Pharmaceutical composition for treating cancer comprising a novel compound that inhibits prostaglandin E2 receptor and an anticancer drug

Abstract

The present invention provides a pharmaceutical composition for treating cancer, comprising a novel compound that inhibits the activity of prostaglandin E2 receptor and an anticancer agent as active ingredients. The novel compound of the present invention inhibits the activity of prostaglandin E2 receptor and inhibits tumor growth in colon cancer and lung cancer tumor models. In addition, it has been found that when administered in combination with other anticancer agents, such as chemotherapeutic agents and / or immune checkpoint inhibitors, it exhibits synergistic effects in anticancer activity. Therefore, the pharmaceutical composition for treating cancer, comprising a novel compound and an anticancer agent as active ingredients, can be effectively used for the prevention and treatment of cancer.

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition for treating cancer, which comprises a novel compound having inhibitory activity against prostaglandin E2 receptors and an anticancer agent as active ingredients. [Background technology]

[0002] Prostaglandins (PGs), like thromboxanes, are physiologically active substances known as prostanoids, which are lipids with a prostanoic acid skeleton. Prostanoids, such as prostaglandins, are biosynthesized from arachidonic acid released from membrane phospholipids by the action of phospholipase A2. Prostaglandins are classified into groups A to J based on the difference in the type of oxygen atom attached to the five-membered ring and the type of double bond. In addition, prostaglandins are classified into groups 1 to 3 based on the member of the double bond to the side chain of the prostanoic acid skeleton. For example, prostaglandin E (PGE) has PGE 1 , P.G.E. 2 and P.G.E. 3 which differ from each other with respect to the number of double bonds in the side chain of the prostanoic acid skeleton.

[0003] Regarding prostaglandins, PGH 2 PGG is synthesized from arachidonic acid by the action of cyclooxygenase I (COX-I) or cyclooxygenase II (COX-II). 2 Then PGD 2 , P.G.E. 2 , P.G.F. 2α are produced based on the difference in the cleavage of bonds between oxygen atoms. The production reaction of each prostaglandin occurs through the action of a specific enzyme, and it is known that these enzymes have tissue specificity. On the other hand, among prostaglandins, PGE plays a role in various important biological activities, and PEG, through the mediation of specific receptors, is considered to be involved in immune system regulation, as well as vasodilation, reduction of blood pressure and uterine contraction. PEG 2The receptor is a seven-transmembrane G protein-coupled receptor, as are other PG receptors. 2 The receptor is abbreviated as EP, and EP has four subtypes (EP 1 , E.P. 2 , E.P. 3 and E.P. 4 Each subtype is involved in various phenomena in vivo. 1 Intracellular Ca 2+ Involved in increasing concentration of EP 2 and E.P. 4 is involved in increasing cAMP levels and EP 3 is involved in the reduction of cAMP levels.

[0004] Meanwhile, cancer is one of the leading causes of death worldwide. Tumors consist of abnormally proliferated malignant cancer cells as well as a functionally supportive microenvironment. This tumor microenvironment is composed of a complex array of cells, extracellular matrix components and signaling molecules, and is established by altered communication between stromal cells and tumor cells. As tumors grow in size, they induce the production of various factors, such as angiogenic factors (promoting blood vessel growth) that may aid in tumor growth or help to evade the attack of the host immune response. In this microenvironment, PGE 2 PGE functions as an immunomodulatory factor produced by tumors. 2 EP receptors, especially EP 2 and E.P. 4 is aberrantly overexpressed in several types of cancer, specifically gastrointestinal (GI) and pancreatic cancer. In addition, PGE 2 and / or EP 2 and / or EP 4 is closely correlated with cancer, such as esophageal squamous cell carcinoma, lung squamous cell carcinoma, prostate cancer, and head and neck squamous cell carcinoma. 2 It is known that signal transduction is mainly involved in the communication between tumor cells and stromal cells, creating a favorable microenvironment for tumor growth. It is noteworthy that some tumor cells overexpress EP2 and / or EP4, so that PGE2 signal transduction can directly induce tumor cell proliferation.

[0005] In addition, PGE 2 Antagonists, e.g., EP 2 and / or EP 4 Antagonists have been reported to be effective in chronic inflammatory diseases and in neurodegenerative diseases such as epilepsy, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and traumatic brain injury.

[0006] In this technical background, prostaglandin E 2 , which can be clinically utilized in various ways, 2 Research into receptor antagonists is ongoing (Korean Patent Application Publication No. 10-2013-0092579), but remains incomplete.

[0007] [Disclosure of the Invention] [Technical issue] Therefore, as a result of research to develop a safe and effective anticancer drug, the present inventors have found that a novel compound having inhibitory activity against prostaglandin E2 receptor exhibits excellent anticancer effect when used in combination with a chemotherapeutic agent and / or an immune checkpoint inhibitor. Based on the above, the present inventors have completed the present invention.

[0008] [Problem Resolution] In order to achieve the above object, in one aspect of the present invention, there is provided a pharmaceutical composition and a kit for treating cancer, comprising a compound of formula I or a solvate, stereoisomer or pharma- ceutically acceptable salt thereof and an anticancer agent as active ingredients. [ka]

[0009] [Effects of the invention] The novel compound of the present invention inhibits the activity of prostaglandin E2 receptor and inhibits tumor growth in colon cancer and lung cancer tumor models.In addition, it has been found that when administered in combination with other anti-cancer drugs, such as chemotherapeutic drugs and / or immune checkpoint inhibitors, it exhibits synergistic effects in anti-cancer activity.Therefore, the pharmaceutical composition for treating cancer, which comprises the novel compound having inhibitory activity against prostaglandin E2 receptor and the anti-cancer drug as active ingredients, can be effectively used for the prevention and treatment of cancer. [Brief description of the drawings]

[0010] [Figure 1] 1 is a graph showing the results obtained by observing the changes in mouse body weight following administration of A01 (Example 34b), an anti-PD-1 antibody, or a combination of A01 and an anti-PD-1 antibody in a mouse-derived colorectal cancer CT26 animal model. [Diagram 2] 1 is a graph showing the results obtained by measuring tumor size following administration of A01, anti-PD-1 antibody, or a combination of A01 and anti-PD-1 antibody in a mouse-derived colorectal cancer CT26 animal model. [Diagram 3] 1 is a graph showing the results obtained by observing the changes in mouse body weight following administration of A02 (Example 1b), an anti-PD-1 antibody, or a combination of A02 and an anti-PD-1 antibody in a mouse-derived MC38 colorectal cancer animal model. [Figure 4] 1 is a graph showing the results obtained by measuring tumor size following administration of A02, anti-PD-1 antibody, or a combination of A02 and anti-PD-1 antibody in a mouse-derived MC38 colorectal cancer animal model. [Diagram 5] 1 is a graph showing the results obtained by measuring tumor size following administration of a combination of cisplatin, pemetrexed and anti-PD-1 antibody, or a combination of cisplatin, pemetrexed, anti-PD-1 antibody and A01 in a mouse-derived lung cancer TC1 animal model.

[0011] [Detailed Description of the Invention] Pharmaceutical composition comprising a prostaglandin E2 receptor inhibitor and an anticancer agent In one aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating cancer, comprising a prostaglandin E2 receptor inhibitor compound, a solvate, a stereoisomer, or a pharma- ceutically acceptable salt thereof, and an anticancer agent.

[0012] Prostaglandin E2 receptor inhibitor One embodiment of the prostaglandin E2 receptor inhibitor compound may be a compound represented by the following formula I, a solvate, a stereoisomer, or a pharma- ceutically acceptable salt thereof: [ka] During the ceremony, One of X and Y is S and the other is CR 1 and [ka] are single or double bonds, two of which are double bonds; R 1 and R 2 is hydrogen, halogen, hydroxy, cyano, amino, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, -NH-(C 1 ~C 6 alkyl), -N(C 1 ~C 6 Alkyl) 2 , C 3 ~C 8 Cycloalkyl and C 6 ~C 10 aryl, 1 ~C 6 Alkyl and C 1 ~C 6 Each alkoxy is independently optionally substituted with one or more halogen, hydroxy, cyano, or amino;3 ~C 8 Cycloalkyl and C 6 ~C 10 Each aryl is independently one or more of halogen, hydroxy, cyano, amino, oxo, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy or C 1 ~C 6 optionally substituted with haloalkoxy; R 3 teeth, [ka] or R 1 is hydrogen, halogen, hydroxy, cyano, amino, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, -NH-(C 1 ~C 6 alkyl), -N(C 1 ~C 6 Alkyl) 2 , C 3 ~C 8 Cycloalkyl and C 6 ~C 10 aryl, 1 ~C 6 Alkyl and C 1 ~C 6 Each alkoxy is independently optionally substituted with one or more halogen, hydroxy, cyano, or amino; 3 ~C 8 Cycloalkyl and C 6 ~C 10 Each aryl is independently one or more of halogen, hydroxy, cyano, amino, oxo, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1~C 6 Alkoxy or C 1 ~C 6 optionally substituted with haloalkoxy; R 2 and R 3 is R 2 and R 3 together with the carbon atom to which it is bonded, [ka] Forming [ka] teeth, [ka] is attached to the nitrogen atom of [ka] One or both of the carbon atoms may be halogen, hydroxy, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl or C 1 ~C 6 optionally substituted with haloalkoxy; W is -(CH 2 ) o -, -(CH 2 ) o -C≡C-, -C(O)-, -O-, -S-, -NH- or -N(C 1 ~C 6 alkyl)-, wherein the CH 2 H is one or more halogen, hydroxy, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl or C1 ~C 6 optionally substituted with haloalkoxy; Cy is C 6 ~C 14 Aryl, 4-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 3 ~C 8 Cycloalkyl and C 3 ~C 8 cycloalkenyl, optionally substituted with one or more R'; R a is hydrogen, halogen, hydroxy, cyano, amino, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, -NH-(C 1 ~C 6 alkyl), -N(C 1 ~C 6 Alkyl) 2 , oxo or -V-Cy 2 and C 1 ~C 6 Alkyl and C 1 ~C 6 The alkoxy may be optionally substituted with one or more halogen, hydroxy, cyano or amino; V is absent or -NH-, -NHCH 2 -, -NHCH 3 -, -CONH-, -NHCO-, -NHSO 2 -, -S-, -SO 2 -, -CH 2 -, -OCH 2 - or -O-, Cy 2 is C 6 ~C 14 Aryl, 4-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 3 ~C 8 Cycloalkyl and C 3 ~C 8 cycloalkenyl, optionally substituted with one or more R″; R' is independently halogen, hydroxy, cyano, amino, oxo, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, -NH-(C 1 ~C 6 Alkyl) and -N(C 1 ~C 6 Alkyl) 2 wherein C is selected from the group consisting of 1 ~C 6 Alkyl and C 1 ~C 6 The alkoxy may be optionally substituted with one or more halogen, hydroxy, cyano or amino; R" is halogen, hydroxy, cyano, amino, oxo, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, -S-(C 1 ~C 6 Alkyl), -SO 2 -(C 1 ~C 6 alkyl), -CO-(C 1 ~C 6 alkyl), -C(O)H, -COO-(C 1 ~C 6 alkyl), -COOH, -CONH 2 , -CONH-(C 1 ~C 6 alkyl), -CON(C 1 ~C 6 Alkyl) 2 , -(CH 2 ) p -NH 2 , -(CH 2 ) p -NH-(C 1 ~C 6 alkyl), -(CH 2 ) p -N(C 1 ~C 6 Alkyl) 2 , -(CH 2 ) p -NH-CO-(C 1 ~C 6alkyl), -(CH 2 ) p -NH-COO-(C 1 ~C 6 alkyl), -(CH 2 ) p -OH, 3-7 membered heterocycloalkyl, C 3 ~C 8 Cycloalkyl and -(CH 2 ) p -(C 3 ~C 8 cycloalkyl), 1 ~C 6 Alkyl and C 1 ~C 6 The alkoxy may be optionally substituted with one or more halogen, hydroxy, cyano or amino, and is selected from the group consisting of 3-7 membered heterocycloalkyl and C 3 ~C 8 The cycloalkyl may be optionally substituted with one or more halogen, hydroxy, cyano, oxo or amino; R 4 is hydrogen or C 1 ~C 6 is alkyl; R 5 , R 6 and R 7 are defined as follows: (i)R 5 and R 6 is H and R 7 is non-existent or (ii)R 5 and R 6 Ga-(CH 2 ) q - together represent R 7 is non-existent, or (iii)R 5 is H and R 6 and R 7 Ga-(CH 2 ) r - together represent, having; P is absent or -CH 2 - but R 7If is nonexistent, then P is nonexistent; R 8 teeth, [ka] and Z is -(CH 2 ) s and R 8’ is hydrogen, hydroxyl, C 1 ~C 6 Alkyl or C 1 ~C 6 is alkoxy; l, m and n are each independently an integer of 0 to 2, and at least one of m and 2 is not 0; P and R 7 If is absent, then l is 0; o and p each independently represent an integer of 0 to 3; q and r are, independently of each other, integers of 1 or 2; s is an integer from 0 to 3.

[0013] In some embodiments, X is S and Y is CR 1 or X is CR 1 and Y is S. In one embodiment, [ka] are single or double bonds, two of which are double bonds, whereby the five-membered ring containing X and Y forms a thiophenyl ring.

[0014] In some embodiments, R 1 is hydrogen, halogen, hydroxy, cyano, amino, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy, -NH-(C 1 ~C 3 alkyl) or -N(C 1 ~C 3 Alkyl) 2 C may be 1 ~C3 Alkyl and C 1 ~C 3 Each alkoxy may be independently optionally substituted with one or more halogen, hydroxy, cyano, or amino. In one embodiment, R 1 is hydrogen, halogen, hydroxy, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl or C 1 ~C 3 In one embodiment, R 1 is hydrogen, halogen, C 1 ~C 3 Alkyl or C 1 ~C 3 It may be a haloalkyl.

[0015] In some embodiments, R 2 is hydrogen, halogen, hydroxy, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Haloalkoxy, C 3 ~C 6 cycloalkyl or phenyl, 1 ~C 3 Alkyl and C 1 ~C 3 Each alkoxy may be independently optionally substituted with one or more halogen, hydroxy, cyano, or amino. In one embodiment, R 2 is hydrogen, halogen, C 1 ~C 3 Alkyl, C 1 ~C 3 It may be haloalkyl, cyclopropyl, cyclobutyl or phenyl. In one embodiment, R 2can be hydrogen, fluoro, chloro, bromo, methyl, ethyl, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, or phenyl, and the like.

[0016] In some embodiments, R 3 teeth, [ka] It is possible.

[0017] In another embodiment, R 2 and R 3 is R 2 and R 3 together with the carbon atom to which it is bonded, [ka] to form a 4H-thieno[3,2-b]pyrrole fused ring, in which [ka] teeth, [ka] can be bonded to the nitrogen atom of

[0018] In one embodiment, [ka] One or both of the carbon atoms may be halogen, C 1 ~C 3 Alkyl or C 1 ~C 3 In one embodiment, [ka] One or both of the carbon atoms may be optionally substituted with fluoro, chloro, bromo, methyl, ethyl, trifluoromethyl, difluoromethyl, and the like. In one embodiment, [ka] One or both of the carbon atoms of 1 ~C 3 It may be optionally substituted with alkyl.

[0019] In some embodiments, W is -(CH 2 ) o -, -(CH 2 ) o -C≡C-, -C(O)-, -O-, -NH- or -N(C 1 ~C 3 alkyl)-, wherein the CH 2 H is one or more halogens, hydroxyl, C 1 ~C 3 Alkoxy or C 1 ~C 3 It may be optionally substituted with haloalkoxy.

[0020] In one embodiment, W is -(CH 2 ) o -, -C(O)-, -O-, -NH- or -N(C 1 ~C 6 In another embodiment, W can be -(CH alkyl). 2 ) o -or-(CH 2 ) o It is possible that -C≡C-.

[0021] In one embodiment, the CH 2 H is one or more halogens, hydroxyl or C 1 ~C 3 In one embodiment, the CH 2The H may be optionally substituted with hydroxy, methoxy, ethoxy, trifluoromethoxy, difluoromethoxy, etc. In one embodiment, o may be an integer of 0, 1, or 2. In one embodiment, o may be an integer of 0 or 1.

[0022] In some embodiments, Cy is C 6 ~C 10 It may be an aryl, a 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, or a 4-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S. In one embodiment, Cy can be phenyl, naphthyl; heteroaryl selected from pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, quinolinyl, and isoquinolinyl; or heterocycloalkyl selected from azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, and morpholinyl.

[0023] In one embodiment, Cy can be phenyl, 5-10 membered heteroaryl containing 1 or 2 nitrogen atoms, or 4-7 membered heterocycloalkyl containing 1 or 2 nitrogen atoms. In one embodiment, Cy can be phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl. In one embodiment, Cy can be phenyl, pyrazolyl, pyridinyl, pyrimidinyl, indolyl, or piperazinyl.

[0024] Said Cy may be optionally substituted with one or more R'. In one embodiment, R' is selected from the group consisting of halogen, hydroxy, cyano, amino, oxo, C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, -NH-(C 1 ~C 3 alkyl) or -N(C 1 ~C 3 Alkyl) 2 In one embodiment, R' can be halogen, amino, C 1 ~C 3 Alkyl or C 1 ~C 3 In one embodiment, R' can be one or more of fluoro, chloro, bromo, amino, methylamino, dimethylamino, ethylamino, or diethylamino, and the like.

[0025] In one embodiment, R a is hydrogen, halogen, amino, C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl, -NH-(C 1 ~C 3 alkyl) or -N(C 1 ~C 3 Alkyl) 2 Or -V-Cy 2 In one embodiment, R a is hydrogen, halogen, C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl or -V-Cy 2 In one embodiment, R a is hydrogen, fluoro, chloro, bromo, methyl, ethyl, trifluoromethyl, difluoromethyl or -V-Cy 2 In one embodiment, R a -V-Cy2 It is possible.

[0026] In some embodiments, V is absent, -NH-, -NHCH 2 -, -NHCH 3 -, -S-, -SO 2 -, -CH 2 -, -OCH 2 In one embodiment, V is absent or -CH 2 In one embodiment, V is absent or -CH 2 -It is possible.

[0027] In some embodiments, Cy 2 is C 6 ~C 10 aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, 4-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, C 3 ~C 8 Cycloalkyl and C 3 ~C 8 In one embodiment, Cy may be selected from the group consisting of cycloalkenyl. 2 may be phenyl; heteroaryl selected from pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, quinolinyl, and isoquinolinyl; heterocycloalkyl selected from azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, and morpholinyl; cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl; or cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl.

[0028] In one embodiment, Cy 2 is a 5- to 10-membered heteroaryl containing 1 or 2 heteroatoms selected from phenyl, N or O, a 4- or 7-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N or O, C 4 ~C 7 Cycloalkyl and C 4 ~C 7 In one embodiment, Cy may be selected from the group consisting of cycloalkenyl. 2 may be phenyl, pyrrolyl, furanyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholine, cyclopentyl, cyclohexyl, cyclopentenyl, or cyclohexenyl. 2 can be phenyl, furanyl, pyrazolyl, pyridinyl, pyrimidinyl, piperidinyl, morpholinyl, cyclohexyl or cyclohexenyl.

[0029] Cy 2 is optionally substituted with R″. In some embodiments, R″ is halogen, hydroxy, cyano, amino, oxo, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, -S-(C 1 ~C 6 Alkyl), -SO 2 -(C 1 ~C 6 alkyl), -COO-(C 1 ~C 6 alkyl), -COOH, -CONH 2 , -(CH 2 ) p -NH 2 , -(CH 2 ) p -NH-(C 1 ~C 6 alkyl), -(CH 2 ) p -N(C 1 ~C 6 Alkyl)2 , -(CH 2 ) p -NH-COO-(C 1 ~C 6 alkyl), -(CH 2 ) p -3-5 membered heterocycloalkyl containing one heteroatom selected from -OH, N, O and S; C 3 ~C 5 Cycloalkyl, and -(CH 2 ) p -(C 3 ~C 5 cycloalkyl), 1 ~C 6 Alkyl and C 1 ~C 6 The alkoxy may be optionally substituted with one or more halogen, hydroxy, cyano or amino, and is selected from the group consisting of 3-5 membered heterocycloalkyl and C 3 ~C 5 Cycloalkyl may be optionally substituted with one or more halogen, hydroxy, cyano, oxo, or amino. In one embodiment, the 3-5 membered heterocycloalkyl is selected from aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, and tetrahydrofuranyl, or C 3 ~C 5 In one embodiment, p can be an integer of 0, 1, or 2. In one embodiment, p can be an integer of 0 or 1.

[0030] In one embodiment, R″ is halogen, hydroxy, cyano, amino, oxo, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkoxy, -S-(C 1 ~C 6 Alkyl), -SO 2 -(C 1 ~C 6 alkyl), -COO-(C1 ~C 6 alkyl), -COOH, -CONH 2 , -(CH 2 ) p -NH 2 , -(CH 2 ) p -NH-(C 1 ~C 6 alkyl), -(CH 2 ) p -N(C 1 ~C 6 Alkyl) 2 , -(CH 2 ) p -NH-COO-(C 1 ~C 6 alkyl), -(CH 2 ) p It can be -OH; azetidinyl or oxetanyl optionally substituted with hydroxy or oxo; cyclopropyl or cyclopropylmethyl optionally substituted with hydroxy or oxo. In another embodiment, R″ is halogen, hydroxy, cyano, amino, oxo, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkoxy, -(CH 2 ) p -NH 2 , -(CH 2 ) p -NH-(C 1 ~C 6 alkyl), -(CH 2 ) p -N(C 1 ~C 6 Alkyl) 2 azetidinyl or oxetanyl, optionally substituted with hydroxy or oxo; cyclopropyl or cyclopropylmethyl, optionally substituted with hydroxy or oxo.

[0031] In one embodiment, R″ is halogen, hydroxy, methyl, ethyl, hydroxymethyl, hydroxyethyl, aminomethyl, aminoethyl, trifluoromethyl, difluoromethyl, trifluoroethyl, difluoroethyl, methoxy, ethoxy, isopropoxy, trifluoromethoxy, difluoromethoxy, cyano, amino, oxo, —S—CH 3 , -S-CH 2 CH 3 , -SO 2 -CH 3 , -SO 2 -CH 2 CH 3 , -COOCH 3 , -COOCH 2 CH 3 , -COOCH 2 CH 2 CH 3 , -COOCH(CH 3 ) 2 , -COOCH 2 CH(CH 3 ) 2 , -COOC(CH 3 ) 4 , -COOH, -CONH 2 , -CH 2 NH 2 , -CH 2 CH 2 NH 2 , -CH 2 NHCOOCH 3 , -CH 2 NHCOOCH 2 CH 3 , -CH 2 NHCOOCH 2 CH 2 CH 3 , -CH 2 NHCOOCH(CH 3 ) 2 , -CH 2 NHCOOCH 2 CH(CH 3 ) 2 , -CH 2 NHCOOC(CH 3 ) 3 , -CH 2 OH, -CH 2 CH2 It can be OH, azetidinyl, oxetanyl, cyclopropyl or cyclobutylmethyl.

[0032] In one embodiment, R a -V-Cy 2 and [ka] has a structure selected from the group consisting of Cy and Cy 2 are each optionally substituted with R′ and R″: [ka] JPEG2025508381000021.jpg120149 In some embodiments, R 4 is hydrogen or C 1 ~C 3 It can be alkyl.

[0033] In some embodiments, R 5 and R 6 may be H, R 7 may be absent, and the structure attached to the amide bond in formula I is the following structure: [ka] where n and m can each be an integer of 1 or 2.

[0034] In another embodiment, R 5 and R 6 Ha-(CH 2 ) q - may be expressed together, R 7 may be absent, in which case the structure attached to the amide bond in formula I is the following structure: [ka] where n, m, and q may each be an integer of 1 or 2.

[0035] In another embodiment, R 5 may be H, R 6 and R 7 Ha-(CH 2 ) r - together, in which case the structure attached to the amide bond in formula I is the following structure: [ka] where n, m, r, and l may each be an integer of 1 or 2.

[0036] In one embodiment, the structure attached to the amide bond of formula I includes isomers of that structure and can be, for example, but not limited to, the following structures: [ka] In some embodiments, R 8 teeth, [ka] Z may be -(CH 2 ) s R may be 8’ is hydroxy or C 1 ~C 6 alkoxy, and s may be an integer of 0 or 1. In one embodiment, s may be 0, and R 8’ may be hydroxy.

[0037] In the present invention, formula I may be formula IA-1 or IA-2: [ka] During the ceremony, R 1 and R2 is hydrogen, halogen, hydroxy, cyano, amino, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, -NH-(C 1 ~C 6 alkyl), -N(C 1 ~C 6 Alkyl) 2 , C 3 ~C 8 Cycloalkyl and C 6 ~C 10 aryl, 1 ~C 6 Alkyl and C 1 ~C 6 Each alkoxy is independently optionally substituted with one or more halogen, hydroxy, cyano, or amino; 3 ~C 8 Cycloalkyl and C 6 ~C 10 Each aryl is independently one or more of halogen, hydroxy, cyano, amino, oxo, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy or C 1 ~C 6 optionally substituted with haloalkoxy; R 3 teeth, [ka] and; W, Cy, Ra, R 4 , R 8 , n, m, r and l are as defined above in Formula I. 1 , R 2 ,W.,C.Y.,R. a , R 4 , R 8The specific examples and embodiments described with respect to n, m, r and l can also be equally applied to formulas IA-1 and IA-2, where structurally permitted.

[0038] In some embodiments of formulas IA-1 and IA-2, R 1 is hydrogen, halogen, hydroxy, cyano, amino, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, -NH-(C 1 ~C 6 alkyl) or -N(C 1 ~C 6 Alkyl) 2 C may be 1 ~C 6 Alkyl and C 1 ~C 6 Each alkoxy may be independently optionally substituted with one or more halogen, hydroxy, cyano, or amino. In one embodiment, R 1 is hydrogen, halogen, hydroxy, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl or C 1 ~C 3 In one embodiment, R 1 is hydrogen, halogen, C 1 ~C 3 Alkyl or C 1 ~C 3 It may be a haloalkyl.

[0039] In some embodiments, R 2 is hydrogen, halogen, hydroxy, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Haloalkoxy, C 3 ~C6 cycloalkyl or phenyl, 1 ~C 3 Alkyl and C 1 ~C 3 Each alkoxy may be independently optionally substituted with one or more halogen, hydroxy, cyano, or amino. 3 ~C 6 Cycloalkyl and phenyl may each be substituted with one or more halogens, C 1 ~C 3 Alkyl or C 1 ~C 3 In one embodiment, R 2 is hydrogen, halogen, C 1 ~C 3 Alkyl, C 1 ~C 3 It may be haloalkyl, cyclopropyl, cyclobutyl or phenyl.

[0040] In some embodiments, W is -(CH 2 ) o -, -(CH 2 ) o -C≡C-, -C(O)-, -O-, -NH- or -N(C 1 ~C 3 In one embodiment, W can be -(CH alkyl). 2 ) o -, -C(O)-, -O-, -NH- or -N(C 1 ~C 6 In this case, the CH 2 H is one or more halogens, hydroxyl or C 1 ~C 6 It may be optionally substituted with alkoxy.

[0041] In some embodiments, Cy is C 6 ~C 10It may be aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, or 4-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S. In one embodiment, Cy may be phenyl, 5-10 membered heteroaryl containing 1 or 2 nitrogen atoms, or 4-7 membered heterocycloalkyl containing 1 or 2 nitrogen atoms. For example, Cy may be phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzimidazolyl, indazolyl, pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl. In one embodiment, Cy may be phenyl, pyrazolyl, pyridinyl, pyrimidinyl, indolyl, or piperazinyl. In one embodiment, Cy may be phenyl, pyrazolyl, or piperazinyl.

[0042] Said Cy may be optionally substituted with one or more R'. In some embodiments, R' is selected from the group consisting of halogen, hydroxy, cyano, amino, oxo, C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, -NH-(C 1 ~C 3 alkyl), or -N(C 1 ~C 3 Alkyl) 2 In one embodiment, R' can be halogen, amino, C 1 ~C 3 Alkyl or C 1 ~C 3 It may be a haloalkyl.

[0043] In some embodiments, R a is hydrogen, halogen, C 1 ~C 3 Alkyl, C 1 ~C 3Haloalkyl or -V-Cy 2 In one embodiment, R a -V-Cy 2 It is possible.

[0044] In some embodiments, V is absent, -NH-, -NHCH 2 -, -NHCH 3 -, -S-, -SO 2 -, -CH 2 -, -OCH 2 In one embodiment, V is absent or -CH 2 It can be - or -O-.

[0045] In some embodiments, Cy 2 is C 6 ~C 10 aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, 4-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, C 3 ~C 8 Cycloalkyl and C 3 ~C 8 In one embodiment, Cy may be selected from the group consisting of cycloalkenyl. 2 is a 5- to 10-membered heteroaryl containing 1 or 2 heteroatoms selected from phenyl, N or O, a 4- or 7-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N or O, C 4 ~C 7 Cycloalkyl and C 4 ~C 7 cycloalkenyl.

[0046] In one embodiment, Cy 2 may be phenyl, furanyl, pyrazolyl, pyridinyl, pyrimidinyl, piperidinyl, morpholinyl, cyclohexyl, or cyclohexenyl. 2can be phenyl, furanyl, pyrazolyl, pyridinyl, morpholinyl, piperidinyl, cyclohexyl or cyclohexenyl.

[0047] Cy 2 is optionally substituted with one or more R″. In some embodiments, R″ is halogen, hydroxy, cyano, amino, oxo, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, -S-(C 1 ~C 6 Alkyl), -SO 2 -(C 1 ~C 6 alkyl), -COO-(C 1 ~C 6 alkyl), -COOH, -CONH 2 , -(CH 2 ) p -NH 2 , -(CH 2 ) p -NH-(C 1 ~C 6 alkyl), -(CH 2 ) p -N(C 1 ~C 6 Alkyl) 2 , -(CH 2 ) p -NH-COO-(C 1 ~C 6 alkyl), -(CH 2 ) p -3-5 membered heterocycloalkyl containing one heteroatom selected from -OH, N, O and S; C 3 ~C 5 Cycloalkyl, and -(CH 2 ) p -(C 3 ~C 5 In this case, the C 1 ~C 6 Alkyl and C 1 ~C 6The alkoxy may be optionally substituted with one or more halogen, hydroxy, cyano or amino, and is selected from the group consisting of 3-5 membered heterocycloalkyl and C 3 ~C 5 The cycloalkyl may be optionally substituted with one or more halogen, hydroxy, cyano, oxo or amino.

[0048] In one embodiment, R″ is halogen, hydroxy, cyano, amino, oxo, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkoxy, -S-(C 1 ~C 6 Alkyl), -SO 2 -(C 1 ~C 6 alkyl), -COO-(C 1 ~C 6 alkyl), -COOH, -CONH 2 , -(CH 2 ) p -NH 2 , -(CH 2 ) p -NH-(C 1 ~C 6 alkyl), -(CH 2 ) p -N(C 1 ~C 6 Alkyl) 2 , -(CH 2 ) p -NH-COO-(C 1 ~C 6 alkyl), -(CH 2 ) p It may be selected from the group consisting of: -OH; azetidinyl or oxetanyl optionally substituted with hydroxy or oxo; and cyclopropyl or cyclopropylmethyl optionally substituted with hydroxy or oxo.

[0049] In some embodiments, R 4is hydrogen or C 1 ~C 3 It can be alkyl.

[0050] In some embodiments, the compound having formula IA-1 or IA-2 above can be represented by formula IA-3 or IA-4: [ka] In the formula, R 1 , R 2 , R 3 , R 4 and R 8 is as defined above in formulas IA-1 and IA-2.

[0051] In the present invention, the compound having the above formula I can be represented by formula IB-1: [ka] During the ceremony, R 1 is hydrogen, halogen, hydroxy, cyano, amino, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, -NH-(C 1 ~C 6 alkyl), -N(C 1 ~C 6 Alkyl) 2 , C 3 ~C 8 Cycloalkyl and C 6 ~C 10 aryl, 1 ~C 6 Alkyl and C 1 ~C 6 Each alkoxy is independently optionally substituted with one or more halogen, hydroxy, cyano, or amino; 3 ~C 8 Cycloalkyl and C 6 ~C 10Aryl may be independently selected from one or more of halogen, hydroxy, cyano, amino, oxo, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy or C 1 ~C 6 optionally substituted with haloalkoxy; [ka] One or both of the carbon atoms may be halogen, hydroxy, cyano, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkyl or C 1 ~C 6 optionally substituted with haloalkoxy; W, Cy, R a , R 4 , R 5 , R 6 , R 7 , R 8 , P, n, m and l are as defined in formula I above.

[0052] W, Cy, R of Formula I a , R 4 , R 8 , R 6 , R 7 , R 8 The specific examples and embodiments described with respect to P, n, m, r, and l may also be equally applied to formula IB-1, where structurally permitted.

[0053] In some embodiments, the compound having formula IB-1 can be represented by formula IB-2, IB-3, or IB-4. [ka]

[0054] In some embodiments of formulas IB-2, IB-3 and IB-4, R 1 is hydrogen, halogen, hydroxy, cyano, amino, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, -NH-(C 1 ~C 6 alkyl) or -N(C 1 ~C 6 Alkyl) 2 C may be 1 ~C 6 Alkyl and C 1 ~C 6 Each alkoxy may be independently optionally substituted with one or more halogen, hydroxy, cyano, or amino. In one embodiment, R 1 is hydrogen, halogen, hydroxy, C 1 ~C 3 Alkyl, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkyl or C 1 ~C 3 It may be a haloalkoxy.

[0055] In some embodiments, [ka] One or both of the carbon atoms may be halogen, C 1 ~C 3 Alkyl or C 1 ~C 3 In one embodiment, [ka] One or both of the carbon atoms of 1 ~C 3 It may be optionally substituted with alkyl.

[0056] In some embodiments, W is -(CH 2 ) o -, -(CH 2 ) o -C≡C-, -C(O)-, -O-, -NH- or -N(C 1 ~C 3 In one embodiment, W can be -(CH alkyl). 2 ) o -or-(CH 2 ) o In this case, the CH 2 H is one or more halogens, hydroxyl or C 1 ~C 6 It may be optionally substituted with alkoxy.

[0057] In some embodiments, Cy is C 6 ~C 10 It may be selected from the group consisting of aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, and 4-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S. In one embodiment, Cy may be phenyl or 5-10 membered heteroaryl containing 1 or 2 nitrogen atoms. In one embodiment, Cy may be phenyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, isoindolyl, benzimidazolyl or indazolyl. In one embodiment, Cy may be phenyl, pyridinyl, pyrimidinyl or indolyl.

[0058] Said Cy may be optionally substituted with one or more R'. In some embodiments, R' is selected from the group consisting of halogen, hydroxy, cyano, amino, oxo, C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl, C 1 ~C 3 Alkoxy, C 1 ~C 3 Haloalkoxy, -NH-(C 1 ~C3 alkyl) or -N(C 1 ~C 3 Alkyl) 2 In one embodiment, R' can be halogen, amino, C 1 ~C 3 Alkyl or C 1 ~C 3 It may be a haloalkyl.

[0059] In some embodiments, R a is hydrogen, halogen, C 1 ~C 3 Alkyl, C 1 ~C 3 Haloalkyl or -V-Cy 2 In this case, V is absent or -NH-, -NHCH 2 -, -NHCH 3 -, -S-, -SO 2 -, -CH 2 -, -OCH 2 In one embodiment, V is absent or -CH 2 In one embodiment, V is absent or -CH 2 -It is possible.

[0060] In some embodiments, Cy 2 is C 6 ~C 10 aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, 4-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, C 3 ~C 8 Cycloalkyl and C 3 ~C 8 In one embodiment, Cy may be selected from the group consisting of cycloalkenyl. 2 can be phenyl or a 5-10 membered heteroaryl containing 1 or 2 nitrogen atoms. 2may be phenyl, pyrrolyl, furanyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholine, cyclopentyl, cyclohexyl, cyclopentenyl, or cyclohexenyl. 2 can be phenyl, pyrazolyl, pyridinyl or pyrimidinyl.

[0061] Cy 2 is optionally substituted with one or more R″. In some embodiments, R″ is halogen, hydroxy, cyano, amino, oxo, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, -S-(C 1 ~C 6 Alkyl), -SO 2 -(C 1 ~C 6 alkyl), -COO-(C 1 ~C 6 alkyl), -COOH, -CONH 2 , -(CH 2 ) p -NH 2 , -(CH 2 ) p -NH-(C 1 ~C 6 alkyl), -(CH 2 ) p -N(C 1 ~C 6 Alkyl) 2 , -(CH 2 ) p -NH-COO-(C 1 ~C 6 alkyl), -(CH 2 ) p -3-5 membered heterocycloalkyl containing one heteroatom selected from -OH, N, O and S; C 3 ~C 5 Cycloalkyl, and -(CH 2 ) p -(C 3 ~C 5cycloalkyl). 1 ~C 6 Alkyl and C 1 ~C 6 The alkoxy may be optionally substituted with one or more halogen, hydroxy, cyano or amino, and is selected from the group consisting of 3-5 membered heterocycloalkyl and C 3 ~C 5 The cycloalkyl may be optionally substituted with one or more halogen, hydroxy, cyano, oxo or amino.

[0062] In one embodiment, R″ is halogen, hydroxy, cyano, amino, oxo, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkoxy, -(CH 2 ) p -NH 2 , -(CH 2 ) p -NH-(C 1 ~C 6 alkyl), -(CH 2 ) p -N(C 1 ~C 6 Alkyl) 2 azetidinyl or oxetanyl optionally substituted with hydroxy or oxo; and cyclopropyl or cyclopropylmethyl optionally substituted with hydroxy or oxo.

[0063] In some embodiments, R 4 is hydrogen or C 1 ~C 3 It can be alkyl.

[0064] In some embodiments, R 8 teeth, [ka] Z may be -(CH 2 ) s R may be 8’ is hydroxy or C 1 ~C 6 In this case, s can be an integer of 0 or 1.

[0065] In one embodiment, l, m, and n may each independently be an integer of 1 or 2. In one embodiment, o and p may each independently be an integer from 0 to 2. In one embodiment, q and r may each independently be an integer of 1 or 2. In one embodiment, s may be an integer of 0 or 1.

[0066] In some embodiments, the compound having formula IB-1 above can be represented by formula IB-5, IB-6, IB-7, or IB-8: [ka] In the formula, R 1 ,W.,C.Y.,R. a , R 4 and R 8 is as defined in formula IB-1.

[0067] In one embodiment, the compound of formula I of the present invention may be a compound selected from the group consisting of the following compounds: [ka] JPEG2025508381000038.jpg150149 JPEG2025508381000039.jpg134149 JPEG2025508381000040.jpg140149 JPEG2025508381000041.jpg151149 JPEG2025508381000042.jpg187147 JPEG2025508381000043.jpg73149 JPEG2025508381000044.jpg125147

[0068] In one embodiment, the compound of formula I of the present invention may be a compound selected from the group consisting of the following compounds: [ka]

[0069] definition All technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art, and unless otherwise noted, conventional measurements, manufacturing methods, conventional components or substances are used in accordance with conventional techniques, e.g., pharmacology, pharmaceutical chemistry, mass spectrometry, NMR, HPLC, biochemistry, and the like.

[0070] Unless otherwise indicated, in this disclosure and the appended claims, "or" and "and" mean "and / or." The terms "include" and "included" are open-ended and mean that the compounds, compositions or methods may include additional features or components in addition to the recited features or components.

[0071] The term "" shown at the end of the linking group of the residue in this specification * " indicates the position where the linking group of the residue is attached to the remainder of the compound.

[0072] In the present disclosure, the term "halogen" can be F, Cl, Br or I.

[0073] In this disclosure, unless otherwise stated, the term "alkyl" refers to a straight or branched chain hydrocarbon residue which may be unsubstituted or substituted. 1 ~C 15 Alkyl, C 1 ~C 12 Alkyl, C 1 ~C 9Alkyl, C 1 ~C 6 Alkyl or C 1 ~C 3 Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 3-methylbut-1-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethyleth-1-yl, n-hexyl, n-heptyl and n-octyl, and all possible isomers thereof.

[0074] In this disclosure, unless otherwise stated, the term "alkoxy" refers to an optionally unsubstituted or substituted straight or branched chain hydrocarbon residue linked with an oxygen. Alkoxy can include, but is not limited to, methoxy, ethoxy, propoxy and butoxy, or all possible isomers thereof, such as isopropoxy, isobutoxy and t-butoxy.

[0075] As used herein, the term "cycloalkyl" refers to a saturated hydrocarbon ring having a specified number of carbon atoms as ring members (i.e., C 3 ~C 8 Cycloalkyl refers to a cycloalkyl group having 3, 4, 5, 6, 7 or 8 carbon atoms as ring members. 3 ~C 15 Cycloalkyl, C 3 ~C 13 Cycloalkyl, C 3 ~C 11 Cycloalkyl, C 3 ~C 8 Cycloalkyl, C 3 ~C 6 Cycloalkyl or C 3 ~C 5 It may be a cycloalkyl, and cycloalkyls having multiple cyclic hydrocarbon rings may have two or more cycloalkyls that are bridged or fused.

[0076] In this disclosure, the term "cycloalkenyl" refers to a non-aromatic unsaturated monocyclic or polycyclic hydrocarbon ring having at least one carbon-carbon double bond and containing the specified number of carbon atoms. For example, cycloalkenyl includes, but is not limited to, cyclopent-1-en-1-yl, cyclohex-1-en-1-yl, cyclohexa-1,3-dien-1-yl, and the like.

[0077] In this disclosure, the term "hydroxyl" refers to an --OH group.

[0078] In this disclosure, the term "oxo" refers to a substituent having the structure =O, in which there is a double bond between the atom and the oxygen atom.

[0079] In the present disclosure, the term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom is replaced by a halogen atom. In some embodiments, one, two or three hydrogen atoms of the alkyl hydrogen atom may be replaced by a halogen atom. In one embodiment, the hydrogen atoms may be replaced by the same halogen atom (e.g., fluoro) or a combination of different halogen atoms (e.g., fluoro and chloro).

[0080] In the present disclosure, the term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom is replaced by a halogen atom, and the description of "haloalkyl" above also applies to "haloalkoxy".

[0081] In the present disclosure, the term "aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon group. Aryl has alternating (resonating) double bonds between adjacent carbon atoms and can include two or more rings that are simply bonded (side chains) or fused together. Aryl includes, for example, C 6 ~C 14 Aryl, C 6 ~C 10 Aryl or C 6 ~C 9It may be aryl, and examples thereof include, but are not limited to, phenyl, biphenyl, naphthyl, toluyl, naphthalenyl, anthracenyl, or all possible isomers thereof. In the present disclosure, the term "heteroaryl" refers to a heterocyclic aromatic group containing at least one heteroatom selected from B, N, O, S, P(=O), Si, and P as a ring-forming atom. Heteroaryl can also include forms in which two or more rings are simply bonded to each other (side chains) or fused.

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

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

[0084] In this disclosure, unless otherwise stated, the term "heterocycloalkyl" 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 the specified number of ring members (i.e., a 3- to 7-membered heterocycloalkyl refers to a heterocycloalkyl group having 3, 4, 5, 6, or 7 ring members, including heteroatoms). A polycyclic heterocycloalkyl can have two or more heterocycloalkyls that are bridged or fused.

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

[0086] For example, heterocycloalkyl groups include aziridinyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrrolinyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothiophenyl, tetrahydrothiophenyl, sulfolanyl, dioxolanyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, thiazolinyl, thiazolidinyl, isothiazolinyl, isothiazolidinyl, oxazolinyl, oxazolidinyl, isoxazolinyl, isoxazolidinyl, triazolinyl, triazolidinyl, tetrazolinyl, tetrazolidinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrothiopyranyl, dihydrothiopyranyl, dioxanyl, tetrahydrotriazinyl, hexahydrotriazinyl, morpholinyl, thiomorpholinyl, piperidinyl, dihydropyridinyl, Tetrahydropyridinyl, piperazinyl, tetrahydropyrimidinyl, dihydropyrimidinyl, dihydropyridazinyl, tetrahydropyridazinyl, tetrahydrooxazinyl, hexahydroazepinyl, perhydroazepinyl, perhydrooxepinyl, indolinyl, isoindolinyl, dihydrobenzimidazolyl, dihydrobenzofuranyl, dihydrobenzoxazolyl, dihydrobenzothiazolyl, chromanyl, iso These include, but are not limited to, chromanyl, azabicyclo[2.2.1]heptanyl, 3-azabicyclo[3.2.1]heptanyl, 7-azabicyclo[4.1.0]-heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, tropanyl, 2-oxa-6-azaspiro[3.3]heptanyl, and their N-oxides, sulfones, or sulfoxides.

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

[0088] In this disclosure, the term "substituted" refers to a group in which one or more hydrogen atoms are replaced with one or more non-hydrogen atom groups, provided that valence requirements are met and that a chemically stable compound is produced by the substitution. In this disclosure, unless expressly described as "unsubstituted", all substituents should be interpreted as being unsubstituted or substituted. The "optionally substituted" moieties described herein are not limited to specific substituents, but include unsubstituted moieties or moieties substituted with any substituent, such as halogen, hydroxy, cyano, amino, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, -NH-(C 1 ~C 6 alkyl), -N(C 1 ~C 6 Alkyl) 2 , C 3 ~C 8 Cycloalkyl, C 6 ~C 14 In one embodiment, the "optionally substituted" moiety includes any of the following: halogen, hydroxy, cyano, amino, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, -NH-(C 1 ~C 6 alkyl) or -N(C 1 ~C 6 Alkyl) 2 Examples of the moiety include those substituted with

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

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

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

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

[0093] In some embodiments, the compounds of the invention may be in the form of a racemate, a single enantiomer, a mixture of enantiomers, a single diastereomer, a mixture of diastereomers, etc., which contain one or more asymmetric centers. In some embodiments, due to the nature of limited rotation or asymmetric centers, the compounds of the invention may be in the form of an enantiomer or diastereomer.

[0094] In cases where two or more asymmetric centers are present in the compounds herein, several diastereomers and enantiomers may exist with the chemical structures disclosed herein, and all pure isomers, separate isomers, partially pure isomers, racemic mixtures, and the like are intended to be within the scope of the present invention.

[0095] The purification of isomers and the separation of isomeric mixtures can be achieved by standard techniques known in the art: for example, diastereomeric mixtures can be separated into the corresponding diastereomers by chromatographic processes or crystallization, and racemates can be separated into the corresponding enantiomers by resolution using chiral phases or by chromatographic processes.

[0096] Additionally, when compounds of the invention contain groups capable of tautomerization, all tautomeric forms are included within the scope of the invention, for example 2-hydroxypyridine may include 2-pyridone, and all such isomeric forms are included within the invention.

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

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

[0099] In addition, the compounds of the present invention can be used in the form of pharma- ceutically acceptable salts derived from inorganic or organic acids, for example, the salts can be salts derived from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, hydroxymaleic acid, benzoic acid, hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, and the like.

[0100] Pharmaceutically acceptable salts of the compounds can be prepared, for example, by dissolving the compound of formula I in a water-miscible organic solvent, such as acetone, methanol, ethanol, acetonitrile, and the like, and adding an excess of an organic acid or an aqueous acid solution of an inorganic acid, followed by precipitation or crystallization, followed by subsequent evaporation of the solvent or excess acid from the mixture, followed by drying to obtain the addition salt, or suction filtration of the precipitated salt.

[0101] On the one hand, the acid addition salt forms of the present invention can be readily converted into the free base form by treatment with an appropriate base, and the base addition salt forms can be readily converted into the free acid form by treatment with an appropriate acid.

[0102] General preparation of compounds Alternatively, the compounds can be prepared via chemical modifications familiar to those skilled in the art of organic / pharmaceutical chemistry, as representatively illustrated below.

[0103] The following general reaction scheme is a general illustration of a representative preparation method of the compound of formula I. Those skilled in the art can easily prepare the compound of formula I by appropriately selecting starting materials, reaction temperatures, reaction conditions, catalysts, solvents, processing methods, etc. suitable for the desired compound based on the preparation methods specifically disclosed in the examples of this specification.

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

[0105] For example, compounds of formula I having a 4H-thieno[3,2-b]pyrrole fused ring can be prepared according to Reaction Scheme 6 below. [ka]

[0106] In preparing compounds according to Reaction Schemes 1-6 above, compounds in which various ring structures are attached to the amide bond can be prepared using the appropriate amino-cycloalkyl-carboxylate compound, e.g., methyl 3-aminocyclobutane-1-carboxylate, methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate, methyl 4-aminobicyclo[1.1.1]octane-1-carboxylate, etc., in place of methyl 3-aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride. The compounds of the present invention, solvates, stereoisomers or pharma- ceutically acceptable salts thereof exhibit tumor growth inhibitory effects.

[0107] In one embodiment of the invention, administration of the compounds to mouse-derived colon and lung cancer tumor models resulted in inhibition of tumor growth compared to controls.

[0108] Anticancer drugs The anti-cancer agent of the present invention may be selected from the group consisting of chemotherapeutic agents, targeted anti-cancer agents, oncolytic viruses, antibody therapeutic agents, cell therapeutic agents, immune checkpoint inhibitors, and combinations thereof.

[0109] As used herein, the term "chemotherapeutic agent" is also referred to as antineoplastic agent or cytotoxic agent. It is a general term for drugs that exhibit anti-cancer activity mainly by acting directly on DNA to block DNA replication, transcription and translation processes, or by interfering with the synthesis of nucleic acid precursors in metabolic pathways and inhibiting cell division. Anti-tumor drugs exhibit cytotoxicity by acting on normal cells as well as tumor cells. Chemotherapeutic agents can be used for maintenance therapy. In addition, as used herein, the term "maintenance therapy" refers to the treatment of cancer with drugs after initial anti-cancer treatment, and refers to a treatment method carried out to prevent or delay the recurrence of cancer.

[0110] Specifically, the chemotherapeutic agent may be any one selected from the group consisting of alkylating agents, microtubule inhibitors, metabolic antagonists, and topoisomerase inhibitors. The alkylating agent may be any one selected from the group consisting of mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, thiotepa, altretamine, procarbazine, busulfan, streptozotocin, carmustine, lomustine, dacarbazine, cisplatin, carboplatin, and oxaliplatin. The microtubule inhibitor may be any one selected from the group consisting of docetaxel, paclitaxel, velban, oncovin, and navelbine. The antimetabolite may be any one selected from the group consisting of fluorouracil, capecitabine, cytarabine, gemcitabine, fludarabine, methotrexate, pemetrexed, and mercaptopurine. The topoisomerase inhibitor may be any one selected from the group consisting of hycamtin, camptosar, vepesid, blenoxane, adriamycin, and cerubidine.

[0111] As used herein, the term "targeted anticancer drug" refers to a therapeutic agent that specifically kills cancer cells by targeting specific proteins or specific genetic changes that appear only in cancer cells and blocking signals involved in the growth and development of cancer. They are classified into monoclonal antibodies that react outside the cell and small molecule substances that act inside the cell. Monoclonal antibodies are anticancer drugs that block cancer cell-inducing signals transmitted to the outside of the cell and act on initiating signals related to amplification, death, etc., while small molecule substances act on complex signal transduction that occurs inside the cell.

[0112] Specifically, the targeted proteins can be EGFR, VEGFR, CD20, CD38, RNAK-L, BTK, Bcr-abl, PDGFR / FGFR family, MEK / RAF / KRAS, HER2 / Neu, ubiquitin, JAK, ALK, PARP, TGFβRI, proteasome, Bcl-2, C-Met, VR1, VR2, VR3, c-kit, AXL, RET, Braf, DNMT, CDK4 / 6, STING, and the like.

[0113] Targeted anticancer drugs include cetuximab, trastuzumab, pertuzumab, gefitinib, erlotinib, osimertinib, panitumumab, axitinib, lenvatinib, bevacizumab, ramucirumab, aflibercept, rituximab, obinutuzumab, daratumumab, denosumab, ibrutinib, dasatinib, nilotinib, imatinib, bosutinib, galunisertib, bactosertib, nintedanib, sunitinib, sorafenib, cabozantinib, regorafenib, masitinib, semaxanib, tivozanib, vandetanib, pazopanib, trametinib, dabrafenib, and sorafenib. It may be any one selected from the group consisting of trastuzumab, afatinib, lapatinib, neratinib, lenalidomide, ixazomib, ruxolitinib, lestaurtinib, pacritinib, cobimetinib, selumetinib, binimetinib, alectinib, crizotinib, venetoclax, bemcentinib, gilteritinib, selpercatinib, pralsetinib, vemurafenib, olaparib, talazoparib, niraparib, rucaparib, azacitidine, decitabine, guadecitabine, abemaciclib, ribociclib, palbociclib, CDN, SB11285, and DMXAA.

[0114] As used herein, the term "epidermal growth factor receptor (EGFR)" refers to a cell membrane receptor that controls cell growth, division, survival and death, and expression of EGFR is increased in tumor tissues of various cancers. Tumor tissues with increased EGFR are known to have high invasiveness, metastasis and resistance to anticancer drugs. An EGFR inhibitor is a substance that inhibits EGFR, and in one embodiment, may be cetuximab, trastuzumab, pertuzumab, gefitinib, erlotinib, osimertinib or panitumumab.

[0115] As used herein, the term "vascular endothelial growth factor receptor (VEGFR)" refers to a cell membrane receptor for vascular endothelial growth factor that induces angiogenesis, and a VEGFR inhibitor inhibits angiogenesis and inhibits tumor growth and metastasis. In one embodiment, the VEGF inhibitor or VEGFR inhibitor can be axitinib, lenvatinib, bevacizumab, ramucirumab, or aflibercept.

[0116] As used herein, the term "CD20 (B-lymphocyte antigen CD20)" is a protein expressed on the surface of B cells and is used as a target protein for the treatment of B-cell lymphoma. The inhibitor targeting CD20 can be rituximab or obinutuzumab.

[0117] As used herein, the term "CD38 (cluster of differentiation 38)" is a protein that controls cell proliferation and death and also acts as a signaling receptor in immune cells, and an inhibitor that targets this protein is daratumumab.

[0118] As used herein, the term "RANK-L (receptor activator of nuclear factor kappa B ligand)" refers to the RANK receptor expressed on the cell surface of osteoclasts, which acts to cause bone destruction when it binds to and is activated by a ligand. RANK-L inhibitors are primarily used in cancer patients suffering from bone metastasis or osteoporosis, and may specifically be denosumab.

[0119] As used herein, the term "BTK (Bruton's tyrosine kinase)" is an enzyme involved in B-cell proliferation, which, when overexpressed, can lead to hematological cancers. In one embodiment, an inhibitor targeting BTK can be ibrutinib.

[0120] As used herein, the term "Bcr-abl" is a fusion protein that is highly expressed in patients with chronic myeloid leukemia and is known to induce abnormal proliferation of blood cells. Specifically, the inhibitor of this protein can be dasatinib, nilotinib, imatinib, or bosutinib.

[0121] As used herein, the term "transgenic growth factor beta receptor (TGFβR)" refers to a cell membrane receptor for a tumor growth factor, which controls the growth, migration, differentiation, death, etc. of epithelial and hematopoietic cells. Inhibitors targeting TGFβR can be, but are not limited to, galunisertib or bactosertib.

[0122] As used herein, the term "PDGFR (platelet-derived growth factor receptor)" is a cell membrane receptor for PDGF that is frequently expressed in cancer cells and is involved in angiogenesis, controlling cancer growth, metastasis and drug resistance. FGFR (fibroblast growth factor receptor) is a receptor for fibroblast growth factor (FGF) and controls various biological processes including cell growth, differentiation, migration, etc. FGFR genes are frequently mutated, and these mutations are commonly observed in breast cancer, uterine cancer, ovarian cancer, cervical cancer, etc. Inhibitors targeting PDGFR or FGFR can be nintedanib, sunitinib, sorafenib, cabozantinib, lenvatinib, regorafenib, masitinib, semaxanib, tivozanib, vandetanib, axitinib or pazopanib.

[0123] As used herein, the term "MEK / RAF / KRAS" refers to an intracellular signaling mediator involved in cell proliferation, cell cycle control, cell survival, angiogenesis, cell migration, etc., and is overactivated in cancer cells. The inhibitor targeting MEK / RAF / KRAS may be trametinib, dabrafenib, or sotrasib.

[0124] As used herein, the term "HER-2 / neu (human epidermal growth factor receptor 2)" controls cell proliferation by activating PI3K / AkT. It is known to be overexpressed in metastatic breast cancer and ovarian cancer, and to induce resistance to anticancer drugs. Anticancer drugs that target Her2 / neu may be trastuzumab, afatinib, lapatinib, or neratinib.

[0125] As used herein, the term "ubiquitin" maintains cellular homeostasis by binding to other proteins and inducing protein degradation by the proteasome, a proteolytic enzyme (ubiquitin-proteasome system, UPS). Abnormal expression or activity of the UPS is observed in various tumors, and UPS inhibitors exhibit anticancer activity. Specifically, inhibitors targeting ubiquitin or proteasomes may be lenalidomide or ixazomib.

[0126] As used herein, the term "JAK (Janus kinase)" refers to an upstream protein of STAT, a transcription factor that controls cell proliferation, cell survival, cell migration and immune response, and JAK inhibitors are known to reduce cell proliferation and induce cell death through inhibition of STAT activity. The inhibitor targeting JAK can be ruxolitinib, lestaurtinib or pacritinib.

[0127] As used herein, the term "MAP2K (mitogen-activated protein kinase kinase)" refers to an intracellular signal transduction mediator involved in cell proliferation, cell cycle control, cell survival, angiogenesis, cell migration, etc., through phosphorylation of MAPK, which is overactivated in cancer cells. The inhibitor targeting MAP2K may be cobimetinib, selumetinib, trametinib, or binimetinib.

[0128] As used herein, the term "ALK (anaplastic lymphoma kinase)" is a signal transduction mediator that promotes cell proliferation, cell migration and angiogenesis, inhibits cell death, and is overactivated in various cancer tissues. An inhibitor that targets ALK can be alectinib or crizotinib.

[0129] As used herein, the term "Bcl-2" refers to a protein that inhibits cell death and is overexpressed or overactivated in various cancer tissues. An inhibitor that targets Bcl-2 can be venetoclax.

[0130] As used herein, the term "C-Met" is a receptor for hepatocyte growth factor (HGF) and activates signal transduction associated with cell growth, formation, motility, survival, angiogenesis, etc. An anti-cancer drug targeting C-Met can be crizotinib or cabozantinib.

[0131] As used herein, the term "VR (vanilloid receptor)" is also known as TRPV (transient receptor potential vanilloid) and exists in any of the forms VR1, VR2, VR3, VR4, VR5 and VR6. VR is known to control the proliferation, death, migration, invasion and angiogenesis of cancer cells at each stage of the cancer progression process.

[0132] As used herein, the term "c-kit", also known as CD117, induces signal transduction that activates cell survival, proliferation and division. c-kit is a proto-oncogene, and overexpression or mutation of this gene is associated with cancer development.

[0133] As used herein, the term "AXL (tyrosine protein kinase receptor UFO)" refers to a tyrosine kinase receptor present on the cell surface that mediates signal transduction involved in cell proliferation and survival. It is known to be involved in resistance to anticancer drugs in anticancer treatment. In one embodiment, the inhibitor targeting AXL can be bemcentinib or gilteritinib.

[0134] As used herein, the term "RET (rearragned upon transfection)" refers to a receptor that mediates signals involved in cell proliferation, cell death and survival, and mutations in RET are known to be involved in the development of cancer. RET-targeting inhibitors can be, but are not limited to, selpercatinib or pralsetinib.

[0135] As used herein, the term "Braf" refers to a MAPK signal transduction mediator involved in cell proliferation, cell cycle control, cell survival, angiogenesis, cell migration, etc., and its genetic mutation is observed in cancer cells. The inhibitor targeting Braf may be vemurafenib.

[0136] As used herein, the term "PARP (poly [ADP ribose] polymerase)" refers to a protein that is activated by recognition of damaged DNA in the nucleus, and then activates DEN repair-related proteins. PARP-targeting inhibitors inhibit DNA repair in cancer cells, thereby inhibiting the proliferation of cancer cells. In one embodiment, the PARP-targeting inhibitor can be olaparib, talazoparib, niraparib, or rucaparib.

[0137] As used herein, the term "DNA methyltransferase (DNMT)" refers to an enzyme that binds methyl groups to histone proteins wrapped around DNA, and through this process, gene expression is inhibited. Inhibitors that target DMMT exhibit anticancer activity by inhibiting hypermethylation of tumor suppressor genes and inducing normal expression of tumor suppressor genes. In one embodiment, the inhibitor that targets DNMT may be azacytidine, decitabine, or guadecitabine.

[0138] As used herein, the term "CDK (cyclin-dependent kinase) 4 / 6" refers to a protein that promotes cell growth by controlling the cell cycle and is overactivated during the development and progression of various malignant tumors. Inhibitors that target CDK4 / 6 exhibit anticancer activity by inhibiting the cell cycle of cancer cells, inhibiting cell proliferation, and inducing cell death. The inhibitors that target CDK4 / 6 can be abemaciclib, ribociclib, or palbociclib.

[0139] As used herein, the term "STING (Stimulator of Interferon Genes)" refers to an in vivo sensor that recognizes DNA fragments in cancer cells and activates immune cells in the body, such as dendritic cells, by stimulating interferon genes. STING agonists exhibit immune enhancing effects and cancer angiogenesis inhibitory effects. For example, STING agonists can be CDN, SB11285, DMXAA, etc.

[0140] As used herein, the term "oncolytic viral therapy" refers to a therapy that kills cancer by inserting a specific gene that targets cancer cells into a virus capable of replicating and infecting the virus. The oncolytic viral therapy may be talimogene laherparepvec.

[0141] As used herein, the term "antibody therapeutic agent" refers to a therapeutic agent that uses an antibody that recognizes a specific protein of a cancer cell as an antigen to exert an anti-cancer effect. The antibody therapeutic agent may be cetuximab, trastuzumab, emtansine, emtansine, rituximab, ibritumomab, tositumomab, brentuximab, ofatumumab, obinutuzumab, necitumumab, bevacizumab, ramucirumab, nivolumab, pembrolizumab, atezolizumab, durvalumab, ipilimumab, etc.

[0142] As used herein, the term "immune cell therapy" refers to a therapeutic agent that exhibits an anti-cancer effect by activating immune responses in the body using immune cells, such as dendritic cells, natural killer cells, T cells, etc. Immune cell therapy agents are used by extracting immune cells in the body, enhancing or genetically modifying them, and then returning them to the body by injection. Representative immune cell therapy agents can include T cell receptor modified T cells (TCR-T), chimeric antigen receptor modified T cells (CAR-T), etc. Specifically, they can be, but are not limited to, tisagenlecleucel or axicabutagenciloleucel.

[0143] As used herein, the term "immune checkpoint inhibitor" refers to a substance that inhibits the activity of immune checkpoint proteins that inhibit the differentiation, proliferation, and activity of immune cells, and is known to eliminate cancer cells by preventing them from exerting functions that allow them to escape the immune system. The immune checkpoint inhibitor may be any one selected from the group consisting of anti-CTLA-4 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-B7-H4 antibody, anti-HVEM antibody, anti-TIM3 antibody, anti-GAL9 antibody, anti-LAG3 antibody, anti-VISTA antibody, anti-KIR antibody, anti-BTLA antibody, and anti-TIGIT antibody. In one embodiment, the immune checkpoint inhibitor may be, but is not limited to, ipilimumab, pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, and durvalumab.

[0144] As used herein, the term "ADC (antibody drug conjugate)" refers to a therapeutic agent that exhibits high anti-cancer effects through targeted delivery by chemical conjugation of an antibody and a cytotoxic drug, such as gemtuzumab ozogamicin, brentuximab vedotin, trastuzumab emtansine, inotuzumab ozogamicin, and eribulin mesylate.

[0145] The anticancer agent may include one or more anticancer agents. Specifically, a compound, its solvate, stereoisomer or pharma- ceutically acceptable salt may be used together with two anticancer agents. For example, the two anticancer agents may be a chemotherapeutic agent and a targeted anticancer agent, a chemotherapeutic agent and an oncolytic virus, a targeted anticancer agent and an antibody therapeutic agent, a chemotherapeutic agent and a cell therapeutic agent, or a chemotherapeutic agent and an immune checkpoint inhibitor. In addition, the two anticancer agents may be a targeted anticancer agent and an oncolytic virus, a targeted anticancer agent and an antibody therapeutic agent, a targeted anticancer agent and a cell therapeutic agent, or a targeted anticancer agent and an immune checkpoint inhibitor. In addition, the two anticancer agents may be an oncolytic virus and an antibody therapeutic agent, an oncolytic virus and a cell therapeutic agent, and an oncolytic virus and an immune checkpoint inhibitor. In addition, the two anticancer agents may be an antibody therapeutic agent and a cell therapeutic agent, or an antibody therapeutic agent and an immune checkpoint inhibitor.

[0146] The compound, its solvates, stereoisomers or pharma- ceutically acceptable salts may be used together with three anti-cancer drugs. In addition to the two anti-cancer drugs, a different anti-cancer drug may also be included and used.

[0147] In one embodiment, the compound, its solvates, stereoisomers, or pharma- ceutically acceptable salts may be used together with two or more chemotherapeutic agents and an immune checkpoint inhibitor, for example, the two or more chemotherapeutic agents may include an alkylating agent and an antimetabolite.

[0148] The compound, its solvates, stereoisomers or pharma- ceutically acceptable salts may be used together with four anti-cancer drugs. In addition to the three anti-cancer drugs, a different anti-cancer drug may also be included and used.

[0149] The compound, its solvates, stereoisomers or pharma- ceutically acceptable salts may be used together with up to five anti-cancer drugs. In addition to the four anti-cancer drugs, different anti-cancer drugs may also be included and used.

[0150] The compound, a solvate, stereoisomer or a pharma- ceutically acceptable salt thereof may be used together with six anti-cancer agents.

[0151] The compounds, solvates, stereoisomers or pharma- ceutically acceptable salts thereof may be used in combination with anti-cancer vaccines.

[0152] As used herein, the term "anti-cancer vaccine" refers to an active immunotherapy that enhances immune function in vivo by administering tumor-specific antigens (TSA) contained in cancer cells to cancer patients to activate the immune system and eliminate cancer cells. Anti-cancer vaccines can include DNA vaccines, peptide vaccines, cellular vaccines, etc., depending on the type of antigen and the method of antigen delivery, and cellular vaccines and DNA vaccines developed by introducing antigens are currently being developed as representatives.

[0153] The compounds, solvates, stereoisomers or pharma- ceutically acceptable salts thereof may be used in combination with anti-cancer agents and anti-cancer vaccines, where the compounds and anti-cancer agents are the same as those described above.

[0154] Pharmaceutical uses, pharmaceutical compositions, and methods of administration The cancer may be, but is not limited to, squamous cell carcinoma, basal cell carcinoma, glioblastoma, bone cancer, stomach cancer, kidney cancer, lung cancer, bladder cancer, prostate cancer, breast cancer, prostate cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, head and neck cancer, renal cell carcinoma, esophageal cancer, pancreatic cancer, brain cancer, gastrointestinal cancer, liver cancer, leukemia, lymphoma, melanoma, multiple myeloma, osteosarcoma, colorectal cancer, cholangiocarcinoma, choriocarcinoma, oral cancer, neuroblastoma, skin cancer, testicular cancer, stromal tumor, germ cell tumor, or thyroid cancer.

[0155] Here, prostaglandin E 2 Overexpression of and / or prostaglandin E 2 Diseases associated with overexpression of the receptor, such as cancer, are characterized by the prostaglandin E 2 and / or prostaglandin E 2 It can be caused by overexpression or overactivation of the receptor.

[0156] In this disclosure, the term "prevent" or "prevention" refers to preventing a disease, e.g., preventing a disease, condition, or disorder in a subject who may be susceptible to the disease, condition, or disorder, but who has not yet experienced or exhibited symptoms or symptoms of the disease.

[0157] In this disclosure, the term "treat" or "treatment" refers to inhibiting a disease, e.g., inhibiting a disease, condition or disorder in a subject experiencing or exhibiting symptoms or symptoms of the disease, condition or disorder, i.e., preventing further occurrence of the symptoms and / or symptoms, or ameliorating a disease, e.g., ameliorating a disease, condition or disorder in a subject experiencing or exhibiting symptoms or symptoms of the disease, condition or disorder, i.e., reversing the symptoms and / or symptoms, e.g., reducing the severity of the disease.

[0158] According to one embodiment, the compound represented by formula I, IA-1, IA-2, IA-3, IA-4, IB-1, IB-2, IB-3, IB-4, IB-5, IB-6, IB-7 or IB-8 is a prostaglandin E 2 Receptors, e.g. EP 2 and / or EP 4 As described above, it exhibits effective inhibitory activity against prostaglandin E 2 Through antagonistic action on the receptors, prostaglandin E 2 Therapeutic effects can be achieved by controlling the activity of

[0159] According to one experimental example of the present invention, when a compound and an anti-PD-1 antibody were administered in combination to a tumor animal model in which mouse-derived colorectal cancer was transplanted, an enhanced anti-cancer effect was observed compared to administration of the compound or the anti-PD-1 antibody alone.

[0160] In addition, according to one experimental example of the present invention, when the compound, a chemotherapeutic agent and an anti-PD-1 antibody were administered in combination to a tumor animal model transplanted with mouse-derived lung cancer, an enhanced anti-cancer effect was observed compared to the standard treatment of administering a combination of a chemotherapeutic agent and an anti-PD-1 antibody.

[0161] Thus, a pharmaceutical composition comprising a compound represented by formula I, IA-1, IA-2, IA-3, IA-4, IB-1, IB-2, IB-3, IB-4, IB-5, IB-6, IB-7 or IB-8, a solvate, stereoisomer or a pharma- ceutically acceptable salt thereof and an anticancer agent as an active ingredient can be used for the treatment of cancer.

[0162] In one embodiment, the pharmaceutical composition may contain conventional pharma- ceutically acceptable carriers, excipients or additives.The pharmaceutical composition may be formulated according to conventional methods and may be prepared in various oral dosage forms, such as tablets, pills, powders, capsules, syrups, emulsions, microemulsions, or parenteral dosage forms, such as intramuscular, intravenous or subcutaneous dosage forms.

[0163] When the pharmaceutical composition is prepared in the form of an oral preparation, examples of the additives or carriers used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifying agents, diluents, etc. When the pharmaceutical composition of the present invention is prepared in the form of an injection, examples of the additives or carriers include water, saline, aqueous glucose solution, similar aqueous sugar solution, alcohol, glycol, ether (e.g., polyethylene glycol 400), oil, fatty acid, fatty acid ester, glyceride, surfactant, suspending agent, emulsifying agent, etc.

[0164] The dosage of the pharmaceutical composition is an amount effective for the treatment or prevention of a subject or patient, and may be administered orally or parenterally as desired. When administered orally, the amount may be 0.01 to 1000 mg, more specifically 0.1 to 300 mg, per kg of body weight based on the active ingredient, or when administered parenterally, the amount may be 0.01 to 100 mg, more specifically 0.1 to 50 mg, per kg of body weight based on the active ingredient, administered once or in several divided doses. It should be understood that the dosage administered to a particular subject or patient should be determined taking into account several relevant factors, such as the patient's weight, age, sex, health condition, diet, administration time, administration method, severity of disease, etc., and may be appropriately increased or decreased by a specialist. The dosages described above are not intended to limit the scope of the present invention in any way. A physician or veterinarian of ordinary skill in the art can easily determine and prescribe the required effective amount of the pharmaceutical composition. For example, dosages of the compounds of the invention employed in pharmaceutical compositions by the physician or veterinarian may be started at levels lower than those required to achieve the desired therapeutic effect and may be gradually increased until the desired effect is achieved.

[0165] In one embodiment, pharmaceutical compositions include within their scope pharmaceutical compositions that contain as an active ingredient a therapeutically effective amount of at least one of the compounds according to one embodiment, alone or in combination with a pharmaceutical carrier. The term "therapeutically effective amount" or "effective amount" refers to an amount sufficient to produce a beneficial or desired clinical result, e.g., an amount sufficient to alleviate, ameliorate, stabilize, reverse, slow or delay the progression of a disease.

[0166] Optionally, the compound according to an embodiment may be administered alone or in combination with other anti-cancer agents, either simultaneously, separately or sequentially.

[0167] In another aspect, a method for preventing or treating cancer is provided, comprising administering to a subject a pharmaceutical composition comprising a compound represented by formula i, IA-1, IA-2, IA-3, IA-4, IB-1, IB-2, IB-3, IB-4, IB-5, IB-6, IB-7 or IB-8, a solvate, a stereoisomer or a pharma- ceutically acceptable salt thereof and an anticancer agent as an active ingredient. Among the terms or elements described in the description of the method, those that are the same as those already described are as described above.

[0168] The administration can be oral or parenteral. When administered orally, the active ingredient can be administered in an amount of 0.01 to 1000 mg, more specifically 0.1 to 300 mg per kg of body weight per day, or when administered parenterally, the active ingredient can be administered in an amount of 0.01 to 100 mg, more specifically 0.1 to 50 mg per kg of body weight per day, which can be administered once or in several divided doses. The dose administered to a particular subject or patient should be determined taking into account several relevant factors, such as the patient's weight, age, sex, health condition, diet, administration time, administration method, severity of disease, etc., and can be appropriately increased or decreased by a specialist.

[0169] In this disclosure, the term "subject" refers to a subject in need of treatment or prevention of a disease, and more specifically means a mammal, such as a human or non-human primate, mouse, dog, cat, horse, and cow.

[0170] In another aspect, there is provided a use of a pharmaceutical composition comprising a compound represented by formula I, IA-1, IA-2, IA-3, IA-4, IB-1, IB-2, IB-3, IB-4, IB-5, IB-6, IB-7 or IB-8, a solvate, a stereoisomer or a pharma- ceutically acceptable salt thereof and an anticancer agent as an active ingredient for preventing or treating cancer. Among the terms or elements described in the description of the method or use, those that are the same as those already described are as described above.

[0171] In another aspect, there is provided a use of a pharmaceutical composition comprising a compound represented by formula I, IA-1, IA-2, IA-3, IA-4, IB-1, IB-2, IB-3, IB-4, IB-5, IB-6, IB-7 or IB-8, a solvate, a stereoisomer or a pharma- ceutically acceptable salt thereof and an anticancer agent as an active ingredient for the manufacture of a medicament for preventing or treating cancer. Among the terms or elements described in the description of the method or use, those that are the same as those already described are as described above.

[0172] kit In another aspect of the present invention, a kit for preventing or treating cancer is provided, which comprises a compound, a solvate, a stereoisomer, or a pharma- ceutically acceptable salt thereof, and an anticancer agent as active ingredients. Among the terms or elements described in the description of the kit, those that are the same as those already described are as described above.

[0173] The present invention will be described in detail below with reference to examples. However, the following examples are merely illustrative of the present invention, and the contents of the present invention are not limited to the following examples.

[0174] [Preparation Example] Preparation Example 1: Methyl 6-aminospiro[3.3]heptane-2-carboxylate hydrochloride [ka]

[0175] Methyl 6-((t-butoxycarbonyl)amino)spiro[3.3]heptane-2-carboxylate (10 g, 37.1 mmol) was added to a solution of 4N HCl in dioxane, stirred for 15 h, and then concentrated under reduced pressure. The resulting crude product was washed with diethyl ether (100 mL) and dried to give intermediate A (7.32 g, 96% yield) as a white solid. 1 H NMR (300Hz, DMSO-d 6 ) δ 8.09 (bs, 2H), 3.58 (s, 3H), 3.03 (p, J = 8.4 Hz, 1H), 2.43 - 2.31(m, 1H), 2.28 - 1.95 (m, 6H).

[0176] Preparation Example 2: Methyl 2-azidoacetate [ka]

[0177] A solution of methyl 2-bromoacetate (7.65 g, 50.0 mmol) in DMSO (0.5 M) was added to NaN 3 (4.88 g, 75.0 mmol) was added and stirred for 24 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with distilled water. The organic layer was extracted with Na 2 SO 4 The mixture was dried at rt and then concentrated under reduced pressure to give Intermediate B (4.09 g, 75% yield) as a colorless liquid. 1 H NMR (300MHz, chloroform-d) δ 3.91 (s, 2H), 3.83 (s, 3H).

[0178] Preparation Example 3: 3-Bromo-2,5-dimethylthiophene [ka]

[0179] To a solution of 2,5-dimethylthiophene (11.2 g, 100 mmol) in acetate (0.2 M) was added NBS (17.8 g, 100 mmol) and stirred for 15 h. The reaction mixture was concentrated, diluted with diethyl ether, and then washed with distilled water, sodium bicarbonate solution, and brine. The organic layer was extracted with Na 2 SO 4 The mixture was dried at rt 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) δ 6.60 - 6.56 (m, 1H), 2.42 (s, 3H),2.35 (s, 3H).

[0180] Preparation 4: Methyl 4-bromo-2,5-dimethylthiophene-3-carboxylate Step 1: Synthesis of 3,4-dibromo-2,5-dimethylthiophene [ka]

[0181] To a solution of tetrabromothiophene (8.0 g, 20.0 mmol, 1.0 equiv) in THF (60 mL, 0.3 M) was added n-BuLi (2.0 M in cyclohexane, 25.0 mL, 50.0 mmol, 2.5 equiv) at −78° C. and stirred at −78° C. for 1 h. Iodomethane (3.8 mL, 60.0 mmol, 3.0 equiv) was added and then stirred at ambient temperature for 20 h. The reaction mixture was diluted with saturated NH 4 The mixture was added to Cl and extracted with EtOAc. The organic layer was washed with MgSO 4 The mixture was dried at 40° C. 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).

[0182] Step 2: Synthesis of 4-bromo-2,5-dimethylthiophene-3-carboxylic acid [ka]

[0183] To a solution of 3,4-dibromo-2,5-dimethylthiophene (4.9 g, 18.1 mmol, 1.0 equiv.) in THF (60 mL) was added n-BuLi (2.0 M in cyclohexane, 8.2 mL, 0.9 equiv.) at −78° C. and stirred at −78° C. for 30 min. An excess of dry ice was added and then stirred at ambient temperature for 30 min. The reaction mixture was added to 1N NaOH and diluted with Et 2 The mixture was extracted with O and the aqueous layer was acidified with 1N HCl solution. The resulting precipitate was removed by filtration, washed with distilled water, and then dried to give 4-bromo-2,5-dimethylthiophene-3-carboxylic acid (3.3 g, 77% yield).

[0184] Step 3: Synthesis of methyl 4-bromo-2,5-dimethylthiophene-3-carboxylate [ka]

[0185] 4-Bromo-2,5-dimethylthiophene-3-carboxylic acid (2.64 g, 11.2 mmol, 1.0 equiv.) in DMF (15 mL) and K 2 CO 3 To a solution of (3.1 g, 22.4 mmol, 2.0 equiv.), iodomethane (1.4 mL, 22.4 mmol, 2.0 equiv.) was added and stirred for 12 h. The reaction mixture was added to distilled water and extracted with DCM. The organic layer was washed with MgSO 4 The mixture was dried at rt and then concentrated under reduced pressure. The crude product was purified by column chromatography to give intermediate D (2.55 g, 91% yield).

[0186] Preparation Example 5: 3-Fluoro-[1,1'-biphenyl]-4-carboxylic acid [ka]

[0187] To 1.0 g of phenylboronic acid (8.20 mmol, 1.0 equiv.) and 1.80 g of 4-bromo-2-fluoro-benzoic acid (8.20 mmol, 1.0 equiv.), 6.47 g of 26% Me 4 Aqueous N OH (18.45 mmol, 2.25 equiv.) was added and stirred at 50 °C. 25 mL of distilled water and 25 mg of 5% Pd / C (0.025 w / w) were added under Ar substitution and stirred at 80 °C for 1.5 h. The reaction mixture was cooled to ambient temperature and Pd / C was removed by filtration through Celite. 2.2 mL of 6 M aqueous HCl (13.12 mmol, 1.6 equiv.) was added to the reaction mixture for neutralization and crystallization, followed by addition of 10 mL of distilled water and stirring 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 (500 MHz, chloroform-d) δ 8.14 (t, J = 7.9 Hz, 1H), 7.65 (d, J =7.2 Hz, 2H), 7.54-7.49 (m, 3H), 7.48-7.41 (m, 2H). LC / MS (ESI) m / z: 217.2 [M+H] + .

[0188] Preparation 6: 2-Amino-[1,1'-biphenyl]-4-carbonyl chloride Step 1: Synthesis of 2-amino-[1,1'-biphenyl]-4-carboxylic acid [ka]

[0189] 3-Amino-4-bromobenzoic acid (5.0 g, 23.2 mmol), 5% Pd / C (255 mg, 0.45 mmol), K 2 CO 3(12.8 g, 92.6 mmol) and phenylboronic acid (3.2 g, 25.5 mmol) were added to a sealed tube. Distilled water (46 mL, 0.5 M) was added and stirred at 100° C. for 12 h. The reaction mixture was cooled to ambient temperature, filtered through a plug of Celite, and then washed with distilled water (2×20 mL). The solution was slowly acidified with 1N citric acid solution, and the precipitate was filtered and then dried to give intermediate F (3.5 g, 71% yield). 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.69 (s, 1H), 7.47 (d, J = 6.5 Hz, 4H), 7.41 - 7.34 (m, 2H), 7.21(dd, J = 7.9, 1.6 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 5.04 (s, 2H).

[0190] Step 2: Synthesis of 2-amino-[1,1'-biphenyl]-4-carbonyl chloride [ka]

[0191] 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) was added thionyl chloride (3.5 mL, 48.1 mmol) with stirring. The reaction mixture was stirred under reflux for 4 hours, then cooled to ambient temperature and concentrated under reduced pressure to give intermediate F (2.95 g).

[0192] Preparation 7: (2'-Methoxy-[1,1'-biphenyl]-4-yl)methanol Step 1: Synthesis of methyl 2'-methoxy-[1,1'-biphenyl]-4-carboxylate [ka]

[0193] 4-(Methoxycarbonylphenyl)boronic acid (1.08 g, 6 mmol), Na in a stirred solution of 2-bromoanisole (0.75 mL, 6 mmol) in toluene (0.6 M). 2 CO 3 (1.91 g, 18 mmol), Pd(OAc) 2 (0.269g, 1.2mmol) and PPh 3 (0.63 g, 2.4 mmol) was stirred at 100° C. for 6 h. The reaction mixture was extracted with ethyl acetate (20 mL×3), and the organic layer was washed with brine solution and added Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane:ethyl acetate=97:3 to 95:5) to obtain methyl 2'-methoxy-[1,1'-biphenyl]-4-carboxylate (507 mg, yield 35%). 1 H NMR (500 MHz, CDCl 3 ) δ 8.08 (d, J = 8.4 Hz, 2H), 7.61 (d, J = 8.4 Hz, 2H), 7.39 - 7.30 (m,2H), 7.04 (s, 1H), 6.99 (d, J = 8.2 Hz, 1H), 3.93 (d, J = 1.9 Hz, 3H), 3.81 (s,3H).

[0194] Step 2: Synthesis of (2'-methoxy-[1,1'-biphenyl]-4-yl)methanol [ka]

[0195] Methyl 2'-methoxy-[1,1'-biphenyl]-4-carboxylate (507 mg, 2.09 mmol) was dissolved in THF (0.2 M) and LiAlH 4 (397 mg, 10.5 mmol) was added and stirred for 3 h. The reaction mixture was cooled to 0° C., and then distilled water (1.6 mL) and aqueous NaOH were added, and Na 2 SO 4The mixture was dried at 40° C. 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 (500 MHz, CDCl 3 ) δ 7.55 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 7.9 Hz, 2H), 7.34 (d, J =7.5 Hz, 2H), 7.05 (s, 1H), 7.01 (d, J = 8.0 Hz, 1H), 4.70 (s, 2H), 3.81 (s, 3H), 2.23 (s, 1H).

[0196] Preparation 8: 3-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline [ka]

[0197] A solution of 3-fluoro-5-bromoaniline (380 mg, 2.0 mmol) in 1,4-dioxane (20.0 mL) was treated with bis(pinacolato)diboron (1.1 g, 4.4 mmol), KOAc (1.18 g, 12 mmol) and Pd(dppf)Cl 2 (146.0 mg, 0.2 mmol) 2 The mixture was added under atmospheric pressure and stirred at 90° C. for 32 hours. The reaction mixture was cooled to ambient temperature, filtered through Celite, and washed with EtOAc. The organic layer was concentrated under reduced pressure to give Intermediate H (1.4 g).

[0198] Preparation 9: 2-(3-fluoro-5-(methylthio)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane Step 1: Synthesis of (3-bromo-5-fluorophenyl)(methyl)sulfane [ka]

[0199] A solution of 3,5-difluorobromobenzene (3 g, 15.54 mmol) in N,N-dimethylformamide (30 mL) was cooled to 0° C. and sodium thiomethoxide solution (7.1 mL, 15.54 mmol) was added and stirred for 30 min. The reaction mixture was diluted with distilled water, extracted with hexane, then washed with brine, and concentrated to 100% Na. 2 SO 4 The organic layer was concentrated under reduced pressure to give (3-bromo-5-fluorophenyl)(methyl)sulfane (2.6 g, 75% yield) as a clear liquid.

[0200] Step 2: Synthesis of 2-(3-fluoro-5-(methylthio)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka]

[0201] (3-Bromo-5-fluorophenyl)(methyl)sulfane (1 g, 4.523 mmol), potassium acetate (2.2 g, 22.615 mmol), (pinacolato)diboron (1.7 g, 6.784 mmol) and Pd(dppf)Cl 2 (complex with DCM; 369 mg, 0.452 mmol) was added to the sealed tube and the 2 After purging under atmosphere, 1,4-dioxane was added and then stirred at 80° C. for 12 hours. The reaction mixture was cooled to ambient temperature, then ethyl acetate was added and the precipitate was removed by filtration through Celite. The organic layer was concentrated under reduced pressure and the crude product was purified by flash column chromatography (hexane / ethyl acetate from 0% to 100%) to give Intermediate I (932 mg, 70% yield) as a yellow liquid.

[0202] Preparation 10: 3-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide Step 1: Synthesis of 3-bromo-5-fluorobenzamide [ka]

[0203] A solution of 3-bromo-5-fluorobenzoic acid (1 g, 4.566 mmol) in thionyl chloride (4 mL) was stirred under reflux conditions for 2 hours. The reaction mixture was concentrated under reduced pressure, 28% aqueous ammonia (1.5 mL) was added, and then stirred for 12 hours. The reaction mixture was washed three times with distilled water to give 3-bromo-5-fluorobenzamide (533 mg, 54% yield) as a white solid. 1 H NMR (300 MHz, chloroform-d) δ 7.74 - 7.72 (m, 1H), 7.49 - 7.45 (m,1H), 7.44 - 7.40 (m, 1H), 5.83 (s, 2H).

[0204] Step 2: Synthesis of 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ka]

[0205] Intermediate J was obtained by reacting 3-bromo-5-fluorobenzamide in the same manner as in Preparation Example 8.

[0206] Preparation 11: 3-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [ka] Intermediate K was obtained by the same method as in Preparation 10, except that in step 1, 3-bromo-5-methoxybenzoic acid was used instead of 3-bromo-5-fluorobenzoic acid. 1 H NMR (300 MHz, DMSO-d 6) δ 8.03 (s, 1H), 7.77 (dd, J = 1.6, 0.9 Hz, 1H), 7.53 (dd, J = 2.7,1.6 Hz, 1H), 7.33 (s, 1H), 7.27 (dd, J = 2.7, 0.9 Hz, 1H), 3.81 (s, 3H), 1.16(d, J = 2.6 Hz, 12H).

[0207] Preparation 12: tert-Butyl (3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate Step 1: Synthesis of (3-bromo-5-methoxyphenyl)methanamine [ka]

[0208] 3-Bromo-5-methoxybenzonitrile (1 g, 4.716 mmol) was dissolved in THF (9 mL) and then BH 3 -THF (1M in THF, 6 mL, 5.895 mmol) was added slowly at 0°C. The reaction mixture was stirred at 80°C for 16 h, then the solvent was concentrated under reduced pressure and acidified by addition of 1N HCl. The reaction mixture was stirred at ambient temperature for 2 h, then EA and distilled water were added and the aqueous layer was extracted. The aqueous layer was neutralized with 2N NaOH (pH 10) and then extracted with EA and brine. The organic layer was concentrated under reduced pressure to give (3-bromo-5-methoxyphenyl)methanamine (741 mg, 72% yield). 1 H NMR (300 MHz, chloroform-d) δ 7.08 - 7.03 (m, 1H), 6.92 (t, J = 2.0Hz, 1H), 6.83 - 6.79 (m, 1H), 3.81 (s, 2H), 3.78 (s, 3H).

[0209] Step 2: Synthesis of tert-butyl (3-bromo-5-methoxybenzyl)carbamate [ka]

[0210] (3-Bromo-5-methoxyphenyl)methanamine (741 mg, 3.429 mmol) and Boc 2 O (749 mg, 3.429 mmol) was dissolved in DCM. TEA (0.53 mL, 3.772 mmol) was added at 0 °C, followed by stirring for 16 h. The DCM was partially concentrated and extracted with EA and brine. The organic layer was treated with MgSO 4 The mixture was dried at rt, then concentrated under reduced pressure and purified by silica column (EA:hexane=1:3) to give tert-butyl (3-bromo-5-methoxybenzyl)carbamate (766 mg, yield 70%). 1 H NMR (300 MHz, chloroform-d) δ 7.00 (s, 1H), 6.94 (t, J = 2.1 Hz,1H), 6.75 (s, 1H), 4.84 (s, 1H), 4.25 (s, 2H), 3.78 (s, 3H), 1.46 (s, 9H).

[0211] Step 3: Synthesis of tert-butyl (3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate [ka]

[0212] Intermediate L was obtained by reacting tert-butyl (3-bromo-5-methoxybenzyl)carbamate in the same manner as in Preparation Example 8. 1 H NMR (300 MHz, chloroform-d) δ 7.30 (s, 1H), 7.22 (s, 1H), 6.95 (s,1H), 4.79 (s, 1H), 4.29 (s, 2H), 3.82 (s, 3H), 1.46 (s, 9H), 1.34 (s, 12H).

[0213] Preparation 13: 3-Fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol Step 1: Synthesis of (3-bromo-5-fluorophenyl)methanol [ka]

[0214] 3-Bromo-5-fluorobenzoic acid (657.0 mg, 3.0 mmol) was added to THF (15.0 mL), cooled to 0° C., and added to BH 3 .DMS (5M, 1.2 mL, 6.0 mmol) was added over 15 min and then stirred for 12 h. The reaction mixture was cooled to 0 °C and excess methanol was added. The solution diluted with ethyl acetate was washed with 1N aqueous sodium hydroxide and brine, and then diluted with Na 2 SO 4 The mixture was dried at rt and then concentrated under reduced pressure. The crude product was purified by column chromatography (0-30% EtOAc / Hexanes) to give (3-bromo-5-fluorophenyl)methanol (400 mg, 65% yield). 1 H NMR (300 MHz, CDCl 3 ) δ 7.33 - 7.28 (m, 1H), 7.17 (dt, J = 8.1, 2.1 Hz, 1H), 7.04 (ddd, J =9.1, 2.4, 1.3 Hz, 1H), 4.69 (s, 2H).

[0215] Step 2: Synthesis of (3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanol [ka]

[0216] Intermediate M was obtained by reacting (3-bromo-5-fluorophenyl)methanol in the same manner as in Preparation Example 8.

[0217] Preparation 14: 3-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol Step 1: Synthesis of 3-(3-bromo-5-methoxyphenyl)oxetan-3-ol [ka]

[0218] To a solution of 1,3-dibromo-5-methoxybenzene (1.06 g, 4.0 mmol) in THF (0.2 M), TMEDA (923 μL, 6.0 mmol) and n-BuLi (2.5 M in THF, 2.4 mL, 6.0 mmol) were added at −78° C. and stirred for 1 h. To the reaction mixture, oxetanone (1.02 mL, 4.8 mmol) was added and allowed to warm slowly to ambient temperature. After 4 h, the resulting mixture was purified by NH 4 The mixture was diluted with aqueous Cl (40 mL) and ethyl acetate (40 mL), and the aqueous layer was extracted with ethyl acetate (40 mL). 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane:ethyl acetate=1:2) to obtain 3-(3-bromo-5-methoxyphenyl)oxetan-3-ol (443.0 mg as a mixture, approximately 320.0 mg, yield 31%) as a colorless oil. 1 H NMR (500 MHz, CDCl 3 ) δ 7.34 (s, 1H), 7.07 (d, J = 2.0Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H),4.86 (d, J = 6.8 Hz, 2H), 4.83 (d, J = 7.0 Hz, 2H), 3.80 (s, 4H).

[0219] Step 2: Synthesis of 3-(3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)oxetan-3-ol [ka]

[0220] Intermediate N was obtained by reacting 3-(3-bromo-5-methoxyphenyl)oxetan-3-ol in the same manner as in Preparation Example 8. 1 H NMR (500 MHz, CDCl 3 ) δ 7.57 (s, 1H), 7.27 (d, J = 2.6 Hz, 1H), 7.19 (dd, J = 2.6, 1.8 Hz,1H), 4.94 (d, J = 6.9 Hz, 2H), 4.87 (d, J = 6.8 Hz, 2H), 3.84 (s, 3H), 1.33 (s,12H).

[0221] Preparation 15: 1-(3-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidin-2-one Step 1: Synthesis of 1-(3-methoxyphenyl)azetidin-2-one [ka]

[0222] A solution of 1-iodo-3-methoxybenzene (936.1 mg, 4.0 mmol) in toluene (0.8 M) was added with azetidinone (340.0 mg, 4.8 mmol), CuI (38.1 mg, 0.2 mmol), K 2 CO 3 (1.1 g, 8.0 mmol) and N,N'-dimethylethylenediamine (43 μL, 0.4 mmol) were added and stirred at 140° C. for 24 h. The reaction mixture was cooled to ambient temperature, diluted with brine (20 mL) and ethyl acetate (20 mL), and the aqueous layer was extracted with ethyl acetate (20 mL). The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane:ethyl acetate=2:1) ​​to give 1-(3-methoxyphenyl)azetidin-2-one (436.0 mg, 61% yield) as a colorless oil (436.0 mg, 61%). 1 H NMR (500 MHz, CDCl 3) δ 7.14 (t, J = 8.1 Hz, 1H), 6.92 (s, 1H), 6.78 (dd, J = 8.1, 1.9 Hz,1H), 6.56 (dd, J = 8.4, 2.5 Hz, 1H), 3.72 (s, 3H), 3.48 (t, J = 4.5 Hz, 2H),2.98 (d, J = 4.5 Hz, 2H).

[0223] Step 2: 1-(3-Methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidin-2-one [ka]

[0224] A solution of 1-(3-methoxyphenyl)azetidin-2-one (436.0 mg, 2.46 mmol) in cyclohexane (0.1 M) was added with [Ir(cod)OMe] 2 (195.7 mg, 0.295 mmol), 4,4'-di-tert-butyl-2'2-bipyridine (dtbpy) (158.5 mg, 0.590 mmol), bis(pinacolato)diboron (1.25 g, 4.90 mmol) and BpinH (42.8 μL, 0.295 mmol) were added and stirred at 80° C. for 24 hours. The reaction mixture was cooled to room temperature and diluted with brine (40 mL) and ethyl acetate (40 mL), and the aqueous layer was then extracted with ethyl acetate (40 mL). The organic layer was concentrated with Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane:ethyl acetate=1:1) to give intermediate O (405.2 mg, 54% yield) as a yellow solid. 1 H NMR (500 MHz, CDCl 3 ) δ 7.32 (t, J = 2.3 Hz, 1H), 7.05 (d, J = 2.5 Hz, 1H), 7.04 (d, J =1.9 Hz, 1H), 3.81 (s, 3H), 3.62 (t, J = 4.5 Hz, 2H), 3.07 (t, J = 4.5 Hz, 2H).

[0225] Preparation 16: tert-Butyl (3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)carbamate [ka]

[0226] Intermediate P was obtained by the same method as in Preparation 12, except that in Step 1 of Preparation 12, 3-bromo-5-fluorobenzonitrile was used instead of 3-bromo-5-methoxybenzonitrile.

[0227] Preparation 17: tert-Butyl 3-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine-1-carboxylate Step 1: Synthesis of tert-butyl 3-(3-bromo-5-fluorophenyl)azetidine-1-carboxylate [ka]

[0228] tert-Butyl 3-(2-((4-methoxyphenyl)sulfonyl)hydrazinylidene)azetidine-1-carboxylate (1.0 g, 2.8 mmol), 3-bromo-5-fluorophenylboronic acid (1.23 g, 5.6 mmol) and cesium carbonate (1.83 g, 5.6 mmol) were added to 1,4-dioxane (10.0 mL, 0.3 M). The tube was sealed and stirred at 110 °C for 15 h. The reaction mixture was cooled to ambient temperature and washed with saturated NaHCO 3 Quench with aqueous solution (30 mL) and then MgSO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by flash column chromatography (10-30% EtOAc / Hexanes) to give tert-butyl 3-(3-bromo-5-fluorophenyl)azetidine-1-carboxylate (261 mg, 28%). 1H NMR (300 MHz, chloroform-d) δ 7.28 (d, J = 3.8 Hz, 1H), 7.16 (dt, J= 8.1, 2.0 Hz, 1H), 7.00 (dt, J = 9.3, 1.8 Hz, 1H), 4.34 (t, J = 8.7 Hz, 2H), 3.93 (dd, J = 8.7, 5.8 Hz, 2H), 3.69 (d, J = 14.4 Hz, 1H), 1.49 (s, 9H).

[0229] Step 2: Synthesis of tert-butyl 3-(3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)azetidine-1-carboxylate [ka]

[0230] Intermediate Q was obtained by reacting tert-butyl 3-(3-bromo-5-fluorophenyl)azetidine-1-carboxylate in the same manner as in Preparation Example 8. 1 H NMR (300 MHz, chloroform-d) δ 7.50 (s, 1H), 7.39 (dd, J = 8.7, 2.2Hz, 1H), 7.14 (dt, J = 9.8, 2.1 Hz, 1H), 4.34 (t, J = 8.7 Hz, 2H), 4.00 (dd, J= 8.6, 6.0 Hz, 2H), 3.77 (ddd, J = 12.8, 7.8, 5.1 Hz, 1H), 1.49 (s, 9H), 1.37(s, 12H).

[0231] Preparation 18: Methyl 6-(methylamino)spiro[3.3]heptane-2-carboxylate hydrochloride Step 1: Synthesis of methyl 6-((tert-butoxycarbonyl)(methyl)amino)spiro[3.3]heptane-2-carboxylate [ka]

[0232] To a stirred solution of methyl 6-((tert-butoxycarbonyl)amino)spiro[3.3]heptane-2-carboxylate (269 mg, 1.0 mmol) in THF (0.1 M) was added 60% NaH (60 mg, 1.50 mmol) and stirred at 0° C. for 15 min. Iodomethane (0.2 mL, 3.0 mmol) was added to the reaction mixture and stirred for 20 h. The reaction mixture was quenched with cold distilled water and extracted with ethyl acetate (20 mL). The organic layer was washed with distilled water and brine and the Na 2 SO 4 Drying at rt and concentration under reduced pressure afforded methyl 6-((tert-butoxycarbonyl)(methyl)amino)spiro[3.3]heptane-2-carboxylate (288 mg, crude) as a yellow liquid. 1 H NMR (400 MHz, chloroform-d) δ 4.6-4.14 (m, 1H), 3.69 (s, 3H), 3.05(p, J = 8.5 Hz, 1H), 2.39-2.25 (m, 1H), 2.2-2.00 (m, 1H), 1.47 (s, 9H).

[0233] Step 2: Synthesis of methyl 6-(methylamino)spiro[3.3]heptane-2-carboxylate hydrochloride [ka]

[0234] To methyl 6-((tert-butoxycarbonyl)(methyl)amino)spiro[3.3]heptane-2-carboxylate (288 mg, 1.02 mmol) was added 4N HCl in dioxane at 0° C. and stirred at ambient temperature for 15 hours. The reaction mixture was concentrated under reduced pressure to give the hydrochloride salt of intermediate R (244 mg) as a yellow solid. 1H NMR (400 MHz, DMSO) δ 9.07 (s, 2H), 3.59 (s, 2H), 3.53-3.39 (m, 1H), 3.22-2.78 (m, 1H),2.37 (s, 3H), 2.34-2.23 (m, 2H), 2.24-2.01 (m, 6H).

[0235] Preparation 19: 4-(((tert-butyldimethylsilyl)oxy)methyl)-2,5-dimethylthiophene-3-carboxylic acid Step 1: Synthesis of 4-bromo-2,5-dimethylthiophene-3-carbaldehyde [ka]

[0236] To a solution of 3,4-dibromo-2,5-dimethylthiophene (6.37 g, 23.6 mmol) and TMEDA (3.9 mL, 26 mmol) in THF (0.4 M) was added n-BuLi (2.5 M in THF, 9.4 mL, 23.6 mmol) at -78°C and stirred for 1 h. DMF was added to the reaction mixture, which was then allowed to warm slowly to ambient temperature and stirred for 15 h. The reaction mixture was quenched with distilled water (20 mL), acidified with 1N HCl solution, and then extracted with ethyl acetate. The organic layer was extracted with Na 2 SO 4 The extract was dried at 40° C., filtered and concentrated under reduced pressure to give 4-bromo-2,5-dimethylthiophene-3-carbaldehyde (3.64 g) as an off-white solid. 1 H NMR (300 MHz, CDCl 3 ) δ 10.03 (s, 0H), 2.74 (s, 1H), 2.38 (s, 1H).

[0237] Step 2: Synthesis of (4-bromo-2,5-dimethylthiophen-3-yl)methanol [ka]

[0238] A solution of 4-bromo-2,5-dimethylthiophene-3-carbaldehyde (1.10 g, 5.02 mmol) in THF (0.2 M) was added to LiAlH 4 (191 mg, 5.02 mmol) was added at 0° C. and stirred for 2 h. The reaction mixture was quenched with EtOAc (1 mL) and ice water (0.3 mL), stirred for 30 min, then filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (20% EtOAc in hexanes) to give (4-bromo-2,5-dimethylthiophen-3-yl)methanol (754 mg, 68% yield) as a colorless liquid. 1 H NMR (400 MHz, DMSO); δ 4.33 (s, 1H), 2.40 (s, 3H), 2.36 (s, 1H), 2.30 (s, 3H).

[0239] Step 3: Synthesis of ((4-bromo-2,5-dimethylthiophen-3-yl)methoxy)(tert-butyl)dimethylsilane [ka]

[0240] To a solution of (4-bromo-2,5-dimethylthiophen-3-yl)methanol (950 mg, 4.30 mmol) in THF (0.2 M, 0° C.), tert-butyldimethylsilyl chloride (777 mg, 5.16 mmol) and imidazole (439 mg, 6.44 mmol) were added and stirred for 24 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with distilled water (2×20 mL). The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (5% EtOAc in hexanes) to give ((4-bromo-2,5-dimethylthiophen-3-yl)methoxy)(tert-butyl)dimethylsilane (937 mg, 65% yield) as a colorless liquid. 1H NMR (300 MHz, chloroform-d) δ 4.60 (s, 1H), 2.45 (s, 2H), 2.35 (s,2H), 1.57 (s, 1H), 0.94 (s, 4H), 0.12 (s, 3H).

[0241] Step 4: Synthesis of 4-(((tert-butyldimethylsilyl)oxy)methyl)-2,5-dimethylthiophene-3-carboxylic acid [ka]

[0242] To a solution of ((4-bromo-2,5-dimethylthiophen-3-yl)methoxy)(tert-butyl)dimethylsilane (335 g, 1.0 mmol) and TMEDA (165 μL, 1.10 mmol) in THF (0.2 M) was added n-BuLi (2.5 M in THF, 0.44 mL, 1.10 mmol) at −78° C. and stirred for 1 h. The reaction mixture was cooled to 5° C. and cooled to 5° C. for 1 h. 2 The mixture was quenched with gas at -78°C, then slowly warmed to ambient temperature and stirred for 15 hours. The reaction mixture was quenched with distilled water (20 mL), acidified with 1N HCl solution, and then extracted with ethyl acetate. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., filtered and then concentrated under reduced pressure. The crude product was purified by column chromatography (20% EtOAc in hexanes) to give Intermediate S (300 mg) as a white solid. 1 H NMR (300 MHz, chloroform-d) δ 4.74 (s, 2H), 2.67 (s, 3H), 2.38 (s,3H), 0.94 (s, 9H), 0.18 (s, 6H).

[0243] Preparation 20: Methyl 3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylate Step 1: Synthesis of methyl (Z)-2-azido-3-(4-bromothiophen-2-yl)acrylate [ka]

[0244] To a solution of 4-bromothiophene-2-carbaldehyde (3.82 g, 20.0 mmol, 1.0 equiv.) and intermediate B (6.91 g, 60.0 mmol, 3.0 equiv.) in MeOH (30 mL), 4 M NaOMe (15 mL, 60.0 mmol) was added at −25° C. and stirred for 2 h at 0° C. Ice was added to the reaction mixture, washed with distilled water, filtered, and the reaction product was then dried to give methyl (Z)-2-azido-3-(4-bromothiophen-2-yl)acrylate. 1 H NMR (300 MHz, chloroform-d) δ 7.37 (dd, J = 1.4, 0.7 Hz, 1H), 7.22 (dd, J = 1.4, 0.6 Hz, 1H), 7.03 (d, J = 0.7 Hz, 1H), 3.90 (s, 3H).

[0245] Step 2: Synthesis of methyl 3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylate [ka]

[0246] A solution of methyl (Z)-2-azido-3-(4-bromothiophen-2-yl)acrylate (4.79 g, 16.6 mmol, 1.0 equiv) in o-xylene (60 mL) was stirred for 1 h at 160° C. The reaction mixture was partially concentrated, filtered, then washed with hexane and dried to give intermediate T. 1 H NMR (300 MHz, chloroform-d) δ 9.10 (s, 1H), 7.23 (s, 1H), 7.15 (d, J= 1.9 Hz, 1H), 3.93 (s, 3H).

[0247] Preparation 21: Methyl 3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate Step 1: Preparation of 4-bromo-5-methylthiophene-2-carbaldehyde [ka]

[0248] To a solution of 5-methylthiophene-2-carbaldehyde (2.78 g, 22.0 mmol) in THF (0.5 M), bromine (1.7 mL, 33 mmol) was added at 0° C. and stirred for 25 h. The reaction mixture was diluted with 10% Na 2 S 2 O 3 Aqueous solution (30 mL) and 10% NaHCO 3 Aqueous solution (30 mL) was added and extracted with EtOAc (150 mL). The organic phase was washed with Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by column chromatography to give 4-bromo-5-methylthiophene-2-carbaldehyde (862 mg, 16% yield) as a colorless solid. 1 H NMR (300MHz, chloroform-d) δ 9.80 (s, 1H), 7.62 (s, 1H), 2.51 (s,3H).

[0249] Step 2: Preparation of methyl (Z)-2-azido-3-(4-bromo-5-methylthiophen-2-yl)acrylate [ka]

[0250] To a solution of 4-bromo-5-methylthiophene-2-carbaldehyde (850 mg, 4.14 mmol) in MeOH (1.5 M) was added 4 M NaOMe (3 mL, 11.6 mmol) and Intermediate B (1.43 g, 12.4 mmol) at −25° C. The reaction mixture was stirred at 0° C. for 2 h, then diluted with EtOAc and washed with brine solution. The organic phase was washed with Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by column chromatography to give methyl (Z)-2-azido-3-(4-bromo-5-methylthiophen-2-yl)acrylate (813 mg, 65% yield) as a yellow solid.1 H NMR (300MHz, chloroform-d) δ 7.15 (s, 1H), 6.99 (s, 1H), 3.91 (s,3H), 2.45 (s, 3H).

[0251] Step 3: Preparation of methyl 3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate [ka]

[0252] A solution of methyl (Z)-2-azido-3-(4-bromo-5-methylthiophen-2-yl)acrylate (795 mg, 2.63 mmol) in 4 mL of xylene was added to o-xylene (5 mL) over 10 min. After stirring at reflux for 1 h, the reaction mixture was cooled to ambient temperature and partially concentrated. The solid was filtered to give intermediate U (554 mg, 77% yield) as an off-white solid. 1 H NMR (300MHz, chloroform-d) δ 8.99 (s, 1H), 7.10 (d, J = 1.9 Hz,1H), 3.93 (s, 3H), 2.50 (s, 3H).

[0253] Preparation 22: Ethyl 3-bromo-6-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate Step 1: Synthesis of 1-(3,4-dibromothiophen-2-yl)ethan-1-one [ka]

[0254] AlCl in DCM (20 mL) 3To a solution of (1.33 g, 10.0 mmol, 2.0 equiv) was added 3,4-dibromothiophene (1.2 g, 5.0 mmol) at 0 °C and stirred for 10 min. Acetyl chloride (360 μL, 5.0 mmol, 1.0 equiv) was added and stirred at 0 °C for 3 h. The reaction mixture was acidified by the addition of 6 M HCl and extracted with DCM. The organic layer was washed with MgSO 4 Drying at rt and concentration under reduced pressure gave 1-(3,4-dibromothiophen-2-yl)ethan-1-one. 1 H NMR (300 MHz, chloroform-d) δ 7.63 (s, 1H), 2.72 (s, 3H).

[0255] Step 2: Synthesis of ethyl 3-bromo-6-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylate [ka]

[0256] 1-(3,4-dibromothiophen-2-yl)ethan-1-one (1.42 g, 5.0 mmol), ethyl isocyanoacetate (600 μL, 5.5 mmol, 1.1 equiv.), CuI (95 mg, 0.5 mmol, 0.1 equiv.) and Cs in DMSO (5 mL). 2 CO 3 A solution of (3.26 g, 10.0 mmol, 2.0 equiv) was stirred at 50 °C for 4 h. Distilled water was added to the reaction mixture and extracted with DCM. The organic layer was washed with MgSO 4 The mixture was dried at rt and then concentrated under reduced pressure. The crude product was purified by flash column chromatography to give intermediate V (806 mg, 56% yield). 1 H NMR (300 MHz, chloroform-d) δ 9.01 (s, 1H), 7.18 (s, 1H), 4.40 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H).

[0257] Preparation 23: Methyl 3-bromo-2-chloro-4H-thieno[3,2-b]pyrrole-5-carboxylate Step 1: Synthesis of 4-bromo-5-chlorothiophene-2-carbaldehyde [ka]

[0258] To a solution of 4-bromothiophene-2-carbaldehyde (500 mg, 2.62 mmol, 1.0 equiv) in DMF (5 mL) was added N-chlorosuccinimide (699 mg, 5.24 mmol) and stirred for 12 h at 70° C. Distilled water was added to the reaction mixture and the solid was filtered, then washed with distilled water and dried to give 4-bromo-5-chlorothiophene-2-carbaldehyde (421 mg, 70% yield). 1 H NMR (300 MHz, chloroform-d) δ 9.76 (s, 1H), 7.60 (s, 1H).

[0259] Steps 2 and 3: Synthesis of methyl 3-bromo-2-chloro-4H-thieno[3,2-b]pyrrole-5-carboxylate [ka]

[0260] Intermediate W was obtained by reacting 4-bromo-5-chlorothiophene-2-carbaldehyde in the same manner as in Preparation Example 20. 1 H NMR (300 MHz, chloroform-d) δ 9.04 (s, 1H), 7.07 (d, J = 1.9 Hz,1H), 3.92 (s, 3H).

[0261] Preparation Example 24: 4'-(Bromomethyl)-3-methoxy-1,1'-biphenyl Step 1: Synthesis of (3'-methoxy-[1,1'-biphenyl]-4-yl)methanol [ka]

[0262] 3-Bromoanisole (935 mg, 5 mmol), 4-(hydroxymethyl)phenylboronic acid (912 mg, 6 mmol), Na 2 CO 3 (1.3 g, 12.5 mmol) and Pd(PPh 3 ) 4 (289 mg, 0.25 mmol) was dissolved in H 2 The mixture was dissolved in a mixture of O and DME and stirred at 85 °C for 24 h. The reaction mixture was cooled to ambient temperature and then filtered through Celite, extracted with EA and brine, and the organic layer was washed with MgSO 4 The crude product was purified by silica gel column (EtOAc:Hexane=1:2) to give (3′-methoxy-[1,1′-biphenyl]-4-yl)methanol (1.00 g, 93% yield) as a yellow oil. 1 H NMR (300 MHz, chloroform-d) δ 7.59 (d, J = 8.2 Hz, 2H), 7.44 (d, J =8.2 Hz, 2H), 7.36 (t, J = 7.9 Hz, 1H), 7.21 - 7.16 (m, 1H), 7.12 (t, J = 2.1Hz, 1H), 6.90 (ddd, J = 8.1, 2.6, 0.9 Hz, 1H), 4.75 (s, 2H), 3.87 (s, 3H).

[0263] Step 2: Synthesis of 4'-(bromomethyl)-3-methoxy-1,1'-biphenyl [ka]

[0264] (3'-Methoxy-[1,1'-biphenyl]-4-yl)methanol (1.00 g, 4.667 mmol) and CBr 4 (1.7 g, 5.134 mmol) was dissolved in DCM (16 mL) and then stirred at 0° C. for 10 min. 3(1.35 g, 5.134 mmol) was slowly added and stirred for 40 min. The organic layer was concentrated under reduced pressure and purified by silica gel column (EtOAc:Hexane=1:25) to give intermediate X (1.14 g, 88% yield). 1 H NMR (300 MHz, chloroform-d) δ 7.57 (d, J = 8.3 Hz, 2H), 7.47 (d, J =8.3 Hz, 2H), 7.37 (t, J = 7.9 Hz, 1H), 7.20 - 7.15 (m, 1H), 7.13 - 7.11 (m,1H), 6.94 - 6.89 (m, 1H), 4.56 (s, 2H), 3.87 (s, 3H).

[0265] Preparation 25: 4'-(bromomethyl)-3-fluoro-5-methoxy-1,1'-biphenyl [ka]

[0266] Intermediate Y was obtained by using (4-bromophenyl)methanol and (3-fluoro-5-methoxyphenyl)boronic acid as starting materials in the same manner as in Preparation 24. 1 H NMR (300 MHz, chloroform-d) δ 7.59 - 7.54 (m, 2H), 7.51 - 7.46 (m,2H), 6.90 (dd, J = 9.2, 2.2 Hz, 2H), 6.64 (dt, J = 10.5, 2.3 Hz, 1H), 4.57 (s,2H), 3.88 (s, 3H).

[0267] Preparation 26: Methyl (2R,4R,6R)-6-aminospiro[3.3]heptane-2-carboxylate hydrochloride Step 1: Synthesis of methyl 6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptane-2-carboxylate [ka]

[0268] 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 added slowly at 0° C. and stirred at ambient temperature for 14 h. The reaction mixture was diluted with NH 4 Extract with aqueous Cl and DCM, then wash the organic layer with MgSO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by silica gel column (EtOAc:Hexane=1:1) to give methyl 6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptane-2-carboxylate (4.4 g, 99% yield). 1 H NMR (300 MHz, CDCl 3 ) δ 7.40 - 7.28 (m, 5H), 5.06 (s, 2H), 4.84 (d, J = 8.3 Hz, 1H), 4.11 -3.97 (m, 1H), 3.65 (s, 3H), 3.01 (p, J = 8.5 Hz, 1H), 2.50 (dt, J = 12.0, 6.6Hz, 1H), 2.43 - 2.21 (m, 4H), 2.12 (ddd, J = 11.7, 8.7, 2.8 Hz, 1H), 1.84 (ddd,J = 15.9, 11.3, 8.7 Hz, 2H).

[0269] Step 2: Purification of methyl 6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptane-2-carboxylate [ka]

[0270] Methyl 6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptane-2-carboxylate (4.34 g) was purified by supercritical fluid chromatography (SFC) under the following conditions to separate into methyl (2S,4S,6S)-6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptane-2-carboxylate (2.99 g) and methyl (2R,4R,6R)-6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptane-2-carboxylate (0.88 g), each as a yellow oil.

[0271] Column: Daicel ChralPak IG (250mm x 4.6mm, 1um) Mobile phase: [Hexane / EtOH]; 80 / 20 (V / V), 9.4 min (2S, 4S, 6S), 10.7 min (2R, 4R, 6R) Step 3: Synthesis of methyl (2R,4R,6R)-6-aminospiro[3.3]heptane-2-carboxylate hydrochloride [ka]

[0272] Methyl (2R,4R,6R)-6-(((benzyloxy)carbonyl)amino)spiro[3.3]heptane-2-carboxylate (312 mg, 1.03 mmol) was dissolved in MeOH (10.3 mL, 0.1 M) and Pd / C 10% (110 mg, 0.1 equiv.) was added. The reaction mixture was stirred for 3 h. 2 The mixture was purged under atmosphere and stirred for 16 hours. The reaction mixture was filtered through Celite and concentrated under reduced pressure. 1,4-dioxane (10.3 mL, 0.1 M) and 4N HCl solution (0.8 mL, 3.09 mmol) were added to the concentrated reaction mixture and stirred for an additional 30 minutes. The reaction mixture was concentrated under reduced pressure to give intermediate Z (180 mg).

[0273] Preparation 27: 4'-(bromomethyl)-3,5-dimethoxy-1,1'-biphenyl [ka]

[0274] Intermediate AA was obtained by using 1-bromo-3,5-dimethoxybenzene and ((4-hydroxy)methylphenyl)boronic acid as starting materials in the same manner as in Preparation 24. 1 H NMR (300 MHz, chloroform-d) δ 7.55 (d, J = 8.3 Hz, 2H), 7.45 (d, J =8.3 Hz, 2H), 6.71 (d, J = 2.2 Hz, 2H), 6.48 (t, J = 2.2 Hz, 1H), 4.55 (s, 2H),3.85 (s, 6H).

[0275] Preparation 28: 4-(2-bromoethyl)-1,1'-biphenyl Step 1: Synthesis of 2-([1,1'-biphenyl]-4-yl)ethan-1-ol [ka]

[0276] A solution of 2-([1,1'-biphenyl]-4-yl)acetic acid (559 mg, 3 mmol) in THF (7 mL) was added to LiAlH 4 (1M in THF, 9.0 mL, 3.0 equiv.) was added at 0° C. and stirred at 75° C. for 4 h, then quenched by careful addition of 1N NaOH. The reaction mixture was filtered through Celite, and the filtrate was poured into distilled water and extracted with EtOAc. The organic layer was washed with MgSO 4 The mixture was dried at rt and then concentrated under reduced pressure to give 2-([1,1'-biphenyl]-4-yl)ethan-1-ol (522 mg, 87% yield). 1 H NMR (300 MHz, chloroform-d) δ 7.62-7.52 (m, 2H), 7.49-7.40 (m, 1H),7.39-7.29 (m, 2H), 3.91 (t, J = 6.5 Hz, 1H), 2.92 (t, J = 6.5 Hz, 1H).

[0277] Step 2: Synthesis of 4-(2-bromoethyl)-1,1'-biphenyl [ka]

[0278] A solution of 2-([1,1'-biphenyl]-4-yl)ethan-1-ol (522 mg, 2.8 mmol, 1.0 equiv.) in DMC (12 mL) was diluted with CBr 4 (1.02 g, 3.1 mmol, 1.1 equiv.) was added at 0° C. and stirred for 15 min, followed by PPh 3 (813 mg, 3.1 mmol, 1.1 equiv) was added and stirred for 40 min. The precipitated solid was filtered to give intermediate BB (639 mg, 87% yield). 1 H NMR (300 MHz, chloroform-d) δ 7.61 - 7.53 (m, 4H), 7.48 - 7.40 (m,2H), 7.38 - 7.29 (m, 3H), 3.91 (t, J = 6.5 Hz, 2H), 2.92 (t, J = 6.5 Hz, 2H).

[0279] Preparation 29: 4'-(bromomethyl)-3-fluoro-1,1'-biphenyl Step 1: Synthesis of (3'-fluoro-[1,1'-biphenyl]-4-yl)methanol [ka]

[0280] (4-(hydroxymethyl)phenyl)boronic acid (1.04 g, 6.857 mmol), 1-bromo-3-fluorobenzene (1 g, 5.714 mmol), Na 2 CO 3 (1.51 g, 14.285 mmol) and Pd(PPh 3 ) 4 (330mg, 0.268mmol) in DME and H 2The mixture was dissolved in 2:1 ethyl acetate and 2,5-dichlorophenyl (EtOH) and then heated to 85° C. and stirred for 24 h. The reaction mixture was extracted with EA and distilled water, and the crude product was purified by flash column chromatography to give (3′-fluoro-[1,1′-biphenyl]-4-yl)methanol (1.26 g) as a white solid. 1 H NMR (300 MHz, chloroform-d) δ 7.63-7.56 (m, 2H), 7.50-7.34 (m, 4H),7.32-7.27 (m, 1H), 7.09-6.99 (m, 1H), 4.76 (s, 2H).

[0281] Step 2: Synthesis of 4'-(bromomethyl)-3-fluoro-1,1'-biphenyl [ka]

[0282] (3'-Fluoro-[1,1'-biphenyl]-4-yl)methanol (304 mg, 1.641 mmol) was dissolved in DCM and PBr 3 (0.59 mL, 6.231 mmol) was added at 0° C. and stirred for 2 h, followed by additional PBr 3 (100 uL) was added and stirred. After 4 h, 1 mL of MeOH was added at 0° C. and the organic layer was concentrated under reduced pressure to give Intermediate CC (1.7 g) as a white solid. 1 H NMR (300 MHz, chloroform-d) δ 7.59-7.53 (m, 2H), 7.51-7.45 (m, 2H),7.43-7.26 (m, 3H), 7.08-7.02 (m, 1H), 4.55 (s, 2H).

[0283] Preparation 30: 2-(4-(bromomethyl)phenyl)pyrimidine [ka]

[0284] Intermediate DD was obtained by the same method as in Preparation 24, except that 2-bromopyridine was used instead of 3-bromoanisole in Step 1 of Preparation 24. 1 H NMR (300 MHz, chloroform-d) δ 8.81 (d, J = 4.9 Hz, 2H), 8.43 (d, J =8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.20 (t, J = 4.8 Hz, 1H), 4.56 (s, 2H).

[0285] Preparation 31: 5-(Bromomethyl)-2-phenylpyrimidine Step 1: Synthesis of (2-phenylpyrimidin-5-yl)methanol [ka]

[0286] (2-Chloropyrimidin-5-yl)methanol (1.156 g, 8 mmol), phenylboronic acid (1.463 g, 12 mmol), Pd(OAc) 2 (179mg, 0.8mmol), Xphos (381mg, 0.8mmol) and Na 2 CO 3 (2.199g, 20mmol) in dioxane / H 2 The mixture was dissolved in 2H2O (4:1, 26 mL), purged under Ar atmosphere, and then stirred at 100° C. for 12 h. The reaction mixture was filtered through Celite and then extracted with EA and brine. The organic layer was concentrated under reduced pressure and purified by silica column (EtOAc:Hexanes=1:1) to give (2-phenylpyrimidin-5-yl)methanol (661 mg, 44% yield). 1 H NMR (300 MHz, chloroform-d) δ 8.82 (s, 2H), 8.22-8.52 (m, 2H),7.58-7.47 (m, 3H), 4.78 (s, 2H).

[0287] Step 2: Synthesis of 5-(bromomethyl)-2-phenylpyrimidine [ka]

[0288] (2-Phenylpyrimidin-5-yl)methanol (661 mg, 3.549 mmol) was dissolved in DCM (11 mL) and then CBr 4 (1.421g, 4.258mmol) and PPh 3 (1.116 g, 4.258 mmol) was added over 10 min at 0° C. and stirred for 40 min. The reaction mixture was concentrated under reduced pressure and purified by silica column (EA:Hexane=1:9) to give intermediate EE (762 mg, 86% yield). 1 H NMR (300 MHz, chloroform-d) δ 8.82 (s, 2H), 8.43-8.46 (m, 2H),7.49-7.51 (m, 3H), 4.48 (s, 2H).

[0289] Preparation 32: (3-bromoprop-1-yn-1-yl)benzene [ka]

[0290] To a solution of (3-hydroxyprop-1-yn-1-yl)benzene (10.0 g, 75.6 mmol, 9.43 mL, 1.00 equiv.) and DMF (276 mg, 3.78 mmol, 0.05 equiv.) in DCM (100 mL) was added PBr 3 (24.5 g, 90.8 mmol, 1.20 equiv) was added at 0° C. and stirred for 1 h. The reaction mixture was cooled to 0° C. and then quenched by the addition of distilled water (50 mL) and extracted with DCM (2×50 mL). The organic layer was diluted with NaHCO 3 Wash with aqueous solution (1×100 mL) and brine (1×100 mL) and add Na 2 SO 4 The mixture was dried at 40° C., 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, 93.5% yield) as a colorless oil.

[0291] Preparation 33: (4-(pyridin-3-yl)phenyl)methanol [ka]

[0292] (4-(hydroxymethyl)phenyl)boronic acid (1.154 g, 7.595 mmol), 3-bromopyridine (1 g, 6.329 mmol), Na 2 CO 3 (1.68 g, 15.823 mmol) and Pd(PPh 3 ) 4 (366 mg, 0.316 mmol) in DME / H 2 The mixture was dissolved in 50 ml of EA (2:1) and then stirred at 85° C. for 12 h. The reaction mixture was cooled to ambient temperature and then extracted with EA and distilled water. The crude product was purified by flash column chromatography to give intermediate GG (1.34 g) as a yellow solid. 1 H NMR (300 MHz, chloroform-d) δ 8.82-8.81 (m, 1H), 8.61-8.59 (m, 1H),8.00 (d, J = 8.0 Hz, 1H), 7.61-7.55 (m, 2H), 7.53-7.45 (m, 3H), 4.78 (s, 2H).

[0293] Preparation 34: (4-(5-fluoropyridin-3-yl)phenyl)methanol [ka]

[0294] Intermediate HH was obtained by using the corresponding starting material in the same manner as in Preparation 33. 1 H NMR (300 MHz, chloroform-d) δ 8.63-8.61 (m, 1H), 8.45-8.44 (m, 1H),7.65-7.45 (m, 5H), 4.78 (s, 2H).

[0295] Preparation 35: (4-(5-methoxypyridin-3-yl)phenyl)methanol [ka]

[0296] Intermediate II was obtained by using the corresponding starting material in the same manner as in Preparation 33. 1 H NMR (300 MHz, chloroform-d) δ 8.49-8.48 (m, 1H), 8.30-8.29 (m, 1H),7.67-7.65 (m, 1H), 7.60-7.50 (m, 4H), 4.79 (s, 2H), 3.99 (s, 3H).

[0297] Preparation 36: (4-(1-benzyl-1H-pyrazol-4-yl)phenyl)methanol [ka]

[0298] (4-Bromophenyl)methanol (1.49 g, 8 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.5 g, 12 mmol), Pd(PPh 3 ) 2 Cl 2 (561mg, 0.8mmol) and Na 2 CO 3 (2.199g, 20mmol) in THF / H 2 The reaction mixture was dissolved in 2:1 HO (16 mL), purged under an Ar atmosphere, and then stirred at 80 °C for 6 h. The reaction mixture was filtered through Celite, then extracted with EA and brine, and washed with MgSO. 4 The mixture was dried at 40° C. and purified by a silica gel column (EA:hexane=1:3) to obtain intermediate JJ (948 mg, yield 63%). 1H NMR (300 MHz, chloroform-d) δ 7.76 (d, J = 0.8 Hz, 1H), 7.62 (d, J = 0.8 Hz, 1H), 7.43 - 7.50 (m, 2H), 7.31 - 7.41 (m, 2H), 4.69 (s, 2H), 3.95 (s,3H).

[0299] Preparation 37: (1-benzyl-1H-indol-5-yl)methanol Step 1: Synthesis of methyl 1-benzyl-1H-indole-5-carboxylate [ka]

[0300] To a solution of methyl 1H-indole-5-carboxylate (2.80 g, 16 mmol) and benzyl bromide (2.1 mL, 17.6 mmol) in DMF (30 mL) was added NaH (460 mg, 19.2 mmol) in small portions at 0 °C and stirred at ambient temperature for 12 h. The reaction mixture was extracted with EA and brine and the organic layer was diluted with MgSO 4 The mixture was dried at 40° C. and then concentrated under reduced pressure. The crude product was purified by silica column (EA:Hexane=1:9) to give methyl 1-benzyl-1H-indole-5-carboxylate (5.083 g, yield 78%). 1 H NMR (300 MHz, chloroform-d) δ 8.42 (dd, J = 0.7, 1.7 Hz, 1H), 7.88(dd, J = 1.7, 8.7 Hz, 1H), 7.25-7.35 (m, 4H), 7.19 (d, J = 3.2 Hz, 1H), 7.06-7.14 (m, 2H), 6.65 (dd, J = 0.9, 3.3 Hz, 1H), 5.35 (s, 2H), 3.93 (s, 3H).

[0301] Step 2: Synthesis of (1-benzyl-1H-indol-5-yl)methanol [ka]

[0302] Methyl 1-benzyl-1H-indole-5-carboxylate (2.0 g, 7.538 mmol) was dissolved in THF (25 mL) and LiAlH 4 (1M in THF, 22.6 mL, 22.615 mmol) was added at 0° C. and stirred at 75° C. for 4 h. The organic layer was filtered through Celite, concentrated under reduced pressure and purified by silica column (EA:Hexane=1:2) to give intermediate KK (1.734 g, 97% yield). 1 H NMR (300 MHz, chloroform-d) δ 7.62 (m, 1H), 7.22-7.31 (m, 4H), 7.18(dd, J = 1.7, 8.5 Hz, 1H), 7.04-7.11 (m, 2H), 6.53 (dd, J = 0.8, 3.1 Hz, 1H), 5.31 (s, 2H), 4.74 (s, 2H).

[0303] Preparation 38: (4-(pyridin-2-yl)phenyl)methanol [ka]

[0304] Intermediate LL was obtained by using the corresponding starting material in the same manner as in Preparation 33. 1 H NMR (300MHz, chloroform-d) δ 8.73 (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).

[0305] Preparation 39: (6-phenylpyridin-3-yl)methanol [ka]

[0306] 1,4-Dioxane / H 2A solution of (6-bromopyridin-3-yl)methanol (940.1 mg, 5.0 mmol) in O (0.25 M) was diluted with phenylboronic acid (914.5 mg, 7.5 mmol), Pd(OAc) 2 (56.1mg, 0.25mmol), Xphos (238.4mg, 0.5mmol) and Na 2 CO 3 (1.59 g, 15.0 mmol) was added and stirred at 100° C. After 18 h, the reaction mixture was cooled to ambient temperature, diluted with brine (50 mL) and ethyl acetate (50 mL), and the aqueous layer was extracted with ethyl acetate (30 mL). 2 SO 4 The mixture was dried at 40° C. 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 (500 MHz, CDCl 3 ) δ 8.66 - 8.62 (m, 1H), 7.99 - 7.93 (m, 2H), 7.77 (dd, J = 8.1, 2.2Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.46 (t, J = 7.5 Hz, 2H), 7.43 - 7.36 (m, 1H),4.75 (s, 2H).

[0307] Preparation 40: (4-pyridin-4-yl)phenyl)methanol [ka]

[0308] Intermediate NN was obtained by using the corresponding starting material in the same manner as in Preparation 33. 1 H NMR (300 MHz, chloroform-d) δ 8.71 - 8.62 (m, 2H), 7.66 (d, J = 8.2Hz, 2H), 7.60 - 7.55 (m, 2H), 7.51 (d, J = 8.2 Hz, 2H), 4.79 (s, 2H).

[0309] Preparation 41: (4-(6-methoxypyridin-2-yl)phenyl)methanol [ka]

[0310] Intermediate OO was obtained by using the corresponding starting material in the same manner as in Preparation 39. 1 H NMR (300 MHz, chloroform-d) δ 8.07 (d, J = 8.3 Hz, 2H), 7.69 - 7.62(m, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.37 (d, J = 7.4 Hz, 1H), 6.72 (d, J = 8.2Hz, 1H), 4.78 (s, 2H), 4.06 (s, 3H).

[0311] Preparation 42: (4-(4-methoxypyridin-2-yl)phenyl)methanol [ka]

[0312] Intermediate PP was obtained by using the corresponding starting material in the same manner as in Preparation 33. 1 H NMR (300 MHz, chloroform-d) δ 8.63 (d, J = 6.3 Hz, 1H), 8.02 (d, J =8.2 Hz, 2H), 7.52 (d, J = 8.2 Hz, 3H), 7.30 (d, J = 2.5 Hz, 1H), 6.97 (dd, J =6.3, 2.5 Hz, 1H), 4.78 (s, 2H), 4.03 (s, 3H).

[0313] Preparation 43: (6-(3-fluoro-5-methoxyphenyl)pyridin-3-yl)methanol [ka]

[0314] Intermediate QQ was obtained by using the corresponding starting material in the same manner as in Preparation 39. 1 H NMR (300 MHz, DMSO-d6) δ 8.63 - 8.60 (m, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.82 (dd, J = 8.1,2.0 Hz, 1H), 7.53 - 7.45 (m, 2H), 6.94 - 6.86 (m, 1H), 5.39 (s, 1H), 4.58 (d, J= 5.6 Hz, 2H), 3.86 (s, 3H).

[0315] Preparation 44: (4-(4-methyl-1H-pyrazol-1-yl)phenyl)methanol [ka]

[0316] (4-Iodophenyl)methanol (234mg, 1mmol), 4-methyl-1H-pyrazole (121uL, 1.5mmol), Cs 2 CO 3 (651 mg, 2 mmol) and Cu(OAc) 2 (18 mg, 0.1 mmol) was dissolved in DMF (5 mL), then the mixture was purged under an Ar atmosphere and then stirred at 100 °C for 12 h. The reaction mixture was extracted with EA and brine, and the organic layer was then treated with MgSO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The mixture was purified by silica chromatography (EA:Hexane=1:3) to give intermediate RR (191 mg, mixture). LC / MS (ESI) m / z: 189.1 [M+H].

[0317] Preparation 45: (4-(3-methyl-5-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl)methanol [ka]

[0318] 3-Methyl-5-(trifluoromethyl)-1H-pyrazole (353 mg, 2.35 mmol), (4-iodophenyl)methanol (500 mg, 2.136 mmol), K 2 CO 3 (590 mg, 4.272 mmol), CuI (41 mg, 0.214 mmol) and N,N-dimethylglycine (44 mg, 0.427 mmol) were dissolved in DMSO, heated to 130° C. and stirred for 24 h. The reaction mixture was cooled to ambient temperature and extracted with EA and distilled water, and the crude product was then purified by flash column chromatography to give intermediate SS (562 mg, 99% yield) as a clear liquid. 1 H NMR (300 MHz, chloroform-d) δ 7.54 - 7.40 (m, 4H), 6.46 (s, 1H),4.78 (d, J = 5.9 Hz, 2H), 2.35 (d, J = 0.7 Hz, 3H), 1.87 (t, J = 5.9 Hz, 1H).

[0319] Preparation 46: (5-(3-fluoro-5-methoxyphenyl)pyridin-2-yl)methanol [ka]

[0320] Intermediate TT was obtained by using the corresponding starting material in the same manner as in Preparation 39. 1 H NMR (300 MHz, DMSO-d6) δ 8.83 (d, J = 2.1 Hz, 1H), 8.13 (dd, J = 8.2, 2.4 Hz, 1H), 7.55 (d,J = 8.2 Hz, 1H), 7.22 - 7.12 (m, 2H), 6.88 (dt, J = 11.0, 2.2 Hz, 1H), 5.49 (t,J = 5.9 Hz, 1H), 4.62 (d, J = 5.9 Hz, 2H), 3.85 (s, 3H). EXAMPLES

[0321] Example 1: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of [1,1'-biphenyl]-4-yl(2,5-dimethylthiophen-3-yl)methanone [ka]

[0322] To a solution of [1,1'-biphenyl]-4-carboxylic acid (7.8 g, 39.3 mmol) in PhCl (45 mL, 0.8 M) and DMF (approximately 0.1 mL), was added SOCl 2 (4.9 g, 41.0 mmol) was added at 0 °C, then the reaction mixture was heated to 50 °C and stirred for 1 h. After 1 h, the mixture was cooled to ambient temperature and dimethylthiophene (4.1 mL, 35.7 mmol) was added. The reaction mixture solution was cooled to 0 °C and 1M TiCl 4 A solution (35.7 mL, 35.7 mmol) was added. After 1 h, the reaction mixture was acidified by the addition of 1N HCl solution and extracted with heptane. The combined extracts were washed with Na 2 SO 4 The mixture was dried at 40° C., then filtered and concentrated. The crude product was purified by column chromatography to give [1,1′-biphenyl]-4-yl(2,5-dimethylthiophen-3-yl)methanone (3.31 g, 32% yield). 1 H NMR (500 MHz, chloroform-d) δ 7.90 (d, J = 8.4 Hz, 2H), 7.71 (d, J =8.4 Hz, 2H), 7.67 (d, J = 7.1 Hz, 2H), 7.51 (t, J = 7.5 Hz, 2H), 7.43 (t, J =7.4 Hz, 1H), 6.85 (s, 1H), 2.63 (s, 3H), 2.46 (s, 3H). LC / MS (ESI) m / z: 293.7[M+H] + .

[0323] Step 2: Synthesis of [1,1'-biphenyl]-4-yl(4-bromo-2,5-dimethylthiophen-3-yl)methanone [ka]

[0324] A solution of [1,1'-biphenyl]-4-yl(2,5-dimethylthiophen-3-yl)methanone (3.29 g, 11.25 mol) and PhCl (14.1 mL, 0.8 M) was added to ZnCl 2 (46.0 mg, 0.34 mmol) was added and the reaction mixture was then cooled to 16° C. 2 (1.8 g, 22.5 mmol) was added over 30 min at 16° C. The reaction mixture was stirred at room temperature for 30 min and the reaction mixture was acidified by the addition of 1N HCl solution. The product was extracted with heptane and the combined extracts were washed with Na 2 SO 4 The mixture was dried at 40° C., then 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)methanone (2.61 g, 63% yield). 1 H NMR (500 MHz, chloroform-d) δ 7.94 (d, J = 7.5 Hz, 2H), 7.72 (d, J =7.7 Hz, 2H), 7.67 (d, J = 7.6 Hz, 2H), 7.50 (t, J = 7.3 Hz, 2H), 7.44 (t, J =7.3 Hz, 1H), 2.42 (s, 3H), 2.38 (s, 3H). LC / MS (ESI) m / z: 373.3 [M+H] + .

[0325] Step 3: Synthesis of 3-([1,1'-biphenyl]-4-ylmethyl)-4-bromo-2,5-dimethylthiophene [ka]

[0326] A solution of [1,1'-biphenyl]-4-yl(4-bromo-2,5-dimethylthiophen-3-yl)methanone (2.61 g, 7.03 mmol) and DCE (14.1 mL, 0.5 M) was added to Et 3 SiH (2.1 g, 17.6 mmol) was added. The reaction mixture was cooled to -8 °C and diluted with 1M TiCl 4 Solution (7.1 mL, 7.1 mmol) was added slowly. The reaction mixture was stirred at ambient temperature for 1 h, then the reaction mixture was acidified by the addition of 1N HCl solution. The product was extracted with heptane and then Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated, and 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 (500 MHz, chloroform-d) δ 7.59 (d, J = 7.6 Hz, 2H), 7.52 (d, J =8.0 Hz, 2H), 7.45 (d, J = 7.6 Hz, 2H), 7.35 (d, J = 7.3 Hz, 1H), 7.24 (d, J =7.9 Hz, 2H), 4.00 (s, 2H), 2.40 (d, J = 4.4 Hz, 6H).

[0327] Step 4: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxylic acid [ka]

[0328] 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 t-butyl ether (14 mL, 0.2 M) was added n-BuLi (1.5 mL, 2.64 mmol) slowly at -65°C and then stirred. The mixture was stirred for 30 min, then an excess of dry ice was added at -65°C and stirred for 1 h. The reaction mixture was acidified by the addition of 1N HCl solution and then extracted with EtOAc and distilled water. The organic layer was extracted with Na 2 SO 4 The extract was dried at 4° C., 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 (500 MHz, DMSO-d 6 ) δ 12.64 (s, 1H), 7.61 (d, J = 7.6Hz, 2H), 7.55-7.52 (m, 2H), 7.44 (t,J = 7.2Hz, 2H), 7.36-7.32 (m, 1H), 7.16-7.12 (m, 2H), 4.17 (s, 2H), 2.55 (s, 3H), 2.31 (s, 3H).

[0329] Step 5: Synthesis of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxamido) spiro[3.3]heptane-2-carboxylate [ka]

[0330] To a solution of 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxylic acid (0.1 g, 0.31 mmol) in DMF (1.1 mL, 0.3 M) was added intermediate A (70 mg, 0.34 mmol), HATU (0.13 g, 0.34 mmol) and DIPEA (0.16 mL, 0.93 mmol) and stirred at ambient temperature for 3 h. The reaction mixture was basified by addition of 1N NaOH solution and then extracted with EtOAc and distilled water. The organic layer was washed with Na 2 SO 4 The mixture was dried at 40° C., then 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-carboxylate (110 mg, 75% yield). 1 H NMR (500 MHz, chloroform-d) δ 7.57 (d, J = 7.6 Hz, 2H), 7.52 (d, J =7.3 Hz, 2H), 7.46 (t, J = 7.3 Hz, 2H), 7.36 (t , J = 7.2 Hz, 1H), 7.19 (d, J =7.6 Hz, 2H), 5.39 (d, J = 7.1 Hz, 1H), 4.28 (m, 1H), 4.00 (s, 2H), 3.66 (s,3H), 2.97 (p, J = 8.9, 8.4Hz, 1H), 2.46 (s, 3H), 2.38 (s, 3H), 2.30 (dd, J =14.1, LC / MS (ESI) m / z: 475.2 [M+H] + .

[0331] Step 6: Synthesis of 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0332] H 2 A solution of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (110 mg, 0.23 mmol) in 1:1:1 THF:MeOH was added with LiOH H 2 O (29 mg, 0.69 mmol) was added and stirred for 4 h. The reaction mixture was acidified by the addition of 1N HCl solution and then extracted with EtOAc and distilled water. The organic layer was extracted with Na 2 SO 4 The mixture was dried at rt, filtered and concentrated to give the compound of Example 1 (86 mg, 81% yield) without any purification. 1 H NMR (500 MHz, DMSO-d 6 ) δ 12.03 (s, 1H), 8.29 (d, J = 7.4 Hz, 1H), 7.61 (d, J = 7.7 Hz, 2H),7.51 (d, J = 7.6 Hz, 2H), 7.45 (t, J = 7.4 Hz, 2H), 7.34 (t, J = 7.2 Hz, 1H),7.19 (d, J = 7.7 Hz, 2H), 4.16 (h, J = 8.3 Hz, 1H), 3.90 (s, 2H), 2.91 (p, J =8.3 Hz, 1H), 2.34 (s, 3H), 2.32 (s, 3H), 2.29-2.13 (m, 4H), 2.11-2.06 (m, 1H),2.02 (s, 1H), 1.87 (s, 1H), 1.85 (d, J = 9.6 Hz, 1H). LC / MS (ESI) m / z: 460.01[M+H] + .

[0333] The compounds of Examples 2 to 5 were prepared in the same manner as Example 1, except for the differences in the preparation method described below.

[0334] [Table 1]

[0335] [Table 2]

[0336] Example 6: 6-(4-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of 2-([1,1'-biphenyl]-4-yl)-1-(2,5-dimethylthiophen-3-yl)methan-1-one [ka]

[0337] To a solution of 2-([1,1'-biphenyl]-4-yl)acetic acid (10.4 g, 49.1 mmol) in toluene (56 mL, 0.8 M) and DMF (~1 mL), SOCl 2 (6.1 g, 51.3 mmol) was added dropwise at 0° C., then the reaction mixture was heated to 50° C. for 1 h. The reaction mixture was cooled to ambient temperature and dimethylthiophene (5.1 mL, 44.6 mmol) was added, then cooled to 0° C. and 1M TiCl 4 The reaction mixture was acidified by the addition of 1N HCl solution, extracted with heptane, and the combined extracts were washed with Na 2 SO 4 The mixture was dried at 40° C., then filtered and concentrated. The crude product was purified by column chromatography to give 2-([1,1′-biphenyl]-4-yl)-1-(2,5-dimethylthiophen-3-yl)methan-1-one (8.8 g, 64% yield). 1 H NMR (500 MHz, chloroform-d) δ 7.60 (t, J = 8.6 Hz, 4H), 7.46 (t, J = 7.5 Hz, 2H), 7.36 (dd, J = 15.0, 7.5 Hz, 3H), 7.14 (s, 1H), 4.17 (s, 2H), 2.71(s, 3H), 2.46 (s, 3H).

[0338] Step 2: Synthesis of 3-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene [ka]

[0339] To a solution of 2-([1,1'-biphenyl]-4-yl)-1-(2,5-dimethylthiophen-3-yl)ethan-1-one (4.0 g, 13.1 mmol) in diethylene glycol (17.7 mL, 0.7 M) was added 80% hydrazine hydrate (2.0 mL) and KOH (2.5 g, 44.5 mmol). The reaction mixture was stirred at reflux for 6 h at 195° C., then the solution was cooled to ambient temperature and 18 mL of distilled water was added, followed by slow pouring into 11 mL of 6N aqueous HCl to induce the formation of a precipitate, thereby obtaining 3-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene (1.97 g, 52% yield). 1 H NMR (500 MHz, chloroform-d) δ 7.63 (d, J = 7.1 Hz, 2H), 7.55 (d, J =6.5 Hz, 2H), 7.47 (t, J = 7.7 Hz, 2H), 7.37 (t, J = 7.4Hz, 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).

[0340] Step 3: Synthesis of 3-(2-([1,1'-biphenyl]-4-yl)ethyl)-4-bromo-2,5-dimethylthiophene [ka]

[0341] 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) was added N-bromosuccinimide (0.13 g, 0.72 mmol). After stirring for 12 h, the solution was added to an excess of ice water and extracted with DCM. The DCM solution was washed with aqueous sodium carbonate and distilled water. The organic layer was diluted with MgSO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure, and 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 (500 MHz, chloroform-d) δ 7.62 (d, J = 8.0 Hz, 2H), 7.55 (d, J =8.2 Hz, 2H), 7.47 (t, J = 7.7 Hz, 2H), 7.36 (t, J = 7.4 Hz, 1H), 7.27 (d, J =8.1 Hz, 2H), 2.85 (p, J = 3.4 Hz, 4H), 2.40 (s, 3H), 2.15 (s, 3H).

[0342] Step 4: Synthesis of 4-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene-3-carboxylic acid [ka]

[0343] To a solution of 3-(2-([1,1'-biphenyl]-4-yl)ethyl)-4-bromo-2,5-dimethylthiophene (159 mg, 0.43 mmol), THF (2.2 mL, 0.2 M) and TMEDA (70 μL, 0.47 mmol) was added n-BuLi (2.5 M in THF, 0.22 mL, 0.56 mmol) slowly at -65°C and stirred. After 30 min, dry ice was added in excess at -65°C and stirred at ambient temperature for 1 h. The reaction mixture was acidified by the addition of 1 M HCl solution and then extracted with EtOAc and distilled water. The organic layer was extracted with Na 2 SO 4The mixture was dried at 4° C., 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 (500 MHz, DMSO-d 6 ); δ 12.69 (s, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.2 Hz, 2H),7.46 (t, J = 7.7 Hz, 2H), 7.35 (t, J = 7.4 Hz, 1H), 7.27 (d, J = 8.2 Hz, 2H), 2.96 (dd, J = 9.4, 6.5 Hz, 2H), 2.75-2.70 (m, 2H), 2.56 (s, 3H), 2.15 (s, 3H).

[0344] Step 5: Synthesis of methyl 6-(4-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene-3-carboxamido) spiro[3.3]heptane-2-carboxylate [ka]

[0345] To a solution of 4-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene-3-carboxylic acid (72 mg, 0.21 mmol), Intermediate A (47 mg, 0.23 mmol) and HATU (87 mg, 0.23 mmol) in DCM (1.1 mL, 0.2 M) was added DIPEA (0.11 mL, 0.63 mmol) and stirred at ambient temperature for 3 h. The reaction mixture was partially concentrated, the organic layer was extracted with 1N NaOH and ethyl acetate, and the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with brine and Na 2 SO 4 The mixture was dried at 40° C., concentrated, and then purified by column chromatography to give methyl 6-(4-(2-([1,1′-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (70 mg, 70% yield). 1H NMR (500 MHz, chloroform-d) δ 7.61 (d, J = 7.1 Hz, 2H), 7.53 (d, J =8.2 Hz, 2H), 7.46 (t, J = 7.7 Hz, 2H), 7.36 (t, J = 7.9 Hz, 1H), 7.20 (d, J =8.2 Hz, 2H), 5.55 (d, J = 7.7 Hz, 1H), 4.45 (h, J = 7.8 Hz, 1H), 3.69 (s, 3H),3.05 (p, J = 8.5Hz, 1H), 2.86 (dd, J = 6.4, 4.0 Hz, 2H), 2.82 (dd, J = 9.8, 6.5Hz, 2H), 2.61 (dt, J = 11.8, 5.5 Hz, 1H), 2.48 (dd, J = 11.8, 7.1 Hz, 1H), 2.45(s, 3H), 2.37 (d, J = 8.4 Hz, 2H), 2.32-2.27 (m, 1H), 2.19 ( s, 3H), 2.16-2.10(m, 1H), 1.92-1.82 (m, 2H); LC / MS (ESI) m / z: 488.3 [M+H] + .

[0346] Step 6: Synthesis of 6-(4-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0347] H 2 A solution of methyl 6-(4-(2-([1,1'-biphenyl]-4-yl)ethyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (70 mg, 0.14 mmol) in 1:1:1 THF:MeOH was added with LiOH H 2 O (18 mg, 0.42 mmol) was added. The reaction mixture was stirred at ambient temperature for 4 h, then acidified by addition of 1N HCl solution and extracted with DCM. The organic layer was washed with Na 2SO 4 The mixture was dried at rt, filtered and concentrated to give Example 6 (46 mg, 69% yield) without purification. 1 H NMR (500 MHz, methanol-d 4 ) δ 8.48 (d, J = 7.2 Hz, 1H),7.61 (d, J = 7.2 Hz, 2H), 7.52 (d, J = 8.2 Hz, 2H), 7.43 (t, J = 7.7 Hz, 2H),7.32 (t, J = 7.4 Hz, 1H), 7.21 (d, J = 8.2 Hz, 2H), 4.36 (dt, J = 13.2, 6.8 Hz,1H), 3.04 (p, J = 8.5 Hz, 1H), 2.88-2.82 (m, 2H), 2.80-2.75 (m, 2H), 2.61-2.55(m, 1H), 2.45-2.42 (m, 1H), 2.41 (s, 3H ), 2.41-2.34 (m, 2H), 2.29-2.24 (m,1H), 2.22-2.16 (m, 1H), 2.11 (s, 3H), 2.10-2.01 (m, 2H). LC / MS (ESI) m / z: 474.3[M+H] + .

[0348] Example 7: 6-(4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of (4-bromo-2,5-dimethylthiophen-3-yl)(3-fluoro-[1,1'-biphenyl]-4-yl)methanone [ka]

[0349] To a solution of intermediate E (0.50 g, 2.31 mmol) in toluene (2.6 mL, 0.8 M) and DMF (approximately 1 mL) was added SOCl 2(0.18 mL, 2.4 mmol) was added at 0° C. The reaction mixture was heated to 50° C. and stirred for 1 h, then intermediate C (0.40 g, 2.1 mmol) was added. The reaction mixture was cooled to 0° C. and TiCl 4 (0.23 mL, 2.1 mmol) was added. 1N aqueous HCl (10 mL) was added and stirred for 5 min, then the organic layer was extracted and the aqueous layer was washed twice with heptane. The organic layer was washed with brine and MgSO 4 The mixture was dried at 40° C., filtered and concentrated to give (4-bromo-2,5-dimethylthiophen-3-yl)(3-fluoro-[1,1′-biphenyl]-4-yl)methanone (200 mg, 25% yield). 1 H NMR (500 MHz, chloroform-d) δ 7.78 (t, J = 7.8 Hz, 1H), 7.65 (d, J = 7.2 Hz, 2H), 7.53-7.49 (m, 3H), 7.46 (d, J = 7.3 Hz, 1H), 7.36 (d, J = 11.9 Hz,1H), 2.48 (s, 3H), 2.39 (s, 3H).

[0350] Step 2: Synthesis of 3-bromo-4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene [ka]

[0351] To a solution of (4-bromo-2,5-dimethylthiophen-3-yl)(3-fluoro-[1,1'-biphenyl]-4-yl)methanone (150 mg, 0.39 mmol) in DCE (0.9 mL, 0.5 M) was added Et 3 SiH (0.18 mL, 1.17 mmol) was added. The reaction mixture was cooled to -8 °C and TiCl 4 (43 μL, 0.39 mmol) was slowly added and the reaction mixture was stirred for 1 h. 1N aqueous HCl (10 mL) was added and stirred for 5 min, then the organic layer was extracted and the aqueous layer was washed twice with heptane. The organic layer was washed with brine and MgSO 4The mixture was dried at 40° C., 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 (500 MHz, chloroform-d) δ 7.57 (d, J = 7.1 Hz, 2H), 7.45 (t, J =7.6 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.30 (d, J = 9.6 Hz, 1H), 7.26 (d, J =6.1 Hz, 1H), 7.00 (t, J = 8.0 Hz, 1H), 4.00 (s, 2H), 2.40 (s, 3H), 2.38 (s, 3H).

[0352] Step 3: Synthesis of 4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxylic acid [ka]

[0353] To a solution of 3-bromo-4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl-2,5-dimethylthiophene (74 mg, 0.20 mmol) and tetramethylenediamine (33 µL, 0.22 mmol) in THF (1.0 mL, 0.2 M) was added n-BuLi (2.5 M in THF, 0.09 mL, 0.22 mmol) slowly at -65 °C, then stirred for 45 min, and an excess of dry ice was added at -65 °C. 1N aqueous HCl (2.0 mL) was added and stirred for 15 min, then the organic layer was extracted and the aqueous layer was washed twice with EA. The organic layer was washed with brine and MgSO 4 The mixture was dried at 40° C., 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 (500 MHz, chloroform-d) δ 7.55 (d, J = 7.1 Hz, 2H), 7.44 (t, J =7.6 Hz, 2H), 7.36 (d, J = 7.3 Hz, 1H), 7.27 (d, J = 9.5 Hz, 1H), 7.22 (d, J =7.9 Hz, 1H), 6.91 (t, J = 8.0 Hz, 1H), 4.24 (s, 2H), 2.70 (s, 3H), 2.33 (s, 3H).

[0354] Step 4: Synthesis of methyl 6-(4-((3-fluoro-1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido) spiro[3.3]heptane-2-carboxylate [ka]

[0355] To a 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) in DMF (0.3 mL, 0.3 M) was added DIPEA (0.05 mL, 0.27 mmol) at ambient temperature and stirred for 3 h. The reaction mixture was concentrated, diluted with 1N aqueous NaOH and ethyl acetate and the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with brine and diluted with MgSO 4 The extract was dried at 40° C., 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-carboxamide) spiro[3.3]heptane-2-carboxylate (12 mg, yield 30%). 1H NMR (500 MHz, chloroform-d) δ 7.57-7.53 (m, 2H), 7.46 (t, J = 7.6Hz, 2H), 7.38 (t, J = 7.9 Hz, 1H), 7.29 (s, 1H), 7.26 (s, 1H), 7.08 (t, J = 7.8Hz, 1H), 5.49 (d, J = 7.8 Hz, 1H), 4.34 (h, J = 8.0 Hz, 1H), 3.98 (s, 2H), 3.67(s, 3H), 2.99 (p, J = 8.5 Hz, 1H), 2.53-2.47 (m, 1H), 2.46 (s, 3H), 2.39-2.36(m, 1H), 2.35 (s, 3H), 2.33-2.29 (m, 2H), 2.21 (dd, J = 11.6, 8.4 Hz, 1H), 2.06-2.00(m, 1H), 1.69-1.65 (m, 1H), 1.61 (dd, J = 11.6, 8.7 Hz, 1H). LC / MS (ESI) m / z:492.4 [M+H] + .

[0356] Step 5: Synthesis of 6-(4-((3-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0357] H 2 A solution of methyl 6-(4-((3-fluoro-[1,1′-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (12 mg, 0.02 mmol) in 2O / THF / MeOH (0.3 M, 0.1 mL) was added with LiOH H 2 2H2O (3.0 mg, 0.06 mmol) was added and stirred for 4 h. The reaction mixture was acidified by addition of 1N aqueous HCl and extracted with EA (3 × 5 mL). The organic layer was washed with MgSO 4The extract was dried at 40° C., filtered, concentrated, and then purified by silica gel column chromatography (n-hexane and ethyl acetate) to obtain the compound of Example 7 (6.0 mg, yield 55%). 1 H NMR (500 MHz, chloroform-d) δ 7.55 (d, J = 7.2 Hz, 2H), 7.46 (t, J =7.6 Hz, 2H), 7.38 (t, J = 7.3 Hz, 1H), 7.27 (d, J = 9.7 Hz, 2H), 7.08 (t, J =7.8 Hz, 1H), 5.48 (d, J = 7.8 Hz, 1H), 4.34 (h, J = 8.0 Hz, 1H), 3.98 (s, 2H),3.03 (p, J = 8.4 Hz, 1H), 2.50 (dt, J = 11.9, 6.3 Hz, 1H), 2.46 (s, 3H),2.41-2.36 (m, 2H), 2.35 (s, 3H), 2.34 (s, 1H), 2.23 (dd, J = 11.7, 8.2 Hz, 1H),2.08 (ddd, J = 11.6, 8.6, 2.2 Hz, 1H), 1.64 (ddd, J = 20.8, 11.4, 8.5 Hz, 2H).LC / MS (ESI) m / z: 478.2 [M+H] + .

[0358] Example 8: 6-(4-((2-amino-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of (2-amino-[1,1'-biphenyl]-4-yl)(4-bromo-2,5-dimethylthiophen-3-yl)methanone [ka]

[0359] AlCl 3To a mixture of (1.74 g, 13.1 mmol) and DCM (42.2 mL, 0.3 M), intermediate C (2.5 g, 13.1 mmol) was added and stirred for 30 min, then intermediate F (2.95 g, 12.7 mmol) was added to the reaction mixture and stirred for 12 h. The reaction mixture was poured onto ice, acidified with 1N aqueous citric acid, and then extracted twice with DCM. The organic layer was washed with distilled water and brine, and concentrated with MgSO 4 The mixture was dried at rt, concentrated under reduced pressure, and then purified by column chromatography to give (2-amino-[1,1'-biphenyl]-4-yl)(4-bromo-2,5-dimethylthiophen-3-yl)methanone (960 mg, 20% yield). 1 H NMR (300 MHz, chloroform-d) δ 7.50 (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).

[0360] Steps 2-5: Synthesis of 6-(4-((2-amino-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka] [ka]

[0361] The compound of Example 8 was prepared by reacting (2-amino-[1,1'-biphenyl]-4-yl)(4-bromo-2,5-dimethylthiophen-3-yl)methanone obtained in Step 1 above in the same manner as in Steps 2 to 5 of Example 7. 1H NMR (300 MHz, chloroform-d) δ 7.50-7.33 (m, 5H), 7.08 (d, J = 7.7Hz, 1H), 6.63 (d, J = 8.7 Hz, 1H), 6.57 (s, 1H), 5.67 (d, J = 8.8 Hz, 1H), 4.27(q, J = 8.0 Hz, 1H), 3.91 (s, 2H), 3.08-2.94 (m, 1H), 2.46 (s, 4H), 2.37 (s,3H), 2.31 (d, J = 8.1 Hz, 3H), 2.26-2.17 (m, 1H), 2.11-2.01 (m, 1H), 1.65-1.50(m, 2H). LC / MS (ESI) m / z: 475.5 [M+H] + .

[0362] Example 9: 6-(2,5-dimethyl-4-(4-morpholinobenzyl)thiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of (4-bromo-2,5-dimethylthiophen-3-yl)(4-fluorophenyl)methanone [ka]

[0363] To a solution of 4-fluorobenzoic acid (3.0 g, 21.3 mmol) in toluene (24 mL, 0.8 M) and DMF (approximately 1 mL), SOCl 2 (1.8 mL, 24.6 mmol) was added at 0° C., then stirred at 50° C. for 5 h. 3-Bromo-2,5-dimethylthiophene (3.7 g, 19.4 mmol) was added at 50° C., then TiCl 4 (2.1 mL, 19.4 mmol) solution was added. 1N aqueous HCl (30 mL) was added and stirred for 5 min, then the organic layer was extracted and the aqueous layer was washed twice with heptane. The organic layer was washed with brine and MgSO 4 The mixture was dried at 40° C., filtered and concentrated to give (4-bromo-2,5-dimethylthiophen-3-yl)(4-fluorophenyl)methanone (1.45 g, 24% yield).

[0364] Step 2: Synthesis of (4-bromo-2,5-dimethylthiophen-3-yl)(4-morpholinophenyl)methanone [ka]

[0365] DMSO:H 2 A solution of (4-bromo-2,5-dimethylthiophen-3-yl)(4-fluorophenyl)methanone (1.45 g, 4.62 mmol) and morpholine (1.2 mL, 13.9 mmol) in 2O (8 mL, 0.6 M) was added to the reaction mixture. 2 CO 3 (0.95 g, 6.5 mmol) was added, then heated to 90 °C and stirred for 8 h. The reaction mixture was diluted with distilled water and extracted twice with DCM. The organic layer was washed with brine and MgSO 4 The mixture was dried at 40° C., filtered and concentrated to give (4-bromo-2,5-dimethylthiophen-3-yl)(4-morpholinophenyl)methanone (1.21 g, 69% yield).

[0366] Step 3: Synthesis of 4-(4-((4-bromo-2,5-dimethylthiophen-3-yl)methyl)phenyl)morpholine [ka]

[0367] To a solution of (4-bromo-2,5-dimethylthiophen-3-yl)(4-morpholinophenyl)methanone (1.21 g, 3.2 mmol) in TFA (8 mL, 0.4 M) was added Et 3 SiH (1.80 mL, 11.2 mmol) was added at -10 °C and stirred at ambient temperature for 12 h. The reaction mixture was poured into 10 mL of ice water and extracted with ethyl acetate (3 x 20 mL) and then saturated NaHCO 3 Wash with aqueous solution (20 mL), distilled water (10 mL) and brine (20 mL) and add Na 2 SO 4After concentration under reduced pressure, 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 (300 MHz, chloroform-d) δ 7.08 (d, J = 8.7 Hz, 2H), 6.86 (d, J = 8.3 Hz, 2H), 3.91 - 3.84 (m, 6H), 3.17 - 3.11 (m, 4H), 2.38-2.34 (m, 6H).

[0368] Step 4: Synthesis of 2,5-dimethyl-4-(4-morpholinobenzyl)thiophene-3-carboxylic acid [ka]

[0369] 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), n-BuLi (2.5 M in THF, 0.73 mL, 1.86 mmol) was added slowly at −65° C. and then stirred for 45 min. An excess of dry ice was added to the reaction mixture at −65° C. and stirred at ambient temperature for 1 h. 1N aqueous citric acid solution (2.0 mL) was added and stirred for 15 min, the organic layer was extracted and the aqueous layer was washed twice with EA. The organic layer was washed with brine and MgSO 4 The mixture was dried at 40° C., then filtered and concentrated to give 2,5-dimethyl-4-(4-morpholinobenzyl)thiophene-3-carboxylic acid. 1 H NMR (500 MHz, chloroform-d) δ 7.03 (d, J = 8.6 Hz, 2H), 6.82 (d, J =8.6 Hz, 2H), 4.14 (d, J = 2.7 Hz, 2H), 3.88 - 3.83 (m, 4H), 3.13 - 3.09 (m,4H), 2.66 (s, 3H), 2.32 (s, 3H).

[0370] Step 5: Synthesis of methyl 6-(2,5-dimethyl-4-(4-morpholinobenzyl)thiophene-3-carboxamido) spiro[3.3]heptane-2-carboxylate [ka]

[0371] To a 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) in DMF (2.2 mL, 0.3 M) was added DIPEA (0.4 mL, 1.98 mmol) and stirred for 3 h. The reaction mixture was concentrated, diluted with 1N aqueous NaOH and ethyl acetate, and the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with brine and diluted with MgSO 4 The extract was dried at 40° C., 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-carboxamide) spiro[3.3]heptane-2-carboxylate (157 mg, 49% yield). 1H NMR (500 MHz, chloroform-d) δ 7.01 (d, J = 8.6 Hz, 2H), 6.85 (d, J =8.7 Hz, 2H), 5.41 (d, J = 7.7 Hz, 1H), 4.27 (h, J = 7.9 Hz, 1H), 3.88 (t, J =4.8 Hz, 6H), 3.68 (s, 3H), 3.14 - 3.10 (m, 4H), 3.00 (p, J = 8.5 Hz, 1H), 2.45(s, 4H), 2.34 (s, 3H), 2.31 (ddd, J = 12.4, 8.6, 4.9 Hz, 3H), 2.21 (dd, J =11.6, 8.4 Hz, 1H), 2.03 (ddd, J = 11.6, 8.6, 2.7 Hz, 1H), 1.57 (dd, J = 11.1,8.5 Hz, 1H), 1.50 (dd, J = 11.6, 8.6 Hz, 1H).

[0372] Step 6: Synthesis of 6-(2,5-dimethyl-4-(4-morpholinobenzyl)thiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0373] H 2 A solution of methyl 6-(2,5-dimethyl-4-(4-morpholinobenzyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (157 mg, 0.32 mmol) in 2O / THF / MeOH (0.3 M, 1.1 mL) was added with LiOH H 2 2H (40 mg, 0.96 mmol) was added and stirred for 4 h. The reaction mixture was acidified by addition of 1N aqueous citric acid and extracted with EA (3×5 mL). The organic layer was diluted with MgSO 4 The extract was dried at 40° C., filtered, concentrated, and then purified by silica gel column chromatography (n-hexane and ethyl acetate) to obtain the compound of Example 9 (12 mg, yield 8%). 1H NMR (500 MHz, chloroform-d) δ 7.01 (d, J = 8.6 Hz, 2H), 6.86 (d, J =8.7 Hz, 2H), 5.42 (d, J = 7.7 Hz, 1H), 4.26 (h, J = 7.9 Hz, 1H), 3.88 (t, J =4.8 Hz, 6H), 3.15 - 3.10 (m, 4H), 3.02 (p, J = 8.3 Hz, 1H), 2.45 (s, 4H), 2.34(s, 3H), 2.31 (dd, J = 11.3, 8.8 Hz, 3H), 2.21 (dd, J = 11.7, 8.0 Hz, 1H), 2.11- 2.05 (m, 1H), 1.57 (dd, J = 11.2, 8.3 Hz, 1H), 1.48 (dd, J = 11.6, 8.4 Hz,1H). LC / MS (ESI) m / z: 469.4 [M+H] + .

[0374] Example 10: 6-(4-([1,1'-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of 4-([1,1'-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carbonitrile [ka]

[0375] To a solution of [1,1'-biphenyl]-4-yl(4-bromo-2,5-dimethylthiophen-3-yl)methanone (1.30 g, 3.5 mmol) obtained in step 2 of Example 1 in DMF (58 mL, 0.06 M) was added CuCN (0.63 g, 7.0 mmol) and stirred at 110 °C for 24 h. The reaction mixture was concentrated and diluted with 1N aqueous HCl and ethyl acetate, then the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with brine and diluted with MgSO 4The extract was dried at 47° C., 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-carbonitrile (610 mg). 1 H NMR (500 MHz, chloroform-d) δ 7.91 (d, J = 8.2 Hz, 2H), 7.75 (d, J =8.2 Hz, 2H), 7.67 (d, J = 7.6 Hz, 2H), 7.51 (t, J = 7.6 Hz, 2H), 7.44 (t, J =7.3 Hz, 1H), 2.67 (s, 3H), 2.43 (s, 3H).

[0376] Step 2: Synthesis of 4-([1,1'-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carboxylic acid [ka]

[0377] 4-([1,1'-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carbonitrile (340 mg, 1.07 mmol) was dissolved in 70% H 2 SO 4 Aqueous solution (5.3 mL, 0.2 M) was added and then stirred under reflux at 110° C. for 1 h. The reaction mixture was poured into ice water, extracted three times with DCM, and the organic layer was diluted with MgSO 4 The mixture was dried at rt, 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, 12% yield). 1 H NMR (500 MHz, chloroform-d) δ 7.85 (d, J = 8.4 Hz, 2H), 7.66 - 7.61(m, 4H), 7.48 (t, J = 7.5 Hz, 2H), 7.42 (t, J = 7.3 Hz, 1H), 2.68 (s, 3H), 2.27(s, 3H).

[0378] Step 3: Synthesis of methyl 6-(4-([1,1'-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carboxamide) spiro[3.3]heptane-2-carboxylate [ka]

[0379] To a solution of 4-([1,1'-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carboxylic acid (12 mg, 0.036 mmol), intermediate A (17 mg, 0.08 mmol) and HATU (31 mg, 0.08 mmol) in DMF (0.3 mL, 0.3 M) was added DIPEA (0.04 mL, 0.22 mmol) and stirred for 3 h. The reaction mixture was concentrated, diluted with 1N aqueous NaOH and ethyl acetate, and the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with brine and diluted with MgSO 4 The extract was dried at 40° C., 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-carboxamide) spiro[3.3]heptane-2-carboxylate (33 mg, yield 55%). 1 H NMR (500 MHz, chloroform-d) δ 7.89 (d, J = 8.4 Hz, 2H), 7.69 (d, J =8.4 Hz, 2H), 7.65 (d, J = 7.2 Hz, 2H), 7.50 (t, J = 7.5 Hz, 2H), 7.43 (t, J =7.3 Hz, 1H), 5.97 (d, J = 7.3 Hz, 1H), 4.09 (dd, J = 16.0, 7.6 Hz, 1H), 3.65(s, 3H), 2.96 (p, J = 8.5 Hz, 1H), 2.60 (s, 3H), 2.34 (s, 4H), 2.26 - 2.17 (m,4H), 2.09 - 2.03 (m, 1H), 1.66 - 1.63 (m, 1H), 1.60 (d, J = 9.0 Hz, 1H). LC / MS(ESI) m / z: 488.4 [M+H] +

[0380] Step 4: Synthesis of 6-(4-([1,1'-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0381] H 2 A solution of methyl 6-(4-([1,1′-biphenyl]-4-carbonyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate (33 mg, 0.07 mmol) in 2O / THF / MeOH (0.3 M, 0.2 mL) was added with LiOH H 2 2H2O (9 mg, 0.21 mmol) was added and stirred for 4 h. The reaction mixture was acidified by addition of 1N aqueous HCl and extracted with EA (3×20 mL). The organic layer was washed with MgSO 4 The extract was dried at 40° C., filtered, concentrated, and then purified by silica gel column chromatography (n-hexane and ethyl acetate) to obtain the compound of Example 10 (20 mg, yield 63%). 1 H NMR (500 MHz, chloroform-d) δ 7.89 (d, J = 8.3 Hz, 2H), 7.69 (d, J =8.3 Hz, 2H), 7.64 (d, J = 7.3 Hz, 2H), 7.50 (t, J = 7.5 Hz, 2H), 7.43 (t, J =7.3 Hz, 1H), 6.03 (d, J = 7.3 Hz, 1H), 4.10 (h, J = 8.1 Hz, 1H), 2.99 (p, J =8.5 Hz, 1H), 2.59 (s, 3H), 2.34 (s, 4H), 2.23 (dt, J = 23.0, 9.6 Hz, 4H), 2.10(t, J = 10.3 Hz, 1H), 1.66 - 1.59 (m, 2H). LC / MS (ESI) m / z: 474.4 [M+H]+

[0382] Example 11: 6-(4-([1,1'-biphenyl]-4-yl(hydroxy)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0383] To a mixture of the compound of Example 10 (10 mg, 0.02 mmol) and ethanol (0.4 mL, 0.05 M), NaBH 4 (1.5 mg, 0.04 mmol) and CaCl 2 (2.0 mg, 0.02 mmol) was added and stirred for 12 h. Distilled water and ethyl acetate were added, and the aqueous layer was then extracted with ethyl acetate (10 mL). The organic layer was diluted with MgSO 4 The mixture was dried at rt, concentrated, and then purified by silica gel column chromatography (DCM and MeOH) to give Example 11 (4.0 mg, yield 40%). 1 H NMR (500 MHz, methanol-d 4 ) δ 8.42 (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, 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] - .

[0384] Example 12: 6-(4-([1,1'-biphenyl]-4-yl(methoxy)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of [1,1'-biphenyl]-4-yl(4-bromo-2,5-dimethylthiophen-3-yl)methanol [ka]

[0385] A mixture of [1,1'-biphenyl]-4-yl(4-bromo-2,5-dimethylthiophen-3-yl)methanone (2.0 g, 5.39 mmol) from step 2 of Example 1 and ethanol (108 mL, 0.05 M) was added with NaBH 4 (0.41 g, 10.8 mmol) and CaCl 2 (0.60 g, 5.39 mmol) was added and stirred for 12 h. Distilled water and ethyl acetate were added, and the aqueous layer was then extracted with ethyl acetate (50 mL). The organic layer was diluted with MgSO 4 The mixture was dried at rt, 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 (300 MHz, chloroform-d) δ 7.65 - 7.57 (m, 4H), 7.46 (dd, J =7.9, 3.8 Hz, 4H), 7.37 (t, J = 7.3 Hz, 1H), 6.13 (dd, J = 10.9, 3.2 Hz, 1H),2.42 - 2.35 (m, 6H).

[0386] Step 2: Synthesis of 3-([1,1'-biphenyl]-4-yl(methoxy)methyl)-4-bromo-2,5-dimethylthiophene [ka]

[0387] A solution of [1,1'-biphenyl]-4-yl(4-bromo-2,5-dimethylthiophen-3-yl)methanol (900 mg, 2.41 mmol) in methanol (80 mL, 0.03 M) was diluted with HCl ( 2 35% in O, 19 mL, 214 mmol) was added and stirred for 12 h. The reaction mixture was concentrated, basified with aqueous sodium bicarbonate and extracted with EA. The organic layer was diluted with MgSO 4 The mixture was dried at rt, concentrated, and then purified by silica gel column chromatography (0-5% MeOH in DCM) to give 3-([1,1'-biphenyl]-4-yl(methoxy)methyl)-4-bromo-2,5-dimethylthiophene (680 mg, 50% yield). 1 H NMR (300 MHz, chloroform-d) δ 7.63 - 7.54 (m, 4H), 7.49 - 7.41 (m,4H), 7.35 (t, J = 7.3 Hz, 1H), 5.68 (s, 1H), 3.45 (s, 3H), 2.41 - 2.35 (m, 6H).

[0388] Step 3: Synthesis of 4-([1,1'-biphenyl]-4-yl(methoxy)methyl)-2,5-dimethylthiophene-3-carboxylic acid [ka]

[0389] 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 Et 2 To a solution of 2H2O (6.7 mL, 0.2 M), n-BuLi (2.5 M in THF, 0.70 mL, 1.73 mmol) was added slowly at -65 °C and stirred for 45 min, then an excess of dry ice was added. 1N aqueous HCl (10 mL) was added and stirred for 15 min, then the organic layer was extracted and the aqueous layer was washed twice with EA. The organic layer was washed with brine and MgSO 4The mixture was dried at 4° C., 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 (300 MHz, DMSO-d6) δ 12.88 (s, 1H), 7.67 - 7.58 (m, 4H), 7.45 (t, J = 7.5 Hz, 2H), 7.36(d, J = 8.1 Hz, 3H), 6.11 (s, 1H), 3.31 (s, 3H), 2.54 (s, 3H), 2.23 (s, 3H).

[0390] Step 4: Synthesis of methyl 6-(4-([1,1'-biphenyl]-4-yl(methoxy)methyl)-2,5-dimethylthiophene-3-carboxamido) spiro[3.3]heptane-2-carboxylate [ka]

[0391] To a 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) in DMF (1.4 mL, 0.3 M) was added DIPEA (0.22 mL, 1.3 mmol) and stirred for 3 h. The reaction mixture was concentrated, diluted with 1N aqueous NaOH and ethyl acetate, and the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with brine and diluted with MgSO 4 The extract was dried at 40° C., 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-carboxamide) spiro[3.3]heptane-2-carboxylate (138 mg, yield 64%). 1H NMR (300 MHz, chloroform-d) δ 7.55 (dt, J = 9.7, 7.2 Hz, 4H), 7.45(t, J = 7.6 Hz, 2H), 7.35 (td, J = 7.6, 3.6 Hz, 3H), 5.63 (s, 1H), 3.97 (h, J =8.3 Hz, 1H), 3.65 (d, J = 4.9 Hz, 3H), 3.52 (d, J = 0.9 Hz, 3H), 2.95 (dt, J =15.0, 8.6 Hz, 1H), 2.58 (d, J = 2.6 Hz, 3H), 2.47 (s, 3H), 2.44 - 2.35 (m, 1H),2.29 - 2.11 (m, 4H), 2.08 - 1.91 (m, 1H), 1.78 - 1.65 (m, 1H), 1.23 - 1.10 (m,1H).

[0392] Step 5: Synthesis of 6-(4-([1,1'-biphenyl]-4-yl(methoxy)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0393] H 2 A solution of methyl 6-(4-([1,1′-biphenyl]-4-yl(methoxy)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (138 mg, 0.27 mmol) in 2O / THF / MeOH (0.3 M, 0.9 mL) was added with LiOH H 2 2H2O (34 mg, 0.81 mmol) was added and stirred for 12 h. The reaction mixture was acidified by the addition of 1N HCl aqueous solution and extracted with EA (20 mL x 3). The organic layer was diluted with MgSO 4The extract was dried at 40° C., 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-carboxamide)spiro[3.3]heptane-2-carboxylic acid (121 mg, yield 90%). 1 H NMR (300 MHz, DMSO-d6) δ 12.02 (s, 1H), 8.41 (d, J = 7.3 Hz, 1H), 7.62 (dd, J = 13.7, 7.8Hz, 4H), 7.41 (tt, J = 15.5, 7.2 Hz, 5H), 5.51 (s, 1H), 4.17 (h, J = 8.0 Hz,1H), 3.30 (s, 3H), 2.92 (p, J = 8.5 Hz, 1H), 2.45 - 2.30 (m, 4H), 2.28 - 2.14(m, 6H), 2.12 - 2.03 (m, 2H), 1.91 (tt, J = 19.4, 8.9 Hz, 2H). LC / MS (ESI) m / z:488.3 [M+H] - .

[0394] Example 13: 6-(4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of 2-([1,1'-biphenyl]-4-ylmethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka]

[0395] 4-Bromomethyl-biphenyl (600 mg, 2.44 mmol) in 1,4-dioxane (12 mL), K 2 CO 3 (1.0 g, 7.28 mmol), (pinacolato)diboron (740 mg, 2.92 mmol) and Pd(PPh 3 ) 4A solution of (140 mg, 0.12 mmol) was stirred at 100° C. for 12 h. Ethyl acetate (20 mL) was added and the precipitate was removed by filtration through Celite, then the organic layer was concentrated under reduced pressure and the crude product was purified by flash column chromatography (0-100% hexanes / EtOAc) to give 2-([1,1'-biphenyl]-4-ylmethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (61 mg, 86% yield) as a white solid. 1 H NMR (300 MHz, chloroform-d) δ 7.60 - 7.54 (m, 2H), 7.49 - 7.45 (m,2H), 7.44 - 7.37 (m, 2H), 7.33 - 7.29 (m, 1H), 7.27 - 7.24 (m, 2H), 2.34 (s,2H), 1.25 (s, 12H).

[0396] Step 2: Synthesis of methyl 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylate [ka]

[0397] N 2 Below, methyl 3-bromobenzo[b]thiophene-2-carboxylate (300 mg, 1.32 mmol), 2-(biphenyl-4-ylmethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (192 mg, 0.528 mmol) and Pd(PPh 3 ) 4 (60 mg) solution, and 2N K 2 CO 3 The aqueous solution was placed in a flask and stirred at 85° C. for 12 h. The reaction mixture was cooled to ambient temperature and then extracted with distilled water and EtOAc. The organic layer was washed with brine and then with MgSO 4The mixture was dried at 40° C., 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. 1 H NMR (400MHz, chloroform-d) δ 10.07 (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, 1H), 7.61 - 7.53(m, 1H), 7.52 - 7.46 (m, 2H), 7.45 - 7.41 (m, 1H), 7.41 - 7.36 (m, 1H), 7.32(d, J = 3.7 Hz, 1H), 3.91 - 3.87 (m, 5H).

[0398] Step 3: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid [ka]

[0399] To a solution of methyl 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylate (121 mg, 0.39 mmol) in THF (0.18 mL) was added 2N aqueous NaOH (0.2 mL) and stirred at 65 °C for 12 h. The reaction mixture was cooled to ambient temperature and then 2N aqueous HCl was added to adjust the pH to 2, stirred for 2 h, and then extracted with EtOAc. The organic layer was washed with brine and then with MgSO 4 The extract was dried at 40° C., 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. 1H NMR (500MHz, chloroform-d) δ 8.28 (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).

[0400] Step 4: Synthesis of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate [ka]

[0401] To a solution of methyl 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylate (30 mg, 0.1 mmol) in DCM (1 mL) was added Intermediate A (20 mg, 0.12 mmol), HATU (36 mg, 0.12 mmol) and DIPEA (0.03 mL, 0.4 mmol) and stirred for 12 h. EtOAc and brine were added to the reaction mixture and the organic layer was washed with MgSO 4 The mixture was dried at 40° C. and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to give methyl 6-(4-([1,1′-biphenyl]-4-ylmethyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (26 mg, 59% yield) as a white solid. 1H NMR (300MHz, chloroform-d) δ 7.63 (d, J = 3.2Hz, 1H), 7.61 - 7.51(m, 4H), 7.45 (ddd, J = 7.6, 6.8, 1.3Hz, 2H), 7.38 - 7.32 (m, 1H), 7.30 (s,1H), 7.27 (s, 1H), 6.97 (dt, J = 3.2, 0.9 Hz, 1H), 5.82 (d, J = 7.7 Hz, 1H),4.39 - 4.27 (m, 1H), 4.23 (s, 2H), 3.68 (s, 3H), 3.02 (p, J = 8.4Hz, 1H), 2.54(tt, J = 7.5, 5.2Hz, 1H), 2.46 - 2.38 (m, 1H).

[0402] Step 5: Synthesis of 6-(4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0403] To a solution of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate (20 mg, 0.04 mmol) in THF was added 2N aqueous NaOH and stirred at 65 °C for 12 h. The reaction mixture was cooled to ambient temperature and then 2N aqueous HCl was added to adjust the pH to 2, stirred for 2 h, and then extracted with EtOAc. The organic layer was washed with brine and then with MgSO 4 The mixture was dried at rt, filtered, concentrated under reduced pressure, and purified by column chromatography to give Example 13 (3.2 mg, 19% yield) as a white solid. 1H NMR (500MHz, chloroform-d) δ 7.61 (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, 0.9 Hz, 1H), 5.80 (d, J = 7.6 Hz, 1H), 4.33 (h, J =8.0 Hz, 1H), 4.21 (s, 2H), 3.04 (p, J = 8.5Hz, 1H), 2.55 - 2.49 (m, 1H), 2.44 LC / MS (ESI) m / z: 432.3 [M+H] + .

[0404] Example 14: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2-methylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid [ka]

[0405] THF / MeOH / H 2 A solution of methyl 4-([1,1′-biphenyl]-4-ylmethyl)thiophene-3-carboxylate (120 mg, 0.4 mmol) from step 2 of Example 13 in 2 / 1 / 2 mL of HO was added with LiOH H 2 2H (51 mg, 1.20 mmol, 3.0 equiv.) was added and stirred for 3 h. The reaction mixture was partially concentrated and acidified with 1N HCl, then the aqueous layer was extracted with EtOAc. The organic layer was washed with MgSO 4The mixture was dried at rt and then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (15% EtOAc / Hexanes) to give 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid (101 mg, 86% yield) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 10.02 (s, 1H), 8.23 ​​(dd, J = 3.1, 1.2Hz, 1H), 7.60 - 7.52 (m, 6H), 7.44 - 7.40 (m, 1H), 7.35 - 7.28 (m, 2H), 6.82(d, J = 3.3 Hz, 1H), 4.31 (s, 2H).

[0406] Step 2: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-2-methylthiophene-3-carboxylic acid [ka]

[0407] To a solution of methyl 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylate (70 mg, 0.12 mmol) in THF (1 mL) cooled to -78°C, n-BuLi (2.5 M in THF, 125 μL, 0.27 mmol) was added and stirred for 30 min. Iodomethane (18 μL, 0.31 mmol) was added slowly at -78°C, and the mixture was stirred at ambient temperature for 12 h. The reaction mixture was quenched with distilled water (15 mL) and EtOAc, then purified by silica gel column chromatography to give 4-([1,1'-biphenyl]-4-ylmethyl)-2-methylthiophene-3-carboxylate (32 mg, 45% yield) as a white solid. 1 H NMR (300 MHz, chloroform-d) δ 7.60 - 7.51 (m, 3H), 7.48 - 7.38 (m,3H), 7.35 - 7.26 (m, 2H), 7.00 (d, J = 5.4 Hz, 1H), 6.50 (d, J = 1.2 Hz, 1H),4.24 (s, 2H), 2.77 (s, 3H).

[0408] Step 3: Synthesis of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2-methylthiophene-3-carboxamido) spiro[3.3]heptane-2-carboxylate [ka]

[0409] To a solution of 4-([1,1'-biphenyl]-4-ylmethyl)-2-methylthiophene-3-carboxylic acid (30 mg, 0.096 mmol) in MeCN (0.6 mL), 4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-4-methyl-morpholin-4-ium chloride (DMT-MM) (27 mg, 0.105 mmol) was added and stirred for 1 h. Intermediate A (15 mg, 0.105 mmol) and N-methylpyrrolidone (25.8 μL) were added to the reaction mixture and stirred for 12 h, then the reaction was quenched 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-carboxamide) spiro[3.3]heptane-2-carboxylate (18 mg, 40% yield). 1H NMR (500 MHz, chloroform-d) δ 7.57 - 7.54 (m, 2H), 7.52 - 7.49 (m,2H), 7.43 (dd, J = 8.5, 6.9 Hz, 2H), 7.36 - 7.32 (m, 1H), 7.25 - 7.21 (m, 2H),6.74 (s, 1H), 5.46 (d, J = 7.7 Hz, 1H), 4.35 - 4.27 (m, 1H), 4.02 (s, 2H), 3.65(s, 3H), 2.96 (q, J = 8.5 Hz, 1H), 2.50 (s, 3H), 2.48 - 2.44 (m, 1H), 2.37 -2.33 (m, 1H), 2.29 (dd, J = 8.5, 4.0 Hz, 2H), 2.20 (dd, J = 11.7, 8.4 Hz, 1H),2.02 (ddd, J = 11.6, 8.6, 2.7 Hz, 1H), 1.66 - 1.61 (m, 2H).

[0410] Step 4: Synthesis of 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2-methylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0411] THF / MeOH / H 2 A solution of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2-methylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (10 mg) in 2HO (2 / 1 / 2 mL) was added to the solution with LiOH H 2 O (2 mg, 3.0 equiv.) was added and stirred for 3 h. The mixture was partially concentrated and then acidified with 1N aqueous HCl. The aqueous layer was extracted with EtOAc and the organic layer was washed with MgSO 4 The mixture was dried at rt and then concentrated under reduced pressure. The crude product was purified by column chromatography (Hexane:EA (60%)) to give Example 14 (2.3 mg, yield 24%). 1H NMR (500 MHz, methanol-d4) δ 7.61 - 7.58 (m, 2H), 7.53 - 7.50 (m,2H), 7.43 (td, J = 7.9, 2.1 Hz, 2H), 7.32 (td, J = 7.2, 1.4 Hz, 1H), 7.24 (t, J= 8.4 Hz, 2H), 6.89 (s, 1H), 4.21 - 4.16 (m, 1H), 4.01 (s, 2H), 2.96 (q, J =8.5 Hz, 1H), 2.44 (s, 3H), 2.43 - 2.37 (m, 1H), 2.35 - 2.26 (m, 3H), 2.16 (dd,J = 11.8, 8.4 Hz, 1H), 2.10 - 2.05 (m, 1H), 1.86 - 1.79 (m, 2H). LC / MS (ESI)m / z: 446.58 [M+H] + , 444.42 [M+H] - .

[0412] Example 15: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid [ka]

[0413] THF / MeOH / H 2 A solution of methyl 4-([1,1′-biphenyl]-4-ylmethyl)thiophene-3-carboxylate (1.3 g, 4.215 mmol) from step 2 of Example 13 in 2 / 1 / 2 mL of HO was added with LiOH H 2 2H (530 mg, 12.645 mmol, 3.0 equiv.) was added and stirred for 12 h. The reaction mixture was partially concentrated and then acidified with 1N aqueous HCl, and the aqueous layer was extracted with EtOAc. The organic layer was washed with MgSO 4The mixture was dried at rt and concentrated under reduced pressure, and the crude product was then purified by silica gel column to give 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid (350 mg, 28% yield) as an ivory solid. 1 H NMR (400 MHz, chloroform-d) δ 8.32-8.28 (m, 1H), 7.64-7.60 (m, 2H),7.60-7.55 (m, 2H), 7.48-7.43 (m, 2H), 7.37-7.32 (m, 3H), 6.89-6.82 (m, 1H),4.34 (s, 2H).

[0414] Step 2: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxylic acid [ka]

[0415] To a solution of 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid (200 mg, 0.66 mmol) in THF (1 mL), Br 2 (0.04 mL, 0.69 mmol) was added at 0 °C and stirred for 4 h. The reaction mixture was acidified with 1N HCl aqueous solution, the aqueous layer was extracted with ether, and the organic layer was then washed with distilled water and MgSO 4 The mixture was dried at 40° C. and concentrated under reduced pressure, and the crude product was purified by silica gel flash column chromatography to give 4-([1,1′-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxylic acid (132 mg, 28% yield) as a brown solid. 1 H NMR (500 MHz, chloroform-d) δ 8.29 (s, 1H), 7.59-7.54 (m, 2H),7.52-7.48 (m, 2H), 7.44-7.40 (m, 2H), 7.36-7.31 (m, 1H), 7.30-7.29 (m, 1H),7.29-7.27 (m, 1H), 4.41-4.36 (m, 2H).

[0416] Step 3: Synthesis of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxamido) spiro[3.3]heptane-2-carboxylate [ka]

[0417] To a solution of 4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxylic acid (50 mg, 0.134 mmol) and HATU (56 mg, 0.147 mmol) in DMF (1 mL) was added DIPEA (0.070 mL, 0.402 mmol), and intermediate A (17 mg, 0.120 mmol) was added to the reaction mixture and stirred for 15 h. The reaction mixture was diluted with ethyl acetate and washed with distilled water and brine solution. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by column chromatography (20% ethyl acetate in hexanes) to give methyl 6-(4-([1,1′-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate (44.9 mg, 64% yield) as an ivory solid. 1 H NMR (500 MHz, chloroform-d) δ 7.56-7.53 (m, 3H), 7.50-7.48 (m, 2H),7.44-7.39 (m, 2H), 7.35-7.31 (m, 1H), 7.26-7.22 (m, 2H), 5.82-5.76 (m, 1H),4.28-4.23 (m, 1H), 4.22 (s, 2H), 3.63 (s, 3H), 3.02- 2.91 (m, 1H), 2.48-2.41(m, 1H), 2.35-2.31 (m, 1H), 2.30-2.25 (m, 2H), 2.22-2.16 (m, 1H), 2.04- 1.96 (m, 1H), 1.68-1.59 (m, 2H).

[0418] Step 4: Synthesis of 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0419] THF / MeOH / H 2 A solution of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (20 mg, 0.038 mmol) in 2HO (2 / 1 / 2 mL) was added with LiOH H 2 O (5 mg, 0.114 mmol, 3.0 equiv) was added and stirred for 3 h. The mixture was partially concentrated and then acidified with 1N HCl, and the aqueous layer was then extracted with EtOAc. The organic layer was washed with MgSO 4 The mixture was dried at 40° C. and then concentrated under reduced pressure. The crude product was purified by silica gel column to give Example 15 (15 mg, 77% yield) as an ivory solid. 1 H NMR (400 MHz, chloroform-d) δ 7.58 (s, 1H), 7.56-7.52 (m, 2H),7.51-7.47 (m, 2H), 7.45-7.40 (m, 2H), 7.36-7.30 (m, 1H), 7.25-7.21 (m, 2H),5.74-5.68 (m, 1H), 4.33-4.26 (m, 1H), 4.23 (s, 2H), 3.05-2.94 (m, 1H),2.50-2.41 (m, 1H), 2.39-2.35 (m, 1H), 2.34-2.29 (m, 2H), 2.24-2.16 (m, 1H),2.07-1.99 (m, 1H), 1.68-1.58 (m, 2H). LC / MS (ESI) m / z: 510.51 [M+H] + ,508.35 [MH] - .

[0420] Example 16: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of methyl 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxylate [ka]

[0421] To a solution of methyl 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylate (100 mg, 0.324 mmol) from step 2 of Example 13 in DMF (3 mL) was added NBS (287 mg, 1.622 mmol) and stirred at 80° C. for 24 h. 10% aqueous sodium bicarbonate and EA were added to the reaction mixture and the organic layer was extracted with MgSO 4 The extract was dried at 40° C. and concentrated to give methyl 4-([1,1′-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxylate (76 mg, 50% yield) as a white solid. 1 H NMR (300 MHz, CDCl 3 ) δ 7.59 - 7.53 (m, 2H), 7.51 - 7.46 (m, 2H), 7.44 - 7.39 (m, 2H), 7.30- 7.33 (m, 1H), 7.18 (d, J = 8.2 Hz, 2H), 4.23 (s, 2H), 3.76 (s, 3H).

[0422] Step 2: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxylic acid [ka]

[0423] THF / MeOH / H 2A solution of methyl 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxylate (76 mg, 0.163 mmol) in 2H2O (1 / 1 / 1 mL) was added to LiOH H 2 O (21 mg, 0.489 mmol) was added and stirred for 12 h. The reaction mixture was partially concentrated and then acidified with 1N aqueous HCl, and the aqueous layer was extracted with EtOAc. The organic layer was diluted with MgSO 4 The extract was dried at rt and 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 H NMR (300 MHz, CDCl 3 ) δ 7.50 - 7.56 (m, 2H), 7.47 (d, J = 8.2 Hz, 2H), 7.45 - 7.40 (m, 2H),7.35 - 7.32 (m, 1H), 7.19 (d, J = 8.2 Hz, 2H), 4.29 (s, 2H).

[0424] Step 3: Synthesis of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxamido) spiro[3.3]heptane-2-carboxylate [ka]

[0425] To a solution of 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxylic acid (35.5 mg, 0.079 mmol) and HATU (33 mg, 0.086 mmol) in DMF (1 mL) was added DIPEA (0.041 mL, 0.237 mmol) followed by intermediate A (18 mg, 0.086 mmol) and stirred for 15 h. The reaction mixture was diluted with ethyl acetate and washed with distilled water and brine solution. The organic layer was extracted with Na 2 SO 4The mixture was dried at 40° C. 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-carboxamide)spiro[3.3]heptane-2-carboxylate (43.8 mg, 92% yield) as a white solid. 1 H NMR (300 MHz, CDCl 3 ) δ 7.57 - 7.51 (m, 2H), 7.50 - 7.40 (m, 4H), 7.37 - 7.30 (m, 1H), 7.20(s, 2H), 5.58 (d, J = 7.9 Hz, 1H), 4.32 - 4.24 (m, 1H), 4.11 (s, 2H), 3.65 (s,3H), 3.02 - 2.91 (m, 1H), 2.50 - 2.42 (m, 1H), 2.25 - 2.40 (m, 3H), 2.20 - 2.17(m, 1H), 2.06 - 1.99 (m, 1H), 1.73 - 1.63 (m, 2H).

[0426] Step 4: Synthesis of 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0427] THF / MeOH / H 2 A solution of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dibromothiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (42 mg, 0.070 mmol) in 2HO (1 / 1 / 1 mL) was added with LiOH H 2 0 (9 mg, 0.209 mmol) was added and stirred for 12 h. The reaction mixture was partially concentrated, then acidified with 1N aqueous HCl and filtered to give Example 16 (4 mg, 4% yield) as a white solid. 1 H NMR (300 MHz, CDCl 3) δ 7.56 - 7.51 (m, 2H), 7.50 - 7.39 (m, 4H), 7.36 - 7.33 (m, 1H), 7.21(d, J = 8.2 Hz, 2H), 5.58 (d, J = 7.7 Hz, 1H), 4.32 - 4.24 (m, 1H), 4.11 (s,2H), 3.06 - 2.95 (m, 1H), 2.51 - 2.29 (m, 4H), 2.25 - 2.17 (m, 1H), 2.14 - 2.04(m, 1H), 1.77 - 1.63 (m, 2H). LC / MS (ESI) m / z: 590.4 [M+H] + .

[0428] Example 17: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dichlorothiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dichlorothiophene-3-carboxylic acid [ka]

[0429] To a solution of 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid (110 mg, 0.374 mmol) from step 3 of Example 13 in DMF (3.6 mL) was added NCS (250 mg, 1.869 mmol), heated to 70° C. and stirred for 24 h. The reaction mixture was quenched with 10% aqueous sodium bicarbonate solution and, after 15 min, extracted with EA and distilled water and diluted with MgSO 4 The mixture was dried at 40° C. and concentrated to give crude 4-([1,1′-biphenyl]-4-ylmethyl)-2,5-dichlorothiophene-3-carboxylic acid (34.4 mg, 25% yield). 1 H NMR (300 MHz, CDCl 3) δ 7.58 - 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 = 8.2 Hz, 2H), 4.29 (s, 2H).

[0430] Steps 2 and 3: Synthesis of 6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dichlorothiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0431] The compound of Example 17 was obtained by reacting 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dichlorothiophene-3-carboxylic acid obtained in Step 1 above in the same manner as in Steps 3 and 4 of Example 16. 1 H NMR (300 MHz, CDCl 3 ) δ 7.57 - 7.51 (m, 2H), 7.50 - 7.39 (m, 4H), 7.34 - 7.31 (m, 1H), 7.22(d, J = 8.2 Hz, 2H), 5.68 (d, J = 7.6 Hz, 1H), 4.33 - 4.25 LC / MS (ESI) m / z: 500.3 [M+H] + .

[0432] Example 18: 6-(3-([1,1'-biphenyl]-4-ylmethyl)thiophene-2-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of 3-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylic acid [ka]

[0433] To a solution of thiophene-2-carboxylic acid (200 mg, 1.561 mmol) in THF (15 mL) was added n-BuLi (10 M in THF, 0.342 mL, 3.434 mmol) slowly over 0.5 h at −78° C., followed by 4-(bromomethyl)-1,1′-biphenyl (772 mg, 3.122 mmol). The reaction mixture was stirred for 6 h, then quenched with 1N aqueous HCl and extracted with EA and distilled water. The organic layer was washed with MgSO 4 The mixture was dried at 40° C. and then concentrated under reduced pressure. The crude product was purified by flash 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 (300 MHz, CDCl 3 ) δ 7.60 - 7.55 (m, 2H), 7.55 - 7.48 (m, 3H), 7.45 - 7.40 (m, 2H), 7.35- 7.28 (m, 3H), 6.93 (d, J = 5.1 Hz, 1H), 4.45 (s, 2H).

[0434] Step 2: Synthesis of methyl 6-(3-([1,1'-biphenyl]-4-ylmethyl)thiophene-2-carboxamido)spiro[3.3]heptane-2-carboxylate [ka]

[0435] To a solution of 3-([1,1'-biphenyl]-4-ylmethyl)thiophene-2-carboxylic acid (26 mg, 0.088 mmol) and HATU (20 mg, 0.097 mmol) in DCM (1 mL) was added DIPEA (0.046 mL, 0.264 mmol) and stirred for 10 min. Intermediate A (20 mg, 0.097 mmol) was added to the reaction mixture and stirred for 15 h. The reaction mixture was diluted with ethyl acetate and washed with distilled water and brine solution. The organic layer was extracted with Na 2SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by column chromatography (20% EtOAc in hexanes) to give methyl 6-(3-([1,1′-biphenyl]-4-ylmethyl)thiophene-2-carboxamido)spiro[3.3]heptane-2-carboxylate (32 mg, 82% yield) as a white solid. 1 H NMR (300 MHz, CDCl 3 ) δ 7.59 - 7.50 (m, 4H), 7.42 (t, J = 7.3 Hz, 2H), 7.34 (d, J = 7.3 Hz,1H), 7.32 - 7.27 (m, 3H), 6.92 (d, J = 5.0 Hz, 1H), 5.84 (d, J = 7.5 Hz, 1H),4.50 - 4.34 (m, 3H), 3.66 (s, 3H), 3.07 - 2.96 (m, 1H), 2.59 - 2.51 (m, 1H),2.46 - 2.40 (m, 1H), 2.35 - 2.22 (m, 3H), 2.14 - 2.07 (m, 1H), 1.87 - 1.76 (m,2H).

[0436] Step 3: Synthesis of 6-(3-([1,1'-biphenyl]-4-ylmethyl)thiophene-2-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0437] THF / MeOH / H 2 A solution of methyl 6-(3-([1,1'-biphenyl]-4-ylmethyl)thiophene-2-carboxamido)spiro[3.3]heptane-2-carboxylate (32 mg, 0.072 mmol) in 2H2O (1 / 1 / 1) was added with LiOH H 2 0 (9 mg, 0.209 mmol) was added and stirred for 12 h. The reaction mixture was partially concentrated, then acidified with 1N aqueous HCl and filtered to give Example 18 (30.7 mg, 99% yield) as a pale yellow solid. 1H NMR (300 MHz, CDCl 3 ) δ 7.59 - 7.50 (m, 4H), 7.42 (t, J = 7.4 Hz, 2H), 7.34 (d, J = 7.4 Hz,1H), 7.31 - 7.26 (m, 3H), 6.92 (d, J = 5.0 Hz, 1H), 5.85 (d, J = 7.5 Hz, 1H),4.47 - 4.29 (m, 3H), 3.11 - 2.99 (m, 1H), 2.60 - 2.52 (m, 1H), 2.46 - 2.40 (m,1H), 2.38 - 2.36 (m, 2H), 2.30 - 2.26 (m, 1H), 2.18 - 2.14 (m, 1H), 1.87 - 1.77(m, 2H). LC / MS (ESI) m / z: 432.4 [M+H] + .

[0438] Example 19: 6-(3-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)thiophene-2-carboxamide)spiro[3.3]heptane-2-carboxylic acid Steps 1 and 2: Synthesis of methyl 6-(3-(4-chlorobenzyl)thiophene-2-carboxamido)spiro[3.3]heptane-2-carboxylate [ka]

[0439] Methyl 6-(3-(4-chlorobenzyl)thiophene-2-carboxamide)spiro[3.3]heptane-2-carboxylate was obtained by the same method as in steps 1 and 2 of example 18, except that in step 1 of example 18, 4-chlorobenzyl bromide was used instead of 4-(bromomethyl)-1,1-biphenyl. 1H NMR (300 MHz, chloroform-d) δ 7.25-7.17 (m, 3H), 7.17-7.09 (m, 2H),6.80 (d, J = 5.0 Hz, 1H), 5.95 (d, J = 7.5 Hz, 1H), 4.42-4.28 (m, 1H), 4.24 (s,2H), 3.64 (s, 3H), 3.06-2.95 (m, 1H), 2.57-2.49 (m, 1H), 2.46-2.36 (m, 1H),2.34-2.22 (m, 3H), 2.17-2.07 (m, 1H), 1.91-1.80 (m, 2H).

[0440] Step 3: Synthesis of methyl 6-(3-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)thiophene-2-carboxamido)spiro[3.3]heptane-2-carboxylate [ka]

[0441] Methyl 6-(3-(4-chlorobenzyl)thiophene-2-carboxamido)spiro[3.3]heptane-2-carboxylate (286 mg, 0.7 mmol), 3-fluoro-5-methoxyphenylboronic acid (178 mg, 1.05 mmol, 1.5 equiv), Pd(OAc) 2 (16 mg, 0.07 mmol, 0.1 equiv.), XPhos (67 mg, 0.14 mmol, 0.2 equiv.) and K 3 PO 4 (297 mg, 1.4 mmol, 2.0 equiv.) was dissolved in 1,4-dioxane / H 2 The mixture was stirred in 200 mL of 100° C. for 2 h at 100° C. The reaction mixture was poured into distilled water and extracted with DCM. The organic layer was diluted with MgSO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by flash column chromatography to give methyl 6-(3-((3′-fluoro-5′-methoxy-[1,1′-biphenyl]-4-yl)methyl)thiophene-2-carboxamido)spiro[3.3]heptane-2-carboxylate.1 H NMR (300 MHz, chloroform-d) δ 7.47 (d, J = 8.2 Hz, 2H), 7.33-7.27(m, 2H), 6.93-6.80 (m, 3H), 6.58 (dt, J = 10.5, 2.3 Hz, 1H), 5.89 (d, J = 7.5Hz, 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).

[0442] Step 4: Synthesis of 6-(3-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)thiophene-2-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0443] The compound of Example 19 was obtained by reacting methyl 6-(3-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)thiophene-2-carboxamide)spiro[3.3]heptane-2-carboxylate obtained in Step 3 above in the same manner as in Step 3 of Example 18. 1 H NMR (300 MHz, methanol-d 4); δ 8.15 (d, J = 7.2 Hz, 1H),7.50 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 5.0 Hz, 1H), 7.26 (d , J = 8.3 Hz, 2H),6.94 (t, J = 1.9 Hz, 1H), 6.92-6.86 (m, 2H), 6.64 (dt, J = 10.7, 2.3 Hz, 1H),4.31-4.23 (m, 3H), 3.83 (s, 3H), 3.07-2.95 (m, 1H), 2.54-2.46 (m, 1H),2.39-2.30 (m, 3H), 2.29-2.14 (m, 2H), 2.07-1.96 (m, 2H). LC / MS (ESI) m / z: 480.4[M+H] + .

[0444] Example 20: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of methyl 4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxylate [ka]

[0445] To a solution containing methyl 4-([1,1'-biphenyl]-4-ylmethyl)thiophene-3-carboxylate (200 mg, 0.649 mmol) from step 2 of Example 13 in AcOH was added N-bromosuccinimide (NBS, 115 mg, 0.649 mmol) slowly at ambient temperature. After stirring for 15 h, the reaction mixture was extracted with DCM and washed with aqueous sodium carbonate and distilled water. The organic layer was washed again twice with distilled water and diluted with MgSO 4 The mixture was dried at 40° C., then 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-carboxylate (150 mg, 59% yield) as a yellow solid.1 H NMR (300 MHz, chloroform-d) δ 8.16 (s, 1H), 7.64-7.59 (m, 2H),7.57-7.53 (m, 2H), 7.49-7.43 (m, 2H), 7.39-7.30 (m, 3H), 4.42 (s, 2H), 3.83 (s,3H).

[0446] Step 2: Synthesis of methyl 4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxylate [ka]

[0447] To a solution of methyl 4-([1,1'-biphenyl]-4-ylmethyl)-5-bromothiophene-3-carboxylate (200 mg, 0.516 mmol) in THF (10 mL) was added iodomethane (0.065 mL, 1.548 mmol, 3.0 equiv.) and cooled to -78°C. n-BuLi (2M in THF, 0.516 mL, 1.032 mmol) was added to the reaction mixture and stirred for 4 h, then allowed to warm slowly to ambient temperature, diluted with ethyl acetate, and washed with distilled water. The organic layer was extracted with Na 2 SO 4 It was dried at 40° C. and concentrated under reduced pressure to give the crude product of methyl 4-([1,1′-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxylate (49 mg) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 7.99 (s, 1H), 7.61-7.59 (m, 2H),7.53-7.51 (m, 2H), 7.46-7.44 (m, 2H), 7.37-7.33 (m, 2H), 7.23-7.22 (m, 1H),4.36 (s, 2H), 3.82 (s, 3H), 2.46 (s, 3H).

[0448] Step 3: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxylic acid [ka]

[0449] THF / MeOH / H 2 A solution of methyl 4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxylate (20 mg, 0.062 mmol) in 2H2O (2 / 1 / 2) was added to LiOH H 2 2H (8 mg, 0.186 mmol, 3 equiv.) was added and stirred for 8 h. The reaction mixture was partially concentrated and then acidified with 1N aqueous HCl. The aqueous layer was extracted with EtOAc and the organic layer was extracted with MgSO 4 The mixture was dried at 40° C. and then concentrated under reduced pressure. The crude product was purified by silica gel column to give 4-([1,1′-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxylic acid (4.3 mg, 22% yield) as an ivory solid. 1 H NMR (300 MHz, chloroform-d) δ 8.10 (s, 1H), 7.59-7.54 (m, 2H),7.50-7.47 (m, 2H), 7.45-7.39 (m, 2H), 7.36-7.31 (m, 1H), 7.22-7.16 (m, 2H),4.34 (s, 2H), 2.44 (s, 3H).

[0450] Step 4: Synthesis of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxamido) spiro[3.3]heptane-2-carboxylate [ka]

[0451] To a solution of 4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxylic acid (7.3 mg, 0.024 mmol) and HATU (10 mg, 0.026 mmol) in DMF, DIPEA (0.013 mL, 0.072 mmol) was added and stirred for 10 min, then Intermediate A (4 mg, 0.026 mmol) was added and stirred for 15 h. The reaction mixture was diluted with ethyl acetate and washed with distilled water and brine. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by column chromatography (20% EtOAc in hexanes) to give methyl 6-(4-([1,1′-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (6.9 mg, 63% yield) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 7.58-7.56 (m, 2H), 7.52-7.50 (m, 2H),7.47-7.43 (m, 2H), 7.41 (s, 1H), 7.38-7.33 (m, 1H), 7.22-7.17 (m, 2H),5.77-5.71 (m, 1H), 4.36-4.28 (m, 1H), 4.19 (s, 2H), 3.67 (s, 3H), 3.04-2.95 (m,1H), 2.52-2.48 (m, 1H), 2.46 (s, 3H), 2.40-2.34 (m, 1H), 2.34-2.27 (m, 2H), 2.26-2.18 (m, 1H), 2.08-2.00 (m, 1H), 1.68-1.63 (m, 2H).

[0452] Step 5: Synthesis of 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0453] THF / MeOH / H 2A solution of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-5-methylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (6.8 mg, 0.015 mmol) in 2H2O (2 / 1 / 2) was added to the reaction mixture with LiOH H 2 2.0 (2 mg, 0.044 mmol, 3.0 equiv) was added and stirred for 3 h. The reaction mixture was partially concentrated and then acidified with 1N aqueous HCl, and the aqueous layer was then extracted with EtOAc. The organic layer was washed with MgSO 4 The mixture was dried at rt and then concentrated under reduced pressure. The crude product was purified by silica gel column to give Example 20 (4.7 mg, 70% yield) as an ivory solid. 1 H NMR (500 MHz, chloroform-d) δ 7.58-7.56 (m, 2H), 7.53-7.50 (m, 2H),7.47-7.43 (m, 3H), 7.38-7.34 (m, 1H), 7.22-7.17 (m, 2H), 5.76-5.71 (m, 1H),4.31-4.29 (m, 1H), 4.19 (s, 2H), 3.05-2.98 (m, 1H), 2.52-2.49 (m, 1H), 2.46 (s,3H), 2.36-2.33 (m, 3H), 2.27-2.22 (m, 1H), 2.10-2.05 (m, 1H), 1.71-1.65 (m,2H). LC / MS (ESI) m / z: 446.11 [M+H] + , 444.28 [MH] - .

[0454] The compounds of Examples 21 and 22 were prepared in the same manner as Example 20, except for the differences in the preparation method described below.

[0455] [Table 3]

[0456] [Table 4]

[0457] Example 23: 6-(4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of 3-bromo-4-(4-chlorobenzyl)-2,5-dimethylthiophene [ka]

[0458] To a solution of (4-chlorophenyl)methanol (427 mg, 3.0 mmol) in DCE (3 mL) was added intermediate C (1.15 g, 6.0 mmol), MsOH (78 μL, 1.20 mmol) and FeCl 3 (194 mg, 1.20 mmol) was added, then heated to 55° C. and stirred for 12 h. The reaction mixture was diluted with ethyl acetate and washed with distilled water and brine solution. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C. 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 (300 MHz, chloroform-d) δ 7.28 - 7.20 (m, 2H), 7.08 (d, J = 8.6 Hz, 2H), 3.91 (s, 2H), 2.37 (s, 3H), 2.35 (s, 3H).

[0459] Step 2: Synthesis of 4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxylic acid [ka]

[0460] To a solution of 3-bromo-4-(4-chlorobenzyl)-2,5-dimethylthiophene (541 mg, 1.71 mmol) and TMEDA (0.3 mL, 1.88 mmol) in THF (10 mL) was added n-BuLi (2.5 M in THF, 0.8 mL, 2.0 mmol) at −78° C. and stirred for 1 h. The reaction mixture was cooled to 5° C. and cooled to 5° C. 2 The mixture was quenched with gas at -78°C and left at ambient temperature for 30 min. The reaction mixture was acidified with 1N HCl solution, diluted with EtOAc, and then washed with distilled water. The organic layer was extracted with Na 2 SO 4 Drying at 40° C. and then concentration under reduced pressure gave 4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxylic acid (450 mg, crude) as a pale yellow solid. LC / MS (ESI) m / z: 281.26 [M+H] + .

[0461] Step 3: Synthesis of methyl 6-(4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxamide) spiro[3.3]heptane-2-carboxylate [ka]

[0462] To a solution of 4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxylic acid (450 mg, 1.60 mmol) and HATU (670 mg, 1.76 mmol) in DMF (8 mL), DIPEA (0.8 mL, 4.81 mmol) was added and stirred for 10 min, then intermediate A (330 mg, 1.60 mmol) was added to the reaction mixture and stirred for 15 h. The reaction mixture was diluted with EtOAc and washed with distilled water and brine solution. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C. 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-carboxamide)spiro[3.3]heptane-2-carboxylate (418 mg, 56% yield) as a white solid. 1H NMR (400MHz, chloroform-d) δ 7.23 (d, J = 8.5 Hz, 2H), 7.04 (d, J =8.4 Hz, 2H), 5.47 - 5.17 (m, 1H), 4.36 - 4.17 (m, 1H), 3.91 (s, 2H), 3.69 (s,3H), 3.02 (t, J = 8.5Hz, 1H), 2.54 - 2.41 (m, 4H), 2.40 - 2.29 (m, 5H), 2.25(dd, J = 11.7, 8.4 Hz, 1H), 2.13 - 2.01 (m, 1H), 1.68 - 1.52 (m, 3H).LC / MS(ESI) m / z: 432.37 [M+H] + .

[0463] Step 4: Synthesis of 6-(4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0464] H 2 A solution of methyl 6-(4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate (43 mg, 0.1 mmol) in 1:1:1 THF:MeOH was added with LiOH H 2 O (13 mg, 0.3 mmol) was added and stirred for 4 h. The reaction mixture was partially concentrated under reduced pressure and acidified (pH approx. 6) by addition of 1N HCl, then extracted with EtOAc. The organic layer was washed with Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by column chromatography to give Example 23 (30 mg, yield 71%). 1H NMR (300 MHz, chloroform-d) δ 7.27-7.18 (m, 2H), 7.04 (d, J = 8.5Hz, 2H), 5.35 (d, J = 7.9 Hz, 1H), 4.27 (d, J = 7.8 Hz, 1H), 3.91 (s, 2H), 3.06(t, J = 8.5 Hz, 1H), 2.53-2.44 (m, 1H), 2.43 (s, 3H), 2.41-2.35 (m, 2H),2.35-2.30 (m, 1H), 2.33 (s, 3H), 2.31-2.21 (m, 1H), 2.17-2.06 (m, 1H), 1.60(dt, J = 11.5, 7.7 Hz, 2H). LC / MS (ESI) m / z: 418.23 [M+H] + .

[0465] The compounds of Examples 24 and 25 were prepared in the same manner as Example 23, except for the differences in the preparation method described below.

[0466] [Table 5]

[0467] [Table 6]

[0468] Example 26: 6-(2,5-dimethyl-4-(4-(pyridin-4-yl)benzyl)thiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of methyl 6-(2,5-dimethyl-4-(4-(pyridin-4-yl)benzyl)thiophene-3-carboxamido) spiro[3.3]heptane-2-carboxylate [ka]

[0469] 1,4-Dioxane:H 2Methyl 6-(4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-carboxylate (27 mg, 0.06 mmol) from step 3 of Example 23, pyridin-4-ylboronic acid (9 mg, 0.075 mmol) and K 3 PO 4 A solution of (13 mg, 0.063 mmol) was diluted with N 2 The atmosphere was replaced, and then Pd 2 (dba) 3 (6 mg, 6.2 μmol) and PCy 3 (3 mg, 9.4 μmol) was added. The reaction mixture was irradiated in a microwave at 110° C. for 1.5 h, then filtered through Celite and concentrated under reduced pressure to give methyl 6-(2,5-dimethyl-4-(4-(pyridin-4-yl)benzyl)thiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate. LC / MS (ESI) m / z: 476.28 [M+2] + .

[0470] Step 2: Synthesis of 6-(2,5-dimethyl-4-(4-(pyridin-4-yl)benzyl)thiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0471] H 2 A solution of methyl 6-(2,5-dimethyl-4-(4-(pyridin-4-yl)benzyl)thiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate (crude product, 0.06 mmol) in 1:1:1 THF:MeOH was treated with LiOH H 2 O (9 mg, 0.18 mmol) was added and stirred for 4 h. The reaction mixture was concentrated under reduced pressure, diluted with distilled water, and then acidified with 1N HCl (pH approx. 6) and extracted with EtOAc. The organic layer was washed with Na 2 SO 4The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by column chromatography to give Example 26 (12 mg, 42% yield) as a white solid. 1 H NMR (300 MHz, methanol-d 4 ) δ 8.92-8.31 (m, 2H), 7.68(dd, J = 14.7, 7.0 Hz, 4H), 7.25 (d, J = 8.1 Hz, 2H), 4.34-3.95 (m, 1H), 4.00(s, 2H), 3.07-2.82 (m, 1H), 2.38 (s, 6H), 2.34-2.19 (m, 3H), 2.20-1.93 (m, 3H),1.91-1.60 (m, 2H). LC / MS (ESI) m / z: 462.31 [M+2] + .

[0472] Example 27: 6-(2,5-dimethyl-4-(4-(pyridin-3-yl)benzyl)thiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0473] Example 27 was obtained as a white solid by the same method as Example 26, except that pyridin-3-ylboronic acid was used instead of pyridin-4-ylboronic acid in step 1 of Example 26. 1 H NMR (500MHz, methanol-d 4) δ 8.78 (s, 1H), 8.51 (d, J =4.2Hz, 1H), 8.08 (d, J = 8.0Hz, 1H), 7.62 - 7.49 (m, 3H), 7.24 (d, J = 8.2Hz,2H), 4.26 - 4.08 (m, 1H), 4.00 (s, 2H), 3.03 - 2.87 (m, 1H), 2.45 - 2.37 (m,1H), 2.38 (s, 6H), 2.35 - 2.21 (m, 3H), 2.13 (dd, J = 8.2 Hz, 1H), 2.10 - 2.00(m, 1H), 1.79 (ddd, J = 24.7, 11.0, 8.9 Hz, 2H). LC / MS (ESI) m / z: 462.24 [M+2] + .

[0474] Example 28: 6-(4-((3',4'-dimethyl-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of methyl 6-(4-((3',4'-dimethyl-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido) spiro[3.3]heptane-2-carboxylate [ka]

[0475] A solution of methyl 6-(4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-carboxylate (50 mg, 0.023 mmol) from step 3 of Example 23 and 3,4-dimethylphenylboronic acid (4.1 mg, 0.027 mmol) in 1,4-dioxane (0.2 mL) was placed in a sealed tube and diluted with distilled water (0.01 mL) and Cs 2 CO 3 (8 mg, 0.046 mmol) was added. 2 (0.5 mg) and Xphos (13 mg, 0.023 mmol) 2The mixture was added under atmospheric pressure and then stirred at 90° C. for 15 hours. The reaction mixture was diluted with ethyl acetate, washed with distilled water, and then added with Na 2 SO 4 The crude product was purified by column chromatography (CHCl 3 in 6% MeOH) to give methyl 6-(4-((3',4'-dimethyl-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido) spiro[3.3]heptane-2-carboxylate (20 mg, mixture). 1 H NMR (500 MHz, chloroform-d) δ 7.48 - 7.45 (m, 2H), 7.32 (d, J = 2.0Hz, 1H), 7.28 (dd, J = 7.8, 2.1 Hz, 1H), 7.19 (d, J = 8.1 Hz, 1H), 7.13 (d, J =8.2 Hz, 2H), 5.38 (d, J = 7.8 Hz, 1H), 4.24 (h, J = 7.9 Hz, 1H), 3.96 (s, 2H),3.63 (s, 3H), 2.96 - 2.90 (m, 1H), 2.43 (s, 2H), 2.42 - 2.39 (m, 2H), 2.35 (s,3H), 2.32 (s, 3H), 2.30 (s, 3H), 2.27 - 2.23 (m, 2H), 2.15 (dd, J = 11.7, 8.5Hz, 1H), 1.96 (ddd, J = 11.7, 8.6, 2.9 Hz, 1H), 1.49 (ddd, J = 14.9, 11.4, 8.5Hz, 2H).

[0476] Step 2: Synthesis of 6-(4-((3',4'-dimethyl-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0477] THF / MeOH / H 2A solution of methyl 6-(4-((3',4'-dimethyl-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (20 mg) in 2H2O (2 / 1 / 2) was added with LiOH H 2 O (4 mg, 0.084 mmol, 3.0 equiv) was added and stirred for 3 h. The reaction mixture was partially concentrated and then acidified with 1N aqueous HCl, and the aqueous layer was extracted with EtOAc. The organic layer was washed with MgSO 4 The mixture was dried at 40° C. and then concentrated under reduced pressure. The crude product was purified by preparative TLC to give Example 28 (3.4 mg, 30% yield). 1 H NMR (500 MHz, chloroform-d) δ 7.49-7.45 (m, 2H), 7.32 (d, J = 2.0Hz, 1H), 7.28 (dd, J = 7.8, 2.1 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 7.14-7.11(m, 2H), 5.35 (d, J = 7.8 Hz, 1H), 4.24 (h, J = 8.0 Hz, 1H), 3.96 (s, 2H), 2.97(p, J = 8.5 Hz, 1H), 2.43 (s, 3H), 2.42-2.36 (m, 2H), 2.36 (s, 3H), 2.32 (s,3H), 2.30 (s, 3H), 2.28 (t, J = 4.1 Hz, 2H), 2.17 (dd, J = 11.7, 8.3 Hz, 1H),1.99 (ddd, J = 11.6, 8.7, 2.4 Hz, 1H), 1.49 (dt, J = 11.7, 9.1 Hz, 2H). LC / MS(ESI) m / z: 488.43 [M+H] + .

[0478] The compounds of Examples 29 to 66 were prepared in the same manner as Example 28, except for the differences in the preparation method described below.

[0479] [Table 7] JPEG2025508381000208.jpg187149 JPEG2025508381000209.jpg195149 JPEG2025508381000210.jpg97149

[0480]

Table 8

[0481]

Table 9

[0482]

Table 10

[0483]

Table 11

[0484]

Table 12

[0485] Example 67: 6-(4-(4-cyclohexylbenzyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of methyl 6-(2,5-dimethyl-4-((2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)thiophene-3-carboxamido) spiro[3.3]heptane-2-carboxylate [ka]

[0486] A solution of methyl 6-(4-(4-chlorobenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (50 mg, 0.11 mmol) from step 3 of Example 23 and 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (27 mg, 0.13 mmol) in 1,4-dioxane (1 mL) was placed in a sealed tube and heated with H 2 O (0.05 mL) and Cs 2 CO 3 (40 mg, 0.22 mmol) was added. 2 (2.5 mg) and Xphos (65 mg, 0.115 mmol) 2 The mixture was added under atmospheric pressure and stirred at 90° C. for 15 hours. The reaction mixture was diluted with ethyl acetate, washed with distilled water, and then with MgSO 4 The crude product was purified by silica gel column chromatography (30% EtOAc in hexanes) to give methyl 6-(2,5-dimethyl-4-((2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)thiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate (59 mg, mixture). 1H NMR (400 MHz, methanol-d 4 ) δ 7.28 - 7.22 (m, 2H), 7.00(d, J = 8.3 Hz, 2H), 6.07 (tt, J = 3.9, 1.7 Hz, 1H), 4.13 - 4.09 (m, 1H), 3.90(s, 2H), 3.66 (s, 3H), 3.02 (p, J = 8.5 Hz, 1H), 2.50 - 2.42 (m, 1H), 2.41 -2.37 (m, 2H), 2.35 (d, J = 5.5 Hz, 6H), 2.32 - 2.25 (m, 2H), 2.24 - 2.13 (m,4H), 2.10 - 2.05 (m, 1H), 1.81 - 1.75 (m, 4H), 1.71 - 1.67 (m, 2H).

[0487] Step 2: Synthesis of methyl 6-(4-(4-cyclohexylbenzyl)-2,5-dimethylthiophene-3-carboxamido) spiro[3.3]heptane-2-carboxylate [ka]

[0488] To a solution of methyl 6-(2,5-dimethyl-4-((2',3',4',5'-tetrahydro-[1,1'-biphenyl]-4-yl)methyl)thiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate (20 mg, 0.042 mmol) in ethyl acetate / methanol (8 / 2, 0.2 mL) was added 10% Pd / C (2.2 mg). The reaction mixture was stirred under hydrogen gas for 24 hours and filtered through Celite with ethyl acetate to give methyl 6-(4-(4-cyclohexylbenzyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate (12 mg). 1H NMR (400MHz, chloroform-d) δ 7.16 - 7.10 (m, 2H), 7.02 (s, 2H),5.32 (d, J = 7.9Hz, 1H), 4.31 - 4.13 (m, 1H), 3.91 (s, 2H), 3.68 (s, 3H), 3.03- 2.95 (m, 1H), 2.52 - 2.46 (m, 1H), 2.45 (s, 3H), 2.40 - 2.36 (m, 1H), 2.35(s, 3H), 2.30 - 2.26 (m, 2H), 2.26 - 2.23 (m, 1H), 2.22 - 2.16 (m, 1H), 2.02 -1.96 (m, 1H), 1.87 - 1.83 (m, 4H), 1.69 - 1.65 (m, 2H), 1.48 - 1.43 (m, 2H),1.40 - 1.32 (m, 5H).

[0489] Step 3: Synthesis of 6-(4-(4-cyclohexylbenzyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0490] THF / MeOH / H 2 A solution of methyl 6-(4-(4-cyclohexylbenzyl)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (12 mg) in 2H2O (2 / 1 / 2) was added to the solution with LiOH H 2 O (3 mg, 0.075 mmol, 3.0 equiv.) was added and stirred for 3 h. The reaction mixture was partially concentrated and then acidified with 1N aqueous HCl, and the aqueous layer was extracted with EtOAc. The organic layer was diluted with MgSO 4 The mixture was dried at 40° C. and then concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain the compound of Example 67 (3.7 mg, yield 32%). 1H NMR (300 MHz, chloroform-d) δ 7.14 - 7.08 (m, 2H), 6.99 (d, J = 8.1Hz, 2H), 5.30 (d, J = 7.8 Hz, 1H), 4.29 - 4.12 (m, 1H), 3.89 (s, 2H), 3.00 (p,J = 8.5 Hz, 1H), 2.52 - 2.45 (m, 1H), 2.42 (s, 3H), 2.40 - 2.35 (m, 1H), 2.33(s, 3H), 2.31 - 2.27 (m, 2H), 2.26 - 2.21 (m, 1H), 2.18 (dd, J = 10.6, 7.2 Hz,1H), 2.06 - 1.96 (m, 1H), 1.82 (d, J = 8.1 Hz, 3H), 1.74 (d, J = 13.0 Hz, 2H),1.47 - 1.31 (m, 6H), 1.30 - 1.22 (m, 1H). LC / MS (ESI) m / z: 466.43 [M+H] + ,464.54 [M+H] - .

[0491] Example 68: 6-(2,5-dimethyl-4-(4-(piperidin-4-yl)benzyl)-thiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Steps 1-3: Synthesis of 6-(4-(4-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0492] 6-(4-(4-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid was obtained as an ivory solid by the same method as in Example 67, except that tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate was used instead of 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in step 1 of Example 67. 1 H NMR (400 MHz, chloroform-d) δ 7.13 (s, 2H), 7.06-7.01 (m, 2H),5.34-5.29 (m, 1H), 4.30-4.20 (m, 3H), 3.91 (s, 2H), 3.05-2.96 (m, 1H),2.86-2.74 (m, 2H), 2.69-2.59 (m, 1H), 2.43 (s, 3H), 2.41-2.38 (m, 1H), 2.35 (s,3H), 2.33-2.27 (m, 4H), 2.15-2.09 (m, 1H), 1.82-1.76 (m, 2H), 1.67-1.54 (m,4H), 1.50 (s,9H).

[0493] Step 4: Synthesis of 6-(2,5-dimethyl-4-(4-(piperidin-4-yl)benzyl)thiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0494] A solution of 6-(4-(4-(1-(tert-butoxycarbonyl)piperidin-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid (14 mg, 0.024 mmol) and 4N HCl in dioxane (0.5 mL) was stirred for 2 h. The reaction mixture was poured into ether and concentrated under reduced pressure to give the hydrochloride salt of Example 68 (4 mg, 33%) as an ivory solid. 1 H NMR (500 MHz, methanol-d 4 ) δ 7.15-7.08 (m, 2H),7.04-6.98 (m, 2H), 4.16-4.09 (m, 1H), 3.86 (s, 2H), 3.49-3.44 (m, 2H),3.16-3.08 (m, 2H), 3.03-2.97 (m, 1H), 2.86-2.79 (m, 1H), 2.41-2.35 (m, 2H),2.33 (s, 3H), 2.30 (s, 3H), 2.26-2.20 (m, 2H), 2.17-2.12 (m, 1H), 2.12-2.06 (m,1H), 2.03-1.98 (m, 2H), 1.93-1.81 (m, 3H), 1.77-1.70 (m, 1H). LC / MS (ESI) m / z :465.7 [MH] - .

[0495] Example 69: 6-(4-((4'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0496] A solution of the compound of Example 23 (30 mg, 0.069 mmol) and 4-fluoroboronic acid (12 mg, 0.083 mmol) in 1,4-dioxane (0.2 mL) was placed in a sealed tube and diluted with H 2 O (0.01 mL) and Cs 2 CO 3 (45 mg, 0.138 mmol) was added.2 (2 mg, 0.007 mmol) and Xphos (33 mg, 0.069 mmol) 2 The mixture was added under atmospheric pressure and stirred at 90° C. for 12 hours. The reaction mixture was diluted with ethyl acetate, washed with distilled water, and added with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated. The crude product was purified using a silica column (hexane:ethyl acetate=1:1) to give Example 69 (3 mg, 12% yield) as an ivory solid. 1 H NMR (500 MHz, chloroform-d) δ 7.55-7.49 (m, 2H), 7.48-7.45 (m, 2H),7.19-7.17 (m, 2H), 7.17-7.12 (m, 2H), 5.46-5.35 (m, 1H), 4.33-4.25 (m, 1H),3.99 (s, 2H), 3.04-2.96 (m, 1H), 2.46 (s, 3H), 2.44-2.41 (m, 0H), 2.38 (s, 3H),2.36 2.30 (m, 4H), 2.22-2.15 (m, 1H), 2.06-1.98 (m, 1H), 1.62-1.49 (m, 3H).LC / MS (ESI) m / z: 478.6 [M+H] + , 476.6 [MH] -

[0497] Example 70: 6-(4-((3'-cyano-5'-fluoro-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0498] The compound of Example 70 can be prepared by the same procedure as in Example 69 except that 3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile is used instead of 4-fluoroboronic acid, and Cs 2 CO 3 Instead of K 3 PO 4This was obtained by the same method as in Example 69, except that 1 H NMR (300 MHz, MeOD) δ 8.28 (d, J = 7.5 Hz, 1H), 7.85 (t, J = 1.5 Hz, 1H), 7.73 (ddd, J =10.1, 2.5, 1.6 Hz, 1H), 7.63 - 7.54 (m, 2H), 7.52 (ddd, J = 8.1, 2.5, 1.3 Hz,1H), 7.23 (d, J = 8.2 Hz, 2H), 4.22 - 4.08 (m, 1H), 3.99 (s, 2H), 2.95 (p, J =8.4 Hz, 1H), 2.49 - 2.38 (m, 1H), 2.39 (s, 3H), 2.37 (s, 3H), 2.35 - 2.20 (m,3H), 2.19 - 2.10 (m, 1H), 2.09 - 1.99 (m, 1H), 1.87 - 1.70 (m, 2H). LC / MS (ESI)m / z: 503.02 [M+H] + .

[0499] Example 71: 6-(4-((3'-fluoro-5'-hydroxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of methyl 6-(4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamido) spiro[3.3]heptane-2-carboxylate [ka]

[0500] Methyl 6-(4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate was obtained by the same method as in step 1 of example 67, except that (3-fluoro-5-methoxyphenyl)boronic acid was used instead of 2-(cyclohex-1-en-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane in step 1 of example 67. 1 H NMR (400 MHz, CDCl 3 ) δ 7.50 - 7.46 (m, 2H), 7.18 (d, J = 8.2 Hz, 2H), 7.01 (d, J = 5.4 Hz,1H), 6.89 (q, J = 2.1, 1.7 Hz, 1H), 6.62 (dt, J = 10.5, 2.3 Hz, 1H), 5.39 (d, J= 7.8 Hz, 1H), 4.28 (q, J = 8.1 Hz, 1H), 3.99 (s, 2H), 3.87 (s, 3H), 3.66 (s,3H), 3.03 - 2.95 (m, 1H), 2.45 (s, 3H), 2.37 (s, 3H), 2.30 (dq, J = 8.6, 4.2,3.4 Hz, 3H), 2.18 (dd, J = 11.7, 8.4 Hz, 1H), 2.02 - 1.97 (m, 1H), 1.58 - 1.51(m, 2H).

[0501] Step 2: Synthesis of 6-(4-((3'-fluoro-5'-hydroxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0502] To a 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-carboxylate (94 mg, 0.18 mmol) in DCM (0.1 M) was added BBr 3 (0.7 mL, 0.72 mmol) was added at 0° C. and stirred at ambient temperature for 5 h. The reaction mixture was quenched with distilled water and stirred for an additional 15 h, then extracted with ethyl acetate (2×20 mL) and washed with brine. The organic layer was concentrated with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (5% MeOH in DCM) to give Example 71 (22 mg, 25% yield) as an off-white solid. 1 H NMR (500 MHz, CDCl 3 ) 1 HNMR (400 MHz, chloroform-d) δ 7.41(d, J = 7.8 Hz, 2H), 7.14 (d, J = 8.0 Hz, 2H), 6.88 (t, J = 1.9 Hz, 1H), 6.83 -6.75 (m, 1H), 6.62 - 6.54 (m, 1H), 5.40 - 5.26 (m, 1H), 4.24 (h, J = 8.1 Hz,1H), 3.98 (s, 2H), 3.02 (p, J = 7.5 Hz, 1H), 2.49 - 2.27 (m, 3H), 2.41 (s, 3H),2.40 (s, 3H), 2.17 - 2.08 (m, 2H), 1.60 (dd, J = 12.1, 8.1 Hz, 1H), 1.38 - 1.22(m, 2H). LC / MS (ESI) m / z: 494.1 [M+H] + .

[0503] Example 72: 6-(4-(4-(2-hydroxypyridin-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Steps 1 and 2: Synthesis of methyl 6-(4-(4-(2-hydroxypyridin-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxamide) spiro[3.3]heptane-2-carboxylate [ka]

[0504] Methyl 6-(4-(4-(2-hydroxypyridin-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate was prepared by the procedure described in Example 71, step 1, using (2-methoxypyridin-4-yl)boronic acid instead of (3-fluoro-5-methoxyphenyl)boronic acid and reacting with Cs 2 CO 3 Instead of K 3 PO 4 This was obtained by the same method as in Example 71, except that

[0505] Step 3: Synthesis of 6-(4-(4-(2-hydroxypyridin-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0506] H 2 A solution of methyl 6-(4-(4-(2-hydroxypyridin-4-yl)benzyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate in O (0.1 M) was stirred for 15 h. The precipitated solid was filtered and dried to give the crude product, which was then purified by column chromatography (15% MeOH in DCM) to give Example 72 as an off-white solid. 1H NMR (300 MHz, MeOD) δ 8.25 (d, J = 7.4 Hz, 1H), 7.61-7.54 (m, 2H), 7.51 (d, J = 7.6 Hz,1H), 7.22 (d, J = 8.2 Hz, 2H), 6.78-6.69 (m, 2H), 4.21-4.08 (m, 1H), 3.99 (s,2H), 2.96 (p, J = 8.4 Hz, 1H), 2.38 (s, 6H), 2.32-1.98 (m, 6H), 1.76 (ddd, J =17.0, 11.4, 8.6 Hz, 2H); LC / MS (ESI) m / z: 477.16 [M+H] + .

[0507] Example 73: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-N,2,5-trimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of 3-([1,1'-biphenyl]-4-ylmethyl)-4-bromo-2,5-dimethylthiophene [ka]

[0508] A solution of [1,1'-biphenyl]-4-ylmethanol (553 mg, 3.0 mmol) in DCE (0.5 M) was diluted with 3-bromo-2,5-dimethylthiophene (918 mg, 4.80 mmol), FeCl 3 (195 mg, 1.20 mmol) and MsOH (78 μL, 1.20 mmol) were added and stirred at 55° C. for 10 hours. Ethyl acetate was added to the reaction mixture, which was washed with distilled water and brine, and the organic layer was then extracted with Na 2 SO 4 The mixture was dried at 40° C. 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. 1H NMR (500 MHz, chloroform-d) δ 7.61-7.57 (m, 2H), 7.52 (m, 2H), 7.44(t, J = 7.7 Hz, 2H), 7.39-7.31 (m, 1H), 7.24 (d, J = 7.9 Hz, 2H), 4.00 (s, 2H),2.41 (s, 3H), 2.40 (s, 3H).

[0509] Step 2: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxylic acid [ka]

[0510] To a solution of 3-([1,1'-biphenyl]-4-ylmethyl)-4-bromo-2,5-dimethylthiophene (169 mg, 0.47 mmol) and TMEDA (78 μL, 0.52 mmol) in THF (0.1 M) was added n-BuLi (0.228 mL, 0.57 mmol) at −78° C. and stirred for 1.5 h. The reaction mixture was cooled to 5° C. and cooled to 5° C. for 1 h. 2 The mixture was quenched with gas at -78°C and then slowly warmed to room temperature over 2 hours. It was acidified with 1N HCl solution, extracted with ethyl acetate and washed with water. The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C. 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, 37% yield) as a white solid.

[0511] Step 3: Synthesis of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-N,2,5-trimethylthiophene-3-carboxamido) spiro[3.3]heptane-2-carboxylate [ka]

[0512] To a solution of 4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxylic acid (52 mg, 0.16 mmol) and HATU (68 mg, 0.18 mmol) in DMF (0.05 M) was added DIPEA (84 μL, 0.48 mmol) and stirred for 10 min, and intermediate R (39 mg, 0.18 mmol) was added and stirred for 15 h. The reaction mixture was diluted with ethyl acetate and washed with distilled water and brine. The organic layer was extracted with Na 2 SO 4 Drying at 40° C., concentration under reduced pressure, and then purification by column chromatography (20% EtOAc in hexanes) afforded methyl 6-(4-([1,1′-biphenyl]-4-ylmethyl)-N,2,5-trimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate (47 mg, 59% yield) as a white solid.

[0513] Step 4: Synthesis of 6-(4-([1,1'-biphenyl]-4-ylmethyl)-N,2,5-trimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0514] H 2 0: A stirred solution of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-N,2,5-trimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (47 mg, 0.1 mmol) in THF:MeOH (0.1 M) was added with LiOH H 2 2H2O (12 mg, 0.3 mmol) was added and stirred for 4 h. The reaction mixture was partially concentrated under reduced pressure, acidified with 2N aqueous HCl (pH approx. 6), and extracted with ethyl acetate (2 x 30 mL). The organic layer was extracted with Na 2 SO 4The mixture was dried at 40° C., concentrated under reduced pressure, and then purified by column chromatography (70% EtOAc in hexanes) to give Example 73 (36 mg, 79% yield) as a white solid. LC / MS (ESI) m / z: 474.25 [M+H] + .

[0515] Example 74: 6-(4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of methyl 4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxylate [ka]

[0516] A mixture of intermediate D (996 mg, 4.0 mmol), 4-phenylphenol (817 mg, 4.8 mmol, 1.2 equiv), CuBr (115 mg, 0.8 mmol, 0.2 equiv) and Cs in pyridine (8 mL) 2 CO 3 A solution of (3.9 g, 12.0 mmol, 3.0 equiv) was irradiated with microwaves and stirred at 150 °C for 1 h. The reaction mixture was filtered through Celite, added to distilled water, extracted with EtOAc, and the organic layer was then washed with MgSO 4 The mixture was dried at 40° C. and then 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-carboxylate (550 mg, 40% yield).

[0517] Step 2: Synthesis of 4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxylic acid [ka]

[0518] THF / MeOH / H 2A solution of methyl 4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxylate (550 mg, 1.62 mmol) in 2H2O (1:1:1) was added to LiOH H 2 O (340 mg, 8.12 mmol, 5.0 equiv) was added and the reaction mixture was stirred at 70 °C for 12 h. The reaction mixture was partially concentrated and then acidified with 1N HCl, and the aqueous layer was then extracted with DCM. The organic layer was washed with MgSO 4 The mixture was dried at rt, then 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, 19% yield).

[0519] Step 3: Synthesis of methyl 6-(4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxamido) spiro[3.3]heptane-2-carboxylate [ka]

[0520] To a 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 equiv.) in DCM (2 mL), DIPEA (80 μL, 0.45 mmol, 1.5 equiv.) was added at 0° C. and stirred for 15 min. A solution of intermediate A (68 mg, 0.33 mmol, 1.1 equiv.) in DCM (1 mL) was added to the reaction mixture, which was then stirred for 8 h. The reaction mixture was added to distilled water and extracted with DCM. The organic layer was washed with MgSO 4 The mixture was dried at 40° C. and then concentrated under reduced pressure. The crude product was purified by column chromatography to give methyl 6-(4-([1,1′-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate (50 mg, 34% yield).

[0521] Step 4: Synthesis of 6-(4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0522] THF / MeOH / H 2 A solution of methyl 6-(4-([1,1'-biphenyl]-4-yloxy)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (50 mg, 0.5 mmol) in 2H2O (1:1:1) was added to the solution of 100 mL of LiOH H 2 O (13 mg, 0.3 mmol, 3.0 equiv.) was added and stirred for 12 h. The reaction mixture was partially concentrated, then acidified with 1N HCl and extracted with EtOAc. The organic layer was washed with MgSO 4 The mixture was dried at 40° C. and then concentrated under reduced pressure. The crude product was purified by column chromatography to give Example 74 (22 mg, 47% yield). 1 H NMR (300MHz, methanol-d 4 ) δ 7.60 - 7.49 (m, 4H), 7.46- 7.34 (m, 2H), 7.34 - 7.23 (m, 1H), 6.98 - 6.87 (m, 2H), 4.12 - 3.96 (m, 1H),2.96-2.85 (m, 1H), 2.52 (s, 3H), 2.36-2.28 (m, 1H), 2.25-2.18 (m, 5H), 2.18 -1.95 (m, 3H), 1.75-1.65 (m, 2H). LC / MS (ESI) m / z: 462.5 [M+H] + .

[0523] Example 75: 6-(4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of methyl 4-amino-2,5-dimethylthiophene-3-carboxylate [ka]

[0524] Intermediate D (1.25 g, 5.0 mmol, 1.0 equiv.) and Cu in NMP (10 mL) 2 To a solution of HO (715 mg, 5.0 mmol, 1.0 equiv.) was added H 2 NH in O 3 (5 mL) was added, heated to 100 °C and stirred for 12 h. The reaction mixture was added to distilled water and extracted with DCM. The organic layer was diluted with MgSO 4 The mixture was dried at 40° C. and then concentrated under reduced pressure. The crude product was purified by column chromatography to give methyl 4-amino-2,5-dimethylthiophene-3-carboxylate (182 mg, 19% yield).

[0525] Step 2: Synthesis of methyl 4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxylate [ka]

[0526] Methyl 4-amino-2,5-dimethylthiophene-3-carboxylate (182 mg, 0.98 mmol), 4-bromobiphenyl (274 mg, 1.18 mmol, 1.2 equiv.), Pd(OAc) in toluene (7 mL). 2 (22 mg, 0.098 mmol, 0.1 equiv.), Xantphos (114 mg, 0.196 mmol, 0.2 equiv.) and Cs 2 CO 3 (639 mg, 1.96 mol, 2.0 equiv) was stirred at 110 °C for 5 h. The reaction mixture was added to distilled water and extracted with DCM. The organic layer was washed with MgSO 4 The mixture was dried at 40° C. 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).

[0527] Step 3: Synthesis of 4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxylic acid [ka]

[0528] THF / MeOH / H 2 A solution of methyl 4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxylate (142 mg, 0.42 mmol) in 2H2O (1:1:1) was added to LiOH H 2 2H 3 O (53 mg, 1.26 mmol, 3.0 equiv.) was added and stirred at 70° C. for 12 h. The reaction mixture was partially concentrated and then acidified with 1N HCl. The precipitated solid was removed by filtration, washed with distilled water, and then dried to give 4-([1,1′-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxylic acid (135 mg, 99% yield).

[0529] Step 4: Synthesis of methyl 6-(4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxamide) spiro[3.3]heptane-2-carboxylate [ka]

[0530] To a 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 equiv.) in DCM (2 mL), DIPEA (110 μL, 0.62 mmol, 1.5 equiv.) was added at 0° C. and stirred for 15 min. A solution of intermediate A (93 mg, 0.45 mmol, 1.1 equiv.) in DCM (1 mL) was added to the reaction mixture and stirred for 12 h. The reaction mixture was added to distilled water and extracted with DCM. The organic layer was washed with MgSO 4The mixture was dried at 40° C. 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-carboxamide)spiro[3.3]heptane-2-carboxylate (126 mg, 65% yield).

[0531] Step 5: Synthesis of 6-(4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0532] THF / MeOH / H 2 A solution of methyl 6-(4-([1,1'-biphenyl]-4-ylamino)-2,5-dimethylthiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (50 mg, 0.1 mmol) in 2H2O (1:1:1) was added to LiOH H 2 O (13 mg, 0.3 mmol, 3.0 equiv.) was added and stirred for 12 h. The reaction mixture was partially concentrated, then acidified with 1N HCl and extracted with EtOAc. The organic layer was washed with MgSO 4 The mixture was dried at rt and then concentrated under reduced pressure. The crude product was purified by flash column chromatography to give Example 75 (20 mg, 43% yield). 1 H NMR (300 MHz, methanol-d 4) δ 7.56-7.47 (m, 2H),7.47-7.30 (m, 4H), 7.28-7.16 (m, 1H), 6.67 (d, J = 8.6 Hz, 2H), 4.16-3.99 (m,1H), 2.92-2.80 (m, 1H), 2.57 (s, 3H), 2.35-2.27 (m, 1H), 2.23 (s, 3H),2.22-2.11 (m, 3H), 2.08-2.02 (m, 1H), 1.98-1.90 (m, 1H), 1.63-1.54 (m, 2H).LC / MS (ESI) m / z: 461.6 [M+1] + .

[0533] Example 76: 6-(4-([1,1'-biphenyl]-4-yl(methyl)amino)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of methyl 6-(4-([1,1'-biphenyl]-4-yl(methyl)amino)-2,5-dimethylthiophene-3-carboxamide) spiro[3.3]heptane-2-carboxylate [ka]

[0534] Methyl 6-(4-([1,1′-biphenyl]-4-yl(methyl)amino)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate (120 mg, 0.25 mmol, 1.0 equiv.) from Step 4 of Example 75 in DMF (3 mL) 2 CO 3 To a solution of (104 mg, 0.75 mmol, 3.0 equiv.), iodomethane (80 μL, 1.25 mmol, 5.0 equiv.) was added and stirred at 80 °C for 5 days. The reaction mixture was added to distilled water and extracted with DCM. The organic layer was washed with MgSO 4The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by flash column chromatography to give methyl 6-(4-([1,1′-biphenyl]-4-yl(methyl)amino)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate (18 mg). 1 H NMR (300 MHz, chloroform-d) δ 7.58 - 7.46 (m, 4H), 7.40 (dd, J =8.4, 6.8 Hz, 2H), 7.32 - 7.26 (m, 1H), 6.72 - 6.67 (m, 2H), 4.27-4.19 (m, 1H),3.60 (s, 3H), 3.20 (s, 3H), 2.96-2.84 (m, 1H), 2.69 - 2.63 (m, 3H), 2.44-2.33(m, 1H), 2.32 - 2.16 (m, 3H), 2.14 - 2.10 (m, 3H), 2.10 - 2.03 (m, 1H), 1.94-1.86 (m, 1H), 1.48-1.38 (m, 2H).

[0535] Step 2: Synthesis of 6-(4-([1,1'-biphenyl]-4-yl(methyl)amino)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0536] THF / MeOH / H 2 A solution of methyl 6-(4-([1,1'-biphenyl]-4-yl(methyl)amino)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate (18 mg, 0.036 mmol) in 2HO (3 / 2 / 3 mL) was added with LiOH H 2 2H2O (5 mg, 0.108 mmol, 3.0 equiv.) was added and stirred for 3 h. The reaction mixture was partially concentrated and then acidified with 1N HCl. The precipitated solid was filtered and diluted with H 2 O and then dried to give Example 76 (12 mg).1 H NMR (500 MHz, methanol-d 4 ) δ7.76 (d, J = 7.2 Hz, 1H),7.56 - 7.51 (m, 2H), 7.47 (d, J = 8.8 Hz, 2H), 7.36 (t, J = 7.8 Hz, 2H), 7.22(t, J = 7.4 Hz, 1H), 6.69 (d, J = 8.7 Hz, 2H), 4.06-4.01 (m, 1H), 3.23 (s, 3H),2.88 - 2.81 (m, 1H), 2.48 (s, 3H), 2.30 (dt, J = 12.1, 6.1 Hz, 1H), 2.21 - 2.18(m, 2H), 2.18 (s, 3H), 2.17 - 2.12 (m, 1H), 2.06-2.02 (m, 1H), 1.96-1.90 (m,1H), 1.60-1.54 (m, 2H. LC / MS (ESI) m / z: 475.7 [M+H] + .

[0537] Example 77: 6-(2,5-dimethyl-4-((4-phenylpiperazin-1-yl)methyl)thiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of 4-bromo-2,5-dimethylthiophene-3-carboxylic acid [ka]

[0538] H 2 A solution of intermediate D (2.25 g, 9.03 mmol) in 2O / THF / MeOH (0.3 M, 30 mL) was added with LiOH H 2 2H2O (1.1 g, 27.1 mmol) was added and stirred for 12 h. The reaction mixture was acidified by addition of 1N HCl solution and extracted with EA (3×30 mL). The organic layer was washed with MgSO 4 The extract was dried at 47° C., 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 (500 MHz, DMSO-d 6 ) δ 13.06 (s, 1H), 2.55 (s, 3H), 2.32 (s, 3H).

[0539] Step 2: Synthesis of (4-bromo-2,5-dimethylthiophen-3-yl)(4-phenylpiperazin-1-yl)methanone [ka]

[0540] To a 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) in DMF (28 mL, 0.3 M) was added DIPEA (4.3 mL, 25.2 mmol) and stirred for 3 h. The reaction mixture was concentrated, diluted with 1N aqueous NaOH and ethyl acetate, and the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with brine and diluted with MgSO 4 The extract was dried at 40° C., concentrated, and then purified by silica gel column chromatography (n-hexane and ethyl acetate) to give (4-bromo-2,5-dimethylthiophen-3-yl)(4-phenylpiperazin-1-yl)methanone (2.92 g, yield 92%). 1 H NMR (500 MHz, chloroform-d) δ 7.34 - 7.29 (m, 2H), 6.95 (dd, J =13.9, 7.6 Hz, 3H), 4.07 (dt, J = 13.0, 5.0 Hz, 1H), 3.92 (dt, J = 13.0, 5.3 Hz,1H), 3.54 (ddd, J = 13.0, 6.6, 3.3 Hz, 1H), 3.45 (ddd, J = 13.0, 7.2, 3.3 Hz,1H), 3.29 (t, J = 5.2 Hz, 2H), 3.24 (ddd, J = 10.7, 7.2, 3.4Hz, 1H), 3.15 -3.09 (m, 1H), 2.41 (s, 3H), 2.37 (s, 3H).

[0541] Step 3: Synthesis of 1-((4-bromo-2,5-dimethylthiophen-3-yl)methyl)-5-phenylpiperazine [ka]

[0542] To a stirred solution of (4-bromo-2,5-dimethylthiophen-3-yl)(4-phenylpiperazin-1-yl)methanone (2.87 g, 7.6 mmol) and THF (19 mL, 0.4 M) was added BH 3 Me 2 S (19.5 mL, 39 mmol) was added and stirred at 40° C. for 12 h. The reaction mixture was cooled to ambient temperature and treated with NaHCO 3 The organic layer was extracted with aqueous solution (70 ml) and EA. 2 SO 4 The mixture was dried at 40° C., filtered, and the crude product was then purified by silica gel column chromatography (ethyl acetate / hexanes) to give 1-((4-bromo-2,5-dimethylthiophen-3-yl)methyl)-5-phenylpiperazine (1.4 g, 51% yield). 1 H NMR (500 MHz, chloroform-d) δ 7.30 - 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).

[0543] Step 4: Synthesis of 2,5-dimethyl-4-((4-phenylpiperazin-1-yl)methyl)thiophene-3-carboxylic acid [ka]

[0544] To a stirred solution of 1-((4-bromo-2,5-dimethylthiophen-3-yl)methyl)-5-phenylpiperazine (500 mg, 1.37 mmol), tetramethylenediamine (0.23 mL, 1.51 mmol) and THF (7.0 mL, 0.2 M), n-BuLi (2.5 M in THF, 0.72 mL, 1.8 mmol) was added slowly at -65 °C and stirred for 1 h, then excess dry ice was added. The mixture was acidified with 1 N HCl and extracted with EtOAc. The organic layer was washed with MgSO 4 The mixture was dried at 40° C., filtered and concentrated to give 2,5-dimethyl-4-((4-phenylpiperazin-1-yl)methyl)thiophene-3-carboxylic acid (502 mg).

[0545] Step 5: Synthesis of methyl 6-(2,5-dimethyl-4-((4-phenylpiperazin-1-yl)methyl)thiophene-3-carboxamido) spiro[3.3]heptane-2-carboxylate [ka]

[0546] To a 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) in DMF (5.1 mL, 0.3 M) was added DIPEA (0.80 mL) and stirred for 3 h. The reaction mixture was concentrated, diluted with 1N aqueous NaOH and ethyl acetate, and the aqueous layer was extracted three times with ethyl acetate. The organic layer was washed with brine and diluted with MgSO 4 The extract was dried at rt, 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-carboxamide) spiro[3.3]heptane-2-carboxylate (102 mg, 14% yield). 1H NMR (500 MHz, chloroform-d) δ 9.73 (d, J = 7.0 Hz, 1H), 7.32 (t, J =7.9 Hz, 2H), 6.94 (dd, J = 17.1, 7.9 Hz, 3H), 4.45 (h, J = 8.2, 7.7 Hz, 1H), 3.68(s, 3H), 3.44 (s, 2H), 3.23 (s, 4H), 3.05 (p, J = 8.5 Hz, 1H), 2.72 (s, 4H),2.62 (s, 4H), 2.47 (dt, J = 12.5, 6.5 Hz, 1H), 2.38 (d, J = 7.0 Hz, 5H), 2.31(dd, J = 11.6, 8.5 Hz, 1H), 2.16 - 2.10 (m, 1H), 1.91 (dt, J = 23.8, 10.4 Hz,2H).

[0547] Step 6: Synthesis of 6-(2,5-dimethyl-4-((4-phenylpiperazin-1-yl)methyl)thiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0548] H 2 A solution of methyl 6-(2,5-dimethyl-4-((4-phenylpiperazin-1-yl)methyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (163 mg, 0.34 mmol) in 2O / THF / MeOH (0.3 M, 1.1 mL) was added with LiOH H 2 2H2O (43 mg, 1.02 mmol) was added and stirred for 12 h. The reaction mixture was acidified by addition of 1N HCl solution and extracted with EA (3×20 mL). The organic layer was washed with MgSO 4 The extract was dried at 40° C., filtered, concentrated, and then purified by silica gel column chromatography (n-hexane and ethyl acetate) to give the compound of Example 77 (12 mg, yield 8%). 1 H NMR (500 MHz, methanol-d 4) δ 7.27 (t, J = 7.8 Hz, 2H),7.00 (d, J = 8.3 Hz, 2H), 6.88 (t, J = 7.3 Hz, 1H), 4.37 (p, J = 8.2 Hz, 1H),3.64 (s, 2H), 3.24 (s, 4H), 3.01 (p, J = 8.4 Hz, 1H), 2.83 (s, 4H), 2.59 (dt, J= 11.7, 6.6 Hz, 1H), 2.53 (s, 3H), 2.41 (s, 4H), 2.39 - 2.31 (m, 2H), 2.28 -2.23 (m, 1H), 2.16 (t, J = 10.1 Hz, 1H), 2.04 (dt, J = 28.7, 9.7 Hz, 2H). LC / MS(ESI) m / z: 468.3 [M+H] + .

[0549] Example 78: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-N,2,5-trimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of methyl 6-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,5-dimethylthiophene-3-carboxamido) spiro[3.3]heptane-2-carboxylate [ka]

[0550] To a solution of intermediate S (300 mg, 1.0 mmol) and HATU (456 mg, 1.20 mmol) in DMF (0.1 M), DIPEA (0.5 mL, 3.0 mmol) was added and stirred for 10 min, intermediate A (169 mg, 1.0 mmol) was added and stirred for 15 h. The reaction mixture was diluted with ethyl acetate and washed with distilled water (3×25 mL) and brine. The organic layer was extracted with Na 2 SO 4The extract was dried at rt, concentrated under reduced pressure and purified by column chromatography (40% EtOAc in hexanes) to give methyl 6-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate (260 mg, 83% yield) as a yellow liquid. 1 H NMR (300 MHz, chloroform-d) δ 7.85 (d, J = 7.6 Hz, 1H), 4.58 (s,2H), 4.55-4.32 (m, 1H), 3.69 (s,3H), 3.06 (p, J = 8.6 Hz, 1H), 2.68-2.59 (m,1H), 2.58 (s, 3H), 2.52-2.41 (m, 1H), 2.41-2.25 (m, 6H), 2.20-2.09 (m, 1H), 2.04-1.85(m, 2H), 0.94 (s, 9H), 0.16 (s, 6H).

[0551] Step 2: Synthesis of methyl 6-(4-(hydroxymethyl)-2,5-dimethylthiophene-3-carboxamido) spiro[3.3]heptane-2-carboxylate [ka]

[0552] To a solution of methyl 6-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,5-methylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate (226 mg, 0.50 mmol) in THF (0.1 M) was added tetra-n-butylammonium fluoride (TBAF) (1.0 M in THF, 0.75 mL, 0.75 mmol) and stirred for 15 h. The reaction mixture was diluted with ethyl acetate and washed with distilled water (3×25 mL) and brine. The organic layer was extracted with Na 2 SO 4It was dried at 40° C., concentrated under reduced pressure and purified by column chromatography (30% EtOAc in hexanes) to give methyl 6-(4-(hydroxymethyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate (171 mg) as a yellow liquid. 1 H NMR (300 MHz, chloroform-d) δ 6.49 (d, J = 7.9 Hz, 1H), 4.53-4.37(m, 3H), 3.69 (s, 3H), 3.05 (q, J = 8.5 Hz, 1H), 2.71-2.58 (m, 1H), 2.54 (s,3H), 2.53-2.44 (m, 1H), 2.40 (s, 3H), 2.38-2.27 (m, 3H), 2.24-2.14 (m, 1H),2.07-1.86 (m, 2H).

[0553] Step 3: Synthesis of methyl 6-(4-(bromomethyl)-2,5-dimethylthiophene-3-carboxamido) spiro[3.3]heptane-2-carboxylate [ka]

[0554] 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) was added PBr 3 (92 μL, 2.03 mmol) was added at 0° C. and stirred for 15 h. The reaction mixture was diluted with ethyl acetate and washed with bicarbonate solution and distilled water. The organic layer was extracted with Na 2 SO 4 It was dried at 40° C., filtered, concentrated under reduced pressure and purified by column chromatography (25% EtOAc in hexanes) to give methyl 6-(4-(bromomethyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate (49 mg, 50% yield) as a white solid. 1H NMR (300 MHz, chloroform-d) δ 6.18 (d, J = 7.0 Hz, 1H), 4.53 (s,2H), 4.53-4.39 (m, 1H), 3.69 (s, 3H), 3.05 (q, J = 8.5 Hz, 1H), 2.74-2.59 (m,1H), 2.57-2.51 (m, 1H), 2.47 (s, 3H), 2.42-2.35 (m, 1H), 2.38 (s, 3H),2.38-2.28 (m, 2H), 2.25-2.15 (m, 1H), 2.11-1.91 (m, 2H).

[0555] Step 4: Synthesis of methyl 6-(2,5-dimethyl-4-((4-phenyl-1H-pyrazol-1-yl)methyl)thiophene-3-carboxamido) spiro[3.3]heptane-2-carboxylate [ka]

[0556] To a solution of 4-phenyl-1H-pyrazole (12 mg, 0.08 mmol) in DMF (0.1 M) was added NaH (5 mg, 0.12 mmol) and stirred for 15 min. Methyl 6-(4-(bromomethyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate (32 mg, 0.08 mmol) was added and stirred for 4 h. The reaction mixture was diluted with ethyl acetate (10 mL) and washed with distilled water (2×10 mL). The organic layer was extracted with Na 2 SO 4 It was dried at 40° C., filtered, concentrated under reduced pressure and purified by column chromatography (40% EtOAc in hexanes) to give methyl 6-(2,5-dimethyl-4-((4-phenyl-1H-pyrazol-1-yl)methyl)thiophene-3-carboxamide) spiro[3.3]heptane-2-carboxylate (16 mg, 43% yield) as a white solid.

[0557] Step 5: Synthesis of 6-(2,5-dimethyl-4-((4-phenyl-1H-pyrazol-1-yl)methyl)thiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0558] H 2 0: A solution of methyl 6-(2,5-dimethyl-4-((4-phenyl-1H-pyrazol-1-yl)methyl)thiophene-3-carboxamido)spiro[3.3]heptane-2-carboxylate (16 mg, 0.03 mmol) in THF:MeOH (1:1:1, 0.1 M) was added with LiOH H 2 O (3 mg, 0.1 mmol) was added and stirred for 15 h. The reaction mixture was partially concentrated, acidified with 1N HCl solution (pH 4) and extracted with ethyl acetate (2×10 mL). The organic layer was washed with Na 2 SO 4 The extract was dried at rt, filtered, concentrated under reduced pressure, and then purified by column chromatography (5% MeOH in DCM) to give Example 78 (5 mg, 32% yield) as a white solid. 1 H NMR (400 MHz, MeOD) δ 7.85 (s, 1H), 7.81 (s, 1H), 7.57-7.50 (m, 2H), 7.36 (t, J = 7.7 Hz,2H), 7.26-7.17 (m, 1H), 5.28 (s, 2H), 4.20 (p, J = 8.1 Hz, 1H), 2.91 (p, J =8.5 Hz, 1H), 2.46 (s, 3H), 2.43-2.32 (m, 1H), 2.40 (s, 3H), 2.31-2.19 (m, 3H),2.17-2.07 (m, 1H), 2.01 (ddd, J = 11.4, 8.7, 2.7 Hz, 1H), 1.93-1.80 (m, 2H).LC / MS (ESI) m / z: 450.09 [M+H] + .

[0559] Example 79: 6-(4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of methyl 4-([1,1'-biphenyl]-4-ylmethyl)-3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylate [ka]

[0560] Intermediate T (780 mg, 3.0 mmol, 1.0 equiv) and Cs in DMF (10 mL) 2 CO 3 (2.44 g, 7.5 mmol, 2.5 equiv.) was added with 4-bromomethyl-biphenyl (890 mg, 3.6 mmol, 1.2 equiv.) and stirred for 12 h. The reaction mixture was poured into distilled water and extracted with DCM, then the organic layer was diluted with MgSO 4 The mixture was dried at 40° C. and then concentrated under reduced pressure. The crude product was purified by flash column chromatography to give methyl 4-([1,1′-biphenyl]-4-ylmethyl)-3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylate (940 mg, 73% yield). 1 H NMR (300 MHz, chloroform-d) δ 7.57-7.48 (m, 4H), 7.44-7.37 (m, 2H),7.36-7.29 (m, 1H), 7.26 (s, 1H), 7.25 (s, 1H), 7.11 (d, J = 8.1 Hz, 2H), 6.14(s, 2H), 3.82 (s, 3H).

[0561] Step 2: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid [ka]

[0562] THF / MeOH / H 2A solution of methyl 4-([1,1'-biphenyl]-4-ylmethyl)-3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylate (940 mg, 2.2 mmol) in 20HO (20 / 10 / 10 mL) was added with LiOH H 2 277 mg, 6.6 mmol, 3.0 equiv. of HO was added and stirred at 70° C. for 12 h. The reaction mixture was partially concentrated and then acidified with 1N HCl solution. The precipitated solid was filtered, then 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). 1 H NMR (300 MHz, chloroform-d) δ 7.58-7.36 (m, 3H), 7.43-7.36 (m, 2H),7.32 (d, J = 6.8 Hz, 2H), 7.11 (d, J = 8.1 Hz, 2H), 6.12 (s, 2H).

[0563] Step 3: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole [ka]

[0564] A solution of 4-([1,1'-biphenyl]-4-ylmethyl)-3-bromo-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (815 mg, 1.97 mmol) and Cu powder (82 mg, 10 wt%) in quinoline (10 mL) was stirred at 140° C. for 12 h. The reaction mixture was cooled and acidified with 6N HCl solution, then diluted with Et 2 The organic layer was extracted with MgSO 4 After drying at rt and concentration under reduced pressure, the crude product was purified by flash column chromatography to give 4-([1,1′-biphenyl]-4-ylmethyl)-3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole (170 mg, 23% yield).

[0565] Step 4: Synthesis of 4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid [ka]

[0566] To a 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 equiv.) in THF (5 mL) was added n-BuLi (2.0 M in cyclohexane, 0.3 mL, 1.2 equiv.) at -78 °C and stirred for 10 min. Dry ice was added to the reaction mixture and stirred at ambient temperature for 1 h, then acidified with 1N HCl solution and extracted with EtOAc. The organic layer was washed with MgSO 4 After drying at rt and concentration under reduced pressure, the crude product was purified by flash column chromatography to give 4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid (100 mg, mixture).

[0567] Step 5: Synthesis of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxamide) spiro[3.3]heptane-2-carboxylate [ka]

[0568] To a 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 equiv.) in DCM (2 mL), DIPEA (80 μL, 0.45 mmol, 1.5 equiv.) was added at 0 °C and stirred for 15 min. Intermediate A (68 mg, 0.33 mmol, 1.1 equiv.) was added to the reaction mixture and stirred for 12 h. The reaction mixture was poured into distilled water, extracted with DCM, and the organic layer was removed by filtration with MgSO 4The mixture was dried at 40° C. and concentrated under reduced pressure. The crude product was purified by flash column chromatography to give methyl 6-(4-([1,1′-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxamide)spiro[3.3]heptane-2-carboxylate (40 mg, 30% yield). 1 H NMR (300 MHz, chloroform-d) δ 7.56-7.50 (m, 2H), 7.50-7.39 (m, 4H),7.36-7.29 (m, 1H), 7.11 (d, J = 8.3 Hz, 2H), 7.00 (dd, J = 2.9, 1.3 Hz, 1H),6.44 (d, J = 2.9 Hz, 1H), 5.99 (d, J = 7.8 Hz, 1H), 5.60 (s, 2H), 4.36-4.28 (m,1H), 3.66 (s, 3H), 3.05-2.94 (m, 1H), 2.54-2.46 (m, 1H), 2.42-2.36 (m, 1H), 2.33-2.30 (m, 2H), 2.27-2.20 (m, 1H), 2.09-2.01 (m, 1H), 1.80-1.71 (m, 2H).

[0569] Step 6: Synthesis of 6-(4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0570] THF / MeOH / H 2 A solution of methyl 6-(4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxamide)spiro[3.3]heptane-2-carboxylate (40 mg, 0.08 mmol) in 2H2O (1:1:1, 9 mL) was added to the reaction mixture with LiOH H 20 (10 mg, 0.24 mmol, 3.0 equiv.) was added and stirred for 12 h. The reaction mixture was partially concentrated and then acidified with 1N HCl solution. The precipitated solid was filtered, washed with distilled water, dried, and the crude product was purified by flash column chromatography to give Example 79 (15 mg, 40% yield). 1 H NMR (300 MHz, methanol-d 4 ) δ 8.34 (d, J = 7.3 Hz, 1H),7.58-7.52 (m, 2H), 7.50-7.44 (m, 2H), 7.44-7.35 (m, 3H), 7.33-7.26 (m, 1H),7.15 (dd, J = 3.0, 1.3 Hz, 1H), 7.02 (d, J = 8.3 Hz, 2H), 6.43 (d, J = 3.0 Hz,1H), 5.56 (s, 2H), 4.25-4.11 (m, 1H), 3.02-2.90 (m, 1H), 2.46-2.38 (m, 1H),2.35-2.23 (m, 3H), 2.22-2.01 (m, 2H), 1.91-1.81 (m, 2H). LC / MS (ESI) m / z: 471.4[M+H] + .

[0571] The compounds of Examples 80 to 89 were prepared in the same manner as Example 79, except for the differences in the preparation method described below.

[0572] [Table 13] JPEG2025508381000271.jpg211149 JPEG2025508381000272.jpg46149

[0573] [Table 14] JPEG2025508381000274.jpg183149

[0574] Example 90: 6-(4-(4-(trifluoromethyl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Steps 1-3: Synthesis of 3-bromo-4-(4-(trifluoromethyl)benzyl)-4H-thieno[3,2-b]pyrrole [ka]

[0575] 3-Bromo-4-(4-(trifluoromethyl)benzyl)-4H-thieno[3,2-b]pyrrole was obtained as a yellow liquid by the same method as in steps 1 to 3 of Example 79, except that 1-bromomethyl-4-(trifluoromethyl)benzene was used instead of 4-bromomethylbiphenyl in step 1 of Example 79. 1 H NMR (300 MHz, chloroform-d) δ 7.60-7.55 (m, 2H), 7.23-7.17 (m, 2H),7.03-6.98 (m, 1H), 6.88-6.85 (m, 1H), 6.44 (d, J = 3.0 Hz, 1H), 5.57 (d, J = 9.4 Hz, 2H).

[0576] Step 4: Synthesis of 4-(4-(trifluoromethyl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid [ka]

[0577] Pd(OAc) 2 (3 mol%) and Xantphos (3 mol%) were placed in an oven drying tube under vacuum and flushed with argon three times, then a solution of formic acid (0.24 mL, 6.258 mmol) and 3-bromo-4-(4-(trifluoromethyl)benzyl)-4H-thieno[3,2-b]pyrrole (322 mg, 0.894 mmol) in DMF (3.0 mL) was added. DCC (37 mg, 0.179 mmol) and Et 3N (0.25 mL, 1.788 mmol) was added, then the tube was sealed and the mixture was stirred at 100° C. for 20 h. The reaction mixture was filtered and concentrated under reduced pressure, then 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, 43% yield) as a white solid. 1 H NMR (300 MHz, chloroform-d) δ 8.09 (d, J = 1.3 Hz, 1H), 7.51 (d, J =8.1 Hz, 2H), 7.11 (d, J = 8.1 Hz, 2H), 6.95 (dd, J = 3.1, 1.3 Hz, 1H), 6.51 (d,J = 3.1 Hz, 1H), 5.81 (s, 2H).

[0578] Steps 5 and 6: Synthesis of 6-(4-(4-(trifluoromethyl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0579] The compound of Example 90 was obtained by reacting 4-(4-(trifluoromethyl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid in the same manner as in steps 5 and 6 of Example 79. 1 H NMR (300 MHz, DMSO-d 6) δ 12.0 (br s, 1H) 8.42 (d, J = 7.5 Hz, 1H), 7.61 (d, J = 8.0 Hz, 2H),7.58 (d, J = 1.3 Hz, 1H), 7.30 (dd, J = 3.0, 1.3 Hz, 1H), 7.16 (d, J = 8.0 Hz,2H), 6.47 (d, J = 3.0 Hz, 1H), 5.68 (s, 2H), 4.18-4.04 (m, 1H), 2.96-2.85 (m,1H), 2.39-2.00 (m, 6H), 1.92-1.85 (m, 2H). LC / MS (ESI) m / z: 463.4 [M+H] + .

[0580] The compounds of Examples 91 to 94 were prepared in the same manner as Example 90, except for the differences in the preparation method described below.

[0581] [Table 15]

[0582] [Table 16]

[0583] Example 95: 6-(4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2-methyl-4H-thieno[3,2-b]pyrrole-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Steps 1-3: Synthesis of 3-bromo-4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2-methyl-4H-thieno[3,2-b]pyrrole [ka]

[0584] 3-Bromo-4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2-methyl-4H-thieno[3,2-b]pyrrole was obtained by using intermediate U and intermediate Y as starting materials in the same manner as in steps 1 to 3 of example 79. 1 H NMR (400 MHz, CDCl 3 ) δ 7.50 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.1 Hz, 2H), 6.92 - 6.79 (m,3H), 6.60 (td, J = 2.3, 10.5 Hz, 1H), 6.37 (d, J = 2.9 Hz, 1H), 5.57 (s, 2H),3.84 (s, 3H), 2.44 (s, 3H). LC / MS (ESI) m / z: 430.2 [M+1].

[0585] Step 4: Synthesis of methyl 4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2-methyl-4H-thieno[3,2-b]pyrrole-3-carboxylate [ka]

[0586] To a 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 mmol, 1.00 equiv) in MeOH (4 mL), Pd(dppf)Cl 2 ·CH 2 Cl 2 (156 mg, 191 umol, 0.2 equiv.) and TEA (289 mg, 2.86 mmol, 398 uL, 3.0 equiv.) were added to N 2The mixture was purged with CO atmosphere three times and then stirred under CO (50 Psi) at 70° C. for 24 h. The reaction mixture was cooled, filtered, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate=50 / 1 to 20 / 1) to give methyl 4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2-methyl-4H-thieno[3,2-b]pyrrole-3-carboxylate (280 mg, 71.7% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO) δ 7.46 (d, J = 8.40 Hz, 2 H), 7.07 (d, J = 8.40 Hz, 2 H), 6.93-6.82(m, 3 H), 6.59 (td, J = 2.40, 10.4 Hz, 1 H), 6.40 (d, J = 3.00 Hz, 1 H), 5.64(s, 2 H), 3.84 (s, 3 H), 3.76 (s, 3 H), 2.69 (s, 3 H).

[0587] Step 5: Synthesis of 4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2-methyl-4H-thieno[3,2-b]pyrrole-3-carboxylic acid [ka]

[0588] A solution of methyl 4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2-methyl-4H-thieno[3,2-b]pyrrole-3-carboxylate (250 mg, 611 umol, 1.00 equiv) in MeOH (1 mL) and THF (1 mL) was added with LiOH H 2 2H2O (1M, 3.66 mL, 6.00 equiv.) was added and stirred at 55° C. for 24 h. The reaction mixture was partially concentrated and then acidified with 1N HCl solution (pH=3) and the aqueous layer was extracted with EtOAc (50 mL×2). The organic layer was washed with brine (50 mL×1) and diluted with Na 2 SO 4The mixture was dried at rt, 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, 91.1% yield) as a yellow solid. 1 H NMR (400 MHz, DMSO) δ 13.29-12.68 (m, 1 H), 7.60 (d, J = 8.40 Hz, 2 H), 7.21 (d, J = 3.00Hz, 1H), 7.09-6.98 (m, 4H), 6.80 (td, J = 2.20, 11.2 Hz, 1H), 6.41 (d, J = 3.00Hz, 1H), 5.66 (s, 2H), 3.81 (s, 3H), 2.61 (s, 3H).

[0589] Steps 6 and 7: Synthesis of 6-(4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2-methyl-4H-thieno[3,2-b]pyrrole-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0590] The compound of Example 95 was obtained by reacting 4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2-methyl-4H-thieno[3,2-b]pyrrole-3-carboxylic acid in the same manner as in steps 5 and 6 of Example 79. 1H NMR (400 MHz, DMSO) δ 12.26 - 11.69 (m, 1 H), 8.40 (d, J = 7.60 Hz, 1 H), 7.57 (d, J =8.20 Hz, 2 H), 7.19 (d, J = 3.00 Hz, 1 H), 7.10 (d, J = 8.20 Hz, 2 H), 7.06 -6.96 (m, 2 H), 6.86 - 6.77 (m, 1 H), 6.35 (d, J = 2.80 Hz, 1H), 5.35 (s, 2 H),4.30 - 4.14 (m, 1 H), 3.82 (s, 3 H), 2.98 - 2.83 (m, 1H), 2.42 (s, 3 H), 2.39- 2.16 (m, 4 H), 2.10 - 1.95 (m, 2 H), 1.91 - 1.77 (m, 2 H). LC / MS (ESI) m / z:533.1 [M+1].

[0591] Example 96: 6-(2-methyl-4-(3-phenylprop-2-yn-1-yl)-4H-thieno[3,2-b]pyrrole-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of 3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid [ka]

[0592] To a solution of intermediate U (3.00 g, 10.9 mmol, 1.00 equiv) in THF (15 mL) and MeOH (15 mL) was added LiOH H 2 HO (1M, 32.8 mL, 3.00 equiv.) was added and stirred at 55° C. for 2 h. The reaction mixture was partially concentrated and acidified (pH=3) with 1N HCl solution, then 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, 94.8% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3 ) δ 7.09 (d, J = 8.60 Hz, 2 H), 6.91 - 6.82 (m, 2 H), 6.77 (d, J = 3.00Hz, 1 H), 6.32 (d, J = 3.00 Hz, 1 H), 5.47 (s, 2 H), 3.79 (s, 3 H), 2.44 (s, 3H).

[0593] Step 2: Synthesis of 3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole [ka]

[0594] To a solution of 3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (2.00 g, 7.69 mmol, 1.00 equiv) in quinoline (20 mL) was added Cu powder (210 mg, 3.32 mmol) and stirred at 140° C. for 12 h. The reaction mixture was washed with 1N HCl (1×150 mL) and brine (1×50 mL). The organic layer was extracted with Na 2 SO 4 The mixture was dried at 40° C., then 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, 48.7% yield) as a grey solid. 1 H NMR (400 MHz, CDCl 3 ) δ8.17 (br s, 1 H), 6.96 (t, J = 2.60 Hz, 1 H), 6.44 (dd, J =2.00, 3.00 Hz, 1 H), 2.47 (s, 3 H).

[0595] Step 3: Synthesis of 3-bromo-2-methyl-4-(3-phenylprop-2-yn-1-yl)-4H-thieno[3,2-b]pyrrole [ka]

[0596] To a solution of 3-bromo-2-methyl-4H-thieno[3,2-b]pyrrole (300 mg, 1.39 mmol, 1.00 equiv) and intermediate FF (406 mg, 2.08 mmol, 1.50 equiv) in DMF (3 mL) was added Cs 2 CO 3 (1.13 g, 3.47 mmol, 2.50 equiv) was added and stirred at 20° C. for 1 h. 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 (3×50 mL) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure, and 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, 39.2% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) δ 7.52 - 7.43 (m, 2 H), 7.39 - 7.28 (m, 3 H), 7.04 (d, J = 2.80 Hz, 1H), 6.40 - 6.32 (m, 1 H), 5.35 (s, 2 H), 2.46 (s, 3 H).

[0597] Steps 4-7: Synthesis of 6-(2-methyl-4-(3-phenylprop-2-yn-1-yl)-4H-thieno[3,2-b]pyrrole-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0598] The compound of Example 96 was obtained as an off-white solid by reacting 3-bromo-2-methyl-4-(3-phenylprop-2-yn-1-yl)-4H-thieno[3,2-b]pyrrole in the same manner as in steps 4 to 7 of Example 95. 1 H NMR (400 MHz, CDCl 3) δ 7.42-7.35 (m, 2H), 7.35-7.29 (m, 3H), 6.98 (d, J = 3.00 Hz, 1H),6.34 (d, J = 3.00 Hz, 1H), 5.92 (br d, J = 7.60 Hz, 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, 16.0 Hz, 2H). LC / MS (ESI) m / z: 433.2 [M+1].

[0599] The compounds of Examples 97 and 98 were prepared in the same manner as Example 96, except for the differences in the preparation method described below.

[0600] [Table 17]

[0601] [Table 18]

[0602] Example 99: 6-(4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid Step 1: Synthesis of methyl 3-bromo-4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole-5-carboxylate [ka]

[0603] 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 azodicarboxylate (0.49 mL, 2.499 mmol) was added slowly and stirred at 50° C. for 12 hours. Saturated NaHCO 3 Aqueous solution was added and the mixture was stirred for 10 min and then extracted with EtOAc. The organic layer was washed with brine and Na 2 SO 4 After drying at rt and concentration under reduced pressure, the crude product was purified by silica gel 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-carboxylate (639 mg, 78% yield). 1 H NMR (300MHz, chloroform-d) δ 8.90 - 8.81 (m, 1H), 8.62 (dd, J =5.1, 1.5 Hz, 1H), 8.17 (dt, J = 8.1, 1.9 Hz, 1H), 7.64 (dd, J = 8.1, 5.1 Hz,1H), 7.51 (d, J = 8.3 Hz, 2H), 7.27 (d, J = 3.7 Hz, 1H), 7.19 (d, J = 8.3 Hz,2H), 6.16 (s, 2H), 3.82 (s, 3H).

[0604] Step 2: Synthesis of 3-bromo-4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole-5-carboxylic acid [ka]

[0605] THF / MeOH / H 2 A solution of methyl 3-bromo-4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole-5-carboxylate (639 mg, 1.4954 mmol) in 2H2O (1 / 1 / 1) was added to LiOH H2 0 (188 mg, 4.4862 mmol) was added and stirred for 12 h. The reaction mixture was partially concentrated, then acidified with 1N HCl solution and washed with distilled water to give 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. 1 H NMR (300 MHz, DMSO-d6) δ 12.82 (s, 1H), 8.93 (d, J = 2.3 Hz, 1H), 8.62 (dd, J = 5.0, 1.5 Hz,1H), 8.21 (dt, J = 8.2, 1.9 Hz, 1H), 7.73 (s, 1H), 7.72 - 7.67 (m, 2H), 7.61(dd, J = 8.0, 5.0 Hz, 1H), 7.35 (s, 1H), 7.06 (d, J = 8.2 Hz, 2H), 6.11 (s, 2H).

[0606] Step 3: Synthesis of 3-bromo-4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole [ka]

[0607] 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 Cu powder (76 mg, 10 wt%) in quinoline (20 mL) was stirred at 140° C. for 12 h. The reaction mixture was cooled and acidified with 6N HCl solution, then diluted with Et 2 The organic layer was extracted with MgSO 4 After drying at rt and concentration under reduced pressure, the crude product was purified by flash column chromatography to give 3-bromo-4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole (crude product).

[0608] Step 4: Synthesis of 4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid [ka]

[0609] Pd(OAc) 2 (3 mol%) and Xantphos (3 mol%) were dried in an oven with N 2 The mixture was added under atmosphere and backfilled with argon three times. A solution of formic acid (0.4 mL, 10.5966 mmol) and 3-bromo-4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole (559 mg, 1.5138 mmol) in DMF (3.0 mL) was added. DCC (62 mg, 0.3028 mmol) and Et 3 N (0.42 mL, 3.0276 mmol) was added, then the tube was sealed and the mixture was stirred for 20 h at 100° C. The reaction mixture was filtered and concentrated under reduced pressure, then the crude product was purified by silica gel column chromatography to give 4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid (crude product).

[0610] Step 5: Synthesis of methyl 6-(4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxamide) spiro[3.3]heptane-2-carboxylate [ka]

[0611] To a solution of 4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxylic acid (512 mg) and HATU (582 mg, 1.531 mmol) in DMF (4 mL) was added DIPEA (0.8 mL, 4.593 mmol) and stirred for 10 min, then intermediate A (315 mg, 1.531 mmol) was added and stirred for 12 h. The reaction mixture was diluted with ethyl acetate and washed with distilled water and brine. The organic layer was extracted with Na 2SO 4 After drying at 40° C. and concentration under reduced pressure, the crude product was purified by column chromatography to give methyl 6-(4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxamide)spiro[3.3]heptane-2-carboxylate (147 mg, 16% yield). 1 H NMR (300 MHz, chloroform-d) δ 8.87 (d, J = 2.1 Hz, 1H), 8.64 (d, J =5.5 Hz, 1H), 8.46 (d, J = 8.1 Hz, 1H), 7.90 (dd, J = 8.1, 5.5 Hz, 1H), 7.48 (d,J = 8.2 Hz, 2H), 7.36 - 7.32 (m, 1H), 7.27 (s, 1H), 7.24 (s, 1H), 6.98 (dd, J =3.0, 1.3 Hz, 1H), 6.47 (d, J = 3.0 Hz, 1H), 6.06 (d, J = 7.7 Hz, 1H), 5.71 (d,J = 5.9 Hz, 2H), 4.37 - 4.29 (m, 1H), 3.66 (s, 3H), 3.07 - 2.95 (m, 1H), 2.62 -2.47 (m, 1H), 2.47 - 2.22 (m, 4H), 2.19 - 2.07 (m, 1H), 1.92 - 1.75 (m, 2H).

[0612] Step 6: Synthesis of 6-(4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid [ka]

[0613] THF / MeOH / H 2 A solution of methyl 6-(4-(4-(pyridin-3-yl)benzyl)-4H-thieno[3,2-b]pyrrole-3-carboxamide)spiro[3.3]heptane-2-carboxylate (147 mg, 0.3027 mmol) in 2H(1 / 1 / 1) was added to LiOH H2 O (38 mg, 0.9081 mmol) was added and stirred for 12 h. The reaction mixture was partially concentrated and then acidified with 1N HCl solution, and the aqueous layer was extracted with EtOAc. The organic layer was washed with MgSO 4 The mixture was dried at rt and then concentrated under reduced pressure to give Example 99 (92 mg, 64% yield). 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.04 (s, 1H), 8.83 (s, 1H), 8.54 (d, J = 4.6 Hz, 1H), 8.48 (d, J =7.5 Hz, 1H), 8.01 (d, J = 8.0 Hz, 1H), 7.63 - 7.59 (m, 2H), 7.58 (d, J = 1.3Hz, 1H), 7.46 (t, J = 6.3 Hz, 1H), 7.31 (dd, J = 3.0, 1.3 Hz, 1H), 7.16 (d, J =8.2 Hz, 2H), 6.45 (d, J = 3.0 Hz, 1H), 5.63 (s, 2H), 4.24 - 4.16 (m, 1H), 2.99- 2.85 (m, 1H), 2.43 - 2.35 (m, 1H), 2.32 - 1.85 (m, 7H). LC / MS (ESI) m / z:472.4 [M+H] + .

[0614] The compounds of Examples 100 to 113 were prepared in the same manner as Example 99, except for the differences in the preparation method described below.

[0615] [Table 19] JPEG2025508381000297.jpg198149 JPEG2025508381000298.jpg197149 JPEG2025508381000299.jpg50149

[0616] [Table 20] JPEG2025508381000301.jpg199149 JPEG2025508381000302.jpg66149

[0617] [Preparation of isomers] Examples 1a and 1b: (2S,4S,6S)-6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxamide) spiro[3.3]heptane-2-carboxylic acid (1a) and (2R,4R,6R)-6-(4-([1,1'-biphenyl]-4-ylmethyl)-2,5-dimethylthiophene-3-carboxamide) spiro[3.3]heptane-2-carboxylic acid (1b) [ka]

[0618] The compound of Example 1 (106 g, 231 mmol, 1.00 equiv.) was purified by supercritical fluid chromatography (SFC) under the following conditions to isolate Example 1a (66.06 g, 143 mmol, 61.9% yield, 99.3% purity) and Example 1b (16.02 g, 34.4 mmol, 14.9% yield, 98.6% purity), each as a white solid.

[0619] Column: DAICEL CHIRALCEL OJ column (250mm x 50mm, 10um) Mobile phase: [Neu-MeOH]; B%: 30%~30%, 4.6; 1860 min.

[0620] Example 1a: 11H NMR (400 MHz, DMSO) δ 12.00 (br s, 1H), 8.26 (br d, J = 7.60 Hz, 1H), 7.60 (br d, J = 7.20 Hz, 2H), 7.51 (d, J = 8.40 Hz, 2H), 7.45 (t, J = 7.60 Hz, 2H), 7.37 - 7.31 (m, 1H), 7.18 (d, J = 8.00 Hz, 2H), 4.22 - 4.11 (m, 1H), 3.90 (s, 2H), 2.91 (m, 1H), 2.38 (br s, 1H), 2.33 (br d, J = 7.60 Hz, 6H), 2.29 - 2.14 (m, 3H), 2.12 - 1.98 (m, 2H), 1.94 - 1.80 (m, 2H). LC / MS (ESI) m / z = 460.2 [M+H] + 。

[0621] Example 1b: 1 1H NMR (400 MHz, DMSO) δ 11.99 (br s, 1H), 8.26 (d, J = 7.60 Hz, 1H), 7.65 - 7.57 (m, 2H), 7.51 (d, J = 8.00 Hz, 2H), 7.45 (t, J = 7.60 Hz, 2H), 7.37 - 7.31 (m, 1H), 7.19 (d, J = 8.00 Hz, 2H), 4.16 (m, 1H), 3.90 (s, 2H), 2.91 (m, 1H), 2.40 - 2.35 (m, 1H), 2.33 (d, J = 7.20 Hz, 6H), 2.29 - 2.14 (m, 3H), 2.12 - 1.99 (m, 2H), 1.93 - 1.80 (m, 2H). LC / MS (ESI) m / z = 460.2 [M+H] + 。

[0622] Examples 34a and 34b: (2S,4S,6S)-6-(4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid (34a) and (2R,4R,6R)-6-(4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid (34b)

[0623] Step 1: Separation of methyl (2S,4S,6S)-6-(4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide) spiro[3.3]heptane-2-carboxylate (34a') and methyl (2R,4R,6R)-6-(4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide) spiro[3.3]heptane-2-carboxylate (34b') [ka]

[0624] Methyl 6-(4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylate (91.0 g, 174 mmol, 1.00 equiv.) obtained in step 1 of example 34 was purified by supercritical fluid chromatography (SFC) under the following conditions to give intermediate 34a' (62.2 g, 119 mmol, 68.3% yield) and intermediate 34b' (24.2 g, 46.4 mmol, 26.5% yield) as a grey solid and an off-white solid, respectively.

[0625] Neutral conditions: DAICEL CHIRALPAK AD column (250mm x 50mm, 10um) Mobile phase: [Neu-ETOH]; B%: 50%-50%, 6.0; 1200 min Intermediate 34a': 1 H NMR (400MHz, CDCl 3 ) δ 7.46 (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] + . Intermediate 34b': 1 H NMR (400 MHz, CDCl 3 ) δ 7.45 (d,J = 8.2 Hz, 2H), 7.16 (d, J = 8.0 Hz, 2H), 6.90-6.81 (m, 2H), 6.60 (td, J =2.2, 10.5 Hz, 1H), 5.40 (br d, J = 7.8 Hz, 1H), 4.34-4.20 (m, 1H), 3.97 (s,2H), 3.85 (s, 3H), 3.64 (s, 3H), 2.96 (quintuple line, J = 8.5 Hz,1H), 2.43 (s, 4H), 2.38-2.24 (m, 6H), 2.17 (dd , J = 8.4, 11.7 Hz, 1H),2.05-1.92 (m, 1H), 1.54 (dt, J = 8.6, 12.3 Hz, 2H). LC / MS (ESI) m / z: 522.1[M+H] + .

[0626] Step 2a: Preparation of (2S,4S,6S)-6-(4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid (34a) [ka]

[0627] THF / MeOH / H 2 To a solution of intermediate 34a' (62.2 g, 119 mmol, 1.00 equiv) in 20O (200 mL, 100 mL, 200 mL), LiOH H 2 2H2O (15.0 g, 358 mmol, 3.00 equiv.) was added and stirred at 20° C. for 3 h. The mixture was partially concentrated and then H 2 The mixture was diluted with 2.00 L of HO and acidified (pH 3) with 1N HCl solution. The aqueous layer was extracted with EtOAc (1.50 L x 2), and the organic layer was washed with brine (2 x 1.00 L) and sodium 2 SO 4 The crude product was triturated with MTBE (300 mL) at 20° C. for 12 h, then with MTBE (100 mL) at 25° C. for 30 min to give Example 34a (30.0 g, 59.1 mmol, 49.7% yield) as a white solid. 1H NMR (400 MHz, 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] + .

[0628] Step 2b: Preparation of (2R,4R,6R)-6-(4-((3'-fluoro-5'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-2,5-dimethylthiophene-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid (34b) [ka]

[0629] Example 34b (10.0 g, 19.7 mmol, 42.4% yield) was obtained as an off-white solid by using intermediate 34b' in the same manner as in step 2a. 1H NMR (400 MHz, DMSO) δ 12.00 (brs, 1H), 8.27 (d, J = 7.5 Hz, 1H), 7.54 (d, J = 8.2 Hz,2H), 7.17 (d, J = 8.2 Hz, 2H), 7.06-6.96 (m, 2H), 6.80 (td, J = 2.2, 10.9 Hz,1H), 4.21-4.09 (m, 1H), 3.89 (s, 2H), 3.82 (s, 3H), 2.90 (quintet, J = 8.5 Hz, 1H), 2.39-2.33 (m, 1H), 2.31 (d, J = 3.3 Hz, 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] + .

[0630] Examples 79a and 79b: (2S,4S,6S)-6-(4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid (79a) and (2R,4R,6R)-6-(4-([1,1'-biphenyl]-4-ylmethyl)-4H-thieno[3,2-b]pyrrole-3-carboxamide)spiro[3.3]heptane-2-carboxylic acid (79b) [ka]

[0631] The compound of Example 79 was purified by supercritical fluid chromatography (SFC) under the following conditions.

[0632] Column: Daicel ChralPak IG column (250mm x 30mm, 10um) Mobile phase: [0.1%NH 3 H 2 OETOH]; B% / 50%~50% for 4.4 min; 70 min The eluate was concentrated, and the residue was added to distilled water (10 mL) and acidified with aqueous HCl (1 M) (pH 1-2). The suspension was filtered, and the white solid filter cake was concentrated to separate Example 79a (171 mg, 356 umol, yield 55.9%, purity 98.0%) and Example 79b (36 mg, yield 11.7%, purity 98%), respectively.

[0633] Example 79a: 1 H NMR (400 MHz, DMSO) δ 12.71-11.10 (m, 1H),8.50 (br d, J = 7.60 Hz, 1H), 7.64-7.56 (m, 3H), 7.54 (d, J = 8.20 Hz, 2H),7.44 (t, J = 7.60 Hz, 2H), 7.39-7.29 (m, 2H), 7.15 (d, J = 8.20 Hz, 2H), 6.46(d, J = 2.80 Hz, 1H), 5.62 (s, 2H), 4.23 (sextet, J = 8.20Hz, 1H), 2.94 (quintet, J = 8.20 Hz, 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] + .

[0634] Example 79b: 1H NMR (400 MHz, DMSO) δ 12.02 (br s, 1H),8.49 (d, J = 7.60 Hz, 1H), 7.63-7.56 (m, 3H), 7.53 (d, J = 8.20 Hz, 2H), 7.43(t, J = 7.60 Hz, 2H), 7.36-7.29 (m, 2H), 7.14 (d, J = 8.20 Hz, 2H), 6.45 (d, J= 3.00 Hz, 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] + .

[0635] Examples 80a and 80b: (2S,4S,6S)-6-(4-([1,1'-biphenyl]-4-ylmethyl)-2-methyl-4H-thieno[3,2-b]pyrrole-3-carboxamide) spiro[3.3]heptane-2-carboxylic acid (80a) and (2R,4R,6R)-6-(4-([1,1'-biphenyl]-4-ylmethyl)-2-methyl-4H-thieno[3,2-b]pyrrole-3-carboxamide) spiro[3.3]heptane-2-carboxylic acid (80b) [ka]

[0636] Example 80 (80.0 g, 165 mmol, 1.00 equiv.) was purified by supercritical fluid chromatography (SFC) under the following conditions to separate Example 80a (30.0 g, 61.9 mmol, 37.5% yield) and Example 80b (10.0 g, 20.6 mmol, 12.5% ​​yield) as a white solid and an off-white solid, respectively.

[0637] Column: DAICEL CHIRALPAK AD column (250mm x 50mm, 10um) Mobile phase: [Neu-ETOH]; B%: 40% - 40%, 14.2; 870 minutes Example 80a: 1 H NMR (400 MHz, DMSO) δ 11.74 - 12.27 (m, 1H) 8.43 (d, J = 7.58 Hz, 1H) 7.60 (d, J = 7.58 Hz, 2H) 7.54 (d, J = 8.19 Hz, 2H) 7.45 (t, J = 7.64 Hz, 2H) 7.32 - 7.38 (m, 1H) 7.20 (d, J = 2.81 Hz, 1H) 7.16 (d, J = 8.19 Hz, 2H) 6.36 (d, J = 2.81 Hz, 1H) 5.35 (s, 2H) 4.18 - 4.29 (m, 1H) 2.86 - 2.95 (m, 1H) 2.43 (s, 3H) 2.33 - 2.40 (m, 1H) 2.16 - 2.31 (m, 3H) 1.96 - 2.11 (m, 2H) 1.79 - 1.93 (m, 2H). LC / MS (ESI) m / z = 485.1 [M+H] + 。 Example 80b: 1 H NMR (400 MHz, DMSO) δ 11.44 - 12.66 (m, 1H) 8.42 (d, J = 7.58 Hz, 1H) 7.60 (d, J = 7.46 Hz, 2H) 7.54 (d, J = 8.19 Hz, 2H) 7.45 (t, J = 7.64 Hz, 2H) 7.32 - 7.37 (m, 1H) 7.20 (d, J = 2.81 Hz, 1H) 7.13 (d, J = 8.19 Hz, 2H) 6.35 (d, J = 2.93 Hz, 1H) 5.35 (s, 2H) 4.19 - 4.29 (m, 1H) 2.90 (quintet, J = 8.47 Hz, 1H) 2.43 (s, 3H) 2.34 - 2.39 (m, 1H) 2.17 - 2.28 (m, 3H) 1.96 - 2.10 (m, 2H) 1.79 - 1.91 (m, 2H). LC / MS (ESI) m / z = 485.1 [M+H] + 。

[0638] [Experimental Example 1: Evaluation of inhibitory activity against EP2 and / or EP4] Experimental Example 1.1: hEP2 cAMP Assay HEK293 cells overexpressing hEP2 were cultured in growth medium (GM:MEM (Gibco™, 11095080) / 10% HI FBS (Gibco™, 10082147) / 1% penicillin / streptomycin). Before the experiment, the growth medium was removed and starvation medium (HBSS (Gibco™, 14025076) / 10% GM) was added. The cells were then incubated for 4 hours. HEK293 cells with hEP2 were detached from the culture dish by non-enzymatic cell dissociation buffer (Gibco™, 15040066). The cells were resuspended in assay buffer (AB:HBSS, 0.1% BSA stabilizer, 0.5 mM IBMX, 5 mM HEPES).

[0639] 1,000 cells in 5 μL of AB were seeded per well of a 384-well plate (Corning® 3570), and stock solutions of test compounds were prepared in DMSO at a concentration of 1 mM and serially diluted in DMSO to the concentrations required for the inhibition dose-response curve (test concentration range of 10 μM to 0.001 nM). 2 (Sigma, P0409, stock solution: 1 μM) was added to EC 50~80 2.5 μL of diluted compound and 2.5 μL of PGE were used as agonists at a final concentration of 400 pM, corresponding to 2 (final concentration 400 pM) was transferred to the assay plate and the plate was then incubated at room temperature for 12 minutes.

[0640] 5 μL each of donor (Eu-cAMP tracer) and acceptor (ULight anti-cAMP) were added, the plate was incubated in the dark at room temperature for 1 hour, and then the results were obtained using a Varioskan LUX multimode microplate reader (excitation: 334 nm, emission: 615 and 665 nm). The obtained FRET fluorescence values ​​(665 nm / 615 nm * 10000) and then calculated as a percentage of cAMP relative to DMSO control values. IC50 Values ​​and curves were generated with GraphPad Prism software using the log(inhibitor) versus response variable slope (4 parameters) and experimental results were expressed as median values ​​from multiple experiments.

[0641] Experimental Example 1.2: hEP4 cAMP Assay HEK293 cells overexpressing hEP4 were cultured in growth medium (GM:MEM (GIBCO™, 11095080) / 10% HI FBS (GIBCO™, 10082147) / 1% penicillin / streptomycin). Before the experiment, the growth medium was removed and starvation medium (HBSS (GIBCO™, 14025076) / 10% GM) was added. The cells were then incubated for 4 hours. HEK293 cells with hEP4 were detached from the culture dish by non-enzymatic cell dissociation buffer (GIBCO™, 15040066). The cells were resuspended in assay buffer (AB:HBSS, 0.1% BSA stabilizer, 0.5 mM IBMX, 5 mM HEPES).

[0642] 1,000 cells in 5 μL of AB were seeded per well of a 384-well plate (Corning® 3570), and stock solutions of test compounds were prepared in DMSO at a concentration of 1 mM and serially diluted in DMSO to the concentrations required for the inhibition dose-response curve (test concentration range of 10 μM to 0.001 nM). 2 (Sigma, P0409, stock solution: 100 μM) was added to EC 50~80 2.5 μL of diluted compound and 2.5 μL of PGE were used as agonists at a final concentration of 20 nM, corresponding to 2 (final concentration 20 nM) was transferred to the assay plate, and the plate was then incubated at room temperature for 18.5 minutes.

[0643] 5 μL each of donor (Eu-cAMP tracer) and acceptor (ULight anti-cAMP) were added, the plate was incubated in the dark at room temperature for 1 hour, and then the results were obtained using a Varioskan LUX multimode microplate reader (excitation: 334 nm, emission: 615 and 665 nm). The obtained FRET fluorescence values ​​(665 nm / 615 nm * 10000) and then calculated as a percentage of cAMP compared to DMSO control values. IC 50 Values ​​and curves were generated with GraphPad Prism software using the log(inhibitor) versus response variable slope (4 parameters) and experimental results were expressed as median values ​​from multiple experiments.

[0644] Experimental Results The inhibitory activities of the compounds of Examples 1 to 113 against EP2 and EP4 measured by the above-mentioned experimental method were evaluated based on the criteria in Table 21 below, and the results are shown in Tables 22 to 25.

[0645] [Table 21]

[0646] [Table 22]

[0647] [Table 23]

[0648] [Table 24]

[0649] [Table 25]

[0650] As shown in the above Tables 22 to 25, the compounds of Examples 1 to 113 exhibited excellent inhibitory activity against EP2 and EP4.

[0651] Experimental Example 2. Evaluation of anti-cancer efficacy of combination administration with immune checkpoint inhibitors in a mouse-derived colon cancer tumor model Experimental Example 2.1. Evaluation of the anticancer efficacy of combination treatments in a mouse-derived colorectal cancer tumor model: CT26 RPMI-1640 medium containing 10% FBS (fetal bovine serum) was used, and the incubation temperature was 37°C and 5% CO 2 Cell incubator (CO 2 CT26 cells were subcultured and maintained in a 20-mL incubator. For the tumor animal model, CT26 cells were cultured at 5 × 10 5 The cells were resuspended at a concentration of cells / 100 μL and 100 μL per mouse was implanted into the subcutaneous region of the right flank of 6- to 7-week-old BALB / c mice (Shanghai Lingchang Biotechnology Co., Ltd, Shanghai) to prepare the CT26 tumor model.

[0652] Tumor size was calculated by measuring the short and long axes using calipers and substituting them into Equation 1 below. [Equation 1] Tumor size (volume, mm 3 )=(minor axis, mm) 2 ×(Long axis, mm)×0.5

[0653] The average tumor size is 70-100 mm 3 Once tumor size reached 100%, mice were randomized into groups for evaluation of drug efficacy (mean tumor size per group = 79 mm 3 Drug efficacy was calculated and compared between groups by substituting the measured tumor size into Equation 2 to calculate tumor growth inhibition potential. [Equation 2] Tumor growth inhibition potential = [{(control group tumor size at time of measurement, C) - (control group tumor size at start of administration, C0)} - {(test group tumor size at time of measurement, T) - (test group tumor size at start of administration, T0)}] / {(control group tumor size at time of measurement, C) - (control group tumor size at start of administration, C0)}

[0654] Drug administration was carried out for 12 days from the day the test groups were divided into a group treated with A01 (Example 34b), a group treated with an anti-PD-1 antibody, which is an immune checkpoint inhibitor, and a group treated with a combination of A01 and anti-PD-1 antibody. Anti-PD-1 antibody (BioXcell, Catalog No. BP0146) was diluted with PBS and administered intraperitoneally once every three days at a concentration of 200 μg / mouse. A01 was used as an excipient and suspended as an excipient by adding Tween 80 to a 0.5% methylcellulose (40000cp) aqueous solution to 0.2%, and orally administered daily at a concentration of 150 mg / kg.

[0655] As a result, when examining the changes in the mice's body weight during the drug administration period based on the start and end points of the study, the body weight of the group administered A01 increased from 20.4±0.4g to 22.2±0.6g, and the body weight of the group administered anti-PD-1 antibody increased from 20.2±0.4g to 22.7±0.4g. In addition, the body weight of the group administered the combination of A01 and anti-PD-1 antibody increased from 19.5±0.3g to 20.7±0.5g. The results were similar to the control group, and no weight loss due to drug administration was observed (Figure 1).

[0656] The tumor size of the mice was measured and compared during the drug administration period based on the start and end points of the study. The tumor size of the control group was 79.4 ± 2.5 mm. 3 From 1725.5±239.8mm 3 In the A01-treated group, the tumor size increased to 79.4 ± 2.3 mm. 3 From 1092.6±237.5mm 3 In the group treated with anti-PD-1 antibody, the tumor size increased to 79.4 ± 2.1 mm, showing a 38.5% tumor growth inhibition effect compared to the control group.3 From 1270.8±200.6mm 3 In the group treated with the combination of A01 and anti-PD-1 antibody, the tumor size increased to 79.4 ± 1.7 mm, showing a tumor growth inhibition rate of 27.6% compared to the control group. 3 From 717.9±110.6mm 3 The tumor growth inhibition rate was increased to 61.2% compared to the control group (Figure 2).

[0657] From the above results, it was found that administration of a combination of A01 and an immune checkpoint inhibitor exhibited superior tumor growth inhibition ability without accompanying weight loss compared to administration of A01 or an immune checkpoint inhibitor alone.

[0658] Experimental Example 2.2. Evaluation of the anticancer efficacy of combination treatments in a mouse-derived colorectal cancer tumor model: MC38 DMEM medium containing 10% FBS (fetal bovine serum) was used, and the incubation temperature was 37°C and 5% CO 2 Cell incubator (CO) 2 MC38 cells were subcultured in a 1×10 6 The cells were resuspended at a concentration of cells / 100 μL and 100 μL per mouse was implanted into the subcutaneous region of the right flank of 6-7 week-old C57B / 6 mice (Shanghai Lingchang Biotechnology Co., Ltd, Shanghai) to prepare tumor models.

[0659] The tumor size was calculated by measuring in the same manner as in Experimental Example 2.1.

[0660] The average tumor size is 70-100 mm 3 Once tumor size reached 100%, mice were randomized into groups for evaluation of drug efficacy (mean tumor size = 91 mm 3 Drug efficacy was evaluated by substituting the measured tumor size into Equation 2 in Experimental Example 2.1 to calculate and compare the tumor growth inhibition potential between groups.

[0661] Drug administration was carried out for 18 days from the day the test groups were divided into a group treated with A02 (Example 1b), a group treated with an anti-PD-1 antibody, which is an immune checkpoint inhibitor, and a group treated with a combination of A02 and an anti-PD-1 antibody. Anti-PD-1 antibody (BioXcell, Catalog No. BP0146) was diluted with PBS and administered intraperitoneally once every three days at a concentration of 200 μg / mouse. A02 was used as an excipient and suspended as an excipient by adding Tween 80 to a 0.5% methylcellulose (40000cp) aqueous solution to 0.2%, and orally administered daily at a concentration of 150 mg / kg.

[0662] As a result, the weight changes of the mice during the drug administration period based on the start and end points of the study were compared and examined. The weight of the group administered A02 increased from 19.1±0.2g to 22.0±0.4g, and the weight of the group administered anti-PD-1 antibody increased from 19.1±0.3g to 21.6±0.5g. In addition, the weight of the group administered the combination of A02 and anti-PD-1 antibody increased from 19.4±0.2g to 20.4±0.5g. The results were similar to the control group, and no weight loss due to drug administration was observed (Figure 3).

[0663] The tumor size of the mice was measured and compared during the drug administration period based on the start and end points of the study. The tumor size of the control group was 91.5 ± 2.9 mm. 3 From 2496.6±238.1mm 3 In the group administered A02, the tumor size increased to 91.5 ± 3.1 mm 3 From 1711.0±236.4mm 3 In the group treated with anti-PD-1 antibody, the tumor size increased to 91.6 ± 3.0 mm, showing a tumor growth inhibition rate of 32.7% compared to the control group. 3 From 1422.1±273.9m 3 In the group treated with the combination of A02 and anti-PD-1 antibody, the tumor size increased to 91.6 ± 3.2 mm, showing a 44.7% tumor growth inhibition effect compared to the control group. 3 From 610.2±156.9mm 3The tumor growth inhibition rate was increased to 78.4% compared to the control group (Figure 4).

[0664] From the above results, it was found that administration of a combination of A02 and an immune checkpoint inhibitor exhibited superior tumor growth inhibition ability without accompanying weight loss compared to administration of A02 or an immune checkpoint inhibitor alone.

[0665] Experimental Example 3. Evaluation of the anticancer efficacy of standard treatments by combination administration in a mouse-derived lung cancer tumor model RPMI1640 medium containing 10% FBS was used, and the incubation temperature was 37℃ and 5% CO 2 TC1 cells were cultured in a cell incubator under conditions. TC1 cells were injected subcutaneously into the right flank area of ​​C57BL / 6 mice at a concentration of 1 × 10 6 The TC1 tumor animal model was prepared by injecting the cells at a concentration of 1000 x 1000 cells / mouse.

[0666] The tumor size was calculated by measuring in the same manner as in Experimental Example 2.1.

[0667] The average tumor size is about 100 mm 3 Once this was reached, mice were randomized into groups for evaluation of drug efficacy.

[0668] The average tumor size is about 100 mm 3 Once this was reached, drug administration was initiated.

[0669] Cisplatin, pemetrexed and anti-PD-1 antibody were diluted with PBS and administered intravenously twice a week at doses of 5 mg / kg, 100 mg / kg and 10 mg / kg, respectively. A01 (Example 34b) was diluted with borate buffer containing 5% ethanol and 20% hydroxypropyl-β-cyclodextrin and administered orally at a dose of 30 mg / kg. As standard treatment for lung cancer, initial treatment was performed in which cisplatin, pemetrexed and anti-PD-1 antibody were administered in three cycles, followed by continuous administration of a combination of pemetrexed and anti-PD-1 antibody as maintenance treatment. In the group administered the combination with A01 (Example 34b), A01 (Example 34b) was additionally administered to the standard treatment.

[0670] The results are shown in Table 26 below and in Figure 5. Mice administered the combination with A01 (Example 34b) showed lower tumor growth rates compared to vehicle control groups (PBS and borate buffer) or compared to groups treated with standard therapy by day 12 after the start of treatment, which was the completion of initial treatment in which the combination of cisplatin, pemetrexed and anti-PD-1 antibody was administered in three cycles. After 17 days of maintenance treatment, the tumor size of mice administered the combination with A01 (Example 34b) was 0 mm 3 In contrast, in the group treated with standard therapy, tumor size decreased by 22 days after the start of treatment, then began to increase again.

[0671] [Table 26]

[0672] From the above results, it was found that administration of a combination of A01, a chemotherapeutic agent and an immune checkpoint inhibitor exhibited superior tumor growth inhibition ability without accompanying weight loss compared to administration of A01, a chemotherapeutic agent or an immune checkpoint inhibitor alone.

[0673] These results suggest that EP 2 and E.P. 4It has been shown that administration of a combination of dual inhibitors, chemotherapeutic agents and / or immune checkpoint inhibitors can provide pharmaceutical compositions for anti-cancer agents and combination therapeutic strategies with superior anti-cancer effects with fewer side effects.

Claims

1. A pharmaceutical composition for preventing or treating cancer, comprising a compound of formula I or a solvate, stereoisomer or pharma- ceutically acceptable salt thereof and an anticancer agent as active ingredients. 【Chemistry 1】 [In the formula, One of X and Y is S and the other is CR １ and 【Chemistry 2】 are single or double bonds, two of which are double bonds; R １ and R ２ is hydrogen, halogen, hydroxy, cyano, amino, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, -NH-(C １ ~C ６ Alkyl), -N(C １ ~C ６ Alkyl) ２ , C ３ ~C ８ Cycloalkyl and C ６ ~C １０ aryl, １ ~C ６ Alkyl and C １ ~C ６ Each alkoxy may be independently optionally substituted with one or more halogen, hydroxy, cyano, or amino; ３ ~C ８ Cycloalkyl and C ６ ~C １０ Each aryl is independently one or more of halogen, hydroxy, cyano, amino, oxo, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy or C １ ~C ６ optionally substituted with haloalkoxy; R ３ teeth, 【Chemistry 3】 or R １ is hydrogen, halogen, hydroxy, cyano, amino, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, -NH-(C １ ~C ６ Alkyl), -N(C １ ~C ６ Alkyl) ２ , C ３ ~C ８ Cycloalkyl and C ６ ~C １０ aryl, １ ~C ６ Alkyl and C １ ~C ６ Each alkoxy may be independently optionally substituted with one or more halogen, hydroxy, cyano, or amino; ３ ~C ８ Cycloalkyl and C ６ ~C １０ Each aryl is independently one or more of halogen, hydroxy, cyano, amino, oxo, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy or C １ ~C ６ optionally substituted with haloalkoxy; R ２ and R ３ is R ２ and R ３ together with the carbon atom to which it is bonded, 【Chemistry 4】 Forming 【Chemistry 5】 teeth, 【Chemistry 6】 is attached to the nitrogen atom of 【Chemistry 7】 One or both of the carbon atoms may be halogen, hydroxy, cyano, １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl or C １ ~C ６ optionally substituted with haloalkoxy; W is -(CH ２ ) ｏ -, -(CH ２ )o-C≡C-, -C(O)-, -O-, -S-, -NH- or -N(C １ ~C ６ alkyl)-, wherein the CH ２ H is one or more of halogen, hydroxy, cyano, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl or C １ ~C ６ optionally substituted with haloalkoxy; Cy is C ６ ~C １４ Aryl, 4- to 14-membered heteroaryl, 4- to 14-membered heterocycloalkyl, C ３ ~C ８ Cycloalkyl and C ３ ~C ８ cycloalkenyl, optionally substituted with one or more R'; R ａ is hydrogen, halogen, hydroxy, cyano, amino, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, -NH-(C １ ~C ６ Alkyl), -N(C １ ~C ６ Alkyl) ２ , oxo or -V-Cy ２ and said C １ ~C ６ Alkyl and C １ ~C ６ The alkoxy may be optionally substituted with one or more halogen, hydroxy, cyano or amino; V is absent or -NH-, -NHCH ２ --NHCH ３ -, -CONH-, -NHCO-, -NHSO ２ -, -S-, -SO ２ --, --CH ２ --, --OCH ２ - or -O-, Cy ２ is C ６ ~C １４ Aryl, 4- to 14-membered heteroaryl, 4- to 14-membered heterocycloalkyl, C ３ ~C ８ Cycloalkyl and C ３ ~C ８ cycloalkenyl, optionally substituted with one or more R″; R' is independently halogen, hydroxy, cyano, amino, oxo, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, -NH-(C １ ~C ６ alkyl) and -N(C １ ~C ６ Alkyl) ２ wherein C is selected from the group consisting of １ ~C ６ Alkyl and C １ ~C ６ The alkoxy may be optionally substituted with one or more halogen, hydroxy, cyano or amino; R" is halogen, hydroxy, cyano, amino, oxo, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, -S-(C １ ~C ６ Alkyl), -SO ２ - (C １ ~C ６ alkyl), -CO-(C １ ~C ６ alkyl), -C(O)H, -COO-(C １ ~C ６ alkyl), -COOH, -CONH ２ , -CONH-(C １ ~C ６ alkyl), -CON(C １ ~C ６ Alkyl) ２ , -(CH ２ ) ｐ -NH ２ , -(CH ２ ) ｐ -NH-(C １ ~C ６ alkyl), -(CH ２ ) ｐ -N(C １ ~C ６ Alkyl) ２ , -(CH ２ ) ｐ -NH-CO-(C １ ~C ６ alkyl), -(CH ２ ) ｐ -NH-COO-(C １ ~C ６ alkyl), -(CH ２ ) ｐ -OH, 3- to 7-membered heterocycloalkyl, C ３ ~C ８ Cycloalkyl and -(CH ２ ) ｐ - (C ３ ~C ８ cycloalkyl), １ ~C ６ Alkyl and C １ ~C ６ The alkoxy may be optionally substituted with one or more halogen, hydroxy, cyano or amino, and is selected from the group consisting of 3-7 membered heterocycloalkyl and C ３ ~C ８ The cycloalkyl may be optionally substituted with one or more halogen, hydroxy, cyano, oxo or amino; R ４ is hydrogen or C １ ~C ６ is alkyl; R ５ , R ６ and R ７ are defined as follows: (i) R ５ and R ６ is H, and R ７ is non-existent or (ii) R ５ and R ６ - (CH ２ ) ｑ - together, R ７ is non-existent, or (iii) R ５ is H, and R ６ and R ７ - (CH ２ ) ｒ - together, having P is absent or -CH ２ -, but R ７ If is non-existent, then P is also non-existent; R ８ teeth, 【Chemistry 8】 and Z is -(CH ２ ) ｓ and R ８’ is hydrogen, hydroxy, C １ ~C ６ Alkyl or C １ ~C ６ is alkoxy; l, m, and n are each independently an integer of 0 to 2, at least one of m and n is not 0, and P and R ７ If is absent, then l is 0; o and p are each independently an integer from 0 to 3; q and r are each independently an integer of 1 or 2; s is an integer from 0 to 3.

2. R １ is hydrogen, halogen, hydroxy, cyano, amino, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, -NH-(C １ ~C ３ alkyl) or -N(C １ ~C ３ Alkyl) ２ and said C １ ~C ３ Alkyl and C １ ~C ３ each alkoxy may independently be optionally substituted with one or more halogen, hydroxy, cyano, or amino; R ２ is hydrogen, halogen, hydroxy, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkyl, C １ ~C ３ Haloalkoxy, C ３ ~C ６ cycloalkyl or phenyl, １ ~C ３ Alkyl and C １ ~C ３ The pharmaceutical composition for preventing or treating cancer according to claim 1 , wherein each alkoxy is independently optionally substituted with one or more halogen, hydroxy, cyano or amino.

3. Cy is C ６ ~C １０ selected from the group consisting of aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, and 4-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, optionally substituted with one or more R'; Cy ２ But, C ６ ~C １０ aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, 4-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, C ３ ~C ８ Cycloalkyl, and C ３ ~C ８ cycloalkenyl, optionally substituted with one or more R″; R' is halogen, hydroxy, cyano, amino, oxo, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, -NH-(C １ ~C ３ alkyl) or -N(C １ ~C ３ Alkyl) ２ and R" is halogen, hydroxy, cyano, amino, oxo, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, -S-(C １ ~C ６ Alkyl), -SO ２ - (C １ ~C ６ alkyl), -COO-(C １ ~C ６ alkyl), -COOH, -CONH ２ , -(CH ２ ) ｐ -NH ２ , -(CH ２ ) ｐ -NH-(C １ ~C ６ alkyl), -(CH ２ ) ｐ -N(C １ ~C ６ Alkyl) ２ , -(CH ２ ) ｐ -NH-COO-(C １ ~C ６ alkyl), -(CH ２ ) ｐ -3-5 membered heterocycloalkyl containing one heteroatom selected from OH, N, O and S; C ３ ~C ５ Cycloalkyl, and -(CH ２ ) ｐ - (C ３ ~C ５ cycloalkyl), １ ~C ６ Alkyl and C １ ~C ６ The alkoxy may be optionally substituted with one or more halogen, hydroxy, cyano or amino, and the 3-5 membered heterocycloalkyl and C ３ ~C ５ The pharmaceutical composition for preventing or treating cancer according to claim 1, wherein cycloalkyl is optionally substituted with one or more halogen, hydroxy, cyano, oxo or amino.

4. Cy is phenyl; heteroaryl selected from pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, quinolinyl, and isoquinolinyl; or heterocycloalkyl selected from azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl, and morpholinyl; Cy ２ The pharmaceutical composition for preventing or treating cancer according to claim 3, wherein is phenyl; heteroaryl selected from pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, indolyl, benzimidazolyl, benzofuranyl, benzothiazolyl, quinolinyl and isoquinolinyl; heterocycloalkyl selected from azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, pyrazolidinyl, imidazolidinyl, thiazolidinyl, oxazolidinyl, isoxazolidinyl, piperidinyl, piperazinyl and morpholinyl; cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; or cyclobutenyl, cyclopentenyl, cyclohexenyl or cycloheptenyl.

5. R ａ Ga-V-Cy ２ and 【Chemistry 9】 but, 【Chemistry 10】 【change】 having a structure selected from Cy and Cy ２ The pharmaceutical composition for preventing or treating cancer according to claim 1, wherein each of

6. R ８ but, 【Chemistry 11】 and Z is -(CH ２ ) ｓ and R ８’ is hydroxy or C １ ~C ６ is alkoxy; The pharmaceutical composition for preventing or treating cancer according to claim 1 , wherein s is an integer of 0 or 1.

7. The pharmaceutical composition for preventing or treating cancer according to claim 1, wherein formula I is formula IA-1 or IA-2. 【Chemistry 12】 [In the formula, R １ and R ２ is hydrogen, halogen, hydroxy, cyano, amino, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, -NH-(C １ ~C ６ Alkyl), -N(C １ ~C ６ Alkyl) ２ , C ３ ~C ８ Cycloalkyl and C ６ ~C １０ aryl, １ ~C ６ Alkyl and C １ ~C ６ Each alkoxy may be independently optionally substituted with one or more halogen, hydroxy, cyano, or amino; ３ ~C ８ Cycloalkyl and C ６ ~C １０ Each aryl is independently one or more of halogen, hydroxy, cyano, amino, oxo, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy or C １ ~C ６ optionally substituted with haloalkoxy; R ３ teeth, 【Chemistry 13】 and W, Cy, Ra, R ４ , R ８ , n, m, r and l are as defined in claim 1.

8. R １ is hydrogen, halogen, hydroxy, cyano, amino, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, -NH-(C １ ~C ６ alkyl) or -N(C １ ~C ６ Alkyl) ２ and said C １ ~C ６ Alkyl and C １ ~C ６ each alkoxy may independently be optionally substituted with one or more halogen, hydroxy, cyano, or amino; R ２ is hydrogen, halogen, hydroxy, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkyl, C １ ~C ３ Haloalkoxy, C ３ ~C ６ cycloalkyl or phenyl, １ ~C ３ Alkyl and C １ ~C ３ each alkoxy may independently be optionally substituted with one or more halogen, hydroxy, cyano, or amino; R ３ but, 【Chemistry 14】 and W is -(CH ２ ) ｏ -, -C(O)-, -O-, -NH- or -N(C １ ~C ６ alkyl)-, wherein the CH ２ H is one or more halogen, hydroxy or C １ ~C ６ optionally substituted with alkoxy; Cy is C ６ ~C １０ selected from the group consisting of aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, and 4-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, optionally substituted with one or more R'; R ａ But hydrogen, halogen, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl or -V-Cy ２ and V is absent or -NH-, -NHCH ２ --NHCH ３ -, -S-, -SO ２ --, --CH ２ --, --OCH ２ - or -O-, and Cy ２ But, C ６ ~C １０ aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, 4-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, C ３ ~C ８ Cycloalkyl, and C ３ ~C ８ cycloalkenyl, optionally substituted with one or more R″; R' is halogen, hydroxy, cyano, amino, oxo, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, -NH-(C １ ~C ３ alkyl) or -N(C １ ~C ３ Alkyl) ２ and R" is halogen, hydroxy, cyano, amino, oxo, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, -S-(C １ ~C ６ Alkyl), -SO ２ - (C １ ~C ６ alkyl), -COO-(C １ ~C ６ alkyl), -COOH, -CONH ２ , -(CH ２ ) ｐ -NH ２ , -(CH ２ ) ｐ -NH-(C １ ~C ６ alkyl), -(CH ２ ) ｐ -N(C １ ~C ６ Alkyl) ２ , -(CH ２ ) ｐ -NH-COO-(C １ ~C ６ alkyl), -(CH ２ ) ｐ -3-5 membered heterocycloalkyl containing one heteroatom selected from OH, N, O and S; C ３ ~C ５ Cycloalkyl, and -(CH ２ ) ｐ - (C ３ ~C ５ cycloalkyl), １ ~C ６ Alkyl and C １ ~C ６ The alkoxy may be optionally substituted with one or more halogen, hydroxy, cyano or amino, and the 3-5 membered heterocycloalkyl and C ３ ~C ５ The cycloalkyl may be optionally substituted with one or more halogen, hydroxy, cyano, oxo, or amino; R ４ is hydrogen or C １ ~C ３ is alkyl; R ８ but, 【Chemistry 15】 and Z is -(CH ２ ) ｓ and R ８’ is hydroxy or C １ ~C ６ is alkoxy; l, m, n, and r are each independently an integer of 1 or 2; o and p are each an integer of 0, 1, or 2; The pharmaceutical composition for preventing or treating cancer according to claim 7 , wherein s is an integer of 0 or 1.

9. R １ is hydrogen, halogen, hydroxy, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkyl or C １ ~C ３ haloalkoxy; R ２ But hydrogen, halogen, C １ ~C ３ Alkyl, C １ ~C ３ haloalkyl, cyclopropyl, cyclobutyl, or phenyl; Cy is phenyl, 5-10 membered heteroaryl containing 1 or 2 nitrogen atoms, or 4-7 membered heterocycloalkyl containing 1 or 2 nitrogen atoms, optionally substituted with one or more R'; R ａ But hydrogen, halogen, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl or -V-Cy ２ and V is absent or -CH ２ - or -O-, and Cy ２ is a phenyl, a 5- to 10-membered heteroaryl containing 1 or 2 heteroatoms selected from N or O, a 4- or 7-membered heterocycloalkyl containing 1 or 2 heteroatoms selected from N or O, C ４ ~C ７ Cycloalkyl, and C ４ ~C ７ cycloalkenyl, optionally substituted with one or more R″; R' is halogen, amino, C １ ~C ３ Alkyl or C １ ~C ３ haloalkyl; R" is halogen, hydroxy, cyano, amino, oxo, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, -S-(C １ ~C ６ Alkyl), -SO ２ - (C １ ~C ６ alkyl), -COO-(C １ ~C ６ alkyl), -COOH, -CONH ２ , -(CH ２ ) ｐ -NH ２ , -(CH ２ ) ｐ -NH-(C １ ~C ６ alkyl), -(CH ２ ) ｐ -N(C １ ~C ６ Alkyl) ２ , -(CH ２ ) ｐ -NH-COO-(C １ ~C ６ alkyl), -(CH ２ ) ｐ The pharmaceutical composition for preventing or treating cancer according to claim 8, wherein the aryl group is selected from the group consisting of -OH; azetidinyl or oxetanyl optionally substituted with hydroxy or oxo; and cyclopropyl or cyclopropylmethyl optionally substituted with hydroxy or oxo.

10. Cy is phenyl, pyrazolyl or piperazinyl; Cy ２ The pharmaceutical composition for preventing or treating cancer according to claim 9, wherein is phenyl, furanyl, pyrazolyl, pyridinyl, morpholinyl, piperidinyl, cyclohexyl or cyclohexenyl.

11. The pharmaceutical composition for preventing or treating cancer according to claim 7, wherein formula IA-1 or IA-2 has formula IA-3 or IA-4. 【Chemistry 16】 [In the formula, R １ , R ２ , R ３ , R ４ and R ８ is as defined in claim 7.

12. The pharmaceutical composition for preventing or treating cancer according to claim 1, wherein formula I has formula IB-1. 【Chemistry 17】 [In the formula, R １ is hydrogen, halogen, hydroxy, cyano, amino, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, -NH-(C １ ~C ６ Alkyl), -N(C １ ~C ６ Alkyl) ２ , C ３ ~C ８ Cycloalkyl and C ６ ~C １０ aryl, １ ~C ６ Alkyl and C １ ~C ６ Each alkoxy may be independently optionally substituted with one or more halogen, hydroxy, cyano, or amino; ３ ~C ８ Cycloalkyl and C ６ ~C １０ Each aryl is independently one or more of halogen, hydroxy, cyano, amino, oxo, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy or C １ ~C ６ optionally substituted with haloalkoxy; 【Chemistry 18】 One or both of the carbon atoms may be halogen, hydroxy, cyano, １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkyl or C １ ~C ６ optionally substituted with haloalkoxy; W, C, R ａ , R ４ , R ５ , R ６ , R ７ , R ８ , P, n, m and l are as defined in claim 1.

13. The pharmaceutical composition for preventing or treating cancer according to claim 12, wherein formula IB-1 is formula IB-2, IB-3 or IB-4. 【Chemistry 19】 [In the formula, R １ is hydrogen, halogen, hydroxy, cyano, amino, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, -NH-(C １ ~C ６ alkyl) or -N(C １ ~C ６ Alkyl) ２ and said C １ ~C ６ Alkyl and C １ ~C ６ Each alkoxy may independently be optionally substituted with one or more halogen, hydroxy, cyano, or amino; 【Chemistry 20】 One or both of the carbon atoms may be halogen, C １ ~C ３ Alkyl or C １ ~C ３ optionally substituted with haloalkyl; W is -(CH ２ ) ｏ - or - (CH ２ ) ｏ -C≡C-, and said CH ２ H is one or more halogen, hydroxy or C １ ~C ６ optionally substituted with alkoxy; Cy is C ６ ~C １０ selected from the group consisting of aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, and 4-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, optionally substituted with one or more R'; R ａ is hydrogen, halogen, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl or -V-Cy ２ and V is absent or -NH-, -NHCH ２ --NHCH ３ -, -S-, -SO ２ --, --CH ２ --, --OCH ２ - or -O-, and Cy ２ is C ６ ~C １０ aryl, 5-10 membered heteroaryl containing 1-3 heteroatoms selected from N, O and S, 4-10 membered heterocycloalkyl containing 1-3 heteroatoms selected from N, O and S, C ３ ~C ８ Cycloalkyl, and C ３ ~C ８ cycloalkenyl, optionally substituted with one or more R″; R' is halogen, hydroxy, cyano, amino, oxo, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkoxy, -NH-(C １ ~C ３ alkyl) or -N(C １ ~C ３ Alkyl) ２ and R" is halogen, hydroxy, cyano, amino, oxo, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, -S-(C １ ~C ６ Alkyl), -SO ２ - (C １ ~C ６ alkyl), -COO-(C １ ~C ６ alkyl), -COOH, -CONH ２ , -(CH ２ ) ｐ -NH ２ , -(CH ２ ) ｐ -NH-(C １ ~C ６ alkyl), -(CH ２ ) ｐ -N(C １ ~C ６ Alkyl) ２ , -(CH ２ ) ｐ -NH-COO-(C １ ~C ６ alkyl), -(CH ２ ) ｐ -3-5 membered heterocycloalkyl containing one heteroatom selected from OH, N, O and S; C ３ ~C ５ Cycloalkyl, and -(CH ２ ) ｐ - (C ３ ~C ５ cycloalkyl), １ ~C ６ Alkyl and C １ ~C ６ The alkoxy may be optionally substituted with one or more halogen, hydroxy, cyano or amino, and is selected from the group consisting of 3-5 membered heterocycloalkyl and C ３ ~C ５ The cycloalkyl may be optionally substituted with one or more halogen, hydroxy, cyano, oxo or amino; R ４ is hydrogen or C １ ~C ３ is alkyl; R ８ teeth, 【Chemistry 21】 and Z is -(CH ２ ) ｓ and R ８ ' is hydroxy or C １ ~C ６ is alkoxy; l, m, and n are each independently an integer of 1 or 2; o and p are each independently an integer from 0 to 2; q and r are each independently an integer of 1 or 2; s is an integer of 0 or 1.

14. R １ is hydrogen, halogen, hydroxy, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkyl or C １ ~C ３ haloalkoxy; 【Chemical 22】 One or both of the carbon atoms of １ ~C ３ Alkyl or C １ ~C ３ optionally substituted with haloalkyl; Cy is phenyl or a 5-10 membered heteroaryl containing 1 or 2 nitrogen atoms; R ａ But hydrogen, halogen, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl or -V-Cy ２ and V is absent or -CH ２ - and Cy ２ is phenyl or a 5-10 membered heteroaryl containing 1 or 2 nitrogen atoms; R' is halogen, amino, C １ ~C ３ Alkyl, or C １ ~C ３ haloalkyl; R" is halogen, hydroxy, cyano, amino, oxo, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ Haloalkoxy, -(CH ２ ) ｐ -NH ２ , -(CH ２ ) ｐ -NH-(C １ ~C ６ alkyl), -(CH ２ ) ｐ -N(C １ ~C ６ Alkyl) ２ 14. The pharmaceutical composition for preventing or treating cancer according to claim 13, which is selected from the group consisting of: azetidinyl or oxetanyl optionally substituted with hydroxy or oxo; cyclopropyl or cyclopropylmethyl optionally substituted with hydroxy or oxo.

15. Cy is selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, and indolyl; Cy ２ The pharmaceutical composition for preventing or treating cancer according to claim 14, wherein is selected from the group consisting of phenyl, pyrazolyl, pyridinyl and pyrimidinyl.

16. The pharmaceutical composition for preventing or treating cancer according to claim 12, wherein formula IB-1 is formula IB-5, IB-6, IB-7 or IB-8. 【Chemistry 23】 [In the formula, R １ , W., Cy., R. ａ , R ４ and R ８ is as defined in claim 12.

17. The compound is the following compound: 【Chemistry 24】 【change】 【change】 【change】 【change】 【change】 【change】 The pharmaceutical composition for preventing or treating cancer according to claim 1, selected from the group consisting of:

18. The compound is the following compound: 【Chemistry 25】 The pharmaceutical composition for preventing or treating cancer according to claim 17, selected from the group consisting of:

19. 2. The pharmaceutical composition for preventing or treating cancer according to claim 1, wherein the anticancer agent is any one selected from the group consisting of a chemotherapeutic agent, a targeted anticancer agent, an oncolytic virus, an antibody therapeutic agent, a cell therapeutic agent, and an immune checkpoint inhibitor.

20. The pharmaceutical composition for preventing or treating cancer according to claim 19, wherein the chemotherapeutic agent is any one selected from the group consisting of alkylating agents, microtubule inhibitors, metabolic antagonists and topoisomerase inhibitors.

21. The pharmaceutical composition for preventing or treating cancer according to claim 20, wherein the chemotherapeutic agent is any one selected from the group consisting of mechlorethamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, thiotepa, altretamine, procarbazine, busulfan, streptozotocin, carmustine, lomustine, dacarbazine, cisplatin, carboplatin, oxaliplatin, docetaxel, velban, oncovin, navelbine, fluorouracil, capecitabine, cytarabine, gemcitabine, fludarabine, methotrexate, pemetrexed, mercaptopurine, hycamtin, camptosar, bepcid, paclitaxel, blenoxane, adriamycin and cervidin.

22. The pharmaceutical composition for preventing or treating cancer according to claim 19, wherein the targeted anticancer drug targets any one protein selected from the group consisting of EGFR, VEGFR, CD20, CD38, RNAK-L, BTK, Bcr-abl, PDGFR / FGFR family, MEK / RAF / KRAS, HER2 / Neu, ubiquitin, JAK, ALK, PARP, TGFβR, proteasome, Bcl-2, C-Met, VR1, VR2, VR3, c-kit, AXL, RET, Braf, DNMT, CDK4 / 6, and STING.

23. The targeted anticancer drug may be cetuximab, trastuzumab, pertuzumab, gefitinib, erlotinib, osimertinib, panitumumab, axitinib, lenvatinib, bevacizumab, ramucirumab, aflibercept, rituximab, obinutuzumab, daratumumab, denosumab, ibrutinib, dasatinib, nilotinib, imatinib, bosutinib, galunisertib, bactosertib, nintedanib, sunitinib, sorafenib, cabozantinib, regorafenib, masitinib, semaxanib, tivozanib, vandetanib, pazopanib, trametinib, dabrafenib, sotrasib, afatinib, la The pharmaceutical composition for preventing or treating cancer according to claim 22, which is any one selected from the group consisting of patinib, neratinib, lenalidomide, ixazomib, ruxolitinib, lestaurtinib, pacritinib, cobimetinib, selumetinib, binimetinib, alectinib, crizotinib, venetoclax, bemcentinib, gilteritinib, selpercatinib, pralsetinib, vemurafenib, olaparib, talazoparib, niraparib, rucaparib, azacitidine, decitabine, guadecitabine, abemaciclib, ribociclib, palbociclib, CDN, SB11285 and DMXAA.

24. The pharmaceutical composition for preventing or treating cancer according to claim 19, wherein the oncolytic virus is talimogene laherparepvec.

25. The pharmaceutical composition for preventing or treating cancer according to claim 19, wherein the antibody therapeutic agent is any one selected from the group consisting of cetuximab, trastuzumab, pertuzumab, panitumumab, emtansine, rituximab, daratumumab, denosumab, ibritumomab, tositumomab, brentuximab, ofatumumab, obinutuzumab, necitumumab, bevacizumab, ramucirumab, nivolumab, pembrolizumab, atezolizumab, durvalumab and ipilimumab.

26. The pharmaceutical composition for preventing or treating cancer according to claim 19, wherein the cell therapy agent is any one selected from the group consisting of tisagenlecleucel and axicabutagenciloleucel.

27. The pharmaceutical composition for preventing or treating cancer according to claim 19, wherein the immune checkpoint inhibitor is any one selected from the group consisting of anti-CTLA-4 antibody, anti-PD-1 antibody, anti-PD-L1 antibody, anti-PD-L2 antibody, anti-B7-H4 antibody, anti-HVEM antibody, anti-TIM3 antibody, anti-GAL9 antibody, anti-LAG3 antibody, anti-VISTA antibody, anti-KIR antibody, anti-BTLA antibody, and anti-TIGIT antibody.

28. The pharmaceutical composition for preventing or treating cancer according to claim 27, wherein the immune checkpoint inhibitor is any one selected from the group consisting of ipilimumab, pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab and durvalumab.

29. The pharmaceutical composition for preventing or treating cancer according to claim 19 , wherein the anticancer agent comprises a chemotherapeutic agent and an immune checkpoint inhibitor.

30. 30. The pharmaceutical composition for preventing or treating cancer according to claim 29, wherein the chemotherapeutic agent comprises an alkylating agent and an antimetabolite.

31. 2. The pharmaceutical composition for preventing or treating cancer according to claim 1, wherein the cancer is selected from the group consisting of squamous cell carcinoma, basal cell carcinoma, glioblastoma, bone cancer, gastric cancer, kidney cancer, lung cancer, bladder cancer, prostate cancer, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, bladder cancer, head and neck cancer, renal cell carcinoma, esophageal cancer, pancreatic cancer, brain cancer, gastrointestinal cancer, liver cancer, leukemia, lymphoma, melanoma, multiple myeloma, osteosarcoma, colorectal cancer, bile duct cancer, choriocarcinoma, oral cancer, neuroblastoma, skin cancer, testicular cancer, stromal tumor, germ cell tumor, and thyroid cancer.

32. A method for preventing or treating cancer, comprising administering to a subject a pharmaceutical composition for preventing or treating cancer according to any one of claims 1 to 31.

33. Use of the pharmaceutical composition for preventing or treating cancer according to any one of claims 1 to 31 in the manufacture of a medicament for preventing or treating cancer.

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