SHP2 inhibitors and uses thereof

Abstract

The present invention relates to an SHP2 inhibitor, a pharmaceutical composition comprising the same for preventing or treating diseases associated with SHP2, a method for treating and preventing diseases using the same, and a use thereof. Therefore, the present invention can effectively prevent or treat diseases associated with SHP2.

Description

Technical Field

[0001] The present invention relates to a compound as a SHP2 inhibitor, its stereoisomer, isotope-labeled compound or solvate, or a pharmaceutically acceptable salt thereof, and use thereof for preventing or treating diseases associated with abnormal SHP2 activity.

[0002] This research was supported by the National New Drug Development Project Support (HN22C0066) from the KOREA DRUG DEVELOPMENT FUND, which was funded by the Ministry of Science and ICT, the Ministry of Trade, Industry and Energy, and the Ministry of Health and Welfare of the Republic of Korea. Background Art

[0003] Src homology 2 domain-containing phosphatase-2 (SHP2) is a protein tyrosine phosphatase (PTP), also known as PTPN11 (protein tyrosine phosphatase non-receptor type 11), PTP-1D (protein tyrosine phosphatase 1D), or PTP-2C (protein tyrosine phosphatase 2C). SHP2 is a signaling molecule that regulates various cellular functions, including cell growth, differentiation, cell cycle, and oncogenic transformation. SHP2, like SHP1, consists of two tandem SH2 domains at its N-terminus. In its inactive state, the N-terminal SH2 domain binds to the PTP domain and blocks substrate binding to the active site, thereby inhibiting SHP2. Upon binding to a phosphotyrosyl residue, the N-terminal SH2 domain is released from the PTP domain, and the enzyme becomes activated.

[0004] Mutations in SHP2 are known to cause Noonan syndrome and Leopard syndrome and are associated with cancers such as juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colorectal cancer, head cancer, head and neck squamous cell carcinoma, gastric cancer, anaplastic large cell lymphoma, glioblastoma, pancreatic cancer, biliary tract cancer, uterine cancer, endometrial cancer, liver cancer, and neurofibromatosis type 1.

[0005] Furthermore, SHP2 inhibitors are known to effectively penetrate the blood-brain barrier (BBB). Therefore, SHP2 inhibitors hold promise as therapeutic agents for primary and metastatic malignant brain tumors due to their excellent brain penetration ability.

[0006] Therefore, there is a need to develop a novel compound capable of inhibiting the activity of SHP2, a method for preparing the same, a pharmaceutical composition comprising the same, and a method for using the same to prevent or treat diseases associated with abnormal SHP2 activity. Summary of the Invention

[0007] Technical issues

[0008] The present invention provides a novel compound capable of inhibiting SHP2 activity, its stereoisomer, isotope-labeled compound or solvate, or a pharmaceutically acceptable salt thereof.

[0009] The present invention provides a pharmaceutical composition for preventing or treating diseases associated with abnormal SHP2 activity, which uses a novel compound capable of inhibiting the activity of SHP2, its stereoisomers, isotope-labeled compounds or solvates, or pharmaceutically acceptable salts thereof.

[0010] The present invention provides a method for preventing or treating diseases associated with abnormal SHP2 activity, which uses a novel compound capable of inhibiting the activity of SHP2, its stereoisomer, isotope-labeled compound or solvate, or a pharmaceutically acceptable salt thereof.

[0011] The present invention provides a novel compound capable of inhibiting the activity of SHP2, its stereoisomers, isotope-labeled compounds or solvates, or the use of pharmaceutically acceptable salts thereof.

[0012] Solution to the problem

[0013] Each description and embodiment disclosed herein may also be applicable to each other description and embodiment. That is, all combinations of the various elements disclosed herein are within the scope of this application. In addition, the scope of this application should not be interpreted as being limited by the specific description set forth below.

[0014] In one aspect, a compound represented by Formula 1 is provided, or a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof:

[0015] [Formula 1]

[0016]

[0017] In Formula 1, Z is N or CH; X is H or halogen; W 1 and W 2 One of them is S and the other is N. 1 It is H, C 6-10 Aryl or optionally C 1-6 Alkoxy-substituted C 1-6 Alkyl; R x and R yEach independently is H or C 1-6 alkyl, It is a single bond or a double bond.

[0018] In some embodiments, the compound represented by Formula 1 can be represented by the following Formula 1A:

[0019] [Formula 1A]

[0020]

[0021] In Formula 1A, X is H or halogen; W 1 and W 2 One of them is S and the other is N. 1A H, C 6-10 Aryl or optionally C 1-6 Alkoxy-substituted C 1-6 Alkyl; R x and R y Each independently is H or C 1-6 Alkyl. For example, W 1 Can be S, W 2 It can be N. Or, W 1 Can be N, W 2 It can be S. In this case, The nitrogen may be connected to a double bond, and The bond to S may be a single bond.

[0022] In Formula 1A, X is H or halogen. In Formula 1A, X can be H, F, Cl, Br, or I. For example, X can be H or Cl.

[0023] In Formula 1A, R 1A It is H, C 6-10 Aryl or optionally C 1-6 Alkoxy-substituted C 1-6 Alkyl. Optionally C 1-6 Alkoxy-substituted C 1-6 The alkyl group may include C 1-6 Alkyl, C 1-5 Alkyl, C 1-6 Alkoxy-substituted C 3-6 Alkyl, C 1-6 Alkoxy-substituted C 4-6 Alkyl, C 1-6 Alkoxy substituted branched C 3-6 Alkyl or C 1-6 Alkoxy substituted branched C 4-6 alkyl.

[0024] In Formula 1A, R 1A It is H, C 6-10Aryl or optionally C 1-6 Alkoxy-substituted C 1-6 In some embodiments, R 1A It can be selected from the group consisting of: H, phenyl, naphthyl and methyl, ethyl, propyl, butyl, pentyl or hexyl optionally substituted with methoxy, ethoxy, propoxy or butoxy. For example, it can be selected from the group consisting of: H, phenyl, CH3, CH2CH3, In some embodiments, R 1A It can be

[0025] In Formula 1A, R x and R y Each independently is H or C 1-6 In some embodiments, R x and R y Can be the same or different. In some embodiments, R x and R y can be independently H or C 1-4 In some embodiments, R x and R y can be independently H or C 1-3 Alkyl. For example, R x and R y They can each be H.

[0026] In some embodiments, in Formula 1A, X is H or Cl, R 1A Selected from the group consisting of: H, phenyl, CH3, CH2CH3, And R x and R y They can each be H.

[0027] In some embodiments, the compound represented by Formula 1A may be represented by the following Formula 1A-1.

[0028] [Formula 1A-1]

[0029]

[0030] In Formula 1A-1, X is H or halogen; R 1a Is H or C 1-6 Alkyl; R x and R y can be independently H or C 1-6 alkyl.

[0031] In Formula 1A-1, X is H or halogen. In some embodiments, X can be H, F, Cl, Br, or I. For example, X can be H or Cl.

[0032] In Formula 1A-1, R 1a Can be H or C 1-6 In some embodiments, R 1a It can be H, methyl, ethyl, propyl, butyl, pentyl or hexyl. For example, R 1a Can be selected from the group consisting of: H, CH3, CH2CH3,

[0033] In Formula 1A-1, R x and R y Each independently is H or C 1-6 In some embodiments, R x and R y Can be the same or different. In some embodiments, R x and R y can be independently H or C 1-4 In some embodiments, R x and R y can be independently H or C 1-3 Alkyl. For example, R x and R y They can each be H.

[0034] In some embodiments, in Formula 1A-1, X is H or Cl, R 1A Selected from the group consisting of: H, CH3, CH2CH3, And R x and R y They can each be H.

[0035] In some embodiments, the compound represented by Formula 1A or Formula 1A-1 may be selected from compounds represented by the following formulas.

[0036]

[0037] In some embodiments, the compound represented by Formula 1 may be represented by the following Formula 1B.

[0038] [Formula 1B]

[0039]

[0040] In Formula 1B, X is H or halogen; R 1B Is H or C 1-6 Alkyl; R x and R y Each independently is H or C 1-6 alkyl.

[0041] In Formula 1B, X is H or halogen. In some embodiments, X can be halogen. For example, X can be Cl.

[0042] In Formula 1B, R 1B Is H or C 1-6 Alkyl. C 1-6 The alkyl group can be C 1-4 Alkyl or C 1-3 In some embodiments, R 1B Can be C 1-6 In some embodiments, R 1B It can be methyl or propyl. In some embodiments, the propyl group can be isopropyl.

[0043] In Formula 1B, R x and R y Each independently is H or C 1-6 In some embodiments, R x and R y Can be the same or different. In some embodiments, R x and R y can be independently H or C 1-4 In some embodiments, R x and R y can be independently H or C 1-3 Alkyl. For example, R x and R y They can each be H.

[0044] In some embodiments, in Formula 1B, X is halogen, R 1B It is C 1-6 Alkyl, and R x and R y They can each be H.

[0045] In some embodiments, the compound represented by Formula 1B may be a compound represented by the following chemical formula.

[0046]

[0047] In one aspect, provided is a compound represented by the following Formula 2, a stereoisomer, a solvate or an isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof:

[0048] [Formula 2]

[0049]

[0050] In Formula 2, Z is N or CH; V is N or CR a2 ; X is H or halogen. R a1 It is H, NRi R ii or C 1-6 Alkyl; R a2 Is H or OH or C 1-6 Alkoxy-substituted C 1-6 Alkyl. Y 1 is O or CH2; Y 2 is N or CH. 2 Selected from H, C 6-10 Aryl, 5 to 7 membered heteroaryl containing heteroatoms selected from N and O, and optionally substituted by OH or C 1-6 Alkoxy-substituted C 1-6 Alkyl; R i and R ii Each independently is H or C 1-6 Alkyl; R x and R y Each independently is H or C 1-6 alkyl.

[0051] In some embodiments, the compound represented by Formula 2 may be represented by the following Formula 2A.

[0052] [Formula 2A]

[0053]

[0054] In Formula 2A, Z is N or CH; Q is N or CH; X is H or halogen; Y 2 is N or CH. 2A It is H, C 6-10 Aryl, 5 to 7 membered heteroaryl containing a heteroatom selected from N and O, or optionally substituted by OH or C 1-6 Alkoxy-substituted C 1-6 Alkyl; R x and Ry are each independently H or C 1-6 alkyl.

[0055] In Formula 2A, Q is N or CH. In some embodiments, when Q is N, Z can be N. In some embodiments, when Q is N, Y 2 It can be CH.

[0056] In Formula 2A, X is H or halogen. In some embodiments, X can be halogen. In some embodiments, X can be F, Cl, Br, or I. For example, X can be Cl.

[0057] In Formula 2A, R 2A It is H, C 6-10 Aryl, 5 to 7 membered heteroaryl containing a heteroatom selected from N and O, or optionally substituted by OH or C 1-6 Alkoxy-substituted C 1-6In some embodiments, optionally OH or C 1-6 Alkoxy-substituted C 1-6 The alkyl group may include C 1-6 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, C substituted by OH 1-6 Alkyl, branched C substituted by OH 3-6 Alkyl, branched C substituted by OH 4-6 Alkyl, C 1-6 Alkoxy-substituted C 1-6 Alkyl, C 1-6 Alkoxy-substituted C 3-6 Alkyl, C 1-6 Alkoxy-substituted C 4-6 Alkyl, C 1-6 Alkoxy substituted branched C 3-6 Alkyl or C 1-6 Alkoxy substituted branched C 4-6 alkyl.

[0058] In some embodiments, R 2A It can be H, phenyl, naphthyl, a 5- to 7-membered heteroaryl group containing N as a heteroatom, or optionally substituted by OH or C 1-6 Alkoxy-substituted C 1-6 Alkyl. For example, R 2A It can be methyl, phenyl, pyridyl, In some embodiments, R 2A It can be In some embodiments, when Z is N, R 2A It can be

[0059] In Formula 2A, R x and R y Each independently is H or C 1-6 In some embodiments, R x and R y Can be the same or different. In some embodiments, R x and R y can be independently H or C 1-4 In some embodiments, R x and R y can be independently H or C 1-3 Alkyl. For example, R x and R y They can each be H.

[0060] In some embodiments, in Formula 2A, X is halogen, R 2AIt is methyl, phenyl, pyridyl, And R x and R y They can each be H.

[0061] In some embodiments, the compound represented by Formula 2A may be represented by the following Formula 2A-1.

[0062] [Formula 2A-1]

[0063]

[0064] In Formula 2A-1, X is H or halogen; Y 2 is N or CH alkyl; R 2a Is H or C 1-6 Alkyl; R x and R y can be independently H or C 1-6 alkyl.

[0065] In Formula 2A-1, X is H or halogen. In some embodiments, X can be halogen. In some embodiments, X can be F, Cl, Br, or I. For example, X can be Cl.

[0066] In Formula 2A-1, Y 2 It is N or CH.

[0067] In Formula 2A-1, R 2a Is H or C 1-6 In some embodiments, R 2a Can be C 1-6 In some embodiments, R 2a Can be methyl, ethyl, propyl, butyl, pentyl or hexyl. In some embodiments, R 2a Can be C 1-4 Alkyl or C 1-3 Alkyl. For example, R 2a It can be CH3.

[0068] In Formula 2A-1, R x and R y Each independently is H or C 1-6 In some embodiments, R x and R y Can be the same or different. In some embodiments, R x and R y can be independently H or C 1-4 In some embodiments, R x and R y can be independently H or C 1-3 Alkyl. For example, Rx and R y They can each be H.

[0069] In some embodiments, in Formula 2A-1, X is halogen, R 2a It is C 1-6 Alkyl, and R x and R y can each independently be H.

[0070] In some embodiments, the compound represented by Formula 2A or Formula 2A-1 may be selected from compounds represented by the following formulas.

[0071]

[0072]

[0073] In some embodiments, the compound represented by Formula 2 may be represented by the following Formula 2B:

[0074] [Formula 2B]

[0075]

[0076] In Formula 2B, Z is N or CH; X is H or halogen. a3 It is NR i R ii or C 1-6 Alkyl. R a4 Is H, or OH or C 1-6 Alkoxy-substituted C 1-6 Alkyl. R 2B selected from H and optionally OH or C 1-6 Alkoxy-substituted C 1-6 Alkyl. R i and R ii Each independently is H or C 1-6 Alkyl. R x and R y Each independently is H or C 1-6 alkyl.

[0077] In Formula 2B, X is H or halogen. In some embodiments, X can be halogen. In some embodiments, X can be F, Cl, Br, or I. For example, X can be Cl.

[0078] In Formula 2B, R 2B selected from H and optionally OH or C 1-6 Alkoxy-substituted C 1-6 Alkyl. C 1-6 The alkoxy group can be methoxy, ethoxy, propoxy, butoxy, pentyloxy, or hexyloxy.1-6 The alkoxy group can be C 1-4 Alkoxy or C 1-3 Alkoxy. For example, C 1-6 The alkoxy group may be a methoxy group. 1-6 The alkyl group may be methyl, ethyl, propyl, butyl, pentyl or hexyl. 1-6 The alkyl group may be methyl, ethyl, propyl or isobutyl. 2B may be optionally OH or C 1-6 Alkoxy-substituted C 1-6 Alkyl. For example, R 2B Can be selected from the group consisting of: CH3,

[0079] In Formula 2B, R a3 It is NR i R ii or C 1-6 Alkyl. R a4 Is H, or OH or C 1-6 Alkoxy-substituted C 1-6 In some embodiments, R a3 It can be NR i R ii , and R a4 It can be H. Alternatively, R a3 Can be C 1-6 Alkyl, and R a4 It can be OH or C 1-6 Alkoxy-substituted C 1-6 In some embodiments, R a3 can be NH2, and R a4 It can be H. In addition, R a3 Can be C 1-4 Alkyl, and R a4 It can be OH or C 1-6 Alkoxy-substituted C 1-4 Alkyl. For example, R a3 It can be NH2, R a4 It can be H. In addition, R a3 It can be methyl, R a4 It may be hydroxymethyl.

[0080] In Formula 2B, R i and R ii Each independently is H or C 1-6 In some embodiments, R i and R ii Can be the same or different. In some embodiments, R i and R iican be independently H or C 1-4 In some embodiments, R i and R ii can be independently H or C 1-3 Alkyl. For example, R i and R ii They can each be H.

[0081] In Formula 2B, R x and R y Each independently is H or C 1-6 In some embodiments, R x and R y Can be the same or different. In some embodiments, R x and R y can be independently H or C 1-4 In some embodiments, R x and R y can be independently H or C 1-3 Alkyl. For example, R x and R y They can each be H.

[0082] In some embodiments, in Formula 2B, X is halogen, R 2B Can be selected from the group consisting of: CH3, And R i 、R ii 、R x and R y can each independently be H.

[0083] In some embodiments, the compound represented by Formula 2B may be represented by the following Formula 2B-1.

[0084] [Formula 2B-1]

[0085]

[0086] In formula 2B-1, X is H or halogen; R 2B selected from H and optionally OH or C 1-6 Alkoxy-substituted C 1-6 Alkyl; R i and R ii Each independently is H or C 1-6 Alkyl; R x and R y Each independently is H or C 1-6 alkyl.

[0087] In Formula 2B-1, X is H or halogen. In some embodiments, X can be halogen. In some embodiments, X can be F, Cl, Br, or I. For example, X can be Cl.

[0088] In formula 2B-1, R 2B selected from H and optionally OH or C 1-6 Alkoxy-substituted C 1-6 Alkyl. C 1-6 The alkoxy group can be methoxy, ethoxy, propoxy, butoxy, pentyloxy, or hexyloxy. 1-6 The alkoxy group can be C 1-4 Alkoxy or C 1-3 Alkoxy. For example, C 1-6 The alkoxy group may be a methoxy group. 1-6 The alkyl group may be methyl, ethyl, propyl, butyl, pentyl or hexyl. 1-6 The alkyl group may be methyl, ethyl, propyl or isobutyl. 2B may be optionally OH or C 1-6 Alkoxy-substituted C 1-6 Alkyl. For example, R 2B Can be selected from the group consisting of: CH3,

[0089] In formula 2B-1, R i and R ii Each independently is H or C 1-6 In some embodiments, R i and R ii Can be the same or different. In some embodiments, R i and R ii can be independently H or C 1-4 In some embodiments, R i and R ii can be independently H or C 1-3 Alkyl. For example, R i and R ii They can each be H.

[0090] In formula 2B-1, R x and R y Each independently is H or C 1-6 In some embodiments, R x and R y Can be the same or different. In some embodiments, R x and R y can be independently H or C 1-4 In some embodiments, Rx and R y can be independently H or C 1-3 Alkyl. For example, R x and R y They can each be H.

[0091] In some embodiments, in Formula 2B-1, X can be a halogen, R 2B Can be selected from the group consisting of: CH3, And R i 、R ii 、R x and R y can each independently be H.

[0092] In some embodiments, the compound represented by Formula 2B or Formula 2B-1 may be selected from compounds represented by the following formulas.

[0093]

[0094]

[0095] In some embodiments, the compound represented by Formula 2 may be represented by the following Formula 2C.

[0096] [Formula 2C]

[0097]

[0098] In Formula 2C, X is H or halogen; R 2C Selected from H, C 6-10 Aryl and optionally OH or C 1-6 Alkoxy-substituted C 1-6 Alkyl. R x and R y Each independently is H or C 1-6 alkyl.

[0099] In Formula 2C, X is H or halogen. In some embodiments, X can be halogen. In some embodiments, X can be F, Cl, Br, or I. For example, X can be Cl.

[0100] In Formula 2C, R 2C Selected from H, C 6-10 Aryl and optionally OH or C 1-6 Alkoxy-substituted C 1-6 Alkyl. C 1-6 The alkoxy group can be methoxy, ethoxy, propoxy, butoxy, pentyloxy, or hexyloxy. 1-6 The alkoxy group can be C 1-4 Alkoxy or C 1-3Alkoxy. For example, C 1-6 The alkoxy group may be a methoxy group. 1-6 The alkyl group may be methyl, ethyl, propyl, butyl, pentyl or hexyl. 1-6 The alkyl group can be C 1-4 Alkyl. For example, C 1-6 The alkyl group may be methyl, ethyl, or butyl (e.g., n-butyl, isobutyl, or tert-butyl). 2C Can be C 6-10 Aryl or optionally OH or C 1-6 Alkoxy-substituted C 1-6 Alkyl. For example, R 2C Can be Methyl, CD3 or phenyl.

[0101] In Formula 2C, R x and R y Each independently is H or C 1-6 In some embodiments, R x and R y Can be the same or different. In some embodiments, R x and R y can be independently H or C 1-4 In some embodiments, R x and R y can be independently H or C 1-3 Alkyl. For example, R x and R y They can each be H.

[0102] In some embodiments, in Formula 2C, X can be a halogen, R 2C It can be OH or C 1-6 Alkoxy-substituted C 1-6 Alkyl, and R x and R y can each independently be H.

[0103] In some embodiments, the compound represented by Formula 2C may be a compound represented by the following formula.

[0104]

[0105] In one aspect, provided is a compound represented by the following formula 3, a stereoisomer, a solvate or an isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof:

[0106] [Formula 3]

[0107]

[0108] In Formula 3, Z is N or CH; R z Is H or C 1-6 Alkyl; X is H or halogen. R 3 It is H, and it is C 1-6 Alkyl-substituted-(C 1-6 Alkylene)-alkoxy, or C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 Cycloalkyl) or -(C 1-6 alkylene)-piperidinyl, each of which is optionally substituted by 1 to 3 R 31 Replacement; R 31 Halogen, cyano, OH, C 1-6 Alkoxy or C 6-12 Aryl. R a1 It is H, NH2, C 1-6 Alkylamino or di(C 1-6 Alkyl)amino. R b and R c Each independently is H or C 1-6 Alkyl groups, or connected to each other, together with the carbon atoms to which they are connected, form Ring A, which is a 5-membered ring optionally containing O. Ring A may be optionally replaced by R A Replace. R A Is H or C 1-6 Alkyl. R x and R y Each independently is H or C 1-6 alkyl.

[0109] In some embodiments, the compound represented by Formula 3 may be represented by the following Formula 3A.

[0110] [Formula 3A]

[0111]

[0112] In Formula 3A, Z is N or CH; X is H or halogen; R z Is H or C 1-6 Alkyl. R 3A It is H, and it is C 1-6 Alkyl-substituted-(C 1-6 Alkylene)-alkoxy, or C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 Cycloalkyl) or -(C 1-6 alkylene)-piperidinyl, each of which is optionally substituted by 1 to 3 R 31A Replace. R 31A is halogen, cyano or C 1-6 Alkoxy. R A Is H or C1-6 Alkyl. R x and R y Each independently is H or C 1-6 alkyl.

[0113] In Formula 3A, X is H or halogen. In some embodiments, X can be halogen. In some embodiments, X can be F, Cl, Br, or I. For example, X can be Cl.

[0114] In Formula 3A, R Z Is H or C 1-6 In some embodiments, R Z Can be H or C 1-4 In some embodiments, R Z Can be H or C 1-3 Alkyl. For example, R Z Can be H or methyl. In some embodiments, when R z It is C 1-6 When it is an alkyl group, Z may be N.

[0115] In Formula 3A, R 3A It is H, and it is C 1-6 Alkyl-substituted-(C 1-6 Alkylene)-alkoxy, or C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 Cycloalkyl) or -(C 1-6 alkylene)-piperidinyl, each of which is optionally substituted by 1 to 3 R 31A Replace. R 31A is halogen, cyano, OH or C 1-6 Alkoxy. Two or more R 31A Can be the same or different. C 1-6 The alkyl group may be methyl, ethyl, propyl, butyl, pentyl or hexyl. 1-6 The alkyl group may be methyl, ethyl, n-propyl, isopropyl or isobutyl. 3-6 Cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 3-6 The cycloalkyl group may be a cyclopropyl group. In some embodiments, -(C 1-6 alkyl)-(C 3-6 Cycloalkyl) can be -(C 1-4 alkyl)-(C 3-6 Cycloalkyl) or -(C 1-3 alkyl)-(C 3-6 Cycloalkyl). For example, -(C 1-6 alkyl)-(C 3-6 Cycloalkyl) may be methyl substituted by cyclopropyl (cyclopropylmethyl-).1-6 Alkyl-substituted-(C 1-6 Alkylene)-alkoxy may be C 1-6 Alkyl-substituted-(C 1-4 Alkylene)-alkoxy or C 1-6 Alkyl-substituted-(C 1-3 For example, C 1-6 Alkyl-substituted-(C 1-6 Alkylene)-alkoxy may be alkoxymethyl. -(C 1-6 Alkylene)-piperidinyl can be -(C 1-4 alkylene)-piperidinyl or -(C 1-3 For example, -(C 1-6 The alkylene)-piperidinyl group may be piperidinylmethyl.

[0116] In some embodiments, R 31A is halogen, cyano or C 1-6 In some embodiments, R 31A Can be halogen, cyano or C 1-4 In some embodiments, R 31A Can be halogen, cyano or C 1-3 Alkoxy. For example, R 31A It can be cyano, F or methoxy.

[0117] For example, R 3A Can be selected from the group consisting of: CH3, In some embodiments, R 3A It doesn't have to be H. or In some embodiments, when Z is N, R 3A It can be

[0118] In Formula 3A, R A Is H or C 1-6 Alkyl. C 1-6 The alkyl group may be methyl, ethyl, propyl, butyl, pentyl or hexyl. A Can be C 1-6 In some embodiments, C 1-6 The alkyl group can be C 1-4 Alkyl or C 1-3 Alkyl. For example, R A It may be methyl.

[0119] In Formula 3A, R x and R yEach independently is H or C 1-6 In some embodiments, R x and R y Can be the same or different. In some embodiments, R x and R y can be independently H or C 1-4 In some embodiments, R x and R y can be independently H or C 1-3 Alkyl. For example, R x and R y They can each be H.

[0120] In some embodiments, in Formula 3A, X can be a halogen, R 3A Can be selected from the group consisting of: CH3, R A Can be C 1-6 Alkyl, and R x and R y can each independently be H.

[0121] In some embodiments, the compound represented by Formula 3A may be represented by the following Formula 3A-1.

[0122] [Formula 3A-1]

[0123]

[0124] In Formula 3A-1, Z is N or CH; X is H or halogen; R 3a It is H, C 1-6 Alkyl or -(C 1-6 alkyl)-(C 3-6 cycloalkyl), each of which is optionally substituted by 1 to 3 R 31a Replacement; R 31a Is halogen, OH or C 1-6 Alkoxy; R A Is H or C 1-6 Alkyl; R x and R y Each independently is H or C 1-6 alkyl.

[0125] In Formula 3A-1, X is H or halogen. In some embodiments, X can be halogen. In some embodiments, X can be F, Cl, Br, or I. For example, X can be Cl.

[0126] In Formula 3A-1, R 3a Is H or C 1-6 Alkyl or -(C 1-6alkyl)-(C 3-6 cycloalkyl), each of which is optionally substituted by 1 to 3 R 31a Replacement; R 31a Is halogen, OH or C 1-6 Alkoxy. Two or more R 31a Can be the same or different. C 1-6 The alkyl group may be methyl, ethyl, propyl, butyl, pentyl or hexyl. 1-6 The alkyl group may be methyl, ethyl, propyl or isobutyl. 3-6 Cycloalkyl can be cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. 3-6 The cycloalkyl group may be a cyclopropyl group. In some embodiments, -(C 1-6 alkyl)-(C 3-6 Cycloalkyl) can be -(C 1-4 alkyl)-(C 3-6 Cycloalkyl) or -(C 1-3 alkyl)-(C 3-6 For example, -(C 1-6 alkyl)-(C 3-6 In some embodiments, R 31a Can be halogen or C 1-6 In some embodiments, R 31a Can be halogen or C 1-4 In some embodiments, R 31a Can be halogen or C 1-3 Alkoxy. For example, R 3a Can be selected from the group consisting of: CH3,

[0127] In some examples, Z can be N, R 3a Can be C 1-6 Alkyl or -(C 1-6 alkyl)-(C 3-6 cycloalkyl), each of which is optionally substituted by 1 to 3 R 3a Replace, and R 3a Can be halogen, OH or C 1-6 Alkoxy.

[0128] In some embodiments, Z may be CH, and R 3a can be H or optionally replaced by R 3a Substituted C 1-6 In this case, R 3a Can be OH or C 1-6 Alkoxy.

[0129] In Formula 3A-1, R A Is H or C 1-6 Alkyl. C 1-6 The alkyl group may be methyl, ethyl, propyl, butyl, pentyl or hexyl. A Can be C 1-6 In some embodiments, C 1-6 The alkyl group can be C 1-4 Alkyl or C 1-3 Alkyl. For example, R A It may be methyl.

[0130] In Formula 3A-1, R x and R y Each independently is H or C 1-6 In some embodiments, R x and R y Can be the same or different. In some embodiments, R x and R y can be independently H or C 1-4 In some embodiments, R x and R y can be independently H or C 1-3 Alkyl. For example, R x and R y They can each be H.

[0131] In some embodiments, in Formula 3A-1, X can be a halogen, R 3A Can be selected from the group consisting of: CH3, R A Can be C 1-6 Alkyl, and R x and R y can each independently be H.

[0132] In some embodiments, the compound represented by Formula 3A or Formula 3A-1 may be selected from compounds represented by the following formulas.

[0133]

[0134]

[0135] In some embodiments, the compound represented by Formula 3 can be represented by the following Formula 3B:

[0136] [Formula 3B]

[0137]

[0138] In Formula 3B, X is H or halogen.3B is optionally OH, C 1-6 Alkoxy or C 6-10 Aryl-substituted C 1-6 Alkyl. R A Is H or C 1-6 Alkyl; R i and R ii Each independently is H or C 1-6 Alkyl; R x and R y Each independently is H or C 1-6 alkyl.

[0139] In Formula 3B, X is H or halogen. In some embodiments, X can be halogen. In some embodiments, X can be F, Cl, Br, or I. For example, X can be Cl.

[0140] In Formula 3B, R 3B is optionally OH, C 1-6 Alkoxy or C 6-10 Aryl-substituted C 1-6 Alkyl. C 1-6 The alkoxy group can be C 1-4 Alkoxy or C 1-3 Alkoxy. For example, C 1-6 The alkoxy group may be a methoxy group. 6-10 Aryl can be phenyl or naphthyl. For example, C 6-10 Aryl may be phenyl. 1-6 The alkyl group may be methyl, ethyl, propyl, butyl, pentyl or hexyl. 1-6 The alkyl group can be C 1-4 Alkyl or C 1-3 Alkyl. For example, C 1-6 The alkyl group may be methyl or isobutyl. 3B Can be C 1-6 Alkoxy or C 6-10 Aryl-substituted C 1-6 Alkyl. For example, R 3B Can include C 1-6 Alkoxy-substituted C 3-6 Alkyl, C 1-6 Alkoxy-substituted C 4-6 Alkyl, C 1-6 Alkoxy substituted branched C 3-6 Alkyl, C 1-6 Alkoxy substituted branched C 4-6 Alkyl or C 6-10 Aryl-substituted C 1-6 In some embodiments, R 3B Can be C1-4 Alkoxy or C 6-10 Aryl-substituted C 1-4 Alkyl. For example, R 3B It can be benzyl or In some embodiments, R 3B It can be

[0141] In Formula 3B, R A Is H or C 1-6 Alkyl. C 1-6 The alkyl group may be methyl, ethyl, propyl, butyl, pentyl or hexyl. A Can be C 1-6 In some embodiments, C 1-6 The alkyl group can be C 1-4 Alkyl or C 1-3 Alkyl. For example, R A It may be methyl.

[0142] In Formula 3B, R i and R ii Each independently is H or C 1-6 In some embodiments, R i and R ii Can be the same or different. In some embodiments, R i and R ii can be independently H or C 1-4 In some embodiments, R i and R ii can be independently H or C 1-3 Alkyl. For example, R i and R ii They can each be H.

[0143] In Formula 3B, R x and R y Each independently is H or C 1-6 In some embodiments, R x and R y Can be the same or different. In some embodiments, R x and R y can be independently H or C 1-4 In some embodiments, R x and R y can be independently H or C 1-3 Alkyl. For example, R x and R y They can each be H.

[0144] In some embodiments, X can be a halogen, R 3B Can be C 6-10 Aryl-substituted C 1-6 Alkyl, R A Can be C 1-6 Alkyl, and R i 、R ii 、R x and R y can each independently be H.

[0145] In some embodiments, the compound represented by Formula 3B may be a compound represented by the following formula.

[0146]

[0147] In some embodiments, the compound represented by Formula 3 may be represented by the following Formula 3C.

[0148] [Formula 3C]

[0149]

[0150] In Formula 3C, X is H or halogen; R 3C is optionally C 6-10 Aryl-substituted C 1-6 Alkyl; R c Is H or C 1-6 Alkyl; R i and R ii Each independently is H or C 1-6 Alkyl; R x and R y Each independently is H or C 1-6 alkyl.

[0151] In Formula 3C, X is H or halogen. In some embodiments, X can be halogen. In some embodiments, X can be F, Cl, Br, or I. For example, X can be Cl.

[0152] In formula 3C, R 3C is optionally C 6-10 Aryl-substituted C 1-6 Alkyl. C 6-10 Aryl can be phenyl or naphthyl. For example, C 6-10 Aryl may be phenyl. 1-6 The alkyl group may be methyl, ethyl, propyl, butyl, pentyl or hexyl. 1-6 The alkyl group can be C 1-4 Alkyl or C 1-3 Alkyl. For example, C 1-6 The alkyl group may be methyl or isobutyl. For example, R 3CIt may be benzyl.

[0153] In formula 3C, R c Is H or C 1-6 Alkyl. C 1-6 The alkyl group may be methyl, ethyl, propyl, butyl, pentyl or hexyl. A Can be C 1-6 In some embodiments, C 1-6 The alkyl group can be C 1-4 Alkyl or C 1-3 Alkyl. For example, R c It may be methyl.

[0154] In formula 3C, R i and R ii Each independently is H or C 1-6 In some embodiments, R i and R ii Can be the same or different. In some embodiments, R i and R ii can be independently H or C 1-4 In some embodiments, R i and R ii can be independently H or C 1-3 Alkyl. For example, R i and R ii They can each be H.

[0155] In formula 3C, R x and R y Each independently is H or C 1-6 In some embodiments, R x and R y Can be the same or different. In some embodiments, R x and R y can be independently H or C 1-4 In some embodiments, R x and R y can be independently H or C 1-3 Alkyl. For example, R x and R y They can each be H.

[0156] In some embodiments, the compound represented by Formula 3C may be a compound represented by the following formula.

[0157]

[0158] As used herein, the term "halogen" or "halogen atom" refers to an atom belonging to Group 17 of the periodic table. Halogen atoms include F, Cl, Br, I, and the like.

[0159] The term "alkyl" refers to a fully saturated branched or unbranched (or straight chain or linear) hydrocarbon. Alkyl groups may be substituted or unsubstituted. 20 The alkyl group may be, for example, C1-C 15 、C1-C 10 , or C1-C6 alkyl. C1-C6 alkyl can be C1-C5, C1-C4, C1-C3, or C 1- C2 alkyl. The alkyl group can be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, isopentyl, neopentyl, isopentyl, or n-hexyl.

[0160] The term "haloalkyl" refers to an alkyl group substituted with at least one halogen.

[0161] The term "hydroxy" refers to an -OH functional group (hydroxyl group).

[0162] The term "carbonyl" refers to -C(=O)-.

[0163] The term "alkoxy" refers to an alkyl group bonded to an oxygen atom. 20 The alkoxy group may be, for example, a C1-C 15 、C1-C 10 , or C1-C6 alkoxy. C1-C6 alkoxy can be C1-C5, C1-C4, C1-C3, or C 1- C2 alkoxy. Alkoxy can be methoxy, ethoxy, propoxy, butoxy, etc.

[0164] The term "alkoxyalkyl" refers to an alkoxy group bonded to an alkyl group. 20 Alkoxyalkyl groups may be, for example, C2-C 15 、C2-C 10 , or C2-C6 alkoxyalkyl. For example, C2-C 20 The alkoxyalkyl group may be (C1-C 10 Alkoxy)-(C1-C 10 The alkoxy group may be, for example, a methoxymethyl group, a methoxyethyl group, an ethoxymethyl group, an ethoxyethyl group, a methoxypropyl group, an ethoxypropyl group, or the like.

[0165] The term "amino" refers to -NH2.

[0166] The term "amine group" refers to a substituent in which one, two or all three hydrogen atoms of an amino group are replaced by an organic functional group, and includes all primary, secondary and tertiary amines, as well as amino groups.

[0167] The term "alkylamine" refers to an amine in which one of the hydrogen atoms of the amino group (-NH2) is replaced by an alkyl group.

[0168] The term "di(alkyl)amine" refers to an amine in which the two hydrogen atoms of the amino group (-NH2) are replaced by alkyl groups. The two alkyl groups in the di(alkyl)amine may be the same or different.

[0169] The term "nitro" refers to -NO2.

[0170] The term "cyano" refers to -CN, a functional group consisting of a triple bond between a carbon atom and a nitrogen atom.

[0171] The term "carboxy" refers to -COOH. A salt of a carboxy group refers to the conjugate base of the carboxylic acid.

[0172] The term "sulfonyl" refers to a -SO2- group.

[0173] The term "cycloalkyl" refers to a saturated non-aromatic monocyclic, bicyclic, or tricyclic hydrocarbon group. The cycloalkyl group may contain 3 to 20 carbon atoms, for example, 5 to 10, 3 to 8, or 3 to 6 carbon atoms. A monocyclic cycloalkyl group may be, for example, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. A bicyclic cycloalkyl group may be, for example, bornyl, decahydronaphthyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, or bicyclo[2.2.2]octyl. A tricyclic cycloalkyl group may be, for example, adamantyl.

[0174] The term "cycloalkane ring" refers to a saturated non-aromatic monocyclic, bicyclic, or tricyclic hydrocarbon ring. The cycloalkane ring can be a full (non-radical) functional group of the above-mentioned cycloalkyl group. The cycloalkane ring can contain 3 to 20 carbon atoms, such as 5 to 10, 3 to 8, or 3 to 6 carbon atoms. The monocyclic cycloalkane ring can be, for example, a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, or a cyclohexane ring.

[0175] The term "aryl" also includes groups in which an aromatic ring is fused to one or more carbon rings. 30 Aryl can be, for example, C6-C 15 or C6-C 10 Aryl. Aryl can be phenyl, naphthyl, or tetrahydronaphthyl.

[0176] The term "arylalkyl" refers to an alkyl group substituted with an aryl group.

[0177] The term "aryloxy" refers to an aryl group bound to an oxygen atom.

[0178] The term "heteroaryl" refers to a compound containing one or more heteroatomic monocycles or bicyclic aromatics, and all the other ring atoms are carbon. Heteroaryl can include, for example, 1 to 5, 1 to 3, 1 or 2 heteroatoms, and can include 5 to 10 ring members." heteroaryl" can be, for example, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, benzofuranyl, benzothienyl, benzopyrazolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl or benzisothiazolyl etc.

[0179] The term "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially unsaturated cyclic hydrocarbon containing at least one heteroatom. The heterocyclyl ring group can be a monocyclic group, a bicyclic group, or a tricyclic group. The bicyclic group can be a spirocyclic group, a bridged ring group, and a fused ring group. The heterocyclyl ring group can contain 3 to 20, 3 to 10, 3 to 8, 3 to 7, 5 to 7, 4 to 6, or 5 to 6 ring atoms. The heteroatom can be any one or more, for example, 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S. For example, the heterocycloalkyl group can be aziridinyl, oxiranyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, tetrahydropyranyl, dihydropyranyl, morpholinyl, thiomorpholinyl, or oxazolidinyl, etc.

[0180] The heteroatom may be any one or more selected from the group consisting of N, O, P and S. The heteroatom may be 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S.

[0181] The term "substituted" included in "substituted or unsubstituted" refers to the replacement of hydrogen atoms and the introduction of other atomic groups when forming a derivative by replacing one or more hydrogen atoms in an organic compound with other atomic groups, and the term "substituent" refers to the introduced atomic group. "Substituted" used herein without any limitation on the substituent may mean substitution with, for example, a halogen atom, a C1-C12 substituted with a halogen atom, 20 Alkyl (e.g., CCF3, CHCF2, CH2F, CCl3, etc.), C1-C 20 Alkoxy, C2-C 20 Alkoxyalkyl, hydroxyl, -NH2, =NH, nitro, cyano, amidino, hydrazine, hydrazone, carboxyl or its salt, sulfonyl, sulfamoyl, sulfonic acid or its salt, phosphoric acid or its salt, C1-C 20 Alkyl, C2-C 20 Alkenyl, C2-C 20 Alkynyl, C6-C 20 Aryl, C6-C 20 Arylalkyl, C6-C 20 Heteroaryl, C7-C20 Heteroarylalkyl, C6-C 20 Heteroaryloxy, C6-C 20 Heteroaryloxyalkyl or C6-C 20 Heteroarylalkyl, etc.

[0182] The term "isomer" included in "stereoisomers" refers to compounds with the same molecular formula but different in terms of the atomic connectivity or spatial arrangement of the constituent atoms in the molecule. Isomers include, for example, structural isomers and stereoisomers. Stereoisomers can be diastereomers or enantiomers. Enantiomers refer to a pair of isomers that are non-superimposable mirror images, such as the relationship between the left hand and the right hand, and are also called optical isomers. When 4 or more substituents are different from each other at the chiral center carbon, enantiomers are divided into R (right: clockwise) and S (left: counterclockwise). Diastereomers refer to non-mirror stereoisomers and are isomers produced by different spatial arrangements of atoms. Diastereomers can be divided into cis-trans isomers and conformers or conformers.

[0183] The term "solvate" refers to a compound solvated in an organic or inorganic solvent. Solvates are, for example, hydrates.

[0184] The term "isotopes" refers to elements that are identical but have different mass numbers, i.e., the same number of protons but different numbers of neutrons. For example, isotopes can include 2 H. 3 H. 11 C. 13 C. 14 C. 13 N. 15 N. 17 O. 18 O. 18 F. 31 P. 32 P. 35 S. 36 Cl, 125 Isotope-labeled compounds may be advantageous because they have greater stability and longer half-lives in vivo.

[0185] The term "salt" refers to inorganic and organic acid addition salts of a compound. Pharmaceutically acceptable salts may be salts that do not cause severe irritation to an organism to which the compound is administered and do not impair the biological activity and properties of the compound. Inorganic acid salts may be hydrochlorides, bromates, phosphates, sulfates, or disulfates. Organic acid salts may be formate, acetate, propionate, lactate, oxalate, tartrate, malate, maleate, citrate, fumarate, besylate, camphorsulfonate, edicylate, trichloroacetate, trifluoroacetate, benzoate, gluconate, methanesulfonate, glycolate, succinate, 4-toluenesulfonate, galacturonate, pamoate, glutamate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, or aspartate. Metal salts may be calcium, sodium, magnesium, strontium, or potassium salts.

[0186] Any one or more compounds of Formulas 1 to 3 may be inhibitors of Src homology region 2 domain-containing phosphatase-2 (SHP2). Src homology region 2 domain-containing phosphatase-2 (SHP2) may be a protein belonging to a protein tyrosine phosphatase (PTP). SHP2 may also be referred to as tyrosine protein phosphatase non-receptor type 11 (PTPN11), protein tyrosine phosphatase 1D (PTP-1D), or protein tyrosine phosphatase 2C (PTP-2C). SHP2 may include two tandem SH2 domains at the N-terminus and SPP1. SHP2 may be a protein comprising the amino acid sequence of Uniprot number Q06124 in humans or the amino acid sequence of Uniprot number P35235 in mice. SHP2 may be wild-type SHP2 or a SHP2 mutant. An inhibitor of SHP2 may be an inhibitor that inhibits the expression or activity of SHP2.

[0187] In another aspect, provided is a pharmaceutical composition comprising the compound according to one aspect, a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof.

[0188] In another aspect, provided is a pharmaceutical composition for preventing or treating a disease associated with abnormal activity of Src homology 2 domain-containing phosphatase-2 (SHP2), the pharmaceutical composition comprising a compound according to one aspect, a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof.

[0189] The above compounds, stereoisomers, solvates, isotope-labeled compounds, pharmaceutically acceptable salts and SHP2 are as described above.

[0190] The disease associated with abnormal activity of SHP2 may be selected from the group consisting of cancer, cancer metastasis, cardiovascular disease, immune disorder, fibrosis and eye disorder.

[0191] The cancer can be selected from the group consisting of ovarian cancer, cervical cancer, endometrial cancer, uterine sarcoma, vulvar cancer, breast cancer, skin cancer, head and neck cancer, pancreatic cancer, lung cancer, colon cancer, colorectal cancer, gastric cancer, prostate cancer, bladder cancer, urethral cancer, liver cancer, kidney cancer, skin cancer, brain and spinal cord tumors, malignant brain tumors (glioblastoma, anaplastic astrocytoma, low-grade glioma, etc.), thymoma, mesothelioma, bronchogenic carcinoma, nasopharyngeal cancer, laryngeal cancer, esophageal cancer, bile duct cancer, testicular cancer, germ cell tumors, thyroid cancer, parathyroid cancer, lymphoma, myelodysplastic syndrome (MDS), myelofibrosis, acute leukemia, chronic leukemia, multiple myeloma, endocrine system cancer and sarcoma.

[0192] Cancer metastasis is the spread of a tumor from its original site to another part of the body where it takes up residence and multiplies. Cancer metastasis can cause cancer cells to spread to blood vessels, lymphatic vessels, or tissues.

[0193] In particular, the compounds of the present disclosure can exhibit improved blood-brain barrier (BBB) permeability properties. Specifically, the compounds of the present disclosure can have a blood-brain concentration ratio of at least 0.05, at least 0.1, at least 0.15, at least 0.2, or at least 0.25. Therefore, the compounds of the present disclosure can show excellent therapeutic effects on brain tumors, such as glioblastomas, anaplastic astrocytomas, low-grade gliomas, and cancers originating from sites outside the brain and metastasizing to the brain, such as lung cancer, breast cancer, melanoma, etc. that metastasize to the brain.

[0194] In some embodiments, the disease associated with abnormal activity of SHP2 can be EGFR / RAS pathway-dependent brain metastasis or glioblastoma. For example, patients with non-small cell lung cancer (NSCLC) who receive EGFR inhibitors may develop brain metastasis.

[0195] Cardiovascular disease refers to diseases that occur in the heart or major arteries (e.g., the aorta, pulmonary artery, carotid artery, cerebral blood vessels, renal artery, and lower limb arteries). Cardiovascular disease can be selected from the group consisting of hypertension, ischemic heart disease, coronary artery disease, angina pectoris, myocardial infarction, atherosclerosis (hardening of the arteries), cerebrovascular disease, stroke, arrhythmia, acute heart failure, chronic heart failure, and hypotension.

[0196] An immune disorder refers to a state in which a normal immune response does not occur. The immune disorder can be selected from the group consisting of acquired immunodeficiency, autoimmune diseases, systemic lupus erythematosus, scleroderma, Sjögren's syndrome, polymyositis, dermatomyositis, polymyalgia rheumatica, temporal arteritis, polyarteritis nodosa, and Behcet's syndrome.

[0197] Fibrosis refers to a condition in which there is an excessive increase in fibrous tissue in a part of a tissue or organ. Fibrosis may be selected from the group consisting of hepatic fibrosis, cystic fibrosis, myelofibrosis, endomyocardial fibrosis, and retroperitoneal fibrosis.

[0198] Ocular disorders refer to disorders that affect various structures of the eye. The ocular disorder may be selected from the group consisting of endophthalmitis, degenerative myopia, degenerative disorders of the eye, ocular hypotonia, intraocular foreign bodies, hemophthalmos, and ocular luxation.

[0199] The disease associated with abnormal activity of SHP2 can be selected from the group consisting of: Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia (JMML), neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colorectal cancer, head cancer, malignant brain tumors (glioblastoma, anaplastic astrocytoma, low-grade glioma, etc.), head and neck squamous cell carcinoma, gastric cancer, anaplastic large cell lymphoma, pancreatic cancer, biliary tract cancer, uterine cancer, endometrial cancer, liver cancer and neurofibromatosis type 1.

[0200] The term "prevention" refers to any action that inhibits the occurrence of a disease associated with SHP2 or delays its onset by administering a pharmaceutical composition. The term "treatment" refers to any action that improves or favorably alters the symptoms of a disease associated with SHP2 by administering a pharmaceutical composition.

[0201] The pharmaceutical composition may include a pharmaceutically acceptable carrier. The carrier is used in the sense of including an excipient, a diluent or an adjuvant. For example, the carrier can be selected from the group consisting of lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum arabic, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, polyvinylpyrrolidone, water, normal saline, buffer (for example, PBS), methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil. The composition may include a filler, an anti-aggregating agent, a lubricant, a wetting agent, a flavoring agent, an emulsifier, a preservative or a combination thereof.

[0202] The pharmaceutical composition can be prepared in any formulation according to conventional methods. The composition can be formulated as, for example, an oral dosage form (e.g., powder, tablet, capsule, syrup, pill or granule) or a parenteral dosage form (e.g., injection). In addition, the composition can be prepared as a systemic formulation or a local formulation.

[0203] In pharmaceutical compositions, solid formulations for oral administration may be tablets, pills, powders, granules, or capsules. Solid formulations may further include excipients. Excipients may be, for example, starch, calcium carbonate, sucrose, lactose, or gelatin. In addition, solid formulations may further include lubricants, such as magnesium stearate or talc. In pharmaceutical compositions, liquid formulations for oral administration may be suspensions, internal solutions, emulsions, or syrups. Liquid formulations may include water or liquid paraffin. Liquid formulations may include excipients, such as wetting agents, sweeteners, fragrances, or preservatives. In pharmaceutical compositions, formulations for parenteral administration may be sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried formulations, or suppositories. Non-aqueous solutions or suspensions may include vegetable oils or esters. Vegetable oils may be, for example, propylene glycol, polyethylene glycol, or olive oil. Esters may be, for example, ethyl oleate. The base of the suppository may be witepsol, polyethylene glycol, Tween 61, cocoa butter, lauric fat, or glycerin gelatin.

[0204] The pharmaceutical composition comprises a compound according to one aspect, a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof as an active ingredient of the pharmaceutical composition. "Active ingredient" refers to a physiologically active substance used to achieve pharmacological activity (e.g., to treat a disease associated with abnormal activity of SHP2).

[0205] The pharmaceutical composition can include a compound according to one aspect, a stereoisomer thereof, a solvate or an isotope-labeled compound, or a pharmaceutically acceptable salt thereof in an effective amount. The term "effective amount" refers to an amount sufficient to show the effect of preventing or treating a disease when administered to a subject in need thereof. An effective amount can be appropriately selected by one of ordinary skill in the art according to cells or subjects to be selected. The preferred dosage of the pharmaceutical composition varies according to the subject's condition and body weight, severity of the disease, drug form, route of administration and duration, but can be appropriately selected by one of ordinary skill in the art. According to the pharmaceutical composition, an effective amount can be about 0.5 μg to about 2g, about 1 μg to about 1g, about 10 μg to about 500mg, about 100 μg to about 100mg or about 1mg to about 50mg. However, the compound, its stereoisomer, solvate, isotope-labeled compound, or pharmaceutically acceptable salt can be administered in an amount of, for example, about 0.0001 mg / kg to about 100 mg / kg or about 0.001 mg / kg to about 100 mg / kg, which can be administered in divided doses 1 to 24 times a day, 1 to 7 times every 2 days to 1 week, or 1 to 24 times every 1 month to 12 months. The pharmaceutical composition can include the compound, its stereoisomer, solvate, isotope-labeled compound, or pharmaceutically acceptable salt in an amount of about 0.0001% by weight to about 10% by weight or about 0.001% by weight to about 1% by weight, based on the total weight of the entire composition.

[0206] The method of administration can be oral or parenteral. The method of administration can be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal or intradermal route. The composition can be administered systemically or topically, alone or in combination with other pharmaceutically active compounds.

[0207] In another aspect, provided is a method for preventing or treating a disease associated with abnormal activity of SHP2, comprising administering to a subject a compound according to one aspect, a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof.

[0208] The above compounds, stereoisomers, solvates, isotope-labeled compounds, pharmaceutically acceptable salts, SHP2, diseases associated with abnormal activity of SHP2, and prevention and treatment thereof are as described above.

[0209] The subject can be a mammal, such as a human, mouse, rat, cow, horse, pig, dog, monkey, sheep, goat, ape, or cat. The subject can be a subject suffering from or at risk of suffering from symptoms associated with a disease associated with abnormal activity of SHP2.

[0210] The method may further comprise administering to the subject an active ingredient known to have the effect of preventing or treating a disease associated with SHP2. The known active ingredient may be administered to the subject simultaneously, separately, or sequentially with the compound according to one aspect, its stereoisomer, solvate, or isotope-labeled compound, or its pharmaceutically acceptable salt.

[0211] The method of administration can be oral or parenteral. The method of administration can be, for example, oral, transdermal, subcutaneous, rectal, intravenous, intraarterial, intraperitoneal, intramuscular, intrasternal, topical, intranasal, intratracheal or intradermal. The pharmaceutical composition can be administered systemically or topically, alone or in combination with other pharmaceutically active compounds.

[0212] The preferred dosage of the pharmaceutical composition varies according to the patient's condition and weight, severity of the disease, pharmaceutical form, route of administration, and duration, but can be appropriately selected by one of ordinary skill in the art. For adults, the dosage can be, for example, within the range of about 0.001 mg / kg to about 100 mg / kg, about 0.01 mg / kg to about 10 mg / kg, or about 0.1 mg / kg to about 1 mg / kg. Administration can be once a day, 2 to 24 times a day, 1 to 2 times every 3 days, 1 to 6 times a week, 1 to 10 times every 2 weeks, 1 to 15 times every 3 weeks, 1 to 3 times every 4 weeks, or 1 to 12 times a year.

[0213] In another aspect, provided is a compound for preventing or treating a disease associated with abnormal activity of SHP2 according to one aspect, a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof.

[0214] The above compounds, stereoisomers, solvates, isotope-labeled compounds, pharmaceutically acceptable salts, SHP2, diseases associated with abnormal activity of SHP2, and prevention and treatment thereof are as described above.

[0215] In another aspect, provided is use of the compound according to one aspect, a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof for manufacturing a medicament for preventing or treating a disease associated with abnormal activity of SHP2.

[0216] The above compounds, stereoisomers, solvates, isotope-labeled compounds, pharmaceutically acceptable salts, SHP2, diseases associated with abnormal activity of SHP2, and prevention and treatment thereof are as described above.

[0217] Effects of the Invention

[0218] Diseases associated with SHP2 can be effectively prevented or treated by SHP2 inhibitors, pharmaceutical compositions for preventing or treating diseases associated with SHP2 comprising the same, methods for treating and preventing diseases using the same, and uses thereof. DETAILED DESCRIPTION

[0219] Hereinafter, the present invention will be described in more detail with the help of the following examples. However, the following examples are only used to illustrate the present invention, and the scope of the present invention is not limited thereto.

[0220] Preparation Example 1: 2-Chloro-6-oxo-spiro[4H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylic acid tert-butyl ester (Medium Intermediate I-1)

[0221]

[0222] Step 1: (2-chlorothiazol-4-yl)methanol

[0223] To the solution of 2-chlorothiazole-4-ethyl formate (30g, 157mmol) in EtOH (300mL), add NaBH (41.5g, 1.10mol), and the mixture was stirred at 50 ℃ for 2 hours.Reactant mixture is quenched with aqueous ammonium chloride (100mL) at 0 ℃, diluted in water (100mL), and then extracted with ethyl acetate (EA) (200mL x 3).The organic layer merged is washed with salt water (200mL x 3), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure.Residue is passed through column chromatography, to obtain (2-chlorothiazole-4-yl) methanol (22g, 94% productive rate) as colorless oil.

[0224] 1 H NMR (400MHz, CDCl3) δ = 7.12 (s, 1H), 4.73-4.70 (m, 2H), 2.52-2.34 (m, 1H); MS (EI) m / z: 150.5 [M+H] + .

[0225] Step 2: (2-chlorothiazol-4-yl)methyl methanesulfonate

[0226] To a solution of ethyl 2-chlorothiazole-4-formate (30g, 157mmol) in dichloromethane (DCM) (300mL) was added triethylamine (TEA) (27.1g, 267mmol) and MsCl (21.4g, 187mmol) at 0°C, and the mixture was stirred at 0°C for 0.5 hours. At 25°C, the reaction mixture was quenched with NaHCO3aqueous solution (100mL), diluted in water (100mL), and then extracted with DCM (200mL x 3). The combined organic layer was washed with brine (100mL x 3), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain (2-chlorothiazole-4-yl) methyl methanesulfonate (28g, crude product) as a yellow oil.

[0227] 1 H NMR (400MHz, CDCl3) δ = 7.29 (s, 1H), 5.19 (s, 2H), 3.01 (s, 3H)

[0228] Step 3: O1-tert-Butyl O4-ethyl 4-[(2-chlorothiazol-4-yl)methyl]piperidine-1,4-dicarboxylate

[0229] By the solution of 2-chlorothiazole-4-ethyl formate (30g, 157mmol) in tetrahydrofuran (THF) (30mL) at-60 ℃ under nitrogen, and then lithium diisopropylamide (LDA) (2M, 81.6mL) is added dropwise thereto.Reactant mixture is stirred 0.5 hour at-60 ℃, and (2-chlorothiazole-4-yl) methyl methanesulfonate (26.5g, 117mmol) is added dropwise in THF (15ml).Reactant mixture is stirred 0.5 hour at-60 ℃, and then temperature is slowly increased to room temperature and stirred 2 hours.Reactant mixture is quenched with aqueous ammonium chloride solution (100mL), diluted in water (200ml), and then extracted with EA (300mL x 3).The organic layer merged is washed with salt water (150mL x 3), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure. The residue was purified by column chromatography (0.1% FA) to afford 01-tert-butyl 04-ethyl 4-[(2-chlorothiazol-4-yl)methyl]piperidine-1,4-dicarboxylate (14 g, 31% yield) as a yellow oil.

[0230] 1H NMR (400MHz, CDCl3) δ = 6.80 (s, 1H), 4.15 (q, J = 7.2Hz, 2H), 3.89 (s, 2H), 2.94-2.84 (m ,4H),2.11(d,J=13.2Hz,2H),1.52-1.47(m,2H),1.45(s,9H),1.24(t,J=7.2Hz,3H).

[0231] Step 4: tert-Butyl 2-chloro-6-oxo-spiro[4H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate

[0232] To a solution of O1- tert-butyl O4- ethyl 4- [(2- chlorothiazol-4-yl) methyl] piperidine -1,4- dicarboxylate (13.8 g, 35.5 mmol) in THF (300 mL) was added LDA (2 M, 44.4 mL) dropwise, and the reaction mixture was stirred at 70 ° C for 0.5 hours. The reaction mixture was quenched with aqueous ammonium chloride (100 mL) at 0 ° C, diluted in water (100 mL), and then extracted with EA (200 mL x 3). The combined organic layer was washed with brine (200 mL x 3), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure. The residue was purified by column chromatography to obtain intermediate I-1 (6.1 g, 50% yield) as a yellow oil.

[0233] 1 H NMR (400MHz, CDCl3) δ = 4.16 (br s, 2H), 3.09-3.02 (s, 2H), 3.01-2.90 (m, 2H), 2.02-1.92 (m, 2H), 1.52-1.48 (m, 11H).

[0234] Preparation Example 2: (R)-2-methyl-N-[(6S)-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-6- [Methyl]propane-2-sulfenamide (Intermediate I-2)

[0235]

[0236] Step 1: (6Z)-6-[(R)-tert-Butylsulfinyl]imino-2-chloro-spiro[4H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylic acid tert-butyl ester

[0237] To a solution of 2-chloro-6-oxo-spiro[4H-cyclo[d]thiazole-5,4'-piperidine]-1'-carboxylic acid tert-butyl ester (3.0 g, 8.75 mmol) and (R)-2-methylpropane-2-sulfinamide (4.24 g, 35.0 mmol) in THF (30 mL) was added dropwise Ti(OEt)4(29.9 g, 131 mmol), and the reaction mixture was stirred at 90 ° C for 12 hours. EA (300 mL) was added to the reaction mixture, diluted in water (50 ml), and then extracted with EA (100 mL x 3). The combined organic layers were washed with brine (100 mL x 3), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure. The residue was purified by column chromatography to give (6Z)-6-[(R)-tert-butylsulfinyl]imino-2-chloro-spiro[4H-cyclopenta[d]thiazole-5,4′-piperidine]-1′-carboxylic acid tert-butyl ester (3.5 g, 90% yield) as a yellow solid.

[0238] 1 H NMR(400MHz, CDCl3)δ=4.28-4.14(m,2H),2.96-2.84(m,4H),2.05-1.91(m,2H),1.61-1.55(m,2H),1.49(s,9H),1.28(s,9H); MS(EI)m / z:446.0[M+H] + .

[0239] Step 2: (6S)-tert-Butyl 6-[[(R)-tert-Butylsulfinyl]amino]spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate

[0240] To a solution of (6Z)-6-[(R)-tert-butylsulfinyl]imino-2-chloro-spiro[4H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylic acid tert-butyl ester (3.5 g, 7.85 mmol) in THF (30 mL) was added BH3.THF (1 M, 31.4 mL) and the reaction mixture was stirred at -70 ° C for 2 hours. The reaction mixture was quenched with MeOH (10 mL) at 0 ° C, diluted in water (100 mL), and then extracted with EA (100 mL x 3). The combined organic layers were washed with brine (50 mL x 3), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure. The residue was purified by column chromatography to obtain tert-butyl (6S)-6-[[(R)-tert-butylsulfinyl]amino]spiro[4,6-dihydrocyclopenta[d]thiazole-5,4′-piperidine]-1′-carboxylate (660 mg, 20%) as a yellow solid.

[0241] 1 H NMR (400MHz, CDCl3) δ = 8.78 (s, 1H), 4.57 (d, J = 8.6Hz, 1H), 4.13-3.95 (m, 2H), 3.65-3.52 (m, 1H), 3.06-2. 98(m,1H),2.95-2.85(m,2H),1.91-1.78(m,2H),1.64(d,J=14.0Hz,2H),1.47(s,9H),1.24-1.21(s,9H).

[0242] Step 3: (R)-2-Methyl-N-[(6S)-spiro[4,6-dihydrocyclopenta[d]thiazol-5,4'-piperidin]-6-yl]propane-2-sulfenamide

[0243] To a solution of (6S)-6-[[(R)-tert-butylsulfinyl]amino]spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylic acid tert-butyl ester (200 mg, 484 μmol) in DCM (6 mL) was added TFA (2.76 g, 24.2 mmol), and the reaction mixture was stirred at 25 ° C for 0.5 hours. The reaction mixture was quenched with saturated K2CO3 aqueous solution (20 mL) at 25 ° C, diluted in water (30 ml), and then extracted with DCM (50 mL x 3). The combined organic layers were washed with brine (20 mL x 3), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain intermediate I-2 (140 mg, crude product) as a yellow solid.

[0244] 1 H NMR (400MHz, CDCl3) δ = 8.77 (s, 1H), 4.58 (d, J = 8.8Hz, 1H), 3.67 (d, J = 8.8Hz, 1H), 3.16-3.05 (m, 2H), 2.9 0-2.84(m,2H),2.60-2.36(m,2H),1.93-1.85(m,2H),1.69-1.61(m,1H),1.59-1.53(m,1H),1.24(s,9H).

[0245] Preparation Example 3: 6-(5-bromopyrazin-2-yl)sulfanyl-5-chloro-3H-quinazolin-4-one (Intermediate I-3)

[0246]

[0247] To a solution of 5-chloro-6-mercaptoquinazoline-4 (3H) -one (880mg, 3.75mmol) in dimethylformamide (DMF) (20mL) is added KCO(1.56g, 11.3mmol) and 2,5-dibromopyrazine (3.57g, 15.00mmol), and the mixture is stirred at 0 DEG C for 2 hours. At 25 DEG C, the reaction mixture is quenched by adding aqueous ammonium chloride solution (50mL), diluted with water (50mL) and extracted with EA (100mL x 3). The combined organic layer is washed with brine (50mL x 3), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain residue. The residue is purified by column chromatography (PE / EA=1 / 1 to 0: 1) to obtain intermediate I-3 (500mg, 36% yield) as a yellow solid.

[0248] 1 H NMR(400MHz,DMSO-d6)δ=12.50(br s,1H),8.71(d,J=1.0Hz,1H),8.46-8.43(m,1H),8.15(s,1H),7.98(d,J=8.8Hz,1H),7.61(d,J=8.8Hz,1H); MS(EI)m / z:371.1[M+H] + .

[0249] Preparation Example 4: (R)-N-[(6S)-1'-[5-[(5-chloro-4-oxo-3H-quinazolin-6-yl)sulfanyl]pyrazine- 2-yl]spiro[4,6-dihydrocyclopenta[d]thiazol-5,4'-piperidin]-6-yl]-2-methyl-propane-2-sulfenamide (intermediate I-4)

[0250]

[0251] To a solution of intermediate I-3 (402 mg, 1.09 mmol) in dioxane (5 mL) was added intermediate I-2 (310 mg, 989 μmol), RuPhos (92.3 mg, 198 μmol), RuPhos-Pd-G2 (76.8 mg, 98.9 μmol) and K2CO3 (410 mg, 2.97 mmol), and the mixture was stirred at 100°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain intermediate I-4 (300 mg, 53% yield) as a yellow solid.

[0252] 1H NMR(400MHz, CDCl3)δ=10.74-10.64(m,1H),8.82(s,1H),8.26(s,1H),8.23(s ,1H),7.98-7.92(m,1H),7.48(d,J=8.8Hz,1H),7.29(s,1H),4.68(d,J=8.8Hz, 1H),4.41(d,J=13.2Hz,1H),4.35-4.26(m,1H),3.29-3.16(m,2H),3.11-3.02 (m,1H),2.99-2.93(m,1H),2.18-1.99(m,2H),1.87-1.75(m,2H),1.27(s,9H).

[0253] Preparation Example 5: 6-((5-bromopyrazin-2-yl)thio)-5-chloro-3-(2-methoxyethyl)quinazoline-4(3H)- Ketone (Intermediate I-5)

[0254]

[0255] Step 1: 2-Ethylhexyl 3-((5-chloro-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)thio)propanoate

[0256] To a solution of ethyl 3-((5-chloro-4-oxo-3,4-dihydroquinazoline-6-yl)thio)propanoate (10g, 25.2mmol) in DMF (100mL) was added 1-bromo-2-methoxy-ethane (4.2g, 30.2mmol), KCO(6.96g, 50.4mmol) and tetra-n-butylammonium iodide (TBAI) (931mg, 2.52mmol), and the mixture was stirred at 55°C for 3 hours. The reaction mixture was quenched with aqueous ammonium chloride (50mL), diluted in water (50mL), and then extracted with EA (100mL x 3). The combined organic layer was washed with brine (50mL x 3), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure. The residue was purified by column chromatography (0.1% formic acid) to give 2-ethylhexyl 3-(5-chloro-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)thio)propanoate (6.8 g, 59% yield) as a yellow solid.

[0257] 1H NMR (400MHz, CDCl3) δ = 8.04 (s, 1H), 7.67-7.59 (m, 2H), 4.15 (t, J = 4.8Hz, 2H), 4.05 (dd, J = 2.0, 5.8Hz, 2H), 3.71-3.65 (m, 2H), 3.33 (s, 3H), 3 .30-3.25(m,2H),2.71(t,J=7.6Hz,2H),1.62-1.54(m,1H),1.40-1.34(m,2H),1.31-1.26(m,6H),0.91-0.85(m,6H); MS(EI)m / z:455.3[M+H] + .

[0258] Step 2 and Step 3: 6-((5-bromopyrazin-2-yl)thio)-5-chloro-3-(2-methoxyethyl)quinazolin-4(3H)-one

[0259] In the same manner as in steps 3 and 4 of Preparation Example 9, using 2-ethylhexyl 3-(5-chloro-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)thio)propanoate as a starting material, Intermediate I-5 (1.4 g, 22%) was obtained as a yellow solid.

[0260] 1 H NMR (400MHz, CDCl3) δ = 8.44 (s, 1H), 8.19 (s, 1H), 8.13 (s, 1H), 7.92 (d, J = 8.4Hz, 1H), 7.65 (d, J=8.4Hz,1H),4.17(t,J=4.8Hz,2H),3.73-3.66(m,2H),3.35(s,3H); MS(EI)m / z:429.1[M+H] + .

[0261] Preparation Example 6: 6-(3-amino-5-chloro-pyrazin-2-yl)sulfanyl-5-chloro-3-(2-methoxyethyl)quinazole Linalool-4-one (Intermediate I-6)

[0262]

[0263] By preparing the mixture of [5- chloro- 3- (2- methoxyethyl) -4- oxo- quinazolin-6-yl] sulfanyl sodium (630 mg, 2.15 mmol), 3- bromo- 6- chloro- pyrazin-2- amine (538 mg, 2.58 mmol), Pd2 (dba) 3 (197 mg, 215 μmol), XantPhos (249 mg, 431 umo) and DIEA (835 mg, 6.46 mmol) in dioxane (dioxane) (20 mL) degassed and purged 3 times with N2, and then stirred at 100 ° C under N2 atmosphere for 12 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by reverse phase flash column chromatography (0.1% FA) to obtain intermediate I-6 (120 mg, 14% yield) as a yellow solid.

[0264] 1 H NMR (400MHz, CDCl3) δ = 8.08 (s, 1H), 7.92 (s, 1H), 7.57-7.53 (m, 1H), 7.49-7.45 (m, 1H), 5.16 (br s,2H),4.16(t,J=4.8Hz,2H),3.68(t,J=4.8Hz,2H),3.33(s,3H); MS(EI)m / z:398.0[M+H] + .

[0265] Preparation Example 7: 6-(3-amino-5-chloro-pyrazin-2-yl)sulfanyl-5-chloro-3-(2-methoxypropyl)quinazole Linalool-4-one (Intermediate I-7)

[0266]

[0267] Step 1: 2-Methoxypropyl 4-methylbenzenesulfonate

[0268] TosCl (12.0 g, 63.2 mmol) and Py (10.0 g, 126 mmol, 10.2 mL) were added to a solution of 2-methoxypropane-1-ol (3.80 g, 42.1 mmol) in DCM (40 mL). The mixture was stirred at 0 ° C for 12 hours. At 25 ° C, the reaction mixture was quenched by adding aqueous ammonium chloride (20 mL), diluted with water (30 mL) and extracted with EA (3x50 mL). The combined organic layer was washed with salt water (3x20 mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=15 / 1-5 / 1) to obtain 2-methoxypropyl 4-methylbenzenesulfonate (9.80 g, 95% yield) as a yellow solid.

[0269] 1 H NMR (400MHz, CDCl3) δ = 7.77 (d, J = 8.0Hz, 2H), 7.33 (d, J = 8.0Hz, 2H), 3.93 (dd, J = 1. 6,4.8Hz,2H),3.55-3.47(m,1H),3.26(s,3H),2.42(s,3H),1.08(d,J=6.4Hz,3H).

[0270] Step 2: 2-Ethylhexyl 3-[5-chloro-3-(2-methoxypropyl)-4-oxo-quinazolin-6-yl]sulfanylpropanoate

[0271] To a solution of 2-ethylhexyl 3-[(5-chloro-4-oxo-3H-quinazolin-6-yl)sulfanyl]propanoate (3.00 g, 7.56 mmol) and 2-methoxypropyl 4-methylbenzenesulfonate (2.40 g, 9.83 mmol) in DMF (30 mL) was added KCO (3.13 g, 22.6 mmol) and TBAI (279 mg, 755 μmol). The reaction mixture was stirred at 50 ° C for 12 hours. At 25 ° C, the reaction mixture was quenched by the addition of aqueous ammonium chloride (20 mL), diluted with water (30 mL) and extracted with EA (3x50 mL). The combined organic layers were washed with brine (3x30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 15 / 1-3 / 1) to afford 2-ethylhexyl 3-[5-chloro-3-(2-methoxypropyl)-4-oxo-quinazolin-6-yl]sulfanylpropanoate (1.00 g, 28% yield) as a yellow solid.

[0272] MS(EI)m / z:469.2[M+H] + .

[0273] Step 3: Sodium [5-chloro-3-(2-methoxypropyl)-4-oxo-quinazolin-6-yl]sulfanyl

[0274] To a solution of 2-ethylhexyl 3-[5-chloro-3-(2-methoxypropyl)-4-oxo-quinazolin-6-yl]sulfanylpropanoate (500 mg, 1.07 mmol) in THF (10 mL) was added t-BuONa (153 mg, 1.60 mmol), and the mixture was stirred at 25° C. for 1 hour. After completion of the reaction, the reaction mixture was filtered and concentrated under reduced pressure to give sodium [5-chloro-3-(2-methoxypropyl)-4-oxo-quinazolin-6-yl]sulfanyl (300 mg, 92% yield) as a yellow solid.

[0275] MS (EI) m / z: 285.1 [M+H] + .

[0276] Step 4: 6-(3-Amino-5-chloro-pyrazin-2-yl)sulfanyl-5-chloro-3-(2-methoxypropyl)quinazolin-4-one

[0277] A mixture of [5-chloro-3-(2-methoxypropyl)-4-oxo-quinazolin-6-yl]sulfanylsodium (327 mg, 1.07 mmol), 3-bromo-6-chloro-pyrazin-2-amine (222 mg, 1.07 mmol), (5-diphenylphosphino-9,9-dimethyl-xanthen-4-yl)-diphenyl-phosphine (123 mg, 213 μmol), Pd2(dba)3 (97.6 mg, 106 μmol) and DIEA (413 mg, 3.20 mmol, 557 μL) in dioxane (10 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 100 ° C under N2 atmosphere for 12 hours. After completion of the reaction, the reaction mixture was quenched by adding aqueous ammonium chloride solution (10 mL) at 25 ° C, and then diluted with water (10 mL) and extracted with EA (3x10 mL). The combined organic layers were washed with brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford a residue. The residue was purified by column chromatography (SiO , petroleum ether / ethyl acetate = 3 / 1-1 / 2) to afford intermediate I-7 (100 mg, 23% yield) as a black solid.

[0278] MS (EI) m / z: 411.9 [M+H] + .

[0279] Preparation Example 8: 5-((3S,4S)-4-(tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro [4.5]Decan-8-yl]pyrazine-2-thiolate sodium (Intermediate I-8)

[0280]

[0281] Step 1: (3S,4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine

[0282] To a solution of (3S, 4S) -3-methyl-2-oxa-8-azaspiro [4.5] dec-4-amine (5.00 g, 20.6 mmol, 2HCl) in DMF (50 mL) was added TEA (6.24 g, 61.7 mmol) and 2,5-dibromopyrazine (4.89 g, 20.6 mmol), and the mixture was stirred at 25 ° C for 12 hours. At 25 ° C, the reaction mixture was quenched by addition of aqueous ammonium chloride (100 mL), and then diluted with water (100 mL) and extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (3 x 100 mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to afford (3S,4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine (6.7 g, crude) as a yellow oil, which was used directly in the next step.

[0283] MS (EI) m / z: 329.1 [M+H] + .

[0284] Step 2: tert-Butyl N-[(3S,4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl]carbamate

[0285] To a solution of (3S, 4S) -8- (5- bromopyrazine -2- bases) -3- methyl -2- oxa -8- azaspiro [4.5] decyl -4- amine (6.7 g, 20.5 mmol) in DMF (50 mL) was added Boc o (6.70 g, 30.7 mmol) and TEA (3.11 g, 30.7 mmol), and the mixture was stirred at 25 ° C for 2 hours. At 25 ° C, the reaction mixture was quenched by adding aqueous ammonium chloride (100 mL), and then diluted with water (100 mL) and extracted with EA (3x200 mL). The combined organic layer was washed with brine (3x100 mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain residue. The residue was purified by column chromatography (PE / EA=5:1) to obtain tert-butyl N-[(3S,4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl]carbamate (5.5 g, 63% yield) as a yellow solid. MS (EI) m / z: 429.1 [M+H] + .

[0286] Step 3: 2-Ethylhexyl 3-((5-((3S,4S)-4-((tert-Butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)propanoate

[0287] A mixture of tert-butyl N-[(3S,4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl]carbamate (5.50 g, 12.9 mmol), 2-ethylhexyl 3-sulfanylpropanoate (4.22 g, 19.3 mmol), Pd(dba) (1.18 g, 1.29 mmol), XantPhos (1.49 g, 2.57 mmol) and DIEA (4.96 g, 38.6 mmol) in dioxane (80 mL) was degassed and purged with N 3 times, and then the mixture was stirred at 110° C. under N atmosphere for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (PE / EA=3:1) to give 2-ethylhexyl 3-[5-[(3S,4S)-4-(tert-butoxycarbonylamino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]pyrazin-2-yl]sulfanylpropanoate (5.00 g, 69% yield) as a yellow oil.

[0288] 1 H NMR (400MHz, CDCl3) δ = 8.08 (s, 1H), 8.06 (s, 1H), 4.63 (d, J = 10.8Hz, 1H), 4.23-4.13 (m, 1H), 4. 01(dd,J=5.8,2.6Hz,2H),3.82-3.59(m,4H),3.57-3.46(m,1H),3.44-3.33(m,1H),3.28(t,J= 7.2Hz,2H),2.69(t,J=7.2Hz,2H),1.92-1.71(m,4H),1.62-1.52(m,2H),1.45(s,9H),1.41-1. 32(m,3H),1.30-1.27(m,6H),1.21(d,J=6.4Hz,2H),0.93-0.86(m,6H); MS(EI)m / z:565.4[M+H] + .

[0289] Step 4: Sodium 5-((3S,4S)-4-(tert-butoxycarbonyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]pyrazine-2-thiolate

[0290] To a solution of 2-ethylhexyl 3-[5-[(3S,4S)-4-(tert-butoxycarbonylamino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]pyrazin-2-yl]sulfanylpropanoate (270 mg, 478 μmol) in THF (5 mL) was added t-BuONa (68.9 mg, 717 μmol), and the mixture was stirred at 25° C. for 0.5 h. The residue was triturated with PE (10 mL) to give intermediate I-8 (150 mg, crude) as a yellow solid, which was used directly in the next step.

[0291] MS(EI)m / z:381.1[M+H] + .

[0292] Preparation Example 9: 7-Bromo-8-chloroisoquinolin-1(2H)-one (Intermediate I-9)

[0293]

[0294] Step 1: (E)-1-(3-Bromo-2-chloro-phenyl)-N-(2,2-dimethoxyethyl)formanimine

[0295] To a mixture of 3-bromo-2-chloro-benzaldehyde (14 g, 63.7 mmol) in toluene (200 mL) was added 2,2-dimethoxyethylamine (6.71 g, 63.7 mmol), and the mixture was stirred at 125° C. for 64 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to obtain (E)-1-(3-bromo-2-chlorophenyl)-N-(2,2-dimethoxyethyl)methanimine (19 g, 97% yield) as a yellow oil.

[0296] 1 H NMR (400MHz, DMSO-d6) δ = 8.68 (s, 1H), 7.94-7.86 (m, 2H), 7.34 (t, J = 7.6Hz, 1H), 4.64 (t, J = 5.4Hz, 1H), 3.78 (d, J = 5.4Hz, 2H), 3.30 (s, 6H).

[0297] Step 2: 7-Bromo-8-chloroisoquinoline

[0298] To a mixture of (E)-1-(3-bromo-2-chlorophenyl)-N-(2,2-dimethoxyethyl)formaniline (2 g, 6.52 mmol) in DCM (20 mL) was added trifluoromethanesulfonic acid (20 mL), and the mixture was stirred at 120 ° C for 0.5 hours. Afterwards, the reaction mixture was cooled to 25 ° C and stirred at 25 ° C for 0.5 hours. After the reaction was completed, methanol (200 mL) was added to the reaction mixture. The mixture was poured into NH3.HO (200 mL) and extracted with EA (3x300 mL). The organic phase was concentrated under reduced pressure. The residue was triturated with water at 25 ° C for 30 minutes to obtain 7-bromo-8-chloro-isoquinoline (820 mg, 51% yield) as a brown solid.

[0299] 1 H NMR (400MHz, DMSO-d6) δ = 9.56 (s, 1H), 8.68 (d, J = 5.6Hz, 1H), 8.06 (d, J = 8.8Hz, 1H), 7.96-7.94 (m, 2H).

[0300] Step 3: 7-Bromo-8-chloro-2-oxido-isoquinolin-2-ium

[0301] To a mixture of 7-bromo-8-chloroisoquinoline (820 mg, 3.38 mmol) in DCM (20 mL) was added m-CPBA (1.37 g, 6.76 mmol, 85% purity) and the mixture was stirred at 25 ° C for 16 hours. After the reaction was completed, Na2O3S2 (50 ml) was added to the mixture. The mixture was concentrated under reduced pressure. The residue was extracted with EA (3x40 mL). The organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate / methanol = 1 / 0 / 0-0 / 10 / 1) to obtain 7-bromo-8-chloro-2-oxo-isoquinolin-2-ium (690 mg, 78% yield) as a yellow solid.

[0302] 1 H NMR (400MHz, DMSO-d6) δ = 8.88 (s, 1H), 8.32 (d, J = 7.2Hz, 1H), 8.06 (d, J = 7.2Hz, 1H), 7.90 (s, 2H).

[0303] Step 4: 7-Bromo-8-chloroisoquinolin-1(2H)-one

[0304] A mixture of 7-bromo-8-chloro-2-oxidation-isoquinolin-2-ium (640 mg, 2.48 mmol) in Ac o (6 mL) was stirred at 120 ° C for 3 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain (7-bromo-8-chloro-1-isoquinoline) acetate (640 mg, crude product). A mixture of (7-bromo-8-chloro-1-isoquinoline) acetate (640 mg, 2.13 mmol) in NaOH (2M, 32.00 mL) and H o (8 mL) was stirred at 100 ° C for 1 hour. After the reaction was completed, the mixture was acidified to pH 6 with citric acid (5% aqueous solution) and extracted with DCM (3x100 mL). The combined organic phases were concentrated under reduced pressure to obtain intermediate I-9 (320 mg, 58% yield) as a yellow solid.

[0305] 1 H NMR (400MHz, CDCl3) δ = 10.76-10.32 (m, 1H), 7.86 (d, J = 8.4Hz, 1H), 7.32 (d, J = 8.4Hz, 1H), 7.19 (d, J = 6.8Hz, 1H), 6.48 (d, J = 7.2Hz, 1H).

[0306] Preparation Example 10: 5-((S)-6-(((R)-tert-butylsulfinyl)amino)-4,6-dihydrospiro[cyclopenta[d]thiazolyl] Sodium 2-thiophene-5,4'-piperidin-1'-yl)pyrazine (Intermediate I-10)

[0307]

[0308] Step 1: (R)-N-((S)-1'-(5-bromopyrazin-2-yl)-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4'-piperidin]-6-yl)-2-methylpropane-2-sulfenamide

[0309] To the solution of intermediate I-2 (500mg, 1.59mmol) in DMF (8mL) DIEA (2.06g, 16.0mmol) and 2,5-dibromopyrazine (1.14mmol, 4.78mmol) was added. The mixture was stirred at 100 ° C for 2 hours. After the completion of the reaction, at 25 ° C, the reaction mixture was quenched by adding aqueous ammonium chloride (20mL), and then diluted with water (30mL) and extracted with EA (3x50mL). The combined organic layer was washed with salt water (20mL), dried over anhydrous sodium sulfate, and filtered and concentrated under reduced pressure to obtain residue. The residue was purified by column chromatography to afford (R)-N-((S)-1′-(5-bromopyrazin-2-yl)-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4′-piperidin]-6-yl)-2-methylpropane-2-sulfenamide (230 mg, 31% yield) as a yellow solid.

[0310] 1 H NMR (400MHz, CDCl3) δ = 8.80 (s, 1H), 8.12 (d, J = 1.2Hz, 1H), 7.90 (d, J = 1.2Hz, 1 H),4.63(d,J=9.2Hz,1H),4.27-4.12(m,2H),3.66(d,J=9.2Hz,1H),3.22-3.08 (m,2H),3.04-2.99(m,1H),2.94(s,1H),2.07-1.96(m,2H),1.80(dd,J=2.4,1 3.2Hz,1H),1.72(dd,J=2.4,13.2Hz,1H),1.23(s,9H); MS(EI)m / z:472.2[M+H] + .

[0311] Step 2: 2-Ethylhexyl 3-((5-((S)-6-(((R)-tert-Butylsulfinyl)amino)-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4'-piperidinyl]-1'-yl)pyrazin-2-yl)thio)propanoate

[0312] A mixture of (R)-N-((S)-1'-(5-bromopyrazin-2-yl)-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidin]-6-yl)-2-methylpropane-2-sulfinamide (230 mg, 489 μmol), 2-ethylhexyl 3-sulfanylpropanoate (128 mg, 587 μmol), Pd(dba) (44.8 mg, 48.9 μmol), Xantphos (56.6 mg, 97.8 μmol) and DIEA (190 mg, 1.47 mmol) in dioxane (5 mL) was degassed and purged with N 3 times, and then the mixture was stirred at 100° C. under N atmosphere for 3 hours. After completion of the reaction, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , PE / EA=3 / 1-1 / 5) to afford 2-ethylhexyl 3-((5-((S)-6-(((R)-tert-butylsulfinyl)amino)-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4′-piperidinyl]-1′-yl)pyrazin-2-yl)thio)propanoate (240 mg, 81% yield) as a yellow solid.

[0313] 1H NMR (400MHz, CDCl3) δ = 8.80 (s, 1H), 8.09 (d, J = 1.2Hz, 1H), 8.06 (d, J = 1.2Hz, 1H), 4.63 (d,J=8.8Hz,1H),4.26-4.14(m,2H),4.13-4.08(m,2H),4.01(dd,J=2.8,5.6Hz,2H),3 .67(d,J=8.8Hz,1H),3.28(t,J=7.2Hz,2H),3.22-3.07(m,2H),3.04-2.89(m,2H),2.0 4-1.95(m,2H),1.83-1.71(m,2H),1.37-1.27(m,9H),1.22(s,9H),0.91-0.86(m,6H).

[0314] Step 3: Sodium 5-((S)-6-(((R)-tert-Butylsulfinyl)amino)-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4'-piperidinyl]-1'-yl)pyrazine-2-thiolate

[0315] To a solution of 2-ethylhexyl 3-((5-((S)-6-(((R)-tert-butylsulfinyl)amino)-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)propanoate (230 mg, 378 μmol) in THF (5 mL) was added t-BuONa (54.5 mg, 568 μmol), and the mixture was stirred at 25 ° C. for 0.5 h. After completion of the reaction, the reaction mixture was concentrated, and the residue was triturated with PE (30 mL) to give intermediate I-10 (170 mg, crude product) as a yellow solid.

[0316] MS (EI) m / z: 424.2 [M-Na] + .

[0317] Preparation Example 11: 7-Bromo-8-chloro-2-methylisoquinolin-1(2H)-one (Intermediate I-11)

[0318]

[0319] To a solution of intermediate I-9 (100 mg, 387 μmol) in DMF (5 mL) was added KCO (160 mg, 1.16 mmol) and MeI (82.4 mg, 580 μmol, 36.1 μL). The mixture was stirred at 25 ° C for 16 hours. After the completion of the reaction, water (20 mL) was added to the mixture and extracted with EA (3x30 mL). The combined organic phases were washed with saline (3x30 mL) and concentrated under reduced pressure. The residue was purified by preparative HPLC to obtain the intermediate I-11 (60 mg, 57% yield) as a white solid.

[0320] 1 H NMR (400MHz, CDCl3) δ = 7.83 (d, J = 8.4Hz, 1H), 7.28 (s, 1H), 7.17 (d, J = 7.2Hz, 1H), 6.41 (d, J = 7.2Hz, 1H), 3.60 (s, 3H).

[0321] Preparation Example 12: (R)-2-methyl-N-[(5S)-spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-5- [Methyl]propane-2-sulfenamide (Intermediate I-12)

[0322]

[0323] Step 1: 3-Bromo-2-(bromomethyl)pyridine

[0324] To a solution of 3-bromo-2-methyl-pyridine (20.0 g, 116 mmol) in CCl4 (200 mL) was added N-bromosuccinimide (NBS) (22.8 g, 128 mmol) and azobisisobutyronitrile (AIBN) (1.91 g, 11.6 mmol), and the mixture was stirred at 80 ° C for 12 hours. The reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by MPLC (PE / EA=30:1) to obtain 3-bromo-2-(bromomethyl)pyridine (12.5 g, 42% yield) as a brown solid.

[0325] 1 H NMR (400MHz, DMSO-d6)δ=8.60-8.53(m,1H),8.16-8.08(m,1H),7.38-7.26(m,1H),4.80-4.70(m,2H); MS(EI)m / z:251.8[M+H] + .

[0326] Step 2: 4-[(3-Bromo-2-pyridinyl)methyl]-4-cyano-piperidine-1-carboxylic acid tert-butyl ester

[0327] To a solution of tert-butyl 4-cyanopiperidine-1-formate (10.1g, 47.8mmol) in THF (100mL), lithium diisopropylamide (LDA) (2M, 23.9mL) was added, followed by stirring at -78 ° C for 0.5 hour. Then, 3-bromo-2-(bromomethyl) pyridine (10.0g, 39.9mmol) was slowly added to the reaction mixture and then stirred at -78 ° C for 2.5 hours. At 0 ° C, the reaction mixture was quenched by adding aqueous ammonium chloride (100mL), diluted with water (100mL) and extracted with EA (3x200mL). The organic layer merged was washed with salt water (3x100mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain residue. The residue was purified by reverse phase flash column chromatography (0.1% FA) to afford 4-[(3-bromo-2-pyridinyl)methyl]-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (13.5 g, 89% yield) as a brown solid. 1 H NMR(400MHz, DMSO-d6)δ=8.60-8.53(m,1H),8.14-8.07(m,1H),7.32-7.24(m,1H),4.01-3.90(m,2H),3.25( s,2H),3.01-2.78(m,2H),2.12-2.03(m,2H),1.73-1.56(m,2H),1.44-1.35(m,9H); MS(EI)m / z:402.0[M+23] + .

[0328] Step 3: tert-Butyl 5-oxospiro[7H-cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate

[0329] By 4-[(3-bromo-2-pyridyl)methyl]-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (5.90g, 15.5mmol), 4-di-tert-butylphosphine-N,N-dimethyl-aniline; Dichloropalladium (Pd(AmPhos)Cl2) (1.10g, 1.55mmol), TEA (6.28g, 62.1mmol) in dimethylacetamide (DMA) (120mL) and H2O (12mL) in a mixture degassed and then purged with N2 3 times. The mixture was stirred at 130 ° C for 12 hours under an N2 atmosphere. At 25 ° C, the reaction mixture was quenched by adding aqueous ammonium chloride (50mL), and then diluted with water (50mL) and extracted with EA (3x100mL). The combined organic layer was washed with brine (3x50mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel chromatography (PE / EA=3:1) to afford tert-butyl 5-oxospiro[7H-cyclopenta[b]pyridine-6,4′-piperidine]-1′-carboxylate (3.2 g, 68% yield) as a brown solid.

[0330] 1 H NMR(400MHz, CDCl3)δ=8.89-8.79(m,1H),8.09-8.00(m,1H),7.40-7.32(m,1H),4.22-4.05(m,2H ),3.10(s,2H),3.12-3.02(m,2H),2.01-1.90(m,2H),1.51-1.44(m,11H); MS(EI)m / z:303.4[M+H] + .

[0331] Step 4: (5Z)-tert-Butyl5-[(R)-tert-Butylsulfinyl]iminospiro[7H-cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate

[0332] To a solution of 5-oxospiro[7H-cyclopenta[b]pyridine-6,4'-piperidine]-1'-tert-butyl formate (3.00g, 9.92mmol) in THF (30mL) was added Ti(OEt)4(34.0g, 149mmol) and (R)-2-methylpropane-2-sulfinamide (4.81g, 39.7mmol). The mixture was stirred at 70°C for 12 hours. The reaction mixture was diluted with EA (300mL) and quenched with water (50mL), and then filtered and extracted with EA (3x100mL). The combined organic layer was washed with brine (3x50mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain residue. The residue was purified by reverse phase flash column chromatography (0.1% ammonium hydroxide) to afford tert-butyl (5Z)-5-[(R)-tert-butylsulfinyl]iminospiro[7H-cyclopenta[b]pyridine-6,4′-piperidine]-1′-carboxylate (3.35 g, 83% yield) as a yellow solid.

[0333] 1 H NMR (400MHz, DMSO-d6) δ8.79-8.74(m,1H),8.69-8.61(m,1H),7.50-7.44(m,1H),4.00-3.93(m,2H),3.00(s,2H),3. 02-2.89(m,2H),1.81-1.68(m,2H),1.58-1.50(m,2H),1.44-1.42(m,9H),1.27-1.22(m,9H); MS(EI)m / z:406.2[M+H] + .

[0334] Step 5: (5S)-tert-Butyl 5-[[(R)-tert-Butylsulfinyl]amino]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylate

[0335] To a solution of (5Z)-5-[(R)-tert-butylsulfinyl]iminospiro[7H-cyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylic acid tert-butyl ester (2.00 g, 4.93 mmol) in THF (20 mL) was added LiBH4 (537 mg, 24.7 mmol), and the mixture was stirred at -70 ° C for 2 hours. At 0 ° C, the reaction mixture was quenched by adding aqueous ammonium chloride (20 mL), and then diluted with water (30 mL) and extracted with EA (3x50 mL). The combined organic layer was washed with brine (3x20 mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC column: Welch Ultimate XB-CN 250*50*10um, mobile phase: [hexane-EtOH (0.1% NH3·H2O)], B%: 10%-50%, for 15 minutes to obtain (5S)-5-[[(R)-tert-butylsulfinyl]amino]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylic acid tert-butyl ester (630 mg, 31% yield) as a yellow solid.

[0336] 1 H NMR (400MHz, CDCl3) δ=8.56-8.51(m,1H),8.33-8.26(m,1H),7.38-7.32(m,1H),4.56-4.51(m,1H),4.07-3.96(m,2H),3.60-3. 51(m,1H),3.36-3.27(m,1H),2.98(s,2H),1.83-1.71(m,1H),1.50-1.47(m,11H),1.34-1.26(m,11H); MS(EI)m / z:408.3[M+H] + .

[0337] Step 6: (R)-2-Methyl-N-[(5S)-spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidin]-5-yl]propane-2-sulfenamide

[0338] To a solution of (5S)-5-[[(R)-tert-butylsulfinyl]amino]spiro[5,7-dihydrocyclopenta[b]pyridine-6,4'-piperidine]-1'-carboxylic acid tert-butyl ester (200 mg, 491 μmol) in DCM (5 mL) was added TFA (1.68 g, 14.7 mmol) and the mixture was stirred at 0 ° C for 1 hour. The reaction mixture was poured into aqueous K2CO3 (20 mL) at 25 ° C and then diluted with water (30 mL) and extracted with DCM (3x50 mL). The combined organic layers were washed with brine (3x20 mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain intermediate I-12 (140 mg, 92% yield) as a yellow solid.

[0339] 1 H NMR(400MHz, CDCl3)=8.49-8.42(m,1H),8.12-8.04(m,1H),7.25-7.19(m,1H),4.55-4.50(m,1H),3.38-3.32(m,2H),3 .26-3.06(m,1H),2.85-2.81(m,2H),2.30-2.14(m,2H),1.99-1.82(m,2H),1.37-1.31(m,11H); MS(EI)m / z:308.4[M+H] + .

[0340] Preparation Example 13: N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinyl Amine (Intermediate I-13)

[0341]

[0342] (1S)-1-((tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester (0.5 g, 1.23 mmol) was dissolved in DCM (6.9 ml, 0.18 M). TFA (1.3 ml, 0.095 M) was slowly added dropwise to the reaction mixture and then stirred at room temperature for 3 hours. After the reaction was completed, the resulting product was concentrated to obtain intermediate I-13.

[0343] MS (EI) m / z: 307.4 [M+H] + .

[0344] Preparation Example 14: 6-((5-bromopyrazin-2-yl)thio)-5-chloro-3-methylquinazolin-4(3H)-one (Intermediate I-14)

[0345]

[0346] Step 1: 2-Ethylhexyl 3-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)thio)propanoate

[0347] To a solution of 2-ethylhexyl 3-[(5-chloro-4-oxo-3H-quinazolin-6-yl)sulfanyl]propanoate (1.00 g, 2.52 mmol) and iodomethane (536 mg, 3.78 mmol) in DMF (10 mL) was added TBAI (93.0 mg, 251 μmol) and KCO (1.04 g, 7.56 mmol). The mixture was stirred at 25 ° C for 12 hours. After the reaction was complete, at 25 ° C, the reaction mixture was quenched by adding aqueous ammonium chloride (30 mL), and then diluted with water (50 mL) and extracted with EA (3x80 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 5 / 1-2 / 1) to afford 2-ethylhexyl 3-(5-chloro-3-methyl-4-oxo-quinazolin-6-yl)sulfanylpropanoate (850 mg, 82% yield) as a yellow solid.

[0348] 1 H NMR (400MHz, DMSO-d6) δ = 8.36 (s, 1H), 7.79 (d, J = 8.8Hz, 1H), 7.60 (d, J = 8.8Hz, 1H), 3.96 (d, J = 5.6Hz, 2H), 3.44 (s, 3H), 3.30 (d, J = 6.8Hz, 2H), 2 .73(d,J=5.2Hz,2H),1.55-1.49(m,1H),1.31-1.26(m,2H),1.24-1.23( m, 1H), 1.22 (d, J = 2.0Hz, 4H), 1.21-1.15 (m, 2H), 0.83 (d, J = 7.2Hz, 6H).

[0349] Step 2: Sodium 5-chloro-3-methyl-4-oxo-3,4-dihydroquinazoline-6-thiolate

[0350] To a solution of 2-ethylhexyl 3-(5-chloro-3-methyl-4-oxo-quinazoline-6-yl)sulfanylpropanoate (750 mg, 1.83 mmol) in THF (20 mL) was added t-BuONa (263 mg, 2.74 mmol). The mixture was stirred at 25 ° C for 1 hour. After the reaction was completed, the reaction mixture was dissolved in PE (50 mL) and filtered. The filter cake was dried to obtain 5-chloro-3-methyl-4-oxo-3,4-dihydroquinazoline-6-thiolate sodium (400 mg, crude product) as a yellow solid, which was used in the next step without further purification.

[0351] Step 3: 6-((5-bromopyrazin-2-yl)thio)-5-chloro-3-methylquinazolin-4(3H)-one

[0352] To the solution of 5-chloro-3-methyl-4-oxo-3,4-dihydroquinazoline-6-thiolate sodium (400mg, 1.61mmol) and 2,5-dibromopyrazine (1.15g, 4.83mmol) in DMF (30mL) is added KCO (666mg, 4.83mmol). The mixture is stirred at 0 DEG C for 4 hours. After the completion of the reaction, at 25 DEG C, the reaction mixture is quenched by adding aqueous ammonium chloride solution (20mL), and then diluted with water (50mL) and extracted with EA (3x50mL). The combined organic layer is washed with brine (20mL), dried over anhydrous sodium sulfate, and filtered and concentrated under reduced pressure to obtain residue. The residue is passed through column chromatography (SiO, petroleum ether / ethyl acetate=5 / 1-2 / 1) purified to obtain intermediate I-14 (180mg, 29% yield) as a white solid.

[0353] 1 H NMR (400MHz, DMSO-d6) δ = 8.72 (d, J = 1.2Hz, 1H), 8.48-8.47 (m, 2H), 7.98 (d, J = 8.4Hz, 1H), 7.64 (d, J = 8.4Hz, 1H), 3.47 (s, 3H).

[0354] Preparation Example 15: 6-((3-amino-5-chloropyrazin-2-yl)thio)-5-chloro-3-methylquinazolin-4(3H)-one (Intermediate I-15)

[0355]

[0356] In Preparation Example 6, sodium 5-chloro-3-methyl-4-oxo-3,4-dihydroquinazoline-6-thiolate was used instead of sodium [5-chloro-3-(2-methoxyethyl)-4-oxo-quinazolin-6-yl]sulfanyl to synthesize Intermediate I-15 (260 mg, 18% yield).

[0357] MS(EI)m / z:354.0[M+H] + .

[0358] Preparation Example 16: 6-((3-amino-5-chloropyrazin-2-yl)thio)-3-benzyl-5-chloroquinazolin-4(3H)-one (Intermediate I-16)

[0359]

[0360] In Preparation Example 6, 6-((3-amino-5-chloropyrazin-2-yl)thio)-3-benzyl-5-chloroquinazolin-4(3H)-one was used instead of 5-chloro-3-(2-methoxyethyl)-4-oxo-quinazolin-6-yl]sulfanyl sodium to synthesize Intermediate I-16 (300 mg, 23% yield).

[0361] MS (EI) m / z: 430.0 [M+H] + .

[0362] Preparation Example 17: 6-((3-amino-5-chloropyrazin-2-yl)thio)-5-chloroquinazolin-4(3H)-one (Intermediate I-17)

[0363]

[0364] In Preparation Example 6, sodium 5-chloro-4-oxo-3,4-dihydroquinazoline-6-thiolate was used instead of sodium [5-chloro-3-(2-methoxyethyl)-4-oxo-quinazolin-6-yl]sulfanyl to synthesize Intermediate I-17 (700 mg, 28% yield).

[0365] 1 H NMR (400MHz, DMSO-d6) δ = 8.09 (s, 1H), 7.74 (s, 1H), 7.57-7.52 (m, 2H), 7.11 (s, 1H), 3.30 (s, 2H).

[0366] Preparation Example 18: 6-((5-bromopyrazin-2-yl)thio)-3-methylquinazolin-4(3H)-one (Intermediate I-18)

[0367]

[0368] In Preparation Example 6, sodium 3-methyl-4-oxo-3,4-dihydroquinazoline-6-thiol was used instead of sodium [5-chloro-3-(2-methoxyethyl)-4-oxo-quinazolin-6-yl]sulfanyl, and 2,5-dibromopyrazine was used instead of 3-bromo-6-chloro-pyrazin-2-amine to synthesize intermediate I-18 (500 mg, 31% yield).

[0369] MS(EI)m / z:349.2[M+H] + .

[0370] Preparation Example 19: ((3S,4S)-8-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazine- tert-Butyl 2-methyl-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate (Intermediate I-19)

[0371]

[0372] In Preparation Example 6, sodium 5-chloro-4-oxo-3,4-dihydroquinazoline-6-thiol was used instead of sodium [5-chloro-3-(2-methoxyethyl)-4-oxo-quinazolin-6-yl]sulfanyl, and the resulting product of Step 2 of Preparation Example 8 was used instead of 3-bromo-6-chloro-pyrazin-2-amine to synthesize intermediate I-19 (200 mg, 34% yield).

[0373] H NMR (400MHz, CDCl3) δ = 11.11 (br s, 1H), 8.24 (d, J = 1.2Hz, 1H), 8.18 (d, J = 1.2

[0374] Hz,1H),7.98(s,1H),7.47(d,J=8.8Hz,1H),7.22(d,J=8.8Hz,1H),4.30 -4.22(m,2H),4.20-4.12(m,1H),3.93(d,J=9.2Hz,1H),3.69(d,J=9.2H z,1H),3.64-3.53(m,2H),3.21-3.10(m,2H),2.11-1.97(m,2H),1.76-1 .63(m,2H),1.29(s,9H),1.24(d,J=6.4Hz,3H); MS(EI)m / z:559.1[M+H] + .

[0375] Preparation Example 20: ((3S,4S)-8-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazine- tert-Butyl 2-methyl-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate (Intermediate I-20)

[0376]

[0377] Step 1: (R)-tert-Butyl(1'-(5-bromopyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamate

[0378] In a round-bottom flask, (R)-3H-spiro [benzofuran -2,4 '-piperidine] -3-amine (200mg, 0.72mmol), 2,5-dibromopyrazine (296mg, 1.08mmol) and TEA (0.8mL, 3.6mmol) were dissolved in DMF (3.6mL, 0.2M) and then stirred at 90 ° C for 5 hours. Di-tert-butyl dicarbonate (0.25mL, 1.08mmol) was added to the reaction mixture and stirred at 90 ° C for 5 hours. The reaction was terminated with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered and concentrated. The product was separated by MPLC (EA:Hx=1:10) and then concentrated to obtain (R)-(1'-(5-bromopyrazine-2-yl)-3H-spiro [benzofuran -2,4'-piperidine] -3-yl) tert-butyl carbamate (200mg, 60%).

[0379] Step 2: (R)-tert-Butyl(1'-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamate

[0380] In a round-bottom flask, tert-butyl (R)-(1'-(5-bromopyrazin-2-yl)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)carbamate (200 mg, 0.43 mmol), intermediate I-8 (164 mg, 0.65 mmol), Pd2(dba)3 (40 mg, 0.043 mmol), XantPhos (25 mg, 0.043 mmol) and DIPEA (0.15 mL, 0.87 mmol) were dissolved in 1,4-dioxane (1.8 mL, 0.25 M) and purged with nitrogen. The reaction mixture was stirred at 120 ° C for 4 hours. The reaction was terminated with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered and concentrated to give intermediate I-20 (243 mg, 94%).

[0381] Preparation Example 21: 6-Bromo-5-chloroquinazolin-4(3H)-one (Intermediate I-21)

[0382]

[0383] Step 1: 6-Amino-3-bromo-2-chloro-benzoic acid

[0384] To the solution of 2-amino-6-chloro-benzoic acid (100g, 583mmol) in DMF (1000mL) is added NBS (114g, 641mmol), and the mixture is stirred at 0 DEG C for 2 hours.After stirring is completed, the reaction mixture is quenched with water (3L) and extracted with ethyl acetate (1.5L x 3).The organic layer merged is washed with salt water (1L x 3), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain residue.Residue is ground together with EA (500mL), to obtain 6-amino-3-bromo-2-chloro-benzoic acid (113g, 77% yield) as brown solid.

[0385] MS(EI)m / z:[M+H] + 251.9, 1 H NMR (400MHz, DMSO-d6) δ = 7.40 (d, J = 8.8Hz, 1H), 6.64 (d, J = 8.8Hz, 1H), 3.42 (br s, 2H).

[0386] Step 2: 6-Bromo-5-chloroisoquinolin-4(3H)-one

[0387] A solution of 6-amino-3-bromo-2-chloro-benzoic acid (80 g, 319 mmol) in formamide (216 g, 4.79 mol) was stirred at 140 ° C for 12 hours. After stirring was completed, at 25 ° C, the reaction mixture was poured into aqueous ammonium chloride solution (500 mL), and filtered and concentrated under reduced pressure to obtain residue. The residue was ground together with MeOH (500 mL) to obtain intermediate I-21 (68 g, 82% yield) as a yellow solid.

[0388] MS(EI)m / z:[M+H] + 261.2, 1 H NMR (400MHz, DMSO-d6) δ = 12.45 (br s, 1H), 8.16-8.06 (m, 2H), 7.54 (d, J = 8.8Hz, 1H).

[0389] Preparation Example 22: Sodium 5-chloro-4-oxo-3,4-dihydroquinazoline-6-thiolate (Intermediate I-22)

[0390]

[0391] Step 1: 2-Ethylhexyl 3-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)propanoate

[0392] By intermediate I-21 (64g, 247mmol), 3-sulfanylpropionic acid 2-ethylhexyl ester (80.8g, 370mmol), Pd2(dba)3(11.3g, 12.3mmol), Xantphos (14.3g, 24.7mmol) and DIEA (95.6g, 740mmol) in dioxane (dioxane) (1000mL) mixture degassed and purged 3 times with N2, and then the mixture was stirred at 100 DEG C for 12 hours under N2 atmosphere. After stirring was completed, the reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by MPLC (petroleum ether / ethyl acetate=1 / 1-1 / 2) to obtain 3-[(5-chloro-4-oxo-3H-quinazolin-6-yl)sulfanyl]propionic acid 2-ethylhexyl ester (81g, 83% yield) as a brown solid.

[0393] MS(EI)m / z:[M+H]+397.2, 1 H NMR(400MHz, CDCl3)δ=11.42-10.88(m,1H),8.10-8.04(m,1H),7.71-7.65(m,2H),4.09-4.0 3(m,2H),3.30(t,J=7.4Hz,2H),2.73(t,J=7.4Hz,2H),1.42-1.25(m,9H),0.94-0.85(m,6H).

[0394] Step 2: Sodium 5-chloro-4-oxo-3,4-dihydroquinazoline-6-thiolate

[0395] To a solution of 2-ethylhexyl 3-[(5-chloro-4-oxo-3H-quinazolin-6-yl)sulfanyl]propanoate (42 g, 106 mmol) in THF (1000 mL) was added t-BuONa (25.4 g, 265 mmol), and the mixture was then stirred at 25 ° C. for 0.5 hours. After stirring, the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was triturated with PE (2 L) to obtain intermediate I-22 (24.5 g, crude product) as a yellow solid.

[0396] MS(EI)m / z:[M+H] + 213.3, 1 H NMR (400MHz, MeOD) δ = 7.91 (s, 1H), 7.89 (d, J = 8.6Hz, 1H), 7.12-7.08 (d, J = 8.6Hz, 1H).

[0397] Preparation Example 23: N-((3S,4S)-8-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrrolidone Oxazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)-2-methylpropane-2-sulfenamide (Intermediate I- 23)

[0398]

[0399] Step 1: 2-Methyl-N-((3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)propane-2-sulfenamide

[0400] To a solution of tert-butyl (3S,4S)-4-(tert-butylsulfinylamino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-carboxylate (40 g, 107 mmol) in DCM (400 mL) was added TFA (244 g, 2.14 mol), and the mixture was stirred at 25 ° C. for 2 hours. After the stirring was completed, the reaction mixture was concentrated under reduced pressure to obtain 2-methyl-N-[(3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl]propane-2-sulfinamide (29.3 g, crude product) as a colorless oil.

[0401] MS(EI)m / z:[M+H] + 275.4

[0402] Step 2: N-((3S,4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)-2-methylpropane-2-sulfenamide

[0403] To 2-methyl-N-[(3S, 4S)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl]propane-2-sulfinamide (29.3g, 107mmol) and 2,5-dibromopyrazine (50.8g, 214mmol) in DMF (200mL) solution, add DIEA (138g, 1.07mol), and the mixture is stirred at 100 DEG C for 3 hours.After stirring is complete, at 25 DEG C, by adding aqueous ammonium chloride solution (200mL) by reaction mixture quenching, and then diluting with water (300mL) and extracting with EA (500mL x3).The organic layer merged is washed with brine (300mL x 3), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain residue. The residue was purified by MPLC (petroleum ether / ethyl acetate = 2 / 1-1:1) to obtain N-[(3S,4S)-8-(5-bromopyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl]-2-methyl-propane-2-sulfenamide (43 g, 93% yield) as a yellow solid.

[0404] MS(EI)m / z:[M+H] + 431.2, 1H NMR (400MHz, CDCl3) δ = 8.10 (d, J = 1.2Hz, 1H), 7.85 (d, J = 1.2Hz, 1H), 4.26-4.20 (m, 1H), 4. 10(td,J=4.4,13.2Hz,1H),4.01(td,J=4.4,13.2Hz,1H),3.87(d,J=9.2Hz,1H),3.67(d,J= 9.2Hz,1H),3.51(dd,J=5.6,10.4Hz,1H),3.35(d,J=10.4Hz,1H),3.18-3.04(m,2H),2.07- 1.93(m,2H),1.74-1.69(m,1H),1.50(d,J=7.6Hz,1H),1.26(s,9H),1.23(d,J=6.4Hz,3H).

[0405] Step 3: N-((3S,4S)-8-(5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)-2-methylpropane-2-sulfenamide

[0406] By intermediate I-22 (24g, 102mmol), N-[(3S, 4S)-8-(5-bromopyrazine-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl]-2-methyl-propane-2-sulfinamide (35.3g, 81.8mmol), Pd2(dba)3(9.37g, 10.2mmol), Xantphos (11.8g, 20.5mmol) and DIEA (39.7g, 307mmol) in dioxane (dioxane) (400mL) mixture degassed and purged with N2 3 times, and then the mixture was stirred at 110 DEG C under N2 atmosphere for 12 hours. After stirring was completed, the reaction mixture was filtered and concentrated under reduced pressure to obtain residue. The residue was purified by column chromatography (petroleum ether / ethyl acetate=0 / 1-EA / MeOH=9 / 1) to obtain a crude product. The residue was triturated with EA:MeOH=3:1 (400 mL) to afford intermediate I-23 (20 g, 34% yield) as a yellow solid.

[0407] MS(EI)m / z:[M+H] + 563.2, 1H NMR (400MHz, CDCl3) δ = 11.11 (br s,1H),8.24(d,J=1.2Hz,1H),8.18(d,J=1.2Hz,1H),7.98(s,1H),7.47(d,J= 8.8Hz,1H),7.22(d,J=8.8Hz,1H),4.30-4.22(m,2H),4.20-4.12(m,1H),3.9 3(d,J=9.2Hz,1H),3.69(d,J=9.2Hz,1H),3.64-3.53(m,2H),3.21-3.10(m,2 H), 2.11-1.97 (m, 2H), 1.76-1.63 (m, 2H), 1.29 (s, 9H), 1.24 (d, J = 6.4Hz, 3H).

[0408] Preparation Example 24: 5-((3S,4S)-4-((tert-butylsulfinyl)amino)-3-methyl-2-oxa-8-azaspiro [4.5]Decan-8-yl)pyrazine-2-thiolate sodium (Intermediate I-24)

[0409]

[0410] Step 1: 2-Ethylhexyl 3-((5-((3S,4S)-4-((tert-butylsulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)propanoate

[0411] A mixture of the obtained product of Preparative Example 23 Step 2 (6.0 g, 13.9 mmol), 2-ethylhexyl 3-sulfanylpropanoate (3.64 g, 16.7 mmol), Pd2(dba)3 (1.27 g, 1.39 mmol), Xantphos (1.61 g, 2.78 mmol) and DIPEA (3.60 g, 27.8 mmol) in dioxane (90 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 100°C under N2 atmosphere for 3 hours. After completion of stirring, the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography to give 2-ethylhexyl 3-[5-[(3S,4S)-4-(tert-butylsulfinylamino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]pyrazin-2-yl]sulfanylpropanoate (7.4 g, 91% yield) as a yellow oil.

[0412] MS(EI)m / z:[M+H] + 569.3.

[0413] 1H NMR(400MHz, CDCl3)δ=8.09-7.99(m,2H),4.27-4.19(m,1H),4.12-4.06(m,1H),4.06-3.97(m,3H),3 .87(d,J=9.2Hz,1H),3.68(d,J=9.2Hz,1H),3.54-3.48(m,1H),3.34(d,J=10.4Hz,1H),3.27(t,J=7.2 Hz,2H),3.17-3.02(m,2H),2.68(t,J=7.2Hz,2H),2.04-1.93(m,2H),1.72(d,J=13.2Hz,1H),1.66-1 .60(m,2H),1.59-1.53(m,1H),1.43-1.31(m,3H),1.31-1.27(m,6H),1.26(s,9H),0.94-0.86(m,6H).

[0414] Step 2: Sodium 5-((3S,4S)-4-((tert-butylsulfinyl)amino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazine-2-thiolate

[0415] To a solution of 2-ethylhexyl 3-[5-[(3S, 4S)-4-(tert-butylsulfinylamino)-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl]pyrazin-2-yl]sulfanylpropanoate (2.0 g, 3.52 mmol) in THF (20 mL) was added t-BuONa (507 mg, 5.27 mmol). The mixture was stirred at 20 ° C for 1 hour. After completion of stirring, the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was triturated with PE (15 mL) at 20 ° C to obtain intermediate I-24 (1.5 g, crude product) as a yellow solid.

[0416] 1 H NMR (400MHz, DMSO-d6) δ = 7.73 (d, J = 1.6Hz, 1H), 7.54 (s, 1H), 4.13-4.05 (m, 1 H),3.77(d,J=8.8Hz,1H),3.69-3.63(m,1H),3.63-3.57(m,2H),3.48-3.42(m ,1H),3.36(d,J=6.4Hz,1H),2.65(d,J=15.6Hz,1H),1.78-1.74(m,2H),1.56- 1.52(m,1H),1.24(d,J=2.0Hz,1H),1.18-1.11(m,9H),1.08(d,J=6.4Hz,3H).

[0417] Preparation Example 25: (R)-N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-yl Sulfonamide (Intermediate I-25)

[0418]

[0419] Step 1: (R)-tert-Butyl 1-((tert-butylsulfinyl)imino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylate

[0420] A mixture of 1-oxospiro[indane-2,4'-piperidine]-1'-tert-butyl formate (1.00g, 3.32mmol), (R)-2-methylpropane-2-sulfinamide (402mg, 3.32mmol) and Ti(OEt)4(2.27g, 9.95mmol) in THF (5mL) was stirred at 70°C for 36 hours. After stirring was completed, the reaction mixture was poured into water (10mL) at 0°C and filtered. The filtrate was diluted with water (10mL) and extracted with EtOAc (2x20mL). The combined organic layer was washed with brine (20ml), dried over Na2SO4, and filtered and concentrated under reduced pressure to obtain residue. The residue was purified by silica gel chromatography (PE:EtOAc=3:1) to obtain tert-butyl 1-[(R)-tert-butylsulfinyl]iminospiro[indan-2,4′-piperidine]-1′-carboxylate (900 mg, 67% yield) as a yellow solid.

[0421] 1 H NMR (400MHz, CDCl3) δ = 8.41 (d, J = 6.4Hz, 1H), 7.55-7.48 (m, 1H), 7.43-7.35 (m, 2H), 4.18-4.08 (m, 2H), 3.06 (s, 2H),3.00-2.86(m,2H),2.04-1.90(m,2H),1.48(s,9H),1.42(d,J=14.4Hz,1H),1.32(s,9H),1.28-1.24(m,1H).

[0422] Step 2: (S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester Under N2 at -78 ° C, to a solution of tert-butyl 1-[(R)-tert-butylsulfinyl]iminospiro[indane-2,4'-piperidine]-1'-carboxylate (800 mg, 1.98 mmol) in THF (10 mL) was added LiBH4 (129 mg, 5.93 mmol). The reaction mixture was stirred at -78-25 ° C for 16 hours. After the stirring was complete, at 0 ° C, the reaction mixture was quenched by adding NH4Cl (10 mL), and then diluted with water (10 mL) and extracted with EtOAc (2x20 mL). The combined organic layers were washed with brine (2x20 mL), dried over Na2SO4, and then filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Welch Ultimate XB-CN 250*70*10 μm; mobile phase: [hexane-EtOH (0.1% NH3·H2O)]; B%: 1%-35%, 15 minutes) to obtain (1S)-1-[[(R)-tert-butylsulfinyl]amino]spiro[indane-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester (540 mg, 67% yield) and (1R)-1-[[(R)-tert-butylsulfinyl]amino]spiro[indane-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester (130 mg, 16% yield) as white solids, respectively.

[0423] Tert-butyl (1S)-1-[[(R)-tert-Butylsulfinyl]amino]spiro[indan-2,4′-piperidine]-1′-carboxylate was used in the next reaction.

[0424] 1 H NMR (400MHz, CDCl3) δ = 7.23 (d, J = 6.4Hz, 1H), 7.18-7.12 (m, 3H), 4.43 (d, J = 9.2Hz, 1H), 4.02-3.87 (m, 2H), 3.57-3 .38(m,1H),3.11-2.74(m,4H),2.69-2.58(m,1H),2.09-1.96(m,1H),1.47-1.42(m,2H),1.39(s,9H),1.22(s,9H).

[0425] Step 3: (R)-N-((S)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfenamide

[0426] A mixture of (1S) -1- [[(R) -tert-butylsulfinyl] amino] spiro [indane -2,4'-piperidine] -1'- carboxylic acid tert-butyl ester (100 mg, 245 μmol) and TFA (1 mL) in DCM (5 mL) was stirred at 0 ° C for 1 hour. After stirring was complete, the reaction mixture was diluted with saturated NaHCO3 aqueous solution (10 mL) and extracted with EtOAc (2x10 mL). The combined organic layer was washed with brine (2x10 mL), dried over Na2SO4, and then filtered and concentrated under reduced pressure to obtain intermediate I-25 (70 mg, 92% yield) as a colorless oil.

[0427] 1 H NMR (400MHz, CDCl3) δ = 7.29 (s, 1H), 7.26-7.19 (m, 3H), 4.49 (d, J = 10.4Hz, 1H), 4.01 (br s,1H),3.63(d,J=10.4Hz,1H),3.20-3.02(m,3H),2.94-2.66(m,3H),2.23-2.21( m,1H),1.72-1.66(m,1H),1.60-1.57(m,1H),1.33(s,9H),1.19(d,J=1.6Hz,1H).

[0428] Preparation Example 26: 5-((S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidinyl] [pyridyl]-1'-yl)pyrazine-2-thiolate sodium (Intermediate I-26)

[0429]

[0430] Step 1: (R)-N-((S)-1'-(5-bromopyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfenamide

[0431] To a solution of intermediate I-25 (2.3 g, 7.50 mmol) in DMF (20 mL) was added 2,5-dibromopyrazine (5.36 g, 22.5 mmol) and DIEA (9.70 g, 75.0 mmol). The mixture was stirred at 100 ° C for 6 hours. After stirring was complete, the reaction mixture was diluted with H2O (10 mL) and extracted with EtOAc (3x200 mL). The combined organic layer was washed with brine (3x200 mL) and concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography ( 40g Silica gel flash column, eluent: 40-50% ethyl acetate / petroleum ether, gradient @ 40 mL / min) to afford (R)-N-[(1S)-1′-(5-bromopyrazin-2-yl)spiro[indan-2,4′-piperidin]-1-yl]-2-methylpropane-2-sulfenamide (2 g, 55% yield) as a light yellow solid.

[0432] MS (EI) m / z: [M+H] + 465.3; 1 H NMR (400MHz, DMSO-d6) δ = 8.20 (d, J = 1.2Hz, 1H), 8.16 (d, J = 1.2Hz, 1H), 7.28-7.24 ( m,1H),7.24-7.19(m,3H),5.65(d,J=10.4Hz,1H),4.42(d,J=10.4Hz,1H),4.27-4.1 5(m,2H),3.14(d,J=16.0Hz,1H),3.11-2.99(m,2H),2.74-2.66(m,1H),2.08-1.99 (m,1H),1.75-1.64(m,1H),1.59(d,J=12.8Hz,1H),1.30-1.24(m,1H),1.19(s,9H).

[0433] Step 2: 2-Ethylhexyl 3-((5-((S)-1-(((R)-tert-Butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidinyl]-1'-yl)pyrazin-2-yl)thio)propanoate

[0434] A mixture of (R)-N-[(1S)-1'-(5-bromopyrazin-2-yl)spiro[indane-2,4'-piperidin]-1-yl]-2-methylpropane-2-sulfinamide (1 g, 2.16 mmol), 2-ethylhexyl 3-sulfanylpropionate (565 mg, 2.59 mmol), Pd2(dba)3(197 mg, 215 μmol), Xantphos (249 mg, 431 μmol) and DIPEA (836 mg, 6.47 mmol) in dioxane (10 mL) was degassed and purged with N2 3 times, and the mixture was then stirred at 100 ° C under N2 atmosphere for 16 hours. After stirring was complete, the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography ( 40g Silica gel flash column, eluent: 35-40% ethyl acetate / petroleum ether, gradient @ 60 mL / min) to afford 2-ethylhexyl 3-[5-[(1S)-1-[[(R)-tert-butylsulfinyl]amino]spiro[indan-2,4'-piperidinyl]-1'-yl]pyrazin-2-yl]sulfanylpropanoate (1.2 g, 90% yield) as a light yellow oil.

[0435] 1 H NMR (400MHz, CDCl3) δ = 8.10-8.03 (m, 2H), 7.35-7.31 (m, 1H), 7.27-7.22 (m, 3H), 4.57 (d, J = 12.0Hz, 1H),4.23-4.16(m,2H),4.04-3.99(m,2H),3.58(d,J=12.0Hz,1H),3.27(t,J=7.2Hz,2H),3.18-3.0 3(m,3H),2.78(d,J=15.6Hz,1H),2.76-2.60(m,2H),2.37-2.27(m,1H),1.95-1.85(m,1H),1.74-1. 66(m,1H),1.59-1.54(m,1H),1.46-1.31(m,5H),1.30(s,9H),1.29-1.24(m,4H),0.92-0.88(m,6H).

[0436] Step 3: Sodium 5-((S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidinyl]-1'-yl)pyrazine-2-thiolate

[0437] To a mixture of 2-ethylhexyl 3-[5-[(1S)-1-[[(R)-tert-butylsulfinyl]amino]spiro[indan-2,4'-piperidine]-1'-yl]pyrazin-2-yl]sulfanylpropanoate (200 mg, 332 μmol) in THF (2 mL) was added t-BuONa (47.9 mg, 499 μmol), and the mixture was then stirred at 25 ° C for 0.5 hours. After completion of stirring, the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was triturated with PE (15 mL) at 20 ° C to obtain intermediate I-26 (110 mg, crude product) as a yellow solid.

[0438] MS(EI)m / z:[M+H]+438.5

[0439] Preparation Example 27: (4-Methyltetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate (Intermediate I-27)

[0440]

[0441] To a solution of (4-methyltetrahydropyran-4-yl)methanol (400mg, 3.07mmol) in DCM (5mL) was added TEA (932mg, 9.22mmol) and 4-methylbenzenesulfonyl chloride (878mg, 4.61mmol). The mixture was stirred at 30 ° C for 12 hours. After the stirring was completed, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was passed through into column chromatography (SiO2, petroleum ether / ethyl acetate=10 / 1-4 / 1) to obtain intermediate I-27 (800mg, 91% yield) as a white solid.

[0442] 1 H NMR (400MHz, CDCl3) δ = 7.79 (d, J = 8.4Hz, 2H), 7.36 (d, J = 8.0Hz, 2H), 3.77 (s, 2H), 3.68- 3.52(m,4H),2.46(s,3H),1.50(dd,J=4.4,13.6Hz,2H),1.34-1.23(m,2H),1.03(s,3H).

[0443] Preparation Example 28: 6-Bromo-5-chloro-3-(2-hydroxy-2-methylpropyl)quinazolin-4(3H)-one (Intermediate I-28) Preparation Example 29: 6-Bromo-5-chloro-3-(2-methoxy-2-methylpropyl)quinazolin-4(3H)-one (Intermediate

[0444]

[0445] To a solution of intermediate I-21 (1g, 3.85mmol) in DMF (20mL) was added CsCO(3.77g, 11.6mmol) and 2,2-dimethyloxirane (2.78g, 38.5mmol). The mixture was stirred at 60°C for 12 hours. After the stirring was completed, at 25°C, the reaction mixture was quenched by adding aqueous ammonium chloride (20mL), and then diluted with water (30mL) and extracted with EA (3x50mL). The combined organic layer was washed with brine (3x20mL), dried over anhydrous sodium sulfate, and filtered and concentrated under reduced pressure to obtain residue. The residue was purified by reversed-phase flash column chromatography (0.1% FA) to obtain intermediate I-28 (540mg, 42% yield) as a white solid.

[0446] 1 H NMR (400MHz, CDCl3) δ = 8.20 (s, 1H), 7.97 (d, J = 8.8Hz, 1H), 7.51 (d, J = 8.8Hz, 1H), 4.08 (s, 2H), 2.16-2.12 (m, 1H), 1.33 (s, 6H).

[0447] I-29) Preparation Example 30: 6-Bromo-5-chloro-3-(1-fluoro-2-methoxy-2-methylpropyl)quinazolin-4(3H)-one (Medium

[0448]

[0449] To a solution of intermediate I-28 (350 mg, 1.06 mmol) in ACN (8 mL) was added Ag2O (1.22 g, 5.28 mmol) and MeI (749 mg, 5.28 mmol). The mixture was stirred at 25 ° C for 12 hours. After stirring was completed, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by reverse phase flash column chromatography (0.1% FA) to obtain the intermediate I-29 (70 mg, 19% yield) as a white solid.

[0450] 1 H NMR (400MHz, CDCl3) δ = 8.22 (s, 1H), 7.94 (d, J = 8.8Hz, 1H), 7.49 (d, J = 8.8Hz, 1H), 4.07 (s, 2H), 3.21 (s, 3H), 1.21 (s, 6H).

[0451] Intermediate I-30) Preparation Example 31:

[0452]

[0453] Step 1: Ethyl 2-(6-bromo-5-chloro-4-oxoquinazolin-3(4H)-yl)-2-fluoroacetate

[0454] To intermediate I-21 (16g, 61.6mmol) and K cO (25.5g, 184mmol) in DMF (200mL) solution add 2- bromo- 2- fluoro- ethyl acetate (12.5g, 67.8mmol).Reactant mixture is stirred 2 hours at 30 DEG C.After stirring is completed, reactant mixture is added in water (1L) and extracted with ethyl acetate (3x200ml).The organic layer merged is washed with salt water (2x200ml), through Na sO dry, and under reduced pressure concentrate, to obtain 2- (6- bromo- 5- chloro- 4- oxo- quinazoline -3- bases) -2- fluoro- ethyl acetate (16g, 71% yield) as yellow solid.

[0455] 1 H NMR (400MHz, DMSO-d6) δ = 8.61 (s, 1H), 8.24 (d, J = 8.8Hz, 1H), 7.63 (d, J = 8.8Hz, 1H), 6.96-6.74 (m, 1H), 4.35-4.20 (m, 2H), 1.20 (t, J = 7.2Hz, 3H).

[0456] Step 2: 6-Bromo-5-chloro-3-(1-fluoro-2-hydroxy-2-methylpropyl)quinazolin-4(3H)-one

[0457] At 0 DEG C, to a solution of 2-(6-bromo-5-chloro-4-oxo-quinazoline-3-yl)-2-fluoro-ethyl acetate (10g, 27.5mmol) in THF (100mL), MeMgBr (3M, 18.3mL) is added. The reaction mixture is stirred at 0 DEG C for 1 hour. After stirring is complete, the reaction mixture is added to saturated NH4Cl solution (500ml) and extracted with EA (3x100ml). The combined organic layer is dried over Na2SO4 and concentrated under reduced pressure. The crude product is purified by reversed-phase flash column chromatography (0.1% FA) to obtain 6-bromo-5-chloro-3-(1-fluoro-2-hydroxy-2-methyl-propyl) quinazoline-4-one (1.4g, 14% yield) as a yellow solid.

[0458] 1 H NMR (400MHz, DMSO-d6) δ = 8.48 (s, 1H), 8.19 (d, J = 8.8Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 6.69-6.53 (m, 1H), 5.53 (s, 1H), 1.39 (s, 3H), 1.01 (d, J = 1.6Hz, 3H).

[0459] Step 3: 6-Bromo-5-chloro-3-(1-fluoro-2-methoxy-2-methylpropyl)quinazolin-4(3H)-one

[0460] By 6- bromo -5- chloro -3- (1- fluoro -2- hydroxy -2- methylpropyl) quinazoline -4- one (0.3g, 858μmol), Ag o (994mg, 4.29mmol) and MeI (609mg, 4.29mmol) in ACN (6mL) solution was stirred in the dark at 60 DEG C for 16 hours. After stirring was completed, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was passed through into column chromatography (SiO , petroleum ether / ethyl acetate=1 / 0-10 / 1) and purified. Subsequently, the residue was purified by preparative TLC (SiO , PE: EA=6: 1) to obtain intermediate I-30 (0.1g, 32% yield) as a white solid.

[0461] 1H NMR (400MHz, DMSO-d6) δ = 8.40 (s, 1H), 8.19 (d, J = 8.8Hz, 1H), 7.58 (d, J = 8.8 Hz, 1H), 6.89-6.56 (m, 1H), 3.25 (s, 3H), 1.41 (s, 3H), 1.06 (d, J = 1.6Hz, 3H).

[0462] Preparation Example 32: 6-Bromo-5-chloro-3-phenylquinazolin-4(3H)-one (Intermediate I-32) 6-Bromo-3-(2-methoxy-2-methylpropyl)quinazolin-4(3H)-one (Intermediate I-31)

[0463]

[0464] Step 1: 6-Bromo-3-(2-hydroxy-2-methylpropyl)quinazolin-4(3H)-one

[0465] To the bromo- 3H- quinazoline -4- one of 6- (1.00g, 4.44mmol) and 2,2- dimethyl oxirane (3.20g, 44.4mmol) in DMF (10mL) add CsCO(4.34g, 13.3mmol).The mixture is stirred at 60 DEG C for 12 hours.After stirring is completed, the reaction mixture is diluted with 30mL water and extracted with EA (3x50mL).The organic layer merged is washed with NaCl aqueous solution (3x30mL), through NaSODry, and then filtered and concentrated under reduced pressure to obtain residue.The residue is passed through into column chromatography (SiO, petroleum ether / ethyl acetate=3 / 1-1 / 1) purified to obtain 6- bromo- 3- (2- hydroxy -2- methylpropyl) quinazoline -4- one (1.10g, 83% yield) as a yellow solid.

[0466] MS(EI)m / z:[M+H] + 299.0

[0467] 1 H NMR (400MHz, CDCl3) δ=8.37 (d, J=2.0Hz, 1H), 8.12 (s, 1H), 7.77 (dd, J=2.4, 8.4Hz, 1H), 7.53 (d, J=8.4Hz, 1H), 4.01 (s, 2H), 1.24 (s, 6H).

[0468] Step 2: 6-Bromo-3-(2-methoxy-2-methylpropyl)quinazolin-4(3H)-one

[0469] To a solution of 6- bromo- 3- (2- hydroxy -2- methyl - propyl) quinazolin-4-one (300 mg, 1.01 mmol), MeI (716 mg, 5.05 mmol, 314 μ L) in ACN (5 mL) was added Ag2O (1.17 g, 5.05 mmol). The mixture was stirred at 60 ° C for 16 hours. After stirring was completed, the reaction mixture was dissolved in EA (50 mL) and filtered. The filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by flash silica gel chromatography (column: Welch Ultimate XB-CN 250 * 50 * 10 μm; mobile phase: [hexane-EtOH (0.1% NH3.H2O)]; concentration gradient: 1%-30% B, 15 minutes) and preparative TLC (SiO2, PE / EA = 1 / 1) to obtain intermediate I-31 (85.0 mg, 27% yield) as a white solid.

[0470] MS(EI)m / z:[M+H] + 311.0.

[0471] 1 H NMR (400MHz, MeOD) δ=8.24-8.22(m,1H),8.13-8.11(m,1H),7.84-7.80(m,1H),7.51-7.47(m,1H),3.26-3.16(m,2H),3.14(s,3H),1.10(s,6H).

[0472] Preparation Example 33: 6-Bromo-5-chloro-3-(pyridin-3-yl)quinazolin-4(3H)-one (Intermediate I-33)

[0473]

[0474] Step 1: Methyl 6-amino-3-bromo-2-chlorobenzoate

[0475] To the solution of 6-amino-3-bromo-2-chloro-benzoic acid (5g, 20.0mmol) in DMF (50mL) add KCO(3.31g, 24.0mmol) and MeI (3.40g, 24.0mmol).The mixture is stirred at 25 DEG C for 12 hours.After stirring is completed, by adding 20mL aqueous ammonium chloride solutions at 25 DEG C, the reaction mixture is quenched, diluted with water (30mL) and extracted with EA (3x100mL).The organic layer merged is washed with salt water (3x50mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain residue.Residue is passed through column chromatography (SiO, petroleum ether / ethyl acetate=20 / 1-10 / 1) purified, to obtain 6-amino-3-bromo-2-chloro-benzoic acid methyl esters (5g, 95% yield) in yellow oil.

[0476] 1 H NMR (400MHz, CDCl3) δ=7.39 (d, J=8.8Hz, 1H), 6.50 (d, J=8.8Hz, 1H), 4.69 (s, 2H), 3.94 (s, 3H).

[0477] Step 2: 6-Bromo-5-chloro-3-phenylquinazolin-4(3H)-one

[0478] To the solution of 6-amino-3-bromo-2-chloro-benzoic acid methyl esters (2.0g, 7.56mmol) in diethoxymethoxyethane (1.68g, 11.3mmol), aniline (845mg, 9.07mmol) and NH4Cl (324mg, 6.05mmol) is added. The mixture is stirred at 100 DEG C for 12 hours. After stirring is completed, the reaction mixture is diluted with ethyl acetate (30mL) and carefully poured into 50mL water. The suspension is filtered, the filter cake is washed with 50mL MeOH, then dried under reduced pressure, to obtain a yellow solid. Solid is ground together with EA (30mL) to obtain the intermediate I-32 (900mg, 35% yield) as a yellow solid.

[0479] m / z ES+[M+H] + 336.9.

[0480] 1 H NMR (400MHz, DMSO-d6) δ = 8.40 (s, 1H), 8.18 (d, J = 8.8Hz, 1H), 7.61 (d, J = 8.8Hz, 1H), 7.60-7.50 (m, 5H).

[0481] ​

[0482]

[0483] Pyridine -3- amine (427mg, 4.54mmol) and NH4Cl (162mg, 3.02mmol) are added to a solution of the obtained product (1g, 3.78mmol) of step 1 of preparation example 32 in diethoxymethoxyethane (840mg, 5.67mmol). The mixture is stirred at 100 DEG C for 12 hours. After stirring is complete, the reaction mixture is diluted with ethyl acetate (50mL) and carefully poured into 100mL water. The suspension is filtered and the filter cake is collected to obtain a yellow solid. The residue is passed through preparative HPLC (column: Welch Ultimate XB-NH2 250*50*10μm; mobile phase: [hexane-EtOH (0.1%NH3.H2O)]; concentration gradient: 1%-35%B, 25 minutes), to obtain intermediate I-33 (230mg, 18% yield) as a yellow solid.

[0484] m / z ES+[M+H] + 337.9.

[0485] 1 H NMR (400MHz, CDCl3) δ = 8.75 (d, J = 4.8Hz, 1H), 8.71-8.66 (m, 1H), 8.11 (s, 1H), 8.02 (d, J=8.8Hz, 1H), 7.85 (dd, J=1.6, 8.0Hz, 1H), 7.57 (d, J=8.8Hz, 1H), 7.27 (s, 1H).

[0486] Preparation Example 34: 6-Bromo-5-chloro-3-((1-methylpiperidin-4-yl)methyl)quinazolin-4(3H)-one (Intermediate I-34)

[0487]

[0488] Step 1: tert-Butyl 4-((6-bromo-5-chloro-4-oxoquinazolin-3(4H)-yl)methyl)piperidine-1-carboxylate

[0489] To the solution of intermediate I-21 (2.0g, 7.71mmol) and tert-butyl 4- (bromomethyl) piperidine -1- formates (3.22g, 11.6mmol) in DMF (20mL) add KCO (3.20g, 23.1mmol) and TBAI (569mg, 1.54mmol). The mixture was stirred at 60 DEG C for 12 hours. After the completion of the reaction, at 25 DEG C, the reaction mixture was quenched by adding aqueous ammonium chloride solution (50mL), and then diluted with water (50mL) and extracted with EA (3x100mL). The collected organic layer was washed with salt water (3x50mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 1-1 / 5) to afford tert-butyl 4-[(6-bromo-5-chloro-4-oxo-quinazolin-3-yl)methyl]piperidine-1-carboxylate (2.83 g, 80% yield) as a white solid.

[0490] 1 H NMR (400MHz, CDCl3) δ = 7.98-7.94 (m, 2H), 7.49 (d, J = 8.8Hz, 1H), 4.21-4.06 (m, 2H), 3.90-3.77 (m, 2H), 2.67 (t, J = 12.0Hz, 2H), 2.17-2.06 (m, 1H), 1.71-1.64 (m, 2H), 1.45 (s, 9H), 1.27-1.17 (m, 2H).

[0491] Step 2: 6-Bromo-5-chloro-3-(piperidin-4-ylmethyl)quinazolin-4(3H)-one

[0492] To a solution of tert-butyl 4-[(6-bromo-5-chloro-4-oxo-quinazolin-3-yl)methyl]piperidine-1-formate (2.8g, 6.13mmol) in DCM (30mL) was added TFA (14.0g, 123mmol), and the mixture was stirred at 25°C for 0.5 hours. After stirring was complete, the reaction mixture was concentrated. The residue was basified to pH=10 with saturated KCOaqueous solution. The suspension was filtered, the filter cake was washed with 30mL water and dried under reduced pressure to obtain 6-bromo-5-chloro-3-(4-piperidinylmethyl)quinazolin-4-one (2g, 83% yield) as a white solid.

[0493] MS(EI)m / z:[M+H] + 358.0, 1H NMR (400MHz, DMSO-d6) δ=8.45(s,1H),8.13(d,J=8.8Hz,1H),7.55(d,J=8.8Hz,1H),3.84(d,J=7.2Hz,2H),3 .07(d,J=12.0Hz,2H),2.57(t,J=12.0Hz,2H),2.00-1.91(m,1H),1.59(d,J=13.2Hz,2H),1.30-1.17(m,2H).

[0494] Step 3: 6-Bromo-5-chloro-3-((1-methylpiperidin-4-yl)methyl)quinazolin-4(3H)-one

[0495] To the chloro-3-of the bromo-5-of 6-(4-piperidinylmethyl)quinazoline-4-one (550mg, 1.54mmol) and HCHO (6.26g, 77.1mmol, 37% purity) solution in MeOH (5mL), add HOAc (278mg, 4.63mmol) and NaBH (OAc) (980mg, 4.63mmol).Mixture was stirred 2 hours at 25 ℃.After stirring was completed, at 25 ℃, by adding NaHCO the aqueous solution (20mL) is quenched by reaction mixture, and then diluted with water (30mL) and extracted with DCM / MeOH (3 / 1) (3x50mL).The organic layer merged is washed with salt water (20mL), through anhydrous sodium sulfate drying, and then filtered and under reduced pressure concentrated, to obtain residue. The residue was purified by column chromatography (Al 2 O 3 , petroleum ether / ethyl acetate=0 / 1-EA / MeOH=10 / 1) to obtain intermediate I-34 (450 mg, 79% yield) as a white solid.

[0496] MS(EI)m / z:[M+H] + 371.8, 1 H NMR (400MHz, DMSO-d6) δ = 8.43 (s, 1H), 8.14-8.07 (m, 1H), 7.54 (d, J = 8.8Hz, 1H), 3.83 (d, J = 7.2Hz, 2H ), 2.73 (d, J = 10.8Hz, 2H), 2.11 (s, 3H), 1.79-1.67 (m, 3H), 1.51 (d, J = 11.6Hz, 2H), 1.31-1.17 (m, 2H).

[0497] Preparation Example 35: (R)-N-((S)-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidin]-6-yl)-2-methyl- 2-Methylpropanesulfenamide (Intermediate I-35)

[0498]

[0499] Step 1: (2-chlorothiazol-4-yl)methanol

[0500] To the solution of 2- chlorothiazole -4- ethyl formate (90g, 467mmol) in EtOH (800mL), NaBH is added (88.8g, 2.35mol), and the mixture is stirred at 50 DEG C for 2 hours. After stirring is completed, at 0 DEG C, by adding aqueous ammonium chloride solution (300mL), the reaction mixture is quenched, and then diluted with water (500mL) and extracted with ethyl acetate (3x800mL). The organic layer collected is washed with salt water (3x300mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain residue. Residue is passed through MPLC (SiO , petroleum ether / ethyl acetate=5 / 1-3 / 1) purified, to obtain (2- chlorothiazole -4- bases) methanol (67g, 95% yield) as yellow oil.

[0501] 1 H NMR (400MHz, CDCl3) δ = 7.12 (s, 1H), 4.71 (s, 2H), 2.59-2.48 (m, 1H).

[0502] Step 2: (2-chlorothiazol-4-yl)methyl methanesulfonate

[0503] At 0 DEG C, TEA (44.6g, 441mmol) and MsCl (35.5g, 310mmol) are added to a solution of (2- chlorothiazol-4-yl) methanol (33g, 221mmol) in DCM (350mL). The mixture is stirred at 0 DEG C for 0.5 hour. After stirring is completed, at 25 DEG C, by adding NaHCOthe aqueous solution (100mL) the reaction mixture is quenched, and then diluted with water (100mL) and extracted with DCM (3x200mL). The organic layer merged is washed with salt water (100mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain (2- chlorothiazol-4-yl) methyl methanesulfonate (42g, crude product) as yellow oil.

[0504] 1 H NMR (400MHz, CDCl3) δ7.36 (s, 1H), 5.25 (s, 2H), 3.07 (s, 3H).

[0505] Step 3: 1-(tert-Butyl)4-ethyl 4-((2-chlorothiazol-4-yl)methyl)piperidine-1,4-dicarboxylate

[0506] O4-ethylpiperidine-1,4-dicarboxylic acid O1- tert-butyl ester (47g, 183mmol) is dissolved in THF (500mL). The solution is cooled to -60 ° C under a nitrogen atmosphere, and LDA (2M, 128mL) is then added dropwise thereto. After the addition is complete, the reaction solution is stirred at -60 ° C for 30 minutes. A solution of (2-chlorothiazol-4-yl) methyl methanesulfonate (41.6g, 183mmol) in THF (150mL) is added dropwise. After the addition is complete, the reaction solution is stirred at -60 ° C for 30 minutes, then slowly warmed to 25 ° C and stirred for 2 hours. After the stirring is complete, at 25 ° C, the reaction mixture is quenched by adding aqueous ammonium chloride solution (100mL), and then diluted with water (200mL) and extracted with EA (3x300mL). The combined organic layer is washed with brine (150mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by MPLC (SiO 2 , petroleum ether / ethyl acetate = 15 / 1-10 / 1) to afford O 1 -tert-butyl O 4 -ethyl 4-[(2-chlorothiazol-4-yl)methyl]piperidine-1,4-dicarboxylate (31 g, 44% yield) as a yellow oil.

[0507] MS(EI)m / z:[M-Boc+H] + 289.3, 1 H NMR (400MHz, CDCl3) δ = 6.82-6.79 (m, 1H), 4.19-4.13 (m, 2H), 3.97-3.82 (m, 2H), 2.97-2. 84(m,4H),2.11(d,J=13.2Hz,2H),1.51(d,J=4.0Hz,2H),1.45(s,9H),1.26-1.22(m,3H).

[0508] Step 4: tert-Butyl 2-chloro-6-oxo-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate

[0509] To a solution of 4-[(2-chlorothiazol-4-yl)methyl]piperidine-1,4-dicarboxylic acid O1- tert-butyl O4-ethyl ester (62g, 159mmol) in THF (1100mL) was added LDA (2M, 199mL), and the mixture was stirred at -70°C for 0.5 hours. After the stirring was complete, at 0°C, the reaction mixture was quenched by adding aqueous ammonium chloride (100mL), and then diluted with water (200mL) and extracted with EA (3x300mL). The combined organic layer was washed with brine (200mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by MPLC (SiO 2 , petroleum ether / ethyl acetate = 15 / 1-10 / 1) to afford tert-butyl 2-chloro-6-oxo-spiro[4H-cyclopenta[d]thiazole-5,4′-piperidine]-1′-carboxylate (22.5 g, 41% yield) as a yellow solid.

[0510] 1 H NMR (400MHz, CDCl3) δ = 4.25-4.10 (m, 2H), 3.06 (s, 2H), 2.98-2.95 (m, 2H), 2.02-1.93 (m, 2H), 1.46-1.40 (m, 11H).

[0511] Step 5: tert-Butyl (R,Z)-6-((tert-butylsulfinyl)imino)-2-chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate

[0512] To a solution of 2-chloro-6-oxo-spiro[4H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-tert-butyl carboxylate (33g, 96.3mmol) in THF (100mL) was added Ti(OEt)4(329g, 1.44mol) and (R)-2-methylpropane-2-sulfinamide (58.3g, 481mmol). The mixture was stirred at 90°C for 12 hours. After stirring was complete, the reaction mixture was diluted with EA (1000mL) and quenched by adding water (500mL). The combined organic layer was washed with brine (3x500mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by MPLC (SiO 2 , petroleum ether / ethyl acetate = 10 / 1-5 / 1) to afford tert-butyl ((6Z)-6-[(R)-tert-butylsulfinyl]imino-2-chloro-spiro[4H-cyclopenta[d]thiazole-5,4′-piperidine]-1′-carboxylate (35 g, 82% yield) as a yellow solid.

[0513] 1H NMR (400MHz, CDCl3) δ=4.27-4.12(m,2H), 2.99-2.85(m,4H), 2.06-1.88(m,2H), 1.58-1.51(m,2H), 1.49(s,9H), 1.28(s,9H).

[0514] Step 6: (S)-tert-Butyl 6-(((R)-tert-Butylsulfinyl)amino)-2-chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate

[0515] To a solution of (6Z)-6-[(R)-tert-butylsulfinyl]imino-2-chloro-spiro[4H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylic acid tert-butyl ester (34 g, 76.2 mmol) in DCM (500 mL) was added DIBAL-H (1 M, 229 mL) and the mixture was stirred at -70 ° C for 1 hour. After stirring was complete, at -70 ° C, the reaction mixture was quenched by adding MeOH (10 mL) and then diluted with DCM (1000 mL). The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 3 / 1-2 / 1) to afford (6S)-6-[[(R)-tert-butylsulfinyl]amino]-2-chloro-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4′-piperidine]-1′-carboxylic acid tert-butyl ester (28 g, 82% yield) as a yellow solid.

[0516] MS(EI)m / z:[M+H] + 448.2, 1 H NMR (400MHz, CDCl3) δ = 4.52 (d, J = 8.8Hz, 1H), 4.13-3.93 (m, 2H), 3.59 (d, J = 7.6Hz, 1H ),3.07-2.74(m,4H),1.90-1.77(m,2H),1.67-1.54(m,2H),1.46(s,9H),1.22(s,9H)

[0517] Step 7: (S)-tert-Butyl 6-(((R)-tert-Butylsulfinyl)amino)-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate

[0518] To a solution of (6S) -6- [[(R) -tert-butylsulfinyl] amino] -2-chloro- spiro [4,6- dihydrocyclopenta [d] thiazole -5,4'- piperidine] -1'- carboxylic acid tert-butyl ester (12g, 26.9mmol) in MeOH (120mL) was added Pd / C (6.00g, 5.65mmol, 10% purity) and TEA (8.13g, 80.4mmol). The mixture was stirred at 40 ° C for 12 hours under an atmosphere of H2 (50psi). After the stirring was completed, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain (6S) -6- [[(R) -tert-butylsulfinyl] amino] spiro [4,6- dihydrocyclopenta [d] thiazole -5,4'- piperidine] -1'- carboxylic acid tert-butyl ester (12g, crude product) as a yellow solid.

[0519] MS(EI)m / z:[M+H] + 414.2, 1 H NMR (400MHz, CDCl3) δ = 8.78 (s, 1H), 4.56 (d, J = 8.8Hz, 1H), 4.12-3.94 (m, 2H), 3.64-3.54 (m, 1H), 3.05 -2.93(m,2H),2.87(s,2H),1.86-1.78(m,2H),1.61(t,J=13.6Hz,2H),1.47-1.45(s,9H),1.22(s,9H).

[0520] Step 8: (R)-N-((S)-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4'-piperidin]-6-yl)-2-methylpropane-2-sulfenamide

[0521] To a solution of (6S)-6-[[(R)-tert-butylsulfinyl]amino]spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylic acid tert-butyl ester (8g, 19.3mmol) in DCM (100mL) was added TFA (17.6g, 155mmol), and the mixture was stirred at 25°C for 1 hour. After the stirring was complete, at 25°C, the reaction mixture was quenched by adding KCOaqueous solution (50mL), and then diluted with water (100mL) and extracted with DCM (3x150mL). The combined organic layer was washed with brine (200mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain intermediate I-35 (3.5g, crude product) as a yellow solid.

[0522] 1H NMR (400MHz, CDCl3) δ = 8.80-8.75 (m, 1H), 4.60 (d, J = 8.8Hz, 1H), 3.83-3.76 (m, 1H), 3.26-3.13 (m, 2H), 2.93-2.93 (m, 1H), 2 .96-2.89(m,1H),2.89-2.82(m,2H),2.01-1.94(m,2H),1.74(dd,J=2.0,12.4Hz,1H),1.67-1.60(m,1H),1.25-1.22(s,9H).

[0523] Preparation Example 36: 5-((S)-4-(((R)-tert-Butylsulfinyl)amino)-4,6-dihydrospiro[cyclopenta[d]thiazolinone Sodium (5,4'-piperidin-1'-yl)pyrazine-2-thiolate (Intermediate I-36)

[0524]

[0525] Intermediate I-36 was prepared in the same manner as in Preparation Example 26, except that Intermediate I-35 was used instead of Intermediate I-25 in Preparation Example 26.

[0526] MS(EI)m / z:[M-Na] + 424.2

[0527] Preparation Example 37: (R)-2-Methyl-N-[(4S)-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-4- [Methyl]propane-2-sulfenamide (Intermediate I-37)

[0528]

[0529] Step 1: 1-(tert-Butyl)4-ethyl 4-((2-chlorothiazol-5-yl)methyl)piperidine-1,4-dicarboxylate

[0530] At -70 ° C, LDA (2M, 64.3 mL) was added to a mixture of O1- tert-butyl O4- ethylpiperidine-1,4-dicarboxylate (30.3 g, 118 mmol) in THF (200 mL). The mixture was stirred at -70 ° C for 1 hour. Then, a solution of 2-chloro-5- (chloromethyl) thiazole (18 g, 107 mmol) in THF (40 mL) was added dropwise to the system. The reaction mixture was stirred at -70 ° C for 1 hour. After stirring was complete, the reaction mixture was poured into a saturated NH4Cl (300 ml) solution and then extracted with EA (3x200 mL). The organic layer was washed with brine (2x200 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (PE / EtOAc=10 / 1) to obtain O1-tert-butyl O4-ethyl 4-[(2-chlorothiazol-5-yl)methyl]piperidine-1,4-dicarboxylate (25 g, 60% yield) as a yellow oil.

[0531] 1 HNMR (400MHz, CDCl3) δ = 7.22 (s, 1H), 4.18 (q, J = 7.2Hz, 2H), 3.97-3.77 (m, 2H), 3.00 (s, 2H), 2 .95(s,2H),2.11(d,J=13.2Hz,2H),1.46(s,9H),1.41(d,J=4.4Hz,2H),1.26(t,J=7.2Hz,3H).

[0532] Step 2: tert-Butyl 2-chloro-4-oxo-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate

[0533] At -70 ° C, LDA (2M, 30.9 mL) was added to a mixture of 4- [(2- chlorothiazol-5-yl) methyl] piperidine -1,4- dicarboxylic acid O1- tert-butyl O4- ethyl ester (15 g, 38.6 mmol) in THF (350 mL). The mixture was stirred at -70 ° C for 1 hour. After the stirring was completed, at 0 ° C, the reaction mixture was poured into a saturated NH4Cl (500 ml) solution and then extracted with EA (3x100 mL). The organic layer was washed with brine (2x200 mL). The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (0.1% NH3.H2O) to obtain 2- chloro-4- oxo-spiro [6H- cyclopenta [d] thiazole -5,4'-piperidine] -1'- tert-butyl formate (4.0 g, 30% yield) as a yellow solid.

[0534] 1 HNMR (400MHz, CDCl3) δ = 4.26-4.03 (m, 2H), 3.11 (s, 2H), 2.99 (t, J = 12.0Hz, 2H),2.03-1.92(m,2H),1.55-1.51(m,1H),1.48(s,9H),1.47-1.44(m,1H).

[0535] Step 3: tert-Butyl (R,Z)-4-((tert-butylsulfinyl)imino)-2-chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate

[0536] To a solution of 2-chloro-4-oxo-spiro[6H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-tert-butyl formate (4g, 11.7mmol) in THF (40mL) was added (R)-2-methylpropane-2-sulfinamide (5.66g, 46.7mmol) and Ti(OEt)4(39.9g, 175mmol), and the mixture was stirred at 95°C for 16 hours. After stirring was complete, the reaction mixture was diluted with EtOAc (150mL) and quenched by adding 200ml of water. The mixture was filtered and extracted with EtOAc (2x100mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , PE / EtOAc=4 / 1) to afford (4Z)-4-[(R)-tert-butylsulfinyl]imino-2-chloro-spiro[6H-cyclopenta[d]thiazole-5,4′-piperidine]-1′-carboxylic acid tert-butyl ester (4.3 g, 76% yield) as a light yellow solid.

[0537] MS(EI)m / z:[M+H] + 446.2, 1 H NMR (400MHz, CDCl3) δ = 4.17 (d, J = 12.0Hz, 2H), 3.12-3.06 (m, 2H), 2.97-2.86 (m, 2H) ,2.17-2.11(m,1H),2.07-1.93(m,2H),1.62-1.56(m,1H),1.49(s,9H),1.28(s,9H).

[0538] Step 4: (S)-tert-Butyl 4-(((R)-tert-Butylsulfinyl)amino)-2-chloro-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate

[0539] To a solution of (4Z)-4-[(R)-tert-butylsulfinyl]imino-2-chloro-spiro[6H-cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylic acid tert-butyl ester (2.0 g, 4.48 mmol) in DCM (30 mL) was added DIBAL-H (1 M, 13.5 mL) and the mixture was stirred at -70 ° C for 2 hours. After stirring was complete, at 0 ° C, the reaction mixture was quenched by adding MeOH (2 mL) and then diluted with DCM (100 mL). The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 1-1 / 3) to afford (4S)-4-[[(R)-tert-butylsulfinyl]amino]-2-chloro-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4′-piperidine]-1′-carboxylic acid tert-butyl ester (1.25 g, 62% yield) as a yellow solid.

[0540] 1 H NMR (400MHz, CDCl3) δ = 4.40 (d, J = 9.2Hz, 1H), 4.05-3.87 (m, 2H), 3.09-3.01 (m, 2H), 2.89-2.73 (m, 2H), 1 .97(t,J=9.6Hz,1H),1.91-1.83(m,1H),1.65-1.61(m,1H),1.59-1.54(m,1H),1.46(s,9H),1.26(s,9H).

[0541] Step 5: (S)-tert-Butyl 4-(((R)-tert-Butylsulfinyl)amino)-4,6-dihydrospiro[cyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylate

[0542] To a solution of (4S)-4-[[(R)-tert-butylsulfinyl]amino]-2-chloro-spiro[4,6-dihydrocyclopenta[d]thiazole-5,4'-piperidine]-1'-carboxylic acid tert-butyl ester (1.2 g, 2.68 mmol) in MeOH (20 mL) was added Pd / C (853 mg, 804 μmol) and TEA (813 mg, 8.03 mmol), and the mixture was stirred under H (50 psi) atmosphere at 40° C. for 12 h. After completion of stirring, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by reverse phase flash chromatography (0.1% FA) to afford tert-butyl (4S)-4-[[(R)-tert-butylsulfinyl]amino]spiro[4,6-dihydrocyclopenta[d]thiazole-5,4′-piperidine]-1′-carboxylate (0.88 g, 79%) as a yellow solid.

[0543] 1H NMR (400MHz, CDCl3) δ = 8.72 (s, 1H), 4.47 (d, J = 9.0Hz, 1H), 4.03-3.87 (m, 2H), 3.69-3.52 (m, 1H), 3.14-3.00 ( m,2H),2.93-2.77(m,2H),2.03-1.94(m,1H),1.92-1.80(m,1H),1.67-1.54(m,2H),1.46(s,9H),1.26(s,9H).

[0544] Step 6: (R)-N-((S)-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4'-piperidin]-4-yl)-2-methylpropane-2-sulfenamide

[0545] To a solution of (4S) -4- [[(R) -tert-butylsulfinyl] amino] spiro [4,6- dihydrocyclopenta [d] thiazole -5,4'- piperidine] -1'- carboxylic acid tert-butyl ester (350 mg, 846 μmol) in DCM (6 mL) was added TFA (2.89 g, 25.4 mmol), and the mixture was stirred at 25 ° C for 1 hour. After the stirring was completed, the reaction mixture was concentrated under reduced pressure to obtain a residue. Then, at 25 ° C, the reaction mixture was quenched by adding K2CO3 aqueous solution (2 mL), diluted with water (5 mL) and extracted with DCM (3x10 mL). The combined organic layer was washed with brine (3x20 mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain intermediate I-37 (260 mg, crude product) as a yellow solid.

[0546] 1 H NMR (400MHz, CDCl3) δ = 8.74 (s, 1H), 4.49 (d, J = 9.2Hz, 1H), 3.84 (d, J = 8.8Hz, 1H), 3.20-3.11 (m, 2H), 3.01-2.96 (m, 1H) ,2.94-2.88(m,2H),2.85-2.80(m,1H),2.04-1.90(m,2H),1.71(d,J=13.2Hz,1H),1.57(d,J=14.0Hz,1H),1.28(s,9H).

[0547] Preparation Example 38: 5-((S)-4-(((R)-tert-Butylsulfinyl)amino)-4,6-dihydrospiro[cyclopenta[d]thiazolinone Sodium (5,4'-piperidin-1'-yl)pyrazine-2-thiolate (Intermediate I-38)

[0548]

[0549] Intermediate I-38 was obtained in the same manner as in Preparation Example 26, except that Intermediate I-37 was used instead of Intermediate I-25 in Preparation Example 26.

[0550] MS(EI)m / z:[M-Na] + 424.5

[0551] Preparation Example 39: 3-((S)-1-(((R)-tert-Butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidinyl] Sodium 1,2,4-triazine-6-thiolate (Intermediate I-39)

[0552]

[0553] Step 1: 3,6-Dibromo-1,2,4-triazine

[0554] To a solution of 6- bromo-1,2,4-triazine-3-amine (2g, 11.4mmol) in MeCN (20mL) was added tert-butyl nitrite (1.89g, 18.3mmol) and CuBr2 (3.32g, 14.9mmol). The mixture was stirred at 70 ° C for 2 hours. After the stirring was completed, the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=20 / 1-10 / 1) to obtain 3,6- dibromo-1,2,4-triazine (1.25g, 46% yield) as a yellow solid.

[0555] 1 H NMR (400MHz, CDCl3) δ = 8.55 (s, 1H)

[0556] Step 2: (R)-N-((S)-1'-(6-bromo-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfenamide

[0557] To a solution of intermediate I-25 (500 mg, 1.19 mmol) in dioxane (8 mL) was added DIEA (1.54 g, 11.9 mmol) and 3,6-dibromo-1,2,4-triazine (284 mg, 1.19 mmol). The mixture was stirred at 60 ° C for 1 hour. After the completion of stirring, the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=3 / 1-2 / 1) to obtain (R)-N-[(1S)-1'-(6-bromo-1,2,4-triazine-3-yl)spiro[indan-2,4'-piperidine]-1-yl]-2-methyl-propane-2-sulfinamide (510 mg, 92% yield) as a yellow solid.

[0558] m / z ES+[M+H] + 466.0

[0559] 1H NMR (400MHz, CDCl3) δ = 8.12 (s, 1H), 7.34-7.29 (m, 1H), 7.27-7.21 (m, 3H), 4.78-4.6 5(m,2H),4.57(d,J=10.4Hz,1H),3.58(d,J=10.4Hz,1H),3.27-3.18(m,2H),3.16-2 .95(m,1H),2.81(d,J=15.6Hz,1H),2.31(dt,J=4.4,12.4Hz,1H),1.84(dt,J=4.4,1 2.4Hz,1H),1.70(dd,J=2.0,13.6Hz,1H),1.38(dd,J=2.0,13.6Hz,1H),1.30(s,9H)

[0560] Steps 3 and 4: Sodium 3-((S)-1-(((R)-tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidinyl]-1'-yl)-1,2,4-triazine-6-thiolate

[0561] In the same manner as steps 2 and 3 of Preparation Example 26, (R)-N-((S)-1'-(6-bromo-1,2,4-triazin-3-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfenamide was used as a starting material to obtain intermediate I-39 (170 mg, 80%) as a yellow solid.

[0562] MS(EI)m / z:[M+H]+418.1

[0563] Preparation Example 40: N-((S)-1'-(3-(hydroxymethyl)-5-mercapto-6-methylpyrazin-2-yl)-1,3-dihydrospiro [Indene-2,4'-piperidinyl]-1-yl)-2-methylpropane-2-sulfenamide (Intermediate I-40)

[0564]

[0565] Step 1: Ethyl 6-bromo-3-((1S)-1-((tert-butylsulfinyl)amino)-1,3-dihydrospiro[indene-2,4'-piperidinyl]-1'-yl)-5-methylpyrazine-2-carboxylate

[0566] To the solution of 6-bromo-3-chloro-5-methyl-pyrazine-2-ethyl formate (0.3g, 1.07mmol) in DMA (6mL), DIEA (694mg, 5.37mmol) and intermediate I-25 (361mg, 859 μmol) are added. The mixture is stirred at 60 ℃ for 4 hours. After stirring is complete, at 25 ℃, by adding aqueous ammonium chloride solution, the reaction mixture is quenched, and then diluted with water (30mL) and extracted with EA (3x50mL). The organic layer merged is washed with salt water (3x20mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 3 / 1-2 / 1) to afford 6-bromo-3-[(1S)-1-(tert-butylsulfinylamino)spiro[indan-2,4′-piperidinyl]-1′-yl]-5-methyl-pyrazine-2-carboxylic acid ethyl ester (450 mg, 76% yield) as a yellow solid.

[0567] MS(EI)m / z:[M+H] + 551.1.

[0568] 1 H NMR (400MHz, CDCl3) δ = 7.32 (d, J = 7.2Hz, 1H), 7.29-7.26 (m, 1H), 7.25-7.21 (m, 2H), 4.53 (d, J = 9. 6Hz, 1H), 4.40 (q, J = 7.2Hz, 2H), 3.94 (d, J = 13.2Hz, 1H), 3.85 (d, J = 13.2Hz, 1H), 3.54 (d, J = 9.6Hz, 1H),3.31-3.20(m,2H),3.15(d,J=16.0Hz,1H),2.80(d,J=16.0Hz,1H),2.53(s,3H),2.20(dt,J=4 .4,12.4Hz,1H),1.86(dt,J=4.4,12.4Hz,1H),1.65-1.59(m,1H),1.43-1.35(m,4H),1.28(s,9H).

[0569] Step 2: N-((S)-1'-(5-bromo-3-(hydroxymethyl)-6-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfenamide

[0570] To a solution of 6-bromo-3-[(1S)-1-(tert-butylsulfinylamino)spiro[indane-2,4'-piperidine]-1'-yl]-5-methyl-pyrazine-2-carboxylic acid ethyl ester (600mg, 1.09mmol) in DCM (15mL) was added DIBAL-H (1M, 4.37mL) and the mixture was stirred at -65 DEG C for 3 hours. After stirring was complete, at -60 DEG C or lower temperatures, the reaction mixture was quenched by adding MeOH (1mL) and then diluted with EA (50mL). The suspension was warmed to room temperature. Then, the suspension was filtered through a celite pad, and the filter cake was washed with EA (3x30mL). The combined filtrate was concentrated and dried to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 2 / 1 to 1 / 1) to afford N-[(1S)-1′-[5-bromo-3-(hydroxymethyl)-6-methyl-pyrazin-2-yl]spiro[indan-2,4′-piperidin]-1-yl]-2-methyl-propane-2-sulfenamide (410 mg, 74% yield) as a yellow solid.

[0571] MS(EI)m / z:[M+H] + 507.1

[0572] 1 H NMR(400MHz, CDCl3)δ=7.33(d,J=7.6Hz,1H),7.27-7.20(m,3H),4.67(s,2H),4.57(d,J =10.0Hz,1H),3.59(d,J=10.0Hz,1H),3.57-3.51(m,1H),3.50-3.43(m,2H),3.16-2.99( m,3H),2.75(d,J=15.8Hz,1H),2.55(s,3H),2.36(dt,J=4.0,12.4Hz,1H),1.99(dt,J=4. 0,12.4Hz,1H),1.66(dd,J=2.4,13.2Hz,1H),1.40(dd,J=2.4,13.2Hz,1H),1.30(s,9H).

[0573] Steps 3 and 4: N-((S)-1'-(3-(hydroxymethyl)-5-mercapto-6-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfenamide

[0574] In the same manner as steps 2 and 3 of Preparation Example 26, using N-((S)-1'-(5-bromo-3-(hydroxymethyl)-6-methylpyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfenamide as a starting material, intermediate I-40 (200 mg, 70%) was obtained as a yellow solid.

[0575] MS(EI)m / z:[M+H] + 461.1

[0576] Preparation Example 41: 6-((3-amino-5-chloropyrazin-2-yl)thio)-5-chloro-3-(2-methoxy-2-methylpropane 4-(3H)-quinazolin-1-one (Intermediate I-41)

[0577]

[0578] Step 1 and Step 2: Sodium 5-chloro-3-(2-methoxy-2-methylpropyl)-4-oxo-3,4-dihydroquinazoline-6-thiolate

[0579] In the same manner as in Step 2 and Step 3 of Preparation 26, using Intermediate I-29 as a starting material, sodium 5-chloro-3-(2-methoxy-2-methylpropyl)-4-oxo-3,4-dihydroquinazoline-6-thiolate (30 mg, 50%) was obtained as a yellow solid.

[0580] MS(EI)m / z:[M+H] + 299.1

[0581] Step 3: 6-((3-amino-5-chloropyrazin-2-yl)thio)-5-chloro-3-(2-methoxy-2-methylpropyl)quinazolin-4(3H)-one

[0582] A mixture of [3-(2-methoxy-2-methyl-propyl)-4-oxo-quinazolin-6-yl]sulfanylsodium (330 mg, 1.15 mmol), 3-bromo-6-chloro-pyrazin-2-amine (216 mg, 1.04 mmol), Pd2(dba)3(106 mg, 115 μmol), Xantphos (133 mg, 231 μmol) and DIEA (447 mg, 3.46 mmol) in dioxane (10 mL) was degassed and purged 3 times with N2, and then the mixture was stirred at 100°C under N2 atmosphere for 1 hour. After completion of stirring, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Welch Ultimate XB-CN 250*50*10 μm; mobile phase: [hexane-EtOH (0.1% NH 3 .H 2 O)]; concentration gradient: 1%-40% B, 15 minutes) to obtain intermediate I-41 (150 mg, 31% yield) as a yellow solid.

[0583] MS(EI)m / z:[M+H] + 426.0

[0584] 1 H NMR (400MHz, CDCl3) δ = 8.20 (s, 1H), 7.92 (s, 1H), 7.55-7.51 (m, 1H), 7.48-7.43 (m, 1H), 5.21 (s, 2H), 4.07 (s, 2H), 3.21 (s, 3H), 1.22 (s, 6H).

[0585] Preparation Example 42: 7-Bromo-8-chloroisoquinolin-1(2H)-one (Intermediate I-42)

[0586]

[0587] Step 1: (E)-1-(3-Bromo-2-chlorophenyl)-N-(2,2-dimethoxyethyl)formaniline

[0588] To a mixture of 3-bromo-2-chloro-benzaldehyde (14 g, 63.7 mmol) in toluene (200 mL) was added 2,2-dimethoxyethylamine (6.71 g, 63.7 mmol), and the mixture was stirred at 125 ° C. for 64 hours. After stirring, the reaction mixture was concentrated under reduced pressure to obtain (E)-1-(3-bromo-2-chlorophenyl)-N-(2,2-dimethoxyethyl)methanimine (19 g, 97% yield) as a yellow oil.

[0589] 1H NMR (400MHz, DMSO-d6) δ = 8.68 (s, 1H), 7.94-7.86 (m, 2H), 7.34 (t, J = 7.6Hz, 1H), 4.64 (t, J = 5.4Hz, 1H), 3.78 (d, J = 5.4Hz, 2H), 3.30 (s, 6H).

[0590] Step 2: 7-Bromo-8-chloroisoquinoline

[0591] To a mixture of (E)-1-(3-bromo-2-chlorophenyl)-N-(2,2-dimethoxyethyl)formaniline (2 g, 6.52 mmol) in DCM (20 mL) was added trifluoromethanesulfonic acid (20 mL), and the mixture was stirred at 120 ° C for 0.5 hours. After that, the reaction mixture was cooled to 25 ° C and stirred at 25 ° C for 0.5 hours. After the stirring was completed, MeOH (200 mL) was added to the reaction mixture. The mixture was poured into NH3 . The organic layer was concentrated under reduced pressure. The residue was triturated with water at 25° C. for 30 minutes to afford 7-bromo-8-chloro-isoquinoline (820 mg, 51% yield) as a brown solid.

[0592] 1 H NMR (400MHz, DMSO-d6) δ = 9.56 (s, 1H), 8.68 (d, J = 5.6Hz, 1H), 8.06 (d, J = 8.8Hz, 1H), 7.96-7.94 (m, 2H).

[0593] Step 3: 7-Bromo-8-chloroisoquinoline 2-oxide

[0594] To a mixture of 7-bromo-8-chloroisoquinoline (820 mg, 3.38 mmol) in DCM (20 mL) was added m-CPBA (1.37 g, 6.76 mmol, 85% purity) and the mixture was stirred at 25 ° C for 16 hours. After stirring was completed, Na2O3S2 (50 mL) was added to the mixture. The mixture was concentrated under reduced pressure. The residue was extracted with EA (3x40 mL). The organic layer was concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, PE / EA / MeOH=1 / 0 / 0-0 / 10 / 1) to obtain 7-bromo-8-chloro-2-oxo-isoquinolin-2-ium (690 mg, 78% yield) as a yellow solid.

[0595] 1H NMR (400MHz, DMSO-d6) δ = 8.88 (s, 1H), 8.32 (d, J = 7.2Hz, 1H), 8.06 (d, J = 7.2Hz, 1H), 7.90 (s, 2H)

[0596] Step 4: 7-Bromo-8-chloroisoquinolin-1(2H)-one

[0597] A mixture of 7-bromo-8-chloro-2-oxidation-isoquinolin-2-ium (640 mg, 2.48 mmol) in Ac o (6 mL) was stirred at 120 ° C for 3 hours. After the completion of stirring, the mixture was concentrated under reduced pressure to obtain (7-bromo-8-chloro-1-isoquinoline) acetate (640 mg, crude product). A mixture of (7-bromo-8-chloro-1-isoquinoline) acetate (640 mg, 2.13 mmol) in NaOH (2M, 32.00 mL) and H o (8 mL) was stirred at 100 ° C for 1 hour. After the completion of stirring, the mixture was acidified to pH 6 with citric acid (5% aqueous solution) and extracted with DCM (3x100 mL). The combined organic layers were concentrated under reduced pressure to obtain intermediate I-42 (320 mg, 58% yield) as a yellow solid.

[0598] 1 H NMR (400MHz, CDCl3) δ = 10.76-10.32 (m, 1H), 7.86 (d, J = 8.4Hz, 1H), 7.32 (d, J = 8.4Hz, 1H), 7.19 (d, J = 6.8Hz, 1H), 6.48 (d, J = 7.2Hz, 1H).

[0599] Preparation Example 43: 7-Bromo-8-chloro-2-methylisoquinolin-1(2H)-one (Intermediate I-43)

[0600]

[0601] To intermediate I-42 (1.0g, 3.87mmol) and CH3I (1.10g, 7.74mmol) in DMF (10mL) solution add K2CO3 (1.60g, 11.6mmol) and TBAI (143mg, 387μmol). The mixture was stirred at 40 DEG C for 2 hours. After stirring was completed, at 25 DEG C, the reaction mixture was quenched by adding aqueous ammonium chloride solution (20mL), and then diluted with water (30mL) and extracted with EA (3x50mL). The combined organic layer was washed with salt water (3x20mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain residue. The residue was passed through column chromatography (SiO2, petroleum ether / ethyl acetate=2 / 1-1 / 1) purified to obtain intermediate I-43 (1.0g, 95% yield) as a yellow solid.

[0602] MS (EI) m / z: [M+H] + 274.0.

[0603] 1 H NMR (400MHz, CDCl3) δ = 7.83 (d, J = 8.8 Hz, 1H), 7.29 (s, 1H), 7.17 (d, J = 7.2 Hz, 1H), 6.41 (d, J = 7.2 Hz, 1H), 3.60 (s, 3H).

[0604] Preparation Examples 44 to 46

[0605] Intermediates I-44 to I-46 were prepared using Intermediate I-42 as a starting material in the same manner as in Preparation Example 43, except that an appropriate alkyl halide was used.

[0606]

Table 1

[0607]

[0608] Preparation Example 47: 7-Bromo-2-(2-methoxy-2-methylpropyl)isoquinolin-1(2H)-one (Intermediate I-47)

[0609]

[0610] Intermediate I-47 was obtained in the same manner as in Preparation Example 31, except that 7-bromoisoquinolin-1(2H)-one was used instead of 6-bromo-3-(2-hydroxy-2-methylpropyl)quinazolin-4(3H)-one in Preparation Example 31.

[0611] m / z ES+[M+H] + 310.0.

[0612] 1 H NMR (400MHz, CDCl3) δ = 8.57 (d, J = 2.0Hz, 1H), 7.71 (dd, J = 2.0, 8.4Hz, 1H), 7.38 (d, J = 8.4Hz ,1H),7.30(d,J=7.6Hz,1H),6.40(d,J=7.6Hz,1H),4.10(s,2H),3.23(s,3H),1.21(s,6H).

[0613] Preparation Example 48: 7-Bromo-2-methylisoquinolin-1(2H)-one (Intermediate I-48)

[0614]

[0615] To a solution of 7-bromoisoquinolin-1-ol (600 mg, 2.68 mmol) in DMA (8 mL) was added CsCO (2.62 g, 8.03 mmol) and MeI (760 mg, 5.36 mmol). The mixture was stirred at 50 ° C for 3 hours. After stirring was complete, at 25 ° C, the reaction mixture was quenched by adding aqueous ammonium chloride (20 mL), and then diluted with water (30 mL) and extracted with EA (3x50 mL). The combined organic layers were washed with brine (3x20 mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate=2 / 1-1 / 1) to obtain intermediate I-48 (600 mg, 94% yield) as a white solid.

[0616] MS(EI)m / z:[M+H]+238.0

[0617] 1 H NMR (400MHz, CDCl3) δ = 8.57 (d, J = 1.6Hz, 1H), 7.71 (dd, J = 1.6, 8.4Hz, 1H), 7.3 9(d,J=8.4Hz,1H), 7.09(d,J=7.2Hz,1H), 6.45(d,J=7.2Hz,1H), 3.61(s,3H).

[0618] Preparation Example 49: 7-((3-amino-5-chloropyrazin-2-yl)thio)-8-chloro-2-methylisoquinolin-1(2H)-one (Intermediate I-49)

[0619]

[0620] Intermediate I-49 was obtained in the same manner as in Preparation Example 41, except that Intermediate I-43 was used instead of Intermediate I-29 in Preparation Example 41.

[0621] MS(EI)m / z:[M+H]+352.9

[0622] 1 H NMR (400MHz, CDCl3) δ = 7.91 (s, 1H), 7.32 (s, 2H), 7.14 (d, J = 7.2Hz, 1H), 6.40 (d, J = 7.2Hz, 1H), 5.24-5.15 (m, 2H), 3.58 (s, 3H)

[0623] Preparation Examples 50 and 51

[0624] Intermediates I-50 and I-51 were prepared in the same manner as in Preparative Example 49 using appropriate intermediates as starting materials.

[0625]

Table 2

[0626]

[0627]

[0628] Preparation Example 52: (R)-2-Methyl-N-((R)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)propane-2-yl Sulfonamide (Intermediate I-52)

[0629]

[0630] Step 1: (R,E)-tert-Butyl 3-((tert-butylsulfinyl)imino)-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate

[0631] Using tert-butyl 3-oxospiro[benzofuran-2,4'-piperidine]-1'-carboxylate instead of tert-butyl 1-oxospiro[indan-2,4'-piperidine]-1'-carboxylate in Step 1 of Preparative Example 25, (R,E)-tert-butyl 3-((tert-butylsulfinyl)imino)-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate (5.4 g, 80% yield) was obtained.

[0632] m / z ES+[M+Na] + 429.2.

[0633] 1 H NMR (400MHz, DMSO-d6) δ = 8.28-8.20 (m, 1H), 7.71-7.64 (m, 1H), 7.23 (d, J = 8.4Hz, 1H), 7.20-7. 10(m,1H),3.36-3.33(m,2H),3.18-2.98(m,2H),1.76-1.70(m,4H),1.43(s,9H),1.22(s,9H).

[0634] Step 2: (R)-tert-Butyl 3-(((R)-tert-butylsulfinyl)amino)-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate To a solution of rac-(3E)-3-[(R)-tert-butylsulfinyl]iminospiro[benzofuran-2,4'-piperidine]-1'-carboxylic acid tert-butyl ester (5.2 g, 12.7 mmol) in DCM (40 mL) was added DIBALH (1 M, 19.2 mL). The mixture was stirred at -78 ° C for 1 hour. After stirring was complete, the reaction mixture was quenched by adding MeOH (10 mL) at -78 ° C, and then slowly warmed to 25 ° C and stirred for 0.5 hours. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate = 1 / 0-3 / 1) to afford tert-butyl rac-(3R)-3-[[(R)-tert-butylsulfinyl]amino]spiro[3H-benzofuran-2,4′-piperidine]-1′-carboxylate (3.4 g, 62% yield) as a yellow solid.

[0635] m / z ES+[M+Na] + 431.1.

[0636] 1 H NMR (400MHz, CDCl3) δ = 7.29 (s, 1H), 7.26-7.20 (m, 1H), 6.94-6.90 (m, 1H), 6.82 (d, J = 8.0Hz, 1H), 4.68-4.60 ( m,1H),4.21-3.99(m,2H),3.72-3.60(m,1H),3.26-3.10(m,2H),1.98-1.65(m,4H),1.47(s,9H),1.26(s,9H).

[0637] Step 3: (R)-2-Methyl-N-((R)-3H-spiro[benzofuran-2,4'-piperidin]-3-yl)propane-2-sulfenamide

[0638] Intermediate I-52 was obtained in the same manner as in Step 3 of Preparation Example 25 (2.2 g, 65% yield).

[0639] m / z ES+[M+H] + 309.1

[0640] Preparation Example 53: 5-((R)-3-(((R)-tert-Butylsulfinyl)amino)-3H-spiro[benzofuran-2,4'-piperidinyl]- [pyridyl]-1'-yl)pyrazine-2-thiolate sodium (Intermediate I-53)

[0641]

[0642] Intermediate 1-52 was used instead of Intermediate 1-25 in Step 1 of Preparative Example 26 to obtain Intermediate 1-53 (3.15 g, 85% yield).

[0643] m / z ES+[M+Na] + 441.1

[0644] Preparation Example 54: 6-Bromo-5-chloro-3-methylquinazolin-4(3H)-one (Intermediate I-54)

[0645]

[0646] Intermediate 1-21 was used instead of Intermediate 1-42 in Preparation Example 43 to obtain Intermediate 1-54 (2.5 g, 79% yield).

[0647] 1 H NMR (400MHz, DMSO-d6) δ = 8.45 (s, 1H), 8.10 (d, J = 8.8Hz, 1H), 7.54 (d, J = 8.8Hz, 1H), 3.45 (s, 3H).

[0648] Preparation Example 55: 6-Bromo-5-chloro-3-(methyl-d3)quinazolin-4(3H)-one

[0649]

[0650] Using CD3I instead of CH3I in Preparation Example 54, intermediate I-55 (100 mg, 75% yield) was obtained.

[0651] 1 H NMR (400MHz, DMSO-d6) δ = 10.01 (s, 1H), 7.73 (d, J = 8.8Hz, 1H), 7.52 (d, J = 8.8Hz, 1H)

[0652] m / z ES+[M+H] + 275.9

[0653] Example 1: (S)-6-((5-(6-amino-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4'-piperidin]-1'-yl)pyrrolidone (2-oxazin-2-yl)thio)-5-chloroquinazolin-4(3H)-one

[0654]

[0655] To a solution of intermediate I-4 (50 mg, 83.0 μmol) in methanol (5 mL) was added HCl / dioxane (4 M, 1.04 mL), and the mixture was stirred at 25 ° C for 0.5 hours. After the reaction was completed, the reaction mixture was concentrated under reduced pressure. The filtrate was purified by column chromatography to obtain the compound of example 1 (30 mg, 73% yield) as a yellow solid.

[0656] 1 H NMR (400MHz, DMSO-d6) δ=9.03(s,1H),8.50(s,1H),8.31(s,1H),8.22(s,1H),8.04(s,1H),7.51(d,J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),4.32-4.18 (m,3H),4.12(s,1H),3.39-3.35(m,1H),3.31-3.25(m,2H),2.88(d,J=13. 2Hz,2H),1.89-1.80(m,1H),1.71-1.60(m,3H); MS(EI)m / z:481.1[M-NH2] + .

[0657] Example 2: (S)-6-((5-(6-amino-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4'-piperidin]-1'-yl)pyrrolidone (2-oxazin-2-yl)thio)-5-chloro-3-methylquinazolin-4(3H)-one

[0658]

[0659] Step 1: (R)-N-[(6S)-1'-[5-(5-chloro-3-methyl-4-oxo-quinazolin-6-yl)sulfanylpyrazin-2-yl]spiro[4,6-dihydrocyclopenta[d]thiazol-5,4'-piperidin]-6-yl]-2-methyl-propane-2-sulfenamide

[0660] To a solution of intermediate I-4 (45 mg, 74.7 μmol) in DMF (1 mL) was added iodomethane (15.9 mg, 112 μmol), K CO (31.0 mg, 224 μmol) and TBAI (2.76 mg, 7.47 mmol), and the mixture was stirred at 25 ° C for 2 hours. The reaction was terminated with a NaHCO aqueous solution, and the mixture was extracted with EA. The EA layer was dried over MgSO , filtered, and then concentrated. The residue was purified by column chromatography to obtain (R) -N- [(6S) -1 '- [5- (5- chloro-3-methyl-4-oxo-quinazolin-6-yl) sulfanylpyrazin-2-yl] spiro [4,6- dihydrocyclopenta [d] thiazole -5,4'-piperidin] -6-yl] -2-methyl-propane-2-sulfinamide (15 mg, 33% yield) as a yellow solid.

[0661] 1H NMR (400MHz, DMSO-d6) δ = 9.06 (s, 1H), 8.50 (s, 1H), 8.35 (s, 1H), 8.31 (s, 1H), 7.50(d,J=8.8Hz,1H),7.18(d,J=8.8Hz,1H),5.97(d,J=10.0Hz,1H),4.51(d, J=10.0Hz,1H),4.39-4.26(m,2H),3.45(s,3H),3.28-3.17(m,2H),3.00-2.92 (m,1H),2.89-2.85(m,1H),1.93-1.84(m,1H),1.82-1.66(m,3H),1.13(s,9H).

[0662] Step 2: (S)-6-((5-(6-amino-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-5-chloro-3-methylquinazolin-4(3H)-one

[0663] The compound of Example 2 (5 mg, 40% yield) was synthesized in the same manner as in Example 1.

[0664] 1 H NMR (400MHz, DMSO-d6) δ=8.99(s,1H),8.49(d,J=1.2Hz,1H),8.36(s,1H),8.30(d,J= 1.2Hz,1H),8.23(s,1H),7.51(d,J=8.8Hz,1H),7.20(d,J=8.8Hz,1H),4.28-4.15(m,2 H),4.05(s,1H),3.44(s,3H),3.42-3.36(m,2H),3.34-3.26(m,2H),2.93-2.87(m,1H ),2.83-2.80(m,1H),1.89-1.78(m,1H),1.71-1.59(m,3H); MS(EI)m / z:495.2[M-NH2] + .

[0665] Examples 3 to 5:

[0666] The compounds of Examples 3 to 5 were prepared in the same manner as in Example 2, except that a suitable alkyl halide compound was used instead of (1R)-1-(3-bromophenyl)ethylamine in Example 2.

[0667]

Table 3

[0668]

[0669] Example 6: (S)-6-((5-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-1'-yl)pyridine (2-oxazin-2-yl)thio)-5-chloro-3-methylquinazolin-4(3H)-one

[0670]

[0671] Step 1: (R)-N-((S)-1'-(5-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-5-yl)-2-methylpropane-2-sulfenamide

[0672] To a solution of intermediate I-14 (80.0 mg, 208 μmol) and intermediate I-12 (64.1 mg, 208 μmol) in dioxane (3 mL) was added KCO (86.4 mg, 625 μmol), [2-(2-aminophenyl)phenyl]-chloro-palladium; dicyclohexyl-[2-(2,6-diisopropoxyphenyl)phenyl]phosphine (16.2 mg, 20.8 μmol) and RuPhos (19.4 mg, 41.7 μmol). The mixture was stirred at 100 ° C for 12 hours. After the reaction was complete, at 25 ° C, the reaction mixture was quenched by adding aqueous ammonium chloride (20 mL), and then diluted with water (20 mL) and extracted with EA (3x30 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 1-1 / 4) to afford (R)-N-((S)-1'-(5-((5-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-5-yl)-2-methylpropane-2-sulfenamide (70.0 mg, 55% yield) as a yellow solid.

[0673] 1 H NMR (400MHz, CDCl3) δ = 8.47 (d, J = 4.4Hz, 1H), 8.29 (d, J = 1.2Hz, 1H), 8.24 (d, J=1.2Hz,1H),8.03-8.00(m,2H),7.46(d,J=8.8Hz,1H),7.30(s,1H),7.20(d d,J=5.2,7.6Hz,1H),4.33-4.24(m,2H),3.57(s,4H),3.34-3.24(m,4H),2.9 4(d,J=16.4Hz,1H),1.80-1.75(m,2H),1.46(d,J=12.0Hz,2H),1.27(s,9H).

[0674] Step 2: (S)-6-((5-(5-amino-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-5-chloro-3-methylquinazolin-4(3H)-one

[0675] The compound of Example 6 (25.6 mg, 62% yield) was synthesized in the same manner as in Example 1.

[0676] 1 H NMR (400MHz, DMSO-d6) δ = 8.49 (s, 1H), 8.38-8.29 (m, 3H), 7.68 (d, J = 7.6Hz, 1H), 7.52(d,J=8.8Hz,1H),7.24-7.16(m,2H),4.34-4.27(m,2H),3.95(s,1H),3.45( s,3H),3.28-3.21(m,2H),3.14(d,J=16.4Hz,1H),2.80(d,J=16.0Hz,1H),1.85- 1.70(m,2H),1.62-1.53(m,1H),1.20(d,J=13.2Hz,1H); MS(EI)m / z:506.2[M+H] + .

[0677] Example 7: (S)-6-((5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazin-2-yl)sulfur (substituted)-5-chloro-3-methylquinazolin-4(3H)-one

[0678]

[0679] The compound of Example 7 was synthesized in the same manner as in Example 6, using Intermediate I-13 instead of Intermediate I-12 in Step 1 of Example 6 (32 mg, 77% yield).

[0680] 1 H NMR (400MHz, DMSO-d6) δ = 8.49 (s, 1H), 8.38-8.36 (m, 1H), 8.31 (d, J = 0.8Hz, 1H), 8.27 (s, 1 H),7.52(d,J=8.8Hz,1H),7.39-7.36(m,1H),7.24-7.20(m,4H),4.30(d,J=13.6Hz,2H),4. 01(s,1H),3.45(s,3H),3.24(d,J=12.0Hz,2H),3.13(d,J=15.6Hz,1H),2.76(d,J=15.6Hz, 1H),1.82-1.68(m,2H),1.55(d,J=12.8Hz,1H),1.29-1.24(m,1H); MS(EI)m / z:506.1[M+H] + .

[0681] Example 8: (S)-6-((3-amino-5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazine-2- (2-(2-methoxyethyl)quinazolin-4(3H)-one)-5-chloro-3-(2-methoxyethyl)thioxo

[0682]

[0683] Step 1: (R)-N-((S)-1'-(6-amino-5-((5-chloro-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfenamide

[0684] To a solution of intermediate I-6 (50 mg, 126 μmol) in DMSO (1 mL) was added DIEA (811 mg, 6.28 mmol) and intermediate I-13 (38.5 mg, 126 μmol), and the mixture was stirred at 100 ° C for 12 hours. The reaction mixture was added into an aqueous ammonium chloride solution and extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The residue was purified by column chromatography to obtain (R)-N-((S)-1'-(6-amino-5-((5-chloro-3-(2-methoxyethyl)-4-oxo-3,4-dihydroquinazoline-6-yl)thio)pyrazine-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (15 mg, 33% yield) as a yellow solid.

[0685] 1 H NMR (400MHz, CDCl3) δ = 8.02 (s, 1H), 7.67 (s, 1H), 7.50-7.46 (m, 1H), 7.35-7.31 (m, 1H),7.27-7.22(m,3H),7.15(d,J=8.8Hz,1H),4.35-4.29(m,2H),4.17-4.11(m,2H) ,3.70-3.67(m,3H),3.33(s,3H),3.20-3.13(m,2H),3.12-3.06(m,1H),2.79(d,J= 15.6Hz,1H),1.89-1.86(m,1H),1.75-1.69(m,1H),1.42-1.36(m,2H),1.31(s,9H).

[0686] Step 2: (S)-6-((3-amino-5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-methoxyethyl)quinazolin-4(3H)-one

[0687] The compound of Example 8 (25 mg, 59% yield) was synthesized in the same manner as in Example 1.

[0688] 1 H NMR (400MHz, CDCl3) δ = 8.02 (s, 1H), 7.69 (s, 1H), 7.46 (d, J = 8.8Hz, 1H), 7.34 (d, J = 5.2Hz, 1H), 7.2 6-7.22(m,3H),7.17(d,J=8.8Hz,1H),4.86(s,2H),4.27-4.19(m,2H),4.18-4.13(m,2H),4.01(s, 1H),3.69(t,J=4.8Hz,2H),3.33(s,3H),3.27-3.17(m,2H),3.11(d,J=15.6Hz,1H),2.75(d,J=15. 6Hz,1H),1.87(d,J=4.4Hz,1H),1.86-1.73(m,2H),1.39(d,J=12.0Hz,1H); MS(EI)m / z:564.3[M+H] + .

[0689] Example 9: 6-((3-amino-5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazine-2- (2-(3H)-1-(4-(2-methoxypropyl)quinazolin-4-one)-3-(2-methoxypropyl)thioxo)-5-chloro-3-(2-methoxypropyl)quinazolin-4-one

[0690]

[0691] The compound of Example 9 was synthesized in the same manner as in Example 6, using Intermediate I-7 instead of Intermediate I-6 in Step 1 of Example 6 (5.10 mg, 20% yield).

[0692] 1 H NMR (400MHz, CDCl3) δ = 8.03 (s, 1H), 7.68 (s, 1H), 7.42 (d, J = 7.2Hz, 2H), 7.31-7.28 (m, 1H), 7.26 (s, 2H),7.15(d,J=8.8Hz,1H),4.96(d,J=11.6Hz,2H),4.39-4.32(m,1H),4.24-4.14(m,2H),4.08(s,1H ),3.73-3.68(m,1H),3.59-3.50(m,1H),3.27(d,J=3.2Hz,3H),3.22-3.16(m,2H),3.12(s,1H),2.8 7-2.80(m,1H),1.62-1.58(m,2H),1.52-1.46(m,2H),1.26(d,J=2.0Hz,3H); MS(EI)m / z:578.3[M+H] + .

[0693] Example 10: (S)-6-((3-amino-5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazine- 2-amino)thio)-5-chloro-3-methylquinazolin-4(3H)-one

[0694]

[0695] The compound of Example 10 was synthesized in the same manner as in Example 6, using Intermediate I-15 instead of Intermediate I-6 in Step 1 of Example 6 (5.85 mg, 13% yield).

[0696] 1 H NMR (400MHz, DMSO-d6) δ = 8.48 (br s, 3H), 7.72 (s, 1H), 7.58-7.52 (m, 3H), 7.36-7.28 (m, 3H), 6.98 (d, J = 8.8Hz, 1H), 6.18 (br s,2H),4.44-4.30(m,3H),3.46(s,3H),3.22-3.14(m,3H),3.05-2.96(m,1H),1.82-1.72(m,2H),1.54-1.49(m,2H); MS(EI)m / z:520.2[M+H] + .

[0697] Example 11: (S)-6-((3-amino-5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazine- 2-amino)thio)-5-chloro-3-(2-hydroxy-2-methylpropyl)quinazolin-4(3H)-one

[0698]

[0699] Step 1: (R)-N-((S)-1'-(6-amino-5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfenamide

[0700] (R)-N-((S)-1'-(6-amino-5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfenamide (90 mg, 50% yield) was synthesized by the same method as Example 8, using intermediate I-17 as the starting material instead of intermediate I-6 in step 1 of Example 8.

[0701] 1H NMR (400MHz, CDCl3) δ = 7.86 (s, 1H), 7.54 (s, 1H), 7.39 (d, J = 8.8Hz, 1H), 7.27-7.23 ( m,2H),7.17(s,2H),7.02(d,J=8.4Hz,1H),4.52(d,J=10.0Hz,1H),4.18(dd,J=4.0, 8.4Hz,2H),3.80(d,J=10.0Hz,1H),3.11-2.95(m,4H),2.72-2.63(m,2H),2.26-2.1 9(m,1H),1.88-1.83(m,1H),1.27(s,9H),1.21-1.15(m,2H); MS(EI)m / z:610.2[M+H] + .

[0702] Step 2: (R)-N-((S)-1'-(6-amino-5-((5-chloro-3-(2-hydroxy-2-methylpropyl)-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfenamide

[0703] To a solution of (R)-N-((S)-1'-(6-amino-5-((5-chloro-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfinamide (35.0 mg, 57.7 μmol) and 2,2-dimethyloxirane (74.9 mg, 1.04 mmol) in DMF (1 mL) was added CsCO (56.4 mg, 173 μmol). The mixture was stirred at 80 °C for 12 hours. After completion of the reaction, the reaction mixture was quenched by the addition of aqueous ammonium chloride (20 mL) at 25 °C and then diluted with water (30 mL) and extracted with EA (3 x 20 mL). The organic layer merged is washed with salt water (3x20mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain residue.Residue is purified by preparative HPLC, to obtain (R)-N-((S)-1'-(6-amino-5-((5-chloro-3-(2-hydroxy-2-methylpropyl)-4-oxo-3,4-dihydroquinazoline-6-yl)thio)pyrazine-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidine]-1-yl)-2-methylpropane-2-sulfinamide (15.0 mg, 38% yield) as a yellow solid.

[0704] 1H NMR (400MHz, DMSO-d6) δ = 8.20 (s, 1H), 7.68 (s, 1H), 7.51 (d, J = 8.8Hz, 1H), 7.26 (s, 2H), 7 .24-7.22(m,1H),7.20-7.17(m,2H),6.98(d,J=8.8Hz,1H),6.17(s,2H),4.82(s,1H),4.0 6(s,2H),3.96(s,2H),3.25(d,J=11.2Hz,2H),3.17(d,J=5.2Hz,1H),3.12-3.07(m,1H),2 .83-2.61(m,2H),2.55(s,2H),1.61-1.56(m,2H),1.42(s,9H),1.24(s,2H),1.12(s,6H).

[0705] Step 3: (S)-6-((3-amino-5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-hydroxy-2-methylpropyl)quinazolin-4(3H)-one

[0706] The compound of Example 11 (4.63 mg, 36% yield) was synthesized in the same manner as in Example 1.

[0707] 1 H NMR (400MHz, DMSO-d6) δ=8.20-8.17(m,1H),7.69(s,1H),7.52(d,J=8.8Hz,1H),7.44-7 .39(m,1H),7.29-7.23(m,3H),6.98(d,J=8.8Hz,1H),6.16(s,2H),4.82(s,1H),4.25(d J=12.0Hz,2H),4.12(s,1H),3.95(s,2H),3.15(d,J=2.4Hz,4H),2.85-2.81(m,2H),1.77-1 .66(m,2H),1.54-1.49(m,1H),1.32(d,J=14.8Hz,1H),1.11(s,6H);MS(EI)m / z:578.3[M+H] + .

[0708] Example 12: 6-((3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8- (3-Benzyl)-5-chloroquinazolin-4(3H)-one

[0709]

[0710] The compound of Example 12 (12.1 mg, 23% yield) was synthesized by the same method as in Step 1 of Example 6, using Intermediate I-16 instead of Intermediate I-6 in Step 1 of Example 6, and using (3S,4S)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-amine instead of Intermediate I-13 as the starting material.

[0711] 1 H NMR (400MHz, DMSO-d6) δ = 8.55 (s, 1H), 7.66 (s, 1H), 7.55-7.52 (m, 1H), 7.35 (d, J = 4.4Hz, 4H), 7 .30(d,J=4.4Hz,1H),7.00-6.96(m,1H),6.16-6.10(m,2H),5.15(s,2H),4.10-4.06(m,1H),3. 90-3.84(m,2H),3.69(d,J=8.4Hz,2H),3.51(d,J=8.4Hz,2H),2.96(d,J=5.2Hz,1H),1.76-1.6 9(m,1H),1.67-1.60(m,1H),1.56-1.45(m,2H),1.09(d,J=6.4Hz,3H); MS(EI)m / z:564.2[M+H] + .

[0712] Example 13: 6-((3-amino-5-(4-(aminomethyl)-4-methylpiperidin-1-yl)pyrazin-2-yl)thio)-3- Benzyl-5-chloroquinazolin-4(3H)-one

[0713]

[0714] The compound of Example 13 (15.1 mg, 60% yield) was synthesized by the same method as Example 6, using intermediate I-16 instead of intermediate I-6 in step 1 of Example 6, and using tert-butyl N-[(4-methyl-4-piperidinyl)methyl]carbamate instead of intermediate I-13 as the starting material.

[0715] 1 H NMR (400MHz, DMSO-d6) δ = 8.55 (s, 1H), 7.65 (s, 1H), 7.52 (s, 1H), 7.38-7.33 (m, 4H), 7.32-7.27 (m, 1H), 6.98 (d, J = 8.8Hz, 1H), 6.12 (s, 2H), 5.15(s,2H),3.89-3.83(m,2H),3.33(s,2H),2.65-2.60(m,2H),1.52-1.44(m,2H),1.40-1.32(m,2H),1.01(s,3H); MS(EI)m / z:522.8[M+H] + .

[0716] Example 14: 7-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazine- 2-(2-methoxypropyl)isoquinolin-1(2H)-one

[0717]

[0718] Step 1: tert-Butyl ((3S,4S)-8-(5-((8-chloro-1-oxo-1,2-dihydroisoquinolin-7-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate

[0719] Intermediate I-9 (150 mg, 0.58 mmol), intermediate I-8 (235 mg, 0.58 mmol), Pd2(dba)3 (53 mg, 0.058 mmol) and XantPhos (67.1 mg, 0.116 mmol) were dissolved in 1,4-dioxane (10 mL), and DIPEA (224 mg, 1.74 mmol) was added. The reaction mixture was purged with nitrogen and then stirred at 100 ° C for 2 hours. The reaction was terminated with H2O, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The resulting product was separated by preparative HPLC and concentrated to afford tert-butyl ((3S,4S)-8-(5-((8-chloro-1-oxo-1,2-dihydroisoquinolin-7-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate (100 mg, 30% yield).

[0720] 1 H NMR (400MHz, CDCl3) δ = 10.28-10.14 (m, 1H), 8.25 (s, 1H), 8.18 (s, 1H), 7.24 (s,1H),7.14(d,J=8.4Hz,1H),7.06(d,J=4.0Hz,1H),6.38(d,J=7.2Hz,1H) ,4.28-4.22(m,2H),4.16(d,J=13.6Hz,1H),3.92(d,J=9.2Hz,1H),3.68(d, J=9.2Hz,1H),3.56-3.48(m,2H),3.24-3.12(m,2H),2.08-1.94(m,2H),1.76 -1.72(m,2H),1.28(s,9H),1.24(d,J=6.4Hz,3H).

[0721] Step 2: tert-Butyl ((3S,4S)-8-(5-((8-chloro-2-(2-methoxypropyl)-1-oxo-1,2-dihydroisoquinolin-7-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate

[0722] To a solution of tert-butyl ((3S,4S)-8-(5-((8-chloro-1-oxo-1,2-dihydroisoquinolin-7-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate (50 mg, 88.9 μmol) in DMF (2 mL) was added 2-methoxypropyl 4-methylbenzenesulfonate (65.1 mg, 266 μmol), K2CO3 (49.1 mg, 355 μmol), and TBAI (3.29 mg, 8.89 μmol), and the mixture was stirred at 80°C for 24 hours. Water was added to the reaction mixture, and the mixture was extracted with EA. The EA layer was dried over MgSO4, filtered, and then concentrated. The residue was purified by column chromatography to afford tert-butyl ((3S,4S)-8-(5-((8-chloro-2-(2-methoxypropyl)-1-oxo-1,2-dihydroisoquinolin-7-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate (40 mg, 70% yield) as a yellow solid.

[0723] 1 H NMR(400MHz, CDCl3)δ=8.22(d,J=14.8Hz,1H),7.82(d,J=8.0Hz,2H),7.36(d,J=8.0Hz,2H),7.18-7.14(m,1H),6 .32(d,J=7.2Hz,1H),4.32(dd,J=2.4,13.2Hz,1H),4.26-4.22(m,1H),4.20-4.12(m,1H),3.96(d,J=5.2Hz,2H),3 .92(d,J=9.2Hz,1H),3.82-3.74(m,1H),3.58-3.52(m,1H),3.38(d,J=10.4Hz,1H),3.30(s,3H),3.26(s,2H),2. 10-1.96(m,1H),1.82-1.76(m,2H),1.74-1.62(m,1H),1.26(s,9H),1.24(t,J=6.8Hz,3H),1.12(d,J=6.4Hz,3H).

[0724] Step 3: 7-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-8-chloro-2-(2-methoxypropyl)isoquinolin-1(2H)-one

[0725] The compound of Example 14 (15.3 mg, 50% yield) was synthesized in the same manner as in Example 1.

[0726] 1 H NMR (400MHz, METHANOL-d4) δ = 8.30 (d, J = 1.2Hz, 1H), 8.26 (s, 1H), 7.40 (d, J = 8.8Hz, 1H), 7.34 (d, J = 7.4Hz, 1H ),7.16(d,J=8.8Hz,1H),6.54(d,J=7.2Hz,1H),4.29-4.26(m,1H),4.24-4.20(m,1H),4.18-4.13(m,2H),3.92 (d,J=9.2Hz,1H),3.82-3.74(m,3H),3.40-3.34(m,1H),3.26(s,3H),3.26-3.24(m,1H),3.20(d,J=4.8Hz,1H ),1.88-1.78(m,3H),1.74-1.66(m,1H),1.26(d,J=6.4Hz,3H),1.20(d,J=5.6Hz,3H); MS(EI)m / z:530.3[M+H] + .

[0727] Example 15: 7-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazine- 2-Methylisoquinolin-1(2H)-one

[0728]

[0729] Step 1: tert-Butyl ((3S,4S)-8-(5-((8-chloro-2-methyl-1-oxo-1,2-dihydroisoquinolin-7-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate

[0730] To a solution of tert-butyl ((3S,4S)-8-(5-((8-chloro-1-oxo-1,2-dihydroisoquinolin-7-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate (25.0 mg, 44.4 μmol) in DMF (2 mL) was added KCO (15.3 mg, 111 μmol) and MeI (25.2 mg, 177 μmol). The mixture was stirred at 25 °C for 12 h. After completion of the reaction, the reaction mixture was partitioned between EA (30 mL) and H0 (20 mL). The organic layer was separated, washed with aqueous NaCl (20 mL), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC to afford tert-butyl ((3S,4S)-8-(5-((8-chloro-2-methyl-1-oxo-1,2-dihydroisoquinolin-7-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate as a yellow solid (6.00 mg, 23% yield).

[0731] 1 H NMR (400MHz, CDCl3) δ = 8.26 (d, J = 1.2Hz, 1H), 8.21-8.17 (m, 1H), 7.25-7.23 (m, 1H), 7. 12(d,J=8.4Hz,1H),7.07(d,J=7.2Hz,1H),6.35(d,J=7.2Hz,1H),4.26(s,2H),4.19-4. 13(m,1H),3.94-3.89(m,1H),3.70(d,J=9.2Hz,1H),3.57(s,3H),3.55-3.50(m,1H),3. 24-3.14(m,2H),2.07-1.97(m,2H),1.78-1.70(m,2H),1.27(s,9H),1.25-1.23(m,3H).

[0732] Step 2: 7-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-8-chloro-2-methylisoquinolin-1(2H)-one

[0733] The compound of Example 15 (3.12 mg, 37% yield) was synthesized in the same manner as in Example 1.

[0734] 1H NMR(400MHz,MeOD)δ=8.57-8.47(m,1H),8.33-8.28(m,2H),7.44-7.36(m,2H),7.18( d,J=8.4Hz,1H),6.58(d,J=7.2Hz,1H),4.36-4.28(m,2H),4.27-4.20(m,1H),4.02-3 .95(m,1H),3.87(d,J=9.2Hz,1H),3.58(s,3H),3.38-3.35(m,2H),3.28-3.21(m,1H) ,1.91-1.81(m,3H),1.77-1.69(m,1H),1.32(d,J=6.4Hz,3H); MS(EI)m / z:472.2[M+H] + .

[0735] Example 16: (S)-7-((5-(6-amino-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4'-piperidin]-1'-yl)pyrrolidone (2-oxazin-2-yl)thio)-8-chloro-2-methylisoquinolin-1(2H)-one

[0736]

[0737] The compound of Example 16 (20.7 mg, 80% yield) was synthesized in the same manner as Example 14, using Intermediate I-11 instead of Intermediate I-9 in Step 1 of Example 14, and Intermediate I-10 instead of Intermediate I-8 as starting materials.

[0738] 1 H NMR (400MHz, MeOD) δ = 9.14 (s, 1H), 8.35 (d, J = 1.2Hz, 1H), 8.29 (d, J = 1.2Hz, 1H), 7.40 (dd, J = 8.0,11.6Hz,2H),7.17(d,J=8.0Hz,1H),6.57(d,J=7.2Hz,1H),4.54-4.48(m,1H),4.48-4.45 (m,1H),4.37(d,J=14.2Hz,1H),3.57(s,3H),3.40-3.38(m,1H),3.30-3.24(m,1H),3.22-3.1 6(m,1H),3.09-3.03(m,1H),1.99-1.90(m,2H),1.88-1.77(m,2H); MS(EI)m / z:494.2[M-NH2] + .

[0739] Example 17: (S)-6-((5-(6-amino-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4'-piperidin]-1'-yl)pyrrolidone (2-oxazin-2-yl)thio)-3-methylquinazolin-4(3H)-one

[0740]

[0741] The compound of Example 17 (16 mg, 85% yield) was synthesized in the same manner as in Example 6, using Intermediate I-18 instead of Intermediate I-14 in Step 1 of Example 6, and Intermediate I-2 instead of Intermediate I-12 as starting materials.

[0742] 1 H NMR (400MHz, CDCl3) δ = 8.78 (s, 1H), 8.23 (d, J = 1.4Hz, 1H), 8.19-8.16 (m, 1 H),8.15(d,J=1.9Hz,1H),8.07-8.05(m,1H),7.71-7.66(m,1H),7.64-7.60 (m,1H),4.29-4.22(m,1H),4.20-4.12(m,2H),3.59-3.56(m,3H),3.39-3. 25(m,2H),3.03-2.89(m,2H),1.84-1.78(m,4H); MS(EI)m / z:461.1[M-NH2] + .

[0743] Example 18: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazine- 2-amino-3-(2-methoxy-2-methylpropyl)quinazolin-4(3H)-one

[0744] [Synthesis Method 1]

[0745]

[0746] Step 1: Tert-butyl ((3S,4S)-8-(5-((5-chloro-3-(2-methoxy-2-methylpropyl)-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate

[0747] To a mixture of intermediate I-19 (300 mg, 532 μmol), 2-methoxy-2-methylpropyl trifluoromethanesulfonate (136 mg, 586 μmol), TBAI (19.6 mg, 53.2 μmol) and KCO (220 mg, 1.60 mmol) in DMF (1 mL) was added TBAI (19.6 mg, 53.2 μmol) at 25° C. The mixture was stirred at 80° C. for 16 hours. After the reaction was complete, the mixture was filtered and the filtrate was concentrated. The residue was purified by reverse phase HPLC (0.1% FA conditions) to afford tert-butyl ((3S,4S)-8-(5-((5-chloro-3-(2-methoxy-2-methylpropyl)-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)carbamate (300 mg, 87% yield) as a yellow solid.

[0748] 1 H NMR (400MHz, CDCl3) δ = 8.27 (d, J = 1.2Hz, 1H), 8.19 (d, J = 1.2Hz, 1H), 8.15 (s, 1H), 7.47 (d, J =8.8Hz,1H),7.25(s,1H),4.64(d,J=10.8Hz,1H),4.24-4.16(m,1H),4.07(s,2H),4.02(dd, J=4.4,10.8Hz,1H),3.86(dd,J=3.6,9.6Hz,1H),3.82-3.76(m,1H),3.73-3.67(m,2H),3.66 -3.60(m,1H),3.56-3.47(m,1H),1.94-1.68(m,4H),1.46(s,9H),1.23(s,3H),1.21(s,6H).

[0749] Step 2: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-methoxy-2-methylpropyl)quinazolin-4(3H)-one

[0750] The compound of Example 18 (27.1 mg, 93% yield) was synthesized in the same manner as in Example 1.

[0751] 1 H NMR (400MHz, CDCl3) δ = 8.26 (s, 1H), 8.21-8.18 (m, 1H), 8.15 (s, 1H), 7.42 (d, J = 8.8Hz ,1H),7.21(d,J=8.8Hz,1H),4.28-4.20(m,2H),4.20-4.17(m,1H),4.06(s,2H),3.98 (d,J=9.2Hz,1H),3.79(d,J=9.2Hz,1H),3.27(d,J=4.4Hz,1H),3.21(s,3H),3.16-3. 14(m,1H),3.13-3.05(m,1H),1.97-1.75(m,4H),1.33(d,J=6.4Hz,3H),1.21(s,6H).

[0752] MS (EI) m / z: 545.3 [M+H] + .

[0753] [Synthesis Method 2]

[0754] The compound of Example 18 (88.5 mg, 57% yield) was synthesized in the same manner as Example 25, using Intermediate I-24 instead of Intermediate I-26 in Step 1 of Example 25, and Intermediate I-29 instead of Intermediate I-28 as starting materials.

[0755] 1 H NMR (400MHz, CDCl3) δ = 8.27 (d, J = 1.2Hz, 1H), 8.21 (d, J = 1.2Hz, 1H), 8.15 (s, 1H), 7.45 (d, J = 8.8Hz,1H),7.28-7.26(m,1H),4.25-4.17(m,1H),4.07(s,2H),4.02-3.89(m,2H),3.84(d,J =8.8Hz,1H),3.71(d,J=8.8Hz,1H),3.55-3.45(m,1H),3.44-3.35(m,1H),3.21(s,3H),3.02 (d,J=4.4Hz,1H),1.97-1.87(m,1H),1.85-1.67(m,3H),1.26(d,J=6.4Hz,3H),1.21(s,6H).

[0756] MS (EI) m / z: 545.3 [M+H] + .

[0757] Examples 19 to 21:

[0758] The compounds of Examples 19 to 21 were prepared in the same manner as in Example 18, except that a compound having an appropriate trifluoromethanesulfonate functional group was used instead of 2-methoxy-2-methylpropyl trifluoromethanesulfonate in Synthesis Method 1 of Example 18.

[0759]

Table 4

[0760]

[0761] Example 22: (R)-6-((5-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazin-2-yl)sulfur (2-(2-methoxyethyl)-5-chloro-3-(2-methoxyethyl)quinazolin-4(3H)-one

[0762]

[0763] The compound of Example 22 (27 mg, 58% yield) was synthesized by the same method as Example 18, using Intermediate I-20 instead of Intermediate I-19 in Step 1 of Example 18, and using 2-bromoethyl methyl ether instead of 2-methoxy-2-methylpropyl trifluoromethanesulfonate as the starting material.

[0764] 1H NMR(500MHz,DMSO)δ8.67(bs,2H),8.57(s,1H),8.36(s,1H),8.29(s,1H),7.63(d,J=7.4H z,1H),7.53(d,J=8.8Hz,1H),7.37(t,J=8.0Hz,1H),7.27(d,J=8.8Hz,2H),7.04-6.98(m,2 H),4.68(d,J=4.7Hz,1H),4.56-4.53(m,1H),4.41-4.39(m,1H),4.13(t,J=5.0Hz,2H),3. 61(t,J=5.0Hz,2H),3.26(s,3H),2.13-2.00(m,2H),1.91-1.80(m,2H); MSm / z:552.0[M+H] + .

[0765] Example 23: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazine- 2-yl)thio)-5-chloro-3-((4-methyltetrahydro-2H-pyran-4-yl)methyl)quinazolin-4(3H)-one

[0766]

[0767] Step 1: N-((3S,4S)-8-(5-((5-chloro-3-((4-methyltetrahydro-2H-pyran-4-yl)methyl)-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)-2-methylpropane-2-sulfenamide

[0768] To a solution of intermediate I-23 (100 mg, 177 μmol) and intermediate I-27 (101 mg, 355 μmol) in DMF (6 mL) was added KCO (73.6 mg, 532 μmol) and TBAI (9.84 mg, 26.6 μmol). The mixture was stirred at 100 ° C for 12 hours. After stirring was complete, the reaction mixture was distributed between EA (40 mL) and H O (20 mL). The organic layer was separated, washed with a NaCl aqueous solution (20 mL), dried over Na SO, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenexluna C18 150*25mm*10μm; mobile phase: [water (FA)-ACN]; concentration gradient: 41%-71% B, 10 minutes) to obtain N-[(3S,4S)-8-[5-[5-chloro-3-[(4-methyltetrahydropyran-4-yl)methyl]-4-oxo-quinazolin-6-yl]sulfanylpyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl]-2-methyl-propane-2-sulfinamide (40.0 mg, 33% yield) as a white solid.

[0769] 1 H NMR (400MHz, CDCl3) δ = 8.19 (d, J = 1.2Hz, 1H), 8.12 (d, J = 1.2Hz, 1H), 7.85 (s, 1H), 7.38 (d, J = 8.8Hz, 1H), 7.19-7.16 (m, 1H) ,4.22-4.14(m,2H),4.10(dd,J=4.0,13.6Hz,1H),3.88-3.86(m,2H),3.85(s,1H),3.78-3.73(m,2H),3.64-3.54(m,3H),3. 46(dd,J=5.6,10.4Hz,1H),3.30(d,J=10.4Hz,1H),3.18-3.13(m,1H),3.12-3.07(m,1H),2.03-1.96(m,1H),1.95-1.86(m ,1H),1.70-1.61(m,1H),1.62-1.57(m,1H),1.30(d,J=13.6Hz,2H),1.20-1.19(m,9H),1.16(d,J=6.4Hz,3H),1.03(s,3H).

[0770] Step 2: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-5-chloro-3-((4-methyltetrahydro-2H-pyran-4-yl)methyl)quinazolin-4(3H)-one

[0771] To a solution of N-[(3S,4S)-8-[5-[5-chloro-3-[(4-methyltetrahydropyran-4-yl)methyl]-4-oxo-quinazolin-6-yl]sulfanylpyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl]-2-methyl-propane-2-sulfinamide (40.0 mg, 59.2 μmol) in MeOH (4 mL) was added HCl / dioxane (4 M, 1 mL). The mixture was stirred at 25° C. for 0.5 hours. After completion of stirring, the reaction mixture was filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water(FA)-ACN]; concentration gradient: 18%-48% B, 7 minutes) to obtain the compound of Example 23 (24.6 mg, 69% yield) as a white solid.

[0772] MS(EI)m / z:[M+H] + 571.2.

[0773] 1 H NMR (400MHz, MeOD) δ = 8.35 (d, J = 1.2Hz, 1H), 8.31 (d, J = 1.2Hz, 1H), 8.24 (s, 1H), 7.49 (d, J = 8.8Hz, 1H), 7.30 (d, J =8.8Hz,1H),4.38-4.30(m,2H),4.30-4.23(m,1H),4.04(s,2H),4.02-3.98(m,1H),3.89(d,J=9.2Hz,1H),3.83( d,J=4.4,11.6Hz,2H),3.72-3.65(m,2H),3.40(d,J=4.4Hz,1H),3.31-3.19(m,2H),1.91-1.87(m,2H),1.86-1.8 1(m,1H),1.75(s,1H),1.71-1.63(m,2H),1.42(d,J=2.8Hz,1H),1.38(s,1H),1.33(d,J=6.4Hz,3H),1.11(s,3H).

[0774] Example 24: 3-(6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrrolidone (4H)-1-oxoquinazolin-2-yl)thio)-5-chloro-4-oxoquinazolin-3(4H)-yl)propionitrile

[0775]

[0776] Step 1: N-((3S,4S)-8-(5-((5-chloro-3-(2-cyanoethyl)-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)-2-methylpropane-2-sulfenamide

[0777] To a solution of intermediate I-23 (50 mg, 88.7 μmol) and TEA (44.9 mg, 443 μmol) in EtOH (1 mL) was added propanenitrile (47.1 mg, 887 μmol). The reaction mixture was stirred at 80 ° C for 2 hours. After stirring was complete, water (20 ml) was added to the reaction mixture and extracted with EA (3x30 ml). The combined organic layer was dried under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (FA)-ACN]; concentration gradient: 28%-68% B, 10 minutes) to obtain N-[(3S,4S)-8-[5-[5-chloro-3-(2-cyanoethyl)-4-oxo-quinazolin-6-yl]sulfanylpyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl]-2-methyl-propane-2-sulfinamide (45 mg, 85% yield) as a white solid.

[0778] 1 H NMR (400MHz, DMSO-d6) δ = 8.48 (d, J = 1.2Hz, 1H), 8.40 (s, 1H), 8.30 (d, J = 1.2Hz, 1H), 7.53 (d, J=8.8Hz,1H),7.21(d,J=8.8Hz,1H),5.13(d,J=12.0Hz,1H),4.24-4.20(m,3H),4.19-4.07(m ,2H),3.89(d,J=8.8Hz,1H),3.52(d,J=8.8Hz,1H),3.46-3.40(m,1H),3.23-3.12(m,2H),3.0 3(t,J=6.4Hz,2H),1.85-1.71(m,2H),1.68-1.53(m,2H),1.16(s,9H),1.10(d,J=6.4Hz,3H).

[0779] Step 2: 3-(6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-5-chloro-4-oxoquinazolin-3(4H)-yl)propionitrile

[0780] To a solution of N-[(3S,4S)-8-[5-[5-chloro-3-(2-cyanoethyl)-4-oxo-quinazolin-6-yl]sulfanylpyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl]-2-methyl-propane-2-sulfinamide (60 mg, 97.3 μmol) in MeOH (2 mL) was added HCl / dioxane (0.5 mL). The reaction mixture was stirred at 25 ° C for 1 hour. After completion of stirring, the reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase HPLC (0.1% FA) to obtain the compound of Example 24 (42.92 mg, 78% yield) as a white solid.

[0781] MS(EI)m / z:[M+H] + 512.3.

[0782] 1 H NMR (400MHz, DMSO-d6) δ=8.47(s,1H),8.41(s,1H),8.30(d,J=1.2Hz,1H),8.24(s,1H),7.53(d,J=8.8Hz,1H),7.23(d,J=8.8Hz,1H),4.24-4.20(m 2H),4.12-4.07(m,1H),4.01-3.91(m,3H),3.74-3.70(m,2H),3.55-3.46(m,2H),3.39-3. 34(m,1H),3.07-3.00(m,3H),1.78-1.65(m,2H),1.61-1.49(m,2H),1.10(d,J=6.4Hz,3H).

[0783] Example 25: (S)-6-((5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazin-2-yl)sulfur (substituted)-5-chloro-3-(2-hydroxy-2-methylpropyl)quinazolin-4(3H)-one

[0784]

[0785] Step 1: N-((S)-1'-(5-((5-chloro-3-(2-hydroxy-2-methylpropyl)-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfenamide

[0786] A mixture of intermediate I-28 (75.0 mg, 226 μmol), intermediate I-26 (99.2 mg, 226 μmol), DIEA (87.7 mg, 678 μmol), Xantphos (26.1 mg, 45.2 μmol) and Pd2(dba)3 (31.0 mg, 33.9 μmol) in dioxane (5 mL) was degassed and purged with N2 three times, and then the mixture was stirred at 100°C under N2 atmosphere for 2 hours. After completion of stirring, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative TLC (petroleum ether / ethyl acetate=0 / 1) to give N-[(1S)-1′-[5-[5-chloro-3-(2-hydroxy-2-methyl-propyl)-4-oxo-quinazolin-6-yl]sulfanylpyrazin-2-yl]spiro[indan-2,4′-piperidin]-1-yl]-2-methyl-propane-2-sulfenamide (90.0 mg, 60% yield) as a white solid.

[0787] MS(EI)m / z:[M+H] + 667.2.

[0788] 1 H NMR (400MHz, DMSO-d6) δ = 8.51 (s, 1H), 8.32 (s, 1H), 8.22 (s, 1H), 7.51 (d, J = 8.8Hz, 1H), 7. 28-7.18(m,5H),5.69(d,J=10.8Hz,1H),4.82(s,1H),4.47(s,1H),4.49-4.43(m,1H),4.3 9(d,J=12.8Hz,2H),4.12-4.08(m,2H),3.96(s,1H),3.14-3.10(m,1H),2.78-2.72(m,1H) ,2.15-2.06(m,1H),1.78-1.64(m,2H),1.33-1.28(m,1H),1.24-1.19(m,9H),1.12(s,6H).

[0789] Step 2: (S)-6-((5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-hydroxy-2-methylpropyl)quinazolin-4(3H)-one

[0790] To a solution of N-[(1S)-1'-[5-[5-chloro-3-(2-hydroxy-2-methyl-propyl)-4-oxo-quinazolin-6-yl]sulfanylpyrazin-2-yl]spiro[indane-2,4'-piperidine]-1-yl]-2-methyl-propane-2-sulfinamide (120 mg, 179 μmol) in MeOH (5 mL) was added HCl / dioxane (3 mL). The mixture was stirred at 25 ° C for 0.5 hours. After the stirring was completed, the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: C18 150×30 mm; mobile phase: [water (FA)-ACN]; concentration gradient: 10%-40% B, 7 minutes) to obtain the compound of Example 25 (84.7 mg, 80% yield) as a white solid.

[0791] MS(EI)m / z:[M+H] + 563.3.

[0792] 1 H NMR (400MHz, DMSO-d6) δ = 8.48 (d, J = 1.2Hz, 1H), 8.30 (d, J = 1.2Hz, 1H), 8.21 (d, J = 4.4Hz, 2H), 7. 52(d,J=8.8Hz,1H),7.37-7.34(m,1H),7.23(s,1H),7.21(d,J=3.6Hz,3H),4.81(s,1H),4.31(s ,1H),4.28(d,J=1.6Hz,1H),3.97(s,1H),3.95(s,2H),3.13-3.09(m,2H),2.73(d,J=15.6Hz,1H ),1.83-1.77(m,1H),1.72-1.66(m,1H),1.55(d,J=13.6Hz,1H),1.25-1.21(m,1H),1.11(s,6H).

[0793] Example 26: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazine- 2-(1-methylpiperidin-4-yl)thio)-5-chloro-3-((1-methylpiperidin-4-yl)methyl)quinazolin-4(3H)-one

[0794]

[0795] The compound of Example 26 (33.3 mg, 78% yield) was synthesized in the same manner as Example 25, using Intermediate I-24 instead of Intermediate I-26 in Step 1 of Example 25, and Intermediate I-34 instead of Intermediate I-28 as starting materials.

[0796] MS(EI)m / z:[M+H] + 570.1, 1H NMR (400MHz, MeOD) δ = 8.52-8.50 (m, 1H), 8.35-8.32 (m, 1H), 8.28 (s, 1H), 8.26 (s, 1H), 7.44 (d, J = 8 .8Hz,1H),7.23(d,J=8.8Hz,1H),4.37-4.21(m,3H),4.02-3.94(m,3H),3.86(d,J=9.2Hz,1H),3.50 -3.43(m,2H),3.41(d,J=4.2Hz,1H),3.30-3.16(m,2H),2.91(t,J=11.6Hz,2H),2.80(s,3H),2.24 -2.12(m,1H),1.94(d,J=13.6Hz,2H),1.90-1.80(m,3H),1.78-1.56(m,3H),1.31(d,J=6.4Hz,3H).

[0797] Example 27: (S)-6-((5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazin-2-yl)sulfur (substituted)-5-chloro-3-(2-methoxy-2-methylpropyl)quinazolin-4(3H)-one

[0798]

[0799] The compound of Example 27 (45 mg, 65% yield) was synthesized in the same manner as in Example 25, using Intermediate I-29 instead of Intermediate I-28 in Step 1 of Example 25 as the starting material.

[0800] MS(EI)m / z:[M+H]+577.3

[0801] 1 H NMR (400MHz, CDCl3) δ = 8.28 (d, J = 1.2Hz, 1H), 8.23 (d, J = 1.2Hz, 1H), 8.15 (s, 1H), 7.46 (d ,J=8.8Hz,1H),7.34(d,J=5.6Hz,1H),7.29(s,1H),7.26-7.21(m,3H),4.32-4.21(m,2H) ,4.07(s,2H),4.01(s,1H),3.34-3.23(m,2H),3.21(s,3H),3.12(d,J=15.6Hz,1H),2.76 (d,J=15.6Hz,1H),1.96-1.78(m,2H),1.67-1.63(m,1H),1.45-1.40(m,1H),1.22(s,6H).

[0802] Example 28: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazine- 2-yl)thio)-5-chloro-3-(1-fluoro-2-methoxy-2-methylpropyl)quinazolin-4(3H)-one

[0803]

[0804] The compound of Example 28 (11.38 mg, 44% yield) was synthesized in the same manner as Example 25, using Intermediate I-30 instead of Intermediate I-28 in Step 1 of Example 25, and Intermediate I-24 instead of Intermediate I-26 as starting materials.

[0805] MS(EI)m / z:[M+H] + 563.3.

[0806] 1 H NMR (400MHz, MeOD) δ = 8.37 (s, 1H), 8.32 (s, 1H), 8.29 (s, 1H), 7.48 (d, J = 8.8Hz, 1H), 7.28(d,J=8.8Hz,1H),6.79-6.61(m,1H),4.30-4.23(m,1H),4.22-4.08(m,2H),3.92 (d,J=8.8Hz,1H),3.77(d,J=8.8Hz,1H),3.48-3.34(m,2H),3.34(s,3H),3.20-3.12 (m,1H),1.90-1.69(m,4H),1.49(s,3H),1.25(d,J=6.4Hz,3H),1.14(d,J=1.6Hz,3H)

[0807] Example 29: (S)-6-((5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazin-2-yl)sulfur (2-(2-methoxy-2-methylpropyl)quinazolin-4(3H)-one

[0808]

[0809] The compound of Example 29 (60.3 mg, 58% yield) was synthesized in the same manner as in Example 25, using Intermediate I-31 instead of Intermediate I-28 in Step 1 of Example 25 as a starting material.

[0810] MS(EI)m / z:[M+H] + 543.5.

[0811] 1H NMR(400MHz, CDCl3)δ=8.23-8.21(m,1H),8.21-8.18(m,1H),8.18-8.13(m,2H),7.70-7 .64(m,1H),7.64-7.59(m,1H),7.40-7.32(m,1H),7.26-7.21(m,3H),4.26-4.11(m,2H) ,4.09-4.04(m,2H),4.03(s,1H),3.31-3.22(m,2H),3.21(s,3H),3.15-3.06(m,1H),2. 81-2.73(m,1H),1.90-1.80(m,2H),1.80-1.77(m,1H),1.46-1.40(m,1H),1.20(s,6H).

[0812] Example 30: (S)-6-((5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazin-2-yl)sulfur (substituted)-5-chloro-3-phenylquinazolin-4(3H)-one

[0813]

[0814] The compound of Example 30 (101 mg, 79% yield) was synthesized in the same manner as in Example 25, using Intermediate I-32 instead of Intermediate I-28 in Step 1 of Example 25 as the starting material.

[0815] m / z ES+[M+H] + 567.1

[0816] 1 H NMR (400MHz, CDCl3) δ = 8.31 (d, J = 1.2Hz, 1H), 8.25 (s, 1H), 8.06 (s, 1H), 7.57-7.49 (m, 5H), 7.44-7.40 (m, 2H), 7.33-7.27 (m, 3H), 7 .27-7.25(m,1H),4.25-4.15(m,3H),3.36-3.25(m,2H),3.22(s,1H),2.89(d,J=16.0Hz,1H),1.93-1.75(m,2H),1.65-1.57(m,2H).

[0817] Example 31: (S)-6-((5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazin-2-yl)sulfur (substituted)-5-chloro-3-(pyridin-3-yl)quinazolin-4(3H)-one

[0818]

[0819] The compound of Example 31 (45 mg, 52% yield) was synthesized in the same manner as in Example 25, using Intermediate I-32 instead of Intermediate I-28 in Step 1 of Example 25 as the starting material.

[0820] m / z ES+[M+H] + 568.3.

[0821] 1 H NMR (400MHz, CDCl3) δ = 8.31 (d, J = 1.2Hz, 1H), 8.25 (s, 1H), 8.06 (s, 1H), 7.57-7.49 (m, 5H), 7.44-7.40 (m, 2H), 7.33-7.27 (m, 3H), 7. 27-7.25(m,1H),4.25-4.15(m,3H),3.36-3.25(m,2H),3.22-3.19(m,1H),2.91-2.86(m,1H),1.93-1.75(m,2H),1.64-1.59(m,2H).

[0822] Example 32: (S)-6-((5-(6-amino-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4'-piperidin]-1'-yl)pyrrolidone (2-oxazin-2-yl)thio)-5-chloro-3-(2-methoxy-2-methylpropyl)quinazolin-4(3H)-one

[0823]

[0824] The compound of Example 32 (55 mg, 58% yield) was synthesized in the same manner as in Example 29, using Intermediate I-36 instead of Intermediate I-26 in Step 1 of Example 29 as a starting material.

[0825] m / z ES+[M+H] + 584.2;

[0826] 1 H NMR (400MHz, CDCl3) δ = 8.78 (s, 1H), 8.28 (s, 1H), 8.24 (s, 1H), 8.15 (s, 1H), 7.46 (d, J = 8.8Hz, 1H), 7.29 (d, J = 8.8Hz, 1H), 4.29 (d, J = 13.2Hz, 1H),4.23-4.16(m,2H),4.07(s,2H),3.41-3.27(m,2H),3.21(s,3H), 3.05-2.91(m,2H),1.99-1.92(m,1H),1.87-1.77(m,3H),1.21(s,6H).

[0827] Examples 33 to 35:

[0828] The compounds of Examples 33 to 35 were prepared in the same manner as in Example 32, except that appropriate intermediates were used instead of Intermediate I-36 in Example 32.

[0829]

Table 5

[0830]

[0831]

[0832] Example 36: (S)-6-((3-amino-5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazine- 2-amino-3-(2-methoxy-2-methylpropyl)quinazolin-4(3H)-one

[0833]

[0834] Step 1: N-((S)-1'-(6-amino-5-((5-chloro-3-(2-methoxy-2-methylpropyl)-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-1,3-dihydrospiro[indene-2,4'-piperidin]-1-yl)-2-methylpropane-2-sulfenamide

[0835] To a solution of 6-(3-amino-5-chloro-pyrazin-2-yl)sulfanyl-5-chloro-3-(2-methoxy-2-methyl-propyl)quinazolin-4-one (80 mg, 188 μmol) in DMSO (3 mL) was added DIEA (2.43 g, 18.8 mmol) and 2-methyl-N-[(1S)-spiro[indan-2,4'-piperidin]-1-yl]propane-2-sulfinamide (57.5 mg). The mixture was stirred at 100 ° C for 12 hours. After stirring was complete, at 25 ° C, the reaction mixture was quenched by adding aqueous ammonium chloride (20 mL), and then diluted with water (30 mL) and extracted with EA (3x50 mL). The combined organic layer was washed with brine (3x20 mL), dried over anhydrous sodium sulfate, and then filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (FA)-ACN]; concentration gradient: 55%-85% B, 10 minutes) to obtain N-[(1S)-1'-[6-amino-5-[5-chloro-3-(2-methoxy-2-methyl-propyl)-4-oxo-quinazolin-6-yl]sulfanyl-pyrazin-2-yl]spiro[indan-2,4'-piperidine]-1-yl]-2-methyl-propane-2-sulfenamide (60 mg, 46% yield) as a yellow solid.

[0836] 1H NMR (400MHz, CDCl3) δ = 8.14 (s, 1H), 7.67 (s, 1H), 7.47 (d, J = 8.8Hz, 1H), 7.34-7.31 (m, 1H), 7.29-7.27 (m ,1H),7.27-7.22(m,2H),7.14(d,J=8.8Hz,1H),4.84(br.s,2H),4.58(d,J=10.0Hz,1H),4.37-4.28(m,2H ),4.07(s,2H),3.60(d,J=10.0Hz,1H),3.21(s,3H),3.20-3.16(m,1H),3.15-3.06(m,2H),2.79(d,J=15 .6Hz,1H),2.33(dt,J=4.4,12.8Hz,1H),1.92-1.84(m,1H),1.49-1.36(m,2H),1.31(s,9H),1.22(s,6H).

[0837] Step 2: (S)-6-((3-amino-5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-methoxy-2-methylpropyl)quinazolin-4(3H)-one

[0838] To a solution of N-[(1S)-1'-[6-amino-5-[5-chloro-3-(2-methoxy-2-methyl-propyl)-4-oxo-quinazolin-6-yl]sulfanyl-pyrazin-2-yl]spiro[indane-2,4'-piperidine]-1-yl]-2-methyl-propane-2-sulfinamide (60 mg, 86.2 μmol) in MeOH (3 mL) was added HCl / dioxane (4 M), and the mixture was stirred at 25 ° C for 0.5 hours. After the stirring was completed, the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was passed through preparative HPLC (column: Waters Xbridge 150*25mm*5 μm; mobile phase: [water (ammonium hydroxide v / v)-ACN]; concentration gradient: 35%-65% B / min) to obtain the compound of example 36 (34 mg, 66% yield) as an off-white solid.

[0839] MS(EI)m / z:[M+H] + 592.3.

[0840] 1H NMR (400MHz, CDCl3) δ = 8.14 (s, 1H), 7.69 (s, 1H), 7.44 (d, J = 8.8Hz, 1H), 7.40-7.33 (m, 1H), 7.26-7.19(m,3H),7.16(d,J=8.8Hz,1H),4.88(s,2H),4.27-4.17(m,2H),4.07(s,2H),4.04 -4.01(m,1H),3.26-3.24(m,1H),3.21(s,3H),3.20-3.16(m,1H),3.12(d,J=15.6Hz,1H),2. 77(d,J=15.6Hz,1H),1.90-1.77(m,2H),1.55-1.50(m,1H),1.45-1.39(m,1H),1.22(s,6H).

[0841] Example 37: 6-((3-amino-5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8- (2-(2-methoxy-2-methylpropyl)quinazolin-4(3H)-one)

[0842]

[0843] The compound of Example 37 (41 mg, 69% yield) was synthesized in the same manner as in Example 25, using the product obtained from Step 1 of Preparative Example 23 instead of Intermediate I-25 in Step 1 of Example 36 as the starting material.

[0844] m / z ES+[M+H] + 560.2.

[0845] 1 H NMR (400MHz, CDCl3) δ=8.14(s,1H),7.67(s,1H),7.43(d,J=8.8Hz,1H),7.14(d,J=8.8H z,1H),4.87(s,2H),4.20-4.17(m,1H),4.07(s,2H),3.98-3.87(m,2H),3.83(d,J=8.8Hz ,1H),3.71(d,J=8.8Hz,1H),3.43-3.40(m,1H),3.36-3.29(m,1H),3.21(s,3H),3.02(d, J=4.4Hz,1H),1.93-1.86(m,1H),1.80-1.70(m,3H),1.26(d,J=6.4Hz,3H),1.22(s,6H).

[0846] Example 38: (S)-6-((5-(6-amino-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4'-piperidin]-1'-yl)pyrrolidone (2-oxazin-2-yl)thio)-5-chloro-3-phenylquinazolin-4(3H)-one

[0847]

[0848] The compound of Example 38 (115 mg, 75% yield) was synthesized in the same manner as Example 25, using Intermediate I-36 instead of Intermediate I-26 in Step 1 of Example 25, and Intermediate I-32 instead of Intermediate I-28 as starting materials.

[0849] m / z ES+[M+H] + 573.1

[0850] 1 H NMR (400MHz, CDCl3) δ = 8.81 (s, 1H), 8.27 (d, J = 9.6Hz, 2H), 8.05 (s, 1H), 7.58-7.45 (m, 4H), 7.41 (d, J = 7.2Hz, 2H), 7. 30(d,J=8.8Hz,1H),4.40-4.17(m,3H),3.38-3.19(m,2H),3.11-2.91(m,2H),2.09-1.89(m,2H),1.89-1.69(m,2H).

[0851] Example 39: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazine- 2-amino-3-(2-methoxypropyl)-5-chloro-3-(2-methoxypropyl)-2-methylquinazolin-4(3H)-one

[0852]

[0853] Step 1: N-((3S,4S)-8-(5-((5-chloro-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)-2-methylpropane-2-sulfenamide

[0854] N-((3S,4S)-8-(5-((5-chloro-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)-2-methylpropane-2-sulfinamide (90 mg, 38% yield) was synthesized by the same method as in Example 25, using intermediate I-24 instead of intermediate I-26 in step 1 of Example 25, and using 6-bromo-5-chloro-2-methylquinazolin-4(3H)-one instead of intermediate I-28 as the starting material.

[0855] 1H NMR (400MHz, DMSO-d6) δ=12.81-11.83(m,1H),8.46(d,J=1.2Hz,1H),8.28(d,J=1.2Hz,1H) ,7.40(d,J=8.8Hz,1H),7.14(d,J=8.8Hz,1H),5.13(d,J=10.8Hz,1H),4.26-4.19(m,1H),4 .18-4.11(m,2H),3.88(d,J=8.8Hz,1H),3.52(d,J=8.8Hz,1H),3.45(s,1H),3.17-3.06(m, 2H), 2.29 (s, 3H), 1.83-1.73 (m, 2H), 1.67-1.53 (m, 2H), 1.16 (s, 9H), 1.10 (d, J = 6.4Hz, 3H).

[0856] Step 2: N-((3S,4S)-8-(5-((5-chloro-3-(2-methoxypropyl)-2-methyl-4-oxo-3,4-dihydroquinazolin-6-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl)-2-methylpropane-2-sulfenamide

[0857] A solution of N-[(3S, 4S)-8-[5-[(5-chloro-2-methyl-4-oxo-3H-quinazolin-6-yl)sulfanyl]pyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl]-2-methyl-propane-2-sulfinamide (70 mg, 121 μmol), 2-methoxypropyl 4-methylbenzenesulfonate (88.8 mg, 363 μmol), K2CO3 (50.2 mg, 363 μmol) and TBAI (4.48 mg, 12.1 μmol) in DMF (2 mL) was stirred at 60 ° C for 2 hours. After stirring was completed, water (40 mL) was added to the reaction mixture and extracted with EA (3x80 mL). The combined organic layers were concentrated under reduced pressure. The residue was purified by preparative TLC (SiO 2 , EA:MeOH=10:1) to afford N-[(3S,4S)-8-[5-[5-chloro-3-(2-methoxypropyl)-2-methyl-4-oxo-quinazolin-6-yl]sulfanylpyrazin-2-yl]-3-methyl-2-oxa-8-azaspiro[4.5]dec-4-yl]-2-methyl-propane-2-sulfinamide (30 mg, 38% yield) as a yellow solid.

[0858] 1H NMR (400MHz, CDCl3) δ = 8.27-8.23 (m, 1H), 8.19 (d, J = 1.2Hz, 1H), 8.03 (s, 1H), 7.40 (d, J = 8.8Hz, 1H), 4. 40-4.20(m,1H),4.28-4.19(m,2H),4.19-4.12(m,1H),3.91(d,J=9.2Hz,1H),3.86-3.77(m,1H),3.69( d,J=9.2Hz,1H),3.56-3.50(m,1H),3.38(d,J=10.4Hz,1H),3.22(s,2H),2.96(s,3H),2.89(s,3H),2.6 6(s,3H),2.12-1.94(m,2H),1.80-1.65(m,2H),1.64-1.60(m,1H),1.27(s,9H),1.24(d,J=6.4Hz,3H).

[0859] Step 3: 6-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazin-2-yl)thio)-5-chloro-3-(2-methoxypropyl)-2-methylquinazolin-4(3H)-one

[0860] The compound of Example 39 (7.41 mg, 26% yield) was synthesized in the same manner as in Step 2 of Example 25.

[0861] MS(EI)m / z:[M+H] + 545.3.

[0862] 1 H NMR (400MHz, MeOD) δ = 8.56-8.50 (m, 1H), 8.30 (s, 1H), 8.27 (s, 1H), 7.37 (d, J = 8.8Hz, 1H), 7.25 ( d,J=8.8Hz,1H),4.33-4.28(m,2H),4.27-4.18(m,2H),3.99-3.89(m,2H),3.85(d,J=9.2Hz,1H) ,3.82-3.70(m,1H),3.36(d,J=4.4Hz,1H),3.29-3.24(m,1H),3.23(s,3H),3.22-3.17(m,1H),2 .66(s,3H),1.88-1.81(m,3H),1.76-1.67(m,1H),1.30(d,J=6.4Hz,3H),1.26(d,J=6.4Hz,3H).

[0863] Example 40: (S)-7-((5-(6-amino-4,6-dihydrospiro[cyclopenta[d]thiazol-5,4'-piperidin]-1'-yl)pyrrolidone (2-(2H)-oxazin-2-yl)thio)-8-chloro-2-isopropylisoquinolin-1(2H)-one

[0864]

[0865] The compound of Example 40 (2.34 mg, 25% yield) was synthesized in the same manner as Example 25, using Intermediate I-36 instead of Intermediate I-26 in Step 1 of Example 25, and Intermediate I-44 instead of Intermediate I-28 as starting materials.

[0866] MS(EI)m / z:[M+H] + 539.0.

[0867] 1 H NMR (400MHz, MeOD) δ = 9.01 (s, 1H), 8.58-8.45 (m, 1H), 8.33 (s, 1H), 8.28 (s, 1H), 7.4 5(d,J=7.6Hz,1H),7.40(d,J=8.8Hz,1H),7.15(d,J=8.8Hz,1H),6.63(d,J=7.6Hz,1 H),5.33-5.18(m,1H),4.46-4.36(m,1H),4.35-4.27(m,1H),4.23(s,1H),3.47-3.3 4(m,2H),3.02(s,2H),2.05-1.87(m,2H),1.84-1.76(m,2H),1.40(d,J=6.8Hz,6H).

[0868] Example 41: (S)-7-((5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazin-2-yl)sulfur (substituted)-8-chloro-2-methylisoquinolin-1(2H)-one

[0869]

[0870] The compound of Example 41 (19 mg, 73% yield) was synthesized in the same manner as in Example 25, using Intermediate I-43 instead of Intermediate I-28 in Step 1 of Example 25 as the starting material.

[0871] MS(EI)m / z:[M+H]+504.3

[0872] 1H NMR(400MHz,MeOD)δ=8.32(s,1H),8.27(s,1H),7.54-7.40(m,1H),7.48-7.30( m,2H),7.36-7.33(m,2H),7.32-7.28(m,1H),7.16(d,J=8.8Hz,1H),6.56(d,J= 7.2Hz,1H),4.50-4.30(m,1H),4.34-4.27(m,2H),3.56(s,3H),3.40-3.30(m,2 H),3.25-3.15(m,1H),3.13-3.05(m,1H),1.88-1.80(m,2H),1.71-1.62(m,2H).

[0873] Examples 42 to 45:

[0874] The compounds of Examples 42 to 45 were prepared in the same manner as in Example 41, except that appropriate intermediates were used instead of Intermediate I-43 in Example 41.

[0875]

Table 6

[0876]

[0877]

[0878]

[0879] Example 46: 7-((5-((3S,4S)-4-amino-3-methyl-2-oxa-8-azaspiro[4.5]dec-8-yl)pyrazine- 2-Isopropyl)thioxo-8-chloro-2-isopropylisoquinolin-1(2H)-one

[0880]

[0881] The compound of Example 46 (10 mg, 66% yield) was synthesized in the same manner as in Example 40, using Intermediate I-24 instead of Intermediate I-36 in Example 40 as the starting material.

[0882] MS(EI)m / z:[M+H]+500.2

[0883] 1H NMR (400MHz, MeOD) δ = 8.30 (s, 1H), 8.26 (d, J = 1.2Hz, 1H), 7.45 (d, J = 7.6Hz, 1H), 7.39 (d, J =8.4Hz,1H),7.15(d,J=8.4Hz,1H),6.62(d,J=7.6Hz,1H),5.25-5.20(m,1H),4.37-4.20( m,3H),3.98(d,J=9.2Hz,1H),3.86(d,J=9.2Hz,1H),3.740(d,J=4.0Hz,1H),3.29-3.14(m ,2H),1.90-1.80(m,3H),1.76-1.68(m,1H),1.40(d,J=6.8Hz,6H),1.31(d,J=6.4Hz,3H).

[0884] Example 47: (S)-7-((3-amino-5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazine- 2-Methylisoquinolin-1(2H)-one

[0885]

[0886] The compound of Example 47 (20 mg, 59% yield) was synthesized in the same manner as in Example 36, using Intermediate I-49 instead of Intermediate I-41 in Example 36 as a starting material.

[0887] MS(EI)m / z:[M+H]+519.2

[0888] 1 H NMR (400MHz, CDCl3) δ = 7.68 (s, 1H), 7.38 (s, 1H), 7.26-7.19 (m, 4H), 7.08-7.04 (m, 2H), 6.34 (d, J = 7.2Hz, 1H), 4.87 (s, 2H), 4.24-4.15 (m, 2H), 4.0 4(s,1H),3.57(s,3H),3.26-3.17(m,2H),3.13(d,J=15.2Hz,1H),2.78(d ,J=15.2Hz,1H),1.89-1.80(m,2H),1.66-1.63(m,1H),1.47-1.45(m,1H)

[0889] Example 48: (S)-7-((3-amino-5-(1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazine- 2-Isopropyl)thioxo-8-chloro-2-isopropylisoquinolin-1(2H)-one

[0890]

[0891] The compound of Example 48 (20 mg, 59% yield) was synthesized in the same manner as in Example 36, using Intermediate I-50 instead of Intermediate I-41 in Example 36 as the starting material.

[0892] MS(EI)m / z:[M+H] + 547.2.

[0893] 1 H NMR (400MHz, CDCl3) δ = 7.67 (s, 1H), 7.39-7.35 (m, 1H), 7.24 (d, J = 2.8Hz, 3H), 7.21 (d, J = 8.4Hz, 1H) ,7.12(d,J=7.2Hz,1H),7.05(d,J=8.4Hz,1H),6.41(d,J=7.2Hz,1H),5.42-5.30(m,1H),4.87(s,2H ),4.25-4.16(m,2H),4.03(s,1H),3.26-3.16(m,2H),3.12(d,J=15.6Hz,1H),2.78(d,J=15.6Hz,1H ),1.90-1.80(m,1H),1.86-1.70(m,1H),1.63-1.59(m,1H),1.46-1.40(m,1H),1.37(d,J=6.8Hz,6H)

[0894] Example 49: 7-((3-amino-5-((S)-1-amino-1,3-dihydrospiro[indene-2,4'-piperidin]-1'-yl)pyrazine- 2-(2-methoxypropyl)isoquinolin-1(2H)-one

[0895]

[0896] The compound of Example 49 (32 mg, 62% yield) was synthesized in the same manner as in Example 36, using Intermediate I-51 instead of Intermediate I-41 in Example 36 as a starting material.

[0897] MS (EI) m / z: [M+H] + 577.3.

[0898] 1H NMR (400MHz, CDCl3) δ = 7.72 (s, 1H), 7.39 (d, J = 4.4Hz, 1H), 7.33-7.29 (m, 2H), 7.27-7.21 (m, 2H), 7.18 (d, J = 7.2H z,1H),7.10(d,J=8.4Hz,1H),6.36(d,J=7.2Hz,1H),4.89(s,2H),4.35(dd,J=2.8,13.6Hz,1H),4.29-4.20(m,2H ),4.05(s,1H),3.87-3.78(m,1H),3.59(dd,J=8.4,13.6Hz,1H),3.31(s,3H),3.29-3.19(m,2H),3.15(d,J=15.6 Hz,1H),2.79(d,J=15.6Hz,1H),1.95-1.83(m,2H),1.82-1.77(m,1H),1.46-1.41(m,1H),1.26(d,J=6.4Hz,3H).

[0899] Example 50: (R)-6-((5-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazin-2-yl)sulfur (substituted)-5-chloro-3-(2-methoxy-2-methylpropyl)quinazolin-4(3H)-one

[0900]

[0901] The compound of Example 50 (49 mg, 48% yield) was synthesized in the same manner as in Example 25, using Intermediate I-53 instead of Intermediate I-26 in Step 1 of Example 25 as the starting material.

[0902] m / z ES+[M-NH2] + 562.3.

[0903] 1H NMR (400MHz, CDCl3) δ = 8.29 (d, J = 1.2Hz, 1H), 8.26 (d, J = 1.2Hz, 1H), 8.15 (s, 1H), 7.47 (d, J = 8.8Hz, 1H), 7.34(d,J=7.2Hz,1H),7.29(d,J=8.8Hz,1H),7.25-7.21(m,1H),6.95(t,J=7.2Hz,1H),6.84(d,J=8.0Hz ,1H),4.36(d,J=13.6Hz,1H),4.26(d,J=13.6Hz,1H),4.16(s,1H),4.07(s,2H),3.60-3.50(m,2H),3.22 (s, 3H), 1.98 (dd, J = 4.0, 8.0 Hz, 2H), 1.92 ( d, J = 13.6 Hz, 1H), 1.82 ( dd, J = 4.8, 12.0 Hz, 1H), 1.22 ( s, 6H).

[0904] Example 51: (R)-6-((5-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazin-2-yl)sulfur (substituted)-5-chloro-3-methylquinazolin-4(3H)-one

[0905]

[0906] The compound of Example 51 (44 mg, 47% yield) was synthesized in the same manner as in Example 50, using Intermediate I-54 instead of Intermediate I-28 in Example 50 as the starting material.

[0907] m / z ES+[M+Na] + 529.1.

[0908] 1 H NMR (CDCl3, 400MHz) δ = 8.30 (d, J = 1.2Hz, 1H), 8.27 (d, J = 1.2Hz, 1H), 7.99 (s, 1H) ,7.47(d,J=8.8Hz,1H),7.38(d,J=7.6Hz,1H),7.29(s,1H),7.25-7.21(m,1H),7. 05-6.90(m,1H),6.85(d,J=8.0Hz,1H),4.46-4.30(m,1H),4.34-4.20(m,1H),4. 21(s,1H),3.57(s,3H),3.56-3.49(m,2H),1.98-1.90(m,2H),1.86-1.80(m,2H).

[0909] Example 52: (R)-6-((5-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazin-2-yl)sulfur (substituted)-5-chloro-3-phenylquinazolin-4(3H)-one

[0910]

[0911] The compound of Example 52 (54 mg, 63% yield) was synthesized in the same manner as in Example 50, using Intermediate I-32 instead of Intermediate I-28 in Example 50 as the starting material.

[0912] m / z ES+[M+Na] + 591.2.

[0913] 1 H NMR (400MHz, CDCl3) δ = 8.32 (d, J = 1.2Hz, 1H), 8.29 (d, J = 1.2Hz, 1H), 8.07 (s, 1H ),7.62-7.48(m,5H),7.43(d,J=1.6Hz,1H),7.41(s,1H),7.37-7.32(m,2H),7.2 5-7.20(m,1H),7.00-6.92(m,1H),6.85(d,J=8.0Hz,1H),4.39(m,1H),4.32-4.2 5(m,1H),4.19(s,1H),3.61-3.52(m,2H),2.00-1.90(m,2H),1.89-1.76(m,2H).

[0914] Example 53: (R)-6-((5-(3-amino-3H-spiro[benzofuran-2,4'-piperidin]-1'-yl)pyrazin-2-yl)thio)-5-chloro-3-(methyl-d3)quinazolin-4(3H)-one

[0915]

[0916] The compound of Example 53 (25 mg, 40% yield) was synthesized in the same manner as in Example 50, using Intermediate I-55 instead of Intermediate I-28 in Example 50 as the starting material.

[0917] m / z ES+[M+H] + 510.2.

[0918] 1H NMR (DMSO, 400MHz) δ = 8.77 (s, 1H), 8.64 (s, 1H), 8.36 (s, 1H), 8.09 (s, 1H), 7 .40(d,J=8.8Hz,1H),7.31(d,J=7.6Hz,1H),7.25(s,1H),7.23-7.19(m,1H) ,7.05-6.87(m,1H),6.82(d,J=8.0Hz,1H),4.44-4.30(m,1H),4.30-4.20(m ,1H),4.18(s,1H),3.54-3.48(m,2H),1.99-1.90(m,2H),1.86-1.80(m,2H).

[0919] Experimental Examples

[0920] Experimental Example 1: Phosphatase Assay (IC 50 )

[0921] IC was measured using 6,8-difluoro-4-methylumbelliferyl phosphate (DiFMUP) as a substrate. 50 Reactions were performed in 384-well plates and fluorescence measurements were obtained using an EnVision plate reader from PerkinElmer.

[0922] SHP2 (full length, diluted to a final concentration of 100 pM in reaction buffer, BPS bioscience, USA) was incubated with SHP2 activating peptide in reaction buffer (60 mM HEPES (pH 7.2), 75 mM NaCl, 75 mM KCl, 1 mM EDTA, 5 mM DTT, 0.05% P-20) for 30 minutes to activate SHP2. After activation, DMSO [1% (V / V) or the compound (concentration range of 0.6 nM to 10 μM)] was added according to the example. As positive controls, the selective SHP2 inhibitors SHP099 (6-(4-amino-4-methylpiperidin-1-yl)-3-(2,3-dichlorophenyl)pyrazin-2-amine, Voxel Biotech, Australia; concentrations ranged from 0.6 nM to 10 μM) and TNO155 ((3S,4S)-8-(6-amino-5-((2-amino-3-chloropyridin-4-yl)thio)pyrazin-2-yl)-3-methyl-2-oxa-8-azaspiro[4.5]decan-4-amine, Chemietek, USA; concentrations ranged from 0.6 nM to 10 μM) were used.

[0923]

[0924] DiFMUP (80 μM) was added to the reaction and incubated for a total of 2 hours to allow the reaction to proceed. Thereafter, fluorescence (340 nm excitation, 450 nm emission) values were measured. IC values were obtained from the concentration-dependent measurements using Graphad's Prism. 50 The IC values of the compounds obtained according to the examples are 50 The values are summarized in Table 7 below.

[0925] In the phosphatase assay (PTPase assay), when IC 50 A value of 100 nM or greater indicates +, and when IC 50 ++ is indicated when the value is 3 nM or greater and less than 100 nM, and when IC 50 Values less than 3 nM are indicated as +++.

[0926]

Table 7

[0927]

[0928]

[0929] Referring to Table 7, it was confirmed that the compounds according to the present invention had excellent SHP2 inhibitory effects.

[0930] Experimental Example 2: Phosphorylated ERK Assay

[0931] H358 cells (20,000 cells / well) were plated in 40 μL of cell culture solution (RPMI, 10% FBS, penicillin, streptomycin) in a 384-well plate. After 24 hours, serially diluted compounds (minimum concentration 0.13 nM, maximum 10 μM) according to the examples were added to 10 μL of cell culture solution, placed in the wells containing cells, and incubated in a cell incubator for 1.5 hours. As a positive control, the selective SHP2 inhibitor TNO155 (Chemietek, USA; concentrations ranged from 0.13 nM to 10 μM) was used.

[0932] Thereafter, phosphorylated ERK was labeled using the AlphaLisa system from PerkinElmer according to the manufacturer's instructions, and fluorescence (680 nm excitation wavelength, 615 nm emission wavelength) values were subsequently measured using a Varioskan instrument from Thermo Fisher Scientific. IC values were obtained from the concentration-dependent measurements using Graphad's Prism. 50 The IC values of the compounds obtained according to the examples are 50 The values are summarized in Table 8 below.

[0933] In phosphorylation of ERK, when IC 50 A value of 1.5 nM or greater indicates a +, and when the IC50 A value of 45 nM or greater and less than 1.5 nM indicates ++, and when IC 50 Values less than 45 nM are indicated as +++.

[0934]

Table 8

[0935]

[0936]

[0937] Intracellular SHP2 activity can be confirmed by measuring the phosphorylation level of ERK (extracellular signal-regulated kinase), which represents the Ras / Raf / ERK downstream signaling pathway of SHP2. The inhibition of ERK phosphorylation by SHP2 inhibitors was confirmed by phosphorylated ERK analysis, demonstrating that the SHP2 inhibitors of the present invention have excellent inhibitory activity against SHP2-mediated ERK phosphorylation.

[0938] Experimental Example 3: Cell Viability

[0939] Human non-small cell lung cancer cell line H358 cells were purchased from the Korean Cell Line Bank. Cancer cell lines were cultured in the recommended RPMI-1640 medium supplemented with 10% fetal bovine serum (FBS) and 1% penicillin / streptomycin. Monolayer cancer cell lines were detached by treatment with trypsin / EDTA, and cells containing 4×10 3 100 μl of cell suspension of each cell was dispensed into SPL3D TM In the 96-well round plate of Cell Floater. After culturing for 72 hours to form spheres, cells were treated separately with the compound according to the example that had been serially diluted (minimum concentration 1.5nM, maximum 10μM), and then cultured in a cell culture incubator for 5 days. In order to analyze cell viability, cells were treated with 50uL 3D CellTiter-Glo, stirred at 500rpm for 5 minutes in a plate shaker from ThermoFisher Scientific, and incubated at room temperature for 25 minutes. Then, luminescence values were measured using the Varioskan device from Thermo Fisher Scientific. IC values were obtained based on the measured values of concentration using GraphPad's Prism. 50 IC values of compounds according to the examples 50 The values are summarized in Table 9 below.

[0940] In cell viability assays, when IC 50 A value of 50 nM or greater indicates +, and when IC 50 ++ is indicated when the value is 10 nM or greater and less than 50 nM, and when IC 50Values less than 10 nM are indicated as +++.

[0941]

Table 9

[0942]

[0943]

[0944] Experimental Example 4: Brain Plasma Pharmacokinetics

[0945] Nine male CD-1 mice (ICR mice) aged 6-9 weeks were treated with the compound according to the example at a concentration of 20 mg / kg. 0.025 mL of blood and brain tissue were collected 1 hour, 8 hours, and 24 hours after treatment, respectively. The collected blood was placed in an EDTA-K2 tube, centrifuged at 3200 × g for 10 minutes at 4 ° C, and the supernatant plasma was collected. After blood collection, CD-1 mice were euthanized and perfused with cold saline for heart perfusion, and brain tissue samples were collected immediately. After collection, the brain tissue was washed with cold saline, wiped and dried, weighed, and homogenized with a buffer solution (15 mM PBS (pH 7.4): MeOH = 2: 1) at a ratio of 1: 3 (1 g tissue to 3 mL buffer solution, a dilution ratio of 4). Plasma and homogenized brain tissue samples were transferred to polypropylene microcentrifuge tubes, respectively, and stored at -60 ° C or lower. The concentrations of the compounds distributed in plasma and brain tissue were analyzed using LC-MS / MS, and the distribution in brain tissue compared to plasma was calculated as follows.

[0946] Brain-to-plasma ratio = AUC(0-t) brain tissue / AUC(0-t) plasma

[0947] In the brain plasma pharmacokinetic assay, + is indicated when the brain plasma ratio is 0.05 or more and less than 0.1, ++ is indicated when the brain plasma ratio is 0.1 or more and less than 0.25, and +++ is indicated when the brain plasma ratio is greater than 0.25.

[0948]

Table 10

[0949] Instance number Brain-to-plasma ratio Instance number Brain-to-plasma ratio 2 ND 34 ++ 3 ND 35 ++ 4 ND 36 + 6 ND 37 + 7 ++ 41 +++ 14 ND 43 +++ 15 + 44 +++ 16 ND 45 ++ 18 +++ 47 ++ 25 + 48 ++ 27 +++ 49 ++ 29 +++ 50 +++ 31 ++ 51 +++ 32 ++ 52 +++

[0950] With reference to Table 10, it was confirmed that the compounds of the present invention have excellent blood-brain barrier penetration properties. Specifically, it was confirmed that the compounds of the present invention have a blood-brain concentration ratio of at least 0.05 or higher, at least 0.1 or higher, at least 0.2 or higher, or at least 0.25 or higher.

Claims

1. A compound represented by Formula 1A, a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof: [Formula 1A] in, X is H or halogen; W 1 and W 2 One of them is S and the other is N; R 1A It is H, C 6-10 Aryl or optionally C 1-6 Alkoxy-substituted C 1-6 alkyl; and R x and R y Each independently is H or C 1-6 alkyl.

2. The compound according to claim 1, or a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein X is H or Cl; R 1A Selected from the group consisting of: H, phenyl, CH3, CH2CH3, and R x and R y Each is H.

3. The compound according to claim 1, or a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

4. A compound represented by Formula 1B, its stereoisomers, solvates or isotope-labeled compounds, or pharmaceutically acceptable salts thereof: [Formula 1B] in, X is H or halogen; R 1B Is H or C 1-6 alkyl; and R x and R y Each independently is H or C 1-6 alkyl.

5. The compound according to claim 4, or a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein X is a halogen; R 1B It is C 1-6 alkyl; and R x and R y Each is H.

6. The compound according to claim 4, or a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

7. A compound represented by formula 2A, its stereoisomer, solvate or isotope-labeled compound, or a pharmaceutically acceptable salt thereof: [Formula 2A] in, Z is N or CH; Q is N or CH; X is H or halogen; Y 2 is N or CH; R 2A It is H, C 6-10 Aryl, 5 to 7 membered heteroaryl containing a heteroatom selected from N and O, or optionally substituted by OH or C 1-6 Alkoxy-substituted C 1-6 alkyl; and R x and R y Each independently is H or C 1-6 alkyl.

8. The compound according to claim 7, or a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein X is a halogen; R 2A It is methyl, phenyl, pyridyl, and R x and R y Each is independently H.

9. The compound according to claim 7, or a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

10. A compound represented by formula 2B, its stereoisomer, solvate or isotope-labeled compound, or a pharmaceutically acceptable salt thereof: [Formula 2B] in, Z is N or CH; X is H or halogen; R a3 It is NR i R ii or C 1-6 alkyl; R a4 Is H, or OH or C 1-6 Alkoxy-substituted C 1-6 alkyl. R 2B selected from H and optionally OH or C 1-6 Alkoxy-substituted C 1-6 alkyl; R i and R ii Each independently is H or C 1-6 alkyl; and R x and R y Each independently is H or C 1-6 alkyl.

11. The compound according to claim 10, or a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein X is a halogen, R 2B Selected from the group consisting of: CH3, And R i 、R ii 、R x and R y Each is independently H.

12. The compound of claim 10, or a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

13. A compound represented by formula 2C, its stereoisomer, solvate or isotope-labeled compound, or a pharmaceutically acceptable salt thereof: [Formula 2C] in, X is H or halogen; R 2C Selected from H, C 6-10 Aryl and optionally OH or C 1-6 Alkoxy-substituted C 1-6 alkyl; and R x and R y Each independently is H or C 1-6 alkyl.

14. The compound of claim 13, or a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein X is a halogen, R 2C Selected from C 6-10 Aryl and optionally OH or C 1-6 Alkoxy-substituted C 1-6 alkyl; and R x and R y Each is independently H.

15. The compound of claim 13, or a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

16. A compound represented by formula 3A, a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof: [Formula 3A] in, Z is N or CH; X is H or halogen; R Z Is H or C 1-6 alkyl; R 3A It is H, and it is C 1-6 Alkyl-substituted-(C 1-6 Alkylene)-alkoxy, or C 1-6 Alkyl, -(C 1-6 alkylene)-(C 3-6 Cycloalkyl) or -(C 1-6 alkylene)-piperidinyl, each of which is optionally substituted by 1 to 3 R 31A replace. R 31A is halogen, cyano or C 1-6 Alkoxy. R A Is H or C 1-6 alkyl; and R x and R y Each independently is H or C 1-6 alkyl.

17. The compound of claim 16, or a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein X is a halogen, R 3A Selected from the group consisting of: CH3, R A It is C 1-6 alkyl, and R x and R y Each is independently H.

18. The compound of claim 16, or a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

19. A compound represented by formula 3B, its stereoisomer, solvate or isotope-labeled compound, or a pharmaceutically acceptable salt thereof: [Formula 3B] in, X is H or halogen; R 3B is optionally OH, C 1-6 Alkoxy or C 6-10 Aryl-substituted C 1-6 alkyl. R A Is H or C 1-6 alkyl. R i and R ii Each independently is H or C 1-6 alkyl; and R x and R y Each independently is H or C 1-6 alkyl.

20. The compound of claim 19, or a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein X is a halogen, R 3B It is C 1-6 Alkoxy or C 6-10 Aryl-substituted C 1-6 alkyl. R A It is C 1-6 alkyl, and R i 、R ii 、R x and R y Each is independently H.

21. The compound of claim 19, or a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:

22. A compound represented by formula 3C, a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof: [Formula 3C] in X is H or halogen; R 3C is optionally C 6-10 Aryl-substituted C 1-6 alkyl; R C Is H or C 1-6 alkyl. R i and R ii Each independently is H or C 1-6 alkyl; and R x and R y Each independently is H or C 1-6 alkyl.

23. The compound of claim 22, or a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein X is a halogen, R 3C It is C 6-10 Aryl-substituted C 1-6 alkyl, R C It is C 1-6 alkyl, R i 、R ii 、R x and R y Each is independently H.

24. The compound of claim 22, or a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula:

25. A pharmaceutical composition for preventing or treating a disease associated with abnormal activity of Src homology 2 domain-containing phosphatase-2 (SHP2), comprising a compound according to any one of claims 1 to 24, or a stereoisomer, solvate, isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof.

26. The pharmaceutical composition of claim 25, wherein the disease associated with abnormal activity of SHP2 is selected from the group consisting of cancer, cancer metastasis, cardiovascular disease, immune disorder, fibrosis and eye disorder.

27. The pharmaceutical composition of claim 25, wherein the disease associated with abnormal activity of SHP2 is selected from the group consisting of Noonan syndrome, Leopard syndrome, juvenile myelomonocytic leukemia, neuroblastoma, melanoma, acute myeloid leukemia, breast cancer, esophageal cancer, lung cancer, colorectal cancer, head cancer, malignant brain tumor, head and neck squamous cell carcinoma, gastric cancer, anaplastic large cell lymphoma, pancreatic cancer, biliary tract cancer, uterine cancer, endometrial cancer, liver cancer, and neurofibromatosis type 1.

28. A method for preventing or treating a disease associated with abnormal activity of SHP2, comprising administering to a subject a compound according to any one of claims 1 to 24, or a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof.

29. A pharmaceutical composition comprising the compound according to any one of claims 1 to 24 or a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof.

30. A compound according to any one of claims 1 to 24, or a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, for use in preventing or treating a disease associated with abnormal activity of SHP2.

31. Use of a compound according to any one of claims 1 to 24, or a stereoisomer, solvate or isotope-labeled compound thereof, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for preventing or treating a disease associated with abnormal activity of SHP2.

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