solution was filtered through diatomaceous earth and concentrated under reduced pressure. Dioxane (10.3 mL, 0.1 M) and 4N HCl solution (0.8 mL, 3.09 mmol) were added to the concentrated reaction solution, and the mixture was stirred for another 30 minutes. The reaction solution was concentrated under reduced pressure to give intermediate Z (180 mg).

[0426] Preparation Example 27: 4'-(bromomethyl)-3,5-dimethoxy-1,1'-biphenyl

[0427]

[0428] Starting with 1-bromo-3,5-dimethoxybenzene and ((4-hydroxy)tolyl)boronic acid, intermediate AA was obtained using the same method as in Preparation Example 24. 1 H NMR (300MHz, Chloroform-d) δ7.55 (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).

[0429] Preparation Example 28: 4-(2-bromoethyl)-1,1'-biphenyl

[0430] Step 1: Synthesis of 2-([1,1'-biphenyl]-4-yl)ethanol-1-ol

[0431]

[0432] At 0 °C, LiAlH4 (1 M THF solution, 9.0 mL, 3.0 equivalent) was added to a THF solution of 2-([1,1'-biphenyl]-4-yl)acetic acid (559 mg, 3 mmol) in 7 mL of THF. The mixture was stirred at 75 °C for 4 hours, and then carefully quenched with 1 N NaOH. The reaction solution was filtered through diatomaceous earth, and the filtrate was poured into distilled water and extracted with EtOAc. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 2-([1,1'-biphenyl]-4-yl)ethanol-1-ol (522 mg, yield 87%). 1H NMR (300MHz, Chloroform-d) δ7.62-7.52(m,2H),7.49-7.40(m,1H),7.39-7.29(m,2H),3.91(t,J=6.5Hz,1H),2.92(t,J=6.5Hz,1H).

[0433] Step 2: Synthesis of 4-(2-bromoethyl)-1,1'-biphenyl

[0434]

[0435] At 0 °C, CBr4 (1.02 g, 3.1 mmol, 1.1 equivalent) was added to a DCM (12 mL) solution of 2-([1,1'-biphenyl]-4-yl)ethanol-1-ol (522 mg, 2.8 mmol, 1.0 equivalent), and the mixture was stirred for 15 minutes. Then, PPh3 (813 mg, 3.1 mmol, 1.1 equivalent) was added, and the mixture was stirred for 40 minutes. The precipitated solid was filtered to give intermediate BB (639 mg, 87% yield). 1 HNMR (300MHz, Chloroform-d) δ7.61-7.53(m,4H),7.48-7.40(m,2H),7.38-7.29(m,3H),3.91(t,J=6.5Hz,2H),2.92(t,J=6.5Hz,2H).

[0436] Preparation Example 29: 4'-(bromomethyl)-3-fluoro-1,1'-biphenyl

[0437] Step 1: Synthesis of (3'-fluoro-[1,1'-biphenyl]-4-yl)methanol

[0438]

[0439] (4-(hydroxymethyl)phenyl)boronic acid (1.04 g, 6.857 mmol), 1-bromo-3-fluorobenzene (1 g, 5.714 mmol), Na₂CO₃ (1.51 g, 14.285 mmol), and Pd(PPh₃)₄ (330 mg, 0.286 mmol) were dissolved in DME and H₂O (2:1), and then heated to 85 °C and stirred for 24 hours. The reaction solution was extracted with EA and distilled water, and the crude product was purified by rapid column chromatography to obtain (3'-fluoro-[1,1'-biphenyl]-4-yl)methanol (1.26 g), a white solid. 1 H NMR (300MHz, Chloroform-d) δ7.63-7.56(m,2H),7.50-7.34(m,4H),7.32-7.27(m,1H),7.09-6.99(m,1H),4.76(s,2H).

[0440] Step 2: Synthesis of 4'-(bromomethyl)-3-fluoro-1,1'-biphenyl

[0441]

[0442] (3'-fluoro-[1,1'-biphenyl]-4-yl)methanol (304 mg, 1.641 mmol) was dissolved in DCM, and PBr3 (0.59 mL, 6.231 mmol) was added at 0 °C. The mixture was stirred for 2 hours, followed by the addition of additional PBr3 (100 μL) and stirring. After 4 hours, 1 mL of MeOH was added at 0 °C. The organic layer was concentrated under reduced pressure to give intermediate CC (1.7 g), a white solid. 1 H NMR (300MHz, Chloroform-d) δ7.59-7.53(m,2H),7.51-7.45(m,2H),7.43-7.26(m,3H),7.08-7.02(m,1H),4.55(s,2H).

[0443] Preparation Example 30: 2-(4-(bromomethyl)phenyl)pyrimidine

[0444]

[0445] Except that 3-bromophenylmethyl ether in step 1 of preparation example 24 was replaced with 2-bromopyridine, intermediate DD was obtained using the same method as in preparation example 24. 1 H NMR (300MHz, chloroform-d) δ8.81 (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).

[0446] Preparation Example 31: 5-(bromomethyl)-2-phenylpyrimidine

[0447] Step 1: Synthesis of (2-phenylpyrimidin-5-yl)methanol

[0448]

[0449] (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), followed by purging under an Ar atmosphere and stirring at 100 °C for 12 hours. The reaction mixture was filtered through diatomaceous earth and then extracted with EA and brine. The organic layer was concentrated under reduced pressure and purified by silica gel column chromatography (EtOAc:hexane = 1:1) to give (2-phenylpyrimidin-5-yl)methanol (661 mg, 44% yield). 1 H NMR (300MHz, Chloroform-d) δ8.82(s,2H),8.22-8.52(m,2H),7.58-7.47(m,3H),4.78(s,2H).

[0450] Step 2: Synthesis of 5-(bromomethyl)-2-phenylpyrimidine

[0451]

[0452] (2-Phenyrimidin-5-yl)methanol (661 mg, 3.549 mmol) was dissolved in DCM (11 mL), and then CBr4 (1.412 g, 4.258 mmol) and PPh3 (1.116 g, 4.258 mmol) were added over 10 minutes at 0 °C, and the mixture was stirred for 40 minutes. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (EA:hexane = 1:9) to give intermediate EE (762 mg, yield 86%). 1 H NMR (300MHz, Chloroform-d) δ8.82(s,2H),8.43-8.46(m,2H),7.49-7.51(m,3H),4.48(s,2H).

[0453] Preparation Example 32: (3-bromoprop-1-yn-1-yl)benzene

[0454]

[0455] At 0 °C, PBr3 (24.5 g, 90.8 mmol, 1.20 equivalent) was added to a DCM (100 mL) solution of (3-hydroxyprop-1-yn-1-yl)benzene (10.0 g, 75.6 mmol, 9.43 mL, 1.00 equivalent) and DMF (276 mg, 3.78 mmol, 0.05 equivalent), and the mixture was stirred for 1 hour. The reaction solution was cooled to 0 °C, quenched with distilled water (50 mL), and extracted with DCM (2 × 50 mL). The organic layer was washed with sodium bicarbonate aqueous solution (1 × 100 mL) and brine (1 × 100 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ether / ethyl acetate = 50 / 1 to 20 / 1) to give intermediate FF (13.8 g, 70.7 mmol, yield 93.5%) as a colorless oil.

[0456] Preparation Example 33: (4-(pyridin-3-yl)phenyl)methanol

[0457]

[0458] (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 hours. The reaction mixture was cooled to room temperature and then extracted with EA and distilled water. The crude product was purified by rapid column chromatography to give intermediate GG (1.34 g), which was a yellow solid. 1 H NMR (300MHz, Chloroform-d) δ 8.82-8.81 (m, 1H), 8.61-8.59 (m, 1H), 8.00 (d, J = 8.0Hz, 1H), 7.61-7.55 (m, 2H), 7.53-7.45 (m, 3H), 4.78 (s, 2H).

[0459] Preparation Example 34: (4-(5-fluoropyridin-3-yl)phenyl)methanol

[0460]

[0461] Using the corresponding starting materials and the same method as in Preparation Example 33, intermediate HH was obtained. 1 H NMR (300MHz, Chloroform-d) δ8.63-8.61(m,1H),8.45-8.44(m,1H),7.65-7.45(m,5H),4.78(s,2H).

[0462] Preparation Example 35: (4-(5-methoxypyridin-3-yl)phenyl)methanol

[0463]

[0464] Using the corresponding starting materials and the same method as in Preparation Example 33, intermediate II was obtained. 1 H NMR (300MHz, Chloroform-d) δ8.49-8.48(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).

[0465] Preparation Example 36: (4-(1-benzyl-1H-pyrazole-4-yl)phenyl)methanol

[0466]

[0467] (4-Bromophenyl)methanol (1.49 g, 8 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-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 stirred at 80 °C for 6 hours. The reaction solution was filtered through diatomaceous earth, extracted with EA and brine, and dried over magnesium sulfate. Purified by silica gel column chromatography (EA:hexane = 1:3) to give intermediate JJ (948 mg, yield 63%). 1 H NMR (300MHz, Chloroform-d) δ7.76 (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).

[0468] Preparation Example 37: (1-Benzyl-1H-indole-5-yl)methanol

[0469] Step 1: Synthesis of methyl 1-benzyl-1H-indole-5-carboxylic acid ester

[0470]

[0471] At 0 °C, NaH (460 mg, 19.2 mmol) was added fractionally to a DMF (30 mL) solution of methyl 1H-indole-5-carboxylate (2.80 g, 16 mmol) and benzyl bromide (2.1 mL, 17.6 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction solution was extracted with EA and brine, and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EA:hexane = 1:9) to give methyl 1-benzyl-1H-indole-5-carboxylate (5.083 g, yield 78%). 1 H NMR(300MHz,Chloroform-d)δ8.42(dd,J=0.7,1.7Hz,1H),7.88(dd,J=1.7,8.7Hz,1H),7.25-7.35(m, 4H),7.19(d,J=3.2Hz,1H),7.06-7.14(m,2H),6.65(dd,J=0.9,3.3Hz,1H),5.35(s,2H),3.93(s,3H).

[0472] Step 2: Synthesis of (1-benzyl-1H-indole-5-yl)methanol

[0473]

[0474] Methyl 1-benzyl-1H-indole-5-carboxylic acid (2.0 g, 7.538 mmol) was dissolved in THF (25 mL), and LiAlH4 (1 M THF solution, 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 diatomaceous earth, concentrated under reduced pressure, and purified by silica gel column chromatography (EA:hexane = 1:2) to give intermediate KK (1.734 g, 97% yield). 1 H NMR(300MHz,Chloroform-d)δ7.62(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, 3.1Hz, 1H), 5.31 (s, 2H), 4.74 (s, 2H).

[0475] Preparation Example 38: (4-(pyridin-2-yl)phenyl)methanol

[0476]

[0477] Using the corresponding starting materials and the same method as in Preparation Example 33, intermediate LL was obtained. 1H NMR (300MHz, chloroform-d) δ8.73(d,J=4.9Hz,1H),8.01(d,J=8.2Hz,2H),7.88-7.73(m,2H),7.49(d,J=8.2Hz,2H),7.32-7.30(m,1H),4.77(s,2H).

[0478] Preparation Example 39: (6-Phenyridin-3-yl)methanol

[0479]

[0480] To a solution of (6-bromopyridin-3-yl)methanol (940.1 mg, 5.0 mmol) in 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 room temperature and diluted with brine (50 mL) and ethyl acetate (50 mL). The aqueous layer was extracted with ethyl acetate (30 mL). The organic layer was dried over sodium sulfate 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, yield 67%) as a white solid. 1 H NMR (500MHz, CDCl3) δ8.66-8.62(m,1H),7.99-7.93(m,2H),7.77(dd,J=8.1,2.2Hz ,1H),7.71(d,J=8.1Hz,1H),7.46(t,J=7.5Hz,2H),7.43-7.36(m,1H),4.75(s,2H).

[0481] Preparation Example 40: (4-pyridin-4-yl)phenyl)methanol

[0482]

[0483] Using the corresponding starting materials and the same method as in Preparation Example 33, intermediate NN was obtained. 1 H NMR (300MHz, 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 = 8.2Hz, 2H), 4.79 (s, 2H).

[0484] Preparation Example 41: (4-(6-methoxypyridin-2-yl)phenyl)methanol

[0485]

[0486] Using the corresponding starting materials and the same method as in Preparation Example 39, intermediate OO was obtained. 1 H NMR(300MHz,Chloroform-d)δ8.07(d,J=8.3Hz,2H),7.69-7.62(m,1H),7.48(d,J= 8.4Hz, 2H), 7.37 (d, J = 7.4Hz, 1H), 6.72 (d, J = 8.2Hz, 1H), 4.78 (s, 2H), 4.06 (s, 3H).

[0487] Preparation Example 42: (4-(4-methoxypyridin-2-yl)phenyl)methanol

[0488]

[0489] Using the corresponding starting materials and the same method as in Preparation Example 33, intermediate PP was obtained. 1 H NMR(300MHz,Chloroform-d)δ8.63(d,J=6.3Hz,1H),8.02(d,J=8.2Hz,2H),7.52(d,J=8 .2Hz, 3H), 7.30 (d, J = 2.5Hz, 1H), 6.97 (dd, J = 6.3, 2.5Hz, 1H), 4.78 (s, 2H), 4.03 (s, 3H).

[0490] Preparation Example 43: (6-(3-fluoro-5-methoxyphenyl)pyridin-3-yl)methanol

[0491]

[0492] Using the corresponding starting materials and the same method as in Preparation Example 39, intermediate QQ was obtained. 1 H NMR (300MHz, DMSO-d6) δ8.63-8.60(m,1H),8.00(d,J=8.2Hz,1H),7.82(dd,J=8.1,2.0Hz,1 H),7.53-7.45(m,2H),6.94-6.86(m,1H),5.39(s,1H),4.58(d,J=5.6Hz,2H),3.86(s,3H).

[0493] Preparation Example 44: (4-(4-methyl-1H-pyrazole-1-yl)phenyl)methanol

[0494]

[0495] (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). The reaction mixture was then purged under an Ar atmosphere and stirred at 100 °C for 12 hours. The reaction mixture was extracted with EA and brine, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The mixture was purified by silica gel chromatography (EA:hexane = 1:3) to give intermediate RR (191 mg, mixture). LC / MS (ESI) m / z: 189.1 [M+H].

[0496] Preparation Example 45: (4-(3-methyl-5-(trifluoromethyl)-1H-pyrazole-1-yl)phenyl)methanol

[0497]

[0498] 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 and heated to 130 °C with stirring for 24 hours. The reaction mixture was cooled to room temperature and extracted with EA and distilled water. The crude product was then purified by rapid column chromatography to give intermediate SS (562 mg, 99% yield), which was a clear liquid. 1 H NMR (300MHz, Chloroform-d) δ7.54-7.40 (m, 4H), 6.46 (s, 1H), 4.78 (d, J = 5.9Hz, 2H), 2.35 (d, J = 0.7Hz, 3H), 1.87 (t, J = 5.9Hz, 1H).

[0499] Preparation Example 46: (5-(3-fluoro-5-methoxyphenyl)pyridin-2-yl)methanol

[0500]

[0501] Using the corresponding starting materials and the same method as in Preparation Example 39, intermediate TT was obtained. 1H NMR (300MHz, DMSO-d6) δ8.83(d,J=2.1Hz,1H),8.13(dd,J=8.2,2.4Hz,1H),7.55(d,J=8.2Hz,1H),7.22 -7.12(m,2H),6.88(dt,J=11.0,2.2Hz,1H),5.49(t,J=5.9Hz,1H),4.62(d,J=5.9Hz,2H),3.85(s,3H).

[0502] [Example]

[0503] Example 1: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0504] Step 1: Synthesis of [1,1'-biphenyl]-4-yl(2,5-dimethylthiophen-3-yl)methyl ketone

[0505]

[0506] At 0 °C, SOCl2 (4.9 g, 41.0 mmol) was added to a PhCl (45 mL, 0.8 M) solution of [1,1'-biphenyl]-4-carboxylic acid (7.8 g, 39.3 mmol) and DMF (approximately 0.1 mL). The reaction mixture was then heated to 50 °C and stirred for 1 hour. After 1 hour, the reaction mixture was cooled to room temperature, and dimethylthiophene (4.1 mL, 35.7 mmol) was added. The reaction mixture was cooled to 0 °C, and 1 M TiCl4 solution (35.7 mL, 35.7 mmol) was added. After 1 hour, the reaction mixture was acidified by adding 1 N HCl solution and extracted with heptane. The extracts were combined, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give [1,1'-biphenyl]-4-yl(2,5-dimethylthiophene-3-yl) methyl ketone (3.31 g, 32% yield). 1 H NMR(500MHz,chloroform-d)δ7.90(d,J=8.4Hz,2H),7.71(d,J=8.4Hz,2H),7.67(d,J=7.1H z, 2H), 7.51 (t, J = 7.5Hz, 2H), 7.43 (t, J = 7.4Hz, 1H), 6.85 (s, 1H), 2.63 (s, 3H), 2.46 (s, 3H). LC / MS(ESI)m / z:293.7[M+H] + .

[0507] Step 2: Synthesis of [1,1'-biphenyl]-4-yl(4-bromo-2,5-dimethylthiophen-3-yl)methyl ketone

[0508]

[0509] Zinc chloride (46.0 mg, 0.34 mmol) was added to a solution of [1,1'-biphenyl]-4-yl(2,5-dimethylthiophen-3-yl) ketone (3.29 g, 11.25 mol) and PhCl (14.1 mL, 0.8 M), and the reaction mixture was cooled to 16 °C. Br₂ (1.8 g, 22.5 mmol) was added at 16 °C over 30 minutes. The reaction mixture was stirred at room temperature for 30 minutes and acidified by adding 1 N HCl solution. The product was extracted with heptane, and the extracts were combined, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give [1,1'-biphenyl]-4-yl(4-bromo-2,5-dimethylthiophen-3-yl) ketone (2.61 g, 63% yield). 1 H NMR(500MHz,chloroform-d)δ7.94(d,J=7.5Hz,2H),7.72(d,J=7.7Hz,2H),7.67(d,J =7.6Hz, 2H), 7.50 (t, J = 7.3Hz, 2H), 7.44 (t, J = 7.3Hz, 1H), 2.42 (s, 3H), 2.38 (s, 3H). LC / MS(ESI)m / z:373.3[M+H] + .

[0510] Step 3: Synthesis of 3-([1,1'-biphenyl]-4-ylmethyl)-4-bromo-2,5-dimethylthiophene

[0511]

[0512] Et3SiH (2.1 g, 17.6 mmol) was added to a solution of [1,1'-biphenyl]-4-yl(4-bromo-2,5-dimethylthiophene-3-yl) ketone (2.61 g, 7.03 mmol) and DCE (14.1 mL, 0.5 M). The reaction mixture was cooled to -8 °C, and 1 MTiCl4 solution (7.1 mL, 7.1 mmol) was slowly added. The reaction mixture was stirred at room temperature for 1 hour, and then acidified by adding 1 N HCl solution. The product was extracted with heptane, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give 3-([1,1'-biphenyl]-4-ylmethyl)-4-bromo-2,5-dimethylthiophene (1.45 g, 58% yield). 1 H NMR(500MHz,chloroform-d)δ7.59(d,J=7.6Hz,2H),7.52(d,J=8.0Hz,2H),7.45(d,J=7.6 Hz, 2H), 7.35 (d, J = 7.3Hz, 1H), 7.24 (d, J = 7.9Hz, 2H), 4.00 (s, 2H), 2.40 (d, J = 4.4Hz, 6H).

[0513] Step 4: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxylic acid

[0514]

[0515] At -65 °C, n-BuLi (1.5 mL, 2.64 mmol) was gradually added to a solution of 3-([1,1'-biphenyl]-4-ylmethyl)-4-bromo-2,5-dimethylthiophene (1.0 g, 2.80 mmol), TMEDA (0.46 mL, 3.08 mmol), and methyl tert-butyl ether (14 mL, 0.2 M), followed by stirring. The reaction mixture was stirred for 30 min, then excess dry ice was added at -65 °C and the mixture was stirred for 1 h. The reaction mixture was acidified by adding 1 N HCl solution, followed by extraction with EtOAc and distilled water. The organic layer was dried over sodium sulfate, then filtered, concentrated, and purified to give 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxylic acid (0.46 g, 51% yield). 1 H NMR(500MHz,DMSO-d6)δ12.64(s,1H),7.61(d,J=7.6Hz,2H),7.55-7.52(m,2H),7.44(t,J =7.2Hz,2H),7.36-7.32(m,1H),7.16-7.12(m,2H),4.17(s,2H),2.55(s,3H),2.31(s,3H).

[0516] Step 5: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane Synthesis of methyl alkyl-2-carboxylic acid

[0517]

[0518] Intermediate A (70 mg, 0.34 mmol), HATU (0.13 g, 0.34 mmol), and DIPEA (0.16 mL, 0.93 mmol) were added to a DMF (1.1 mL, 0.3 M) solution of 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxylic acid (0.1 g, 0.31 mmol) and stirred at room temperature for 3 hours. The reaction mixture was alkalized by adding 1 N NaOH solution and then extracted with ethyl acetate and distilled water. The organic layer was dried over sodium sulfate, filtered, concentrated, and purified by column chromatography to give methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (110 mg, 75% yield). 1H NMR(500MHz,chloroform-d)δ7.57(d,J=7.6Hz,2H),7.52(d,J=7.3Hz,2H),7.46(t,J=7.3H z,2H),7.36(t,J=7.2Hz,1H),7.19(d,J=7.6Hz,2H),5.39(d,J=7.1Hz,1H),4.28(m,1H),4. 00(s,2H),3.66(s,3H),2.97(p,J=8.9,8.4Hz,1H),2.46(s,3H),2.38(s,3H),2.30(dd,J=1 4.1,7.1Hz,4H),2.21-2.14(m,1H),1.99(d,J=19.5Hz,1H),1.53(dt,J=19.1,10.0Hz,2H). LC / MS(ESI)m / z:475.2[M+H] + .

[0519] Step 6: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane Synthesis of alkyl-2-carboxylic acids

[0520]

[0521] LiOH·H2O (29 mg, 0.69 mmol) was added to a solution of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (110 mg, 0.23 mmol) in H2O:THF:MeOH (1:1:1) and the mixture was stirred for 4 hours. The reaction mixture was acidified by adding 1N HCl solution and then extracted with ethyl acetate and distilled water. The organic layer was dried with sodium sulfate, filtered, and concentrated to give the compound of Example 1 (86 mg, 81% yield) without purification. 1 H NMR (500MHz, DMSO-d6) δ12.03(s,1H),8.29(d,J=7.4Hz,1H),7.61(d,J=7.7Hz,2H),7. 51(d,J=7.6Hz,2H),7.45(t,J=7.4Hz,2H),7.34(t,J=7.2Hz,1H),7.19(d,J=7.7Hz,2H) ,4.16(h,J=8.3Hz,1H),3.90(s,2H),2.91(p,J=8.3Hz,1H),2.34(s,3H),2.32(s,3H), 2.29-2.13(m,4H),2.11-2.06(m,1H),2.02(s,1H),1.87(s,1H),1.85(d,J=9.6Hz,1H). LC / MS(ESI)m / z:460.01[M+H]+ .

[0522] Except for the different preparation methods described below, the compounds of Examples 2 to 5 were prepared using the same method as in Example 1.

[0523] [Table 1]

[0524]

[0525]

[0526] [Table 2]

[0527]

[0528] Example 6: 6-(4-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0529] Step 1: Synthesis of 2-([1,1'-biphenyl]-4-yl)-1-(2,5-dimethylthiophen-3-yl)ethyl-1-one

[0530]

[0531] At 0 °C, SOCl2 (6.1 g, 51.3 mmol) was added dropwise to a solution of 2-([1,1'-biphenyl]-4-yl)acetic acid (10.4 g, 49.1 mmol) and DMF (approximately 1 mL) in toluene (56 mL, 0.8 M). The reaction mixture was then heated to 50 °C for 1 hour. The reaction mixture was cooled to room temperature, and dimethylthiophene (5.1 mL, 44.6 mmol) was added. The mixture was then cooled to 0 °C, and 1 M TiCl4 solution (45 mL, 44.6 mmol) was added. The reaction mixture was acidified by adding 1 N HCl solution, extracted with heptane, and the extracts were combined, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to give 2-([1,1'-biphenyl]-4-yl)-1-(2,5-dimethylthiophene-3-yl)acet-1-one (8.8 g, 64% yield). 1 H NMR(500MHz,chloroform-d)δ7.60(t,J=8.6Hz,4H),7.46(t,J=7.5Hz,2H),7.36(dd,J=15.0,7.5Hz,3H),7.14(s,1H),4.17(s,2H),2.71(s,3H),2.46(s,3H).

[0532] Step 2: Synthesis of 3-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene

[0533]

[0534] To a solution of 2-([1,1'-biphenyl]-4-yl)-1-(2,5-dimethylthiophene-3-yl)ethyl-1-one (4.0 g, 13.1 mmol) in diethylene glycol (17.7 mL, 0.7 M), 2.0 mL of 80% hydrazine hydrate and 2.5 g of KOH (44.5 mmol) were added. The reaction mixture was refluxed and stirred at 195 °C for 6 hours. The mixture was then cooled to room temperature, and 18 mL of distilled water was added. This solution was then slowly poured into 11 mL of 6N HCl aqueous solution to induce precipitation, yielding 3-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene (1.97 g, 52% yield). 1 H NMR(500MHz,chloroform-d)δ7.63(d,J=7.1Hz,2H),7.55(d,J=6.5Hz,2H),7.47(t,J=7.7Hz,2H),7.37(t,J=7 .4Hz,1H),7.27(d,J=8.1Hz,2H),6.55(s,1H),2.91-2.87(m,2H),2.82-2.77(m,2H),2.44(s,3H),2.22(s,3H).

[0535] Step 3: Synthesis of 3-(2-([1,1'-biphenyl]-4-yl)ethyl)-4-bromo-2,5-dimethylthiophene

[0536]

[0537] N-bromosuccinimide (0.13 g, 0.72 mmol) was added to a solution of 3-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene (0.21 g, 0.72 mmol) in AcOH (4 mL). After stirring for 12 hours, the reaction mixture was added to excess ice water and extracted with DCM. The DCM solution was washed with aqueous sodium carbonate solution and distilled water. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The remaining solution was purified by column chromatography to give 3-(2-([1,1'-biphenyl]-4-yl)ethyl)-4-bromo-2,5-dimethylthiophene (159 mg, 60% yield). 1 H NMR(500MHz,chloroform-d)δ7.62(d,J=8.0Hz,2H),7.55(d,J=8.2Hz,2H),7.47(t,J=7.7Hz,2H ), 7.36 (t, J = 7.4Hz, 1H), 7.27 (d, J = 8.1Hz, 2H), 2.85 (p, J = 3.4Hz, 4H), 2.40 (s, 3H), 2.15 (s, 3H).

[0538] Step 4: Synthesis of 4-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene-3-carboxylic acid

[0539]

[0540] At -65 °C, n-BuLi (0.22 mL, 0.56 mmol in 2.5 M THF solution), THF (2.2 mL, 0.2 M), and TMEDA (70 μL, 0.47 mmol) was gradually added to a solution of 3-(2-([1,1'-biphenyl]-4-yl)ethyl)-4-bromo-2,5-dimethylthiophene-3-carboxylic acid (72 mg, 51% yield). The mixture was stirred. After 30 minutes, excess dry ice was added at -65 °C, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified by adding 1 M HCl solution and then extracted with EtOAc and distilled water. The organic layer was dried over sodium sulfate, filtered, and concentrated to give 4-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene-3-carboxylic acid (72 mg, 51% yield). 1 H NMR (500MHz, DMSO-d6); δ12.69(s,1H),7.65(d,J=8.0Hz,2H),7.59(d,J=8.2Hz,2H),7.46(t,J=7.7Hz,2H),7.35( t,J=7.4Hz,1H),7.27(d,J=8.2Hz,2H),2.96(dd,J=9.4,6.5Hz,2H),2.75-2.70(m,2H),2.56(s,3H),2.15(s,3H).

[0541] Step 5: 6-(4-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene-3-carboxamido)spiro [3.3] Synthesis of heptane-2-carboxylic acid methyl ester

[0542]

[0543] DIPEA (0.11 mL, 0.63 mmol) was added to a DCM (1.1 mL, 0.2 M) 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), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was partially concentrated, and the organic layer was extracted with 1N NaOH and ethyl acetate, while the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, concentrated, and then purified by column chromatography to obtain methyl 6-(4-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (70 mg, 70% yield). 1H NMR(500MHz,chloroform-d)δ7.61(d,J=7.1Hz,2H),7.53(d,J=8.2Hz,2H),7.46(t,J=7.7Hz,2H),7.36(t,J=7.9Hz,1H ),7.20(d,J=8.2Hz,2H),5.55(d,J=7.7Hz,1H),4.45(h,J=7.8Hz,1H),3.69(s,3H),3.05(p,J=8.5Hz,1H),2.86(dd,J=6 .4,4.0Hz,2H),2.82(dd,J=9.8,6.5Hz,2H),2.61(dt,J=11.8,5.5Hz,1H),2.48(dd,J=11.8,7.1Hz,1H),2.45(s,3H),2. 37(d,J=8.4Hz,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] + .

[0544] Step 6: 6-(4-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene-3-carboxamido)spiro [3.3] Synthesis of heptane-2-carboxylic acid

[0545]

[0546] LiOH·H2O (18 mg, 0.42 mmol) was added to a solution of methyl 6-(4-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid ester in H2O:THF:MeOH (1:1:1). The reaction mixture was stirred at room temperature for 4 hours, then acidified by adding 1N HCl solution and extracted with DCM. The organic layer was dried over sodium sulfate, filtered, and concentrated to give the compound of Example 6 (46 mg, yield 69%), without the need for purification. 1H NMR (500MHz, Methanol-d4) δ8.48(d,J=7.2Hz,1H),7.61(d,J=7.2Hz,2H),7.52(d,J=8.2Hz,2H),7. 43(t,J=7.7Hz,2H),7.32(t,J=7.4Hz,1H),7.21(d,J=8.2Hz,2H),4.36(dt,J=13.2,6.8Hz,1H),3.0 4(p,J=8.5Hz,1H),2.88-2.82(m,2H),2.80-2.75(m,2H),2.61-2.55(m,1H),2.45-2.42(m,1H),2.4 1(s,3H),2.41-2.34(m,2H),2.29-2.24(m,1H),2.22-2.16(m,1H),2.11(s,3H),2.10-2.01(m,2H). LC / MS(ESI)m / z:474.3[M+H] + .

[0547] Example 7: 6-(4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0548] Step 1: Synthesis of (4-bromo-2,5-dimethylthiophen-3-yl)(3-fluoro-[1,1'-biphenyl]-4-yl)methyl ketone

[0549]

[0550] At 0 °C, SOCl2 (0.18 mL, 2.4 mmol) was added to a toluene (2.6 mL, 0.8 M) solution of intermediate E (0.50 g, 2.31 mmol) and DMF (approximately 1 mL). The reaction mixture was heated to 50 °C and stirred for 1 hour, then intermediate C (0.40 g, 2.1 mmol) was added. The reaction mixture was cooled to 0 °C, and TiCl4 (0.23 mL, 2.1 mmol) was added. 1 N HCl aqueous solution (10 mL) was added and stirred for 5 minutes, then the organic layer was extracted. The aqueous layer was washed twice with heptane. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give (4-bromo-2,5-dimethylthiophene-3-yl)(3-fluoro-[1,1'-biphenyl]-4-yl) methyl ketone (200 mg, yield 25%). 1 H NMR(500MHz,Chloroform-d)δ7.78(t,J=7.8Hz,1H),7.65(d,J=7.2Hz,2H),7.53-7. 49(m,3H),7.46(d,J=7.3Hz,1H),7.36(d,J=11.9Hz,1H),2.48(s,3H),2.39(s,3H).

[0551] Step 2: Synthesis of 3-bromo-4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene

[0552]

[0553] Et3SiH (0.18 mL, 1.17 mmol) was added to a DCE (0.9 mL, 0.5 M) solution of (4-bromo-2,5-dimethylthiophene-3-yl)(3-fluoro-[1,1'-biphenyl]-4-yl) methyl ketone (150 mg, 0.39 mmol). The reaction solution was cooled to -8 °C, and TiCl4 (43 μL, 0.39 mmol) was slowly added while stirring for 1 hour. 10 mL of 1 N HCl aqueous solution was added and stirred for 5 minutes. The organic layer was then extracted, and the aqueous layer was washed twice with heptane. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give 3-bromo-4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene (74 mg, 53% yield). 1 H NMR(500MHz,Chloroform-d)δ7.57(d,J=7.1Hz,2H),7.45(t,J=7.6Hz,2H),7.37(t,J=7.4Hz,1H),7.30 (d,J=9.6Hz,1H),7.26(d,J=6.1Hz,1H),7.00(t,J=8.0Hz,1H),4.00(s,2H),2.40(s,3H),2.38(s,3H).

[0554] Step 3: Synthesis of 4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxylic acid

[0555]

[0556] At -65°C, n-BuLi (0.09 mL, 0.22 mmol in 2.5 M THF solution) was slowly added to a THF solution of 3-bromo-4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene (74 mg, 0.20 mmol) and butanediamine (33 μL, 0.22 mmol) in 1.0 mL, 0.2 M, and stirred for 45 min. Excess dry ice was then added at -65°C. 2.0 mL of 1 N HCl aqueous solution was added and stirred for 15 min. The organic layer was then extracted, and the aqueous layer was washed twice with EA. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give 4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxylic acid (30 mg, 45% yield). 1H NMR(500MHz,Chloroform-d)δ7.55(d,J=7.1Hz,2H),7.44(t,J=7.6Hz,2H),7.36(d,J=7.3Hz,1H),7.27 (d,J=9.5Hz,1H),7.22(d,J=7.9Hz,1H),6.91(t,J=8.0Hz,1H),4.24(s,2H),2.70(s,3H),2.33(s,3H).

[0557] Step 4: 6-(4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro [3.3] Geng alkyl Synthesis of methyl 2-carboxylate

[0558]

[0559] At room temperature, DIPEA (0.05 mL, 0.27 mmol) was added to a DMF (0.3 mL, 0.3 M) solution of 4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxylic acid (30 mg, 0.09 mmol), intermediate A (21 mg, 0.1 mmol), and HATU (38 mg, 0.1 mmol), and the mixture was stirred for 3 hours. The reaction solution was concentrated, diluted with 1 N NaOH aqueous solution and ethyl acetate, and the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, concentrated, and purified by silica gel column chromatography (n-hexane and ethyl acetate) to give methyl 6-(4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (12 mg, 30% yield). 1 H NMR(500MHz,Chloroform-d)δ7.57-7.53(m,2H),7.46(t,J=7.6Hz,2H),7.38(t,J=7.9Hz,1H),7.29(s,1 H),7.26(s,1H),7.08(t,J=7.8Hz,1H),5.49(d,J=7.8Hz,1H),4.34(h,J=8.0Hz,1H),3.98(s,2H),3.67(s ,3H),2.99(p,J=8.5Hz,1H),2.53-2.47(m,1H),2.46(s,3H),2.39-2.36(m,1H),2.35(s,3H),2.33-2.29( m,2H),2.21(dd,J=11.6,8.4Hz,1H),2.06-2.00(m,1H),1.69-1.65(m,1H),1.61(dd,J=11.6,8.7Hz,1H). LC / MS(ESI)m / z:492.4[M+H]+ .

[0560] Step 5: 6-(4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro [3.3] Synthesis of heptane-2-carboxylic acid

[0561]

[0562] LiOH·H2O (3.0 mg, 0.06 mmol) was added to a solution of methyl 6-(4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (12 mg, 0.02 mmol) in H2O / THF / MeOH (0.3 M, 0.1 mL), and the mixture was stirred for 4 hours. The reaction mixture was acidified by adding 1 N HCl aqueous solution and extracted with EA (3 × 5 mL). The organic layer was dried over magnesium sulfate, filtered, concentrated, and then purified by silica gel column chromatography (n-hexane and ethyl acetate) to give the compound of Example 7 (6.0 mg, 55% yield). 1 H NMR(500MHz,Chloroform-d)δ7.55(d,J=7.2Hz,2H),7.46(t,J=7.6Hz,2H),7.38(t,J=7.3Hz,1H),7.27( d,J=9.7Hz,2H),7.08(t,J=7.8Hz,1H),5.48(d,J=7.8Hz,1H),4.34(h,J=8.0Hz,1H),3.98(s,2H),3.03( p,J=8.4Hz,1H),2.50(dt,J=11.9,6.3Hz,1H),2.46(s,3H),2.41-2.36(m,2H),2.35(s,3H),2.34(s,1H) ,2.23(dd,J=11.7,8.2Hz,1H), 2.08(ddd,J=11.6,8.6,2.2Hz,1H), 1.64(ddd,J=20.8,11.4,8.5Hz,2H). LC / MS(ESI)m / z:478.2[M+H] + .

[0563] Example 8: 6-(4-((2-amino-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0564] Step 1: Synthesis of (2-amino-[1,1'-biphenyl]-4-yl)(4-bromo-2,5-dimethylthiophen-3-yl) methyl ketone

[0565]

[0566] Intermediate C (2.5 g, 13.1 mmol) was added to a mixture of AlCl3 (1.74 g, 13.1 mmol) and DCM (42.2 mL, 0.3 M), and the mixture was stirred for 30 minutes. Then, intermediate F (2.95 g, 12.7 mmol) was added to the reaction mixture, and the mixture was stirred for 12 hours. The reaction mixture was poured into ice, acidified with 1 N citric acid aqueous solution, and then extracted twice with DCM. The organic layer was washed with distilled water and brine, dried over magnesium sulfate, concentrated under reduced pressure, and then purified by column chromatography to obtain (2-amino-[1,1'-biphenyl]-4-yl)(4-bromo-2,5-dimethylthiophene-3-yl) methyl ketone (960 mg, yield 20%). 1 H NMR (300MHz, chloroform-d) δ7.50 (d, J = 4.4Hz, 4H), 7.44-7.40 (m, 1H), 7.31 (d, J = 1.2Hz, 1H), 7.26-7.22 (m, 2H), 4.02 (s, 2H), 2.41 (s, 3H), 2.37 (s, 3H).

[0567] Steps 2 to 5: 6-(4-((2-amino-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide Synthesis of spiro[3.3]heptane-2-carboxylic acid

[0568]

[0569]

[0570] The compound of Example 8 was prepared by reacting (2-amino-[1,1'-biphenyl]-4-yl)(4-bromo-2,5-dimethylthiophen-3-yl) methyl ketone obtained in step 1 above with the same method as steps 2 to 5 in Example 7. 1 H NMR(300MHz,chloroform-d)δ7.50-7.33(m,5H),7.08(d,J=7.7Hz,1H),6.63(d,J=8.7Hz,1H),6.57(s,1H),5.67(d,J=8.8Hz,1H),4.27(q,J=8.0H z,1H),3.91(s,2H),3.08-2.94(m,1H),2.46(s,4H),2.37(s,3H),2.31(d ,J=8.1Hz,3H),2.26-2.17(m,1H),2.11-2.01(m,1H),1.65-1.50(m,2H). LC / MS(ESI)m / z:475.5[M+H] + .

[0571] Example 9: 6-(2,5-dimethyl-4-(4-morpholinylbenzyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0572] Step 1: Synthesis of (4-bromo-2,5-dimethylthiophen-3-yl)(4-fluorophenyl)methyl ketone

[0573]

[0574] At 0 °C, SOCl2 (1.8 mL, 24.6 mmol) was added to a solution of 4-fluorobenzoic acid (3.0 g, 21.3 mmol) and DMF (approximately 1 mL) in toluene (24 mL, 0.8 M), and the mixture was stirred at 50 °C for 5 hours. 3-Bromo-2,5-dimethylthiophene (3.7 g, 19.4 mmol) was added at 50 °C, followed by a solution of TiCl4 (2.1 mL, 19.4 mmol). 30 mL of 1 N HCl aqueous solution was added and the mixture was stirred for 5 minutes. The organic layer was then extracted, and the aqueous layer was washed twice with heptane. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give (4-bromo-2,5-dimethylthiophene-3-yl)(4-fluorophenyl) methyl ketone (1.45 g, 24% yield).

[0575] Step 2: Synthesis of (4-bromo-2,5-dimethylthiophen-3-yl)(4-morpholinophenyl) methyl ketone

[0576]

[0577] To a solution of (4-bromo-2,5-dimethylthiophen-3-yl)(4-fluorophenyl) methyl ketone (1.45 g, 4.62 mmol) and morpholine (1.2 mL, 13.9 mmol) in DMSO:H₂O (8 mL, 0.6 M), K₂CO₃ (0.95 g, 6.5 mmol) was added, and the mixture was heated to 90 °C and stirred for 8 hours. The reaction mixture was diluted with distilled water and extracted twice with DCM. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give (4-bromo-2,5-dimethylthiophen-3-yl)(4-morpholinephenyl) methyl ketone (1.21 g, 69% yield).

[0578] Step 3: Synthesis of 4-(4-((4-bromo-2,5-dimethylthiophen-3-yl)methyl)phenyl)morpholine

[0579]

[0580] At -10 °C, Et3SiH (1.80 mL, 11.2 mmol) was added to a TFA (8 mL, 0.4 M) solution of (4-bromo-2,5-dimethylthiophen-3-yl)(4-morpholinophenyl) ketone (1.21 g, 3.2 mmol), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into 10 mL of ice water, extracted with ethyl acetate (3 × 20 mL), washed with saturated sodium bicarbonate aqueous solution (20 mL), distilled water (10 mL), and brine (20 mL), and dried over sodium sulfate. The mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (ethyl acetate / hexane) to give 4-(4-((4-bromo-2,5-dimethylthiophen-3-yl)methyl)phenyl)morpholine (0.62 g, yield 53%). 1 H NMR (300MHz, Chloroform-d) δ7.08 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.3 Hz, 2H), 3.91-3.84 (m, 6H), 3.17-3.11 (m, 4H), 2.38-2.34 (m, 6H).

[0581] Step 4: Synthesis of 2,5-dimethyl-4-(4-morpholinylbenzyl)thiophene-3-carboxylic acid

[0582]

[0583] At -65°C, n-BuLi (0.73 mL, 1.86 mmol in 2.5 M THF solution) was slowly added to a solution of 4-(4-((4-bromo-2,5-dimethylthiophen-3-yl)methyl)phenyl)morpholine (0.62 g, 1.69 mmol), TMEDA (48 μL, 1.86 mmol), and THF (8.5 mL, 0.2 M), and the mixture was stirred for 45 minutes. Excess dry ice was added to the reaction mixture at -65°C, and the mixture was stirred at room temperature for 1 hour. 1 N citric acid aqueous solution (2.0 mL) was added and stirred for 15 minutes. The organic layer was extracted, and the aqueous layer was washed twice with EA. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give 2,5-dimethyl-4-(4-morpholinobenzyl)thiophene-3-carboxylic acid. 1 H NMR(500MHz,Chloroform-d)δ7.03(d,J=8.6Hz,2H),6.82(d,J=8.6Hz,2H),4.14( d,J=2.7Hz,2H),3.88-3.83(m,4H),3.13-3.09(m,4H),2.66(s,3H),2.32(s,3H).

[0584] Step 5: 6-(2,5-dimethyl-4-(4-morpholinylbenzyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Synthesis of methyl ester

[0585]

[0586] DIPEA (0.4 mL, 1.98 mmol) was added to a DMF (2.2 mL, 0.3 M) solution of 2,5-dimethyl-4-(4-morpholinobenzyl)thiophene-3-carboxylic acid (220 mg, 0.66 mmol), intermediate A (148 mg, 0.72 mmol), and HATU (273 mg, 0.72 mmol), and the mixture was stirred for 3 hours. The reaction solution was concentrated, diluted with 1 N NaOH aqueous solution and ethyl acetate, and the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, concentrated, and then purified by silica gel column chromatography using n-hexane and ethyl acetate to give methyl 6-(2,5-dimethyl-4-(4-morpholinobenzyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (157 mg, yield 49%). 1 H NMR(500MHz,Chloroform-d)δ7.01(d,J=8.6Hz,2H),6.85(d,J=8.7Hz,2H),5.41(d,J=7.7Hz,1H ),4.27(h,J=7.9Hz,1H),3.88(t,J=4.8Hz,6H),3.68(s,3H),3.14-3.10(m,4H),3.00(p,J=8.5Hz ,1H),2.45(s,4H),2.34(s,3H),2.31(ddd,J=12.4,8.6,4.9Hz,3H),2.21(dd,J=11.6,8.4Hz,1H) ,2.03(ddd,J=11.6,8.6,2.7Hz,1H), 1.57(dd,J=11.1,8.5Hz,1H), 1.50(dd,J=11.6,8.6Hz,1H).

[0587] Step 6: 6-(2,5-dimethyl-4-(4-morpholinylbenzyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Synthesis

[0588]

[0589] LiOH·H2O (40 mg, 0.96 mmol) was added to a solution of methyl 6-(2,5-dimethyl-4-(4-morpholinylbenzyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (157 mg, 0.32 mmol) in H2O / THF / MeOH (0.3 M, 1.1 mL), and the mixture was stirred for 4 hours. The reaction mixture was acidified by adding 1 N citric acid aqueous solution and extracted with ethyl acetate (3 × 5 mL). The organic layer was dried over magnesium sulfate, filtered, concentrated, and then purified by silica gel column chromatography (n-hexane and ethyl acetate) to give the compound of Example 9 (12 mg, yield 8%). 1H NMR(500MHz,Chloroform-d)δ7.01(d,J=8.6Hz,2H),6.86(d,J=8.7Hz,2H),5.42(d,J=7 .7Hz,1H),4.26(h,J=7.9Hz,1H),3.88(t,J=4.8Hz,6H),3.15-3.10(m,4H),3.02(p,J=8 .3Hz,1H),2.45(s,4H),2.34(s,3H),2.31(dd,J=11.3,8.8Hz,3H),2.21(dd,J=11.7,8. 0Hz, 1H), 2.11-2.05 (m, 1H), 1.57 (dd, J=11.2, 8.3Hz, 1H), 1.48 (dd, J=11.6, 8.4Hz, 1H). LC / MS(ESI)m / z:469.4[M+H] + .

[0590] Example 10: 6-(4-([1,1'-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0591] Step 1: Synthesis of 4-([1,1'-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carboxynitrile

[0592]

[0593] CuCN (0.63 g, 7.0 mmol) was added to a DMF (58 mL, 0.06 M) solution of [1,1'-biphenyl]-4-yl(4-bromo-2,5-dimethylthiophene-3-yl) methyl ketone (1.30 g, 3.5 mmol) obtained in step 2 of Example 1, and the mixture was stirred at 110 °C for 24 hours. The reaction solution was concentrated, diluted with 1 N HCl aqueous solution and ethyl acetate, and the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, concentrated, and then purified by silica gel column chromatography (n-hexane and ethyl acetate) to give 4-([1,1'-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carboxynitrile (610 mg). 1 H NMR(500MHz,Chloroform-d)δ7.91(d,J=8.2Hz,2H),7.75(d,J=8.2Hz,2H),7.67(d,J =7.6Hz, 2H), 7.51 (t, J = 7.6Hz, 2H), 7.44 (t, J = 7.3Hz, 1H), 2.67 (s, 3H), 2.43 (s, 3H).

[0594] Step 2: Synthesis of 4-([1,1'-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carboxylic acid

[0595]

[0596] 340 mg (1.07 mmol) of 4-([1,1'-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carboxylic acid was added to 5.3 mL (0.2 M) of 70% H2SO4 aqueous solution and stirred under reflux at 110 °C for 1 hour. The reaction solution was poured into ice water and extracted three times with DCM. The organic layer was dried over magnesium sulfate, concentrated, and then purified by silica gel column chromatography (DCM and MeOH) to give 4-([1,1'-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carboxylic acid (42 mg, yield 12%). 1 H NMR (500MHz, Chloroform-d) δ7.85 (d, J = 8.4Hz, 2H), 7.66-7.61 (m, 4H), 7.48 (t, J = 7.5Hz, 2H), 7.42 (t, J = 7.3Hz, 1H), 2.68 (s, 3H), 2.27 (s, 3H).

[0597] Step 3: 6-(4-([1,1'-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane Synthesis of methyl alkyl-2-carboxylic acid

[0598]

[0599] DIPEA (0.04 mL, 0.22 mmol) was added to a DMF (0.3 mL, 0.3 M) 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), and the mixture was stirred for 3 hours. The reaction solution was concentrated, diluted with 1 N NaOH aqueous solution and ethyl acetate, and the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, 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-carboxylic acid (33 mg, yield 55%). 1H NMR(500MHz,Chloroform-d)δ7.89(d,J=8.4Hz,2H),7.69(d,J=8.4Hz,2H),7.65(d, J=7.2Hz,2H),7.50(t,J=7.5Hz,2H),7.43(t,J=7.3Hz,1H),5.97(d,J=7.3Hz,1H),4. 09(dd,J=16.0,7.6Hz,1H),3.65(s,3H),2.96(p,J=8.5Hz,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 = 9.0Hz, 1H). LC / MS(ESI)m / z:488.4[M+H] + .

[0600] Step 4: 6-(4-([1,1'-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane Synthesis of alkyl-2-carboxylic acids

[0601]

[0602] LiOH·H2O (9 mg, 0.21 mmol) was added to a solution of methyl 6-(4-([1,1'-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (33 mg, 0.07 mmol) in H2O / THF / MeOH (0.3 M, 0.2 mL), and the mixture was stirred for 4 hours. The reaction mixture was acidified by adding 1 N HCl aqueous solution and extracted with EA (3 × 20 mL). The organic layer was dried over magnesium sulfate, filtered, concentrated, and then purified by silica gel column chromatography (n-hexane and ethyl acetate) to give the compound of Example 10 (20 mg, yield 63%). 1 H NMR(500MHz,Chloroform-d)δ7.89(d,J=8.3Hz,2H),7.69(d,J=8.3Hz,2H),7.64(d,J=7.3Hz,2H),7.50(t,J=7.5Hz,2H),7.43(t,J=7.3Hz,1H),6.03(d,J=7 .3Hz,1H),4.10(h,J=8.1Hz,1H),2.99(p,J=8.5Hz,1H),2.59(s,3H),2.34(s, 4H), 2.23 (dt, J=23.0, 9.6Hz, 4H), 2.10 (t, J=10.3Hz, 1H), 1.66-1.59 (m, 2H). LC / MS (ESI) m / z: 474.4 [M+H] + .

[0603] Example 11: 6-(4-([1,1'-biphenyl]-4-yl(hydroxy)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0604]

[0605] To a mixture of the compound of Example 10 (10 mg, 0.02 mmol) and ethanol (0.4 mL, 0.05 M), NaBH4 (1.5 mg, 0.04 mmol) and CaCl2 (2.0 mg, 0.02 mmol) were added, and the mixture was stirred for 12 hours. Distilled water and ethyl acetate were added, and the aqueous layer was extracted with ethyl acetate (10 mL). The organic layer was dried over magnesium sulfate, concentrated, and then purified by silica gel column chromatography (DCM and MeOH) to give the compound of Example 11 (4.0 mg, 40% yield). 1 H NMR(500MHz,Methanol-d4)δ8.42(t,J=7.8Hz,1H),7.61(t,J=7.0Hz,2H),7.55(dd,J=8 .3,6.4Hz,2H),7.44(t,J=7.5Hz,2H),7.36-7.31(m,3H),5.94(d,J=3.9Hz,1H),4.00-3 .89(m,1H),2.90(dq,J=32.3,8.5Hz,1H),2.49(d,J=1.9Hz,3H),2.42(d,J=2.1Hz,3H), 2.37-2.15(m,4H),2.14-1.94(m,3H),1.74(dt,J=20.8,10.7Hz,1H),1.57-1.51(m,1H). LC / MS(ESI)m / z:474.3[M+H] - .

[0606] Example 12: 6-(4-([1,1'-biphenyl]-4-yl(methoxy)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0607] Step 1: Synthesis of [1,1'-biphenyl]-4-yl(4-bromo-2,5-dimethylthiophen-3-yl)methanol

[0608]

[0609] To a mixture of [1,1'-biphenyl]-4-yl(4-bromo-2,5-dimethylthiophen-3-yl) methyl ketone (2.0 g, 5.39 mmol) and ethanol (108 mL, 0.05 M) obtained in step 2 of Example 1, NaBH4 (0.41 g, 10.8 mmol) and CaCl2 (0.60 g, 5.39 mmol) were added, and the mixture was stirred for 12 hours. Distilled water and ethyl acetate were added, and the aqueous layer was extracted with ethyl acetate (50 mL). The organic layer was dried over magnesium sulfate, concentrated, and then purified by silica gel column chromatography (DCM and MeOH) to give [1,1'-biphenyl]-4-yl(4-bromo-2,5-dimethylthiophen-3-yl)methanol (1.3 g, 62% yield). 1 H NMR (300MHz, Chloroform-d) δ7.65-7.57(m,4H),7.46(dd,J=7.9,3.8Hz,4H),7.37(t,J=7.3Hz,1H),6.13(dd,J=10.9,3.2Hz,1H),2.42-2.35(m,6H).

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

[0611]

[0612] Hydrochloric acid (35% aqueous solution, 19 mL, 214 mmol) was added to a methanol (80 mL, 0.03 M) solution of [1,1'-biphenyl]-4-yl(4-bromo-2,5-dimethylthiophene-3-yl)methanol (900 mg, 2.41 mmol), and the mixture was stirred for 12 hours. The reaction solution was concentrated, alkalized with an aqueous sodium bicarbonate solution, and extracted with EA. The organic layer was dried over magnesium sulfate, concentrated, and then purified by silica gel column chromatography (0 to 5% MeOH in DCM solution) to give 3-([1,1'-biphenyl]-4-yl(methoxy)methyl)-4-bromo-2,5-dimethylthiophene (680 mg, 50% yield). 1 H NMR (300MHz, Chloroform-d) δ7.63-7.54(m,4H),7.49-7.41(m,4H),7.35(t,J=7.3Hz,1H),5.68(s,1H),3.45(s,3H),2.41-2.35(m,6H).

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

[0614]

[0615] At -65°C, n-BuLi (2.5M THF solution, 0.70 mL, 1.73 mmol) was slowly added to a solution of 3-([1,1'-biphenyl]-4-yl(methoxy)methyl)-4-bromo-2,5-dimethylthiophene (517 mg, 1.33 mmol), TMEDA (0.22 mL, 1.46 mmol), and Et₂O (6.7 mL, 0.2 M). The mixture was stirred for 45 minutes, and then excess dry ice was added. 10 mL of 1N HCl aqueous solution was added and stirred for 15 minutes. The organic layer was then extracted, and the aqueous layer was washed twice with EA. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give 4-([1,1'-biphenyl]-4-yl(methoxy)methyl)-2,5-dimethylthiophene-3-carboxylic acid (151 mg, 32% yield). 1 H NMR(300MHz,DMSO-d6)δ12.88(s,1H),7.67-7.58(m,4H),7.45(t,J=7.5Hz,2H ),7.36(d,J=8.1Hz,3H),6.11(s,1H),3.31(s,3H),2.54(s,3H),2.23(s,3H).

[0616] Step 4: 6-(4-([1,1'-biphenyl]-4-yl(methoxy)methyl)-2,5-dimethylthiophene-3-carboxamido) Synthesis of methyl spiro[3.3]heptane-2-carboxylate

[0617]

[0618] DIPEA (0.22 mL, 1.3 mmol) was added to a DMF (1.4 mL, 0.3 M) solution of 4-([1,1'-biphenyl]-4-yl(methoxy)methyl)-2,5-dimethylthiophene-3-carboxylic acid (151 mg, 0.43 mmol), intermediate A (96 mg, 0.47 mmol), and HATU (179 mg, 0.47 mmol), and the mixture was stirred for 3 hours. The reaction solution was concentrated and diluted with 1 N NaOH aqueous solution and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, concentrated, and then purified by silica gel column chromatography (n-hexane and ethyl acetate) to give methyl 6-(4-([1,1'-biphenyl]-4-yl(methoxy)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (138 mg, yield 64%). 1H NMR(300MHz,Chloroform-d)δ7.55(dt,J=9.7,7.2Hz,4H),7.45(t,J=7.6Hz,2H),7.35( td,J=7.6,3.6Hz,3H),5.63(s,1H),3.97(h,J=8.3Hz,1H),3.65(d,J=4.9Hz,3H),3.52(d ,J=0.9Hz,3H),2.95(dt,J=15.0,8.6Hz,1H),2.58(d,J=2.6Hz,3H),2.47(s,3H),2.44-2 .35(m,1H),2.29-2.11(m,4H),2.08-1.91(m,1H),1.78-1.65(m,1H),1.23-1.10(m,1H).

[0619] Step 5: 6-(4-([1,1'-biphenyl]-4-yl(methoxy)methyl)-2,5-dimethylthiophene-3-carboxamido) Synthesis of spiro[3.3]heptane-2-carboxylic acid

[0620]

[0621] LiOH·H2O (34 mg, 0.81 mmol) was added to a solution of methyl 6-(4-([1,1'-biphenyl]-4-yl(methoxy)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (138 mg, 0.27 mmol) in H2O / THF / MeOH (0.3 M, 0.9 mL), and the mixture was stirred for 12 hours. The reaction mixture was acidified by adding 1N HCl aqueous solution and extracted with EA (20 mL × 3). The organic layer was dried over magnesium sulfate, filtered, concentrated, and purified by silica gel column chromatography (n-hexane and ethyl acetate) to give 6-(4-([1,1'-biphenyl]-4-yl(methoxy)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (121 mg, 90% yield). 1 H NMR (300MHz, DMSO-d6) δ12.02(s,1H),8.41(d,J=7.3Hz,1H),7.62(dd,J=13.7,7.8Hz,4H),7.41(tt,J=15.5,7.2Hz,5H),5.51(s,1H),4.17( h,J=8.0Hz,1H),3.30(s,3H),2.92(p,J=8.5Hz,1H),2.45-2.30(m,4H),2.28-2.14(m,6H),2.12-2.03(m,2H),1.91(tt,J=19.4,8.9Hz,2H). LC / MS(ESI)m / z:488.3[M+H] - .

[0622] Example 13: 6-(4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0623] Step 1: 2-([1,1'-biphenyl]-4-ylmethyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane synthesis

[0624]

[0625] A solution of 4-bromomethylbiphenyl (600 mg, 2.44 mmol), K₂CO₃ (1.0 g, 7.28 mmol), (pinacol)diboron (740 mg, 2.92 mmol), and Pd(PPh₃)₄ (140 mg, 0.12 mmol) in dioxane (12 mL) was stirred for 12 hours at 100 °C. Ethyl acetate (20 mL) was added, and the precipitate was removed by diatomaceous earth filtration. The organic layer was concentrated under reduced pressure, and the crude product was purified by rapid column chromatography (0 to 100% hexane / EtOAc) to give 2-([1,1'-biphenyl]-4-ylmethyl)-4,4,5,5-tetramethyl-1,3,2-dioxane (61 mg, yield 86%) as a white solid. 1 H NMR(300MHz,Chloroform-d)δ7.60-7.54(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).

[0626] Step 2: Synthesis of methyl 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylate

[0627]

[0628] Under N2 conditions, methyl 3-bromobenzo[b]thiophene-2-carboxylate (300 mg, 1.32 mmol), 2-(biphenyl-4-ylmethyl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane (192 mg, 0.528 mmol), and Pd(PPh3)4 (60 mg) in THF (18 mL) and 2N K2CO3 aqueous solution were placed in a flask and stirred at 85 °C for 12 hours. The reaction mixture was cooled to room temperature and then extracted with distilled water and EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by silica gel column chromatography to give methyl 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylate (306 mg, 75% yield) as a pale yellow oil. 1H NMR(400MHz,chloroform-d)δ10.07(s,1H),8.12(d,J=3.6Hz,1H),7.99-7.94(m,1H),7.78-7.73(m,1H),7.67-7.62(m,1 H),7.61-7.53(m,1H),7.52-7.46(m,2H),7.45-7.41(m,1H),7.41-7.36(m,1H),7.32(d,J=3.7Hz,1H),3.91-3.87(m,5H).

[0629] Step 3: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid

[0630]

[0631] A solution of methyl 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid (121 mg, 0.39 mmol) in THF (0.18 mL) was added to a solution of 2N NaOH (0.2 mL), and the mixture was stirred at 65 °C for 12 hours. The reaction mixture was cooled to room temperature, and the pH was adjusted to 2 by adding 2N HCl solution. The mixture was stirred for 2 hours and then extracted with EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid (51 mg, 42% yield) as a white solid. 1 H NMR(500MHz,chloroform-d)δ8.28(d,J=3.6Hz,1H),7.59-7.57(m,2H),7.54(d,J=7.9Hz,2H) ,7.47-7.44(m,2H),7.33(s,1H),7.32-7.28(m,2H),6.83(dd,J=2.8,1.7Hz,1H),4.31(s,2H).

[0632] Step 4: 6-(4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Ester Synthesis

[0633]

[0634] Intermediate A (20 mg, 0.12 mmol), HATU (36 mg, 0.12 mmol), and DIPEA (0.03 mL, 0.4 mmol) were added to a DCM solution of methyl 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylate (30 mg, 0.1 mmol) in 1 mL, and the mixture was stirred for 12 hours. EtOAc and brine were added to the reaction mixture, and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (26 mg, yield 59%) as a white solid. 1 H NMR(300MHz,chloroform-d)δ7.63(d,J=3.2Hz,1H),7.61-7.51(m,4H),7.45(d dd,J=7.6,6.8,1.3Hz,2H),7.38-7.32(m,1H),7.30(s,1H),7.27(s,1H),6.97(d t,J=3.2,0.9Hz,1H),5.82(d,J=7.7Hz,1H),4.39-4.27(m,1H),4.23(s,2H),3.6 8(s,3H),3.02(p,J=8.4Hz,1H),2.54(tt,J=7.5,5.2Hz,1H),2.46-2.38(m,1H).

[0635] Step 5: 6-(4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid synthesis

[0636]

[0637] A solution of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (20 mg, 0.04 mmol) in THF was added to a solution of 2N NaOH aqueous solution, and the mixture was stirred at 65 °C for 12 hours. The reaction mixture was cooled to room temperature, and the pH was adjusted to 2 by adding 2N HCl aqueous solution. The mixture was stirred for 2 hours and then extracted with EtOAc. The organic layer was washed with brine, dried over magnesium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to give the compound of Example 13 (3.2 mg, yield 19%) as a white solid. 1H NMR(500MHz,chloroform-d)δ7.61(d,J=3.2Hz,1H),7.58-7.55(m,2H),7.54-7.50(m,2H),7.45- 7.40(m,2H),7.36-7.31(m,1H),7.27(s,2H),6.95(dt,J=3.3,0.9Hz,1H),5.80(d,J=7.6Hz,1H), 4.33(h,J=8.0Hz,1H),4.21(s,2H),3.04(p,J=8.5Hz,1H),2.55-2.49(m,1H),2.44-2.38(m,1H), 2.35(dd,J=8.5,2.6Hz,2H),2.26(dd,J=11.8,8.2Hz,1H),2.12-2.08(m,1H),1.78-1.71(m,2H). LC / MS(ESI)m / z:432.3[M+H] + .

[0638] Example 14: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2-methylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0639] Step 1: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid

[0640]

[0641] To a solution of methyl 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid (120 mg, 0.4 mmol) obtained in step 2 of Example 13, LiOH·H2O (51 mg, 1.20 mmol, 3.0 equivalent) was added, and the mixture was stirred for 3 hours. The reaction mixture was partially concentrated, acidified with 1N HCl, and the aqueous layer was extracted with EtOAc. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (15% EtOAc / hexane) to give 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid (101 mg, yield 86%) as a white solid. 1 H NMR (400MHz, Chloroform-d) δ10.02 (s, 1H), 8.23 ​​(dd, J = 3.1, 1.2Hz, 1H), 7.60-7.5 2(m,6H),7.44-7.40(m,1H),7.35-7.28(m,2H),6.82(d,J=3.3Hz,1H),4.31(s,2H).

[0642] Step 2: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-2-methylthiophene-3-carboxylic acid

[0643]

[0644] To a THF (1 mL) solution of methyl 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid (70 mL, 0.12 mmol) cooled to -78 °C, n-BuLi (125 μL, 0.27 mmol, 2.5 M THF solution) was added, and the mixture was stirred for 30 min. Iodomethane (18 μL, 0.31 mmol) was slowly added at -78 °C, and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with distilled water (15 mL) and EtOAc, and then purified by silica gel column chromatography to give 4-([1,1'-biphenyl]-4-ylmethyl)-2-methylthiophene-3-carboxylic acid (32 mg, 45% yield) as a white solid. 1 H NMR(300MHz,Chloroform-d)δ7.60-7.51(m,3H),7.48-7.38(m,3H),7.35-7.26 (m, 2H), 7.00 (d, J = 5.4Hz, 1H), 6.50 (d, J = 1.2Hz, 1H), 4.24 (s, 2H), 2.77 (s, 3H).

[0645] Step 3: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2-methylthiophene-3-carbamate)spiro[3.3]heptane- Synthesis of methyl 2-carboxylate

[0646]

[0647] Add 4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-4-methyl-morpholine-4-hydrochloride (DMT-MM) (27 mg, 0.105 mmol) to a MeCN (0.6 mL) solution of 4-([1,1'-biphenyl]-4-ylmethyl)-2-methylthiophene-3-carboxylic acid (30 mg, 0.096 mmol) and stir for 1 hour. Add intermediate A (15 mg, 0.105 mmol) and N-methylpyrrolidone (25.8 μL) to the reaction solution and stir for 12 hours. Then quench the reaction with distilled water and EtOAc. The crude product was purified by column chromatography (hexane: EA (35%)) to give methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2-methylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (18 mg, yield 40%). 1H NMR(500MHz,Chloroform-d)δ7.57-7.54(m,2H),7.52-7.49(m,2H),7.43(dd,J=8.5,6.9Hz,2H),7.3 6-7.32(m,1H),7.25-7.21(m,2H),6.74(s,1H),5.46(d,J=7.7Hz,1H),4.35-4.27(m,1H),4.02(s,2H) ,3.65(s,3H),2.96(q,J=8.5Hz,1H),2.50(s,3H),2.48-2.44(m,1H),2.37-2.33(m,1H),2.29(dd,J= 8.5, 4.0Hz, 2H), 2.20 (dd, J=11.7, 8.4Hz, 1H), 2.02 (ddd, J=11.6, 8.6, 2.7Hz, 1H), 1.66-1.61 (m, 2H).

[0648] Step 4: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2-methylthiophene-3-carbamate)spiro[3.3]heptane- Synthesis of 2-carboxylic acid

[0649]

[0650] LiOH·H2O (2 mg, 3.0 equivalent) was added to a THF / MeOH / H2O (2 / 1 / 2 mL) solution of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2-methylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (10 mg), and the mixture was stirred for 3 hours. The reaction mixture was partially concentrated and then acidified with 1N HCl aqueous solution. The aqueous layer was extracted with EtOAc, and the organic layer was dried over magnesium sulfate 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, yield 24%). 1 H NMR(500MHz,Methanol-d4)δ7.61-7.58(m,2H),7.53-7.50(m,2H),7.43(td,J=7.9, 2.1Hz,2H),7.32(td,J=7.2,1.4Hz,1H),7.24(t,J=8.4Hz,2H),6.89(s,1H),4.21-4 .16(m,1H),4.01(s,2H),2.96(q,J=8.5Hz,1H),2.44(s,3H),2.43-2.37(m,1H),2.3 5-2.26(m,3H),2.16(dd,J=11.8,8.4Hz,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] - .

[0651] Example 15: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0652] Step 1: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid

[0653]

[0654] To a THF / MeOH / H2O (2 / 1 / 2 mL) solution of methyl 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid (1.3 g, 4.215 mmol) obtained in step 2 of Example 13, LiOH·H2O (530 mg, 12.645 mmol, 3.0 equivalent) was added, and the mixture was stirred for 12 hours. The reaction solution was partially concentrated and then acidified with 1N HCl aqueous solution. The aqueous layer was extracted with EtOAc. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid (350 mg, yield 28%) as a milky white solid. 1 H NMR(400MHz,Chloroform-d)δ8.32-8.28(m,1H),7.64-7.60(m,2H),7.60-7.55 (m,2H),7.48-7.43(m,2H),7.37-7.32(m,3H),6.89-6.82(m,1H),4.34(s,2H).

[0655] Step 2: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxylic acid

[0656]

[0657] At 0 °C, Br2 (0.04 mL, 0.69 mmol) was added to a THF (1 mL) solution of 200 mg (0.66 mmol) of 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid, and the mixture was stirred for 4 hours. The reaction solution was acidified with 1 N HCl aqueous solution, the aqueous layer was extracted with diethyl ether, and the organic layer was washed with distilled water, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel rapid column chromatography to obtain 4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxylic acid (132 mg, yield 28%) as a brown solid. 1H NMR(500MHz,Chloroform-d)δ8.29(s,1H),7.59-7.54(m,2H),7.52-7.48(m,2H),7.44-7 .40(m,2H),7.36-7.31(m,1H),7.30-7.29(m,1H),7.29-7.27(m,1H),4.41-4.36(m,2H).

[0658] Step 3: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carbamate)spiro[3.3]heptane-2- Synthesis of methyl carboxylate

[0659]

[0660] DIPEA (0.070 mL, 0.402 mmol) was added to a DMF (1 mL) solution of 4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxylic acid (50 mg, 0.134 mmol) and HATU (56 mg, 0.147 mmol), and intermediate A (17 mg, 0.120 mmol) was added to the reaction solution. The mixture was stirred for 15 hours. The reaction solution was diluted with ethyl acetate and washed with distilled water and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane solution of 20% ethyl acetate) to give methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (44.9 mg, yield 64%) as a milky white solid. 1 H NMR(500MHz,Chloroform-d)δ7.56-7.53(m,3H),7.50-7.48(m,2H),7.44-7.39( m,2H),7.35-7.31(m,1H),7.26-7.22(m,2H),5.82-5.76(m,1H),4.28-4.23(m,1H ),4.22(s,2H),3.63(s,3H),3.02-2.91(m,1H),2.48-2.41(m,1H),2.35-2.31(m, 1H),2.30-2.25(m,2H),2.22-2.16(m,1H),2.04-1.96(m,1H),1.68-1.59(m,2H).

[0661] Step 4: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carbamate)spiro[3.3]heptane-2- Synthesis of carboxylic acids

[0662]

[0663] LiOH·H2O (5 mg, 0.114 mmol, 3.0 equivalence) was added to a solution of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (20 mg, 0.038 mmol) in THF / MeOH / H2O (2 / 1 / 2 mL), and the mixture was stirred for 3 hours. The reaction mixture was partially concentrated, acidified with 1N HCl, and the aqueous layer was extracted with EtOAc. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the compound of Example 15 (15 mg, 77% yield) as a milky white solid. 1 H NMR(400MHz,Chloroform-d)δ7.58(s,1H),7.56-7.52(m,2H),7.51-7.47(m,2H) ,7.45-7.40(m,2H),7.36-7.30(m,1H),7.25-7.21(m,2H),5.74-5.68(m,1H),4.3 3-4.26(m,1H),4.23(s,2H),3.05-2.94(m,1H),2.50-2.41(m,1H),2.39-2.35(m, 1H),2.34-2.29(m,2H),2.24-2.16(m,1H),2.07-1.99(m,1H),1.68-1.58(m,2H). LC / MS (ESI) m / z: 510.51 [M+H] + 508.35 [MH] - .

[0664] Example 16: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0665] Step 1: Synthesis of methyl 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxylic acid

[0666]

[0667] NBS (287 mg, 1.622 mmol) was added to a DMF (3 mL) solution of methyl 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylate (100 mg, 0.324 mmol) obtained in step 2 of Example 13, and the mixture was stirred at 80 °C for 24 hours. A 10% aqueous solution of sodium bicarbonate and EA were added to the reaction mixture. The organic layer was dried over magnesium sulfate and concentrated to obtain methyl 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxylate (76 mg, 50% yield), a white solid. 1H NMR (300MHz, CDCl3) δ7.59-7.53(m,2H),7.51-7.46(m,2H),7.44-7.39(m,2H),7.30-7.33(m,1H),7.18(d,J=8.2Hz,2H),4.23(s,2H),3.76(s,3H).

[0668] Step 2: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxylic acid

[0669]

[0670] To a solution of methyl 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxylic acid (76 mg, 0.163 mmol) in THF / MeOH / H₂O (1 / 1 / 1 mL), LiOH·H₂O (21 mg, 0.489 mmol) was added, and the mixture was stirred for 12 hours. The reaction mixture was partially concentrated and then acidified with 1N HCl aqueous solution. The aqueous layer was extracted with EtOAc. The organic layer was dried over magnesium sulfate and then concentrated to give 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxylic acid (35.5 mg, 47% yield) as a white solid. 1 HNMR (300MHz, CDCl3) δ7.50-7.56(m,2H),7.47(d,J=8.2Hz,2H),7.45-7.40(m,2H),7.35-7.32(m,1H),7.19(d,J=8.2Hz,2H),4.29(s,2H).

[0671] Step 3: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxamido)spiro[3.3]heptane Synthesis of methyl alkyl-2-carboxylic acid

[0672]

[0673] DIPEA (0.041 mL, 0.237 mmol) was added to a DMF (1 mL) solution of 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxylic acid (35.5 mg, 0.079 mmol) and HATU (33 mg, 0.086 mmol), followed by intermediate A (18 mg, 0.086 mmol). The mixture was stirred for 15 hours. The reaction solution was diluted with ethyl acetate and washed with distilled water and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (43.8 mg, 92% yield), as a white solid. 1H NMR (300MHz, CDCl3) δ7.57-7.51(m,2H),7.50-7.40(m,4H),7.37-7.30(m,1H),7.20(s,2H),5.58(d,J=7.9Hz,1H),4.32-4.24(m,1H),4.1 1(s,2H),3.65(s,3H),3.02-2.91(m,1H),2.50-2.42(m,1H),2.25-2.40(m,3H),2.20-2.17(m,1H),2.06-1.99(m,1H),1.73-1.63(m,2H).

[0674] Step 4: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxamido)spiro[3.3]heptane Synthesis of alkyl-2-carboxylic acids

[0675]

[0676] LiOH·H2O (9 mg, 0.209 mmol) was added to a solution of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (42 mg, 0.070 mmol) in THF / MeOH / H2O (1 / 1 / 1 mL), and the mixture was stirred for 12 hours. The reaction solution was partially concentrated, acidified with 1N HCl aqueous solution, and filtered to obtain the compound of Example 16 (4 mg, 4% yield) as a white solid. 1 H NMR (300MHz, CDCl3) δ7.56-7.51(m,2H),7.50-7.39(m,4H),7.36-7.33(m,1H),7.21(d,J=8.2Hz,2H),5.58(d,J=7.7Hz,1H),4 .32-4.24(m,1H),4.11(s,2H),3.06-2.95(m,1H),2.51-2.29(m,4H),2.25-2.17(m,1H),2.14-2.04(m,1H),1.77-1.63(m,2H). LC / MS(ESI)m / z:590.4[M+H] + .

[0677] Example 17: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dichlorothiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0678] Step 1: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dichlorothiophene-3-carboxylic acid

[0679]

[0680] NCS (250 mg, 1.869 mmol) was added to a DMF (3.6 mL) solution of 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid (110 mg, 0.374 mmol) obtained in step 3 of Example 13, and the mixture was heated to 70 °C and stirred for 24 hours. The reaction solution was quenched with 10% sodium bicarbonate aqueous solution, and after 15 minutes, it was extracted with EA and distilled water, dried over magnesium sulfate, and concentrated to give crude 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dichlorothiophene-3-carboxylic acid (34.4 mg, yield 25%). 1 H NMR (300MHz, CDCl3) δ7.58-7.52(m,2H),7.52-7.46(m,2H),7.42(td,J=8.2,1.8Hz,3H),7.36(s,1H),7.23(d,J=8.2Hz,2H),4.29(s,2H).

[0681] Steps 2 and 3: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dichlorothiophene-3-carboxamido)spiro[3.3] Synthesis of heptane-2-carboxylic acid

[0682]

[0683] The compound of Example 17 was prepared by reacting the 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dichlorothiophene-3-carboxylic acid obtained in step 1 above with the same method as in steps 3 and 4 of Example 16. 1 H NMR (300MHz, CDCl3) δ7.57-7.51(m,2H),7.50-7.39(m,4H),7.34-7.31(m,1H),7.22(d,J=8.2Hz,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] + .

[0684] Example 18: 6-(3-([1,1'-biphenyl]-4-ylmethyl)thiophene-2-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0685] Step 1: Synthesis of 3-([1,1'-biphenyl]-4-ylmethyl)thiophene-2-carboxylic acid

[0686]

[0687] At -78 °C, n-BuLi (10 M THF solution, 0.324 mL, 3.434 mmol) was slowly added to a THF (15 mL) solution of thiophene-2-carboxylic acid (200 mg, 1.561 mmol) for 0.5 h, followed by the addition of 4-(bromomethyl)-1,1'-biphenyl (772 mg, 3.122 mmol). The reaction mixture was stirred for 6 h, then quenched with 1 N HCl aqueous solution, and extracted with EA and distilled water. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The crude product was purified by rapid column chromatography to give 3-([1,1'-biphenyl]-4-ylmethyl)thiophene-2-carboxylic acid (28 mg, 6% yield) as a white solid. 1 H NMR (300MHz, CDCl3) δ7.60-7.55(m,2H),7.55-7.48(m,3H),7.45-7.40(m,2H),7.35-7.28(m,3H),6.93(d,J=5.1Hz,1H),4.45(s,2H).

[0688] Step 2: 6-(3-([1,1'-biphenyl]-4-ylmethyl)thiophene-2-carboxamido)spiro[3.3]heptane-2-carboxylic acid Ester Synthesis

[0689]

[0690] DIPEA (0.046 mL, 0.264 mmol) was added to a DCM (1 mL) solution of 3-([1,1'-biphenyl]-4-ylmethyl)thiophene-2-carboxylic acid (26 mg, 0.088 mmol) and HATU (20 mg, 0.097 mmol), and the mixture was stirred for 10 minutes. Intermediate A (20 mg, 0.097 mmol) was added to the reaction mixture, and the mixture was 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 sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (20% EtOAc in hexane) to give methyl 6-(3-([1,1'-biphenyl]-4-ylmethyl)thiophene-2-carboxamido)spiro[3.3]heptane-2-carboxylic acid (32 mg, 82% yield) as a white solid. 1H NMR (300MHz, CDCl3) δ7.59-7.50(m,4H),7.42(t,J=7.3Hz,2H),7.34(d,J=7.3Hz,1H),7.32-7.27(m,3H),6.92(d,J=5.0Hz,1H),5.84(d,J=7.5Hz,1H ),4.50-4.34(m,3H),3.66(s,3H),3.07-2.96(m,1H),2.59-2.51(m,1H),2 .46-2.40(m,1H),2.35-2.22(m,3H),2.14-2.07(m,1H),1.87-1.76(m,2H).

[0691] Step 3: 6-(3-([1,1'-biphenyl]-4-ylmethyl)thiophene-2-carboxamido)spiro[3.3]heptane-2-carboxylic acid synthesis

[0692]

[0693] LiOH·H2O (9 mg, 0.209 mmol) was added to a THF / MeOH / H2O (1 / 1 / 1) solution of methyl 6-(3-([1,1'-biphenyl]-4-ylmethyl)thiophene-2-carboxamido)spiro[3.3]heptane-2-carboxylic acid (32 mg, 0.072 mmol) and stirred for 12 hours. The reaction solution was partially concentrated, acidified with 1N HCl aqueous solution, and filtered to obtain the compound of Example 18 (30.7 mg, 99% yield) as a pale yellow solid. 1 H NMR (300MHz, CDCl3) δ7.59-7.50 (m, 4H), 7.42 (t, J = 7.4Hz, 2H), 7.34 (d, J = 7 .4Hz,1H),7.31-7.26(m,3H),6.92(d,J=5.0Hz,1H),5.85(d,J=7.5Hz,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] + .

[0694] Example 19: 6-(3-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)thiophene-2-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0695] Steps 1 and 2: Synthesis of methyl 6-(3-(4-chlorobenzyl)thiophene-2-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0696]

[0697] Except for replacing 4-(bromomethyl)-1,1'-biphenyl in step 1 of Example 18 with 4-chlorobenzyl bromide, methyl 6-(3-(4-chlorobenzyl)thiophene-2-carboxamido)spiro[3.3]heptane-2-carboxylic acid was obtained using the same method as in steps 1 and 2 of Example 18. 1 H NMR(300MHz,chloroform-d)δ7.25-7.17(m,3H),7.17-7.09(m,2H),6.80(d,J=5.0Hz,1H),5.95(d,J=7.5Hz,1H),4.42-4.28(m,1H),4.2 4(s,2H),3.64(s,3H),3.06-2.95(m,1H),2.57-2.49(m,1H),2.46-2.36(m,1H),2.34-2.22(m,3H),2.17-2.07(m,1H),1.91-1.80(m,2H).

[0698] Step 3: 6-(3-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)thiophene-2-carboxamide )screw [3.3] Synthesis of heptane-2-carboxylic acid methyl ester

[0699]

[0700] Methyl 6-(3-(4-chlorobenzyl)thiophene-2-carboxamido)spiro[3.3]heptane-2-carboxylic acid (286 mg, 0.7 mmol), 3-fluoro-5-methoxyphenylboronic acid (178 mg, 1.05 mmol, 1.5 equivalents), Pd(OAc)2 (16 mg, 0.07 mmol, 0.1 equivalents), XPhos (67 mg, 0.14 mmol, 0.2 equivalents), and K3PO4 (297 mg, 1.4 mmol, 2.0 equivalents) were stirred for 2 hours in dioxane / H2O (10 / 1 mL) under microwave irradiation at 100 °C. The reaction mixture was poured into distilled water and extracted with DCM. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by rapid column chromatography to obtain methyl 6-(3-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)thiophene-2-carboxamido)spiro[3.3]heptane-2-carboxylic acid. 1H NMR(300MHz,chloroform-d)δ7.47(d,J=8.2Hz,2H),7.33-7.27(m,2H),6.93-6.80(m,3H),6.58(dt,J=10.5,2.3Hz,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).

[0701] Step 4: 6-(3-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)thiophene-2-carboxamido)spiro [3.3] Synthesis of heptane-2-carboxylic acid

[0702]

[0703] The compound of Example 19 was prepared by reacting methyl 6-(3-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)thiophene-2-carboxamido)spiro[3.3]heptane-2-carboxylic acid obtained in step 3 above with the same method as in step 3 of Example 18. 1 H NMR(300MHz, Methanol-d4); δ8.15(d,J=7.2Hz,1H),7.50(d,J=8.2Hz,2H),7.42 (d,J=5.0Hz,1H),7.26(d,J=8.3Hz,2H),6.94(t,J=1.9Hz,1H),6.92-6.86(m,2H ),6.64(dt,J=10.7,2.3Hz,1H),4.31-4.23(m,3H),3.83(s,3H),3.07-2.95(m,1 H),2.54-2.46(m,1H),2.39-2.30(m,3H),2.29-2.14(m,2H),2.07-1.96(m,2H). LC / MS (ESI) m / z: 480.4 [M+H] + .

[0704] Example 20: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0705] Step 1: Synthesis of methyl 4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxylic acid

[0706]

[0707] At room temperature, N-bromosuccinimide (NBS, 115 mg, 0.649 mmol) was slowly added to an AcOH solution of methyl 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid (200 mg, 0.649 mmol) obtained in step 2 of Example 13. After stirring for 15 hours, the reaction solution was extracted with DCM and washed with aqueous sodium carbonate solution and distilled water. The organic layer was washed twice with distilled water, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel (hexane) column chromatography to give methyl 4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxylic acid (150 mg, yield 59%) as a yellow solid. 1 H NMR (300MHz, Chloroform-d) δ8.16(s,1H),7.64-7.59(m,2H),7.57-7.53(m,2H),7.49-7.43(m,2H),7.39-7.30(m,3H),4.42(s,2H),3.83(s,3H).

[0708] Step 2: Synthesis of methyl 4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxylic acid ester

[0709]

[0710] Iodomethane (0.065 mL, 1.548 mmol, 3.0 equivalence) was added to a THF (10 mL) solution of methyl 4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxylic acid (200 mg, 0.516 mmol) and the mixture was cooled to -78 °C. n-BuLi (2 M THF solution, 0.516 mL, 1.032 mmol) was added to the reaction mixture, and the mixture was stirred for 4 hours. The mixture was then slowly heated to room temperature, diluted with ethyl acetate, and washed with distilled water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain crude methyl 4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxylic acid (49 mg), which was a yellow oil. 1 H NMR(400MHz,Chloroform-d)δ7.99(s,1H),7.61-7.59(m,2H),7.53-7.51(m,2H),7.46-7 .44(m,2H),7.37-7.33(m,2H),7.23-7.22(m,1H),4.36(s,2H),3.82(s,3H),2.46(s,3H).

[0711] Step 3: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxylic acid

[0712]

[0713] LiOH·H2O (8 mg, 0.186 mmol, 3 equivalents) was added to a THF / MeOH / H2O (2 / 1 / 2) solution of methyl 4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxylic acid (20 mg, 0.062 mmol) and stirred for 8 hours. The reaction mixture was partially concentrated and then acidified with 1N HCl aqueous solution. The aqueous layer was extracted with EtOAc, and the organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give 4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxylic acid (4.3 mg, yield 22%) as a milky white solid. 1 H NMR(300MHz,chloroform-d)δ8.10(s,1H),7.59-7.54(m,2H),7.50-7.47(m,2H),7 .45-7.39(m,2H),7.36-7.31(m,1H),7.22-7.16(m,2H),4.34(s,2H),2.44(s,3H).

[0714] Step 4: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carbamate)spiro[3.3]heptane- Synthesis of methyl 2-carboxylate

[0715]

[0716] DIPEA (0.013 mL, 0.072 mmol) was added to a DMF solution of 4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxylic acid (7.3 mg, 0.024 mmol) and HATU (10 mg, 0.026 mmol), and the mixture was stirred for 10 minutes. Then, intermediate A (4 mg, 0.026 mmol) was added, and the mixture was 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 sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (20% EtOAc in hexane) to give methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxamido)spiro[3,3]heptane-2-carboxylic acid (6.9 mg, 63% yield) as a yellow solid. 1H NMR(400MHz,chloroform-d)δ7.58-7.56(m,2H),7.52-7.50(m,2H),7.47-7.43(m,2H), 7.41(s,1H),7.38-7.33(m,1H),7.22-7.17(m,2H),5.77-5.71(m,1H),4.36-4.28(m,1H ),4.19(s,2H),3.67(s,3H),3.04-2.95(m,1H),2.52-2.48(m,1H),2.46(s,3H),2.40-2 .34(m,1H),2.34-2.27(m,2H),2.26-2.18(m,1H),2.08-2.00(m,1H),1.68-1.63(m,2H).

[0717] Step 5: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carbamate)spiro[3.3]heptane- Synthesis of 2-carboxylic acid

[0718]

[0719] LiOH·H2O (2 mg, 0.044 mmol, 3.0 equivalence) was added to a THF / MeOH / H2O (2 / 1 / 2) solution of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid ester (6.8 mg, 0.015 mmol) and stirred for 3 hours. The reaction mixture was partially concentrated and then acidified with 1N HCl aqueous solution. The aqueous layer was then extracted with EtOAc. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the compound of Example 20 (4.7 mg, 70% yield) as a milky white solid. 1 H NMR(500MHz,chloroform-d)δ7.58-7.56(m,2H),7.53-7.50(m,2H),7.47-7.43(m,3H),7.38-7.34(m,1H),7.22-7.17(m,2H),5.76-5.71(m,1H),4.31-4 .29(m,1H),4.19(s,2H),3.05-2.98(m,1H),2.52-2.49(m,1H),2.46(s,3H), 2.36-2.33(m,3H),2.27-2.22(m,1H),2.10-2.05(m,1H),1.71-1.65(m,2H). LC / MS (ESI) m / z: 446.11 [M+H] + 444.28 [MH] - .

[0720] Except for the different preparation methods described below, the compounds of Examples 21 and 22 were prepared using the same methods as in Example 20.

[0721] [Table 3]

[0722]

[0723]

[0724] [Table 4]

[0725]

[0726] Example 23: 6-(4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0727] Step 1: Synthesis of 3-bromo-4-(4-chlorobenzyl)-2,5-dimethylthiophene

[0728]

[0729] Intermediate C (1.15 g, 6.0 mmol), MsOH (78 μL, 1.20 mmol), and FeCl3 (194 mg, 1.20 mmol) were added to a DCE (3 mL) solution of (4-chlorophenyl)methanol (427 mg, 3.0 mmol), and the mixture was heated to 55 °C and stirred for 12 hours. The reaction solution was diluted with ethyl acetate and washed with distilled water and brine. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The crude product was purified by column chromatography to give bromo-4-(4-chlorobenzyl)-2,5-dimethylthiophene (541 mg, 57% yield) as a white solid. 1 H NMR (300MHz, chloroform-d) δ7.28-7.20 (m, 2H), 7.08 (d, J = 8.6Hz, 2H), 3.91 (s, 2H), 2.37 (s, 3H), 2.35 (s, 3H).

[0730] Step 2: Synthesis of 4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxylic acid

[0731]

[0732] At -78 °C, n-BuLi (2.5 M THF solution, 0.8 mL, 2.0 mmol) was added to a THF solution of 3-bromo-4-(4-chlorobenzyl)-2,5-dimethylthiophene (541 mg, 1.71 mmol) and TMEDA (0.3 mL, 1.88 mmol) in 10 mL of THF, and the mixture was stirred for 1 hour. The reaction solution was quenched with CO2 gas at -78 °C and allowed to stand at room temperature for 30 minutes. The reaction solution was acidified with 1 N HCl solution, diluted with EtOAc, and then washed with distilled water. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to give 4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxylic acid (450 mg, crude product) as a pale yellow solid. LC / MS (ESI) m / z: 281.26 [M+H] + .

[0733] Step 3: 6-(4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Ester Synthesis

[0734]

[0735] DIPEA (0.8 mL, 4.81 mmol) was added to an 8 mL DMF solution of 4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxylic acid (450 mg, 1.60 mmol) and HATU (670 mg, 1.76 mmol), and the mixture was stirred for 10 minutes. Then, intermediate A (330 mg, 1.60 mmol) was added to the reaction mixture, and the mixture was stirred for 15 hours. The reaction mixture was diluted with EtOAc and washed with distilled water and brine. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The crude product was purified by column chromatography to give methyl 6-(4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (418 mg, yield 56%) as a white solid. 1 HNMR(400MHz,chloroform-d)δ7.23(d,J=8.5Hz,2H),7.04(d,J=8.4Hz,2H),5.47-5.17(m,1H),4.36-4.17(m,1H),3.91(s,2H),3.69(s ,3H),3.02(t,J=8.5Hz,1H),2.54-2.41(m,4H),2.40-2.29(m,5H),2.25(dd,J=11.7,8.4Hz,1H),2.13-2.01(m,1H),1.68-1.52(m,3H). LC / MS(ESI)m / z:432.37[M+H] + .

[0736] Step 4: 6-(4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid synthesis

[0737]

[0738] LiOH·H2O (13 mg, 0.3 mmol) was added to a solution of methyl 6-(4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (43 mg, 0.1 mmol) in H2O:THF:MeOH (1:1:1), and the mixture was stirred for 4 hours. The reaction mixture was partially concentrated under reduced pressure, acidified by adding 1N HCl (pH approximately 6), and then extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give the compound of Example 23 (30 mg, 71% yield). 1 H NMR(300MHz,chloroform-d)δ7.27-7.18(m,2H),7.04(d,J=8.5Hz,2H),5.35(d,J=7.9Hz,1H),4.27(d,J=7.8Hz,1H),3.91(s,2H),3.06(t,J=8.5Hz,1H) ,2.53-2.44(m,1H),2.43(s,3H),2.41-2.35(m,2H),2.35-2.30(m,1H),2.33 (s,3H),2.31-2.21(m,1H),2.17-2.06(m,1H),1.60(dt,J=11.5,7.7Hz,2H). LC / MS (ESI) m / z: 418.23 [M+H] + .

[0739] Except for the different preparation methods described below, the compounds of Examples 24 and 25 were prepared using the same method as in Example 23.

[0740] [Table 5]

[0741]

[0742] [Table 6]

[0743]

[0744] Example 26: 6-(2,5-dimethyl-4-(4-(pyridin-4-yl)benzyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0745] Step 1: 6-(2,5-dimethyl-4-(4-(pyridin-4-yl)benzyl)thiophene-3-carboxamido)spiro[3.3]heptane- Synthesis of methyl 2-carboxylate

[0746]

[0747] Under a nitrogen atmosphere, a solution of methyl 6-(4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (27 mg, 0.06 mmol), pyridin-4-ylboronic acid (9 mg, 0.075 mmol), and K3PO4 (13 mg, 0.063 mmol) in dioxane:H2O (2:1) was substituted, and then Pd2(dba)3 (6 mg, 6.2 μmol) and PCy3 (3 mg, 9.4 μmol) were added. The reaction solution was microwaved at 110 °C for 1.5 hours, then filtered through diatomaceous earth and concentrated under reduced pressure to obtain methyl 6-(2,5-dimethyl-4-(4-(pyridin-4-yl)benzyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate. LC / MS(ESI) m / z: 476.28 [M+2] + .

[0748] Step 2: 6-(2,5-dimethyl-4-(4-(pyridin-4-yl)benzyl)thiophene-3-carboxamido)spiro[3.3]heptane- Synthesis of 2-carboxylic acid

[0749]

[0750] LiOH·H2O (9 mg, 0.18 mmol) was added to a solution of methyl 6-(2,5-dimethyl-4-(4-(pyridin-4-yl)benzyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (crude, 0.06 mmol) in H2O:THF:MeOH (1:1:1), and the mixture was stirred for 4 hours. The reaction solution was concentrated under reduced pressure, diluted with distilled water, acidified with 1N HCl (pH approximately 6), and extracted with EtOAc. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give the compound of Example 26 (12 mg, yield 42%) as a white solid. 1 H NMR(300MHz, methanol-d4)δ8.92-8.31(m,2H),7.68(dd,J=14.7,7.0Hz,4H),7.25(d,J=8.1Hz,2H),4.34-3.95 (m,1H),4.00(s,2H),3.07-2.82(m,1H),2.38(s,6H),2.34-2.19(m,3H),2.20-1.93(m,3H),1.91-1.60(m,2H). LC / MS(ESI)m / z:462.31[M+2] + .

[0751] Example 27: 6-(2,5-dimethyl-4-(4-(pyridin-3-yl)benzyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0752]

[0753] Except that the pyridine-4-ylboronic acid used in step 1 of Example 26 was replaced with pyridine-3-ylboronic acid, the compound of Example 27 was obtained by using the same method as in Example 26, and was a white solid. 1 H NMR (500MHz, methanol-d4) δ8.78 (s, 1H), 8.51 (d, J = 4.2 Hz, 1H), 8.08 (d, J = 8. 0Hz,1H),7.62-7.49(m,3H),7.24(d,J=8.2Hz,2H),4.26-4.08(m,1H),4.00(s ,2H),3.03-2.87(m,1H),2.45-2.37(m,1H),2.38(s,6H),2.35-2.21(m,3H),2 .13(dd,J=8.2Hz,1H),2.10-2.00(m,1H),1.79(ddd,J=24.7,11.0,8.9Hz,2H). LC / MS (ESI) m / z: 462.24 [M+2] + .

[0754] Example 28: 6-(4-((3',4'-dimethyl-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0755] Step 1: 6-(4-((3',4'-dimethyl-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-methyl Synthesis of methyl 2-carboxylic acid ester (amido)spiro[3.3]heptane-2-carboxylic acid

[0756]

[0757] A solution of methyl 6-(4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-carboxylate (50 mg, 0.023 mmol) and 3,4-dimethylphenylboronic acid (4.1 mg, 0.027 mmol) in dioxane (0.2 mL) was placed in a sealed tube, and distilled water (0.01 mL) and Cs₂CO₃ (8 mg, 0.046 mmol) were added. Pd(OAc)₂ (0.5 mg) and Xphos (13 mg, 0.023 mmol) were added under a N₂ atmosphere, and the reaction mixture was stirred at 90 °C for 15 hours. The reaction mixture was diluted with ethyl acetate, washed with distilled water, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (6% MeOH in CHCl3 solution) to obtain methyl 6-(4-((3',4'-dimethyl-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (20 mg, mixture).1 H NMR(500MHz,Chloroform-d)δ7.48-7.45(m,2H),7.32(d,J=2.0Hz,1H),7.28(dd,J=7.8,2.1Hz,1H),7.19(d ,J=8.1Hz,1H),7.13(d,J=8.2Hz,2H),5.38(d,J=7.8Hz,1H),4.24(h,J=7.9Hz,1H),3.96(s,2H),3.63(s,3H ),2.96-2.90(m,1H),2.43(s,2H),2.42-2.39(m,2H),2.35(s,3H),2.32(s,3H),2.30(s,3H),2.27-2.23(m, 2H), 2.15(dd,J=11.7,8.5Hz,1H), 1.96(ddd,J=11.7,8.6,2.9Hz,1H), 1.49(ddd,J=14.9,11.4,8.5Hz,2H).

[0758] Step 2: 6-(4-((3',4'-dimethyl-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-methyl Synthesis of amide group)spiro[3.3]heptane-2-carboxylic acid

[0759]

[0760] LiOH·H2O (4 mg, 0.084 mmol, 3.0 equivalence) was added to a THF / MeOH / H2O (2 / 1 / 2) solution of methyl 6-(4-((3',4'-dimethyl-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (methyl ester) (20 mg), and the mixture was stirred for 3 hours. The reaction mixture was partially concentrated and then acidified with 1N HCl aqueous solution. The aqueous layer was extracted with EtOAc. The organic layer was dried over magnesium sulfate 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). 1H NMR(500MHz,chloroform-d)δ7.49-7.45(m,2H),7.32(d,J=2.0Hz,1H),7.28(dd,J=7.8,2.1Hz,1H),7. 19(d,J=7.8Hz,1H),7.14-7.11(m,2H),5.35(d,J=7.8Hz,1H),4.24(h,J=8.0Hz,1H),3.96(s,2H),2.97( p,J=8.5Hz,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, 8.3Hz, 1H), 1.99 (ddd, J=11.6, 8.7, 2.4Hz, 1H), 1.49 (dt, J=11.7, 9.1Hz, 2H). LC / MS(ESI)m / z:488.43[M+H] + .

[0761] Except for the different preparation methods described below, the compounds of Examples 29 to 66 were prepared using the same method as in Example 28.

[0762] [Table 7]

[0763]

[0764]

[0765]

[0766]

[0767]

[0768] [Table 8]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774] [Table 9]

[0775]

[0776]

[0777]

[0778] [Table 10]

[0779]

[0780]

[0781]

[0782]

[0783] [Table 11]

[0784]

[0785]

[0786]

[0787]

[0788]

[0789]

[0790]

[0791] [Table 12]

[0792]

[0793]

[0794]

[0795]

[0796]

[0797] Example 67: 6-(4-(4-cyclohexylbenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0798] Step 1: 6-(2,5-dimethyl-4-((2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)thiophene- Synthesis of methyl 3-formamido)spiro[3.3]heptane-2-carboxylic acid

[0799]

[0800] A solution of methyl 6-(4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (50 mg, 0.11 mmol) and 2-(cyclohexyl-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxane (27 mg, 0.13 mmol) in 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 solution was diluted with ethyl acetate, washed with distilled water, dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (30% EtOAc in hexane solution) to obtain methyl 6-(2,5-dimethyl-4-((2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (59 mg, mixture). 1 H NMR(400MHz, Methanol-d4)δ7.28-7.22(m,2H),7.00(d,J=8.3Hz,2H),6.07(tt, J=3.9,1.7Hz,1H),4.13-4.09(m,1H),3.90(s,2H),3.66(s,3H),3.02(p,J=8.5Hz ,1H),2.50-2.42(m,1H),2.41-2.37(m,2H),2.35(d,J=5.5Hz,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).

[0801] Step 2: 6-(4-(4-cyclohexylbenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Synthesis of methyl ester

[0802]

[0803] 10% Pd / C (2.2 mg) was added to an ethyl acetate / methanol (8 / 2, 0.2 mL) solution of methyl 6-(2,5-dimethyl-4-((2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (20 mg, 0.042 mmol). The reaction mixture was stirred under hydrogen atmosphere for 24 hours and then filtered through diatomaceous earth with ethyl acetate to obtain methyl 6-(4-(4-cyclohexylbenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (12 mg). 1 H NMR(400MHz,Chloroform-d)δ7.16-7.10(m,2H),7.02(s,2H),5.32(d,J=7.9Hz,1H),4.31- 4.13(m,1H),3.91(s,2H),3.68(s,3H),3.03-2.95(m,1H),2.52-2.46(m,1H),2.45(s,3H),2 .40-2.36(m,1H),2.35(s,3H),2.30-2.26(m,2H),2.26-2.23(m,1H),2.22-2.16(m,1H),2.0 2-1.96(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).

[0804] Step 3: 6-(4-(4-cyclohexylbenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Acid Synthesis

[0805]

[0806] LiOH·H2O (3 mg, 0.075 mmol, 3.0 equivalent) was added to a THF / MeOH / H2O (2 / 1 / 2) solution of methyl 6-(4-(4-cyclohexylbenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (12 mg), and the mixture was stirred for 3 hours. The reaction mixture was partially concentrated and then acidified with 1N HCl aqueous solution. The aqueous layer was extracted with EtOAc. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give the compound of Example 67 (3.7 mg, yield 32%). 1HNMR(300MHz,Chloroform-d)δ7.14-7.08(m,2H),6.99(d,J=8.1Hz,2H),5.30(d,J=7.8Hz,1H),4 .29-4.12(m,1H),3.89(s,2H),3.00(p,J=8.5Hz,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=10.6,7.2Hz,1H),2.06-1 .96(m,1H),1.82(d,J=8.1Hz,3H),1.74(d,J=13.0Hz,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] - .

[0807] Example 68: 6-(2,5-dimethyl-4-(4-(piperidin-4-yl)benzyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0808] Steps 1 to 3: 6-(4-(4-(1-(tert-butyloxycarbonyl)piperidin-4-yl)benzyl)-2,5-dimethylthiophene-3-formyl Synthesis of (amino)spiro[3.3]heptane-2-carboxylic acid

[0809]

[0810]

[0811] Except that 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane in step 1 of Example 67 was replaced with 4-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester was obtained using the same method as in Example 67, and 6-(4-(4-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid was obtained as a milky white solid. 1H NMR(400MHz,Chloroform-d)δ7.13(s,2H),7.06-7.01(m,2H),5.34-5.29(m, 1H),4.30-4.20(m,3H),3.91(s,2H),3.05-2.96(m,1H),2.86-2.74(m,2H),2 .69-2.59(m,1H),2.43(s,3H),2.41-2.38(m,1H),2.35(s,3H),2.33-2.27(m ,4H),2.15-2.09(m,1H),1.82-1.76(m,2H),1.67-1.54(m,4H),1.50(s,9H).

[0812] Step 4: 6-(2,5-dimethyl-4-(4-(piperidin-4-yl)benzyl)thiophene-3-carboxamido)spiro[3.3]heptane- Synthesis of 2-carboxylic acid

[0813]

[0814] A solution of 6-(4-(4-(1-(tert-butyloxycarbonyl)piperidin-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (14 mg, 0.024 mmol) and dioxane (0.5 mL) in 4N HCl was stirred for 2 hours. The reaction solution was poured into diethyl ether and concentrated under reduced pressure to give the hydrochloride salt (4 mg, 33%) of the compound of Example 68 as a milky white solid. 1 HNMR(500MHz,Methanol-d4)δ7.15-7.08(m,2H),7.04-6.98(m,2H),4.16-4.09(m,1 H),3.86(s,2H),3.49-3.44(m,2H),3.16-3.08(m,2H),3.03-2.97(m,1H),2.86-2.79 (m,1H),2.41-2.35(m,2H),2.33(s,3H),2.30(s,3H),2.26-2.20(m,2H),2.17-2.12 (m,1H),2.12-2.06(m,1H),2.03-1.98(m,2H),1.93-1.81(m,3H),1.77-1.70(m,1H). LC / MS(ESI)m / z:465.7[MH] - .

[0815] Example 69: 6-(4-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0816]

[0817] A solution of the compound from Example 23 (30 mg, 0.069 mmol) and 4-fluoroboric acid (12 mg, 0.083 mmol) in dioxane (0.2 mL) was placed in a sealed tube, and H₂O (0.01 mL) and Cs₂CO₃ (45 mg, 0.138 mmol) were added. Under a nitrogen atmosphere, Pd(OAc)₂ (2 mg, 0.007 mmol) and Xphos (33 mg, 0.069 mmol) were added, and the mixture was stirred at 90 °C for 12 hours. The reaction solution was diluted with ethyl acetate, washed with distilled water, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (hexane:ethyl acetate = 1:1) to give the compound from Example 69 (3 mg, 12% yield), as a milky white solid. 1 H NMR(500MHz,Chloroform-d)δ7.55-7.49(m,2H),7.48-7.45(m,2H),7.19-7.17(m,2H),7.17-7.12(m,2H),5.46-5 .35(m,1H),4.33-4.25(m,1H),3.99(s,2H),3.04-2.96(m,1H),2.46(s,3H),2.44-2.41(m,0H),2.38(s,3H),2.36 2.30(m,4H),2.22-2.15(m,1H),2.06-1.98(m,1H),1.62-1.49(m,3H). LC / MS (ESI) m / z: 478.6 [M+H] + 476.6 [MH] - .

[0818] Example 70: 6-(4-((3'-cyano-5'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0819]

[0820] Except that the 4-fluoroboronic acid used in Example 69 was replaced with 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane-2-yl)benzonitrile and the Cs2CO3 was replaced with K3PO4, the compound of Example 70 was obtained using the same method as in Example 69. 1HNMR(300MHz,MeOD)δ8.28(d,J=7.5Hz,1H),7.85(t,J=1.5Hz,1H),7.73(ddd,J=10.1,2. 5,1.6Hz,1H),7.63-7.54(m,2H),7.52(ddd,J=8.1,2.5,1.3Hz,1H),7.23(d,J=8.2Hz,2H) ,4.22-4.08(m,1H),3.99(s,2H),2.95(p,J=8.4Hz,1H),2.49-2.38(m,1H),2.39(s,3H), 2.37(s,3H),2.35-2.20(m,3H),2.19-2.10(m,1H),2.09-1.99(m,1H),1.87-1.70(m,2H). LC / MS(ESI)m / z:503.02[M+H] + .

[0821] Example 71: 6-(4-((3'-fluoro-5'-hydroxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0822] Step 1: 6-(4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3- Synthesis of Methyl Formamido(spiro[3.3]heptane-2-carboxylic Acid)

[0823]

[0824] Except that 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxacyclopentaborane used in step 1 of Example 67 was replaced with (3-fluoro-5-methoxyphenyl)boronic acid, methyl 6-(4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid was obtained using the same method as in step 1 of Example 67. 1H NMR (400MHz, CDCl3) δ7.50-7.46(m,2H),7.18(d,J=8.2Hz,2H),7.01(d,J=5.4Hz,1H),6.89(q ,J=2.1,1.7Hz,1H),6.62(dt,J=10.5,2.3Hz,1H),5.39(d,J=7.8Hz,1H),4.28(q,J=8.1Hz,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(d q,J=8.6,4.2,3.4Hz,3H),2.18(dd,J=11.7,8.4Hz,1H),2.02-1.97(m,1H),1.58-1.51(m,2H).

[0825] Step 2: 6-(4-((3'-fluoro-5'-hydroxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-methyl Synthesis of amide group)spiro[3.3]heptane-2-carboxylic acid

[0826]

[0827] At 0 °C, BBr3 (0.7 mL, 0.72 mmol) was added to a DCM (0.1 M) solution of methyl 6-(4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (94 mg, 0.18 mmol), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched with distilled water and stirred for another 15 hours. The mixture was then extracted with ethyl acetate (2 × 20 mL) and washed with brine. The organic layer was dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The crude product was purified by column chromatography (5% MeOH in DCM solution) to give the compound of Example 71 (22 mg, 25% yield) as a grayish-white solid. 1 H NMR (500MHz, CDCl3) 1H NMR(400MHz,Chloroform-d)δ7.41(d,J=7.8Hz,2H),7.14(d,J=8.0Hz,2H),6.88( t,J=1.9Hz,1H),6.83-6.75(m,1H),6.62-6.54(m,1H),5.40-5.26(m,1H),4.24(h, J=8.1Hz,1H),3.98(s,2H),3.02(p,J=7.5Hz,1H),2.49-2.27(m,3H),2.41(s,3H) ,2.40(s,3H),2.17-2.08(m,2H),1.60(dd,J=12.1,8.1Hz,1H),1.38-1.22(m,2H). LC / MS (ESI) m / z: 494.1 [M+H] + .

[0828] Example 72: 6-(4-(4-(2-hydroxypyridin-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0829] Steps 1 and 2: 6-(4-(4-(2-hydroxypyridin-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxamido)spiro [3.3] Synthesis of heptane-2-carboxylic acid methyl ester

[0830]

[0831] Except that the (3-fluoro-5-methoxyphenyl)boronic acid used in step 1 of Example 71 was replaced with (2-methoxypyridin-4-yl)boronic acid and Cs2CO3 was replaced with K3PO4, methyl 6-(4-(4-(2-hydroxypyridin-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid was obtained using the same method as in Example 71.

[0832] Step 3: 6-(4-(4-(2-hydroxypyridin-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxamido)spiro [3.3] Synthesis of heptane-2-carboxylic acid

[0833]

[0834] 6-(4-(4-(2-hydroxypyridin-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxyl amine The methyl heptane-2-carboxylic acid ester (H2O 0.1M) solution was stirred for 15 hours. The precipitated solid was filtered and dried to obtain a crude product, which was then purified by column chromatography (15% MeOH in DCM solution) to obtain the compound of Example 72, which was a grayish-white solid. 1HNMR(300MHz,MeOD)δ8.25(d,J=7.4Hz,1H),7.61-7.54(m,2H),7.51(d,J=7.6Hz,1H),7.22(d,J=8.2Hz,2H),6.78-6.69(m,2H),4.21-4.08(m ,1H),3.99(s,2H),2.96(p,J=8.4Hz,1H),2.38(s,6H),2.32-1.98(m,6H),1.76(ddd,J=17.0,11.4,8.6Hz,2H); LC / MS(ESI)m / z:477.16[M+H] + .

[0835] Example 73: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-N,2,5-trimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0836] Step 1: Synthesis of 3-([1,1'-biphenyl]-4-ylmethyl)-4-bromo-2,5-dimethylthiophene

[0837]

[0838] To a DCE (0.5 M) solution of [1,1'-biphenyl]-4-ylmethanol (553 mg, 3.0 mmol), 3-bromo-2,5-dimethylthiophene (918 mg, 4.80 mmol), FeCl3 (195 mg, 1.20 mmol), and MsOH (78 μL, 1.20 mmol) were added, and the mixture was stirred at 55 °C for 10 hours. Ethyl acetate was added to the reaction mixture, and the solution was washed with distilled water and brine. The organic layer was then dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane) to give 3-([1,1'-biphenyl]-4-ylmethyl)-4-bromo-2,5-dimethylthiophene (466 mg, 43% yield) as a white solid. 1 H NMR(500MHz,chloroform-d)δ7.61-7.57(m,2H),7.52(m,2H),7.44(t,J=7.7Hz,2H ),7.39-7.31(m,1H),7.24(d,J=7.9Hz,2H),4.00(s,2H),2.41(s,3H),2.40(s,3H).

[0839] Step 2: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxylic acid

[0840]

[0841] At -78 °C, n-BuLi (0.228 mL, 0.57 mmol) was added to a THF (0.1 M) solution of 3-([1,1'-biphenyl]-4-ylmethyl)-4-bromo-2,5-dimethylthiophene (169 mg, 0.47 mmol) and TMEDA (78 μL, 0.52 mmol), and the mixture was stirred for 1.5 h. The reaction mixture was quenched with CO2 gas at -78 °C, and then slowly heated to room temperature over 2 h. The reaction mixture was acidified with 1 N HCl solution, extracted with ethyl acetate, and washed with water. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane) to give 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxylic acid (56 mg, yield 37%) as a white solid.

[0842] Step 3: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-N,2,5-trimethylthiophene-3-carboxamido)spiro[3.3] Synthesis of heptane-2-carboxylic acid methyl ester

[0843]

[0844] DIPEA (84 μL, 0.48 mmol) was added to a DMF (0.05 M) 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), and the mixture was stirred for 10 minutes. Intermediate R (39 mg, 0.18 mmol) was then added, and the mixture was 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 sodium sulfate, 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-carboxamido)spiro[3.3]heptane-2-carboxylic acid (47 mg, 59% yield) as a white solid.

[0845] Step 4: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-N,2,5-trimethylthiophene-3-carboxamido)spiro[3.3] Synthesis of heptane-2-carboxylic acid

[0846]

[0847] LiOH·H₂O (12 mg, 0.3 mmol) was added to a stirred solution of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-N,2,5-trimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (47 mg, 0.1 mmol) in H₂O:THF:MeOH (0.1 M) and stirred for 4 hours. The reaction mixture was partially concentrated under reduced pressure, acidified with 2N HCl aqueous solution (pH approximately 6), and extracted with ethyl acetate (2 × 30 mL). The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and then purified by column chromatography (70% EtOAc in hexane solution) to give the compound of Example 73 (36 mg, 79% yield) as a white solid. LC / MS (ESI) m / z: 474.25 [M+H] + .

[0848] Example 74: 6-(4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0849] Step 1: Synthesis of methyl 4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxylic acid ester

[0850]

[0851] A solution of intermediate D (996 mg, 4.0 mmol), 4-phenylphenol (817 mg, 4.8 mmol, 1.2 equivalents), CuBr (115 mg, 0.8 mmol, 0.2 equivalents), and Cs₂CO₃ (3.9 g, 12.0 mmol, 3.0 equivalents) in pyridine (8 mL) was microwave-irradiated and stirred at 150 °C for 1 hour. The reaction solution was filtered through diatomaceous earth, added to distilled water, extracted with EtOAc, and the organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography to give methyl 4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxylic acid (550 mg, yield 40%).

[0852] Step 2: Synthesis of 4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxylic acid

[0853]

[0854] LiOH·H2O (340 mg, 8.12 mmol, 5.0 equivalence) was added to a THF / MeOH / H2O (1:1:1) solution of methyl 4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxylic acid (550 mg, 1.62 mmol). The reaction mixture was stirred at 70 °C for 12 hours. The reaction mixture was partially concentrated, acidified with 1N HCl, and the aqueous layer was extracted with DCM. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxylic acid (100 mg, yield 19%).

[0855] Step 3: 6-(4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane Synthesis of methyl alkyl-2-carboxylic acid

[0856]

[0857] At 0 °C, DIPEA (80 μL, 0.45 mmol, 1.5 equivalents) was added to a DCM (2 mL) solution of 4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxylic acid (100 mg, 0.3 mmol) and HATU (137 mg, 0.36 mmol, 1.2 equivalents), and the mixture was stirred for 15 minutes. A DCM (1 mL) solution of intermediate A (68 mg, 0.33 mmol, 1.1 equivalents) was added to the reaction mixture, and the mixture was stirred for 8 hours. The reaction mixture was then extracted with DCM in distilled water. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The crude product was purified by column chromatography to obtain methyl 6-(4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (50 mg, yield 34%).

[0858] Step 4: 6-(4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane Synthesis of alkyl-2-carboxylic acids

[0859]

[0860] LiOH·H2O (13 mg, 0.3 mmol, 3.0 equivalence) was added to a THF / MeOH / H2O (1:1:1) solution of methyl 6-(4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (methyl ester) (50 mg, 0.5 mmol) and stirred for 12 hours. The reaction mixture was partially concentrated, acidified with 1N HCl, and extracted with EtOAc. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The crude product was purified by column chromatography to give the compound of Example 74 (22 mg, 47% yield). 1H NMR(300MHz, methanol-d4)δ7.60-7.49(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] + .

[0861] Example 75: 6-(4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0862] Step 1: Synthesis of methyl 4-amino-2,5-dimethylthiophene-3-carboxylate

[0863]

[0864] Ammonia solution (5 mL) was added to a 10 mL NMP solution of intermediate D (1.25 g, 5.0 mmol, 1.0 equivalent) and Cu₂O (715 mg, 5.0 mmol, 1.0 equivalent), and the mixture was heated to 100 °C and stirred for 12 hours. The reaction mixture was then added to distilled water and extracted with DCM. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The crude product was purified by column chromatography to give methyl 4-amino-2,5-dimethylthiophene-3-carboxylic acid (182 mg, yield 19%).

[0865] Step 2: Synthesis of methyl 4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxylate

[0866]

[0867] A solution of methyl 4-amino-2,5-dimethylthiophene-3-carboxylate (182 mg, 0.98 mmol), 4-bromobiphenyl (274 mg, 1.18 mmol, 1.2 equivalents), Pd(OAc)₂ (22 mg, 0.098 mmol, 0.1 equivalents), Xantphos (114 mg, 0.196 mmol, 0.2 equivalents), and Cs₂CO₃ (639 mg, 1.96 mol, 2.0 equivalents) in toluene (7 mL) was stirred for 5 hours at 110 °C. The reaction mixture was added to distilled water and extracted with DCM. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The crude product was purified by column chromatography to give methyl 4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxylate (147 mg, 44% yield).

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

[0869]

[0870] LiOH·H2O (53 mg, 1.26 mmol, 3.0 equivalence) was added to a THF / MeOH / H2O (1:1:1) solution of methyl 4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxylic acid (142 mg, 0.42 mmol), and the mixture was stirred at 70 °C for 12 hours. The reaction mixture was partially concentrated and then acidified with 1N HCl. The precipitated solid was removed by filtration, washed with distilled water, and dried to give 4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxylic acid (135 mg, 99% yield).

[0871] Step 4: 6-(4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane Synthesis of methyl alkyl-2-carboxylic acid

[0872]

[0873] At 0 °C, DIPEA (110 μL, 0.62 mmol, 1.5 equivalence) was added to a DCM (2 mL) solution of 4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxylic acid (135 mg, 0.41 mmol) and HATU (186 mg, 0.49 mmol, 1.2 equivalence) and stirred for 15 minutes. A DCM (1 mL) solution of intermediate A (93 mg, 0.45 mmol, 1.1 equivalence) was added to the reaction solution and stirred for 12 hours. The reaction solution was added to distilled water and extracted with DCM. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The crude product was purified by column chromatography to give methyl 6-(4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (126 mg, yield 65%).

[0874] Step 5: 6-(4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane Synthesis of alkyl-2-carboxylic acids

[0875]

[0876] LiOH·H2O (13 mg, 0.3 mmol, 3.0 equivalence) was added to a THF / MeOH / H2O (1:1:1) solution of methyl 6-(4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (methyl ester) (50 mg, 0.1 mmol) and stirred for 12 hours. The reaction mixture was partially concentrated, acidified with 1N HCl, and extracted with EtOAc. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The crude product was purified by rapid column chromatography to give the compound of Example 75 (20 mg, 43% yield). 1 H NMR (300MHz, Methanol-d4) δ7.56-7.47(m,2H),7.47-7.30(m,4H),7.28-7.16(m,1H),6.67(d,J=8.6Hz,2H),4.16-3.99(m,1H),2.92- 2.80(m,1H),2.57(s,3H),2.35-2.27(m,1H),2.23(s,3H),2.22-2.11(m,3H),2.08-2.02(m,1H),1.98-1.90(m,1H),1.63-1.54(m,2H). LC / MS(ESI)m / z:461.6[M+1] + .

[0877] Example 76: 6-(4-([1,1'-biphenyl]-4-yl(methyl)amino)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0878] Step 1: 6-(4-([1,1'-biphenyl]-4-yl(methyl)amino)-2,5-dimethylthiophene-3-carboxamido)spiro [3.3] Synthesis of heptane-2-carboxylic acid methyl ester

[0879]

[0880] To a DMF (3 mL) solution of methyl 6-(4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (120 mg, 0.25 mmol, 1.0 equivalent) and K2CO3 (104 mg, 0.75 mmol, 3.0 equivalent), iodomethane (80 μL, 1.25 mmol, 5.0 equivalent) was added, and the mixture was stirred at 80 °C for 5 days. The reaction solution was added to distilled water and extracted with DCM. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The crude product was purified by rapid column chromatography to obtain methyl 6-(4-([1,1'-biphenyl]-4-yl(methyl)amino)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (18 mg). 1HNMR(300MHz,Chloroform-d)δ7.58-7.46(m,4H),7.40(dd,J=8.4,6.8Hz,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).

[0881] Step 2: 6-(4-([1,1'-biphenyl]-4-yl(methyl)amino)-2,5-dimethylthiophene-3-carboxamido)spiro [3.3] Synthesis of heptane-2-carboxylic acid

[0882]

[0883] LiOH·H2O (5 mg, 0.108 mmol, 3.0 equivalent) was added to a THF / MeOH / H2O (3 / 2 / 3 mL) solution of methyl 6-(4-([1,1'-biphenyl]-4-yl(methyl)amino)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (18 mg, 0.036 mmol) and stirred for 3 hours. The reaction solution was partially concentrated and then acidified with 1N HCl. The precipitated solid was filtered, washed with water, and dried to give the compound of Example 76 (12 mg). 1 H NMR(500MHz, Methanol-d4)δ7.76(d,J=7.2Hz,1H),7.56-7.51(m,2H),7.47(d,J=8.8Hz,2H),7.36 (t,J=7.8Hz,2H),7.22(t,J=7.4Hz,1H),6.69(d,J=8.7Hz,2H),4.06-4.01(m,1H),3.23(s,3H),2. 88-2.81(m,1H),2.48(s,3H),2.30(dt,J=12.1,6.1Hz,1H),2.21-2.18(m,2H),2.18(s,3H),2.17- 2.12(m,1H),2.06-2.02(m,1H),1.96-1.90(m,1H),1.60-1.54(m,2H). LC / MS(ESI)m / z:475.7[M+H] + .

[0884] Example 77: 6-(2,5-dimethyl-4-((4-phenylpiperazin-1-yl)methyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0885] Step 1: Synthesis of 4-bromo-2,5-dimethylthiophene-3-carboxylic acid

[0886]

[0887] LiOH·H2O (1.1 g, 27.1 mmol) was added to a solution of intermediate D (2.25 g, 9.03 mmol) in H2O / THF / MeOH (0.3 M, 30 mL), and the mixture was stirred for 12 hours. The reaction mixture was acidified by adding 1 N HCl solution and extracted with EA (3 × 30 mL). The organic layer was dried over magnesium sulfate, filtered, concentrated, and then purified by silica gel column chromatography (n-hexane and ethyl acetate) to give 4-bromo-2,5-dimethylthiophene-3-carboxylic acid (1.97 g, 93% yield). 1 H NMR (500MHz, DMSO-d6) δ13.06(s,1H),2.55(s,3H),2.32(s,3H).

[0888] Step 2: Synthesis of (4-bromo-2,5-dimethylthiophen-3-yl)(4-phenylpiperazin-1-yl)methyl ketone

[0889]

[0890] DIPEA (4.3 mL, 25.2 mmol) was added to a DMF (28 mL, 0.3 M) solution of 4-bromo-2,5-dimethylthiophene-3-carboxylic acid (1.97 g, 8.4 mmol), 1-phenylpiperazine (1.4 mL, 9.24 mmol), and HATU (3.5 g, 9.24 mmol), and the mixture was stirred for 3 hours. The reaction solution was concentrated and diluted with 1 N NaOH aqueous solution and ethyl acetate. The aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, concentrated, and then purified by silica gel column chromatography (n-hexane and ethyl acetate) to give (4-bromo-2,5-dimethylthiophene-3-yl)(4-phenylpiperazine-1-yl) methyl ketone (2.92 g, 92% yield). 1H NMR(500MHz,Chloroform-d)δ7.34-7.29(m,2H),6.95(dd,J=13.9,7.6Hz,3H) ,4.07(dt,J=13.0,5.0Hz,1H),3.92(dt,J=13.0,5.3Hz,1H),3.54(ddd,J=13.0 ,6.6,3.3Hz,1H),3.45(ddd,J=13.0,7.2,3.3Hz,1H),3.29(t,J=5.2Hz,2H),3. 24(ddd,J=10.7,7.2,3.4Hz,1H),3.15-3.09(m,1H),2.41(s,3H),2.37(s,3H).

[0891] Step 3: Synthesis of 1-((4-bromo-2,5-dimethylthiophen-3-yl)methyl)-5-phenylpiperazine

[0892]

[0893] BH3·Me2S (19.5 mL, 39 mmol) was added to a stirred solution of (4-bromo-2,5-dimethylthiophen-3-yl)(4-phenylpiperazin-1-yl) methyl ketone (2.87 g, 7.6 mmol) and THF (19 mL, 0.4 M), and the mixture was stirred at 40 °C for 12 hours. The reaction mixture was cooled to room temperature and extracted with NaHCO3 aqueous solution (70 mL) and EA. The organic layer was dried over sodium sulfate and filtered. The crude product was purified by silica gel column chromatography (ethyl acetate / hexane) to give 1-((4-bromo-2,5-dimethylthiophen-3-yl)methyl)-5-phenylpiperazine (1.4 g, yield 51%). 1 H NMR(500MHz,Chloroform-d)δ7.30-7.26(m,2H),6.94(d,J=7.8Hz,2H),6.87(t,J=7.3 Hz,1H),3.49(s,2H),3.21-3.16(m,4H),2.67-2.63(m,4H),2.46(s,3H),2.38(s,3H).

[0894] Step 4: Synthesis of 2,5-dimethyl-4-((4-phenylpiperazin-1-yl)methyl)thiophene-3-carboxylic acid

[0895]

[0896] At -65°C, n-BuLi (0.72 mL, 1.8 mmol in 2.5 M THF solution) was slowly added to a stirred solution of 1-((4-bromo-2,5-dimethylthiophen-3-yl)methyl)-5-phenylpiperazine (500 mg, 1.37 mmol), butanediamine (0.23 mL, 1.51 mmol), and THF (7.0 mL, 0.2 M). The mixture was stirred for 1 hour, followed by the addition of excess dry ice. The reaction solution was acidified with 1 N HCl and extracted with EtOAc. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 2,5-dimethyl-4-((4-phenylpiperazine-1-yl)methyl)thiophen-3-carboxylic acid (502 mg).

[0897] Step 5: 6-(2,5-dimethyl-4-((4-phenylpiperazin-1-yl)methyl)thiophene-3-carboxamido)spiro[3.3] Synthesis of heptane-2-carboxylic acid methyl ester

[0898]

[0899] DIPEA (0.80 mL) was added to a DMF (5.1 mL, 0.3 M) solution of 2,5-dimethyl-4-((4-phenylpiperazin-1-yl)methyl)thiophene-3-carboxylic acid (576 mg, 1.52 mmol), intermediate A (0.34 g, 1.67 mmol), and HATU (0.63 g, 1.67 mmol), and the mixture was stirred for 3 hours. The reaction solution was concentrated, diluted with 1 N NaOH aqueous solution and ethyl acetate, and the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, concentrated, and then purified by silica gel chromatography (n-hexane and ethyl acetate) to give methyl 6-(2,5-dimethyl-4-((4-phenylpiperazin-1-yl)methyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (102 mg, yield 14%). 1 H NMR(500MHz,Chloroform-d)δ9.73(d,J=7.0Hz,1H),7.32(t,J=7.9Hz,2H),6.94(dd,J=1 7.1,7.9Hz,3H),4.45(h,J=8.2,7.7Hz,1H),3.68(s,3H),3.44(s,2H),3.23(s,4H),3.05 (p,J=8.5Hz,1H),2.72(s,4H),2.62(s,4H),2.47(dt,J=12.5,6.5Hz,1H),2.38(d,J=7.0 Hz, 5H), 2.31 (dd, J=11.6, 8.5Hz, 1H), 2.16-2.10 (m, 1H), 1.91 (dt, J=23.8, 10.4Hz, 2H).

[0900] Step 6: 6-(2,5-dimethyl-4-((4-phenylpiperazin-1-yl)methyl)thiophene-3-carboxamido)spiro[3.3] Synthesis of heptane-2-carboxylic acid

[0901]

[0902] LiOH·H2O (43 mg, 1.02 mmol) was added to a solution of methyl 6-(2,5-dimethyl-4-((4-phenylpiperazin-1-yl)methyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (163 mg, 0.34 mmol) in H2O / THF / MeOH (0.3 M, 1.1 mL), and the mixture was stirred for 12 hours. The reaction mixture was acidified by adding 1 N HCl solution and extracted with EA (3 × 20 mL). The organic layer was dried over magnesium sulfate, filtered, concentrated, and then purified by silica gel column chromatography (n-hexane and ethyl acetate) to give the compound of Example 77 (12 mg, 8% yield). 1 H NMR(500MHz, Methanol-d4)δ7.27(t,J=7.8Hz,2H),7.00(d,J=8.3Hz,2H),6.88(t, J=7.3Hz,1H),4.37(p,J=8.2Hz,1H),3.64(s,2H),3.24(s,4H),3.01(p,J=8.4Hz,1 H),2.83(s,4H),2.59(dt,J=11.7,6.6Hz,1H),2.53(s,3H),2.41(s,4H),2.39-2.3 1(m,2H),2.28-2.23(m,1H),2.16(t,J=10.1Hz,1H),2.04(dt,J=28.7,9.7Hz,2H). LC / MS (ESI) m / z: 468.3 [M+H] + .

[0903] Example 78: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-N,2,5-trimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0904] Step 1: 6-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,5-dimethylthiophene-3-carboxamide Synthesis of methyl 2-heptan-2-carboxylic acid ester (3.3)

[0905]

[0906] DIPEA (0.5 mL, 3.0 mmol) was added to a DMF (0.1 M) solution of intermediate S (300 mg, 1.0 mmol) and HATU (456 mg, 1.20 mmol), and the mixture was stirred for 10 minutes. Then, intermediate A (169 mg, 1.0 mmol) was added, and the mixture was stirred for 15 hours. The reaction mixture was diluted with ethyl acetate and washed with distilled water (3 × 25 mL) and brine. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (40% EtOAc in hexane) to give methyl 6-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (260 mg, yield 83%) as a yellow liquid. 1 H NMR(300MHz,chloroform-d)δ7.85(d,J=7.6Hz,1H),4.58(s,2H),4.55-4.32(m,1H),3.69(s,3H),3.06(p,J=8.6Hz,1H),2.68-2 .59(m,1H),2.58(s,3H),2.52-2.41(m,1H),2.41-2.25(m,6H),2.20-2.09(m,1H),2.04-1.85(m,2H),0.94(s,9H),0.16(s,6H).

[0907] Step 2: Methyl 6-(4-(hydroxymethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Synthesis

[0908]

[0909] To a THF (0.1 M) solution of methyl 6-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (226 mg, 0.50 mmol), tetrabutylammonium fluoride (TBAF) (1.0 M THF solution, 0.75 mL, 0.75 mmol) was added, and the mixture was stirred for 15 hours. The reaction solution was diluted with ethyl acetate and washed with distilled water (3 × 25 mL) and brine. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (30% EtOAc in hexane solution) to give methyl 6-(4-(hydroxymethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (171 mg), a yellow liquid. 1H NMR(300MHz,chloroform-d)δ6.49(d,J=7.9Hz,1H),4.53-4.37(m,3H),3.69(s,3H),3.05(q,J=8.5Hz,1H),2.71-2 .58(m,1H),2.54(s,3H),2.53-2.44(m,1H),2.40(s,3H),2.38-2.27(m,3H),2.24-2.14(m,1H),2.07-1.86(m,2H).

[0910] Step 3: Methyl 6-(4-(bromomethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid Synthesis

[0911]

[0912] At 0 °C, PBr3 (92 μL, 2.03 mmol) was added to a stirred solution of methyl 6-(4-(hydroxymethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (82 mg, 0.24 mmol) in DCM (0.1 M), and the mixture was stirred for 15 hours. The reaction solution was diluted with ethyl acetate and washed with bicarbonate solution and distilled water. The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (25% EtOAc in hexane solution) to give methyl 6-(4-(bromomethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (49 mg, 50% yield) as a white solid. 1 H NMR(300MHz,chloroform-d)δ6.18(d,J=7.0Hz,1H),4.53(s,2H),4.53-4.39(m,1H),3.69(s,3H),3.05(q,J=8.5Hz,1H),2.74-2.5 9(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).

[0913] Step 4: 6-(2,5-dimethyl-4-((4-phenyl-1H-pyrazol-1-yl)methyl)thiophene-3-carboxamido)spiro [3.3] Synthesis of heptane-2-carboxylic acid methyl ester

[0914]

[0915] NaH (5 mg, 0.12 mmol) was added to a DMF (0.1 M) solution of 4-phenyl-1H-pyrazole (12 mg, 0.08 mmol) and stirred for 15 minutes. Methyl 6-(4-(bromomethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (32 mg, 0.08 mmol) was added and stirred for 4 hours. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with distilled water (2 × 10 mL). The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography (40% EtOAc in hexane) to give methyl 6-(2,5-dimethyl-4-((4-phenyl-1H-pyrazole-1-yl)methyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (16 mg, 43% yield) as a white solid.

[0916] Step 5: 6-(2,5-dimethyl-4-((4-phenyl-1H-pyrazol-1-yl)methyl)thiophene-3-carboxamido)spiro [3.3] Synthesis of heptane-2-carboxylic acid

[0917]

[0918] LiOH·H2O (3 mg, 0.1 mmol) was added to a solution of methyl 6-(2,5-dimethyl-4-((4-phenyl-1H-pyrazol-1-yl)methyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (16 mg, 0.03 mmol) in H2O:THF:MeOH (1:1:1, 0.1 M) and stirred for 15 hours. The reaction mixture was partially concentrated, acidified with 1N HCl solution (pH approximately 4), and extracted with ethyl acetate (2 × 10 mL). The organic layer was dried over sodium sulfate, filtered, concentrated under reduced pressure, and then purified by column chromatography (5% MeOH in DCM solution) to give the compound of Example 78 (5 mg, yield 32%) as a white solid. 1 H NMR(400MHz,MeOD)δ7.85(s,1H),7.81(s,1H),7.57-7.50(m,2H),7.36(t,J =7.7Hz,2H),7.26-7.17(m,1H),5.28(s,2H),4.20(p,J=8.1Hz,1H),2.91(p, J=8.5Hz,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=11.4,8.7,2.7Hz,1H),1.93-1.80(m,2H). LC / MS (ESI) m / z: 450.09 [M+H] + .

[0919] Example 79: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrolo-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0920] Step 1: Methyl 4-([1,1'-biphenyl]-4-ylmethyl)-3-bromo-4H-thiopheno[3,2-b]pyrrole-5-carboxylic acid ester synthesis

[0921]

[0922] To a DMF (10 mL) solution of intermediate T (780 mg, 3.0 mmol, 1.0 equivalent) and Cs₂CO₃ (2.44 g, 7.5 mmol, 2.5 equivalent), 4-bromomethylbiphenyl (890 mg, 3.6 mmol, 1.2 equivalent) was added, and the mixture was stirred for 12 hours. The reaction mixture was poured into distilled water and extracted with DCM. The organic layer was then dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by rapid column chromatography to give methyl 4-([1,1'-biphenyl]-4-ylmethyl)-3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (940 mg, 73% yield). 1 HNMR(300MHz,chloroform-d)δ7.57-7.48(m,4H),7.44-7.37(m,2H),7.36-7.29( m,1H),7.26(s,1H),7.25(s,1H),7.11(d,J=8.1Hz,2H),6.14(s,2H),3.82(s,3H).

[0923] Step 2: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid

[0924]

[0925] LiOH·H₂O (277 mg, 6.6 mmol, 3.0 equivalent) was added to a THF / MeOH / H₂O (20 / 10 / 10 mL) solution of methyl 4-([1,1'-biphenyl]-4-ylmethyl)-3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (940 mg, 2.2 mmol) and stirred at 70 °C for 12 h. The reaction mixture was partially concentrated and then acidified with 1 N HCl solution. The precipitated solid was filtered, washed with distilled water, and dried to give 4-([1,1'-biphenyl]-4-ylmethyl)-3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (815 mg, 90% yield). 1H NMR (300MHz, chloroform-d) δ7.58-7.36(m,3H),7.43-7.36(m,2H),7.32(d,J=6.8Hz,2H),7.11(d,J=8.1Hz,2H),6.12(s,2H).

[0926] Step 3: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-3-bromo-2-methyl-4H-thiopheno[3,2-b]pyrrole

[0927]

[0928] A solution of 4-([1,1'-biphenyl]-4-ylmethyl)-3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (815 mg, 1.97 mmol) and copper powder (82 mg, 10 wt%) in quinoline (10 mL) was stirred at 140 °C for 12 hours. The reaction mixture was cooled, acidified with 6N HCl solution, and then extracted with Et2O. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by rapid column chromatography to give 4-([1,1'-biphenyl]-4-ylmethyl)-3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole (170 mg, yield 23%).

[0929] Step 4: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid

[0930]

[0931] At -78°C, n-BuLi (0.3 mL of 2.0 M cyclohexane solution, 1.2 equivalences) was added to a THF (5 mL) solution of 4-([1,1'-biphenyl]-4-ylmethyl)-3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole (170 mg, 0.46 mmol, 1.0 equivalences) and stirred for 10 minutes. Dry ice was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The mixture was then acidified with 1 N HCl solution and extracted with EtOAc. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by rapid column chromatography to obtain 4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid (100 mg, mixture).

[0932] Step 5: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxamido)spiro [3.3] Synthesis of heptane-2-carboxylic acid methyl ester

[0933]

[0934] At 0 °C, DIPEA (80 μL, 0.45 mmol, 1.5 equivalence) was added to a DCM (2 mL) solution of 4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid (100 mg, 0.3 mmol) and HATU (137 mg, 0.36 mmol, 1.2 equivalence), and the mixture was stirred for 15 minutes. Intermediate A (68 mg, 0.33 mmol, 1.1 equivalence) was added to the reaction mixture, and the mixture was stirred for 12 hours. The reaction mixture was poured into distilled water and extracted with DCM. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The crude product was purified by rapid column chromatography to obtain methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrolo-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (40 mg, yield 30%). 1 H NMR(300MHz,chloroform-d)δ7.56-7.50(m,2H),7.50-7.39(m,4H),7.36-7.29(m,1H),7.1 1(d,J=8.3Hz,2H),7.00(dd,J=2.9,1.3Hz,1H),6.44(d,J=2.9Hz,1H),5.99(d,J=7.8Hz,1H ),5.60(s,2H),4.36-4.28(m,1H),3.66(s,3H),3.05-2.94(m,1H),2.54-2.46(m,1H),2.42 -2.36(m,1H),2.33-2.30(m,2H),2.27-2.20(m,1H),2.09-2.01(m,1H),1.80-1.71(m,2H).

[0935] Step 6: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-4H-thienro[3,2-b]pyrrole-3-carboxamido)spiro [3.3] Synthesis of heptane-2-carboxylic acid

[0936]

[0937] LiOH·H2O (10 mg, 0.24 mmol, 3.0 equivalent) was added to a THF / MeOH / H2O (1:1:1, 9 mL) solution of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrolo-3-carboxamido)spiro[3,3]heptane-2-carboxylate (40 mg, 0.08 mmol) and stirred for 12 hours. The reaction mixture was partially concentrated and then acidified with 1N HCl solution. The precipitated solid was filtered, washed with distilled water, dried, and then purified by rapid column chromatography to give the compound of Example 79 (15 mg, 40% yield). 1H NMR(300MHz, methanol-d4)δ8.34(d,J=7.3Hz,1H),7.58-7.52(m,2H),7.50-7.44( m,2H),7.44-7.35(m,3H),7.33-7.26(m,1H),7.15(dd,J=3.0,1.3Hz,1H),7.02(d, J=8.3Hz,2H),6.43(d,J=3.0Hz,1H),5.56(s,2H),4.25-4.11(m,1H),3.02-2.90(m ,1H),2.46-2.38(m,1H),2.35-2.23(m,3H),2.22-2.01(m,2H),1.91-1.81(m,2H). LC / MS(ESI)m / z:471.4[M+H] + .

[0938] Except for the different preparation methods described below, the compounds of Examples 80 to 89 were prepared using the same method as in Example 79.

[0939] [Table 13]

[0940]

[0941]

[0942]

[0943]

[0944] [Table 14]

[0945]

[0946]

[0947]

[0948]

[0949] Example 90: 6-(4-(4-(trifluoromethyl)benzyl)-4H-thieno[3,2-b]pyrrolo-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0950] Steps 1 to 3: Synthesis of 3-bromo-4-(4-(trifluoromethyl)benzyl)-4H-thieno[3,2-b]pyrrole

[0951]

[0952] Except that 4-bromomethylbiphenyl in step 1 of Example 79 is replaced with 1-bromomethyl-4-(trifluoromethyl)benzene, 3-bromo-4-(4-(trifluoromethyl)benzene)-4H-thieno[3,2-b]pyrrole is obtained by the same method as steps 1 to 3 of Example 79, which is a yellow liquid. 1 H NMR (300MHz, chloroform-d) δ7.60-7.55(m,2H),7.23-7.17(m,2H),7.03-6.98(m,1H),6.88-6.85(m,1H),6.44(d,J=3.0Hz,1H),5.57(d,J=9.4Hz,2H).

[0953] Step 4: Synthesis of 4-(4-(trifluoromethyl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid

[0954]

[0955] Pd(OAc)₂ (3 mol%) and Xantphos (3 mol%) were placed in a vacuum-dried tube and purged three times with argon. Then, a DMF solution (3.0 mL) of formic acid (0.24 mL, 6.258 mmol) and 3-bromo-4-(4-(trifluoromethyl)benzyl)-4H-thieno[3,2-b]pyrrole (322 mg, 0.894 mmol) was added. DCC (37 mg, 0.179 mmol) and Et₃N (0.25 mL, 1.788 mmol) were added, and the tube was sealed. The mixture was stirred at 100 °C for 20 hours. The reaction solution was filtered, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to give 4-(4-(trifluoromethyl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid (124 mg, yield 43%) as a white solid. 1 H NMR(300MHz,chloroform-d)δ8.09(d,J=1.3Hz,1H),7.51(d,J=8.1Hz,2H),7.11( d, J=8.1Hz, 2H), 6.95 (dd, J=3.1, 1.3Hz, 1H), 6.51 (d, J=3.1Hz, 1H), 5.81 (s, 2H).

[0956] Steps 5 and 6: 6-(4-(4-(trifluoromethyl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxamido)spiro [3.3] Synthesis of heptane-2-carboxylic acid

[0957]

[0958] The compound of Example 90 was reacted using the same method as steps 5 and 6 of Example 79 to give the compound of Example 90. 1H NMR(300MHz,DMSO-d6)δ12.0(br s,1H)8.42(d,J=7.5Hz,1H),7.61(d,J=8.0Hz,2H),7.58(d,J=1.3Hz,1H),7.30(dd,J=3.0,1.3Hz,1H),7.16(d,J=8.0H z, 2H), 6.47 (d, J = 3.0Hz, 1H), 5.68 (s, 2H), 4.18-4.04 (m, 1H), 2.96-2.85 (m, 1H), 2.39-2.00 (m, 6H), 1.92-1.85 (m, 2H). LC / MS(ESI)m / z:463.4[M+H] + .

[0959] Except for the different preparation methods described below, the compounds of Examples 91 to 94 were prepared using the same method as in Example 90.

[0960] [Table 15]

[0961]

[0962]

[0963] [Table 16]

[0964]

[0965]

[0966] 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

[0967] Steps 1 to 3: 3-bromo-4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2-methyl-4H-thia Synthesis of phen[3,2-b]pyrrole

[0968]

[0969] Using intermediates U and Y as starting materials, and employing the same method as steps 1 to 3 of Example 79, 3-bromo-4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)2-methyl-4H-thieno[3,2-b]pyrrole was obtained. 1H NMR (400MHz, CDCl3) δ7.50(d,J=8.3Hz,2H),7.18(d,J=8.1Hz,2H),6.92-6.79(m,3H),6. 60(td,J=2.3,10.5Hz,1H),6.37(d,J=2.9Hz,1H),5.57(s,2H),3.84(s,3H),2.44(s,3H). LC / MS(ESI)m / z:430.2[M+1].

[0970] Step 4: 4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2-methyl-4H-thiopheno[3, Synthesis of methyl pyrrole-3-carboxylate [2-b]

[0971]

[0972] Under a nitrogen atmosphere, Pd(dppf)Cl2.CH2Cl2 (156 mg, 191 μmol, 0.2 equivalent) and TEA (289 mg, 2.86 mmol, 398 μL, 3.0 equivalent) were added to a MeOH (4 mL) solution of 3-bromo-4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)2-methyl-4H-thieno[3,2-b]pyrrole (410 mg, 953 μmol, 1.00 equivalent) and MeOH (4 mL). The reaction solution was purged three times under a CO atmosphere, and then stirred for 24 hours under CO (50 Psi) and 70 °C. The reaction solution was cooled, filtered, and concentrated. The crude product was then purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 20 / 1) to obtain methyl 4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2-methyl-4H-thieno[3,2-b]pyrrole-3-carboxylic acid (280 mg, yield 71.7%), which was a yellow oil. 1 H NMR (400MHz, DMSO) δ7.46 (d, J = 8.40Hz, 2H), 7.07 (d, J = 8.40Hz, 2H), 6.93-6.82 (m, 3H), 6.59 (td, J=2.40,10.4Hz,1H),6.40(d,J=3.00Hz,1H),5.64(s,2H),3.84(s,3H),3.76(s,3H),2.69(s,3H).

[0973] Step 5: 4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2-methyl-4H-thiopheno[3, Synthesis of 2-b]pyrrole-3-carboxylic acid

[0974]

[0975] LiOH·H₂O (1M, 3.66 mL, 6.00 equivalent) was added to a solution of methyl 4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2-methyl-4H-thieno[3,2-b]pyrrole-3-carboxylic acid ester (250 mg, 611 μmol, 1.00 equivalent) in MeOH (1 mL) and THF (1 mL), and the mixture was stirred at 55 °C for 24 hours. The reaction mixture was partially concentrated and then acidified with 1N HCl solution (pH = 3). The aqueous layer was extracted with EtOAc (50 mL × 2). The organic layer was washed with brine (50 mL × 1), dried with sodium sulfate, filtered, and concentrated under reduced pressure to give 4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2-methyl-4H-thieno[3,2-b]pyrrole-3-carboxylic acid (220 mg, yield 91.1%), as a yellow solid. 1 H NMR (400MHz, DMSO) δ13.29-12.68(m,1H),7.60(d,J=8.40Hz,2H),7.21(d,J=3.00Hz,1H),7.09-6.98( m, 4H), 6.80 (td, J = 2.20, 11.2Hz, 1H), 6.41 (d, J = 3.00Hz, 1H), 5.66 (s, 2H), 3.81 (s, 3H), 2.61 (s, 3H).

[0976] Steps 6 and 7: 6-(4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2-methyl-4H-thiophene Synthesis of [3,2-b]pyrrole-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0977]

[0978] Using the same method as steps 5 and 6 of Example 79, 4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2-methyl-4H-thieno[3,2-b]pyrrole-3-carboxylic acid was reacted to give the compound of Example 95. 1H NMR (400MHz, DMSO) δ12.26-11.69(m,1H),8.40(d,J=7.60Hz,1H),7.57(d,J=8.20Hz ,2H),7.19(d,J=3.00Hz,1H),7.10(d,J=8.20Hz,2H),7.06-6.96(m,2H),6.86-6.77 (m,1H),6.35(d,J=2.80Hz,1H),5.35(s,2H),4.30-4.14(m,1H),3.82(s,3H),2.98- 2.83(m,1H),2.42(s,3H),2.39-2.16(m,4H),2.10-1.95(m,2H),1.91-1.77(m,2H). LC / MS(ESI)m / z:533.1[M+1].

[0979] Example 96: 6-(2-methyl-4-(3-phenylprop-2-yn-1-yl)-4H-thiopheno[3,2-b]pyrrolo-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[0980] Step 1: Synthesis of 3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid

[0981]

[0982] LiOH·H₂O (1M, 32.8 mL, 3.00 equivalent) was added to a solution of intermediate U (3.00 g, 10.9 mmol, 1.00 equivalent) in THF (15 mL) and MeOH (15 mL), and the mixture was stirred at 55 °C for 2 hours. The reaction mixture was partially concentrated, acidified with 1N HCl solution (pH = 3), and the aqueous layer was extracted with EtOAc (50 mL × 2). The organic layer was filtered and concentrated under reduced pressure to give 3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (2.70 g, 10.38 mmol, yield 94.8%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ7.09 (d, J=8.60Hz, 2H), 6.91-6.82 (m, 2H), 6.77 (d, J= 3.00Hz, 1H), 6.32 (d, J = 3.00Hz, 1H), 5.47 (s, 2H), 3.79 (s, 3H), 2.44 (s, 3H).

[0983] Step 2: Synthesis of 3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole

[0984]

[0985] Copper powder (210 mg, 3.32 mmol) was added to a quinoline (20 mL) solution of 3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (2.00 g, 7.69 mmol, 1.00 equivalent), and the mixture was stirred at 140 °C for 12 h. The reaction solution was washed with 1 N HCl (1 × 150 mL) and brine (1 × 50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (FA conditions) to give 3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole (810 mg, 3.75 mmol, yield 48.7%) as a gray solid. 1 H NMR (400MHz, CDCl3) δ8.17 (br s, 1H), 6.96 (t, J = 2.60Hz, 1H), 6.44 (dd, J = 2.00, 3.00Hz, 1H), 2.47 (s, 3H).

[0986] Step 3: Synthesis of 3-bromo-2-methyl-4-(3-phenylprop-2-yn-1-yl)-4H-thiopheno[3,2-b]pyrrole

[0987]

[0988] Cs₂CO₃ (1.13 g, 3.47 mmol, 2.50 equivalent) was added to a DMF (3 mL) solution of 3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole (300 mg, 1.39 mmol, 1.00 equivalent) and intermediate FF (406 mg, 2.08 mmol, 1.50 equivalent), and the mixture was stirred at 20 °C for 1 hour. The reaction mixture was partially concentrated and extracted with 50 mL of distilled water and EA (2 × 50 mL). The organic layer was washed with brine (3 × 20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by preparative HPLC (FA conditions) to give 3-bromo-2-methyl-4-(3-phenylprop-2-yn-1-yl)-4H-thieno[3,2-b]pyrrole (180 mg, yield 39.2%) as a yellow solid. 1 H NMR (400MHz, CDCl3) δ7.52-7.43(m,2H),7.39-7.28(m,3H),7.04(d,J=2.80Hz,1H),6.40-6.32(m,1H),5.35(s,2H),2.46(s,3H).

[0989] Steps 4 to 7: 6-(2-methyl-4-(3-phenylprop-2-yn-1-yl)-4H-thieno[3,2-b]pyrrole-3-carboxyl Synthesis of (amino)spiro[3.3]heptane-2-carboxylic acid

[0990]

[0991]

[0992] Using the same method as steps 4 to 7 of Example 95, 3-bromo-2-methyl-4-(3-phenylprop-2-yn-1-yl)-4H-thiopheno[3,2-b]pyrrole was reacted to give the compound of Example 96, which was a grayish-white solid. 1 H NMR (400MHz, CDCl3) δ7.42-7.35(m,2H),7.35-7.29(m,3H),6.98(d,J=3.00Hz,1H),6.34(d,J=3.00Hz,1H),5.92(br d,J=7.60Hz,1H),5.16(s,2H),4.54-4.40(m,1H),3.09-2.99(m,1H),2.64-2.59(m,3H),2.59-2.53(m ,1H),2.49-2.34(m,3H),2.31-2.22(m,1H),2.15-2.06(m,1H),1.92(ddd,J=8.60,11.2,16.0Hz,2H). LC / MS(ESI)m / z:433.2[M+1].

[0993] Except for the different preparation methods described below, the compounds of Examples 97 and 98 were prepared using the same method as in Example 96.

[0994] [Table 17]

[0995]

[0996]

[0997] [Table 18]

[0998]

[0999] Example 99: 6-(4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrolo-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid

[1000] Step 1: Synthesis of methyl 3-bromo-4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole-5-carboxylic acid ester become

[1001]

[1002] Intermediate GG (392 mg, 2.1145 mmol) was dissolved in THF and cooled to 0 °C. Then, intermediate T (500 mg, 1.9223 mmol) and tributylphosphine (0.62 mL, 2.499 mmol) were added. Di-tert-butyl azodicarbonate (0.49 mL, 2.499 mmol) was slowly added, and the mixture was stirred at 50 °C for 12 hours. Saturated sodium bicarbonate aqueous solution was added, and the reaction mixture was stirred for 10 minutes, followed by extraction with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, concentrated under reduced pressure, and then the crude product was purified by silica gel column chromatography (petroleum ether:EtOAc = 80:20 to 50:50) to give methyl 3-bromo-4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (639 mg, yield 78%). 1 H NMR(300MHz,Chloroform-d)δ8.90-8.81(m,1H),8.62(dd,J=5.1,1.5Hz,1H),8.17(dt,J=8.1,1.9Hz,1H),7.64(dd ,J=8.1,5.1Hz,1H),7.51(d,J=8.3Hz,2H),7.27(d,J=3.7Hz,1H),7.19(d,J=8.3Hz,2H),6.16(s,2H),3.82(s,3H).

[1003] Step 2: Synthesis of 3-bromo-4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole-5-carboxylic acid

[1004]

[1005] LiOH·H2O (188 mg, 4.4862 mmol) was added to a THF / MeOH / H2O (1 / 1 / 1) solution of methyl 3-bromo-4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (639 mg, 1.4954 mmol), and the mixture was stirred for 12 hours. The reaction solution was partially concentrated, acidified with 1N HCl solution, and washed with distilled water to obtain 3-bromo-4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (609 mg, 98% yield) as a white solid. 1H NMR (300MHz, DMSO-d6) δ12.82(s,1H),8.93(d,J=2.3Hz,1H),8.62(dd,J=5.0,1.5Hz,1H),8.21(dt,J=8.2,1.9Hz, 1H),7.73(s,1H),7.72-7.67(m,2H),7.61(dd,J=8.0,5.0Hz,1H),7.35(s,1H),7.06(d,J=8.2Hz,2H),6.11(s,2H).

[1006] Step 3: Synthesis of 3-bromo-4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole

[1007]

[1008] A solution of 3-bromo-4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (759 mg, 1.8365 mmol) and copper powder (76 mg, 10 wt%) in quinoline (20 mL) was stirred at 140 °C for 12 hours. The reaction mixture was cooled, acidified with 6N HCl solution, and then extracted with Et2O. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by rapid column chromatography to obtain 3-bromo-4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole (crude product).

[1009] Step 4: Synthesis of 4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid

[1010]

[1011] Pd(OAc)₂ (3 mol%) and Xantphos (3 mol%) were added to a dried tube under a nitrogen atmosphere, and then the tube was filled with argon three times. A DMF 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) was added (3.0 mL). DCC (62 mg, 0.3028 mmol) and Et₃N (0.42 mL, 3.0276 mmol) were added, and the tube was sealed. The reaction mixture was stirred at 100 °C for 20 hours. The reaction mixture was filtered, concentrated under reduced pressure, and 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).

[1012] Step 5: 6-(4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrolo-3-carboxamido)spiro [3.3] Synthesis of heptane-2-carboxylic acid methyl ester

[1013]

[1014] DIPEA (0.8 mL, 4.593 mmol) was added to a DMF (4 mL) 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), and the mixture was stirred for 10 minutes. Then, intermediate A (315 mg, 1.531 mmol) was added, and the mixture was stirred for 12 hours. The reaction mixture was diluted with ethyl acetate and washed with distilled water and brine. The organic layer was dried over sodium sulfate, concentrated under reduced pressure, and 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-carboxylic acid (147 mg, yield 16%). 1 H NMR (300MHz, Chloroform-d) δ8.87(d,J=2.1Hz,1H),8.64(d,J=5.5Hz,1H),8.46(d,J=8.1Hz,1H),7.90( dd,J=8.1,5.5Hz,1H),7.48(d,J=8.2Hz,2H),7.36-7.32(m,1H),7.27(s,1H),7.24(s,1H),6.98(dd,J=3. 0,1.3Hz,1H),6.47(d,J=3.0Hz,1H),6.06(d,J=7.7Hz,1H),5.71(d,J=5.9Hz,2H),4.37-4.29(m,1H),3.6 6(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).

[1015] Step 6: 6-(4-(4-(pyridin-3-yl)benzyl)-4H-thienro[3,2-b]pyrrolo-3-carboxamido)spiro [3.3] Synthesis of heptane-2-carboxylic acid

[1016]

[1017] LiOH·H2O (38 mg, 0.9081 mmol) was added to a THF / MeOH / H2O (1 / 1 / 1) solution of methyl 6-(4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrolo-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (147 mg, 0.3027 mmol) and stirred for 12 hours. The reaction mixture was partially concentrated and then acidified with 1N HCl solution. The aqueous layer was extracted with EtOAc. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to give the compound of Example 99 (92 mg, 64% yield). 1H NMR (300MHz, DMSO-d6) δ12.04(s,1H),8.83(s,1H),8.54(d,J=4.6Hz,1H),8.48(d,J=7 .5Hz,1H),8.01(d,J=8.0Hz,1H),7.63-7.59(m,2H),7.58(d,J=1.3Hz,1H),7.46(t,J=6 .3Hz,1H),7.31(dd,J=3.0,1.3Hz,1H),7.16(d,J=8.2Hz,2H),6.45(d,J=3.0Hz,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] + .

[1018] Except for the different preparation methods described below, the compounds of Examples 100 to 113 were prepared using the same method as in Example 99.

[1019] [Table 19]

[1020]

[1021]

[1022]

[1023]

[1024]

[1025]

[1026]

[1027] [Table 20]

[1028]

[1029]

[1030]

[1031]

[1032]

[1033] [Preparation of isomers]

[1034] Examples 1a and 1b: (2S,4S,6S)-6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (1a) and (2R,4R,6R)-6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (1b)

[1035]

[1036] The compound of Example 1 (106 g, 231 mmol, 1.00 equivalent) was purified by supercritical fluid chromatography (SFC) under the following conditions to separate 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%), which were white solids.

[1037] Chromatographic column: DAICEL CHIRALCEL OJ column (250mm×50mm, 10μm)

[1038] Mobile phase: [Neu-MeOH]; B%: 30%-30%, 4.6; 1860 min.

[1039] Example 1a: 1 H NMR(400MHz,DMSO)δ12.00(br s,1H),8.26(br d,J=7.60Hz,1H),7.60(brd,J=7.20Hz,2H),7.51(d,J=8.40Hz,2H),7.45(t,J=7.60Hz,2H),7. 37-7.31(m,1H),7.18(d,J=8.00Hz,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=7.60Hz,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] + .

[1040] Example 1b: 1H NMR(400MHz,DMSO)δ11.99(br s,1H),8.26(d,J=7.60Hz,1H),7.65-7.57(m,2H),7.51(d,J=8.00Hz,2H),7.45(t,J=7.60Hz,2H),7.37-7.31(m,1H),7.19(d,J=8.00Hz,2H) ,4.16(m,1H),3.90(s,2H),2.91(m,1H),2.40-2.35(m,1H),2.33(d,J= 7.20Hz,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] + .

[1041] Examples 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)

[1042] Step 1: (2S,4S,6S)-6-(4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-di Methylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid methyl ester (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 Separation of ester (34b')

[1043]

[1044] The methyl 6-(4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid obtained in step 1 of Example 34 (91.0 g, 174 mmol, 1.00 equivalent) was purified by supercritical fluid chromatography (SFC) under the following conditions to give intermediate 34a' (62.2 g, 119 mmol, yield 68.3%) and intermediate 34b' (24.2 g, 46.4 mmol, yield 26.5%), which were gray solid and off-white solid, respectively.

[1045] Neutral conditions: DAICL CHIRALPAK AD column (250 mm × 50 mm, 10 μm)

[1046] Mobile phase: [Neu-ETOH]; B%: 50%-50%, 6.0; 1200 min

[1047] Intermediate 34a': 1 H NMR(400MHz,CDCl3)δ7.46(d,J=8.3Hz,2H),7.17(d,J=8.3Hz,2H),6.91 - 6.80(m,2H),6.60(td,J=2.2,10.6Hz,1H),5.37(br d,J=7.7Hz,1H),4.27(q,J=8.2Hz,1H),3.98(s,2H),3.85(s,3H),3.65(s,3H),3.02 - 2.90(m,1H),2.44(s,4H),2.38 - 2.24(m,6H),2.17(dd,J=8.3,11.6Hz,1H),1.98(ddd,J=2.5,8.7,11.5Hz,1H),1.54(dt,J=8.6,12.3Hz,2H). LC / MS(ESI)m / z:522.1[M + H] + .

[1048] Intermediate 34b': 1 H NMR(400MHz,CDCl3)δ7.45(d,J=8.2Hz,2H),7.16(d,J=8.0Hz,2H),6.90 - 6.81(m,2H),6.60(td,J=2.2,10.5Hz,1H),5.40(br d,J=7.8Hz,1H),4.34 - 4.20(m,1H),3.97(s,2H),3.85(s,3H),3.64(s,3H),2.96(quin,J=8.5Hz,1H),2.43(s,4H),2.38 - 2.24(m,6H),2.17(dd,J=8.4,11.7Hz,1H),2.05 - 1.92(m,1H),1.54(dt,J=8.6,12.3Hz,2H). LC / MS(ESI)m / z:522.1[M + H] + .

[1049] Step 2a: (2S,4S,6S)-6-(4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5- Preparation of dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (34a)

[1050]

[1051] To a solution of intermediate 34a' (62.2 g, 119 mmol, 1.00 equivalence) in THF / MeOH / H2O (200 mL, 100 mL, 200 mL), LiOH·H2O (15.0 g, 358 mmol, 3.00 equivalence) was added, and the mixture was stirred at 20 °C for 3 hours. The reaction mixture was partially concentrated, diluted with H2O (2.00 L), and acidified with 1 N HCl solution (pH = 3). The aqueous layer was extracted with EtOAc (1.50 L × 2), the organic layer was washed with brine (2 × 1.00 L), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was milled with MTBE (300 mL) at 20 °C for 12 hours, and then milled with MTBE (100 mL) at 25 °C for 30 minutes to give the compound of Example 34a (30.0 g, 59.1 mmol, yield 49.7%) as a white solid. 1 H NMR (400MHz, DMSO) δ12.01(brd,J=2.5Hz,1H),8.27(d,J=7.5Hz,1H),7.54(d,J=8 .2Hz,2H),7.17(d,J=8.2Hz,2H),7.07-6.96(m,2H),6.80(td,J=2.1,11.0Hz,1H), 4.23-4.10(m,1H),3.89(s,2H),3.82(s,3H),2.97-2.84(m,1H),2.40-2.33(m,1H ), 2.31 (d, J = 3.3Hz, 6H), 2.28-2.13 (m, 3H), 2.12-1.97 (m, 2H), 1.92-1.79 (m, 2H). LC / MS(ESI)m / z=508.1[M+H] + .

[1052] Step 2b: (2R,4R,6R)-6-(4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5- Preparation of dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (34b)

[1053]

[1054] Using intermediate 34b' in the same manner as in step 2a, the compound of Example 34b (10.0 g, 19.7 mmol, yield 42.4%) was obtained as a grayish-white solid. 1H NMR(400MHz,DMSO)δ12.00(brs,1H),8.27(d,J=7.5Hz,1H),7.54(d,J=8.2Hz,2H) ,7.17(d,J=8.2Hz,2H),7.06-6.96(m,2H),6.80(td,J=2.2,10.9Hz,1H),4.21-4. 09(m,1H),3.89(s,2H),3.82(s,3H),2.90(quin,J=8.5Hz,1H),2.39-2.33(m,1H) ,2.31(d,J=3.3Hz,6H),2.28-2.13(m,3H),2.11-1.95(m,2H),1.93-1.78(m,2H). LC / MS (ESI) m / z: 508.3 [M+H] + .

[1055] Examples 79a and 79b: (2S,4S,6S)-6-(4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrolo-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (79a) and (2R,4R,6R)-6-(4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrolo-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (79b)

[1056]

[1057] The compound of Example 79 was purified by supercritical fluid chromatography (SFC) under the following conditions.

[1058] Chromatographic column: Daicel ChiralPak IG column (250mm×30mm, 10μm)

[1059] Mobile phase: [0.1% NH3H2O ​​ETOH]; B% / 50%-50%, 4.4 min; 70 min

[1060] The eluent was concentrated, and the residue was added to distilled water (10 mL) and acidified with an aqueous HCl solution (1 M) (pH 1 to 2). The suspension was filtered and concentrated into a white solid filter cake, from which the compounds of Example 79a (171 mg, 356 μmol, yield 55.9%, purity 98.0%) and Example 79b (36 mg, yield 11.7%, purity 98%) were separated.

[1061] Example 79a: 1H NMR(400MHz,DMSO)δ12.71-11.10(m,1H),8.50(br d,J=7.60Hz,1H),7.64-7.56(m,3H),7.54(d,J=8.20Hz,2H),7.44(t,J=7 .60Hz,2H),7.39-7.29(m,2H),7.15(d,J=8.20Hz,2H),6.46(d,J=2.80Hz, 1H),5.62(s,2H),4.23(sxt,J=8.20Hz,1H),2.94(quin,J=8.20Hz,1H),2. 45-2.37(m,1H),2.33-2.19(m,3H),2.16-2.03(m,2H),2.02-1.89(m,2H). LC / MS (ESI) m / z: 470.9 [M+H] + .

[1062] Example 79b: 1 H NMR(400MHz,DMSO)δ12.02(br s,1H),8.49(d,J=7.60Hz,1H),7.63-7.56(m,3H),7.53(d,J=8.20Hz,2H) ,7.43(t,J=7.60Hz,2H),7.36-7.29(m,2H),7.14(d,J=8.20Hz,2H),6.45 (d,J=3.00Hz,1H),5.62(s,2H),4.30-4.13(m,1H),2.99-2.90(m,1H),2. 44-2.36(m,1H),2.32-2.18(m,3H),2.16-2.02(m,2H),2.01-1.86(m,2H). LC / MS (ESI) m / z: 471.0 [M+H] + .

[1063] Examples 80a and 80b: (2S,4S,6S)-6-(4-([1,1'-biphenyl]-4-ylmethyl)-2-methyl-4H-thieno[3,2-b]pyrrolo-3-carboxamido)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]pyrrolo-3-carboxamido)spiro[3.3]heptane-2-carboxylic acid (80b)

[1064]

[1065] 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%), which were white solid and off-white solid, respectively.

[1066] Chromatographic column: DAIICEL CHIRALPAK AD column (250mm × 50mm, 10μm)

[1067] Mobile phase: [Neu-ETOH]; B%: 40%-40%, 14.2; 870 minutes

[1068] Example 80a: 1 H NMR (400MHz, DMSO) δ11.74-12.27(m,1H)8.43(d,J=7.58Hz,1H)7.60(d,J=7.58Hz,2H)7 .54(d,J=8.19Hz,2H)7.45(t,J=7.64Hz,2H)7.32-7.38(m,1H)7.20(d,J=2.81Hz,1H)7. 16(d,J=8.19Hz,2H)6.36(d,J=2.81Hz,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] + .

[1069] Example 80b: 1H NMR(400MHz, DMSO)δ11.44-12.66(m,1H)8.42(d,J=7.58Hz,1H)7.60(d,J=7.46Hz,2H)7.5 4(d,J=8.19Hz,2H)7.45(t,J=7.64Hz,2H)7.32-7.37(m,1H)7.20(d,J=2.81Hz,1H)7.13(d ,J=8.19Hz,2H)6.35(d,J=2.93Hz,1H)5.35(s,2H)4.19-4.29(m,1H)2.90(quin,J=8.47Hz ,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] + .

[1070] [Experimental Example: Evaluation of Inhibitory Activity Against EP2 and / or EP4]

[1071] 1. hEP2cAMP assay

[1072] HEK293 cells overexpressing hEP2 were cultured in growth medium (GM:MEM (Gibco)). TM ,11095080) / 10%HI FBS(Gibco TM (10082147) / 1% penicillin / streptomycin). Before the experiment, remove the growth medium and add starvation medium (HBSS (Gibco)). TM (14025076) / 10% GM). Cells were then incubated for 4 hours. Enzyme-free cell dissociation buffer (Gibco) was used. TM HEK293 cells carrying hEP2 were isolated from the culture dish (15040066). The cells were resuspended in assay buffer (AB: HBSS, 0.1% BSA stabilizer, 0.5mM IBMX, 5mM HEPES).

[1073] 5 μL of AB containing 1000 cells was seeded into a 384-well plate. In each well of the 3570, a stock solution of the analyte compound at a concentration of 1 mM was prepared in DMSO and serially diluted in DMSO to the concentration required for the inhibitor-response curve (test concentration range 10 μM to 0.001 nM). PGE2 (Sigma, P0409, stock solution: 1 μM) was used as the agonist, with a final concentration of 400 pM, corresponding to EC 100 mM. 50-80. Transfer 2.5 μL of the diluted compound and 2.5 μL of PGE2 (final concentration 400 pM) to the detection plate, and then incubate the plate at room temperature for 12 minutes.

[1074] Add 5 μL of donor (Eu-cAMP tracer) and 5 μL of acceptor (ULight-cAMP antibody) to each plate, incubate at room temperature in the dark for 1 hour, and then obtain results using a Varioskan LUX multi-functional microplate reader (excitation: 334 nm, emission: 615 and 665 nm). Convert the obtained FRET fluorescence values ​​(665 nm / 615 nm * 10000) and calculate the percentage of cAMP relative to the DMSO control value. Calculate the IC50 using logarithm (inhibitor) and reaction-variable slope (4 parameters) software in GraphPad Prism. 50 The values ​​and curves were calculated, and the median value from multiple experiments was taken as the experimental result.

[1075] 2. hEP4cAMP assay

[1076] HEK293 cells overexpressing hEP4 were cultured in growth medium (GM:MEM (Gibco)). TM ,11095080) / 10%HI FBS(Gibco TM (10082147) / 1% penicillin / streptomycin). Before the experiment, remove the growth medium and add starvation medium (HBSS (Gibco)). TM (14025076) / 10% GM). Cells were then incubated for 4 hours. Enzyme-free cell dissociation buffer (Gibco) was used. TM HEK293 cells carrying hEP4 were isolated from the culture dish (15040066). The cells were resuspended in assay buffer (AB: HBSS, 0.1% BSA stabilizer, 0.5mM IBMX, 5mM HEPES).

[1077] 5 μL of AB containing 1000 cells was seeded into a 384-well plate. In each well of the 3570, a stock solution of the analyte compound at a concentration of 1 mM was prepared in DMSO and serially diluted in DMSO to the concentration required for the inhibitor-response curve (test concentration range 10 μM to 0.001 nM). PGE2 (Sigma, P0409, stock solution: 100 μM) was used as an agonist, with a final concentration of 20 nM, corresponding to EC 100 mM. 50-80 2.5 μL of the diluted compound and 2.5 μL of PGE2 (final concentration 20 nM) were transferred to the detection plate, and the plate was then incubated at room temperature for 18.5 minutes.

[1078] Add 5 μL of donor (Eu-cAMP tracer) and 5 μL of acceptor (ULight-cAMP antibody) to each plate, incubate at room temperature in the dark for 1 hour, and then obtain results using a Varioskan LUX multi-functional microplate reader (excitation: 334 nm, emission: 615 and 665 nm). Convert the obtained FRET fluorescence values ​​(665 nm / 615 nm * 10000) and calculate the percentage of cAMP relative to the DMSO control value. Calculate the IC50 using logarithm (inhibitor) and reaction-variable slope (4 parameters) software in GraphPad Prism. 50 The values ​​and curves were calculated, and the median value from multiple experiments was taken as the experimental result.

[1079] 3. Experimental Results

[1080] The inhibitory activity of the compounds in Examples 1 to 113 against EP2 and EP4, as determined by the experimental methods described above, was evaluated according to the criteria in Table 21 below, and the results are shown in Tables 22 to 25.

[1081] [Table 21]

[1082]

[1083] [Table 22]

[1084]

[1085]

[1086] [Table 23]

[1087]

[1088]

[1089] [Table 24]

[1090]

[1091]

[1092] [Table 25]

[1093]

[1094]

[1095] As shown in Tables 22 to 25 above, the compounds in Examples 1 to 113 exhibited excellent inhibitory activity against EP2 and EP4.

Claims

1. A compound of formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [Formula I] ， in, one of X and Y is S and the other is CR 1 , and is a single or double bond, wherein there are two double bonds; R 1 The group is selected from the group consisting of hydrogen, halogens, and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted with one or more halogens; R 2 The group selected is composed of hydrogen, halogens, C1-C6 alkyl groups, C3-C8 cycloalkyl groups, and phenyl groups, wherein the C1-C6 alkyl groups are optionally substituted with one or more halogens; and R 3 For ; or R 2 and R 3 Together with the carbon atoms they are attached to form ,in, and The nitrogen atoms on it are connected, and One or two carbon atoms are optionally substituted with C1-C6 alkyl groups; W stands for -(CH2) o -、-(CH2) o -C≡C-, -C(O)-, -O-, -NH- or -N(C1-C6 alkyl)-, wherein the H in the CH2 is optionally substituted with one or more hydroxyl groups or C1-C6 alkoxy groups; Cy is selected from the group consisting of phenyl, pyrazolyl, pyridyl, pyrimidinyl, indolyl, and piperazineyl, and is optionally substituted by one or more R'; R a It is hydrogen, halogen, C1-C6 alkyl, or -V-Cy2, wherein the C1-C6 alkyl is optionally converted to one or more halogens. Where V represents non-existence, or -CH2- or -O-, Cy2 is selected from the group consisting of phenyl, furanyl, pyrazolyl, pyridyl, pyrimidinyl, piperidinyl, morpholinyl, cyclohexyl, and cyclohexenyl, and is optionally substituted by one or more R''. R' is independently selected from the group consisting of halogens, amino groups, and C1-C6 alkyl groups, wherein the C1-C6 alkyl groups are optionally substituted by one or more halogens; R'' can be selected from halogen, hydroxyl, cyano, amino, C1-C6 alkyl, C1-C6 alkoxy, -S-(C1-C6 alkyl), -SO2-(C1-C6 alkyl), -COO-(C1-C6 alkyl), -COOH, -CONH2, -CONH-(C1-C6 alkyl), -CON(C1-C6 alkyl)2, -(CH2) p -NH2、-(CH2) p -NH-(C1-C6 alkyl), -(CH2) p -N(C1-C6 alkyl)2, -(CH2) p -NH-CO-(C1-C6 alkyl), -(CH2) p -NH-COO-(C1-C6 alkyl), -(CH2) p The group consisting of -OH, aziridine, and oxetidine, wherein the C1-C6 alkyl and C1-C6 alkoxy groups are optionally substituted with one or more halogens, hydroxyl groups or amino groups, and the aziridine and oxetidine groups are optionally substituted with one or more hydroxyl groups or oxo groups. R 4 is hydrogen or Ci-C6alkyl; R 8 For wherein Z is -(CH2) s and R 8' is hydroxyl or C1-C6alkoxy; o is an integer of 1 or 2; p is an integer of 0, 1, or 2; and s is an integer that is 0.

2. The compound of formula I as claimed in claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 1 is hydrogen, halogen, or C1-C3alkyl, wherein said C1-C3alkyl is optionally substituted with one or more halogens; and R 2 is hydrogen, halogen, C1-C3 haloalkyl, cyclopropyl, cyclobutyl, or phenyl.

3. The compound of formula I as claimed in claim 1, or its stereoisomer or pharmaceutically acceptable salt, wherein, R a is -V-Cy2, and having a structure selected from the group consisting of: 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , ,and ; In this context, Cy and Cy2 are each arbitrarily replaced by R' and R''.

4. The compound of formula I as claimed in claim 1, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 8 For wherein Z is -(CH2) s and R 8' is hydroxyl, and s is an integer that is 0.

5. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein, The compound is a compound of formula IA-3: [Formula IA-3] ， R 1 is hydrogen, halogen, or C1-C3alkyl, wherein said C1-C3alkyl is optionally substituted with one or more halogens; R 2 It can be hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, C3-C6 cycloalkyl or phenyl; R 3 for ; W is -(CH2) o -CH2-, -C(O)-, -O-, -NH-, or -N(Ci-C6alkyl)-, wherein the H of CH2is optionally substituted with one or more hydroxyl or Ci-C6alkoxy; Cy is selected from the group consisting of phenyl, pyrazolyl, and piperazine, and is optionally substituted by one or more R'; R a It is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl or -V-Cy2, wherein V is absent or -O-, and Cy2 is selected from the group consisting of phenyl, furanyl, pyrazolyl, pyridyl, piperidinyl, morpholinyl, cyclohexyl and cyclohexenyl, and optionally substituted by one or more R''. R' is a halogen, amino, C1-C3 alkyl, or C1-C3 haloalkyl; R'' can be selected from halogen, hydroxyl, cyano, amino, 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 The group consisting of -OH, aziridine, and oxetidine, wherein the C1-C6 alkyl and C1-C6 alkoxy groups are optionally substituted with one or more halogens, hydroxyl groups or amino groups, and the aziridine and oxetidine groups are optionally substituted with one or more hydroxyl groups or oxo groups. R 4 is hydrogen or C1-C3alkyl; R 8 For wherein Z is -(CH2) s and R 8' is hydroxyl or C1-C6alkoxy; o is an integer of 1 or 2; p is an integer of 0, 1, or 2; and s is an integer of 0.

6. The compound of formula I as claimed in claim 5, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein, R 1 is hydrogen, halogen, C1-C3 alkyl, or C1-C3 haloalkyl; R 2 is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl, cyclopropyl, cyclobutyl, or phenyl; Cy is phenyl, pyrazolyl, or piperazineyl, and is optionally substituted by one or more R'; R a It is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl or -V-Cy2, wherein V is absent or -O-, and Cy2 is selected from the group consisting of phenyl, furanyl, pyrazolyl, pyridyl, piperidinyl, morpholinyl, cyclohexyl and cyclohexenyl, and optionally substituted by one or more R''. R' is a halogen, amino, C1-C3 alkyl, or C1-C3 haloalkyl; and R'' can be selected from halogen, hydroxyl, cyano, amino, 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; optional nitrogen-containing heterocyclic butyl or oxocyclic butyl groups substituted with hydroxyl or oxo groups.

7. The compound of claim 1, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein The compound is of formula IB-5: [Formula IB-5] ， in, R 1 halo, or C1-C3 alkyl, wherein said C1-C6 alkyl and C1-C6 alkoxy are each independently optionally substituted with one or more halogens; one or both carbon atoms in the group -C(R6)2- is optionally substituted by C1-C3 alkyl; W is -(CH2) o - or -(CH2) o - C≡C-, wherein the H in said CH2is optionally substituted by one or more hydroxyl or C1-C6alkoxy; Cy is selected from the group consisting of phenyl, pyrimidinyl, pyridinyl, and indoleyl, and is optionally substituted by one or more R'; R a It is hydrogen, halogen, C1-C3 alkyl, C1-C3 haloalkyl or -V-Cy2, wherein V is absent or -CH2-, and Cy2 is selected from the group consisting of phenyl, pyrimidinyl, pyridinyl and pyrazolyl, and optionally substituted by one or more R''. R' is a halogen, amino, C1-C3 alkyl, or C1-C3 haloalkyl; R'' is selected from the group consisting of halogen, hydroxyl, cyano, amino, C1-C6 alkyl, and C1-C6 alkoxy, wherein the C1-C6 alkyl and C1-C6 alkoxy are optionally substituted by one or more halogens; R 4 is hydrogen or C1-C3alkyl; R 8 For wherein Z is -(CH2) s and R 8' is hydroxyl or C1-C6alkoxy; o is an integer from 0 to 2; and s is an integer of 0.

8. The compound of claim 1, stereoisomers or pharmaceutically acceptable salts thereof, wherein, The compounds mentioned are selected from the group consisting of the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and .

9. The compound of claim 8 of Formula I, or a stereoisomer or pharmaceutically acceptable salt thereof, wherein, The compounds mentioned are selected from the group consisting of the following compounds: 、 、 、 、 、 、 and .

10. A compound, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein, The compounds mentioned are selected from the group consisting of the following compounds: , , and .

11. A pharmaceutical composition comprising, as an active ingredient, a compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, as any one of claims 1 to 10.

12. The pharmaceutical composition of claim 11, wherein, The pharmaceutical composition is used for the prevention or treatment of colorectal cancer.

13. Use of a compound, its stereoisomer, or a pharmaceutically acceptable salt as described in any one of claims 1 to 10, or a pharmaceutical composition as described in claim 11, in the preparation of a medicament for the prevention or treatment of colorectal cancer.

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